Design of Hydroxy-Functionalized Thermoresponsive Copolymers

Oct 23, 2017 - The improved synthesis and aqueous solution properties of hydroxy-functional vinyl ether (OH-VE) copolymers with lower critical solutio...
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Article Cite This: Macromolecules XXXX, XXX, XXX-XXX

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Design of Hydroxy-Functionalized Thermoresponsive Copolymers: Improved Direct Radical Polymerization of Hydroxy-Functional Vinyl Ethers Shinji Sugihara,*,† Ayano Yoshida,† Satoshi Fujita,‡ and Yasushi Maeda† †

Department of Applied Chemistry and Biotechnology, Graduate School of Engineering, University of Fukui, 3-9-1 Bunkyo, Fukui 910-8507, Japan ‡ Department of Frontier Fiber Technology and Science, Graduate School of Engineering, University of Fukui, 3-9-1 Bunkyo, Fukui 910-8507, Japan S Supporting Information *

ABSTRACT: The improved synthesis and aqueous solution properties of hydroxy-functional vinyl ether (OH-VE) copolymers with lower critical solution temperatures (LCST) in water are presented. A series of OH-VE copolymers were directly prepared by free radical polymerization. Effects of water and comonomers on the free radical polymerization using 2-hydroxyethyl vinyl ether (HEVE) were investigated in detail. The free radical polymerization of HEVE at 40−60 wt % in water proceeded with complete monomer conversion. The copolymerizations of HEVE with other vinyl ethers (VEs) or vinyl acetate (VAc) also proceeded smoothly. In each case, the primary key to success in the free radical copolymerization is proper hydrogen bonding between the VE oxygen and hydroxyl group in the pendant or nonacidic water as a solvent. In particular, the copolymerization of OH-VE and VE without a hydroxy group is enabled by a hydrogen-bonded monomer complex. Using the resulting copolymers, we demonstrated the existence of thermoresponsive behavior for the water-soluble copolymers. By choosing appropriate compositions for the copolymers, i.e., an appropriate hydrophilic/hydrophobic balance in the composition or in the side chain, LCST-type thermoresponsive behavior was observed in water. The product copolymers include poly(HEVE-co-VAc), the alkalihydrolyzed poly(HEVE-co-vinyl alcohol), poly(diethylene glycol monovinyl ether-co-VAc), poly(HEVE-co-VE) [VE: 2methoxyethyl vinyl ether, isobutyl vinyl ether, n-butyl vinyl ether, and 4-hydroxybutyl vinyl ether (HBVE)], and poly(HBVE-coVAc). These direct radical copolymerizations allow the design of various thermoresponsive hydroxy-functional polymers with negligible cytotoxicity and tunable LCST.

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INTRODUCTION

as a binding and coating agent including moisture barriers and protection properties.1−5 Another synthetic hydroxyl groupcontaining polymer is poly(2-hydroxyethyl methacrylate) (PHEMA), which is well-known as a synthetic biocompatible material useful for contact lenses and intraocular lens applications.6−8 The analogous poly(2-hydroxyethyl acrylate) (PHEA) is also a biocompatible material9,10 with similar properties as the widespread PHEMA. These hydroxyfunctionalized vinyl polymers have characteristic solubility:

Hydroxy-functionalized polymers have utility as hydrogen bonding sites and can be postreacted with acids, epoxies, and isocyanates to generate novel polymer properties and architectures. Given that some 50% of the world production of polymers is based on free radical polymerization, it is opportune that hydroxy-functionalized vinyl polymers are also produced via direct free radical polymerization. One of the most well-known synthetic hydroxyl group-containing polymers is poly(vinyl alcohol) (PVA). PVA has excellent biocompatibility, hemocompatibility, and degradability in the environment (by microoganisms), and is utilized in a wide range of industrial, commercial, medical and food applications © XXXX American Chemical Society

Received: September 26, 2017 Revised: October 15, 2017

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DOI: 10.1021/acs.macromol.7b02084 Macromolecules XXXX, XXX, XXX−XXX

