Cu2O2 Core Research Articles

Experimental Evidence and Mechanistic Description of the Phenolic H-Transfer to the Cu2O2 Active Site of oxy-Tyrosinase.

Tyrosinase is a ubiquitous coupled binuclear copper enzyme that activates O2 toward the regioselective monooxygenation of monophenols to catechols via a mechanism that remains only partially defined. Here, we present new mechanistic insights into the initial steps of this monooxygenation reaction by employing a pre-steady-state, stopped-flow kinetics approach that allows for the direct measurement of the monooxygenation rates for a series of para-substituted monophenols by oxy-tyrosinase. The obtained biphasic Hammett plot and the associated solvent kinetic isotope effect values provide direct evidence for an initial H-transfer from the protonated phenolic substrate to the Cu2O2 core of oxy-tyrosinase. The correlation of these experimental results to quantum mechanics/molecular mechanics calculations provides a detailed mechanistic description of this H-transfer step. These new mechanistic insights revise and expand our fundamental understanding of Cu2O2 active sites in biology.

Counter-Anions Rendered Weak-Interactions Perturb the Stability of Tyrosinase-Mimicked Peroxo-Dicopper(II) Active Site: Unraveling Computational Indicators.

It has been observed in literature that the stability of tyrosinase-mimicked μ-η2 :η2 -peroxo-dicopper(II) (P) can be perturbed in presence of counter-anions (CAs) such as PhCO2 - , CF3 SO3 - , TsO- and SbF6 - . In this work, we unravel computational indicators using density functional theory to screen and study the stability of P in experimentally-reported cases. These indicators are Gibbs energies, geometrical parameters such as distances and angles, independent gradient model based on Hirshfeld partition (IGMH) generated data, orbitals' overlap, and distortion-interaction (DI) energies. Our DFT computed Gibbs energies indicate that P is stable in case of PhCO2 - and TsO- . CF3 SO3 - allows P and its isoelectronic species bis-μ-oxo-dicopper (O) to coexist. SbF6 - shows that O is in excess. Our indicators reveal that the stability of P in case of PhCO2 - and TsO- is due to the better placing of P and its CA, thus leading to better interactions and overlap of orbitals. Other indicator displays that the plane of Cu2 O2 core in P is more bend in PhCO2 - and TsO- cases as compared to the plane in the other two cases. In addition, the IGMH-based indicator displays higher values in the case of PhCO2 - and TsO- than the other CAs.

Calcium-Ion Binding Mediates the Reversible Interconversion of Cis and Trans Peroxido Dicopper Cores.

Coupled dinuclear copper oxygen cores (Cu2 O2 ) featured in type III copper proteins (hemocyanin, tyrosinase, catechol oxidase) are vital for O2 transport and substrate oxidation in many organisms. μ-1,2-cis peroxido dicopper cores (C P) have been proposed as key structures in the early stages of O2 binding in these proteins; their reversible isomerization to other Cu2 O2 cores are directly relevant to enzyme function. Despite the relevance of such species to type III copper proteins and the broader interest in the properties and reactivity of bimetallic C P cores in biological and synthetic systems, the properties and reactivity of C P Cu2 O2 species remain largely unexplored. Herein, we report the reversible interconversion of μ-1,2-trans peroxido (T P) and C P dicopper cores. CaII mediates this process by reversible binding at the Cu2 O2 core, highlighting the unique capability for metal-ion binding events to stabilize novel reactive fragments and control O2 activation in biomimetic systems.

Calcium‐Ion Binding Mediates the Reversible Interconversion of Cis and Trans Peroxido Dicopper Cores

AbstractCoupled dinuclear copper oxygen cores (Cu2O2) featured in type III copper proteins (hemocyanin, tyrosinase, catechol oxidase) are vital for O2 transport and substrate oxidation in many organisms. μ‐1,2‐cis peroxido dicopper cores (CP) have been proposed as key structures in the early stages of O2 binding in these proteins; their reversible isomerization to other Cu2O2 cores are directly relevant to enzyme function. Despite the relevance of such species to type III copper proteins and the broader interest in the properties and reactivity of bimetallic CP cores in biological and synthetic systems, the properties and reactivity of CP Cu2O2 species remain largely unexplored. Herein, we report the reversible interconversion of μ‐1,2‐trans peroxido (TP) and CP dicopper cores. CaII mediates this process by reversible binding at the Cu2O2 core, highlighting the unique capability for metal‐ion binding events to stabilize novel reactive fragments and control O2 activation in biomimetic systems.

