Synthesis of enantiopure homo and copolymers by raft polymerization and investigation of their enantioselective lipase-catalyzed esterification

Article abstract of DOI:10.1002/pola.26272

Homo and copolymers were synthesized from enantionpure (R)- and (S)-1-(4-vinylphenyl)ethanol by reversible addition-fragmentation chain transfer polymerization. The polymerization conditions were optimized resulting in dioxane as the preferred reaction solvent. First-order polymerization kinetics and well-defined enantiopure homopolymers with low dispersities were obtained. In agreement with their enantiomeric composition, the (R) and (S)-polymers gave opposite optical rotation of light. Polymer analogous esterification of the chiral hydroxy groups catalyzed by enantioselective Candida antarctica Lipase B was strongly (R)-selective. Esterification on the homopolymer and copolymers could be achieved to a maximum of around 50 %.

Full text of DOI:10.1002/pola.26272

JOURNAL OF
POLYMER SCIENCE
ARTICLE
WWW.POLYMERCHEMISTRY.ORG
Synthesis of Enantiopure Homo and Copolymers by RAFT
Polymerization and Investigation of Their Enantioselective
Lipase-Catalyzed Esterification
1
1
1
Bahar Yeniad,1,2 N. Oruc¸ Koklu¨ kaya, Hemantkumar Naik, M. W. Martin Fijten,
€
Cor E. Koning,1,2 Andreas Heise1,3
1Laboratory of Polymer Chemistry, Technische Universiteit Eindhoven, Den Dolech 2, P.O. Box 513,
5600 MB Eindhoven, The Netherlands
2Dutch Polymer Institute (DPI), P.O. Box 902, 5600 AX Eindhoven, The Netherlands
3School of Chemical Sciences, Dublin City University, Glasnevin, Dublin 9, Ireland
Correspondence to: A. Heise (E-mail: andreas.heise@dcu.ie)
Received 25 May 2012; accepted 15 July 2012; published online
DOI: 10.1002/pola.26272
ABSTRACT: Homo and copolymers were synthesized from
enantionpure (R)- and (S)-1-(4-vinylphenyl)ethanol by reversi-
ble addition-fragmentation chain transfer polymerization.
The polymerization conditions were optimized resulting in
dioxane as the preferred reaction solvent. First-order poly-
merization kinetics and well-defined enantiopure homopoly-
mers with low dispersities were obtained. In agreement
with their enantiomeric composition, the (R) and (S)-poly-
mers gave opposite optical rotation of light. Polymer analo-
gous esterification of the chiral hydroxy groups catalyzed by
enantioselective Candida antarctica Lipase was strongly
B
(R)-selective. Esterification on the homopolymer and copoly-
mers could be achieved to a maximum of around 50 %.
C
V
2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym
Chem 000: 000–000, 2012
KEYWORDS: chiral; enzymes; reversible addition fragmentation
chain transfer (RAFT)
INTRODUCTION Biocatalysis has become an attractive alter-
native to chemical catalysis for the synthesis and modifica-
tion of polymers.1–8 Initially, research in this area had been
motivated by the replacement of conventional catalysts or
harsh reaction conditions for existing materials like polycar-
bonates, polyamides, and most prominently polyesters. Other
research explored the combination of enzymatic and chemi-
cal polymerization (chemoenzymatic polymerizations) with
the intention to further increase and benefit from the macro-
molecular complexity achievable by enzymatic catalysis. For
example, the successful combinations of lipase catalyzed
ring-opening polymerization with atom transfer radical poly-
merization,9–15 nitroxide-mediated polymerization (NMP),16
and reversible addition-fragmentation chain transfer (RAFT)
polymerization17 for the synthesis of block and graft copoly-
mers were disclosed. However, few of the reported examples
exploit the clear advantages offered by enzymes like high
enantio-, regio-, and chemo-selectivity to design novel mate-
rials or concepts not available by chemical catalysis. One
example was reported by Gross and coworkers using the
regioselectivity of Candida antarctica Lipase B (CALB, Novo-
zym 435) in the copolymerization of sorbitol, adipic acid,
and octanediol.18 The reaction occurred predominantly at
the primary alcohol groups of sorbitol with a regioselectivity
of 95% and allowed multifunctional monomers to be directly
polymerized into linear polymers while avoiding the neces-
sity of protective group chemistry. Similar polymerizations
with glycerol or bis(hydroxymethyl)butyric acid resulted in
terpolymers with free hydroxy or carboxylic acid groups,
respectively.19 Palmans reported another example for the po-
lymerization of isopropyl aleuritate with Novozyme 435 with
a regioselectivity close to 100%.20
We have recently begun to explore enzyme enantioselectivity
in polymeric materials. This was motivated by the fact that
in many naturally occurring polymers, such as proteins,
DNA, and cellulose the chiral composition plays a key role
in, for example, molecular recognition and catalytic activity.
Introducing functional groups into polymers susceptible to
enantioselective enzyme response might open new possibil-
ities in enzyme-responsive materials and be complementary
to selective enzyme stimuli previously reported.21–26 In this
regard, the extraordinary enantioselectivity of lipases offers
new perspectives toward these materials and examples of
Additional Supporting Information may be found in the online version of this article.
C
V
2012 Wiley Periodicals, Inc.
WWW.MATERIALSVIEWS.COM
JOURNAL OF POLYMER SCIENCE PART A: POLYMER CHEMISTRY 2012, 000, 000–000
1

JOURNAL OF
POLYMER SCIENCE
ARTICLE
WWW.POLYMERCHEMISTRY.ORG
lipase-catalyzed synthesis of chiral polymers from racemic
monomers have been reported. Most published examples rely
on kinetic resolution, that is, the significantly faster polymeriza-
tion of one enantiomer over the other as was shown for the poly-
merization of racemic substituted caprolactones.16,27–32
Recently, also chemoenzymatic dynamic kinetic resolution was
successfully used in the synthesis of chiral polymers.33–37 In this
process, a racemization catalyst dynamically racemizes the
slower reacting enantiomer or polymer end-group in situ,
thereby constantly supplying the preferred enantiomer for the
polymerization. However, none of the polymers synthesized by
these approaches have chiral functional groups available for
further enantioselective modification. Therefore, we recently
introduced a new concept in which polymers were encoded
using enantiomerically pure monomers. (R) and (S)-1-(4-vinyl-
phenyl)ethanol were obtained by selective alcohol dehydrogen-
ase (ADH) reduction of the corresponding ketone 4-vinyl aceto-
phenone and copolymerized with styrene by free radical
polymerization to afford enantiomerically pure copolymers.38
Both (R) and (S) copolymers had identical chemical and physi-
cal properties and could only be distinguished by their optical
rotation or enantioselective bioresponse. The selective esterifi-
cation of the pendant chiral alcohol groups on the polymer with
vinyl acetate by immobilized CALB was only successful for the
copolymer comprising the (R)-enantiomer, resulting in a change
of thermal properties for this polymer as a function of (R)-con-
tent. The same concept was recently extended to dendrimers
with enantiomerically pure end-groups.39 However, questions
about the effect of enantiomer distribution along the polymer
backbone, molecular weight and possible effects of dilution
with ‘‘neutral’’ monomers like styrene on the enantioselective
postmodification are still unanswered. To address these ques-
tions, chiral homo and random copolymers from enantiopure
(R)- and (S)-1-(4-vinylphenyl)ethanol of controlled molecular
weight and composition were synthesizing by RAFT mediated
polymerization. Here, we report the optimization of the poly-
merization conditions with respect to reaction kinetics and
copolymerization parameters. These polymers were systemati-
cally investigated in the enantioselective postesterification of
their secondary hydroxy groups catalyzed by CALB.
