Theoretical Study On Palladium Catalyzed Selective C(sp~3)-H Arylation Of Aliphatic Amines

In the field of organic synthesis,the study of C-H bond activation of aliphatic amines has always played an important role,because it has important application value in pharmaceutical,agricultural chemical synthesis,bioactive molecule preparation and other fields.In the past few decades,rapid progress has been made in the study of C-H bond activation,which has transformed the original ideal into a practical and common synthesis method.However,there are still some challenges in the experimental process,such as substrate selectivity and regioselectivity.In this paper,the mechanism of distal inert C(sp3)-H bond activation of aliphatic amines was discussed by means of density functional theoretical(DFT)calculation,in order to provide theoretical guidance for the development of more efficient and green synthesis methods.In chapter 3,structure-reactivity relationship(SRR)studies to understand theα-substitution steric effect toward Pd-catalyzed γ-C(sp3)-H arylation enabled by catalytic transient directing groups(TDG)have carefully been performed by DFT calculations.With the increase of the number of substituents on α-position of amines,the calculated free energy barriers of the rate-determining transition states decreased.As the number of substituents at the α-position of the substrate increases,the terminal methyl group will approach the palladium to form a agostic complex and weakenγ-C(sp3)-H bond,and the C-H bond dissociation energy of the intermediate also decreases,leading to the decrease of the energy barrier in the C-H activation step.In chapter 4,the α-substitution electron effect and β-substitution steric effect of Pd-TDG co-catalyzed γ?C(sp3)-H arylation of primary amines are further studied.The results show that the electron-withdrawing group at the α-position is more advantageous in this reaction.In addition,when β-position of substrate replaced two methyl groups can not effectively reduce the energy barrier of rate determining step.when the substitution number is one,the reactivity increases,but the effect is weaker than that of α-substitution.In Chapter 5,we study the mechanism of palladium-catalyzed functionalization of aliphatic amine δ-C(sp3)-H bond with TDG and ligand,and discuss the origin for the regioselectivity.The results show that the rate-determining step is C-H bond activation step and the barrier is low.It is proved that the activation of the amine substrate δ-C(sp3)-H bond is active when the transient guide group forms a five-membered ring with Pd center,because of the lower ring strain.However,the reaction still tends to activate γ-C(sp3)-H bond in the presence of γ-methylene andδ-methyl.DIAS model analysis shows that this is because the ring distortion energies of γ-C(sp3)-H activation process is covered by strong interaction energy.