L. Brinchi et al. / Tetrahedron Letters 44 (2003) 2027–2029
2029
The esterification we carried out in a new ionic liquid is
operationally simple and safe, fast, and allows reuse of
the reaction media (Scheme 2).‡ Table 1 summarizes
optimized conditions with a variety of alkyl halides and
carboxylate sodium salts, and shows that the desired
esters were generally obtained in excellent yields, gener-
ally better than 95%. These results are comparable, and
sometimes even better, than those for similar reactions
carried out in solvents such as DMF, HMPA and
DMSO7 with the main difference that the Ionic liquids
are not toxic. In the absence of the ionic liquid as
reaction media, reactions do not proceed: we tried the
reaction of acetate and liquid benzyl chloride, and also
the reaction of benzoate with benzyl chloride, but no
reaction occurs in the experimental conditions that give
quantitative yields in the presence of the ionic liquid.
When the esters produced were not volatile, yields by
weight were evaluated, and they were comparable to
yields determined by g.c. with the internal standard
(entries 15, 17, 20). The amount of ionic liquid used as
reaction media was generally small, the ratio of IL/car-
boxylate being 1.5. Furthermore after reaction, it was
possible to reuse the IL in a further run: after extrac-
tion with diethyl ether, the ionic liquid is dried under
vacuum to eliminate traces of the solvent and simply
reused.
this low ratio gives rise to very heterogeneous and quite
viscous systems. Therefore, we initially used a higher
ratio, up to 3, thinking that it was necessary to work
with more fluid systems (entries 14, 16). Nevertheless,
both quite heterogeneous, viscous and fluid systems
give the same excellent results.
For the more hydrophobic laurate the ionic liquid
MMIM, also used at the ratio IL/carboxylate of 3,
gives poor results (entry 18). In this case only a modifi-
cation in the structure of the ionic liquid, and the use of
the more hydrophobic BEIM (entry 19) really leads to
a quantitative yield. Also in this case the system is fluid
with a ratio of BEIM/laurate of 3, and is very heteroge-
nous and viscous with a ratio of 1.5, but results are
excellent in both cases (entries 19 and 20). This change
in the ionic liquid structure, with a small increase in the
hydrophobicity, allows the reaction of laurate with
benzyl chloride to proceed quantitatively: in this case,
therefore, the concept of ‘designer solvent’ is at work.
We are currently proceeding more deeply to search for
possible structure-function relationships, in order to
finally be able to predict and modulate the properties of
the solvent.
References
The time and the ratio carboxylate/alkyl halide
required for complete esterification varied depending on
the carboxylate and alkyl halide used. Not only pri-
mary alkyl halide (entry 1) react fast with acetate, but
also secondary halides (entry 3) and dibromides (entries
4, 5). Both liquid and solid halides (entries 9, 11, 12) do
react similarly. The more hydrophobic lauryl bromide
(entry 2) requires a longer time, and a higher excess of
carboxylate (entry 2), When an aromatic moiety is
present in the alkyl halides (entries 7, 8) the reactions
proceed easier, as is the case for benzyl and phenacyl
halides (entries 9, 10, 11, 12, 13).
1. For recent reviews on ionic liquids: (a) Freemantle, M.
Chem. Eng. News. 1998, 76, 32–37; (b) Welton, T. Chem.
Rev. 1999, 99, 2071–2083; (c) Olivier-Bourbogou, H.;
Magna, L. J. Mol. Cat A: Chem. 2002, 182, 419–437.
2. Schwegler, M. A.; van Bekkum, H. Appl. Catal. 1999, 74,
191–194.
3. Deng, Y.; Shi, F.; Beng, J.; Qiao, K. J. Mol. Cat. A:
Chem. 2001, 165, 33–36.
4. Fraga-Dubreuil, J.; Bourahla, K.; Rahmouni, M.;
Bazureau, J. P.; Hamelin, J. Cat. Comm. 2002, 3, 185–190.
5. Shaw, J. E.; Kunerth, D. C.; Sherry, J. J. Tetrahedron Lett.
1973, 9, 689–692.
6. Dean, F. M.; Amin, J. H.; Pattison, F. L. M. Org. Synth.
The procedure has proven to have validity also with
several carboxylates, including butyrate (entry 13), cin-
namate (entries 14, 15) and benzoate (entries 16, 17). As
we have already pointed out, the ratio of IL/carboxy-
late was generally 1.5, but with benzoate and cinnamate
Coll. Vol. V, 1973, 580–582.
7. Ogliarusso, M. A.; Wolfe, J. F. In The Synthesis of Car-
boxylic Acids and Esters and their Derivatives; Patai, S.;
Rappoport, Z., Eds.; Wiley: Chichester, 1991.
‡ General procedure for esterification in ionic liquid. In a 4-ml vial a
mixture of ionic liquid and the sodium carboxylate was heated to
90°C with stirring for ca. 15 minutes. The alkyl halide was then
added, under nitrogen, and the mixture was stirred for the necessary
time. At the end of reaction, after cooling to room temperature,
tBu-benzene was added, as internal standard; water was added, and
the mixture was extracted with diethyl ether (3×10 ml); the com-
bined organic extracts were washed with sodium bicarbonate, dried
over Na2SO4, and analyzed by GC. When yields by weight were
determined, no internal standard was added at the end of reaction,
and the organic solvent was eliminated from the combined extracts
by rotatory evaporation.