Letter pubs.acs.org/macroletters
Expanding the Cationic Polycarbonate Platform: Attachment of Sulfonium Moieties by Postpolymerization Ring Opening of Epoxides Nathaniel H. Park,†,‡ Mareva Fevre,†,‡ Zhi Xiang Voo,†,§ Robert J. Ono,†,∥ Yi Yan Yang,§ and James L. Hedrick*,† †
IBM Almaden Research Center, 650 Harry Road, San Jose, California 95120, United States Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, The Nanos, Singapore 138669, Singapore
§
S Supporting Information *
ABSTRACT: Postpolymerization modification is a critical strategy for the development of functional polycarbonate scaffolds for medicinal applications. To expand the scope of available postpolymerization functionalization methods, polycarbonates containing pendant thioether groups were synthesized by organocatalyzed ring-opening polymerization. The thioether group allowed for the postpolymerization ring-opening of functional epoxides, affording a wide variety of sulfonium-functionalized A-B diblock and A-B-A triblock polycarbonate copolymers. The pendant thioether groups were found to be compatible with previously developed postsynthesis functionalization methods allowing for selective and orthogonal modifications of the polycarbonates.
P
limitations, several postpolymerization strategies of polycarbonates have been developed to gain access to myriad pendant functionalities. These reactions include amidation, azide− alkyne cycloaddition, Schiff base formation, and amine quaternization via alkylation (III, Figure 1).31−46 Polycarbonate materials prepared by postpolymerization modifications have been extensively utilized in many biomedical and nanomedicine applications.47−49 Thus, in order to expand access to novel
ostpolymerization modification processes have garnered significant interest due to their potential for (i) extending the variety of functional groups that can be attached onto a polymer chain, including the installation of multiple moieties on the same backbone using orthogonal chemistries, (ii) circumventing tedious monomer synthesis and the use of functional monomers that are incompatible with well-known polymerization techniques, (iii) preparing a library of materials from an easily characterized single batch of polymer, and (iv) taking advantage of highly efficient reactions that have been well-established.1−4 Many polymers, including polystyrenics,5 poly(meth)acrylics, polyolefins,6 polyesters and polycarbonates,7,8 polyoxazolines,9 and polypeptides10,11 have been modified via postpolymerization transformations.1 Commonly used postpolymerization functionalization reactions include the following: transesterification or amidation of activated esters,12 conjugate addition, azide−alkyne cycloaddition,13−15 thiol−ene or thiol−yne,16−21 ring opening,22−25 Schiff base formation, and alkylation.1 The robustness of these approaches has led to their utilization in numerous areas, including biomedical7,10,26 and surface modification27 applications. Postpolymerization functionalization is a critical strategy for the development of new classes of functional, biocompatible and biodegradable polycarbonate platforms. This is due to several inherent drawbacks that plague the synthesis of functionalized polycarbonates, including the following: (i) the fragility of the polymer backbone, (ii) the tedious synthesis of cyclic carbonate monomers, and (iii) the incompatibility of ring-opening polymerization (ROP) protocols28−30 with functional groups such as amines and alcohols. To overcome these © XXXX American Chemical Society
Figure 1. Postsynthesis modifications of functional polycarbonate platforms. Received: September 15, 2016 Accepted: October 24, 2016
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ACS Macro Letters Scheme 1. Synthesis of Di- and Triblock Polycarbonate Copolymers via Organocatalyzed ROPa
Determined by 1H NMR. Mn (GPC) and Đ were determined by Gel Permeation Chromatography (GPC) calibrated with polystyrene standards and using THF as the eluent. DBU = 1,8-diazabicycloundec-7-ene, TU = N-(3,5-bistrifluoromethyl)phenyl-N′-cyclohexylthiourea. a
functional polycarbonate platforms, new approaches are needed for effective postpolymerization modification. Alkylation reactions are a promising approach for postsynthesis modification, as they can install both charge and other functional groups in a single step. Charged polymers often display unique properties, such as an unusual self-assembly behavior or antimicrobial characteristics.50−53 Typically, positive charges are installed on pendant groups by reacting a thioether, amine, or phosphine with an alkyl halide.45,46,54−57 The ring-opening of epoxides by thioethers to generate sulfonium ions with a β-hydroxyl group (II, Figure 1) represents a potential alternative route to install a charge on a polymer backbone. This reaction has been extensively utilized for the synthesis of small molecules such as α-glucosidase or platelet inhibitors58−63 and for the modification of peptides and proteins.64,65 Recently, Deming et al. have shown that sulfonium ions could be readily installed on poly(L-methionine) by ring-opening of substituted epoxides by thioether groups in the presence of acetic acid.66 The functionalization of poly(Lmethionine) was compatible with a wide variety of functional epoxides, including examples of the selective functionalization of methionine in short peptides with competing nucleophiles.66 This approach has also been employed for the functionalization of poly(ethylene oxide) derivatives with thioether moieties.67 Additionally, the generated β-hydroxy sulfonium species have been demonstrated by Deming et al. to be more stable in a variety of aqueous buffers as compared to their counterparts prepared via alkylation, making them ideal for use in biological systems.54,55,66 Based on these precedents, we hypothesized that ring-opening of epoxides by pendant thioethers would be an efficient strategy to prepare new charged polycarbonate scaffolds for biomedical applications.
