Article pubs.acs.org/Macromolecules
Multifunctional Homopolymers: Postpolymerization Modification via Sequential Nucleophilic Aromatic Substitution Tomohiro Kubo, C. Adrian Figg, Jeremy L. Swartz, William L. A. Brooks, and Brent S. Sumerlin* George & Josephine Butler Polymer Research Laboratory, Center for Macromolecular Science & Engineering, Department of Chemistry, University of Florida, PO Box 117200, Gainesville, Florida 32611-7200, United States S Supporting Information *
ABSTRACT: Despite recent progress for efficient and precise synthesis of functional polymers, few reports describe postpolymerization functionalization strategies for the controlled incorporation of multiple pendent groups per repeat unit. Cyanuric chloride, or 2,4,6-trichloro-1,3,5-triazine (TCT), offers a facile method to introduce distinct pendent functionalities. An acrylamide monomer containing a triazine ring with two electrophilic sites was prepared from TCT and polymerized via reversible addition−fragmentation chain transfer (RAFT) polymerization. Subsequent nucleophilic aromatic substitution reactions using a combination of amine and thiol nucleophiles introduced two functionalities into each repeat unit of the RAFTderived polymers. The success of each postpolymerization modification reaction was confirmed by 1H NMR spectroscopy and size-exclusion chromatography, and small molecule model studies corroborated the high chemoselectivity of the nucleophilic aromatic substitution reactions. This postpolymerization modification strategy based on TCT enables a facile and efficient synthesis of multifunctional homopolymers.
■
INTRODUCTION The number, type, and placement of functional groups are key characteristics that define the properties and utility of macromolecular materials.1,2 Through the installation of suitable pendent groups via postpolymerization functionalization, polymers can offer performance enhancement and expanded applicability over unfunctionalized analogues. In particular, polymers with multiple distinct functionalities provide several advantages as compared to their nonfunctional or monofunctional counterparts3−5 and enable new applications in areas ranging from surface engineering6−8 to polymeric nanomedicine.9,10 Postpolymerization modification, which has been widely utilized to introduce functionality not compatible with polymerization, characterization, or processing conditions,11 allows modular syntheses while keeping important variables (e.g., average degree of polymerization) constant,12−17 thus allowing structure−property relationships of polymers to be systematically investigated. However, one limitation of postpolymerization functionalization is the requirement for efficient reactions, as steric hindrance and neighboring group effects in macromolecules often decrease conversions in reactions on polymers. Moreover, as compared to small © XXXX American Chemical Society
molecule reactions in which unreacted starting materials can generally be readily removed from desired products, inefficient reactions on polymers result in unreacted groups that are covalently linked via the polymer structure to reacted units.11 Synthesizing multifunctional homopolymers, defined here as polymers bearing multiple functionalities in each repeat unit, by postpolymerization modification not only requires reactions that are efficient but also necessitates transformations that are selective.18 As a result, imparting more than one functional group per repeat unit has proven challenging, and only a limited variety of chemical transformations (e.g., azide−alkyne cycloaddition, thiol−ene/yne chemistry) have been commonly employed.19 The challenge of incorporating multiple functionalities per repeat unit has compelled many research groups to explore efficient synthetic routes to multifunctional homopolymers.20−25 For example, polymers containing glycidyl groups allow multifunctionalization by sequentially reacting the epoxide with a nucleophile and then functionalizing with an electrophile.26−31 This synthetic strategy has also been applied Received: January 26, 2016 Revised: February 17, 2016
A
DOI: 10.1021/acs.macromol.6b00181 Macromolecules XXXX, XXX, XXX−XXX
Article
Macromolecules
Scheme 1. Synthesis and Reversible Addition−Fragmentation Chain Transfer Polymerization of Acrylamide Monomers Derived from 2,4,6-Trichloro-1,3,5-triazine (TCT)
Figure 1. Data from the reversible addition−fragmentation chain transfer (RAFT) polymerization of monomer 2: (a) pseudo-first-order kinetic plot for the RAFT polymerization of 2; (b) number-average molecular weight (Mn,SEC‑MALS) and polymer molar-mass dispersity (Mw/Mn) as a function of conversion; (c) size-exclusion chromatograms at different polymerization time points.
nucleophiles (i.e., amines or thiols), and highly efficient ω,ωheterodifunctionalized end-group installation was confirmed via matrix-assisted laser desorption−ionization time-of-flight mass spectrometry. In this study, we utilize TCT for the synthesis of multifunctional homopolymers. Although TCT has been previously employed for the preparation of functional polymers,41,42,57−62 its chemoselectivity has not been exploited for polymer repeat-unit heterodifunctionalization. We performed reversible addition−fragmentation chain transfer (RAFT)63 polymerization of an acrylamide monomer prepared from TCT to synthesize well-defined polymers possessing two electrophilic sites in each repeat unit. The activated polymers were reacted with one nucleophile or two distinct nucleophiles to afford homo- or heterodifunctionalized polymers, respectively. This facile, efficient, and modular postpolymerization modification approach provides access to otherwise laboriously prepared multifunctional homopolymers.
