Consequences of folding a water-soluble polymer around an organocatalyst

Article abstract of DOI:10.1002/anie.201207123

Give'em structure: The presence of structuring elements in polymers that were functionalized with catalytic units resulted in a new class of enzyme mimics, which are only active in the folded state (see picture). The conformationally adaptive hydrophobic

Full text of DOI:10.1002/anie.201207123

.
Angewandte
Communications
DOI: 10.1002/anie.201207123
Supramolecular Chemistry
Consequences of Folding a Water-Soluble Polymer Around an
Organocatalyst**
Elisa Huerta, Patrick J. M. Stals, E. W. Meijer,* and Anja R. A. Palmans*
Dedicated to Dr. Jef Vekemans on the occasion of his 65th birthday
Natureꢀs ability to perform catalytic reactions in a fast and
specific way has been a source of inspiration for chemists who
seek to enhance catalytic efficiency. In addition to small-
molecule catalysts, several artificial polymeric systems have
been developed in recent years based on the current under-
standing of the action of enzymes.[1] Foldamers,[2] dendrim-
ers,[3] and star polymers[4] are effective macromolecular
catalysts in organic solvents, and high enantioselectivities
are attained in a number of reactions. The ability of artificial
metalloenzymes,[5] DNA-based catalysts,[6] amphiphilic block
copolymers,[7] and micellar systems[8] to form hydrophobic
domains in water in order to significantly increase the
effectiveness of catalysts that are normally not compatible
with water has been explored. In these systems, the impor-
tance of isolating the site of the catalytically active center is
well recognized.
We recently introduced a novel concept that combines
classic polymer chemistry and supramolecular chemistry to
create polymers that fold ꢁon demandꢀ into a single-chain
polymeric nanoparticle (SCPN) that possesses a structured
inner compartment.[9] The benzene-1,3,5-tricarboxamide
(BTA) moiety was applied as the structuring unit in these
SCPNs. BTAs self-assemble into helical stacks, which are
stabilized by threefold intermolecular hydrogen bonding
between consecutive discs.[10] The introduction of Ru-based
complexes into the SCPNs allowed efficient transfer hydro-
genations in water.[11] However, the necessity of the hydro-
phobic compartment, which is created by the self-assembly of
the BTA units, to be conformationally adaptable for efficient
catalysis was not proven. Inspired by Class I aldolase
enzymes,[12] we explored the consequences of folding
a water-soluble polymer around an organocatalytic unit
based on l-proline (l-Pro), and discovered the importance
of structuring conformationally adaptive elements within an
SCPN to achieve efficient organocatalysis in water.
The effectiveness of many organocatalyts is often low in
water because of a lack of hydrophobic shielding. For
À
example, while l-Pro catalyzes a wide variety of C C bond
forming reactions, such as conjugated additions and aldol
reactions,[13] its efficiency in water is typically poor,[14] and low
yields/selectivities are obtained.[15] Herein, we show that
hydrophobic, structured compartments, which isolate the l-
Pro catalytic site from the bulk medium, are created through
folding of the polymer (Figure 1). The compartments provide
an appropriate environment for catalysis to occur, and they
bring substrates into close proximity to each other, thus
increasing the effective molarity.[16] The high local concen-
tration of substrates and catalytic sites in the interior of the
nanoparticles results in an unprecedentedly active catalyst,
thus allowing us to use low catalyst loadings at low substrate
concentrations.
By employing reversible addition–fragmentation chain-
transfer (RAFT) polymerizations,[17] we synthesized water-
soluble methacrylate random copolymer P1a, which contains
5% of l-Pro as catalytic units, 10% of chiral S-BTAs as
structuring elements, and 85% of oligo(ethylene glycol)
(OEG) units to ensure water-compatibility (Figure 1). The
self-assembly of BTAs into helical stacks in combination with
the hydrophobicity of the polymer backbone ensures the
folding of the polymer in water.[11] P1a was fully characterized
by 1H NMR spectroscopy, size-exclusion chromatography
(SEC, see Figures S1 and S4 in the Supporting Information),
dynamic light scattering (DLS, Figure S5 and Table S1), and
Maldi-TOF mass spectrometry (Figure S6). SEC shows
a number-average molecular weight (Mn) of 28.5 kDa and
a polydispersity index (PDI) of 1.56 (DMF, PEG standards),
while the DLS data show that P1a forms SCPNs in water with
a hydrodynamic radius of 6.3 nm.
