Theoretical Studies On The Reaction Mechanisms Of NHC-catalyzed [2+3] Annulation Reaction And Oxidative NHC-catalyzed ?-C(sp~3) Activation Reaction Of Saturated Carbonyl Compounds

In recent years,more and more chemists rely on theoretical calculations and simulations to study organic chemical reactions with the rapid improvement of computer technology.Using theoretical calculations and simulations to study organocatalysis is one of the most important methods to lead chemists to deeply understand the organic catalytic reaction mechanism and the origin of chemoselectivity,including stereoselectivity and regioselectivity.During the N-heterocyclic carbene(NHC)-catalyzed organic reactions,unsaturated carbonyl compounds are often used as substrates,while the studies on saturated carbonyl compounds are rare.In this thesis,two asymmetric synthesis reactions catalyzed by NHC are selected as research objects.The reaction mechanisms and origin of stereoselectivity of these two reactions were discussed in detail by using density functional theory(DFT)and Gaussian 09 suite of programs.We believe that our calculation results could help experimental chemists to understand the mechanism and the nature of chemical reactions from molecular level and can provide guiding significance for future theoretical research and experimental work.The first chapter of this thesis briefly introduces the development of computational chemical theories,including the breakthroughs and their limitations.The electronic structure of NHC,its properties and the NHC-catalyzed reactions are also introduced.Finally,some common and useful theoretical analytic methods are introduced,such as distortion analysis,non-covalent interactions analysis,global reactivity index and so on.The second chapter of this thesis introduces the reaction mechanism and the origin of stereoselectivity of ring expansion reactions of oxaziridines catalyzed by NHC.The third chapter of this thesis introduces the DFT study of direct?-sp~3 C activation of saturated acid chloride catalyzed by oxidative NHC.The fourth chapter of this thesis is the summary of the full thesis.The following sections are brief introduction of these two model reactions.1.A DFT study on the mechanism and the origin of stereoselectivity of NHC-catalyzed ring expansion reactionsOxazolidin-4-ones are a class of compounds that are rare but useful in nature.In recent years,some experimental chemists started to use oxaziridines as the substrates to synthesize oxazolidine-4-ones and its derivatives.For the reaction of NHC-catalyzed ring expansion reaction of oxaziridines to generate oxazolidine-4-ones,we proposed the catalytic mechanism of this reaction and carried out the detailed DFT calculations.Our calculation results show that the reaction needs the deprotonation process of precatalyst assisted by cesium carbonate to obtain the true NHC catalyst firstly.The subsequent catalytic cycle includes six steps:(1)nucleophilic attack of NHC to saturated aldehyde substrate;(2)[1,2]-proton transfer of zwitterionic intermediate;(3)elimination of p-nitrobenzoic acid;(4)ring-opening of oxaziridine;(5)ring-closure process;(6)dissociation of NHC catalyst.We also performed the DFT calculations on the possible side pathways in the second step and the fourth step of the reaction.And we excluded these side reactions based on our calculation results.The fourth step of this reaction is the rate-determining step and the stereoselectivity-determining step of the entire catalytic reaction.Our calculation results show that the reaction pathway of the R-configuration is more energetically favorable pathway while the S-configuration pathway is an unfavorable pathway.The distortion/interaction analysis and non-covalent interaction analysis were carried out to suggest that the R configuration pathway has more hydrogen bond interactions so that the corresponding product is more favorable.Global reactivity index analysis was calculated to show that the NHC catalyst can enhance the nucleophilicity of saturated aldehyde substrate during the reaction,which enable the substrate to react smoothly with oxaziridine.We also considered the case of ketene as the substrate,and performed theoretical calculations and analysis of this model,which also explained the importance of the NHC catalyst and reflected the reliability of out calculation model.2.Mechanistic study on oxidative NHC-catalyzed directing?-C(sp~3)activation reaction of saturated acid chlorideNHC-catalyzed C-H bond and C-X bond activation reactions are always a hot topic in the field of organocatalysis.While a direct method for activating the?or?carbon of saturated acid chlorides catalyzed by NHC via a Breslow intermediate are still not realized.In 2018,Hui and co-workers have reported the direct activation of?-sp~3 C saturated acid chlorides under oxidative NHC catalysis.The detailed DFT study was carried out to investigate the possible reaction mechanism.Whole catalytic reaction included 9 steps:(1)nucleophilic attack of NHC catalysis to saturated acid substrate;(2)deprotonation process assisted by TBD;(3)[1,4]-proton transfer process assisted by TBD;(4)oxidative process of homoenolate intermediate;(5)nucleophilic attack of oxidative Breslow intermediate;(6)deprotonation process;(7)[1,4]-proton transfer process assisted by TBDH~+;(8)ring-closure process;(9)dissociation of NHC catalysis.The deprotonation process of precatalyst assisted by TBD is also calculated,which is firstly occurred before the whole catalytic reaction.The fifth step,i.e.,the nucleophilic attack of R2 to oxidative Breslow intermediate is stereoselectivity determining step.The calculation results show that the RS-configurational pathway is the most favorable pathway,which is consistent with experiment.The distortion/interaction analysis and noncovalent interaction(NCI)analysis were carried out to explain why the RS configuration is the most favorable configuration in these four pathways.The transition state TS5RS has the most intermolecular weak interactions in TS5s.We replaced the substituent on the NHC catalyst and show that the new NHC catalyst can provide a steric hindrance on the Si face,which make the Gibbs free energy barriers for attack on Si-face higher than that for Re-face.Finally,global reactivity index(GRI)analysis and NBO analysis were calculated to suggest the role of NHC catalyst,which show that NHC catalyst can enhance the acidity of?-H to promote the deprotonation and[1,4]-proton transfer processes,and the nucleophilicity of saturated acid chloride substrate to promote the subsequent oxidation and nucleophilic attack processes.