Palladium on carbon-bromobenzene mediated esterification and transesterification

Article abstract of DOI:10.1016/j.tetlet.2013.08.009

A series of carboxylic acids were converted into their corresponding esters using the Pd/C catalyzed hydrogenation conditions in the presence of catalytic bromobenzene in alcohols and the method could also be applicable for the transesterification of esters. Good to excellent yields were obtained for different aliphatic or aromatic starting materials. The success of this esterification relies on the in situ generation of hydrobromic acid (HBr) from bromobenzene which provides a mild and acidic reaction environment. The palladium catalyst exhibits a remarkable activity and is reusable for up-to three consecutive cycles.

Full text of DOI:10.1016/j.tetlet.2013.08.009

Accepted Manuscript
Palladium on carbon-bromobenzene mediated esterification and transesterfica‐
tion
Sanjeev Kumar Aavula, Anil Chikkulapalli, N. Hanumanthappa, Indira Jyothi,
C.H. Vinod Kumar, Sulur G. Manjunatha
PII:
S0040-4039(13)01346-4
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.08.009
TETL 43366
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
15 April 2013
30 July 2013
2 August 2013
Please cite this article as: Aavula, S.K., Chikkulapalli, A., Hanumanthappa, N., Jyothi, I., Vinod Kumar, C.H.,
Manjunatha, S.G., Palladium on carbon-bromobenzene mediated esterification and transesterfication, Tetrahedron
Letters (2013), doi: http://dx.doi.org/10.1016/j.tetlet.2013.08.009
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Graphical Abstract
Palladium on carbon-bromobenzene mediated esterification and
transesterfication
Sanjeev Kumar Aavula,* Anil Chikkulapalli, Hanumanthappa N, Indira Jyothi, Vinod Kumar CH,
and Sulur G. Manjunatha
Bromobenzene
10% Pd/C
H2 (1-6 bar Pressure)
R-COOR' + H2O
R-COOH + R'OH
R = Ph, PhCH2
R' = Me, Et, iPr, n-Bu, t-Bu, C8H17, Ph, PhCH2
Bromobenzene
10% Pd/C
H2 (5-6 bar Pressure)
R-COOR'' + R'OH
R-COOR' + R''OH
R = Ph, PhCH2
R' = Me, Et, n-Bu, t-Bu, C8H17
R'' = Me, Et, iPr, n-Bu, t-Bu, PhCH2

Palladium on carbon-bromobenzene mediated esterification and
transesterfication
Sanjeev Kumar Aavula,* Anil Chikkulapalli, Hanumanthappa N, Indira Jyothi, Vinod Kumar CH,
and Sulur G. Manjunatha
Pharmaceutical Development, AstraZeneca India Pvt. Ltd, Off Bellary Road, Hebbal, Bangalore 560 024, India
∗Corresponding author. Tel.: +918066213000; fax: +918023622011; e-mail: Sanjeev.aavula@astrazeneca.com
Abstract
A series of carboxylic acids were converted into their corresponding esters using the Pd/C
catalyzed hydrogenation conditions in the presence of catalytic bromobenzene in alcohols
and the method could also be applicable to the transesterfication of esters. Good to excellent
yields were obtained for different aliphatic or aromatic starting materials. The success of this
esterification relies on the in situ generation of hydrobromic acid (HBr) from bromobenzene
which provides a mild and acidic reaction environment.The palladium catalyst exhibits
remarkable activity and is reusable for up-to three consecutive cycles.
Keywords: Esterification, palladium, bromobenzene, transesterification.
Esterification of carboxylic acids and transesterification of esters have wide industrial
applications. Esters are common in organic chemistry and biological materials, and often
have a characteristic pleasant, fruity odor. This leads to their extensive use in the fragrance
and flavor industry. Ester bonds are also found in many polymers, pharmaceutical and
agricultural compounds. Many useful and reliable esterification of carboxylic acids and
transesterification of esters have been reported in the literature.1-8 In the course of our
research efforts, we found that Pd/C-catalyzed hydrogenation conditions in the presence of
bromobenzene additive can accomplish simultaneous esterification and transesterification
reactions in a highly efficient manner.
In an ongoing medicinal chemistry program, we wished to synthesize 2, which we planned to
prepare by hydrogenation of 4-chlorocinnamic acid 1 in the presence of 10% Pd/C (50% wet)
using methanol as a solvent. To our surprise, only 10% of the desired 3-(4-chlorophenyl)-
propanoic acid 2 was obtained. Instead, the reaction proceeded to produce 90% of the methyl-