(DDMAT) was synthesized according to a literature proce-
dure.40 4-Vinylacetophenone was synthesized as described
previously.38
Synthesis of rac-1-(4-vinylphenyl)ethanol (2Rac)
1-(4-Vinylacetophenone) (36 g, 0.24 mol) was dissolved in
ethanol/THF ((v/v:1/1), 300 mL) and inserted into an ice
bath. NaBH4 (12.05 g, 0.32 mol) was added slowly. After dis-
solution of NaBH4, the reaction mixture was allowed to stir
at room temperature overnight. The mixture was treated
with excess of ice/water and then extracted in diethyl ether.
The organic layer was washed with brine, dried over magne-
sium sulfate, and concentrated under reduced pressure.
Before polymerizations, the crude product was purified by
passing through a silica column (t-butyl methyl ether/hep-
tane: 1/4) and was obtained as a colorless liquid.
Yield: 81.5%. 1H NMR (400 MHz, chloroform-d, d: ppm):
1.49 (d, J ¼ 6.46 Hz, 3H), 4.88 (dq, J ¼ 6.42, 6.42, 6.37, 2.86
Hz, 1H), 5.24 (dd, J ¼ 10.89, 0.88 Hz, 1H), 5.75 (dd, J ¼
17.60, 0.91 Hz, 1H), 6.72 (dd, J ¼ 17.61, 10.89 Hz, 1H), 7.36
(dd, J ¼ 28.17, 8.22 Hz, 4H); Gas chromatography–mass
spectrometry (GC-MS) (m/z (%)): 147.8 (8%) [Mþ ꢀ H], 131
(100 %) [C10H11þ], 105 (30%) [C8H8þ]; Chiral GC: retention
time ¼ 13.30 min and 13.46 min.
Synthesis of (R)-1-(4-vinylphenyl)ethanol (2R)
One gram (6.7 mmol) of 4-vinylacetophenone was dissolved
in a mixture of 2-propanol (40 mL) and a phosphate-buf-
fered saline (PBS) solution (0.01 M, pH 7.4, 160 mL) contain-
ing 20 mM NADPH and 0.5 mM MgCl2 and maintained at
37ꢁC with uniform mixing. ADH-LB (50 mL, 4100 U/mL) was
then added to the reaction mixture and the mixture was
allowed to stir overnight. The progress of the reaction was
monitored by thin layer chromatography (TLC) and Chiral
GC. The mixture was treated with excess of water and
extracted in methyl t-butyl ether. The organic layer was
washed with brine, dried over magnesium sulfate, and con-
centrated under reduced pressure.
Yield: 90%. [a]D ¼ þ26.21 deg mL gꢀ1 dm (c ¼ 0.01 g
22
mLꢀ1 in ethylacetate). 1H NMR (400 MHz, chloroform-d, d:
ppm): 1.49 (d, J ¼ 6.45 Hz, 3H; CH3), 4.88 (q, J ¼ 6.45 Hz,
1H; CHACH3), 5.24 (d, J ¼ 10.88 Hz, 1H; CH¼¼CH2), 5.75 (d, J
¼ 17.60, 1H; CH¼¼CH2), 6.71 (dd, J ¼ 17.61, 10.89 Hz, 1H;
CH¼¼CH2), 7.36 (m, 4H; Ar H); 13C NMR (400 MHz, chloro-
form-d, d: ppm): 25.1 (CHACH3), 70.1 (CHACH3), 113.7
(CH¼¼CH2), 125.6 (Ar CH), 126.3 (Ar CH), 136.5 (CH¼¼CH2),
136.8 (Ar C4), 145.5 (Ar C4); FTIR (neat): v ¼ 3353 (b, OH),
2972 (m, CH), 1630 (m, C¼¼C), 1088 (s, CAO), 840 (s, Ar
CAH) cmꢀ1; GC-MS (m/z (%)): 148.0 (12.5%) [Mþ ꢀ H], 131
(35%) [C10H11þ], 105 (100%) [C8H8þ], 77.1 (16%) [C6H5þ];
Chiral GC: retention time ¼ 13.28 min, ee (%) ¼ 99.9.
EXPERIMENTAL
Materials
All the chemicals were purchased from Sigma-Aldrich and
used as received unless otherwise noted. All solvents were
obtained from Biosolve and of technical grade. Anhydrous
tetrahydrofuran (THF) and toluene were dried on an alu-
mina column. Nicotinamide adenine dinucleotide phosphate
(NADPH) and alcohol dehydrogenase from Lactobacillus
brevis (4100 U/mL) (ADH-LB) and Thermoanaerobacter sp.
(331 U/mL) (ADH-T or ADH5) were purchased from Julich
Chiral Solutions GmbH, Germany. Novozyme 435 (immobi-
lized C. antarctica, Lipase B) was obtained from Novozymes.
Styrene (Sigma Aldrich, 99.9%) was purified by passing
over a column of basic aluminum oxide. 2,2-Azobis(isobutyr-
onitrile) (AIBN) was recrystallized from methanol before
use. 2-(Dodecylthiocarbonothioylthio)-2-methylpropionic acid
Synthesis of (S)-1-(4-vinylphenyl)ethanol (2S)
The same procedure described above was used with the
exceptions that the reaction was carried out in PBS solution
without MgCl2 and that ADH-T (285 mL, 331 U/mL) was used.
