Methanogenic archaea produce CH₄ through a multi-enzymatic pathway, the last step of which is reversibly mediated by methyl-coenzyme M reductase (MCR). This enzyme relies on an F₄₃₀ cofactor, wherein a unique monoanionic N₄-donor macrocycle supports the active Ni center in reversibly cleaving a methyl thioether (methyl-coenzyme M, CoMS–Me) and a thiol (coenzyme B, H–SCoM), to release CH₄. The gas is thought to form or dissociate between the two S atoms, yet some mechanistic proposals implicate other routes involving Ni–H or Ni–Me moieties. Thus, although MCR makes a gigaton of CH₄ annually in several living systems, we still do not know precisely how it makes and breaks CH₄, an incredibly robust molecule (105 kcalmol⁻¹). To address this, we are studying a family of Ni complex salts [Ni(mac)]X (X = PF₆, BAr^F₄) featuring rare monoanionic macrocycles reminiscent of F₄₃₀.
Our Ni complexes are tunable in terms of ligand donicity, steric bulk and pendant N-alkyl functionality. For example, alkyl groups can be electron-withdrawing (4-fluorobenzyl), -donating (methyl) or have acid-base reactivity (2-, 3-picolyl). Lastly, we have prepared bis(thioether) derivatives that can be cleaved to give complexes in which two thiols are proximal to Ni. This new paradigm may afford reactive disulfides tethered to Ni, which is the very arrangement that MCR exploits to cleave CH₄. We present our experimental (ESI-MS, ESI-MS², ICP-MS, XRD, NMR, …) and theoretical (DFT) progress toward recapitulating the remarkable outer-sphere reactivity of the Ni cofactor.

Nishita Deb

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