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Amines, Aromatic 1

Amines, Aromatic
Amines, Aliphatic; Aminophenols; Aniline; Benzidine and Benzidine Derivatives; Naphthalene Derivatives;
Phenylenediamines and Toluenediamines; Toluidines and Xylidines are separate keywords
Peter F. Vogt, Mobay Chemical Corp., Pittsburgh, Pennsylvania 15205, United States(Chaps 2 – 4)

John J. Gerulis, Mobay Chemical Corp., Pittsburgh, Pennsylvania 15205, United States(Chap. 5)

1. Introduction . . . . . . . . . . . . . . 1 3.1.2. Catalytic Hydrogenation . . . . . . . 9


2. Physical and Chemical Properties 3 3.2. Nucleophilic Substitution . . . . . 12
2.1. Physical Properties . . . . . . . . . . 3 3.2.1. Exchange of Halide . . . . . . . . . . 13
2.2. Chemical Properties . . . . . . . . . 3 3.2.1.1. Activated Halides . . . . . . . . . . . 13
2.2.1. Acetylation and Similar Reactions . 3 3.2.1.2. Unactivated Halides . . . . . . . . . . 13
2.2.2. N-Alkylation and Condensations . . 4 3.2.2. Exchange of Hydroxyl and Ether
2.2.3. C-Alkylation . . . . . . . . . . . . . . 4 Groups . . . . . . . . . . . . . . . . . . 14
2.2.4. Cyclization . . . . . . . . . . . . . . . 4 3.2.3. Exchange of Sulfo Groups . . . . . . 15
2.2.5. Diazotization . . . . . . . . . . . . . . 5 3.3. Other Processes . . . . . . . . . . . . 15
2.2.6. Halogenation . . . . . . . . . . . . . . 6
4. Economic Aspects . . . . . . . . . . 15
2.2.7. Nitration . . . . . . . . . . . . . . . . . 6
5. Toxicology, Occupational Health,
2.2.8. Oxidation . . . . . . . . . . . . . . . . 6
and Environmental Protection . . 15
2.2.9. Sulfonation . . . . . . . . . . . . . . . 6
2.2.10. Reduction . . . . . . . . . . . . . . . . 7 5.1. Toxicity . . . . . . . . . . . . . . . . . 15
2.2.11. Other Reactions . . . . . . . . . . . . 7 5.2. Exposure Limits . . . . . . . . . . . 16
3. Production . . . . . . . . . . . . . . . 7 5.3. Protective Measures . . . . . . . . . 17
3.1. Reduction . . . . . . . . . . . . . . . . 7 5.4. Environmental Monitoring . . . . 18
3.1.1. Chemical Reduction . . . . . . . . . . 7 6. References . . . . . . . . . . . . . . . 18

1. Introduction Nomenclature. Aromatic amines most often


are named by adding the suffix “amine” to the
Definitions. Aromatic amines are organic name of the radical (or radicals) replacing one
nitrogen compounds that may be considered or more of the hydrogen atoms in ammonia, ex-
derivatives of ammonia (NH3 ) with at least one cept when some trivial name exists. According
of the hydrogen atoms replaced by an aryl group. to IUPAC nomenclature, the amino (NH2 ) or
The nitrogen must be bound directly to the aro- modified amino group (NHR, NRR ) is consid-
matic ring and so be able to interact with the ered a substituting group of the aromatic hydro-
aromatic π-electron system. The amine can be carbon. Therefore, these compounds are named
primary, secondary, or tertiary depending on as derivatives of benzene, toluene, naphthalene,
whether one, two, or three of the protons are and others, e.g., N,N-dimethylaminobenzene,
replaced by alkyl or aryl groups. The simplest C6 H5 N(CH3 )2 .
aromatic amine is derived from benzene and is Aniline is generally used as the parent struc-
called aniline or benzenamine (C6 H5 NH2 ). The ture for its derivatives unless a carbon atom
amines from toluene are referred to as toluidines is attached to the benzene ring or unless a
and from naphthalene as naphthylamines. Pyri- function of higher seniority than amino is
dine, pyrrole, and others in which nitrogen forms present in the molecule. Important derivatives
part of the ring are treated not as aromatic amines of aniline are named as such, e.g., N-methyl-
but as heterocyclic compounds. aniline, p-nitroaniline, chloroaniline, whereas
the sulfonic acids are named as derivatives

c 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim


10.1002/14356007.a02 037
2 Amines, Aromatic

of benzene (aminobenzenesulfonic acid) or decreased markedly in the United States to less


by their trivial names (metanilic acid for m- than 4 % of its former magnitude. Once over 700
aminobenzenesulfonic acid). If two of the hy- dyes listed in the Colour Index (C. I.) [2] were
drogen atoms of ammonia are replaced by aryl prepared from aniline and its derivatives; now
groups, the compounds are generally described only a few are produced in commercial quanti-
as diarylamines, with diphenylamine (DPA) ties.
as the parent compound. Aromatic amines The production and sales volume for the ani-
with two amino groups on the same benzene line derivatives as a group is generally grow-
ring are named phenylenedi-amines. Chemical ing only at the average rate of expansion of the
Abstracts called these compounds benzenedi- chemical market as a whole. United States pro-
amines in 1972. duction of many of them has ceased, and the sup-
ply is shifting to Japan, Korea, China, and other
Historical Development. In 1826 East Asian countries along with textile and dye
O. Unverdorben first obtained aniline by the production.
dry distillation of indigo and called it “krys- p-Nitroaniline [100-01-6], with a United
tallin”. In 1834 F. Runge found it in coal tar; States production of 6200 t in 1981 [3] and an
in 1841 C. F. Fritzsche prepared the same import volume of 630 t in 1983 [4], is probably
oily liquid by heating indigo with potash and the largest in this group. p-Nitroaniline is used
gave it the name “aniline,” from “anil” (the Por- mainly in the production of dyes, antioxidants,
tuguese word for indigo), which was identical and pharmaceuticals.
to the “benzidam” of N. N. Zinin (1841). The Anisidines, especially o-anisidine [90-04-0],
structure was proved by A. W. von Hofmann in with a limited United States production and im-
1843, who showed that it was obtained from the ports of 570 t in 1983 [4], is an important in-
reduction of nitrobenzene. This is still the most termediate for pigments and azo dyes. Japan re-
common method of production. Diphenylamine, ported a production of only 320 t in 1981 [5],
the simplest diarylamine, was first prepared by down from a high of 997 t in 1974. Chloroani-
von Hofmann in 1863 by destructive distilla- lines are used mostly for agricultural prod-
tion of triphenylmethane dyes. ucts. 4,4 -Diamino-2,2 -stilbenedisulfonic acid
[81-11-8] has maintained its strength as the
Major Uses and Importance. Analgesics largest volume raw material for optical bright-
and Antipyretics; Antioxidants; Azo Dyes; eners (United States use 5000 t in 1984).
Chemotherapeutics; Fungicides, Agricul- By far the largest share of the aniline con-
tural; Insect Control; Optical Brighteners; sumption (67 % of total 1984 consumption) is
Ozone; Photography; Pigments, Organic; used for the manufacture of isocyanates, primar-
Polyurethanes; Rubber 4., Chemicals and Addi- ily for 4,4 -methylenebis(phenylisocyanate),
tives; Weed Control are separate keywords. (MDI) to make polyurethanes. About 20 %
Aromatic amines are widely used as dye in- of the aniline consumption in the United
termediates, especially for azo dyes, pigments, States and in Western Europe versus 27 % in
and optical brighteners; as intermediates for Japan is used in the rubber industry for the
photographic chemicals, pharmaceuticals, and manufacture of antioxidants; vulcanization ac-
agricultural chemicals; in polymers via iso- celerators, such as 2-mercaptobenzothiazoles
cyanates for polyurethanes; and as antioxidants. (MBT) [149-30-4]; diphenylguanidines; for
They have been listed as corrosion inhibitors of condensation products of aniline with alde-
mild steel in the pickling process [1]. hydes and ketones, e.g., 2,2,4-trimethyl-1,2-
The oldest use of aromatic amines is as inter- dihydroquinoline (TMDHQ) [147-47-7] and its
mediates for dyes. Substituted anilines and es- polymer [26780-96-1]. Many herbicides, fungi-
pecially naphthylamines have been precursors cides, insecticides, and animal repellents are
of azo dyes since the middle of the 1800s. Even made from aniline or its derivatives. Between
with the replacement of the once predominant 1960 and 1980, United States aniline consump-
anthraquinone dyes with more and more azo tion grew at an average rate of 8.8 % annually
dyes derived from aromatic amines, the previous and then slowed down to an average rate of 3.1 %
strong demand of aniline in the dye industry has in the period 1980 – 1984.From 1980 to 1993
Amines, Aromatic 3

