Alternating Radical Ring-Opening Polymerization of Cyclic Ketene

Article Cite This: Macromolecules XXXX, XXX, XXX−XXX

Alternating Radical Ring-Opening Polymerization of Cyclic Ketene Acetals: Access to Tunable and Functional Polyester Copolymers Megan R. Hill, Tomohiro Kubo, Sofia L. Goodrich, C. Adrian Figg, and Brent S. Sumerlin* George & Josephine Butler Polymer Research Laboratory, Department of Chemistry, Center for Macromolecular Science & Engineering, University of Florida, Gainesville, Florida 32611, United States

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ABSTRACT: Radical ring-opening polymerization of cyclic ketene acetals (CKAs) provides a route to synthesize degradable polyesters or to impart degradability onto traditionally nondegradable vinyl polymers under the mild conditions afforded by radical polymerization. Copolymerization of CKAs with vinyl monomers is a promising strategy to prepare functional degradable polymers. However, such copolymerizations often result in poor incorporation of the ester moiety due to low relative reactivity of CKAs and the propensity to polymerize through the exomethylene bond via 1,2-addition, without ring-opening to the ester moiety. We demonstrate that the copolymerization of 5,6-benzo-2-methylene-1,3-dioxepane (BMDO) with a variety of maleimides proceeds in a highly alternating fashion with quantitative ring-opening of BMDO to the ester, producing alternating polyester copolymers. Modifying the N-substituent of the maleimide provided a straightforward route to tuning the thermal properties of the polymers and introducing functionality for postpolymerization modification. Additionally, a hydrophilic macro-chaintransfer agent was chain extended via alternating copolymerization of BMDO and a maleimide to yield amphiphilic block copolymers that self-assembled into degradable nanoparticles.

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INTRODUCTION The prolific production and accumulation of nondegradable polymers over the past century have emphasized the importance of developing useful materials with the ability to break down and degrade within our lifetime.1 Ideally, instilling degradability should proceed without sacrificing specific polymer properties, performance, or established synthetic methods. Radical ring-opening polymerization (rROP), in which a cyclic monomer with an exomethylene bond undergoes ring-opening under radical conditions, is an attractive route to synthesize degradable polymers using straightforward radical polymerization techniques.2,3 In particular, the ability to copolymerize with traditional vinyl monomers to impart degradability onto standard vinyl polymers is an appealing aspect of rROP. The most studied monomers employed in rROP are cyclic ketene acetals (CKAs), which ring-open to yield ester moieties in the polymer backbone. Copolymerization of CKAs with most vinyl monomers, however, typically results in low incorporation of the degradable moiety due to both the low relative reactivity of most CKAs in copolymerizations and the propensity of CKAs to polymerize through the CC carbon double (as in traditional vinyl polymerization) bond via 1,2-addition, resulting in the ring-retaining acetal structure rather than ring-opening to the ester.3,4 Recently, we demonstrated that the CKA 2-methylene-4phenyl-1,3-dioxolane (MPDL) undergoes alternating copoly© XXXX American Chemical Society

merization with N-ethylmaleimide (NEtMI), following the concepts of donor−acceptor radical copolymerization (e.g., styrene−maleic anhydride).5 While this alternating monomer sequence provides high and regular incorporation of degradable moieties, about 30% of the incorporated CKA polymerized through the methylene bond rather than ringopening to the degradable ester. Similarly, Agarwal et al. had previously reported the alternating copolymerization of the CKA 2-methylene-1,3-dioxepane (MDO) with N-phenylmaleimide (NPhMI) and observed that the CKA polymerized mostly through the methylene bond without ring-opening, unless high temperatures (120 °C) and high feed ratios of CKA (9:1 CKA:maleimide) were used (Figure 1A).6 While the aforementioned copolymerizations provide a method to produce copolymers with a high degree of CKA incorporation, full ring-opening is desirable to achieve a truly alternating polyester copolymer with ester groups periodically placed along the polymer backbone. Poly(CKA)s polymerized via 1,2-addition are susceptible to side-chain acetal degradation; however, the ester moiety is necessary for backbone degradation in CKA copolymers.7,8 We therefore hoped to develop a system that would lead to quantitative ring-opening of the CKA comonomer to impart a higher degree of monomer Received: April 25, 2018 Revised: June 16, 2018

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DOI: 10.1021/acs.macromol.8b00889 Macromolecules XXXX, XXX, XXX−XXX

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Figure 1. Alternating radical ring-opening copolymerization of CKAs and maleimides: (A) alternating copolymerizations with 2-methylene1,3-dioxepane (MDO) and 2-methylene-4-phenyl-1,3-dioxolane (MPDL) resulting in 50% and 70% ring-opening of CKA comonomers, respectively, and (B) alternating copolymerization of 5,6-benzo-2-methylene-1,3-dioxepane (BMDO) resulting in quantitative ring-opening to the ester moiety.

sequence control and, in turn, a higher degree of degradability.9,10 Herein, we report our investigation of the copolymerization of 5,6-benzo-2-methylene-1,3-dioxepane (BMDO) with a variety of maleimides to provide fully ringopened, alternating polyester copolymers with straightforward tunability of the polyester properties via the N-substituent of the maleimide comonomer.

