Organocatalytic tunable amino acid polymers prepared by controlled radical polymerization

Article abstract of DOI:10.1021/ma1008447

Two families of organocatalytically active polystyrene-based copolymers with tunable incorporations of 4-hydroxyproline have been synthesized using two different controlled radical polymerization technologies: nitroxide-mediated polymerization (NMP) and reversible addition-fragmentation chain transfer (RAFT) polymerization. Both of these methodologies allow ready access to a number of polymeric species with controllable molecular weights, narrow molecular weight distributions (ca. 1.2), and reliable functionality incorporations (between 3 and 26%). The organocatalytic activity and selectivity of the NMP-derived family of copolymers with variable incorporations of l-proline have been investigated using the aldol reaction, which provided high conversion to products (>95%) with very good diastereo- and enantioselectivities. We propose that these materials have potential as highly efficient recoverable organocatalyst supports whose solubility and loading can be readily tailored to the desired application.

Full text of DOI:10.1021/ma1008447

6374 Macromolecules 2010, 43, 6374–6380
DOI: 10.1021/ma1008447
Organocatalytic Tunable Amino Acid Polymers Prepared by Controlled
Radical Polymerization
Amanda C. Evans,† Annhelen Lu,‡ Courtney Ondeck,† Deborah A. Longbottom,*,† and
Rachel K. O’Reilly*,‡
†Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, U.K., and
‡Department of Chemistry, University of Warwick, Gibbet Hill Road, Coventry CV4 7AL, U.K.
Received April 16, 2010; Revised Manuscript Received June 24, 2010
ABSTRACT: Two families of organocatalytically active polystyrene-based copolymers with tunable incorpora-
tions of 4-hydroxyproline have been synthesized using two different controlled radical polymerization techno-
logies: nitroxide-mediated polymerization (NMP) and reversible addition-fragmentation chain transfer (RAFT)
polymerization. Both of these methodologies allow ready access to a number of polymeric species with con-
trollable molecular weights, narrow molecular weight distributions (ca. 1.2), and reliable functionality incorpora-
tions (between 3 and 26%). The organocatalytic activity and selectivity of the NMP-derived family of copolymers
with variable incorporations of L-proline have been investigated using the aldol reaction, which provided high
conversion to products (>95%) with very good diastereo- and enantioselectivities. We propose that these
materials have potential as highly efficient recoverable organocatalyst supports whose solubility and loading can
be readily tailored to the desired application.
Introduction
-Proline and L-proline derivatives such as 4-hydroxy-L-proline
intermediate. In order to maintain
groups, the majority of reported organocatalytically active proline-
based polymers have involved the attachment of a single -proline
L-proline’s key active functional
L
L
(Figure 1) are well-established organocatalytic species, able to
catalyze a number of chemical transformations in a highly effi-
cient and enantioselective manner.1 These transformations, which
usually proceed in high yield and result in high diastereo- and
enantioselectivities, include key organic reactions such as the
aldol reaction, Michael addition, and Robinson annulation,
among many others. For a more comprehensive overview of
organocatalysis, see the following recent reviews in the area.2-19
derivative to a preformed polymer or bead, with polystyrene
(PS)26-29 and poly(ethylene glycol) (PEG)30-32 dominating as
supports for covalent attachment.33,34
L-Proline derivatives have
also been supported on dendrimers35-37 and peptides38,39 and
incorporated into ionic liquids40,41 in order to produce highly
selective supported organocatalysts. Although a number of these
approaches facilitate the incorporation of specific loadings, they do
not generally allow for the addition of a second reactive center to the
support.
L-Proline is known to behave as a bifunctional substrate, and its
nucleophilic secondary amine group in combination with the
Brønsted acid activity of its carboxylic acid group renders it a
particularly selective and efficient organocatalyst.
Most recently, suspension copolymerization techniques have
been used by Hansen and co-workers to synthesize methacrylate
polymer beads incorporating L-proline derivatives and other
The controllable incorporation of L-proline-derived monomer
organocatalytically active species. A high degree of selectivity
and reactivity of this family of copolymers has then been
demonstrated in a variety of reaction contexts.42-45 This poly-
merization technique does result in functional monomer incor-
poration that is a direct reflection of equivalents of monomer
added although it does not readily allow for the synthesis of more
complex polymer architectures such as block copolymers. In
addition, recent work by Gallardo described the synthesis of
hydroxyproline-based methacrylic polybetaines and their cataly-
tic activity in pure organic solvents.46
We are interested in developing the use of controlled radical
polymerization techniques such as NMP47-50 and RAFT51-59
for the synthesis of further tunable organocatalytic polymers.
Both NMP and RAFT are highly tolerant of functional groups
and allow for the controlled polymerization of prefunctionalized
monomers that yield well-defined polymers with unique proper-
ties and capabilities. In addition, the ability of CRP to allow for
the chain extension and selective chain end functionalization
of polymers is an important feature in the future applications
of these materials. Copolymerization using both NMP and RAFT
is well-precedented and facilitates access to a broad range of
tunable polymeric architectures. In the case of RAFT-derived
units into highly defined polymeric species holds great interest for
polymer and organic chemists alike. Such polymers could be
readily used as diastereo- and enantioselective organocatalysts,
with their degree of active monomer incorporation controllable,
or tunable, via the copolymerization reaction. By altering both
incorporations and polymeric backbones, these materials may be
tuned to be environment or stimuli-responsive substances, allow-
ing for solution-phase product evolution and facile recycling of
the organocatalytically active polymer species.
