Substituent effects on the stability of 1,4‐benzodiazepin‐2‐one tautomers: A density functional study

The relative stability of 1,4‐benzodiazepin‐2‐one tautomers in the gas phase and model solvents was calculated at the M06 and ωB97XD levels of theory. The two density functionals were benchmarked earlier and demonstrated as excellent models to study tautomerism in a vast array of chemical systems. A number of commercially available 1,4‐benzodiazepin‐2‐ones were investigated computationally for the first time. In addition, some biologically active and newly devised benzodiazepines were considered, which may be important in designing structures with desired (bio)chemical features. Special attention was paid to determine substituent effects on the Gibbs free energies of keto, enol, and iminol forms for each respective benzodiazepine. It was demonstrated that (i) the replacement of the benzene ring by the heterocyclic ring in the benzodiazepine system may stabilize the iminol tautomer, and (ii) the electron‐withdrawing substituent at the C3‐position of the respective benzodiazepine may stabilize the enol tautomer relative to the parent keto form. It is concluded that substituent effects may govern the chemical reactivity and biological properties of selected benzodiazepines.