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Macromolecules

polymerization of OH-VEs using a nonacidic azo-initiator such as dimethyl 2,2′-azobis(2-methylpropionate) (V-601), conventional free radical vinyl polymerization occurred with sufficiently high number-average molecular weight. For example, poly(HEVE) was produced from the corresponding HEVE monomer with Mn = 26400 in high yield, ≥75%. Furthermore, cyanomethyl methyl(phenyl)carbamodithioate (CMPCD) was found to be an efficient RAFT agent, enabling the RAFT radical polymerization of OH-VEs. The primary key to success in the radical polymerization of vinyl ethers is proper hydrogen bonding between the vinyl ether oxygen and the hydroxyl group in the pendant of the vinyl ether. This hydrogen bonding reduces the reactivity of the growing radical, suppressing unfavorable side reactions31,32 such as β-scission and hydrogen abstraction in the radical polymerization of vinyl ether monomers. Before its discovery, living cationic polymerization of protected OH-VEs was known to be a versatile technique for the synthesis of well-defined poly(OH-VE)s. However, the synthesis involves some troublesome steps as follows: synthesis of the protected monomer, its cationic polymerization, and subsequent removal of the protecting groups. Consequently, there have been few, if any, applications for controlled-structure OH-VE-based (co)polymers. Therefore, the discovery of radical polymerization of OH-VEs undoubtedly makes it possible to directly synthesize the above-mentioned hydroxyl groupcontaining, nontoxic, thermoresponsive polymers. In the present study, we report the improved direct radical (co)polymerization of OH-VEs and various thermoresponsive copolymers including poly(HEVE-co-VAc) and alkali-hydrolyzed poly(HEVE-co-VA) random copolymers by (RAFT) radical copolymerization. In order to prepare such copolymers as shown in Figure 1, we investigated in detail the effects of water and comonomers on the free radical (co)polymerization of OH-VEs. Using the products, we studied their solubility as a function of temperature and demonstrated the existence of

water-soluble for PVA (PHEA) or water-swellable for PHEMA (DP > 40).11 Yet another hydroxy-functionalized vinyl polymer is the biocompatible and water-soluble poly(N-hydroxyethyl acrylamide) (PHEAA). PHEAA has been applied to antifouling and biodegradable nanogels with 2-(methacryloyloxy) ethyl trimethylammonium.12 Thus, in any backbone, water-swellable and hydroxy-functionalized polymers often exhibit interesting biocompatibility. Most hydroxy-functionalized copolymers show LCST-type thermoresponsiveness with the more hydrophobic or hydrophilic units for PVA (PHEA, PHEAA) or PHEMA, respectively. LCST-type thermoresponsiveness means that a range of small molecules and polymers are soluble in water but become insoluble above a certain temperature, known as the lower critical solution temperature (LCST). Such thermoresponsive polymers have generated significant interest for nanotechnology and biomedical applications.13−17 By designing the hydroxy-functionalized monomer from scratch, thermoresponsive polymers can be synthesized such as poly(2-hydroxypropyl acrylate)18 and poly(4-hydroxybutyl vinyl ether) prepared from a protected monomer.19 There are a few reports on copolymers including a vinyl alcohol (VA) unit, which is only partially hydrolyzed PVAc (VA/VAc copolymer), that show thermoresponsive behavior.20−23 However, the versatile PVA and partially hydrolyzed PVAc essentially cannot be synthesized by direct radical polymerization of the corresponding monomer; i.e., VA is unstable. To the best of the authors’ knowledge, there have been no reports on VAc/HEMA, VAc/HEA, and VAc/HEAA copolymers because the vinyl ester and (meth)acrylate or acrylamide are expected to have extremely different reactivities.24−27 Even for the analogous acrylate/methacrylate, i.e., HEA/HEMA copolymers, the reactivity ratios of HEMA were much higher than that of HEA: rHEMA = 1.6 and rHEA = 0.15.9 As we reported previously, an appropriate hydrophilic/hydrophobic balance along the copolymer main chain induces sensitive LCST-type thermoresponsive behavior in water.28 Thus, to fulfill such a balance, the monomer composition and sequence distribution (random sequence) are also important. Therefore, the development of a hydroxyl group-containing, nontoxic, thermoresponsive polymer that can be prepared via direct radical copolymerization by an industrially useful method is indispensable for various biorelated applications. Quite recently, we succeeded in the direct free radical homopolymerization of commercial hydroxy-functional vinyl ethers (OH-VEs) such as 2-hydroxyethyl vinyl ether (HEVE), 4-hydroxybutyl vinyl ether (HBVE), diethylene glycol monovinyl ether (DEGV), and 1,4-cyclohexanedimethanol monovinyl ether (CHMVE) to synthesize pure vinyl polymers without polyacetals obtained by self-polyaddition polymerization as shown in Scheme 1.29,30 In the case of bulk Scheme 1. RAFT Polymerization of OH-VEs

Figure 1. Chemical structures of thermoresponsive copolymers including OH-VE in this work. B

