Synthesis of Diblock Copolymer Nanoparticles via RAFT Alcoholic

Liam P. D. Ratcliffe , Claudie Couchon , Steven P. Armes , and Jos M. J. ..... Yiwen Pei , Kevin Jarrett , Martin Saunders , Peter J. Roth , Craig E. ...
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Synthesis of Diblock Copolymer Nanoparticles via RAFT Alcoholic Dispersion Polymerization: Effect of Block Copolymer Composition, Molecular Weight, Copolymer Concentration, and Solvent Type on the Final Particle Morphology Daniel Zehm,† Liam P. D. Ratcliffe, and Steven P. Armes* Dainton Building, Department of Chemistry, The University of Sheffield, Brook Hill, Sheffield, South Yorkshire S3 7HF, UK S Supporting Information *

ABSTRACT: Various poly(2-hydroxyethyl methacrylate-b-benzyl methacrylate) (PHEMAn−PBzMAm) and poly(2-hydroxypropyl methacrylate-b-benzyl methacrylate) (PHPMAn−PBzMAm) nanoobjects have been prepared via reversible addition−fragmentation chain transfer (RAFT) alcoholic dispersion polymerization. Using either a PHPMA or PHEMA macro-CTA as a steric stabilizer, chain extension with BzMA was conducted in methanol, ethanol, or isopropanol. In each case, in situ self-assembly is driven by the growing PBzMA chains, which become insoluble in lower alcohols above a certain critical chain length. Empirically, PHPMA macroCTA proved to be much more effective than PHEMA macro-CTA in such syntheses, since the former conferred higher colloidal stability in alcohol. By constructing two detailed phase diagrams, the final nanoparticle morphology is shown to be sensitive to the DP of the core-forming block (PBzMA), the total solids content, and also the mean DP of the stabilizer block (PHPMA). The latter effect is readily demonstrated for PHPMA macro-CTAs possessing mean DPs of 48 and 63. Using PHPMA48 as a steric stabilizer, a range of nano-objects (spheres, worms or vesicles) can be accessed simply by tuning the DP of the core-forming PBzMA block. In contrast, using the PHPMA63 stabilizer only produces spherical morphologies. Presumably this is because the latter confers more effective steric stabilization, which prevents the efficient fusion of spheres to form worms. Nevertheless the PHPMA63−PBzMAn formulation may still be useful, since it allows access to spherical nanoparticles with tunable mean diameters of 29−100 nm. Such phase diagrams are essential for the reproducible targeting of copolymer morphologies, since they enable mixed phase regions to be avoided and allow the predictable synthesis of pure spheres, worms, or vesicles at a given concentration. Finally, a block copolymer “jellyfish” was observed during these PISA syntheses, which suggests that such intermediates are most likely a generic feature of the in situ conversion of worms into vesicles.

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conventional free radical polymerization.27 In contrast, the formation of diblock copolymer nanoparticles, e.g., spherical micelles,28,29 worm-like micelles (worms),30−32 rod-like micelles,33−35 vesicles,36−45 nanotubes,46 toroids,47 etc., is typically only conducted in dilute solution (< 1% solids) in academic laboratories using microfluidic flow devices48,49 or processing techniques such as dialysis,42,50 a pH switch,41,51 or thin film rehydration52,53 in order to control the self-assembly process. However, there has been strong interest in applying the principle of “polymerization-induced self-assembly” (PISA) to CRP formulations in order to generate diblock copolymer nanoparticles in situ using either emulsion54−59 or dispersion60−71 polymerization formulations. This approach now provides robust synthetic routes for the preparation of pure spherical micelles, worms or vesicles at high concentrations in either water or alcohol. For example, Charleux et al. have

INTRODUCTION It is well known that block copolymers can self-assemble to form either sterically stabilized nanoparticles in selective solvents1−3 or nanostructured thin films in the solid state.4 Since the development of controlled radical polymerization (CRP) techniques such as nitroxide-mediated polymerization (NMP),5 atom transfer radical polymerization (ATRP),6,7 and reversible addition−fragmentation chain transfer (RAFT) polymerization,8,9 the synthesis of a wide range of f unctional block copolymers has been reported by many research groups.1,7,10−13 These new materials have been evaluated for various potential applications such as drug delivery,14 nanoscale templating of inorganic materials,15−18 antireflective coatings,19,20 nanoporous membranes,21,22 and nanolithography.23 CRP methods have also been applied to heterogeneous formulations such as emulsion,24−26 miniemulsion,25,26 microemulsion,25,26 and dispersion polymerization,26 which are important technologies for the preparation of near-monodisperse copolymer latexes. Latex particles can be easily produced on an industrial scale at high solid contents using © 2012 American Chemical Society

