Narrow or Monodisperse, Physically Cross-Linked, and “Living

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Narrow or Monodisperse, Physically Cross-Linked, and “Living” Spherical Polymer Particles by One-Stage RAFT Precipitation Polymerization Congguang Zheng, Yan Zhou, Yanpeng Jiao, and Huiqi Zhang*

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State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Functional Polymer Materials (Ministry of Education), Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), and College of Chemistry, Nankai University, Tianjin 300071, P. R. China S Supporting Information *

ABSTRACT: Controlled preparation of narrow or monodisperse, physically cross-linked, and “living” spherical polymer particles by one-stage reversible addition−fragmentation chain transfer (RAFT) precipitation polymerization (RAFTPP) is described for the first time. The introduction of RAFT polymerization mechanism into precipitation polymerization system, together with the use of methacrylic acid (MAA) (capable of forming hydrogen bonding) as the monomer, allows ready generation of uniform spherical poly(MAA) (PMAA) particles with surface-bound “living” dithioester groups, easily tunable sizes, and low molecular weights in the absence of any cross-linking monomer. The polymerization parameters (i.e., monomer loading, molar ratio of the RAFT agent to free radical initiator, and polymerization temperature) showed much influence on the morphologies and yields of PMAA particles, and their simple adjustment allows fine-tuning of “living” PMAA particle sizes. The presence of dithioester groups on such PMAA particles was confirmed not only by their light pink color and characteristic UV−vis absorbance peak of dithioester units but also by their capability of directly grafting cross-linked apolar polymer shells. Some uniform “living” PMAA-based functional copolymer microspheres were also prepared in a one-stage process by simply incorporating glycidyl methacrylate, 2-hydroxyethyl methacrylate, or a fluorescent monomer into the RAFTPP of MAA, demonstrating the high versatility and general applicability of the RAFTPP system. The polymerization of MAA in RAFTPP proved to occur both in the continuous phase and on PMAA particle surfaces instead of inside particles, and a combined “grafting from” and “grafting to” particle growth mechanism is proposed for RAFTPP.

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INTRODUCTION Recent years have witnessed considerable interest in the development of uniform polymer micro- or nanospheres because of their great potential in many applications such as sample separation, bioanalyses, and various biomedical uses.1−5 So far, some effective approaches have been developed for preparing such uniform spherical polymer particles, including emulsion polymerization, dispersion polymerization, and precipitation polymerization. Among them, precipitation polymerization is particularly attractive because of its simple performance, high compatibility with functional monomers, easy tuning of particle sizes, and no need for any surfactant.2,3 Since the early 1990s, precipitation polymerization has been rapidly developed into a facile and efficient approach to obtaining uniform spherical polymer micro- or nanoparticles.3,6 It starts from a diluted homogeneous system, where all the monomers and initiators are soluble in the solvents. After the polymerization system is initiated, soluble oligomers are first generated in the solution. Their molecular weights quickly increase to such an extent that the resulting polymers are beyond their solubility limit in the reaction medium and © XXXX American Chemical Society

precipitate out of the continuous phase, leading to the formation of particle nuclei. Subsequently, the particle growth process begins, which mainly involves the capture of oligomeric radicals from the reaction medium by their reacting with the residual vinyl groups on the surfaces of the existing particles and some surface-initiated free radical polymerization of monomers by the above-formed surface-bound free radicals (note that all radicals in the traditional precipitation polymerization system become quickly dead because of the occurrence of significant radical−radical termination). It has been well demonstrated that the presence of a divinyl cross-linking monomer is typically required for the preparation of uniform spherical polymer particles by precipitation polymerization (which plays an important role in the growth of the polymer particles), and its molar ratio to monovinyl monomer has a significant influence on the morphologies of the resulting polymer particles.6−8 Received: September 20, 2018 Revised: December 7, 2018

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DOI: 10.1021/acs.macromol.8b02031 Macromolecules XXXX, XXX, XXX−XXX

