Direct catalytic asymmetric aldol reactions on chiral catalysts assembled in the interface of emulsion droplets

Article abstract of DOI:10.1016/j.jcat.2007.06.017

An amphiphilic proline-based organocatalyst was assembled on the interface of water and oil, resulting in a W/O emulsion. The chiral catalyst in emulsion significantly enhances the reactivity and stereoselectivity of the direct asymmetric aldol reactions,

Full text of DOI:10.1016/j.jcat.2007.06.017

Journal of Catalysis 250 (2007) 360–364
www.elsevier.com/locate/jcat
Research Note
Direct catalytic asymmetric aldol reactions on chiral catalysts assembled
in the interface of emulsion droplets
Lin Zhong a, Qiang Gao a, Jinbo Gao a, Jianliang Xiao a,b, Can Li a,∗
a
State Key Laboratory of Catalysis, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China
b
Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, UK
Received 10 May 2007; revised 14 June 2007; accepted 15 June 2007
Available online 30 July 2007
Abstract
An amphiphilic proline-based organocatalyst was assembled on the interface of water and oil, resulting in a W/O emulsion. The chiral catalyst
in emulsion significantly enhances the reactivity and stereoselectivity of the direct asymmetric aldol reactions, which can be attributed mainly to
the larger interfacial surface area and uniformly distributed catalyst molecules in the interface of the emulsion droplets.
© 2007 Elsevier Inc. All rights reserved.
Keywords: Aldol reaction; Asymmetric synthesis; Emulsion catalysis; Interface
1. Introduction
the role of water in these reactions remains unclear [23–25].
Although emulsion and emulsion-related systems have aroused
much interest recently because of their significant beneficial ef-
fects on the reaction [26–30], whether emulsion formation is a
prerequisite for an aldol reaction in the presence of water is not
clear [21,22]. For instance, the reactions reported by Barbas III
and co-workers [21] and Hayashi et al. [22] were performed al-
most equally well in DMSO or without water at all. Thus, there
clearly exists an incentive to gain more insight into the effect of
emulsion on the organocatalytic aldol reaction.
In our previous work on ultra-deep desulfurization of diesel
and selective oxidation of alcohols catalyzed by amphiphilic
catalysts [31,32], we found that the amphiphilic catalysts can
be assembled in the interface of water and oil to form emulsion
droplets. The catalyst in the emulsion significantly increases the
activity and selectivity of the reactions. These findings have
stimulated us to extend the concept of emulsion catalysis to
asymmetric aldol reaction with an intention of determining the
role of water in the aldol reaction with amino acid catalyst.
Herein we report that the reactivity and stereoselectivity of di-
rect asymmetric aldol reactions are significantly enhanced by
chiral emulsion catalysis, which can be attributed mainly to the
large interfacial area and uniformly distributed catalyst mole-
cules in the emulsion system.
The direct asymmetric aldol reaction is one of the most
important C–C bond-forming reactions and has been widely
used in constructing natural and nonnatural products [1–3].
Numerous methods based on biologic catalysis, organometal-
lic catalysis, and organocatalysis for this transformation have
been reported [4–9]. In particular, organocatalysis has attracted
growing interest, and extensive investigations have been con-
ducted to improve the organocatalytic efficiency and enantio-
selectivity [10–12]. Previous studies have shown that a small
amount of water can accelerate the reaction [13–15], whereas
a large excess of water is detrimental to the reaction [16–19].
Recently, Hayashi et al. [20] and Barbas III and co-workers
[21] independently reported highly diastereoselective and enan-
tioselective aldol reactions in the presence of water without
using any organic solvents. Very recently, Hayashi et al. [22] re-
ported successful cross-aldol reactions catalyzed by a combined
proline/surfactant organocatalyst in water. However, there is a
debate as to whether these reactions are really “all wet,” and
*
Corresponding author. Fax: +86 411 84694447.
E-mail address: canli@dicp.ac.cn (C. Li).
0021-9517/$ – see front matter © 2007 Elsevier Inc. All rights reserved.
doi:10.1016/j.jcat.2007.06.017