to the preparation of various polymeric topologies such as hydrogels, 32 hyperbranched polymers, 33 and polymer brushes.34 Kakuchi and Theato performed efficient, sequential sulfoamidation−Mitsunobu reactions using two nucleophiles (i.e., amines followed by alcohols) to prepare multifunctional homopolymers.35 Multicomponent reactions have also allowed installation of two or more functionalities within macromolecular scaffolds.36−40 However, many of the current approaches rely on rather unique, and often, rare chemical transformations to achieve multifunctional homopolymers, potentially limiting substrate/substituent scopes. In search of potential strategies to facilitate the synthesis of multifunctional homopolymers, we decided to explore the utility of 2,4,6-trichloro-1,3,5-triazine (TCT) for installing two reactive groups onto polymers for subsequent functionalization via straightforward nucleophilic aromatic substitution. Simanek and co-workers have extensively studied TCT for dendrimer synthesis,41−48 and the compound has also been employed in a number of other ways, including as immobilized reagents,49 nucleophile scavengers,50 PET imaging probes,51 targeting conjugates,52 porous materials,53 and sequence-defined polymers.54 TCT undergoes sequential nucleophilic aromatic substitution reactions at increasing temperatures because each substitution step decreases the reactivity of the triazine ring through loss of σ-bond electron withdrawal of a chlorine atom and gain of π-orbital electronic donation of added nucleophiles.55 TCT’s controlled electrophilicity thus allows chemoselective and sequential functionalization that parallels previous multifunctional polymer synthesis techniques, yet can accommodate a broad scope of readily available nucleophiles. For example, we recently reported that TCT can be used to synthesize ω,ω-heterodifunctional monomethyl ether poly(ethylene glycol) (mPEG).56 Namely, a TCT-mPEG conjugation product was sequentially reacted with different
■
RESULTS AND DISCUSSION Monomer and Polymer Synthesis. We reasoned that TCT could be used to prepare functional monomers that could subsequently be polymerized by RAFT and then sequentially functionalized to install two distinct pendent groups on each monomer unit of a well-defined polymer. To prepare the reactive monomer, N-hydroxyethylacrylamide (1) was reacted with 1.50 equiv of TCT to afford dichlorotriazine-containing acrylamide monomer 2 in good yield (80%) after chromatographic purification (Scheme 1). A stock solution of monomer 2 in 1,4-dioxane was prepared (ca. 40 wt %, determined by 1H NMR spectral analysis) and was found to be stable when stored at 2−8 °C. The RAFT polymerization of monomer 2 was performed at 70 °C using a [monomer]:[chain transfer agent]:[initiator] B
DOI: 10.1021/acs.macromol.6b00181 Macromolecules XXXX, XXX, XXX−XXX
Article
Macromolecules
substitution reactions were performed using a slight excess of one nucleophile (Scheme 2). Model nucleophiles were chosen to allow facile characterization of reaction products by NMR spectroscopy. More specifically, 2.10 equiv of furfurylamine or furfuryl mercaptan was reacted at 80 °C with polymer 3 to synthesize homodifunctionalized polymers 4 and 5, respectively (Table 1). Conversions for these model reactions were determined by 1H NMR spectroscopy via peak integrations of the methylene protons (Ha and Hc) at 4.0−4.6 ppm and furyl protons (Hd) at 6.0−6.5 ppm (Figure 2a). Both amine and thiol nucleophiles yielded >95% reaction conversions, and efficient functionalization was also suggested by SEC-MALS characterization that showed an increase in absolute molecular weight after reaction (Figure 2b). Although the experimental absolute molecular weights were higher than the theoretical values, this deviation was attributed to a small amount of potential branching that could be induced by residual thiols that could result from loss of the trithiocarbonate group from the RAFT-generated polymers upon addition of the nucleophiles (Scheme S1).64 Nevertheless, these results for homodifunctionalization reactions illustrated a concise method to densely and efficiently incorporate a single functionality along the polymer backbone. Heterodifunctionalization Reactions. We were interested in taking advantage of the chemoselective nature of TCT functionalization to perform successive postpolymerization modifications to prepare multifunctional homopolymers. This approach allows access to a variety of tailored polymeric scaffolds by employing a diverse set of nucleophiles. Synthesizing multifunctional homopolymers using TCT requires chemoselectively replacing one chlorine atom during the first step of postpolymerization modification. Our previous report illustrated an efficient and successive functionalization of
Scheme 2. Homodifunctionalization of Activated Polymers with Amine and Thiol Nucleophiles
