Dehydration reactions in water. Bronsted acid-surfactant-combined catalyst for ester, ether, thioether, and dithioacetal formation in water

Article abstract of DOI:10.1021/ja026241j

Dehydration reactions in water have been realized by a surfactant-type catalyst, dodecylbenzenesulfonic acid (DBSA). These reactions include dehydrative esterification, etherification, thioetherification, and dithioacetalization. In these reactions, DBSA and substrates form emulsion droplets whose interior is hydrophobic enough to exclude water molecules generated during the reactions. Detailed studies on the esterification revealed that the yields of esters were affected by temperature, amounts of DBSA used, and the substrates. Esters were obtained in high yields for highly hydrophobic substrates. On the basis of the difference in hydrophobicity of the substrates, unique selective esterification and etherification in water were attained. Furthermore, chemospecific, three-component reactions under DBSA-catalyzed conditions were also found to proceed smoothly. This work not only may lead to environmentally benign systems but also will provide a new aspect of organic chemistry in water.

Full text of DOI:10.1021/ja026241j

Published on Web 09/13/2002
Dehydration Reactions in Water. Brønsted
Acid-Surfactant-Combined Catalyst for Ester, Ether,
Thioether, and Dithioacetal Formation in Water
Kei Manabe, Shinya Iimura, Xiang-Min Sun, and Shuj Kobayashi*
Contribution from the Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo,
CREST, Japan Science and Technology Corporation (JST), Hongo,
Bunkyo-ku, Tokyo 113-0033, Japan
Received March 20, 2002
Abstract: Dehydration reactions in water have been realized by a surfactant-type catalyst, dodecylben-
zenesulfonic acid (DBSA). These reactions include dehydrative esterification, etherification, thioetherification,
and dithioacetalization. In these reactions, DBSA and substrates form emulsion droplets whose interior is
hydrophobic enough to exclude water molecules generated during the reactions. Detailed studies on the
esterification revealed that the yields of esters were affected by temperature, amounts of DBSA used, and
the substrates. Esters were obtained in high yields for highly hydrophobic substrates. On the basis of the
difference in hydrophobicity of the substrates, unique selective esterification and etherification in water
were attained. Furthermore, chemospecific, three-component reactions under DBSA-catalyzed conditions
were also found to proceed smoothly. This work not only may lead to environmentally benign systems but
also will provide a new aspect of organic chemistry in water.
Introduction
product side. A representative example is acid-catalyzed direct
esterification of carboxylic acids with alcohols. Generally, direct
Recently, use of water as a reaction solvent has received
considerable attention in synthetic organic chemistry for several
reasons.1 First, water is a cheap, safe, and environmentally
benign solvent when compared with organic solvents, which
are normally used for organic reactions. Use of water will reduce
the use of harmful organic solvents and is regarded as an
important research topic in green chemistry.2 Second, in aqueous
reactions, it is unnecessary to dry solvents, substrates, and
reagents before use. Thus, consumption of drying agents, energy,
and time can be reduced. Third, water has unique physical and
chemical properties, and by utilizing these it would be possible
to realize reactivity or selectivity that cannot be attained in
organic solvents.3 In addition, because the “solvent” in living
organisms is water, aqueous reaction systems may lead to
development of artificial enzymes or molecular-level machines
that work in biological systems.
esterification is carried out in organic solvents and requires either
of two methods to shift the equilibrium to afford the product
(ester) in good yields: continuous removal of water during the
reaction (azeotropically or using dehydrating agents) and use
of a large excess of one of the reactants.5 In any case, the pre-
sence of large excess amounts of water as a solvent should have
a detrimental effect on the equilibrium of the dehydration
reaction.
Although water as a solvent impedes dehydration, there are
some examples of dehydrative esterification in water.6 Saam et
al. reported direct polyesterification of 1,10-decanediol and
nonanedioic acid in water in the presence of catalysts such as
(4) Reviews: (a) Aqueous-Phase Organometallic Catalysis. Concepts and
Applications; Cornils, B., Herrmann, W. A., Eds.; Wiley-VCH: Weinheim;
1998. (b) Engberts, J. B. F. N.; Feringa, B. L.; Keller, E.; Otto, S. Recl.
