From Click Chemistry to Cross-Coupling: Designer Polymers from One

Oct 2, 2017 - To date, PPM of RDRP derived polymers using Pd-SMC is underutilized, in spite of the minimal limitations impeding its implementation out...
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From Click Chemistry to Cross-Coupling: Designer Polymers from One Efficient Reaction David H. Howe, Riki M. McDaniel, and Andrew J. D. Magenau* Department of Materials Science and Engineering, Drexel University, Philadelphia, Pennsylvania 19104, United States S Supporting Information *

ABSTRACT: Palladium-catalyzed Suzuki−Miyaura cross-coupling was demonstrated to be a versatile reaction platform to install functional groups onto well-defined polymers derived from reversible addition−fragmentation chain-transfer (RAFT) polymerization. Cross-coupled products were achieved utilizing a range of functional boronic acids including, but not limited to, furan, alkyloxyphenyl, methacrylamide, trifluorophenyl, anthracene, and dimethylaminophenyl. High to quantitative degrees of functionalization were obtained by employing convenient reaction conditions at low to moderate temperatures (23−60 °C), within short reaction times (2−16 h), while using air-stable reagents at 1.5−3.0 equiv. of boronic acid. Specifically, a custom monomer, N-[2-(4-bromophenyl)ethyl]acrylamide (BPEA), was synthesized bearing a reactive handle for subsequent cross-coupling, and its chemical structure was verified using nuclear magnetic resonance. RAFT polymerization of BPEA revealed attributes of a successful reversible-deactivation radical polymerization (RDRP) yielding polymers with predetermined molecular weights and narrow dispersity values (Đ < 1.3). The retention of living chain ends was evidenced by efficient chain extension of poly(BPEA) with N-isopropylacrylamide producing a low dispersity diblock copolymer. Optimal functionalizations were found to be achieved through removal of the RAFT chain transfer agent and, in specific instances, by functionalizing statistical copolymers. The utility of this functionalization strategy, when combined with RDRP, has the ability to provide potentially thousands of structurally diverse functionalized polymers, elucidate quantitative structure−property relationships, and create new avenues to advanced polymeric architectures.

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INTRODUCTION Precision macromolecules derived from state-of-the-art chemical transformations and controlled/living polymerizations have brought within reach an unprecedented array of advanced soft materials having targeted properties, multifunctionality, and sophisticated architectures and morphologies.1,2 One viable route to such designer macromolecules is through the versatile and powerful combination of reversible-deactivation radical polymerization (RDRP) and highly efficient postpolymerization modification (PPM).3−7 PPM is of vital importance to macromolecular design because it enables particular functionalities to be site-specifically generated onto polymer chain-ends, pendent groups, and within regional locations of macromolecules. Further utility of PPM is in its unique ability to install functional groups onto polymers that would otherwise participate in deleterious side-reactions during polymerization, bypassing, for example, undesired cross-linking or chaintransfer events if directly polymerized.1,8 Moreover, the elucidation of quantitative structure−property relationships through PPM is ideal, as one parent polymer can be used to create a multitude of functional variants independent of structural deviations from the degree of polymerization, dispersity, or tacticity.1,6 PPM also serves as an essential tool for combinatorial material science by supporting the bottom-up synthesis of advanced polymer architectures and soft-material © XXXX American Chemical Society

libraries from versatile, precise, and functional macromolecular building blocks. In recent decades, the advent of click chemistry and other highly efficient transformations have propelled forward PPM as a synthetic avenue to functionalized soft materials.9 As astutely outlined by Barner-Kowollik and co-workers, PPMs are particularly useful when they are rapid, innocuous, highyielding, orthogonal, amenable to large-scale purification, and efficient under equimolar conditions,1,10 paralleling the stringent criteria of click chemistry set forth by Sharpless et al.11 To date, a handful of chemical transformations conform to these requirements, albeit to various degrees, notably the copper-catalyzed azide−alkyne cycloaddition,11−15 “thiol−X” chemistries,16−20 activated esters,21,22 Diels−Alder cycloadditions,23−25 and isocyanate modifications,26−30 among other recent and efficient transformations.1,8,31−35 Collectively, such chemical transformations have led to a significant body of research and a large number of technological advancements. However, each functionalization reaction embodies specific strengths and weaknesses limiting its applicability, thus requiring judicious reaction selection based upon the functional group desired, intended end-use, and the material’s design Received: September 22, 2017

