S-Carboxyanhydrides: Ultrafast and Selective Ring-Opening Polymerizations Towards Well-defined Functionalized Polythioesters

Article abstract of DOI:10.1002/anie.202016228

Aliphatic polythioesters are popular polymers because of their appealing performance such as metal coordination ability, high refractive indices, and biodegradability. One of the most powerful approaches for generating these polymers is the ring-opening polymerization (ROP) of cyclic monomers. However, the synthesis of precisely controlled polythioesters via ROP of thiolactones still faces formidable challenges, including the minimal functional diversity of available thiolactone monomers, as well as inevitable transthioesterification side reactions. Here we introduce a hyperactive class of S-carboxyanhydride (SCA) monomers derived from amino acids that are significantly more reactive than thiolactones for ultrafast and selective ROP. Inclusion of the initiator PPNOBz ([PPN]=bis(triphenylphosphine)-iminium) with chain transfer agent benzoic acid, the polymerizations that can be operated in open vessels reach complete conversion within minutes (1–2 min) at room temperature, yielding polythioesters with predictable molecular weight, low dispersities, retained stereoregularity and chemical recyclability. Most fascinating are the functionalized SCAs that allow the incorporating of functional groups along the polythioester chain and thus finely tune their physicochemical performance. Computational studies were carried out to explore the origins of the distinctive rapidity and exquisite selectivity of the polymerizations, offering mechanistic insight and explaining why high polymerizability of SCA monomer is able to facilitate exquisitely selective ring-opening for enchainment over competing transthioesterification and backbiting reactions.

Full text of DOI:10.1002/anie.202016228

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How to cite: Angew. Chem. Int. Ed. 2021, 60, 10798–10805
International Edition:
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doi.org/10.1002/anie.202016228
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Polymerization
Hot Paper
S-Carboxyanhydrides: Ultrafast and Selective Ring-Opening
Polymerizations Towards Well-defined Functionalized Polythioesters
Yanchao Wang, Maosheng Li, Shixue Wang, Youhua Tao,* and Xianhong Wang
Abstract: Aliphatic polythioesters are popular polymers
because of their appealing performance such as metal coordi-
nation ability, high refractive indices, and biodegradability.
One of the most powerful approaches for generating these
polymers is the ring-opening polymerization (ROP) of cyclic
monomers. However, the synthesis of precisely controlled
polythioesters via ROP of thiolactones still faces formidable
challenges, including the minimal functional diversity of
available thiolactone monomers, as well as inevitable trans-
thioesterification side reactions. Here we introduce a hyper-
active class of S-carboxyanhydride (SCA) monomers derived
from amino acids that are significantly more reactive than
thiolactones for ultrafast and selective ROP. Inclusion of the
initiator PPNOBz ([PPN] = bis(triphenylphosphine)-imini-
um) with chain transfer agent benzoic acid, the polymeri-
zations that can be operated in open vessels reach complete
conversion within minutes (1–2 min) at room temperature,
yielding polythioesters with predictable molecular weight, low
dispersities, retained stereoregularity and chemical recyclabil-
ity. Most fascinating are the functionalized SCAs that allow the
incorporating of functional groups along the polythioester
chain and thus finely tune their physicochemical performance.
Computational studies were carried out to explore the origins
of the distinctive rapidity and exquisite selectivity of the
polymerizations, offering mechanistic insight and explaining
why high polymerizability of SCA monomer is able to facilitate
exquisitely selective ring-opening for enchainment over com-
peting transthioesterification and backbiting reactions.
including high refractive index, improved crystallinity, and
enhanced depolymerizability. Because of these subtle and
profound changes, polythioesters possess great potential in
dynamic and responsive materials,[5] chemically-recyclable
materials,[6] and degradable biomaterials.[7]
Generally, aliphatic polythioesters can be directly pre-
pared from mercaptoacetic acid by polycondensation under
azeotropic distillation conditions,[8] but ring-opening poly-
merization (ROP) of thiolactones is commonly favoured
because it enables the generation of higher molecular weight
polythioesters and allows for the use of mild reaction
conditions (Figure 1).[9] As ROP of thiolactones is a trans-
thioesterification reaction, competitive transthioesterification
of the resultant polymer can result in widening of the
molecular weight distribution, relying on the relative rates
of propagation (ring-opening) and chain transfer (trans-
thioesterification, backbiting). For instance, an interesting
work by Kiesewetter et al. described the organocatalytic ROP
of e-thiocaprolactone.[9b] However, the obtained polythioest-
ers were featured by broad molecular weight distribution
(“ = 1.4–2.1) and unsatisfactory Mnꢀs commonly lower than
30 kDa due to transthioesterification side reactions.
