Hironobu Watanabe,Masami Kamigaito
Direct Radical Copolymerizations of Thioamides To Generate Vinyl Polymers with Degradable Thioether Bonds in the Backbones
Direct radical addition reactions of thiocarbonyl (C=S) groups unaccompanied by β-scission have rarely been reported despite their potential for constructing various sulfur-containing compounds. Herein, we report direct radical copolymerizations of the C=S double bonds of simple thioamide derivatives and the C=C double bonds of common vinyl monomers to produce novel degradable vinyl polymers that contain thioether units in the backbones. In particular, N-acylated thioformamides copolymerized smoothly with various vinyl monomers, such as methyl acrylate, vinyl acetate, N,N-dimethylacrylamide, and styrene. RAFT copolymerization was also successfully mediated. The resultant copolymers had high glass transition temperatures and were readily degradable under ambient conditions. This work will expand the potential for use of thiocarbonyl compounds in radical reactions and develop novel poly(thioether)-vinyl polymer hybrid materials with unusual properties.
Direct Radical Copolymerizations of Thioamides To Generate Vinyl Polymers with Degradable Thioether Bonds in the Backbones

Direct radical addition reactions of thiocarbonyl (C=S) groups unaccompanied by β-scission have rarely been reported despite their potential for constructing various sulfur-containing compounds. Herein, we report direct radical copolymerizations of the C=S double bonds of simple thioamide derivatives and the C=C double bonds of common vinyl monomers to produce novel degradable vinyl polymers that contain thioether units in the backbones. In particular, N-acylated thioformamides copolymerized smoothly with various vinyl monomers, such as methyl acrylate, vinyl acetate, N,N-dimethylacrylamide, and styrene. RAFT copolymerization was also successfully mediated. The resultant copolymers had high glass transition temperatures and were readily degradable under ambient conditions. This work will expand the potential for use of thiocarbonyl compounds in radical reactions and develop novel poly(thioether)-vinyl polymer hybrid materials with unusual properties.

Thiocarbonyl compounds are fundamentally useful in radical chemistry and are extensively utilized to produce various molecules and macromolecules in reactions such as the Barton–McCombie reaction and reversible addition–fragmentation chain transfer (RAFT) polymerization. In these reactions, β-scission of the intermediate radical formed upon radical addition to the sulfur atom of the C=S double bond plays a vital role (Figure 1A). In contrast, direct radical additions to C=S double bonds unaccompanied by β-scission have been limited to spin trapping and intramolecular cyclization. This is most likely due to the instabilities of most thioaldehydes and thioketones in air and favorable backward and β-scission reactions of the intermediate radicals formed from typical bench-stable thiocarbonyl compounds. Radical polymerization is most effective for a wide variety of vinyl monomers and produces various vinyl polymers containing stable C–C bonds in the backbone (Figure 1B). Although the properties of the vinyl polymers can be varied with substituents, the degradability, which is now important from a sustainability perspective, is generally poor. Accordingly, radical ring-opening polymerizations (rROPs) of cyclic monomers, such as cyclic ketene acetals and thionolactones, have been increasingly studied to add degradable units into the vinyl polymer backbones formed by radical polymerization. However, the rROP approach requires delicate design of the cyclic monomer to achieve high reactivity and to control the ratio of ring-opened and cyclic structures. Therefore, a simple and facile approach with which to diversify the polymer backbone would be attractive. Direct radical copolymerizations of thiocarbonyl compounds and vinyl monomers should be among the most promising approaches because thioether linkages could be constructed in the vinyl polymer backbones, and the main-chain methylene carbons would be replaced by sulfur atoms (Figure 1C). These copolymers could exhibit superior degradability compared to vinyl polymers due to the thioether bonds in the backbone. In addition, the copolymers could be unique hybrid materials exhibiting the advantages of both vinyl polymers and poly(thioether)s, since poly(thioether)s have shown promise for application in optical materials, functional hydrogels, heavy metal removal, drug delivery, and oxidation-responsive materials. Nevertheless, direct radical addition