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Macromolecules requirements.36 Furthermore, an inherent limitation curtailing the broader utility of all chemical transformations is the number and range of commercially available reaction partners. Commercially available precursors, frequently, have inadequate structural diversity or a lack of specialized functional groups, whereby custom synthesis is then necessary for obtaining the requisite compounds containing the reactive handle and desired chemical moiety. Akin to the vaunted click and associated chemistries, Pdcatalyzed cross-couplings exhibit incredible synthetic diversity and efficiency, building from the foundational work of Heck,37,38 Negishi,39,40 and Suzuki.41,42 Pd-catalyzed crosscouplings have had an enormous impact in organic synthesis, as summarized in many excellent reviews,43−45 because of their mild reaction conditions, extensive functional group tolerance, high chemoselectivity, and orthogonality along with their importance being further underscored by receipt of the 2010 Nobel Prize in Chemistry. Such chemical reactions have allowed the formation of carbon−carbon bonds between inactive/active and unhindered/hindered reaction partners to build stable carbon skeletons for a vast range of complex chemical compounds. In particular, Pd-catalyzed Suzuki− Miyaura cross-coupling has had even further appeal because it employs boron compounds that are generally considered to have reduced toxicity evidenced by their adoption by the pharmaceutical industry.46,47 Owing to these attributes, Pdcatalyzed cross-couplings have found application in numerous industrially relevant processes and exhibit broad utility in the synthesis of fine chemicals, natural products, and biologically active compounds,48,49 for instance, the potent antitumor agent (+)dynemicin A.50 Cross-coupling reactions hold great promise to serve as yet another highly efficient chemical transformation for PPM, especially the underutilized Pd-catalyzed Suzuki−Miyaura cross-coupling (Pd-SMC), because of their many appealing attributes apart from those mentioned above. From a practical standpoint, the scope of commercially available boron-based reagents for Pd-SMC is immense, where boronic acid precursors alone number in the thousands, not including other amenable functionalities including boronate esters, trifluoroborate salts, and MIDA boronates (see reference for specific values).51 Structurally, unlike many of the previously mentioned transformations, Pd-SMC grants access to stable carbon−carbon bond formation, biaryls, and conjugated structures which have implications in application-driven research for organic electronic devices, medicinal compounds, and liquid-crystalline and optical materials.52−54 Pd-SMC is also convenient experimentally: by tolerating moisture, enabling room temperature reactions, and employing air-stable reagents.55,56 Furthermore, literature examples demonstrate the capacity for Pd-SMC to remain high yielding even at catalytic levels of 0.01−0.000001 mol % Pd with nearstoichiometric quantities of each reaction partner.57,58 Aspiring to develop a versatile and robust platform for creating well-defined and functional macromolecular building blocks, we sought to combine Pd-SMC, a highly efficient chemical transformation, with RAFT, a versatile RDRP technique prescribing low dispersity and predetermined molecular weight polymer substrates. To date, PPM of RDRP derived polymers using Pd-SMC is underutilized, in spite of the minimal limitations impeding its implementation outside the interference of thiol or thioester blocking groups.8,59 Accounts of Pd-catalyzed cross-coupling for PPM have been reported;

however, focus has resided primarily on Sonogashira crosscoupling of functional alkynes onto bromine functional homopolymers60,61 and iodine functional hyperbranched polymers.62 In the limited instances of Pd-SMC and RAFT, Pd-SMC has been almost exclusively explored as a tool for creating core−shell nanoparticles,63−65 as a cross-linking method for homopolymers and block copolymers,66 and for synthesizing cyclic bottlebrushes via a “grafting-to” approach.67 Mori and co-workers demonstrated RAFT polymerization of bromophenyl vinyl sulfide and its subsequent Pd-SMC; however, a limited scope of boronic acids were explored consisting of two fully hydrocarbon boronic acids.68 Outside of RDRP, only one instance of Pd-SMC has been reported for the purposes of PPM, whereby Holdcroft et al. functionalized a disperse poly(thiophene) derivative (Đ ∼ 1.51) with bromine69 followed by cross-coupling with a series of functional boronic acids. 70 This two-step PPM yielded high degrees of functionalization by employing multiday reactions at elevated temperatures of 80 °C; however, double bond, stimuliresponsive, or fluorinated functionalities were not explored nor the impact of functionalization on molecular weight or dispersity. As evidenced by the installation of 11 functional boronic acids, this initial study establishes Pd-SMC as a viable PPM procedure to synthesize precision macromolecules under mild reaction conditions using well-defined polymers derived from RAFT polymerization (Scheme 1). A range of functional groups (FGs) were successfully installed, including those wellsuited for quantitative structure−property relationships (FG: 1, 3, 4, 5−7), dynamic-covalent reactions (FG: 2), unique surface and solution properties (FG: 3, 4), reactive alkenes (FG: 8, 9), Scheme 1. Functionalization Strategy via Pd-SMC and RAFT: RAFT Polymerization (1 → P1); Trithiocarbonate End-Group Removal by Aminolysis−Michael Addition (P1 → P2); Functionalization with Pd-SMC (P2 → P3)