The investigation into preparing sulfonium functionalized polycarbonates began by synthesizing the thioether appended cyclic carbonate monomer (MTC-TE, Scheme 1) via transesterification of the corresponding pentafluorophenyl ester precursor with 3-(methylthio)-1-propanol.68 MTC-TE was subsequently polymerized via organocatalyzed ROP using either mPEG (Mn = 5000 g/mol) or dihydroxytelechelic-PEG (Mn = 10000 g/mol) as macroinitiators, to afford A-B diblock (1a, Scheme 1) or A-B-A triblock copolymers (1c, Scheme 1), respectively. The PEG macroinitiators were selected due to their biocompatibility and importance in many nanomedicine applications such as the generation of micellar drug-delivery systems and hydrogels for sustained drug release.69,70 The molar masses of the polycarbonate blocks were controlled by adjusting the monomer(s)-to-PEG initial ratio and the degree of polymerization (DP) was verified by 1H NMR spectroscopy. Additionally, these polymers prepared with MTC-TE exhibited a dispersity of 1.19 and 1.15 for 1a and 1c, respectively (entries 1 and 3, Scheme 1). The homopolymerization of MTC-TE using benzyl alcohol as an initiator also demonstrated a similar degree of control, see Supporting Information (SI). MTC-TE could also be readily copolymerized with a cyclic carbonate bearing a benzyl group (1b, Scheme 1), affording a diblock copolymer with a predictable DP based on the initial ratio of benzyl to thioether-containing monomers and a dispersity of 1.28 (entry 2, Scheme 1). This result is significant as controlling the benzyl:thioether ratio allows for further finetuning the overall hydrophobicity in the resultant charged sulfonium polycarbonate and hence directly impacts further processing into charged micelles or hydrogels.71,72 When MTCBnCl was used as a comonomer with MTC-TE, the resulting polymer 1d (entry 4, Scheme 1) was found to have higher 1248
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ACS Macro Letters
sulfonium species (δ ≈ 3.0 ppm, DMSO-d6). Increasing the amount of allyl glycidyl ether to 10 equiv improved the functionalization of 2a to 96% (Table 1). Although achieving high levels of functionalization requires a large excess of epoxide, it does demonstrate that the degree of functionalization can be easily adjusted, which is desirable from the standpoint of building diverse polycarbonate libraries from a single batch of polymer. In other examples, using only 3 equiv of epoxide gave results similar to 2a, with moderate amounts of functionalization being obtained (2b and 2c, Table 1). Lower degrees of functionalization occurred when a (±)-α-tocopherolmodified epoxide was utilized (2d, Table 1). This result could potentially arise from the steric blocking of unfunctionalized thioether residues by neighboring sulfoniums with appended tocopherol moieties. Finally, a control reaction without any epoxide added to the reaction medium was performed to assess the stability of the polycarbonate backbone in neat acetic acid. The 1H NMR spectrum of the recovered polymer was identical to that of the pristine material, demonstrating that minimal, if any, degradation of the carbonate repeating units occurred under these conditions. In order to make this postpolymerization approach as broadly applicable as possible, a second set of reaction conditions that utilized solvents other than glacial acetic acid was developed. Prior work found that only low conversion was obtained when conducting these reactions in solvents other than acetic acid.25 However, after investigating several conditions (see SI), we found that using 6 equiv of trifluoroacetic acid (TFA) and the epoxide in dichloromethane at 35 °C allowed for moderate to high levels of functionalization of the polycarbonate triblock copolymers (Route B, Table 1). A control experiment conducted in the absence of epoxide showed a small amount of cleavage of the polycarbonate backbone by 1H NMR analysis. This may be a result of the slightly elevated temperatures used relative to similar conditions reported for the removal of Boc-protecting groups from guanidine containing polycarbonates.73 However, this degradation side reaction was not observed in the presence of the epoxide under similar reaction conditions. These conditions could readily be applied to diblock polycarbonate copolymers (1a and 1b, Scheme 1) as well, allowing the installation of an array of different epoxides with moderate to high degrees of functionalization of the pendant thioethers (Table 2). While the glacial acetic acid conditions are more tolerant of epoxides with acid-labile groups (2c, Table 1), the trifluoracetate counterion can offer several advantages. These include improved antimicrobial properties as well as a convenient and unambiguous 19F NMR handle to gauge the efficacy of additional anion exchanges.74 Given the successful modification of tri- and diblock polycarbonate copolymers, these conditions could be extended to facilitate multiple selective functionalization reactions of polycarbonates. As acidic conditions are needed for the alkylation of thioethers by alkyl or benzyl halides,54,55 we hypothesized that a copolymer containing pendant benzyl chloride and thioether functional groups could be sequentially functionalized to afford polycarbonates with mixed ammoniumsulfonium residues. This would be highly advantageous as it would allow highly selective introduction of different functional groups on either the benzyl chloride or thioether, potentially generating new classes of densely functionalized, charged polycarbonates.