22
Yield: 95%. [a]D ¼ ꢀ29.13 deg mL gꢀ1 dm (c ¼ 0.01 g
mLꢀ1 in ethylacetate). 1H NMR (400 MHz, chloroform-d, d:
2
JOURNAL OF POLYMER SCIENCE PART A: POLYMER CHEMISTRY 2012, 000, 000–000

JOURNAL OF
POLYMER SCIENCE
ARTICLE
WWW.POLYMERCHEMISTRY.ORG
ppm): 1.49 (d, J ¼ 6.45, 3H; CH3), 4.88 (q, J ¼ 6.45 Hz, 1H;
CHACH3), 5.24 (d, J ¼ 10.88 Hz, 1H; CH¼¼CH2), 5.75 (d, J ¼
17.61 Hz, 1H; CH¼¼CH2), 6.72 (dd, J ¼ 17.60, 10.88 Hz, 1H;
CH¼¼CH2), 7.36 (m, 4H; Ar H); 13C NMR (400 MHz, chloro-
form-d, d: ppm): 25.1 (CHACH3), 70.1 (CHACH3), 113.7
(CH¼¼CH2), 125.6 (Ar CH), 126.3 (Ar CH), 136.5 (CH¼¼CH2),
136.8 (Ar C4), 145.4 (Ar C4); FTIR (neat): v ¼ 3359 (b,
OAH), 2973 (m, CAH), 1630 (m, C¼¼C), 1088 (s, CAO), 840
(s, Ar CAH) cmꢀ1; GC-MS (m/z (%)): 147.8 (5%) [Mþ ꢀ H],
131 (100%) [C10H11þ], 105 (30%) [C8H8þ]); Chiral GC:
retention time ¼ 13.45 min, ee (%) ¼ 99.9.
ple were 5000 g/mol and 1.13, respectively, and the conver-
sion estimated by GC was 53%. Yield: 33%.
Copolymers
The same procedure as described for homopolymerizations
was used with the exceptions that a mixture of styrene and
(R)-1-(4-vinylphenyl)ethanol was used.
A representative
example for copolymerizations in dioxane is as follows: To a
10-mL glass reaction vessel equipped with a magnetic stir
bar, DDMAT (35.1 mg, 0.096 mmol), AIBN (3.97 mg, 24.2 ꢂ
10ꢀ3 mmol), 0.5 mL mesitylene, and 3.3 mL dioxane in total
were transferred using a fixed volume pipettor. (R)- or (S)-1-
(4-vinylphenyl)ethanol (0.71 g, 4.8 mmol) and styrene were
added (0.51 g, 4.9 mmol) to the vessel. The tube was sealed
and deoxygenated by flushing with argon through solution
for ꢃ30 min. Then, the vessel was placed in a preheated oil
bath at 70ꢁC. During the polymerization, samples were taken
at different times of conversion and used for analysis. The
reaction was stopped after a certain time by cooling the flask
in an icebath and addition of THF. The polymer was recov-
ered by precipitation in a generous amount of stirring
diethyl ether (>50 mL), filtered, and dried under vacuum
overnight. Mn and D obtained from SEC for this particular
sample were 3400 g/mol and 1.16, respectively. Yield: 17%.
Synthesis of (R)-1-(4-vinylphenyl)ethyl acetate
(R)-1-(4-vinylphenyl)ethanol (35 g, 0.2 mol) was weighed
into a vial charged with Novozyme-435 (12 wt % with
respect to the monomer, 3.60 g) and 3 Å molecular sieves.
Then, the vial was filled with nitrogen and dry toluene (700
mL), followed by vinyl acetate (69.8 g, 0.81 mol). The reac-
tion mixture was stirred at 45ꢁC for 2 days. The reaction
mixture was then filtered and dried under vacuum. The
crude product was purified by passing through a silica col-
umn (dichloromethane/hexane: 3/2) and the product was
obtained as a colorless liquid.
Yield: 84.9%. [a]D ¼ þ113.1 deg mL gꢀ1 dm (c ¼ 0.02 g
22
mLꢀ1 in THF). 1H NMR (400 MHz, chloroform-d, d: ppm):
1.57 (d, J ¼ 6.60 Hz, 3H; CHACH3), 2.11 (s, 3H; COACH3),
5.29 (d, J ¼ 10.87, 1H; CH¼¼CH2), 5.78 (d, J ¼ 17.60, 1H;
CH¼¼CH2), 5.91 (dd, J ¼ 13.14, 6.57 Hz, 1H; CHACH3), 6.75
(dd, J ¼ 17.58, 10.89, 1H; CH¼¼CH2), 7.4 (dd, J ¼ 30.93, 8.12
Hz, 4H; Ar H). 13C NMR (400 MHz, chloroform-d, d: ppm):
21.3 (CHACH3), 22.2 (COACH3), 72.1 (CHACH3), 114.1
(CH2¼¼CH), 126.3 (ArAH), 136.4 (CH¼¼CH2), 137.3 (ArAC4),
141.2 (ArAC4), 170.3 (C¼¼O). FTIR (neat): v ¼ 2982 (m,
CAH), 1731 (s, C¼¼O), 1630 (m, C¼¼C), 1060 (s, CAO), 838
(s, Ar CAH). GC-MS (m/z (%)): 190.0 (20%) [Mþ], 148.0
(50%) [C10H12Oþ], 131.0 (100%) [C10H11þ], 105.2 (15%)
[C8H8þ]; Chiral GC: retention time ¼ 13.12, ee (%) ¼ 99.
CALB-Catalyzed Esterifications
For all reactions the [OH] concentration, mol equivalence of
vinyl acetate to [OH] and weight percentage of CALB were
kept constant and only the amount of solvent was varied in
different reactions. The esterification of polymers is given as
a representative example: Poly((R)-1-(4-vinylphenyl)ethanol),
(Poly2R), (120 mg, Mn ¼ 5400 g/mol, D ¼ 1.20) was
weighed into a vial. The vial was then charged with Novo-
zyme-435 (12 wt % with respect to the polymer, 14.4 mg)
and 3 Å molecular sieves and vacuum dried at 60ꢁC over-
night to remove traces of moisture. Then, the vial was filled
with nitrogen, dry THF (1.5 mL), and dry toluene (3 mL) fol-
lowed by vinyl acetate (0.7 mL). The reaction mixture was
stirred at 45ꢁC for 2 days. The samples were filtered and
dried before being analyzed by NMR to determine the extent
of grafting onto the hydroxyl groups.
