Controlled Radical Copolymerization of Cinnamic Derivatives as

Oct 25, 2018 - Shanmugam, Cuthbert, Kowalewski, Boyer, and Matyjaszewski. 2018 51 (19), pp 7776–7784. Abstract: We report a novel photoiniferter ...
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Controlled Radical Copolymerization of Cinnamic Derivatives as Renewable Vinyl Monomers with Both Acrylic and Styrenic Substituents: Reactivity, Regioselectivity, Properties, and Functions Yuya Terao, Kotaro Satoh,* and Masami Kamigaito* Department of Molecular and Macromolecular Chemistry, Graduate School of Engineering, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8603, Japan

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S Supporting Information *

ABSTRACT: A series of cinnamic monomers, which can be derived from naturally occurring phenylpropanoids, were radically copolymerized with vinyl monomers such as methyl acrylate (MA) and styrene (St). Although the monomer reactivity ratios were close to zero for all the cinnamic monomers, such as methyl cinnamate (CAMe), cinnamic acid (CA), N-isopropyl cinnamide (CNIPAm), cinnamaldehyde (CAld), and cinnamonitrile (CN), they were incorporated into the copolymers and significantly increased the glass transition temperatures despite the relatively low incorporation rates of up to 40 mol % due to their rigid 1,2-disubstituted structures. The regioselectivity of the radical copolymerization of CAMe was evaluated on the basis of the results of ruthenium-catalyzed atom transfer radical additions as model reactions. The obtained products suggest that the radicals of MA and St predominantly attack the vinyl carbon of the carbonyl side of CAMe and that the propagation of CAMe mainly occurs via the styrenic radical. The ruthenium-catalyzed living radical polymerization, nitroxide-mediated polymerization (NMP), and reversible addition− fragmentation chain transfer (RAFT) polymerization provided the copolymers with controlled molecular weights, narrow molecular weight distributions, and controlled comonomer compositions. The copolymers of N-isopropylacrylamide (NIPAM) and CNIPAm prepared via RAFT copolymerization showed thermoresponsivity with a lower critical solution temperature (LCST) that could be tuned by altering the comonomer incorporation and a higher LCST than the copolymers of NIPAM and St, which possessed similar molecular weights and similar NIPAM contents, due to the additional N-isopropylamide groups in the CNIPAm units compared to the St units.

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reaction,31 some of natural material is still extracted from plants and used in the flavor, food, fragrance, perfume, cosmetic, pharmaceutical, medicinal, health care, and other related industries.32−35 Cinnamic acid, also known as phenylacrylic acid, is a 1,2disubsituted vinyl compound possessing conjugated phenyl and carbonyl groups on each vinyl carbon and is thus regarded as either a β-substituted styrene or an acrylic acid derivative, as it can be used to generate both styrenic and acrylic radicals. However, cinnamic acid and its derivatives are difficult to homopolymerize and only give oligomers36 due to the steric hindrance around the vinyl group, similar to what is seen with most 1,2-disubsituted vinyl monomers.37 While radical copolymerizations between cinnamic monomers and other vinyl monomers such as styrene have been studied in conventional radical polymerizations, the copolymerizability of such monomers is generally low and only results in copolymers with low cinnamic monomer incorporations.38−50

INTRODUCTION The judicious utilization of renewable resources is important from the viewpoint of sustainable developments in our lives and industrially. In the field of polymers, various biobased polymers have been synthesized directly or indirectly from biobased raw materials, and some are commercialized and widely used.1−27 Biobased polymers can have the same structures as those obtained from petrochemical materials; biobased polymers can involve the same monomers that are derived from naturally occurring compounds via chemical or biological transformations, or they may have different structures, which originate from specific naturally occurring compounds that cannot be easily derived from simple petrochemical compounds. Although they have each advantages and disadvantages, biobased polymers with novel structures originating from natural compounds are interesting, especially from scientific viewpoints. Cinnamic acid and its derivatives are major naturally occurring phenylpropanoids consisting of C6 and C3 fragments, and they are biologically synthesized in various plants such as Cinnamomum cassia, the oil of which is known as cassia oil.28−30 Although most commercially available cinnamic acid is now produced via chemical synthesis such as via the aldol condensation of benzaldehyde and acetic anhydride, i.e., Perkin © XXXX American Chemical Society

Special Issue: Biomacromolecules BPC Received: August 27, 2018 Revised: October 12, 2018

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DOI: 10.1021/acs.biomac.8b01298 Biomacromolecules XXXX, XXX, XXX−XXX

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Biomacromolecules Scheme 1. Controlled Radical Copolymerization of Cinnamic Derivatives and Vinyl Monomers

ques,76 that is, metal-catalyzed living radical or atom transfer radical polymerization (ATRP),77−90 reversible addition− fragmentation chain transfer (RAFT) polymerization,91−93 and nitroxide-mediated polymerization (NMP).94,95 Furthermore, we investigated the thermal properties of the copolymers originating from the rigid 1,2-disubsituted structures as well as the thermoresponsivity of the copolymers of N-isopropylacrylamide (NIPAM) and CNIPAm originating from the Nisopropylamide units in the copolymers.

