Highly efficient and green esterification of carboxylic acids in deep eutectic solvents without any other additives

Article abstract of DOI:10.1080/00397911.2017.1390138

A protocol that carboxylic acids esterifies with the quaternary ammonium salt of deep eutectic solvent (DES) is presented, which opens a new access to ester using DES as alkylating agent, solvent, and catalyst. The reaction runs smoothly in DES without any other additives. Substituted cinnamic acids, aromatic acids, and aliphatic acids can be esterified in moderate to good yields. The advantages of this reaction include excellent functional group compatibility and simple reaction procedure.

Full text of DOI:10.1080/00397911.2017.1390138

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
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Highly efficient and green esterification of
carboxylic acids in deep eutectic solvents without
any other additives
Sumera Yasmin, Wen-Bing Sheng, Cai-Yun Peng, Atta-ur Rahman, M. Iqbal
Choudhary, Duan-fang Liao & Wei Wanga
To cite this article: Sumera Yasmin, Wen-Bing Sheng, Cai-Yun Peng, Atta-ur Rahman, M. Iqbal
Choudhary, Duan-fang Liao & Wei Wanga (2017): Highly efficient and green esterification of
carboxylic acids in deep eutectic solvents without any other additives, Synthetic Communications,
DOI: 10.1080/00397911.2017.1390138
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Date: 28 October 2017, At: 06:49

Highly efficient and green esterification of carboxylic acids in
deep eutectic solvents without any other additives
Sumera Yasmin
TCM and Ethnomedicine Innovation & Development Laboratory, Sino-Pakistan TCM and
Ethnomedicine Research Center, School of Pharmacy, Hunan University of Chinese Medicine,
Changsha, PR China
HEJ, Research Institute of Chemistry, International Center for Chemical and Biological
Sciences, University of Karachi, Karachi, Pakistan.
Wen-Bing Sheng
TCM and Ethnomedicine Innovation & Development Laboratory, Sino-Pakistan TCM and
Ethnomedicine Research Center, School of Pharmacy, Hunan University of Chinese Medicine,
Changsha, PR China
Cai-Yun Peng
TCM and Ethnomedicine Innovation & Development Laboratory, Sino-Pakistan TCM and
Ethnomedicine Research Center, School of Pharmacy, Hunan University of Chinese Medicine,
Changsha, PR China
1

Atta-ur Rahman
HEJ, Research Institute of Chemistry, International Center for Chemical and Biological
Sciences, University of Karachi, Karachi, Pakistan.
M. Iqbal Choudhary
HEJ, Research Institute of Chemistry, International Center for Chemical and Biological
Sciences, University of Karachi, Karachi, Pakistan.
Duan-fang Liao
TCM and Ethnomedicine Innovation & Development Laboratory, Sino-Pakistan TCM and
Ethnomedicine Research Center, School of Pharmacy, Hunan University of Chinese Medicine,
Changsha, PR China
Wei Wanga
TCM and Ethnomedicine Innovation & Development Laboratory, Sino-Pakistan TCM and
Ethnomedicine Research Center, School of Pharmacy, Hunan University of Chinese Medicine,
Changsha, PR China
TCM and Ethnomedicine Innovation & Development Laboratory, Sino-Pakistan TCM and
Ethnomedicine Research Center, School of Pharmacy, Hunan University of Chinese Medicine,
Changsh, PR China
2

