Article Cite This: Macromolecules XXXX, XXX, XXX−XXX
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Azide−para-Fluoro Substitution on Polymers: Multipurpose Precursors for Efficient Sequential Postpolymerization Modification Janina-Miriam Noy,† Yuman Li,‡ Willi Smolan,†,§ and Peter J. Roth*,‡ †
Centre for Advanced Macromolecular Design, University of New South Wales, Kensington, Sydney, New South Wales 2052, Australia ‡ Department of Chemistry, University of Surrey, Guildford, Surrey GU2 7XH, U.K.
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S Supporting Information *
ABSTRACT: The 2,3,4,5,6-pentafluorobenzyl group has become a popular reactive functionality in polymer chemistry because of its high susceptibility to para-fluoro substitution with thiols. Herein, it is demonstrated postpolymerization that the para-fluoride can be substituted using sodium azide and that the resulting 4-azido-2,3,5,6tetrafluorobenzyl-functional polymers are versatile precursors for a multitude of onward modifications with click-like efficiencies. Quantitative azide−para-fluoro substitution was found for poly(2,3,4,5,6-pentafluorobenzyl methacrylate) and the related Passerini ester−amide (meth)acrylic (co)polymers when heated in DMF with sodium azide to 80 °C for 60−90 min. Conversely, the azidation of poly(2,3,4,5,6-pentafluorostyrene) under similar conditions resulted in ∼90% substitution efficiency. Azidefunctional (co-)polymers were thermally stable below 100 °C and were subsequently modified with (i) four different alkynes (CuBr, triethylamine, DMF, 55 °C, overnight) to give 1,4-substituted 1,2,3-triazoles in >95% conversions; (ii) potassium thioacetate (DMF, RT, 15 min) with quantitative amidation to the acetanilide derivative; and (iii) DL-dithiothreitol (methanol/ DMF, RT, 90 min), resulting in complete reduction of the azides to primary amines, which were subsequently acylated with two different acyl chlorides. Products were characterized by 1H NMR, 19F NMR, Fourier transform infrared spectroscopies, and size exclusion chromatography. Given their adaptability, perfluorophenylazides have huge potential as multipurpose intermediates in polymer and materials chemistry.
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INTRODUCTION Postpolymerization modification of vinyl polymers1,2 is an expedient synthetic strategy to produce well-defined functional materials from pre-made precursors. Its applications include, among others, the preparation of biocompatible polymers,3 stimulus-responsive polymers,4 advanced biomaterials,5,6 and functional surfaces.7,8 Key to successful postpolymerization modification is a robust and efficient chemistry of selectively reactive (but otherwise stable) functional groups. Prototypical click reactions,9−11 such as Diels−Alder cycloadditions, copper catalyzed azide−alkyne cycloaddition (CuAAC),12 and thiolene and thiol-yne additions,13 have enjoyed great popularity in the polymer field,13−16 in part perhaps also because of the common misconception that any combination of their starting materials would behave in a “click”-like fashion. The coppercatalyzed reaction of alkynes with the electron-deficient sulfonyl azides, as an example to the contrary, does not give the expected 1,2,3-triazole “click products” but reactive coppercontaining ketenimines through loss of dinitrogen.17 The introduction of “clickable” groups into vinyl polymers, however, highlights inherent difficulties in combining the two individually powerful concepts of click chemistry and reversible deactivation radical polymerization methods. Double bonds (required for Diels−Alder cycloadditions and thiol-ene additions) and triple bonds (needed for CuAAC and thiol© XXXX American Chemical Society
yne reactions) are largely incompatible with radical polymerizations. Thiols undergo radical RS−H abstraction reactions, leading to RS-initiated polymers. Azide-functional vinyl monomers, although found throughout the literature, have been shown to undergo cycloaddition reactions with vinyl groups.18 Consequently, additional postpolymerization modifications can be needed to facilitate click reactions.19−21 Another impact of click chemistry has been that reactions that do not meet all of the stringent click criteria have been overlooked in the shadow of the above chemistries (this, in turn, has led to a more liberal usage of the term “click chemistry”22 in order to promote, sometimes deservedly, efficient reactions). An example is the nucleophilic aromatic thiol−para-fluoro substitution on 2,3,4,5,6-pentafluorobenzyl (PFB) derivatives. Significantly, the PFB functional group is stable during (radical) polymerization conditions and, in polar non-protic solvents and in the presence of base,23 reacts highly efficiently and selectively with thiols. Unlike other electrophilic groups (such as the halobenzyl functionality), the PFB group is not prone to unwanted hydrolysis or alcoholysis.24 Not surprisingly, the recent years have seen a growing interest25,26 Received: January 16, 2019 Revised: March 27, 2019
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DOI: 10.1021/acs.macromol.9b00109 Macromolecules XXXX, XXX, XXX−XXX
