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Towards greener solvents for the bleach oxidation of alcohols catalysed by
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stable N-oxy radicals

Michiel H. A. Janssen,a Juan F. Chesa Castellana,a Hayley Jackman,b Peter J. Dunnb and
Roger A. Sheldon*a,c
Received 13th October 2010, Accepted 14th January 2011
DOI: 10.1039/c0gc00684j

We conducted a solvent screening study aimed at identifying greener alternatives for the
commonly used solvent dichloromethane in N-oxy catalysed bleach oxidations of various alcohol
substrates. We found that environmentally acceptable ester solvents, notably isopropyl acetate and
methyl acetate, gave results comparable to or better than dichloromethane. However, there was no
apparent correlation between common solvent properties and performance. A comparison of two
co-catalysts, NaBr and borax, revealed that borax gave better results with cinnamyl alcohols
whereas NaBr was generally better with the other alcohols. We also studied the effect of catalyst
loading. In the oxidation of 3-phenyl-1-propanol the amount of N-oxy catalyst could be effectively
reduced to a mere 0.1 mol%. Overall, we conclude that due to the complex nature of these systems,
there is not a single set of conditions that gives good results for all alcohols. However, by
employing a simple screening approach to assess solvent, catalyst and co-catalyst combinations,
similar or even better results can often be achieved in solvents other than dichloromethane.

Introduction the design of bleach based catalytic oxidations with greener

solvents is important to the field of Green Chemistry.
The selective oxidation of alcohols to the corresponding car- A current widely accepted method for alcohol oxidations em-
bonyl compounds is a very important reaction in organic ploys the stable nitroxyl (N-oxy) radical 2,2,6,6-tetramethyl-1-
synthesis.1 The most commonly used benign oxidants are oxygen piperidinyloxy I (TEMPO)3,4 as an organocatalyst and aqueous
(air), hydrogen peroxide and sodium hypochlorite (household sodium hypochlorite as the terminal oxidant.5,6 The standard
bleach), these three oxidants lead to benign co-products such protocol involves the use of 1 mol% (relative to the alcohol
as water and sodium chloride. At first glance oxygen could be substrate) of TEMPO in combination with 10 mol% NaBr as
considered as the greenest of these oxidants as it has the highest co-catalyst and a biphasic mixture of dichloromethane–water as
atom efficiency, however the use of molecular oxygen presents solvent, see Scheme 1.
significant safety issues associated with the flammability of mix-
tures of oxygen with volatile organic solvents in the gas phase.2
The same arguments apply to the use of hydrogen peroxide as it
undergoes decomposition to afford oxygen. For a large volume
industrial product these concerns can be engineered out, but for
a pharmaceutical or small volume fine chemical product it may
be preferable to use sodium hypochlorite and standard reactors
as the environmental and cost benefits of using simple air or
Scheme 1 Bleach oxidation of alcohols catalysed by TEMPO and
oxygen would not justify the capital investment required. Hence
sodium bromide in a biphasic solvents mixture of CH2 Cl2 –water.

In addition to TEMPO, good or even better results have

a
CLEA Technologies B.V., Delftechpark 34, 2628 XH, Delft, the been obtained with 4-acetamido-TEMPO II (AA-TEMPO),
Netherlands. E-mail: m.janssen@clea.nl, r.sheldon@clea.nl; Tel: +31 4-methoxy-TEMPO, and the oligomeric analogue PIPO7 III
(0)15 760 0300 (Fig. 1). The latter is especially attractive because it can be
b
Pfizer Pharma Therapeutic Research Group, Sandwich, Kent, UK CT13 derived from the cheap and readily available polymer addi-
9NJ
c tive Chimassorb 944. Moreover, depending on the solvent,
Laboratory of Biocatalysis and Organic Chemistry, Department of
Biotechnology, Delft University of Technology, Julianalaan 136, 2628 PIPO is insoluble (i.e. a heterogeneous catalyst) and can be
BL, Delft, the Netherlands readily recovered and recycled. The terminal oxidant sodium

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Fig. 1 Stable N-oxy radicals (from left to right): TEMPO I, AA-TEMPO II and PIPO III.