Until recently, controlled radical polymerization had not been
used to incorporate proline-derived monomer units into copolymers
in a manner that would leave these key organocatalytically active
functional groups available to stabilize reaction transition states.20,21
Endo and co-workers have reported the use of controlled radical
polymerization techniques to facilitate the incorporation of both
proline and hydroxyproline units into polyacrylamide backbones
using the amino group as a functional tether;22-25 however, this
monomer incorporation strategy prevents the amino nitrogen from
playing its necessary role in the formation of the catalytic enamine
*Corresponding authors. E-mail: dal28@cam.ac.uk (D.A.L.); r.k.o-reilly@
warwick.ac.uk (R.K.O.).
pubs.acs.org/Macromolecules
Published on Web 07/09/2010
r 2010 American Chemical Society

Article
Macromolecules, Vol. 43, No. 15, 2010 6375
filtered through a plug of silica prior to use and stored at -5 °C.
AIBN (2,20-azo-bis(isobutyronitrile)) was recrystallized twice from
methanol and stored in the dark at 4 °C. Universal alkoxyamine
initiator (N-tert-butyl-O-(1-(4-(chloromethyl)phenyl)ethyl)-N-
(2-methyl-1-phenylpropyl)hydroxylamine), pyrene-functionalized
RAFT initiator (3), and (2S,4R)-dibenzyl 4-hydroxypyrrolidine-
1,2-dicarboxylate were prepared as reported in the literature.20,50
Dialysis tubing was purchased from Medicell International Ltd.
with a molecular weight cutoff of 7 kDa. 1H NMR spectra were
recorded at 400 or 500 MHz on a Bruker Avance DPX-400/
DPX-500 spectrometer using CDCl3 and d6-DMSO. For spectra
recorded in CDCl3, residual protic solvent CHCl3 (δH=7.26 ppm)
was used as an internal reference. 13C NMR spectra were recorded
on the same spectrometers at 100 or 125 MHz, using the central
resonance of CDCl3 (δC=77.0 ppm) as the internal reference. For
spectra recorded in d6-DMSO, residual protic solvent DMSO
(δH = 2.50 ppm) was used as an internal reference. 13C NMR
spectra were recorded on the same spectrometers using the central
resonance of d6-DMSO (δC=39.7 ppm) as the internal reference.
Size exclusion chromatography/gel permeation chromatography
(SEC/GPC) measurements were performed using a Viscotek
VE1122 solvent delivery system with a Viscotek VE3580 refractive
index detection system using tetrahydrofuran as an eluent at a flow
rate of 1 mL/min, unless otherwise stated. The molecular weights
of polymers were calculated relative to 10 polystyrene standards
(Mp 580-377 400 Da) with two PLgel 5 μm mixed C columns
(300 mm ꢀ 7.5 mm).
Figure 1. Structures of L-proline and 4-hydroxy-L-proline.
copolymers, further structural diversity can be introduced at the
polymer chain end via postpolymerization modification of the
thiocarbonyl end groups.60 The application of these controllable
polymerization techniques should allow for the incorporation of
organocatalytically active species, such as L-proline and its deri-
vatives, into copolymeric species in a highly tolerable and tunable
manner.
To this end, in 2009 our groups reported the application of
RAFT polymerization chemistries for the synthesis of proline-
functionalized polystyrenes in both mono- and bis-protected
forms.20 In this work 4-hydroxyproline provided a useful starting
point for monomer construction, as the 4-hydroxy group afforded
a means for attachment that would leave both amine and carboxy-
late functional groups available to potentially provide organo-
catalytic activity. However, racemization of the key stereocenter at
C2 was observed during monomer synthesis, a phenomenon that
did not impact that original work but did imply that an alternative
strategy for monomer generation would be necessary in order to
ensure that only enantiomerically pure monomeric units would be
incorporated into polymer, an essential feature for the creation of
organocatalytic materials.
Infrared spectroscopy was recorded on a Perkin-Elmer Spec-
trum 100 FT-IR spectrometer. UV-vis spectra were recorded on a
Varian Cary 4000 UV-vis spectrophotometer in tetrahydrofuran
unless otherwise stated. HPLC analysis was performed using
supercritical fluid chromatography (SFC) on a Berger Minigram
using a Chiralpak ADH column (0.46 ꢀ 25 cm). Specific rotation
measurements were recorded in CHCl3 on a Perkin-Elmer 241
polarimeter using a sodium source (λ=589 nm). Mass spectroscopy
data were obtained on a Bruker MicroTOF ESI. Microanalyses
were performed using a CE-440 elemental analyzer. Hydrogenation
was performed using a 100 mL Roth reactor at varying temperatures
under varying atmospheres of hydrogen.
