Synthesis of polymer microspheres functionalized with chiral ligand by precipitation polymerization and their application to asymmetric transfer hydrogenation

Article abstract of DOI:10.1002/pola.24118

Monodisperse, crosslinked poly(divinylbenzene) and poly(methacrylic acid-co-ethylene glycol dimethacrylate) microspheres with (1R,2R)-N ¹-toluenesulfonyl-1,2-diphenylethylene-1,2-diamine ((R,R)-TsDPEN) moiety were successfully prepared by precipitation polymerization. Introduction site of the (R,R)-TsDPEN moiety into the polymer microspheres could be controlled by changing the order of addition of the corresponding monomers. The functionalized polymer microspheres were applied to asymmetric transfer hydrogenation of ketone and imine. Polymer microsphere-supported chiral catalysts showed good reactivity and enantioselectivity in the catalytic asymmetrie transfer hydrogenations. Chiral secondary alcohol was quantitatively obtained with 94% ee in the asymmetric transfer hydrogenation of acetophenone in water. We also found that introduction site of the chiral catalyst and hydrophobiclty of the microspheres, as well as degree of the crosslinking, affected the yield and enantioselectivity of chiral product in this reaction.

Full text of DOI:10.1002/pola.24118

Synthesis of Polymer Microspheres Functionalized with Chiral Ligand
by Precipitation Polymerization and Their Application to Asymmetric
Transfer Hydrogenation
NAOKI HARAGUCHI, AKIHIRO NISHIYAMA, SHINICHI ITSUNO
Department of Environmental and Life Sciences, Graduate School of Engineering, Toyohashi University of Technology,
Hibarigaoka, Tenpaku-cho, Toyohashi, Aichi 441-8580, Japan
Received 3 March 2010; accepted 4 May 2010
DOI: 10.1002/pola.24118
Published online in Wiley InterScience (www.interscience.wiley.com).
ABSTRACT: Monodisperse, crosslinked poly(divinylbenzene)
and poly(methacrylic acid-co-ethylene glycol dimethacrylate)
microspheres with (1R,2R)-N1-toluenesulfonyl-1,2-diphenylethy-
lene-1,2-diamine ((R,R)-TsDPEN) moiety were successfully pre-
pared by precipitation polymerization. Introduction site of the
(R,R)-TsDPEN moiety into the polymer microspheres could be
controlled by changing the order of addition of the correspond-
ing monomers. The functionalized polymer microspheres were
applied to asymmetric transfer hydrogenation of ketone and
imine. Polymer microsphere-supported chiral catalysts showed
good reactivity and enantioselectivity in the catalytic asymmet-
ric transfer hydrogenations. Chiral secondary alcohol was
quantitatively obtained with 94% ee in the asymmetric transfer
hydrogenation of acetophenone in water. We also found that
introduction site of the chiral catalyst and hydrophobicity of
the microspheres, as well as degree of the crosslinking,
affected the yield and enantioselectivity of chiral product in
C
V
this reaction. 2010 Wiley Periodicals, Inc. J Polym Sci Part A:
Polym Chem 48: 3340–3349, 2010
KEYWORDS: catalysts; chiral; microgels; radical polymerization;
supports
INTRODUCTION Functional polymer microspheres are attrac-
tive industrial materials because of their potential applica-
tions in coatings, adhesives, inks, leather finishing, construc-
tion, biomedicine, catalysis, paints, and in electronics.1
Techniques such as dispersion polymerization, emulsion
polymerization, and precipitation polymerization have been
used to prepare polymer microspheres. A number of poly-
mer microspheres with controlled size distribution have
been made by advanced synthetic techniques, and their func-
tionalization and performance have been explored. Narrowly
disperse crosslinked polymer microspheres have been widely
applied in chromatography,2 as controlled reservoirs3 and
carriers,4 and as supports in biomedical,5 environmental,6
and catalysis fields.7
by the method, and tuning the size and porosity of the
resulting particles can be achieved via the polymerization
conditions.
One of the interesting applications of functionalized polymer
microspheres is as polymeric catalysts. Some polymer micro-
spheres functionalized with catalyst have been applied to or-
ganic reactions. For example, poly(DVB-co-methacrylic acid)
microsphere-stabilized gold metallic colloids were used in the
reduction of nitrophenol with NaBH4 in water.14 Chitosan
microsphere-supported palladium complexes were applied in
Mizoroki-Heck reaction of aryl halides with phenylboronic
acid.15 Core-shell poly(styrene-methyl methacrylate) micro-
spheres with palladium-iminodiacetic acid were used as cata-
lyst in Suzuki and Heck reactions in aqueous media.16 How-
ever, the synthesis of narrowly disperse polymer microspheres
with chiral ligands and their application to catalytic asymmetric
reactions have been much less investigated.
Sto¨ver and coworkers have established precipitation poly-
merization of divinylbenzene (DVB) as a precise synthetic
method for preparing narrowly disperse poly(DVB) micro-
spheres.8–13 In this system, DVB is polymerized at monomer
loadings below 5 vol % in acetonitrile, or mixtures of aceto-
nitrile and toluene, by free radical polymerization using
AIBN as initiator. They found that the particles increase in
size by a reactive growth mechanism in which oligomeric
radicals are captured from solution by reaction with surface
double bonds on existing particles. Nearly monodisperse,
spherical particles can be routinely prepared in good yield
Narrowly disperse microspheres seem to be suitable sup-
ports for chiral ligands or catalysts because of their high sur-
face area, facile dispersibility, and mechanical strength. In
addition, an advantage of polymer microspheres is the ability
to control their hydrophilic–hydrophobic balance, which
offers suitable microenvironments for catalytic asymmetric
reactions.
