Synergetic Organocatalysis for Eliminating Epimerization in Ring-Opening Polymerizations Enables Synthesis of Stereoregular Isotactic Polyester

Article abstract of DOI:10.1021/jacs.8b09739

Ring-opening polymerization of O-carboxyanhydrides (OCAs) can furnish polyesters with a diversity of functional groups that are traditionally hard to harvest by polymerization of lactones. Typical ring-opening catalysts are subject to unavoidable racemization of most OCA monomers, which hampers the synthesis of highly isotactic crystalline polymers. Here, we describe an effective bifunctional single-molecule organocatalysis for selective ring-opening polymerization of OCAs without epimerization. The close vicinity of both activating groups in the same molecule engenders an amplified synergetic effect and thus allows for the use of mild bases, thereby leading to minimal epimerization for polymerization. Ring-opening polymerization of manOCA monomer (OCA from mandelic acid) mediated by the bifunctional single-molecule organocatalyst yields highly isotactic poly(mandelic acid) (PMA) with controlled molecular weights (up to 19.8 kg mol^-1). Mixing of the two enantiomers of PMA generates the first example of a crystalline stereocomplex in this area, which displayed distinct T_m values around 150 °C. Remarkably, the bifunctional catalysts are moisture-stable, recyclable, and easy to use, allowing sustainable and scalable synthesis of a stereoregular functional polyester.

Full text of DOI:10.1021/jacs.8b09739

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Article
A synergetic organocatalysis for eliminating epimerization in ring-opening
polymerizations enables synthesis of stereoregular isotactic polyester
Maosheng Li, Yue Tao, Jiadong Tang, Yanchao Wang, Xiaoyong Zhang, Youhua Tao, and Xianhong Wang
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b09739 • Publication Date (Web): 04 Dec 2018
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A synergetic organocatalysis for eliminating epimerization in
ring-opening polymerizations enables synthesis of
stereoregular isotactic polyester
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Maosheng Li, †,# Yue Tao, †,‡ Jiadong Tang, †,‡ Yanchao Wang, †,‡ Xiaoyong Zhang, § Youhua Tao, *,†
Xianhong Wang*,†
†Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences,
Renmin Street 5625, Changchun 130022, People’s Republic of China.
#University of Chinese Academy of Sciences, Beijing 100039, People’s Republic of China.
‡
University of Science and Technology of China, Hefei 230026, People’s Republic of China.
§
Department of Chemistry, KU Leuven Celestijnenlaan 200F, Leuven 3001, Belgium.
ABSTRACT: Ring-opening polymerization of O-carboxyanhydrides (OCAs) can furnish polyesters with a diversity of functional
groups that are traditionally hard to harvest by polymerization of lactones. Typical ring-opening catalysts are subject to unavoidable
racemization of most OCA monomers, which hampers the synthesis of highly isotactic crystalline polymers. Here, we describe an
effective bifunctional single-molecule organocatalysis for selective ring-opening polymerization of OCAs without epimerization.
The close vicinity of both activating groups in the same molecule engenders amplified synergetic effect thus allows for the use of
mild bases, thereby leading to minimal epimerization for polymerization. Ring-opening polymerization of manOCA monomer
(OCA from mandelic acid) mediated by the bifunctional single-molecule organocatalyst yields highly isotactic poly(mandelic acid)
(PMA) with controlled molecular weights (up to 19.8 kg mol-1). Mixing of the two enantiomers of PMA generates the first example
of crystalline stereocomplex in this area, which displayed distinct Tm values around 150 oC. Remarkably, the bifunctional catalysts
are moisture-stable, recyclable, and easy for operation, allowing sustainable and scalable synthesis of stereoregular functional
polyester.
