Protic acid immobilized on solid support as an extremely efficient recyclable catalyst system for a direct and atom economical esterification of carboxylic acids with alcohols

Article abstract of DOI:10.1021/jo900614s

(Chemical Equation Presented) A convenient and clean procedure of esterification is reported by direct condensation of equimolar amounts of carboxylic acids with alcohols catalyzed by an easy to prepare catalyst system of perchloric acid immobilized on silica gel (HClO₄-SiO₂). The direct condensation of aryl, heteroaryl, styryl, aryl alkyl, alkyl, cycloalkyl, and long-chain aliphatic carboxylic acids with primary/secondary alkyl/cycloalkyl, allyl, propargyl, and long-chain aliphatic alcohols has been achieved to afford the corresponding esters in excellent yields. Chiral alcohol and N-t-Boc protected chiral amino acid also resulted in ester formation with the representative carboxylic acid or alcohol without competitive N-t-Boc deprotection and detrimental effect on the optical purity of the product demonstrating the mildness and chemoselectivity of the procedure. The esters of long-chain (>C₁₀) acids and alcohols are obtained in high yields. The catalyst is recovered and recycled without significant loss of activity. The industrial application of the esterification process is demonstrated by the synthesis of prodrugs of ibuprofen and a few commercial flavoring agents. Other protic acids such as H₂SO₄, HBr, TfOH, HBF₄, and TFA that were adsorbed on silica gel were less effective compared to HClO₄-SiO₂ following the order HClO₄-SiO ₂ ? H₂SO₄-SiO₂ > HBr-SiO ₂ > TfOH-SiO₂ ? HBF₄-SiO₂ ≈ TFA-SiO₂. When HClO₄ was immobilized on other solid supports the catalytic efficiency followed the order HClO₄-SiO ₂ > HClO₄-K10 > HClO₄-Al ₂O₃ (neutral) > HClO₄-Al₂O ₃ (acidic) > HClO₄-Al₂O₃ (basic).

Full text of DOI:10.1021/jo900614s

pubs.acs.org/joc
Protic Acid Immobilized on Solid Support as an Extremely Efficient
Recyclable Catalyst System for a Direct and Atom Economical
Esterification of Carboxylic Acids with Alcohols
Asit K. Chakraborti,* Bavneet Singh, Sunay V. Chankeshwara, and Alpesh R. Patel
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research
(NIPER), Sector 67, S. A. S. Nagar 160 062, Punjab, India Fax: (+91) 0172- 2214 692
akchakraborti@niper.ac.in
Received March 23, 2009
A convenient and clean procedure of esterification is reported by direct condensation of equimolar
amounts of carboxylic acids with alcohols catalyzed by an easy to prepare catalyst system of
perchloric acid immobilized on silica gel (HClO4-SiO2). The direct condensation of aryl, heteroaryl,
styryl, aryl alkyl, alkyl, cycloalkyl, and long-chain aliphatic carboxylic acids with primary/secondary
alkyl/cycloalkyl, allyl, propargyl, and long-chain aliphatic alcohols has been achieved to afford the
corresponding esters in excellent yields. Chiral alcohol and N-t-Boc protected chiral amino acid also
resulted in ester formation with the representative carboxylic acid or alcohol without competitive
N-t-Boc deprotection and detrimental effect on the optical purity of the product demonstrating the
mildness and chemoselectivity of the procedure. The esters of long-chain (>C10) acids and alcohols
are obtained in high yields. The catalyst is recovered and recycled without significant loss of activity.
The industrial application of the esterification process is demonstrated by the synthesis of prodrugs of
ibuprofen and a few commercial flavoring agents. Other protic acids such as H2SO4, HBr, TfOH,
HBF4, and TFA that were adsorbed on silica gel were less effective compared to HClO4-SiO2
following the order HClO4-SiO2 . H2SO4-SiO2 > HBr-SiO2 > TfOH-SiO2 . HBF4-SiO2 ≈
TFA-SiO2. When HClO4 was immobilized on other solid supports the catalytic efficiency followed
the order HClO4-SiO2 > HClO4-K10 > HClO4-Al2O3 (neutral) > HClO4-Al2O3 (acidic) >
HClO4-Al2O3 (basic).
Introduction
group,2 constitutes 28% of all the transformations involved
in drug synthesis,3 and amounts to one-fourth of the bulk
reactions in the manufacturing of drugs and pharmaceuti-
cals.4 These advantages make esterification one of the most
important organic reactions to occupy a prominent place in
the desire to develop benign and sustainable methodologies5
for industrial applications.
Organic esters are important products/intermediates in
the chemical and pharmaceutical industries where they are
extensively used for the production of fragrances, polymers,
polyesters, plasticizers, fatty acids, and paints which are
considered as high production-volume (HPV) chemicals.1
Esterification provides a means of masking carboxylic acid
Dialkyl sulfates are popular as O-alkylation agents6 and
chemoselective carboxyl O-alkylation with dialkyl sulfates is
*To whom correspondence should be addressed. Fax: 91-(0)-172 2214692.
Phone: 91-(0)-172 2214683.
