Multimode Self-Folding Polymers via Reversible and

Article pubs.acs.org/Macromolecules

Multimode Self-Folding Polymers via Reversible and Thermoresponsive Self-Assembly of Amphiphilic/Fluorous Random Copolymers Yuta Koda, 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: Multimode self-folding polymers were created via the reversible and thermoresponsive self-assembly of amphiphilic/fluorous random copolymers bearing poly(ethylene glycol) (PEG) and perfluoroalkyl pendants in water, N,N-dimethylformamide (DMF), and 2H,3H-perfluoropentane (2HPFP). The random copolymers with precision primary structure were synthesized by ruthenium-catalyzed living radical copolymerization of PEG methyl ether methacrylates and perfluoroalkyl methacrylates. Owing to three distinct properties of the hydrophobic backbone, hydrophilic PEG chains, and fluorous perfluorinated pendants, the random copolymers allowed various self-assembly modes for different folded structures by changing solvents. Namely, they form self-folding polymers of fluorous and/or hydrophobic cores in water or DMF, while they in turn provide reverse self-folding polymers of hydrophilic PEG cores in 2HPFP. The reverse folding in 2HPFP was further promoted by lower critical solution temperature-type phase separation of the PEG units upon heating.

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INTRODUCTION Single-chain folding (self-folding) of polymers has attracted attention as a promising approach to create functional polymeric nanomaterials with globular three-dimensional architectures and precision nanocompartments.1−24 Selective self-folding involves the precision design of polymeric precursors generally based on functional and/or amphiphilic random copolymers with well-controlled primary structure. Such random copolymers effectively allow the intramolecular association of the functional pendants (side chains) via physical interactions (e.g., hydrophobic,8−11 hydrogen bonding,12−15,16a host−guest,16b,23 and coordination16c) by selecting solvents, adding molecules, and/or giving stimuli (e.g., temperature), while they can also undergo the intramolecular cross-linking of the pendants via covalent bond formation.11b,17−22 Particularly interesting, the former self-folding system can provide reversibly folded/unfolded polymers with “dynamic” singlechain nanospaces that directly reflect the precision primary structure of the precursor polymers. Self-folding functional polymers have been also employed as novel functional nanospaces for unique catalysis.15 Recently, we have created self-folding polymers in water with amphiphilic random copolymers bearing hydrophilic poly(ethylene glycol) (PEG) and hydrophobic alkyl pendants.11 This is one of the simplest systems of self-folding polymers (i.e., unimer micelles) via hydrophobic interaction in water. The random copolymers were efficiently synthesized by rutheniumcatalyzed living radical polymerization25 of PEG methyl ether methacrylate (PEGMA) and alkyl methacrylates (RMA) © XXXX American Chemical Society

including dodecyl methacrylate (DMA) and octadecyl methacrylate. By the optimization of the primary structure in terms of degree of polymerization (DP) and monomer composition, we typically found that PEGMA/DMA random copolymers with 20−40 mol % DMA (DP ∼ 200) self-folded in water with the hydrophobic interaction of the backbone and the multiple dodecyl pendants to form compact unimer micelles. The folding structures are thus reversibly transformed by external stimuli: i.e., unfolded upon heating or by the addition of methanol. However, such PEGMA-based copolymers have limitation in self-folding condition and structure: the selffolding takes place just in water to result in unimer micelles consisting of a hydrophobic core and a hydrophilic PEG shell. To go beyond such limitation, perfluorination of PEGMAbased random copolymers would be one possibility. Perfluorinated compounds possess “fluorous” nature that is generally immiscible with water and common organic solvents [e.g., toluene, N,N-dimethylformamide (DMF), hexane, alcohols];26 they are soluble only in specific solvents (e.g., fluorinated solvents, supercritical CO2). Thus, perfluorinated random or block copolymers comprising hydrophobic or hydrophilic segments are soluble and/or dispersed in water and common organic solvents27−32 but effectively induce micellization27,28,30 and self-assembly via the local association of the perfluorinated segments: 29,32 e.g., block copolymers of MMA and Received: May 15, 2016 Revised: June 6, 2016

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DOI: 10.1021/acs.macromol.6b00998 Macromolecules XXXX, XXX, XXX−XXX

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Scheme 1. (a) Synthesis of Amphiphilic/Fluorous Random Copolymers via Ruthenium-Catalyzed Living Radical Polymerization of Poly(ethylene glycol) Methyl Ether Methacrylate (PEGMA: l = 4.5, 9) and Perfluoroalkyl Methacrylates (RFMA: 13FOMA, 17FDeMA) and (b) Reversible and Thermoresponsive Folding Properties of the Copolymers in Water, DMF, and 2HPFP

The newly designed copolymers comprise a hydrophobic polymethacrylate backbone and hydrophilic/thermoresponsive PEG and fluorous perfluoroalkyl pendants (Scheme 1b). Thus, by changing solvents as environments, the copolymers allow various folding and association mode: (1) self-folding with hydrophobic/fluorous core and hydrophilic PEG shell in water, (2) self-folding via local fluorous association in DMF, and (3) reverse self-folding with hydrophilic PEG core and fluorous perfluoroalkyl shell in 2HPFP. The reversely folded structure was further promoted thermoresponsively, as an external stimulus, via LCST-type phase separation of the PEG pendants in 2HPFP. To our best knowledge, this is the first example of multimode self-folding polymers in various environments and by external stimuli.