The folding–unfolding behavior of BTA/l-Pro/OEG co-
polymer P1a in water was studied using temperature-
dependent ultraviolet (UV) and circular dichroism (CD)
spectroscopy. The transition from the unfolded state (high
temperatures, no BTA aggregation) to the folded state (low
temperature, aggregated BTAs) of polymer P1a in water is
clearly evidenced in the UV spectrum by a shift of lmax from
204 nm at 808C to 196 nm at 08C (Figure 2A). The folding
can be probed in more detail by CD spectroscopy, because of
the chirality of the BTA moiety. At room temperature, P1a
shows a negative Cotton effect at 223 nm, indicating helical
aggregates with a preferred left-handed (M) helical sense,[10a,d]
[*] Dr. E. Huerta, P. J. M. Stals, Prof. Dr. E. W. Meijer,
Dr. A. R. A. Palmans
Laboratory of Macromolecular and Organic Chemistry
Institute for Complex Molecular Systems
Eindhoven University of Technology
P.O. Box 513, 5600 MB Eindhoven (The Netherlands)
E-mail: e.w.meijer@tue.nl
a.palmans@tue.nl
[**] This work was supported by the European Research Council (ERC
Advanced Grant No. 246829), the National Research School
Catalysis (NRSC-C), and Marie Curie Actions SCPNANOPart FP7-
PEOPLE-2010-IEF-274668 (E.H.). Z. Brdid and T. F. E. Paffen are
acknowledged for their help in the synthesis. M. A. J. Gillissen and
J. L. J. van Dongen are acknowledged for fruitful discussions.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201207123.
2906
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 2906 –2910

Angewandte
Chemie
bonds that stabilize the helical stacks.[10] In addition, we
investigated the stability of the folded conformation of P1a
in conditions that we apply during catalysis (see below).
The addition of an excess of cyclohexanone (10 mL,
17000 equiv) in water as co-solvent does not interfere
with BTA stacking. In addition, the cooling curves before
and after the addition cyclohexanone are almost super-
imposable (Figure 2C and D, gray traces).
After establishing the polymer folding, we assessed the
catalytic activity of P1a in a model aldol reaction between
p-nitrobenzaldehyde and cyclohexanone (Table 1). Reac-
tions were carried out in water with an aldehyde concen-
tration of 50 mm and a variable amount of cyclohexanone
(Table 1, entries 1–3). With an aldehyde/ketone ratio of
1:10, the highest conversion was reached after 24 hours
(74%, Table 1, entry 2); an increase of the aldehyde/ketone
ratio to 1:50 resulted in a small decrease in conversion
(Table 1, entry 3). The diastereomeric excess (de) slightly
decreased upon increasing the aldehyde/ketone ratio
(Table 1, entries 1 and 2), while the enantiomeric excess
(ee) remained constant. In all cases, the aldol product was
obtained quantitatively after 120 hours with high diaste-
reoselectivity and moderate enantioselectivity (Table 1,
Figure 1. Chemical structure of l-proline-functionalized catalytic polymer
P1a (top) and schematic representation of the unfolded polymer and the
formation of the compartmentalized catalytic structure in water (bottom).
Table 1: Aldol reaction catalyzed by l-proline containing polymer P1a.[a]
Load.[b]
[mol%]
Ratio
a/k[c]
t
[h]
Conv.[d,e]
[%]
deanti
[%]
eeanti
[%]
[e]
[f]
Entry
1
2
3
4
5
6
7
1.6
1.6
1.6
1.6
1.6
1.6
0.8
1:5
24
24
24
120
120
120
120
30
74
52
99
99
98
88
94
90
90
92
91
91
91
70
71
n.d.
73
72
70
74
1:10
1:50
1:5
1:10
1:50
1:5
[a] Reactions were carried out in water (0.5 mL) at room temperature
using p-nitrobenzaldehyde (1 equiv, 0.025 mmol), cyclohexanone (5, 10
or 50 equiv), and catalytic polymer P1a. [b] Loading of catalytic polymer.
[c] Ratio of p-nitrobenzaldehyde (a) to cyclohexanone (k). [d] Conversion
of aldehyde into aldol product. [e] Determined by 1H NMR spectroscopy.
[f] Measured by HPLC on a chiral stationary phase (Chiralpak-IA) in
Figure 2. Spectroscopic characterization of polymer P1a in water.
