Simplest Monodentate Imidazole Stabilization of the oxy‐Tyrosinase Cu2O2 Core: Phenolate Hydroxylation through a CuIII Intermediate

Tyrosinases are ubiquitous binuclear copper enzymes that oxygenate to CuII2O2 cores bonded by three histidine Nτ-imidazoles per Cu center. Synthetic monodentate imidazole-bonded CuII2O2 species self-assemble in a near quantitative manner at −125 °C, but Nπ-ligation has been required. Herein, we disclose the syntheses and reactivity of three Nτ-imidazole bonded CuII2O2 species at solution temperatures of −145 °C, which was achieved using a eutectic mixture of THF and 2-MeTHF. The addition of anionic phenolates affords a CuIII2O2 species, where the bonded phenolates hydroxylate to catecholates in high yields. Similar CuIII2O2 intermediates are not observed using Nπ-bonded CuII2O2 species, hinting that Nτ-imidazole ligation, conserved in all characterized Ty, has functional advantage beyond active-site flexibility. Substrate accessibility to the oxygenated Cu2O2 core and stabilization of a high oxidation state of the copper centers are suggested from these minimalistic models.