INTRODUCTION
Polyesters, including polylactide (PLA), are attractive
biodegradable and biocompatible polymers that could provide
various applications in biomedicine, agriculture and textile
industry.1-12 Most polyesters, however, lack pendant
functionality, which precludes subsequent applications in
biomedical research.13 A promising approach to functionalized
polyesters is the ring-opening polymerization (ROP) of O-
carboxyanhydrides (OCAs), which can be prepared from
amino acid or hydroxyl acid precursors that inherently provide
rich pendant functionality (Figure 1A).14 Since 2006,15
Bourissou, Dove and others have reported OCA monomers
those of the corresponding atactic polymers.23 Considering
almost endless opportunities of ligand/metal combinations, no
surprise that metal-based catalysts have some examples for
stereoregular ROP of OCAs.24-27 For example, Cheng and
Tong reported the ROP of OCAs by Zn complex with β-
diiminate ligands (BDI)Zn resulted in the formation of
isotactic polyesters.24 However, the metal residues and
difficulties in operation are accelerating the development of
organocatalysts. To today, the stereoregular polymerization of
OCAs using organocatalysts is challenging, owing to their
strong proneness to racemization under basic condtions, which
leads to loss of stereoregularity, and changes in the
performances of the resulting polymers.13,17,18,22,28 More
specifically, these challenges are especially difficult to address
for manOCA, because of its increased C-H acidity.22,29
Therefore, no example of the crystallization behavior of PMA
has been reported until now, regardless of whether they were
achieved via organic catalysts or organometallic complexes. It
has no doubt that design of viable organocatalysts that can
lead to highly stereo-controlled ROP of OCAs, in particular,
manOCA, is of great significance, but is a challenge.
deriving from glutamic acid,16
malic acid,17 serine,18
lysine,19,20 and so on, for the efficient preparation of
functionalized polyesters under mild conditions. Among these,
OCA prepared from mandelic acid (manOCA) is particularly
intriguing, because ROP of manOCA leads to the synthesis of
poly(mandelic acid) (PMA), an aryl analogue of PLA, which
exhibits properties comparable to polystyrene, including a
high Tg (≈ 100 oC), but is degradable as PLA.21,22
Stereocontrol is very significant in polymer science as the
stereoregularity is a prerequisite for crystalline polymers,
which often possess mechanical performances superior to
In our attempt to develop a catalyst that can eliminate
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competitive epimerization reactions in challenging
organocatalytic OCA polymerization would be obtained.
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Herein, we report the first bifunctional single-molecule
organocatalysis for selective ROP of OCAs, resulting in
highly isotactic polymers with controlled molecular weights
(Figure 1C). For that purpose, we prepared bifunctional
organocatalyst consisting of a thiourea linked to a pyridine
derivative. The premise of our catalyst design was the reduced
basicity of the pyridine derivative relative to the DMAP. As
the pyridine ring can be modified by various substituent
groups, this design could enable the delivering of a series of
organocatalysts with basic and/or steric variations. Further
changes to the scaffold and the H-bond donor group would
considerably increase the diversity of catalysts.
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RESULTS AND DISCUSSION
Initially, 3,5-bis(trifluoromethyl)phenyl isothiocyanate was
reacted separately with aminopyridine 2a-d in dry CH2Cl2
(Figure S1). After stirring for 2 h, single-molecule thiourea-
pyridine organocatalysts 3a-d were isolated as air-stable solids
via filtration and recrystallization (Figure 2). The structures of
catalysts 3a-d was confirmed by NMR spectroscopy, and high
resolution mass spectrometry (Figures S14-S21). To
demonstrate the potential of the aforementioned
organocatalysts, we chose the challenging ROP of
enantiomerically pure D-manOCA (D-1), which was prepared
from D-mandelic acid using a simple one-step synthesis
(Figures S2-S3).
Figure 1. Bifunctional single-molecule organocatalysis for
ROP of O-carboxyanhydrides (OCAs). (A) ROP of OCAs to
prepare functional polyesters. (B) Previous catalysts for ROP
of OCAs. (C) Bifunctional single-molecule organocatalysis
proposed in this work.
