L-proline functionalized pH-responsive copolymers as supported organocatalysts for asymmetric aldol reaction in water

Article abstract of DOI:10.1016/j.reactfunctpolym.2020.104544

pH-Responsive copolymers with reversible transformation ability have been investigated as new effective carriers for L-proline to catalyze asymmetric aldol reaction in water. A series of block copolymers of mPEG-b-P(DEA_x-co-L-ProlA_y)

Full text of DOI:10.1016/j.reactfunctpolym.2020.104544

Journal Pre-proof
L-proline functionalized pH-responsive copolymers as supported
organocatalysts for asymmetric aldol reaction in water
Yu Tang, Qinya Wang, Lexuan Wu, Kuan Liu, Wenjing Wang,
Yinghua Shen, Yuyuan Xue, Sheng Dai
PII:
S1381-5148(19)31319-7
DOI:
https://doi.org/10.1016/j.reactfunctpolym.2020.104544
REACT 104544
Reference:
To appear in:
Reactive and Functional Polymers
Received date:
Revised date:
Accepted date:
9 December 2019
27 February 2020
2 March 2020
Please cite this article as: Y. Tang, Q. Wang, L. Wu, et al., L-proline functionalized
pH-responsive copolymers as supported organocatalysts for asymmetric aldol reaction
in water, Reactive and Functional Polymers (2019), https://doi.org/10.1016/
j.reactfunctpolym.2020.104544
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2019 Published by Elsevier.

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L-proline functionalized pH-responsive copolymers as supported
organocatalysts for asymmetric aldol reaction in water
1
1
1
1
1
1,
Yu Tang , Qinya Wang , Lexuan Wu , Kuan Liu , Wenjing Wang , Yinghua Shen *,
1
2,
Yuyuan Xue , Sheng Dai *
1
College of Chemistry and Chemical Engineering, Taiyuan University of Technology,
Taiyuan 030024, China.
2
Department of Chemical Engineering, Brunel University London, Uxbridge, UB8
3
PH, United Kingdom.
*
Corresponding author: Yinghua Shen (E-mail: shenyinghua@tyut.edu.cn); Sheng
Dai (E-mail: sheng.dai@brunel.ac.uk).
ABSTRACT
pH-Responsive copolymers with reversible transformation ability have been
investigated as new effective carriers for L-proline to catalyze asymmetric aldol
reaction in water. A series of block copolymers of mPEG-b-P(DEAx-co-L-ProlAy)
(
mPEG-PDL) bearing L-proline catalytic sites and pH-responsive poly
(diethylaminoethyl methacrylate) (PDEA) segments were synthesized by the
reversible addition-fragmentation chain transfer (RAFT) polymerization in the
presence of methyl polyethylene glycol (mPEG) trithiocarbonate macro-RAFT agent.
The pH-induced self-assembly behaviors of three copolymer catalysts with different
contents of PDEA, were investigated via the combination of UV-visible spectrometer
(UV-vis), dynamic light scattering (DLS) and transmission electron microscopy
(TEM). Catalytic activity and stereoselectivity of these copolymer catalysts were
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evaluated by direct asymmetric aldol reaction of p-nitrobenzaldehyde and
cyclohexanone in water. The results indicated that catalytic activity and
stereoselectivity effected by the pH value of aqueous solution and the structures of
copolymer catalyst assemblies. mPEG-PDL-2 give the aldol product with high conv.,
yield, anti/syn, and ee (92%,91%, 92/8, 96%), respectively at pH 7.0. Furthermore,
these pH-responsive copolymers supported L-proline are easily recycled by a
reversible phase transition.
Keywords: L-Proline, pH Responsiveness, Self-assembly, Catalysis, Aldol reaction
1
Introduction
L-Proline has been widely used as a chiral organocatalyst for asymmetric aldol
reactions with a range of ketones and aldehydes [1–3]. However, the large amount of
L-proline loading and difficulty associated with recycling have undermined its wide
application in industry. In addition, the high catalytic efficiency of L-proline to aldol
reaction could only be accomplished in organic solvents or in presence of trace
amount of water rather than in aqueous environment [4–7]. In attempts to sort out
these issues, L-proline was anchored onto various carriers to catalyze direct
asymmetric aldol reaction, such as inorganic nanoparticles [8], ionic liquid [9] and
polymers [10].The use of polymer carrier, which could to an extent be considered as a
peptide-backbone mimic, is one of the most attractive approaches. The use of polymer
carrier not only facilitates catalysis performance but may also enlarge the application
of L-proline catalyzing reactions from organic solvents to water [11].
