The anomeric effect

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Anomeric effect

The preferred conformation of the tetrahydropyran ring is the chair conformation. [Hassel, 1947]

As for cyclohexanes, one would expect that substituted tetrahydropyranes would adopt the chair conformation having the largest substituents in the equatorial position. But why then is the preferred conformation (98 % in solution) of tri-O-benzoyl-b-xylopyranolsyl chloride the conformation 1 with all the substituents in an axial position. [Luger, 1974]

1

The answer is the anomeric effect, which states that electronegative substituents at the anomeric center of pyranoses prefer to adopt an axial configuration. [Kirby, 1983] How is the anomeric effect explained ? It can be explained in glycosyl chlorides by overlap of the one of the lone pairs on oxygen with the antibonding s*-orbital of the C-Cl bond. The overlap is efficient only when one of the electron lone pairs on the oxygen is antiperiplanar with the C-Cl bond.

The description is very similar to a frontier orbital description of an SN2 reaction between a halide and a nucleophile.

The highest occupied molecular orbital (HOMO) of the nucleophile interacts with the LUMO of the halide, which is the antibonding s-orbital of the C-X bond. The difference here is that one have an intermolecular interaction with s-symmetry, whereas in the glycosyl chloride the interaction is intramolecular with p-symmetry.

The anomeric effect does not only apply to carbohydrates or cyclic compounds, but also to acyclic compounds (and not only to a-halo ethers). The most stable conformation of chloromethoxy methane is for instance gauche and not antiperiplanar [Planje, 1965], [Aroney, 1966]. This is attributed to a generalized anomeric effect. [Lemieux, 1971]

The preference for a gauche conformation of a R-O-C-X bond, is a clear manifestation of the anomeric effect, but the anomeric effect also have influence on bond lengths and bond angels. a-Halomethyl ethers, for instance, have short O-CH2 bonds but rather long C-X bonds [Hayashi, 1980]. This is reasonable if we think of the non-bonding electronpair on oxygen is mixing with the antibonding orbital of the C-Cl bond, what would be described as 2 in valence bond terminology.

2

The anomeric effect on bond length is also nicely demonstrated in cis-2,3-dichloro-2,4-dioxane [Romers, 1967]. For the C-Cl at C2, where the anomeric effect is operating, the bond is longer than for the C-Cl at C3 where there is no anomeric effect. For the C-O bond its the other way around.

The magnitude of the anomeric effect is dependent on a number of things; the substituent on the anomeric carbon, substituents other places in the system. The solvent also has an effect.

The stronger the electron-withdrawing property is of the substituent on the anomeric carbon, the larger is the anomeric effect. Following series has been quoted [Romers, 1967]: halogen>PhCO2>AcO>AcS>MeOH>OH>NH2. This means that a-halo ethers are the compounds showing the largest anomeric effect. For glycosyl halides the anomeric effect is round 2,5 - 3,0 kcal mol -1; while less electronegative substitutents on the anomeric carbon, give a value from 0,5 - 1,5 kcal/mol [Kirby, 1983].

The anomeric value is largest in nonpolar solvents and lowest in hydroxylic solvents. The major difference is between water and organic solvents [Kirby, 1983].