3-phenylpropanoate 3 (Scheme 1). This finding encouraged us to study the influencing
factors for the unprecedented esterification reaction.
10% Pd/C (50% wet)
H2 gas (5 bar), 40 oC
CH3OH solvent
1
2
3
10% (expected product) 90% (unexpected product)
Scheme 1.Catalytic hydrogenation of alkene derivative 1
The probable mechanism of this unprecedented esterification could be the result of the in situ
generation of HCl from 4-chlorocinnamic acid 1 in the presence of palladium catalyst under
hydrogen pressure, which provides a mild and an acidic reaction environment.
These results prompted us to explore further this unprecedented esterfication reaction, and an
optimization study was undertaken. First, we decided to employ bromobenzene as an external
acid source to consider whether the esterification is accessible. Thus, phenylacetic acid 4
(0.0036 moles), bromobenzene (0.00018 moles), 10% Pd/C (0.01 g) and methanol (3 mL)
were placed in an autoclave vessel. Autoclave was pressurized with 1-2 bar of nitrogen
followed by 1-2 bar of hydrogen gas. The reaction mixtures were then warmed to 25oC
temperature and stirred for 1 h at 300 rpm. The methyl phenyl acetic acid ester 5 could be
isolated in 98% yield (Scheme 2).
Table 1. Palladium-catalyzed esterification of phenylacetic acid under different reaction conditionsa
Additive (0.05 equiv)
10% Pd/C (50% wet)
H2 gas (1-2 bar), 25 oC
CH3OH solvent
5
4
Entry
Catalyst
Additive
Hydrogen
Source
Isolated
Yield of 5 (%)
1
2
3
10% Pd/C (dry)
10% Pd/C (50% wet)
10% Pd/C (50% wet)
Bromobenzene
Bromobenzene
Chlorobenzene
H2 gas
H2 gas
H2 gas
98
98
80
4
5
10% Pd/C (50% wet)
10% Pd/C (50% wet)
Bromobenzene
Bromobenzene
HCOONH4
--
No reaction
No reaction

6
7
10% Pd/C (50% wet)
--
--
H2 gas
H2 gas
No reaction
No reaction
Bromobenzene
8
10% Pd/C (50% wet)
Bromobenzene + 0.5
H2 gas
No reaction
eq of n-BuNH2
a
Reaction conditions: Phenylacetic acid (1.0 g, 0.00734 mol), bromobenzene (0.11 g, 0.000734 mol),
chlorobenzene (0.08 g, 0.000734 mol), Catalyst 10% Pd/C (0.1 g of 10% wt of 4), methanol (3 mL), H2 pressure
(1-2bar ), temperature 25oC and time 2 h.
A series of combinations of reagents were screened, and the results are presented in Table 1.
Esterfication reaction proceeded smoothly when halo benzenes used in presence of catalytic
amount of palladium under 1-2 bar of hydrogen pressure (entries 1-3). During attempts to
conduct the reaction with palladium and bromobenzene in the absence of hydrogen gas (entry
5), no esterification occurred and starting material was recovered almost quantitatively by
column chromatography. Furthermore, in the absence of either bromobenzene or palladium
no product formation 5 observed (entries 6&7).
From entry 1 and 2, it is clear that esterification progressed by the in situ generation of HBr
from bromobenzene. In support of this hypothesis, the addition of 0.5equiv of n-butylamine
to the reaction mixture did not render 5, which should neutralize the liberated HBr acid,
inhibits the esterification reaction (entry 8, Table 1). This observation indicates that a
Brønsted acid is involved in the mechanism. Alternatively a reaction sample of entry 1 was
withdrawn for gas chromatography mass spectral analysis (GCMS) after 1 h. Two peaks
corresponding to mass 78 and 150 were observed, which corresponds to the structure of
benzene and methyl phenyl acetate (Table 2, entry 1), GCMS traces indicated that
bromobenzene converted completely to benzene.
The probable mechanism for the unprecedented esterification of the aryl/aliphatic acids with
alcohols could be the oxidative insertion of Pd(0) into the Ar–X bond to produce an aryl
palladium halide under the present reaction conditions. This aryl palladium species in contact
with hydrogen gas leads to generation of anhydrous HBr acid, Pd(0) and benzene as the by-
products. Proton transfer from the generated HBr to carbonyl oxygen increases
electrophilicity of carbonyl carbon of acid followed by the Fischer esterification with alcohol.