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In previous literatures, hydrophobic segments in supported L-proline polymers
generally create hydrophobic “pockets” in water as active center for water-insoluble
aldol reactants, where reactions could be significantly accelerated because of the
concentration of reactants through solubilization in the hydrophobic pockets [12–14].
However, the recycling process of these copolymer catalysts is complex, including
precipitation, collection and purification processes [15–17]. To improve the
recyclability of polymer supported L-proline, stimuli-responsive polymer attracted
more attention owing to its reversible phase transition under external stimulation [18].
In recent years, most reported cases of responsive polymer supported L-proline are
thermo-responsive copolymers [19], which could assemble to a variety of structures in
aqueous solution by changing temperature with their hydrophobic domains as
nanoreactors for organic reaction. Suzuki et al. [20] prepared thermo-responsive block
copolymers supported L-proline of thermo-responsive N-isopropylamide (NIPAM)
and hydrophilic oligo (ethylene glycol) methyl ether acrylate (OEGA), the
copolymers catalyzed direct asymmetric aldol reaction in water with 10 mol% catalyst
loading at 50 °C for 24 h (86% conv., 72/28 anti/syn and 96% ee). In order to improve
the conv. and stereoselectivity, we prepared P(NIPAM-co-L-ProlA)-b-POEGA with
three different POEGA block contents to catalyze the asymmetric aldol reaction in
water with 10 mol% catalyst loading at 50 °C for 24 h [21], and
P(NIPAM60-co-L-ProlA5)-b-POEGA15 showed the highest conv. (96%), anti/syn (94/6)
and ee (99%).
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In addition to thermo-responsive polymers, pH-responsive polymers have also
been studied extensively [22, 23]. This kind of polymer is responsive to external pH
and undergoes structural or property changes, such as surface activity, chain
conformation, solubility and configuration [24–26]. Prado et al. [27] studied the
amphoteric copolymer supported L-proline catalyzed aldol reaction. The research
showed that the hydrophobic aggregate was favorable for the formation of high
stereoselectivity near the isoelectric point, and the hydrophilicity of the aggregates
could increase the conv. effectively but reduce the stereoselectivity. To date, only a
few examples have been reported on pH-responsive polymer supported L-proline
catalyst with high activity and high stereoselectivity [14].
In this work, we report the synthesis of a series of L-proline functional
pH-responsive copolymers with diethylaminoethyl methacrylate (DEA) [28] as
pH-responsive monomer by RAFT polymerization using trithiocarbonate RAFT agent
(DDMAT) bearing methyl polyethylene glycol (mPEG). Phase transition, induced by
pH, and factors influenced the assembly structure were investigated. Subsequently,
the catalytic activity of synthesized copolymers supported L-proline were tested using
a model aldol reaction between p-nitrobenzaldehyde and cyclohexanone. In addition,
recycling performance of these copolymers catalysts was also investigated.
2
Experimental
2
.1. Materials
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N-tert-butoxycarbonyl-O-acryloyl-trans-4-hydroxy-L-prolinec and 2-(dodecyl
trisulfide carbonate) -2-methyl propionic acid (DDMAT) were prepared following the
literature [29, 30]. Diethylaminoethyl methacrylate (DEA) was purchased from
Sigma-Aldrich and purified by vacuum distillation. Methoxy poly (ethylene glycol)
(
mPEG) with a mean degree of polymerization (DP) of 22 (Mn = 1000 g/mol,
Mw/Mn=1.16) was purchased from Sigma-Aldrich. 2,2′-Azobis (isobutyronitrile)
AIBN) was recrystallized twice from ethanol. All the other chemicals were purchased
from Aladdin and used without further purification.
