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

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.