Homopolymers
Individual stock solutions of the radical initiator (AIBN) and
chain transfer agent (CTA, (DDMAT)) were prepared with the
respective solvent to ensure accurate reactant ratios for a set
of reactions at a given condition. A representative example for
polymerizations in 1,4-dioxane is as follows: In a 10-mL glass
reaction vessel equipped with a magnetic stirring bar, DDMAT
(49.3 mg, 0.135 mmol), AIBN (5.55 mg, 33.8 ꢂ 10ꢀ3 mmol),
1 mL mesitylene, and 6.7 mL dioxane were transferred using
a fixed volume pipettor. 1-(4-Vinylphenyl)ethanol (2 g, 13.5
mmol) was added to the vessel. The tube was sealed and
deoxygenated by flushing with argon through the solution for
ꢃ30 min. Then, the vessel was placed in a preheated oil bath
at 70ꢁC. During the polymerization, samples were taken at
different times of conversion and used for analysis. The reac-
tion was stopped after a certain time by cooling the flask in
an icebath followed by the addition of THF. The polymer was
recovered by precipitation in diethyl ether (50 mL), filtered,
and dried under vacuum overnight. Mn and D obtained from
size exclusion chromatography (SEC) for this particular sam-
Methods
1H and 13C NMR spectra were recorded on a Varian Mercury
Vx spectrometer operating at 400 MHz at 25ꢁC. Multiplicities
are given as s (singlet), d (doublet), t (triplet), q (quartet), m
(multiplet), and br (broad) for 1H spectra. Coupling con-
stants, J, are reported in Hz. Infrared spectra were recorded
on a Jasco FT-IR-460 Plus spectrometer equipped with a Spe-
cac MKII Golden Gate Single Reflection Diamond ATR System
and reported in wave numbers (cmꢀ1). GC-MS spectra were
recorded on a Varian 450-GC gas chromatograph equipped
with an autosampler and a Varian 220-MS mass selective de-
tector on a factor four capillary column VF-5ms 30 M ꢂ 0.25
MM with Injector and flame ionization detector (FID) tem-
peratures at 300ꢁC, using the following gradient oven tem-
perature program: from 35ꢁC (for 5 min) to 270ꢁC at 10ꢁC/
min holding at 280ꢁC for 15 min. The enantiomeric excess
(ee %) was determined by chiral gas chromatography using
WWW.MATERIALSVIEWS.COM
JOURNAL OF POLYMER SCIENCE PART A: POLYMER CHEMISTRY 2012, 000, 000–000
3

JOURNAL OF
POLYMER SCIENCE
ARTICLE
WWW.POLYMERCHEMISTRY.ORG
mer was calculated by using the equation obtained by linear
fitting of the data points of this monomer. Then, the calcu-
lated reaction time was multiplied by the slope of the kinetic
plot of the second monomer to calculate the conversion of
the second monomer (Slope ꢂ time ¼ ln(1/(1 ꢀ conver-
sion))) at that specific time. By knowing the conversion of
both monomers at a certain time, the incorporated fractions
of monomers were calculated and plotted as a function of
monomer feed composition.
RESULTS AND DISCUSSION
Polymer Synthesis
Enantiopure monomers were synthesized by selective ADH
reduction of the corresponding ketone 1-(4-vinylphenyl)etha-
none 1. Two commercially available enantio-complementary
ADHs, that is, (R)-producing Lactobacillus (ADH-LB) and (S)-
producing Thermoanaerobacter sp. (ADH-T) were used
(Scheme 1). Both ADHs depend on NADPH as a cofactor,
which serves as a hydride source in the reaction. An excess
of a second substrate (‘‘cosubstrate’’—isopropanol) was used
for recycling of the cofactor from NADPþ to NADPH to
reduce the cost of the hydride source and to drive the reac-
tion to completion.42–44 The reduction of 1 resulted in mole-
cules (S)-1-(4-vinylphenyl)ethanol (2S) and (R)-1-(4-vinylphe-
nyl)ethanol (2R) that bear both an alkene (polymerizable
group) and a chiral phenyl ethanol (enzyme sensitive unit).
The reactions were monitored by FTIR and 1H NMR. The
appearance of a characteristic ACH peak at 4.9 ppm confirmed
the reduction at the prochiral carbon. FTIR spectra showed
the presence of an alcoholic AOH band at 3353 cmꢀ1 and the
disappearance of the characteristic ketone C¼¼O peak at 1674
cmꢀ1. The enantiomeric excess (ee) of 2S and 2R was found to
be >99% as determined by chiral gas chromatography (GC).
The racemic monomer (Rac)-1-(4-vinylphenyl)ethanol (2Rac)
was synthesized by the chemical reduction of 1 with NaBH4 in
ethanol/THF (1/1) at room temperature.
SCHEME 1 Synthesis of enantiopure monomers 2R and 2S via
ADH reductions of 1-(4-vinylphenyl)ethanol 1 and RAFT-medi-
ated (co)polymerization of racemic (2Rac) and the enantiopure
monomers 2S and 2R.
a Varian 430-GC on a CP Chiralsil-DEXCB column (25 M ꢂ
0.25 MM) with injector at 200ꢁC and FID 250ꢁC, and the fol-
lowing gradient temperature program: from 50ꢁC (for 5
min) to 195ꢁC at 15ꢁC/min holding at 195ꢁC for 2 min.
Monomer conversions were determined using Varian 450-GC
on a CP-Wax 52CB column (25 M ꢂ 0.4 MM) with injector at
250ꢁC and FID 300ꢁC and the following gradient tempera- RAFT was chosen for the polymerization of the enantiopure
ture program: from 40ꢁC (for 5 min) to 200ꢁC at 10ꢁC/min monomers because of its tolerance to various solvents and
holding at 200ꢁC for 5 min. Optical rotations were deter- functional groups.45–47 Because DDMAT was shown to be
mined using a JASCO DIP-370 Digital Polarimeter (589 nm, compatible with styrene and substituted styrene derivatives
Na D-line, 25ꢁC) with a cylindrical glass cell (/ 3.5 ID ꢂ 50
it was selected as CTA together with 2,20-azobis(2-methyl-
mm) at a concentration of 10 mg mLꢀ1 in THF. SEC was per- propionitrile) (AIBN) as a radical initiator.48 2Rac was used
formed on a Waters Alliance system equipped with a 1515 for the initial kinetic studies and a single set of reaction con-
Isocratic HPLC pump, a Waters 2707 autosampler, a Waters ditions (T ¼ 70ꢁC, [Monomer] ¼ 2 mol/L and [Monomer]0:[-
2414 refractive index detector (35ꢁC), a Waters 2996 Photo- I]0:[CTA]0 ¼ 100:0.25:1) was used for all polymerizations.
diode Array detector, a PSS SDV 5-m guard column followed The polarity of the stereoisomers of 2 and their correspond-
by 2 SDV 5 m, 500 Å (8 ꢂ 300 mm) columns in series at ing polymers dictated the use of a polar polymerization sol-
40ꢁC. THF (stabilized with BHT, Biosolve) with 1 v/v % ace-
vent. Because the choice of solvent might dramatically affect
tic acid was used as eluent at a flow rate of 1.0 mL minꢀ1
.
the polymerization kinetics of the hydroxyl-functional styr-
The molecular weights were calculated against polystyrene enes as well as the Mn profiles, toluene, N-methyl-2-pyrroli-
standards (Polymer Laboratories, Mp ¼ 580 Da up to Mp ¼ done (NMP), and 1,4-dioxane where systematically investi-
21,000 Da). Before SEC analysis was performed, the samples gated as polymerization solvents while keeping all other
were filtered through a 0.2-mm poly(tetra fluoro ethylene) reaction parameters constant (Table 1). As can be seen in
(PTFE) filter (13 mm, PP housing, Alltech). Copolymer com-
Figure 1, ln([M]0/[M]t) versus time as well as Mn versus con-
positions were determined from the kinetics plots (ln([M]0/ version increase linearly for the styrene polymerizations in
[M]t) versus time) following a literature procedure.41 First, all solvents. The rate of the polymerization was found to
the reaction time to reach a certain conversion of one mono- decrease in the order NMP
>
dioxane
>
toluene.