Correspondence to: N. Haraguchi (E-mail: haraguchi@ens.tut.ac.jp)
C
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Journal of Polymer Science: Part A: Polymer Chemistry, Vol. 48, 3340–3349 (2010) 2010 Wiley Periodicals, Inc.
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ARTICLE
We report herein synthesis of narrowly disperse polymer
microspheres with chiral N1-toluenesulfonyl-1,2-diphenyl-
ethylene-1,2-diamine (TsDPEN) moieties by precipitation po-
lymerization and their application to asymmetric transfer hy-
drogenation of ketone and imine.
ethyl acetate–hexane as an eluent). Removal of the solvents
under reduced pressure gave 1 (1.37 g, 3.62 mmol) as a
white powder.
1
Yield 85%; [a]D ¼ ꢀ36.7 (c ¼ 1.00 g/dL in CHCl3); H NMR
(300 Hz, CDCl3, d ¼ 0 ((CH3)4Si)): d ¼ 3.96 (d, J ¼ 7.3 Hz,
1H, CH), 4.34 (d, J ¼ 7.4 Hz, 1H, CH), 5.36 (d, J ¼ 10.9 Hz,
1H, vinyl), 5.88 (d, J ¼ 17.6 Hz, 1H, vinyl), 6.69 (dd, J ¼
10.9, 11.2 Hz, 1H, vinyl), 6.91–7.42 ppm (m, 14H, Ar-H); 13C
NMR (75 MHz, CDCl3, d ¼ 0 ((CH3)4Si)): d ¼ 60.64, 64.86,
117.05, 126.06, 126.38, 126.51, 126.57, 127.27, 127.34,
127.40, 127.59, 135.44, 139.77, 140.10, 140.28, 142.50 ppm;
FTIR (KBr): m ¼ 3350, 3294 (NH2), 3160 (NH), 3086, 3026
(CH¼¼CH2), 2861 (CH), 1323, 1152 cmꢀ1 (SO2); ELEM. ANAL.
for C22H22N2O2S: calcd. C, 69.8; H, 5.86; N, 7.40; S, 8.47%;
found: C, 69.6; H, 5.83; N, 7.36; S, 8.57%.
EXPERIMENTAL
General
Unless otherwise stated, all solvents, divinylbenzene (DVB),
styrene, ethylene glycol dimethacrylate (EGDMA), ketones,
formic acid, and triethylamine were distilled from calcium
hydride under reduced pressure or ambient pressure. DVB
(96%) was supplied from Nippon Steel Chemical. Methacrylic
acid (MA) and 2-hydroxyethyl methacrylate (HEMA) were
distilled under reduced pressure. N,N0-Bisazoisobutyronitrile
(AIBN) and sodium formate were used as received. (1R,2R)-
1,2-Diphenylethane-1,2-diamine ((R,R)-DPEN) was purchased
from Fujimoto Molecular Planning and used without
purification.
Preparation of Polymer Microsphere Chiral Ligand
Preparation of Poly(DVB) Microsphere Functionalized
with (R,R)-TsDPEN (Copolymer Type, Poly(DVB-co-1),
P(DVB)95-COP)
Measurements
Reactions were monitored by TLC using Merck precoated
silica gel plates (Merck 5554, 60F254). Column chromatogra-
phy was performed with a silica gel column (Wakogel C-200,
100–200 mesh). 1H (300 MHz) and 13C (75 MHz) spectra
were measured on a Varian Mercury 300 spectrometer using
tetramethylsilane as an internal standard, and J values are
reported in Hertz. IR spectra were recorded with a JEOL JIR-
7000 FTIR spectrometer and are reported in reciprocal cen-
timeters (cmꢀ1). Elemental analyses were performed at the
Microanalytical Center of Kyoto University. Scanning electron
microscope (SEM) measurements were conducted by using
JASCO JSM-6300 at an acceleration voltage of 8.0 kV. The
number-average diameter (Dn) and the polydispersity index
(Dw/Dn) were determined from the SEM image. GC analyses
were performed with a Shimadzu Capillary Gas Chromato-
graph 14B equipped with a capillary column (SPERCO b-
DEX325, 30 m ꢁ 0.25 mm). HPLC analyses were performed
with a JASCO HPLC system composed of a three-line degas-
ser DG-980, HPLC pump PV-980, column oven CO-965,
equipped with a chiral column (CHIRALCEL OJ-H or OD, Dai-
cel) using hexane/2-propanol as eluent. A UV detector
(JASCO UV-975 for JASCO HPLC system) was used for the
peak detection. Optical rotations were taken on a JASCODIP-
A
30-mL HDPE narrow-mouth bottle (NALGENE) was
charged with DVB (96%) (1.09 g, 7.98 mmol), 1 (0.159 g,
0.420 mmol), AIBN (22 mg, 0.134 mmol), and 28.8 mL of
dry CH3CN or 1:4 (v/v) 2-butanone/heptane mixed solvent
under dry nitrogen. The solution was heated at a constant
ꢂ
temperature of 70 C for 24 h in a reactor that provides gen-
tle agitation by rolling the bottles horizontally at 8 rpm. Af-
ter the reaction mixture was cooled to room temperature,
the soluble oligomer and polymer were separated from in-
soluble fraction by centrifugation, and the insoluble fraction
was washed with THF, methanol, and acetone three times.
