Laboratory of Organic and Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Department of Chemistry, St John's College, University of Cambridge, St John's Street, Cambridge CB2 1TP, UK.
Molecules. 2018 Sep 15;23(9):2363. doi: 10.3390/molecules23092363.
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, ) was large; the entropy term () took a large negative value, indicating significant order in the transition structure, which includes solvating water molecules.
非平面酰胺通常是过渡态结构，涉及酰胺键的旋转和氮原子的反转，但也有一些最低基态非平面酰胺被报道。非平面酰胺通常对水或其他亲核试剂敏感，因此酰胺键容易断裂。在本文中，我们研究了碱催化水解 7-氮杂双环[2.2.1]庚烷酰胺的反应性，这些酰胺显示出酰胺氮原子的三角锥形化，我们比较了 7-氮杂双环[2.2.1]庚烷和相关的单环化合物的苯甲酰胺的碱催化水解的动力学。出乎意料的是，基于 7-氮杂双环[2.2.1]庚烷骨架的非平面酰胺被发现能够抵抗碱催化水解。计算的吉布斯自由能与这一实验结果一致。热校正（熵项， ）的贡献很大；熵项（ ）取很大的负值，表明在过渡态结构中存在显著的有序性，其中包括溶剂化水分子。
