Radical Approach to Thioester-Containing Polymers

Article abstract of DOI:10.1021/jacs.8b12154

A new approach to radical ring-opening polymerization is presented that employs a new thionolactone monomer to generate polymers with thioester-containing backbones. The use of a thiocarbonyl acceptor overcomes longstanding reactivity problems in the field to give complete ring-opening and quantitative incorporation into a variety of acrylate polymers. The resulting copolymers readily degrade under hydrolytic conditions, in addition to cysteine-mediated degradation through transthioesterification. The strategy is compatible with reversible addition-fragmentation chain transfer (RAFT) polymerization and permits the synthesis of block polymers for the preparation of well-defined macromolecular structures.

Full text of DOI:10.1021/jacs.8b12154

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Communication
A Radical Approach to Thioester-Containing Polymers
Ronald A. Smith, Guanyao Fu, Owen McAteer, Mizhi Xu, and Will R. Gutekunst
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b12154 • Publication Date (Web): 12 Jan 2019
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A Radical Approach to Thioester-Containing Polymers
Ronald A. Smith, Guanyao Fu, Owen McAteer, Mizhi Xu, and Will R. Gutekunst*
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School of Chemistry and Biochemistry, Georgia Institute of Technology, 901 Atlantic Drive NW, Atlanta, Georgia 30332,
United States.
Supporting Information Placeholder
ABSTRACT: A new approach to radical ring-opening polymeri-
A) Traditional Radical Ring-Opening Polymerization with Cyclic Ketene Acetals
zation is presented that employs a new thionolactone monomer to
O
O
1
O
O
Pn
addition/
generate polymers with thioester-containing backbones. The use of
a thiocarbonyl acceptor overcomes longstanding reactivity prob-
lems in the field to give complete ring-opening and quantitative in-
corporation into a variety of acrylate polymers. The resulting co-
polymers readily degrade under hydrolytic conditions, in addition
to cysteine-mediated degradation through transthioesterification.
The strategy is compatible with reversible addition-fragmentation
chain transfer (RAFT) polymerization and permits the synthesis of
block polymers for the preparation of well-defined macromolecular
structures.
+
Pn
O
O
fragmentation
O
n
cyclic ketene acetal (1)
B) General Concept for Thiocarbonyl-Mediated Copolymerization
Pn
S
S
O
O
Pn
Z
Z
Pn
R
+
Z
R
S
R
C) Thionoester Chain Transfer Agent - Meijs and Rizzardo (1992)
S
O
addition/
Pn
Pn
+
+
O
S
fragmentation
styrene and
methyl acrylate
One of the central features of polymers prepared using radical
polymerization is an all-carbon backbone. While this feature has
led to robust materials, it has also prevented potential pathways for
degradation.1 For next-generation materials, there is a need to up-
grade these traditional polymers and establish systems with chem-
ical diversity in the backbone that can breakdown in response to a
stimulus.2 The potential to diversify the backbone chemistry of rad-
ical polymers has long been available through radical ring-opening
polymerization (rROP). In this process, a radical addition-fragmen-
tation mechanism permits specialized cyclic monomers, such as cy-
clic ketene acetals (CKAs) 1, to install esters into the polymer chain
(Figure 1A).3 Although rROP techniques were initially identified
by Errede in 1961 and significantly developed by Bailey and Endo
through the 1980’s, the concept has been recently revived to pre-
pare degradable polymers for biomedical applications.4 For this end
goal, only a minimum number of these monomers needs to be in-
troduced for polymer breakdown, if homogeneously incorporated.
Despite significant efforts in the field, classical radical ring-open-
ing monomers have poor reactivity with many common vinyl mon-
omers, thereby limiting this direction.1, 5
D) This Work: Radical Ring-Opening Polymerization of Thionolactone Monomers
S
S
S
O
O
O
Pn
Pn
+
Pn
2
Figure 1. (A) Radical ring-opening polymerization (rROP) with a
cyclic ketene acetal; (B) Concept of tunable thiocarbonyl mono-
mers for rROP; (C) Thionoester derivative as chain-transfer agent
(CTA) for styrene and methyl acrylate; (D) Developed thionolac-
tone monomer design.
However, the required use of maleimides greatly limits the scope
of this strategy. A creative strategy to polymerize macrocycles was
recently reported by Niu and coworkers.9 This work does not rely
on a ketene acetal functionality, and instead fragments through an
allyl sulfone addition/fragmentation cascade with sulfur dioxide
extrusion. In this communication, a new concept for radical ring-
opening polymerization is described using a thionolactone mono-
mer to achieve excellent copolymerization with a range of acrylates
to broaden the scope of rROP methodologies.
