Polymerizations of Nitrophenylsulfonyl-Activated Aziridines

Article Cite This: Macromolecules XXXX, XXX, XXX−XXX

Polymerizations of Nitrophenylsulfonyl-Activated Aziridines Pierre Canisius Mbarushimana, Qiaoli Liang, Jared M. Allred, and Paul A. Rupar* Department of Chemistry, The University of Alabama, Tuscaloosa, Alabama 35487-0336, United States S Supporting Information *

ABSTRACT: 1-((p-Nitrophenyl)sulfonyl)aziridine (pNsAz) and 1-((o-nitrophenyl)sulfonyl)aziridine (oNsAz) were synthesized, and their polymerization chemistry was studied. Upon heating, pNsAz formed an insoluble white powder. In contrast, poly(oNsAz) is soluble in DMF and DMSO. Attempts were made to convert poly(oNsAz) to linear poly(ethylenimine) (lPEI) through removal of the o-nosyl group using sodium thiomethoxide. Although some evidence for the formation of lPEI was found, formation of pure lPEI was not possible. oNsAz is susceptible to spontaneous polymerization when stored neat or in a polar solvent (e.g., DMSO and DMF). Poly(oNsAz), formed from the spontaneous polymerization of oNsAz, was analyzed by MALDITOF mass spectrometry and composed of signals consistent with either OH or H2O acting as initiators for an anionic polymerization. Experiments studying the kinetics of oNsAz showed that the rate of polymerization was first order with respect to monomer concentration. It was also possible to initiate the anionic polymerization of oNsAz using BnN(Li)Ms. At low oNsAz:BnN(Li)Ms ratios, some control over molecular weight was achieved; however, at higher ratios, control was no longer possible, likely due to the presence of protic impurities that contaminate the monomer. Chain extension and propargyl chloride termination experiments were also performed with BnN(Li)Ms initiated polymerization of oNsAz.

■

Scheme 1. Living Anionic Polymerization of NSulfonylaziridines5

INTRODUCTION The polymerization of aziridines is surprisingly complex despite their apparent structural simplicity and similarity to the more widely studied oxiranes.1−4 Unsubstituted aziridine polymerizes exclusively via a cationic mechanism to generate branched poly(ethylenimine) (bPEI) instead of linear poly(ethylenimine) (lPEI). This branching occurs because the secondary amines of the forming polymer chains are nucleophilic and capable of ring-opening Lewis acid activated aziridine. The polymerization chemistry of N-substituted aziridines has been investigated, and in general, these molecules also polymerize cationically and exhibit branching.5−11 However, when sterically bulky substituents are used, branching can be inhibited to produce linear polymers. In the cases of tertbutylaziridine11 and 2-tetrahydropyranylaziridine7 , the resulting polymers can be converted to linear poly(ethylenimine) (lPEI). Aziridines can be made to undergo anionic polymerizations by installing electron-withdrawing groups on the nitrogen. Bergman and Toste reported the living anionic polymerization of 2-alkyl-1-sulfonylaziridines to form polysulfonylaziridines of controlled molecular weights and narrow molecular weight distributions (Scheme 1).5 More recently, Wurm and Taton have expanded upon this work, showing that a wide range of 2substituted-1-sulfonylaziridines can undergo living polymerizations.12−17 In these polymerizations, the electron-withdrawing sulfonyl groups activate the aziridine toward anionic ring-opening. The electron-withdrawing groups also inhibit © XXXX American Chemical Society

branching as they deactivate the nitrogen lone pairs along the polymer backbone. Furthermore, the sulfonyl groups can be reductively removed to give the corresponding polyimine (Scheme 1). 1-Sulfonylaziridines (i.e., non-2-alkyl-substituted) can also undergo anionic ring-opening, although attempts at polymer formation are complicated by the poor solubility of the resulting polymer. For example, anionic polymerization of 1tosylaziridine only gives short oligomers; longer oligomers rapidly precipitate from solution.5,17 In an effort to overcome these solubility problems, we recently showed that the copolymerization of two different 1-sulfonylaziridine monomers results in the formation of a random polysulfonylaziridine copolymer which maintains solubility in solvents such as DMSO and DMF.18 An inherent difficulty when using polysulfonylaziridines as precursors to polyimines is that the removal of the sulfonyl Received: October 5, 2017 Revised: January 13, 2018