hypochlorite is a readily available and inexpensive oxidant Table 1 Solubilities of selected solvents in water at room temperature
and, because of the relatively small product volumes involved,
Solvent Solubility in water (g per 100 g) Ref.
the coproduction of sodium chloride is not an issue in the
synthesis of pharmaceutical intermediates. By the same to- MeOAc 24.5 17
ken, the use of 10 mol% NaBr as a co-catalyst is perfectly MeTHF 14.0 18
acceptable. EtOAc 7.7 17
MTBE 4.3 17
However, a major issue with this protocol is the use of iPrOAc 2.9 17
dichloromethane, which is subject to increasingly stringent CH2 Cl2 1.3 17
regulations because of health and environmental hazards, as Heptane 0.005 17
solvent. Consequently, there is a definite need to develop a Isooctane 0.0002 19
method which employs a greener solvent and has broad scope
with alcohols containing a variety of functional groups. We
were particularly interested in water immiscible solvents as this the benchmark solvent for this reaction on both laboratory5 and
would allow for easy work up. One of us7,8 had previously shown large scale10,16 and we also tried a few reactions without any
that PIPO-catalysed reactions worked well in either an ethereal solvent. The solubility of the selected solvents in water is shown
solvent (methyl tert-butyl ether, MTBE) or a hydrocarbon in Table 1.
solvent (hexane). Ester solvents such as methyl acetate9 and The aim of this study was to examine these selected solvents
ethyl acetate10 had been used by pharmaceutical companies in in the bleach oxidation of a series of alcohols with different
the scale up of TEMPO-catalysed reactions. Consequently, we functional groups to afford functionalised aldehydes that are
decided to focus on pharmaceutically acceptable hydrocarbon, important intermediates for the pharmaceutical industry. These
ester and ethereal solvents. were 3-phenyl-1-propanol 1 (minimal structural complexity),
We considered four common hydrocarbon solvents: pentane, cinnamyl alcohol 2a (conjugated double bond), some ring-
hexane, heptane and isooctane. Hexane was rejected as this substituted cinnamyl alcohols e.g. 4-methylcinnamyl alcohol
solvent is one thousand times more toxic than any other common 2b, 4-chlorocinnamyl alcohol 2c, 4-nitrocinnamyl alcohol 2d,
aliphatic hydrocarbon solvent.11 Pentane was rejected because 3-(pyridin-3-yl)-1-propanol 3 (heteroaromatic), and N-Boc-L-
of its flammability (flash point -49 ◦ C) which would make it phenylalaninol 4 (protected amine), see Fig. 2. Furthermore, we
undesirable and in most cases unacceptable for use on a pilot also wanted to study the effects of several other parameters on
plant scale. Heptane and isooctane have reasonable boiling the aldehyde yield, such as N-oxy type and amount, co-catalyst
points (97 ◦ C and 98 ◦ C) and reasonable flash points (-4 ◦ C type and amount, and pH.
and -12 ◦ C) and were selected for the study. Toluene could
also have been selected but this solvent had been previously
studied.12
Furthermore, we considered four common ethereal sol-
vents: diisopropyl ether, diethyl ether, MTBE and 2-
methyltetrahydrofuran (MeTHF). Diisopropyl ether was re-
jected on the basis of the fact that it forms explosive peroxides
several hundred times faster than any common, water insoluble
ether.13 Its involvement in explosions on both laboratory and
large scale is well documented.14,15 Diethyl ether was rejected
because of its volatility and low flashpoint (-40 ◦ C) which
renders it unusable in nearly all scale-up facilities. Thus, MeTHF
and MTBE were selected for this study.
Esters are generally thought of as green solvents due to
their low toxicity and ready biodegradation. We selected methyl Fig. 2 Selected alcohol substrates: 3-phenyl-1-propanol 1, cinnamyl
acetate, ethyl acetate and isopropyl acetate as we wanted to study alcohol 2a, 4-methylcinnamyl alcohol 2b, 4-chlorocinnamyl alcohol 2c,
a group of solvents with very different water solubility. Finally, 4-nitrocinnamyl alcohol 2d, 3-(pyridine-3-yl)-1-propanol 3 and N-Boc-
we included dichloromethane because it can be considered as L-phenylalaninol 4.

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Table 2 Best results obtained in the oxidation of selected alcohols catalysed by N-oxy radicals and a co-catalyst in CH2 Cl2 a

Entry Alcohol Conversion (%) Yield (%) Selectivity (%) N-oxy Co-catalyst

1 1 95 94 99 AA-TEMPO NaBr
2 1 94 92 98 AA-TEMPO Borax
3 2a 96 82 85 PIPO NaBr
4 2a 72 42 58 PIPO Borax
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5 3 96 73 76 PIPO NaBr
6 3 91 80 88 PIPO Borax
7 4 96 81 84 AA-TEMPO NaBr
8 4 97 72 74 AA-TEMPO Borax
a
Reaction conditions: 0.9 M alcohol, 1 mol% TEMPO, 10 mol% NaBr or 0.85 mol% borax, 1.05 equivalents NaOCl pH 9.5, 0 ◦ C, vigorous stirring,
2 h reaction time after all NaOCl had been added.