aniline consumption grew from 0.29 to 0.49 Mio The effect of the phenyl groups becomes even
t in th United States, in Western Europe from more dominant in diphenylamine (K B = 10−14 ),
0.30 to 0.59 Mio t, and in Japan from 0.07 to which can form salts only with strong acids that
0.16 Mio t [6]. are completely ionized in water, whereas triph-
Analgesics and sulfonamides are examples enylamine rarely forms salts and has no basic
of important pharmaceuticals derived from aro- properties.
matic amines. Many sulfa drugs start from ac- The physical properties of the most important
etanilide (antifebrin) [103-84-4], which itself aromatic amines are given under → Aniline.
has been used as an antipyretic and analgesic
agent.
Diarylamines readily donate their amine hy- 2.2. Chemical Properties
drogen atom to terminate various free-radical
reactions. For this reason they are widely used The chemical reactions of aromatic amines are
as antioxidants for various polymers and elas- similar to those of aliphatic amines. These reac-
tomers, and as stabilizers for nitrocellulose [7]. tions are influenced greatly by the basicity of
Nearly all commercial synthetic rubbers are pro- the amine nitrogen. Therefore, such electron-
tected with alkylated diphenylamines. Because withdrawing substituents as nitro and cyano re-
they darken on oxidation, diphenylamines can- duce the base strength of the amine nitrogen
not be used in light colored rubber and polymer when substituted in the ortho or para positions of
compositions. In this case N,N -di-β-naphthyl- the benzene ring(s). Aromatic amines undergo a
p-phenylenediamines are used instead. Some di- variety of chemical reactions. The ones of great-
arylamines retard the effect of intense gamma or est industrial significance are described in this
neutron radiation [8]. Diarylamines have been section.
used to stabilize sulfur trioxide, are used as cor-
rosion inhibitors in roofing asphalt, and are es-
sential in promoting cross-linking in poly(vinyl 2.2.1. Acetylation and Similar Reactions
chloride) [9] and in polyethylene [10]. Diaryl-
Primary and secondary aromatic amines re-
amines containing other functional groups, such
act with carboxylic acids, acid chlorides, an-
as amino or hydroxy, are used as dye interme-
hydrides, and esters to form a wide variety
diates [11], antiozonants, in color photography,
of commercially important amides. For exam-
and for hair dyeing and have been patented for
ple, p-acetanisidine, N-(4-methoxyphenyl)acet-
use in the image formation process in photo-
amide [51-66-1], is obtained in nearly theoret-
graphic films [12], [13].
ical yield, especially if the water formed is re-
moved (e.g., by distillation).
2. Physical and Chemical Properties

2.1. Physical Properties

All aromatic amines are either solids or liquids at


room temperature. The ones without other func- Acid chlorides, in general, give the best
tional groups are colorless, high-boiling mate- yields of pure product. Polymeric aromatic
rials having a characteristic odor. Most oxidize amides have been made from m- and p-
on exposure to air and darken. They are only phenylenediamines by reaction with iso- or
slightly soluble in water. terephthaloyl chloride. These so-called aramid
In contrast to the aliphatic amines, which fibers are marketed by Du Pont (United
are stronger bases than ammonia, the aromatic States) under the trade names Nomex, poly(1,3-
amines are only weakly basic with basicity phenyleneisophthalamide) [24938-60-1], and
constants K B  10−10 in water. Their onium as Kevlar, poly(1,4-phenyleneterephthalamide)
salts, therefore, are ionized in water and act as [24938-64-5] [14], [15] (→ Fibers, 4. Synthetic
Brønsted acids. Organic).
4 Amines, Aromatic

The reaction with phosgene gives isocyanates


or ureas depending on the reaction conditions.

The resulting products, as such, or after fur-


Commercially important isocyanates
ther acetylation of the hydroxy groups, are im-
are obtained from toluenediamine, methy-
portant coupling compounds for azo dyes.
lenedianiline, and other aromatic primary di-
Aldehydes, ketones, acetals, and orthofor-
amines. The monoisocyanates are used in such
mates give a variety of condensation products
agricultural products as herbicides, insecticides,
depending on the reaction conditions. For ex-
bacteriostats, fungicides, and pesticides. The
ample the reaction of aromatic amines with
major use of the diisocyanates is as intermedi-
ketones gives Schiff bases that can be hydro-
ates for polyurethanes.
genated to the alkyl-substituted amines. In the
Reaction with dimethylformamide in the
case of phenylenediamine derivatives, impor-
presence of sodium methoxide yields N-
tant antioxidants and antiozonants for rubber
arylformamides in 45 – 88 % yield [16], [17].
are produced, such as N-(1,3-dimethylbutyl)-
With aromatic aldehydes, Schiff bases (azome-
N  -p-phenylenediamine [793-24-8], which is
thines, Ar - CH = N - Ar ) are formed, and
sold under various trade names: Vulkanox
with chloral and hydroxylamine, oximinoac-
4020 (Mobay, Bayer), Flexone 7L (Uniroyal),
etanilides result in 80 – 91 % yield [18]. Dithio-
Santoflex 13 (Monsanto), UOP 588 (UOP),
carbamic acid ammonium salts are formed with
Wingstay 300 (Goodyear).
CS2 and NH3 in toluene. These salts give aryl
isothiocyanates (70 – 90 % yield) when treated
with phosgene [19].

Instead of toluene, water also can be used as


the solvent, followed by treatment with heavy
metal salts, e.g., Pb(NO3 )2 , CuSO4 , FeCl3 [20].
Using CS2 alone in ethanol or acetone, aromatic 2.2.3. C-Alkylation
amines react to yield N,N  -diarylthioureas.
With cyanogen chloride, N,N-diarylguani- Under Friedel – Crafts conditions, the aromatic
dines are formed in 90 % yield. ring can be alkylated with alkenes to form the
corresponding alkylanilines at temperatures of
200 – 280 ◦ C and 20 MPa (200 bar). The alky-
lation takes place in the positions ortho to
the amino group and if one is occupied only
2.2.2. N-Alkylation and Condensations monoalkylation results [25–29].
These compounds are used as chain exten-
Alkylation of aromatic amines to the cor- ders for polyurethanes (e.g., 3,5-diethyl-2,4-
responding N-alkyl- and N,N-dialkylamines diaminotoluene), and for herbicides (e.g., 2,6-
is generally of importance only for aniline diethylaniline and 2-methyl-6-ethylaniline).
(→ Aniline), [21–24].
Substituted mono- or diethanolamines can be
produced in high yields from ethylene or propyl- 2.2.4. Cyclization
ene oxide and an aromatic amine.
Aromatic amines undergo numerous cyclization
reactions to give a variety of N-heterocyclic
Amines, Aromatic 5

compounds. Quinoline derivatives are obtained Diphenylamines form carbazoles when


with aldehydes and ketones. Aniline condenses heated with iodine as the catalyst, whereas heat-
with acetone in the presence of hydrochloric ing diphenylamine with sulfur in the presence
acid, p-toluenesulfonic acid, acidic clays, or of various catalysts results in phenothiazine
acidic ion-exchange resins to give 2,2,4-trimeth- [92-84-2].
yl-1,2-dihydroquinoline (TMDHQ) [147-47-7],
which on oligomerization is used as an antioxi-
dant in the rubber industry. 2.2.5. Diazotization

Primary aromatic amines react with nitrous acid


to form diazonium salts.

