Degradable vinyl copolymers through thiocarbonyl addition-ring-opening (TARO) polymerization

Article abstract of DOI:10.1039/c8cc08287a

The radical copolymerization of the thionolactone dibenzo[c,e]oxepane-5-thione with acrylates, acrylonitrile, and N,N-dimethylacrylamide afforded copolymers containing a controllable amount of backbone thioesters which could be selectively cleaved. The pr

Full text of DOI:10.1039/c8cc08287a

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Degradable vinyl copolymers through
thiocarbonyl addition–ring-opening (TARO)
polymerization†
Cite this: Chem. Commun., 2019,
55, 55
Received 16th October 2018,
Accepted 22nd November 2018
Nathaniel M. Bingham and Peter J. Roth
*
DOI: 10.1039/c8cc08287a
rsc.li/chemcomm
The radical copolymerization of the thionolactone dibenzo[c,e]oxepane- product which remains reactive toward radicals and can lead
5-thione with acrylates, acrylonitrile, and N,N-dimethylacrylamide to unwanted crosslinking.10 Further, both of these systems
afforded copolymers containing a controllable amount of backbone introduce esters into the backbone. Conditions required to
thioesters which could be selectively cleaved. The process is com- cleave these backbone esters are likely to cleave also the esters
patible with RAFT polymerization and promising for the development of (meth)acrylic or vinyl ester repeat units and alter the
of advanced degradable polymers.
chemical nature of the polymer.
Herein, the RROP of thionolactones is presented. The process
Vinyl polymers constitute an important class of materials. The has been termed thiocarbonyl addition–ring-opening (TARO)
recent advent of reversible deactivation radical polymerization polymerization and involves the radical addition onto a CQS
methods specifically has led to immense interdisciplinary research double bond, followed by ring-opening which produces an
efforts in exploiting well-defined vinyl-based (nano)materials for
biomedical applications including tissue engineering and drug
delivery.1–3 Featuring C–C backbones, however, vinyl polymers are
inherently non-degradable which limits their applicability.4–6
Radical ring-opening polymerization (RROP) enables the incor-
poration of labile linkages (typically esters) into vinyl polymer
backbones. This method uses cyclic compounds that add onto a
radical chain end and then ring-open to produce a secondary
radical able to propagate the chain and install a modified section
of the ring into the backbone.7,8 Since the development of RROP
in the 1960s, two types of RROP monomers—cyclic ketene acetals9
and allyl sulfide lactones10–12—have emerged as the main candi-
dates for bestowing degradability (Scheme 1A and B). However,
these systems are not without drawbacks. Cyclic ketene acetals
generally show low reactivity during radical copolymerizations
with (meth)acrylic and styrenic monomers (meaning that only
small quantities of the feed are incorporated into the product)8
although recent work has demonstrated high incorporation of
cyclic ketene acetals during copolymerizations with vinyl ethers,13
vinyl esters,14 N-vinyl pyrrolidone,15 and maleimides.16,17 The
cyclic allyl sulfide monomer family, while allowing additional
in-ring functionality,11,18 installs a methylene group into the
Scheme 1 Synthesis of degradable vinyl copolymers through radical ring-
opening polymerization (RROP): literature examples (A9 and B)10 that install
esters into the backbone and proposed RROP of thionolactones (C) with
monomer candidates prepared in this study (D). Of the shown structures
the caprothionolactone derivative 6 underwent RROP.
Department of Chemistry, University of Surrey, Guildford, Surrey, GU2 7XH, UK.
