Letter pubs.acs.org/macroletters
Living Anionic Copolymerization of 1‑(Alkylsulfonyl)aziridines to Form Poly(sulfonylaziridine) and Linear Poly(ethylenimine) Louis Reisman, Canisius P. Mbarushimana, S. Joel Cassidy, and Paul A. Rupar* Department of Chemistry, The University of Alabama, Tuscaloosa, Alabama 35487-0336, United States S Supporting Information *
ABSTRACT: The anionic ring-opening copolymerization of 1-(methylsulfonyl)aziridine (MsAz) and 1-(sec-butylsulfonyl)aziridine (sBsAz) produces a soluble random copolymer P(MsAz-r-sBsAz), which can subsequently be converted to linear poly(ethylenimine) (lPEI). The copolymerization of MsAz and sBsAz is living and allows for the synthesis of copolymers with low molecular weight distributions. Sequential anionic polymerization of MsAz and sBsAz with 2-methyl-1-(methylsulfonyl)aziridine (MsMAz) creates P(MsAz-r-sBsAz)-b-P(MeMsAz). Removal of the sulfonyl groups from P(MsAz-r-sBsAz)-bP(MsMAz) gives lPEI-b-poly(propylenimine). For the first time, lPEI can be synthesized by a controlled anionic polymerization.
D
(POX) suffer from difficulties in control at high degrees of polymerization and incomplete conversion of the POX to lPEI.1b In an effort to form a poly(1-sulfonylaziridine), we first attempted to initiate the AROP of 1-(methylsulfonyl)aziridine (MsAz) with BnN(K)Ms. Similar to what was observed by Wurm with 1-tosylaziridine which only produced oligomers upon polymerization,8 the reaction mixture became turbid as short oligomers precipitated from solution (Scheme 1). We next attempted to polymerize 1-(sec-butylsulfonyl)aziridine (sBsAz), believing that the racemic sec-butyl group would improve the solubility of the resulting polymer. Unfortunately, the resulting oligomers also became insoluble when the degree of polymerization (Dp) exceeded 25 repeat units (Scheme 1). Larger oligomers of P(MsAz) and P(sBsAz) appear to be insoluble in all common solvents at all temperatures. We rationalized that a random copolymer of two different 1(alkylsulfonyl)aziridines would improve the solubility of poly(1-sulfonylaziridine)s by interrupting interchain packing. We copolymerized MsAz and sBsAz in a 1:1 mol ratio using BnN(K)Ms as an anionic initiator to form P(MsAz-r-sBsAz) (Scheme 1). As anticipated, the resulting polymer retained solubility during the course of the reaction. Attempts at copolymerization of 3:1 or 1:3 molar ratios of MsAz and sBsAz resulted in the formation of turbid solutions due to polymer precipitation. Therefore, a mole ratio of 1:1 for MsAz and s BsAz was used throughout the remainder of this study. P(MsAz-r-sBsAz) is soluble in DMF, DMSO, and HMPA, and
espite the structural similarities between aziridine and ethylene oxide (EO), their polymerization behaviors are very different. While the polymerization of EO to form poly(ethylene oxide) can be controlled and occurs through anionic or cationic mechanisms, the polymerization of aziridine is exclusively cationic, is not controlled, and produces branched poly(ethylenimine) (bPEI) rather than linear poly(ethylenimine) (lPEI).1 Toste and Bergman,2 and more recently Wurm,3 have shown that racemic 2-methyl-1-sulfonylaziridines undergo living anionic ring-opening polymerizations (AROPs) to form atactic poly(2-methyl-1-sulfonylaziridine)s. These AROPs are facilitated by the sulfonyl groups which activate the aziridine toward nucleophilic ring opening4 and inhibit chain branching. In postpolymerization, the sulfonyl groups can be removed to produce linear poly(propylenimine).2 Related 1-sulfonylaziridines with other alkyl and alkoxy groups at the 2-position have also been reported.2,3,5 In their original report, Toste and Bergman noted that only atactic poly(2-methyl-1sulfonylaziridine)s were soluble in common solvents.2 In contrast, otherwise identical tactic polymers were completely insoluble at higher molecular weights. Surprisingly, there are no reports on the polymerization of 1sulfonylaziridines (i.e., not 2-alkylated) to form poly(1sulfonylaziridine)s.6,7 