Sugar anomerism ± a short and sweet digression Perspective on ` ` The application of ab initio molecular orbital theory to the anomeric e ect ' ' Je rey GA , Pople JA , Radom L ( 1972 ) Carbohydr

The subject paper presented the ®rst confor-mational analysis of the anomeric e€ect within the context of molecular orbital theory, discussed the utility of Fourier decomposition of a torsional coordinate as a method for analyzing disparate electronic in¯uences on that coordinate, and helped settle debate on the nature of anomeric stabilization. Sugars are the stepchildren of the biomonomer family. Unlike their more popular siblings peptides and nucleic acids, the study of which occupies a swarm of researchers , sugars appeal to a coterie of devotees. Yet sugars are wonderfully appealing to those attracted to puzzles. Capable of exhibiting multiple tau-tomeric forms at equilibrium, festooned with functional groups generating potentially thousands of rotational isomers, and profoundly in¯uenced by aqueous solva-tion, they are a theorists dream (or nightmare) vis-aÂ-vis challenge! I choose to focus here on the contributions of Je€rey, Pople, and Radom (JP&R) [1] to fostering our early understanding of one particularly fascinating feature of sugar energetics, namely the anomeric e€ect [2±7]. This stereoelectronic e€ect was ®rst noted in sugars, where the axial anomer of mannopyranose, for instance, is observed [8] to predominate over the equatorial anomer (this situation being contrary to expectations based on standard precepts of conformational analysis as applied to substituted cyclohexanes). However, the generality of the anomeric e€ect, or``negative hyperconjugation'' as it is sometimes called, has come to be widely recognized, and it is a key component in the conformational analysis of a diverse array of organic and inorganic molecules [9, 10]. Its physical basis was poorly understood in 1972. At the time two hypotheses (that were regarded for the most part as being mutually exclusive) had been put forward to account for the anomalous preference of electron-accepting substituents to orient themselves axially at the 2 positions in pyranose rings (i.e., the position next to the ring oxygen). In one analysis, the preference was ascribed to dipole±dipole and/or other Coulombic e€ects between the substituent group and the ring oxygen atom with its associated bonds [11, 12]. However, these models were of limited utility for predicting either experimental equilibria or geometrical di€erences between various pyranoside anomers; the latter were becoming increasingly available from X-ray crystallographic studies [13]. Indeed, crystal structure observations of lengthened axial bonds in 2-halopyranosides with concomitant shortening of the ring C(2)AO bonds led to an alternative proposal rationalizing the anomeric e€ect by invoking double bond±no bond resonance structures [14], i.e., negative hyperconjugation. This model, however, failed …