DFT Study on the Homogeneous Palladium-Catalyzed N-Alkylation of Amines with Alcohols

DFT methods and the energetic span model have been used to study the mechanism of the N-alkylation of amines with alcohols catalyzed by the PdCl2/dppe/LiOH system (dppe = 1,2-bis(diphenylphosphino)ethane). The energetic results indicate that the most favorable pathway is the inner-sphere hydrogen transfer pathway, which consists of initiation of the three-coordinated active alkoxide complex [Pd(PhCH2O)(dppe)](+) (Int4i) and the catalytic cycle CC1. Initiation of Int4i includes two sequential steps: (i) generation of the three-coordinated active species [Pd(OH)(dppe)](+) and [Pd(PhNH)(dppe)(+) and (ii) PhCH2OH deprotonation with the aid of [Pd(PhNH)(dppe)}(+) to afford Int4i. Catalytic cycle CC1 includes three sequential steps: (i) beta-H elimination of Int4i to generate benzaldehyde and the Pd hydride species [PdH(dppe)(+), (ii) condensation of benzaldehyde with aniline to give the imine, and (iii) imine reduction to supply the amine product and to regenerate Int4i. The calculated turnover frequencies (TOFs) support that CC1 is the most favorable, although it is inhibited by the reverse process of PhCH2OH deprotonation catalyzed by [Pd(PhNH)(dppe)](+). By calculating the degree of TOF control, we identify the TOF-determining intermediate (TDI) and the TOF-determining transition state (TDTS) in CC1, and find that all the influential intermediates are the off-cycle LiCl2--coordinated complexes in the overall reaction pathway, which leads us to conclude that LiCl2- is the TOF-affecting key species. Our additional calculations show that the TOF may be improved by the addition of AgOTf or AgBF4, which can scavenge the Cl- and supply the weak ligand OTf- or BF4-. Hopefully, these results are useful for further catalyst development.