Asymmetric aldol reaction on water using an organocatalyst tethered on a thermoresponsive block copolymer

Full text of DOI:10.1246/cl.130711

doi:10.1246/cl.130711
Published on the web September 7, 2013
1493
Asymmetric Aldol Reaction on Water Using an Organocatalyst Tethered
on a Thermoresponsive Block Copolymer#
Noriyuki Suzuki,*1 Takahiro Inoue,1 Takumi Asada,1 Ryuji Akebi,1 Go Kobayashi,1 Masahiro Rikukawa,1
Yoshiro Masuyama,1 Masamichi Ogasawara,2 Tamotsu Takahashi,2 and San H. Thang3
1Department of Materials and Life Sciences, Faculty of Science and Technology, Sophia University,
7-1 Kioi-cho, Chiyoda-ku, Tokyo 102-8554
2Catalysis Research Center, Hokkaido University, Kita-ku, Sapporo, Hokkaido 001-0021
3CSIRO Materials Science and Engineering, Bag 10, Clayton South, Vic. 3169, Australia
(Received July 31, 2013; CL-130711; E-mail: norisuzuki@sophia.ac.jp)
L-Proline moieties, which serve as organocatalysts, were
tethered on block copolymers that consisted of thermoresponsive
poly(N-isopropylacrylamide) and PEG-grafted polyacrylate
blocks. The copolymer dissolved in water at temperatures below
the LCST (25 °C), whereas they formed micelles at temperatures
above the LCST (50 °C). Aldol reactions between an arylalde-
hyde and a ketone were conducted in this aqueous solution. The
aldol products were obtained in high yield with high diastereo-
and enantioselectivity (96% ee). The catalyst solution could be
Figure 1. Micelle formation by thermoresponsive block copolymer.
reused up to three times.
hydrophobic polystyrene “frozen core,” and a tedious extraction
operation may be required.
Organic reactions in water receive much attention from the
viewpoint of sustainable and environmentally benign technol-
ogy.1 Surfactants in water form micelles where organic reactions
can be carried out in the hydrophobic core.2-5 Hydrophilic-
hydrophobic block copolymers also form polymer micelles in
water, which can be used for organic reactions.6-10 However,
micelle formation is normally irreversible, and the recovery of
products, starting materials, and catalysts from the hydrophobic
core can be problematic.
Poly(N-isopropylacrylamide) (PNIPAAm) is a thermores-
ponsive polymer that has a lower critical solution temperature
(LCST) of 32 °C, and the homopolymer is hydrophilic at
temperatures below the LCST and hydrophobic at temperatures
above the LCST. Block copolymers of PNIPAAm and a
hydrophilic polymer form polymer micelles at high temper-
atures and the micelle dissociates at temperatures below the
LCST.11-18 Such a copolymer provides a useful reaction
medium for organic synthesis, because organic reactions can
proceed in the hydrophobic core at higher temperatures, while
organic molecules are released from the micelles at lower
temperatures. We employed poly(ethylene glycol) (PEG) mono-
methyl ether acrylate as the hydrophilic macromonomer. The
grafted PEG chains form “broom-type” hydrophilic segments
and are expected to form a hydrophilic corona that would
effectively surround a hydrophobic core to form o/w polymer
micelles.
In the present study, we designed a block copolymer that
consists of a PNIPAAm segment and PEG-grafted polyacrylate.
L-Proline moieties were introduced in the PNIPAAm segment by
random copolymerization. This copolymer dissolved in water at
rt, while it form micelles that provide hydrophobic reaction
media including catalytic sites at higher temperatures (Figure 1).
