Anomeric effect in six-membered rings: An NBO perspective

The anomeric effect arises from a subtle balance between steric, electrostatic, and orbital interactions, yet its relative energetic origins remain debated. Here, we present a systematic computational study of substituted cyclohexanes, tetrahydropyrans, and thianes (Y = CH 3 , CF 3 , F, and Cl) to disentangle these contributions. Conformational energies were evaluated in the gas phase and in implicit water, and natural bond orbital (NBO) analyses were employed to decompose steric exchange, electrostatic (NCE), and electron-delocalization effects. While cyclohexane derivatives largely follow steric expectations, heterocycles containing oxygen or sulfur display pronounced axial stabilization for electronegative substituents, consistent with the anomeric effect. This stabilization is dominated by n X → σ* C–Y hyperconjugation and supported by favorable electrostatics, whereas steric effects act mainly as a modulating factor and appear underestimated within the present partitioning scheme. Importantly, the qualitative balance between electrostatic and hyperconjugative contributions persists in polar solution, indicating that intramolecular dipolar interactions remain operative even under high-dielectric conditions. • NBO analysis disentangles steric, electrostatic, and hyperconjugative effects • Axial stabilization in heterocycles is dominated by n → σ* interactions • Anomeric effect persists in polar solution despite high dielectric screening