The Roots of Organic Development

Industrial Chemistry Library, Volume 8
The Roots of
Organic Development
Industrial Chemistry Library
Advisory Editor: S.T. Sie, Faculty of Chemical Technology and Materials Science
Delft University of Technology, Delft, The Netherlands
Volume 1 Progress in C1 Chemistry in Japan

(Edited by the Research Association for C 1 Chemistry)
Volume 2 Calcium Magnesium Acetate. An Emerging Bulk Chemical for

Environmental Applications
(Edited by D.L. Wise, Y.A. Levendis and M. Metghalchi)
Volume 3 Advances in Organobromine Chemistry I

(Edited by J.-R. Desmurs and B. Gdrard)
Volume 4 Technology of Corn Wet Milling and Associated Processes

(by P.H. Blanchard)
Volume 5 Lithium Batteries. New Materials, Developments and Perspectives

(Edited by G. Pistoia)
Volume 6 Industrial Chemicals. Their Characteristics and Development

(by G. Again)
Volume 7 Advances in Organobromine Chemistry II

(Edited by J.-R. Desmurs, B. Gdrard and M.J. Goldstein)
Volume 8 The Roots of Organic Development

(Edited by J.-R. Desmurs and S. Ratton)
Industrial Chemistry Library, Volume 8
The Roots of Organic

Development
Edited by
Jean-Roger Desmurs
Rh6ne Poulenc Industrialisation, CRIT/Carrikres, 85 Avenue des Frbres Perret,
69192 Saint-Fons Cedex, France
Serge Ratton
Rh6ne Poulenc Organic Intermediates Enterprise, 25 Quai Paul Doumer,

92408 Courbevoie Cedex, France
1996
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FOREWORD
It is our belief within RHONE-POULENC that the key to building long term
customer relationship in our industry is superior technology backed up by
outstanding service.
Benefits of superior technology in Organic Chemistry are multiple : lower cost
raw materials, shorter synthesis routes, improved yields, selectivity and kinetics,
resulting in better productivity. Higher transformation rates of less hazardous
materials leads to healthier, cleaner operations with reduced waste disposal issues.
Last but not least, process safety is continually upgraded as more intimate
knowledge of chemical reactions and other unit operations is achieved.
For our worldwide customers such technical progress creates multifaceted
value: reliability, shorter response time, more competitive economics, improved
quality leading to faster registration, and safer and more environmentally
responsible operations. Furthermore, it enables us to extend the use of this expertise
to the adaptation of decisive physical or chemical properties of molecules to provide
our customers with desired use properties.
Making our overall skills available to customers to solve their problems is
indeed the basis of our ,, Chimie Nouvelle ,, approach.
In this spirit we expect and look forward to provide, along with our Organic
Intermediates technology, whatever services are required to make our joint success
complete : efficient pilot facilities, advanced analytical equipment with expert staff,
toxicology and eco toxicology support, environmental services, formulation
capabilities, ... we do this throughout the world.
This is the way we aim to become your preferred partner in organic chemistry,
to gain your confidence and be able to participate early in your most important
projects.
May this book demonstrate to all our existing or potential partners our
commitment to top level organic chemistry.
We are proud of the achievements and expertise of our teams. May our partners
keep challenging them to build leaderships together.
Bertrand LOUVET Ted ZIEMANN

Rh6ne-Poulenc Chemical Sector President of Rh6ne-Poulenc
Executive vice-President Organic Intermediates Enterprise
This Page Intentionally Left Blank
PREFACE
It seems to us, symbolic, important, and above all promising for the furore, that
the year in which Rh6ne-Poulenc holds its centenary celebrations also sees the
publication of a scientific review, gathering together organic chemistry research
carried out in common by groups from universities and other large organisations,
and with Rh6ne-Poulenc research workers.
The development of an industrial group, especially one such as Rh6ne-Poulenc,
is directly linked to the possibility of innovation.
For this, it is necessary to rely, not just on the groups own resources and
strengths, but also on the research and discoveries made by external research
bodies.
The General Management of the Group, as far back as 1974, was aware of this
need to have a closer association with upstream research, and so signed the first
contract with the CNRS (National Research Centre).
This was only the first step, although an important one, and several years passed
before Rh6ne-Poulenc opened its research doors to the outside world. From 1981
until the present day, with the support and constant incitement of the Group
managers, a network of collaborators has been set up, at first in France, and then
abroad. This has required, from everyone involved, efforts regarding mutual
understanding, always within a climate of trust.
The first organised meetings were RP-CNRS symposia based on themes, and
focusing on problems directly related to the Groups chemical interests
(homogeneous catalysis, chemical reactivity, regioselectivity...) during which our
research workers and those of the CNRS exchanged information and results and
initiated future collaborations. Today these symposia have been replaced by
,, Journ6es RP-CNRS ,, where several themes are examined over a two day period,
using a format akin to a seminar.
It was then decided to modify these <, Journ6es Scientifiques ,,, originally
reserved for Rh6ne-Poulenc research workers, by orienting them towards a
particular theme (silicon chemistry, reactivity in organic chemistry, materials
science, molecular biology, etc.) and by inviting, under the presidency of an
internationaly renowned scientist, not only Rh6ne-Poulenc research workers, but
also the best specialists from France and abroad, interested in the theme under
examination, and by asking them to actively participate through written or oral
presentations.
VII
The assessment of these ~ Journ6es ,, has been particularly positive, allowing on
the one hand high-level research workers to discover our own research interests,
and on the other, allowing the Group to take advantage of their expertise and to
possibly have future Rh6ne-Poulenc scientists trained in their laboratories.
At pratically the same time, Rh6ne-Poulenc set up a Scientific Council,
assembling internationally renowned scientists, each working in the different areas
of research relevant to the Group.
The role of this council is essentially to provide ideas and propositions
concerning the great scientific problems, as well as an external and independant
audit, ready at any moment to notify the General and Scientific Management of any
new discoveries or advances likely to modify the direction of our research.
In 1987, the organisation of the Scientific Management was improved, with
directors being nominated for the following three areas : chemistry (J.M. Lehn),
physical-chemistry (P.G. De Gennes) and biology (C. H616ne), each being assisted
by an internal consultant, establishing permanently the opening of our research to
the external scientific world.
Today, always with this same preoccupation, under the impetus of Philippe
Desmarescaux, General Manager, and of Claude H616ne, now Scientific Director,
this collaboration has culminated in the Bio-Avenir programme, which represents a
model for the interaction between public research and industry.
But let us return to the various themes presented in this book. They represent an
image, albeit a rather incomplete one ; but an image which exemplifies this research
in common, and of the results achieved by such a methodology.
It must also be noted that everything which has just been evoked, has only been
possible because of the enthusiasm, support, trust and the willingness to persevere,
of all the research workers concerned, whatever their affiliation.
Also, it must be added that the management of the large organisations, in
particular the Management of the Chemical Sector of the CNRS, the Research
Directors of our sectors as well as the group leaders of our Research Centres, have
all contributed to this development through their encouragement and financial aid.
This continuing exciting adventure is a long term exercise. Mutual respect,
esteem and the desire to work together does not come over night. Time is needed in
order to know one another, to ~ tame one another ,, as the fox in the ~, Little Prince ,,
by Saim-Exup6ry said.
It is also important, as we have seen, to allow enough time to set up high level
competences in new areas, by accepting the failures which arrive at the start,
perseverance often bringing about the sought after results, especially in the case of
difficult scientific hurdles.
VIII
Today this long term policy is bearing fruit.
We wish that this book be the first of many in the area of chemistry and perhaps
in other areas as well.
Thank you, once again, to all those who made what was once only a wish,
become a daily reality.
C. JEANMART J.M. LEHN

Correspondant Member of Nobel Prize Winner
the Academy of Sciences Presidem of the Sciemific Council
IX
ACKNOWLEDGEMENTS
We would like to thank the Rh6ne-Poulenc Organic Intermediates Enterprise for

the financial backing that has enabled this book to be published, and especially Ted
Ziemann, president of Rh6ne-Poulenc Organic Intermediates Enterprise.
We would also like to thank :

- M r s Th6r6se Fessetaud who co-ordinated all the authors and the company
Proman.
-The Mrs Marthe Di Rollo, Dominique Trouillet, Laurence Ouled and Elisabeth
Di Rollo from Proman who did all the typing for this work.
- Mrs Tavernier for her help in translating various articles.
-The Mrs St6fanie de Rouville and Martine Pinard from the communications
management of the chemicals sector for their help and advice.
Lastly, we would like to thank all the authors for their work that enabled the
publication of this book.
Jean-Roger DESMURS Serge RATTON

CONTENTS
FOREWORD
B. Louvet, T. Ziemann, . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . V
PREFACE
C. Jeanmart, J.M. Lehn . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . VII
ACKNOWLEDGEMENTS .......................................................... X
INTRODUCTION
J.R. Desmurs, C. H61~ne, D. Michelet, S. Ratton . . . . . . . . . . . . . . . . . . . . 1
SYNTHESIS
ACYLATION
Friedel-Crafts acylation : interactions between Lewis acids / acyl chlorides and

Lewis acids / aryl ketones
R. Ashforth, J.R. Desmurs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Bismuth (III) salts in the Friedel-Crafts acylation

J.R. Desmurs, M. Labrouill6re, J. Dubac, A. Laporterie,
H. Gaspard, F. Metz . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Friedel-Crafts acylation of aromatics using zeolites

M. Spagnol, L. Gilbert, D. Alby . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
COC12 catalyzed trifluoroacetylation of aromatics using trifluoroacetic anhydride

J. Ruiz, L. Gilbert, D. Astruc . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
XI
ALKYLATION
Catalysis by rare earth phosphate II 9 Selective O-methylation of phenols by

methanol in vapor phase
L. Gilbert, M. Janin, A.M. Le Govic, P. Pommier, A. Aubry ..... 48
Catalysis by rare earth phosphate III : Characterisation of samarium phosphate and

samarium phosphate-cesium hydrogenophosphate as key catalysts for O-alkylation
of phenols
A.M. Le Govic, P. Pommier, A. Aubry, L. Gilbert, M. Janin ..... 62
AROMATIC FUNCTIONALISATION
Selective functionalisation of fluoroaromatics via organosilicon intermediates

B. Bennetau, P. Babin, J. Dunogues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
Arylation of amines and alcohols catalyzed by nickel, copper or palladium

complexes
H.J. Cristau, J.R. Desmurs, S. Ratton,
S. Rignol, M. Taillefer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90
The isomerisation of 1,2,4-trichlorobenzene : a theoretical study

S. Firkins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
CARBOXYLATION
Carboxylation of hydroxy aromatic compounds

I. Bonneau-Gubelmann, M. Michel, B. Besson,
S. Ratton, J.R. Desmurs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116
CHLORINATION
Access to polychlorophenols, chemistry of intermediates

J.R. Desmurs, S. Ratton, R. Jacquerot, J. Dananch6,
B. Besson, J.C. Leblanc . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
XII
Diastereoselective halogenations
P. Duhamel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176
ENZYMATIC CATALYSIS
Enzymatic hydrolysis of adiponitrile into 5-cyanovaleric acid, an intermediate for

Nylon 6
E. Cerbelaud, M.C. Bontoux, F. Foray, D. Faucher,
S. Levy-Schil, D. Thibaut, F. Soubrier, J. Crouzet, D. P6tr6 .... 189
FLUORINATION
Reagents with trifluoromethyl substituents

H.G. Viehe, Z. Janousek . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201
Fluorination of aromatic compounds by halogen exchange with fluoride anions

(,, Halex ,, reaction)
B. Langlois, L. Gilbert, G. Forat . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 244
4-Fluorophenol : a key intermediate for agrochemicals and pharmaceuticals

C. Mercier, P. Youmans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 293
Fluorodecarboxylation of arylchloroformate : a new access to fluoroaromatics

H. Garcia, L. Gilbert, M.C. Perrod, S. Ratton, C. Rochin ....... 301
Mild trifluoromethylation of organic compounds

C. Wakselman, M. Tordeux . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 313
FORMYLATION
Formylation of aromatic compounds in superacidic medium

L. Saint-Jalmes, C. Rochin, R. Janin, M. Morel . . . . . . . . . . . . . . . . . . . . 325
XIII
HYDROGENATION
High selectivities in hydrogenation of halogenonitrobenzenes on Pd, Pt or Raney

Nickel as catalysts
G. Cordier, J.M. Grosselin, R.M. Ferrero . . . . . . . . . . . . . . . . . . . . . . . . . . . 336
HYDROXYALKYLATION
Influence of the cation in condensation of glyoxylic acid on phenols in aqueous

hydroxide solution
M.F. Wuthrick, C. Maliverney . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 343
HYDROXYLATION
Selective access to hydroquinone ,, Fuchsone ,, route

M. Costantini, E. Fache, D. Michelet, D. Manaut . . . . . . . . . . . . . . . . . . 350
NITRATION
The mechanisms of nitration of phenol

P. M6tivier, T. Schlama . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 368
OXIDATION
Oxidation of alkylphenols to hydroxybenzaldehydes

E. Fache, D. Laucher, M. Costantini, M. Beclere,
G. Perrin-Janet . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 380
Large pore Ti-Beta zeolite with very low aluminium comem : an active and
selective catalyst for oxidations using hydrogen peroxide
M.A. Camblor, M. Costantini, A. Corma, P. Esteve, L. Gilbert,
A. Martinez, S. Valencia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 391
XIV
PEPTIDE SYNTHESIS
Peptide synthesis by SAPPHO technology

J.M. Bernard, K. Bouzid, J.P. Casati, M. Galvez,
C. Gervais, P. Meilland, V. P6v6re, M.F. Vandewalle,
J.P. Badey, J.M. Enderlin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 405
A new and practical removal of allyl and allyloxycarbonyl group promoted by

water-soluble Pd(0) catalysts
S. Lemaire-Audoire, M. Savignac, J.P. Genet, J.M. Bernard .... 416
SAFETY
Safety of chlorination reactions

J.L. Gustin, A. Fines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 431
APPLICATIONS
Sodium amide in organic synthesis

J.M. Poirier . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 445
Delivery systems for controlled release of active materials

C. Prud'homme . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 469
Anisole : an excellent solvent

J.R. Desmurs, S. Ratton . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 481
The use of phenolic compounds as free-radical polymerization inhibitors

F. Lartigue-Peyrou . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 489
ANALYSIS
Tracing back the origin of vanillin by SNIF-NMR

G.J. Martin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 506
XV
NMR under high gas pressure
F. Metz, M. Lanson, A. Merbarch, U. Frey . . . . . . . . . . . . . . . . . . . . . . . . 528
Lactic derivatives : methods for determining the optical purity of various

intermediates
F. Marcenac, D. Bernard, F. Boyer, J. Chabannes,
Y. Danion, M. Minfray, N. Peyre, E. Zandanel, M. Hillairet,
J.C. Marsault, E. Pilot . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 536
A U T H O R INDEX . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 550
S U B J E C T INDEX . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 552
XVI
INTRODUCTION
JEAN-ROGER DESMURS a), CLAUDE H E L E N E b), DANIEL MICHELET b)

AND SERGE RATTON c~
a) Rh6ne-Poulenc Industrialisation, Centre de Recherche, d'Ing6nierie et de

Technologie, 85 Avenue des Fr~res Perret, 69192 Saint-Fons Cedex, France.
b) Direction Scientifique, 25 Quai Paul Doumer, 92408 Courbevoie Cedex,
France.
c) Interm6diaires Organiques, 25 Quai Paul Doumer, 92408 Courbevoie Cedex,
France.
This book is a collection of papers dealing with various aspects of inorganic

chemistry:
- from exploratory work on the reactivity and selectivity of new reactions to studies
on the reaction mechanisms of well known reactions,
-from work highlighting the potential of certain technologies for new reactions
(bioconversion, organometallic catalysis, etc.), to studies illustrating the potential
for synthesis of certain reactants (e.g. sodamide),
-from work on the choice and development of industrial synthesis pathways for
new Fine Chemical intermediates, to studies aimed at understanding chemical
phenomena linked to process Safety,
- from work dealing with the treatment and formation of organic solids in order to
tailor their properties, to development of analytical techniques enabling detection of
the origin of products,
- and work on the development of new analytical methods in order to provide better
characterisation of reaction processes and products.
The diversity of topics covered in this book clearly shows the scope required
nowadays, in terms of fields of knowledge and expertise, to enable the development
of new processes and to the industrialisation and commercialisation of new
intermediates.
The speed with which the complex new process or product development
procedure must take place, starting from exploratory research right through to the
launch of the industrial production process, implies the contribution of numerous
scientific disciplines, in other words the existence of major centres of competency,
as well as perfect harmony between all the experts involved.
The major centres of competency in Organic Chemistry, the foundation of
Rh6ne-Poulenc Group Chemicals Sector's technical activity, are the fruit of many
years of basic research.
This type of research is often initiated by Rh6ne-Poulenc Group's Sciemific
Direction or benefits from its support before being fully taken over by the
Chemicals sector for confirmation of new concepts and scientific orientation
towards high potential targets.
Fundamental type research is often performed in association with the CNRS and
internationally renowned university laboratories.
This book contains a certain number of articles written by joint RP - University
Laboratory teams, which is a good illustration of the spirit of trust that motivates
researchers who are getting to know and appreciate one another more and more.
FRIEDEL-CRAFTS ACYLATION : INTERACTIONS B E T W E E N L E W I S
ACIDS / ACYL C H L O R I D E S AND L E W I S ACIDS / ARYL K E T O N E S
REBECCA ASHFORTH AND JEAN-ROGER DESMURS
Rh6ne-Poulenc Industrialisation, Centre de Recherche, d'Ing6nierie et de

Technologie, 85 Avenue des Fr6res Perret, B.P. 62, 69192 Saint-Fons Cedex,
France.
INTRODUCTION
The Friedel-Crafts acylation reaction is one of the most important in aromatic
chemistry used in particular to prepare aryl ketones (eqn. 1)
0
+ R--C + HC1 (1)
R' \C1 R'
The reaction is catalysed by a Lewis acid such as AIC13, FeC13, TIC14, SbC15,
NbC15, etc (refs. 1-5).
The major drawback of the Friedel-Crafts reaction lies in the need to use the
Lewis acid in stoichiometrical quantities relative to the acetone formed, which in
industrial terms poses large effluent problems.
The use of stoichiometrical quantities of Lewis acid results in the formation of a

complex at the end of the reaction between the aryl ketone formed and the Lewis
acid.
~__C/? .....MCln
/ u
To resolve the effluent problem, much work has been performed investigating
the conditions or catalysts that enable the Friedel-Crafts acylation to be performed
with catalytic quantities of Lewis acid.
Whilst the Friedel-Crafts acylation mechanism remains to be accurately

determined (ref. 6) it is reasonable to postulate four stages.
The activation of acid chloride by the Lewis acid (eqn. 2).
O 0,,
R--C//'\ + MCln "- R--C ~
\
%'MCln
/
(2)
C1 CI"
The reaction of the activated acid chloride with the aromatic compound to give a
complex (eqn.3).
0E~.......
MCln_
O, R ~ 1 (3)
-~ + R--C ~" """MCln ~
R' \cr"'" R'
The aromatisation of the complex (eqn. 4).
|
O..........,.AICI3
/0 ............,-MCIn
~ C,, R,,,-"" +HC1 (4)
R'
The decomplexation between the Lewis acid and the aryl ketone formed
(eqn. 5).
o .....M C h
+ MCln (5)
R,~\ ~ / xR R,/k / R
The Friedel-Crafts acylation with catalytic quantities of Lewis acid requires a
knowledge of the equilibria (2) and (5).
INTERACTIONS W I T H LEWIS ACIDS OF M E T A L HALIDE TYPE
Complexation of acid chlorides

D.E.H. Jones and J.L. Wood (ref. 7) used infrared spectroscopy to study the
chloride complexes of acidic A1CI3. The study of the complexation of acetyl
chloride by the various metal halides (Table 1) was performed by measuring the
variation of the vibration intensity (CO) at 1808 cm -1.
Table 1. Complexation of acetyl chloride in equimolar mixtures of CH3COC1 and metal halides
(infrared).
% acetyl chloride a)
Lewis acid
complexed by the Lewis acid
A1CI3 94
AIBr3 Insoluble
All3 79
SnC14
SnC12
TiC14 13
FeCI3 Insoluble
GaC13 b) 89
SbC15 b) 84
SbCIs 21
NbC15 b) 22
a) 0.2 M solution in CHzC12

b) Precipitation after 30 minutes
These results obtained using IR are confirmed with NMR in accordance with the
method described by G. Sartori (ref. 8) (Table 2).
Table 2. NMRS3C of acetyl chloride in equimolar mixtures of CH3COC1and metal halides a)
Lewis acid ~13C (C --" 0)ppm A~13C (C = 0)ppm
170.3
1,OM A1C13 207.4 36.7
SnC14 170.8 0.2
TIC14 171.0 0.7
Solvent 9CD2C12
NMR Bruker AMX 300
As described by G. Sartori (ref. 8), NMR shows that acetyl chloride is either
found free or in a 1"1 complex with A1C13.
Complexation of ketones
The complexation of p-methyl acetophenone 1 with various metal halides has
been determined using infrared by monitoring the change in vibration intensity (CO)
at 1683 m -1 (Table 3).
H 3 C ~ O
Table 3. Complexation of p-4-methyl acetophenone 1 with equimolar mixtures of (1) and metal
halides.
Lewis acid % of complexed p-methyl

acetophenone
A1C13 83
A1Br3 85
All3 100
SnC14 82
SnC12
TiC14 100
FeC13 100
GaC13 b) 100
SbC15 b) 100
SbC13 38
NbC15 b) 100
Ti(OCH(CH3)2)4
a) 0.2 M solution in CH2C12

b) Precipitation
All metal halides have electron deficiencies which complex the methyl
acetophenone.
The data obtained by infrared are perfectly confirmed by N M R (Table 4).

Table 4. NMR13C of 4-methyl acetophenone 1 with equimolar mixtures of 1 and metal halides.
Lewis acid ~13C (C -- 0) ppm A~13C (C = 0) ppm
197.7
1,0M A1C13 214.9 17.2
SnC14 209.3 11.6
GaC13 215.3 17.6
197.9
A1C13 214.6 16.7
A1Br3 215.4; 215.6 [ 17.5; 17.7

!
All3 214.9 17.0
SnC12 Insoluble
0,2 M TIC14 Precipitation
FeC13 Paramagnetic
SbC15 Precipitation
SbC13 200.2 2.3
NbC15 215.5 17.6
As opposed to acetyl chloride, we can observe a continuous change in the

chemical shift of the carbon in the carbonyl group given in Figure 1 as a function of
a varying aluminium chloride / 4-methyl benzophenone ratio.
A1C13
Me ~
1,30
1,20
1,00
1
_ ~ _ =
i i i
0,80
0,60
. . . . . .
l 0,50
,, , ,,,, _
0,30
/
0,20
.... J_ !
0,16
0,10
. ._. . . . . [ Pure p-MePhCOMe
Fig. 1. $13C of the CO in 4-methyl acetophenone as a function of the aluminium chloride / 4-

methyl acetophenone ratio.
9
A similar change is also seen in NMR of 27A1 (Fig. 2)
AI I C=O
1,30
0,80
9 , , =
0,50
,, , , , , J i i,,
0,20
ppm 120 100 80
Fig. 2. S27A1 as a function of the A1C13 / 4-methyl acetophenone ratio.

These observations could be due to the existence of several complexes of
different stoichiometry and geometry as suggested by various pieces of work
(refs. 9,10).
KETONE-CHLORIDE COMPETITION RELATIVE TO THE

COMPLEXATION OF LEWIS ACIDS
NMR and IR studies have enabled us to show that equilibria (2) and (5) were
strongly shifted towards the complex form,
O O,,
//
R--C + MCln _.. "-- R--C ~" .......MCln (2)
\C1 \ C1"''"
0 .....MCln ~~__c//0 + MCIn (5)

"R
We have sought to determine the competitive behaviour of a mixture of acetyl

chloride and 4-methyl acetophenone relative to metal halides.
Table 5 shows a considerable favouring of 4-methyl acetophenone when a Lewis
acid equivalent quantity is added to an equimolar solution of 4-methyl acetophenone
and acetyl chloride.
Table 5. The degree of complexed 4-methyl acetophenone measured by infrared in an equimolar
mixture of 4-methyl acetophenone and acetyl chloride.
Lewis acid % complexed

% Complexed CH3COCI
p-MePhCOMe
A1C13 92
A1Br3 92
All 3 100
SnC14 96 13
SnC12
TiC14 100 14
FeC13 62 30
GaC13 100 16
SbC15 100 29
SbC13 42 12
NbC15 100
a) 0.2 M solution of 4-methyl acetophenone in CH2C12, 0.2 M of CH3COC1 / 0.2 M metal

halide T = 25.
An increase in the CH3COC1 / 4-methylacetophenone ratio, 5"1 instead of 1"1

does not change the degree of complexed ketone (Table 6) which shows that the
interaction between ketone and Lewis acid is much greater than the interaction
between the acid chloride and the Lewis acid in the case of the metal halides
studied.
12
Table 6. Degree of complexed 4-methyl acetophenone measured by infrared using a mixture of
acetyl chloride (5 eq.), 4-methyl acetophenone (1 eq.).
Metal halide % complexed

p-MePhCOMe
A1C13 88
A1Br3 100
All3 100
SnC14 86
SnC12
TiC14 100
FeC13 69
GaC13 100
SbC15 76
SbC13 37
NbC15 84
CONCLUSION
Complexation with aryl ketone is much favoured by using conventional Lewis
acids such as metal halides.
In solution, the equilibrium (5) is in fact totally shifted towards the complex
form at ambient temperature.
// ....MCIn
C + MCln ..~
R' \R (5)
R '''~ / ~R
Because of this, the Friedel-Crafts acylation catalysed by metal halides such as

A1C13, FeC13, TiCI4, etc. requires near stoichiometric quantities of Lewis acids.
To make Lewis acids catalytic for the Freidel-Crafts reaction various solutions
can be considered :
9 Finding weaker metal halides such as BiC13 (ref. 11) in order to limit the
complexation with aryl acetone and favour complexation with the chlorine in the
acid chloride,
9 Using solid catalysts in order to hinder aryl ketone complexation (ref. 12),
9 Using less complex forming salts than metal halides with aryl acetone in the
same way as rare earth triflates (refs. 13, 14),
9 Increasing acylation temperature (ref. 4) but this is often a source of
secondary reactions.
References
1. C. Friedel, J.M. Crafts, Bull. Soc. Chim. Fr., 27,482, (1877).
2. C. Friedel, J.M. Crafts, Bull. Soc. Chim. Fr., 27,530, (1877).
3. A. Noguchi, T. Ikawa, Y. Shimada, J. Org. Syn. Chem. Japan, 39, 714, (1966).
4. I.P. Tsukervanik, N.V. Veber, Dold. Akad. Navk. SSSR, 180, 892, (1968).
5. J.J. Scheele in "Electrophilic Aromatic Acylation", Thesis, Delf, (1991).
6. J. March in "Advanced Organic Chemistry, Reactions, Mechanisms and Structure" 4 ed., J.
Wiley, pp , New York, (1992).
7. D.E.N. Jones, J.L. Wood, J. Chem. Soc. (A), 3132, (1971).
8. F. Bigi, G. Casmati, G. Sartori, G. Predieri, J. Chem. Soc. Perkin Trans II, 1319, (1991).
9. S. Starowieyski, S. Pasynkiewicz, A. Sporzynski, A. Chwojnowski, I. Organometal. Chem.,
94, 361 (1975).
10. N.L. Chikina, Yu. V. Kobdazhnyl, G.A. Osipov, Zh. OBBshch Khim, 45, 1354, (1975).
11. J.R. Desmurs, M. Labrouill6re, J. Dubac, A. Laporterie, H. Gaspard, F. Metz. This book.
12. M. Spagnol, L. Gilbert, D. Alby. This book.
13. A. Kawada, S. Mitamura, S. Kabayashi, J. Chem. Soc., Chem. Commun. 1157, (1993).
14. L. Hachiya, M. Moriwaki, S. Kobayashi Tetrahedron Lett. 36, 409, (1995).
B I S M U T H (III) SALTS IN F R I E D E L - C R A F T S A C Y L A T I O N
JEAN-ROGER DESMURS a), MIREILLE LABROUILLERE b), JACQUES

DUBAC b) ANDRE LAPORTERIE b) HAFIDA GASPARD b~ AND
FRAN(~OIS METZ a~

Technologie des Carri6res, 85, Avenue des Fr6res Perret, BP 62, 69192
Saint-Fons Cedex, France.
b) H6t6rochimie Fondamentale et Appliqu6e (URA CNRS 477), Universit6
Paul-Sabatier, 118 route de Narbonne, 31062 Toulouse Cedex, France.
INTRODUCTION
The acylation reaction is one of the most important reactions in organic
chemistry (ref. 1) (eqn. 1). The substituted atom Y is generally hydrogen, but
can be an organometallic group of silyl type (refs. 2, 3).
ZY -~ z--C--R (1)
II
0
This reaction involves an acylating reagent (acyl halides, carboxylic acids or

anhydrides) in the presence of an activator, usually a Lewis acid. However, as
a result of the complexation of this Lewis acid with the formed ketone, more
than one mole of catalyst is required per mole of reagent. It cannot be reused
because the ketone is isolated after hydrolysis of the complex. Such is the
dilemma of Friedel-Crafts acylation (refs. 4-6) in the presence of the traditional
catalyst, aluminum chloride (eqn. 2).
ArH + RCOX + A1C13 ~ Ar~C--R + HX

II
O ... A1C13 (2)
H-,O
- ~ Ar~CO--R + Alsalts
CX- c~ o c (o), R_..)

Consequently, a lot of research has been carried out in this area in order to
find convenient catalysts, i.e. those able to activate the acylating reagent while
giving labile complexes with ketones, in particular in hot conditions. Ferric
chloride is the most common catalyst when the reaction is achieved in this
manner (refs. 7, 8). With this same view, Friedel-Crafts acylation in the
presence of small quantities of catalysts (for example FeC13), is strongly
activated by microwave irradiation, in particular when the catalyst is on a
graphite substrate (ref. 9).
Other recent works concerning the catalytic acylation of aromatic ethers
concern :
- t h e use of Lewis acid-lithium or silver salt (AgC104 or AgSbF6) systems
(ref. 10), boron (ref. 11) or metallic triflates (ref. 12), the latter being reusable
catalysts, or also zinc chloride on a clay substrate ("Clayzic") (ref. 13) ;
- the study of the regiochemistry of the acylation of 2-methoxynaphtalene in the
presence of metallic chlorides (ref. 14) ;
- and the preparation of 4-alkanoylaryl-benzylethers (ref. 15).
Catalysis by Br6nsted acids requires very strong concentrations (refs. 4-6),
and is restricted to the more stable reagents and substrates. In this respect,
anisole is not acylated with a good yield in presence of 1 % of triflic acid
(ref.tl6).
R E C E N T RESULTS CONCERNING CATALYSIS BY BISMUTH (HI)

SALTS
Whilst numerous metallic salts are used in catalysis, some of them have
been relatively little studied. Such is the case of bismuth (III) salts including the
chloride. Bismuth, relatively inexpensive, with a metallic character marldedly
more pronounced than that of As or Sb, and giving much less toxic derivatives
(ref. 17), might play an increasing role in catalysis, in particular for the
substitution of some industrial catalysts affected by stricter standards on wastes.
Many works concern Bi (V) compounds in stoichiometric oxidations
involving the BiV/Bi m redox pairing (ref. 18). The use of Bi (III) compounds in
organic reactions is less developed, but the literature includes some references,
especially for the catalytic oxidation of alkenes or arenes (Bi (III) complexes
and molybdates) (refs. 19-23), acyloins (Bi203/AcOH) (ref. 24), and in
oxidative cleavage of epoxides (Bi (III) mandelate / DMSO) (ref. 25), ~-glycols
(Ph3Bi / NBS) (ref. 26), and ~-ketols (Bi (III) mandelate) (ref. 27).
Concerning BiC13, this weak Lewis acid proved an unexpected catalyst in
the Mukaiyama-cross aldol and -Michael reactions from enoxysilanes (ref. 28),
because other metallic chlorides (TIC14, A1C13, SnC14...) and stronger Lewis
acids, are required in stoichiometric proportion for these reactions (ref. 29). On
the other hand, more recently, i has been shown that :
- the BiC13 catalytic activity in these reactions could be considerably enhanced
by addition of some metallic iodides (ref. 30) ;
- the coupling of aldolisation and halogenation reactions, giving 13-haloketones
or -esters, is possible owing to these catalytic systems (ref. 31) ;
- these Bi (III) halide systems allow strong Lewis acid sensitive compounds to
be used (furane cpds) (ref. 32).
Moreover, BiC13 on its own acts as catalyst for the Knoevenagel reaction
(ref. 33) and is a strong activator of the Si-C1 bond (ref. 34).
Associated with some metals (A1, Fe, Zn), BiC13 gives Bi(0) which is a
catalyst for the allylation of aldehydes and amines (ref. 35), and for the
reduction of aromatic nitro compounds to azoxy compounds (ref. 36). When
associated with sodium borohydride, BiC13 gives an efficiem system for the
selective reduction of nitroarenes and azomethines (ref. 37).
As far as catalysis of acylation is concerned, BiC13 has been little studied.
Two references report the use of this salt for the acetylation of toluene (ref. 38)
and for the benzoylation of anisole (ref. 39), with average results for the latter,
but poor for toluene. More recently, Le Roux and al. showed that BiC13-
metallic iodide systems efficiently catalyze the acylation reaction of
enoxysilanes and allylsilanes for which they represent the first known catalysts
(refs. 30b, 40).
Although involving organosilanes, these last results encouraged us on to
investigate the catalytic approach of Friedel-Crafts acylation using bismuth (III)
salts, on their own, associated with co-catalysts, or on a substrate. We present
here our initial results (ref. 41).
BISMUTH (III) SALTS IN THE FRIEDEL-CRAFTS ACYLATION OF

AROMATIC ETHERS
Anisole is a reactive aromatic substrate for acylating reagents. For large
extent, the recent works of Scheele (ref. 42) focus on this compound.
Therefore, in order to give good comparison, we have chosen to carry out our
first tests on Friedel- Crafts acylation using anisole 1 (eqn. 3).
MeO-~ RCOX_
HX -~ M e O ~ C R + MeO-~
(3)
o /
RC
[I
2 O 3_
X = CL OC (O) R
R = Me (a), Me2CH (b), Me3C (e),
Me (CH2)4(d), Ph (e)
Acylation of anisole by acyl chlorides

The reaction between anisole and acyl chlorides (eqn. 3, Z = C1) was
carried out with an excess of aromatic substrate, without solvent (Table 1).
Table 1. Acylation of anisole by acyl chlorides (eq. 1, E = C1)a
Entry Catalyst (% mol) R Conditions b Yield (%)~
1 BiC13 (10) Me 50~ 2h 60 ; 50 d

2 BiC13 (10) Me2CH 85~ 6h 100 ; 87 d
3 BiC13 (1) Me2CH 85 ~ 6h 40
4 BiC13 (10) Me3C 85~ 6h 90 ; 80 a
5 BiC13 (10) Ph 85~ 6h 100 ; 90 d
6 Claybis c (5) f Me 50~ lh 50
7 Claybis: (5) f Me2CH 70~ 2h 92 ; 85 d
8 Claybis c (5) f MeaC 70~ 2h 90 ; 80 d
9 Bi203 (5) Me2CH 85~ 4h 90 ; 80 d
l0 Bi203 (0.5) Me2CH 85 ~ 4h 35
a. Without solvent; anisole / RCOC1 = 4/1; heating in an oil bath.

b. Temperature of the oil bath.
c. Conversion toward RCOCI ; 2_a,b,c,e / 3 a,b,c,e > 90/10
d. Yield in isolated product after aqueous workup.
e. BiC13 / K 10 Montmorillonite prepared as "Clayzic" (ref. 13).
f. 5% mol. in BiC13.
The Bi (III) salts, used bath chloride and oxide, gave comparable or often
better results to those previously described in the literature. For instance, in the
same experimental conditions Scheele observed 40 to 50% conversion of acetyl
chloride in presence of 25 % mol. of catalyst (FeC13, TiCI4, SnCI4) (ref. 42).
We have obtained 60 % conversion of acetyl chloride with only 10 % mol. of
BiC13 (Table 1, entry 1). With a less volatile reagent, isobutyryl chloride, the
reaction temperature can be increased, and the conversion was quantitative after
6h of heating at 85~ (Table 1, emry 2). In this case, 1% mol. of BiC13 led to
40 % conversion (entry 3). Isovaleryl chloride and benzoyl chloride also gave
high yields (entries 4, 5). With the oxide Bi203, the yields are comparable to
those obtained with the chloride (entries 9, 10).
Deposited on K 10 Montmorillonite ("Claybis"), BiC13 becames more active
than ZnC12 (ref. 13), the acylation reaction takes place at lower temperature and
with a shorter reaction time (entries 7, 8), with only 5 % mol. of BiC13-
equivalent.
Furthermore, some experiments with various Bi (III) salts and
organometallic derivatives (for example : bismuth oxychloride, -acetate, -
salicylate, -carbonate oxide, -zirconate, -germanium oxide, triphenylbismuth)
have shown that these derivatives are also catalysts for the acylation of anisole
by acyl chlorides (ref. 41).
Comparative tests were carried out with some catalysts under the same
experimental conditions (Table 2). BiC13 is the most efficient of the 4 metallic
chlorides used (Table 2, entries 1-6), but the difference is more pronounced
with the oxides (entries 7-10), a point that will be turned to account and
discussed further.
Table 2. Acylation of anisole by hexanoyl chloride. Comparative tests with various
catalystsa
Entry Catalyst (% mol) Reaction time Y/d (%)b
1 BiCI3 (5) 6h 65
2 BiC13 (10) 6h 87
3 SbC13 (10) 6h 27
4 FeC13 (5) 6h 58
5 FeCI3 (10) 6h 44
6 ZnC12 (5) 6h 46
7 Bi203 (5) 4h 80
8 Sb203 (5) 4h 20
9 Fe203 (5) 6,5h < 5
10 ZnO (5) 6,5h 60
a. Without solvent 9anisole / RCOCI = 4/1 9heating at 80~ in an oil bath.

b. In isolated product after aqueous workup; 2 d / 3 d > 90/10.
A study of solvents (Table 3) shows that dichloromethane associated with

ether (10/1) gives acceptable yields, but benzene, not acylated in these
conditions, and nitromethane give better yields. BiC13 is soluble in these last
two solvents, at room temperature in MeNO2, and the reaction proceeds in
homogeneous conditions.
Acylation of anisole by acid anhydrides

Table 4 reports the results using 10 % tool. of BiC13 with acetic and
isobutyric anhydrides as reagents (eq. 3, Z = OC(O)R). The acetylation of
anisole by (MeCO)20 is outstanding (Table 4, entries 1,2), particularly by
refluxing, towards acylation by MeCOC1 (Table 1, entries 1,6). On the other
hand, acylation with (MezCHCO)20 is more difficult than with MezCHCOC1.
The oxide Bi203 is not an acylation catalyst with an acid anhydride as
reagent. However, the addition of chlorine-mobile agent to Bi203 gives an
efficient catalytic system, for example Bi203,6 MeCOCI (5 % mol) or BieO 3, 6
Me3SiC1 (5 % mol).
In the acylation of anisole by acetic anhydride, bismuth trichloride appears
as a better catalyst than iron and zinc chlorides (Table 4, entries 2,5,6).
20
Table 3. Acylation of anisole by acyl chlorides RCOC1 in the presence of a solvent a
Entry Catalyst (% tool) R Solvent Conversion ( ~o)b

Conditions
1 BiC13 (5) Me CH2C12, Et20 (10/1) 28

reflux, 3h
2 BiC13 (10) Me - 40
3 Bi203 (5) Me - 55
4 BiC13 (10) Me MeNO2, 80~ 2h 80
5 Bi203 (5) Me2CH CH2C12, Et20 (10/1) 70
reflux 4h
6 BiC13 (10) Me2CH C6H6, reflux 4h 70
7 Bi203 (5) Me2CH C6H 6, reflux 4h 85 968c
8 BiC13 (10) Me2CH MeNO2, reflux 3,5h 90" 80c
a. Anisole / RCOC1 = 1/1.2.

b. Conversion toward anisole" 2 a,b / ~ a,b > 90/10.
c. Yield in isolated product after aqueous workup.
Acylation of veratrole
The acylation of 1,2-dimethoxybenzene or veratrole was carried out in the
same conditions as those of anisole, either using acyl chlorides or acid
anhydrides (eqn. 4) (Table 5).
MeO MeO
(4)
MeO /N~ RCOX MeO~N~~_C[ R
o
_4 5
x = EL OC(O)R
R = Me (a), Me2CH (b)
21
Table 4. Acylation of anisole by acid anhydrides (eq. 1, Z = OC(O)R) a.
Entry Catalyst (% mol) R Conditions Conversion ( %)b
1 BiC13 (10) Me 85~ c, 6h 87

2 BiC13 (10) Me reflux, 3h 100
3 BiC13 (10) Me2CH 85~ r 6h 67
4 BiC13 (10) Me2CH reflux, 3h 75
5 FeC13 (10) Me reflux, 6h 70
6 ZnC12 (10) Me reflux, 6h 66
a. Without solvent 9anisole / (RCO)20 = 4/1.

b. Conversion toward the acid anhydride; 2 a,b / 3 a,b > 90/10.
c. Temperature of the oil bath.
Bismuth chloride is a good catalyst for veratrole acylation by RCOC1

(entries 1,2), but the crude product may contain about 5 % of an impurity
idemified (GC-MS) as compound 6, which would arise from cleavage of an
ether group by HC1. The reaction is more difficult with acid anhydrides
(entries 4,5) relative to anisole (Table 4, entries 2,4).
MeO
M e O ~ c o R
22
Table 5. Acylationof veratrolea
Entry Catalyst (% mol) Acylating Conditions b Conversion ( %)c

reagent
1 BiCI3 (10) MeCOCI 50~ lh 80

2 BiC13 (10) Me2CHCOC1 85~ 6h 100 " 88 d
3 Bi203 (5) Me2CHCOC1 85~ 4h 70 958 d
4 BiC13 (10) (MeCO)20 140~ 7h 65
5 BiC13 (10) (Me2CHCO)20 140~ 7h 24
a. Without solvent; veratrole / acylating agent = 4/1 ; heating in an oil bath.

b. Temperature of the oil bath.
c. Conversion of 5 toward acylating agent.
d. Yield in isolated product after aqueous workup.
Mechanistic aspects
The mechanistic aspects of Friedel-Crafts acylation have been widely
developed, in particular concerning identification of the intermediate complexes
between the acylating reagent and the catalyst (refs. 1, 5, 6, 43). The general
opinion is that these species exist in solution as an equilibrium mixture of ionic
(oxocarbenium salts) and molecular (donor-acceptor complexes) forms whose
relative concentrations depend on solvent and temperature.
As a result of the insolubility of bismuth chloride in chloromethanes, a
spectrometric study of RCOC1-BiC13 mixtures has been carried out in
nitromethane.
An equimolecular mixture of MeCOC1-BiC13 in MeNO2 (0.2 mol. 1-1)
analyzed by infrared spectrometry showed the lack of characteristic absorptions
of oxocarbenium ions around 2200-2300 cm -1 (refs. 43, 44), but a marked
modification of the carbonyl stretching absorption. Two bands at 1715 and 1756
cm -1 took the place of the strong band at 1810 cm -1 of the free acetyl chloride,
indicative of the perturbed carbonyl frequency of a dative structure
C =O-+BiC13 (ref. 43).
Multinuclear NMR has been very useful for the analysis of these complexes
(ref. 43), in particular for the acetyl chloride-aluminum chloride system (ref.
45). A 1H and 13C-NMR study has been achieved with nitromethane solutions
of acetyl chloride-BiC13 system (Table 6). Experiments using carbon 13 labelled
acetyl-13C2 chloride in CD3NO 2 prove the existence of only one coordination
species. Indeed, the 13C-NMR spectra show one carbonyl signal (doublet) at
low field (A6 = 6 ppm) of the carbonyl signal of free acetyl chloride, and one
methyl signal (doublet) at high field (A6 = -13 ppm) of the methyl signal of
free acetyl chloride. With two equivalents of BiC13, the acetyl chloride appears
completely complexed. The chemical shifting of the protons of the methyl
group is not influenced by the complexation.
With 4-methoxyacetophenone 2, a similar experiment in nitromethane
shows any modification of the chemical shift of the 13C-carbonyl signal after
introduction of BiC13. Addition of MeCOC1 to this mixture causes the
appearance of the characteristic signals of MeCOC1-BiC13 interaction.
The actual stoichiometry of the RCOC1-BiC13 complex will be possible to
define after further studies and its eventual isolation. Owing to the low basicity
of bismuth, its interaction with the chlorine atom of RCOC1 must be envisaged.
This would also explain the preferential complexation of BiC13 with acyl
chlorides relative to ketones, that is the key of a catalytic system for Friedel-
Crafts acylation.
We must point out the possibility of rt complexes between BiC13 and
aromatic compounds (ref. 46). Considering the lability of these complexes,
these interactions do not play a prominent role in the mechanism of Friedel-
Crafts acylation, but they can improve the solubility of bismuth salts.
Table 6. N M R data for acetyl-13C2 chloride-BiC13 a mixtures.
Mixtures 51H 513C (Me) b 513C(O)b
MeCOC1 2.66 33.9 172.5
MeCOC1, BiCI3 33.9 172.5

20.6 176.5
MeCOC1, 2 BiC13 2.67 20.9 178.8
a. Chemical shifts relative to TMS (ppm) 9 solvent CD3NO2 " t e m p e r a t u r e 300K.

b. doublet, Ij(13C/13C) = 56 Hz.
24
A remarkable and somewhat surprising result is the catalytic activity of
numerous bismuth (III) derivatives for the acylation of anisole by acyl
chlorides. This result is indicative of likely oxygen-chlorine exchange between
the Bi-O bond containing compound and acyl chloride giving BiC13, the true
active species.This exchange is also involved in the Bi203-MeCOC1 and Bi203-
Me3SiC1 systems, active catalyst with acid anhydrides.
CONCLUSION
Whilst bismuth (III) chloride is an efficient catalyst for the aromatic ether
acylation by acid chlorides or anhydrides, it is not strong enough to carry out
the acylation of non activated aromatics. However, the potential of using a wide
range of Bi (III) salts as catalysts (ref. 41), in particular the oxide, the
oxychloride and the carboxylates, all non hygroscopic compounds, offers
advantages, and is indicative of the great versatility of Bi (III) derivatives.
Moreover, the Bi salts obtained after hydrolytic workup are directly reusable.
The para-selectivity of the described acylations is very high. In the case of
the bismuth (III) salt, the ortho effect (refs. 42, 47), with its disadvantages,
does not appear.
Since the molecular chemistry is well developed, it seems to us possible to
undertake the synthesis and study of the catalytic power of new bismuth (III)
derivatives containing suitable ligands to activate the Lewis acidity of this
element.
References
1. a) J. March, "Advanced Organic Chemistry. Reactions, Mechanisms, and Structure",
4th edition,Wiley, pp. 487-495,539-542, 598-599, New York, (1992).
b) R. Taylor, "Electrophilic Aromatic Substitution", J. Wiley, New York, (1990) ;
and references therein.
2. a) I. Fleming, J. Dunogu~s, R. Smithers, Organic Reactions, 37, 57, 148-154, (1989).
b) I. Fleming, J. Dunogu~s, R. Smithers, Organic Reactions, 37,446-474, (1989).
3. B. Benneteau, J. Dunogu~s, Synlett, 171, (1993).
4. J. March, ~ Advanced Organic Chemistry, Reaction, Mechanisms and Structure ,,,
4th edition, pp. 539-542, J. Wiley, New York, (1992).
5. G.A. Olah in "Friedel-Crafts Chemistry", Wiley, New York, (1973) and references
therein.
25
6. a) H. Heaney in "Comprehensive Organic Synthesis", B.M. Trost, ed., Pergamon,
Oxford, Vol. 2, 733, (1991).
b) G.A. Olah, R. Krishnamurti, G.K.S. Prakash, id., Vol. 3, 293, (1991) ; and
references therein.
. D.E. Pearson, C.A. Buehler, Synthesis, 533, (1972).
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27
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28
FRIEDEL-CRAFTS ACYLATION OF AROMATICS USING ZEOLITES
MICHEL SPAGNOL, LAURENT GILBERT AND DANIEL ALBY

Technologie, 85 Avenue des Fr6res Perret, B.P. 62, 69192 St Fons Cedex, France
INTRODUCTION
The Friedel-Crafts acylation as well as the related Fries rearrangemem of
aromatics are methods of choice in todays organic chemistry for synthesizing
aromatic ketones as reactive intermediates for the production of fine chemicals.
The conventional method of preparation of these aromatic ketones is the
homogeneous Friedel-Crafts acylation of aromatic hydrocarbons with carboxylic
acid derivatives using Lewis acids (A1C13, FeC13, BF3, ZnC12, TIC14) or Bronsted
acids (polyphosphoric acid, HF). For this purpose, stoichiometric to excess amounts
of the catalyst are required for the reaction to proceed (ref. 1).
On an industrial scale, the use of metal halides type acids, which are preferred
catalysts, is particularly penalizing. Indeed, during the workup of acylation
mixtures, catalysts are distroyed and produce relatively large amounts of
hydrochloric acid in the off-gas or in the effluent. This hydrochloric acid, which as
to be disposed of, originates both from the catalyst and also from the acyl chloride
employed for the acylation. In addition, to this disposal as a considerable
environmental problem, the corrosion problem, due to the hydrochloric acid, must
be solved. Therefore, a process that could be both environmemally friendly and also
inexpensive, with respect to the disadvantages indicated, is clearly desirable.
This article presents an alternative to the classical Friedel-Crafts catalysis using
heterogeneous catalysts such as zeolites as we believe them to be ultimate catalysts
for the future production of aromatic ketones.
29
RESULTS AND DISCUSSION
Literature Background
Although much attention has been recently given to zeolites in the area of
catalysis (petrochemistry in particular), there are few examples in the literature of
the utilisation of solid acids such as clay (ref. 2) or zeolite (ref. 3) catalysts to the
acylation of aromatics. On the other hand, the Fries rearrangement of phenylacetate
has been well described (ref. 4).
Y-faujasite-type zeolite exchanged with Ce 3+ cation have shown remarkable
reactivity in the acylation of aromatic hydrocarbons such as toluene, especially
when use in conjunction with straight-chain carboxylic acids (C12-C20) as acylating
agents (ref. 3f). In all cases, excellent para selectivity is observed that can be
explained by invoking a shape-selectivity argument. HY and Hb are also effective
para-selective catalysts in the acylation of anisole by phenylacetyl and
phenylpropanyl chloride without any noticeable demethylation reaction occurring
(ref. 3e). In this particular article, the modification of catalyst parameters such as
the influence of the level of Na + exchanged of the zeolite as well as the Si-to-A1
ratio has been examined (eqn. 1).
OCH3 OCH3
o
catalyst
+ C1/~CH2Ph (1)
78~ CC14
H2Ph
!
It was found that the initial rate for the formation of the aromatic ketone 1 is a
linear correlation of the Na + exchanged indicating that all the acid sites are active
in catalysing the acylation reaction. Therefore, a material does not need to have
very strong acid sites to exhibit high activity. On the other hand, it is better to use a
zeolite with a high framework Si-to-A1 ratio in order to insure a good reaction.
Very interesting Friedel-Crafts acylation reactions using zeolites can also be found
in the work of Bayer's team (ref. 3d) as well as Prins (ref. 3c). In both cases, work
was realized on activated aromatics such as anisole. In the latter, Hb were found to
exhibit particularly hight activity and selectivity independently of the Si-to-A1 ratio
of the zeolite.
30
When examining in detail these results it appeared very difficult for us to build
upon these experimental results as the reaction condition differ drastically from one
paper to the other. This prompted us to reinvestigate the scope and limitation of the
Friedel-Crafts acylation using heterogeneous solid as catalysts in trying as much as
we could to rationalized the observed effects.
Catalysis Experiments
We first focus our attention on the batch acylation of anisole in the liquid phase
by fixing primary parameters (acylating agent, solvent, temperature, ratio
anisole/acylating agent, % weight of catalyst), varying only the nature of the
catalyst. These parameters were chosen according in part to ref 3c. The results are
presented in Table 1.
Table 1. Acylation of anisole by acetic anhydridea
OCH3 OCH3
cata
+ Ac20 ~ + CH3COOH
90~ 6 h
H3
Entry Catalyst Yield (%) b Selectivity(%)

,,
1 HZSM5 12 > 98
2 H Mordenite 29 > 98
3 Hb 70 > 98
4 HY 69 > 98
5 exchanged clay 14 > 98
6 A1 clay 16 > 98
..
7 H3PW6Mo6040 21 > 98
a) reaction conditions 9molar ratio anisole/acetic anhydride = 5, 10% weight of powerded

catalyst, 90~ 6h.
b) yields were determined by GC using an internal standard.
Eventhough all the catalysts tested show a very high selectivity, zeolite are
clearly the preferred catalysts to carry out this reaction under mild conditions.
31
Among them the HY and Hb exhibit the best activity as previously reported
(refs. 3c, 3d). Optimisation of the reaction parameters underlines the following
trends" In general, an increase of the molar ratio anisole/acetic anhydride, the
amount of catalyst as well as the temPerature, is benefitial for the activity.
In changing the substrate to a more activated aromatic such as veratrole, the
following results were obtained.
Table 2. Acylation of veratrole by acetic anhydridea
OCH3 OCH 3
CH3 10 % cata OCH3

+ Ac20 + CH3COOH
90~ 6 h
Entry Catalyst Yield (%) b Selectivity( %)

1 HZSM5 12 > 98
2 H Mordenite 25 > 98
3 Hb 53 > 98
4 HY 95 > 98
a) reaction conditions " molar ratio veratrole/acetic anhydride = 5, 10% weight of powerded
catalyst, 90~ 6h.
b) yields were determined by GC using an internal standard.
For this reaction, only zeolite catalysts were found to show some activity which
are presented in Table 2. HY not only stand out as the best material, but in this
case, the reaction was much faster, in accordance with the classical electrophilic
substitution rules of more activated substrate. The Hb which was as active as the
HY in the case of anisole is now much less active with veratrole (entry 3 and 4),
underlining the effect of secondary parameters related to the catalyst itself. Such
parameters includes, the structure of the zeolite, the size and the shape of the pores,
the diffusion and chimisorption of both the substrate and the acylating agent.
H mordenite (entry 2) are not very active due to the monodimensional structure
which disfavor bimolecular reaction. On the other hand, HZSM5, Hb and HY have
a tridimensional structure which pore sizes and intersection volumes are presented
in Table 3.
32
Table 3. Intersection volume and pore sizes for HZSM5, Hb, HY.
Entry Zeolite pore sizes intersection volume

(A3)
HZSM5 [010] 5.3 x 5.6 150
[100] 5.1 x 5.5
2 Hb [001] 7.6 x 6.4 310
[100] 5.5 x 5.5
3 HY [111] 1700 (supercage)
The acylation reaction should proceed through a Wheland type intermediate

formed presumably within the intersection of the pores. If we compared the size of
these intermediates with the intersection volume (Table 4) we can draw the
following conclusion"
Table 4. Volume and size of the postulated intermediate
Entry Weyland interm. size (AxAxA) volume (A3)
0CH3
10 x 5.8 x 5.0 290
CH3
OCH3
~ .~~/OCH3
10.4 x 8.0 x 5.3 440
H//~CH3
O
In the HZSM5, the intersection volume does not allow the intermediate to be
formed and therefore, everything seems to happen at the outer surface of the
catalyst. With this in mind, it is interesting to note that the yield obtained in the case
of anisole and veratrole is the same indicating that the acylation of anisole on
.)..3
HZSM5 might also proceed at the surface of the catalyst. The same observation can
also be made in the case of H mordenite.
The volume intersection of Hb is well suited for the acylation of anisole (compare
Table 3 entry 2 with Table 4 entry 1) which is slightly superior to HY in term of
activity, where the Weyland intermediate does not beneficiate from the confinement
effect (ref. 5). On the other hand, it appears clearly that the acylated intermediate,
in the case of veratrole can not be formed in the Hb, this intermediate being bigger
than the allowed intersection volume. However, this situation is not encountered
when HY are employed explaining the good catalytic results observed.
In order to compare the versatility of this new process with classical Friedel-
Crafts reactions, we examined the reaction of anisole with benzoic anhydride: The
results are presented in Table 5.
Table 5: Benzoylation of anisole catalyzed by zeolitesa
OCH3 ?CH3
10 % cata
+ (PhCO)20 + PhCOOH
90~ 6 h
b
Entry Catalyst Yield (%) Selectivity (%)
1 HZSM5 13 > 98
2 Mordenite 16 > 98
3 Hb 13 > 98
4 HY 15 > 98
a) reaction conditions 9molar ratio anisole/benzoic anhydride - 5, 10% of powdered catalyst,

90~ 611.
b) Yields were determined by GC using an internal standard.
Eventhough, selectivity was found to be very high in all cases, the activity was
low. It appears obvious from these experiments that the benzoylation of anisole is
independent on the pore sizes of the zeolites.
Taking into account the size of the postulated Wheyland intermediate, calculated to
be around 604 A3, and the intersection volume of the different zeolites (Table 3),
one can clearly see that none of the tested catalysts have the required space to allow
34
the formation of the reactive intermediate. In addition, the same yield obtained in
all cases reinforces this argument suggesting that the reaction only happens at the
outer surface of the catalysts.
Any attempts in trying to optimize the reaction by varying primary parameters,
failed.
Having examined the influence of the size of the acylating agent, we focused
our attention on the use of acylchlorides as potential partners for the zeolite
catalyzed process.
The results are presented in Table 6.
Table 6. Acylation of anisole using acylchloridesa
OCH3 OCH3
10 % cata
+ RCOCI ~ + HC1
90~ 6h
b
Entry R Catalyst Yield (%)
1 CH3 Mordenite 6
. . .
2 CH 3 Hb 0
3 CH 3 HY 7
4 C6H5 Mordenite 0
,.,
5 C6H5 Hb 0
6 C6H5 HY 6
a) reaction conditions 9molar ratio anisole/acylchloride = 5, 10% of powdered catalyst, 90~

6h.
b) Yields were determined by GC using an internal standard.
There is no reaction when an acylchloride is used in conjunction with a zeolite

independently of its structure. This observation might suggest that the Bronsted
acidity of the zeolite is no well suited for acylchloride as opposed to typical lewis
acid such as aluminium chloride.
35
In order to understand this reactivity difference, we carry out 13C NMR
experiments, examining the C = O shift of an anhydride or an acylchloride when
complexed with a Lewis acid (A1C13) or a Bronsted acid (HC104) (Table 7).
Table 7. 13C NMR complexation Experiments
dl3(c =O) D d'~C

Entry Substrate
(lmol/1; CD2C12) (ppm)
1 CH3COC1 170.6
2 CH3COC1-A1C13 207.4 36.4
3 CH3COC1-HC104 184.6 14
4 (CH3CO)20 166.9
5 (CH3CO)20-A1C13 171.7 4.8
6 (CH3CO)20-HCIO4 179 12.1
7 (CH3CO)20-AIC13-CH3COC1 171.5 4.6
8 (CH3CO)20-HC1Oa-CH3COC1 184.3 13.7
These X3C NMR experiments fit the observed results we obtained "
a) Bronsted acids activate more strongly acetic anhydride than Lewis acids do
(compare entry 6 and 7).
b) On the other hand, Lewis acids exhibit a high complexation affinity with
acylchloride compare to Bronsted acids (entries 2 and 3) which may in part accounts
for the low reactivity observed in the case of zeolites.
This may suggest that doping the zeolite with Lewis acid might improve the
reaction.
We therefore engaged our effort toward the synthesis and the test of zeolites
exchanged with metals such as cobalt, zinc or cerium. The results are presented in
Table 8 :
Table 8. Acylation of anisole with acetylchloride catalyzed by metal exchanged Y-zeolites
OCH3 OCH3
10 % cata
+ CH3COC1 + HC1
90~ 6 h
H~3
36
Entry Catalyst Yield (%)
1 CoY 25
2 ZnY 25
,.
3 CeY 27
The results obtained are slightly higher than the crude zeolite itself (compare
Table 6, Entries 1-3 and Table 8). However, one" can not clearly conclude on the
advantage of using these type of exchanged catalysts as analysis of the reaction
mixture after reaction show significant amount of metal in solution. One can
therefore expect the leaching of one of the metal to be excluded by including the
metal in the zeolite framework.
CONCLUSION
We have demonstrated that anisole and veratrole can be very efficiently acylated
in liquid phase by acetic anhydride with zeolite catalysts under mild conditions,
without undergoing demethylation, giving rise only to the para isomer. The pore
sizes of the zeolite was found to be a critical parameter in order to ensure a good
reactivity. This reactivity was correlated with comparing the volume of the
Weyland's Friedel-Crafts intermediates and the intersection of the pore sizes of the
catalyst. The nature as well as the structure of the acylating agent is essential and it
was found that acylchloride, at this point, do not work in the reaction. In general,
we have shown, using NMR technics, that acetic anhydride is well activated by
Bronsted type acids whereas acylchlorides have a higher propensity to be activated
by Lewis acids.
In addition, this acylating reaction turns out to be very "environmentally
friendly" process compared to the classical Friedel-Crafts reaction catalyzed by
aluminium chloride, generating only byproducts such as acidic acid which can
easily be recovered and recycled.
37
References
1. G.A. Olah in "Friedel-Crafts and related reactions", Wiley-Interscience, Vol. I-IV,
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G.A. Olah in "Friedel-Crafts Chemistry", Wiley-Interscience, New York, (1973).
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3. a) For a general reference see : P.B. Venuto, Microporous Materials, 2, 297, (1994).
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Mol. Catalysis, 93, 169, (1994).
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38
CoCI 2 CATALYZED TRIFLUOROACETYLATION OF AROMATICS USING
TRIFLUOROACETIC ANHYDRIDE
JAIME RUIZ a), LAURENT GILBERT b) AND DIDIER ASTRUC a)
a) Laboratoire de Chimie Organique et Organom6tallique, URA CNRS N ~ 35,

Universit6 Bordeaux I, 351 Cours de la Lib6ration, 33405 Talence C6dex, France
b) Rh6ne-Poulenc Industrialisation, Centre de Recherche, d'Ing6nierie et de
Technologie, 85 Avenue des Fr~res Perret, B.P. 62, 69192 Saint-Fons C6dex,
France.
ABSTRACT
Trifluoroacetic anhydride (TFA) reacts at room temperature with anisole in the
presence of COC12 as catalyst to give regiospecifically p.methoxytrifluoro-
acetophenone and 4,4'-dimethoxydiphenyle. The experimental conditions (anisole /
TFA ratio) can orientate the system towards either reaction. Para-methylanisole
reacts under these conditions to give exclusively trifluoroacetylation in ortho
position with respect to the methoxy group without formation of a dimer. Similarly,
13-methoxynaphthalene reacts to give regiospecifically 1-trifluoroacetyl, 2-methoxy-
naphthalene. Meta-dimethoxybenzene exclusively gives 1,3-dimethoxy, 4-
trifluoroacetyl benzene. Veratrole does not react, probably because of the formation
of a stabilized chelate complex with Co n. The reaction medium oxidizes ferrocene
to ferricinium without trifluoroacetylation whereas 1,2,3,4-tetramethylbenzene is
inert, which indicates the requirement of at least one methoxy substituent.
INTRODUCTION
Fifty years ago, Simons et al. synthesized trifluoroacetophenone for the first
time (eqn. 1, refs. 1,2). Since then, the trifluoroacetylation of aromatic compounds
has continuously attracted the interest of chemists (refs. 3-16). Indeed, the classic
Friedel-Crafts reaction (refs. 1,2) requires sub-stoichiometric quantities of
aluminium chloride and trifluoroacetylchloride whose boiling point, - 27~ makes
it difficult to use. Moreover, some F/C1 exchange between trifluoro-acetophenone
39
and aluminium chloride is suspected. The trifluoroacetylation of activated aromatics
such as azulene (ref. 6), anthracene (ref. 7), thiophene (refs. 8,9), furanne (refs.
9,10), pyrrole (refs. 8,9,11), indole (ref. 9),N,N-dimethylaniline (refs. 9,12),
pyrogallol trimethyl ether (ref. 9) can proceed using trifluoroacetic anhydride
(TFA) at 200~ (refs. 6,7) or the triflate at 80~ (eqn. 2, ref. 8).
Trifluoroacetophenones are more easily synthesized by reaction between a Li,
Mg, Zn or Mn derivative and trifluoroacetic acid or ethyl - or Li trifluoroacetate
(eqn. 3, refs 14-20). Another recent method uses 2-trifluoroacetoxypyridine, but
requires the recycling of the compound (eqn. 4, ref. 21).
A1C13
CF3COC1 + ArH ~ ArCOCF3 (1)
+ 80~ 44 h .
CF3CO2SO2CF 3 +
COCF 3
(2)
I
H
CF3COX + ArM ~ CF3COAr + MX (3)

X = OH, OR, C1, OCOCF3
A1C13
+ ArH ~ CF3COAr + (4)
OCOCF3 - 10~ - 0~ O
Given the broad field of application of Friedel-Crafts reactions and the above
problems, in particular the formation of large quantities of aluminic waste, a major
drawback for industry, considerable investigation has recently been undertaken in
search for catalysts (eqn. 5, refs. 22-31).
ArH + (RCO)20 cat. ArCOR + RCO2H (5)
40
For instance, Iqbal has published a preliminary result for the acylation of
anisole catalyzed by COC12 involving the intermediacy of arene radical cations as
shown by the formation of duplication products (eqn. 6, ref. 31).
OMe OMe OCOCH3

OMe
.----M .---,
+ CH3COC1 + + ((~~~---~~~ + CH3COCOCH3 (6)
.____. / .
MeO
COCH3 COCH3
Until now, no research has been reported on truly catalytic trifluoroacetylation.

We report here the first results on the CoG12 catalyzed trifluoroacetylation of
anisole and other mono - and dimethoxyaromatics using TFA. We know that 1,3,5-
trimethoxybenzene can be trifluoroacetylated by TFA due to the production of
CF3CO + according to equation (7) whereas resorcinol (1,3-dimethoxybenzene) is
inert (refs. 8,32).
(7)
(CF3CO)20 -.. --- CF3C O + , CF3CO2-
RESULTS
Anisole reacts at room temperature with TFA in the presence of CoC12 as the
catalyst. For instance, in the presence of five equivalents of TFA for one equivalent
of anisole in the presence of 10 % CoC12, we have obtained 34 % of p-trifluoro-
acetylanisole and 54 % of dimerization in para position. The dimerization of anisole
reported to occur in the course of the acetylation reaction is referred to the ortho
structure, which we have not found. The difference in structure (para versus ortho)
can be due either to a mechanistic difference or to an erroneous attribution. The
variation in the proportions of anisole and TFA in the reaction medium has a
dramatic influence on the competition between the trifluoroacetylation and
dimerization pathways. For instance, the reaction between one equivalent of anisole
and one equivalent of TFA at 100~ regiospecifically leads to the para-dimerization
of anisole with a 96 % yield (eqn. 8).
41
CH30-~ + (CF3CO)20 COC12 10 %.._ C H 3 0 ~ ~ ~ / ~ _ O C H 3
100~ 15 h.
1 eq. 1 eq. 96 % (8)
Thus, it appears that a large excess of TFA should lead to the exclusive
formation of p-trifluoroacetophenone. Indeed, a 80-fold excess of TFA (as solvent)
leads to a 25 % yield of trifluoroacetophenone after one month at room temperature
without formation of the dimer (the only other product being anisole). Under the
same conditions, at 100~ in 15 days, the yield of p.trifluoroacetophenone is 96 %
(eqn. 9).
OCH3 OCH3
~ + (CF3CO)20 C~ 10% ~ + CF3CO2H

excess 100~ 15 d.
COCF3
96 % (9)
This reaction is totally inhibited by ligands such as CH3CN or PPh 3, a strong

indication for the coordination of the reactants to cobalt, thus for an inner-sphere
mechanism. When the reaction is carried out at 150~ an insoluble black tar is
formed.
In p.methylanisole, the para position at which trifluoroacetylation occurs in
anisole is now blocked by the methyl substiment. With 5 equivalents of TFA, we
have obtained the product resulting from the exclusive regiospecific trifluoro-
acetylation in ortho position with respect to the methoxy group without formation of
a dimer (eqn. 10). The yield is lower than in the case of anisole, however, if the
reaction time is only 15 h. at 100~ and unreacted p.methylanisole can be
recovered.
42
( CH3 OCH3
+ (CF3CO)20 C~ 10 % COCF3
+ CF3CO2H
IO0~ 15 h.
CH3 CH3
1 eq. 5 eq. 40 % (10)
Since no dimer was formed in this case, we re-investigated the acetylation

reported in the literature to give the ortho-ortho dimer (ref. 31). The only
compound found under the conditions mentioned in the literature (ref. 31) is the one
resulting from o-acetylation along with the starting material, but the ortho-ortho
dimer was again not observed.
We have carried out reactions with other substrates, in particular 13-methoxy-
naphthalene. The reaction is remarkably facile and leads to 1-trifluoroacetyl
2-methoxynaphthalene as the only reaction product, in 68 % yield (eqn. 11). In this
case, the most reactive position is position 1 (the position para with respect to the
methoxy group is now blocked). Reactivity in position 6 has been observed in a
limited number of cases, for the acetylation, especially when zeolites are used
(ref. 33).
COCF3
~ O C H 3 + (CF3CO)20 COC12 10 % ~ O C H 3
100~ 15 h.'- ~ + CF3CO2H
1 eq. 1 eq. 68 % (11)
Finally, we have investigated the CoC12 catalyzed trifluoacetylation using TFA

for dimethoxyaromatics : veratrole (ortho-dimethoxybenzene) and meta-dimethoxy-
benzene. Veratrole did not react despite several attempts (eqn. 12) and meta-
dimethoxybenzene is the subject of trifluoroacetylation in the position ortho/para
(eqn. 13).
43
~
OCH3
OCH3 COC12 10 %
+ (CF3CO)20 X w no reaction (12)
100~
veratrole
1 eq. 5 eq.
OCH3 (~CH3
CoC12 10 %
+ (CF3CO)20 ~ + CF3COzH
OCH3 100~ 15 h. OCH3
COCF3
1 eq. 5 eq. 87 % (13)
In spite of the activation in para positions by the methoxy group in veratrole,

such positions are not sufficiently reactive although there is no steric effect. Under
the same reaction conditions, ferrocene is oxidized to ferricinium but no
trifluoroacetylation product is found. Durene does not react (eqns. 14 and 15).
Since COC12 is not an oxidant, this confirms the intermediate formation of oxidizing
Co nI species by reaction between COC12 and TFA.
~
CH3
CH3 CoC12 10 %
+ (CF3CO)20 /N/
N "- no reaction (14)
CH3 IO0~
CH3
1 eq. 5 eq.
44
+
CoCle 10 % ~ X-
Fe + (CF3CO)20 ~-- Fe (15)
100~
1 eq. 2 eq. (X- = C1- or OAc-)
MECHANISM
It appears that a methoxy substituent on the aromatic ring is necessary to make
the CoC12 catalyzed trifluoroacetylation by TFA work. The lack of reactivity of
veratrole is not clear but it is possible that the purple Co II (veratrole) "+ complex
which forms is too stable to react because of its chelate structure. Indeed, the para
position with respect to the first methoxy group should be even more reactive in
veratrole as compared to anisole.
An essential mechanistic feature is the inhibition of the reaction by coordinating
solvents such as acetonitrile or by other ligands such as triphenylphosphine. This
inhibition by ligands indicates that coordination of the substrates is a key step in this
process.
The formation of dimers and ferricinium indicates that Co IH species are formed
(eqns. 16-19).
2 [COIIC12] + (CF3C0)20 > [CoIIIc12(CF3CO)] + [(CoIIIc12(CF3CO2)] (16)
It is also clear that these Co nI species can either oxidize the aromatic or react by
electrophilic attack (refs. 34,35). The aromatic dimer is formed as a result of this
monoelectronic oxidation :
[CoIIIc12(O2CCF3)] + PhOCH 3 > [COIIC12] + (PhOCH3) "+, CH3CO 2- (17)
PhOCH3~ + PhOCH 3 > dimer H + H + (18)
dimer H + [CoIII(o2CCF3)]----~ dimer + CFaCO2H + Con (19)
45
The real mechanistic alternative is indeed whether the C-C bond is formed by a
classic electrophilic attack (eqn. 20) or by the interaction of [ColII(c1)2(COCH3)]
with the radical cation of the aromatic (eqn. 21).
PhOMe + [ComC12(COCF3)] > p-CF3COPhOCH3 + [CoIII(c1)] q-HC1 (20)
PhOMe"+ + [CoIIIc12(COCF3)] > p-CF3CPhOCH3 + [ColICI2] -k- H + (21)
The latter possibility has been suggested by Iqbal in the case of the Co II
catalyzed acetylation of anisole by acetylchloride (ref. 31). However, no
experimemal support of the mechanism has been provided so far. Oxidation and
electrophilic attack can be competitive pathways or oxidation can be a common
pathway for both dimerization and trifluoroacetylation.
CONCLUSION
We have reported here the catalyzed trifluoroacetylation of methoxyaromatics
by TFA for the first time. No solvent is used in the reaction (coordinating solvents
inhibit the reaction). In the case of anisole, variations of the experimental conditions
allow to selectively lead to either paradimerization or trifluoroacetylation. Given the
inconvenience of the production of large quantities of aluminium waste in the A1C13
induced process and the delicate handling of trifluoroacetic chloride due to its
boiling point o f - 27~ the finding reported here should prove very practical for
the trifluoroacetylation of methoxyaromatics on the industrial scale.
References
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46
13. T.R. Forbus, J.C. Martin, J. Org. Chem. 44, 313, (1979)
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16. X. Creary, J. Org. Chem., 52, 5026, (1987)
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19. D. Naumann, M. Finke, H. Lange, W. Dukat, W. Tyrra, J. Fluorine Chem., 56, 215,
(1992)
20. X. Creary, J. Org. Chem., 52, 5026, (1987)
21. T. Keumi, M. Shimada, M. Takahashi, H. Kitajima, Tet. Lett. 1990, 783.
22. M. Hiro, K. Arata Chem. Lett., 325, (1978)
23. K. Nomita, Y. Sugaya, S. Sasa, M. Miwa, Bull. Soc. Chim. Japn., 53, (1981)
24. T. Yamaguchi, A. Mitoh, K. Tanabe, Chem. Lett., 1229, (1982)
25. F. Effenberger, G. Epple, Angew. Chem. Int. Ed. Engl., 11,300, (1972)
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27. T. Mukaiyama, H. Nagaoka, M. Ohshima, M. Murakani, Chem. Lett. 165, (1988)
28. T. Mukaiyama, T. Ohno, T. Nishimura, S.J. Han, S. Kobayashi, Chem. Lett., 1059,
(1991)
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30. A. Kawada, S. Mitamura, S. Kobayashi, Synlett, 545, (1994)
31. J. Iqbal, M.A. Khan, N.K. Nayyar, Tet. Lett., 5179, (1991)
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VCH, Chapter 7, New York, (1995)
47
CATALYSIS BY RARE EARTH PHOSPHATE II 9 SELECTIVE
O - M E T H Y L A T I O N OF PHENOLS BY M E T H A N O L IN VAPOR PHASE
LAURENT GILBERT a) MARCELLE JANIN a) ANNE-MARIE LE GOVIC b)

PASCALE POMMIER b) AND ALAIN AUBRY b)

Technologie, 85 Avenue des Fr~res Perret, B.P. 62, 69192 Saint-Fons, France
b) Rh6ne-Poulenc Recherches, Centre de Recherches d'Aubervilliers, 52 rue de la
Haie Coq, 93308 Aubervilliers Cedex, France
ABSTRACT
Vapor phase catalytic alkylation of phenols with methanol was carried out on
various phosphates as catalysts. The best activity and selectivity was observed on
boron, rare-earth and niobium phosphate. With boron phosphate, the reaction is
very selective for O-alkylation even at high temperature. On this catalyst o-
methoxy-phenol is selectively obtained from 1-2-dihydroxybenzene. With rare-
earth phosphate calcinated at 400~ and with niobium phosphate, O-alkylation
selectivity decreases with an increase of reaction temperature. For rare-earth
phosphates it is possible to improve the selectivity by calcination at higher
temperature or by a wetness impregnation of cesium hydrogenophosphate. An
explanation of these results is proposed.
INTRODUCTION
Alkylaryl ethers have distinctive, pleasant odors flavors which make then
valuable for the perfume and flavor industries. They are also valuable intermediates
for agrochemicals, pharmaceuticals, food preservatives and antioxidants (ref. 1).
Among those products, 2-methoxyphenol 1 (guaiacol) is especially interesting as it
is used as intermediate for the synthesis of important food additives like vanilline.
48
The most versatile method of preparation is the williamson ether synthesis
(ref. 2) particularly by reaction of sodium phenate with halogen derivatives of
hydrocarbons. To obtain a higher reactivity, this reactant can be substituted by a
dialkyl sulfate or dialkylcarbonate but those alkylating agents scarcely contribute to
a more economic process.
The preparation of methylarylether by reaction between phenols and methanol
was the object of many studies as such a process present main advantages on an
economic point of view due to the lower cost of methanol compare to
methylchloride and an environmental advantage due to the limitation, and even the
total removal of saline effluents. However, to be an attractive one, such a process
needs to be highly selective in O-alkylated products with a strict limitation of C-
alkylated by-products.
Numerous studies concerning O-alkylation of phenol were reported (refs. 3-9).
Described catalysts belong to all the catalyst families 9oxides (ref. 3) ; phosphates
(refs. 4, 5) ; metallosilicates (ref. 6) ; aluminophosphates (ref. 7) ; ion exchange
resin (ref. 8). On the other hand, the selective mono-O-alkylation of diphenols was
little reported and mainly in patent literature (ref. 9). The main studies deal with
synthesis of guaiacol by methylation of 1-2-dihydroxybenzene 2 (catechol) (eqn. 1)
catalyzed by boronphosphate eventually doped or supported (ref. 9). The main
difficulties of this reaction consists in physical instability of the catalyst which is
eluted in the reaction stream conducting to the formation of methylborate as a by-
product which has to be separated. It is then needed to add some new catalyst
continuously.
We have studied the O-alkylation of catechol in guaiacol by solid-gas catalysis.
In this reaction, 1,2-dimethoxybenzene 3 (veratrole) can be produced as a coproduct
and also some C-alkylated derivatives as by-products. We have chosen to mainly
study phosphates derivatives and to realize a large screening of catalysts.
In the preoccupation to screen all the periodic classification of the elements, we
have tested numerous metallic phosphates that we have arbitrarily classified as a
function of the cation valence. As far as it was possible, we have limited the
synthetic routes of catalysts to one or two to be able to compare their intrinsic
activity.
~~]
OH OCH 3
.,~ OH
catalyst
+ CH3OH + H20 (1)
vapor phase
2 1
49
EXPERIMENTAL
Catalysts preparation : the various metallic phosphates were prepared by wet
synthesis except for niobium oxide phosphate which was obtained from CBmm.
According to the solubility of the metallic precursor, two synthetic routes were
used:
- precipitation (for a totally soluble precursor)
- dissolution, reprecipitation (for a less soluble precursor)
For precipitation, the synthetic process consists of addition of orthophosphate
anions to an aqueous solution of the metallic salt. The precipitated metallic
orthophosphate was then recovered by filtration, then washed, dried at l l0~ and
then calcinated at various temperature. By this method CaHPO4, FePO4,
Ce(HPO4)2, Zr(HPO4)2 were obtained. The dissolution, reprecipitation process
consists of preparing a metallic salt suspension of known solubility and in adding to
it an aqueous orthophosphate anion solution in order to displace the following
equilibrium:
M x Ly + z Hz-n PO4 n+ -" "- Mx H(z-n)PO4 + Y L t-

n from 1 to 3 with nz = ty
L = CO32-, OH-, C204 z-
The metallic orthophosphate is then recovered using the same workup as

reported for the precipitation method.
Phosphates of rare earth metals were prepared by this method using rare earth
carbonates as precursors, boron phosphate starting from orthoboric acid, and
yttrium phosphate from yttrium oxyde.
Cesium phosphate synthesis is a little special due to its high solubility in water
and cesium phosphate crystals were obtained by water evaporation from an aqueous
solution of cesium hydrogenophosphate resulting from the neutralization of an
aqueous solution of cesium hydroxyde by phosphoric acid.
Crystalline structure (DRX) and specific surface area (BET method) were
systematically determined on the dried and calcinated catalysts at 400~ Rare earth
phosphates were more precisely characterized and the results are reported in the
following paper (ref. I0).
Catalytic tests 9The reactions were performed in a vapor phase tubular quartz
reactor packed with the catalyst (stationary bed) and heated in a shell oven under
nitrogen at the test temperature. During the catalyst's reactions screening were
performed between 250 and 390~ using 2.5 ml of catalyst. After thermal
50
equilibria has been reached, nitrogen was introduced via volumetric flow meter
(1 l/h). A catechol solution (2.25 mmol/g) in methanol (molar ratio CH3OH /
C 6 H 6 0 2 = 10) was introduced with the aid of a syringe at a flow of about 5.5 g per
hour. The reaction products were collected and were analysed by liquid
chromatography.
Catalytic activity of metallic phosphate

Table 1 summarize the catalytic performances of metallic orthophosphates at
270~ The main following conclusions can be then extracted :
- calcium phosphate has no activity
- generally the other metallic phosphate are selective for the O-alkylated products.
Cesium hydrogenophosphate presents the lowest selectivity but as for zirconium and
cerium IV hydrogenophosphate the measurement of selectivity is rather imprecised
due to a low activity. Moreover with cesium hydrogenophosphate another difficulty
is linked to its high physical instability and so a rapid decrease of the conversion,
- in those conditions cerium III and samarium phosphate are the only catalysts
giving a significant (# 5 %) yield of veratrole,
- the best activities are obtained for boron, rare earth (lanthanum, samarium,
cerium) phosphates and niobiumoxyphosphate.
All those conclusions are simplified in Figure 1 which show that in terms of
productivity, trivalent and pentavalem metallic phosphates are the most active
catalysts for this reaction.
On the other hand, if we reported the activity as a function of specific surface
area (Figure 2) we observed a very high activity of cesium hydrogenophosphate, all
the other active catalysts showing a comparable activity.
Table 1. Activity of metallic phosphates
Phosphate S BET(m2/g) RX WHSV Conversion Selectivity Selectivity

(hl) (%) guaiacol (%) veratrole (%)
Cs2HPO4 <0,5 (400~ Cs4P207 2,1 11 53 0
CaHPO4 12 (dry) cubic 2,6
21 (400~ Ca2P207
YPO4 137 (400~ quadratic 2,3 20 100
i
LaPO4 100 (dry) hexagonal 1,7 60 98

92 (400~
CePO4 123 (dry) hexagonal 1,7 60 92
112 (400~
SmPO 4 124 (dry) hexagonal 1,8 72 96
!
107 (400~
BPO4 !
16 (400~ quadratic 2,9 37 99
FePO4 34 (dry) monoclinical 3,6 11 85
i
31,, (400~
Ce(HPO4)2i 22 (dry) Ce(HPO4)2 3,5 100
13 (400~ CeP207
Zr(HPO4)2 !
5 (400~ monoclinical 2,8 7 61 0
NbOPO4 121 (400~ amorphous 3,3 62 99 0
Fig. 1. Influence of phosphate nature on yield in guaiacol
52
Fig. 2. Catalytic activity at 270~ per unit surface
Influence of the reaction temperature on selectivity in O-alkylated products

The influence of temperature on the selectivity was examined systematically.
This study had not drown an interesting catalytic activity for catalyst which are
weakly active at 270~ but had shown some important variation in selectivity for
the more active catalysts : boron, lanthanum, cerium III, samarium phosphate and
niobium oxyphosphate. Catalytic results for those catalysts as a function of the
temperature are reported in Table 2 and selectivity in O-alkylated products is
simplified on Figure 3.
For BPO4 (Table 2, entry 1) an increase in the temperature leads to an increase
of the activity without loss in guaiacol selectivity. This activity increase did not
permit to obtain the di-O-alkylated product with a significant yield, the conversion
being still limited. Those results are in good agreement with the published results
(ref. 9).
With rare earth phosphates (Table 2, entries 2, 3, 4) as catalysts, an increase in
the reaction temperature leads to an high increase of the activity, the catechol
conversion being nearly complete at 300~ Then a consistent amount of di-O-
alkylated products are producted. On the other hand, selectivity in O-alkylated
products drops in a significant manner on behalf of C alkylated derivatives.
For NbOPO4 (Table 2, entry 5), an increase in the temperature leads to a low
increase of the activity, but as for rare earth phosphate, we observed for
temperature higher than 330~ an important fall down of selectivity in
O-alkylation.
53
Fig. 3. Selectivity in O-alkylated products
Those catalysts (REPO4, NbOPO4) are more active, productively speaking, than
boron phosphate but they also favored C-alkylated products, mainly at high
temperature.
The influence of catalyst calcination temperature was studied in the case of
samarium phosphate as those products show a thermal phase transition between 600
and 700~ (ref. 10). Catalytic results are summarized in Table 3.
Table 3. Influence of samarium phosphate calcination temperature on selectivity in O-

methylation of catechol
" smPO] Calcinated at 400~ StoP04 calcinated at 700~

(SS = 107 rn2/g) (SS = 39 m2/g)
Temp. Conversion Selectivity Selectivity Conversion Selectivity Selectivity
(of) (%) (%) (%) (%) (%) (%)
Guaiacol Veratrole Guaiacol Veratrole
300 88 88 12 77 95 5
330 92 60 10 83 91 9
360 94 35 5 95 90 9
Samarium phosphate calcinated at 700~ and then of monoclinical structure,

shows a very promissing activity and selectivity in O-alkylated products even at
high conversion of catechol.
54
Table 2. Catalytic results as a function of temperature
Reaction temperature Reaction temperature Reaction temperature

27( )~ 300~ 330~
....,
0 o -~ 0
._ -~
~D o~ d r~
Phosphate ~,-~ =
a ._. ";,~ ~
Entry -9
.~ 0
~
nature ._>
o
rn 5~
BPO4 37 99 99 58 99 99 76 98 100
....
LaPO4
60 98 98 77 98 98 82 64 64
(ex carbonate)
CePO4 60 92 97 79 89 100 95 24 28
SmP04
72 96 99 88 88 100 92 6C 70
(ex carbonate)
NbOPO4 62 99 99 63 92 92 64 68 68
55
Cesium hydrogenophosphate presents a remarkable catalytic activity since its
specific surface area is very low. However, this solid cannot be used as a catalyst
due to its physically instability under the reaction conditions. We, therefore,
focussed our attention in trying to support this catalyst, supports being chosen
among the one active in the reaction : BPO4, REPO4 (RE = Sm, La) and
NbOPO4. The different catalysts are prepared by wetness impregnation. Initially,
we have fixed arbitrarily the cesium hydrogenophosphate content to 10 % in
weight. This value is superior to the one needed to generate a monolayer and we
can therefore observe, the intrinsic activity of the supported cesium
hydrogenophosphate.
Table 4. Catalytic activity of Cs2HPO4 impregnated metallic phosphate
Entry Catalyst Temperature Conversion Selectivity Selectivity

(~ (%) Guaiacol(%) Veratrole (%)
1 LaPO4 300 77 98 0
' 330 l' 82 ..... 64 ' 0
360 i 88 57 0
LaPO4, CszHPO4 300 52 98 0
(Cs 10 % p/p) 330 86 88 10
360 97 64 26
SmPO 4 300 88 88 12
330 ii 92 60 10
360 ' 94 " ' 35 ' 5
4 S m P O 4, Cs2HPO4 300 71 100 0
(Cs 10 % p/p) 330 90 90 10
360 98 75 24
5 BPO4 300 58 99 0
330 76 98 2
360 83 96 3
BPO4, Cs2HPO4 300 18 100 0
i
(Cs 10 % p/p) 330 30 100 i 0
360 32 100 0
7 NbOPO4 300 52 92 0
330 |
63 i
68 |
0
360 64 38 0
8 NbOPO4,Cs2HPO 300 51 98 2
4
(Cs 10 % p/p) 330 59 86

360 61 81
56
Boron phosphate, as previously seen, effectively catalyzed the O-alkylation of
catechol to guaiacol (Table 4, entry 5). At different temperature, the reaction leads
selectively to guaiacol. The consecutive reaction of veratrole formation being
limited even at high conversion. The impregnation of this catalyst by cesium
hydrogeno-phosphate gives rise to an heterogeneous product as it was
demonstrated by the RX, STEM analysis. The cesium is concentrated in
amorphous zones without any interaction with the boron phosphate crystallites.
The obtained catalyst presents a lower activity but still an excellent selectivity in
guaiacol (Table 4, entry 6). Niobium phosphate exhibits a lower selectivity in O-
alkylated products, in particular at high temperature (360~ (Table 4, entry 7).
The impregnation of this catalyst by cesium hydrogenophosphate leads to an
uniform cesium distribution. The activity of niobium phosphate is not greatly
enhanced while the selectivity is increased (Table 4, entry 8). However, cesium
hydrogenophosphate interacts mildly with niobium phosphate since it is eluted
under the reaction conditions. In the case of rare earth phosphates (Table 4, entries
1-4), the impregnation by cesium hydrogeno-phosphate does not modify noticeably
the activity. However the selectivity in O-alkylated products is greatly enhanced.
At high conversion one can also observed the formation of veratrole in
significative amount by consecutive O-alkylation of guaiacol. Those catalysts
having a good activity as well as selectivity were further characterized. The results
of this studies are presented in the following article (ref. 10).
The influence of the cesium hydrogenophosphate content was examined in the
case of lanthanum phosphate. Figure 1 presents the selectivity observed at 330~
for a 80 % conversion.
100
8O
~, 60
~ 4o
~ 2o
0 I Content of Cs2HP4 (% p/p)
0 3 6 9 12 15
Fig. 1. Influence of cesium hydrogenophosphate content
5?
This curve shows that an excellent selectivity in O-alkylated products is
obtained starting at about 5 % of Cs2HPO4. This value corresponds to the cesium
hydrogeno-phosphate quantity which is necessary to obtain a monolayer. The
increase in the cesium hydrogenophosphate content does not lead to a lower
activity.
The study of O-methylation of phenol as well as 1,4-dihydroxybenzene in
anisole and 4-methoxyphenol respectively and the condensation of catechol with
ethylene glycol demonstrates that the use of L a P O 4 , Cs2HPO4 as a catalyst is a
powerfull methodology to selectively access numerous alkylarylethers. Results are
presented in Table 5.
Table 5. O-alkylation of phenols catalyzed by LaPO 4, Cs2HPO 4
Reaction Catalyst Reaction conditions Results

OH OCH3
LaPO 4 Cs2HPO 4 MeOH/PhOH = 10 Conversion = 53 %
(8 % p/p) 0 = 360~ Selectivity = 90 %
tc# ls. o-cresol 10 %
OH OMe
LaPO 4 Cs2HPO 4 MeOH/H20/H Q = Conversion = 25 %
(8 % p/p) 16/7/1 Selectivity = 94 %
OH OH
0 = 330~
tc# ls.
LaPO 4 Cs2HPO 4 Ethylene Conversion = 100 %
(8 % p/p) Glycol/PC = 10w1 Selectivity = 98 %
OH HO
0 = 330~
tc# ls.
DISCUSSION
The sum of results published in the literature on phenol alkylation using
methanol are not clear and one cannot easily conclude to the relation between the
acidity and the basicity of the catalyst and the selectivity in O or C alkylated
products. However it seems that O-alkylation products can be obtained by the use
of acidic catalysts (ref. 11). An increase of the acidity of oxide type catalysis (ref.
3) or mixed aluminium phosphate-alumina (ref. 12) gives rise to an increase of
selectivity in O-alkylated products. However for strongly acidic catalysts C-
alkylated products, which are the more thermodynamically stable, can be obtained
either by isomerization or by reaction between phenol and methylarylether.
58
On mildly acidic catalysts, C-alkylated products can also be obtained by
competitive reaction on residual basic sites. This latter mechanism is generally
evidenced by examining the regioselectivity of the reaction, a mechanism
involving a basic site leading to the ortho isomer via a surface phenolate.
When strongly basic catalysts are used, C-alkylated products are mainly
formed.
O and C-alkylation mechanisms necessitate the cooperation between acid and
basic site in order to activate at the same time phenol and methanol.
With this results in mind, we believe that it is now possible to explain the
observed datas. The catalysts having shown the best activity are acidic catalysts.
The niobium phosphate has a high activity (ref. 13) that may originate from the
low selectivity in O-alkylated products at high reaction temperature. Rare earth
phosphates calcinated at 700~ (ref. 10) and boron phosphate which have a
medium acidity correlate well with a good selectivity in O-alkylation. In the case
of rare earth phosphate calcinated at 400~ the decrease in selectivity while
increasing the reaction temperature is due to the presence of basic sites on the
catalyst. On the other hand, the good to excellent selectivity in O-alkylated
products observed with cesium hydrogenophosphate alone or supported is difficult
to explain. Indeed this catalyst is exclusively basic. The absence of C-alkylated
products by the reaction between guaiacol and methanol tends to suggest that the
guaiacolate intermediate at the surface has a different behaviour on lanthanum
phosphate as well as lanthanum phosphate doped with cesium hydrogenophosphate.
59
R
OH OH ~OCH3
I
~ B~(~)~OCH3
R
path A A~
o•R
H(E) MeOI--I
H\o/CH3 [ ~ R
H|
R
"- R CH3~o/H
R Ho e !e
pathBr_ ~ MeOI-I = I A ~ _ ~
H20
@ OCH3
H20
%oc.3 ,
R
Scheme 1. Proposed mechanism for the basic catalysis alkylation of phenol
In addition, cesium hydrogenophosphate has an interaction with the rare earth

phosphate as it was demonstrated by further characterization. The mechanism in
basic catalysis goes via a phenolate anion that can be chemosorbed either by an
acidic site (path A) or on a neighbouring Lewis acid site (path B). Methanol will
be activated by an acid site and therefore will be able to react in O or C alkylation.
The C alkylation will be favoured as the acidic site chemosorbing the phenolate
will be harder. For example, the excellent selectivity in O-alkylated products
observed on cesium hydrogenophosphate is due to the softness of the cesium ion,
60
(A e = Cs 9 in path B), while path A seem to be favoured (A 9 = La3e) on LaPO4
calcinated at 400~
CONCLUSION
In this study, we have demonstrated that boron, niobium and rare earth
phosphates are excellent catalysts for the selective O-alkylation of pyrocatechine in
guaiacol and veratrole. The reaction is conducted in the vapor phase using
methanol as the alkylating agent. In the case of rare earth phosphates the
calcination temperature has a very important effect on the selectivity of the
reaction. This phenomenon, linked to the synthetic procedure, is due to the
residual basicity on the rare earth phosphate calcinated at 400~ Wetness
impregnation of rare earth phosphate by cesium hydrogenophosphate give rise to
very active as well as selective catalysts.
References
1. Kirk Othmer Encyclopedy, 4th Edition, John Wiley, Chap. 9, p. 860, New York, (1995).
2. J. March in "Advanced organic chemistry", 4th Edition, John Wiley, pp. 386-387, (1992).
3. T. Kotanigawa, M. Yamamoto, K. Shimokawa, Y. Yoshida, Bull. Chem. Soc. Jpn. 47, 950,
(1974).
A.B. Mossman, US 4.611.084 (25/11/1985), (to AMOCO Corp).
D. Farcassu, US 4.487.976, (30/08/1982), (to EXXON US).
4. F. Nozaki, I. Kinuira, Bull. Chem. Soc. Jpn, 50, (3), 614, (1977).
5. P. Pierantozzi, A.F. Nordguist, Appl. Catal., 2!, (2), 263, (1986).
F.M. Bantista, J.M. Campelo, A. Garcia, D. Luna, J.M. Marinas, A. Romero, J.A. Navio,
M. Macias, Appl. Catal. A, 99, (2), 161, (1991).
. M. Marczewski, G. Perot, M. Guisnet et al. (Eds), in "Studies in surface science and
catalysis", p. 273, Elsevier (Science Publishers BV ?), Amsterdam, (1988).
E. Fischer, O. Skiner, G. Wih, Wiss. Z. Univ. Rostock, Naturwiss, Reihe, 39, (7), 67,
(1990).
V. Durgakumari, S. Narayanan, L. Guczi, Catal. Letters, 5, 377, (1990).
G.A. Olah, J. Kaspi, J. Org. Chem., 43, 16, (1978).
Y. Shioni, Y. Nakamura, T. Manabe, S. Furusaki, M. Matsuda, M. Saito, EP 509927,
(16/04/1992), (to Ube Industries).
S. Furusaki, M. Matsuda, M. Saito, Y. Shiomi, (03/04/1991), (to Ube Industries).
S.P. Bhatnagar, A. Prakash, S.C. Misra, M.S. Raiker, IN 158895, (18/11/1983), (to Reckitt
and Colman).
10. A.M. Le Govic, A. Aubry, L. Gilbert, P. Pommier, M. Janin, following paper in this issue.
11. F.M. Bautista, J.M. Campelo, A. Garcia, D. Luna, J.M. Marinas, A. Romero, Applied
Catalysis A: , 99, 161, (1993).
2. E. Santa Cesaria, D. Grasso, Applied Catalysis, 64, 83, (1990).
3. A. Florentino, P. Cartraud, M. Magnoux, M. Guisnet, Applied Catalysis, 89, 143, (1992).
R.L. Martins, W.J. Schitine, F.R. Castro, Catalysis today, 5, 483, (1989).
CATALYSIS BY RARE E A R T H P H O S P H A T E lII. C H A R A C T E R I S A T I O N
OF SAMARIUM P H O S P H A T E AND SAMARIUM P H O S P H A T E - C E S I [ ~
H Y D R O G E N O P H O S P H A T E AS KEY CATALYSTS FOR O - A L K Y L A T I O N
OF P H E N O L S
ANNE-MARIE LE GOVIC a~, PASCALE POMMIER a~, ALAIN AUBRY a~,

LAURENT GILBERT b~AND MARCELLE JANIN b~
a) Rh6ne-Poulenc Recherches, Centre de Recherches d'Aubervilliers, 52 rue de la

Haie Coq. 93308 Aubervilliers Cedex, France
b)Rh6ne-Poulenc Industrialisation, Centre de Recherche, d'Ing6nierie et de
Technologie, 85 Avenue des Fr~res Perret, BP 62, 69192 Saint-Fons Cedex,
France
SUMMARY
Samarium phosphates, impregnated or not by cesium hydrogenophosphate,
selective catalysts for O-alkylation of phenols, have been characterised by various
techniques. This study has shown that :
- the cesium salt added by wetness impregnation (10 % w/w) has a sintering
effect on its calcination. The examination of structural and textural datas shows that
the cesium does not enter the crystalline network. The cesium salt is uniformly
distributed on the crystalline surface and the special morphology of samarium
phosphate makes the cesium retained in the porosity of the solid.
- Samarium phosphate has an intrinsic acidic activity which can only be observed
on products calcinated at a temperature of 700~ and which therefore possess a
monoclinic structure.
Samarium phosphate calcinated at lower temperatures, with an hexagonal
structure has acido-basic characteristics highly dependant on the synthetic route
use :
- a totally basic activity is observed for samarium phosphate being neutralized
with ammonia after precipitation.
62
- products which have not been treated according to the previous step present an
acidic activity
- the addition of cesium by wetness impregnation on the dry catalyst produces a
totally basic behavior.
INTRODUCTION
Even if the use of rare-earth phosphates in heterogeneous catalysis for fine
chemicals has been reported from more that 20 years, those catalysts were little
characterized. Recently, doping those catalysts with cesium salts has greatly
improved the activity, selectivity of the transformation as well as the life time of the
catalysts (refs. 1,2).
Particularly, a synergism between cesium hydrogenophosphate and samarium
phosphate has been observed for the O-alkylation of dihydroxy-benzene (ref. 2).
We described in this paper some characterizations of this solid doped or not, that
may allow to explain catalytic results.
EXPERIMENTAL
Samarium phosphate was prepared by wet synthesis starting from samarium
carbonate (Sm2(CO3)3, originated RP). Precipitation of phosphate by phosphoric
acid is conducted at 80~ by addition of a samarium carbonate suspension in a
vessel containing phosphoric acid. After the end of the addition, the solid could be
treated by ammonia at pH - 9. Cesium hydrogenophosphate is introduced by
wetness impregnation of the dried (110~ solid.
Transmission microscopy is realized using a Philips CM30 apparatus at
300 KV. DRX spectra were realized on a diffractometer Philips 1700 by scanning
between 5 to 70 ~ at l~ Porous distribution is determined by mercury intrusion
after elimination of gas over night at 200~ in an oven (Autopore II 9220 V3.01).
Acidobasic properties characteristics of solids were estimated by studying the
reactivity of 2-methyl 3-butyn-2-ol (MBOH) (ref. 3).
I n f l u e n c e of th e c e s i u m salt on t h e r m a l stability
We have compared the specific surface area thermal evolution of samarium
phosphate just dried or samarium phosphate impregnated by cesium hydrogeno-
63
phosphate (10 % w/w) between 400~ and 800~ Results are reported in Figure 1
and Table 1 and show a sintering effect of the cesium salt.
Table 1. Specific surface area of SmPO4, SmPO4, Cs2HPO4 as a function of calcination

temperature
Temperature (~ SmP04 (m2/g) SmPO4, Cs2HPO 4 (m2/g)
dried 124 91
400 107 84
500 97 67
700 39 10
140 ;pecific surface

area
9 (m2/g)
120
100
80
--0-- SmP04 I
SmP04, Cs2HP04
60
40
20
, | . , , |
200 300 400 500 600 700 800
Temperature (~
Fig. 1. Specific surface area of SmPO4" SmPO4, Cs2HPO 4 as a function of calcination

temperature
64
~ T I V E I~IOll vl 0I~4ETER
+ tnil'mltofl. 9e x t ~ m l l ~
I I IHii-i t- ..... '..