As is obvious from its low copolymerizability, there have been almost no studies on the properties of the copolymers of cinnamic monomers or on their controlled/living radical copolymerizations. Although cinnamoyl groups have been extensively used as platforms for the modification or functionalization of synthetic polymers via specific photoinduced [2 + 2] dimerizations,51−59 vinyl groups are rarely used as polymerizable groups for preparing functional polymers. We have been interested in controlled polymerizations of naturally occurring vinyl monomers with specific structures, which are observed in various terpenes and phenylpropanoids, and the development of novel biobased vinyl polymers by utilizing specific natural structures.60−75 Most notably for phenylpropanoids, we previously reported controlled/living cationic and radical copolymerizations of β-methylstyrenes, such as anethole and isoeugenol, for the synthesis of novel biobased styrene copolymers with high glass transition temperatures. More recently, we reported that ferulic acid, which is member of the phenylpropanoid family, can be easily transformed into 4-vinylguaiacol, also known as 4-hydroxy-3methoxystyrene, via decarboxylation, and that it can be controllably polymerized via RAFT polymerization into polymers with phenolic moieties through protection and deprotection of the phenolic groups. In this study, we investigated the direct copolymerization of a series of cinnamic monomers, including cinnamic acid (CA), methyl cinnamate (CAMe), N-isopropyl cinnamide (CNIPAm), cinnamaldehyde (CAld), and cinnamonitrile (CN), with common vinyl monomers, such as methyl acrylate (MA) and styrene (St), to clarify the reactivity and regioselectivity in the radical copolymerization (Scheme 1). Especially, the regioselectivity was analyzed in detail using rutheniumcatalyzed atom transfer radical addition (ATRA) between CAMe, which can generate acrylic or styrenic radicals depending on the regioselectivity, and organic chlorides that can generate a similar radical derived from either MA or St via ruthenium-catalyzed activation of the C−Cl bond. We also focused on controlling the copolymerizations using three widely used controlled/living radical polymerization techni-

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EXPERIMENTAL SECTION

Materials. Methyl cinnamate (CAMe) (Tokyo Kasei, >99%), cinnamaldehyde (CAld) (Aldrich, >99%), cinnamonitrile (CN) (Tokyo Kasei, >95%), methyl acrylate (MA) (Tokyo Kasei, >99%), styrene (St) (Kishida, 99.5%), dimethyl fumarate (DMFu) (Tokyo Kasei, >98%), methyl dichloroacetate (MDCA) (Tokyo Kasei, >99%), α,α-dichlorotoluene (DCT) (Tokyo Kasei, >95%), methyl α-chloropropionate (MCP) (Tokyo Kasei, >97%), 1-phenylethyl chloride (PEC) (Tokyo Kasei, >97%), nBu3N (Wako, >98%), DMF (Kanto; 99.5%), and 1,2,3,4-tetrahydronaphthalene (tetralin) (Wako, 97%) were distilled over calcium hydride under reduced pressure before use. Cinnamic acid (CA) (Aldrich, >97%) and α,α-azobis(isobutyronitrile) (AIBN) (Kishida, >99%) were recrystallized from methanol. N-Isopropylacrylamide (NIPAM) (TCI, >98%) was recrystallized from hexane and toluene (10/1 v/v). trans-Stilbene (STB) (Tokyo Kasei, >98%) was recrystallized from acetone. Toluene (KANTO, >99.5%; H2O CA > CAld > CAMe; however, the consumption stopped at a lower conversion for CAld. The molecular weights of the resulting polymers as measured by size-exclusion chromatography (SEC) were over 10 000 (Table 1), whereas the polymer prepared with CAld had a lower molecular weight, which was most likely due to an irreversible chain-transfer reaction. The copolymerizations with St were similarly investigated under the same conditions and were slower than those with MA due to the generally lower reactivity of styrene compared to MA (Figure 2). However, conversions of some cinnamic monomers, such as CN, CAMe, and CAld, reached slightly higher values than those in the copolymerizations with MA. In addition, the conversions of St in the copolymerizations with CN and CAMe were higher than those of MA. These kinetic results indicate that the copolymerizabilities of CN and CAMe with St are higher than those with MA. In addition, the molecular weights of the obtained copolymers with St were

