Employing a Sugar-Derived Dimethacrylate to Evaluate Controlled

Article pubs.acs.org/Macromolecules

Employing a Sugar-Derived Dimethacrylate to Evaluate Controlled Branch Growth during Polymerization with Multiolefinic Compounds Sunirmal Pal, William L. A. Brooks, Daniel J. Dobbins, and Brent S. Sumerlin* George & Josephine Butler Polymer Research Laboratory, Center for Macromolecular Science & Engineering, Department of Chemistry, University of Florida, P.O. Box 117200, Gainesville, Florida 32611-7200, United States S Supporting Information *

ABSTRACT: Radical copolymerization of divinyl monomers in the presence of chain transfer agents leads to soluble hyperbranched polymers. In this work, hyperbranched poly(poly(ethylene glycol) methyl ether methacrylate) (PPEGMA) with degradable cross-linker branch points derived from glucarodilactone methacrylate was prepared via reversible addition−fragmentation chain transfer (RAFT) polymerization to provide insight into hyperbranch formation during copolymerizations of multiolefinic compounds. The numberaverage molecular weight of the polymers increased nonlinearly with monomer conversion, implying that the incorporation of the divinyl cross-linker led to chain branching and a rapid increase in molecular weight at high conversion. The degree of branching was varied by controlling the feed ratio of monomer to cross-linker to chain transfer agent. Hydrolytic degradation of the sugar-derived dilactone branch points was examined under acidic, neutral, and basic aqueous conditions. To provide fundamental insight into the growth of primary chains during RAFT polymerizations of multiolefinic compounds, the resulting hyperbranched polymers were subjected to cross-link cleavage to obtain linear polymers. The molecular weights of the resulting polymer segments were similar to the theoretical molecular weights expected for linear analogues prepared with similar ratios of monomer to RAFT agent. Not only does this approach lead to new examples of degradable polymers with complex architectures, but also to important mechanistic insights into hyperbranch formation via polymerization of multiolefinic compounds.

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stationary phases for chemical separations,7 bioimaging platforms,8 gene transfection agents,9 antibacterial/antifouling materials,10 catalysts,11 drug delivery vehicles,12,13 and biosensing platforms.14 Of particular interest for many biological applications are degradable linear,15−17 star,18,19 and hyperbranched20−22 polymers. Examples of previously utilized degradable linkages include disulfides that undergo reduction20 and thermally labile azo linkages,23,24 as well as esters25 and acetals26,27 that degrade by hydrolysis. Segmented hyperbranched polymers containing degradable units have been evaluated for controlled drug release through the degradation of their branch points to yield linear chains.28,29 Of the wide variety of biological building blocks that can be employed to prepare synthetic materials, sugars are remarkably diverse in structure, are derived from renewable resources, and offer interesting functionalities that make them excellent candidate components for materials syntheses. Sugar-derived materials offer a high density of functional groups for modification, have the potential for degradation, and generally demonstrate no toxicity. The sugar-derived dilactone glucar-

INTRODUCTION Hyperbranched polymers represent an interesting class of macromolecules, particularly due to their shared characteristics with dendrimers.1 Although they have a less well-defined structure than their dendritic analogues, hyperbranched polymers have the advantage of comparatively facile synthesis. While dendrimers require step-by-step syntheses and iterative purification steps, hyperbranched polymers are generally prepared by step-growth or chain-growth polymerization. Stepgrowth polymerization of hyperbranched polymers involves selfcondensing ring-opening polymerization or polycondensation of ABx type monomers, while chain-growth polymerization often occurs through the polymerization of multiolefinic monomers. While hyperbranched polymers synthesized by step-growth polymerization often have high branching densities and functionalities, chain-growth preparation of hyperbranched polymers has become increasingly more accessible through the use of reversible deactivation radical polymerization (RDRP) carried to high monomer conversion while avoiding gelation.2 Hyperbranched polymers have reduced chain entanglement, high chain end functionalities, increased solubilities, lower solution and melt viscosities, and smaller hydrodynamic volumes as compared to their linear counterparts.3 These important properties make them useful for a wide range of applications as surface modifiers and dispersants for nanoparticles,4 coatings,5,6 © XXXX American Chemical Society

