Theoretical study of nimetazepam, a real-life chiral molecule without an asymmetric carbon atom

Abstract

We investigate the potential energy landscape and the spectroscopic properties of the nimetazepam molecule using a density functional theory approach. Our calculations show that despite the lack of a chiral carbon atom or a stereochemically active bond, this molecule exhibits two conformational enantiomers, M and P. For the isomerization process we find an activation energy of 16.7 kcal/mol. The conformers are inseparable at room temperature, and consequently, the nimetazepam drug exists as a racemic mixture. The theoretical spectroscopic analysis of these enantiomers including IR, VCD, NMR, UV-Vis, and ECD has been performed, to identify suitable experimental techniques to detect the individual stereoisomers. The infrared spectrum of nimetazepam agrees well with the experimentally observed one, and vibrational bands have been assigned. Moreover, the 1H and 13C NMR experimental chemical shifts have been well reproduced using the gauge independent atomic orbital method. The calculations suggest a dynamic 1H NMR effect that can be used to follow the isomerization process. The TD-DFT approach enables us to simulate the UV-Vis spectra, and the obtained results coincide satisfactorily with the observed spectrum. The M and P conformers show a complementary behavior in their predicted VCD and ECD spectra.