A) UV and B) CD spectra at different temperatures; C) CD trace, and
D) CD signal versus temperature monitored at l=223 nm, of polymer
P1a (black traces) and P1a after addition of cyclohexanone (10 mL,
working conditions, grey traces). cBTA =50 mm, optical-path
length=0.5 cm.
hexane/THF=75:25, 1 mLminÀ1
.
entries 4–6). When the loading of the catalyst was decreased
by 50%, the system still exhibited good conversion and
selectivity after 120 hours (Table 1, entry 7).
and an intensity and shape similar to BTA/OEG-based
copolymers that lack the l-proline unit.[11] These observations
suggest that l-Pro does not interfere with the stacking of BTA
units within the polymer chain. As expected, the intensity of
the CD effect varies with temperature. At 808C, the CD
signal almost disappears, indicating the absence of stacked
BTAs (Figure 2B and D, black trace). Hysteresis was not
observed in the folding and unfolding of this polymer
(Figure S6). The full reversibility of this folding–unfolding
process accounts for the dynamic nature of the hydrogen
It is noteworthy that catalysis is efficient in this random
copolymer system, which comprises many different micro-
environments around the catalytic units. In fact, we expected
that differences in the polymer sequence, length or compo-
sition, can have a significant effect on the catalytic activity.
Thus, we prepared a variety of water-soluble copolymers,
P1b–e, P2, and P3, which contained different numbers of l-
proline as catalytic units per chain (see Table 2, and Schem-
es S3 and S4 in the Supporting Information).
Angew. Chem. Int. Ed. 2013, 52, 2906 –2910
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 2907

.
Angewandte
Communications
Table 2: Characteristics of the RAFTpolymers as determined by SEC, and
Table 3: Aldol reaction catalyzed by l-proline-containing polymer P1a.[a]
1H NMR and CD spectroscopy.
[e]
[f]
Entry
Polymer
Load.[b]
[mol%]
Ratio
a/k[c]
Conv.[d,e]
[%]
deanti
eeanti
[a]
[b]
Catalyst l-Pro BTA Mn
PDI[a] Mn
BTA[c] l-Pro[c]
CD[d]
[%]
[%]
[%]
[%] [kDa] (À)
[kDa]
[mdeg]
1
2
P1a
P1a
P1a
P1b
P1b
P1c
P1c
P1d
P1d
P1e
P1e
P2
1.6
1.6
1.6
1.0
1.0
1.0
1.0
1.6
1.6
1.6
1.6
0.5
0.5
2.4
2.3
1.4
1:5
1:10
1:5
1:5
1:10
1:5
1:10
1:5
1:10
1:5
1:10
1:5
1:10
1:10
1:10
1:10
30
74
0
94
92
–
0
33
0
70
71
–
P1a
P1b
P1c
P1d
P1e
P2
P3
PC1
PC2
5
5
5
5
5
10
2
2
10
10
10
10
10
10
10
0
28.5 1.56
37.1 2.19 135.2 19.2
38.5 2.19 140.9 20
27.6 1.48
27.5 1.56
44.5 1.58
40.7 1.28 110.0 20
34.9 1.28
21.9 1.30
58.3 12.2
6.1
9.6
10
5.9
5.9
19.7
4.2
À15
À13
À18
0
À14
À16
À21
n.a.
n.a.
3[g,i]
4
87
95
85
99
41
86
54
81
96
99
96
0
46(0)[h]
56.5 11.8
56.5 11.8
95.1 19.7
5
6
7
8
45(2)[h]
25(À29)[h]
0
41(À11)[h]
67
67
72
72
33
50
72
–
66
95.0
62.6
0
0
4.3
6.9
9
68
67
5
0
10
11
12
13
14[i]
15[i]
16[i]
70
[a] Determined by SEC in DMF with LiBr (10 mm), 1 mLminÀ1, PEG
standards. Measured before cleavage of tBoc group. [b] Based on
conversion determined by 1H NMR spectroscopy. [c] Average number of
units per polymer chain. [d] CD intensity at 223 nm and 208C at
BTA =50 mm in H2O, optical-path length=0.5 mm. n.a=not applicable.
DMF=N,N-dimethylformamide, PEG=poly(ethylene glycol).
55(6)[h]
P2
P3
PC1
PC2
54(2)[h]
63
–
–
c
0
–
[a] Reactions were carried out in water (0.5 mL) for 24 h at room
temperature, using p-nitrobenzaldehyde (1 equiv, 0.025 mmol), cyclo-
hexanone (5 or 10 equiv), and the catalytic polymer. In all the cases, the
overall concentration of l-proline in the reaction is the same (10 mol%).
[b] Loading of catalytic polymer. [c] Ratio of p-nitrobenzaldehyde (a) to
cyclohexanone (k). [d] Conversion of aldehyde into aldol product.
All polymers contained 10% of BTA units to promote the
folding into SCPNs. Polymers P1b and P1c contain the same
loading of l-Pro and S-BTA per chain (5 and 10%,
respectively) as P1a, but differ in length and polydispersity.