L. Zhong et al. / Journal of Catalysis 250 (2007) 360–364
361
2. Experimental
silica gel column chromatography gave the pure aldol product.
Ee and dr were determined by HPLC on a Chiralpak AD-H or
Chiralcel OD-H column.
All chemicals were obtained commercially. NMR spectra
were recorded on a Bruker DRX 400 spectrometer. Chemical
shifts are given in δ relative to TMS, and coupling constants,
J , are given in Hz. Infrared spectra were recorded on a Nico-
let Nexus 470 spectrometer. HPLC was performed on HPLC
1100 using Chiralpak AD-H and Chiralcel OD-H columns.
Optical microscopy was performed using a Nikon TE2000-E
inverted fluorescence microscope equipped with a Qimaging
Ltd. RET-2000R-F-CLR-12-C cooled CCD camera, a 100 W
Nikon C-LHG1 mercury lamp, and Nikon B-2A fluorescence
filters (excitation filter, 450–490 nm; dichroic mirror, 505 nm;
emission filter, >520 nm). Light-scattering measurements were
performed on a COULTER N4 Plus Submicron Particle Sizer.
The amphiphilic catalysts were prepared as described previ-
ously [22]. Emulsions were formed by the addition of a given
amount of catalysts to cyclohexanone, followed by the addi-
tion of a specific amount of water under vigorous stirring. The
optical microscopy and light scattering of the emulsions were
measured immediately thereafter.
3. Results and discussion
Families of the amphiphilic proline-based organocatalysts
1 ((2S,4R)-4-(decanoyloxy)pyrrolidine-2-carboxylic acid), 2
((2S,4R)-4-(dodecanoyloxy)pyrrolidine-2-carboxylic acid) and
3 ((2S,4R)-4-(stearoyloxy)pyrrolidine-2-carboxylic acid) were
synthesized to meet the requirement for the formation of emul-
sion droplets when the organocatalyst acts as a surfactant
(Scheme 1). W/O emulsions were indeed formed by the ad-
dition of a given amount of catalyst to cyclohexanone, followed
by the addition of a specific amount of water under vigorous
stirring. Figs. 1a–1c show an optical microscopy image of the
W/O emulsion droplets formed from the amphiphilic catalysts.
Metastable emulsions were formed with catalyst 1 and cata-
lyst 2, whereas catalyst 3 resulted in an unstable emulsion.
The catalyst 2 (11.8 mg, 0.038 mmol) was stirred in 1 ml
cyclohexanone for 10 min at room temperature, the 400 µl of
water was added into the mixture under vigorous stirring, re-
sulting in an emulsion. Aldehyde (0.25 mmol) was added into
the emulsion and the reaction mixture was vigorously stirred
at room temperature for 6–70 h. The reaction mixture was then
treated with saturated ammonium chloride solution, and the lay-
ers were separated. The aqueous layer was extracted several
times with ethyl acetate, and the combined organic layers were
dried with anhydrous MgSO4 and evaporated. Purification by
Scheme 1. The amphiphilic chiral organocatalysts evaluated in this study.
Fig. 1. Optical micrograph of emulsions: (a) mixture of 0.019 mmol catalyst 1, 400 µl water and 1 ml cyclohexanone, (b) mixture of 0.019 mmol catalyst 2, 400 µl
water and 1 ml cyclohexanone, (c) mixture of 0.019 mmol catalyst 3, 400 µl water and 1 ml cyclohexanone and (d) mixture of 0.019 mmol catalyst 2, 500 µl
cyclohexanone and 3.5 ml water.