HEJ, Research Institute of Chemistry, International Center for Chemical and Biological
Sciences, University of Karachi, Karachi, Pakistan.
Address correspondence to M. Iqbal Choudhary, HEJ, Research Institute of Chemistry,
International Center for Chemical and Biological Sciences, University of Karachi,
Karachi-75270, Pakistan. Tele: +86-731-84589451. Fax: +86-731-88458227. E-mail:
iqbalhej@yahoo.com
Address correspondence to Wei Wanga, TCM and Ethnomedicine Innovation & Development
Laboratory, Sino-Pakistan TCM and Ethnomedicine Research Center, School of Pharmacy,
Hunan University of Chinese Medicine, Changsha 410208, PR China. Tele: +86-731-84589451.
Fax: +86-731-88458227. E-mail: wangwei402@hotmail.com
Sumera Yasmin and Wen-Bing Sheng these authors contribute equally
Full experimental detail, 1H and 13C NMR spectra. This material can be found via the
“Supplementary Content” section of this article’s webpage.
ABSTRACT
A protocol that carboxylic acids esterifies with the quaternary ammonium salt of deep
eutectic solvent (DES) is presented, which opens a new access to ester using DES as alkylating
agent, solvent, and catalyst. The reaction runs smoothly in DES without any other additives.
Substituted cinnamic acids, aromatic acids and aliphatic acids can be esterified in moderate to
3

good yields. The advantages of this reaction include excellent functional group compatibility and
simple reaction procedure.
GRAPHICAL ABSTRACT
KEY WORDS: carboxylic acids, catalyst-free, deep eutectic solvent, esterification
Introduction
Esters are a synthetically important class of compounds because of their utilities as
protecting groups[1] and as synthetic intermediates in natural product synthesis,[1,2] polymer
industry, and pharmaceutics,[2,3] food and cosmetics,[4] and material science.[5] Esters were
–
synthesized classically by condensation of carboxylic acids with alcohols[1 3,6] or alkyl halide,[7,8]
and some less common methods involve carboxylic acids and alkylating agents such as
dimethylcarbonate (DMC),[9] triazine,[10] and catalytic activation of inert C(sp3)-H bond.[11]
However, these reported methods needed sulfuric acid, hydrochloric acid, or some other
inorganic acids as catalysts and suffered from long reaction time associated with the use of
potentially toxic solvents.
In recent years, quaternary ammonium salts in combination with hydrogen bond donors
(HBD) are used to prepare green, renewable, recyclable, and biodegradable solvents with
4

negligible vapour pressure. They are defined as deep eutectic solvents (DES) and can replace
high boiling point organic solvents.[12,13] DESs are newly emerging low melting point mixtures
of quaternary ammonium salt and HBD. Among the quaternary ammonium salts, choline
chloride (ChCl) is the most commonly used one.[14] At the same time, DES is an effective
catalyst for the esterification of carboxylic acids and alcohol.[15–17]
During the studies of Heck-decarboxylation reaction, we accidently found that carboxylic
acids were esterified with DES without any other additives. Carboxylic acid was heated at 140
°C in DES then generated corresponding esters in moderate yields (Eq. 1) and the alkyl group of
ester came from the quaternary ammonium salt of DES1. In this reaction, DES acted as the
alkylating agent, solvent, and catalyst. Compared to conventional esterification methodology,
DES enabled carboxylic acids to esterify without any other additives and mediated the reaction
in moderate to good yields.
DES R2NX:HBD


4
R1×COOH 2h,140°CR1×COOR2
R=alkyl,aryl
42%-81%
(1)
DESiscomposedofR24NXand HBD
Results and Discussion
1Note: In consideration of the decomposition of quaternary ammonium salt in deep eutectic
solvent, tertiary amines were put into the reaction and the results were listed in Table 2 (entry 5
and 6), the results of Table 2 showed that tertiary amines were not good alkylating agent of
carboxylic acids.
5