Influence of the amine donor on hybrid guanidine-stabilized Bis(μ-oxido) dicopper(III) complexes and their tyrosinase-like oxygenation activity towards polycyclic aromatic alcohols

The tyrosinase-like activity of hybrid guanidine-stabilized bis(μ-oxido) dicopper(III) complexes [Cu2(μ-O)2(L)2](X)2 (L = 2-{2-((Diethylamino)methyl)phenyl}-1,1,3,3-tetramethylguanidine (TMGbenzNEt2, L2) and 2-{2-((Di-isopropylamino)methyl)phenyl}-1,1,3,3-tetramethylguanidine (TMGbenzNiPr2, L3); X = PF6−, BF4−, CF3SO3−) is described. New aromatic hybrid guanidine amine ligands were developed with varying amine donor function. Their copper(I) complexes were analyzed towards their ability to activate dioxygen in the presence of different weakly coordinating anions. The resulting bis(μ-oxido) species were characterized at low temperatures by UV/Vis and resonance Raman spectroscopy, cryo-ESI mass spectrometry and density functional theory calculations. Small structural changes in the ligand sphere were found to influence the characteristic ligand-to-metal charge transfer (LMCT) features of the bis(μ-oxido) species, correlating a redshift in the UV/Vis spectrum with weaker N-donor function of the ligand. DFT calculations elucidated the influence of the steric and electronic properties of the bis(μ-oxido) species leading to a higher twist of the Cu2O2 plane against the CuN2 plane and a stretching of the Cu2O2 core. Despite their moderate stability at −100 °C, the bis(μ-oxido) complexes exhibited a remarkable activity in catalytic oxygenation reactions of polycyclic aromatic alcohols. Further the selectivity of the catalyst in the hydroxylation reactions of challenging phenolic substrates is not changed despite an increasing shield of the reactive bis(μ-oxido) core. The generated quinones were found to form exclusively bent phenazines, providing a promising strategy to access tailored phenazine derivatives.

Spectroscopic evidence of chirality in tetranuclear Cu(II)-Schiff base complexes, catalytic potential for oxidative kinetic resolution of racemic benzoin

Two chiral Schiff base ligands 2-((1-hydroxy-3-phenylpropan-2-ylimino)methyl)-6-methoxyphenol (L1H2 ) and 2-(4-hydroxy-3-isopropylbut-1-enyl)-6-methoxyphenol (L2H2 ) have been synthesized by the condensation of l-phenylalaninol/l-valinol and o-vanillin (2-hydroxy-3-methoxy benzaldehyde). A tetranuclear homometallic Cu(II) complex [Cu4(L1H)2(L1)2] (ClO4)2 (C1) and a hexanuclear heterometallic complex [Cu4(L2)4Na2(DMF)2(H2O)] (ClO4)2 (C2) have been synthesized with the ligands. Both the complexes possess cubane like Cu4O4 core with interesting structural variations and inherit the chirality of their corresponding ligands. The catalytic potential of the complexes has been explored for the oxidative kinetic resolution of racemic benzoin. The electronic, optical and chiroptical properties of the ligands and the complexes have been studied by DFT and TD-DFT calculations.

A novel Cu(II) distorted cubane complex containing Cu4O4 core as the first tetranuclear catalyst for temperature dependent oxidation of 3,5-di-tert-butyl catechol and in interaction with DNA & protein (BSA).