Figure 2. Conventional radical copolymerization of 5,6-benzo-2methylene-1,3-dioxepane (BMDO) (0.25 M) and N-ethylmaleimide (NEtMI) (0.25 M) at 85 °C with 2 mol % AIBN: (A) 1H NMR spectrum of P(BMDO-alt-NEtMI); (B) 13C NMR spectrum of P(BMDO-alt-NEtMI); (C) SEC trace of products from copolymerization and subsequent degradation to low molecular weight.

RESULTS AND DISCUSSION We hypothesized that alternating copolymerizations of CKAs and maleimides could proceed with quantitative ring-opening of the CKA with a few optimizations. First, CKA BMDO replaced MPDL as the CKA comonomer. BMDO has a higher propensity to ring-open during copolymerizations due to the release of strain of the 7-membered ring and the enhanced stability of the resulting benzylic radical after ring-opening.11,12 Second, higher temperatures (80−90 °C) and more dilute solution conditions (0.5 M total monomer in toluene) were used to further favor ring-opening. Under these conditions, we found that conventional radical copolymerization of BMDO with equimolar NEtMI or N-benzylmaleimide (NBnMI) and AIBN (0.02 equiv) resulted in copolymers with a 1:1 incorporation of both BMDO and MI by 1 H NMR spectroscopy (Figure 2A, Figure S2, and Table 1, entry 1). Analysis of the 13C NMR spectrum revealed the absence of any ketal carbons from 100 to 110 ppm (Figure 2B), confirming the quantitative ring-opening of BMDO. Furthermore, size exclusion chromatography (SEC) showed complete degradation of the copolymers in 1 wt % KOH MeOH/THF (1/10 v/ v) to Mn = ∼400 g mol−1 by SEC (expected degraded alternating unit Mn = 305 g mol−1) (Figure 2C). To gain insight into the copolymer monomer sequence, matrix-assisted laser desorption−ionization time-of-flight mass spectrometry (MALDI-ToF MS) was employed to analyze P(BMDO-alt-NBnMI) and P(BMDO-alt-NEtMI) synthesized

using reversible addition−fragmentation chain transfer (RAFT) polymerization13,14 to access low molecular weight copolymers. As shown in Figure 3, the MALDI-ToF mass spectrum of poly(BMDO-alt-NBnMI) revealed five polymer distributions, each with a repeat unit of 349.5 Da, the expected repeat unit molecular weight for the alternating copolymer. Distribution 1 is attributed to equal amounts of BMDO and NBnMI incorporation. Distributions 2 and 3 are attributed to polymer chains with one extra BMDO or NBnMI, respectively. These extra monomer additions could arise from defects in the alternating sequence or, more likely, due to an extra monomer at either the alpha or omega chain end. The minor distributions 4 and 5, conversely, arise from two and three extra NBnMI additions, which are due to defects in the alternating sequence. However, polymer chains with higher MI to BMDO content are expected, given the previously reported reactivity ratios of CKAs and MIs (rCKA ∼ 0, rMI ∼ 0.2).5,6 MALDI-ToF MS of P(BMDO-alt-NEtMI) demonstrated a similar trend but revealed an additional polymer distribution with four extra MI monomers, which is consistent with previous work demonstrating the enhanced propensity of MI homopolymerization based on the N-substituent of the maleimide (Figure S3).15 Access to high MW RAFT-derived polymers16 was additionally obtained as shown in Figure S10. Copolymerization of BMDO with NEtMI proceeded with good control over polymerization as demonstrated by the linear pseudo-first-

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DOI: 10.1021/acs.macromol.8b00889 Macromolecules XXXX, XXX, XXX−XXX

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Macromolecules Table 1. Copolymerization of BMDO with N-Substituted Maleimidesa

entry

R

Mn,MALS (g mol−1)

Mw/Mn

BMDO incorpd (%)

Tg (°C)

Td (°C)