ꢂ
Insoluble solid was dried under vacuum at 40 C for 24 h to
give a white powder (0.839 g).
Yield 69%; FTIR (KBr): m ¼ 1640 cmꢀ1 (NH2), 1333, 1161
cmꢀ1 (SO2); ELEM. ANAL. for C10.6H10.6N0.10O0.10S0.05: calcd. C,
89.91; H, 7.55; N, 0.99; O, 1.13; S, 1.13%; found: C, 85.8; H,
7.87; N, 0.86%. Chiral ligand contents: 4.35 mol %, 0.292
mmol/g.
Preparation of Poly(DVB) Microsphere with (R,R)-TsDPEN
(Core-Shell Type, Core: Poly(DVB), Shell: Poly(DVB-co-1),
P(DVB)95-SH)
149 digital polarimeter using
microcell.
a
10-cm thermostated
A 30-mL HDPE narrow-mouth bottle was charged with DVB
(96%) (1.09 g, 7.98 mmol), AIBN (22 mg, 0.134 mmol), and
28.8 mL of dry CH3CN under dry nitrogen. The solution was
heated at 70 ꢂC with rolling the bottles horizontally at
8 rpm. After 12 h, 1 (0.159 g, 0.420 mmol) was added to the
mixture and keep rolling the reactor at 70 ꢂC for additional
12 h. The reaction mixture was cooled to room temperature,
and the insoluble fraction was collected by centrifugation
and washed with THF, methanol, and acetone three times. In-
soluble solid was dried under vacuum at 40 ꢂC for 24 h to
give a white powder (0.775 g).
Synthesis of (1R,2R)-N1-(4-Vinylbenzenesulfonyl)-1,2-
diphenylethane-1,2-diamine (1)
A 50-mL round-bottomed flask equipped with a magnetic
stirring bar was charged with (1R,2R)-1,2-diphenylethane-
1,2-diamine (0.997 g, 4.70 mmol), triethylamine (0.950 g,
9.39 mmol), and 7 mL of dry CH2Cl2 under dry nitrogen. 4-
Vinylbenzene-1-sulfonyl chloride17 (0.865 g, 4.27 mmol) aꢂnd
3 mL of dry CH2Cl2 were then added to the mixture at 0 C,
and the mixture was stirred under an atmosphere of dry
nitrogen. After the mixture was stirred for 24 h, the solvent
was removed with a vacuum pump, and the residual solid
was purified by silica gel column chromatography (with 1:1
Yield 64%; FTIR (KBr): m ¼ 1609 cmꢀ1 (NH2), 1348, 1153
cmꢀ1 (SO2); ELEM. ANAL. for C10.6H10.6N0.10O0.10S0.05: calcd. C,
89.91; H, 7.55; N, 0.99; O, 1.13; S, 1.13%; found: C, 85.9; H,
SYNTHESIS OF FUNCTIONALIZED POLYMER MICROSPHERES, HARAGUCHI, NISHIYAMA, AND ITSUNO
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JOURNAL OF POLYMER SCIENCE: PART A: POLYMER CHEMISTRY DOI 10.1002/POLA
7.85; N, 0.70%. Chiral ligand contents: 3.54 mol %, 0.238
mmol/g.
6.83; N, 1.32; O, 31.60; S, 1.51%; found: C, 58.8; H, 7.31; N,
1.09%. Chiral ligand contents: 4.14 mol %, 0.389 mmol/g.
Preparation of Poly(DVB) Microsphere with (R,R)-TsDPEN
(Core-Corona Type, Core: Poly(DVB), Corona: Poly(DVB-co-1),
P(DVB)95-COR)
Preparation of Polymer Microsphere Chiral Catalyst
Preparation of Polymer Microsphere
Chiral Catalyst in CH3CN
A 30-mL HDPE narrow-mouth bottle was charged with poly
(DVB) microsphere (1.04 g, DVB: 7.98 mmol), 1 (0.159 g,
0.420 mmol), AIBN (22 mg, 0.134 mmol), and 28.8 mL of
dryꢂCH3CN under dry nitrogen. The solution was heated at
70 C for 24 h with rolling the bottles horizontally at 8 rpm.
After the reaction mixture was cooled to room temperature,
the insoluble fraction was collected by centrifugation (crude
yield was quantitative) and washed with THF, methanol, and
acetone three times. Insoluble solid was dried under vacuum
A 10-mL round-bottom flask equipped with a magnetic stir-
ring bar was charged with polymer microsphere chiral ligand
(diamine: 0.015 mmol), [RuCl2(p-cymene)]2 (0.0050 mmol),
and 1 mL of CH3CN under argon. After three cycles of
freeze-thaw under liquid nitrogen, the mixture was heated to
80 ꢂC. After 1 h, removal of the solvent under high vacuum
gave polymer-immobilized chiral catalyst as a yellow solid.
The resulting chiral catalyst was directly used for the next
asymmetric transfer hydrogenation of ketone and imine.
ꢂ
at 40 C for 24 h to give a white powder (0.775 g).
