Hemiacetals stereoelectronic effects

The formation or the hydrolysis of an acetal function proceeds by the mechanism described in Fig. 16 in which oxonium ions and hemiacetals occur as intermediates. It has also been established (76) that the rate determining step in acetal hydrolysis is generally the cleavage of the C—bond of the protonated acetal 100 to form the oxonium ion 111, This ion is then rapidly hydrated to yield the protonated hemiacetal 112 which can give the aldehyde product after appropriate proton transfers. It is pertinent therefore to find out if stereoelectronic effects influence the rate determining step (110 111) of this hydrolysis reaction. 

Many of the stereoelectronic effects in the list above govern reactivity, but the next section will deal with how stereoelectronic effects affect structure—and in particular conformation. Some of the most important saturated oxygen heterocycles are the sugars. Glucose is a cyclic hemiacetal—a pentasubstituted tetrahydropyran if you like—whose major conformation in solution is shown below. About two-thirds of glucose in solution exists as this stereoisomer, but hemiacetal formation and cleavage is rapid, and this is in equilibrium with a further one-third that carries the hemiacetal hydroxyl group axial (<1% is in the open-chain form). 

The addition of nucleophiles to cyclic acetals and hemiacetals is an efficient method to access substituted THFs in high diastereoselectivity which is, in general, predictable and can be explained by stereoelectronic effects (1999JA12208). In this transformation, the intermediate is an oxocarbe-nium, which preferentially adopts an envelope conformation, and the nucleophile attacks on the inside face of the envelope. In the presence of a methyl at C3, the conformer possessing pseudoequatorial substituents is favored and the, 2>-trans product is obtained as the major product (63 64) (Scheme 33). It is worthy of note that when an alkoxy group is present at C3, the 1,3-ds product, resulting from an inside attack on the diaxial conformer, is favored (65 66) (Scheme 33). 

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