Anomeric effect

In organic chemistry, the anomeric effect or Edward-Lemieux effect (after J. T. Edward and Raymond Lemieux) is a stereoelectronic effect that describes the tendency of heteroatomic substituents adjacent to a heteroatom within a cyclohexane ring to prefer the axial orientation instead of the less-hindered equatorial orientation that would be expected from steric considerations.^[1] This effect was originally observed in pyranose rings by J. T. Edward in 1955 when studying carbohydrate chemistry.

The term anomeric effect was introduced in 1958.^[2] The name comes from the term used to designate the lowest-numbered ring carbon of a pyranose, the anomeric carbon. Isomers that differ only in the configuration at the anomeric carbon are called anomers. The anomers of D-glucopyranose are diastereomers, with the beta anomer having a hydroxyl (−OH) group pointing up equatorially, and the alpha anomer having that (−OH) group pointing down axially.

The anomeric effect can also be generalized to any cyclohexyl or linear system with the general formula C−Y−C−X, where Y is a heteroatom with one or more lone pairs, and X is an electronegative atom or group.^[3] The magnitude of the anomeric effect is estimated at 4-8 kJ/mol in the case of sugars, but is different for every molecule.

In the above case, the methoxy group −O−CH₃) on the cyclohexane ring (top) prefers the equatorial position. However, in the tetrahydropyran ring (bottom), the methoxy group prefers the axial position. This is because in the cyclohexane ring, Y = carbon, which is not a heteroatom, so the anomeric effect is not observed and sterics dominates the observed substituent position. In the tetrahydropyran ring, Y = oxygen, which is a heteroatom, so the anomeric effect contributes and stabilizes the observed substituent position. In both cases, X = methoxy group.

The anomeric effect is most often observed when Y = oxygen, but can also be seen with other lone pair bearing heteroatoms in the ring, such as nitrogen, sulfur, and phosphorus.^[4] The exact method by which the anomeric effect causes stabilization is a point of controversy, and several hypotheses have been proposed to explain it.