Very recently, O’Reilly, Monteiro, and co-workers reported
proline-tethered poly(NIPAAm-block-N,N-dimethylacrylamide)
based on a similar idea.29
NIPAAm (20 mmol) was copolymerized with O-acryloyl-
trans-4-hydroxy-L-proline hydrochloride (1, 1.05 mmol) in the
presence of 2 (0.10 mmol) as a RAFT (reversible addition-
fragmentation chain transfer) agent and 2,2¤-azobis(isobutyro-
nitrile) (AIBN) (0.04 mmol) in N,N-dimethylacetamide (DMA,
12.5 cm3) at 60 °C for 15 h. A portion of the obtained random
copolymer 3¢HCl was neutralized in water with triethylamine to
adjust its pH to 6.3, and then purified by dialysis to give 3. The
molecular weight of 3¢HCl was Mn = 8500 with Mw/Mn = 1.3.
PEG monomethyl ether acrylate (4, Mn = 480, 1.8 mmol) was
added to 3¢HCl (0.18 mmol) in DMA (13 cm3) in the presence of
AIBN (0.036 mmol). The obtained block copolymer 5¢HCl was
neutralized to afford poly[(NIPAAm-ran-1)-block-4] (5) whose
molecular weight was estimated by 1H NMR (Mn = 11500)
(Scheme 1). Random terpolymer poly(NIPAAm-ran-1-ran-4)
(6), which consisted of NIPAAm, 1 and 4, and poly(NIPAAm-
block-4) without proline units 7, were prepared for comparison.30
NMR observation and elemental analysis indicated that 5
contained 87 mol % of NIPAAm units, 5 mol % of proline units,
and 8 mol % of 4. The “broom-type” block copolymer 5
dissolved in water at room temperature to give a clear aqueous
solution, whereas the solution turned opaque when it was
warmed to 50 °C, consistent with its LCST behavior (Figure 2).
Dynamic light scattering (DLS) analysis of an aqueous
solution of 5 showed that its LSCT was between 40 and 45 °C
L-Proline is one of the most promising organocatalysts for
promoting asymmetric cross-aldol reaction.19-21 Proline-cata-
lyzed aldol reactions were originally conducted in organic
solvents such as DMSO, and using a proline catalyst in water
is an attractive subject.22,23 Polymer-tethered proline is one
approach to proline-catalyzed reactions in aqueous media, and
many examples have been reported.24 Proline molecules tethered
on polystyrene gel,25-27 for example, can serve as a catalyst
“on water.”23,28 However, the products are often retained in the
Chem. Lett. 2013, 42, 1493-1495
© 2013 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

1494
40
30
20
10
0
25 °C
50 °C
10
100
1000
Figure 4. Hydrodynamic diameters (Dh,app) of the particles in aqueous
solution of 5 (1 mg cm¹3) at 25 (open plot) and 50 °C (closed plot) by DLS.
Scheme 1. Thermoresponsive-hydrophilic block copolymer that contains
L-proline moieties.
Scheme 2. Asymmetric aldol reaction on water.
several modified polymers were studied (Table 1). Almost no
aldol products were obtained using L-proline in water under our
conditions (Entries 1 and 2). Copolymer 3 afforded 8 in low
yield at rt, while it afforded 8 in 76% yield at 50 °C (Entries 3
and 4). These results suggested that the hydrophobic environ-
ment formed by the PNIPAAm block facilitated the proline-
catalyzed reaction. On the other hand, interestingly, 5 afforded 8
in moderate yield even at rt (Entry 5) although stereo- and
enantioselectivities were inferior to those in Entry 6. Although
the role of the PEG-grafted polyacrylate block in 5 remained
unclear, a possible explanation is that condensed PEG chains
effectively included organic compounds, even at rt, and
promoted the reactions.
Figure 2. Appearance of aqueous solution of 5, left: 25 °C, right: 50 °C.
Random terpolymer 6 gave the product in 86% yield, but
with lower stereo- and enantioselectivity (Entry 7). The terpol-
ymer 6 dissolved in water at rt and did not show LCST behavior
up to 56 °C, which could be one reason for the low selectivity.
The reaction did not proceed in the presence of the diblock
copolymer 7 and untethered L-proline or 4-hydroxyproline
(Entries 8 and 9), probably because proline molecules dissolved
in the aqueous phase and were ineffective as catalysts. This
suggests that the organocatalysts have to be immobilized on
polymer matrices to promote the reaction.
