Exploring the Conformational Effects of N- and C-Methylation of N-acylhydrazones

N-acylhydrazones (NAH) are privileged structures in chemistry and medicinal chemistry. The alkylation of NAH can profoundly alter the structural properties of this subunit. In this study, we describe the conformational effects of N- and C-methylated N-acylhydrazones derivatives, combining theoretical and experimental data analysis. Methylation of NAH significantly affects the structure through electronic influences and changes in the lowest energy conformation. The introduction of the methyl group induces a substantial steric impact, evident from the alterations in the conjugation of the NAH framework as analyzed by theoretical studies and nuclear magnetic resonance (NMR) data. Among the series, the compound with two methyl groups is the most anomalous. Despite having two methyl groups, this compound exhibits greater polarity than the compound with a single methyl group on the amide nitrogen, as determined by thin-layer chromatography. This study contributes to a deeper understanding of the chemical properties of alkylated NAH derivatives and can guide their application in various branches of chemistry and medicinal chemistry.