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Macromolecules

(soluble), and “living” spherical polymer particles is thus highly desirable. Over the past few years, our group has developed some controlled/“living” radical precipitation polymerization (CRPP) approaches by introducing various CRP mechanism into precipitation polymerization system, including atom transfer radical precipitation polymerization (ATRPP),21,22 RAFT precipitation polymerization (RAFTPP),23,24 and iniferter-induced “living” radical precipitation polymerization (ILRPP).25 Although they have proven highly powerful for the one-pot preparation of narrow or monodisperse, highly crosslinked, and “living” polymer microspheres,3,4 their versatility for the one-pot and one-stage preparation of uniform, soluble, and “living” spherical polymer particles without chemically cross-linked networks has not been demonstrated yet. Herein, we report for the first time a versatile one-pot and one-stage polymerization strategy to obtaining narrow or monodisperse, physically cross-linked, and “living” spherical polymer particles via RAFTPP of MAA or a mixture of MAA and a functional comonomer (Scheme 1). The resulting

To date, several different types of precipitation polymerization techniques have been developed for preparing uniform polymer micro- or nanospheres, including thermo- or photoinitiated traditional precipitation polymerization, distillation precipitation polymerization, and controlled/“living” radical precipitation polymerization (CRPP).2 They have been mostly used for preparing chemically cross-linked uniform spherical polymer particles. By contrast, although easily soluble uniform spherical polymer particles without chemically cross-linked networks are highly promising sacrificial templates in fabricating various hollow polymer particles,2 the reports on their successful synthesis via the precipitation polymerization of monovinyl monomers have been rather limited, mainly because of the absence of vinyl groups on the surfaces of the resulting polymer nuclei in this case (which makes the particle growth difficult). Several research groups have reported the preparation of some uniform thermoresponsive polymer submicro- or nanoparticles via the precipitation polymerization of N-isopropylacrylamide (NIPAAm), but they are typically cross-linked microgels because of the occurrence of self-crosslinking during the polymerization process.9−11 Yang and coworkers reported the synthesis of narrowly dispersed spherical poly(methacrylic acid) (poly(MAA) or PMAA) particles with diameters ranging from 60 to 290 nm via distillation precipitation polymerization.12 The presence of hydrogenbonding interactions between the carboxylic acid groups proved to result in the formation of polymer particles with surface-adsorbed MAA molecules, which played a decisive role in the particle growth process. These uniform PMAA particles were capable of acting as sacrificial templates for fabricating hollow spherical particles with cross-linked polymer shells.13 However, some vinyl groups had to be introduced onto such PMAA particles to achieve this goal.12,13 Moreover, the uncontrolled characteristics of the traditional free radical polymerization involved in the distillation precipitation polymerization typically led to PMAA particles with high molecular weights and broad molecular weight distributions, which might have adverse influence on the efficient removal of such PMAA cores through the cross-linked polymer shells during the preparation of hollow polymer particles (e.g., a rather long etching time of 2 weeks was required in this case13). Furthermore, the controlled surface modification of the resulting PMAA particles in the above system (e.g., controlled grafting of polymer brushes with desired chain length and narrow molecular weight distributions) is also difficult due to the absence of “living” initiating or chaintransfer groups on their surfaces. Controlled/“living” radical polymerization techniques (CRPs) have proven highly versatile for preparing well-defined polymers with “living” end-groups under mild reaction conditions.14−16 In recent years, many efforts have also been devoted to the preparation of uniform, soluble, and “living” spherical polymer particles by using controlled/“living” heterogeneous radical polymerizations of monovinyl monomers.17−20 For example, the combination of CRPs (e.g., atom transfer radical polymerization (ATRP)18 and reversible addition−fragmentation chain transfer (RAFT) polymerization19,20) and dispersion polymerization was applied to prepare uniform, un-cross-linked (soluble), and “living” polymer microspheres, but a “two-stage” polymerization strategy had to be used to achieve uniform spherical homopolymer18,19 or copolymer20 particles. The development of new strategies for the one-stage preparation of such uniform, un-cross-linked

Scheme 1. Schematic Illustration for the Preparation of Narrow or Monodisperse, Physically Cross-Linked, and “Living” Spherical Polymer Particles via One-Pot and OneStage RAFTPP

polymer particles proved to have surface-bound “living” dithioester groups, uniform and easily tunable sizes (numberaverage diameters from 0.129 to 2.894 μm), varying compositions and functionality (e.g., fluorescence), and low molecular weights. The effects of some polymerization parameters (i.e., monomer loading, molar ratio of the RAFT agent to free radical initiator, and polymerization temperature) on the morphologies and yields of the PMAA particles were studied. In particular, the polymer particle formation mechanism was also elucidated. Such uniform, easily soluble, and “living” spherical polymer particles have proven to be highly promising sacrificial templates in the development of advanced functional hollow spherical polymer particles.

