Ground state, anomeric effect

This review is an attempt to resolve the conceptual and experimental difficulties encountered in the application of ALPH as an axiom. A physical theory has only to fail once for it to be discredited as a fundamental explanation the electronic explanation of the data supporting ALPH in terms of a kinetic anomeric effect is therefore unlikely to be correct. Indeed, there are aspects of the operation of the ground-state anomeric effect itself which are not readily reconciled with the frontier-orbital view of its origin. 

We have seen how ALPH, whilst it successfully rationalises a number of observations of reactivity of compounds at the acyl level of oxidation, nonetheless fails as a general principle, and that these failures are particularly frequent in the reactions of compounds at the aldehyde level of oxidation, such as acetals. Moreover, its theoretical foundation, the frontier orbital explanation of the anomeric effect, seems to be, at the very least, incomplete in its rationalisation of ground state effects, and therefore an insecure basis on which to found a dogma about transition states. 

Sialosides have a distinct mechanism of hydrolysis for its unusual sugar structure of sialic acid. For example, the large 8-dideuterium and small primary kinetic isotope effects observed at the anomeric carhon and the large secondary kinetic isotope effect observed at the carboxylate carbon in the acid-catalyzed solvolysis of CMP-Af-acetyl neuraminate 24 support an oxocarbenium ion-like transition state 25 having the 5S conformation without nucleophilic participation of carboxylate and with the carboxylate anion in a looser environment than in the ground state [15] (O Fig. 3). Such a zwitterion structure is consistent with the results from calculations using the COSMO-AMI method for aqueous solutions [16]. 

The paucity of information on the mechanism of reactions, and on the structure of the transition state, and the role of the anomeric effect in its stabilization, constitutes the main reason why qualitative interpretation of reactivity as shown in the aforementioned examples is still very rare. An alternative, more-popular estimation of the relative reaction-rates of con-formers is based on the lone-pair orbital interactions, and their symmetry and energy in the ground state, and could be loosely associated with the perturbation theory of chemical reactivity. ... 

It may be that the mechanism is, in general, the same as that of equation 1 (see p. 28), but that a combination of steric and electronic effects destabilizes the conjugate acids of aryl a-D-hexopyranosides, increasing the free energy of the ground state. This is discussed in Section III, lb (see pp. 47-49) under anomeric effects for phenyl glycosides. 

There are two main manifestations of the anomeric effect concerning energy (Section IV.A) and concerning structure (Section IV.B). In this section, however, the energies of ground states are not considered further since they are an essential part of the definition of the anomeric effect. We shall deal here only with energies of transition states, in particular with transition states of chemical reactions (bond breaking) and transition states for rotation about bonds to an anomeric atom. 

If it is assumed that effects on the ground state are amplified in the transition state, this purely empirical thermodynamic anomeric effect is transformed into a predictive kinetic anomeric effect (Kirby, 1983). In the transition state for breakdown of a tetrahedral species containing the X—C—X—C fragment, breakdown of the isomer with the scissile bond antiperiplanar to a heteroatom lone pair will proceed more rapidly, under stereoelectronic acceleration (Scheme 17). The theory has obvious utility in predicting product distribution when a single species may break down by a number of possible pathways (Deslongchamps, 1983). However, the hypothesis has not been without its detractors. Some of the experimental work used... 

In order to propose a kinetic anomeric effect in nucleophilic substitution reactions at phosphorus, it is necessary (i) to extend the observations of a generalized anomeric effect in the TBP intermediate and the tetrahedral ground state to the transition state, and (ii) to show that the effect is amplified in the transition state. Consequently, Gorenstein et al. (1979) constructed models of the transition states for hydrolysis of dimethyl phosphate monoanion and subjected these to similar ab initio STO-3G calculations. The reactive intermediates along this hypothetical reaction coordinate are derived from the dimethoxy hydroxyphosphoranes [56] [58]. 

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