Preparation of Polymer Microsphere Chiral
Catalyst in Water
Yield 64%; FTIR (KBr): m ¼ 1600 cmꢀ1 (NH2), 1347, 1166
cmꢀ1 (SO2); ELEM. ANAL. for C10.6H10.6N0.10O0.10S0.05: calcd. C,
89.91; H, 7.55; N, 0.99; O, 1.13; S, 1.13%; found: C, 84.0; H,
7.36; N, 0.53%. Chiral ligand contents: 2.95 mol %, 0.198
mmol/g.
A 10-mL round-bottom flask equipped with a magnetic stir-
ring bar was charged with polymer microsphere chiral ligand
(diamine: 0.015 mmol), [RuCl2(p-cymene)]2 (0.0050 mmol),
and 1 mL of degassed water under argon. After three cycles
of freeze-thaw under liquid nitrogen, the mixture was heated
to 40 ꢂC. After 1 h, removal of the solvent under high vac-
uum gave polymer-immobilized chiral catalyst as a yellow
solid. The resulting chiral catalyst was used for asymmetric
transfer hydrogenation without further purification.
Preparation of Poly(MA-co-EGDMA) Microsphere with
(R,R)-TsDPEN (Copolymer Type, Poly(MA-co-EGDMA-co-1),
P(MA)90-COP)
A 30-mL HDPE narrow-mouth bottle was charged with MA
(0.888 g, 10.3 mmol), EGDMA (0.114 g, 0.573 mmol), 1
(0.217 g, 0.573 mmol), AIBN (22 mg, 0.134 mmol), and 25
mL of dry 2-butanone under dry nitrogen. The solution was
Asymmetric Transfer Hydrogenation
Asymmetric Transfer Hydrogenation of Imine
(2) in CH3CN (Table 2, entry 9)
ꢂ
heated at 70 C for 24 h with rolling the bottles horizontally
at 8 rpm. After the reaction mixture was cooled to room
temperature, the soluble oligomer and polymer were sepa-
rated from insoluble fraction by centrifugation, and the insol-
uble fraction was washed with THF, methanol, and acetone
three times. Insoluble solid was dried under vacuum at
A 10-mL round-bottom flask equipped with a magnetic stir-
ring bar was charged with 2 (0.209 g, 1.00 mmol), polymer
microsphere chiral catalyst P(DVB)95-COR (core-corona
type) (Ru: 0.010 mmol), 5:2 (v/v) HCO2H/Et3N azeotropic
mixture (HCO2H: 5.00 mmol), and 2.0 mL of CH3CN under
argon. After three cycles of freeze-thaw under liquid nitro-
gen, the mixture was stirred at room temperature for 24 h.
After adding saturated Na2CO3, the mixture was filtrated by
glass filter. The solvent of the filtrate was removed with a
vacuum pump, and the residual solid was purified by silica
gel column chromatography (with 1:4 (v/v) ethyl acetate–
hexanes as an eluent). N-Benzyl-1-phenylethanamine (3) was
obtained as a colorless liquid.
ꢂ
40 C for 24 h to give a white powder (0.902 g).
Yield 74%; FTIR (KBr): m ¼ 1164 cmꢀ1 (SO2); ELEM. ANAL. for
C5.2H7.2N0.10O2.1S0.05: calcd. C, 58.74; H, 6.83; N, 1.32; O,
31.60; S, 1.51%; found: C, 57.4; H, 7.32; N, 1.42%. Chiral
ligand contents: 5.39 mol %, 0.507 mmol/g.
Preparation of Poly(MA-co-EGDMA) Microsphere with
(R,R)-TsDPEN (Core-Shell Type, Core: Poly(MA-co-EGDMA),
Shell: Poly(MA-co-EGDMA-co-1), P(MA)90-SH)
Yield: 66% by 1H NMR in CDCl3; 70% ee by HPLC analysis
(Chiralcel OJ-H, hexane/2-propanol ¼ 99:1 (v/v), 0.4 mL
minꢀ1, rt, 254 nm, t(S) isomer (minor) ¼ 39.2 min, t(R) iso-
mer (major) ¼ 41.2 min).
A 30-mL HDPE narrow-mouth bottle was charged with MA
(0.888 g, 10.3 mmol), EGDMA (0.114 g, 0.573 mmol), AIBN
(22 mg, 0.134 mmol), and 25 mL of dry 2-butanone under
dry nitrogen. The solution was heated at 70 ꢂC with rolling
the bottles horizontally at 8 rpm. After 12 h, 1 (0.217 g,
0.573 mmol) was added to the mixture and keep rolling the
reactor at 70 ꢂC for additional 12 h. The reaction mixture
was cooled to room temperature, and the insoluble fraction
was collected by centrifugation and washed with THF, meth-
anol, and acetone three times. Insoluble solid was dried
under vacuum at 40 ꢂC for 24 h to give a white powder
(0.805 g).
Asymmetric Transfer Hydrogenation of Acetophenone (4)
in H2O (Table 3, entry 9)
A 10-mL round-bottom flask equipped with a magnetic stir-
ring bar was charged with 4 (0.120 g, 1.00 mmol), polymer
microsphere chiral catalyst P(MA)90-SH (core-shell type)
(Ru: 0.010 mmol), HCO2Na (0.340 g, 5.00 mmol), and 2.0 mL
of degassed water under argon. After three cycles of freeze-
ꢂ
thaw under liquid nitrogen, the mixture was stirred at 40 C
Yield 66%; FTIR (KBr): m ¼ 1633 cmꢀ1 (NH2), 1140 cmꢀ1
for 24 h. After cooling to room temperature, the organic
compound was extracted with Et2O twice. The solvent of
(SO2); ELEM. ANAL. for C5.2H7.2N0.10O2.1S0.05: calcd. C, 58.74; H,
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ARTICLE
SCHEME 1 Synthesis of poly(DVB)
microspheres functionalized with
chiral TsDPEN moieties by precipi-
tation polymerization. [Color figure
can be viewed in the online issue,
which is available at www.interscience.
wiley.com.]