slightly higher than those with MA, especially for CN and CAMe. The incorporation of cinnamic monomers was then evaluated by 1H NMR spectroscopy of the resulting copolymers after removal of the remaining monomers and low molecular weight compounds by preparative SEC. The observed incorporations of cinnamic monomers ranged from 15 to 40 mol % and were close to the values calculated based on the monomer feed ratios and conversions, suggesting that the copolymerizabilities of the cinnamic monomers are lower than those of MA and St and that most of the reacted monomers were incorporated into the copolymers. The incorporations of CAMe, CA, and CN were higher for St than for MA, suggesting that they can be more easily copolymerized with St than with MA. In addition, among all the cinnamic monomers, CAMe shows the highest incorporations for both MA and St. To further evaluate the copolymerizabilities, the monomer reactivity ratios were determined by analyzing the comonomer compositions of the copolymers obtained at initial stages (total conversion ≤15%) of the radical copolymerizations at various monomer feed ratios (Figure 3). All the plots were above the diagonal lines, which indicates that the incorporations of the comonomers (MA and St) were consistently higher than that of the cinnamic comonomer and that the reactivities of the

Table 1. Free Radical Copolymerization of Cinnamic Monomers and MA or Sta entry

M1

M2

[M1]0/[M2]0 (M)

Time (h)

conv (M1/M2)c (%)

Mnd

Mw/ Mnd

M1/M2e (calcd)

M1/M2f (NMR)

Tg (°C)

Td5 (°C)

r1g

r2g

1 2b 3b 4 5 6 7b 8b 9 10

CAMe CA CNIPAm CAld CN CAMe CA CNIPAm CAld CN

MA MA MA MA MA St St St St St

2.0/2.0 1.0/1.0 1.0/1.0 2.0/2.0 2.0/2.0 2.0/2.0 1.0/1.0 1.0/1.0 2.0/2.0 2.0/2.0

810 460 210 365 60 700 390 300 485 150

40/79 21/62 22/72 12/49 18/86 41/76 20/51 17/61 21/56 45/93

18900 12500 11900 4700 14100 21200 10800 14200 8800 24000

1.88 1.68 2.14 1.60 2.39 1.74 2.18 1.91 1.75 1.92

34/66 25/75 23/77 20/80 17/83 35/65 28/72 22/78 27/73 33/67

29/71 20/80 23/77 17/83 16/84 39/61 33/67 16/84 16/84 31/69

58 100 92 46 49 130 167 134 119 154

315 203 289 162 313 323 310 322 213 348

0.08 0.01 0 0 0.06 0.09 0.04 0.02 0 0.04

2.33 3.30 3.13 4.00 10.2 1.29 1.84 4.30 8.37 4.90

Polymerization conditions: [AIBN]0 = 20 mM, toluene, 60 °C. b[AIBN]0 = 10 mM, DMF, 60 °C. cDetermined by 1H NMR analysis of reaction mixtures. dDetermined by size-exclusion chromatography. eDetermined by the monomer feed ratio and monomer conversion. fDetermined by 1H NMR analysis of the obtained polymers. gDetermined by Kelen−Tüdõs method for the copolymerizations at varying monomer feed ratios. a

