A R T I C L E S
Manabe et al.
sulfuric acid, dodecylbenzenesulfonic acid, and sodium dode-
cylbenzenesulfonate.7 The authors claimed that the reaction
mechanism was not acid-catalyzed but alkylation of the car-
boxylate with sulfate or sulfonate esters generated in situ.
Although the degrees of polymerization were modest, they
exceeded those normally expected from dehydrative esterifica-
tion in water.
Another example of dehydrative esterification in water is lip-
ase-catalyzed ester or polyester formation in water. Okumura
et al. reported that, in the presence of a lipase, esterification of
oleic acid with various alcohols (1.8-14 equiv) proceeded to
give the corresponding esters, in some cases, in high yields.8
Later, Okumura et al.9 and Matsumura et al.10 applied the system
to polyester formation in water, and Kobayashi et al. pointed
out a unique feature of the lipase-catalyzed polyesterification
where dehydrative ester formation proceeded in aqueous
media.11
Although these examples realized dehydration reactions in
water, the methodology is still limited in terms of substrate and
reaction applicability and, further, lacks detailed mechanistic
studies to explain how dehydration becomes feasible in water
as a solvent. To address these issues, we initiated our investiga-
tions on dehydration reactions in water. Our strategy is based
on previous work on surfactant-aided catalysis in water. We
and others have developed surfactant-aided Lewis12,13 or
Brφnsted acid14,15 catalysis that mediates carbon-carbon bond-
forming reactions in water. Under the reaction conditions,
emulsion droplets were formed from catalytic amounts of these
catalysts and reaction substrates.12i,14c,16 These droplets, although
dispersed in water, are hydrophobic enough for protecting water-
labile substrates or intermediates from hydrolytic decomposi-
tion.17 We expected that these reaction systems would be suitable
to study acid-catalyzed dehydration reactions in water without
using a large excess of one of the reactants.
Figure 1. Illustration of direct esterification by dehydration in the presence
of a surfactant-type catalyst in water.
and organic substrates (carboxylic acids and alcohols) in water
would form emulsion droplets, which have a hydrophobic
interior, through hydrophobic interactions. The surfactant
molecules would concentrate proton (for Brønsted acid catalysis)
or metal cations (for Lewis acid catalysis) onto the surface of
the droplets and then enhance the rate to reach equilibrium. For
hydrophobic substrates, the equilibrium position between the
substrates and the products (esters) would lie at the ester side,
because water molecules generated during the reaction would
be removed from the droplets due to the hydrophobic nature of
their interior. As a result, the dehydration reactions would
efficiently proceed even in the presence of a large amount of
water as a solvent. Indeed, this type of thermodynamic prefer-
ence of the ester formation based on the heterogeneous nature
of the system has been regarded as one reason why dehydration
reactions proceed in water.7,11b
The acid-catalyzed direct formation of simple esters with the
aid of surfactants in water has not been reported as far as we
know, although surfactants have been occasionally used to
accelerate the reactions to the opposite direction, hydrolysis of
esters.18 Furthermore, this dehydration reaction system has
several advantages when compared with the lipase-catalyzed
reactions mentioned above. First, although enzymes often show
severe substrate specificity based on highly efficient recognition
processes, the acid catalysts with surfactants do not. Therefore,
it should, in principle, be possible to apply these catalysts to
various substrates, although they may be limited to highly
hydrophobic ones. Second, the surfactant-aided catalysis can
tolerate drastic reaction conditions such as high temperature.
Third, the catalysts should be applicable to various types of
acid-catalyzed reactions other than esterification. These advan-
tages will enable us to study dehydration reactions in water in
detail and to apply the reaction system to synthetically useful
reactions. Herein we report detailed studies on the direct
esterification of lipophilic substrates in water using a surfactant-
type Brønsted acid and on the extension of the reaction system
to other dehydration reactions including etherification, thioet-
herification, and dithioacetalization in water.19
The concept of dehydrative esterification in water using a
surfactant-type acid catalyst is shown in Figure 1. The catalyst
(7) Baile, M.; Chou, Y. J.; Saam, J. C. Polym. Bull. 1990, 23, 251.
(8) Okumura, S.; Iwai, M.; Tsujisaka, Y. Biochim. Biophys. Acta 1979, 575,
156.
