Convenient esterification of carboxylic acids by SN2 reaction promoted by a protic ionic-liquid system formed in situ in solvent-free conditions

Article abstract of DOI:10.1080/00397911.2014.933353

The reaction of esterification of benzoic acid with benzyl chloride was chosen as a model reaction to study the esterification by SN₂ promoted by tertiary amine as deprotonating agent. The use of ionic liquid (IL) 1,3-dimethylimidazolium methanesulfonate [MMIm][OMs] as reaction medium has proven to give quantitative yield of the ester, but interestingly the reaction does occur even in solvent-free conditions, where the acid + the amine form a liquid system (a protic IL) in situ. This last methodology was extended to several carboxylic acids in conditions of atom economy (i.e., without excess of any reagent), giving moderately good yields of esters (54-78%) recovered by weight in pure form.

Full text of DOI:10.1080/00397911.2014.933353

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Convenient Esterification of Carboxylic
Acids by S 2 Reaction Promoted by a
N
Protic Ionic-Liquid System Formed in Situ
in Solvent-Free Conditions
a
a
a
Fabio Cardellini , Lucia Brinchi , Raimondo Germani & Matteo
a
Tiecco
a
Dipartimento di Chimica, Biologia e Biotecnologie, CEMIN, Centro
di Eccellenza Materiali Innovativi Nanostrutturati , Università di
Perugia , Perugia , Italy
Accepted author version posted online: 24 Jun 2014.Published
online: 04 Sep 2014.
To cite this article: Fabio Cardellini , Lucia Brinchi , Raimondo Germani & Matteo Tiecco (2014):
Convenient Esterification of Carboxylic Acids by S 2 Reaction Promoted by a Protic Ionic-Liquid
N
System Formed in Situ in Solvent-Free Conditions, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, DOI: 10.1080/00397911.2014.933353
To link to this article: http://dx.doi.org/10.1080/00397911.2014.933353
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Synthetic Communications , 0: 1–9, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2014.933353
CONVENIENT ESTERIFICATION OF CARBOXYLIC
ACIDS BY S 2 REACTION PROMOTED BY A PROTIC
N
IONIC-LIQUID SYSTEM FORMED IN SITU IN
SOLVENT-FREE CONDITIONS
Fabio Cardellini, Lucia Brinchi, Raimondo Germani, and
Matteo Tiecco
Dipartimento di Chimica, Biologia e Biotecnologie, CEMIN, Centro di
Eccellenza Materiali Innovativi Nanostrutturati, Universit a` di Perugia,
Perugia, Italy
GRAPHICAL ABSTRACT
Abstract The reaction of esterification of benzoic acid with benzyl chloride was chosen as
a model reaction to study the esterification by S
nating agent. The use of ionic liquid (IL) 1,3-dimethylimidazolium methanesulfonate
MMIm][OMs] as reaction medium has proven to give quantitative yield of the ester,
N
2 promoted by tertiary amine as deproto-
[
but interestingly the reaction does occur even in solvent-free conditions, where the acid þ
the amine form a liquid system (a protic IL) in situ. This last methodology was
extended to several carboxylic acids in conditions of atom economy (i.e., without excess
of any reagent), giving moderately good yields of esters (54–78%) recovered by weight
in pure form.
Keywords Esterification; methanesulfonate anion; nucleophilic substitution; protic ionic
liquids; solvent-free reaction; triethylamine
INTRODUCTION
Esterification is an important reaction widely used for the protection or
manipulation of the carboxylic acid functional group. Esterification is also
important in the industrial synthesis of various products, some of which are high
[
1–3]
production volume (HPV) chemicals.
of esterification there is the nucleophilic substitution of carboxylate salts with
Among the several synthetic procedures
[
4–6]
alkylating agents, such as alkyl halides, sulfates, and phosphates. This procedure
is attractive especially because alkyl halides are cost-effective starting materials.
Received March 20, 2014.
Address correspondence to Raimondo Germani, Department of Chemistry, Biology and
Biotechnology, CEMIN, Centro di Eccellenza Materiali Innovativi Nanostrutturati, University of
Perugia, Via Elce di Sotto n. 8, Perugia I-06123, Italy. E-mail: raimondo.germani@unipg.it
1

