Amine-initiated Controlled Polymerization Of N-substituted Glycine NTA Towards Functional Polypeptoids

Polypeptoids,aka.Poly（N-substituted glycine）s,are emerging biomaterials.The absence of inter-and intra-molecular hydrogen bonds promotes the solubility and processibility of polypeptoids in various solvents unlike polypeptides which are prone to form secondary structures.The good biocompatibility and design flexibility make polypeptoids promising materials for scientists.Ring-opening polymerization（ROP）of N-substituted glycine N-carboxyanhydrides（NNCAs）is a classic way to prepare polypeptoids,which can synthesize polypeptoids with high molecular weights（MWs）.Nevertheless,NNCAs are sensitive to nucleophilic impurities.The synthesis and polymerization of NNCAs require extremely anhydrous environment,which restricts the application and scale-up of NNCA polymerization.N-substituted glycine N-carboxyanhydrides（NNTAs）have been developed as promising monomers to synthesize polypeptoids since last decade with good tolerance to water and heat during synthesis,purification and storage.However,few solvents can serve as the reaction medias for NNTA polymerizations so far.Due to low activity of NNTAs and limited polymerization solvents,only macroinitiators and highly active rare earth initiators have been reported for controlled polymerization of NNTAs.Herein,we report the synthesis of N-ethyl glycine NTA（NEG-NTA）.In optimized polymerization conditions,benzylamine initiates the controlled polymerizations of Sar-NTA and NEG-NTA in acetonitrile and tetrahydrofuran,respectively.The prepared polypeptoids are characterized by ¹H nuclear magnetic resonance（¹H NMR）spectra,MALDI-To F mass spectra and size exclusion chromatography（SEC）.Successful block copolymerization and kinetic investigation demonstrate that the amine-initiated NNTA polymerization is a living polymerization.By changing the feed ratios of[NNTA]/[initiator],the molecular weights（MWs,4.2–40.9 kg/mol）and degrees of polymerization（DPs）of polypeptoids can be tailored while the dispersities keep low（1.12–1.31）.PSar with DP up to 262 and PNEG with DP up to 287 are synthesized.NNTA monomers are stable to water,alcohols and mercaptans.Initiator-equivalent water（<1,000 ppm）does not influence the controllability of the polymerizations,while monomer-equivalent water（>10,000 ppm）decreases the yields of polymerizations and DPs of polymers are lower than the feed ratios.Hydrogen sulfide（H₂S）generated from the hydrolysis between polymerization byproduct carbonyl sulfide（COS）and water is responsible for the transformation of NNTAs into cyclic oligomers,which competes with the polymerization.The side reaction is suppressed by the bubbling of argon to expel byproduct gases from the polymerization mixture.PSar with high MW（M_n=11.2kg/mol,?=1.25）is successfully synthesized even in the presence of large amount of water（>10,000 ppm）.Thiols and common alcohols cannot initiate the polymerization of NNTA.When aminoethanol and aminopropanol are used as initiators which can form intramolecular hydrogen bonds,hydroxyl groups are activated and able to initiate the polymerization of NNTA as amino groups.By using aminomecarptans and aminoalcohols with long alkyl chains as initiators for NNTAs’polymerizations,thiol-and hydroxyl-functionalized polypeptoids are prepared in one step.The high tolerance to nucleophiles makes NNTA polymerization an efficient and convenient approach to synthesizing functional polypeptoids in the presence of various impurities.We investigate the polymerization of NNTAs in amide solvents.When there are 1to 3 stoichiometric amounts of acetic acid（AA）over monomers in polymerization solutions,ROPs of NNTAs initiated by amines can be carried out in amide solvents.N,N-dimethylacetamide（DMAc）,N,N-dimethylformamide（DMF）and N-methyl-2-pyrrolidone（NMP）are suitable solvents for AA-promoted NNTA polymerizations.The polypeptoids prepared have controlled molecular weights and low dispersities（1.06–1.12）.PSar with MW up to 35.2 kg/mol is synthesized.According to kinetic studies,AA promotes the polymerization by accelerating propagation and suppressing side reactions simultaneously.The presence of AA keeps thiocarbamic chain end protonated,which further forms a special transition state with AA for fast COS release.Meanwhile AA decreases the H₂S dissolved in polymerization solution.Benzoic acid promotes the polymerization as AA,while the stronger acid phosphoric acid and trifluoroacetic acid fail to promote the polymerization and the weaker acid phenol also fails to promote NNTA polymerizations in amide solvents.Only acids which have similar acidities and carboxyl groups as AA can serve as the promoters.Unprecedently,_L-Met,_L-Trp and _L-Phe dissolving in the mixture of AA and DMF initiate the polymerization of Sar-NTA toward well-defined PSar with the end group of amino acid residues.In DMAc,lyophobic vancomycin initiates the polymerization of N-butyl glycine NTA（NBG-NTA）.The amphiphilic PNBG-modified vancomycin can dissolve in dichloromethane and emulsify water in dichloromethane.The results broaden the solvent scope for NNTA polymerizations and therefore lie the foundation for NNTA polymerizations in modification of biomolecules and preparation of functional polypeptoids.NNTAs with unprotected carboxyl groups are synthesized and polymerized.The synthesis of N-carboxypentyl glycine NTA（CPG-NTA）,N-carboxybutyl glycine NTA（CBG-NTA）and iminodiacetic acid（IDA-NTA）are achieved at first time.Promoted by its own carboxyl group,CPG-NTA polymerizes in DMAc into poly（N-carboxypentyl glycine）s（PCPG）with controlled MWs（2.8–9.3 kg/mol）and low dispersities（1.08–1.12）.Successful random and block copolymerizations of CPG-NTA with NEG-NTA demonstrate CPG-NTA’s ability to construct complicated polypeptoids.On the contrary,IDA-NTA cyclizes at amine chain end as cyclic dimer,which terminates the polymerization.The reaction regio-selectively transforms amines into carboxyl groups in high efficiencies（>99%）and yields（>89%）.Density functional theory calculation shows that the amidation of the amine chain end with IDA unit has lower energy barrier than that with CPG unit.CBG-NTA also polymerizes into corresponding polypeptoids,which indicates that NNTA bearing carboxylalkyl are commonly active in polymerizations.Because of abundant carboxyl groups,the semi-crystalline poly CPG shows p H-responsive solubility in water and excellent adhesive ability（33–229 k Pa）to various materials.