Convergent Approach to Boronic Acid Functionalized Polycarbonates

Feb 27, 2017 - (1, 2) One approach to facilitate responsiveness in materials is via the .... backbone allows for further installment of different char...
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Convergent Approach to Boronic Acid Functionalized Polycarbonates: Accessing New Dynamic Material Platforms Nathaniel H. Park,† Zhi Xiang Voo,‡ 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

‡

S Supporting Information *

ABSTRACT: Polycarbonates are routinely utilized for diverse medicinal applications and are highly efficacious scaffolds for drug delivery and antimicrobial treatments. In order to provide for robust, dynamic platforms for biomedical applications, we have developed new routes for the incorporation of boronic acids into the polycarbonate backbone. These routes take advantage of straightforward postsynthesis modification of established polycarbonate backbones, enabling the preparation of a diverse array of boronic acid functionalized polycarbonates from readily accessible polycarbonates. In particular, this approach circumvents the need for de novo monomer synthesis, functional group incompatibilities, and deprotection steps that often limit other methods. This strategy has been demonstrated using a broad array of unprotected boronic acids to produce both neutral and cationic boronic acid functionalized polycarbonates.

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Scheme 1. Approaches to Preparing Boronic Acid Functionalized Polycarbonates

esponsive materials are highly desired for their ability to dynamically respond to external stimuli, which can enable predictable and precise control over material behavior in different environmental contexts.1,2 One approach to facilitate responsiveness in materials is via the incorporation of aryl boronic acids within the polymer backbone. Such materials have been utilized in numerous different applications, including selective insulin release, HIV barriers, drug delivery, and glucose responsive hydrogels.3−6 The responsiveness of boronic acid-based materials is primarily due to the facile equilibrium between the free boronic acid and the boronic ester via diol complexation.3−8 This equilibrium can be directly influenced by a number of factors including: the pH of the medium, the pKa of the boronic acid and the diol, the dihedral angle of the diol, and the steric encumbrance of aryl boronic acid.3−10 As such, the bulk material properties can be directly tuned via use of the appropriate functional boronic acid.3−8,11 Despite the demonstrated benefits and versatility of boronic acid based material platforms, there are very few reports of boronic acid containing polycarbonate scaffolds.12−14 Given the numerous biomedical applications of polycarbonate scaffolds and their inherent biocompatibility,12−17 we sought to develop new routes to access boronic acid functionalized polycarbonates. Previous approaches to boronic acid incorporation into polycarbonates relied upon either the preparation of a boronic acid functionalized carbonate monomer for ring-opening polymerization or postsynthesis modification of a polycarbonate scaffold (Scheme 1).12−15 Unfortunately, the synthesis of carbonate monomers limits the types of functional groups that may be present on the aryl boronic acid as they may interfere with the ring-opening polymerization process. Moreover, the boronic acid itself must be protected for successful polymer© XXXX American Chemical Society

ization and hence requires an additional deprotection step after polymerization.12,13 Prior postsynthesis modification approaches relied upon the polymerization of a benzyl ester carbonate monomer, which necessitated an additional step of postpolymerization hydrogenolysis prior to boronic acid incorporation.14 Although these routes were successful in accessing new polycarbonate materials for biomedical applications, more direct approaches are needed. Specifically, the incorporation of highly functionalized boronic acids without the need for deprotection steps is needed to fully exploit the versatility of polycarbonates in the context of responsive materials. Received: November 16, 2016 Accepted: February 22, 2017

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Figure 1. Synthesis of polycarbonate substrates for boronic acid functionalization. Table summarizes the results of the polymerization reactions. a Determined by 1H NMR analysis of the isolated polymer. bDetermined via GPC using polystyrene standards and THF as the eluent. Reagents and conditions: Ring-opening polymerization: monomer, PEG initiator, triflic acid, CH2Cl2, rt or monomer, mPEG5K, DBU, TU, CH2Cl2, rt; Amine functionalization: 1c, 1e, or 1f, amine, Et3N, THF, rt or 1d, DABCO, THF, rt. DABCO = 1,4-Diazabicyclo[2.2.2]octane, DBU = 1,8Diazabicycloundec-7-ene, TU = N-(3,5-bistrifluoromethyl)phenyl-N′-cyclohexylthiourea, THF = tetrahydrofuran.