H2
R
HX
H+
-H+
R
R
R
R
R
R
Ar-Pd-X
Ar-Pd-H
-H+
R
R
Pd(0)
R
OR
OR
R
Ar-X
Ar-H
H2O
Figure 1: A proposed mechanism of the reaction
We proceeded to examine the substrate scope of the reactionof model acid 4 with different
alcohols (methanol, ethanol, 1-butanol, 1-octanol, benzyl alcohol, isopropanol, t-butanol and
Phenol) with bromobenzene as an additive to determine the scope of this procedure. The
results are given in Table 2.
The results obtained in the esterification of model acid 4 under the optimized reaction
conditions were, in general, good to excellent. Thus, when alcohols were used (entries 1-6)9
we obtained the corresponding esters in excellent yields. However, when more hindered
hydroxyl groups (secondary or tertiary or phenol, entries 6, 7 and 8) were studied, poor
results or no products were observed.
Table2. Esterification of phenyl acetic acid with various alcoholsa
Additive (0.05 equiv)
10% Pd/C (50% wet)
H2 gas (1-2 bar), 25 oC
Alcohol
R
Ester
4

Entry
Alcohol
CH3OH
C2H5OH
Time (h)
0.5
Product (R)
C6H5CH2COOCH3
Yieldb (%)
1
2
3
4
5
6
7
8
95
91
84
80
75
1.0
2.0
2.0
2.0
15
48
48
C6H5CH2COOC2H5
C6H5CH2COOC4H9
C6H5CH2COOC8H17
C6H5CH2COOCH2C6H5
C6H5CH2COOCH(CH3)2
C6H5CH2COOC(CH3)3
C6H5CH2COOC6H5
n-C4H9OH
n-C8H17OH
C6H5CH2OH
(CH3)2CHOH
(CH3)3COH
C6H5OH
64
No reaction
No reaction
a
Reaction conditions: Acid (1.0 equiv), bromobenzene (0.1 equiv), catalyst 10% Pd/C (50% wet) (0.2g),
methanol (3 mL), 5-6 bar H2 pressure, temperature 55-60oC and time 4-8 h.
b Isolated yields
The rate of esterification becomes much slower when the methanol is replaced with a more
sterically hindered alcohol, such as isopropanol. Thus, when we treated phenylacetic acid 4
with a mixture of MeOH and iPrOH in the presence of catalytic amounts of bromobenzene
and palladium under 1 bar of hydrogen pressure, 96%yield of ester 5 was obtained (Scheme
2).
10% Pd/C, Bromobenzene
H2 gas (1 bar), 25 oC, 0.5 h
MeOH
iPrOH
(96%)
5
4
Scheme 2. Chemoselective esterification of acid 4 with a mixture of MeOH and iPrOH
The results led us to investigate further this highly chemoselective esterification process
which distinguishes between aliphatic and aromatic carboxylic acids. A mixture of
phenylacetic acid and benzoic acid with catalytic amounts of palladium and bromobenzene in
methanol solvent was investigated under similar reaction conditions (Scheme 3).The aliphatic
primary acid was converted into its methyl ester in 98% yield, whereas the aromatic
carboxylic acid was stable under the reaction conditions for 30 mins and a 90% of benzoic
acid was recovered after the basic work-up.
10% Pd/C, Bromobenzene
H2 gas (1 bar), 25 oC, MeOH
(3.0 mL), 0.5 h
5
6
4
6
90%
99%
Scheme 3. Chemoselective esterification of acids 4 and 6 with MeOH solvent