Catalysts 3a-d were then tested in the ROP of -1 at 25 °C
D
with CH3OH as the initiator ([D-1]/[Catalyst]/[CH3OH] =
50/2/1). Reactions carried out with the bifunctional
organocatalysts, 3a and 3b, afforded polymers having low
number-average molecular weight (Mn ≤ 3.1 kg/mol; Table 1,
entries 1-2). Neither 3c nor 3d, in which thiourea moiety
epimerization in polymerization, we turned to bifunctional
hydrogen-bonding organocatalysts for inspiration.30-39 These
catalysts usually have both a base group and a hydrogen-bond
linked to pyridine directly, can catalyze ROP of -1 (Table 1,
donor group appropriately positioned on
a
scaffold.
D
entries 3 and 4). The stereostructures of the resultant
Bifunctional hydrogen-bonding organocatalysts have exhibited
great versatility and selectivity to promote many
transformations, because of their ability for cooperative dual
acid and base activation. Among them, the thiourea-amine
catalyst has been widely used in many different
enantioselective catalytic processes such as the Mannich,40 and
Michael reactions.41,42 Although the use of bifunctional single-
1
polyesters were carefully examined by H NMR spectra. As
shown in Figure 3, poly(D-1) produced under DMAP
demonstrated substantial racemization and atactic polyester
features with broad peaks for the methine moiety, consistent
with previous literature reports.24 Notably, poly(D-1) mediated
by 3a and 3b showed partial suppression of the racemization.
A dominant singlet signal for the methine moiety in the
polyester, attributable to isotactic enrichment of the polyester
molecule
thiourea-amine
organocatalysts
in
the
stereocontrolled preparation of small organic compounds has
been extensively researched, when we focus on the preparation
of polymers, publishing quantity using bifunctional
organocatalysts is incomprehensibly diminished.43-45 Extensive
studies have mainly focused on bicomponent thiourea/amine
catalyzed controlled ROP of cyclic esters.46-59 Generally, the
close vicinity of both activating groups in the same molecule
engenders amplified cooperative effect thus allows for the use
of mild bases, thereby leading to high chemoselectivities for
ROP.60 In this sense, bifunctional single-molecule
organocatalysis for ROP represents a significant reaction
modality and opens new avenues for the development of
selective ROP.
1
was seen in H NMR spectra. Additionally, 13C NMR spectra
further demonstrated stereo-control to some extent (Figure
S79A).
In an attempt to further improve the Mn and stereo-control,
we decided to expedite screening and prepare a library of
bifunctional organocatalysts (3e-o) from the corresponding
isothiocyanate and aminopyridine (Figure S1, detail
procedures for the synthesis of catalysts 3e-o see SI section).
As such, the electronic and steric properties of the two
building blocks can easily be adjusted, providing significant
flexibility and allowing the properties of the bifunctional
organocatalysts to be tuned. This library was evaluated for
behaviour in the selective ROP of D-1 in CHCl3 at 50 oC using
CH3OH as the initiator (Table 1). Pleasingly, extensive
screening of the catalysts led us to identify Ortho-substituted
chloropyridine-derived catalyst 3e as a superb catalyst for the
desired polymerization, furnishing the targeted polymer with
Mn (8.8 kDa) close to the theoretical value (6.7 kDa) and with
a low Đ (Đ = Mw/Mn) of approximately 1.2 (Table 1, entry 5).
Most importantly, polymer mediated by 3e demonstrated
An effective approach to overcoming significant
epimerization in OCA polymerization is to decrease the
basicity of the catalyst. However, the reduced basicity would
significantly compromise the catalytic activity. Therefore, we
proposed to exploit
a
bifunctional single-molecule
organocatalysis strategy for the ROP of OCA. Our hope was
that through the cooperative effects of the H-bond donor and
the weaker base, rapid rates of ring-opening with minimal
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Figure 2. Screening of bifunctional organocatalysts for chemoselective ROP of OCAs.