Received: July 13, 2012 Revised: November 26, 2012 Published: December 14, 2012 128

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articles describing the synthesis of spherical micelles, worms, or vesicles in alcohol using polystyrene as a core-forming block combined with various alcohol-soluble stabilizer blocks.62,68−70,79,80 However, careful inspection of this work reveals that only substantially incomplete monomer conversions (30−70%) were achieved, even after 48 h at 80 °C. Thus, such formulations are wholly unsuitable for industrial scale-up, since the removal of unreacted styrene monomer is both problematic and expensive. More recently, both our group and also Charleux and co-workers have reported that much higher monomer conversions can be achieved using an allmethacrylic formulation for RAFT alcoholic dispersion polymerization in which the core-forming block is based on benzyl methacrylate, rather than styrene.81−83 The French group used a statistical copolymer macro-CTA comprising methacrylic acid and oligo(ethylene glycol) monomethacrylate repeat units. In our study, we reported the use of four types of macro-CTAs with either nonionic, zwitterionic, anionic, or cationic character. In each case, the nanoparticles could be conveniently transferred from the alcoholic reaction solution into aqueous solution via dialysis without loss of colloidal stability. In the present work, we report the scalable synthesis of hydroxy-functionalized diblock copolymer nanoparticles via an all-methacrylic RAFT alcoholic dispersion polymerization protocol. More specifically, poly(2-hydroxyethyl methacrylateb-benzyl methacrylate) (PHEMAn−PBzMAm) and poly(2hydroxypropyl methacrylate-b-benzyl methacrylate) (PHPMAn−PBzMAm) nanoparticles are synthesized at relatively high monomer conversions in alcoholic solvents. The latter formulation is investigated in particular detail, with the influence of the following parameters on the final copolymer morphology being investigated: (i) the solvent selected for the dispersion polymerization, (ii) the total solids content used in these syntheses, (iii) the mean degree of polymerization of the core-forming PBzMA chains, and (iv) the mean degree of polymerization of the stabilizer macro-CTA. It is perhaps worth emphasizing here that, unlike the earlier RAFT aqueous dispersion polymerization formulations, PHPMA (and PHEMA) is utilized as a stabilizer block, rather than as a coreforming block. Moreover, neither stabilizer block is sufficiently hydrophilic to allow transfer of the resulting sterically stabilized “nano-objects” from alcohol into aqueous solution without causing colloidal instability.

