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 CDCI3. 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 (nu) and the carbonyl oxygen atoms (no) 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 sigma-sigma repulsion along the amide linkage between the sigma(N1N2), and sigma(C1C2) orbitals in the anti-periplanar arrangement and between the C-NICS and sigma(C1C2) orbitals in the syn-periplanar arrangement, which lead to the overwhelming E -preference in Nacyl pyrazoles/triazoles. In the case of N-acyl imidazoles, similar vicinal sigma-sigma 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.