Anomeric effect in six-membered rings: An NBO perspective

Area of Science:

• Computational Chemistry
• Organic Chemistry
• Molecular Interactions

Background:

• The anomeric effect, a conformational preference in cyclic molecules, arises from complex interactions.
• Its precise energetic contributions (steric, electrostatic, orbital) remain a subject of debate.

Purpose of the Study:

• To computationally investigate the origins of the anomeric effect in substituted cyclohexanes, tetrahydropyrans, and thianes.
• To differentiate the roles of steric, electrostatic, and orbital interactions in determining conformational preferences.

Main Methods:

• Systematic computational study of substituted cyclic systems (YCH3, CF3, F, Cl).
• Conformational energy evaluation in gas phase and implicit water.
• Natural Bond Orbital (NBO) analysis to decompose interaction types.

Main Results:

• Heterocycles (oxygen, sulfur) show axial stabilization for electronegative groups, unlike cyclohexanes.
• Stabilization is primarily due to nX → σ*CY hyperconjugation and favorable electrostatics.
• Steric effects modulate but do not dominate the anomeric effect.

Conclusions:

• The anomeric effect in heterocycles is significantly influenced by orbital delocalization and electrostatics.
• These intramolecular interactions persist even in polar solvents.
• The study clarifies the energetic balance governing the anomeric effect.