to drug-delivery applications.12,15−17,23,24 Additionally, we polymerized a benzyl chloride functionalized carbonate monomer 1b to afford the diblock copolymer 1f (Figure 1), to allow for further functionalization with amine containing boronic acids. After preparing the polycarbonate starting materials, we investigated the functionalization of 1c, 1d, and 1f to generate neutral boronic acid containing polymers. After evaluating several conditions using 4-aminomethyl boronic acid, we found that stirring the reaction at room temperature in DMF with triethylamine afforded 51% functionalization of the polymer backbone (2a, Figure 2). Higher functionalization could be achieved when additional equivalents of the boronic acid were utilized (2a, Figure 2). Additionally, we observed that the polymer backbone was stable to these reaction conditions, as determined by GPC measurements of an analogous pinacolprotected substrate (see Supporting Information). Similar reaction conditions enabled the incorporation of 2-aminomethyl-4-fluorophenyl boronic acid and a Wulff-type boronate with moderate levels of functionalization (2b and 2d, respectively, Figure 2). These conditions could also be utilized on triblock polycarbonates, giving the desired product with 71% functionalization (2e, Figure 2). 3-Aminophenylboronic acid was found to be much less reactive than the benzyl or

Previously, we have disclosed methods for direct functionalization of polycarbonates by starting from a polycarbonate containing pendant pentafluorophenyl ester or benzyl chloride functional groups.18−20 These platforms allowed for easy access to polycarbonates with pendant amides or quaternary amines with high levels of functionalization. Due to the robustness of these approaches, we felt that they would be ideally suited for incorporation of free boronic acids into polycarbonate backbones. This would allow for the direct incorporation of important functional boronic acids such as Wulff-type boronates,21 which are frequently used in material and sensing applications.3−6,22 These types of boronic acid containing polycarbonates would otherwise be inaccessible via traditional de novo monomer synthesis and polymerization. To accomplish this, we prepared several different polycarbonates that could be utilized as starting materials to access neutral or cationic boronic acid functionalized polycarbonate scaffolds (Figure 1). Starting from thepentafluorophenyl ester cyclic carbonate monomer 1a, we synthesized three different polycarbonates via acid-catalyzed ring-opening polymerization (1c, 1e, 1f, Figure 1). We focused on using the appropriate PEG macroinitiator to prepare di- and triblock polycarbonates with short chain lengths (10−20 units) due the importance of these types of copolymers in nanomedicine, particularly with regard 253

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containing polycarbonates, we first prepared amine functionalized polycarbonates 1g−j via either transamidation of pentafluorophenyl ester polycarbonates or by quaternization of the pendant benzyl chloride (Figure 1). Next, we functionalized 1g and 1h (Figure 1) by treating them with commercially available bromomethylphenyl boronic acids, affording high levels of boronic acid incorporation in the polycarbonate backbone (3a and 3b, Figure 3a). A cationic DABCO containing polycarbonate (1i, Figure 4) could also be further alkylated in a similar manner to obtain the doubly charged polycarbonates (3c and 3d, Figure 3a). These conditions were also applicable to ABA triblock copolymers with pendant dimethylamino groups, affording the corresponding charged polycarbonate with 73% functionalization (3f, Figure 3a). Direct quaternization of a piperazine containing boronic acid with 1d (Figure 1) allowed for the generation of a cationic polymer containing a Wulff-type boronate (3e, Figure 3). As accessing charged polycarbonate scaffolds proved to be highly successful, we also investigated the substoichiometric functionalization of heteroaryl containing polycarbonates with boronic acids. Partial functionalization of the polycarbonate backbone allows for further installment of different charged groups, enabling additional fine-tuning of the material properties.30 Thus, by treating the imidazole functionalized diblock polycarbonate (1g, Figure 1) with a substoichiometric amount (per imidazole residue) of 3-bromomethylphenyl boronic acid, afforded 35% functionalization of the backbone (3g, Figure 3b). Further alkylation 1,3-propane sultone gave the desired mixed charged boronic acid containing polycarbonate (3h, Figure 3b). Given that boronic acid containing polymer scaffolds are frequently utilized for binding a variety of diols,3−10 we sought to examine the feasibility of one of our prepared systems to complex with a small molecule diol. For this, we selected 3fluorocatechol, as fluorine containing molecules offer a convenient and highly sensitive NMR handle and have been previously utilized in sensing applications involving boronic acids.31−33 Model studies on a small molecule system were conducted initially using 3-fluorocatechol and p-tolylboronic acid (Figure 4A−C). These studies revealed, that in the presence of an amine base, a new upfield peak at −144 ppm is formed, likely corresponding to the boronate ester of 3fluorocatechol and p-tolylboronic acid (Figure 4C).34 In the absence of base, no new upfield peak is observed (Figure 4B). In contrast, when 3e was treated with 3-fluorocatechol in the absence of base, we were able to observe the formation of a small new peak at −143 ppm,35 likely indicating the formation of a new complex between the polymer 3e and 3-fluorocatechol (Figure 4). This observation is consistent with the enhanced diol affinity exhibited by Wulff boronates.3−6,9 Additionally, the result is promising, as it demonstrates the clear potential for further polycarbonate material development via fine-tuning of the boronic acid properties. Boronic acid containing polymers have been extensively demonstrated to have unique, dynamic properties that afford them a multitude of applications. Despite the utility of boronic acid containing materials, very little attention has been paid to preparing boronic acid functionalized polycarbonate platforms. To address this, we have demonstrated several effective strategies for modifying polycarbonate backbones with unprotected boronic acids. These approaches circumvent common limitations associated with polycarbonates, namely, functional group incompatibilities with the ring-opening

