Precision Synthesis of Imine-Functionalized Reversible Microgel Star

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Precision Synthesis of Imine-Functionalized Reversible Microgel Star Polymers via Dynamic Covalent Cross-Linking of Hydrogen-Bonding Block Copolymer Micelles Yusuke Azuma, Takaya Terashima,* and Mitsuo Sawamoto* Department of Polymer Chemistry, Graduate School of Engineering, Kyoto University, Katsura, Nishikyo-ku, Kyoto 615-8510, Japan S Supporting Information *

ABSTRACT: Imine-functionalized reversible microgel star polymers were synthesized by dynamic covalent cross-linking of hydrogen-bonding block copolymer micelles in organic media. This approach allows the precision and wide range control of molecular weight (Mw = 100−10 000 K; Mw/Mn = ∼1.1) of star polymers via preforming micelles of block copolymers. For this, a urea and aniline-functionalized methacrylate (ApUMA) was newly designed as a key monomer. The block copolymer of methyl methacrylate (MMA) and ApUMA, prepared by ruthenium-catalyzed living radical polymerization, efficiently self-assembled into micelles via hydrogen-bonding interaction of the urea pendants in dichloromethane and dichloromethane/N,Ndimethylformamide mixture. The subsequent treatment with terephthalaldehyde gave imine-cross-linked star polymers with quite narrow distribution in high yield. The molecular weight of the star polymers was successfully controlled by tuning solvents, concentration, and the block copolymer structure (PMMA arm and ApUMA segment length). Imine-functionalized star polymers have dynamic covalent and multifunctional microgels to afford pH-responsive or transimination-mediated structure transformation, pH-sensing, and postfunctionalization.

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Living radical polymerization31,32 is particularly effective for functional star polymers owing to high tolerance to polar functional groups. Dramatic advances on the catalytic/initiating systems have afforded one-pot functionalization of the desired sites of star polymers with amide,33 phosphine,17 poly(ethylene oxide),14 perfluorinated alkyl,16 and quaternary ammonium,34 among others.18,19 However, it is still difficult to precisely control the molecular weight of microgel star polymers with narrow molecular weight distribution. Indeed, this is a longstanding and fundamental issue in microgel star polymers prepared by arm linking process. Microgel star polymers are formed via intermolecular and intramolecular cross-linking of linear polymers.12 Here, the arm number determining the molecular weight of star polymers is controlled by the size balance (volume fraction) between arm layers and central microgel cores, and the cross-linking efficiency is dependent on the total concentration of arm polymers and linking agents. Thus, typically, a large amount of linking agents efficiently induces intermolecular cross-linking of arm polymers to give large core star polymers with high molecular weight, whereas the molecular weight distribution tends to be broad because star−star coupling process is also promoted beyond convergence into uniform globular structure.33,35 To overcome these issues, the cross-linking of block copolymer micelles would be promising. This is effective to

INTRODUCTION Microgel star polymers1−3 are one class of compartmentalized functional macromolecules,1−11 featuring versatile design, selective functionalization, and stimuli-responsibility. In contrast to micelles, vesicles, and nanogels via physical association of polymer chains, microgel star polymers carry covalently cross-linked cores that are covered by shell layers of multiple linear arm polymers.12 Since the cores are totally solubilized yet locally isolated from outer environments, various corefunctionalized star polymers have been designed and developed for nanocapsules, nanocarriers, and nanoreactors.1−3,13−19 In that context, dynamic covalent bond (e.g., ester, imine, acetal, disulfide, and alkoxyamine) is attracting attention as a functional cross-linking unit that is reversibly cleavable upon external stimuli (e.g., temperature, pH) or chemical reactions.11,13−15,20−25 Among them, imine bond is not only reversibly formed or exchangeable by pH or transimination but also has multiple functions including pH-sensing, pHresponsive release of molecules, self-healing, and coordination to metals.15,26−28 Thus, imine-functionalized microgel star polymers are quite intriguing as reversible and multifunctional compartments that are potentially useful for diverse applications. The prerequisite to create such microgel star polymers is precision control of molecular weight, arm numbers, and core density, in addition to selective functionalization. Microgel star polymers are generally synthesized by cross-linking linear arm polymers (living polymers, macroinitiators, and macromonomers) with divinyl compounds via living polymerization.29−32 © XXXX American Chemical Society

Received: November 5, 2016 Revised: December 12, 2016

A

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Scheme 1. (a) Synthesis of Imine-Microgel Star Polymers via the Imine-Crosslinking of Hydrogen-Bonding Block Copolymer Micelles in Organic Media and (b) Functions of the Star Polymers

Table 1. Synthesis of MMAm/ApUMAn Block Copolymers codea

m/nb

ApUMAc (mol %)

time (h)

convd (%)

Mne (SEC)

Mw/Mne (SEC)