Thus, our new synthetic strategy for the preparation of
L-proline-derived monomer units involves the use of an alter-
native coupling strategy which ensures the chirality of the proline is
maintained upon tethering to the styrene scaffold. Herein we report
the successful and tunable incorporation of a novel L-proline-
derived styrenic monomer unit into polystyrene using two con-
trolled radical polymerization techniques: nitroxide-mediated poly-
merization (NMP) and reversible addition-fragmentation chain
transfer (RAFT) polymerization. We have employed a chain trans-
fer agent (CTA) for our RAFT-mediated polymerizations that
incorporates a pyrene moiety into the copolymer chain end. This
widely employed fluorescent “reporter group” enables facile deter-
mination of end-group fidelity and tracking of the functional poly-
mer in solution. These functional copolymers were then success-
fully deprotected, unveiling the amine and acid functionalities
simultaneously, and their utility as highly selective organocatalytic
materials is subsequently reported.
(2S,4R)-Dibenzyl 4-(4-vinylbenzoyloxy)pyrrolidine-1,2-dicarboxy-
late (1). A solution of 4-vinylbenzoic acid (1.0 g, 6.76 mmol, 1.20
equiv), EDCI HCl (1.30 g, 6.76 mmol, 1.20 equiv), and DMAP
3
(0.14 g, 1.1 mmol, 0.2 equiv) in DMF (10 mL) was added to a dry
round-bottomed flask and stirred for 1 h until the solution changed
from cloudy to transparent. Then a solution of (2S,4R)-dibenzyl
4-hydroxypyrrolidine-1,2-dicarboxylate (2.0 g, 5.6 mmol, 1.0 equiv)
and DIEA (1.53 g, 11.8 mmol, 2.1 equiv) in DMF (8 mL) was
added to the reaction. The reaction mixture was then stirred at
room temperature for 7 days, at which point it was quenched with a
saturated solution of cold ammonium chloride (10 mL), extracted
with EtOAc (3 ꢀ 10 mL), and dried (MgSO4), and the solvent was
removed in vacuo. The crude product was purified by flash column
chromatography (2:1, petroleum ether:EtOAc) to yield 1.96 g
(71%) of 1 as a white crystalline solid. 1H NMR (500 MHz,
d6-DMSO, 27 °C): δ 7.91 (2H, d, J=8.5 Hz, H-6), 7.60 (2H, d, J=
8.5 Hz, H-7), 7.41-7.26 (10H, m, Ar), 6.81 (1H, dd, J=17.5, 11.0
Hz, H-8), 6.01 (1H, d, J= 17.5, H-9b), 5.46 (1H, s, H-4), 5.43
(1H, d, J=11.0 Hz, H-9a), 5.18 (1H, s, Bn)*, 5.11 (1H, s, Bn)*, 5.08
(1H, s, Bn)*, 5.02 (1H, s, Bn)*, 4.59 (1H, 2t, J=7.5 Hz, H-2)*, 3.78
(2H, m, H-5a and H-5b)*, 2.63 (1H, m, H-3b)*, 2.37 (1H, m,
H-3a)* (asterisk denotes rotamers). 13C NMR (125 MHz, d6-
DMSO, 27 °C): δ 170.8, 164.5, 153.5, 141.4, 135.3, 131.2, 129.0,
128.9, 128.6, 127.6, 127.4, 127.3, 127.2, 127.1, 126.9, 126.2, 115.8,
(71.4 and 72.1)*, 66.4, 66.0, (56.9 and 57.2)*, (51.3 and 51.7)*, (34.7
and 35.7)* (asterisk denotes rotamers). 1H NMR (500 MHz, d6-
DMSO, 100 °C): δ7.91 (2H, d, J=8.0 Hz, H-6), 7.60 (2H, d, J=8.0
Hz, H-7), 7.42-7.23 (10H, m, Ar), 6.83 (1H, dd, J=17.0, 11.0 Hz,
H-8), 5.94 (1H, d, J=17.0, H-9b), 5.50 (1H, br s, H-4), 5.43 (1H,
d, J=11.0 Hz, H-9a), 5.15 (2H, s, Bn), 5.12 (2H, m, Bn), 4.61 (1H,
t, J=7.5 Hz, H-2), 3.82 (1H, dd, J=10.0, 5.0 Hz, H-5a), 3.75
The ability to accurately “tune” the degree of L-proline incor-
poration into our copolymers provides us with a means to control
and tune the solubility of our copolymers. One of the biggest
drawbacks of using proline as an organocatalyst is its limited
solubility in organic solvents, a property that a number of
synthetic groups have addressed on a small-molecule scale.61-65
We have attempted to address this issue of solubility by creating
polymers with varying degrees of hydrophobicity and hydro-
philicity, depending upon the degree of incorporation of the
L-proline-derived monomer unit. This level of tuning provides us
with a series of polymeric organocatalysts with varying solubilities
that can be deployed, for example, under mild hydrophobic condi-
tions and that have the potential to be recovered by posthydrophilic
work-up. We propose that ultimately, by incorporating these sup-
ported catalysts into polymeric nanostructures, the materials can
thus be tuned to provide small enzyme-like hydrophobic “pockets of
reactivity” within an environmentally friendly aqueous environment.
Experimental Section
Unless otherwise stated, chemicals were used as received from
Aldrich, Fluka, and Acros. Styrene was distilled over CaH2 or

6376 Macromolecules, Vol. 43, No. 15, 2010
Evans et al.
