Studies in detoxication. 31. The isolation of m- and p-cyanophenols as metabolites of cyanobenzene (benzonitrile) and the problem of the orientation of hydroxyl groups formed in vivo

Abstract

A study was made of the hydroxylation of cyano[long dash]benzene and benzoic acid in the rabbit. No evidence was obtained of the oxidation of benzoic acid; the only metabolites obtained here were the unchanged acid, its glycine derivative and glucuronide. Cyanobenzene is very slowly eliminated and undergoes considerable change in vivo. About 60% is excreted as oxygen conjugates, 10% is transformed to benzoic acid and it is suggested that another 5% forms a mercapturic acid. The ethereal sulfate fraction of cyanobenzene urine contains m-and p-cyano phenols, which were isolated. The formation of m-cyanophenol is believed to be the first reported case of meta-hyttfoxylation in vivo. The nature of the glucuronide fraction was not elucidated. The azobenzene-4-carbonyl esters, 2,4-dinitrophenyl ethers and benzylamine salts of the cyanophenols were synthesized and used as reference compounds. The pKa''s of o-, m- and p-cyanophenols have been measured. The results are discussed in the light of current theories concerning diol formation in vivo and aromatic substitution in vitro,.