Results and discussion catalyst effect was observed in the oxidation of 3-(pyridine-3-
yl)-1-propanol 3 where borax proved to be a more effective
Oxidation and co-catalyst screening under standard conditions co-catalyst than NaBr. PIPO was the best N-oxy catalyst of
We first tested the oxidation of the alcohols in the benchmark the three, giving 80% aldehyde yield (borax co-catalysis). The
solvent CH2 Cl2 using the three N-oxy catalysts of Fig. 1 under oxidation of N-Boc-L-phenylalaninol 4 gave high conversions
industrially relevant standard conditions (0.9 M alcohol, 1 mol% (>95%) with all three N-oxy catalysts, but the highest aldehyde
N-oxy, 10 mol% NaBr, 1.05 equivalents NaOCl, 0 ◦ C). The pH yield (81%) was obtained with AA-TEMPO. NaBr was the best
of bleach was adjusted to pH 9.5 with NaHCO3 which was co-catalyst.
found to be the optimum pH for the oxidation (results not
shown). NaBr is an effective co-catalyst because it is converted Solvent screening
in situ into hypobromous acid. The latter is more reactive than In view of the poor results obtained with 2-phenoxyethanol, 2-
hypochlorous acid,20 despite being a weaker oxidant. Recently, (phenylthio)ethanol and citronellol we excluded these alcohols
borax (Na2 B4 O7 ·10H2 O) was also shown21,22 to be an effective from further studies. We conducted the solvent screening with
co-catalyst in bleach oxidations. Its catalytic role is not clearly the remaining alcohols. For each alcohol we selected the best N-
understood but it could conceivably react with bleach to give a oxy catalyst and co-catalyst from the reaction in CH2 Cl2 , except
less aggressive species such as the ClOB(OH)3 - anion, analogous for 3-phenyl-1-propanol 1 where we decided to include all three
to the formation of the peroxoborate anion, HOOB(OH)3 - , N-oxy catalysts for comparison. Some of the results are shown
from reaction of B(OH)3 with NaOH and H2 O2 . The low in Table 3 with further results in Fig. 3 and 4. The oxidation
concentration (0.85 mol%) at which it was used is obviously of 3-phenyl-1-propanol 1 generally gave good yields in the ester
very attractive. This prompted us to also compare these two
co-catalysts in our oxidation study. The best results for each
combination of alcohol and co-catalyst are presented in Table 2.
The oxidation of 3-phenyl-1-propanol 1 in CH2 Cl2 was very
smooth, as expected, giving high aldehyde yields and selectivities
with all three N-oxy catalysts. NaBr gave slightly better results
than borax.
Initially we had also included 2-phenoxyethanol, 2-
phenylthioethanol and citronellol in our study. However, poor
selectivities were obtained (results not shown) in the oxidation
of 2-phenoxyethanol and 2-phenylthioethanol, irrespective of
the N-oxy catalyst and co-catalyst. This was a result of
competing chlorination of the activated aromatic ring and the
known3 uncatalysed oxidation of the thioether functionality to
the corresponding sulfoxide, respectively. Similarly, very poor
selectivities were observed in the oxidation of citronellol, again
irrespective of the N-oxy catalyst or co-catalyst. Pradhan et al.
showed23 that this was due to a competitive ene-type addition
of the TEMPO oxoammonium cation to trisubstituted alkenes,
which inactivated the N-oxy catalyst. Fig. 3 Scatter plot of yields obtained in the oxidation of 3-phenyl-
1-propanol (1) in various solvents. Markers are coloured by catalyst
The oxidation of cinnamyl alcohol 2a using TEMPO or AA-
(TEMPO, green; AA-TEMPO, red; PIPO blue) and shaped by co-
TEMPO also gave poor results, in agreement with those of
catalyst (circle, NaBr; triangle, borax). Data were taken from a set
Anelli et al.,5 owing to competing addition of hypohalous acid of 63 reactions where N-oxy catalyst loading was 0.5 or 1 mol% and
to the double bond. In contrast, and much to our surprise, an the co-catalyst was limited to NaBr (10 mol%) or borax (0.4 mol%).
82% cinnamaldehyde yield was obtained with PIPO and NaBr, Duplicate experiments are reported as a single data point (an average of
which was a better co-catalyst than borax. The opposite co- the duplicates). To avoid overlap the markers are jittered.

