Site‐Specific Acid–Base Properties of Tenoxicam

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.