Using Chou’s 5-Step Rule to Evaluate the Stability of Tautomers: Susceptibility of 2-[(Phenylimino)-methyl]-cyclohexane-1,3-diones to Tautomerization Based on the Calculated Gibbs Free Energies

Robert Dobosz,Jan Mućko,Ryszard Gawinecki

doi:10.3390/en13010183

Abstract

Gibbs free energies, based on DFT (Density Functional Theory) calculations, prove that enaminone (2-(anilinemethylidene)cyclohexane-1,3-dione) and ketamine (2-[(phenylimino)-methyl]cyclohexane-1,3-dione) are the most and least stable tautomeric forms of the studied systems, respectively. 1H and 13C NMR spectra prove that 2-(anilinemethylidene)cyclohexane-1,3-diones are the only tautomeric species present in dimethylsulfoxide solution (a very weak signal can be seen only for the p-methoxy derivatives). The zwitterionic character of these enaminones is strengthened by naphthoannulation and by the insertion of the electron-withdrawing substituent into the benzene ring (the latter weakens the intramolecular hydrogen bond in the compound). Substituent and naphtoannulation have no effect on the stability of the studied tautomers. Slight twisting of the benzene ring, with respect to the CArNC plane (seen in the crystalline state), was proven to also take place in vacuum and in solution.

Highlights

Tautomerism plays a very important role in biochemistry, organic chemistry, pharmacology, and molecular biology
A low energy barrier between tautomers causes the process of tautomerization to be influenced by many external and internal factors, such as: molecule structure, possible formation of intramolecular hydrogen bonds, introduction of a substituent to the molecule, or ring benzoannulation [1,2,3]
The tools of structural bioinformatics ([9] and papers cited therein), whose rapid development led to an unprecedented revolution in medical chemistry [10], come to our aid

Summary

Introduction

Tautomerism plays a very important role in biochemistry, organic chemistry, pharmacology, and molecular biology. A low energy barrier between tautomers causes the process of tautomerization to be influenced by many external (e.g., temperature changes, solvent) and internal (structural) factors, such as: molecule structure, possible formation of intramolecular hydrogen bonds, introduction of a substituent to the molecule, or ring benzoannulation [1,2,3]. The enaminone and enolimine forms can be stabilized by the stabilized by thehydrogen intramolecular bond, inand the solid state and solutionssolvents in nonpolar intramolecular bond, hydrogen both in the solidboth state in solutions in in nonpolar [15]. 5,6-positions stabilizes the enaminone tautomer 3,4-benzoannulated (enaminone) [12,13].

Enaminones

Methods

Results and Discussion

Conclusions