The tri-dentate Schiff base ligand 3-(2-hydroxyethylimino)-1-phenylbut-1-en-1-ol (L) produced the tetra-nuclear Cu(II) distorted cubane complex which contain Cu4O4 core, upon reaction with Cu(II)acetate.H2O. The complex was structurally characterized by X-ray crystallography and found that, in this tetrameric and tetra-nuclear distorted cubane structure, each two-fold deprotonated Schiff base ligand coordinated to a Cu(II) center with their alcoholic oxygens and imine nitrogens and formed six and five-membered chelate rings. At the same time, each ligand bridged to a neighboring Cu(II) atom by its alcoholic oxygen, thus the metal centers became penta-coordinated. The copper(II) complex with μ-ɳ2-hydroxo bridges and Cu….Cu distance about 3 Å was structurally similar to the active site of natural catechol oxidase enzyme and exhibited excellent catecholase activity in aerobic oxidation of 3,5-di-tert-butyl catechol to its o-quinone. The kinetics and mechanism of the oxidation of 3, 5-DTBCH2 catalyzed by [CuL]4 complex, were studied at four different temperatures from 283 to 313K by UV-Vis spectroscopy. Interaction of [CuL]4 complex with FS-DNA was investigated by UV-Vis and fluorescence spectroscopy, viscosity measurements, cyclic voltammetry (CV), circular dichroism (CD) and agarose gel electrophoresis. The main mode of binding of the complexes with DNA was intercalation. The interaction between [CuL]4 complex and bovine serum albumin (BSA) was studied by UV-Vis, fluorescence and synchronous fluorescence spectroscopic techniques. The results indicated a high binding affinity of the complex to BSA. Invitro anticancer activity of the complex was evaluated against A549, Jurkat and Ragi cell lines by MTT assay. The complex was remarkably active against the cell lines and can be a good candidate for an anticancer drug. Theoretical docking studies were performed to further investigate the DNA and BSA binding interactions.

Role of Amino Acid Residues for Dioxygen Activation in the Second Coordination Sphere of the Dicopper Site of pMMO.

Formation of an active oxygen species at the dicopper site of pMMO is studied by using density functional theory (DFT) calculations. The role of the amino acid residues of tyrosine (Tyr374) and glutamate (Glu35) located in the second coordination sphere of the dicopper site is discussed in detail. The phenolic proton of the tyrosine residue is transferred to the Cu2O2 core in a two-step manner via the glutamate residue, and an electron is directly transferred to the Cu2O2 core. These proton- and electron-transfer processes induce the O-O bond cleavage of the μ-η2:η2-peroxodicopper(II) species to form the (μ-oxo)(μ-hydroxo)CuIICuIII species, which is able to play a key role of methane hydroxylation at the dicopper site of pMMO ( Inorg. Chem. 2013 , 52 , 7907 ). This proton-coupled electron-transfer mechanism is a little different from that in tyrosinase in that the proton of substrate tyrosine is directly transferred to the dicopper site ( J. Am. Chem. Soc. 2006 , 128 , 9873 ) because there is no proton acceptor in the vicinity of the dicopper site of tyrosinase. The rate-determining step for the formation of the (μ-oxo)(μ-hydroxo)CuIICuIII species is determined to be the O-O bond cleavage. These results shed new light on the interpretation of the role of the tyrosine and glutamate residues located in the second coordination sphere of the dicopper site of pMMO.

3D supramolecular networks based on hydroxyl-rich Schiff-base copper(II) complexes

Reactions of the Schiff base ligand OH-C6H4-CHNC(CH2OH)3 (H4L) with copper(II) salts in various reaction media afforded complexes [Cu4(H2L)4]·MeOH (1·MeOH), [Cu2(O2CMe)2(H3L)2] (2), [Cu4(H2L)4(H2O)2]·1.5dmf (3·1.5dmf), [Cu4(H2L)4(H2O)]·MeOH (4·MeOH) and [Cu4(H2L)4]2·2H2O·7MeOH (5·2H2O·7MeOH). Compounds 1, 3 and 4 consist of neutral tetranuclear entities in which the CuII ions are coordinated by the tridentate Schiff base ligands, forming a tetranuclear Cu4O4 cubane-like configuration. Compound 5 contains similar cubane-like tetranuclear entities which are further linked through the hydroxyl groups of the ligands thus forming dimers of cubanes. Compound 2 contains a neutral dinuclear entity in which the CuII ions are bridged through the Schiff base and the acetate ligands, comprising distorted Cu2O2 core. The Schiff base ligand adopts five different coordination modes and two deprotonation states in the structures of 1–5 acting simultaneously as chelating and bridging agent between the metal ions. The lattice structures of 1–5 exhibit interesting 3D networks based on hydrogen bonded metal clusters and they are studied with Hirshfeld Surface analysis methods.