Wurm recently attempted to polymerize 1-tosylaziridine, but the reaction only produced small oligomers which precipitated at very low degrees of polymerization (i.e., n = 10).8 If the polymerization of a 1-sulfonylaziridine was successful, it would demonstrate that it is possible to anionically polymerize a nitrogen analogue of EO and could be used as a precursor to lPEI. Novel, controlled routes to lPEI continue to be highly sought after due to the use of lPEI in high value applications such as nonviral gene-transfection agents.9 Moreover, the current methods to lPEI via poly(2-oxazoline)s © XXXX American Chemical Society
Received: July 12, 2016 Accepted: September 14, 2016
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DOI: 10.1021/acsmacrolett.6b00538 ACS Macro Lett. 2016, 5, 1137−1140
Letter
ACS Macro Letters
and GPC data. MALDI-TOF MS of lPEI11 derived from low molecular weight P(MsAz-r-sBsAz)18 (subscripts indicate Dp = 18) revealed a Dp of 18.4 for the lPEI with a PDI of 1.02 (Figure S15). A larger polymer, P(MsAz-r-sBsAz)70, was also deprotected to lPEI. Since higher molecular weight lPEI is difficult to analyze by mass spectrometry and GPC,11 lPEI derived from P(MsAz-r-sBsAz)70 was reacted with excess isobutyryl chloride to yield poly(2-isopropyl-2-oxazoline) (P(iPrOx)). GPC traces of lPEI-derived P(iPrOx) were monomodal with a PDI of 1.11 (vs PS standard) (Figure S2). The observations that the PDIs of the lPEI and lPEIderived P(iPrOx) remained low imply that the polymer backbone is not degraded in the reductive removal of the sulfonyl groups. Degradation can occur during the deprotection of P(MsAzr-sBsAz) to form lPEI under certain conditions. For example, MALDI-TOF MS of a lPEI sample prepared using sodium metal (rather than lithium) at room temperature for 24 h showed the presence of only short oligomers (Figure S16). A sequential anionic polymerization was performed to confirm that the copolymerization of MsAz and sBsAz is indeed living and to create a block copolymer. First, living P(MsAz-r-sBsAz)30 was prepared by the BnN(K)Ms-initiated copolymerization of MsAz and sBsAz. After monomers MsAz and sBsAz were consumed, MsMAz was added to the reaction mixture, and the polymerization was continued for another 2 days to form P(MsAz-r-sBsAz)30-b-P(MsMAz)150 (Scheme 2).
Scheme 1. Polymerization of 1-Sulfonylaziridines
low molecular weight P(MsAz-r-sBsAz) is sparingly soluble in CHCl3. In order to determine if the AROP of MsAz and sBsAz can be controlled, a series of copolymerizations were performed where the ratio of the total moles of monomers vs BnN(K)Ms was varied. Dp as measured by 1H NMR spectrometric endgroup analysis closely matched theoretically expected values (Table S1); the plot of the ratio of Dp vs monomers:initiator was linear (Figure 1); and GPC traces were monomodal with
Scheme 2. Polymerization of P(MsAz-r-sBsAz)-b-P(MsMAz)
The measured Dp of both blocks was consistent with theoretical predictions. The GPC trace of the block copolymer had a decreased retention time compared to the GPC trace of an aliquot of the P(MsAz-r-sBsAz)30 macroinitiator, and the PDI remained low (1.10); only a small amount of nonextended P(MsAz-r-sBsAz)30 was observed (Figure 2). Using the Li sulfonyl deprotection procedure, the poly(sulfonylaziridine) block copolymer was converted to lPEI-b-poly(propylenimine) (PPI) (Scheme 2). As with the lPEI previously, we reacted lPEI-b-PPI with isobutyryl chloride to form P(iPrOx)-b-poly(4methyl-2-isopropyl-2-oxazoline) (P(MeiPrOx)) in order to determine if chain degradation had occurred during the sulfonyl removal. As expected, the GPC traces of the lPEI-bPPI derived P(iPrOx)-b-P(MeiPrOx) was monomodal, with a PDI of 1.08 (Figure S3). We note that lPEI-b-PPI is the imine analogue of PEO/poly(propylene oxide) (PPO) block copolymers, which are among the most well-studied block copolymer systems and are of significant medical and industrial importance;12 the imine analogues may be of similar interest.