E-mail: p.roth@surrey.ac.uk
† Electronic supplementary information (ESI) available: Instrumentation; synth-
esis of lactones, thionolactones, and (co-)polymers, determination of copolymer-
ization parameters; degradation experiments. See DOI: 10.1039/c8cc08287a
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in-chain thioester (–C(QO)S–) functionality, Scheme 1C. Radical a bench (ambient light, RT, air) without observable signs of
addition to CQS bonds and subsequent fragmentation through change. Heating DOT in DMSO to 150 1C, however, resulted in
b-scission are well-documented in the literature; they form the isomerization to the thioester (–C(QO)S–) derivative. DOT was
basis of the Barton McCombie reaction and the mechanism of found to inhibit radical polymerizations of vinyl acetate and
reversible addition–fragmentation chain transfer (RAFT).19 Meijs N-vinylcarbazole and to retard radical polymerizations of styrene
and co-workers investigated the non-cyclic analogue benzyl without being incorporated. It was a bystander in radical polymer-
thionobenzoate as an irreversible chain transfer agent in radical izations of methyl methacrylate, presumably due to the addition
polymerizations.20 Hannachi et al. calculated favourable radical equilibrium (first reaction in Scheme 2A) being on the left side
addition and fragmentation reactions for two thionophthalides. and favouring the tertiary methacrylic radicals. An attempted AIBN-
Synthetic results were, however, limited to an example in which initiated homopolymerization of DOT in acetonitrile-d3 reached
the open-ring radical was ill-suited for re-initiation.21 Cyclic o1% conversion after heating to 80 1C overnight. Conversely, DOT
trithiocarbonates have been used in an addition–ring-opening copolymerised with methyl acrylate, poly(ethylene glycol)methyl
mechanism to provide (presumably degradable) in-chain trithio- ether acrylate (PEGA), N,N-dimethyl acrylamide, and acrylonitrile.
carbonate functionality,22 which, however, remains reactive toward IR and NMR spectroscopic analysis of purified polymers confirmed
radicals. TARO polymerization, on the other hand, produces the incorporation of aromatics into the polymers (see Fig. 1 and
thioesters which are not susceptible to radical attack but offer ESI†). The proposed TARO mechanism (Scheꢀm1e 2A) is supported
chemistries distinct from those of oxoesters.23–25
by observed IR vibrations at n = 1680 cm (assigned to the
Our initial attempts at TARO polymerization were based on thioester CQO stretching) and n = 907 cmꢀ1 (C–S stretching)
g-phenyl-g-butyrothionolactone, 1, and four thionophthalides, which increased with an increasing DOT feed and the presence
2–5, prepared through thionation with Lawesson’s reagent of of 13C NMR signals at d = 192.6 ppm and 191.1 ppm, character-
the commercially available lactones (see ESI†). Compounds 1–5 istic of a thioester carbonyl (–C(QO)S–) (see ESI†).
inhibited attempted radical polymerizations of vinyl acetate
The relative reactivities of two monomers in a copolymeriza-
(presumably through H abstraction or CQS addition in the tion can be expressed through reactivity ratios, r1, r2, assigned
absence of ring-opening and re-initiation) and were not incor- to the comonomers (1, 2) for a given combination. A reactivity
porated during the radical polymerizations of styrene, methyl ratio r1 4 1 indicates a preference of monomer 1 to homo-
acrylate, and methyl methacrylate.
polymerise; r1 o 1 (and the extreme r1 = 0) indicates that a
Thereupon, we designed and prepared dibenzo[c,e]oxepane- growing chain terminated in monomer 1 prefers to cross-
5-thione (DOT, 6) under the assumption that the biphenyl propagate and add monomer 2, while ideal behaviour (i.e. no
system would provide additional ring-strain and would, when apparent distinction between the monomers) is found for
ring-opened, rotate to move the benzylic radical into a position r1 = r2 = 1. Apparent reactivity ratios (thus called because RROP
ideal for propagation (Scheme 2A). At the same time, the two monomers involve two radical species)8 were estimated through non-
benzene rings were expected to stabilise the adduct and open- linear regression for the AIBN-initiated free radical copolymerization
ring radical, respectively. Benzylic radicals have been employed of DOT and methyl acrylate as a model vinyl monomer to be
for the initiation of acrylic polymerizations.26 DOT was pre- rDOT = 0.003 and rMA = 0.424, see Fig. 2 and ESI.† Unlike cyclic
pared in two steps from diphenic anhydride (see ESI†) and ketene acetals, DOT copolymerizes rapidly with acrylates with a
presented as yellow crystals (mp 134–135 1C). It could be stored tendency of both monomers to form alternating sequences.
for ten months in a fridge (darkness, 5 1C, air) or for 45 days on Retardation (i.e. lower-than-expected monomer consumption at
a given time) was found for increasing amounts of DOT in the
Scheme 2 Proposed mechanism of TARO copolymerization of DOT with
structures of vinyl comonomers (A) and expected products of thioester
cleavage (B).