• ~ --
-i i
__ _.., . . . .
i!ll ! /IIIIILL~__$___!
..... iillili I1 i'~"il~
i.~ , -,
.4
...... l!t~'--,r
..... i ~1"t-I-i~;--! . i
-.' .... tbt4.-t-,~-/~if.bt-l-i-i .... ! ,, -
_i /!lit 1/i!Iilili ] !i
0.:'
O.l l
9 i roLL._!.......~--
:i I- ~ ii'i
_L~_L..,
O. O.Ol
100 iO i
OIiUtr[l~ . ( licromtt~s )
~io "3 Porous repartition of SmPO4
CUHUt.ATIVE IHTRU6IOH vl OIAHETEH
+ tntJ~ltOn m ixt.r~ston
' ,.I_4~H_~L y
i ~il]ill
, i l t I i.~. ili]i i ! t 1.,11, i I 111,~,~ I : t
I [tNitl! i
[ i,li!!t,
,l!I tt ,~,~i[! LIiLLLl~
I !l!i]li
I-!
. il II I l
O.II
-~--~l!Ii-[~i-
i ti .. .tiltlii
0.1 !it~i!t!i!l
i iii!i!'il!, l!il i !/ ' ' !t:~
1!1:! ~tli~li liilli t i!i[!li
~ t0
ilil . .~!.!!!!!, ~!i!i!l i ..
1 o. ! 0.01
,
oz.uq~n~. ( eicroutar~ )
Fig. 3. Porous repartition of SmPO4, Cs 2 HPO4
65
For the same thermal treatment (fixed duration and temperature), specific
surface area of SmPO4, Cs2HPO4 are systematically weaker of about 20 m2/g (or
even 30 m2/g) than those of SmPO4. On an other hand, we have checked that the
ammonia treatment has no effect on specific surface area.
Those results have been maked up, in the case of solid calcinated at 500~ by
porosity measuremem and by electronic microscopy analysis.
9 Poro$imetry 9 samples expand a porous volume of 0,69 cm3/g with a
microporous volume of 0,20 cm3/g. Introduction of cesium lower the porous
volume without any change in the porous repartition (Table 2, Figs. 2 and 3).
Table 2. Porous repartition of SmPO, and SmPO4, Cs2HPO4
Catalyst Total porous Porous volume Porous volume Medimn pore Medium pore
voltt3Ine between 30 ~,d between 0,1 rn diameter (m) diameter (A)
(cm /g) 0,1 m (cm/g) and 37 A
SmPO4 0,69 0,45 0,20 15 65
SmPO4, Cs2HPO4 0,56 0,40 0,16 12 7o
Electronic microscoov
The sintering effect of the cesium salt has been made visible by transmission
electronic microscopy. Comparison of electronic microscopic stereotypes of product
calcinated at 500~ (6 h.) without (Fig. 4) or with Cs2HPO4 (Fig. 5) leads to the
following remarks 9
- SmPO4 is formed of agglomerated polydispersed small stick of size between 10
and 100 nm.
- In the case of SmPO4, the periphery of those sticks is well defined (frame
bones).
- In the case of SmPO4, Cs2HPO4, the periphery of the sticks is badly defined and
they are linked by amorphous zone of molten aspect enriched in cesium, as shown
on cartography analysis (Fig. 6). The STEM-EDS cartography analysis does not
show if the cesium is uniformly widespread on each cristallite or if it creates a solid
solution in the cristalline structure of the phosphate. It is the reason why a DRX
structural analysis was realized.
66
Samarium phosphate precipitates as an hexagonal phase and shows a phase
transition between 600 and 700~ to form a more closed monoclinic phase. Those
results are in good agreement with schneider's published datas (ref. 4) reviewing
crystalline structure studies about rare earth orthophosphates.
Rare earth orthophosphates can be subdivided into several families according to
their crystalline structures and the polymorphic modification as a function of the
temperature. The first family regroups light rare earth (so called ceric phosphates)
including the following elements : La, Ce, Pr, Nd, Sm, Eu. Those phosphates are
dimorphiques. Indeed, they precipitate at low temperature under hexagonal phase
and evoluate at higher temperature to the thermodynamically stable phase, the
monoclinic one, isomorphic to monasite CePO4. The phase transition temperature is
accompanied by an exothermic phenomena linked to the cation ionic radius and is
higher as the cation radii is lower (ref. 5).
9 DRX
DRX studies of SmPO4 and SmPO4, Cs2PO4 calcinated at various temperatures
(between 200 and 800~ show that cesium has no visible effect on crystalline
structure of products :
- the crystalline phase transition (from hexagonal to monoclinic) occurs between
600 and 700~ independently on the presence of cesium (Table 3)
- the mesh parameters are similar for SmPO4 and SmPO4, CszHPO4 (Table 4)
DRX shows no formation of cesium pyrophosphate which is usually obtained as
early as 300 ~
The complete analysis of the crystalline structure by DRX and EXAFS of
impregnated structure shows that the cesium does not enter the crystalline network
in SmPO4.
The comparison of those results and the electronic microscopy analysis leads to
the conclusion that the cesium is uniformly distributed on crystallite surface and that
the excess of cesium is retained in the porosity of the solid, probably as amorphous
cesium phosphate.
67
Fig 5. Electronic microscopy of SmPO4,CsHPO 4
68
Fig. 6-2. STEM - EDS cartography of Sm PO4, Cs2HPO 4
| localisation of P
69
Fig. 6-3. STEM - EDS cartography of Sm PO4, Cs2HPO4
| localisation of Cs
ACIDO-BASIC PROPERTIES
Characterization of SmPO4
We have examined the influence of surface chemistry of SmPO4 on its acido-
basic properties. Characterization by reactivity of MBOH was realized for product
treated at pH = 9 with an ammoniacal solution or not. The MBOH test permits to
determine without any doubt the acido-basic characteristic of surface site.
We have reported in Table 5, methylbutynol conversion at the 12th pulse and
the acidic (A), basic activities (B) and activity due to acid base pairs (B) obtained
for each samarium phosphate. The evolution of acido properties - conversion of
MBOH and selectivity in the various products formed as a function of preparation
methods and calcination temperatures are reported Figures 7 and 8.
9 The acidic selectivity is the sum of selectivity in 3-methyl 3-buten-l-yne
(MBYNE) and in prenal which are formed on acidic sites.
9 The basic selectivity is the selectivity in acetone or acetylene which are formed
on basic sites.
70
9 The acid base pairs selectivity is the sum of selectivity in 3-hydroxy 3-methyl
butan-2-one, in 3-methyl 3-buten 2-one and methylisopropylketone which are
formed supposedly to be on acid-base pairs.
Table 5. Acidobasicity of samarium phosphate determined by reaction of MBOH
Catalyst Calcination Conversion of A B AB

temperature MBOH (%)
dried 11 94 1 5
S m P O 4 500~ 14 97 1 2
700~ 30 98 1 1
S m P O 4 dried 27 2 98 -
treated by an 500~ 24 7 93 -
ammoniacal solution 700~ 91 8 1
SmPO4 dried 0,7 _ _ _
Cs2HPO4
,,
(10 % p/p) 500~ 0,5
SmPO4, dried 32 100
Cs2HPO4 (10 % p/p) 500~ 39 100
(treated by an
ammoniacal solution)
If we compare products calcinated at 500~ SmPO4 without treatment has a

totally acidic behaviour while the sample treated at pH = 9 as a totally basic
behaviour. The basic behaviour observed for SmPO4 treated at pH = 9 indicates
the presence of residual anions coming from the ammoniacal neutralization step.
When calcinated at 700~ both products present comparable behaviour with an
higher acidity for the phosphate not treated. At 700~ we find the intrinsic acidic
activity of samarium phosphate.
SmPO4, Cs2HPO4 was also characterized by the MBOH test. Results reported in
Table 5 show that the presence of the cesium salts exalt the surface basicity. The
addition of the cesium salts induces a totally basic like behaviour of this catalyst.
The observed difference in activity should be interpreted with some caution due to
the high basic activity of cesium oxide, the presence of which, even in small
quantities, can not be excluded.
Conversion of
40-,
MBOH (%)
3O
A
w
,.,
--43- SmPO4 without treatment
20-
SmPO4 treated at pH = 9
100~
[
i
0
100 200 300 400 500 600 700
Calcination temperature of SmPO4 (~
A
40-
30 J
- - u - SmPO4 without treatment
20~,
L
10~
~ ,
v
0'
100 200 300 400 500 600 700
Calcination temperature of SmPO4 (~
A 9activity = mmol MBOH transformed per surface unit and per hour
Fig. 7. Acido-basic properties of samarium phosphate
SmP04
Selectivity (%)
100
80
--{3--
60 ---o- % MBYNE (Acidity) ~
I,
% Prenal (Acidity)
40 ~
2o ~
100 200 300 400 500 600 700
Calcination temperature of SmP04 (~
72
Selectivity (%)
100
80 -i L
60 - - o - % Acetylene (basicity) i
% Acetone (basicity)
40 ~
- - I - % MBYNE (acidity) :
20- r % Prenal (acidity)
O~ v
_20100 200 300 400 500 600 700
Calcination temperature of SmPO 4 (~
Fig. 8. Acido-basic properties of samarium phosphate 9selectivity on each catalyst
CONCLUSION
This study leads to the following conclusions.
Cesium salt added by wetness impregnation (10 % w/w) has a sintering effect
on the calcination of samarium phosphate. The examination of structural and
textural data shows that the cesium does not enter the crystalline network. The
cesium salt is uniformly distributed on crystallites surface and the special
morphology of samarium phosphate makes the cesium retained in the porosity of the
solid.
Samarium phosphate has an intrinsic acidic activity which can only be observed
on products calcinated at 700~ and therefore with a monoclinic structure.
Samarium phosphates calcinated at a lower temperature, with an hexagonal
structure has acido-basic characteristics highly dependant on the synthetic route
used
- a totally basic activity is observed for samarium phosphate being neutralized
with ammoniac after preparation
- products which have not been treated according to the previous step present an
acidic activity
- the addition of cesium by wetness impregnation on the wet product gives it a
totally basic activity.
73
References
1. P.J. Tirel, C. Doussain, L. Gilbert, M. Gubelmann, H. Pernot, J.M. Popa, Studies in
surface science and catalysis, 78,693, (1983)
2. L. Gilbert, M. Janin, A.M. Le Govic, P. Pommier, A. Aubry, Preceeding paper in this
issue
3. H. Lauron-Pernod, F. Luck, J.M. Popa, Applied Catalysis, 78,213, (1991)
4. L. Niinist6, M. Leskelii in "Handbook on the Physics and Chemistry of rare earth"
F.A. Gschneider, J.R. Eyring, L. Eyring Eds., Vol. 9, Chapter 59, p. 91.
5. R. Kijkowna, Nieorg. Zwiazki Fosforowe, 7,239, (1976)
74
SELECTIVE FUNCTIONALISATION OF FLUOROAROMATICS VIA
ORGANOSILICON INTERMEDIATES
BERNARD BENNETAU a), PIERRE BABIN b) AND JACQUES DUNOGUES a)
a) Laboratoire de Chimie organique et organom6tallique (URA 35 CNRS),

Universit6 Bordeaux I, 351, Cours de la Lib6ration, 33405 Talence, France
b) Laboratoire de Pharmacie chimique, Universit6 Bordeaux II, Place de la
Victoire, 33000 Bordeaux, France
INTRODUCTION
The importance of fluorinated organic compounds is demonstrated by the
increase in the number of published novel compounds prepared during the last two
decades. This fact reflects the interest of scientists, both academic and industrial, in
utilizing fluorine to modify the physical and chemical properties of organic
compounds. The introduction of fluorine increases thermal and oxidative stability,
lipophilicity and also closely mimics hydrogen in particular from a sterical point of
view. These properties range from the high stability of fluorinated polymers to the
enhanced properties of agrochemicals and phamaceuticals. For instance,
organofluorine compounds have been used as lubricants, refrigerants, fire
extinguisher agents, inhalation anesthesics and surfactants. Otherwise, many
fluoroaromatics find wide use in biomedical applications (ref. 1), agrochemicals and
pharmaceuticals (ref. 2) because their efficacy is improved by the presence of
fluorine (lower dosage, lower toxicity and increased selectivity).
The regioselective functionalisation of fluoroaromatics or the selective
introduction of fluorine into aromatic molecules under mild conditions are of great
importance to the chemical industry and are a considerable challenge to organic
chemists. So, the regio- and stereospecific requirements have created needs for
developing special reagents and procedures; many strategies to introduce fluorine
into a fluorinated aromatic ring or to introduce substituents into fluoroaromatics
have been developed.
75
The aim of the present account is to provide comprehensive, if not exhaustive,
highligths of the selective functionalisation of fluoroaromatics, and in a few cases,
electrophilic fluorination of arylsilanes.
E L E C T R O P H I L I C CLEAVAGE REACTIONS OF CARBON SILICON

BONDS IN FLUORO-ARYLSILANES WITH OR WITHOUT FRIEDEL-
CRAFTS CATALYSTS
Eaborn et al. (ref. 3) have shown that the displacement of the trimethylsilyl
moiety in aryl(trimethyl)silanes by electrophiles was analogous to that of hydrogen
in electrophilic aromatic substitution :
iMe3 iMe3
RO -..
E+
"~ R
Nu-
~ R
0E + Me3Si~Nu
slow fast
Scheme 1.
Moreover, the efficacy of the ipso factors for a series of electrophilic

desilylation processes gave rise to the expectation that aryl(trimethyl)silanes might
be successfully employed for synthetic purposes; this was confirmed by many
works reviewed in 1993 (ref. 4).
With fluoroaromatics, the ipso effect of the trimethylsilyl group was involved
for regiospecific electrophilic substitutions. For example, the increasing
sophistication of nuclear medicine techniques has presented challenges to the
synthetic chemist involved in the preparation of imaging agents labeled with
radionuclides. In order to compare their utility as substrates for regiospecific
aromatic halogenation, some para-substituted aryltrimethylsilicon,-germanium, and
-tin compounds were treated with no-carrier-added (n.c.a.) 77Br and 131I (ref. 5).
Results are summarized in Scheme 2 :
76
Radiochemical yield (%)
F F .A.
77Br 131I
Si 18 <10
Sn 81 96
MMe3 X
Ge 51 88
i) "77Bror 131I"
M = Si, Ge, Sn
Scheme 2.
It was observed that the rate of aromatic halodemetalation decreases in the

sequence Sn > Ge > Si.
On the other hand, only few examples of direct electrophilic fluorination of
aromatics have been reported since the ability of fluorine to behave as an
electrophile is not easily achieved; however, radiofluorination of aromatic
compounds has been described but, in the reactions which have been reported, it is
apparent that strong electron-donating groups are required on the aromatic ring
when mild fluorinating reagents are used. Nevertheless, without activating groups,
an alternative route to 18F-labeled radiopharmaceuticals, using 18F-labeled reagents
has been proposed, involving arylsilanes (ref. 6). The scope of this
fluorodemetalation reaction as well as the influence of the metal displaced and of
aromatic substituents has been studied (ref. 7). The reaction is given and the yields
mentioned in Scheme 3.
Chemical yield (%)

Y Y
Sn Ge Si
i
74 56 30.5
CF3 35 10.5 2.5

MMe3 18F
i) [18F]-F2 or [18F]-CH3CO2F
M = Si, Ge, Sn
Y = F, CF3
Scheme 3.
77
As previously noted (ref. 5), yields are lower when arylgermanium or -silicon
derivatives are used. However, for activated aromatic systems, it was pointed out
that aromatic halodesilylation proceeds under convenient conditions and arylsilanes
being less expensive than their germanium and tin analogues and much less toxic
than the corresponding aryltins. Another example of electrophilic fluorination of
fluoro(trialkyl)silanes by acid-catalyzed metal-metal exchange is given below
(ref. 8):
X X
X ArF (%)
43
CF3 <5
SiMe3 F
i) Pb(OAc)4 9BF3.Et20 9room temp.

X = F, CF3
Scheme 4.
More recently, the electrophilic cleavage of carbon-silicon bonds in neutral

hexacoordinated silicon compounds such as diorgano(phtalocyaninato)silicons,
[(Pc)Si (RX)(R2)], with N-bromosuccinimide, halogens, copper (II) halides and 3-
chloroperbenzoic acid was reported (ref. 9). Only one example concerns with
fluorinated aromatics ( R ~ or R 2= C6H4CF3) and in this case, the yield was very
low (14% at the best). In this area, an original method for the regiospecific
functionalisation of fluorobenzene in ortho- or para-position has been proposed
(refs. 10-13) according to Scheme 5 :
78
F F
Me3Si~ E i v
Yield %
F F F J
I MeCO 68
PhCO 52
O ~--~
Me3Si/ "<,/
65 %
SiMe~i
" .~
Me3Si~/SiMe3
64 %
Br
I
51
32
F F
I
Me3Si~
Yield %
Me3SiCI / Li / THF 0-5~ 9 h') aromatisation 9
m')E-CI iv)KF / DMF/ H20 " v) CF3CO2H/ CC14 MeCO
PhCO
Me3SiOSO2
HzNSO2
I
Scheme 5.
The silylation of the fluorobenzene can also be achieved by electrochemical

reduction (ref. 14).
As the ipso effect is sometimes ineffective with strong-electron donating groups,
advantage of the possible electrophilic substitution of the allylsilane intermediate
was taken to perform the acylation of phenols in the meta position according to
Scheme 6 (refs. 15 - 17) :
OMe O O OH
i, ii iii iv
e3Si E E
F F F
72 %
Yield (%) Yield (%)
i) Me3SiC1 / THF / 0-5~ 9ii) H30 + / H 2 0 MeCO 60 MeCO 70
iii) E-C1 9iv) CuBr2-LiBr / CH3CN, reflux PhCO 50 PhCO 77
Scheme 6.
79
Another important way to polysubstituted aromatics and, of course,
fluoroaromatics, is provided by proton abstraction from activated arenes. The
organometallic intermediates are generated by hydrogen/metal exchange (ref. 17)
(with common reagents such as phenyl- or butyllithium). The regiochemistry is
provided by various directing metalation groups, usually heteroelements or halogens
(F, CF 3 or C1). However, when electrophiles are not compatible with lithium
reagents or when the reaction requires higher temperatures, e. g. fluoroaromatics
and weak electrophiles, this route is not possible because of the formation of
benzynes. So, an attractive alternative for the functionalisation in position-2 of 1,3-
disubstituted benzenes involving arylsilanes has been proposed (refs. 18, 19)
according to Scheme 7 :
x. Y X .Y
1)RLi
i, ii S ~ / l e 3
E
X ~ , Y E+ J,.
Yield (%) E=~ MeCO I SO3SiMe3 (%)

X=CI'Y=F 90 X=CI'Y=F 92 70 80
X=Y=F 90 X=Y =F 90 70 80
i) n-BuLi(1.1 equiv.), THF,-75~
ii) Me3SiC1(1.1 equiv.) 94N HC1
Scheme 7.
80
As a part of recent investigations in the chemistry of arylisoxazoles and
arylpyrazoles, respectively used as herbicides (ref. 20) and fungicides (ref. 21),
fluorinated acetophenones were prepared (ref. 22) following a similar methodology
(Scheme 8) :
SiMe3 COMe
i ii
Y Y
Yield (%) Yield (%)
X = F ; Y =C1 83 75
X = F ; Y = Br 88 75
i) n-BuLi (1.1 equiv.), THF, -78~ ; Me3SiC1 (4 equiv.) ; 4N HC1

ii) AIC13,MeCOC1, 0-25~ CH2C12
Scheme 8.
E L E C T R O P H I L I C CLEAVAGE REACTIONS OF CARBON SILICON

BONDS IN FLUOROARYLSILANES W I T H N U C L E O P H I L I C CATALYSTS
Reports in the literature on reactions of aldehydes with
trimethylsilyl(pentachloro)- ou trimethylsilyl(pentafluoro)benzenes (ref. 23) under
thermal conditions (the cleavage of the Ar-Si bond being be rate-determining step)
have led to the assumption (ref. 24) that a mechanism different from that formulated
by Eaborn (ref. 3) might be operative in these cases. However, 2-
nitrophenyl(trimethyl)silane, as phenyltrimethylsilane, does not react thermally with
benzaldehyde even upon heating at 100~ in DMF for three days. But, if a
nucleophilic catalyst (potassium tert-butanolate, potassium- or cesium fluoride ) is
added, electrophilic substitution proceeds a t - 6 0 ~ within 1 h in 92% yield (with
t-BuOK). The reaction was extended to some other substituted benzenes and, among
them, o-fluoro(trimethylsilyl)-benzene (ref. 25).
soe3
F
+ PhCHO i
F OH
76%
1)KOCMe3 / DMF / H20
Scheme 9.
In the presence of furan, elimination to dehydrobenzenes takes place as a

competitive reaction in the base-catalyzed carbodesilylation (ref. 26). Elimination is
preferred with decreasing leaving tendancy of the halides (I > Br > > C1 > F) 9
OH
_~SiMe3 CO i _~/[~ph @
R + R1CHO+ r_- R + R
v "X
i) KOCMe 3 / DMF / H20
X = F, C1, Br, I
R 1 -- H, Pr
Scheme 10.
Attack of the base, at the silicon atom, is postulated as the first step in the
reaction sequence with subsequent dissociation of the pentacoordinated intermediate
in the rate-determining step; the carbanion thus liberated would rapidly react with
benzaldehyde. Because the C-Si bond is not enough polarized, activation is required
by fluoride ions to form a pentacoordinated silicate which is assumed to be a soft
nucleophile or generates a nucleophilic anion species (ref. 27) :
OH
I
ArmSi m
F
~
..,,,
R--CHO
Ar--Si Ar" ~ Ar
I F
Scheme 11.
It must be mentioned that the existence of the free postulated carbanion is not
absolutely necessary since a concerted mechanism, without elimination of Me3SiF,
leads to the same result 9
..,,|
Ar~Si + E-Nu ~ ~ Ar-E + Me3Si-N
I" I[
F
F (regenerated)
Scheme 12.
As an example, the behaviour of benzyltrimethylsilane which adds solely in 1,2-

position to the chalcone (ref. 28), in the presence of fluoride ion, strongly suggests
that the free carbanion is not formed.
With polyhaloarylsilanes and non-enolizable aldehydes, using
tris(diethylamino)sulfonium difluorotrimethylsilicate (TASF) as the catalyst, the
corresponding benzhydrols are obtained (ref. 29) upon hydrolysis as shown below:
OH
RCHO + Me3Si-Ar i, ii ~ R/J',.. Ar

44-89 %
i) TASF, THF - ii) HC1-MeOH R = Ph, PhCH = CH2 9t-Bu 9

Ar = C6F5 93,5-C12-C6F3 94-H-C6F4 94-n-Bu-C6F4
Scheme 13.
In the presence of a catalytic amount of potassium cyanide-18-crown-6 complex,

treatment of C6Fs-SiMe3 with enolizable ketones, gives the corresponding
trimethylsilyl enol ethers (ref. 30).
The cross-coupling reaction is defined as the reaction of an organometallic
compound R-M with an organic compound R'-X (wherein X is a leaving group) to
give a coupled product R-R'. Although various organometallic compounds with
M = Mg, B, A1, Zr, Sn, Cu, etc. have been studied extensively, a few of them
fulfill all the criteria generally required. Organosilicon compounds also couple with
organic halides or triflates in the presence of a fluoride ion promoter and a
palladium catalyst (ref. 31).
However, with aryl(trialkyl)silanes, sometimes for electronic reasons, the
reaction does not take place. In order to reduce the electron density on the silicon
atom, alkyl groups were replaced by fluorine. The fluorine effect could be
explained as follows: i) the van der Waals radius of fluorine is roughly comparable
to that of hydrogen and hence the fluorine-substituted silyl group is not so bulky
than the trimethylsilyl one; ii) electronegativity of fluorine favours the formation of
the reactive pentacoordinated silicate, enhances the Lewis acidity of the silicate and
favours also a nucleophilic assistance. The reaction is quite general (ref. 32) and so
alkyl-, alkynyl-, alkenyl- and, of course, arylsilanes were used. Unsymmetrical
fluorinated biaryls have been prepared by the cross-coupling reaction of
aryl(alkyl)difluoro-silanes and aryl iodides (refs. 33, 34) 9
Arl-Si(R)F 2 + Ar2-I ,-, ~ Arl-Ar 2
i) n3-C3H3PdC1)2(5 mol % 9 Ar2 Yield (%)

KF (2 equiv.) 9D M F 3-MeO-C6H 4 52
Here reported 9 3-HOCH2-C6H 4 67
Arl = C6Ha-CF 3 4-AcO-C6H 4 47
R = Me
Scheme 14.
As indicated with a strong electron-withdrawing group such as C F 3 , the reaction

gave lower yields of products. When the coupling reaction of aryl(alkyl)difluoro-
silanes and aryl iodides is carried out under an atmospheric pressure of carbon
monoxide, unsymmetrical fluorinated diaryl ketones were obtained (refs. 35, 36) :
O o
" )F2
CF 3 I CF 3
i) CO (1 atm) 9nLC3H3PdC1)2(2.5 mol %) 38 %

KF (1.1 equiv.)" DMI, IO0~
Scheme 15.
More recently, the scope of the reaction has been extended and further
mechanistic aspects have been discussed (ref. 37). Cleavage of C-Si bonds of
organosilicon compounds is continually receiving much attention in view of its
versatile utility in organic synthesis. With functional silicon compounds such as
fluoro-, chloro-, alkoxy-, and aminosilanes, the oxidative cleavage of C-Si bonds,
giving corresponding alcohols (ref. 38) (Scheme 16), is of special interest for the
84
synthesis of natural products because of the wide presence of hydroxyl groups in
these molecules :
i
R-SiX 3 + H202 ~ R-OH
i) 30 % H202 / KF / (KHCO3) / MeOF / THF

SiX3 = SiMe2H, SiMenF3_n, SiM%CI3_., SiMen(OR)3_.
Scheme 16.
Peracids and peroxides are also used as oxidizing reagents, but the most
characteristic feature is that the presence of at least one heteroatom (or functional
group) on silicon is essential for performing the oxidation.
In this context, an attractive route to fluorinated phenols was proposed
according a two-step pathway :
1) synthesis of aryl(methyldiethoxy)silanes from bromoarenes and
tetraethoxy(dimethyl)disilane (ref. 39) as depicted (Scheme 17 and Table 1) :
Br SiMe(OEt)2
i) (EtO)2MeSiSiMe(OEt)2 ; Pd (Ph3)4 / A
X = H, Y = F, CF 3
X=F, Y = F , OMe
Scheme 17.
Table 1. Silylation of Bromoarenes
Bromoarenes Arylsilanes Yield (%)

3-CF3-C6H4OH 3-CF3-C6H4SiMe(OEt)2 80
4-CF3-C6H4OH 4-CF3-C6H4SiMe(OEt)2 70
2-F-C6H4OH 2-F-C6H4SiMe(OEt)2 80
2,4-FzC6H3OH 2,4-F2C6H3SiMe(OEt)2 65
3,5-F2C6H3OH 3,5-F2C6H3 SiMe(OEt)2 75
3-F-4-MeO-C6H3OH 3-F-4-MeO-C6H3SiMe(OEt)2 45
85
Fluorinated arylsilanes are conveniently prepared from fluorinated bromoarenes
and disilanes in the presence of palladium catalysts (refs. 40- 42) and especially
from hexamethyldisilane (refs. 40,41).
2) oxidative cleavage of the C-Si bond was achieved with hydrogen peroxide
(ref. 43) as follows (Scheme 18 and Table 2) :
StMe(OEt)2 OH
X ~ X
Y Y
i) 30 % H202 (2.4 equiv.) ; CzH5OH ;KF (1 equiv.)

X = H, OMe, F
Y = F, CF 3
Scheme 18.
Table 2 Oxidative Cleavage of Fluorinated Silylbenzenes
Arylsilanes Phenols Yield (%)

3-CF3-C6H4SiMe(OEt)2 3-CF3-C6H4OH 60
4-CF3-C6H4SiMe(OEt)2 4-CF3-C6HnOH 62
2-F-C6H4SiMe(OEt)2 2-F-C6H4OH 75
3-F-C6H4SiMe(OEt)2 3-F-C6H4OH 60
4-F-C6H4SiMe(OEt)2 4-F-C6HaOH 56
2,4-F2C6H3S i M e ( O E t ) 2 2,4-F2C6H3OH 60
3,5-F2C6H3SiMe(OEt)2 3,5-F2C6H3OH 70
3-F-4-MeO-C6H3SiMe(OEt)2
. . . . . . . .
3-F-4-MeO-C6
H3OH 70
86
Concerning the oxidation cleavage of the C-Si bond (Scheme 18), a possible
mechanism was proposed (ref. 38) (Scheme 19) 9
x x
I F
.
....... R
H202 ~. ..eR ]
.Si .........R -.. X~Si
J
X ~ S i .... O 7 0 H !
x~ "~R' [ "~R'
F . . . . .
- x
H20
x Zi si R--OH
,/ H i "~R'
F
Scheme 19.
The oxidative cleavage of the C-Si bond may be also explained (ref. 43) as
below 9
~+
x x - x ~.-OH
.Si .........Ph X-- i<,~h X ~/ [

M i-
6 -
_ H
X/ "~Me
F F
[PhOH]
H3O+ ~ Ph~OH
Scheme 20.
When oxidation with hydrogen peroxide leads to undesired products, it is

noteworthy that the bistrimethylsilylperoxide, for which a very cheap and
convenient synthesis was proposed (ref. 44), may be successfully used (ref. 43).
The behaviour of bis(trimethylsilyl)peroxide supports the second interpretation.
Indeed, the replacement of HO-OH by Me3SiO-OSiMe 3 in the first mechanism
involves, in the last step, the reaction of Me3SiOSiMe3 on the pentacoordinated
silicon moiety which seems very unlikely.
The present reaction offers a high synthetic utility since functional groups on the
aromatic ring, sensitive to organometallic reagents, are compatible; moreover, it
87
involves a disilane, readily available, since obtained by ethoxylation of industrial
disilane residue.
This account, focalized on the regioselective functionalisation of fluorinated
arylsilanes, illustrates the potentialities of the organosilicon chemistry in the
aromatic series. Considering the results here reported, this way constitutes an
attractive alternative to the other methods usually involved for the electrophilic
substitution.
ACKNOWLEDGEMENTS
The authors are indebted to Drs. N. Crenne and S. Ratton for their constant
support and stimulating discussions and Rh6ne-Poulenc Chimie is aknowledged for
his financial support.
References
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89
ARYLATION OF AMINES AND ALCOHOLS CATALYZED BY NICKEL,
COPPER OR PALLADIUM COMPLEXES
HENRI-JEAN C R I S T A U a),, JEAN-ROGER DESMURS b) , SERGE RATTON c)

SANDRINE RIGNOL a) AND MARC TAILLEFER a)
a) Laboratoire de Chimie Organique E.N.S.C.M. (Unit6 de Recherche Associ6e

au CNRS n ~ 458), 8 rue de l'Ecole Normale, 34053 Montpellier Cedex,
France.
b) Rh6ne Poulenc Industrialisation, Centre de Recherche, d'Ing6nierie et de
Technologie, 85 avenue des Fr6res Perret, 69192 Saint-Fons Cedex, France.
c) Interm6diaires organiques, 25 quai Paul Doumer, 92408 Courbevoie Cedex,
France.
ABSTRACT
The arylation reaction of primary and secondary amines has been investigated
using nickel or palladium complexes as catalysts, and bromo- or chloroarenes as
arylating agents. Among the complexes tested, the more efficient catalyst is the
bis (bipyridyl) nickel (II) bromide, bipy2NiBr 2, which affords for example high
yields in the arylation of allylamine with m-bromotrifluoromethylbenzene. The
reduction of the haloarene, sometimes observed with the nickel complexes, becomes
predominant with palladium catalysts whatever the complex used.
For the arylation of primary or secondary alcohols, the same nickel complex,
bipy2NiBr2 (in presence of base, particularly KHCO3), prove to be the more active
catalyst, even in regard to various usual copper catalysts. The reaction affords good
yields in alkylarylethers, under relatively mild conditions.
An attempted mechanism, based on a catalytic cycle with a nickel(I) active
species, is formulated on account of earlier mechanistic investigations described in
the literature.
Lastly, an unexpected aminolysis of nitriles catalyzed by the nickel (II)
bromide, which affords an interesting new way to amides, is described.
90
INTRODUCTION
The arylation of nucleophiles or electrophiles is particularly importam in the
field of industrial synthesis (ref. 1). However, to meet the actual needs for
sophisticated aromatic compounds, these classical reactions present numerous
limitations. So for example, in the arylation of nucleophiles (ref. 2) : on the one
hand the scope of substrates obtainable by the direct SNAr mechanism is restricted
by the necessary presence of electron withdrawing groups on the starting aryl
halide, on the other hand, the arylation of strongly basic nucleophiles through the
"aryne mechanism", although applying to non activated haloarenes, suffers most
often from the lack of regioselectivity associated to the possibility of cine
substitution.
In absence of activating substituents or even more in the presence of electron-
donating groups, a catalysis with transition metal complexes, mainly with the
copper complexes is used (ref. 1) : for example in the Ullmarm diaryl ether
synthesis by arylation of aroxide nucleophiles, in the Goldberg synthesis of N-
arylamides or imides, or further in the Hurtley arylation of enolates... However,
the presence of secondary reactions such as the reduction of the haloarenes, and the
sometimes drastic reaction conditions can restrict the industrial applications of the
copper catalysis. At the moment, works are still in progress to make the copper
systems more efficiem (ref. 1). But promising solutions to the arylation of
nucleophiles by non-activated haloarenes can also be found using other catalytic
systems, for example complexes of palladium or nickel. Examples are already
known mainly in the arylation of soft nucleophiles such as thiolates or selenolates
(refs. 3, 4, 5), but their generalization to the more difficult cases of chlorinated
arylating agents and/or hard nucleophiles was scarcely investigated.
The present work situated in this general context, deals with the arylations
catalyzed by nickel or palladium complexes, of hard oxygen or nitrogen
nucleophiles, using bromo-or chloroarenes (eqn. 1). If necessary, the comparison
with the copper systems was also undertaken (ref. 6).
cat. [Pd], [Cu] or [Ni]

Ar~X + H--Nu ~ Ar--Nu (1)
- HX
X - Br, C1
Nu = NRR', OR"
Arylation of amines
As previously pointed out, till now few works have been done in the field of
arylation using nickel or palladium systems (refs. 5, 7). Only one detailed study
(ref. 7) concerns the arylation of amines by haloarenes using nickel (0) or
nickel (II) complexes as catalysts : with bromobenzene, ammonia does not react and
usually the arylation yields (indeed the GC-conversion rates of a tenfold excess of
amine into arylamine) are rather low (12-38 %), even if the best results mentionned
for dimethylamine and piperidine reach 57-85 % yield.
In the same way, except in isolated cases (ref. 8), palladium does not seem to
have been used for the arylation of this type of hard nucleophiles.
The arylating agents chosen to realize our investigations are
halo (trifluoromethyl)-benzene, the aminolyse of which presenting an industrial
interest.
Nickel-Catalysis
A preliminary comparison of various nickel compounds as catalysts was made,
in the same operating conditions (18h, 160~ in monoglyme), for the arylation of
allylamine by m-trifluoromethylbromobenzene (eqn. 2) (Table 1).
[Ni] cat _ ~
F3C + H2N--CH2--CH=CH2 ~ F3C + HBr
monoglyme (2)
- \ 18 h / 1 6 0 ~
Br NH--CH2~CH=CH2
Table 1. Arylation of allylamine by m-trifluoromethylbromobenzene, catalyzed by nickel-

complexes (eqn.2).
Entry [Ni] a) Cat. b)(%) Yield c) (%)
1 Ni(PPh3)4 5 5
2 bipy2NiBr2 5 50
3 NiC12 5 20
4 NiBr2 10 22
5 pheneNiBr2 10 30
a) Nickel complex : "bipy" and "phen" mean respectively 2,2'-bipyridine and

1,10-phenanthroline.
b) Catalyst molecular ratio to the starting aryl halide.
c) G.C. yield (formation rate) in m-F3C-C6H4-NHCH2-CH=CH2.
92
In the presence of a nickel (0) complex such as Ni(PPh3)4 the arylation of
allylamine occurs in a very low yield (5 %). With nickel (II) salts or complexes, the
yields are higher and the best results are obtained for bipyzNiBr 2 (50%) or to a less
extent for phen2NiBr e (30%). It is noteworthy that Cramer and coll. (ref. 7) pointed
out, on the contrary, that "diamines which coordinate strongly to nickel (II)
interfered in the reaction of dimethylamine with chlorobenzene and reduced by a
factor of ten (ethylenediamine) or even inhibit (o-phenamroline) the arylation".
According to the first results, the reactivity of some primary or secondary
amines towards m-bromo or p-chlorotrifluoromethylbenzene has then been tested in
presence of bipy2NiBr2, used in catalytic amount (eqn. 3) (Table 2).
F3C _• X
+ H--NRR'
bipy2NiBr2 (5 % molar)
monoglyme
~- F3C---~(..) ) + H--X (3)
\ - / "NRR'
X = m-Br, p-C1
Table 2. Arylation of amines catalyzed by bipy2NiBr2 (eqn. 3) ~)
emry ArX H-NRR' T (~ Product Yield

Conv. b) (%) Time (h) (%)
m-F3C-C6H4Br - ~ ~ 160~ 95
m-F3C--C6H4I N / - - ~
95 18h
7 m-F3C-C6H4Br H2N-CH2CH =CH2 160~ m-F3C-C6H4NHCHzCH= CH2 75

75 48h
m-F3C-C6H4Br H2N-CHzPh 160 ~ m-F3C-C6H4NH-CH2Ph 46

75 48h
9 p-F3C-C6H4C1 N ~ 200~ 77
p_F3C__C6H4__N/---~
85 18h
10 p-F3C-C6H4C1 H2N-CH2Ph 200~ c)

37 18h
a) Operating conditions 9ArX (2 mmol), catalyst (0.1 mmol), amine (20 mmol).
b) Conversion rate of aryl halide.
c) Formation of the reduction product F3C-C6H5 9yield 16%.
In the operating conditions used, the piperidine and allylamine are arylated in
high yields (respectively 95 % and 75 %) by m-trifluoromethylbromobenzene with
a complete selectivity (entries 6 and 7).
93
To the best of our knowledge, it is the first example of the direct arylation of
allylamine catalyzed by a nickel complex (ref. 9).
For benzylamine (entry 8) the arylation reaction with m-trifluoromethylbenzene
remains the main process (yield 46 %). The only other fluorinated product
observed, but the starting compound, is the trifluoromethylbenzene (29 %). In a
parallel way, the arylation reaction is apparently accompanied by a partial amine
dehydrogenation into the corresponding imine 1, whose formation could explain the
presence of N-benzylidene benzylamine 2, and dibenzylamine 3, this last one being
detected in small amount. These results are described in the Scheme 1 in which the
nickel complex could act as a catalyst for the (de)-hydrogenation processes
(refs. 10, 11).
[Ni] PhCH2NH2
PhCH2NH2 ~ H2 + [PhCH=NH]
!
1
PhCH2NHCH2Ph ~
3_
H2 /[Nil']
PhCH=N--CH2Ph
2_
- NH3
[P:::NHCH2Phl
Scheme 1. Amine dehydrogenation catalyzed by nickel complexes.
Good results are also obtained from the chlorinated arylating agent on account
of its lower reactivity (the reaction takes place at 200~ instead of 160~ for the
bromoarene). So the arylation of piperidine by p-chlorotrifluoromethylbenzene
occurs in 77 % yield with a 90 % selectivity (entry 9). This result is somewhat
surprising taking into consideration Cramer's work (ref. 7), who noticed that the
arylation reaction of p-chlorotrifluoromethylbenzene by a secondary amine such as
dimethylamine, in presence of NiC12 as catalyst, did not occur. The piperidine is
also a secondary amine, therefore, it appears that the complex bipy2NiBr 2, likely
owing to the presence of o-donor n-acceptor ligands, has a better efficiency than
NiC12 in such reactions.
However, still with p-chlorotrifluoromethylbenzene and the same nickel
catalyst, benzylamine gives only the reduction product (entry 10) 9 in the
competition between arylation and (de)-hydrogenation process, the last one
overbalance owing to the less efficient arylating agent.
The reduction of the aromatic substrates, sometimes observed with the nickel
complex bipy2NiBr2, becomes predominant in presence of palladium catalysts even
for the good arylating agents as shown in the following paragraph.
94
Palladium-Catalysis
The reactivity of various primary or secondary amines with p-chloro or m-
bromo-trifluoromethylbenzene has been investigated in the presence of various
Pd(0) or Pd(II) complexes (Scheme 2) (Table 3).
The conversion of trifluoromethylphenyl halide _44 is almost quantitative (90-
100 %), in heterogeneous (Pd/C), as well as in homogeneous conditions [ ( P h 3 ) n P d ,
bipyPdCl2, (Ph3P)zPdC12] (Scheme 2). However, the product of the nucleophilic
arylation is formed only in very low yield, in both palladium(0) and palladium(II)
catalysis. On the other hand, whatever the complex used, the formation of the
reduction product, the trifluoromethylbenzene, is important, even with apparently a
moderate yield (which can be explained by a partial loss of trifluoromethylbenzene,
a highly volatile product " Any other aromatic product apart 6 and 7 cannot be
detected in the reaction mixture).
/ CH2R'
F3C R + HX
_ @ X CH2R' [Pd] cat. 5 %
/ 6 (< 10 %)
F3C + H--N
\R monoglyme /--'---x
2 mmol 20 mmol 180~ 919 h F3C__~~~ + ~--N=CH--R']

\~J/
_4a "p-Cl 5
4 b 9m-Br 7_ 8
(30-70 %)
[Pd] cat. 9Pd/C, (Ph3P)4Pd, bipyPdCl2, (Ph3P)2PdC12
/
H--N H-- H-- Ph H2N.-"'N~
\
R
5 5a 5b 5c
Scheme 2. Arylation of amines catalyzed by palladium complexes
The mechanism which can be proposed for the observed reduction is similar to
the one indicated for the reduction of a haloarene by an alcohol, catalyzed by the
palladium (ref. 12). In the case of a palladium(0) catalysis, the different steps of
this mechanism are shown in the following Scheme 3, involving in particular the
dehydrogenation of the amine [the same reactions performed without any amine
leads to exclusive formation of the reduction product _7 in a very low yield ( < 5 %).
95
7 ~ Pd(O) ~ ~ .~---- Ar--X
- (a)~,,X ~ 4_
(a)
Ar~Pd--H Ar~Pd--H R
I
H--N--CH2R"
( 5_
-~ (d)
I I H--X
8 H
I N--R Ar~Pd--N(CH2R')R
Ar~Pd ..~- II
CH--R" (e)~
Scheme 3. Attempted mechanism for the reduction of haloarenes (for clarity, those ligands
attached to palladium which do not participate in the reaction are not indicated).
The mechanism would proceed through an oxidative addition of the haloarene

on a palladium(0) moiety (step a). The palladium(II) species formed in this way
reacts with an amine equivalent to lead to an aminopalladiated entity (step b). This
last one, after 13 elimination (step c) (ref. 13) and dissociation of an imine (step d)
(ref. 14), leads by reductive elimination (step e) to the in situ reduced aromatic
product with regeneration of the catalytically active species (Scheme 3).
In the case of a palladium(II) catalysis, the same mechanisms can be considered,
because a lot of Pd(II) complexes, such as (Ph3P)2PdC12 or PdCI2 are reduced in
situ into palladium(O) under similar experimental conditions (ref. 14).
In order to avoid the concurrent dehydrogenation of amines into intermediate
imines, the starting amines have been chosen without mobile hydrogen a to
nitrogen (t-butylamine and aniline). Under similar conditions, even in presence of
m-bromotrifluoromethylbenzene _4 b, and at high temperature (200~ no reaction
occurs, whatever the complex used, [(Ph3P)4Pd or (Ph3P)2PdC12]. Similarly,
ammonia is not arylated by p-bromotrifluoromethylbenzene.
96
Arylation of alcools
To improve the results of the amines arylation, several experiments were
carried out on the catalytic SYstem. Concerning the solvent for example, the 2-
methoxyethanol was used in place of the usual 1,2-dimethoxyethane in order to
reach a better solubility of the nickel(II) precursors : but, in this case, besides the
expected arylated amines, the reactions afford also some amounts of the 2-
methoxyethoxyarene. The literature does not mention such arylation of alcohol
catalyzed by nickel complexes ; accordingly, it was interesting to investigate this
new way for the synthesis of alkylarylethers.
The first experiments concerning the catalytic system demonstrate the necessity
of use of a nickel complex in presence of base (eqn. 4) (Table 3).
[Ni] (7 % mol.)
N C ~ B r + HO~(CH2)2OMe ~ NC O(CH2)2OMe (4)
NPr3 / reflux
+
66 h
(- Pr3NHBr)
Table 3. Necessity of the presence of both nickel complex and base to perform the arylation of
2-methoxyethanol (eqn. 4) a)
Base b) ArBr Yield d)

Entry Catalyst
Conv. c) (%)
11 Pr3N <5 0
12 bipyzNiBr2 <5 0
13 bipyENiBr2 Pr3N 80 80
a) Operating conditions : ArX(1 mmol), catalyst (0.07 mmol), amine (1 ml), 2-methoxyethanol
(6 ml).
b) In order to avoid secondary reactions, the tri-n-propylamine (a tertiary amine) was chosen.
c) Conversion rate of arylbromide.
d) Isolated yield.
Concerning their catalytic activity, various nickel complexes were investigated

specially in regard to the influence of the nitrogen, oxygen or phosphorus ligands
(Table 4).
97
Table 4. Comparison of the activity of various nickel catalysts for the arylation of 2-
methoxyethanol (eqn. 4) ~)
Coordinating Catalyst b)
Atom Yield (%) c)
en2NiBr2 bipy2NiBr2 phen2NiBr2
11% 80 % 31%
(dppe)NiBr2 a) bdpNiBr2 a) Ni(PPh3)4 a)
21% 14% <5%
NiBr2 e) Ni(acac)2 Ni(OAc)2
38 % 8% 6%
a) Operating conditions : see table 3.

b) The abbreviations for the ligands are usual : en (ethylenediamine), bipy (2,2'-bipyridine),
phen (1,10-phenanthroline), dppe [1,2-bis (diphenylphosphinoethane)], bdp [ 1,2-
bis (diphenylphosphino) benzene], acac (acetylacetonate).
c) Isolated yield.
d) Phosphonium salts corresponding to the arylated ligands were detected after precipitation of
the reaction mixtures in ether.
e) The nickel bromide, NiBr2, in solution is probably complexed with the 2-methoxyethanol.
As for the arylation of amines, the best results have been obtained here with the
bipy2NiBr2 complex, probably owing to the cy-donor/Tt-acceptor properties of the
2,2'-bipyridyl ligand (to the 1,10-phenantroline ligand belong similar electronic
properties, but in this case the lower yields are probably related to a lower
solubility).
Concerning the other cy-donor /Tt-acceptor phosphorus ligands, the low yields
(5-21 %) are probably induced by a concurrent arylation of the phosphine
destroying the starting complex during the reaction 9such phosphine arylations are
already described in the literature (ref. 15) and phosphoniums salts were actually
detected in the reaction mixture at the end of the reaction.
In order to compare the new nickel catalytic system with the classical copper
catalysis used for the arylation of alcohols (ref. 16), several experiments were
performed with various copper catalysts (eqn. 5) (Table 5).
[Cu] (7 % mol.)
NC--~Br + HO~(CH2)2OMe -- NC O(CH2)2OMe (5)
NPr3 / reflux66 h
+
[Cu] = Cu (I) or Cu (II) (- Pr3NHB-r)
98
Table 5. Comparison of the activity of various copper catalysts for the arylation of 2-
methoxyethanol (eqn. 5) a)
Coordinating Atom b) Catalyst Yield (%) o
CuBr e) 4
CuCI(PPh3)3 0
phen2CuBr 0
CuBr2 a) 0
Cu(acac)2 6
Cu(OAc) 2 12
a) For the operating conditions and the ligands abbreviations : see table 4.
b) Nature of the coordinating atoms bounded to the copper halogenide moiety.
c) Isolated yield.
d) The copper bromide is assimilated to an oxygen complex in the mixture.
All the copper(I) or copper(II) complexes exhibit a very low activity (the yields
are less than 12 %), under the same conditions already used successfully with the
nickel complexes (affording up to 80 % yield).
Indeed, as the catalysis with copper is likely working through an intermediate
cuprous alcoholate, the poor results obtained with the copper complexes are
probably connected with the absence of alcoholates under the catalytic conditions
used.
To improve the nickel catalyzed arylation of alcohols and to reach a lower
temperature and/or a shorter time as well as a smaller ratio of catalyst, the influence
of the base was investigated more thoroughly, using the bromobenzene as arylating
agent (in order to avoid any secondary reaction on the cyano group of the p-
bromobenzonitrile used in the preliminary investigations) (eqn. 6) (Table 6).
bipy2NiBr2 or CuBr (7 % molar) / ~

--~Br + HO--(CH2)2OMe (X(~//X--O(CHz)2OMe (6)
base / reflux
99
Table 6. Influence of the base on the nickel or copper catalyzed arylation of 2-methoxyethanol
(eqn. 6) ~)
Catalyst bipy2NiBr2 CuBr
Base Pr3N d) K2CO3 K H C O3 KOAC K2CO3 KHCO3

Time (h) 66 20 20 20 20 20
Yield (%) b), c) 40 70 100 10 40 < 5%
a) Operating conditions : PhBr (1 ml), bipy2NiBr2 (0.07 mmol), base (1.1 mmol),
2-methoxyethanol (6 mmol).
b) GC. yield.
c) In all cases a full conversion of the starting arylhalide into arylated alcohol is observed.
d) 4.4 mmol.
The best results were obtained for the potassium carbonates, specially for the
hydrogenocarbonate which affords a quantitative yield in 1-phenoxy 2-
methoxyethane, after only 20 h.
It must be pointed out that, in this case too, the comparison experiments Ni vs.
Cu prove the better catalytic activity of the nickel complex (the difference of the
results, Ni vs. Cu, is higher for KHCO 3 than for K2CO 3 demonstrating probably the
specific sensitivity of the copper catalysis to the alcoholate concentration (higher for
K2CO 3 than for KHCO3).
Using the best operating conditions previously determined but with a half
quantity (3.5 %) of the nickel complexe, the scope of the arylation of alcohols was
roughly investigated by changing the alcohol and the arylating agent (eqn. 7)
(Table 7).
/R bipy2NiBr,
- (3 59 % molar) /R
ArX + HO--CH ~ Ar--O--CH (7)
\R' 20 h, 125oC (- HX) \R'
100
Table 7. Influence of the substrate on the bipy2NiBr2 catalyzed arylation of alcohols (eqn. 7)
HO-CHRR' ArX Yield b) (%)
MeOCH2CH2OH C6HsBr 100

nPrMeCHOH C6HsBr d) 40
BuOH C6HsBr 100
BuOH p-MeOC6H4Br 90
BuOH p-HOC6H4Br 0
BuOH C6H5C1 c) 30
BuOH p-F3CC6HnC1 100
,..
a) Operatingconditions : ArX (1 mmol), alcohol (6 ml).

b) G.C. yield.
c) Reactiontime : 4 days.
d) Reactiontime: 7 days.
Primary alcohols can be arylated in excellent yields by bromoarenes, even with

electron donating substituents (for example by p-bromoanisole) with the exception
of the p-bromophenol (which is probably transformed in the much less reactive p-
bromophenolate). Although less reactive, the chloroarenes can also act as arylating
agents for the primary alcohols and the yields can even by excellent if electron
withdrawing substituents are present on the phenyl ring.
Secondary alcohols, such as 2-pentanol, can also be arylated by bromobenzene,
even if the arylation is more difficult (the yields are lower even after a longer
time); but, it must be pointed out that the selectivity towards bromobenzene
continues to be excellent (100 %).
Attempted mechanism for the catalyzed arylation of hard nucleophiles

The mechanism of the amines or alcohols arylation catalyzed by nickel(II)
complexes has not been elucidated until now (refs. 7, 17), even though the arylation
of nucleophiles catalyzed by nickel(0) complexes is better understood. In this last
case it is generally admitted that the reaction proceeds by an oxidative addition step,
followed by a nucleophilic substitution, and then a reductive elimination of the
arylation product (Scheme 4). According to the work of Kochi (ref. 18), the
oxidative addition of the haloarene on a nickel(0) complex takes place through a
monoelectronic transfer from the metal to the aryl halide with simultaneous
formation of a nickel(I) intermediate, the actual catalyst of the reaction (ref. 6).
101
-L
Ni ~ 4 --. Ni ~ 3
+L
+
~ -
~ ArX
[ (NilL3") (ArX ~ ]
I Ar--Nu I +
[ (NilL2 ~) ( A r X ' ) ]
+
[ ArNi 1~INuL2~ ] [ (ArX~) ] [ArNin XL2 ]
Nu
[ ArNinNuL2 ] , ~ ~ . . . . . . . . _ . . _ _ _ _ . ~ X
Scheme 4. Attempted mechanism for the arylation of hard nucleophiles catalyzed by Ni(0)
complexes.
In the case of the amines or alcohols arylation catalyzed by nickel(II), it is

possible, as a result of a thermal dismutation of the nickel(II) into nickel(I) and
nickel(Ill) ; to consider the similar intervention of a nickel(l) complex as a
catalytically active species ; but then the formation of this intermediate still has to
be proved. Another possibility of mechanism is based on an oxidative addition
process directly on the nickel(II) entity (ref. 4d). However this reaction, well
known for the metals in their low oxydation degrees is disadvantaged by higher
oxydation degrees, and further it would result in a transient nickel(IV) complex, a
non usual oxidation degree for this metal.
Aminolysis of nitriles
As an unexpected result of our investigations on the arylation of amines, a new
catalysis with nickel complexes was pointed out for the aminolysis of nitriles 9
indeed, in the reaction of the p-bromobenzonitrile with the 4-phenylpyridine in the
presence of catalytic amounts of NiBr2, in addition to the expected arylamine, the
amide resulting from the aminolysis of the cyano group (and subsequent hydrolysis
during the work-up) was isolated (eqn. 8).
102
Ph----( N--H + Br CN
/
NiBr2 diglyme ~ / ~ (8)

(cat. 3.5 % mol.) reflux" 14 h Ph----( N---~(..__~)//K----CN
(62 %)
0
\ / N )------Ph
(15%)\ /
The usual ways to obtain amidines (or amides after subsequent hydrolysis) by
addition of primary or secondary amines to nitriles are :
(i) the metallation of the amines, to improve their nucleophilicity (refs. 19, 20),
(ii) the acidic activation of the nitriles to increase their electrophilicity either by
H C 1 / R O H (the Pinner method (refs. 20, 21), or by a Lewis acid such as A1C13
(ref. 22).
In other respects, the cyano group coordinated on various tervalents (Co, Rh,
Ir, Ru) or divalents (Pt, Pd, Ni) transition metals can undergo nucleophilic addition
in the coordination sphere with modification of the nitrogen ligand which remains
coordinated on the metal (refs. 23, 24, 25).
But, till now, to the best of our knowledge, there is no example for the
aminolysis of nitriles catalyzed by nickel complexes.
This reaction was investigated using the 2-phenylethylamine as substrate and by
analyzing, for facility reasons, the amides resulting from the hydrolysis of the
corresponding amidines, after the reaction (if the conditions used are anhydrous) or
during the reaction (performed in presence of water) (eqn. 9) (Table 8).
NiBr2 (cat. 3.5 % rnol_) [ /,tN--R' H20 //O

R--CN + R'NH2 "-
"- l R - - C -~ R--C (9)
140~ " 65 h \NH--R' (- R'NH2) \NH--R'
Of course, it must be pointed out that the reaction of benzonitrile with the amine
needs the nickel catalysis : the reaction without NiBr2 affords only tiny amounts of
the N-substituted benzamide.
103
Table 8. Aminolysis of nitriles catalyzed by NiBr2 [eqn. (9) 9R ' N H 2 = Ph(CHz)2NH2]
R-CN H20 Amide Yield (%)
~ CN
o
XNH(CH2)2Ph
60
~ ---CN
~%H(CH2)2Ph
o
55
Nc-4
Ph(CH2)2NH
%Br,
O
66 a)
O O
N C ~ C N 60
/ \
Ph(CH2)2NH \ / NH(CH2)2Ph
O
NCm(CH2)4mCN \XC--(CH2)4 m C N 50 b)
/
Ph(CH2)2NH
a) As secondary product, the arylated amine Ph(CH2)2NH-pC6H4-CN (17%) is also formed in

the reaction.
b) The reaction affords also 10 % of a "Thorpe-Ziegler-like"
cyclization product 9 Ph(CH2)2NH
CN
The amides are obtained in good yields starting from (un)-substituted

benzonitriles. For example with the terephtalonitrile the interesting diamide
N,N'-bis (2-phenylethyl)terephtalamide is obtained in good conditions (an extension
of this reaction starting from diamines could lead to the formation of polyamides).
However, the same reaction performed with adiponitrile, affords mainly the
monoamide as the monoaminolysis product.
This nitrile aminolysis reaction, involving a nickel catalysis, permits moreover
to obtain the synthesis of N,N'-disubstituted amidines, the classical methods leading
only to the corresponding N-unsubstituted amidines.
104
CONCLUSION
In the following figure are summarized the differem transformations discussed
before : bromoarenes (but also in some cases chloroarenes) can be transformed into
aromatic hydrocarbons or into more interesting industrial products such as
arylamines or arylethers.
cat. Pd ~ i ArH [
HNR2 <
ArBr ca . " i
(ou ArCl)
ROH cat. Ni (or Cu) ~ ]ArOR ]
All these transformations show that arylbromides, by using metallic catalysts

such as palladium, nickel or copper complexes, can exhibit a diversified reactivity
like their aliphatic analogs.
Particularly, among the catalysts used, the bipy2NiBr2 complex is the more
efficient catalyst for the arylation of primary or secondary amines. Moreover with
the same catalyst, the first examples of arylation catalyzed by a nickel complex for
primary or secondary alcohols have also been obtained.
Accordingly the arylation of nucleophiles catalysed by the nickel(II) complex
bipy2NiBr2 can be considered as a good synthetic tool and at least as an interesting
alternative to the usual copper catalysis.
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b) J.A. Gautier, M. Miocque, C. Fauran, A.Y. Le Cloarec, Bull. Soc. Chim. Fr., 200,
(1970).
20. R.L. Shriner, F.W. Neumann, in Patai, "The Chemistry of Amidines and imidates",
Wiley, p. 359, New-York, (1975).
21. F.C. Schaefer, G.A. Peters, j. Org. Chem., 26, 412, (1961).
22. a) P. Oxley, M.W. Partridge, W.F. Short, J. Chem. Soc., 1110, (1947).
b) F.C. Cooper, M.W. Partridge, Org. Synth., 36, 64, (1956).
23. F.A. Cotton, G. Wilkinson in "Advanced Inorganic Chemistry", fifth edition, Wiley,
p. 361, New-York, (1988).
24. a) P. Paul, K. Nag, Inorg. Chem., 26, 1586, (1987).
b) P. Paul, K. Nag, J. Chem. Soc., Dalton Trans., 2373, (1988).
25. B.C. Challis, A.R. Butler, in Patai, "The Chemistry of Amino Group", Wiley, p. 289,
New-York, (1968).
106
THE ISOMERISATION OF 1,2,4-TRICHLOROBENZENE :
A THEORETICAL STUDY
SIMON FIRKINS

Technologie, 85 Avenue des Fr6res Perret - B.P. 62 - 69192 Saint-Fons Cedex -
France
INTRODUCTION
Theoretical techniques have been applied to the problem of the isomerisation of
1,2,4-trichlorobenzene (124TCB). Semi-empirical methods have been used to
study three proposed mechanisms for the isomerisation of 1,2,4-trichlorobenzene
into 1,2,3 and 1,3,5-trichlorobenzene as well as examining the thermodynamic
stabilities of protonated species and final products. Comparison with experimental
observations has been possible.
HYPOTHESES CONCERNING THE ISOMERISATION REACTION

MECHANISM
Ionic, via 1,2 intermolecular shift

The isomerisation of 1,2,4-trichlorobenzene in this mechanistic scheme would
begin by protonation, and would be followed by a 1,2 shift passing via a
chloronium ion.
107
Cl Cl I Cl Cl
H "* " ~ ,,.Cl
b,~ ~ 4" H §
c, ~
Cl
Cl CI Cl Cl
Cl Cl
~ CI l [ ~ CIl
Cl _.. ~ + H§
H Cl
H Cl "Cl
Homolytic scission after protonation

In this case, following protonation of the 1,2,4-trichlorobenzene, homolytic
scission of the protonated species occurs, with the formation of a radical cation and
a chlorine radical.
Next, the chlorine radical would attack either the radical cation or the chlorine
radical in order to produce a protonated species which would then deprotonate to
form a new trichlorobenzene.
H
Cl CI
+ c , . _ _ +
Cl ~
[ ~ CI CI Cl Cl
Cl
CI ~H+ CI CI Cl Cl
+ Cl" ~, ~ Cl ~ ""- + H+
H Cl
H
Ionic, dissociative
This mechanism would involve, after protonation, a chloride ion leaving the
ring thus forming a neutral aromatic and a C1 § This cation would then attack the
ring in order to form a new protonated species.
108
H Cl
-.., ~ + Cl + ~,, C l - ~ ...C + H+
c,
Cl Cl Cl Cl
Cl
Cl CI Cl Cl
~ C I [~Cl
_,....... + Cl + , H ~ + H§
Cl Cl
M E T H O D S USED FOR THE CALCULATIONS
Drawing of the molecules

In order to draw the molecules, the CHEM-X (ref. 1) suite of programs was
used. This software also interfaces the graphic environment with the programs
which perform the calculations.
Calculation of optimised structures and energies

The optimised geometries and energies of the neutral, protonated and radical
molecules, as well as the transition states were calculated at the semi-empirical,
PM3 (ref. 2) level of theory using the program MOPAC (ref. 3), version 6.0.
RESULTS AND THEIR INTERPRETATION
Isomeric distribution of neutral molecules

Calculations carried out on the neutral molecules give the following values for
the energies 9
109
Cl
I
E = - 1706,98743 eV
c,
E = - 1706,94755 eV
c.
E = - 1707,02296 eV
This leads to the following order of stability 9
Cl CI Cl
c,.Gc, c.
increasing stability
Using these energies, and the Boltzmann equation, it is possible to calculate the
isomeric distribution of 1,2,3 and 1,3,5-trichlorobenzene at the time of the
isomerisation of 1,2,4-trichlorobenzene.
Cl Cl Cl Cl
c, _ +
CI
Cl
Theoretical 16,2 % 83,8 %
distribution
These results are very close to those obtained after a reaction time of
3 1/2 hours.
110
CI Cl Cl Cl
c, .
Cl
Cl
TT1,2,4 -- 36,7 % RT1,2.3 = 18 % RT1,3.5 = 57,9 %
Experimental 23,8 % 76,2 %
distribution
Isomeric distribution of protonated species

The following energies are obtained from calculations on the protonated
species 9
Cl cI H Cl
1 cl i cl
Cl
Cl Cl
E/ev - 1714,20984 - 1714,10547 - 1713,95052
AE/kcalmol -~ + 2,4 + 3,6
Cl Cl Cl
HH Cl ~cl I~Hcl
H Cl
Ol CI
- 1713,94434 - 1713,75184 - 1713,66541
+ 0,1 + 4,4 + 2,0
Using these values and once again, the B o l t z m a n n equation, the relative
d i s t r i b u t i o n o f each m o l e c u l e can be calculated. W i t h respect to the m o s t a b u n d a n t
species, the two active m o l e c u l e s , m e a n i n g those w h i c h allow the f o r m a t i o n of
i s o m e r s , h a v e relative c o n c e n t r a t i o n s of 2.4 10 .3 and 2.6 10 -5. These values are by
no m e a n s ridiculous for this type of reaction.
111
Comparison of the mechanisms leading to the formation of 1,2,3 and
1,2,4-trichlorobenzene
In order to compare the mechanisms, the energies of all protonated species and
intermediates have been calculated with respect to the active protonated forms.
Formation of 1.3,5-trichlorobenzene
CI
+ CI §
Mechanism 3
+ 95,1 kcal mo1-1
(dissociative, ionic)
N CI
+ CI
Mechanism 2
(single electron transfer) + 44,7 kcal mo1-1
CI
Mechamsm 1
(intramolecular, ionic) + 23,0 kcal mo1-1
H ci
ci
ci
0 k c a l mo1-1 + 13,1 kcal mol-1
112
Formation of 1,2,3-trichlorobenzene
~ Cl + el §
Mechanism 3
+ 91,4 kcal mol-~
~
(dissociative, ionic)
N
Cl+ Cl"
Mechanism 2
+ 38,2 kcal mo1-1
(single electron transfer)
G CI
Y
Mechanism 1
(intramolecular, ionic) + 17,7 kcal mo1-1
CI CI
CI H
0 kcal mo1-1 + 2,4 kcal mol-1
C o m p a r a i s o n of the different mechanisms for the formation of 1,2,3 and

1,3,5-trichlorobenzene
Taking into account the energy difference between the two active protonated
forms (4.5 kcal tool-l), the following diagram is obtained 9
113
CI CI
[ ~ + CI§ + CI§
Cl
Mechanism 3 + 45,1 kcal mol -] + 9 5 , 9 kcal mo1-1
~
CI Cl
+ Cl
Cl+ cI "
Cl
Mechanism 2 + 4 4 , 7 kcal mo1-1 + 42,7 kcal mol 1

CI CI
c,~ ~-c'
"CI
Mechanism 1 + 23,0 kcal mol 1 + 22,2 kcal mol -]
CI
ci
'
cI ci
I H
+ 13,1 kcal mol -] H CI
+ 6 , 9 k c a l mo1-1
cl 4,5 kcal mo1-1
0 kcal mo1-1
DISCUSSION
The general conclusions drawn from these calculations are :
- The 1,2 intramolecular shift is the most favorable of the mechanisms.
- The ionic, dissociative mechanism is very unlikely.
- The mechanism which proceeds via the formation of radicals appears difficult,
but cannot be excluded as a possibility at high temperatures.
- The thermodynamically stable product is the 1,3,5-trichlorobenzene, but the
energy difference between the isomers is reasonably small.
- The activation energies for the formation of both 1,2,3 and 1,3,5-trichloro-
benzene are very close, indicating that a mixture of products would probably be
produced.
114
EXPERIMENTAL RESULTS
Initial 124TCB : 98.8 % 123TCB : 0.7 % 135TCB : 0.4 %

Composition
After 1 hour of 124TCB : 86.2 % 123TCB : 10.2 % 135TCB : 2.9 %

reaction at 450~
- The isomerisation is observed with an acidic zeolite at 400-500~

- No evidence is found to support the mechanism involving homolytic fission
(single-electron transfer).
- It seems probable that the intramolecular mechanism operates within the acidic
zeolite environment.
CONCLUSIONS
The intramolecular ionic mechanism is the most energetically favorable,
although the radical mechanism could be considered possible in the gas phase at
elevated temperatures, despite the lack of experimental evidence thus far.
The dissociative mechanism is very unlikely, with an activation energy of
approximately 90 kcal mo1-1.
The thermodynamically favoured species is 1,3,5-trichlorobenzene, but due to
comparable activation energies, the formation of a certain quantity of
1,2,3-trichlorobenzene seems reasonable. Therefore, in order to favorise the
formation of 1,2,3-trichlorobenzene, it was thought necessary to limit further
isomerisation of this compound, that is, to defavorise the protonation of
1,2,3-trichlorobenzene. In order to do this, the use of solid catalysts (eg. zeolites)
which can introduce a selectivity based on size and shape at the protonation stage
seems the best option. The experimental results obtained from such an approach
validate this hypothesis.
References
1. CHEM-X Chemical Design Ltd, Roundway House, Cromwell Park, Chipping Norton,
OX7 5SR, Grande-Bretagne
2. J.J.P. Stewart, J. Comp. Chem., 10, 221, (1989)
3. J.J.P. Stewart, Frank J. Seiler Reasearch Laboratory, U.S.A.F., CO 80840
115
C ARBOXYLATION OF HYDROXY AROMATIC COMPOUNDS
ISABELLE BONNEAU-GUBELMANN a), MURIELE MICHEL b), BERNARD

BESSON c), SERGE RATTON a) AND JEAN-ROGER DESMURS b)
a) Rh6ne-Poulenc Recherches, Centre de Recherches d'Aubervilliers, Rue de la

Haie Coq, 93308 Aubervilliers, France.
Technologie, 85 Avenue des Fr~res Perret, 69192 Saint-Fons Cedex, France.
c) Rh6ne-Poulenc Industrialisation, Centre de Recherche, d'Ing6nierie et de
Technologie, 24 Avenue Jean-Jaur~s, B.P. 166, 69151 D6cines-Charpieu
Cedex, France.
d) Interm6diaires Organiques, 25 Quai Paul Doumer, 92408 Courbevoie Cedex,
France.
INTRODUCTION
The carboxylation of hydroxyaromatic compounds in the form of alkaline salts
(the Kolbe Schmitt reaction) is well known and applied in the synthesis of acids
such as salicylic acid, para-hydroxybenzoic acid and ortho-cresotinic acid.
It was in 1860 that Kolbe first produced salicylic acid by heating a mixture of
phenol and sodium in the presence of carbon dioxide at atmospheric pressure. In the
years that followed, the importance of CO2 pressure, temperature of the system and
the role of water was highlighted. Consequently, this reaction, that is often known
as ,, the Kolbe Schmitt reaction ,, has given rise to several variants :
116
Table 1. Kolbe, Kolbe Schmitt and Marasse reactions
Conditions
Reactions P (CO2) T Name
Bar ~
-
180-200 Kolbe
COONa
5-7 120-200 Kolbe-

Schmitt
COONa
~ OH + K2CO3 + C O 2
(excess)
,~- ''- (,(,),)---'-OH
20-100 150-250 Marasse
COOK
)'---OM + M2CO3 + CO ,-. ~ ~___~OM + HCOOM modified

50 200-250
(M = K ou Na) Marasse
COOM
The Kolbe Schmitt reaction is different from the Kolbe reaction due to the CO2
pressure. Increasing this pressure in fact shifts the equilibrium towards the
salicylate form (single salt).
THERMODYNAMIC CONSIDERATIONS
Theoretical calculations (on phenol)

These thermodynamic calculations were performed using Thergas software for
the following reaction"
OH OH
+ CO2 ~
COOH
The thermodynamic values were calculated by the additive nature of the bonds
and correspond to the hypotheses of a gas phase reaction. The software does not
take account of phenol salts.
117
Table 2. Thermodynamic data (according to Thergas)
T (K) 298 398 498 598 698

o
R (kcal.mol-1) - 29,59 - 30,78 - 31,61 - 32,13 - 32,67
AG~ (kcal.mo1-1) 11,70 14,72 17,84 21,03 24,26
Strictly speaking the phenol carboxylation reaction is exothermic.

AG~ is positive and increases as a function of temperature : this shows that the
direct carboxylation of phenol is impossible ; it is essential to perform the reaction
using a phenate.
Measured data (on potassium phenate)

This thermodynamic data is taken from the description of a Ueno process
(ref. 1) for the preparation of para-hydroxybenzoic acid.
OK OK OH
+ CO2 AH (x~ (298 K) = - 7 kcal.mo1-1 (1)
(solid) (gas) COOK
OK OH OH OK
AH (2) (298 K) = 0 kcal.mo1-1 (2)
COOK COOK
The formation of the bisalt A is exothermic.
MECHANICAL CONSIDERATIONS
Principle
It has been shown that the carboxylation reaction of phenol, that has previously
been salified, occurs through an electrophilic substitution mechanism, via a complex
formed between the phenol, the CO2 molecule and the alkaline metal (ref. 2).
118
In theory, this reaction takes places in two stages (Fig. 1) 9
- the carboxylation of phenate (eqn. 3) and
- restructuring between the carboxylate / phenate / phenol (eqn. 4).
OM OM,CO2
+ CO2 (3)
OM.CO2 OM OH
(4)
COOM
(M = Na or K)
Fig. 1. Mechanism for the carboxylation of phenol
The intermediate has been represented in simplified form. In fact two

hypotheses exist for the structure (refs. 3, 4) but neither has been definitively
proven.
,M,,
& ............ ::o
I o
Complex formation
OM.CO2 J
OCOOM
Formation of phenyl carbonate
The reaction passing through a metallic complex is that most commonly

described in literature.
In any case the key intermediate is the bisalt.
119
OM
~ .COOM
Mechanisms for the carboxylation of sodium phenate and potassium phenate

(Figs. 2, 3) are given below.
OH ONa
aq
~, .......Na.
~
ONa OH
~o ,COONa
(6)
+ CO2 ....C~O
OH ONa ONa OH
,COONa + _ .COONa +
(7)
Kinetic and
them~dymmic
product (stable)
Fig. 2. Carboxylation of sodium phenate
120
OH OK
+ KOH + H2~O (8)

aq
OK OH
~
(~ ......... K ,,
+ ,o
,,,, COOK
(9)
+ CO2 -., "- .......C"~O
OH OK OK OH
(10)
Kinetic product
(stable)
OK OK OK
2 ~~~,./COOK COOK +
(11)
COOK
OK OK OK
OOK
+ "~ 2 (12)
COOK COOK
Thermodynamic
product (stable)
Fig. 3. Carboxylation of potassium phenate
In summary 9
The key intermediate in all cases is the metallic bisalt.
In the case of sodium, this bisalt can be respresented as a cyclic complex with
6 thermally stable centres.
121
+
Na~)
-0" 0
\ONa
The carboxylation of sodium phenate gives excellent selectivity in producing

salicylic acid.
As far as potassium is concerned, bipotassium salicylate is not thermally stable
and restructures itself intermolecularly to form tri-potassium isophthalate and
potassium phenate.
This mechanism has been proven and the intermediates have been identified
(ref. 4).
The carboxylation of potassium phenate gives excellent selectivity in producing
parahydroxybenzoic acid.
PARAMETERS GOVERNING THE REACTION
Cation type
As has been described above, the key imermediate is the bimetallic salicylate :
- With small (hard) cation Li + and Na +, this bisalt has a metallo complex structure
with 6 thermally stable centres which leads to a carboxylation process.

-With large cations (soft) K +, Rb +, Cs +, this bisalt is not thermally stable and
parahydroxybenzoic acid is formed via isophtalate to phenate. This mechanism is
possible with potassium and is favoured at low CO2 pressures (~ 1 bar) and at high
temperatures ( > 180~
Temperature
The temperature influences both the reactivity of the phenate and the selectivity,
as shown in Table 3.
122
Table 3. The influence of temperature 9carboxylation of potassium phenate
T Selectivities (%) Yield

,,,
(~ A.S. pHBA (%)

140 59 41 39
190 29 70 43
210 6 94 48
250 > 98 > 48
Conditions 9 Bulk carboxylation

Duration 9salification 1 h30mn
Carboxylation 4h
P (CO2) = 1 bar
These values show clearly the thermal restructuring of bipotassium salicylate in

parahydroxybenzoic acid, as shown in figure 3.
C O 2 pressure
The minimum required pressure for the carboxylation of phenate corresponds to
the dissociation pressure of the complex formed between the phenol, the alkaline
metal and the CO2 molecule, and to the applied temperature (ref. 5). Between
120~ and 160~ the dissociation pressure of the complex (sodium phenate CO2)
is around 4 bars.
At a given temperature, an increase in CO2 pressure, above this minimum value
has no effect on the system selectivity, but it can favour the reaction kinetics.
The role of water

The presence of traces of water leads to a reduction in yields (Table 4).
Table 4. The influence of residual water in the phenol / phenate mixture on the carboxylation
yield
H20 content (ppm) Yield loss (%)

5O0 1.25
5 000 12.5
In fact, any molecule of water present, breaks down the phenate into a molecule
of alkaline hydroxide, which then consumes some CO2, to regenerate water
(eqns. 13-15).
123
OM OH
2 ~ +2 H20 + 2 MOH (13)
2 MOH + CO 2 ,~. "~ M2CO3 + H20 (14)
OM OH
+H20+CO2-
2 + M2CO 3 (15)
The water can also form in situ by 9
2 MOH + CO 2 ~, "~ M2CO3 + H20 (16)
Ueno (ref. 5) draws attention to the fact that the production of water can also be
due to a parasite etherification process (eqns. 17, 18).
OH
~ O - - ~ + H20 (17)
OH
+ CO 2 + 2 H20 (18)
II
o
The influence of the system

The carboxylation reaction of phenol requires total anhydricity.
This condition can be fulfilled :
- either in solid phase : good selectivity will be achieved is the gas / solid exchanges
are efficient. These conditions requires the use of special technology.
124
- o r in suspension in an inert solvent (biphenyl ether, kerosene, di-or terphenyl,
etc.).
- or in a phenol phase system.
SYNTHESIS OF OTHER HYDROXYAROMATIC COMPOUNDS
The influence of substitute core groups

The reactivity of the substrate is influenced by the steric space requirement and
the core substitute groups.
- An alkyl group (either ortho or para) favours the ortho-carboxylation of the phenol
group.
- A donor group (NH2, OCH3, OH, X, etc.) enables good yields to be achieved
( > 80%).
- An acceptor group (NO 2, CN, COOR, etc.) will inhibit the reaction.
The differences in reactivity and orientation are summarised in Table 4.
125
Table 5. The influence of substituents (ref. 6)
Substituents Substrate Majority

Conditions Yield Ref.
product
HO--@R H O - ~ R
HOOC
t ~ = 160- 220~
P = 4 0 - 100 b
dur6e = 4 - 8 h
25 h 85 %
(7) (8) (9)
(10) (11)
(12)(13)
HOOC
Alkyl _ ~ t ~ = 125- 175~ (7) (8) (9)
(CH3, OH P = 100b 70~83 % (12) (13) (14)
C2H5"" ") R dur6e=4-8h (15) (16)
R
R R
t ~ = 200~
P = 40b 37 % (13)
dur6e = 6 h
R R
t ~ = 200~
(7) (13)
P = 40b 3O %
(17) (18)
dur6e = 6 h
R' HOOC R'
HOOC
t ~ = 210oC
HO-~R' P = 35 b 17 % (18) (19)
HO@~R'
dur6e = 40 h (20)
R
R
Phenyl
.o-@~ HOOC
t ~ = 250~
P= 30b
dur6e = 5 h
90 % (7)
t ~ = 180~
(7) (21)
P=63b 84 %
(22)
dur6e = 5 h
HOOC
Donor
(NH2,
Ho- G t~ =90-225~ (7) (13)
P = 8 - 100b 5-90 % (23) (24)
OMe,
HOOC dur6e = 4 - 43 h (25) (26)
OH, X...)
~
Acceptor
t ~ = 210~
(NO2, CN,
P =40b 0-19% (13)
COOR...)
HOOC dur6e = 4 h
126
CONCLUSIONS
The carboxylation reaction of phenol by CO2 is well known and industrially
developed using various technologies.
Chemically speaking the key parameters are shown in Table 6.
Key parameters Selectivity

ortho para
Cation Na K
P (CO2) equilibrium shift
T~ 130 + 50 210 + 30
a
Three main technology types can be used :

- fluidised bed, ,, LIST ,, reactor,
- in a dispersion system,
- bulk.
References
1. ,, Liquid crystal polymers ,,, SRI, report N~ 86 C.

2. J. March in ,, Advanced Organic Chemistry ,,, 3ieme Edition, John Wiley, p. 491-492, New-
York, (1985).
3. R. Schmitt, J. Prakt. Chem., 397, (1885).
4. A.J. Rostron, A.M. Spivey, J. Chem. Soc., 39, (1964).
5. Ueno Ryuzo, Masada Yoshiyasu, EP 254 596, (1986).
6. A.S. Lindsey, H. Jesrey, Chem. Rev., 583, (1957).
7. O. Bame, G.F. Adamson, J. Org. Chem., 19, 510, (1954).
8. F. Beilstein, A. Kuhlberg, Ann., 156, 206, (1870).
9. B.I.O.S. Final report N ~ 664, His Majesty's Stationery Office, London.
10. D. Cameron, H. Jeskey, J. Org. Chem., 15,233, (1950).
11. R. Ihle, J. Prakt. Chem., 2 (14), 443, (1876).
12. P. Spika, Gazz. Chim. Ital., 8, 421, (1878).
13. F. Wessely, K. Benedikt, Monatsh, 81, 1071, (1950).
14. C. Brunner, Ann., 351,320, (1907).
15. A. Engelhardt, J. Russian. Phys. Chem. Soc., 1, 220, (1869).
16. M. Filiti, Gazz. Chim. Ital., 16, 126, (1886).
17. R.C. Fuson, J. Corse, J. Amer. Chem. Soc., 63, 2645, (1941).
18. L. Palfray, Bull. Soc. Chim., 956, (1948).
19. J.A. Jesurun, Ber., 19, 1414, (1886).
20. H. Kolbe, E. Lautemann, Ann., 115,201, (1860).
21. Heyden, Fabrik, German patent 61125, (1891) ; Frdl 3,828.
22. H. Schwazz, Ber., 13, 1643, (1880).
23. M. Calvin, US 2 493 654, (1950) ; CA. : 44, 2559, (1950).
127
24. L.N. Ferguson, R.R. Holmes, J. Amer. Chem. Soc., 72, 5315, (1950).
25. V.M. Rodionov, Bull. Acad. Sci. U.R.S.S., Classe Sci. Chim., 3 (421), (1940) ; C.A. : 35,
5101, (1941).
26. L. Varnholt, J. Prakt. Chem., 2 (36), 19, (1897).
128
ACCESS TO POLYCHLOROPHENOLS : CHEMISTRY OF INTERME-
DIATES
JEAN-ROGER DESMURS a), SERGE RATTON b), RENE JACQUEROT a), JEAN
DANANCHE a), BERNARD BESSON a) AND JEAN-CLAUDE LEBLANC ~

France.
b) Interm6diaires Organiques, 25 quai Paul Doumer, 92408 Courbevoie Cedex,
France.
c) Rh6ne-Poulenc Chimie, B.P. 17, 38800 Le Pont-de-Claix, France.
INTRODUCTION
U.S. production between 1977-1980, shown in Table 1, illustrates the industrial
importance of these aromatic derivatives, used either as synthesis intermediates, or
active components for some agrochemical compounds or pharmaceuticals
specialities.
129
Table 1. Production levels and uses of chlorophenols (ref. 1)
Product US production
Uses
t/year
OH
~ C 1
a few thousands tons intermediates
OH
CI
23000 intermediates
C1
OH
C1 C1 19000 fungicide used in wood
protection formulations
C1
The agrochemicals sector provides the main outlets for chlorophenols, as shown
in Table 2 which shows a few well-know products.
130
Table 2. Shows agrochemical and pharmaceuticals specialities prepared from chlorophenols.
Structure Trade-mark
C1
I~~-O--CH2COOH 24 D Acid
(herbicide)
C1
~ H3
C1----~,,),/x----O--CH--COO H Dichloroprop
(herbicide)
C1
/-.~ ~ CH3
Hoelon
C1 - - - - ~ . ) / ~ O--~~)//x--- O-- CH-- COOH3 (herbicide)
C1
Bifenox
CI-~O~~N~--NO2 (herbicide)
COOCH3
CI
c3.7 Sportak
C1-----{( ) )---O--CH-~--CH2--N _
(fungicide)
\~_;( - ,c_N.~N
~C1 O// \--/
C1
// Guanochlor
\ -(X O~CH2~CH2~NH--NH~CxNH2 (antihypertensor)
C1
CI
NH-- Diclofenac
(analgesic)
C1 CH2CO2H
131
Generally a quality problem is created when heavy chlorophenols
(trichlorophenols, tetrachlorophenols and pentachlorophenols) are processed.
Impurities such as polychlorophenoxyphenols, polychlorodibenzodioxins,
polychlorodibenzofurans and polychlorodihydroxybiphenyls, are quite often found
in some industrial products. Table 3 below shows the influence of the structure of
the series of dibenzodioxins on the DL 50 (refs. 2, 3) (number and position of the
chlorine atoms).
Table 3. Shows LD 50 by mouth of various polychlorodibenzodioxins.
DCDD TCDD HCDD OCDD

(2,3,7,8 isomer) (mixed isomers)
r j
mouse 0.114 mg/kg > 4000 mg/kg
J 0.022 mg/kg 100 mg/kg

rat
> 1000 to 0.045 mg/kg > 1000 to
2000 mg/kg 2000 mg/kg
J 0.0006 mg/kg
guinea-pig {
0.0021 mg/kg
0.115 mg/kg
J (0.275 mg/kg)
- through
rabbit percutaneous
route
> 0.252 mg/kg
I through
intraperitoneal
route
2,3,7,8-Tetrachlorodibenzodioxin 1 has a toxicity clearly above that of all the

other compounds of this series. Thus it is imperative that industrial products are
free of this impurity or its precursors.
132
Literature on this subject tells that chlorophenols cause these unwanted by-
products to form (refs. 4, 5, 6) when exposed to thermal, photochemical or basic
conditions (eqn. 1).
OH
+ Cim ~ C CI~ + 2HCI (1)
C1 H ~ "O"
But information provided in the literature is not sufficient to explain how these
by-products, observed during experiments carried out on chlorination reactions, are
formed. Consequently our objective was to study chemical phenomena occurring
during the phenol chlorination process in order to understand how by-products were
formed with the aim of reducing the amount formed.
HYPOTHESIS
It seems that the creation of polychlorophenoxyphenols, polychlorodibenzo-
furans or polychlorodibenzodioxins is closely related to the varying degrees of
chlorination. During the mono and dichlorination of phenol, no parasite chemistry
appears. But if we introduce a third and especially a fourth or fifth chlorine atom
within the aromatic core then a problem is created. This is problably linked to the
high activating quality of the OH group which tends to orientate an electrophilic
substitution - in an ortho or para positioning (Fig. 1).
OH OH
"x cl cl Cl cl
Fig. 1. Activated position towards an electrophilic attack of chlorine
When the carbon has already been substituted by an atom, ipso attack leads to
some polychlorinated gem-dichlorocyclohexadienones (Fig. 2).
133
0 0 0
C1 CI~.~C1 C I ~ C I
C1 C1
0 0
,C1 C1 C1
C ~1 "1
Fig. 2. Polychlorinatedgem-dichlorocyclohexadienones generated by chlorination of 2,4 or 2,6-

dichlorophenols or 2,4,6-trichlorophenol
We assumed for this process that gem-dichlorocyclohexadienones were actual

intermediates acting in the formation of chlorophenols (eqn. 2) containing one or
two atoms of chlorine in meta position relative to the OH group.
0 OH
C1 .C1 .~ C I ~ C 1
(2)
isomerisation
y "C1
C1
but they could also be the precursors of polychlorophenoxyphenols (eqn. 3)
0 OH 0 OH
C1 CI+CI CI .9 . C I ~ C I 9 _~ C I - . ~ C 1
condensation (3)
"- ~CU. ~" C1
y "C1
o
CI CI
C1 CI
+ HCI
Cl
134
or polychlorodibenzodioxins (eqn.3)
OH
I
?
d + HCI (4)
+clQ
I
CI
1) Red
2) -HC1
or polychlorodibenzofurans (eqn.5)
135
and polychlorohydroxydiphenyls (eqn. 6)
O OH OH
C1 CI ~~/C1 9 C l ~
+ ~ + HC1 (6)
C1 k~.,.OH
C1
To verify these hypotheses, we have successive by performed the following actions :

- synthesising polychlorinated gem-dichlorocyclohexadienones ;
- developing a method of analysis enabling characterization and quantitative analysis
of the products ;
- d e m o n s t r a t i n g that polychlorinated gem-dichlorocyclohexadienones existed within
chlorination reaction masses, and establishing how the formation of gem-
dichlorocyclohexadienones and that of polychloro by-products were correlated ;
- examining the reactivity of polychlorinated gem-dichlorocyclohexadienones.
SYNTHESIS OF POLYCHLORINATED GEM-DICHLOROCYCLOHEXA-

DIENONES
Polychlorinated gem-dichlorocyclohexadienones can be obtained through the
action of t-butyl hypochlorite (ref. 7), hypochlorous acid (ref. 8) or chlorine in
acetic acid (refs. 9, 10) with a chloro phenol.
OH O O
1 I
C1 C1 C I ~ C 1 CI C1
(7)
ch ch
c1 c1
+ tBuOC1 + tBuOH
n=0.1 or2
The methods described by P. SVEC (ref. 6) enabled us to prepare

2,4,4,6-tetrachlorocyclohexa-2,5-dien- 1-one 2, 2,3,4,4,6-pentachlorocychlohexa
136
2,5-dien- 1-one 3, 2,3,4,4,5,6-hexachlorocyclohexa-2,5-dien- 1-one and
2,3,4,5,6,6-hexachlorocyclohexa-2,5-dien- 1-one 5.
0 0 0 0
C1 C1 C1 CI C I ~ C 1 CI.~~C1
C1 CI"Ol./~.cI'CI~.. C1 C1
C1
2 3 4 5
ANALYSIS OF POLYCHLORINATED GEM-DICHLOROCYCLOHEXA-

DIENONES
As our aim was to bring to light the polychlorinated gem dichloro
cyclohexadienones, within chlorination reaction masses, one of the most important
parts of our study was to develop an efficient method of analysis capable of
detecting traces amounts of these intermediates.
The only items of interest to be found in the literature are those provided by P.
SVEC and coll. fiefs. 6, 11) using gas phase chromatography in c.c.m.. P. SVEC
and V. KUBELKA (ref. 11) observed that the polychlorinated gem-
dichlorocyclohexadienones were broken down in gas phase chromatography. This
result was confirmed in the laboratory by work performed on different gas phase
chromatography columns which showed almost quantitative reversion of the
polychlorinated gem-dichlorocyclohexadienones back to the initial state of
chlorophenol (eqn. 8). For this reason GPC cannot be used.
0 OH
C1 C1 C1 CI
G P C - 2 0 0 to 250 ~
(8)
C1
Some polychlorinated gem-dichlorocyclohexadienones were separated by

P. SVEC (6) using thin-layer chromatography on a silica plate with eluants of
hexane, cyclohexane, and benzene type. Using hexane as an eluant it was possible
to transpose this separation of elements to HPLC with a silica column (Fig. 3).
137
Column : HIBAR MERCK
Si 60 (5 u) ; L = 12.5 cm
Hexane eluant
t
N h m
\D Y)
*I /,
-
-.
?'
rr.
r-
..-.
Fig. 3. Chromatogram of the separation of polychlorinated gem-dichlorocyclohexadienonesand

gem-dichlorocyclohexenones with silica column
138
These separation conditions proved difficult to handle, especially for
chlorination masses, since the large quantities of chlorophenols introduced caused
the base line to shift rapidly. This resulted in any quantitative analysis being
impossible.
These circumstances obliged us to research into other conditions using HPLC.
We observed that the polychlorinated gem-dichlorocyclohexadienones were eluted
(Fig. 4) when placed under the conditions that we used to quantitatively analyse the
chlorophenols, but unfortunately the retention periods were interfering with those of
the chlorophenols (Fig. 5).
139
,.j],
"el-
.,...,
7,
*'2. i
-...
*. :21
r.
- r, !
u-.
--. ~.~
I-- i.-.,
~4
,2.-, L.L.I
,-,-, L , J J C':,CI
r'_L~_ ~ i.."~- ." L"-: ".'-'

I
(..-_"
o- -o
,2,-_. ,--, ,.,

;'%
~-" "2".
k - J L.~
9 .,:-- :-~
P.-..4
_.,
Fig. 4. 2,4,4,6-Tetrachlorocyclohexa-2,5-diene-l-one on coiunm R.P. 18

e l u a n t methanol- acetate buffer pH 4.1 (78.22)
140
,.j],
"el-
.,...,
7,
*'2. i
-...
*. :21
r.
- r, !
u-.
--. ~.~
I-- i.-.,
~4
,2.-, L.L.I
,-,-, L , J J C':,CI
r'_L~_ ~ i.."~- ." L"-: ".'-'

I
(..-_"
o- -o
,2,-_. ,--, ,.,

;'%
~-" "2".
k - J L.~
9 .,:-- :-~
P.-..4
_.,
Fig. 4. 2,4,4,6-Tetrachlorocyclohexa-2,5-diene-l-one on coiunm R.P. 18

e l u a n t methanol- acetate buffer pH 4.1 (78.22)
140
Because similar retention periods are used for some chlorophenols and
polychlorinated gem-dichlorocyclohexadienones a problem of peak times was
created and it was necessary to use a double detection method enabling
differentiation of both products. In order to obtain the best possible sensitivity and
specificity for the polychlorinated gem-dichlorocyclohexadienones, we opted for
electrochemical detection based on reduction of gem-dichlorocyclohexadienones at
an imposed potential o f - 0 volt (Fig. 6).
,.C1
0 O" 00
C1 C1 C1 C1 C1 C1
~ ~ + C1| (9)
C1 C1
C1| + 2 e- ~~. C1| (10)
The chlorophenols, cyclohexadienones, benzoquinones and chlorophenoxy-

phenols are analysed using UV detection. Simultaneous electrochemical detection
enables specific analysis of electro active compounds in reduction.
This analytical technique proved to be very efficient as only one injection
provided us with all the required information on the composition of the reaction
masses.
142
8.67 - 2 , 3 , 6 - T r i c h l o r o p-benzoquinone 15.92- 2,3,4,4,6-Pentachlorocyclo
9.95 - Chloranil hexa-2,5-dien-l-one
11.48 - 2,4,4,6-Tetrachlorocyclohexa- 18.33 - 2,3,4,6-Tetrachlorophenol
2,5-dien-l-one 19.67 - Pentachlorophenol
14.14- 2,4,6-Trichlorophenol
~i!j;I ~ r.
9o
<>
~
~
.--. .
"~
-
. . .
.-,
"
. .
:,
7.
,i
.
" 9 r.~,
..'~ ..,-"
'i
, !
- "i.
Fig. 6. Benzoquinones, cyciohexadienones and phenols mixture in UV and electrochemical

detection
143
The limit of detection of polychlorinated gem-dichlorocyclohexadienones by
HPLC using equipment fitted with a double detection system, UV and
electrochemical, is approximately 0.01% in a synthetic chlorophenol mixture.
D E T E C T I O N OF POLYCHLORINATED GEM-DICHLOROCYCLOHEXA-
DIENONES WITHIN THE CHLORINATION MASS
Since the analytical method we used enabled us to detect down to 0 . 0 1 % of
polychlorinated gem-dichlorocyclohexadienone in a chlorophenol mixture, we were
able to detect this compound in a chlorination reaction mass. This confirmed some
of the assumptions we had made when we started work on the subject.
Detection of the polychlorinated gem-dichlorocyclohexadienones was performed
by means of numerous tests and only one example of the chlorination of
2,4,6-trichlorophenol in the presence of A1C13 (ref. 12) is described below :
OH OH
C1 CI
MC13 ~ C1 i1
+ C12 (11)
1
C1 C1
2,4,6-Trichlorophenol and A1C13 are heated to a temperature of 100~ Then

chlorine is introduced at the rate of 5 1/hour. Samples of the product are taken at
the following times : corresponding to each of the respective, introduced quantities
of chlorine :
164.6 mM (equivalent 0.5)
329.2 mM (equivalent 1)
658.4 mM (equivalent 1.5)
987.6 mM (equivalent 2)
The formation of 2,4,4,6-tetrachlorocyclohexa-2,5-dien-l-one is observed from

the very first sample.
Formation of dichlorobenzoquinone, trichlorobenzoquinone, tetrachloro-phenol
and polychlorinated phenoxyphenols is also observed (Fig. 7).
144
0
c
0
.L(
a
m
N
C
m
0
I
!
I
,
Fig. 7. Chromatogram of the chlorination of 2,4,6-trichloropheno1 after introduction of 0.1 of

chlorine equivalent
145
During the 2,4,6-trichlorophenol chlorination process (Fig. 8), the concentration
of 2,4,4,6-tetrachlorocyclohexa-2,5-dien-l-one remains more or less constant while
a marked increase of other impurities is noted.
From these results, the following observations can be made :
-Chlorophenoxyphenols and other polychlorinated impurities were released when
the polychlorinated gem-dichlorocyclohexadienones were generated in the reaction
mixture. This fact confirms our hypothesis that polychlorinated gem-dichlorocyclo-
hexadienones are probably the cause of the parasite chemistry.
- The content of polychlorinated gem-dichlorocyclohexadienones remains
approximately constant afterwards, and this fact supports our assumption that
intermediates for the reaction with one or two chlorine atoms in meta position could
be used.
Whilst these initial results showed us that our assumption was correct, we still
had to demonstrate that the polychlorinated gem-dichlorocyclohexadienones, placed
under the conditions of the chlorination process, were capable of producing the
different products observed during the experiment. An in-depth study conducted on
the reactivity of the polychlorinated gem-dichlorocyclohexadienones confirmed
these facts.
146
During the 2,4,6-trichlorophenol chlorination process (Fig. 8), the concentration
of 2,4,4,6-tetrachlorocyclohexa-2,5-dien-l-one remains more or less constant while
a marked increase of other impurities is noted.
From these results, the following observations can be made :
-Chlorophenoxyphenols and other polychlorinated impurities were released when
the polychlorinated gem-dichlorocyclohexadienones were generated in the reaction
mixture. This fact confirms our hypothesis that polychlorinated gem-dichlorocyclo-
hexadienones are probably the cause of the parasite chemistry.
- The content of polychlorinated gem-dichlorocyclohexadienones remains
approximately constant afterwards, and this fact supports our assumption that
intermediates for the reaction with one or two chlorine atoms in meta position could
be used.
Whilst these initial results showed us that our assumption was correct, we still
had to demonstrate that the polychlorinated gem-dichlorocyclohexadienones, placed
under the conditions of the chlorination process, were capable of producing the
different products observed during the experiment. An in-depth study conducted on
the reactivity of the polychlorinated gem-dichlorocyclohexadienones confirmed
these facts.
146
REACTIVITY OF POLYCHLORINATED GEM-DICHLOROCYCLOHEXA-
DIENONES
Since 2,2,4,6-tetrachlorocyclohexa-3,5-dien-l-one changes very rapidly, when

in chlorophenol medium, to give 2,4,4,6-tetrachlorocyclohexa 2,5-dien 1-one
(eqn. 12), we deliberately restricted the scope of our study to only deal with this
last compound. This was because we wanted to avoid analysis of mixtures for which
the interpretation would have been very difficult.
0 0
Cl~....~C1 70~ C1 ,Cl
~ T ~ "C1 "~ (12)
trichlorophenol
C1
Thus we examined in turn :

- the intrinsic thermal stability of polychlorinated gem-dichlorocyclohexadienones,
-the thermal stability of polychlorinated gem-dichlorocyclohexadienones within

chlorophenols,
- the behaviour of polychlorinated gem-dichlorocyclohexadienones with acids,
-the action of water and chlorine on polychlorinated gem-dichlorocyclohexa-

dienones.
T H E R M A L STABILITY OF POLYCHLORINATED GEM-DICHLORO-

CYCLOHEXADIENONES
Literature does not provide any information on this subject. Before studying the
reactivity itself, it seemed important to us to know the range of temperatures which
could be used, by examining the basic thermal stability of these compounds
(Table 4).
Since a chlorination process takes 8 hours on average, we opted to use this time
period to perform all trials necessary to conduct the study.
148
Table 4. Percentage of polychlorinated gem-dichlorocyclohexadienonestransformed after heating
for 8 hours at different temperatures.
Temperatures
Cyclohexadienones Melting point 70~ 125 ~ 180~
O
C1y [~,CI
122 ~ 0 % 0 % 100 %
C1/ ~C1
C1 ,C1
112 ~ 0% 0% 100 %
xCl
0
C1 Cl
106 ~ 0 % 0 % 100 %
When heated throughout, polychlorinated gem-dichlorocyclohexadienones

remain stable up to a temperature of 150~ and do not produce the impurities
observed during the chlorination process.
At a temperature of 180~ the formation of polychlorodibenzodioxins is
observed with several break-down products.
149
Table 5. Amount of dioxins in ppm formed after heating polychlorinated gem-dichlorocyclo-
hexadienones for 8 hours at a 180~
0i
0 0
CI~ CI Cl~ c1
ci i
Dioxins
C1/ C1
Cl C I ~ ~C1 C
1,3,6,8-Tetrachlorodibenzodioxin 10 not detected not detected
2,3,6,8-Tetrachlorodibenzodioxin not detected not detected not detected
Pentachlorodibenzodioxins 16 1 3
Hexachlorodibenzodioxins 8 40 < 3
Heptachlorodibenzodioxins 50 1000 < 3
Octachlorodibenzodioxin 140 260 4200
THERMAL STABILITY OF POLYCHLORINATED GEM-DICHLORO-

CYCLOHEXADIENIONES IN CHLOROPHENOLS
Since polychlorinated gem-dichlorocyclohexadienones possibly formed during
the process of chlorination are in contact with chlorophenols, we determined their
stability in the presence of chlorophenols. This experiment was performed with
mixtures of 1 mM of polychlorinated gem-dichlorocyclohexadienonesand 10 m M of
chlorophenols heated for 8 hours at different temperatures.
Obtained results indicate the strong influence of the type of phenol and
polychlorinated gem-dichlorocyclohexadienones on the changes in reaction mixture.
This is the reason why we will distinguish : a) the process related to phenols
containing chlorine atoms with a 2.4.6 position from that b) of phenols containing at
least one hydrogen with a 2.4.6 position.
Process performed with chlorinated atoms with a 2.4.6 position

In the presence of 2,4,6-trichlorophenol, 2,3,4,6-tetrachlorophenol or penta-
chlorophenol no significant transformation of the cyclohexadienone 2 occurs when
performed at temperatures up to 150~ (refer to tables 4, 5, 6).
150
Table 6. Percentage of 2,4,4,6-tetrachlorocyclohexa-2,5-dien-l-one 2 transformed after heating
for 8 hours at different temperatures.
Melting point 70~

temperature 9 180~
Phenols
of phenol 125~
OH
c' 7c
65~ 2%
C!
OH
CI~,~ C1
114~ 4%
CV' ' ~ I~
CI
OH
CI.~ C1
173~ 4% 4% 100 %
Cl~'~~C1
CI
At 180~ 2,3,4,6-tetrachlorocyclohexa-2,5-dien-l-one 2 in pentachlorophenol

isomerizes to tetrachlorophenol 6 with a 75 % yield.
0 OH
C1 ,C1 180o C1 ,C1
(13)
Pentachlorophenol
C1
C1
2 6__
151
With pentachlorocyclohexadienone 3, we observe the same stability.
C1 C1
C1
Table 7. Percentage of 2,3,4,4,6-pentachlorocyclohexa-2,5-dien-l-one 3 transformed after

heating for 8 hours at different temperatures.
Temperatures
Phenols Phenol melting 70 ~ C 125 ~ C 180 ~ C

point
OH
Cl~/~]./CI
65 ~ 5 %
C1
OH
CI.~ /CI
114 ~ 3%
Cl
OH
CI~ CI
173 ~ 2% 2% 99 %
c1
When the process is performed at 180 ~ with pentachlorophenol, an exchange

reaction can be observed with 2,3,4,4,6-pentachlorocyclohexa-2,5-dien-l-one 3
leading to the formation of tetrachlorophenol and 2,3,4,4,5,6-hexachlorocyclohexa-
2,5-dien- 1-one _4.
152
Parallel to this reaction, an isomerization process of 2,3,4,4,6-pentachloro-
cyclohexa-2,5-dien-l-one 3 in pentachlorophenol _7 takes place.
Hexacyclohexadienone 4 i s even stable up to 180~ as indicated in the Table 8.
O
C I ~ C 1
CIcl cl'c1
Table 8. Percentage of 2,3,4,4,5,6-hexachlorocyclohexa-2,5-dien-l-one _4 transformed after

heating for 8 hours at different temperatures.
Temperatures
Phenol Phenol melting

70 ~ C 125 ~ C 180 ~ C
point
OH
C1 C1
65 ~ 2 %
CI
OH
114 ~ 2%
C1~
CI
OH
civic
CI.~ C
173 ~ 1% 2 % 2%
Cl
153
At first sight, polychlorinated gem-dichlorocyclohexadienones seem to have
thermal stability in the presence of trihalogenated phenols in 2.4.6 position. But
detailed analysis of the reaction mass - now possible thanks to the development of
the analytical method described above - shows that in all the cases a 3 to 15 %
formation of polychloro phenoxyphenols occurs. After heating for 8 hours at 70~
the 2,4,4,6-tetrachlorocyclohexa-2,5-dien-l-one 2 (lmM) in 2,4,6-tetrachloro-
phenol (10 mM), the following products : 2,4-dichloro 6-(2,4,6-tetrachlorophenoxy)
phenol 8 and 2,6-dichloro 4-(2,4,6-trichlorophenoxy) phenol 9 (Fig. 9) are detected
within the reaction mass.
~ 1JV
0
" ~ ' ~ . . . . CI~CI
: :.,,,: ~~,.~. ... . ...-..
----t
o g ~
- ' "~"': " . . . . . . . J CI~ "C!