(1) Otera, J. Esterification: Methods, Reactions and Applications; Wiley-
VCH: Weinheim, Germany, 2003.
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2005, 9, 253.
(2) Greene, T. W.; Wuts, P. G. M. Protective Groups Organic Synthesis,
3rd ed.; Wiley: New York, 1999.
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Miyamoto, J.; Polyakoff, M.; Tumas, W. Pure Appl. Chem. 2000, 72, 1207.
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(3) Carey, J. S.; Laffan, D.; Thomson, C.; Williams, M. T. Org. Biomol.
Chem. 2006, 4, 2337.
(6) Basak (nee Nandi), A; Nayak, M. K.; Chakraborti, A. K. Tetrahedron
Lett., 1998, 39, 4883 and the references cited therein.
DOI: 10.1021/jo900614s
r
Published on Web 07/21/2009
J. Org. Chem. 2009, 74, 5967–5974 5967
2009 American Chemical Society

Chakraborti et al.
JOCArticle
an alternative to the diazoalkane protocol.7 However, the
lack of commercial availability of different dialkyl sulfates
limits their application to methyl/ethyl esters and indicates
the necessity for better and general alkylating agents.
and primary alcohols as substrates. The carboxylic acid
activation strategies15 require stoichiometric amounts of addi-
tional reagent such as tetramethylfluoroformamidinium hex-
afluorophosphate (TFFH) (not available commercially and
requires special efforts for preparation) or di-tert-butyl dicar-
bonate and toxic 4-dimethylaminopyridine (DMAP)16 as the
catalyst. The Lewis acid catalyzed decarboxylative esterifica-
tion of carboxylic acids with dialkyl dicarbonates17 is not atom
economical and requires costly reagents. Therefore, the search
remains for a general and practical esterification procedure.18
We were influenced by the awareness of the use of solid
acids19 and chemical processes on solid surfaces20 as envir-
onmentally friendly approaches in organic synthesis. In
pursuit of designing/choosing a suitable catalyst system, we
realized that the usual homogeneous catalysts are often
destroyed during product isolation and this “once through”
utilization of the catalyst can result in unacceptably high
manufacturing costs. A heterogeneous catalyst system, on
the other hand, may be easily recovered by filtration and
recycled. This has advantages in that the extra processing
steps are eliminated and spent catalyst disposal is minimized.
To this endeavor we discovered two novel catalyst systems,
e.g., perchloric acid immobilized on silica gel (HClO4-SiO2)
and fluoroboric acid immobilized on silica gel (HBF4-SiO2),21
that were found to be highly effective for various organic
transformations.21,22 These catalyst systems (HClO4-SiO2
and HBF4-SiO2) are/were not commercially available and
were invented by Chakraborti and Gulhane and used for the
first time for organic synthesis.21 We were delighted to observe
Dimethyl carbonate (DMC) is considered a safer methylat-
ing reagent8 and has been used for reaction with nucleophiles
such as phenols, primary amines, sulfones, thiols, and active
methylene derivatives.9 But the lack of commercial availability
of a variety of dilakyl carbonates is a disadvantage for their
general use. Although DMC can be considered an environ-
mentally benign compound, the reported reaction conditions
for methylation with DMC are not apparently green as these
require high temperature (>160 °C) that implies an autogenic
pressure (>3 bar). The reactions are carried out either under
continuous flow or batch reactors in the presence of base
catalysts. The limited reports on carboxyl-O-methylation with
DMC involve the treatment in the presence of NaY faujasite at
165 °C in a stainless-steel autoclave for 13-20 h,10 heating in
the presence of stoichiometric amounts of DBU under reflux,11
or circulating the reaction mixture in a microwave reactor
preheated to 160 °C at 20 bar under microwave irradiation.12
The condensation of a carboxylic acid with alcohol
appears to be the most straightforward and general route
for the synthesis of esters. However, the difficulty arises due
to the reversibility of the reaction. Therefore, it necessitates
the need to use excess amounts of one of the reactants over
the other or the continuous removal of the water formed to
drive the reaction equilibrium toward the product (ester).
The former process is not preferred on the grounds of “atom
economy”.13 Water removal by azeotropic distillation or by
the use of dehydrating agents does not make the desired
conversion/yield easy to achieve. An ideal esterification
process should be the one that offers quantitative conver-
sion/yield from molar equivalents (1:1 ratio) of the car-
boxylic acid and the alcohol and avoids the necessity of a
dehydration process. Thus, efforts have been directed
toward esterification with 1:1 ratio of carboxylic acid and
the alcohol.14 However, some of these methodologies still
require heating (azeotropic water removal) in solvents such
as o-xylene, 1,3,5-mesitylene, or toluene14a-c and dehydrat-
ing agents.14a,d The other esterification procedure involving
heating in Brønsted acidic ionic liquids as solvent14e,f or
using surfactant-combined14g/Brønsted acidic ionic
liquid14h catalysts is limited to a few simple carboxylic acids
that soon after the original work on its invention Chakraborti’s
21a,c
novel catalyst system HClO4-SiO2
caught the attention
of other researchers globally who started applying HClO4-
SiO2 as catalyst for a large variety of organic reactions/
syntheses (e.g., amidoalkylation of naphthols, construction
of heterocyclic scaffolds, homoallyl amines, R-bromo and
β-amino/sulfido carbonyl compounds, trisubstituted alkenes,
acylals, carbohydrates, etc.).23 We now report HClO4-SiO2 as
an extremely efficient and reusable catalyst system for a
general and practical esterification process by direct condensa-
tion of carboxylic acids with alcohols in atom economical
fashion.24
Results and Discussion
Various protic acids adsorbed on solid supports were
studied for their efficiency toward the esterification of
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5968 J. Org. Chem. Vol. 74, No. 16, 2009

Chakraborti et al.
