Insights into Cytochrome P450 Enzymes Catalyzed Defluorination of Aromatic Fluorides.

The biodegradability of many fluorinated compounds is limited due to the robustness of the C-F bond. Recently, experimental studies suggested the potential involvement of cytochrome P450 enzymes in facilitating aromatic defluorination, raising questions where this can be applied in biocatalysis. Our study offers an in-depth computational examination into the oxidative defluorination process of a drug molecule, mediated by cytochrome P450 Compound I. We explored a large number of potential mechanisms, and identify two competitive low-energy pathways that are initiated with an electrophilic attack on the aromatic ring, and followed by either a 1,2-fluorine shift or a ring-closure to form an epoxide intermediate. Both of these intermediates are shown to react rapidly through defluorination assisted by a solvent proton. Interestingly, defluorination in the vicinity of a heme group may generate a stable iron(III)-fluoride complex, potentially leading to enzyme inactivation.