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(376 MHz, CDCl3): δ/ppm −142.7 (2F, ortho), −151.7 (2F, meta); FT-IR ν/cm−1: 2962 (w, C−H stretch), 2120 (s, asymmetric N NN stretch), 1734 (m−s, CO stretch), 1652 (w, CC stretch), 1490 (s, CC stretch), 1230 (m, symmetric NNN stretch), 1128 (m, C−F stretch). Azide modification of the Passerini polymers, 1b and 1c, followed the same procedure. Poly[2-(cyclohexylamino)-2-oxo-1-(4-azido2,3,5,6-tetrafluorophenyl) ethyl methacrylate] 2b, 19F NMR (376 MHz, CDCl3): δ/ppm −141.6 (2F, ortho), −152.5 (2F, meta); FT-IR ν/cm−1: 2931, 2854 (w, C−H stretch), 2121 (s, asymmetric NN N stretch), 1740 (CO ester stretch), 1680 (CO amide stretch), 1489 (s, CC stretch), 1231 (m, symmetric NNN stretch). Poly[2-(cyclohexylamino)-2-oxo-1-(4-azido-2,3,5,6tetrafluorophenyl)ethyl acrylate] 2c, 19F NMR (376 MHz, CDCl3): δ/ppm −141.8 (2F, ortho), −152.5 (2F, meta); FT-IR ν/cm−1: 2931, 2854 (w, C−H stretch), 2122 (s, asymmetric NNN stretch), 1746 (CO ester stretch), 1652 (CO amide stretch), 1490 (s, CC stretch), 1234 (m, symmetric NNN stretch). Azide modification of 1c-co-PEGA followed the same procedure. The product was not isolated but subjected to reduction directly. Poly[(2-(cyclohexylamino)-2-oxo-1-(2,3,4,5,6-pentafluorophenyl) ethyl acrylate)0.30-co-(oligo(ethylene glycol) methyl ether acrylate)0.70], 2c-co-PEGA, 19F NMR (282 MHz, CDCl3): δ/ppm −141.4 (2F, ortho), −152.1 (2F, meta). Azide−para-Fluoro Substitution Reaction on pPFS (3 → 4). The procedure followed the above example with heating to 80 °C overnight. Poly(4-azido-2,3,5,6-pentafluorostyrene), 4, 1H NMR (400 MHz, CDCl3): δ/ppm 2.97−2.20 (m, 1H, CH backbone), 1.94 (2H, CH2 backbone); 19F NMR (376 MHz, CDCl3): δ/ppm −142.0, 143.0 (2F, ortho), −152.3 (2F, meta). Residual signals of 3 indicated conversions of ∼90%. Copper-Catalyzed Azide−Alkyne Cycloaddition on 4-Azido2,3,5,6-tetrafluorobenzyl-functional Polymers (2 → 7). Azidefunctional polymer (0.097 mmol of azide groups, 1 equiv), triethylamine (17.6 mg, 24.2 μL, 0.17 mmol, 1.8 equiv), and CuBr (2.1 mg, 0.014 mmol, 0.14 equiv) were added to DMF (2.4 mL) in a vial. The mixture was degassed by bubbling nitrogen through the solution in an open vial for 2 min before alkyne (0.14 mmol, 1.4 equiv) was added. The vial was sealed and heated to 55 °C overnight. The products were isolated by filtering through Al2O3 and precipitation, followed by drying in vacuum. Reaction of 2a with 1-Dodecyne (7a/A). Reaction in CDCl3 instead of DMF (to enable NMR monitoring); product not isolated. 19 F NMR (376 MHz, CDCl3): δ/ppm −140.4, −140.7 (2F, ortho), −146.6 (2F, meta). Reaction of 2b with 1-Dodecyne (7b/A). Precipitation into methanol. 1H NMR (400 MHz, CDCl3): δ/ppm 8.06 (br s, 1H, C CH−N), 6.27 (br s, 2H, ArCH, NH), 3.78 (m, 3H, NHCH, CC− CH2), 2.50−0.60 (m, Cy, (CH2)8CH3, backbone); 19F NMR (376 MHz, CDCl3): δ/ppm −138.9 (2F, ortho), −146.0 (2F, meta); FT-IR ν/cm−1: 2925, 2854 (s, C−H stretch), 1741 (m, ester CO stretch), 1687 (m−s, amide CO stretch), 1666 (s, triazole CN stretch), 1523, 1498 (s, CC stretch). Reaction of 2b with Propargyl Acrylate (7b/B). Reaction in CDCl3 instead of DMF. Precipitation into diethyl ether−hexane 4:1. 1 H NMR (400 MHz, CDCl3): δ/ppm 8.05 (br s, 1H, CCH−N), 6.43, 6.13, 5.97 (m, 5H HHCCHR, ArCHR, NH), 5.40 (br s, 2H, COOCH2), 3.75 (br s, 1H, NHCH), 2.50−0.50 (m, Cy, backbone); 19 F NMR (376 MHz, CDCl3): δ/ppm −138.6 (2F, ortho), −145.8 (2F, meta); FT-IR ν/cm−1: 2931, 2856 (m, C−H stretch), 1725 (s, esters CO stretch), 1689 (s, amide CO stretch), 1525, 1498 (s, CC stretch). Reaction of 2b with 1-Hexyne (7b/C). Precipitation into diethyl ether−hexane 4:1. 1H NMR (400 MHz, CDCl3): δ/ppm 8.04 (br s, 1H, CCH−N), 6.27 (br s, 2H, ArCH, NH), 3.80 (m, 3H, NHCH, CC−CH2), 2.57−0.50 (m, Cy, CH2CH2CH3, backbone); 19F NMR (376 MHz, CDCl3): δ/ppm −139.0 (2F, ortho), −146.1 (2F, meta); FT-IR ν/cm−1: 2931, 2858 (s, C−H stretch), 1737 (m, ester CO stretch), 1658 (m−s, amide CO stretch), 1523, 1498 (s, CC stretch).
in the post-synthesis modification of PFB-functional polymers, such as poly(2,3,4,5,6-pentafluorostyrene) (pPFS) and poly(2,3,4,5,6-pentafluorobenzyl methacrylate) (pPFBMA)27 with thiols, including for the cross linking of copolymer nanoparticles,28 the modification of surfaces,29,30 the manipulation of conjugated polymers,31,32 and the synthesis of polymer networks,33 stimulus-responsive polymers,27 bifunctional copolymers,34−37 and glycopolymers.38,39 Recently, our group has showed that pPFBMA can also be modified with amines and carbonylthiolates, though with less efficiency.27 Efficient chemistry on polymer-bound PFB groups is thus largely limited by the availability of functional thiols. A reaction that has, to the best of our knowledge, been reported only for small-molecule PFB derivatives40 is the azide−para-fluoro substitution. The resulting 4-azido-2,3,5,6tetrafluorobenzyl functionality has been used as a photoaffinity label40,41 and is known to be reactive toward thioacids,42,43 enamines44−49 and phosphines.50,51 The purpose of this work is twofold. First, we explore the azide−para-fluoro substitution reaction postpolymerization on several PFBfunctional polymers and demonstrate that the efficiency of this reaction varies among different polymer types. Although sluggish for pPFS, the reaction was found to proceed to completion within 1.5 h at 80 °C for pPFBMA and polymers of Passerini-made52 (meth)acrylates. It, therefore, presents a straightforward method of quantitatively introducing azide functionality into the repeat units of vinyl polymers. Second, we show that the resulting azide-functional polymers are sufficiently stable to be stored and demonstrate their reaction versatility in three examples: (i) CuAACone of the most important modification routes for (alkyl) azides; (ii) amidation through an azide−thioacid couplinga reaction that is very efficient for electron-poor azides;42 and (iii) the selective reduction of the azide to an amine, thus providing access to another functional groupexploited herein through an amine−acyl chloride modification as a third sequential step. With a wide range of perfluorophenylazide-based chemistries known for small-molecule examples, we anticipate that this work will facilitate the adaption of these efficient methods for the modification of more challenging substrates, including polymers.
