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May 9, 2016 - 1023−1033. (6) Blanazs, A.; Madsen, J.; Battaglia, G.; Ryan, A. J.; Armes, S. P.. Mechanistic insights for block copolymer morphologie...
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In Situ Synthesis of Block Copolymer Nanoassemblies via Polymerization-Induced Self-Assembly in Poly(ethylene glycol) Chengqiang Gao,† Heng Zhou,† Yaqing Qu,† Wei Wang,† Habib Khan,† and Wangqing Zhang*,†,‡ †

Key Laboratory of Functional Polymer Materials of the Ministry of Education, Institute of Polymer Chemistry and ‡Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Nankai University, Tianjin 300071, China S Supporting Information *

ABSTRACT: A new formulation of polymerization-induced self-assembly in poly(ethylene glycol) (PEG) named PEG-PISA to synthesize diblock copolymer nanoassemblies via macromolecular RAFT agent mediated dispersion polymerization is reported. In PEG-PISA, the viscous PEG with molecular weight ranging from 200 to 1000 Da is used as polymerization medium. The utilization of the viscous PEG as the polymerization medium affords the advantages including fast polymerization rate, good control over the synthesis of diblock copolymers, and in situ synthesis of both amphiphilic and doubly hydrophobic diblock copolymer nanoassemblies at polymer concentration of up to 50%. Also ascribed to the viscous polymerization medium of PEG, two new and/or interesting diblock copolymer nanoassemblies of ellipsoidal vesicles and nanotubes are formed via PEG-PISA, and the reason on formation of ellipsoidal vesicles and nanotubes is discussed. The proposed PEG-PISA is anticipated to be an effective method to synthesize block copolymer nanoassemblies combining the advantages of alcoholic/aqueous PISA and versatility of poly(ethylene glycol).

1. INTRODUCTION Recently, the polymerization-induced self-assembly (PISA) especially via dispersion polymerization mediated with macromolecular RAFT (macro-RAFT) agents has been proven to an effective strategy to synthesize AB diblock copolymer nanoassemblies with controlled morphology and relatively high polymer concentration up to 30 wt %,1−3 and the research groups led by Armes,4−11 Pan,12−16 Lowe,17−21 and Zhang22−31 as well as others32−50 have made contributions on PISA. In macro-RAFT agent mediated dispersion polymerization under PISA condition, a soluble macro-RAFT agent to form solvophilic A block, a soluble monomer to form solvophobic B block, a soluble initiator, and a suitable polymerization medium, usually alcohols or water, were fed. When the B block extends, the synthesized amphiphilic AB diblock copolymer nucleates to form diblock copolymer nanoassemblies during RAFT polymerization. The PISA formulation has the advantages including one-pot preparation of concentrated diblock copolymer nanoassemblies and convenient tuning their morphology and/or size through changing either polymerization degree (DP) of the solvophilic block or macro-RAFT agent, 7,10,25,28,42 DP of the solvophobic block,4−50 monomer concentration,5−11,26 or solvent character.10,31,46,47 However, strict selection of polymerization medium for PISA is usually needed. The polymerization medium for PISA must meet at least two requirements. First, all reactants, e.g., macro-RAFT agent, monomer, and initiator, can dissolve in the polymerization medium at polymerization temperature. Second, the resulting amphiphilic AB diblock © XXXX American Chemical Society

copolymer cannot molecularly dissolve in the polymerization medium but forms supramolecular nanoassemblies. These requirements limit the choice of the polymerization medium, e.g., water for 2-hydroxypropyl methacrylate in aqueous dispersion RAFT polymerization4−6,42 and alcohols for styrenic monomers in alcoholic dispersion RAFT polymerization.12−16,35−38 Generally, volatile organic solvents of alcohols are chosen as the polymerization medium in most cases of PISA.9−19,32−40 More recently, much effort has been made to broad the polymerization medium, and the long-chain nalkanes,7,20,21 mineral oil,8 supercritical carbon dioxide,48,49 and ionic liquids29,50 have been used as the polymerization medium in PISA. However, either these solvents are uneconomical or their character cannot be finely tuned. Consequently, seeking a new suitable polymerization medium other than alcohols or water for PISA is highly desirable. Poly(ethylene glycol) (PEG) is extensively studied as a green solvent for organic reactions;51,52 however, utilization of PEG as polymerization solvent is scarcely reported.53,54 From a green chemistry viewpoint, the utilization of PEG as solvent for controlled radical polymerization has many advantages including the low volatile organic content, nontoxicity, nonflammability, low cost, and availability of PEG with different molecular weight.51,52 Besides, Perrier and co-workers found that the RAFT polymerization of methyl methacrylate in PEG Received: April 4, 2016 Revised: May 3, 2016

A

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Macromolecules Table 1. Synthesis and Characterization of Macro-RAFT Agents Mn (kDa) entry

macro-RAFT agents

[M]0:[R]0:[I]0

time (h)

conva (%)

Mn,thb

Mn,GPCc

Mn,NMRd

Đe

A B C D E1 E2 E3 E4 E5 F1 F2 F3 F4

mPEG113-TTC PDEGMA56-TTC PDMA19-TTC P4VP54-TTC PNIPAM10-TTC PNIPAM18-TTC PNIPAM29-TTC PNIPAM34-TTC PNIPAM46-TTC PMMA60-TTC PMMA79-TTC PMMA98-TTC PMMA120-TTC

