Unimolecular Anion-Binding Catalysts for Selective Ring-Opening Polymerization of O-carboxyanhydrides

Article abstract of DOI:10.1002/anie.202011352

Anion-binding can regulate anion transport in chloride channels through dynamic non-covalent interactions, which gives insights into the designing of new organocatalytic transformations but is surprisingly unexplored in polymerization catalysis. Herein, we describe an effective unimolecular anion-binding organocatalysis where 4-(dimethylamino)pyridine is anchored to a thiourea for ring-opening polymerization of O-carboxyanhydrides (OCAs) to furnish highly isotactic poly(phenyllactic acid) (Ph-PLA) with molecular weight (MW) up to 150.0 kDa, which well addresses the formidable challenge of synthesizing high MW stereoregular polyesters. Calculations and experimental studies indicate a dynamic cooperative anion-binding mechanism, where the dynamic anion-binding interaction of thiourea moiety to propagating species facilitates efficient chain propagation and the synergetic decarboxylation retains high selectivity for OCA ring-opening over side reactions (such as cyclization, epimerization, and transesterification).

Full text of DOI:10.1002/anie.202011352

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Unimolecular Anion-Binding Catalysts for Selective Ring-opening
Polymerization of O-carboxyanhydrides
Authors: Maosheng Li, Shuai Zhang, Xiaoyong Zhang, Yanchao Wang,
Jinlong Chen, Youhua Tao, and Xianhong Wang
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202011352
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10.1002/anie.202011352
Angewandte Chemie International Edition
RESEARCH ARTICLE
Unimolecular Anion-Binding Catalysts for Selective Ring-opening
Polymerization of O-carboxyanhydrides
Maosheng Li,[a] Shuai Zhang,[a] Xiaoyong Zhang,[b] Yanchao Wang,[a] Jinlong Chen,[a] Youhua Tao,*[a]
Xianhong Wang*[a]
[a]
[b]
M. Li, S. Zhang, Y. Wang, J. Chen, Y. Tao, X. Wang.
Key Laboratory of Polymer Ecomaterials,Changchun Institute of Applied Chemistry,Chinese Academy of Sciences ,Changchun 130022 , P. R. China
E-mail: youhua.tao@ciac.ac.cn; xhwang@ciac.ac.cn
X. Zhang.
Department of Chemistry, KU Leuven, Celestijnenlaan 200F, Leuven 3001, Belgium
Supporting information for this article is given via a link at the end of the document.
Abstract: Anion-binding can regulate anion transport in chloride
channels via dynamic non-covalent interactions, which gives insights
into the designing of new organocatalytic transformations, but is
surprisingly unexplored in polymerization catalysis. Herein, we
describe an effective unimolecular anion-binding organocatalysis
where 4-(dimethylamino)pyridine is anchored to a thiourea for ring-
opening polymerization of O-carboxyanhydrides (OCAs), which well
addresses the formidable challenge of synthesizing high molecular
weight (MW) stereoregular polyesters. Ring-opening polymerization
of PheOCA (OCA from phenylalanine) mediated by unimolecular
So far, a variety of organic and metal-based catalysts have
been found capable of catalyzing of the ROP of OCAs.[6]
However, the synthesis of high MW stereoregular polyesters via
ROP of OCA still faces formidable challenges, including the
trade-off between minimal epimerization and efficient chain
propagation
(Figure
1A).
For
instance,
4-
(dimethylamino)pyridine (DMAP), a typical organocatalyst, have
recently been employed for ROP of OCA.[6f] However, these
organobases inevitably results in epimerization of the α-methine
hydrogen in OCAs accompanied by the simultaneous chain
transfer or termination, and thus diminishes control over MW
and stereoregularity.[6f] The weakly basic catalysts typically
anion-binding
organocatalyst
generates
highly
isotactic
poly(phenyllactic acid) (Ph-PLA) with MW up to 150.0 kDa.
Specifically, high MW Ph-PLA exhibits 30-fold increase in the
elongation at break in comparison to its low MW congener. Moreover, significantly reduced.[6g] In this premise, most polyesters
suppress
epimerization, but the polymerization activity is
active species of the polymerization are moisture-tolerant and can
be conducted in unpurified solvent, facilitating facile synthesis of
high MW stereoregular polyesters with pendant functional groups.
Calculations and experiment studies indicate a dynamic cooperative
anion-binding mechanism where the dynamic anion-binding
interaction of thiourea moiety to propagating species facilitates
efficient chain propagation and the synergetic decarboxylation
obtained from the organocatalytic ROP of OCAs have relatively
low MWs (< 50.0 kDa).[6h] Metal-based catalysts, such as Zn
complex with β-diiminate ligands, have been applied for the
controlled OCA polymerization.[7] However, they are also subject
to a compromise between minimal epimerization and efficient
chain propagation, thus still cannot efficiently produce polyesters
with high MW. It is considered that metal-based catalysts
retains high selectivity for OCA ring-opening over side reactions (e.g., typically exhibit strong coordination ability to the carbonate anion
cyclization, epimerization and transesterification).
of growing chain, thereby beneficial to overcoming significant
epimerization but resulting in inefficient decarboxylation and
inactive metal-carbonate during the chain propagation (Figure
1A), especially at high degree of polymerization.[6h] Until
recently, Tong et al. utilized photoredox Ni/Ir catalysis for OCA
polymerization, which has been used for photoredox
decarboxylation of anhydrides, and obtained high MW (> 140.0
kDa) polyesters without epimerization.[8] However, the metal
residues impede the applications of these polyesters in
optoelectronic and biomedical materials.[1l, 9] It has no doubt that
devising a viable organocatalyst that can catalyze well-controlled
ROP to generate high MW, isotactic functionalized polyesters is
the ideal yet challenging.