TraV. Chim. Pays-Bas 1996, 115, 457. (c) Fringuelli, F.; Piermatti, O.;
Pizzo, F.; Vaccaro, L. Eur. J. Org. Chem. 2001, 439. (d) Genet, J. P.;
Savignac, M. J. Organomet. Chem. 1999, 576, 305. (e) Kobayashi, S.;
Manabe, K. In Stimulating Concepts in Chemistry; Shibasaki, M., Stoddart,
J. F., Vo¨gtle, F., Eds.; Wiley-VCH: Weinheim, 2000. (f) Kobayashi, S.;
Manabe, K. Acc. Chem. Res. 2002, 35, 209.
(5) (a) Larock, R. C. ComprehensiVe Organic Transformations; John Wiley
& Sons: New York, 1999. (b) Greene, T. W.; Wuts, P. G. M. ProtectiVe
Groups in Organic Synthesis, 3rd ed.; John Wiley & Sons: New York,
1999. (c) Otera, J.; Dan-oh, N.; Nozaki, H. J. Org. Chem. 1991, 56, 5307.
(d) Izumi, J.; Shiina, I.; Mukaiyama, T. Chem. Lett. 1995, 141. (e) Ishihara,
K.; Ohara, S.; Yamamoto, H. J. Org. Chem. 1996, 61, 4196. (f) Ishihara,
K.; Ohara, S.; Yamamoto, H. Science 2000, 290, 1140. (g) Masaki, Y.;
Tanaka, N.; Miura, T. Chem. Lett. 1997, 55. (h) Storck, S.; Maier, W. F.;
Salvado, I. M. M.; Ferreira, J. M. F.; Guhl, D.; Souverijins, W.; Martens,
J. A. J. Catal. 1997, 172, 414. (i) Zhang, G.-S. Synth. Commun. 1999, 29,
607. Esterification of carboxylic acids with equimolar amounts of alcohols
without using dehydrating tools has been reported: (j) Wakasugi, K.;
Misaki, T.; Yamada, K.; Tanabe, Y. Tetrahedron Lett. 2000, 41, 5249.
(6) Esterification under water-toluene two-phase conditions has been reported,
although the yields of esters are low: Okuhara, T.; Kimura, M.; Kawai,
T.; Xu, Z.; Nakato, T. Catal. Today 1998, 45, 73.
Although various efficient catalytic systems in water have
been developed so far,4 there are still many types of reactions
which are difficult to carry out in water. One such reaction is
dehydration in which water molecules generated during the re-
action must be removed to shift equilibrium to the dehydrated
* To whom correspondence should be addressed. E-mail: skobayas@
mol.f.u-tokyo.ac.jp.
(1) (a) Organic Synthesis in Water; Grieco, P. A., Ed.; Blackie Academic and
Professional: London, 1998. (b) Li, C.-J.; Chan, T.-H. Organic Reactions
in Aqueous Media; John Wiley & Sons: New York, 1997.
(2) (a) Anastas, P.; Warner, J. C. Green Chemistry: Theory and Practice;
Oxford University Press: Oxford, 1998. (b) Tundo, P.; Anastas, P, Black,
D. StC.; Breen, J.; Collins, T.; Memoli, S.; Miyamoto, J.; Polyakoff, M.;
Tumas, W. Pure Appl. Chem. 2000, 72, 1207.
(3) For example: (a) Rideout, D. C.; Breslow, R. J. Am. Chem. Soc. 1980,
102, 7816. (b) Breslow, R. Acc. Chem. Res. 1991, 24, 159. (c) Engberts,
J. B. F. N.; Blandamer, M. J. Chem. Commun. 2001, 1701.
9
10.1021/ja026241j CCC: $22.00 © 2002 American Chemical Society
J. AM. CHEM. SOC. 2002, 124, 11971-11978
11971

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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Dehydration Reactions in Water
A R T I C L E S
Table 1. Dehydrative Esterification in Water with Various
Catalysts
Figure 2. Initial rates of esterification in water. Conditions: lauric acid/
3-phenyl-1-propanol ) 1/1, at 30 °C in water (3 mL/0.5 mmol of lauric
acid). Open circle: with 10 mol % of DBSA. Open triangle: with 10 mol
% of OBSA. Closed circle: with 10 mol % of TsOH.
a Isolated yield.
tant-type ones. The reaction was carried out in water with stirring
(1400 rpm) using a magnetic stirring bar and quenched after
24 h with a 1:1 mixture of saturated aqueous NaHCO3 and brine.