1 2 3 4 5 6

Et EG3 Ph Bn Bnb Et, EG3, Bnc

12 200 13 200 7 980 13 500 7 240 10 050

1.31 1.63 1.59 1.27 1.15 1.32

50 48 50 48 48 45

122 −17 147 114 97 65

277 282 258 287 265 279

Unless otherwise noted, reactions were conducted in dry toluene with a total monomer concentration of 0.5 M at 85 °C with 2 mol % AIBN and [BMDO]:[maleimide] of 1:1. bPolymerized under RAFT conditions with dodecylsulfanylthiocarbonylsulfanyl-2-methylpropionic acid as the CTA and a ratio [BMDO]:[NBnMI]:[CTA]:[AIBN] = 60:40:1:0.1 at 85 °C. cWhere [BMDO]:[NEtMI]:[NEG3MI]:[NBnMI] = 3:1:1:1. dPercent incorporation of BMDO into final polymer, determined by 1H NMR spectroscopy. a

Figure 3. MALDI-ToF MS spectrum of P(BMDO-alt-NBnMI) showing alternating copolymerization product with five distributions: (1) equal incorporation of BMDO and NBnMI; (2) one excess BMDO; (3) one excess NBnMI; (4) two excess NBnMI; (5) three excess NBnMI.

order kinetic plot and increasing Mn with conversion. However, the experimental MWs observed during the copolymerizations were consistently ∼20% lower than theoretical values. This is potentially the result of cycloadditions between BMDO and the maleimide comonomers, which often accompany alternating copolymerizations due to the disparate electron density between the monomers and the formation of charge-transfer complexes.17 Additionally, after attempts at copolymerizing BMDO with maleic anhydride, we found that incubation of the monomers in CDCl3 overnight led to ∼40% cycloadduct (Figure S11). We believe that the reduced electron disparity between BMDO and maleimides (as compared to maleic anhydride)5 results in a reduced rate of cycloaddition but that this side reaction occurs concurrent to alternating copolymerization, thereby lowering the effective monomer concentration which leads to lower than expected MWs. To demonstrate the copolymerization versatility, BMDO was copolymerized with a variety of N-substituted maleimides

(Figures S4−S9). As shown in Table 1, all copolymerizations resulted in copolymers with ∼1:1 incorporation of CKA and MI. The copolymers demonstrated a diverse range of glass transition (Tg) values, from 147 °C when N-phenylmaleimide (NPhMI) was employed as the comonomer (Table 1, entry 3) to −17 °C with N-(methoxytriethylene glycol)maleimide (NEG 3 MI) as the comonomer (Table 1, entry 2). Furthermore, copolymerization with two or more maleimides significantly altered the Tg compared to the original copolymers (Table 1, entry 6), demonstrating the ability to easily tune the copolymer thermal properties by incorporating various maleimides. One significant challenge in ROP of cyclic esters is producing polyesters with high thermal and mechanical properties due to the difficulty in synthesizing cyclic monomers that incorporate rigid backbone functionality, particularly backbone aromatic groups.18,19 rROP of BMDO with maleimides provides a platform for incorporating backbone aromatic groups and facile tuning of the resulting polymer properties by manipulation of the N-substituent on C

DOI: 10.1021/acs.macromol.8b00889 Macromolecules XXXX, XXX, XXX−XXX

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NMR spectrum, as shown in Figure 4A, and the increase in molecular weights by SEC (Table 2, entries 2 and 3). Benzylamine was subsequently used for the second conjugation at 80 °C. Appearance of benzyl proton peaks in the 1 H NMR spectrum confirmed incorporation within copolymers; however, conjugation of benzylamine to the furfurylamine−TCT conjugate polymer resulted in a decrease in molecular weight by SEC (Table 2, entry 4). Previously, we demonstrated that functionalization of TCT with amines led to reduced electrophilicity of the triazine due to efficient π-orbital overlap of the ring with the lone pair of the nitrogen.23 Conversely, with thiols, the larger size of sulfur decreases electron density donation of the lone pairs into the triazine, thereby causing the triazine ring to retain its electrophilicity. Therefore, we believe that the deactivation of the triazine when nitrogen nucleophiles are added first enables a competitive rate of aminolysis of the ester backbone, rather than the preferential reaction with the triazine. As shown in Figure 4, functionalization of polymer 3 (furfurylthiol-conjugated TCT copolymer) proceeded with quantitative functionalization and no appreciable aminolysis of the polymer backbone. The molecular weight of polymer 5 is higher than expected, potentially due to a loss of low MW sample during purification by dialysis (Table 2, entry 5). Given the sensitivity of CKAs to many reactive moieties, postpolymerization modification of TCT-derived copolymers enables the synthesis of responsive or functional moieties that would otherwise be incompatible with the initial polymerization. Amphiphilic copolymers were next synthesized by chainextending a RAFT-derived macro-chain-transfer agent (macroCTA), poly(N,N-dimethylacrylamide) (PDMA, Mn = 15 300, Mw/Mn = 1.05), with BMDO and NBnMI, NEG3MI, or a 50:50 mixture of NBnMI and NEG3MI (Figure 5A and Figures S14−S16A). The resulting block copolymers (BCPs) were selfassembled into nanostructures by dialyzing against water (5 mg/mL in DMF) or by dialyzing under the same conditions with 10 wt % Nile red (NR). All BCPs were found to assemble into nanoparticles with hydrodynamic diameters (Dh) = 160− 200 nm, as confirmed by dynamic light scattering (DLS) (Figures S14−S16B) and transmission electron microscopy (TEM) (Figures 5B−D). While these sizes are larger than would be expected for typical block copolymer micelles, the