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Table 3 Oxidation of selected alcohols in various solventsa

Entry Alcohol Conversion (%) Yield (%) Selectivity (%) Solvent N-oxy catalyst

9 1 95 88 93 MeOAc AA-TEMPO
10 1 93 86 92 MeOAc PIPO
11 2a 93 73 78 iPrOAc PIPO
12 2a 86 70 81 MeTHF PIPO
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13 3b 77 70 91 MeTHF PIPO
14 3b 84 69 82 EtOAc PIPO
15 4 97 84 87 EtOAc AA-TEMPO
16 4 97 77 79 iPrOAc AA-TEMPO
a
Reaction conditions: 0.9 M alcohol, 1 mol% N-oxy, 10 mol% NaBr, 1.05 equivalents NaOCl pH 9.5, 0 ◦ C, vigorous stirring, 2 h reaction time after
all NaOCl had been added. b Same but using 0.86 mol% borax instead of 10 mol% NaBr.

TEMPO and NaBr afforded the best yield in EtOAc (84%),

Fig. 4 Scatter plot of yields obtained in the oxidation of 3-(pyridin-
3-yl)-1-propanol (3) and cinnamyl alcohol (2a) in various solvent,
N-oxy catalyst and co-catalyst combinations. Markers are coloured
by alcohol substrate (red, 3-(pyridin-3-yl)-1-propanol; blue, cinnamyl
alcohol), shaped by co-catalyst (circle, NaBr; triangle, borax), and
labelled by N-oxy catalyst type (I, TEMPO; II AA-TEMPO; III, PIPO).
Data set sizes are 23 and 30 experiments for 3-(pyridin-3-yl)-1-propanol
and cinnamyl alcohol respectively; catalyst loading was 0.5 or 1 mol%
and co-catalyst was limited to NaBr (10 mol%) or borax (0.4 mol%).
Duplicate experiments are reported as a single data point (an average of
the duplicates). The markers are jittered to avoid overlap.
solvents, and was hardly influenced by the N-oxy catalyst species.
The highest yield was 88%. For comparison, the best yield in
CH2 Cl2 was 94%. The yields obtained in the other solvents were
generally lower and markedly influenced by the N-oxy catalyst.
The only exception was the oxidation with TEMPO in heptane
which gave 86% yield. We also performed the oxidation without
solvent (neat), but this gave poor yields (47–55%) which was
consistent with the results obtained by Dijksman et al.7 in the
absence of NaBr. Oxidations in heptane and isooctane were
omitted with many of the alcohol substrates because of their
poor solubility in these solvents.
The oxidation of cinnamyl alcohol 2a catalysed by PIPO and
NaBr gave relatively good yields in iPrOAc (73%) and MeTHF
(70%), considering that the best yield in CH2 Cl2 was 82%. The
best yields with 3-(pyridin-3-yl)-1-propanol 3 were obtained
with PIPO, in combination with borax, in MeTHF and EtOAc.
The oxidation of N-Boc-L-phenylalaninol 4 catalysed by AA-
followed by the other esters and MeTHF. The yield in EtOAc
was even slightly better than the best yield in CH2 Cl2 (81%).
However, it should be mentioned here that we are not comparing
optimised results.
The data obtained from the solvent screen were submitted to
statistical analysis in an attempt to identify a correlation with
several solvent properties (e.g. water solubility in solvent, solvent
solubility in water, dielectric constant, Hildebrand solubility
parameter, and log P) and the aldehyde yields. Unfortunately,
this did not reveal a correlation between any solvent property
and good performance. We had expected to observe a correlation
between the over-oxidation of the aldehyde to the carboxylic
acid (which would result in a lower yield) and water solubility
of the solvent because the over-oxidation is generally thought to
proceed via the aldehyde hydrate. However, in view of the fact
that MeOAc, which has a high water-solubility (Table 1), showed
a good performance in many instances it is unlikely that water
solubility of the solvent alone is a cause of bad performance. The
only conclusion that could be drawn was that many good results
were obtained with MeOAc and iPrOAc, often almost as good as
with CH2 Cl2 . EtOAc may also be a good solvent. However, even
the ester solvents gave a bad performance in some reactions, so
a more systematic screening approach is needed to draw more
powerful conclusions. From an industrial point of view, iPrOAc
and EtOAc are preferred ester solvents because downstream
processing is facilitated by their low solubility (and in the case
of iPrOAc very low solubility) in water. With MeOAc, a large
fraction will dissolve in the aqueous phase, which needs to be
removed.
Influence of N-oxy catalyst loading
There is an obvious economic and environmental advantage
to reducing the loading of the N-oxy catalyst. However, we
assumed that the alcohols that already suffered from a poor or
moderate selectivity in the oxidation with 1 mol% N-oxy were
unlikely to give better results at even lower N-oxy amounts.
Indeed, both the conversion and the selectivity of the oxidation
of cinnamyl alcohol 2a were adversely affected by lowering the
N-oxy amount to 0.05–0.5 mol% (results not shown). The results
obtained with 3-phenyl-1-propanol 1 were much better (see
Table 4). By lowering the amount of AA-TEMPO by a factor
of 10 to a mere 0.1 mol% the final conversion and aldehyde
yield were not affected, irrespective of the solvent (iPrOAc or