developed efficient RAFT- and NMP-mediated aqueous emulsion polymerization protocols for the production of welldefined diblock copolymer micelles, worms or vesicles. Thus, various water-soluble homopolymer or statistical copolymer stabilizer precursors can be chain-extended with either styrene or methyl methacrylate54,56−59 or n-butyl acrylate55 to form a second structure-directing insoluble block. The hydrophilic/ hydrophobic balance of the targeted block copolymer dictates the copolymer curvature,72,73 which in turn controls the final copolymer morphology of the sterically stabilized “nanoobjects”. In principle, dispersion polymerization offers a conceptually simpler formulation than emulsion polymerization, since the monomer, initiator, and (co)polymer stabilizer are all molecularly dissolved in the initially homogeneous reaction solution. Once a critical degree of polymerization is reached, the core-forming chains become insoluble while the stabilizer chains prevent particle precipitation. This mechanism applies to both conventional free radical chemistry,74 where stabilizer grafting occurs,75 and also RAFT chemistry, which leads to the formation of diblock copolymers.76−78 In the latter case, spherical thermosensitive “nanogels” have been prepared via RAFT aqueous dispersion polymerization by taking advantage of the well-known LCST behavior of either poly(Nisopropylacrylamide) or poly(oligo(ethylene glycol) monoacrylate), either of which forms the insoluble core-forming block when synthesized in hot aqueous solution. However, the formation of worm-like or vesicular morphologies using such formulations has only recently been reported by us.60,61,64 This protocol involves chain extension of a water-soluble poly(glycerol methacrylate) (PGMA) macro-CTA using 2-hydroxypropyl methacrylate (HPMA). This monomer is water-miscible up to 10 % at the polymerization temperature of 70 °C and forms a water-insoluble core-forming block during its in situ polymerization. Very high HPMA conversions are obtained within 2 h at 70 °C, since monomer partitioning within the growing nanoparticles leads to a relatively high local concentration. If the dimethacrylate impurities typically found in commercial batches of HPMA are carefully removed, nearmonodisperse PGMA−PHPMA diblock copolymers (Mw/Mn < 1.20) can be obtained, as judged by DMF GPC.60 TEM studies revealed the formation of exclusively spherical micelles, worms, or vesicles for certain diblock copolymer compositions. Furthermore, a detailed kinetic study provided a much better mechanistic understanding of the nature of the worm-to-vesicle transition, with remarkable “octopi” and “jellyfish” intermediate nanostructures being observed.60 In a separate study, the PGMA macro-CTA was replaced by PMPC [where PMPC = poly(2-(methacryloyloxy)ethyl phosphorylcholine)], and a detailed phase diagram was established on the basis of post mortem TEM studies of the final diblock copolymer morphologies observed at high conversions.66,67 This systematic approach is essential to avoid the undesirable mixed phase regions and hence ensure reproducible syntheses of pure diblock copolymer spheres, worms or vesicles. More recently, this RAFT aqueous dispersion polymerization formulation was extended to include anionic polyelectrolyte-stabilized particles,65 but here it was found that the high charge density on the stabilizer chains strongly impedes diblock copolymer selfassembly in aqueous solution unless sufficient salt is added to screen the unfavorable electrostatic repulsive forces. Regarding RAFT nonaqueous dispersion polymerization formulations, Pan and co-workers have published a series of

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EXPERIMENTAL SECTION

Materials. 2-Hydroxyethyl methacrylate (HEMA), 2-hydroxypropyl methacrylate (HPMA), 4,4′-azobis(4-cyanopentanoic acid) (ACVA), and 2,2′-azobis(isobutyronitrile) (AIBN) were purchased from Sigma-Aldrich and were used as received. Benzyl methacrylate (BzMA; 96%, Aldrich) was passed through a basic alumina column to remove its inhibitor prior to polymerization. All solvents used for both polymerizations and subsequent purification were analytical grade and were used as received. The synthesis of 4-cyano-4-(2-phenylethane sulfanylthiocarbonyl)sulfanylpentanoic acid (PETTC) has been recently reported elsewhere.65 PETTC was selected for this study because it is well suited for the RAFT synthesis of controlled-structure methacrylic polymers. Moreover, it is easier to synthesize (and purify) than the commonly used dithiobenzoates, and it bears a phenyl group that serves as a convenient 1H NMR label for end-group analysis. Moreover, trithiocarbonates are less prone to hydrolysis, which can occur if the alcoholic solvent is not rigorously dried (as is the case in this study). 2-Phenylethanethiol was utilized rather than benzyl mercaptan because the latter is a good leaving group, which could cause problems during the RAFT polymerization.9,84 129

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Scheme 1. (a) Synthesis of PHPMAn−PBzMAm Block Copolymer Nanoparticles.a (b), an Increase of the PBzMA Block Length Leads to the Formation of Spherical Micelles, Cylindrical Micelles, and Vesicles

a The macro-CTA PHPMA are first synthesized by reversible addition−fragmentation chain transfer (RAFT) polymerization in ethanol at 65 °C, followed by a RAFT-mediated alcoholic dispersion polymerization at 65 °C.