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Figure 1. (A) Monomer conversion and first-order kinetic plot as a function of time and (B) number-averaged molecular weight (Mn) and dispersity (Đ) as a function of monomer conversion during the RAFT polymerization of BPEA in DMSO. RAFT was conducted using a [BPEA] = 1.35 M at 70 °C with molar ratios of [BPEA]:[CTA]:[AIBN] = 124:1:0.025. (C) SEC traces illustrating the evolution of molecular weight with time during polymerization. (D) 1H NMR spectra with peak assignments of purified poly(BPEA) in CDCl3. (E) SEC traces before and after chain extension of poly(BPEA)-CTA with NIPAM. Chain extension with RAFT was conducted using 36 wt % of NIPAM in DMSO at 70 °C for 5 h.

in 4 h (Figure 1A). First-order behavior was observed indicative of a constant concentration of propagating species confirmed through the linearity of the first-order plot. SEC analysis during the course of polymerization revealed characteristics of a wellcontrolled RDRP process producing a linear increase in the number-averaged molecular weight (Mn) and a decrease in dispersity (Đ) to ∼1.1 with monomer conversion (Figure 1B). The SEC traces of Figure 1C show a monomodal distribution of species, narrowing molecular weight distribution, and gradual evolution toward higher molecular weight. After polymerization, the polymer was purified by successive precipitations, and its structure was confirmed by 1H NMR (Figure 1D). NMR analysis allowed identification of chemical signatures associated with the aryl bromide pendent group, i.e., “a” and “b”, and those associated with the alpha- and omega-polymer chain ends from the chain transfer agent, i.e., “f”, “g”, and “h”. To confirm the chain-end fidelity and living nature of our prior RDRP, a chain extension with N-isopropylacrylamide (NIPAM) was conducted using RAFT. High chain-end fidelity was observed by the nearly complete disappearance of poly(BPEA) and formation of a higher molecular weight block copolymer, poly(BPEA-b-NIPAM) (Figure 1E), while maintaining a low dispersity of ∼1.13. These results revealed that our aryl bromide monomer was amenable to RAFT polymerization and that its functionality had no observable negative impacts on the RDRP process. Optimization of Pd-Catalyzed Cross-Coupling. Initial attempts at functionalizing our polymer substrate using PdSMC were explored under modified conditions from those reported by Fu et al. (Table 1).56 Such conditions were appealing for postpolymerization functionalization because they utilized common organic solvents which readily solubilize many polymers (e.g., THF or dioxane), employed air-stable reagents, utilized low catalyst loadings, and could be conducted at room temperature while maintaining high yields.55−57,71 It should be

or stimuli-responsive characteristics (FG: 10, 11). Consequently, this work provides a synthetic avenue to predetermined molecular weight and low-dispersity polymers with a wide range of notable functional groups envisioned as building blocks for higher-order structures and the elucidation of quantitative structure−property relationships.

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RESULTS AND DISCUSSION Monomer Synthesis and RDRP. Our endeavor to create one polymer substrate capable of multiple transformations via Pd-SMC began by selecting an appropriate reactive moiety and synthesizing its analogous monomer. Based upon many significant developments in the literature, an aryl bromide functionality was chosen because it exhibited versatility with a variety of boronic acids in high yields under convenient reaction conditions.55,57 The desired aryl bromide functional monomer, N-[2-(4-bromophenyl)ethyl]acrylamide (BPEA) in Scheme 1 (1), was prepared in high yields with minimal purification through acetylation of 2-(4-bromophenyl)ethylamine with acryloyl chloride. The chemical structure of BPEA was verified with 1H and 13C NMR, and the peak assignments are provided within the spectra in Figures S1 and S2 of the Supporting Information. This acrylamide monomer was preferred over commercially available 4-bromostyrene because of its relatively large propagation rate coefficient, thus promoting rapid polymerization, and because of the precursor and product polymers’ (Scheme 1, P2 and P3) favorable solubility in common size exclusion chromatography (SEC) eluents. Polymerization of this new acrylamide was next explored with RDRP having the goal of synthesizing well-defined polymers in a controlled fashion with high chain-end fidelity. RAFT was conducted in DMSO at 70 °C using AIBN and a trithiocarbonate chain transfer agent (CTA), as shown in Scheme 1, resulting in polymerization of ca. 65% of the BPEA C