Once we studied the effectiveness of our method for different kinds of alcohols (Table 2), we
decided to establish the versatility of our process. We extended the method to a series of
benzoic acid derivatives under 5-6 bar of hydrogen pressure and temperature (55-60oC) using
methanol as alcohol for the esterification. To our satisfaction, the results obtained in the
esterification of the acids (Table 3, entry 1-7 and 9-11)9 were good to excellent, except for the acid in
(Table 3, entry 8),9 along with esterification, the vinyl group also got hydrogenated to ethyl group.
The results obtained in the reactions are summarized in Table 3.
A few of the acids (Table 3, entries 1, 3, 5 and 7) were treated with methanol in order to
understand the effect of substituent’s on the reaction rate (Figure 2). The results clearly
demonstrate the substituent dependence on the rate of the reaction, though not so prominent.
In case of the esterification of the electron rich amino substituted acid (entry 5), the reaction
rate was comparatively sluggish, which could be due to the salt formation of liberated HBr
with amine leading to less availability (in terms of low dissociation of salt in methanol) of
acid for the esterification.
Figure 2. Rates of esterification reaction
Table 3: Esterification of aromatic acids with methanola
10% Pd/C, Bromobenzene,
H2 gas (5 bar), 55-60 oC, 4-8 h,
MeOH (3.0 mL)
R-COOCH3
R-COOH

Entry
R
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
9
C6H5
4
4
4
4
8
4
8
6
4
8
4
90
88
92
87
80
85
88
90
86
85
85
o-CH3OC6H4
p-CH3OC6H4
3,5-(CH3)2C6H3
p-(CH3)2NC6H4
1-Naphthy
p-FC6H4
p-CH2=CHC6H4
2-Furyl
10
11
1,4-(COOH)2C6H4
p-CH3C6H4
a
Reaction conditions: Acid (1.0 equiv), bromobenzene (0.1 equiv), catalyst 10% Pd/C (50% wet) (0.2g),
methanol (3 mL), 5-6 bar H2 pressure, temperature 55-60oC and time 4-8 h.
b Isolated yields
We further extended our study to the transesterfication reaction under the same conditions
utilized for esterification of aromatic acids with methanol. The results obtained in
transesterification reactions are summarized in Table 4. Transesterfication of methyl ester of
phenyl acetic acid proceeded smoothly with different alcohols (Table 4, entries 1-5)10 with
good yields, while with hindered alcohols like t-butyl alcohol (Table 4, entry 6) did not
proceed even at high temperatures and pressures. Transformations of esters of higher
homologues were easily transesterified with methanol to form methyl phenyl acetate with
good yields (Table 4, entries 7 and 8).10 The transesterification of methyl benzoate to ethyl
benzoate and vice versa (Table 4, entry 9 & 10)10 were accomplished with ease, whereas with
hindered alcohols like isopropanol (Table 4, entry 11) the reaction did not proceed.
Table 4. Transesterfication of carboxylic acid esters with alcoholsa
Entry
Ester
Alcohol
C2H5OH
Product
Yieldb (%)
1
2
3
4
5
6
7
8
9
C6H5CH2COOCH3
C6H5CH2COOCH3
C6H5CH2COOCH3
C6H5CH2COOCH3
C6H5CH2COOCH3
C6H5CH2COOCH3
C6H5CH2COOC8H17
C6H5CH2COOC4H9
C6H5COOC2H5
C6H5CH2COOC2H5
C6H5CH2COOC4H9
C6H5CH2COOC8H17
C6H5CH2COOC7H7
C6H5CH2COOCH(CH3)2
C6H5CH2COOC(CH3)3
C6H5CH2COOCH3
C6H5CH2COOCH3
C6H5COOCH3
80
78
70
72
n-C4H9OH
n-C8H17OH
C6H5CH2OH
(CH3)2CHOH
(CH3)3COH
CH3OH
72
No reaction
75
70
70
CH3OH
CH3OH
10
11
C6H5COOCH3
C6H5COOC2H5
C2H5OH
(CH3)2CHOH
C6H5COOC2H5
C6H5COOCH(CH3)2
75
No reaction
a
Reaction conditions: Ester (1.0 equiv), bromobenzene (0.2 equiv), catalyst 10% Pd/C (50% wet) (0.2g),
methanol (3 mL), 5-6 bar H2 pressure, temperature 55-60oC and time 4-8 h.
b Isolated yields