Figure 1. Degree of polymerization (Dp) vs monomer:initiator ratio (●). Polydispersity vs monomer:initiator ratio (○).
low PDIs (Figure S1). MALDI-TOF mass spectrometric (MS) analysis of the polymers showed signals consistent with each chain containing a Bn(N)Ms moiety (Figure S14). The removal of the sulfonyl groups from P(MsAz-r-sBsAz) to create lPEI was accomplished using Li and tBuOH in HMPA and THF (Scheme 1) over 5 h at −5 °C.10 A 13C NMR spectrum of the polymer after the deprotection procedure contained a single signal at 48 ppm (Figure S8), indicative of the linear form of PEI. NMR spectroscopy also revealed that a significant percentage of the initiator benzyl groups was cleaved from the polymer chain during sulfonyl group removal. This was not unexpected as benzyl groups can be removed from amines under reductive conditions. Proof that the polymer chain was not degraded during removal of the sulfonyl groups came from mass spectrometric 1138
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synthesize polymers with complex architectures that contain P(MsAz-r-sBsAz) and lPEI.
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsmacrolett.6b00538. Experimental procedures, NMR spectra, MALDI-TOf mass spectra, chromatograms, WAXS, and thermal analysis plots (PDF)
Figure 2. GPC trace of P(MsAz-r-sBsAz)30 prior to block copolymer chain extension (---). GPC trace of P(MsAz-r-s BsAz) 30 -b-P(MsMAz)150 (―).
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Notes
In a recent report, Wurm studied how changes in the electronic properties of the sulfonyl substituents influenced the AROP of 2-alkyl-1-sulfonylaziridine.3 Electron-withdrawing sulfonyl groups (e.g., SO2C6H5NO2) were found to promote faster polymerization rates compared to more electron-rich sulfonyl groups (e.g., SO2Me). By exploiting these differences in rates, Wurm was able to synthesize multiblock gradient copolymers in one-pot, one-step reactions with up to five different 2-alkyl-1-sulfonylaziridines.3 In our present work, the electronics of MsAz and sBsAz are similar, and although the sBs group is bulkier than Ms, the sulfonyl groups of MsAz and sBsAz are distant enough from the site of nucleophilic attack on the aziridine ring that we expected both monomers to be incorporated into the polymer at similar rates; we anticipated P(MsAz-r-sBsAz) to be a random copolymer.13 1H NMR spectroscopic analysis of a copolymerization of MsAz and sBsAz at low conversion revealed that incorporation of the two monomers into the polymer was nearly identical to the feed ratio of the monomers and that little-to-no compositional drift occurred (see Supporting Information). WAXS showed that P(MsAz-r-sBsAz) is slightly crystalline, but its spectrum is distinct from those of P(MsAz) and P(sBsAz) oligomers (Figure S19). Finally, DSC traces of P(MsAz-r-sBsAz) showed a distinct set of Tg, Tm, and Tc transitions that were not observed in the P(MsAz) and P(sBsAz) oligomers (Figure S18). We note that although the NMR, WAXS, and thermal data are consistent with a random copolymer the data do not rule out the possibility of an alternating polymer architecture. The living nature of the P(MsAz-r-sBsAz) copolymerization allows for the rapid synthesis of polymer conjugates. For example, a copolymerization of MsAz and sBsAz was terminated with propargyl bromide to form P(MsAzr-sBsAz)nCCH, thereby allowing the possibility of azide−alkyne Huisgen cycloaddition and thio−yne click chemistry (Figure S12).14 In summary, we have shown that copolymerization of 1(alkylsulfonyl)aziridines MsAz and sBsAz results in the formation of a soluble P(MsAz-r-sBsAz) random copolymer. The polymerization is living. P(MsAz-r-sBsAz) can be converted to linear polyethylenimine (lPEI), allowing, for the first time, the synthesis of lPEI by a controlled, anionic polymerization. The living nature of the polymerization permits sequential anionic polymerization, the synthesis of an imine analogue of a PEO/PPO block copolymer, and the synthesis of telechelic P(MsAz-r-sBsAz) polymers. We are currently exploiting the copolymerizations of MsAz and sBsAz to
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank the Petroleum Research Fund (55075-DNI7) and the University of Alabama (UA) for financial support. We thank Prof. Jared Allred and Matthew A. Davenport (UA) for collection of the WAXS data, Qiaoli Liang (UA) for help in collecting mass spectra, Prof. Colleen Scott (Mississippi State University) for collection of thermal data, and Prof. Chris Brazel (UA) for the use of his DSC.
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REFERENCES
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