.... _ .... ".-- " _ - J OH
CI ~ C I
C1
CI
CI"~Oc_ ~
CIHO CI
- o~ ~ ~ ~
CI CI
Fig. 9. Chromatogram of a mixture of tetrachloroclohexadienone 2 and 2,4,6-trichlorophenol

after being processed for 8 hours at a temperature of 70~
154
OH
C,o C, C1
oH C1
C1
CI 0
C1 C1 C1
C1
9 8
The formation of phenoxyphenols 8 and 9 at 70~ which was only observed

with the mixture of tetrachlorocyclohexadienone, 2,4,6-trichloro-phenol (Table 4)
seemed to be a transformation of the 2,4,6-trichlorophenol catalysed by
tetrachlorocyclohexadienone.
Table 9. Formation of phenoxyphenols after a heating for 8 hours, on different mixtures of

products.
0 OH CI~ CI C1
C1 0/ 7C1
Reactants
initial composition in % C1CI~C1CI c,
CI
O
0% not detected not detected
100 %
O OH
CICI~C1CI +CI~ ~CI

2% 9.6 % 6.4 %
CI
10,5 % 89,5 %
OH
7.c, not detected not detected
100 %
155
Phenoxyphenols 8 and 9 are the result of an attack by SN2 or SN' 2 of
2,4,6-trichlorophenol on cyclohexadienone 2 with intermediate formation of
polychlorophenoxycyclohexadienones 10 and 11.
0 (SN'2 OH
C1 I~C1 + C1 Cl
C1~ N/C
]--~~'~SN 2
2_ C1
(16)
0 0
CI~ /u,,. ~C1 C1 .C1 C1
C1 + ' 0 ~
]~ C1 C1 C1
1_!
C1
As a second step the polychlorophenoxycyclohexadienones 10 and 11 oxidise

2,4,6-trichlorophenol back to tetrachlorocyclohexadienone 2 and polychloro-
phenoxyphenols 8 and 9.
156
cl*cl
c1A
+
C1
-
11
+ “0c1 c1
-
Ci
3
c1
8
-
This mechanism shows the catalytic role of polychlorinated gem-

dichlorocyclohexadienone 2 explained in a different way. (Fig. 10)
157
OH 0
CI /CI
O
Cl Cl
9 / "~ - HCl
Cl C1 CC1~IO~
C1 C1 C1
Fig. 10. Catalytic process of the formation of polychlorophenoxyphenols
At temperatures up to 150~ for 7 hours, chlorophenols on their own do not

produce any chlorophenoxyphenols.
At the same temperature and time as above, polychlorinated gem-dichlorocyclo-
hexadienones do not produce any chlorophenoxyphenols and consequently are stable
products.
A mixture of 2,4,6-trichlorochlorophenol and polychlorinated gem-dichloro-
cyclohexadienones produces some polychlorophenoxyphenols.
A balance of this reaction indicates that the polychlorophenoxyphenols formed
are the result of the condensation of the two chlorophenol molecules.
Polychlorinated gem-dichlorocyclohexadienones have a catalyst function.
This very important result shows the essential part played by the polychlorinated
gem-dichlorocyclohexadienones in the parasite chemistry of the chlorination of
phenols.
Process performed with chlorophenols containing at least one hydrogen atom in

a 2,4,6 position
Apart from their greater reactivity, the behaviour of these chlorophenols with
polychlorinated gem-dichlorocyclohexadienones is close to that of trihalogenated
chlorophenols with a 2.4.6 position.
158
In this case too, the development of the mixture is a function of both the phenol
(number and position of the chlorine atoms) and the polychlorinated gem-dichloro-
cyclohexadienone.
Table 10. Percentage of transformed cyclohexadienones after heating 1 mM of

cyclohexadienones in 10 mM of phenol at 70~ for 8 hours.
% of transformed cyclohexadienones
O O
CI C1 CI~C1 C I ~ C I
Phenol
C1CI~-CI C1CI~-cfCI
--OH 100 % 100 % 53 %
C1
100% 15 % 7%
C I @ O H 100 % 100% 49 %
C1
10% 10% 6%
C1
CI
70 % 18% 7%
The reactivity of polychlorinated gem-dichlorocyclohexadienones decreases as

the number of chlorine atoms increases.
Most of the by-products formed during these reactions belong to the polychloro
phenoxyphenols category. This is shown in the following example with the
2,4-dichlorophenol.
159
0 OH C1 CI
C1 C1 C1
12 % yield
HO C1
2 C1 12
c1 C1
+ C1 27 % yield
C1
13
C1 C1
+ C1 6 % yield
9 el HO C1
C1 C1
8 % yield
8 C1 C1
C1
+ C1 OH 26 % yield
C1
The formation of the structures 12 and 13 is easily explained by the

condensation of SN 2 and SN' 2 of 2,6-dichlorophenol on tetrachlorocyclo-
hexadienone 2, via phenoxycyclohexadienones 14 and 15 (eqns. 19, 20).
2,4,6-Trichlorophenol is the result of an intramolecular transfer of the chlorine
according to the following equations "
160
.CI
0 OH OH
V " 0 ~ ~ 1 +
c1 Cl C1 Cl Cl Cl
1__4 1__2
0 OH OH OH
CI CI 1 C1 C1 CI
+ (20)
C1 C C1 0 CI
C 13 [
Cl
0 OH OH
C1 C1 1 C1
~ 2 (21)
2 el C1
The 2,4,6-trichlorophenol thus formed produces polychloro phenoxy phenols 8

and 9 through the process described in the previous section.
Equations 19, 20 and 21 show the capacity of 2,4-dichlorophenol to be
chlorinated by the ipso intermediates which results in consumption of
polychlorinated gem-dichlorocyclohexadienones. This explanation easily
demonstrates that phenols with a smaller amount chlorine appear to have the highest
reactivity.
As soon as they reach 70~ phenols with low chlorine content (phenol,
monochlorophenols, dichlorophenols) produce polychloro phenoxyphenols in the
presence of polychlorinated gem-dichlorocyclohexadienones. In this case there is
some consumption of polychlorinated gem-dichlorocyclohexadienones.
161
BEHAVIOUR OF P O L Y C H L O R I N A T E D GEM-DICHLOROCYCLOHEXA-
D I E N O N E S W I T H ACIDS
Chlorination of 2,4,6-trichlorophenol to tetrachlorophenol or pentaclorophenol
is usually performed with an acid (refs. 12, 13). For this reason it was important to
observe the reactivity of polychlorinated gem-dichlorocyclohexadienones in
chlorophenols in the presence of acids. To do this we studied the behaviour of a
mixture containing the following components at 70~ :
- 1 mM of a polychlorinated gem-dichlorocyclohexadienone
- 10 mM of a phenol
- 2 mM of acid
As the type of phenol used is mainly responsible for the formation of products,
we will distinguish - as we did for the thermal stability - trihalogenated phenols in
2.4.6 position, and phenols containing at least one hydrogen atom in position 2.4.6.
Process performed with phenols containing chlorine atoms with a 2.4.6.

position
In the presence of either a Lewis acid or a strong Bronsted acid, the main
reaction observed is the isomerization of polychlorinated gem-dichlorocyclohexa-
dienone to chlorophenols (eqns. 22, 23). 2,4,6-Trichlorophenol acts as a solvent in
this process.
0 OH
C1 C1 AIC13(2.5 mM) 70 ~ - 8 h ~ C I ~ / ~ C 1
Yield = - 90 % (22)
2,4,6-Trichlorophenol CI
(10 mM)
2 Cl
OH
C I ~ C 1 A1C13(2.5 mM) 70 ~ - 8 h
Yield =-~ 80 % (23)
2,3,4,6-Tetrachlorophenol E1~ C1
C%l.><Cl (10 mM)
C1
162
When performed under similar conditions, gaseous hydrochloric acid formed
during the chlorination process hardly creates any isomerization of polychlorinated
gem-dichlorocyclohexadienones to chlorophenols. This difference in reactivity
explains why it is necessary to use either a strong acid or a Lewis acid to reach the
tetra or penta stage.
The yield produced by isomerization varies according to the nature of the acid
used. This is shown in the table below :
Table 11. Reactivity of 2,4,4,6-tetrachlorocyclohexa-2,5-dien-l-one 2 in the presence of acid at

70~ and for 8 hours.
Yield relative to the introduced cyclohexadienone

O
Acid CI~ 7C! c,yyc, OH OH CI CI Cl
C!~" ~C1 ci~

_2
transformed%
without acid 2 % 1% 9,6 % 6,4 %
CF3SO3H 100 % 90 % 5,7 %
cH3~so3rt rho 72 % 25,3 % 1,5 % 15 %
H2SO 4 at 98 % l 100 % 14,5 % 0,8 % 7,5 %

HC10 4 at 70 % 100 % 1% 0,7 % 22 %
HC1 at 37 % 28 % 11,5 % 3,4 % 2,7 %
[A1C13 100 % 90 % 0,7 % 2,8 %
TIC14 99 % 90 % 7,4 % 6%
TiC13 50 % 2%
FeC13 100 % 85 % 2,9 % 11,6 %
The yield of the tetrachlorophenol, the nature and quantity of

chlorophenoxyphenols vary according to the type of acid used. A1C13 appears to be
the acid which produces the least parasite chemistry. This is confirmed by the
chlorination experiments performed indicating that, generally, A1C13 is the best
catalyst.
Trifluoromethanesulphonic acid does not produce any 2,4-dichloro
6-(2,4,6-trichlorophenoxy) phenol 9.
163
OH C1
I
c1 _9
This result can be of interest since this type of chlorophenol is a precursor of

polychlorodibenzodioxins.
According to the polychlorinated gem-dichlorocyclohexadienone and acid used,
the reaction mechanism is either intermolecular, or intramolecular.
Consequently the transformation of 2,3,4,4,6-pentachlorocyclohexa-2,5-dien-1-
one 3 (1 mM) in the presence of A1C13 (2.5 mM) in 2,4,6-trichlorophenol
(10 mM) leads to the formation of a unique product : 2,3,4,6-tetrachlorophenol. As
a whole, this process appears to be intermolecular.
0 OH
I I
c l ~ c 1 AIC13(2.5 raM) c1 c1
2 (24)
CI~I
" > ~ C 1 U" " 70~ 8hr C1
OH
CI
3 C1 C1
1.68 mM
intermolecular
(10 mM)
C1
The reaction starts off with chlorine transfer to pentachlorocyclo-hexadiene 3

with 2,4,6-trichlorophenol to produce some 2,3,4,6-tetrachlorophenol and
tetrachlorocyclohexadienone 2 (eqn. 25).
164
O OH OH 0
c, c, +Cl c, c, c, c,+ .Cl
(25)
CI~cI.~C 1 CU T
C1 C1
3 2
OH
C1 ,C1
A1Cl3
2
CI
CI
During the following step the cyclohexadienone 2 isomerizes to

tetrachlororophenol in an intramolecular way. This last point was perfectly
demonstrated by heating a mixture of tetrachlorocyclohexadienone 2 (1 mM) and
2,3,4,6-tetrachlorophenol (10 mM) in the presence of A1C13, at a temperature of
70 ~ for 8 hours.
0 OH OH
CI~CI+ CI~,/C1 A1C13 C1 CI
absence of penta-
chlorophenol (26)
(21/ "(21 CU T C1
2 C1 C1
As opposed to this, the transformation process of the same cyclohexadienone 3

(1 mM) under the same conditions with trifluoromethanesulphonic acid produces a
mixture of 2,3,4,6-tetrachlorophenol and pentachlorophenol, by intermolecular and
intramolecular processes.
OH OH
CI~CI CF3SO3H(2.5 mM) CI jCl?l~ [~Cl
2 (27)
70~ - 8 h CI CI~ CI
ClcI,,/~-Cl OH
CI CI
CI~CI
0.5 mM 0.67 mM
INTERMOLECULAR INTRAMOLECULAR
[ (10 mM)
CI
165
Results obtained can be explained by the following reaction mechanisms 9
OH OH
C! ~:~CI
-- cICI~~CI
CI
0 0......H|
~MOLECULAR
CIcI~C! CI - H+ CICI~CI CI (28)
x ~~
~,,,,,,,H
OH OH
CI CI~/CI+
Cl H CIl ~ C i CI _-
CU y C1/ y
CI CI CI
Fig. 11. Intramolecularand intermolecular mechanisms
To conclude, strong acids and Lewis acids transform polychlorinated gem-

dichlorocyclohexadienones in chlorophenols. Polychlorinated gem-dichlorocyclo-
hexadienones are true intermediates in the formation of chlorophenols that have one
chlorine atom in meta position of the OH.
According to the reaction system used (nature of the acid, of the polychlorinated
gem-dichlorocyclohexadienone, and of the polychlorophenol) either an
intramolecular migration of the chlorine (isomerization) or a intermolecular transfer
occurs.
- I n addition to the transformation of polychlorinated gem-dichlorocyclohexa-
dienones to polychlorophenols, formation of polychlorophenoxyphenols - in
quantities varying according to the acid used in the process - also takes place.
Process performed with chlorophenols containing at least one hydrogen atom in

a 2.4.6. position
When these chlorophenols are used to run the process, hardly any
transformation of polychlorinated gem-dichlorocyclohexadienones in chlorophenols
takes place.
166
O OH
C1 C1 Acid CI~ C1
X (28)
Chlorophenol containing at least c1
one hydrogen element in 2.4.6 C1
The products formed are mostly polychlorophenoxyphenols and polychloro

dihydroxybiphenyls, which are other families of by-products found in the
chlorination masses.
Polychloro dihydroxybiphenyls are mostly found with phenol and
o'-chlorophenol (eqns. 30, 31).
0 OH AICI3(2.5 mM) OH
Cl~/Cl + I~~..;.Cl or
CF3SO3H (2.5 mM)

CI,,.~C1
(29)
70 ~ - 8 h
"~ "C1
C1~ "CI 10 mM
C1
1 mM
Yield =2%
CI
+ CI ~ O H
HO CI C1
Yield = -~60 %
O OH A1CI3(2.5 mM) C1 C1
OF
CF3SO3H(2.5 raM)
+C I ~ ~ ~ - O H
70~ - 8 h (30)
cl Icl c + / \ 17
1 10 mM HO C1
1 mM Yield = - 40 %
3
Preparation and characterization of the biphenyls was performed using the

following technique.
167
CI
c1 c1
The formation of polychlorodihydroxybiphenylsis the result of a nucleophilic

attack on the protonated form of the cyclohexadienone (Fig. 12).
168
.H
o o~ O"
CI~ C1 -.. H+ ,._ C I. ' ~ ~ ,L, _ u C _I C1 C1
OH
OH
OH
1
OH
CI .C1
C1 /~"~OH
Fig. 12. Mechanism of formation of polychlorodihydroxybiphenyls
When the process is performed with 2,6-dichloro and 2,4-dichlorophenol,

polychlorophenoxyphenols formed as well as polychlorodihydroxybiphenyls
(eqn. 31).
169
cQcy$ NCI3 - 8h
70"(2.5mM) *
CI c1
1 rnM 10 rnM 0.94 rnM
OH
I
c1
0.04 mM
Cl
0.18 rnM
c1
0.45 mM CI
The formation of biphenyl 20 can be explained by the oxydation of 2,4-dichloro

phenol by 2,4,4,6-tetrachlorocyclohexa-2,5-dien-l-one2 (eqn. 32).
170
0 OH OH
C1 C1 CI CI C1
2 + 2 ~ 2 + 2 HC1 (32)
C1 C1 C1
2_
OH r/"~
C1 CI
+
c1 20
Fig. 13. Mechanism of formation of biphenyls 20
Polychlorinated gem-dichlorocyclohexadienonesin the presence of a strong acid

do not change into chlorophenols when processed in chlorophenols containing at
least one hydrogen atom in ortho or para position. The main products formed are :
polychlorophenoxyphenols and polychlorodihydroxybiphenyls.
REACTIVITY WITH WATER

P. SVEC (ref. 6) demonstrated that polychlorinated gem-dichlorocyclohexa-
dienones hydrolysed in halogenated benzoquinones.
O O
C1 C1 c1 c1
+ H20
(33)
Chlorinated benzoquinones are also a family of by-products produced during the

chlorination of heavy chlorophenols (trichlorophenols, tetrachlorophenols,
pentachlorophenols) (Fig. 13).
We observed that the quantity of benzoquinones formed is linked to the presence
of water contained in the reactants.
171
0 OH OH
C1 C1 CI CI C1
2 + 2 ~ 2 + 2 HC1 (32)
C1 C1 C1
2_
OH r/"~
C1 CI
+
c1 20
Fig. 13. Mechanism of formation of biphenyls 20
Polychlorinated gem-dichlorocyclohexadienonesin the presence of a strong acid

do not change into chlorophenols when processed in chlorophenols containing at
least one hydrogen atom in ortho or para position. The main products formed are :
polychlorophenoxyphenols and polychlorodihydroxybiphenyls.
REACTIVITY WITH WATER

P. SVEC (ref. 6) demonstrated that polychlorinated gem-dichlorocyclohexa-
dienones hydrolysed in halogenated benzoquinones.
O O
C1 C1 c1 c1
+ H20
(33)
Chlorinated benzoquinones are also a family of by-products produced during the

chlorination of heavy chlorophenols (trichlorophenols, tetrachlorophenols,
pentachlorophenols) (Fig. 13).
We observed that the quantity of benzoquinones formed is linked to the presence
of water contained in the reactants.
171
REACTIVITY WITH CHLORINE
Chlorine reacts with polychlorinated gem-dichlorocyclohexadienones to produce
polychlorinated cyclohexenones (ref.6) (eqns. 34, 35).
O O
+ C1 ~ C (34)
C1 l i ~
Clcl.><cl'cl c cl
O O
CI~C1 CI~/~/C1
/ ~ C 1 + C12 ~ Cll~fl - - / ~ C 1 (35)
C1 C1 C1~ ~ C1
C1 C1
We were able to detect and segregate the polychlorinated cyclohexenones from

the chlorination reaction masses.
o O o
CI~C1 Cl~.~/C1 CI~/~/C1
C1 C C1 C1~ "~ "C1

C1 C1
This action again confirms the essential part played by the polychlorinated gem-
dichlorocyclohexadienones in the parasite chemistry.
CONCLUSION
The development of an efficient analytical method enabled us to detect the
presence of polychlorinated gem-dichlorocyclohexadienones in chlorination reaction
masses.
An in-depth study conducted on reactivity demonstrated that polychlorinated
gem-dichlorocyclohexadienones had a very high degree of reactivity (Fig. 14), but
above all explained how the mechanisms related to these compounds - which may
have sometimes a catalytic quality - worked.
173
REACTIVITY WITH CHLORINE
Chlorine reacts with polychlorinated gem-dichlorocyclohexadienones to produce
polychlorinated cyclohexenones (ref.6) (eqns. 34, 35).
O O
+ C1 ~ C (34)
C1 l i ~
Clcl.><cl'cl c cl
O O
CI~C1 CI~/~/C1
/ ~ C 1 + C12 ~ Cll~fl - - / ~ C 1 (35)
C1 C1 C1~ ~ C1
C1 C1
We were able to detect and segregate the polychlorinated cyclohexenones from

the chlorination reaction masses.
o O o
CI~C1 Cl~.~/C1 CI~/~/C1
C1 C C1 C1~ "~ "C1

C1 C1
This action again confirms the essential part played by the polychlorinated gem-
dichlorocyclohexadienones in the parasite chemistry.
CONCLUSION
The development of an efficient analytical method enabled us to detect the
presence of polychlorinated gem-dichlorocyclohexadienones in chlorination reaction
masses.
An in-depth study conducted on reactivity demonstrated that polychlorinated
gem-dichlorocyclohexadienones had a very high degree of reactivity (Fig. 14), but
above all explained how the mechanisms related to these compounds - which may
have sometimes a catalytic quality - worked.
173
All the products formed from polychlorinated gem-dichlorocyclohexadienones in
the presence of chlorophenols are indeed those identified in the chlorination of
phenol.
These results confirm our hypothesis, and prove the essential role of
polychlorinated gem-dichlorocyclohexadienonesas reaction intermediates which can
react to give either noble products (chlorinated phenols in meta), or unwanted
condensation products (polychloro phenoxy phenols, polychloro dihydroxy
biphenyls, etc.).
Improvement of the quality of chlorophenols implies that the chemical evolution
of the polychlorinated gem-dichlorocyclohexadienones is controlled during the
chlorination reaction.
References
1. Kirk Othmer Encyclopedia of Chimical Technology Third Edition, John Wiley, Wol. 15,
p. 916 ; vo1. 13, p. 39, Ed. 1981 ; vol. 5, pp. 797, 1979, (1981).
. Cahier de notes documentaires, 99, 243, (1980).
3. Chlorodioxins - Origin and Fak., p. 55, Advances in chemistry series - American Chemical
Society.
. M. Kulka - Can. J. Chem., 39, 1973, (1961).
5. H.I. Joschek, S.I. Miller, J. Amer. Chem. Soc., 88 (14), 3269, (1966).
6. J.R. Plimmer, U.I. Klingebiel ; Science, 174, 407, (1971).
7. P. Svec, Th6se Pragues, (1973).
8. H. Miiller, H. Linde, J. Prakt. Chem., 4 (5), 77, (1957).
9. R. Fort, Ann. Chim., 13 (4), 203, (1959).
10. P. Svec, M. Zbirovsky, Collect. Czech. Chem. Comm., 4_9_0(10), 3029, (1975).
11. P. Svec, V. Kubelka, Fresenius Z. Anal. Chem., 277 (2), 113, (1975).
12. Monsanto, US 1213090 (1969), (to Monsanto).
13. JA 61' 7017 (1958), (to Toyana Chemical Industry Company).
175
DIASTEREOSELECTIVE HALOGENATIONS
P. DUHAMEL
Universit6 de Rouen, URA C.N.R.S 464 et I.R.C.O.F.

76821, Mont-Saint-Aignan Cedex, France.
INTRODUCTION
Diastereoselective halogenations using removable chiral auxiliaries have been
the purpose of recent significant developments, a-Halo aldehydes, or-halo ketones
and c~-halo carboxylic acid derivatives are very useful precursors involved for total
syntheses of pharmaceutical drugs and phytochemicals. In most cases, the biological
activity is associated with one of the two enantiomers. So, diastereoselective
halogenation of carbonyl compounds and carboxylic acid derivatives has attracted
considerable attention in recent years, as a tool for the production of
enantiomerically pure substances. The numerous examples of diastereoselective
halogenation of compounds with non removable chiral adjuvants are outside the
scope of this review.
ASYMMETRIC HALOGENATION OF KETONES VIA ENAMINES OF L-

PROLINE ESTERS
K. Hiroi and S.I. Yamada have reported for the first time, in 1973, the
asymmetric synthesis of ~ halo ketones by the diastereoselective bromination of
~-enamines of L-proline esters (ref. 1). Thus cyclohexanone was converted, via its
enamine, to the (R)-2-bromo cyclohexanone (Fig. 1).
176
0 ~'~COOEt COOEt
'
H
I Br2,
CHC13, -15~
~ ..Br
" (R) .., Aq. HC1 / benzene
Br-~,
~COOEt
.Br(R)
ee% :37
yield from cyclohexanone : 47 %
Fig. 1. Asymmetric synthesis of (R)-2-bromo cyclohexanone
ASYMMETRIC HALOGENATION OF KETALS DERIVED FROM

TARTARIC ACIDS ESTERS
Asymmetric halogenation of chiral acetals has been realized by C. Giordano
(refs. 2-7). Using alkyl esters of optically active tartaric acids as chiral auxiliaries, a
high diastereoselectivity is obtained even at room temperature. The results are best
explained by a fast electrophilic addition of bromine on the electron rich enol ether,
originating from an acid-catalyzed equilibrium with the chiral acetal. If (2R, 3R)-
tartaric acid is involved, a S-configuration prevails at the new stereogenic center.
Finally, cautious hydrolysis provides a set of 2-bromo alkyl aryl ketones, which can
be obtained in enantiomerically pure form after crystallization (Fig. 2) :
177
MeOOC COOMe MeOOC COOMe
H+
0 0 O_ OH
Ar~X~ Ar~
Me Me
Br2; CC14" 15~
MeOOC COOMe
O
1~ H20, CH3SO3H, 20~
Ar S) 0 0 Br
2 ~ Crystallisation
Me Ar~(s)
ee% > 9 8 Me
64 < de % < 88
90 < yd % < 98
Ar"
X = H, Me, iBu, C1
Fig. 2. Synthesis of enantiomerically pure 2-bromoalkyl aryl ketones
The diastereomeric ratio is only slightly affected by change of solvent (ref. 3)

(Table 1).
178
Table 1. Solvent effect on the diastereoselectivity of the bromination
MeOOC COOMe MeOOC COOMe
0 0 0 0
Br2 ~ ~ B r
"- (s)
Me
MeO MeO
Temp. Reaction
Solvent (of) Yd % De %
time (h)
Ethyl acetate - 10 8.5 89 88
Toluene - 10 2.5 88 86
Carbon tetrachloride - 10 2.0 98 86
Carbon tetrachloride + 15 1.0 98 84
Dichloromethane - 10 1.0 96 80
Owing to the simplicity, selectivity and economy of this new procedure, the c~-
bromo alkyl aryl acetals have been proposed as starting materials for the industrial
production of some 2-aryl propionic acids such as the important pharmaceutical
drugs, Ibuprofen and Naproxen. For instance, the preparation of enantiomerically
pure Naproxen has been carried out, in one step, by means of the highly
stereoselective Lewis acid catalyzed rearrangement of a starting a-bromo acetal,
involving a 1,2-aryl shift (ref. 3) (Fig. 3) :
MeOOC COOMe
0 O~ Ag+
Br" 1~ Ag+BF4- COOH
2~aq.HCl, 85~ M e O ~
MeO
ee% >98 Enantiomerically pure
NAPROXEN
yield 993 %
Fig. 3. Synthesis of Naproxen
179
ASYMMETRIC HALOGENATION OF CARBOXYLIC ACIDS
DERIVATIVES PREPARED FROM C A M P H O R - 1 0 - S U L F O N I C ACID
In the same way as enantiomerically pure ~-halo ketones, o~-halo esters have
been prepared in high diastereomeric excesses by asymmetric halogenation of silyl
ketene acetals generated from chiral esters 9So, a successfull procedure was first
introduced in 1985, by W. Oppolzer (refs. 8,9), using derivatives of camphor-10-
sulfonic acid as chiral auxiliaries (Fig. 4).
Si
O "',, R2 R2 X
H NXS
O
2 ~ LDA, TMSCI H
SO2NR12 OTMS
84 < crude de% < 96

68 < crude yield % < 91
R1- cyclohexyl
R2" Me nBu Ph iBu nCsH17 After crystallisation 9
X 9 CI C1,Br C1 Br C1, Br de% > 96
54 < yield % < 77
Fig. 4. Asymmetric halogenation of silyl enol ethers derived from camphor-10-sulfonic acid
esters.
The results, c~-halo esters of (S) configuration, are consistent with an

electrophilic addition of the "halonium" on the less hindered Si face of the 13-
carbon of the keten acetals. Obviously, a-halo esters with (R) configuration are
obtained if the antipode of the aforementioned chiral auxiliary is used. It is
noteworthy that this procedure not only affords crude a-halo esters in high
diastereoisomeric excess but, allows, by a simple crystallisation, to obtain them, in
quantitative diastereoisomeric excess.
Similarly, using bornane [10,2] -sultam as a chiral auxiliary, provides, via the
bromination of the intermediate boryl enolates, an alternative route to
diastereoisomerically pure a-halo esters (ref. 10) (Fig. 5) :
180
R
NO ~ Bu2BOTf . ~ NBS ~ R ~i
EtNiPr2 R THF,-78~ N Br
" CH2C12,-5~
O
85 < de% < 100
Fig. 5. Asymmetric bromination of boryl enolates of bornane-10,2-sultams
These diastereoisomerically pure derivatives were not converted in free a-halo

carboxylic acids, but transformed into halohydrins, terminal epoxides (ref. 8) and
c~-amino acids (refs. 9,10).
ASYMMETRIC HALOGENATION OF CHIRAL IMIDE ENOLATES

Asymmetric halogenation of carboxylic acid derivatives has also been achieved
by D.A. Evans (refs. 11,12) via chiral N-acyl oxazolidones. For instance, an N-
acyl oxazolidone prepared by acylation of the (4S)-benzyl-2-oxazolidone chiral
auxiliary derived from (S)-phenylalanine, is converted to its (Z)-dibutyl boron
enolate, which is added to a NBS slurry, at low temperature (Fig. 6) :
0 ~.~NH
O O
O
.o R Bn
\ (
Bn
Bu2BOTf,
iPr2NEt,
CH2C12, -78~
Bu\ / Bu
O O o/B~o
NBS
CH2C12 -78~
\ (,
Bn
Br \(
Bn
88 < de % < 92 R : Ph-CH2, iPr, iPr-CH2; tBu; allyl
Fig. 6. Asymmetric halogenation of chiral imide enolates.

181
The sense of asymmetric induction is consistent with an electrophilic
bromination of the Si face of the boron enolate, yielding an c~-halocarboximide of
(S) configuration and displaying a high level of diastereoselectivity.
The c~-halo carboximides are not hydrolyzed to free carboxylic acids, but
converted to c~-amino acids, by a procedure implicating the involvement of
intermediate a-azido carboximides (refs. 11,12).
ASYMMETRIC HALOGENATION OF KETENE ACETALS DERIVED

FROM ESTERS OF D-(+)-GLUCOSE DIACETONIDE
Finally, free G~-chloro acids have been prepared in high enantiomeric excess by
chlorination of silyl keteneacetals using D-(+)-glucose diacetonide as chiral
auxiliary (refs. 13,14). The most outstanding features of this very efficient chiral
auxiliary are the cheapness, and the easy hydrolysis of the final G~-halo esters, that
allows the removal of the chiral auxiliary under nonracemising conditions :
moreover, this compounds is non toxic and is commercially available.
According to the usual procedure, the carboxylic esters of D-(+)-glucose
diacetonide are converted into silyl ketene acetals. The chlorination by N-chloro
succinimide (NCS) carried out in THF, at low temperature, provided ~-chloro
esters, with a high diastereoselectivity. Hydrolysis without racemization to the free
~-chlorocarboxylic acids is best realized either in acidic conditions (aq. HC1), or
using LiO2H. With the first method, the chiral auxiliary is also hydrolyzed,
nevertheless it can be recovered undamaged in quantitative yield using the second
method instead (Fig. 7) :
182
C1
R(S)~ OH
~ J OH O
R i i
"~ 85 < ee % < 95
O 66 < yield % from 1 < 79
R 9Me, Pr, iPr, nBu, tBu...
LiOOH
/
O TMSO
o oJ.v~ ,~ o
~O---~ ] LDA, C1SiMe3 ...~O. O R NCS
~'O~o/..~. ~ THF, - 70~ THF, -70~ ~.O.O O
,o.)__
1 E 990-100 % 85 < de % < 95
Fig. 7. Asymmetric halogenation of silyl ketene acetals derivated D-(+)-glucose diacetonide.
It is noteworthy that the level of the enantiomeric excess and the configuration
of the a-chloro esters, were found to be not affected by the double bond
configuration. Thus, with the same chiral auxiliary, i.e. D-(+)-glucose diacetonide,
the electrophilic attack proceeds always on the same Si-face of the silyl ketene
acetal whatever the E or Z configuration of the starting material (Fig. 8).
TMSO
TMSO
Me
O--- ot O..~
1 ~ NCS
2 ~ LiOOH
~ HO ,
(~1
Me 1~ NCS
2 ~ LiOOH
\
~
O ee'90 %
Z E
Fig. 8. 13-Controlled diastereoselective chlorination
183
At this stage, we have to answer the question : what happens if an c~-chloro acid
of (R) configuration is desired instead of an (S) one ? According to the Latent
Trigonal Center (L.T.C.) Concept (ref. 15) (Fig. 9 bis) asymmetric additions
belong either to a-controlled or to 13-controlled reactions. In the first group (or-
control), using the same chiral auxiliary, just changing the configuration of the
starting enolate from E (or Z) to Z (or E) is enough to obtain a final product of
opposite configuration. In the second group (13-control), asymmetric additions on
enolates carried out with the same chiral auxiliary, lead to a final product of same
configuration whatever the E or Z configuration of the double bond (Fig. 9). In this
last case, availability of the two enantiomers of the chiral auxiliary is required, if
the two final products of opposite configuration are wanted.
C1+ C1+
C1
-~'cMe
H O2R*
(E) (E)
C1+ C1+
C1
-~
Me~CO2R*
(Z) (Z)
13-Controlled Chlorination a-Controlled Chlorination
The E and Z isomers lead The E and Z isomers lead
to the same isomer to different isomers
Fig. 9. Latent Trigonal Center (L.T.C.) concept (ref. 15)
184
LATENT TRIGONAL CENTER (LTC)
CONCEPT
(P. DUHAMEL)
or-control 13-control
Z and E lead to Z and E lead to
different the same
enantiomers enantiomer
a and/or b = electrondonating groups; c, d = H, substituents: e = electrophilic species
185
Obviously, the chlorination of silyl ketene acetals belonging to the group of 13-
controlled asymmetric additions, it is necessary, if a-chloro acids with (R)-
configuration are wanted, to operate with the chiral auxiliary of opposite
configuration, i.e., the very expensive L-(-)-glucose diacetonide. Whenever it
occurs that the mirror image of a very cheap natural product is a very expensive
molecule, as for instance L-(-)-glucose, it sounds like a good idea to look for its
unnatural but cheap "chiral equivalent". Thus, it was shown in preliminary studies,
that the furanic oxygen, and the two oxygenated functions in 1,2 positions of D-
(+)-glucose diacetonide are not essential for the efficiency of this chiral auxiliary.
Therefore, the very expensive L-(-)-glucose diacetonide required for the asymmetric
synthesis of (R)-a-chloro acids, can be successfully replaced by a simple
enantiomerically pure molecule synthesised from cyclopentanone (ref. 16) (Fig. 10)
~ J
- 0
- 0 .-.O
i
S
Chiral equivalent of
D ( +)-Glucose diacetonide L (-)-Glucose diacetonide
L (-)-Glucose diacetonide
OH
HO OH
OH HO 0
D (+)-Glucose L (-)-Glucose
Fig. 10. Chiral equivalent of L-(-)-glucose diacetonide.
This partially undressed L-(-)-glucose behaves as the chiral equivalent of L-(-)-

glucose diacetonide affording ot-chloro propionic acid of (R)-configuration, with the
same enantiomeric excess (Fig. 11) "
186
TMSO O " O
OTMS
_
Memo H i
' (R)
c1 ! Cl
/.I i
NCS ee "90 % i ee-90 % ~-,~
NCS ~
\
o..).._
O .~
Fig. 11. Asymmetric chlorination using chiral equivalent of L-(-)-glucose diacetonide.
Finally, the lowest enantiomeric excess obtained with c~-chloro propionic acid
can be raised up to enantiomeric purity, by simply introducing a methylene group in
place of the oxygen atom in the 5-position (ref. 16) (Fig. 12) 9
TMSO
1o NCS, THF,-70~ HO ( S ) ~ / , Me
i
2 o LiOOH C1
X O CH2
\ o
ee 90 % > 99 %
Fig. 12. Improvement of the stereoselection by modification of the chiral auxiliary
References
1. K. Hiroi, S.I. Yamada, Chem. Pharm. Bull. (Tokyo), 21, 54 (1973).
2. G. Castaldi, S. Cavicchioli, C. Giordano, F. Uggeri, Angew. Chem. Int. Ed. Eng., 25,
259, (1986).
3. G. Castaldi, S. Cavicchioli, C. Giordano, F. Uggeri, J. Org. Chem., 52, 3018, (1987).
4. G. Castaldi, S. Cavicchioli, C. Giordano, A. Restelli, EP 217, 375, (1987), (to Zambon
S.p.a.).
5. G. Castaldi, S. Cavicchioli, C. Giordano, A. Restelli, EP 217, 376, (1987), (to Zambon
S.p.a.).
6. G. Castaldi, C. Giordano, Synthesis, 1039, (1987).
7. C. Giordano, L. Coppi, A. Restelli, J. Org. Chem., 55, 5400, (1990).
8. W. Oppolzer, P. Dudfield, Tetrahedron Lett., 26, 5037, (1985).
9. W. Oppolzer, R. Pedrosa, R. Moretti, Tetrahedron Lett., 27, 831, (1986).
187
10. W. Oppolzer, Pure Appl. Chem., 62, 1241, (1990).
11. D.A. Evans, J.A. Ellman, R.L. Dorow, Tetrahedron Lett., 28, 1123, (1987).
12. D.A. Evans, T.C. Britton, J.A. Ellman, R.L. Dorow, J. Am; Chem. Soc., 112, 4011,
(1990).
13. L. Duhamel, P. Angibaud, J.R. Desmurs, J.Y. Valnot, Synlett, 807, (1991).
14. P. Angibaud, J.L. Chaumette, J.R. Desmurs, L. Duhamel, G. PI6, J.Y. Valnot,
P. Duhamel, Tetrahedron : Asymmetry, in press.
15. P. Duhamel, L. Duhamel, C.R. Acad. Sci., 320 IIb, 689, (1995).
16. J.L. Chaumette, J.Y. Valnot, unpublished results.
188
ENZYMATIC HYDROLYSIS OF ADIPONITRILE INTO 5-CYANO
VALERIC ACID, AN INTERMEDIATE FOR NYLON 6
EDITH CERBELAUD a), MARIE-CLAUDE BONTOUX a), FLORENCE FORAY a),

DIDIER FAUCHER b), SOPHIE LEVY-SCHIL b), DENIS THIBAUT b),
FABIENNE SOUBRIER b), JOEL CROUZET b) AND DOMINIQUE PETRE a)

Technologie, 85 Avenue des Fr&es Perret, BP 62, 69192 Saint-Fons Cedex,
France.
b) Rh6ne Poulenc Rorer Gencell, CRVA/IBV, 13, quai Jules Guesde, B.P. 14,
94403 Vitry-sur-Seine Cedex, France.
An industrial process must be economic and safe for the environment. The
chemical hydrolysis of nitrile in acid is well known (ref. 1). Nearly all nitriles react
with either basic or acid catalysts, but considerable quantities of inorganic salts are
always produced as by-products. The only way to suppress these by-products is to
produce the ammonium carboxylate under neutral pH and then to recover the
ammonia by dissociation of the salt between the weak base and acid. Therefore, we
suggest the route shown in Figure 1.
Nrt3 ~'~"NH
[NYLON 6[
CN ~" CO2",NH4+ O
Adiponitrile Ammonium Caprolactame

5-cyanovalerate
Fig. 1. The chemo-enzymatic route for caprolactame
Apart from the neutral pH, a second challenge for the catalyst is to select the
cyano group of adiponitrile without affecting the one in ammonium 5-cyanovalerate
(CVA). For these two main reasons, mild conditions and chemo-selectivity, we
attempted enzymatic catalysis.
189
Microbial hydrolysis of organic nitriles has been found to proceed by two major
enzymatic pathways (see figure 2).
nitrile~ RCONH2
RCN I amidase
RCO2_,NH4+
Fig. 2. The two different enzymatic pathways for the hydrolysis of nitrile into ammonium
carboxylate.
The first pathway via the amide uses two different enzymes 9a nitrile hydratase
and an amidase, and in the second one, the nitrile is directly hydrolysed into
ammonium carboxylate by a nitrilase. When the enzymes are not pure, we often
discriminate between the two routes by using the amide, a substrate which is present
only in the first system.
If we focus on the enzymatic hydrolysis of adiponitrile, we find that the
literature contains references to a great number of strains producing these different
enzymes (Table 1).
Table 1: Strains hydrolysing the adiponitrile.
Micro-organisms Reference
Brevibacterium B222 Novo Industri (ref. 2)

Brevibacterium R312 Yamada et al (ref. 3) ; Galzy et al (ref. 4)
Fusarium oxysporum f. sp. melonis Godlust et al (ref. 5)
Fusarium solani MN7030 Kikuchi et al (ref. 6)
Pseudomonas sp. 13 Yanase et al (ref. 7)
Rhodococcus AK-32 Asahi Chem. (ref. 8)
Rhodococcus sp. CH5 Novo Ind. (refs. 9, 10, 11)
Rhodococcus sp. YK 196 Nissei K.K. (ref. 12)
Rhodococcus rhodochrous PA34 Nippon Mining (ref. 13)
Rhodococcus rhodochrous NCIB 11216 Gutman et al (ref. 14)
Rhodococcus rhodochrous K22 Yamada et al (refs. 15, 16)
Generally, the reaction products are not clearly identified and we cannot
evaluate the selectivity. However, in both Brevibacterium strains isolated by
P. Galzy, such an idemification was possible. With Brevibacterium R312, the CVA
is a kinetic product and the best yield is 50% with other by-products such as
190
adipamic acid and adipamide being formed (ref. 4). In a patent, Novo Nordisk
exemplified the hydrolysis of AdN in CVA using Brevibacterium B222 with a 90 %
yield (ref. 1).
With both these strains, the enzymatic system is composed of nitrile hydratases
and amidases. The nitrile hydratase gene of Brevibacterium R312 is cloned,
sequenced (ref. 17) and over expressed in Rhodococcus rhodochrous ATCC12674
(pKRNH2) (ref. 18). The best selectivity which can be hoped for with this nitrile
hydratase is 93 % (ref. 4). Moreover, the cyanovaleramide with its poor solubility
must not be accumulated and requires a biocatalyst with a superactivated amidase
activity. The nitrile hydratase is less stable than amidase and the biocatalyst with
these two enzymes would not be sufficiently robust for an industrial application.
Consequently, we looked for a nitrilase which removes the problem of
regulation between the two activities and give directly the CVA, a very soluble
product. To design this biocatalyst, we followed four different steps :
-finding the strains producing a nitrilase activity by microbiological screening
starting from samples of earth,
- selecting the best enzymes by purification and characterization,
-overexpressing the nitrilase activity in a recombinant strain using molecular

biology,
- improving the selectivity of the enzymes by mutagenesis.
RESULTS
Microbiological screening
The following screening which allowed isolation of the correct nitrilases was
initially designed to select enzymes degrading AdN into ammonium adipate (ADO).
As the slow steps of this reaction were generally the hydrolysis of ionic compounds
(ammonium adipamate (Adm) and ammonium 5-cyanovalerate), the sodium 5-cyano
valerate was used as a unique nitrogen source for the selection pressure. The
method of screening was very classical with four main steps "
1) enrichmem of earth samples with relevant strains in minimum liquid as an
unique nitrogen source using sodium 5-cyano valerate . The earth samples were
collected under peach, walnut, and almond trees and on different plants producing
nitrile compounds. After three or four days of culture, the micro-organisms were
collected and put again into the same fresh medium but with a higher CVA
concentration. Thereafter, the CVA concentration was increased six times.
191
2) At each step of enrichment, the micro-organisms were isolated in a Petri dish
using the medium A with 2 % agar-agar and then purified in the same medium.
3) To evaluate the strains that were isolated, each clone was cultivated in 3 ml
liquid medium A using 1.5 g/1 CVA. The cells were collected by centrifugation and
the pellets was added to 25 mM CVA and 50 mM pH 7 phosphate buffer. The best
ones, seventy strains, were thus selected.
4) To confirm the performance of these strains, their activities for the production
of AdO starting from CVA and AdN were measured and compared to those of
B r e v i b a c t e r i u m R312. The four best ones were identified and are listed in Table 2.
Table 2. Strains issuing from the microbial screening having the best activities for the
production of AdO starting from AdN and CVA.
Microorganisms Specific activities

(mole/h.kg dried cell)
AdN CVA
Brevibacterium R312 0,17 0,22
Comamonas testosteroni 2.9 1.6
Bacillus sp. 0.8 2.7
Brevibacterium sp. 0.2 0.4
Comamonas acidovorans 2.3 1.2
Common conditions 9T~ 25 9[AdN] = [CVA] = 50 mM 950 mM Phosphate buffer pH 7
The C o m a m o n a s NIl activities were determinated on AdN and four putative

intermediates 95-cyanovaleramide, CVA, adipamate and adipamide (Table 3).
Table3. Comamonas NIl activity on adiponitrile, ammonium 5-cyanovalerate, 5-cyano

valeramide, ammonium adipamate and adipamide
Conditions Specific activity

Substrate [nitrile] [driedcell]
mM (g/l) (mole/h.kg of DC)
Adiponitrile 50 3.4 8
Ammonium 5-cyano valerate 37 13 2.2
Common conditions 950 mM phosphate buffer pH 7 - T~ = 25.
During the AdN hydrolysis into adipate, the ammonium 5-cyanovalerate was the
unique intermediate product. Moreover, for the other compounds, no intermediate
was detected. These different kinetic data predicted a conversion of adiponitrile into
CVA catalysed by a nitrilase.
192
Putative nitrilase purification of Comamonas N i l
The purification steps were mainly carried out in 50 mM TrisHC1 buffer,
pH 7.5, 1 mM dithioerythrytol. At each step, the nitrilase activity of the fractions
was determinated at pH 7 and at 25 ~ in 10 mM phosphate buffer in the presence
of 10 m M adiponitrile. The protein concentration was determined by the
Commassie blue method. The protein pannel was analysed by SDS PAGE
(Phasystem pharmacia| The data from each of the steps are listed in Table 4.
Table 4. Purification of the nitrilase of Comamonas NIl
Activity Yield
Purification Step Vol. Protein total specific protein activity PF
(rnl) (mg) (kU) (U/protein mg) (%) (%)
1- Crude extract 61 920 62 68 100 100 1
2- Q Sepharose FF 130 250 47 190 27 76 2.8
,,
3- Gel filtration 36 27 56 2100 2.9 90 30

, , ,
4- Hydroxyapatite column 3 12 49 4100 1.3 79 60

5- Phenyl Superose 51 11 11 1000 1.1 18 15
6- Gel filtration 9 2.7 6.3 2300 0.3 10 34
7- Mono Q HR 5/5 2.9 1 1.2 1200 0.01 2 18
Abbreviations 9U gmole/h 9Vol volume 9PF purification factor
Apart from the nitrilase, two other enzymes were purified, a nitrile hydratase
acting on ammonium 5-cyanovalerate (ref. 19) and an amidase acting on adipamate
(ref. 20).These enzymes were separated on the Q sepharose fast flow column.
Consequently, the specific activity after the second step was due to the nitrilase
alone and would be higher than 9300 U/mg of pure nitrilase.
Taking the purified protein, the N-terminal sequence of 27 amino-acids was
determined by Edman automatic sequential degradation :
Met Lys Asn Tyr Pro Thr Val Lys Val Ala Ala Val Gin Ala Ala
1 5 10 15
Val Phe Met Asn Leu Glu Ala Thr Val Asp Lys Thr
16 20 25 30
193
A search of sequence libraries made it possible to find a 53 % identity with the
nitrilase of Klebsiella pneumoniae active on Bromoxynil (ref. 21).
The enzyme gave a single band of 38 kDa on SDS-PAGE and the native molecular
weight was 490 kDa by gel filtration corresponding to dodecameric protein. Among
the sixteen published nitrilases, 60 % have an average molecular weight of 550 kDa
with an average monomeric unit of 41 kDa.
The activity of the purified nitrilase was determined on differem nitriles at the
optimal pH of 4 but also at pH 7 for adiponitrile and ammonium 5-cyanovalerate
(Table 5).
Table 5. Specific activity of pure nitrilase on some nitriles
Substrate pH Relative activity

(%)
Adiponitrile 4 100
7 97
Ammonium 5-cyano valerate 4 22
7 1.5
5-Cyano valeramide 4 28
Acrylonitrile 4 23
Propionitrile 4 6
Benzonitrile 4 4
Common conditions 9acetate buffer 910 mM pH 4 " phosphate buffer 910 mM pH 7 9substrate
10 mM - T~ 25 9enzyme (step 6) 3 to 30 gg of protein/ml.
For the adiponitrile, the nitrilase activity was independam of pH and for
ammonium 5-cyanovalerate, the higher its ionic feature the worse the nitrilase
activity. Therefore, the chemo-selectivity of the nitrilase between adiponitrile and
ammonium 5-cyanovalerate was 64 % at pH 4 and 97 % at pH 7.
The nitrilase activities were determined for other dinitriles and compared to that
of adiponitrile (Fig. 3). For each compound, the chemo-selectivity was identical to
that obtained for adiponitrile.
194
Legend: Fumaronitrile (Fum) Succinonitrile (Nit)
Glutaronitrile (Glu) Adiponitrile (AdN)
Pimelonitrile (Pim) Azelaonitrile (Aze)
Sebaconitrile (Seb)
Fig. 3. Relative activities of nitrilase on dinitrile
Nitrilase cloning and overexpression of the nitrilase (ref. 22)

Briefly, the genomic DNA of Comamonas Nil was digested with several
restriction enzymes and analyzed by Southern blot using a 26 met probe synthesized
from a NH2-terminal sequence. The best signal without ambiguity was obtained
with an SstI-SstI fragment of about 4 kb. This fragment was cloned using pUC19
plasmid and the host strain, E. coli DH5c~. Two clones which had inserted, in both
orientations, the same fragment of about 4.1 kb were analysed in detail. The
nitrilase gene was carried by this 1194 bp insert and was sequenced (Fig. 3).
An analysis of the sequence obtained made possible an open reading frame of
1064 bp, called the nitA gene, coding for 354 residues corresponding to the
molecular weight of 38725 Da. This polypeptide comprises the NH2-terminal
sequence used to synthesize the probe, as well as three internal sequences
determined on tryptic fragments of the purified nitrilase.
Optimal expression of nitA was obtained by using the E. coli P trp and the RBS
of LcII gene to give the PXL2158 plamid. The E. coli TG1 (pXL2158) expressed a
heterologous protein (38 kDa) representing approximately 30 % of total proteins of
which only 10 % was found to be soluble.
The solubilisation of the nitrilase was greatly improved with the co-expression
of a E. coli GroE chaperone (ref. 23). For that, the plasmid pXL2035 was
constructed by cloning into the vector pDSK519, the 2.2 kb fragment containing the
groES and groEL genes coding for the two subunits of GroE. The E. coli
195
(pXL2158,2035) overexpressed the GroE which solubilizes the bulk of the nitrilase
expressed from pXL2158.
The activity of these different recombinant strains are listed in Table 6 and
compared to those of the wild Comamonas Nil.
ct=9~162 72
tgaggaagacagca, RTG RRR RRT TRT CCT RCR GTC RRG GTR GCR GCR GTG CRR GCT 12~
~ e t Lgs Rsn Tgr Pro Thr Ual Lgs Ual R l a R i o Ual Gin RIo 14
GCT CCT GTR TTT RTG RRT CTR O~O GCA RCR OTR GRT RRR RCT TOT RRO TTR RTR 102
Rio Pro Ual Phe Met Rsn Leu Olu Rla Thr Ual Rsp L~$ Thr C~s Ly$ Leu I l e 32
GCR GRR GCR GCR TCT ~TG gOC OCC RRG GTT flTC GGC TTC CCR GRR GCR TTT RTT 236
RIo Glu RI~ Rla Set Met Gly i l i a L~s Uai l l e GI~ Phe Pro O l u RIo Phe l i e 50
CCC GGC TRT CCR TRT TOG RTT TGG RCR TCR RRT RTG GRC TTC RCT GGR RTG RTO 290
Pro Gig Tg~ Pro Tgr Trp l i e Trp Thr Set Rsn Met flsp Phe Thr GI~ Met Met 60
TGG GCC GTC CTT TTC RAG RRT OCO RTT ORR RTC CCR RGC RRR GRR GTT CAR CRR 344
Trp R{a Ua| L~u Phe Lys ASh Rla l i e Otu l i e Pro Ser L~s G[u Ual Gin Otn 86
RTT RGT GRT GCT GC.R RRR RRG RRT OOfl GTT TRC GTT TGC OTT TCT OTR TCR GRG 398
l i e Set Rsp Rio Rla Lgs Lgs Rsn Gig UoI Tgr UoI C~s UoI Set UoI Set GSu 104
Rflfl GRT RRT GCC TCG CTR TRT TT6 RCG CRR TTO TOO TTT GRC COG RRT GOT RRT 452
Lgs Rsp Rsn R i o Set Leu Tgr Leu Thr Gin Leu TPp Phe Rsp Pro Rsn Gig Rsn 122
TTO RTT GGC RRO CRC RGO RRR TTC RRG CCC RCT ROT ROT GRR RGR OCT GTR TGG 506
Leu l i e Gig Lgs His Rrg L~s Phe L~s Pro Thr Set Set Olu Rrg Rla Ual TPp 140
GGR GRT GGO GeT OGR RGC RTG OCT CCC OTR TTT RRR RCR GRG TRT GGG RRT CTT 56e
Ofg Rsp Gig Rsp Gig S i r Met RIa Pro Ual P h i Lgs ThP Olu T~P Oly Rsn Leu 150
. . . .
ooG Go~ e r e c ~ o r o e TGG GRR CRT GCT CTC CCR TTR RRC RTT GCG GCG RTG GOC 614
01g 01g Le~IIIG~nC~s Trp Glu H i s Rla Leu Pro Leu Rsn t i e RIo Rio Met Gig 176
TCR TTG RRC GRR CRG GTR CRT GTT 6CT TCC TGG CCfl GCC TTC GTC CCT RRR GGC 668
Set Leu Rsn g l u Gin Ual H i s U=! Rla Ser Trp Pro Rla Phe Ual PPo Lgs Gig 194
GCR GTR TCR TCCRGR GTR TCR TCC flOC OTC TGT OCG TCT RCT flRT GCG RTG CflT 722
Ala Ual Set Ser Rrg UoI S i r S i r Ser UoI C~s R i a Ser Thr Rsn Rla Met H i s 212
CRG RTC RTT ROT CRG TTT TRC OCO RTC AGC RAT CRG GTR TRT GTA RTT RTG TCR 776
Gin l i e l i e S e t Gin Phi T~r RIo l i e Set Rsn Gin Uol Tgr UoI t l e Me~ Set 230
RCC FI~T CTC GTT GGC CRR GRC RTG RTT GRC RTG RTT GGG RRR ORT GRR TTT TCC 830
Thr Rsn Leu U=I Gig Gin Rsp Met l i e Rsp Me~ l i e GIV L~s Rsp Glu Phe Set 248
RRR RRC TTT CTR CCG CTT GOT TCT OGR RRC RCR GCG RTT RTT TCT RRC RCC GGT 884
Lgs Rsn Phe Leu Pro Leu GI~ Set Gig Rsn T h r R i o l i e l i e Set Rsn Thr Gig 256
ORG RTT TTG GCR TCfl RTT CCR CRR GRC GCG GRG GGR RTT GCT GTT GCR GRG RTT 038
Olu l i e Leu i l i a Ser l i e Pro Gin Rsp Rio Olu Gig I l l RIo Uol RIo Olu l i e 284
ORC CTT RRC CRR RTR RTT TRT GOR RRG TOG TTR CTG ORT CCC GCC GOT CRT TRC 992
~sp Leu flsn Gin l i e l i e Tgr Gig Lgs Trp Leu Leu flsp Pro RIo Gig H i s T~P 3~2
TCT RCT CCC GGC TTC TTR RGT TTG RCR TTT ORT CRG TCT ORR CRT GTR CCC GTR 1046
Set Thr Pro Gi~ Phe Leu Set Leu Thr Phe Rsp Gin Set Olu H i s Uol Pro Uol 320
RR~ RRR RTR GOT GAG CRG RCR ~ C CRT TTC RTC TCT TRT GRR GRC TTR CRT O~R 1100
L9$ LgS I10 O19 O(u Gin Thr Rsn His Phe t i e S e r ' T ~ r Olu Rsp Leu His Olu 338
GAr RRR RTG GRT RTG CTR RCG RTT CCG COG ~GG COC GTR GeE RCR GCG TGR tcgc 1155
~s~ L~s Met Rsp Met Leu Thr lie Pro Pro Rrg Fb-g Uol RIo Thr Rla 354
cgcctctcggggcg~tcggttgctgatagcca~r 1194
Fig. 4. Sequence of the nitrilase gene from Comamonas Nil
196
Table 6. Determination of the different recombinant strains expressing the nitrilase and their
control strains on ammonium 5-cyanovalerate and adiponitrile
Strain Substrate Activity

. . . .
Nature (g/l) (U/kg de DC)

Comamonas NIl 3,4 AdN 8
CVA 2,2
E. coli (pXL2035) 0.06 AdN
E.coli (pXL2158) 0,24 AdN 270
1,2 CVA 8
E.coli (pXL2158,2035) 0,06 AdN 1300
0,2 CVA 67
Common conditions 950 mM phosphate buffer pH 7 9T~ 25-28, [substrate] = 50 mM.

Abbreviations 9U moles of hydrolysed adiponitrile/h. 9DC dried cells.
The activities of recombinant strains have confirmed the intensities of the bands
on SDS-PAGE (data not shown). Compared to the wild strain Comamonas N I l , the
activity was 160 times higher on AdN and 30 times on CVA. The different ratio
between the rates on CVA and AdN was due to the presence of other enzymes
which catalyse the transformation of CVA into AdO. The chemo-selectivity of
recombinant strains was too weak to develop an industrial process.
Chemo-selectivity improvement of the nitrilase

The mutagenesis of the pXL2158 plasmid was carried out in vitro using a
mutagenic agent, the hydroxylamine which changes G,C into AT. The mutagenised
plasmids were re-introduced into E. coli (pXL2035). The resulting strains were then
screened in 96 well plates using a specific ammonia assay with Nessler's reactant.
Among the 560 clones, three of them had the same activity on adiponitrile and a
lower one on CVA compared to normal E. coli (pXL2158,2035). The nitrilases of
two mutant clones, 12D1 and 1F3, were purified and the measurements of KM and
Vm were carried out (Table 7).
197
Table 7. The kinetic constants, KM and Vm, of the mutant nitrilases
Kinetics constants Chemo-

Nitrilase AdN (pH7) CVA (pH5) selectivity
KM1 Vm 1 KM11 Vmll
(mM) (Us) (mM) (Us) (%)
wild type 4.1 2910 5 430 75
,, .
mutation 1F3 1.8 2500 1.2 8.6 99.3

mutation 12D1 8.8 3200 1. 6.6 99.5
mutation 12D land 1F3 4 500 nd 0.3 99.8
Common conditions 9AdN 100 mM phosphate buffer pH 7 , CVA 100 mM acetate buffer pH 5 9
T~ 25-28, [substrate] = 50 mM.
Abbreviation 9Us gmole of substrate/h.mg of protein 9chemo-selectivity
(VmI-VmlI)/(Vm I + Vm II)
Both mutagenised nitA, were sequenced. In each case, one mutation alone was
found.
Starting from both mutations, the double mutant was created by a site-directed
mutagenesis. The resulting enzyme was purified and characterised (Table 7). Its
chemo-selectivity was excellent but unfortunately the activity on adiponitrile was
lower.
A l l the r e c o m b i n a n t w h o l e cells p r o d u c i n g the d i f f e r e n t nitrilases w e r e e v a l u a t e d
for the hydrolysis rate on AdN and for its chemo-selectivity (Table 8).
Table 8. Activity of the whole cells producing the nitrilase and its mutants
Conditions
Strains Substrate Activity Selectivity
(nature) (g/l) (raM) (U/kg of DC) (%)
E. coli (pXL2158,2035) 0,05 AdN 2000 87
0,2 CVA 136
mutant 1F3 0,12 AdN 870 98
0,6 CVA 7
mutant 12D 1 0,13 AdN 970 99

0,7 CVA 7
double mutant 1F3-12D1 2,1 AdN 83 100
2,1 CVA 0
Common conditions " 50 mM phosphate buffer pH 7 " T~ 25-28 9[substrate] = 200 mM.
Abbreviation 9U mole of substrate/h 9DC dried cell
198
CONCLUSION
Using the different methods, it was possible to design an excellent catalyst for a
bulk product such as caprolactam. The first advantage of the biocatalysis in this
route is able to carry out this reaction at neutral pH. The second is to selectively
obtain the a,03-cyanoacid starting from the a,c0-dinitrile. No other type of catalysis
can do this.
For that, the following steps were carried out :
1- Finding a new enzyme by screening to transform directly the adiponitrile into
ammonium 5- cyanovalerate
2- Eliminating the other activities (nitrile hydratase and amidase),
3- Over-expressing the nitrilase,
4- Solubilizing the nitrilase
5- Improving its selectivity.
We can conclude that biocatalysis, which uses diverse sciences such as
microbiology, biochemistry and molecular biology, is a powerful method to design
a catalyst and not only for the high value compounds but for bulk chemical
compounds as well.
ACKNOWLEDGEMENTS
This work has been performed as part of -Bioavenir program ,, financed by
Rh6ne-Poulenc with the participation of the Minister for Research and Space, as
well as the Minister of Industry and Trade.
References
1. J. March in ,, Advanced organic chemistry ,,, third edition, J. Wiley & Sons, pp. 788-789,
New-York, (1985).
2. EP 178 106, (01/10/84), (to Novo Industri).
3. T. Nagasawa, K. Ryuno, H. Yamada, Biochem. Biophys. Res. Comm., 139 (3), 1305-1312,
(1986).
4. J.L. Moreau, F. Bigey, S. Azza, A. Arnaud, P. Galzy, Biocatalysis, 10, 325, (1994).
5. A. Godlust, Z. Bohak, Biotechnol. and Appl. Biochem., 11,581, (1989).
6. M. Kuwahara, H. Yanase, Y. Ishida, Y. Kikuchi, J. Ferment. Technol., 58 (6), 573, (1980).
7. H. Yanase, T. Sakai and K. Tonomura, Agric. Biol. Chem., 46, 2925, (1982).
8. JP 4-341185, (12/11/90), (to Asahi Chemical).
9. K. Ingvorsen, B. Yde, S.E. Godfredsen, R.T. Tsuchiya, CIBA Found. Symp., 140, 16-31,
(1988).
10. M.A. Cohen, J. Sawden, N.J. Turner, Tetrahedron Lett., 31 (49), 7223, (1990).
11. P. HOnicke-Schmidt, M.P. Schneider, J. Chem. Soc., Chem. Commun., 648, (1990).
12. Nissei Kagaku Kogyo JP 01074996, (16/09/87).
199
13. T.C. Bhalla, A. Miura, A. Wakamoto, Y. Ohba, K. Furuhashi, Appl. Microbiol.
Biotechnol., 37, 184, (1992).
14. C. Bengis-Garber, A.L. Gutman, Appl. Microbiol. Biotechnol., 32, 11, (1989).
15. I. Watanabe, Y. Satoh, K. Enomoto, Agric. Biol. Chem., 51 (12), 3193, (1987).
16. M. Kobayashi, N. Yanaka, T. Nagasawa, H. Yamada, J. Bacteriol., 172 (9), 4807, (1990).
17. J.F. Mayaux, E. Cerbelaud, F. Soubriet, D. Faucher, D. Pdtr6, J. Bacteriol., 172, 6764,
(1990).
18. EP 0502476, (04/03/91), (to Nitto chemical Ind. Co).
19. E. Cerbelaud, J. Crouzet, S. Levy-Schill, F. Soubriet, D. P6tr6, FR 93-09990 (10/08/93).
20. E. Cerbelaud, J. Crouzet, S. Levy-Schill, D. P6tr6, FR 93-1062, (27/01/93).
21. D. Stalker, WO 89-00193, (08/07/87).
22. S. Levy-Schil, F. Soubrier, A. M. Crutz-Le Coq, D. Faucher, J. Crouzet, D. P6tr6, Gene,
161, 15-20, (1995)
23. S.M. Hemmingsen, C. Woolford, S.M. Van der Vies, K. Tilly, D.T. Devenis, C.P. Georgo-
Poulos, R.W. Hendrix, R.J. Ellis, Nature, 333,330, (1988).
200
REAGENTS WITH TRIFLUOROMETHYL SUBSTITUENTS
HEINZ GUNTER VIEHE AND ZDENEK JANOUSEK
Laboratoire de Chimie organique, Bfitiment Lavoisier, Place Louis Pasteur 1,

B- 1348 Louvain-la-Neuve, Belgium.
INTRODUCTION
Reactivity or inertness from fluorine substitution 9The Electronegativity Effect

Fluorine substitution on carbon confers particular reactivity because of its
particular properties : Fluorine as the most electronegative element forms very
strong CF bonds which are sized to "cover" perfluorocarbons tightly.
Polytetrafluoroethylene (Teflon) is one practical example illustrating the exceptional
chemical and thermal stability of saturated perfluorocarbons in a sharp contrast to
explosive tetrafluoroethylene or to fluoroacetylenes.
The discovery that tert-butylfluoroacetylene oligomerised spontaneously (ref. 1)
could be explained by ground state destabilisation resulting from combining
electronegative sp-carbon with fluorine. The "Electronegativity Effect" (ref. 2)
produces maximal thermodynamic stability for substituents on carbon with
complementary polarity, whereas equal polarity generally leads to destabilisation
(Scheme 1, ref. 3).
F F F F
F ,
F (it F
F
F F
F
Scheme 1.
The high chemical reactivity of tetrafluoroethylene and also that of the safer
trifluorochloroethylene permits smooth thermal biradical [2 + 2] cyclodimerisation
or cycloadditions to C-C double or triple bonds. Useful fluorinated reagents are
obtained, such as the trifluorochloro-cyclobutene esters arising from more facile
201
cycloaddition to captodative (ref. 4) ~x-thioether-acrylates followed by oxidative
elimination of the thioether, rather than from propiolic esters in a single step (ref.
5).
COOR
COOR ~ S \ C O O R COOR
S--R F F F F F C1
F C1 F C1 F F
CF-~--CFC1
Scheme 2.
These "trifluorochloroethane-bridged" acrylates (or analogous tetrafluorocyclo-

butenes described below) combine the high reactivity of a strained and fluoroalkyl
destabilised double bond with unusual thermal stability towards ring-opening due to
the presence of fluorine atoms on sp3 carbon. Thermal ring opening to butadienes
(ref. 5) occurs only at -- 500 ~ also because of the Electronegativity Effect by
fluorine leading to destabilisation of the double bonds.
The fluorine-destabilised multiple bonds also add nucleophiles easier than their
chlorine analogs (ref. 6) and the direction of addition is opposite : From
nucleophilic alpha-addition to fluorine and beta to chlorine results the relative ease
of fluorine substitution inspite of the strong CF-bond, whereas the beta-adducts to
chloroacetylenes form triple bonds by c~-elimination and rearrangement (ref. 7,
Scheme 3).
r~
R~S 1
I
RS| RS|
Nucleophilic Halogen Substitution
via c~-Addition [3-Addition c~-Elimination
+ rearrangement
Scheme 3.
Fluorosubstitution on saturated (sp3) carbon confers polarity together with

chemical inertness and imparts lipophilicity, particularly by the CF 3- or Rf-group.
202
Therefore, the synthesis of reagents with CF3-substitution or generally with a Rf
group is a challenging problem which elicits much current interest.
In practice, CF3-groups are generally and industrially derived from CCI 3 by
exchange with HF under relatively harsh conditions according to the Swarts-
reaction which is most often applied to C 1-hydrocarbons themselves or to activated
CC13 groups next to carbonyl, vinyl or aryl moieties. This gives rise to CF 3-
substituted reagents themselves or to their derivatives such as shown in the
Scheme 4.
//o
C13C--Y C13C--C6H5 C I 3 C - -\ C C13C--CH--CH2
C1
//O
F3C~Y F3C~C6H5 F3C--C\ F3C--CH:CH2
F
Y = C1, SR, NR2, H

Reagents with a CF3-Substiment
C1 C1~Aryl C2~ C3~
Scheme 4.
CF3-substituted reagents may be classified according to their number of carbon

atoms. The C 1-reagents may furnish F3C-radicals, radical ions or ions. c2 reagents
containing a CF 3 group may readily be obtained from trifluoroacetic acid or its
aldehyde or alcohol.
This report describes mainly C2-C4 CF3-substituted reagents derived from
trifluoroacetic acid, trifluoroacetoacetate or from trifluoropropene. Several useful
C2 reagents with CF3-substitution were obtained from N-tertiary
trifluorothioacetamides as shown in the schemes to be detailed below. We have also
elaborated the chemistry of the so far hardly studied trifluoroacetic dithioesters and
of several CF3-substituted iminium salts (schemes 5a and 5b).
203
C2-Reagents with CF 3
o / O S S
II ii / P2S5 ii / II
F3C__C__OJ HN\ F3CmC--N FsC--C--N F3C~C~S~
\ \
N-ten. -amides Thioamide Dithioesters
/ ch /
), CH3X I .2V
J
Cl Slj S"
/ i / i e/ He ! /
F3C~CH2~N F3C~C--N F3C--C=N F3C~ C - - N
\ i \ \ i \
Cl xe H
Amine Amide Thio amidium Thio-aminal
chloride salt of Fluoral
CF3-Iminium
Salts e/
F3CmC--N
I'/ J
. CF3-Iminium
Salts ,,
. CF3-Mannich i \ F3C--C--N ,, CFs-Mannich
Salts ,, Cl i \
R Salts ,,
cP Thioaminals
Scheme 5a.
CF3 Iminitma- Salts

SIf
S/ F3C-C//O ) 2 0 F~C | /
i e/ NaBI-I4 I / I
F3C~C--N r-- F3C--C--N C=N F3C-,,~N ~
\
CH3CN Hi \ O
II
ff \
F3C~C~SR O~/CF 3
| (~O--C~CF 3
II
O
CI
O
11 O--OH
/
F3C~CH2~N F3C~CH2~N
\ \
95 %
Scheme 5b.
C3-reagents were obtained from t r i f l u o r o b r o m o a c e t o n e or from t r i f l u o r o p r o p e n e

( S c h e m e 6).
204
C 3 - Reagents
o o s
II $8 / HNR II II
F3C--CmCH2Br ~ F3C--C--C--NR 2
CF3 CF3 CF3 CF3 CF3

/
s~ s~ so2~ O SO2~
Scheme 6.
C4-reagents from trifluoroacetoacetate and other reagents (Scheme 7)
C4-Reagents
O 0 F3C~O
F3C ]l II I1 OR
NH2 OR
N:
Various Cn-Reagents
CF3
~ (O)n
x = SR, COOR
F F
13-Trifluoroacetyl-lactam Tetrafluoro-cyclobutene derivatives
L 0
II
F3C~CH2~S
CF3-Dipoles Trifluoroethyl-t-butylsulfoxide
Scheme 7.
Trifluoromethyl substituted C2-reagents derived from trifluoroacetamide,

-thioamide or-thioester
Whereas the tertiary trifluoroacetamides obtained by aminolysis of methyl
trifluoroacetate are rather inert, the corresponding thioamides permit an
205
S-alkylation to thioamidium salts and chlorination to amide chlorides (ref. 8,
Scheme 8). The thioamidium salts react with hydride or other nucleophiles to give
many useful intermediates.
CF3-substitution on the carbon of the iminium function causes high reactivity
arising from the captodative (ref. 9) functionality on the cation : CF3-destabilisation
and amino-stabilisation.
We have reported already on the trifluoroacetamide chloride as mainly covalem
distillable liquid. This o~,ot'-dichloroamine comproportionates quantitatively on
heating to give the ct,c~'-dichloro-isomer in contrast to alkyl or aryl analogs which
undergo the von Braun dechloroalkylation (ref. 8, Scheme 8).
C1 C1 C1
i / I / > 130~ i /
F3C~C=N(~ _., ,-- F3C_C_ N F3C--C--N
ClI )
C1| I-t) H '. Cl)
I _HC1 x~HC1 +.c)/
I I
C1 C1, N F3Cx N
J / = = E
F3C~C--N F 3 C ~ _~
e \
|
E E E E
C1 C1
i / A I
R--C=N | R--C=N~
\ - CH3C1
CI| R = alkyl, aryl,
Scheme 8.
The 1,3 "dipolar" redox isomerisation of C-captor-substituted amide chlorides is

general, first order and independent of solvent polarity : it is the fastest with the
strongest captor groups (ref. 10). Since ionisation induced by counterion
complexation of these amide chlorides blocks the isomerisation, either homolysis of
CCl-bonds in cd-position or a concerned elimination to the interceptable dipole and
readdition of HC1 could explain the reaction mechanism. But what is the driving
force of the rearrangement ? Again the Electronegativity Effect (ref. 2) is certainly
206
an important factor together with sterical "decongestion". The electronegative
chloride migrates away from electronegative neighbors. We have found now
analogous 1,3-dipolar isomerisations of CF3-carbon substituted dithio-orthoamides
(refs. 11, 12, Scheme 9).
/MeMe Me
S/ MeMe s/MIM
I e S/ Me S Mej-
F3C_C=N/| MeSH~ F3C--C--NI/ Toluene A~ F3C--C--N + F3C--C--N/
I II
+ F3C--C--N
\ I \ 8d. I \ HI \ Me \
Me S\ Me H / Me
X(9 Me S
,
]-HS--Me ~ 160o
- HX~ [ J neat~ 66 ~ 6% 2%
(DBU) ~ ] J "~ (37% 22 % 41%)
" U
[ // Ph F3C~/" )
J " o 2G- o
I
Ph
Scheme 9.
In refluxing toluene the main reaction is the 1,3-dipolar isomerisation apparently

via the interceptable CF3-dipole. In neat phase at higher temperatures reduction to
the thioaminal and elimination of dimethylsulfide become the major reactions.
Further results arise from trifluorothioamidium salts with varying N-substitution.
Addition of cyanide furnished substituted thioaminals with two captor substituents
and their thermal behaviour was studied (refs. 1, 13, Scheme 10).
207
S/ R S/
I / KCN, CH3CN I
F3C~C=N \ | w..- F3C--C--NR2
R
25~ 2 hr I
C
III
CH30~SO3 (~ N
Thermal isomerisation
/
S
Toluene A
H )
R = CH3 F3C- N 100 % conversion
3 hrs, H2SO4 cat. \
C
III
N
I
F3C. N.
12 hrs N------C~
0 70%
O O
/)~N-- Ph I
Ph
But with
R--C2H5 and
~NR2 = ~ N ~ X no isomerisation in the absence ot~
H S ~ C 1 H
F3C~C--N + C1
C
III
N
190~ o
F3C--C--N (by the ESR)
I
C
III
N
Scheme 10.
Again a dipolar adduct to N-phenyl-maleinimide was obtained. Surprisingly, the

NN-diethyl-trifluoromethyl-cyano or the pyrrolidino analog did not isomerise even
at higher temperatures in refluxing xylene, whereas acid catalysis led to
decomposition. At 190 ~ ESR signals showed homolysis of the C-S-bond (ref. 14).
2o8
Correspondingly, p-chlorothiophenol produced a reduction of the C-S-bond with
formation of the pyrrolidino 3,3,3-trifluoropropionitrile, a derivative of alanine.
For comparison, non-fluorinated thioamidium salts were also reacted with
cyanide and both the phenyl- and the ten-butyl derivative were obtained, but instead
of the dicyano thioaminal, mainly the (presumably radical) dimer was found
(Scheme 11).
/
S
KCN, CH2C12 A, Toluene

)
,,..._
N
\ 12 hrs, 25~ \ 24 hrs \
C
i(9 III III
N N
Sj S/
/ KCN, CH2C12 / A, Toluene /
C6H5 I--N| C6H5. N C6H5 N
\ 12 hrs, 25~ \ 24 hrs \
C
i(9 III
N
/
S" S/
N=C
/
[--N|
KCN, CH2C12
N--=C
/ 25~
N~C ] + N~C------H
\ 12 hrs, 25~ \ /2
c C C
CF3~SO30 III III III
N N N
major minor
Scheme 11.
The three thioamidium salts differ in reactivity because of steric, electronic and
polar substituent-effects, the thioaminals isomerised normally only in the ten-butyl
case, lost the S-substituent by H-reduction in the phenyl derivative and yielded
dimerisation of N,N-dimethyl amino and dicyanomethyl residue. The reduction of
the C-phenyl derivative is suppressed when S-phenyl replaced S-methyl. Now the
dipolar isomerisation occurs again (Scheme 12).
209
/ Ph
.Ph S
C1
1 PhS| s-I
/ H )
t / I
C6Hs~C=N (9 C6Hs~C--N -~ C6Hs~C--N
\ 2 CN| I \ I \
C C
cf~ III III
N N
Scheme 12.
Possible intermediates are the dipoles for the isomerisation, the radical pairs for
the dimerisation and for the reduction arising with the S-CH 3 group.
Breaking the C-S bond could be accompanied or followed by formation of the
interceptable dipole, the addition of RSH, the coupling or reduction depending on
the relative stability of the intermediates.
While further studies and the discussion are planned to be published elsewhere,
it can be concluded that trifluorothioacetamides, their amidium salts, their amide
chlorides, their thioacetals and 1,3-dipoles are useful reagents with CF 3-
substitution. The trifluoromethyl iminium salts, the trifluoroethyl-t-butyl sulfoxide,
and the already mentioned trifluoro-dithioacetates are treated in the following
sections.
T R I F L U O R O M E T H Y L IMINILWI SALTS
As summarized already in the introduction these iminium salts of fluoral are
readily available either with trifluoroacetic acid anhydride (TFAA) and N-oxide of
trifluoroethylamine (Potier-Polonowsky reaction, ref. 15) or from N-O or N-S
acetals formerly accessible by electrochemical amine oxidation and now by hydride
reduction of thioamidinum salts (ref. 11).
These "CF3-Iminium" salts can be isolated and even be distilled (X - CF3COO-)
but they were most often used in situ.
/ /
F3C~C--N | ~ F3C-CH--N
I \ t \
H X
X|
Scheme 13.
210
Thus condensation occurs with carbonyl activated methylene groups in high
yields to [3-trifluorovinylcetones "trifluoroethylidenation" which are again useful
CF3-reagents such as heterodienes for cycloaddition to vinylethers.
"CF3-Iminium"-salts condense with aromatics or olefins (ref. 16) and even with
those too little activated towards the parent Eschenmoser-B6hme iminium salts
(Schemes 14, 15, 16).
e/
Eschenmoser- B6hme IminiumSalt CH2=N X|
\
Scheme 14.
| R
F3C--CH---N\ X|
R
O
II
R = CH3 X = O--C--CF3
O
Ph1 ~ 0 ~
Ph
4d 25~
5d
CF3 CF3
88% 76%
O O
4d CF3 CF3
84 % 88%
O O
A, CH2C12 ~ CF3 F 3 C ~ CF3
4d
96 %
N
O
F3C (~/'
~---OEt A, CH2C12 \-(
10d COOEt
C
89%
Scheme 15.
211
R = ~CH2~CH2~O--CH2~CH2~
CF3
OJ CH2Ch
/ 25~ 0/--~NR,
/ ---60%
F3C
F3C
/N/
0 ---NR2
CH2C12
25~
) F,cA-o)
45% 48%
CH2C12
~ CF3
88%
25~ Ph NR-,
CH3 OCH3
O CH2C12
25~ 80%
F3 R2
~y CH2C122"5oC~ ~ F3 94 %
Scheme 16.
TRIFLUORODITHIOESTERS
This class of compounds is only scarcely known, such as the ethyl ester and its
activity in a Diels Alder reaction (ref. 17). The already mentioned new preparation
from the trifluorothioacetamidium salts with H2S or from the trifluoroacetamide
chloride with successive HSR and HzS treatment produces these reactive
compounds. Some examples of their synthesis and their high reactivity follow
(ref. 18, Scheme 17).
212
R
S/
i / H2S
F3C--C-'N@ R
\
CH3
| t-C4H9
S
II
F3CmCmS--R CH2.,""~
C1 CH2COOEt
F3c-c'=@ 1. HSR 50 - 70 % CH2--Ph
o-C6Ha~COOMe
2. H2S
C1|
S
II
F3C~C~S~CH 3
:F:. 95%
20~ neat
N2CHCOOEt P(OCH3)3 F3C COOEt

F3C~~_~COOEt
ether /S H ether
100 % /S H
92 %
H
/
Ph3P=C\ Sm
C
% C CF3
40- 50 %
COOH
COOH
@NH
I1 CF3 66 %
CH2C12 NEt 3
S| ,.CH3
S"
F3C I S~S 93%
SH H
t BuOK (cat)
Scheme 17.
213
REAGENTS FROM TRIFLUOROPROPENE WITH ~-SULFUR
SUBSTITUENTS
The known ~-phenylsulfide 2 of trifluoropropene 1 can be oxidized to the
sulfoxide 3 and further to the sulfone 4 and to its epoxide 5 (Scheme 18, ref. 18).
CF3 CF3 CF 3 CF 3 O
,/ .~ ~ .~ / ._ / / N,/CF3
SPh SOPh SOzPh SOzPh
1 2 3 4 5
Scheme 18
Compouds 1-4 are useful for nucleophilic additions and for cycloadditions,
whereas the epoxide 5 reacts well with 1,n bis-nucleophiles giving 2, 3,
4_ heterocyclisations (refs. 18, 19, 20). As we found, trifluoropropene -ct-thio-
derivatives are prone to 1,3 dipolar additions (ref. 21, Scheme 19).
H
I
N~ N CF3
CH2N2 ~/ N (O)n n=l N" / ~
2-4
Et20 (/b~p h 80~ .v \\
--- 2 hrs, 20~ CF3
- 100 % 66 %
n=0 distillable
n=2 A ~ decomposition
N2CH--COOEt EtOvC //N,,N~H

2-4 76- 100
CF3
PhCHN2 / ~ CF3
100 %
C6H6 ~ 50~ Ph SPh
Ph
PheUN 2 .~ ---~__ C
(F3 A, CH3COOEt ~ Ph\-'--, /CF 3 76 %
Et20 A, 15 min. - SO2Ph S~a "7
SO2Ph
MeO~N~SiMe 3 CF3
CHzPh ~ O)nPh
2,3,4 65 - 84
H | , CH2C12
I
CH2Ph
Scheme 19.
214
1,4 Cycloadditions to trifluoropropene derivatives
Generally all derivatives 2-4 react, but the sulfone 4 gave nearly quantitative
yields at mild temperatures (ref. 19, Scheme 20).
CF3
~ S P h
A, C6H 6
2 + 72 %
24 hrs
3 + @ A,5dEt20---,-- endo - exo - isomers 98 %
4 + ~ Et20 ~ endo - exo 99 % (4 91)

\\ q 20~ 1 d
A, CH2C12 ~ C F 3 (..~.~CF3
4 + 4d "- ~"SO2Ph + ~ "SO2Ph 99 %
83 9 17
Scheme 20.
Michael addition of alcohols, thiols and amides expectedly gave high yields
with all three sulfur derivatives 2-4 of trifluoropropene and interestingly the
sulfoxide 3 furnished with thiophenol beyond the expected monoaddition the
dithioacetal of trifluoropropanal (Scheme 21).
CF 3 PhmS CF3
PhSH + ( ~ ) / --100%
//S~Ph Ph~S
O
Scheme 21.
Enamines revealed differentiation of reactivity towards 2-4. The more polar

sulfoxide 3 and the sulfone 4 reacted with pyrrolidinocyclohexene or morpholino-
cyclopentene simply by addition, whereas the thioether 3 went further by HF
elimination and bicyclisation. After hydrolysis the bicyclic ketones were isolated in
good yields. Malonate reacted with 3 by addition followed by HF elimination. With
4 or fi only addition was observed. Acetone dicarboxylate reacted with 3 by addition
followed by HF elimination and then by heterocyclisation to the difluoro-pyrane
215
derivative, whereas the sulfoxide furnished the substituted fluorobenzene and its
phenol by hydrolysis (ref. 19, Scheme 22).
1) CH2Ch;, A , NEt3
3
2) HCliHzO
F
1) CH2C12, A, NEt;
4 or 5 n=l 55%
2) HClIH2O 1 n=2 46%
1) CH2Cb, A, NEt3
3
2) HCI I H20
F
1) CH2C12, A , NEtj
4 or 5 n=l 31%
2) HCIiHzO n=2 68%
0 0
1 ) CH2C12, A , NEt3
4 or 5 n= 1
2) HCI/H20 Me0
Me0
0 0 (0)"
216
P ooEt +phi2j_2oot
O
1) CH2C12, A, NEt3
2) HCI / H20
F O F 22 / 36 %
~t~ ~
O
0 OH 0 0 OH 0
1) CH2C12, A, NEt 3
2) HC1 / H20
r
Meo ' OM O OMe
45/16%
Eto-~
O
Scheme 22.
HETEROCYCLISATION WITH or- OR I3-TRIFLUOROMETHYL

EPOXYSULFONES
Generally nucleophilic 13-attack to epoxysulfones followed by sulfinate
eliminations generates carbonyl groups. The crystalline cz-trifluoromethyl
epoxysulfone 5 follows this pattern and is particularly useful as 1,2-biselectrophile
in heterocyclisations (ref. 20, Scheme 23).
217
O
~ i , , , ~ CF3 74 %
PhS CF3
PhS Q SO2Ph
5_
S CF3
II
5 + H2N'~NH2 S
S.~N 91%
NH2
' + O. _
NH2 CF3
I
H
5 + ~ 46 %
NH2 N CF3
5 +
~XSI~NH,
Scheme 23.
The 13-trifluoromethyl epoxysulfone reacts with opposite regiochemistry and

arose the still unanswered question of bis-trifluoromethyl derivatives related to the
already mentioned and studied tetrafluorocyclobutene derivatives or of their
trifluorochloroanalogs (Scheme 24).
X X
F3C CF3 F F (el)

F F
Scheme 24.
218
T E T R A F L U O R O - AND T R / F L U O R O C I ~ O R O C Y C L O B U T E N E R E A G E N T S
In agreement with the captodative concept, 2 + 2 cycloaddition of cd-olefins to
trifluoroethylene via biradical intermediates is more facile than to captor-substituted
olefines, or to the captor-substituted acetylenes. Phenylthioacetylene reacts
smoothly and permits S-oxidation of the adducts (ref. 21, Scheme 25).
SPh
=< COOCH3
COOCH3 SPh
80%
120~ 8 hrs C1
F
F F
- COOCH3
__S COOCH3
F C1
190~ 16 hrs [Cl 35%
F F
S--Ph KF, DMF ~S--Ph

S--Ph
80~ 8 hrs F C1 80~, 30' F
50% F F F F
Scheme 25.
Both series of cyclic olefins with activation by the trifluorochloroethane (or

tetrafluoroethane) bridge are interesting dieno- and dipolarophiles (ref. 22), leading
to so far hardly accessible annelated structures (Schemes 26, 27).
219
Ph
I
COOMe
F c1
67 Yo
COOMe
F G C l
F F
COOMe
F
180°C 7hrs
F F F F
& I
70 Yo 51 %
Me
\ \
Scheme 26
220
O~s02Ph
i fX = F F--j i x
J 65% F F
/SO2Ph i
r
X=F
X 88% S02Ph
F F
F F
X=CI
"--..i
85% "-..
X=F 93%
SO2Ph
i ' R T , neat phase, ~ 12 hrs
F F
Scheme 27.
The tosylate of trifluoroethanol furnishes by substitution and subsequem

oxidation the tert-butylthioether and its sulfoxide as useful reagems for the
attachmem of trifluoroethylthioethers or their sulfoxides to multiple bonds according
to the following scheme (Scheme 28, ref. 19).
221
O
Nail, DMF II
F3C--CH2OTos + HS F3C--CH2~S ~ F3C--CH2~S
80 ~
72 % ~ 90%
TFA / T F A A ~ CH2C12/-
. . . . . . . . 40 ~ 0~ 1 A, Toluene
[ ] [
O ~" O
"
F3C--CH2~S--O--C--CF3 F3C--CH2~S~H " }
/
MeOOC - : COOMe/
i
+ < F3C._._~ ~/~ Oil
O
S--.-/ O--C--CF 3 85%
F3C--CH2~{ / H
\_/ F3C_____N 0 MeOOC COOMe

II
S O~C--CF 3 70% 87%
7-8"
</~
d II
O--C--CF 3
82 %
F3C
/,,,,.,//
+ isomer 83 % (7 : 3)
F3C~S'~-~ O ,.CF3
[I
O
F 3 C ~ S ~ ~ ~
\ 94 %
O. ,.CF3
"C"
II
0
Scheme 28.
222
AMINOSULFURATION OF BROMOTRIFLUOROACETONE TO TRIFLUORO-
PYRUVIC THIOAMIDES
Sulfur dissolved in DMF thionates in the presence of sec-amines methylene
groups activated by a captor group. The halogen is then replaced by the amine, the
overall sequence leading to thioamides. This is shown below for bromotrifluoro-
acetone (Scheme 29, refs. 23, 24).
O O
Br $8, HNR2 NR2 I
F3C ~ F3C + F3C--CH
DMF, 20~
S NR2
6 7 (trace)
Scheme 29.
The yields of trifluoropyruvic thioamides 6 with common secondary amines are

mostly fair and do not exceed 65 %. The reduction products - trifluorolactic
thioamides 7 are formed in certain cases as by-products (about 5 %).
Trifluoroacetone yields under the Willgerodt-Kindler conditions only 7 (30-35 %),
besides other products. These lactic products 7 are therefore formed more
expediently by reduction of 6 using ammonium formate at 100~
The reactivity of 6 as starting materials for the synthesis of heterocycles was
explored, since the parent trifluoropyruvic acid (ref. 25) had already been used for
this purpose. As it turned out, the heterocyclisations proceed sluggishly because of
the low reactivity of the thioamide group and monocondensations at the highly
reactive trifluoroacetyl group (e.g. imine or azine formation) can be observed. Thus
only ortho-phenylenediamine gave the expected quinazoline in a 65 % yield upon
heating the components at 120~ (Scheme 30).
6
N~ CF3
N NR2
Scheme 30.
The use of TIC14 did not facilitate the cyclisation and led to the formation of a
double imine consuming 2 eq. of 6. Accordingly, primary amines form in the
presence of TiCI4 the corresponding imines 8 and the same result is obtained when
iminophosphoranes are applied (Scheme 31).
223
' .i R'
R'NH2, TiCI4 R'~ N Zn, HOAc HN
/NR2 NR2
or qb3P= NR' F3C F3C
S S
_8 9
Scheme 31.
N,N dimethylhydrazine reacts in the same fashion, while hydrazine gave only
9 % of the azine together with the reduction product _7. The reduction of imines
8 yields the corresponding trifluoro-alanine derivatives 9. The hindered imines 8 are
very stable and do not undergo [4+2] cycloadditions or addition of butyl-lithium,
and even LiA1H4 reacts very sluggishly.
Amines 9 are also only moderately basic but react with strong electrophiles as
exemplified for phosgeniminium chloride (PI) (Scheme 32).
NMe2
C1 N,~S
9_(R'= H)+ ')==:~qMe2C1e -
CI/ "-
F3C NR2
10 86%
Scheme 32.
In this case the thioamide sulfur also participates and trifluoromethyl thiazole 10
is obtained in a very good yield. Amine 9 R = M e reacts similarly with phosgene to
form the corresponding thiazolone in a 99 % yield.
While 6 does not react properly with stabilized anions (Knoevenagel Reaction),
organolithium and magnesium reagents give alcohols 11 in excellent yields (ref 26,
Scheme 33).
1. R' Metal OH
[ //S
6_ ~ F3C--C--C 11 ~ 80 %
I \
2. NH4C1 R' NR2
Scheme 33.
224
CF3 F3C NR2
SOC12 ~ P h ~ S 1. N2H4 ~ ~N.N
11 (R = PhCH2)
or P205 R2N 2. S8 or MnO2 Ph
I
H
12 13 86 %
Scheme 34.
Compounds 11 can be chlorinated when R'=C6H 5 or benzyl. The latter

eliminates HC1 to the corresponding trifluoromethyl cinnamic thioamide (12,
Scheme 34).
Compound 12 cyclizes with hydrazine to give a pyrazoline which can be
dehydrogenated to afford pyrazole 13. Many trifluoromethylated pyrazoles are
known as described in an excellent review (ref. 27). Alcohols 11 can be methylated
using NaH/TfOMe. These methyl ethers could not be hydrolyzed to the
corresponding Mosher acid. As the hydroxyl is now protected by an alkyl group,
the thioamide moiety can be chlorinated to give the amide chloride 14. This
unstable compound was directly cyclized with benzothiazole (Scheme 35).
~NH2
OMesI/// C12 O[Mex~\~,/