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EXPERIMENTAL SECTION
Instrumentation, materials, and synthesis of the pentafluorobenzylfunctional polymers 1a, 1b, 1c, and 1c-co-poly[poly(ethylene glycol) methyl ether acrylate] (PEGA, monomer Mn = 480 g/mol) (1c-coPEGA) are given in the Supporting Information (including Figures S1−S5). Azide−para-Fluoro Substitution Reaction on PFB-Functional Polymers (1 → 2). Sample 1a is described as an example. pPFBMA (50 mg, 0.188 mmol of PFB groups) was dissolved in N,Ndimethylformamide (DMF) or N,N-dimethylacetamide (DMAc) (2.3 mL) (no difference between these solvents was observed).23 Sodium azide (30.6 mg, 0.47 mmol, 2.5 equiv) was added, and the mixture was stirred at 80 °C. After approximately 1 h, a sample (0.1 mL) was withdrawn, diluted with CDCl3 (0.5 mL) and subjected to 19F NMR spectroscopic analysis (see below for chemical shifts; a signal of the replaced para-F was usually not visible because of poor solubility of the side product NaF in DMF and DMAc). When the reaction was deemed to be complete (typically after 60−90 min), heating was stopped. The product was isolated by precipitation into water followed by decanting, washing, and drying in vacuum. Poly(4-azido2,3,5,6-tetrafluorobenzyl methacrylate) 2a, 1H NMR (400 MHz, CDCl3): δ/ppm 5.06, 5.00 (2H, CH2COO, splitting because of tacticity),27 1.99−1.57 (2H, CH2), 1.42−0.69 (3H, CH3); 19F NMR B
DOI: 10.1021/acs.macromol.9b00109 Macromolecules XXXX, XXX, XXX−XXX
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Macromolecules Reaction of 2b with N-Propargyl-4-cyano 4-(Dithiobenzoyl)valeramide (7b/D). Purification by dialysis against methanol. 1H NMR (400 MHz, CDCl3): δ/ppm 7.85 (br s, 2H, ArCS2), 7.52 (br s, 1H, ArCS2), 7.35 (br s, 2H, ArCS2), 6.40 (br s), 4.65 (br s), 3.81 (br s), 2.59−0.80 (m) (signals broadened because of poor solvation); 19F NMR (376 MHz, CDCl3): δ/ppm −138.8 (2F, ortho), −146.3 (2F, meta) (signals broadened because of poor solvation); FT-IR ν/cm−1: 2933, 2854 (w, C−H stretch), 1741 (m, ester CO stretch), 1693 (shoulder, amide CO stretch), 1673 (s, triazole CN stretch), 1521, 1500 (s, CC stretch), 1045 (m, CS stretch). Azide−Thioacid Coupling (2 → 8). The reaction was performed with quantitative conversion either on isolated poly(4-azido-2,3,5,6tetrafluorobenzyl methacrylate) 2a or directly following azide−parafluoro substitution on 1a without isolation of the azide intermediate. To azide-functional polymer 2a (0.56 mmol of repeat units; made from 149.7 mg of 1a) in DMF (7 mL) (in the one-pot procedure, the mixture also contained sodium fluoride and residual excess sodium azide) was added potassium thioacetate (119 mg, 1.04 mmol, 1.86 equiv) dissolved in DMF (2 mL). The mixture was stirred at RT for 15 min. Poly(4-acetamido-2,3,5,6-tetrafluorobenzyl methacrylate) 8a was isolated by dialysis against water and freeze-drying. 1H NMR (400 MHz, DMSO-d6): δ/ppm 10.12 (br s, 1H, NH), 5.00 (br s, 2H, ArCH2), 2.05 (br s, 3H, COCH3), 1.95−1.20 (m, 2H, backbone CH2), 1.20−0.45 (m, 3H, backbone CH3). 19F NMR (376 MHz, CDCl3): δ/ppm −144.0 (2F, ortho), −145.6 (2F, meta); FT-IR ν/ cm−1: 3255 (w, N−H stretch), 2956 (w, C−H stretch), 1733 (m−s, CO stretch), 1690 (m−s, N−H bend), 1654 (m, CC stretch), 1502, 1479 (s, CC stretch), 1141 (m, C−F stretch). Reduction of Tetrafluorophenylazide-Functional Polymers to Amines (4 → 9, 2 → 10). Reduction of azides to amines was performed without isolation of the azide derivatives. Typically, pentafluorobenzyl-functional polymer (1a, 1c, 1c-co-PEGA, 3, 125 mg, 1 equiv of repeat units) was heated in DMF (7 mL) with sodium azide (2.5 equiv; 76 mg in case of 1a) to 80 °C as described above. After complete substitution, the mixture