These results indicated that the best result for both yield and
stereoselectivity were obtained with 5 at 50 °C (Entry 6). It
has been proposed that water content in reaction media is an
important factor for controlling stereoselectivity.31 In the present
study, the formation of a hydrophobic PNIPAAm core sur-
rounded by PEG chains must efficiently, but not thoroughly,
exclude water molecules to form a pseudo-hydrophobic environ-
ment that is effective for controlling the stereoselectivity in
proline-catalyzed aldol reactions.
Figure 3. DLS intensity of an aqueous solution of 5 (1 mg cm¹3) at
various temperatures.
(Figure 3). The diameter of the particles was found to be 80-
90 nm at rt and larger (100-150 nm) at 50 °C (Figure 4).
This suggests that 5 aggregated to form micellar structures
in water at 50 °C. Thus we examined cross-aldol reactions using
an aqueous solution of 5 (Scheme 2).30 Typically, 4-nitro-
benzaldehyde (1 mmol) and cyclohexanone (5 mmol) were
added to a solution of 5 (325 mg, containing 0.1 mmol proline
units) in water (7.5 cm3). After stirring at 50 °C for 24 h, the
mixture was cooled to 0 °C and extracted with diethyl ether. The
aldol product 8 was obtained in 89% isolated yield. Note that the
reaction proceeded in a highly stereoselective manner, and the
anti/syn ratio was 93:7 with 96% ee, indicating that the proline-
tethered copolymer 5 was highly effective for the reaction on
water.
Next, we studied the reusability of the aqueous catalyst
solution. After extraction, additional aldehyde and ketone were
added to the remaining aqueous solution, and the mixture was
kept at 50 °C. The results are summarized in Table 2.30 The aldol
product was successfully obtained even after the second and
third cycles although the yield gradually decreased. It should be
In order to obtain information on the effect of the
thermoresponsive block copolymer on the catalytic reactions,
Chem. Lett. 2013, 42, 1493-1495
© 2013 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

1495
Table 1. Cross-aldol reaction in aqueous mediuma
Entry
1
Catalyst
Temp/°C
Polymer compositionb
Yield/%
<1
anti/syn
ee/%c
L-proline
rt
50
rt
®
2
3
L-proline
3
®
3
10
92/8
91
93
86
4
5
3
5
50
rt
76
62
89/11
79/21
6
7
5
6
50
50
89
86
93/7
96
76
72/28
8
9
L-proline/7
50
50
0
0
®
®
®
®
4-hydroxy-
L-proline/7
aConditions: 4-nitrobenzaldehyde 1 mmol, cyclohexanone 5 mmol, catalyst containing 0.1 mmol of proline units, water 7.5 cm3, 24 h.
bLegend: : proline structure,
macromonomer unit. ee% of the anti-isomer, determined by HPLC using a chiral column.
: hydrophilic PNIPAAm segment,
: hydrophobic PNIPAAm segment,
: PEG
c
9
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Table 2. Reuse of the catalyst solution of 5
Cycle
Yield/%
anti/syn
ee/%
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noted that diastereo- and enantioselectivity were maintained
even after three cycles. The reason for the decreasing yields
remains unclear, and it is presumably because small amounts of
the copolymer was lost owing to its dissolution into organic
layers during extraction. Further investigation of organic
reactions using the thermoresponsive copolymer catalysts is
now in progress in our laboratory.
T. Oshima, Prof. M. Fujita, and Prof. Y. Takeoka at Sophia
Univ. are acknowledged for assistance in polymer analyses.
This work was supported by the Cooperative Research Program
of the Catalysis Research Center, Hokkaido University (Grant
No. 13B1005).
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#
Presented at the 93rd Annual Meeting of The Chemical Society of Japan,
Kusatsu, March 22-25, 2013, 1PB024.
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Chem. Lett. 2013, 42, 1493-1495
© 2013 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/