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)]⁺ (<b>Int4i</b>) and the catalytic cycle <b>CC1</b>. Initiation of <b>Int4i</b> 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 <b>Int4i</b>. Catalytic cycle <b>CC1</b> includes three sequential steps: (i) β-H elimination of <b>Int4i</b> 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 <b>Int4i</b>. The calculated turnover frequencies (TOFs) support that <b>CC1</b> 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 <b>CC1</b>, 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