A rapid and facile esterification of na-carboxylates with alkyl halides promoted by the synergy of the combined use of DMSO and an ionic liquid under ambient conditions

Article abstract of DOI:10.1080/00397910903457357

The synergy of the combined use of DMSO and an ionic liquid viz. (bbim) has brought about a rapid and efficient esterification of sodium carboxylates with acyl and alkyl halides under ambient conditions in excellent isolated yields (90-95%) in short reaction times (12-40min). Copyright Taylor & Francis Group, LLC.

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A Rapid and Facile Esterification of
Na-Carboxylates with Alkyl Halides
Promoted by the Synergy of the
Combined Use of DMSO and an Ionic
Liquid Under Ambient Conditions
Satish N. Dighe a , Ravindra V. Bhattad a , Raghunath R. Kulkarni a ,
Kishor S. Jain a & Kumar V. Srinivasan a
a Department of Pharmaceutical Chemistry, Sinhgad College of
Pharmacy, Pune, India
Version of record first published: 05 Nov 2010.
To cite this article: Satish N. Dighe , Ravindra V. Bhattad , Raghunath R. Kulkarni , Kishor S. Jain &
Kumar V. Srinivasan (2010): A Rapid and Facile Esterification of Na-Carboxylates with Alkyl Halides
Promoted by the Synergy of the Combined Use of DMSO and an Ionic Liquid Under Ambient Conditions,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 40:23, 3522-3527
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Synthetic Communications1, 40: 3522–3527, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903457357
A RAPID AND FACILE ESTERIFICATION OF
Na-CARBOXYLATES WITH ALKYL HALIDES
PROMOTED BY THE SYNERGY OF THE COMBINED
USE OF DMSO AND AN IONIC LIQUID UNDER
AMBIENT CONDITIONS
Satish N. Dighe, Ravindra V. Bhattad, Raghunath R. Kulkarni,
Kishor S. Jain, and Kumar V. Srinivasan
Department of Pharmaceutical Chemistry, Sinhgad College of Pharmacy,
Pune, India
The synergy of the combined use of DMSO and an ionic liquid viz. (bbim)þBrꢀ has
brought about a rapid and efficient esterification of sodium carboxylates with acyl and alkyl
halides under ambient conditions in excellent isolated yields (90–95%) in short reaction
times (12–40 min).
Keywords: Acyl halide; alkyl halide; DMSO; esterification; ionic liquid
INTRODUCTION
Esterification[1] is one of the most fundamental reactions in synthetic organic
chemistry and is extensively employed for the protection and further manipulation
of the carboxylic acid functional group. Esterification processes are widespread in
the industrial synthesis of a variety of end-products such as fragrances, monomers,
plasticizers etc., many of which are also classified as high production volume
(HPV) chemicals. In addition, applications to lower volume, high value pharmaceu-
tical and fine chemicals targets are prominent, and often require more stringent coup-
ling protocols to achieve the desired chemo- and stereoselectivity. In view of their
importance, esterification protocol should occupy a prominent place in the desire
to advance benign and sustainable chemical technologies into industrial process
development.[2] Esterification of carboxylic acids by reaction with alkyl halides is a
fundamental transformation in organic chemistry.[3] Potassium and cesium salts have
proved useful for this purpose. Clerk et al. in their extensive studies revealed that KF
to be effective, but unfortunately, the reaction usually requires a high temperature
(110–113 ꢁC).[4] Sato et al. also reported CsF- promoted esterification of carboxylic
acids.[5] Saegusa et al. reported a Cu(I) – isonitrile complex promoted esterification
process.[6] All these esterification processes suffer from the drawback of requiring
Received August 4, 2009.
Address correspondence to Kumar V. Srinivasan, Organic Chemistry, Sinhghad College of
Pharmacy, Dr. Homi Bhabha Road, Pune-411008, India. E-mail: kumarv.srinivasan@gmail.com
3522