ꢂ
the mixture was removed with a vacuum pump to afford
40 C. The reaction monitored by TLC and stopped when the
1-phenylethanol (5) as a yellow liquid.
spot of 4 was disappeared.
1
Yield: >99% by H NMR in CDCl3 and GC; 94% ee by HPLC
RESULTS AND DISCUSSION
analysis (Chiralcel OD, hexane/2-propanol ¼ 20:1 (v/v), 0.4
mL minꢀ1, 30 ꢂC, 254 nm, t(R) isomer (major) ¼ 22.8 min,
t(S) isomer (minor) ¼ 25.9 min).
Synthesis of Polymer Microspheres Functionalized with
Chiral TsDPEN
Polymer microspheres with chiral TsDPEN moiety were syn-
thesized by precipitation polymerization as illustrated in
Scheme 1. A solution of DVB, 1, and AIBN in CH3CN was
heated at 70 ꢂC to prepare P(DVB)95-COP. The total amounts
of monomers and initiator were set at 4 vol % relative to sol-
vent and 2 wt % with respect to the total amount of mono-
mers, respectively.8,9,11 After 1 h, white turbidity of the solu-
tion was observed, and precipitation of small particles
occurred after 3 h. The amount of precipitated particles
increases with increasing polymerization time. After 24 h, the
reaction mixture was worked up to give a white powder in
69% yield. Stable particles were obtained by precipitation po-
lymerization without the aid of a surface stabilizing surfactant.
Reuse Test
Procedure A
After the first reaction mixture was cooled to room tempera-
ture, it was extracted with Et2O twice. The aqueous layer with
polymer microsphere chiral catalyst was centrifuged, and the
ꢂ
precipitate was dried under vacuum at 40 C. A 10-mL round-
bottom flask equipped with a magnetic stirring bar was charged
with 4 (0.120 g, 1.00 mmol), polymer microsphere chiral cata-
lyst, HCO2Na (0.340 g, 5.00 mmol), and 2.0 mL of degassed
water under argon. After three cycles of freeze-thaw under liq-
ꢂ
uid nitrogen, the mixture was stirred at 40 C for 24 h.
Procedure B
All the operation was carried out under argon. After the first
reaction mixture was cooled to room temperature, it was
centrifuged and the liquid part was removed. A 10-mL
round-bottom flask equipped with a magnetic stirring bar
was charged with the precipitate (polymer microsphere chi-
ral catalyst), 4 (0.060 g, 0.50 mmol), HCO2Na (0.170 g, 2.50
mmol), and 1.0 mL of degassed water. After three cycles of
freeze-thaw under liquid nitrogen, the mixture was stirred at
Figure 1 shows FTIR spectra of the as-prepared poly(DVB)
(spectrum A) and after functionalization with chiral TsDPEN
(spectrum B). The characteristic absorptions at 1161 and
1333 cmꢀ1 due to SO2 stretch of the sulfonamide group and
at 1640 cmꢀ1 due to NAH bend of the amino group can be
clearly observed in spectrum B, but not in spectrum A. The
content of chiral ligand in P(DVB)95-COP was calculated
from the nitrogen content determined by elemental analysis.
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JOURNAL OF POLYMER SCIENCE: PART A: POLYMER CHEMISTRY DOI 10.1002/POLA
2.30 lm, and the Dw/Dns of these were 1.02 and 1.02,
respectively.
Because the formation of stable spherical microspheres by
precipitation polymerization was strongly dependent on the
degree of crosslinking of the particles, we added styrene as a
monomer to investigate the effect on the yield, Dn, and Dw/
Dn. A total of 5, 25, and 45 mol % of styrene were added to
DVB and 1 before polymerization. When the proportion of
styrene was increased, Dn and Dw/Dn were inclined to
became larger, which was quite similar to the results for the
original poly(DVB-co-styrene) microspheres.
FIGURE 1 FTIR spectra of P(DVB) (A) and P(DVB)95-COP (B).
We next prepared different types of polymer microspheres
with chiral TsDPEN. MA and EGDMA were used as mono-
mers for the preparation of hydrophilic polymer micro-
spheres, as illustrated in Scheme 2. Sto¨ver and coworkers
have previously reported that narrowly disperse micro-
spheres can be synthesized by precipitation polymerization
of MA/EGDMA mixtures in 2-butanone with a wide range of
MA/EGDMA feed ratios.18 P(MA)90-COP, in which (R,R)-
TsDPEN was dispersed over the whole microsphere surfaces,
was obtained in moderate yield.
Even though the observed value of chiral ligand (0.29 mmol/
g) was slightly smaller than the calculated value (0.34
mmol/g), there is no doubt that the chiral ligand was incor-
porated in the polymer microspheres. Figure 2 shows a SEM
image of P(DVB)95-COP. The number-average diameter (Dn)
was 2.19 lm, and the size distribution was quite narrow,
with a polydispersity index (Dw/Dn) being 1.03. 1:4 (v/v) 2-
Butanone/heptane mixed solvent was used for the prepara-
tion of narrowly disperse polymer microspheres (yield: 55%,
Dn: 4.10 lm, Dw/Dn: 1.02).11 These results clearly indicated
that monodisperse microspheres of crosslinked poly(divinyl-
benzene) with (R,R)-TsDPEN, in which (R,R)-TsDPEN was dis-
persed over the whole microsphere, were successfully pre-
pared by precipitation polymerization.