Fig. 1 1H NMR spectrum of poly(DOT26-co-PEGA141) with assignments.
The integrals are normalised to 1 H (PEGA) = 1.00. For this composition,
1 H (DOT and direct neighbours) E 0.20.
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Fig. 2 Mole fraction of degradable units in the copolymer, F, versus mole
fraction of cyclic monomer in the feed, f: data measured for DOT–methyl
acrylate (MA) (black squares) and least-squares fit of measured data
for rDOT = 0.003 and rMA = 0.424 (line a). The system has an azeotrope
around fDOT = 0.37. For comparison, plots of two extreme (and rarely
encountered) scenarios, r1 = r2 = 0 (alternating copolymer, horizontal
line b) and r1 = r2 = 1 (ideal copolymerization, diagonal line c) and two
literature examples of cyclic ketene acetals with acrylate comonomers,
Fig. 3 Size exclusion chromatograms of PEGA homopolymer (black line)
and after stirring with isopropylamine in dichloromethane (green line)
(A) and of DOT–PEGA copolymers (dark blue lines) and after identical amine
treatment (light blue lines) for poly(DOT2-co-PEGA244) (B), poly(DOT5-co-
PEGA235) (C), poly(DOT26-co-PEGA141) (D), poly(DOT20-co-PEGA46) (E), and
of poly(DOT22-co-PEGA64) (dashed line) and after stirring in methanol at RT
overnight (yellow line) (F) with measured PMMA-equivalent molar masses
(first respective number, in g molꢀ1) and dispersities (second respective
numbers, Ð = Mw/Mn) indicated.
r
BMDO = 0.08, rBuA = 3.7 (reported for 5,6-benzo-2-methylene-1,3-dioxepane
and n-butyl acrylate,30 line d), and rMDO = 0.00235, rMA = 26.535 (reported for
2-methylene-1,3-dioxepane and methyl acrylate,31 line e) are shown.
feed, with DOT-rich formulations requiring 6 hours to reach the degraded fragments were larger than expected from
global monomer conversions of 5–15%, see Table S1 (ESI†). The the molar copolymer compositions when assuming complete
situation appears similar to that of the related dithiobenzoates thioester cleavage. For example, sample poly(DOT2-co-PEGA244),
(PhC(QS)SR0) which can cause retardation in RAFT radical with a measured MSnEC = 18 kg molꢀ1 and featuring an average
polymerizations, attributed to slow fragmentation (here: ring- of two cleavable sites per chain, was degraded into a product
opening) and termination reactions of the intermediate with a measured MSnEC = 15 kg molꢀ1 (Fig. 3B). Disparate
(adduct) radical.27–29
reactivity ratios can cause a compositional drift along the
Next, a series of copolymers was prepared from DOT and copolymer chains. For the DOT–acrylate system it is presumed
PEGA with varying comonomer feed ratios and in the presence of that low feeds of DOT are incorporated fully into copolymers in
S-benzyl-S0-propyl trithiocarbonate as a RAFT agent. Tuneable the early stages of polymerization, resulting in the formation of
molar compositions (measured DOT mole fraction in copolymers non-degradable homo-acrylate chains for the remainder of the
0–0.30) and narrow molecular weight distributions, Ð = 1.19–1.36, polymerization.33 However, in this context it is also worth
were achieved indicating that the two sulfur-based mechanisms, noting that SEC separates polymers by size (not mass) and
RAFT and TARO, can function side-by-side, Fig. 3.