100:1:1/6 20:1:1/5 60:1:1/4 10:1:1/4 20:1:1/4 30:1:1/4 35:1:1/4 50:1:1/4 60:1:1/10 80:1:1/10 100:1:1/10 120:1:1/10

3 1.5 12 2.5 2 2 2 2 5 6 6 7

56 94 90 97 91 97 97 92 100 99 98 100

5.3 10.8 2.1 5.9 1.4 2.3 3.5 4.1 5.5 6.3 8.2 10.1 12.3

10.5 14.6 3.4 5.9 3.4 3.6 3.8 3.9 4.7 8.9 12.8 16.8 17.5

5.2 11.7 2.3 6.9 1.7 3.2 4.9 6.1 6.8 6.7 8.5 10.2 12.8

1.03 1.21 1.03 1.09 1.02 1.03 1.07 1.06 1.06 1.11 1.09 1.09 1.13

a The monomer conversion determined by 1H NMR spectroscopy. bThe theoretical molecular weight determined by monomer conversion. cThe molecular weight measured by GPC. dThe molecular weight determined by 1H NMR spectroscopy. eThe Đ (Mw/Mn) value measured by GPC.

trithiocarbonate (DDMAT) and 4-cyano-4-(ethylsulfanylthiocarbonyl)sulfanylpentanoic acid (ECT) were synthesized following the reported procedures.56,57 The initiator of 2,2′-azobis(isobutyronitrile) (AIBN, >99%, Tianjin Chemical Company, China) was recrystallized twice from ethanol prior to use. The poly(ethylene glycol) series with molecular weight Mn at 200, 400, 1000, and 6000 Da (PEG200, PEG400, PEG1000, and PEG6000, Alfa) were used as received unless noted otherwise. All other chemicals were of analytical grade and used as received. 2.2. Synthesis of Macro-RAFT Agents. Six macro-RAFT agents including S-1-dodecyl-S′-(α,α′-dimethyl-α″-acetic acid) trithiocarbonate-terminated poly(ethylene glycol) monomethyl ether (mPEG113TTC, herein the subscript means the number of repeated units or DP of the corresponding monomers and TTC means the RAFT terminal of trithiocarbonate), poly[di(ethylene glycol)methyl ether methacrylate] trithiocarbonate (PDEGMA-TTC), poly(N,N-dimethylacrylamide) trithiocarbonate (PDMA-TTC), poly(4-vinylpyridine) trithiocarbonate (P4VP-TTC), poly(methyl methacrylate) trithiocarbonate (PMMA-TTC), and poly(N-isopropylacrylamide) trithiocarbonate (PNIPAM-TTC) were employed in the present study, and their synthesis is listed in Table 1. mPEG113-TTC was prepared by esterification between poly(ethylene glycol) monomethyl ether and DDMAT as described in the Supporting Information,25 and the other five macro-RAFT agents were synthesized with solution polymerization as summarized in Table 1. Herein, synthesis of PDMA-TTC is typically introduced, and preparation of other macro-RAFT agents could be found in the Supporting Information. To a 25 mL Schlenk flask with a magnetic stir bar were added DMA (2.00 g, 0.0202 mol), ECT (0.266 g, 1.01 mmol), AIBN (33.1 mg, 0.202 mmol), and 1,4-dioxane (4.00 g). The flask content was degassed with nitrogen at 0 °C, and then RAFT polymerization was conducted at 70 °C for 1.5 h and finally quenched through cooling the flask in an iced water bath. The monomer conversion of 94% could be determined by 1H NMR through comparing the signal of N,N-dimethylacrylamide at δ = 5.64−5.69 ppm with that of the 1,3,5-trioxane internal standard at δ = 5.16 ppm. The synthesized PDMA19-TTC was purified by precipitation into excess cold diethyl ether and then dried in vacuo overnight. 2.3. PEG-PISA and Synthesis of mPEG113-b-PS Nanoassemblies. The mPEG113-TTC mediated dispersion polymerization of styrene was conducted in PEG (PEG200, PEG400, PEG1000, and PEG6000) or MeOH at 70 °C under [monomer]0:[macro-RAFT]0: [initiator]0 = 300:1:1/3 with 10−50 wt % solid content. Note: the solid content means the total weight fraction of the fed monomer and the macro-RAFT agent in the polymerization mixture. Herein, a typical example performed in PEG400 with 20 wt % solid content was introduced. mPEG113-TTC (0.170 g, 0.0321 mmol), AIBN (1.75 mg, 0.0107 mmol), PEG400 (4.68 g), and styrene (1.00 g, 9.60 mmol)