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Table 4 Oxidation of 3-phenyl-1-propanol 1 with different N-oxy catalyst amountsa

N-oxy catalyst
Entry Type Amount (mol%) Solvent Conversion (%) Yield (%) Selectivity (%)

17 AA-TEMPO 0.5 iPrOAc 93 91 98

18 AA-TEMPO 0.1 iPrOAc 93 91 98
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19 AA-TEMPO 0.05 iPrOAc 88 66 75

20 AA-TEMPO 0.5 MeOAc 94 89 95
21 AA-TEMPO 0.1 MeOAc 95 94 99
22 AA-TEMPO 0.05 MeOAc 90 69 77
23 PIPO 0.5 iPrOAc 92 92 100
24 PIPO 0.1 iPrOAc 92 86 93
25 PIPO 0.05 iPrOAc 91 84 92
26 PIPO 0.5 MeOAc 94 90 96
27 PIPO 0.1 MeOAc 94 85 90
28 PIPO 0.05 MeOAc 88 70 80
a
Reaction conditions: 0.9 M alcohol, 0.05–0.5 mol% N-oxy, 10 mol% NaBr, 1.05 equivalents NaOCl pH 9.5, 0 ◦ C, vigorous stirring, 2 h reaction
time after all NaOCl had been added.

Table 5 Oxidation of cinnamyl alcohol 2 in iPrOAc with different co-catalyst amountsa

Co-catalyst

Entry Type Amount (mol%) Conversion (%) Yield (%) Selectivity (%)

33 NaBr 0.4 98 75 77
34 NaBr 2 94 77 82
35 NaBr 5 95 75 79
36 NaBr 10 93 73 78
37 borax 0.4 92 83 90
38 borax 2 97 73 75
a
Reaction conditions: 0.9 M alcohol, 1 mol% PIPO, 1.05 equivalents NaOCl pH 9.5, 0 ◦ C, vigorous stirring, 2 h reaction time after all NaOCl had
been added.

MeOAc). However, at 0.05 mol% AA-TEMPO, a drop in alde-
hyde yield and selectivity was observed. Similarly, the amount
of PIPO could effectively be reduced to 0.1–0.5 mol% without a
significant loss in conversion and aldehyde yield. We believe that
the low selectivities at low N-oxy concentrations were caused by
an imbalance between the bleach addition rate and the bleach
consumption rate by oxidation of the hydroxylamine species
of the N-oxy catalyst. Under ideal conditions, all bleach that
is added (dropwise) is immediately “neutralised” (consumed)
by the hydroxylamine, which is accelerated by the co-catalyst
when present. Indeed, some N-oxy catalysed bleach oxidations
of alcohols are practically instantaneous. Thus, the reaction
rate should be limited by the bleach addition rate. It should,
however, also not exceed the cooling capacity of the reactor
as higher temperatures not only promote side reactions but also
the inactivation of the N-oxy catalyst5 But upon lowering the N-
oxy catalyst amount, its concentration will become rate-limiting
at some point. This effectively results in an accumulation of
bleach in the reaction mixture and a longer reaction time, which
promotes side reactions and therefore a lower selectivity.
Influence of co-catalyst amount, surfactant and phase-transfer
catalyst
Next, we examined the influence of the co-catalyst loading on
the oxidation of 3-phenyl-1-propanol 1 in iPrOAc catalysed by
1 mol% PIPO. The amount of NaBr co-catalyst was varied
over a wide range (0.4, 2, 5, and 100 mol%) but this had little
influence on the conversion and aldehyde yield. The only co-
catalyst concentration that was significantly better than the rest,
was the generally used amount of 10 mol% NaBr. Without a
co-catalyst, we obtained 85% conversion but only 70% aldehyde
yield.
We conducted a similar study with cinnamyl alcohol 2a in
iPrOAc (see Table 5). The amount of NaBr could effectively be
reduced to 0.4 mol% without adversely affecting the conversion
and aldehyde yield. Similar results were obtained with 2 mol%
borax, but with 0.4 mol% the aldehyde yield was increased to
83%, which was even better than with 0.4 mol% NaBr.
Next, we examined the effect of a surfactant, sodium do-
decylsulfate (SDS), and an organic phase-transfer catalyst,
tetraoctylammonium bromide (TOABr). An effect with the
former would indicate a role of interfacial catalysis while an
effect with the latter, as reported by Siedlecka et al.,24 would
indicate the involvement of a phase-transfer process. SDS (1–
5%) had no effect on the PIPO-catalysed oxidation of 3-phenyl-
1-propanol 1 or cinnamyl alcohol 2a in iPrOAc, irrespective of
the co-catalyst (results not shown). Thus, we ruled out interfacial
catalysis. TOABr (5%) had a detrimental effect on the selectivity
of the PIPO/NaBr-catalysed oxidation of 3-phenyl-1-propanol
1 in iPrOAc, giving 84% conversion but only 46% aldehyde yield
(results not shown). This was in agreement with conclusions by
others5 that these phase transfer catalysts are only effective when
the presence of strongly basic ClO- or BrO- is required in the