that different (co-)polymers (including poly(DOT-co-PEGA), its
Thioester-functional polymers (that are accessible through PEGA-based fragments, and the PMMA calibration standards) do
other synthetic routes) have been attracting an increasing not usually show the same mass–size relationships. Nonetheless, the
amount of interest in the smart materials arena.32 Herein, the SEC data shown in Fig. 3 demonstrates that it was possible to create
degradation of TARO-made DOT–PEGA copolymers through well-defined copolymers with varying molar compositions which
aminolysis was investigated. Copolymers, together with a PEGA degraded into fragments of tuneable sizes. More significantly, the
homopolymer control, were stirred in 5.8 M isopropylamine in TARO concept allowed for a selective degradation of the main
dichloromethane overnight to ensure complete cleavage of chain without affecting the side chains by virtue of the established
thioesters. Products were isolated through evaporation and reactivity difference between esters and thioesters.25 Conversely,
analysed by size exclusion chromatography, Fig. 3. For the in a control experiment DOT–PEGA copolymers could be stirred
PEGA control sample a slight shift (though only at the higher (and dialysed) in methanol without observable signs of backbone
molar mass end) of the molar mass distribution curve was degradation, suggesting that these materials can be stored and
observed (Fig. 3A). 1H NMR spectroscopic analysis of the handled without unintended degradation, Fig. 3F.
product showed that, within the error of integration, 495%
Summarising, a novel type of RROP monomers is presented.
of side group esters were still intact, indicating that no The investigated thionolactone dibenzo[c,e]oxepane-5-thione
significant cleavage of side group esters had occurred. For showed a tendency to form alternating copolymers with acrylates.
DOT–PEGA copolymers, however, an observable shift of the This behaviour is encouraging for the future development
molar mass distribution curve occurred, which increased with of fully alternating degradable vinyl copolymers that degrade
the molar DOT content and was attributed to a cleavage of the exclusively into small molecule fragments. At the same time,
backbone thioesters, Fig. 3B–E. The measured molar masses of thiocarbonyl addition–ring-opening is compatible with RAFT
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´
13 A. Tardy, J.-C. Honore, J. Tran, D. Siri, V. Delplace, I. Bataille,
D. Letourneur, J. Perrier, C. Nicoletti, M. Maresca, C. Lefay,
D. Gigmes, J. Nicolas and Y. Guillaneuf, Angew. Chem., Int. Ed.,
2017, 56, 16515–16520.
radical polymerization, suggesting that the concept can be
combined with other advanced macromolecular design strategies
in the preparation of materials with controllable degradability. Based
on the established reactivity of thioesters toward thiolates,24 it
is anticipated that TARO-made vinyl copolymers that degrade
through intracellular glutathione may be beneficial for drug
delivery applications.
The authors acknowledge the Department of Chemistry
at the University of Surrey for funding, Nicolas Busatto for
the synthesis of a PEGA control polymer, Max Attwood for DFT
calculations, and Daniel Driscoll and Janella de Jesus for mass
spectrometry measurements.
14 G. G. Hedir, C. A. Bell, N. S. Ieong, E. Chapman, I. R. Collins,
R. K. O’Reilly and A. P. Dove, Macromolecules, 2014, 47, 2847–2852.
15 G. G. Hedir, A. Pitto-Barry, A. P. Dove and R. K. O’Reilly, J. Polym.
Sci., Part A: Polym. Chem., 2015, 53, 2699–2710.
´
16 M. R. Hill, E. Guegain, J. Tran, C. A. Figg, A. C. Turner, J. Nicolas and
B. S. Sumerlin, ACS Macro Lett., 2017, 6, 1071–1077.
17 M. R. Hill, T. Kubo, S. L. Goodrich, C. A. Figg and B. S. Sumerlin,
Macromolecules, 2018, 51, 5079–5084.
18 L. P. D. Ratcliffe, C. Couchon, S. P. Armes and J. M. J. Paulusse,
Biomacromolecules, 2016, 17, 2277–2283.
19 G. Moad, E. Rizzardo and S. H. Thang, Aust. J. Chem., 2012, 65,
985–1076.