From SEM images (Fig. 3) it is apparent that uniform spheri-
cal microspheres were formed. The average diameter was
0.67 lm, which was smaller than for poly(DVB) micro-
spheres. The diameter distribution was quite narrow (Dw/Dn
¼ 1.02), and the polymer microspheres showed high hydro-
philicity. These results indicated that both hydrophobic and
hydrophilic polymer microspheres with different structures
can be synthesized by precipitation polymerization.19
Encouraged by these results, we synthesized other poly
(DVB) microspheres, namely P(DVB)y-SH and P(DVB)y-COR,
with different sites for introduction of the chiral ligand and
different microsphere structures. The (R,R)-TsDPEN was dis-
persed over the whole microsphere shell surface in P(DVB)y-
SH and over the whole microsphere corona in P(DVB)y-COR.
The introduction site of the (R,R)-TsDPEN moiety into the
polymer microspheres was controlled by changing the order
of addition of the corresponding monomers, as illustrated in
Scheme 1. The size and size distribution of the polymer
microspheres with chiral ligands are summarized in Table 1.
The Dns of P(DVB)95-SH and P(DVB)95-COR were 2.30 and
Preparation of Polymer Microsphere-Supported
Chiral Catalyst
To apply the polymer microspheres functionalized with chi-
ral TsDPEN to catalytic asymmetric reactions, we examined
the complexation of the chiral ligand. Among the various chi-
ral catalysts reported for asymmetric transfer hydrogenation,
the most significant to date is the ruthenium(II) complex
with optically active TsDPEN that was developed by Ikariya
and Noyori’s group.20 As the catalytic system, chiral
FIGURE 2 SEM image of P(DVB)95-COP. [Color figure can be viewed in the online issue, which is available at www.interscience.
wiley.com.]
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ARTICLE
TABLE 1 Characterization of Polymer Microspheres with Chiral TsDPEN Moietiesa
First Monomers
(mol %)
Second Monomers
(mol %)
Yield (%) Dn (lm)b Dw/Dn
b
Code
Type
Solvent
P(DVB)95-COP Copolymer DVB(95), 1(5)
P(DVB)95-COP Copolymer DVB(95), 1(5)
None
None
Acetonitrile
69
2.19
4.10
2.20
3.10
2.90
2.30
3.30
3.30
2.30
2.32
0.67
0.68
0.69
0.72
1.03
1.02
1.23
1.21
1.14
1.02
1.05
1.08
1.02
1.03
1.02
1.01
1.01
1.02
1/4 (V/V) 2-Butanone/heptane 55
P(DVB)90-COP Copolymer DVB(90), styrene(5), 1(5) None
P(DVB)70-COP Copolymer DVB(70), styrene(25), 1(5) None
P(DVB)50-COP Copolymer DVB(50), styrene(45), 1(5) None
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
2-Butanone
2-Butanone
2-Butanone
2-Butanone
67
62
46
64
55
52
64
60
74
76
78
66
P(DVB)95-SH Core-shell
P(DVB)90-SH Core-shell
P(DVB)70-SH Core-shell
DVB(95)
DVB(90)
DVB(70)
1(5)
Styrene(5), 1(5)
Styrene(25), 1(5)
1(5)
P(DVB)95-COR Core-corona Poly(DVB)(95)
P(DVB)75-COR Core-corona Poly(DVB)(75)
Styrene(20), 1(5)
P(MA)90-COP Copolymer MA(90), EGDMA(5), 1(5) None
P(MA)85-COP Copolymer MA(85), EGDMA(10), 1(5) None
P(MA)65-COP Copolymer MA(65), EGDMA(30), 1(5) None
P(MA)90-SH
Core-shell
MA(90), EGDMA(5)
1(5)
a
b
These samples consisted of 4 vol % monomer with 2 wt % AIBN.
Determined from SEM image.
TsDPEN/RuCl2(p-cymene) complex is well known as
a
orange, which is typical of [RuCl2(p-cymene)]2, and the color
of the polymer microspheres was unchanged [image (A)].
As shown in image (B), the solution became transparent,
whereas the polymer microspheres became pale yellow after
heating for 1 h. This suggests that the ruthenium(II) complex
was formed on the polymer.
highly effective and enantioselective catalyst for asymmetric
transfer hydrogenation of various kinds of ketones and
imines.20,21
The polymeric metal complex was prepared by reaction of
chiral TsDPEN ligand on the polymer microspheres with
[RuCl2(p-cymene)]2, as illustrated in Scheme 3. The complex-
ation followed Ikariya’s procedure. The polymer-supported
chiral TsDPEN was treated with [RuCl2(ꢂp-cymene)]2 for 1 h
Asymmetric Transfer Hydrogenation of
Imine (2) in CH3CN
Asymmetric transfer hydrogenation of imines is a popular
method for preparation of chiral amines, which are highly
important intermediates or building blocks for biologically
active molecules in medical, pharmaceutical, and agricultural
science.22–24 The catalytic activity of the polymer microsphere
ꢂ
in either CH3CN at 80 C or water at 40 C. The color change
of the reaction mixture before and after complexation is
shown in Figure 4. After adding [RuCl2(p-cymene)]2 to poly-
mer microspheres with chiral TSDPEN, the solution turned
SCHEME 2 Synthesis of poly(MA-co-EGDMA) microspheres functionalized with chiral TsDPEN moieties by precipitation polymer-
ization. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]
SYNTHESIS OF FUNCTIONALIZED POLYMER MICROSPHERES, HARAGUCHI, NISHIYAMA, AND ITSUNO
3345

JOURNAL OF POLYMER SCIENCE: PART A: POLYMER CHEMISTRY DOI 10.1002/POLA
FIGURE 3 SEM image of P(MA)90-COP.
