Redox-Responsive Dynamic-Covalent Assemblies: Stars and

Article pubs.acs.org/Macromolecules

Redox-Responsive Dynamic-Covalent Assemblies: Stars and Miktoarm Stars Abhijeet P. Bapat,† Jacob G. Ray,‡ Daniel A. Savin,‡ and Brent S. Sumerlin*,†,§ †

Department of Chemistry, Southern Methodist University, 3215 Daniel Avenue, Dallas, Texas 75275-0314, United States School of Polymers and High Performance Materials, The University of Southern Mississippi, Hattiesburg, Mississippi 39406, United States § George & Josephine Butler Polymer Research Laboratory, Center for Macromolecular Science and Engineering, Department of Chemistry, University of Florida, PO Box 117200, Gainesville, Florida 32611-7200, United States ‡

S Supporting Information *

ABSTRACT: Dynamic-covalent macromolecular stars were prepared by cross-linking block copolymers containing reactive maleic anhydride units with a disulfide-containing diamine. Here we report the synthesis of disulfide-cross-linked star polymers obtained by the arm-first process. Well-defined block copolymers containing a reactive poly(styrene-alt-maleic anhydride) (P(S-alt-MAn)) segment and an inert polystyrene or poly(N-isopropylacrylamide) segment were obtained by reversible addition−fragmentation chain transfer (RAFT) polymerization. Facile ring-opening of the pendant anhydride groups in the block copolymers by a disulfide-linked diamine cross-linker led to core-cross-linked stars with redox-responsive cores. The reductive cleavage of the disulfide linkages in the cross-linked cores resulted in star dissociation into linear arms with pendant thiol groups. Oxidation of the pendant thiol units of the resulting unimers in the presence of air led to reassembly or self-healing of the stars without the need for an externally added oxidizing agent.

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als.6 However, stronger reversible links that respond to specific stimuli while being otherwise stable can afford dynamic polymers with increased stability while demonstrating reversibility only under specific conditions.7 Dynamic-covalent chemistry8 offers a promising alternative to supramolecular motifs9 for the construction of dynamic/ reorganizable polymers. The higher strength of many dynamiccovalent bonds as compared to supramolecular interactions potentially leads to increased structural stability while retaining the benefits of reversibility. Consequently, the assembly of dynamic-covalent architectures like macrocycles, 10 dendrimers,11 and reorganizable polymers12 has been an area of growing interest. Based on the concept of dynamic-covalent chemistry, macromolecular stars containing alkoxyamine,13 Diels−Alder,14,15 acylhydrazone,16 imine,17 boroxine,18 boronic ester,19 and disulfide linkages20 have been investigated. The ability of dynamic-covalent stars to reversibly reconfigure their composition/structure in response to a stimulus can lead to smart nanostructures with various potential applications. Disulfides are commonly encountered dynamic-covalent bonds in biological systems. The reversible formation of disulfides by oxidative coupling of cysteine residues is a key step that contributes to protein activity and tertiary/quaternary

INTRODUCTION The development of controlled polymerization techniques1 has facilitated the synthesis of various macromolecular architectures (e.g., hyperbranched, star, comb). Star polymers with several linear polymeric chains (or arms) emanating from a central core represent the simple example of regularly branched macromolecules.2 Star polymers are generally prepared using one of the two common synthetic routes, namely the arm-first and core-first methods, in combination with living/controlled polymerization techniques.3 The branched architecture of star polymers leads to a compact globular structure, a high density of functional groups, and unique properties in solution, melt, and the solid state.4 Because of their highly branched structure and unique solution properties, star polymers have been investigated for their potential utility as nanoreactors, catalysts, compatiblizers for polymer blends, photovoltaics, sensors, polymer electrolytes, building blocks for higher order selfassemblies, and in biomedical and therapeutic applications.5 While several examples of star polymers have been reported, the incorporation of a characteristic of dynamics (e.g., potential for controlled degradability, self-healing) into these branched macromolecules may be beneficial for their potential use as drug delivery vehicles, lubricant additives, and coatings. Star polymers based on supramolecular motifs like hydrogen bonding, ionic interactions, solvophobic host−guest interactions, and metal−ligand complexes offer the possibility of controlled degradation and a bottom-up design of nanomateri© 2013 American Chemical Society

Received: January 24, 2013 Revised: February 22, 2013 Published: March 8, 2013 2188

dx.doi.org/10.1021/ma400169m | Macromolecules 2013, 46, 2188−2198

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Instrumentation and Analyses. Molecular weight and polydispersity were determined by size exclusion chromatography (SEC) in dimethylacetamide (DMAc) with 50 mM LiCl at 55 °C and a flow rate of 1.0 mL min−1 (Viscotek SEC pump, columns: Guard + two ViscoGel I-series G3078 mixed bed columns: molecular weight range 0−20 × 103 and 0−100 × 104 g mol−1). Detection consisted of a Viscotek VE 3580 refractive index detector operating at 660 nm. Molecular weights were determined using narrow polydispersity polystyrene standards for column calibration. 1H NMR spectroscopy was conducted with a JEOL Delta 500 spectrometer at 500 MHz. Single angle dynamic light scattering (DLS) was conducted at 173° with a Malvern Zetasizer Nano-ZS equipped with a 4 mW, 633 nm He−Ne laser and an Avalanche photodiode detector. Variable-angle dynamic light scattering (DLS) and static light scattering (SLS) measurements were made employing 35 mW incident light with a wavelength of 633 nm from a Research Electro-Optics He−Ne laser. The angular dependence of the time−intensity autocorrelation functions was measured using a Brookhaven Instruments BI-200SM goniometer with an avalanche photodiode detector and TurboCorr correlator. The mutual diffusion coefficients (Dm) were calculated from the relation

structure. Polymer chemists have effectively capitalized on the facile reversibility of disulfides to prepare a variety of adaptable materials.20 Disulfides can undergo two types of dynamiccovalent reactions (Scheme 1a,b) by either their reversible cleavage into thiols under reducing conditions or disulfide exchange in which a newly added thiol results in a new disulfide bond. Scheme 1. (a) Reversible Disulfide Cleavage/Coupling and (b) Thiol−Disulfide Exchange Reaction

Γ = Dmq2 where Γ and q2 are the decay rate of the autocorrelation function and the square of the scalar magnitude of the scattering vector, respectively. The hydrodynamic radius (Rh) was then calculated from the Stokes−Einstein equation.

