Precision Synthesis of Polylactide-Based Thermoresponsive Block

6 days ago - Macroinitiators with a hydroxy group at the ω-end were also synthesized using water (Figure S3)(45) or ethylene glycol (Figure S4) as a ...
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Precision Synthesis of Polylactide-Based Thermoresponsive Block Copolymers via Successive Living Cationic Polymerization of Vinyl Ether and Ring-Opening Polymerization of Lactide Yukiko Seki,† Arihiro Kanazawa,† Shokyoku Kanaoka,† Tomoko Fujiwara,‡ and Sadahito Aoshima*,† †

Department of Macromolecular Science, Graduate School of Science, Osaka University, Toyonaka, Osaka 560-0043, Japan Department of Chemistry, The University of Memphis, 213 Smith Chemistry Building, Memphis, Tennessee 38152, United States

‡

S Supporting Information *

ABSTRACT: A new class of polylactide (PLA)-based block copolymers with thermoresponsive poly(vinyl ether) [poly(VE)] were precisely synthesized via successive living cationic polymerization of VE and ring-opening polymerization of lactide (LA). The synthetic route starts with precise end-functionalization of poly(VE) by living cationic polymerization to produce a macroinitiator having a hydroxy group at the α- and/or ω-end for ring-opening polymerization of LA. End-functionalized polymers of 2-methoxyethyl VE (MOVE) with highly controlled structures were obtained by either an initiation or a termination method under optimized conditions. Subsequent ring-opening polymerization of LA from the hydroxy group of the macroinitiator yielded block copolymers with welldefined structures. The obtained block copolymers were demonstrated to exhibit a thermoresponsive solubility transition in water; this transition was induced by the thermosensitivity of the poly(MOVE) segments. The transition between micelle-like aggregates and phase separation was reversible with a shorter PLA chain, whereas irreversible precipitation was observed with a longer PLA segment. The permanent precipitation upon heating is most likely attributable to crystalline formation of the longer PLA segments. The solution and bulk properties of the block copolymers with enantiomeric PLA were also governed by stereocomplex formation between poly(L-lactide) (PLLA) and poly(D-lactide) (PDLA) segments.

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acrylate].25,26 More precise synthesis of various block copolymers of PLA has recently become viable through the use of highly controlled ring-opening polymerization of lactide (LA) by metal-free organocatalyst systems.27−29 The precision synthesis of a series of functionalized block copolymers of PLA can be facilitated by the use of a single living polymerization system for diverse functional monomers. To this end, living cationic polymerization of vinyl ethers (VEs) is a powerful tool for producing various PLA-based functional copolymers.30 Easy access of a series of VE monomers with various pendant functional groups, such as hydroxy, oxyethylenic, azo, carboxy, and amino groups, allows us to readily synthesize various-shaped polymers with functions including hydrophilicity,31,32 thermosensitivity,32 light-responsiveness,33 and pH-responsiveness.34,35 For example, poly(VE)s with oxyethylenic side chains undergo a sharp solubility transition in water or organic solvents in response to temperature. In addition, the transition temperature can be changed by the length of the oxyethylene units and the kind of alkyl groups. More importantly, attaining high sensitivity requires high control of molecular weight and molecular weight distribution

INTRODUCTION Polylactide (PLA) has been of broad and great interest in various fields as engineering and biomedical materials because of its characteristics such as hydrophobicity, crystallinity, and good biocompatibility.1−3 Another important feature of PLA is stereocomplex formation between poly(L-lactide) (PLLA) and poly(D-lactide) (PDLA), which enhances the mechanical and thermal properties of PLA.4−6 These features have spurred many studies on the synthesis of copolymers consisting of PLA and functional polymer segments to add specific properties such as hydrophilicity, thermosensitivity, or pH responsiveness. For example, diblock copolymers composed of PLA and poly(ethylene glycol) (PEG) blocks were shown to form micellar aggregates in water with a core of PLA block.7−10 In particular, properties such as shape, size, and critical micellar concentration of the aggregates were observed to be dependent on both the length of the PLA units and the primary structures of block copolymers. This combination of the segments in a block copolymer was also shown to successfully generate thermoresponsive hydrogels.11,12 Efficient physical gelation was also achieved through stereocomplex formation between PLLA and PDLA segments of block copolymers.13−15 Other polymers studied for block copolymers with PLA include poly(Nisopropylacrylamide) [poly(NIPAM)], 16−22 poly(acrylic acid), 23−25 and poly[N,N-dimethylamino-2-ethyl(meth)© XXXX American Chemical Society

Received: November 1, 2017 Revised: January 8, 2018

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DOI: 10.1021/acs.macromol.7b02329 Macromolecules XXXX, XXX, XXX−XXX

