Structural and Reactivity Models for Copper Oxygenases: Cooperative Effects and Novel Reactivities

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Dioxygen is widely used in nature as oxidant. Nature itself has served as inspiration to use O-2 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 O-2 by reducing it to more reactive peroxide (O-2(2-)) or superoxide (O-2(-)) forms. Over the years, the development of model systems containing transition metals has become a convenient tool for unravelling O-2-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 O-2-activating enzyme, whose structure and reactivity have been widely studied, and that serves as a paradigm for O-2 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 O-2 binding and formation of bis(mu-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(mu-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(mu-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-XYLN3N4) whose dicuprous complex reacts with O-2 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 O-2 binding properties. Site specific metalation led to the generation of dimeric heterometallic M'CuO2CuM' species from intermolecular O-2 binding at copper sites. ​
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