JOCArticle
TABLE 1. Direct Esterification of 1 with 2 Catalyzed by Protic Acids
Immobilized on Solid Supportsa
SCHEME 1. Direct Condensation of 4 and 5 To Form 6 in the
Presence of HClO4-SiO2, H2SO4-SiO2, and HBr-SiO2
SCHEME 2. Direct Condensation of 7a-c and 8 Catalyzed by
HClO4-SiO2 and H2SO4-SiO2 To Form 9a-c
entry
catalyst
yield (%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
SiO2
nilc
15c
30c
nilc
nilc
nilc
98
Montmorillonite K10
Montmorillonite KSF
Al2O3 (neutral)
Al2O3 (acidic)
Al2O3 (basic)
HClO4-SiO2
HClO4-K10
90
HClO4-Al2O3 (neutral)
HClO4-Al2O3 (acidic)
HClO4-Al2O3 (basic)
H2SO4-SiO2
85
65c
60c
95
effect (entries 1-6). It is likely that the role of silica gel may
not merely be to provide the surface area. The significantly
superior catalytic activity of the perchloric acid adsorbed on
silica gel than on other solid supports such as alumina
(acidic/basic) indicates that silica gel enhances the Bronsted
acidic property. However, the simple role of silica as a water
sequestering agent may be ruled out since perchloric acid
adsorbed on other solid supports exhibits inferior catalytic
properties. Thus, while alumina is known for its dehydrating
property, the inferior catalytic activity of perchloric acid
adsorbed on alumina (acidic/basic) compared to that of
HClO4-SiO2 does not substantiate that silica gel in
HClO4-SiO2 serves only to sequester the water.
As comparable results were obtained in using HClO4-
SiO2, H2SO4-SiO2, and HBr-SiO2, we decided to judge the
most effective catalyst system. For this, the Fischer conden-
sation of benzoic acid (4) (2.5 mmol) (as the carbonyl carbon
of aromatic carboxylic acid is less electrophilic compared to
that in 1) with 2-octanol (5) (2.5 mmol) (a representative
sterically hindered alcohol compared to 2) was considered
as the model (Scheme 1). The desired product octan-2-yl
benzoate (6) was obtained in 95%, 90%, and 40% yields,
respectively, at 80 °C after 20 h.
Further efforts were made for the evaluation of mildness
and efficiency of the HClO4-SiO2 and H2SO4-SiO2 for the
esterification of 4-chlorobenzoic acid (7a), 4-nitrobenzoic
acid (7b), and 2-fluoro-5-nitrobenzoic acid (7c) [repre-
sentatives of moderately and strongly deactivated aromatic
carboxylic acids compared to 4] with an acid sensitive alcohol
propargyl alcohol (8) under identical reaction conditions
(Scheme 2). The desired esters prop-2-ynyl 4-chlorobenzoate
(9a), prop-2-ynyl 4-nitrobenzoate (9b), and prop-2-ynyl
2-fluoro-5-nitrobenzoate (9c) were obtained in 80%, 79%,
and 78% yields, respectively, in using HClO4-SiO2 compared
to 20%, 46%, and 38% yields of the corresponding products
for the H2SO4-SiO2 catalyzed reactions and established that
HClO4-SiO2 is the most effective catalyst system.
Having on hand HClO4-SiO2 as an efficient catalyst for
direct esterification, efforts were made to optimize the reac-
tion conditions by varying the various reaction para-
meters such as catalyst loading and reaction conditions
(e.g., reaction temperature and solvent). For the determina-
tion of the effective amount of HClO4-SiO2, the reaction of
HBr-SiO2
95
HBF4-SiO2
15c
10c
85
TFA-SiO2
TfOH-SiO2
aThe mixture of 1 (2.5 mmol) and 2 (2.5 mmol) in the presence of the
catalyst (1 mol %) was heated for 3.5 h at 80 °C under solvent-free
conditions. bIsolated yield of purified 3. cThe unreacted starting materi-
als remained unchanged.