The product was extracted with ethyl acetate easily even in the
presence of a surfactant-type catalyst. One of keys in this reac-
tion is use of a small amount of the surfactant. As shown in
Table 1 (entries 1-3), when Lewis acid-surfactant-combined
catalysts (LASCs), which were used in our previous work on
aldol reactions in water,12b-e,g,i were used, 3-phenyl-1-propyl
laurate was obtained in very low yields. On the other hand, do-
decylbenzenesulfonic acid (DBSA),20 which can act as a Brøn-
sted acid-surfactant-combined catalyst (BASC),14 was found
to catalyze the reaction efficiently and afforded the ester in 60%
yield in 24 h at 40 °C (entry 4). Simple Brφnsted acids such as
sulfuric acid and p-toluenesulfonic acid (TsOH) catalyzed the
reaction very slowly (entries 5 and 6), and sodium dodecyl-
benzenesulfonic acid was also not effective (entry 7). These
results contrast with those of polyesterification by Saam et al.,7
indicating that the reaction mechanism is an acid-catalyzed one,
not alkylation of the carboxylate as they claimed. Octylbenze-
nesulfonic acid (OBSA), which has a shorter alkyl chain than
DBSA, was less active than DBSA (entry 8). Perfluoroalkane-
sulfonates were also inferior to DBSA (entries 9 and 10).
The difference between DBSA and OBSA or TsOH is
noteworthy. According to a study on the initial rates of the
esterification at 30 °C (Figure 2), DBSA was found to catalyze
the reaction 2.3 times faster than OBSA and 59 times faster
than TsOH (for DBSA, 5.4 × 10-3 M h-1; for OBSA, 2.4 ×
10-3 M h-1; for TsOH, 9.1 × 10-5 M h-1). These results clearly
demonstrate that the long alkyl chain of DBSA is crucial for
the efficient catalysis.
Figure 3. (a) Reaction mixture of the DBSA-catalyzed esterification of
lauric acid with 3-phenyl-1-propanol in water. (b) Optical micrograph of
the reaction mixture.
in the present reaction system was confirmed by optical
microscopy (Figure 3b). The emulsion formation is attributed
to the property of DBSA as a surfactant, and as shown in Figure
1, this property should be important to accelerate the rate of
the esterification.21
Equilibrium Position of Esterification in Water. Figure 4
shows the profiles of the DBSA-catalyzed reaction of lauric
acid with 3-phenyl-1-propanol (1:1) at 40 °C in water (closed
circle). The reaction reached its maximum yield of 84% in 170
h. We also conducted hydrolysis of the corresponding ester
(open square). Both esterification and hydrolysis finally led to
the same composition of the reaction mixture, indicating that
the reaction reached its equilibrium position. The high yield at
the equilibrium position should be attributed to the formation
of a hydrophobic area in water as shown in Figure 1.
We next studied the effects of temperature on the equilibrium
position. At the equilibrium position at 40 °C, the yield of the
ester reached its maximum of 84% as mentioned above. Raising
the temperature to 60 °C slightly decreased the maximum yield
to 80%, although the reaction rate to reach the equilibrium
became faster than that at 40 °C. Increase of the reaction
temperature to 100 °C resulted in a further decrease of the ester
yield at the equilibrium position to 60%, confirming that
increasing the temperature has adverse effects on the maximum
yields of the ester.
In the case using DBSA, the reaction mixture became a white
turbid emulsion (Figure 3a), as in the case of the DBSA-
catalyzed Mannich-type reactions, in which the formation of
white turbid mixtures was important to attain good yields of
the desired Mannich adducts.14 Formation of emulsion droplets
(21) Stirring (usually 1400 rpm) of the reaction mixture was not very important
to keep it an emulsion system. Without stirring, large, visible droplets were
formed, but the aqueous phase was still a white turbid solution (the yield
of 3-phenylpropyl laurate is 58% after 24 h at 40 °C without stirring). Cf.
ref 12i.
(20) Dodecylbenzenesulfonic acid (soft type) was purchased from Tokyo Kasei
Kogyo Co., Ltd. This is a mixture of linear alkylbenzenesulfonic acids. Its
molecular weight was regarded as 326.50.
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A R T I C L E S
Manabe et al.
Figure 5. Reaction mixture of esterification in water in the presence of
200 mol % of DBSA.
Table 3. Yield at the Equilibrium Position in the Reaction of
CH3(CH2)nCO2H with 3-Phenyl-1-propanol in Watera
entry
n
yield (%)
Figure 4. Reaction profiles for DBSA-catalyzed reactions in water. Closed
circle: esterification of lauric acid with 3-phenyl-1-propanol (1:1). Open
square: hydrolysis of 3-phenyl-1-propyl laurate.