polymerizations of thiocarbonyl compounds have rarely been reported. A pioneering report was published in 1967 by Sharkey et al. on radical polymerizations of fluorinated thiocarbonyl monomers such as S=CF2 and S=CClF. However, the syntheses and handling of these unique monomers were cumbersome. The polymerizations typically required very low temperatures (−78 to −120 °C). Very recently, a few reports on radical polymerizations of cyclic thiocarbonyl compounds indicated that some thionolactones were incorporated into a polymer as a mixture of ring-opened and cyclic structures with and without β-scission, respectively, which depended on the monomer structure and the polymerization conditions. Herein, we demonstrate direct radical copolymerizations of the C=S double bonds of simple thioamide derivatives and the C=C double bonds of vinyl monomers to generate novel vinyl polymers with degradable thioether bonds in the backbones. We herein chose thioamide derivatives: First, thioamides are bench-stable and easily available from common commercial compounds. Second, the likelihood for β-scission reactions of the growing radicals formed upon radical addition to the thioamides is assumed to be minor compared to those of other thiocarbonyl compounds, such as thionoesters and dithioesters, because formation of imines after β-scission is energetically unfavorable (Figure S1). Finally, the reactivity of the thioamide and the properties of the resultant polymer can be tuned by varying the substituents on the N atom. We used three easily available thioformamides, N,N-dimethylthioformamide (Me2ThiFA), N-acetyl-N-methylthioformamide (AcMeThiFA), and N-acetyl-N-cyclohexylthioformamide (AcCyThiFA) (Figure 1), as comonomers in radical copolymerizations with common vinyl monomers (Scheme S1 and Figure S2). First, we investigated the radical polymerization of Me2ThiFA. No homopolymerization occurred at 60 °C in DMF for at least 170 h. In addition, attempted copolymerizations of Me2ThiFA with vinyl monomers such as methyl acrylate (MA), styrene (St), and vinyl acetate (VAc) in 1:1 molar ratios merely resulted in vinyl homopolymers (Table 1, entries 1–3). This was most likely caused by the high stability of the C=S bond of Me2ThiFA due to conjugation with the lone pair of the nitrogen atom. To improve the reactivity, AcMeThiFA, in which conjugation of the C=S bond with N is weakened by the electron-withdrawing acetyl group, was investigated. Interestingly, the radical copolymerizations of AcMeThiFA with various vinyl monomers (MA, N,N-dimethylacrylamide (DMAA), St, VAc) successfully proceeded (Table 1, entries 4–7), although homopolymerization of AcMeThiFA did not proceed under the same conditions. All of the obtained copolymers had relatively high molecular weights (Mn ≥ 2 × 104). The NMR spectra of the obtained copolymers are shown in Figure 2 and Figures S3–S6. Signals assignable to the AcMeThiFA unit were clearly observed in the spectra (Figure S7). In particular, the 1H, 13C, and 2D NMR spectra of the AcMeThiFA-MA copolymers (Figures 2A, S3, and S8) revealed that the S=C double bond successfully underwent addition polymerization to form thioether linkages in the main chain. The incorporation ratio of AcMeThiFA calculated from the signal d assignable to the main-chain methine proton was 16 mol %. The molecular weight and incorporation of AcMeThiFA increased at lower temperature (20 °C) (Figure S9). The copolymerization of AcMeThiFA and DMAA was also successful, resulting in a copolymer with 22 mol % AcMeThiFA (Figure 2B and Figure S4). AcMeThiFA was also copolymerized with St, but the incorporation ratio was lower (10 mol %) (Figure S5). The most significant result was obtained with VAc. A bulk copolymerization of AcMeThiFA and VAc gave a copolymer with Mn greater than 4 × 104. The 1H NMR spectrum of the obtained copolymer was totally different from that of the VAc homopolymer (Figure 2C and Figure S7). The incorporated AcMeThiFA/VAc ratio was 58/42. Given the poor ability of AcMeThiFA for homopolymerization, the copolymer likely had an alternating-rich sequence. The monomer reactivity ratio as well as the probability of head-to-head linkages, which are common in conventional VAc polymerization, is currently being evaluated. To clarify the reactivity of AcMeThiFA, ab initio calculations were carried out on the addition reactions of the St and VAc radicals to AcMeThiFA. The results showed that the barriers for these additions were quite low, suggesting that the reactions were fast (Figure 3). However, the adduct of the St radical and AcMeThiFA was less stable than the reactant, while