4-phenylbutyric acid (1) with equimolar amounts of n-octa-
nol (2) in the absence of any solvent at 80 °C (Table 1). The
desired ester n-octyl 4-phenylbutyrate (3) was obtained 98%,
95%, and 95% yields in the presence of HClO4-SiO2,
H2SO4-SiO2,24,25a,b and HBr-SiO2 (entries 7, 12, and
13, Table 1), respectively. The use of Montmorillonite
K10/KSF provided lesser yield (90%) but the use of other
solid supports such as alumina24,25a,c (neutral/basic/acidic)
in place of silica gel was found to be far less effective. The
solid supports alone did not exhibit any significant catalytic
(23) Representative work of other research groups on the use of HClO4-
SiO2: (a) Agarwal, A.; Rani, S.; Vankar, Y. D. J. Org. Chem. 2004, 6137.
(b) Misra, A. K.; Tiwari, P.; Madhusudan, S. K. Carbohydr. Res. 2005, 340,
325. (c) Mukhopadhyay, B.; Russell, D. A.; Field, R. A. Carbohydr. Res.
2005, 340, 1075. (d) Du, Y.; Wei, G.; Cheng, S.; Hua, Y.; Linhardt, R. J.
Tetrahedron Lett. 2006, 47, 307. (e) Maheswara, M.; Siddaiah, V.; Damu, G.
L. V.; Rao, C. V. ARKIVOC 2006, 201. (f) Khan, A. T.; Ghosh, S.;
Choudhury, L. H. Eur. J. Org. Chem. 2006, 2226. (g) Kamble, V. T.; Jamode,
V. S.; Joshi, N. S.; Biradar, A. V.; Deshmukh, R. Y. Tetrahedron Lett. 2006,
47, 5573. (h) Das, B.; Majhi, A.; Banerjee, J. Tetrahedron Lett. 2006, 47, 7619.
(i) Narasimhulu, M.; Reddy, T. S.; Mahesh, K. C.; Prabhakar, P.; Rao, Ch.
B.; Venkateswarlu, Y. J. Mol. Catal. A: Chem 2007, 266, 114. (j) Nagarapu,
L.; Paparaju, V.; Pathuri, G.; Kantevari, S.; Pakkiru, R. R.; Kamalla, R.
J. Mol. Catal. A: Chem. 2007, 267, 53. (k) Bigdeli, M. A.; Nemati, F.;
Mahdavinia, G. H. Tetrahedron Lett. 2007, 48, 6801. (l) Colinas, P. A.;
Bravo, R. D. Carbohydr. Res. 2007, 342, 2297. (m) Naik, T. R. R.; Naik, H. S.
B.; Raghavendra, M.; Bindu, P. J.; Mahadevan, K. M. J. Sulf. Chem. 2007,
28, 589. (n) Nagarapu, L.; Aneesa; Peddiraju, R.; Apuri, S. Catal. Commun.
2007, 8, 1973. (o) Meshram, H. M.; Reddy, P. N.; Murthy, P. V.; Yadav, J. S.
Synth. Commun. 2007, 37, 4117. (p) Shaterian, H. R.; Yarahmadi, H.;
Ghashang, M. Tetrahedron 2008, 64, 1263. (q) Heydari, A.; MaMani, L.
Appl. Organomet. Chem. 2008, 22, 12. (r) Gupta, R.; Gupta, M.; Paul, S.;
Gupta, R.; Loupy, A. Lett. Org. Chem. 2008, 5, 153.
(24) Chakraborti, A. K.; Chankeshwara, S. V.; Singh, B. Indian patent
2764/DEL/2007 (Dec 28, 2007).
(25) (a) Bhagat, S.; Ph.D. Thesis, Aug 2008, National Institute of Pharma-
ceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar, Punjab 160
062, India. (b) Mukhopadhyay, B. Tetrahedron Lett. 2006, 47, 4337. (c) Sheritan,
H. R.; Khorami, F.; Amirzadeh, A.; Ghashang, M. Phosphorus Sulfur Relat.
Elem. 2008, 183, 2865.
J. Org. Chem. Vol. 74, No. 16, 2009 5969

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TABLE 2. DirectEsterificationof1with2, 10with11, and13withMeOH
Catalyzed by HClO4-SiO2 under Varying Reaction Temperaturea
entry
acid
alcohol
temp (°C)
time (h)
yield (%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
1
1
1
1
2
2
2
2
2
11
11
11
rt
60
80
100
100
rt
60
80
100
rt
60
80
80
100
100
24
24
3.5
3.5
2
6
6
6
3.5
24
24
3
2
3
nilc
44c
98
99
74
1
10
10
10
10
13
13
13
13
13
13
50c
70c
100
70
11
nilc
62c
95
FIGURE 1. Graphical representation of the time required for
direct condensation of 10 (2.5 mmol) with 11 (2.5 mmol) in the
presence of various amounts of HClO4-SiO2 to form 12.
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
80
96
dihydrocinnamic acid (10) with allyl alcohol (11) was con-
sidered as the model. When the reactions were carried out with
lower amounts of the catalyst (0.1 and 0.5 mol %) either trace
amounts of product were formed or incomplete conversion of
the starting materials to the product was observed after
10 h at 80 °C. Excellent (100%) conversion to prop-2-enyl
3-phenylpropionate (12) took place with 1 and 2 mol % of
HClO4-SiO2 after 6 h at 80 °C. No significant reduction in
time was observed in increasing the catalyst loading to 2 mol %
(Figure 1). Thus the effective/convenient catalyst loading was
found to be 1 mol %.