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Macromolecules Table 1. Precursors and Functionalized Polymers Using Pd-Catalyzed Suzuki−Miyaura Cross-Coupling polymer precursor

cross-coupling conditions

product

entry

functionality (FG no.)

PDI

composition (BPEA/NIPAM)

[B(OH)2]/[Aryl-Br]/[Pd]

temp (°C)

time (h)

PDI

% ff

a,b

1: phenyl 1: phenyl 1: phenyl 2: furan 2: furan 3: fluorophenyl 4: trifluorophenyl 5: ethoxyphenyl 6: butoxyphenyl 7: octyloxyphenyl 8:methacrylamide 9: styrene 10: dimethylamino 11: anthracene

1.14 1.14 1.16 1.14 1.14 1.14 1.14 1.16 1.16 1.17 1.17 1.17 1.25 1.22

P(BPEA)-CTA P(BPEA) P(BPEA0.53-co-NIPAM0.47) P(BPEA) P(BPEA) P(BPEA0.51-co-NIPAM0.49) P(BPEA0.54-co-NIPAM0.46) P(BPEA0.53-co-NIPAM0.47) P(BPEA0.53-co-NIPAM0.47) P(BPEA0.52-co-NIPAM0.48) P(BPEA0.52-co-NIPAM0.48) P(BPEA0.52-co-NIPAM0.48) P(BPEA0.52-co-NIPAM0.48) P(BPEA0.22-co-NIPAM0.78)

1.5/1/0.06 1 5/1/0.06 1.5/1/0.06 1.5/1/0.06 1.5/1/0.015 1.5/1/0.06 1.5/1/0.06 1.5/1/0.06 1.5/1/0.06 1.5/1/0.06 3.0/1/0.06 3.0/1/0.06 3.0/1/0.06 3.0/1/0.06

45 45 45 45 23 45 45 45 45 45 23 23 60 60

5 5 5 5 5 5 5 5 5 5 4 2 16 16

1.41 1.29 1.25 1.18 1.18 1.33 1.11 1.19 1.23 1.30 1.30 1.30 1.39 1.32

35 60 >99 >99 >99 >99 >99 >99 95 >99 90 98 >99 >99

1 2b 3b 4b 5b 6b 7b 8b 9b 10b 11c 12c 13c,d,e 14c,d,e a

Performed without removal of the CTA end-group. bConducted with [Aryl-Br] = 0.25 M. cConducted with [Aryl-Br] = 0.125 M. dCross-coupling was performed in a 50 vol % mixture of THF in DMSO. eSEC was performed with THF SEC instead of DMac SEC. f% f values were calculated by 1 H NMR.