was cooled to RT. Triethylamine (5 equiv; 327 μL in case of 1a) and DL-dithiothreitol (5 equiv; 362 mg in case of 1a) dissolved in methanol (1.5 mL) were added. The solution was stirred for 1.5 h at RT. Completion of the reaction was confirmed by withdrawing a sample (100 μL), diluting with CDCl3, and measuring a 19F NMR spectrum. The aminefunctional polymers were isolated by dialysis against methanol. Poly(4-amino-2,3,5,6-tetrafluorostyrene) 9, 19F NMR (376 MHz, CDCl3): δ/ppm −146.5, 146.9 (2F, ortho), −163.2 (2F, meta) with residual signals of 3 (∼10%). Poly(4-amino-2,3,5,6-tetrafluorobenzyl methacrylate) 10a, 1H NMR (300 MHz, CD3CN): δ/ppm 4.93 (m, 2H, ArCH2), 4.78 (br s, 2H, NH2), 1.87−1.56 (m, 2H, backbone CH2), 1.02, 0.82, 0.64 (m, 3H, CH3); 19F NMR (282 MHz, CD3CN): δ/ppm −146.7, 147.0 (2F, ortho), −163.1 (2F, meta); FT-IR ν/cm−1: 3490, 3363 (m, N−H stretch), 2965 (w, C−H stretch), 1724 (m−s, CO stretch), 1670 (s, CC stretch), 1519, 1500 (s, CC stretch), 1297 (m, C−N stretch). Poly[2-(cyclohexylamino)-2-oxo-1-(4-amino-2,3,5,6-tetrafluorophenyl) ethyl acrylate] 10c, 19F NMR (376 MHz, CDCl3): δ/ ppm −145.1 (2F, ortho), −162.9 (2F, meta); 10c-co-PEGA. The product was isolated by dialysis in water. 19F NMR (282 MHz, CDCl3): δ/ppm −145.1 (2F, ortho), −162.7 (2F, meta); FT-IR ν/ cm−1: 3542, 3334 (w, N−H stretch), 2927, 2863 (m, C−H stretch), 1731 (m, CO ester stretch), 1671 (w, CO amide stretch), 1525, 1504 (s, CC stretch), 1087 (s, C−O stretch). Amine−Acyl Chloride Coupling (10 → 11). Poly(4-acrylamido2,3,5,6-tetrafluorobenzyl methacrylate) 11a → E. Poly(4-amino2,3,5,6-tetrafluorobenzyl methacrylate) 10a (10 mg, 0.038 mmol of amino groups, 1 equiv) was dissolved in anhydrous acetonitrile (1 mL) in a vial containing a magnetic stir bar. The solution was cooled to 0 °C and triethylamine (11.5 mg, 15.9 μL, 0.114 mmol, 3 equiv) was added. Acryloyl chloride (10.3 mg, 9.3 μL, 0.114 mmol, 3 equiv) was added dropwise. The vial was sealed with a rubber septum and stirred for 6 h at 0 °C. The product was isolated by precipitation into diethyl ether−petroleum spirit (4:1) and dried in air. Poly(4acrylamido-2,3,5,6-tetrafluorobenzyl methacrylate) 11a/E, 1H NMR
(400 MHz, CD3CN): δ/ppm 9.64 (br s, 1H, NH), 6.62 (br s, 1H, HHCCHR), 6.35 (br s, 1H, HHCCHR), 5.80 (br s, 1H, HHCCHR), 5.03 (br s, 2H, ArCH2), 2.10−0.70 (m, backbone); 19 F NMR (376 MHz, CD3CN): δ/ppm −144.7 (2F, ortho), −146.2 (2F, meta); FT-IR ν/cm−1: 3411 (w, N−H stretch), 1728 (m−s, ester CO stretch), 1689 (m, amide CO stretch), 1624 (m, N−H bend), 1475 (s, CC stretch). Poly(4-(3,5-dinitrobenzamido)-2,3,5,6-tetrafluorobenzyl methacrylate) 11a/F. Poly(4-amino-2,3,5,6-tetrafluorobenzyl methacrylate) 10a (10 mg, 0.038 mmol of amino groups, 1 equiv) was dissolved in anhydrous acetonitrile (0.5 mL) in a vial containing a magnetic stir bar. The solution was cooled to 0 °C, and triethylamine (19.2 mg, 26.5 μL, 0.19 mmol, 5 equiv) was added. 3,5-Dinitrobenzoyl chloride (43.8 mg, 0.19 mmol, 5 equiv) dissolved in anhydrous acetonitrile (0.5 mL) was added dropwise. The vial was sealed with a rubber septum, and the brown solution was stirred overnight at RT. The product was isolated by two precipitations into diethyl ether−hexane (4:1) and dried in vacuum. Poly(4-(3,5-dinitrobenzamido)-2,3,5,6tetrafluorobenzyl methacrylate) 11a/F, 1H NMR (400 MHz, CD3CN): δ/ppm 10.62 (br s, 1H, NH), 9.09, 8.95 (m, 3H, ArH), 5.08 (br s, 2H, ArCH2), 2.10−0.70 (m, backbone); 19F NMR (376 MHz, CD3CN): δ/ppm −143.2 (2F, ortho), −144.7 (2F, meta); FTIR ν/cm−1: 3409 (w, N−H stretch), 1733 (m−s, ester CO stretch), 1691 (m, amide CO stretch), 1628 (w, N−H bend), 1540 (s, dinitroaryl CC stretch), 1477 (s, perfluoroaryl CC stretch), 1344 (m, C−N stretch).