Received: September 26, 2016 Revised: November 25, 2016

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polymers. We triggered the degradation of the branching units to obtain the linear chain building blocks that composed the parent hyperbranched polymers to investigate whether the growth of the linear segments of the polymers proceeds in a controlled manner. GDMA, which generates the branching points between the linear chains of PPEGMA, decomposed under basic conditions to generate linear PPEGMA with a predetermined chain length and narrow dispersity. Therefore, this approach allowed us to analyze the growth of branch segments during RAFT polymerization of monomers and divinyl cross-linkers.

odilactone (GDL) is prepared from glucose and can be employed as an alternative to petroleum-based compounds (e.g., bisphenol A).30 GDL has been used to make linear polyhydroxy polyamides and polyurethanes via the ring-opening of the dilactone with various diamines31 and by coupling with isocyanates, which decompose under mild aqueous conditions.32−34 Core crosslinked methacrylate thermosets35 and linear undecenoate polymers36 of GDL have been shown to degrade under basic conditions but remain stable under acidic and neutral conditions. On the basis of this degradability, we reasoned that GDL-derived cross-linkers could be exploited to prepare degradable hyperbranched polymers and to elucidate the mechanism of radical polymerization of multiolefinic monomers. RDRP has been employed in the synthesis of hyperbranched polymers by a variety of techniques, including self-condensing vinyl polymerization (SCVP)37 and the copolymerization of vinyl monomers with divinyl cross-linkers.38,39 SCVP is one of the more straightforward routes for the preparation of hyperbranched polymers, because functional vinyl monomers can act as both an initiator and as a branch point.40 SCVP has been demonstrated through multiple RDRP approaches, including atom transfer radical polymerization (ATRP),41−44 nitroxidemediated radical polymerization (NMP),45−47 and RAFT polymerization.37,48−55 Another straightforward and versatile route to prepare hyperbranched polymers is by the copolymerization of vinyl monomers with a divinyl comonomer, which leads to branching during polymerization. During copolymerization, it is possible to synthesize cross-linked gels,56 microgels,57 or highly branched (co)polymers,58,59 depending on the reaction conditions (e.g., monomer and cross-linker concentration, temperature, stoichiometry, and conversion). Sherrington and co-workers synthesized hyperbranched poly(methyl methacrylate) by the copolymerization of methyl methacrylate with a multifunctional methacrylate comonomer through batch copolymerization,60 ATRP,61 or by using dodecanethiol as a chaintransfer agent (CTA).62,63 Hyperbranch synthesis via RAFTmediated polymerization of multiolefinic compounds38 is arguably simpler than the combination of SCVP with RAFT37 due to the ready availability of divinyl cross-linkers. Rimmer et al.64 and Perrier et al.65 prepared some of the first examples of hyperbranched polymers by RAFT polymerization of multiolefinic monomers. We have reported the synthesis of hyperbranched poly(N-isopropylacrylamide)20 and modular hyperbranched copolymers55 via this approach. Herein, we investigate the nature of branch growth in hyperbranched polymers prepared via RAFT copolymerization of mono- and difunctional monomers. In our study, we employed the sugar-derived glucarodilactone methacrylate (GDMA) as a degradable cross-linker to prepare hyperbranched polymers that can be degraded to their linear components to provide insight into the control afforded by this synthetic approach. The polymers were synthesized via RAFT, controlling the ratio of monomer to divinyl comonomer, and assuming that the divinyl comonomer is incorporated into the growing chain and forms branch points along the chain. Therefore, the incorporation of degradable segments at the branch points of the hyperbranched polymers results in macromolecules that can form linear polymers upon degradation. In this report, poly(ethylene glycol methyl ether methacrylate) (PEGMA) was used as the primary monomer with GDMA acting as a branch forming agent. During RAFT polymerization, the molecular weights and dispersities of hyperbranched polymers are much higher than analogous linear

