Mechanistic Studies Of Acylation Of Amines Catalyzed By Lanthanum Or Nickel Complexes

The amide is an important class of organic compounds that has biological and pharmaceutical activities.Since amide bonds can play a role in building core functional groups in peptides,polymers,natural products and drug molecules,the synthesis of amides has received intense attention.The conventional preparation method of amides is a direct condensation of carboxylic acids with amines.It is well?known that this method is not highly suitable in terms of atom economy and requires very harsh conditions.Recently,metal?catalyzed acylation of carboxylic acid derivatives with amines and amino carbonylation involving carbon monoxide have achieved remarkable progress.However,the theoretical understanding about the mechanism such as factors affecting the catalytic activity is relatively deficient,which to a certain extent hinders the further development of this type of catalytic system.In this paper,the density functional theory?DFT?is used to study the acylation mechanism of amines with different electrophilic reagents catalyzed by rare?earth and late?transition?metal complexes,respectively,and explore related influence factors.The main research results are as follows:?1?The acylation mechanism of N?methylbenzylamine and p?chlorobenzaldehyde catalyzed by rare earth metal complex La[N?SiMe₃?₂]₃ was studied.Based on DFT calculations,the catalytic active species was proposed as L₂La[N?Me??Bn?]?I?instead of the previously reported L₂La[OCHArN?Me??Bn?]?II?.It was found that by?product alcohol as a proton transfer reagent can reduce the reaction energy barrier and can participate in the regeneration of active species I.Interestingly,the theoretical results show that adding a small amount of alcohol to the initial reaction system can accelerate the reaction,which is also confirmed by experiments.?2?The nickel?catalyzed acylation mechanism of methyl esters and amines was studied by DFT theoretical calculations.It was found that the reaction followed three steps:oxidative addition,proton transfer and reduction elimination.Based on the mechanism,the effect of different ligands on the catalytic performance was discussed.The results show that the electronic effect of the ligand is the main factor affecting the reaction performance.Compared with phosphine ligands,the nitrogen heterocyclic carbene ligand has stronger orbital interaction with the metal center and renders the catalyst higher catalytic activity.?3?Through DFT calculations,the mechanism of the acylation reaction of2?aminopyridine with alkyl iodide and carbon monoxide catalyzed by a nickel complex was studied.This reaction includes ligand exchange,S_N2?type activation of C–I bond,carbon monoxide migration insertion,outer nucleophilic attack,and catalyst regeneration.After the nucleophilic attack,the reaction produces a cationic intermediate,which then undergoes proton transfer with 2?aminopyridine to form the final product.In the process of nucleophilic attack,the inner mechanism is ruled out due to the higher activation energy.The coordination effect of different polar molecule on nucleophilic attack is also investigated.The results show that the coordination of polar molecules is not conducive to the process of nucleophilic attack.Energy decomposition analysis indicated that the deformation energy is the key factor controlling the stability of nucleophilic attack transition state.