Table 1. Screening of bifunctional organocatalysts for ROP of D-1 a
c
d
e
f
Entry
Catalyst
s
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3o
3n
4+6
5+6
5+6
6
[D-1]/[cat]
/[CH3OH]
50:2:1
50:2:1
50:2:1
50:2:1
50:2:1
50:2:1
50:2:1
50:2:1
50:2:1
50:2:1
50:2:1
50:2:1
50:2:1
50:2:1
50:2:1
50:2:1
50:2:1
100:2:1
50:2:1
Temp.
(oC)
25
25
25
25
50
50
50
50
50
50
50
50
50
50
50
Time
(h)
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24
48
48
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48
48
48
48
48
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48
48
48
48
48
96
48
Conv.b
(%)
>99
>99
0
Mn,calcd.
Mn,NMR
Mn,SEC
Đ
(Mw/Mn)e
1.08
1.08
--
Pm
(kg/mol)
6.7
6.7
--
(kg/mol)
3.5
3.1
--
(kg/mol)
3.1
3.0
--
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
0.57
ndg
--
0
--
--
--
--
--
>99
>99
>99
>99
>99
0
6.7
6.7
6.7
6.7
6.7
--
8.3
9.6
3.8
5.2
3.6
--
8.8
10.0
3.4
5.4
3.3
--
1.20
1.30
1.10
1.14
1.12
--
0.90
0.86
nd
0.65
nd
--
--
0
--
--
--
--
>99
>99
>99
0
6.7
6.7
6.7
--
5.6
5.2
5.7
--
5.8
5.6
5.9
--
1.21
1.21
1.29
--
0.75
0.78
nd
--
--
50
50
50
50
0
--
--
--
--
>99
>99
0
6.7
6.7
--
10.0
12.2
--
8.2
10.9
--
1.68
1.51
--
0.66
0.64
--
b
1
aPolymerization conditions: [D-1] = 2 M, solvent = CHCl3, initiator = CH3OH. Determined by H NMR analysis of the reaction
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mixture. Mn,calcd.=[M(monomer)-M(CO2)] × [M] / [I] × Conversion (monomer)+M(CH3OH). dDetermined from the relative
integration of the signals for a-H and chain ends by H NMR analysis of the polymer samples. Determined by SEC at 50 °C in
DMF relative to PMMA standards. Pm is the probability of forming a new isotactic dyad. The tacticities of the atactic polymer
c
1
e
f
g
samples were difficult to determine from NMR results.
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Figure 3. The effect of basicity of catalysts on the methine resonances. The polymerization catalyzed by DMAP showed
racemization of the a-methine in H NMR spectrum of poly(D-1) while the application of 3e retained the isotacticity of the
polyesters.
1
bis(trifluoromethyl)phenyl thiourea moiety was optimal.
excellent isotacticity. A single resonance for α-methine region
was seen in the 1H NMR spectrum (Figure 3). Meanwhile, 13
C
Having identified 3e as the best catalyst for -1, we further
D
NMR spectrum displayed singlet signal corresponding to a-
carbons, also demonstrating perfect stereo-regulate (Figure
4A). The isotacticity of poly(D-1) (Pm= 0.90) was evaluated by
fitting the tetrad resonances seen in the quantitative 13C NMR
spectrum with the values predicted by Bernoullian statistics
(Figure S80-S81, Table S2-S5).61,62
explored this ROP in details. The polymerization of D-1 by the
single-molecule
organocatalyst
3e
exhibits
several
characteristics of controlled polymerization.63,64 With higher
catalyst loading (3e of 2 equiv relative to CH3OH), the Mn
values of obtained poly(D-1) increased linearly with initial [D-
1]/[CH3OH] ratios from 25 to 150, along with the unimodal
distributions (Figure 4B, C). The determined molecular
weights by SEC (Mn,SEC) and 1H NMR(Mn,NMR) were consistent
with Mn,calcd calculated from the [D-1]0/ [CH3OH]0 molar ratio
and conversion (Figure S94). The methoxy group at the α-end
of the polymer was clearly seen at δ = 3.78 ppm (Figure S65).