A

DOI: 10.1021/acs.macromol.7b02125 Macromolecules XXXX, XXX, XXX−XXX

Article

Macromolecules Scheme 2. Reaction of an o-Nosyl-Protected Amine with a Thiolate

The organic layer was washed with brine (2 × 200 mL) and water (200 mL) and dried over MgSO4. The solvent was removed under vacuum, and the resulting white solid was purified by flash chromatography in hexane and ethyl acetate (2:3 ratio) (Rf = 0.75) (4.79 g, 98.1%). 1H NMR (360 MHz, CDCl3): 8.38 (d, 2H), 8.09 (d, 2H), 5.88 (s, 1H), 3.59 (t, 2H), 3.39 (q, 2H) (Figure S3). 13C NMR (500 MHz, CDCl3): δ 43.43, 44.71, 124.43, 128.16, 145.76, 150.15 (Figure S4). HRMS: [M]+ = 263.9972 (theoretical), 263.9975 (observed); [M − CH2Cl]+ = 215.0127 and 215.0111 (theoretical), 215.0120 (observed). Anal. Calcd for C8H9ClN2O4S: C, 36.30; H, 3.43; N, 10.58. Found: C, 36.24; H, 3.38; N, 10.40. Synthesis of 1-((o-Nitrophenyl)sulfonyl)aziridine (oNsAz). N(2-Chloroethyl)-2-nitrobenzenesulfonamide (3.40 g, 12.8 mmol) was dissolved in toluene (150 mL). Next, a separately prepared solution of LiOH (1.85 g, 77.0 mmol) in water (10.0 mL) was added to the sulfonamide solution to form a biphasic mixture which was stirred for 15 h. The mixture was then filtered, and the organic layer was separated, washed with brine (2 × 200 mL), dried over MgSO4, and filtered. The resulting mixture was further dried over 3 Å molecular sieves for 24 h. After removing the molecular sieves by centrifugation, toluene was removed under reduced pressure to yield a yellow, straw color oil (2.60 g, 77.3%). 1H NMR (360 MHz, CDCl3): 8.30−8.28 (d, 1H), 7.88−7.81 (m, 3H), 2.71 (s, 4H) (Figure S5). 13C NMR (500 MHz, C6D6): δ 28.78, 123.70, 129.02, 130.68, 131.26, 133.88, 148.61 (Figure S6). 14N NMR (500 MHz, C6D6, referenced to NH4NO3 at 380 and 23 ppm): δ 67.02 (br, aziridine ring nitrogen), δ 374.21 (s, NO2). Additional characterization (e.g., mass spectrometry and elemental analysis) was not possible because neat samples of oNsAz undergo spontaneous polymerization. Synthesis of 1-((p-Nitrophenyl)sulfonyl)aziridine (pNsAz). N(2-Chloroethyl)-4-nitrobenzenesulfonamide (3.40 g, 12.8 mmol) was dissolved in toluene (150 mL). Next, a separately prepared solution of LiOH (1.85 g, 77.0 mmol) in water (10.0 mL) was added to the sulfonamide, and the mixture was stirred. After 15 h, the mixture was filtered, and the organic layer was separated, washed with brine (2 × 200 mL), and dried over MgSO4. The solvent was removed under vacuum, and the resulting residue was purified by sublimation at 80 °C and 44 mTorr onto a coldfinger (0 °C) to yield a white crystalline solid (2.39 g, 71.0%). 1H NMR (360 MHz, CDCl3): 8.43−8.40 (d, 2H), 8.20−8.15 (d, 2H), 2.50 (s, 4H) (Figure S7). 13C NMR (500 MHz, CDCl3): δ 28.10, 124.31, 129.28, 143.86, 150.73 (Figure S8). 14 N NMR (500 MHz, C6D6, referenced to NH4NO3 at 380 and 23 ppm): δ 69.00 (br, aziridine ring nitrogen), δ 369.31 (s, NO2). Polymerization of Neat oNsAz at 100 °C. A vessel containing oNsAz (1.00 g, 4.38 mmol) was placed under vacuum and heated to 100 °C for 5 h. The resulting glassy polymer was dissolved in DMF, precipitated in water, and dried to yield a white powder (0.87 g, 87%). 1 H NMR (600 MHz, CDCl3): 8.00−7.60 (b m, 4H), 3.53−3.40 (b, 4H) (Figure S9). GPC (polystyrene standard, DMF, 60 °C): Mn 112 kDa, Mw 134 kDa, Đ 1.19. DSC (heating/cooling rate of 10 °C/min): Tg 78 °C. Polymerization of Neat pNsAz at 100 °C. A vessel containing pNsAz monomer (1.00 g, 4.38 mmol) was placed under vacuum and heated to 100 °C for 18 h. The resulting white powder was insoluble in all solvents examined.22 DSC (heating/cooling rate of 10 °C/min): Tg 66 °C. BnN(Li)Ms Initiated Polymerization of oNsAz. To a solution of BnN(Li)Ms in DMF solution (20.0 mM, 10.0 mL, 0.0200 mmol), generated in situ from lithium diisopropylamide (LDA) and BnN(H)Ms, was added oNsAz (0.100 g, 0.440 mmol) (calculated for a 20:1 monomer to initiator ratio). The solution was stirred for 18

groups can be challenging. In all cases to date, strong reducing agents such as lithium naphthalenide, Red-Al, and lithium metal are needed to form polyimines from polysulfonylaziridines.5,13 These harsh conditions are potentially incompatible with many functional groups, thus limiting the use of polysulfonylaziridines as precursors to polyimine containing polymer conjugates. In this context, we now report the polymerization of 1sulfonylaziridines, where the sulfonyl group is either o- or pnitrophenylsulfonyl (nosyl). The nosyl group was chosen as it is removed under mild conditions, using a thiol in the presence of a base (Scheme 2), thus providing a potential route to synthesize lPEI.19−21

