Abstract
A critique of objections to the 'antiperiplanar lone pair hypothesis' (ALPH) and the 'reverse anomeric effect' (RAE) is presented. Whilst early fears that ALPH is incompatible with the Curtin-Hammett principle (CHP) were apparently unfounded, objections to ALPH based on the reactions of cyclic hemiorthoesters and amidinium salts are debatable. (The unreactivity of Kirby's bicyclic bridgehead acetal supports ALPH convincingly.) Objections to RAE were based on its apparent incompatibility with ALPH, studies on several models indicating (dubiously) the existence of a weak anomeric effect rather than RAE. However, this may well suggest that a normal anomeric effect is being offset by RAE. This apparently indicates different bases for the ground state and kinetic anomeric effects: the classical 'electrostatic gauche repulsive interaction' (EGRI) and the 'orbital interaction' (OI) respectively. The evidence against free oxocarbenium ions, but favouring the ion pair and the 'exploded transition state' (ETS) models apparently raises the question 'Whither ALPH?'. A rigorous application of the CHP to the stereochemistry of displacements at glycosyl anomeric centres, indicates that the alpha anomers react retentively via ion pairs, whereas the beta anomers react with inversion via the ETS. (A substantial reassessment of the 'in situ anomerisation technique' is also indicated.)
Highlights
Stereoelectronic theory represents an important thrust area of modern organic chemistry, having provided a major boost to mechanistic research in recent decades
The reverse anomeric effect (RAE) can only be justified on the basis of electrostatic gauche repulsive interaction’ (EGRI).: it is, incomprehensible vis-à-vis antiperiplanar lone pair hypothesis’ (ALPH), because orbital interaction’ (OI) should be enhanced in the above conjugate acid forms, via a lowering of the energy of the σ* orbital (LUMO) involved. [With a positively charged substituent (X+) at the anomeric centre in a glycoside or a THP derivative, the LUMO of the C-X+ bond would be considerably lowered by the electron withdrawal by the X+, enhancing the charge transfer from the oxygen lone pair to the LUMO.]
ALPH has stimulated a generation of physical organic chemists, and inspired a magnificent research effort spread over a quarter of a century.[1,2,38]
Summary
Stereoelectronic theory represents an important thrust area of modern organic chemistry, having provided a major boost to mechanistic research in recent decades. The major impetus for the evolution of ALPH is the fact that it provides the mechanistic underpinning for glycosyl transfer – the key process in the burgeoning area of carbohydrate chemistry, which is set to play a prime role in chemical biology It is apparently widely believed – this by no means implies a consensus – that the present conceptual status of ALPH is highly satisfactory, and that the broad contours are well established: ALPH will be fleshed out further, no ISSN 1424-6376. On the other hand, the view has gained ground that the free oxocarbenium ion – an ‘old faithful’ among the reactive intermediates – is practically a chimera!9 Instead, the heterolytic reactions of the acetals and the glycosides are believed to occur via rate-determining nucleophilic attack on an (oxocarbenium) ion pair This development does not dethrone ALPH, it does raise fundamental questions about its role in structure and reactivity. This paper charts a course away from both the proponents and the detractors of ALPH, in the belief that ALPH is supportable – but only after a dispassionate reevaluation. (That stereoelectronic theory and ALPH remain in the forefront of chemical research, is indicated by the vigorous experimental and theoretical work that continues to be reported.10)
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