With aldehydes and styrenes, 1,2,3,4-


tetrahydroquinolines result [30], and with glyc- This reaction has considerable general util-
erol or acrolein, quinoline [91-22-5] is formed ity and forms the basis for azo dye production
in the Skraup synthesis [31]. Many of the sub- by coupling of the diazonium salt with aromatic
stituted quinolines are intermediates for an- amines and phenols (→ Azo Dyes). In the Sand-
timalarial agents. In the Combes quinoline meyer reaction the diazo group is replaced by
synthesis [32], aniline and 1,3-diketones are chlorine from a CuCl solution. The reaction also
condensed to make 2,4-disubstituted quino- is used for the introduction of Br, CN, I, and
lines. With hydroxyketones or with haloke- sometimes also aryl and alkyl groups. Secondary
tones, aromatic amines yield substituted indoles aromatic amines react with nitrous acid to form
[33]. Aromatic amines and 2-aminophenols N-nitroso compounds in the same way as do
condense with CS2 to form 2-mercapto- aliphatic amines.
1,3-benzothiazole. With sulfur monochloride Tertiary aromatic amines do not give N-
(S2 Cl2 ) 1,2,3-benzodithiazole is formed and nitroso compounds but undergo C-nitrozation.
can be hydrolyzed to the corresponding 2-
aminothiophenol in yields of up to 93 % [34].

Diaryldiazenes are obtained by the oxidation


of aromatic amines with KMnO4 in aqueous
KOH [36] or by the reaction of aromatic amines
with aromatic nitrosamines [37].

o-Phenylenediamines react with nitrite at


neutral to slightly acidic pH to undergo ring clo-
Benzofuroxane [480-96-6] results from sure to the corresponding benzotriazoles [38],
the treatment of o-nitroaniline with sodium [39]; these are important corrosion inhibitors for
hypochlorite [35]. Cu-containing alloys.
6 Amines, Aromatic

2.2.6. Halogenation

The chlorination of aniline salts in aqueous


solutions is so fast that only the trichloroani-
line can be isolated [40]. Chlorine in the pres-
ence of hydrogen chloride in an anhydrous Oxidation with MnO2 or Na2 Cr2 O7 in sulfu-
solvent yields 2,4,6-trichloroaniline [634-93-5] ric acid leads to quinones; e.g., 1-naphthylamine
[41]. In aqueous sulfuric acid at 110 ◦ C ani- is oxidized to 1,4-naphthoquinone. Oxidation of
line gives chloranil, 2,3,5,6-tetrachloro-2,5-cy- aniline with dichromate or chlorate in the pres-
clohexadiene-1,4-dione [118-75-2], in 91 % ence of copper or vanadium yields aniline black.
yield [42].

2.2.9. Sulfonation
2.2.7. Nitration
Reaction of aromatic amines with sulfuric acid,
Generally, nitration of aromatic amines with oleum, or sulfur trioxide leads to the introduction
nitric acid results in concomitant oxidation of of the sulfonic acid group mainly in the positions
the amino function. If it is protected, predom- ortho or para to the amino group. 2-Methoxy-
inantly the para- and ortho-nitro isomers are 5-methylaniline [120-71-8] is sulfonated with
formed. Nitration of p-acetanisidine [51-66-1] in fuming sulfuric acid to 4-amino-5-methoxy-2-
sulfuric acid yields 2-nitro-4-acetaminoanisole methylbenzenesulfonic acid [6471-78-9] (the
[50651-39-3] as the major product. This com- intermediate to make the dye FD & C Red 40
pound can be hydrolyzed subsequently to the [25956-17-6] [2]).
free amine.

The nitration of p-acetaminotoluene


1-Naphthylamine [134-32-7] is sulfonated
[103-89-9], however, leads predominantly to
with oleum at room temperature to give 1-
substitution ortho to the acetamino group.
amino-4- [84-86-6] and 5-naphthalenesulfonic
acid [84-89-9].
Many aromatic amines also sulfonate via the
baking process in which the amine sulfate is
heated to 220 ◦ C under vacuum to yield ei-
ther the para- or ortho-sulfonic acid. The pro-
cess is very selective and gives high yields
2.2.8. Oxidation of the p-sulfonic acid, e.g., aniline leads to
sulfanilic acid (4-aminobenzenesulfonic acid
Aromatic amines are very susceptible to oxida- [121-57-3]). If the para position is occupied,
tion and most turn brown or black if exposed sulfonation takes place ortho to the amino
to air for extended periods. The course of oxida- group; e.g., p-toluidine [106-49-0] gives 2-
tion depends on the nature of the oxidizing agent. amino-5-methylbenzenesulfonic acid [88-44-8]
With hydrogen peroxide and percarboxylic acids [45]. 1-Naphthylamine yields only 1-amino-4-
(e.g., peracetic acid), oxidation to the corre- naphthalenesulfonic acid [84-86-6], also known
sponding N-phenylhydroxylamine or to nitroso as naphthionic acid [11]. This compound is used
or nitrobenzene may occur, depending on tem- as a dye intermediate for Congo Red, Fast Red
perature and the amount of oxidizing agent A, Azo Rubin, and others.
present [43]. 2,6-Dichloroaniline [608-31-1] is
oxidized to 2,6-dichloronitrobenzene by tri-
fluoroperacetic acid [44].
Amines, Aromatic 7

2.2.10. Reduction Only the first two reaction types are of gen-
eral importance. Chemical rearrangements and
Hydrogenation of aromatic amines results in degradations seldom lead to clean reaction prod-
the corresponding cycloaliphatic amines. This ucts in high yield.
process is of greatest importance with amines
that do not contain other easily reducible func-
tional groups. Such catalysts as Raney nickel, 3.1. Reduction
cobalt – alumina, and more exotic ones are
used [46]. Hydrogenation of aniline using an All aromatic carbon – nitrogen compounds with
alumina–silicate catalyst [47] leads to 80 % nitrogen oxidation numbers  − 2 can be re-
cyclohexyl-amine [108-91-8] and 15 % dicy- duced to aromatic amines (for a summary see
lohexylamine [101-83-7]; bis(4-amino-3-meth- [52]). Only the reduction of nitro compounds
ylphenyl)methane is reduced in 89 % yield has gained widespread industrial acceptance,
on an alumina catalyst [48]. Hydrogenation be-cause the starting materials can be prepared
of aniline over a Raney nickel catalyst gives with a high degree of specificity for a wide va-
95 % dicyclohexylamine [49]. Good results riety of compounds. Other aromatic nitrogen
have been obtained with rhodium catalysts. 4,4 - compounds cannot be produced economically
Methylenedianiline (MDA) [101-77-9] has been enough to be used as starting materials for aro-
hydrogenated on a 5 % rhodium – aluminum cat- matic amines.
alyst to give bis(4-aminocyclohexyl)methane in
good yield [48].
3.1.1. Chemical Reduction
2.2.11. Other Reactions In the chemical reduction of aromatic nitro
compounds to aromatic amines, the hydrogen
In a reversal of the Bucherer reaction, naphthy-
that becomes attached to the nitrogen normally
lamines can be hydrolyzed to the corresponding
comes from the solvent, in many cases water,
naphthol in yields approaching 100 %. Sulfonic
or from the added acid. The most important re-
acid groups on the ring accelerate the reaction
ductants are metals, such as iron, tin, and zinc;
[50], [51].
phosphorus, sulfides, sulfites, and sulfur dioxide
are used also. Because oxidation of the reduc-
ing agent may result in a useless waste product,
which has to be removed in an environmentally
safe way, chemical reduction has lost its impor-
tance in favor of catalytic reduction for the large-
scale production of products.
3. Production Reduction with Iron. The reduction with
Generally, three types of reactions are used for iron in dilute acid was described by Béchamp in
the production of aromatic amines: 1854 and the process still carries his name. Iron
is still the most important metal for the reduc-
1) Reductions: using such metals as Fe, Zn, Sn, tion of nitro compounds to aromatic amines, and
and Al or their salts; sulfur compounds; elec- generally, all nitro compounds can be reduced
trochemical methods; and catalytic hydro- to the corresponding aromatic amines with iron
genation in water and acid. Side products are expected
2) Nucleophilic substitutions: replacement of only if the molecule contains other substituents
such substituents as halogen, hydroxyl, that can be reduced easily (e.g., nitroso, azo, hy-
alkoxy, and sulfo groups drazine, sulfoxide, and other nitro groups) or
3) Rearrangements and degradations: includ- can be saponified [52]. Carbon – carbon multi-
ing the benzidine and Beckmann rearrange- ple bonds are not attacked. Bayer (Germany)
ments, and the Schmidt and Hofmann degra- and Mobay (United States) both use this iron
dations.
8 Amines, Aromatic