Introduction
The development of novel catalytic techniques and
polymerization processes continues to drive innovation in
polymer chemistry.[1] Ring-opening polymerization (ROP) is a
powerful and widespread polymerization method.[2] It has proven
especially useful for the furnishing of biodegradable polymers,
starting from lactones and related monomers. Recently, ROP of
O-carboxyanhydrides (OCAs) has emerged as a promising route
towards functionalized polyesters (Figure 1A).[3] The key
advantage of this process over the ROP of lactones and lactides
for the generation of polyesters is the large number and diversity
of functional monomers that are easily synthesized from amino
acid precursors which inherently possess abundant pendant
functionality.[4] For example, OCA prepared from phenylalanine
(PheOCA) is extremely attractive, as ROP of PheOCA can
generate poly(phenyllactic acid) (Ph-PLA), a phenyl-substituted
PLA analogue, where the aromatic ring should lead to
degradable polymers with enhanced hydrophobic interactions
and rigidity.[5]
The chloride channels, found throughout biology, catalyze
the rapid flow of chloride anions across cell membranes, thus
adjusting electrical excitation in skeletal muscle and the flow of
salt and water across epithelial barriers.[10] Anion-binding plays a
considerable role in chloride channels, in which anion-binding
site are constructed by bringing together specific amino acids
from four separate regions (Figure 1B).[11] A prominent feature of
anion-binding is that it does not form tight ion pairs via direct
1
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10.1002/anie.202011352
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RESEARCH ARTICLE
Figure 1. (A) ROP of OCAs and side reactions commonly observed in the polymerization. (B) Anion-binding in nature chloride channel. (C) Representative
examples of anion-binding concept for organocatalytic transformations. (D) This work: Unimolecular anion-binding for ROP.
charge-charge contact; instead, the chloride anion is dynamic
stabilized through non-covalent hydrogen bonding thus
promotes rapid flow of ions, which leads to the development of
molecular recognition, sensors and transporters for anionic
species in supramolecular chemistry,[12] further gives insights
into the designing of new organocatalytic transformations.[13] For
instance, Jacobsen et al. has exploited a variety of chiral anion-
binding catalysts derived from urea and thiourea for
enantioselective nucleophilic ring-opening of episulfonium
(Figure 1C, a),[13a] Pictet-Spengler Cyclization,[13b] and alkylation
of R-arylpriopionaldehdyes.[13c] Similarly, Seidel et al.
demonstrated the enantioselective O to C acyl transfer of
azlactones (Steglich rearrangement, Figure 1C, b)[13d] and kinetic
resolution of amines[13e] using chiral thiourea-based anion-
binding catalysts. While the anion-binding concept has been
applied to great success in organic chemistry, it remains
surprisingly unexplored in polymer synthesis and/or in
polymerization catalysis. Considering that ionic intermediates or
reagents are ubiquitous in numerous polymerization processes,
it is extraordinarily worthy of pursuing anion-binding catalysis to
address the unresolved challenges in polymerizations.
but also to form noncovalent interactions with carbonate anion of
the propagating polymer chain via anion-binding. In this anion-
binding catalytic mode, stabilization of the carbonate anion of
growing chain end by the thiourea should serve to maintain the
livingness of propagating chains, while this type of anion-binding
is less stronger than the metal-carbonate, which facilitate the
efficient decarboxylation during the chain propagation, a process
similar to the chloride anion transport in chloride channels. In
addition, the thiourea moiety may potentially serve as a Lewis
acid capable of modulating the basicity of DMAP moiety or
propagating chain ends to enable minimal competitive
epimerization reactions.[2i, 6g]
Herein, we document an unprecedented unimolecular anion-
binding organocatalysis for ROP of OCAs, leading to efficient
chain propagation and high selectivity for ring-opening over side
reactions (e.g., epimerization and cyclization), delivering high
MW (reached 150.0 kDa) isotactic polyesters bearing diverse
functionality. We believe this unimolecular anion-binding
organocatalysis strategy not only paves the way for synthesis of
high MW isotactic polyesters but also opens novel avenues for
the advance of chemoselective ROP.
Inspired by the unique anion-binding concept, we envisioned
the cooperative use of DMAP and a thiourea catalyst might allow
for the controlled ROP of various OCAs to afford high MW
isotactic polyesters (Figure 1C). Specifically, the thiourea
bonding moiety is not only expected to activate the monomers
by classical H-bonding interactions with carbonyl groups,[1l, 9, 14]
2
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10.1002/anie.202011352
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RESEARCH ARTICLE
Results and Discussion
occur when applying less acidic urea 3e (Table 1, entry 17).