(1H, m, H-5b), 2.61 (1H, m, H-3b), 2.38 (1H, m, H-3a). 13C NMR
(125 MHz, d6-DMSO, 100 °C): δ 170.8, 164.5, 153.5, 141.7, 135.4,
131.4, 129.2, 128.7, 128.4, 127.9, 127.8, 127.5, 127.3, 127.2, 126.8,
125.8, 116.8, 71.5, 66.4, 66.0, 57.5, 52.1, 35.4. Elem. Anal. Found C,
71.33; H, 5.61; N, 2.92 (C29H27NO6); expected C, 71.74; H, 5.61; N,
2.88. νmax(neat)/cm-1: 1737 (CdO ester), 1702 (CdO carbamate),
1496 and 1453 (CdC aromatic). HR-ESI: [M þ H]þ 486.1918
(Calcd), 486.1922 (Found). [R]2D5=-30 o (c=0.9, CHCl3).
Scheme 1. Synthesis of Monomer 1
General Procedure for the Polymerization of Styrene and
Functional L-Proline Monomer. A general polymerization pro-
tocol adapted from literature precedent is reported. A solution
of styrene (2.0 g, 0.019 mol), 1, and CTA 3 or NMP initiator was
added to a dry ampule containing a dry stirrer bar. The solution
was degassed using 3-5 freeze-pump-thaw cycles, backfilled
with nitrogen gas, sealed, and placed in a preheated oil bath at
the required temperature (110 °C for RAFT polymerizations
and 125 °C for NMP polymerizations). After a certain amount
of time, an aliquot was removed for 1H NMR analysis to deter-
mine percent conversion of monomer. The polymerization was
quenched by the addition of a minimal amount of tetrahydro-
furan (THF) and rapid cooling in liquid nitrogen. The THF/
polymer solution was precipitated dropwise into rapidly stirred
cold methanol (or petroleum ether), and the precipitated polymer
was isolated from the solvent by filtration and dried in a vacuum
oven at 40 °C overnight. Molecular weights and polydispersity
indices were measured by GPC, and 1H NMR spectroscopy was
used for the determination of end-group functionality, percentage
incorporation of monomer 1, and molecular weight determination
by integrating polymer backbone signals and characteristic mono-
mer 1 signals relative to characteristic end-group signals.
stir at room temperature for 2 days. This solution was then
directly precipitated into cold isopropanol and isolated by
filtration. The resulting pink precipitate was dried and analyzed
for successful removal of Cbz and Bn groups (disappearance of
1H NMR signals in the region δ 5.0-5.3 ppm (4Hp, m, CH2 on
Cbz and Bn)) (see Figure S5).
General Protocol for the Organocatalytic Application of NMP-
Derived Polymers to the Aldol Reaction. A sample of polymer
(26% incorporation, 10 mol %, 25 mg) was dissolved in DMSO
(0.75 mL); deionized water (0.25 mL) followed by 4 equiv of
cyclohexanone (103 μL, 1.0 mmol, 4.0 equiv) was then added,
and the solution was allowed to stir for 30 min. 4-Nitrobenzal-
dehyde (38 mg, 0.25 mmol, 1.0 equiv) was subsequently added,
and the reaction mixture was allowed to stir for 24 h at room
temperature. The reaction was quenched with aqueous lithium
bromide (10 mL, 4 wt %) and partitioned into ethyl acetate
(10 mL). The aqueous layer was extracted into ethyl acetate
(2ꢀ10 mL), and the organic layers were combined and dried
over MgSO4. Analysis of the aqueous layer by NMR and IR
analyses confirmed the presence of the polymer. The solvent
was removed in vacuo, and the crude residue was analyzed by
1H NMR for diastereomer ratios (syn:anti ratios calculated by
comparison of the integration of the signals at 5.4 ppm (syn)
with 4.9 ppm (anti)). The crude residue was then either directly
analyzed by supercritical fluid chromatography (SFC) or puri-
fied by column chromatography (2/1 to 1/1, 40-60 petroleum
ether/ethyl acetate).
(S)-2-((R)-Hydroxy(4-nitrophenyl)methyl)cyclohexan-1-one, 6.
1H NMR (400 MHz, CDCl3): δ 8.23 (2H, d, J=8.7 Hz), 7.53
(2H, d, J=8.7 Hz), 4.92 (1H, dd, J=8.4, 3.2 Hz), 4.10 (1H, d, J=
3.2 Hz), 2.35 (3H, m), 2.05 (1H, m), 1.53 (5H, m). 13C NMR (150
MHz, CDCl3): δ 214.8, 148.4, 147.6, 127.9, 123.6, 74.0, 57.2,
42.7, 30.8, 27.7, 24.7. HR-ESI: [M þ Na]þ 272.0901 (Calcd),
272.0908 (Found). [R]2D5=þ8.0° (c=1.3, CHCl3). HPLC: Daicel
Chiralpak AD-H, SFC (20% 1/1, isopropanol/ethanol in CO2),
2 mL/min recorded at 210 nm, 100 bar tR(minor)=10.50 min
and tR(major) = 14.42 min. Based on repeated injections the
errors in ee were estimated at ca. 4-5%. Based on the analysis of
multiple integrations, the errors in syn/anti ratio were estimated
at ca. 3%.
