Theoretical Study On N-Heterocyclic Carbene Catalyzed Carbonyl C-C Bond Activation/Cyclization Reactions

Besides enzyme catalysis and transition-metal catalysis,organocatalysis has become an important asymmetric catalysis strategy for construction of chiral molecule,and has been widely applied in modern organic synthesis field.However,the detailed mechanism and selectivity of this type of organocatalytic reaction cannot be explained clearly in experiments.Therefore,revealing the detailed mechanism and selectivity of organocatalytic reactions through theoretical calculations has become an ideal pathway in this field.In this thesis,density functional theory(DFT)has been employed to theoretically study the detailed mechanism of Lewis base N-hetreocyclic carbene(NHC)-catalyzed activation of inert carbonyl C-C bond and cascade cyclization reaction.Further analysis was carried out to explore the role of the catalyst and origin of the stereoselectivity.The obtained results provide a theoretical basis for the rational design of more efficient organocatalytic reactions.The first chapter of this thesis mainly introduces the development background of computational chemistry and the employed theoretical methods.Then,the two kinds of Lewis bases(i.e.NHC and isothiourea)and their corresponding organocatalytic reactions,were briefly introduced in this part.The main research contents and computed results have been provided and discussed in the second,third,and fourth chapters of the thesis.In the second and third chapters,the detailed mechanism and the origin of selectivity of NHC-catalyzed inert carbonyl C-C activation and cascade cyclization reactions were investigated theoretically,whereas the detailed mechanism of isothiourea-catalyzed alkenyl ketone to carboxylic acid cyclization was studied in the fourth chapter,and the brief abstracts on the three chapters have been provided as following:Although NHC-catalyzed carbonyl C-C bond activation strategy has achieved a breakthrough,understanding the role of NHC as well as origin of the chemo-and stereoselectivities is still one of the most challenging questions in the organocatalysis field.Herein,we proposed a NHC and NHC·H+ cooperatively catalytic model for these kinds of reactions for the first time,and performed density functional theory calculations with a case of NHC-catalyzed[α,δ]-[4+ 2]annulation reaction of conjugated dienals and α-aryl ketone.The calculated results indicate that the most favorable pathway occurs by the following steps:nucleophilic addition of NHC to the dienals,[1,2]-proton transfer to give a Breslow intermediate,oxidation of the Breslow intermediate by DQ,Cα’-Cδ bond formation to form two chiral carbon atoms,six-as well as four-membered ring-closure processes,NHC·H+-mediated carbonyl Cα-C2 bond activation for CO2 release,abstraction of one proton and two electrons by DQ,and abstraction of H+by the base DABCO to generate the axially chiral product.In addition,the organocatalyst either works as a Lewis base to prevent the bad FMO overlap mode to promote[2+2]cycloaddition or as a noncovalent organocatalyst to provide a hydrogen bond to facilitate releasing of CO2,which is remarkably different from its well-known role of a Lewis base.To predict the origin of unexpected chemoselectivity,we proposed a new strategy of calculating the atomic electrophilicity indexes of the four potential reaction sites C(α-δ),which predicts that C(8)is the actual site for the stereoselective Cα’-Cδ bond formation involved in[4+2]cycloaddition.Atoms-in-molecules analysis quantitatively shows that hydrogen bonds(C-H…O)significantly contribute to the favorability of the SR-configured pathway,which is associated with the R-configured axial chirality of the main product.Further calculations confirm that the volume of the substituent is the key for maintenance of the high axial chirality.The obtained insights will be valuable for prediction and rational design of new types of organocatalytic inert carbonyl C-C activations with special chemoselectivity and high stereoselectivity.In Chapter 3,we performed density functional theory calculations with a case of NHC-catalyzed[4+2]annulation reaction of α-bromoenal and 2-aminoaldehyde to further confirm that the NHC/NHC·H+cooperative catalysis model is general.The calculated results are consistent with the main conclusions obtained in Chapter 2,indicating that the NHC/NHC·H+cooperative catalysis mechanism should be the general mechanism for these kinds of reactions.These calculation results provide theoretical support for the actual role of NHC and the general mechanism of NHC-catalyzed decarboxylation of β-lactones.In the fourth chapter,a theoretical study on the possible mechanisms,origin of diastereoselectivity,and efficiency of catalysts of isothiourea-catalyzed asymmetric cyclization of carboxylic acids and alkenyl ketones was performed by using density functional theory(DFT).The calculated results show that the reaction is divided into several steps,including nucleophilic attrack by isothiourea,C-C bond formation,[4+2]cycloaddition,and dissociation of isothiourea.The atoms-in-molecules(AIM)analysis shows that bonding interaction and hydrogen bonds(C-H…O)contribute significantly for the favorability of SS-configured product.The catalytic efficiency of isothioureas was explored and predicted by atomic nucleophilicity energy Ea-.Chapter 5 is a summary of the calculated results and conclusions on the above topics,and gives outlook for the theoretical research in future.