Synthesis of Poly(2-hydroxyethyl methacrylate) [PHEMA] Macro-CTA. In a typical protocol, a mixture of HEMA (5.00 g, 38.42 mmol), PETTC (130.3 mg, 0.38 mmol; target DP = 100), ACVA (21.5 mg, 0.0768 mmol; CTA/ACVA molar ratio = 5.0), and anhydrous ethanol (10.0 mL) was purged with nitrogen, sealed, and placed in a preheated oil bath at 65 °C. After 5 h, the reaction was quenched by cooling to 20 °C, and an aliquot was withdrawn to determine the final conversion by 1H NMR analysis (58%). Finally, the crude mixture was precipitated twice into excess diethyl ether and dried under vacuum overnight to obtain 2.90 g of purified PHEMA62 macro-CTA. Based on the monomer conversion, the theoretical number-average molecular weight, Mn, should be 7500 g mol−1. DMF GPC studies (RI detector) indicated an Mn of 14 400 g mol−1 and an Mw/Mn of 1.17 (vs poly(methyl methacrylate) calibration standards). The mean degree of polymerization for this macro-CTA was calculated to be 62 (which corresponds to a Mn of 7800 g mol−1) by end-group analysis using 1H NMR spectroscopy (CD3OD). Thus, the integrated area of the five aromatic protons due to the RAFT chain end at 7.07− 7.24 ppm with those due to the two −COOCH2− protons of the HEMA residues at 3.9 ppm. 1H NMR (250 MHz, CD3OD): δH = 0.83 (br s, CH3), 0.99 (br s, CH3), 1.84 (br s, −CH2− backbone), 1.91 (br s, −CH2− backbone), 3.67 (br s, −CH2CH2OH), 3.93 (br s, −CH2CH2COO). Synthesis of Poly(2-hydroxypropyl methacrylate) [PHPMA] Macro-CTA. In a typical protocol, a mixture of HPMA (25.00 g, 0.173 mol), PETTC (735 mg, 2.16 mmol; target DP = 80), ACVA (121.5 mg, 0.433 mmol; CTA/ACVA molar ratio = 5.0), and anhydrous ethanol (50 mL) was purged with nitrogen, sealed, and placed in a preheated oil bath at 65 °C. After 3 h, the reaction was quenched by cooling to 20 °C, and an aliquot was withdrawn to determine the final conversion by 1H NMR analysis (38%). Finally, the crude mixture was precipitated twice into excess diethyl ether and dried under vacuum overnight to obtain ∼9.55 g of the purified PHPMA48 macro-CTA. Based on the NMR conversion, the theoretical Mn was 5300 g mol−1. DMF GPC (RI detector) gave a Mn of 10 400 g mol−1 and an Mw/Mn of 1.25 (vs poly(methyl methacrylate) calibration standards). Again, end-group analysis was used to calculate the mean degree of polymerization for this macro-CTA by comparing the integrated

aromatic protons due to the RAFT chain-end with those assigned to the two −COOCH2− protons due to the HPMA residues. This analysis gave a mean degree of polymerization of 48 (or a Mn of 7200 g mol−1), which suggests a CTA efficiency of ∼74% for this RAFT solution polymerization of HPMA. However, it is also possible that the precipitation protocol used to purify this macro-CTA may have led to some degree of fractionation (i.e., loss of lower molecular weight oligomers). 1H NMR (250 MHz, CD3OD): δH = 0.81 (br s, CH3), 0.98 (br s, CH3), 1.11 (br d, −CHCH3), 1.84 (br s, −CH2− backbone), 1.91 (br s, −CH 2 − backbone), 3.48 (br s, −COOCH2CH− minor isomer), 3.73 (br s, −COOCH2CH− major isomer), 3.89 (br s, −COOCH2− major isomer), 4.78 (br s, −COOCH2CH− minor isomer). [N.B. HPMA actually comprises ∼75% 2-hydroxypropyl methacrylate, with its minor isomer being 2hydroxyisopropyl methacrylate.85] The synthesis of the PHPMA63 macro-CTA (9.6 g yield) followed the same protocol except that the following reagent quantities were utilized: HPMA (21.15 g, 0.146 mol), PETTC (500 mg, 1.46 mmol; target DP = 100), ACVA (82.2 mg, 0.293 mmol; CTA/ACVA molar ratio = 5.0), and anhydrous ethanol (42 mL) were used. According to the conversion (45%), the theoretical Mn should be 7500 g mol−1, whereas THF GPC (RI detector) indicated an Mn of 13 000 g mol−1 and an Mw/Mn of 1.22 (vs poly(methyl methacrylate) calibration standards). 1H NMR (300 MHz, CD3OD) indicated a mean degree of polymerization of 63 for this macro-CTA, which corresponds to an Mn of 9400 g mol−1. This suggests a CTA efficiency of ∼80%. Diblock Copolymer Synthesis via Alcoholic Dispersion Polymerization. In a typical dispersion polymerization synthesis conducted at 20% w/w total solids targeting PHPMA48−PBzMA250, the protocol was as follows: PHPMA48 macro-CTA (150 mg, 20.6 μmol) was dissolved in anhydrous ethanol (4.24 g). To this solution, BzMA (910 mg, 5.16 mmol) and AIBN (1.13 mg, 6.88 μmol) were added, and this reaction mixture was purged with nitrogen, sealed, and placed in a preheated oil bath at 65 °C. To ensure a high final BzMA conversion, the reaction was conducted for 24 h at this temperature before quenching by exposure to air. 130