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EXPERIMENTAL SECTION

Materials. Calcium D-glucarate (Alfa Aesar, 98%), 2-isocyanatoethyl methacrylate (ICM, TCI, > 98%), anhydrous N,N-dimethylformamide (DMF, Sigma, 99.8%), dibutyltin dilaurate (DBTDL, Sigma, 95%), acetone (Fisher), diethyl ether (Fisher), sodium hydroxide (NaOH, Fisher), sulfuric acid (H2SO4, Fisher), hydrochloric acid (HCl, Fisher), CDCl3 (Cambridge Isotope Laboratories, D, 99.8%), D2O (Cambridge Isotope Laboratories, D, 99.9%), and NaOD (D, 99.5%) 40% in D2O were used as received. PEGMA (Sigma-Aldrich, average Mn = 300 g mol−1) was purified by passing through a basic alumina column prior to polymerization. 2,2′-Azobis(isobutyronitrile) (AIBN, Sigma, 98%) was recrystallized twice from methanol. Dichloromethane (DCM) and tetrahydrofuran (THF) were purified using a solvent purification system. The RAFT agent 4-cyano-4-(dodecylsulfanylthiocarbonyl)sulfanyl pentanoic acid (CDP) was synthesized according to a previously reported procedure.66 D-Glucaro-1,4:6,3-dilactone (GDL) was synthesized according to a previously reported procedure.67−69 The divinyl cross-linker D-2,5-di-O-(carbamate ethylene methacrylate)1,4:6,3-glucarodilactone (GDMA) was synthesized according to a procedure described elsewhere.35 Instrumentation. NMR spectra were recorded in acetone-d6, DMSO-d6, CDCl3, or D2O on an Inova2 500 MHz or a Varian Mercury 300 MHz spectrometer. Molecular weights and molecular weight distributions of the hyperbranched polymers were determined by sizeexclusion chromatography (SEC) in N,N-dimethylacetamide (DMAc) with 0.05 M LiCl at 50 °C and a flow rate of 1.0 mL/min (Agilent isocratic pump, degasser, and autosampler, columns: PLgel 5 μm guard + two ViscoGel I-series G3078 mixed bed columns: molecular weight range (0−20) × 103 and (0−10) × 106 g/mol). Detection consisted of a Wyatt Optilab T-rEX refractive index detector operating at 658 nm and a Wyatt miniDAWN Treos light scattering detector operating at 659 nm. Absolute number-average molecular weights (Mn) and molar mass dispersities (Đ) were calculated using the Wyatt ASTRA software. Synthesis of D-Glucaro-1,4:6,3-dilactone (GDL). As shown in Scheme 1, concentrated sulfuric acid (3.12 g, 31.2 mmol) was added

Scheme 1. Synthesis of D-glucaro-1,4:6,3-dilactone (GDL)

over a period of 10 min to a suspension of calcium D-glucarate tetrahydrate (10.0 g, 31.2 mmol) in 95:5 (v/v) acetone−water (50 mL) in a 250 mL round-bottom flask. The mixture was heated to reflux for 2 h and cooled to room temperature with continuous stirring for 2 h. The precipitated calcium sulfate was removed by filtration and washed with 95:5 acetone−water (50 mL). The volatile acetone was removed under reduced pressure, and the concentrated aqueous solution was dried by lyophilization. The D-glucaric acid was placed in 100 mL roundbottomed flask. The flask was heated slowly to 110 °C in an oil bath under high vacuum. After 8 h, the reaction was allowed to cool to room temperature at atmospheric pressure. The glassy D-glucaro-1,4:6,3dilactone was transferred to a vial by dissolving in a minimum volume of dry acetone. The resulting concentrated solution was dried under B

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Macromolecules vacuum. 1H NMR in acetone-d6 (δ, ppm): 5.71 (br s, 2H, OHa and OHf), 5.39 (dd, 1H, Hc), 5.06 (m, 1H, Hd), 4.89 (d, 1H, Hb), 4.40 (m, 1H, He). Synthesis of D-2,5-Di-O-(carbamate ethylene methacrylate)1,4:6,3-glucarodilactone (GDMA). The degradable cross-linker GDMA was synthesized according to a previously published method.35 ICM (5.87 g, 37.9 mmol) was added to a solution of GDL (3.00 g, 17.2 mmol) in dry THF (20 mL) in an oven-dried round-bottomed flask equipped with a magnetic stir bar. DBTDL (20.2 μL, 34.4 μmol) was added to the flask, and the mixture was stirred at room temperature for 6 h. The mixture was precipitated from diethyl ether, and the white crystalline powder was collected by filtration and dried under vacuum. 1 H NMR in DMSO-d6 (Figure 1, δ, ppm): 8.06 (Hk, 1H, t), 8.00 (Hf,