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distilled over calcium hydride and then lithium aluminum hydride. Toluene and dichloromethane were dried by solvent purification columns (Glass Contour). 2-(Vinyloxy)ethyl acetate (AcOVE) was prepared from an addition reaction of 2-chloroethyl VE with sodium acetate in the presence of tetrabutylammonium iodide at 95 °C and was subsequently distilled twice over calcium hydride under reduced pressure. The adduct of AcOVE (MOVE) with acetic acid, AcOEA (MOEA), was prepared from an addition reaction of AcOVE (MOVE) with acetic acid at room temperature (60 °C) and then distilled twice over calcium hydride under reduced pressure. SnCl4 (Sigma-Aldrich, 1.0 M solution in heptane), Et1.5AlCl1.5 (Nippon Aluminum Alkyls, 1.0 M solution in toluene), and LiBH4 (Sigma-Aldrich, 2.0 M solution in tetrahydrofuran) were used without further purification. Sodium hydroxide (Nacalai Tesque, 97%) for alkaline hydrolysis and ethylene glycol (Nacalai Tesque, 99.5%) as a quencher were used as received. All chemicals except for LA, toluene, dichloromethane, and sodium hydroxide were stored in brown ampules under dry nitrogen. Synthesis of Macroinitiators. The polymerization was conducted under a dry nitrogen atmosphere in a glass tube fitted with a three-way stopcock; the tube was baked using a heat gun (Ishizaki; PJ-206A; blow temperature: approximately 450 °C) under dry nitrogen for 10 min before use. A prechilled Et1.5AlCl1.5 solution was added to a prechilled mixture containing a cationogen such as AcOEA or MOEA, a weak Lewis base (THF or 1,4-dioxane), a DTBP solution in toluene, and a solvent at 0 °C using a dry medical syringe. The polymerization reaction was initiated by the successive addition of a prechilled SnCl4 solution and a monomer to the prechilled mixture at −20 °C. After a predetermined period, the polymerization was quenched using methanol containing a small amount of an aqueous ammonia solution. The quenched reaction mixture was diluted with dichloromethane and subsequently washed with dilute hydrochloric acid and then water to remove the initiator residues. The product polymer was recovered from the organic layer by evaporation of volatiles under reduced pressure and subsequently vacuum-dried for at least 6 h. The monomer conversion was determined by a gravimetric method. The acetoxy group, introduced at the α-end of a poly(VE) with the use of AcOEA as a cationogen for polymerization, was hydrolyzed via the following method. To a 1 wt % acetone solution of the poly(VE), a prechilled aqueous sodium hydroxide (0.2 M; 20 equiv relative to the acetoxy units) was added at 0 °C. The reaction mixture was stirred with a magnetic stir bar at room temperature for 24 h. The hydrolysis reaction was quenched with aqueous HCl (1.0 M). Volatiles of the quenched mixture were evaporated under reduced pressure. The residue was purified by dialysis against distilled water for at least 2 days and subsequently against Milli-Q purified water for 1 day. The macroinitiator was obtained through the evaporation of water and subsequent vacuum drying. The aldehyde moiety, introduced at the ω-end of a poly(VE) with the use of water as a quencher for polymerization, was reduced via the following method. To a 10 wt % solution of the poly(VE), a prechilled LiBH4 solution in THF (0.2 M; 4.4 equiv of hydride moieties relative to the aldehyde units) was added at 0 °C. The reaction mixture was stirred with a magnetic stir bar at 0 °C for 1 h. The reduction reaction was quenched with an aqueous acetic acid solution (5 wt %). The residue was purified by dialysis against distilled water for at least 2 days and subsequently against Milli-Q water for 1 day. The macroinitiator was obtained through the evaporation of water and subsequent vacuum drying. Synthesis of Block Copolymers. A macroinitiator was dried either via an azeotropic method using toluene or via freeze-drying using liquid nitrogen. The dried macroinitiator was dissolved in dichloromethane, and the solution was then added to a tube containing LA. To this solution, DBU in dichloromethane was added to start the polymerization. After a predetermined period, the reaction was quenched using acetic acid. The quenched mixture was diluted with dichloromethane and then washed with water. The product polymer was recovered from the organic layer by evaporation of volatiles under reduced pressure and subsequent vacuum drying. The monomer conversion was determined by 1H NMR analysis.

(MWD) of poly(VE)s. Thus, our group has developed initiating systems for living cationic polymerization of various VEs using various metal chlorides as catalysts, enabling the synthesis of stimuli-responsive poly(VE)s with high sensitivity. Combining the versatility of poly(VE)s and the uniqueness of PLA, such as hydrophobicity, alkali degradability, and crystallinity, a new type of block copolymer will be prepared and can be used as functional materials in biosensors, drug delivery systems, and smart films. To produce block copolymers consisting of poly(VE) and PLA segments (Scheme 1), living cationic polymerization36 of Scheme 1. Poly(lactides), Thermoresponsive VEs with Oxyethylene Side Chains, and Di- and Triblock Copolymersa

a Tps exhibits the phase separation temperature of aqueous solutions of homopolymers (ref 32).

VEs and ring-opening polymerization of LA27,28 must be conducted in sequence. In this study, precise synthesis of a thermoresponsive poly(VE) with a hydroxy group at either or both of the α- and ω-ends was first examined through living cationic polymerization of VE with an oxyethylene moiety. Subsequently, ring-opening polymerization of LA was conducted via an initiation reaction from the hydroxy group at the chain end of the poly(VE) macroinitiator to yield block copolymers. The resulting diblock and triblock copolymers were shown to form micelle-like structures with a core of PLA segments and a corona of poly(VE) segments in water. Moreover, the copolymers exhibited thermosensitivity in water reversibly through hydration and dehydration of the poly(VE) segments. Interestingly, the thermoresponsive behavior was critically dependent on the length of PLA segments. Stereocomplex formation between PLLA and PDLA segments also affected the thermoresponsivity and bulk properties of the copolymers.

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EXPERIMENTAL SECTION

Materials. 2-Methoxyethyl VE (MOVE; Maruzen Petrochemical) and 2-ethoxyethyl VE (EOVE; Maruzen Petrochemical) were distilled twice over metallic sodium. 2-(2-Ethoxy)ethoxyethyl VE (EOEOVE; Maruzen Petrochemical) was distilled twice over metallic sodium under reduced pressure. L-Lactide (LLA; TCI, >98.0%) and D-lactide (DLA; PURAC, 99%) were recrystallized from 1,4-dioxane and then toluene before being dried for more than 3 h prior to use. 2,6-Di-tertb u t y l p y r i di n e ( D T B P , S i g m a -A l dr i c h ; 97 %) a n d 1 , 8 diazabicyclo[5.4.0]undec-7-ene (DBU; TCI, >98%) were distilled twice over calcium hydride under reduced pressure. 1,4-Dioxane (Wako, >99.5%) and tetrahydrofuran (THF; Wako, >97%) were B