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Polymer Characterization. 1H NMR Spectroscopy. 1H NMR spectra were recorded using either a 250 MHz Bruker spectrometer in CD3OD (homopolymers) or d6-DMSO (diblock copolymers). Gel Permeation Chromatography (GPC). Molecular weight analysis was conducted by DMF GPC using two Polymer Laboratories PL gel 5 μm mixed C columns and one PL polar gel 5 μm guard column arranged in series and maintained at 60 °C, followed by a Varian 390 LC refractive index detector. The eluent contained 10 mM LiBr, and the flow rate was 1.0 mL min−1. A series of nearmonodisperse poly(methyl methacrylate) standards ranging from 625 to 618 000 g mol−1 (K = 2.094 × 10−3, α = 0.642)65 were used for calibration. Dynamic Light Scattering (DLS). Scattered light was detected at an angle of 173° (backscattering detection) using a Malvern Instruments Zetasizer Nanoseries instrument equipped with a 4 mW He−Ne laser operating at 633 nm, an avalanche photodiode detector with high quantum efficiency, and an ALV/LSE-5003 multiple τ digital correlator electronics system. Autocorrelation functions were analyzed using the CONTIN method. Transmission Electron Microscopy (TEM). TEM studies were conducted with a Philips CM 100 instrument operating at 100 kV. TEM samples were prepared as follows: 5 μL of a diluted dispersion (0.25% w/w) was dropped on a carbon-coated copper grid, dried for 1 min, stained using uranyl formate, and dried under ambient conditions.

10 g scale with high end-group fidelity. Indeed, 1H NMR and GPC analyses confirmed the synthesis of near-monodisperse PHEMA62 (see Table S1 and Figure S1 in the Supporting Information), PHPMA48 and PHPMA63 macro-CTAs (see Figure 1 and Tables S2, S4 and Figures S3, S9). Our initial

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RESULTS AND DISCUSSION The general synthetic strategy is outlined in Scheme 1 for the RAFT synthesis of a PHPMA macro-CTA and its subsequent chain extension using benzyl methacrylate (BzMA) under dispersion polymerization conditions in alcohol at 65 °C. Essentially the same protocol was utilized for the PHEMA macro-CTA. Since both PHPMA and PHEMA chains are soluble in alcohol, such formulations should in principle lead to colloidally stable diblock copolymer “nano-objects” via a steric stabilization mechanism.86 For a fixed stabilizer DP, increasing the DP of the core-forming block progressively reduces the copolymer curvature, which should favor the formation of higher order morphologies (i.e., worms or vesicles, as opposed to spheres).72,73 In this study, BzMA was selected instead of styrene for the core-forming block because (i) an all-methacrylic formulation should be better suited for the synthesis of high-quality diblock copolymers and (ii) the rate of BzMA polymerization was expected to be significantly faster than that of styrene, thus allowing high conversions to be achieved within relatively short reaction times. Moreover, the difference between the Hildebrand solubility parameters for methanol (δ = 29.7 [MPa]1/2), ethanol (δ = 26.2 [MPa]1/2), or isopropanol (δ = 23.8 [MPa]1/2), and that of PBzMA (δ = 15.3 [MPa]1/2) is greater than that between the same three solvents and polystyrene (δ = 19 [MPa]1/2).87 Thus, these alcohols are stronger nonsolvents for PBzMA than for polystyrene, which should lead to stronger segregation between the PHPMA (or PHEMA) stabilizer block and the core-forming PBzMA block and also less solvated PBzMA cores. This scenario should be contrasted with that for our previously reported PGMA− PHPMA (or PMPC−PHPMA) RAFT aqueous dispersion polymerization formulations, in which the PHPMA coreforming chains are only weakly hydrophobic.88,89 Choice of the Stabilizer Macro-CTA. Three macro-CTAs, namely PHEMA62, PHPMA48, and PHPMA63, were successfully prepared in ethanol at 65 °C. In each case, the polymerization was terminated at 40−60% conversion to ensure the production of well-defined macro-CTAs on approximately a