prompted us to investigate the impact of the CTA end-group on cross-coupling efficiency and the resultant molecular weight distribution. The influence of the terminal trithiocarbonate group on cross-coupling was explored by first cleaving the CTA from the polymer through a one-pot aminolysis−Michael addition reaction, in a similar fashion to established literature protocols,73−75 developed, in part, by concerns of their potential biological toxicity when used in biomedical applications.76 Trithiocarbonate cleavage and conversion to a thiol ether end-group was performed using hexylamine (HexylNH2) and a dimethylphenylphosphine catalyst (Me2PPh), according to Scheme 1 (P1 → P2), in the presence of an acrylate, e.g., ethylene glycol methyl ether acrylate (EGMEA), to prevent disulfide formation from the otherwise terminal thiol chain-ends.75 Successful removal of the CTA end-group was verified by UV−vis and NMR analysis. UV−vis spectra of poly(BPEA) after aminolysis−Michael addition exhibited a lack of the characteristic trithiocarbonate absorption band at ca. 300−310 nm (Figure 2B).77−79 Furthermore, these results were bolstered by 1H NMR analysis showing the disappearance of trithiocarbonate resonances at 0.88 and 1.25 ppm associated with the −C12H25 functional group of the CTA (Figure S3). Upon removal of trithiocarbonate, Pd-catalyzed cross-coupling was repeated (Table 1, entry 2) using identical conditions as previously employed. In alignment with our hypothesis, we instead observed a monomodal distribution of polymers having a lower dispersity (Đ ≈ 1.29), as shown in Figure 2C, following the cross-coupling reaction with phenylboronic acid. However, in spite of this success, the % f only increased to ca. 60%, which we speculated to be a result of limited solubility of the intermediate phenyl-functionalized product in the reaction medium. In an effort to counteract this and gain a more soluble reaction product, a 1:1 molar copolymer of BPEA and NIPAM was synthesized and employed in cross-coupling with phenylboronic acid (Table 1, entry 3). Fortuitously, the poly(BPEAco-NIPAM) substrate yielded a quantitative functionalization according to NMR with a monomodal and narrow Đ of 1.25. Accompanying 1H NMR spectra and SEC traces can be found in Figures S4 and S5.

noted that all functionalizations reported in this work were formulated under ambient conditions in the presence of O2 and then brought into a glovebox where deoxygenated THF was charged into the reactor to commence cross-coupling. Our first cross-coupling reactions were performed between poly(BPEA)-CTA, i.e., P1 in Scheme 1, and phenylboronic acid (Table 1, entry 1). Reaction mixtures were typically formulated using a slight excess of boronic acid to aryl bromide, i.e., [B(OH)2]:[Aryl-Br] = 1.5:1, and observed to be heterogeneous in nature accompanied by a color change in the early stages of reaction. After 5 h, the reaction product was purified through successive precipitations and subsequent NMR analysis revealed ca. 35% functionalization (% f). Characterization with SEC revealed a bimodal molecular weight distribution having peak molecular weights of 31 800 and 65 400 g/mol (Figure 2A, red trace). Interestingly, the higher molecular weight population had a molecular weight value nearly double that of the lower molecular weight population, indicative of two polymer chains associating to form the higher molecular weight product. Similar molecular weight observations were also reported by Endo et al.66 SEC analysis also suggested these associations were noncovalent in nature as the relative fractions of the high and low molecular weight populations were observed to fluctuate within a sample depending on work-up. From the observed behavior and literature, we hypothesized complexation with palladium was likely occurring through the terminal trithiocarbonates of two polymer chains. Support for this conjecture is, in part, based upon the fact that many Pd scavenging resins operate through sulfur-based functional groups, e.g., methylthiourea in QuadraSil MTU and alkylmercaptans in QuadraSil MP. Furthermore, numerous literature accounts detail sulfur’s propensity to interact35 and complex with palladium,72 in addition to its known tendency to promote side reactions and poison cross-coupling catalysts.6 Therefore, we speculated that the bimodal product would revert to a monomodal distribution upon removal of residual Pd, hence causing disassociation of the coordinating polymer chains. In fact, after exposing a crude reaction mixture to a metal scavenging resin, i.e., QuadraSil MP, the higher molecular weight population decreased gradually over the course of 3 days as shown in Figure 2A (gray and black traces). These results D

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Figure 2. (A) SEC traces after Pd-SMC using a trithiocarbonate-terminated polymer, poly(BPEA)-CTA, and SEC traces at various times after exposure to a metal-scavenging resin. (B) UV−vis spectra of a chain-transfer agent (CTA), poly(BPEA)-CTA before aminolysis−Michael addition, and poly(BPEA) after aminolysis−Michael addition. (C) SEC traces before and after Pd-catalyzed cross-coupling using poly(BPEA) without a terminal trithiocarbonate functionality. (D) 1H NMR spectra of a poly(BPEA) before and after functionalized with furan boronic acid and (E) corresponding SEC traces. (F) 1H NMR spectra of a poly(BPEA-co-NIPAM) after functionalized with styreneboronic acid.