Motivated by the importance of the targets, the labora-
tories of Gutekunst,[10] Bowman,[11] Suzuki,[12] Lu,[13] Ren[14]
and Chen[15] have developed elegant strategies for more
Introduction
Sulfur-containing polymers are fascinating materials that
have received increasing attention due to their unique
properties, such as metal coordination ability,[1] high optical
features,[2] self-healing capability,[3] and so forth. Among all of
the sulfur-containing functional polymers, polythioesters are
particularly interesting because they exhibit intriguing chem-
ical properties different from those of oxoester analogues,[4]
[*] Y. Wang, M. Li, S. Wang, 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
Y. Wang, Y. Tao
University of Science and Technology of China
Hefei 230026 (P. R. China)
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under https://doi.org/10.
1002/anie.202016228.
Figure 1. Methods for the synthesis of polythioesters.
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controlled sulfur-based ROP towards polythioesters. How-
(for library generation) and large-scale preparation of
ever, the synthesis of precisely controlled polythioesters via
ROP of thiolactones still faces formidable challenges, includ-
ing the minimal functional diversity of available thiolactone
monomers, as well as the trade-off between selectivity and
efficient chain propagation: running polymerizations to full
conversion enhances the efficiency but also promotes com-
petitive transthioesterification. The suppression of undesired
functionalized polythioesters, even when the glovebox,
Schlenk line and dry solvents are not available. Computa-
tional studies were also carried out to provide mechanistic
insight into the ROP process utilizing highly polymerizable
SCAs.
transthioesterification can be achieved by the use of fused or Results and Discussion
bridged-ring thiolactone monomers,[11,13] but this strategy can
be complicated by the moderate accessibility and the
generation of well-defined polythioesters to full monomer
conversion is still precluded by transthioesterification side
reactions (Figure 1). For example, Bowman et al. demon-
strated polymerization of fused-ring thiolactone, furnishing
DNA-mimicking polythioesters with fairly low “ in the scope
of 1.2–1.3 for the first time.[11] Nevertheless, the highest Mn of
the polythioesters described was 7.6 kDa with a monomer
conversion of 27%. Lu very recently implemented trans-
thioesterification-free ROP of geminal-dimethyl-substituted
thiolactones in the preparation of precision polythioesters,[6]
but the the highest monomer conversion observed was 70%.
Another example of polythioester was produced through
alternating copolymerization of cyclic thioanhydride and
episulfide,[16] which addresses the increasing need for struc-
turally diverse polythioesters. However, this approach faces
similar compromise between selectivity and efficient chain
propagation, and side reactions cannot be eliminated when
running polymerizations to full conversion. Therefore, more
general strategies that improve the selectivities for ring-
opening relative to transthioesterification but still maintain
the versatile functionality are highly required.
To address these challenges, we turned to 1,3-oxathiolan-
2,5-diones,[17] so-called S-carboxyanhydrides (SCAs) for in-
spiration. We wondered if SCAs that are significantly more
reactive than thiolactones would generate precisely con-
trolled polythioesters based on the hypothesis that the highly
polymerizable monomer allows for the use of softer catalysts
and promotes highly selective ring-opening of the monomer
for enchainment over competing transthioesterification reac-
tions. Moreover, the crucial advantage of this approach over
the ROP of thiolactones for producing polythioesters is the
large number and diversity of functional monomers that are
easily synthesized from a-amino acid precursors which
inherently possess diverse functionality,[18] allowing for finely
tuning of properties and post-polymerization modification.