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EXPERIMENTAL SECTION

Materials. Methacrylic acid (MAA, Tianjin Jiangtian Chemicals, 99%) was purified by distillation under vacuum. Glycidyl methacrylate (GMA, Adamas Reagent, Ltd., 99%) was purified by passing through a neutral aluminum oxide column. 2-Hydroxyethyl methacrylate (HEMA, Creasyn Finechem (Tianjin) Co. Ltd., 98%) was purified according to the literature method.26 Divinylbenzene (DVB, Shanghai Aladdin Bio-Chem Technology Co. Ltd., 80%) was purified by passing it through a basic aluminum oxide column. Styrene (St, Tianjin Chemical Reagent Co. Ltd., analytical grade (AR)) was washed with an aqueous solution of sodium hydroxide (5%), dried over anhydrous magnesium sulfate, and then distilled under vacuum. Acetonitrile (Tianjin Chemical Reagent Co. Ltd., AR) was refluxed over calcium hydride and then distilled. Methanol (Tianjin Jiangtian B

DOI: 10.1021/acs.macromol.8b02031 Macromolecules XXXX, XXX, XXX−XXX

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Macromolecules Table 1. Synthesis and Characterization Data for the PMAA-Based Particles entrya

polym time (h)

MAA/CDB/AIBN (molar ratio)b

monomer loadingc (vol %)

temp (°C)

yield (%)

Dn,AFMd (μm)

Ud

1 2 3a 3b 3c 3d 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

24 24 24 24 24 24 24 12 24 24 24 24 24 24 24 24 6 12 18 36 48 24 6 6 24 12 12

1400/7/1 1400/7/1 1400/7/1 1400/7/1 1400/7/1 1400/7/1 1400/7/1 1400/7/1 1400/7/0.75 1400/7/1.25 1400/0/1 1400/2/1 1400/4/1 1400/7/1 1400/7/1 1400/7/1 1400/7/1 1400/7/1 1400/7/1 1400/7/1 1400/7/1 1400/2/1 1400/2/1 1400/1.5/1 1200/200/7/1 1000/400/7/1 1400/14/7/1

1 2 3 3 3 3 4 4 3 3 3 3 3 3 3 3 3 3 3 3 3 1 1 1 3 3 3

60 60 60 60 60 60 60 60 60 60 60 60 60 55 65 70 60 60 60 60 60 70 70 70 60 60 70

8 20 25 23 25 21 31 10 16 29 97 52 38 12 43 55 3 8 15 41 55 51 10 12 21 12 21

0.283 0.714 1.225 1.202 1.201 1.109

1.155 1.018 1.004 1.002 1.003 1.006

1.241 1.153 1.247 0.975 1.152 1.181 1.033 1.284 1.299 0.693 0.822 0.982 1.433 1.561 0.252 0.132 0.129 1.231 2.894 1.270

1.003 1.006 1.002 1.004 1.005 1.001 1.007 1.005 1.002 1.010 1.007 1.004 1.002 1.004 1.032 1.068 1.081 1.008 1.004 1.008

Dn,DLSe (μm)