reduction for the production of iron oxides with hydrogensulfide in the presence of ammonia can
aniline as the resulting side product. For a further be used [57], [60].
discussion, → Aniline, Section 2.3, and [52–55]. The reduction of aromatic nitro, nitroso, or
Another example of industrial impor- azo compounds with sulfite or hydrogensulfite
tance is the reduction of 4,4 -dinitro-2,2 - to the corresponding aromatic amines is known
stilbenedisulfonic acid to 4,4 -diamino-2,2 - as the Piria reaction (Piria, 1851). In aqueous
stilbenedisulfonic acid [81-11-8], which is still or alcoholic medium, mainly N- and C-sulfonic
done exclusively using iron in neutral medium. acids result [61]. On treatment of these with
Also, many small-volume dye intermediates are mineral acid, a mixture of aromatic amines and
reduced with iron. aminobenzenesulfonic acids is formed.
The quinone oxime intermediate facilitates
Reduction with Other Metals. Aromatic substitution of hydrogensulfite onto the aro-
nitro groups also can be reduced with zinc, tin, matic ring in the reduction of ortho- and para-
and aluminum, or their salts in acidic, neutral, nitrosophenols or naphthols:
or alkaline medium [52].
These reducing agents are generally very
mild and do not interfere with, e.g.,-OH, -OR,
-COOH, -CO-Ar, halogen, or -CN groups. How-
ever, except for laboratory applications they are
not of any industrial significance. Instead, cat-
alytic hydrogenation is used because of waste
water regulations.

Reductions with Sulfide, Hydrogensulfite, If the hydroxyl group is in the para position,
and Sulfur Dioxide. Compounds with sev- the sulfo group will enter in the 2 – position. Sub-
eral nitro groups can be reduced to nitro stituents in the 3 – position (e.g., Cl or COOH)
amines if a stoichiometric amount of sulfide are replaced by H [62].
is used [56], [57]. In this case, sodium or Only after methods were found to reduce the
ammonium sulfide is the reagent of choice. amount of C-sulfonation did reduction with SO2
m-Nitroaniline [99-09-2] can be obtained in gain industrial importance. This reduction is best
87 % yield from 1,3-dinitrobenzene [56]: carried out in a closed system in strongly acidic
media (e.g., 15 – 40 % aqueous sulfuric acid) at
temperatures of 80 – 180 ◦ C with iodine, hydro-
gen iodide, or iodine salts as catalysts. Glass-
lined reactors are the best [63].
Sodium dithionite reduces the aromatic nitro
and nitroso group nearly quantitatively [64]:

The addition of sulfur reduces the required


amount of sodium sulfide. 4-Nitrotoluene
is reduced nearly quantitatively to 4- When possible, reductions with sulfide, sul-
aminobenzaldehyde [556-18-3] with sodium fite, and other sulfur compounds have been re-
sulfide and sulfur [58], [59]. placed by catalytic hydrogenations, resulting in
Azo groups stay unchanged if the reduction cleaner reaction mixtures, less corrosion (result-
with sodium sulfide is carried out at 40 – 70 ◦ C, ing when SO2 is used), and fewer environmental
if the reaction times are kept short, and if sulfide problems.
is not in excess. However, halogen substituents
are replaced easily by -SH [56], [57]. When ex-
Electrochemical Reduction of Nitro Com-
cess reducing agent is not a problem, ammonium
pounds. Electrochemical reduction is generally
Amines, Aromatic 9

a special case of the chemical reduction. An in- [69], [70]. Ideally 1 mol of hydrazine gives four
organic compound is used as the reducing agent; reduction equivalents depending on the pH and
the oxidized form is then reduced at the cathode catalyst, but in practice fewer are formed, and an
and can react again. excess of hydrazine must be used. Carbon – car-
bon double bonds and carbonyl groups are not
attacked [71]. Depending on the reaction condi-
tions, the intermediates of the reduction can be
isolated.

The cathode is made of Pb, Sn, Ni, or Cu, and


15 – 20 % hydrochloric acid is used on the cath-
ode side of a semi-permeable membrane. On the
anode side 30 % sulfuric acid is employed [65]. In the reduction using hydrazine without a
Although electrochemical reductions have catalyst, carbonyl-containing compounds are re-
been known for more than 100 years, they have duced to the corresponding hydroxy compounds
remained mostly curiosities and have not been via the hydrazone intermediate [72]. The reduc-
used commercially to any great extent in the tion of aromatic nitro compounds with hydrazine
past. However, interest is growing as better has no advantage over catalytic reduction with
cells and membranes become available. Some much cheaper hydrogen, except for laboratory
products have been produced electrochemi- work and very small product volumes, where it
cally, especially in India; e.g., p-aminobenzoic allows use of normal pressure. Examples of cat-
acid [150-13-0], p-aminophenol [123-30-8], and alytic reduction with hydrazine hydrate on Pd / C
many others have reached pilot-plant scale or be- and on Raney nickel can be found in [70], [73–
yond [66], [67]. 75].

3.1.2. Catalytic Hydrogenation

Reduction with Hydrazine. The reduction


of aromatic nitro compounds with hydrazine
represents, in most cases, a special variation
of catalytic hydrogenation, where hydrazine is Cyclohexene also has been used on a labora-
the source of the hydrogen. The mechanism of tory scale as a hydrogen source for the catalytic
decomposition of hydrazine on precious-metal hydrogenation of polynitro compounds [76].
catalysts differs depending on the pH value, with
the amount of hydrogen generated per mole of Reduction with Hydrogen. Primary aro-
hydrazine increasing with higher pH [68]. At matic mono- or polyamines generally are pro-
weakly alkaline or neutral conditions, 1 mol H2 duced by the catalytic hydrogenation of the cor-
is generated: responding nitro compound, either in the vapor
or in the liquid phase, with or without a solvent
[46], [77–79]. All large-scale products, such
as aniline (→ Aniline), or o- and p-toluidine
If barium hydroxide or calcium carbonate is (→ Toluidines), 2,4- and 2,6-diaminotoluene
added, 2 mol of H2 are formed: (→ Phenylenediamines and Toluenediamines),
and 1-naphthylamine (→ Naphthalene Deriva-
tives), are produced in this way. For the reaction
meachanism see [80], [81].
The reduction with hydrazine sometimes oc- Catalytic reduction of nitro compounds is
curs without a catalyst but in most cases is done very exothermic. In the hydrogenation of ni-
in the presence of a hydrogenation catalyst, such trobenzene in the liquid phase, 553.5 kJ/mol are
as Raney nickel, Pd on carbon, or Pd on CaCO3 released, whereas hydrogenation in the vapor
10 Amines, Aromatic