DOI: 10.1021/acs.macromol.7b02084 Macromolecules XXXX, XXX, XXX−XXX

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Macromolecules Table 1. Copolymers Including OH-VEs Prepared by Radical Copolymerization at 70 °C for 48 ha composition in copolymerb

comonomer entry

M1

M2

OH-VE (M1) in feed

total convn (%)b

M1

M2

Mnc

Mw/Mnc

solubility in waterd (°C)

e

HEVE

HBVE

HEVE

VAc

DEGV

VAc

HBVE

VAc

HEVE

MOVE

HEVE

IBVE

HEVE

NBVE

1.00 0.80 0.35 0.30 0.25 0.20 0.15 0 0.70 0.67 0.65 0.62 0.60 0.59 0.55 0.50 1.00 0.55 0.50 0.40 0.33 0.90 0.80 0.75 0.70 0.50 0.80 0.60 0.50 0.40 0.20 0.04 0 0.80 0.50 0.20 0 0.80 0.50 0

75.2 73.1 72.2 70.1 68.8 68.2 67.0 65.0 74.0 74.4 73.9 73.2 73.5 73.0 72.5 71.7 73.8 69.0 69.5 69.0 69.5 41.9 50.6 59.8 60.5 76.9 71.1 61.2 52.9 49.6 37.5 47.9 24.3 54.8 70.5 69.3 15.9 60.5 67.4 52.5

1.00 0.81 0.37 0.30 0.25 0.19 0.16 0 0.68 0.65 0.62 0.59 0.55 0.54 0.52 0.44 1.00 0.53 0.49 0.38 0.31 0.85 0.73 0.64 0.62 0.43 0.83 0.62 0.56 0.47 0.17 0.05 0 0.87 0.66 0.36 0 0.85 0.61 0

0 0.19 0.63 0.70 0.75 0.81 0.84 1.00 0.32 0.35 0.38 0.41 0.45 0.46 0.48 0.56 0 0.47 0.51 0.62 0.69 0.15 0.27 0.36 0.38 0.57 0.17 0.38 0.44 0.53 0.83 0.95 1.00 0.13 0.34 0.64 1.00 0.15 0.39 1.00

26400 23100 22000 21400 20000 19900 19500 18100 36100 48000 48000 36400 46300 44000 45400 36100 29700 22800 22000 21200 18500 23000 26000 26000 30700 33700 27800 21200 18100 16200 11300 13800 5000 25900 17700 7300 1200 21100 15800 1400

2.23 1.92 1.91 1.89 1.88 1.90 1.88 1.87 2.45 2.45 2.80 2.50 2.33 2.50 2.50 2.90 3.42 2.78 2.50 2.59 2.60 1.82 1.92 2.11 2.36 3.16 2.16 2.02 1.95 1.79 1.78 1.65 1.72 1.81 1.85 1.76 1.49 1.92 1.88 1.24

○ ○ 78.4 69.3 66.3 60.0 57.6 40.0 57.5 54.4 45.6 40.4 36.3 27.2 20.1 × ○ 40.0 31.2 18.2 12.1 32.7 26.4 16.7 14.8 8.1 ○ ○ ○ ○ ○ 70.5 66.0g 64.0 × × × >90h × ×

1 2 3 4 5 6 7 8e 9f 10 11 12 13 14 15 16 17e 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 a

[Comonomers]0: [V-601] = 500:1. bCalculated by 1H NMR analysis. Typical 1H NMR results are shown in Figures S4−S9. cBy GPC using PSt calibration (DMF eluent with 10 mM LiBr). d○ = soluble and × = insoluble, measured with 1.0 wt % solutions at ambient temperature. The denoted temperature is the cloud point (TPS) which is defined as the temperature at a 50% transmittance of 500 nm light beam on heating. e Reference 29. fThe MWD is shown in Figure 5C. gReference 41. (Mn = 20000, Mw/Mn = 1.09 prepared by living cationic polymerization). hVisual observation. calcium hydride. VAc (Wako; >98.0%) was distilled over calcium hydride. Cyanomethyl methyl(phenyl)carbamodithioate (CMPCD) as a RAFT agent was purchased from Sigma-Aldrich and used as received. Dimethyl 2,2′-azobis(isobutyrate) (V-601, Wako; >97.0%) was recrystallized from methanol. For the solvent, ultrapure water (Wako) was used after controlling the pH by either aqueous sodium hydroxide or hydrochloric acid. Polymerization Procedure. Typical copolymerizations were carried out at 70 °C under a dry nitrogen atmosphere. All reagents were added to a Schlenk tube, followed by three freeze−pump−thaw cycles and then the tube was filled with nitrogen and immersed in a preheated oil bath. For example, to prepare poly(HEVE-co-VAc) via RAFT bulk polymerization (corresponding to entry 9 in Table 1), 2.56 g of HEVE (29 mmol), 2.5 g of VAc (29 mmol), 0.027 g of V-601

