Copper(I)-Dioxygen Adducts and Copper Enzyme Mechanisms

Abstract

Primary copper(I)-dioxygen (O₂) adducts, cupric-superoxide complexes, have been proposed intermediates in copper-containing dioxygen-activating monooxygenase and oxidase enzymes. Here, mechanisms of C-H activation by reactive copper-(di)oxygen intermediates are discussed, with an emphasis on cupric-superoxide species. Over the past 25 years, many synthetically derived cupric-superoxide model complexes have been reported. Due to the thermal instability of these intermediates, early studies focused on increasing their stability and obtaining physical characterization. More recently, in an effort to gain insight into the possible substrate oxidation step in some copper monooxygenases, several cupric-superoxide complexes have been used as surrogates to probe substrate scope and reaction mechanisms. These cupric superoxides are capable of oxidizing substrates containing weak O-H and C-H bonds. Mechanistic studies for some enzymes and model systems have supported an initial hydrogen-atom abstraction via the cupric-superoxide complex as the first step of substrate oxidation.

Keywords: copper; cupric superoxide; dioxygen activation; enzymes; monooxygenase mechanisms.

Figure 1

A) X-ray structure of the oxy-form of PHM.^[13] B) Catalytic reactions of copper-containing monooxygenases PHM, DβM, and TβM.^[7]

Figure 2

A) X-ray structure of the LPMO-AA9 from T. aurantiacus.^[20] B) Schematic of the copper active sites observed in LPMOs AA9^[20] and AA10^[21] (Cu(II) with two coordinated water ligands) and AA11^[18] and AA13^[22] (reduced Cu(I)). AR=amino acid residue. C) Glycosidic bond cleavage via hydroxylation at either the C1 or C4 position in cellulose by LPMOs.^[8]

Figure 3

A) X-ray structure of a GO and its enzymatic reaction.^[24] B) X-ray structure of an AO and its enzymatic reaction.^[25]

Figure 4

A) Crystal structure^[50] and UV-Vis spectrum of [Cu^II(TMG₃tren)(O₂^•−)]⁺ (TMG₃tren = tris(tetramethylguanidine)tri-ethyleneamine). B) Crystal structure and UV-Vis spectrum of [Cu^II(HB(3-^tBu-5-ⁱPrpz)₃(O₂^•−)] (HB(3-^tBu-5-ⁱPrpz)₃ = tris(3-tert-butyl-5-iso-propylpyrazolyl)hydroborate.^[49]

Figure 5

The chelating polydentate synthetically derived ligands utilized in the complexes of Table 1.

Figure 6

Secondary dioxygen adducts formed with N₂S and ^DMMN₃S ligands.^[79,80,85]

Scheme 1

Reaction pathways proposed in the catalytic mechanism of copper-containing monooxygenase enzymes (PHM, DβM and LPMOs).

Scheme 2

Primary and secondary dioxygen adducts formed from addition of O₂ to ligand-Cu^I mononuclear compounds. Binuclear LCu^II₂(O₂²⁻) complexes may possess trans-µ-1,2-peroxide, cis-µ-1,2-peroxide (with an additional 2^nd bridging ligand) or side-on µ-η²:η²-peroxide structures. The ligand (L) may also favor a form in which the copper ions each provide an additional electron, giving rise to a bis-µ-oxo-dicopper(III) structural form.

Scheme 3

Substrate oxidation performed by synthetic cupric-superoxide model complexes.

Scheme 4

Reactivity of [Cu^II(TMG₃tren)(O₂^•−)]⁺ with phenol and acid/reductant.

Scheme 5

Nucleophilic reactivity of [Cu^II(PDCA)(O₂^•−)]⁻.^[91]

Scheme 6

Comparison of Hammett reactivity studies done for: A) DβM;^[94] and B) PEDACO-EtPh-R^[68] cupric-superoxide complexes.