phase at 200 ◦ C releases 493.2 kJ/mol. Unless Deionized water can be added to remove the heat
this heat is dissipated properly, explosions can of reaction by continuous evaporation. The wa-
result, especially if thermal decomposition of ter also affects the activity of the catalyst; e.g.,
the nitro compound occurs or condensation re- the more water present in the batch hydrogena-
actions are initiated as with chloro – nitro com- tion of dinitrotoluene without solvent, the lower
pounds [52]. To reduce these hazards, the con- the activity of the Pd on carbon catalyst [91],
centration of nitro compound, the amount and [92]. If the amine shows good water solubil-
partial pressure of hydrogen, the temperature, ity, water can be used as the solvent. Water also
and the activity of the catalyst are controlled. can be used in cases where the nitro compound
Vapor-Phase Hydrogenation. Industrial use forms water-soluble salts with alkali, such as
of vapor-phase hydrogenation is limited by the with nitrocarbonic or sulfonic acids. Sometimes
boiling point and the thermal stability of the nitro 30 – 40 % solutions of the amine in water can be
compounds. Most aniline produced in the United produced directly in the hydrogenation reactor
States is made by vapor-phase hydrogenation without an additional concentration step [52],
of nitrobenzene over copper – silica catalyst in [93].
 99 % yield, whereas Pd – alumina is used by Solvents. Methanol and 2-propanol are pre-
Bayer in Europe and Brazil. ferred; also dioxane, tetrahydrofuran, and N-
Liquid-Phase Hydrogenation. It is prefer- methylpyrrolidone have been used; e.g., o-
able to hydrogenate most aromatic nitro com- nitrophenol is hydrogenated in good yields
pounds in the liquid phase. In this case the pres- in methanol with Pt on carbon. The concen-
sure and temperature can be changed indepen- tration of the nitro compound can vary sub-
dently. The temperature is limited by the hydro- stantially. According to [94] a 33 wt% solu-
genation reaction of the aromatic ring which oc- tion of dinitrotoluene in methanol is fed into
curs above 170 – 200 ◦ C. Normally the reduction the hydrogenation reactor, whereas Olin rec-
is carried out at 100 – 170 ◦ C. Some compounds ommends a 15 – 35 wt% solution [95]. In the
(e.g., 1-bromo-4-nitrobenzene) must be hydro- hydrogenation with a water-immiscible sol-
genated at lower temperatures (20 – 70 ◦ C) to vent, such as toluene, the water must be re-
avoid cleavage of sensitive groups. Pressures of moved, as in solvent-free hydrogenation, in or-
1 – 15 MPa (10 – 150 bar) are used industrially. der to maintain the activity of the catalyst.
For the hydrogenation of sensitive nitro aromatic Very polar nitro compounds, e.g., bis(4-amino-
compounds lower pressures are advisable (0.1 – 3-nitrophenyl)sulfone, are hydrogenated in liq-
5 MPa, 1 – 50 bar) [82–84]. Generally the pres- uid ammonia [96].
sure only influences the speed of the reaction by Hydrogenation Catalysts. For vapor-phase
increasing the phase transfer and saturation of hydrogenation only metals or metal derivatives
the catalyst with hydrogen. The reaction time on supports are used in fixed beds or fluidized
depends on many parameters, such as hydro- beds, whereas metals with large surfaces (Raney
gen pressure, concentration, temperature, activ- nickel) or metals and metal derivatives on sup-
ity and concentration of the catalyst, and mixing. ports with large surfaces (carbon, alumina) are
Often an induction period is observed, which is used for the liquid-phase hydrogenation. In prac-
independent of the activity of the catalyst [85], tice only Raney nickel, Raney nickel – iron,
[86]. Generally the reaction time is from a few Raney cobalt, and Raney copper are used as
minutes to several hours. Considerably longer pure-metal catalysts because of their relatively
times are necessary if these parameters are not low cost. Precious-metal catalysts, such as Pt
optimized. and Pd, generally are used at concentrations
Because of the exothermic nature of the reac- of 0.5 – 5 wt% on support material with large
tion, many safety precautions must be observed, surfaces, such as charcoal, silica, aluminum
especially for the industrial hydrogenation of oxide, or alkaline-earth carbonates. The pow-
aromatic polynitro compounds in the liquid dered form of the catalyst is used in slurries and
phase without solvents [87–89]. The exothermic the pellet form in fixed beds [97]. Because the
reaction is controlled by the continuous addi- support material may activate or deactivate the
tion of small quantities of the nitro compound, catalyst [81], it is important to find the optimum
thus keeping its concentration below 2 % [90]. conditions that not only allow the catalyst to
Amines, Aromatic 11

be used repeatedly and to be regenerated but out loss of activity or selectivity while chlo-
also are economical for large-scale (> 500 t/a) rine cleavage was kept  0.1 %; yield of 2,5-
products [88], [98]. Decomposition and oxi- dichloroaniline [95-82-9] was 97 %. Also a 1 %
dation products generally deactivate catalysts Pt on carbon catalyst was treated with dimeth-
by blocking the active surfaces [81]. Even in ylsulfoxide in water before it was used in the hy-
small quantities, compounds containing sul- drogenation of chloronitro aromatic compounds
fur, arsenic, or antimony are catalyst poisons. in 98.4 % yield [104]. Additional treatment with
However, with increased oxidation state (e.g., hydrazine hydrate increased the activity of the
As3− → As5+ or S2− → S4+ ) these compounds catalyst with yields of 99.6 % for 2-chloroaniline
have less effect as catalyst poisons. With noble [95-51-2]. Modification of Pt on carbon with
metal catalysts, such ions as halide, sodium, and lead, bismuth, or silver salts for the hydro-
magnesium, cobalt metal, and CO2 reduce the genation of chloronitrobenzene at 100 ◦ C gave
activity. Nitro aromatic compounds containing chloroaniline in 99 % yield, whereas untreated
sulfur are better reduced with molybdenum or catalyst at 77 ◦ C resulted in 100 % hydroly-
tungsten sulfide [99], or with nickel catalysts sis [105]. 3-Bromonitrobenzene has been hydro-
that contain zinc or calcium carbonate [102]. In genated using Pt on barium or strontium carbon-
the hydrogenation with Pd on carbon, copper ate at 20 ◦ C, 0.1 MPa (1 bar) [106]. The catalytic
salts are catalyst poisons, whereas in the hy- activity of Raney nickel can be modified also.
drogenation of dinitrotoluene, both nitrophenol For the hydrogenation of 3-chloronitrobenzene
and nitrocresol are strong catalyst poisons and the addition of 0.1 – 20 % of thiocyanate to the
decomposition activators [46], [101]. catalyst has proved beneficial [84].
Hydrogenation of Halide-Substituted Nitro Equipment and Construction Materials. Hy-
Compounds. Whereas most aromatic nitro com- drogenation in the vapor phase is carried out
pounds are hydrogenated at 100 – 170 ◦ C, lower only continuously, but in the liquid phase it
temperatures are used with halogen-substituted can be done in batch or continuous operation
nitro compounds to avoid halide – hydrogen ex- de-pending on volume. Continuous liquid-phase
change. The catalysts have reduced activity, hydrogenation is used exclusively for a relatively
e.g., sulfide-poisoned metal catalysts. 1-Chloro few large-scale products, such as dinitrotoluene,
2 – nitrobenzene can be reduced at 80 ◦ C and nitrotoluene, and 1-nitronaphthalene [92]. The
1.0 – 5.0 MPa (10 – 50 bar) with a 5 wt% Pt on vast majority of aromatic amines have small
carbon catalyst, which is treated at 22 ◦ C with annual volumes (< 500 t) and are produced by
dilute sulfuric acid, then with H2 followed by batch hydrogenation with catalyst slurries. This
H2 S [102]. The catalyst can be recycled up allows fast changeover from one product to an-
to 30 times without any further purification. other, which is not possible when fixed-bed cat-
The reaction time is 30 min per batch and only alysts are used. The intensive mixing of the three
0.1 % chlorine is cleaved. Therefore, a product phases (hydrogen gas, nitro compound solution,
of high purity and stability can be obtained in and solid catalyst) is of great importance. The
nearly quantitative yield. Also 3-chloroaniline transport of the reactants toward the active cen-
[108-42-9], 4-chloroaniline [106-47-8], 2,5- ters of the catalyst, and of the products away
dichloroaniline [95-82-9], 3,4-dichloroaniline from them, must be rapid for good reaction.
[95-76-1], 2,6-dichloroaniline [608-31-1], 6- Although batch catalytic hydrogenations tra-
chloro-2-aminotoluene [87-60-5], and 4-chloro- ditionally are done in stirred, steel or stain-
2-aminotoluene [95-79-4] can be prepared in less steel autoclaves (Fig. 1), improvements
high yield and purity by this method. in performance are being realized increas-
A similar sulfide-poisoned catalyst has been ingly through loop reactor technology. Produc-
described [103], in which 5 % platinum on tion units employing the loop reactor princi-
carbon catalyst was treated with 1 % aque- ple (Fig. 2) have been available for the last two
ous sulfuric acid, hydrogen, and sodium sul- decades and have been applied successfully to
fide solution. 2,5-Dichloronitrobenzene was hy- the catalytic hydrogenation of aromatic nitro
drogenated with this catalyst at 90 – 100 ◦ C, compounds by Buss (Basel, Switzerland) [107–
1.0 – 3.0 MPa (10 – 30 bar), 40 min per batch. 110]. The major advantages reported over stirred
The catalyst was recycled at least 30 times with- autoclaves are increased heat and mass trans-
12 Amines, Aromatic