DOI: 10.1021/acs.macromol.7b02329 Macromolecules XXXX, XXX, XXX−XXX

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Scheme 2. Synthesis of (A) a Macroinitiator Having a Hydroxy Group at the α-Chain End and (B) a Diblock Copolymer Consisting of a Thermoresponsive Poly(VE) and PLLA Segments and (C) Its Alkaline Hydrolysis

Figure 1. MWD curves and MALDI-TOF-MS spectra of poly(MOVE)s obtained in polymerization with Et1.5AlCl1.5 or Et1.5AlCl1.5/SnCl4: [MOVE]0 = 0.50 M, [AcOEA]0 = 10 mM, [DTBP]0 = 5.0 mM; (A, B) [Et1.5AlCl1.5]0 = 20 mM, [1,4-dioxane]0 = 1.2 M, or (C) [Et1.5AlCl1.5]0 = 20 mM, [SnCl4]0 = 10 mM, [THF]0 = 0.20 M; in toluene at 0 or −20 °C. *The difference of the m/z values (76) corresponds to the mass value of the alcohol (CH3OCH2CH2OH) eliminated from the side chain of poly(MOVE). Alkaline Hydrolysis. A block copolymer was dissolved in THF/ water (1/1 v/v). A mixture of aqueous sodium hydroxide and THF (0.1 M NaOH) was added to the polymer solution to start the hydrolysis reaction. After a predetermined period, the reaction was quenched with aqueous HCl solution (1.0 M). The quenched mixture was diluted with dichloromethane and washed with water to remove

the resulting salts. The volatiles were removed under reduced pressure to yield the hydrolysis products. Characterization. The molecular weight distribution (MWD) of polymers in chloroform was measured at 40 °C using gel permeation chromatography (GPC) with polystyrene gel columns [Tosoh TSKgel GMHHR-M × 2 or 3 (exclusion limit molecular weight = 4 × 106; bead C

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Macromolecules size = 5 μm; column size = 7.8 mm i.d. × 300 mm; flow rate = 1.0 mL min−1)] connected to a Tosoh DP-8020 pump, a CO-8020 column oven, a UV-8020 ultraviolet detector, and an RI-8020 refractive index detector. The number-average molecular weight (Mn) and polydispersity ratio [weight-average molecular weight/number-average molecular weight (Mw/Mn)] were calculated from the chromatographs with respect to 16 polystyrene standards (Tosoh; 2921.09 × 106, Mw/Mn ≤ 1.1). 1H NMR spectra were recorded at 25 °C using a JEOL ECA 500 (500 MHz) or a JEOL ECS 400 (400 MHz) spectrometer. Matrix-assisted laser desorption ionization time-of-flight mass spectroscopy (MALDI-TOF-MS) was conducted using a Shimadzu/Kratos AXIMA-CFR spectrometer (linear mode) using dithranol as a matrix and sodium trifluoroacetate as an ionizing agent. The transmittance of aqueous polymer solutions was measured at 500 nm using a JASCO V500 UV−vis spectrometer equipped with a Peltier-type thermostatic cell holder, model ETC-505. The heating and cooling rates were 1.0 °C min−1. The particle size was measured by dynamic light scattering (DLS; Otsuka Electronics FPAR-1000HG, λ = 632.8 nm, scattering angle = 90°). Static contact angle measurements on the polymer films were conducted using a contact angle system (Kyowa Interface Science DM 501). The contact angles of the surface at 22 and 48 °C were determined using the water-drop method and were averaged from values obtained at a minimum of three different positions. The films were prepared on a glass substrate by a spin-coating method from a 1 wt % polymer solution in THF for 60 s at 200 rpm. The films were subsequently dried under vacuum for 6 h at room temperature before the measurements were performed. Differential scanning calorimetry (DSC; EXSTER-6000, Seiko Instruments Inc.) was used to determine the glass transition temperature (Tg), the crystallization temperature (Tc), and the melting temperature (Tm) of the product copolymers. The heating and cooling rates were 10 °C min−1.

electron-withdrawing effect of the acetoxy moiety40−42 and/or the possible interaction between the acetoxy moiety and a Lewis acid catalyst (Et1.5AlCl1.5). Thus, SnCl4, a highly efficient catalyst for controlled polymerization reactions of various VEs,43 was used in conjunction with THF, instead of 1,4dioxane, as a weak Lewis base. Et1.5AlCl1.5 was also employed to convert the acetic acid adduct into an HCl adduct in situ (an efficient conversion is not achieved with SnCl4 alone44). This initiating system allowed superior control over polymerization compared to the reaction using Et1.5AlCl1.5 alone, yielding a polymer with a very narrow MWD (the MWD curve in Figure 1C). MALDI-TOF-MS analysis exhibited a single series of peaks (the spectrum in Figure 1C), indicating the occurrence of polymerization free from side reactions. Moreover, the Mn values of the product polymers increased linearly, as shown in Figure 2, suggesting that highly controlled polymerization

