Mechanisms Of N-Heterocyclic Carbene Catalyzed Oxidative Transformation Of Carbonyl Compounds

Due to the unique electronic and spatial structure effects,N-heterocyclic carbene(NHC)has emerged as one of the most powerful organocatalysts in many novel asymmetric catalytic reactions.Especially in the past decade,NHC-catalyzed oxidative transformation reaction of carbonyl compounds has attracted more and more attention because of its ability of rapid construction of C-X(X=C,O,N,etc.)bond,which further promotes the expansion and application of NHC catalysis in the area of asymmetric synthesis.However,due to the limitations of experimental methods,understanding the mechanism and origin of selectivities of such kinds of reactions has always been one of the most challenging questions in the field of asymmetric catalysis,whereas theoretical calculation research has become an effective method for solving these issues.This thesis is to study the detailed mechanism and origin of chemo-/stereoselectivities of NHC-catalyzed oxidativeα-,β-,γ-C(sp3)-H activation/transformation reaction by performing theoretical calculations.In the first chapter of this paper,theoretical calculation methods and the research background of the NHC-catalyzed oxidative α-β-,γ-C(sp3)-H activations/transformation reactions of carbonyl compounds were introduced briefly.Chapters 2 to 5 respectively systematically study the detailed mechanism and origin of selectivity of the selected NHC catalytic oxidative transformation reactions.The following parts are the brief descriptions on the research contents:The second chapter is a theoretical study on NHC-catalyzed α-C(sp3)-H activation of aliphatic aldehydes and cascade[2+2]cycloaddition with ketimines.We have performed systematical computations on the possible mechanism and origin of selectivity by using density functional theory(DFT).The calculated results demonstrate that NHC can enhance the nucleophilicity of aldehydes and the acidity ofα-C(sp3)-H bond,and oxidant 3,3’,5,5’-tetra-tent-butyl diphenoquinone(DQ)does act as a two-electron acceptor and a proton acceptor,and thus promotes the α-C(sp3)-H deprotonation.Subsequently,the[2+2]cycloaddition of azolium enolate to the C=N bond,rather than the C=O bond of ketimine,is revealed to be chemo-/stereo-selectivity determining step.The reaction chemoselectivity can be well explained by comparing the energy gap between the frontier molecular orbitals(FMOs)of the two reacting parts involved in the[2+2]cycloaddition transition states.Moreover,we propose a new strategy to predict the origin of the reaction chemoselectivity,namely the local nucleophilic index can efficiently predict the active site of ketimine.The third chapter is to disclose the detailed mechanism and origin of stereoselectivity of NHC-catalyzed α-C(sp3)-H activation of saturated aldehyde and cascade[2+3]cycloaddition with azomethine imine by performing DFT calculations.The computational results indicate that NHC catalyst can avoid the poor shoulder-to-head FMO overlap mode,and thus significantly lowers the energy barrier of[2+3]cycloaddition.These works should not only be helpful to understand the NHC-catalyzed[2+n](n=2,3,4)cyclization reactions of saturated aldehydes,but also expand the applications of FMO theory in the organocatalysis field.In the fourth chapter,we use the ω+N index to predict the chemoselectivity of NHC catalyzed reactions of saturated/unsaturated carbonyl compounds with the other nucleophiles/electrophiles,in which ω is the global electrophilic index of electrophilic part and N is the global nucleophilic index of nucleophilic part.In fact,after the combination of NHC with saturated carbonyl compounds,the subsequent processes of oxidation and α-,β-C(sp3)-H activation generate several possible active intermediates,including Breslow intermediate,enolate,and acylazolium intermediate,which acts as either a nucleophile(Nu)or an electrophile(E)to react with other E/Nu partner.The intermediate transformation processes indicate that the key for predicting chemoselectivity is to calculate the(nucleophilic/electrophilic)reactivity of different intermediates and compare the stability of intermediates and products.To support this point,we selected and studied several NHC-catalyzed reaction models of carbonyl compounds,and the index ω+N was employed to exactly predict the energy barrier of chemoselective step in theory.This work can not only deepen the understanding of the chemoselectivity of NHC-catalyzed reactions,but also provides a simple and fast method to predict the chemoselectivity of the nucleophilic or electrophilic reaction.The fifth chapter is a systematical study on the possible mechanism and origin of stereoselectivity of NHC-catalyzed γ-C(sp3)-H activation of alkylenals and cascade[4+2]cycloaddition with alkenylisoxazoles by using DFT method.The computed results indicate that the oxidation of Breslow intermediate is achieved by DQ via a hydride(one proton and two electrons)transfer from the Breslow intermediate to the oxygen atom(HTO pathway)of DQ.In addition,the non-covalent interaction analysis demonstrates that oxidant DQ plays double roles,i.e.,strengthening the acidity of the γ-C-H bond of alkylenal and forming π…π interactions with conjugated C=C bonds to promote the γ-C(sp3)-H deprotonation.In the Michael addition step,the hydrogen bond network between the NHC and substrate is a key factor in determining the stereoselectivity.Additional DFT calculations reveal that the nonpolar solvent can make the nonpolar R-configured transition state more stable in the stereoselectivity-determining step.The sixth chapter of this paper is a summary of the above theoretical works and prospects for some scientific research in future.