Furthermore, the MALDI-TOF-MS of poly(D-1) consists of an
array of peaks separated by a 134 Da interval, which
corresponds to the molar masses of the repeating unit (Figure
4D). The MALDI-TOF-MS result also indicated the polymer
contained methoxy moiety at the initiating terminal and intact
hydroxyl end-group at the capping terminal. Interestingly, the
SEC plots of poly(D-1) after complete monomer consumption
and prolonged reaction times showed similar peak shape and
elution time, indicative of minimal transesterification of
polymer chains (Figure S93). This is similar to other thiourea-
based organocatalytic polymerization reported by Waymouth,
and co-workers.52 In addition, other alcohols, such as 3-
phenylpropanol, also effectively initiated the polymerization,
which proceeded in quantitative yields and afforded polymers
having a low Đ (Đ = 1.22; Table 2, entry 4; Figure S91).
The use of pyridine with sterically bulkier substituent had a
negligible impact on the suppression of the racemization. The
polymerization catalyzed by 3f also gave satisfactory stereo-
control but with mediocre molecular weight control (Table 1,
entry 6). However, the position and electronic properties of the
substituents on the pyridine ring had a significant effect on
stereo-structures. More basic meta-substituted pyridine
derivative (3g and 3h) gave inferior result (Figure 3).
Electron-donating group (3i) gave only low Mn polymers with
atactic structure (Table 1, entry 9, and Figure S79B). The
above experiments obviously indicate that the decreased
basicity of ortho-substituted chloropyridine compared to
DMAP is responsible for the significant suppression of the
racemization. Furthermore, polymerization with 3j and 3k did
not proceed, probably due to the even weaker basicity of the
pyridine ring (Table 1, entries 10-11, Figure S88). These
results again demonstrate that subtle variation of the position
of chlorine group in pyridine ring can siginificantly change
polymerization efficiency and stereo-structures.
With the best scaffold and base moiety identified, we turned
our attention to H-bond donor group. Both 3l containing one
CF3 substituent and 3m containing zero CF3 substituent gave
mediocre stereo-control (see Figure S79B) and demonstrated
faster polymerization rate than that 3e (Table 1, entries 12-13,
Figure S88). Meanwhile, the role of the N-H in the thiourea
appears important, as evidenced by the poor stereo-control
exhibited by the methylated thiourea 3o (Table 1, entry 14,
and Figure 3). 3o also exhibited reaction rate faster than its
nonmethylated counterpart 3e (Figure S89). Furthermore,
Polymerization did not occur when using less acidic urea 3n
(Table 1, entry 15). These results illuminate that the H-bond
donor group might also contribute to the stereochemical
outcome as well as the polymerization rate, and that the 3,5-
These results again demonstrate that 3e-mediated ROP of -1
D
exhibited a controlled feature. However, the polymerizations
show some deviations from an ideal “living” behavior.64 With
lower catalyst loading, the observed molecular weights do not
correlate to those predicted from the conversion and the ratio
[D-1]0/[ CH3OH]0 (Table 2, entries 1-2).
To highlight the versatility of our single-molecule
organocatalytic system, we used the 3e for ROP reactions of
five other OCA monomers, including methyl (L-LacOCA, L-2),
benzyl protected hydroxyl (L-Ser(Bn)OCA, L-3), benzyl
protected carboxyl (L-MalOCA, L-4), phenyl (L-PheOCA, L-5),
and Cbz protected amino groups (L-LysOCA, L-6)
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Figure 4. Organocatalytic chemoselective ROP of OCAs. (A) Proposed tetrad stereosequence assignments for the methine carbon
of 13C NMR spectrum (Quantitative, 150 MHz, CDCl3) of isotactic poly (D-1) on the basis of Bernoullian statistics (Table 1, entry
5). (B) Plots of Mn (square, black) and Đ (circle, red) versus [M]/[I] ratio (3e of 2 equiv relative to CH3OH). (C) Representative
SEC traces of poly(D-1) in panel (B). (D) MALDI-TOF-MS of poly(D-1) prepared by 3e/CH3OH. (E) Plot of -1 conversion vs.