D

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with the St monomer only 1.29 times more frequently than it does with the CAMe monomer regardless of the steric hindrance around the 1,2-disubstituted vinyl group and further suggests that CAMe is relatively easily incorporated into polystyrene chains via copolymerization. When r2, namely, rSt, values in the radical copolymerizations between St and cinnamic monomers are compared with those of the radical copolymerizations between St and acrylic monomers that have similar substituents to the cinnamic derivatives as model monomers, very different trends are observed. In the copolymerization between St and the model acrylic monomers, such as methyl acrylate (MA), acrylic acid (AA), acrylamide (AAm), acrolein (AAld), and acrylonitrile (AN), the rSt values decrease in the following order: AAm (1.1−1.3) > MA (0.6−0.7) > AN (0.3−0.4) > AAld (0.2− 0.25) ≥ AA (0.15−0.25).99 This order roughly corresponds to that of electron deficiency of the vinyl groups of the acrylic monomers, indicating that the St radical has a higher propensity to react with more electron-deficient acrylic vinyl groups. However, for cinnamic monomers, the rSt values decrease in the following order: CAld (8.37) > CN (4.90) > CNIPAm (4.30) > CA (1.84) > CAMe (1.29). The order is also affected by steric hindrance around the vinyl group of the cinnamic monomers. In addition, for cinnamic monomers, the St radical most likely attacks the vinyl carbon adjacent to the carbonyl or nitrile group, unlike the corresponding acrylic monomers, as discussed later. The thermal properties of the copolymers were evaluated by differential scanning calorimetry (DSC) and thermal gravimetric analysis (TGA). For all the copolymers, the glass transition temperatures (Tg) were higher than those of the homopolymers, namely, 10 °C for poly(MA) and 100 °C for poly(St). In addition, the Tg values increased by 30 to 90 °C for both polymers, and these increases were dependent not only on the cinnamic monomers but also on the incorporated content. However, incorporations of only 15 to 40 mol % substantially increased the Tg values, indicating that cinnamic monomer units are effective for increasing the thermal properties of the copolymers due to their rigid 1,2disubstituted fragments. The decomposition temperatures (Td5) were also dependent on cinnamic monomer incorporation, and the temperatures were slightly lower than those of

Figure 3. Copolymer composition curves for the radical copolymerization of cinnamic monomers as M1 and MA (A) or St (B) as M2 at 60 °C with AIBN obtained at varying monomer feed ratios ([M1]0/ [M2]0 = 1/5, 1/3, 1/1, 3/1, 5/1, 9/1): [M1]0 + [M2]0 = 4.0 M, [AIBN]0 = 20 mM, in toluene for M1 = CAMe, CAld, CN; [M1]0 + [M2]0 = 2.0 M, [AIBN]0 = 10 mM, in DMF for M1 = CA, CNIPAm. The dotted lines were fitted by the Kelen−Tüdõs method for the terminal model (see r1 and r2 values in Table 1).

cinnamic monomers were lower than those of MA and St. The plots were analyzed by terminal model and were fitted well with the dashed lines, which were obtained by the monomer reactivity ratios based on the Kelen−Tüdõs method.37,76,98 The r1 and r2 values are summarized in Table 1, where M1 and M2 correspond to cinnamic monomers and comonomers (i.e., MA or St), respectively. The r1 values were close to zero for all the cinnamic monomers independent of the comonomer, indicating that all these 1,2-disubstituted cinnamic monomers generate very little of their homosequences even in the copolymerizations, as previously reported for radical copolymerizations of St with several cinnamates, cinnamides, or cinnamonitrile.99 In addition, a good fitting based on the terminal model indicates negligible penultimate effects on the copolymerizations. The r2 values of St for CAMe, CA, and CN were lower than those of MA, indicating that the St radical more frequently reacts with these cinnamic monomers than the MA radical in each copolymerization. This is because the more electron-rich St radicals have a higher relative propensity to react with the electron-deficient vinyl group of these cinnamic monomers than do the electron-deficient MA radicals. Specifically, the r2 value of 1.29 for St with CAMe means that St radical reacts

Figure 4. Ruthenium-catalyzed living radical copolymerization of CAMe and MA or St with H-(MMA)2-Cl/RuCp*Cl(PPh3)/nBu3N in toluene at 60 °C: [CAMe]0 = [MA or St]0 = 2.0 M, [H-(MMA)2-Cl]0 = 40 mM, [RuCp*Cl(PPh3)]0 = 4.0 mM, [nBu3N]0 = 40 mM. (A) Mn and Mw/Mn values against total monomer conversion. The diagonal red and blue lines indicate the calculated Mn assuming the formation of one polymer chain per H-(MMA)2-Cl molecule for CAMe/MA and CAMe/St copolymerizations, respectively. (B) SEC curves of poly(CAMe-co-MA). (C) SEC curves of poly(CAMe-co-St). E

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Figure 5. 1H NMR spectra of poly(CAMe-co-MA) (A) and poly(CAMe-co-St) obtained in the ruthenium-catalyzed living radical copolymerization of CAMe and MA or St with H-(MMA)2-Cl/RuCp*Cl(PPh3)/nBu3N in toluene at 60 °C: [CAMe]0 = [MA or St]0 = 2.0 M, [H-(MMA)2-Cl]0 = 40 mM, [RuCp*Cl(PPh3)]0 = 4.0 mM, [nBu3N]0 = 40 mM.