To find out the best operative reaction temperature we
considered the following sets of model reaction: condensa-
tion of (i) 1 (a representative arylalkyl carboxylic acid) with 2
(a representative high boiling alcohol), (ii) 10 with 11
(a representative acid sensitive alcohol), and (iii) benzoic
acid 13 (a representative aryl carboxylic acid) with MeOH
(a representative low-boiling alcohol). The reactions were
performed under varying reaction temperature and time with
1 mol % of HClO4-SiO2 (Table 2). The optimum/best result
was obtained at 80 °C.
We next planned to determine the influence of solvent on
the catalytic efficiency of HClO4-SiO2 during the reaction
of a equimolar ratio of 10 and 11. The presence of solvent was
found to have a detrimental impact on the yields of 12. No
esterification took place in DCM or hexane and dioxane
afforded moderate yield (50%). However, better yields were
observed when the reactions were performed with toluene
(95%) and MeCN (80%) but the best yield (98%) was
obtained under solvent-free conditions.
To extend the scope of the reaction as a general and
practical procedure for esterification, we carried out the
reaction of a series of aryl, heteroaryl, styryl, arylalkyl,
aliphatic, and cycloalkane carboxylic acids with equimolar
amounts of primary/secondary aliphatic, allylic, pro-
pargylic, benzylic, aryl alkyl, and cycloalkyl alcohols under
solvent-free conditions at 80 °C in the presence of HClO4-
SiO2 (1 mol %). The reactions were completed after 3-20 h
affording excellent yields of the corresponding esters
(Table 3). No competitive side reactions such as the rearran-
gement of unsaturated alcohols, decomposition of acid
sensitive substrates, or decarboxylation of the carboxylic
acids were observed. In the case of esterification with chiral
alcohol, the enantiomerically pure ester was obtained in
excellent yields without any racemization (entry 12). The
esterification was performed with acid-sensitive carboxylic
acids (entries 34-36) affording corresponding ester deriva-
tives in high yields. The mildness/chemoselectivity of the
2
79c
aThe acid (2.5 mmol) was treated with the alcohol (2.5 mmol) in the
presence of HClO4-SiO2 (1 mol %) at the specified temperature (oil
bath) for the specified time under solvent-free conditions until max-
imum/complete conversion (TLC/GCMS). bYield of the corresponding
ester after purification. cThe unreacted starting materials remained
unchanged.
HClO4-SiO2 catalyzed reaction was further demonstrated
with N-t-Boc amino acid (entry 43) that resulted in the
chemoselective formation of the corresponding ester in
excellent yield without any effect on the N-t-Boc function-
ality. The reaction with proline (entries 37 and 38) further
demonstrated the chemoselectivity as no competitive
N-alkylation products were formed. The formation of the
desired esters (entries 37, 38, and 43) in optically pure form
(based on specific rotation) demonstrates the applicability of
the methodology for chiral substrates. In most of the cases,
the products obtained after the usual workup were pure
(spectral data) and did not require additional efforts of
purification. Wherever required, the purification was per-
formed by column chromatography.
Keeping in view the wide industrial application of ester-
ification for synthesis of drugs, drug intermediates, fine
chemicals, and auxiliary agents like flavoring agents we
planned to investigate the application of the catalyst system
for syntheses of compounds used in industry.
Prodrugs are synthesized by converting the parent drug
molecule to esters to improve solubility or bioavailability.
Ibuprofen(14) istherapeutically usedforitsanti inflammatory
and analgesic action. However, it causes gastric irritation and
if taken in higher doses for long periods of time can cause
gastric ulcers. This side effect of the drug can be reduced if it is
taken as a prodrug and the most effective prodrugs were the
corresponding 2-propyl and n-butyl esters.26 However, the
syntheses of these prodrugs involved the traditional acid
chloride strategy that generates acidic waste, requires elabora-
tive purification, and affords moderate yields. The HClO4-
SiO2 catalyzed direct esterification of 14 with n-butanol and
2-propanol afforded these prodrugs n-butyl and 2-propyl
esters of ibuprofen 15 and 16 in 82% and 76% yields after
9 and 14 h, respectively (Scheme 3).
Fatty acid esters are used as emulsifiers or as oiling agents
for foods and textiles, personal care emollients, surfactants
(26) (a) Bansal, A. K.; Khar, R. K.; Dubey, R.; Sharma, A. K. Indian J.
Exp. Biol. 2001, 39, 280. (b) Bansal, A. K.; Khar, R. K.; Dubey, R.; Sharma,
A. K. Pharmazie 1994, 49, 422.
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a
TABLE 3. Direct Esterification of Various Carboxylic Acids with Different Alcohols Catalyzed by HClO4-SiO2
aThe carboxylic acid (2.5 mmol) was treated with the alcohol (2.5 mmol) in the presence of HClO4-SiO2 (1 mol %) at 80 °C. bIsolated yield. cAll
products were characterized by IR, 1H/13C NMR, and EI-MS. dNo N-alkylated product was formed. eThe desired ester was obtained in optically pure
form (based on optical rotation values).
and base materials for cosmetics, lubricants, and plastics.