1
2
3
4
5
6
7b
0
2
4
6
8
10
10
5
39
72
78
81
84
15
Table 2. Yield at the Equilibrium Position in the Esterification in
the Presence of Various Amounts of DBSA in Watera
entry
amount of DBSA (mol %)
yield (%)
1
2
3
4
10
50
100
200
84
71
58
32
a Conditions: CH3(CH2)nCO2H/3-phenyl-1-propanol ) 1/1, DBSA (10
mol %), at 40 °C in water (3 mL/0.5 mmol of the carboxylic acid). b Ethanol
was used instead of 3-phenyl-1-propanol. The yields were determined by
1H NMR.
a Conditions: lauric acid/3-phenyl-1-propanol ) 1/1, at 40 °C in water
1
(3 mL/0.5 mmol of lauric acid). The yields were determined by H NMR.
The amounts of DBSA used were also found to affect the
equilibrium position (Table 2). Each equilibrium position was
confirmed by conducting both esterification of the carboxylic
acid with the alcohol and hydrolysis of the ester. The times
required to reach the equilibrium positions became shorter as
the amount of DBSA increased (ca. 120 h for 10 mol % of
DBSA, 96 h (at longest) for 50 mol % of DBSA, 72 h (at
longest) for 100 and 200 mol % of DBSA; we have not carried
out the reaction with less than 10 mol % of DBSA because of
the very long reaction time required to reach the equilibrium
position). Table 2 clearly shows that an increase of the amount
of DBSA resulted in a decrease of the yield of the ester at the
equilibrium position. This result may be attributable to the size
difference of the emulsion droplets which were formed by the
hydrophobic substrates and the surfactant in water. As the
amount of the surfactant-type catalyst increases, the size of each
droplet may decrease, because the emulsion system may become
a microemulsion system where the substrates are solubilized in
water by a large amount of the surfactant.22 In fact, while 10
mol % of DBSA gave the white turbid mixture (Figure 3a), the
reaction mixture was almost clear in the presence of 200 mol
% of DBSA (Figure 5), indicating that the size of the droplets
became smaller. The smaller the droplets, the larger the sum of
the surface area of the droplets. As a result, the organic phase
and water can contact each other, and the hydrolysis of the ester
becomes a favorable process. These results suggest that a large
hydrophobic area inside the emulsion droplets is important to
attain high yields at the equilibrium position.
Figure 6. Reaction profiles for esterification of lauric acid with 3-phenyl-
1-propanol in the presence of 10 mol % of DBSA. Closed circle: in water.
Open circle: under neat conditions.
(entries 1-6). In addition, use of a water-soluble alcohol such
as ethanol resulted in lower yield of the ester (entry 7). These
results emphasize the importance of hydrophobicity of substrates
in the dehydration reactions in water. Hydrophobic substrates
themselves form a hydrophobic area dispersed in water and
facilitate the ester formation. Although these effects are the cause
of substrate limitation in the present reaction system, they also
enable selective esterification and transesterification as men-
tioned later.
Comparison with Neat Conditions. To compare the esteri-
fication in water with that under neat conditions, the esterifi-
cation of lauric acid with 3-phenyl-1-propanol in the presence
of DBSA was carried out without any solvents (Figure 6). Since
DBSA is soluble in organic substrates, the reaction mixture was
homogeneous at the beginning. Therefore, the reaction system
is regarded to be similar to that with conventional dry conditions
but in high concentration without dehydrating agents. It is
noteworthy that, although the reaction under neat conditions
was faster than that in water probably because of the absence
of competitive protonation between the substrate and a large
number of water molecules under the neat conditions, the yield
of the ester at the equilibrium position was unchanged. Under
Effects of substrates on the equilibrium position were next
studied (Table 3). As expected, when various alkanecarboxylic
acids were used for the DBSA-catalyzed esterification in water,
carboxylic acids with a longer alkyl chain afforded the corre-
sponding esters in higher yields at the equilibrium position
(22) Jo¨nsson, B.; Lindman, B.; Holmberg, K.; Kronberg, B. Surfactants and
Polymers in Aqueous Solutions; John Wiley & Sons: West Sussex, 1998.
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Dehydration Reactions in Water
A R T I C L E S
Table 5. DBSA-Catalyzed Selective Esterification in Water
Table 4. DBSA-Catalyzed Esterification of Various Substrates in
Water
a NMR yield. b Under neat conditions. c 120 h.
reactions with a saturated aqueous solution of NaHCO3 and
brine. According to this procedure, the organic phase can be
easily separated from the aqueous phase even in the presence
of the surfactant.