PDIe

0.270 0.188 0.168

0.022 0.105 0.100

a

The solvent used in all the studied systems is acetonitrile, the volume of the solvent used in all the studied systems is 25 mL except the entry 3d (100 mL of acetonitrile was used), and the stirring rate of all the polymerization systems is 200 rpm; entries 3a, 3b, and 3c are the repetition experiments, and entry 3d is the upscaled experiment of entry 3a. bThe data listed in this column are the molar ratios of MAA to CDB to AIBN in entries 1−21 and those of MAA to the comonomer (GMA (entry 22), HEMA (entry 23), or AnHEMA (entry 24)) to CDB to AIBN in entries 22, 23, and 24, respectively. cThe volume percentage of the monomer(s) relative to the total reaction medium. dDn,AFM and U refer to the numberaverage diameters and polydispersity indices of the polymer particles determined by AFM. eDn,DLS and PDI refer to the hydrodynamic diameters and particle dispersion indices of the polymer nanoparticles determined by DLS in acetonitrile. Chemicals, AR) was distilled prior to use. Azobis(isobutyronitrile) (AIBN, Tianjin Guangfu Fine Chemical Research Institute, AR) was recrystallized from ethanol. Cumyl dithiobenzoate (CDB) was prepared according to a literature procedure.27 (2-Hydroxyethylanthrancene-9-carboxylate) methacrylate (AnHEMA) was prepared following our previously reported procedure.28 (Trimethylsilyl)diazomethane (Infinity Scientific (Beijing) Co. Ltd., 2.0 M in hexanes), anthracene-9-carboxylic acid (Beijing Ouhe technology Co. Ltd., 98%), thionyl chloride (Tianjin Damao Chemical Reagent Factory, AR), and all the other reagents were commercially available and used as received. Preparation of Physically Cross-Linked “Living” Spherical PMAA Particles by RAFTPP. The recipes for the RAFTPP of MAA are listed in Table 1 (entries 1−21). A typical procedure is presented as follows (entry 3a in Table 1): MAA (795 μL, 9.33 mmol), CDB (12.65 mg, 46.43 μmol), dried acetonitrile (25 mL), and AIBN (1.09 mg, 6.64 μmol) were added into a one-neck round-bottom flask (50 mL) successively. The resulting clear purple reaction mixture was purged with argon for 30 min in an ice−water bath, sealed, immersed into a thermostated oil bath at 60 °C, and then magnetically stirred (using an oval-shaped stir bar with a length of 2.0 cm, 200 rpm) for 24 h. The resulting polymer particles were collected by centrifugation and subsequently washed with acetonitrile thrice. After being dried at 40 °C under vacuum to a constant weight, a light pink powder was obtained in a yield of 25%. A series of other “living” spherical PMAA particles were also prepared similarly following the above procedure by changing the polymerization parameters including the monomer loading, molar

ratio of CDB to AIBN, polymerization temperature, and polymerization time, and the experimental results are summarized in Table 1 (entries 1−21). Two experiments with the totally same recipe as the entry 3a were also performed to check the reproducibility of the RAFTPP system (Table 1, entries 3b and 3c). In addition, another experiment with the same reactant composition as the entry 3a but with a larger scale (4 times) was also performed to test the scalability of the RAFTPP system (Table 1, entry 3d). Note that a one-neck round-bottom flask (250 mL) and an oval-shaped stir bar with a length of 3.0 cm were used in the larger scale experiment. Preparation of Physically Cross-Linked “Living” Poly(MAAco-GMA) Microspheres by RAFTPP. MAA (682 μL, 8.00 mmol), GMA (176 μL, 1.33 mmol), CDB (12.70 mg, 46.62 μmol), dried acetonitrile (25 mL), and AIBN (1.09 mg, 6.64 μmol) were added into a one-neck round-bottom flask (50 mL) successively. The resulting clear purple reaction mixture was purged with argon for 30 min in an ice−water bath, sealed, immersed into a thermostated oil bath at 60 °C, and then magnetically stirred for 24 h at a stirring rate of 200 rpm. The resulting polymer particles were collected by centrifugation and subsequently washed with acetonitrile thrice. After being dried at 40 °C under vacuum to a constant weight, a light pink powder was obtained in a yield of 21% (Table 1, entry 22). Preparation of Physically Cross-Linked “Living” Poly(MAAco-HEMA) Microspheres by RAFTPP. MAA (568 μL, 6.67 mmol), HEMA (325 μL, 2.67 mmol), CDB (12.66 mg, 46.47 μmol), dried acetonitrile (25 mL), and AIBN (1.09 mg, 6.64 μmol) were added into a one-neck round-bottom flask (50 mL) successively. The C