Obviously, polymerization activity exhibits
a
remarkable
correlation with the acidity of the thiourea (urea) moiety:
polymerization is faster with higher acidity of the thiourea (3b >
3c > 3d > 3e). This reactivity trend suggests that the activation
of the monomer through H-bonding to the thiourea (urea) moiety
plays a key role in influencing the polymerization activity. More
acidic thiourea moiety is more effective for activating the
monomer toward nucleophilic attack, and hence the chain
propagation. Overall, the above results suggested that the H-
bond donor unit could also contribute to the MW outcomes as
We used -PheOCA (L-1) as a model monomer, which was
L
readily prepared from -phenylalanine through a simple two-step
L
procedure (Figure 2A). At the outset, an anion-binding
organocatalyst 3a, featuring a thiourea moiety in the meta-
position of DMAP (Figure 2B), was prepared in a six-step
procedure requiring purification by recrystallization (Scheme S1,
detailed synthesis procedure, see Supporting Information). NMR
and MS analysis revealed the desired 3a structure (Figures S9-
10). Since 3a was both an initiator and
a catalyst, for
well
as
the ROP
activities
and that
the 3,5-
convenience, we termed 3a as organocatalyst in the following
studies. 3a was initially tested in the polymerization of
bis(trifluoromethyl)phenyl thiourea unit was optimal.
Having confirmed 3b as the best catalyst for L-1, the
enantiomerically pure -1 at 25 °C in dichloromethane (DCM) at
L
polymerization was further explored in details. ROP of -1 by the
L
different monomer to 3a ratios ([L-1]0/[3a]0) ranging from 100:1 to
500:1 (Table 1, entries 1–3). Reaction carried out at a lower [L-
1]0/[3a]0 ratio of 100:1, led to 100% L-1 conversion in 1 h and
formation of poly(L-1) with a number average molecular weight
(Mn) of 16.6 kDa and a molecular weight distribution (Đ = Mw/Mn)
of 1.24 (entry 1). However, at a higher [L-1]0/[3a]0 ratio of 500:1,
uncontrolled polymerization occurred, generating poly(L-1) with a
unimolecular anion-binding catalyst 3b displays several
characteristics of controlled polymerization. Poly(L-1) with varied
Mn can be successfully prepared by regulating [L-1]0/[3b]0 ratio.
The Mn values of obtained poly(L-1) increased from 10.9 kDa to
150.0 kDa as [L-1]0/[3b]0 ratio increased from 25:1 to 800:1
(Figure 3B, Table 1 entry 4-8, and Table S1 entry 11-15). SEC
traces showed unimodal distributions with low Đ (Đ, around
1.05-1.22) at different [L-1]0/[3b]0 ratios (Figure 3C). Meanwhile,
the evolution of Mn exhibited a linear correlation with monomer
Mn of 49.0 kDa, much lower than the targeted one (Mn,calcd.
=
74.4 kDa) (entry 3). To synthesize high MW polymers with
nucleophilic initiators, Waymouth had suggested that the
initiating nucleophile should exhibit relatively poor leaving group
ability (low nucleofugality).[15] This fact indicated that meta-
substituted catalyst 3a might exhibit strong nucleofugality, which
was detrimental to the synthesis of high MW polymers.
conversion while
Đ (1.05-1.17) remains low (Figure 3D).
Importantly, the SEC curves of poly(L-1) after 100% L-1
conversion and prolonged reaction times exhibited a very similar
peak profile, indicating minimal transesterification and formation
of carbonate instead of alkoxide propagating species (Figure
S43A). Together the data suggested that 3b-mediated
In view of these results, we decided to prepare and explore
unimolecular anion-binding catalyst with low nucleofugality for
the synthesis of isotactic high MW polyesters. Given the steric-
hindrance effect of ortho-substituent groups, we foresaw that
DMAP with thiourea attached to the ortho-position should
polymerization of L-1 showed
a controlled characteristic.
However, the 3b-mediated ROP exhibit some deviations from an
ideal “living” behavior.[17] Plots of the Mn versus monomer
conversion extrapolate to a nonzero intercept (Figure 3D); the
observed MWs do not conform to the [L-1]0/[3b]0 ratio and are
significantly higher than the predicted value (Figure 3B).
display low nucleofugality (Figure S40).[16] Thus,
a new
unimolecular anion-binding catalyst 3b, where thiourea was
anchored into ortho-position of DMAP, was prepared by the
route described in Figure 2C (for detailed procedures see
Supporting Information). Next, 3b was investigated for the
polymerization of L-1 in DCM at 25 °C (Table 1). Surprisingly,
when the [M]0/[3b]0 = 800:1, high MW polyesters with Mn up to
150.0 kDa and a low Đ of 1.20 were achieved by unimolecular
anion-binding organocatalyst for the first time (Table 1, entry 8),
which was approximately 3 times as much as that of polyesters
from ROP mediated by DMAP.[6h] Importantly, neither DMAP nor
thiourea/DMAP bicomponent system could mediate controlled
ROP of L-1 under similar conditions to furnish high MW
polyesters (Table 1, entry 9-14, and Table S1, entry 18), thus
pointing to the importance of the covalent-linking between
DMAP and thiourea for high MW. Moreover, no epimerization of
the α-methine hydrogen occurred even for high MW sample, as
We further explored the chain extension reaction with -1 ([L-
L
1]0/[3b]0=50:1). Upon 100% conversion of the initial L-1, an
additional 50 equiv of L-1 were added, and the polymerization
was allowed to continue to completion. SEC plots (Figure S43B)
indicated an ascend of poly(L-1) Mn from 20.6 to 39.8 kDa mol-1
and a change in Đ from 1.10 to 1.06 (Table S1, entry 17). The
latter values were consistent with those for polyesters
independently
polymerization (Mn = 41.1 kDa, Đ = 1.07). These results also
indicated controlled manner of 3b-mediated OCA
polymerization.