■

EXPERIMENTAL SECTION

Materials and Characterization. All chemicals were purchased from commercial suppliers and were used directly without further purification unless otherwise stated. Anhydrous DMF was purchased from Sigma-Aldrich, freeze−pump−thawed, and stored over 3 Å molecular sieves before use. Anhydrous DMSO was also purchased from Sigma-Aldrich and stored over 3 Å molecular sieves before use. BnN(Li)Ms was prepared as previously reported.16 All reactions were performed under an N2 atmosphere unless otherwise stated. MALDITOF mass spectra were obtained using a Bruker Ultraflex I MALDITOF mass spectrometer equipped with a pulsed 50 Hz 337 nm nitrogen laser. DSC analysis was performed using a TA Q200 with a heating/cooling rate of 10 °C/min. All samples were subjected to three complete heating/cooling cycles, and the third cycle was reported. Gel permeation chromatography (GPC) was performed on a 2100 Malvern Viscotek gel permeation chromatograph with an RI detector, an automatic sampler, a pump, an injector, an inline degasser, a column oven (60 °C), two in-series Malvern t6000 M GPC columns, and a DMF mobile phase. Wide-angle X-ray scattering (WAXS) was performed on a Bruker D2 Phaser with Cu Kα radiation operated at 30 kV and 10 mA. Data were collected using a LynxEye 1D detector. Synthesis of N-(2-Chloroethyl)-2-nitrobenzenesulfonamide. 2-Chloroethylamine hydrochloric acid (2.00 g, 17.3 mmol) and triethylamine (6.00 mL, 43.0 mmol) were dissolved in DCM (100 mL) and cooled to 0 °C. o-Nitrophenylsulfonyl chloride (4.60 g, 20.7 mmol) was added, and the solution was stirred at room temperature. After 15 h, the solution was poured into acidic water (1% aqueous HCl, 200 mL) and was extracted with DCM (3 × 100 mL). The organic layer was washed with brine (2 × 200 mL) and water (200 mL) and dried over MgSO4. The solvent was removed under vacuum, and the resulting yellow wax was purified by flash chromatography in hexane and ethyl acetate (2:3 ratio) (Rf = 0.80) to yield a white solid (4.70 g, 96.3%). 1H NMR (360 MHz, CDCl3): δ 8.16−8.12 (m, 1H), 7.92−7.88 (m, 1H), 7.78−7.75 (q, 2H), 5.88 (s, 1H), 3.63 (t, 2H), 3.48 (t, 2H) (Figure S1). 13C NMR (500 MHz, CDCl3): δ 43.19, 45.35, 125.62, 130.72, 132.98, 133.83, 147.97 (Figure S2). HRMS: [M − CH2Cl]+ = 215.0127 (theoretical), 215.0126 (observed). Anal. Calcd for C8H9ClN2O4S: C, 36.30; H, 3.43; N, 10.58. Found: C, 36.38; H, 3.29; N, 10.45. Synthesis of N-(2-Chloroethyl)-4-nitrobenzenesulfonamide. 2-Chloroethylamine hydrochloric acid (2.00 g, 17.3 mmol) and triethylamine (6.00 mL, 43.0 mmol) were dissolved in DCM (100 mL) and cooled to 0 °C. p-Nitrophenylsulfonyl chloride (4.60 g, 20.7 mmol) was then added, and the solution was stirred at room temperature. After 15 h, the solution was poured into acidic water (1% aqueous HCl, 200 mL) and was extracted with DCM (3 × 100 mL). B

DOI: 10.1021/acs.macromol.7b02125 Macromolecules XXXX, XXX, XXX−XXX

Article

Macromolecules

Figure 1. 1H NMR spectrum of poly(oNsAz) initiated by BnN(Li)Ms ([M]/[I] = 20).

Figure 2. MALDI-TOF mass spectrum of a BnN(Li)Ms initiated poly(oNsAz) ([M]/[I] = 20). The “∗” series is attributed to [BnMs·(oNsAz)n· Na]+, and the “#” series is attributed to [OH·(oNsAz)n·Na]+. h at room temperature and then precipitated into water. The polymer was collected by centrifugation and dried under vacuum for 18 h. The product was recovered as a white powder and analyzed using 1H NMR spectroscopy (Figure 1), MALDI-TOF MS (Figure 2), and GPC (entry 1 in Figure 3) (0.0870 g, 87.0%). 1H NMR (600 MHz, DMSOd6): 7.95−7.70 (br, 118H), 7.29 (s, 5H), 4.29 (s, 2H), 3.55−3.3 (br, 87H), 2.92 (s, 3H). 13C NMR (500 MHz, CDCl3): δ 36.24, 45.29, 47.97, 125.14, 126.80, 128.92, 129.82, 131.35, 133.13, 135.26, 147.98. MALDI-TOF mass spectra of the polymer were taken in reflectron positive mode. To prepare the sample for MALDI-TOF, 0.5 μL of KI (50 mg/mL) in MeOH was spotted first onto the plate, followed by 1 μL of the synthesized poly(oNsAz) (10 mg/mL) in DMF and allowed to dry for 18 h. Then, 2 μL of dithranol (20 mg/mL) in THF was spotted on top of both KI and poly(oNsAz). BnN(Li)Ms Initiated Polymerization of oNsAz End-Functionalized with Propargyl Chloride. To a solution of BnN(Li)Ms in DMF (20.0 mM, 10.0 mL, 0.0200 mmol), generated in situ from LDA