was highly faster compared to general organic solvents, and they revealed that the accelerated polymerization was due to the much high viscosity of PEG.53 Furthermore, it is known that PEG is a good solvent for many polar polymers but a poor solvent for nonpolar polymers, and self-assembly of amphiphilic diblock copolymers in PEG was demonstrated.55 This means that PEG may be a qualified medium for PISA. However, it is surprising that PISA in PEG is still unexplored so far. In this contribution, we report a new PISA formulation via dispersion RAFT polymerization in PEG. Initially, the poly(ethylene glycol) monomethyl ether (mPEG) based macroRAFT agent mediated dispersion polymerization in PEG, which is named PEG-PISA, is performed. The dispersion polymerization in PEG runs significantly faster than that in methanol (MeOH), and it provides good control over the synthesis of the block copolymer of poly[(ethylene glycol) monomethyl ether]block-polystyrene (mPEG-b-PS). Besides, mPEG-b-PS nanoassemblies prepared by PEG-PISA have different morphologies from those prepared by alcoholic dispersion RAFT polymerization. Finally, this PEG-PISA is extended, and well-defined amphiphilic and doubly hydrophobic diblock copolymer nanoassemblies such as poly[di(ethylene glycol) methyl ether methacrylate]-block-polystyrene (PDEGMA-b-PS), poly[(ethylene glycol) monomethyl ether]-block-poly(tert-butyl acrylate) (mPEG-b-PtBA), poly(N,N-dimethylacrylamide)block-polystyrene (PDMA-b-PS), poly(4-vinylpyridine)-blockpolystyrene (P4VP-b-PS), poly(N-isopropylacrylamide)-blockpolystyrene (PNIPAM-b-PS), and poly(methyl methacrylate)block-polystyrene (PMMA-b-PS) have been prepared via PEGPISA. Our results demonstrate that this PEG-PISA is a valid and versatile formulation to synthesize both amphiphilic and doubly hydrophobic diblock copolymer nanoassemblies.

2. EXPERIMENTAL SECTION 2.1. Materials. The monomers of N,N-dimethylacrylamide (DMA, >99.5%, Alfa Aesar), 4-vinylpyridine (4VP, 96%, Alfa Aesar), methyl methacrylate (MMA, >99%, Tianjin Chemical Company, China), styrene (St, >98%, Tianjin Chemical Company, China), and tert-butyl acrylate (tBA, >99%, Alfa) were distilled under prior to use. The monomer of di(ethylene glycol) methyl ether methacrylate (DEGMA, 96%, Sigma-Aldrich) was purified by passing a basic alumina column. N-Isopropylacrylamide (NIPAM, >99%, Acros Organics) was purified by recrystallization from the acetone/n-hexane mixture (1:1, v/v) before being used. S-1-Dodecyl-S′-(α,α′-dimethyl-α″-acetic acid) B

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Macromolecules were weighed into a 25 mL Schlenk flask with a magnetic stir bar. The flask content was degassed with nitrogen at 0 °C, and then polymerization was conducted at 70 °C under gentle stirring. After a given time of polymerization, polymerization was quenched through cooling the flask in an iced water bath. The conversion of styrene could be determined by UV−vis at 245 nm as described by Gao et al.30 To check the synthesized colloids, a drop of the colloidal dispersion was diluted with methanol and observed by TEM. To obtain copolymer for GPC and 1H NMR analysis, the resultant colloidal dispersion of mPEG113-b-PS was diluted with dichloromethane and precipitated into excess methanol or methanol/water mixture containing 5−10 wt % water (note: water helps to deposit mPEG113-b-PS especially for that containing a short PS block). The precipitate was isolated by centrifugation (10 000 rpm, 10 min), then washed three times with methanol, and finally dried in vacuo to obtain mPEG113-b-PS. To compare PEG-PISA with alcoholic dispersion RAFT polymerization, dispersion RAFT polymerization of styrene in MeOH under [monomer]0:[macro-RAFT]0:[initiator]0 = 300:1:1/3 with 20 wt % solid content was also performed similarly. 2.4. Synthesis of a Series of Diblock Copolymer Nanoassemblies through PEG-PISA. The diblock copolymer nanoassemblies of mPEG-b-PtBA, PDMA-b-PS, PDEGMA-b-PS, P4VP-bPS, PNIPAM-b-PS, and PMMA-b-PS were also synthesized via PEGPISA. The synthesis of these diblock copolymer nanoassemblies is shown in the Supporting Information. 2.5. Characterization. The 1H NMR spectroscopic measurements were conducted on a Bruker Avance III 400 MHz NMR spectrometer in CDCl3 containing 0.03% tetramethylsilane (TMS). Two gel permeation chromatography (GPC) systems were employed to determine molecular weight (Mn,GPC) and dispersity (Đ, Đ = Mw/ Mn) of synthesized polymers. For poly(4-vinylpyridine)-based polymers, GPC analysis was conducted on a Waters 600E GPC with three SHODEX columns in DMF containing LiBr (0.01 mol/L) operating at the flow rate of 0.8 mL/min at 50.0 °C using an RL 2000 refractive index detector, and the system was calibrated with the nearmonodisperse polystyrene standards; for all the other polymers, GPC analysis was conducted on a Waters 600E GPC with the TSK-GEL columns in THF operating at the flow rate of 0.6 mL/min using a Waters 2414 refractive index detector, and the system was calibrated with the near-monodisperse polystyrene standards. Transmission electron microscope (TEM) observation was conducted at 200 kV on a Tecnai G2 F20 electron microscope. Atomic force microscope (AFM) observation was conducted in the tapping mode on a Bruker MultiMode atomic force microscope. Scanning electron microscope (SEM) observation was conducted on a JEOL JSM-7500F field emission-gun microscope.