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Table 6 Oxidation of 4-methylcinnamyl alcohol 2b, 4-chlorocinnamyl alcohol 2c, cinnamyl alcohol 2a, and 4-nitrocinnamyl alcohol 2d in iPrOAc
and MeOAca

Entry Alcohol N-oxy catalyst Solvent Conversion (%) Yield (%) Selectivity (%)

39 2b TEMPO iPrOAc 72 58 81
40 2b AA-TEMPO iPrOAc 82 75 91
41 2b PIPO iPrOAc 80 72 90
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42 2c TEMPO iPrOAc 76 67 88
43 2c AA-TEMPO iPrOAc 80 73 91
44 2c PIPO iPrOAc 98 97 99
45 2a PIPO MeOAc 97 91 94
46 2c PIPO MeOAc 98 89 91
47 2d PIPO MeOAc 99 99 100
a
Reaction conditions: 0.9 M alcohol, 1 mol% N-oxy, 0.4 mol% borax, 1.05 equivalents NaOCl pH 9.5, 0 ◦ C, vigorous stirring, 2 h reaction time after
all NaOCl had been added.

organic phase. However, as expected, this also promotes the over
oxidation of the alcohols to the corresponding carboxylic acids.
Oxidation of 4-substituted cinnamyl alcohols
Encouraged by the good result obtained in the oxidation of
cinnamyl alcohol 2a with 1 mol% PIPO and 0.4 mol% borax in
iPrOAc, we decided to examine the oxidation of several cinnamyl
alcohols ring-substituted at the para-position with substituents
with different electronic effects. We chose the electron donating
4-methyl group, the inductive electron withdrawing 4-chloro
group and the inductive and resonance electron withdrawing 4-
nitro group. The results are shown in Table 6. We started with the
oxidation of 4-methylcinnamyl alcohol 2b and 4-chlorocinnamyl
alcohol 2c in iPrOAc using the conditions that we found to
be optimal for the oxidation of cinnamyl alcohol 2a. The best
results with 4-methylcinnamyl alcohol 2b were obtained with
AA-TEMPO and PIPO as N-oxy catalyst but they were not as
good as for cinnamyl alcohol 2a. With 4-chlorocinnamyl alcohol
2c excellent results were obtained with PIPO as the N-oxy
catalyst (98% conversion, 97% aldehyde yield). 4-Nitrocinnamyl
alcohol 2d was only sufficiently soluble in MeOAc containing a
few % water from the 0.4% borax solution, thus we switched to
this solvent for a comparative study with cinnamyl alcohol and
4-chlorocinnamyl alcohol 2c. We were surprised by the very good
yield of cinnamaldehyde and 4-chlorocinnamaldehyde, and even
more by the excellent yield of 4-nitrocinnamaldehyde. This was
probably due to the electronic properties of these substituents,
which may have reduced the reactivity of the conjugated double
bond towards electrophilic attack by HO- X+ .
A screening approach
Our results from the oxidations of 3-phenyl-1-propanol 1 are
shown in Fig. 3. At a glance it can be seen that dichloromethane
is a very good solvent for the oxidation of this substrate. However
by selecting the correct catalyst and co-catalyst combinations
excellent yields of around 90% can also be obtained in MeOAc
and iPrOAc.
The results of our oxidations of cinnamyl alcohol 2a and
3-(pyridin-3-yl)-1-propanol 3 are shown in Fig. 4. For these
substrates there is no advantage of using dichloromethane but by
selecting the best catalyst and co-catalyst combination excellent
results (in excess of 90% yield) can be obtained with the greener
ester solvents EtOAc and MeOAc. Good results can also be
obtained in MTBE using PIPO as catalyst and borax as co-
catalyst.
Conclusions
We have shown that there are several greener alternatives to
CH2 Cl2 that can be successfully used as a solvent in bleach
oxidations catalysed by N-oxy radicals. Furthermore, when
combined with a further optimisation of the type and amount of
N-oxy catalyst and co-catalyst (NaBr or borax), in many cases
results can be obtained that approach or surpass those obtained
in CH2 Cl2 . Of the alternative solvents examined in this study,
many good results were obtained with ester solvents. The PIPO-
catalysed oxidation of cinnamyl alcohol and cinnamyl alcohols
containing an electron withdrawing group at the para-position
was particularly effective with borax co-catalysis in MeOAc or
iPrOAc, giving >90% yields. We found no evidence of interfacial
catalysis and the use of a cationic phase transfer catalyst had a
detrimental effect on the selectivity of the bleach oxidation.