Two significant challenges exist in current radical ring-opening
systems featuring cyclic ketene acetal monomers. The first is min-
imal control over the rate of addition to the CKA due to the high
energy radical intermediate. This leads to reduced rates of copoly-
merization with less activated monomers, such as acrylates and sty-
renes, resulting in copolymers of heterogeneous composition.5-6
Secondly, the rate of propagation of the intermediate radical com-
petes with the rate of ring-opening, leading to nondegradable link-
ages. Recently, researchers have resolved some of these issues
through judicious monomer selection. The O’Reilly, Dove, and Ni-
colas groups have employed vinyl acetate and vinyl ether deriva-
tives that exhibit good reactivity ratios with CKAs. This method
yielded high incorporations of the esters into polyfunctional poly-
mer platforms ideal for biomedical applications.7 The Sumerlin and
Nicolas groups overcame both issues by using maleimides.8 These
charge-transfer mediated copolymerizations offered perfect alter-
nating behavior and were compatible with controlled methods.
The thiocarbonyl motif has a privileged status in the history of
small molecule and macromolecular radical chemistry.10 Its use as
a radicophile was initially exploited by Barton in the development
of powerful deoxygenation and decarboxylation technologies that
have significantly impacted small molecule synthesis.11 Later, this
reactivity was employed by Rizzardo, Moad, and Thang in the de-
sign of reversible-activation fragmentation-transfer radical (RAFT)
polymerization.12 When considering a new design for rROP, a thi-
ocarbonyl radical acceptor appeared to solve two of the limitations
of existing rROP monomers. Depending on the substituents, the
thiocarbonyl acceptor would permit variable rates of radical addi-
tion, while preventing undesired 1,2 polymerization pathways due
to its reversible reaction with radical species. The general concept
for this design is shown in Figure 1B in which the Z and R groups
could be modified to tune the radical stability for different
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group in polymer science for the design of responsive materials.21
Further, it was anticipated that the benzylic radical resulting from
fragmentation could be reversibly deactivated for compatibility
with controlled polymerization methods.22
Scheme 1. Synthesis of Thionolactone Monomer 2.
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To test this hypothesis, a short synthesis of thionolactone 2 was
developed starting from commercial diphenic anhydride (3)
(Scheme 1). Following literature procedures,23 the anhydride was
reduced with sodium borohydride to give a desymmetrized carboxy
alcohol that cyclizes to lactone 4 on workup with hydrochloric acid.
Thionation with Lawesson’s reagent24 provided the desired thiono-
lactone 2 in 38% yield as bright yellow-orange crystals. Unambig-
uous characterization was provided by single molecule X-ray dif-
fraction, highlighting the nonplanar nature of the thionolactone
biaryl axis. Initial tests to examine the efficacy of 2 in rROP were
performed with tert-butyl acrylate (95:5) under free radical condi-
tions. Compared to tert-butyl acrylate homopolymerization, the
rate of copolymerization was slower, but a visual change of the re-
action solution from orange to colorless strongly suggested con-
sumption of the thionolactone (Figure S1). Further isolation and
examination of the polymer by 1H NMR spectroscopy (Figure S2)
highlighted the presence of broad aromatic peaks, suggesting in-
corporation of the biaryl in the backbone.