To study the esterification reaction, we started with the screening of time, temperature
and different organic solvents along with DES prepared from ChCl and Urea for the
esterification of cinnamic acid 1. Tested conditions are presented in Table 1. There was no
product observed from 100 °C to 120 °C (Table 1, entries 1-3). To our delight when the reaction
was carried out at 140 °C for 2 hours (Table 1, entry 4), the desired product, methyl ester of
cinnamic acid 2 was obtianed in 20% yield. When reaction time was decreased to 1 hour, the
yield decreased to 8% (Table 1, entry 5). However, the yield did not improve significantly
increasing the reaction time to 4 hours, (Table 1, entry 6). To compare our results with
conventional organic solvents, we tried reactions in organic solvents such as NMP, DMF, H2O
and DMSO using ChCl as an alkylating agent for the synthesis of esters. The required ester was
obtained in NMP with 15% yield (Table 1, entry 7) compared to the previously reported
transesterification reaction.[18] In DMF and water, no reaction was observed (Table 1, entries 8
and 9), while there were two products formed in DMSO (Table 1, entry 10). This can be
envisioned when reaction was carried out in DMSO alone, the product was (methylsulfinyl)
methyl cinnamate (Table 1, entry 11).
With the first indication of product formation using DES as solvent and alkylating
reagent, we focused on increasing the yield of reaction by optimzing reaction time and quantity
of DES. When the reaction time was prolonged to 6 hours, 12 hours, and 24 hours with 2 mL
DES (Table 1, entries 12, 13, and 14), the yield of the reaction increased to 50%, 54%, and 56%
6

respectively. Unfortunately, with long reaction time, the amount of unidentified side-products
also increased. Next, we ran reactions by increasing the quantity of DES, without increasing
reaction time i.e. 2 hours. When 6 mL of DES were used, the yield increased to 66% without
side-products (Table 1, entry 15). When 12 mL of DES were used, 62% of the product was
obtained (Table 1, entry 16). It was observed that the reaction with increased quantity of DES
was cleaner as compared to the reaction with increased reaction time. On the basis of these
results, then the standard conditions was decided, that is to say, 1 mmol cinnamic acid was
heated in 6 mL DES at 140 °C for 2 hour.
Different DESs were tested and the results were summaried in table 2. For aliphatic
alkylating agents, as chain length increased, the product yield increased a little from methyl＜
ethyl＜butyl (Table 2, entry 1, 2 and 4). Compared to amine with the similar alkyl group,
pronounced yield were observed for methyl ester (Table 2, entry 1 and 5) and ethyl ester (Table
2, entry 2, 6 and 7) in DESs. This may be explained by the alkyl transferability and the stability
of tertiary amine formed. Quaternary ammonium salts resulted into formation of R3N and HX
whereas amine resulted in R2HN. As the number of alkyl groups decreased, the ability to transfer
alkyl group also decreased in order of R4NX＞R3N＞R2NH＞RNH2. Quaternary ammonium salt
containing alkyl and benzyl groups was used in DES 3 and benzyl ester was major product
(Table 2, entry 3 and 8), the product ratio between benzyl cinnamate and methyl cinnamate was
7

4:1 (NMR ratio). The result that the transferability of benzyl group is better than that of alkyl
group.
After selection of alkylating agent, then we examined substrates scope under the
optimized reaction conditions. Different substituted cinnamic acids were tested and the results
were summarized in Table 3. For cinnamic acid, the yield increased with an increasing chain
length for aliphatic esters whereas benzylic esters give higher yields than aliphatic esters (Table
3, entry 1, 2a, 2g, 2s, and 2l). All para-substituted cinnamic acids gave moderate yields.
Interestingly, the yields of 4-methylcinnamic acid (Table 3, entry 2) were higher than that of
4-trifluoromethylcinnamic acid (Table 3, entry 3) and 4-halogenocinnamic acid (Table 3, entry
4 and 5). This may be explained that the cinnamic acids with electron-donating groups are more
ready to alkylate with DES than the cinnamic acids with electron-withdrawing groups. At the
same time, 4-chlorocinnamic acid (2d, 2j, 2o, and 2v) gave a better yield compared to
4-bromocinnamic acid (2e, 2k, 2p, and 2w) that could be attributed by the usual decrease in
reactivity moving down the halogen group in periodic table. Some differences were observed
when strongly deactivating electron-withdrawing 4-nitrocinnamic acid which gave lower
reaction yield and also some undesired by-products except for benzyl ester (2r). When
disubstituted cinnamic acid such as trans-ferulic acid was tested, methyl and benzyl ester formed
with a lower yield (2f and 2q) whereas ethyl ester and butyl ester did not form. This may be
attributed to the halide counter ion present in alkyl ammonium salt.[19] The side product HCl is a
8

