Figure 3.4 Microspeciation of cetirizine, a three-pi^ molecule [142], The numeric quantities refer to micro-pKa values. The asterisks denote the principal species at various pH states. [Avdeef, A., Curr. Topics Med. Chem., 1, 277-351 (2001). Reproduced with permission from Bentham Science Publishers, Ltd.]

thermodynamic experiment is a proton-counting technique. It cannot identify the site in the molecule from which the proton comes. It can only be said that a proton emerges from somewhere in the molecule. On the other hand, microconstants are characteristic of individual species, of which there may be more than one with the same composition.

Various relationships between macro- and microconstants have been derived in the cited literature. The microspecies and microconstants of cetirizine (triprotic molecule with macroconstant pKa values 2.12, 2.90, and 7.98) are shown in Fig. 3.4, based on the impressive work of Tam and Queré [142]. The microspecies denoted by an astrisk in Fig. 3.4 are the principal species present in solution. As pH increases, the protonated nitrogen nearest the phenyl groups is the first center to shed charge. The corresponding dication ! monocation reaction has the micro-pKa 2.32. The next principal center to shed a proton is the carboxylic group, leading to the formation of a zwitterion (micro-pKa 2.70). The highest-pH principal depro-tonation consists of the protonated nitrogen nearest the carboxylate group losing its proton (micro-pKa 7.98) to form the anionic species on the right side of Fig. 3.4.

In cetirizine, the carboxylic group has four different micro-pKa values in the range, 2.70-5.47, depending on the neighboring-group charge state. The nitrogen nearest the phenyl groups has the micro-pKa values in the range 2.02-7.33. The other nitrogen has values in the range 2.77-7.98.

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