synthesized
from
a
100:1
[L-1]0/[3b]0
a
Early work by Waymouth has demonstrated that the polymer
MWs can be regulated by alcohol initiators, during the ROP of
lactones catalyzed by nucleophilic catalysts, such as NHC and
evidenced by homodecoupled 1H NMR analysis (Table 1, entry 8; DBU.[1l, 15] In stark contrast, when benzyl alcohol (BnOH) was
Figure 3A and Figure S21-23), indicating that the thiourea
moiety could modulate the basicity of propagating anions to
enable minimal competitive epimerization reactions.
used and [L-1]0/[BnOH]0 ratios were systematically varied
between 50:1 and 200:1, reactions carried out with the
unimolecular anion-binding catalyst 3b, afforded polyesters
whose MWs did not differ markedly and were substantially close
to that in the absence of BnOH (Table 1, entries 5, 18-20).
These results indicated that competitive side reactions (e.g.,
alcohol-initiated chain propagation, chain transfer to alcohol)
were significantly suppressed due to the reduced nucleofugality
of 3b and rapid polymerization kinetics.
With the base unit identified, we have further examined the
effect of different H-bond groups on the ROP (Figure 2B). Both
3c with one CF3 substituent and 3d with zero CF3 substituent
resulted in high MW polyesters with Mn > 50.0 kDa (Table 1,
entry 15-16), indicating that the ortho-substituent of DMAP is
critical to produce high MW polyesters. However, polymerization
with 3c and 3d demonstrated slower polymerization activities
than 3b (see Figure S42). Moreover, ROP did not efficiently
It is challenging to carry out OCA polymerizations in the
presence of water and impurities, which induce unwanted side
3
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Figure 2. (A) Scope of OCAs. (B) Screening of anion-binding catalysts. (C) Typical synthesis route of catalyst 3b.
Table 1. Screening of unimolecular anion-binding catalysts for controlled ROP of L-1 a
Entry
Catalyst
[L-1]0/[cat]0/[alcohol]0
Time
(h)
Mn,calcd.
Mn,SEC
Đ(Mw/Mn)c
(kDa)b
(kDa)c
1
2
3
4
5
6
7
3a
3a
3a
3b
3b
3b
3b
100:1:0
200:1:0
500:1:0
50:1:0
1
15.2
30.0
74.4
7.8
16.6
26.9
49.0
23.3
41.1
72.7
123.2
1.24
1.34
1.35
1.09
1.07
1.14
1.22
1
8
0.5
1
100:1:0
200:1:0
500:1:0
15.2
30.0
74.4
2
24
8
3b
DMAP
DMAP
DMAP
DMAP+4
DMAP+4
DMAP+4
3c
800:1:0
100:1:0
200:1:0
500:1:0
100:1:0
200:1:0
500:1:0
100:1:0
100:1:0
100:1:0
100:1:0.5
100:1:1
100:1:2
50:1:0
24
1
118.8
14.9
29.7
74.1
14.9
29.7
74.1
15.2
15.1
15.2
29.7
14.9
7.5
150.0
19.0
32.7
45.0
6.6
1.20
1.28
1.34
1.33
1.37
1.34
1.31
1.12
1.15
--
9
10
11
1
8
12
13
14
15
16
17d
18e
19e
20e
21f
22f
23f
1
1
15.3
48.2
55.8
54.0
--
2
2
3d
2
3e
2
3b
1
41.0
40.4
40.0
26.6
44.5
148.8
1.07
1.08
1.10
1.09
1.08
1.19
3b
1
3b
1
3b
0.5
1
7.8
3b
100:1:0
800:1:0
15.2
118.8
3b
24
aThe polymerizations of L-1 were performed in dry DCM (water contents, 20ppm) at 25oC with [L-1]0=0.5M. All of polymerizations (except for entry 17, in which no
obvious polymerization was observed for 2 h) were terminated after achieving 100 % monomers conversion, which were measured by 1H NMR. bMn,calcd. = 148×[L-
1]0/[cat]0 ×Conv.+Mcat.
cMeasured by SEC (DMF, 0.02M LiBr, 50 oC), PMMA calibration. The samples were measured without purification, except for entries 8,
and 23, that were measured after precipitating into methanol, facilitating subsequent mechanical properties tests. dOnly trace conversion of monomers was
f
observed. eBnOH was added as initiator, Mn,calcd. = 148×[L-1]0/[ BnOH]0 ×Conv.+MBnOH. Polymerizations were performed in unpurified DCM (water contents,
465ppm).
