An evaluation of amide group planarity in 7-azabicyclo[2.2.1]heptane amides. Low amide bond rotation barrier in solution

Yuko Otani; Osamu Nagae; Yuji Naruse; Satoshi Inagaki; Masashi Ohno; Kentaro Yamaguchi; Gaku Yamamoto; Masanobu Uchiyama; Tomohiko Ohwada

doi:10.1021/ja036644z

An evaluation of amide group planarity in 7-azabicyclo[2.2.1]heptane amides. Low amide bond rotation barrier in solution

J Am Chem Soc. 2003 Dec 10;125(49):15191-9. doi: 10.1021/ja036644z.

Authors

Yuko Otani¹, Osamu Nagae, Yuji Naruse, Satoshi Inagaki, Masashi Ohno, Kentaro Yamaguchi, Gaku Yamamoto, Masanobu Uchiyama, Tomohiko Ohwada

Affiliation

¹ Contribution from the Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.

PMID: 14653754
DOI: 10.1021/ja036644z

Abstract

Here we show that amides of bicyclic 7-azabicyclo[2.2.1]heptane are intrinsically nitrogen-pyramidal. Single-crystal X-ray diffraction structures of some relevant bicyclic amides, including the prototype N-benzoyl-7-azabicyclo[2.2.1]heptane, exhibited nitrogen-pyramidalization in the solid state. We evaluated the rotational barriers about the amide bonds of various N-benzoyl-7-azabicyclo[2.2.1]heptanes in solution. The observed reduction of the rotational barriers of the bicyclic amides, as compared with those of the monocyclic pyrrolidine amides, is consistent with a nitrogen-pyramidal structure of 7-azabicyclo[2.2.1]heptane amides in solution. A good correlation was found between the magnitudes of the rotational barrier of N-benzoyl-7-azabicyclo[2.2.1]heptanes bearing para-substituents on the benzoyl group and the Hammett's sigma(p)(+) constants, and this is consistent with the similarity of the solution structures. Calculations with the density functional theory reproduced the nitrogen-pyramidal structures of these bicyclic amides as energy minima. The calculated magnitudes of electron delocalization from the nitrogen nonbonding n(N) orbital to the carbonyl pi orbital of the amide group evaluated by application of the bond model theory correlated well with the rotational barriers of a variety of amides, including amides of 7-azabicyclo[2.2.1]heptane. The nonplanarity of the amide nitrogen of 7-azabicyclo[2.2.1]heptanes would be derived from nitrogen-pyramidalization due to the CNC angle strain and twisting of the amide bond due to the allylic strain.