Study Of Free Dual-Ligand Enabled Hydrogen-Deuterium Exchange Reaction Catalyzed By Palladium

Deuterium is a stable isotope of hydrogen,which is widely used in analytical chemistry,biomedicine,pharmacy,organic optics and other fields for its unique atomic properties and bonding properties.There are various methods to introduce deuterium into organic molecules,such as chemical building block,functional group conversion,etc.Hydrogen isotope exchange(HIE)reaction may directly replace the hydrogen isotopic atoms in the substrate with other hydrogen isotopic atoms.The HIE reaction efficiency is generally low,and the yield decreases gradually in multiple rounds of deuterium applications because of the side reactions.In this thesis,we found that in the palladium-catalyzed CMD mechanism HIE reaction,the ligand may directly regulate the electronic and spatial characteristics of the catalyst,thus greatly improve the efficiency of HIE reaction.Moreover,in the functionalization of C-H activation of some CMD mechanisms and the HIE reaction,the same ligand structure has quite different effects on the reaction direction.In this thesis,the C-H activation reaction of Pdcatalyst was studied,which is divided into two chapters.Using divalent palladium as catalyst,MPAA ligand and pyridine ligand as two-ligand catalytic system,a free dual ligand-promoted palladium-catalyzed deuteration method for aromatic hydrocarbons was developed.A series of detailed conditions were optimized for the model substrate tent-butylbenzene,and the optimal reaction conditions were finally determined.Substrate expansion was carried out for substrates containing different functional groups,and about 40 substrates containing drug-ready molecules were efficiently deuterated.Based on the aromatic unguided HIE method developed in Chapter 2,this paper finds that the side chain structure regulating aliphatic MPAAs has an effect on the deuterated velocity of tert-butylbenzene,that is,the steric hindrance of the side chain group is increased,and the deuteration rate is accelerated,which is the opposite of the law of alkenated functional grouping under the same conditions reported in the literature.Based on the CMD mechanism,this paper proposes a possible deuterated cycle process,calculates the reaction series based on the kinetic equation,and attempts to calculate the HIE process using a mathematical model.Finally in order to explain the experimental phenomenon,calculation of C-H activation process for different ligand combinations and energy barrier changing data of C-H activation is carried out as proof.