20 G. F. Meijs, E. Rizzardo, T. P. T. Le and Y.-C. Chen, Makromol. Chem.,
1992, 193, 369–378.
´
21 D. Hannachi, N. Ouddai, M. Arotçarena and H. Chermette, Mol.
Conflicts of interest
Phys., 2015, 113, 1541.
22 J. Hong, Q. Wang, Y. Lin and Z. Fan, Macromolecules, 2005, 38,
2691–2695.
There are no conflicts to declare.
23 E. A. Castro, J. Sulfur Chem., 2007, 28, 401.
24 P. J. Bracher, P. W. Snyder, B. R. Bohall and G. M. Whitesides,
Origins Life Evol. Biospheres, 2011, 41, 399.
Notes and references
1 S. Binauld and M. H. Stenzel, Chem. Commun., 2013, 49, 2082–2102. 25 W. Yang and D. G. Drueckhammer, J. Am. Chem. Soc., 2001, 123,
2 C. Boyer, V. Bulmus, T. P. Davis, V. Ladmiral, J. Liu and S. Perrier,
Chem. Rev., 2009, 109, 5402–5436.
3 J. F. Quinn, M. R. Whittaker and T. P. Davis, Polym. Chem., 2017, 8,
97–126.
4 R. P. Brannigan and A. P. Dove, Biomater. Sci., 2017, 5, 9–21.
5 V. Delplace and J. Nicolas, Nat. Chem., 2015, 7, 771.
6 B. D. Ulery, L. S. Nair and C. T. Laurencin, J. Polym. Sci., Part B:
Polym. Phys., 2011, 49, 832–864.
7 J. Bailey, J. L. Chou, P. Z. Feng, V. Kuruganti and L. L. Zhou, Acta
Polym., 1988, 39, 335–341.
11004–11009.
26 J. Y. Quek, P. J. Roth, R. A. Evans, T. P. Davis and A. B. Lowe,
J. Polym. Sci., Part A: Polym. Chem., 2013, 51, 394–404.
27 C. Barner-Kowollik, M. Buback, B. Charleux, M. L. Coote, M. Drache,
T. Fukuda, A. Goto, B. Klumperman, A. B. Lowe, J. B. McLeary,
G. Moad, M. J. Monteiro, R. D. Sanderson, M. P. Tonge and P. Vana,
J. Polym. Sci., Part A: Polym. Chem., 2006, 44, 5809–5831.
28 D. Konkolewicz, B. S. Hawkett, A. Gray-Weale and S. Perrier,
Macromolecules, 2008, 41, 6400–6412.
29 G. Moad, Macromol. Chem. Phys., 2014, 215, 9–26.
8 A. Tardy, J. Nicolas, D. Gigmes, C. Lefay and Y. Guillaneuf, Chem. 30 J. Huang, R. Gil and K. Matyjaszewski, Polymer, 2005, 46,
Rev., 2017, 117, 1319.
11698–11706.
9 S. Agarwal, Polym. Chem., 2010, 1, 953–964.
10 R. A. Evans, G. Moad, E. Rizzardo and S. H. Thang, Macromolecules,
1994, 27, 7935.
11 J. M. J. Paulusse, R. J. Amir, R. A. Evans and C. J. Hawker, J. Am.
Chem. Soc., 2009, 131, 9805.
12 M. Phelan, F. Aldabbagh, P. B. Zetterlund and B. Yamada, Polymer,
2005, 46, 12046–12056.
31 L. F. Sun, R. X. Zhuo and Z. L. Liu, J. Polym. Sci., Part A: Polym.
Chem., 2003, 41, 2898.
32 S. Aksakal, R. Aksakal and C. R. Becer, Polym. Chem., 2018, 9,
4507–4516.
33 D. Gigmes, P. H. M. Van Steenberge, D. Siri, D. R. D’Hooge,
Y. Guillaneuf and C. Lefay, Macromol. Rapid Commun., 2018,
39, 1800193.
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