Disulfides have been employed for the design of dynamiccombinatorial libraries, interlocked molecules, molecular capsules, macrocycles, degradable and self-healing polymers, polymer prodrugs, and redox-responsive nanostructures for therapeutic applications.21 However, disulfide cross-linked stars that can reversibly undergo redox-responsive dissociation− reassembly for multiple cycles would be interesting as smart, repairable nanomaterials and as precursors to macroscopic selfhealing materials. The ability of covalent macromolecular architectures to undergo reversible disassembly can potentially be used to induce subtle changes in solution and bulk properties and as on/off switches for modulation of catalytic activity. Here we report the synthesis of disulfide-cross-linked stars and miktoarm stars obtained by an arm-first process. Welldefined block copolymers containing a reactive poly(styrenealt-maleic anhydride) (P(S-alt-MAn)) segment were obtained by reversible addition−fragmentation chain transfer (RAFT) polymerization. Facile ring-opening of the pendant anhydride groups in the block copolymers by a disulfide-linked diamine cross-linker led to core-cross-linked stars with redox-responsive cores. The reductive cleavage of the disulfide linkages in the cross-linked cores resulted in star dissociation into linear arms with pendant thiol groups. Oxidation of the pendant thiol units of the resulting unimers in the presence of air led to reassembly or self-healing of the stars without the need for an externally added oxidizing agent.

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Dm ≈ D0 =

k bT 6πηR h

The molecular weight (Mw) of the aggregates was determined by analyzing the intensity of several sample concentrations via a Debye analysis (at a 90° scattering angle) using the equation Kc 1 = + 2A 2 c Rθ Mw where K, c, Rθ, Mw, and A2 are the optical coefficient, concentration, Rayleigh ratio, weight-average molecular weight, and second virial coefficient, respectively. The solutions were directly filtered into scattering samples through 0.45 μm Millipore filters (PTFE). TEM images were obtained using a JEOL JEM-2100 LaB6 electron microscope operating under ultrahigh vacuum with an acceleration voltage of 200 kV. 0.1−1 mg/mL disulfide star aggregate solutions were spotted onto a 300 mesh carbon-coated copper grid and allowed to dry at room temperature. Staining was performed by placing a drop of 1 wt % uranyl acetate (negative stain) or phosphotungstic acid (positive stain) in water onto spotted grids, wicking after ca. 1 min, and allowing to dry at room temperature. Images were taken between 10 000× and 40 000× magnification. Synthesis of P(S-alt-MAn)20-b-PS66 (P1). RAFT copolymerization of styrene and maleic anhydride was performed at [styrene]: [MAn]:[DMP]:[AIBN] = 101:20:1:0.1. Styrene (5.31 g, 51.8 mmol), maleic anhydride (1.01 g, 10.3 mmol), DMP (0.186 g, 0.509 mmol), strioxane (internal standard for NMR spectroscopy, 0.230 g, 2.55 mmol), AIBN (8.2 mg, 0.05 mmol), and 1,4-dioxane (7 mL) were sealed in a 20 mL reaction vial equipped with a magnetic stirbar, and the resulting solution was purged with nitrogen for 20 min. The vial was placed in a preheated heating block at 70 °C. The polymerization was quenched after 7 h by removing the vial from the heating block and opening to expose the contents to atmospheric oxygen. The resulting polymer was isolated by precipitation into cold diethyl ether (×3) and vacuum-dried at 50 °C for 10 h to give the pure polymer (P1) (43% styrene conversion, Mn,NMR = 5900 g/mol, Mw/Mn = 1.18). Synthesis of P(S-alt-MAn)20-b-PS47 (P2). RAFT copolymerization of styrene and maleic anhydride was performed at [styrene]: [MAn]:[DMP]:[AIBN] = 160:20:1:0.1. Styrene (7.98 g, 76.6 mmol), maleic anhydride (1.00 g, 10.2 mmol), DMP (0.186 g, 0.479 mmol), strioxane (0.231 g, 2.56 mmol), AIBN (8.3 mg, 0.051 mmol), and 1,4dioxane (4 mL) were sealed in a 20 mL reaction vial equipped with a

EXPERIMENTAL SECTION

Materials. N-Isopropylacrylamide (NIPAM, TCI) was recrystallized twice from hexane. 2,2′-Azobis(isobutyronitrile) (AIBN) (98%, Sigma-Aldrich) was recrystallized from ethanol. 2-Dodecylsulfanylthiocarbonylsulfanyl-2-methylpropionic acid (DMP) was prepared as previously reported.22 Styrene (99%, EMD) and 1,4-dioxane (Alfa Aesar) were passed through a column of basic alumina before polymerization. Tetrahydrofuran (THF) (99.9%, Fisher), s-trioxane (99.5%, Acros), methanol (EMD, HPLC grade), maleic anhydride (99%, Acros Organics), cystamine dihydrochloride (97%, Acros), triethylamine (99.7%, Acros), tributylphosphine (Bu3P) (97%, SigmaAldrich), diethyl ether (EMD), DMSO-d6, and CDCl3 (Cambridge Isotopes) were used as received. 2189