and BnNHMs, was added oNsAz monomer (0.100 g, 0.440 mmol) (calculated for a 20:1 monomer-to-initiator ratio). The solution was stirred for 20 min, and then 0.0100 mL (0.1400 mmol) of propargyl chloride was added. The solution was stirred for 18 h at room temperature and then precipitated into water. The polymer was collected by centrifugation and dried under vacuum. The product was recovered as a white powder and analyzed using 1H NMR spectroscopy (Figure S12), GPC (in DMF), and MALDI-TOF MS (Figure S17). MALDI-TOF mass spectra of the polymer were taken in reflectron positive mode. To prepare the sample for MALDI-TOF data collection, 0.5 μL of KI (50 mg/mL) in MeOH was spotted first onto the plate, followed by 1 μL of the synthesized poly(oNsAz) (10 mg/ mL) in DMF and allowed to dry for 18 h. Next, 2 μL of dithranol (20 mg/mL) in THF was spotted on top of both KI and poly(oNsAz). Poly(oNsAz) Chain Extension Experiment. To a BnN(Li)Ms solution in DMSO-d6 solution (20.0 mM, 10.0 mL, 0.0200 mmol) generated in situ from LDA and BnNHMs was added oNsAz (0.100 g, C

DOI: 10.1021/acs.macromol.7b02125 Macromolecules XXXX, XXX, XXX−XXX

Article

Macromolecules

thiomethoxide (MeSNa) (1.44 g, 21.9 mmol) were dissolved in DMF (50 mL) and stirred at 50 °C for 18 h with the flask open to air. The mixture was dried under vacuum, and the resulting orange solid was dissolved in concentrated HCl and stirred for 1 h. The formed slurry was centrifuged, and the isolated supernatant was dried and dialyzed for 5 h against deionized water and 18 h against water (3500 MWCO). The resulting white precipitate was dried and characterized by 1H NMR spectroscopy (Figure S14) and HSQC NMR spectroscopy (Figure S15).

■

RESULTS AND DISCUSSION 1-((o-Nitrophenyl)sulfonyl)aziridine (oNsAz) and 1-((pnitrophenyl)sulfonyl)aziridine (pNsAz) were synthesized using procedures similar to those previously reported.21 Starting from chloroethylamine hydrochloric acid, the nosyl groups were attached to the amine to form N-(2-chloroethyl)nitrobenzenesulfonamide using the appropriate sulfonyl chloride and a base (Scheme 3). Subsequent ring closing, induced by lithium hydroxide, produced the desired aziridine monomers oNsAz and pNsAz. oNsAz was isolated as a strawcolored oil, and pNsAz was obtained as a white crystalline solid, both in good yields. A requirement for many anionic polymerizations is the thorough removal of impurities, especially protic sources, from the monomer. Unfortunately, a rigorous purification of oNsAz was not possible in our hands. Although the synthesis of oNsAz yielded product that was essentially pure by 1H NMR spectroscopy (Figure S5), further efforts to remove trace impurities (e.g., adventitious water) by distillation or sublimation were ultimately unsuccessful, as oNsAz readily undergoes spontaneous polymerization. Interestingly, oNsAz does not spontaneously polymerize when dissolved in dry toluene. Therefore, in an attempt to remove trace amounts of water from oNsAz, toluene solutions of oNsAz were stored over 3 Å molecular sieves. In contrast to oNsAz, pNsAz was easily purified by successive sublimations. The improved stability of pNsAz likely results from pNsAz being a crystalline solid at room temperature, while oNsAz is a viscous oil at room temperature. We attempted to remove traces amounts of water from the monomers by heating samples to 100 °C under vacuum. In the case of pNsAz, heating to 100 °C produced a white powder, presumed to be poly(pNsAz), that was insoluble in common

Figure 3. GPC trace of poly(oNsAz) synthesized from the BnN(Li)Ms initiated polymerization of oNsAz. See Table 1 for a summary of the conditions. 0.440 mmol) (calculated for a 20:1 monomer-to-initiator ratio). The solution was stirred for 30 min, after which half of the reaction mixture was precipitated in water, and the polymer was collected by centrifugation and dried under vacuum. To the remaining half of the reaction mixture, additional oNsAz monomer (0.100 g, 0.440 mmol) was added, and the reaction mixture was stirred for 18 h and then precipitated into water. The polymer was collected by centrifugation and dried under vacuum for 18 h. The polymers were analyzed using GPC (in DMF) (Figure S20). GPC (Polystyrene standard, DMF, 60 °C): Precursor polymer before chain extension Mn 5.74 kDa, Mw 6.25 kDa, Đ 1.09 (theoretical Mn 4.75 kDa); after chain extension Mn 7.48 kDa, Mw 8.15 kDa, Đ 1.09 (theoretical Mn 9.31 kDa). Kinetic Study of the Spontaneous Polymerization of oNsAz by 1H NMR Spectroscopy. oNsAz (0.100 g, 0.44 mmol) and acetonitrile (13.0 μL, 0.250 mmol) (used as an internal NMR integration standard) were dissolved in dry DMSO-d6 (1.00 mL). The polymerization was monitored over an 8 h period by 1H NMR spectroscopy (Figure S13). Attempted Removal of Nosyl Group from Poly(oNsAz). Poly(oNsAz) (1.00 g, 4.38 mmol of oNs groups) and excess sodium