C1 1 "~" "SH .._ ~ ~ ~ /QMe
F3c I \ I - (, CF3
Me NMe2 Me Me2 Me
C1|
1~ 14 ~5
Scheme 35.
The O-mesyl compound was prepared in view of the subsequent elimination

which would give the interesting a-CF 3 acrylic thioamide. But in the basic medium
used (Nail), the methyl of the mesylate was deprotonated and the anion cyclized at
the thiocarbonyl function, thus leading to the unusual sultone structures 16
(refs. 28, 29, Scheme 36a).
225
/SO2~Me
SO2
O' S
NaH
F3C -~ /~ 16
R
R = Me, Et, Bz, Allyl, Ph
Scheme 36a.
E T H Y L T R I F L U O R O A C E T O A C E T A T E (TFAE) AS A USEFUL BUILDING

B L O C K IN H E T E R O C Y C L I C SYNTHESIS
TFAE has already been largely studied as a very versatile synthon. It contains
two electrophilic centers (ester and a trifluoroacetyl carbonyl) as well as a very
activated methylene group. In pure phase it is enolized up to 90 %. A very good
review on this and similar compounds exists in the literature (ref. 30).
We have more particularly studied the primary enamine 17 and the diazo-
derivative 18 (Scheme 36b).
Chemistry of ethyl-2-diazotrifluoroacetoacetate 18
In order to prepare larger amounts of 18 the method of Weygand and Bestmann
was used which involves the acylation of ethyl diazoacetate by trifluoroacetic
anhydride (TFAA) (ref. 31, Schema 36b).
0 0 0 0
F3C
~ OEt F3C
F3C~OEt
H2N CO2Et N2
17
TFAE
F3C H. /CO2Et TFAA

18 90 %
pyfid~
HO CO2Et N2
90 %
Scheme 36b.
226
Diazo-tranfer upon TFAA works also properly. For mechanistical studies we
have also prepared 15N marked 18 by using Na15NO2 and glycine (ref. 32).
It was expected that 1-diethylaminoprop-l-yne would undergo a 1,3-dipolar
cycloaddition with 18 leading first to trifluoroacetyl isopyrazole 19 which could
then undergo a 1,5 sigmatropic shift (von Alphen-HiJttel rearrangement)
(Scheme 37).
O
#
18 F3C~N~N - 9
H3C NEt2 ~ E" ~__~\ ~ ~
Et2N \
1--9
Scheme 37.
In as much as the trifluoroacetyl group was absent in the final product, we

concluded that the ynamine reacted in a [2 + 2] cycloaddition across the activated
carbonyl. This would lead to oxetene 20 which could open to a diazo glutaconic
derivative 21. Its cyclization in situ would afford the 3H-pyrazole 2__22and finally the
observed N-carbamoyl pyrazole 23 (Schema 38).
NEt2
Ynamine O -NEt2 Me,_ CONEb O "/ - ' ~ )K"~N
18 ~N
,._ / / ,._ C/~YN2 " ,.._
F3CE F3 Me/
E F3C E
20 21 22
OF.E*2
Me~ _ _ _ _ ~N
23, 64%
1.5
F3C E
Scheme 38.
Subsequently, however, we have prepared a series of diazocompounds 21a,b

closely ressembling 21, via the Wittig and Horner-Emmons-Wittig (HEW)
olefination vide infra, and observed that none of them cyclized even upon heating. It
227
became obvious that 20 rearranges directly to 2_22. The latter undergoes a
spontaneous 1,5-carbamoyl shift to give 23. Its structure was secured by X-ray
crystallography. 23 undergoes very slowly another 1,5-carbamoyl shift, and also the
carbamoyl group can be removed by methanol to give the parent pyrazole. Due to
its enolic structure TFAE does not react with Wittig reagents and the like. This
enolization is suppressed in 18 and a number of Wittig and HEW olefinations could
be performed. It should be noted that strongly basic Wittig reagents lead only to
decomposition. The results are summarized in the schemes 39 and 40.
R
o
~ N 2 liaR ether,r.t. N2
F3C + ~ F3C
CO2Et PPh3 CO2Et
21
R = CO2Et, 88 %
R = CO2tBu, 56 %
R=COMe, 77 %
R = C N , E / Z = 1"2,86%
Scheme 39.
O 1. LiCkMeCN
RI'~ R2 2. EtN(iPr)2
F3C~'~ N2 F3C'@ N2
CO2Et o~P(OEt)2 CO2Et
21
R ~ = H, R2 -- CO2Et, 82 %
R 1 = H, R2 = CO2tBu, 62 %
Ra = H , R 2 =CN, E / Z = 1 : 2 , 8 4 %
R1 = F, R2 = CO2Et, 15 %
Scheme 40.
Compounds 2_!_1 react with triphenyl phosphine to give the corresponding

phosphazines. When the starting diazocompound carries a vinyl group substituted
by a carbonyl function, an intramolecular Aza-Wittig reaction provides an
interesting entry to CF3-substituted pyridazines 24 (Scheme 41, ref. 33).
The results are similar when the reaction sequence is inversed, namely 18 is
converted first to its phosphazine which is in turn olefinated as shown above. Aza-
Wittig reactions are resumed in ref. 34 and the recent chemistry of the diazo group
in ref. 35.
228
The parent diazo compound 18 is thermally very stable even in the presence of
Rh-based catalysts, but one report (ref. 36) nevertheless describes the trapping of
the carbene which may also react as a 1,3-dipol with ethyl vinyl ether at IO0~
under pressure (Scheme 42).
R R R
O Ph3P O Ph3PO N
F3C 2 --N-.XPPh3 F3C Nil

F3C
E E E
24
R = OEt, 83 %
R = tBu, 57 %
R = M e , 64%
Scheme 41.
COzEt
OEt Rh2(OAc)4
1___88 - - /
E t O ~ C F 3
100 ~ 8 h
Scheme 42.
R R R R
0 700~ ,._ 0
~v
F3C 2 F3C F3C (9

F3C E
E E E 25
R=OMe, 62% 9 R=Me, 68% " R-tBu, 0% E= CO2Et
Scheme 43.
CF3-substituted diazoglutaconates are as inert as 18 and elegant reactions of

H.M.L. Davies (ref. 37) performed on diazoglutaconates could not be materialised
in our case. The flash vacuum pyrolysis (FVP) of our diazoglutaconates was more
rewarding. While the starting material is recovered intact even at 450~ but at
700~ the cyclization occurs to give CF3-furanes 25 (ref. 38, Scheme 43).
Pyridazones belong to the category of electron-poor azadienes and they could be
229
expected to react with electron-rich multiple bonds (refs. 39, 40). In practice,
enamines gave only ill-defined products, but an ynamine in refluxing toluene gave
pyridine 26 via loss of a nitrile (Scheme 44).
N llO~
+ Me : - NEt2
F3C NIl
E
2_!4 26 70 %
Scheme 44.
Chemistry of 2-benzyloximino TFAE

The known oxime of TFAE was benzylated to form 27 which is another non-
enolizable derivative of TFAE and is able to undergo the Wittig olefination
(Scheme 45, ref. 38). Products 28 are formed in very good yields even with non-
stabilized Wittig reagents.
0 N--OBu R
~-~ + /~'Pq~3 ~ ~NOBu
F3C E R F3C
E
27 28
Scheme 45.
Chemistry of hydrazones of TFAE

H.J. Bestmann has prepared the phosphazine of TFAE from 18 and triphenyl
phosphine. This compound is hydrolyzed by ZnC12/H20 to give the parent
hydrazone 29 and it can be transformed to the corresponding tris carbonyl
compound using HNO2 (ref. 41). In analogy to the studies by H. Neuenhoffer, we
have N-acylated 29 by acid anhydrides to obtain crude N-acylhydrazones 30 in
about 50 % yield (Scheme 46).
230
0 0 E
o
F3C II F3C 0 F3C
+ (R--C--Oh ~ -~
N~NH2 N. ~,. HOAc N N
"N
H R "~
R
29 3O 3_!1
Scheme 46.
Intermediates 30 being 1,5-bis-electrophiles react with ammonia to give

1,2,4-triazines 31. These electron-poor azadienes give with enamines the
corresponding CF 3- pyridines 32 via a loss of nitrogen (Scheme 47).
With ynamine, one can observe two pathways which occur simultaneously :
there is either a loss of N 2 giving pyridine 33 or a loss of cyanoformate leading to
pyrimidine 34 (Scheme 48).
As an exception, 31, R = Ph gives the corresponding pyrimidine as a unique
product in a 79 % yield.
E
/N~ 110~ F 3 C ~
31 + ~n ~ ~...~ )n 32
1 0-30 rain. N
R
R=Me n = 1, 73 % 9 n = 2 , 71%
R = Ph n = 1, 78 % 9 n = 2 , 77 %
Scheme 47.
F31L-N[[
NEtz Me
Me - - NEt2 F3C-~/NEt2
31 R=Me -- N.. N
Me
33 49% 34 34%
Scheme 48.
231
The reactivity of ethyl-3-amino-4,4,4-trifluorocrotonate 1_7_7
The quite acidic TFAE reacts with ammonia to form only the corresponding
ammonium enolate. This salt upon heating at 100~ for 1-2 h forms the desired
enamine 1_7_7together with some trifluoroacetyl acetamide (15-20 %). Pure 17 is
obtained upon careful distillation (Spinning Band) in a 7 1 % yield (refs 23, 42, 43),
as a low melting (30-35~ solid. Its configuration Z (amino and ester groups are
on the same side) was established by NMR-studies (ref. 44).
Enamine 17 reacts with PI salts via condensation at the amino group which is
followed by a de-chloroalkylation of the ester leading to cyclized products: 4-CF 3-
1,3-oxazin-6-one 35 (refs. 23, 43, Scheme 49). The isomeric 2-CF3-1,3-oxazin-6-
ones 36 were studied by W. Steglich (ref. 45).
F3C
PI F3C~O =.j..S ~
HzN CO2Et CHCI3 N.yO N .~,.O
NR2 CF3
17 35 - 90 % 36
Scheme 49.
The reactions of the Vilsmeier-Haack-Arnold reagent or N,N-dimethyl

benzamide chloride stop at the azadiene stage and phosgene failed to react
altogether. 35 Where dimethyl amino is replaced by a phenyl 37 could be prepared
in high yield by N-benzoylation of 17, followed by chlorination of the amide using
oxalyl chloride and subsequent heating at 130~ The N-trifluoroacetylated product
of 17 could be chlorinated only with difficulty (PCI5/POC13) and the very stable
imidoyl chloride hereby obtained failed to cyclize. Acetimidoyl chloride derived
from 17 apparently did cyclize, but 35, R = Me instead of NR2 was hydrolyzed
during the aqueous work-up.
Surprisingly, dialkylamino oxazinones 35 and the 2-phenyl analogue 37
underwent cycloadditions with acetylene diester and ethyl propiolate, albeit under
harsh conditions (reflux in xylene or chlorobenzene) (Scheme 50, refs. 23, 46).
Other electron-poor dienophiles failed to react, as well as the electron-rich ones,
where only decomposition was observed. The follow-up chemistry of 35 and 37 was
studied and has led to numerous trifluoromethyl substituted heterocycles
(refs. 43, 44).
232
F 3 C ~ O R2 ~. :::~ g F 3 C ~ R2 RI = N
/
'"~---
R2 =H,E
~
R: R1 yield - 80 %
3__~5,3__2_7
Scheme 50.
Aminolysis of benzoxazines 35, 37

Oxazinones possess an activated lactame moiety and react easily with
nucleophiles. A general picture is given in the Scheme 51. Thus water gives the
previously unknown trifluoro aminocrotonamide. Amines may yield different
products according to their substitution and basicity. Primary amines and 35 lead
usually to ring-opening followed by re-cyclization to pyrimidine-4-ones 37a. On the
other hand, 35 gives ring-opened products 3.8. With primary amines a Michael
addition can take place leading to the corresponding aminals 39. Aromatic amines
react only once to furnish enamines 40. Pyrrolidino cyclohexene acted only as a
source of pyrrolidine yielding 4_!1. Ethylene diamine gives rise to a cyclic aminal
structure 4_22. Mono-substituted hydrazines react similarly to five-membered ring
aminals 43 which eliminate readily the amide function present to give pyrazolones
43 (Scheme 51, ref. 44).
233
F3C'~~ O O
FsC H. ~NMe2
N'~/Nx R, H Nx~'~INR'2 "N O
Ph F3C~-.~NH R
R" \'0 O RHN
37a 38 39
HNR'2
F3C
FsC'x.~'~O F3C
H.N~N/" ~ ~ Pyrrolidino- H20,A N~~..~[
II ~ cyclohexene N.~o H2
NMe2
Me2N" \'O O R= NMe2,Ph
R O
4_, j
0
2N(CH2)2NH2
'~NMe~
F3C H-_N'
H2N(CH2)2NH2 F3c~O
H"N~ - - - - N H A r H..--N N~H
MezN..~O O 42
40 O
H.,"N"~R
F3C~ H20,A F3C"~
H~N"N"~::~O H..N.N/~O
I I
R' R'
4__33 44
Scheme 5 1.
REACTION OF 3-AMINOCROTONATE 17 WITH ISOTHIOCYANATES

AND SOME FOLLOW-UP REACTIONS
Enamine 17 reacts smoothly at 20~ with isothiocyanates to furnish
4-trifluoromethyl thiouracils 45 (Scheme 52, ref. 44).
234
F3C DMSO, 20oC~ F 3 C ~ O C12 n , , F 3 C ~ O
+ RN =C'--S
H2N CO2Et tert. butyl OK N,~NR 0oc N.~NR
/ /
SH SCI
!.7_7 4__55 4__66
R = Me, n-Butyl, Cyclohexyl, Phenyl, alkyl
Yields 63 - 98 %
Scheme 52.
An analogous reaction with isocyanates has already been explored (ref. 47).
The parent compound 45, R = H has been prepared from TFAE and thiourea as
early as in 1948 (ref. 48) but N-substituted thioureas do not seem to react (ref. 47).
Interestingly, 45 can be transformed to the versatile sulphenyl chloride 46 upon
chlorination at 0~ At a higher temperature one observes also C-chlorination
which can be avoided.
Compounds 46 are not very stable, but they give all the typical reactions of
sulphenyl chlorides, thereby leading to many interesting structures. The parent 45
behaves in a complete analogy to arenethiols (S-alkylation, Michael addition,
S-oxidation and dimerisation).
The nucleophilic reactivity of 17 can be increased by N-deprotonation and the
best results were obtained with the in situ generated lithium salts. The latter react
with acrylates by Michael addition and ring closure to give a single product. The
problem of regioselectivity arises because the enamine anion 47 is delocalized and
can react both at the nitrogen anion and/or at the enamine carbon. Both cases are
known in the literature with similar substrates (ref. 49). These two pathways should
lead to the isomeric dihydro co- or 7-pyridones (Scheme 53).
E E
o
=(
E RN_aack R
C-attack
R = H, Me
-(CH2)2OH
F3C F3C NH Li |
I
H H
48 47 49
Scheme 53.
235
The differentiation between 48 and 49 by spectroscopical means is not obvious
but the X-rays of the crystalline product derived from ethyl acrylate upon oxidation
to pyridone have unambiguously established its c~-pyridone structure 50
(Scheme 54).
Similar structures containing a cyano group at the 5-position have already been
studied for their cardiotonic activity (ref. 50).
S8, A E ~
49 ~ 50, 50 %
F3C O
I
H
Scheme 54.
TRIFLUOROMETHYLATED HETEROCYCLES FROM 13-TRIFLUORO-

A C E T Y L A T E D LACTAMS AND BENZOLACTAMS
Trifluoroacetylation of C-H acidic compounds using TFAA or methyl
trifluoroacetate is a well-established process. It introduces a trifluoroacetyl group
which is prone to various transformations. There is a number of reports dealing
with trifluoroacetylation of ketones (ref. 51), lactones (ref. 52) and even of tert-
amides (ref. 53). In contrast, only one report deals with trifluoroacetylation of a
cyclic lactame - N-methylpyrrolidone (NMP) (ref. 54), but it could not be
duplicated.
Finally, the best results for obtaining 52 are shown in the Scheme 55 (refs. 55,
56, 57). The occurrence of the gem-diol 51 is not surprising.
F3C ,OH F3C

Nail ~ O H Dist. 0
O CF3CO2Et 70~ at 0,1 Torr

I I I
Me Me Me
NMP 51 52
Scheme 55.
This procedure was extended to higher lactams and the N-substituent was also
varied. Benzoannelated lactams gave also mostly satisfactory yields.
236
Compound 52 formed readily the corresponding hydrazone 53 which cyclized
upon the treatment with POCI 3 to give dihydropyrrolopyrazole 54 (Scheme 56,
ref. 58).
H
F3C I
CF3
H| ~N..Me
POCI3
52 + MeNHNH2
Tol, A Pyr., 20~
I M/ \Me
Me
53 54
Scheme 56.
The corresponding N,N-dimethyl hydrazone and oxime of 52 were prepared as

well.
Hydrazine reacted normally with 52 leading to the corresponding hydrazone in a
74 % yield. With other trifluoroacetyl lactams and hydrazine or phenylhydrazine an
interesting ring-opening of the lactame function, followed by ring-closure (RORC)
occurred. This leads to unusual zwitterionic pyrazoles 55 (Scheme 57).
0
\\ |
C~CF3 MeH2Nn ~ CF3
( ~ RNHNH2 ,._
55 60-70%
o
I I
Me Me
Scheme 57.
These compounds could not be ring-closed (enolate anion is a latent carbonyl)

using a variety of conditions (ref. 58). Dihydrocompound 54 could be oxidized
using MnO2 to the corresponding aromatic bicyclic product. Guanidine reacted also
properly with 52. The intermediary guanidino enamine 56 could be isolated and it
cyclized uneventfully to 57 in the presence of POC13 (Scheme 58, ref. 59).
237
HN
F3C~ ~ N H 2 F3C
Guanidine ,_.___~~N POC13 ~/~N\

52
~- ( N . ~ O,,H refll~ 1 hr ~- Q,N,~N/--NH2
I I
Me Me
5___6673% 5__2_740%
Scheme 58.
The reactions with benzamidine were less straightforward and needed harsher
conditions (heating to 100~176 with the neat base) (Scheme 59).
CF3 CF3 Ph
~
I I
Me Me
n= 1,2,3 58
CF3 CF3 H
N N~ ' j ( C H 2 ) 4 - N I
@ ~ N ~i -Me
+ Ph + PhJ 2"N
" "~">
I~O
I
Me
59 60
Scheme 59.
Compound 58 is the expected intermediate which accompanied the cyclization

product 59 (n = 1). With n = 3, none of the 58 was formed, 59 was present in
31% yield, together with 60 (41%). This compound arises through the opening of
the lactam moiety. Generally, the isolated 58 could again be cyclized to 59 using
POC13.
The picture was quite similar with annulated benzo-lactams (ref. 59) which lead
to tricyclic systems.
As with TFAE, the corresponding enamine 61 could be prepared by the method
of Swartz (refs. 42, 60). This versatile compound was reacted with amide chloride
238
of N-methyl piperidone to give the azadiene 62 (Scheme 60). Further cyclization
did not occur.
F3C. F3cMeNN/~
H-~
I
+ @ I
:~
0
COC12
CHC13,A
I
N
Me Me Me
61 62
Scheme 60.
Compounds 52 and homologues reacted invariably with 1,4-bis-nucleophiles

such as ethylenediamine and 2-aminoethanol at the CF3CO group by forming
oxazolidines 63 and imidazolidines 64 (Scheme 61, ref. 62). Similar behaviour was
encountered with ethyl trifluoroacetoacetate (ref. 61).
F3C H
XH 63, x = o
52 + H2N
reflux ~ ~N~~ ---~ 64, X=NH
I
Me
Scheme 61.
RORC products 65 may also predominate when benzolactams are reacted with
phenyl and methyl hydrazine (Scheme 62, ref. 63).
The POC13 induced cyclization of 65 failed, but in one case 66 reacted by
bridging to form a phospha-cycle 67 (Scheme 63, ref. 63).
H
F3C F3C \N-Me
n O -
I I
Me Me
I
R
n=l,2 65 52-71%
Scheme 62.
239
F3C F3C
"Me POCI3, reflux

.[~"-;2N_p/O~
v Me 67 30%
NH
M/ Me/ g XC1
66
Scheme 63.
A recent study describes the behaviour of trifluoroacetylated (benzo) lactams

toward 2-aminopyridine, 2-aminobenzimidazole and 3-amino-l,2,4-triazole
(ref. 64).
Robinson annelation with 52

1,3-Dicarbonyl compound 52 being strongly acidic undergoes a Michael
addition with methyl vinylketone (MVK) and the intermediate products can be
cyclized to spiro-cyclohexenone 68 (Scheme 64, ref. 65).
1. NaHcat
52 + MVK - ~ 68 65%
Phil, 20~ F3
2. AcOH, piperidine
Phil reflux I
Me
Scheme 64.
The synthetic potential of 68 was explored further. Thus its trifluoroacetylation

using LDA and ethyl trifluoroacetate gives 69 together with its gem-diol in a 56 %
yield (Scheme 65, ref. 65). The cyclization with benzamidine gave 70 in low yield.
240
Ph
O
F3C H F3C
benzamidine
68 / 70 28 %
"- ~ N / ~ O CF3 F3
Me Me
69
Scheme 65.
The picture was quite similar with annulated benzo-lactams (ref. 64) which lead
to polycyclic systems.
Aminothiophenol formed a spiro-compound using the vinyl ketone carbonyl.
Compound 68 was subjected to another annelation with MVK to give the
tricyclic spiro-ketone 71. It was also transformed to spiro-dienone 72 via a
selenation-elimination process.
71 35% ( /~ 7__~2 70%

" F3 N
I I O
Me Me
Scheme 66.
CONCLUSION
The selection of results shows the usefulness of simple and readily available
trifluoromethylated compounds deriving mainly from trifluoroacetic acid or
trifluoropropene as CF3-carrying reagents. Such an approach avoids tedious C1-F
exchange reactions and leads directly to convergent synthesis of more complex
trifluoro-methylated molecules.
241
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611, (1993).
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243
FLUORINATION OF AROMATIC COMPOUNDS BY HALOGEN
E X C H A N G E W I T H F L U O R I D E ANIONS ("HALEX" R E A C T I O N )
BERNARD LANGLOIS a~, LAURENT GILBERT b~ AND GERARD FORAT u~
a) Universit6 Claude B e r n a r d - Lyon I, Laboratoire de Chimie Organique 3,

associ6 au CNRS, 43 Boulevard du 11 Novembre 1918, 69622 Villeurbanne,
France.
b) Rh6ne-Poulenc Industrialisation, Centre de Recherche et d'Ing6nierie,
85 Avenue des Fr~res Perret - 69192 Saint-Fons, France.
GENERAL FEATURES
Halogen exchange with a fluoride anion is one of the two main techniques to
introduce a fluorine atom on an aromatic nucleus, which is a useful complement of
diazotization of anilines in hydrogen fluoride or thermal decomposition of
arenediazonium fluoroborates (Schiemann reaction). It is used on an industrial scale
to produce, for example, 2,6-difluorobenzonitrile (the precursor of the insecticide
Diflubenzuron) or 2,4-difluoroaniline (the precursor of Diflufenican or other
herbicides).
C1 F F
C1 F F
F
o
\NH~ NH@ C1
F
Diflubenzuron - (Philips Duphar)
244
KF
NO2 F ~ - NO2 H2 w_ F - ~ NH2 r
Cat. w.-
c1 F F
O
CF3
Diflufenican- (Rh6ne-Poulenc)
Scheme 1. Industrial process involving a "Halex" step
The earliest experiments have been reported as soon as 1936 for the fluorination
of polyhalobenzenes at very high temperature (ref. 1) but, to perform the reaction
under more realistic conditions, an electron-withdrawing substituent is needed to
activate the displacement of the leaving group. Mesomeric electron-withdrawing
substituents are better than purely inductive ones and the following efficiencies have
been observed :
NO2 > pyridinic N > CN > CF3 > COX (X = Hal, OR) > CHO-~ COR > C1n
These electron-withdrawing substituents must be located in ortho or para
position to the leaving group and, sometimes, their efficiency can be enhanced by
an halogen in meta position. Some comparative examples are given below (ref. 4) :
NO2 NO2
X C1 ~ X F
DMF
Table 1. Influence of substituents X
Conditions ArF (%)
NO2 140-150~ / 0.5 h 77
CF3 160~ / 3.5 h 76
COzMe 155~ / 4 h 67
245
The leaving ability of the group to be displaced is as follows :
R3N + > NO2 > C1 > Br
Displacement of ammonium moieties is of huge interest for the rapid synthesis,
under very mild conditions, of 18F-labelled radio-pharmaceuticals useful for medical
imaging. Following Clark's work and some others in the 80's (refs. 2,3) increasing
interest is paid to fluorodenitration but this method is limited by the availability of
1,2 or 1,4 dinitrobenzenes. Thus, on an industrial scale, exchange of F for C1 is
much preferred (ref. 5).
The kinetics of chlorine displacement is strongly dependent on the position of
the activating substituent : 4-chloronitrobenzene reacts faster than 2-chloronitro-
benzene with potassium fluoride whereas, in 2,4-dichloronitrobenzene, chlorine in
the 2-position is exchanged more rapidly than chlorine in the 4-position (refs. 4 - 8).
These observations are consistent with an addition-elimination process involving an
anionic adduct (Meisenheimer's complex) which has been observed by 1H and 19F
NMR (ref. 9) or UV spectroscopy (ref. 3) :
E W G ~ C 1 +F | ~ C1 -CI@
-.. "- EWG 4-- ~ EWG
-F| \ / F + C1 @
EWG = electron-withdrawing group
Scheme 2. Addition-elimination process for aromatic halogen exchange.
When located in 2- or 4-position to the chlorine atom, the nitro group stabilizes
the Meisenheimer's adduct both by inductive and mesomeric effects, the latter one
being predominant. To maximize this effect, the nitro group must be coplanar with
the aromatic ring. This is not the case when a bulky chlorine atom is presem in
ortho position : the nitro group is then twisted out the plane and
2-chloronitrobenzene is less reactive than 4-chloronitrobenzene. In
2,4-dichloronitrobenzene, mesomeric activation of 2- and 4- positions is affected to
the same extend and inductive effect becomes predominant. Nevertheless, this effect
decreases very fast with the distance so that the ortho position is more activated than
the para one.
Inductive activation by halogens can also explain the higher reactivity of
3,4-dichloronitrobenzene compared to 4-chloronitrobenzene. The same phenomenon
has been observed with 2-chloropyridines (ref. 10) :
246
X2 X1
C1 Me2S02
Table 2. Inductive effects in the "Halex" reaction
X1 X2 Conditions Fluoropyridine
(%)
H 200- 210~ h 49.5

C1 201~ h 65
C1 194~ h 70
Concerning the effect of the magnitude of twisting in chloronitrobenzenes, we

observed that 2,6-dichloronitrobenzene, in which the nitro group is more twisted
than in 2,4-dichloronitrobenzene, does not react under conditions where the latter
isomer is quite completely transformed (sulfolane / 180~ / 11 h).
If the Meisenheimer's adduct is stabilized by the electron-withdrawing
substituent, it is also destabilized by +I~ interactions between the negative charge
and the p-electrons of the two halogens. Thus, the formation of this adduct can be
considered as an equilibrated process since +I~ effect is more pronounced with
fluorine than with chlorine, which forms longer bonds than fluorine. On the other
hand, as fluorine is more electronegative than chlorine, fluoroaromatics should be
more electrophilic than chloroaromatics, and the second step in Scheme 2 could be
also considered as an equilibrium. It will be seen that, under some conditions,
chloroaromatics can be generated from fluoroaromatics and chloride anions.
Nevertheless, reactions depicted in Scheme 2 are usually shifted to the right because
C-F bonds are stronger than C-C1 ones (542 kJ/mol vs 339 kJ/mol) (ref. 11).
The first " H a l e x " experiments have been carried out with neat chloroaromatics
at high temperatures (400 - 500~ but the introduction of dipolar aprotic solvents
in the late 50's brought a dramatic improvement for the use of this process on a
large scale under realistic conditions (0 ~ _< 2 0 0 - 250~ (ref. 4). It can be noticed
that protic solvents, which decrease the nucleophilicity of the fluoride anion by
strong hydrogen-bonding, are less adapted than aprotic ones. Commonly used
dipolar aprotic solvents are : dimethylsulfoxide (DMSO), tetramethylenesulfone (or
247
sulfolane), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAc), N-
methylpyrolidinone (NMP) or benzonitrile. For fluorodenitration, the following
order of efficiency has been reported : DMSO > tetramethylenesulfoxide >
DMAc > NMP > sulfolane (ref. 12). For other "Halex" reactions, DMSO
remains the best solvent (provided that the reaction temperature is lower than
150~ but some changes can be observed in the order of efficiency for other
solvents. It can be noticed that, under rather drastic conditions, some by-products
can result from the solvent, for instance N,N-dimethylanilines from DMF (refs.
13,14) or thioanisoles from DMSO (ref. 15). Thus, because of its low cost, its
thermal stability (up to 250~ and its high boiling poim (Eb760 -- 285~
sulfolane is often preferred.
Potassium fluoride is the cheapest source of fluoride and is thus widely used on
large scale. However, it is only slightly soluble in aprotic solvents and large
difficulties arise from this fact both on a process point of view and on a
fundamental point of view (concerning the elucidation of the mechanism). Thus, the
"Halex" reaction has been also studied with organosoluble fluorides.
F L U O R I N A T I O N WITH ORGANOSOLUBLE FLUORIDES

Tetraalkylammonium fluorides, commonly available, are soluble in a wide
range of solvents. However, they are very hygroscopic (ref. 16) and several
hydrates are known for Me4NF.nH20 (n - 1,2,3,4), Et4NF.nH20
(n = 1,2,2.75,3,5), (n-C3H7)4NF.nH20 (n = 2,3,6), (n-C4H9)4NF.3H20 or
BnMeaNF.H2 O (Bn = benzyl) (ref. 16). Among them, Me4NF.4H2 O,
Et4NF.2H20, Bu4NF.3H20 and BnMe3NF.H20 are commercialy available. Even
under high vacuum, complete dehydration fails at room temperature and Hoffman
degradation occurs, under heating at 60~ when hydrogen is present in [3-position
to the nitrogen centre (refs. 17,18) :
|
R3N_CH2~CH2~ R, Fe A R3N + R ' - C H - - C H 2 + HF
| |
R4N--CH2~CH2~R' Fe+ HF R4N--CH2~CH2~R' HF2e
Azeotropic dehydration with benzene also fails (refs. 17, 18).
248
Table 3. Dehydration of R4NF, nH20 according to (ref. 17) and (ref. 18)
R4NF, nH20 Treatment State Residual Observed species

water (19F NMR)
(Karl-Fischer) (see below)
none solid n=3 F-, nH20
20~ mbar/13h solid n = 2.5 F-, nH20
lyophilization solid n=2 F-, nH20 -at-HF2-(traces)
Bu4NF, 3H20 20~ sieves oil F-, nH20 + HF2- (40-60%)
60~ mbar/20 h oil n =0.6 HF 2-
60~ mbar/27 h oil n = 0.2 HF 2-
Me4NF, 4H20 45~ mbar/22 h solid n=2 F-, nI-I20
azeotropic (C6H6) . . . .
solid n=2 F-, nH20
BnMe3NF, azeotropic (C6H6) solid n = 1 F-, H20
H20
Hydrated tetraalkylammonium fluorides can be, nevertheless, used in " H a l e x "

reactions but water, the nucleophilicity of which is enhanced by hydrogen-bonding
with F-, competes with the fluoride and delivers phenols and diaryl ethers as by-
products. A typical situation is shown below for 3,4-dichloronitrobenzene (ref. 17).
249
C1 C1 CI
R4NF, nH20
O2N~-~-C1 O 2 N @ F + O 2 N @ OH
Solvent/120~
(F-/Solv. = 1/25 mol/mol)
1 2 ~
C1
Table 4. Reaction of 3,4-dichloronitrobenzene with soluble hydrated tetraalkylammonium

fluorides according to (ref. 17).
RaNF, nH20 Solvent Conv. 1 Yield 2 Yield (3 + 4) Initial rate of

(%) (%) (%) formation for 2
102.Vo (min-1)
Sulfolane 60 42 20 4.29
BuaNF, 3H20 DMSO 56 20 3.11
DMF 43 20 3.91
Me4NF, 4H20 Sulfolane 60 48 12 4.85
Et4NF, 2H20 Sulfolane 55 45 10 4.17
BnMe3NF, H20 Sulfolane 52 47 5 2.41
Table 4 shows that :

- The initial rate of formation of aryl fluoride, but also the yield of oxygenated
by-products, increase with the water content of the reagent,
- The final yield of aryl fluoride increases with the solvent polarity,
- The initial rate of formation of aryl fluoride increases when the solvent polarity
decreases.
The effect of the water content in the ammonium fluoride is illustrated on
Figure 1 (from (refs. 17,18))
250
NO 2 NO 2
1
BnMe3NF, n H20
CI Sulfolane/120~ / 2 h
F
100
80
"5 6O
- - I - - Yield 2
40-
20 m
m
w
0 | | I
0 1 2 3 4
n H20
Fig. 1. Influence of water on the reaction of 3,4-dichloronitrobenzene with BnMe3NF, nH20

(refs. 17,18)
Thus, such extended side-reactions constitute a severe drawback for the use of
hydrated alkylammonium fluorides in aromatic fluorination. This problem can be
+ -
avoided by using other solvates of onium fluorides, especially species like RaM F ,
nHF and, for instance, BuaN+HF2 - (n = 1), BunN+H2F3 - (n = 2), Bu4N+H3F4 -
(n = 3), Bu4P+HF2 -, PhnP+HF2 - or Ph4As+HF2 -. These compounds are easily
prepared from R4M § nH20 or R4M § by phase-transfer techniques
(refs. 17,19 - 21) or ion-exchange on resins (refs. 17, 20, 22 - 27). However, their
ability to displace aromatic chlorine is dramatically dependent on the degree of
solvation of the fluoride, as shown on Figure 2 (refs. 17,18) :
251
NO2 NO2
Bu4NF, n HF (1 eq.)
Sulfolane / 120~ 92 h.
~]~C1
(HF2-/solv. = 1/25)
C1
80
60
O
E 40
2O
v ! |
0 1 2 3 4
n (F-, n HF)
Fig. 2. Influence of the degree of solvation in Bu4NF, nHF on the fluorinating power
(refs. 17,18).
In practice, only monohydrogenofluorides are efficient for "Halex" reactions.

Moreover, two equivalents of Bu4NHF 2 are needed to obtain quite quantitatively 2_
from 1 but, under the above conditions, the reaction is completely chemoselective
(Fig. 3) (refs. 17,18).
252
NO2 NO2
Bu4NHF2 ,._,._
Sulfolane
CI
120~ 92 h C1
C1
100
80
6O
9
40
20
"V" | !
0 1 2 3
Mol.ratio Bu4NHF 2 / 1
Fig. 3. Influence of the excess of Bu4NHF2 on the fluorination yield
This p h e n o m e n o n can be explained by the f o r m a t i o n of n o n - r e a c t i v e higher-

solvated f l u o r i d e s w h e n the reaction p r o c e e d s 9
ArC1 + Q + HF2- ~- A r F + Q +CI + H F
Q + HF2- + HF Q+H2F 3-
ArC1 + Q + H2F3- /N/

~ ,.._ ArF
ArC1 + 2 Q+HF2 ArF + Q + C1- + Q + H2F3-
253
Fluorination yields are less sensitive to solvent effects with Bu4NHF 2 than with
BuaNF, 3 H20 (Tables 4 and 5) but the same tendency is observed. It can be
noticed that this effect can be correlated to the variation of 19F NMR chemical shifts
for solvated F- in different solvents (see below). Thus, the measurement of 19F
chemical shifts could be a fruitful guide to choose a convenient solvent for
fluorination.
C1 C1
~ ~ _ _ R4M +HF2-(2 eq.)
O2N CI ~ O2N F
Solvent (HF2- / solv. = 1/25)
120~ / 2 h
_1 2
Table 5. Fluorination of 3,4-dichloronitrobenzene with onium hydrogenofluorides according to

(ref. 17).
RaM+HF2- Solvent Yield 2 102.Vo

(%) (min1)
DMSO 92 7,34
Bu4N+HF2 DMF 91 8,08
Sulfolane 88 8,10
Bu4P+HF2- Sulfolane 68
Ph4P+HF2 Sulfolane 44
Ph4As+HF2- Sulfolane 60
Table 5 clearly shows that ammonium hydrogenofluorides are far better

fluorating agents than other onium hydrogenofluorides 9
BuNHF 2 > Bu4PHF 2 > Ph4AsHF 2 > Ph4PHF 2
As previously mentionned, the possibility of a reverse reaction, that is the

formation of chloroaromatics from fluoroaromatics, must be investigated, especially
with onium halides since, in this case, no solubility problem can disturb the eventual
equilibria. Table 6 indicates that tetrabutyl ammonium or phosphonium chlorides,
when dried, react to a very limited extend with fluoroaromatics, even in
concentrated medium with very activated substrates like 2,4-dinitrochlorobenzene
(ref. 17).
254
However, water enhances dramatically this " R e t r o - H a l e x " reaction but only
when performed on very activated substrates (ref. 17).
An explanation could be found in the fact that the fluoride anion can be far more
strongly solvated than the chloride anion : hydration could thus be an effective
driving force for the "Retro-Halex" reaction.
X X X
O2N-~F + BunM+CI, xH20 Solvent ~ O 2 N - ~ C 1 + O2N~OH
(1 eq.) 120~ / 2 h
Table 6. Displacement of aromatic fluorines by onium chlorides.
X M x(H20) Solvent* Conv. ArF Yield ArC1 Yield ArOH

(%) (%) (%)
N 1 Sulfolane 52 44 8
DMF 80 68 12
NO2
N 0 DMF 8
P 0 DMF 13
C1 N 1 Sulfolane
* CI- / Solv. = 1/2 (mol/mol)
As already noticed, the anionic fluorinated species are cominuously changing as

the halogen exchange proceeds in homogeneous media and this reaction is sensitive
to the nature of the solvent. In order to have a better knowledge of the process at
every moment and to quantify the solvent-solute interactions, 19F N M R spectra of
different solvated fluorides have been recorded in several solvents (refs. 17,18)
(Table 7).
255
T a b l e 7. C h e m i c a l shifts (19F N M R ) f o r s o l v a t e d f l u o r i d e s in d i f f e r e n t s o l v e n t s ( f r o m (ref. 17))
19F N M R ; 8 ( p p m vs. CHCl3)a'b); JHF ( H z ) o r Av ( H z )

|
Solvent 2~C-VHg_
Bu4NF, Bu4NH2F 3 Bu4NH3F4 MeaNF, MeaNF, EtaNF,
Bu4NHF2 d) d) 2 H20 4 H20 2 H20 NMe-T,
3 H20
H20
HCONMe 2 -93.2 - 131.7 - 152.0
DMSO - 104.0 - 143.8 - 160.2 - 99.7 - 108.6 - 101.9 - 97.4

(Av=12)
DMSO-d6 - 150.1 - 161.8

(d,J=119)
CH3COCH3 - 109.4 - 151.3 - 167.6
HCONHMe - 113.2 - 144.3 - 163.6
CD2C12 - 118.7 - 1 5 3 . 8 c) - 170.4 - 170.6 - 118.1
EEl 4 - 113.2 - 144.8 - 164.9
HMPT - 114.1 - 150.4 - 168.2
MeCN - 114.1 - 149.9 - 165.4 - 111.7

(Av= 10)
DMF -114.4 -149.4 - 166.3 - 112.6
(Av=10)
DMAc - 116.1 - 150.6 - 166.4 - 114.6
(Av=31)
PhNO 2 - 116.5 - 153.0 - 164.5 - 119.4
(Av=32)
PhCN - 116.5 - 151.3 - 167.7
DMPU - 116.5 -155.1 - 169.3
DMEU - 118.1 - 155.8 - 168.8
Sulfolane - 120.4 - 155.9 - 168.4 -114.3 -120.7

(zXv=40)
MeOH - 147.4 - 160.1 - 172.5
C1CH2CH2C1 - 157.4 - 167.6
HMPT = hexamethylphosphoramide ;DMPU = N,N-dimethylpropyleneurea ;

DMEU = N,N-dimethylethyleneurea
a) Singlet if no other indication provided

b) F- / s o l v . = 1 / 5 0 ( m o l / m o l )
c) becomes a doublet at- 56~ (8 = - 1 4 2 . 5 p p m ; JHr = 120 H z )
d) large singlets
256
The chemical shifts have been correlated satisfactorily with the solvent
parameters AN (acceptor number (ref. 28)), DN (donor number (ref. 29)) and
(dielectric constant) for a set of nine solvents (acetone, acetonitrile, DMF, DMAc,
nitrobenzene, sulfolane, HMPT, benzonitrile, methanol) (ref. 17) (Fig. 4). The
predominant weight of AN indicates clearly the basic character of solvated fluorides
which, however, is strongly modulated by HF-solvation and can be quantified in
that way. Thus, the correlation between the chemical shift and the reactivity of
soluble fluoride anions could, in principle, allow to predict their fluorination
efficiency in any solvent.
FLUORINATION WITH ALKALINE FLUORIDES

Because of their price and availability, alkaline fluorides are the most attractive
anionic fluorinating agents. Caesium fluoride is the most reactive of them but,
because of its price, is only devoted to the preparation of products with very high
added values. At the other bottom, lithium and sodium fluorides are completely
unreactive. Thus, potassium fluoride, which presents the best ratio between cost and
reactivity, is the most popular reagent to perform the "Halex" reaction on a large
scale. In fact, no other inorganic fluorides than alkaline ones have been claimed for
this technique. Taking into account that all inorganic fluorides and chlorides are
sparingly soluble in aprotic solvents and that solubility could be a significant
parameter in the "Halex" process, this point can be understood when looking at the
lattice energy of solid inorganic fluorides and chlorides. Indeed, a reaction in which
one reagent and one product are both in the solid state, must be favoured if the
lattice energy of the product is larger than the lattice energy of the reagent. In fact,
the lattice energies of fluorides are always larger than those of chlorides. This gap
is partly balanced by a higher solvation energy for fluorides and a larger energy for
C ~ F bonds (452 kJ/mol) than for C----C1 bonds (339 kJ/mol) (ref. 11).
Nevertheless, minimizing the difference between lattice energies of chlorides and
fluorides must favour the process. This difference lies between -196 and
-83 kJ/mol for alkaline salts, between- 146 and-280 kJ/mol for alkaline earth salts
and between-272 a n d - 1 8 8 kJ/mol for transition metal salts (ref. 31). Thus,
alkaline fluorides appear to be the less unadapted reagents for substitutive aromatic
fluorination. Some of their thermodynamic data are reported on Table 8.
257
BU4NF.3H20 Bu4NHF2
Y( I)=89.6+ I.16 AN+O. 14 DN+0.2 c Y(2)= 144.3 + 0.29 AN -0.04 DN + O.14 r
150 170
165
140
'~ 160
E CI,BOH
130
//"
Dr.l~
ca
155 I
I Sulfolanea
6 120 d
G 150
t.)
eL!
II0 145
140,
I00
i 9 l 9 , _
140 150 160 170

" ! " i 9 i 9 ! 9
100 110 120 130 140 150

Y expeMmental (ppm)
Y experimental (ppm)
Bu4 N H2. F3
Y(3)= 16 I.I +0.2 AN +0.09 DN +0.04 c
175
E
e,t
170
4D
U
>" 165
160 9 i 9 i 9
160 165 170 175

Y expeMmental (ppm)
Fig. 4. Correlations between ]9F NMR chemical shifts of solvated fluorides and. solvent
parameters (NEMROD program (ref. 30)).
258
ArC1 + MF ~ ArF + MCI
Table 11. Thermodynamic data for alkaline fluorides and chlorides
M EL('MF)a) EL(MC1)a) AEL (MC1-MF) a) AG~176 b) AH(ArC1---~ArF)c)

(kJ/mol) (kJ/mol) (kJ/mol) (kJ/mol) (kJ/mol)
Li 1030 834 -196 194 +83
Na 910 769 -141 152 +28
K 808 701 -107 122 -6
Rb 774 680 -94 114 -19
Cs 744 657 -87 102 -26
Fr 715 632 -83 -30
a) E L = lattice energy; according to (ref. 31) and (ref. 32)

b) according to (ref. 33)
c) according to (ref. 11)
Table 11 can only provide general tendencies since it cannot explain the fact that
caesium fluoride is not much more soluble than potassium fluoride and, even, can
be less soluble, as reported from our o w n measurements in Table 12.
259
Table 12. Apparent solubilities of caesium and potassium fluoride (electrochemical analysis of
the supernatant solution after stirring for 1 h and decantation for 10 min at 0~
Solvent [KF] (ppm) [CsF] (ppm)
40~ lO0~ 150~ 40~ IO0~ 150~
2,4-C12C6H4-NO2 23 65 <1
Benzonitrile 42 105 25 24 10
DMAc 18 290 40 28 155 165
DMF 25 70 110 20 120 150
N,N-Diethyl acetamide 85 225 170 50 50 70
Acetonitrile 50 20
m m
Sulfolane 44 490/190" 200 48 135 230
Sulfolane + 1% H20 70 100 240 //

m
Sulfolane + 5 % H20 30 130 130

m
NMP 81/20" 635/160" 360/140" 41 215 90
DMSO 20 70/80* 40 35 75 220
DMPU 135/20" 335/100" 140/70" 610 190 240

* Results from two experiments
These results are not completely accurate and reproducible since they are very
dependent on the quality of the fluoride. Sometimes, the figures given in Table 12
do not constitute a real solubility value but the analysis of a ,, colloidal ,, suspension,
as demonstrated from analyses before and after ultrafiltration of the supernatant
solution:
Table 13. Real solubility of potassium fluoride
Solvent [KF] before filtration [KF] after filtration

(• = 0.45 p m - Millipore HV)
Sulfolane 44
DMSO 20
260
Thus, solubility values from Table 12 (or other papers) must be taken with care
for kinetic calculations, especially when relations for homogeneous systems are
used. For instance, these values cannot be taken into account to explain the reported
difference of reactivity between several alkaline fluorides in "Halex" reaction
(ref. 17)
C1 C1
_ _ ~ Sulfolane (2 eq.)
O2N C1 + MF ~ O2N F
150~ h
leq. 2eq. M =Na 0 %
M=K 5%
M=Rb 6%
M = Cs 95 %
When we started to study this reaction, reported informations, which, on the

other hand, were dispersed and sometimes difficult to link together, led us to think
that the "Halex" process, when performed with alkaline fluorides, was more
complex than already reported. Thus, we tried to quantify the effect of all
significant parameters in a reliable way, in order to optimize the results, especially
for the manufacture of 2,4-difluoronitrobenzene, and to have a deeper knowledge of
the mechanism.
Fluorination with pure caesium fluoride

Caesium fluoride is really the most efficient fluoride since it reacts significantly
with 2,4-dichloronitrobenzene (DCNB) at a temperature as low as 80~ and
converts quite completely this substrate at 120~ whatever is the supplier of the
fluoride. However, the rates of formation of the different products seem to be
dependent on the origin of this fluoride (Table 14).
261
NO2 NO2 NO2 NO 2
C1 F+ C~ .F
CsF (--- 3 eq.)/0~ h
,,,..._
Sulfolane
(CsF/Sulf. -- 0.5 wt/wt)
C1 C1 F F
DCNB 4CI2FNB 2C14FNB DFNB
Table 14. Aromatic fluorination with caesium fluoride
CsF (origin) 0~ conv.DCNB Yield DFNB 4C12FNB + 2C14FNB 2C14FNB

(%) (%) (%) 4C12FNB
80 33.8 2.5 30.9 0.23

90 74.3 18.6 52.6 0.22
Chemetall
120 97.5 78.2 2.1 0.80
130 97.6 79.7 2.4 2.00
90 73.9 17.3 51.4 0.21

Janssen 120 96.3 67.6 12.8 0.18
130 97.3 70.0 3.6 0.61
Fluka 120 94.3 50.9 26.4 0.17
Aldrich 120 95.9 58.0 18.5 0.18
This dispersion could be related to the fact that caesium fluoride is very difficult
to dry thoroughly (more than potassium fluoride). As a consequence, fluorination
with CsF ~ 180~ is quite completely matched by the formation of oxygenated by-
products.
Fluorination with pure potassium fluoride
Influence of w a t e r
Potassium fluoride is also very hygroscopic as shown in Figure 5 for
commercial KF submitted, at room temperature, to an atmosphere with a relative
humidity of 50 % (ref. 17).
262
[ % H20 in KF
40 ~. (wt/wt) ....1o
30 I
I
J
20 KF Riedel de Ha/m
10
Time (h)
! ! | - !
0,0 0,5 1,0 1,5 2,0
Fig. 5. Absorption of water by KF (Riedel de Ha6n) at 20~ under a 50% relative humidity (ref.
17)
The reverse process, that is drying, is far much more difficult because of very
strong hydrogen bonds between water and the fluoride anion, which is the smallest
and the most electronegative halide.
As depicted in Figure 6, water contents below 0,4 % in weight are difficult to
reach by usual techniques (ref. 17).
k %H20 in KF
2~ o
llO~
IB
Time (h)
i | ! | ! | |
0 1 2 3 4 5 6 7
Fig. 6. Drying of KF at ll0~ under atmospheric pressure (ref. 17)
However, small amounts of water have been claimed to be beneficial for the
" H a l e x " reaction (refs. 34 - 40) and we examined this point quantitatively. It is
very clear that at 180~ the temperature needed to get a valuable conversion of
dichloronitrobenzenes, water has a deleterious effect on the yield of
263
fluorocompounds : whatever is its concentrations, water competes with F- and
oxygenated by-products increase dramatically for water contents in KF above 1 %
(by weight). Nevertheless, at lower temperatures, which usually deliver low
conversions of the substrates and thus are not useful for industrial application, a
m a x i m u m value is observed for both conversion and yield for a given water content
of KF which is dependent on the nature of the substrate and temperature (Table 15).
Table 15. Influence of water on aromatic fluorination with K F
Substrate Conditions H20 in Conv. ArCI ArF A conv. A select.

KF
( % wt/wt) (%) yield select. (relative) (relative)
(%) (%)
a) DMF / 120~ / 0.4 D~ 67.3 67.3 100
2h 8.6 97.4 c)
O2N 92.1 94.6 + 45 % -5 %
NO2
a) Sulfolane / 150~ 0.4 ~) 11.7 11.7 100
/4 h 13.4 c3
O2N--~C1 13.4 c) 100 + 15 % 0 %
c1
Sulfolane / 120~ 0.4 o) 6.0 4.2 70
OzN / 11 h 5.6 6.0 5.2 86c~ 0 % +23 %
C l - ~ Cl 7.0 10.0 c) 6.0 60 + 67 % -14 %
Sulfolane / 150~ 0.4 D) 40.0 35.0 87.5

/ llh 2.5 44.0 c~ 38.0 c~ 86.3 + 10 % -1%
a) from (ref. 17) b) standard condition c) m a x i m u m value observed
It must be noticed that water does not influence yield and selectivity in the same
way. On the other hand, separated analyses of the liquid and solid phases during
reaction indicate that, for initial water contents of potassium fluoride below 1% wt,
water remains on the solid. This observation is consistent with the fact that small
additions of water on KF do not increase the solubility of this salt in aprotic solvents
(Table 12).
The effect of water could be rationalized by considering that water weakens the
interaction between K § and F- at the surface of the solid and F- is thus more
available for the reaction. But fluoride is consequently hydrated and becomes less
nucleophilic. This could explain that, during the fluoration of 2,4-
dichloronitrobenzene, water favours to a larger extend the formation of
chlorofluoronitrobenzenes than the formation of difluoronitrobenzene. On the other
264
hand, this latter compound is more sensitive to hydrolysis than the former ones, so
that the presence of water becomes rapidly a drawback concerning the final yield.
It has been already reported that, with organosoluble ammonium chlorides,
water favours the "Retro-Halex" reaction which competes with hydrolysis. Similar
experiments showed that this process does not occur under heterogeneous conditions
(aromatic fluoride and solid KC1 or CsC1 in aprotic solvent), whatever are the
substrates, the solvent and the source of inorganic chloride, provided that the water
content of the latter remains around or below 1 % by weight. This point has been
confirmed independently in a very recent paper (ref. 41). However, when 10 % wt
of water is added to potassium chloride, the "Retro-Halex" has been observed,
though hydrolysis was the major process (ref. 17) :
NO2
NO2
KC1 + 10 % H20
NO2
('~'~ + + heavy pdts
DMF/120~ h
NO2 NO2 NO2
F C1 OH
conv. = 42 % yields = 2 % 13 % 27 %
Influence of the solvent

The nature of the aprotic solvent plays a crucial role for the aromatic
fluorination with fluorides. Some accurate determinations have been performed
either on 3,4-dichloronitrobenzene (ref. 17) (Table 16) or 2,4-dichloronitrobenzene
(Table 17).
265
C1 C1
O2N C1 r- O2 N
Solvent (50 eq.)
160~ h
Table 16. Influence of the solvent on "Halex" reaction for 3,4-dichloronitrobenzene
Solvent Yield ArF 103.Vo (min-1)

(%)
DMSO 100 28.1

HMPT 53 5.02
DMAc 45 3.73
Sulfolane 37 3.21
DMPU 34 3.01
DMEU 23 3.52
NMP 16 2.56
HMPT = Hexamethylphosphoramide" DMPU = N,N-dimethylpropyleneurea

DMEU = N,N-dimethylethyleneurea
In all cases (Tables 16, 17), DMSO is the best solvent, concerning both kinetics
and yields of the halogen exchange, but its sensitivity to bases and its poor thermal
stability do not favour its use in practice. For other solvents, the scale of efficiency
is somewhat dependent on the substrate (and may be, as a consequence, on the
temperature). For instance, sulfolane is better than NMP in the case of 3,4-
dichloronitrobenzene and the reverse is true for 2,4-dichloronitrobenzene. Reactions
are very slow in benzonitrile which, in practice, is devoted to " H a l e x " reactions on
very stable substrates, like polychlorobenzenes, at temperatures above 300~ N,N-
dimethylethyleneurea (DMEU) and N,N-dimethylpropyleneurea (DMPU), claimed
to replace advantageously the carcinogenic HMPT, are not suited to aromatic
halogen-exchange.
266
NO2 NO2 NO2 NO 2
CI F C1 .F
KF (3 eq.)
,,,,._
Solvent
(KF/solv. = 0.5 wt/wt)
C1 0~ h C1 F F
,v
DCNB CFNB DFNB
Table 17. Influence of the solvent on "Halex" reaction for 2,4-dichloronitrobenzene
Solvent 0~ conv. DCNB Yield DFNB Yield CFNB

(%) (%) (%)
DMSO 130 71.0 21.8 51.5

Sulfolane 130 3.4 0 3.4
Sulfolane 180 83.0 25.8 45.0
Sulfolane 180 92.7 46.8 32.6
+ DMSO2*
NMP 130 24.4 1.1 16.0
NMP 180 95.9 44.3 12.1
DMEU 180 92.4 4.3 6.2
DMPU 180 84.3 19.4 17.6
PhCN 180 6.1 0.2 0.9
* DMSO 2 = dimethylsulfone
Influence of the reagent ratios

Usually, the literature recommends to use 2 equivalents of fluoride for each
chlorine to replace. However, we observed, for 2,4-dichloronitrobenzene at 180~
that 1.5 equivalent per chlorine are sufficient. For higher ratios, conversions and
yields remain almost constant, except that hydrolysis of 2,4-difluoronitrobenzene
increases a little because of the supplementary water brought with the excess of
potassium fluoride. Very recently, Smyth et al. (ref. 41) reported that 3.75
equivalents of potassium fluoride are needed, in D M F at 125~ to convert
completely D C N B to DFNB.
Nevertheless, the ratio KF/substrate influences a little bit the isomeric ratio of
chlorofluoronitrobenzenes obtained at the end of the reaction. For instance,
2C14FNB/4C12FNB moves from 1/5 (when K F / D C N B = 1.5) to 1/3.8 (when
267
KF/DCNB = 3). This difference, concerning the kinetics of monofluorination, will
be discussed later.
Fluorination with KHF2

As for the "Halex" reaction in homogeneous medium, it could be thought that
potassium hydrogenofluorides would be a valuable alternative to potassium fluoride
all the more so since its lattice energy is close to that of potassium chloride :
E L (KX) = 808 (X = F), 703 (X = HF2), 701 (X = CI) (kJ/mol)
However, results are exactly the same, wether 3,4-dichloronitrobenzene is

opposed to KHF2 (2 equivalents) or KF (2 equivalents) at 150~ or 180~ in
sulfolane (ref. 17). With less reactive substrates like 2,4-dichloronitrobenzene,
potassium hydrogenofluoride is far less effective than potassium fluoride (Table
18). Corrosion of the glass vessel by KHF2 is a supplementary drawback.
NO2 NO2
C1 ~ NO2
/ F C1 F
KF, nHF (x eq.) ~ ['("-")"~ + +
Solvent
(KF, nHF/solv. - 0 , 4 - 0,6 wt/wt)
Cl Cl F F
v
DCNB CFNB DFNB
Table 18. Aromatic fluorination with KHF 2
Solvent Conditions conv.DCNB Yield DFNB Yield CFNB

(%) (%) (%)
130~ h 3.0 3.4 0 3.4
5.2 0.9 0 0.8

Sulfolane
180~ h 2.1 82.3 26.1 47.9
2.1 24.9 0.3 10.9
DMSO 130~ h 4.5 77.7 28.8 52.5
5.0 8.7 0.5 8.1
DMF 130~ h 4.9 3.7 3.7
268
Fluorination by KF catalysed with CsF
Comparison between Tables 14 and 15 clearly demonstrates that caesium
fluoride is far more effective than potassium fluoride towards 2,4-
dichloronitrobenzene. As some papers reported about the addition of CsF as catalyst
in the "Halex" reaction using KF (refs. 42 - 46), we quantified the behaviour of
CsF-KF mixtures to look for some synergistic effect.
It can be answered positively to this question when examining the reaction of
KF-CsF mixtures with 2,4-dichloronitrobenzene at 130~ for 6 h in sulfolane
(Fig. 7). As pure KF is not reactive under these conditions, line A was expected to
represent the variation of DCNB conversion against the molar ratio of CsF in the
fluorinating agent. However, curve B was obtained concerning the DCNB
conversion and lines C and D represented the selectivities for chloronitrobenzenes
and difluoronitrobenzene. Thus, a catalytic effect of CsF is really observed in
sulfolane and is particularly interesting for molar ratios (CsF/CsF + KF) below
5 %, as detailed in Table 19. CsC1 and RbF, though being a little bit less effective,
behave in the same way in sulfolane.
However, the caesium effect is less pronounced in DMSO (Table 19).
Concerning the role of the solvent in the "Halex" reaction, it can be observed that
the scale of efficiency is not modified when the molar ratio of CsF remains lower
than 8 % but, for larger ratios, all the solvents, except DMSO, tend to become
similar.
Some other inorganic fluorides (SbF 3, CdF 2, ZnF2) have a positive catalytic
effect, though less pronounced than that of CsF, whereas AgF and CuC1 inhibit the
reaction to a large extend (Table 20).
269
% ArF
100
90
8O
70 +
60
A-
50
40
30 /
20
10
CsF
% Mol
CsF + KF
0 5 10 20 30 40 50 60 70 80 90 100
Fig. 7. Fluorination of 2,4-dichloronitrobenzene with KF + CsF in sulfolane at 130~ for

6 h (F-/DCNB = 3.0 mol/mol; F-/solvent = 0.3 to 0.5 mol/mol).
A Theoretical conversion of DCNB from CsF only
B Experimental conversion of DCNB
C Selectivity for chlorofluoronitrobenzenes
D Selectivity for 2,4-difluoronitrobenzene
270
NO2 NO2 NO2
~O2 C1
( I ~ + MX) (3 eq.)
Solvent/6 h
0~
C1 C1 F F
v
DCNB CFNB DFNB
Table 19. Catalysis of the "Halex" reaction with caesium or rubidium salts
Solvent MX MX Conv. DCNB Yield DFNB Yield CFNB

MX+KF (%) (%) (%)
(%)
i
0.00 83.0 i 45.0 25.8
o
I
0.90 99.5 71.9 12.2
CsF 2.50 100 95.3 4.7
Sulfolane 5.00 100 96.4 3.6
(180~
CsC1 1.00 98.6 65.0 21.0
,
RbF 4.70 95.4 48.2 32.8

,
0.00 71.0 51.5 21.8
DMSO 1.01 94.3 53.9 37.9

(130~ CsF 2.50 95.0 55.7 36.3
6.50 96.9 64.0 31.3
271
Table 20. Catalytic effect of inorganic salts on "Halex" reaction
MX MX A (conv.DCNB) A(DFNB) A(CFNB + DFNB)

KF+MX conv.DCNB DFNB CFNB + DFNB
(%) (%) (%) (%)
SbF3 (sulfolane; 180~ 10 +8 + 33 -5
CdF2 (sulfolane 130~ + 37 +71 + 33
ZnF2* (sulfolane; 130~ +18 +43 +21
AgF (DMSO- 130~ -52 - 87 -55
CuC1 (DMSO" 130~ -53 - 92 -64
* To be compared to (ref. 47)
Fluorination by KF with phase-transfer catalysts

Phase-transfer agents are the most popular catalysts for the " H a l e x " reaction
with alkaline fluorides. All types of transfer agents have been claimed : tetraalkyl-
ammonium halides (refs. 34, 48), Aliquat 336 (ref. 49), branched pyridinium
halides (eventually supported on a polymer) (refs. 50 to 53), tetraalkylphosphonium
chlorides (refs. 42, 54 - 57) or bromides (ref. 12), crown-ethers (refs. 58, 59)
eventually associated with Ph4PBr (refs. 43, 60), tris-(dioxa-3,6-heptyl)amine
(TDA- 1) (ref. 61) or polyethyleneglycols (PEG) (ref. 62).
All these references provide very dispersed indications. Thus, we wished to
estimate quantitatively the effectiveness of some phase-transfer catalysts under the
same conditions and to compare them to caesium fluoride.
Indeed, onium salts improve dramatically the results for the substitutive
fluorination of 3,4-dichloronitrobenzene in sulfolane at 120~ as shown from the
relative initial rates (ref. 17) :
272
C1 C1
O2N-~C1 Sulfolanel20oc O2N~Q~-
Catalyst : - Vo = 1 (relative)
Bu4NC1 125
Bu4PC1 111
PhaPC1 114
PhnAsC1 124
18-crown-6 5
These figures indicate clearly that all onium salts, including tetraphenylarsonium
chloride which has not been tested before, are far more effective than 18-crown-6 at
120~ in sulfolane. The same is true in DMSO. However, at 160~ the crow-
ether, which is more thermally stable than onium salts, becomes the best catalyst.
In our hands, the following results were obtained with 2,4-dichloronitro-
benzene (Table 21).
The [2.2.2] cryptand is not more effective than tetramethylammonium chloride
and cannot be used in very low concentrations (no effect for 0.02 %). Thus, its cost
and toxicity preclude its industrial use. Other catalysts like TDA-1 or Et3N,3HF
have no significant effect. Phtaloyl dichloride, though claimed to be useful for the
"Halex" reaction (refs. 63, 64), does not bring any improvement in sulfolane, even
at 180~ and, moreover, induces side-reactions in DMSO. The same is true for
polyethyleneglycols.
273
NO2
C11 NO2 NO2 NO 2
KF (3 eq.) F C1 ~~~]/F
Catalyst/solvent + +
0~ h
C1 C1 F F
9 ,, 9
-y
DCNB CFNB DFNB
Table 21. Influence of phase-transfer catalysts on the fluorination of 2,4-dichloronitrobenzene.
Solvent 0~ Cata. Cata Conv. Yield Yield

~(%)
KF DCNB DFNB CFNB
(%) (%) (%)
none 0.0 3.4 0.0 3.4
MeaNC1 4.1 78.6 26.8 47.7
Sulfolane 130~ PI~PC1 1.3 83.7 32.2 43.1
Ph3SC1 1.5 46.7 6.2 33.3
180~ none 0.0 83.0 25.8 45.0
Me4NC1 3.0 90.5 35.2 35.6
none 0.0 71.0 21.8 51.5
Me4NC1 2.2 100.0 93.1 1.8
Ph3SC1 3.9 99.0 65.6 18.6
DMSO 130~ Ph4AsC1 3.9 100.0 66.6 0.6
BnMe3NBr 4.1 99.9 76.8 9.2
BnMe3NHF2 4.4 98.7 71.5 18.0
[2.2.2] 1.45 100.0 85.3 2.8
Under conditions mentionned in Table 21, tetramethylammonium chloride is

more effective than caesium fluoride to improve the " H a l e x " reaction on DCNB at
130~ (refs. 65 - 67). However, a synergistic effect is observed when combining
these two catalysts (Table 22).
274
Table 22. Comparison of CsF and Me4NC1 as catalysts of the "Halex" reaction on DCNB
(130~ h/3eq.KF/KF:Solv. = 0.5).
Solvent CsF/KF Me4NC1/KF Conv. DCNB Yield DFNB Yield CFNB

(%) (%) (%) (%) (%)
DMF 24.0 64.0 15.1 48.7

2.5 99.5 78.3 14.7
DMAc 23.0 56.5 10.5 44.0
31.2 97.7 55.5 25.5
71.0 21.8 51.5
DMSO 6.5 96.9 64.0 31.3
2.15 100.0 93.1 1.8
3.4 0.0 3.4
5 22.7 1.5 22.3
Sulfolane 8.7 33.4 2.3 30.1
4.1 78.6 26.8 47.7
4.4 89.4 40.8 41.6
NMP 24.4 1.1 16.0

8.0 47.9 7.9 44.6
C u r i o u s l y , the increase of conversions and yields due to the catalysts does not
se e m to be s i m p l y c o r r e l a t e d to an increase of the K F solubilities (Table 23).
Table 23. Solubilities of KF and CsF in the presence of Me4NC1
Solvent [KF] (ppm) [CsF] (ppm)

40~ * 100~ 150~ 40~ 100~ 150~
Sulfolane 490/190 200 48 135 230
DMSO 70/80 40 35 75 220
Sulfolane + Me4NC1 250 650 140 290 800
DMSO + Me4NC1 5 330 90 110 250
* after filtration
275
The same remark has been reported by Rieux (ref. 17) and, very recently, by
Smyth et al. (ref. 41) who observed that the solubility of KF in DMF is not
proportional to the concentration of added cetyltrimethylammonium bromide.
Influence of the pre-treatment of KF

As the "Halex" reaction using alkaline fluorides is carried out in an
heterogeneous system, the influence of the physical state of the solids must be taken
into account. Several pre-treatments of potassium fluoride have been proposed to
improve its performances which are evidently linked to the area of the solid surface.
Spray-drying (refs. 68, 69) and freeze-drying (ref. 70) are now considered as more
activating treatments of KF than calcination. Very recently, however, slow
recrystallisation in methanol has been claimed to deliver a potassium fluoride which
is even more effective than the spray-dried one (ref. 41). Some comparisons are
given on Figure 8, Table 24 and Pictures 1 and 2.
Table 24. Pre-activation of potassium fluoride
Drying Mean size Specific Density Typical

technique of particles area (g/~) water content
(~tm) (m2/g) (%)
Calcination 200-300 0.1 1.4-1.6 0.30
Spray-drying (30 %) 10-50 1.3 0.3-0.7 0.24
Freeze-drying (5 %) 38 0.72 0.24
Recryst. MeOH 0.80
276
Picture 2. Spray dried potassium fluoride (ISC Co)
277
CI~NO2 KF > F ~ N O 2
DMSO
% ArF
% ArF freeze-dried KF
spray-dried KF
10o
lOO
SO
calcined KF t / ~ calcinedKF
o 9 9 v ~ 0
0 1 2 3 4 5 h 0 1 2 3 4 5 h
(from (ref. 68)) (from (ref. 70))
Fig.8. Reactionprogresswithpre-treatedKF
For our part, we verified that spray-dried KF is more effective when obtained
from a methanolic solution than from an aqueous solution, since, in the former
case, the B.E.T. surface area is larger than in the latter one. Scanning electron
microscopy (SEM), associated with differential calorimetric analysis, confirms that,
in the latter case, small crystals of anhydrous KF are often aggregated by an
~ amorphous ,, coating of hydrated KF (KF, 2H20 ). SEM revealed also that
potassium chloride, which is formed during the reaction, does not syncrystallize
with potassium fluoride, the surface of which is available all along the reaction
since most of KC1 crystals are segregated from KF crystals.
Spray-dried potassium fluoride is known to aggregate rather rapidly (ref. 71)
and absorption of carbon dioxide (0.4 to 2 %) have been claimed to prevem this
phenomenon (ref. 71). However, in our hands, commercial spray-dried KF did not
show any difference in structure and reactivity with calcined KF.
Thus, we needed a technique which would be simple enough and as rapid as
possible to activate potassium fluoride just prior use. Sonication and grinding in situ
fulfill these criteria. Sonication is the most effective activating technique but
grinding in the easiest to scale-up.
Pre-sonication of potassium fluoride (20 kHz, 20 to 200 W/cm 2) deagglomerates
efficiently the aggregates, the mean size of which decreases from 100 ~tm to 30 ~tm
278
as shown on Figure 9 (distribution in size) and Figure 10 (distribution in area).
Sonification can be also carried out during the "Halex" reaction, either in a
continuous mode or in a pulsed one which, though less energy-consuming, is more
effective (Table 25). ,,,A,,~,,~ ,~,,c,,o,,~,,~,
, oo ~o~ , o2 , os
~ - ......... pre l'reat, gO" U5 ]
; \
/ \ .i
~ ~" ~'o
~,- ~
~ oo ~o 9 , o2 , os
Fig. 9. Influence of sonication on the size of KF particles (Sympatec laser granulometer)

t~loo tot toe ,to3
.. . . . . . .
. US=O
.- ...
..
.: . ................. US=,I O i OOY,
- '. ::" .... "- _ C)

(3_
~q
- _ r,1
: - - " r~
(~ " " - " tr
(Z) ,, -: . _ _. \_ I I I I i 1
Fig. 10. Influence of sonication on the surface area of KF (Sympatec laser granulometer)
279
This activation mode deagglomerates the potassium fluoride all along the
reaction but prevents also the growing of KC1 crystals (Pictures 4 and 5).
NO2 NO2 NO2

C1
KF (3 eq.)
DMSO
Me4NC1 (0.1 eq.)
C1 130~ min C1 F
,0
F
.t
DCNB CFNB DFNB
Table 25. Activation of the "Halex" reaction by sonication.
Activation Conv. DCNB Yield DFNB Yield CFNB

mode (%) (%) (%)
None 43.8 4.0 34.3
Sonication (10 min) prior 79.0 30.0 49.0
reaction
Sonication during reaction 67.1 13.9 52.0
(continuous mode)
Sonication during reaction
(pulsed mode " 0.25 sec/sec) 84.0 34.0 47.0
Dynamic grinding of potassium fluoride, prior reaction, in a Netzsch grinder

(LME1 type, 50~ 1 h, 2620 rpm) decreases also dramatically the mean size of
KF particles, which drops from 65 ~tm to 11 ktm, and, consequently, the same
chemical results can be reached within 3 hours instead of 4.5 hours without
treatment. Grinding is not so effective as sonication concerning the reaction rate but
allows to use more concentrated reaction media without increasing the stirring
energy (Table 26). Microwave activation has been also tested but failed 9a sharp
increase of the initial rate was observed but the reaction was rapidly blocked and
side-reactions occurred. S.E.M. revealed that, in this case, potassium fluoride was
coated by potassium chloride.
280
Picture 4. KC1 crystals after Halex reaction on DCNB for 30 nan at 130~ in DMSO with
continuous sonication (leaflets = Me4NC1)
281
NO2 NO2 NO2 NO2
,C1 KF (3 eq.) F C1 .F
.~ +
Me4NCI (4 %)
DMSO/130~
C1 C1 F F
DCNB CFNB DFNB
Table 26. Influence of the activation of KF
Activation Reaction Conv. DCNB Yield DFNB Yield CFNB

mode duration (h) (%) (%) (%)
None 4.5 99.7 90.3 9.4
Pre-sonication 100.0 92.0 8.0
(10 mn)
Pre-grinding 100.0 92.0 8.0
(1 h)
Kinetic and mechanistic considerations

Because of the high lattice energy of inorganic fluorides, substitutive
fluorination with alkaline fluorides in aprotic solvents is always a two-phase
reaction which is very dependent on the origin and the preparation of the solid
reagent.
In order to get new improvements, it is now necessary to have a better
knowledge of the reaction at the molecular scale and, especially, to determine if the
process is limited by physics (that means by the solubilization of the fluoride) or by
chemistry. In the latter case, the problem is to know if the reaction occurs in the
liquid phase or on the surface of the solid. Some insight could be given by kinetic
measurements and comparison of the influences of the reaction parameters on rate
values. Four cases must be considered depending on the rate-limiting step :
282
Table 27. Nature and consequences of the different rate-limiting processes.
Limitation Consequences Homogeneous Interracial

process process
l . Casel I Case 2 ]
Rate-limiting step Solubilization of KF Diffusion of substrate
Physics rate order for ArC1 1
important parameters 9 Solvent Solvent

9 Temperature Temperature
9 PT catalysts
9 Surfacestate
I Case3 i I Case4 I
rate order for ArC1 1 1
Chemical important parameters 9 Solvent 9 Solvent
reaction 9 Temperature 9 Temperature
9 PT catalysts 9 PT catalysts
(reactivity of F) 9 Surface state
Several observations argue, on a qualitative point of view, against the

hypothesis of an homogeneous process (cases 1 and 3) :
- Potassium hydrogenofluoride, which is more soluble than potassium fluoride,
does not provide better results under the same conditions.
- The reverse " H a l e x " reaction, which is possible with stoichiometric amounts of
tetraalkylammonium chlorides, does not occur with potassium chloride.
- It has been demonstrated that small amounts of water, which can be beneficial
to the " H a l e x " reaction, do not increase proportionally the solubility of potassium
fluoride (Table 12) and remain located on the surface of the solid.
- In the same way, the solubility of F- cannot be correlated to the added amount
of onium salts as indicated in Table 23 and in the literature (ref. 41). Quantitative
determinations show that ammonium salts are mainly located on the surface of the
undissolved potassium fluoride (ref. 17).
- During the incomplete fluorination of 2,4-dichloronitrobenzene, the ratio
between chlorofluoronitrobenzenes is dependent on the initial excess of potassium
fluoride over DCNB. This fact is not compatible with an homogeneous process.
On a quantitative point of view, it can be noticed from Table 16, that the initial
rates cannot be correlated to the solvent parametres (DN, AN, ~, ~t.... ) as in
homogeneous processes.
283
In order to choose between situation 1 and others, the solubilization rate of KF
have been studied in DMSO and sulfolane at 160~ (Fig. 11)
50
160"C
E
c~
o,.
v
I w
i.i.
20
~9 DMSO
+ Sulfo1~ne
10
0 | , |
0 10 20 30 40 50 6O
Minules
Fig. 11. Solubilisation rate of KF at 160~ (from ref. 17).
Surprisingly, the solubilization of KF is a slow process, the rate of which is of

the same order of magnitude as that of the " H a l e x " reaction. Moreover, the lowest
solubilization rate is observed in DMSO which, however, is the best solvent for
fluorination. Despite this contradiction, such a solubilization rate could be
consistent with case 1 (Table 27), concerning the rate-limiting step. However, a
simple treatment of the conversion of aryl chloride against time clearly
demonstrates that this process is first-order relative to ARC1. Such a result rules out
case 1. The same conclusion has been drawn in a very recent paper (ref. 41).
More sophisticated determinations are needed to choose between cases 2 and 4.
Concerning the fluorination of 2,4-dichloronitrobenzene, the following scheme must
be considered (Scheme 2) :
284
NO2
] ,C1
4F2C1NB NO2
~O2 ,C1 F
C1
DCNB
CI
2F4CINB
Scheme 2.
Provided that the second fluorinations are first-order (relative to the substrates)
like the first ones, the following mathematical model can be settled 9
Y1 = 1- e "Kt K = kll + k12
kll (e-Kt _e-k21 t)

Y2 - k21 _ K
k 1 2 (e-Kt _e-k22t)
Y3 = k22_ K
y4= ikllk21+k12k22-k21k22i( e -Kt kll (e -k21t - 1) + k12 (e -k22t -1)

-1) +
(k 21 - K) (k 22 - K) k21_K k22 _ K
where Y1 " - conversion of DCNB

Y2 = yield of 4F2C1NB
Y3 = yield of 2F4C1NB
Y4 -- yield of DFNB
285
This system can be computed in order to fit the calculated curves Yn = f(Y1)
with the experimental ones (figure 12) by optimization of the expression
i=n
Z (Y4Y1exp. -Y4exp.) 2 +(Y3Ylexp.-Y3) 2 + (Y2Ylexp._ Y2exp.) 2
i=l
The rate constants kij result from the fitting. The variations of kij with the
reactions parameters can be thus estimated. In the hypothesis of an homogeneous
process, all kij must be affected in the same way and k12/k11 as well as k22/k21 ratios
must not change. According to this criterium, Table 28 demonstrates that the
homogeneous hypothesis must be ruled out since k12/kll and k22/k21 vary with the
origin of potassium fluoride, the dilution and the presence of CsF or Me4NC1.
Thus, the whole process, including catalysis by CsF or onium salts, must be
interpreted in terms of interfacial reactions.
286
I ! !
Y,-4
~
NO, NO2 NO2 NO~
..C!
KF ~ + +
0.8 Sulfolane
180~
C! Ci F F
DCNB 4C12FNB 2CI4FNB DFNB
0.6
0.'~
Y3
0.2
Y2
! t !
o o.P o.~ 0.6 0.8

YI
ka2/kll = 3 . 5 8 D + 00
k21/kll = 2 . 3 4 D + 00
k22/kll = 2 . 2 0 D + 00
kll = 5.45D-02
k12 = 1.95D-01
k21 = 1.28D-01
k22 = 1.20D-01
f DFNB +
Exp. 2C14FNB X
4C12FNB O
Calc.
Fig. 12. Yn = f(Y1) " calculated (solid lines) and experimental (o, + , x)
287
NO2
~ O2 NO2 NO2
C1
C1
KF (3 eq.)
Sulfolane
180~
~ CI
F
F
C1
F
F
Table 28. Rates constants against some reaction parameters
Conditions 102.kll 102.k12 102.k21 102.k22 kl2/kll k22/k21

(1.mol-l.h-1) (1.mol-l.h-1) (1.mol-l.h"1) (1.mo1-1.h -1)
Standard run
KF type A 5.45 19.5 12.8 12.0 3.58 0.94
KF/solv. =0.47
KF type B 8.11 24.8 5.45 12.4 3.06 2.28
KF/Solv. =0.47
KF type C 7.28 22.6 14.0 11.0 3.10 0.79

KF/solv. =0.47
KF type D I 8.63 17.7 15.5 8.44 2.05 0.54

KF/solv. = 0 . 4 7
KF type E 9.0 19.2 12.5 9.88 2.13 0.79

KF/solv. =0.31
KF type A 10.0 24.5 10.4 13.0 2.42 1.25
KF/solv. =0.31
Standard but KF 5.58 19.0 13.1 9.42 3.40 0.72
added in 4 times
Standard + 11.3 37.5 29.1 20.8 3.32 0.71

2.5 % CsF
Standard + 12.1 I 39.2 36.1 21.6 3.25 0.60

5.0 % CsF
Standard + 11.5 29.5 12.8 21.2 2.55 1.65

2.5 % Me4NC1
A = Riedel de HaEn- calcined

B = Riedel de HaEn- spray-dried by Rh6ne-Poulenc
C = Aldrich- spray-dried
D = Riedel de HaEn - dried in a Turbosphere (R.P.)
E = Morita- spray-dried
288
This hypothesis is corroborated by the kinetic interpretation of experiments
using KF which has been previously activated by sonication or grinding 9 some
pathways can be favoured over others depending on the surface state (Table 29) 9
NO2 NO2 NO2 NO2

C1 F CI+ F
KF (3 eq.)
Me4NC1 (4 %) +
DMSO/130~
C1 C1 F F
Table 29. Influence of sonication and grinding on rate constants
Activation kll k12 k21 k22 kl2/kll k22/k21

(h-1) (h-1) (h-1) (h-1)
None 0.35 0.88 0.98 0.60 2.47 0.61
KF pre-treated 0.72 2.24 1.52 1.60 3.11 1.05
by sonication
(10 ran)
KF pre-treated 0.37 1.66 0.60 0.89 4.49 1.48
by grinding
(1 h)
, ,
The interfacial hypothesis has been also proposed independently and very
recently by Smyth et al. (ref. 41) who correlate the rate constants with the Hammett
parameters (P and o-) and found that the solubilization of KF cannot be the rate-
limiting step since P is as large as + 6.4.
To explain more accurately the observed phenomena, we propose the following
model (Scheme 3) in which the reaction proceeds in a border-phase at the solid-
liquid interface. By analogy with Sasson (ref. 72), this phase could be named
co-phase.
289
Ca--~ ~, )/'---r~ 2
phase
Me 4.N
§ . . . . . Ca . . . . +
9 :~OG "'NMe 4 - - . Ca"

r ~
(31 ..... F"~ .~ .o
K§ F'J §NMe 4
Me, N§ F" KF K*
K§ K§ . (31
Ca F ~ ' ~ ' ~
F" K§ Ca" +
NMe 4
+
Me 4N* Ca- NMe 4
Scheme 3. Border-phase model
This model can explain the results given by the kinetic study :
- The reaction occurs at the solid-liquid interface. Thus, the kinetic rates must
depend on the surface state of the solid and include an absorption term which can
vary from one substrate to another one. With this hypothesis, the formation and
consumption of 2C14FNB and 4C12FNB can vary independently with the surface
state.
- Small amounts of water are known to favour the formation of the c0-phase
(ref. 72).
- Inside the co-phase, which is mainly constituted by solvent, the rules of
homogeneous chemistry can be applied. Thus, the reaction kinetics is dependent on
the nature of the solvent and the concentrations, the conversion of the aromatic
chloride is a first-order process and oniums salts, which concentrate in the c0-phase,
are effective to enhance the nucleophilicity of fluoride anions. This last hypothesis
is consistent with the 19 value ( + 6.4) given by Smyth (ref. 41) who, on the other
hand, also determined activation parameters which are consistent with a
Meisenheimer's process (AH ~ = 24.4 + 4 kcal/mol, AS~ = -14.3 + 2.2 kcal/mol).
290
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292
4-FLUOROPHENOL : A KEY INTERMEDIATE FOR AGROCHEMICALS
AND PHARMACEUTICALS
CLAUDE MERCIER a) AND PATRICK YOUMANS b)
a~ Rh6ne-Poulenc Industrialisation, Centre de Recherche, d'Ing6nierie et de

Technologie, 85 Avenue des Fr~res Perret, B.P. 62, 69192 Saint-Fons Cedex,
France
b) Rh6ne-Poulenc Chemicals, St-Andrew's road, Avonmouth, Bristol, BS11 9YF,
England
INTRODUCTION
4-Fluorophenol is widely used intermediate in the industrial production of
pharmaceuticals (Cisapride and Sabeluzole from Janssen, Sorbinil from Pfizer,
Progabide from Synthelabo (Fig. 1) and more recently an agrochemical specialities
(Fig. 2).
The current methods described in the literature to prepare 4-fluorophenol are
shown in Figure 3 (refs. 1 to 10) where fluorine atom introduction into the
molecule occurs either during the initial (methods B, C, F, H) or final reaction
steps (methods A, D, E, I). All these various methods display both economic or
technologial benefit and disadvantages and none of them seems to be entirely
satisfactory for the industrial production of this compound. To reach productivity
and low cost target needed by the agrochemical market, much work is being
carried out to find profitable methods for 4-fluorophenol production (refs. 1 - 10).
293
NH 2
C1 Cisapride
(Janssen) EP 76530
OMe Gastroprokinetic
OMe
Sabeluzole
I
(Janssen)
Cognition Enhancer
HN.~ 0
0
Sorbinil
(PFizer) EP 172 719
Amidiabetics
Progabide
OH O
(Synthelabo) EP 2400
Antiepileptic
C1
Fig. 1. Pharmaceutical products using 4-fluorophenol as an intermediate
294
Azoles (Fungicides)
,~--x\ Bayer EP 22969 (1978)
N ~,,,, N
(Fungicide)
Du Pont US 4497807 (1978)
SXN= = ~ 0
C1
F O
Br N NCHF 2
Triazolones (Herbicides)
F.M.C. WO 8700730 (1985)
RO
F O
Tetrahydrophtalimide s
(Herbicides)
Sumitomo EP 61741 (1981)
RO O
cl
4-Phenoxyquinoline (Fungicide)
Dow-Elanco
C1
Fig. 2. Agrochemical families using 4-fluorophenol as an imermediate
295
NH-~
Br (C1) OH
F
NH2
OH
Sandmeyer ( D /
OH A l k a l ~ B) (C) Hydrolysis ~ F l u o r o
Hydrolysis N ~ %
dediazoniation
H
(A)
OH
Fluorination ~ ~ Fluorodealkylation
R O
(I) .. h,. _A
(F)
Hydroxylation F Bayer-Villiger
Rearrangement
F Fluoro- ,/ , 4 F
decarboxylation/(H) olysis
~H / HN--OTs
[
Fig. 3. Methods for preparation of 4-fluorophenol
Method A (direct fluorination) or method I (hydroxylation) starts from very

cheap raw materials but present problems of regioselectivity and low yield. Fluoro
dediazoniation (method D) starting from easily available raw material, presents
poor selectivity and problems of technology, recycling on scale-up.
296
The only two industrial methods to produce 4-fluorophenol are currently using
4-fluoroaniline (method C) or 4-bromofluorobenzene (method B) as starting
material, (Fig. 4).
Br (Cl)
I
,,
NO 2
C1 CI F F
4-FLUOROPHENOL 9 M = 112
Mp = 48 ~ (WHITE)
Bp 760 186~~"
pKA = 9.92 (25~ - H20)
Fig. 4. The industrial production and physical properties of 4-fluorophenol
Both of the two industrial synthesis start, in fact, from the same raw material
(Benzene) to access by similar chemistry (nitration, reduction, halogenation, etc.)
in five steps to the production of 4-fluorophenol. Only a fine analysis of the global
process in terms of effluent, technology required and quality of the product allows
selection of the most suitable access.
The alkaline hydrolysis of 4-bromobenzene (ref. 2a - 2b) needs very drastic
conditions (-- 190~ 5-20 bar, in the best conditions) (ref. 2c) with effluent
containing copper salt and stoichiometric amounts of barium bromide. Another
main drawback of this process is the selectivity and specification with regard to
isomers of 4-fluorophenol and content of phenol resulting from hydrogenolysis, as
reported by M. Bedoukian (ref. 2a). As phenol is nearly impossible to remove
from 4-fluorophenol (identical boiling point), on the quality point of view the best
process is the one which does not produce phenol, 2 and 3-fluorophenol.
297
By Sandmeyer hydrolysis (ref. 3 a - 3e) (diazotisation, acidic hydrolysis without
copper salts) the target specification (Table 1) is reached without difficulty but the
process has two major drawbacks for industrialisation, as underlined in the recent
patent from Octel Chemicals (ref. 3c) : safety and corrosion on using convention
equipment.
Table 1. Standard specification for 4-fluorophenol
Purity (assay): 99 % minimum

Impurities content :
2-Fluorophenol 0.1% max. (w/w)
Phenol 0.1% max. (w/w)
3-Fluorophenol 0.1% max. (w/w)
4,4'-Difluorophenylether 0.2 % max. (w/w)
Any other impurities 0.1% max. (w/w)
The preparation of phenols by hydrolysis of benzediazonium ions is well

known in the literature (ref. 10). It involves the preparation of a diazonium salt,
e.g. the diazonium hydrogenosulfate by treatment of the aniline hydrogen sulphate
with sodium nitrite in dilute aqueous sulphuric acid, followed by hydrolysis in
more concentrated aqueous sulphuric acid. The temperature of the hydrolysis is
maintained at the boiling point of the aqueous acid by proper adjustment of the
concentration of the sulphuric acid and the phenol formed removed from the
reaction medium by means of steam distillation in order to minimise the coupling
of the formed phenol with the diazonium salt introduced.
In the production of 4-fluorophenol from 4-fluoroaniline (ref. 4a - 4g) a major
problem arises with corrosion of glass lined vessels by hydrofluoric acid release.
The hydrofluoric acid is considered to arise by nucleophilic displacement of the
fluoride from the 4-fluorobenzene diazonium hydrogen sulphate (Fig. 5). This is
not surprising since the diazonium group is one of the most electron withdrawing
group known.
298
~ F
NH 2 HSO4- OH
I
H2S04 H20 / H +
~ + N2
NaNO 2
(0-5 o c )
F
1
HSO4" OH
o.
Tars
OH OH
_- F- O +HSO4- ~ .....
Fig. 5. By products from the 4-fluoroaniline process
Octel Chemicals have patented a process to decompose the diazonium at nearly

room temperature using a copper salt of hydroxy carboxylic acid, allowing them to
use conventional glass lined reactors, but with poor productivity and problems of
copper effluent in aqueous.
In Rh6ne-Poulenc, using the classical technique (steam distillation) we have
developed specific reactors to avoid the corrosion due to HF in this semi-
continuous process and be able to reach a multitons production scale using our
Salindres and Avonmouth facilities and obtaining competitive manufacturing costs
due to a good integration on raw material.
CONCLUSION
The data reported shows that 4-fluorophenol can be advantageously prepared
from 4-fluoro-aniline in good yield and quality using conventional techniques. It is
certainly the leading industrial production to be able to reach specification and
price of the agrochemical market as well as the integration pollution control (IPC)
regulation.
299
References
1. a S. Misaki, J. Fluorine Chem., 21, 191, (1982).
b R.E. Banks, I. Sharif, J. Fluorine Chem., 55,207, (1991).
c I. Takemoto and K. Yamasaki, Biosci. Biotechn. Biochem., 58,495, (1994).
d T. Unemoto, Organic Synthesis, 69, 129, (1990).
e R.E. Banks, US 5086 178, (20.09.90), (to Air Products).
f JP 90 399 143, (12.12.90), (to Sumitomo).
2. a M.M. Bedoukian, R.J. Eber, W.E. Kuehlewind, R.E. Mc Arthur, J. Org. Chem., 26,
4641, (1961).
b JP 04 208241 A, (30.11.90), (to Ihara Chem. Ind.).
c DE 3430 554, (20.08.84), (to Hoechst).
d US 4940 821, (10.07.90), (to Dow Chemical).
e R.G. Pews, J.A. Gall, J. Fluorine Chem., 50, 377, (1990).
f JP 89, 319 448 (to T.R.A.N.A.D.)
g US 2934 569, (26.04.60), (to Olin).
h JP 85 04, 144, (23.06.83), (to Cemral Glass).
3. a JP 62,238,226, (09.04.86), (to Nippon Kayagu).
b G.C. Finger, J. Amer. Soc., 81, 94, (1959).
c EP 596 684, (05.11.92), (to Octel Chemicals).
d JP 91 246 244 A2, (01.11.91), (to Ihara Chem.).
e JP 62,29544, (31.07.85), (to Nippon Kayagu).
4. a N. Yoneda, J. Fluorine Chem., 45, 106, (1989).
b T. Fukuhara, N. Yoneda, K. Takamura, A. Suzuki, J. Fluorine Chem., 51,299 (1991)
c P.H. Cheek, J. Amer. Chem. Soc., 71, 1863, (1949).
d EP 430 434, (22.11.89), (to ICI).
e K. Hisashi, Y. Yoda, JP 90143 335, (23.05.90), (to Mitsui Toatsu Chemicals).
f N. Yoneda, T. Fukuhara, JP 89 233 232, (12.03.88), (to Mitsubishi Kasei Corp).
g JP 84 204 143, (06.05.83), (to Morita Kagaku Kogyo).
5. S. Stavber, Z. Planinske, I. Kosir, M. Zupan, J. Fluorine Chem., 59, 409, (1992).
6. a L. Conte, M. Napoli, G.P. Gambaretto, A. Guerrato, F.M. Carlini, J. Fluorine Chem.,
67, 41, (1994).
b M. Gubelmann, EP 320 346, (11.12.87), (to Rh6ne-Poulenc Chimie).
7. W.R. Dolbier, L. Celewicz, K. Ohnishi, Tetrahedron Letters, 30 (37), 4929, (1989).
8. a H. Garcia, L. Gilbert, EP 427 603, (06.11.89), (to Rh6ne-Poulenc Chimie).
9. a M. Nango, Y. Kimura, JP 92 29950, (31.01.92), (to Ihara).
b P. Partha, J. Amer. Chem. Soc., 113, 5322 (1991).
c M. Gubelmann, P.J. Tirel, EP 341 113, (02.05.88), (to Rh6ne-Poulenc Chimie).
10. H. Wallach, A. Heusler, Annalen, 243,228, (1898).
300
FLUORODECARBOXYLATION OF ARYLCHLOROFORMATE : A NEW
ACCESS TO FLUOROAROMATICS
HERVE GARCIA a~, LAURENT GILBERT a~, MARIE-CECILE PERROD a~,

SERGE RATTON b~AND CHRISTOPHE ROCHIN c~
a)Rh6ne-Poulenc Industrialisation, Centre de Recherche, d'Ing6nierie et de

France
b) Interm6diaires Organiques, 25 quai Paul Doumer, 92408 Courbevoie Cedex,
France
c) Rh6ne-Poulenc Chemicals PO Box 46, Avonmouth Bristol BS 11 9VF, England
SU/VIMARY
The catalytic fluorodecarboxylation of arylchloroformate to fluorobenzene and
analogues has been achieved with high yield in an anhydrous hydrogen fluoride
vapor phase flow reactor. This methodology can be successfully applied to various
derivates, the main limitation being the stability of substituents under the reaction
conditions. The best catalysts are chromium and aluminium oxyfluoride. The
reaction proceeds between 300 and 400~ and occurs in a short space of time. The
catalytic activity decreases by coking but can be fully recovered by an oxydative
treatment at high temperature. An ionic mechanism is proposed.
INTRODUCTION
The formation of carbon - fluorine bonds is always a challenging synthetic
reaction. Direct fluorination with fluorine leads to fragmentation and highly
fluorinated products, making this non selective route unsuitable for the preparation
of fluorobenzene and analogues. Therefore the preparation of fluorobenzene,
generally requiring the introduction of fluorine via an appropriately functionalized
benzene derivative has held the attention of chemists for nearly a century (ref. 1).
The Balz-Schiemann reaction (ref. 2) and the improved direct diazotisation of
aniline with sodium nitrite and subsequent dediazoniation in hydrogen fluoride
without isolation of the intermediate salt (ref. 3) are the main industrial ways to
301
prepare fluorobenzene and its substituted analogues. The main drawbacks of this
reaction are the toxicity of starting aromatic amines, thermal instability of
diazonium salt and the inevitable formation of water in the diazotation reaction.
Therefore, much effort has been devoted to the research of new industrializable
routes to fluorinated aromatics derivatives which are as far as possible versatile
and without the drawbacks of classical processes. Among the reported reactions
(refs. 4-7) aryl fluoroformate decarboxylation seems to be very attractive. Aryl
fluoroformates are easily prepared from the corresponding phenol, phosgene and
anhydrous hydrogen fluoride, which are widely available and cheap raw materials.
The decarboxylation of arylchloroformate (ref. 8) or thiochloroformate (ref. 9)
into the corresponding chloroaromatic and the decarboxylation of aliphatic
fluoroformate occurs by an ionic mechanism (ref. 10). But, the arylfluoroformate
decomposition by this mechanism does not lead to the formation of fluorinated
aromatics but instead to phenols and tars (ref. 4a).
Even if dinitrogen and carbon dioxide can be considered as similar leaving
groups (ref. 11) and if the evolution of carbon dioxide from a carboxylium ion
should provide a large exothermic driving force similar to that obtained by
elimination of dinitrogen from the diazonium ion, it appears that
arylfluoroformates are very resistant to decarboxylation. This is attributed to the
higher stability of the ArOCO + cation which can undergo a Friedel-Crafts reaction
rather than decomposing to phenyl cation.
The thermal, selective, decarboxylation of arylfluoroformate was reported for
the first time by Christe and Pavlath (ref. 4). The use of vapor phase conditions
and of temperatures as high as 700 - 800~ permits the selective transformation
even without catalyst. Under the conditions, the use of Pt gauze as the catalyst
improves the selectivity of the reaction. Fluorobenzene can then be obtained with
high yield (up to 90 %), but this methodology is of little versatility. Yields are
much lower with substituted aryl fluoroformates (ref. 4b). Moreover, these
temperatures are considered to be beyond the scope of common industrial practice
and particularly for the preparation of fine chemicals.
A major improvement was described by Ashton and Co. (ref. 5) which showed
that the reaction could be driven in the vapor phase at 350~ using as catalyst a
noble metal supported on 7-alumina.
Fluorobenzene can then be obtained with initial yields of about 60 %. But,
yields reported are rather low and the reaction is not general although for
(2,4,6-trimethylphenyl)-fluoroformate the same yield can be obtained 4-
chlorophenylfluoroformate decomposition to the corresponding phenol and
carbonate occurs.
302
The authors interpret the lack of selectivity in this case to a reaction between the
fluoroformate and hydroxyl from the surface of ), alumina.
Even if this conditions represent an important improvement, this technology is
not applicable on an industrial scale as the catalyst deactivates irreversibly by
fluorination (ref. 12). Moreover, if the use of fluorinated aluminas leads to the
improvement of initial selectivity, it can not avoid the catalyst deactivation which
is transformed during the course of the reaction to aluminium fluoride, a non
selective catalyst (ref. 12).