From the discussion so far it is clear that optimising one single
factor (such as solvent choice, catalyst choice or co-catalyst
choice) will not guarantee a successful reaction and indeed
some of these factors will not be independent of each other.
To optimise these reactions a screening approach is required.
Such an approach is very common in industry where advances
in laboratory automation have made reaction screening very
efficient and rapid to carry out. A convenient way of visualising
data from many experiments, whether generated by automated
means or as in this case through conventional laboratory work,
is to use scatter plots.
Experimental
General
All alcohol substrates, aldehyde products, reagents and solvents
were purchased from commercial suppliers, unless mentioned
otherwise, and used without further purification. N-Boc-L-
phenylalaninol25 4, 4-methylcinnamyl alcohol26 2b and 4-
chlorocinnamyl alcohol26 2c were prepared following literature
procedures. The identity of the aldehyde products prepared by
bleach oxidation was confirmed by NMR and GC analysis by
comparing it with an authentic sample when possible. Aldehyde

910 | Green Chem., 2011, 13, 905–912 This journal is © The Royal Society of Chemistry 2011

products that were not commercially available were prepared by
bleach oxidation and further purification. All bleach oxidation
reactions were exposed to air. The NaOCl solution (1.3–1.8 M)
was stored in a refrigerator and titrated daily. Before use it was
adjusted to pH 9.5 with saturated NaHCO3 . GC analysis was
performed on a Shimadzu equipped with an AOC autosampler
using a Varian CP Sil 5 CB column (50 m ¥ 0.53 mm ¥ 1.0
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mm) or a Varian CP Wax 52 CB (50 m ¥ 0.53 mm ¥ 2.0 mm).
HPLC analysis was performed on Phenomenex Gemini C18
110 A column (150 ¥ 4.6 mm ¥ 5 mm) using UV detection at
254 nm. The mobile phase consisted of MeOH–H2 O 8 : 92 v/v
with 0.1% TFA (4-nitrocinnamaldehyde) or MeOH–H2 O 60/40
v/v with 0.1% TFA (N-Boc-L-phenylalaninal) at a flow rate of
1 mL min-1 . 1 H and 13 C NMR spectra were recorded on a Bruker
Avance-400 at 400 MHz and compared with literature spectra
for product identification.
General bleach oxidation procedure
To a vigorously stirred and ice water-cooled biphasic mixture of
organic solvent-water containing 5.0 g (0.9 M) alcohol, 1 mol%
N-oxy catalyst, 10 mol% NaBr was added 1.05 equiv. NaOCl
buffered to pH 9.5 with sodium bicarbonate over a period of
60–90 min. After all the bleach had been added, the reaction
mixture was stirred for 2 more hours at 0 ◦ C. The layers
were separated and the aqueous layer extracted twice with one
volume of the solvent. The organic layers were collected and
dried over anhydrous sodium sulfate. After filtration, the solvent
was evaporated at reduced pressure and the crude product was
analysed by GC or HPLC (4-nitrophenylcinnamyl alcohol).
Reported conversions refer to the alcohol substrate and were
calculated from the remaining alcohol amount in the crude
product using external standard analysis. Reported aldehyde
yields refer to the crude product and were calculated using
external standard analysis. Reported selectivities refer to the