Figure 1. (a) DMF gel permeation chromatograms (calibrated using PMMA standards) obtained for PHPMA48 and a series of nine PHPMA48−PBzMAm diblock copolymers (where H denotes HPMA and B denotes BzMA), namely PHPMA48−PBzMA60, PHPMA48− PBzMA75, PHPMA48−PBzMA100, PHPMA48−PBzMA125, PHPMA48− PBzMA 1 5 0 , PHPMA 4 8 −PBzMA 1 7 5 , PHPMA 4 8 −PBzMA 2 0 0 , PHPMA48−PBzMA225, and PHPMA48−PBzMA250 synthesized via RAFT-mediated dispersion polymerization in ethanol at 65 °C and 15% w/w solids. (b) DMF gel permeation chromatograms (calibrated using PMMA standards) obtained for PHPMA 48 −PBzMA500, PHPMA48−PBzMA750, and PHPMA48−PBzMA1000 diblock copolymers and the corresponding PHPMA48 macro-CTA via RAFTmediated dispersion polymerization in ethanol at 65 °C and 15% w/ w solids.

attempts focused on the synthesis of PHEMAn−PBzMAm diblock copolymers. Thus we examined a PHEMA62 macroCTA for the in situ RAFT alcoholic dispersion polymerization of BzMA, while systematically increasing the mean target DP of the core-forming PBzMA chains. Ethanol was selected rather than methanol, since the former has a higher boiling point. The initially homogeneous mixture became increasingly turbid as the BzMA polymerization proceeded, indicating nucleation and in situ self-assembly of the growing diblock copolymer chains. However, such ethanolic formulations proved to be colloidally unstable: macroscopic phase separation invariably occurred 131

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Figure 2. Representative TEM images revealing the structural evolution of a series of six PHPMA48−PBzMAm(15) diblock copolymers synthesized via RAFT dispersion polymerization in ethanol (15% w/w solids), where the PBzMA block is systematically increased to PHPMA48−PBzMA75 (a), PHPMA48−PBzMA100 (b), PHPMA48−PBzMA125 (c), PHPMA48−PBzMA150 (d), PHPMA48−PBzMA200 (e), and PHPMA48−PBzMA225 (f).

53 800 g mol−1, Mw/Mn = 1.20), PHPMA48−PBzMA750, (Mn = 67 900 g mol−1, Mw/Mn = 1.21), and even PHPMA48− PBzMA1000 (Mn = 92 400 g mol−1, Mw/Mn = 1.26) were obtained with good control over the molecular weight distribution in each case (see Figure 1b). The growing PBzMA chains are initially soluble in the continuous phase, but once nucleation occurs to form PBzMA-core micelles in situ, it is likely that the unreacted BzMA monomer enters the micelles and solubilizes the PBzMA chains, leading to a relatively high local monomer concentration.81,82 In the RAFT aqueous dispersion polymerization formulation previously reported by us,60,64 the HPMA monomer used to generate the core-forming block is typically contaminated with a low level ( 100). Conversely, spherical nanoparticles prepared using a relatively long stabilizer block may become kinetically trapped due to the reduced mobility of the core-forming chains. An additional consideration here is that a longer stabilizer block should confer more effective steric stabilization than a shorter block. This is likely to prevent the 1D fusion of spheres to form worms and hence lead to kinetically trapped spheres comprising molecularly frustrated copolymer chains. Similarly, it is clear that PISA syntheses conducted at lower concentrations are more likely to produce only spheres since the interparticle collision frequency during such polymerizations will be lower than that at higher concentrations. Conversely, the higher order copolymer morphologies predicted on the basis of a change in the molecular packing parameter are likely to be thermodynamically stable structures. Thus these phase diagrams comprise both kinetically trapped and equilibrium copolymer morphologies and hence differ significantly from traditional phase diagrams constructed for block copolymers. Whether the lack of morphological complexity within the phase diagram shown in Figure 6 is viewed as a problem or a

