Structural and reactivity models for copper oxygenases: cooperative effects and novel reactivities.

Dioxygen is widely used in nature as oxidant. Nature itself has served as inspiration to use O2 in chemical synthesis. However, the use of dioxygen as an oxidant is not straightforward. Its triplet ground-state electronic structure makes it unreactive toward most organic substrates. In natural systems, metalloenzymes activate O2 by reducing it to more reactive peroxide (O2(2-)) or superoxide (O2(-)) forms. Over the years, the development of model systems containing transition metals has become a convenient tool for unravelling O2-activation mechanistic aspects and reproducing the oxidative activity of enzymes. Several copper-based systems have been developed within this area. Tyrosinase is a copper-based O2-activating enzyme, whose structure and reactivity have been widely studied, and that serves as a paradigm for O2 activation at a dimetal site. It contains a dicopper center in its active site, and it catalyzes the regioselective ortho-hydroxylation of phenols to catechols and further oxidation to quinones. This represents an important step in melanin biosynthesis and it is mediated by a dicopper(II) side-on peroxo intermediate species. In the present accounts, our research in the field of copper models for oxygen activation is collected. We have developed m-xylyl linked dicopper systems that mimick structural and reactivity aspects of tyrosinase. Synergistic cooperation of the two copper(I) centers results in O2 binding and formation of bis(μ-oxo)dicopper(III) cores. These in turn bind and ortho-hydroxylate phenolates via an electrophilic attack of the oxo ligand over the arene. Interestingly the bis(μ-oxo)dicopper(III) cores can also engage in ortho-hydroxylation-defluorination of deprotonated 2-fluorophenols, substrates that are well-known enzyme inhibitors. Analysis of Cu2O2 species with different binding modes show that only the bis(μ-oxo)dicopper(III) cores can mediate the reaction. Finally, the use of unsymmetric systems for oxygen activation is a field that still remains rather unexplored. We envision that the unsymmetry might infere interesting new reactivities. We contributed to this topic with the development of an unsymmetric ligand (m-XYL(N3N4)), whose dicuprous complex reacts with O2 and forms a trans-peroxo dicopper(II) species that showed a markedly different reactivity compared to a symmetric trans-peroxo dicopper(II) analog. Nucleophilic reactivity is observed for the unsymmetric trans-peroxo dicopper(II) species against electrophilies such as H(+), CO2 and aldehydes, and neither oxygen atom transfer nor hydrogen abstraction is observed when reacting with oxygen atom acceptors (triphenyl phosphine, sulfides) and substrates with weak C-H bonds. Instead, electrophilic monooxygenase-like ortho-hydroxylation reactivity is described for these unsymmetric species upon reaction with phenolates. Finally, by using a second dinucleating unsymmetric ligand (L(N3N4)), we have described copper(I) containing heterodimetallic systems and explored their O2 binding properties. Site specific metalation led to the generation of dimeric heterometallic M'CuO2CuM' species from intermolecular O2 binding at copper sites.