P1 P2 P3 P4 P5 P6

125/8 125/15 125/28 253/15 253/28 253/46

6 11 18 6 10 15

10 8 10 18 14 24

78 77 79 74 74 60

18 100 21 300 25 000 30 300 35 000 37 500f

1.23 1.25 1.23 1.24 1.36 1.39f

a

P1−P6: [AUpMA]/[PMMA−Cl]/[RuCp*Cl(PPh3)2]/[4-methylamino-1-butanol] = 100 (P1, P4) or 200 (P2, P3, P5, P6)/10 (P1, P2) or 5.0 (P3- P5) or 2.5 (P6)/1.0 (P1−P3) or 0.5 (P4−P6)/40 (P1−P3) or 10 (P4−P6) mM in DMF at 40 °C. bDegree of polymerization of MMA (m) and ApUMA (n) in block copolymers. cMole fraction of ApUMA units in block copolymers. dMonomer conversion determined by 1H NMR. e Determined by SEC in DMF (10 mM LiBr) with PMMA standard calibration. fA main part of the P6 block copolymer.

general micellization and subsequent cross-linking of amphiphilic block copolymers in aqueous media.36 Our micellization system would allow versatile design of arm polymers free from water-soluble or water-dispersed properties. Moreover, iminefunctionalized star polymers afforded structural transformation between star and linear by pH or transimination, pH-sensing via color change, and post core-functionalization. For this, we focused on the marriage of hydrogen-bonding micellization of block copolymers and dynamic covalent crosslinking of the micelle cores via imine bond formation. Thus, we newly designed a key monomer: a functional methacrylate bearing both urea37,38 and aniline units (ApUMA). For poly(methyl methacrylate) (PMMA)-arm star polymers,

design core- or shell-cross-linked micelles with narrow size distribution, where preorganized micelles determine the size of cross-linked products therefrom. Given these backgrounds, we herein report the precision synthesis of imine-functionalized microgel star polymers via dynamic covalent cross-linking of hydrogen-bonding block copolymer micelles in organic media (Scheme 1). This is a novel micelle cross-linking strategy to create core-functionalized star polymers, particularly featuring precision and widerange controllability of molecular weight (Mw = 100 000− 10 000 000) with narrow molecular weight distribution (Mw/ Mn = ∼1.1). Importantly, hydrogen-bonding block copolymers induces micellization in “organic media”, in sharp contrast to B

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Figure 1. (a) DLS intensity size distribution and (b) 1H NMR spectra of a MMA/ApUMA block copolymer (P1): (a) [polymer] = 50 mg/mL in DMF or CH2Cl2 at 25 °C; (b) [polymer] = 20 mg/mL in DMF-d7 or CD2Cl2 at 25 °C.

had bimodal distribution partially including high molecular weight (Mn = 42100, Mw/Mn = 2.5). Since ApUMA includes a tiny amount of divinyl compound as side product ( 28) were slightly turbid (mostly soluble: P3, P5) or insoluble (P6) in CH2Cl2. Thus, micellization for star polymer synthesis was examined in CH2Cl2 or CH2Cl2/DMF mixed solvents as discussed later. Synthesis of Imine-Microgel Star Polymers via Micelle Cross-linking. The synthesis of imine-microgel star polymers was investigated by cross-linking P1 micelles with multifunctional aldehydes in CH2Cl2 at 25 °C (Table 2, Figure 2, Figure S5). Here, we examined effects of concentration ([polymer] = 1−100 mg/mL) and aldehydes (1, 2) on star polymer formation, keeping the molar ratio of ApUMA aniline unit and the aldehyde ([−NH2]0/[−CHO]0 = 1/1). Typically, 1 was directly added into the micelle solution of P1 in CH2Cl2 (50 mg/mL). The mixture immediately turned yellow, indicating the aromatic imine linkage was formed through dehydration between ApUMA aniline and the aldehyde. 1 was consumed up to 95% in 24 h, efficiently giving a star polymer (S3) with high molecular weight and quite narrow molecular weight distribution (Mw/Mn = 1.09) in high yield [87%, by size-exclusion chromatography (SEC)] (Table 2, entry 3, Figure 2a). Characterized by multiangle laser light scattering coupled with SEC (SEC-MALLS) and DLS, S3 had 360000 of absolute weight-average molecular weight (Mw,star), 20 of arm number (Narm), and 9.2 nm of Rh in

MMAm/ApUMAn block copolymers (P1−P6) were prepared by ruthenium-catalyzed living radical polymerization.32 The degree of polymerization of MMA and ApUMA (m/n) were varied to control the size of micelles and resultant star polymers. The ApUMA unit plays dual roles: (1) the urea induces hydrogen-bonding micellization of the block copolymers, and (2) the aniline subsequently allows imine-crosslinking of the micelles with terephthalaldehyde (1) or benzene1,3,5-tricarboxaldehyde (2). Aldehydes (1, 2) are efficiently accumulated within the micelle cores via hydrogen-bonding interaction to quickly form dynamic covalent imine linkages. The molecular weight and size of the star polymers were controlled with preorganized micelles by tuning polymer concentration, solvents, and block copolymer structure (MMA and ApUMA segment length).

