Protonation Sites of Indoles and Benzoylindoles

Indomethacine ( 1 ) and acemethacine ( 2 ) contain the substituents ‐OCH 3 , ‐CH 2 COOH, ‐CH 2 COOCH 2 COOH, C‐indole and O‐benzoyl, which are susceptible to protonation in highly acidic media. To determine the protonation sites and the substituent effects reliably, the dissociation constants of the set of structurally related compounds 1‐benzoyl‐3‐methylindole ( 3 ), 1‐benzoyl‐5‐methoxyindole ( 4 ), 1‐benzoylindole ( 5 ), 5‐methoxy‐2‐methylindole ( 6 ), (2‐methylindol‐3‐yl)acetic acid ( 7 ) and (5‐methoxy‐2‐methylindol‐3‐yl)acetic acid ( 8 ) were investigated in concentrated perchloric acid. The UV/Visible spectral curves were studied by the Hammett, Bunnett–Olsen and excess acidity methods, and the observed medium effects of 1 to 5 were analysed by the vector analysis and excess acidity methods. Acemethacine ( 2 ) displays two acid–base equilibria with p K ( i ) = –2.3 and p K = –4.2, corresponding to the ester and amide groups. The benzoylindoles 1 , 3 , 4 and 5 each show a single amide equilibrium p K ≈ –4.2, independently of the substituent. Indoles 6 – 8 are stronger bases than benzoylindoles. Substitution of the indole H (NH) by the benzoyl group strongly reduces the N basicity, and increases the O basicity with protonation of the CO group. The solvation parameters, m * = 0.70 for benzoylindoles and m * = 1.3 for indoles, reveal greater charge location and less solvation requirements in the latter. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)