Examining hyperconjugative interactions in the anomeric effect of six-membered rings using Quasi-atomic Orbital Analysis

<jats:p>We investigate the anomeric effect of 6-membered rings, i.e. the axial-over-equatorial conformational preference of polar substituents in aliphatic heterocycles, from a molecular orbital perspective. Using several levels of theory and the quasi-atomic orbital analysis (QUAO), the direct pairwise interactions between the p-orbitals of the ring heteroatom and the 𝜎 bond of the substituent atom are examined. The anomeric effect has been traditionally attributed to hyperconjugative interactions, though more recently, evidence for the electrostatic argument has emerged. While not excluding the role of electrostatics, this analysis showed strong evidence for the presence of hyperconjugative interactions in the anomeric effect. Our analysis presents direct evidence for the interaction for the lone pair orbitals of the ring heteroatom and the substituent 𝜎 bond, which is stronger in axial conformation. Moreover, examining the populations of the respective localized orbitals showed a small transfer of electron density from the lone pair to the 𝜎∗ orbitals. We also observed a reduction in the strength of the ring-substituent 𝜎 bond in the axial conformation, further suggesting the transfer of electron density to the 𝜎∗ orbital.</jats:p>