Theoretical Study On The Formation Of Carbon-carbon Bonds Catalyzed By Palladium

Palladium-catalyzed carbon-carbon bond formation is one of most important tools in organic synthesis.With the aid of density functional theory?DFT?methods,we investigated the mechanisms of two types of related reactions,by which the favorable mechanism was elucidated and the factors controlling reaction rate and selectivity were clarified.The obtained conclusions were listed below:?1?Using C-X bond as a traceless directing group,palladium-catalyzed cross couplings of ortho-tert-butyl-substituted aryl halide derivatives with alkyl halides and CH₂Br₂ via C-H activation/carbon-carbon formation provide one-pot methods for the synthesis of alkylated benzocyclobutenes and indane derivatives.DFT calculation indicated that the Pd-catalyzed couplings of 2-tert-butylaryl halides with alkyl halides is likely to proceed via aryl-Br oxidative addition,C?sp³?-H activation,alkyl-Cl oxidative addition,aryl-alkyl reductive elimination,aryl-H activation and aryl-C?sp³?reductive elimination to generate alkylated benzocyclobutenes.The couplings of aryl iodides with CH₂Br₂ is likely to generate indane derivatives via aryl-I oxidative addition,C?sp³?-H activation,alkyl-Br oxidative addition,aryl-CH₂Br reductive elimination,alkyl-Br oxidative addition,C?sp³?-alkyl reductive elimination and reduction of palladium dibromide complexes by amines.By comparison,the metathesis of alkyl chlorides on Pd?II?intermediates and the pathway involving palladium-carbene intermediates are found to be less favored.Meanwhile,the coordination of in situ generated salts KI,KBr,KHCO₃ to palladium complexes,which is less considered in previous mechanistic studies,is found to lead to more energetically favored pathways in most of the steps.Finally,the oxidative addition of alkyl halides generating Pd?IV?intermediates or the reduction of palladium dibromide complexes by amines,rather than the previously-proposed C?sp³?-H activation,is found to be the rate-determining step in the two types of coupling reactions.This result does not go against the reported primary kinetic isotope effect?KIE?because the C?sp³?-H activation is irreversible according to our calculations.?2?Beller group recently reported ligand-controlled selective palladium-catalyzed carbonylation of alkynes to generate mono-and diesterification products.The calculation based on the previously-proposed mechanism indicated that the alcoholysis is the rate-determining step for both of the cases using 1,3-bis?tert-butyl?pyridine-2yl?phosphanyl?propane L1 and1,2-bis??di-tertbutylphosphanyl?methyl?benzene L9 as ligands.Meanwhile,the migratory insertion of alkynes or alkenes is the regio-selectivity determining step.The pyridine ring on L1ligand can assist the alcoholysis as a proton acceptor to facilitate the second carbonylation,and thus diesterfication product can be obtained.By contrast,L9 does not bear pyridine ring and the second alcoholysis becomes kinetically impossible,and thus monoesterification product was obtained.