Finally, the corresponding amino acid precursors contain
stereogenic centers, which can be both an asset and a chal-
lenge for synthesizing polythioesters of controlled tacticity.[19]
Herein, we introduce a new paradigm of amino acid-
derived SCAs for ultrafast and selective ROP (Figure 1).
Through the application of the highly polymerizable SCAs,
historical challenges in the field have been addressed to
prevent undesired side reactions. As such, in our system,
a series of well-defined polythioesters were obtained with
controlled molecular weights (MWs), low “, retained stereo-
regularity, versatile functionality and chemical recyclability.
Moreover, SCA polymerization can be conducted in an open
vessel, using undried solvents, facilitating parallel synthesis
As a preliminary evaluation of the relative reactivity of
thiolactone, thiolactide and LacSCA, the reactions 1, 2 and 3
simulation the growth step of the ROP were computationally
studied. ROP of LacSCA was predicted to be thermodynami-
cally much more preferred than that of thiolactone and
thiolactide,[20] the liberating of a CO2 molecule being an
extensive driving force for entropic reason (Figure S1).
Figure 2 displayed the preparation and chemical structure
of five amino acid-derived SCA monomers, denoted as D-
SerSCA (D-1), D-GluSCA (D-2), D-LysSCA (D-3), D-
TyrSCA (D-4) and rac-PheSCA (rac-5), respectively. Briefly,
the SCA monomer was prepared in three steps from a-amino
acid. Diazotization with sodium nitrite in hydrogen bromide
solution, followed by substitution with sodium hydrosulfide,
led to the corresponding a-mercapto acid. Subsequent treat-
ment with triphosgene in the presence of activated charcoal
afforded SCA as white needle crystal. 1H NMR, and
13C NMR confirmed the monomer structure (Figures S2–
S11).
Initial attempts of polymerizing enantiomerically pure D-
1 at 258C in toluene at monomer to initiator ratio [D-1]0/[I]0 =
50/1, using organobases as initiators, such as triethylamine
(TEA), and 4-(N, N-dimethylamino) pyridine (DMAP),
either formed an oligomer or gave lower polymer MWs than
the theoretical values (Table 1, entries 1,2, Figures S29,S30).
This can be attributed to zwitterionic ring-opening polymer-
ization,[21] thus easily generating cyclic polythioesters with low
MWs via liberating the organic base. The stereostructures of
the obtained polythioesters were analyzed by 13C NMR. As
demonstrated in Figure 3, polythioester obtained under TEA
=
or DMAP showed broad multiplets for the C O and CH2
regions, typical of a random stereosequence distribution
suggestive of base-mediated racemization of the SCA result-
ing in atactic polythioester.
In an effort to enhance the MWs and stereocontrol, we
turned our attention to PPNCl ([PPN] = bis(triphenylphos-
phine) iminium), an organic ammonium salt, as the initiator
to induce the SCA polymerization. However, PPNCl still
mediated ill-controlled ROP, and the observed MW is
significantly higher than the predicted value (entry 3). This
suggests a slow rate of initiation relative to propagation, due
to the much higher nucleophilicity of the sulfide anion chain
ends relative to chloride anion.
The employment of other organic ammonium salts,
dodecyltrimethylammonium bromide (DTMeAB)[22] and tet-
raoctylammonium bromide [(Oct)4Br][23] also gave unsatis-
factory control over polythioester MW (entries 4,5), therefore
we decided to screen chain transfer agents (CTAs). The
addition of benzyl mercaptan (BnSH) had little effect on the
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Figure 2. Typical synthesis route and ROP of SCA and Structures of initiators and chain transfer agents (CTA).