fers and improved reaction selectivity. In con- ment at the nozzle exit. The autoclave acts as a
tinuous hydrogenation, generally shorter batch holding vessel. A loop reactor allows for simple
cycle times and higher product yields result. In and reliable transfer from pilot plant to produc-
addition catalyst usage is often lower. tion, because the scaleup is based only on the
nozzle configuration and pump-around rate. In
the case of a stirred autoclave, scaleup is more
difficult because of the ratio between a small
pilot vessel and a large production vessel (e.g.,
1 : 1500 to 1 : 12500). Temperature and concen-
tration gradients as well as longer reaction times
in the production vessel often result in undesired
side reactions and a decreased product yield.
Loop reactors minimize these problems by limit-
ing the reaction to a highly agitated, well-defined
zone, with a considerably decreased cycle time.

Figure 1. Conventional stirred autoclave system [107–109] 3.2. Nucleophilic Substitution


a) Reactor with internal coil; b) Recirculation pump;
c) Heater; d) Cooler; e) Catalyst preparation vessel; f) Agi- Practically all non-carbon substituents on the
tator; g) Expansion vessel; h) Hydrogen; i) Reactant; j) Sol-
vent; k) Catalyst; l) Product; a Cold water supply; b Cold aromatic ring can be exchanged for amino
water return; c Temperature control; d Pressure control groups. However, only a few of these substitu-
tion reactions are of industrial importance, in-
cluding:
1) Exchange of halide
2) Exchange of hydroxyl and ether groups
3) Exchange of sulfo groups

Figure 2. Loop reactor system [107–109]


a) Reactor with mixing nozzle; b) Primary loop recircu-
lation pump; c) Primary loop heat exchanger; d) Catalyst
preparation vessel; e) Secondary loop recirculation pump;
f) Secondary loop cooler; g) Secondary loop heater; h) Sec-
ondary loop expansion vessel; i) Seal fluid cooler; j) Hydro-
gen; k) Reactant; l) Solvent; m) Catalyst; n) Product; a Cold
water supply; b Cold water return; c Temperature control;
d Pressure control; e Flow control

The basic operating principle of a loop reac-


tor is shown in Figure 3 [107–110]. The batch
charge and slurry-type catalyst are pumped con-
tinuously through an external heat exchanger to
a mixing nozzle in the top head of the autoclave.
The nozzle acts as an eductor, and the action
of the slurry passing through it creates intimate
gas – liquid – solid mixing. The chemical reac- Figure 3. Operating principle of a loop reactor
tion primarily takes place in a well-defined zone a) Autoclave; b) Mixing and reaction zone; c) Reactant,
solvent, catalyst suspension; d) Flow; e) Primary loop re-
inside the nozzle prior to gas – liquid disengage- circulation pump; f) Primary loop heat exchanger
Amines, Aromatic 13

3.2.1. Exchange of Halide 3.2.1.2. Unactivated Halides


Exchange of halide is universally useful for the Unactivated halides undergo elimination – ad-
production of amines with mono-, poly-, or hete- dition reaction through a benzyne intermediate.
rocyclic substituents as well as for diaryl-amines This requires higher temperatures than nucle-
[111–113], and arylpolyamines [114], [115]. ophilic aromatic substitution and results in iso-
Many of the products are used as dye or pigment meric mixtures if other substituents are present.
intermediates. The substitution of a halide on the The industrial usefulness of this reaction is
aromatic ring with ammonia or with amines oc- therefore limited.
curs via two different mechanisms, depending
on whether the halide is activated or unactivated.

3.2.1.1. Activated Halides


Aromatic halides containing ortho and/or
para electron-withdrawing substituents, e.g.,
- NO2 or - CN, undergo nucleophilic aro-
matic substitution [116], [117]. Both o- and
p-chloronitrobenzene react with ammonia at Chlorobenzene and ammonia react at a rea-
170 ◦ C, whereas 2,4-dinitrochlorobenzene re- sonable rate only above 200 ◦ C [122], generally
quires only 70 ◦ C and no catalyst [118], [119]. with the addition of a catalyst, such as copper(I)
and copper(II) salts or their amine complexes
[115], [123], [124]. Also metal amides (e.g.,
NaNH2 , LiNEt2 ) are used. The energy needed
to exchange the halide is the reverse of the order
for activated halides: F  Cl  Br > I

The more basic the amine (unless it is ster- Reaction Conditions. The reaction is gener-
ically hindered), the faster the reaction with ally carried out in aqueous suspension or in so-
the haloaromatic compound. In the reaction lution at elevated temperature and pressure. Be-
of methylamine and ammonia with a solution cause the reaction of arylhalides with amines
or suspension of 2,4-dinitrochlorobenzene at is exothermic, it is especially important in the
higher temperature, good yields of N-methyl- batch process to watch the temperature while
2,4-dinitroaniline are obtained, rather than 2,4- heating to reaction conditions. This normally
dinitroaniline [120]. poses no problem in the continuous reaction. The
Reaction Conditions. 4-Nitroaniline hydrogen halide released during the reaction is
[100-01-6] is produced in an agitated tita- neutralized either by excess ammonia or by the
nium reactor in 99.3 % yield by reacting 4- addition of bases, such as sodium carbonate or
chloronitrobenzene [100-00-5] with a tenfold calcium oxide [113]. With excess amine the re-
excess of aqueous ammonia at 175 ◦ C and action generally proceeds with nearly quantita-
4.2 MPa (42 bar) for 10 h [121]. tive yield. With an insufficient excess of strongly
4-(4-Methylanilino)−3-nitrobenzenesulfon- basic amines in aqueous solution, side reac-
amide tions such as hydrolysis or the formation of di-
is prepared in 90.1 % yield by heat- arylamines, can occur. Cyano groups are hy-
ing 4-chloro-3-nitrobenzenesulfonamide and drolyzed to amides in aqueous solution, but this
p-toluidine [106-49-0] for 5 h at 130 ◦ C reaction can be avoided by using an inert sol-
[111]. 4-Nitrodiphenylamine [836-30-6] (pre- vent. Carboxylic acids are converted easily to the
cursor for antiozonants for rubber) is made corresponding amide by reaction in nonaqueous
by the condensation of 4-nitrochlorobenzene media.
with aniline in chlorobenzene. N-Alkylated p-
phenylenediamine derivatives, however, cannot
be produced in aqueous medium.
14 Amines, Aromatic