Scheme 3. Synthesis of oNsAz and pNsAz Monomersa

a

Reagents and conditions: (a) oNsCl, triethylamine, DCM, 0 °C, 18 h; (b) pNsCl, triethylamine, DCM, 0 °C, 18 h; (c) LiOH, toluene, RT, 18 h. D

DOI: 10.1021/acs.macromol.7b02125 Macromolecules XXXX, XXX, XXX−XXX

Article

Macromolecules solvents;23 further characterization of this material was not attempted. oNsAz also polymerizes, but the resulting poly(oNsAz) is soluble in both DMF and DMSO. 1H NMR spectroscopic data of poly(oNsAz) were consistent with the proposed structure of the polymer (Figure S9). We could reproducibly isolate high molecular weight poly(oNsAz) (>115 kg/mol vs a polystyrene standard) from these heated samples of neat oNsAz. MALDI-TOF MS of poly(oNsAz) samples formed from heating oNsAz showed a major mass series consistent with polymer chains composed of oNsAz repeat units and a single H2O moiety (Figure S16). This suggests that the polymerization of oNsAz is initiated by trace amounts of H2O (or hydroxide). The handling of oNsAz is made difficult by its tendency to undergo spontaneous polymerization when stored as a neat sample at room temperature or when left for brief amounts of time in polar solvents. We assumed that the spontaneous polymerization of oNsAz is initiated by impurities present in the monomer samples and is likely ionic in nature. Our hypothesis that the polymerization is ionic is supported by the fact that solutions of oNsAz in nonpolar solvents such as toluene are stable, while oNsAz rapidly undergoes polymerization in more polar solvents (e.g., THF, DMF, and DMSO). MALDI-TOF mass spectrometric analysis of poly(oNsAz) formed during spontaneous polymerizations at room temperature was nearly identical to those formed from neat oNsAz at 100 °C and consisted of polymer chains composed of oNsAz repeat units and a single H2O moiety (Figure S16). On the basis of this information, we postulate that water or hydroxide is initiating the ring-opening polymerization of oNsAz. We attempted to remove trace amounts of either water or base by stirring oNsAz over acidic desiccating agents such as P2O5, but this did not inhibit the spontaneous polymerization of the aziridine. Basic drying agents such as CaH2 also induced the polymerization of oNsAz. Nosyl amides are typically transformed to the corresponding amines by removal of the nosyl group using a thiol in the presence of a base.21,23−25 In an effort to convert poly(oNsAz) to lPEI, we screened many different conditions but were ultimately unsuccessful in obtaining pure lPEI. The most promising results came from using sodium thiomethoxide (Scheme 4). After completion of the deprotection procedure

spectrum of the residue also showed many unidentified signals that could not be attributed to lPEI, poly(oNsAz), or methyl(2nitrophenyl)sulfane that form during deprotection (Scheme 4). The difficulties encountered in removing the nosyl groups from the polymer chain were surprising, as the ease of deprotection of nosyl amides is widely reported.18−20 However, there are examples in the literature where attempts at deprotection of nosyl amides can lead to a Smiles rearrangement.28−30 In the case of the deprotection of poly(oNsAz), this would result in intramolecular transfer of the nitrophenyl group to previously deprotected amines along the polymer backbone. Indeed, the 1H NMR spectra of the residue that forms during the deprotection of poly(oNsAz) do exhibit weak signals consistent with an o-nitrophenyl group and are not due to methyl(2-nitrophenyl)sulfane (Figure S14). Efforts to better identify the exact composition of the polymeric residue that forms from the attempted deprotection of poly(oNsAz) were not successful. Attempts were made to initiate the polymerization of pNsAz and oNsAz using BnN(Li)Ms. Prior work has shown that BnN(M)Ms (M = Li, Na, K, Cs) is a good initiator for the anionic polymerization of sulfonylaziridines.5,13,15,16 For oNsAz, the 1H NMR spectrum of the resulting poly(oNsAz) was consistent with the proposed structure of the polymer and showed the presence of the BnNMs initiator (Figure 1). The signals in the MALDI-TOF mass spectrum of poly(oNsAz) were also consistent with polymer chains initiated by BnN(Li)Ms and terminated with a proton, although there was some evidence of H2O initiated polymer chains (Figure 2). In the case of pNsAz, polymerization of pNsAz does appear to occur upon addition of BnN(Li)Ms; however, after very low conversion, poly(pNsAz) begins to precipitate and, as described above, is insoluble in every solvent examined.22 Given that all prior examples of poly(1-sulfonylaziridine) homopolymers are insoluble in common solvents,5,18 the insolubility of poly(pNsAz) is not surprising. Rather, it is the solubility of poly(oNsAz) that is unusual. We propose that the improved solubility of poly(oNsAz) is due to the presence of the o-nosyl group, which frustrates polymer chain packing. This hypothesis is consistent with the observation that poly(1tosylaziridine)5 and poly((1-methylsulfonyl)aziridine),18 which have more symmetrical organic moieties on the sulfonyl group, are completely insoluble in common solvents. Differential scanning calorimetry showed poly(oNsAz) to have a glass transition (Tg) at 78 °C and poly(pNsAz) at 66 °C (Figures S24 and S25). Wide-angle X-ray scattering showed both poly(oNsAz) and poly(pNsAz) to be semicrystalline (Figures S28 and S29) although we were unable to observe melting or crystallization transitions in the DSC traces of these polymers. Both poly(oNsAz) and poly(pNsAz) displayed good thermostability, showing mass losses of 5% at 280 and 310 °C, respectively (Figures S26 and S27). Experiments were performed in which the ratio of oNsAz to initiator was varied in an effort to control the molecular weights of the resulting polymers, realizing that the presence of impurities in the monomer would likely interfere with this objective. The monomer-to-initiator ratios ([M]/[I]) were varied from 20 to 400 (Table 1 and Figure 3), and the average molecular weights of the resulting polymers were estimated by both 1H NMR spectroscopic end-group analysis (Mn,NMR) and GPC (Mn,GPC). The 1H NMR end-group analysis was attempted using the methylene protons of the initiator; however, as discussed below, Mn,NMR is certainly overestimated.

