Imidazolate-Stabilized Cu(III): Dioxygen to Oxides at Type 3 Copper Sites.

Imidazole ligation of metals through histidine is extensive among metalloproteins, yet the role of the imidazolate conjugate base is often neglected, despite its potential accessibility when bonded to an oxidized metal center. Using synthetic models of oxygenated tyrosinase enzymes ligated exclusively by monodentate imidazoles, we find that deprotonation of the μ-η:η-peroxidodicopper(II) species triggers redox isomerization to an imidazolate-ligated bis(μ-oxido)dicopper(III) species. Formal two-electron oxidation to Cu(III) remains biologically unprecedented, yet is effected readily by addition of base. Spectrophotometric titrations by UV/Visible/near-IR and copper K-edge X-ray absorption spectroscopies are interpreted most simply as two cooperative, 2H transformations in which the peroxide O-O is cleaved in the first step. Elaboration from simple imidazoles to a protected histidine extends this isomerization into an amino acid environment. The role of phenolate as a base suggests this four-electron reduction of O is energetically viable in a biological context and requires only two copper centers, which act as two-electron shuttles when imidazole deprotonation assists. This existential precedent of viable imidazolate intermediates invites speculation into an alternative mechanism for phenol hydroxylation not previously considered at Type 3 copper sites such as tyrosinases. Structural biological evidence suggests imidazolate ligation of copper may be more widespread than generally understood.