D
time at various 3e concentrations. [D-1] = 2 M; [D-1]/[ CH3OH] =100:1.
Table 2. Controlled ROP of OCAs mediated by 3e a
c
d
e
g
Entry
OCA
[M]/[3e]
/[I]
Conv.b
(%)
47
Mn,calcd.
(kg/mol)
Mn,NMR
(kg/mol)
Mn,SEC
(kg/mol)
Đ (Mw/Mn)
Pm
e
1
2
D-1
D-1
D-1
D-1
L-1
L-2
L-3
L-4
L-5
L-6
50:0.5:1
50:1:1
50:2:1
50:2:1
50:2:1
50:2:1
50:2:1
50:2:1
50:2:1
50:2:1
3.2
4.9
6.7
6.8
6.7
3.6
8.9
10.3
7.4
6.5
8.1
8.3
6.9
8.5
3.7
8.4
8.7
7.9
8.9
8.8
7.9
9.1
3.9
7.1
6.9
1.21
1.25
1.20
1.22
1.26
1.22
1.29
1.29
1.22
1.21
0.88
0.89
0.90
0.90
0.84
>0.99
>0.99
>0.99
>0.99
>0.99
73
3
>99
>99
>99
>99
>99
>99
>99
>99
4f
5
6
7
8
9
7.5
9.6
5.2
5.4
10
13.1
o
aPolymerization conditions: [OCA] = 2 M, solvent = CHCl3, initiator = CH3OH, temperature = 50 C, time = 48h.b Determined by
c
1H NMR analysis of the reaction mixture. Mn,calcd.=[M(monomer)-M(CO2)] × [M] / [I] × Conversion (monomer)+M(initiator).
1
dDetermined from the relative integration of the signals for a-H and chain ends by H NMR analysis of the polymer samples.
f
eDetermined by SEC at 50 °C in DMF relative to PMMA standards. initiator = PhCH2CH2CH2OH. gPm is the probability of
forming a new isotactic dyad.
first-order with respect to the OCA concentration (Figure 4E).
(Figure 2,Table 2, entries 6-10, detail procedures for the
The reaction orders with respect to 3e were 1.21 ± 0.05
(Figure 4E and Figure S90C), whereas the reaction was zero-
order with respect to CH3OH (Figure S90D). These
experiments demonstrated that the propagation rate was
independent of CH3OH. In additional, these results indicated
that the overall rate law can be described as follows:
synthesis of monomers see SI section). In all cases,
polymerization control was excellent, similar to that for the
formation of poly(D-1); all the Ð values were < 1.3, and the α-
methine region did not epimerize (Figure S69-78).
A notable feature of single-molecule organocatalyst 3e is
that it can be recycled and reused with negligible loss of
activity and controllability (Table S1, entry 6). Recovered 3e
-d[D-1]/dt = kp [3e]1.21[D-1]
(1)
where kp is the propagation rate constant.
1
remained structurally intact, as evidenced by H NMR and
ESI-MS (Figure S96-S97).
We have further investigated the hydrogen bonding between
3e, D-1 and CH3OH in CDCl3 via 1H NMR spectra. At 3e/D-1 =
1/1, the H-bond interaction was obviously demonstrated by
shift of peaks attributed to NH groups from 6.69/7.87 to
To obtain an insight into the polymerization mechanism
catalyzed by 3e, we firstly carried out the kinetic experiments
to determine reaction orders of -1 and 3e. Analysis of a plot
of ln([M]0/[M]) vs. time indicated that the polymerization was
D
1
6.76/8.25 ppm (Figure 5 and Figure S95). Conversely, the H
NMR spectrum of a mixture of 3e and CH3OH revealed the
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activation of CH3OH by chloropyridine moiety could be too
acylpyridinium intermediates gradually converted into methyl
weak to be realistic (Figure S82).48 Meanwhile, DFT
calculations and 1H-1H NOESY studies indicated that thiourea
moiety was found to preferentially interact with C5-carbonyl
of OCA (Figures S98-S99). Of interest, the 1H NMR spectrum
mandelate within 12 hours through decarboxylation process
and substitution with CH3OH (Figure S86C). This resulted in
the formation of the end -OCH3 group of poly(D-1), as clearly
illuminated by MALDI-TOF MS (Figure 4D). Increasing the
monomer amount to 5 equiv (3e/D-1/CH3OH = 5/1/1), the
substitution with CH3OH was completed in 4 hours (Figure
S87). In the actual polymerization process, the existence of
excess monomers allowed the substitution reaction to occur
more quickly, which was confirmed by the regulation of Mn
via [D-1]/[CH3OH] ratios (Figure 4B).