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RESULTS AND DISCUSSION Synthesis and Micellization of Hydrogen-Bonding Block Copolymers. To control molecular weight of star polymers by cross-linking block copolymer micelles, we designed six kinds of MMAm/ApUMAn block copolymers with different PMMA and PApUMA length (P1−P6, Table 1). Two kinds of PMMAs with different degree of polymerization (m = 125, 253) were prepared, while each PMMA unit was coupled with three PApUMA segments (ApUMA = 6−18 mol %). Chlorine-capped poly(methyl methacrylate)s (PMMA− Cls, m = 125: Mn = 12800, Mw/Mn = 1.13, m = 253: Mn = 25500, Mw/Mn = 1.14) were first synthesized via Ru(Ind)Cl(PPh3)2/n-Bu3N-catalyzed living radical polymerization of MMA with a chloride initiator (ethyl 2-chloro-2-phenylacetate, Supporting Information). ApUMA was then polymerized from PMMA−Cl (m = 125: ,P1−P3; m = 253: P4−P6) with a ruthenium catalytic system [RuCp*Cl(PPh3)2/4-methylamino1-butanol] in DMF 40 °C (Table 1). The feed ratio of ApUMA to PMMA−Cl was varied as follows: [ApUMA]0/[PMMA− Cl]0 = 10/1 (P1), 20/1 (P2), 40/1 (P3), 20/1 (P4), 40/1 (P5), and 80/1 (P6). In all cases, block copolymerization efficiently proceeded to give corresponding MMA/ApUMA block copolymers. P1 − P5 had controlled molecular weight with narrow molecular weight distribution (e.g., P1: Conv. 78%, 10 h, Mn (SEC) = 18100, Mw/Mn = 1.23, Mn (NMR) = 14800, n = 8, Figure S3). In contrast, P6 with a long ApUMA segment C

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than that of P1. Thus, the remaining low molecular weight fraction originates from block copolymers of relatively short ApUMA segment (e.g., n = 1−3). Although they can react with terephthalaldehyde to form aldehyde-bearing block copolymers, the block copolymers would have low efficiency of “intermolecular” cross-linking within micelles or not effectively form micelles owing to weak hydrogen-bonding interaction. Owing to the core-forming imine linkage, S3 exhibited UV−vis absorption around 350−450 nm (Figure 2b). The yield of imine bond formation was approximately estimated as 70% against the in-core aniline units, calculated from the calibration plots of the UV−vis absorption of a bifunctional linking agent (3) as a core-forming linker analogue at 396 nm. In contrast, such efficient synthesis of imine-microgel star polymers was not achieved in the absence of micellization of a MMA/ApUMA block copolymer in DMF (Table 2, entry 6, Figure S6c). The cross-linking of P1 with 1 required much longer time (96 h) to achieve over 70% yield of a star polymer (S6), where the molecular weight distribution was broader than that of S3. Thus, the effects of mixed solvents of CH2Cl2 and DMF on star polymer formation was investigated in detail later. Moreover, a conventional linking method with PMMA−Cl (arm) and a bisurea/imine dimethacrylate (3) was not so effective for an imine-microgel star polymer (Figure S7). The molecular weight distribution of the star polymer turned broad (Mw/Mn > 2), while the yield (∼60%) was much lower than that of S3 via micelle cross-linking; a large amount of unreacted PMMA−Cl was remained. This means that the intermolecular/ intramolecular cross-linking of PMMA/3 block arms and the resulting intermediates (star polymers with small arm number) proceeded more preferentially than block copolymerization of 3 from PMMA−Cl. The chloride terminal of the bisurea/imine dimethacrylate block segment might be more favorably activated with the ruthenium catalyst than that of PMMA− Cl. Thus, hydrogen bond-mediated micellization of MMA/ ApUMA block copolymers is a key to efficiently produce iminemicrogel star polymers with “narrow molecular weight distribution”. A trifunctional aldehyde (2) was also effective for crosslinking of the MMA/ApUMA block copolymer micelles in CH2Cl2, giving a corresponding star polymer (S4, Figure 2a). It should be noted that S4 had almost identical absolute molecular weight (Mw), arm numbers (Narm), and size (Rh) to S3 obtained with a bifunctional 1, independently of the linking agents (Table 2, entry 4). This result demonstrates that the micelle effectively serves as a template to control the size of

Figure 2. (a) Synthesis of S3 and S4 via the cross-linking of P1 micelles with 1 or 2 in CH2Cl2 at 25 °C for 24 h. Conditions: see entries 3 and 4 in Table 1. (b) UV−vis spectra of S3 (red), S4 (blue), P1 (black), bifunctional (3, red dash) or trifunctional (4, blue dash) imine linkers, and 1 (green) in DMF at 25 °C: [1−4] = 0.2 mM, [S3, P1] = 1.25 mg/mL, and [S4] = 1.69 mg/mL.