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monomer families, in analogy to the RAFT process. Despite some
suggestions of this potential reaction pathway via computation13
and in a patent14, this approach has not been successfully demon-
stratedin the literature to date.15 A key precedent for this concept
was reported by Meijs and Rizzardo in 1992 where acyclic thio-
noesters were used as chain-transfer agents (Figure 1C). Im-
portantly, this report demonstrated successful control of styrene
and methyl acrylate, both of which exhibit poor copolymerization
behavior with CKAs.16 From this work, a first-generation rRO
monomer system was envisioned by cyclizing the known transfer
agent, leading to thionolactone 2. If competent in radical ring-open-
ing polymerization, thioester functional groups would be incorpo-
rated into the polymer backbone which are resistant to further rad-
ical chemistry (Figure 1D).17 In addition to its synthetic utility in
native chemical ligation18, the Fukuyama reduction19, and the
Liebeskind-Srogl reaction20, the thioester is an emerging functional
To better understand the radical copolymerization, controlled
polymerization techniques were explored. It was anticipated that
the copolymerization would readily operate under RAFT condi-
tions, as both methods rely fundamentally on thiocarbonyl addi-
tions. This was found to be true, and results of the optimized system
1
are shown in Figure 2. From H NMR, the RAFT chain-ends are
clearly intact after polymerization at 3.4 and 4.7 ppm, and new
peaks emerge in the 3.7 - 4.0 ppm range consistent with α-thioester
protons. Analysis by size-exclusion chromatography (SEC) offered
further evidence of the controlled polymerization. Using a 5% feed
of the thionolactone, a variety of polymer molecular weights could
Thionolactone
Feed
5 %
5 %
5 %
5 %
10 %
Thionolactone tBA
Theoretical Mn
(g/mol)
3.3 k
Entry a Target DP
Mn (g/mol) c Đ c
Conversion b
≥ 98 %
≥ 98 %
≥ 98 %
≥ 98 %
≥ 98 %
94 %
Conversion b
≥ 98 %
≥ 98 %
97 %
1
2
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7
25
50
4.4 k
1.05
1.05
1.10
1.27
1.12
1.08
1.06
6.5 k
7.6 k
100
250
100
100
100
12.9 k
31.7 k
13.3 k
13.8 k
11.2 k
13.4 k
32.6 k
16.8 k
14.5 k
12.2 k
95 %
96 %
76 %
57 %
35 %
50 %c
67 %
aCopolymerization of tBA and 2 was carried out using DoPAT and AIBN in DMF at 70 ºC. b Conversions were determined by 1H NMR. c
Molecular weights and molecular weight distributions were obtained using MALS.
Figure 2. (A) RAFT polymerization of tBA and thionolactone; (B) 1H-NMR of copolymer highlighting diagnostic protons; (C) Size exclu-
sion chromatograms selected entries.
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and 2 delivered a higher molecular weight diblock polymer (Mn
11,200). Importantly, a complete shift in the retention time of the
diblock without residual macroinitiator highlights the high degree
of chain-end fidelity and livingness of the polymers produced in the
thionolactone rROP. This also shows the compatibility with other
acrylate monomers. Further experiments with methyl, benzyl, and
trifluoroethyl acrylates gave low dispersity copolymer products
suggesting this process is quite general (Figure S12).
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A central challenge in radical ring-opening polymerization is the
slow rate of copolymerization with more-activated monomer fam-
ilies. For instance, when methyl acrylate is copolymerized with
CKA 1, only 7% of the ester linkages are integrated into the poly-
mer chain starting from a 50% monomer feed.6 To explore the ki-
netics of this system, a series polymerizations were initiated with a
target DP of 100 using 5% thionolactone 2 and stopped at different
time intervals to determine the relative rates of monomer conver-
sion (Figure 4). The unusual kinetic behavior of this system is as-
cribed to the high concentration of reversibly deactivating thio-
noesters early in the polymerization, combined with the decrease in
total monomer concentration over time. Importantly, these results
demonstrate that 2 not only readily copolymerizies with tert-butyl
acrylate but is consumed at an even faster rate – a trend not previ-
ously observed for acrylates in the rROP literature. This implies the
product polymer possesses a slight gradient of comonomer distri-
bution, though thioesters should still be present throughout the pol-
ymer chain.
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Figure 3. Synthetic scheme and SEC trace of 5% tBA copolymer
chain extension with 5% nBA copolymer.
be accurately targeted by varying the monomer to initiator ratio
from 25 to 250. In each case, high degrees of conversion were ob-
tained with complete consumption of 2 while retaining low disper-
sities. The feed ratio of thionolactone 2 was varied in a separate
series of polymerizations. It was found that the comonomer feed
could be increased up to 50%, though lower conversion was ob-
tained. Interestingly, further increase of the comonomer feed failed
entirely under the reaction conditions (Table S3). The low conver-
sion at higher feed ratios and lack of homopolymerization is possi-
bly due to the slow initial rates of polymerization, as each comon-
omer can act as a reversible deactivating group before ring-open-
ing.
To support the livingness of the product polymer, chain-exten-
sion experiments were performed (Figure 3). A 3.9 k molecular
weight poly(tert-butyl acrylate) copolymer was prepared contain-
ing 5 mol% of the thioesters. Resubjection of the isolated macroin-
itiator to RAFT polymerization conditions with n-butyl acrylate
Figure 5. (A) Reaction scheme and (B) SEC traces of the degrada-
tion of a 5% tBA copolymer using sodium methoxide and cysteine
methyl ester.