1H,1H,2H,2H-perfluorooctyl methacrylate (13FOMA) dynamically formed fluorinated-core micelle in DMF,30a while amphiphilic/fluorous random copolymers of PEGMA and 1H,1H,2H,2H-perfluorodecyl methacrylate (17FDeMA) turned large and stable aggregates with fluorinated cores in water.32 In addition to such solubility dependence, thermoresponsiveness based on lower critical solution temperature (LCST)-type phase separation33−40 would be also another promising trigger for stimuli-responsive self-folding/self-assembly of polymers. Recently, we found that 2H,3H-perfluoropentane (2HPFP), a hydrofluorocarbon, not only is miscible with both common hydrophobic solvents (e.g., CHCl3, toluene) and fluorous perfluorinated solvents but also induces LCST-type phase separation of PEGMA-based polymers.40 The thermoresponsive properties are actually effective for micellization of PEGMA/MMA block copolymers in 2HPFP via the aggregation of PEGMA segments. The micelles are uniquely composed of hydrophilic PEG core and hydrophobic PMMA shell, i.e., reverse globular structure generally formed with the same copolymers in water. Given these features, we herein report multimode self-folding polymers built via the reversible and thermoresponsive selfassembly of amphiphilic/fluorous PEGylated and perfluorinated random copolymers in water, DMF, and 2HPFP (Scheme 1). It should be noted that reversible folding process and structure are controllable with solvents and/or temperature. Various copolymers with different monomer composition and species were prepared by ruthenium-mediated living radical copolymerization of PEGMA [CH 2 C(CH 3 )CO 2 (CH2CH2O)lCH3, PEG4.5MA: Mn = 300 (l = 4.5) or PEG9MA: Mn = 500 (l = 9)] and perfluoroalkyl methacrylates (RFMA: 13FOMA and 17FDeMA). Self-folding and association properties of the copolymers were investigated in detail in water, DMF, and 2HPFP by size-exclusion chromatography (SEC), light scattering, and proton and fluorine nuclear magnetic resonance (1H, 19F NMR) spectroscopy.

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RESULTS AND DISCUSSION Synthesis of Amphiphilic/Fluorous Random Copolymers. Amphiphilic/fluorous random copolymers (P2, P3, P5− P10) and amphiphilic homopolymers (P1, P4) were synthesized by living radical (co)polymerization of poly(ethylene glycol) methyl ether methacrylate [CH2C(CH3)CO2(CH2CH2O)lCH3, PEG4.5MA: Mn = 300 (l = 4.5) or PEG9MA: Mn = 500 (l = 9)] and perfluoroalkyl methacrylates [RFMA, 1H,1H,2H,2H-perfluorooctyl methacrylate: 13FOMA or 1H,1H,2H,2H-perfluorodecyl methacrylate: 17FDeMA] with a ruthenium catalyst [RuCp*Cl(PO-2)2/n-Bu2NH (Cp*: pentamethylcyclopentadienyl, PO-2:1,2-bis(diphenylphosphino)ethane monooxide)]41 and a chloride initiator (ECPA, ethyl-2-chloro-2-phenylacetate) in toluene at 80 °C. The amphiphilic and fluorous properties of the polymers were controlled with monomer species and feed ratio. The target degree of polymerization (DP) at 80% monomer conversion (m = 0.8 × [PEGMA]0/[ECPA]0, n = 0.8 × [RFMA]0/ [ECPA]0) was thus given: m/n = 200/0−80/120, where the molar ratio of PEGMA and RFMA was changed from 10/0 to 4/6 (Table 1). As controlled samples, homopolymers of B


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Macromolecules Table 1. Synthesis and Characterization of PEGMA/RFMA Random Copolymersa code P1 P2 P3 P4 P5 P6 P7 P8 P9 P10

RFMAa 13FOMA 13FOMA 13FOMA 13FOMA 13FOMA 13FOMA 17FDeMA 17FDeMA

l/m/nb

time (h)

conv (%)c PEGMA/RFMA

Mnd (SEC)

Mw/Mnd (SEC)

m/nobsde (NMR)

Mne (NMR)

Mw,DMFf (MALLS)

4.5/200/0 4.5/160/40 4.5/120/80 9/200/0 9/160/40 9/120/80 9/100/100 9/80/120 9/160/40 9/120/80