thermoresponsive behavior for water-soluble copolymers of a certain composition. Furthermore, we showed by cytotoxity assays that the resulting (co)polymers including OH-VE units have the potential for applications as a biomedical polymer such as an antithrombotic material.

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EXPERIMENTAL SECTION

Materials. Hydroxy-functional vinyl ethers of HEVE (>98.0%), DEGV (>99.0%), and HBVE (>99.0%) were donated from Maruzen Petrochemical and were distilled over calcium hydride under reduced pressure. Other VEs of MOVE (>99%) (Maruzen Petrochemical), IBVE (TCI; >99.0%), and NBVE (TCI; >98.0%) were washed with aqueous alkaline solution and water and then distilled twice over C

DOI: 10.1021/acs.macromol.7b02084 Macromolecules XXXX, XXX, XXX−XXX

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Macromolecules (1.16 × 10−4 mol), and 0.0645 g of CMPCD (2.9 × 10−4 mol) were used. After the desired time, the reaction was quenched via rapid cooling in an ice bath and exposure to air. In the case of water-soluble copolymers, the absence of oligomers was directly verified by GPC analysis. The product was purified by dialysis against deionized water using semipermeable cellulose tubing (SPECTRA/POR, corresponding to a molecular weight cutoff of 1000 Da) with at least six changes of deionized water under the LCST, followed by lyophilization. For water-insoluble copolymers (or thermoresponsive copolymers with lower cloud point in water than room temperature), the volatiles were removed under reduced pressure at room temperature, and then the residue was vacuum-dried for a day at room temperature. All the monomer conversions of the resulting copolymers were determined by 1 H NMR analysis of the just quenched mixture. The molecular weight distributions (MWDs) were directly assessed by gel permeation chromatography (GPC) without purification. Alkali Hydrolysis of Poly(HEVE-co-VAc). A purified polymer (0.37 g) was dissolved in methanol (18.14 g), and 2 wt % of KOH in methanol (18.51 g) was added. The mixture was stirred at room temperature for a day. The mixtures were neutralized using hydrochloric acid. The product polymers were diluted in pure water and then purified by dialysis against deionized water using semipermeable cellulose tubing as well as water-soluble copolymers. Polymer Characterizations. MWDs were assessed by GPC in N,N-dimethylformamide (DMF) with 10 mM LiBr at 40 °C using polystyrene gel columns (TSK gel G-MHHR-MX × 2; flow rate 1.0 mL/min) connected to a Tosoh CCPM-II pump and RI-8012 and UV-8000 refractive and UV detectors, respectively. The RI detector was mainly used for determination of number-average molecular weight (Mn) and polydispersity (Mw/Mn). Some Mns were doubly checked by GPC in THF at 40 °C using polystyrene gel columns [T6000 M (CLM3009) × 3; flow rate 1.0 mL/min] connected to a RI detector (Viscotec GPC2502) and a LALS/RALS (light scattering) detector for absolute molecular weight (Viscotek 270max model with 270 dual detector, Malvern) of the acetylated samples. The 1H NMR spectra to determine the detailed structures of the polymers were recorded on JEOL JNM-ECX500 (500 MHz) spectrometers. When obtaining an accurate chemical shift value or longitudinal relaxation time, a coaxial insert (Wilmad-LabGlass) was used with the NMR tube for external locking (reference: CDCl3 with 0.1% TMS). Characterization of Aqueous Copolymer Solutions. Aqueous solutions of the copolymers were prepared by dissolving the polymer in Milli-Q water (18.2 MΩ·cm) and diluting the sample to the desired concentration. The phase separation temperatures of the solutions were measured by monitoring the transmittance of a 500 nm light beam through a 1 cm glass sample cell at a rate of 1.0 °C/min during heating and cooling scans between 5 and 85 °C. The transmittance was recorded on a JASCO V-500 UV/vis spectrometer equipped with a Peltier-type thermostatic cell holder ETC-505. The LCST of the resulting copolymer was determined using the cloud point (TPS), which is defined as the temperature at a 50% transmittance of a 500 nm light beam. Cytotoxicity was evaluated by a metabolic activity measurement using a colorimetric assay kit (Cell Count Reagent SF, Nacalai Tesque, Kyoto, Japan). Murine fibroblasts (NIH-3T3) suspended in 100 μL of Dulbecco’s modified Eagle medium supplemented with 10% fetal bovine serum were seeded and cultured on 96-well plates at 2500 cells/well in the presence of copolymer solutions, which were diluted to the desired concentration with phosphate buffered saline and filtered with a 0.22-μm membrane for sterilization. After incubation for 24 h at 37 °C, the absorbance of each well at 450 nm was measured using a microplate spectrophotometer (Multiskan GO, Thermo Fisher Scientific). The cell viability (%) was calculated from the absorbance relative to that in cells cultured in the absence of copolymers. Cells were observed with a phase contrast microscope (Olympus, CKX41).