for the core-forming block (from 200 to at least 250), it seems unlikely to be simply due to a polydispersity effect, as previously suggested.96 This observation serves to illustrate our incomplete understanding of such PISA formulations and clearly warrants further study. Very recently, Blanazs et al. found that the phase diagrams obtained for a RAFT aqueous dispersion polymerization formulation are also sensitive to the DP of the stabilizer block, with broadly similar results.96 DLS studies of selected spherical nanoparticles also provided some interesting insights. Thus the intensity-average diameters of PHPMA 63 − PBzMA100(15) and PHPMA48−PBzMA75(15), which contain the same mole f raction of PBzMA, were 34 and 43 nm, respectively. At first sight this appears to be counterintuitive, since, for a given stabilizer block DP, the longer core-forming block should favor a higher aggregation number (and hence larger size), while the longer stabilizer chains of the same diblock should ensure a thicker coronal shell. However, these apparently conflicting data can be rationalized if it is assumed that the shorter core-forming block leads to a higher degree of core solvation. Thus, the PHPMA63−PBzMA100 spheres have relatively compact nonsolvated cores, while the PHPMA48− PBzMA75 diblock forms nanoparticles with somewhat more mobile core-forming chains due to solvent plasticization. Such 135

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Figure 6. Phase diagram for PHPMA63−PBzMAm(Y) diblock copolymer nano-objects prepared in ethanol at 65 °C. Structural evolution was achieved by systematic variation of (i) the mean target degree of polymerization (DP) of the PBzMA block (m) and (ii) the total solids concentration (Y). TEM images for representative morphologies: the nanoparticles of (a) PHPMA63−PBzMA75(10) (spheres), and (b) PHPMA63− PBzMA250(10) (spheres) were prepared at identical copolymer concentration, i.e., at 10% w/w solids. (c) PHPMA63−PBzMA250(15) (spheres), (d) PHPMA63−PBzMA250(20) (spheres), (e) PHPMA63−PBzMA250(25) (vesicles), and (f) PHPMA63−PBzMA250(30) (vesicles) are identical diblock copolymers synthesized at different copolymer concentration. (g) PHPMA63−PBzMA125(30) (worms) and (h) PHPMA63−PBzMA75(30) (worms) are diblock copolymers prepared under identical conditions used for image (f), i.e., at 30% w/w solids.

Figure 7. (a) DLS size distributions obtained for a series of PHPMA63−PBzMAm(10) dispersions (where H denotes HPMA and B denotes BzMA) synthesized at 10% w/w solids. For the sake of clarity, the hydrodynamic diameter (Dh) and polydispersity index (in parentheses) are only quoted for selected samples (see Table S4 for a more comprehensive summary). (b) Relationship between the mean TEM core diameter (Dc) and DP of PBzMA for the series of PHPMA63−PBzMAm(10) and PHPMA63−PBzMAm(15) formulations. The Dc values were obtained by measuring 20 nanoparticles and applying a power law of the form d = kNα. This analysis leads to an approximate scaling exponent, α, of 0.58 for spheres synthesized at 10% and 15% w/w solids.

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work for a RAFT alcoholic dispersion polymerization formulation suggests that they have generic significance, rather than being merely an unusual feature of a specific formulation.