56 34 47 24 27 33 34 34 31 48

82/− 78/76 71/76 82/− 69/77 72/81 71/80 70/81 81/82 76/81

69 200 63 700 54 400 85 300 68 400 68 200 68 800 40 500 88 500 70 000

1.27 1.27 1.17 1.41 1.33 1.30 1.15 1.29 1.31 1.29

233/0 195/56 132/101 203/0 140/36 119/83 96/108 70/126 170/42 139/88

70 100 82 900 83 300 102 000 85 900 95 600 94 600 90 000 108 000 117 000

106 000 128 000 n.d.i 194 000 147 000 177 000 n.d.i n.d.i 183 000 203 000

ADMFg 1.19 1.22 1.35 1.28 1.42

1.29 1.34

Mw,H2Of (MALLS) 136 000 143 000 1 980 000 226 000 155 000 203 000 n.d.j n.d.j 175 000 272 000

AH2Oh 1.29 1.12 1.17 1.05 1.14

0.96 1.34

[PEGMA]0 + [RFMA]0/[ECPA]0/[RuCp*Cl(PO-2)2]0/[n-Bu2NH]0 = 750/3.0/1.5/15 mM in toluene at 80 °C. RFMA: 1H,1H,2H,2Hperfluorooctyl methacrylate (13FOMA) and 1H,1H,2H,2H-perfluorodecyl methacrylate (17FDeMA). bTargeted degree of polymerization (DP) at 80% monomer conversion: m = 0.80 × [PEGMA]0/[ECPA]0; n = 0.80 × [RFMA]0/[ECPA]0. cMonomer conversion: determined by 1H NMR. d Number-average molecular weight (Mn) and molecular weight distribution (Mw/Mn): determined by size-exclusion chromatography (SEC) in DMF (10 mM LiBr) with PMMA standards. eObserved DP’s of PEGMA (m) and RFMA (n) and Mn: determined by 1H NMR. fAbsolute weightaverage molecular weight (Mw): determined by multiangle laser light scattering (MALLS) coupled with SEC in DMF (10 mM LiBr) or H2O. g Association number in DMF: ADMF = Mw,DMF(MALLS)/[Mn(NMR) × Mw/Mn(SEC)]. hAssociation number in H2O: AH2O = Mw,H2O(MALLS)/ Mw,DMF(MALLS). iMw(MALLS) in DMF was not determined because the dn/dc were quite small (P3, P7) or minus (P8) values. jMw(MALLS) in H2O. a

index to the concentration (dn/dc) linearly decreased with increasing RFMA composition from 0 to 60 mol % per a chain (Figure 2). As a result, the copolymer with 60 mol % 13FOMA unit (P8) uniquely showed a negative SEC signal in DMF.

PEG4.5MA and PEG9MA (P1, P4) were also prepared with the identical system. In all copolymerization, PEGMA (l = 4.5 or 9) and RFMA were simultaneously and smoothly consumed up to 70−80% to give well-controlled random copolymers (P2, P3, P5−P10) with narrow molecular weight distribution (Mn = 40 500− 88 500, Mw/Mn = 1.2−1.4, determined by SEC calibrated against PMMA standards) (Figure 1). The synchronized

Figure 2. Refractive index increment (dn/dc) of PEGMA homopolymers (P1, P4) and PEGMA/RFMA random copolymers (P2, P3, P5−P10) in DMF as a function of RFMA content [100n/(m + n)]. P4−P8: filled circle. P1−P3: open square. P9, P10: open triangle.

Analyzed by 1H NMR, random copolymers (P2, P3, P5− P10) clearly showed proton signals assignable to polymethacrylate backbone, PEG pendants, and perfluorinated alkyl pendants in acetone-d6. For instance, P6 (40 mol % 13FOMA) exhibited methylene and methyl protons of PEG chains (c: 4.2−4.0 ppm; d: 3.8−3.7 ppm; e: 3.7−3.6 ppm; f: 3.6−3.4 ppm; g: 3.4−3.3 ppm) and methylene protons of perfluorinated octane pendants (h: 4.5−4.2 ppm; i: 2.8−2.6 ppm), in addition to polymethacrylate protons (a: 2.2−1.4 ppm; b: 1.4−0.7 ppm) and the aromatic protons of a ECPA initiating terminal (7.3− 7.1 ppm) (Figure 3c). DP of PEGMA and RFMA (m/nobs), estimated from the area ratio of their pendant units to the phenyl group of the initiator, was almost consistent with DP calculated from the feed ratio of both monomers to ECPA and the conversion (Table 1). The number-average molecular

Figure 1. (a) Time−conversion curves of PEG9MA (blue) and 13FOMA (orange) for P6. (b) SEC curves of P3, P6, and P10 obtained from ruthenium-catalyzed living radical copolymerization of PEGMA (l = 4.5 or 9) and RFMA (13FOMA or 17FDeMA) for PEGMA/R F MA (120/80) random copolymers: [PEGMA] 0 / [RFMA]0/[ECPA]0/[RuCp*Cl(PO-2)2]0/[n-Bu2NH]0 = 450/300/ 3.0/1.5/15 mM in toluene at 80 °C.