4
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Figure 3. ROP of OCAs mediated by unimolecular anion-binding catalyst. (A) Homodecoupling 1H NMR spectrum of the α-methine region of poly (L-1) (B) Plots of
Mn(square, black) and Mw/Mn (circle, red) vs [L-1]0/[3b]0 ratio. (C) SEC chromatograms of poly (L-1) in panel B. (D) Mn and Mw/Mn vs conversion of L-1. (E) SEC
chromatograms of poly (L-1) ([L-1]0/[3b]0=50/1, black), the block copolymer poly (L-1)-b-poly (L-4) ([L-1]0/[L-4]0/[3b]0=50/50/1, blue), and the random copolymer poly
(L-1)-co-poly (L-4) ([L-1]0/[L-4]0/[3b]0=50/50/1, red). (F) Kinetic plots of ln([M]0/[M]t) vs time with [L-1]0=0.5 M and different [L-1]0/[3b]0.
Table 2. Controlled polymerization of OCAs mediated by 3ba
Entry
Monomer
[M]0/[3b]0
Time
(h)
2
Mn,calcd.
(kDa)b
16.3
Mn,SEC
(kDa)c
49.0
Đ(Mw/Mn)c
1
2
L-2
L-2
100:1
200:1
500:1
100:1
200:1
500:1
100:1
200:1
500:1
50:50:1
50:50:1
1.15
1.18
5
33.2
81.4
73.5
139.2
54.9
3
L-2
24
1.22
4
L-3
2
23.1
1.20
5
L-3
5
45.8
81.5
1.17
6
L-3
24
113.9
7.6
145.3
27.9
1.21
7
L-4
1
1.10
8
L-4
2
24
14.8
43.8
1.22
9
L-4
36.4
50.0
1.22
10d
11e
L-1+ L-4
L-1+ L-4
0.5/0.5
1
7.8/11.4
11.4
23.0/37.7
38.0
1.14/1.16
1.14
aThe polymerizations of OCAs mediated by 3b were performed in dry DCM at 25oC with [M]0=0.5M. All of polymerizations were terminated after achieving 100%
monomers conversion, which were measured by 1H NMR. bMn,calcd. = (M(OCA)- M(CO2))×[M]0/[cat]0 ×Conv.+Mcat. cDue to the poor solubility in DMF, these samples
were measured by SEC in THF (35oC, PS calibration). d Block copolymerization of L-1 and L-4 via sequential monomer addition. eRandom copolymerization of L-1
and L-4.
reactions that result in ill-defined polyestes. Therefore, these
polymerizations are generally carried out applying a Schlenk line
or a glovebox to maintain stringent water-free polymerization
conditions.[7-8] Encouraged by the aforementioned findings, we
propose that the low nucleofugality of 3b and rapid
polymerization kinetics might also minimize water-induced side
more convenient to implement ROP of OCAs if a glove box or
Schleck line is not available.
To evaluate the versatility of our unimolecular anion-binding
catalyst, we applied the 3b for ROP of three other OCAs,
including para-tolyl (L-MePheOCA, -2), bromophenyl groups (L-
L
BrPheOCA, L-3), and methyl (L-LacOCA, L-4), (Figure 2A). Under
similar conditions, 3b was able to initiate and polymerize all
three OCAs. The SEC result displayed high MW polyesters with
a low Đ (Đ < 1.25) were obtained (Table 2, entries 1-9).
Particularly, when [M]0/[3b]0 was 500:1, we were pleased to
observe poly(L-3) with a Mn = 145.3 kDa, and a Đ value of 1.21
was achieved. No epimerization of the α-methine hydrogen
occurred (Figures S24−S32). Block copolymer could also be
synthesized via one pot sequential ROP of L-1 and L-4, achieving
controlled Mn and Đ values (Figure 3E, Table 2, entry 10, and
reactions. Therefore, we examined the 3b-mediated ROP of -1
L
using unpurified DCM as solvent. It was found that high MW (Mn
= 26.6-148.8 kDa) polyesters with narrow distributions (Đ =
1.08−1.19) were obtained, in analogy to that produced under
stringent anhydrous conditions (Table 1, entry 21-23). Moreover,
similar well-controlled polymerization behavior was observed
when titrated amounts of water were added to the dry DCM
(Table S1, entry 19). These results are vital because it will be
5
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10.1002/anie.202011352
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Figure S35-37). We also found the random copolymerization of
L-1 and L-4 (50/50) led to full monomers consumption and
formation of a random copolymer with a Mn of 38.0 kDa and a Đ
initiated DMAP moiety in Figure 4C and Figure S50A), resulting
in negatively charged carbonate propagating species, which
were stabilized by the thiourea moiety of 3b via anion-binding
of 1.14, close to the corresponding diblock copolymer (Figure 3E, (shift of the proton signals of NH group in Figure 4C and Figure
Table 2, entry 11, and Figure S38-39).
S50A).
To elucidate the OCA ROP mechanism mediated by
unimolecular anion-binding organocatalyst 3b, we carried out
several kinetic experiments by varying initial [L-1]0/[3b]0 ratios
between 100:1 and 300:1 and monitoring the monomer
FTIR spectrum obtained from the reaction of -1 and 3b in a
L
1:1 molar ratio showed four carbonyl peaks in the 1900-1550
cm−1 range (Figure S52A). Three peaks at 1759, 1716, and 1685
cm-1 were due to the ester of the backbone, carbonyl adjacent to
DMAP moiety and carbonate end-group, consistent with the
proposed carbonate anion propagating species bearing one 3b
moiety at one chain end and carbonate at the other (Figure 4C).