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RESULTS AND DISCUSSION Synthesis of 4-Azido-2,3,5,6-tetrafluorophenyl-Functional Polymers. The first step in assessing the versatility of polymer-bound perfluorophenyl azides was the postpolymerization modification of PFB-functional polymers with sodium azide. PPFBMA (1a), two Passerini-made (meth)acrylic analogues (1b, 1c), pPFS (3) (all formally containing a PFB group), the activated ester poly(2,3,4,5,6-pentafluorophenyl acrylate) (5), and a novel 2,3,4,5,6-pentafluorophenyl etherfunctional polyacrylate (6) were thus treated with an excess of sodium azide in either N,N-dimethylformamide (DMF) or N,N-dimethylacetamide (DMAc) as common non-protic polar solvents at 80 °C (Scheme 1). An overview of all polymer samples with size exclusion chromatography (SEC)-measured molar masses and molar mass dispersities is given in Table S1 in the Supporting Information. Gratifyingly, polymers 1a, 1b, and 1c reached full conversion after 60−90 min, evident through the disappearance of the para-F signal and approximately +10 ppm shift of the meta-F resonance in the 19 F NMR spectra of the products [Figures 1(i/ii), S6(i/ii), and S7(i/ii)] and the presence of strong IR absorbances at ν = 2120 cm−1 and ν = 1230 cm−1 of the purified polymers characteristic of the asymmetric and symmetric NNN stretching vibration of azides, respectively [Figures 2(i/ii) and S8(i/ii)]. The disappearance of the characteristic red color originating from the dithiobenzoate RAFT end groups indicated that the dithioester groups were cleaved in the procedure. Under the same conditions, pPFS (3), on the other hand, in various runs reached only around 90% conversion after heating for 24 h, as judged by 19F NMR spectroscopy [Figure S9(i/ii)]. Further heating did not increase the conversion but led to the formation of brown and black products. Reactions at lower temperatures or in acetone−water did not lead to higher conversions. Indeed, a literature precedent53 reports the exposure of an ATRP-made pPFS to sodium azide (DMF, 50 °C, 6 h), whereby only the ATRPderived bromide end groups were replaced. Our previous work already suggested a higher reactivity of pPFBMA toward C
DOI: 10.1021/acs.macromol.9b00109 Macromolecules XXXX, XXX, XXX−XXX
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Macromolecules Scheme 1. Overview of Postpolymerization Azide−paraFluoro Substitution Reactions
Figure 1. 19F NMR spectra (376 MHz) of methacrylic polymers featuring (i) PFB (1a) (CDCl3), (ii) 4-azido-2,3,5,6-tetrafluorobenzyl (2a) (CDCl3), (iii) 4-n-octyl-1,2,3-triazole (7a/A) (CDCl3), (iv) acetamide (8a) (DMSO-d6), (v) 2,3,5,6-tetrafluoroaniline (10a) (CD3CN), and (vi) 3,5-dinitrobenzamide (11a/F) (CD3CN) functionality. The respective left-most signals were assigned to the fluorine atoms ortho to the benzylic position. Splitting is because of backbone tacticity.27
amines compared to pPFS,27 although the present study offers the first direct comparison of the two PFB-functional species under identical reaction conditions. Presumably, the reactivity of the para-F in the (meth)acrylic samples is enhanced through the slightly higher group electronegativity of the COOCH2 fragment compared to the secondary alkyl backbone of the styrene derivative.54 When the activated ester polymer 5 was heated with sodium azide, a black material was formed together with 2,3,4,5,6-pentafluorophenol (identified through 19 F NMR spectroscopy, not shown). Presumably, acyl substitution occurred and gave poly(acryloyl azide), which likely underwent a Curtius rearrangement to poly(vinyl isocyanate),55 followed by further reactions. A 2,3,4,5,6pentafluorophenyl ether-functional copolymer, 6-co-PEGA, did not react with sodium azide at 80 °C in DMF. Presumably, the electron-donating effect of the ether oxygen deactivated the para position toward nucleophilic substitution (Scheme 1). Thermal Stability of Azide-Functional Polymers. Organic azides are thermally labile, and species with a high nitrogen-to-carbon ratio can decompose explosively.56 In order to determine the thermal stability and confirm their safe handling, the azide-functional polymers 2a and 4 were initially prepared on a milligram scale and analyzed by differential
Figure 2. FT-IR spectra of (i) poly[2-(cyclohexylamino)-2-oxo-1(2,3,4,5,6-pentafluorophenyl) ethyl methacrylate] 1b; (ii) its azide derivative 2b and after CuAAC modification with (iii) dodecyne, 7b/ A; (iv) alkyne-functional dithioester, 7b/D; and (v) propargyl acrylate, 7b/B, with relevant vibrations highlighted.
scanning calorimetry (DSC) and thermogravimetric analysis (TGA) (Figure 3). TGA revealed a first mass loss of both polymers between 110 and 190 °C. For the azide-functional methacrylate, 2a, the measured mass loss of 9.7% agreed well with the value calculated for the expected loss of dinitrogen from every repeat unit. DSC showed exothermic processes of both samples in the same temperature range. The measured heat flow of 177.0 kJ/mol of azide-functional repeat units of 2a was comparable to the reported decomposition heat of trityl azide of 174.6 kJ/mol.56 Importantly, this heat was released over a wide temperature range from 110−200 °C (corresponding to 9 min of experiment time). It was thus concluded that the azide-functional polymers can be handled safely at D
DOI: 10.1021/acs.macromol.9b00109 Macromolecules XXXX, XXX, XXX−XXX
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(electron-rich) alkyl azides. For the electron-poor perfluorophenylazide species in hand, the reaction conditions were first optimized on a small-molecule model compound, 2-(tertbutylamino)-2-oxo-1-(4-azido-2,3,5,6-tetrafluorophenyl) ethyl acetate (see Table S2). Very high (95%) to quantitative conversions of the model compound and the azide-functional polymers 2a and 2b to the desired functional 1,2,3-triazoles with various alkynes (1.2−1.4 equiv per azide) were found for the catalytic system CuBr (0.12−0.14 equiv) and triethylamine (1.8 equiv) in DMF after heating to 55−80 °C overnight. Four alkynes were chosen to demonstrate this modification, including three commercially available examples (A−C) and a custom-made propargyl-functional dithiocarbonate chain transfer agent (D); see structures of triazole-functional polymers 7a,b in Scheme 2. The modification of the polymers was evident through the downfield shift of both 19F NMR signals see Figures 1(iii) and S6(iii−vi). FT-IR analysis of the purified products indicated the complete disappearance of the azide stretch bands and the appearance of signals associated with the newly introduced functional groups, viz. methylene groups [7b/A, Figure 2(iii)], a thiocarbonyl group [7b/D, Figure 2(iv)], and an additional ester functionality [7b/B, Figure 2(v)]. Evidence of the intended CuAAC reaction came from 1H NMR spectroscopic analysis, which showed a broad singlet at δ ≈ 8.0 ppm, characteristic of a 1,4-substituted 1,2,3triazole, in addition to signals associated with the introduced functionalities; see Figures 4 and S10. SEC was performed on the pentafluorobenzyl-functional precursors, the azide-functional intermediates, and the CuAAC-modified products. All values are summarized in Table S1, and exemplary curves are plotted in Figure 5A. Gratifyingly, SEC showed monomodal curves for all samples with measured dispersities, Đ, between
Figure 3. TGA (black curves, left axis) and DSC (red curves, right axis) of poly(4-azido-2,3,5,6-tetrafluorobenzyl methacrylate) 2a (solid lines) and poly(4-azido-2,3,5,6-tetrafluorostyrene) 4 (x = 0.89) (dashed lines) with measured relative mass loss (2a) and integrated heat flows indicated. The measured heat flows correspond to 177.0 kJ/mol for 2a and 118.6 kJ/mol for 4 per 1 mol of respective azidefunctional repeat units.