radical polymerization of the corresponding monomers (Scheme 1). Most of the radical polymerizations of OH-VE were conducted in bulk to promote hydrogen bonding between OH-VEs. The 1H NMR spectrum of the OH-VEs reveals that the vinyl proton next to the ether oxygen of the OH-VEs shifted downfield relative to alkyl vinyl ether (alkyl VE), which is difficult to radically homopolymerize. This is supplementally supported by the simulated 1H NMR chemical shifts from DFT calculations.29 In addition, in using DMF as the solvent which cleaves hydrogen bonds between OH-VEs, the resulting Mn was decreased as the amount of DMF increased (Figure S1 of the Supporting Information). Thus, the primary key to success in the direct radical (co)polymerization of VEs is considered to be the hydrogen bonding between ether and hydroxy groups. However, solution polymerization using water as a representative hydroxy group and the copolymerization between VEs with and without hydroxy groups have remained untested. Prior to copolymerization, free radical polymerization of HEVE as a typical example of OH-VE in water was examined. The aqueous polymerization was carried out with V-601 at 70 °C. Figure 2A shows the influence of HEVE monomer concentrations on monomer conversion for aqueous solution polymerization. The different curves correspond to different concentrations of HEVE monomer. At 10% monomer

Figure 2. Free radical homopolymerization of HEVE at 70 °C in water (pH ∼ 7): [HEVE]0/[V-601]0 = 500/1. (A) Kinetic plots depending on monomer concentration in water: [HEVE]0 = 10−80 wt % or bulk (100%; triangle-like plot). RAFT bulk polymerization of HEVE is also shown as a reference (●): [HEVE]0/[CMPCD]0/[V-601]0 = 500/ 2.5/1. (B) Mn and Mw/Mn vs conversion for representative polymerization at [HEVE]0 = 60 wt % (■, □). The results of poly(HEVE) via RAFT radical bulk polymerization are also shown (●, ○).

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RESULTS AND DISCUSSION Improved Free Radical Polymerization of OH-VE. Welldefined poly(OH-VE)s were obtained directly by (RAFT) D

DOI: 10.1021/acs.macromol.7b02084 Macromolecules XXXX, XXX, XXX−XXX

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Macromolecules

These significant hydrogen-bonding effects caused by water and hydroxy groups in the monomer are applicable to the aqueous solution system and copolymerization of HEVE, which provide an increase in polymerization rate and enable the copolymerization of VEs. However, the solvent selection is also important for the polymerization of HEVE. For solvents containing hydroxy groups such as methanol and 2-propanol, much slower vinyl polymerization occurred (Figure 4). Since

concentration, no polymerization occurred. At over 40% monomer concentration, polymerization progressed after an induction period of 2 h, gradually slowing at higher conversions owing to the depletion of the monomer since the monomer and initiator concentrations decreased with time. In the range of 40 to 60% monomer concentration, the conversion varied smoothly with time to reach full conversion. The Mnconversion curve also showed typical chain polymerization, showing the presence of relatively high-molecular-weight polymer molecules at all percentages of conversion (Figure 2B). However, at over 80% monomer concentration, the attained conversion showed signs of leveling off at about 70% as in the bulk polymerization. The order of these polymerization rates is different from common radically polymerizable monomers in organic solvents. In general, the polymerization rate increases with increasing monomer concentration. In some cases of radical polymerization at high monomer concentrations, there is often an increasing polymerization rate from autoacceleration due to the increasingly difficult diffusion of macromolecular radicals by the changing viscosity.33 However, aqueous solution polymerizations often exhibit special features not encountered in organic solvents including bulk polymerization systems due to the action of hydrogen bonds from water molecules. These are confirmed by the detailed measurement of propagation rate coefficients of water-soluble monomers by means of pulse laser polymerization in conjunction with size exclusion chromatography (PLP-SEC), 34−38 and also supported by DFT calculations using the polymerization of (meth)acrylamide with water molecules.39 In these systems, the decrease of propagation rate upon increasing monomer concentration is explained by the fluidizing action of the aqueous environment. In our system of OH-VEs, the local mobility of HEVE (50 wt %) as a model in water was evaluated using longitudinal relaxation times (T1) of the carbons (a−d) as determined by 13 C NMR spectroscopy (Figure 3). Although HEVE and water were hydrogen bonded, all T1s with water (in water) were larger than those without water (bulk). Likewise, in the transition state structure, it is considered that the water molecules also enhance internal rotational motion for propagation and thus enhance the associated pre-exponential factor.

