Going beyond structural effects: explicit solvation influence on the rotational isomerism of C-glycosylated flavonoids

Abstract

C-Glycosyl-flavonoids are phytochemical natural products that possess different biological applications. Several compounds from this class exhibit rotational isomerism, evidenced by NMR signal duplication. This phenomenon is usually associated with the restricted rotation of the C(sp³)–C(sp²) bond in the sugar-aglycone, however the reasons for its occurrence remain underexplored and demand further investigation. Herein, we conducted a DFT (B3LYP-D3/6-311++G(d,p)/IEFPCM) investigation to elucidate the origin of rotational isomerism in a diverse set of C-glycosyl-flavonoids, including isoschaftoside (1), schaftoside (2), vitexin (3), puerarin (4), and prunetin-8-C-glucoside (5), rationally chosen to understand the substituent effects in different positions in the flavonoid backbone. Our outcomes reveal that the rotation around the sugar-aglycone bond at the 8-C position of the flavonoid moiety has the most energetic barrier, although the value is not sufficient to induce NMR signal duplication (ΔG^‡ = 14.5 ± 0.5 kcal mol⁻¹). Only by simulating the solvent molecules explicitly, using a hybrid cluster-continuum model, we were able to identify the occurrence of rotational isomerism, revealing that the flavonoid–solvent interactions play an important role to the NMR signal duplication. The calculated rotational barriers range from 17.3 to 20.9 kcal mol⁻¹, which is sufficient to cause bond hindrance rotation and identification of NMR double signals due to slow interconversion between the rotamers.