An Evaluation of Amide Group Planarity in 7-Azabicyclo[2.2.1]heptane Amides. Low Amide Bond Rotation Barrier in Solution

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.

Resonance Structures of the Amide Bond: The Advantages of Planarity

“…Similar effects introduced by bulky substituents [57] and with differing ring sizes [58] have been reported in the literature.…”

“…For instance, Otani et al [58] found a good correlation between the experimental rotational free-energy barrier in solution of a series of N-benzoyl-7-azabicycloA C H T U N G T R E N N U N G [2.2.1]heptanes with respect to the delocalization indexes derived from differences in the relative ratio of the coefficients for the n N orbital and the p* CO orbital between the transition state and the ground state configuration. However, the use of indexes such as d ON to characterize electron delocalization has the appeal of being a well-defined quantum mechanical quantity, being in principle less dependent on the choice of molecular orbitals, and not relying on an arbitrary partitioning of the electron density.…”

3-Oxoisoxazole-2(3H)-carboxamides and isoxazol-3-yl carbamates: Resistance-breaking acetylcholinesterase inhibitors targeting the malaria mosquito, Anopheles gambiae

“…The extent of resonance between the endocyclic N (N1) and the amide carbonyl carbon (C8) appears to be low based on the out-of-plane twisting of the dimethylcarbamoyl group. The magnitude of amide twist can be expressed as the τ value 29,30 along a given N-C bond. As expected, the endocyclic amide bond N1-C7 has a low value (-12.6°), as does the dimethylamino amide bond N2-C8 (8.6°).…”

Bicyclic β-amino acids

“…This is characterized by the sum of the valent angles centered at this atom, which is nearly 345-350° (instead of 360° for the planar configuration). 149 This feature was reported to affect several different properties of the compounds discussed. In particular, N-nitroso derivatives 329 -331 were shown to release NO upon irradiation with visible light (λ = 420 nm) ( Figure 18).…”