strong acid than HBr and remain dissociated that can better stabilize newly formed ammonium
salt R3HNCl.
With satisfying results in hand we next explored aromatic acids under the optimized
reaction conditions, the results were summarized in table 4. Benzoic acid gave benzyl ester
(Table 4, entry 1, 4a), ortho-hydroxybenzoic acid was not only esterification on the carboxyl but
also hydrocarbylation on the hydroxyl (Table 4, entry 2, 4b), and while ortho- and
meta-disubstituted benzoic acids also gave products (Table 4, entry 3, 4c). Whereas, no products
was observed when the substituted benzoic acids were tested in DES 1, DES 2, and DES 4. This
might be low reactivity of aliphatic group compared to benzylic group. Surprisingly,
4-nitrobenzoic acid gave the corresponding esters in all DESs (4d1, 4d2, 4d3, and 4d4).
When aliphatic dicarboxylic acids were tried with double amounts of DES under the
standard reaction conditons, dibenzyl esters were observed in 79% and 81% yields (Scheme 1,
eq.2 and 3). Yields were high in straight chain carboxylic acids as only benzyl group gave
product, other salts tried containing alkyl groups did not gave products.
Overall moderate yields were observed in esterification reactions, the reason might be the
fact that carboxylic acids could act as hydrogen bond donor in the preparation of DESs.[12,13]
Based on this fact, certain amounts of acids used in the esterification remained unreacted no
matter how long would be the time reaction.
9

Though the exact mechanism is still not clear at present, some information has been
gathered: (1) (C2H5)4NBr and cinnamic acid were heated in NMP under the same condition, 12%
ethyl ester was detected after reaction. 13% benzyl ester was gotten when
(CH3)2Bn(C2H4OH)NCl was instead of (C2H5)4NBr. (2) Trimethylamine or triethylamine was
reacted with cinnamic acid under the standard reaction and less than 5% ester was got. Then the
result was gotten that the mechanism of DES reacted with carboxylic acid was different with that
of quaternary ammonium salts or tertiary amine. According to the above results and the
literatures,[20,21] the proposed mechanism was listed as Figure 1.
The proposed mechanism of the esterification was below, urea combined with carboxylic
acids via hydron bond, which could intensify the nucleophilicity of oxygen atom. Then
carboxylic acids attached the alkyl of quaternary ammonium salts and ester was got.
Conclusions
In summary, we developed a new and green method for the esterification of carboxylic
acids by employing DESs as alkylating agents, solvent, and catalyst. The present reaction
procedure has precedence in terms of simplicity, reaction time, and workup associated with
organic solvent. Cinnamic acids, aromatic acids, and aliphatic dicarboxylic acids worked well in
42-81% yield.
Experimental
10

All chemicals were of reagent grade quality, purchased commercially from
Energy-Chemicals, and used without further purification. TLC analyses were performed using
silica gel GF254 plates. NMR spectra were recorded on Bruker Avance III (600 MHz); chemical
shifts, given in ppm, are relative to Me4Si as the internal standard or to the residual solvent peak.
LRMS data were obtained using Shimadzu GC-MS QP2010.
Typical procedure for the esterification of carboxylic acid in DES.
A 10-mL test-tube was equipped with magnetic stirring bar and charged with 1 mmol
cinnamic acid and 6 mL DES, heated at 140 °C in a preheated oil bath for 2 hours, then the
mixture was cooled to room temperature, extracted with ethyl acetate (3*15 mL), combined and
evaporated under vacuum. Pure product was obtained by silica gel column chromatography with
petroleum ether and ethyl acetate. All the compounds, after purification, were weighted and
1
characterized by MS, H NMR, 13C NMR, and then compared them with the spectral data of
authentic samples. A total of thirty two carboxylic esters were synthesized by this method, and
all the compounds were reported earlier in literature. [21–36]
Acknowledgments
This work was supported by the National Natural Science Foundation of China
(81374062), the Natural Science Foundation of Hunan Province (2015JJ6082), the Education
Department of Hunan Province (17C1612) and Hunan Science and Technology Department
Funds (2014SK4037, 2014FJ1007).
11

