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Molecules 2018, 23(9), 2363; https://doi.org/10.3390/molecules23092363 (registering DOI)

Unexpected Resistance to Base-Catalyzed Hydrolysis of Nitrogen Pyramidal Amides Based on the 7-Azabicyclic[2.2.1]heptane Scaffold

1
Laboratory of Organic and Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
2
Department of Chemistry, St John’s College, University of Cambridge, St John’s Street, Cambridge CB2 1TP, UK
*
Author to whom correspondence should be addressed.
Academic Editor: Michal Szostak
Received: 25 August 2018 / Revised: 10 September 2018 / Accepted: 12 September 2018 / Published: 15 September 2018
(This article belongs to the Special Issue Amide Bond Activation)
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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. View Full-Text
Keywords: non planar amide; base-catalyed hydrolysis; water solvation; entropy non planar amide; base-catalyed hydrolysis; water solvation; entropy
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Ocampo Gutiérrez de Velasco, D.A.; Su, A.; Zhai, L.; Kinoshita, S.; Otani, Y.; Ohwada, T. Unexpected Resistance to Base-Catalyzed Hydrolysis of Nitrogen Pyramidal Amides Based on the 7-Azabicyclic[2.2.1]heptane Scaffold. Molecules 2018, 23, 2363.

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