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fitting of the resulting SEC chromatograms. Star formation at [MAn]: [−NH2] = 1:1, 1:2, and 1:3 equiv was studied in a similar manner. DLS analysis was performed on samples (30 μL) diluted with THF (1 mL) and filtered through a PTFE syringe filter (0.450 μm). Investigation of the Effect of Polymer Concentration on Star Formation during Ring-Opening of the Pendant MAn Groups of P(S-alt-MAn)20-b-PS66 (P3) with Cystamine Dihydrochloride at a Fixed [MAn]:[−NH2] Stoichiometry. The effect of polymer concentration on star formation was studied at [MAn]:[−NH2] = 1:1 equiv. A typical procedure for the investigation of the star formation reaction at various polymer concentrations was as follows. P3 (50 mg, 0.088 mmol in MAn) was dissolved in THF (0.900 mL) in a 4 mL glass vial equipped with a magnetic stirbar. Into a separate 4 mL vial, cystamine dihydrochloride (80 mg, 0.36 mmol), triethylamine (110 μL, 0.79 mmol), and methanol (690 μL) were transferred, and the contents were mixed on an autoshaker until a translucent solution was obtained. The translucent solution was filtered through a 0.2 μm nylon filter to remove the triethylammonium chloride product, and the resulting clear solution [100 μL, 0.089 × 10−3 equiv in (−NH2)] was added dropwise under vigorous stirring to the vial containing the polymer solution. The reaction mixture was further stirred at room temperature. Samples were withdrawn periodically for SEC analysis, and the conversion of arms to stars was calculated by Gaussian multipeak fitting of the resulting SEC chromatograms. Star formation at an effective [P3] = 100 and 150 mg/mL was studied in a similar manner. Purification of Core-Cross-Linked Stars Obtained from P(Salt-MAn)20-b-PS66 (P3) by Fractional Precipitation. The solution of stars (0.3 mL) obtained from P3 ([MAn]:[−NH2] = 1:1 equiv, [P3] = 150 mg/mL) was transferred to a 2 mL polyethylene minicentrifuge tube with a press-fit cap. Cold methanol was added dropwise to this solution with intermittent shaking until persistent turbidity was observed. The turbid solution was then centrifuged at 4000 rpm for 5 min to separate the precipitated stars. The precipitated stars were immediately redissolved in THF (0.3 mL), and the fractional precipitation and dissolution process was repeated twice. Successful purification of the stars was confirmed by SEC analysis. Star Formation by Ring-Opening of the Pendant MAn Groups of P(S-alt-MAn)20-b-PS14 (P1), P(S-alt-MAn)20-b-PS47 (P2), and P(S-alt-MAn)35-b-PNIPAM120 (P5) with Cystamine Dihydrochloride. Core-cross-linked stars were obtained by ringopening of the pendant MAn groups of P1, P2, and P5 with cystamine dihydrochloride at an effective polymer concentration of 100 mg/mL and [MAn]:[−NH2] = 1:1 equiv. The stars were obtained by following a procedure similar to that employed for investigation of star formation with P3 described above. DLS measurements were performed on a sample of the star solution (30 μL) diluted with THF or methanol (1 mL). Miktoarm Star Formation. Stars were obtained by ring-opening of the pendant MAn groups in a 1:1 (w/w) mixture of P3 and P5 with cystamine dihydrochloride following a procedure similar to that employed for star formation using P3 or P5 alone. P3 (100 mg, 0.176 mmol in MAn) and P5 (100 mg, 0.167 mmol in MAn) were dissolved in THF (1.380 mL) in a 4 mL glass vial equipped with a magnetic stirbar. Into a separate 4 mL vial, cystamine dihydrochloride (100 mg, 0.445 mmol), triethylamine (154 μL, 1.10 mmol), and methanol (646 μL) were transferred, and the contents were mixed on an autoshaker until a translucent solution was obtained. The translucent solution was filtered through a 0.2 μm nylon filter to remove the triethylammonium chloride product, and the resulting clear solution (620 μL, 0.690 × 10−3 equiv in (−NH2), [MAn]:[−NH2] = 1:2 equiv) was added dropwise to the vial containing the polymer solution under vigorous stirring. DLS measurements were performed on reaction samples (30 μL) diluted with THF (1 mL). Formation of Superaggregates by Self-Assembly in DI Water. A portion of the miktoarm stars in THF (0.1 mL) was transferred into a 4 mL reaction vial equipped with a magnetic stirbar and a screw-cap septum. Under vigorous stirring, DI water (3.9 mL) was added dropwise at a rate of 50 μL/10 s, and the resulting translucent white solution was further stirred for 10 min, followed by sonication for 30 min. DLS size measurements were made after

