The benzodiazepine derivatives are known for their wide applications in medicinal chemistry since they are used as anticonvulsant, anti-anxiety, analgesic, hypnotic, sedative, antidepressant, and anti-inflammatory agents.

Since few years we have been studying tautomerism [1-5]. Lately, we have been focused on substituent influence on the tautomeric equilibria in benzodiazoles [4] and their aza analogues [5].

The aim of the present study has been to investigate tautomerism of the aza analogues of benzodiazepines: the pyridodiazepines. The geometry and energetic differences between the pyridodiazepine tautomers have been studied based on the Gibbs free energies calculated in standard conditions at the DFT/B3LYP/cc-pVTZ level. The calculations were performed for both the gas-phase and the water surrounding simulated by the polarizable continuum model (IEF-PCM).

 The results indicate that for the pyrido[1,2]- and pyrido[1,4]-diazepines the N₁-H tautomer is more stable than the other two tautomers. However, for the pyrido[1,3]diazepine, the N₃-H tautomer is more stable if the N atom is placed in the position 7 and 8 of the pyrido ring, whereas the N₁-H tautomer is more stable when it is placed in the position 6. For the pyrido[1,5]-diazepine where N1 and N5 positions are somehow equivalent by symmetry, the N₁-H tautomer is more stable when the N atom is placed in the position 7 (or 9) of the pyrido ring whereas the N₅-H tautomer when it is placed in the position 6 (or 8). The aromaticity of the studied structures is studied in details by means of the HOMA aromaticity index. It is shown that aromaticity of the pyridodiazepine tautomer is the main factor for its stability.

References:

[1] M. Kurzepa, J. Cz. Dobrowolski, A. P. Mazurek, J. Mol. Struct., 2001, 565‑566, 107.

[2] M. Jarończyk, J. Cz. Dobrowolski, A. P. Mazurek, J. Mol. Struct.(Theochem), 2004, 673, 17.

[3] M. Jarończyk, J. Cz. Dobrowolski, A. P. Mazurek, Chem. Phys. Lett., 2005, 406, 173.

[4] M. Jarończyk, J. Cz. Dobrowolski, J. Mol. Struct.(Theochem), 2008, 858, 77.

[5] M. Jarończyk, J. Cz. Dobrowolski, Comput. Theoret. Chem, 2011, 974,  9.

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