DOI: 10.1021/acs.macromol.8b02031 Macromolecules XXXX, XXX, XXX−XXX

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Macromolecules resulting clear purple reaction mixture was purged with argon for 30 min in an ice−water bath, sealed, immersed into a thermostated oil bath at 60 °C, and then magnetically stirred for 12 h at a stirring rate of 200 rpm. The resulting polymer particles were collected by centrifugation and subsequently washed with acetonitrile thrice. After being dried at 40 °C under vacuum to a constant weight, a light pink powder was obtained in a yield of 12% (Table 1, entry 23). Preparation of Physically Cross-Linked “Living” Fluorescent Poly(MAA-co-AnHEMA) Microspheres by RAFTPP. MAA (795 μL, 9.33 mmol), AnHEMA (30.83 mg, 92.30 μmol), CDB (12.67 mg, 46.51 μmol), dried acetonitrile (25 mL), and AIBN (1.09 mg, 6.64 μmol) were added into a one-neck round-bottom flask (50 mL) successively. The resulting clear purple reaction mixture was purged with argon for 30 min in an ice−water bath, sealed, immersed into a thermostated oil bath at 70 °C, and then magnetically stirred for 12 h at a stirring rate of 200 rpm. The resulting polymer particles were collected by centrifugation and subsequently washed with acetonitrile thrice. After being dried at 40 °C under vacuum to a constant weight, a light pink powder was obtained in a yield of 21% (Table 1, entry 24). Preparation of Core−Shell-Structured Polymer Microspheres with a PMAA Core and a Poly(DVB) or Poly(DVB-coSt) Shell (i.e., PMAA@Poly(DVB) or PMAA@Poly(DVB-co-St)). The core−shell-structured polymer microspheres were prepared via the surface-initiated RAFT polymerization with the “living” PMAA particles as the seeds. A detailed procedure for the grafting of a poly(DVB) layer onto the “living” PMAA particles is presented as follows: To a one-neck round-bottom flask (50 mL), “living” PMAA particles (30 mg, Table 1, entry 3d), dried acetonitrile (30 mL), DVB (58.50 mg, 0.45 mmol), and AIBN (0.21 mg, 1.28 μmol) were added successively. After the reaction mixture was degassed by bubbling argon for 30 min in an ice−water bath, the polymerization was performed at 60 °C for 2 h and then at 70 °C for 24 h under magnetic stirring (400 rpm). After centrifugation, the resulting solid product was washed with acetonitrile thrice and then dried at 40 °C under vacuum to a constant weight. A weight increase of 27% was observed for the resulting PMAA@Poly(DVB) particles in comparison with the starting PMAA particles. The grafting of a poly(DVB-co-St) layer onto the “living” PMAA particles was also implemented following the above polymerization procedure, except that St (46.87 mg, 0.45 mmol) was also added into the above reaction system together with DVB in the same time. A weight increase of 32% was observed for the resulting PMAA@ Poly(DVB-co-St) particles in comparison with the starting PMAA particles. Preparation of Hollow Polymer Microspheres by Etching the PMAA Core from Core−Shell-Structured PMAA@Poly(DVB) and PMAA@Poly(DVB-co-St) Particles. The core−shellstructured polymer particles (10 mg) were added into methanol (3 mL), and the dispersed mixtures were ultrasonically treated for 5 min. The centrifugation of the above dispersed mixtures led to solid products, which were further etched under the same conditions (i.e., they were redispersed into methanol (3 mL) and treated with ultrasonication for 5 min) twice, and then dried at 40 °C under vacuum to a constant weight. 99% and 98% of PMAA cores were removed from PMAA@Poly(DVB) and PMAA@Poly(DVB-co-St) particles, respectively, on the basis of the weight reduction of the resulting hollow polymer particles. Characterization. 1H NMR spectra were recorded on a Bruker Avance III 400 MHz NMR spectrometer. A NTEGRA (NT-MDT, Russia) atomic force microscope (AFM) was used to characterize the morphologies (including the particle shape, size, and size distribution index) of the polymer particles. The AFM tips are high-resolution noncontact “GOLDEN” silicon AFM probes (NSG01 series) with a 6 nm typical tip curvature radius. The samples were dispersed in an appropriate solvent (acetonitrile for solid particles and methanol for hollow particles) (5 mg/mL) and dropped onto freshly cleaned micas. After evaporation of the solvent in dry air, the topographic images were acquired by the tapping measurement mode of the AFM. The diameters of the polymer

particles were evaluated from their AFM height profiles. All of the AFM size data reflected the averages of more than 100 particles, which were calculated by using the following formulas:7,21 k