They are also used as solvents, cosolvents, and oil carriers in
the agricultural industry. The Fischer esterification of various
long-chain fattyacids was carried outwithlong-chain alcohols
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SCHEME 3. The HClO4-SiO2 Catalyzed Synthesis of Pro-
drugs of Ibuprofen
TABLE 5. The HClO4-SiO2 Catalyzed Synthesis of Various Flavor-
ing Agentsa
TABLE 4. Synthesis of Fatty Acid Esters by Direct Esterfication of
Long-Chain Aliphatic Carboxylic Acid with Long-Chain Alcohols Cata-
a
lyzed by HClO4-SiO2
aThe carboxylic acid (2.5 mmol) was treated with the alcohol
(2.5 mmol) in the presence of HClO4-SiO2 (1 mol %) at 80 °C for
aThe carboxylic acid (3 mmol) was treated with the appropriate
alcohol (3 mmol except for entry 4) in the presence of perchloric acid
catalyst (1 mol %) at 80 °C. bIsolated yield. cAll products were
characterized by IR, 1H/13C NMR, and EI-MS. dThe reaction was
carried out with the alcohol (MeOH) as the solvent.
c
10 h. bIsolated yield. All products were characterized by IR, 1H/13
NMR, and EI-MS.
C
catalyzed by HClO4-SiO2 under solvent-free conditions af-
fording the corresponding esters in excellent yields (Table 4).
Further, the HClO4-SiO2 catalyzed direct esterification
procedure was found to be highly effective in the synthesis of
various commercially used flavoring agents in excellent
yields (Table 5).
a
TABLE 6. Reusability of HClO4-SiO2
entry
catalyst use
yield (%)b,c
1
2
3
4
5
fresh
92
92
90
83
80
To demonstrate the catalyst reuse, the esterification of
stearic acid (2.85 g, 10 mmol) with stearyl alcohol (2.70 g,
10 mmol, 1 equiv) was performed at 80 °C for 10 h in the
presence of HClO4-SiO2 (1 mol %) under solvent-free
conditions. After the completion of the reaction (TLC), the
reaction mixture was diluted with EtOAc and filtered
through a plug of cotton. The cotton plug was washed with
EtOAc (3 ꢀ 2 mL) and the combined filtrates were concen-
trated to isolate the product. The cotton plug retaining the
catalyst was transferred to a round-bottomed flask (25 mL)
and dried under rotary vacuum evaporation when the cata-
lyst separated out from the cotton. The recovered
catalyst was dried under vacuum (10 mmHg) at 80 °C for
24 h and reused for four consecutive fresh batches of reac-
tions without significant decrease of its catalytic activity
(Table 6).
1st recycle
2nd recycle
3rd recycle
4th recycle
aThe mixture of stearic acid (10 mmol) and stearyl alcohol (10 mmol)
was heated at 80 °C under solvent-free conditions for 10 h in the presence
of HClO4-SiO2 (1 mol %). bIsolated yield of the ester. cThe product was
characterized by IR, 1H/13C NMR, and EI-MS.
reuse the catalyst simply by filtration and washing resulted
in lower conversion to the product indicating that the
solvent (used during washing) or the moisture (due to
exposure) inactivates the catalyst probably by blocking/
coordinating with the Bronsted acidic sites of the catalyst
e
system.
To compare the advantage of the use of HClO4-SiO2
over the reported procedures, the esterification of 1, 10,
trans-cinnamic acid 17, 13, cyclohexanecarboxylic acid 18,
and furan-2-carboxylic acid 19 with appropriate alcohols
was considered as a few representative examples (Table 8).
For the esterification involving long-chain aliphatic car-
boxylic acids and alcohols, esterification of palmitic acid
20 with stearyl alcohol 21 was considered. While in most of
these cases better or comparative yields of the desired esters
were obtained following the HClO4-SiO2 catalyzed proce-
dure developed under this investigation, the reported proce-
dures required stoichiometric amounts of additives,14d
special apparatus (reaction assembly),14a,c,d solvent,14,15a
costly and moisture-sensitive catalysts,14a,d corrosive/toxic
reagents/catalyst,15,16 high temperature,14c additional efforts
of derivatization/activation of the carboxylic acid,15a cumber-
some workup, etc. These results clearly demonstrate that
For small/laboratory scale reaction (up to 50 mmol) where
a small amount (up to 0.5 g) of the catalyst is required, the
catalyst was preferably recovered by passing the reaction
mixture through a cotton plug rather than classical filtration
(using filter paper) to avoid loss of the catalyst due to
possible adhering of some amount of the catalyst to the
surface of the filter paper. We anticipated that the catalyst
recovery following this process may not be convenient for
industrial/large-scale preparation. Therefore the reaction of
13 (1 mol) with MeOH (1 mol) was carried out and after the
completion of the reaction the catalyst was recovered by
usual filtration (Table 7). The recovered catalyst was reused
after drying repetitively for a fifth run (fourth recycle) and
was found to retain its catalytic activity after which the
recovered catalyst was observed to have a decrease in its
activity as it required longer time (∼10 h). An attempt to
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TABLE 7. Reusability of HClO4-SiO2 for a Larger (1 mol) Scale Reaction of 13 with MeOHa
entry
cat. use
scaleb (mol)
amt of cat. used (g)
amt of cat. recovered (g)
time (h)
yield (%)c,d
1
2
3
4
5
fresh
1
20
10
5
2
1
19.8
9.6
4.8
1.9
0.9
3
3
3.5
3.5
4
95
94
93
89
88
1st recycle
2nd recycle
3rd recycle
4th recycle
0.5
0.25
0.1
0.05
aThe equimolar mixture of 13 and MeOH was heated at 80 °C (oil bath) in the presence of HClO4-SiO2 (1 mol %). bIsolated yield of methyl benzoate.