To evaluate the influence of a preferred helicity, P1d, which
bears achiral BTAs that form equal amounts of P and M
helical aggregates, was synthesized. In addition, the effect of
a higher content of apolar domains in the polymer chain was
evaluated with polymer P1e, which contains an additional
amount of hydrophobic propargyl groups (5%). On the other
hand, polymers P2 and P3, which contain 10 and 2% of l-Pro,
respectively, were used to investigate the effect of the local
concentration of catalytic units per polymer chain. As
a control, polymers PC1 and PC2, which contain 2 and 5%
of l-Pro, respectively, and 10% of n-dodecyl chains as a BTA
surrogate (Table 2, Scheme S5), were prepared in order to
assess the consequence of a dynamically folded compartment
for efficient catalysis.
The new series of (l-Pro/BTA/OEG)-based copolymers
was fully characterized using 1H NMR spectroscopy, SEC,
and DLS (Table 2 and Table S1). It is worth mentioning that
the proline methacrylate has a negative influence on the
control of the polymerization, and consequently the PDI.
DLS showed similar hydrodynamic radii for all the polymers,
even under working conditions (Table S1). UV and CD
spectroscopy gave spectra similar to that discussed for P1a:
BTAs are aggregated at room temperature and negative
Cotton effects for P1b, P1c, P1e, P2, and P3 indicate
a preferred M-helicity. Moreover, the intensity of the CD
signal at 223 nm (room temperature, cBTA = 50 mm in water) is
approximately the same for the polymers P1a–c, P1e, P2, and
P3. The magnitudes of the CD effect correspond well with
those of similar BTA/OEG-based copolymers that lack l-
proline, even in the case of P2, which contains twice as much
l-Pro per chain.[11] The CD cooling curves were measured for
all these polymers and showed the same type of behavior
(Figures S9–S15 in the Supporting Information).
1
[e] Determined by H NMR spectroscopy. [f] Measured by HPLC on
a chiral stationary phase (Chiralpak-IA) in hexane/THF=75:25,
1 mLminÀ1, l=269 nm. [g] Reaction conducted in CHCl3 (0.5 mL).
[h] The ee value measured for the syn diasteromer is given in brackets.
[i] Conversion measured after 120 h.
water at room temperature and with an aldehyde concen-
tration of 50 mm. The overall concentration of l-Pro sites was
identical in all cases (Table 3). In general, there are notable
differences between polymers that appear rather similar.
Polymers P1b (Mn,GPC = 37.1 kDa) and P1c (Mn,GPC
38.5 kDa) showed significantly higher conversions after
24 hours (Table 3, entries 3–6) compared to P1a (Mn,GPC
=
=
28.5 kDa, Table 3, entries 1 and 2). Interestingly, the catalytic
reaction that was performed with these polymers, was not
diastereoselective anymore, and the enantioselectivity was
significantly reduced. In addition, polymers P1d and P1e,
which have similar molecular weights as P1a (P1d: Mn,GPC
=
27.6 kDa, P1e: Mn,GPC = 27.5 kDa), showed similar conver-
sions after 24 hours. P1d resulted in a moderated diastereo-
selectivity (67%, Table 3, entries 7 and 8) compared to that
obtained with P1a (94%, Table 3, entry 1). When P1e was
employed (Table 3, entries 9–10), a slight increase in diaste-
reoselectivity (72%) was observed compared to P1d, whereas
the enantioselectivity (67%) remained the same. The results
of the catalysis with P1d, which bears achiral BTAs, can be
rationalized as follows: either the chirality of the pocket does
not affect the stability of the transition state of the con-
densation reaction, or the catalytic sites are too remote from
the helical stack to be affected. Because these polymers have
a random sequence of monomers in the chain, the proximity
of the chiral apolar domains to the catalytic sites is not
ensured. Therefore, the effect on the selectivity is almost
negligible.
The catalytic activity of all the aforementioned polymers
in the model aldol reaction was assessed by comparing the
conversions after 24 hours. All reactions were carried out in
The local concentration of catalytic l-Pro units per
polymer chain has a significant effect on the activity of the
2908 www.angewandte.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 2906 –2910

Angewandte
Chemie
catalysts. P2 and P3 showed an increase and decrease,
respectively, in activity compared to P1a. In fact, the activity
of polymer P2 is unprecedentedly high for a synthetic
polymer under these aqueous conditions.[15e–h] The aldol
reactions proceed very efficiently, even at substrate concen-
trations lower than 5 mm (see below) and loadings of the
catalytic polymer as low as 0.05 mol% (Table S3, entries 11–
20). The selectivity of polymer P3 is similar to that of P1e,
whereas P2 showed lower diastereo- and enantioselectivity
(Table 3, entries 11–13).