Dn =

k

∑ niDi /∑ ni ; i=1

i=1

k

Dw =

k

∑ niDi 4 /∑ niDi 3; i=1

U = Dw /Dn

i=1

where Dn (or Dn,AFM) is the number-average diameter, Dw the weightaverage diameter, U the size distribution index, k the total number of the measured particles, Di the particle diameter of the ith polymer particle, and ni the number of polymer particles with a diameter Di. The hydrodynamic diameters and particle dispersion indexes (PDIs) of the polymer nanoparticles (Table 1, entries 19−21) were determined with a dynamic light scattering (DLS) spectrometer (Zetasizer Nano S90 from Malvern Instruments Corporation, UK). The scattered light of a vertically polarized He−Ne laser (633 nm, 10 mW) was measured at an angle of 90° at 20 °C. The polymer particles were first dispersed in acetonitrile (0.05 mg/mL) by an ultrasonic device for 30 min prior to their DLS characterization. Fourier transform infrared (FT-IR) spectra of the polymer particles were recorded on a Bruker Alpha FT-IR spectrometer by using the attenuated total reflectance (ATR) method. The fluorescence microscopy image of the fluorescent poly(MAAco-AnHEMA) microspheres was obtained by using a Nikon Eclipse Ts2-FL inverted fluorescent microscope equipped with a Nikon DSFi3 microscope camera and a 385 nm LED lamp (C-LEDLH385 LED unit) as an excitation light source. A UV−vis scanning spectrophotometer (TU1900, Beijing Purkinje General Instrument Co. Ltd.) was utilized to obtain the UV−vis spectra of the studied sample solutions at 25 °C and to determine the concentrations of CTAs in the continuous phase of the RAFTPP system. An HPLC (Scientific System Inc., USA) equipped with a UV−vis detector and two Ameritech Accurasil C18 columns (250 mm × 4.6 mm, 0.5 μm) was used to determine the AIBN concentrations in the continuous phase of the RAFTPP system. The detailed procedures for quantifying the concentrations of CTAs and AIBN are described in the Supporting Information. The molecular weights and molar mass dispersities (Đ) of PMAA particles were characterized with a Waters gel permeation chromatograph (GPC) equipped with a Waters 717plus autosampler, a Waters 515 HPLC pump, a set of three Waters UltraStyragel columns (HT2, HT3, and HT4; 30 cm × 7.8 mm; 10 μm particles; exclusion limits: 100−10000, 500−30000, and 5000−600000 g/mol, respectively) (the column oven temperature was 35 °C), and a Waters 2414 refractive index detector. Tetrahydrofuran (THF) was used as the mobile phase at a flow rate of 1.0 mL/min, and the calibration curve was obtained by using polystyrene standards. Note that since PMAA has low solubility in THF, the studied PMAAs were esterified with (trimethylsilyl)diazomethane to make them soluble in THF prior to GPC measurements, following a literature method (100% of methylation was achieved for PMAAs, as revealed by 1H NMR characterization of the esterified PMAAs; figures not shown).29

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RESULTS AND DISCUSSION It has been well established that surface-initiated “living” radical polymerization techniques are highly powerful for the controlled surface functionalization of a wide range of different substrates by the facile surface-grafting of well-defined crosslinked polymer layers or functional polymer brushes.3,4,30 In addition, physically cross-linked uniform polymer beads have proven to be promising sacrificial templates for fabricating hollow spherical polymer particles.2,13 The development of facile and versatile approaches for the direct preparation of uniform, physically cross-linked, and “living” polymer micro- or nanospheres with surface-bound chain transfer moieties (e.g., dithioester groups) would thus pave the way for their broad applications in many fields such as materials science and D