Table 1: Optimization and Ring-opening Polymerization Results of D-SerSCA (D-1).[a]
Entry
Initiator
(I)
[D-1]0/
[CTA]0/[I]0
t
Mn,calcd
Mn,SEC
“
[min]
[kDa][b]
[kDa][c]
(Mw/Mn)[c]
1
2
3
4
5
Et3N
DMAP
PPNCl
DTMeAB
(Oct)4NBr
PPNCl
50/0/1
50/0/1
50/0/1
50/0/1
50/0/1
<1
<1
<1
<1
<1
<1
2
2
2
2
2
2
2
2
2
2
2
2/6
9.8
9.8
9.7
9.8
9.8
9.6
9.6
9.6
4.9
18.7
37.4
60.7
116.5
4.9
9.6
18.7
9.6
6.5
1.4
2.13
1.10
1.34
1.40
1.44
1.35
1.26
1.26
1.24
1.26
1.27
1.28
1.29
1.27
1.27
1.26
1.23
1.26/1.28
151.0
118.0
80.7
149.5
9.6
6[d]
7
8
9
10
11
12
13
14[e]
15[e]
16[e]
17[f]
18
2500/50/1
2500/50/1
2500/50/1
2500/100/1
2500/25/1
2500/12/1
2500/7/1
3000/4/1
2500/100/1
2500/50/1
2500/25/1
2500/50/1
2500/2500/50/1
PPNCl
PPNOBz
PPNOBz
PPNOBz
PPNOBz
PPNOBz
PPNOBz
PPNOBz
PPNOBz
PPNOBz
PPNOBz
PPNOBz
9.5
5.1
18.6
36.9
54.1
96.2
5.2
9.8
19.0
9.4
9.6/19.1
9.2/18.7
[a] The polymerizations of D-1 were performed in dry toluene at room temperature, with [D-1]=0.1 M, CTA=benzoic acid (BzOH). All of
polymerizations were terminated after achieving >99% monomers conversion, which were measured by 1H NMR. [b] Mn,calcd =194”[D-1]0
/([CTA]0 +[I]0) ” Conv.+ MW(terminal group). [c] Measured by SEC (THF, 358C), PS calibration. [d] BnSH was added as CTA. [e] Polymerizations were
performed in open vessels using undried toluene as solvent (water contents, 355 ppm). [f] Polymerizations were performed in open vessels using
dried toluene + 5% water (relative to toluene) as solvent.
polymerization rate and polymer MW (entry 6). Indeed, the
proton cannot be exchanged between the growth polymer
chain end-capped with -COCH(R)SÀ and BnSH since the
-COCH(R)SH end group has a higher acidity than BnSH.
To produce polymers with uniform molecular weights,
Coates had suggested that chain transfer rate should be faster
than or match propagation rate.[24] Therefore, more acidic
chain transfer agent is more effective for regulating polymer
MW in hyperactive SCA system. The polymerization showed
a promising result when using benzoic acid (BzOH) as CTA:
the MW control was markedly improved (entry 7).
Finally, the anion of the organic ammonium salt was
further optimized, and satisfying results were achieved using
PPNOBz ([OBz] = benzoyloxy, Figures S12,S13) with BzOH,
delivering ultrafast polymerization and reaching complete
conversion in just 2 min at 258C for a related [D-1]0/
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=
responding to the C O and CH regions, illuminating retained
stereoregularity (Figure 3, Figure S15). These results indicate
that the induction of PPNOBz/BzOH does not influence the
chiral centers of SCAs with high tolerance of pendent
functionalities, due to the ultrafast polymerization rate and
reduced basicity and nucleophilicity of PPNOBz relative to
DMAP.
Polythioesters with predictable Mn values ranging from
5.1 kDa to 96.2 kDa can be readily synthesized by controlling
the [D-1]0/[CTA]0 ratio (entries 9–13, Figure 4A). The exper-
imental polythioester Mn values generally concur with the
theoretical values calculated from the conversion and [D-
1]0/[CTA]0 ratio. Notably, the evolution of Mn exhibited
a linear correlation with monomer conversion while “
remained relatively low (< 1.3) up to high monomer con-
version (Figure 4B), and even after prolonged reaction time,
indicating minimal transthioesterification (Figure S31, Ta-
ble S2). Additionally, the quantitative incorporation of CTA
Figure 3. Stereostructures of polythioester from ROP of D-1 determined
by 13C NMR (CDCl3) in the C O and CH regions. The polymerization
=
1
initiated by Et3N or DMAP displayed epimerization of a-methine, while
the utilization of PPNOBz/BzOH showed retained stereoregularity.
in the obtained polythioester was illuminated by H NMR
spectroscopy (Figure S32). High-resolution electrospray ion-
ization mass spectrometry analysis also suggested the poly-
thioester contained benzoic anhydride group at the initiating
terminal and thiol group at the capping terminal (Figure S33).