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L. Zhong et al. / Journal of Catalysis 250 (2007) 360–364
Table 1
Table 2
Aldol reaction of cyclohexanone with p-nitrobenzaldehyde catalyzed by the
amphiphilic chiral organocatalyst 2
Cross aldol reactions of cyclohexanone with different aldehydes catalyzed by 2
in emulsion
a
c
b
Entry
X
Time
(h)
Yield
(%)
Ee
Dr
a
b
c
Entry Reaction
media
Time
(h)
Yield
(%)
Dr
Ee
(%)
Emulsion
stability
(%)
(%)
1
2
3
4
5
3-NO
2-NO
4-Cl
4-H
4-MeO
4-NO
12
18
38
38
70
6
98
94
40
94
70
98
92
76
80
76
86
74
98
93
95
90
95
95
2
2
d
1
2
3
4
5
6
7
Organic solvent
Neat
Neat
W/O emulsion
W/O emulsion
W/O emulsion
O/W emulsion
14
14
36
14
13
22
24
<5
<5
30
97
96
97
95
n.d
n.d
86
94
92
94
92
n.d No emulsion
n.d No emulsion
78 No emulsion
>99 Metastable
99 Metastable
99 Unstable
e
f
d
6
2
a
Isolated yield after separation by silica gel.
g
99 Metastable
b
c
d
Determined by analysis of the mixture of anti/syn product.
Determined by HPLC (Chiralpak AD-H and Chiralcel OD-H).
Cyclopentanone as ketone donor.
a
b
c
d
e
f
Isolated yield after separation by silica gel.
Determined by analysis of the mixture of anti/syn product.
Determined by HPLC (Chiralpak AD-H).
DMSO, THF, CH CN, or MeOH as solvent.
3
yield, 92% dr, and 99% ee (Table 1, entry 7). Interestingly, the
two types of emulsions (W/O and O/W) formed from 2 resulted
in an aldol product with the nearly same yield and stereose-
lectivity (Table 1, entries 4 and 7), indicating that the aldol
reaction can occur efficiently in emulsion even if with an ex-
cess amount of water. It should be noted that all of the aldol
reactions in emulsion (W/O or O/W) were performed under
continuous stirring because the emulsion is metastable. As long
as the emulsion was formed, the change in stirring rate did not
make a significant difference in the reaction rate.
Although the reaction mechanism of the aldol reaction in
emulsions (W/O and O/W) is not very clear at this moment,
we can propose that the assembly of the amphiphilic chiral
organocatalyst in emulsion is an indispensable requirement for
enhancing the activity and stereoselectivity of the aldol reac-
tion. The catalyst molecules in nonemulsion media (neat or
organic solvent) are distributed randomly, whereas the catalyst
molecules in emulsion are distributed uniformly on the emul-
sion droplet surface at the molecule level. Thus, the surface area
of active catalyst is increased, and more uniform active centers
are created. The catalyst on the interface of emulsion droplets
also could be beneficial for the reaction if water acts as a weak
Brønsted acid to accelerate the reaction, because the catalyst in
either W/O or O/W can intimately contact the water [20]. As a
result, emulsion catalysis has higher activity and stereoselectiv-
ity than nonemulsion catalysis [26–34].
The direct asymmetric aldol reactions using the amphiphilic
organocatalyst 2 in emulsion also was examined for cyclo-
hexanone and different aldehydes (Table 2). Generally, the reac-
tion of cyclohexanone with reactive aldehydes gives aldol prod-
ucts with high yields and stereoselectivities. More than 90% ee
was obtained in the case of an electron-rich aldehyde, although
the yield was modest. The reaction with cyclopentanone, an-
other water-immiscible ketone, also was performed efficiently
in emulsion, affording an aldol product with high yield and
enantioselectivity (Table 2, entry 6). These results demonstrate
that chiral emulsion can act as an efficient reaction media for
the direct asymmetric aldol reactions.
1 as catalyst.
3 as catalyst.
0.5 ml cyclohexanone and 3.5 ml water.
g
Compared with catalyst 3, the former two catalysts have shorter
alkyl chains and lower hydrophilic-lipophilic balance values.
Dynamic light-scattering showed that the sizes of the spherical
emulsion droplets formed from 1 and 2 were about 0.1–0.2 µm.
Interestingly, a metastable O/W emulsion can be obtained when
the ratio of the catalyst to cyclohexanone is optimized (Fig. 1d).
The metastable emulsions (either W/O or O/W) can be read-
ily formed using 2 as a surfactant possibly because the chain
length of alkyl group in 2 is more suitable for emulsion forma-
tion.
The emulsion catalytic system was then tested for the aldol
reaction of p-nitrobenzaldehyde with cyclohexanone (Table 1).
The reaction was very slow in neat or an organic solvent with
catalyst 2, where emulsion was not formed due to the absence
of water (Table 1, entries 1 and 2). Prolonging the reaction time
to 36 h, the reaction in neat gave the aldol product with only
30% yield, 86% dr, and 78% ee (Table 1, entry 3). However, the
reaction in the W/O emulsion formed from 2 (Fig. 1b) was en-
hanced significantly and gave an aldol product with 97% yield,
94% dr, and >99% ee in 14 h (Table 1, entry 4). The reactivity
and stereoselectivity of the reaction also were enhanced signif-
icantly when the W/O emulsions formed from 1 (Fig. 1a) and 3
(Fig. 1c) were used as reaction media. The two catalytic emul-
sion systems showed approximately the same isolated yields
and stereoselectivity as the W/O emulsion formed with 2 (Ta-
ble 1, entries 4–6). The results indicate that emulsion plays a
vital role in promoting catalytic activity and stereoselectivity
in the aldol reaction. The fact that the metastable emulsions
formed from 1 and 2 allowed completion of the aldol reac-
tion more quickly compared with the unstable emulsion formed
from 3 further demonstrates the important effect of the emul-
sion on this reaction (Table 1, entries 4–6). It should be noted
that the reaction in the O/W emulsion formed with 2 (Fig. 1d)
also was performed efficiently and afforded a product with 95%

