Abstract
Metalloenzymes called nitrogenases (N(2)ases) harness the reactivity of transition metals to reduce N(2) to NH(3). Specifically, N(2)ases feature a multimetallic active site, called a cofactor, which binds and reduces N(2). The seven Fe centers and one additional metal center (Mo, V, or Fe) that make up the cofactor are all potential substrate binding sites. Unraveling the mechanism by which the cofactor binds N(2) and reduces N(2) to NH(3) represents a multifaceted challenge because cofactor activation is required for N(2) binding and functionalization to NH(3). Despite decades of fascinating contributions, the nature of N(2) binding to the active site and the structure of the activated cofactor remain unknown. Herein, we discuss the challenges associated with N(2) reduction and how transition metal complexes facilitate N(2) functionalization by coordinating N(2). We also review the activation and/or reaction mechanisms reported for small molecule catalysts and the Haber-Bosch catalyst and discuss their potential relevance to biological N(2) fixation. Finally, we survey what is known about the mechanism of N(2)ase and highlight recent X-ray crystallographic studies supporting Fe-S bond cleavage at the active site to generate reactive Fe centers as a potential, underexplored route for cofactor activation. We propose that structural rearrangements, beyond electron and proton transfers, are key in generating the catalytically active state(s) of the cofactor. Understanding the mechanism of activation will be key to understanding N(2) binding and reduction.