(
2
.2. Characterization
1
H NMR spectra were recorded on a Bruker DPX400 (400 MHz) spectrometer,
using CDCl3 as a solvent at room temperature. Gel permeation chromatography (GPC)
analysis were carried out on a Viscotek GPC Max Ve2001 solvent/sample module
equipped a TDA305 Triple detector, DAWN HELEOS 8 light scattering photometer,
Visco Star viscometer and Optilabr EX interferometric refractometer, and three
Mz-Gel SD plus 10 μm columns, tetrahydrofuran (THF) was used as eluent at a flow
rate of 1.0 mL/min at 25 °C and monodisperse polystyrenes were used as the
calibration standard. Optical rotation of these copolymers at 1 mg/mL was measured
by a Rodolph Autopol Ⅳ-T polarimeter. The circular dichroism (CD) was measured
using a JASCO J-720 spectropolarimeter. The critical micelle concentrations (cmc)
were determined by a Horiba Fluoromax 4 spectrofluorometer using pyrene probe at
room temperature. The emission spectra were recorded between 350 and 550 nm, and
the excitation wavelength was 335 nm. Dynamic light scattering (DLS) studies were
conducted using a Malvern Instruments Zeta sizer Nano ZS90 with a He-Ne laser
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(
633 nm) and 90° collecting optics. High performance liquid chromatography (HPLC)
was performed on a Waters ACQUITY UPC 2 ultraperformance chromatograph
equipped with five CHIRALCEL-OJ chiral columns, and 20 wt.% methanol was used
as eluent (1mL/min).
2
.3. Synthesis of mPEG-DDMAT
mPEG was conjugated with RAFT reagent by a condensation reaction. mPEG22
(
0.25 g, 0.25 mmol) was dissolved in dichloromethane (DCM) (10 mL) in a
three-neck flask and dried to remove the water. DDMAT (0.18 g, 0.5 mmol) and
-dimethylaminopyridine (DMAP, 0.03 g, 0.25 mmol) were added in an ice bath,
4
followed by adding dicyclohexyl carbodiimide (DCC, 0.21 g, 1.0 mmol) and allowing
to react at ambient temperature for 24 h. The dicyclohexylurea was removed by
filtration, the product was precipitated and dried at 30 °C under vacuum.
2
.4. Synthesis of P(DEA -co-N-boc-L-ProlA )
x
y
P(DEAx-co-N-boc-L-ProlAy) (N-boc protected PDL) was synthesized via RAFT
polymerization, as shown in Scheme S1. The ratio of [DEA]: [N-boc-L-ProlA]:
DDMAT]: [AIBN] was 100: 10: 1: 0.2. DDMAT (36.0 mg, 0.1 mmol), AIBN (1.64
[
mg, 0.01 mmol), DEA (1.85 g, 10 mmol), and N- boc-L-ProlA (286.5 mg, 1 mmol)
were dissolved in 1,4-dioxane (10 mL). The mixture was stirred at 70 °C for 17 h
under nitrogen atmosphere. The product (P(DEA23-co-N-boc-L-ProlA2)) was
precipitated by n-hexane and dried at 30 °C under vacuum.
2
.5. Synthesis of mPEG-b-P(DEA -co-N-boc-L-ProlA )
x
y
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mPEG-b-P(DEAx-co-N-boc-L-ProlAy) (N-boc protected mPEG-PDL) were
synthesized
via
RAFT
polymerization
(Scheme
1).
mPEG-b-P(DEA54-co-N-boc-L-ProlA4) (N-boc protected mPEG-PDL-2) was
synthesized under [DEA]: [N-boc-L-ProlA]: [mPEG-DDMAT]: [AIBN] = 200: 10: 1:
0
1
.2. mPEG-DDMAT (136.5 mg, 0.1 mmol), AIBN (1.6 mg, 0.01 mmol), DEA (1.9 g,
0.0 mmol) and N-boc-L-ProlA (286.5 mg, 1.0 mmol) were dissolved in 1,4-dioxane
(10.0 mL). The mixture was stirred at 70 °C for 17 h under nitrogen atmosphere.
N-boc protected mPEG-PDL-2 was precipitated by n-hexane and dried at 30 °C under
vacuum. Preparation steps of N-boc protected mPEG-PDL-1 and N-boc protected
mPEG-PDL-3 were the same as above, and the feeding ratios were changed to [DEA]:
[N-boc-L-ProlA]: [mPEG-DDMAT]: [AIBN] = 100: 10: 1: 0.2 and [DEA]:
[N-boc-L-ProlA]: [mPEG-DDMAT]: [AIBN] = 400: 10: 1: 0.2, respectively.
