Theoretical Investigation On The Mechanism And Regio/chemoselectivity Of N-heterocyclic Carbene Catalyzed Construction Of Carbon-carbon/heteroatom Bond

N-Heterocyclic carbene（NHC）organocatalysis has emerged as a powerful strategy in modern organic synthesis.A large number of synthetically important transformations have been developed in the presence of NHC-based organocatalysts,realizing the construction of carbon-carbon and carbon-heteroatom bonds.Especially in the field of chemistry and regioselective organic synthesis,NHCs catalysts have attracted extensive interest due to their high catalytic efficiency,good selectivity,environmental friendliness,and excellent performance.Nowadays,computational chemistry has become a powerful tool to study the mechanism of organic reactions,especially the organocatalyst has become an important and active field of computational organic chemistry.Therefore,in order to clarify the origin of high catalytic activity of two typical NHC catalysts and the effects of reaction conditions on the reaction mechanism,and regio/chemoselectivity of oxidative coupling reactions with carbon-heteroatom bond construction were studied by density functional theory（DFT）.The main contents of the thesis are as follows:DFT calculations have been performed to study the role of NHC and DBU on the possible mechanism and regioselectivity for the NHCs catalyzed oxidative epoxidation of alkenes with aldehyde at the B3LYP-D3/6-31G**level.This NHC catalyzed reaction comprises four steps:the formation of phenacyl bromide and Breslow intermediate,C–C coupling,epoxidation process,and regeneration of the catalyst.The computational results show that the C–C bond formation is the diastereoselectivity-determining step.Noncovalent interaction（NCI）analysis results reveal thatπ…πstacking and C–H…O interactions are the main contributors to the origin of the regioselectivity.Frontier molecular orbital was applied to illustrate how NHCs could promote the reaction through the umpolung strategy.NHC enhanced the nucleophilicity of the substrate by a significant increase of the HOMO energy and a moderate increase of the LUMO.DBU acts as a strong base to promote the generation of the real NHC catalyst and deprotonation of theα-C（sp³）–H to generate the key Breslow intermediate.The possible catalytic mechanism was proposed and studied comprehensively at the M062X/6-31G**level of theory for a recently reported chemoselective intermolecular S_N2nucleophilic substitution of aldehydes with alkanoamine.The calculated results show that the catalytic cycle occurs through five stages including the nucleophilic attack of active NHC on the substrate,generation of the Breslow intermediate,oxidative addition of NBS and alkanolamine,S_N2 nucleophilic substitution,and finally regeneration of the NHC along with the release of the product.The double molecules of alkanoamines assisted oxidative addition was demonstrated to be the chemoselectivity-determining step.Moreover,our results showed that the N-bromoamine intermediate was favored both thermodynamically and kinetically than hypobromite by 14.2kcal/mol,which is consistent with the fact that only N-acylation product is observed in the experiment.In addition,we found that alkanolamine not only acts as a reactant but also as a proton-shuttle and stabilizer to stabilize the structure of chemoselectivity favored transition state by multiple N–H…N and N–H…O hydrogen bonding interactions.Et₃N firstly acts as a base to promote the formation of active catalyst NHC,then the protonated Et₃N as proton-shuttle to accelerate Breslow intermediate formation and lower the activation barrier.The Parr functions and frontier molecular orbital analyses of key species indicate that NHC enhances remarkably the nucleophilicity of substrate aldehyde,leading to a significant increase of the HOMO energy and a moderate increase of the LUMO energy.We hope this work could give deeper insight into the fundamental mechanisms of the Et₃N assisted NHC-catalyzed S_N2 substitution reactions.