1
2
3
4
5
6
7
8
o
of 3e by mixing with D-1 at 50 C after 0.5 h(shift of the
proton signal of chloropyridine moiety from 7.85/7.27 to
7.59/7.38 ppm, shift of the proton signal of NH group from
6.69/7.87 to 13.07/11.70 ppm, Figure 5B and 5D) revealed
some information about the nucleophilic ring-opening of
activated monomer D-1 by chloropyridine moiety, leading to
acylpyridinium intermediate, which was stabilized by dual
hydrogen bonding to the thiourea.36,37 The structure of
acylpyridinium intermediate was also confirmed by FTIR and
13C NMR (Figure S83-S84). On the other hand, neither
monofunctional analogue 6 nor thiourea/base bicomponent
system 4+6, could react with D-1 under the same conditions
(Table 1, entries 16 and 19, Figure S85). When using strong
thiourea/base bicomponent system 5+6, uncontrolled
polymerization occurred, affording polymer with bimodal
molecular weight distribution (Table 1, entries 17-18 and
Figure S91). These results indicated that the close vicinity of
thiourea moiety and pyridine in the same molecule resulted in
significantly magnified synergistic effect thus allows for the
use of mild bases, thereby minimizing unexpected side
reactions and leading to high chemoselectivities for ROP.
Conversely, this cooperative effect was entropically
disfavored for thiourea/pyridine bicomponent system in
solution.65 It should also be noted that the thiourea/strong base
(e.g.: phosphazene, and guanidine) bicomponent system
offered obvious synergistic effect,51,56,57,66 suggesting the
significant differences in catalytic pathways in these related
processes.
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Based on the aforementioned findings, we therefore
postulate a polymerization mechanism mediated by 3e (Figure
6). The polymerization starts with the activation of -1 to the
D
thiourea moiety of 3e (a). In this premise, nucleophilic ring-
opening by chloropyridine moiety in the same molecule occurs
with the formation of acylpyridinium intermediate (b)
cooperatively, followed by decarboxylation process, and
substitution with either the alcohol or the growing polymer
chain (c), keeping the configuration at the α-methine carbon.
The coordination of the incoming monomer to 3e, facilitates
decarboxylation and substitution process. Zero-order reaction
kinetics for alcohol (Figure S90D) implied that the rate-
determining step in the propagation was the nucleophilic
attack of 3e on the monomer, further corroborating this
hydrogen bonding assisted nucleophilic monomer activation
mechanism. Remarkably, significant synergistic effect of both
thiourea and pyridine groups in the same molecule, allowed
control over the polymerization of OCA as shown by the
controlled molecular weights and the low molecular weight
distributions.