crude aldehyde product and are calculated as (mmol aldehyde) ¥
(mmol alcohol converted)-1 ¥ 100%.
Preparation of aldehyde products and alcohol substrates
3-(Pyridine-3-yl)propanal. Bleach oxidation of the alcohol 3
(1 g, 7 mmol) and work up gave the aldehyde (0.7 g, 71%) as a
brown oil; d H (400 MHz; CDCl3 ; Me4 Si) 2.82 (2 H, t, CH2 ), 2.96
(2 H, t, CH2 ), 7.22 (1 H, dd, CHO), 7.53 (1 H, d, Ph) and 8.46
(2 H, m, Ph).
N-Boc-L-phenylalaninol 4. To a solution of 2-amino-3-
phenyl-1-propanol (10.0 g, 66 mmol) in 130 ml ethanol was
added Boc anhydride (17.5 g, 80 mmol). The mixture was stirred
at room temperature and after 50 min the reaction was com-
pleted (TLC, SiO2 , ethanol, UV). The solvent was evaporated
to dryness under reduced pressure. The residue was dissolved
in 200 ml ethyl acetate, washed with diluted hydrochloric acid
(100 ml, 0.5 M), washed with brine (200 ml) and dried over
anhydrous magnesium sulfate. The product was concentrated to
dryness obtaining a white solid (20.6 g). This compound was
recrystallised from ethyl acetate obtaining white crystals that
contained 10% tert-butanol (1 H-NMR). Percolation on silica
using dichloromethane as eluent and evaporation of the solvent
gave a pure white solid (11.1 g, 67%); d H (400 MHz; CDCl3 ;
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Me4 Si) 1.41 (9 H, s, 3 Me), 2.35 (1 H, d, CH2 ), 2.84 (1 H, d,
CH2 ), 3.55 (1 H, m, CH2 ), 3.67 (1 H, m, CH2 ), 3.86 (1 H, bs,
OH), 4.74 (1 H, bs, CH), 7.18–7.35 (5 H, m, Ph), 9.65 (1 H, bs,
NH).
N-Boc-L-phenylalaninal. Bleach oxidation of the alcohol 4
(1 g, 4 mmol) and work up gave the N-Boc-L-phenylalaninal as a
white solid. It was purified by column chromatography on silica
using heptane–ethyl acetate as eluent to give the aldehyde (0.8 g,
80%) as a yellowish oil; d H (400 MHz; CDCl3 ; Me4 Si) 1.40 (9
H, s, 3 Me), 3.13 (2 H, dd, CH2 ), 4.44 (1 H, m, CH), 5.05 (1 H,
bs, NH), 7.17–7.35 (5 H, m, Ph) and 9.64 (1 H, s, CHO).
4-Methylcinnamyl alcohol 2b. 4-Methylcinnamyl alcohol 2b
was prepared following a literature procedure.26 The product was
purified by column chromatography on silica using heptane–
dichloromethane–methanol mixtures of increasing polarity as
eluent to give a white solid (14 g, 75%); d H (400 MHz; CDCl3 ;
Me4 Si) 1.62 (1 H, bd, OH), 2.35 (3 H, s, Me), 4.32 (2 H, d, CH2 ),
6.33 (1 H, dt, CH), 6.60 (1 H, d, CH), 7.14 (2 H, d, Ph),
7.30 (2 H, d, Ph).
4-Chlorocinnamyl alcohol 2c. 4-Chlorocinnamyl alcohol 2c
was prepared following a literature procedure.26 The product was
purified by column chromatography on silica using mixtures of
isooctane–dichloromethane as eluent to give the alcohol as a
white solid (19.8 g, 77%); d H (400 MHz; CDCl3 ; Me4 Si) 1.65 (1
H, bs, OH), 4.34 (2 H, dd, CH2 ), 6.35 (1 H, dt, 15.9, CH), 6.59
(1 H, d, CH) and 7.10–7.35 (4 H, m, Ph).
4-Chlorocinnamaldehyde. Bleach oxidation of the alcohol
2c (1 g) and work up gave 4-chlorocinnamaldehyde as yellow
crystals (1 g, 90%); d H (400 MHz; CDCl3 ; Me4 Si) 6.70 (1 H, dd,
CH), 7.40–7.50 (3 H, m, CH + Ph), 7.52 (2 H, d, Ph) and
9.72 (1 H, d, CHO).
Acknowledgements
We thank George Bandurek (Pfizer) for the statistical analysis.
JFC thanks Pfizer for financial support.
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