2
.6. Deprotection of copolymer mPEG-b-P(DEA -co-N-boc-L-ProlA )
x
y
N-boc protected mPEG-PDL-2 (1.0 g) was dissolved in dichloromethane (10.0 mL)
and stirred at room temperature for 5 min. The whole system was placed in an ice
bath, trifluoroacetic acid (TFA, 10.0 mL) was added dropwise from an addition funnel
to the flask while stirring. The reaction was allowed to proceed for 3 h at the ambient
temperature. The product was washed and precipitated by n-hexane several times and
the yellow solid was obtained after drying at 30 °C under vacuum.
2
.7. Catalysis of aldol reaction
mPEG-PDL-2 (10 mol %, i.e. amount of L-proline on the polymer relative to
p-nitrobenzaldehyde) was dissolved in 1 mL water at a certain pH value (4.0, 7.0, or
-
4
9
.0). A mixture of p-nitrobenzaldehyde (1.54 × 10 mol) and cyclohexanone (7.7 ×
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-
4
1
0
mol) was sonicated until p-nitrobenzaldehyde was fully dissolved. Then, the
mixture was added to the above aqueous solution and reacted for 24 h at ambient
temperature, and CO2 was introduced to disassemble the copolymers. The aldol
product was separated from catalytic systems by extracting with 4 mL ice ether. The
organic phase was evaporated and purified by silica gel column chromatography
using petroleum ether and ethyl acetate (4:1, v/v) as eluents to afford the pure aldol
product. The yield is calculated by weighing the pure product. The reaction conv. and
1
anti/syn of crude products were determined by H NMR spectroscopy, and the
enantioselective was determined by HPLC.
2
.8. Recycling procedure
After the termination of the aldol reaction, the product was extracted and the
remaining copolymer aqueous system was used for next cycle of the catalytic reaction.
CO2 was exhausted from the copolymer aqueous solution by N2 bubbling until the pH
value to around 7.0. The remaining steps were the same as the above aldol reaction.
Scheme 1. Synthesis of mPEG-DDMAT and mPEG-PDL.
3
Results and discussion
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3
3
.1. Preparation and characterization of PDL and mPEG-PDL
.1.1. Catalystsynthesis
Based on previous research [20], the contents of hydrophobic moieties play an
important role in copolymer self-assembly and catalytic performance. To elucidate the
influence of PDEA length to catalytic performance, three copolymers with different
PDEA chain lengths were synthesized. These successful DEA chain propagation and
1
presence of functional L-proline were confirmed by FT-IR spectra, H NMR spectra
and GPC analysis.
The FT-IR spectra of mPEG-DDMAT and N-boc protected mPEG-PDL-2 are
shown in Fig. 1A. In Fig. 1A-(a), the C-O-C telescopic vibration band of
-
1
polyethylene glycol are located at 1100 cm [31]. The characteristic band of
-
1
mPEG-DDMAT at 1645 cm is detected due to C=O on the ester group. In Fig.
-
1
-1
1
A-(b), the new absorption bands at 1730 cm and 1171 cm correspond to the
vibration of C=O in PDEA and C-N stretching vibration in PDEA and L-proline,
-
1
respectively [32]. The bands at 2973, 2925, 2872 cm correspond to the asymmetric
CH3, asymmetric CH2 and symmetric CH2 stretching vibration of alkyl groups,
respectively. The successful synthesis of mPEG-DDMAT and mPEG-PDL-2 was
preliminarily confirmed by FT-IR analysis.
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Fig. 1. FT-IR spectra of mPEG-DDMAT (a) and mPEG-PDL-2 (b).
1
The H NMR characteristic peaks of mPEG-DDMAT and mPEG-PDL-2 can be
seen from Fig. 2. The chemical shift δ = 4.25 ppm (d) corresponds to the proton of the
methylene proton adjacent to the ester group (-CH2-O(C=O)), and δ = 3.62–3.64 ppm
(
b, c) is corresponding to methylene protons (-CH2-O-CH2-) of mPEG. In addition to
the characteristic peak of mPEG-DDMAT, the peak of PDEA ((-CH3) δ = 0.87 ppm(e),
-O-CH2-) δ= 4.0 ppm (f), (-N-CH2-) δ = 2.72 ppm (g)) can be observed in Fig. 2(b)
(
and (c), respectively. Based on comparison of Fig. 2(a) and 2(b), the peak at δ = 1.30
ppm (j) is proton peak in t-butyl ester group (-COOC(CH3)3) of protective group
(N-boc-) and the disappearance of the peak indicated that L-proline deprotection was
successful.