Quantitative % f values were determined via 1H NMR, i.e., by integration of the furanyl region, “e” and “f”, versus the pendent methylene protons of poly(BPEA), i.e., “c” at 2.82 ppm. For all other functionalizations, the reader is directed to the Supporting Information for details. The ability to install furan functional groups on every repeat unit clearly indicated the efficiency of the Pd-catalyzed crosscoupling reaction, which encouraged us to explore diminished catalyst concentrations and reduced reaction temperatures. Following literature accounts which utilized lower catalyst loadings at ambient temperature (Table 1, entry 5),55 we employed a cross-coupling reaction at 1.5 mol % Pd at 23 °C using 2-furanboronic acid. To our surprise, even with a 4-fold reduction in catalyst and an accompanying ∼20 deg temperature drop, quantitative functionalization was possible within 5 h while maintaining a monomodal and narrow Đ of 1.18 (Figure 2E). Success with furan functionalization was particularly exciting because radical polymerization processes with furfuryl moieties are typically prone to side reactions,81,82 making high molecular weight furan functional polymers difficult to polymerize directly from monomer, validating a postpolymerization functionalization strategy. Moreover, furan functionalities are useful for synthesizing dynamic-covalent materials via (retro) Diels−Alder reactions. To further expand the structural diversity of functional groups, we next explored fluorine functional boronic acids (FG: 3, 4) for producing semifluorinated polymers, potentially exhibiting unique surface and solution properties,83 and functionalities having subtle structural variations for predicting polymer properties (FG: 5−7). Structural variations in polymer pendent groups have been shown to dramatically impact polymer properties and are important for determining underlying quantitative structure−property relationships, e.g.,

Structural Diversity of Pd-SMC for PPM. Our prior success prompted us to investigate the scope of functional groups which could be installed via Pd-SMC and probe reaction conditions at lower catalyst concentrations and temperatures. The prospect of installing a range of functional groups which could impart tailored properties or unique attributes were of particular interest, i.e., for quantitative structure−property relationships (FG: 1, 3, 4, 5−7), dynamic-covalent bonding (FG: 2), fluorocarbon-based surface and solution properties (FG: 3, 4), reactivity (FG: 8, 9), and stimuli-responsiveness (FG: 10, 11). In this initial work, 11 boronic acids were installed to high degrees of functionalization (% f ≥ 90), thus demonstrating the versatility of this method as an avenue to functionalized polymers. Scheme 1 and Table 1 summarize the structures, reaction conditions, and results of each of these postpolymerization functionalizations. Utilizing the conditions established with phenylboronic acid, cross-coupling was investigated with BPEA homopolymer and 2-furanboronic acid (Table 1, entry 4). Anticipating favorable solubility of a furan functional polymer in THF, we rationalized this coupling reaction could be easily accomplished using poly(BPEA) homopolymer instead of the previously required poly(BPEA-co-NIPAM) copolymer. Indeed, after cross-coupling the % f was determined to be quantitative via both 1H and 13 C NMR analysis. From the 1H NMR spectra shown in Figure 2D, functionalization was evident by the appearance of new resonance signals corresponding to the furanyl functionality at 7.35 “d”, 6.49 “e”, and 6.36 “f” ppm. Furthermore, 13C NMR analysis bolstered the prior 1H NMR results, indicating that the furan functionalization was quantitative, due to the absence of signals from the aryl bromide (Figure S7), most notably the bromine bonded carbon at 120 ppm. Peak assignments were made from the literature80 and using predictive software. E