or polystyrene standard calibration. These results indicate that CAMe, which possesses substituents on the vinyl carbons similar to those of MA and St, can be copolymerized with MA and St in a living fashion in a ruthenium-catalyzed living radical polymerization. The obtained copolymers were then analyzed by 1H NMR (Figure 5). The copolymers exhibit their main signals in similar regions, namely, the pendent phenyl (6.0−7.5 ppm) and methyl ester (3.2−4.0 ppm) protons, in addition to broad peaks for the main-chain methylene and methine protons (1.2−3.2 ppm). The copolymers of CAMe and MA show more intense and relatively sharper peaks at approximately 3.2−4.0 ppm due to the superimposition of the methyl ester protons of both the CAMe and MA units (Figure 5A), whereas the spectra of CAMe and St show more intense peaks in the aromatic region (6.0−7.5 ppm) due to the superimposition of the phenyl protons of both the CAMe and St units (Figure 5B). The incorporation ratios of CAMe/MA or CAMe/St, which were calculated from the peak area ratios, were close to those calculated from the monomer feed ratios and conversions. These results indicate that the consumed monomers were almost quantitatively incorporated into the copolymers. In addition to these main signals, the α- and ω-terminal protons can be observed at approximately 1.0 ppm and 4.0− 5.3 ppm for methyl protons of the initiating methacrylate dimer unit and the methine protons adjacent to the terminal chloride, respectively, in both polymers. For the ω-terminal protons, the copolymers of CAMe and MA show two clearly discriminable signals at approximately 4.0−4.3 and 4.8−5.3 ppm, which can be assigned to the chloride ω-terminal proton adjacent to the carbonyl group of the MA unit and adjacent to the phenyl group of the CAMe unit, respectively. In contrast, the copolymers of CAMe and St show two peaks with similar shifts at approximately 4.2−4.6 and 4.7−4.9 ppm, which can be assigned to the chloride ω-terminal proton adjacent to the phenyl group of the St unit and the proton adjacent to the phenyl group of the CAMe unit, respectively. In both

the homopolymers of MA and St due to the presence of three consecutive substituted carbon atoms in the main chains, unlike the backbones of the homopolymers of MA and St. This is related to the fact that thermal decomposition occurs at a lower temperature for head-to-head structures, namely, two consecutive substituted carbon atoms, in vinyl polymers obtained in radical polymerization, although Td5 is also affected by the terminal structures of the polymer. Ruthenium-Catalyzed Living Radical Copolymerization of Methyl Cinnamate with Methyl Acrylate or Styrene. Living radical copolymerizations of CAMe with MA or St were investigated using an initiating system consisting of H-(MMA)2-Cl, RuCp*Cl(PPh3)2, and nBu3N, which is effective for living radical homopolymerizations of both MA and St,100 and these reactions were conducted at a 1:1 feed ratio of CAMe to MA or St in toluene at 80 °C. This initiating system is expected to be appropriate even for CAMe, which can potentially give both MA- and St-like radicals depending on the regioselectivity. As shown in Figure S1A, CAMe and MA were consumed simultaneously even with the ruthenium-based initiating system, although the consumption of CAMe was slower than that of MA as in the free radical copolymerization discussed above. The same initiating system induced a similar and slightly slower copolymerization for CAMe and St than that for CAMe and MA (Figure S1B), which is also similar to what was seen in the free radical copolymerizations. The SEC curves were unimodal throughout the reactions and shifted to high molecular weights as the copolymerization proceeded (Figure 4). The molecular weight distributions (MWDs) were narrower for the copolymers with St, which is similar to what is observed with the homopolymers of MA and St obtained with the same initiating system.78,100 The numberaverage molecular weights (Mn) increased in direct proportion to the monomer conversions and agreed well with the calculated values, assuming that one molecule of H(MMA)2-Cl generates one polymer chain, although these values were measured by SEC using poly(methyl methacrylate) F

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Figure 6. 1H NMR spectra (in CDCl3, at 25 °C) of the products obtained in the ruthenium-catalyzed atom transfer radical additions between CAMe and MDCA (A) or DCT (B) with RuCl2(PPh3)3/nBu3N in bulk at 100 °C. (A) [CAMe]0 = 2.1 M, [MDCA]0 = 4.2 M, [RuCl2(PPh3)3]0 = 10 mM, [nBu3N]0 = 100 mM; (B) [CAMe]0 = 1.8 M, [DCT]0 = 3.6 M, [RuCl2(PPh3)3]0 = 10 mM, [nBu3N]0 = 100 mM.

