A new twist on amide solvolysis.

deviation from planarity—such as observed during cis/trans isomerization occurring in protein folding—should result in major changes in reactivity and other chemical properties of the amide bond. For example, rotation of the amide bond is coupled with formal rehybridization of the nitrogen atom to sp, with attendant pyramidalization and greatly increased basicity. The most common experimental approach to studying non-planar amides involves rigging a system such that the poor amide bond has no choice but to exist in a highly destabilized perpendicular arrangement. The most common way to do this is to embed the amide into a bicyclic ring system (Scheme 1b). Such molecules have both enhanced reactivity and basicity relative to planar amides. For example, Kirby s “most twisted amide” hydrolyzes in less than a minute and has a pKa of ca. 5.2 (still attenuated relative to a typical trialkyl amine because the carbonyl group is such a strong electron-withdrawing group). Now, Lloyd-Jones, Booker-Milburn, and co-workers have shown that one need not resort to such drastic measures to dramatically enhance the reactivity of amide bonds. Their approach is based in part on the group s previously reported solvolysis of ureas, which they proposed to proceed through an initial “proton switch” step, mediated by solvent, that led to the high-energy intermediate shown (Scheme 2a). This