A combined TD-DFT and spectroscopic investigation of the solute-solvent interactions of efavirenz.

Abstract

This study examined the solute-solvent interactions of efavirenz, a first-line antiretroviral agent for HIV/AIDS, whose clinical utility is limited by poor aqueous solubility. Using UV-visible spectrophotometry, proton NMR spectroscopy, and time-dependent density functional theory (TD-DFT) calculations, the spectral behavior of efavirenz was characterized across solvents of varying polarity. Two principal UV absorption bands were identified at 246–260 nm (band I) and 291–295 nm (band II). A bathochromic shift of approximately 13.69 nm in band I and a smaller bathochromic and hyperchromic shift in band II were recorded upon moving from cyclohexane to DMSO. These shifts are attributed to charge-transfer effects and intra- and intermolecular hydrogen bonding involving the amino (NH) and carbonyl (CO) groups. In NMR experiments, aromatic and amine protons exhibited greater deshielding in DMSO-d6 compared with CDCl3, consistent with increased delocalization of lone-pair electrons on the amino nitrogen in higher-polarity environments. TD-DFT-derived theoretical spectra showed strong concordance with experimental observations.

Mechanism

The amino (NH) and carbonyl (CO) functional groups of efavirenz drive charge-transfer and intra-/intermolecular hydrogen bonding, producing bathochromic UV shifts and increased NMR deshielding as solvent polarity increases due to enhanced lone-pair electron delocalization on the amino nitrogen.