highly satisfactory, and more than 99% of mPEG113-OH is converted into mPEG113-TTC (Figure S1). PDEGMA-TTC, PDMA-TTC, P4VP-TTC, and PNIPAM-TTC were synthesized via solution polymerization employing ECT as RAFT agent at suitable monomer conversion, and all of them can be molecularly dissolved in PEG at room temperature or at the polymerization temperature of 70 °C (note: PEG6000 is a solid at room temperature and becomes a liquid at temperature above about 57 °C). Besides, PMMA-TTC, which is usually deemed to be hydrophobic, with different DPs was prepared with the similar procedures as described by Perrier and coworkers.53 Interestingly, PMMA-TTC was insoluble in water and MeOH, while it can be molecularly dissolved in PEG200, PEG400, and PEG1000; therefore, it has the potential to act as macro-RAFT agent in PEG-PISA. The characterization of these macro-RAFT agents was performed by 1H NMR and GPC analysis, and these results indicate all macro-RAFT agents have well-controlled molecular weight and relatively narrow molecular weight distribution with Đ around 1.1 (Table 1). 3.2. PEG-PISA and Synthesis of mPEG113-b-PS Nanoassemblies. In this section, the typical PEG-PISA to synthesize mPEG113-b-PS nanoassemblies in PEG as shown in Scheme 1 was introduced in detail, and polymerization kinetics Scheme 1. mPEG113-TTC Mediated Dispersion Polymerization of St in PEG

of the dispersion polymerization and morphology of the prepared mPEG113-b-PS nanoassemblies with increasing length of the PS block were investigated. Furthermore, the parameters including the PEG molecular weight and monomer concentration (or solid content) affecting PEG-PISA were also investigated. This PEG-PISA performed in PEG400 under [monomer]0: [macro-RAFT]0:[initiator]0 = 300:1:1/3 with 20 wt % solid content was initially investigated. It was optically observed that the PEG-PISA underwent an initial homogeneous polymerization in about 7 h at about 29% monomer conversion and then a subsequent heterogeneous polymerization until to 94% monomer conversion in 24 h (Figure 1A). Correspondingly, a ln([M]0/[M]) vs time plot containing two stages can be found (Figure 1B). The initial gradient stage in the plot corresponds to the homogeneous polymerization, and the subsequent steep stage corresponds to the heterogeneous one. In the initial stage below 29% monomer conversion in 7 h, mPEG113-b-PS contains a short PS block and hence can dissolve in PEG400 at polymerization temperature of 70 °C. When the PS block further extends, mPEG113-b-PS became molecularly insoluble to form micelles, which acted as nanoreactors for the incoming monomers, and then subsequent heterogeneous RAFT polymerization took place predominantly in these nanoreactors to afford the mPEG113-b-PS nanoassemblies. As reported,58 the apparent polymerization rate constants (kpapp) can be determined by the slope of the ln([M]0/[M]) vs time plot. Herein, kpapp at heterogeneous and homogeneous stages is 0.20 and 0.048 h−1, indicating accelerated RAFT polymerization in the heterogeneous stage. The accelerated RAFT polymerization

3. RESULTS AND DISCUSSION 3.1. Synthesis of Macro-RAFT Agents. For alcoholic or aqueous dispersion polymerization, the macro-RAFT agent must meet the requirement of being molecularly soluble in alcohols or water, and therefore hydrophilic polymers such as PEG,5,12,24−29,50 PDMA,30,45 poly[2-(dimethylamino)ethyl methacrylate] (PDMAEMA),10,11,13,17 poly[poly(ethylene glycol) methyl ether acrylate] (PPEGMA), 18,32,39,42 and P4VP14,15,23,33,38 are usually employed as macro-RAFT agent. Considering that the PEG polymerization medium is polar, five hydrophilic macro-RAFT agents of mPEG113-TTC, PDMA19TTC, PDEGMA56-TTC, P4VP54-TTC, and PNIPAM-TTC as listed in Table 1 were synthesized. mPEG113-TTC was synthesized by esterification between poly(ethylene glycol) monomethyl ether and DDMAT as described in the Supporting Information (see the GPC and 1H NMR analysis of mPEG113TTC in Figures S1 and S2). The esterification degree, which is evaluated via comparing the signals at δ = 4.25 ppm [f, −CH2− O(CO)] and δ = 3.26 ppm (d, CH3−(CH2)10−CH2S), is C

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Figure 1. Polymerization kinetics (A, B) for PEG-PISA in PEG400, the GPC traces (C), and molecular weight evolution and Đ values (D) of mPEG113-b-PS diblock copolymers. Polymerization conditions: [monomer]0:[macro-RAFT]0:[initiator]0 = 300:1:1/3, 20 wt % solid content, 70 °C.