L. Zhong et al. / Journal of Catalysis 250 (2007) 360–364
363
Scheme 2. Schematic description of direct asymmetric aldol reaction using an amphiphilic chiral organocatalyst assembled on emulsion droplets.
The direct asymmetric aldol reactions in the W/O emulsion
are depicted schematically in Scheme 2. The amphiphilic chi-
ral organocatalyst with proper hydrophilic–lipophilic balance
values can be distributed uniformly in the water–oil interface,
forming a assembly around the water droplets. The amphiphilic
catalyst acts as a surfactant to maintain stable emulsion droplets
and so provides high interfacial surface areas, resulting in high
reactivity. The catalyst in emulsion can be organized as a well-
ordered two-dimensional chiral surface, which may be respon-
sible for the high activity and enantioselectivity observed in the
direct aldol reactions [28,33–35].
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4. Conclusion
We have developed emulsion catalytic systems (W/O and
O/W) using chiral amphiphilic organocatalysts as surfactants.
The direct asymmetric aldol reactions were found to occur in
the emulsion where the catalyst molecules are distributed uni-
formly in the water–oil interface and form a chiral surface. The
chiral catalyst in emulsion significantly enhanced the reactivity
and stereoselectivity of the reactions, which can be attributed
mainly to the large interfacial area and uniformly distributed
catalyst molecules in the emulsion system. The chiral emul-
sion catalysis may provide a general and efficient approach for
asymmetric synthesis.
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Acknowledgments
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Financial support was provided by the National Natural Sci-
ence Foundation of China (grant 20321303). The authors thank
Mr. Shi-Shan Sheng for the dynamic light-scattering measure-
ments, Dr. Bo Song for the optical microscopy, and Professor
Qihua Yang for useful discussions.
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