We now report that the fluorodecarboxylation of arylchloroformates can be
achieved in an anhydrous hydrogen fluoride vapor phase reaction using aluminium
fluoride as a catalyst.
Fluorobenzene 2 can be obtained with a yield greater than 95 %; the reaction is
very selective as the only by products observed are chlorobenzene (less than 2 %)
and phenol (less than 1 % ) (Scheme 1).
A1F3 ' 3 0 0 ~
Off1 + HF ~ F + CO 2 + HC1
II tc= is
O HF / c h l o r o f o r m a t e = 50
! 2 Y i e l d _2_> 95
S c h e m e 1. F l u o r o d e c a r b o x y l a t i o n of phenylchloroformate
High yields are achievable by using an excess of anhydrous hydrogen fluoride

as shown in Table I. The increase of this ratio to a value of 75 does not greatly
improve the activity and selectivity.
303
Table 1 " Fluorodecarboxylation of phenylchloroformate-Influence of the ratio HF/C6HsOCOC1
A1203, 300~
OCOC1 + HF W F + CO 2 + HC1
Entry HF/C6H5OCOC1 Yield (%)

1 18 76
2 56 94
3 74 97
Without catalyst, we do not obtain at this temperature any fluorinated

derivatives (Table 2, emry 1). Several catalysts (Table 1) are suitable for the
fluorodecarboxylation of phenylchloroformate to fluorobenzene; such as
oxyfluoride (AI, entry 2; Cr, entry 4; Zr, entry 5; Ti, entry 10) or fluorides (A1,
entry 3; La, entry 6; Ce entry 7; Mg entry 9). The best activity and selectivity is
observed using as catalyst aluminium fluoride or oxyfluoride (entries 2 and 3).
Table 2 9 Fluorodecarboxylation of phenylchloroformate - Influence of catalyst nature
Entry Catalyst Temperature (~ Yield PhF (%)

1 without catalyst 400 < 1
2 A1203 300 > 95
3 A1F3 300 > 95
4 Cr203 300 70
5 ZrO2 300 46
6 LaF3 300 40
7 CeF3 300 40
8 ZnO 300 14
MgF2 400 14
10 TiO2 220 54
304
In contrast to the decarboxylation of arylfluoroformate, anhydrous hydrogen
fluoride vapor phase fluorodecarboxylation of alkylchloroformate can be
successfully applied to many substrats (Table 3).
Cresylchloroformates react in a similar way as phenyl chloroformate (entry 1
to 3). The use of more electrodonating substituents like methoxy is also successfull
eg for the synthesis of 4-fluoro anisole (entry 4). But, the obtained yield is modest
due to demethylation of 4-fluoro anisole or of the starting material leading to tars.
For electron withdrawing groups, reactivity is lower but fluoro-chloro, fluoro-
bromo and difluorobenzene are prepared in high yield (entries 6 to 8).
Table 3. Fluorodecarboxylation of arylchloroformate on aluminium oxyfluoride
O-- R
OCOC1 + HF ~
Vapour phase
R
F + HC1 + CO2
Emry Substituent (R) Temperature (~ Yield (ArF) (%)

1 2-CHs 300 > 95
2 3-CH3 300 > 95
3 4-CH3 300 > 95
4 4-CH30 400 24
5 4-F 300 < 1
6 4-F 400 > 95
7 4-C1 300 85
8 4-Br 400 70
9 4-NO2 300 Traces
10 1-Ph 350 24
11 1-naphthyl 300 10
12 1-naphthyl 400 > 95
Tars are obtained starting from 4-nitrophenylchloroformate (entry 9); this

substrate is mostly unstable under the chosen reaction conditions.
2-Phenyl phenyl chloroformate 3 reacts in a different manner leading to a mixture
of 1-fluorobiphenyl 4 (yield 24 %, entry 10) and of 5 obtained by an
intramolecular acylation (yield 50 %) (Scheme 2).
305
F~
O Fluorodecarboxylation
II
HF. Al203 ~.. / _4

r
300~
3 Vapour phase
v
Internal Friedel & Crafts
5
Scheme 2. Fluorodecarboxylation of 2-phenylphenylchoroformate
Finaly 1-fluoronaphthalene can be obtained with a very high yield from c~-
naphthylchloroformate (entry 12).
The influence of reaction temperature was examined in the case of the
decarboxylation of meta-tolylchloroformate 6 in 3-fluorotoluene _7. Results are
given in Table 4 and Figure 1. To proceed, the reaction needs a minimum
temperature. At low temperature (250~ entry 1), cresol and cresylcarbonate are
obtained in rather significant quantities.
Table 4. Fluorodecarboxylation of 3-tolylchloroformate - Influence of the temperature
~
/
OCOC1 + HF ~
/
F + CO2 + HC1
CH 3 6 CH 3 7
Entry Temperature Yield (%) Yield (%) Yield (%) Yield (%)
(~ 3-fluorotoluene 3-chlorotoluene m-cresol carbonate
1 250 78 0,6 10,5 10,5
2 300 92 2 6 0
3 350 90 6 3 1
306
Yield 7 m
Yield 8, 9, 10
100 - 30
90
20 -E}-- Yield 7
80 - ~ - Yield 8
Yield 9
70 Yield 10
10
60
50 0
20O 250 300 350 400
Temperature (~
Fig. 1 Influence of the temperature on the selectivity of fluorodecarboxylation of 3-

tolylchloroformate
m-Cresol 8 is probably obtained by decomposition of chloro (or fluoro)

formate by anhydrous hydrogen fluoride following "
/~OCX + HF ~ ~ O H + FCOX
II
O / 8
CH 3 X = C1, F CH 3
Cresylcarbonate 9 result from an acylation of cresyl haloformate by ArOCO +

cation 9
~--~OCX + ~r~OCQ) XO ~ (~XQ ~

,, ,,
/
CH3 O CH3 O /
CH3 C
II"X CH3
X=C1, F O
+ X2CO
/ O \
CH3 9 CH3
An increase of temperature favours fluorodecarboxylation and limits this side

reactions, the main coproduct becomes then 3-chlorotoluene 10 which results from
a intramolecular decarboxylation.
307
~OCC1 "- ~ , ~
II " C1 + CO 2
/ O /
CH3 CH3 10
The synthesis of fluorinated aromatics by the elimination of a small molecule

starting from the phenol derivative has been successfully generalized to various
derivatives (Table V) like diphenylcarbonate (entry 1), phenylchlorothioformate
(entry 2), ot,c~,ct-trifluoroanisole (entry 5). The reaction proceeds also very
selectively starting from phenylfluoroformate. For each substrats, an acidic
activation (Lewis or Bronsted) is necessary to produce an activated intermediate,
probably the cation ArOCO § or an analogue, by the liberation of phenol or
hydrogen fluoride.
Table V 9 Influence of the leaving group nature
X
~ O ~ Y HFvaporphaseA1203
~- F + COX + HY
Entry Temperature (~ Yield (ArF) (%)

1 O OPh 300 60
2 S C1 300 91
3 O F 300 > 95
4 C12 CI 400 23
5 F2 F 400 50
R E A C T I O N A L MECHANISM
For the decarboxylation of arylfluoroformates, Christe and Pavlath suggest an
internal nucleophilic substitution mechanism (Scheme 3).
0 8+ 8-
OC --F ~ O ~ F + CO 2
R
R
Scheme 3. Internal nucleophilic substitution mechanism
308
This mechanism was preferred to a mechanism via the cation ArOCO § due to
the high stability of the acylium cation. This cation does not decarboxylate under
the usual conditions for the decarboxylation of arylchloroformate and
alkylfluoroformate. Decarboxylation of arylfluoroformiate on 7-alumina (ref. 4d)
or fluorodecarboxylation of arylchloroformate under anhydrous hydrogen fluoride
did not seem to proceed via the same mechanism. Indeed, the high activation
energy of the internal nucleophilic substitution explains why such high
temperatures such as 700-800~ are needed. At lower temperatures, the reaction
must proceed via a nucleophilic displacement of carbon dioxide in the cation
ArOCO § To obtain a very high selectivity in fluoro aromatics, it is necessary to
have available nucleophilic fluoride ; the lower selectivity obtained in
decarboxylation of phenyl fluoroformate using aluminium fluoride as catalyst can
be explained assuming that the fluoride is not nucleophilic enough to permit the
reaction. This is in accordance with the necessity of a large excess of anhydrous
hydrogen fluoride for the fluorodecarboxylation of arylchloroformate on
aluminium fluoride. So, this methodology permits the preparation of aryl
fluoroformate with various susbtituents. The use of a large excess of anhydrous
hydrogen fluoride compensates for the lack of reactivity of some
arylchloroformates.
OCX + HF ~ CQ XHF -------~ F +CO2 + HX

"
0 R )~"J/ R
X = C1, F
Scheme 4. Bimolecular nucleophilic substitution mechanism
Also the transformation of phenol to fluorobenzene using a mixture of

hydrogen fluoride and antimony pentafluoride has been previously described (ref.
7), we have shown that under our conditions phenol is not reactive. Fluorobenzene
is thus produced mainly from phenylchloroformate or phenylfluoroformate.
Scheme 5 shows the reaction routes for the main products :
309
OH
+HF/ "COF2
'
+ HF ~ ~OF
- CO2 ~ -HC1
+ _ CO2
-CO 2 " ~ ~
C1
G
Scheme 5. Fluorodecarboxylation of arylchloroformate 9product's filiation
The reaction of substituted arylfluoroformate shows a high retention of

regiochemistry in accordance with the proposed mechanism. In the case of
fluorotoluene no isomerisation is observed under the reaction conditions.
310
C A T A L Y S T LIFE TIME
The catalyst life time was examined in the case of 3-fluorotoluene preparation
by fluorodecarboxylation of 3-methylphenylchloroformate decarboxylation. We
observed a rapid deactivation of the catalyst after 5 hours of continuous running.
This deactivation is linked to the formation of non volatile derivatives. After 5
hours the amount of carbon on the catalysis is 4 %. The catalyst activity can be
recovered by calcination under air for 3 hr at 450~ In this way, several reaction
- reactivation cycles have been realised without significant modification of the
catalytic activity (Scheme 6).
CH 3 CH 3
I
HF vapour phase f"/"'N"l
A1203, 300~
OCOC1
Yield (%)
100
80
60
40
20
0 10 20 30 40 50 60 70 80
Duration on stream (h.)
Scheme 6. Fluorodecarboxylation of 3-methylphenylchloroformate 9catalyst life time
311
CONCLUSION
The fluorodecarboxylation of arylfluoroformates in the vapor phase, under
anhydrous hydrogen fluoride has been successfully realised by using catalysts such
as aluminium fluoride or aluminium or chromium oxyfluoride. This transformation
is quite versatile, the main limitation being the stability of substrates or products
under the reaction conditions. The catalyst used, deactivates rapidly by coking but
can be reactivated by a simple oxidative treatment. This new access to fluorinated
aromatics derivatives appears to be an attractive industrial alternative to the
diazotisation of anilines.
References
1. R.D. Chambers in "Fluorine in Organic Chemistry", Wiley-Interscience, New York,
(1973).
2. G. Balz, G. Schiemann, Ber., 60, 1186, (1927).
H. Susdritsky in "Adv. in Fluorine Chem.", vol. 4, M. Stacey, J.C. Tatlow,
A.G. Sharpe, Eds., Butherwerthesm, London, (1965) ; Organofluorine chemistry :
principles and commercial applications, Banks, Smart, Tatlow Eds, Plenum Press, chap.
9, (1994).
3. R.L. Ferm, C.A. Van Der Werf, J. Am. Chem. Soc., 72, 4809, (1950).
4. a) K.O. Christe, A.E. Parlath, J. Org. Chem., 30, 3170, (1965).
b) K.O. Christe, A.E. Parlath, J. Org. Chem., 30, 4104, (1965).
c) K.O. Christe, A.E. Parlath, J. Org. Chem., 31,559, (1966).
5. D.P. Ashton, T.A. Ryan, B.R. Webster, B.A. Wolfmdale, J. Fluorine Chem., 27, 263,
(1986), EP 118241, (1983) (to ICI).
6. N. Isvashenko US 3.499.942, (1966).
I. Hisamoto, C. Maeda, M. Nishiwaki EP 57443 (1981), (to Daikin Kogyo)
J.F. Bieron, D.Y. Tang, US 4792 618, (1984), (to Occidental Chem. Corp.).
M. Tojo, S. Fukuoka, J 63054332 and J 63088146, (1986), (to Asahi Chem. Ind.).
F.J. Weignet, US 4754 084, (1987), (to Du Pont de Nemours).
1) L. Gilbert, H. Garcia, B. Langlois 2) L. Gilbert, H. Garcia, C. Rochin 3) L. Gilbert,
B. Langlois, FR 2647106, FR 2647107, FR 2647111, (1989), (to Rh6ne-Poulenc).
7. J.I. Darragh GB 1582427 (1976), (to ICI).
8. A. Werckmann, GE 857 350, (1943).
9. H. Erlingafeld, Angew Chem., 72, 836, (1960).
10. S. Nakanishi, J. Am. Chem. Soc., 77, 3099, (1955).
11. P. Beak, R.J. Trancik, D.A. Simpson, J. Am. Chem. Soc., 91, 5073, (1969).
12. M. Janin, B. Langlois, L. Gilbert, M.C. Perrod, Private communication
312
MILD T R I F L U O R O M E T H Y L A T I O N OF ORGANIC COMPOUNDS
CLAUDE WAKSELMAN AND MARC TORDEUX
SIRCOB-CNRS, Equipe Fluor, B~timent Lavoisier, Universit6 de Versailles,

45 avenue des Etats-Unis, 78 000 Versailles, France
INTRODUCTION
Numerous organic molecules bearing a trifluoromethyl group have found
industrial applications as pharmaceutical or agrochemical products (ref. 1). They
are classicaly prepared by the use of aggressive or toxic reagents. However, the
understanding of the reactivity of a small fluorinated molecule has recently allowed
the proposal of new trifluoromethylation ways in much milder conditions.
PROPERTIES OF FLUORINATED SUBSTITUENTS

Owing to the extreme electronegativity of fluorine (4.0 on the Pauling scale),
fluorinated groups behave inductively as electron-withdrawing substituents. The
trifluoromethyl group shows an electronegativity (3.5) higher than that of the
chlorine atom (3.0) (ref. 2). The inductive effect is balanced by the mesomeric one
in trifluoromethoxy and trifluorothiomethoxy groups as for an halogen substiment
(ref. 3).
On the other hand, fluorination can exert an influence on the lipophilicity of
organic molecules, particularly at positions adjacent to atoms or groups having
electrons. Hansch constants derived from octanol/water partition coefficients of
substituted benzenes (ref. 4) are summarized in Table 1.
313
Table 1. Hydrophobic constants of various substimems
Substituent OCH 3 F CH 3 SCH 3 C1 CF 3 OCF 3 SCF 3

. ,
n -002 0.14 0.56 0.61 0.71 0.88 1.04 1.44
* Hansch constants derived from octanol/ water partition coefficients of subtituted benzenes
(ref. 4).
These data are more appropriate to the nonspecific equilibrium binding of the
various compounds to tissues in general than to their genuine kinetics of absorption
and distribution in living systems (ref. 5). They can explain the interest for the
introduction of the trifluomethylated substituents CF3, OCF3, SCF3 (considered to
induce a higher lipophilicity than chlorine) in pharmaceutical and agrochemical
products.
CLASSICAL PREPARATIONS
The industrial route employed for the elaboration of the trifluoromethyl group is
based on an halogen exchange in hydrogen fluoride (Fig. 1) (refs. 1,2). Only very
stable molecules can survive in such drastic conditions.
HF HF
ArCC13 ~ ArCF 3 ArYCC13 ~ ArYCF3 (Y = O, S)
Fig. 1. Halogen exchange reactions
Numerous alternative preparations have been described (ref. 2). They often
make use of toxic (CF3SC1) or fragile (CF3Cu, CF3SCu) reagents. Radical
trifluoromethylation can also occur starting from the expensive trifluoromethyl
iodide.
R E A C T I V I T Y OF T R I F L U O R O M E T H Y L HALIDES
Trifluoromethyl halides CF3X (X = I, Br) are known to be resistam to
nucleophilic attack on the carbon atom (refs. 6, 7). This behaviour is explained by
the unusual polarisation of the C - X bond (Fig. 2) and also by steric effects and
lone-pair repulsion forces associated with fluorine substituents.
314
5- S +
CF3mX ( X = B r , I)
Fig 2: Polarization of the CF3-X bond
Pioneering studies showed that attack by strong nucleophiles (alcoholates...) on

the larger halogen X can occur, as shown by the formation of fluoroform in protic
medium (Fig. 3) (ref. 8).
solvent
Nu- + CF3X ~ NuX + CF3 ~ CF3H
Fig. 3. Halogenophilic attack
However, since the mid 1970s, some reactions of trifluoromethyl iodide with
soft nucleophilic reagents, enamines (ref. 9), or thiolates (ref. 10), have been
interpreted as single electron transfer (SET) processes (Fig 4, X = I) (refs. 9, 10,
11).
Nu- + CF3X N u " + [CF3X] 9
[CF3X] 9 X" + CF3"

o
Nu + CF 3 9 [NuCF3] 9
[NuCF3] . " + CF3X NuCF3 + [CF3X] "
Fig 4. SET process with a charged nucleophile.
Trifluoromethyl bromide, produced as a fire extinguishing agent (refs .12, 13),

is much cheaper than the corresponding iodide. Unfortunatly, its reactivity is much
lower too. At that time, this bromide was considered as rather inert.
315
T R I F L U O R O M E T H Y L BROMIDE REACTIONS
1. First substitution reaction by thiolates

Thiolates are powerful nucleophilic reagents. However, we observed no
reaction when trifluoromethyl bromide is bubbled through a potassium
thiophenoxide solution in DMF at room temperature. This failure was in agreement
with the inertness reputation of this halide. Assuming that a mechanism involving
radical anions (Fig. 4, X = Br) could occur, a minimal concentration of the halide
should be necessary to maintain the chain process. In order to increase the amount
of trifluoromethyl bromide in solution, we performed the reaction under pressure.
Indeed, condensation occurred at room temperature in a glass apparatus under 2-
3 bars (Fig. 5) (refs. 16,17). Inhibition of this condensation by nitrobenzene was
clearly observed, in agreement with the SET process (Fig 4, X = Br). A similar
trifluoromethylation of thiols by trifluoromethyl bromide in liquid ammonia under
UV irradiation has also been described (ref. 18).
ArSK + CF3Br ArSCF3 + KBr
Fig 5. Trifluoromethylation of potassium thiophenoxide.
2. Reaction with metals and carbonyl compounds

We remarked that the first step of the radical-anion chain mechanism (Fig. 4)
can be considered as a reduction of the halide by the nucleophile. Consequently, we
tried to use well known reductants such as zinc. However, no reaction occurred
when the halide is placed in the presence of zinc in various solvents. By analogy
with the thiophenoxide condensation, we attempted the transformation in DMF
under slight pressure. Consumption of the reagents was only observed when
electrophilic substrates, such as carbonyl compounds, are present since the
beginning of the reaction. These Barbier like condensations started more easily in
pyridine than in DMF (ref. 19). Moderate yields were obtained with aldehydes as
substrates (Fig. 6).
2-4 bars / CF3X

RCHO + Zn RCH(OH)CF3
lutidine
Fig 6. Barbier condensation with aldehydes.
316
The reaction was more difficult with ketones. In the case of acetone, no addition
product was even observed. Curiously enough, the presence of this simple ketone
initiated the formation of trifluoromethyl zinc derivatives (Fig. 7).
2-4 bars
CF3Br + Zn CF3ZaaBr + (CF3)2Zn
pyridine
acetone
Fig 7. Formation of trifluoromethylzinc derivatives.
When benzaldehyde was subsequently introduced into such a medium, no

condensation product was detected, showing that these strongly solvated
organometallics are poorly reactive.
In the case of an a-keto ester, the addition of the trifluoromethyl group
occurred as expected to the keto group (Fig. 8).
CF3
2-4 bars !
RCOCOOEt + Zn + CF3Br R COOEt
pyridine I
OH
Fig. 8. Addition to ketoesters.
Simple esters did not lead to addition products. However, the Barbier procedure
was effective, even at atmospheric pressure, when the ester was activated by an
electron-withdrawing group; ethyl trifluoropyruvate and hexafluoroacetone were
respectively obtained from diethyl oxalate and ethyl trifluoroacetate (Fig. 9).
2-4 bars
EtO2CCO2Et + Zn + CF3Br ~ EtO2CCOCF3
pyridine
id.
CF3CO2Et + Zn + CF3Br ~ CF3COCF3
Fig. 9. Reaction with activated esters.
317
Some acid anhydrides were also trifluoromethylated (Fig. 10).
O O
~ O 3-4 bars
+ Zn + CF3Br
pyridine
O
Fig. 10. Trifluoromethylation of phtalic anhydride
It is well known that iminium salts show a reactivity comparable to that of

carbonyl compounds towards organometallics. Consequently, we tried a similar
Barbier condensation with the Eschenmoser's salt, but without success (Fig 11).
3-4 bars
CH2zN+Me2 + Zn + CF3Br CF3CH2NMe2
pyridine
Fig. 11. Failure of the Barbier condensation with the Eschenmoser's salt
This failure can shed some light on the nature of the intermediate involved in
these Barbier condensations. In contrast to the case of carbonyl compounds,
iminium ions do not present a partial negative charge able to coordinate with the
metal. On the contrary, carbonyl adsorption leaves the possibility for these
compounds to play the part of a ligand around the nascent organometallic, formed at
the zinc surface, and to react in the coordination sphere. Following this
interpretation, the nascent organozinc intermediate is not completly surrounded with
pyridine. It can be more reactive than the strongly solvated organometallics detected
in the pyridine-acetone medium (vide supra).
3. Chemical synthesis of triflic acid

Barbier conditions were also employed for the trifluoromethylation of
thiocyanates (Fig. 12) (ref. 20).
2-5 bars
RSCN + Zn + CF3Br RSCF3
pyridine
Fig 12. Trifluoromethylation of thiocyanates
318
Benzyltrifluoromethylsulfide, formed from benzylthiocyanate, can lead to triflyl
chloride by oxidative chlorination under slight pressure (Fig. 13). Cleavage of the
carbon-sulfur bond was easy in this example because the benzyl group is able to
stabilize a positive charge.
El2, 4 bars
C6H5CH2SCF3 C6HsCH2C1 + CF3SOaC1
H20, 5~
Fig. 13. Formation of triflyl chloride by oxidative chlorination of benzyltrifluoromethylsulfide
Owing to a limited yield obtained in the preparation of benzyltrifluoro-

methylsulfide another route to triflic acid was prefered " the direct Barbier
condensation with sulfur dioxide (Fig. 14) (ref. 21).
3-4 bars
SO2 + Zn + CF3Br CF3SO2ZaaBr
DMF
Fig. 14. Formation of zinc bromide trifluoromethanesulfinate
In contrast to the carbonyl condensations, where no reaction occurred between

the substrate and the metal, an initial attack on zinc by sulfur dioxide in DMF was
actually observed. Then, introduction of trifluoromethyl bromide under slight
pressure led to the formation of zinc triflinate.
Homologous zinc sulfinates have been obtained from the much more reactive
long-chain perfluoroall~l iodides when these halides were introduced at
atmospheric pressure, before or after sulfur dioxide, in a suspension of zinc-copper
couple in DMSO or DMF (ref. 22). This condensation was imerpreted as occurring
at the metallic surface and was tought to involve an adsorbed organozinc
intermediate (ref. 23). In order to check this hypothesis, we performed the
following experiment : the supernatant liquid formed in the reaction of sulfur
dioxide with zinc in DMF was transfered to a second flask containing
perfluorohexyl iodide. Formation of the corresponding sulfinate was detected by
NMR. Consequently, a reaction had occurred in this solution. Moreover, inhibition
of sulfinate formation was noticed when nitrobenzene was mixed with the
perfluoroalkyl iodide. These results can be interpreted by a single electron transfer
process (Fig. 15) (refs. 19, 21) involving an intermediate trifluoromethyl radical.
319
Zn + 802 ~-- Zn+ + 502 "-( ~ 1/2-O2SSO2)
j,
SO2-- + CF3Br SO2 + Br" + CF3-
SO2-- + CF3- .~ CF3SO2"
Fig. 15. SET prosess for the triflinate formation
This condensation with sulfur dioxide is rather peculiar. To the difference with
carbonyl electrophiles, sulfur dioxide is more easily reduced than trifluoromethyl
bromide. As already pointed out, initial consumption of zinc by this anhydride was
obvious, producing the sulfoxylate radical anion which is known to be in
equilibrium with the dithionite anion (Fig. 15). Incidentally, this salt mixed with
sodium bicarbonate in aqueous acetonitrile was used for the transformation of
liquid perhalogenoalkyl halides into their corresponding sulfinates (ref. 24). We
have been able to transform the gaseous and poorly reactive trifluoromethyl
bromide into sodium trifluoromethanesulfinate. However, the reaction conditions
(Fig. 16) (ref. 25) were modified because no transformation occurred in the medium
employed for the sulfinato-dehalogenation of the liquid halides.
13 bars
Na2S204 + CF3Br + Na2HPO4 -- CF3SO2Na
DMF-H20
Fig. 16. Formation of sodium trifluoromethanesulfinate from sodium dithionite
The triflinate salt was also obtained with sodium hydroxymethanesulfinate

(Rongalite) in the presence of sodium metabisulfite in anhydrous DMF (Fig. 17)
(ref. 25).
3-5 bars
NaO2SCH2OH + CF3Br + Na2S205 ~ CF3SO2Na
DMF
Fig. 17. Formation of sodium trifluoromethanesulfinate from sodium hydroxymethanesulfinate
The triflinate salt can be transformed to its corresponding triflate derivative by

oxidation with hydrogen peroxide, then to triflic acid by action of sulfuric acid
(Fig. 18).
320
30 % H20 2 H2SO4
CF3SO2Na ~ CF3SO3Na ~ CF3SO3H
Fig. 18. T r a n s f o r m a t i o n o f s o d i u m triflinate to triflic acid
4. Trifluoromethylation of aromatic compounds

We have interpreted the formation of zinc triflinate by a SET process (Fig. 15).
In order to test for the presence of the electrophilic trifluoromethyl radical in this
reaction, we have added anilines to the medium. Indeed, alkylation at electron-rich
positions of the ring was observed (Fig. 19) (ref. 26).
NH2 NH2 NH2
Zn + SO2 + CF3Br, 3-5 bars
Na2S203, DMF
~/ /CF3
+
CF3
Fig. 19. Trifluoromethylation of aniline
In this experiment, a decimolar quantity of zinc and sulfur dioxide was used. In
order to explain such a catalytic effect, we have considered that the sulfur dioxide
which is formed in the medium (Fig. 15) can be reduced back to its radical anion by
an intermediate cyclohexadienyl radical. This step could induce a chain formation
of the trifluoromethyl radical (Fig. 20) (refs. 26, 27).
X
X X ~ "~CF3
X ~ CF3 CF3
cv3- ~ I-i+
SO2 . $02
Br . ~
CF3Br 9 " " CF3Br
Fig. 20. Radical trifluoromethylation of aromatic compounds
321
Other electron-rich aromatic compounds can be employed as substrates.
Pyrroles were trifluoromethylated regioselectively at the 2-position (ref. 27).
Recently, the system trifluoromethyl iodide-zinc-sulfur dioxide in DMF at low
temperature was used for the trifluoromethylation of aminonaphtalenes and
aminoquinolines (ref. 28). Computational results support the mechanism in which
the electrophilic trifluoromethyl radical intertact with the aromatic ring at the sites
with the greatest electron density of the HOMO orbitals.
Similar trifluoromethylation reactions of anilines, phenols or pyrroles were
performed in the presence of sodium dithionite (ref. 27).
5. Trifluoromethylation of disulfides
Owing to the susceptibility of the weak sulfur-sulfur bond in disulfides to free
radical attack, the trifluoromethylation of these compounds was attempted. Indeed,
trifluoromethyl sulfides were obtained (Fig. 21) (ref 29).
SO2 9precursor
RSSR + CF3Br RSCF3
Na2HPO4, DMF-H20
Fig. 21. Trifluoromethylation of disulfides
Experimems were performed with various sulfoxylate radical anion precursors:

sodium dithionite, sodium hydroxymethanesulfinate or a mixture of sulfur dioxide
with a reductant, such as zinc or sodium formate (refs. 29, 30).In contradistinction
with the trifluoromethylation of aromatic compounds (Figs. 19, 20), a
stoiechiometric amount of the sulfoxylate radical anion precursor was necessary. In
the disulfide case, there is no intermediate able to reduce back the sulfur dioxide
which is formed in the medium (Fig. 22).
SO2"- + CF3Br ~ CF3" + X + SO 2
CF3 + RSSR ~ RSCF3 + RS.
2 RS. ~ RSSR
Fig. 22. Mechanism of the disulfide trifluoromethylation
322
CONCLUSION
For many years now, the reactivity of trifluoromethyl bromide has been
underestimated. During the past decade the major breakthrough in this area has
been the realisation that trifluoromethylation of organic compounds with this halide
can be induced by mild reductants such as thiolates, zinc or sulfoxylate radical
anion. Nowadays, a great variety of fluorinated products are available by these new
methods : sodium triflinate and triflic acid, trifluoromethylated alcohols,
trifluoromethyl-containing aromatic compounds, ethyl trifluoropyruvate,
trifluoromethylsulfides ....
AKNOWLEDGEMENTS
Cooperation between Rh6ne-Poulenc and our CNRS team began with Dr. C.
Kaziz and was kept on with Drs. J-C. Lanet and S. Ratton. We thank all of them
for their interest in this research programm. Part of the work has been developed at
the " Centre de Recherche, d'Ing6nierie et de Technologie des Carri6res " in Lyon.
We thank Drs. B. Langlois, J-L. Clavel, R. Nantermet and the other members of
the Rh6ne-Poulenc laboratory for this close cooperation. Similarly, we aknowledge
the active participation of Dr. C. Francese during the preparation of her thesis in
our laboratory.
References
1. R. E. Banks, B. E. Smart , J. C. Tatlow in " Organofluorine Chemistry: Principle and
Commercial Applications ", Plenum Press, New York (1994).
2. M.A. McClinton, D. A. McClinton, Tetrahedron, 48, 6555, (1992).
3. L. M. Yagupolskii, A. Ya. Ilchenko, N. V. Kondratenko, Russian Chem. Rev., 43, 32,
(1974).
4. C. Hansch, A. Leo in " Substituent Constants for Correlation Analysis in Chemistry and
Biology ", Wiley, New York, (1979).
5. P.N. Edwards in ref. 1, p.530.
6. R.D. Chambers in " Fluorine in Organic Chemistry ", Wiley, New York, (1973).
7. C. Wakselman, A. Lantz, in ref. 1, p. 178.
8. J. Banus, H. J. Emeleus, R. N. Haszeldine, J. Chem. Soc., 60, (1951).
9. D. Cantacuzene, C. Wakselman, R. Dorme, J. Chem. Soc., Perkin Trans. 1, 1365, (1977).
10. V. N. Boiko, G. M. Schchupak, L. M. Yagupolskii, Zhur. Org. Khim., 1057, (1977).
11. C. Wakseman, J. Fluorine Chem., 59, 367, (1992).
12. Until now the main application of trifluoromethyl bromide was its use as Halon 1301 in
aeronautic ( ref. 13).Unfortunatly, Halons are implicated in the depletion of stratospheric
ozone. The participants of the 1992 Montreal Protocol Meeting in Copenhagen agreed to
phase out Halon production by the year 1994, except for some essential fire-fighting uses.
Research on alternative agents have been initiated in order to find new products with low or
zero Ozone Depletion Potential. However, the numerous candidates examined so far present
323
massive problems: toxicity (CF2I),harmful production of hydrogen fluoride on discharge into
the hot flame (CF3CHFCF3, CF3CHF2, CF3H), atmospheric life time higher than a millenary
(CF3CF2CF 3, CF3CF2CF2CF 3) (refs. 14, 15). Another question is related to the quantity of
material needed to put out a fire owing to the lower efficiency of the alternative agents. This
issue is crucial for aircrafts where weight carried is a critical factor. These difficulties
explain why Halon 1301 is still in use. However, introduction of possible substitutes should
leave important stocks of this classical extinguishing agent. Their use for trifluoromethylation
reactions should be more useful than a simple destruction.
13. C. Wakselman, A. Lantz, in ref. 1, p.185.
14. R. E. Banks, J. Fluorine Chem., 67, 193, (1994).
15. M. Freemantle, Chem. Eng. News, 29 , (september 19 issue, 1994); idem, 25 (january 30
issue, 1995).
16. C. Wakselman, M. Tordeux, J. Chem. Soc., Chem. Comm., 793, (1984).
17. C. Wakselman, M. Tordeux, J. Org. Chem., 50, 4047 (1985).
18. N. V. Ignatev, V. N. Boiko, L. M. Yagupolskii, Zh. Org. Khim., 21,653, (1985).
19. M. Tordeux, C. Francese, C. Wakselman, J. Chem. Soc., Perkin Trans. 1, 1951, (1990).
20. M. Tordeux, C. Francese, C. Wakselman, J. Fluorine Chem., 43, 27, (1989).
21. C. Wakselman, M. Tordeux, Bull. Soc. China., 868, (1986).
22. H. Blancou, P. Moreau, A. Commeyras, J. Chem. Soc., Chem. Comm., 885, (1976).
23. A. Commeyras, Ann. Chim. (Paris), 9, 673, (1984).
24. W-Y. Huang, J. Fluorine Chem., 32, 179, (1986).
25. M. Tordeux, B. Langlois, C. Wakselman, J. Org. Chem., 54, 2452, (1989).
26. C. Wakselman, M. Tordeux, J. Chem. Soc., Chem. Comm., 1701, (1987).
27. M. Tordeux, B. Langlois, C. Wakselman, J. Chem. Soc., Perkin Trans. 1, 2293, (1990).
28. L. Strekowski, M. Hojjat, S. E. Patterson, A. S. Kiselyov, J. Heterocycl. Chem., 1413,
(1994).
29. C. Wakselman, M. Tordeux, J-L. Clavel, B. Langlois, J. Chem. Soc., Chem. Comm., 993,
(1991).
324
FORMYLATION OF AROMATIC COMPOUNDS IN SUPERACIDIC
MEDIUM
LAURENT SAINT-JALMES, CHRISTOPHE ROCHIN, ROBERT JANIN AND

MARCEL MOREL

France.
INTRODUCTION
Chemists were always interested in introducing in one step a formylgroup into
aromatic rings to obtain aldehydes 9
O
II
ArH ~ Ar~C--H
Several methods to obtain aromatic aldehydes are well-known.
For example the reaction between aromatics and :
-disubstituted formamides in presence of phosphorus oxychloride : Vilsmeier-
Haack reaction (ref. 1),
- chloroform in basic medium : Reimer-Tiemann reaction (ref. 2),
- zinc cyanide in acidic medium (for example HCI) : Gattermann rea ction (ref. 3).
Carbon monoxide and formic derivatives can also be used to make
formylations of aromatic compounds (ref. 4) in acidic or superacidic medium.
Superacidic medium are characterized as medium whose acidity is superior to
those of H2SO 4 (100 %) (ref. 5).
In these medium the acidity cannot be measured by pH. The ,, Hammet-Deyrup
acidity function ,,, Ho (ref. 6), which shows the facility of protonation of a weak
base by a superacid, allows to class the superacids (ref. 7) (Fig. 1).
325
H2SO4
100 %
10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25
1 I I I I I I I ~---HO
tl I I I I L Illlllllll
2,4 A A 4~ A A A A
A
HF HF/BF3 HF/SbF5 FSO3H/SbF5

CF3CO2H ( 1 0 0 / 1) (1 / 1)
CF3SO3H
FSO3H
CFsSOsH/SbF5
(90 / 10)
Fig. 1. Hammet-Deyrupacidity scale
Formylation using carbon monoxide

The first example of electrophilic formylation was reported by Gattermann and
Koch in 1897 (ref. 8). They found that carbon monoxide and HC1 can react with
alkylbenzenes in presence of A1C13 and cuprous chloride to give aldehydes
(Fig. 2).
0
mc~3 II
ArH + CO + HC1 Ar~C--H
CuC1
Fig. 2. Gattermann-Koch reaction
From this first example, others acidic systems have been studied to try to
generalize this type of formylation and to study selectivities.
Formylation of aromatic rings with carbon monoxide requires the use of
superacidics to activate carbon monoxide by protonation and to protonate the
formed aldehyde which is the thermodynamic driving force of the reaction.
O
II
Even if the formyl cation H--Ce was never observed, the mechanism of
formylation by CO / superacids seems to be an electrophilic one.
326
Highly basic aromatic rings can be protonated in superacid medium to give
or-complex. In this case, the formylation rates of these basic compounds decrease,
which is consistent with an electrophilic mechanism.
The use of HF-BF 3 mixture as catalyst for aromatic formylation has been
reported mostly in the patent literature (refs. 10, 11). Formylations of
alkylbenzenes can be obtained with good yields (Fig. 3).
+ CO + HF + BF3 ~ (ref. 10)

_ 25oc
20 bars 10 eq. 1,2 eq.
2
79 % yield
Fig. 3. Formylation of alkylbenzenes with CO / HF/BF 3
In the cases of phenols, formylations by C O / H F / B F 3 system require

pressures of carbon monoxide of about 50 to 100 bars to obtain good yields
(refs. 12, 13)(Fig. 4).
OH OH
CO 40 bars
+ HF + BF3 ~ (ref. 13)
40~
50 eq. 2 eq. 1h
3_
4 80%
Fig. 4. Formylation of phenol with CO / HF / BF 3
Others catalysts such as HF-SbF 5 (ref. 14), HF-SbF 7 (refs. 15, 16),
HSO3F-SbF5 (ref. 17) have also been used to make formylation of alkylbenzenes
with carbon monoxide.
Triflic acid, alone (ref. 18) or in presence of Lewis acid (ref. 19), catalyses
formylation of alkylbenzenes by CO. Even if CO is much more soluble in
CF3SO3H than in H2SO 4, pressures of CO superior to 100 bars are required to have
good yields in benzaldehydes if Lewis acids are not present (Fig. 5).
327
CH3 CH3
0 + CF3SO3H
6 eqt
CO (1200 psi)
3,5 h- RT~
-~ 79%
~H3 CH3
CO (1 atm)
+ CF3SO3H + SbF5 :-- 59%
3, 5 h, 0~
Fig. 5. Formylation with CO / triflic acid
Formylation using formic derivatives

Very few Friedel-Crafts methods equivalent to the acylation with acyl halides
or anhydrides are available to make formylation, undoubtly because halides and
anhydrides of formic acids are very unstable.
Formyl chloride has been shown to be stable at less than-60~ (ref. 20).
Formic anhydride, which can be obtained from formic acid by deshydratation,
is unstable above -40~ Formic anhydride gives formates with phenols but fails to
formylate aromatic rings (ref. 21).
Mixed anhydrides of formic acid with acids, such as acetic formic anhydride,
are stable but give acetylation of aromatic compounds with evolution of carbon
monoxide (ref. 22).
Formyl fluoride is the more stable halide of formic acid. It can be prepared
from formic acid with potassium fluoride and benzoyl chloride in 16 % yield
(ref. 23), other fluorinating agents are also used such as KHF2 (ref. 22) (Yield :
35,4 %). Reaction of sodium formate with benzoyl fluoride give also formyl
fluoride (ref. 24) with 36 % yield.
Formyl fluoride in presence of boron trifluoride forms a complex which has
been used in aromatic formylations of alkylbenzenes (ref. 22, Table 1).
328
Table 1. Formylation with HCOF / BF 3
Aromatic Product Yield, %

Benzene _7 Benzaldehyde 8 56
Toluene Tolualdehyde 75
Xylene Dimethylbenzaldehyde 78
Naphtalene 9 Naphtaldehyde 10 20 - ot isomer
67 - [3 isomer
Methyl formate, a stable and commercialy available compound, is a C-1

building block (ref. 25) and so can be a theoretical formylating agent.
We have found that formylation of a large type of aromatic substrates can be
obtained with fair to good yields using methylformate in the presence of HF-BF3
complex (ref. 26).
The aromatic compound and methylformate are diluted in anhydrous
fluorhydric acid and a pressure of boron trifluoride is added to the mixture.
Amounts of boron trifluoride can be changed to increase yields. Table 2
summarizes the obtained results.
Benzene can be formylated very easily. Fluorobenzene gives
fluorobenzaldehyde with a total selectivity in para isomer. On the contrary chloro
and bromobenzene are transformed in poor yield, and chloro and bromo toluenes
17 are obtained next to halobenzaldehydes 16, showing that methyl formate can act
as an alkylating agent.
Table 2. Formylation with H C O 2 C H 3 / HF / BF 3
BF3 conver- Yields

Substrates a) HF pressure T~ time sion Major %
at 0 ~ % products
CHO
40 eq. 10 bar 50 ~ 6h 90 % 72
11
9 12
10 bars 60~ 6h 95 % ~ ) 81%

40 eq.
13 2,5 bars 40 ~ 4h 55 % 51%
CHO
9 14 .
. .
329
-
BF3 anver-
Major Yields
Substrates a) HF pressure To time sion products %
at 0°C %
CI
I
c1
I
bCH3
40 eq. 10 bars 60°C 6h 15 %
+ II
9
--
5 bars 50°C 5h 80 % 50 %
? 40 eq. 10 bars 50°C 5h 85 % 53 %
10 bars 30°C 5h 20 %
22 13 %
OH OH
&"' (yo"
rcHo
40 eq. 5 bars 50°C 5h 90 % 40 %
I 21
-
CHO
-
OCH;
23
-
I
15 %
0 22
40 eq. 10 bars 50°C 4h 25 %
-0
OCHj
I
I
24
11 %
CHO
--
@\ 40 eq. 2.5 bars 40°C 4h 69 % 49 %
25 - --
a) in every case 1,3 eq. HC0,Me
330
Two by-products 27, 28, (Fig. 6) are obtained during formylation of
diphenylether 18 next to diphenylaldehyde. The formation of 27 and 28 can be
explained by hydride transfer (Fig. 6), a type of transfer in acidic medium already
mentionned in literature (ref. 27).
C o-o 18
(y~ 19 CHO
C
C< I OH-.~.H
27 0 28
Fig. 6. Formation of by-products during formylation of diphenylether
Formylation of guaiacol 20 gives not only vanilline 21 but also aldehyde 29

and surprisingly acetophenone 30 (Fig. 7).
~
OH OH OMe OH
OMe OMe OMe OMe
20
C 3
yield 40 % 30 % 18 %
21 29 30
Fig. 7. Formylation of guaiacol with HCO2Me / HF / BF3 system
In the case of anisole 22, acetophenone 31 is also observed (Fig. 8).
331
OCH3 OCH3 (~CH3 OCH3
CHO
v- + ~ +
22
CH3
11% 15% 5 % yield
24 23 31
Fig. 8. Formylation of anisole with HCO2Me / HF / BF3 system
Phenol is not formylated with H C O 2 M e / H F / B F 3. On the contrary phenyl

formate 32 gives by Fries rearrangment p-hydroxybenzaldehyde 33 (Fig. 9).
Phenol does not give phenyl formate 32 with methyl formate in the presence of
HF / BF 3 (Fig. 9).
OH
/
HCO2Me, HF, BF3
X ~CHO
o
II
O--C--H
HCO2Me, HF, BF3
X
o
II
O--C--H OH
I-IF/BF 3
33
32 CHO
Fig. 9. Formylation of phenol with HCOzMe / HF / BF3
1,3,5-Trimethoxybenzene and 1,4-dimethoxybenzene do not give formylation

in our conditions, but demethylations of these compounds are noted.
During the reaction, formation or carbon monoxide is noted, showing that
methyl formate is, in part, decomposed in the reaction conditions.
Two mechanisms can explained the reaction of formylation with methyl formate in
HF / BF 3 medium.
332
In route A (Fig. 10), methyl formate is decomposed in CO and methanol.
Carbon monoxide is protonated to give formylation of an aromatic ring.
In route B (Fig. 10), methyl formate is protonated without decomposition and
can be attacked by an aromatic ring to give formylation.
0
II
H--C--O--CH 3
| -H
II
H--C--O--CH3
Route A ~ , , -'/ xx,,, RouteBH
O"
I
CO + CH3OH + H+ H--C--O--CH3
(9
O OH
R
O
[ +] H OCH3
~~ CHO
/(
CH3OH
R
R
Fig. 10. Mechanism of formylation with HCOzMe / HF / BF3 system
Acetylated products which are formed during formylation of guaiacol or anisol

are difficult to explain.
We can suppose that methanol which is the by-product in the reaction of
formylation with methyl formate is, in part, deshydrated in our superacid
conditions to give the carbocation CH3 + (Fig. 11). This carbocation can be
attacked by CO in a nucleophilic way, like in Koch-Haft formylation of aliphatic
333
O
compounds, to give the acyl cation CH3 , which is attacked by aromatic rings
to give acetophenones.
H§
CH3~OH | + H20
O
CH3~ICI |
0 R
CH3~
Fig. 11. Supposed mechanism of acetylation 9a side reaction during formylation
Why this acetylated compounds are only formed starting from guaiacol and
anisol is not explained.
In conclusion, formylation of aromatic rings can be obtained in HF-BF3
medium using methyl formate, a stable and cheap material.
High pressures are not required to make these formylations. Different
functionalized aromatic rings are formylated in our conditions with fair to good
yields. Optimizations of the yields obtained will be studied in the future.
References
. C. Jutz, Adv. Org. Chem., 9, part 1,225, (1976).
2. H. Wynberg, E.W. Meijer, Org. React., 28, 1, (1982).
3. W.E. Truce, Org. React., 9, 37, (1957).
4. G.A. Olah, L. Ohannessian, M. Arvanaghi, Chem. Rev., 4, 671, (1987).
5. R.J. Gillepsie, T.E. Peel, Adv. Phys. Org. Chem., 9, 1, (1972).
6. L.P. Hammet, A.J. Deyrup, J. Am. Chem. Soc., 54, 2721, (1932).
7. G.A. Olah, G.K.S. Prakash, J. Sommer in "Superacids", J. Wiley & Sons, (1985).
8. L. Gattermann, J.A. Koch, Chem. Ber., 30, 1622, (1897).
9. M. Tanaka, M. Fujiwara, H. Ando, J. Org. Chem., 60, 2106, (1995).
10. S. Fujiyama, B.E. Patent 887021, (1981), (to Mitsubishi Gas Chem).
11. S. Fujiyama, T. Kasahara, Hydrocarbon Process, 57, 147, (1978).
334
12. K. Kudo, N. Sugita, H. Teranishi, Y. Takezaki, Sekign Gakkaishi, 11,690, (1968).
13. L. Weisse, R. Neunteufel, H. Strutz, EP 599148, (1992), (to Hoechst).
14. J.M. Oelderik, A. Kwantes, GB 1 128 966, (1968), (to Shell).
15. M. Tanaka, Y. Souma, J. Chem. Soc. Chem. Comm., 1551, (1991).
16. M. Tanaka, M. Fujiwara, H. Ando, Y. Souma, J. Org. Chem., 58, 3213, (1993).
17. M. Tanaka, J. Iyoda, Y. Souma, J. Org. Chem., 57, 2677, (1992).
18. B.L. Booth, T.A. E1-Fekk~, G.F.M. Moori, J. Chem. Soc., Perkin I, 181, (1980).
19. G.A. Olah, K. Laali, O. Faroqs, J. Org. Chem., 50, 1483, (1985).
20. H.A. Staab, A.P. Datta, Ang. Chem. Int. Ed. Engl., 3, 132, (1964).
21. G.A. Olah, Y.D. Vankar, M. Arvanaghi, J. Sommer, Ang. Chem. Int. Ed. Engl., 18,
614, (1979).
22. G.A. Olah, S.J. Kuhn, J. Am. Chem. Soc., 82, 2380, (1960).
23. A.N. Nesmejanov, E.J. Kahn, Chem. Ber., 67,370, (1934).
24. A.I. Mashentseo, J. Gen. Chem. USSR, 1_.6_,203, (1946).
25. J.S. Lee, J.C. Kim, Y.G. Kim, Applied Catalyst, 57, 1, (1990).
26. C. Rochin, M. Crochemore, S. Ratton, EP 300861, (1988), (to Rh6ne-Poulenc Chimie).
27. R.M. Roberts, J. Org. Chem., 52, 1591, (1987).
335
H I G H S E L E C T I V I T I E S IN HYDROGENATION OF H A L O G E N O N I T R O -
B E N Z E N E S ON Pd, Pt OR RANEY NICKEL AS CATALYSTS
GEORGES CORDIER, JEAN-MICHEL GROSSELIN AND ROSE-MARIE

FERRERO

Technologie, 24 Avenue Jean Jaur~s, 69153 D6cines-Charpieu Cedex, France.
INTRODUCTION
z
+ 2 H20
X y
NO2 NH 2 X, Y, Z (CI, Br, F, CF3)
Aromatic haloamines have a wide range of applications in the production of

pharmaceuticals and agrochemical substances. The main route to these haloanilines
involves reduction from the corresponding nitro compounds either with group VIII
metal catalysts and hydrogen or with iron and hydrochloric acid. Most of the time
the reduction of halonitroaromatic to the corresponding amine is accompanied by
simultaneous dehalogenation which lowers the yield and results in the formation of
corrosive halogen acids.
At least 2 families of haloanilines can be distinguished.
One of these families is included molecules in which the fluorine atom is
contained within a CF 3 group bonded to the benzene core.
This CF 3 group is insensitive to hydrogenation under operating conditions that
are commonly used to reduce the NO2 group in the nitrated precursor.
The other family includes molecules containing at least one fluorine atom that is
directly bonded to the aromatic core. Sometimes this aromatic core also contains
chlorine atoms.
These fluorine and chlorine atoms can be removed under conventional
hydrogenation conditions for the NO2 group, by reaction with hydrogen.
336
Such hydrodehalogenation is often unwanted, but it is sometimes necessary,
especially in terms of the chlorine atom when we want to obtain haloanilines from
halogenonitrobenzenes.
Such hydrodechlorination can occur at the same time as the hydrogenation of the
NO2 group with the same catalyst. It can also occur after the hydrogenation of the
NO2 group, possibly with a different catalyst.
HYDROGENATION CATALYSTS
The literature is filled with various processes and catalyst compositions and
systems for these transformations. Promoted platinum and sulfided platinum are the
most selective group VIII metal catalysts but depending on reaction conditions and
the nature of the halogenonitrobenzene, some undesirable halo-azo and azoxy
compounds are left in the product (refs. 3, 11).
Catalysts suppliers as Johnson-Mattey (ref. 12), A.G. Degussa (ref. 13) or
Heraeus provide special platinum on carbon catalysts at industrial scale.
Depending the reaction conditions they claim for these catalysts very high
selectivities in halogenoanilines.
One other well known catalyst for these hydrogenation is the Raney Nickel
catalyst.
This catalyst is a very attractive industrial catalyst because of its low cost
compared to platinum. However it is also well known to cause extensive
dehalogenation during the hydrogenation of halonitroaromatics (ref. 14). Numerous
methods have been employed to overcome this problem including modification of
the nickel catalyst by adding base (ref. 15) phosphorus (ref. 16), amines (refs. 17,
18) and various sulfided additives (refs. 19, 20).
Since the catalytic systems in the literature were not suitable for our application,
we tried to develop precious metal or Raney Nickel based catalysts which offer high
performance (selectivity, activity and stability) for the hydrogenation of various.
In the particular case of Raney Nickel, Rh6ne-Poulenc Chimie has patemed in
1990 Raney Nickel catalysts promoted by iodides (ref. 21) or thiourea (ref. 22).
Some Industrial Hydrogenation Processes

One of the most common hydrogenation processes is the batch process in liquide
phase with a slurry catalyst ; in a stirred tank reactor (STR) or in a loop reactor as
Buss Loop for example.
337
This process decreases hydrodehalogenation especially on the chlorine atom
which is one of the most removal. It increases heavy products formed by coupling
reactions on intermediaries of hydrogenation and favours by-products coming from
nucleophilic substitution on the aromatic fluorine atom.
One other process is to proceed by nitro-compound injection at the same rate it
is consumed. So there is no accumulation of intermediaries in solution.
This process is also carried out in liquid phase with slurry catalyst in STR or
loop reactors. It favours hydrodehalogenation and absolutely needs an adapted and
selective catalyst. It decreases heavy products and especially suppresses HF
formation coming from nucleophilic substitution on the aromatic fluorine atom.
Some results at Laboratory and Industrial scale

The results given as examples in this paper have been obtained by the way of
injection pressure as indicated previously.
We selected five of the current halogenonitrobenzenes which give very
representative pictures in selectivities and activities regarding the type of catalyst
involved in hydrogenation.
Table 1 gives the results obtained with 0.5 % Pd / A1203 and Table 2 with 0.4 g
of 0.5 % Pt / A120 3.
Table 1. Hydrogenation of halogenonitrobenzenes over 0.5 % Pd / A1203
Injection Yield %
Nitro 1 ~mp. rate Yield % Yield % Other in wanted
compounds ~ mole h-1 g-~ chlorides fluorides by-products halogeno
(catalyst) aniline
4-CNB 353 1.2 13 Aniline" 13 % ,,,
-~ 85
4-FNB 373 1.25 0.12 Aniline 90.12 % 99,8
3-C-4-FNB 333 0.55 19 7 4-Fluoroaniline " 13 % ~75
i
4-Chloroaniline 95 %
Aniline" 6 %
3,4-DCNB 353 1.05 13.5 4-Chloroaniline 911% 85
3-Chloroaniline 2.5 %
3,5-DCNB 353 0.95 9.5 3-Chloroaniline 7.5 % 85
Aniline 910 %
CNB = chloronitrobenzene
DCNB = dichloronitrobenzene
FNB = fluoronitrobenzene
C-FNB = chlorofluoronitrobenzene
338
Table 2. Hydrogenation of halogenonitrobenzenes over 0.5 % Pt / A1203
Injection Yield Yield Yield Yield %

Nitro Temp. rate % Other in wanted
-1 % %
compounds (~ mole h -1 g C1- F- Azo + by-products halogeno
(catalyst) Azoxy aniline
4-CNB 373 0.37 1.9 - 0.05 Aniline: 1.9 % = 98
4-FNB 373 0.35 - < 0.05 - Aniline : traces < 99,9
3-C 4-FNB 353 0.20 0.5 0 0.087 4-Fluoraniline : 0 . 5 % = 99,4
3,4-DCNB 353 0.26 0.75 - 0.12 4-Chloroaniline : 0.7 % = 99.0
373 0.32 1.8 - 0.032 4-Chloroaniline : 1.4 % = 98
Aniline : 0 . 2 %
3,5-DCNB 353 0.22 0.4 0.08 3-Chloroaniline : 0.4 % = 99.5
375 0.31 0.5 0.035 3-Chloroaniline : 0.4 % = 99.5
Hydrogenation on Raney Nickel

W i t h R a n e y N i c k e l catalyst we p e r f o r m e d the h y d r o g e n a t i o n s first w i t h o u t and
t h e n with selectivity p r o m o t e r s .
Hydrogenation on Raney Nickel without promoters

At preselected injection rates of the halogenonitrobenzene as described
p r e v i o u s l y we c o m p a r e d the activity and selectivity for e a c h h a l o g e n o n i t r o b e n z e n e
at 353 ~ T h e r e s u l t s w e r e as follows.
9 R E A C T I O N R A T E ( m o l e h -1 g-1 Ni)
3,5-DCNB 3,4-DCNB 4-CNB 4-FNB

3-C-4-FNB
........... t .......... t ............... t .......................... t ........ "-

0.18 0.23 0.4 0.7
* TOTAL HYDRODEHALOGENATION Y I E L D (%)
4-FNB 3,5-DCNB 3,4-DCNB 4-CNB 3-C-4-FNB
-t ........... t .......... t ............. t .......................... t ........ -

3 8 10 14 21
339
H y d r o g e n a t i o n on Raney Nickel with promoters
A calculated and optimized quantity of selectivity p r o m o t e r was added to the
catalyst and solvent mixture before the halogenonitrobenzene was injected to obtain
the best c o m p r o m i s e b e t w e e n reaction rate and selectivity because all the p r o m o t e r s
tested partially deactivated the catalyst.
Table 3 shows the comparative results obtained with 3,4-dichloronitrobenzene in
the p r e s e n c e o f the previously k n o w n promoters (Na2S, thiophene, cyanoguanidine)
and our n e w one, thiourea.
Table 3. Effect of promoters on the hydrogenation of 3,4-dichloronitrobenzene
Promoter (P) Catalyst Injection Yield Yield Temp. Pres. Yield

rate % % %
mole h -1 g-1 CI mzo + in wanted
(P) g/1 g/1 (catalyst) Azoxy ~ bar halogeno-
aniline
Cyanoguanidine 3.0 20 0.18 0.7 < 0.001 353 20 ~ 99.3
Thiophene 0.3 20 0.18 3.5 < 0.001 353 20 ~ 96.5
Na2S- 9 H20 3.3 20 0.18 0.4 < 0.001 353 20 = 99.5
Thiourea 1.0 20 0.18 0.4 < 0.001 353 20 ~ 99.5
??????????? as p r o m o t e r in halogenonitrobenzene hydrogenation.
Table 4. Effect of thiourea on the hydrogenation of halogenonitrobenzenes over Raney Nickel
Nitro T P Thiourea Catalyst Injection Yield Yield Yield

compound rate % % %
mole h -1 g-1 C1- Azo + in wanted
~ bar g/1 g/1 (catalyst) or Azoxy halogeno-
F- aniline
4-CNB 353 20 1.0 20 0.28 0.6 _<0.001 = 99.4
4-FNB 373 20 1.13 20 0.45 < 0.05 - ~100
3-C-4-FNB 353 20 3.30 20 0.13 0.7 - = 99.3
3,4-DCNB 353 20 1.0 20 0.20 0.4 - ~ 99.4
3,5-DCNB 353 20 1.0 20 0.16 0.25 - = 99.7
Finally Table 5 shows that in the hydrogenation o f 3,4-dichloronitrobenzene

o v e r R a n e y Nickel catalyst p r o m o t e d by thiourea, the catalyst may be recycled
m a n y times without loss of activity or selectivity.
340
Table 5. Recycle of Raney Nickel promoted with thiourea in the hydrogenation of 3,4-
dichloronitrobenzene
Cycle T P Injection Yield % Yield % Sulphur Yield %

Number rate C1- Azo + in solution in 3,4-dichloro-
~ bar moleh-~ g-1 Azoxy (ppm) aniline
(catalyst)
1 353 20 0.20 0.4 < 0.001 13 99.5
2 353 20 0.20 0.6 < 0.001 8 99.4
3 353 20 0.20 0.6 < 0.001 8 99.4
4 353 20 0.20 0.6 < 0.001 8 -~ 99.4
DISCUSSION
In all cases the most selective catalyst was Raney Nickel doped with thiourea
which gave a hydrogenation selectivity up to 99 % without forming azo and azoxy
compounds (_< 10 ppm).
The thiourea to Raney Nickel ratio must be selected for each halogenonitro-
benzene since each one was affected differently by this change in ratio. In all cases
an increase in this ratio decreased the hydrogenation rate but also decreased the
hydrodehalogenation side-reaction rate, but to different degrees for each substrate.
Another important benefit of the promoter, thiourea, is that the Raney Nickel may
be recycled many times without appreciable loss of either activity or selectivity.
This was amply demonstrated on hydrogenation of 3,4-dichloronitrobenzene where
300 kg of the nitro compound was hydrogenated per kg of catalyst without loss of
activity or selectivity.
CONCLUSIONS
A new selectivity promoter, thiourea is efficient, for selective hydrogenation of
halogenonitrobenzenes on Raney Nickel. This promoter stays on the catalyst which
can be reused without loss of activity or selectivity. The activity of the thiourea
doped Raney Nickel catalyst is good enough (0.1 - 0.5 x 103 mole h -1 kg -1 of
catalyst, depending on the halogenonitrobenzene) for an industrial application.
The 0.5 % Pt / A1203 catalyst is also a good catalyst for selective hydrogenation
processes (more than 98.5 %) but it generates azo and azoxy compounds. With
3,4-dichloronitrobenzene the yield of these compounds can be reduced from 0.12 %
to 0.03 % by increasing the temperature from 353 to 373 ~ This, however is done
at the cost of higher hydrodehalogenation, 1.8 % rather than 0.75 % at the lower
341
temperature. In the special case of 4-fluoronitrobenzene hydrogenation, the 0.5 %
P d / A120 3 is the recommended catalyst on the basis of its selectivity, activity and
high productivity and stability. This catalyst can be used successfully in
hydrogenation of 2-FNB or 2,4-DFNB. It gives selectivities close to 99.9 % wanted
fluoroanilines and the productivity remaines very high. Like the 0.5 % Pt / A120 3,
it is very easy to continuously separate from the liquid phase without loss of fine
particles of catalyst and metal.
From an industrial point of view Raney Nickel promoted by thiourea or by
iodides is a very attractive catalyst especially in the hydrogenation of halogeno-
nitrobenzenes containing chlorine atoms.
This catalyst can works in batch or in continuous process in STR or loop
reactors. In the case of the hydrogenation of fluoronitrobenzenes Pd catalysts are
good catalyst.
P d / A 1 2 0 3 catalyst is a very suitable catalyst but P d / C can also work. The
choice depend only on the type of used process.
References
. US 4 140 719, (1979), (to Merck).
2. US 5 294 742, (1995), (to Hoechst).
3. US 3 067 253, (1962), (to Dow Chemical).
4. GB 1 498 722, (1978), (to ICI).
5. JP 49 728, (1973), (to Mitsui Toastsu Kagaku).
6. F.S. Dovell, H. Greenfield, J. Am. Chem. Soc., 2767, (1965).
7. H. Greenfield, Ann. N.Y. Acad. Sci., 145, 108, (1967).
8. EP 307 777, (1987), (to Bayer).
9. EP 347 796, (1988), (to Hoechst).
10. DE 3 811 919, (1988), (to Hoechst).
11. US 5 068 436, (1991), (to Dupont de Nemours).
12. F. King, Perf. Chem., 19, (1988).
13. A. Str~itz, O.R.C.S., (1984).
14. FR 2 245 615, (1974), (to Nippon Kayaku).
15. GB 1 191 610, (1970), (to Bayer).
16. H.C. Yao, P.H. Emett, J. Am. Chem. Soc., 84, 1086, (1962).
17. H.D. Burge, D.J. Collins, B.H. Davis, Ind. Eng. Chem. Prod. Res. Dev., 19, 389,
(1980).
18. J. Wisniak, M. Klein, Ind. Eng. Chem. Prod. Res. Dev., 23, 44, (1984).
19. V.I. Savchenko, T.V. Denisenko, S.Y. Sklyar, V.D. Simonov, Zh. Org. Khim., 11,
2149, (1975).
20. FR 1 600 519, (1970), (to Bayer).
21. FR 2 649 978 (1989), (to Rh6ne-Poulenc).
22. FR 2 649 979, (1989), (to Rh6ne-Poulenc).
342
INFLUENCE OF THE CATION IN CONDENSATION OF GLYOXYLIC
ACID ON PHENOLS IN AQUEOUS HYDROXIDE SOLUTION
MARIE-FRANCE WUTHRICK AND CHRISTIAN MALIVERNEY

Technologie - 85 avenue des Fr~res Perret- BP 62 - 69192 Saint-Fons Cedex -
France.
INTRODUCTION
Hydroxy and alkoxy aromatic aldehydes are very important products, used
primarily as flavors and fragrances, secondly as intermediates in the manufacture of
agrochemicals, pharmaceuticals, cosmetics and in the electroplating industry, etc
(ref. 1).
Ortho and para hydroxybenzaldehydes, vanillin, ethyl vanillin, protocatechu-
aldehyde, veratraldehyde and piperonal are the most important products.
Different processes are proposed for the synthesis of aromatic aldehydes but
only very few are satisfactory for industrial applications.
The main processes for the manufacture of hydroxybenzaldehydes are based on
the functionalisation of phenol, catechol and catechol derivatives (guaiacol,
guetol .... ).
Ortho substitutions can be specific, as in the condensation of phenyl metaborate
with formaldehyde to give salicylaldehyde after catalytic oxidation of intermediate
saligenin (ref. 2), but generally, condensations with carbon electrophilic reagents
give mixtures of ortho and para isomers (ref. 3).
The more interesting challenge is the regiospecific preparation of para

substitution products for the manufacture of 4-hydroxybenzaldehyde, vanillin and
ethyl vanillin.
One of the classical methods is the condensation of a phenol with glyoxylic acid in
basic media to give substituted mandelic acids as intermediates. The corresponding
343
aromatic aldehydes are obtained after homogeneous catalytic oxidative
decarboxylation (ref. 4) (Fig. 1).
OH ONa OH
02, cata
COOH NaOH H20, OH"
OH
CHO
R = H, OMe, OEt
COONa
Fig. 1. Preparationof hydroxybenzaldehydesfrom phenols and glyoxylic acid.
The base usually used for the condensation between phenols and glyoxylic acid
is sodium hydroxide. The reaction is selective for the para position, but the 2- and
4-hydroxymandelic acids produced are more reactive than the phenols, and the
consecutive reaction is the formation of dimandelic acid (Fig. 2).
OH
R O ~ + CHOI NaOH
COOH H20
R = Me, Et
OH OH COOH OH COOH
II
RO, R O ~ o H RO OH
+ ~ +
OOH
"para . . . . ortho . . . . di"
Fig. 2 . Condensationbetween phenols and glyoxylic acid in basic media
To minimize dimandelic acid formation, the phenol is used in excess, generally

two or more equivalents. Results are listed in Table 1 (ref. 5).
344
Table 1. Results for the condensation between 2-alkoxyphenols and glyoxylic acid (GA) in
aqueous sodium hydroxide.
ArOH molar ratio Conv. Yield (/GA) % Selectivity (/ArOH) %
NaOH/(ArOH +GA) ArOH % para ortho di para ortho di
guaiacol 0.95 47.5 84.2 5.2 8.7 86.5 5.3 9.5
molar ratio ArOH/glyoxylic acid (GA) = 2 9[H20 ] p/p = 82 % 935~ - 4 hours
Our goal was to increase the chemical yield and selectivity into the para
mandelic acid.
T H E P A R A S E L E C T I V I T Y O F THE CONDENSATION
Different parameters such as temperature, pH and the conversion of guaiacol
have no effect upon paraselectivity. We thought that changing the nature of the
base, in particular the steric hindrance generated by the cation around the phenol
function, could increase the paraselectivity, even in aqueous solution, as proposed
by the Japanese company UBE, with cyclodextrins (ref. 6). Unfortunately, no
increase of paraselectivity has been observed !
In the same way, the replacement of sodium hydroxide by potassium hydroxide
leads to bad results (ref. 7), especially because consumption of glyoxylic acid by the
Cannizzaro dismutation (ref. 8).
Normally, however, we can expect the paraselectivity to be improved when the

size of the cation is increased. The literature mentions at least three cases 9 the
Kolbe reaction (ref. 9), the Reimer-Tiemann reaction (ref. 10) and the
hydroxymethylation of phenols in alcoholic media (ref. 11), where with hydroxide
anion the para/ortho ratio is increased following the series of the cations N a + <
K + < Cs + < R4 N + .
345
Finally, we have discovered that the use of a tetra-alkylammonium hydroxide
dramatically increases the paraselectivity of the reaction in aqueous media. Our
initial results are listed in Table 2 (ref. 12).
Table 2. Increase of paraselectivity by the use of tetra-alkylammonium hydroxides.
a) conversion selectivity (/guaiacol) %

cation (M +) guaiacol % para ortho di
Na b) 47.5 86.5 5.3 4.5
NMe 4 38.5 96.0 2.7 1.0
NEt4 49.0 95.4 2.5 1.2
NPr4 40.0 95.6 3.3 1.1
NBu 4 21.3 95.9 3.0 1.1
NMe3Bz 33.0 95.0 3.9 1.0
a) MOH/(guaiacol +GA) = 1 , except for b) 90.95 " guaiacol/GA = 2 9

35 ~ 93 h (except for b) " 4 h).
Differences in conversion are explained in certain cases by the heterogeneity of

the mixture. Tetraethylammonium hydroxide was used for all of the following
experiments.
To have the best process using tetraethylammonium hydroxide, we have

searched for those parameters giving the best yield and lowest price combined "
influence of the quantity of base, guaiacol/glyoxylic acid ratio, concentration ....
INFLUENCE OF RATIO OF TETRAETHYLAMMONIUM HYDROXIDE

Firstly, the amount of hydroxide (molar ratio Et4NOH/(guaiacol + G A ) ) has an
influence on the rate of reaction : after four hours at 35~ conversion is at a
maximum for ratios between 0.75 and 0.9. To either side of this range (0.7 and
0.96), some glyoxylic acid remains and the corresponding yields are lower. If the
reaction is continued, these increase negligably.
346
The yields increase regularly from ratio 0.7 to ratio 0.855 decreasing thereafter.
The paraselectivity increases in the same way, from ratio 0.7 (93 %) to ratio 0.96
(97.2 %). T h e results of these experiments are listed in Table 3 and Figure 3.
Table 3. Influence of molar ratio of tetraethylammonium hydroxide
Et4NOH/ conv. % Yield (/GA) % Selectivity (/guaiacol) %
guaia +GA guaiacol para ortho di E para ortho di E
0.7 47.4 88.2 4.8 3.4 96.4 93.0 5.1 1.8 99.9
0.75 49.3 92.5 4.4 3.2 100.0 93.8 4.5 1.6 99.9
0.8 49.5 94.0 4.0 3.2 101.2 95.0 4.0 1.6 100.6
0.855 50.0 96.0 3.6 2.8 102.4 96.0 3.6 1.4 101.0
0.9 49.0 94.5 3.1 2.5 100.1 96.4 3.2 1.3 100.9
0.96 48.2 93.7 2.7 2.1 98.5 97.2 2.8 1.1 101.1
molar ratio guaiacol/glyoxylic acid = 2 935 ~ 94 hours
95
85
-- Conversion of guaiacol
75
A yield of para
- selectivity of para
65
55
45 §
0.7 0.75 0.8 0.86 0.9 0.96

ratio Et4NOH
Fig. 3. Conversion, yield and selectivity functions of molar ratio of hydroxide
347
INFLUENCE OF CONCENTRATION AND M O L A R R A T I O G U A I A C O L /
GLYOXYLIC ACID
Neutralisation of guaiacol with sodium hydroxide results in a guaiacol-sodium
guaiacolate complex of which the solubility depends on temperature and dilution.
To carry out the condensation with glyoxylic acid, it is necessary to have an
homogeneous mixture. The temperature can be raised, but due to the Cannizzaro
reaction of glyoxylic acid, it is economically uninteresting, and productivity
decreases with dilution.
If the analogous complex with tetraethylammonium hydroxide exists, it is
completely soluble in all cases, and it is possible to increase productivity by
increasing the concentration.
Glyoxylic acid and quaternary ammonium hydroxide are sold in aqueous
solution, at 50 % and 40 % weight respectively. To increase the concentration, the
only possibility is to reduce the quantity of water initially mixed with guaiacol.
Usually, for the process using sodium hydroxide, the initial mixture is composed of
1.25 mole of guaiacol per litre of distilled water (,~ Co >, = 1.25 mol/1). If the initial
volume of water is divised by four (--> ,, Co ~> = 5 tool/l), the volume of the final
mixture is reduced by one third.
In the Table 4 are listed results obtained with a molar ratio
Et4NOH/(guaiacol + G A ) = 0.855 after four hours at 35~
Table 4 . Influence of excess of guaiacol and concentration
guaiacol ,, Co ,, conv.* % yield (/GA) % Selectivity (/guaiacol) %
/ GA guaiacol para ortho di E para ortho di E
2.5 5 98.2 96.0 3.6 2.4 102 97.7 3.7 1.2 102.6
2 1.25 100.0 96.0 3.9 3.0 103 96.0 3.9 1.5 101.0
1.75 5 98.1 93.0 3.2 3.5 99.7 95.4 3.2 1.8 100.0
1.5 2.5 96.8 91.3 3.2 4.4 98.9 94.4 3.2 2.3 99.9
,, Co ,, = number of moles of guaiacol / volume of water
conv.* = observed conversion of guaiacol/theoretical maximum conversion

and theoretical maximum conversion = 100 x molar ratio GA/guaiacol
348
CONCLUSION
We have discovered that the use of tetra-alkylammonium hydroxide in place of
sodium hydroxide increases dramatically the paraselectivity of the condensation
between guaiacol and glyoxylic acid in aqueous media. The other advantages are the
possibility to increase the productivity, increasing initial concentration, with a lower
ratio of base. The new conditions for condensation can be used for other
2 alloxyphenols for example 2 ethoxyphenol.
References
1. C. Maliverney, M. Mulhauser, "Hydroxybenzaldehydes" in Encyclopedia of Chemical

Technology 4th ed., Vol.13, pp.1030-1042, John Wiley, New-York, (1994).
2. a) J. Le Ludec, DE 2,612,844, (1976), (to Rhbne-Poulenc).
b) P.A.R. Marchand, J.B. Grenet, US 3,321,526, (1967), (to Rh6ne-Poulenc).
3. H. Wynberg, Chem. Rev., 60, 169 (1960).
4. P. Maggioni, F. Minisci, BE 85,993, (1979), (to Brichima S.P.A.).
5. I. Jouve, Internal Report.
6. T. Huemura, JP 54,061,142, (1979), (to UBE).
7. D. Nobel, Internal Report.
8. E.R. Alexander, J. Am. Chem. Soc., 69, 289 (1947).
9. A.S. Lindsey and H. Jeskey, Chem. Rev., 57,588 (1957).
10. H. Wynberg, Org. React. 28, 1-36 (1982).
11. H. Iwane, T. Sugawara, EP 485,613, (1990), (to Mitsubishi Petrochem)~
12. a) D. Nobel, FR 92-08,578, (1992), (to Rhbne-Poulenc Chimie).
b) C. Malivemey, Internal Report.
349
SELECTIVE ACCESS TO HYDROQUINONE 9,, FUCHSONE ,, ROUTE
MICHEL COSTANTINI* a) ERIC FACHE a) DANIEL MICHELET b) AND

DANIEL MANAUT a)

France.
b) Rh6ne-Poulenc, Direction Scientifique, 25 Quai Paul Doumer,
92400 Courbevoie, France.
INTRODUCTION
Hydroquinone (HQ, 4-hydroxyphenol) and catechol (PC, 2-hydroxyphenol or
pyrocatechol) are industrially prepared using the following process paths 9
i) selective access to HQ by aniline oxidation using manganese dioxide in

sulphuric medium (ref. 1) (Fig. 1).Yields are high, but the process suffers from the
stoichiometric co-production of mineral salts [MnSO4, (NH4)2SO4,...) which is the
cause of serious environmental problems :
2 ~ N H 2 + MrlO2 + 5 H2SO4 + (NH4)2SO4 + 4 MnSO4 + 4 H20
o O
H2
2HQ
Fig. 1. Synthesis of HQ the from aniline
350
ii) selective access of HQ through autoxidation of p. diisopropylbenzene in
corresponding dihydroperoxide, which is then converted in HQ and acetone through
a acid catalysis (ref. 2) (Fig. 2). This is a complex process involving a very high
conversion of diisopropylbenzene and co-production of corresponding
hydroxyhydroperoxide and dicarbinol which compels the acid scission to be
performed in the presence of hydrogen peroxide in order to convert these products
to H Q :
OH
O2 ~ HOO) ~ ( OOH -''H+-~"2 +2)=0

OH
Fig. 2. Synthesis of HQ from diisopropylbenzene
iii) Simultaneous access to HQ and PC through phenol hydroxylation by hydrogen

peroxide in the presence of either a homogeneous or heterogeneous catalyst
(Fig. 3). This process has been studied in more depth than other processes. It was
the incentive for setting up the most recent and highest performance industrial
plants.
on OH OH
catalyst ~,OH
+ H202 ~ + + H20
OH
Fig. 3. Hydroxylationof phenol by hydrogen peroxide
Heterogeneous catalysis : The best known catalyst is titanium silicate - (TS-1) a

synthetic zeolite of ZSM family which does not contain any aluminium and in which
titanium atoms replace some silicium atoms within the crystal lattice (Ti/Si= 5 %)
(ref. 3). A process based on this catalysis is used in Italy (ref. 4). Although its
performance levels are good, and the HQ/PC ratio can be modified (ref. 5) the high
cost of the catalyst and its uncertain lifetime are the major handicaps preventing its
extension.
351
Homogeneous catalysis : The old ,, Fenton ,, process (hydroxylation carried out
in aqueous medium with catalysis by Fe : yield < 60 % with formation of
resorcinol, difficult to separate from HQ) is not used any more.
The discovery by Rh6ne-Poulenc of phenol hydroxylation by hydrogen peroxide
catalysed by strong acids (perchloric, triflic, sulphuric acids) was a decisive
contribution to the HQ and PC synthesis, as it avoids the drawbacks of the former
processes (ref. 6). This hydroxylation is performed by simple contact of hydrogen
peroxide with phenol in the presence of a strong mineral acid (AH) acting as
catalyst. The acido-basic process of the reaction is schematized in Figure 4 :
A-H + H202 -.. "- A-H ... H 2 0 2 -.. "- A" ... H 3 0 2 + --, "- A'+ H302 +
~
OH OH
H + A
H302 + + PHENOL OH ~ A H + H Q + PC
- H20
H (A)
Fig. 4. Hydroxylation of phenol by hydrogen peroxide catalysed by acids
By-products (polyhydroxylated polyphenyls) are formed by addition of phenol

and, most of all, of diphenols to the carbocations (A). So phenol conversion must
be limited to approximately 5 % in order to obtain acceptable yields of ,, diphenols ,~
(HQ + PC)(80-85 %/H202 and 90 %/phenol).
Since Rh6ne-Poulenc's process produces HQ and PC simultaneously, if must be
very flexible in relation to the para/ortho isomeric ratio, to meet market needs. A
major industrial objective is to acquire complete control of this ratio.
Concerning this ratio, it should be noted that :
1. The HQ/PC ratio increases with the strength of the catalyst acid.
Table 1. HQ / PC ratio versus strengh of acid catalyst
RT = selectivity versus
ACIDS pKa * RT / H202 HQ/PC t ~/~ (min)
consumed product.
Ar SO3H -- 0.7 79 % 0.44 10
H2SO 4 -" 1 80 % 0.50 10
HC10 4 < -1 85 % 0.70 3 * in H 2 0
352
The weaker the AH acid is, the more it can be found in form of (A-, H § ion
pairs linked to phenolic hydrogen and thus facilitating, under the action of H202,
the ortho hydroxylation (Fig. 5).
OH O/H ....A', H+ O / H ....A',

3o2.
A,n+ + { ~
OH
~ ~ ~ J l fOlH
+ AH + H20
Fig. 5. Orthohydroxylation of phenol by hydrogen peroxide in the presence of a ,, weak acid ,~
This effect is still limited and insufficient to meet variations in requirements.
2. As apposed to this, co-catalysis by benzophenone - as well as by all

benzophenones with electro-donating groups - noticeably increases HQ selectivity
(ref. 7). This para-directing effect is notably reinforced by polar aprotic solvents
with basicity less than that of benzophenone co-catalyst (nitriles, sulfolane,
propylene carbonate...) (ref. 8).
Table 2. Hydroxylation of phenol by hydrogen peroxide, catalysed by acids. Effect of the use of
ketones as co-catalysts. Effect of solvents.
ketones solvents Selectivity Ratio t 1/2 Remark "

(100 % / (25 % / RT HQ/PC (min) Acetophenone has a very
H:O2 max) phenol max) H202 important kinetic effect
without without 85 0.7 3 without modifying the
benzophenone without 85 1.0 1 HO/PC ratio
_
benzophenone CH3CN 85 1.2 -

benzophenone propylene 85 1.3 -
carbonate
acetophenone without 85 0.7 << 1
acetophenone CH3CN 85 0.7 -
Study of the mechanism of this co-catalysis by benzophenones has shown (not

published works) that the process involves hemipercetal ! most probably leading to
353
dioxiranne 2 which is a very reactive and paraselective entity by steric bulking of
the two aryl groups (Fig. 6).
Ar Ar + H20, Ar OH H+ Ar O
\ - \/ + \ /i
C=O + H+ --' "- ~2+OH -~- "~ C ~
Ar/ 'O--OH -H o oI
2_
- H+ I + PhOH
HQ + Ar2C=O
Fig. 6. Hydroxylation of phenol by hydrogen peroxide catalysed by acids.
Mechanism of co-catalysis by benzophenones
A relatively high HQ paraselectivity is obtained (HQ/PC = 1.2-1.3).

Unfortunately, sometimes it is not enough, which is why we conducted research to
find a process that was more selective in terms of hydroquinone.
3. By heating a phenol / benzophenone / CF3SO3H mixture (2 / 1 / 0.5 molar

ratio, T = 70~ At = 19 hr) we isolated compound 3 ,< fuchsone ,,.
C--O + CF3SO3H
(filchsone) + H20 (1)
/ (conversion= 26 %) 0 / (yield= 26 %)
The absence of any 'ortho'compound is of note. This means that it is a

paraselective condensation (which is also quantitative relative to reactive
compounds).
In addition, from a sample of fuchsone synthesized from Ar2CC12/Phenol
(ref. 9), we have demonstrated that in the presence of the stoichiometry of hydrogen
peroxide and traces of a strong acid, this fuchsone 3 quantitatively leads to HQ and
benzophenone (which is then regenerated) 9
354
g HC104
A r 2 C ~ O + H202 ~ Ar2C-O + HO OH (2)
CH3CN
3_
Thus, equations (1) and (2) show that it is possible to access HQ selectively
from phenol/H202 'via' fuchsone (ref. 10) in two stages.
One can conceive the possibility of significantly increasing the HQ selectivity of
a diphenols industrial unit - either by introducing the required quantity of fuchsone
to the hydroxylation medium, or by reacting fuchsone with H202, and then sending
the formed HQ and benzophenone to the distillation part of the unit.
FUCHSONE SYNTHESIS
Selection of acid catalyst
Besides triflic acid, other acids may also be considered initially. Table 3 shows
performances obtained with other acids (Bronsted and Lewis as well as
heterogeneous solid acids) in arbitrary and non-optimized conditions.
355
Table 3
Entry Benzophenone Acids 0 AT Conversion Yield

(mmol) (mmol) (~ (h.) (Benzophenone) (Fuchsone)
1 100 HBr (14) 75 23 12
2 100 HC1 (gas) 75 5 0
3 100 HC104 (50) 70 28
4 100 H4P207 (50) 150 3 ---1 --1
5 200 HF (4000) 80 3 36 31
6 100 NAFION (50) 145 1 9.5 8
7 100 US-Y 150 5 --2 ---2
8 100 K.O. 150 2 --1 --1
9 100 AIC13 (50) 80 4 16 9
10 100 TiC14 (50) 80 3 6.5 1
11 100 ZnC12 (50) 140 18 0.5
12 100 ZnC12 (50) 140 22 0
I I
13 20 CFsSO3H (10) 80 23 22
14 20 CFsCOOH (80) 80 - traces
15 20 CHsSO3H (40) 110 23 22
Phenol = 200 mmol for all the experiments, except emry 3 (300 mmol).
Only the strong acids are active. On account of their performances and easy use
sulphonic acids seem to be the best compounds for these catalysis fuchsone
formation (CH 3 SO3H , Ar SO3H, p. CH 3 Ar SO3H ...). But a study was also
conducted on some solid catalysts that are easy to recycle : sulphonic resins,
zeolites, clays...
Synthesis in h o m o g e n e o u s liquid phase

Kinetic approach 9 Our objective was merely to determine the main factors
governing the reaction (never to establish a quantitative and complete kinetic
model).
Kinetic measurements were conducted at constant volume (co-solvent =
p. xylene) and with CF3-SO3 H as catalyst. It was observed that the rate of the
phenol/benzophenone condensation is 9
[phenol] [acid] [benzoquinone]

V=k
[Fuschsone] [H20]
356
- Influenc~ of thiols 9 the presence of thiols enables great increase the catalytic
activity to be achieved (initial rate multiplied by approximatively 10 for 20 nd % of
thiol benzophenone), and to rapidly reach very high conversions of benzophenone
(Table 4).
Table 4
Conversion Yield
THIOL At
TT (ArCOAr) RR (FUCHSONE)
0hr30 5.6 5.6

lhr 6.4 6.4
without 2hr 8 8
3hr 12 12
4hr 15.2 14
0hr30 34 30.5
lhr 42 38
with 2hr 53.5 49
3hr 59.6 53.5
4hr 62 57.5
.....
PHENOL / BENZOPHENONE / Ar SO3H / Ar2CH2SH = 10 / 1 / 2 / 0 or 0.1 in.moles

Kinetic plots are shown in Diagram 1.
With C F 3 S O 3 H , the effect is even more marked with a total conversion of
benzophenone within one hour, and almost complete selectivity in Fuchsone.
/
\ TT (Ar2C=O)
70
60
50--
40--
30--
20--
10--
0 I I I I f
OH 1H 2H 3H 4H Time (R)
Diagram 1. 1. experiment 17 with thiol

2. experiment 16 without thiol
357
This kinetic effect is virtually independent of the use of a thiol, (except in the
case of bulky aromatic or heterocyclic thiols and dithiols liable to form cyclic
sulphurs or disulphurs).
Remark : the azeotropic elimination of the formed H20 (by a co-solvent such as
toluene) is another way of increasing the rate, but the kinetic gain obtained remains
very small, without any great increase in benzophenone conversion.
- By-products 9 Under good condensation conditions (e.g. 9

PhOH / Ph2C = O / CH3SO3H = 10 / 1 / 8 in moles, 110~ the only visible by-
product is the biphenol p, p'-Ar2C (ArOH) 2 obtained with a yield of less than to
1%.
At higher temperatures (190~ a mixture of PhCH2Ph, Ph3CH, and probably
also 4 are identified - identification by NMR and/or mass spectrometry- all these
products are in trace amounts, and the preceeding biphenol still remains the main
by-product.
~~==O
These compounds, when treated with H202, do not generate to HQ or

benzophenone.
-Fuchsone and Carbinol : Fuchsone 3 extracted from its synthesis medium
(treatment with H20 and organic solvent such as AcOEt - separation and washing of
the organic phase - elimination of AcOEt) is in fact a mixture of fuchsone (60 %)
and the corresponding carbinol fi (40 %).
)H
ArzC~O + H20 "- A r 2 C ~ O H
3_ 5__
Pure fuchsone can be obtained by means of simple azeotropic dehydration (in

boiling p-xylene). Recrystallisation is performed with n-hexane (P.F = 144 ~ C,
NMR purity > 95 %).
Pure carbinol can also be synthesized simply by performing complete hydration
of the fuchsone - carbinol mixture in the presence of H20 / AcOEt/ H3PO4 with
extraction and recrystallisation (PF = 180~ NMR purity = 100 %).
358
Fuchsone, as used throughout this document, refers to the mixture of fuchsone
and carbinol.
Optimization
Table 5 below shows balances of all the experiments conducted to perform
optimizations of the synthesis of fuchsone.
Table 5
Reactive agents
Yields Yields
E n t r y . equiv, amounts T~ of
Ph2CO THIOL reaction TT RR RT TT RR RT
h h
Ph.CO Fuchsone Fuchsone Ph.CO Fuchsone Fuchsone
18 1 0.2 110 4 99.2 84.6 85.3 . . . .
19 1 0.2 80 4 96.4 75.8 78.6 5 97.6 79.6 81.6
20 1 0.05 80 4 80 75 93.8 7 88.7 86 97
21 1 0.05 110 4 91 86.3 94.8 6 94.3 93.3 98.9
22 1 0 110 4 47 46.3 98.5 6 58 55.3 95.3
23 i 1 0.05 140 4 95 88 92.6 . . . .
24 1.5 0.05 110 5 76.9 76 98.8 7 80.7 78.4 97.2
25 1 0.005 110 4 65.7 65 98.9 7 75 72.7 96.9
i
26 i 1 0.2 110 4 99 83.7 84.5 . . . .
27 0.5 0 110 4 56.6 55.3 97.7 7 74 70.7 95.5
28 1 0 140 5 84.8 73 86.1 7 89.7 77.8 86.7
29 1 0 110 4 45.2 43.7 96.6 7 60.5 57.8 95.5
I
30* 1 0 110 4 43.6 41.3 94.8 7 59 58.7 99.4
31 i 2 0 110 4 34 33.5 98.5 7 44 43.5 98.9
32 2 0.005 110 4 41 40.5 98.8 7 50 50 100
33 2 0.05 110 4 59.5 58 97.5 7 66.5 65 97.7
34 2 0.1 110 4 67 64.5 96.3 7 74.5 67.5 90.6
35 3 0 110 4 22.3 22.3 100 7 30 30 100
Phenol = 10 equivalent amounts - CHaSO3H = 8 equivalent amounts

T T = c o n v e r s i o n - R R = yields - R T - s e l e c t i v i t i e s
* Recycling o f methasulfonic acid (trial 29)
Most of the time it appears that on one hand the selectivity of fuchsone
decreases as the temperature rises, and on the other hand that the thiol concentration
can be greatly reduced whilst retaining a marked kinetic effect and high selectivity
(entries 20-21).
But, strong acid can never be a catalyst in the real sense of the term, as
observed throughout the preceeding experiments. We will see that it is
359
stoichiometrically consumed to form a stable salt with the fuchsone, and it will
become a catalyst only after the hydrolysing action of this salt releases fuchsone and
acid (which can then be recycled).
Synthesis mechanism for fuchsone "

All the above experiments confirm the following process 9
Ar2C=O + R--SO3H --.. Ar2C+__OH,-O3S_R _.. "- Ar2C+OH + O3S--R (3)
Ar2C+--OH + ArOH
O3S--R
2 'S OH
OH OH
Ar2C OH (4)
"O3S--R + RSO3H
OH
Ar2C OH + R--SO3H w-- A r 2 C ~ O H , "O3S--R + H20 (5)
Ar2C~OH,-O3S--R ~ ....... ~ A r 2 C @ O + R--SO3H (6)
OH
+nH20 I ~
Ar2C OH,O3S--R .,t-- ~ Ar2C OH + R--SO3H
(7)
A r 2 C ~ O
Carbocation which results from protonation of benzophenone (eqn. 3) is

paraselectively added to phenol (this paraselectivity results from the steric hindrance
created by the two nuclei attached to the same carbon atom) to give carbinol
(reaction 4). Carbinol under the action of a strong acid R-SO3H dehydrates
immediately to produce a salt (eqn. 5) which is the stable form of fuchsone in this
medium. The formation of this salt leads to the consumption of one mole of strong
acid per mole of fuchsone formed (the acid is therefore not catalytic).
360
We are mistaken when we imagine, at first, that the use of a weaker acid would
give a protonation of benzophenone (eqn. 3) without dehydrating the formed
carbinol (eqn. 5). In reality this is impossible since the benzophenone is less basic
(donor number DNN 17) (ref. 11) than carbinol (DNN 38). So protonation of
benzophenone needs a strong enough acid causing the dehydratation of carbinol and
the formation of a salt.
Hydrolysing the salt (eqn. 7) is necessary to isolate the fuchsone (mixed with
carbinol). The regenerated acid CH3SO3H remains in the aqueous phase, and the
fuchsone is extracted by an appropriate organic solvent (e.g. : isopropyl ether).
Trials conducted on the synthesis of the fuchsone at high temperatures, aiming
to shift equilibrium (6) to the right, and to give back the catalytic acid, resulted in
failure. This was confirmed by the I.R. study on the salt at variable temperature (1"
240~ in which there is no modification of spectra.
The formation of the main by-product 6 is explained by the addition of phenol to
the cationic part of the dissociated salt (eqn. 8) :
Ar2C~OH, O3SCH3 --- A r 2 C L - ~ O H + CH3SO3
+A H
OH
(8)
Ar2C __(~OH
- .- Ir
6_
OH
A clear demonstration of the existence of the three equilibria was made : it was
brought to light that this biphenol within a strong acid turns completely into
fuchsone salt, and that fuchsone in a phenol system with low acidity leads
quantitatively to the biphenol.
The influence of thiols results from a rapid addition of this product to the
protonated benzophenone Ar2C + - O H (A) to form an hemithioketal which
immediately reacts to give a new electrophilic species (B) :
361
/
OH
[ Ar2C+OH ] + A~SH -.. "~ ar2C ~., "- [ Ar2C+---S--R ] + H20
(A) \ S - - R + H+ 03)
Fig. 7. Addition of thiols to the protonated benzophenone
This species fixes on the phenol and gives a sulphide (C) which - through proton
action- releases the cation (D), and regenerates the thiol.
SR
I Ar2C+---S~ R
1 _H§
~ ArzC
(C)
OH A r 2 C ~ O H + R--SH (13)
(D)
The kinetic effect is explained by the fact that since (B) is more electrophilic
than (A), the limiting step of the overall process (addition of A on phenol) is
replaced by a quicker reaction (addition of B to the phenol).
Synthesis trials conducted in liquid phase and with heterogenous catalysis

Processing of the heterogenous acid catalysts (sulphonic resin, zeolites, clays...)
is conducted the same way as it is for homogeneous catalysis: the active acid parts
are progressively blocked as 'fuchsone salts'. Regeneration of these parts takes
place through hydrolysis which releases the formed fuchsone. Heterogeneous
catalysis will have to work first in absorption (the salt is formed) and then in
desorption (washing with H20 + organic solvent). Between each of the cycle the
washing water is eliminated through drying.
It was observed that the efficiency of acid parts of sulphonic resins (NAFION or
BAYER K 2431 : 0.8 to 5 meq. H+/g resins) always remains low (1-1.5 mole of
fuchosne/10 equivalent amounts H § and that the use of prohibitive quantities of
resins is necessary. The same procedure applies to resins having very large pores
(BAYER K 1221, LEWATIT 4 % DVB).
With mineral solid acids, efficiency is lower than in the previous examples
(zeolites, clays, metallic oxides ..... ).
362
Synthesis trials conducted in gaseous phase on mineral solid acid catalysts 9
A few trials were conducted on various solid acids (SiO 2 - A1203 - Nb205,
HZSM-5, ...) "
Phenol/benzophenone/Argon = 2 / 1 / 1 in moles 0 = 350~

Hold up time = 1 to 4 sec. WHSV = 2 - 3.5 h -1
(WHSV = weight hour space velocity
Fuchsone is an instable product under these conditions which explains why it is

always absent in the process, although benzophenone is always partly transformed.
The process cannot be improved by reducing the hold up time.
R E A C T I O N O F F U C H S O N E W I T H H202
We saw before that H202 reacts stoichiometrically with fuchsone leading
selectively to HQ and benzophenone (reaction 2). How does this reaction work ?
.Co-catalysed hydroxylation of phenol by fuchsone. Influence of [Fuch~oneJ on

RR .(diphenols) and on HQ/PC ratio.
Several hydroxylation experiments of phenol (by H202/HC104) were conducted
starting with increasing quantities of fuchsone. All the results are shown in Table 6
and Diagram 3.
Table 6
(Fuchsone / (HC104 / (H202 Conversion Selectivity Selectivity Selectivity

Trials H202)o HzO2)o phenol)o TT RT RT RT PC/HQ
% mol % mol % mol (H202) (HQ) (PC) (DP)
BP/36 4.65 0.95 5.35 1 99 39.5 41.5 81 1.05

BP/37 10.3 0.85 5.0 1 100 42.5 40 82.5 0.94
BP/38 14.5 0.95 5.2 1 100 44.5 36 80.5 0.80
BP/39 19.9 0.80 5.25 1 100 48 34.5 82.5 0.72
BP/40 21.8. 0.88 4.4 0,5 100 47.5 34.5 82 0.73
BP/41 33 0.75 5.3 0,5 100 54 29 83 0.54
BP/42 57 0.89 4.65 0,5 100 68.5 18 86.5 0.26
BP/43 77.2 0.87 4.7 0,5 100 81 9 90 0.11
BP/44 101 0.80 5.1 0,5 100 93.5 2 94.5 0.02
DP " Diphenols
363
PC/HQ Selectivity% RT (PC +HQ)
1,5 95
1 90
PC/HQ (2)
0,5 85
RT (PC + HQ) / H202 (1)
0 80
0 25 50 75 100
ratio (Fuchsone / H202)o % MOL.
Diagram 3.
By increasing the initial ratio (fuchsone/H202) both the selectivity in HQ and the
diphenol yield are also increased.
These results show to what extent cost savings could be made by using a phenol
process in parallel with a fuchsone plant functioning with a (H202/FUCHSONE)
molar ratio = 1 and producing hydroquinone with much greater yields of phenol
and H20 2 ( - - 9 5 % ) than those achieved (80 %/H202 and 88 %/phenol) using
phenol hydroxylation with H202/HC104 (with or without benzophenone).
Remark : when co-cocatalysis is performed using fuchsone, a modulation of the
PC/HQ ratio can be obtained with a reduced circulation of benzophenone, this ratio
being very much higher than when co-catalysis of benzophenone occurs on its own
(ref. 7) (best result for benzophenone co-catalysis : (HQ/PC) - 1 (Diagram 4).
Ratio PC/HQ
1,5
J...... BENZOPHENONE I
FUCHSONE
0,5
I i i i
0 10 20 30 40 50
Ratio (Benzophenone / H202) 0 % moI.
Diagram 4.
364
It is thought that within the hydroxylation process in which fuchsone is the co-
catalyst, this product will first react with H202. It was demonstrated that fuchsone is
approximatively 200 times more reactive than phenol, quantitatively producing HQ
and benzophenone. Hydroxylation continues further in the presence of the formed
benzophenone. Total selectivity of HQ is due to the ex-fuchsone HQ on one hand,
and on the other hand to the co-catalysis of hydroquinone.
The above indicates that fuchsone is a mixture of fuchsone and carbinol, and
that these two compounds lead to the same compounds in the presence of H202. But
it is to be noted that carbinol is 5 times less reactive than fuchsone (i.e. approx. 40
times more reactive than phenol).
Important remark : Proper separation of the fuchsone from its synthesis medium
(CH3SO3 H) is a key element ensuring the adequate oxidation of this product by
H202 as the yields percentage will not exceed 30%, with a HQ/PC r a t i o - 0,5 in
the presence of CH3SO3H. This demonstrates that the fuchsone salt does not react
with H202 and that non-identified secondary reactions occur.
Bv-oroduct of the oxidation of fuchsone

,, A
4-Hydroxy benzophenone (Yield = 1.5%) is the only by-product identified.