Synthesis of Linear Poly(poly(ethylene glycol) methyl ether methacrylate) (PPEGMA). A typical procedure was as follows. A mixture of PEGMA (500 mg, 1.66 mmol), CDP (6.10 mg, 15.1 μmol), and AIBN (0.250 mg, 1.51 μmol) was dissolved in DMF (2.00 g) and placed in a 25 mL Schlenk flask equipped with a magnetic stir bar. The reaction mixture was degassed by three freeze−pump−thaw cycles, backfilled with nitrogen, and placed in a preheated oil bath at 70 °C. Monomer conversion was determined by 1H NMR spectroscopy, and the Mn and Đ were obtained by SEC. The polymerization was quenched by cooling in an ice−water bath and exposure to air. The polymer was precipitated from diethyl ether (×5) to give a light yellow viscous liquid that was dried under high vacuum for 24 h. Degradation of Dilactone Units in the Hyperbranched Polymers. The degradation of HBP1 was studied under basic, neutral, and acidic conditions at room temperature, and the results were evaluated by 1H NMR spectroscopy and SEC analysis. HBP1 (21.5 mg) was dissolved in D2O (1.2 mL), equally divided between two centrifuge tubes, and NaOD (12 μL, 40 wt % NaOD in D2O) was added to each centrifuge tube to make a 0.2 M NaOD solution. The basic solution was transferred to NMR tubes for NMR analysis. HBP1 (10.5 mg) was also dissolved in an HCl (0.2 M) solution in a centrifuge tube, shaken for 3 days, dried by lyophilization, and then dissolved in D2O for NMR analysis. Finally, the dilactone cleavage experiment was carried out in deionized water, 0.2 M NaOH, and 0.2 M HCl at ambient temperature. In a typical procedure, HBP7 (0.1 g) was dissolved in DI water (15 mL). The HBP7 solution was equally divided among three vials. The solutions were treated with NaOH (0.2 M), deionized water, and HCl (0.2 M), respectively. Each vial was stirred for 2 days at room temperature. Aliquots of each solution were withdrawn periodically and dried by lyophilization for SEC analysis to monitor degradation of the hyperbranched polymers. Additionally, PPEGMA (20.5 mg) was dissolved in 0.2 M NaOH to monitor the hydrolysis of the ester group by SEC.

Figure 1. 1H NMR spectrum of the dilactone cross-linker D-2,5-di-O(carbamate ethylene methacrylate)-1,4:6,3-glucarodilactone (GDMA).

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1H, t), 6.07 (Ha,o, 2H, d), 5.68 (Hb,p, 2H, t), 5.45 (Hg, 1H, d), 5.31 (Hh,i, 2H, m), 5.05 (Hj, 1H, d), 4.10 (Hd,m, 4H, m), 3.31 (He,l, 4H, m), 1.88 (Hc,n, 6H, d). Synthesis of Hyperbranched Poly(poly(ethylene glycol) methyl ether methacrylate-co-D-2,5-di-O-(carbamate ethylene methacrylate)-1,4:6,3-glucarodilactone) [P(PEGMA-co-GDMA)] Copolymers by RAFT Polymerization. A typical procedure was as follows. A mixture of PEGMA (2.00 g, 6.66 mmol), GDMA (96.8 mg, 0.200 mmol), CDP (26.9 mg, 66.6 μmol), and AIBN (1.10 mg, 6.66 μmol) was dissolved in DMF (8.00 g) and placed in a 25 mL Schlenk flask equipped with a magnetic stir bar. The reaction mixture was degassed by three freeze−pump−thaw cycles, backfilled with nitrogen, and placed in a preheated oil bath at 70 °C. Monomer conversion was determined by 1H NMR spectroscopy, and the Mn and Đ were obtained by SEC. The polymerization was quenched by cooling in an ice−water bath and exposure to air. The polymer was precipitated from diethyl ether (×5) to give a light yellow viscous liquid that was dried under high vacuum for 24 h.

RESULTS AND DISCUSSION Our goal was to synthesize degradable hyperbranched polymers that could decompose into their individual linear components. The hyperbranched polymers were prepared by polymerization of the PEGMA monomer and the GDMA comonomer, which served as a branching agent. GDMA contains dilactone units, which are able to decompose under basic conditions and generate individual linear chains. Degradation of the hyperbranched polymers was studied by NMR spectroscopy and SEC to examine the hydrolysis of the dilactones and the concomitant reduction in molecular weight, which denotes the transition from a branched to a linear architecture. This approach allowed us to retroactively investigate the growth of primary linear chains within the hyperbranched polymers.