Selective Esterification. We next carried out selective
esterification of two substrates in this reaction system. When a
1:1 mixture of lauric acid and acetic acid was esterified with
dodecanol in the presence of DBSA under neat conditions at
40 °C for 48 h, the laurate ester and the acetate ester were
obtained in 63% and 35% yields, respectively (Table 5, entry
1). On the other hand, when the same reaction was conducted
in water, the laurate ester was predominantly obtained in 81%
yield, and the yield of the acetate was only 4% (entry 2). Similar
selective esterification of lauric acid over acetic acid was also
observed in the reaction of another alcohol (entry 4). Further-
more, even cyclohexanecarboxylic acid, which is an R-disub-
stituted acid, was preferentially esterified in the presence of
acetic acid (entries 5 and 6). These selectivities are attributed
to the hydrophobic nature of lauric acid and cyclohexanecar-
boxylic acid and to the high hydrophilicity of acetic acid.24 These
unique selectivities became possible by using water as a solvent.
Selective esterification based on the difference in hydrophobicity
was also attained in the reaction of two alcohols, one of which
is hydrophobic and the other is water-soluble (eq 1).24
a Isolated yield. b For 96 h. c For 288 h. d At 60 °C.
neat conditions, the amount of water in the reaction mixture
must be less than 1 equiv to the substrates. On the other hand,
a large excess of water is present in the reaction in water. The
result that these two sets of conditions gave the same yield at
the equilibrium position is surprising and is a characteristic
feature of the present system.
Application to Various Substrates. This catalytic esterifi-
cation in water was applied to various substrates as shown in
Table 4.23 Many hydrophobic substrates were successfully
esterified by DBSA in water, and the use of 2 equiv of the alco-
hols improved the yields to greater than 90% in most cases.
Not only R-monosubstituted carboxylic acids (entries 1-14) but
also R-disubstituted (entries 15 and 16) and R-trisubstituted acids
(entry 17) gave the corresponding products in high yields.
Primary alcohols reacted smoothly, but the reactions were very
slow in the case of secondary alcohols (entries 5 and 6). Func-
tional groups such as a bromide (entry 12) and a double bond
(entries 13 and 14) survived under the reaction conditions.
In the workup procedure for the esterification, the crude
products were extracted with ethyl acetate after quenching the
Table 5 also lists examples of selective esterification of
nonconjugated carboxylic acids over aromatic or conjugated
carboxylic acids25 (entries 7-9). These selectivities are due to
the difference in reactivity between these acids. In fact, the
esterification of benzoic acid or cinnamic acid with 3-phenyl-
1-propanol in the presence of DBSA (10 mol %) in water (40
(23) For a typical experimental procedure, see the Supporting Information.
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A R T I C L E S
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Table 6. Transesterification of Methyl Esters in Water
Table 7. Transesterification of a Triglyceride in Water
a Isolated yield.
a Isolated yield. b Triglyceride:HOR ) 1:6.
°C, 24 h) afforded the corresponding esters in very low yields
(2% for benzoic acid, 6% for cinnamic acid). Furthermore,
hydrolysis of 3-phenyl-1-propyl benzoate (DBSA: 10 mol %,
40 °C, 24 h) gave a trace amount of the hydrolyzed product.
On the basis of this difference in reactivity, esterification of an
alcohol having a benzoyloxy group was possible under the
DBSA-catalyzed conditions as shown in eq 2. It should be noted
that the benzoate group remained intact and that the reaction
system differentiated two kinds of ester groups.
Table 8. DBSA-Catalyzed Etherification in Water
a Isolated yield. b For 7 h at 30 °C. c At 80 °C. d 2 equiv of R′OH was
used. e At 50 °C.
Transesterification. The results of the selective esterification
based on the difference in hydrophobicity of substrates prompted
us to study transesterification, in which esters and alcohols were
used as substrates.26 First, we tested the reactions of methyl
esters with hydrophobic alcohols in the presence of DBSA in
water. As shown in Table 6, the reactions proceeded smoothly
to give the desired esters in high yields. In these cases, methanol,
which is generated during the reactions, dissolved mostly in
the aqueous phase, and thus, the equilibrium of the reactions
favors the formation of the transesterified products.