that of the VAc radical was more stable than the reactant. These results can be explained as follows: when the propagating radical derived from the vinyl monomer is relatively stable, such as the St radical, the equilibrium for the addition reaction to AcMeThiFA lies on the reactant side, leading to relatively little incorporation of the AcMeThiFA, as demonstrated in the above experiment. In contrast, when the propagating radical is highly reactive or unstable, such as the VAc radical, the equilibrium favors the product and leads to selective and fast addition of the VAc radical to AcMeThiFA. In the case of Me2ThiFA, which hardly copolymerized, the free energy profile demonstrated that addition was energetically less favorable than that to AcMeThiFA (Figure S10). These results showed that additions of the radical species to the ThiFAs were reversible due to the small exothermicity for conversion of the C=S double bond of the ThiFAs into two C–S single bonds and that the reactivity and reversibility were tunable with the ThiFA substituent. Furthermore, the reactivity of AcMeThiFA toward St radicals was enhanced by adding salts. The addition of LiNTf2 to the copolymerization with St accelerated the consumption of AcMeThiFA. The incorporation ratio of AcMeThiFA increased significantly from 10 to 32 mol % (entry 8 in Table 1; Figure 2D and Figure S11). LiNTf2 most likely coordinated to the amide oxygen and weakened the conjugation between C=S and N to enhance the monomer reactivity. Thus, the appropriate design of additives could also tune the reactivity of AcMeThiFA, which is being studied. Control of the molecular weights of the AcMeThiFA copolymers was possible with a RAFT agent. The copolymerization of MA and AcMeThiFA in the presence of a trithiocarbonate RAFT agent generated copolymers with molecular weights that increased linearly with monomer conversion and narrow size-exclusion chromatography (SEC) traces (Figure 4A). The trithiocarbonate-type RAFT agent was also effective in copolymerizations with VAc (Figure 4B), whereas xanthate was not effective (Figure S12). Another acetyl ThiFA with a bulky cyclohexyl group, i.e., AcCyThiFA, was also used for radical copolymerizations. Despite the bulkiness, the ThiFA unit was similarly incorporated into the copolymers to generate another series of copolymers with different pendant groups on the amide nitrogen (entries 9–11 in Table 1 and Figures S13–S15). The thermal properties of the copolymers were evaluated by differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). The copolymers of AcMeThiFA with MA, VAc, and St showed Tg values of 34 °C, 103 °C, and 115 °C, respectively, which were higher than those of the corresponding vinyl homopolymers (10 °C, 30 °C, and 100 °C, respectively) (Figure S16). The high Tg values of the copolymers were most likely due to the highly polar pendant amide groups. In this regard, the copolymer with DMAA showed a Tg (116 °C) close to that of the DMAA homopolymer (124 °C) because DMAA has a similarly polar pendent amide. Bulky cyclohexyl substituent further increased the Tg up to 145 °C for the copolymer of AcCyThiFA and St because of the lower mobility of the copolymer (Figure S17). According to TGA, the thermal decomposition temperatures (Td5) of the copolymers were 200–270 °C, which were lower than those of typical vinyl homopolymers. This was most likely because of the weakness of the C–S bond (typical bond dissociation energy: 272 and 346 kJ/mol for C–S and C–C bonds, respectively). Finally, the degradabilities of the copolymers with main-chain thioether linkages were investigated under ambient conditions by using AgNO3 solutions. The SEC curves for the products obtained after treatment with the AgNO3 at room temperature for 24 h were dramatically shifted to low molecular weights, which depended strongly on the incorporation ratio of the ThiFA units (Figure 5 and Figure S18). These results indicated that these simple and bench-stable thioamide derivatives were efficiently copolymerized with various common vinyl monomers to introduce sulfur atoms into the main chains as key components for degradability. In conclusion, we have demonstrated a facile approach with which to produce novel vinyl polymers containing degradable thioether units in the backbone. We confirmed the successful direct radical copolymerizations of thioformamides with various vinyl monomers. Further studies of the thiocarbonyl monomer structures will enable the development of various degradable polymers as well as novel hybrid materials exhibiting the advantages of both the vinyl polymers and poly(thioether)s.