This indicates that polymerization runs faster in low-molecularweight PEG except that in PEG6000. The “abnormal” order of the polymerization rate in PEG6000 is probably ascribed to the macroscopical phase separation of mPEG113-b-PS in PEG6000, which changes the accessibility of the styrene monomer to the mPEG113‑b-PS aggregates and therefore leads to the “abnormal” polymerization rate. As discussed elsewhere,10,31 dispersion RAFT polymerization underwent faster in alcoholic solvents with higher polarity, and the reason was attributed to fast copolymer nucleation in higher polar solvent under PISA condition. In the present PEG-PISA, the PEG polarity, which slightly decreases or almost keeps constant with the increasing PEG molecular weight, may exert certain influence on the polymerization rate. However, the polarity effect should be far less important than the high viscosity of PEG and/or the decreased radical termination in PEG as discussed above, since the RAFT polymerization in PEG is much slower than in the highly polar solvent of MeOH. Figure 1C summarizes the GPC traces of mPEG113-b-PS synthesized via PEG-PISA in PEG400, and its molecular weight Mn,GPC and distribution (Đ) can be afforded (Figure 1C). From the GPC traces of mPEG113-b-PS synthesized at high monomer conversion, a slight shoulder is observed, and therefore slight bimolecular termination possibly occurs in PEG-PISA. As Figure 1D indicates, the linear increase of Mn,GPC with monomer conversion is observed, and Đ is generally kept below 1.15. The mPEG113-b-PS was also characterized by 1H NMR spectroscopy (Figure S1), and the molecular weight Mn,NMR was determined based on peak area ratio of the signals at δ = 3.64 ppm (g) and 6.25−6.85 ppm (l). Mn,NMR of mPEG113-b-PS is well consistent with the theoretical molecular weight Mn,th calculated by eq S1, whereas Mn,GPC is a little larger than Mn,th. The overestimation of Mn,GPC is probably resulted from the polystyrene standards used in the GPC analysis. These

can be attributed to the compartmentalization effect or radical segregation under heterogeneous condition as well clarified by Zetterlund and co-workers.59 In comparison with alcoholic dispersion RAFT polymerization under the same conditions, the present PEG-PISA in PEG400 runs much faster (Figure 1A). For example, the monomer conversion of 57% could be obtained in 10 h via PEG-PISA, whereas the alcoholic dispersion RAFT polymerization just afforded 15% monomer conversion in 10 h. In a homogeneous RAFT polymerization performed in PEG, Perrier and co-workers found that the high viscosity of PEG was ascribed to the accelerated polymerization, and the polarity of PEG had no or very slight influence on the polymerization rate.53 Furthermore, Beuermann and co-workers also found that the PEG unit attached onto the methacrylate monomer could reduce the termination rate coefficient, kt, in the radical polymerization and therefore to accelerate the polymerization.60 Herein, the high viscosity of the PEG polymerization medium and the reduced termination rate coefficient kt contribute mainly to the accelerated rate of PEG-PISA. Besides, the solvent polarity may also exert somewhat influence on polymerization rate, which will be further discussed subsequently. It is also found that a wide range of PEG such as PEG200, PEG400, and PEG1000 with different molecular weight could be employed as polymerization medium for PEG-PISA to afford uniformly dispersed mPEG113-b-PS nanoassemblies. However, macroscopical precipitates of mPEG113-b-PS are found in PEG6000, indicating that PEG with molecular weight higher than 6000 Da is not the suitable medium for PEG-PISA. Furthermore, as indicated out by Figure 1A, the PEG molecular weight exerts somewhat effect on the polymerization rate. For example, the polymerization rate in PEG follows PEG200 ≈ PEG400 slightly > PEG6000 slightly > PEG1000 > MeOH. D

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Macromolecules two cases of molecular weight linearly increase with monomer conversion despite the slight difference between Mn,NMR and Mn,GPC. These results as well as the low Đ values indicate good control over the preparation of mPEG113-b-PS nanoassemblies in PEG-PISA. The mPEG113-b-PS nanoassemblies synthesized via PEGPISA in PEG400 at different polymerization time were examined by TEM. Figure 2 indicates the morphology of

Figure 3. TEM images of the mPEG113-b-PS nanoassemblies synthesized via the mPEG113-TTC mediated dispersion polymerization in MeOH (A), PEG200 (B), PEG400 (C), and PEG1000 (D). Polymerization conditions: [monomer]0:[macro-RAFT]0:[initiator]0 = 300:1:1/3, 20 wt % solid content, 70 °C. Figure 2. TEM images of the mPEG113-b-PS nanoassemblies prepared via PEG-PISA in PEG400 at 7 h (A), 8 h (B), 10 h (C), 12 h (D), 14 h (E), and 24 h (F). Polymerization conditions: [styrene]0:[macroRAFT]0:[initiator]0 = 300:1:1/3, 20 wt % solid content, 70 °C.

