Determination of the sequential order of acidity in a polyhydroxylated benzophenone series. Consequence on the oxidation reaction in relation to hepatotoxicity

Abstract

The pK_a values of successive acid-base equilibria involved in the pyrogallol ring ionization of exifone, 2,3,4-trihydroxybenzophenone 1, and related methoxy derivatives were determined by UV–VIS absorption spectrometry and potentiometric titration. Due to strong intramolecular hydrogen bonding, the sequential order of acidity of the three hydroxy groups of 1 was found to be 4-OH > 3-OH > 2-OH. The polyhydroxylated benzophenones were oxidized to 3,4-quinone only in a narrow range of acidity in which the monoanionic 4-olate species predominated in solution. The attachment of an amino-alcohol residue resulted in the trapping of the transient 3,4-quinone and provided a convenient route to novel 1,4-benzoxazine derivatives. Cytotoxicity experiments in rat hepatocytes indicated that some of these compounds were significantly less toxic than the parent exifone.