cThe product was characterized by IR, 1H/13C NMR, and EI-MS.
TABLE 8. Comparison of the HClO4-SiO2 Catalyzed Direct Esterification
Conclusion
with Reported Procedures with a Few Representative Common Substratesa
We have described herein HClO4-SiO2 as an extremely
efficient reusable catalyst system for a general and practical
esterification by direct condensation of carboxylic acids with
alcohols in atom economical fashion. The advantages, such
as (a) the use of a cheap and easy to handle catalyst, (b)
solvent-free reaction conditions, (c) short reaction times, (d)
high yields, (f) feasibility of large-scale operation, and (h)
catalyst reuse, fulfill the “triple bottom line philosophy” of
green chemistry.5
Experimental Section
Typical Procedure for the Preparation of Perchloric Acid
Immobilized on Silica Gel (HClO4-SiO2). The catalyst system
HClO4-SiO2 was prepared following the originally reported
procedure.21a,c To a suspension of silica gel (23.75 g, mesh no.
230-400) in Et2O (50 mL) was added HClO4 (1.25 g, 12.5 mmol,
1.78 mL of a 70% aq solution of HClO4) and the mixture was
stirred magnetically for 30 min at rt. The Et2O was removed
under reduced pressure (rotary evaporator) and the residue
heated at 100 °C for 72 h under vacuum to afford HClO4-
SiO2 (0.5 mmol g-1) as a free-flowing powder.
Typical Procedure for the Synthesis of Ester by a Direct
Condensationbetween a Carboxylic Acidand anAlcohol Catalyzed
by HClO4-SiO2: n-Octyl 4-Phenylbutyrate (Table 2, Entry 3).
The mixture of n-octanol (0.33 g, 2.5 mmol), 4-phenylbutyric acid
(0.41 g, 2.5 mmol, 1 equiv), and HClO4-SiO2 (0.05 g, 1 mol %) in
a round-bottomed flask (25 mL) was stirred magnetically at 80 °C
until complete consumptionof 4-phenylbutyric acid (3.5 h, TLC).
The reaction mixture was diluted with EtOAc (25 mL) and
filtered to remove the catalyst. The filtrate was washed with
satd aq NaHCO3 (2ꢀ5 mL) and water (5 mL), dried (MgSO4),
and concentrated under rotary vacuum evaporation to afford
n-octyl 4-phenylbutyrate (0.65 g, 94%) as a clear oil. IR (Neat) ν
1739 cm-1; 1H NMR (CDCl3, 300 MHz) δ 0.88 (t, J = 3.3 Hz,
3H), 1.28-1.43 (m, 10 H), 1.56-1.63 (m, 2 H), 1.90-2.02 (m,
2 H), 2.31 (t, J = 7.4 Hz, 2 H), 2.64 (t, J = 7.4 Hz, 2 H), 4.05 (t,
J = 3.3 Hz, 2 H), 7.15-7.29 (m, 5 H); 13C NMR (CDCl3,
75 MHz) δ 14.7, 23.2, 26.5, 27.2, 29.2, 29.8, 34.2, 35.7, 65.06,
126.5, 128.9, 129.1, 142.0, 174.1; MS (EI) m/z 276 (Mþ), identical
with an authentic sample.14d The cotton plug retaining the
recovered catalyst was put in a round-bottomed flask (10 mL)
and dried in a rotary evaporator whereupon the catalyst sepa-
rated out from the cotton (45 mg, 90%). The catalyst was
activated on heating under reduced pressure (10 mmHg) at
100 °C for 12 h and reused for four consecutive direct esterifica-
tions of 4-phenylbutyric acid (2.5 mmol), n-octanol (2.5 mmol),
and HClO4-SiO2 (0.1 g, 0.05 mmol, 1 mol %) affording 92%,
90%, 83%, and 80% yields of n-octyl 4-phenylbutyrate after 4, 4,
5, and 5 h, respectively. The remaining reactions were carried out
following this general procedure and in most cases the products
obtained after the usual workup were pure (spectral data).
Wherever required (isolated yield <85%), the purification was
performed by column chromatography (60-120 mesh silica gel,
EtOAc:hexane). The spectral data (IR, NMR, and MS) of known
aThe acid was treated with the alcohol in the presence of the
catalyst under the specified conditions. bYield of the corresponding
ester after purification. cReference 14a. dReference 14d. eReference 15a.
fReference 14c.
