Mechanism of N–N Bond Formation by Transition Metal–Nitrosyl Complexes: Modeling Flavodiiron Nitric Oxide Reductases

Nitric oxide (NO) has a number of important biological functions, including nerve signaling transduction, blood pressure control, and, at higher concentrations, immune defense. A number of pathogenic bacteria have developed methods of degrading this toxic molecule through the use of flavodiiron nitric oxide reductases (FNORs), which utilize a nonheme diiron active site to reduce NO → N₂O. The well-characterized diiron model complex [Fe₂(BPMP)­(OPr)­(NO)₂]²⁺ (BPMP⁻ = 2,6-bis­[(bis­(2- pyridylmethyl)­amino)­methyl]-4-methylphenolate), which mimics both the active site structure and reactivity of these enzymes, offers key insight into the mechanism of FNORs. Presently, we have used computational methods to elucidate a coherent reaction mechanism that shows how one and two-electron reduction of this complex induces N–N bond formation and N₂O generation, while the parent complex remains stable. The initial formation of a N–N bond to generate hyponitrite (N₂O₂^2–) follows a radical-type coupling mechanism, which requires strong Fe–NO π-interactions to be overcome to effectively oxidize the iron centers. Hyponitrite formation provides the largest activation barrier with ΔG^‡ = 7–8 kcal/mol (average of several functionals) in the two-electron, super-reduced mechanism. This is followed by the formation of a N₂O₂^2– complex with a novel binding mode for nonheme diiron systems, allowing for the facile release of N₂O with the assistance of a carboxylate shift. This provides sufficient thermodynamic driving force for the reaction to proceed via N₂O formation alone. Surprisingly, the one-electron “semireduced” mechanism is predicted to be competitive with the super-reduced mechanism. This is due to the asymmetry imparted by the BPMP^– ligand, allowing a one-electron reduction to overcome one of the primary Fe–NO π-interactions. Generally, mediation of N₂O formation by high-spin [{M-NO⁻}]₂ cores depends on the ease of oxidizing the M centers and breaking of the M–NO π-bonds to formally generate a “full” ³NO^– unit, allowing for the critical step of N–N bond formation to proceed (via a radical-type coupling mechanism).