2
F. CARDELLINI ET AL.
However, so far, industrial application is limited due to drawbacks. In fact, this
reaction is usually carried out in dipolar aprotic solvents (dimethylformamide
[
both the salts and the alkylating agent are soluble, and phase-transfer catalysis has
DMF], dimethylacetamide [DMA], hexamethylphosphoramide [HMPA]) where
[7]
also been used. The main drawbacks of this method are the use of toxic volatile
dipolar aprotic solvents and the difficulty of obtaining efficient carboxylate salts,
especially in multifunctional molecules. The carboxylate anion can also be generated
in situ by reaction of a base with the carboxylic group. The chosen base should have
reduced nucleophilicity to avoid competition with the carboxylate anion towards the
[
8]
alkylating agent. As an example, nonquaternizable tertiary amines or 1,8-diazabicy-
[9]
clo[5.4.0]undecen-7-ene (DBU) in benzene have been used. Also in this case organic
volatile solvents have to be used, and furthermore base separation from the crude pro-
duct is another major problem. Alternatively, the carboxylic group has been activated
[10,11]
through the fluoride anion.
Most of the recent research work dealing with esterification has been associated
[
12]
with the desire to advance benign and sustainable chemical technologies. In fact,
replacement of conventional organic solvents by new reaction media such as water or
ionic liquids (ILs) has been extensively studied, as shown in the review of Otera
[1]
and Nishikido. In fact, ILs are organic nonvolatile salts, liquid at or near room
temperature; nowadays they are considered good candidates in developing environ-
mentally benign chemical processes and are widely used as ‘‘greener’’ alternative
[
13–17]
to classical volatile organic solvents.
Furthermore, their physical and chemical
properties can be tailored to facilitate the reactivity of specific reactions. ILs have
[
1,18,19]
proven utility in improving various procedures of esterification, including
carboxylate alkylation. In this regard, we have previously reported our results
[1,20–23]
about the use of ILs 1,3-dimethylimidazolinium [MMIm][MsO] and 1-butyl-3-
ethylimidazolinium [BEIm][MsO] methanesulfonates as efficient systems for the
esterification of carboxylates with alkyl halides, in mild conditions, and also for
esterification of carboxylic acids by reaction with alkyl halides activated by KF,
[
24–28]
with chemoselectivity in the cases of hydroxybenzoic acid and amino acids.
In continuation of our research on the use of ILs in preparation of esters, we
started a study about esterification of carboxylic acids with alkyl halides in the
presence of tertiary amine as deprotonating agent. Deprotonating action of sterically
hindered tertiary amines has already been used in the literature for this kind of reac-
tion, using only one kind of ionic liquid (1-butyl-3-methyl-4,5-dihydroimidazolinium
[
29]
hexafluorophosphate) as reaction medium, and for other reactions, for instance,
to obtain phenyl ethers in solvent-free condition.
gation was a comparison of dipolar aprotic solvents generally used for such kinds
[
30]
The initial aim of our investi-
of reactions, such as dimethylsulfoxide (DMSO), DMF, and CH CN, and the use
3
of IL of different structures, with variations in both the nature of the anion and
the cation of the IL, as shown in Scheme 1. During the experimental work, we found
out, with surprise, that the model reaction, esterification of benzoic acid with benzyl
chloride in the presence of triethylamine, could be also carried out in solvent-free
conditions, without molecular solvent or ionic liquid. As far as we know, there are
not examples of this reaction carried out in solvent-free conditions in the literature.
Actually, esterification via S 2 nucleofilic substitution reaction has been
N
carried out in solvent-free conditions but the reaction between carboxylate-based

SOLVENT-FREE ESTERIFICATION BY S
N
2 REACTION
3
Scheme 1. Chemical structures and acronyms of ILs used in this work.
[
31]
ionic liquids with alkyl halides has been used. Therefore it was necessary to pre-
pare the corresponding ionic liquids with the appropriate carboxylate as counterion,
and globally two synthetic steps were involved: the quaternization of tertiary amine
and the subsequent ion exchange reaction to introduce the carboxylate anion.
The solvent-free procedure developed by us is more convenient and immediate,
relying on simple salification of the carboxylic acid with a tertiary amine. Therefore
herein we report the procedure that was developed in solvent-free conditions.
RESULTS AND DISCUSSION
Herein, we report for the first time a fast reaction for esterification of
carboxylic acid with benzyl chloride in the absence of any solvent and ionic liquid,
with amine as base used to form the carboxylate salt in situ (Scheme 2).
Initially we used the reaction of benzyl chloride (widely used in protection
routes) with solid benzoic acid, in the presence of triethylamine (TEA), as a model
reaction to screen a series of reaction media (molecular solvents and ionic liquids).
Table 1 summarizes the results of nonoptimized conditions. The use of different mol-
ecular solvents did not lead to good results, except DMF and DMSO, which have
good performance (>75%, Table 1, entries 4 and 5) but are quite harmful. Various
types of ionic liquids were tested, and results in Table 1 show that the nature of the
anion varied with the widely used tetrafluoroborate [BF ], hexafluorophosphate
4
[
PF ], bis(trifluromethylsulfonyl)imide [NTf ], and methanesulfonate [MsO] playing
6 2
important roles, and excellent yields (95%) are obtained only with methanesulfonate
as counterion (Table 1, entry 10). Variations in the cation from [BMIm] to [MMIm]
and to tetrabutylammonium, [TBMA] led to even better results, with quantitative
yields in the last two cases (Table 1, entries 11 and 12). More interesting, we found
out that the reaction occurred with excellent yield (Table 1, entry 13) in the absence
of any molecular or IL solvent. The addition of the TEA to solid benzoic acid
Scheme 2. General scheme for esterification reaction.