Figure 9 shows its formation mechanism 9
,,OH
O"
Ar2C~O H202~ Ar2CI~ O H
Ar2C+O~OH H20 Ar2C--O + HQ (14)

(1)~
0+
+H +
- H20
4-'~0~ ---OH _-
O
+ ArOH
Fig. 9.
The main reaction is (1) as the nucleophilic group p-HO-Ar migrates more
easily than the Ar group which is less nucleophilic.
365
FUCHSONE-SELECTIVE PROCESS IN HYDROQUINONE
We thought it would be better to let the fuchsone dissolve in the appropriate
solvent (isopropyl ether) until its transformation to HQ by H202 occurs, rather than
isolating fuchsone in solid state and facing the various difficulties of this technique.
Synthesis of fuchsone
Phenol / benzophenone / CH3SO3H = 10 / 1 / 8 in moles ; 0 = 110~ ; 7 h.
The duration of the reaction can be be shortened by adding thiols (such as
water-soluble HS (CH2)2SO3H which can be recycled using the same procedure as
that for CH3SOaH ).
Processing of the reaction mass

Isopropyl ether and water are added to the above reaction mass (hydrolysis of
the salt to fuchsone/carbinol with acid release) : the aqueous phase contains 97.5 %
of introduced CH3SO3H with a small quantity of phenol and trace amounts of
fuchsone.
The organic phase contains almost the entire quantity of phenol which did not
react, fuchsone (corresponding to a yield of 58.5 %/benzophenone) and the
residual benzophenone (conversion = 59.8 %).
Oxidation of fuchsone by H 2 0 2 :
A trace amount of HC104 is added to the organic phase, and then the
stoichiometric quantity of H202 is added dropwise. Temperature is maintained at
40~ for one hour. HQ with a yield of 100 % / fuchsone is obtained, together with
benzophenone with 100 % recovery rate. Then this organic phase is sent towards
the distillation section of the diphenols unit.
Recycling of CI-I3803I-I :
The aqueous phase containing CH3SO3H is first dehydrated at atmospheric
pressure, then at reduced pressure. This action ends with a temperature of 176~ in
the boiler at 50 tors). CH3SO3H recovery rate is approx. 97 %. Then this acid is
recycled to the fuchsone synthesis process without any loss of either activity or
selectivity.
366
CONCLUSION
This fuchsone route allows increase, as required of the HQ selectivity of a
RHONE-POULENC type diphenols unit, while yields versus H202 and phenol are
also increased. It is based on the principle of working with two independent
hydroxylation processes (phenol and fuchsone) before joining the two fluxes to
continue the process.
New finding~ are : the paraselectivity of the condensation of benzophenone on
the phenol and high HQ selectivity, of oxidation of fuchsone by H202_ (and high
benzophenone selectivity which becomes a catalytic compound).
This process solves the problem raised by the flexibility of the HQ/PC ratio
required by a unit producing HQ and PC at the same time.
References
1. W.H. Sheard and co-workers, Ind. Eng. Chem. 44, 1730, (1952).
2. a) M. Dorn and co-workers, EP 368.292 (09/11/1988), (to Peroxide Chemie).
b) E. Nowak and co-workers, U.S. 4.463.198 (23/08/1982), (to Goodyear).
3. M. Taramasso and co-workers, BP 2.024.790 (22/06/1978), (to Snamprogetti S.p.A.).
4. a) A. Esposito and co-workers, FP 2.523.575 (19/03/1982), (Anic).
b) G. Bellussi and co-workers, EP 200-260 (23/04/1985), (to Enichem Sintesi).
5. a) M. Marinelli and wo-workers, FP 2.657.346 (19/01/1990), (to Enichem Synthesis) ;
b) A. Thangaras, P. Ratnasamy and A. Kumar, J. Catal., 131,294 (1991).
c) Y. Ben Taarit, C. Naccache, J. Mol. Catal., 68, 45, (1991).
6. a) F. Bourdin, M. Costantini, M. Jouffret, G. Lartigau, FP 2.071.464 (30/12/1969), (to
Rh6ne-Poulenc).
b) J. Varagnat, Incl. Eng. Chem. Prod. Res. Dev, 15 (3), 212, (1976).
7. M. Costantini, M. Jouffret, EP 480.800 (04/10/1991), (to Rh6ne-Poulenc).
8. M. Costantini, D. Laucher, EP 558.376 (01/09/1993), (to Rh6ne-Poulenc).
9. a) H. Burton, G.W.H. Cheesman, J. Chem. Soc., 1955, 3089.
b) W.T. Lewis and co-workers, J. Am. Chem. S0c., 101, 5717, (1979).
10. M. Costantini, D. Michelet, D. Manaud, EP 606.182 and 606.183 (08/01/1993), (to
Rh6ne-Poulenc).
11. Y. Marcus in ,, Ion Solvation ,,, John Wiley and Sons Ed., (1985).
367
THE MECHANISMS OF NITRATION OF PHENOL
PASCAL METIVIER AND THIERRY SCHLAMA

France
INTRODUCTION
Nitration of phenol is an old reaction that has been described for the first time
in 1875 (ref. 1). Nitrophenols are of great interest for the industry since they can
be used as precursors for dyes, pharmaceuticals (e.g. acetominophen), and
agrochemicals (e.g. parathion, phosalone). Documents dating from 1898 (ref. 2)
can be found in the archives of the Rh6ne-Poulenc company indicating the early
industrial interest toward this reaction. To our knowledge, Rh6ne-Poulenc is the
only company carrying out this reaction on a large industrial basis. This reaction
has the reputation to be messy (ref. 3), and despite important studies, the different
mechanisms involded in this reaction have not been completely solved. Two
mechanisms are currently considered to be active in this reaction. The first one
which is well established and has been fully studied in aqueous media involves two
steps, nitrosation followed by and oxidation (Scheme 1). Nitrosation is an
electrophilic aromatic substitution involving the nitrosonium ion and is mainly para
selective (refs. 4, 5), and the oxidation is due to the nitrogen dioxide in
equilibrium with nitrous acid and nitric acid. Two mechanisms involving nitrogen
dioxide have been proposed for the oxidation step (ref. 6). This total
paraselectivity can only be obtain in a two step procedure where nitrosation is
performed in the absence of nitric acid followed by oxydation to paranitrophenol
by addition of nitric acid to the mixture.
368
OH OH
+ HNO 2
3 + H20
~N
O"
OH OH
I
+ HNO 3 + HNO 2
0-~ N 0~. N+ O-
OH OH
+ HNO 3 + H20
r
..N+
0 O-
Scheme 1. 9The nitrosation / oxydation pathway, a para selective route to nitrophenol
The reaction of phenol with nitric acid catalysed by nitrous acid conducts to
mixture of para and ortho nitro phenols, with a varying ratio and low yield in
aqueous media, and an unvariable 55/45 ortho/para ratio when the reaction is
carried out in biphasic media. The biphasic procedure, named nitrous acid
catalysed nitration of phenol in the literature has been first pointed out by Kagan
and coworkers (ref. 7) and has been since, subject to many studies. J.H. Ridd and
coworkers, have shown throught CIDNP effects (Chemical Induced Dynamic
Nuclear Polarisation) in the nitration reaction that the mechanism involves the
ArO'NO2 radical pair (ref. 8). M.J. Thompson and P.J. Zeegers (ref. 9), have
correlated the ortho/para ratio of the nitration of various phenols with the unpaired
electron spin density of phenoxy radicals using semi-empirical calculations and
shown that they are in very good agreement with the experiments. They have
proposed a mechanism in which the phenoxy radical is the key intermediate. In
this mechanism the first step is an electron transfer with NO + as the transfer agent,
followed by a deprotonation step leading to the phenoxy radical which than reacts
with nitrogen dioxide to give the nitrophenols (Scheme 2). This mechanism, also
369
enables to explain the formation of the major side product which is benzoquinone.
The phenoxy radical can be over oxidated throught another electron transfer step,
leading to the phenoxonium cation which reacts with water to give hydroquinone
and is then oxidised to benzoquinone.
HNO 2 + H+ ..,, "- H20 + NO +
OH OH
+ NO + # + + NO
OH O.
[~ ~ ~ + H+
O, OH
+ NO 2
NO + 2 HNO 3 ..., "- 3 NO 2 + H20
2 NO 2 + H20 _.., ~ HNO 2 + HNO 3
~
OH OH
I
[ ~ + HNO 3 ~N/~_ + H20
Scheme 2. 9Nitrous acid catalysed nitration of phenol, mechanism proposed in literature
Both mechanisms (nitrosation / oxydation and nitrous acid catalysed) involve

an initial step with NO + as the reacting specy. In water, it would react as an
electrophilic reagent and in organic media as an electron transfer acceptor. Results
obtained in our laboratory are not in good agreement with this explanation, and we
decided to try to identify more precisely the role of each active specy in this
reaction.
370
RESULTS
Experiments were carried out with different oxydation states of nitrogen to try
to identify the species that are active in the different mechanisms. The approach
chosen was to react phenol with NIII, NIV and NV in water and in organic media
and to observe the different products that are formed. This basic procedure which
seems simple needs to be undertaken caustiously. Nitrophenols are very pourly
soluble in water (2 g/1 for orthonitrophenol at 20~ and tends to demix from
water giving two liquid phases. Since this reaction is considered to be messy, one
must be sure that the carbon balance is correct so to avoid misinterpretation. All
the reactions were carried out in relative dilute state ( 1 % ) and reaction medias are
quenched with aqueous cold water containing sulfamic acid to destroy nitrous
oxydes, and titration of products is done throught HPLC analysis.
Nitrosation : In aqueous media, as described in literature (refs. 4, 5) the main
reaction product is paranitrogophenol. Side products are paranitrophenol and
orthonitrophenol (Table 1).
Table 1. 9 Nitrosation of phenol in aqueous media with NaNO2 (2 equivalents) / H2SO4 system
n2so4 (%) weight 42 42 70 70

Temperature (~ 23 -4 25
Conversion (%) 41.9 63.8 24.1
. . . . .
41.3
Paranitrosophenol (%) 35.2 44.4 19.9 23.7
YIELD Paranitrophenol ( %) 1.7 0.8 2.8 5.5
HPLC Orthonitrophenol (%) 0.6 0.3 0.6 0.2
titration Benzoqu inone ( %) 0.5
2,4-Dinitrophenol (%)
Carbon balance (%) 96.1 91.7 98.6 88.4
At 23~ paranitrophenol becomes as important as paranitrosophenol, whereas

orthonitrophenol remains very low. This can be explained by the dismutation
equilibrium of NIII in water to give NIV and NII (ref. 10). This NIV specy can
then oxidise the paranitrosophenol to give paranitrophenol. The small quantity of
orthonitrophenol formed indicates clearly that the nitrosation mechanism is
preponderant.
371
In organic media (Table 2) results are more surprising in that, that according to
the proposed ,, nitrous acid catalysed ,, mechanism, one would not have predicted
paranitrosophenol to be the main product. Particularly, in toluene or
dichloromethane where biphasic nitration of phenol takes place very rapidly, no
reaction is observed.
Table 2. 9 Nitrosation of phenol in acetonitrile media with NOBF4
CH3CN
Temperature (~ 50 3 -1
Conversion (%) 72 83 56.4
Paranitrosophenol (%) 44.3 65 37.2
YIELD Paranitrophenol (%) 1.56
HPLC Orthonitrophenol (%) 0.8 1.5 3.2
titration Benzoquinone (%) 0.6
2,4-Dinitrophenol (%) 0.5
Carbon balance (%) 75 84 83.8
The carbon balance is not very good when reaction takes place, so
interpretation must be cautious. But even if this carbon loss reveals an electron
transfer from phenol to NO + , this reaction is slow and does not explains results
obtained in ,, nitrous acid catalysed ,, nitration of phenol.
Reaction of phenol with dinitrogen tetroxide (N204) : In contrast to nitrosation
in organic media, reaction with N204 in organic media is fast and leeds to the
caracteristic products of ,, nitrous acid catalysed ,, nitration (Table 3). A striking
exemple is reaction in toluene where nitrosation does not take place whereas
reaction occurs with N204 leading to nitrophenols, benzoquinone and no trace of
paranitrosophenol. Furthermore the ortho/para ratio is roughly invariable and
corresponds exactly to the expected ratio for ,, nitrous acid catalysed ,~ nitration.
Dinitrophenol and especially 2,4-dinitrophenol is formed in small quantities during
this reaction. We have looked at the compared reactivity of ortho and
paranitrophenol and show that paranitrophenol reacts more quickly with N204 than
orthonitrophenol to give dinitrophenol. Nitration of orthonitrophenol when it
occurs leads to a ratio of 65/35 in favour of 2,4-dinitrophenol. From these
372
experiments we can conclude that in organic medium, nitrogen tetroxide is the
reagent involved in the first step of the nitration leading to the phenoxy radical.
Table 3. 9 Reaction of phenol using N204 in organic solvents
Toluene CH2C12 CH3CN Stflfolane AcOEt
,,Temperature (~ 0 24 24 0 24 0 24 24 0 24 24
N204 0.5 0.5 0.6 0.5 0.5 0.5 0.5 0.5 1.1 1.1 0.5
Conversion (%) 90 57.8 56.8 64.8 73.5 96.5 55.8 43.6 100 100 81.7
p aranitrosopheno! . (%) / / / / / / / / / / /
..Paranitrophenol '% ) 34.3 11.6 11.0 21.5 10.8 40.6 18.3 15.1 40.3 30.9 29.9
Orthonitrophenol ( %) 40.9 23.5 25.3 24.6 28.4 47.2 19.6 18.8 47.0 35.6 34.5
Benzoquinone ( %) 4.2 1.9 1.7 1.3 1.8 2.1 1.3 1.0 1.9 1.9 1.7
.2,4-Dinitrophenol (%) 0.8 7.7 8.5 1.5 15.7 0.8 5.6 / 2.0 14 3.2
2,6- Dintrophenol ( %) / / / / / / 2.6 / 1.0 6.3 1.0
Carbon balance (%) 90 86.5 89.4 84.6 83.3 94.4 91.7 91.6 92.0 88.7 88.5
(ONP+2,6-DNP) / 54.0 54.8 54.8 51.6 51.8 53.7 50.8 55.5 53.2 48.3 51.8
2; nitrophenols
Reaction w i t h . N204 ~ aqueous media and DMSO : As described in literature,

introduction of N204 in an aqueous media results in an immediate dismutation to
nitrous acid and nitric acid (ref. 10). As a result of this dismutation results of this
type of reaction leads to the same results than with nitrous acid in diluted sulfuric
acid, i.e. nitrosation is the predominent mechanism (Table 4), with no trace of
benzoquinone. In dimethyl sulfoxide (DMSO), the same type of result is obtained.
This means that D M S O behaves the same way than water toward N204. This is
confirmed through literature results, N204 is known to racemise chiral sulfoxide
(ref. 11), and that its action on an O18 maked sulfoxide leads to an oxygene
exchange between the two molecules (ref. 12). The explanation of this reactivity
passes throught the dismutation of N 204 in sulfoxides as described in Scheme 3.
373
Table 4. - Reaction o f . N204. in water and in DMSO with phenol
WATER DMSO
Temperature (~ 24 24 24
N204 (eq.) 0.5 0.5 0.5
Conversion (%) 38.5 26.7 42.1
Paranitrosophenol (%) 26.8 23.8 14.3
Paranitrophenol (%) 0.9 1.1 8.3
Orthonitrophenol (%) 1.5 1.4 1.9
Benzoquinone (%) / / /

Carbon balance (%) 90 99.5 89.0
o,. o C H~
O
II
S--O N-. o-
CH3- O O CH3 N~O
N. ' ~ S-:'-O" "- *

"n- ~' 9 "- S---O
I_
"~ CH 3 N'-----O CH 3 'N--O O
O
O~N*IO
/S*---Or, )
H3
I
O~N'~O- OH 3 s'---o- O~
I_ ~ N--O
I "N
CH3 II
O O
O~N-tO
CH3 O~\ O
ae I
/
S'-"-O- 4-
N*-"'-N"
9
/
S---O
O-~ N
CH 3 O O C,H3 II
O
Scheme 3. " Dismutation of N204 with DMSO
374
Reaction of the nitronium ion in organic media : reaction of phenol with NO2 +
in organic media leads to the same type of results than with N204 (Table 5). The
formation of benzoquinone is systematically observed and the ortho/para ratio is
again invariable. A small quantity of paranitrosophenol is observed which
corresponds to nitrosonium contained in the nitronium product used as starting
material (-- 4 % for NO2SbF6).
Table 5. 9 Reaction of NO2+ in organic media
CH3CN CH2C12
Temperature (~ 24 24 24
Conversion (%) 28.1 64.8 63.3
Paranitro sophenol ( %) 3.3 1.2 0.3
YIELD Paranitrophenol ( %) 9.2 20 18.7
HPLC Orthonitrophenol ( %) 12.0 24.0 21.8
TITRATION Benzoquinone (%) 1.85 2.6 0.3
2,4-Dinitrophenol ( %) 4.4
Carbon balance (%) 99.0 93.1 83.0
Nitration agent NO2SbF6 NOzBF4 NO2SbF6
(ONP + 2,6-DNP) / E nitrophenols (%) 56,5 % 54,5 % 49 %
Reaction of $ulfonitric medium with ohenol " Reactions in sulfonitric media are
carried out using either sulfamic acid or urea as nitrous acid scavenger. Results
obtained with different sulfuric acidities are given in Table 6. With diluted sulfuric
acid and a nitrous acid scavenger, no reaction takes place, indicating that nitric
acid by itself is not an active specy. With 80 % sulfuric acid, where the nitronium
ion begins to be significative (ref. 13), the results are the same than in organic
media. With 70 % sulfuric acid, a non expected result is obtain, in that, the
ortho/para ratio moves up to 65/35. In that case the reaction is more orthoselective
than ever. With sulfuric acid concentration over 80 %, the preponderant reaction is
sulphonation of phenol. With intermediate type sulfuric acids (30-60 %), after a
varying induction time where no reaction takes place, the media turns suddenly to
tars and results are not interpretable.
375
Table 6. : Reaction of phenol with various sulfonitric medium
Nitrous acid scavenger no urea urea urea urea urea

H2S04 (%) 80 80 80 70 70 20
Temperature (~ 24 24 0 0 24 24
Conversion (%) 100 100 78.2 35.7 83.5 2.8
Paranitrosophenol 0.1 / / 0.4 0.3 /
YIELD Paranitrophenol 32.8 35.1 35.1 11.8 27.3 /
HPLC Orthonitrophenol 42.2 45.9 42.4 22.1 51.9 /
TITRATION Benzoquinone 0.1 / / / / /
2,4-Dinitrophenol 5.5 2.8 / / / /
2,6-Dinitrophenol 2.4 1.2 / / / /
Carbon balance (%) 83.1 85.0 99.3 98.7 96.0 97.2
(ONP+2,6-DNP) / 53.8 55.4 54.7 65.0 65.0 /
Z nitrophenols
GENERAL DISCUSSION
From our results, it appears clearly that the first step in nitrous acid catalysed
nitration of phenol is not a monoelectronic transfer from phenol to the nitrosonium
specy, but rather a reaction with N204 leading to the formation of the phenoxy
radical, nitrous acid and NO2. The mechanism that we proposed for this reaction
of phenol with N204 passes throught the intermediate formation of phenylnitrate,
which then decomposes homolytically to form the phenoxy radical and NO2
(Scheme 4). Semi-empirical calculation (MNDO, PM3) on the homolytic scission
of phenylnitrate shows that the Enthalpy of reaction to give the phenoxy radical
and NO2 is -1,7 kcal/mol and though should be spontanneous (ref. 14). The N204
reaction with phenol that we propose here is formally the same then the reaction of
water (ref. 17) with N204 leeding to dismutation into nitrosonium nitrate, also the
same than the desmutation reaction with DMSO (ref. 15) and aliphatic alcools.
This mechanism corresponds also partially to the one proposed by R.G. Coombes
(ref. 18) for the reaction of 2,4,6-trialkylphenol with nitrogen dioxide in organic
solution.
376
O
H~ II
H~oc/N~,.O.
o-\ /
o-
N~---N *
+ N O 2-
Same reaction as described
for aliphatic alcohols
O O
II
H ~ O (." N~,.O. 0 / N~"~0 - l ROH ~ RONO 2
+ N O 2- + HN02 t
1
J
0
II
Semi empirical calculations
I
+ NO 2 &H = - 1,7 kcal/mol.
i
H OH
~
t NO 2
+ NO 2 > [ ~ +
NO 2
45% 55 %
Scheme 4. 9 Proposed mechanism for nitrous acid catalysed nitration of phenol
With the nitronium ion results indicate that the same intermediate phenylnitrate
is formed, which then follows the same path to give 55/45 ortho/para mixture of
nitrophenols (Scheme 5). It is interesting to note that in organic medium the N204
nitration of phenol is much faster than with the nitronium ion. This mechanism
involving the initial formation of the phenylnitrate which decomposes
homolitycally to the phenoxyradical and NO2" has already been proposed by J.H.
Ridd in the case of nitration of paranitrophenol with the nitronium ion (ref. 16).
H~O NO2 NO 2 . .
OH ~" O" O + NO 2 OH
+ NO2 + ~ ~ ~ ~ NO 2
Scheme 5. 9 Proposed mechanism for the nitration of phenol with the nitronium ion
377
The case of nitration with at 70 % sulfonitric mixture seems particular. In this
zone of acidity, the main specy is neither the nitronium ion neither nitric acid but
protonated nitric acid HzNO3 + (ref. 13). In this case one can invoque a cyclic
transition state to explain the ortho selectivity that is observed.
CONCLUSION
According to our results, three mechanisms can be effective in the nitration of
phenol. The first one which has been well described is the nitrosation oxydation
pathway, which is paraselective and involves paranitrosophenol as the key
intermediate. The two other mechanisms involve the same key intermediate : the
phenoxy radical which combines with NO2 to give a 55/45 ortho/para nitration
mixture. This intermediate can be formed either via fast reaction with dinitrogen
tetroxide (N204), or slow reaction with the nitrosonium ion. The results we obtain
suggest that the first step is the formation of the phenylnitrate intermediate, which
undergoes an homolitic breakage of the oxygen-nitrogen bond leading to the
phenoxy radical and nitrogen dioxide. In the case,
OH
I
H20 N204
O
0 0
ONO 2 O. OH
NO2
O ~ +
Scheme 6. 9 The ,, nitrous acid ,~ catalysed nitration of phenol - overall proposed mechanism
of the biphasic procedure, the formation of N204 results from the well know
reaction of nitric acid with nitrous acid. This N204 is then extracted to the organic
media where fast reaction with phenol takes place as depicted in Scheme 6.
378
References
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12. C.R. Johnson, Jr D. Mc Cams, J. Am. Chem. Soc., 86, 2935, (1964) ;
C. Lagercrantz, Acta Chem. Scand., 23, 3259, (1969).
13. D.S. Ross, K.F. Kuhlman, R. Malhotra, J. Am. Chem. Soc., 105, 4299, (1983) ;
G.F. Scheats, A.N. Stachan, Can. J. Chem., 56, 1280-1283, (1978) ;
R.B. Moodie, K. Schofield, P.G. Taylor, J. Chem. Soc., Perkin trans. II, 133, (1979).
14. Phenylnitrate is not described in literature.
15. C.R. Johnson, J.R.D. Mc Cant, J. Am. Chem. Soc., 86, 2935, (1964) ;
C. Lagercrantz, Acta Chem. Scand., 23, 3259, (1969).
16. J.H. Ridd, H.A. Clemens, J.P.B. Sandall, J. Chem. Soc., Perkin trans. II, 1667-1672,
(1984).
17. T.A. Turney, G.A. Wright, Chem. Rev., 59, 497, (1959).
18. R.J. Coombes, A.W. Diggle, S.P. Kempsel, Tetrahedron Lett., 34, 8557, (1993).
379
OXIDATION OF ALKYLPHENOLS TO HYDROXYBENZALDEHYDES
ERIC FACHE, DOMINIQUE LAUCHER, MICHEL COSTANTINI, MONIQUE

BECLERE AND GILLES PERRIN-JANET

Technologie des Carri6res, 85, Avenue des Fr6res Perret, BP 62, 69192 Saint-Fons
Cedex, France.
4-methylphenol is oxidized into p-hydroxybenzaldehyde by oxygen or air, in

water / acetic acid media, in the presence of catalysts like Pd / C or Pd-Sn / C
(66 % selectivity for total conversion). The former catalysts are not able to yield o-
hydroxybenzaldehyde from 2-methylphenol. However, good performances are
reach with a Pd-Pt / C catalyst (60 % selectivity for total conversion )
INTRODUCTION
Among hydroxybenzaldehydes, the o- and p- hydroxy isomers are the most
important for commercial applications in agricultural, flavor and fragance,
pharmaceutical or polymer fields (ref. 1). The two main processes for the
manufacture of hydroxybenzaldehydes are both based on phenol. The most widely
used process is the saligenin process. Hydroxybenzyl alcohols (o- and p- isomers)
are produced from base - catalyzed reaction of formaldehyde with phenol (ref. 2).
Air oxidation of these alcohols over a suitable catalyst (based on palladium or
preferentially on platinum) produces hydroxybenzaldehydes (ref. 3). The Reimer -
Tiemann process allows the coproduction of o- and p- hydroxybenzaldehydes
(ref. 4). Treatment of phenol with aqueous chloroform and sodium hydroxide leads
to benzal chlorides which are rapidly hydrolyzed by alkaline medium to aldehydes.
The previous processes need two chemical steps and produce salt effluents.
More recently, the direct formation of hydroxybenzaldehydes by the oxidation of
the corresponding alkylphenols was reported. However, the oxidation of 4- and 2-
methylphenol respectively into p- and o-hydroxybenzaldehydes remains difficult,
leading very often to heavies. For instance, the catalytic systems used for the
38O
oxidation of substituted cresols (Table 1) are no efficient and / or no selective in the
case of o- and p-cresols (ref. 6).
Table 1 : Usual catalytic systems for the oxidations of substituted cresols or derivatives
Catalysis type Catalysts Substrates References
Basic tBuOK (Stoichiometric reaction) 2,6-tert-butyl-4-methylphenol 5a

Homogeneous Ce(OAc)3 2,6-tert-butyl-4-methylphenol 5b
2,6-dimethoxy-4-mrthylphenol
Homogeneous Co(OAc)2 + Mn(OAc)2 3,4,5-trimethoxytoluene 5c
Homogeneous CuC12 + amines or oximes 2,4,6-trimethylphenol 5d
Heterogeneous Pd/C 2,4,6 trimethylphenol 5e
However, with cobalt or iron catalysts, good results are obtained when the
phenol group is protected, either under its acetate form after reaction with acetic
anhydride in an acetic acid medium (ref. 7), or as phenate when the oxidation takes
place in a basic medium (at least three equivalents of base versus cresol) (ref. 8).
These oxidations suffer from great drawbacks : in acetic medium, the reaction leads
to poor selectivities at high conversions (acid formation) and needs one more step to
recover the aldehyde under the phenolic form. The main limitation of the oxidation
in basic media is the large coproduction of salt. Moreover, the oxidation of o-cresol
appears more difficult than the p-cresol one.
In this paper, we wish to report efficient methods to oxidize 4-methylphenol and 2-
methylphenol into the corresponding aldehydes which avoid the previous
drawbacks.
OXIDATION OF 4-METHYLPHENOL IN ACETIC MEDIA IN THE

PRESENCE OF PALLADIUM-BASED CATALYSTS
Oxidations of methylaromatic compounds, without phenolic group, in the
presence of palladium based catalysts are well documented (ref. 9). Toluene
(ref. 9), o-, m-, p-xylene (refs. 9c-e), mesitylene (ref. 9c), hexamethylbenzene
(ref. 9c), o-methylanisole (ref. 9e) and p-methylanisole (ref. 9d) are among the
main substrates which have been studied. The solvent of choice for the reaction is
acetic acid and the main product is the corresponding benzylic acetate. Aldehyde
381
selectivity is low. According to our knowledge, the oxidation of 4-methylphenol in
acetic acid medium has been reported only one time with a catalyst based on
palladium, bismuth and chromium or manganese or silicium (ref. 10). Under these
conditions, the main product is 4-hydroxybenzylacetate.
As expected, we found that the oxidation of 4-methylphenol in acetic acid medium
in the presence of Pd-Sn / C * catalyst leads to 4-hydroxybenzylic acetate with a
good selectivity (Table 2, entry 2). The study of the reactionnal intermediates in
such a medium shows the difficulty to oxidize the acetate into 4-hydroxy-
benzaldehyde under these conditions (Table 2, entry 5) while the esterification of
alcohol by acetic acid is complete (Table 2, entry 3).
OXIDATION OF 4-METHYLPHENOL IN WATER / ACETIC MEDIA IN

THE PRESENCE OF PALLADIUM-BASED CATALYSTS
In the case of Pd-Sn / C catalysts, the addition of water to the acetic medium
allows the shift of the oxidation selectivity from the acetate towards 4-hydroxy-
benzaldehyde (Table 2, entry 1). Moreover, in this new medium, 4-hydroxy-
benzylic alcohol is converted into 4-hydroxybenzaldehyde with 61% selectivity
(Table 2, entry 4).
The best selectivities in aldehyde are reached with media containing at least 50% in
volume of water (Table 2, entries 1, 2, 6-7). At lower water concentration,
4-hydroxybenzylacetate is the main product of the reaction (entry 2). The presence
of water is necessary to allow the equilibrium between 4-hydroxybenzylacetate,
which is not oxidized, and 4-hydroxybenzylalcohol which is easily converted into
4-hydroxybenzaldehyde (Scheme 1).
OH~CH2OAc
OH OH
~ ~ ,IOH H20
CHO COOH
NNN~ O H ~ C H 2 O H / ~
Scheme 1 : Oxidation of 4-methylphenol in the presence of Pd-based catalysts in water-acetic

acid media.
382
T a b l e 2. 9Oxidation o f cresols with palladium-based catalysts in acetic acid / water m e d i a
Ea'ms' Substrate AcOH/ Catalyst At Conver- Selectivities %

H20 (h) sion
ml/ml Nature mmol Pd % 1 2 3
1 p-cresol 25 / 25 Pd-Sn/C 0.25 2 87 2 9 64 9
2 p-cresol 50 / 0 Pd-Sn/C 0.25 0.25 84 5 70 10 3
3 4-hydroxybenzylalcohol 50 / 0 Pd-Sn/C 0.25 0.2 100 100
4 4-hydroxybenzylalcohol 20 / 30 Pd-Sn/C 0.25 1 100 - - 61 7
5 4-hydroxybenzylacetate 50 / 0 Pd-Sn/C 0.25 2 35 - - 47 11
6 p-cresol 40 / 10 Pd-Sn/C 0.25 2 93 3 27 50 6
7 p-cresol 10 / 40 Pd-Sn/C 0.25 2 76 1 7 60 8
8 p-cresol 25 / 25 Pd/C 0.15 2.5 55 8 20 61 5
9 p-cresol 25 / 25 Pd/C 0.15 21 99.5 e e 66 31
10 o-cresol 25 / 25 Pd/C 0.15 4 95 - - - 4
11 o-cresol 25 / 25 Pd-Pt/C** 0.27 4 70 - - 14 -
12 o-cresol 25 / 25 Pd-Pt/C 0.27 4 100 - - 60

+BiO(NO3) Rt/Bi=2.45
Substrate " 10 m m o l " K O A c " 10 m m o l 100~ 9o x y g e n - 5 1/h.
! " 2 or 4 - h y d r o x y b e n z y l a l c o h o l 92 2 or 4 - h y d r o x y b e n z y l a c e t a t e 9
3 " 2 or 4 - h y d r o x y b e n z a l d e h y d e 94 - 2 or 4 - h y d r o x y b e n z o i c acid
383
CATALYSTS USED TO OXIDIZE 4-METHYLPHENOL IN WATER-
ACETIC MEDIA
Various Pd-based catalysts used in acetic acid / water media allow the oxidation
of 4-methylphenol into 4-hydroxybenzaldehyde with good selectivity. The best
results are obtained with two kinds of catalysts : Pd-Sn / C and prereduced Pd/C*
(Table 2, entries 1 and 8). With total conversion of cresol, 4-hydroxybenzaldehyde
can be obtained with an average selectivity of 65 %. 4-hydroxybenzoic acid is the
main by-product (Table 1, entry 9).
The key of the oxidation seems to be the oxidation degree of palladium which
has to be as low as possible (reduction of Pd(OAc)2 by Sn (II) derivatives in the
case of Pd-Sn catalysts, or reduction, for instance by hydrogen, in the case of Pd /
C catalysts). Hence, in the transformation of 4-hydroxybenzylalcohol into 4-
hydroxybenzaldehyde, palladium behaves as a dehydrogenation catalyst and has to
be at a low oxidation degree. Moreover, it is also well known that low oxidation
state palladium is implicated in benzylic oxidations, via the cleavage of the benzylic
C-H bond, while more electrophilic palladium with high oxidation degree favors the
attack and functionnalization of the aromatic ring (ref. 11).
MAIN SIDE-REACTIONS IN THE CASE OF 4-METHYLPHENOL

OXIDATION IN WATER / ACETIC MEDIA IN THE PRESENCE OF
PALLADIUM-BASED CATALYSTS
When initial concentration of 4-methylphenol is increased, the selectivity in
aldehyde and more generally in the corresponding alcohol, acetate, aldehyde and
acid decreases (Table 3).
The loss of selectivity in concentrated media, is mainly due to polyethers like :
C H 3 ~ O(---CH2~ O)O- - CnH 2 ~
Formation of these compounds, not or poorly oxidable under the reactionnal

conditions, is due to the nucleophilic reaction of 4-methylphenol on
4-hydroxybenzylalcohol or on the corresponding acetate.
With these results, we can complete the reactionnal scheme (Scheme 2).
384
Table 3- Oxidation of p-cresol in water-acetic acid (1/1) media by palladium-based catalysts -
Influence of the concentration of p-cresol on the selectivity of the oxidation
[p-cresol] M Conversion % Selectivities %

3 !+2+3+4
0.2 99.5* 66 97
2.0 80** 35 50
KOAc 910 mmol; Pd/C (3 % Pd, Pd 0.15 mmol), AcOH / H20 =25 / 25 ml; 100~
oxygen 95 1 / h., * 21 h and p-cresol 10 mmol, ** 26 h, p-cresol 110 mmol and KOAc
100 mmol.
1" 4-hydroxybenzylalcohol" 2- 4-hydroxybenzylacetate; 3 4-hydroxybenzaldehyde;
4_ :4-hydroxybenzoic acid.
~ Cresol OH
1
Polyethers
CHO
HO--@CH2ObI
/
Scheme 2 9 Oxidation of 4-methylphenol in water-acetic acid media in the presence of palladium
based catalysts 9
H o w e v e r , the formation of previous by-products can be strongly decreased by

continuous injection of cresol in the medium in order to keep a low instantaneous
concentration of cresol in the medium. M o r e o v e r addition of bismuth allows a
significant increase on aldehyde selectivity (Table 4).
385
Table 4 " Oxidation of p-cresol in water-acetic acid (1/1) media by palladium based-catalysts.
Continuous injection of cresol.
BiONO3/Pd Conversion % Selectivities %

3 1+2+3+4
0 96.5 50 70
0.3 93.8 65 82
KOAc " 28 mmol; Pd/C (3% Pd, Pd 0.15 mmol), AcOH / H20 = 12.5 / 12.5 ml- 100~ -
oxygen" 5 1 / h, 20 h initial p-cresol 4 mmol, injection of p-cresol 41 mmol (12 h).
1" 4-hydroxybenzylalcohol; 2 94-hydroxybenzylacetate" 3 94-hydroxybenzaldehyde;
_4:4-hydroxybenzoic acid.
RECYCLING O F C A T A L Y S T S ; E X A M P L E O F T H E O X I D A T I O N O F 4-
METHYLPHENOL
The industrial reality of a catalyst is only achieved if it can be easily recovered
and if it keeps its activity and selectivity. These conditions are nearly gathered only
with Pd-Bi / C catalysts (Figs 1-2).
Finally, it has been found that promotion of palladium by bismuth not only
increases the selectivity in aldehyde but also limits the deactivation of the catalysts.
Similar results have been published in the past decade on the partial oxidation of
alcohols with similar catalytic systems (ref. 13). Various interpretations on the role
of bismuth have been suggested : among them, resistance of Pd/C against over-
oxidation and surface orientation of the reactant suppressing the formation and
strong adsorption of poisoning intermediates are also problably the main reasons of
the improved performances in the oxidation of p-cresol.
386
100
90
80
l"
70
60
Conversion with Pd/C I
TT% 50
,[! Conversion with Pd/C + Bi
40
30
20
10
0 1 , , ,
0 1 2 3 4
Recycle
Fig. 1 9 Influence on the activity with the recycling of catalysts Pd / C and Pd / C + Bi

(conditions described in Table 4)
80
70 B [l
60
50
I II Selectivity with Pd/C I
4O m Selectivity with Pd/C + Bi
RT %
30
2O
10
0
1 2 3 4
Recycle
Fig.2 9 Influence on the selectivity with the recycling of catalysts Pd / C and Pd / C +Bi
(conditions described in Table 4)
O X I D A T I O N OF O T H E R C O M P O U N D S IN W A T E R / A C E T I C ACID
M E D I A IN T H E P R E S E N C E OF Pd B A S E D C A T A L Y S T S . C A S E OF
2 - M E T H Y L P H E N O L (ref. 14)
Of course, previous catalytic systems allow the oxidation of other
methylaromafic compounds into aldehydes, especially compounds which are not
phenolic and which bear electrodonnating groups on the aromatic ring
(p-methylanisole, 3,4-(methylenedioxy)toluene for instance). However, different
catalytic methods already exist for the oxidation of these kinds of substituted cresols
(Table 1). So, the new systems would be really interesting only if they allow the
oxidation of substrates, which are very difficult to oxidize by classical methods.
387
Among these substrates, we can find not only 4-methylphenol but also
2-methylphenol.
Unfortunatly, oxidation of 2-methylphenol with the previous catalysts (Pd-Sn/C
and Pd/C) only gives small amounts of 2-hydroxybenzoic acid and heavies (table 2,
entry 10). These heavies are polyethers probably obtained by reaction of o-cresol
itself with 2-hydroxybenzylacetate or 2-hydroxybenzylalcohol. Apparently,
palladium catalysts activate the benzylic C-H bond of o-cresol, but the oxidation of
the intermediates seems less rapid than side reactions. On the other hand, we have
check that platinum catalysts, which are known to be excellent catalysts for the
oxidation of 2-hydroxybenzylalcohol into 2-hydroxybenzaldehyde in basic
aqueous medium (ref. 3), is unable to activate efficiently the benzylic C-H bond of
cresols. We synthesized bimetallic catalysts, Pd-Pt / C** , with the hope that
palladium would activate benzylic C-H bond and platinum would accelerate the
oxidation of intermediate alcohols. Effectively, this new catalyst allows to recover
2-hydroxybenzaldehyde with 14 % selectivity at 70% conversion (Table 2,
entries 11-12). Addition of bismuth salts are known to improve the aldehyde yield
in the saligenin process. With such additives, the selectivity of the aldehyde can
reached 60% for a total cresol conversion. Of course Pd-Pt / C can also oxidize
4-methylphenol but it does not bring significant improvement compared to initial
catalysts.
CONCLUSION
So, we have discovered new and original catalytic conditions which allow an
easy transformation of alkylphenols into the corresponding hydroxybenzaldehydes.
Hence, 4-methylphenol is oxidized into p-hydroxybenzaldehyde by oxygen or air, in
water / acetic acid media, in the presence of catalysts like Pd/C or Pd-Sn/C (66 %
selectivity for total conversion). The former catalysts are not able to yield
o-hydroxybenzaldehyde from 2-methylphenol. However, good performances are
reach with a Pd-Pt/C catalyst (60 % selectivity for total conversion).
References
1. In ,, Encyclopedia of chemical Technology ~,, Kirk-Other, third edition, 13, pp.70,
John Wiley (New-York), (1981).
2. K.C. Eapen and L. M. Yeddanapalli, Makromol. Chem., 1968, 119, 4.
3. J. Le Ludec, Ger Often 2,612,844, (1976), (to Rh6ne-Poulenc SA).
4. H. Wynberg, Chem. Rev., 60, 169, (1969).
388
5. a) A. Nishinaga, T. Itahara, T. Shimizu, T. Matsuura, J. Am. Chem. Soc., (1978), 100
(6), 1820.
b) T. Yuschikuni, J. Mol. Catal., 1992, 72, 29 ; N. Kitajima, S. Sunaga, Y. Moro-Oka, T.
Yoshikuni, M. Akada, Y. Tomotaki, M. Taniguchi, Bull. Chem. Soc. Jpn., 61, 1035
(1988).
c) N. Kitajima, S. Sunaga, Y. Moro-Oka, T. Yoshikuni, M. Akada, Y.Tomotaki,
M. Taniguchi, Bull. Chem. Soc. Jpn., 61,967, (1988).
d) M. Shimuzu, Y. Watanabe, H. Orita, T. Hayakawa, K. Takehira, Bull. Chem. Soc.
Jpn., 66, 251 (1993). M. Shimuzu, Y. Watanabe, H. Orita, T. Hayakawa, K. Takehira,
Tet. Lea., 32 (18), 2053 (1991). K. Takehira, M. Shimuzu, Y. Watanabe, H. Orita,
T. Hayakawa, Tet. Lett., 31 (18), 2607, (1990).
e) U.S. 4, 915,875 (04/11/1986), (to Dow Chemical).
6. S . N . Sharma, S. B. Chandalia, J. Chem. Tech. Biotechnol., 49, 141, (1990), and
references therein.
7. JP 63154644, (1986) (to Mitsui Petrochemical),
JP 62242644 A, (1986), (to Mitsui Petrochemical).
8. J. Dakka, D. A. Sheldon, NL. 9200968-A (1992) (to DSM NV) ; JP 2172940, 2172941
and 2172942 (1988) (to Sumitomo) ; T. A. Andrew, M. Needham, US. Pat. 4,453,016
(1982) and U.S. Pat. 4, 471, 140 (1984) (to Dow Chemical) ; K. Freimund RShrscheid,
U.S. Pat. 4, 748, 278 (31/05/1988) (to Hoechst), EP 323290-A (1987) (to Air Liquide) ;
A. Schnatterer, H. Flege, US. 4929766 (1989) and US.Pat. 5130493 (1991), (to Bayer),
A. Nishinaga, T. Itahara and T Matsuura, Angew. Chem. Internat. Edit., 14 (5), 356,
(1975).
9. a) S.K. Tanielyan, R. Augustine, J. Mol. Catal., 87, 311, (1994).
b) E. Benazzi, H. Mimoun, C. J. Cameron, J. Catal., 140, 311, (1993). E. Benazzi,
C.J. Cameron and H. Mimoun, J. Mol. Catal., 69, 299 (1991).
c) D.R. Bryant, J. E. McKeon, B. C. Ream, J. Org. Chem., 33 (11), 4125 (1968).
d) A.B. Goel, Inorg. Chim. Acta, 129, L31, (1987). A. B. Goel, Inorg. Chim. Acta, 121,
L l l , (1986). A. B. Goel, Inorg. Chim. Acta, 90, (1984), L15. C. H. Bushweller, Tet.
Lett., 58, 6123 (1968).
e) D.R. Bryant, J. E. McKeon, B. C. Ream, Tet. Lett., 30, 3371, (1968)
10. Matsuda, Teruo and Shirafuji, Tamio, JP 7879832 (1976), (to Sumitomo Chemical Co,
Ltd).
11. J.E. Lyons, Catalysis Today,1988, 3, 245.
12. J.F. Lepage, in ,< Catalyse de contact ,,, Tecnnip Editions, 1978.
13. T. Mallat, Z. Bodnar, P. Hug and A. Baiker, J. Catal., 153, 131, (1995) and references
therein.
14. E. Fache, M. Costantini, D. Laucher, FR 9207950, (29/06/92) and FR 9303488,
(26/03/93) (to Rh6ne-Poulenc).
Pd-Sn / C catalyst is obtained by adding to a solution of 2.44 g palladium (II) acetate

(10 mmol, Johnson-Matthey), 9.82 g of potassium acetate (100 mmol) in 400 ml acetic acid
firstly 20 g of Ceca 3S charcoal (optionally treated with concentrated nitric acid according to
known procedure (ref. 9b)) and then 16.1 g tin (II) 2-ethylhexanoate (39,75 mmol, Strem).
The suspension is vigourously stirred and heated at 100~ for 4 hours. After cooling, the
catalyst is recovered by filtration, washed with acetic acid and water and dried 5 hours under
reduced pressure (50 mbar) at 50~ (Pd : 4,3 %; Sn : 2%).
389
Pd / C catalysts are synthezised according to usual methods (ref. 12). For instance, catalyst
can be prepared by adding to a solution of 0.32 g palladium (II) acetate (1.4 mmol, Johnson-
Matthey) and 0.98 g of potassium acetate (10 mmol) in 100 ml acetic acid 5 g of ceca 3S
charcoal (optionally treated with concentrated nitric acid according to known procedure9b).
The suspension is introduced in a stainless steel autoclave, heated at 100~ under 20 bar of
hydrogen for 15 hours. After cooling, the catalyst is recovered by filtration, carefully washed
with water and dried 5 hours under reduced pressure (50 mbar) at 50~ (Pd : 3.5%).
Immediatly before the oxidation, the catalyst is reduced by hydrogen (200~ hydrogen : 1
l/h, 2 hours)
** The Pd-Pt / C catalyst is prepared according to the procedure describe for Pd / C catalyst, by
mixing with the palladium salt, a platinum (II) or (IV) salt (hexachloroplatinic acid for
instance) in the ratio (Pd: 2.85 %; Pt : 0.25 %).
390
LARGE P O R E TI-BETA ZEOLITE WITH VERY LOW ALUM]NIUM
CONTENT 9AN ACTIVE AND SELECTIVE CATALYST FOR OXIDATIONS
USING HYDROGEN PEROXIDE
MIGUEL A. CAMBLOR a) MICHEL COSTANTINI b) AVELINO CORMA a)

PATRICIA ESTEVE a) LAURENT GILBERT b) AGUSTIN MARTINEZ a) AND
SUSANA VALENCIA a)
a) Instituto de Tecnologia Quimica (CSIC-UPV), Avda. Los Naranjos s/n, 46071

Valencia, Spain.
Technologie des Carri~res, 85 Avenue des Fr~res Perret, B.P. 62, 69192 Saint-
Fons Cedex, France.
ABSTRACT
The new large pore Ti-Beta zeolite has been synthesized in a wide range of
chemical compositions and its activity and selectivity in the epoxidation of olefins and
the hydroxylation of phenol has been tested. Several new synthetic procedures have
been developed yielding innovative materials with chemical compositions out of the
range previously known for zeolite Beta and with a predesigned composition profile
in the crystallites. Catalysts with a reduced A1 content of up to 0.1 A1 atoms per unit
cell of 64 tetrahedra and below with all the A1 confined into the very inner core of the
crystallites show a good activity in the epoxidation of n-hexane with an enhanced
selectivity to the epoxide. Optimization of the catalyst and of the reaction conditions
for the selective hydroxylation of phenol can yield a valuable catalyst for this
industrially important reaction.
INTRODUCTION
Zeolites are microporous crystalline solids which find a wide variety of industrial
applications in the fields of ion exchange and separation, purification and catalytic
transformation of organic compounds. As heterogeneous catalysts, most of their uses
have been as acid catalysts where the combination of high acidity, high specific
surface area and the shape selectivity derived from the size and shape of their
391
microporous channel systems made zeolites outstanding materials with no competitors
in catalytic cracking and other petroleum and petrochemical processes. This has been
the field of zeolites for over 30 years. However, recent advances in zeolite science
are spreading the interest of zeolites as catalyst for a number of applications other
than acid catalysis, including base and oxidation catalysis and photochemistry. An
increased importance of zeolite catalysis in commodities and fine chemicals
production can be thus envisaged.
The interest of zeolites as oxidation catalysts begun with the synthesis of TS-1
(titaniumsilicalite-1) (ref. 1) and the subsequent reports on its catalytic performance
using hydrogen peroxide in the presence of water. TS-1 is an active and selective
catalyst in the epoxidation of olefins, the hydroxylation of aromatics, the
ammoxidation of cyclohexanone (with NH 3 and H202), the oxidation of alcohols to
ketones (ref. 2) and even the oxidation of alkanes to alcohols and ketones (refs. 3, 4).
It has the outstanding property of being highly active in the presence of water, in
contrast to other heterogeneous catalysts, even if they have the same overall
composition (like the TiO2/SiO2 catalyst of Shell) (ref. 5). This can be an effect of
having Ti species confined into the hydrophobic microporous channels, or of having
Ti in a special environment or coordination, and makes Ti-zeolites an important
subject of study from both the academic and the industrial points of view.
TS-1 has a medium pore channel (-5.5,4,) which imposes severe geometrical
restrictions to the size of the organic substrates to be oxidized (ref. 6), and also
restricts the use of oxidating agents to H202. To overcome this limitations Ti-zeolites
with larger pores were desirable. Along these lines of thought we reported the first
synthesis of a large pore zeolite, Ti-Beta, with a tridimensional system of large pore
channels (7-6.5A) (ref. 7). It was shown that this material while having lower
intrinsic activity than TS-1 for the oxidation of organic substrates small enough to
have no restrictions to enter the TS-1 pores, is more active than TS-1 for carrying out
the oxidation of larger compounds (ref. 8). Additionally, Ti-Beta is active in
oxidation reactions using tertbutyl hydroperoxide (ref. 9). Up to now, all the Ti-Beta
samples reported contain A1 in framework positions. This implies that in activated
samples, besides the Ti Redox sites, acid sites associated to framework A1 will also
be present. The presence of the acid sites or the associated A1 may negatively affect
the oxidation activity, but it certainly can catalyze other reactions such as formation
of diols from epoxides, and undesired polymerization reactions. It is therefore of
clear interest to prepare A1 free Ti-Beta zeolite by direct synthesis.
Here we report a synthesis strategy which has allowed us to produce Ti-Beta
samples with a much higher Si/A1 ratio than any one reported up to now, together
with predesigned zeolite crystals containing very low A1 content all of it located in the
392
inner core of the crystallites, while leaving Ti in the outershell. This was expected to
influence the catalytic activity and selectivity of Ti-Beta, and the results will be
presented here.
EXPERIMENTAL
Synthesis
The synthesis mixtures were prepared using tetraethylammonium hydroxide
(40 % aqueous solution, Alfa or 35 % aqueous solution, Aldrich) with a very low
alkali cations content (Na < 2ppm, K < 0.Sppm), deionized water,
tetraethylorthotitanate (TEOT) or tetrabutylorthotitanate (TBOT) as a source of Ti
and amorphous silica (Aerosil 200, Degussa) or tetraethylorthosilicate (TEOS,
Aldrich) as the source of silica. Depending on the synthesis method a source of
aluminum can be directly added to the synthesis mixture (metal A1, aluminum
halide, etc.) or incorporated in the seeds of aluminosilicate zeolite Beta. Four
synthetic procedures were developed and Table 1 summarizes the typical ranges of
chemical composition of the initial mixture and the typical results of the syntheses.
The methods are denoted according to the nature of the silica source and, in one case,
the use of seeds. The preparation of the reaction mixtures was as follows"
Amorphous silica method - TEAOH was diluted in a certain amount of water and
the TEOT and Aerosil were added sequentially under stirring. Finally, a solution of
aluminum nitrate in TEAOH and water was also added. (ref. 10)
TEOS method- TEOS is hydrolized in an aqueous solution of TEAOH with
stirring, then TEOT is also hydrolized. Finally, a solution of aluminum nitrate in
TEAOH and water is added and the mixture is left, while stirring, until all the ethanol
formed in the hydrolisis is evaporated. (ref. 11)
TEOS/seeds method - TEOS is hydrolized in an aqueous solution of TEAOH
under stirring, then TEOT is also hydrolized and the mixture is left, while stirring,
until complete evaporation of the ethanol produced. If desired, H202 can be added
either before or after TEOT addition. Then seeds are added to the clear solution
formed and the mixture is kept under stirring to get an homogeneous mixture.
Typically, the amount of seeds is around 2.5-3 g of zeolite Beta crystals per 100 g of
SiO2 in the reaction mixture. No A1 solution is added. (ref. 12)
TiO2/SiO 2 cogel method - A TiO2/SiO 2 coprecipitate is used as the source of Si
and Ti and this is wetness impregnated with a solution containing A1 and TEAOH.
The TiO2/SiO 2 cogel is prepared by first hydrolizing TEOS in a mildly acidic solution
(HC1). Then a solution of TBOT in isopropanol is added under stirring. The pH of
the resulting clear solution is then rised to 6.0 by addition of a small amount of a base
(typically, tetraethylammonium hydroxide or tetrapropylammonium hydroxide). This
393
causes the precipitation of the TiO2/SiO 2 cogel, which is then dried to 110~ The
dried cogel is then wetness impregnated with a solution containing TEAOH and a
source of A1. (ref. 13)
The synthesis mixtures were crystallized by heating at the crystallization
temperature (usually 135-145~ in PTFE lined stainless steel 60 ml autoclaves.
During crystallization the autoclaves are rotated at 60 rpm. After quenching with tap
water, the solids are recovered by centrifugation and washed with distillate water
until pH < 9. Then the solids were dried at 100~ for several hours and calcined at
580~ to remove the tetraethylammonium cations occluded into the zeolitic channels.
Characterization
Phase purity of the zeolites was determined by conventional X Ray powder
diffraction (XRD) methods using a Philips 1060 diffractometer with a graphite
monochromator and a variable divergence slit operating in the constant area mode.
Cu K~ radiation (k = 1.541A) was used. The crystallinity was determined by
measuring the total area under the main diffracted peak (2 0 -- 22.5 o) and comparing
it with that of a highly crystalline aluminosilicate zeolite Beta. The chemical
composition was determined by atomic absorption spectroscopy using a Spectra A-10
Plus Varian spectrometer. The absence of Ti oxides out of the zeolite framework was
checked by diffuse reflectance Uv/Visible spectroscopy (Shimadzu UV-210PC
spectrophotometer, reference BaSO4).
Catalytic tests
1-hexene oxidation was carried out at 50~ in a round bottom glass flask
equipped with a condenser and a magnetic stirrer. In a typical run 33 mmol of 1-
hexene, 23.6 g of methanol and 0.8 g of H202 aqueous solution (35 wt %) are mixed
in the flask and heated to the reaction temperature under vigorous agitation. Then
0.2 g of catalyst is added to the reaction mixture (time zero). The kinetics of the
reaction was followed by taking aliquots at five reaction times (between 0.5 and
5 hours). The products were analyzed by gas chromatography using a capillary
column (5 % methylphenylsilicone, 25 m length) and a FID detector. For the H202/1-
hexene ratio used the maximum conversion of 1-hexene would be 25 %.
The catalytic oxidation of phenol with hydrogen peroxide was performed in a
round-bottom flask equipped with a condenser and a magnetic stirrer. In a typical
reaction, given amounts of catalyst, phenol and solvent were mixed in the flask and
heated to 80~ under vigorous agitation. The reaction was started by dropwise
addition of 35 wt % aqueous hydrogen peroxide solution using a perfusion pump
(addition time --1 min.). The reaction was stopped at 3 h by cooling the flask to
394
room temperature and then, the mixture was filtered to remove the catalyst. When
water was used as solvent, methanol was added before filtering to homogenize the
mixture. Products were analized by HPLC in a Waters Associates 440 apparatus
equipped with a UV detector (254 nm) using a 100 RP-18 column (5 ~tm, 125 mm.).
The amount of unreacted hydrogen peroxide was determined in both cases by
iodometric titration.
Design of the synthetic procedure

Four methods have been developed for synthesizing highly crystalline zeolite Ti-
Beta. The aim was to prepare a catalyst with as low Al content as possible, in view of
the detrimental effect of the acid character and the hydrophilic nature of the material
in the catalytic oxidations with H202. Two of these methods afford Ti-beta with Si/A1
ratios more than 50 % larger than those previously claimed for zeolite Beta (5-100).
However, the A1 content was still high. Then we designed a synthesis procedure
which, while producing Ti-Beta with very high Si/A1 ratios, yields a material with
extreme chemical zoning: an inner core of aluminosilicate zeolite is covered by a
titanosilicate outer shell. The following illustrates how this synthesis procedure was
designed.
The first methods reported for the synthesis of Ti-Beta involved the
crystallization, without the aid of seeds, of synthesis mixtures prepared using one of
two different sources of Si (amorphous silica (7) and TEOS (11)) in the absence of
alkali cations. Both methods gave similar results (Table 1) except that the TEOS
method produced, for the same crystallization time, temperature and overall chemical
composition in the starting mixture, higher Si/A1 ratios in the final zeolite. That just
means that TEOS is a more reactive silica source than Aerosil. However, the upper
limit for the Si/A1 ratio of the zeolite was the same in both cases (--150) (14). The
isomorphous substitution of Si by Ti was evidenced by XRD, IR, XANES and
EXAFS, (ref. 15) and the catalysts were found active in the oxidation of alkanes to
alcohols and ketones (ref. 7) and in the oxidation of olefins (ref. 11) using hydrogen
peroxide or tert-bu~l hydroperoxide (ref. 9). However, when H202 was used as the
oxidant selectivity to the epoxide was found to be low due to the presence of acid sites
that catalyzed the addition of the solvent (usually methanol) to the oxirane ring (see
below). Using tert-butyl hydroperoxide as the oxidant afforded -- 100% selectivity to
the epoxide with a somewhat lower oxidation rate. (ref. 9)
395
Interestingly, we observed a competition between Ti 4+ and A13+ in the
crystallization of zeolite Ti-Beta (ref. 14). This competition was reflected in the
following facts :
-the higher the A1 content in the initial mixture, the lower the Ti content in the
zeolite.
-the higher the Ti content in the initial mixture, the lower the A1 content in the
zeolite.
- the Si/A1 (or (Si + Ti)/A1) ratios of Ti-Beta largely exceed the upper limit previously
found for zeolite Beta synthesized from gels containing alkali cations in the absence
of Ti (Si/A1 ---40) (ref. 16).
- t h e surface chemical analysis (XPS) indicated that, for Ti-Beta samples with Si/A1
ratios higher than 100, the outer shell of the crystallites contained no A1 at all,
contrarily to what is found in the absence of Ti.
To explain this competition we hypothesized that Ti could play a role similar to
that of A1 in the crystallization of zeolite Beta, that is, the creation of negative charges
in the framework and thus its stabilization by interaction with the TEA § templating
cations. This hypothesis was also supported by the fact that the amount of TEA §
cations decomposing at T > 6 2 0 K in air (as determined by thermal analysis) was
dependent on the total amount of A1 + Ti, rather than only on A1 (ref. 14). This
hypothesis required the ability of zeolitic Ti to change its coordination number,
something which obtained substantial support from XANES and EXAFS
measurements (ref. 15).
As a result from this early work we thought that zeolite Beta crystals can grow
without the incorporation of a trivalent element (A1, Ga, B, Fe,...) provided that Ti is
incorporated into the framework. This was actually supported by the fact that, as
mentioned above, Ti-Beta samples with Si/A1 ratios higher than 100 have no A1 in its
outer shell, which means that in the last steps of its crystallization these samples grow
without A1 incorporation. Unfortunately, we were unable to synthesize Ti-Beta in the
absence of aluminium (or other T3+), the conclusion being that a trivalente element is
necessary for zeolite Beta to nucleate.
Obviously, crystallization of pure titaniosilicate zeolite Beta without A1 could then
be possible if the nucleation problem was solved. We have done this by seeding with
highly active zeolite Beta seeds comprised of very small zeolite Beta crystals
(typically --0.05 mm and below) showing good stability in the synthesis media
(TEOS/Seed method) (ref. 12). In this way it is possible to synthesize highly
crystalline zeolite Ti-Beta with Si/A1 ratios well above those obtained by other
synthesis procedures, for example Si/A1 ratios about 1000. Additionally, as shown by
XPS, the crystals obtained by this procedure consist of an inner core of
396
aluminosilicate composition (which are basically the seeding crystals) covered by an
outer shell of titanosilicate composition and essentially free of A1. The Ti-Beta outer
shell can account for up to about 97.5 % of the mass of crystals. Fig. 1 schematically
illustrates the chemical zoning in these "second generation" Ti-Beta materials.
Fig. 1. Schematic representation of chemical zoning in Ti-Beta catalysts prepared by the

TEOS/Seed method
Finally, we have developed still another synthetic procedure (TiO2/SiO 2 cogel

method), aimed to afford very high yields of Ti-Beta zeolite using a small amount of
tetraethylammonium hydroxide (ref. 13). The method consists in the crystallization of
a TiO2/SiO 2 cogel after wetness impregnation with a solution containing A13+ and
TEAOH. This method gives good results for intermediate Si/A1 ratios but it doesn't
allow the synthesis of Ti-Beta with A1 contents as low as those obtained with the
TEOS/Seed method (Table 1).
397
Table 1. Methods for the synthesis of zeolite Ti-Betaa
Typical gel compositions Typical Ti-Beta products
Method SiO2/A1203 H20/SiO2 SiO2frio 2 TEAOH/SiO2 Si/A1 %TiO2 Yieldd
Zeolite Betaa 30-800 10-15 0.3-0.5 1140 0 0-10

Amorphous 50-800 10-15 20400 0.5 50-150 1-6 -- 10
silica , . .
TEOS 50-800 10-15 20400 0.5 50-150 1-6 --- 10
TEOS/seeds 400-2000 b 10-15 20-1000 0.5 100-1(130b 0.3-6 c 15-30

TiO2/SiO2 50-800 5 30-120 0.4 50-300 1-6 15-30
cogel
a. The synthesis of zeolite Beta with no Ti is included for comparison (16)

b. All the A1 is incorporated to the synthesis mixture in the aluminosilicate zeolite Beta seeds,
and is confined to the inner core of the final product.
c. Ti is incorporated to the outer shell of the crystallites.
d. g of zeolite per 100g of initial mixture.
To further illustrate the differences between the methods, Fig. 2 and 3 show the
yield and the Si/A1 ratio, respectively, of the zeolite as a function of time of
crystallization for synthesis runned by the four methods. Obviously, it is not possible
to compare synthesis with the same chemical compositions because of the differences
of the methods. Accordingly, in Fig. 2 and 3 we compare synthesis runs that gave,
for every method, high Si/A1 ratios and high zeolite yields. In this figures it is seen
how our "classical" syntheses of Ti-Beta zeolite (amorphous silica and TEOS
methods) have been surpassed by the new, previously unpublished methods
(TEOS/seed and cogel methods), if the Si/A1 ratio of the zeolite and its yield are
compared. Furthermore, the TEOS/seed method is the most versatile one in terms of
varying the chemical composition of the zeolite, and thus we have prepared materials
wich are essentially pure silica (A1 plus Ti contents below 0.2 atoms per unit cell of
64 tetrahedra).
398
g zeolite / 100 g gel
25
20 J
S
15
10
0
0 5 10 15
Time (days)
Fig. 2. Variation of the yield of Ti-Beta zeolite as a function of crystallization time at 135~ Gels
prepared by the amorphous silica (o), TEOS (+), TEOS/Seed (*) and cogel ( I ) methods
Si / A1 in zeolite
1.000
800
600
400
200
_____.-.+
O L
0 5 10 15
Time (days)
Fig. 3. Variation of Si/A1 ratio of Ti-Beta zeolite as a function of crystallization time at 135~
Gels prepared by the amorphous silica ( ) , TEOS (+), TEOS/Seed (*) and cogel (n)
methods.
399
C A T A L Y T I C TESTS
Epoxidation of 1-hexene
Table 2 lists results obtained in the oxidation of 1-hexene with H20 2 using
representative Ti-Beta zeolites prepared by the new TEOS/seed and cogel methods.
The influence of the A1 content of Ti-Beta on the selectivity to the epoxide is
clearly seen in Table 2. For the same level of 1-hexene conversion, the lower the A1
content in the catalyst the higher the selectivity to the epoxide. This is a consequence
of the presence of strong acid sites due to the presence of A104- units in the
framework. These acid sites act as catalysts for the opening of the oxirane ring by
addition of either water produced in the decomposition of H20 2 (to give the glycol
product) or methanol (to give the methyl glycol ether). The relationship between the
selectivity and the A1 contem for a given conversion is not linear, being the
enhancemem in selectivity as the A1 content increases more remarkable, when the
lower the A1 content is.
Table 2. Influence of the A1 content of the Ti-Beta on the selectivity to epoxide during the
oxidation of 1-hexene at -- 4 % hexene conversion
Si / A1 ratio epoxide selectivity (%)
43 3
300 43
470 61
550 73
700 85
The epoxide selectivity problem can be completely solved by exchanging the

zeolitic H § by Na § The Na § form of the catalyst show a --100% selectivity to the
epoxide, while only a minor decrease in the activity is found (Table 3). However, it
should be considered the leaching of Na § with time.
400
Catalyst React ion 1-c6 Product selectivity (mol %) H202 (niol %)
Time conver. TON
Type SilAl %Ti02 Epoxide Glycol MGE Conv. Selec.
(h) (mol%) (moVmol of Ti
1 1
L'ogel 43 4.2 0.5 2.32 8.09 0 91.91 10.94 80.95 7.5
I 3.38 0 96.62 23.51 63.09 12.5
2
3.5
i:::
9.13
1.36
0.71
0
0
98.64
99.29
36.79
50.95
67.85
68.35
21.1
29.4
5 10.97 I 0.46 0 99.54 I 58.09 72.02 35.3
Cogel 300 4.7 0.5
2
1
3.75
5
3.68
6.25
9.47
13.72
15.66
I
I
I
45.94
25.87
15.28
9.69
7.63
0
0
0
0
1.47
54.06
74.13
84.72
90.31
90.90
I
I
17.80
75.93
78.61
77.76
10.6
18.0
27.3
39.5
78.42 45. I
TEOSIS 470 3.3 0.5
2
1
3.75
5
1.84
3.25
5.35
8.10
10.22
II
I 87.73
66.49
46.11
32.96
27.30
0
0
0
0
3.15
12.27
33.51
53.89
67.04
69.55
I
I
7.76
52.83
90.94
80.38
74.03
7.8
13.7
22.6
34.3
43.2
TEOS/S 550 3.0 0.5
2
1
3.83
5
2.00
i::;
1 1.20
12.12
1
I
1
98.72
75.82
52.00
33.38
31.74
0
0
0
0.35
2.09
1.28
24.18
48.00
66.27
66.17
I
I
I
8.23
30.34
59.66
92.12
79.49
76.88
9.1
16.4
28.9
50.7
54.9
TEOSIS 550 (Na')' 3.0 0.5
1
2
3.83
5
1.10
2.41
5.03
11.03
12.93
1
I
I
100.00
100.00
100.00
99.27
98.47
0
0
0
0
0
0
0
0
0.73
1.53
I
I
4.72
59.66
88.92
81.16
82.91
5.0
10.9
22.8
50.0
58.6
TEOSIS 700 6.3 0.5 7.02 I 56.11 0 43.89 1 35.90 84.39 15.I
1.2 12.17 37.73 0.9 61.37 26.1
2 16.37 27.77 4.40 67.83 72.5 I 97.40 35.2
3.5 19.93 19. I7 5.66 75.17 42.8
5 19.68 8.59 7.13 84.28 94.10 90.22 42.3
a) Nat form of Ti-Beta zeolite, obtained by contacting the zeolite with a Na acetate solution under reflux conditions.
In addition to the effect on the product selectivity, it is seen in Table 3 that, for a
given synthetic method, the activity (1-hexene and H202 conversion) as well as the
selectivity of H202 increases as the A1 content of the zeolite decreases. These results
show that the AI content of zeolite Ti-Beta is one of the most important factors in
determining its activity and selectivity in oxidation reactions, and the benefits that the
new methods of synthesizing Ti-Beta with low A1 content can provide.
Hydroxylation of phenol
For this reaction a high selectivity to diphenols with a high para-selectivity is
desired. It appears that both parameters are related, so generally the higher the
selectivity to diphenols the lower the catechol/hydroquinone ratio. We have found
with Ti-Beta catalysts that the synthesis procedure is very important in determining
this relationship. Thus, as it is shown in Fig. 4 (hydroxylation using acetone as a
solvent), with catalysts synthesized by the TEOS/seed procedure it is possible to
obtain a much higher selectivity to diphenols for a given catechol/hydroquinone ratio.
Diphenols selectivity (mol/100rnol H202)

70
60 . . . . . . . . . . . . . . . . . . . . ' . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
a
9 w
40 . . . . . . . . . . . . . . .
30
20
1 1,1 1,2 1,3 1,4 1,5 1,6 1,7 1,8 1,9 2 2,1 2,2
CTOL/HO.
Fig. 4. Selectivity to diphenols (in mol % relative to H202) vs catechol to hydroquinone ratio in
the hydroxylation of phenol with H202 using several Ti-Beta catalysts.
Phenol / acetone / U20 = 50 / 65 / 6.5 (mol) : Ti-Beta / phenol = 4.5 g/mol ;
H202/phenol = 5 % (mol). Reaction temperature 80~ 3h Reaction time. Ti-Beta
materials prepared by TEOS / Seed (=), cogel (11), aerosil (+) and TEOS (*) methods.
402
In Table 4 we presem the results of catalytic tests in several conditions using a Ti-
Beta prepared by the cogel method. There it can be seen that water is a good solvent
from the point of view of activity and selectivity and that it is possible to obtain about
equimolecular amounts of catechol and hydroquinone while keeping the selectivity to
diphenols above 50 %.
Table 4. Hydroxylation of phenol using a Ti-Beta catalysta
Reaction conditions Results referred to H202 (molar)

H20 Solvem T Time Conversion HQ CTOL Total CTOL/HQ
(g) (g) (~ (h) ( %) diphenols
0.23 Acetone, '7.55 80 3 94 17.5 23 40.5 1.3
1.55 t-BOH, 7.4 80 3 95.5 14 13 27 0.95
- t-BOH,7.4 80 3 98 17 16 33 0.92
9.4 - 94 3 100 24.5 24.5 49 1.0
9.4 - 80 3 98 25 22 47 0.88
18.8 - 80 3 100 24.5 24.5 49 1.0
18.8 - 80 1b 98.5 27 28.5 55.5 1.05
18.8 - 80 3c 100 26.5 25 51.5 0.94
- CH3CN18.8 80 3 94 17.5 28.5 46 1.6
9.0 Dioxane, 1.6 80 3 97 23 21 44 0.91
a) 9.4g phenol; H202/phenol:5%mol 9 0.45g catalyst, Ti-Beta (cogel method), Si/A1 73,
3.4%TIO2.
b) 0.9g catalyst
c) 1.35g catalyst
CONCLUSIONS
It has been presented here that there is not a unique Ti-Beta material, but the
characteristics and catalytic performance strongly depend on chemical composition
and synthesis procedure. Then, new synthesis procedures which allow to prepare
samples with much lower A1 content than any one reported before have been
developed. Moreover, by using highly reactive and stable seeds, crystals of Ti-Beta
zeolite have been produced, which have an inner core of aluminosilicate composition,
covered by an outer shell of Titanosilicate which accounts for about 98 % of the
mass. These synthesis methods have lead to samples which present an improved
catalytic behaviour for reactions such as olefin oxidation and phenol hydroxylation
using H202 as oxidant.
403
References
1. M. Taramasso, G. Perego, B. Notari, U.S. 4 410 501, (1983).
2. U. Romano, A. Esposito, F. Maspero, C. Neri, M.G. Clerici, Stud. Surf. Sci. Catal., 55, 33,
(1990).
3. T. Tatsumi, M. Nakamura, S. Negishi, H. Tominaga, J. Chem. Soc., Chem. Commun., 476,
(1990).
4. Huybrechts, D.R.C., L. De Bruycker, P.A. Jacobs, Nature, 345,240, (1990).
5. R.A. Sheldon, J. Mol. Catal., 7, 107, (1980).
6. T. Tatsumi, M. Nakamura, S. Negishi, H. Tominaga, J. Chem. Soc., Chem. Commun., 476,
(1990).
7. M.A. Camblor, A. Corma, A. Martinez, J. P6rez-Pariente, J. Chem. Soc., Chem. Commun.,
589, (1992).
8. A. Corma, M.A. Camblor, P. Esteve, A. Martinez, J. P6rez-Pariente, J. Catal., 145, 151,
(1994).
9. A. Corma, P. Esteve, A. Martinez, S. Valencia, J. Catal., 152, 18, (1995).
10. M.A. Camblor, A. Corma, J. P6rez-Pariente, Sp. Pat. 2,037,596, (1993).
11. M.A. Camblor, A. Corma, A. Martinez, J. P6rez-Pariente, S. Valencia, Stud. Surf. Sci.
Catal., 82, 531, (1994).
12. M.A. Camblor, A. Corma, M. Costantini, L. Gilbert, J. P6rez-Pariente, S. Valencia,
FR Pat. 95/01824, (to Rh6ne-Poulenc), (17/02/95).
13. M.A. Camblor, A. Corma, M. Costantini, L. Gilbert, J. P6rez-Pariente, S. Valencia,
FR Pat 95/01823, (to Rh6ne-Poulenc), (17/02/95).
14. M.A. Camblor, A. Corma, J. P6rez-Pariente, Zeolites, 13, 82, (1993).
15. T. Blasco, M.A. Camblor, A. Corma, J. P6rez-Pariente, J. Am. Chem. Soc., 115, 11806,
(1993).
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404
PEPTIDE SYNTHESIS BY SAPPHO TECHNOLOGY
JEAN-MARIE BERNARD, KAMEL BOUZID, JEAN-PIERRE CASATI, MARIE

GALVEZ, CHRISTIAN GERVAIS, PIERRE MEILLAND, VIRGINIE PEVERE,
MARIE-FRANCE VANDEWALLE, JEAN-PAUL BADEY AND JEAN-MARIE
ENDERLIN
Rh6ne Poulenc Industrialisation, Centre de Recherche, d'Ing6nierie et de

Technologie, 85 Avenue des fr~res Perret, B.P. 62, 69192 Saint Fons Cedex,
France.
INTRODUCTION
Peptides are molecules very active at low concentration. They are used in
pharmaceutical, agrochemical and nutritional areas. The synthesis of these
compounds (ref. 1) is very dependant on the sequence and the quantity required.
To synthesize short peptides, at high volume and low cost, chemist prefer to use the
N carboxyanhydrides (NCA) of aminoacids, protected if necessary on the side chain
reactive functional groups. This is the case for intermediates of angiotensing
converting enzyme peptides such as L-alanyl-L-proline and Ne-(TFA)-L-lysyl-L-
proline.
This method is however very difficult to use repetitively for long peptides,
because it gives quantities of oligomers (more than 2 - 3 %) at each coupling step
and the purity of the final peptides is poor.
This is the reason why peptide chemists, to decrease the problems of
purification prefer for long peptides to use protecting groups (tert-butyloxycarbonyl
(t-Boc), benzyloxycarbonyl (Z), fluorenylmethyloxycarbonyl (FMOC) .... ) and
classical reagents such as T.B.T.U. (O-1H-benzotriazol-l-yl)-l,l,3,3-tetramethyl
uronium tetrafluoroborate), B.O.P.(benzotriazol-l-yl-oxy-tris (dimethylamino)
phosphonium hexafluorophosphate and so on in polar solvents such as
N,N-dimethylformamide or N-methylpyrrolidone. But this solvents are not
compatible with the acidic deprotection reagents such as trifluoroacetic acid and
405
necessite many solvent exchange or precipitation at each coupling or deprotection
step. That is the reasons these methods are long and expensive.
Recently, we have searched new, for economical ways to synthesize long
peptides. We have now developed new methodology to produce peptides at low
cost, continuously and automatically without precipitation and isolation at different
steps of the synthesis. The name of this process is SAPPHO (in french : Synth~se
Automatis6e de Peptides en Phase HOmog~ne).
Different peptides or peptide fragments have been synthesize by this technology.
We present here the synthesis of fragments of the salmon calcitonin.
THE SAPPHO TECHNOLOGY

SAPPHO is a powerful new innovative technology for the automated large scale
synthesis of peptides in solution phase, which can lead to significant cost saving of
up to 50 % compared to the traditional technologies (in homogeneous phase or
Merrifield phase).
SAPPHO technology which combines a modular approach to synthesis with an
innovative solubilisation system guarantees 9
- the simplicity and reproducibility of the synthetic process
- the direct synthesis of the final product in high purity
- on line quality control at each stage.
The patented solubilisation system enables the same solvent to be maintained
throughout each coupling cycle, thus avoiding any need for interim purification,
precipitation or difficult solvent exchange.
The solubilisation system comprises 9
- An organic solvent, non miscible with water (ref. 2).
- A phenolic additive to enhance solubility (ref. 2), which gives no side reaction
with the peptides all along the coupling cycle. The additive gives hydrogen bonds
with the amide groups of the peptide and decreases the interactions between the
molecules of peptide.The major consequences are a better solubilisation of the
peptides in the medium which permits synthesis at high molar concentration.
- A lipophilic, non polymeric, aromatic carboxyl protecting group protector
(ref. 3), having good solubility in the organic solvent, stable throughout the
synthesis. This protecting group is easily cleaved at the end of the synthesis by
classical reactions like saponification, hydrogenolysis or other technologies. The
choice of this protecting group and the cleavage method is dependent of peptide
sequence and functional alpha amino and side chains protecting groups.
406
Each successive amino acid is coupled with the growing peptidic chain through
the repetition of a simple 4 step cycle: coupling, extraction, drying, and
deprotection of the alpha nitrogen protecting group.
In the SAPPHO process, the N-tert-butyloxycarbonyl (N-t-BOC), the N-
allyloxycarbonyl (N-ALLOC), and the N,N-diallyl can be used for the protection of
the alpha amino function. The functional side chains can be protected by different
classical orthogonal protecting groups.
Different coupling reagents such as N-hydroxysuccinimide activated esters of
amino acids, T.B.T.U. ((O-1H-benzotriazol-l-yl)-l,l,3,3-tetramethyl-uronium
tetrafluoroborate), or N protected N carboxyanhydrides of amino acids (UNCA),
and so on can be used in the SAPPHO technology.
The excess of reagents (coupling reagents and N protected amino acids) is very
low (10 to 20 %, compared with the excess used (400 to 600 %) in solid phase
synthesis (Merrifield synthesis)).
After the coupling step, the excess reagents are transformed into hydrophilic
species eliminated with the co-products during aqueous washing.
The N protecting group is cleaved by the appropriate patented method. (ref. 4).
For the cleavage of the N-ALLOC protecting group, the drying step can be
avoided.
Quality control at each step of the cycle enables high yields of 97.5 % per cycle
(more than 99.5 % for the coupling and deprotection steps) to be achieved and
simplifies the final purification.
The SAPPHO process also permits peptide fragment coupling.
This technology has been successfully applied to the synthesis of various
peptides (Leucine Enkephaline, Luteinising Hormone Releasing Hormone
(L.H.R.H.), calcitonin fragments...).
CALCITONIN FRAGMENTS SYNTHESIS

Salmon calcitonin is a calcium regulated hormone which inhibits the bone
resorption of calcium ions. It is a polypeptide of 32 amino acids. The Salmon
calcitonin is currently manufactured by solid or liquid phase synthesis.
Two protected fragments of the salmon calcitonin (1 to 10 and 25 to 32) have
been synthesized by the SAPPHO process.
All the aminoacids have the L configuration.
407
P r o t e c t e d (1-10) salmon calcitonin
Boc~Cys~Ser(O- BzI)- Asn-- Leu--Ser (O-Bzl)--Thr (O-BzI)--Cys-- Val~ Leu--Gly--COOH

! I
S S
I t
P r o t e c t e d (25 - 32) s a l m o n calcitonin
HC1, Thr (O-Bzl)-Asn-Thr(OBzl)-Gly-Ser(OBzl)-Gly-Thr(O-Bzl)-Pro-O-GPC
The structure of the GPC group (carboxylic protective group) is 9
SYNTHESIS OF P R O T E C T E D (25 - 32) SALMON CALCITONIN

The procedure of Gisin (ref. 5) has been used for esterification of L proline.The
cesium salt of the N-tBoc L-Proline reacts with the (3-phenoxybenzyl) 4
chloromethylbenzoate (CI-GPC), in N,N-dimethylformamide (DMF). (Fig. 1)
Cs § CI
o -o 9 -o
CI-GPC 80~
+ CSCI
Fig. 1. Synthesis of the lipophilic ester of N-tBoc L-proline
Then, after deprotection of the N-tBoc group with dry HC1 gas, the protected N
tBoc aminoacids are successively introduced, at room temperature, on the
chlorhydrate of the lipophilic L-Proline ester, by using T.B.T.U. as coupling
reagent and diisopropylethylamine (Fig. 2.). A 15 % excess of T.B.T.U and N tBoc
amino acids is used for the coupling steps.
408
Thr Asn Thr Gly Ser Gly Thr Pro
Boc-Pro-OGPC
Boc-Thr(OBzl) -Pro-OGPC
Boc-Gly -Thr(OBzl) -Pro-OGPC
Boc-Ser(OBzl)-Gly -Thr(OBzl) -Pro-OGPC
Boc-Gly-Ser(OBzl)-Gly-Thr(OBzl) -Pro-OGPC
Boc-Thr(OBzl)-Gly-Ser(OBzl)-Gly-Thr(OBzl) -Pro-OGPC
Boc-Asn-Thr(OBzl)-Gly-Ser(OBzl)-Gly-Thr(OBzl) -Pro-OGPC
Boc-Thr(OBzl)Asn-Thr(OBzl)-Gly-Ser(OBzl)-Gly-Thr(OBzl) -Pro-OGPC
coupling reagent: TBTU / Room temperature//deprotection reagent: dry HC1 gas//SAPPHO process
Fig.2. Scheme of synthesis of protected (25-32) Salmon Calcitonin
The molar concentration of the peptide in the solvent ranges between 0.25 M/L
for the dipeptide Boc Thr (O-Bzl) - Pro - GPC and 0.1 M/L for the octapeptide Boc
Thr (O-Bzl) - A s n - T h r (O Bzl) - Gly - Ser (O-Bzl) - Gly -Thr (O-Bzl) - Pro -
OGPC.
The co-products (hydroxybenzotriazol, N,N,N',N'- tetramethylurea and the
excess of N tBoc amino acids) are eliminated by aqueous extractions.
The N tBoc group is cleaved with dry HC1 gas which gives volatile co-products
(CO2, isobutene and tButyl chloride) eliminated by distillation.
Yields of each coupling and deprotection steps are always more than 99.5 %.
The reaction times of coupling and deprotection are always, respectively, less than
6 hours and less than 2 hours.
100 g of the protected (25 - 32) salmon calcitonin is isolated by precipitation
with diisopropyl ether (71.5 %).
The high performance liquid chromatography (HPLC) profile of the crude product
is given in Figure 3.
409
--\
\
ql I . 7~.
' ;4.,06
.~1
--'-~_ :," . : :
j , ~,
.......
"~" " ~ ,~: . $ 6
I
~
ClATG ~ .'3 31X Z : ~
Fig.3. HPLC Profile of protected (25 - 32) Salmon Calcitonin
S Y N T H E S I S O F P R O T E C T E D (1 - 10) S A L M O N C A L C I T O N I N
The synthesis of this fragment has been synthesized, using the same
procedure. (Fig. 4.)
Cys Ser Asn Leu Ser Thr Cys Val Leu Gly
Boc-Gly-OGPC
Boc-Leu--- GIy-OGPC
Boc-Val . . . . Leu --- Gly OGPC
Boc-Cys(S-Acm)-Val . . . . Leu--- GIy-OGPC
Boc-Thr(OBzl)-Cys(S-Acm)-Val . . . . L e u - - - Gly-OGPC
Boc-Ser(OBzl)-Thr(OBzl)-Cys(S-Acm)-Val . . . . Leu --- G ly-OGPC

Boc-Leu . . . . Ser(OBzl)-Thr(OBzl)-Cys(S-Acm)-Val . . . . Leu --- GIy-OGPC
Boc-Asn---Leu . . . . Ser(OBzl)-Thr(OBzl)-Cys(S-Acm)-Val . . . . Leu --- GIy-OGPC
Boc-Ser(OBzl)-Asn---Leu . . . . Ser(OBzl)-Thr(OBzl)-Cys(S-Acm)-Val . . . . Leu --- Gly-OGPC
Boc-Cys(S-Trt)-Ser(OBzl)-Asn---Leu . . . . Ser(OBzl)-Thr(OBzl)-Cys(S-Acm)-Val . . . . Leu--- GIy-OGPC

coupling reagent: T B T U / R o o m t e m p e r a t u r e / / d e p r o t e c t i o n reagent: dry HCI g a s / / S A P P H O process
Fig. 4. Synthesis of the protected (1-10) Salmon Calcitonin
410
We have observed that T.B.T.U. gives a little dehydration of the side chain of
asparagine. This side reaction has been confirmed by synthesis of an authentic
cyanoalanyl peptide and HPLC analysis. Optimisation conditions have been fc,und
to decrease the level of this side reaction : low temperature, minimisation of the
quantity of diisopropylethylamine used during the coupling step and use of
hydroxysuccinimide ester of asparagine as the activated aminoacid. The cyano
alanyl peptide can be eliminated by preparative HPLC at the end of the synthesis.
The analysis data (Mass spectra and HPLC profile) of the crude protected (1-10)
salmon calcitonin are given in Figure 5 and Figure 6.
AutoSpecEQ FAB+ Magnet EpM:243 Bpi:22003712 TIC:99330400 Flags:NORM

File T e x t : K B - 1 5 9 7 - D M F / N B A
100% 24311 ....... 50.00 ............ lo0.o0 ......... i 2i2E
0E7
90.
8E7
80.
5E7
70
307.08 3E7
60
1 IE7
5o~
40
91.00 6E6
30_
364.14 4 4E6
20. t , 14q~.15 661.26
10 165.08 l,.lt,i~.lt/ 4160.1~ 552,-2~08 27 [ 759.37 90,.4 ;0 ~ ~ 2~.6
IIIdtll, ddJI, Ldt.lll .... k k . . ~ . L i ~ , , l ,.~, ~ ' ~ , _ l J . . . . . . J,. _.i~,m,.i,_L . . . . . tx o . . . . 0E0
0
"'-STxo.... 26o -~--S~o . . . . . 4;0 .... i6o .... 6;0 .... 7~o . . . . .do .... 950 . . . . ./=
x100.00 2 2E7
100~
2 0E7
9o_~
1 8E7
8o~ 1702 75
1 5E7
70-
1 3E7
60
1 IE7
50
_8 8E6
40
6 6E6
30
4 4E6
lO.~
1425.62
i
i ..... 1579.74
]~..t [ ,L_. I ........... _t ~ __.~j_ 0 0 E O
2 2E6
1600 1700 1800 1900 2000 M/Z

" i ~ ' .
ii00 1200 1300 1400 1500
Boc__ ?ys--Ser-- Asn- Leu--Ser-- Thr--?ys-- Val-- Leu--Gly OH

SFrt OBzl OBzl S-Acre
L..
243 91
(100 %) (35 %)
[MH]+ = 1679 - B ~ 1579 -Acm"-- 1508
S-Trt
[MNa]+ = 1701 ~ 1425
Fig.5. Mass spectra of the crude protected (1-10) salmon calcitonin
411
" E"
Z
~, .
s:. 2 "
Fig. 6. H.P.L.C. profile of the crude protected (1-10) salmon calcitonin
The protected peptide is isolated, before disulfide bridge formation, by

precipitation from its N-methylpyrrolidone solution (95.5 % yield) with water.
After saponification in DMF, the carboxylic protected (1 - 10) salmon calcitonin
fragment is isolated by precipitation with acidic aqueous medium. The precipitate is
washed with acetonitrile to give a white powder (80.5 %).
The scheme of the the disulfide bridge synthesis is shown in Figure 7.
Different protecting groups (S-Trityl, S-Acetamidomethyl...) have been
introduced on the cysteine side chains to optimise the reaction conditions of
disulfide bridge formation. The conditions developed by Kamber and his group
have been used to make the disulfide bridge (ref. 5). The best results have been
obtained when we use S trityl on the L-cysteine and S-acetamidomethyl on the
7 cysteine in N,N-dimethylformamide in the presence of an excess of iodine
(4 equivalents). The excess of iodine is eliminated with ascorbic acid. The final
peptide is isolated by precipitation with water.
412
Boc--CysmSer(O-Bzl) - Asn~ Leu--Ser (O-Bzl)- Thr (OBzI)--Cys-- Val-- Leu~Gly--O nGPC
I I
SwTrt SmAcm
R.T. 1 NaOH
Boc~Cys--Ser(O- Bzl)- Asn~ LeuwSer (O- Bzl)- Thr(OBzl)--Cysm Val-- Leu--GIy--COOH

I I
S--Trt S--Acm
DMF I I2
R.T.
Boc--Cys--Ser(O-BzI)-AsnmLeumSer (O-BzI)-Thr (OBzt)--Cys--ValmLeu--Gly--COOH

I I
S S
1 I
Fig. 7. Synthesis of protected ( S - S) (1-10) salmon calcitonin
The protected (S - S) (1-10) salmon calcitonin is purified by preparative

chromatography on silica as stationary phase with a solvent mixture
(dichoromethane / methanol / acetic acid (93 / 7 / 2 v / v / v)) as eluent phase.
After precipitation with water the pure product is analysed by HPLC on
Lichrospher 100 RP 18 (125 x 4 mm) 5 micron as stationary phase and with a
mobile phase (methanol / water / N,N-dimethylformamide / trifluoracetic acid 70 /
30 / 5 / 0.4 v / v / v / v). The D M F is introduced in the eluent phase to solubilise
the protected ( S - S) (1-10) salmon calcitonin. The H P L C profile of the pure
protected (S - S) (1-10) salmon calcitonin is shown in Figure 8.
413
, |ll
. . . . , II II ".
9~ - 1 4
~ oeoo
"Jo,~
JPE -1~. :-:
_
t
i , |
7 oam
. . . . . . . ~111~ 9
i
Fig. 8. HPLC profile of the pure protected (S - S) (1-10) salmon calcitonin
The protected (S - S) (1-10) salmon calcitonin has been successfully coupled on

a (11-32) protected fragment grafted on a polystyrene resin. After final HF
deprotection, the salmon calcitonin has been obtained with a better yield than
stepwise synthesis on a polystyrene resin. A gain of 50 % of final salmon calcitonin
is obtained using this procedure.
CONCLUSIONS
We have demonstrated that the SAPPHO process is a new and powerful method
of synthesizing peptides, at a low cost, with very good yield and purity. It is the
first automated peptide synthesis technology which can be used to synthesize
peptide or peptide fragments from 3 to 15 aminoacids.
414
References
1. a Methoden der Organischen Chemie / Houben Weyl 15 / 1 and 2 Published Georg Thieme
Verlag Stuttgart, ( )
b Peptides / Gross Meienhoffer N~
c Principles of Peptide Synthesis - M. Bodansky Ed. Springer- Verlag 2, ( )
M.F. Maurice, M. Galvez, EP 0432022 (02/10/1989), (to Rh6ne-Poulenc Chimie).
3. J.M. Bernard, K. Bouzid, C. Gervais, EP 0421848, (02/10/1989), (to Rh6ne-Poulenc
Chimie).
4. V. P6v~re, EP 0537089 (11/10/1991) (to Rh6ne-Poulenc Chimie),
J.M. Bernard, E. Blart, J.P. Genet, M. Savignac, EP 0566459 (15/04/1992 ~ (to Rh6ne-
Poulenc Chimie) J.M. Bernard, E. Blart, J.P. Genet, S. Lemaire-Audoire, M. Savignac,
French Applications, N ~ 930423; N ~ 9304232 and N ~ 9304233, (09/04/1993), (to Rh6ne-
Poulenc).
5. B.F. Gisin, Helv. Chim. Acta, 56,1476, (1973)
6.' B. Kamber and coll Helv. Chim. Acta. :51, 2061, (1968); Idem 53,556, (1970); Idem 54,
398, (1971)
415
A NEW AND PRACTICAL REMOVAL OF ALLYL AND ALLYLOXY-
CARBONYL GROUPS PROMOTED BY WATER-SOLUBLE Pd(0)
CATALYSTS
SANDRINE LEMAIRE-AUDOIP~ a), MONIQUE SAVIGNAC a), JEAN-PIERRE

GENET a) AND JEAN-MARIE BERNARD b)
a) Laboratoire de Synth~se Organique associ6 au CNRS URA 1381, Ecole

Nationale Sup6rieure de Chimie de Paris, 11 rue Pierre et Marie Curie, 75231
Paris Cedex 05, France
France.
INTRODUCTION
Among the usual protecting groups for amino, hydroxyl and carboxylic
functions, the allyloxycarbonyl (Alloc) and the allyl moieties were largely
developed during the last twenty years, since a new methodology using n-allyl
palladium complexes was introduced for their cleavage (ref. 1).
O
II Pd(O)Ln
R~ z / C ~ o . ' " ' - . ~
Z=N,O
C02
NuH
\_ _- R--ZH +
....
I | + RZ | Pd(0)Ln
-,} ~ R _ Z Z " - . . ~
Pd(0)Ln
Scheme 1.
416
In literature, various conditions involving different allyl scavengers such as
formic acid (ref. 2), morpholine (ref. 3), tributyltinhydride (ref. 4), or potassium
2-ethylhexenoate (ref. 5) in anhydrous medium have been reported. However, these
systems suffer some limitations, especially for the deprotection of secondary amines
which leads to the competitive undesired reaction of N-allylation (Scheme 1,
path (2)). Although recent progress has been made using silylated amines as allyl
scavengers (ref. 6), a simple and unexpensive method for the cleavage of allyl
carbamates derived from secondary amines would be of great interest. In addition,
one of the greatest drawbacks of homogeneous metal catalysis is the separation of
the reaction product from the active catalyst, which often requires costly and toxic
procedures. A solution to this problem consists in anchoring the catalyst on an
organic or inorganic polymer (ref. 7) insoluble in the reaction medium. Another
elegant alternative consists in using water soluble ligands which once complexed to
the metal make the catalyst poorly soluble in organic media. These systems combine
the advantages of homogeneous and heterogeneous catalysis : easy separation of the
product from the catalyst, high reactivity and high selectivity. At presem,
sulfonated phosphines, e.g. TPPMS (ref. 8) and TPPTS (ref. 9), constitute the most
widely used class of water soluble ligands.
They found various industrial applications in the field of hydrogenation
(ref. 10), hydroformylation (ref. 11), reduction of saturated and unsaturated
aldehydes (ref. 12) and coupling reactions (ref. 13). In our continuing imerest in the
area of palladium promoted reactions (ref. 14), we have developed a water soluble
catalyst prepared in situ from Pd(OAc)2 and the water soluble ligand TPPTS. This
system demonstrated high activity for various cross-coupling reactions in aqueous
medium (ref. 15). We have also found that this catalyst allowed smooth and
selective removal of allyl and Alloc groups in the presence of diethylamine as allyl
scavenger, in homogeneous (CH3CN/H20) and biphasic (CaH7CN/H20) media
(ref. 16). This palladium promoted deprotections proceed with high to quantitative
yields, and the use of a two-phase system allows the reaction to occur with
remarkable selectivity, in particular for the cleavage of allylcarbamates derived
from secondary amines. Moreover, we developed the first efficient conditions for
the chemoselective removal of allylcarbamates in the presence of substituted allyl
carboxylates ; in the same way, allyloxycarbonates can be cleaved without affecting
dimethylallylcarbamates in the same molecule (ref. 17).
417
Deprotection of alcohols and carboxylic acids

The cleavage of allyloxycarbonates was investigated in the presence of molar
2 % of Pd(0) catalyst and diethylamine as nucleophile ; our results are summarized
in Table 1. Using 5 eq. of HNEt 2, primary alcohols such as (R)-citronellol were
deprotected in homogeneous medium (CH3CN/H20) with excellent yield (emry 1).
When HNEt 2 was replaced by formic acid, the yield and the rate of the reaction
considerably decreased. The deprotection of allyloxycarbonates derived from
secondary alcohols 2 was also performed under the above conditions (Pd(OAc)2 /
TPPTS (1/2) tool 2 % ; HNEt2) to recover the parent molecules with good yield
(entry 2). Moreover, our catalytic system allowed the selective and quantitative
cleavage of the allyloxycarbonyl moiety from 6-O-Alloc-methyl-2,3-dibenzyl-ot-L-
glucopyranoside 3 without affecting the other protecting groups present on the
molecule (entry 3). The reaction was then carried out in a biphasic medium
(C3HTCN/H20), and 1-menthol could be quantitatively deprotected within
30 minutes. Taking advantage of a two-phase system, we were able to recycle the
water-soluble catalyst up to 10 times with no loss of efficiency, which is a major
asset from an industrial view point (see scheme given in ref. 18). In addition, the
use of HNEt2 as an unexpensive allyl scavenger is very attractive since both the
allylated by-product and the excess of nucleophile are simply removed by
evaporation, affording after extraction very clean crude products.
The above procedure was also applied to the cleavage of allylic esters. In the
presence of tool 2 % of Pd(OAc)2/TPPTS and 5 eq. of HNEt 2 in homogeneous
medium, phenylacetic acid was rapidly deprotected, in quantitative yield (entry 5).
In the same way, the allyl group was smoothly removed from the carboxylic acid of
the base sensitive cephalosporine 6 with 93 % yield (entry 6).
418
Table 1. Deprotection of Alcohols and Carboxylic Acids using Pd(OAc)2/TPPTS catalyst
!
F_my Substrate HNEt2! Solvent ' Cat Product [ Time l Yield i

(eq.) (mol %) (min.) i (%)
I I I
o/A lloc
CH3CN / OH 5 94 a)
H20
2.2 CH3CN /
H20
~ ---OH 10 80
Alloc O ~ . . . . O7OCH3 HO. ~ . . . . O7OCH3

2.2 CH3CN / 20 99
HO...... "// ......OCH2Ph H:O HO...... T ......OCH2Ph
/ ,
OCH2Ph OCH2Ph
3
2.2 C3H7CN/ 2.2 30 100

! H20 .-. OH
OAlloc
4
D
5 _fA
lj~,,,,x,~O~ 5 CH3CN /
H20
5
~y OH
5 100
a) with HCOOH as nucleophile 9t = 2.5 h" yld = 51%
Deprotection of primary and secondary amines

Then, we have investigated the cleavage of allylcarbamates (Table 2). The
reaction was first conducted on primary amines in homogeneous medium. Under
treatment with mol 2 % of Pd(0) catalyst and 2.2 eq. of nucleophile N-Allocbenzyl-
amine _7 was quantitatively cleaved to recover the parent molecule within 10 minutes
(entry 1). However, when N-allyloxycarbonyl-N-methyl benzylamine 8 was
allowed to react under the same conditions, the undesired reaction of N-allylation
419
occurred preferentially to give a (30/70) mixture of the free amine and the
N-allylated side product 9 (entry 2).
This competition between the nucleophile and the flee secondary amine for the
capture of the rt-allyl palladium complex intermediate is explained by the
mechanism of deprotection (Scheme 2).
L. L
"Pd~ |
o I
II
R-.z~C-.o/'--.~ ~ ~'~..~, CO~
Z=N,O
L\pd~L |
I
Pd(O)Ln
R--ZH + Et2N / ' ' ' ~ Et2NH
Scheme 2.
In the first step, oxidative addition of the zerovalem palladium species on the
allyl moiety of the protected substrate leads to a rt-allyl complex, followed by
decarboxylation of the carbamate. Then, intermediate A is trapped by the
nucleophile (diethylamine in the present case) resulting in the deprotected product
with regeneration of the palladium (0) species (path a). Nevertheless, when RZ- has
a strong nucleophilic character, and this is the case of secondary amide bases, it
also acts as an allyl trapping agent to give the undesired N-allylated side-product
(path b). Anticipating that the reaction may be more selective in a biphasic system,
the deprotection was carried out in C3H7CN/H20 (6/1) medium, with mol 5 % of
Pd(0) catalyst ; under these conditions, the free secondary amine was quantitatively
recovered without any undesired N-allylated product (entry 3). The use of a two-
phase system thus offers an interesting alternative for the efficient removal of
420
allylcarbamates derived from secondary amines, avoiding the competitive
N-allylation. It is reasonable to think that in such a biphasic medium there is almost
no contact between the catalyst present in the aqueous phase and the deprotected
substrate liberated in the organic layer, resulting in an enhanced selectivity toward
path a. Other protected secondary amines such as (1R, 2S)-N-allyloxycarbonyl-
ephedrine 10 and N-allyloxycarbonyl-L-proline !1 reacted equally well upon
treatment with 5 fold excess of HNEt 2 (entries 4 and 5).
Table 2. Deprotectionof Primary and Secondary Amines using Pd(OAc)2/TPPTS catalyst
F_my Substrate HNEt2 Solvent Cat Product Time Yield