200 to 1000 Da. Besides, in PEG1000, which has the highest molecular weight and is the most viscous, ellipsoidal mPEG113b-PS vesicles are formed, whereas in the low molecular weight PEG, e.g., PEG200 and PEG400, spherical mPEG113-b-PS vesicles are prepared. Ellipsoidal vesicles of amphiphilic block copolymers have been theoretically predicted by simulation,61 whereas no further experimental proof has been reported. Herein, it is expected that the viscous PEG medium under stirring exerts a shear force on the mPEG113-b-PS spherical vesicles to elongate spherical vesicles to ellipsoidal ones as shown in Scheme 2, which will be further discussed subsequently. Note: see Figure S3 for GPC traces of these mPEG113-b-PS diblock copolymers.

mPEG113-b-PS nanoassemblies changes from nanospheres to vesicles when DP of the PS block increases above 102, which is somewhat similar to aqueous or alcoholic dispersion RAFT polymerizations as described elsewhere.12,32 Since the PEG viscosity increases with its molecular weight and the polymerization rate in different PEG is slightly different, it is expected that the PEG molecular weight can affect morphology of mPEG113-b-PS nanoassemblies. To check influence of the PEG molecular weight on size/morphology of mPEG113-b-PS nanoassemblies, a series of PEG-PISA with the PEG molecular weight ranging from 200 to 1000 Da as well as the alcoholic dispersion RAFT polymerization under the same conditions were performed, and all polymerizations were quenched at 92−96% monomer conversion, and then mPEG113-b-PS nanoassemblies were further examined by TEM (Figure 3). Obviously, due to the similar monomer conversion and the fixed ratio of [monomer]0:[macro-RAFT]0: [initiator]0, DP of the PS block in all mPEG113-b-PS nanoassemblies, which is centered at about 280, is similar to each other as depicted in Figure 3. Note: the alcoholic dispersion polymerization ran much slower, and just 69% monomer conversion was achieved even the polymerization was prolonged to 48 h; therefore, the mPEG113-b-PS206 nanoassemblies including a slightly short PS block were just prepared. As shown in Figure 3, the three cases of PEG-PISA afforded the vesicles of mPEG113-b-PS, and the alcoholic dispersion RAFT polymerization afforded the 31 nm mPEG113b-PS206 nanospheres. By carefully checking the mPEG113-b-PS vesicles prepared via PEG-PISA, it is found that the PEG molecular weight really exerts influence on size/morphology of mPEG113-b-PS vesicles. For example, the mean size of mPEG113-b-PS vesicles changes from 190 ± 50 nm (Figure 3B) to 220 ± 60 nm (Figure 3C) and finally to 310 ± 90 nm (Figure 3D), when the PEG molecular weight increases from

Scheme 2. Possible Formation Mechanism of Ellipsoidal Vesicles and Nanotubes under PEG-PISA

Benefitting from the viscous PEG polymerization medium, which can stabilize block copolymer nanoassemblies, highly concentrated diblock copolymer colloids with copolymer concentration at 20−50 wt % can be synthesized via PEGPISA in PEG400. At 20−50 wt % solid content, these dispersion RAFT polymerizations under a fixed ratio of [monomer]0:[macro-RAFT]0:[initiator]0 ran at similar rate, and the similar monomer conversion of 92−96% could be obtained in 24 h; whereas at 10 wt % solid content, the dispersion polymerization ran slower, and the monomer E

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Figure 4. TEM images of the synthesized mPEG113-b-PS nanoassemblies via PEG-PISA in PEG400 with the solid content at 10 (A), 20 (B), 30 (C), and 50 wt % (D). SEM (E) and AFM (F) images of the mPEG113-b-PS288 vesicles prepared in PEG400 with 50% solid content. (G, H) Crosssectional height profiles along lines 1 and 2 in (F). Polymerization conditions: [monomer]0:[macro-RAFT]0:[initiator]0 = 300:1:1/3, 70 °C.

conversion of 92% was afforded when the polymerization was extended to 72 h. Because of the fixed ratio of [styrene]0: [macro-RAFT]0:[initiator]0 and the similar monomer conversion, all mPEG113-b-PS nanoassemblies synthesized via PEGPISA contain a PS block with a similar DP at around 280 (see Figure S4 for the GPC traces). The TEM images of obtained mPEG113-b-PS nanoassemblies via PEG-PISA at 10−50 wt % solid content are shown in Figure 4, and it indicates that all cases of PEG-PISA lead to mPEG113-b-PS vesicles, although the size of these vesicles is slightly different. Interestingly, PEGPISA at 50 wt % solid content afforded ellipsoidal vesicles of mPEG113-b-PS in PEG400 (Figure 4D), which is somewhat like the ellipsoidal vesicles prepared at 20 wt % solid content in PEG1000 (Figure 3D). Clearly, these two cases of PEG-PISA to afford the ellipsoidal mPEG113-b-PS diblock copolymer vesicles have similar character of the viscous polymerization mixture, which is ascribed to either the highly concentrated solid content or the high molecular weight of the PEG polymerization medium. These ellipsoidal mPEG113-b-PS vesicles were further characterized by SEM (Figure 4E) and AFM (Figures 4F−H), from which the ellipsoidal structure is confirmed. 3.3. Synthesis of Amphiphilic Diblock Copolymer Nanoassemblies. Besides the mPEG113-b-PS nanoassemblies, many other amphiphilic diblock copolymer nanoassemblies can also be synthesized via PEG-PISA by changing the polymerized monomers or macro-RAFT agents. Figure 5 shows the typical amphiphilic block copolymer nanoassemblies of the mPEG113b-PtBA 300 vesicles (Figure 5A), the PDEGMA 56 -b-PS 282 nanospheres (Figure 5B), the PDMA19-b-PS292 ellipsoidal vesicles (Figure 5C), and the P4VP54-b-PS291 vesicles (Figure 5D) prepared via PEG-PISA in PEG400. The four amphiphilic block copolymers containing the hydrophobic PtBA or PS blocks with the similar DPs but the different hydrophilic blocks are similar to the amphiphilic diblock copolymer nanoassemblies as discussed elsewhere.4−8,10−50 Note: see Figure S5 for the GPC traces. Up to now, several block copolymer nanotubes prepared through the self-assembly strategy have been reported.62−66 However, controlled synthesis of diblock copolymer nanotubes