4
F. CARDELLINI ET AL.
Table 1. Screening of different reaction media for the model reaction of benzyl chloride with benzoic acid
a
in the presence of triethylamine
Entry
Reaction medium
Water
Yield (%)
1
2
3
4
5
6
7
8
9
15
55
16
79
75
4
3
CH CN
Dioxane
DMF
DMSO
Toluene
[BMIm][BF
[BMIm][PF
4
]
]
77
82
75
95
100
100
96
6
2
[BMIm][NTf ]
1
1
1
1
0
1
2
3
[BMIm][MsO]
[MMIm][MsO]
[TBMA][MsO]
None
a
ꢀ
Temperature ¼ 90 C; reaction time ¼ 2 h; amine=benzyl chloride=benzoic acid ¼ 1.2:1.1:1.0; IL ¼ 0.3 g;
molecular solvent ¼ 3 mL.
formed a liquid system at reaction temperature, which can be considered a protic
IL formed in situ. This allowed us to carry out the reaction in a liquid system with
magnetic stirring, with a simple procedure.
The procedure was thereafter tested with variation of the amine structure.
Variations introduced were aimed at shifting the basicity=nucleophilicity ratio of
the amine towards the basicity, and steric hindrance around nitrogen was the main
factor considered. An increase in the alkyl chain length in aliphatic acyclic tertiary
amines led to an unexpected decrease of the amine performance in IL: In fact, with
N(n-Pr) the product yield was 90%. Introduction of oxygen atom was also tested
3
[
32]
and triethanolamine, which is very useful because of its lower toxicity,
led to product formation in only moderate yield, 53%.
but it
This solvent-free procedure was finally tested with different acids to assess the
scope of the reaction. With the aim of using the procedure for preparation of esters,
yields by weight were evaluated and conditions of atom economy were used (i.e.,
without any reagent in excess). Results are shown in Table 2, where melting points
of carboxylic acids are also reported. For all tested acids, at reaction temperature
ꢀ
9
0 C with molar ratio carboxylic acid=TEA 1:1, the reaction mixture was liquid,
except with isonicotinic acid. In these conditions of atom economy the yield of the
model reaction is less than in conditions used in the reaction reported in Table 1
(
with an excess of the amine and a little excess of the benzyl chloride): In fact the
model reaction gives a yield of only 64% in atom economy conditions (Table 2, entry
), but it can be considered good because it is in terms of pure recovered ester. The
1
procedure gives similar yields (ca. 65%) with the shortest of the aliphatic acids tested,
and also with highly hindered acids such as pivalic acid (Table 2, entries 2 and 4).
This last result is interesting because carboxylate alkylation is generally negatively
[44]
affected by steric hindrance in the acid. For the other acids tested, different kinds
of structural variations were introduced, such as double bond, aromatic moiety, sub-
stituents in the aromatic ring, and others, mainly chosen to have a high melting point

SOLVENT-FREE ESTERIFICATION BY S
N
2 REACTION
5
Table 2. Esterification of carboxylic acids with benzyl chloride in the presence of triethylamine in
a
solvent-free conditions
ꢀ
Entry
1
Carboxylic acid
Acid mp ( C)
Ester yield (%)
64
Ref.
[33]
121–125
2
3
HCOOH
CH COOH
8.2–8.4
16.2
66
68
[34]
[35]
3
4
32–35
63
56
[36]
5
6
ꢁ34,5
ꢁ5
[35]
[37]
b
54
7
8
9
45–48
78
62
[38]
[39]
132–135
76–78
130
70
75
[40]
[41]
1
0
1
1
138–140
158–161
78
65
[39]
[42]
1
1
1
2
3
4
237–240
74
[33]
[43]
>300
40
a
ꢀ
Isolated yields; all mixtures of these acids are liquid at temperature ¼ 90 C; reaction
ꢀ
temperature ¼ 90 C; reaction time ¼ 2 h; amine ¼ benzyl chloride ¼ benzoic acid ¼ 1 mmol. The structures
1
of esters were identified through the comparison of H NMR spectra data with those reported in literature.
b
Yield after purification by chromatography column.