magnetic stirbar, and the resulting solution was purged with nitrogen for 20 min. The vial was placed in a preheated heating block at 70 °C. The polymerization was quenched after 18.5 h by removing the vial from the heating block and opening to expose the contents to atmospheric oxygen. The resulting polymer was isolated by precipitation into cold diethyl ether (×3) and vacuum-dried at 50 °C for 10 h to give the pure polymer (P2) (50% styrene conversion, Mn,NMR = 9300 g/mol, Mw/Mn = 1.17). Synthesis of P(S-alt-MAn)20-b-PS14 (P3). RAFT copolymerization of styrene and maleic anhydride was performed at [styrene]: [MAn]:[DMP]:[AIBN] = 219:20:1:0.1. Styrene (10.9 g, 105 mmol), maleic anhydride (0.942 g, 9.61 mmol), DMP (0.175 g, 0.480 mmol), s-trioxane (0.211 g, 2.34 mmol), AIBN (11.8 mg, 0.0719 mmol), and 1,4-dioxane (3 mL) were sealed in a 20 mL reaction vial equipped with a magnetic stirbar, and the resulting solution was purged with nitrogen for 20 min. The vial was placed in a preheated heating block at 70 °C. The polymerization was quenched after 24 h by removing the vial from the heating block and opening to expose the contents to atmospheric oxygen. The resulting polymer was isolated by precipitation into cold diethyl ether (×3) and vacuum-dried at 50 °C for 2 days to give the pure polymer (P3) (51% styrene conversion, Mn,NMR = 11 300 g/mol, Mw/Mn = 1.27). Synthesis of P(S-alt-MAn)35 Macro-Chain-Transfer Agent (MacroCTA) (P4). RAFT copolymerization of styrene and maleic anhydride was performed at [styrene]:[MAn]:[DMP]:[AIBN] = 50:50:1:0.1. Styrene (4.01 g, 38.4 mmol), maleic anhydride (3.77 g, 38.4 mmol), DMP (0.280 g, 0.767 mmol), s-trioxane (0.174 g, 1.93 mmol), AIBN (12.6 mg, 0.0767 mmol), and 1,4-dioxane (8 mL) were sealed in a 20 mL reaction vial equipped with a magnetic stirbar, and the resulting solution was purged with nitrogen for 20 min. The vial was placed in a preheated heating block at 60 °C. The polymerization was quenched after 2 h by removing the vial from the heating block and opening to expose the contents to atmospheric oxygen. The resulting polymer was isolated by precipitation into cold diethyl ether (×3) and vacuum-dried at 50 °C for 2 days to give the pure polymer (P4) (43% styrene conversion, Mn,SEC = 7400 g/mol, Mw/Mn = 1.27). Synthesis of P(S-alt-MAn)35-b-PNIPAM120 (P5). RAFT polymerization of N-isopropylacrylamide (NIPAM) was performed at [NIPAM]:[ P(S-alt-MAn)35 macroCTA]:[AIBN] = 285:1: 0.14. NIPAM (3.48 g, 30.8 mmol), P(S-alt-MAn)35 macroCTA (P4) (0.801 g, 0.108 mmol), s-trioxane (0.069 g, 0.766 mmol), AIBN (2.5 mg, 0.015 mmol), and 1,4-dioxane (16 mL) were sealed in a 50 mL round-bottom flask equipped with a magnetic stirbar and a rubber septum. The resulting solution was purged with nitrogen for 20 min. The flask was placed in a preheated oil bath at 70 °C. The polymerization was quenched after 8.7 h by removing the flask from the oil bath and opening to expose the contents to atmospheric oxygen. The resulting polymer was isolated by precipitation into cold diethyl ether (×3) and vacuum-dried at 50 °C for 2 days to give the pure polymer (P5) (60% NIPAM conversion, Mn,SEC = 21 000 g/mol, Mw/Mn = 1.38). Investigation of the Effect of [MAn]:[−NH2] Stoichiometry on Star Formation during Ring-Opening of the Pendant MAn Groups of P(S-alt-MAn)20-b-PS66 (P3) with Cystamine Dihydrochloride. Star formation was studied at an effective P3 concentration of 50 mg/mL and at [MAn]:[−NH2] = 1:0.5, 1:1, 1:2, and 1:3 equiv. A typical procedure was as follows. P3 (50 mg, 0.088 mmol in MAn) was dissolved in THF (0.950 mL) in a 4 mL vial equipped with a magnetic stirbar. Into a separate 4 mL vial, cystamine dihydrochloride (80 mg, 0.36 mmol), triethylamine (110 μL, 0.790 mmol), and methanol (690 μL) were transferred, and the contents were mixed on an autoshaker until a translucent solution was obtained. The translucent solution was filtered through a 0.2 μm nylon filter to remove the triethylammonium chloride product, and the resulting clear solution (50 μL, 0.022 mmol in cystamine dihydrochloride, [−NH2] = 0.044 × 10−3 equiv) was added dropwise under vigorous stirring to the vial containing the polymer solution ([MAn]:[−NH2] = 1:0.5 equiv). Stirring was further continued at room temperature. Samples were withdrawn periodically for SEC analysis, and the conversion of arms to stars was calculated by Gaussian multipeak 2190


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Scheme 2. (a) Synthesis of Poly(styrene-alt-maleic anhydride)-b-polystyrene by One-Step Cascade Block Copolymerization of Styrene (S) and Maleic Anhydride (MAn); (b) Synthesis of P(S-alt-MAn)35-b-poly(N-isopropylacrylamide)120 Block Copolymer via Chain Extension of a P(S-alt-MAn)35 Macro-Chain-Transfer Agent

dilution of 50 μL of the superaggregate solution in DI water (1 mL) under vigorous stirring, sonication for 15 min, and filtration through a 0.450 μm PTFE syringe filter. Investigation of the Effect of Disulfide:Bu3P ([S−S]:[Bu3P]) Stoichiometry on Star Dissociation. P3 (500 mg, 0.885 mmol in MAn) was dissolved in THF (4 mL) in a 20 mL vial equipped with a magnetic stirbar and a screw-cap septum. Into a separate 4 mL vial, cystamine dihydrochloride (160 mg, 0.710 mmol), triethylamine (220 μL, 1.57 mmol), and methanol (1.380 mL) were transferred, and the contents were mixed on an autoshaker until a translucent solution was obtained. The translucent solution was filtered through a 0.2 μm nylon filter to remove the triethylammonium chloride product, and the resulting clear solution (1.00 mL, 0.444 mmol in cystamine dihydrochloride, 0.888 × 10−3 equiv in (−NH2)) was added dropwise under vigorous stirring to the vial containing the polymer solution. The solution was left stirring at room temperature for 14 h, and star formation was confirmed by SEC and DLS. Equal portions of the resulting solution of stars (0.250 mL, 0.022 mmol in disulfide) were transferred into three different 4 mL vials with magnetic stirbars. Increasing volumes of Bu3P (2.75, 5.5, and 11 μL) were added to each of the three vials at [S−S]:[Bu3P] = 1:0.5, 1:1, and 1:2 equiv. The solutions were stirred at room temperature, and samples were withdrawn after 40 min for SEC and DLS analysis. Investigation of the Kinetics of Star Dissociation. A portion of the stars prepared from P3 (0.250 mL, 0.022 mmol in disulfide) was transferred into a 4 mL vial equipped with a magnetic stirbar and a screw-cap septum. Under stirring, Bu3P (5.5 μL, 0.022 mmol) was added, and the solution was stirred at room temperature. Samples were withdrawn after 5, 20, and 40 min and analyzed by SEC to determine the extent of star dissociation. Investigation of the Dynamics of Reversible Star Formation and Dissociation. P3 (500 mg, 0.885 mmol in MAn) was dissolved in THF (4 mL) in a 20 mL vial equipped with a magnetic stirbar and a screw-cap septum. Into a separate 4 mL vial, cystamine dihydrochloride (160 mg, 0.710 mmol), triethylamine (220 μL, 1.57 mmol), and methanol (1.380 mL) were transferred, and the contents were