To support the kinetics study and verify the presence of thioe-
sters in the copolymer, a set of degradation experiments were per-
formed (Figure 5). Initial conditions explored sodium methoxide in
Figure 4. Kinetic plot showing the faster conversion of 2 compared
to tBA in a 5% copolymerization experiment.
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methanol at room temperature, as these conditions should rapidly
facility. We thank the Stingelin Lab for use of analytical instru-
ments and Dr. John Basca for assistance with X-ray crystallog-
raphy.
lead to thioester methanolysis. This was confirmed by SEC where
an initial copolymer (Mn 30,800) containing 5% thioester was re-
duced to a broad low molecular weight oligomer. This significant
degree of degradation is consistent with the kinetic profile ob-
served, where the thioesters are evenly distributed along the poly-
mer backbone. To further confirm the presence of thioesters in the
polymer backbone, a distinct approach for degradation was con-
ducted using cysteine methyl ester. Thioesters are well known to
undergo rapid thiol-thioester exchange.21c, 21d, 25 When this process
is used with cysteine derivatives, an intramolecular S-to-N acyl
transfer occurs to give a stable amide bond. Upon reaction with
cysteine methyl ester, once again a substantial reduction in the pol-
ymer molecular weight was observed by SEC analysis. This prod-
uct had slightly higher molecular weight fragments, which could
derive from cysteine chain-end effects or slightly less efficient pol-
ymer degradation. This presents significant evidence for a thioester
linkage, as virtually no other functional groups would give de-
graded products under these conditions.
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The twisted biaryl units that result in the backbone of the copol-
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incorporation ratio was found, leading to materials with Tg’s rang-
ing from 46–81 ºC (Figure S10). Thermogravimetric analysis
(TGA) of this copolymer series provided additional insight into the
polymer compositions. Degradation of tert-butyl acrylate has an
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ters. As the comonomer percentage increases, the relative loss of
mass at this stage decreases, correlating well with the relative
comonomer ratios seen by NMR analysis (Figure S11).
In conclusion, thionolactones have been introduced as a new
monomer class for radical ring-opening polymerization. Through
the application of a thiocarbonyl radical acceptor, historical chal-
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reactions and enable polymerization with a variety of acrylate mon-
omers to generate well-defined materials. The introduction of thi-
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directions for the engineering of materials that can respond to
chemical stimuli and modulate thermal properties. Further, the po-
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lead to control of the copolymer microstructure and compatibility
with other monomer families.26
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ASSOCIATED CONTENT
The Supporting Information is available free of charge on the
ACS Publications website at DOI:.
Experimental details and characterization data (PDF)
X-ray crystallographic data for 2 (CIF)
AUTHOR INFORMATION
Corresponding Author
*willgute@gatech.edu
ORCID
Will R. Gutekunst 0000-0002-2427-4431
Notes
The authors declare no competing financial interests.
(8.) (a) Hill, M. R.; Guégain, E.; Tran, J.; Figg, C. A.; Turner, A. C.;
Nicolas, J.; Sumerlin, B. S., Radical Ring-Opening Copolymerization of
Cyclic Ketene Acetals and Maleimides Affords Homogeneous Incorpora-
tion of Degradable Units. ACS Macro Lett. 2017, 1071-1077; (b) Hill, M.
R.; Kubo, T.; Goodrich, S. L.; Figg, C. A.; Sumerlin, B. S., Alternating
Radical Ring-Opening Polymerization of Cyclic Ketene Acetals: Access to
Tunable and Functional Polyester Copolymers. Macromolecules 2018, 51,
5079-5084.
ACKNOWLEDGMENT
This work was supported by start-up funds generously provided by
the Georgia Institute of Technology and the American Chemical
Society Petroleum Research Fund (59312-DNI7). We
acknowledge support from Science and Technology of Material In-
terfaces (STAMI) at GT for use of the shared characterization
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(9.) Huang, H.; Sun, B.; Huang, Y.; Niu, J., Radical Cascade-Triggered
Controlled Ring-Opening Polymerization of Macrocyclic Monomers. J.
Am. Chem. Soc. 2018, 140, 10402-10406.
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Lim, C.-H.; Domaille, D. W.; Pattanayak, S.; McBride, M. K.; Musgrave,
C. B.; Bowman, C. N., Dynamic and Responsive DNA-like Polymers. J.
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