consumption of two monomers supports the random incorporation of both amphiphilic PEGMA and fluorous RFMA into polymer chains without any biased sequence distribution such as gradient copolymers.42 Owing to the perfluorinated segments, the copolymers exhibited unique refractive index properties in DMF: the increment of refractive C


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Figure 3. (a−e) 1H NMR (500 MHz) and (f−j) 19F NMR (470 MHz) spectra of P6 in (a, f) D2O, (b, g) DMF-d7, (c, h) acetone-d6, (d, i) CD2Cl2, and (e, j) 2HPFP at 30 °C.

weight (Mn) was determined by 1H NMR: Mn = 82 900− 117 000 (Table 1, e.g., P6: m/nobs = 119/83; Mn = 95 600). All random copolymers (P2, P3, P5−P10) further clearly showed 19 F NMR signals derived from the perfluorinated alkyl pendants in acetone-d6. A typical 19F NMR spectrum for P6 is shown in Figure 3h (A: −113.3 to −114.4 ppm, B: −123.7 to −124.4 ppm, C: −122.0 to −122.7 ppm, D: −123.1 to −123.7 ppm, E: −126.4 to −127.1 ppm, F: −81.4 to −82.1 ppm). Absolute weight-average molecular weights [Mw,DMF(MALLS)] of P1, P2, P4−P6, P9, and P10 were determined to be 106 000−203 000 by SEC-MALLS in DMF (Table 1). In all cases, Mw,DMF(MALLS) was almost close to Mw,calcd calculated from the corresponding Mn by 1H NMR and Mw/Mn by SEC [Mw,calcd = Mn(NMR) × Mw/Mn(SEC)]. Thus, the association numbers in DMF (ADMF), defined as ADMF = Mw,DMF(MALLS)/Mw,calcd, were close to 1, indicating that they exist as unimer in DMF. Mw,DMF(MALLS) of P3, P7, and P8 could not be determined because of the quite small or negative dn/dc values (Figure 2), while Mn by SEC was close that of the other copolymers. Therefore, P1−P10 are unimolecularly dissolved in DMF. Folding/Association Properties. With the three different (i.e., hydrophilic, hydrophobic, and fluorous) affinities within a single molecule (Scheme 1b), the random copolymers (P2, P3, P5−P10) may induce self-folding and/or association not only in water but also in organic and/or fluorinated solvents, in contrast to amphiphilic random copolymers of PEG9MA and hydrophobic methacrylates.11 Thus, P6 was first analyzed by 1H and 19F NMR in various solvents including D2O, DMF-d7, CD2Cl2, and 2H,3Hperfluoropentane [2HPFP: CF3(CHF)2CF2CF3] (Figure 3). The methacrylate protons (a, b), the methylene protons of the perfluorooctyl pendants (h), and the fluorine signals of the perfluorinated units (A−F) slightly broadened in DMF-d7 (Figure 3b,g), compared with those in acetone-d6 and

CD2Cl2 (Figure 3c,d,h,i). This indicates that the perfluorinated units should partially associate each other within a single polymer in DMF-d7. In D2O, the proton and fluorine signals for the methacrylate and the perfluorinated pendants turned much broader than in any other organic solvents, indicating the hydrophobic and fluorous segments effectively aggregates to be less mobile. In contrast, in 2HPFP, the proton signals of the PEG chains (d, e, f, g) selectively broadened (Figure 3e), while the other proton and fluorine signals (Figure 3j) are almost identical to those in acetone-d6 and CD2Cl2. This uniquely suggests that PEG chains in turn associate each other in 2HPFP. On the basis of these preliminary results, we further investigated the self-folding and/or association properties of amphiphilic/fluorous radom copolymers in DMF, H2O, and 2HPFP by SEC-MALLS, dynamic light scattering (DLS), and 1 H and 19F NMR measurements. Local Association/Self-Folding in DMF. The compactness of amphiphilic/fluorous random copolymers (P2, P3, P5− P10) in DMF were evaluated with the values of the Mn (SEC) divided by the corresponding M n (NMR) [M n (SEC)/ Mn(NMR)]. Here, Mn(SEC) determined with PMMA standard calibration in DMF is normalized by Mn(NMR) in acetone-d6, a good solvent for their polymers (Figure 4). In a PEG9MA homopolymer and PEG9MA/13FOMA copolymers (P4−P8: m/n = 200/0−80/120), Mn(SEC)/Mn(NMR) values slightly decreased around 0.7−0.8 with increasing 13FOMA up to 50 mol % and then sharply decreased to 0.45 at 60 mol % 13FOMA. This suggests that with increasing 13FOMA composition the copolymers partially and locally induce the association of the perfluoroalkyl pendants and P8 with 60 mol % 13FOMA eventually self-folds to be compact. The copolymers with 40 mol % RFMA, PEG4.5MA/13FOMA (P3), PEG9MA/13FOMA (P6), and PEG9MA/17FDeMA D


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Figure 4. Mn(SEC)/Mn(NMR) of PEG4.5MA/13FOMA (P1−P3: open square), PEG9MA/13FOMA (P4−P8: filled circle), and PEG9MA/17FDeMA (P9, P10: open triangle) random copolymers as a function of the 13FOMA content [100n/(m + n)]. Mn(SEC): determined by SEC in DMF with PMMA standards. Mn(NMR): determined by 1H NMR in acetone-d6.