ESTERIFICATION OF Na-CARBOXYLATES
3523
catalysts to promote the reaction, which most then be recovered, recycled, and suit-
ably disposed of, adding to the overall cost of the process.
The use of room temperature ionic liquids (ILs) as solvents for chemical reac-
tions offers several advantages from the environmental perspective.[7,8] These solvents
are non-inflammable, thermally stable, exhibit negligible vapor pressure (non-volatile),
and offer the potential of recyclability.[9] For these reasons, the replacement of current
esterification protocols with a more environmentally benign process involving the use
of ionic liquids appeared to be an area worthy of further investigation.
Several reports are available for the esterification of alkyl halides using ionic
liquids. McNulty et al.[10] reported the esterification process in phosphonium salt
ionic liquid. Brinchi et al. reported the esterification process by using imidazolium
ionic liquid, i.e., (MMim) and (BEim)[11] and also by fluoride ion catalyzed[12] esteri-
fication process in the same ILs. All of these processes, however, suffer from either
the need for high temperatures or catalyst-promoted reactions or both. Another fre-
quent preparation of esters is based on the alkylation of carboxylate salts with alco-
hols. Triethylammonium sulfate, triethylammonium dihydrogen phosphate and
triethylammonium tetrafluoroborate were applied as ionic liquid catalyst and
medium for the esterification of carboxylic acids with primary alcohols.[13] In such
conventional esterification cases, the development of procedures employing dipolar
aprotic solvents such as DMSO, DMF, and HMPA or the phase transfer catalyzed
reactions are of key importance. These media are usually used because they acceler-
ate the reaction.[14,15] However, esterification by using these solvents also require
higher temperatures over longer periods.
EXPERIMENTAL
General Procedure for Esterification in IL þ DMSO (0.1:1)
The IL [bbim] Br was synthesized as per the procedure reported by us.[16]
A mixture of alkyl halide (2 mmol) and sodium salt of the carboxylic acid
(2.2 mmol) was stirred at 30 ꢁC in the presence of IL and DMSO in 0.1:1 (0.5 g:
5 g) proportion by weight. After the completion of the reaction as monitored by
TLC, ice was added and the mixture was extracted with a mixture of n-hexane
and ethyl acetate (4:1 v=v) (2 ꢂ 25 ml). The organic layer was separated from the
aqueous layer; the product which showed a single spot in TLC was isolated by evap-
orating the solvent and then completely characterized. The IL could be recovered for
recycle by subjecting the aqueous layer to distillation under reduced pressure of
2 mmHg at 100–150 ꢁC in a scaled up version of the methodology.
RESULTS AND DISCUSSION
Herein, we report for the first time a fast and efficient esterification of Na-
carboxylates at room temperature in the absence of any added catalyst using a
combination of DMSO and an ionic liquid [bbim]þBrꢀ in the proportion of 1:0.1
to generate the corresponding esters in excellent isolated yields (90–95%) in short
reaction times (12–40 min.) (Scheme 1).

3524
S. N. DIGHE ET AL.
Scheme 1. General scheme for esterification.
Table 1. Screening of different solvents for model reaction of phenacyl bromide with sodium benzoate
Sr. No.
Solvent
Time
Isolated yield (%)
1
2
3
4
5
DMSO
DMF
THF
15 min.
1 h
85
78
–
No reaction
4 h
Above 5 h
Acetone
Acetonitrile
56
55
For the model reaction of phenacyl bromide with Na-benzoate at 100 ꢁC, we
screened several dipolar aprotic solvents for their efficacy. The results are shown
in Table 1. DMSO which gave the best results was selected as the dipolar aprotic sol-
vent for further investigations.
Our next step was to take a look at the synergistic effect of DMSO in combi-
nation with ILs. Hypothetically, it was expected that the IL in view of its inherent
acidity and polarity would polarize the C-halide bond making the alkyl C more elec-
tropositive. Likewise, DMSO by its inherent property will lead to the non-solvation
of the carboxylate anion rendering it highly reactive as a ‘naked’ anion. It is also
probable that the DMSO, together with the IL, may somehow increase the polarity
and inherent bronsted acidity of the reaction medium. This would lead to an increase
in the polarization of the C-halide bond making the carbon more positive for the
nucleophilic attack. This hypothesis was tested for the model reaction of phenacyl
bromide with sodium benzoate using the various combination of the IL viz. [bbim]
Br with DMSO in different proportions at room temperature. To establish the syn-
ergy of the combined use of DMSO and IL, the model reaction was performed in
DMSO, IL and a combination of both the solvents. The results are shown in Table 2.
Table 2. Screening of individual solvents and combination with each other for the model reaction
Sr. No.
IL and DMSO proportion
Time
Isolated yield (%)
1
2
3
4
5
(bbim)þBrꢀ Only
DMSO Only
16 h
No reaction even after 16 h
80
–
DMSO þ IL (1:1)
DMSO þ IL (1:0.1)
DMSO þ IL (0.1:1)
30 min
15 min
4 h
92
95
90