the maleimide comonomers, allowing access to a range of thermal, mechanical, and functional properties. While the array of available or easily synthesized Nsubstituted maleimides provides abundant opportunities for tuning the resulting alternating BMDO copolymer properties, postpolymerization modification of polymers enables the incorporation of functionality that may be incompatible with the polymerization conditions.20,21 We therefore synthesized a maleimide containing two pendent electrophilic sites using cyanuric chloride or 2,4,6-trichloro-1,3,5-triazine (TCT). We have previously reported on the facile and chemoselective modification of TCT end- and side-chain-functional polymers with amines and thiols.22−24 To demonstrate its applicability in alternating BMDO polyesters, the TCT−maleimide (TCTMI) conjugate was copolymerized with BMDO, producing high MW functionalizable polyester copolymers (Table 2, entry 1). Table 2. Functionalization of TCT-Derived Polyester Copolymersa polymer M0b (g/mol) 1 2 3 4 5

451.26 511.92 528.96 582.62 599.66

Mn,theoreticalc (g/mol)

Mn,MALSd (g/mol)

Mw/Mn

16 110 16 650 18 330 18 870

14 200 16 300 16 200 15 700 21 300

1.66 1.63 1.43 1.34 1.35

First functionalization reactions were run in THF at 0 °C to rt with [triazine]:[nucleophile]:DIPEA = 1:1:1.05. Second functionalization reactions were run in 1,4-dioxane at 80 °C with [triazine]: [nucleophile]:[DIPEA] = 1:1.1:1.1. bTheoretical molecular weight of (conjugated) TCT-MI repeat unit. cTheoretical molecular weight of polymer assuming quantitative conversion of functionalization reactions. dDetermined by SEC with light scattering detection. a

Subsequent nucleophilic aromatic substitution reactions on the pendent triazine using model nucleophiles afforded the incorporation of two distinct side chain groups within each repeat unit. TCT-derived copolymers were first conjugated with either furfurylamine or furfurylthiol from 0 °C to room temperature to achieve chemoselective single substitution of the triazine group. Incorporation of 1 equiv of the furfuryl group was confirmed by the appearance of furfuryl proton peaks in the 1H

Figure 4. (A) Reaction scheme of hetero-difunctionalization of TCT-functional polyester and (B) 1H NMR spectra overlay of polymer functionalizations. 1: poly(BMDO-alt-TCTMI); 3: functionalization with furfuryl thiol; 5: functionalization with benzylamine. D

DOI: 10.1021/acs.macromol.8b00889 Macromolecules XXXX, XXX, XXX−XXX

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Figure 5. (A) Block copolymer synthesis by chain extension of PDMA macro-CTA with BMDO and maleimides; TEM images of nanostructures after self-assembly and encapsulation of Nile red: (B) PDMA-b-P(BMDO-alt-NBnMI), (C) PDMA-b-P(BMDO-alt-NEG3MI), and (D) PDMA-bP[(BMDO-alt-NBnMI)-co-(BMDO-alt-NEG3MI). (E) Fluorescence emission spectra of freeze-dried polymers after Nile red encapsulation (λexcitation of 530 nm) to determine loading capacity. (F) Fluorescence analysis (λexcitation of 530 nm and λemission of 622 nm) of degradation of PDMA-b-P(BMDO-alt-NBnMI) particles and release of Nile red with increasing pH over 12 h.

NR release increased with increasing pH, and a slower, steady release of NR was demonstrated at pH 7. Degradation of the P(BMDO-alt-NBnMI) block was confirmed by 1H NMR (Figure S17). Such systems could be advantageous for controlled release of drugs in nanotherapies as well as for applications in agriculture, as we have previously reported.26,27

aggregates are expected to contain hydrophobic regions that contain degradable ester functionality and to be stabilized by the PDMA hydrophilic segments. To demonstrate degradation of the polyester component of the particles, encapsulation and release of NR as a model hydrophobic molecule was investigated. Encapsulation of NR was found to be significantly dependent on the composition of the core. While PDMA-bP(BMDO-alt-NBnMI) particles demonstrated a loading capacity (LC) of ∼6.5%, PDMA-b-P(BMDO-alt-NEG3MI) particles demonstrated little-to-no encapsulation of NR (LC =