2. Other Dehydration Reactions in Water. Etherification.
Although the Williamson ether synthesis is probably one of the
most common methods for preparation of ethers,27 the method
required strongly basic conditions and initial conversion of
alcohols to halides or tosylates. On the other hand, acid-
promoted dehydration of alcohols provides an alternative
important method of preparing ethers.28 As an extension of the
DBSA-catalyzed reactions, we next investigated dehydrative
ether formation from two alcohols in water.
First, we tried formation of symmetric ethers from benzylic
alcohols in water using 10 mol % of DBSA as a catalyst. The
reactions were found to proceed smoothly in water to afford
the corresponding symmetric ethers in high yields (Table 8,
entries 1 and 2). It should be noted that the etherification of the
substrate shown in entry 1 in the presence of TsOH instead of
DBSA gave only a trace amount of the product. This result
indicates that the long alkyl chain of DBSA, which leads to the
formation of emulsion droplets, is essential for the efficient
catalysis as in the case of the dehydrative esterification. We
then carried out unsymmetrical etherification of two alcohols,
a primary alcohol and a benzylic alcohol (2 equiv). The reactions
Transesterification of a triglyceride was also realized by the
DBSA-catalyzed reactions in water (Table 7). This system will
provide a useful method to convert natural triglycerides into
other hydrophobic esters directly without using excess alcohols.
(24) Water-octanol partition coefficients, log Poct, have been used to indicate
hydrophobicity of organic compounds (log Poct for lauric acid: 4.6, acetic
acid: -0.17, 3-phenyl-1-propanol: 1.88, ethanol: -0.30): Sangster, J. J.
Phys. Chem. Ref. Data 1989, 18, 1111.
(25) For examples of selective esterification of nonconjugated carboxylic acids
over aromatic or conjugated carboxylic acids, see: (a) Blossey, E. C.:
Turner, L. M.; Neekers, D. C. Tetrahedron Lett. 1973, 1823. (b) Bertin, J.;
Kagan, H. B.; Luche, J.-L.; Setton, R. J. Am. Chem. Soc. 1974, 96, 8113.
(c) Rehn, D.; Ugi, I. J. Chem. Res. Synop. 1977, 119. (d) Banerjee, A.;
Sengupta, S.; Adak, M. M.; Banerjee, G. C. J. Org. Chem. 1983, 48, 3106.
(e) Matsumoto, I. Jpn. Kokai Tokkyo Koho JP 59 152,347 [84 152,347]
(Cl. C07C67/08), Chem. Abstr. 1985, 102, 5952w. (f) Ogawa, T.; Hikasa,
T.; Ikegami, T.; Ono, N.; Suzuki, H. J. Chem. Soc., Perkin Trans. 1 1994,
3473. (g) Ram, R. N.; Charles, I. Tetrahedron 1997, 53, 7335. (h)
Rodr´ıguez, A.; Nomen, M.; Spur, B. W. Tetrahedron Lett. 1998, 39, 8563.
(i) Lee, A. S.-Y.; Yang, H.-C.; Su, F.-Y. Tetrahedron Lett. 2001, 42, 301.
(26) Recently, excellent methods of transesterification have been reported: (a)
Xiang, J.; Toyoshima, S.; Orita, A.; Otera, J. Angew, Chem, Int. Ed. 2001,
40, 3670. (b) Xiang, J.; Orita, A.; Otera, J. AdV. Synth. Catal. 2002, 344,
84. (c) Baumhof, P.; Mazitschek, R.; Giannis, A. Angew, Chem, Int. Ed.
2001, 40, 3672. See also ref 5j.
(27) (a) Williamson, A. W. J. Chem. Soc. 1852, 4, 229. (b) Baggett, N. In
ComprehensiVe Organic Synthesis; Barton D., Ollins, W. D., Eds.;
Pergaman: Oxford, 1979; Vol. 1.
(28) For recent examples of acid-catalyzed etherification, see: (a) Sharma, G.
V. M.; Mahalingam, A. K. J. Org. Chem. 1999, 64, 8943. (b) Ooi, T.;
Ichikawa, H.; Itagaki, Y.; Maruoka, K. Heterocycles 2000, 52, 575. (c)
Sharma, G. V. M.; Prasad, T. R.; Mahalingam, A. K. Tetrahedron Lett.
2001, 42, 759. (d) Zhu, Z.; Espenson, J. H. J. Org. Chem. 1996, 61, 324.