adjacent to the halogen are observed. All the signals are sharp but are somewhat complicated, suggesting the formation of low molecular weight products and diastereomers due to the lack of stereoselectivity or regioselectivity. Although the absence of stereoselectivity is obvious due to the achiral ligand,101 the lack of regioselectivity is unexpected and should be clarified. To identify the products, each of the regioisomers (1 and 4) was synthesized using two symmetrical vinyl compounds, that is, dimethyl fumarate (DMFu) and trans-stilbene (STB), with similar ruthenium-catalyzed ATRA reactions with DCT and MDCA, respectively (Figures S4 and S5). The obtained products were the expected adducts, 1 and 4 (Figures S6B and S7B), and they were formed with no stereoselectivity. The 1H NMR spectra of the products obtained via the ATRAs between CAMe and MDCA or DCT were compared with those of 1 and 4, respectively (Figures S6A and S7A). These comparisons revealed that the main adduct obtained via ATRA between CAMe and MDCA was 1 (91%), whereas that obtained via ATRA between CAMe and DCT was 3 (93%). The 2D 1 H−13C heteronuclear multiple bond correlation (HMBC) spectra also indicated that the main products of these reactions were 1 and 3, respectively (Figures S8 and S9). These results indicate that both the model acrylic and styrenic radicals, derived from MDCA and DCT, respectively, predominantly attack the vinyl carbon of the carbonyl side of CAMe, generating the styrenic radical. Similar results were also obtained using the other model compounds, such as methyl 1-chloropropionate [CH3CHCl(CO2Me); MCP] or 1-phenylethyl chloride [CH3CHClPh; PEC], in the rutheniumcatalyzed ATRAs with CAMe, and in these cases, the radical additions predominantly occurred at the vinyl carbon of the carbonyl side of CAMe Figures S10 and S11. These model reactions indicate that the radical copolymerization of CAMe occurs regioselectively via styrenic radical propagation, although this was previously suggested by the results of Kharasch addition reactions between CCl3Br and CAMe under photoirradiation.42,102

polymers, the terminal chloride methine protons adjacent to the phenyl group of the CAMe unit were observed at a relatively low magnetic field due to the adjacent chloride and phenyl groups. However, almost no terminal chloride methine protons adjacent to the carbonyl group of the CAMe unit were observed; however, their weak signals might overlap with the other chloride terminal protons. These results suggest that the propagating radicals of MA and St preferentially attack the vinyl carbon of the carbonyl side of CAMe to generate the styrenic propagating radical species, which was clarified by model radical addition reactions, as discussed in the next section. Furthermore, the Mn values [Mn(NMR)] calculated from the integrations of these ω-terminal protons relative to the pendent methyl ester and phenyl protons were close to the values obtained by SEC [Mn(SEC)], indicating the high chainend fidelity in the ruthenium-catalyzed living radical copolymerization. Regioselectivity Clarified by Model Radical Addition Reaction. To clarify the regioselectivity in the radical addition to the cinnamic monomers, the ruthenium-catalyzed Kharash addition or atom transfer radical addition (ATRA) reaction to CAMe was examined using a ruthenium catalyst [RuCp*Cl(PPh3)2 or RuCl2(PPh3)3] and an additive (nBu3N) for CAMe and methyl dichloroacetate [CHCl2(CO2Me); MDCA] or α,α-dichlorotoluene (CHCl2Ph; DCT), which potentially generate radicals similar to those generated from MA and St, respectively, via ruthenium-catalyzed activation of the C−Cl bond. The model radical addition reaction was carried out with excess of the halide with respect to CAMe ([halide]0/ [CAMe] 0 = 2/1) in bulk at 80 and 100 °C using RuCp*Cl(PPh3)2 or RuCl2(PPh3)3 (Figures S2 and S3). Although the reactions were slow, both compounds were consumed in an almost 1:1 ratio with over 50% conversion of CAMe, especially at 100 °C using RuCl2(PPh3)3. The obtained products were first analyzed by 1H NMR spectroscopy. The 4.5−5.2 ppm regions of the spectra are shown in Figure 6, as this is where the characteristic signals of the methine protons G

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Figure 7. Nitroxide-mediated copolymerization of CAMe and MA or St with PE-TIPNO in bulk at 90 °C: [CAMe]0 = [MA]0 = 4.0 M, [PETIPNO]0 = 80 mM or [CAMe]0 = [St]0 = 3.6 M, [PE-TIPNO]0 = 72 mM. (A) Mn and Mw/Mn values against total monomer conversion. The diagonal red and blue lines indicate the calculated Mn assuming the formation of one polymer chain per PE-TIPNO molecule for CAMe/MA and CAMe/St copolymerizations, respectively. (B) SEC curves of poly(CAMe-co-MA). (C) SEC curves of poly(CAMe-co-St).