HClO4-SiO2 is the best catalyst for direct esterification of
carboxylic acids.
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Chakraborti et al.
JOCArticle
compounds were found to be identical with those reported in the
literature. The spectral data (IR, NMR, and MS) of new com-
pounds are provided below.
40.45 mL, 1 mol), benzoic acid (122.22 g, 1 mol, 1 equiv), and
HClO4-SiO2 (20.0 g, 1 mol %) in a round-bottomed flask
(500 mL) was stirred magnetically at 80 °C until complete con-
sumption of benzoic acid (3 h, TLC). The reaction mixture was
diluted with EtOAc (100 mL) and filtered through a filter paper to
remove the catalyst. The filtrate was washed with satd aq NaH-
CO3 (2ꢀ25 mL) and water (25 mL), dried (MgSO4), and con-
centrated under rotary vacuum evaporation to afford the methyl
Typical Procedures for Large-Scale Synthesis of Esters by
Direct Esterification of a Carboxylic Acid with an Alcohol
Catalyzed by HClO4-SiO2 and Catalyst Recycle. a. Reaction
on a 50 mmol Scale and Catalyst Recovery by Using a Cotton
Plug: n-Octyl 3-Phenylpropionate. The mixture of n-octanol
(6.50 g, 50 mmol), 3-phenylpropionic acid (7.50 g, 50 mmol,
1 equiv), and HClO4-SiO2 (1.0 g, 1 mol %) in a round-
bottomed flask (50 mL) was stirred magnetically at 80 °C until
complete consumption of 3-phenylpropionic acid (4 h, TLC).
The reaction mixture was diluted with EtOAc (50 mL) and
filtered to remove the catalyst. The filtrate was washed with satd
aq NaHCO3 (2ꢀ10 mL) and water (10 mL), dried (MgSO4), and
concentrated under rotary vacuum evaporation to afford the
n-octyl 3-phenylpropionate (12.4 g, 95%) as clear oil. IR (Neat)
ν 1736 cm-1; 1H NMR (CDCl3, 300 MHz) δ 0.88 (t, J = 3.3 Hz,
3 H), 1.27 (s,10 H), 1.58 (t, J = 3.3 Hz, 2 H), 2.61 (t, J = 7.8 Hz,
2H), 2.94 (t, J = 7.8 Hz, 2 H), 4.05 (t, J = 3.3 Hz, 2 H), 7.16-7.3
(m, 5 H); MS (EI) m/z 262 [Mþ], identical with an authentic
sample.27 The cotton plug retaining the recovered catalyst was
put in a round-bottomed flask (25 mL) and dried in a rotary
evaporator whereupon the catalyst separated out from the
cotton (0.48 g, 96%). The catalyst was activated on heating
under reduced pressure (10 mmHg) at 100 °C for 12 h. The
repetition of the reaction of 3-phenylpropionic acid (25 mmol)
with n-octanol (25 mmol) in the presence of HClO4-SiO2 (0.5 g,
1 mol %) afforded the n-octyl 3-phenylpropionate (6.0 g; 93%)
and the recovered catalyst (0.44 g, 90%) after the usual workup.
b. Reaction on a 1 mol Scale and Catalyst Recovery by Simple/
UsualFiltration:MethylBenzoate. The mixture ofMeOH(32.04g,
benzoate (129.29 g, 95%) as a clear oil. IR (Neat) ν 1724 cm-1
;
1H NMR (CDCl3, 400 MHz) δ 3.89 (s, 3H, COOCH3), 7.39-7.43
(m, 2H, ArCH), 7.50-7.54 (m, 1H, ArCH), 8.02-8.8.04 (m, 2H,
ArCH); MS (EI) m/z 136.2 [Mþ], identical with an authentic
sample.7 The filter paper retaining the catalyst was air-dried. The
recovered catalyst (19.8 g) was placed on a beaker (100 mL) and
treated at 100 °C for 12 h ina vacuum oven under reduced pressure
(10 mmHg) to remove any moisture and volatile organic solvent
that might block the catalytic sites. The recovered catalyst was
used for four consecutive batches of reactions and on each
occasion the recovered catalyst was used for the next batch. Thus,
the repetition of the reaction of benzoic acid on 0.5, 0.25, 0.1, and
0.05 mol reactions with equimolar amounts of MeOH following
this generalized procedure afforded the methyl benzoate in 94%,
93%, 89%, and 88%, respectively.
Acknowledgment. The authors thank the Organisation
for the Prohibition of Chemical Weapons (OPCW), Hague,
The Netherlands for financial support.
Supporting Information Available: Typical experimental
procedures, spectral data of all compounds, and scanned spectra
of a few representative known and all unknown compounds.
This material is available free of charge via the Internet at http://
pubs.acs.org.
_
(27) Salome, C.; Kohn, H. Tetrahedron 2009, 65, 456.
5974 J. Org. Chem. Vol. 74, No. 16, 2009