(eq.) (mol%)[ (mill.) (%)
i
1 ~/~All~ N 2"2 CH3

H20
CN/ 0"5 (" l ~ "NH2 10 100
2 ~ _8
/~I AII~
Me
2 CH3CN /
H20
2 100
30 %
70 %
5 C3H7CN/ 2 100 % 0% 100

H20
OH OH
4 p h / ~I ! Me 5 CH3CN / ph.d./Me 15 100
_ H20
Me/N~Albc Me/N~H
10
~N~"~COOH 2.2 CH3CN / '"'N Z C O O H 15 100

I H20 i
Alloc H
1_!1
421
This efficient and unexpensive methodology thus allows the removal of allyl and
allyloxycarbonyl groups from various substrates and the particularly mild conditions
are compatible with polyfunctionalized molecules. Moreover, both Pd(O) catalyst
and N-allyl diethylamine by-product are easily separated from the free alcohols,
amines and carboxylic acids which are recovered in almost pure form.
Chemoselective removal of allylic protecting groups

At this stage of our study, we have compared the rate of deprotection of several
phenyl acetic allyl esters under the above homogeneous or biphasic aqueous
conditions. We found that in (CH3CN/H20) medium the dimethylallyl group is
cleaved at a lower rate than the cinnamyl group in the presence of 2 to 2.5 mol %
of palladium (0). Under the same conditions, the allyl moiety is instantaneously
removed. By comparison, in a biphasic system (C3HTCN/H20), the cinnamyl and
the dimethylallyl groups remain imact in the presence of mol 5 % of Pd(0) water
soluble catalyst, even after 3 days at room temperature ; whereas the allylic ester is
still cleaved to give phenyl acetic acid in excellent yield.
Based on these results we investigated the selective cleavage of an
allylcarbamate in the presence of a dimethylallyl carboxylate in the same molecule
(ref. 19).
0 O...~~/R1 Pd(OAc)2fI~PTS(12) O~O..~~RI

mol 1%
CH3CN/H20
N HNEt2 5eq. N
I
0~0~.., ~ H
Pd(OAc)2flTPTS (1:2)
mol 3 to 5 %
o ..ou
CH3CN/H20
HNEt2 5 eq.
I
H
422
As shown in table 3, the allyloxycarbamate of isonipecotic acid 12 was
selectively and quantitatively cleaved under homogeneous conditions, in the
presence of 1% of Pd(0), without affecting the dimethylallyl carboxylate (entry 1).
The resulting monodeprotected product 13 was then deprotected using a higher
amount of catalyst (mol 5 %). The same scheme of selective deprotections was
achieved on a base sensitive cephalosporin 14 (entry 2) ; with 2.5 % of water
soluble catalyst the Alloc moiety was selectively removed to give the dimethylallyl
carboxylate 15 within 30 minutes, and then the carboxylic acid was quantitatively
recovered using 5 % of Pd(0).
423
Table 3. Selective Cleavage of Allyloxycarbamates in the presence of Substituted Allyl Carboxylates
Entry Substrate Product Time Yield c) Time Yield d~

Product
(min.) (%) (min.) (%)
H
1 20 96 10 100
H
O....~O,,,,,N,~ H 13
12
.~.N/O...~NH -S H2N~ S " - . ]
O O ~ N ~/~CH3 O ~ N/N......~CH3
30 100 a) 60 100
!_5
14
O O
H -( 30 99
H 45 100
17
16
o ~__ o O
H H 40 86
4 -=-\Ph
18 19
a) Pd(0) 9mol 2.5 % 9b) solvent 9butyronitrile-water " c) crude product 9d) isolated yield
We also applied these conditions of selective deprotection on amino acids ; it
was possible to cleave the N-allyloxycarbamate of the L-proline derivative 16
without affecting the carboxylic acid protected by the dimethylallyl moiety
(entry 3).
Nevertheless, when the dimethylallyl group was replaced by the cinnamyl
group, the use of 1% of Pd(0) in homogeneous medium led to complete removal of
the allyloxycarbonyl group with a certain amount of the deprotected carboxylic acid
(ref. 20). In order to overcome this difficulty it was necessary to operate under
biphasic conditions, in the presence of 1 % of catalyst, giving the expected
cinnamyl-L-prolinate 17 in quantitative yield (entry 4).
Then, the selective cleavage of aUyloxycarbonates in the presence of
dimethylallylcarbamates was performed with high efficiency (Table 4).
0
H
0 0. ~. . ~ . . . ~ . . Pd(OAc)2/TPPTS(1:2)
I mol 5 % OHI
; (C)
) C3H7CN/H20
N HNEt2 5 eq. N
Pd(OAc)2/TPPTS (1:2)
mol 5 % OH
I
CH3CN/H20
HNEt2 5 eq. N
A first attempt to cleave selectively the allyloxycarbonate from (1R, 2S)-(-)-

ephedrine doubly protected 20, under homogeneous conditions, using 1% of Pd(0),
led to total deprotection of the amino function together with partial removal of the
dimethylallyloxycarbonyl group. Taking advantage of a biphasic medium, the
reaction was thus conducted in a butyronitrile-water system with 5 % of Pd(0) ;
under these conditions, the allyloxycarbonyl group was smoothly removed from
oxygen without affecting the dimethylallylcarbamate. In a second step, the amine
could be deprotected using an homogeneous medium, with acetonitrile as co-
solvent, to recover the parent molecule within 15 minutes, with 100 % yield
425
(entry 1). An other example on 1-(2-O-Allyloxycarbonylethyl)-N-dimethylallyloxy-
carbonyl piperazine 22 gave similar results, and thus confirmed the selective
cleavage of an allyloxycarbonate in the presence of N-dimethylallylcarbamate in the
same molecule (entry 2).
426
Table 4. Selective Cleavage of Allyloxycarbonates in the presence of Dimethylallyl carbamates
Time Yield c~ Time Yield dr

Entry Substate Product Product
(min.) (%) (rain.) (%)
O
OH
OH
ph.~,,,.,~CH3
p h ~ . . , . ~ CH3 ph,,."k-,,,,/CH3
20 100 15 100
CIt3/N o ~ O ' ~ ~ llq
CH3 \H
O
21
20
U H
I
)
o.~o~
r J iS
r
OH OH
O 23
22
a) Pd(0) 9mol 5 % / butyronitrile-water / crude product 9b) Pd(0) 9mol 5 % / acetonitrile-water / isolated yield
CONCLUSION
In summary, we have developed a smooth and efficient methodology for the
cleavage of allyloxycarbonates, allylcarbamates and allyl carboxylates using
Pd(OAc) 2 / TPPTS catalyst in aqueous medium. The free parent molecules are
easily isolated from the reaction mixture by simple aqueous work-up and
extraction; they are generally pure enough to be used in another step without any
further purification. Moreover, the use of a two-phase system (C3HvCN/H20)
affords a valuable solution for the deprotection of secondary amines which are
obtained without any N-allylated side product. In addition, in a biphasic medium the
recycling of the active catalyst is particularly attractive from an industrial view
point. Finally, chemoselective deprotection of bifunctional molecules containing
differently substituted allylic groups was performed with high efficiency. Various
applications of this technique are under investigation in our laboratory, especially in
the field of peptide synthesis.
References
1. J.W. Greene, P.G.M. Wut in ,~ Protective group in organic synthesis >,, Ed. John Wiley,
New-York (1991).
2. a) I. Minami, Y. Ohashi, I. Shimizu, J. Tsuji, Tetrahedron Lett., 26, 2449, (1985).
b) Y. Hayakawa, S. Wakabayashi, H. Kato, R. Noyori, J. Am. Chem. Soc., 11.2, 1691,
(1990).
3. a) H. Kunz, H. Waldmann, Angew. Chem. Int., Ed. Engl., 23, 71, (1984).
b) H. Kunz, H. Waldmann, U. Klinkhammer, Helv. Chim. Acta, 71, 1868, (1988).
c) H. Kunz, C. Unverzagt, Angew. Chem. Int. Ed. Engl., 23,436 (1984).
4. a) F. Guib6, Y. Saint M'Leux, Tetrahedron Lett., 22, 3591, (1981).
b) F. Guib6, O. Dangles, G. Balavoine, A. Loffet, Tetrahedron Lett., 30, 2641, (1989).
c) O. Dangles, F. Guib6, G. Balavoine, S. Lavielle, A. Marquet, J. Org. Chem., 52, 4984,
(1987).
d) P. Boullanger, G. Descotes, Tetrahedron Lett., 27, 2599, (1986).
5. P.D. Jeffrey, S.W. McCombie, J. Org. Chem., 47, 587, (1982).
6. A. Mermouk, F. Guib~, A. Loffet, Tetrahedron Lett., 33,477, (1992).
7. P.W. Wang, M.A. Fox, J. Org. Chem., 59, 5358, (1994).
8. S. Ahrland, J. Chatt, N.R. Davies, A.A. William, J. Chem. Soc., 276, (1958).
TPPMS = Triphenylphosphinomonosulfonate sodium salt.
9. E.G. Kuntz, US Patent 4 248 802 (1981), (to Rh6ne-Poulenc Industries) ; D. Sinou, Bull.
Soc. Chim. Fr. (3), 480, (1987). TPPTS = Triphenylphosphinotrisulfonate sodium salt.
10. a) Y. Dror, J. Manassen, J. Mol. Catal., 2, 219-222, (1977).
b) A.F. Borwski, D.J. Cole-Hamilton, G. Wilkinson, Nouv. J. Chim., 2, 137, (1978).
c) F. Joo, Z. Toth, M.T. Beck, Inorg. Chim. Acta, 25, L61, (1977).
d) C. Larpent, R. Dabard, H. Patin, Tetrahedron Lett., 28, 2507, (1987).
C. Larpent, H. Patin, J. Mol. Cat., 61, 65, (1990).
11. a) W.A. Hermann, J. Kellner, H. Riepl, J. Organomet. Chem., 3_8_9_,103, (1990).
b) P. Escoffre, A. Thorez, P. Kalck, J. Chem. Soc., Chem. Commun., 146, (1987).
428
12. a) E. Fache, F. Senocq, C. Santini, J.M. Basset, J. Chem. Soc. Chem. Commun., 1776,
(1990).
b) A. B6nyei, F. Joo, J. Mol. Catal., 58, 151, (1990).
c) J.M. Grosselin, C. Mercier, G. Allmang, F. Grass, Organometallics, 10, 2126, (1991).
13. N.A. Bumagin, P.G. More, L.P. Beletskaya, J. Organomet. Chem., 371,397, (1989).
14. a) D. Ferroud, J.M. Gaudin, J.P. Gen6t, Tetrahedron Lea., 27, 845, (1986).
b) J.P. Gen6t, J.M. Gaudin, Tetrahedron, 43, 5315, (1987).
c) J.P. Gen6t, S. Jug6, S. Achi, S. Mallart, J. Ruiz-Mont6s, G. Levif, Tetrahedron, 44,
5263, (1988).
d) J.P. Gen6t, S. Grisoni, Tetrahedron Lea., 29, 4543, (1988).
e) J.P. Gen6t, J. Uziel, S. Jug6, Tetrahedron Lett., 29, 4559, (1988).
f) J.P. Gen6t, M. Port, A.M. Touzin, S. Roland, S. Thorimbert, S. Tanier, Tetrahedron
Lett., 33, 77, (1992).
g) J.P. Gen6t, N. Kardos, Tetrahedron : Asymmetry, 5, 1525, (1994).
15. a) J.P. Gen6t, E. Blart, M. Savignac, Synlett, 715, (1992).
b) E. Blart, J.P. Gen6t, M. Sail, M. Savignac, D. Sinou, Tetrahedron, 50, 505, (1994).
16. a) J.P. Gen6t, E. Blart, M. Savignac, J.M. Paris, Tetrahedron Lett., 34, 4189, (1993).
b) J.P. Gen6t, E. Blart, M. Savignac, S. Lemeune, S. Lemaire-Audoire, J.M. Paris,
J.M. Bernard, Tetrahedron, 50, 497, (1994).
17. S. Lemaire-Audoire, M. Savignac, E. Blart, G. Pourcelot, J.P. Gen6t, J.M. Bernard,
Tetrahedron Lett., 35, 8783, (1994).
18. The catalytic system can be recycled up to 10 times as presented in the following scheme
(the procedure is applied on N-methyl N-allyloxycarbonyl benzylamine), without loss of
efficiency. After completion of the reaction, the first schlenck tube containing the free
amine in the organic layer and the catalyst in the aqueous layer is linked, by a siphon
tube, to another schlenck tube containing the protected amine dissolved in butyronitrile.
The aqueous layer with the active catalyst is transferred under argon pressure into the
second tube, over the fresh solution of N-allyloxycarbonyl-N-methyl benzylamine.
aqueous layer
catalytic system
Argon --I~ Argon

II., I,II
~TC,..
Ph~N,H T
)(
I
Me I Ph~N ~ ' ~
~'~~mEt2 + HNEt2 ///'// "] ~" l~le
C3HTCN V = 3ml ~__~ ~ ~HNEt,. (2.2 eq)
Catalyst + H20
V -- 0.5 mi
)( ~C3HTCN V = 3ml
429
19. The doubly protected substrates are readily prepared by addition of allyl chloroformate on
the amino function, followed by esterification of the carboxylic acid with the appropriate
substituted allylic bromide in the presence of DBU.
20. When the substrate was treated with mol. 1 % Pd(O) under homogeneous conditions, the
cinnamyl carboxylate was partially cleaved, and the reaction led to a mixture of the
selectively N-deprotected prolinate with the fully deprotected amino acid in a (65 : 35)
ratio.
430
SAFETY OF C H L O R I N A T I O N REACTIONS
JEAN-LOUIS GUSTIN AND ALEXANDRE FINES
Rh6ne-Poulenc, Centre de Recherche, d'Ing6nierie et de Technologie, 24 Avenue

Jean Jaur~s - 69151 D6cines - France
ABSTRACT
Chlorination reactions are part of various processes in the chemical industry, to
manufacture heavy chemicals, specialty chemicals, pesticides and pharmaceuticals,
in inorganic and organic chemistry. They are a valuable tool in organic synthesis.
The hazard of processing chlorine involves :
- Gas phase explosion ;
- Runaway reaction or thermal explosion in the condensed phase.
Gas phase explosion hazard with chlorine as an oxidizer is present in gas phase
chlorination processes as well as in chlorinations in the condensed phase.
Gas phase chlorination processes are mostly continuous processes operating in the
flammable area. Gas phase explosion hazard is related to burner malfunctions.
Where chlorination is made by chlorine injection in the liquid phase, gas phase
explosion hazard is related to chlorine evolution in the vapour phase, giving a
flammable mixture with the solvent or reaction mixture vapour. Here hazard
assessment is achieved by comparing the gas phase composition with the flammable
area of the gaseous mixtures. Auto-ignition is also considered because the auto-
ignition temperature of gaseous mixtures containing chlorine is close to the ambient
temperature.
The relevant flammability data is obtained in a specially designed 20 litre sphere.
The main features of this explosion vessel include : Hastelloy C 276 walls, central
ignition with spark, hot wire or pyrotechnic ignition source, 200 bar pressure
resistance, ambient to 300~ initial temperature, easily opened for frequent
cleaning. This apparatus allows precise determination of the flammability limits,
autoignition temperature, explosion overpressure, rate of pressure rise and flame
speed. A review of flammability data in chlorine is given.
431
Runaway reaction hazard in chlorination reactions is related to a series of
dangerous process situations or process deviations such as :
- Delay in reaction initiation
- Reaction mixture instability
- Production of unstable species like chloramines, nitrogen trichloride, chloro
nitroso compounds.
- Demixion or segregation of unstable species in case of chlorination made in
aqueous solution, because the chlorinated compounds are less soluble in water than
the initial reactant.
A full review in runaway reaction hazard in chlorination reactions is given with
examples from the literature and from the laboratory.
INTRODUCTION
Quite similar to oxygen, chlorine is used as an oxidizer in a wide range of
chemical processes where it is reacted with organic and inorganic compounds to
produce chlorinated products or intermediates. A wide range of useful products are
obtained such as bleach, metallic chlorides, reactive monomers to manufacture
plastics, heat exchange fluids, chlorinated solvents and intermediates in organic
synthesis to produce specialty chemicals, pesticides and pharmaceuticals.
Chlorine is involved in a wide range of process situations including gas phase
reactions in a burner or on a catalyst, solid/gas reactions in a fluid bed, gas/liquid
reactions in a packed column, gas/liquid reactions by injecting chlorine in a liquid
phase in a semi-batch process or in a continuous process. The reaction of chlorine
takes place without catalyst, in the presence of a catalyst or in photochemical
reactions.
Compared to oxygen, chlorine is a more reactive gas because it is processed as a
pure gas whereas oxygen is mostly reacted using air. More problems would occur
with oxygen if the use of pure oxygen was widespread in the chemical industry.
Compared to pure oxygen, chlorine is even more reactive. The self-ignition
temperature of gaseous mixtures of organic vapours with chlorine is much lower
than that of their mixtures with oxygen. Natural light can split the chlorine molecule
to produce reactive chlorine radicals. Many reactions of chlorine take place near the
ambient temperature. The combustion of iron in chlorine can be initiated at
temperatures slighly above 100~
Chlorine is toxic to man and animals. Many chlorinated compounds are also
toxic.
432
For all the above reasons, the chemical processes where chlorine is involved are
submitted to careful safety studies where the specific chemical properties of
chlorine are considered
T H E R M A L E X P L O S I O N HAZARD IN THE CONDENSED PHASE

Chlorine is a strong oxidizer. Mixtures of chlorine and organic fuels may have a
high energy content and are unstable. The thermal instability of condensed phases
containing chlorine can appear in various process conditions "
9 When chlorine is injected in a liquid reaction mixture, the chlorination reaction
may not start immediately allowing chlorine to accumulate in the reaction
mixture. The reaction may start suddenly when a large concentration of chlorine
is present in the reaction mixture and give a severe runaway reaction producing a
large quantity of insoluble HC1. An example of such an induction period in
chlorination is mentionned in the literature for the chlorination of ketones in
methanol (ref. 1). To avoid this type of incident, the reaction onset should be
checked before allowing a large concentration of unreacted chlorine to be
dissolved in the liquid phase.
When chlorine is reacted with an organic fuel in a liquid reaction mixture, highly
unstable substitution products may be obtained. This process situation is
dangerous in two cases :
- if a high concentration of unstable chlorination product is obtained in the
condensed phase
if a chlorinated liquid phase separates from the bulk liquid phase "by
segregation".
The latter situation is frequent in the chlorination of aqueous solutions of

organic reactants because the chlorinated products are less soluble in water than the
initial reactants.
Examples of this dangerous process situation are the synthesis of alcohol
hypochlorites by injecting chlorine in an alcaline aqueous solution of alcohol.
Traugott Sandmeyer described the synthesis of methyl and ethyl hypochlorites
(refs. 2, 3) and suffered severe injuries.
Roland Fort and Leon Denivelle (ref. 4) described the synthesis and properties
of a series of other alcohol hypochlorites obtained following Sandmeyer's Method.
The oxidation of organic compounds containing nitrogen in their formula
(amines, amides, cyanides) using chlorine, gives unstable chloramines. The very
unstable nitrogen trichloride is finally obtained. NC13 is only slightly soluble in
433
water and can separate from aqueous solutions giving a very sensitive dense oil.
Liquid NC13 can detonate.
NC13 can be obtained by chlorination of aqueous solutions containing
ammonium ions. NC13 compound was first obtained by Pierre Louis Dulong (1785 -
1838) by chlorination of ammonium chloride solutions. Dulong was seriously
injured by several explosions of liquid NC13. (ref. 5)
At least one accident is known where liquid NC13 could separate in a waste-
water treatment where bleach was used to oxidize cyanide ions. After an agitation
failure, the actuation of a bottom valve triggered the detonation. Direct chlorination
would lead to the same dangerous situation.
The chlorination of organic compounds with a N - O bound will leave this
chemical bound unaffected. The chlorination of oximes will give chloro oximes or
chloronitroso compounds (refs 6, 7) which can demix from aqueous solutions giving
an unstable dense oil.
This ends in process situations similar to NC13 formation and demixion.
9 Accumulation of unstable chlorinated compounds in the bulk liquid phase.
The accumulation of unstable chlorinated products in the bulk liquid phase is
most likely when a solvent is used where this product is soluble. The most common
example is nevertheless the accumulation of NC13 produced by electrolysis of KC1
or NaC1 salt containing ammonium ions, in a NC13 removal process using extraction
in carbon tetrachloride. If NC13 is not continuously thermally decomposed, high
NC13 concentrations in the CC14 solution are obtained with a potential runaway
decomposition hazard.
Such an incident is known in the literature (ref. 8). Note that the decomposition
kinetics of NC13 in CC14 solutions is strongly influenced by the wall material.
Recommendations
When chlorine is reacted with organic reactants, specially if nitogen comaining
compounds or ammonium ions are present, the possible formation of unstable
chlorinated compounds should be considered. Any segregation of a separate phase
from the bulk liquid is potentially dangerous and should be investigated carefully.
The demixion of an unstable liquid phase may induce a high vapour pressure of the
unstable product in the gas phase because the gas phase is in equilibrium with the
separated unstable liquid. This problem should be considered.
If no segregation occurs, the process situation is safer, however it is necessary
to check for low concentration of unstable chlorinated compounds (NC13, alcohol
hypochlorites, others...) in the bulk liquid phase.
434
GAS PHASE EXPLOSION HAZARD IN CI-~O INATION REACTIONS
Gas phase explosion hazard is present when chlorine is mixed with a fuel in the
gas phase. The fuel may be hydrogen, a solvent or organic vapour, ammonia, etc.
When chlorine is reacted with a fuel in a burner, as in the manufacture of HC1
from Hydrogen and chlorine or in the manufacture of chlorinated solvents from
hydrocarbons and chlorine, most incidents occur when the burner is set on-stream,
either by lighting the burner with a pilot flame or by preheating the gas and the
burner. Of course the gas mixture is in the flammable range and explosions occur
due to maloperation.
When chlorine is reacted with a fuel on a catalyst bed, maloperation will result in
catalyst burn- out and/or gas phase explosion before or after the catalyst. Here the
determination of the fuel gas flammable limits in chlorine are of interest if the feed
gas is not in the flammable range in normal process conditions.
When chlorine is injected or bubbled in a liquid phase containing a reactant
and/or a solvent, chlorine evolution in the gas phase may produce a flammable
mixture with the reactant, product, solvent or reaction mixture vapour. Here
inertizing is difficult as in other oxidation processes because the oxidizer is bubbled
through the liquid reaction mixture.
As far as possible, it is recommended to keep the gas phase composition outside
the flammable range. Various methods are used :
1) Lowering the fuel vapour pressure below the Lower Flammability Limit in
chlorine by lowering the process temperature.
2) Raising the fuel vapour pressure above the Upper Flammability Limit in chlorine
by raising the process temperature.
3) Inertizing the gas phase by flushing the reactor gas phase with an inert gas such
as Nitrogen, CO2, HC1.
To keep the reactor gas phase below the L.F.L. in chlorine (method 1) is the
safer method where only proper temperature control is necessary.
To keep the reactor gas phase above the U.F.L. in chlorine (method 2) may not
be quite safe. On start-up the temperature must be set to the process normal value
ensuring enough fuel vapour pressure before chlorine injection. If a condensor is
used where the fuel vapour pressure is depleted, the gas flow composition may
enter the flammable range. Glass condensors are better not used or protected from
light.
Inertizing (method 3) is a difficult technique when the chlorine flow evolving
from the liquid reaction mixture may change.
435
If chlorine does not evolve in the gas phase in normal process conditions, an
inert gas flush in the reactor gas phase is recommended (see below). If a chlorine
flow evolves from the liquid reaction mixture unreacted, enough inert gas flush
must be provided in the reactor gas phase to lower the chlorine concentration below
the minimum oxidizer concentration (MOC) of the fuel flammable range.
If HC1 is released in the gas phase, this gas contributes to the reactor gas phase
blanketing. However one should take into account rapid changes in the process
conditions, if the wanted chlorination reaction stops due to catalyst depletion or
reactant consumption. More unreacted chlorine can be released in the gas phase, the
HC1 production can disappear. Therefore monitoring of the gas phase chlorine
concentration using a chlorine analyser is recommended.
SELF-IGNITION, DEFLAGRATION AND DETONATION IN THE GAS

PHASE
Self-ignitions of gaseous mixtures containing chlorine and a fuel, near the
ambient temperature, are known. Self-ignitions can turn into severe deflagrations or
detonations.
Self-ignition occurs in mixtures with a composition both in the flammable range
and outside the previously determined flammable range. This phenomenon can be
explained as follows :
- The self-ignition temperature of gaseous mixtures is not a clear-cut limit. It is
best represented by an induction period versus temperature relation. Self-ignition
will be observed at lower temperature if a longer induction period is allowed.
- Near the self-ignition temperature, the flammable area is enlarged to a wide
range of equivalence ratios.
- When long induction periods are necessary, weak ignition sources can initiate the
explosion, such as light, wall effects, tar deposits, catalyst deposits on the wall,
NCI3 decomposition flame (refs. 5, 9).
A combination of these influences may explain the above mentioned self-ignition
phenomenon outside the flammable range.
As an example, the self-ignition of gas phase mixtures of dioxane and chlorine
was thoroughly investigated by F. Battin-Leclerc (refs. 10, 11). Dioxane is
sometimes mentioned as a solvent for chlorination processes (ref. 12) whereas self-
ignitions of dioxane + chlorine mixtures is easily obtained near the ambient
temperature.
436
The flammable limits of dioxane + chlorine mixtures were determined in a 4.6
litre explosion vessel together with the explosion overpressures and maximum rates
of pressure rise (ref. 12).
The explosion overpressures obtained are of the same order of magnitude of that
of explosion of gaseous fuel in air but half of the expected thermodynamic
explosion overpressures in chlorine.
The gas phase detonation of gaseous mixtures of dioxane and chlorine was
successfully investigated in shock tubes by A. Elaissi (refs. 13, 14).
This mixture was shown to be very sensitive to detonation compared to mixtures
of fuel in air or oxygen.
The full investigation of this example, chosen for convenience, shows that
mixtures of organic fuels with chlorine can exhibit self-ignition followed by
deflagration and detonation thus explaining violent explosions observed in the past.
EXPERIMENTAL SET-UP TO STUDY EXPLOSION LIMITS, EXPLOSION

CHARACTERISTICS AND SELF-IGNITION OF GASEOUS MIXTURES
A new explosion vessel, a 20 litre sphere, was built to investigate gas phase
explosions with special attention for experiments using chlorine as an oxidizer
(Fig. 1).
Fig. 1. 20 litres explosion vessel
437
This new facility allows the measuremem of :
- The flammability limits of gaseous mixtures using various ignition sources :
single spark, fusing wire, chemical ignitors.
- The explosion characteristics i.e. explosion overpressure and maximum rate of
pressure rise.
- The laminar burning velocity deduced from the pressure-time history of the
explosion. (ref. 15) The pressure is recorded at a rate of 20.000 Points/s.
- The self-ignition temperature and induction period of gaseous mixtures, down to
a few minutes. Sampling is possible to check for gas phase reaction.
- Flash points in chlorine
The main features of this explosion vessel are :

- Hastelloy C276 walls to lower wall effects i.e. to prevent the reaction of chlorine
with fuel before ignition, catalysed by stainless steel.
- The vessel is made of two half-spheres connected through a flange assembly kept
tight by clamps.
The upper half-sphere is fixed, the lower half-sphere is movable, using a

pneumatic jack, to allow quick opening of the vessel for frequent cleaning.
Combustion in chlorine produces soot deposits on the walls, which may promote or
prevent ignition of subsequent mixtures. Cleaning after each positive test is
necessary to obtain reliable flammable limits in chlorine.
The vessel design pressure is 200 bar, thus allowing initial pressure of 10 to 20
bar according to the expected explosion pressure. The vessel temperature can be set
between ambient temperature and 300~ Mixing is ensured before ignition using a
propeller mixer. Central ignition is made using spark, hot wire or a pyrotechnic
ignition source.
REVIEW OF FLAMMABILITY DATA OF GASEOUS MIXTURES

CONTAINING C H L O R I N E
Flammability limits
A review of flammability limits of gaseous mixtures containing chlorine was
first given by Mal'tseva, Roslovskii and Frolov (refs. 16, 17). The experimental
set-up used to obtain these data was a double-wall vertical glass cylinder, 80 mm in
diameter and 120 mm high. The experiment initial temperature was set by
thermostating the vessel. The fuel was introduced after evacuation, and allowed to
438
vaporize. Then chlorine was admitted in the explosion vessel. Mixing was only by
molecular diffusion (no stirring). A 10 min waiting time was observed before
ignition by a spark.
Our comment on this method is that the wall material is correct, mixing is poor
or not effective and the waiting time before ignition is too long and may have
allowed the mixture to react before ignition. The results are summarized in Table 1
for the reader convenience.
439
Table 1. Flammability limits of gaseous fuels in chlorine.
Data of Mal'tseva (refs. 16, 17)
Fuel Temperature LFL UFL

(~ % vol % vol
Hydrocarbons
| i
CH4 20- 22 5,6 63,0

C2 H6 i20 - 22 ,4,95 , 55,4
I
C3 H8 '20 - 22 !4,30 50,0

C4 H 10 20 - 22 3,31 49,5
i i |
C5 H12 120 - 22 2,42 43

i
Alcohols
CH3 OH 70 13,8
I
73,5
C2 H5 OH 83 5,06 64,1
C3 H7 OH 102 3,03 51,5
C4 H9 OH 120 2,53 48,8
C5 Hll OH 143 il,98 37,6
Carboxylic acids
H COO H
| i 105 ' 27,62
,
82,0
!
]
CH3 COO H 122 15,83 56,0
, i ,i
C2 H5 COO H 145 '9,33 50,8

C3 H7 COO H 170 7,81 49,8
C4 H9 COO H 190 5,84 48,8
Chloro-alkanes
CH3 C1 20 10,2 56,0
CH2 C12 '50 116,7 52,9
| i
CH C13 not combustible
C2 H5 C1 20 8,98 49,2
|
1-2 C2 H4 C12 100 16,4 136,8

! J ,
i C2 H3 C13 not combustible

C3 H7 C1 60 6,88 41,8
C3 H6 C12 100 9,95 35,0
C3 H5 C13 not combustible
C4 H9 C1 100 5,42 44,5
NB compositions are in percents by volume.
440
Dokter (ref. 18) and Medard (ref. 19) published some more data collected in
Table 2, together with interesting discussions.
Table 2. Flammability limits of gaseous fuels in chlorine.

Data published by Dokter (ref. 18) and Medard (ref. 19).
Fuel Temperature LFL UFL Ref

(~ % vol % vol
H2 3,5 89 (18)
cn4 5,51 63 (18)
CH4 00 .. 3,6 66 (18)
CH4 200 0,6 (18)
CH3 C1 10,2 63 (18)
C~. H6 4,95 58,8 (18)
H2 86 (19)
CH4 20 5,6 70 (19)
cn4 100 3,6 (19)
cn4 200 0,6 (19)
C2 H6 6,1 58 " (19)
C3 H8 5 40 (19)
CH3 C1 10 63 (19)
CH2 C12 16 53 (19)
Further flammability data obtained either using our 4.6 litre stainless steel
cylinder (ref. 12) (C) or our 20 litre Hastelloy C sphere,(S) are given in Table 3.
Table 3. Flammability limits of gaseous fuels in chlorine
Fuel Temperature LFL UFL Apparatus

(~ % vol % vol
CH3 C1 25 7 65 (C)
C3 H8 70* 2 60 (S)
C3 H6 C12 200** 4,5 (S)
MTBE 60 2 33 (C)
1-4 Dioxane 80 2,5 41 (C)
CH3 c o o H 120 5 36 ...... (c)
Acetone 60 4,5 60 (C)
Chlorobenzene 130 7,5 43,5 (S)
Toluene 160 3,5 50 (S)
2 chloro toluene 150 5 45 (C)
a chloro toluene 160 4 (S)
c~ dichloro toluene 160 6 (S)
c~ trichloro toluene 160 9 (S)
2 Fluoro toluene 100 4 37 (C)"
* Po = 1,7 Atmosphere abs. (C) = 4.6 litre cylinder
** Po = 1,3 Atmosphere abs. (S) = 20 litre sphere
441
Miscellaneous data can be found in the literature, like the flammability limits of
benzene in chlorine (ref. 20) 9L F L = 8 % vol, UFL = 52 % vol.
The experimental data is given under atmospheric initial pressure, unless
otherwise specified.
Self-ignition temperatures
Data on self-ignition temperature of gaseous mixtures of fuel and chlorine are
given by Mal'tseva (ref. 17), Dokter (ref. 18) and others. A collection of data is
given in Table 4.
Table 4. Auto-ignition temperature of gaseous fuels in chlorine
Fuel AIT in chlorine Author

(~
CH4 318 (17)
C2 H6 280 (17)
dimethyl ether ambient (17)
C 1-C3 carboxylic acids 300 - 320 (17)
C4-C7 carboxylic acids 230 - 190 (17)
C2-C4 carboxylic anhydrides 290- 215 (17)
C3-C5 ketones 325 - 205 (17)
C1-C8 alcohols 1225 - 210 (17)
C2-C7 aldehydes ,110 - 160 (17)
H2 207 (18)
CH3 C1 215 (18)
CH2 C12 , 262 (18)
C2 H6 205 (18)
C3 H6 150- 100 (18)
1,2 C3 H6 C12 180 (18)
Dioxane (0,26 ATA) 100 (10 - 11)
chloro benzene > 165~ 20 litre sphere
i !
C3 H8 (1,7 ATA) 165 ~ 20 litre sphere

1 | I
C 3 H6 (1,7 ATA) 160~ . 20 litre sphere
442
CONCLUSION
Owing to the importance of chemical reactions involving free chlorine in the
chemical industry, the collection of experiences and experimental data is of great
interest. This should contribute more to process safety than information on less
dangerous chemicals or processes. It is surprising that only limited effort or support
is devoted to collect safety data on chlorination reactions. The literature on the
safety of chlorination reactions is very limited compared to the literature on
oxidation reactions using oxygen. The authors hope that their contribution will
promote further experimental work in this field. The new 20 litre explosion vessel,
specially designed to study the flammability of gaseous mixtures containing chlorine
as an oxidizer will allow the obtention of reliable data at a reasonnable cost, for a
wide range of initial conditions.
References
1. R.R. Gallucci, R. Going, J. org. chem., 46, 2532, (1981).
2. T. Sandmeyer, Ber. XIX, 857, (1886).
3. T. Sandmeyer, Ber. XVIII, 1767, (1885).
4. R. Fort, L. Denivelle, C.R. Acad. Sci., 234, 1109, (1954).
5. F. Baillou, Thesis dissertation, 27 Septembre 1990, Universit6 d'Orl6ans, France.
6. Piloty, Steinbock, Ber. 35, 3113, (1902).
7. W. Steinkopf, W. Mieg, J. Herold, Ber. 53, 1148 (1920).
8. "Nitrogen Trichloride, a collection of reports and papers", The Chlorine Institute, Report
n~ Ed.2, New York, (1975).
9. F.Baillou, R. Lisbet,G. Dupr6, C. Paillard, J.L. Gustin, "Gas phase explosion of nitrogen
trichloride : Application to the safety of chlorine plants and chlorination processes", 7th
International Symposium on Loss prevention and Safety promotion in the Process Industries.
Taormina, Italy, May 1992, Paper n ~ 106.
10. F. Battin-Leclerc, Thesis dissertation, 15 Jan. 1991, INPL-ENSIC, Nancy, France, (1991).
11. F. Battin-Leclerc, P.M. Marquaire, G.M. Come, F. Baronnet, J.L. Gustin, "Auto-ignition of
gas phase mixtures of 1,4 Dioxane and chlorine", 7th International Symposium on Loss
prevention and Safety promotion in the Process Industries, Taormina, Italy, May 1992,
Paper n ~
12. J.L. Gustin, "Gas-phase explosions of mixtures of organic compounds with chlorine", 6th
International symposium Loss prevention and Safety Promotion in the Process Industries,
Oslo, Norway, June 19- 22, Paper n ~ 91, (1989).
13. Abdelkrim Elaissi, "Propri6t6s explosives des m61anges 1,4 Dioxanne + chlore en phase
vapeur", Thesis dissertation, University of Orleans, France, 14 March 1994.
14. A.Elaissi, G. Dupr6, C. Paillard, paper presented at the 8th International Symposium Loss
prevention and Safety promotion in the Process Industries, Antwerpen, (1995).
15. D. Bradley, A. Mitcheson, Combustion and Flame, 26, 201-217, (1976).
16. A.S. Mal'tseva, Yu. E Frolov, V.L. Sushchinskiy, The Soviet Chemical Industry, 1, 23-25,
(1971).
17. A.S. Mal'tseva, A.T. Rozlovskii, Yu. E. Frolov, Zhurnal Vses. Khim. Ob-va im.
Mendeleeva, 19, 5,522-551, (1974).
443
18. T. Dokter, J. Hazardous Materials 10, 73-87, (1985).
19. L. Medard, Les explosifs occasionnels, i, pp. 172-173, Lavoisier Ed., Paris, (1987)
20. G. Calingaert, W. Burt, I.E.C., 43 (10), 1341, (1951).
444
SODIUM AMIDE IN ORGANIC SYNTHESIS
JEAN-MARIE POIRIER
URA n ~ 464 du CNRS, UFR Sciences, Universit6 de Rouen et IRCOF,

F-76821 Mont Saint Aignan Cedex, France.
Sodium amide, NaNH2 (mp 210~ is slightly soluble in liquid ammonia, about
1 mole per litre at -33~ NaNH2 is a powerful basic reagent and very useful in
organic synthesis. This compound acts essentially as a deprotonating reagent but in
some cases as a nucleophilic reagent.
The acidic acetylenic proton of alkynes can be easily removed by treatment with
sodium amide in anhydrous liquid ammonia and the resulting anion reacted with
various electrophilic reagems (refs. 1-4). In the same manner, the anion of indole
(ref. 5) is methylated leading to the 1-methylindole in high yield. Diphenyl methane
is metallated by NaNH2 and alkylated in 90-95 % yields (ref. 6).
The disodiosalts of 13-diketones have been prepared and alkylated (refs. 7-8) or
acylated (ref. 9) (Fig. 1). These salts can be reacted with chloro- and bromoacid
salts leading to dioxocarboxylic acids (ref. 10). The acid salts must be prepared
beforehand because of the rapid reaction of an excess of NaNH2 with the halogen of
the acid. Treated with 2 equivalents of NaNH2 in liquid ammonia, unsymmetrical
13-diketones lead to disodiosalts in which two alkylation sites are possible (refs. 11-
13). When R 1 = H , R 2 = Me (Fig. 1) the methylation is very selective on the a
site (a " b = 89 911). Increasing the steric hindrance on the b site (R 1, R 2 - - Me)
yields almost exclusively methylation on the a site (a : b = 99 : 1) except when the
anion is stabilized by resonance (R 1 = H, R 2 = Ph), in this case the methylation
takes place on the b site. With unsymmetrical f3-diketones the following rule of
selectivity has been proposed (refs. 9, 12) : phenylacetyl > acetyl > propionyl >
isobutyryl. This order is valid whatever the alkyl halide used and the authors
suggest that it is also valid for acylation and carbonatation.
445
Sodium enolates of ketones have been prepared by reaction of these ketones
with NaNH2. For example, the alkylation of the sodium enolate of cyclohexanone
by allylbromide (Fig. 2) leads to 2-allylcyclohexanone accompanied by a little of
the dialkylated product (ref. 14). Dimethyl ethynyl carbinol was obtained by
reaction of the enolate of acetone (prepared by reaction of solid NaNH2 in ether)
with acetylene. Although a prepared ketone enolate is used, this reaction can also
be considered as an aldolisation reaction of the acetylide with acetone (ref. 15).
Hauser and coll. react sodioenolates of ketones prepared in ether (ref. 16) with acid
chlorides (Fig. 2).
O O O O
1) NaNH2 .-,-- / ~ J ~ ~ O
2) X(CH2)nCO2M
3) H + OH
X =C1, Br n = 1-3,5,6,10 M =Li, Na
0 0 -0 -0 --O --O
/ / ~ / R 1 NaNH2~ ~ R 1
R2 ~ R2
site a site b
O O O O OH
R . ~ ~ 1) NaNH2 ~ R ~ O
2) CO2
3) H +
R = Ph, Me, Ph(CH2)2, n-Bu, PhCH=CH, Ph2C=CH, H, OEt
Fig. 1. Reaction of disodiosalts of diketones.
446
~ O
NaNH2 ,.._
NH3 liq.
ONa //-,.,....,,Br
EhO
O ONa
NaNH2 1) C2H2
NH3 liq. 2) H +
O ONa O O
RI~.,/R 2 NaNH2 0~ R3COCI
R I ~ R2 R I ~ R 3
Et20
R2
O R
R
~...I C1 NaNH2
NH3 N O
)<
R CH2OH
R = Me, Ph, PhCH2
Fig. 2. Reaction of sodium enolates of ketones.
This reaction mainly leads to 13-diketones which do not react with acid chloride in
their reaction conditions. With the use of a,13-unsaturated acid chlorides, the
corresponding 13-diketones are prepared but in low yields (28-60%). The sodium
enolates prepared in this way are also able to react with ethyl ester (ref. 17). With
the use of dihalocompounds, cyclic ketones have been obtained (refs. 18, 19). In
the case of (z-haloketones an intermediate epoxide is formed and may be opened.
With c~-chloroketones, the reaction leads to an oxazoline (ref. 20).
Esters can also be deprotonated by NaNH2 in liquid ammonia, the resulting
enolates are then alkylated (refs. 21-23). In order to prepare trialkylacetic acid from
acetic acid, this process does not give good results since an amide is obtained. To
reduce this side reaction a bulky alkoxy group must be used (ref. 24). With the use
of triethylcarbinol esters (the starting ester is prepared as described in Fig. 3), the
trialkylacetic acids are obtained in fairly good yields.
Sodium enolates of esters also give aldol reactions with ketones (ref. 25).
Ethyl-, isopropyl- or t-butylacetate readily react with benzophenone to yield the
corresponding [3-hydroxyesters (Fig. 3). Only one equivalent of NaNH2 and a short
447
reaction time is needed to reduce the retroaldol reaction. With the use of two
equivalents of NaNH2 and a longer reaction time no aldol product is obtained. The
aldol reaction is also possible with lithium amide. This reaction type is only
possible with ketones which do not bear an a-hydrogen atom to the carbonyl group.
With acetophenone, it is only the enolate of the ketone which is obtained.
However, the enolate of ethyl chloroacetate can react with acetophenone (ref. 26)
because of the following epoxidation cyclisation leading to a glycidic ester (Darzens
condensation) (Fig. 3). Glutaramides have been prepared (ref. 27) by treatment of
13-substituted glutaric acid diesters with NaNH2 in liquid ammonia.
R2
Ph/~/OR1 1) NaNH2 / NH3 liq. / Et20 phi/OR1
O 2) R2Br
0
OCEt3 R1
1) NaNH2 1) NaNH2
Et3COH RI~o
2) R1R2CHCOC1 2) R3X
R2 OH
3) HE1
Ph
-•OR
0
1) NaNH2 / NH3 liq.
2) Ph2CO
Ph
I l OHl O
/
OR
1) NaNH2 Me~./O
p h / ~ - . L i COOEt
O 2) PhCOMe
~
CH2CO2Me NaNH2 / NH3
R--( NH
CH2CO2Me
O
Fig. 3. Reactions of sodium enolates of esters.
448
The sodium dianions obtained from acids, treated by NaNH2 in liquid ammonia
are easily alkylated (refs. 28-30). These dianions have also been used for Michael
addition with benzalacetophenone or ethyl cinnamate. A similar Michael addition
(ref. 31) is also observed with the enolate of ethyl phenylacetate (Fig. 4). Nitriles
can also be deprotonated with NaNH2 in liquid ammonia. The resulting anion was
able to give aldol reaction followed by dehydration (ref.32) or an alkylation
reaction (ref. 33).
R
O 1) NaNH2 (2 equiv.) / NH3 l i q . /~f#O
Ph/~ 2) RC1 ~ Ph
OH 3) H + OH
OH R1 R2
1) NaNH2 (2 equiv.) / NH3 liq.
.
R2
OH Ph
2) R I ~ O 3) H +
Ph
1) NaNH2 / NH3
ph/~CN p h @ Ph
2) Ph2CO
CN
Fig.4. Alkylation or aldolisation reactions of sodium enolates of ketones and of nitriles.
Methylated pyridines and quinoleines have been metallated by NaNH2 in liquid

ammonia. In this case the 4-methyl is deprotonated (Fig. 5) contrarywise to n-BuLi
or PhLi which yields the deprotonation on the 2-methyl (refs. 34-36). These results
have been interpreted by a coordination of the lithium by the nitrogen leading to the
deprotonation of the 2-methyl. When the cation used (sodium) is not as effective as
lithium in coordinating with nitrogen or when the solvents employed (ammonia or
diisopropylamine) are more strongly basic and thus more strongly coordinating, the
metallation of 4-methyl occurs. According to this hypothesis, the use of NaNH 2 in
ether yields a mixture of the two anions. All these anions have been reacted with
electrophilic reagents (alkyl halides, aldehydes, ketones or esters).
449
CH2-
CH3 R~CH3
R~CH3 ~ ~ ~ ' ~ ~ ~CH3
R =H, Me nBuLi or PhLi

Et20, hexane
R CH2-
CH3 CH2-
(,"1 ~ f 2 H 3 NaNH2 r.-~" I~I~H 3
Fig. 5. Metallation of methylpyridinesand methylquinoleinesby NaNH2.
NaNH2 in HMPA reacts at 45-50~ with diphenyl imines. The anion is

alkylated in medium yields. In this case, best results are obtained with the use of
lithium diethylamide (ref. 37). Tosylhydrazones are converted into ethylenic
compounds (Fig. 6) by treatment with NaNH2 in decaline (ref. 38).
R"bin N NaNH2 R,,,,~

Me/ "NHTs
Fig. 6. Reaction of hydrazoneswith NaNH2.
l-Sodiocyclopropene is instantaneously and quantitatively formed by addition of

cyclopropene to a slight excess of NaNH2 in liquid ammonia. This anion can be
alkylated (Fig. 7) in fair to good yields depending on the structure of the halide
(high yield with primary unsubstituted halides). Dehydrohalogenation becomes a
competing reaction in the case of secondary and tertiary halides (ref. 39). With the
use of more than one equivalent of NaNH2 a dialkylation of the starting
cyclopropene is obtained.
450
In some cases NaNH2 is described as an isomerisating reagent by deprotonation
of dienes or alkynes (refs. 40, 41). Cyclopropenyl ketones or vinyl cyclopropyl
ketones treated by NaNH2 in HMPA or DMSO (ref. 42) lead to the cis- and trans-
cyclopropyl ketones (Fig. 7).
.R
~ 1) NaNH2 / NH3 l i q - ~/j
2) RX
\ k( NaNH2 ~ - ':
or HMPA or DMSO +
COMe COMe COMe COMe
Fig 7. Reaction of NaNH2 with cyclopropenyl derivatives.
NaNH2 is basic enough to deprotonate alkyl triphenyl phosphonium bromide.

Mixture prepared from these bromides and powdered NaNH 2 can be stored upon
addition of an etheral solvent. They immediately generate the ylide which then may
be reacted with carbonyl compounds. The use of such "instant-ylide" mixtures
offers several advantages, the most interesting are very good yields and particularly
a high cis/trans ratio (refs. 43-47). This ratio can be enhanced with the
modification of the substituents at the phosphorus atom (Fig. 8).
NaNH2 is also a basic reagent of choice for dehydrohalogenation.
Dehydrohalogenation is easily achieved by treatment of bromo- or chloroaliphatic
or bromovinylic compounds with a suspension of NaNH2. For example stearolic
acid (ref. 48), 10-undecynoic acid (ref. 49) or diethoxyacetylene (ref. 50) have
been so prepared (Fig. 9). In the same conditions phenylacetylene has been
obtained from 2-bromostyrene (ref. 51), 2-butyn-l-ol from 3-chloro-2-buten-l-ol
(ref. 52) but more drastic conditions are required to prepare cyclohexylpropyne
from the corresponding vinyl bromide (ref. 53).
451
R 1~ O A.r3PCH2R2, Br
NaNH2 .v_ R1/~
R2
RI
Ar R2 n-CsHll Ph
cis/trans cis/trans
Ph Me 91/9 87/3
Ph Et 96/4 96/4
Ph n-Pr 96.5/3.5
2-furyl Me 94.5/4.5 91.5/8.5
2-thienyl Me 99/1 81.5/18.5
o, o ' -difluorophenyl Me 99/1 99/1
o-tolyl Me 98/2 94.5/5.5
Fig. 8 Cis / trans ratio of the ethylenic compounds prepared with "instant ylides".
Propargylic aldehyde diethyl acetals have also been prepared in good yields by
dehydrohalogenation of 2,3-dibromo-1,1-dialkoxy propane. The intermediate
acetylide may be alkylated (Fig. 10) (refs. 3, 54). Inamoto and coll. (ref. 55)
reported the first formation of a bridgehead alkene by dehydrobromination. When
treated with NaNH2 in refluxing toluene the bromide (Fig. 9) gives the alkene in
52 % yield. The ready formation of this compound which violates the Bredt rule is
considered to involve a planar cis elimination of bromine and the 2 - e x o hydrogen
atom. 1-Chlorobicyclopropyl is dehydrochlorinated by NaNH 2 in liquid ammonia,
the intermediate anion is then protonated by NH3 leading to bicyclopropylidene
(ref. 56) a valuable intermediate in the synthesis of polycyclopropylidenes ( [n]-
rotanes).
Cyclopropene acetals (Fig. 10) can be prepared from dichloroacetone (ref. 57).
The first step needs 3 equivalents of NaNH2 (the use of a smaller amount of base
results in the formation of the acetal of the chlorocyclopropanone), the third
equivalent of NaNH2 is consumed by the formation of the sodium salt which can be
alkylated (70-77% yield). Cyclopropenes have also been synthesized from allyl
chlorides in various solvents (refs. 58-61). Results are summarized in Fig. 10.
Methyl cyclopropenes are generally accompanied by 1,3-butadiene. It is to be noted
that the use of KNH2 or of a complex base (NaNH2 /t-BuONa) with methallyl
chloride leads to methylene cyclopropane (ref. 62).
452
Aziridines have been obtained from chloroallylamines by treatment with NaNH2
in liquid ammonia (Fig. 11). These reactions are highly dependent on the ratio
amine-NaNH2 and in some cases the acetylenic amine becomes the major product
(refs. 63, 64).
Br ~ Br OH
O 1) 3 NaNH2 / NH3 l i q .
2) HC1
/,/,4"~
OH
O
Br
NaNH2
EtO~ ./H OEt OEt
OEt
OEt
OEt <
OEt
NaNH2 / NH3 liq.
Br~OEt
Br OEt
(
OEt
NaNH2 / Toluene
Br
C1
NaNH2
NH3 liq.
Fig. 9. Dehydrohalogenation with NaNH2.
453
3 NaNH2 RX
w.--
O O NH3 liq.
CI--.~~-- C1
C1 Na R
~ ,,/C1 NaNH2 / THF ~ //~

Me
~x,,,/C1 NaNH2,tBuONa / THF ~
_~..~/C1 NaNH2, NaOH / dioxane .._ /~~
NaNH2, NaOH / dioxane A

~~Cl , %
"Me
Fig. 10. Dehydrochlorination with NaNH2.
x S-7
~j/NHR NaNH2/ NH3 l i q . NHR
"- N\ + /
R
Fig. 11. Treatment of chloroallylamines with NaNH2.
13-Chloroacetals or ethers treated by NaNH2 lead to the corresponding acetylenic

compounds (Fig. 12) by elimination of HC1 and ROH (refs. 65, 66). Acetylenic or
ethylenic 1,4-bisethers undergo 1,4-elimination of ROH upon treatment with
NaNH2 in liquid ammonia leading to 1,3-dienylethers or enyne ethers (refs. 67-
70). A similar reaction also occurs with acetals yielding an enyne or a cumulene
(refs 71,72) according to the starting structure. Similar results are obtained with
alkylthio derivatives, for example phenylthioacetylene has been obtained by
dehydrobromination of the bromovinyl sulfide (ref. 73).
454
C1
/•./OEt
OEt
1) NaNH2 / NH3 liq.r_- R
2) RX
~
OEt
1) 3 NaNH2 / NH3 liq.

C1 2) NH4C1
~ ~.,,,,,j",x OH
O R ~ OR 1) NaNH2 / NH3 liq.

2) H20
R = Me, tBu, Ph
OR
/ / NaNH2
OR ~OR
OMe
EtOyO,~J NaNH2 ~C=C____~~Me
Fig. 12. Reaction of acetals and ethers with NaNH2.
Treated with NaNH2, aromatic halides lead to the elimination of a hydrogen

halide and the formation of benzyne (refs. 74-77). This reaction can be followed by
the addition of the amide ion, resulting in the obtention of anilines. The reaction
occurs on the two reactional centres of the benzyne. Using 14C labelled
chlorobenzene leads almost to a 1"1 ratio of aniline 1-14C and 2-14C (Fig. 13).
Fluorides are less reactive than chlorides which are less reactive than bromides.
When the halobenzene bears a substituent there are several possibilities (Fig. 13).
With a halogen in the meta position, two benzynes are possible, the direction of the
elimination is predictable on the basis of which hydrogen is more acidic. With an
ortho or a para substiment only one benzyne is produced but the amination takes
place according to the nature of the substiment (refs. 74-79).
Various anions (ketones enolates for example) are able to react with arynes
(Fig. 13) leading to the phenylated compound (refs. 80, 81). When the anion is
generated from the starting material, the reaction leads to a cyclisation product
(refs. 82-84). These reactions are also possible with other aromatic compounds
(ref. 85).
455
NaNH2
0 ] . (7N 2 C ,H 2
X
R ~ NaNH2
Favored if R is an electronwithdrawinggroup
NH2
R~NH2
H2N NH2
Favored if R is an electrondonatinggroup
X
__~ NaNH2 R~Z
R
Z-
O
,4 R
NaNH2 _~ 2
R4 R3
- - ~ C 1 CN NaNH2 ~ ~ CN
Fig. 13. Arynes from haloaromaticcompoundsin the presence of NaNH2.
In closely related conditions 2-bromothiophene leads to the migration of the

bromine atom onto the 3-position (ref. 86) while KNH2 gives an amination on this
site (refs. 87, 88). A similar reaction-type is also obtained with substituted
bromothiophenes; a transhalogenation mechanism has been proposed (ref. 89)
(Fig. 14).
456
Br NH2
NaNH2 /~Br KNH2 /~XS,,~
Me Br Me Me
/~Br NaNH2 ~~ NaNH2 Br~
Fig 14. Reactionof bromothiopheneswithNaNH2.
With ammonium salts, NaNH2 can promote two possible rearrangements

(ref. 90) : the Stevens rearrangement in which an alkyl group migrates from the
quaternary nitrogen atom to the a-carbon atom of a second alkyl group and the
Sommelet-Hauser rearrangement which involves migration to the ortho position of a
benzyl quaternary ammonium salt.
The Stevens rearrangement, which is an intramolecular process, is favoured if
an electron withdrawing group (EWG) is present. When the substituent ZCH2 is an
allylic group the migration can occur on the c~- and ~,-carbon atom (ref. 91). When
the benzylic substituent is optically active, the migration is realized with retention
of configuration in the two rearranged products (Fig. 15).
R3 ~R3
+1
Z~N--R2 NaNH2 ~ Z,,,,],/N"
"R2
R1 t R1
Z = EWG
Ph
+/ R Ph
~//""N~ NaNH2 ~ _ ~ /
Ph J'x R N[ j
Fig. 15. Stevensrearrangemem.
457
In the presence of NaNH2 benzylic quaternary ammonium salts generally lead to
the Sommelet-Hauser rearrangement (refs. 90, 92-104). An ortho alkylation takes
place via an exomethylene intermediate. If the two ortho and ortho' positions are
methylated, the methylene compounds can be isolated (refs. 92, 93). The first anion
formed in this reaction can be trapped at a very low temperature (-80~ in an aldol
reaction for example (ref. 103). At -30~ the isomerization and the rearrangemem
occur (Fig. 16).
In some cases, the Stevens rearrangement or an elimination (when a 13-hydrogen
atom is present) can compete with the Sommelet-Hauser rearrangement (ref. 104)
as shown in Table I.
+ ~ +
"XNMe3 NaNH2
~NMe2
H
~jNMe2
Fig. 16. Sommelet-Hauser rearrangement.
Table I. Competition between the three reaction processes for the ammonium salts.
+Me /
Ph~/~-.Me
R
Elimination Sommelet-Hauser Stevens

% rearrangement % rearrangement %
i-Pr 12 88 0
cyclopropyl 33 67 0
cyclobutyl 3 97 0
cyclohexyl 31 23 46
t-Bu 14 6 62
CH2CD3 24 76a 0
a) two rearranged products as shown in Fig. 17 below.
458
"'Me NH3 liq. "- ,,Me +
CH2CD3 N\CH2CD3 /NMe2
CD3
Fig. 17. Products obtained by Sommelet-Hauserrearrangement.
In some cases ring expansion has been obtained during the Sommelet-Hauser
rearrangement (refs. 94, 100). This rearrangement also occurs with naphthalenic
derivatives (Fig. 18) and with many other heterocyclic compounds (refs. 105-107).
NaNH2 .----
NH3 liq
/ " e Me
CH2NMe3 Me
( ~ NaNH2 ~ ' CH2NMe2
CH2NMe2
@ + NaNH2 /~N
CH2NMe3 ~ Me
I
Me I
Me
CN
NaNH2
R R
Fig. 18. Sommelet-Hauserrearrangementpromoted by NaNH2.
When non-enolizable ketones are treated with NaNH2 in aromatic solvents

(generally benzene or toluene) at reflux, the cleavage of a carbon-carbon bond is
obtained leading to the formation of an amide and a hydrocarbon (ref. 108), this
459
process is called the Hailer-Bauer reaction. When an aryl alkyl ketone is used the
aliphatic amide is generally obtained, c~,ot,et',c~'-Tetraalkyldiamides are easily
prepared in this way from the following diketones (Fig. 19) by Hailer-Bauer
reaction (ref.108). 1,1-Dialkyl-3-butenyl phenyl ketones treated in the Hailer-Bauer
conditions yield the corresponding pyrrolidone by internal cyclization.
In some cases such reactions have been reported not to be effective with
commercial sodium amide. The use of NaNH2 with 1,4-diazabicyclo[2.2.2]octane
(DABCO) increases the activity of commercially available NaNH2 avoiding the
preparation of this reagent in liquid ammonia followed by evaporation of this
solvent (ref. 109).
Ar~= O NaNH2 R.~O

+ ArH
R NH2
R1 ..- R I . ~ O
NaNH2 + R2H
R2 NH2
R1, R2 = alkyl
P h ~ / P h NaNH2 H 2 N ~ N H 2
O O O O
n=3to14
O R
/R
~ P h NaNH2 ~Me~ /~O
R R N
I
H
Fig. 19. Hailer-Bauerreaction of non-enolizableketones.
The cleavage of alicyclic phenyl ketones generally leads to benzene and

alicyclic carboxamides. Nevertheless, the use of 1-methyl cyclopropyl phenyl
ketone yields benzamide and a cyclopropane. Using this property with a chiral
compound, Imposimato and Walborsky (ref. 110) have shown that this reaction
proceeds with retention of configuration (Fig. 20).
460
Me
_
_
Me
_
~
.- ..
'~COPh NaNH2 ~ ~~'~H

Toluene
Ph Ph (-)R Ph Ph (+)s
Fig. 20. Hailer-Bauer reaction with cyclopropyl phenyl ketones.
Originally the Hailer-Bauer reaction was designed to serve as a method for

amides synthesis (ref. 108). More recently the process has been extended to the
preparation of hydrocarbons by replacement of a benzoyl group by a hydrogen
atom (ref. 111). Applied to optically active ketones (Fig. 21), the Hailer-Bauer
rearrangement leads to the optically active hydrocarbons with about 45 % of
retention (ref. 112) with NaNH2 (best results are obtained with the use of potassium
t-butoxide). The selectivity can be enhanced with the use of refluxing n-butylamine
as the solvent (ref. 113).
O
~.,R NaNH2 j,, PhCONH2 + ~e~...,,R
Ph 'Ph benzene,reflux Ph
Me
NaNH2 ~ Ph,,
PhCO H
solvent % retention
benzene 44
butylamine 82
Fig. 21. Preparation of hydrocarbons by Hailer-Bauer reaction.
When the starting ketone bears a double bond (Fig. 22) the reaction leads
essentially to the expected hydrocarbon but accompanied by cyclic structures and
"dehydro" product (ref. 114). A similar reaction-type is observed if a cyclopropane
or a cyclobutane (ref. 115) is borne on the side chain (Fig. 22). These reactions are
highly dependent on the nature of the solvent.
461
Me Ph,, Me
O
18%
NaNH2 62 % ~" ....Me
Ph Me benzene
Ph,,,. Me
15%
5% ~ M e
Ph
~ NaNH2
Me
solvent % % %
benzene 50 42 7
THF 83 15 1
heptane 63 32 3
Fig. 22. Hailer-Bauer reaction with unsaturated- and cyclopropylketones.
Owing to the interest of optically active C-centered organosilanes, Paquette and

co-workers (refs. 116-118) have applied the Hailer-Bauer reaction to optically
active non-enolizable c~-silyl phenyl ketones. An optically active silane (Fig. 23)
was obtained with retention of configuration (96 to 98 %). These results are
interpreted on the basis of an initial ~-silyl carbanion formation within a solvent
shell that also encases benzamide.
O 0
Phi.,
Me3Si
R
Me
NaNH2
ph/~ NH2 +
Me3Si Me
R = n-Pe, PhCH2, Ph-CH2-CH2, CH2C=CMe2
Me Me
P h C O ~ NaNH2
Me3Si,,,"~ j Me Me3Si~ Me
Fig. 23. Hailer-Bauer reaction of ot-silylketones.

462
The Cram cleavage of diphenylcarbinols (refs. 114, 115) is generally obtained
with alkoxides but NaNH 2 can also be used leading in the following example (Fig.
24) to a mixture of rearranged products. This reaction has been explained by the
formation of free-radical intermediates.
OH M Me
NaNH2
Ph ~ Ph
benzene 4% 3% 29% Me
Me
16 % 15 %
Fig. 24. Cram cleavage of diphenylcarbinols with NaNH2.
The reaction of 1, 2, 3, 4, 5-pentaphenyl carbinol with NaNH2 in isoamylether

(IAE) at 173 ~ leads after quenching with water to an enone (Fig. 25). If H20 was
added at room temperature the kinetically controlled product was prepared while
the thermodynamically controlled enone is observed by adding H20 at 173~
(ref. 119).
Ph Ph Ph Ph Ph Ph
1) NaNH2 Ph 1) NaNH2
O ,~
2) H20, RT OH 2) H20, 173 ~
Ph Ph Ph
Ph Ph Ph
Fig. 25. Reaction of polyphenyl carbinols with NaNH2.
The reaction of NaNH2 in aprotic medium on tri- or tetracyclic

benzocyclobutanols (Fig. 26) leads to a rearrangement of the cyclic structure into a
phenylcyclohexanone or into a cyclooctanone depending on the polarity of the
solvent. When R I = R 2 = M e a Hailer-Bauer rearrangement is observed on the
octanone leading to an amide (ref. 120).
463
O R1 RI\ R2
R3 R2 O R3
NaNH2 ~ R3
solvent Ph
v i x - -~
16" "R4 R4 R4
R5 R6 R5 R5
solvent % % total
yield(%)
R1-R6 = H DME 70 30 70
R1-R6 = H HMPA 100 0 70
R4 = Me, R1-R3, R5, R6 = H DME 61 39 76
R4=Me, R1-R 3, R5, R6 =H HMPA 80 20 75
R1, R 6 = Me, R2-R 5 = H DME 0 100 80
Fig 26. Reaction of NaNH 2 with benzocyclobutanols.
Finally like methyllithium (ref. 121) ammonium fluoride (ref. 122), tris-
(dialkylamino)sulfonium salts (ref. 123) or alkali alkoxides (ref. 124), alkali amides
in liquid ammonia are able to cleave the silicium-oxygen bond of silyl enol ethers
(refs. 125, 126) leading to enolates. The sodium enolate obtained (Fig. 27) by
treatment of a silyl enol ether with NaNH2 can be equilibrated in the medium,
leading to two alkylated products, nevertheless no polyalkylated species is detected.
With the use of LiNH 2 only the expected reaction product is prepared but the use of
KNH2 leads to a mixture of C-mono and dialkylated and O-alkylted products (ref.
125).
OSiMe3 O O O
1) NaNH2 / NH3 l i q . + +
33.8 % 34.6 % 31.6 %
Fig. 27. Cleavage of a silicon-oxygen bond with NaNH2.
Sodium alkoxides which also cleave the silicon-oxygen bond, can be produced
in-situ by reaction of NaNH2 with an alcohol. For example the sodium enolate of
464
prenal produced in this way can be reacted with aldehydes such as benzaldehyde
(Fig. 28) yielding a dihydropyran and a silylated dihydropyran in high yield
(ref.t127). These two compounds treated in acidic medium lead to a
polyunsaturated aldehyde (refs. 124, 128).
OH OSiMe 3
1) NaNH2 /ROH
~OSiMe3
2) PhCH O
Fig. 28. Reaction of the sodium enolate of prenal with benzaldehyde.
NaNH2 is a powerful basic reagent which was widely used in chemical

laboratories until lithium diisopropylamide was discovered and became more
commonly used as it is much more soluble in classical solvents such as ether and
tetrahydrofuran. NaNH2 is also a powerful reagent when associated with potassium
t-butoxide to become a "complex base" (not described here) as shown by the
research work of Caubere and co-workers (ref. 62).
Nevertheless NaNH2 remains a widely-used reagent in the chemical industry as
shown by the numerous patents using NaNH2 (316 between 1983 and 1993)
reported in the literature.
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468
DELIVERY SYSTEMS FOR CONTROLLED RELEASE OF ACTIVE
MATERIALS
CHRISTIAN PRUD'HOMME

Technologie des Carri~res, 85 avenue des Fr~res Perret, B.P. 62, 69192 Saint Fons
Cedex, France
INTRODUCTION
For many years, the major focus of active material related research has been the
discovery and the synthesis of new molecules. In the last decades, increasing
attention was devoted to the manner in which these compounds are delivered. There
has been considerable interest in developing controlled-release systems in a wide
range of applications such as drug delivery, crop and seed protection in agriculture,
animal nutrition, food additives, dyes and inks, personal care, household products,
detergents, chemical reagents, curing agents and catalysts.
The benefits offered by controlled delivery are now well known. In
pharmaceutical applications, drug administration may be improved by using a
delivery system designed for continuously maintaining the plasma levels of the
active molecule in a therapeutically desirable range. Drugs can be released in a
precise and prolonged manner (up to over one year) without necessitating repeated
and sometimes painful administration (i. e., injection). Harmful side effects can be
reduced and patient compliance may be improved. Other advantages of controlled-
release technology in drug development include localized delivery to a particular
compartment of the body, and preservation of active agents which have short
lifetimes in the body.
In agricultural area, standard procedures for administration of pesticides result
in a great deal of waste. The use of controlled-release systems can reduce the
necessary dosage, and facilitate handling problems related to toxicity hazard.
In various kinds of applications, there is a need to protect active ingredients
against chemical or physical degradation, or to mask unpleasant odor or taste.
Materials which would react with one another on contact, or need to be protected
469
from light, moisture, microorganisms or oxygen, can be incorporated in a polymer
system specially designed to isolate them during the storage period, and to release
them to the application site at the desired moment.
The composition of the structural material and the choice of the fabrication
process are important in the preparation of controlled-release systems. Over the past
decades, great advances have been made in the engineering of multicomponent,
polymer-based, structural materials. These materials were designed to release active
substances by different mechanisms (ref. 1) including diffusion, chemical control
(polymer degradation) and solvent activation (swelling or osmotic pressure). In
some cases, combinations of such mechanisms have been used. Experimental
methods and theoretical analysis of mass transport phenomena in these materials
have been developed (refs. 2,3).
Various fabrication methods can be used in the preparation of controlled-release
systems. These methods include molding and extrusion techniques, pan coating,
encapsulation, and gellation procedures. The selection of the fabrication process is
based on considerations like active agent's stability and solubility, compatibility of
agent with other ingredients, desired size and shape of the final system, productivity
and cost.
The purpose of this paper is to give illustrative examples of the controlled-
release approach, and to discuss the principles and the challenges of this promising
technology. The following examples are based on studies conducted in our
laboratories.
CONTROLLED RELEASE IN ANIMAL NUTRITION

One typical example of a controlled-release approach is the Smartamine T M
system for ruminants developed and commercialized by Rh6ne-Poulenc Animal
Nutrition. Smartamine TM products are rumen-protected amino-acids which are added
to the feed of dairy cows in order to increase the protein content of the milk.
It is well known that some amino-acids are limiting in the diets of ruminants. It
has been demonstrated that effective absorption of methionine and lysine in the
digestive system of cattle improves growth in steers and milk production in dairy
cows. However, when unprotected amino-acids are given as feed additives to
ruminants, they pass first into the rumen where they are degraded by
microorganisms. Consequently, they never reach the absorptive sites of the
gastrointestinal tract and cannot be used by the animal for protein synthesis. This is
the reason why investigators are searching for supplemental forms of methionine
and lysine which are resistant to microbial degradation and subject to absorption in
a post-ruminal part of the digestive system of ruminants (Fig. 1).
470
Various routes have been proposed to prepare protected amino-acids. The
desired use and method of administration greatly affects the choice of the system. In
this case, the size of the system should not exceed a few millimeters because of the
transfer from the rumen to the abomasum.
GASTROINTESTINAL TRACT OF RUMINANTS
Fig. 1. Selection of the release mechanism
A first critical problem was the ability to achieve a good stability in the rumen
and to find a mechanism which would trigger a rapid and total release of the active
ingredients in a post-ruminal site. To accomplish this, the protective material of the
system was designed to be sensitive to a pH change in the medium along the
gastrointestinal tract. Most controlled-release systems can be formulated in two
basic configurations : matrices and reservoirs. In a matrix system, the active
substance is uniformly distributed throughout a solid material. In a reservoir
system, a core of active ingredient is surrounded by a wall. Reservoir systems
include membrane systems which are of the greatest value to achieve constant and
precisely controlled release rates.
Smartamine TM is a multiparticulate reservoir system consisting of amino-acid
cores surrounded by a pH-sensitive coating (Fig. 2). In the present case, the
principal advantage of a reservoir system is to allow high amino-acid contents.
471
SMARTAMINE TM
HYDROPHOBIC INGREDIENTS
(LIPIDS)
COATING ~ "4"
pH-SENSITIVE
POLYMER
AMINO-ACID CORE
Fig. 2. A multiparticulate reservoir system
The methionine and lysine monohydrochloride cores are produced by a melt-

binder extrusion spheronization process. Particle diameters are ranging from 1.5 to
2.5 mm. The coating is composed of hydrophobic substances and a pH-sensitive
polymer which is able to dissolve or swell in the acidic abomasal medium. The
cores are coated in a fluid-bed coater using a solvent-free process (Fig. 3).
AMINO ACIDS (POWDER) pH-SENSITIVE POLYMER IN

AQUEOUS SOLUTION OR EMULSION
WET GRANULATION PRocEss I

(EXTRUSION-SPHERONIZATION)l MELTED FATTY ACIDS
AMINO ACID CORES

! DISPERSION I
)
COATING EMULSION
COATED AMINO ACIDS
Fig. 3. A solvent-free encapsulation process
The pH-sensitive ingredient is a copolymer of 2-vinylpyridine and styrene

(ref. 4). At low pH values, this copolymer becomes hydrophilic because of the
protonation of its pyridine pendent groups. It is synthesized by radical emulsion
polymerization of a mixture containing 65 % 2-vinylpyridine by weight and 35 %
styrene (Fig. 4). After polymerization, unreacted monomers are eliminated using a
472
specific treatment. The coating material contains 20% copolymer and 80% stearic
acid. This system has been approved by the U. S. Food and Drug Administration
and by the European Authorities.
CH=CH2 CH=CH2 ~CH-CH2--CH--CH2~
Na2S208
50~ pH 13
styrene 2-vinylpyridine
35% 65% Copolymer
Fig. 4. Synthesisof the copolymer of 2-vinylpyridine and styrene
The use of chitosan as a means of controlling the release of amino-acids has

been also investigated by Rh6ne-Poulenc (ref. 5). Chitosan (deacetylated chitin) is
extracted from shrimp and crab shells. It is known as a non-toxic, biodegradable
polymer (Fig. 5). It is insoluble in water at neutral pH and has the capacity to
dissolve at low pH values. Chitosan solutions are prepared by dissolving the
polymer in dilute acetic acid. Stearic acid and oleic acid are the hydrophobic
constituents in the chitosan-based coatings.
473
CH3
Chitin \
C--O
H / H H
t~ .CH2OH HO~ / .Nil / [ CH2OH
Poly-~ (1-4)-
~C~]cH~O C~[ ~C. ..C~ [ ~O
--~ ~ C l q ~, / " CH /- - "O ~ \\ CH \ / N-acetyl-
HO~ c I c c / o .... c c D-glucosamine
H
, NH
\
H fl ~H2OH "" I
H
~\ fl
C--O C--O
Chitosan (partially deacetylated chitin)

H H u H
I CH2OH
. . . . HO-
. / NH2 ]" I CH2OH
,
~C~ I ~0 --C~l ~C. ~C~l ~O D-glucosamine
9 -"CH . . . . CH"-- XO/ " -"CH'"-
(> 7O%)
.,-,~C l C C / 0 .... C l C
nw IH l~H2 i~I iJ.i ~H20H raw] 1~_i2 i~I
R-,,,c~O
I
O-
H ra + u H
Chitosan salts CH20H /" NH3 /1' HO.~
J .CH2OH -- ,
jC:-... [ ~O C~[ ~C. ~.C~ [ ~O
\ CH \ I CH I ~ O / \ CH \
\ CH \ / 0 ~ /JCH...~ / \ /CH~ \ /
HO~ T I y T / "" HO~ T I Y
.1 NH3 H H CHgOH I NH3 H
H + " I-1 +
O- o
I I
Fig. 5. Chitin and chitin derivatives
The coating emulsions are obtained by dispersing melted fatty acids (stearic acid
or a mixture of stearic acid and oleic acid) in the chitosan solution or in the
copolymer emulsion at 90~ The amino-acid cores are fluidized with hot air in the
coater. The coating emulsion is pumped through a spray nozzle, atomized with a
high pressure air stream, wetting the surface of the cores (Fig. 6). The heat of the
fluidizing air drives the water away from the layer, leaving the coating ingredients
behind (Fig. 7).
474
ii
i i I . ~
9o ' ~ ~ UIDIZED CORES

COATING EMULSION e
' I o 90"C
o~L 0 9Ip~I,ll
HEATEDFLUIDiZlNGAIR
Fig. 6. Spray-coating process
Fig. 7. Scanning electron micrograph of the coating (cross section, chitosan-coated methionine
granules)
In-vitro laboratory testing is important for the development of controlled-release

systems. In-vitro protection of the coated amino-acids was evaluated by measuring
the amount of methionine or lysine released from the particles at 40~ in a
phosphate buffer at pH 6. In-vitro release behavior was determined by dissolution
test at 40~ in a buffer at pH 2.
475
These studies have shown that numbers of parameters such as the coating weight
and the coating composition can significantly affect the protection/release properties
of the coated granules. For example, high levels of oleic acid in the coating
improve resistance to water at pH 6. The physical properties of the amino-acids are
also important. Highly hydrophilic lysine hydrochloride is more difficult to protect
than methionine, and requires higher coating weights and more oleic acid.
The behavior of the system can be strongly influenced by the microstructure of
the coating material. For the chitosan-comaining products, excellent protection in
rumen and good release rate at pH 2 were achieved using very low levels of pH-
sensitive component (only 3 % chitosan) in the coating composition (Fig. 8). This
result can be explained by the continuous network structure formed by chitosan salt.
This microstructure was observed using electron microscopy, by examination of a
thin section of the coating after dissolving the fatty acids in toluene (Fig. 9). The
formation of this particular structure was determined by the choice of the coating
process and the coating conditions.
100 % METHION!NE RELEASED

90
80
7O
60
50
40
30
2O
10
0 2 4 6 8 10 12 14 16 18 20 22 24
TIME (HOURS)
Fig. 8. In-vitro testing of rumen-protected methionine granules

Release rate at pH 2 and pH 6
Methionine loading in coated granule 981%, coating weight" 8 %
Coating composition" 87 % stearic acid, 10 % oleic acid, 3 % chitosan (acetate)
476
Fig. 9. Transmissionelectron micrograph of the chitosan microstructure of the coating
The products were also tested by in-vivo techniques. For example, evaluation of
the rumen stability was carried out using samples placed in porous nylon bags and
incubated in the rumen and in the intestine of cows. In other experiments, the
products were given orally to the animals and the levels of amino-acids in the GI
tract and in the blood plasma were measured. The impact of the protected amino-
acid intake on the quality of the milk production was also studied in collaboration
with institutes and universities in different countries. The increase of protein
production is significant (0.9 g to 1.7 g / liter / animal) and economically
interesting for dairy farmers. The higher levels of protein in milk also improve
cheese manufacturing.
It can be expected that the use of the Smartamine TM system will expand into
other areas, such as veterinary applications where medicaments cannot be orally
administrated because the biologically active molecule is subject to degradation in
the rumen.
CONTROLLED RELEASE OF IODINE SALTS FOR FIGHTING IODINE

DEFICIENCY
A second example of an application of the controlled-release technology
developed by Rh0ne-Poulenc is the Rhodifuse | system (ref. 6). This system is
commercialized by Rh6ne-Poulenc RORER for the treatment of iodine deficiency.
Lack of iodine in the diet can cause serious disorders such as goiter and cretinism in
adults, growth disorders in children, and fetal death in pregnant women. This
477
problem is affecting several hundred million people in the world. Fighting against
iodine deficiency is a world-wide priority for international health authorities.
Rhodifuse | Iode was designed to deliver sodium iodide in a source of drinking
water continuously over a one-year period. It can be placed in a well to release a
therapeutic supply of iodine (100 ~tg / day / individual) at a nearly constant rate. It
is a modular matrix system which is composed of three polypropylene baskets, each
of them containing three matrices (Fig. 10). The cylinder-shaped matrices are
loaded with 30% NaI by weight. They are prepared by molding a dispersion of NaI
powder in a two-component silicone RTV (platinum catalyzed).
Fig. 10. A modular matrix system
The use of silicone elastomers for controlled release is well known. The
delivery of contraceptive steroids has been one of the most widely studied
applications. In these systems, the release of the drug occurs via the diffusion of the
active molecules through the polymer network. Such a mechanism is not suitable for
the delivery of water-soluble compounds like sodium iodide.
In the case of Rhodifuse | lode, the release mechanism (refs. 7, 8) is based on
the osmotic properties of NaI (Fig. 11). In a first step, water diffuses through the
silicone matrix and starts dissolving the NaI particles which are embedded in the
polymer. Gradually, the particle dispersion is changing into a dispersion of growing
cavities filled with NaI solution. As a result of high osmotic pressure, the size of the
cavities keeps increasing, creating high local stresses and causing polymer cracking.
478
Finally, the iodine salt escapes from the matrix through the water-filled
interconnecting network of cracks and cavities which is generated by this
mechanism. The release rate of NaI is influenced by the mechanical properties of
the silicone elastomer, the size and the shape of the matrix, the initial loading of
iodine salt and the size distribution of the salt particles.
The same mechanism can be used to release molecules which are less
hydrophilic than NaI. In this case, the active ingredient should be co-formulated
with an osmotic agent like NaC1 (refs. 9,10).
Fig. 11. Release mechanism
Rhodifuse | has been successfully tested in African villages where drinking

water had very low iodine contents. Normal urinary iodine levels were measured
after six months of supplementation. A significant regression in the prevalence of
endemic goiter was observed among the population after one year.
CONCLUSION
Controlled release of active materials is an important area of research.
Controlled-delivery systems offer a number of potential advantages in many fields
of applications. The design and the development of a new controlled-release system
require a multidisciplinary approach. Polymer and material sciences play an
important role. The selection of the formulation and the choice of the fabrication
process are critical. In many cases, ingredients used in formulations should satisfy
479
requirements related to toxicity, to biocompatibility and to biodegradation,
especially when used in food, in feed, and in medical applications. Various physical
and chemical phenomena, such as erosion, swelling, diffusion, dissolution, etc ....
can be used to trigger and to control the release of the active agent. Theoretica!
models are available to aid in the application of these phenomena to a specific
problem. Zero-order release kinetics (constant release rates) are often desired. A
good laboratory evaluation of the products is also needed in the development of
controlled-release systems. Good correlations should be made between in-vitro and
in-vivo experiments, because the release behavior is often affected by the
surrounding medium.
References
1. R.S. Langer, Chem. Eng. Commun., 6, 1, (1980).
2. N. A. Peppas, Mathematical models for controlled release kinetics, in Medical Application
of Controlled Release, R. S. Langer, D. L. Wise, (Eds), CRC Press, Vol. II, p. 169, Boca
Raton, FL, (1984).
3. N. A. Peppas, Mathematical modelling of diffusion processes in drug delivery systems in
Controlled Drug Bioavailability, Wiley, Vol. 1, Drug Product Design and Performance,
V.F. Smolen, L.A. Ball, (Eds), 203, New York (1984).
4. C. Prud'homme, P. Bourrain, H. Porte, Proceed. Intern. Control. Rel. Bioact. Mater., 18,
548, (1991).
5. C. Prud'homme, Proceed. Intern. Control. Rel. Bioact. Mater., 21, 112, (1994).
6. G. Torres, Proceed. Intern. Control. Rel. Bioact. Mater., !8, 403, (1991).
7. V. Carelli, G. Di Colo, J. Pharmaceutical Sci., 72, 316, (1983)
8. R. Schirrer, P. Thepin, G. Torres, J. Mater. Sci., 27, 3424, (1992).
9. V. Carelli,, G. Di Colo, C. Guerrini, E. Nannipieri, Int. J. Pharm., 50, 181, (1989).
10. G. Di Colo, Proceed. Intern. Control. Rel. Bioact. Mater., 18, 317, (1991).
480
A N I S O L E : AN E X C E L L E N T S O L V E N T
JEAN-ROGER DESMURS a) AND SERGE RATTON b)

Technologie, 85 Avenue des Fr~res Perret, BP 62, 69192 Saint-Fons Cedex,
France.
b) Interm6diaires Organiques, 25, quai Paul Doumer, 92408 Courbevoie Cedex,
France.
INTRODUCTION
For a few years, the number of solvents available for the synthesis industry has
been significamly reduced for safety and security reasons. Environmemal
constraints on chlorinated solvents are constamly increasing (ref. 1).
Consequently, chemists have had to research new solvents and anisole is
mentioned in several of their works. There is no doubt that for the chemist anisole
has interesting characteristics (ref. 2) as indicated below :
melting point 937 ~ C

boiling point : 154 oC
solubility in water : 1.6 g/litre
self-ignition temperature : 475 ~
as well as low toxicity 9
DL 50 (rat) : > 5,000 mg/kg

DL 50 (rat) : 3700 g/kg
This document aims to review of the use of anisole as a solvent.
481
ORGANIC SYNTHESIS
Grignard reaction
Anisole, as a solvent, has been widely used in the Grignard reaction.
R.N. Lewis and J.R. Wright (ref. 3) report that anisole, which is a slightly
basic solvent, gives a quick reaction between Grignard's reagent and acetone.
Anisole
+ ~MgCI
0 OH
Other authors also describe different synthesis reactions 9

via an organomagnesium compound in anisole (ref. 4 )
HO /~ HO /
--N / MeMgI /
Anisole
t=2h. T= 85~
or in ether/anisole mixtures (ref. 5).
OH
MeMgI
oi< ~ Ether
Anisole
1 -0,33 h
Organolithium condensation
Besides lithiation of anisole, anionisations by butyllithium of more acidic
compounds can be obtained (ref. 6).
482
BuLi (1,6 M)
CuC12
S ~ ~ Hexane/ Et20 / Anisole
- 1 0 . 100 ~
(2 eq.) Yield = 90 %
Halide exchange
Anisole has been used to perform the synthesis of fluorinated compounds
through halide exchange (ref.7).
~ "<'/ "Cl
NO2 ZnF2 (3,3 eq.) / Anisole
t=gh. T=154 ~
~ N O 2
"<I" "F
Yield =49 %
Hydrogenation
Hydrogenation of nitroaromatic compounds was performed by W. Theilacker
and Coll. in Anisole with platinium as catalyst (ref. 8).
NO2
H2/Pt
t- h -70o
H2N
Yield 965 %
Carbonylation
Anisole as a solvent for the carbonylation reaction is described in many
publications.
483
Hydroxycarbonylation of 4-chloroiodobenzene produce 4-chlorobenzoic acid
with palladium as a catalyst (ref.9).
NaO O
i
CO /NaOH / PdCl2 (P~)3)2 ~ ~/)

t=10h. T=80-90~
C1 C1
The preparation of methacrylate (ref. 10) or anydride was described by the Shell
company (ref. 11).
"-J~-/~OH CO /Pd(OAc)2 / Anisole

P= 39 bar O O
Conversion: 64 % t=2h.
T =90~ Selectivity : 95 %
O
CO / Pd(OAc)2 / P~bO3 / Anisole I [
+ CH3OH
"- ~ O J
T = 115oc
P=21 bar
Selectivity :95 %
Peptidic synthesis
The properties of anisole have been widely used for peptidic synthesis as shown
in the works on synthesis carried out by T. Abiko and H. Sekino (ref. 12)
Boc-Tyr(Bzl)- Boc-Thr(Bzl)- TFA Boc-Tyr(Bzl)-

Leu-Gln- + Ala-Leu- Anisole Leu-Gln-
Ser(Bzl)-Leu-NHNH2 Lys(Z)- Ser(Bzl)-Leu-
Arg(Mts)-OBzl Thr(Bzl)-Ala-
Leu-Lys(Z)-
Arg(Mts)-OBzl
Boc-Tyr(Bzl)-Leu- Boc-Thr(Bzl)- Boc-Tyr(Bzl)-Leu-Gln-
Gln-Ser(Bzl)-Leu Ala-Leu-Lys(Z)- Ser(Bzl)-Leu-Thr(Bzl)-
NHNH2 Arg(Mts)-OBzl Ala-Leu-Lys(Z)-Arg(Mts)-
OBzl
484
by N. Fujii, A.Otaka, S. Funakoshi, K. Bessho, T. Watanabe, K. Akaji, H.
Yajima (ref. 13),
Z-Ala-Gly- TTFA Z-Ala-Gly-

Thr-Ala- TFA Thr-Ala-
Asp(OBz)- Anisole Asp(OBzl)-
Cys(MBzl)- ~ Cys(S1)-Phe-
Phe- Trp(Mts)-
Trp(Mts) ~ Lys(Z)-Tyr~
or by H. Yajima, N. Fujii, S. Funakoshi, T. Watanabe, E. Murayama,

A. Otaka (Ref. 24).
Z-Ala-GIy- TTFA H-Ala-Gly-

Thr-Ala- TFA Thr-Ala-Asp--
Asp(OBzl)- TMSOTf Cys(S1)-Phe-
Cys(MBzl)- Anisole Trp-Lys-Tyr-
Phe- m-cresol Cys(S1)-Val-
Trp(Mts)@ ~ OH (S1) @
t2 = 3h
0~
Chromatography
De-protection of peptides was also performed in anisole by H.B. Arzeno and

D.S. Kemp (ref. 15).
Arg (N(omega) TFA

-Ans)-Pro- (anhydrous)
Pro-Gly-Phe- PhSMe Arg-Pro-Pro-
Ser-Pro-Phe- Anisole Gly-Phe-Ser-
Arg(N(omega) Pro-Phe-Arg
-Ans) Ans@ t =4h
25~
Decarboxylation
When heated with reflux of anisole for two and a half hours, 4-benzoyl 3-
carboxy-2-methylthio-pyrimidine decarboxylates giving 4-benzoyl-2-methylthio
pyridine with a yield of 98 % (ref. 18).
485
0 OH 0
o
Anisole
MeS T = reflux t = 2,5 h.
Several other examples of the decarboxylation of pyrimidine are cited by

J. Arukwe and F. Undheim (ref. 16).
Esterification
Gallic acid is esterified by lauric alcohol in a nitrobenzene and anisole mixture
in the presence of 2-naphtalenesulfonic acid (ref. 17).
OH 2-naphtalene sulfonic OH
HO ~ O H H acid HO OH
nitrobenzene-anisole
+ H20
ij + "-
0 ''~~OH t = 20 h.
APPLICATIONS
Additive for fuel

Anisole is mentioned in the literature as an additive for fuel. Introducing
between 2 and 9 % of anisole produces, high octane ratings (ref. 18-20).
The use of surfactants in solution with acetophenone or anisole (refs. 30 - 34) was
also described.
Paint and varnish strippers

Anisole is a solvent used in the composition of products to scour paints
(ref. 21).
486
Binders
Binders for sand moulds, which are based on an aqueous solutions of phenolic
resins and aromatic ether, such as anisole, are described in the literature (ref. 22).
Paints, varnishes
Anisole was also mentioned as a solvent for paints polyimide type (ref. 23), and
polyester type (ref. 24) paints or those based on isocyanate (ref. 25).
Mitsubishi (refs. 26-29) describes the use of anisole for oxygen-proof and
damp-proof materials which have a protecting function.
Cleaning agents
Anisole is one of the substitutes to chlorinated or fluorinated solvents used as
cleaning agents (refs. 30, 31).
CONCLUSION
Anisole, a compound easily produced by methylation of phenolate, has chemical
and physical characteristics, low toxicity and low cost which make it worth being
systematically examined by the chemists working either on synthesis or
applications.
References
. R. Rapp - L'Actualit6 Chimique, 62 (November 1994)
2. MSDS Rh6ne-Poulenc - Version 3 (September 16, 1994)
3. R.N. Lewis, J.R. Wright, J. Amer Chem. Soc., 7__A,1253, (1952)
4. R.M. Anker, A.H. Cook, J. Chem. Soc, 58, (1946)
5. J. Rigaudy, J.M. Farthouat, Bull. Soc. Chim. Fr., 1266, (1954)
6. A. Berlin, G.A. Pagani, F.S. Sannicolo, J. Chem. Soc. Chem. Comm. 22, 1663, (1986)
7. JP 3284135, (1989), (to Mitsui Toatsu Chem.).
8. W. Theilacker, W. Berger, P. Popper, Ber. Deutsch Chem., 89, 970, (1956)
9. X. Huang, J.L. Wu Chem. Ind, 17, 548, (1990)
10. E. DRENT, EP 293053 (1988) (to Shell)
11. E. DRENT, EP 186 228 (1986) (to Shell)
12. T. Ab;,ko, H. Sekino, Chem. Pharm. Bull, 35, (5), 2016, (1987)
13. N. Fujil, A. Otaka, S. Funakoshi, K. Bessho, T. Watanabe, K. Akaji, H. Yajima, Chem.
Pharma. Bull; 35 (6), 2339, (1987)
14. H. Yajima, N. Fujii, S. Funakoshi, T. Watanabe, E. Murayama, A. Otaka, Tetrahedron
44 (3), 805, (1988)
15. H.B. Arzeno, D.S. Kemp, Synthesis, (1), 32, (1988)
487
16. J. Arukwe, JF. Undheim, Acta. Chem. Scan. B, 4__.00(7), 588, (1986).
17.
18. N. Yokoyama, JP 06192667 ,(1994), (to Nippon Oil Co).
19. R.G. Temple, N.R. Gribble- Prep. Pap., Am Chem. Soc., Div. Fuel Chem., 37 (4),
1829, (1992)
20. H.G. Unzelman, Oil Gas J., 89 (19), 44, (1991)
21. J.P. Lallier, S. Fouqay- EP 93-401372 (June 2nd, 1992), (to ELF Atochem).
22. K. Kiuchi, H. Funada, A. Kura, S. Nikai, JP 04118148 (1990) (to KAO CORP.)
23. T. Kigami, A. Morinaga, JP 05059169 (1990) (to Mitsubishi)
24. T. Kigami, A. Morinaga, EP 367493 (1988) (to Mitsui)
25. T. Kigami, A. Morinaga, JP 04029964 (1990) (to Nippon Paint)
26 A. Hiroshi, T. Nishikawa, K. Sonada, A. Yoshiko, H. Adachi, Y. Aiba, FR 2659343
(1989) (to Mitsubishi Denki K.K.).
27. Y. Aiba, H. Adachi, E. Adachi, JP 040663883 (1990) (to Mitsubishi Denki K.K.).
28. H. Adachi, S. Yamamoto, DE 4138180 (1990), to Mitsubishi Denki K.K.)
29. S. Yamamoto, H. Adachi, DE 4117667 (1990) (to Mitsubishi Electric Corp.).
30. T. Yasukochi, S. Akimoto, JP 0311496 (1989), (to Nippon Oil and Fats Co.).
31. G. Ferroni, C. Khouzam, WO 921346 (1991) (to Silvani Antincendi S.P.A.).
488
THE USE OF PHENOLIC COMPOUNDS AS FREE-RADICAL
POLYMERIZATION INHIBITORS
FRANCOISE LARTIGUE-PEYROU

Technologie, 85 Avenue des Fr6res Perret, 69192 Saint-Fons Cedex, France.
INTRODUCTION
The inhibition of radical polymerization is very important in the chemical
industry for preventing premature polymerization during the manufacture, storage
and transportation of unsaturated monomers such as vinyl monomers which
polymerize with a radical mechanism.
Runaway polymerization during these steps may accelerate autocatalytically
and, in extreme cases, may generate substantial heat and pressure which can cause
considerable damage. Though less dramatic but more commonly encountered, slow
unwanted polymerizations during storage or transportation may lead to an unusable
monomer due to the internal build up of polymer over time.
In order to avoid unwanted polymerization, various (high reactivity) inhibitors
can be used. According to their function, these can be classified as follows :
(a) storage and transportation inhibitors (monomer stabilizers),
(b) process inhibitors used during the manufacture of the monomer (e.g.
distillation),
(c) short-stop inhibitors used for "killing" (or stopping) the polymerization very
quickly,
(d) retarding inhibitors used for regulating the polymerization in progress,
(e) inhibitors used to stop a polymerization when the desired conversion has been
obtained and to increase the stability of the polymer (e.g. antioxidants).
In points (a) to (c), the aim is to completely stop the polymerization with
inhibitors in relatively low concentration (5 ppm to 2000 ppm by weight based on
monomer). On the other hand, for applications (d) and (e) the inhibitors (or
retarders) are used in relatively high concentration. In this article, only the two
main points (a) and (b) will be discussed.
489
The performance of inhibitors varies depending upon their conditions of use.
Therefore, inhibitors which are preferred for monomer manufacturing may not be
suitable, for example, for storage conditions. The key to monomer stability lies in
selecting the proper types and amounts of polymerization inhibitors. Worldwide,
phenolic compounds are used in large scale.
OVERALL MECHANISMS OF INHIBITION
Overview of free-radical polymerization

In order to explain how inhibitors work, we need to quickly describe the
mechanism of free radical polymerization encountered for the ethylenically
unsaturated monomers. For more details, several reviews (refs. 1-7) also described
free radical polymerization.
Under normal conditions, we have four elementary steps : Initiation,
Propagation, Transfer and Termination.
Initiation step
X ~ 2R"
R" + M --> RM"
In these equations, X and M are initiator and monomer, respectively, R" is the
primary radical and RM" is the propagating radical. The free radical can be
generated by a thermal process or by dissociation of an initiator such as benzoyl
peroxide or azobisisobutyronitrile These radicals are reactive enough to react with
the monomer giving the first propagating radical RM'.
Propagation step
RM" + M --~ RM 2"
RM 2" + M ---> RM 3"
RMn" + M --> RM'n+I

RM'n is the propagating radical.
The propagation reaction occurs during the continuous addition of monomer.
This reaction will grow the polymer chain as long as the monomer is available in
the medium.
Chain transfer step

RM n" + AH ---> RMnH + A"
490
RM n H is the polymer chain containing n monomer units and AH is a chain transfer
agent or an inhibitor.
The active radical site is transfered to another molecule.
Termination step
by radical combination RM n" + RMm ~ --~ RMn+mR
by disproportionation RM n. + RM m" --~ RMnH + Pm
Pm is a polymer chain.
These two reactions lead to radical destruction.
General concepts of inhibition

Inhibitors are substances that stop radical polymerization. Those have quite a
rapid action on initiator and propagator radicals. They transformed them either into
a non radical form or into a radical with low reactivity in propagation reaction.
They will block the radical polymerization over a so-called induction period that
will vary according to its concentration in the reaction environment and to the
experimental conditions (temperature, catalyst, etc.). Beyond this induction period,
polymerization will occur at the same rate as it would if the inhibitor was not
present. (ref. 8).
The reaction scheme for ideal inhibition is set out below
X --> 2 R"
R" + Z --> inactive product (rate constant kz)
This reaction competes with the chain-growth process :
R" + M --> RM" (rate constant kp)
On this basis, it is then possible to determine an inhibition constam.
This constant requires an exact kinetical analysis of each separate process,
which has not been carried out in most cases. Generally only the ratio kz/kp is
obtained. Some values (refs. 9 - 11) are shown in Table 1.
491
Table 1. Inhibition constants at 50~
Inhibitor Monomer z = kz/kp

Nitrobenzene Styrene 0.326
Methyl acrylate 0.00464
Vinyl acetate 11.2
1,4-Dinitrobenzene Styrene 13.52
Vinyl acetate (45~ 68.5
1,3,5-Trinitrobenzene Styrene 64.2
Methyl acrylate 0.204
Vinyl acrylate 404
p-Benzoquinone Styrene 518
Acrylonitrile 0.91
Methyl methacrylate 5.7
Chloranile Styrene 2040
Methyl methacrylate (44~ 0.26
Copper (II) chloride Styrene 11000
Acrylonitrile (60~ 100
Methyl methacrylate (60~ 1027
Diphenylpicrylhydrazine (DPPH) Methyl methacrylate (44~ 2000
Hydroquinone Vinyl acetate 0.7
1,2,3-Trihydroxybenzene Vinyl acetate 5
2,4,6-Trimethylphenol Vinyl acetate 0.5
Oxygen Styrene 14600
Methyl methacrylate 33000
Phenol Methyl acrylate 0.0002
Vinyl acetate 0.012
p-Nitrophenol Methyl acrylate 0.0649
References 9, 10 and 11.
It can be noticed that the inhibition constant kz/kp initially varies considerably
as a function of the reactivity and the polarity of the chain growth radical. It is
therefore difficult to extrapolate the efficiency of an inhibitor for a given monomer
such as styrene to other monomers, for instance of acrylic type.
Furthermore, as this table shows, oxygen is one of the strongest known free
radical inhibitors : it acts on alkyl radicals to form peroxy radicals. However, these
peroxy radicals can also graft onto the monomer to form an oxidized polymer. The
492
fact is that oxygen can have a dual role : one as an inhibitor (blocking the alkyl
radicals in the reaction medium) and the other as polymerization initiator.
To illustrate this, we can try to diagramatically represent an inhibition
mechanism that is close to reality (Scheme 1).
X ~- [R~ 02 ~ ROO* M ~ RO2M 9 02

RO2MOO
ZH
@ z RM
Scheme 1. Inhibition mechanism of free-radical polymerization
In fact the inhibition mechanism is much more complex than showed above
since the propagating radicals can be alkyl radicals and/or peroxy radicals.
THE RANGE OF M O L E C U L A R INHIBITORS

Radical polymerization inhibitors are therefore molecules that are able of
reacting with the radicals present in the monomer (either alkyl radicals or peroxy
radicals) to give very low reactive radicals which will stop the chain growth. It
should be noted that the formation of these products (inert in terms of the
polyaddition reaction) can result from several basic and consecutive reactions. This
is why inhibition mechanism can sometimes be rather complex.
Generally speaking, the chemical structures of these free radical inhibitors can
be classified into two main family (ref. 12) :
- acceptor type radical inhibitors,
- donor type radical inhibitors.
Acceptor type radical inhibitors

Acceptor radical inhibitors will be capable of oxidizing the alkyl radicals R" by
accepting an hydrogen atom or even an electron by means of an addition
493
mechanism. They are more reactive in an oxygen deficient environments. The main
chemical families are presented below.
Quinones
Quinones are the most extensively studied inhibitors of radical polymerization
and they represent an important inhibitor class. They have complex behaviour and
numerous inhibition mechanisms.
Even if some details are not yet fully understood, it is now accepted that the
main mode of reaction is an addition of the propagating radical to the oxygen of the
quinone, as in the following reaction :
Rn" + O ~ O ~ R n O @ O *
This aryloxyl radical may terminate a second chain as follows
R n O ~ O ~ + Rm~ .~ RnO~ORm
According to F.Tudos's investigations (ref. 13) on styrene polymerization,

quinones can be divided into three groups :
- Benzoquinone and its non-halogen-substituted derivatives (1,4-Benzoquinone
(BQ), 2-Me-BQ, diMe-BQ, triMe-BQ, tetraMe-BQ, MeiPr-BQ, diiPr-BQ, Bu-BQ
etc...)
- Halogen-substituted derivatives of benzoquinone (C1-BQ, Chloranil, etc...)
- Quinones with condensed ring systems (Naphtoquinone, Anthraquinone,
Phenanthrenequinone etc...)
Aromatic nitro compounds

This class includes compounds such as : nitrobenzene, (di)nitrobenzenes,
dinitrophenols, (di)nitrocresols or even (di)nitro(alkyl)phenols or cresols.
Generally, these compounds are more effective with electron-rich monomers
(vinyl acetate or styrene) but have very little effect on methyl methacrylate or
methyl acrylate. Here again there are several inhibition mechanisms (ref. 14).
494
Nitroso compounds
This inhibitor class can be broken down into two sub-groups:
- aromatic nitroso compounds type O N - ~ ~ ) ~ R with R = H, Me, Et, OH,
OMe, C1, p-NH2, NHCH3, NMe2, N(Alkyl), NPh2 or Nitrosonaphtol, 2-methyl

4-nitrosophenol, Me-nitrosophenol
- N-nitroso compounds (N-nitrosodiphenylamine, N-nitrosophenylhydroxylamine,
Cupferron...)
Metal salts
A number of metal salts are well known to be radical inhibitors under certain
conditions. In fact besides the rather pro-degrading nature of metal reactions
3+ 2+ +
[ Fe + RH ~ Fe + H + R ~ ], metals salts may performed stabilization
reactions depending on the redox potential of the system in question. Metal salts
may also have some radical-trapping type stabilizing reactions. This is often the
2+ + +
case for copper ions: Cu + R" ~ Cu + R 9
For example propagating radicals derived from acrylonitrile could be terminated
by Fe(III), Mo(III), Ti(III), Cr(II)...
Other inhibitors
Besides these main products, other inhibitors can also be mentioned such as :
- dibenzofulvene derivatives
- aromatic azo compounds
- phenylacetylene
- pyridinic derivatives
etc...
Donor type radical inhibitors

Donor radical inhibitors tend to reduce peroxy radicals by giving an hydrogen
atom or an electron by transfer. They act most favourably in oxygen-rich
environments. The main chemical families are presented below.
Phenolic compounds
Phenolic compounds (phenol, hydroquinone, hydroquinone monomethylether,
methylhydroquinone, tertbutylhydroquinone, catechol, tertbutylcatechol etc...)
495
represent the major class of polymerization inhibitors for vinyl monomers. Phenols
inhibition mechanism can be represented as follows :
ROO ~ + HO ~ X ~ ROOH + "O X
Phenolic inhibitors in this case exhibit a so called oxygen synergy. This reaction
is much more rapid than the transfer reaction on an alkyl radical. Moreover, the
slightest trace of oxygen will very rapidly form a peroxy radical from an alkyl
radical.
Aromatic amines
Alkyl diphenylamines, alkyl p-phenylenediamines, phenothiazine are the main
amines which are used.
.oo- ~ N H - R ' ~ ROOH + R

,
The same oxygen synergy as with phenolic inhibitors is exhibited with diphenyl
aromatic compounds and phenylene diamine compounds (ref. 15). However,
phenothiazine is a rather different case. Indeed it is well known that phenothiazine
directly reduces alkyl radicals and not peroxy radicals (ref. 16), and that it works
better in anaerobic environments (ref. 17).
A lky lh y drox y lamin e s
RO0~ + \ N-OH ~ ROOH + \ N --0"

/ /
This type of compound (diethylhydroxylamine, dibutylhydroxylamine etc...) can
form both a donor and an acceptor inhibitor system since the nitroxylated radicals
that are so-formed are excellent acceptor inhibitors. They may therefore have either
function according to the operating conditions in which they are used.
Metals salts
It is again the redox potential of the environment that will determine whether
certain metal salts act as donor inhibitors, as is the case for copper ions e.g.
+ + 2+
Cu + H + ROO ~ --) Cu + ROOH
496
THE USE OF P H E N O L I C INHIBITORS IN THE VINYL M O N O M E R
INDUSTRY
The importance of phenolic inhibitors in the vinyl monomer industry.

