Ionization processes of some harmala alkaloids.

The ionization and UV-visible spectral properties of some harmala alkaloids have been investigated spectrophotometrically. Harmaline and harmine were found to have pKa values of 9.55 +/- 0.04 and 7.45 +/- 0.03, respectively. The ionization of harmalol was characterized by two processes which could be spectrophotometrically isolated from one another, allowing pKa values of 8.62 +/- 0.15 and 11.30 +/- 0.23 to be determined. The lower of these was ascribed to the phenolic group and the higher to the enamino site. Support for this assignment lay in the yellow color (lambda max 433 nm) at intermediate pH values, which was typical of a formally neutral quinone-methide structure. For harmol, pKa values of 7.90 and 9.47, reported at 21 degrees by Perrin [N.Z.J. Sci. Technol. 388:688-694 (1957)], were reassigned with the lower value reflecting phenolic ionization, as opposed to the original literature assignment. Partition coefficients at pH 7.4 (n-heptane/water) were determined. The comparative pharmacology of these alkaloids is discussed and related to both their pKa values and the relative stability of the neutral quinone-methide structure.