temperatures well below 100 °C (including during their synthesis performed at 80 °C) and do not decompose explosively when heated. Azide-functional polymers were stored at −20 °C and were usually protected from light to avoid photodecomposition. Subsequent Postpolymerization Modification through CuAAC. The modification of perfluorophenylazidefunctional polymers through copper-catalyzed azide−alkyne cycloaddition (CuAAC) was investigated next. This is a very common and highly efficient reaction for the modification of
Scheme 2. Overview of Subsequent Modifications of 2,3,5,6-Tetrafluorophenylazide Functional Polymers
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Figure 6. 1H NMR spectra (400 MHz) of (i) pPFBMA 1a (CDCl3), (ii) 2,3,5,6-tetrafluorophenylazide 2a (CDCl3), and (iii) acetamide 8a (DMSO-d6) (prepared in one pot directly from 1a) with relevant signals assigned. Figure 4. 1H NMR spectra (400 MHz, CDCl3) of (i) poly[2(cyclohexylamino)-2-oxo-1-(2,3,4,5,6-pentafluorophenyl) ethyl methacrylate] 1b and (ii) following azide substitution and CuAAC modification with propargyl acrylate, 7b/B, with relevant signals assigned.
suggesting a much smaller hydrodynamic size, poor solubility in the eluent THF, and potential undesired column interactions caused by the amide groups. These data suggested the formation of the expected acetamide-functional polymer. Its poor solubility in THF and observed insolubility in chloroform were attributed to intra- and inter-polymer hydrogen bonding. Importantly, the reaction was found to be complete after 15 min at room temperature, suggesting “click”like potential of this reaction in the polymer arena. The amidation reaction could also be performed in one pot with the preceding azide substitution. In that case, the PFBfunctional polymer was heated with sodium azide in DMF and, after cooling to room temperature, potassium thioacetate was added without any prior purification. Following dialysis, this one-pot reaction led to the same product as the two-step route. Subsequent Postpolymerization Modification through Azide-to-Amine Reduction. The polymer-bound azide groups were selectively reduced using DL-dithiothreitol (DTT) in methanol in the presence of triethylamine. For the azide-functional styrene derivative, 4 (see Scheme 3), the reduction was complete after 90 min at room temperature, as judged by 19F NMR spectroscopy [Figure S9(iii)]. The reduction could be done directly following the azide−parafluoro substitution without requiring the removal of excess sodium azide. The conversion of the azide side group to the
1.26 and 1.37, suggesting the absence of side reactions that influence the molecular weight distribution. The CuAACmodified products had higher apparent molar masses that reflected their actual weight increases. For example, the dithioester-functionalized Passerini derivative 7b/D with a repeat unit molecular weight of 730.8 g/mol demonstrated that the CuAAC reaction was efficient even for this sterically demanding system. Subsequent Postpolymerization Modification through Azide−Thioacid Coupling. After successful CuAAC modification, a less-common reaction of azides was demonstrated postpolymerization: thiocarboxylate amidation42 (product 8a in Scheme 2). The azide-functional polymer 2a was treated with potassium thioacetate in DMF at room temperature. These mild conditions led to a quantitative shift of the 19F NMR signals [Figure 1(iv)], the appearance of FTIR signals associated with an amide bond [Figure S8(iii)], and 1 H NMR signals attributed to the NH and CH3 groups of an acetamide (Figure 6). SEC analysis of the product (Figure 5B) indicated a drastic shift toward lower apparent molar masses,
Figure 5. SECs of (A) (i) poly[2-(cyclohexylamino)-2-oxo-1-(2,3,4,5,6-pentafluorophenyl) ethyl methacrylate] 1b (DP = 60), (ii) its azido derivative 2b, and triazoles 7b after CuAAC modification with (iii) propargyl acrylate (7b/B), (iv) 1-hexyne (7b/C), (v) 1-dodecyne (7b/A), and (vi) the alkyne-functional dithioester (7b/D) measured in DMAc with PS calibration; (B) (i) pPFBMA 1a (DP = 65), (ii) its azido derivative 2a, and (iii) acetamide 8a measured in tetrahydrofuran (THF) with PMMA calibration; (C) (i) pPFBMA 1a (DP = 145), (ii) its 2,3,5,6tetrafluoroaniline derivative 10a, and amides 11a after modification with (iii) acryoloyl chloride (11a/E) and (iv) 3,5-dinitrobenzoyl chloride (11a/F) measured in DMAc with PS calibration. F
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−0.3,58 confirming the very low basicity of this aniline nitrogen. Nonetheless, full modification was achieved in a third postpolymerization step (following azidation and reduction) when the amine-functional polymer 10a was reacted with two exemplary acyl chlorides, acryloyl chloride (E) and 3,5-dinitrobenzoyl chloride (F), to give products 11a/ E,F (Scheme 2). The 19F NMR spectra of the amide products [sample 11a/F shown representatively in Figure 1(vi)] were similar to that of the acetamide product formed directly from potassium thioacetate [8a, Figure 1(vi)], confirming the characteristic fluorine resonances of 2,3,5,6-tetrafluoroanilides and demonstrating the considerable change in chemical shift of the meta-fluorines (Δδ ≈ 18 ppm) compared to the 2,3,5,6tetrafluoroaniline species [Figure 1(v)]. FT-IR spectroscopy [Figure S8(v/vi)] provided evidence of amide formation through observed bands assigned to amide CO stretching vibrations (ν = 1690 cm−1) and, in the case of 3,5dinitrobenzoyl chloride, additional aromatic CC stretch vibrations (ν = 1540 cm−1). 