experiments were carried out at substrate concentrations
ranging from 10 mm to 2 mm to asses for Michaelis–Menten
behavior. The system showed saturation at a substrate con-
centration of around 5 mm. Above this value, the rate of the
reaction was constant (Figure S19). The catalytic polymer P2
showed an apparent Michaelis–Menten constant (KM,app) of
5.36 mm and an apparent catalytic constant (kcat,app) of
0.053 sÀ1 (see the Supporting Information for experimental
details).[22] The efficiency (Kcat,app/KM,app) of this system is
comparable to those of some aldolase mutants[12] and much
higher than those of computationally designed systems,[23]
although wild-type Class I aldolase enzymes are still supe-
rior.[12]
In conclusion, we introduced folded, catalytically active
polymers that behave comparable to an enzyme, as their
catalytic activity is only expressed in their folded conforma-
tion. The necessity for a structured and conformationally
adaptive environment around the catalytic center is shown by
a large number of reference experiments. Moreover, with the
model substrates selected here, recyclability becomes a very
simple process. The consequences of the enzyme-like behav-
ior of these catalytically active single-chain polymeric nano-
particles allowed us to obtain an exceedingly active catalyst.
Indeed, low catalyst loadings and substrate concentrations
can be used to achieve very efficient catalysis. However, the
system needs subtle optimization of the folded microstructure
around the catalytic site in order to control other features,
such as (stereo-)selectivity. With this contribution we are
opening the way for a new family of efficient and selective
enzyme-like catalysts. The effective shielding of the active site
makes these catalysts highly promising for multi-step cascade
reactions in water.[24]
Remarkably, only those polymers that contain the struc-
turing element showed catalytic activity. PC1 and PC2, which
lack the BTAunits, do not show any activity in water, not even
after long reaction times, thus signifying that the presence of
a structured, conformationally adaptable pocket is a require-
ment to achieve efficient catalysis. To further evaluate the
importance of compartmentalization, we carried out the
reaction with polymer P1a in chloroform, a solvent in which
BTAs do not aggregate (Table 3, entry 3, and Figure S16).[18]
At the low substrate concentration applied here, the polymer
did not exhibit any catalytic activity, and no conversion was
observed, even after long reaction times. This result is
consistent with our hypothesis that a high effective molarity
is crucial for this system to be active, and this is only achieved
in the folded state and in the presence of structured hydro-
phobic compartments. Furthermore, control experiments that
were performed with unsupported l-proline,[19] BTA/OEG-
based copolymer that lacks the l-proline unit, and a mixture
of unsupported l-proline and BTA/OEG-based copolymer[20]
(Table S2) did not yield any aldol product under similar
conditions. As in natural enzymatic systems, the catalytic
activity of this polymeric system is only expressed in the
folded state. However, in contrast to enzymes, this system
consists of randomly distributed catalytic sites and structuring
units.
Experimental Section
General procedure for aldol reaction in water: Catalytic polymer was
dissolved in deionized water (0.5 mL). Aldehyde (1 equiv,
0.025 mmol) and ketone (5 equiv, 0.125 mmol or 10 equiv,
0.25 mmol) were added to the solution and the mixture was stirred
at room temperature. Aldol products were extracted with diethyl
ether (3 ꢂ 1 mL) and dried under air. The crude products were
In order to show the usefulness of this catalytic system, we
also tested its recyclability with polymer P1e. For that, the
aldol reaction was carried out under the conditions previously
described. After 48 hours, the products were filtered off, fresh
substrates were added to the aqueous layer, which contained
the catalyst, and the reaction was continued for an additional
48 hours. After three consecutive cycles, the conversion was
higher than 90% and the diastereo- and enantioselectivities
remained unchanged (see Table S5 in the Supporting Infor-
mation). Degradation of l-proline was not observed in any of
the cases.[21] Thus, the catalyst can be easily recovered from
the aqueous phase after separation of the aldol products by
filtration and reused without additional purification.
We were intrigued by the general mechanism by which
these compartmentalized polymers catalyze the aldol reac-
tion, and whether it fits a Michaelis–Menten model. Thus, the
kinetic profile of the reaction between cyclohexanone and p-
nitrobenzaldehyde was measured at different substrate (alde-
hyde) concentrations in order to assess for enzyme-like
behavior. The kinetics experiments were carried out with P2,
because this polymer showed the highest activity. P2 showed
full conversion at an aldehyde concentration of 5 mm and
0.5 mol% loading of catalytic polymer after 96 h (Table S3,
entry 20 in the Supporting Information) Preliminary kinetic
1
analyzed by H NMR spectroscopy (CDCl3) and HPLC on a chiral
stationary phase (Chiralpak IA) without further purification.