chiral catalysts in CH3CN was investigated through asymmetric
transfer hydrogenation of imine (2). The reaction was carried
out by adding HCO2H/Et3N (5:2, v/v, 5 equiv) as a hydrogen
source to 2 in CH3CN at room temperature and allowing reac-
tion to take place for 24 h. The substrate/catalyst (S/C) ratio
was 100 (Scheme 4). The results are summarized in Table 2.
Asymmetric transfer hydrogenation of 2 occurred smoothly
using the polymer microsphere chiral catalyst derived from
P(DVB)95-COP to give (R)-N-benzyl-1-phenylethanamine
((R)-3) in 49% yield with 58% ee (Table 2, entry 1). In situ
asymmetric transfer hydrogenation following the complex
formation also proceeded, but the reaction did not proceed
at all when the polymer was removed before the reaction.
When the polymer microsphere chiral catalyst derived from
P(DVB)95-COP, which was prepared in 1:4 (v/v) 2-buta-
none/heptane, was used in the reaction, both the yield and
enantioselectivity were increased (entry 1 vs. 2). Lowering
the degree of crosslinking (5, 25, or 45 mol % of styrene
was incorporated into poly(DVB)) improved both the reactiv-
ity and the enantioselectivity (entries 1, 3–5). When we used
core-shell–type microspheres P(DVB)95-SH, the yield and
enantioselectivity were found to be similar to those of
P(DVB)95-COP (entry 1 vs. 6). We supposed that the flexibil-
ity of catalyst moiety and the accessibility of 2 were similar
in P(DVB)95-SH and P(DVB)95-COP. By contrast, the use of
core-corona–type microspheres P(DVB)95-COR apparently
improved both the reactivity and the enantioselectivity of the
reaction, probably because the catalyst moiety was intro-
FIGURE 4 Reaction mixture before (A) and after (B)
complexation.
duced into the polymer chain of the flexible corona (entries
1, 6, and 9).
As the hydrophobic polymeric chiral catalysts were found to
be suitable for asymmetric transfer hydrogenation of 2,
hydrophilic polymeric complexes prepared from P(MA)90
-
COP and P(MA)90-SH were also used in the reaction to
investigate the effect of hydrophilicity. Even though the enan-
tioselectivity of the products was similar to that of P(DVB),
the yield was lower, indicating that the reaction rate was
slow when the hydrophilic polymeric complex was used in
the reaction in CH3CN (entries 11 and 12).
We performed asymmetric transfer hydrogenation of 2 using
polymer microsphere-supported chiral catalyst in CH3CN.
The object chiral secondary amine was obtained with good
yield and enantioselectivity by use of hydrophobic
P(DVB)95-COR. The effects of the introduction site of the
SCHEME 3 Complexation of polymer microsphere-supported
chiral TsDPEN with [RuCl2(p-cymene)]2.
SCHEME 4 Asymmetric transfer hydrogenation of imine (2) in
CH3CN.
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INTERSCIENCE.WILEY.COM/JOURNAL/JPOLA

ARTICLE
TABLE 2 Asymmetric Transfer Hydrogenation of Imine (2)
Catalyzed by Polymer-Supported Chiral Catalyst in CH3CNa,b
TABLE 3 Asymmetric Transfer Hydrogenation of Acetophenone
Catalyzed by Polymer-Supported Chiral Catalyst in Watera,b
3
5
Entry
Microsphere Code
Yield (%)
ee (%)c
Config.
Temp. Yield ee
Entry Microsphere Code
(ꢂC)
(%)
(%)c Config.
1
P(DVB)95-COP
P(DVB)95-COPd
P(DVB)90-COP
P(DVB)70-COP
P(DVB)50-COP
P(DVB)95-SH
P(DVB)90-SH
P(DVB)70-SH
P(DVB)95-COR
P(DVB)75-COR
P(MA)90-COP
P(MA)90-SH
49
57
50
55
65
46
50
54
66
60
34
32
58
61
60
66
63
56
58
58
70
67
56
48
R
R
R
R
R
R
R
R
R
R
R
R
1
P(DVB)95-COPd
P(DVB)95-SH
P(DVB)95-COR
P(MA)90-COP
P(MA)90-COP
P(MA)85-COP
P(MA)65-COP
P(MA)90-SH
40
40
40
rt
<5
<5
ND ND
ND ND
ND ND
2
2
3
3
<5
4
4
58
95
92
92
92
94
94
91
R
R
R
R
R
R
R
5
5
40
40
40
rt
97
6
6
>99
80
7
7
8
8
63
9
9
P(MA)90-SH
40
>99
>99
10
11
12
a
10e
Silica-supported TsDPEN 40
a
The reactions were carried out with [RuCI2(p-cymene)]2 and HCO2Na
(5 equiv to 4) for 24 h.