Scheme 2. Synthesis of Hyperbranched Copolymer P(PEGMA-co-GDMA) by RAFT

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Table 1. Results of the Synthesis of P(PEGMA-co-GDMA) Hyperbranched Copolymers by RAFT Polymerization of PEGMA and GDMA at 70 °C in DMF under Various Reaction Conditions sample name

[PEGMA]/[GDMA]/[CDP]/[AIBN]

time (h)

conva (%)

Mn,Theob (g/mol)

Mn,SECc (g/mol)

Đc

DBd

RBe

PPEGMA HBP1 HBP2 HBP3 HBP4 HBP5 HBP6 HBP7

110/0/1/0.1 10/1/1/0.1 25/1/1/0.1 50/1/1/0.1 100/1/1/0.1 100/2/1/0.1 100/3/1/0.1 100/4/1/0.1

4 23 23 23 24 40 50 50

93 94 97 95 95 96 99 97

31100 3700 7900 14600 29400 30200 31500 31000

33500 10500 14000 24300 37700 44500 96200 120900

1.07 3.40 2.00 1.93 1.32 2.02 4.16 3.89

− 0.275 0.155 0.069 0.037 0.045 0.058 0.095

− 3.63 6.45 14.5 27.0 22.2 17.2 10.5

a

Calculated by 1H NMR spectroscopy for the combination of PEGMA and GDMA. bTheoretical number-average molecular weights of analogous RAFT polymerizations of PEGMA in the absence of GDMA cNumber-average molecular weights (Mn,SEC) and molecular weight distributions (Đ) obtained by size-exclusion chromatography (SEC). dDegrees of branching (DB) calculated from 1H NMR spectroscopy. eAverage repeat units per branch (RB) = 1/DB.

Figure 2. SEC chromatograms of P(PEGMA-co-GDMA) hyperbranched copolymers obtained with different feed ratios of PEGMA and GDMA by RAFT copolymerization (A) maintaining [GDMA]:[CDP] = 1:1 or (B) maintaining [PEGMA]:[CDP] = 100:1.

Figure 3. (A) Pseudo-first-order kinetic plot for the RAFT copolymerization of PEGMA and GDMA in DMF at 70 °C. (B) ■ represents the numberaverage molecular weight (Mn) evolution of HBP1 with monomer conversion. (C) SEC chromatograms for HBP1 as a function of polymerization time. (D) Molar mass dispersity (Đ) as a function of monomer conversion for the synthesis of HBP1.

transfer agent70,71 and AIBN as the initiator in DMF at 70 °C generated branched PPEGMA, with the molecular weight and degree of branching of the final material being determined by the

Synthesis and Characterization of Hyperbranched Polymers. Copolymerization of PEGMA with the divinyl comonomer GDMA in the presence of CDP as the chainD

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hyperbranched polymers (HBP1) are shown in Figure 3C, where chromatograms shifted toward lower elution times as the reaction progressed. As the polymerization proceeded, the chromatograms transitioned from a sharp, uniform peak to wider, nonuniform peaks, often exhibiting a high molecular weight shoulder, a phenomenon that can be attributed to chain termination by macromolecular radicals or reaction of propagating macroradicals with macromolecular vinyl groups.20 The dispersity of hyperbranched polymers depends on monomer conversion, with higher monomer conversions resulting in an increase in Đ (Figure 3D). We attribute the growth of Đ during polymerization to the increasing congestion present in the hyperbranched polymers late in the polymerization, which likely leads to a reduced rate of degenerative transfer (i.e., exchange between dormant and active end groups) and therefore a broadening of the molecular weight distribution (MWD). Degree of Branching. The degree of branching (DB) is the average fraction of monomer units that act as branching points in a polymer. In this work, 1H NMR spectroscopy was used to determine the DB. Traditionally, the DB has often been calculated using the following equation:

feed ratio of [monomer]:[divinyl cross-linker]:[CTA] (Scheme 2).20 The copolymerization reaction was carried out in two series. In the first, the ratio of [GDMA]:[CDP] was maintained at 1:1 while varying the feed ratio of [PEGMA]:[GDMA] from 10:1 to 100:1. In the second series, the ratio of [PEGMA]:[CDP] was maintained at 100:1, while the feed ratio of [GDMA]:[CDP] was varied from 1:1 to 4:1. The copolymerization reaction conditions and results are summarized in Table 1. The structure of P(PEGMA-co-GDMA) was confirmed by 1H NMR spectroscopy (Figure S1). The resonance signals of the branching units (−O−CH2−CH2−NH−) and the terminal units (−S−CH2−C11H23) were assigned to the peaks at 3.21 and 3.12 ppm, respectively. The vinyl peaks of the branching units in the polymer at 6.08 and 5.68 ppm are absent, suggesting both polymerizable moieties of the branching units were consumed during polymerization. The number-average molecular weights (Mn) of the polymers were determined by SEC (Figure 2). For the polymerizations where the feed ratios of [PEGMA]:[GDMA] were varied from 10:1 to 100:1 while keeping a constant 1:1 ratio of [GDMA]: [CDP], the Mn of the polymers varied from 10,500 to 37,700 g/ mol with corresponding Đ values of 3.40 and 1.32, respectively. The molecular weights of the polymers were much higher than the theoretical Mn of analogous polymerizations carried out in the absence of GDMA. The Đ increased with increasing branching units in the feed composition (Table 1). Similarly, for polymerizations where the feed ratio of [PEGMA]:[GDMA] was varied from 100:1 to 100:4 while keeping a constant 100:1 ratio of [PEGMA]:[CDP], the Mn of the polymers varied from 37,700 to 120,900 g/mol with corresponding Đ of 1.32 and 3.89, respectively. The molecular weights and Đ for both polymers gradually increased with increasing cross-linker content (and when compared at similar conversions), which is consistent with the polymerization transitioning from a conventional RAFT process with no divinyl compound present to a hyperbranching RAFT process with increased divinyl content. Notably, HBP6, with a monomer to cross-linker ratio of 100:3, had a Đ of 4.16, which is higher than the Đ of HBP7 (3.89), with a monomer to cross-linker ratio of 100:4. The lower dispersity of HBP7 might be a result of lower monomer conversion during its synthesis as compared to HBP6, resulting in less interchain coupling (i.e., condensation) between hyperbranched polymers. These results suggest the dispersity depends not only on the monomer to cross-linker ratio, but also on monomer conversion. RAFT Polymerization Kinetics. The copolymerization kinetics were studied by 1H NMR spectroscopy and SEC analysis. Linear pseudo-first-order kinetics (Figure 3A) were observed, as expected for a RAFT polymerization, indicating a constant concentration of propagating radicals during polymerization. The polymerization started after a short induction period of 25−30 min, which could be a result of trace amounts of impurities. The molecular weight of the linear segments was dictated by the feed ratio of monomer to CTA and the monomer conversion. The molecular weights of the hyperbranched polymers were much higher than the theoretical molecular weights of the analogous linear polymers (Figure 3B). Figure 3B shows that the molecular weights of the hyperbranched polymers increase linearly early in the polymerization, but begin to increase sharply at higher conversion (>90%). These results suggest that the primary chain length increases through traditional chain propagation by the RAFT process, and the hyperbranch molecular weight increases through interchain coupling/ branching late in the polymerization. SEC traces of growing

DB =

B+T B+T+L

(1)

where T, L, and B are the number of terminal, linear, and branching units, respectively. The above equation has been used to determine the DB for branched polymers prepared by polycondensation,72,73 ATRP,44,74 RAFT,20,75 and SCVP.76 Divinyl branching units generate two branches per incorporation during RAFT copolymerization. Therefore, for this study, the degree of branching (DB) was calculated using eq 1, where B is two times the area of one of the methylene units within each GDMA-derived branch point (CO2−CH2CH2NH) at 3.21 ppm, T is two times the area of the −S−CH2− in each CTA-derived Zgroup chain terminus at 3.12 ppm, and L is the area of the −CO2−CH2− units in the PEGMA units at 4.06 ppm. The DB and the repeat units per branch (RB) were measured at high monomer conversions (95−99%) and are listed in Table 1. The DB of the polymers decreased from 0.275 to 0.037, and the RB increased from 3.63 to 27.0 when the feed ratio [PEGMA]: [GDMA] was increased from 10:1 to 100:1 while keeping the ratio of [GDMA]:[CDP] constant. When the feed ratio of [PEGMA]:[GDMA] was changed from 100:1 to 100:4 and the ratio of [PEGMA]:[CDP] kept constant, the DB increased from 0.037 to 0.095. Under both reaction conditions, the DB increased with increasing cross-linker concentration. The effect of RAFT agent concentration on DB was also investigated. For HBP2 and HBP7, the ratio of [PEGMA]:[CDP] was varied from 25:1 to 100:1 while maintaining a constant [PEGMA]:[GDMA] ratio. HBP2, which had a higher concentration of RAFT agent, had a DB of 0.155, while the lower concentration of RAFT agent in HBP7 resulted in a DB of 0.095. In general, higher concentrations of RAFT agent increased the number of terminal units, resulting in a higher DB. Given that dendrimers have a DB equal to 1, cyclic polymers have a DB equal to zero, and the DB of linear polymers approaches zero with increasing molecular weight, these results indicate that the obtained polymers do, in fact, have branched architectures. Degradation. One of the purposes of incorporating a degradable linkage in our materials was to evaluate the chain growth of hyperbranched polymers prepared through RAFT copolymerizations. The hydrolytic degradation of glucarodilactone units has been previously demonstrated.35,36 The proposed E

