Quantum Chemical Calculation of Tautomeric Equilibria

Abstract

IntroductionTautomerism can be considered as a special case of isomerism where the movement of an atom or group of atoms between two sites occurs rapidly enough to establish chemical equilibrium at room temperature. Hence, both thermodynamic as well as kinetic criteria have to be used to draw an approximate distinction line between tautomerism and conventional isomerism. Assuming a lower limit of K = 10 −8 for the experimental determination of equilibrium constants and a rate constant of k = 10 −5 s −1 distinguishing mobile systems from stable ones, at room temperature G • < 8 kcal mol −1 and G = < 25 kcal mol −1 characterize a tautomeric system [1]. Most interconversion between the individual species occurs by movement of a hydrogen atom (prototropism), as in simple keto-enol [2], lactam-lactim, and annular prototropism in heterocycles [3], or azo-hydrazo [4] tautomerism. Transformation between tautomeric structures by movement of atoms other than hydrogen involves formation of cyclic acetals/ketals, for example, furanose/pyranose forms of sugars, ring-chain tautomerism in oxo carboxylic acid derivatives [1], or azido-tetrazole and related equilibria [5]. Coping with tautomeric equilibria has become a hot topic in chemoinformatics as well as drug discovery. Obviously, reliable predictions of tautomeric equilibria by computational procedures would be of great help. This importance is also revealed by the fact that in the third round of the statistical assessment of the modeling of proteins and ligands (SAMPL) challenge (SAMPL2) the calculation of tautomer energies was included [6]. However, as stated by Martin [7], ''In summary, although quantum chemical calculations provide much insight into the relative energies of tautomers, there appears to be no consensus on the optimal method.'' Frequently, energy differences are quite small and hence require very accurate calculations which can be fiendishly difficult. Thus, the choice of an appropriate electronic structure procedure is very important. Furthermore, environmental influences (solvent) have a profound effect on the position of tautomeric equilibria. Consequently, a proper description of solvation is essential. Alternatively, some property that might be useful to distinguish between tautomers could be Tautomerism: Methods and Theories, First Edition. Edited by Liudmil Antonov.

Favipiravir tautomerism: a theoretical insight

“…The keto–enol tautomerism of 2-hydroxy pyridine ( 1 ) is one of the most studied tautomeric cases, both theoretically and experimentally. Very detailed description of the effects of the used level of theory can be found in [ 7 , 29 , 30 ]. For gas phase, most of the density functionals overestimate (some of them very strongly) the keto form stability, while HF and post-HF methods predict more, but not dramatically, stable 1E .…”

“…The M06-2X functional [ 49 , 50 ] was used with def2TZVP [ 51 ] basis set. This fitted hybrid meta-GGA functional with 54% HF exchange is specially developed to describe main-group thermochemistry and non-covalent interactions, showing very good results in prediction of the position of tautomeric equilibria [ 27 – 29 , 52 – 54 ]. In addition, TautLYP [ 55 ], a specially optimized to predict the tautomerism in azodyes and Schiff bases, B3LYP-based functional, was used with 6–31 ++Gdp basis set.…”

Tautomerism in Azo and Azomethyne Dyes: When and If Theory Meets Experiment

“…While the potentially tautomeric structures can be easily distinguished either theoretically or experimentally [23], the study of real tautomeric equilibria in solution is a challenge. On one side, the real equilibrium from the viewpoint of the detection limits of analytical chemistry means Gibb’s free energy in the range roughly from −2 to +2 kcal/mol, which is a challenge for quantum chemistry even now [24]. On the other side, the exact estimation of the ΔG values (derived from the tautomeric constant K T , defined as keto/enol, [ K ]/[ E ] ratio, Scheme 2), requires isolated tautomeric forms, a condition that is impossible in most of the cases.…”

Favipiravir Tautomerism: A Short Theoretical Report

“…The keto-enol tautomerism of 2-hydroxy pyridine (1) is one of the most studied tautomeric cases, both theoretically and experimentally. Very detailed description of the effects of the used level of theory can be found in 7,36,37 . For gas phase most of the density functionals overestimate (some of them very strongly) the keto form stability, while HF and post-HF methods predict more, but not dramatically, stable 1E.…”

“…The M06-2X functional 23,24 was used with def2TZVP 25 basis set. This fitted hybrid meta-GGA functional with 54% HF exchange is specially developed to describe main-group thermochemistry and non-covalent interactions, showing very good results in prediction of the position of tautomeric equilibria [26][27][28][29][30][31] . In addition, a specially optimized to predict the tautomerism in azodyes and Schiff bases, B3LYP based functional TautLYP 32 was used with 6-31++Gdp basis set.…”