Abstract
Non-planar amides are usually transitional structures, that are involved in amide bond rotation and inversion of the nitrogen atom, but some ground-minimum non-planar amides have been reported. Non-planar amides are generally sensitive to water or other nucleophiles, so that the amide bond is readily cleaved. In this article, we examine the reactivity profile of the base-catalyzed hydrolysis of 7-azabicyclo[2.2.1]heptane amides, which show pyramidalization of the amide nitrogen atom, and we compare the kinetics of the base-catalyzed hydrolysis of the benzamides of 7-azabicyclo[2.2.1]heptane and related monocyclic compounds. Unexpectedly, non-planar amides based on the 7-azabicyclo[2.2.1]heptane scaffold were found to be resistant to base-catalyzed hydrolysis. The calculated Gibbs free energies were consistent with this experimental finding. The contribution of thermal corrections (entropy term, –TΔS‡) was large; the entropy term (ΔS‡) took a large negative value, indicating significant order in the transition structure, which includes solvating water molecules.
Highlights
In non-planar amides, distortion of the amide bond can arise from both twisting about theC-N bond and pyramidalization at the nitrogen atom (Scheme 1) [1,2]
In order In to order estimate the strength of amideof we compared the reactivities of planarof to estimate the strength ofbonding, amide bonding, we compared the reactivities ofand planar and non-planar pyrrolidine amides
We examined, the hydrolysis of the bicyclic compounds under the same conditions
Summary
In non-planar amides, distortion of the amide bond can arise from both twisting about the. C-N bond and pyramidalization at the nitrogen atom (Scheme 1) [1,2]. These transformations of the amide bond are essentially mutually correlated, and the transition states of the amide rotation involved bond twisting and nitrogen pyramidalization at the same time [3] (see Reference [4]). The partial double-bond character of planar amides limits rotation about the C-N bond, and this feature contributes to stabilization, due to electron-delocalization. Decrease in sp nitrogen character, with increase of sp character, tends to weaken the C-N bond and increase the electrophilicity of the carbonyl carbon atom [1].
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