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Macromolecules thermal and rheological,84 polymer hydrophobicity,85 and biological properties.86,87 Two fluorinated boronic acids were attempted, 4-fluorobenzeneboronic acid and 2,4,6-trifluorobenzeneboronic acid (Table 1: entries 6 and 7, respectively), and in both cases quantitative NMR analysis of the final products revealed complete functionalization as shown in Figures S8A and S9A. Furthermore, characterization with SEC showed monomodal populations having low to moderate dispersity values of ∼1.1−1.3; however, a slight shoulder was observed with 4-fluorobenzeneboronic acid. Although 4fluorobenzeneboronic acid has been demonstrated to be stable using a similar catalytic system,88 the observed shoulder in SEC (Figure S8) is speculated to arise from an unidentified side reaction, the origin of which is the subject of current investigations in our laboratory. Higher catalyst loadings were employed in these cases to ensure that quantitative functionalization occurred within 5 h as initial attempts with phenylboronic acid at low concentrations yielded incomplete functionalization. In addition to fluorinated boronic acids, a series of alkyloxyphenylboronic acids (ethoxy-, butoxy-, and octyloxy-substituted, FG: 5−7) were investigated under identical reactions conditions as shown in Table 1, entries 8− 10. In each instance, % f values of ≥95 were achieved on poly(BPEA-co-NIPAM) substrates while maintaining narrow dispersity values of ca. ∼1.2−1.3. 1H NMR spectra with peak assignments and SEC traces for FG: 5−7 can viewed in Figures S10−S12. The last set of functional boronic acids we sought to explore were inherently incompatible with radical polymerization processes (FG: 8, 9) or which exhibit stimuli-responsive characteristics (FG: 10, 11). To evaluate the former, alkenecontaining moieties were explored via cross-coupling with (3methacrylamidophenyl)boronic acid and 4-vinylphenylboronic acid (Table 1, entries 11 and 12) because of their utility as reactive handles for building advanced macromolecular architectures. Our initial attempts at functionalizing poly(BPEA-co-NIPAM) with pendent methacrylamide functional groups resulted in incomplete functionalization (% f ≈ 12) or gelation and broad dispersities (Đ ≈ 10) due to intermolecular cross-linking reactions. Therefore, additional experimentation was conducted, as summarized in Table S1, to minimize dispersity and maximize % f as a function of temperature, catalyst concentration, substrate concentration, and excess boronic acid to aryl bromide. Through these experiments, optimal conditions were discovered yielding % f values of ∼90 with dispersity values of ∼1.3 by utilizing short reaction times, room temperature reactions, dilute substrate concentrations, and a 3-fold excess of boronic acid (Table 1, entry 11, and Figure S13). These optimized conditions were also utilized during functionalization with styrene (FG:9) giving nearquantitative functionalization of ca. 98% and minor amounts of cross-linking (Table 1, entry 12). 1H NMR analysis clearly showed resonances from the double bonds, i.e., a, a′, and b (Figure 2F), and a slight high molecular weight shoulder in the SEC trace (Figure S14). To finalize our efforts, we investigated pH-responsive (4dimethylamino)phenylboronic acid and UV-responsive anthraceneboronic acid (Table 1, entries 13 and 14). Installation of both functional groups was achieved to quantitative levels as indicated by NMR, and these groups were observed to have broader dispersity values of ∼1.3−1.4 from SEC analysis (Figures S15 and S16). To achieve quantitative functionalization in these instances, modified Pd-

SMC conditions were required. Dissolution of the boronic acids and functionalized polymer products necessitated a mixed solvent system of DMSO and THF, in addition to higher temperatures and a 3-fold excess of boronic acid to promote faster reaction rates. In the case of anthracene, an even larger mole fraction NIPAM copolymer was required to prevent the intermediate functionalized polymer product from becoming insoluble in the reaction mixture, as specified in Table 1, entry 14.

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CONCLUSION High to quantitative functionalizations with 11 different boronic acids were demonstrated with Pd-SMC on poly(BPEA) and poly(BPEA-co-NIPAM) substrates. Versatility of this PPM was shown by its broad functional group tolerance evidenced through installation of reactive double bonds, fluorinated functionalities, heterocyclic species, and photoand pH-responsive moieties. This work thus provides a synthetic avenue to obtain controlled molecular weight and low dispersity polymers with a wide range of useful or notable functional groups. High degrees of functionalization were obtained by employing convenient reaction conditions at low to moderate temperatures (23−60 °C) within short reaction times (2−16 h), while using air-stable reagents at 1.5−3.0 equiv of boronic acid. The present work sets the foundation for utilizing Pd-SMC in combination with RDRP-derived polymers to explore quantitative structure−property relationships, sophisticated architectures, and macromolecular building blocks by exposing a rich compositional space of commercially available functional groups numbering in the thousands. Future investigations are anticipated using Pd-SMC in several areas, including highly active catalytic systems at diminished concentrations, solid-support catalysts, alternative reaction partners (e.g., boronic esters, trifluoroborate salts, and MIDA boronates), and for development of quantitative structure− property relationships.

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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.7b02041. Experimental details; Figures S1−S16 and Table S1 (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail [email protected] (A.J.D.M.). ORCID

Andrew J. D. Magenau: 0000-0002-7565-9075 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the Department of Education Graduate Assistance in Areas of National Need (GAANN) Fellowship Award #P200A150240 and Drexel University Startup Funds. Johnson Matthey is also gratefully acknowledged for supplying metal scavengers and MarvinSketch for their generous allowance of an academic license for this work. F

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DOI: 10.1021/acs.macromol.7b02041 Macromolecules XXXX, XXX, XXX−XXX