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RESULTS AND DISCUSSION Precision Synthesis of Poly(VE) Macroinitiators with Hydroxy Groups at the Chain Ends via Living Cationic Polymerization. A macroinitiator with a hydroxy group at the α-end was first synthesized via cationic polymerization of MOVE using AcOEA,37,38 which is a cationogen with an acetoxy moiety as a concealed hydroxy group (Scheme 2A). The reaction conditions, including the temperature and the catalysts used, were critical to the synthesis of a macroinitiator with a well-defined structure. The polymerization was first conducted using Et1.5AlCl1.5 as a Lewis acid catalyst in the presence of 1,4-dioxane and DTBP at 0 °C. A polymer with a relatively narrow MWD was obtained (the MWD curve is presented in Figure 1A); however, MALDI-TOF-MS analysis (the spectrum is included in Figure 1A) suggested that elimination reactions of an alcohol molecule from the main chain of poly(MOVE) occurred during the polymerization.39 The spectrum had a series of peaks, the m/z values of which were 76 smaller than those of the main series. The minor peaks were assigned to the structures resulting from the elimination reactions, as also indicated by 1H NMR analysis (Figure S1). To suppress the elimination reaction, we conducted the polymerization at −20 °C under similar conditions. The polymerization smoothly proceeded, yielding a polymer with a MWD slightly narrower than that obtained at 0 °C (Figure 1B). In this case, the product polymer had no undesirable structures: its MALDI-TOF-MS spectrum showed only a single series of peaks of which the m/z values agreed with those of the expected structures. It is indicative of a successful living polymerization free from side reactions. The MWDs of the obtained polymers were, however, broader than those of the poly(MOVE)s produced using other cationogens in our previous study, possibly because of inefficient, uneven initiation reactions from AcOEA due to the

Figure 2. Mn and Mw/Mn values of the poly(MOVE)s obtained by polymerization using Et1.5AlCl1.5/SnCl4: [MOVE]0 = 0.50 M, [AcOEA]0 = 10 mM, [Et1.5AlCl1.5]0 = 20 mM, [SnCl4]0 = 10 mM, [DTBP]0 = 5.0 mM, [THF]0 = 0.20 M, in toluene at −20 °C.

proceeded in a living manner. Both an efficient initiation reaction and a suitable dormant-active equilibrium through the catalysis by SnCl4 were most likely responsible for the controlled molecular weight and very narrow MWD of the product. A macroinitiator with a hydroxy group was produced by hydrolysis of the acetoxy group located at the α-end of the poly(MOVE) under alkaline conditions. The hydrolysis reaction was conducted for 24 h in acetone at 30 °C using NaOH(aq). The deprotection of the acetoxy group proceeded quantitatively, as confirmed by the disappearance of the peak at 2.1 ppm, assigned to the acetoxy group, in the 1H NMR spectrum (Figure 3A). In addition, peaks in the MALDI-TOFMS spectrum shifted by a m/z value of 42 after hydrolysis; this value corresponds to the mass value of the removed part (C2H2O) (Figure 1C). Macroinitiators with a hydroxy group at the ω-end were also synthesized using water (Figure S3)45 or ethylene glycol (Figure S4) as a quencher for the living cationic polymerization (Scheme 3). Polymerization of MOVE was conducted using MOEA as a cationogen under reaction conditions similar to the aforementioned conditions. When the living polymerization was quenched with water, an aldehyde structure was formed quantitatively at the ω-end via the formation with subsequent degradation of a hemiacetal structure [MI-2: Mn(GPC) = 1.00 × 104, Mw/Mn(GPC) = 1.06; MI-3: Mn(GPC) = 1.03 × 104, Mw/Mn(GPC) = 1.08]. The aldehyde moiety was then reduced using LiBH4 as a reductant, which yielded a macroinitiator with D

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DBU was used as a base catalyst29 at room temperature to reach almost quantitative conversion in 3 h. Products obtained using the macroinitiators with a hydroxy group at the α- and/or ω-ends exhibited very narrow MWDs, as shown in Figure 4. Moreover, the peak tops of all the MWD curves shifted to the higher-MW region compared to those of the starting macroinitiators, indicating that controlled block copolymerization proceeded. A very small peak derived from a PLLA homopolymer generated through the initiation reactions from adventitious water appeared in the low-MW region (see Figure S5 for the 1H NMR spectra of the high- and low-MW portions separated by preparative GPC). This undesired portion, which may affect the properties discussed below, was removed from the target block copolymer using preparative GPC. 1 H NMR analysis (Figure 3B,C) of the block copolymers indicated that high initiation efficiency from the hydroxy groups of the macroinitiators was achieved in block copolymerization. The spectrum of the diblock copolymer obtained using the macroinitiator with a hydroxy group at the α-end exhibited a peak assigned to the methylene group adjacent to the ester group (peak k), which was generated through the initiation reaction of the LA polymerization from the hydroxy group, at 4.3 ppm (Figure 3B). The integral ratios of this peak, the peak assigned to the other chain-end of the macroinitiator fragment (peak g), the methyl peak derived from the cationogen used for the synthesis of the macroinitiator (peak f), and the methine peak assigned to the terminus of the PLLA segment (peak l) were consistent with the calculated values, demonstrating the generation of a well-defined diblock copolymer. In addition, the integral ratios of the corresponding peaks in the spectrum of the triblock copolymer (peaks f, k, m, and l) agreed relatively well with the calculated values, confirming the successful synthesis of the copolymer (Figure 3C). The numbers of MOVE and LLA units were also determined from the integral ratios of the peaks for main chains and cationogen fragments. Block copolymers with PDLA segments (Scheme 1) were also synthesized using DLA as a monomer in a manner similar to the reaction using LLA (entries 5 and 6 in Table 1). In addition, block copolymerization was feasible with macroinitiators derived from other VE monomers. EOVE and EOEOVE (Scheme 1), monomers with longer alkyl and oxyethylenic units than MOVE, respectively, were polymerized under conditions similar to those for the living cationic polymerization of MOVE to yield macroinitiators with a hydroxy group at the α-end [poly(EOVE): Mn(GPC) = 0.74 × 104, Mw/Mn(GPC) = 1.11; poly(EOEOVE): Mn(GPC) = 1.00 × 104, Mw/Mn(GPC) = 1.09]. The diblock copolymers obtained using these macroinitiators also had well-defined structures (entries 7 and 8 in Table 1). Hydrolysis of PLA Segment under Alkaline Conditions. The PLA segments in block copolymers were completely hydrolyzed under alkaline conditions because of the degradation of the ester moieties. The result obtained using the triblock copolymer is shown in Figure 4D. The MWD curve of the hydrolysis product (purple curve) shifted to the lowerMW region compared to that of the original block copolymer (black curve). In particular, the peak top and shape were very similar to those of the macroinitiator used, indicating that the PLA segments were degraded into low-MW fragments and a moiety derived from the macroinitiator remained. 1H NMR analysis (Figure S6) also suggested successful hydrolysis reactions.