(9) Okumura, S.; Iwai, M.; Tominaga, Y. Agric. Biol. Chem. 1984, 48, 2805.
(10) Matsumura, S.; Takahashi, J. Makromol. Chem., Rapid Commun. 1986, 7,
369.
(11) (a) Kobayashi, S.; Uyama, H.; Suda, S.; Namekawa, S. Chem. Lett. 1997,
105. (b) Suda, S.; Uyama, H.; Kobayashi, S. Proc. Jpn. Acad. 1999, 75-
(B), 201.
(12) (a) Kobayashi, S.; Wakabayashi, T.; Nagayama, S.; Oyamada, H. Tetra-
hedron Lett. 1997, 38, 4559. (b) Kobayashi, S.; Wakabayashi, T. Tetra-
hedron Lett. 1998, 39, 5389. (c) Manabe, K.; Kobayashi, S. Synlett 1999,
547. (d) Manabe, K.; Kobayashi, S. Tetrahedron Lett. 1999, 40, 3773. (e)
Manabe, K.; Mori, Y.; Kobayashi, S. Tetrahedron 1999, 55, 11203. (f)
Kobayashi, S.; Mori, Y.; Nagayama, S.; Manabe, K. Green Chem. 1999,
1, 175. (g) Manabe, K.; Mori, Y.; Nagayama, S.; Odashima, K.; Kobayashi,
S. Inorg. Chim. Acta 1999, 296, 158. (h) Manabe, K.; Kobayashi, S. Chem.
Commun. 2000, 669. (i) Manabe, K.; Mori, Y.; Wakabayashi, T.; Nagayama,
S.; Kobayashi, S. J. Am. Chem. Soc. 2000, 122, 7202. (j) Mori, Y.;
Kakumoto, K.; Manabe, K.; Kobayashi, S. Tetrahedron Lett. 2000, 41, 3107.
(k) Manabe, K.; Aoyama, N.; Kobayashi, S. AdV. Synth. Catal. 2001, 343,
174.
Results and Discussion
(13) (a) Otto, S.; Engberts, J. B. F. N.; Kwak, J. C. T. J. Am. Chem. Soc. 1998,
120, 9517. (b) Rispens, T.; Engberts, J. B. F. N. Org. Lett. 2001, 3, 941.
(14) (a) Manabe, K.; Mori, Y.; Kobayashi, S. Synlett 1999, 1401. (b) Manabe,
K.; Kobayashi, S. Org. Lett. 1999, 1, 1965. (c) Manabe, K.; Mori, Y.;
Kobayashi, S. Tetrahedron 2001, 57, 2537.
(15) (a) Akiyama, T.; Takaya, J.; Kagoshima, H. Synlett 1999, 1426. (b)
Akiyama, T.; Takaya, J.; Kagoshima, H. Tetrahedron Lett. 1999, 40, 7831.
(16) Emulsion systems have been used for organic reactions. One successful
example is emulsion polymerization. For example: Harkins, W. D. J. Am.
Chem. Soc. 1947, 69, 1428.
(17) We have also reported that even boron enolates, which are highly water-
labile, are produced and react with aldehydes in an emulsion system in
water: Mori, Y.; Manabe, K.; Kobayashi, S. Angew. Chem., Int. Ed. 2001,
40, 2815.
1. Dehydrative Esterification in Water. Catalyst Screening.
To study dehydrative esterification in water, we selected the
esterification of lauric acid with 3-phenyl-1-propanol as simple
model substrates and tested various catalysts including surfac-
(18) Feiters, M. C. In ComprehensiVe Supramolecular Chemistry; Atwood, J.
L., Davies, J. E. D., MacNicol, D. D., Vo¨gtle, F., Eds; Elsevier Science:
Oxford; 1996; Vol. 10.
(19) For preliminary reports, see: (a) Manabe, K.; Sun, X.-M.; Kobayashi, S.
J. Am. Chem. Soc. 2001, 123, 10101. (b) Kobayashi, S.; Iimura, S.; Manabe,
K. Chem. Lett. 2002, 10.
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11972 J. AM. CHEM. SOC. VOL. 124, NO. 40, 2002