ESTERIFICATION OF Na-CARBOXYLATES
3525
Table 3. Esterification of sodium carboxylates with various substituted acyl and alkyl Halides
Time Isolated
(min) yield (%)
Halide 1
Sodium salt of acid 2
Product 3
15
15
95
92
40
93
20
40
35
90
90
91
30
94
13
12
91
93
30
15
91
92

3526
S. N. DIGHE ET AL.
It was found that in IL alone, the reaction took 16 h for completion at room
temperature, whereas in DMSO alone, no reaction was observed even after 16 h.
at 30 ꢀC. The combination of DMSO and IL in the proportion of 1:1 considerably
accelerated the reaction to afford the ester in 95% yield in just 30 min. With the
IL as the reaction medium and minor proportion of DMSO (1:0.1), the esterification
could be completed in 4 h with a very good yield (90%) under ambient conditions.
However, it was a pleasant surprise to observe that with DMSO as reaction medium
and minor proportion of the IL (1:0.1), the reaction was complete in just 15 min. at
room temperature with an isolated product yield of 95%. Reducing the proportion of
the IL has resulted in doubling the reaction rate with marginally better yield of the
product. It may be noted, however, that with reference to the substrates, the
proportion of the IL results in being nearly equimolar. It is obvious that the effect
of the IL by virtue of its inherent acidity and polarity on the C-halogen bond is much
more significant than the naked anion non-solvation effect. This system was
therefore chosen as the solvent medium for exploring the scope of the reaction with
different substrates. The results are shown in Table 3.
A variety of substrates including acyl, alkyl, aralkyl, and heteroaralkyl halides
were treated with Na-benzoate and Na-nicotinate, respectively, at room temperature
to generate the corresponding esters in excellent isolated yields in a short time under
ambient conditions. The time required for completing the esterification varied
depending upon the carboxylate and alkyl halide used as shown in Table 3. Electron
withdrawing group in phenacyl bromide substrate such as chloro has shortened the
reaction time whereas the electron-donating group such as the methyl group has
taken more time to complete the reaction. With alkyl halide; the nicotinate has
reacted more quickly than on the benzoate.
Analytical Data for Compounds 3g and 3j
3g. mp 188–190 ꢀC; IR (cmꢁ1) 1686, 1726, ;1H NMR 2.6 (s, 3H, SCH3 at 3);
5.3 (s, 2H, CH2 at 6); 7.2–9.3 (m, 10H, ArH at 1 and 6); MS 393(Mþ); 324; 287.
3j. mp 250–252 ꢀC; IR (cmꢁ1) 1733, 1686; 1H NMR 13.04 (s, 1H, NH at 3); 9.32
(s, 1H, H at 6); 8.84 (s, 1H, H at 4); 8.43 (s, 1H, H at 3); 7.50 (s, 1H, H at 2); 7.06 (s,
1H, H at 8); 5.43 (s,2H, H at 2); 2.71 (s, 3H, H at 7); 2.60(s,3H, H at 9); MS 366(Mþ),
260, 243, 215.
ACKNOWLEDGMENT
The authors thank Professor M. N. Navale, founder president Sinhgad
Technical Education Society, for providing us with the necessary financial support
and infrastructure for carrying out this work.
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