Figure 3. 1H NMR spectra of (A) macroinitiator (MI-1) [Mn(GPC) = 8.8 × 103, Mw/Mn(GPC) = 1.12; see Figure S2 for the full spectrum of the polymer before hydrolysis of the acetoxy group], (B) poly(MOVEb-LLA) (the sample shown in Figure 4A), and (C) poly(LLA-bMOVE-b-LLA) [Mn(GPC) = 22.2 × 103, Mw/Mn(GPC) = 1.12; the spectrum was recorded after the low-molecular-weight portion was removed by preparative GPC] (see Figure 4 for polymerization conditions; 500 MHz in CDCl3 at 25 °C). *Water and residual monomer.

a hydroxy group at the ω-end. The use of ethylene glycol as a quencher directly generated a hydroxy group at the ω-end through the reaction of the propagating species with one of the two hydroxy groups of the molecule. Moreover, a telechelic macroinitiator with two hydroxy groups was produced when both AcOEA was used as a cationogen and water or ethylene glycol was used as a quenching agent [Scheme S1; MI-4: Mn(GPC) = 9.5 × 103, Mw/Mn(GPC) = 1.09]. Synthesis of Diblock and Triblock Copolymers Consisting of PLA and Thermoresponsive Poly(VE) Segments. Di- and triblock copolymers consisting of poly(MOVE) and PLLA segments were synthesized via the ringopening polymerization of LLA using the macroinitiators prepared through the aforementioned method (entries 1−4 in Table 1). LLA was smoothly consumed in the reaction where E

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Scheme 3. Synthesis of (A) a Macroinitiator Having a Hydroxy Group at the ω-Chain End by Quenching the Polymerization by Addition of (i) Water and (ii) Ethylene Glycol and (B) a Diblock Copolymer

Table 1. Synthesis of Block Copolymers Containing Poly(VE) and PLA Segmentsa entry

monomer

macroinitiator

1 2 3 4 5 6 7 8

LLA

poly(MOVE)

DLA

poly(MOVE)

LLA LLA

poly(EOVE) poly(EOEOVE)

OHc

[M]0/[OH]0

time (h)

conv (%)

Mn × 10−4 (GPC)b

Mw/Mn (GPC)b

VE/LAd

α ωI ωII α, ωI α α, ωI α α

50 20 50 25 20 25 50 50

3 2 3 3 2 3 3 3

96 89 95 95 91 70 95 96

1.62 1.13 1.65 1.67 1.18 1.33 1.38 1.74

1.08 1.10 1.08 1.08 1.08 1.09 1.12 1.08

94/56 99/16 102/46 93/46 94/21 88/36 63/45 62/48

a

[LLA]0 or [DLA]0 = 0.20 (except for entries 2 and 5) or 0.08 M (entries 2 and 5), [macroinitiator]0 = 4.0 mM, [DBU]0 = 5.0 mM, in CH2Cl2 at 25 °C. bDetermined by GPC with polystyrene calibration. Value for the main peak. cThe position of hydroxy group(s). α: α-end (MI-1); ωI: ω-end (MI-2); or ωII: ω-end (MI-3). dDetermined by 1H NMR.

Figure 4. MWD curves of (AC) poly(MOVE-b-LLA) and (D) poly(LLA-b-MOVE-b-LLA) using poly(MOVE) as a macroinitiator: [LLA]0 = 0.20 M (for A, C, and D) or 0.08 M (for B), [poly(MOVE)]0 = 4.0 mM, [DBU]0 = 5.0 mM, in CH2Cl2 at 25 °C. The purple curve in (D) is the MWD curve of a product obtained via alkaline hydrolysis of the triblock copolymer. *Values for main peaks.

Thermoresponsive Behavior of Block Copolymers in Water: Reversible Micellization and Irreversible Precipitation. Diblock copolymers composed of approximately 90 units of MOVE and 19, 33, or 47 units of LLA were soluble in water at room temperature. The copolymers most likely

dissolved in water in a state of aggregation similar to a micelle with a corona of the poly(MOVE) segments because the PLA chains are insoluble in water. This aggregation state is supported by the disappearance of the peaks of the PLA segments in the 1H NMR spectrum measured in D2O, in F

