Mechanisms of the formation of imines in aqueous solution and the effect of the pH: a theoretical analysis

Abstract

Theoretical modeling of the formation imines in aqueous medium from the reaction of amines with aldehydes is difficult due to formation of charged species, zwitterions, acid-base equilibria and a substantial solvent effect. In this work, a model reaction of methylamine with acetaldehyde was investigated involving neutral and ionic pathways, influence of the pH and different approaches for treating the solvent effect. We have found a mechanism able to explain the fast kinetics of this system, involving the zwitterion formation followed by its isomerization to the carbinolamine and an easy iminium ion formation via an ionic elimination mechanism.

Bifunctional Primary Amino‐thiourea Asymmetric Catalysis: The Imine‐Iminium Ion Mechanism in the Michael Addition of Nitromethane to Enone

“…In a polar medium, the iminium ion can be formed only as an ion pair. Direct elimination of hydroxide ion from carbinolamine intermediate should be difficult because there is not enough solvation to stabilize this high energy ion [33,34] . On the other hand, acids present in the medium, even as an impurity, can work as an efficient catalyst, leading to the elimination of water instead of hydroxide ion [35,36] .…”

Nucleophilic catalysis ofp-substituted aniline derivatives in acylhydrazone formation and exchange

“…Calculations in implicit water yielded virtually identical results, with differences in the relative energies of the calculated stationary points smaller than 1 kcal mol −1 (see the ESI †). As a referee noted, water and protic solvents could change the reaction mechanism acting as a proton shuttle and/or favoring the elimination of hydroxide ions from carbinolamine intermediates, 45 although such theoretical predictions have not been confirmed experimentally. 46,47 To study the performance of the catalysts at physiological pH, the reaction between aldehyde 1 (0.09 mM) and acylhydrazide 6 (0.9 mM) to yield acylhydrazone 7 was performed according to our previous work in a Tris buffer solution, using an excess of acylhydrazide to achieve fast conversion at reasonable reaction times.…”

Theoretical Insights into the Effect of Halogenated Substituent on the Electronic Structure and Spectroscopic Properties of the Favipiravir Tautomeric Forms and Its Implications on the Treatment of COVID-19

“…to visualize this process on an atomic scale) quantitatively, which can, in principle, provide excellent opportunities for the design of new drugs. [31][32][33][34][35] In this study, we focused on elucidating the effect of halide (fluorine, chlorine, and bromine) on the electronic structure, spectroscopic (nuclear magnetic resonance, infrared, Raman, electron ionization mass spectrometry, UV-Vis, circular dichroism, and emission) properties, and tautomerism of the favipiravir compounds from a computational perspective.…”

“…In addition, since solvation has been known to play an important role in the tautomeric equilibrium, [30][31][32][33][34] the solvent effect was considered in the transition state calculations for the tautomerism of the isolated, mono-hydrate, di-hydrate and tri-hydrated forms of the different halogenated favipiravir compounds. Herein, we also used in silico modelling for predicting the possible effects of drug-metabolism in terms of action and toxicity for the halogenated favipiravir compounds against the SARS-CoV-2 using both M pro and RdRp sites as model systems.…”