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1
Fig. 2. H NMR spectra of mPEG-DDMAT (a), N-boc protected mPEG-PDL-2 (b) and
mPEG-PDL-2 (c) in CDCl
3
.
The GPC traces of PDL and three mPEG-PDL are shown in Fig. 3, where
number-averaged molecular weight (Mn) increases with increasing the amount of feed
DEA monomer and are with relatively narrow molecular weight distributions (PDI =
1
.07–1.25). The tailored polymer chain length will be benefit for self-assembly in
water and provide microenvironment for aldol reaction.
The degree of polymerization (DP) and Mn of PDL and three mPEG-PDL were
calculated by integrating areas of the characteristic hydrogen peaks of PDEA,
1
N-boc-L-ProlA and mPEG-DDMAT in H NMR (Fig. S2–S4) and the results are
shown in Table 1.
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Fig. 3. GPC traces of PDL and three mPEG-PDL.
Table 1
Summary of synthesized mPEG-DDMAT, PDL, and three mPEG-PDL.
a
a
a
b
b
Sample
mPEG-DDMAT
PDL
DPDEA
-
DPN-boc-L-ProlA
M
n1 (kDa)
M
n2 (kDa)
1.1
PDI
1.07
1.14
1.22
1.19
1.25
-
1.4
25
2
2
4
3
4.7
2.9
mPEG-PDL-1
mPEG-PDL-2
mPEG-PDL-3
23
6.0
4.5
54
11.1
23.9
8.4
130
15.8
a
1
Calculated from H NMR spectroscopy.
b
Determined by GPC in THF using PS standard.
3
.1.2. Chiropticalproperty
The chiroptical properties of mPEG-PDL-2 were characterized by circular
dichroism (CD) and polarimeter measurement (Fig. 4). A positive absorption peak of
mPEG-PDL-2 is at around 207 nm, which corresponds to the special absorption peak
on L-proline around 215 nm. It can be seen that a negative absorption of
mPEG-PDL-2 is observed at around 209 nm. To explain this phenomenon, we
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examined the CD spectra of homopolymers PDEA and mPEG and found that similar
two negative signals appeared in two homopolymers curves, respectively. Therefore,
it is speculated that the negative peak, appearing on the CD spectrum of the
mPEG-PDL-2, is caused by the polymer skeleton [33, 34]. The slight blue-shift of
mPEG-PDL-2 is attributed to the minor structure change of trithiocarbonate
substitution groups after polymerization. The optical rotation (α) and specific rotation
2
5
2
-1
(
α ) of mPEG-PDL-2 are -0.0031(°) and -3.10 (°·cm ·g ), respectively (Table 2).
D
This is also consistent with the positive and negative values of L-proline molecule
[35]. In conclusion, mPEG-PDL-2 has the same chirality and optical activity as
L-proline molecule, and the copolymer also retains the catalytic properties of
L-proline.
Fig. 4. CD spectra of L-proline, PDEA, mPEG and mPEG-PDL-2 in water.
Table 2
2
5
Optical rotation (α) and specific optical rotation ([α] ) of L-proline and mPEG-PDL-2 aqueous
D
solution.
Sample
L-proline
mPEG-PDL-2
α
(° )
-0.0727
-0.0031
2
D
5
2
-1
[
α] (°·m ·g )
-72.7
-33.1
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3
.2. Self-assembly of copolymer catalysts
The copolymer hydrodynamic size distributions at pH values of 4.0, 7.0 and 9.0
were measured by DLS, as shown in Table 3. Taking mPEG-PDL-2 as an example,
the hydrodynamic size of the copolymer in water gradually increases with the increase
of pH value (Fig. 4 (b)). This is mainly due to deprotonation of the side tertiary amine
groups of PDEA segments, and the hydrophobicity of PDEA segments increased with
increasing pH values. [36–41]. TEM image of mPEG-PDL-2 at pH 7.0 in Fig. 4 (d)
indicates that assemblies are almost near-sphere and their average size is nearly 90 nm.
Moreover, the size determined by TEM is smaller than that by DLS, which could be
attributed to its shrinkage after water evaporation [42]. At the pH value of 4.0,
copolymers containing PDEA are hydrophilic after protonation and display
hydrodynamic sizes between 18 and 23 nm. When pH is 7.0 (close to the pKa value
(Figs. S5)), the hydrodynamic size of the copolymers gradually increases from 105 to
2
04 nm with the increasing hydrophobic PDEA block length. The hydrodynamic sizes
of three mPEG-PDL increase to 220, 243, and 344 nm at pH 9.0, respectively,
indicating that the tertiary amine groups are almost completely deprotonated and the
PDEA blocks become hydrophobic. This can be seen in optical photographs as well
(Figs. S6).