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copolymer never dissolved again in water upon the subsequent cooling scan. This behavior is possibly due to the crystallization property of the longer PLLA segments at 7080 °C (Figure 7). The dehydration of poly(MOVE) segments at high temperature possibly triggered the aggregation of polymer chains that originally formed micelles at low temperatures. In the aggregate, the PLA segments likely formed crystalline components, thereby preventing the block copolymer from redissolving in water. In addition, the relatively high transition temperature of poly(MOVE) segments is possibly responsible for the irreversible behavior. Indeed, NIPAM−LA diblock copolymers with sufficient lengths of PLA segments (LA188-bNIPAM46,79,or100; 188 units of LA correspond to 94 units in this study), which underwent phase transition at 30−40 °C in water, were reported to exhibit reversibility with the exception of a LA188-b-NIPAM100 copolymer, although the maximum temperature reached in the research was not shown.19 Stereocomplex formation of PLLA segments4−6 also affected the thermoresponsive behavior of block copolymers. The turbidity of the mixture solution of poly(MOVE90-b-LLA33) and poly(MOVE90-b-DLA33) changed at a temperature similar to those of each homopolymer solution upon heating. However, the once-formed precipitate did not dissolve again in water upon the subsequent cooling scan (Figure 6D), unlike the case where either of the two copolymers was used [Figure 6B for poly(MOVE90-b-LLA33)]. Thus, the irreversibility appeared to be caused by stereocomplex formation between the PLLA and PDLA segments at 7080 °C (Figure 7). Stereocomplex formation was promoted by the formation of large aggregates or precipitates, resulting in the micelle-like aggregates being tightly tethered in a manner similar to the crystallization-induced aggregation of the copolymer with a longer PLLA segment (Figure 6C). DLS analysis of copolymers in water at different temperatures (Figure 8), conducted at much lower concentrations compared to the turbidity measurements, agreed relatively well with the aforementioned results. The particle size (red circles in Figure 8) of poly(MOVE104-b-LLA18) in water at a concentration of 0.01 wt % was 14.3 ± 3.6 nm at 30 °C, indicating the formation of micelle-like aggregates with a core composed of the PLLA segment. This size is comparable or slightly smaller compared to the micelles of diblock copolymers consisting of poly(NIPAM) and PLA segments reported in previous studies.16,21 Upon heating, the particle size increased to 32.3 ± 4.9 nm at 72 °C, indicative of the generation of larger aggregates due to the aggregation of the poly(MOVE) segments. After subsequent cooling to 30 °C, the particle size decreased again as a result of dissociation of the large aggregates through redissolution of the poly(MOVE) segments. A counterpart with a DLA segment, poly(MOVE104-b-DLA19), exhibited similar behavior (green circles). By contrast, a mixed solution of poly(MOVE104-b-LLA18) and poly(MOVE104-bDLA19) underwent an irreversible increase in particle size during heating and cooling cycles (filled circles). The particle size increased upon heating, whereas the size did not decrease upon the subsequent cooling scan. The irreversible change most likely resulted from the aggregation of PLLA and PDLA segments through stereocomplex formation, in a manner similar to the behavior observed in the turbidity measurement. This result indicates that the stereocomplex formation was triggered or promoted at high temperatures as a result of the aggregation of poly(MOVE) segments and that dissociation of the stereocomplex did not occur at low temperatures.

contrast to the spectrum recorded in CDCl3 (Figure 5). This drastic change is ascribed to the substantial decrease of mobility of the PLA segments, suggesting the aggregation of the PLA segments in water.

Figure 5. 1H NMR spectra of poly(MOVE90-b-LLA33) [Mn(GPC) = 1.45 × 104, Mw/Mn(GPC) = 1.07; in (A) CDCl3 and (B) D2O at 25 °C; *water].

The block copolymers underwent thermally induced phase separation in water, which was caused by the thermoresponsive property of the poly(MOVE) segments. The turbidity of 0.5 wt % aqueous solutions of diblock copolymers with different PLLA lengths was measured upon heating scan to approximately 80 °C, a temperature higher than the cloud point of poly(MOVE) in water,32 and upon the subsequent cooling scan. The results are shown in Figure 6. Diblock copolymers, poly(MOVE90-bLLA17) (green curves in Figure 6A) and poly(MOVE90-bLLA33) (Figure 6B), became insoluble at approximately 65 °C upon heating and dissolved in water again upon cooling, with a very small hysteresis. This solubility transition resulted from the dehydration of the poly(MOVE) segments at high temperatures and subsequent rehydration upon cooling (Figure 7). In addition, a diblock copolymer with a poly(EOVE) segment, poly(EOVE58-b-LLA19), exhibited similar sharp transition (purple curves in Figure 6A) at a lower temperature, corresponding to the clouding point of a poly(EOVE) chain (∼20 °C). These thermoresponsive behavior is similar to block copolymers consisting of poly(NIPAM) and PLA segments,16−22 although responsive temperature can be tuned via the length of the oxyethylene units at side chains in this study. Interestingly, the thermoresponsive behavior of copolymers was greatly influenced by the length of the PLA segments. A longer PLLA segment [poly(MOVE90-b-LLA47)] made the solubility transition irreversible (Figure 6C), in sharp contrast to the aforementioned examples with a shorter PLA chain. On heating, the copolymer became insoluble in water at a temperature similar to the response temperatures of the block copolymers with shorter PLLA segments, whereas the G

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Figure 6. Turbidity measurements of poly(VE-b-LA) in water. (A) 0.5 wt % MOVE90-b-LLA17 [Mn(GPC) = 1.04 × 104, Mw/Mn(GPC) = 1.22], 0.25 wt % EOVE58-b-LLA19 [Mn(GPC) = 1.16 × 104, Mw/Mn(GPC) = 1.13], (B) 0.5 wt % MOVE90-b-LLA33 [Mn(GPC) = 1.45 × 104, Mw/Mn(GPC) = 1.07], (C) 0.5 wt % MOVE90-b-LLA47 [Mn(GPC) = 1.52 × 104, Mw/Mn(GPC) = 1.13], and (D) 0.5 wt % mixture of MOVE90-b-LLA33 [Mn(GPC) = 1.45 × 104, Mw/Mn(GPC) = 1.07] and MOVE90-b-DLA33 [Mn(GPC) = 1.38 × 104, Mw/Mn(GPC) = 1.08] (scan rate: 1 °C/min; solid line: heating; broken line: cooling).

Figure 8. Particle size of poly(MOVE-b-LA) measured by DLS. MOVE104-b-LLA18 [Mn(GPC) = 1.41 × 104, Mw/Mn(GPC) = 1.08], MOVE104-b-DLA19 [Mn(GPC) = 1.48 × 104, Mw/Mn(GPC) = 1.08], and a mixture of MOVE104-b-LLA18 and MOVE104-b-DLA19 (0.01 wt % in water at 30 or 72 °C).