9
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Dehydration Reactions in Water
A R T I C L E S
Table 9. DBSA-Catalyzed Thioetherification in Water
Figure 7. Reaction profiles for DBSA-catalyzed etherification of dodecanol
with benzhydrol in water. Red triangle: for benzhydryl dodecyl ether. Purple
square: for dibenzhydryl ether (the yield is based on the benzhydryl group
used). Blue circle: for benzhydrol.
a Isolated yield. b 2 equiv of R′OH was used. c At 50 °C. d For 12 h.
e For 16 h.
also proceeded smoothly to give the desired ethers in high yields
(entries 3-5).
Figure 7 shows the reaction profile of the etherification of
dodecanol with benzhydrol (1 equiv) in the presence of 10 mol
% of DBSA in water at 80 °C. The formation of the unsym-
metrical ether (benzhydryl dodecyl ether) was found to reach
the equilibrium position in 72 h (red triangle). In this reaction,
dibenzhydryl ether derived from two benzhydrol molecules was
generated, and the formation is also plotted in Figure 7 (purple
square). The yield of the symmetrical ether went up to its
maximum (25%) in 4 h and then slowly decreased to reach the
equilibrium position, indicating that dibenzhydryl ether once
formed also acted as a benzhydryl group source.
Selective etherification based on the difference in hydropho-
bicity of two alcohols was also possible in the present reaction
system (eq 3). When an equimolar mixture of dodecanol and
propanol was etherified with benzhydrol in the presence of
DBSA in water, benzhydryl dodecyl ether was selectively
obtained. On the other hand, the ratio of benzhydryl dodecyl
ether to benzhydryl propyl ether decreased significantly under
neat conditions (58% yield and 25% yield, respectively). This
result of the selective reaction based on the difference in
hydrophobicity29 again emphasizes a characteristic feature of
the present dehydration system.
Figure 8. Reaction profiles for DBSA-catalyzed thioetherification of
dodecanethiol with benzhydrol in water. Red triangle: for benzhydryl
dodecyl sulfide. Purple square: for dibenzhydryl ether (the yield is based
on the benzhydryl group used). Blue circle: for benzhydrol.
Not only the trityl thioether but also benzhydryl, 4-butoxybenzyl,
and 4-methoxybenzyl thioethers were obtained in high yields
(entries 2-4). Tritylation of other thiols such as benzyl thiol
and thiophenol in water also gave the desired thioethers (entries
5 and 6). These results demonstrate that this direct thioetheri-
fication in water provides a useful method to protect thiols.
The reaction profile of the thioetherification of dodecanethiol
with benzhydrol (1 equiv) is shown in Figure 8. In contrast to
the etherification shown in Figure 7, the equilibrium positionof
the thioetherification largely lies to the thioether side, affording
the thioether in excellent yield. Although dibenzhydryl ether
was generated in maximum yield of around 40% in 2 h, the
yield declined and finally diminished at the equilibrium position.
This result indicates that the formation of dibenzhydryl ether is
kinetically comparable to the thioether formation but thermo-
dynamically unfavorable under these conditions.
Thioetherification. Thioethers are, in general, synthesized
from halides and thiolates.5b However, a drawback to this
method is that aerobic oxidation to disulfides is prone to occur.
An alternative route to thioethers is acid-promoted condensation
of thiols and activated alcohols such as benzylic alcohols.30
Along this line, we expected that the DBSA-catalyzed dehydra-
tion in water would be applicable to thioetherification. Indeed,
the reaction of dodecanethiol with trityl alcohol proceeded
smoothly in the presence of DBSA in water (Table 9, entry 1).
Dithioacetalization. Dithioacetals are useful in organic syn-
thesis as protective groups for carbonyl compounds,5b as pre-
(29) log Poct for dodecanol: 5.13, propanol: 0.25.24
(30) For examples of acid-catalyzed thioetherification in the presence of water,
see: (a) Pastuszak, J. J.; Chimiak, A. J. Org. Chem. 1981, 46, 1868. (b)
Breitschuh, R.; Seebach, D. Synthesis 1992, 83. (c) Stewart, A. S.; Drey,
C. N. J. Chem. Soc., Perkin Trans. 1 1990, 1753.
9
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A R T I C L E S
Manabe et al.