Scheme 4. Attempted Deprotection of Poly(oNsAz) To Form lPEI

and subsequent purification, an off-white residue was isolated. The 1H NMR spectrum of the residue showed complete removal of the nosyl groups from poly(oNsAz), as demonstrated by the loss of the aromatic signals at 7.8−8.4 ppm. Furthermore, 1H NMR spectroscopic signals attributed to the polymer backbone between 3.1 and 3.5 ppm appeared to shift to a broad singlet at 2.73 ppm (Figure S14). The 1H−13C HSQC NMR spectrum of the residue showed a correlation between a carbon signal at 49.7 ppm, which is diagnostic of lPEI, and the proton signal at 2.73 ppm (Figure S15).7,26,27 These assignments were supported by spiking the NMR sample with authentic lPEI (Figures S15). However, the NMR E

DOI: 10.1021/acs.macromol.7b02125 Macromolecules XXXX, XXX, XXX−XXX

Article

Macromolecules

second aliquot showed that the Mn,GPC of the polymer increased from 5.74 to 7.48 kDa (vs a PS standard). In addition, the GPC traces clearly show that almost all of the polymer chains undergo chain extension (Figure S20). We attempted to study the kinetics of the ring-opening polymerization of oNsAz. The rate of the BnN(Li)Ms initiated polymerization was too fast to study by NMR spectroscopy, as the polymerization of oNsAz appears to typically be complete in less than 20 min. Qualitatively, the polymerization rate of oNsAz is significantly faster than that of 1-(alkylsulfonyl)aziridines.18 The faster rate of polymerization of oNsAz compared to 1-(alkylsulfonyl)aziridines is consistent with observations by Wurm and co-workers that showed that 2methyl-1-sulfonylaziridines with more electron withdrawing sulfonyl groups undergo faster polymerization rates.15 On the other hand, the rates of polymerizations that were spontaneously initiated in DMSOd6 were much slower and therefore could be monitored by 1H NMR spectroscopy (Figure S13). Polymer formation was visible in 1H NMR spectra within 10 min of the monomer being transferred into DMSO-d6. There appears to be little-to-no onset period. In most experiments, spontaneous polymerization of oNsAz is first-order with respect to the concentration of the monomer (Figure S22). A factor that complicated our analysis of the spontaneous oNsAz polymerizations is that the rate of the reaction varied depending on the specific monomer sample; i.e., polymerizations of oNsAz from monomer samples prepared on different days could have different rates of polymerizations under otherwise identical conditions. This is in spite of the fact that both monomer samples appear identical by 1H NMR spectroscopy. The variation in polymerization rates is consistent with our hypothesis that the spontaneous polymerization of oNsAz occurs due to the presence of trace impurities in the monomer and that the concentration of these impurities varies from sample to sample. Attempts at studying the impact of water on the spontaneous polymerization rates of oNsAz were also complicated by inconsistencies in rates from sample to sample under apparently identical conditions.

Table 1. Comparison of Number-Average Molecular Weight (GPC and 1H NMR) to the [M]/[I] Ratio entries

[M]:[I]

Mn,NMRa (kDa)

Mn,GPCb (kDa)

Đb

1 2 3 4 5 6 7

20:1 40:1 60:1 80:1 100:1 200:1 400:1

5.77 10.8 11.0 15.14 21.22 35.13 40.8

5.74 7.88 7.69 6.72 11.2 7.23 12.5

1.09 1.23 1.21 1.35 1.25 1.39 1.28

a

Based on comparing the 1H NMR spectroscopic integration of the signals attributed to the methylene protons of the BnNMs initiator and the polymer aromatic signals. These values are overestimated as this assumes that each polymer chain was initiated by BnN(Li)Ms, which MALDI-TOF MS analysis shows to be incorrect. bDetermined via GPC vs PS standards.