mixed on an autoshaker until a translucent solution was obtained. The translucent solution was filtered through a 0.2 μm nylon filter to remove the triethylammonium chloride product, and the resulting clear solution (1 mL, 0.444 mmol in cystamine dihydrochloride, 0.888 × 10−3 equiv in (−NH2)) was added dropwise under vigorous stirring to the vial containing the polymer solution. After 14 h, star formation was confirmed by SEC and DLS. The resulting solution of stars (1.0 mL, 0.088 mmol in disulfide) was transferred into a 4 mL vial with a magnetic stirbar, and Bu3P (22 μL, 0.088 mmol) was added under stirring at room temperature. Small amounts of the reaction mixture (∼30 μL each) were withdrawn for SEC and DLS analysis to confirm star dissociation after 40 min. The solution of unimers was briefly opened to air, recapped, and allowed to stir at room temperature in order to allow oxidation of the pendant thiol groups. Samples (∼30 μL each) were withdrawn after 10 h for SEC and DLS analysis, and the reassembly of stars was confirmed. Another aliquot of Bu3P (22 μL, 0.088 mmol) was added under stirring at room temperature to cause reductive dissociation of the reassembled stars. This process of star formation and dissociation was repeated for up to four cycles. The reversible dynamics of star formation and dissociation were studied in a similar manner for P5 for up to two cycles.

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RESULTS AND DISCUSSION Synthesis of Poly(styrene-alt-maleic anhydride)-bpolystyrene (P(S-alt-MAn)-b-PS) by One-Step Cascade Block Copolymerization of Styrene and Maleic Anhydride (MAn). Styrene and maleic anhydride were copolymerized via RAFT at three different [styrene]:[MAn]:[DMP]: [AIBN] ratios (i.e., 219:20:1:0.15, 160:20:1:0.1, and 101:20:1:0.1) at 70 °C in 1,4-dioxane using DMP as the CTA and AIBN as the initiator (Scheme 2a).15,23,24 In each case, an excess of styrene with respect to MAn was employed to obtain block copolymers in a one-pot cascade-like manner with alternating copolymerization occurring until MAn was ex2191


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in the 1H NMR spectra of the polymers, assuming complete consumption of the CTA and MAn, and a perfectly alternating tendency.15,23,25 The resulting Mn,NMR indicated good agreement between experimental and theoretical values (Table 1). The considerable difference between Mn,SEC and theoretical values, especially for P1 with a short PS block, is likely due to the less than ideal nature of conventional polystyrene calibration given the highly extended nature of MAn-containing copolymers.26 Synthesis of P(S-alt-MAn)35-b-poly(N-isopropylacrylamide)120 (P(S-alt-MAn)35-b-PNIPAM120). To obtain a block copolymer containing a star passivating segment other than polystyrene, a P(S-alt-MAn)35 macroCTA was first synthesized by RAFT copolymerization of styrene and MAn (Scheme 2b). Again, the Mn,SEC of the resulting macroCTA was found to be higher than the Mn,theo due to the less than ideal nature of conventional polystyrene calibration given the highly extended nature of the MAn-containing polymers (Table 1). The broad, poorly resolved peaks of the CTA alkyl chain protons in the 1H NMR spectra of the resulting polymer precluded successful molecular weight calculation via end-group analysis. The P(Salt-MAn)35 macroCTA was used for mediating the RAFT polymerization of N-isopropylacrylamide (NIPAM) to obtain a well-defined block copolymer (P(S-alt-MAn)35-b-PNIPAM120) with a reactive P(S-alt-MAn) segment and an inert PNIPAM block. The clean shift of the SEC trace for the block copolymer toward lower elution volume compared to the macroCTA indicated successful chain extension (Figure 1). Although there was a slight increase in the Mw/Mn after chain extension, the unimodal SEC trace of the block copolymer indicated the chain extension was fairly well-controlled. Dynamic-Covalent Star Formation via Ring-Opening of Pendant Anhydride Groups by Cystamine Dihydrochloride as a Cross-Linker. We recently demonstrated the facile functionalization of block copolymers containing a P(Salt-MAn) segment via ring-opening with functional amines leading to monoamide formation.15 Similar ring-opening of

Table 1. Results for the Synthesis of Diblock Copolymers with Reactive P(S-alt-MAn)-b-PS Segments and Inert Polystyrene or Poly(N-isopropylacrylamide) Segments entry P1 P2 P3 P4 P5

copolymer P(S-alt-MAn)20-bPS14 P(S-alt-MAn)20-bPS47 P(S-alt-MAn)20-bPS66 P(S-alt-MAn)35 P(S-alt-MAn)35-bPNIPAM120

Mn,theoa (g/mol)

Mn,NMRb (g/mol)

6800

5900

8800

1.18

10100

9300

8600

1.17

13850

11300

12 300

1.27

7400 21000

1.25 1.38

4700 26700

Mn,SECc (g/mol)

Mw/Mnc

a Calculated from monomer conversions determined by 1H NMR spectroscopy. bCalculated by comparison of the area of the peaks corresponding to the phenyl protons of styrene to that of the alkylbackbone protons in the 1H NMR spectra. cDetermined by SEC (conventional polystyrene calibration).