4
JOURNAL OF POLYMER SCIENCE PART A: POLYMER CHEMISTRY 2012, 000, 000–000

JOURNAL OF
POLYMER SCIENCE
ARTICLE
WWW.POLYMERCHEMISTRY.ORG
TABLE 1 Results of RAFT-Mediated Polymerizations of Styrene and 2Rac in 1,4-Dioxane, Toluene, and NMP (T 5 708C, [Monomer]
5 2 mol L21, and [Monomer]0:[I]0:[CTA]0 5 100:0.25:1)
Conversion
(GC) (%)
Mn, (th)
(g/mol)a
Mn, (SEC)
(g/mol)b
Entry
Monomer
Solvent
Time (h)
D
1
2
3
4
5
6
Styrene
Styrene
Styrene
2Rac
Dioxane
Toluene
NMP
30
30
30
26
5
34
27
41
54
23
60
3,900
3,172
4,628
10,132
3,768
9,244
3,500
2,800
3,800
5,700
2,100
6,500
1.1
1.1
1.4
1.1
1.1
1.2
Dioxane
Toluene
NMP
2Rac
2Rac
27
a
b
Mn,
was calculated according to the following equation: MCTA
þ
SEC calibrated with polystyrene standards.
MM ꢂ tCh onversion ꢂ [M]0/[CTA]0.
Experimental Mn values obtained by SEC were in very good
agreement with Mn, th values for the polymerizations in tolu-
ene and 1,4-dioxane, and the polymers exhibited low disper-
sities (D ꢃ 1.1), signifying good control over the process.
Only in the case of NMP, a low molecular weight tailing was
observed in the SEC trace, which resulted in a higher disper-
sity around 1.4. The polymerization of 2Rac also revealed a
linear increase of ln([M]0/[M]t) as a function of time and of
Mn as a function of conversion for all solvents with the rate
of polymerization decreasing in the order toluene > dioxane
> NMP. Along with the low dispersities obtained, these
results indicate a good control over the polymerization of
2Rac in all tested solvents. When compared with styrene,
2Rac polymerized faster in all three solvents, that is, four
times faster in toluene, 2.8 times faster in 1,4-dioxane, and
2.4 times faster in NMP (calculated by the slope of ln([M]0/
[M]t) versus time graph). In all cases, Mn values measured
by SEC were lower than Mn, th values. This is believed to be
due to the difference between the hydrodynamic volume of
poly2Rac and the polystyrene SEC standards. During the po-
lymerization of 2Rac in toluene, a precipitation of polymer
was observed after 5 h (22% conversion, Mn ¼ 2100 g/mol).
Although no precipitation occurred during the polymeriza-
tion in NMP, similar to styrene polymerization, a tailing at
the low molecular weight side was observed in the SEC
traces resulting in higher dispersities (1.2 to 1.3). Based on
these results, 1,4-dioxane was selected for the polymeriza-
tion of enantio-pure 2R and 2S to obtain chiral
homopolymers.
As expected, the reaction kinetics of both 2R and 2S were
found to be identical to that of 2Rac (SI). Four different
[M]0/[CTA]0 ratios were used in the polymerization of 2R
and the results are summarized in Table 2. Poly2R with mo-
lecular weights ranging from 5,400 to 13,300 g/mol were
synthesized as well as a poly2S with a Mn of 5,000 g/mol. In
agreement with their enantiomeric composition, poly2R and
poly2S gave opposite optical rotation of light (þ39.4ꢁ and
ꢀ36.1ꢁ, respectively), whereas poly2Rac (Table 1, entry 4)
did not lead to any significant rotation of light (þ0.062ꢁ).
Moreover, to provide polymers to study the effect of chiral
group density on the CALB esterification, copolymers of 2R
and styrene were synthesized (Scheme 1). Five different
[2R]/[styrene] feed ratios (f1) were aimed at (1/1, 2/3, 3/2,
1/4, and 4/1) and all copolymerizations were performed in
dioxane at 70ꢁC with a total monomer concentration of 2M
and a [M]/[I]/[CTA] ratio of 100/0.25/1 (Table 3). For all
monomer ratios, a linear increase of ln([M]0/[M]t) versus
time was monitored for both monomers. When compared
FIGURE 1 Kinetic (top) and molecular weight plot (bottom) for
the homopolymerization of 2Rac and styrene in 1,4-dioxane,
toluene, and NMP at 70ꢁC using DDMAT as CTA and AIBN as
radical initiator.
WWW.MATERIALSVIEWS.COM
JOURNAL OF POLYMER SCIENCE PART A: POLYMER CHEMISTRY 2012, 000, 000–000
5

JOURNAL OF
POLYMER SCIENCE
ARTICLE
WWW.POLYMERCHEMISTRY.ORG
TABLE 2 Results of RAFT-Mediated Polymerizations of 2R and 2S at 708C in 1,4-Dioxane
Conversion
(GC) (%)
Mn, th
(g/mol)a
Mn, SEC
(g/mol)b
Optical
Rotation (ꢁ)
Monomer
[M]0/[CTA]0
Time (h)
D
2R
2S
2R
2R
2R
a
100
100
200
400
600
30
20
24
25
23
51
53
48
40
55
8,356
5,400
5,000
8,600
11,500
13,300
1.1
1.1
1.3
1.2
1.2
þ39.4
ꢀ36.1
þ40.6
ND
8,356
14,572
24,044
49,204
ND
b
Mn, was calculated according to the following equation: MCTA þ MM
SEC calibrated with polystyrene standards.
th
ꢂ Conversion ꢂ [M]0/[CTA]0.
with the homopolymerizations, it was noticeable that the po-
lymerization rate of 2R decreased, whereas the rate of styrene
increased. For example, in the 1/1 copolymerization, 2R
reached an ln([M]0/[M]t) ¼ 0.49 in 22 min, whereas a value
of 0.80 was reached in the homopolymerization after the
same time. A comparatively smaller difference was observed
for styrene, reaching ln([M]0/[M]t) ¼ 0.30 in 22 min in the
homopolymerization and 0.46 in the copolymerization after
the same reaction time. All copolymerizations proceeded well-
controlled irrespective of momomer feed ratio, as evidenced
form the linear increase of Mn with conversion (Fig. 2 and
Supporting Information) and the narrow dispersities < 1.2.
random copolymers with expected properties intermediate
to those of the two homopolymers.
Enantioselective Enzymatic Polymer Modification
Poly2R and poly2S (Table 2, entry 1 and 2) are identical in
structure and functionality and very similar in molecular
weight, implying that they are chemically indistinguishable
by common polymer characterization techniques. Although
this was not specifically tested, it is reasonable to assume
that the enantiomeric secondary hydroxy groups are equally
reactive in any polymer analogous chemical modification.