Figure 5. SEC curves of (a) P2, (b) P6, (c) P8, and (d) P9 in DMF (black) and H2O (blue) calibrated with PEO standards. DLS intensity distribution of (e) P2, (f) P6, (g) P8, and (h) P9 in H2O (blue) and 2HPFP (red) at 25 °C: [polymer] = 10 mg/mL in H2O or 2HPFP.

(P10) copolymers, had close values of Mn(SEC)/Mn(NMR) [0.66 (P3, P10), 0.71 (P6)]. The local mobility and association for P3, P8, and P10 were further evaluated with 1H and 19F NMR in DMF-d7 (Figure S1). P8 and P10 showed their methacrylate protons (a, b), the methylene protons of perfluorinated alkyl pendants (h), and the fluorine signals of the perfluorinated units (A−D) broader than P3 and P6. This demonstrates that highly fluorous P8 and P10 (P8: 60 mol % 13FOMA; P10: long perfluorinated 17FDeMA) effectively induce the intramolecular association of the perfluoroalkyl pendants because DMF is a poor solvent for perfluoroalkyl segments.30 The reduced mobility (i.e., broadness) for the hydrophobic methacrylate backbones would be attributed to the aggregation of the perfluorinated pendants since DMF is originally a good solvent for the backbones. Self-Folding/Multichain Aggregation in Water. Owing to the hydrophilic PEG chains, P1−P10 are soluble in water. To determine the aggregation number (AH2O) in water, the copolymers were analyzed by SEC-MALLS in water. The molecular weight [Mw,H2O(MALLS)] for P1−P6, P9, and P10 was determined as 136 000−1 980 000 (Table 1). AH2O of P1, P2, P4−P6, P9, and P10 was close to 1, calculated from the following equation: AH2O = Mw,H2O(MALLS)/Mw,DMF(MALLS). P3 consisting of short PEG4.5 chains and 40 mol % 13FOMA had molecular weight of 1 980 000 apparently larger than Mw expected for a single chain (∼100 000) in water, forming a large aggregate. P7 and P8 with over 50 mol % 13FOMA gave quite large aggregates with the molecular weight beyond the exclusion limit (MW > 7 000 000). Thus, PEG9MA-based random copolymers with below 40 mol % RFMA existed as unimer in H2O, independent of RFMA species (13FOMA or 17FDeMA). This is because relatively long and multiple PEG9 chains effectively cover the fluorous perfluorinated pendants and hydrophobic polymethacrylate backbones to unimolecularly solubilize the copolymers in water. The compactness of self-folding polymers (P2, P5, P6, and P9) in water was evaluated with the SEC peak-top molecular weight in water [Mp(H2O)] and DMF [Mp(DMF)] (Figure 5). Both SEC systems were calibrated with PEO standards. As

described above, the random copolymers virtually unfold in DMF thought the perfluoroalkyl pendants are partially associated (Figure 4 and Figure S1). The SEC curves for P2, P5, P6, and P9 shifted to lower molecular weight in water compared with those in DMF (Figure 5a,b,d). This indicates that the copolymers form compact structure in water. As shown in Figure 6, Mp(H2O)/Mp(DMF), the compactness index in water, demonstrates that PEG9MA/13FOMA random copolymers (P5, P6) turned compact in water more than corresponding PEG9MA/dodecyl methacrylate (DMA) counterparts.11 This result demonstrates that fluorous perfluorinated alkyl pendants induce self-folding of polymers in water more

Figure 6. Mp(H2O)/Mp(DMF) of PEGMA/RFMA random copolymers (P2: open triangle; P5 and P6: filled circle; P9: filled triangle) and PEGMA/dodecyl methacrylate (DMA) random copolymers (open square)11 as a function of RFMA or DMA content [100n/(m + n)]. Mp(H2O) and Mp(DMF): peak-top molecular weight of the SEC curves of the samples in H2O and DMF, respectively, calibrated against PEO standard. E


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Macromolecules Table 2. Hydrodynamic Radii of PEGMA/RFMA Copolymersa

a b

code

PEGMA (l)

P1 P2 P3 P4 P5 P6 P8 P9 P10

4.5 4.5 4.5 9 9 9 9 9 9

RFMA 13FOMA 13FOMA 13FOMA 13FOMA 13FOMA 17FDeMA 17FDeMA

RFMA (%)