All polymerizations reached 100% conversion as observed by the complete consumption of the monomer by NMR. Overall, it appears that at lower [M]/[I] modest control over molecular weights is possible, but at higher ratios, control is lost. Analysis of the polymer from entry 1 ([M]/[I] = 20) by MALDI-TOF MS showed that most polymer chains were initiated by BnN(Li)Ms; however, signals consistent with H2O/−OH initiation were visible, but with much lower intensity (Figure 2). The GPC data show poorer correlation between [Mn]GPC and [M]/[I], and most of the GPC traces are multimodal. We believe that these observations can be explained by the inability to properly purify the oNsAz monomer and that protic impurities (e.g., water) are quenching the initiator molecules and active chain ends. The resulting deprotonated impurities (e.g., hydroxide) are likely capable of initiating new polymer chains, which contribute to the multimodal distributions observed in the GPC traces. As a consequence, the Mn’s provided by 1H NMR end-group analysis are most certainly overestimated. The possibility that the multimodal GPC traces arose due to polymer aggregatation was excluded by the fact that the GPC traces did not change when the GPC analyte concentration was decreased or heated prior to analysis. Furthermore, samples of high molecular weight poly(oNsAz) (e.g., Mn > 115 kg/mol), synthesized by heating neat oNsAz to 100 °C (see above), did not exhibit multimodal traces. While we are unable to purify oNsAz sufficiently to permit living polymerization conditions at higher [M]/[I] ratios, polymerizations performed with lower [M]/[I] do show some characteristics of a living polymerization. For example, a polymerization with a [M]/[I] ratio of 20 was performed in which we terminated the polymerization with propargyl chloride. 1H NMR spectroscopic analysis of the polymer confirmed the presence of the propargyl group (Figure S12). In addition, the MALDI-TOF mass spectrum of the polymer indicated that the chain ends were successfully terminated by the propargyl chloride (Figure S17). This clearly shows that the anion at the end of the growing polymer chain is somewhat persistent within the time frame of the experiment. We were also able to perform a chain extension experiment with a DMF solution of oNsAz initiated with BnN(Li)Ms, with an initial [M]/[I] ratio of 20:1. After the oNsAz was consumed, an additional portion of oNsAz was added and the polymerization was allowed to continue. GPC measurements of the resulting poly(oNsAz) from before and after addition of the

■

CONCLUSIONS In summary, the polymerization chemistry of pNsAz and oNsAz was explored. For pNsAz, all attempts at polymerization resulted in the formation of insoluble material. With oNsAz, the resulting poly(oNsAz) was soluble in both DMF and DMSO. The improved solubility of poly(oNsAz) is attributed to the ortho substitution of the nitrophenyl group, which disrupts chain packing. This is significant as it is the first example of a soluble poly(1-sulfonylaziridine) homopolymer; prior examples were limited to copolymer systems. The fact that lower symmetry sulfonyl groups improve solubility in poly(sulfonylaziridines) will be useful in designing related polymeric materials in the future. The primary motivation toward studying the polymerization chemistry of the pNsAz and oNsAz monomers was to use the resulting polymers as precursors to linear poly(ethylenimine) (lPEI). Although evidence was found for the formation of lPEI from the deprotection of poly(oNsAz), satisfactory purification of the lPEI was not achievable. Control over the molecular weight of poly(oNsAz) was attempted by initiating the anionic polymerization of oNsAz with BnN(Li)Ms. Based on MALDI-TOF mass spectrometric data, the resulting poly(oNsAz) was a mixture of the BnN(Li)Ms initiated polymer chains and hydroxyl initiated F