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Table 3
Hydrodynamic sizes of PDL and mPEG-PDL in aqueous solution.
Hydrodynamic size (nm)
Sample
pH=4.0
21
pH=7.0
102
pH=9.0
144
PDL
mPEG-PDL-1
mPEG-PDL-2
mPEG-PDL-3
20
105
220
18
154
243
23
204
344
Fig. 4. (A) Size distribution curves of mPEG-PDL-1, (B) mPEG-PDL-2, (C) mPEG-PDL-3 in
water at different pH value and (D) TEM image at pH value of 7.0 of mPEG-PDL-2.
3
.3. Copolymer catalysts for asymmetric aldol reaction
The catalytic activity and stereoselectivity of synthesized three copolymers
supported L-proline were assessed in a model reaction of p-nitrobenzaldehyde and
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cyclohexanone in water. The aldol reaction condition, such as catalyst dosage,
reactant feed ratio and reaction temperature were selected based on previous
researchers’ work [15, 17, 20] and our work [21, 44]. The reaction time was also kept
2
4 hours, because there is no obvious change in the conversion of
p-nitrobenzaldehyde by prolonging reaction (Table S1). With these optimum
conditions in hand, we then decide to vary the aqueous pH value and explore the
influence of self-assembly structure of mPEG-PDL on the catalytic activity and
stereoselectivity of aldol reaction.
As above mentioned, the assemble structures of mPEG-PDL influenced by pH
value, therefore, the efficiency of catalysts were studied at different pH values (4.0,
7
.0 and 9.0) primarily (Table 4). The yield and stereoselectivity of PDL and
mPEG-PDL-1 at pH 7.0 are higher than those of at pH 4.0 or 9.0, supporting the
effect of the hydrophobic pocket for efficient catalysis. However, the secondary
aggregation or sedimentation of assemblies influence the mass transfer rate of the
reaction substrate at pH 9.0. To highlight the efficiency of mPEG-PDL, catalysis
using PDLand free 4-hydroxy L-proline were also carried out at the same conditions.
The catalytic activity and stereoselectivity of three mPEG-PDL have shown a
remarkable increase compared with PDL and free 4-hydroxy-L-proline at pH 7.0,
which is closely related to size and dispersity of hydrophobic assembly of
mPEG-PDL in water [13, 45]. For mPEG-PDL copolymers, hydrophobic PDEA core
and hydrophilic mPEG corona can be formed in the presence of assemblies at pH 7.0,
which can avoid large amounts of water near the active center to destroy the transition
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state and reduce the formation of by-products [13, 46]. Assembly behavior and aldol
reaction catalysis process of mPEG-PDL in aqueous solution are shown in Scheme 2.
It is worth noting that mPEG-PDL-2 represents the highest catalytic activity and
stereoselectivity (92% conv., 90% yield, 92/8 anti/syn and 96% ee) among three
copolymers, which may be attributed to the suitable ratio of hydrophilic to
hydrophobic segment attracting the reaction substrate to the catalytic site effectively
[21, 27]. The catalytic activity of mPEG-PDL-3 is slightly below that of
mPEG-PDL-2, probably due to the longer PDEA block length than mPEG-PDL-2
limiting the mass transfer in catalytic process.
Scheme 2. Assembly behavior and aldol reaction catalysis process of mPEG-PDL in aqueous
solution.
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Table 4
Summary of aldol reaction between p-nitrobenzaldehyde and cyclohexanone in water catalyzed by
4
-hydroxy-L-proline, PDL and three mPEG-PDL.
O
OH
O
CHO
H O, 24 h
2
+
catalyst, 10 mol%
O N
2
O N
2
a
b
c
b
d
Sample
pH
%conv.
yield
anti/syn
%ee
4
-hydroxy-L-proline
7.0
4.0
7.0
9.0
4.0
7.0
9.0
7.0
7.0
9
8
61/39
56/44
78/22
76/24
52/48
76/24
73/27
92/8
n.d.
