Computational analysis indicates that the anomeric effect results from a blend of factors and is not confined to hyperconjugation alone. Researchers assert that this ‘curiosity-driven’ investigation serves as a reminder to chemists that attributing the effect to one primary cause simplifies a ‘fundamentally intricate phenomenon’.
The anomeric effect aids chemists in understanding why substituents adjacent to a heteroatom in a ring tend to prefer an axial configuration over the less sterically hindered equatorial arrangement. The hyperconjugation of a heteroatom’s lone pair of electrons into the anti-bonding orbital of a neighboring substituent is frequently cited as a primary explanation for this phenomenon.
Nonetheless, earlier studies propose that additional factors such as stereoelectronics and solvent interactions also contribute. Researchers from Florida State University in the US have recently attempted to quantify the impact of these factors.
To achieve this, the team undertook a computational analysis of 49 monosubstituted tetrahydropyrans – rings comprising five carbon atoms and one oxygen atom – across various parameters, simulating steric, electrostatic, and stereoelectronic influences. The substituents comprised alkyl chains, aromatic and heteroatomic rings, peroxides, halogen atoms, and alcohols. ‘We employed a relatively extensive set of molecules to ensure that it would be impossible to account for the molecules’ configurations based solely on one factor,’ elucidates Igor Alabugin, who spearheaded the research.
The team correlated the intensity of the anomeric effect in a molecule to the energy difference between the axial and equatorial conformers and modeled the molecules across three environments: water, toluene, and in the gas phase.
Subsequently, the team linked the energy differences of all 49 molecules with various parameters. Numerous statistically significant factors were identified that impact the anomeric effect.
Hyperconjugation appeared as a central factor, as anticipated. Variations in conformers regarding overall molecular surface area and differences in orbital hybridization at the anomeric carbon were also notable, while the steric bulk of the substituent had minimal influence on a molecule’s conformation. The researchers further discovered that electrostatic effects that favor the axial configuration became progressively significant in polar solvents like water. Alabugin notes that there’s a balance among all these factors and explains that ‘molecules find a way to minimize their overall energy by utilizing every avenue available’.
Rodrigo Cormanich at the State University of Campinas in Brazil believes this research aids in ‘eliminating bias from a debate that has persisted for decades, replacing it with a quantitative perspective’. ‘Rather than questioning whether the anomeric effect is due to “hyperconjugation” or “electrostatics” or reverting to sterics when no other explanation is apparent, the authors [of the study] consider conformational preference as the collective result of several contributors.’
Conversely, Yirong Mo at the University of North Carolina at Greensboro points out that the selection of the computational model might amplify whether, for instance, hyperconjugation or stereoelectronics is preeminent. He suggests that examining substituted cyclohexane rings – devoid of an oxygen atom – in conjunction with those analyzed by Alabugin and his colleagues could enable a more direct comparison.
As computational representations of molecules increasingly align with reality, Cormanich believes that chemists will undoubtedly continue to utilize models like hyperconjugation to clarify chemical phenomena, as they remain ‘straightforward, applicable, and elucidative at the human scale’.
Alabugin emphasizes that while chemists often possess their distinct rationalizations for the anomeric effect, he points out that ‘in science, it’s easy to become infatuated with your own notion – maintaining a balanced perspective is crucial’.