DMF (Table 2, entry 3). Importantly, a well-controlled star polymer was obtained in 80% yield just in 1h. Such fast and efficient imine cross-linking is due to the accumulation of 1 into hydrogen-bonding micelle cores (Figure S4). However, a trace of low molecular weight fraction was still remained in the product. The peak top molecular weight was slightly smaller

Table 2. Synthesis of Imine-Microgel Star Polymers with a MMA/ApUMA Block Copolymera entry codea 1 2 3 4 5 6

S1 S2 S3 S4 S5 S6

aldehydea

solvent

conc (mg/mL)

time (h)

1 1 1 2 1 1

CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 DMF

1 10 50 50 100 50

96 24 24 24 24 96

conv (%)b yieldc Mw,stard (MALLS) Mw/Mne (SEC) 93 94 95 99 95 96

78 82 87 88 89 72

430 000 310 000 360 000 380 000 430 000 165 000

1.17 1.12 1.09 1.09 1.12 1.46

Narmf

Rhg (CH2Cl2)

Rhg (DMF)

26 18 20 21 26 9.7

13.2 11.2 12.5 12.4 14.3 −

10.3 8.8 9.2 9.3 11.6 7.4

a

S1−S6: Synthesized by the linking reaction of P1 with aldehydes (1, terephthalaldehyde; 2, benzene-1,3,5-tricarboxaldehyde) in CH2Cl2 or DMF at 25 °C: [ApUMA (−NH2)]0/[−CHO]0 = 1/1; [polymer] = 1−100 mg/mL. bConversion of 1 or 2 determined by 1H NMR. cStar polymer yield estimated from the SEC curve area ratio of star polymers in products. dAbsolute weight-average molecular weight (Mw) of star polymers determined by SEC-MALLS in DMF (10 mM LiBr). eMolecular weight distribution of star polymers determined by SEC in DMF (10 mM LiBr) with PMMA standard calibration. fArm numbers (Narm): [(weight fraction of arm) × Mw,star (MALLS)]/Mw,arm(SEC). gDetermined by DLS in CH2Cl2 or DMF at 25 °C: [polymer] = 10 mg/mL. D

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Macromolecules Table 3. Synthesis of Imine-Microgel Star Polymers with Various Block Copolymersa codea

block

m/n

CH2Cl2/DMF (v/v)

time (h)

yieldb

Mw,starc (MALLS)

Mw/Mnd (SEC)

Narme

Rhf (CH2Cl2/DMF)

Rhf (DMF)

S7 S8 S9 S10 S11 S12 S13 S14 S15 S16 S17

P1 P2 P2 P3 P4 P4 P4 P5 P5 P5 P6

125/8 125/15 125/15 125/28 253/15 253/15 253/15 253/28 253/28 253/28 253/46

95/5 95/5 100/0 95/5 100/0 95/5 90/10 100/0 95/5 90/10 90/10

24 24 24 24 24 24 24 24 24 24 24

81 93 92 97 90 88 87 72 89 86 91

290 000 520 000 2 030 000 940 000 2 570 000 690 000 590 000 25 720 000 2 220 000 1 900 000 10 000 000

1.17 1.09 1.36 1.07 1.34 1.12 1.19 2.97 1.12 1.13 1.16

17 28 109 40 72 20 16 661 51 44 220

9.8 11.5 19.8 12.6 28.2 15.4 14.8 63.3 20.0 18.8 29.9

8.2 10.0 18.4 12.1 22.6 12.0 11.2 53.1 16.5 15.5 25.6

a

S7−S17: synthesized by the cross-linking of block copolymer (P1−P6) micelles with terephthalaldehyde (1) in CH2Cl2/DMF (100/0, 95/5, and 90/10) mixed solvents at 25 °C: [−NH2]0/[−CHO]0 = 1/1; [polymer] = 10 mg/mL. bStar polymer yield estimated from the SEC curve area ratio of star polymers to products. cAbsolute weight-average molecular weight (Mw) of star polymers determined by SEC-MALLS in DMF (10 mM LiBr). d Molecular weight distribution of star polymers determined by SEC in DMF (10 mM LiBr) with PMMA standard calibration. eArm numbers (Narm): [(weight fraction of arm) × Mw,star (MALLS)]/Mw,arm(SEC). fDetermined by DLS in DMF/CH2Cl2 mixed solvents (corresponding to respective micelle solutions) or DMF at 25 °C (10 mg/mL).

star polymers. S4 also showed UV−visible absorption originating from the core-forming trifunctional imine linkage (4: Figure S2) around 300−400 nm (Figure 2b). Effects of block copolymer concentration (1−100 mg/mL) on star polymer formation was further investigated. With over 10 mg/mL, the block copolymer efficiently formed micelles to provide corresponding star polymers (S2, S3, S5) with narrow molecular weight distribution (Mw/Mn = ∼1.1). The size and molecular weight increased with concentration (Table 2, entries 2, 3, and 5, Figure S6b,d). S2 had size identical to the original micelle before cross-linking (Figure S6e,f). At low concentration (1 mg/mL), the block copolymer did not form micelles in CH2Cl2, confirmed by DLS. However, this condition also provided a star polymer (S1) with narrow molecular weight distribution (Mw/Mn < 1.2), while over 96 h was required to achieve about 80% yield (Figure S6a). Here, the block copolymer reacting 1 and/or the intermediates of star polymers with small arm number might form micelle in CH2Cl2 during linking reaction to result in narrow molecular weight distribution of S1, because cross-linking of P1 with 1 in DMF under non-micellization condition without CH2Cl2 gave S6 with broad molecular weight distribution (Mw/Mn ∼ 1.5) in low yield. Precision Size Control by Micelle Cross-Linking. Various MMAm/ApUMAn block copolymers of different PMMA (m) and PApUMA (n) length were utilized to control the molecular weight of star polymers (Table 3). We first employed three block copolymers of different PApUMA length (P1, P2, and P3: PMMA m = 125; PApUMA n = 8, 15, and 28). To homogeneously solubilize the copolymers, a CH2Cl2/ DMF (95/5, v/v) mixed solvent was used: [polymer] = 10 mg/ mL. All of the block copolymers formed micelle, where the size increased with PApUMA length (Rh = 9.5, 11.7, 12.7 nm, Figure 3a−c). By directly adding 1 into these solutions ([−NH2]0/[−CHO]0 = 1/1), imine-microgel star polymers (S7, S8, and S10) with narrow molecular weight distribution (Mw/Mn < 1.2) were efficiently obtained in high yield (81− 97%) (Figure 3d−f, Table 3). The yield and molecular weight (Mw,star) of star polymers increased with ApUMA segment length. The decrease of the low molecular weight fraction (unreacted arm residue) is attributed to the increased efficiency of hydrogen-bonding micellization of the block copolymers.