42
76
84
37
89
82
96
94
PDL
32
57
45
28
83
65
92
72
30
54
41
26
75
59
91
70
PDL
PDL
mPEG-PDL-1
mPEG-PDL-1
mPEG-PDL-1
mPEG-PDL-2
mPEG-PDL-3
91/9
a
Carried out using p-nitrobenzaldehyde and cyclohexanone, PDL and three mPEG-PDL catalysts
10 mol%) in water (1mL) at room temperature for 24 h.
(
b
1
Conversion of p-nitrobenzaldehyde was determined by H NMR spectroscopy from crude
reaction mixture.
c
Isolated yields
d
Determined by HPLC using OJ chiral column.
n.d. No determined.
Reusability of the aqueous catalyst solution is investigated subsequently, and the
detailed recycling process is shown in Scheme S2. The results are summarized in
Table 5. Aldol products were successfully obtained even after four cycle of three
mPEG-PDL, but their conv. decreased. The reason for the decrease conv. is
presumably small amounts of the copolymers were lost during extraction [17]. In
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addition, the catalytic system of mPEG-PDL-2 has the highest catalytic activity after
four cycles, which related to copolymer composition and uniform assemblies.
Table 5
Recycling data for aldol reaction between cyclohexanone and p-nitrobenzaldehyde in water (pH=
7
.0) at room temperature catalyzed by mPEG-PDL-1, mPEG-PDL-2, and mPEG-PDL-3 for 24 h
with 10 mol % catalyst loading.
a
a
a
mPEG-PDL-1
mPEG-PDL-2
mPEG-PDL-3
Cycle
b
b
c
b
b
c
b
b
c
%
conv.
83
anti/syn
76/24
70/30
66/34
58/42
% ee
89
% conv.
92
anti/syn
92/8
% ee
96
% conv.
72
anti/syn
% ee
1
2
3
91/9
94
93
90
92
71
85
85
89/11
91/9
93
70
89/11
85/15
86/14
55
80
79
96
66
4
32
76
61
90/10
95
60
a
Carried out using p-nitrobenzaldehyde and cyclohexanone, three mPEG-PDL catalysts (10 mol%)
in water (1.0 mL, pH=7.0) at room temperature for 24 h.
b
1
Conversion of p-nitrobenzaldehyde was determined by H NMR spectroscopy from crude
reaction mixture.
c
Determined by HPLC using OJ chiral column.
4
Conclusion
In this study, we successfully incorporated L-proline to a series of pH-responsive
mPEG-PDL repared by RAFT polymerization. Assembly structures of mPEG-PDL
are affected by contents of hydrophobic segments and pH value. The hydrophobic
domains of the assemblies can be used to catalyze a model aldol reaction. mPEG-PDL
shows better catalytic performance at pH 7.0 rather than other pH values. Moreover,
mPEG-PDL-2, containing an optimized hydrophilic to hydrophobic composition ratio,
1
9

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gives rise to the best catalytic performance at pH 7.0. These polymers also bring high
stereoselectivity (anti/syn and ee) in recycling measurement. This research might
guide future design on pH-responsive polymer catalysts.
Declaration of Competing Interest
The authors declare no competing financial interest.
Acknowledgements
This work is financially supported by the National Natural Science Foundation of
China (NSFC) (No. 21908158), the International Scientific & Technological
Cooperation Project in Shanxi Province (No. 201803D421075) and the Graduate
Education Innovation Program in Shanxi Province (No. 2019SY188)
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Yinghua Shen: Conceptualization, methodology supervision, writing-review &
editing, resources, project administration, funding acquisition.
Yu Tang: Writing, methodology, data curation, original draft preparation,
validation, formal analysis.
Qinya Wang: Investigation, editing, validation, formal analysis.
Lexuan Wu: Writing, editing, software, formal analysis.
Kuan Liu: Editing, validation, formal analysis.
Wenjing Wang: Writing, editing, formal analysis.
Yuyuan Xue: Supervision, writing-Review & Editing, resources, funding
acquisition.
Sheng Dai: Supervision, writing-Review & Editing, resources.
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The authors declare no competing financial interest.
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Highlights:

A series of copolymers supported L-proline containing hydrophilic mPEG and
pH-responsive PDEAwere synthesized via RAFT polymerization.
These pH-responsive copolymers could form stable assemblies in water, and the

assembled structures were determined by the ratio between hydrophilic and hydrophobic
segments.

These resultant micellar structures could be utilized to catalyze the asymmetric
aldol reaction at low catalyst loading with decent activity, selectivity and recyclability.
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