The band at 1697 cm-1 was presumably originated from the
vibrational coupling of carbonate anions due to the anion-binding.
1
conversion by H NMR. Analysis of a plot of ln([M]0/[M]t) vs time
revealed that the ROP was first-order dependence on L-1
concentration (Figure 3F). The polymerization orders with
respect to 3b were 1.14 ± 0.08 (Figures 3F and S46). The above
data demonstrated that the overall rate law can be described as
follows:
We next end-capped the aforementioned low MW poly(L-1)
with electrophiles (e.g., acetylchloride, AcCl) at 25 oC. The 1H
NMR and MALDI-TOF MS results of the afforded product
revealed the polymer chain ends contained one 3b and one
acetoxycarbonyl or acetyl moiety (Figure S53-54). The
generation of acetoxycarbonyl end-groups was also revealed by
FTIR analysis, as confirmed by the appearance of the
characteristic anhydride peak at 1834 cm−1 (Figure S52B).[18]
The bands assigned to the ester of the backbone and the
carbonyl adjacent to DMAP moiety at 1759 and 1716 cm−1
remained unchanged. These findings were consistent with the
proposed carbonate anion propagating intermediates (Figure
4C). Importantly, these observations, coupled with the fact that
high MWs and successful chain extension experiments involved
carbonate ions, reveal that the carbonate anions of growing
chain remains dynamically stable and maintains reactive due to
the synergetic anion-binding interaction. In addition, the
stabilization of reactive carbonate anions by the thiourea moiety
of 3b via anion-binding would also be retained in other
halohydrocarbon (e.g., CHCl3 and ClCH2CH2Cl, see Table S1,
entries 5-6), but would be weakened in the presence of
interaction between thiourea moiety and solvents (e.g., THF),
resulting in slower polymerization and failure to generate high
MW polymers (see Table S1, entry 7).
-d[L-1]/dt=kp[3b]1.14[ L-1]t
(1)
where kp is the propagation rate constant. Meanwhile, initiation
was comparable to propagation, also confirmed by the linear
dependence of ln([M]0/[M]t) on time. A slow initiation relative to
enchainment would lead to curved profiles with gradually
ascending slopes.[18] In addition, the kinetics results revealed
that the monomer activation in current system was weaker than
that in Lewis pairs catalytic systems,[1k] where the kinetics
obeyed zero-order of monomer concentrations due to the strong
monomer activation. The theoretical deduction of the chain
propagation rate law was also in keeping with the above rate law
and had first-order dependence on [3b] and [M]t (see Figure S47
and Derivation of the propagation rate law).
In an effort to gain more insight into the polymerization
mechanism, 3b was allowed to react with L-1 in 1:1 ratio at 25 oC
in CD2Cl2 ([L-1] = 0.025 M). The solution changed from light-
green to yellow-green instantaneously. 1H NMR result of the
reaction mixture (Figure S48) revealed the disappearance of the
monomers and the appearance broad proton resonances
because of low MW poly(L-1). This result again indicated that
initiation was comparable to chain propagation, consistent with
the kinetics results. 1H NMR analysis of purified low MW poly(L-1)
also revealed some information about the nucleophilic ROP of
monomers by DMAP moiety (shift of the proton signals of
Figure 4. Nucleophilic ROP of OCA by DMAP moiety of 3b and the generation of carbonate anion propagating species synergistically. (A) 1H NMR spectrum of
-
L
1. (B) 1H NMR spectrum of 3b. (C) 1H NMR spectrum of low MW poly(L-1) (initial ratio, [L-1]0/[3b]0=10:1, precipitated into n-hexane for purification) in CD2Cl2.
6
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10.1002/anie.202011352
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RESEARCH ARTICLE
Figure 5. Quantum chemical simulations of selective ROP of OCA. (A) Reaction diagram for ROP of OCA by 3b. The structures described here are
corresponding to the optimized reaction coordinate (see Figure S64) for the transition states and intermediates. H-bonding interactions are indicated with purple
dashed lines. Breaking and forming bonds are indicated with green dashed lines. Grey regions exhibit that the carbonate anion is stabilized via anion-binding to
the thiourea moiety of 3b. The calculations indicate a dynamic cooperative anion-binding mechanism where the dynamic stability of the carbonate anion
propagating intermediate facilitates efficient chain propagation and the synergetic decarboxylation retains high selectivity for monomer ring-opening over side
reactions. (B) Energy profile of the mechanism for 3b-mediated ROP of OCA. All energies are relative to the separated reactants in the unit of kcal/mol (red
numbers).
The calculations reveal the initial formation of a reactant
These results further support that the thiourea moiety aids in the
complex (RC) comprising the thiourea moiety of 3b hydrogen-
bonded to both endocyclic and exocyclic oxygen atom of the L-4,
which is an exergonic process by 2.9 kcal/mol more stable than
activation of the monomers and subsequently stabilizes the
carbonate anion propagating species.