Together the data suggested that PPNOBz/BzOH -mediated
polymerization of SCA monomer is well-controlled with the
high selectivity for enchainment over competitive trans-
thioesterification reactions.
[CTA]0/[I]0 ratio of 2500/50/1 (entry 8). Having identified the
much higher reactivity of SCA relative that of thiolactone, we
further identified the controlled feature of the targeted
polythioester exhibiting a low molecular weight distributions
(“ = 1.26) and Mn close to the theoretical value (entry 8).
Most importantly, 13C NMR spectrum of polythioester medi-
ated by PPNOBz/BzOH demonstrated narrow singlets cor-
To further manifest the controlled nature of the SCA
polymerization, a chain extension experiment, where the
Figure 4. ROP of SCAs. A) Plots of Mn and “ as a function of the [M]0/[CTA]0 ratio. Inset: Overlay of SEC profiles at different [M]0/[CTA]0 ratios.
B) Profiles of Mn and “ as a function of D-1 conversions at the [D-1]0/[CTA]0/[I]0 ratio of 5000/50/1. Inset: Overlay of SEC profiles at different D-
1 conversions. C) SEC chromatograms of poly(D-1) ([D-1]0/[CTA]0/[I]0 =1000/40/1) and the block copolymer poly(D-1)-b-poly(D-2) ([D-1]0/[D-2]0/
[CTA]0/[I]0 =1000/1000/40/1). D) Kinetic profiles of ln([M]0/[M]) vs. time with varied PPNOBz equivalents at the [M]0/[CTA]0 ratio of 50/1.
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adding of 50 equiv D-1 to a pre-formed poly(D-1) of Mn =
9.2 kDa and “ = 1.26 in the presence of 1:50 PPNOBz/BzOH
resulted in a clean chain extension to furnish a poly(D-1) with
Mn improved to 18.7 kDa while remaining a low “ = 1.28
(Figure S34).
To expand the monomer scope, we explored the ROP of
D-GluSCA (D-2), D-LysSCA (D-3), D-TyrSCA (D-4) and
rac-PheSCA (rac-5), respectively (Figure 2A). In all cases,
rapid and controlled polymerizations were realized, similar to
that of D-1; all the “ values were < 1.3, and no epimerization
of the a-methine region was watched (Table 2, Figure S16–
S23).[25] The corresponding polythioester with pendant amino
groups was recovered by cleavage of carbobenzyloxy (Cbz)
protecting groups of poly(D-3) (Figure S35,S36). Further-
more, a random copolymerization of D-1 and D-2 gave
copolymers with excellent control, shown by both Mn and “
(Table 2, entry 5). Sequential ROP of D-1 and D-2 in one-pot
synthesis gave a well-defined block copolymer poly(D-1)-b-
poly(D-2), once again highlighting the controlled nature of
the ROP (Table 2, entry 6; Figure 4C, Figure S24–S27). Over-
all, the ROP of SCA monomers offered controllability and
tunability over Mn, “, stereoregularity, and side-chain func-
tionalities.
To elucidate the SCA ROP mechanism by PPNOBz,
combined with BzOH, we carried out several kinetic experi-
ments at various PPNOBz concentrations. Every one of the
kinetic profiles exhibits an induction period (1–3 min) where
the conversion of D-1 stays at zero (Figure 4D). Following the
induction period is a first-order kinetic profile, in accord with
the ring-opening of D-1 to polythioester. Increasing PPNOBz
concentration led to the similar first-order kinetic plot but
a faster reaction (Figure 4D). The corresponding rate con-
stant (kobs), achieved from the slope of the best-fit linear line
to the plot of ln([D-1]0/D-1]t) vs. time, was 1.254 Æ 0.050,
0.851 Æ 0.050, and 0.528 Æ 0.016 minÀ1.
Figure 5. A) Open-vessel polymerization of SCA at 5 g scale. B) The
photograph of poly(rac-5) as a transparent film obtained by hot
compression at 1208C. C) Tg values of the functionalized polythioest-
ers.