RH, H2O (nm)

RH, CH2Cl2 (nm)

RH, 2HPFP (nm)

0 20 40 0 20 40 60 20 40

9.6 7.9 18 14 6.5 5.5 90 7.4 (135)b 10.7

6.1 9.2 11 7.5 5.8 6.8 15 7.2 9.5

11 9.0 18 9.2 9.6 7.6 8.7 9.0 8.4

Determined by DLS in H2O, 2HPFP, or CH2Cl2 at 25 °C: [polymer] = 10 (2HPFP, H2O), 25 (CH2Cl2) mg/mL; [P8] = 1.4 mg/mL in H2O. The value in parentheses: RH for the minor light intensity distribution.

Figure 7. (a−f) 1H NMR (500 MHz) and (g−l) 19F NMR (470 MHz) spectra of (a, g) P3, (b, h) P5, (c, (i) P6, (d, j) P7, (e, k) P8, and (f, l) P10 in D2O at 30 °C.

were overlapped with e. In addition, fluorine signals of the perfluorinated pendants (A−D) for the aggregates are virtually undetected and/or much broader than those for self-folding polymers (P5, P6, P10) (Figure 7g−l). These results demonstrate that single chain-folding polymers in water are less mobile than those in acetone, CH2Cl2, and DMF but more dynamic than multichain aggregates in water. Importantly, the self-folding of amphiphilic/fluorous random copolymers in water is triggered by the association of both hydrophobic methacrylate backbones and fluorous perfluorinated pendants. Thermoresponsive Reverse Folding in 2HPFP. PEGMA/RFMA random copolymers (P2, P3, P5−P10) and PEGMA homopolymers (P1, P4) were fully soluble in 2HPFP at room temperature. Analyzed by DLS, P1−P6 and P8−P10 showed single modal light intensity distribution to have small RH of 7.6−18 nm in 2HPFP (Figure 5e−h and Table 2).

effectively than hydrophobic dodecyl counterparts. Additionally, hydrodynamic radius (RH) of P1−P6 and P8−P10 was determined by DLS in H2O and CH2Cl2 at 25 °C (Table 2 and Figure 5e−h). Self-folding copolymers (P2, P5, P6, P9, P10) have RH in H2O (5.5−11 nm) as small as in CH2Cl2 (5.8−9.5 nm), whereas P3 and P8 (Figure 5g) own RH in H2O (18, 90 nm) larger than in CH2Cl2 (∼10 nm) because of multichain aggregation. The local mobility of random copolymers (P3, P5−P8, P10) was evaluated with 1H and 19F NMR in D2O at 30 °C (Figure 7). The methacrylate backbone protons (b) and the adjacent methylene protons (c) for self-folding polymers (P5, P6, P10) were yet observed as broad signals even in D2O (Figure 7b,c,f), while those for multichain aggregates (P3, P7, P8) completely disappeared (Figure 7a,d,e). In all cases, hydrophobic methylene protons (a, h, i) were not observed and protons d F


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of the perfluoroalkyl pendants. The NOE signal intensity for one proton (NOE/NH) at 50 °C was estimated as 1.4 × 10−4 (c), 1.7 × 10−4 (h), and 1.5 × 10−5 (d, e), all of which were smaller than the corresponding values at 30 °C. This importantly indicates that the reverse self-folding of the copolymer is promoted upon heating via the LCST-type aggregation of the PEG pendants. The mobility of their PEG chains was evaluated by 1H spin− lattice relaxation time (T1) and 1H spin−spin relaxation time (T2) measurements of P3, P6, P8, and P10 in 2HPFP at 30 °C (Table 3). Both T1 and T2 for the PEG units of P6 (peak e;

Similarly to P6 (Figure 3e), P3, P8, and P10 also showed broad proton signals of their PEG chains in 2HPFP (Figure S2), suggesting that their copolymers induce the association of the PEG to form reverse self-folding structure with hydrophilic PEG core in 2HPFP. To investigate the detail structure, P6 was evaluated by 1H nuclear Overhauser effect (NOE) difference spectroscopy in 2HPFP at 30 °C (Figure 8). When the protons of 2HPFP

Table 3. 1H T1 and T2 Measurements of PEG Chains of Copolymersa code

solvent

T1 (s)

T2 (s)

P3 P6 P6 P6 P6 P6 P8 P10

2HPFP D2O DMF-d7 acetone-d6 CD2Cl2 2HPFP 2HPFP 2HPFP

0.69 0.61 2.6 2.6 1.1 0.69 0.69 0.31

0.42 0.26 0.97 1.5 0.62 0.48 0.35 0.10

a

T1 and T2 of the PEG signals (peak e) for P3, P6, P8, and P10 were determined in various solvents at 30 °C.

