Dissociation constants of clonidine and structurally related imidazolidines.

The dissociation constants of clonidine and 27 structurally related imidazolidines have been determined by potentiometric titration of diluted aqueous solutions of the hydrochlorides with aqueous sodium hydroxide. Considerable differences in pKa' exist within this selection of congeneric substances. The pKa' is correlated with several electronic substituent parameters and the reaction constant has been calculated. The dissociation reaction of the present imidazolidine ions appears moderately sensitive to the electrical effects of the phenyl-attached substituents and is probably determined by one conformation of the molecules only. A major involvement can be attributed to inductive forces, whereas reasonance contribution seems of less importance, although it cannot be ignored. The dissociation constants are examined more closely with respect to their usefulness in biological systems. The influences of ionic strength and temperature on the dissociation of the compounds concerned are verified experimentally and compared with the values resulting from theoretical considerations. By making the corrections for ionic strength and temperature the acid/base equilibria as such present under physiological conditions have been calculated.