Representative Characterization Data for the Copolymeriza-
tion of Styrene and Monomer 1 Using NMP, Polymers 2a-e.
1H NMR (400 MHz, CDCl3): δ 2.32-0.85 (3 Hs þ 5Hp (polymer
backbone of 1 (3Hp), and CH2COC (2Hp)), 3.30-3.20 (1Heg, m,
PhCH of nitroxide end group), 3.90-3.73 (2Hp, br m, CH2-
NCbz), 4.60-4.50 (1Hp, d, CHCO2Bn), 5.27-5.01 (4Hp, m,
CH2 on Cbz and Bn), 5.50 (1Hp, s, CHOCO), 7.50-6.40 (5Hs
and 14Hp, m, aromatic peaks for styrene and 1), where Hs =
protons from polystyrene, Hp = protons from monomer 1 in
polymer, and Heg=protons from end group.
Representative Characterization Data for the Copolymeriza-
tion of Styrene and Functional Monomer 1 Using RAFT, Poly-
mers 4a-c. 1H NMR (400 MHz, CDCl3): δ 2.32-0.85 (3 Hs þ
5Hp (polymer backbone of 1 (3Hp), and CH2COC (2Hp)),
3.38-3.35 (2Heg, br m, CH2CO2CH2CH2S), 3.53-3.51 (2Heg,
br m, CH2CO2CH2CH2S), 3.90-3.80 (2Hp, br m, CH2NCbz),
4.24-4.23 (2Heg, br m, CH2 CH2CO2CH2CH2S), 4.60-4.50
(1Hp, d, CHCO2Bn), 5.23-5.01 (4Hp, m, CH2 on Cbz and Bn),
5.50 (1Hp, s, CHOCO), 7.50-6.40 (5 Hs, 4Hp, m, aromatic peaks
for styrene and 1), 8.15-7.84 (9Heg, m, pyrene signals on poly-
mer chain end).
General Protocol Used for All Percent Incorporations for the
Deprotection of NMP-Derived Polymers Using Hydrogenation.
Deprotection of NMP-derived polymers via hydrogenation was
attempted using several conditions. A portion of the polymer
(1.2 ꢀ 10-5 mmol, 1 equiv) was dissolved in 2 mL of solvent
(EtOAc, toluene, etc.), and 100 mg of palladium on carbon
(10 wt %) was then added. After 72 h, palladium was removed
by filtration through Celite or a Pore 4 frit, solvent was removed
in vacuo, and the resulting crude product was dried and analyzed
for successful removal of Cbz and Bn groups. Specifically, the
disappearance of 1H NMR signals in the region δ 5.0-5.3 ppm
(4Hp, m, CH2 on Cbz and Bn) was focused upon. This region of
the 1H NMR spectrum was compared to the original polymer to
determine the degree of deprotection.
Results and Discussion
Bis-Protected Monomer Synthesis, 1. In order to success-
fully incorporate a hydroxyproline-derived functionality
into a polystyrene-based copolymer, the catalytically active
acid and amino functional groups on the proline-derived
monomer were protected prior to controlled radical copoly-
merization. It was desirable to employ a universal deprotec-
tion strategy in order to reveal both of these functional groups
simultaneously once monomer incorporation into a polystyrene
backbone had been achieved: thus, benzyl carbamate and
benzyl ester were selected for this purpose.
General Protocol Used for All Percent Incorporations for the
Deprotection of NMP-Derived Polymers Using Hydrobromic/
Acetic Acid. A sample of NMP polymer (0.017 mmol, 1 equiv)
was taken up in 45% HBr in acetic acid (5 mL) and allowed to
Monomer 1 was readily synthesized in three steps and 24%
overall yield from commercially available 4-hydroxyproline

Article
Macromolecules, Vol. 43, No. 15, 2010 6377
Table 1. Summary of the Bulk NMP-Mediated Copolymerization of
Styrene with 1 at 125 °C
%
incorporation Mn(NMR),c Mn(GPC),d Mwd/
relative
sample equivalentsa
of 1b
kDa
kDa
Mn
2a
2b
2c
2d
2e
97:3:1
95:5:1
92.5:7.5:1
90:10:1
80:20:1
3
5
7
10
26
11.9
12.6
15.6
16.0
18.4
11.3
11.0
13.4
14.5
16.1
1.10
1.11
1.10
1.19
1.13
a Ratio of [styrene]:[1]:[alkoxyamine]. b Calculated by 1H NMR spectro-
scopy in CDCl3. c Calculated by 1H NMR spectroscopy in CDCl3.d Samples
were measured by GPC (THF) using polystyrene standards.