Figure 1. SEC overlay showing successful chain extension of P(S-altMAn)35 macroCTA with poly(N-isopropylacrylamide) to give P(S-altMAn)35-b-PNIPAM120.

hausted, followed by continued chain extension with the remaining styrene. The number-average molecular weights (Mn,NMR) of the resulting polymers were calculated by comparison of the area of the peaks corresponding to the phenyl protons of styrene to that of the alkyl-backbone protons

Scheme 3. Formation and Disassembly of Dynamic-Covalent Stars with Redox-Cleavable Disulfide Linkages

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Figure 2. (a) SEC refractive index traces showing the progress of the star formation reaction between P(S-alt-MAn)20-b-PS66 (P3) and cystamine dihydrochloride ([polymer] = 100 mg/mL and [MAn]:[−NH2] = 1:1 equiv). (b) SEC traces showing stars before (red line) and after (blue line) fractional precipitation. (c) Solution size distributions of P(S-alt-MAn)20-b-PS66 measured by DLS showing an increase from 5 nm for the unimers to 24 nm for the stars. (d) TEM image of the core-cross-linked stars (scale bar = 50 nm, negative stain).

pendant anhydride groups in the P(S-alt-MAn) segment of block copolymers has also been employed for the synthesis of hollow polymer nanocapsules.27 We hypothesized that using a similar synthetic strategy, arm-first core-cross-linked stars could be directly obtained via reaction of the P(S-alt-MAn) segment in the various block copolymers listed in Table 1 with a diamine cross-linker such as cystamine dihydrochloride (Scheme 3). We reasoned that the inert (passivating) block (e.g., polystyrene) in the block copolymers should limit cross-linking to the nanoscale, resulting in discrete, well-defined macromolecular stars. Moreover, due to the presence of redox-cleavable disulfide linkages in the cross-linked cores, the stars were expected to demonstrate dynamic-covalent disassembly and reassembly on alternating exposure to reducing and oxidizing conditions. SEC, light scattering, and TEM were used to investigate star formation by the reaction of the block copolymers with cystamine dihydrochloride. For example, SEC analysis of the stars obtained at room temperature (∼25 °C) from P(S-altMAn)20-b-PS66 (100 mg/mL) and cystamine dihydrochloride ([MAn]:[−NH2] = 1:1 equiv) in THF showed a new peak at a lower elution volume, consistent with the formation of higher molecular weight core-cross-linked stars within 15 min of addition of the cross-linker (Figure 2a). The area of the deconvoluted SEC peak corresponding to stars increased gradually with time, while that of the peak for individual unimers decreased simultaneously. After 24 h, the Gaussian multipeak fitting analysis of the SEC traces indicated 80% of the unimers had been incorporated into the core-cross-linked stars. SEC traces of the stars purified by fractional precipitation indicated complete removal of low molecular weight products (unreacted arms and possibly products composed of a very small number of arms), though an increase in the apparent molecular weight of the purified stars was also observed. This

Table 2. Typical Results for Synthesis of Disulfide-CrossLinked Stars via the Ring-Opening of Anhydride-Functional Block Copolymers by Cystamine Dihydrochloride polymer (star precursor) P(S-alt-MAn)20-b-PS14 P(S-alt-MAn)20-b-PS47 P(S-alt-MAn)20-b-PS66 P(S-alt-MAn)35-bPNIPAM120

Mn,arm (g/mol)

Mw,star (g/mol)

Nagg (arms/star)

Dh (nm)

5900a 9300a 11300a 21000b

−d 663000c 468000c 1931000c

−d 71e 41e 92e

−d 26f 24f 30f

a

Calculated by 1H NMR spectroscopy. bDetermined by SEC (PS conventional calibration). cDetermined by static light scattering. d Cross-linked gel obtained after 48 h. eApproximate aggregation number calculated by dividing Mw,star by Mn,arm (note that these values are approximate as the molecular weight of the arms are Mn values determined by 1H NMR or SEC and the molecular weight of the stars are Mw values determined by light scattering). fDetermined by dynamic light scattering.

Figure 3. Kinetics of star formation determined by deconvolution of the SEC traces obtained during the reaction between P(S-alt-MAn)20b-PS66 (P3) and cystamine dihydrochloride at (a) varying amounts of cystamine dihydrochloride ([polymer] = 50 mg/mL) and (b) varying polymer concentration ([MAn]:[−NH2] = 1:1 equiv).

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Figure 4. (a) SEC refractive index traces obtained periodically during the disulfide-cross-linked star formation by reaction between P(S-alt-MAn)35b-PNIPAM120 (P5) and cystamine dihydrochloride ([MAn]:[−NH2] = 1:1 equiv and [polymer] = 100 mg/mL) at room temperature (∼25 °C). (b) Kinetics of star formation determined by deconvolution of the SEC traces. (c) TEM image of the core-cross-linked stars (scale bar = 50 nm, negative stain).