Received: September 3, 2012
Revised: October 10, 2012
Published online: December 11, 2012
Keywords: enzyme mimics · foldamers · l-proline ·
.
nanoparticles · supramolecular chemistry
[1] a) J. Meeuwissen, J. N. H. Reek, Nat. Chem. 2010, 2, 615 – 621;
b) M. J. Wiester, P. A. Ulmann, C. A. Mirkin, Angew. Chem.
2011, 123, 118 – 142; Angew. Chem. Int. Ed. 2011, 50, 114 – 137.
[2] a) R. A. Smaldone, J. S. Moore, Chem. Eur. J. 2008, 14, 2650 –
2657; b) M. M. Mꢃller, M. A. Windsor, W. C. Pomerantz, S. H.
Gellman, D. Hilvert, Angew. Chem. 2009, 121, 940 – 943; Angew.
Chem. Int. Ed. 2009, 48, 922 – 925; c) G. Maayan, M. D. Ward, K.
Kirshenbaum, Proc. Natl. Acad. Sci. USA 2009, 106, 13679 –
13684; d) T. Hasegawa, Y. Furusho, H. Katagiri, E. Yashima,
Angew. Chem. Int. Ed. 2013, 52, 2906 –2910
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 2909

.
Angewandte
Communications
Angew. Chem. 2007, 119, 5989 – 5992; Angew. Chem. Int. Ed.
2007, 46, 5885 – 5888; e) Y. Akai, T. Yamamoto, Y. Nagata, T.
Ohmura, M. Suginome, J. Am. Chem. Soc. 2012, 134, 11092 –
11095; f) T. Yamamoto, T. Yamada, Y. Nagata, M. Suginome, J.
Am. Chem. Soc. 2010, 132, 7899 – 7901; g) T. Yamamoto, M.
Suginome, Angew. Chem. 2009, 121, 547 – 550; Angew. Chem.
Int. Ed. 2009, 48, 539 – 542; h) O. Altintas, C. Barner-Kowollik,
Macromol. Rapid Commun. 2012, 33, 958 – 971.
[11] T. Terashima, T. Mes, T. F. A. De Greef, M. A. J. Gillissen, P.
Besenius, A. R. A. Palmans, E. W. Meijer, J. Am. Chem. Soc.
2011, 133, 4742 – 4745.
[12] A. Heine, G. De Santis, J. G. Luz, M. Mitchell, C.-H. Wong, I. A.
Wilson, Science 2001, 294, 369 – 374.
[13] K. Sakthivel, W. Notz, T. Bui, C. F. Barbas III, J. Am. Chem. Soc.
2001, 123, 5260 – 5267.
[14] Catalytic activity has been shown in buffered aqueous media
with poor diasteroselectivity and no enantioselectivity: A.
Córdova, W. Notz, C. F. Barbas III, Chem. Commun. 2002,
3024 – 3025.
[15] l-Proline, when properly modified, exhibits good performance
in aqueous environment: a) Y. Hayashi, T. Sumiya, J. Takahashi,
H. Gotoh, T. Urushima, M. Shoji, Angew. Chem. 2006, 118, 972 –
975; Angew. Chem. Int. Ed. 2006, 45, 958 – 961; b) Y. Hayashi, S.
Aratake, T. Okano, J. Takahashi, T. Sumiya, M. Shoji, Angew.
Chem. 2006, 118, 5653 – 5655; Angew. Chem. Int. Ed. 2006, 45,
5527 – 5529; c) N. Mase, Y. Nakai, N. Ohara, H. Yoda, K. Takabe,
F. Tanaka, C. F. Barbas III, J. Am. Chem. Soc. 2006, 128, 734 –
735; d) M. Gruttadauria, F. Giacalone, A. M. Marculescu, P. L.
Meo, S. Riela, R. Noto, Eur. J. Org. Chem. 2007, 4688 – 4698;
e) E. G. Doyagꢃez, F. Parra, G. Corrales, A. Fernµndez-Mayor-
alas, A. Gallardo, Polymer 2009, 50, 4438 – 4446; f) E. G.
Doyagꢃez, G. Corrales, L. Garrido, J. Rodrꢆguez-Hernµndez,
A. Gallardo, A. Fernµndez-Mayoralas, Macromolecules 2011,
44, 6268 – 6276; g) T. E. Kristensen, K. Vestli, K. A. Fredriksen,
F. K. Hansen, T. Hansen, Org. Lett. 2009, 11, 2968 – 2971; h) A.
Lu, T. P. Smart, T. H. Epps III, D. A. Longbottom, R. K.