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obtained at a monomer loading of 1% under the studied condition, which might be attributed to their generation in the early stage of the particle growth, as normally observed in many traditional precipitation polymerization systems.31−33 The second nucleation was found to take place in the RAFTPP system at a monomer loading of 4%, as indicated by the formation of PMAA particles with most of them having uniform larger sizes and some with smaller sizes (Figure S1d). Nevertheless, uniform PMAA particles were obtained at a monomer loading of 4% by shortening the polymerization time to 12 h (Table 1, entry 5, and Figure S1e). A similar phenomenon was also observed previously in other “living” precipitation polymerization systems at higher monomer loadings.25 Both the sizes and yields of the polymer particles increased with increasing the monomer loadings (Table 1, entries 1−3), just as observed in the traditional precipitation polymerization systems.6,7 For example, the Dn values of the polymer microspheres increased from 0.283 μm for a monomer loading of 1 vol % (Table 1, entry 1) to 1.225 μm for a monomer loading of 3 vol % (Table 1, entry 3a), and the yields of the corresponding polymer microspheres increased from 8 to 25% in the meantime. Note that our RAFTPP system could readily provide uniform, easily soluble, and “living” polymer particles in a one-pot and one-stage process, which is quite different from some previously reported “living” dispersion polymerization systems.18,19 All the above-obtained spherical PMAA particles were found to have surface-bound “living” dithioester groups, as revealed by their light pink color (Figure 2-a2), which is in sharp contrast to the white spherical PMAA particles prepared via the traditional precipitation polymerization (in the absence of CDB) (Figure 2-a3 and Figure S2f). This was also confirmed by their UV−vis characterization results (Figure 2-b2), where a solution of PMAA particles obtained via RAFTPP showed a strong absorption peak around 300 nm in its UV−vis spectrum (Figure 2-b2) (which is similar to that of the CDB solution (Figure 2-b1)), whereas no absorption peak was observed around 300 nm for the solution of PMAA particles prepared via the traditional precipitation polymerization (Figure 2-b3). Such “living” spherical PMAA particles proved to be easily soluble in many common solvents such as water, methanol, ethanol, N,N-dimethylformamide, and dimethyl sulfoxide (DMSO), which makes them promising sacrificial templates for fabricating hollow polymer particles, as demonstrated in the following “PMAA Particle Formation Mechanism” section. Effect of the Molar Ratio of CDB to AIBN. It has been demonstrated that the molar ratio of the chain transfer agent to free radical initiator has a significant influence on the polymerization rate of the RAFT polymerization and its controllability.34 The effects of the molar ratios of CDB to AIBN on the morphologies and yields of the PMAA particles prepared via RAFTPP were also studied (Table 1, entries 3a, 6, 7, 9, and 10). For this purpose, two types of RAFTPP experiments were designed by changing either the AIBN or CDB concentration in the polymerization system. A series of RAFTPP experiments were first performed by only changing their AIBN concentration with the other polymerization parameters being remained constant (Table 1, entries 3a, 6, and 7). Uniform spherical PMAA particles with smooth surfaces were obtained in all the studied AIBN concentrations (Figure 1b and Figure S2a−c), and their sizes increased with an increase in the initiator concentration (Table 1). According to Horák and co-workers,35 increasing the