ratio of 75:1:0.1 to synthesize polymer 3 (Scheme 1). The pseudo-first-order kinetic plot (Figure 1a) and number-average molecular weight (Mn) determined by size-exclusion chromatography (SEC) equipped with a multiangle light scattering (MALS) detector appeared to increase linearly up to 60% monomer conversion by 1H NMR spectroscopy (Figure 1b), while a low molar mass dispersity (Mw/Mn < 1.20) was maintained throughout the polymerization. A short (ca. 30 min) inhibition period was observed, which may be attributed to adventitious chemical species (e.g., oxygen) in the polymerization medium. SEC traces of samples taken throughout the polymerization showed monomodal and symmetric polymer traces shifting to shorter retention times with increasing monomer conversion (Figure 1c). Collectively, these data support the formation of well-defined polymers, as expected for RAFT polymerization techniques. Homodifunctionalization Reactions. To confirm the reactivity of the two electrophilic sites on each repeat unit of dichlorotriazine-containing polymer 3, nucleophilic aromatic
Table 1. Results of Homodifunctionalization (4, 5), Monofunctionalization (6, 7), and Heterodifunctionalization Reactions (8− 11) of 2,4,6-Trichloro-1,3,5-triazine-Derived Polymers
a
Equivalents of nucleophiles with respect to triazine groups in the polymer. bDetermined by 1H NMR spectroscopy. cReaction conditions and conversions are for the second substitution reactions. C
DOI: 10.1021/acs.macromol.6b00181 Macromolecules XXXX, XXX, XXX−XXX
Article
Macromolecules
Figure 3. Heterodifunctionalization of 2,4,6-trichloro-1,3,5-triazinederived polymers (3) using two different amine nucleophiles. (a) 1H NMR spectra and (b) SEC chromatograms of 3, 6, and 8. Values of Mn,theoretical were calculated assuming quantitative conversion of each nucleophilic aromatic substitution. Tributylphosphine (PBu3) was included during SEC of 8 to prevent disulfide formation from thiolterminated chains that may result during treatment with nucleophiles.
Figure 2. Homodifunctionalization of 2,4,6-triazine-1,3,5-triazinederived polymers (3) using furfurylamine or furfuryl mercaptan. (a) 1 H NMR spectra and (b) SEC chromatograms of 3, 4, and 5. Values of Mn,theoretical were calculated assuming quantitative conversion of each nucleophilic aromatic substitution. Tributylphosphine (PBu3) was included during SEC of 4 and 5 to prevent disulfide formation from thiol-terminated chains that may result during treatment with nucleophiles.
mPEG end groups using TCT.56 In this current study, the same reaction conditions (i.e., 1.00 equiv, 0 °C to rt, 16 h) were
Scheme 3. Synthesis of Multifunctional Homopolymers with Amine and Thiol Nucleophiles
D
DOI: 10.1021/acs.macromol.6b00181 Macromolecules XXXX, XXX, XXX−XXX
Article
Macromolecules
Table 2. Product Distribution of the Model Monosubstitution Reaction Using a Stoichiometric Amount of Furfurylamine or Furfuryl Mercaptan
X
product ratio 12:A:B
NH S
3:97:95% conversion of the reaction (Figure S1a). The SEC chromatogram of the product showed a high molecular weight shoulder, suggesting that branching events, similar to those previously discussed, likely occurred during the substitution reaction (Figure S1b). A deviation between observed and theoretical molecular weight (Mn,SEC‑MALS = 23 200 g/mol, Mn,theoretical = 20 700 g/mol) also indicated possible branching events. To further explore and exploit the broad nucleophile scope of TCT, successive postpolymerization modification was performed using two different types of nucleophiles (i.e., amine and thiol). Amine monoadduct polymer 6 was reacted with a thiol nucleophile using the previously employed conditions (i.e., 1.10 equiv, 80 °C, 16 h) to access polymer 10 (Scheme 3). However, the conversion of the reaction was
Figure 4. Heterodifunctionalization of 2,4,6-trichloro-1,3,5-triazinederived polymers using a thiol nucleophile followed by an amine nucleophile (a) 1H NMR spectra and (b) SEC chromatograms of 3, 7, and 11. Values of Mn,theoretical are based on the assumption that 100% conversion of each nucleophilic aromatic substitution was achieved. Tributylphosphine (PBu3) was included during SEC of 11 to prevent disulfide formation from thiol-terminated chains that may result during treatment with nucleophiles.
employed (Scheme 3). The full incorporation of amine (polymer 6, Figure 3a) or thiol (polymer 7, Figure 4a) nucleophiles to form monofunctionalized polymers was observed by 1H NMR spectroscopy (Table 1). The conversion was determined by comparing the peak integrations of the methylene protons (Ha and Hc) at 4.0−4.6 ppm to those of two furyl protons (Hd) at 6.0−6.5 ppm. SEC was employed to further characterize the efficiency of the substitution reactions (Figures 3b and 4b). The SEC chromatograms of monofunctionalized polymers 6 and 7 showed negligible shifts in retention time as compared to starting polymer 3. However, absolute molecular weights obtained by SEC-MALS agreed with the theoretical molecular weights calculated by assuming quantitative conversion of the first postpolymerization modification reaction. The polymer molar mass dispersities E
DOI: 10.1021/acs.macromol.6b00181 Macromolecules XXXX, XXX, XXX−XXX
Macromolecules
■
minimal (
