Elucidation of the E-Amide Preference of N-Acyl Azoles

The conformational properties of N -acyl azoles (imidazole, pyrazole, and triazole) were examined. The N -2′,4′,6′-trichlorobenzoyl azoles were stable in methanol at room temperature, and no hydrolyzed products were observed over 7 days in the presence of 5% trifluoroacetic acid or 5% triethylamine in CDCl 3 . The high stability may be explained by the double-bond amide character caused by the steric hindrance due to the ortho -substituents in the benzoyl group. While specific E -amide preferences were observed in N -acyl pyrazoles/triazoles, the amides of the imidazoles gave a mixture of E and Z . One of the conceivable ideas to rationalize this conformational preference may be repulsive interaction between two sets of lone-pair electrons on the pyrazole 2-nitrogen (n N ) and the carbonyl oxygen atoms (n O ) in the Z -conformation of N -acyl pyrazoles/triazoles. However, analysis of orbital interactions suggested that in the case of the E -conformation of N -acyl pyrazoles, such electron repulsion is small because of distance. The interbond energy calculations suggested that the Z -conformer is involved in strong vicinal σ–σ repulsion along the amide linkage between the σ N1N2 and σ C1C2 orbitals in the anti -periplanar arrangement and between the σ N1C5 and σ C1C2 orbitals in the syn -periplanar arrangement, which lead to the overwhelming E -preference in N -acyl pyrazoles/triazoles. In the case of N -acyl imidazoles, similar vicinal σ–σ repulsions were counterbalanced, leading to a weak preference for the E -conformer over the Z -conformer. The chemically stable and E -preferring N -acyl azoles may be utilized as scaffolds in future drug design.