Figure 5. TEM images of the mPEG113-b-PtBA300 (A), PDEGMA56-bPS282 (B), PDMA19-b-PS292 (C), and P4VP54-b-PS291 (D) nanoassemblies prepared via PEG-PISA in PEG400. Note: the mPEG113-bPtBA300 vesicles were stained with phosphotungstic acid. Polymerization conditions: [monomer]0 :[macro-RAFT] 0 :[initiator]0 = 300:1:1/3, 20 wt % solid content, 70 °C, 24 h.

by PISA have yet not been achieved. Inspired by the synthesis of the new morphology of the PDMA19-b-PS292 ellipsoidal vesicles and the mPEG113-b-PS ellipsoidal vesicles through PEG-PISA, the synthesis of diblock copolymer nanotubes through PEG-PISA is tried. Our try to prepare nanotubes is based on Scheme 2. That is, spherical vesicles, ellipsoidal vesicles, and nanotubes have the similar vacant structure but different height and/or length. If the spherical vesicles are compressed or elongated by an oriented force, spherical vesicles may convert into ellipsoidal vesicles or nanotubes. As noted above, mPEG113-b-PS nanoassemblies undergo nanospheres-to-vesicles transition when DP of the PS block increases. Herein, with five PNIPAM-TTC macro-RAFT agents with DP ranging from 10 to 46 in hand, the PNIPAM-b-PS F

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PAM block becoming shorter. It is known that the morphology of amphiphilic block copolymer nanoassemblies is firmly dependent on the packing parameter p of the solvophobic/ solvophilic blocks.68 By changing chain length of solvophilic and/or solvophobic blocks, p increases and therefore spheresto-worms-to-vesicles transition occurs.69 Herein, the nanospheres-to-vesicles-to-nanotubes transition of PNIPAM-b-PS during PEG-PISA is an extension of the block copolymer morphology evolution. Now, we intend to give a possible explanation of the formation mechanism of ellipsoidal vesicles or nanotubes under PEG-PISA. Spherical vesicles, ellipsoidal vesicles, and nanotubes have a similar vacant structure, and the spherical vesicles may be the precursors of the latter two morphologies. From the above-mentioned TEM images, e.g., Figures 4D and 5C, it is found that ellipsoidal vesicles are larger in size than spherical vesicles, and this possibly indicates that vesicle fusion may be involved in the formation of the latter two morphologies. From the TEM images of the PNIPAM29-b-PS220 nanotubes−vesicles joints (Figure 6C), the fusion of two vesicles and the fusion of a short nanotube and a vesicle, which are indicated by blue and red arrows, have been further confirmed. The fusion of block copolymer vesicles had been studied previously,70−74 and the reason was ascribed to decrease of the interfacial area.72 Herein, in the present PEG-PISA, the PEG polymerization medium is not as polar as alcohols, and therefore it is somewhat compatible with the PS block in the PS-based amphiphilic block copolymers, which therefore can promote the vesicle fusion. Besides, under PEG-PISA, the stirred viscous PEG medium makes the shear force, which is positively correlative to the viscosity of the polymerization medium and is much higher than in alcoholic dispersion RAFT polymerization, on the vesicles to elongate the vesicles into ellipsoidal vesicles or nanotubes. Therefore, it is supposed that the fusion of vesicles to reduce the interfacial area and the elongation of the vesicles triggered by the shear force as shown in Scheme 2 may be involved in formation of ellipsoidal vesicles or nanotubes under PEG-PISA, although exact formation mechanism of ellipsoidal vesicles or nanotubes needs further study. 3.4. Synthesis of the Doubly Hydrophobic Block Copolymer Nanoassemblies of PMMA-b-PS. Hitherto, aqueous or alcoholic dispersion polymerization has been

nanoassemblies, in which DP of the core-forming PS block keeps almost a constant of 220 and whereas the PNIPAM block is different, are synthesized via PEG-PISA. It is found that the PNIPAM10-b-PS aggregates containing the shortest PNIPAM10 block cannot be uniformly dispersed in PEG400, since the PNIPAM10 block is too short to stabilize the PNIPAM10-b-PS aggregates in PEG400. For other four samples of PNIPAM-bPS containing a longer PNIPAM block, they can form stable colloids. As depicted in Figure 6, when DP of the PNIPAM

Figure 6. TEM images of the PNIPAM46-b-PS229 (A), PNIPAM34-bPS231 (B), and PNIPAM29-b-PS220 (C) nanoassemblies. TEM (D, E) and SEM (F) images of the PNIPAM18-b-PS215 nanoassemblies prepared via PEG-PISA in PEG400. Polymerization conditions: [monomer]0:[macro-RAFT]0:[initiator]0 = 300:1:1/3, 20 wt % solid content, 70 °C.