Figure 3c) in 2HPFP were shorter than those in DMF-d7, acetone-d6, and CD2Cl2. The low mobility of PEG chains is also consistent with the reverse self-folding structure of an aggregated PEG core. The mobility of PEG chains was dependent on perfluorinated monomers (13FOMA or 17FDeMA) and almost independent of monomer composition (PEGMA/RFMA) and PEGMA (l = 4.5 or 9): 13FOMA-based copolymers (P3, P6, P8) had almost close T1 and T2 for their PEG units, whereas a 17FDeMA-copolymer (P10) had T1 and T2 values smaller than P6. This means that the shell comprising long and stiff perfluorinated alkanes (17FDeMA) reduced the mobility of the inner PEG cores. Folded Structure. As clarified above, a PEGMA/13FOMA random copolymer (P6, 40 mol %13FOMA) self-folds in water into a fluorous/hydrophobic core unimer micelle covered by PEG shell, while P6 reversely folds in 2HPFP into a hydrophilic PEG core unimer micelle covered by perfluoroalkyl shell. The folded structures of P6 in water or 2HPFP were thus analyzed by transmission electron microscopy (TEM) (Figure 9). For this, the aqueous or 2HPFP solutions of P6 (10 mg/mL) were

Figure 8. (a) 1H NMR (500 MHz) and NOE spectra of P6 in 2HPFP at (b) 30 °C and (c) 50 °C.

(5.4−5.0 ppm) were irradiated, the NOE signals for methylene protons adjacent to methacrylate backbone (c, h), methacrylate proton (b), and PEG protons (d, e) were observed, while the NOE signals for the tip methyl and methylene protons of PEG chains ( f, g) were not detected. In general, the intensity (i.e., area ratio) of 1H NOE signals depends on the distance between the proton and an irradiated proton (NOE/NH ∝ r−6, NH: proton numbers, r: distance).43 Thus, the area ratio for NOE signals per a single proton (NOE/NH) was further estimated in order to investigate the distance between the respective NOE signal segments and 2HPFP. Here, the area of irradiated 2HPFP (irr in Figure 8b) was set to 100 as integral normal, and the proton numbers of respective NOE peaks were given: NH = 2 × mobs (c); 2 × nobs (h); 32 × mobs (d, e). The NOE signal intensity for one proton (NOE/NH) were thus estimated as 1.7 × 10−4 (c), 2.4 × 10−4 (h), and 2.2 × 10−5 (d, e); the NOE signal for PEG chains (d, e) is much less than that for methylene protons adjacent to methacrylate backbone (c, h). This result supports that PEG chains are effectively accumulated within the self-folding interior that is spatially isolated from 2HPFP. In addition, PEGMA homopolymers are known to show lower critical solution temperature (LCST)-type phase separation in 2HPFP at 46 °C. 40 Focusing on the thermoresponsive properties, we conducted the 1H NOE measurement of P6 in 2HPFP at 50 °C. Even at 50 °C above the LCST of PEGMA homopolymers, the copolymer was still homogeneously soluble in 2HPFP owing to the high solubility

Figure 9. TEM images of P6 cast on carbon coat grids from (a) the aqueous solution or (b) 2HPFP solution. The samples were stained with OsO4. G


Article

Macromolecules cast on carbon coat grids at 25 °C; the samples were then stained with vapor of the aqueous solution of OsO4. By the efficient staining of the hydrophilic PEG units, both samples from the aqueous or 2HPFP solutions clearly exhibited black nanoparticles with spherical structure. Importantly, the size was dependent on the solvents: the black dots from the 2HPFP solution (averaged diameter: Dave = 16 nm) were smaller size than those from the aqueous solution (Dave = 38 nm). This is probably due to the location of PEG chains: self-folding polymers in water carry PEG chains as outer shell of the fluorous/hydrophobic cores, while reverse-folding polymers in 2HPFP in turn accumulate PEG chains as inner core. Taking all these results into accounts, self-folding/association properties of amphiphilic/fluorous PEGMA/RFMA random copolymers in H2O or 2HPFP were summarized as follows (Figure 10):

Figure 10. Folding/association properties of PEG9MA/13FOMA random copolymers [13FOMA: 40 mol % (P6), 60 mol % (P8)] in H2O or 2HPFP. Gray segments: intra- or intermolecularly associating units.

Figure 11. Transmittance of the aqueous solutions of PEG9MA/ 13FOMA copolymers (P5−P8) and a PEGMA homopolymer (P4) monitored at 670 nm by changing temperature (heating/cooling rate: 1 °C/min) between 20 and 100 °C: (a) reversible phase-separation of P6; (b) effects of 13FOMA content on cloud points (Cp) for P4−P8: [others] = 4 mg/mL, [P8] = 1.4 mg/mL.