Figure 7. Schematic illustration of micelles, micellar aggregation, crystallization, and stereocomplex formation of poly(MOVE-b-LLA) and poly(MOVE-b-DLA) in water.

Thermoresponsive Behavior on the Surface of Diblock Copolymer Films and Reversible Physical Gelation of Triblock Copolymers. Thermoresponsive behavior was also observed on the surface of films prepared from diblock copolymers (Figure 9). Self-standing films were successfully prepared through the spin-coating method on glass substrates from block copolymers of PLA segments with sufficient lengths because of the high Tg of PLA segments (vide infra). The contact angle of water on a film of a diblock copolymer with a poly(EOEOVE) segment as a thermoresponsive moiety, poly(EOEOVE62-b-LLA41), was 20° at 22 °C, indicating that the film surface was hydrophilic at this temperature. By

Figure 9. Photographs of water drops (1.5 μL) deposited on the surface of films of poly(EOEOVE62-b-LLA41) [Mn(GPC) = 1.74 × 104, Mw/Mn(GPC) = 1.08].

contrast, the film surface became hydrophobic at higher temperatures, as demonstrated by the increased contact angle H

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Macromolecules of 53° at 48 °C. The change in the hydrophilic property in this temperature range is consistent with the response temperature of an EOEOVE homopolymer in water: 40 °C. Moreover, the thermoresponsive behavior on the film surface was reversible: the contact angle of water became small again after the temperature was lowered (22° at 22 °C). A triblock copolymer with PLA segments at its outer ends, poly(DLA18-b-MOVE88-b-DLA18), exhibited reversible gelation behavior (Figure 10) in a solvent mixture of THF/water (7/3

thermal properties derived from both the PLA and poly(MOVE) segments. A triblock copolymer, poly(LLA42-bMOVE88-b-LLA42), exhibited a Tc of 88 °C and a Tm of approximately 130 °C (Table S1). These temperatures are consistent with the Tc and Tm of an LA homopolymer,49 although the values for the copolymer are slightly lower than those of the homopolymer. Stereocomplex formation affected the thermal properties of a mixture of the PLLA-containing and the PDLA-containing triblock copolymers. The Tm value of the mixture was 178 °C, a value 40−50 °C higher than the Tm of each copolymer (Table S1). The change in the DSC curves at around 0 °C likely corresponds to glass transition. This value is lower than the Tg of homo-PLA.49 However, block copolymers such as PLA−PEG and PLA−DMAEMA were also reported to exhibit Tg lower than that of homo-PLA.26,50

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Figure 10. Photographs of poly(DLA 18 -b-MOVE 88 -b-DLA 18 ) [Mn(GPC) = 1.33 × 104, Mw/Mn(GPC) = 1.09] in approximately 15 wt % THF/water (7/3 v/v) at different temperatures.

CONCLUSION Various block copolymers with thermoresponsive poly(VE) and PLA segments were successfully synthesized through living cationic polymerization of a VE and subsequent ring-opening polymerization of LA. Poly(VE)-based macroinitiators with well-defined structures were synthesized through elaborate design of initiating systems for living cationic polymerization of a VE using AcOEA as a cationogen. Subsequent controlled ring-opening polymerization of LA using the obtained macroinitiators was observed to proceed smoothly, yielding welldefined block copolymers. The copolymers exhibited unique behaviors in water because of the properties of both segments, such as thermoresponsivity, hydrophobicity, crystallinity, and stereocomplex formation. The length of PLA segments and stereocomplex formation of PLLA and PDLA segments were shown to affect the reversibility of the thermoresponsivity of copolymers. We expect the results presented in this study to contribute to the development of new PLA-based materials with unique characteristics.

v/v). The copolymer was first dissolved in THF alone at 20 wt % polymer concentration. Water was subsequently added dropwise to obtain a mixture containing approximately 15 wt % of the polymer. The mixture was a slightly turbid solution at 50 °C, becoming a gel upon cooling. The physical gelation was caused by the aggregation of the PLA segments due to the solvophobic property at 25 °C.46 By contrast, a precipitate was formed at 70 °C, a temperature higher than the cloud point of MOVE homopolymer, as a result of the aggregation of the poly(MOVE) segments. The gelation and precipitation formation behavior was reversibly displayed upon iterative cooling and heating scans. A similar type of triblock copolymer consisting of an inner PEG segment and outer PLA or poly(LA-co-glycolic acid) segments was reported to exhibit physical gelation behavior in water in past studies.47,48 However, our thermoresponsive behavior, in which the physical gelation occurred on cooling, was different from that of the past examples. In our example, we used a THF/water (7/3 v/v) mixture as solvents, in which both PLA and poly(MOVE) segments exhibit thermoresponsivity. Thermal Properties of Triblock Copolymers. DSC analysis (Figure 11) revealed that triblock copolymers exhibited

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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.macromol.7b02329.

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Polymerization data, 1H NMR spectra, MALDI-TOF-MS spectra, and thermal properties of polymers (PDF)

AUTHOR INFORMATION

Corresponding Author

*E-mail [email protected] (S.A.). ORCID

Arihiro Kanazawa: 0000-0002-8245-6014 Sadahito Aoshima: 0000-0002-7353-9272 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was partially supported by JSPS KAKENHI Grant 17H03068. We thank Prof. Tadashi Inoue’s group (Osaka University) for DSC measurements and Dr. Yu Shinke (Prof. Aoshima’s group) for helpful discussions.