To better understand the mechanism of 3b-mediated
the reactants (Figure 5B). Subsequent nucleophilic attack of the
selective OCA polymerization, we employed the dispersion
DMAP moiety in 3b onto the hydrogen-bonding activated
corrected B3LYP-D3 density functional in conjunction with the 6-
carbonyl group of L-4 occurs via transition state TS1 with an
31G (d,p) basis set, to identify structures of the transition states
activation barrier of about 16.1 kcal/mol. The resulting carbonate
(TS) and intermediates (INT), and to determine free energies of
anion intermediate INT1 is stabilized via anion-binding to the
the reaction pathways (Figure 5, for detailed Methods,
thiourea moiety of 3b, which agrees with 1H NMR (Figure 4C
Optimized structures and Coordinates, see Computational
and Figure S50A) and FTIR studies (Figure S52). The binding of
methodology in SI). For the sake of clarity and simplicity,
an additional -4 monomer to 3b facilitates dynamic dissociation
L
monomer L-4 was used as a model monomer in the computation.
7
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10.1002/anie.202011352
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RESEARCH ARTICLE
of intermediate INT1 to afford the intermediate INT2. This result
implies that the anion-binding interaction is dynamic similarly to
the chloride anion transport in chloride channel, in contrast to
that of traditional metal-mediated polymerization where the tight
metal-carbonate was formed, which is critical for the efficient
chain propagation and synthesis of high MW polyesters. The
decarboxylation of INT2 and nucleophilic attack of the alkoxy
onto the carbonyl group of L-4 proceeds cooperatively (TS2) with
an activation barrier of 15.8 kcal/mol to give tetrahedral
intermediate INT3. Ring-opening of the tetrahedral INT3 is facile
and requires a low barrier of 4.1 kcal/mol (TS3) to produce
carbonate anion propagating intermediate INT4 for further
enchainment. The calculations also suggest that direct
decarboxylation to form the alkoxide anion intermediate (via
TS2’, Figure 5B and S64C) is energetically less favoured
compared to synergetic decarboxylation (activation barrier of
TS2 vs TS2’, 15.8 kcal/mol vs 33.7 kcal/mol). This result offers a
rationale for the high selectivity of the unimolecular anion-
binding catalyst system for OCA ring-opening over epimerization,
cyclization, and transesterification: the undesired highly basic
alkoxide propagating species is avoided due to the synergetic
decarboxylation, thereby minimizing extensive side reactions.
potential side reactions (e.g., cyclization, transesterification and
epimerization) by reducing the basicity and nucleophilicity of the
anionic propagating species via the synergetic decarboxylation.
In addition, deviation of the polyester Mn,SEC from the
theoretical values may be attributed to the unique self-
association of 3b as evidenced by calculations (see geometry
optimizations for 3b, Figure S64A) as well as its broadened and
overlapped proton resonances as compared to the methylated
1
counterpart 3f in variable-temperature 19F and H NMR spectra
(Figure S58-61), resulting in significantly reduced initiation
efficiency. The initiation efficiency, estimated as the
Mn,calcd/Mn,SEC × 100 %, ascends from 37% to 79% as [L-1]0/[3b]0
ratio raises from 25:1 to 800 :1 (Figure S62). This result seems
reasonable as the lower concentration of 3b disfavored self-
association behavior and hence promoted high initiation
efficiency. Indeed, similar intramolecular self-association was
also observed in the typical Takemoto’s catalytic system,[22]
which was different from the intermolecular association in
bicomponent thiourea/amine catalytic systems.[23] It is also
postulated that the self-association accounts for the deviation
from the ideal “living” behavior in our system.
Poly(phenyllactic acid) (Ph-PLA) is a phenyl-substituted PLA
polymer, where the aromatic ring could lead to enhanced
hydrophobic interactions and rigidity.[5] So far, all of the
previously reported Ph-PLA are very brittle with a very low
elongation at break due to low MW less than 50.0 kDa,[6h]
limiting possible commodity and biomedical applications. It is
well known that mechanical properties of a polymer increase as
the MW increases. In this context, the stress-strain behavior of
Ph-PLA with different Mns were comparatively studied (Figure 6).
As expected, the mechanical properties of high MW Ph-PLA
(Mn= 150.0 kDa) were quite different from those of low MW
congener (Mn= 41.1 kDa). The measured tensile strength for
high MW Ph-PLA was 4.3-fold higher than that measured for low
MW analog. Importantly, the elongation at break of high MW Ph-
PLA was approximately 30 times higher than its low MW
counterpart. Therefore, it is of importance to obtain high MWs
polyesters for improving their mechanical properties.
Computational studies support the hypothesis of a dynamic
cooperative anion-binding mechanism where the dynamic
stability of the carbonate anion propagating intermediate
facilitates efficient chain propagation and the synergetic
decarboxylation retains high selectivity for monomer ring-
opening over side reactions. This is in contrast to classical
thiourea-based organocatalytic polymerization[1l, 2g, 2i, 9, 14] and our
previous chloropyridine-thiourea system[6g] where the thiourea
moiety is only considered as a H-bonding donor to activate
monomers, or the thiourea moiety is deprotonation to yield
thioimidate to activate the alcohol. Computational studies also
indicate that the abstraction of α-H of L-4 by DMAP moiety is less
preferred and the transition state (TS1’, Figure 5B and S64B)
has a higher barrier than that of initiation and propagation (TS1,
TS2 and TS4), further attesting to the disfavour of epimerization
side reactions.