Figure 8. RAFT copolymerization of cinnamic monomers and MA with CPETC/AIBN at 60 °C: [M1]0 = [MA]0 = 2.0 M, [CPETC]0 = 40 mM, [AIBN]0 = 20 mM, in toluene for M1 = CAMe, CAld, CN; [M1]0 = [MA]0 = 1.0 M, [CPETC]0 = 20 mM, [AIBN]0 = 10 mM, in DMF for M1 = CA, CNIPAm.

Figure 9. RAFT copolymerization of cinnamic monomers and St with CPETC/AIBN at 60 °C: [M1]0 = [St]0 = 2.0 M, [CPETC]0 = 40 mM, [AIBN]0 = 20 mM, in toluene for M1 = CAMe, CAld, CN; [M1]0 = [St]0 = 1.0 M, [CPETC]0 = 20 mM, [AIBN]0 = 10 mM, in DMF for M1 = CA, CNIPAm.

Living Radical Copolymerization by NMP and RAFT. Control of the radical copolymerization of cinnamic monomers with MA and St was also investigated using NMP and RAFT. The copolymerization of CAMe with MA or St was investigated using PE-TIPNO, which is effective for both radical homopolymerizations of MA and St,94,95 at a 1:1 monomer feed ratio in bulk at 90 °C without using a free radical initiator. The monomers were consumed in a similar way to the free radical and ruthenium-catalyzed living radical copolymerizations in which the consumption of CAMe was slower than that of MA or St. The obtained polymers possessed narrow MWDs, but they were slightly broader than those of the polymers obtained with RuCp*Cl(PPh3)2. They

also showed controlled molecular weights, which increased in direct proportion to the total monomer conversion (Figure 7). The MWDs obtained in the copolymerization with St were narrower than those with MA, which is similar to the results of the ruthenium-catalyzed living radical copolymerizations. The controlled radical copolymerization was thus also feasible using TIPNO because the propagating radical species in these copolymerizations is either an acrylic or a styrenic radical, which TIPNO can efficiently and reversibly cap to control the propagation. Then, the RAFT system, which is one of the most versatile controlled radical polymerization methods, was investigated for radical copolymerizations of a series of cinnamic monomers H

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Biomacromolecules Table 2. RAFT Copolymerization of NIPAM with CNIPAm or Styrene and Thermoresponsivitya comonomer (M1)

[M1]0/[NIPAM]0 (mM)

time (h)

conv (M1/NIPAM)b (%)

Mnc

Mw/Mnc

M1/NIPAMd

cloud pointe (°C)

CNIPAm CNIPAm CNIPAm St St St

1800/1200 1500/1500 1000/2000 160/1840 100/1900 50/1950

480 460 75 18 12 7

8/41 11/53 6/42 80/35 83/34 82/43

7300 8600 8700 7900 8700 6800

1.22 1.25 1.11 1.16 1.11 1.10

15/85 9/91 5/95 14/86 9/91 5/95

13.5 19.7 23.8 8.9 13.9 17.1

Polymerization conditions: [CPETC]0 = 20 mM, [AIBN]0 = 10 mM, DMF, 60 °C. bDetermined by 1H NMR analysis of reaction mixtures. Determined by size-exclusion chromatography of the fractionated polymers. dDetermined by 1H NMR analysis of the fractionated polymers. e Conditions: polymer concentration = 10 mg/mL, heating rate = 1.0 °C/min. The cloud point was determined by the temperature, at which the transmittance (λ= 500 nm) of aqueous solution became 50%. a c

heating (Figure 10). The LCSTs decreased as the contents of NIPAM decreased. In addition, the LCSTs of the copolymers