Additionally, it should be noted that a distinct induction
period was observed for the 3e-mediated ROP of -1 (Figure
D
4E). Similar induction periods were observed in the
zwitterionic ROP of lactones reported by Hedrick, Waymouth,
and co-workers, and is attributed to slow initiation
behavior.47,67,68 It is also postulated that the slow initiation
accounts for the deviation from the ideal “living” behavior in
our system.69
Poly(mandelic acid) (PMA) is an aryl analogue of
poly(lactic acid) (PLA) and a biodegradable analogue of
polystyrene. Unfortunately, all of the previously reported
PMAs are amorphous,21,22 limiting possible commodity and
biomedical applications. Physical blending of enantiomers of
chiral polymers in a stoichiometric ratio allows the formation
of crystalline stereocomplexed materials that often display
improved properties.69 In this context, a stereocomplex from
the 1:1 mixture of (D)-PMA (Mn =13.5 kg mol-1, PDI=1.27)
and (L)-PMA (Mn =13.4 kg mol-1, PDI=1.28) was analyzed by
DSC and the thermal properties were compared to the
enantiopure polymers (Figure 7). In the second heating scans
(after cooling at 10°C/min) the enantiomeric polymers
displayed only a glass transition temperature Tg of ~100°C. On
the other hand, we were delighted to find that the
stereocomplex was semicrystalline, and DSC profile displayed
a melting peak of Tm = 150 °C (Tc = 118°C). Such obvious
melting and crystallization behaviors of PMA have not been
observed in the previous report. Both the highly isotactic
structures coupled with the stereocomplexation between two
opposite enantiomeric polymers are responsible for the
crystallization behavior we observed. The promotion of
crystallization by stereocomplexation was also confirmed by
Coate, Chen and other’s paper.27,70-72
Figure 5. The activation of bifunctional organocatalyst 3e to
OCA via hydrogen-bonding interaction, and the formation of
acylpyridinium intermediate cooperatively. (A) 1H NMR
1
1
spectrum of D-1. (B) H NMR spectrum of 3e. (C) H NMR
1
spectrum of 3e/D-1 (1/1). (D) H NMR spectrum of 3e by
mixing with D-1 (1:1) at 50 oC after 0.5 h in CDCl3.
1H NMR spectra of a mixture of 3e, D-1 and CH3OH (1
o
equiv of each) were measured in CDCl3 at 50 C by varying
the time (Figure S86). In the presence of CH3OH, all of
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Figure 6. Proposed polymerization mechanism for ROP of OCA. Chain initiation and growth routes are presented upon the
cooperative catalysis of bifunctional organocatalyst 3e in the presence of alcohol. Species (a)-(c) were revealed by Figure 5 and
Figure S82-S87.
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moiety and Ortho-substituted chloropyridine group in the
same molecule for achieving this degree of control. We
anticipate that the operational simplicity of these
organocatalysts, together with their recyclability and
capability to impart exquisite control on ROP will make them
valuable to the chemistry community. More generally, the
concept of using the synergistic effects between the weaker
base and the H-bond donor to minimize epimerization and to
improve the catalytic activity is general and should prove
useful for various catalytic reactions.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge via the
Internet at http://pubs.acs.org.
Details on materials and methods, experimental procedures,
characterization data.
AUTHOR INFORMATION
Corresponding Author
*E-mail: youhua.tao@ciac.ac.cn, xhwang@ciac.ac.cn.
NOTES
The authors declare no competing financial interests.
Figure 7. DSC thermograms of (A) isotactic (D)-PMA, (B)
ACKNOWLEDGEMENT
isotactic (L)-PMA, and (C) the stereocomplexed mixture of
both polymers. Heating rate 10oC/min for (D)-PMA and (L)-
PMA or 5 oC/min for stereocomplex.
This work is supported by the National Natural Science
Foundation of China (Grants 21474101, 21805272, and
51873211) and the Jilin Science and Technology Bureau
(Grants 20160414001GH and 20180201070GX). Helpful
discussions with Prof. Jun-Peng Zhao (South China University
of Technology, China) are gratefully acknowledged.
CONCLUSION
In summary, we report
a bifunctional single-molecule
organocatalytic system for the chemoselective polymerization
of OCAs without epimerization, affording stereoregular
polyesters bearing various functional side chain groups. Of
importance, mixing of the two enantiomers of poly(mandelic
acid) (PMA) generates the first example of crystalline
stereocomplex in this area. The mechanistic study highlighted
the key roles played by the close vicinity of both the thiourea
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