Kinetic studies using the alkoxyamine initiator for the
copolymerization of styrene and monomer 1 (95:5:1, [styrene]:
[1]:[alkoxyamine]) were performed in order to further evaluate
the polymerization. It was possible to determine the conversion
Figure 2. 1H NMR spectrum of monomer 1 in d6-DMSO (100 °C,
1
for both monomers during the polymerization by H NMR
500 MHz).
spectroscopy, and this was used to generate plots of ln([M]0/
[M]) against time for both 1 and styrene in the same copoly-
merization reaction. These plots confirmed pseudo-first-order
behavior of the copolymerization and indicated a constant
radical concentration during the polymerization. These kinetic
plots (Figure S1) also make explicit the increased polymeriza-
tion rate of 1 relative to styrene, with 1 polymerizing faster than
styrene (kp(styrene)=0.0056 min-1 and kp(1)=0.0152 min-1).
This indicates that the resultant polymers are composed of a
blocky-type structure. Evidence for controlled radical poly-
merization was also demonstrated by the linear dependence
of molecular weight (Mn) on overall percentage conversion
of both monomers by the close correlation of experimental
with theoretical molecular weight values and by the de-
creasing polydispersity indices with increasing conversion
(Figure S2).
RAFT-Mediated Copolymerization of Bis-Protected Mono-
mer 1 with Styrene. In order to widen the scope of the controlled
radical polymerization methods for the incorporation of bis-
protected monomer 1 into a polystyrene copolymer, we
proceeded to utilize RAFT-mediated in addition to NMP-
mediated polymerization techniques. An advantage of explor-
ing the RAFT polymerization method is the ready incorpora-
tion of functional units atthe polymer chainend:therefore, we
sought to incorporate a fluorescent handle into our polymer
structure using a pyrene-trithiocarbonate charge-transfer agent
(CTA, 3) which we have previously reported.20 This CTA can
be employed for polymer fluorescent labeling and was used in
a number of RAFT-mediated copolymerizations of styrene
and 1 to yield a range of copolymers (4a-c) with various
incorporations of 1 (Scheme 3).
Scheme 2. NMP of Cbz/Benzyl Proline Monomer 1 and Styrene
(Scheme 1). Carbamate protection of the secondary amine
was followed by benzylation of the carboxylic acid; the result-
ing bis-protected secondary alcohol was then coupled to 4-vinyl-
benzoic acid using standard esterification conditions, affording
desired monomer product 1. High-temperature NMR at 100 °C
resolved all rotameric effects observed in room temperature
spectra and confirmed that the revised monomer synthesis
maintains optical purity, resulting in a single diastereoisomer
of product 1 (Figure 2).
NMP-Mediated Copolymerization of Bis-Protected Mono-
mer 1 with Styrene. Incorporation of bis-protected monomer 1
into a polystyrene copolymer was achieved using two different
controlled radical polymerization strategies. Initially, we focused
on using NMP-mediated copolymerization techniques for the
incorporation of monomer 1 into a polystyrene backbone,
employing the well-established universal alkoxyamine initiator
reported by Hawker and co-workers (Scheme 2).49 Conditions
for such an NMP-mediated polymerization of monomer1 with
styrene were unprecedented at that time, but it was pleasing to
find that when standard conditions for the polymerization of
styrene were employed, well-defined polymers with a range of
tailorable incorporations of 1 were afforded (Table 1).
As the polymerization of similar styrene-functionalized
monomers had not been reported in the literature, a range of
reagent ratios were first investigated using standard RAFT
conditions for unfunctionalized styrenic derivatives. Using
these conditions, we thus optimized the copolymerization and
were able to obtain L-proline-functionalized copolymers with
controlled molecular weights and polydispersities (Table 2).
Monomer conversion was determined, as for the NMP-derived
1
Examination of the H NMR spectra of the copolymers
(2a-e) synthesized using NMP afforded ready identification
of the signals resulting from monomer 1 (specifically the two
benzylic singlets at 5.0-5.3 ppm) for quantification and con-
firmation of successful incorporation of monomer 1 into the
styrene backbone. Comparison of the integration of the peaks
assigned to the copolymer with those assigned to the NMP
end group (3.2-3.3 ppm, m, PhCH (nitroxide)) allows for
molecular weight determination, assuming complete end-
group fidelity. The polydispersities of all of the NMP-derived
polymers were low (1.1-1.2), and molecular weights deter-
mined by GPC analysis relative to polystyrene standards were
found to be in most cases quite close to those determined by
NMR analysis.
1
copolymers, by examination of H NMR data, comparing
polymer backbone integrals with those for characteristic
benzylic proton signals resulting from monomer1(twobenzylic
multipets at 5.0-5.2 ppm). Integral comparison between sig-
nals assigned to copolymer with the characteristic end-group
signals from the pyrene functionality (7.8-8.2 ppm) afforded
theoretical molecular weight estimates (Mn(NMR)) of the
resultant polymer, reliant upon the assumption of complete
end-group fidelity.

6378 Macromolecules, Vol. 43, No. 15, 2010
Scheme 3. RAFT-Mediated Copolymerization of Styrene and 1 Using a Pyrene-CTA, 3
Evans et al.
Table 2. RAFT-Mediated Bulk Copolymerization Conditions for
Styrene and 1
Scheme 4. Deprotection of Copolymers 2a, 2c, and 2e
%
incorporation Mn(NMR),c Mn(GPC),d Mwd/
relative
sample equivalentsa
of 1b
kDa
kDa
Mn
4a
4b
4c
95:5:1
92.5:7.5:1
90:10:1
5
7
9
10.2
9.7
12.5
9.2
8.3
11.7
1.15
1.16
1.19
a Ratio of [styrene]:[1]:[3]. b Calculated by 1H NMR spectroscopy in
CDCl3. c Calculated by 1H NMR spectroscopy in CDCl3. d Samples were
measured by GPC (THF) analysis using polystyrene standards.