OꢀReilly, Macromolecules 2011, 44, 7233 – 7241; i) J. Paradow-
ska, M. Pasternak, B. Gut, B. Gryzło, J. Mlynarski, J. Org. Chem.
2012, 77, 173 – 187; j) B. H. Lipshutz, S. Ghorai, Org. Lett. 2012,
14, 422 – 425.
[3] a) S. Hecht, J. M. J. Frꢄchet, Angew. Chem. 2001, 113, 76 – 94;
Angew. Chem. Int. Ed. 2001, 40, 74 – 91; b) A. W. Bosman, H. M.
Janssen, E. W. Meijer, Chem. Rev. 1999, 99, 1665 – 1688; c) S. M.
Grayson, J. M. J. Frꢄchet, Chem. Rev. 2001, 101, 3819 – 3867;
d) B. Helms, J. M. J. Frꢄchet, Adv. Synth. Catal. 2006, 348, 1125 –
1148; e) B. Helms, E. W. Meijer, Science 2006, 313, 929 – 930;
f) K. Mitsui, S. A. Hyatt, D. A. Turner, C. M. Hadad, J. R.
Parquette, Chem. Commun. 2009, 3261 – 3263.
[4] a) B. Helms, S. J. Guillaudeu, Y. Xie, M. McMurdo, C. J. Hawker,
J. M. J. Frꢄchet, Angew. Chem. 2005, 117, 6542 – 6545; Angew.
Chem. Int. Ed. 2005, 44, 6384 – 6387; b) Y. Chi, S. T. Scroggins,
J. M. J. Frꢄchet, J. Am. Chem. Soc. 2008, 130, 6322 – 6323; c) V.
Rodionov, H. Gao, S. Scroggins, D. A. Unruh, A.-J. Avestro,
J. M. J. Frꢄchet, J. Am. Chem. Soc. 2010, 132, 2570 – 2572; d) T.
Terashima, A. Nomura, M. Ito, M. Ouchi, M. Sawamoto, Angew.
Chem. 2011, 123, 8038 – 8041; Angew. Chem. Int. Ed. 2011, 50,
7892 – 7895; e) T. Terashima, M. Ouchi, T. Ando, M. Sawamoto,
J. Polym. Sci. Part A 2010, 48, 373 – 379.
[5] M. Dꢃrrenberger, T. Heinisch, Y. M. Wilson, T. Rossel, E.
Nogueira, L. Knçrr, A. Mutschler, K. Kersten, M. J. Zimbron, J.
Pierron, T. Schirmer, T. R. Ward, Angew. Chem. 2011, 123,
3082 – 3085; Angew. Chem. Int. Ed. 2011, 50, 3026 – 3029.
[6] A. J. Boersma, J. E. Klijn, B. L. Feringa, G. Roelfes, J. Am.
Chem. Soc. 2008, 130, 11783 – 11790.
[16] a) D. M. Vriezema, M. C. Aragonꢄs, J. A. A. W. Elemans,
[7] a) B. M. Rossbach, K. Leopold, R. Weberskirch, Angew. Chem.
2006, 118, 1331 – 1335; Angew. Chem. Int. Ed. 2006, 45, 1309 –
1312; b) M. Bortenschlager, N. Schoellhorn, A. Wittmann, R.
Weberskirch, Chem. Eur. J. 2007, 13, 520 – 528; c) I. M. Okhap-
kin, E. E. Makheava, A. R. Khokhlov, Adv. Polym. Sci. 2006,
195, 177 – 210.
J. J. L. M. Cornalissen, A. E. Rowan, R. J. M. Nolte, Chem.
ˇ
´
Rev. 2005, 105, 1445 – 1490; b) I. Coric, B. List, Nature 2012, 483,
315 – 319.
[17] a) G. Moad, E. Rizzardo, S. H. Thang, Acc. Chem. Res. 2008, 41,
1133 – 1142; b) Handbook of RAFT-polymerization (Eds: C.
Barner-Kowollik), Wiley-VCH, Weinheim, 2008.
[18] (BTA/l-Pro/PEG)-based polymethacrylates do not aggregate in
solvents such as chloroform and a CD effect is therefore not
observed. See also reference [9c].
[8] a) K. T. Kim, J. J. L. M. Cornelissen, R. J. M. Nolte, J. C. M.
van Hest, Adv. Mater. 2009, 21, 2787 – 2791; b) T.-H. Ku, M.-P.