The role of phenolic compounds as stabilizers and antioxidants has been studied
very extensively in polymers and copolymers (refs. 18, 19). Many papers are
devoted to this problem. Studies have been made on the optimization of phenolic
structure based on hydroquinone (ref. 20) or catechol (ref. 21) as an antioxidant in
polypropylene for example. Others have dealt with the influence of the polarity or
stearic effect for different phenolic compounds or substituted phenols on the kinetics
of antioxidation reactions - for example in polyvinyl acetate (ref. 22). Lastly, many
papers have discussed on kinetic effects.
However, it is rather surprising that this type of product has not represented a
major role as an inhibitor of the radical polymerization of vinyl monomers. No in-
depth theoretical research has been published, as it is the case of antioxidants,
specifically dealing with the inhibition of monomers. The sparse information that is
available is limited to a few papers and reviews.
This is indeed less surprising since the problem of stabilization of vinyl
monomers (particularly styrene, butadiene, (meth)acrylates, etc...) during
manufacture and storage is as important as the commercial stabilization of
polymers.
The fact is that all vinyl monomers tend to polymerise very easily, especially at
high temperatures. During their industrial production, a purification operation is
generally needed to obtain products of the required purity. Since distillation is the
most commonly used process to perform this purification; inhibition of the
polymerization of vinyl monomers during distillation (sometimes carried out at high
temperature) is of great importance. If polymerization takes place during this
distillation step, the formation of high molecular weight compounds of different
structures may occur and cause deposits on the internal surface of processing
equipment, often rendering it inoperative. This undesirable effect results in a loss of
monomer, limits plants efficiency, increases security risks and lowers product
quality. Inhibitors used in these processes belong to various classes of compounds.
The principal selection criteria of such "process-inhibitors" are the radical trapping
efficiency and the ease of separation from the final product. The consumption of the
phenolic inhibitors used during this process step is either on their own or mixed
with other inhibitors from different families and represents around 50 % of the total
consumption of process inhibitors.
497
On the other hand, the stabilization of monomers for storage in the factory or
during road, rail or sea transportation, is a great problem in terms of monomer
quality, and especially in terms of safety. Indeed, for all vinyl monomers, the
polymerization reaction is exothermic and autocatalytic once initiated. It is therefore
very difficult to have storage equipment that can withstand such pressures (ref. 23).
The main selection criteria for such "package-inhibitors" are their effectiveness at
ambient temperature, their colourlessness and their ability to be removed before
polymerization or to be overcome by the use of moderate amounts of initiator under
the customer's polymerization conditions.
At the present time, phenolic inhibitors are greatly preferred by all the major
production companies in the vinyl monomer industry. Therefore the consumption of
phenolic inhibitors represents over 95 % of the consumption of package inhibitors.
As mentionned in the introduction, inhibitors which are preferably use during
manufacturing may not be suitable under stockage conditions. In any case the
choice of phenolic products is clearly manifest.
In fact, in the vinyl monomer industry, over 50 % of the polymerization
inhibitors (process and package) are phenolic compounds.
Synergistic effect with oxygen.

The particularity of the phenolic inhibitors used in industry, is their synergistic
effect with oxygen. These inhibitors require a minimum amount of oxygen in order
to be as effective as possible. This effect has been described in literature for the
stabilization by hydroquinone or paramethoxyphenol of acrylic acid (refs. 24, 25),
methacrylic acid (ref. 17), methyl methacrylate (ref. 26), vinyl acetate (refs. 27,
28) and styrene (refs. 29, 30).
The effect occurs due to the extremely rapid reaction of the first alkyl radical
with oxygen [R" + 02 ~ ROO'], several orders of magnitude faster than

either termination reaction [R ~ + ZH --> RH + Z ~ or propagation
[R" + M - - ~ RM'] e.g.. for methacrylic acid kl = 20,000 kp. The resulting
peroxy radical reacts very rapidly with the phenolic inhibitor in a termination step.
Industrially, the presence of oxygen in the production lines arises from the contact
between hydrocarbons and air, or gases containing oxygen and in systems operating
at reduced pressure as a consequence of leaks in the equipement. Therefore
inhibitors which work in aerobic conditions are the most common. Generally for
storage and transportation of such monomer, contact with air or a 50/50
nitrogen/air mixture is maintained.
498
Specifications for radical polymerization inhibitors
There are a certain number of factors to consider when selecting an inhibitor to

avoid unwanted polymerization. The main key factors to take into account are :
- the operating environment (distillation column, reboiler, condenser, tank, drum,
etc)
- the nature of chemical compounds in the operating system (liquid, gas, pH,
reactivity of these products with inhibitors)
- temperature and pressure
- presence of oxygen
- ecotoxicity with respect to recycling or elimination of process effluents.
Consequently the characteristics of a process inhibitor and a package inhibitor
are not the same. The main factors in selecting a process-inhibitor and a package-
inhibitor are summarized in the Table 2.
Table 2. Characteristics of process inhibitor and package inhibitor
Inhibitor Process-inhibitor Package inhibitor

Concentration range 20 ppm to 1% 2 ppm to 2000 ppm
Characteristics - trapping efficiency - trapping effectiveness
- ease of separation from the final - color formation
product - solubility
- solubility in crude monomer, raw - ease of handling
material and coproducts - ease of removal or ability
- thermal stability to override
- volatility - toxicity
- degradability
- toxicity
- ease of handling
- price
Selection of an inhibitor must therefore be made carefully while keeping in mind

these characteristics. Several phenolic compounds may have the right profile in each
inhibitor category and not effecting the quality and cost of monomer production.
Amongst other things, this explains the success of phenolic inhibitors in the vinyl
m o n o m e r industry.
499
Examples of phenolic inhibitors for few vinylic monomers
Styrenic m o n o m e r s
Styrenic monomers are the aromatic vinyl monomers such as styrene,
vinyltoluene, a-methylstyrene and divinylbenzene (DVB).
Styrene is one of the most important monomers produced by the chemical
industry today. It is separated from the products of dehydrogenation of ethylbenzene
by a multi-stage rectification. The process inhibitors for styrene are mainly
nitroaromatic compounds or aromatic amines and phenolic compounds such as p-
tertbutylcatechol or 2,6 ditertbutylhydroxytoluene mixed with other radical acceptor
inhibitor.
Regarding stabilization for storage and transportation of these monomers, the
best known inhibitor is paratertbutylcatechol (p-TBC) which is widely used by
every styrenic monomer producer. It imparts no color, but does require a minimum
of 15 - 20 ppm oxygen. It is easy to remove prior to polymerization by alkaline
washing, by distillation or by passing through an activated alumina column. The
amount of p-TBC varies between 12 and 50 ppm for styrene, vinyltoluene and a-
methylstyrene and could rise to about 1000 ppm for DVB. An illustration of the
effectiveness of p-TBC is shown in Figure 1.
500
J
25- J
J
20 J
J
15 J
J
10 J
J 0 ppm
_ J ppm
m
0,2.'
TIME (hours)
Figure 1. Styrene polymerization at IO0~ Influence of concentration of p-TBC
Butadiene
The most important source of butadiene world-wide is C4 fractions obtained as
a by-product from the cracking of naphta and gas oil for ethylene. Butadiene a
colourless flammable gas, may polymerize in three ways briefly described as :
- to a liquid dimer which appear in small quantities during storage. However, the
major portion tends to remain dissolved in the liquid.
- to a dark rubber-like heavy polymer usually formed in the liquid phase. This
type can cause trouble by plugging lines and equipment.
- to a crystalline-like white polymer called "popcorn" usually formed in the
vapour phase. It causes severe trouble by plugging up refining still columns, valves,
pumps, pipes.
Different process-inhibitors may be used during manufacturing depending on
each producer. The most widely used phenolic process-inhibitor is the p-TBC with a
mixture of other non phenolic process-inhibitors, p-TBC is the best inhibitor for
retarding the "popcorn seed" formation.
501
On the other hand, p-TBC is generally used in the final butadiene product
between 70 and 150 ppm. The 2,6-ditert-butylhydroxytoluene (BHT) could also be
used as an alternative.
(Meth)acrylic acid and (Meth)acrylates

Acryclic acid is obtained by the catalytic oxidation of propylene and acrylates
(methyl acrylate, ethyl acrylate, butyl acrylate, 2-ethylhexyl acrylate...) by alcohol
esterification of the acid. The preparation of methacrylic acid involves the acidic
hydrolysis of acetone cyanohydrin and methyl methacrylate is obtained by a similar
process involving the methanolysis of acetone cyanohydrin.
During their manufacture, these very reactive monomers are found in very
diverse chemical systems with great acidity (H2SO 4 may be a catalyst) or basic pH
(caustic soda may be a neutralizer). Process inhibitors are also often mixed with
inhibitors from different chemical families that are capable of being effective in
each system that is encountered. Industrially, inhibitors as diverse as benzoquinone,
cupferron, manganese or cerium salts, hydroxylamine, copper alkyldithio-
carbamate, hydroquinone, phenothiazine, etc. may also be used. The current world-
wide trend is to use a mixture of phenothiazine and hydroquinone as a process
inhibitor system. For package inhibitors, manufacturers use hydroquinone (HQ),
hydroquinonemethylether or paramethoxyphenol (HQMME or PMP), 2,4-dimethyl
6-tertbutyl phenol and BHT as an alternative. However the most common is the
hydroquinonemonomethylether due to its colourlessness and its efficiency (ref. 31).
As an example, the concentration of PMP in the products usually varies between
10 and 300 ppm for methyl acrylate and methacrylic acid respectively.
In summary, Table 3 presents a certain number of phenolic inhibitors that are
used either during the process or storage of the main monomers including vinyl
monomers such as acrylonitrile, vinyl acetate or acrolein.
502
Table 3. E x a m p l e of few phenolic inhibitors in vinyl monomer
Inhibitor HQ PMP TBC BHT 2,4-diMe 6-

tBu Phenol
+ +
OH OH OH OH OH
Formula
OH OCH3 CH3 CH3
acrylic acid *
methyl acrylate *
ethyl acrylate *
butyl acrylate *
2-ethylhexyl acrylate *
methacrylic acid *
methyl methacrylate *
ethyl methacrylate *
2-ethylhexyl methacrylate *
acrylonitrile *
vinyl acetate *
vinylidene chloride
acroleine *
styrene
c~-methylstyrene
vinyl toluene
divinylbenzene
butadiene
isoprene
chloroprene
CONCLUSION
The inhibition of radical polymerization is important in the chemical industry to
prevent unwanted polymerization of vinyl monomers during processing, storage and
transportation. Having discussed some of the principles of free-radical
polymerization, a brief overview of possible inhibition mechanisms is presented. A
short summary of the major classes of radical inhibitors gives an idea of the wealth
of choice of chemical compounds available for use in this application. Owing to
specifications for industrial inhibitors and the attractive intrinsic properties of
503
phenolic compounds, these inhibitors are the most common class used in this
industrial application world-wide. In fact phenolic inhibitors are either used on their
own or mixed with other inhibitors from different chemical families. In virtually all
vinyl monomer synthesis processes they are either as a process or as a package
inhibitor. Finally, a brief overview of some phenolic products used for this
application is presented for a few vinyl monomers.
References
1. G.Odian in "La Polym6risation Principes et applications", Polytechnica, Paris, (1994).
2. G.C.Eastmond in "Comprehensive chemical kinetics", Bamford, Tipper, Eds Elsevier,
Vol 14A, pp127- 152, Amsterdam, (1976).
3. P.J. Flory in "Principles of polymer chemistry", Comell Univ. Press, Ithaca, New York
(1953).
4. G.E.Ham in "Vinyl polymerization", Ed Ham, Dekker, New-York, (1967).
5. J.C.Bevington in "Comprehensive Polymer Science" Allen, Bevington, Eds Pergamon Press,
Vol 3, Ch.6, pp 65, (1989).
6. J.C. Bevington in "Radical polymerization", Academic Press, (1961).
7. Encyclopedia of Polymer Science and Engineering, Wiley, Vol 13, New York, (1988).
8. J.C.Bevington, N.A.Ghanem, H.W.Melville, J.Chem.Soc., 2822, (1955).
9. Encyclopedia of polymer science and technology, Wiley, Vol 7, pp 658, New York, (1969).
10. J.Brandrup, E.H.Immergut in "Polymer Handbook", Interscience publishers, (1975).
11. G.C.Eastmond in "Comprehensive chemical kinetics", Bamford, Tipper, Eds Elsevier,
Vol 14A, pp153, Amsterdam, (1976).
12. F.Tudos, Z.Fodor, M.Iring in "Oxidation inhibition in organic materials", Eds Pospisil,
Klemchuk, Vol II, p. 219, CRC, (1990).
13. F.Tudos, T.Foldes-Berezsnich, Prog. Polym.Sci., 14, 717-761, (1989)
14. G.C.Eastmond in "Comprehensive chemical kinetics" Eds Bamford, Tipper, Eds Elsevier,
Vol 14 A, Chapter 2, p. 104, Amsterdam, (1976).
15. R.E.Winkler and E.B.Nauman, J.Polym.Sci., Polym. Chem.Ed, 26, 2853, (1988)
16. L.B.Levy, J. Polym. Sci., Polym. Chem. Ed., 23, 1505, (1985).
17. A.Nicolson Plant/Operations Progress, 10 (3), 171, (1991).
18. Atmospheric oxidation and antioxydants, G.Scott Eds Elsevier (1993).
19. Oxidation inhibition in organic materials, J. Pospisil, P. P. Klemchuk Eds, CRC Press
(1990).
20. J.Pospisil, L.Kotulak, L.Taimr in "Stabilization of polymers and stabilizer processes
advances in chemistry series 85, R. F. Gould Ed., American Chemical Society Publications,
Chapter 14, (1968).
21. J.Pospisil, L.Kotulak, L.Taimr in "Stabilization of polymers and stabilizer processes
advances in chemistry series 85, R. F. Gould Ed., American Chemical Society Publications,
Chapter 13, (1968).
22. M.Simonyl, F.Tudos, J.Pospisil, Eur.Polym.J.,3, 101, (1967).
23. J.L.Gustin, P.Vandermarliere presented at the " 7th International Symposium on Loss
Prevention and Safety Promotion in the Process Industries", Taormina, Italy 4 - 8 May 1992.
24. L.B.Levy Plato/Operations Progress, 6 (4), 188-189, (1987).
25. J.J.Kurland, J. Polym. Sci., Polym. Chem. Ed., 18, 1139, (1980).
26. R.G.Caldwell, J.L.Ihrig, J. Am. Chem.Soc., 84, 2878, (1961).
27. L.B.Levy, Process Safety Progress, 12 (1), 47, (1993).
5o4
28. L.B.Levy, L.Hinojosa, Journal of Applied Polymer Science, 45,537, (1992).
29. G.L.Batch, C.W.Macosko, Thermochimica Acta, 166, 185- 198 (1990).
30. A.A.Miller, F.R.Mayo, J.Am.Chem.Soc., 78, 1017, (1956).
31. L.S.Kirch, J.A.Kargol, J.W.Magee, W.S.Stuper Plant/Operations Progress, 7 (4), 270-274,
(1988).
505
T R A C I N G B A C K T H E O R I G I N O F V A N I L L I N BY S N I F - N M R
GERARD J. MARTIN
Universit6 de Nantes - Laboratoire de R6sonance Magn6tique Nucl6aire

et R6activit6 Chimique -URA CNRS/472 - France
INTRODUCTION
A chemically pure compound, such as 99.99 % vanillin, is in fact a complex
mixture of isotopomers, themselves a combination of isotopes of the elements
concerned (C, H and O), and distributed according to their isotopic abundances.
Probability rules predict 884736 isotopomers of vanillin molecule, C8H80 3. At the
natural abundance of the stable isotopes of C, H and O (Table 1) the light
isotopomer of vanillin, 12C 81H816r'-'3, has an occurrence probability of 0.90685,
whereas the heavy isotopomer, 13C82H81803, has only a 6.4478 E-55 chance of
occurring in nature. In other words, we would have to produce a mass of vanillin
much larger than the mass of the Sun to be able to observe its heavy isotopomer !
Table 1. Isotopic abundances (in ppm) of the natural isotopes of H, C and O.

The boxes indicates the nuclei which have a non-zero magnetic moment and may be
studied by NMR. The brakets indicates radioactive nuclei.
HYDROGEN CARBON OXYGEN
1 12 16
988887.67 997625.81
1H 999844.26 6C O
8
2 13 17
H 155.74 6C 11112.33 8~ 373.00
1
10-10
[1%
6 ] 10-6
18
2001.9
8~
506
From a practical point of view, NMR spectroscopy is able to observe 13
isotopomers of vanillin containing one heavy isotope (8 for 13C and 5 for 2H,
Fig.l a, l b), and in extreme signal-to-noise conditions, may detect the double
natural labels 2H-13C. On the other hand, Isotope Ratio Mass Spectrometry (IRMS)
and Liquid Scintillation Counting (LSC) or Tandem Mass Spectrometer Ion
Accelerator (TMSIA) lead to overall contents in 2H, 13C, 180 and 3H, 14C
respectively. This isotopic fingerprint is a very powerful means for assigning the
origin of vanillin and can also provide useful indications on the transformation
processes undergone by the raw materials and precursors of vanillin, since the
isotopic abundances of a given chemical species do not follow random distributions
bqt obey well defined physical, chemical or biochemical laws.
So I yen'l"
I 2 3 4
Ref. 5
, , I , , , , i , , W , l , l , w | ' ' ' W l W W ' ~ l ~ ' l w ' ' ~ l w ' ' ' 21 ' 9
t0.0 9.0 8.0 7.0 6.0 5.0 4.0 3.0 .0
PPN
Fig. la.
Fig. 1.2H (Fig. la) and ]3C (Fig. lb) NMR spectra of vanillin sample prepared from guaiacol,
recorded at 11.4 T
507
So I v e n t
i 2 3 4 5 6 7
9 " ' 9 I 9 "' ' ', i " , '~ 9 ~ ,- ., i.. i i.. ~ T. i , ~ , i 9 "" r 9 ] 9
DD~ 180 160 t 0 120 t00 80 60
Fig. lb.
The thermodynamic and kinetic isotope effects which are always associated with
a transformation (i.e. distillation, chemical reaction...), induce varying degrees of
isotopic fractionation of the product with respect its substrate. However, these
differences in isotopic composition may be very small and accurate and precise
quantitation methods are required if NMR Spectroscopy or Mass Spectrometry are
to be used for isotopic analysis.
The following points will be presented successively to illustrate the ability of
isotopic analysis to trace back the origin of vanillin :
i - NMR and isotopic methodologies.
ii - Authentication of the natural or synthetic status of vanillin : the analytical
aspect.
iii - Explanation of the isotopic fractionation observed 9the mechanistic aspect.
508
M E T H O D O L O G Y O F I S O T O P I C ANALYSIS BY N M R S P E C T R O S C O P Y
Individual resonances in {1H} decoupled 2H, 13C... spectra correspond to well
defined isotopomers and their abundances are directly proportional to the signal
intensities. In the case of the 2H-spectrum of vanillin, five signals are observed at
11.4 T
H~
1 "C~ O
3
4 6
08CH3
OH
since even at this high field, the H 3 and H7 resonances are deceptively equivalent.
The chemical shifts are presented in Table 2.
Table 2. Chemical shifts of vanillin in ppm/TMS
Site 1 2 3 4 5 6 7 8
82H/TMS 9.8 / 7.2 7 8.1(OH)) / 7.2 4
5X3C/TMS 153.2 91.7 88.5 77.1 114.6 110 72.1 17.6
For curve fitting procedures, it is more conveniem to assign isotopomers in

decreasing chemical shift order which give respectively 9
for 2H
Isotopomer : 1 2 3 4 5
Chemical shift : 1 5 3,7 4 8
for 13C
Isopotomer 1 2 3 4 5 6 7 8
Chemical shift 1 5 6 2 3 4 7 8
The assignment of 2H and 13C signals to the isotopomers of vanillin presents no

difficulties. On the other hand a precise and accurate determination of line
intensities is a considerable challenge. Precision depends mainly on the signal-to-
noise ratio (S/N) achievable in a reasonable period of time which in turn is a
function of the acquisition time, AQ, the delay between pulses, PD, and the number
509
of scans, NS. In the case of the 2H spectrum of vanillin, a value of 3.4s for AQ
easily fulfills the condition of complete relaxation of the nuclei after a 90 ~ pulse
width (PW) and a minimum of 2400 scans are required to obtain a (S/N) value
higher than 200 for most of the isotopomers examined at 11.4T.
To limit random errors which could be associated to short term instabilities of
the spectrometer, a given spectrum is repeated three times. Using an automatic
sample changer, three vanillin samples can therefore be studied in 24 hours.
The sensitivity requirements of 13C spectroscopy are somewhat less severe than
for 2H-NMR. Usually, S/N values higher than 200 are obtained for 13C isotopomers
in 2 hours at l l.4T for a mixture of vanillin and relaxation reagents. (AQ=6.8s
N S = 128 and P W = 9 0 ~ (ref. 1). The precision of the intensity determination,
expressed in terms of repeatability (mean standard deviation of NE replications of
NS scans) is of the order of 0.5 % to 2 % in relative values depending on the nature
of the isotopomer and for a given treatment of the FID's.
Analytical methods used for quality control purposes must also be accurate.
Accuracy is defined as the closeness of agreement between the true value and the
mean of a series of replicates.
Reference materials certified by international organizations are available for
judging the accuracy of an analytical procedure. As far as NMR spectroscopy is
concerned, systematic errors which are frequently related to the lack of accuracy
arise mainly during the acquisition step and in the treatment of the FID's. In order
to minimize bias in signal acquisition, oversampling and very stable decoupling
procedures are recommended, and, to obtain very reproducible intensity values, an
operator independem curve fitting procedure should be implemented in the
analytical sequence.
The Interliss algorithm developed in Names (ref. 2) iterates in the complex
plane from the raw frequency spectrum obtained after Fourier transformation
without any phasis nor base line correction. The reproducibility of the FID
treatment is thus optimized and small differences in the line intensities of different
samples can be clearly shown.
The 2H isotope ratios of vanillin are usually obtained by internal referencing
from the signal intensity according to equation (1).
PwsMvmwsSi (D / H)ws (1)

(D / H) i =
PiVMwsmvSwstv
where m, M, Pi and S are respectively the weights of products used and their
molecular weights, the number of equivalent hydrogen in position i and the signal
510
intensity of the vanillin sample V and of the working standard WS. (D/H)ws is the
isotope ratio of the reference used as the working standard and tv the weight/weight
parity of vanillin.
The site-specific isotope ratios (D/H)i are related to the overall isotope ratio
(D/H) of the whole vanillin sample, obtained by IRMS after combustion of the
product, by equation (2).
n
Z Pi(D / H)i
(D/H)i= i n (2)
ZPi
i
where the summation is carried out on the n isotopomers observable at the field
considered.
(D/H)i may therefore also be computed from IRMS data, (D/H), if for any reason,
the NMR spectra of vanillin are run without addition of the working standard ws 9
n fi
(D / H) i = Z. P i l l1 (D/H) (3)
1
fi is the observed molar ratio of isotopomer i computed from the ZH-NMR spectrum
Si
fi- n (4)
ZSi
i
Equations 1 to 4 apply for all elements considered and the isotope ratio R,
which are related to the isotopic abundance A
A
R - (5)
A-1
are usually reported with respect to the international references V. Smow (2H and
180) and PDB (13C). The isotope ratios of these standards (Rref) were determined
by rigourous international studies (Table 1) and are also used to define a relative
scale of isotopic contents 5, expressed in per mil (%0):
511
5i =
((Ri))
Rref - 1 * 1000 (6)
Equations 3 and 4 are recommended to determine the Site-specific Isotope

Ratios of carbon, since the existence of differential residual Nuclear Overhauser
Enhancements in vanillin samples doped with Cr(AcAc)3 may induce more or less
significant bias.
To conclude this section, it should be recalled that data treatment is an
important part of the analytical approach. The results of a SNIF-NMR experiment
constitute a matrix of data where the variables are the isotope ratios or signal
intensities of the different isotopomers and the individuals are the NE observations
for a given sample. In this sense, SNIF-NMR is a second-order procedure (ref. 3)
and multi-variate analysis is the appropriate method for evaluating the results if a
linear behaviour of the variables may be assumed.
When the whole set of vanillin samples from different origins is considered, we
are faced with the necessity of choosing a classification procedure and defining
belonging rules.
A first approach which assumes a Gaussian distribution of the measurements is
based on the computation of the Mahalanobis distances (ref. 4) from the means and
the variances of the different groups considered.
d2(M) = (~--g) C -1 (x-g) (7)
where C is the variance-covariance matrix of the n isotope ratios measured for the n
authentic vanillins of the group, ~t the vector mean of the group and x the
coordinates of the unknown.
It is recommended to associate to d(M) a probability P which will delineate the
contour of the group as a function of Z2(et;n). In fact, the Mahalonobis distance
gives a default classification since it does not take into account the random errors of
measurement and the non Gaussian contribution in the distribution of the data.
A better way to determine wether an unknown belongs to a reference group and
to compute any mixture composition is to carry out a Monte-Carlo simulation
(ref. 5). An overall belonging probability P is computed in the form of the
summation of the different Gaussian distributions associated to each of the different
measurements which constitute the reference group R.
However it happens frequently that an unknown does not belongs frankly to a
group of well defined origin but is in fact a mixture (A) of several origins (m) :
512
A = a 1 + a 2 ........ a m (8)
The measurement function R M (1,n) determined on the unknown is a linear

combination of the n isotope ratios Rij of the m origins and A is readily computed
from the least square solution
A = ( R R ) -1 R -1 RM (9)
A multi-variate probability may also be computed if we include the dispersion

(variance) of the reference group by computing the Mahalanobis distances between
the unknown and well defined mixtures of vanillins from different origins.
It is obvious that the same limits as those described for the classification step
apply to this procedure and a Monte-Carlo simulation should refine the
determination of the mixture composition. The only drawback of the Monte-Carlo
approach is the computation time since in the case of four isotope ratios measured
for three groups of vanillins, a 1% precision requires 10Ell tests, i.e. one week of
computation for a 60 MHz-Pentium based micro-computer (ref. 5) !
Even if the Mahalanobis distance gives less precise results, it is preferable to
the Monte-Carlo simulation for most routine analyses.
A U T H E N T I C A T I O N OF V A N I L L I N S F R O M D I F F E R E N T O R I G I N S : THE
ANALYTICAL APPROACH
The vanillin market is in fact shared by two products : the natural vanillin
contained in vanilla beans, an extremely highly priced (~ 4000 $/kg) and scarce
product, and the synthetic (from phenols) or hemisynthetic (from lignin) vanillins
which are produced in large quantities and are relatively cheap (40 $/kg).
According to the main food industry regulations in the European Union and the
USA, a flavour is said to be natural (Table 3) only if the raw material comes from
the living pool and if physical or biochemical processes only have been involved
during the different manufacturing steps.
513
Table 3. Classification of the status of a food additive (i.e. aroma) as a function of the nature
of the raw material and process used in its manufacture
RAW MATERIAL PRODUCT CLASSIFICATION
Living Natural Natural Artificial

(named botanical) (oiotechnological (hemisynthetic)
product)
Fossil Artificial Artificial Artificial

(Biotechnological (synthetic)
product)
Process Physical Biotechnical Chemical
Obviously, such a situation is likely to encourage cupidity and in the food

industry fairly substantial quantities of vanillin ex-lignin have been mislabelled as
natural. Various compositional criteria have been developed in an attempt to combat
such fraud but give the considerable price difference between both qualities of
vanillin, adjusting the chemical composition of adulterated samples to resemble that
of the natural product was not a great price to pay. As far as stable isotope analysis
is concerned, 13C-IRMS would have been a choice method to detect such
adulteration, since, as shown in Table 4, there is a very significant difference
between natural 613C ---20.5 %o and hemisynthetic vanillin (613C -- -28 %o).
514
Table 4. SNIF-NMR determination of the isotope ratios of vanillin isopotomers
2H Isotopomer
.,
1 2 3 4 5 Total
VN 130 (a) 160 200 130 145
ppm/V.SMOW , VL 110 (a) 130 175 110 130
VG 350 (a) 140 150 120 160
X3CIsotopomer 1 2 to 7 8 Total
VN -45 -10 -50 -20
%o/PDB VL -55 -20 -55 -28
VG -50 -20 -85 -30
180 Isopotomer (b) 1 2 3 Total
I VN 2O
%o/V.SMOW , VL (c) (c) (c) 16
L vc 18
(a) Due to fast chemical exchange with lable hydrogens of the medium this site is irrelevant
for authentivation of vanillins
(b) SMRI determination
(c) Not yet available
Unfortunately, the natural product is heavier than its synthetic counterpart and it
is relatively easy and not prohibitively expensive to add a small quantity of 13C
enriched vanillin to the synthetic product. From this point of view, vanillin ex-
lignin is preferred to vanillin ex-guaiacol since the quantity of labelled material
required is lower. Applying isotopic dilution equations, it is apparent that less than
13
one hundred milligrams of 99% C-labelled vanillin are required to transform l kg
vanillin ex-lignin into lkg natural vanillin !
As early as the 1980's, it was possible to purchase 0.1g of such enriched
compounds for 300 to 600 $, depending on whether the carbonyl, methoxy or ring
was labelled. This rendered invalid the ~13Ccriterion for authenticating vanillins
and lead to the investigation of deuterium NMR as a potential method to
discriminate between synthetic and natural products (ref. 6).
As shown in Table 4, the deuterium finger print of natural vanillin exhibits
large differences to those of its synthetic analogues. The Mahalanobis distance dM
between the gravity centres of natural and guaiacol vanillin is twenty times larger
than between those of natural and lignin vanillin. However, even in this less
favourable case, dM is much greater than the 99% probability contour of the
natural vanillins defined by Z2(0.99 ; 4).
515
It is even possible to characterize the addition of 5 % lignin vanillin in the
natural product at a 95 % confidence level.
In fact the existence domain of a given group defined by 4 isotope ratios is a
hyper-ellipse and it is more convenient to represent the populations of the three
main groups of vanillin in a plane constructed from the two canonical functions D~
and D2.
Figure 2 illustrate the ability of 2H-NMR to discriminate between the vanillin
groups. Since three groups are involved, the whole variance is distributed in only
two orthogonal directions. The main axe D1 is closely related to the deuterium
content of the formyl group, whereas the second function D2 makes a clear
distinction between natural and lignin vanillin. The classification is 100% complete
at a 99.9 % confidence level.
516
b...,.
to
o I0.00
26.70%
o
8.00
<
6.00 / . ..::\ j "

j -
[]
0 r'l ,
4.00
=_
0
2.00 vanillins ex-bean$ []
I:1
rl i:l []
I:1 \
[]
/,
0.00~ ...... F
t .... I ...... [. . . . . . . -- I " . 6 [] "a ~ i : l ' lib /
. B .. "73.3o
I:1
-2.00 //- a -~
o
vanillins ex-guaiac01
-4.00
o ~ da a a
-6.00
vanlllinsex-lignln
~..J. -8.00 8.00 10.0
-8.00 -6.00 -4.00 -2.00 0.00 2.00 4.00 6.00
o
A careful examination of each group enables some of them to be split into
characteristic sub-groups. For example, beans grown in the Madagascar and Comor
area exhibit significant differences with those found in the Eastern Pacific area.
The case of hemisynthetic and synthetic vanillins is also worth a specific
mention and their investigation brings to light some interesting mechanistic aspects.
Lignin vanillins may be split into two subgroups according to the value of
(D/H)1. Since the 2H content of this group is related to that of the propanoid
fragment of lignin, the sub-group characterized by low (D/H)1 values could be
associated to raw materials grown in very northern areas.
The group containing the vanillins synthetized form phenols via guaiacol is
clearly split into three subgroups in the plane of the first two canonical functions
(Fig. 3) but a careful examination of the upper cluster shows that three samples are
situated above the D1, D2 plane (z coordinate : 4.35) and all the other samples lie
below (z coordinate : -1.45).
518
e4
I t
Hi
9 i
mmim m -
~s
..
. . . .
,w
v 0 i I
Fig. 3. Representation of vanillins ex-guaiacol in the plane of the two discriminant functions
519
In the case of synthetic vanillin, the discriminant functions were computed from
four (D/H)i and one (13C/12C) ratios. Indeed the 613C value may be a good criterion
for distinguishing chemical substances from a C1 or C2 origin and in the case of
lignin vanillin, it seems that there is no special interest to enrich guaiacol in 13C !
Groups 1 and 2 have similar (D/H)i values for the ring hydrogen, but they are
characterized by different (D/H)I and 813C ratios. The differences between the
samples belonging to the subgroups 3a and 3b are mainly related to the existence of
specific 2H and 13C contents of the methoxyl fragment.
MECHANISTIC EXPLANATION OF THE ISOTOPIC FRACTIONATION

OBSERVED IN VANILLIN
The gross variations of ~3C content in natural and fossil materials may be easily
rationalized. In the living pools, the three main groups of products with 813C values
turning around-10 %0,-20 %o a n d - 3 0 %o may be associated to three basic
different photosynthetic metabolisms C4, CAM and C3. Natural vanillin is extracted
from Vanilla Planifolia Andrews or Vanilla Tahitensis Moore, species belonging to
the orchydea family which has a crassulacean acid metabolism (CAM).
Hemisynthetic vanillins are mainly elaborated from plants having a C3 metabolism
for example, pinetrees (vanillin ex-lignin) or clove oil (vanillin ex-eugenol). On the
other hand, the ~3C content of materials from a fossil origin is roughly centred
around -28%0 for products synthetized from C2, C3 olefins or naphta but may be
strongly depleted in 13C if there are prepared from natural gas.
These are primary factors that explain the more important differences in 13C
content ; more subtle variations however may be observed and depend essentially
on the existence of 13C/12C kinetic isotope effects (KIE).
As far as deuterium is considered, the largest isotopic fractionations observed
are mainly related to environmental effects for natural products and to KIE for
synthetic materials.
It is therefore worth considering now the mechanism of isotopic fractionation
during a chemical transformation, and to illustrate this with the case of aromatic
formylation.
520
ISOTOPIC FRACTIONATION ASSOCIATED TO THE F O R M A T I O N OF
AN AROMATIC ALDEHYDE FUNCTION
From a general point of view, the mass and isotopic balance of a chemical
transformation will govern the observed ffactionation between product (P) and
substrate (S).
A(So) = XpAp + (1- Xp)A(Soo) (10)
where
n
XpAp = ~xiA(Pi)
i
Pl
P2
Pi
So
Pn
Scx:,
The isotopic fractionation ~(Pi) of Pi with respect to So is given by 9
A(So) (11)
~(Pi) - A(Pi)
and in the case of 2H, the isotopic abundance A may be safely replaced by the
isotopic ratio R.
It is interesting to express ~(Pi) in terms of the two main parameters of a
chemical reaction, P, the transformation rate and k/k* the kinetic isotope effects
(KIE) where * stands for the heavy isotope "
(" k*'~
[1 - ( l - P ) k /
(12)
Or(p) P
521
and the fractionation between the remaining substrate (Soo) after the reaction and So
is given by 9
1 _ (1 - O) --s
(k, ) (13)
a(s)
This simple model is valid in fact for 13 isotope effects and does not take into
account the existence of intermolecular competitive reactions which occur
frequently in transformations involving C-H bond breaking (refs. 7, 8). Indeed the
abstraction of a hydrogen atom from a group in the substrate having n equivalent
germinal and m equivalent vicinal positions AHn BHm, involves a set of different
isotope effects
nkH
AHn BHm + .............. YHn-IBHm + ZH (a)
ot
YHn-2DBHm + ZH (b)
AHn-1 BDHm + ............
YHn-IBHm + ZD (c)
AHnBHm-1D + ........... YHn-IBHm-1 D + ZH (d)
Neglecting any 13KIE, the isotopic fractionation of the remaining substrate

c~(Soo) is given by (ref. 8)
VlIkD/+(n-l)[k~I ] 1]
1 _ (1- p)Ln\kH j n ~,~HH)- J (14)
~(s)
and for the product or(p) we have

r r ( ~ (k ~ "~]]
I I Lt kD /+(n-1)l ~H III
]1-(11_o)Lni,ks ) n /kH)Jll
I I
_ n rI g) 1I L ]
(k~i/k (15)
OL(kD/ kH) + ( n - 1)(k~ / kH) J
For example, the oxidation of toluene into benzyl alcohol will involve a primary
and a secondary KIE and the isotopic fractionation observed may be very large.
522
In organic chemistry, the aromatic formylation reactions show great diversity
and several hundred examples may be found in the literature (ref. 9) although only
a few reactions are of any industrial interest. It should be kept in mind, however,
that very highly priced 2H, 13C or 130 enriched vanillins are required to adulterate
the synthetic commercial vanillins in order to match the isotopic contents found in
vanilla beans. From this point of view, some exotic formylation reactions may be of
great interest for the fraudsters.
Basically, we may consider three kinds of aromatic formylation which are likely
to involve significant differences in the nature of isotopic fractionation :
the direct formylation of an aromatic ring, which leads frequently to significant
-
carbon isotopic discrimination

- the oxidative formylation of hypohypsic aromatic substrates in which oxygen
fractionation may occur
- the reduction of oxidized aromatic substrates, carboxylic acids and derivatives.
In these three categories of reactions, greater or lesser hydrogen fractionation is
observed, the larger effect being related to reactions involving proton abstraction.
As far as KIE of aromatic formylations are concerned, most of the works
published deal with the determination of kn/kD. A recent review (ref. 10) has drawn
up an inventory of kH/kD values for typical formylation precursors and reactions
- hydroxylation of toluene :
Radical proton abstraction catalyzed by transition metals involves strong KIE
(kH/ko = 5 to 7). When the transition state is relatively dissymmetric, the KIE
value is decreased to 2 or 3.
- halogenation of toluene :
Radical halogenation by NBS or hypohalides induces a strong KIE (4.5 to 6)
and at a low temperature (212 K), values up to 16 were observed. Conversely, the
high temperature (376 K) chloration by C12 is characterized with a small effect
(1.8).
- oxidation of benzylic alcohols :
The subsequent oxidation of the hydroxymethyl group into aldehyde shows very
large variations in the KIE values according to whether proton abstraction is
concerted with C-O bond formation (kH/kD = 1.6) or wether the tunnelling effect
contribution is great ( k H / k D -- 5 0 ) . However oxidations with chromium derivatives
have normal primary KIE (5 to 6). Similar values are observed during the oxidation
of benzylamines
- oxidative breakage of C =C double bonds :
523
The transformation of styrene derivatives into substituted benzaldehyde
(chromate, ferrocyanide, ozone ...) is characterized by an inverse KIE of the order
of 0.8 to 0.98
- decarboxylation of aromatic ct-hydroxy acids :
Substituted mandelic acids are key compounds in the synthesis of vanillin from
phenols. However, the KIE observed during the oxidative degradation of mandelic
acid into benzaldehyde is extremely dependent on the experimental conditions.
Strong KIE (4 to 9) are measured in the presence of chromic or ferric acids but
small values (1 to 2) are observed with NaOC1, N-bromo acetamide or
vanadium V.
To conclude, it is interesting to discuss in more detail the synthesis of vanillin
from 4-hydroxy-3-methoxymandelic acid. According to scheme 1, glyoxylic acid
reacts with guaiacol to give the substituted mandelic acid.
524
| |
naphta ethylene biomass
maleic anhydrid
ethanol
ff-~CH3OH (D/H)(cH2) = 120 to 140 ppm
methyl fumarate
(D/H)(CH=) = 140 to 150 ppm
glyoxal
l
methyl glyoxylate
glyoxylic acid (B)

glyoxylic acid (A)
(D/H)(CHO) = 500 to 550 ppm
(D/H)(cHO) = 220 to 240 ppm
OH
130 ~ / O C H 3
130 130 ppm
OH
135 ~ OCH3
130 ~ 130 ppm

HO-CH-COOH
/
OH OH
135 ~
130 " ~ 1 3 0
OCH3
135
130
CHO CHO
210 to 230 ppm 350 to 400 ppm

Vanillin A Vanillin B
Scheme 1.
525
The isotopic fractionation observed may be rationalized in the light of the previous
considerations. Glyoxylic acid may be synthesized from maleic anhydride or from
ethanol : in these compounds the CH= and CH2- groups have nearly the same
(D/H) value, of the order of 140 ppm. Methyl fumarate (the substrate) is oxidized
with a small inverse KIE into glyoxylic acid A (the product) which is slightly
enriched in 2H. On the other hand, the oxidation of the methylene group of ethanol
into the formyl group of glyoxal is characterized by a strong direct KIE : the
leaving hydrogen is depleted in 2H but the remaining atom in the substrate
(glyoxylic acid B) is strongly enriched. When glyoxylic acids A and B react with
guaiacol, we observe indeed two different vanillins A and B which have very
different isotope ratio values for the formyl group, the other isotopomers of the
aromatic ring remain unchanged during the reaction.
References
1. V. Caer, M. Trierweiler, G.J. Martin, M.L. Martin, Determination of site-specific
carbon isotope ratios at natural abundance 13C-NHR Spectroscopy, Anal. Chem., 63,
2306, (1991)
2. Y.L. Martin, A Global Approach to Accurate and Automatic Quantitative Analysis of
NMR Spectra by Complex Least-Squares Curve Fitting.
Journal of Magnetic Resonance, Series A 111, 1-10 (1994)
3. K.S. Booksh, B.R. Kowalski, Theory of Analytical Chemistry : A guiding theory of
analytical chemistry can be used to specify what information can be extracted from the
data produced by an analytical instrument or method, Anal. Chem., 66, 782A, (1994)
4. P. Dagnelie in "Analyse statistique h plusieurs variables", Les Presses Agronomiques de
Gembloux, 1982.
5. Y.L. Martin, Ph. D Thesis, Paris, (1995).
6. C. Maubert, C. Gu6rin, F. Mabon, G.J.Martin, D6termination de l'origine de la vanilline
par analyse multidimensionnelle du fractionnement isotopique naturel sp6cifique de
l'hydrog~ne, Analysis, 16, 434, (1988)
7. L. Melander, W.H. Jr. Saunders in "Reaction Rates of Isotopic Molecules"
John Wiley & Sons, New York, (1979).
8. a) M.L. Martin, G.J. Martin in "Deuterium NMR in the study of Site-specific Natural
Isotope Fractionation (SNIF-NMR). NMR Basic Principles and Progress", Ed.
H. #Gtinther Springer-Verlag, Heidelberg, 23, 1, (1990).
b) G.J. Martin, S. Hanneguelle, G. Remaud Parfums, Cosm6tiques, Ar6mes, 94, 95, (1990)
9. J. March in "Advanced organic chemistry : reactions, mechanisms and structure";
(IV~ - John Wiley & Sons, New York, (1992).
10. G. Heck, Ph D Thesis, Nantes, (1995).
11. Craig H., Isotopic standards for carbon and oxygen and correction factors for mass-
spectrometric analysis of carbon dioxide, Geochim. Cosmochim. Acta, 12, 133-149,
(1957).
12. Craig H., Standard for reporting concentrations of deuterium and oxygen-18 in natural
waters, Science, 133, 1833-1834, (1961).
13. Gonfiantini R., Standards for stable isotope measurements in natural compounds, Nature,
271,534-536, (1978).
526
14. Guillou C. and Martin G.J., Characterization of reference tetramethylurea (TMU) for the
determination of the H/D ratio in alcohols by SNIF-NMR, Commission European
Communities, BCR Information, 1993, EUR 14396EN.
15. Martin G.J. and Naulet N., Precision, accuracy and referencing of isotope ratios
determined by NMR, Fresenius Z. Anal. Chem., 332, 648-651, (1988).
16. Martin G.J., Trierweiler M., Ristow R., Hermann A. and Belliardo J.J., The certification
of the three reference ethanols by SNIF-NMR : BCR Certified Reference Material
CRM123, Commission European Communities, BCR Information, 1994, EUR14396EN,
EUR15347EN.
17. O'Leary M.H., Carbon isotopes in photosynthesis, Bioscience, 38, 328-336, (1988).
18. Olsson I.U., Radiocarbon variations and absolute chronology , Nobel Symposium 12th
Proc., Wiley Ed., New York, 1970.
19. Stuiver M. and Polach H., Discussion of 14C data, Radiocarbon, 19, 355-363, (1977).
527
NMR UNDER HIGH GAS PRESSURE
FRANCOIS METZ a) MARC LANSON a) ANDRE MERBACH b) AND URBAN

FREY b)

France.
b) Universit6 de Lausanne, Institut de Chimie Min6rale et Analytique, BCH,
CH- 1015 Lausanne, Switzerland.
NMR UNDER HIGH GAS PRESSURE : WHY ?

A fine understanding of reaction mechanisms is of crucial importance to the
control and optimisation of chemical processes. On account of this, various
spectroscopic techniques for mechanistic studies and reaction monitoring have been
continuously developed. However, in situ analytical techniques still remain rare in
the case of reactions involving liquids under high gas pressure, for example
reactions in which a gaseous reactant is used (carbonylation, hydrogenation,
carboxylation, phosgenation, chlorination,) or reactions performed at high
temperatures in closed vessels in which an autogenic pressure results. Among the
techniques, high pressure NMR seems the most promising. Although it has the
disadvantages of relatively low sensitivity and a long time scale, the multinuclear
chemical shifts and couplings can provide detailed structural, kinetic and dynamic
information. As a result, this technique has recently been developed.
NMR UNDER HIGH GAS PRESSURE : HOW ?

High-pressure NMR experiments have been performed for more than 40 years
using techniques ranging from hydrostatic methods employing hydraulic presses and
titanium alloy vessels to the use of glass and sapphire tubes. In this article we will
focus on sapphire tubes because they represent the only high-pressure NMR tool we
are utilising.
528
Sapphire tubes, fastened to titanium alloy heads, were described in 1985 by C.
Roe (ref. 1) and utilised to perform experiments at pressures of up to about 130 bar
and a temperature range of-100~ to 150~ This arrangement has recently been
improved by Merbach's group (ref. 2). The single-crystal sapphire tube (od "
10 mm ; id 98 mm) is glued to a titanium alloy flange with an epoxy adhesive. A Ti
alloy valve assembly allowing pressurisation is then screwed into the flange and a
sample volume of 3 - 5 ml is obtained. The entire tube and valve assembly weigh
approximatively 50 g and generally spins in a commercial cryo-magnet. Even
though the tubes have a flat bottom and do not meet the specifications of typical
NMR tubes, 1H line widths obtained on a 300 MHz instrument are about 1 Hz.
For obvious security reasons, the tube is fastened before pressurisation in a
Plexiglas | protective casing, also designed in Lausanne (Figs. 1, 2). It is then
possible to pressurise the assembly (Pmax up to 100 bar) (ref. 3), agitate it on a
shaking unit in order to ensure a good gas to liquid transfer, and heat it (Tmax =
200 ~ with a specially adapted heating mantle.
Thus, the complete sequence for a high pressure NMR experiment proceeds as
follows 9
- introduction of the solution into the sapphire tube and closing of the titanium alloy
valve,
- fastening of the assembly into the protective casing,
- pressurisation to the working pressure with the desired gas,
- agitation and optional heating,
- NMR analysis (possibly at variable temperature).
529
Fig. 1. Drawing of a high-pressure sapphine tube by Merbach et al.
530
i lil,x
i, ,is
\"\\ I -":
,.'\
.~' I \\
""
xl, ,
I ,.',,
,.\, ~ ~~ ~,
,.x,
\,,
?4 ,<,
,.'x
\\
,.N I ',4"
\\
,.x,
i.'~' \\
"b "
, I o o
"5
I
I
I '
I
' L-1-- 1
I
r- -i 9 1
Fig. 2. H P N M R sapphine tube in its protective casing
531
NMR U N D E R H I G H G A S P R E S S U R E : POSSIBILITIES
The applications of high pressure NMR are numerous and various : examples
from studies carried out at the RP Research Centre include :
- d e t e r m i n a t i o n of the solubility of gases (CO, CO2, butadiene, propylene) at
variable pressure and temperature,
- k i n e t i c monitoring of chemical transformations involving liquids under high gas
pressure or systems evolving autogenic pressure. The experiment being performed
in a closed vessel, it is essentially product-conservative and ensures therefore a
quantitative analysis,
- detection, identification and quantification of catalytic intermediates : for example,
the organophosphorus palladium complex, HPdBr(PPh3)2, has been detected for the
first time and identified in situ during the carbonylation of bromobenzene (ref. 3), a
model reaction for the access to phenolic aldehydes by hydrogenocarbonylation
(Scheme 1), (Fig. 3).
-visualisation of exchange processes between free and bonded forms of a gaseous
molecule (examples in organic and organometallic systems).
pd(PPh3) 4 Pd(PPh3) 2 + 2 PPh 3

Pd(PPh3) 2 + PhBr PhPdBr(PPh3)2
PhPdBr(PPh3)2 + CO Ph(CO)PdBr(PPh3) 2
Ph(CO)PdBr(PPh3)2 + H 2 PhCHO + HPdBr(PPh3)2
HPdBr(PPh3) 2 + R3N Pd(PPh3) 2 + R3NHBr
Scheme 1. Palladium- catalysed hydrogenocarbonylation of bromobenzene
532
i
i
i
(b)
_J
5 0 -5 -10
8
Fig. 3. 1H NMR spectrum in [2H8] thf of the products of the reaction between
t r a n s PhPdBr(PPh3)2 and H2 (gas) after depressurisation at -50~ Insert is an
expeansion of the metal hydride region at (a) 25 ~ (b) -50~
N M R U N D E R H I G H GAS P R E S S U R E : C O N C L U S I O N
High pressure NMR allows the large potentialities of "classical" NMR
spectroscopy to be extended to reactions involving a high gas pressure (gaseous
reactants or autogenic pressure). This attractive new field has been illustrated by a
few, non-limiting examples. Last but not least, since the sapphire tubes we have
described are transparent, they constitute a perfect screening autoclave allowing the
reaction mixture under pressure to be continuously visualised. One is thus able to
record any interesting phenomena such as colour changes and product or catalyst
precipitation or solubilisation occuring during the reaction.
533
(f)
(e)
(d)
(c)
' ~ ~ (b)
9 ~ " ' ~ (a)
2O 0
App. 3. In situ 31P NMR spectra of the reaction between trans Ph(CO)PdBr(PPh3)2 and H2 (gas 9
80 bar) at 60~ to give trans HPdBr(PPh3) 2. The asterisked peak is due to trans
PdBr2(PPh3) 2. t = 0 (a), 2 (b), 4 (c), 6 (d), 8 (e) and 10h (f).
534
References
1. D.C. Roe, J. Magn. Reson., 63,388-391, (1985).
2. G. Laurenczy, L. Helm, A. Ludi, A. Merbach, Helv.Chim. Acta, 74, 1236-1238, (1991).
G. Laurenczy, L. Helm, A. Ludi, A. Merbach, Inorganica Chimica Acta, 189, 131, (1991).
3. G. Laurenczy, A. Merbach, J. Chem. Soc., Chem. Commun., 187, (1993).
The burst pressure of the sapphire tubes was checked in a safe environment : a sapphire tube
was loaded with - 2 ml water, fastened in its protective casing and placed in a bunker box
behind a safety pane. It was then pressurised with 200 bar N2 (cylinder pressure) without
any change. The pressure was raised with a water pump ; at approximatively 550 bar, the
tube was ejected out of the flange (without any damage !) because the adhesive gave way.
The experiment was repeated and the same results were observed. Thus, limiting the working
pressure to 100 bar offers a reasonable margin of safety.
4. B.T. Heaton, S.P. Hebert, J.A. Iggo, F. Metz, R. Whyman, J. Chem. Soc. Dalton Trans.,
3081, (1993).
535
LACTIC DERIVATIVES : METHODS F O R D E T E R M I N I N G THE O P T I C A L
PURITY OF VARIOUS INTERMEDIATES
FRANCOISE MARCENAC a) DIDIER BERNARD a) FERNANDE BOYER a)

JACQUES CHABANNES a) YVES DANION a) MICHEL MINFRAY a)
NICOLE PEYRE a) EUZEBE ZANDANEL a) MARGUERITE HILLAIRET t,)
JEAN-CLAUDE MARSAULT b) AND ELIANE PILOT b)

France.
b) Rh6ne-Poulenc Chimie, B.P. 30, 79500 Melle, France.
INTRODUCTION
Optically active esters of a-chloropropionic acid are precursors of agrochemical
compounds. These esters are prepared from lactic acid using the synthesis path
described in Figure 1. D-lactic acid is obtained by fermentation. Initially, this
compound was esterified to methyl lactate which itself was transformed to (L) c~-
methyl chloropropionate (c~-CPM). The content of the minority enantiomer in these
three compounds was of between 1.5 and 2.5 %.
In order to meet market needs, Rh6ne-Poulenc has had to produce very high
optical purity D-lactic acid on one hand and esterify it to isobutyl lactate on the
other. This product is then transformed to the corresponding a-chloropropionate.
The detection limit of the minority enantiomer in the three compounds must be as
low as possible (0.1% for lactic acid and 0.5 % for both esters).
Methods for determining the optical purity (= minority enantiomer / E of the
two enantiomers) have considerably evolved over the years.
The use of chiral stationary phases both in gas chromatography (GC) and in
liquid chromatography (LC) and the development of enzymatic techniques have
enabled the required detection limits to be achieved.
This article summarizes on all the methods that we have developed and on those
that we have chosen to check the purity.
536
~COOH
Fermentation .
OH
D-lactic acid
~Esterification x
~.COOMe ~COOiBu
.
OH OH
D-methyl lactate D-isobutyl lactate
1
.~COOMe
Chlorination
1
.~COOiBu
C1 C1
L-methyl chloropropionate L-isobutyl chloropropionate
Fig. 1. Diagramrepresenting the synthesis of esters of ot-chloropropionic acid from lactic acid
LACTIC ACID
Summary of the methods developed

Table 1 summarises all the methods for the determination of the optical purity of
lactic acid as well as their respective advantages and drawbacks.
Enzymatic method
The method used was developed to check L-lactic acid in biological and food
systems (ref. 1).
In the presence of L-lactate dehydrogenase (L-LDH), L-lactic acid (lactate) is
oxidized by nicotinamide-adenine dinucleotide (NAD) to pyruvate (eqn. 1).
L-LDH
L-lactate + NAD+ _.. "- pyruvate + NADH + H+ (1)
The equilibrium of these reactions lies almost completely on the side of lactate.
However, by trapping the pyruvate in a subsequent reaction catalyzed by the
enzyme glutamate-pyruvate transaminase (GPT) in the presence of L-glutamate, the
equilibrium can be displaced in favour of pyruvate and NADH (eqn. 2).
537
GPT
Pyruvate + L - ~ t e --. "- L-alanine + c~-ketoglu~ate (2)
The amount of NADH formed in the above reaction is stoichiometric with the
concentration of L-lactic acid for D-lactic acid, respectively. The increase in
N A D H is determined by means of its absorbance at 340 nm.
This method gives the L-lactic acid content in the sample. In order to calculate
the optical purity, the lactic acid title is performed using reverse phase liquid
chromatography.
The detection limit of L-lactic acid is extremely low ( < 0 . 0 5 % ) and the
accuracy is of the order of 5 relative % for contents of L-lactic acid in D-lactic
acid of between 0.1 and 0.5 %.
GC method with a cyclodextrine type CSP

(Analysis of methyl o-Trifluoroacetyl lactate type derivatives)
Analysis of the lactic acid is performed using a double derivatization of the
sample.
Table 1. Summary of the methods for determining the optical purity of lactic acid
Disadvantages detection limits

Advantages
L/L + D %
enzymatic method Direct method, very Provides the L-lactic
sensitive, very high acid content
0.05 %
specificity The lactic acid title is
performed using HPLC
GC on cyclodextrine Analysis of methyl Requires double

type CSP of the O-TFA lactate O-TFA form. derivatization with the
derivative of methyl Good resolution use of diazomethane
0.1%
lactate between the two
enantiomers
Good reproducibility
LC on Daicel WH CSP Direct method Detection limit too high around 1%
GC on cyclodextrine No racemization of the Difficult integration of

type CSP of a sample on the peaks
Derivatization of the <0.5%
dioxolanone type derivatization
derivative sample
538
- esterification of the acidic group with diazomethane.
- esterification of the alcohol group with trifluoroacetic anhydride. The methyl ester
is obtained of O-trifluorinated acetyl lactic acid. These two derivatization reactions
are non racemizing. The separation of the two enantiomers of the derivative
compound is obtained by GC on a chiral stationary phase (CSP) comprising a
derivative of y-cyclodextrine. (Fig. 2)
The derivative corresponds to the octakis (2,6 di O pentyl-3-O trifluoroacetyl) -
y-cyclodextrine
These CSP were developed by D.W. Armstrong (refs. 2-4).
The developed method enables the two enantiomers of the derivative compound
to be completely resolved (Fig. 3).
The detection limit of L-lactic acid is extremely low ( < 0 . 0 5 % ) and the
accuracy is of the order of 5 relative % for contents of L-lactic acid in D-lactic acid
of between 0.1 and 0.5 %.
Analytical method using LC on a CSP

The two enantiomers are directly separated using liquid chromatography.
A chiral stationary phase is used comprising a silica substrate on which is fixed
an amino acid. The mechanisms developed are of the "ligand exchange" type. The
distinction between two enantiomers is possible due to the formation of mixed
diastereoisomerical complexes (chiral solute - transition metal - amino acid fixed on
the silica substrate). The transition metal is added to the mobile phase. (Fig. 4)
The direct method does not provide sufficient resolution between the two lactic
acid enantiomers to achieve the required detection limits.
This method was not able to be used to check industrial samples (Fig. 5).
539
O6R
R6Q O ,3 ~ O
, ~ ~ O
/ OR2 OR3 ~ "0

~, "~ R~o'V
O"~ OR3 D r', ~ O~,
\(~o~ ~-~/
~6o.~~. ~o4 ~o6.
~--.,-, OR3 /I---O
u.. R30 ~ O
o~o~ o~i~
-~~OR3 OR2 9 R 3 ~ / / ~
~6o~ ~o o~o/"'o' o'6~ ,
R60
R2 = R 6=pentyl
R3 = trifluoroacetyl
Fig. 2 Structure of the derivative of 7-cyclodextrine used as a stationary phase
Derivatized D-lactic acid containing 2.5 % of L-lactic acid

i
/
f
f
Fig. 3 Separation of the enantiomers of methyl lactate O-TFA using GC. Chromatographic
conditions ; column : Chiraldex GTA (length = 30 m, internal diameter : 0.25 mm
Column temperature : 75~ injector : 150~ detector ; 200~ carrier gas : hydrogen.
The retention time of the D-enantiomer is 3.3 minutes, that of the L-enantiomer is
4 minutes.
540
O
H " ~ ~O-
N~ .,~....---O-
\ / ._Cu2+ \
pr~..x N-'-"--"-~ ~
-\ n CO
K
H
SILICA GEL D-AMIN0 ACID
H " ~ / ~\ / '~
..Cu2+,,~.---- O"\
N -'------~ ~ CO
SPACER \ H ~
~ ~ R
/,," "-,,,
SILICA GEL L-AMINO ACID
B
Fig. 4 Representation of the ternary complex forming during the analysis of chiral solutes by
"ligand exchange" (in this case the chiral is an amino acid)
Lactic a c i d - I L / L + D = 1.5 %
L
L
Fig. 5 Direct separation of lactic acid enantiomers using an LC column 9 Daicel Chiralpak
WH, 250 mm x 4.6 mm 9 eluant " CuSO4 = 0.25 mmol/1, p H = 5 . 6 9 flowrate 9
1 ml/min 9detection UV, ~, = 235 nm.
541
GC analytical method for lactic acid enantiomers derivatized in the form of
dioxolanones
This method was proposed by P. Husek (ref. 5) and involves the analysis of the
lactic acid in the form of dioxolanone using GC on a chiral stationary phase
comprising a derivative of the [3-cyclodextrine heptakis (2,3,6 tri O methyl) 13-
cyclodextrine. The derivatization reaction is as follows 9
.J,Q, / CF2C1 .~ ""F'--O,,~CF2Cl

HO COOH + O===q + H20
CF2Cl 0~.~-0" "CF2C1
Lactic acid Dichlorotetrafluoroacetone
The tested method did not give sufficient resolution between the two
enantiomers of the derivative to enable the required detection limits to be achieved.
Discussion and conclusion

Among the four methods tested, only the first two give the required detection
limits.
Comparative analyses have been carried out with the two methods. The results
are given in Table 2.
The correlation between results is excellent. Both methods appear to be fully
complementary (correlation coefficient = R = 0.999) (Fig. 6).
CORRELATION OF DATA
ENZYMATIC METHOD
2.5
2.0
1.5
1.0
0.5
0
0 0.5 1.0 1.5 2.0 2.5
CHROMATOGRAPHY
Fig. 6 Correlation of results obtained using the enzymatic and chromatographic methods. The
results given are for [L-lactic / (L-lactic + D-lactic) x 100].
542
Table 2 Comparison of the results obtained using the enzymatic and chromatographic methods
for the analysis of various samples of D lactic acid obtained by fermentation. [L-lactate
content = (L-lactic / L-lactic + D-lactic) x 100]
Sample Chromatographic Enzymatic

,,
N~ 0.34 % 0.33 %
N~ 0.46 % 0.43 %
N~ 0.40 % 0.38 %
N~ 0.39 % 0.37 %
N~ 0.43 % 0.39 %
N~ 0.39 % 0.38 %
N~ 2.3 % 2.3 %
N~ 0.43 % 0.38 %
N~ 0.40 % 0.39 %
N ~ 10 0.23 % 0.20 %
N ~ 11 0.94 % 0.93 %
L A C T I C A C I D E S T E R S ( M E T H Y L AND I S O B U T Y L E S T E R S )
Summary of the developed methods

Table 3 summarises the various methods for determining the optical purity of
lactic acid with their respective advantages and disadvantages.
GC m e t h o d with a cyclodextrine CSP

(Analysis of methyl o-Trifluoroacetyl lactate type derivatives)
Analysis of the lactic acid is performed after esterification of the alcohol group
with trifiuoroacetic anhydride.
The analytical conditions are identical to those described in Figure 3. Figure 7
represents the separation of the enantiomers of the isobutyl ester of lactic acid (O
trifluoroacetyl derivative).
Under these analytical conditions the detection limit of the L-enantiomer in the
D-enantiomer is around 0.1% and the accuracy is of the order of 5 relative % for
L-enantiomer coments in D-enantiomer of between 0.1 and 0.5 %.
Analytical method using LC on a "Pirkle" type C S P

The enantiomers of m e t h y l , ethyl, isopropyl esters of lactic acid can be directly
separated using a "Pirkle" chiral stationary phase.
This phase comprises NH 2 grafted silica onto which is fixed 3-5-dinitrobenzoyl
phenyl glycine using ionic bonds (Fig. 8).
543
NO2
~Si-O ~Si~CH2~CH2~CH2~NH3 |
@ NO2
Fig. 8. Structure of the stationary phase used.
Table 3. Recap of the methods for determination of the optical purity of methyl and isobutyl
esters of lactic acid.
Advantages detection limits

Disadvantages
L/L + D %
Enzymatic method after Very sensitive, very Requires hydrolysis of
hydrolysis of the ester high specificity the ester. The lactic
<0.1%
by lactic acid method, identical to the acid contem is
method for analysing measured using HPLC.
lactic acid
GC on cyclodextrine Acceptable resolution Requires double

type CSP of the O-TFA between the two derivatization
<0.3%
derivative of the lactic enantiomers
Unknown column
acid ester Good reproducibility of stability over time
the method
LC on Pirkle CSP Direct method Reproducibility

around 0.5 %
problems
GC on a conventional No racemization of the Long and difficult

column using a sample on derivatization
"Mosher " type derivatization <0.5%
derivative
Analysis on a
conventional column
544
?
D-isobutyl lactate
L-isobutyl lactate
Fig. 7 Separation of the enantiomers of isobutyl lactate O . T F A by GC. Analytical conditions

identical to those described in figure 3.
Retention time of the D-enantiomer 97.9 min. 9of the L-enantiomer " 7.5 min.
L S Methyl
~ ....... R Ethyl
~ --- " ~ S
~ 9 ... Isopropyl
~ -===-=---- R
Fig. 8 Direct separation of the enamiomers of methyl, ethyl and isopropyl esters of lactic acid
by LC on CSP of "Pirkle" type (racemic mixtures).
Column : Pirlde ionic - L phenyl glycine, 250 cm x 4.6 rnm, 3~tm ; Eluant : (Heptane /
Ethanol) : (99.5 0.5); Flow rate : 1 ml / min ; detection ; U V , ~. = 210 nm.
545
The stationary phase used is specially prepared for the analysis of lactic acid
ester enantiomers. Indeed, conventional commercial CSP's contain D-phenyl
glycine. With this type of substrate, the "L" enantiomers are eluted after the "D"
enantiomers. Because of this, the detection limits of the "L" enantiomer in the "D"
enantiomer are greater than 1%.
The use of a CSP containing L phenyl glycine enables the elution order to be
reversed for the enantiomers (L then D) and in this way to reduce the detection
limits to 0.5 %.
However, this limit is still greater than the required values and the method has
therefore been discarded.
Conventional G C m e t h o d : a n a l y s i s of ,, M o s h e r ,, d e r i v a t i v e s
The lactates to be analysed are converted to esters of (S)
methoxytrifluoromethyl acetic acid (or Mosher (S) acid)) by the reaction described
in figure 10 (refs. 6,7,8).
The diastereoisomers that are thus obtained are separated using GC on a semi-
capillary column using a polymethyl phenyl siloxane phase.
Chromatograms corresponding to the separation of the enantiomers of
derivatives of methyl and isobutyl esters of lactic acid are presented in Figure 11.
The method developed is non racemizing and gives results comparable with those
given by GC on cyclodextrine type CSP.
OMe OMe O~
F3 : COOH
F3 " COOR
~f/COOR !,.._
OH
R = Me, iBu
Fig. 9. Derivatization reaction of lactic acid esters.
546
Methyl
D
7
t Isobutyl
f D
Fig. 10. Separation of the "Mosher" derivatives of methyl and isobutyl esters of lactic acid
Column : JW DB17, 30 m x 0.537 mm, film : 1 ~tm ; column temperature : 10 min at
160~ then 160 to 260 ~ at 4 ~ / min ; injector temperature : 220~ ; detector
temperature : 220~ ; Detection FID.
Discussion
Among the methods developed, only the LC method was rejected due to its lack
of sensitivity and accuracy.
Nonetheless, the four methods gave very similar results as shown in Table 4 for
the analysis of isobutyl lactate samples.
ESTERS OF a - C H L O R O P R O P I O N I C A C I D
Two methods using GC on chiral stationary phases were developed. Both
enabled direct analysis of the two esters of (z-chloropropionic acid.
The first of these used a non-polar stationary phase containing a chiral metal
complex ("Ni-R-Cam"). This phase was developed by a German university
(SchiJrig) and was not a commercial by available. It was therefore discarded.
The second method used GC on a CSP comprising a derivative of f~-cyclodextrine
(heptakis (30 acetyl, 2-6 di O pentyl) ~-cyclodextrine).
It enables direct separation of the methyl and isobutyl esters of a-chloropropionic
acid.
547
The detection limits of the D enantiomer in the L enantiomer are of around
0.5 % and are compatible with the values required to check industrial samples.
Figure 12 shows an example of analysis of methyl and isobutyl a-
chloropropionate samples.
GENERAL CONCLUSION
In order to meet market requirements, it is necessary to produce high optical
purity lactic acid derivatives (greater than 99.5 %).
To do this, the methods used to check these derivatives have had to be redefined
so as to achieve the required detection limits.
Every possible approach for analysing the enantiomers has, at one time or
another, been assessed, these being :
- the specific method for one enantiomer (enzymatic method)
- direct analysis methods on chiral stationary phases, both in GC and LC
- analytical methods on CSP after transformation to a derivative
- formation of diastereoisomers and analysis using conventional GC methods.
According to the type of product, one or even several of these approaches has
been proven to be suited to the problems to be resolved.
Over ten methods have been developed, assessed and chosen or eliminated
according to their performance levels.
The broad-based nature of this study has enabled the problems linked with the
analysis of chiral molecules to be extensively understood, enabling progress to be
made in this field.
Table 4 Comparison of the results obtained by the various methods developed during the
analysis of various isobutyl lactate samples.
L / L + D(%)
Isobutyl lactate Enzymatic GC on Mosher

GC on CSP LC on CSP
method esters
N~ 0.23 0.24 0.21 nd
N~ 0.51 0.47 ~0.5 0.47
N~ 0.44 nd 0.47 0.43
N~ 2.30 2.40 2.20 2.26
N~ 1.90 1.84 1.88 1.98
548
Methyl chloropropionate 9D / D + L = 2.4 %
/----- . II tll I D
7-
Isobutyl chloropropionate 9D / D + L = 1.9 %

f_ , ,,
f
Fig. 11 Chromatograms corresponding to the analysis of methyl and isobutyl chloropropionate
enantiomers (industrial samples)
Chromatographic conditions : column : Lipodex D, 50 m x 0.25 mm, column
temperature (85~ (methyl ester), 65~ (isobutyl ester), Injector temperature : 150~
Detector temperature : 220~ detection FID
References
1. Methods of enzymatic food analysis, Boehringer Mannhein Biochemica, (1984), technical
document.
2. D.W. Armstrong, H.L. Jin, J. Chrom., 502, 154, (1990).
3. D.W. Armstrong, W. Li, J. Pitha, Anal. Chem., 62,214, (1990).
4. W. Li, H.L. Jin, D.W. Armstrong, J. Chrom., 509, 303, (1990).
5. Chrompack News, 2, (1990).
6. J.A. Dale, D.L. Dull, H.S. Mosher, J. Org. Chem., 34, 2543, (1969).
7. J.A. Dale, H.S. Mosher, J. Amer. Chem. Soc., 95,512, (1973).
8. P. Mohr, L. R6sslein, C. Tamm, Helv. Chim. Acta, 70, 142, (1987).
9. V. Schurig, R. Weber, J. Chrom., 217, 51, (1981).
549
AUTHOR INDEX F
Fache E. 350,380
Faucher D. 189
Ferrero R.M. 336
A
Fines A. 431
Alby D. 29
Firkins S. 107
Ashforth R. 3
Foray F. 189
Astruc D. 39
Frey U. 528
Aubry A. 48,62
G
B
Galvez M. 405
Babin P. 75
Garcia H. 301
Badey J.P. 405
Gaspard H. 15
Beclere M. 380
Genet J.P. 416
Bennetau B. 75
Gervais C. 405
Bernard D. 536
Gilbert L. 29,39,48,62,301,391
Bernard J.M. 405,416
Grosselin J.-M. 336
Besson B. 116,129
Gustin J.L. 431
Bonneau-Gubelmann I. 116
Bontoux M.C. 189
Bouzid K. 405
Boyer F. 536 H
Hillairet M. 536
C
Camblor M.A. 391 J
Casati J.P. 405 Jacquerot R. 129
Cerbelaud E. 189 Janin M. 48,62
Chabannes J. 536 Janin R. 325
Cordier G. 336 Janousek Z. 201
Corma A. 391
Costantini M. 350,380,391
Cristau H.J. 90 L
Crouzet J. 189 Labrouillere M. 15
Lanson M. 528
Laporterie A. 15
D Lartigue-Peyrou F. 489
129 Laucher D. 380
Dananche J.
536 Leblanc J.C. 129
Danion Y.
3,15,90,116,129,481 Le Govic A.M. 48,62
Desmurs J.R.
15 Lemaire-Audoire S. 416
Dubac J.
176 Levy-Schil S. 189
Duhamel P.
Dunogues J. 75
M
Maliverney C. 343
E
405 Manaut D. 350
Enderlin J.M.
391 Marcenac F. 536
Esteve P.
Marsault J.C. 536
550
Martin G.J. 506 Viehe H.G. 201
Martinez A. 391
Meilland P. 405
Merbach A. 528 W
Mercier C. 293 Wakselman C. 313
Metivier P. 368 Wuthrick M.F. 343
Metz F. 15,528
Michel M. 116
Michelet D. 350 Y
Minfray M. 536 Youmans P. 293
Morel M. 325
P Z
Perrin-Janet G. 380 Zandanel E. 536
Perrod M.C. 301
Petre D. 189
Pevere V. 405
Peyre N. 536
Pilot E. 536
Poirier J.M. 445
Pommier P. 48,62
Prud'homme C. 469
R
Ratton S. 90,116,129,301,481
Rignol S. 90
Rochin C. 301,325
Ruiz J. 39
S
Saint-Jalmes L. 325
Savignac M. 416
Schlama T. 368
Soubrier F. 189
Spagnol M. 29
T
Taillefer M. 90
Thibaut D. 189
Tordeux M. 313
V
Valencia S. 391
Vandewalle M.F. 405
551
SUBJECT INDEX
A
Acetic anhydride 20
Acetominophen 368
Acetyl chloride 8,19
Acidity 325
Acido-basic properties of samarium phosphate 72
Acrylonitrile 194
Acylation of anisole 18,31
Acylation of aromatics ethers 17
Acylation of 1,2-dimethoxybenzene 21
Acylation of phenols 79
Acylation of veratrole 21,32
Acylchloride 35
Additive for fuel 486
Adipamate 192
Adipamide 192
Adiponitrile 189,192
A1C13 5,144,163
Alcohol hypochlorites 434
Alkylation mechanisms 60
Alkylation of phenols 62
Alkylation of sodium enolates of ketones 449
Alkylation of sodium enolates of nitriles 449
Allyloxycarbonates 417
Aluminium chloride 15
Aminoacids 405
Aminolysis of nitriles 102
Ammonium 192
Analysis of polychlorinated gem dichloro cyclohexadienones 137
Aniline 350
Animal nutrition 470
Anisole 17,32,481
Aromatic halodemetalation 77
Arylation of alcohols 90
Arylation of allylamine 92
Arylation of amines 90
Arylation of 2-methoxyethanol 97
Arylsilanes 80
Asymmetric halogenation of carboxylic acids 180
Asymmetric halogenation of chiral imide 181
Asymmetric halogenation of ketals 177
Asymmetric halogenation of ketene acetals 182
Asymmetric halogenations of ketones 176
Authentication of vanillins 513
Auto-ignition 431
552
B
Balz-Schiemann reaction 301
Barbier condensation 319
Bayer-Villiger Rearrangement 296
Benzonitrile 194
Benzoquinone 372
Benzoylation of anisole 34
BiC13 17
Binders 487
Bi203 20
Bipy2NiBr2 93
Bismuth salts 16
Boltzmann equation 110
Boron phosphate 55
Bromobenzene 92
(R)-2-Bromo cyclohexanone 176
4-bromofluorobenzene 297
Bronsted acid 162
Bu4NHF2 252
Butadiene 501
2-Butyn- 1-ol 451
C
Caesium fluoride 261
Calcitonin 407
Calcitonin fragments synthesis 407
Cannizzaro dismutation 345
Caprolactame 189
Carbon dioxide 117
Carbon monoxide 326
Carbonylation 483
Carbonylation of bromobenzene 532
Carboxylation 116
Carboxylation of hydroxy aromatic compounds 116
Carboxylation of phenate 120
Carboxylation of phenol 118
Carboxylation of potassium phenate 121
Carboxylation of sodium phenate 120
Catalysis by rare earth phosphate II 48,62
Catalytic activity of metallic phosphate 51
Catalytic tests 50
Catechol 350,495
Cesium hydrogenophosphate 50
CF3SO3H 163
Characterization of SmPO4 70
Chitin 474
Chitosan 473
Chloramines 433
Chlorination of 2,4,6-trichlorophenol 144
553
Chlorination of oximes 434
Chlorine 431
Chlorine injection 431
Chlorobenzene 93
4-Chlorophenyl fluoroformate 302
Cisapride 294
Claybis 19
Cleaning agents 487
Cleavage of allyloxycarbamates 424
Cleavage of allyloxycarbonates 418
Cleavage of a silicon-oxygen bond with NaNH2 464
CO2 116
CoC12 44
Comamonas Nil 196
Combustion 432
Complexation of Lewis acids 11
[3-Controlled diastereoselective chlorination 183
Controlled release 469
Controlled release of active materials 469
Controlled release of iodine salts 477
Copolymer of 2-vinylpyridine and styrene 473
Copper 90
Cram cleavage 463
CsC1 269
5-cyano valeric acid 189
Cyanovaleramide 192
~,-Cyclodextrine 540
D
Decarboxylation 485
Decarboxylation of arylfluoroformate 302
Deflagration 436
Deprotection of alcohols 419
Deprotection of carboxylic acids 419
Deprotection of primary amines 419
Deprotection of secondary amines 419
Detonation 436
Dehydrobromination 452
Dehydrohalogenation 452
Dehydrohalogenation with NaNH2 453
Diastereoselective halogenations 176
Dibenzodioxines 132
Dichlorobenzoquinone 144
2,4-Dichloronitrobenzene 268
3,4-Dichloronitrobenzene 340
2,4-Dichloro 6-(2,4,6-tetrachlorophenoxy) phenol 154
2,6-Dichloro 4-(2,4,6-trichlorophenoxy) phenol 154
Diflubenzuron 244
Diflufenican 245
554
2,4-Difluoroaniline 271
2,6-Difluorobenzonitrile 244
Digestive system of ruminants 471
1,2-Dihydroxybenzene 49,351
Diisopropylbenzene 351
Dimandelic acid 344
1,2-Dimethoxybenzene 49
Dimethylamine 93
Dinitrogen tetroxide 372
2,4-Dinitrophenol 372
Dynamic grinding of potassium fluoride 280
E
Electrochemical reduction 79
Electrophilic substitution 79
Enzymatic hydrolysis 189
Enzymatic hydrolysis of adiponitrile 190
Enzymes 190
Epoxidation of 1-hexene 400
Esterification 486
Ethyl trifluoroacetoacetate 226,239
Ethyl trifluoropyruvate 317
Ethyl vanillin 343
Explosion 431
F
FeC13 13,163
Ferric chloride 16
Flammability limits 438
Fluorination 296,301
Fluorination by KF catalysed with CsF 269
Fluorination by KF with phase-transfer catalysts 272
Fluorination of aromatic compounds 244
Fluorination of 3,4-dichloronitrobenzene 254
Fluorination with alkaline fluorides 257
Fluorination with KHF2 268
Fluorine 201
4-Fluoroaniline 297
Fluoroaromatics 301
Fluoroarylsilanes 81
Fluorobenzene 301,309
1-Fluorobiphenyl 305
Fluorodecarboxylation 296
Fluorodecarboxylation of arylchloroformate 301
Fluorodecarboxylation of phenylchloroformate 303
Fluorodecarboxylation of 2-phenylphenylchloroformate 306
Fluorodecarboxylation of 3-tolylchloroformate 306
1-Fluoro naphthalene 306
555
4-Fluoronitrobenzene 342
4-Fluorophenol 293,296
Formation of triflyl chloride 319
Formyl cation 326
Formylation 326
Formylation of alkylbenzenes 327
Formylation of aromatic compounds 325
Formylation of phenol 327
Free-radical polymerization inhibitors 489
Friedel-Crafts acylation 3
Friedel-Crafts reaction 15,39,302
Fuchsone 354
Functionalisation of fluoroaromatics 75
G
Gas chromatography 536
Gas phase explosion hazard in chlorination 435
Gattermann-Koch reaction 326
Glyoxylic acid 343
GPC 137
Grignard reaction 482
Guaiacol 348
Guaiacol vanillin 515
Guetol 343
H
Halex reaction 247
Halide exchange 483
Hailer-Bauer reaction 460
Hammet-Deyrup acidity scale 326
HC1 163
HC104 163
Heptachlorodibenzodioxins 150
2,3,4,4,5,6-Hexachlorocyclohexa-2,5-dien 1-one 137
2,3,4,5,6,6-Hexachlorocyclohexa-2,5-dien 1-one 137
Hexachlorodibenzodioxins 150
Hexacychlohexadienone 153
Hexafluoroacetone 317
HF/BF 3 327,332
High pressure NMR 528
Hoffman degradation 248
HPLC 137,413
H2504 163
Hydrogen fluoride 309
Hydrogenation 483
Hydrogenation catalysts 337
Hydrogenation of 3,4-dichloronitrobenzene 340
Hydrogenation of halogenonitrobenzenes 336
556
Hydrogen peroxide 354,391
Hydroquinone 350,495
Hydroxybenzaldehydes 380,382,385
4-Hydroxybenzaldehyde 343
4-Hydroxybenzoic acid 385
4-Hydroxybenzylacetate 382,385
4-Hydroxybenzylalcohol 384,385
Hydroxylation 296
Hydroxylation of phenol 351,391,401
I
Influence of the solvent on "Halex" reaction 266
Inhibition constants 492
Intramolecular migration of the chlorine 166
L-Isobutyl chloropropionate 537
D-Isobutyl lactate 537
Isomerisation of 1,2,4-trichlorobenzene 107
Isotopic analysis by NMR 509
Isotopic fractionation 521
Isotopomers 506
K
KHF 2 268
KNH2 456
Knoevenagel reaction 17
Kolbe reaction 117
Kolbe Schmitt reaction 116
L
L-alanyl-L-proline
L-lactate dehydrogenase 537
Lactic acid enantiomers 541
Lanthanum phosphate 59
Latent Trigonal Center Concept 184
Leucine Enkephaline 407
Lewis acids 4,15,29,163
L.H.R.H. 407
Liquid chromatography 536
Lignin vanillin 515
L-lactate dehydrogenase 537
D-Lactic acid 536
L-Lactic acid 537
Lower Flammability Limit 435
Luteinising Hormone Releasing Hormone 407
Lysine 472
557
M
Mechanism for the carboxylation of phenol 119
Mechanism for the nitration of phenol 377
Mechanism of arylation 101
Meisenheimer's complex 246
Merrifield synthesis 407
Metallation of methylpyridines 450
Metallation of methylquinoleines 450
Methanol 48
Methionine 472
2-Methoxy-phenol 344
4-Methyl-acetophenone 11
2-Methyl-3-butyn-2-ol 63
Methylbutynol conversion 70
L-Methyl chloropropionate 537
Methyl formate 332
Methylhydroquinone 495
Methyl lactate 536
D-Methyl lactate 537
2-Methylphenol 38O
Michael addition 449
Minimum oxidizer concentration 436
Molecular inhibitors 493
Morpholohy of samarium phosphate 62
Mosher derivatives 546
m-trifluoromethylbromobenzene 92
Mutagenesis 197
N
NaNH 2 445,449,452
Naproxen 179
Natural vanillin 515
Niobium oxyphosphate 53
Niobium phosphate 57
Nickel 90
Ni(PPh3)4 93
Nitration of orthonitrophenol 372
Nitration of phenol 368
Nitrile hydratase 190
Nitrogen dioxide 368
Nitrogen trichloride 433
4-Nitrophenyl chloroformate 305
Nitrosation 368
Nitrosation of phenol 371
Nitrous acid 368
Nitric acid 368
NMR 23,528
N-Nitrosodiphenyl 495
N-Nitrosophenylhydroxylamine 495
558
O
O-Alkylation of catechol 49,57
O-Alkylation of guaiacol 53
O-Alkylation of phenols 49,62
Octachlorodibenzodioxins 150
O-methylation of catechol 54
O-methylation of 1,4-dihydroxybenzene 58
O-methylation of phenols 48
Onium hydrogenofluorides 254
Optical purity of lactic acid 538
Oragnolithium condensation 482
Orthonitrophenol 371,372
Overexpression of the nitrilase 195
Oxidation 380,394
Oxidation of alkylphenols 38O
Oxidation of 4-methylphenol 381
Oxidative cleavage of fluorinated silylbenzenes 86
P
Paints 487
Paints and varnishes strippers 486
Palladium 90,384
Paranitrophenol 368
Paranitrosophenol 371
Parathion 368
p-Chlorotrifluoromethylbenzene 93,94
Pd(OAc)2/TPPTS 421
2,3,4,4,6-Pentachloro cyclohexa-2,5-dien 1-one 136
Pentachlorodibenzodioxins 150
Peptides 406
Peptides synthesis 405
Peptidic synthesis 484
Phenol 368,495
Phenothiazine 496
Phenoxycyclohexadienones 161
2-Phenylethylamine 103
2-Phenyl phenyl chloroformate 3O5
Phosalone 368
Piperonal 343
"Pirkle" chiral stationary phase 543
Polychlorodibenzodioxines 132
Polychlorodibenzofurans 132
Polychlorophenols 129,132
Polychlorophenoxyphenols 156
Polychlorinated gem dichloro cyclohexadienones 136
Polytetrafluoroethylene 201
Potassium fluoride 257
Pre-activation of potassium fluoride 276
Preparation of hydroxybenzaldehydes 344
559
Progabide 294
Propionitrile 194
Proposed mechanism for the alkylation of phenol 60
Protocatechualdehyde 343
Protonation 108
R
Raney Nickel 337
Rare earth phosphates 53
RbF 269
Reaction of acetals with NaNH2 455
Reaction of bromothiophenes with NaNH2 457
Reaction of disodiosalts of diketones 445
Reaction of hydrazones with NaNH2 450
Reaction of sodium enolates of esters 448
Reaction of sodium enolates of ketones 447
Reactivity of polychlorinated gem dichloro cyclohexadienones 148
Reimer-Tiemann reaction 325,345
Release of amino-acids 473
Release of iodine salts 477
Retro-Halex reaction 255
Rhodifuse 477
Robinson annelation 240
S
Sabeluzole 294
Safety of chlorination reactions 431
Salicylic acid 122
Salmon calcitonin 410
Samarium phosphate 53,62
Samarium phosphate-cesium hydrogenophosphate 62
Sandmeyer hydrolysis 296
Sapphire tubes 528
Sappho technology 405
Schiemann reaction 244
Self-ignition 436
Silicone elastomers 478
Silylation of bromoarenes 85
Silylation of fluorobenzene 79
Smartamine 470
Sodium amide 445
Sodium hydroxymethanesulfinate 320
Sodium trifluoromethanesulfinate 320
Solubility of gases 532
Sommelet-Hauser rearrangement 457,458
Sonication 280
Sorbinil 294
Specific surface area 63
560
Stevens rearrangement 457
Styrene 492,500
Styrenic monomers 500
Superacidic medium 325
Superacids 326
Synthesis of aryl(methyldiethoxy)silanes 85
Synthesis of 4-fluoroanisole 305
Synthesis of polychlorinated gem dichloro cyclohexadienones 136
Synthesis of triflic acid 318
Synthesis of zeolite 398
T
TDA 273
Tertbutylcatechol 495
Tertbutylhydroquinone 495
Tetraalkylammonium fluorides 248
Tetrabuty lorthotitanate 393
2,2,4,6-Tetrachlorocyclohexa- 3,5-dien- 1-one 148
2,4,4,6-Tetrachlorocyclohexa-2,5-dien- 1-one 136,148
1,3,6,8-Tetrachlorodibenzodioxin 150
Tetrachlorophenol 144
2,3,4,6-Tetrachlorophenol 164
Tetraethylammonium hydroxide 346
Tetraethylorthosilicate 393
Tetraethylorthotitanate 393
Thermal explosion 433
Thermal stability of polychlorinated gem dichlorocyclohexadienones 148
Thermodynamic data for alkaline fluorides 260
TIC13 163
TIC14 163
Titaniumsilicalite 392
TPPTS 417
1,2,4-Trichlorobenzene 107
1,3,5-Trichlorobenzene 107
Trichlorobenzoquinone 144
2,4,6-Trichlorophenol 134
Triflic acid 328
Trifluoroacetic anhydride 39
Trifluoroacetophenone 42
Trifluoroacetylation 236
Trifluoroacetylation of aromatics 39
1-Trifluoroacetyl 2-methoxynaphthalene 43
Trifluorodithioesters 212
Trifluoroethyl-t-butylsulfoxide 205
Trifluoromethanesulphonic acid 163
c~-Trifluoromethyl epoxysulfone 217
13-Trifluoromethyl epoxysulfone 218
561
Trifluoromethyl iodide 322
Trifluoromethylation 313
Trifluoromethylation of aniline 321
Trifluoromethylation of aromatic compounds 321
Trifluoromethylation of disulfides 322
Trifluoromethylation of phtalic anhydride 318
Trifluoromethylation of potassium thiophenoxide 316
Trifluoromethylation of thiocyanates 318
Trifluoromethyl bromide 315,320
Trifluoromethyl halides 314
Trifluoromethyl iminium salts 210
Trifluoropyruvic thioamides 223
Trifluorothioamidium salts 207
Tris-(dioxa-3,6-heptyl)amine 272
U
Upper Flammability Limit 435
V
Vanillin 343,506
Vapor phase 48
Varnishes 487
Veratraldehyde 343
Veratrole 49
Vilsmeier-Haack-Arnold reagent 232
Vilsmeier-Haack reaction 325
2-Vinylpyridine 472
W
Water-soluble Pd(O) catalysts 416
Wheyland intermediate 34
Y
Yttrium phosphate 50
Z
Zeolite 30,391
Zinc triflinate 319
ZnCI2 19
562

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Industrial Chemistry Library, Volume 8

Volume 1 Progress in C1 Chemistry in Japan

Volume 2 Calcium Magnesium Acetate. An Emerging Bulk Chemical for

Volume 3 Advances in Organobromine Chemistry I

Volume 4 Technology of Corn Wet Milling and Associated Processes

Volume 5 Lithium Batteries. New Materials, Developments and Perspectives

Volume 6 Industrial Chemicals. Their Characteristics and Development

Volume 7 Advances in Organobromine Chemistry II

Volume 8 The Roots of Organic Development

The Roots of Organic

Rh6ne Poulenc Organic Intermediates Enterprise, 25 Quai Paul Doumer,

9 1996 Elsevier Science B.V. All rights reserved.

No part of this publication may be reproduced, stored in a retrieval system or transmitted in

This book is printed on acid-free paper.

Printed in The Netherlands

Bertrand LOUVET Ted ZIEMANN

C. JEANMART J.M. LEHN

We would like to thank the Rh6ne-Poulenc Organic Intermediates Enterprise for

We would also like to thank :

Jean-Roger DESMURS Serge RATTON

Friedel-Crafts acylation : interactions between Lewis acids / acyl chlorides and

Bismuth (III) salts in the Friedel-Crafts acylation

Friedel-Crafts acylation of aromatics using zeolites

COC12 catalyzed trifluoroacetylation of aromatics using trifluoroacetic anhydride

Catalysis by rare earth phosphate II 9 Selective O-methylation of phenols by

Catalysis by rare earth phosphate III : Characterisation of samarium phosphate and

Selective functionalisation of fluoroaromatics via organosilicon intermediates

Arylation of amines and alcohols catalyzed by nickel, copper or palladium

The isomerisation of 1,2,4-trichlorobenzene : a theoretical study

Carboxylation of hydroxy aromatic compounds

Access to polychlorophenols, chemistry of intermediates

Enzymatic hydrolysis of adiponitrile into 5-cyanovaleric acid, an intermediate for

Reagents with trifluoromethyl substituents

Fluorination of aromatic compounds by halogen exchange with fluoride anions

4-Fluorophenol : a key intermediate for agrochemicals and pharmaceuticals

Fluorodecarboxylation of arylchloroformate : a new access to fluoroaromatics

Mild trifluoromethylation of organic compounds

Formylation of aromatic compounds in superacidic medium

High selectivities in hydrogenation of halogenonitrobenzenes on Pd, Pt or Raney

Influence of the cation in condensation of glyoxylic acid on phenols in aqueous

Selective access to hydroquinone ,, Fuchsone ,, route

The mechanisms of nitration of phenol

Oxidation of alkylphenols to hydroxybenzaldehydes

Peptide synthesis by SAPPHO technology

A new and practical removal of allyl and allyloxycarbonyl group promoted by

Safety of chlorination reactions

Sodium amide in organic synthesis

Delivery systems for controlled release of active materials

Anisole : an excellent solvent

The use of phenolic compounds as free-radical polymerization inhibitors

Tracing back the origin of vanillin by SNIF-NMR

Lactic derivatives : methods for determining the optical purity of various

JEAN-ROGER DESMURS a), CLAUDE H E L E N E b), DANIEL MICHELET b)

a) Rh6ne-Poulenc Industrialisation, Centre de Recherche, d'Ing6nierie et de

This book is a collection of papers dealing with various aspects of inorganic

REBECCA ASHFORTH AND JEAN-ROGER DESMURS

Rh6ne-Poulenc Industrialisation, Centre de Recherche, d'Ing6nierie et de

The use of stoichiometrical quantities of Lewis acid results in the formation of a

Whilst the Friedel-Crafts acylation mechanism remains to be accurately

The activation of acid chloride by the Lewis acid (eqn. 2).

The aromatisation of the complex (eqn. 4).

INTERACTIONS W I T H LEWIS ACIDS OF M E T A L HALIDE TYPE

Complexation of acid chlorides

a) 0.2 M solution in CHzC12