However, selective postfunctionalization of these polymers
with hydroxy groups of opposite chirality is possible with an
enzyme that inherently exhibits distinctive enantioselectivity.
CALB immobilized on a macroporous resin (Novozym 435)
has been shown to be highly selective for the (R)-1-phenyl-
ethanol moiety with esterification rates 1,300,000 times
higher than for the (S)-enantiomer.50 Before carrying out the
CALB-mediated esterification of the enantiopure homopoly-
mers, the required reaction conditions were investigated by
performing model reactions. Although solvent effects are com-
plex, CALB generally shows optimum activity in organic sol-
vents with higher log P values (hydrophobic solvent).51,52
However, the chiral homopolymers synthesized in this study
are not soluble in common hydrophobic solvents like hexane
or toluene. Thus, different organic solvent systems, both polar
as well as mixtures of polar and apolar solvents, were used
for the CALB-mediated esterification with vinylacetate (Sup-
porting Information). The concentration of secondary OH
groups was kept at 0.1 mol/L in all model reactions at a reac-
tion temperature of 45ꢁC and the extent of conversion was
Because of overlapping peaks, the average copolymer compo-
1
sition could not be determined by H NMR spectroscopy. An
alternative method proposed by Mu¨ller was used deriving
the data from the kinetics plots (ln([M]0/[M]t) versus time)
of the copolymerizations.41 The plot in Figure 3 shows the
good agreement between the copolymer composition and the
molar fraction (F2R) of 2R in the monomer feed for the
copolymerization of 2R and styrene. The reactivity ratios (r)
of the statistical copolymerizations were determined by non-
linearized least square fitting of the composition data-aver-
age copolymer composition (monomer sequence distribu-
tion) as a function of the monomer feed composition.49
Reactivity ratios of 1.19 (60.1) and 1.14 (60.1) for 2R and
styrene, respectively, were determined by this method.
Although the reactivity ratios were determined at relatively
high monomer conversion (30%), the almost identical kinetic
plots of both monomers imply no influence of a composi-
tional drift at this conversion. The r-values together with the
linear relation between f1 and F1 suggest the formation of
1
determined by H NMR. This reaction was first performed on
TABLE 3 RAFT-Mediated Copolymerization of 2R and Styrene at Different Monomer Feed Ratios and Corresponding Average
Copolymer Composition Determined from Kinetic Plots
Feed Ratio
[M]:[Sty]
Conversion
GC (%)
Mn, GPC
(g/mol)a
Compositionb
[M]:[Sty]
Entry
Time (h)
D
1
2
3
4
5
a
20:80
40:60
50:50
60:40
80:20
25
29
26
29
29
37
39
42
51
51
b
3,800
4,200
4,400
5,000
5,800
1.2
1.2
1.2
1.2
1.2
19:81
39:61
51:49
62:38
81:19
Calibrated with polystyrene standards.
Obtained from ln([M]0/[M]t) versus time plots.
6
JOURNAL OF POLYMER SCIENCE PART A: POLYMER CHEMISTRY 2012, 000, 000–000

JOURNAL OF
POLYMER SCIENCE
ARTICLE
WWW.POLYMERCHEMISTRY.ORG
yield of esterification on the polymer. When poly2S was also
exposed to CALB under the same reaction conditions, no ester-
ification was observed in 1H NMR, as expected (Supporting In-
formation). Increasing the molecular weight of poly2R from
5400 g/mol to 16,200 g/mol resulted in a decrease of the
esterification yield (55% to 42%, Table 4 entry 6 and 9,
respectively). This suggests that steric factors play a role in the
esterification, although it cannot be ruled out that a decrease
of polymer solubility in toluene/THF (2/1) with increasing mo-
lecular weight also contributes to this result.
An experiment was carried out to investigate whether the
selectivity of esterification is retained in the presence of mix-
tures of enantiopure polymers. A mixture (50/50 wt/wt)
containing a lower molecular weight poly2S (4700 g/mol)
and a higher molecular weight poly2R (10,100 g/mol) was
exposed to CALB at 45ꢁC for 2 days in the presence of vinyl
acetate. SEC analysis confirmed an increase in molecular
weight of only the poly2R in this process, consistent with a
selective esterification of this polymer (Fig. 5). According to
1H NMR analysis, 17% of the total amount of hydroxyl
groups were esterified, corresponding to 34% of (R)-[OH]. A
similar result was obtained for a polymer mixture containing
a lower Mn Poly2R (5400 g/mol) and a higher Mn poly2S
(9600 g/mol) (Supporting Information).
Finally, copolymers of 2R and styrene with different copoly-
mer composition were exposed to CALB enzyme in toluene/
THF (2/1) at 45ꢁC for postmodification (Table 5). An increase
in the conversion was observed when the copolymer composi-
tion ratio of 2R/styrene increased from 0.25 to 4 (from 21 to
53%, respectively) in toluene/THF (2/1) at 45ꢁC. However, fur-
ther increase in enzyme-sensitive monomer concentration in
the backbone did not improve the extent of esterification fur-
ther (the maximum reached in these conditions with
FIGURE 2 Kinetics plot for the copolymerization of 2R and sty-
rene with 50/50 feed ratio (f1) at 70ꢁC in 1,4-dioxane (top), and
molecular weights (Mn) and dispersity (D) plotted against con-
version of 2R in the copolymerization with styrene at different
feed ratios (bottom).
(R)-1-phenylethanol and 2R. Both model compounds gave full
conversions in a range of pure solvents and solvent mixtures
within 5 min except in NMP, DMSO, and DMF for which the
reaction did not occur at all. This is probably due to the abil-
ity of these solvents to strip the essential water layer off the
enzyme, which is necessary for its activity.53,54
The esterification of homopolymers in the same solvents was
either not successful or the yields were much lower compared
with the corresponding yields for the model compounds (Table
4). Toluene/THF (2/1) was found to be the most appropriate
solvent mixture for the postfunctionalization of poly2R. Figure
4 shows a comparison of the esterification of both model com-
pounds and poly2R (Table 4, entry 1,) in toluene/THF (2/1).
Both low molecular weight compounds reached 100% conver-
sion within 5 min after the exposure to CALB, whereas poly2R
reached its maximum conversion of 55% after 30 h under the
same conditions. Extended reaction times or increasing the
polymer OH concentration to 0.2 mol/L did not increase the
FIGURE 3 Average molar composition expressed as molar
fraction of 2R (F2R) in the copolymer for the copolymerization
of styrene and 2R as a function of the molar fraction of 2R in
the monomer feed (f2R) at 33% conversion.
