Amination of Ketenes: Evidence for a Mechanism Involving Enols of Amides as Intermediates

Abstract

The amination reaction of ketenes has been studied both theoretically and experimentally as a model reaction for amide bond formation. Calculations are performed using both ab initio molecular orbital theory (MO) and density functional theory (DFT) methods. Solvent effects are modeled by different methods: Onsager SCRF, PCM, and SCI-PCM electrostatic continuum solvation models, as well as explicit inclusion of actively participating water molecules, representative of a polar protic solvent, at different hydrogen bond donor−acceptor sites of the solutes. Both the concerted process and the two-step reaction, via a 1-amino-1-hydroxy ene intermediate, have been investigated at high level of theory. These intermediates are formally enols of amides. A comparison with uncatalyzed amide bond formation indicates that the active participation of a second ammonia molecule reduces the energy barrier in favor of the two-step reaction. When a water molecule acts as catalyst instead of a second ammonia molecule, this energy barrier is reduced even further, which emphasizes the catalytic role of a protic solvent molecule present in the bulk. Kinetic evidence for the formation of enols of amides has also been presented, which is consistent with the theoretical view, showing preference of a two-step reaction including the intermediacy of an enol of the amide. This enol was generated as an intermediate in the amination of the sterically hindered ketenes, bis(pentamethylphenyl) ketene and bis(mesityl) ketene, by primary and secondary amines in aprotic solvent. The kinetics of formation of the enol of the amide of these specific ketenes reveal a first-order dependency on amine concentration, and the rates of addition of several amines have been determined. The first-order rate constants suggest a reaction involving free amine molecules rather than dimers, presumably due to the low dimer concentration or to their steric bulk, and in line with the preference of amine−water complex as reactants.