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Macromolecules Scheme 3. Hydrolytic Degradation of Hyperbranched Copolymer at Room Temperature

Table 2. Preparation of Hyperbranched P(PEGMA-co-GDMA) Copolymers (HBP7) Followed by Hydrolysis in 0.2 M NaOH at Room Temperature before hydrolysis (hyperbranched) a

entry

time (min)

conv (%)

1 2 3 4 5

120 150 210 450 3000

23 33 44 73 97

Mn,SECb

(g/mol)

7200 29400 37300 63600 120900

after hydrolysis (cleaved primary chains) Đ

b

1.21 1.46 1.95 2.28 4.16

Mn,Theoc (g/mol)

Mn,SECb (g/mol)

Đb

branches per chain

7600 10700 14100 23200 31000

6900 12400 15300 24100 32200

1.18 1.39 1.32 1.48 1.36

1.04 2.37 2.43 2.63 3.75

a

Calculated by 1H NMR spectroscopy. bNumber-average molecular weights (Mn,SEC) and molar mass dispersity (Đ) obtained by size exclusion chromatography (SEC). cTheoretical number-average molecular weights (Mn,Theo) of analogous RAFT polymerizations of PEGMA in the absence of GDMA.

Figure 4. (A) SEC chromatograms as a function of time during the synthesis of HBP7 hyperbranched polymer (top) and the corresponding linear PPEGMA (bottom) after glucarodilactone hydrolysis in the presence of 0.2 M NaOH; (B) number-average molecular weight (Mn) and molar mass dispersity (Đ) of hyperbranched PPEGMA as a function of monomer conversion during RAFT; (C) Mn and Đ of the corresponding cleaved linear PPEGMA as a function of monomer conversion.

in D2O. In neutral and acidic D2O, the 1H NMR signals of dilactone at 5.2−5.7 ppm showed no change with time (Figure S2A). However, cleavage of the dilactone was observed in NaOD solution, as the 1H signals of the branching dilactone units (5.2−

degradation process of the hyperbranched polymers is shown in Scheme 3. Degradation was investigated by SEC and 1H NMR spectroscopy under neutral, acidic, and basic conditions. Degradation of HBP1 was monitored by 1H NMR spectroscopy F

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Figure 5. (A) SEC chromatograms showing the degradation of HBP7 with time; (B) kinetics of degradation with respect to number-average molecular weight (Mn) and molar mass dispersity (Đ) determined by SEC; (C) SEC chromatograms of PPEGMA treated with NaOH (0.2 M) for 48 h. No change in molecular weight was observed because no hydrolysis of the ester in the linear PPEGMA chain took place.

was similar to the calculated molecular weight (Mn,Theo = 31,000 g/mol in Table 1), assuming linear homopolymerization of PEGMA monomer via RAFT polymerization. Degradation of the hyperbranched polymers was also evaluated at neutral and acidic pH, though the SEC chromatograms remained unchanged after treatment for 2 days, suggesting that glucarodilactone units are stable under these conditions. To ensure the molecular weight reduction observed during degradation was the result of hydrolysis of the glucarodilactone units and not due to cleavage of the PEG side chains through hydrolysis of the methacryoyl ester groups, the linear PPEGMA was treated with 0.2 M NaOH for 2 days (Figure 5C). As compared to the hyperbranched polymers that contained the GDMA units, the SEC traces of these linear polymers did not shift after extended treatment with base. Both 1H NMR spectroscopy and SEC results are consistent with the cleavage of glucarodilactone branch points. Indeed, the degradation of the branching units in the hyperbranched polymers suggests that primary chains do, in fact, begin to grow as expected in a RAFT polymerization before being incorporated into the hyperbranched polymer through interchain coupling via residual vinylic units in the cross-linker. These results agree with our previous investigations into the mechanism of SCVP with reversible-covalent ATRP inimers.44