practical opportunity for the precise size-controlled synthesis of spherical nanoparticles depends on which morphology is of most interest. For example, spherical nanoparticles are solely obtained for the PHPMA63−PBzMAm(10) and PHPMA63− PBzMAm(15) formulations, which allows systematic variation of the mean spherical diameter from around 29 nm (m = 75) to 100 nm (m = 1000) with essentially zero concentration dependence (see Figure 7 and also Table S4). This point is further illustrated in Figure 7b, since the core diameters of the spherical nanoparticles prepared at Y = 10% w/w and Y = 15% w/w exhibit relatively little scatter. By fitting a power law of the form d = kNα, the core diameter, d, can be related to the mean DP (or N) of the core-forming PBzMA block by a scaling exponent, α, of ∼0.58 for spherical nanoparticles prepared at either 10 or 15% w/w solids. This value is somewhat lower than that expected on the basis of the strong segregation theory for diblock copolymers,28 which suggests that the core-forming PBzMA chains are only partially stretched within these nanoobjects. However, this interpretation should be treated with some caution, since the core diameters were estimated by analyzing a relatively small number of spheres and hence may not be statistically robust. Finally, it is noteworthy that we have also observed some block copolymer “jellyfish” during these PISA syntheses; see TEM image shown in Figure 8. These nano-structures are a

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CONCLUSIONS In summary, a convenient polymerization-induced selfassembly (PISA) protocol was developed for the reproducible and predictable synthesis of various hydroxy-functionalized block copolymer nanoparticles. More specifically, either a PHPMA or PHEMA macro-CTA was chain-extended with BzMA via RAFT alcoholic dispersion polymerization in either ethanol or isopropanol. In both solvents, the in situ selfassembly is driven by the growing PBzMA chains which become increasingly solvatophobic and hence insoluble. The gradual reduction in the molecular curvature of the diblock copolymer chains leads to the formation of spheres, worms or vesicles, with essentially no concentration dependence being observed. Empirically, it was found that PHPMA was preferred to PHEMA as a macro-CTA in such syntheses, since the former macro-CTA conferred much better colloidal stability in alcohol. Furthermore, two detailed phase diagrams were elucidated which confirmed that the final diblock copolymer morphology is sensitive to the DP of the core-forming block, the total solids content, and also the mean DP of the stabilizer block. Such phase diagrams are essential for reproducible copolymer morphologies, since they enable the undesirable mixed phase regions to be avoided. While a full range of pure copolymer morphologies (spheres, worms, or vesicles) can be accessed with a relatively low DP macro-CTA, using a higher DP macro-CTA led to spherical nanoparticles becoming the predominant morphology. However, the latter formulation was also of considerable interest, since it allows access to a wide range of spherical nanoparticles with tunable mean diameters in the 29−100 nm range. Finally, block copolymer “jellyfish” were observed during these alcoholic PISA syntheses, similar to those reported elsewhere for aqueous PISA syntheses. This suggests that such transient nanostructures are important generic intermediates in the morphological evolution from block copolymer worms to vesicles.

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ASSOCIATED CONTENT

S Supporting Information *

Additional GPC, 1H NMR, and DLS data as well as representative TEM images for all of the diblock copolymers synthesized in this study. This material is available free of charge via the Internet at http://pubs.acs.org.

Figure 8. Transmission electron micrograph of a “jellyfish” formed by a PHPMA63−PBzMA200(30). This remarkable nanostructure is believed to be a key intermediate in the evolution of worms into vesicles. Such “jellyfish” have been recently reported for related RAFT aqueous dispersion polymerizations (see ref 60). Their observation in the present nonaqueous formulation suggests that they are generic intermediates, rather than merely an esoteric artefact of a specific RAFT formulation. In this particular case, the “jellyfish” are observed as a minor species at almost full conversion within a mixed phase comprising mainly spheres, worms, and vesicles.

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AUTHOR INFORMATION

Corresponding Author

*E-mail s.p.armes@sheffield.ac.uk. Present Address †

Fraunhofer-Institut für Angewandte Polymerforschung IAP, Geiselbergstr. 69, D-14476 Potsdam-Golm, Germany.

Notes

minority species observed at the end of the synthesis of PHPMA63−PBzMA200 at 30% w/w solids, which produces a mixed phase of spheres, worms, and vesicles. They are strikingly similar to the “jellyfish” reported earlier by Blanazs et al. during in situ studies of the morphological evolution for a RAFT aqueous dispersion polymerization formulation.60 Such intermediate morphologies are believed to shed new light on the worm-to-vesicle mechanism. Their observation in the current

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS S.P.A. thanks the University of Sheffield and the EPSRC for a KTA post-doc grant to support D.Z. Scott Bader (UK) is also thanked for support of a PhD studentship for one of the coauthors (L.P.D.R.). 137

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