The reactions were carried out with [RuCI2(q-cymene)]2 and HCO2H:
Et3N (5:2, vlv, 5 equiv to 2) at room temperature for 24 h.
b
S/C¼ 100.
c
Determined by HPLC analysis with a Daicel Chiralcel OD column.
b
S/C¼100.
d
Prepared in acetonitrile.
See ref. 32.
c
Determined by HPLC analysis with a Daicel Chiralcel OJ-H column.
e
d
Prepared in 2-butanone/heptane ¼ 1/4.
Then, the catalytic activity of hydrophilic poly(MA-co-
EGDMA) microsphere-supported chiral catalysts was investi-
gated, because poly(MA-co-EGDMA) microspheres seemed to
be a more suitable support in water. The polymeric chiral
catalyst prepared from P(MA)90-COP showed good catalytic
activity, and (R)-1-phenylethanol ((R)-5) was obtained with
95% ee in 58% yield (entry 4). Elevating the reaction tem-
perature to 40 ꢂC resulted in a quantitative yield (entry 5).
As the ratio of MA was reduced, the yield tended to decrease
(entries 5, 6, and 7). The yield and enantioselectivity
obtained using P(MA)90-SH were similar to those for
P(MA)90-COP (entry 4 vs. 8, and 5 vs. 9). Interestingly, the
enantioselectivity of P(MA)90-SH is higher than that of
silica-supported chiral TsDPEN32 (entry 9 vs. 10).
chiral catalyst and the hydrophobicity of the microspheres,
as well as the degree of crosslinking, are significant in this
reaction.
Asymmetric Transfer Hydrogenation of
Ketone (4) in H2O
As the chiral TsDPEN- RuCl2(p-cymene) system is known to
be tolerant to water, several studies of asymmetric transfer
hydrogenation in aqueous media have been reported.25–28
We previously reported asymmetric transfer hydrogenation
of ketones and imines using polymer-supported chiral cata-
lysts in neat water.29–31 The polymer microsphere-supported
chiral catalysts we prepared were used in this study for
asymmetric transfer hydrogenation of acetophenone (4) in
water. The reaction was carried out for 24 h, in neat water
at 40 ꢂC or at room temperature with sodium formate as
hydrogen source (Scheme 5). The results are summarized in
Table 3.
These results clearly indicated that the hydrophilic polymer
microsphere-supported chiral catalysts P(MA)y-COP and
P(MA)y-SH were more effective in the asymmetric transfer
hydrogenation of acetophenone in water.
We first carried out the reaction using the poly(DVB) micro-
sphere-supported chiral catalysts P(DVB)95-COP, P(DVB)95
-
Reuse Test
SH, and P(DVB)95-COR. Interestingly, these catalysts were
not suitable for the reaction, probably because of the shrink-
age in water (Table 3, entries 1, 2, and 3).
A reuse test of the polymer microsphere-supported chiral
catalysts P(MA)90-COP and P(MA)90-SH was performed for
asymmetric transfer hydrogenation of acetophenone in water.
As these polymer microspheres were dispersed in both
water and organic solvent, easy separation by simple filtra-
tion or centrifugation was possible. The results are summar-
ized in Table 4. A quantitative yield and high enantioselectiv-
ity were obtained in the first cycle. These polymeric
catalysts were recovered according to the Procedure A
described in the Experimental section and used for next
cycle. In the second cycle, the enantioselectivity was similar
to that in first cycle, but unfortunately the yield decreased
SCHEME 5 Asymmetric transfer hydrogenation of acetophe-
none in water.
SYNTHESIS OF FUNCTIONALIZED POLYMER MICROSPHERES, HARAGUCHI, NISHIYAMA, AND ITSUNO
3347

JOURNAL OF POLYMER SCIENCE: PART A: POLYMER CHEMISTRY DOI 10.1002/POLA
TABLE 4 Reuse Test of Polymer Microsphere-Supported Chiral Catalysta
5
Microsphere Code
Procedure
Cycle
Temp. (ꢂC)
Time (h)
Yield (%)
ee (%)b
Config.
P(MA)90-COP
P(MA)90-COP
P(MA)90-COP
P(MA)90-SH
P(MA)90-SH
P(MA)90-SH
P(MA)90-COP
P(MA)90-COP
P(MA)90-COP
P(MA)90-COP
a
A
A
A
A
A
A
B
B
B
B
1
2
3
1
2
3
1
2
3
4
40
40
40
40
40
40
40
40
40
40
24
24
24
24
24
24
8
>99
85
92
93
93
94
93
94
94
94
94
94
R
R
R
R
R
R
R
R
R
R
32
>99
90
40
>99
>99
>99
>99
8
8
8
b
The reactions were carried out with [RuCI2(p-cymene)]2 and HCO2Na
(5 equiv to 4).
Determined by HPLC analysis with a Daicel Chiralcel OD column.
with repeated cycles. The results indicated that the active
site of these catalysts decreased with cycles. Diethyl ether
was used for the extraction of the reaction mixture in the
Procedure A; while Xiao and coworkers mentioned that the
life time for this type of catalyst was significantly shortened
in diethyl ether.33 In addition, Ikariya and coworkers men-
tioned that the hydride prepared from the catalytic cycle
may react with oxygen.34
ble suggestions. This work was partially supported by a com-
petitive fund from Toyohashi University of Technology.
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3349