Material of Construction. The presence of resorcinol and ethanolamine or 3-amino-


halides and amines at elevated temperature and 1 – propanol [128]. A similar process uses an
pressure can cause severe corrosion; therefore, acid activated alumina – silica catalyst [129].
the selection of materials and equipment be- 3) In a multiphase system, nitrophenols and am-
comes difficult. Autoclaves of normal steel can monia react to yield nitroanilines, preferably
be used for laboratory work, but considerable re- using a solvent in which the reaction product
duction in the wall thickness must be expected has good solubility [130]. Many of the new
(several millimeters per year). In addition, stress phase-transfer catalysts are being applied to
corrosion can lead to much faster deterioration these reactions.
of the reactor. Low-alloy steels are not useful 4) p-Nitrosoaniline and p-nitroso-N-phenyl-
for production units, especially with continuous aniline [156-10-5] have been produced in
working reactors. Stainless steels (chromium- liquid ammonia in the presence of either an
and nickel-containing austenitic steels of the 316 ammonium salt or a tertiary amine, respec-
types) were used with success for reactions in tively, and an organic solvent [131].
aqueous media. Because even these materials 5) p-Nitrosophenols are reacted with alkyl-
become pitted, other more corrosion-resistant al- amines via the p-nitrosophenylethers to
loys, such as Hastelloy and Inconel, have come give the corresponding N-substituted p-
into use. In addition, zirconium, titanium, and nitrosoanilines. The water that is eliminated
tantaclad (explosion clad tantalum on steel) have in this process must be removed to drive the
been used as reactor materials [121]. reaction to completion [132].
6) The Halcon process is the industrially impor-
tant vapor-phase amination of phenol [133],
3.2.2. Exchange of Hydroxyl and Ether [134]. Phenols or naphthols react in the gas
Groups phase with ammonia at 250 ◦ C on metal-
lic or nonmetallic oxides, e.g., MgO, B2 O3 ,
The displacement of an aromatic hydroxyl group Al2 O3 , SiO2 , TiO2 , or mixtures of these.
by an amine is not only possible with phenols The Halcon process has been used by U.S.
and cresols but also with quinoline and iso- Steel Chemicals since 1982 in its plant at
quinoline derivatives. In addition ammonia can Haverhil, Ohio for the production of aniline
replace alkoxy groups that are activated by ni- from phenol (aniline capacity 100000 t/a)
tro, halo, or cyano in the ortho or para positions. [135].
For example, 2,4-dinitroanisole [119-27-7] re- 7) The Bucherer reaction is the reaction of 1-
acts with ammonia at 50 – 200 ◦ C to form 2,4- or 2-naphthols with aqueous amine or am-
dinitroaniline [97-02-9] in 50 – 90 % yield [125]. monium solutions using hydrogen sulfite as
Interest in the reaction of phenols with amines the catalyst. It is nearly exclusively used for
is often a function of the cost of the phenol raw the naphthalene series [116]. The use of hy-
material. The principal exchange processes are: drogensulfite reduces the reaction tempera-
ture by 50 – 150 ◦ C and results in high yield
(85 – 95 %) and purity. The reaction mecha-
1) Reaction in aqueous medium without a cat- nism has been elucidated [136].
alyst. 3-Nitrosalicylic acid reacts with aque-
ous ammonia at increased temperature and
pressure to yield 2-amino-3-nitrobenzoic
acid [126].
2) Reaction in the presence of an acid cat-
alyst. m-Aminophenols are produced in
the reaction of resorcinol [108-46-3] and
aqueous ammonium hydroxide or alky-
lamines with boric acid as the cata-
lyst [127]. Under anhydrous conditions
with the same catalyst, 3-(β- and γ-hy-
droxyalkylamino)phenols are obtained from
Amines, Aromatic 15

3.2.3. Exchange of Sulfo Groups 5. Toxicology, Occupational Health,


and Environmental Protection
Ammonia can replace the sulfo groups in ben-
zene, naphthalene, and anthraquinone deriva- 5.1. Toxicity
tives. However, only in the anthraquinone se-
ries is this exchange of industrial importance The toxicity of aromatic amines has long been of
(→ Anthraquinone Dyes and Intermediates). concern to the chemical industry because of the
Until recently 1-aminoanthraquinones were serious nature of both acute and chronic effects
made by reaction of 1-sulfoanthraquinones with of exposure to aromatic amines. Despite this,
amines. To destroy the released hydrogensulfite, the toxicology of many of the individual com-
stoichiometric amounts of an oxidizing agent, pounds has not been studied thoroughly. There-
e.g., sodium 3-nitrobenzenesulfonate, were fore, a discussion of aromatic amine toxicity in
added. Increasingly 1-aminoanthraquinone general is more appropriate than a discussion of
[82-45-1] is made by reduction of the individual compounds.
corresponding nitroanthraquinone. This The primary hazards associated with aro-
method avoids the mercury-catalyzed sul- matic amine exposure are methemoglobinemia
fonation to the 1-sulfoanthraquinone. 1- and carcinogenesis. Both of these effects are at-
Cyclohexylaminoanthraquinone-5-sulfonic tributed to activation products of metabolic N-
acid is obtained from anthraquinone-1,5- oxidation [142]. Acute exposure, from either in-
disulfonic acid and cyclohexyl-amine in aque- halation or skin contact, results in anoxia be-
ous medium under pressure at 100 – 200 ◦ C cause of an impairment of the oxygen transport
[138]. The hydrogensulfite is oxidized with system of the blood. In aromatic amine expo-
sodium perchlorate or 3-nitrobenzenesulfonic sure the heme iron of hemoglobin is oxidized
acid. from Fe(II) to Fe(III). The resulting product,
methemoglobin, cannot combine with oxygen
or carbon monoxide. The development of methe-
3.3. Other Processes moglobinemia after exposure is often insidious;
i.e., the onset of symptoms may be delayed for
Only a few of all other possible methods for hours. Usually the first symptom is headache;
the production of aromatic amines described in anoxia, including cyanosis of lips, nose, and ear-
the literature should be mentioned here. 4,4 - lobes, develops when the methemoglobin blood
Methylenedianiline is produced on a large scale level reaches 15 %. At levels of 40 %, weakness
by condensation of aniline with formaldehyde and dizziness are experienced, and at > 70 %,
in aqueous or aqueous – methanolic solution. coma and death may occur.
Diphenylamine is made by vapor-phase con- The extent to which various aromatic amines
densation of aniline over alumina or titanium can cause methemoglobin formation varies
catalyst at 450 – 500 ◦ C [139] or in the liq- widely. However, the arylhydroxylamines are
uid phase at 175 – 450 ◦ C [140]. The rearrange- recognized as the strongest methemoglobin for-
ment of arylhydroxylamines in dilute sulfuric mers in this group. The reason for their potency
acid leads to o- and p-aminophenols [141]. 3,3 - is that they are involved in a cyclic reaction.
Dichlorobenzidine [91-94-1], an important pig- Phenylhydroxylamine reacts with hemoglobin
ment intermediate, is produced by Bofors (plant to form methemoglobin and nitrosobenzene
in Muskegan, MI) using the benzidine rearrange- [143]. Nitrosobenzene is then reduced back to
ment starting from o-chloronitrobenzene. phenylhydroxylamine, which then is available
to oxidize more hemoglobin. A small amount
of nitrosobenzene appears to be reduced all the
4. Economic Aspects way to its amine, which eventually stops the re-
action. As much as 50 mmol of methemoglobin
The economically most important aromatic may be produced by 1 mmol of hydroxylamine
amines are discussed in separate keywords. For [144].
the others, data are generally unavailable.
16 Amines, Aromatic