Polymer Deprotection Strategies. In order to create an
organocatalytically active polymer-supported catalyst, it
was necessary to deprotect both the amine and the acid
groups of polymer-incorporated monomer 1 via the planned
simultaneous deprotection strategy. Initially hydrogenation
was employed to remove both carbamate (Cbz) and the
benzyl (Bn) protecting groups on both NMP and RAFT-
derived copolymers. However, it was disappointing to find
that thorough trials using a range of solvents, pressures,
temperatures, bases, and even sonification conditions pro-
vided only surprisingly poor results for both sets of polymers
2a-e and 4a-c (maximum ca. 25% deprotection), and
therefore an alternative method for protecting group re-
moval was required. The NMP-derived copolymers were
selected for this purpose, and results detailing this study
and subsequent catalytic trials are detailed below.
Deprotection of NMP-Derived Copolymers 2a-e. Follow-
ing the failure of hydrogenation conditions to remove the
two protecting groups, it was pleasing to find that simulta-
neous removal of both the carbamate and the benzyl pro-
tecting groups could be achieved upon exposure of the NMP
copolymer to a 45% solution of hydrogen bromide in acetic
acid over a 48 h period at ambient temperature (Scheme 4).
These conditions yielded complete deprotection of both Cbz
and Bn groups in high yield (80-92%) as confirmed by
disappearance of benzylic signals at 5.0-5.3 ppm in the
1H NMR spectrum (Figure S2). Using these conditions, we
were able to fully deprotect copolymers possessing 3, 7, and
26% incorporation of monomer 1 (from samples 2a, 2c, and
2e, respectively). In addition, the resulting copolymers 5a
and 5c were further analyzed by GPC analysis (with THF
as an eluent) and showed only a slight increase in poly-
dispersity from the starting polymer, which may be due to the
interaction of the functional groups with the columns used
for GPC analysis (Mw/Mn’s ca. 1.20) (Table S1). We were
unable to examine the higher loading polymer 5e using GPC
techniques, probably due to strong interactions of the free
L-proline units with the GPC columns used for analysis.
Organocatalytic Properties of NMP-Derived Copolymers.
In order to evaluate the organocatalytic properties of our
Scheme 5. Screening for Solvent Conditions for Aldol Condensation
Catalyzed by 4e
Table 3. Results for Solvent Screening Conditions
entry
solvent
% conversiona
syn/antib
% eec
1
2
3
4
5
6
7
8
THF
CH2Cl2
CH3CN
H2O
DMF
DMSO
DMF/water (1/1)
DMF/water (3/1)
DMF/water (1/3)
DMSO/water (3/1)
DMSO/water (1/3)
no reaction
no reaction
no reaction
18/82
15/85
11/89
3/97
3/97
5/95
3/97
8
52
31
95
95
98
99
96
84
82
91
94
94
94
97
97
9
10
11
5/95
a Evaluated by 1H NMR spectroscopy. b Evaluated by 1H NMR
spectroscopy. c Evaluated by SFC analysis.
copolymers, the well-precedented aldol reaction was chosen
for initial trials. These were conducted using the copolymer
5e, which has the highest loading of functionality (26%
incorporation by 1H NMR analysis). This incorporation of
functional polymer corresponds to a loading of ca. 1 mmol/g,
which compares well with typical literature loadings for
supported L-proline catalysis. We began our studies with a
solvent screen to optimize both diastereo- and enantioselec-
tivity for a commonly examined aldol reaction between cyclo-
hexanone and nitrobenzaldehyde (Scheme 5, Table 3).44
Normally, L-proline reactions are performed in polar sol-
vents to promote solubility of the organocatalyst, and fre-
quently polar aprotic solvents such as DMSO or DMF have
proven to be the optimal media in which to conduct these reac-
tions. In this case, given the high proline content unfortunately

Article
Macromolecules, Vol. 43, No. 15, 2010 6379
Scheme 6. Screening for Catalyst Loading Conditions
Scheme 7. Screening for Optimal Proline Loading Conditions
Table 4. Results for Catalyst Loading Screen
Table 5. Results for Optimal Loading Conditions Screen
entry polymer incorporation (%) % conversiona syn/antib % eec
entry
loading (mol %)
% conversiona
syn/antib
% eec
1
2
3
4
5
10
5
99
62
22
98
96
3/97
3/97
3/97
3/97
3/97
97
95
92
98
98
1
2
3
26 (5e)
7 (5c)
3 (5a)
99
97
95
3/97
5/95
5/95
97
97
98
1
5d
1e
a Evaluated by 1H NMR spectroscopy. b Evaluated by 1H NMR
spectroscopy. c Evaluated by chiral SFC analysis.
a Evaluated by 1H NMR spectroscopy. b Evaluated by 1H NMR
spectroscopy. c Evaluated by SFC analysis. d Reaction allowed to run
for 48 h. e Reaction allowed to run for 72 h.