The possibility to reuse palladium catalyst was determined, at the end of the reaction. The
catalyst was separated, washed with a mixture of hot methanol and water, and reused as such
for subsequent experiments (up to three cycles) under similar reaction conditions (Table 2,
entry 1). It was noticed that yields of the product remained comparable in these experiments
and thereby pointing to the recyclability and reusability of the catalyst without any significant
loss in catalytic activity.
Table 4. Recycling test of palladium catalyst
Recyclising run
Yield (%)
1
2
3
95
89
91
In conclusion, we have demonstrated a new method for esterification by a simple
condensation of carboxylic acid with alcohol under Pd/C-catalyzed hydrogenation conditions
in the presence of catalytic amount of bromobenzene additive and method could also be
applicable to the transesterfication of esters. The success of this esterification relies on the in
situ generation of HBr from bromobenzene (additive). This method is very simple and
environmentally benign (e.g., heterogeneous catalyst). The palladium catalyst exhibits
remarkable activity and is reusable for upto three consecutive cycles.
Acknowledgments
We thank Sudhir Nambiar, R. Sridharan, Bill Moss, Ramachandra Puranik and Srinivasa Rao
for useful discussions in the manuscript preparation.
References and notes
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(9) General procedure for the esterification: Benzoic acid (Table 3, entry 1) (1.0 g, 0.0081
moles), bromobenzene (0.125 g, 0.0081 moles), 10% palladium on carbon (50% wet) (0.2 g)
and methanol (3 mL) were placed in autoclave vessel. Autoclave was pressurized with 1-2
bar of nitrogen followed by 1-2 bar of hydrogen gas and then put under the desired pressure
o
of hydrogen (5-6 bar). The reaction mixtures are then warmed to 55-60 C temperature and
stirred for 4 h at 300 rpm. After reaction, the catalyst was filtered through celite bed. Filtrate
was added with water (30 mL). The reaction mixture was extracted with isopropyl acetate (2
x 15 mL). The combined organic layers were washed with 5% aqueous sodium bicarbonate

solution (2 x 15 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was evaporated
under vacuum to give of methyl benzoate product.
(10) General procedure for the transesterification: Methyl phenyl acetate (Table 3, entry 1) (1.0
g, 0.0067 mol), ethanol (3.0 mL), bromobenzene (0.1 g, 0.0067 mol), 10% palladium on
carbon (50% wet) (0.1 g) and ethanol (3 mL) were placed in autoclave vessel. Autoclave was
pressurized with 1-2 bar of nitrogen followed by 1-2 bar of hydrogen gas and then put under
the desired pressure of hydrogen (5-6 bar). The reaction mixtures are then warmed to 55-60
oC temperature and stirred for 4 h at 300 rpm. After reaction, the catalyst was filtered through
celite bed. Filtrate was added with water (30 mL). The reaction mixture was extracted with
isopropyl acetate (2 x 15 mL). The combined organic layer was washed with 5% aqueous
sodium bicarbonate solution (2 x 15 mL), dried over anhydrous Na2SO4 and filtered. The
filtrate was concentrated in vacuo to yield the crude product, which was purified by column
chromatography (hexane: ethyl acetate, 9:1) to give ethyl phenyl acetate.