Altering the Acidity and Solution Properties of Bilirubin. Methoxy and Methylthio Substituents.
Substitution of electron-withdrawing groups at the alpha-position of an aliphatic carboxylic acid can be expected to increase the acidity of the acid. Methoxy and methylthio groups are especially effective; they increase the acidity of acetic acid by approximately 1.1 pK(a) units. Bilirubin, the water-insoluble pigment of jaundice, has two propionic acids, and an alpha-methoxy or alpha-methylthio substituent in each propionic acid can be expected to lower the pK(a) similarly and thus alter its solubility properties. (A previously synthesized analogue, alpha,alpha'-difluororubin (4), is soluble in water.) Two new analogues of bilirubin, alpha,alpha'-dimethoxyrubin (1) and alpha,alpha'-bis(methylthio)rubin (2), have been synthesized, separated into diastereomers, and analyzed. The isomers are shown by NMR to adopt intramolecularly hydrogen-bonded ridge-tile-shaped conformations. Like bilirubin, both 1 and 2 are insoluble in water. Unlike bilirubin, 1 is soluble in dilute aqueous bicarbonate, but 2 is insoluble, which would not be predicted from the expectation that 1 and 2 have the same pK(a). The data hint at a much larger steric size of SCH(3) relative to OCH(3).
Boiadjiev
Stefan E.
SE
Department of Chemistry, University of Nevada, Reno, Nevada 89557-0020.
Lightner
David A.
DA