dispersity (1.69), presumably due to a minor loss of control over the polymerization. Nonetheless, 1H NMR analysis revealed a DP consistent with the monomer-to-initiator feed ratio, as well as, the initial ratio of thioether to benzyl chloride residues. Having synthesized the poly(MTC-TE) diblock and triblock copolymers, we next sought to evaluate their reactivity with various functional epoxides. Initially, conditions analogous to those reported by Deming et al. for the functionalization of poly(L-methionine) were investigated.66 By reacting the poly(MTC-TE) triblock copolymer 1c with 3 equiv of allyl glycidyl ether in neat glacial acetic acid, the desired sulfonium containing polycarbonate was obtained with 63% functionalization of the pendant thioethers (2a, Table 1). The functionalization was verified by 1H NMR spectroscopy, specifically by the large downfield shift of the signal corresponding to the methyl group of the pendant thioether (δ = 2.1 ppm, DMSO-d6) to that of the newly formed Table 1. Synthesis of Sulfonium Functionalized Triblock Polycarbonate Copolymers
a
Reagents and conditions: Route A: 1c (1 equiv), epoxide (3 equiv), AcOH, 37 °C, 16 h. bReagents and conditions: 1c (1 equiv), epoxide (10 equiv), AcOH, 37 °C, 16 h. Route B: 1c (1 equiv), epoxide (6 equiv), TFA (6 equiv), CH2Cl2, 35 °C, 24 h. The percent functionalization was determined by 1H NMR analysis of the isolated material. TFA = trifluoroacetic acid. 1249
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ACS Macro Letters Table 2. Synthesis of Sulfonium Functionalized Diblock Polycarbonate Copolymers
Scheme 2. Synthesis of Mixed Sulfonium-Ammonium Functionalized ABA Triblock Polycarbonate Copolymera
a Reagents and conditions: (a) 1d (1 equiv), N,N-dimethylbenzylamine (4.5 equiv), MeCN, rt, 24 h, >95% quaternization; (b) 4a (1 equiv), propylene oxide (12 equiv), TFA (12 equiv), CH2Cl2, 35 °C, 24 h, 87% functionalization. The percent quaternization with N,Ndimethylbenzylamine and functionalization with propylene oxide were determined by 1H NMR analysis of the isolated material.
a Reagents and conditions: 1a (1 equiv), epoxide (6 equiv), TFA (6 equiv), CH2Cl2, 35 °C, 24 h. bReagents and conditions: 1b (1 equiv), epoxide (6 equiv), TFA (6 equiv), CH2Cl2, 35 °C, 24 h. cReagents and conditions: 1b (1 equiv), epoxide (12 equiv), TFA (12 equiv), CH2Cl2, 35 °C, 24 h. The percent of functionalization was determined by 1H NMR analysis of the isolated material.
containing polycarbonates offer as substrates for the postpolymerization modification strategies described here, we believe that it will broaden the scope of biomedical applications involving functional polycarbonates.
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To accomplish this, 1d (Scheme 1) was subjected to standard quaternization conditions developed for benzyl chloride containing polycarbonates,45 which afforded the desired ammonium-containing polycarbonate 4a with a high degree of quaternization (Scheme 2). Following purification of this intermediate via dialysis, the ammonium functionalized polycarbonate 4a was reacted with propylene oxide and TFA to give the desired mixed ammonium-sulfonium triblock polycarbonate 4b with a high degree of thioether functionalization (Scheme 2). This result demonstrates the efficacy of sequential and orthogonal functionalizations of polycarbonate scaffolds, opening the way for development of new multifunctional materials. Due to inherent limitations in the preparation of functional polycarbonates, postpolymerization modification offers entry into various scaffolds that would be challenging to access otherwise. To circumvent these difficulties, we have designed new polycarbonates containing thioether groups, which enable facile access to new platforms of functional polycarbonates via the ring-opening of epoxides. This reaction was demonstrated to be highly effective with a broad array of epoxides, including ones bearing galactose, tocopherol, or carbazole substituents, potentially enabling applications as new hydrogels and antimicrobials. Additionally, different comonomers could be introduced in order to fine-tune the aqueous self-assembly of these amphiphilic block copolymers or allow for selective, sequential and orthogonal functionalizations to generate new charged polycarbonates. Given the versatility that thioether-
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsmacrolett.6b00705. Procedures to prepare the polymers and perform the postpolymerization reactions, as well as NMR spectra of all materials (PDF).
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Present Address ∥
University of Washington, Department of Chemistry, 36 Bagley Hall, Seattle, WA 98195, U.S.A. Author Contributions ‡
These authors contributed equally (N.H.P. and M.F.).
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This study was funded by IBM Almaden Research Center, and Institute of Bioengineering and Nanotechnology (Biomedical Research Council, Agency for Science, Technology and Research, Singapore). 1250
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