Figure 4. Examples of carcinogenic amines

The carcinogenic potential of aromatic to the nucleic acid bases of DNA. The follow-
amines is of greatest concern. A number of ing reaction sequence has been proposed, where
them are known or are suspected of being car- ArNH2 is the aromatic amine [153].
cinogens. Indeed it has been reported that the
epidemiology of aromatic amine carcinogene-
sis is essentially the epidemiology of human
cancer of industrial origin [145]. The first sus-
picion of aromatic amine carcinogenesis was
raised in 1895 when cases of bladder cancer in
Swiss dye workers were reported [146]. Since This reaction sequence implies that structural
then a number of epidemiologic investigations factors in the aromatic amine favoring the cation
and animal studies have identified which aro- formation (e.g., electron-donating substituents
matic amines are carcinogenic [147–149]. Be- ortho and para to the amino group) enhance car-
cause most aromatic amines have not been ex- cinogenicity. Figure 4 is a sampling of some car-
amined thoroughly for carcinogenic potential, cinogenic amines [154].
researchers are attempting to develop theoreti- In addition to the effects cited in Table 1
cal models for determining which ones are car- [144], aromatic amines can cause a wide va-
cinogenic [150–152]. Structural requirements, riety of other symptoms, such as eye and skin
such as the type of aromatic ring system, the irritation. By drawing correlations from animal
position of the amine group on the ring, and the studies, exposure to some of these compounds
presence and position of other substituents, are may lead to liver and kidney damage.
believed to be important to carcinogenic poten-
tial. Chemical carcinogens exert their effect by
causing DNA damage, which leads to tumor for- 5.2. Exposure Limits
mation. The metabolic reaction products, rather
than the aromatic amines themselves, are be- Various countries have established their own ex-
lieved to damage the DNA. These reaction prod- posure limits for workers [156–160]. As an il-
ucts are electrophilic and are covalently bonded lustration, Table 2 lists those aromatic amines
Amines, Aromatic 17
Table 1. Effects of the chronic administration of primary amines on the blood, liver, and bladder of dogs

Methemoglobin Toxicity and/or Bladder


formation carcinogenesis (liver) carcinogenesis

4-Aminobiphenyl [92-67-1] +++ - +++


2-Naphthylamine [91-59-8] + - ++
1-Naphthylamine [134-32-7] - - -
Benzidine [92-87-5] - - +
Aniline [62-53-3] ++ - -
Dichlorobenzidine [91-94-1] - + ++
Methylenedianiline [101-77-9] - +++ +- b ∗
4,4 -Methylene-bis(2- - + ++
chloroaniline)
[101-14-4]
4,4 -Methylene-bis(2-methyl- - +++ -
aniline)
[838-88-0]
Bis aniline A [2479-47-2] - +- +
4-Aminobiphenylamine - ++ +- b ∗
[101-54-2]

∗ Indicates only preneoplastic changes, no tumors.

Table 2. ACGIH aromatic amines workplace exposure limit (mg/m3 ) [161]

Substance TWAa STELb MAKc

4-Aminobiphenyl (skin) [92-67-1] A/b d A/b d III A 1 f


Aniline & homologues (skin) [62-53-3] 10 20 A2 e
Anisidine (o-, p-isomers) (skin) [29191-52-4] 0.5 - 0.5
ANTU (1-Naphthylthiourea) [86-88-4] 0.3 0.9 0.3
Benzidine (skin) [92-87-5] A/b d A/b d III A 1 f
3,3 -Dichlorobenzidine (skin) [91-94-1] A2 e A2 e III A 2g
N,N-Dimethylaniline (skin) [121-69-7] 25 50 25
Diphenylamine [122-39-4] 10 20 -
N-Isopropylaniline (skin) [643-28-7] 10 20 -
N-Methylaniline (skin) [100-61-8] 2 5 9
4,4 -Methylene-bis(2-chloroaniline) (skin) [101-14-4] 0.22, A 2 e - III A 2g
4,4 -Methylenedianiline (skin) [101-77-9] 0.8 4 -
2-Naphthylamine [91-59-8] A/b d A/b d III A 1 f
p-Nitroaniline (skin) [100-01-6] 3 - 6
N-Phenyl-2-naphthylamine [135-88-6] A2 - A2 e
p-Phenylenediamine [106-50-3] 0.1 (skin) - 0.1
o-Tolidine [119-93-7] A2 e - A2 e
o-Toluidine (skin) [95-53-4] 9, A 2 e - -
Triphenylamine [603-34-9] 5 - -
m-Xylene-α,α -diamine [1477-55-0] C h 0.1 - -
Xylidene (all isomers except 2,4-xylidene) [1300-73-8] 10 (skin) - 25
a
Time-weighted average (8-h workday and a 40-h week);
b
Short-term exposure limit (15-min TWA exposure);
c
Maximum concentration values in the workplace;
d
A recognized carcinogen. No assigned TLV. No exposure permitted by any route;
e
A suspect carcinogen for man. Exposures should be controlled carefully;
f
Compounds capable of inducing malignant tumors as shown by experience with humans;
g
Unmistakably carcinogenic in animal experimentation only;
h
Ceiling limit; TLV should not be exceeded even instantaneously, avoid skin contact, exposures are likely by skin absorption.

with exposure limits established in the United 5.3. Protective Measures


States (ACGIH) [161] and the Federal Republic
of Germany (MAK) [162]. These recommenda- Exposure to aromatic amines occurs primarily
tions are in addition to the U.S. Occupational through two routes: skin contact and inhalation.
Safety and Health Administration’s Subpart Z Because of the potential health hazards, strict
exposure limits [163]. control measures are necessary to prevent ex-
posure. From an industrial hygiene standpoint,
18 Amines, Aromatic

exposure is best prevented through the use of 4. United States International Trade Commission,
engineering controls. Whenever possible, pro- Publication 1548, “Import of Benzenoid
cesses containing aromatic amines should be Chemicals and Products 1983,” Graphics
enclosed. In a closed process exposure can oc- Branch, Washington, D.C., July 1984, pp. 10,
cur only when equipment fails or when process 23.
streams are sampled. If a process is not enclosed, 5. Japan Dyestuff Industry Assn., Japan Chem.
ventilation (both general diluted and local ex- 1982 (April 15) 8.
haust) should be used to prevent or reduce expo- 6. K. Weissermel, H.-J. Arpe, Industrielle
sure. Ventilation specifications for a number of Organische Chemie, Wiley-VCH, Weinheim
1998.
industrial processes are available [164]. When
7. W. L. Semon in Davis, Bake (ed.): The
ventilation controls are not sufficient to lower
Chemistry and Technology of Rubber,
exposure, respirators should be used until ef- Reinhold Publ. Co., New York 1937, p. 414.
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are used, a complete respiratory protection pro- 1, (1959) 351.
gram should be instituted that includes regular 9. G. S. Petrov, V. F. Prosvirkina, Zh. Prikl. Khim.
training, maintenance, inspection, cleaning, and (Moscow) 30, (1956) 1660. Chem. Abstr. 52
evaluation. Where skin contact may occur, work- (1958) 5028 f.
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