New Polymerization Method And Mechanism Study Of NCA And NTA

As excellent biocompatible materials,polypeptides and polypeptoids are widely used in biomaterial and medicine fields.The most promising technique towards polypeptides and polypeptoids is ring-opening polymerization（ROP）of cyclic monomers,including amino acid N-carboxyanhydrides（NCAs）and N-thiocarboxyanhydrides（NTAs）.The challenge in ROP consists of designing novel polymerization systems,introducing new monomers and topological structures,and clarifying polymerization mechanism.In the dissertation,we developed a new polymerization system called Interlocked Polymerization Inside（single）Cocrystal（i Pi C）,which employs single cocrystals of racemic monomer pair as reactors.The single cocrystals of racemic methionine NTA are able to be immersed into hexane,which are further initiated by n-hexylamine at room temperature.The number-average degrees of polymerization（DP）of prepared syndiotactic polypeptides are as high as 148 with narrow distribution（dispersity=1.13）.By using DL-cocrystal and L-rich（ee=60%）crystals of methionine NTA as the monomer,the i Pi C is confirmed to occur inside crystals.The formation of secondary structure（α-helix）in L-rich case leads to physical termination of amino end due to the destroy of lattice and shrink of propagation polypeptide chains.With the help of theoretical calculation and Monte Carlo simulation,we have established a relationship between dispersity（（?））of polymer and distribution of crystal size,which agrees well with the experimental results.It is of vital importance to reveal the mechanism in synthetic route towards monomer.Aiming at traditional Leuchs route,density functional theory（DFT）calculations have been employed to establish the reaction pathway and find the rate determining step（RDS）.The synthetic route of alanine-NTA catalyzed by phosphorous tribromide（PBr₃）is calculated as model reaction under M06-2X/6-311++G（d,p）.According to calculation results,the Leuchs route contains a ring-closing step and a SN2 substitution step,and RDS is the SN2 step with a Gibbs free energy barrier of 24.6kcal/mol.Both the ring-closing and the SN2 steps in PCl₃ route are confirmed with higher energy barriers than those in PBr₃ route,which is benchmarked by three different calculation levels.The N-substitution effect is reviewed by comparing alanine-NTA and sarcosine-NTA,which indicates that sarcosine-NTA is easier to be prepared.Alanine-NTA and alanine-NCA are also examined and the NCA route shows lower energy barrier in SN2 than the NTA one.For racemization of optical pure NTA monomer,DFT calculations confirms that the racemization occurs after the formation of NTA monomer rather than any intermediate or reagent.For alanine-NTA,the energy barrier of racemization is higher than that of SN2,but still accessible at room temperature.When applying NTA monomer with large substitution group like isoleucine-or valine-NTA,the energy barriers of racemization are significantly increased.Generally speaking,low temperature,short reaction time and large substitution help suppress the racemization.The ROP of NCA initiated by primary amine and small secondary amine usually follows normal amine mechanism（NAM）.We investigate the N-substitution effect in ROP of N-substituted glycine-NCAs（NNCAs）.The propagation chain end is taken,instead of simple amine in initiation,to carry out the calculation under B3LYP/6-31G（d,p）.The single-point energies of all intermediates and transition states are obtained under B3LYP/aug-cc-p VTZ//B3LYP/6-31G（d,p）.The results confirm that ROP of NNCA follows NAM and RDS is the carbonyl addition step.For NNCA monomer bearing a linear orγ-branched alkyl side group,the energy barriers of carbonyl addition differ a little,but a long side group aggregates during polymerization leading to a drop of polymerization rate.In the polymerization of the NNCA withβ-branched side group,the energy barrier of carbonyl addition is much larger than that of linear substituted ones.To reveal the nature of trimethylsilyl-amine（TMS-amine）in ROP of NCA,DFT calculations are carried out in ROP of alanine-NCA and sarcosine-NCA initiated by Me NHTMS under B3LYP/6-311++G（d,p）.NAM-TMS mechanism is proposed to explain TMS-amine initiated polymerization,the“-TMS”means that the transfer moiety is TMS group.We excluded concerted mechanism and traditional NAM mechanism（proton transfer）by comparing energy barriers.The steps in NAM-TMS are similar as that in NAM,but the RDS transfer to decarboxylation,and the result is benchmarked by PBE0/6-311++G（d,p）and M06-2X/6-311++G（d,p）.The energy barriers in NAM-TMS will slight decrease when using solvation model.NAM-TMS is also suitable for NNCA monomers like sarcosine-NCA.It is the first calculation evidence supporting the decarboxylation as RDS in the NAM mechanism.