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

Abstract

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 PdCl 2 /dppe/LiOH system (dppe = 1,2-Bis(diphenylphosphino)ethane). The energetic results indicate the most favorable pathway is the inner-sphere hydrogen transfer pathway, which consists of initiation of the threecoordinated active alkoxide complex [Pd(PhCH 2 O)(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)] + , (ii) PhCH 2 OH deprotonation with the aid of [Pd(PhNH)(dppe)] + to afford Int4i. Catalytic cycle CC1 includes three sequential steps: (i) β -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 CC1 is the most favorable, although it is inhibited by the reverse process of PhCH 2 OH 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 LiCl − 2 -coordinated complexes in the overall reaction pathway, which leads us to conclude that LiCl − 2 is the TOF-affecting key species. Our additional calculations show that the TOF may be improved by the addition of AgOTf or AgBF 4 , which can scavenge the Cl − and supply the weak ligand OTf − or BF − 4 . Hopefully, these results are useful for further catalyst development.

Zinc‐Catalyzed N‐Alkylation of Aromatic Amines with Alcohols: A Ligand‐Free Approach

“…[5] In this context, several homo-and heterogeneous catalytic systems based on Ru, Rh, Ir, Pd, Pt, Mn, Fe, Cr, Co, Ni, have been developed to prepare the N-alkylated amines in an efficient manner. [6][7][8] Although the reported catalyst systems are quite effective, most of the homogeneous based catalytic systems were designed using a combination of a metal salt and precious organic ligand, which sometimes may require multistep synthesis. [6][7][8] On the other hand, heterogeneous based metal catalysts also suffer from high catalyst loading, selectivity, and harsh reaction conditions.…”

“…[6][7][8] Although the reported catalyst systems are quite effective, most of the homogeneous based catalytic systems were designed using a combination of a metal salt and precious organic ligand, which sometimes may require multistep synthesis. [6][7][8] On the other hand, heterogeneous based metal catalysts also suffer from high catalyst loading, selectivity, and harsh reaction conditions. [9][10] Thus, the development of lowcost metal catalysts [11] or efficient catalytic systems with high turnover numbers under mild reaction conditions [12] toward the synthesis of N-alkylation reaction is highly desirable and always remains in demand.…”

Iridium complexes with a new type of N^N′‐donor anionic ligand catalyze the N‐benzylation of amines via borrowing hydrogen

“…On one side, this condensation has been considered rapid and easily accomplished without the intervention of the catalyst by some authors. [ 53–55 ] Other authors have reported that this process is more favored by water [ 56 ] or alcohols [ 57 ] than by some metallic species. In contrast, other theoretical [ 21,58,59 ] and experimental [ 21 ] studies indicate that the condensation step takes place in the coordination sphere of the catalyst.…”

Nickel‐Catalyzed N‐Alkylation of Acylhydrazines and Arylamines Using Alcohols and Enantioselective Examples

“…The most straightforward synthesis of chiral alkylamines is arguably direct N‐alkylation of amines using cheap, readily available alcohols by the so‐called “borrowing hydrogen reaction” or hydrogen autotransfer reaction (Scheme a) . A typical process involves dehydrogenation of an alcohol to form a ketone by a metal catalyst, in situ condensation to a ketimine, and subsequent addition of the metal hydride catalyst . No prior chemical activation of alcohols is needed and ideally water is the only byproduct.…”