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13

Table 1. Optimization of the reaction conditions a
Entry
1
Solvent
T/°C
80
t/h
2
DES/mL
1
Yieldb /%
0
DES(ChCl +
Urea)
2
3
4
5
6
7
DES(ChCl +
Urea)
100
120
140
140
140
140
2
2
2
1
4
2
1
1
1
1
1
1
0
0
DES(ChCl +
Urea)
DES(ChCl +
Urea)
20
8
DES(ChCl +
Urea)
DES(ChCl +
Urea)
22
15
ChCl + NMP
14

8
ChCl + DMF
ChCl + H2O
ChCl + DMSO
DMSO
140
140
140
140
140
2
2
2
2
6
1
1
1
1
2
0
0
9
10
11
12
10
c
-
DES(ChCl +
Urea)
50
54
56
66
62
13
14
15
16
DES(ChCl +
Urea)
140
140
140
140
12
24
2
2
2
DES(ChCl +
Urea)
DES(ChCl +
Urea)
6
DES(ChCl +
Urea)
2
12
a Reaction conditions: 1 mmol cinnamic acid. b GC yields based on 1. c (methylsulfinyl)methyl cinnamate.
15

Table 2. Selection of alkylating agents a
Entry
1
Alkylating Agent
Product(R2)
CH3
Yieldb /%
66
DES1 ((CH3)3(C2H4OH)NCl +
Urea)
2
3
DES2 ((C2H5)4NBr+ Urea)
C2H5
Bn
72
80
DES3 ((CH3)2Bn(C2H4OH)NCl+
Urea)
4
5
6
7
8
DES 4((C4H9)4NCl+ imidazole)
(CH3)3N + NMP
C4H9
CH3
C2H5
C2H5
Bn
75
＜5
＜5
12
(C2H5)3N + NMP
(C2H5)4NBr + NMP
(CH3)2Bn(C2H4OH)NCl + NMP
13
a Conditions: 1 mmol cinnamic acid, solvent 6 mL, 140 °C, 2 hours. b GC yields based on 1.
16

Table 3. Esterification of cinnamic acid derivatives a
Entry
R1
R2 and yieldb/%
CH3
2a 60
2b 65
2c 64
2d 62
2e 42
2f 55
CH3CH2
C6H5CH2
2l 75
CH3(CH2)3
2s 70
1
2
3
4
5
6
4-H(1a)
4-CH3(1b)
4-CF3(1c)
4-Cl(1d)
4-Br(1e)
2g 66
2h 72
2i 68
2m 80
2n 71
2o 75
2t 74
2u 68
2j 74
2k 53
2v 77
2p 60
2q 59
2w 58
3-OCH3,
OH(1f)
4-NO2(1g)
7
2r 52
a Conditions: 1 mmol acid, DES 6 mL, 140 °C, 2 h. b Isolated yield.
17

Table 4. Esterification of aromatic acids a
Entry
R1 group
Product 4
Yieldb /%
1
2
H (3a)
C6H5CH2(4a)
70
72
2-OH (3b)
(4b)
3
4
2-OH, 4-Br (3c)
4-NO2 (3d)
C6H5CH2(4c)
57
75
65
67
69
C6H5CH2(4d1)
CH3(4d2)
CH3CH2(4d3)
CH3(CH2)3(4d4)
a Conditions: 1 mmol acid, DES 6 mL, 140 °C, 2 h. b Isolated yield.
18

Figure 1. Proposed mechanism esterification of carboxylic acids and DES.
19

Scheme 1. Esterification of aliphatic dicarboxylic acids.
20