and MA or St using a trithiocarbonate-type RAFT agent, CPETC, which is effective for controlling the polymerization of most conjugated monomers,76,91−93 in the presence of AIBN in toluene (for CAMe, CAld, and CN) or DMF (for CA and CNIPAm) at 60 °C. In all cases, the copolymerizations afforded polymers with narrow MWDs and controlled molecular weights, although the SEC curves of the copolymers of CAld showed tails that were most likely due to irreversible chain transfer to the aldehyde moiety (Figures 8 and 9). In addition, the MWDs were narrower for all the copolymers obtained with St than those with MA, which is similar to the results of the other controlled/living radical polymerizations discussed above. These results indicate that various cinnamic monomers can be copolymerized with acrylates and styrenes via RAFT systems in a controlled manner to be incorporated into copolymers. Thermoresponsive Copolymers Prepared by RAFT Copolymerization of N-Isopropyl Cinnamide and NIsopropylacrylamide. Polymers of NIPAM are known as thermoresponsive polymers with lower critical solution temperatures (LCSTs), and these polymers are soluble in water at low temperatures but become insoluble at a certain temperature (approximately 32 °C) due to the dehydration of water from the pendent N-isopropylamide groups.103−105 Here, copolymers of NIPAM with CNIPAm were prepared by RAFT copolymerization, and the thermoresponsive behaviors were examined and compared with those of the copolymers of NIPAM and St, which have similar molecular weights and similar contents of NIPAM units. The RAFT copolymerizations of NIPAM and CNIPAm were investigated by varying the monomer feed ratios (3/2, 1/ 1, and 1/2) in DMF at 60 °C to prepare controlled copolymers with varying NIPAM contents in the copolymers. In all the RAFT copolymerizations, both monomers were consumed simultaneously, and the consumption of NIPAM was faster than that of CNIPAm, similar to what was seen in the copolymerization of CNIPAm with MA and St. All of the obtained copolymers possessed narrow MWDs (Mw/Mn ≤ 1.3) and controlled molecular weights (Figure S12). The obtained copolymers were then fractionated by preparative SEC to give copolymers with similar molecular weights (Mn = 7300−8700) and varying NIPAM contents (85, 91, and 95 mol %) (entries 1−3 in Table 2). The copolymers of NIPAM and St were similarly synthesized by RAFT copolymerization and were fractionated into copolymers with similar molecular weights (Mn = 6700−8700) and similar NIPAM contents (86, 91, and 95 mol %) (entries 4−6 in Table 2). All the copolymers showed relatively sharp transitions and became insoluble in water at certain temperatures upon

Figure 10. Transmittance (λ = 500 nm) of aqueous solutions of poly(CNIPAm-co-NIPAM) (closed symbols) and poly(St-coNIPAM) (open symbols) having almost the same NIPAM contents: Polymer concentration = 10 mg/mL, heating rate = 1.0 °C/min.

of CNIPAm were consistently higher than those of St when comparing batches of copolymers with similar NAPAM contents. This is apparently due to the presence of additional N-isopropylamide units in the copolymers of CNIPAm compared with those of St due to the 1,2-disubstituted vinyl monomer unit, although the effects of the rigid structures and consecutive N-isopropylamide groups are unknown. These results indicate that thermoresponsive behaviors can be observed even for the copolymers of NIPAM and a cinnamic monomer, CNIPAm, and the behaviors can be tuned by the monomer contents.

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CONCLUSIONS In conclusion, a series of cinnamic monomers having both acrylic and styrenic substituents were radically copolymerized with acrylic and styrenic monomers and were incorporated into the copolymers at up to 40 mol % with a monomer feed ratio of 1:1. Although the monomer reactivity ratios of the cinnamic monomers were close to zero, indicating no homopolymerizability, the rigid 1,2-disubstituted vinyl polymer structures increased the Tg values despite the relatively low monomer incorporation. Model radical addition reactions revealed that the propagation of CAMe predominantly proceeds via the styrenic radical. Controlled radical copolymerizations could be achieved by ruthenium-catalyzed living radical polymerization, NMP, and RAFT systems, and these reactions provided copolymers with controlled molecular I

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weights, narrow MWDs, and controlled comonomer contents. The copolymers of NIPAM and CNIPAm showed tunable thermoresponsivity and higher LCSTs than those of NIPAM and St due to the additional N-isopropylamide groups in the CNIPAm units. These studies thus revealed the reactivity and regioselectivity in the radical copolymerization of cinnamic monomers as well as the properties and functions of the resulting copolymers. We hope that these studies will contribute to the development of biobased polymers with novel properties and functions based on renewable vinyl monomers.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.biomac.8b01298.

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Time-conversion curves for different polymerizations and 1H NMR spectra of products (PDF)

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Kotaro Satoh: 0000-0002-3105-4592 Masami Kamigaito: 0000-0001-7584-5524 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported in part by JSPS KAKENHI Grant Number JP18H04647 for M.K. in Hybrid Catalysis for Enabling Molecular Synthesis on Demand and the Funding Program (Green Innovation GR051; Precision Polymerization of Plant-Derived Vinyl Monomers for Novel Bio-Based Polymers) for Next-Generation World-Leading Researchers for M.K. from the Cabinet Office, Government of Japan.

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REFERENCES

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