Anomeric effect cannot be explained by hyperconjugation alone

 

Computational analysis suggests that the anomeric effect arises from a combination of factors and is not limited to just hyperconjugation. Researchers say that this ‘curiosity-driven’ work reminds chemists that attributing the effect to one dominant cause oversimplifies a ‘fundamentally complex phenomenon’.

The anomeric effect helps chemists rationalise why substituents next to a heteroatom in a ring preferentially adopt an axial configuration, rather than the less sterically hindered equatorial orientation. Hyperconjugation of a heteroatom’s lone pair of electrons into the anti-bonding orbital of an adjacent substituent is a common explanation for this effect.

However, previous studies suggest that other factors such as stereoelectronics and solvent interactions also play a part.1 Researchers at Florida State University in the US have now tried to quantify the influence of such factors.2

To do this, the team computationally analysed 49 monosubstituted tetrahydropyrans – rings with five carbon atoms and one oxygen atom – across a range of parameters, modelling steric, electrostatic and stereoelectronic factors. Substituents included alkyl chains, aromatic and heteroatomic rings, peroxides, halogen atoms and alcohols. ‘We used a relatively broad set of molecules so that there’s no way that it would be possible to describe the molecules’ configurations by only one factor,’ explains Igor Alabugin, who led the study.

The team related the strength of the anomeric effect in a molecule to the energy difference between the axial and equatorial conformers and modelled the molecules across three environments: water, toluene and in the gas phase.

Then, the team correlated the energy differences of all 49 molecules with various parameters. Several statistically significant factors were found that influence the anomeric effect.


Hyperconjugation emerged as a dominant factor, as expected. Changes between conformers in overall molecular surface area and differences in orbital hybridisation at the anomeric carbon were also significant, while the substituent’s steric bulk had little effect on a molecule’s conformation. The researchers also found that electrostatic effects that favour the axial configuration became increasingly important in polar solvents such as water. Alabugin says that there’s a balance between all these factors and explains that ‘molecules find a way to minimise their overall energy using everything possible’.

Rodrigo Cormanich at the State University of Campinas in Brazil thinks this work helps ‘to remove bias from a debate that has lasted for decades and replace it with a quantitative way of thinking’. ‘Instead of asking whether the anomeric effect is “hyperconjugation” or “electrostatics” or falling back on sterics when nothing else is obvious, the authors [of the study] treat conformational preference as the combined outcome of several contributors.’

However, Yirong Mo at the University of North Carolina at Greensboro explains that the choice of computational model may exaggerate whether, for example, hyperconjugation or stereoelectronics are dominant. He suggests that analysing substituted cyclohexane rings – without an oxygen atom – alongside those studied by Alabugin and his team may allow for a more direct comparison.


As computational descriptions of molecules more faithfully reflect the real world, Cormanich thinks that chemists will undoubtedly still use models like hyperconjugation to explain chemical observations, as they are ‘simple, usable and explanatory at the human scale’.

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