Exploring unusual antioxidant activity in a benzoic acid derivative: a proposed mechanism for citrinin

A mechanism is proposed for the unusual antioxidant activity in citrinin based on computed O-H bond dissociation enthalpies (BDE). These data suggest that citrinin itself is not the active species, but rather a pair of hydrated Michael addition products consisting of substituted 2,6-dihydroxy benzoic acids. These diastereomers act as radical scavengers via O-H bond dissociation with computed BDE's ranging from 78.9-80.9 kcal/mol for the active groups present. These data represent an unusually facile O-H bond dissociation for a phenol containing a strongly electron withdrawing group. This atypical reactivity arises from an intramolecular network of hydrogen bonds that both stabilize the incipient radical and facilitate extended delocalization through atoms external to the aromatic ring. The additional influence of stereochemistry on BDE is computed to be 2.0 kcal/mol. Data presented are for gas phase molecules, but solvents are unlikely to strongly modify these results since most polar groups are involved in intramolecular hydrogen bonds and thus less available for association with solvent. Citrinin and the Michael addition products are likely too toxic for use as antioxidants in organisms but this study clearly identifies specific reaction sites in the active form, thus guiding rational design of synthetic derivatives with more favorable biocompatibility.