WWW.MATERIALSVIEWS.COM
JOURNAL OF POLYMER SCIENCE PART A: POLYMER CHEMISTRY 2012, 000, 000–000
7

JOURNAL OF
POLYMER SCIENCE
ARTICLE
WWW.POLYMERCHEMISTRY.ORG
TABLE 4 Esterification of poly2R with CALB in Different Solvents
Entry
Mn (g/mol)
Mw (g/mol)
D
Solvent
Esterification on (R)-OHa (%)
[OH] (mol/L)
1
6,500
6,800
6,800
6,800
6,800
5,400
10,000
13,100
16,200
6,800
6,800
6,800
6,800
29,300
6,800
6,800
7,800
7,700
7,700
7,700
7,700
6,500
11,800
15,000
17,700
7,700
7,700
7,700
7,700
66,900
7,700
7,700
1.2
1.2
1.2
1.2
1.2
1.2
1.7
1.2
1.1
1.2
1.2
1.2
1.2
2.2
1.2
1.2
THF
0
0.2
0.1
0.2
0.1
0.1
0.2
0.1
0.1
0.1
0.1
0.1
0.1
0.2
0.2
0.2
0.2
2
THF
<5
30
31
55
52
53
51
42
42
45
0
3
THF/toluene (1/1)
THF/toluene (1/1)
THF/toluene (1/2)
THF/toluene (1/2)
THF/toluene (1/2)
THF/toluene (1/2)
THF/toluene (1/2)
THF/toluene (1/3)
Tol/acetone (1/1)
DMA/AcNitrile (2/3)
DMA/AcNitrile (2/3)
DMA/AcNitrile (2/3)
DMA/acetone (2/3)
t-BuOH/pyr (1/1)
4
5
6
7
8
9
10
11
12
13
14
15
16
a
0
0
0
0
The conversion values were calculated by 1H NMR. The integrals
ppm) (2 and 20, respectively, Supporting Information Fig. 1) were
used.
of the peaks with respect to ACH (4.9 ppm) and ester form (5.8
homopolymer was 55%). This result is surprising, as one
would expect that the maximum esterification of hydroxy
groups should be obtained irrespective of the copolymer com-
position. This might suggest that not only steric effects play a
role but possibly also the local environment of the hydroxy
groups. Further research needs to be carried out to investigate
this observation.
first-order polymerization kinetic and well-defined homopoly-
mers with low dispersities were obtained. The concept was
extended to the synthesis of random copolymerization, for
which kinetic investigations confirmed that the enantiopure
monomers and styrene have similar reactivity ratios resulting
in random copolymers. It was further found that the lipase
catalyzed polymer analogous esterification of the chiral
hydroxy groups was strongly (R)-selective. The lipase enantio-
slectivity is retained for mixtures of (R)- and (S)-
CONCLUSIONS
Enantiopure homo and copolymers were synthesized from
enantionpure (R)- and (S)-1-(4-vinylphenyl)ethanol by RAFT
polymerization. Using dioxane as a polymerization solvent,
FIGURE 4 CALB-catalyzed esterification of 2R, (R)-acetophenol
and poly2R (Table 4, entry 1, Mn ¼ 5400 g/mol) with vinyl ace-
tate in a toluene/THF (2/1) mixture at 45ꢁC.
FIGURE 5 Molecular weight distributions of poly2R and poly2S
mixture before and after enzymatic modification (Poly2S (Mn
4700 g/mol) and poly2R (Mn ¼ 10,100 g/mol)).
¼
8
JOURNAL OF POLYMER SCIENCE PART A: POLYMER CHEMISTRY 2012, 000, 000–000

JOURNAL OF
POLYMER SCIENCE
ARTICLE
WWW.POLYMERCHEMISTRY.ORG
TABLE 5 CALB-Mediated Esterification with Vinyl Acetate on poly(2R-co-S) Copolymers in
Toluene/THF (2/1) at 458C
Ratio
Mn
Esterification
(%)a
Entry
2R
Sty
(2R/Sty)
(g/mol)
D
1
2
3
4
5
a
1
2
1
3
4
4
3
1
2
1
0.25
0.67
1
3,200
3,700
3,400
3,900
4,300
1.2
1.2
1.2
1.2
1.2
21
30
37
38
53
1.5
4
The amount of esterification was determined by 1H NMR with respect to ACH (4.9 ppm) and ester formed
(5.8 ppm).
16 Van As, B. A. C.; Thomassen, P.; Kalra, B.; Gross, R. A.;
Meijer, E. W.; Palmans, A. R. A.; Heise, A. Macromolecules
2004, 37, 8973–8977.
homopolymers. Esterification on the polymer was limited to
around 50 % most probably due to sterical factors. The suc-
cessful RAFT polymerization of the enantiopure monomers
will allow further studies on polymers with different chiral
architectures.
17 Thurecht, K. J.; Gregory, A. M.; Villarroya, S.; Zhou, J.;
Heise, A.; Howdle, S. M. Chem. Commun. 2006, 4383–4385.
18 Kumar, A.; Kulshrestha, A. S.; Gao, W.; Gross, R. A. Macro-
molecules 2003, 36, 8219–8221.
ACKNOWLEDGMENTS
19 Kulshrestha, A. S.; Sahoo, B.; Gao, W.; Fu, H.; Gross, R. A.
Macromolecules 2005, 38, 3205–3213.
This research forms part of the research program of the Dutch
Polymer Institute (DPI), project #684. The authors thank Hans
Heuts for his comments and useful discussion during the prep-
aration of this manuscript. A. Heise is a SFI Stokes Senior
Lecturer (07/SK/B1241).
20 Veld, M. A. J.; Palmans, A. R. A.; Meijer, E. W. J. Polym.
Sci. Part A: Polym. Chem. 2007, 45, 5968–5978.
21 Ulijn, R. V. J. Mater. Chem. 2006, 16, 2217–2225.
22 Amir, J. R.; Zhong, S.; Pochan, D. J.; Hawker, C. J. J. Am.
Chem. Soc. 2009, 131, 13949–13951.
23 Thornton, P. D.; Heise, A. J. Am. Chem. Soc. 2010, 132,
2024–2028.
REFERENCES AND NOTES
1 Heise, A.; Palmans, A. R. A. Adv. Polym. Sci. 2010, 237, 79-113.
24 Anderson, D. G.; Burdick, J. A.; Langer, R. Science 2004,
305, 1923–1924.
2 Puskas, J. E.; Sen, M. Y.; Seo, K. S. J. Polym. Sci. Part A:
Polym. Chem. 2009, 47, 2959–2976.
25 Alexander, C.; Shakesheff, K. M. Adv. Mater. 2006, 18,
3 Kobayasi, S.; Uyama, H. Adv. Polym. Sci. 2006, 194, 133–158.
3321–3328.
4 Varma, I. K.; Albertsson, A. C.; Rajkhowa, R.; Srivastava, R. K.
Prog. Polym. Sci. 2005, 30, 949–981.
26 Yang, Z.; Liang, G.; Wang, L.; Xu, B. J. Am. Chem. Soc.
2006, 128, 3038–3043.