Figure 3. (a−c, g−i) DLS intensity size distribution of block (a, P1; b, P2; c, P3) or star (g, S7; h, S8; i, S10) polymers: [polymer] = 10 mg/ mL in CH2Cl2/DMF (95/5, v/v) at 25 °C. (d−f) Synthesis of star polymers (d, S7; e, S8; f, S10) via the cross-linking of MMA/ApUMA block copolymer micelles (d, P1; e, P2; f, P3) with 1 in CH2Cl2/DMF (95/5, v/v) at 25 °C for 24 h.

The arm number (Narm) thereby increased from 17 to 40 with ApUMA segment. It should be noted that S10 with high molecular weight (Mw,star ∼ 1 000 000) still had quite narrow molecular weight distribution (Mw/Mn = 1.07). This feature is one of the most important advantages of our micelle crosslinking method, because it is generally difficult to maintain narrow distribution for microgel star polymers with high molecular weight via conventional arm linking methods.33,35 The size of all of the star polymers is in good agreement with that of corresponding micelles (Figure 3g,h,i). Thus, the molecular weight of star polymers can be precisely controlled by reflecting micelle size. Then, we further employed MMA/ApUMA block copolymers consisting of longer PMMA segment (m = 253: P4−P6). In CH2Cl2/DMF (90/10, v/v), the three block copolymers were homogeneously soluble and efficiently formed micelles. The size increased with increasing ApUMA units (Figure S8, Rh = 15.0, 19.0, 30.3 nm). Similarly, direct addition of 1 into these mixtures led to corresponding microgel star polymers (S13, S16, S17) with large molecular weight and narrow molecular weight distribution (Mw/Mn ∼ 1.1) in high yield (>86%) E

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Figure 4. (a) Logarithm plots of Mw of star polymers (S7-S17) against hydrodynamic radius (Rh) in DMF (filled circles, S7, S8, S10, S12, S13, and S15−S17; open circles, S9, S11, and S14). (b, c) SEC curves and (d, e) AFM images of star polymers [b, d, S12 obtained in CH2Cl2/DMF (95/5, v/v); c, e, S11 obtained in CH2Cl2]. AFM images were obtained from spin-cast of CH2Cl2 polymer solutions (1 ng/mL) on mica.

Figure 5. Synthesis of imine-microgel star polymers via cross-linking a MMA125/ApUMA15 block copolymer (P2) with 1 in CH2Cl2/DMF mixed solvents (100/0−0/100, v/v) at 25 °C: [polymer] = 10 mg/mL, [-NH2]/[−CHO] = 1/1. (a) SEC curves of star polymers, (b) Mw of star polymers and Rh of P2 or P2 micelles as a function of CH2Cl2/DMF (100/0−0/100, v/v) ratio, and (c) the proposed mechanism of cross-linking with block copolymer unimers.

solvents (5 vol % vs 10 vol %, e.g., S12 vs S13, Table 3). Interestingly, Narm decreased with increasing PMMA arm length (m = 125, S8; m = 253, S12) under the identical coreforming PApUMA length (n = 15) and solvent conditions (CH2Cl2/DMF = 95/5, v/v). This is because the volume fraction of shell-forming PMMA arms increased, compared with that of core-forming ApUMA segment. In CH2Cl2, P2, P4, and P5 further provided star polymers with quite large molecular weight (Mw,star > 2 000 000), whereas the molecular weight

(Table 3). It should be noted that P6 consisting of long PMMA and PApUMA segments gave a quite large star polymer (S17: Mw,star = 10 000 000 by MALLS). The weight-average molecular weight (Mw) of S17 was estimated as 824 000 from RI detector with linear poly(MMA) standard calibration, importantly indicative of the compact globular structure distinct from linear PMMA. The molecular weight and arm numbers of star polymers further increased with decreasing DMF content in mixed F