Scheme 4. Formation of Miktoarm Stars with Redox-Cleavable Disulfide-Cross-Linked Cores and Arms Comprising PS66 and PNIPAM120 Chains

Figure 5. (a) SEC refractive index traces showing the progress of the miktoarm star formation reaction between a 1:1 (w/w) mixture of P(S-altMAn)20-b-PS66 and P(S-alt-MAn)35-b-PNIPAM120 and cystamine dihydrochloride ([polymer] = 100 mg/mL, [MAn]:[−NH2] = 1:2 equiv). (b) Kinetics of star formation determined by deconvolution of SEC traces. (c) TEM image of the miktoarm stars (scale bar = 200 nm, positive stain).

observation is likely a result of removal of low molecular weight star fractions or potentially star−star coupling during fractionation (Figure 2b). DLS analysis indicated an increase in the Dh from 5 nm for unimers to 24 nm for the stars (Figure 2c). Aggregates with slightly larger size were observed by TEM

(Figure 2d); indeed, the images are consistent with the spherical nature of the solution aggregates. The slight discrepancy in size could be due to either agglomeration during TEM sample preparation or a haloing effect of the negative stain. Static light scattering (via Debye analysis) was 2194


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defined aggregate formation arising from the poor steric stabilization afforded by the shorter PS blocks (Figure S4a). Moreover, the P(S-alt-MAn)20-b-PS14 star solution transformed into a cross-linked gel after 48 h, indicating the inability of the very short PS block to prevent macroscopic cross-linking. Interestingly, addition of tributylphosphine resulted in a gel to sol transformation via reductive cleavage of the disulfide linkages within 2 h (Figure S4b). Further insight into the assembly and star formation process was obtained by considering the effects of the (i) maleic anhydride:amine ([MAn]:[−NH2]) stoichiometry and (ii) overall P(S-alt-MAn)20-b-PS66 block copolymer concentration. As expected, the rate of conversion of the P(S-alt-MAn)20-bPS66 unimers to core-cross-linked stars varied with varying amounts of cystamine dihydrochloride (i.e., [MAn]:[−NH2] = 1:0.5, 1:1, 1:2, and 1:3 equiv). The initial rate of star formation was lowest in the presence of a less than stoichiometric amount of the cystamine dihydrochloride cross-linker (0.5 equiv) and increased with increasing amount of cross-linker (Figure 3a). However, the extent of star formation was found to be the highest in the presence of 1 equiv of cystamine dihydrochloride, with up to 71% of the arms being incorporated into the corecross-linked stars after 28 h. The rate and extent of conversion of unimers to core-cross-linked stars also depended on the overall block copolymer concentration. At a constant ratio of [MAn]:[−NH2] = 1:1 equiv, the reaction between cystamine dihydrochloride and P(S-alt-MAn)20-b-PS66 was investigated at three different polymer concentrations. After more than 22 h of reaction, the conversion of unimers to stars at [polymer] = 50, 100, and 150 mg/mL was 71, 80, and 85%, respectively (Figure 3b). However, the SEC trace of stars obtained at [polymer] = 150 mg/mL was significantly broader, indicating possible star− star coupling side reactions at this higher polymer concentration (Figure S5). Similarly, core-cross-linked stars were also obtained via the reaction between P(S-alt-MAn)35-b-PNIPAM120 and cystamine dihydrochloride. SEC, light scattering, and TEM confirmed the successful formation of core-cross-linked stars in THF (Figure 4). In the presence of a stoichiometric equivalent of cross-linker and [polymer] = 100 mg/mL, 79% conversion of linear arms into core-cross-linked stars was achieved in 17 h (Figure 4b). DLS analysis indicated an increase in Dh from 6 nm for unimers to 30 nm for the stars. Aggregates of similar size were observed by TEM (Figure 4c). Static light scattering was used to calculate Mw,star = 1930 kg/mol, corresponding to an aggregation number (Nagg) of ∼92 arms per star (Table 2).

Figure 6. (a) Proposed self-assembly of miktoarm stars into superaggregates in DI water. (b) Solution size distribution of a mixture of P(S-alt-MAn)35-b-PNIPAM120 and P(S-alt-MAn)20-b-PS66 (unimers) and miktoarm stars in THF and the superaggregates obtained in DI water.

used to calculate the Mw,star = 468 kg/mol, corresponding to an effective aggregation number (Nagg) of ∼41 arms per star (Table 2). Similarly, stars were obtained via the cross-linking of the anhydride functional segments in block copolymers with shorter PS segments. P(S-alt-MAn)20-b-PS47 and P(S-altMAn)20-b-PS14 were reacted with cystamine dihydrochloride ([polymer] = 100 mg/mL and [MAn]:[−NH2] = 1:1 equiv). The Dh, Mw,star, and corresponding Nagg of the stars obtained from P(S-alt-MAn)20-b-PS47 with a shorter passivating PS block were higher than those for P(S-alt-MAn)20-b-PS66 (Table 2 and Figure S3 in Supporting Information). These results are consistent with our recent observation that Dh, Mw,star, and corresponding Nagg of dynamic-covalent stars increase with decreasing length of the passivating block in arm precursors.15 The multimodal SEC trace of stars obtained from P(S-altMAn)20-b-PS14 after 20 h indicated the presence of very high molecular weight aggregates, possibly due to both the formation of larger stars and an increased tendency of ill-

Figure 7. (a) SEC traces showing the extent of reductive dissociation of stars in the presence of varying amounts of tributylphosphine (Bu3P) after 40 min. (b) SEC traces showing the progress of the reductive dissociation of stars on addition of tributylphosphine ([S−S]:[Bu3P] = 1:1 equiv). 2195


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Figure 8. (a) SEC traces of unimers (solid lines) and stars (dashed lines) obtained during the investigation of reversible formation and dissociation of disulfide cross-linked stars from P(S-alt-MAn)35-b-PS66. (b) Solution size measured by dynamic light scattering during investigations of dynamiccovalent star assembly (solid line) and dissociation (dashed line).