Theoretical Study of the Oxidation of Methane to Methanol by the [CuIICuII(μ-O)2CuIII(7-N-Etppz)]1+ Complex

The reactivity patterns of a series of trivalent copper complexes have been studied to gain a better understanding of the chemical reactions occurring at the active site of particulate methane monooxygenase (pMMO). In this study, hybrid density functional theory is used to study the oxidation of methane to methanol mediated by the [CuIICuII(μ-O)2CuIII(7- N-Etppz)]1+ complex. Reaction mechanisms in different spin states were explored. Based on the calculated free-energy profile, a mechanism is suggested for the reaction of the oxidation of methane to methanol. The first step (1 → 2) is a hydrogen transfer to the bridged oxygen in the Cu2O2 core from the methane to form a methyl radical. The second step (2 → 3) is the radical recombination, in which the bridged hydroxyl rotates upward and exposes the oxygen moiety toward the methyl radical to form methanol. The radical recombination step is rate-limiting, with a calculated free-energy barrier of 19.6 kcal mol-1, which is in good agreement with the experimental value of 18.4 kcal mol-1. The mixed valent bis(μ-oxo)CuIICuIII species in the Cu3O4 core is directly responsible for the C-H activation of methane.

Simplest Monodentate Imidazole Stabilization of the oxy-Tyrosinase Cu2 O2 Core: Phenolate Hydroxylation through a Cu(III) Intermediate.

Tyrosinases are ubiquitous binuclear copper enzymes that oxygenate to Cu(II) 2 O2 cores bonded by three histidine Nτ-imidazoles per Cu center. Synthetic monodentate imidazole-bonded Cu(II) 2 O2 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 Cu(II) 2 O2 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 Cu(III) 2 O2 species, where the bonded phenolates hydroxylate to catecholates in high yields. Similar Cu(III) 2 O2 intermediates are not observed using Nπ-bonded Cu(II) 2 O2 species, hinting that Nτ-imidazole ligation, conserved in all characterized Ty, has functional advantage beyond active-site flexibility. Substrate accessibility to the oxygenated Cu2 O2 core and stabilization of a high oxidation state of the copper centers are suggested from these minimalistic models.

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

AbstractTyrosinases 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.

New copper(II) tetramer with arylhydrazone of barbituric acid and its catalytic activity in the oxidation of cyclic C5–C8 alkanes

2-(2-(2,4,6-Trioxotetrahydropyrimidin-5(2H)-ylidene)hydrazinyl)terephthalic acid (H5L) was synthesized by azocoupling of diazonium salts of 2-aminoterephthalic acid with barbituric acid and characterized by IR, 1H and 13C NMR spectroscopies and ESI-MS analysis. In solution and solid state, H5L exists in the hydrazone form. The reaction of H5L with copper(II) nitrate hydrate in methanol affords the tetramer species [Cu2(μ2-1κNOO′:2κO′O″-H3L)2]2 (1) where carboxylate groups bridge two Cu(II) centers in a bridging chelate μ2-(O,O′,O′) fashion, giving rise to a cyclic Cu4O4 core. A rare and intense intermolecular non-covalent interaction of the type Ocarboxylic(lone pair)⋯π(pyrimidine), with O⋯centroid distance of 2.705Å, was found in 1. In addition, medium intense NH⋯O and OH⋯O contacts expand the structure to a 3D network. Compound 1 behaves as efficient catalyst in the mild oxidation, by aqueous H2O2 in acidic MeCN/H2O media, of different cyclic C5–C8 alkanes to produce the corresponding alcohols and ketones. Overall product yields up to ca. 25% (based on alkane) were achieved.

Tetracopper complexes with two-mode cubane-like Cu4O4 core from similar hydroxyl-rich salicylaldehyde Schiff bases: Structure and magnetic properties

The reaction of water-soluble hydroxyl-rich salicylaldehyde Schiff base ligands with the metal salt Cu(OAc)2·H2O affords three novel tetracopper complexes via solvothermal method: [Cu4(H2L1)4]·CH3OH(1), [Cu4(HL2)2(Py)2(OAc)2](2), [Cu4(HL3)2(Py)2(OAc)2](3). The X-ray crystal structures reveal the cubane Cu4O4 for complex 1 with μ3-alkoxo bridges and quasi-stepped cubane Cu4O4 for 2 and 3 bearing two central copper atoms bridged by two alkoxy groups and two peripheral copper atoms bridged with central copper atoms by one another alkoxy oxygen. Temperature-dependent magnetic measurements indicate that the dominant ferromagnetic interactions among metal ions within the cubic core of 1 with J1=+27.44cm−1, J2=−0.21cm−1 (g=2.1157) while there are antiferromagnetic interactions between two metal centers in 3 with J1=−268cm−1, J2=−297cm−1 (g=2.068).