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Macromolecules distribution became bimodal and broad (S9, S11, and S14, Mw/ Mn > 1.3). This suggest that hydrogen-bonding interaction of ApUMA units was enhanced in CH2Cl2 to change the structure of block copolymer micelles and/or resulting star polymers. Thus, the shape and density of star polymers obtained in CH2Cl2/DMF (95/5 or 90/10, v/v) mixtures (S7, S8, S10, S12, S13, S15−S17) were evaluated by the logarithmic plots of the absolute weight-average molecular weight (Mw) as a function of the hydrodynamic radius (Rh) in DMF (Figure 4a: filled circles). Mw is proportional to the power of three of Rh. This implies that these star polymers have spherical core− shell structures with constant density, where the radius and molecular weight increased with MMA and ApUMA length. Confirmed by atomic force microscopy (AFM), S12 cast on mica from the CH2Cl2 solution actually had spherical structure (Figure 4d). On the other hand, Mw and Rh for star polymers obtained in CH2Cl2 without DMF (S9, S11, and S14: Figure 4a open circles) deviated from the proportional logarithmic plots of those obtained in CH2Cl2/DMF. As described earlier, the star polymers uniquely had bimodal molecular weight distribution (SEC: Figures 4c and S9). Typically, the low molecular weight fraction of S11 (part b in Figure 4c: Mw = ∼ 730000 by MALLS) had almost identical molecular weight to S12 obtained in CH2Cl2/DMF (95/5, v/v), while the high molecular weight fraction (part a: Mw = ∼ 3 300 000 by MALLS) had 4−5 times larger Mw than the part b. The size of P4 micelle in CH2Cl2 (Rh = ∼ 29 nm) was also almost identical to that of S11 in CH2Cl2 (Rh = ∼ 28 nm), indicating that the micelle size was reflected to the star polymer. Analyzed by AFM, S11 obtained in CH2Cl2 had anisotropic (elongated) globular shape and/or star−star coupled (aggregated) structure, in sharp contrast to S12 (Figure 4d,e). Considering these results, P4 block copolymer would form anisotropic, rod-like micelles in CH2Cl2 owing to the selfassembly of the relatively long and rigid PApUMA segment via hydrogen-bonding interaction, although P4 forms spherical micelles in the presence of small amount of DMF. The two proposed mechanisms could be considered for the bimodal size distribution. (1) The cross-linking of anisotropic micelles competitively allows the whole fixation into anisotropic star polymers (part a) and the fixation/fission of the micelles into spherical star polymers (part b) with thermodynamically stable structure. (2) As another possibility, P4 concurrently form anisotropic or spherical micelles in CH2Cl2 owing to a certain distribution of ApUMA units (n); the two kinds of micelles were cross-linked respectively to give anisotropic or spherical star polymers. The star−star coupled structure of S11, observed in AFM, would be formed during the linking stage of the anisotropic (rod-like) micelles. Although DMF generally disrupts hydrogen-bonding interaction, a very small amount of DMF is rather effective to form thermodynamically stable spherical micelles into spherical star polymers with narrow size distribution. In contrast, strong self-assembly of rigid PApUMA units would be also attractive as one possibility to modulate the three-dimensional architecture of microgel star polymers. To further clarify the effects of DMF on star polymer formation, we synthesized star polymers with a MMA125/ ApUMA15 block copolymer (P2) and 1 in various CH2Cl2/ DMF mixtures (100/0−0/100, v/v) at 25 °C, keeping the polymer concentration (10 mg/mL) (Figure 5, Table S1). In the solvents including 0−20 vol % DMF, P2 formed micelles via hydrogen-bonding interactions (Rh = 10−19 nm). The size

decreased with increasing DMF owing to the gradual disruption of hydrogen-bonding of the pendant ApUMA units by DMF. The micelles are quickly cross-linked with 1 to give iminemicrogel star polymers with narrow molecular weight distribution in 24 h. Keeping high yield (>89%), the molecular weight decreased with corresponding micelle size (Mw,star = 320 000−2 030 000, Figure 5a,b). Thus, molecular weight of star polymers can be controlled using an identical block copolymer by changing mixed solvent ratio. This is one of the simplest ways to control the molecular weight of star polymers. On the other hand, in CH2Cl2/DMF mixtures including over 50 vol % DMF, P2 did not form micelles owing to full disruption of the intermolecular hydrogen bonding. As described earlier, star polymers were nevertheless obtained in the absence of micellization of P2, whereas they required longer time (96 h) and molecular weight distribution turned broad. The molecular weight of the star polymers was independent of the mixed solvent ratio (Figure 5). In this case, 1 first reacts with the ApUMA pendants of P2, giving aldehyde and/or aniline-bearing block copolymers. The resulting block copolymers are then intermolecularly cross-linked to gradually form star polymers with large molecular weight. The microgel formation process via cross-linking the block copolymer (unimer) with 1 is close to the intermolecular/intramolecular linking process of linear arm polymers with divinyl compounds.12,33 Thus, in the absence of micellization of block copolymers, the molecular weight of star polymers is determined by the ratio of PMMA arm length and ApUMA core-forming segment. Imine cross-linking of hydrogen-bonding micelles allows us to precisely control the molecular weight by changing concentration, mixed solvents, and MMA and ApUMA block length. Figure 6 summarized absolute weight-average molecular

Figure 6. Scope of imine-microgel star polymers obtained with MMA/ ApUMA block copolymers [PMMA arm: m = 125 (red symbols), 253 (blue symbols)] and terephthalaldehyde (1) in CH2Cl2/DMF (100/0, filled circle; 95/5, open square; 90/0, 80/20, 50/50, and 0/100, filled triangle): [polymer] = 10 mg/mL.

weight of star polymers (Mw,star) as a function of core weight fraction (mass fraction of ApUMA and 1 in total star polymer), where star polymer synthesis was conducted at 10 mg/mL (constant concentration). The molecular weight of star polymers increased with increasing arm length (m = 125, 253) and/or core weight fraction. Mw,star can be widely controlled between 100 000 and 10 000 000, keeping narrow G

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Figure 7. (a) pH-Sensing, (b) pH-responsive reversible formation, (c) postfunctionalization, and (d) transimination-mediated decomposition of imine-microgel star polymers.