5.7 ppm) disappeared due to hydrolysis (Figure S2B). Four minor peaks appeared (3.93, 4.07, 4.11, and 4.14 ppm) due to the formation of glucaric acid (Figure S2B), a byproduct of glucarodilactone degradation. Through quantitative cleavage of branching points, the hyperbranched polymers were transformed into linear polymers. Because the molecular weights were reduced as the hydrolysis proceeded, SEC was used to monitor reaction progression. During a RAFT copolymerization ([PEGMA]:[GDMA]:[CDP] = 100:4:1), aliquots were taken at various times to determine monomer conversion and molecular weight, while a portion of each aliquot was precipitated and dried for the degradation study. The results for the kinetics investigation are summarized in Table 2. The SEC chromatograms shifted to lower elution times with increasing reaction times (Figure 4A). The molecular weight and Đ increased nonlinearly with broad distributions (Figure 4B), as expected for the synthesis of hyperbranched polymers. The resulting molecular weights and Đ of the hyperbranched polymers are listed in Table 2. To evaluate the molecular weight characteristics of individual chains that condensed to form the hyperbranched polymers, the aliquots of precipitated hyperbranched polymers were exposed to 0.2 M NaOH solution at room temperature for 2 days to hydrolyze the glucarodilactone units, followed by lyophilization of the degradation products before SEC analysis. The resulting linear chains (i.e., primary chains) exhibited a molecular weight very similar to the predicted theoretical molecular weight of linear RAFT polymers prepared with the same ratio of [PEGMA]:[CDP]. The Đ of the linear polymer chains was also relatively low, as seen in Figure 4C. These degradation results suggest the primary chains grow in a controlled fashion, and that the high molecular weights and dispersities of the parent hyperbranched polymers are the result of interchain condensation of well-defined polymer chains. The number of branches per chain can be calculated by dividing the absolute molecular weight of the hyperbranched polymer by that of the linear degradation products. For HBP7, this corresponds to 3.75 branches per chain at Entry 5 in Table 2. The number of branches per chain calculated for the other hyperbranched polymers is listed in Table S1. As seen in Figure 5A, the SEC chromatograms of HBP7 shifted to higher elution volumes with increasing time of exposure to NaOH. The Mn,SEC of HBP7 decreased from 120,900 to 57,500 g/mol within 30 min and further decreased to 29,200 g/mol after 24 h. No further significant differences were observed with extended reaction times (Figure 5B). The molecular weight distributions became narrower and increasingly unimodal with time. Significantly, the Mn,SEC of the linear chains

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CONCLUSIONS In summary, we have synthesized a series of water-soluble hyperbranched polymers by RAFT copolymerization of a multiolefinic monomer containing the sugar-derived GDMA dilactone. During polymerization, the molecular weight distribution of the polymers was narrow at low monomer conversion, with molar mass dispersity increasing at high monomer conversion. The branching density in the resulting polymers was readily tuned by varying the comonomer and RAFT agent feed ratios. The hyperbranched polymers were degraded under basic conditions through hydrolysis of the lactone in GDMA but remained stable under acidic and neutral conditions. Not only does this route grant access to degradable branched polymers, but also cleavage of the branching points provided insight into the controlled growth of primary chains during the copolymerization with multiolefenic compounds. After degradation, the remaining linear segments (i.e., primary chains) had low dispersities and molecular weights that were nearly equivalent to the theoretical molecular weights expected for linear polymers prepared with the same ratio of monomer to RAFT agent. Therefore, we believe controlled RAFT copolymerization in the presence of multiolefinic compounds leads to growth of well-defined linear segments, with branch formation G

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occurring via propagation through pendent vinyl groups and interchain condensation.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.macromol.6b02079. 1 H NMR spectra and results for the hydrolysis of hyperbranched P(PEGMA-co-GDMA) copolymers (PDF)

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AUTHOR INFORMATION

Corresponding Author

*(B.S.S.) E-mail: [email protected]fl.edu. Fax: +1 352 392 9741. ORCID

Brent S. Sumerlin: 0000-0001-5749-5444 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 (DMR-1410223 and DMR-1606410). Acknowledgment is made to the donors of the Petroleum Research Fund, administered by the American Chemical Society (53225-ND7), for partial support of this research.

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