(1) In H2O, PEGMA/RFMA random copolymers with 20− 40 mol % RFMA self-fold to form spherical unimer micelles of fluorous/hydrophobic core and hydrophilic PEG shell, while PEG9MA/13FOMA random copolymers with over 50 mol % 13FOMA result in multichain aggregates. (2) In 2HPFP, PEGMA/RFMA (120/80, 80/120) random copolymers induce the intramolecular association of the PEG chains to form reverse unimer micelles with PEG core and fluorous shell. The reverse folding was further promoted upon heating via LCST-type association of the PEG units. Thermoresponsive Solubility in Water. PEG-based polymers often show lower critical solution temperature (LCST)-type phase separation in water.11,33−38 Thus, the cloud points of the aqueous solutions of PEGMA/RFMA random copolymers (P3, P5−P8, P10) were determined by temperature-dependent UV/vis measurements where the transmittance of the solutions were monitored at λ = 670 nm by changing temperature ([polymer] = 4 mg/mL, heating or cooling speed = 1 °C/min) (Figure 11). The cloud point (Cp) was defined as the temperature at which the transmittance became 90% upon heating.39 Typically, a PEG9MA/13FOMA (120/80) random copolymer (P6) was phase-separated in water upon heating. The Cp (77 °C) was lower than that for PEG9MA homopolymer (P4: 90 °C), and the LCST phase separation was reversible (Figure 11a). Other PEGMA/RFMA copolymers (P3, P5, P7, P8, P10) also exhibited LCST phase separation, while the behavior and the Cp were dependent on the monomer composition and species.

In PEG9MA/13FOMA (P5−P7), Cp gradually decreased with increasing 13FOMA content from 20 to 50 mol % (Figure 11b and Table S1; P5: 88 °C; P6: 77 °C; and P7: 70 °C). P10 with 40 mol % 17FDeMA uniquely had Cp (87 °C) higher than P6 with 40 mol % 13FOMA (77 °C) (Table S1). The high Cp for P10, rather close to that for P4, demonstrates that the long perfluorodecyl pendants are effectively aggregated within the folded structure to form stable and fluorous core that is spatially segregated from PEG chains. A similar tendency was also observed for the Cp of PEGMA/RMA (160/40) amphiphilic random copolymers [RMA: n-butyl methacrylate (79 °C); octadecyl methacrylate (89 °C)].11 In contrast, the aqueous solution of P8 with 60 mol % 13FOMA began to be slightly turbid at around 60 °C but was not perfectly clouded even around 100 °C (Cp = 95 °C) (Figure 11b). After keeping the solution at 100 °C for 5 min, the transmittance further decreased to ∼60%. The phase separation behavior was irreversible by cooling: i.e., the solution was still turbid even at 20 °C (transmittance: ∼60%, Figure S3). This unique behavior for P8 would be attributed to the large aggregate structure and high 13FOMA content. Namely, the multichain aggregate already formed at 20 °C (RH = 90 nm, Table 2) is quite stable up to high temperature owing to the strong fluorous association of the multiple perfluorinated pendants, so that the stiff aggregate with a large fluorous core and a short PEG shell cannot smoothly undergo association and dissociation for sharp and reversible phase separation. A H


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similar tendency was also observed for the multichain aggregate of P3 in water (Figure S3).

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CONCLUSIONS We produced multimode self-folding polymers via the solventdependent and/or thermoresponsive intramolecular selfassembly of amphiphilic/fluorous random copolymers carrying PEG chains and perfluorinated alkyl pendants in water, DMF, and 2HPFP. The random copolymers were efficiently obtained from ruthenium-catalyzed living radical copolymerization of PEGMA (l = 4.5, 9) and perfluoroalkyl methacrylates. Importantly, the inherent affinity and properties of the hydrophobic polymethacrylate backbone and hydrophilic/ thermoresponsive PEG and fluorous perfluoroalkyl pendants afforded various self-folding polymers with different structure and local association: self-folding with fluorous/hydrophobic core in water, self-folding via local fluorous association in DMF, and thermoresponsive reverse self-folding with PEG core in 2HPFP. Such selective and reversible self-folding involves not only the precursor design based on hydrophilic/thermoresponsive PEG chains and fluorous perfluoroalkyl pendants but also precision primary structure. Multimode self-folding polymers would open new avenue as stimuli-responsive polymeric materials and nanocapsules to molecular encapsulation, delivery, and release technologies and wide variety of applications.

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.macromol.6b00998. Experimental details, characterization, NMR spectra of polymers, and cloud points of polymers in H2O (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail [email protected] (T.T.). *E-mail [email protected] (M.S.). Notes

The authors declare no competing financial interest.

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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) and Young Scientist (B: 24750104), by The Sumitomo Foundation (131302), and by Research Institute for Production Development, for which T.T. is grateful. Y.K. is grateful to the Japan Society for the Promotion of Sciences (JSPS) for a Grant-inAid for JSPS Research Fellows (DC1:24-6140). We also thank Professor Kazunari Akiyoshi (Kyoto University) for supporting TEM experiments.

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REFERENCES

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Multimode Self-Folding Polymers via Reversible and

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