2 min to generate expected polythioesters with variable and
controllable MWs (Mn = 5.2–19.0 kDa), and low dispersity
(“ < 1.3) (entries 14–17), in analogy to that produced under
stringent anhydrous conditions.
The functionalized polythioesters can be manufactured
into a transparent film by hot compression at 1208C with no
detectable decomposition (Figure 5B). In the tensile test,
poly(rac-5) displayed a tensile strength of 9.8 MPa and
a elongation at break of 40% (Figure S37). Most of these
polythioesters were soluble in common solvents (e.g., di-
chloromethane, toluene, and tetrahydrofuran) (Table S3).
The glass-transition temperatures (Tg) of these polythioesters
were strongly influenced by the substituents of the SCAs
(Figure 5C). Tg was À2.58C for the polythioesters from D-
GluSCA, and it increased to 8.38C for the polythioesters from
D-SerSCA, and it was further raised to 36.58C for the
polythioesters from D-TyrSCA (Table S4, Figure S38). The
wide Tg scope enables these polythioesters potentially as
elastomers or plastics. Another remarkable feature of poly-
thioesters that was obtained by SCA polymerization is their
depolymerization ability. Initial attempts on the depolymeri-
zation of polythioester poly(D-1) using triethylamine as the
catalyst in CDCl3 at 258C gave a quantitative recovery of the
The ROP of thiolactone is sensitive to water and is
commonly implemented using a Schlenk line or a glovebox
utilizing dry solvents.[6,9b] Encouraged by the aforementioned
findings, we propose that the reduced basicity of propagating
species and ultrafast polymerization kinetics might also
minimize water-induced side reactions. Therefore, we exam-
ined the PPNOBz/BzOH-mediated ROP of D-1 in open
vessels outside of the glovebox, utilizing undried toluene as
solvent (Figure 5A). Excitingly, the ROP is water-insensitive
and occurs smoothly, reaching > 99% conversion in only
Table 2: Controlled polymerization of SCAs mediated by PPNOBz/BzOH.
Entry
Monomer
[M]0/[CTA]0/[I]0
t
Mn,calcd
Mn,SEC
“
[min]
[kDa][b]
[kDa][c]
(Mw/Mn)[c]
1
2
3
D-2
D-3
D-4
1000/40/1
1000/40/1
1000/40/1
1000/40/1
1000/1000/40/1
1000/1000/40/1
5
15
20
12
5
5.9
6.9
6.7
4.1
10.6
4.9/10.6
5.7
6.7
6.5
3.6
10.7
4.4/10.8
1.28
1.29
1.27
1.21
1.27
1.24/1.28
4
rac-5
D-1+D-2
D-1/D-2
5[d]
6[e]
3/5
[a] The polymerizations of SCAs were performed in DCM at room temperature. with [M]=0.1 M. All of polymerizations were terminated after achieving
>99% monomers conversion, which were measured by 1H NMR. [b] Mn,calcd =[MW(SCA) À44]”[M]0/([CTA]0 +[I]0) ” Conv.+ MW(CTA).
[c] Determined by SEC at 358C in THFrelative to PS standards. [d] Random copolymerization of D-1 and D-2. [e] Block copolymerization of D-1 and D-2
via sequential monomer addition.
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corresponding cyclic dithioester monomer (Figure S40). Fur-
SCA monomer. Moreover, the calculated energy barrier for
ther detailed investigation of the depolymerization behaviors
is still undergoing in our laboratory.
chain backbiting involving nucleophilic attacking onto the
terminal anhydride was 6.6 kcalmolÀ1 higher than that of
chain propagation (14.5 vs. 7.9 kcalmolÀ1) (Figure S43).
Overall, computational studies illustrated the high polymer-
izability of SCA monomer, the exquisite selectivity and well-
controlled nature of the polymerizations.
Additionally, CD measurement of poly(D-1) exhibited
obvious Cotton effect, demonstrating chiral properties of the
resultant polythioesters. Enantiomer of D-1 was similarly
polymerized to furnish poly(L-1) with approximate opposite
Cotton effect (Figure S41).