DOI: 10.1021/acs.macromol.7b02125 Macromolecules XXXX, XXX, XXX−XXX

Article

Macromolecules

(14) Bakkali-Hassani, C.; Rieger, E.; Vignolle, J.; Wurm, F. R.; Carlotti, S.; Taton, D. Chem. Commun. 2016, 52, 9719. (15) Rieger, E.; Alkan, A.; Manhart, A.; Wagner, M.; Wurm, F. R. Macromol. Rapid Commun. 2016, 37, 833. (16) Rieger, E.; Gleede, T.; Weber, K.; Manhart, A.; Wagner, M.; Wurm, F. R. The living anionic polymerization of activated aziridines: a systematic study of reaction conditions and kinetics, 2017. (17) Thomi, L.; Wurm, F. R. Macromol. Rapid Commun. 2014, 35, 585. (18) Reisman, L.; Mbarushimana, C. P.; Cassidy, S. J.; Rupar, P. A. ACS Macro Lett. 2016, 5, 1137. (19) Cardullo, F.; Donati, D.; Merlo, G.; Paio, A.; Salaris, M.; Taddei, M. Synlett 2005, 2005, 2996. (20) Kan, T.; Fukuyama, T. Chem. Commun. 2004, 353. (21) Farràs, J.; Ginesta, X.; Sutton, P. W.; Taltavull, J.; Egeler, F.; Romea, P.; Urpí, F.; Vilarrasa, J. Tetrahedron 2001, 57, 7665. (22) The solubility of the polymer was tested in the following solvents at 25 °C and at their respective boiling points: hexane, benzene, toluene, DCM, chloroform, THF, acetone, acetonitrile, water, DMF, and DMSO. (23) Maligres, P. E.; See, M. M.; Askin, D.; Reider, P. J. Tetrahedron Lett. 1997, 38, 5253. (24) Sutton, P. W.; Bradley, A.; Farràs, J.; Romea, P.; Urpí, Fèlix; Vilarrasa, J. Pseudoaxially Disubstituted Cyclo-β3-tetrapeptide Scaffolds. Tetrahedron 2000, 56, 7947. (25) Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron Lett. 1995, 36, 6373. (26) Tanaka, R.; Ueoka, I.; Takaki, Y.; Kataoka, K.; Saito, S. Macromolecules (Washington, DC, U. S.) 1983, 16, 849. (27) Tauhardt, L.; Kempe, K.; Knop, K.; Altuntaş, E.; Jäger, M.; Schubert, S.; Fischer, D.; Schubert, U. S. Linear Polyethyleneimine: Optimized Synthesis and Characterization - On the Way to “Pharmagrade” Batches. Macromol. Chem. Phys. 2011, 212, 1918. (28) Holden, C. M.; Greaney, M. F. Chem. - Eur. J. 2017, 23, 8992. (29) Wilson, M. W.; Ault-Justus, S. E.; Hodges, J. C.; Rubin, J. R. Tetrahedron 1999, 55, 1647. (30) Wuts, P. G. M.; Northuis, J. M. Tetrahedron Lett. 1998, 39, 3889.

chains. Even though control over the molecular weight was ultimately not possible, BnN(Li)Ms initiated polymerizations with low [M]/[I] ratios could be terminated with propargyl chloride and were capable of undergoing chain extension experiments. The purification and storage of oNsAz were difficult due to the fact that it readily undergoes spontaneous polymerization. The spontaneous polymerization of oNsAz appears to be initiated by trace amounts of either water or hydroxide, as evident by MALDI-TOF mass spectrometric measurements. It seems likely that if oNsAz could be satisfactorily purified, its tendency to spontaneously polymerize could be reduced and deliberately initiated anionic polymerization could be made living.

■

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.macromol.7b02125. NMR spectroscopy, MALDI-TOF mass spectrometry, gel permeation chromatography, differential scanning calorimetry, thermal gravimetric analysis data (PDF)

■

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected] (P.A.R.). ORCID

Paul A. Rupar: 0000-0002-9532-116X Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS We thank the Petroleum Research Fund (55075-DNI7) and the University of Alabama (UA) for financial support. We thank Dr. Aymara Albury for the collection of DSC data.

■

REFERENCES

(1) Goethals, E. J.; Schacht, E. H.; Bruggeman, P.; Bossaer, P. In Ring-Opening Polymerization; American Chemical Society: 1977; Vol. 59, p 1. (2) Kobayashi, S. Prog. Polym. Sci. 1990, 15, 751. (3) Jager, M.; Schubert, S.; Ochrimenko, S.; Fischer, D.; Schubert, U. S. Chem. Soc. Rev. 2012, 41, 4755. (4) Herzberger, J.; Niederer, K.; Pohlit, H.; Seiwert, J.; Worm, M.; Wurm, F. R.; Frey, H. Chem. Rev. 2016, 116, 2170. (5) Stewart, I. C.; Lee, C. C.; Bergman, R. G.; Toste, F. D. J. Am. Chem. Soc. 2005, 127, 17616. (6) Pooley, S. A.; Canessa, G. S.; Rivas, B. L. Poly[N-(2hydroxyethyl)ethyleneimine-co-(1,2,3,6-tetrahydrophthalic anhydride)] by spontaneous copolymerization. Macromol. Chem. Phys. 1998, 199, 2293. (7) Weyts, K.; Goethals, E. New synthesis of linear polyethyleneimine. Polym. Bull. 1988, 19, 13. (8) Goethals, E. J.; Bossaer, P.; Deveux, R. The polymerization behaviour of 1-benzyl-2,2-dimethylaziridine. Polym. Bull. 1981, 6, 121. (9) Demember, J. R.; Taylor, L. D. J. Polym. Sci., Polym. Chem. Ed. 1979, 17, 1089. (10) Saegusa, T.; Ikeda, H.; Fujii, H. Macromolecules 1972, 5, 108. (11) Bossaer, P. K.; Goethals, E. J. Makromol. Chem. 1977, 178, 2983. (12) Thomi, L.; Wurm, F. R. Macromol. Symp. 2015, 349, 51. (13) Rieger, E.; Manhart, A.; Wurm, F. R. ACS Macro Lett. 2016, 5, 195. G

DOI: 10.1021/acs.macromol.7b02125 Macromolecules XXXX, XXX, XXX−XXX