Electronic circular dichroism prediction on monomeric and dimeric γ-lactone derivatives: An important role of conformational averaging

Abstract

The electronic circular dichroism (ECD) of a series of monomeric and dimeric γ-lactones was investigated using time-dependent density functional theory (TDDFT) and simplified TDDFT. Given the inherent conformational flexibility of these compounds, a multi-conformer conformational replica exchange sampling technique (CREST) and commandline energetic sorting (CENSO) approach to obtain low-lying energy conformers was employed for spectral simulation. Our results show that the simplified sTD-DFT/GFN2-xTB tight-binding model fails to consistently describe the observed Cotton effects. In contrast, TD-CAM-B3LYP calculations correctly reproduced these experimental data. Detailed analysis of the electric and magnetic transition dipole moments reveal that subtle structural variations such as ring puckering or side-chain rotations can significantly affect the relative direction of the electric and magnetic transition dipole moments. These geometric shifts directly cause the sign changes in rotational strength and the cotton effect, emphasizing the critical necessity of accounting for the Boltzmann-weighted conformational ensemble to achieve reliable absolute configuration assignments.