IR study on the electrochemical generation of a nitro radical anion by a hepatotoxic N,N′-disubstituted benzimidazole-2-thione

Abstract

In the course of our study on the hepatotoxicity of 1,3-disubstituted-1H-benzo[d]imidazole-2(3H)-thiones, we generated and characterized the radical anion of methyl 3-[3-(3-methoxy-3-oxopropyl)-5-nitro-2-thioxo-2,3-dihydro-1H-benzimidazol-1-yl]propanoate which shows the highest toxicity within the studied series. The reduction of the title compound was carried out electrochemically and the spectral and structural changes arising from the conversion were described based on IR spectra and DFT calculations. Repeated monitoring of IR spectra over time demonstrated successful generation of the radical anion accompanied by strong frequency decrease of NO stretching vibrations and increase of CN stretching vibration. The neutral compounds and the radical anion are characterized by coplanar orientation of the nitro group towards the aromatic system which most likely contributes to the observed toxicity. The structure of the radical anion shows extended electronic conjugation compared to the neutral compound. The NBO spin population analysis of the radical anion indicated that 0.707 of the odd electron is localized over the nitro group, while 0.293 is spread over the benzimidazole-2-thione fragment. Based on calculated energy of the lowest unoccupied molecular orbital (ELUMO) for the neutral compound, energy difference between the lowest unoccupied and the highest occupied molecular orbital (ΔEL−H), and adiabatic electron affinity (EA), it was estimated that the propensity of methyl 3-[3-(3-methoxy-3-oxopropyl)-5-nitro-2-thioxo-2,3-dihydro-1H-benzimidazol-1-yl]propanoate to generate a radical anion in biological systems would be comparable to that of nitrobenzene and nimesulide and much lower than those of nitrofurantoin.