block decreases from 46 to 18, the 73 nm nanospheres of PNIPAM46-b-PS229 (Figure 6A), the nanospheres/vesicles mixture of PNIPAM34-b-PS231 (Figure 6B), the nanotubes− vesicles joints of PNIPAM29-b-PS220 (Figure 6C and Figure S7), and the nanotubes of PNIPAM46-b-PS215 (Figure 6D−F and Figure S8) are formed. Note: Figure 6E shows the TEM image of the PNIPAM46-b-PS215 nanotubes stained by phosphotungstic acid and RuO4 following the similar procedures as discussed elsewhere.67 These results clearly indicate successful synthesis of PNIPAM-b-PS nanotubes by PEG-PISA and also suggest a nanospheres-to-vesicles-to-nanotubes transition with the PNI-

Figure 7. TEM images of the PMMA120-b-PS294 (A), PMMA98-b-PS295 (B), PMMA79-b-PS293 (C), PMMA60-b-PS293 (D, H), PMMA60-b-PS49 (E), PMMA60-b-PS148 (F), and PMMA60-b-PS225 (G) nanoassemblies synthesized via PEG-PISA in PEG400. Polymerization conditions: [monomer]0: [macro-RAFT]0:[initiator]0 = 50−300:1:1/3, 20 wt % solid content, 70 °C, 24 h. G

DOI: 10.1021/acs.macromol.6b00688 Macromolecules XXXX, XXX, XXX−XXX

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Macromolecules proven to be an effective way to synthesize amphiphilic diblock copolymer nanoassemblies,4−9,11−50 although very rare examples of doubly hydrophobic diblock copolymer nanoassemblies such as poly(2-hydroxypropyl methacrylate-block-benzyl methacrylate) have been synthesized.10 This is certainly due to the macro-RAFT agents used in aqueous or alcoholic dispersion RAFT polymerization being generally hydrophilic. As introduced above, PMMA-TTC can be molecularly dissolved in PEG400, which affords the precious chance to synthesize the doubly hydrophobic nanoassemblies of PMMA-b-PS via PEGPISA, which is beyond aqueous or alcoholic dispersion polymerization. Figure 7 depicts TEM images of PMMA-b-PS nanoassemblies synthesized via PEG-PISA in PEG400. Note: see Figure S9 for GPC traces of these PMMA-b-PS block copolymers. The TEM images demonstrate two cases of morphological evolutions, e.g., nanaospheres-to-worms-tospherical vesicles-to-ellipsoidal vesicles (Figure 7A−D) and worms-to-lamellae-spherical vesicles-to-ellipsoidal vesicles (Figure 7E−H), by decreasing DP of the PMMA block and increasing DP of the PS block, respectively. The morphological evolution of nanospheres-to-worms-to-vesicles of amphiphilic block copolymers during alcoholic or aqueous dispersion RAFT polymerization has been widely documented,6−11,17−21,34−42 and the reason is generally attributed to the extension of the solvophobic block changing the interfacial curvature of solvophilic/solvophobic blocks with proceeding of RAFT polymerization.3 Herein, the PMMA-b-PS morphological transition via PEG-PISA is deemed to follow the similar mechanism. We believe this PEG-PISA can afford a large range of doubly hydrophobic block copolymer nanoassemblies, which is ongoing in our lab.

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AUTHOR INFORMATION

Corresponding Author

*(W.Z.) E-mail [email protected], Tel 86-22-23509794, Fax 86-22-23503510. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the financial support by the National Science Foundation for Distinguished Young Scholars (No. 21525419), PCSIRT (IRT1257), and the National Science Foundation of China (Nos. 21274066 and 21474054).

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REFERENCES

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4. CONCLUSIONS In summary, a new PISA formulation of PEG-PISA via dispersion RAFT polymerization in PEG is introduced. This PEG-PISA employs PEG with its molecular weight ranging from 200 to 1000 Da as the polymerization medium for dispersion polymerization, which affords fast polymerization rate and synthesis of doubly hydrophobic and amphiphilic diblock copolymer nanoassemblies at polymer concentration up to 50%. Following this PEG-PISA, a large range of amphiphilic diblock copolymer nanoassemblies including mPEG113-b-PS, mPEG113-b-PtBA, PDEGMA-b-PS, PDMA-bPS, P4VP-b-PS, and PNIPAM-b-PS and the doubly hydrophobic diblock copolymer nanoassemblies of PMMA-b-PS have been prepared. Besides the general diblock copolymer nanoassemblies including nanospheres, lamellaes, worms, and vesicles, two new and/or interesting diblock copolymer morphologies of ellipsoidal vesicles and nanotubes have been prepared through PEG-PISA. The viscous PEG polymerization medium is ascribed to formation of the new and/or interesting diblock copolymer morphologies of ellipsoidal vesicles and nanotubes. It is supposed that PEG-PISA is a useful extension of PISA and will have promising application in preparation of well-defined block copolymer nanoassemblies.

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Experimental details and Figures S1−S9 (PDF)

ASSOCIATED CONTENT

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