Figure 2. Preparation of boronic acid containing polycarbonates. Reagents and conditions: polymer (1 equiv), boronic acid (1.0−2.4 equiv per OC6F5), Et3N (2.2−2.4 equiv per OC6F5), DMF, rt, 24 h; (a) DMF/THF (1:1) used as solvent; (b) HOBt (1.2 equiv per OC6F5) used instead of Et3N; (c) polymer (1 equiv), boronic acid (2.2 equiv per BnCl), DIEA (2.2 equiv per BnCl), DMF/MeCN (1:1), 60 °C, 18 h. Percent functionalization was determined by 1H NMR analysis of isolated material. Et3N = triethylamine, DIEA = diisopropylethylamine, DMF = N,N-dimethylformamide, MeCN = acetonitrile, and HOBt = 1-hydroxybenzotriazole.

aliphatic amino-boronic acids and did not incorporate into the polycarbonate backbone under the standard reaction conditions. Instead, by using 1-hydroxybenzotriazole (HOBt) as an activating agent in place of triethylamine, we were able to observe 55% functionalization of the polycarbonate (2c, Figure 2). A control experiment conducted in the absence of the boronic acid showed little, if any incorporation of HOBt into the polymer backbone.25 Finally, we also investigated the possibility of direct alkylation of an ortho-amino boronic acid with the benzyl chloride polycarbonate 1d. In this case, only 16% functionalization was attained (2f, Figure 2), presumably due to the attenuated nucleophilicity of the amine as a result of B−N interactions.22 Having successfully prepared neutral boronic acid modified polymers, we next examined conditions to prepare cationic polycarbonates containing boronic acids. The development of new routes to cationic materials is highly important as charged polymers have numerous and wide ranging applications including tissue engineering, antimicrobials, gene therapy, and drug delivery.26−29 In order access cationic boronic acid 254

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Figure 3. Synthesis of cationic boronic acid polycarbonates and dual functionalization of a polycarbonate scaffold. (A) Reagents and conditions: polymer (1 equiv), boronic acid (1 equiv), DMF/MeCN (1:1), 60 °C, 24 h. (B) (a) 1g (1 equiv), boronic acid (0.36 equiv per imidazole), DMF/ MeCN (1:1), 60 °C, 24 h; (b) 3g (1 equiv), 1,3-propane sultone (2.5 equiv per imidazole), DMF/MeCN (1:1), 60 °C, 24 h. Percent functionalization determined by 1H NMR analysis of isolated material.

dynamic, biocompatible boronic acid containing polycarbonates.

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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/acsmacrolett.6b00875. Experimental details and NMR spectra (PDF).

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID Figure 4. 19F NMR spectra of 3-fluorocatechol binding experiments: (A) 3-fluorocatechol in MeOD; (B) 3-fluorocatechol/ArB(OH)2 (1:1) in MeOD; (C) 3-fluorocatechol/ArB(OH)2 (1:1) in MeOD with 2 equiv DIEA; (D) 3-fluorocatechol/3e (2 equiv 3-fluorocatechol; per boronic acid residue) in MeOD. ArB(OH)2 = 4-methylphenylboronic acid and DIEA = diisopropylethylamine.

Nathaniel H. Park: 0000-0002-6564-3387 Yi Yan Yang: 0000-0002-1871-5448 James L. Hedrick: 0000-0002-3621-9747

polymerization and postpolymerization deprotection steps. Additionally, this postpolymerization functionalization approach with boronic acids avoids tedious monomer synthesis, enabling a more synthetically convergent approach to boronic acid containing polycarbonates. Thus, by side-stepping many of the traditional disadvantages in the preparation of functional polycarbonates, we have enabled access to new classes of

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Notes

The authors declare no competing financial interest.

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