6
F. CARDELLINI ET AL.
ꢀ
of the acid up to 300 C. The systems carboxylic acid þtriethylamine are always
ꢀ
liquid at 90 C. The reaction tolerates double bonds (Table 2, entry 6 and 8), the phe-
nolic hydroxyl group in salicylic acid (Table 2, entry 12), and yields are generally
moderately good (54–78% of recovered pure ester) in a short reaction time (2 h) a
part from the isonicotin acid, but in this case the system was quite viscous.
We may say that alkylation of several carboxylic acid in the presence of TEA
can be carried out in solvent-free conditions, with a protic ionic liquid system formed
in situ. According to green chemistry principles, organic synthesis in the absence of
solvent is of great value. The method in solvent-free conditions was used in atom
economy conditions (none of reagents in excess) giving moderately good yields
(54–78%) in short times, under mild and safe conditions, with most of the several
carboxylic esters tested.
EXPERIMENTAL
Ionic liquids were prepared by procedures reported previously in the
[
25,45]
literature.
All other reagents, carboxylic acids, amines, benzyl chloride, t-butyl-
benzene, and organic solvents were of analytical grade, purchased from commercial
sources (Sigma-Aldrich). Melting points were determined with a Barloworld Scientific
Stewart SMP3 apparatus and are uncorrected. Gas chromatography (GC) analyses
were performed with an Agilent 6850 Series II Network GC instrument (column
DB-35MS l 30m, d 0.32mm, film 0.25 mm). Thin-layer chromatography (TLC) was
1
performed on silica gel on aluminum foil. H NMR spectra were registered on
a Bruker 200-MHz instrument using CDCl as solvent. Chemical shifts are given
in parts per million (ppm) relative to the signal of TMS.
3
Esterification in IL or in Molecular Solvents
The amount of 0.3 g of IL was weighed in a screw-capped 3-ml vial, equipped
with a magnetic stirrer; thereafter, the carboxylic acid was added, and then the amine
was introduced by a syringe (TEA=benzoic acid ¼ 1.2:1.0). The mixture was magneti-
ꢀ
cally stirred and heated to 90 C until a clear colorless liquid phase was obtained.
Finally, benzyl chloride (BnCl=benzoic acid 1.1:1 molar ratio) was added by means
a syringe to the homogenous mixture. At the end of reaction, after cooling to rt,
water and ethyl ether were added to the reaction mixture, and the mixture was
transferred as quantitatively as possible (rinsing with both water and ethyl ether were
carried out) to a separatory funnel, where also t-butylbenzene was added, as internal
standard. The organic phase was washed twice with water (10 mL), twice with
NaHCO solution, and twice with 3 M HCl, and with water again until neutrality;
3
it was thereafter dried over anhydrous Na SO and analyzed by GLC.
2
4
For reaction in traditional molecular solvents, the amount of 1 mmol of
carboxylic acid was weighed in a screw-capped 5-ml vial, equipped with a magnetic
stirrer, and then 3 mL of solvent were added. Thereafter, the amine, in the chosen
molar ratio, was introduced by a syringe. The homogeneous mixture was magneti-
ꢀ
cally stirred and heated to 90 C. Finally, benzyl chloride (BnCl=carboxylic acid
1.1:1 molar ratio) was added by means a syringe to the homogenous mixture.
Further elaboration was as described previously.

SOLVENT-FREE ESTERIFICATION BY S
N
2 REACTION
7
1
Identification of the products was carried out by comparison of the H NMR
spectra with those of authentic samples and with those reported in the literature
(Table 2).
Esterification in Solvent-Free Conditions
The amount of 1 mmol of carboxylic acid was weighed in a screw-capped 3-ml
vial, equipped with a magnetic stirrer; thereafter, the appropriate amount of TEA
was introduced by a syringe (carboxylic acid=TEA 1:1). The mixture was magneti-
ꢀ
cally stirred and heated to 90 C until a clear colorless liquid phase was obtained
(about 15 min). Finally, benzyl chloride (BnCl=carboxylic acid 1:1 molar ratio)
was added by means a syringe to the homogenous mixture. At the end of reaction
and at rt, the mixture had a semi-solid waxy appearance. Further elaboration was
as described for the reaction in the presence of IL.
When yields by weight were determined, no internal standard was added at the
end of reaction, and the organic solvent was eliminated by rotary evaporation. The
product was thereafter dried and weighed; GC was performed to establish purity,
which was always >97%.
FUNDING
Support of this work by MIUR (Ministero dell’Istruzione, dell’Universit a` e
della Ricerca Scientifica), Italy, is acknowledged.
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37. H NMR of benzyl (9Z,12Z)-9,12-octadecadienoate (200 MHz CDCl ): d 1.29 (tr, 3H,
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2
3
2
2
CH
7
2
-O); 2.80 (m, 2H, C=C-CH
.34 (m, 5H, Ar).
2
-C=C); 5.13 (s, 2H, CH
2
-Ar); 5.37 (m, 4H, CH olefinic);
3
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3
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Chem. 2008, 73, 5147–5150.
4
4
4
4
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4