Synthesis And Polymerization Of N-Substituted Glycine NTAs And Properties Of Polypeptoids

Polypeptoids are a group of biomaterials with polyglycine backbones and side groups substituted on nitrogen atoms. As analogouses of polypeptides but without hydrogen bonding along backbone, polypeptoids possess excellent properties. Due to the challenge of synthesis and potential in biomedical applications, increasing attention has been paid to polypeptoids.N-substituted glycine N-thiocarboxyanhydrides (R-NTAs) are alternative monomers to prepare polypeptoids. Compared to the corresponding N-carboxyanhydrides (NCAs), NTAs are more stable to moisture and heat without extremely anhydrous and anaerobic environment during synthesis and purification, which are much more suitable for large-scale production. However, synthesis of high molecular weights (MWs) polypeptoids from R-NTAs is still a challenging issue due to their low reactivities. In this work, sarcosine NTA (Sar-NTA, also known as N-methylglycine NTA) and N-butylglycine NTA (NBG-NTA) are prepared as monomers for ring-opening polymerization. Particularly, NBG-NTA is a novel monomer synthesized and well characterized for the first time.Polysarcosines (PSars) with high yields (> 90%) and low polydispersities (D< 1.2) are synthesized from Sar-NTA at 60℃ initiated by primary amines including poly(ethylene glycol) amine (PEG-NH2). The lengths of PSar segments are controlled by various feed ratios of Sar-NTA to initiator. PEG-b-PSar is a class of novel double-hydrophilic diblock copolymers. Due to the different solubilities of PEG and PSar blocks in organic solvents, PEG-b-PSar copolymers can be used as emulsifiers, which are effective in stabilizing oil-in-water emulsions in nano- and micro-scale. PEG-b-PSar is totally nontoxic, biocompatible and degradable for both segments, which makes it very promising as a new environmental responsive surfactant in food and medical applications. In a reverse way, PEG-b-PSar copolymers form micelles in organic solvents (e.g., dioxane and ethyl acetate) with the capability to incorporate metal cations including Cu2+ and Ni2+, which suggests potential application of PEG-b-PSar in encapsulating water-soluble cargos at nanoscale.Rare earth borohydrides [RE(BH4)3(THF)3, RE=Sc, Y, La, Nd, Dy and Lu] have been first applied in the polymerization of Sar-NTA and NBG-NTA to achieve high MWs hydrophilic and hydrophobic polypeptoids. MWs of the polypeptoids are varied with the rare earth metals and reaction temperature. Controlled polymerization of Sar-NTA and NBG-NTA with high yields and moderate polydispersities (D<1.4) are achieved at 60℃ by using Y(BH4)3(THF)3 in acetonitrile and Lu(BH4)3(THF)3 in THF, respectively. MWs of polypeptoids are controlled by feed molar ratios. For instance, at 60℃ after 48 h polymerization in acetonitrile with feed ratio of [Sar-NTA]/[Y(BH4)3(THF)3]=516 and [Sar-NTA]=0.5 mol/L, PSar is produced successfully in 99% yield with an absolute Mn of 27.7 kDa (DP=390) and D of 1.14. Polymerization kinetics of Sar-NTA and NBG-NTA has been measured, and the results reveal that both ln(Mo/Mt) vs time plots of the two monomers are linear with low monomer conversions. The polymerization under open systems with continuous argon flow is faster than that in sealed tubes. Thermoresponsive random copolypeptoids poly(sarcosine-r-N-butylglycine)s [P(Sar-r-NBG)s] are also obtained with reversible phase transitions (cloud point temperature) in aqueous solution. PSar and P(Sar-r-NBG) exhibit minimal cytotoxicity comparable to PEG, which is promising in various biomedical and biotechnological applications. Thermal properties of homo- and co-polypeptoids are investigated by TGA and DSC measurements.A series of thermoresponsive copolypeptoids are synthesized by copolymerization of Sar-NTA with NBG-NTA initiated by benzylamine in THF at 60 ℃. Polypeptoids with degree of polymerization over 150 are obtained for the first time through primary amine-initiated R-NTA polymerizations. The MWs and compositions of P(Sar-r-NBG)s are controlled by feed molar ratios of [Sar]/[NBG]/[benzylamine]. Thermal behaviors of copolypeptoids are investigated, which demonstrate lower Tgs than PSar and no Tm of PNBG. Reactivity ratios of Sar-NTA and NBG-NTA are determined as 1.70(7) and 0.63(7), respectively, when initiated by benzylamine, indicating a random distribution of two monomers in polypeptoid products. The precise structure and amino chain end of P(Sar-r-NBG) are confirmed by MALDI-ToF mass analysis, which reveals that benzylamine-initiated R-NTA polymerization undergoes normal amine mechanism (NAM). P(Sar-r-NBG)s have lower critical solution temperatures (LCST) and exhibit reversible phase transitions in aqueous solution. Cloud point temperatures (Tcps) of P(Sar-r-NBG) are tunable from 27 to 71℃ in aqueous solution, which exhibit linear relationship with copolymer compositions. Tcp and transition window (AT) increase with the decreasing polymer MW and concentration. The extent of Tcp decrease caused by salt additives is accordant to the trend of Hofmeister series with Na2SO4> NaCl> NaBr. The copolypeptoids present broad Tcp transition windows for the strong tendency to aggregate in aqueous solution below Tcps. The cytotoxicity of P(Sar-r-NBG)s is related to composition of polypeptoids, i.e. increasing toxicity upon exposure of more hydrophobic NBG moieties. Easily accessible from R-NTA polymerizations, thermoresponsive polypeptoids are therefore novel biomaterials with controlled cytotoxicity and backbone degradability for biomedical applications.