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CONCLUSIONS We successfully achieved the precision synthesis of iminefunctionalized reversible microgel star polymers by crosslinking hydrogen bond-mediated block copolymer micelles with aldehydes in organic media. The micelle cross-linking technique allowed the wide range control of molecular weight of star polymers with narrow molecular weight distribution (Mw = 100 000−10 000 000, Mw/Mn = ∼ 1.1). For this, a urea and aniline-bearing methacrylate (ApUMA) was designed. MMA/ ApUMA block copolymers, prepared by Ru-catalyzed living radical polymerization, efficiently formed micelles in CH2Cl2 and CH2Cl2/DMF mixtures. The micelle size was controlled by tuning concentration, mixed solvents, and the MMA and ApUMA segment length; it is directly reflected to the size (molecular weight) of generating star polymers. Iminefunctionalized star polymers further afforded pH-sensing by protonation, pH-responsive or transimination-mediated structure transformation, and efficient postfunctionalization. Thus, this work brings one a versatile strategy to design iminefunctionalized microgel star polymers potentially applicable as multifunctional polymeric capsules.

distribution (Mw/Mn < 1.2). Increase of DMF content in mixed solvents was also effective to decrease Mw,star by partial disruption of hydrogen-bonding interaction within micelles. Reversible Formation and Functionalization. Focusing on the functions of in-core imine linkage, we investigated pHresponsive properties of an imine-microgel star polymer (S3). By adding one drop of trifluoroacetic acid (TFA, 0.035 mL), the yellow CH2Cl2 solution of S3 (20 mg/mL, [in-core imine] = 1.0 × 10−2 M) immediately turned red, indicating the protonation of the in-core imine linkage (Figure 7a). Confirmed by TFA titration experiments (Figure S10), S3 (1.5 mg/mL, [in-core imine] = 7.5 × 10−4 M) effectively detected low concentration of TFA (15−150 ppm) in CH2Cl2. S3 thus potentially works as pH-sensing materials. By adding TFA (0.07 mL, 0.91 mmol) and a H2O/DMF (1/ 1, v/v) mixture (0.04 mL) into a CH2Cl2 solution of S3 ([S3] = 20 mg/mL, [in-core imine] = 1.0 × 10−2 M, 2.0 mL), S3 was in turn transformed into a non-cross-linked micelle via the cleavage of the imine linkage (confirmed by UV−vis, Figure S11); the solution turned colorless. The decomposition of S3 into block copolymers was confirmed by SEC in DMF (Figure 7b). Importantly, the non-cross-linked micelle again formed a star polymer with identical size in CH2Cl2 by adding Na2CO3 (80.0 mg, 0,75 mmol), i.e., changing pH to basic condition. Similarly, transimination with extra amount of 2,4-dimethoxybenzaldehyde or n-butylamine (50 equiv to in-core ApUMA) was also effective to transform S3 into linear block copolymers (Figure 7d, Figure S12, [S3] = 10 mg/mL). The former aldehyde gave a corresponding imine-functionalized block copolymer, while the latter amine provided an original MMA/ApUMA block copolymer (P1). Such reversible and/ or cleavable properties of star polymers using dynamic covalent imine linkage would be attractive for stimuli-responsive nanocapsules and delivery vessels. Additionally, S3 still has in-core remaining aniline units (30 mol % in-core ApUMA) and thereby affords postfunctionalization by adding aldehydes. For instance, the mixing of S3 with 1-pyrenecarboxaldehyde resulted in a pyrene-labeled P3 (pyrene: 5 mol %/in-core ApUMA, Figure 7c, Figure S13).

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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.6b02403. Experimental details, SEC curves, and 1H NMR, IR, and UV−vis spectra of polymers (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*(T.T.) Telephone/Fax: +81-75-383-2603. E-mail: terashima@ living.polym.kyoto-u.ac.jp. *(M.S.) E-mail: [email protected]. ORCID