1H NMR spectroscopy [Figure 7(ii,iii)] showed easily discernible alkene (11a/E) and aromatic (11a/F) signals expected for the quantitative amidations, respectively. The measured SEC traces of the amidated polymers [Figure 5C(iii,iv)] showed drastic shifts to higher apparent molar masses compared to their common pentafluoro- and amine-functional precursors [Figure 5C(i,ii)]. The curves had slight shoulders toward higher molar masses but were otherwise similar in shape to those of their parent materials. The measured data suggested quantitative conversion and demonstrated three successive postpolymerization modification reactions (azidation, reduction, amidation), each with quantitative conversions, and the possibility to install further reactive groups, such as the acrylate functionality in sample 11a/E. The modifications had profound impacts on the properties of the polymers. The solubility of four functional polymer examples in various aqueous and organic solvents is contrasted in Table S3. Most noticeably, the aniline derivative 10a was soluble in alcohols but insoluble in chloroform and dichloromethane, whereas the amidated derivative 11a was less polar and insoluble in alcohols, but soluble in the two chlorinated solvents.
Scheme 3. Reduction of Poly(4-azido-2,3,5,6tetrafluorostyrene) 4 to the Aniline Derivative 9
amine made the polymer more polar and soluble in alcohols, including methanol. Azide-to-amine reductions were also carried out on the polymethacrylate 2a, the Passerini-derived acrylate homopolymer 2c, and statistical copolymers of 2c and poly[poly(ethylene glycol) methyl ether acrylate] (PEGA), with 19F NMR spectroscopy indicating complete reduction when measured after 90 min at room temperature; see Figure 1(v) (10a) and Figure S7(iii) (10c-co-PEGA). FT-IR spectroscopy [representative example of 10a shown in Figure S8(iv)] confirmed the complete disappearance of the asymmetrical azide vibration band at ν = 2120 cm−1 and showed a new band at ν = 1670 cm−1, assigned to an N−H band characteristic of primary amines. A broad singlet at 4.8 ppm, observed by 1H NMR spectroscopy [Figure 7(i)] was attributed to the NH2
Figure 7. Sections of 1H NMR spectra (CD3CN) of (i) poly(4amino-2,3,5,6-tetrafluorobenzyl methacrylate) 10a (300 MHz) and after coupling with (ii) acryloyl chloride 11a/E (400 MHz) and (iii) 3,5-dinitrobenzoyl chloride 11a/F (400 MHz) with assigned signals.
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CONCLUSIONS The PFB functionality enabled the postpolymerization introduction of azide groups. This reaction was found to be complete for several (meth)acrylic (co-)polymers, including sterically challenged Passerini derivatives. Conversely, the azide substitution reaction was less efficient on pPFS, presumably because of the lacking slight electron-withdrawing effect of the ester (and amide) groups. Compared to the azidation of chloromethyl groups, the pentafluorobenzyl moiety is not prone to unwanted hydrolysis/alcoholysis and enabled monitoring through 19F NMR spectroscopy with characteristic chemical shifts observed over a relatively large range of ∼25 ppm. The resulting 4-azido-2,3,5,6-tetrafluorobenzyl-functional polymers were sufficiently stable to be stored and proved to be multipurpose reagents. Of the three demonstrated sequential postpolymerization modifications, (the prototypical click reaction) CuAAC was, perhaps surprisingly, the least efficient, requiring heating overnight and a relatively high (15 mol %) amount of CuBr catalyst. Nonetheless, (near-)quantitative conversions were achieved under optimized conditions with four different alkynes, including a dithioester RAFT agent. The azide−thioacid reaction, on the other hand, proceeded under
resonance. Analysis by SEC revealed unimodal distributions of the pentafluoro-functional starting material and its aniline derivative [Figure 5C(i,ii)], with the latter species displaying a higher apparent molar mass, indicating a larger size in the eluent DMAc. A similar observation was made for the Passerini acrylate 1c/10c (Figure S11B), whereas the SEC curves of 1cco-PEGA, azide 2c-co-PEGA, and aniline 10c-co-PEGA remained largely unchanged (Figure S11A). As primary amino groups are incompatible with RAFT agents,57 their introduction into RAFT polymers usually requires protecting groups. The synthetic route presented here represents a straightforward strategy to introduce primary amine side groups into styrenic and (meth)acrylic RAFT-made polymers. Postpolymerization Modification of Primary Amine Side Groups. Amino groups are versatile precursors by virtue of their nucleophilicity. In the present case, the tetrafluoroaniline groups, however, were expected to be considerably less nucleophilic. The conjugate acid of the comparable smallmolecule pentafluoroaniline, F5C6NH3+, has a reported pKa of G