A Binuclear Copper(II) Complex with Diphenoxido-bridges: Synthesis, Characterisation, Crystal Structure and Predicting the Magnetic Coupling Constant

Reaction of copper(II) acetate with 1,1′-[(2,2-dimethylpropane-1,3-diyl)bis(nitrilomethylidyne)]-di-2-naphthol (H2L) gave the diphenoxido-bridged binuclear copper(II) complex [Cu2L2]. Its crystal structure shows a slightly distorted square pyramidal geometry around both of the copper(II) ions. In the symmetric Cu2O2 core, each of the phenoxido bridges occupies an equatorial position around one of the copper(II) centres. A broken symmetry (BS) computation based on density functional theory (DFT) evaluated the magnetic interaction in the complex using the (U)B3LYP level of theory in association with the basis sets LANL2DZ for the copper atoms and 6-31G** for the other atoms. The calculations showed ferromagnetic interaction between the two magnetic copper(II) centres with a magnetic coupling constant (J) of 1.16 cm−1.

Synthesis, Crystal Structures and Magnetic Properties of Three New Polynuclear Cu(II) Complexes Based on the Methoxybenzoate Isomers

In this paper, self-assembly reactions of copper(II) ions, methoxybenzoate isomers and 2,2′-bipyridine yield two copper-oxygen polynuclear complexes: [Cu2(bpy)2(2-C8H7O3)3]·(2-C8H7O3)·14H2O 1, [Cu4(bpy)4(H2O)(OH)4]·4(3-C8H7O3)·17H2O 2, and a simple mononuclear complex [Cu(bpy)(H2O)(4-C8H7O3)2] 3. (bpy = 2,2′-bipyridine, C8H7O3 = methoxybenzoate ion). Single crystal X-ray diffraction analyses reval that compound 1 is a dinuclear copper(II) complex which bridged by three carboxylate groups, and 2 presents a discrete step-like tetra-nuclear copper Cu4O4 core. Compound 3 shows a square pyramidal mononuclear geometry. The magnetic susceptibility of complex 1 measured from 2 to 300 K, revealed an antiferromagnetic interaction between the Cu(II) ions. Furthermore, the results about IR spectra and thermal analyses were discussed.

The Cu2O2 torture track for a real-life system: [Cu2(btmgp)2O2](2+) oxo and peroxo species in density functional calculations.

Density functional theory (DFT) calculations of the equilibrium geometry, vibrational modes, ionization energies, electron affinities, and optical response of [Cu2(btmgp)2(μ-O)2](2+) (oxo) and [Cu2(btmgp)2(μ-η(2):η(2)-O2)](2+) (peroxo) are presented. Comprehensive benchmarking shows that the description of the oxo-peroxo energetics is still a torture track for DFT, but finds the molecular geometry to be comparatively robust with respect to changes in the exchange-correlation functionals and basis sets. Pure functionals favor the oxo core found experimentally, whereas hybrid functionals shift the bias toward the peroxo core. Further stabilization of peroxo core results from relaxing the spin degrees of freedom using the broken-symmetry (BS) approach. Dispersion effects, conversely, tend to favor the oxo configuration. Triple-zeta basis sets are found to represent a sensible compromise between numerical accuracy and computational effort. Particular attention is paid to the modification of the electronic structure, optical transitions, and excited-state energies along the transition path between the oxo and peroxo species. The excited-state potential energy surface calculations indicate that two triplet states are involved in the transition that stabilize the BS solution. Charge decomposition and natural transition orbital analyses are used for obtaining microscopic insight into the molecular orbital interactions. Here, the crucial role of guanidine π-interactions is highlighted for the stabilization of the Cu2O2 core.

New μ-OAC bridged dinuclear copper(II) complex with tridentate Schiff base ligand: Synthesis, characterization, crystal structure, and CuO nano-particles formation

A new (μ-acetato)-bridged dinuclear copper(II) complex [Cu2(L)2(μ-OAc)2] (I) has been synthesized by the reaction of a tridentate N2O Schiff base ligand (HL) with Cu(OAC)2 in methanol at refluxed conditions and characterized by elemental analysis (CHN) and FT-IR spectroscopy. The crystal structure of I was investigated by single-crystal X-ray diffraction (CIF file CCDC no. 1013907). X-ray results showed that two OAC groups bridge the copper(II) ions in a Cu2O2 core of a binuclear complex. Each copper(II) ion adopts a distorted square-pyramidal geometry with one imine nitrogen, one amine nitrogen and one phenolato oxygen from the tridentate Schiff base ligand, completed by two acetate oxygen atoms. Finally, the complex was thermally decomposed in order to obtain CuO nano-particles. The particles were characterized by powder X-ray diffraction, which confirmed the formation of the CuO nano-particles with the average size of 24 nm.

