Abstract
The Hammett approach, as a new deductive tool, was introduced to characterize the otherwise inaccessible minor protonation pathway of tenoxicam (1), the non‐steroidal anti‐inflammatory drug. A total of eight compounds, constituting a systematic series of side chain‐substituted analogues of tenoxicam and piroxicam (2), were synthesized and studied in terms of acidbase properties and Hammett constants to identify the ideal replacement of the unprotonated pyridin‐2‐yl group, a key moiety in both molecules. Hammett constants of the phenyl substituents have been found to be in a linear correlation with the experimental log K values of the enolate sites, the basic moiety of the extended conjugated system in this family of piroxicam derivatives. Then, a similar correlation was observed for the analogous tenoxicam derivatives. After identifying the 2‐aza Hammett constant of the pyridin‐2‐yl group and the corresponding log K value, the site‐specific acid–base properties of tenoxicam could be quantitated. This novel method is assessed to be a fine‐tuning tool to find the ideal substituent by using analogue‐based deductive method to obtain site‐specific constants of the minor protonation/deprotonation pathway in drugs and biomolecules. The tenoxicam microconstant values indicate that the enolate moiety is of extremely low basicity (reflected by the $ \log \it k^{\rm{O}} $=3.70 and $ \log \it k_{\rm{N}}^{\rm{O}} $=1.09 values), which can, however, be interpreted in terms of the peculiar ring system and the overwhelming electron‐withdrawing effects of the adjacent heteroatoms. A diagram depicting the pH‐dependent distribution of 1 microspecies is also presented.