New insights into the mechanism of Schiff base synthesis from aromatic amines in the absence of acid catalyst or polar solvents

Abstract

Extensive computational studies of the imine synthesis from amines and aldehydes in water have shown that the large-scale structure of water is needed to afford appropriate charge delocalization and enable sufficient transition state stabilization. These insights cannot, however, be applied to the understanding of the reaction pathway in apolar solvents due their inability to form extensive hydrogen-bonding networks. In this work, we perform the first computational studies of this reaction in nonpolar conditions. This density-functional study of the reaction of benzaldehyde with four closely related aromatic amines (aniline, o-toluidine, m-toluidine and p-toluidine) shows that, although an additional molecule of amine may provide some stabilization of the first transition state even in the absence of a hydrogen bonding network, this is insufficient to achieve high reaction rates. Our computations also show that when an extra proton is added to the spectator amine, the activation energies become so low that even picomolar amounts of protonated base are enough to achieve realistic rates. Additional computations show that those minute amounts of protonated base may be obtained under reaction conditions without the addition of extraneous acid through the auto-protolysis of the amines themselves. To our knowledge, this is the first report of a role for the auto-protolysis of anilines in their extensive reactional repertoire.

No Transition Metals Required – Oxygen Promoted Synthesis of Imines from Primary Alcohols and Amines under Ambient Conditions

“…From a kinetic perspective, path B presents the lowest barriers, ΔG ‡ max = 15.6 kcal/mol, which suggest that given the right environment, F2 would be produced in higher amounts -a finding in line with experimental observations. The condensation to the final imine, from the amine and the in situ generated benzaldehyde proceeds via a well-known exergonic C-N coupling pathway with a reaction barrier of ΔG ‡ = 16 kcal/mol [12] for this step (see SI for details). The released water promotes the main water-assisted reaction pathway -accelerating benzaldehyde formation.…”

Exploring the mechanism of the reductive amination of acetophenones via the Borch approach: the role of the acid catalyst

“…[33][34][35] In this case, an auxiliary protic solvent in the nucleophilic attack reduces the energy barrier, 36 and under nonpolar conditions without acid catalysis, the reaction occurs through the auto-protolysis of the amines. 37 The next step, consisting of the selective reduction of the iminium ion forming the amine, can be performed in one-pot or stepwise depending on the strength of the reducing agent employed. A common approach for this reaction is to shift the equilibrium by removing water from the medium and, after complete conversion of the carbonyl compound to the iminium ion, use LiAlH 4 or NaBH 4 as a reducing agent.…”