Table 10. DBSA-Catalyzed Dithioacetalization in Water
It is noteworthy that the thiol parts of the mercaptoalcohols were
selectively transformed to the thioethers and the alcohol parts
to the esters. A chemospecific reaction of a mercaptocarboxylic
acid was also possible as shown in eq 6. Under these conditions,
thioester formation is thermodynamically unfavorable.34 Thus,
these chemospecificities are attributed to thermodynamic stabil-
ity of the products and are controlled under equilibrium
conditions.35
a Isolated yield. b 1,3-Propanedithiol was used instead of 1,2-ethanedithi-
ol. c For 24 h. d At 80 °C.
cursors of acyl carbanion equivalents,31 or as electrophiles under
Lewis acidic conditions.32 The DBSA-catalyzed system was
found to be also applicable to dithioacetalization in water33
(Table 10). The reactions proceeded smoothly not only for
aldehydes (entries 1-3) but also for ketones (entries 4 and 5)
under mild conditions.
In addition, easy workup has been realized without the use
of organic solvents when the products are solid and insoluble
in water. In fact, the dithioacetalization of cinnamaldehyde on
a 10 mmol scale with 1 mol % of DBSA proceeded smoothly
to deposit crystals. The pure product was obtained in excellent
yield after the crystals were filtered and washed with water (eq
4). This simple procedure is one of the advantages of the present
reaction system.
Conclusion
We have described dehydration reactions in water in the
presence of DBSA as a Brønsted acid-surfactant-combined
catalyst (BASC). This reaction system was found to be appli-
cable to various reactions including esterification, etherification,
thioetherification, and dithioacetalization. In addition, unique
selective esterification and etherification have successfully been
carried out, and interesting chemospecific reactions have also
been realized. Detailed studies on the reactions have revealed
the importance of the hydrophobic nature of DBSA and sub-
strates. The reactions need neither dehydrating agents nor
azeotropic removal of water. Instead, the catalyst and substrates
in the present system assemble together through hydrophobic
interactions to form emulsion droplets whose interior is hydro-
phobic enough to exclude water molecules. Furthermore, since
both the sole byproduct and the solvent in the reactions are
water, the reactions may lead to a method which solves
some environmental problems. This work will not only lead to
reaction systems which work in water but also provide a new
aspect of organic chemistry in water.
Chemospecific Dehydration of Two Functional Groups.
With several types of DBSA-catalyzed dehydration in hand, we
tried chemospecific reactions of substrates having two reactive
functional groups. As shown in eq 5, mercaptoalcohols such as
2-mercaptoethanol and 6-mercapto-1-hexanol were subjected to
reactions in the presence of both triphenylmethanol and lauric
acid in an aqueous solution of DBSA. These three-component
reactions predominantly gave tritylthioalkyl laurates in high
yields, accompanied with small amounts of tritylthioalcohols.
Acknowledgment. This work was partially supported by a
Grant-in-Aid for Scientific Research from the Japan Society of
the Promotion of Science.
Supporting Information Available: Experimental section
(PDF). This material is available free of charge via the Internet
at http://pubs.acs.org.
JA026241J
(31) (a) Seebach, D. Synthesis 1969, 17. (b) Ager, D. J. In Umpoled Synthons.
A SurVey of Sources and Uses in Synthesis; Hase, T. A. Ed.; John Wiley
& Sons: New York; 1987.
(32) (a) Reetz, M. T.; Giannis, A. Synth. Commun. 1981, 11, 315. (b) Trost, B.
M.; Murayama, E. J. Am. Chem. Soc. 1981, 103, 6529. (c) Ohshima, M.;
Murakami, M.; Mukaiyama, T. Chem. Lett. 1985, 1871. (d) Saigo, K.;
Hashimoto, Y.; Kihara, N.; Hara, K.; Hasegawa, M. Chem. Lett. 1990,
1097.
(33) For an example of dithioacetalization in water, see: Ceschi, M. A.; Felix,
L. A.; Peppe, C. Tetrahedron Lett. 2000, 41, 9695.
(34) Thioester formation in the presence of water is thermodynamically
unfavorable compared with ester formation: (a) Bruice, T. C. In Organic
Sulfur Compounds; Kharasch, N., Ed.; Pergamon Press: New York; 1961.
Formation of thioesters is also a kinetically unfavorable process under acidic
conditions compared with ester formation. See: (b) Iimura, S.; Manabe,
K.; Kobayashi, S. Chem. Commun. 2002, 94.
(35) For examples of a similar type of reactions, see: (a) Scholl, T.; Roth, H.
J. Arch. Pharm. (Weinheim) 1985, 318, 624. (b) Siedlecka, R.; Skarzewski,
J. Polish J. Chem. 2000, 74, 1369.
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11978 J. AM. CHEM. SOC. VOL. 124, NO. 40, 2002