Synthesis of Miktoarm Stars. Miktoarm stars were also prepared via the reaction of a mixture of P(S-alt-MAn)35-bPNIPAM120 and P(S-alt-MAn)20-b-PS66 (1:1 w/w) and cystamine dihydrochloride ([polymer] = 100 mg/mL, [MAn]: [−NH2] = 1:2 equiv) (Scheme 4). Gaussian multipeak fitting analysis of the SEC traces of the star products rapidly reached ∼75% conversion of arms to stars after 1 h (Figure 5). Allowing the reaction to proceed to 22 h did not significantly increase the conversion. DLS analysis indicated an increase in Dh from 6 nm for unimers to 31 nm for the miktoarm stars. Slightly larger aggregates were observed by TEM Since the miktoarm stars were composed of both hydrophilic (PNIPAM) and hydrophobic (PS) arms, it was expected that they would further form superaggregates in a selective solvent (e.g., water) (Figure 6a). Indeed, when a small amount of the miktoarm stars in THF (solution size ≈ 31 nm) was diluted by dropwise addition of DI water under vigorous stirring, larger aggregates with an average size of 97 nm were obtained (Figure 6b). These superaggregates are likely formed via hydrophobic self-assembly of PS arms between multiple stars. Reversibility of the Dynamic-Covalent Macromolecular Star Formation. The redox-cleavable disulfide linkages in the cross-linked cores allowed the reversible dissociation of stars to unimers in presence of a suitable reducing agent such as tributylphosphine (Bu3P). Bu3P is a highly efficient reducing agent for rapid reduction of disulfides to thiols in presence of trace moisture. Compared to other reducing agents like dithiothreitol, Bu3P is relatively less sensitive to oxidation in air and is highly selective and efficient in disulfide reduction. Moreover, the byproduct Bu3PO obtained as a result of disulfide reduction is not expected to interfere with subsequent recoupling of resulting thiols to disulfides in the presence of atmospheric oxygen. The reductive dissociation of the stars obtained from P(S-altMAn)20-b-PS66 was studied in presence of different amounts of added Bu3P (i.e., [S−S]:[Bu3P] = 1:0.5, 1:1, and 1:2 equiv). SEC analysis of the products of the reduction reaction with a lower than stoichiometric amount of Bu3P ([S−S]:[Bu3P] = 1:0.5 equiv) resulted in only partial dissociation of stars to unimers, as expected (Figure 7a). In the presence of a stoichiometric amount or higher of Bu3P (i.e., [S−S]:[Bu3P] = 1:1, and 1:2 equiv), complete dissociation of the stars was achieved. Similarly, the kinetics of dissociation of stars to unimers were also studied in the presence of a fixed amount of Bu3P ([S−S]:

[Bu3P] = 1:1 equiv). Within 5 min of the addition of Bu3P, the SEC trace of the reaction product indicated a large fraction of the stars had already dissociated, although a higher molecular weight residue consistent with partially dissociated stars was still observed (Figure 7b). A tiny, high molecular weight shoulder appeared to be present in the SEC trace of the product after 20 min, while that after 40 min indicated nearquantitative reduction of the disulfide-cross-linked cores into unimers. Thus, a stoichiometric amount of Bu3P ([S−S]: [Bu3P] = 1:1 equiv) and a minimum reaction time of 40 min were required for complete dissociation of the stars to unimers. Because the unimers resulting from the reductive cleavage of the disulfide-linked stars possessed pendant thiol groups capable of oxidative coupling to give disulfides, the stars could be reassembled merely by stirring the solution in the presence of ambient air at room temperature (Scheme 4). Thus, the reaction vial containing the solution of dissociated stars was opened to ambient air, recapped, and left stirring at room temperature. Star reassembly was monitored by SEC and DLS. The SEC trace of the solution after 10 h indeed demonstrated a shift to lower elution volume consistent with star reassembly via interchain disulfide formation (Figure 8a, cycle 2). The increase in the DLS solution size from 5 to 23 nm also further confirmed the star reassembly (Figure 8b). The process of star formation/dissociation could be repeated over at least four cycles under the experimental conditions employed. Interestingly, the time required for star reassembly increased for every subsequent cycle with 34 and 70 h needed for star reassembly during the third and the fourth cycle, respectively. The reduction in the rate of star reassembly for every subsequent cycle is potentially the result of a gradual buildup of a slight excess of unreacted Bu3P during each reduction cycle. The excess Bu3P likely competes for the available oxygen required for oxidative recoupling of thiols to disulfides or reduces the disulfides back to thiols until it is completely oxidized to Bu3PO. Similarly, the stars obtained from P(S-altMAn)20-b-PS47 and P(S-alt-MAn)35-b-PNIPAM120 could be dissociated on reduction of the disulfide linkages with Bu3P (Figures S3 and S6).

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CONCLUSIONS

The core-cross-linked macromolecular stars described here are constructed via dynamic-covalent disulfide linkages capable of redox-induced cleavage/reassembly. Disulfide-containing star polymers based on this chemistry may be useful as drug vectors 2196


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that can release a payload under reducing conditions in the body. However, until now the ability of disulfide-linked stars to undergo reversible architectural transformation to linear chains had been unexplored. In this case, the cleavage of disulfide cross-links yielded linear block copolymers with pendant thiols capable of reoxidation into disulfides, thus rendering these nanomaterials self-healable. The cross-linked cores of the stars may also be useful for site isolation of catalysts or chromophores and for delivery of drugs under increased glutathione levels. Further, while the work described here focuses on assemblies in solution, applications in the bulk, particularly in the area of rehealable materials, can also be envisioned.

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ASSOCIATED CONTENT

S Supporting Information *

Additional 1H NMR spectra, size exclusion chromatography and DLS results, photographs, and relevant discussion. This material is available free of charge via the Internet at http:// pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]fl.edu. Author Contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This material is based upon work supported by the National Science Foundation (CAREER DMR-0846792). Prof. Nicolay V. Tsarevsky is acknowledged for his valuable discussions.

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REFERENCES

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