Primary Amine Stabilization of a Dicopper(III) Bis(μ-oxo) Species: Modeling the Ligation in pMMO

Here we report the formation of the first examples of dicopper(III) bis(μ-oxo) complexes ligated by the primary amines, propylenediamine, and N,N,-dimethyl propylenediamine. Stabilization of these new compounds is effected at -125 °C by "core capture"- introduction of exogenous ligand to a preformed dicopper(III) bis(μ-oxo) complex supported by the peralkylated tetramethyl propylenediamine. Primary amine ligation in these compounds matches the single primary amine coordination of the putative active site of particulate methane monooxygenase (pMMO) and polysaccharide monooxygenase. Reactivity studies presented here show primary amine ligated cores are competent oxidants, capable of activating C-H bonds by an H-atom abstraction mechanism. Trends in spectroscopy, structure, and reactivity provide hints to the potential role of primary amine ligation in pMMO: increased substrate accessibility to the redox active orbitals of the Cu2O2 core and greater stabilization of the oxidant without attenuation of oxidizing power.

BOX Ligands in Biomimetic Copper‐Mediated Dioxygen Activation: A Hemocyanin Model

AbstractThe μ‐η2:η2‐peroxodicopper(II) core found in the oxy forms of the active sites of type III dicopper proteins have been a key target for bioinorganic model studies. Here, it is shown that simple bis(oxazoline)s (BOXs), which are classified among the so‐called “privileged ligands”, provide a suitable scaffold for supporting such biomimetic copper/dioxygen chemistry. Three derivatives R,HBOX‐Me2 (R = H, Me, tBu) with different backbone substituents have been used. Their bis(oxazoline)‐copper(I) complexes bind dioxygen to yield biomimetic μ‐η2:η2‐peroxodicopper(II) species. O2 can be reversibly released upon an increase in temperature. Their formation kinetics have been studied under cryo‐stopped‐flow conditions for the tBu derivative, giving activation parameters ΔH‡on = (2.27 ± 0.18) kcal mol–1, ΔS‡on = (–46.3 ± 0.8) cal K–1 mol–1 for the binding event and ΔH‡off = (11.7 ± 1.9) kcal mol–1, ΔS‡off = (–16.1 ± 8.2) cal K–1 mol–1 for the release of O2, as well as thermodynamic parameters ΔH° = (–10.0 ± 1.7) kcal mol–1 and ΔS° = (–32.7 ± 7.4) cal K–1 mol–1 for this equilibrium. The μ‐η2:η2‐peroxodicopper(II) complexes have been isolated as surprisingly stable solids and investigated in depth by a variety of methods, both in solution and in the solid state. Resonance Raman spectroscopy revealed a characteristic isotope‐sensitive stretch $\tilde {\nu}$O–O = 731–742 cm–1 (Δ[18O2] ≈ –39 cm–1) and an intense feature around 280 cm–1 diagnostic for the fundamental symmetric Cu2O2 core vibration. A slight butterfly‐shape of the Cu2O2 core has been derived from EXAFS data and DFT calculations. SQUID magnetic data evidenced strong antiferromagnetic coupled CuII2 (–2J ≥ 1000 cm–1). Thermal degradation in solution yields bis(hydroxo)‐bridged [(tBu,HBOX‐Me2)(L)Cu(OH)]2(PF6)2 (L = H2O, MeCN or THF); whereas in the case of H,HBOX‐Me2, ligand oxygenation has been detected. Preliminary reactivity studies with the substrate 2,4‐di‐tert‐butylphenol indicate the formation of the C–C coupling product 3,3′,5,5′‐tetra‐tert‐butyl‐2,2′‐biphenol, whereas ortho‐hydroxylation was not observed. The copper(I) complex [(tBu,HBOX‐Me2)Cu(MeCN)]PF6 as well as two dicopper(II) complexes [(L)(tBu,HBOX‐Me2)Cu(OH)]2(PF6)2 have been characterised by single‐crystal X‐ray diffraction. Considering the vast number of known BOX derivatives, a rich and versatile Cu/O2 chemistry based on this platform is anticipated.