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(7) Arnold, R. M.; Patton, D. L.; Popik, V. V.; Locklin, J. A Dynamic Duo: Pairing Click Chemistry and Postpolymerization Modification To Design Complex Surfaces. Acc. Chem. Res. 2014, 47, 2999−3008. (8) Jo, H.; Theato, P. Post-polymerization Modification of SurfaceBound Polymers. In Controlled Radical Polymerization at and from Solid Surfaces; Vana, P., Ed.; Springer International Publishing: Cham, 2016; pp 163−192. (9) Iha, R. K.; Wooley, K. L.; Nyström, A. M.; Burke, D. J.; Kade, M. J.; Hawker, C. J. Applications of Orthogonal “Click” Chemistries in the Synthesis of Functional Soft Materials. Chem. Rev. 2009, 109, 5620−5686. (10) Kempe, K.; Krieg, A.; Becer, C. R.; Schubert, U. S. “Clicking” on/with polymers: a rapidly expanding field for the straightforward preparation of novel macromolecular architectures. Chem. Soc. Rev. 2012, 41, 176−191. (11) Tunca, U. Click and Multicomponent Reactions Work Together for Polymer Chemistry. Macromol. Chem. Phys. 2018, 219, 1800163. (12) Golas, P. L.; Matyjaszewski, K. Marrying click chemistry with polymerization: expanding the scope of polymeric materials. Chem. Soc. Rev. 2010, 39, 1338−1354. (13) Hoyle, C. E.; Lowe, A. B.; Bowman, C. N. Thiol-click chemistry: a multifaceted toolbox for small molecule and polymer synthesis. Chem. Soc. Rev. 2010, 39, 1355−1387. (14) Anseth, K. S.; Klok, H.-A. Click Chemistry in Biomaterials, Nanomedicine, and Drug Delivery. Biomacromolecules 2016, 17, 1−3. (15) Marrocchi, A.; Facchetti, A.; Lanari, D.; Santoro, S.; Vaccaro, L. Click-chemistry approaches to π-conjugated polymers for organic electronics applications. Chem. Sci. 2016, 7, 6298−6308. (16) Xi, W.; Scott, T. F.; Kloxin, C. J.; Bowman, C. N. Click Chemistry in Materials Science. Adv. Funct. Mater. 2014, 24, 2572− 2590. (17) Yoo, E. J.; Ahlquist, M.; Bae, I.; Sharpless, K. B.; Fokin, V. V.; Chang, S. Mechanistic Studies on the Cu-Catalyzed ThreeComponent Reactions of Sulfonyl Azides, 1-Alkynes and Amines, Alcohols, or Water: Dichotomy via a Common Pathway. J. Org. Chem. 2008, 73, 5520−5528. (18) Ladmiral, V.; Legge, T. M.; Zhao, Y.; Perrier, S. “Click” Chemistry and Radical Polymerization: Potential Loss of Orthogonality. Macromolecules 2008, 41, 6728−6732. (19) Durmaz, H.; Sanyal, A.; Hizal, G.; Tunca, U. Double click reaction strategies for polymer conjugation and post-functionalization of polymers. Polym. Chem. 2012, 3, 825−835. (20) Kubo, T.; Easterling, C. P.; Olson, R. A.; Sumerlin, B. S. Synthesis of multifunctional homopolymers via sequential postpolymerization reactions. Polym. Chem. 2018, 9, 4605−4610. (21) Moldenhauer, F.; Theato, P. Sequential Reactions for Postpolymerization Modifications. In Multi-Component and Sequential Reactions in Polymer Synthesis; Theato, P., Ed.; Springer International Publishing: Cham, 2015; pp 133−162. (22) Barner-Kowollik, C.; Du Prez, F. E.; Espeel, P.; Hawker, C. J.; Junkers, T.; Schlaad, H.; Van Camp, W. “Clicking” Polymers or Just Efficient Linking: What Is the Difference? Angew. Chem., Int. Ed. 2011, 50, 60−62. (23) Noy, J.-M.; Koldevitz, M.; Roth, P. J. Thiol-reactive functional poly(meth)acrylates: multicomponent monomer synthesis, RAFT (co)polymerization and highly efficient thiol-para-fluoro postpolymerization modification. Polym. Chem. 2015, 6, 436−447. (24) Albuszis, M.; Roth, P. J.; Pauer, W.; Moritz, H.-U. Two in one: use of azide functionality for controlled photo-crosslinking and clickmodification of polymer microspheres. Polym. Chem. 2016, 7, 5414− 5425. (25) Agar, S.; Baysak, E.; Hizal, G.; Tunca, U.; Durmaz, H. An emerging post-polymerization modification technique: The promise of thiol-para -fluoro click reaction. J. Polym. Sci., Part A: Polym. Chem. 2018, 56, 1181−1198. (26) Delaittre, G.; Barner, L. The para-fluoro-thiol reaction as an efficient tool in polymer chemistry. Polym. Chem. 2018, 9, 2679− 2684.
click-like conditions with full conversion observed after 15 min at room temperature. The poor commercial availability of the thioacid starting materials, however, may impede a widespread use of this chemistry. Finally, azide reduction using DLdithiothreitol afforded simple access to primary aminefunctional polymers, which were successfully acylated in a third successive postpolymerization modification. The azidebased chemistries constitute a promising toolbox for the (sequential) modification of polymers and the preparation of well-defined multifunctional materials.
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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.9b00109.
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Full experimental section, list of all polymers with SECmeasured data, 1H and 19F NMR spectra, FT-IR spectra, optimization of CuAAC conditions, SEC curves, solubility table (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Peter J. Roth: 0000-0002-8910-9031 Present Address §
Department of Functional Materials in Medicine and Dentistry, University of Würzburg, 97070 Würzburg, Germany. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS Funding for J.-M.N. from the Faculty of Engineering at the University of New South Wales is acknowledged. P.J.R. acknowledges Rhiannon Batchelor, Ann-Katrin Friedrich, Jonas Kölsch, Ariella Kristanti, Yicheng Zhu (all UNSW), and Nicolas Busatto (University of Surrey) for providing polymer samples and/or assistance with synthesis, and Violeta Doukova (University of Surrey) for DSC and TGA measurements.
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REFERENCES
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