Theoretical Study Of Pd(Ⅱ)-Catalyzed Nondirected C-H Bond Cyanation Of Toluene In Dual-ligand System

Recently,the C-H bond functional group reaction catalyzed by transition metals has become an important means in the field of organic synthesis and has been widely used in the synthesis of natural products and pharmacological compounds.Among them,one of the most attractive reactions is the synthesis of aromatic nitrile.Despite the versatility of cyano group for organic synthesis and the importance of aromatic nitrile for dyes,agrochemicals and drugs,there are few direct methods for the synthesis of aromatic nitrile.With the development of synthesis and application of aromatic nitrile,a C-H bond cyanation strategy catalyzed by transition metal Pd without directed groups has been developed.The catalyst active species in this strategy are formed by nitrogen-containing heterocyclic ligands and mononuclear amino acid-protected ligands complexation with transition metals.Moreover,this catalytic system has a wide range of substrates selection and functional group tolerance,it is suitable for direct cyanation of several commercially available small molecule drugs,common pharmacodynamic groups and organic dyes.Compared with the traditional conversion of functional groups,this C-H bond cyanation strategy is an attractive research direction,and it is one of the most effective methods in organic synthesis.It is consistent with the concept of green chemistry,and more atomic economy and environmental friendliness.In this work,the detailed mechanism of transition metal palladium-catalyzed nondirected C-H cyanation of toluene was studied.The potential energy surface includes the following steps:the dissociation of the tri-palladium acetate,equilibrium of resting state,C-H bond activation,molecular isomerization rearrangement（intramolecular proton transfer）,migration and insertion of cyanide,transmetalation,reductive elimination,and regeneration of active species.Using hexafluoropropanol（HFIP）as solvent,1:1:1 stoichiometric complex consists of the N-acetylisoleucine（Ac-lle-OH）,quinoxaline and Pd（OAc）₂.The cyanide ions slowly released from K₃Fe（CN）₆reacts with silver salts to form stable compounds,and involved in the transmetalation.The silver salts as terminal oxidants and electron donors participate in the reduction and regeneration of active species of catalysts.The main contents of this work include the following two aspects:1.The mechanism of Pd（II）catalyzed toluene C（sp²）-H bond cyanation reaction was investigated by density functional theory.All non-metal atoms were calculated using 6-31G（d,p）basis set and pseudopotential SDD basis set for Pd atoms.The calculation results show that the morphology of the active species is necessary for the observed the coordination metallization-deprotonation（CMD）step,and the CMD mechanism is a favorable path to C-H activation.And the aryl-palladium complexes formed by the transition state of cyclic palladium C-H activation.Comparing the free barriers of all stages,we find that the migration insertion of metal-cyanide in the C-H bond cyanation reaction of toluene resulted in a large barrier such that the transmetalation step acts as a rate-determining step to control the whole reaction.Moreover,we speculate that the spatial and electronic properties of MPAA substituents may affect C-H activation as well as the cyanation process.2.The pathaway of Pd（II）catalyzed toluene C-H bond cyanation was calculated by using the DFT theory,in which N-acetylamino acid（Ac-Gly-OH）substituted Ac-lle-OH.The CMD mechanism is still favorable on the potential energy surface of the reaction.The catalytic reaction under the same conditions has the same results as the above study:C-H bond activation is thermodynamically reversible in principle.The transmetalation process is also the rate-determining step of the whole reaction.And the substitution of MPAA ligand is focused in this section.Our calculations show that the electronic and spatial properties of substituents on MPAA ligand greatly influence C-H cyanation reactions.The regioselectivity of C-H bond cyanation depends on the stericl effect between substrate and catalyst,as well as the slight electronic effect given by the methyl of toluene.To sum up,the regioselectivity of toluene nondirected C-H cyanation reaction is determined by the combination of electron and space dual control.We hope our results can help to better understand the mechanism of C-H cyanation reaction.It can provide a reasonable basis for the development of improved palladium catalyst system and provide valuable information for the development of more selective synthesis methods.