Letter pubs.acs.org/macroletters
Radical Ring-Opening Copolymerization of Cyclic Ketene Acetals and Maleimides Affords Homogeneous Incorporation of Degradable Units Megan R. Hill,†,‡ Elise Guégain,‡ Johanna Tran,‡ C. Adrian Figg,† Andrew C. Turner,† Julien Nicolas,*,‡ and Brent S. Sumerlin*,† †
George and Josephine Butler Polymer Research Laboratory, Department of Chemistry, Center for Macromolecular Science and Engineering, University of Florida, Gainesville, Florida 32611, United States ‡ Institut Galien Paris-Sud, UMR CNRS 8612, Univ Paris-Sud, Faculté de Pharmacie, 5 rue Jean-Baptiste Clément, F-92296 Châtenay-Malabry cedex, France S Supporting Information *
ABSTRACT: Radical copolymerization of donor−acceptor (D-A) monomer pairs has served as a versatile platform for the development of alternating copolymers. However, due to the use of conventional radical polymerization, the resulting copolymers have generally been limited to nondegradable vinyl polymers. By combining radical D-A copolymerization with radical ring-opening polymerization (rROP), we have synthesized an alternating copolymer with a high incorporation of degradable backbone units. Copolymerization of N-ethyl maleimide (NEtMI) with the cyclic ketene acetal (CKA) 2-methylene4-phenyl-1,3-dioxolane (MPDL) was demonstrated to proceed in an alternating fashion, and controlled polymerization was achieved using reversible addition−fragmentation chain transfer (RAFT) polymerization. Spontaneous copolymerization, in the absence of an exogenous initiating source, occurred when the mixture of monomers was heated, presumably due to the large electron disparity between the comonomers. Chain-extension with styrene afforded well-defined P(MPDL-alt-NEtMI)-bpolystyrene copolymers, and degradation of the homopolymers and block copolymers showed complete breakdown of the alternating copolymer.
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electron poor and sterically hindered, thereby discouraging homopolymerization or lowering the homopropagation rate. This combined electronic deficiency and steric hindrance increases the alternating tendency in copolymerizations with electron-rich monomers (e.g., styrene, vinyl acetate, etc.). Lutz et al. have extensively demonstrated the ability to synthesize precision polymers using the copolymerization of styrene and MIs with nitroxide-mediated polymerization or atom transfer radical polymerization.12−20 In particular, Lutz has utilized the increased cross-propagation rate of D-A monomer pairs to place MIs in specific regions of growing polystyrene (PS)
ontrolling monomer sequence in chain-growth polymerization has been a continuous challenge in the attempt to synthetically mimic the precise nature of many biological macromolecules.1,2 Although alternating copolymerization of two monomers provides a rather simple primary sequence (-AB-A-B-), the synthesis of nearly perfectly alternating polymers is readily achievable through radical copolymerization of donor− acceptor (D-A) monomer pairs.3 Furthermore, employing reversible-deactivation radical polymerization (RDRP) techniques4−8 imparts additional control over polymer synthesis through predetermined chain lengths, simultaneous growth of all polymer chains, and narrow molecular weight distributions. Maleic anhydride (MAnh) and N-substituted maleimides (MI) are widely used as acceptor monomers in alternating copolymerizations.9−11 The vinyl bonds of MAnh and MI are © XXXX American Chemical Society
Received: August 2, 2017 Accepted: September 6, 2017
1071
DOI: 10.1021/acsmacrolett.7b00572 ACS Macro Lett. 2017, 6, 1071−1077
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ACS Macro Letters chains, creating polymers with precisely placed functionality. MIs have additionally been employed to synthesize 1:2 (ABB) sequence-controlled chain-growth polymers by copolymerizing with limonene.21−23 The extensive range of available or easily accessible MIs,24 along with the tendency to form alternating copolymers with most donor monomers, gives rise to a library of easily accessible precision and sequence-controlled polymers. D-A radical copolymerization affords a versatile and robust route to functional, responsive, and precision polymers; however, the use of radical polymerization traditionally leads to polymers with nondegradable carbon−carbon backbones. The biological and environmental fate of polymeric materials is a significant concern, and the ability for polymers to break down after use has become increasingly important. We therefore hoped to extend the versatility of D-A copolymerizations to afford copolymers that contained both alternating repeat units and a degradable backbone. The use of radical ring-opening polymerization (rROP) offers an effective route to incorporate degradable linkages into the backbone of vinyl polymers.25,26 The rROP mechanism relies on cyclic monomers with exomethylene groups that are susceptible to radical addition and subsequent ring-opening to impart degradable moieties onto the polymer backbone. Cyclic ketene acetals (CKAs), in particular, have been used to synthesize polyesters or to incorporate degradable ester moieties in vinyl polymers under radical conditions.27 However, with the exception of less-activated monomers such as vinyl acetate,28,29 copolymerization of CKAs with most vinyl monomers (e.g., styrenics, acrylates, methacrylates, acrylamides, etc.) typically results in a low incorporation of CKA into the copolymer.30 High equivalents of CKA relative to the comonomer must therefore be used to achieve a reasonable degree of degradable units into the polymer, and even then, the CKA likely incorporates in a gradient fashion (during RDRP) rather than randomly along the backbone. However, to achieve homogeneous degradation, the incorporation of regularly placed degradable moieties is necessary. Synthesis of degradable polymers by copolymerization of CKAs is further complicated by the fact that ring-opening of the CKA is required to yield the desired ester moiety needed for degradability. However, in many cases, the 1,2-addition across the vinyl group of the CKA (i.e., without ring opening) is highly competitive. Therefore, an ideal scenario for preparing degradable polymers from CKAs would be one where there is a high and uniform distribution of CKA units along the backbone and where the fraction of CKA units that undergo ring opening is high. Given the electron-rich nature of CKAs, we postulated that copolymerization with electron-deficient MAnh and MIs could result in alternating copolymers with a regular and high incorporation of degradable moieties. While 2-methylene-1,3dioxepane (MDO, also termed MDP) is often employed in rROP copolymerization to mimic poly(ε-caprolactone), we believed 2-methylene-4-phenyl-1,3-dioxolane (MPDL)31 would be a better candidate given the resulting ring-opened benzylic radical (analogous to propagating styrenics),32−34 which may increase the alternating tendency of copolymerization with acceptor monomers (Figure 1). Herein, we demonstrate that the large electron disparity between MPDL and cyclic anhydrides elicits spontaneous reactions and enhances the alternating tendency of copolymerization, thereby enabling the synthesis of alternating copolymers with a high incorporation of backbone degradable moieties via D-A radical copolymerization.
Figure 1. Synthesis of alternating degradable polymers from conventional and RAFT-mediated radical ring-opening copolymerization of MPDL and NEtMI.
In the first attempt to synthesize alternating MPDLcontaining copolymers, we employed MAnh as the electrondeficient comonomer due to its well-known tendency to alternate with electron-rich monomers and its inability to homopolymerize. However, mixing equimolar MPDL and MAnh in dioxane led to an exothermic reaction and rapid color change (from clear, to red, then brown) at room temperature. Attempts at free radical copolymerization of MPDL and MAnh led to low yielding (