evaluated. Of interest is that the lower incorporations of 1 in
copolymers 5a and 5c actually afforded increased organic sol-
vent solubility (in solvents such as chloroform and tetra-
hydrofuran), a highly sought-after property for L-proline-
derived organocatalysts, and a key result indicating the
solvent tunability of this family of copolymers for optimized
organocatalysis.
the polymer solubility was an issue in THF, CH2Cl2, and
MeCN (Table 3, entries 1-3), leading to no reaction in each
of these cases. Although 8% conversion was observed in
water (Table 3, entry 4), the hydrophobic nature of the poly-
styrene backbone prevented complete dissolution of the
copolymer and hence hindered organocatalytic activity. A
switch to DMF or DMSO afforded complete copolymer
dissolution, but over a 24 h time period only moderate to low
conversions were observed, albeit with fairly good diastereo-
and enantioselectivities (Table 3, entries 5 and 6). Given the
gradient structure of the copolymers, and the subsequent
hydrophobic/hydrophilic balance inherent within them, it
was postulated that subtle conformational effects which
hinder organocatalytic activity might exist in different sol-
vent systems. Therefore, it was thought that a means toward
optimizing solvent might be achieved by combining aqueous
with organic in order to allow complete dissolution and
organocatalyst exposure to substrate. Gratifyingly, when
solvent mixtures of either DMF or DMSO with water were
used, excellent conversions, diastereo- and enantioselecti-
vities were observed (Table 3, entries 7-11), and the optimal
system proved to be a 3:1 mixture of DMSO:water (Table 3,
entry 10), providing the desired aldol product 6 in 99%
conversion, 3/97 dr (syn/anti) and 97% ee (compared to the
reaction under identical conditions with L-proline which
afforded only 11% conversion, 14/86 dr (syn/anti) and
90% ee). It is interesting to note that further studies using
this solvent system have already demonstrated that the
reaction is at 40% conversion in 3 h, and more detailed
kinetic analysis is currently underway.
Catalyst loadings of 10, 5, and 1 mol % were then evaluated
for organocatalytic activity by varying the amount of added
polymer 5e, and it was found that in order to achieve efficient
(24 h) conversion, a 10 mol % loading of catalyst was optimal
(Scheme 6, Table 4). However, allowing extended reaction
times was found to result in negligible differences in conver-
sion as well as diastereo- and enantioselectivities when com-
paring the 10 mol % loading with both the 5 mol % and even
1 mol % loading. Thus, lower loadings of polymer organo-
catalyst can be used as long as extended reaction times are also
allowed.
Finally, different monomer 1 incorporations for the NMP-
derived copolymers (5a, 5c, and 5e) were evaluated for organo-
catalytic activity using a 10 mol % catalyst loading (Scheme 7,
Table 5). It was observed that the copolymers all demonstrated
excellent organocatalytic activity regardless of the percentage
incorporation of monomer 1, resulting in high conversions and
diastereo- and enantioselectivities for the three copolymers
Conclusions
We here report the successful incorporation of hydroxypro-
line-derived monomer units into a polystyrene backbone using
two different controlled radical polymerization techniques, NMP
and RAFT. These copolymers all demonstrate a high degree of
polymerization control, with low polydispersities and tunable
degrees of active monomer incorporation. The family of NMP-
derived copolymers has been deprotected and utilized in an organo-
catalytic intermolecular aldol reaction, resulting in very high con-
versions and excellent diastereo- and enantioselectivities. Given
the novelty and remaining scope of this work, a great deal remains
to be explored in future investigations. The organocatalytic activity
of the RAFT-derived copolymers remains to be evaluated, and a
thorough investigation of the material properties of both families
of copolymers as well as their correlation with monomer incor-
poration tuning must also be carried out. We propose that the
application of controlled radical polymerization techniques toward
the creation of unique tunable organocatalytic materials can be used
to incorporate other active organocatalytic monomers, and there
remain a variety of other reaction contexts in which both families of
copolymers reported here could be used as organocatalysts.
Acknowledgment. The EPSRC, Leverhulme Trust, and Royal
Society are thanked for financial support as are the University of
Cambridge and University of Warwick. D.A.L. thanks Homerton
College and the Department of Chemistry for support, A.C.E.
thanks Murray Edwards College, and C.O. thanks the Churchill
Foundation for supporting this work. Professor Steven V. Ley and
Dr. Richard Turner are thanked for SFC access and support. Alan
Dickerson and Dr. Patricia Irele are thanked for obtaining ele-
mental analysis data. The GPC equipment used in this research
was obtained through Birmingham Science City: Innovative Uses
for Advanced Materials in the Modern World (West Midlands
Centre for Advanced Materials Project 2), with support from
Advantage West Midlands (AWM) and part funded by the
European Regional Development Fund (ERDF).
Supporting Information Available: Figures showing the
kinetics of the NMP and RAFT polymerization of styrene and 1,
1H NMR spectra before and after deprotection, characterization
data for the polymers 5. This material is available free of charge via
the Internet at http://pubs.acs.org.

6380 Macromolecules, Vol. 43, No. 15, 2010
Evans et al.
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