Tautomeric and Microscopic Protonation Equilibria of Anthranilic Acid and Its Derivatives

The acid-base chemistry of three zwitterionic compounds, namely anthranilic (2-aminobenzoic acid), N-methylanthranilic and N-phenylanthranilic acid has been characterized in terms of the macroconstants Ka1, Ka2, the isoelectric point pHI, the tautomerization constant Kz and microconstants k11, k12, k21, k22. The potentiometric titration method was used to determine the macrodissociation constants. Due to the very poor water solubility of N-phenylanthranilic acid the dissociation constants pKa1 and pKa2 were determined in MDM-water mixtures [MDM is a co-solvent mixture, consisting of equal volumes of methanol (MeOH), dioxane and acetonitrile (MeCN)]. The Yasuda-Shedlovsky extrapolation procedure has been used to obtain the values of pKa1 and pKa2 in aqueous solutions. The pKa1 and pKa2 values obtained by this method are 2.86 ± 0.01 and 4.69 ± 0.03, respectively. The tautomerization constant Kz describing the equilibrium between unionized form ⇌ zwitterionic form was evaluated by the Kz method based on UV-VIS spectrometry. The method uses spectral differences between the zwitterionic form (found at isoelectric pH in aqueous solution) and the unionized form (formed in an organic solvent of low dielectric constant). The highest value of the Kz constant has been observed in the case of N-methylantranilic acid (log10Kz = 1.31 ± 0.04). The values of log10Kz for anthranilic and N-phenylanthranilic acids are similar and have values of 0.93 ± 0.03 and 0.90 ± 0.05, respectively. The results indicate that the tested compounds, in aqueous solution around the isoelectric point pHI, occur mainly in the zwitterionic form. Moreover, the influence of the type of substituent and pH of the aqueous phase on the equilibrium were analyzed with regard to the formation and the coexistence of different forms of the acids in the examined systems.