This mechanism is reminiscent of that proposed for the
polymerization mediated by the N-heterocyclic carbene (NHC),[1l,
15, 19]
a versatile organic catalyst for ROP. In contrast to widely
studied zwitterionic ring-opening polymerization mediated by
18, 20]
NHC where the cyclic products were generated,[15,
no
respective cyclic congeners were obtained via liberating the 3b
in our system, as evidenced by MALDI-TOF-MS analysis (Figure
S54). This can be attributed to the reduced nucleofugality of 3b
and anion-binding interactions (or more specifically synergetic
decarboxylation), thus suppressing possible cyclization side
reactions and allowing the synthesis of high MW polyesters.
Indeed, the calculations also reveal that the synergetic
decarboxylation and back-biting of alkoxy of INT4’ (Figure 5B
and S64D) onto the carbonyl group of initiating acylpyridinium is
unfavorable (TS4’).[21] In addition, computational studies verify
our previous speculation that the BnOH-initiated chain
propagation is significantly suppressed compared to the
synergetic decarboxylation and ring-opening propagation
(activation barrier of TS2’’ vs TS2 or TS4, 25.9kcal/mol vs 15.8
kcal/mol or 13.6 kcal/mol, see Figure 5B, S64 and S65).
Collectively, the unique dynamic anion-binding interactions is
critical for the controlled polymerization behavior and high MW.
In addition to facilitating the efficient chain propagation, anion-
binding maintained by the thiourea moieties also manage
Figure 6. Stress-strain curves of low MW Ph-PLA (SA, red curve, E=1076 Mpa,
σb= 5.1MPa, εb=0.5%, Mn,SEC= 41.1 kDa, entry 5 in Table 1) and high MW Ph-
PLA (SB, blue curve, E=1370 Mpa, σy= 22.3MPa, εb=15%, Mn,SEC= 150.0 kDa,
entry 8 in Table 1). Break point indicated by “X”. Inset data between 0 and
1.0% strain.
8
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RESEARCH ARTICLE
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Conclusion
Inspired by the nature of anion-binding, we developed here,
an unimolecular anion-binding organocatalysis for the efficient
ring-opening polymerization of OCAs, generating high MW
isotactic polyesters bearing diverse functionality. High MW
polyester shows significantly improved mechanical properties in
comparison to the low MW congeners. The experimental and
DFT calculations highlighted the key roles played by the unique
dynamic anion-binding interaction of thiourea moiety to
propagating species and the synergistic decarboxylation for
addressing the tradeoff issue between efficient chain
propagation and minimal epimerization. The moisture-tolerant of
these unimolecular anion-binding catalysts, coupled with their
ability to impart potent control on ring-opening polymerization,
illustrate their potential to the chemistry community.
Organocatalytic ring-opening polymerization via thiourea-based
H-bond organocatalysts have been reported previously;[1l, 9b, 14a-c]
however, this is the first time that a process based on anion-
binding, which represents an advanced binding mode has been
used for selective ring-opening polymerization of OCAs, and has
potential feasibility for other monomers, such as N-
carboxyanhydrides (NCA) and propiolactones. Furthermore, We
believe that the concept of utilizing the dynamic anion-binding to
suppress side reactions (e.g., cyclization, transesterification and
epimerization) and to facilitate the chain propagation is universal
and valuable that is often inaccessible to more conventional
organobases or transition metal-based catalysts.
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Acknowledgement
This work is supported by the National Natural Science
Foundation of China (Grants 91856113, 51873211, 52073274,
and 22001243) and the Jilin Science and Technology Bureau
(Grant 20200301023RQ). Helpful discussions with Prof.
Junpeng Zhao (South China University of Technology, China)
and Dr. Fengchao Cui (Changchun Institute of Applied
Chemistry, Chinese Academy of Sciences) are gratefully
acknowledged.
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Conflict of interest
The authors declare no competing financial interests.
Keywords:
Anion-binding
catalysis;
O-carboxyanhydrides;
Ring-opening
polyesters;
polymerization;
stereoregularity
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cyclization reaction through liberating nucleophile catalyst would easily occur
in high monomer conversion, thereby detrimental to the synthesis of high
molecular weight polymers. In order to compare the nucleofugality between
catalyst 3a and 3b more intuitively, we conducted nucleophilic substitution
model reactions between methanol (MeOH) and the anion-binding electrophilic
intermediates produced via mixing of catalyst 3a or 3b with succinic anhydride
(SA) at 1:1 ratio (See Figure S40).
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Entry for the Table of Contents
RESEARCH ARTICLE
[a]
[b]
M. Li,[a] S. Zhang,
X. Zhang,
[a]
Y.
[a]
Wang,
J. Chen,
Y. Tao,*[a] X.
Wang*[a]
Page No. – Page No.
Unimolecular
Anion-Binding
Catalysts for Selective Ring-opening
Polymerization
of
O-
carboxyanhydrides
11
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