biomedical areas. In the following study, RAFTPP of MAA was utilized to prepare uniform, physically cross-linked, and “living” polymer micro- or nanospheres in a one-pot and one-stage process. The effects of some polymerization parameters including the monomer loading, molar ratio of the chain transfer agent (CDB) to free radical initiator (AIBN), and polymerization temperature on the morphologies (including the particle shape, size, and size distribution index) and yields of the resulting PMAA particles were studied. In addition, the high versatility and general applicability of the RAFTPP were also demonstrated by the successful one-stage preparation of narrowly dispersed “living” spherical PMAA particles with smaller sizes down to Dn = 129 nm and some “living” PMAAbased functional copolymer microspheres. Furthermore, the PMAA particle formation mechanism of the RAFTPP system was also elucidated. Effects of Polymerization Parameters on the Morphologies and Yields of the Resulting PMAA Particles. Effect of the Monomer Loading. The monomer loading has proven to have a significant influence on the morphologies and yields of the resulting polymer particles in precipitation polymerizations systems, and uniform spherical polymer particles could be obtained only in a suitable range of monomer loadings.6,7,21,22,25 A series of RAFTPPs of MAA were thus performed at different monomer concentrations in the reaction media with the other polymerization parameters (including the stirring rate (200 rpm), reactant composition (the molar ratio of MAA to CDB to AIBN is 1400/7/1), polymerization temperature (60 °C), and polymerization time (24 h)) being held constant (Table 1, entries 1−5) to study the effect of the monomer loading on the morphologies and yields of the resulting polymer particles. AFM characterization revealed the successful generation of narrow or monodisperse PMAA microspheres with smooth surfaces when the monomer loadings were 2% and 3% (relative to the total reaction medium) (Figure 1a and Figure S1), whereas PMAA particles with relatively polydisperse characteristics were obtained at a monomer loading of 1 and 4% (Figure S1). PMAA particles with a rather small size (Dn = 0.283 μm), relatively larger polydispersity index (U = 1.155), and low yield (8%) were

Figure 1. AFM height images of the representative “living” PMAA particles prepared via RAFTPP of MAA (samples a, b, c, and d correspond to entries 3a, 7, 9, and 13 in Table 1, respectively). E

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Macromolecules

Figure 2. (a) Photograph of CDB (a1), the representative “living” PMAA particles prepared via RAFTPP (a2, Table 1, entry 3d), and PMAA particles prepared via traditional precipitation polymerization in the absence of CDB (a3, Table 1, entry 8). (b) UV−vis spectra of the CDB solution in methanol (b1, 0.1 mg/mL), the solution of the “living” PMAA particles (prepared via RAFTPP; b2, Table 1, entry 3d) in methanol (1.5 mg/mL), and the solution of PMAA particles (prepared via traditional precipitation polymerization; b3, Table 1, entry 8) in methanol (1.5 mg/ mL).

PMAA particles. An increase in the polymerization temperature was found to result in enhanced polymerization rates (Table 1, entries 3a and 11−13), as indicated by the increased polymer yields from 12% to 55% with an increase in the polymerization temperature from 55 to 70 °C. Uniform PMAA microspheres with smooth surfaces and a light pink color were readily obtained within the studied polymerization temperature range (Figure 1d and Figure S3). The Dn values of the resulting polymer microspheres increased from 1.033 to 1.299 μm with an increase in the polymerization temperature from 55 to 70 °C, which might be attributed to the increased solvency of the continuous phase for the oligomeric polymer chains with increasing the polymerization temperature, thus leading to fewer particle nuclei in the RAFTPP system and consequently larger particle sizes.21,36 On the basis of the above studies, we can reach a conclusion that the polymerization parameters have much influence on the morphologies and yields of the resulting “living” PMAA particles, and the sizes of PMAA particles could be easily adjusted by fine-tuning the polymerization parameters. To confirm the reliability of the above conclusions, we also performed repetition experiments for the entry 3a in Table 1. The results presented in Table 1 (entries 3a−3c) and Figure S4a−c clearly showed very good reproducibility of the RAFTPP system. In addition, uniform “living” spherical PMAA particles were also readily generated in a larger scale polymerization system (4 times) (Table 1, entry 3d, and Figure S4d), demonstrating the scalability of the RAFTPP of MAA. Somewhat smaller particle sizes were observed for the resulting uniform “living” PMAA particles in the larger scale polymerization. This might be caused by their different sizes of the reaction flasks and the magnetic stir bars used, which might influence the agitation situation for different reactions, thus leading to their different particle sizes. A similar phenomenon was also observed in our previously reported ATRPP system.21 Preparation of Narrowly Dispersed, Physically CrossLinked, and “Living” Spherical PMAA Particles with Smaller Sizes and PMAA-Based Functional Copolymer Particles. To satisfy different application purposes, uniform spherical polymer particles with tailor-made physical and chemical structures and different size ranges are highly desirable. For instance, spherical polymer nanoparticles with diameters