Figure 11. DSC curves of (A) LLA42-b-MOVE88-b-LLA42 [Mn(GPC) = 2.22 × 104, Mw/Mn(GPC) = 1.09], (B) DLA36-b-MOVE88-b-DLA36 [Mn(GPC) = 2.04 × 104, Mw/Mn(GPC) = 1.10], and (C) the mixture of (A) and (B). The heating rate was 10 °C/min under N2 flow. (A, B) Second and (C) third heating run. I

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(20) You, Y.; Hong, C.; Wang, W.; Lu, W.; Pan, C. Preparation and Characterization of Thermally Responsive and Biodegradable Block Copolymer Composed of PNIPAAM and PLA by Combination of ROP and RAFT Methods. Macromolecules 2004, 37, 9761−9767. (21) Kim, S. H.; Tan, J. P. K.; Nederberg, F.; Fukushima, K.; Yang, Y. Y.; Waymouth, R. M.; Hedrick, J. L. Mixed Micelle Formation through Stereocomplexation between Enantiomeric Poly(lactide) Block Copolymers. Macromolecules 2009, 42, 25−29. (22) Zhang, X.; Tan, B. H.; He, C. Tailoring the LCST of PNIPAAM-b-PLA-b-PNIPAAM Triblock Copolymers via Stereocomplexation. Macromol. Rapid Commun. 2013, 34, 1761−1766. (23) Johnson, R. M.; Fraser, C. L. Metalloinitiation Routes to Biocompatible Poly(lactic acid) and Poly(acrylic acid) Stars with Luminescent Ruthenium Tris(bipyridine) Cores. Biomacromolecules 2004, 5, 580−588. (24) Xue, Y.-N.; Huang, Z.-Z.; Zhang, J.-T.; Liu, M.; Zhang, M.; Huang, S.-W.; Zhuo, R.-X. Synthesis and Self-Assembly of Amphiphilic Poly(acrylic acid-b-DL-lactide) to Form Micelles for pH-Responsive Drug Delivery. Polymer 2009, 50, 3706−3713. (25) Petzetakis, N.; Dove, A. P.; O’Reilly, R. K. Cylindrical Micelles from The Living Crystallization-Driven Self-Assembly of Poly(lactide)Containing Block Copolymers. Chem. Sci. 2011, 2, 955−960. (26) Spasova, M.; Mespouille, L.; Coulembier, O.; Paneva, D.; Manolova, N.; Rashkov, I.; Dubois, P. Amphiphilic Poly(D- or Llactide)-b-poly(N,N-dimethylamino-2-ethyl methacrylate) Block Copolymers: Controlled Synthesis, Characterization, and Stereocomplex Formation. Biomacromolecules 2009, 10, 1217−1223. (27) Dechy-Cabaret, O.; Martin-Vaca, B.; Bourissou, D. Controlled Ring-Opening Polymerization of Lactide and Glycolide. Chem. Rev. 2004, 104, 6147−6176. (28) Kamber, N. E.; Jeong, W.; Waymouth, R. M.; Pratt, R. C.; Lohmeijer, B. G. G.; Hedrick, J. L. Organocatalytic Ring-Opening Polymerization. Chem. Rev. 2007, 107, 5813−5840. (29) Lohmeijer, B. G. G.; Pratt, R. C.; Leibfarth, F.; Logan, J. W.; Long, D. A.; Dove, A. P.; Nederberg, F.; Choi, J.; Wade, C.; Waymouth, R. M.; Hedrick, J. L. Guanidine and Amidine Organocatalysts for Ring-Opening Polymerization of Cyclic Esters. Macromolecules 2006, 39, 8574−8583. (30) Aoshima, S.; Kanaoka, S. Synthesis of Stimuli-Responsive Polymers by Living Polymerization: Poly(N-Isopropylacrylamide) and Poly(Vinyl Ether)s. Adv. Polym. Sci. 2007, 210, 169−208. (31) Sugihara, S.; Hashimoto, K.; Matsumoto, Y.; Kanaoka, S.; Aoshima, S. Thermosensitive Polyalcohols: Synthesis via Living Cationic Polymerization of Vinyl Ethers with a Silyloxy Group. J. Polym. Sci., Part A: Polym. Chem. 2003, 41, 3300−3312. (32) Aoshima, S.; Oda, H.; Kobayashi, E. Synthesis of ThermallyInduced Phase Separating Polymer with Well-Defined Polymer Structure by Living Cationic Polymerization. I. Synthesis of Poly(vinyl Ether)s with Oxyethylene Units in the Pendant and Its Phase Separation Behavior in Aqueous Solution. J. Polym. Sci., Part A: Polym. Chem. 1992, 30, 2407−2413. (33) Yoshida, T.; Kanaoka, S.; Aoshima, S. Photo-Responsive Copolymers with Azobenzene Side Groups Synthesized by Living Cationic Polymerization: Efficient Amplification of Photosensitivity in Aqueous Photo-Switching System. J. Polym. Sci., Part A: Polym. Chem. 2005, 43, 5337−5342. (34) Shinke, Y.; Kanazawa, A.; Kanaoka, S.; Aoshima, S. Precise Synthesis of pH-Responsive Copolymers with Naphthoic Acid Side Groups via Living Cationic Polymerization. J. Polym. Sci., Part A: Polym. Chem. 2013, 51, 5239−5247. (35) Oda, Y.; Kanaoka, S.; Aoshima, S. Synthesis of Dual pH/ Temperature-Responsive Polymers with Amino Groups by Living Cationic Polymerization. J. Polym. Sci., Part A: Polym. Chem. 2010, 48, 1207−1213. (36) For reviews on controlled cationic polymerization: (a) Sawamoto, M. Modern Cationic Vinyl Polymerization. Prog. Polym. Sci. 1991, 16, 111−172. (b) Kennedy, J. P.; Ivan, B. Designed Polymers by Carbocationic Macromolecular Engineering: Theory and Practice; Hanser: New York, 1992. (c) Matyjaszewski, K.; Sawamoto, M. In Cationic

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K

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