5 Gross, R. A.; Kumar, A.; Kalra, B. Chem. Rev. 2001, 101, 2097–2124.
27 Peeters, J. W.; van Leeuwen, O.; Palmans, A. R. A.; Meijer,
E. W. Macromolecules 2005, 38, 5587–5592.
6 Yeniad, B.; Naik, H.; Heise, A. Adv. Biochem. Eng. Biotechnol.
2011, 125, 69–95.
28 Kuellmer, K.; Kikuchi, H.; Uyama, H.; Kobayashi, S. Macro-
mol. Rapid. Commun. 1998, 19, 127–130.
7 Nyanhongo, G. S.; Kudanga, T.; Prasetyo, E. N.; Gubitz, G. M.
Adv. Biochem. Eng. Biotechnol. 2011, 125, 47–68.
29 Kikuchi, H.; Uyama, H.; Kobayashi, S. Polym. J. 2002, 34,
8 Zimmermann, W.; Billig, S. Adv. Biochem. Eng. Biotechnol.
2011, 125, 97–120.
835–840.
30 Al-Azemi, T. F.; Kondaveti, L.; Bisht, K. S. Macromolecules
2002, 35, 3380–3386.
9 Meyer, U.; Palmans, A. R. A.; Loontjens, T.; Heise, A. Macro-
molecules 2002, 35, 2873–2875.
31 Yan, X.; Cummins, D.; Palmans, A. R. A.; Koning, C. E.;
Heise, A. Soft Matter 2008, 4, 593–599.
10 de Geus, M.; Peters, R.; Koning; C. E.; Heise, A. Biomacro-
molecules 2008, 9, 752–757.
32 van Buijtenen, J.; van As, B. A. C.; Verbruggen, M.; Rou-
men, L.; Vekemans, J. A. J. M.; Pieterse, K.; Hilbers, P. A. J.;
Hulshof, L. A.; Palmans, A. R. A.; Meijer, E. W. J. Am. Chem.
Soc. 2007, 129, 7393–7398.
11 de Geus, M.; Schormans, L.; Palmans, A. R. A.; Koning, C. E.;
Heise, A. J. Polym. Sci. Part A: Polym. Chem. 2006, 44, 4290–4297.
12 Zhang, B.; Li, Y.; Xu, Y.; Wang, S.; Ma, L.; Wang, J. Polym.
Bull. 2008, 60, 733–740.
33 Hilker, I.; Rabani, G.; Verzijl, G. K. M.; Palmans, A. R.
A.; Heise, A. Angew. Chem. Int. Ed. Engl. 2006, 45,
2130–2132.
13 Duxbury, C. J.; Wang, W. X.; de Geus, M.; Heise, A.; How-
dle, S. M. J. Am. Chem. Soc. 2005, 127, 2384–2385.
34 van As, B. A. C.; van Buijtenen, J.; Mes, T.; Palmans, A. R.
A.; Meijer, E. W. Chemistry 2007, 13, 8325–8232.
14 Zhou, J.; Villarroya, S.; Wang, W.; Wyatt, M. F.; Duxbury, C.
J.; Thurecht, K. J.; Howdle, S. M. Macromolecules 2006, 39,
5352–5358.
35 Kanca, U.; van Buijtenen, J.; van As, B. A. C.; Korevaar, P.;
Vekemans, J. A. J. M.; Palmans, A. R. A.; Meijer, E. W. J.
Polym. Sci. Part A: Polym. Chem. 2008, 46, 2721–2733.
15 Xiao, Y.; Coulembier, O.; Koning, C. E.; Heise, A.; Dubois, P.
Chem. Commun. 2009, 2472–2474.
WWW.MATERIALSVIEWS.COM
JOURNAL OF POLYMER SCIENCE PART A: POLYMER CHEMISTRY 2012, 000, 000–000
9

JOURNAL OF
POLYMER SCIENCE
ARTICLE
WWW.POLYMERCHEMISTRY.ORG
36 van As, B. A. C.; van Buijtenen, J.; Heise, A.; Broxterman, Q.
B.; Verzijl, G. K. M.; Palmans, A. R. A.; Meijer, E. W. J. Am.
Chem. Soc. 2005, 127, 9964–9965.
45 Perrier, S.; Takolpuckdee, P. J. Polym. Sci. Part A: Polym.
Chem. 2005, 43, 5347–5393.
46 Shipp, D. A. Polym. Rev. 2011, 51, 99–103.
37 van Buijtenen, J.; van As, B. A. C.; Meuldijk, J.; Palmans, A.
R. A.; Vekemans, J. A. J. M.; Hulshof, L. A.; Meijer, E. W.
Chem. Commun. 2006, 30, 3169–3171.
47 Moad, G.; Rizzardo, E.; Thang, S. H. Polymer 2008, 49,
1079–1131.
48 Zhang, H.; Deng, J.; Lu, L.; Cai, Y. Macromolecules 2007, 40,
38 Duxbury, C. J.; Hilker, I.; Wildeman, S. M. A.; Heise, A.
Angew. Chem. Int. Ed. Engl. 2007, 46, 8452–8454.
9252–9261.
€
49 van Herk, A. M.; Droge, T. Macromol. Theory Simul. 1997,
39 Yeniad, B.; Naik, H.; Amir, R.; Koning, C. E.; Hawker, C. J.;
Heise, A. Chem. Commun. 2011, 47, 9870–9872.
6, 1263–1276.
50 Magnusson, A. O.; Takwa, M.; Hamburg, A.; Hult, K. Angew.
Chem. Int. Ed. Engl. 2005, 44, 4582–4585.
40 Lai, J. T.; Filla, D.; Shea, R. Macromolecules 2002, 35, 6754–6756.
41 Roos, S. G.; Muller, A. H. E. Macromolecules 1999, 32,
8331–8335.
51 Chua, L. S.; Sarmidi, M. R. J. Mol. Catal.
111–119.
B 2004, 28,
42 Nakamura, K.; Yamanaka, R.; Matsuda, T.; Harada, T. Tetra-
hedron: Asymmetry 2003, 14, 2659–2681.
52 Ottosson, J. O.; Fransson, L.; King, J. W.; Hult, K. Biochim.
Biophys. Acta 2002, 1594, 325–334.
43 Kroutil, W.; Mang, H.; Edegger, K.; Faber, K. Curr. Opin.
Chem. Biol. 2004, 8, 120–126.
53 Nakamura, K.; Takebe, Y. S.; Kitayama, T.; Ohno, A. Tetrahe-
dron Lett. 1991, 32, 4941–4944.
44 Naik, H. G.; Yeniad, B.; Koning, C. E.; Heise, A. Org. Biomol.
Chem. 2012, 10, 4961–4967.
54 Chen, C.-S.; Sih, C. J. Angew. Chem. Int. Ed. Engl. 1989, 28,
695–707.
10
JOURNAL OF POLYMER SCIENCE PART A: POLYMER CHEMISTRY 2012, 000, 000–000