Takaya Terashima: 0000-0002-9917-8049 Notes

The authors declare no competing financial interest. H

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(16) Koda, Y.; Terashima, T.; Sawamoto, M. Fluorous Microgel Star Polymers: Selective Recognition and Separation of Polyfluorinated Surfactants and Compounds in Water. J. Am. Chem. Soc. 2014, 136, 15742−15748. (17) (a) Terashima, T.; Nomura, A.; Ito, M.; Ouchi, M.; Sawamoto, M. Star-Polymer-Catalyzed Living Radical Polymerization: MicrogelCore Reaction Vessel by Tandem Catalyst Interchange. Angew. Chem., Int. Ed. 2011, 50, 7892−7895. (b) Terashima, T.; Nomura, A.; Ouchi, M.; Sawamoto, M. Efficient and Robust Star Polymer Catalysts for Living Radical Polymerization: Cooperative Activation in MicrogelCore Reactors. Macromol. Rapid Commun. 2012, 33, 833−841. (18) Kanaoka, S.; Yagi, N.; Fukuyama, Y.; Aoshima, S.; Tsunoyama, H.; Tsukuda, T.; Sakurai, H. Thermosensitive Gold Nanoclusters Stabilized by Well-Defined Vinyl Ether Star Polymers: Reusable and Durable Catalysts for Aerobic Alcohol Oxidation. J. Am. Chem. Soc. 2007, 129, 12060−12061. (19) Chi, Y.; Scroggins, S. T.; Fréchet, J. M. J. One-Pot MultiComponent Asymmetric Cascade Reactions Catalyzed by Soluble Star Polymers with Highly Branched Non-Interpenetrating Catalytic Cores. J. Am. Chem. Soc. 2008, 130, 6322−6323. (20) Rowan, S. J.; Cantrill, S. J.; Cousins, G. R. L.; Sanders, J. K. M.; Stoddart, J. F. Dynamic Covalent Chemistry. Angew. Chem., Int. Ed. 2002, 41, 898−952. (21) Corbett, P. T.; Leclaire, J.; Vial, L.; West, K. R.; Wietor, J.-L.; Sanders, J. K. M.; Otto, S. Dynamic Combinatorial Chemistry. Chem. Rev. 2006, 106, 3652−3711. (22) Otsuka, H. Reorganization of Polymer Structures Based on Dynamic Covalent Chemistry: Polymer Reactions by Dynamic Covalent Exchanges of Alkoxyamine Units. Polym. J. 2013, 45, 879− 891. (23) Amamoto, Y.; Higaki, Y.; Matsuda, Y.; Otsuka, H.; Takahara, A. Programmed Thermodynamic Formation and Structure Analysis of Star-like Nanogels with Core Cross-linked by Thermally Exchangeable Dynamic Covalent Bonds. J. Am. Chem. Soc. 2007, 129, 13298−13304. (24) Jiang, J.; Qi, B.; Lepage, M.; Zhao, Y. Polymer Micelles Stabilization on Demand through Reversible Photo-Cross-Linking. Macromolecules 2007, 40, 790−792. (25) Kamada, J.; Koynov, K.; Corten, C.; Juhari, A.; Yoon, J. A.; Urban, M. W.; Balazs, A. C.; Matyjaszewski, M. Redox Responsive Behavior of Thiol/Disulfide-Functionalized Star Polymers Synthesized via Atom Transfer Radical Polymerization. Macromolecules 2010, 43, 4133−4139. (26) Belowich, M. E.; Stoddart, J. F. Dynamic Imine Chemistry. Chem. Soc. Rev. 2012, 41, 2003−2024. (27) Kovaricek, P.; Lehn, J.-M. Merging Constitutional and Motional Covalent Dynamics in Reversible Imine Formation and Exchange Processes. J. Am. Chem. Soc. 2012, 134, 9446−9455. (28) Gupta, K. C.; Sutar, A. K. Coord. Synthesis, X-Ray Crystallography and DFT Studies of Ni(II) Complex with Tetradentate. Coord. Chem. Rev. 2008, 252, 1420−1450. (29) Eschwey, H.; Burchard, W. Star Polymers from Styrene and Divinylbenzene. Polymer 1975, 16, 180−184. (30) Shibata, T.; Kanaoka, S.; Aoshima, S. Quantitative Synthesis of Star-Shaped Poly(vinyl ether)s with a Narrow Molecular Weight Distribution by Living Cationic Polymerization. J. Am. Chem. Soc. 2006, 128, 7497−7504. (31) Matyjaszewski, K.; Tsarevsky, N. V. Macromolecular Engineering by Atom Transfer Radical Polymerization. J. Am. Chem. Soc. 2014, 136, 6513−6533. (32) Ouchi, M.; Terashima, T.; Sawamoto, M. Transition MetalCatalyzed Living Radical Polymerization: Toward Perfection in Catalysis and Precision Polymer Synthesis. Chem. Rev. 2009, 109, 4963−5050. (33) Baek, K.-Y.; Kamigaito, M.; Sawamoto, M. Core-Functionalized Star Polymers by Transition Metal-Catalyzed Living Radical Polymerization. 2. Selective Interaction with Protic Guests via Core Functionalities. Macromolecules 2002, 35, 1493−1498. (34) Fukae, K.; Terashima, T.; Sawamoto, M. Cation-Condensed Microgel-Core Star Polymers as Polycationic Nanocapsules for

ACKNOWLEDGMENTS This research was supported by the Ministry of Education, Science, Sports and Culture through Grants-in-Aid for Scientific Research (A, 24245026; C, 26410134), by the Sumitomo Foundation (131302), and by Research Institute for Production Development, for which T.T. is grateful. We thank Prof. Nobuhiko Hosono and Prof. Susumu Kitagawa (Kyoto University) for AFM measurements, Mr. Kohei Kuraoka for experimental supports, and Showa Denko K.K. for the kind supply of 2-isocyanatoethyl methacrylate.

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