On the basis of the aforementioned results, we thus
postulate a polymerization mechanism for ROP of SCA
mediated by PPNOBz/BzOH (Figure 7). The polymerization
starts with the nucleophilic attacking of PPNOBz to the
highly reactive SCA. Then the formed sulfide anion gets
protonated by another carboxylic acid immediately because
of its high basicity, furnishing a thiol and another carboxylate.
This initiation step proceeds iteratively until all the carboxylic
acids are exhausted. After that, the proton transfer between
dormant (thiol) and active (sulfide anion) chain ends,
proceeds simultaneously with the chain growth in an ultrafast
manner, leading to the propagation of polythioester chains.
When PPN cation was replaced by other cations (e.g.,
tetrabutylammonium), well-controlled polymerization could
also be achieved, which further verified the proposed
polymerization mechanism (Table S1, entry 19). This mecha-
nism is closely analogous to that postulated for the carboxyl-
initiated polymerization of epoxide mediated by an organo-
base.[26] Owing to the large acidity discrepancy between the
initiating and propagating species, along with the low
initiator-to-CTA ratio, chain growth is self-inhibited in the
initiation step. Indeed, computational investigations also
reveal that the reaction of carboxylic acid with sulfide anion
by proton transfer is energetically more preferred (4.3 kcal
molÀ1) relative to the chain propagation (Figure S44, Fig-
ure 6B). The ROP therefore displays a distinct controlled
The ultrafast polymerization rates and selectivity for ring-
opening relative to other competing reactions (transthioes-
terification and backbiting) are typical features of these SCA
monomers. To address the underlying reason for exquisite
selectivity, we evaluated nucleophilic attack on SCA mono-
mer (propagation) and polymer mid-chain (transthioesterifi-
cation or backbiting) with DFT computations (Figure 6A,
Figure S43,S44 and “Computational methodology” Section in
SI). For clarity and simplicity, methyl was utilized as the side
chain in the model reactions. The exothermic chain propaga-
tion had a net free energy decline of 8.6 kcalmolÀ1 in toluene
(INT1 to INT3). Nucleophilic attack of the sulfide anion onto
the carbonyl group of SCA occurs via transition state TS1 with
an activation barrier of 7.9 kcalmolÀ1 (Figure 6B, INT1 to
TS1). By contrast, examination of the model transthioester-
ification (INT1 to 2-INT3) in Figure 6B suggested an energy
barrier ꢀ16.0 kcalmolÀ1. The 8.1 kcal. molÀ1 discrepancy in
the energy barrier between propagation and transthioester-
ification demonstrated a ꢀ 8.40 ” 105-times rate discrepancy
at room temperature.[13] The calculations also implied that the
ring opening and liberation of CO2 were then discrete
processes rather than concerted. These results provide clear
mechanistic support for the hypothesis that the exquisite
selectivity towards monomer propagation over transthioes-
terification is a consequence of the high polymerizability of
Figure 6. Quantum chemical simulations of ultrafast and selective SCA polymerization. A) Postulated propagation and transfer intermediates
(INT) and transition states (TS) in the ROP of SCA in toluene. B) Calculated free energy of each INT and TS.
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Figure 7. Plausible mechanistic pathway of PPNOBz/BzOH -mediated ROP of SCAs.
feature despite the existence of induction period. Most
importantly, the unique high polymerizability of SCA mono-
mer is critical for the controlled polymerization behavior. In
addition to facilitating highly selective ring-opening of the
monomer for enchainment over competing transthioesterifi-
cation and backbiting reactions as demonstrated by DFT
calculations, the highly polymerizable monomer also allows
for the use of softer and very small amount of initiators, thus
reducing chain-end nucleophilicity so that potential side
reactions (e.g., transthioesterification and epimerization) is
further prevented.
Conflict of interest
The authors declare no conflict of interest.
Keywords: polythioesters ·ring-opening polymerization ·
S-carboxyanhydrides ·stereoregularity ·ultrafast reactions
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Foundation of China (Grants 91856113, and 51873211).
Helpful discussions with Prof. Junpeng Zhao (South China
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Manuscript received: December 6, 2020
Accepted manuscript online: February 18, 2021
Version of record online: March 24, 2021
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