Figure 4. Vinyl polymerization (%) in water (pH = 6, ■), methanol (▲), or 2-propanol (●): [HEVE]0/[V-601]0 = 500/1, [HEVE]0 = 60 wt %. The dashed line is that in water (pH ∼ 7) shown in Figure 2A. The resulting Mn (Mw/Mn) values of poly(HEVE)s for 24 h polymerization are 17100 (2.42), 12000 (1.72), and 8200 (1.61) for water at pH = 6, methanol, and 2-propanol, respectively.

small amounts of acetals and aldehyde which is the decomposed products derived from HEVE with such alcohols were obtained (total 0.9% in methanol and 1.1% in 2-propanol for 24 h polymerization), vinyl polymerization (%) instead of conversion are employed. In the bulk polymerization of HEVE, the electron-donating property of the VE oxygen is significantly decreased by the formation of inter/intrahydrogen bonding between HEVEs. As a result, vinyl polymerization selectively proceeds without acetal and aldehyde formation. Although both water and alcohols are hydrogen bond donor, in the aqueous solution polymerization of HEVE, there are effectively multiple hydrogen bonds between HEVEs or HEVE and water. It seems that these hydrogen bonds by water promote faster radical polymerization of VE due to the combined effect of the reduced reactivity of the growing radical and the fluidizing action of the aqueous environment. However, aqueous polymerization using acidic water forms (poly)acetals as in eqs 1−3. In weak acidic water (pH = 6) and

neutral or alkaline water (pH = 7 or 8), the acetal contents varied from 21.8% and almost 0, respectively (Figure 4 and S2). Thus, vinyl polymerization proceeds selectively at pH ≥ 7. In the case of acidic water below pH = 4, the resulting polymers were all polyacetals. The acetal contents (%) were calculated by

Figure 3. Longitudinal relaxation time (T1) measurements of the carbons for HEVE (black bars) and those in water at 50 wt % (gray bars) by 13C NMR spectroscopy. ΔT1 means T1 in water minus T1 in bulk for each carbon, indicating the mobility of HEVE. E

DOI: 10.1021/acs.macromol.7b02084 Macromolecules XXXX, XXX, XXX−XXX

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Macromolecules the peak intensity ratio of the methyl proton of (poly)acetals at 1.1−1.2 ppm in eqs 1 and 2, the methylene proton of the main chain derived from poly(OH-VE) at 1.3−1.9 ppm, and the aldehyde proton at 9.5 ppm in eq 3. The aldehyde formation was negligibly small or undetectable. Hence, we found that free radical polymerization of HEVE in weak alkaline water proceeds successfully in the monomer concentration range from 40 to 60% with full monomer conversion. Free Radical Copolymerizations between OH-VEs. Since OH-VE itself was found to be radically homopolymerizable due to its own hydroxy group, radical copolymerization between HEVE and other OH-VEs was performed to produce random copolymers. In particular, for HBVE as an example of an OH-VE, the resulting copolymers were expected to exhibit thermally induced phase separation at a threshold of ca. 42 °C, equivalent to the LCST of poly(HBVE).19 The cloud point (TPS) of 42 °C can be controlled by the appropriate hydrophilic/hydrophobic balance, i.e., the composition of the copolymer.40 Table 1 lists all the polymerization results. Entries 1−8 show results of the aforementioned poly(HEVE-co-HBVE) prepared via free radical copolymerization. The copolymerization between HEVE and HBVE proceeded smoothly in the same manner as homopolymerization of HEVE, regardless of the comonomer contents. The relative reactivities for HEVE and HBVE were determined by the Fineman−Ross method at total conversion