Cheng, M. P. Thompson, R. S. Sinkovits, N. H. Olson, T. S.
Baker, N. C. Gianneschi, J. Am. Chem. Soc. 2011, 133, 8392 –
8395; c) A. D. Ievins, X. Wang, A. O. Moughton, J. Skey, R. K.
OꢀReilly, Macromolecules 2008, 41, 2998 – 3006; d) A. C. Evans,
A. Lu, C. Ondeck, D. A. Longbottom, R. K. OꢀReilly, Macro-
molecules 2010, 43, 6374 – 6380; e) P. Cotanda, A. Lu, J. P.
Patterson, N. Petzetakis, R. K. OꢀReilly, Macromolecules 2012,
45, 2377 – 2384.
[19] l-proline and its derivatives can indeed catalyze aldol reactions
of a wide number of substrates in chloroform: a) J. T. Suri, S.
Mitsumori, K. Albertshofer, F. Tanaka, C. F. Barbas III, J. Org.
Chem. 2006, 71, 3822 – 3828; b) S. P. Mathew, M, Klussmann, H.
Iwamura, D. H. Wells, Jr., A. Armstrong, D. G. Blackmond,
Chem. Commun. 2006, 4291 – 4293; c) F. Capitta, A. Frongia, J.
Ollivier, P. P. Piras, F. Secci, Synlett 2011, 89 – 93; d) S. M. Sarkar,
Y. Taira, A. Nakano, K. Takahashi, J. Ishihara, S. Hatakeyama,
Tetrahedron Lett. 2011, 52, 923 – 927.
[20] Y. Chi, S. T. Scroggins, E. Boz, J. M. J. Frꢄchet, J. Am. Chem. Soc.
2008, 130, 17287 – 17289.
[21] N. Zotova, A. Franzke, A. Armstrong, D. G. Blackmond, J. Am.
Chem. Soc. 2007, 129, 15100 – 15101.
[22] Kcat gives a direct measure of the catalytic formation of product
under optimum conditions (saturated enzyme), and is described
as Vmax = Kcat[E]T. In this case, we considered [E]T as the total
concentration of the catalytic polymer under optimum condi-
tions.
[23] a) F. Tanaka, R. Fuller, C. F. Barbas III, Biochemistry 2005, 44,
7583 – 7592; b) L. Jiang, E. A. Althoff, F. R. Clemente, L. Doyle,
D. Rçthlisberger, A. Zanghellini, J. L. Gallaher, J. L. Betker, F.
Tanaka, C. F. Barbas III, D. Hilvert, K. N. Houk, B. L. Stoddard,
D. Baker, Science 2008, 319, 1387 – 1391.
[9] a) E. J. Foster, E. B. Berda, E. W. Meijer, J. Am. Chem. Soc.
2009, 131, 6964 – 6966; b) E. J. Foster, E. B. Berda, E. W. Meijer,
J. Polym. Sci. Part
A 2011, 49, 118 – 126; c) T. Mes, R.
van der Weegen, A. R. A. Palmans, E. W. Meijer, Angew.
Chem. 2011, 123, 5191 – 5195; Angew. Chem. Int. Ed. 2011, 50,
5085 – 5089.
[10] a) M. P. Lightfoot, F. S. Mair, R. G. Pritchard, J. E. Warren,
Chem. Commun. 1999, 1945 – 1946; b) L. Brunsveld, A. P. H. J.
Schenning, M. A. C. Broeren, H. M. Janssen, J. A. J. M. Veke-
mans, E. W. Meijer, Chem. Lett. 2000, 292 – 293; c) J. Roosma, T.
Mes, P. Leclꢅre, A. R. A. Palmans, E. W. Meijer, J. Am. Chem.
Soc. 2008, 130, 1120 – 1121; d) M. M. J. Smulders, A. P. H. J.
Schenning, E. W. Meijer, J. Am. Chem. Soc. 2008, 130, 606 – 611;
e) P. J. M. Stals, J. F. Haveman, R. Martꢆn-Rapffln, C. F. C. Fitiꢄ,
A. R. A. Palmans, E. W. Meijer, J. Mater. Chem. 2009, 19, 124 –
130; f) P. J. M. Stals, M. M. J. Smulders, R. Martꢆn-Rapffln,
A. R. A. Palmans, E. W. Meijer, Chem. Eur. J. 2009, 15, 2071 –
2080.
[24] B. Voit, Angew. Chem. 2006, 118, 4344 – 4346; Angew. Chem. Int.
Ed. 2006, 45, 4238 – 4240.
2910 www.angewandte.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 2906 –2910