Observation of a Cu(II)₂(μ-1,2-peroxo)/Cu(III)₂(μ-oxo)₂ Equilibrium and its Implications for Copper-Dioxygen Reactivity

Abstract

Synthesis of small molecule Cu₂O₂ adducts has provided insight into the related biological systems and their reactivity patterns including the interconversion of the Cu^II₂(μ-η²:η²-peroxo) and Cu^III₂(μ-oxo)₂ isomers. In this study, absorption spectroscopy, kinetics, and resonance Raman data show that the oxygenated product of [(BQPA)Cu^I]⁺ initially yields an “end-on peroxo” species, that subsequently converts to the thermodynamically more stable “bis-μ-oxo” isomer (K_eq = 3.2 at −90 °C). Calibration of density functional theory calculations to these experimental data suggest that the electrophilic reactivity previously ascribed to end-on peroxo species is in fact a result of an accessible bis-μ-oxo isomer, an electrophilic Cu₂O₂ isomer in contrast to the nucleophilic reactivity of binuclear Cu^II end-on peroxo species. This study is the first report of the interconversion of an end-on peroxo to bis-μ-oxo species in transition metal-dioxygen chemistry.

Dioxygen binding and activation by hemocyanin, catechol oxidase, tyrosinase, and hydroxy-anilinase^[1] have inspired exploration of the preparative chemistry and structure-function correlations of small molecule Cu₂O₂ adducts.^[2] Only the “side-on peroxo” (Cu^II₂(μ-η²:η²-peroxo)) binding motif has been observed in these enzymes,^[1] while two additional structural types are commonly found in small molecule adducts: “end-on peroxo” (Cu^II₂(μ-1,2-peroxo)) and “bis-μ-oxo” (Cu^III₂(μ-oxo)₂) isomers (Figure 1).^[2] The side-on peroxo and bis-μ-oxo species have been found to be in equilibrium, suggesting the possibility of either functioning as the electrophile in tyrosinase that o-hydroxylates phenol during catalysis. Indeed, both mechanistic possibilities are supported by model studies^[3] In contrast, the end-on peroxo species typically behaves as a nucleophile.^{[2d, 4]}

Figure 1.

Cu₂O₂ isomers.

Thus, we were intrigued by a recent report of phenolate ortho-hydroxylation by an end-on peroxo adduct,^[5] a reaction otherwise believed to proceed via electrophilic aromatic substitution.^{[3a, 3d]} This led us to consider the possible involvement of an unobserved bis-μ-oxo species that possesses the electrophilic character needed to affect a phenol-to-catechol conversion. Depar

Presented here is a reevaluation of the chemistry of a binuclear Cu₂(O₂) complex that employs the tripodal amine scaffold, bis(2-quinolylmethyl)-(2-pyridylmethy1)amine (BQPA, Figure 2),^[7] that explicitly demonstrates, for the first time, an end-on peroxo to bis-μ-oxo equilibrium, deduced from UV/Vis and resonance Raman (rR) spectroscopies. The calibration of density functional theory (DFT) calculations to experimental thermodynamic data support involvement of a bis-μ-oxo rather than an end-on peroxo species as the electrophile in the reported^[5] phenolate hydroxylation.

Figure 2.

Ligand scaffolds.

Following earlier investigations into the O₂-reactivity of [(BQPA)Cu^I]PF₆ in EtCN,^[7–8] Figure 3 illustrates the UV-Vis spectroscopic progression of the reaction of [(BQPA)Cu^I]B(C₆F₅)₄ 1 with O₂ in THF. Initially, complex 2 with 545 and 620 (sh) nm features forms rapidly and has a similar absorption spectrum to those of previously characterized end-on peroxo species.^[9] Within a few seconds, 2 begins converting to species 3 with an intense 380 nm band. However the transformation is not complete, but rather approaches an equilibrium mixture of 2 and 3 in approximately a 1:3 ratio.

Figure 3.

Time-dependent UV-vis spectra (207 s) for the oxygenation of [(BQPA)Cu^I]⁺ 1 in THF at –98.6 °C and absorbance–time traces at 380 nm and 550 nm (insert). Initially, the 370 nm band of 1 decays as the spectral features of 2 forms (—) followed by the decay of 2 and the growth of 3 (- -).

The structure of the oxygenated species 2 and 3 were further probed by rR spectroscopy. Excitation of a solution that contains mostly 2 with 568 nm laser radiation resulted in the observation of four apparent oxygen isotope sensitive features clustered in two distinct regions, 835 cm⁻¹ and 821 cm⁻¹ (¹⁸O₂: 793 cm⁻¹ and 777 cm⁻¹) and 542 cm⁻¹ and 504 cm⁻¹ (¹⁸O₂: 521 cm⁻¹ and 488 cm⁻¹, Figure 4). The former region is consistent with the intraperoxide stretch (νO—O) and the later is consistent with metal-ligand stretch (νCu—O) of an end-on peroxide core.^[9–10] Excitation of a frozen solution of mostly 3 with 380 nm laser light enhanced an oxygen isotope sensitive feature at 584 cm⁻¹ (¹⁸O₂: 560 cm⁻¹) (Figure 5).

Figure 4.

Resonance Raman spectra of 2, prepared with natural abundance O₂ (—) and ¹⁸O₂ (—) with 568 nm excitation in THF. Inset: Spectrum scaled 5X

Figure 5.

Resonance Raman spectra of 3 prepared with natural abundance O₂ (—) and ¹⁸O₂ (—) with 380 nm excitation in THF.

Based on its energy and isotope shift, this feature is assigned as the symmetric νCu—O breathing mode of a bis-μ-oxo species; a similar rR spectrum was observed for the crystallographically characterized [{(Me₂tpa)Cu^III}₂(μ-O)₂]²⁺ (Figure 2).^[11] These results indicate that the two oxygenated products of [(BQPA)Cu^I]⁺ that are in equilibrium are an end-on peroxo (2) and a bis-μ-oxo species (3) (Figure 6).^[12]

Figure 6.

End-on peroxo/Bis-μ-oxo isomerization.

The detailed assignment of the rR spectra of 2 is complicated by the observation of two νO—O features. This suggested the presence of two peroxo adducts, attributed to the non-symmetric BQPA ligand that would lead to two possible orientations of the pyridyl substituent in the interdigitated dimer (Figure 6), C₁ symmetric “syn” (2^syn) and overall C_i symmetric “anti” (2^anti) that contains a C_2h Cu₂O₂ core. DFT calculations on these two isomers indicate that 2^anti is favored by ~3 kcal (Supporting Information, Table S9). Group theory considerations predict that in the effective

C_2h symmetry (2^anti), only the νCu—O_sym vibration transforms as A_g and would be allowed, whereas in C₁ symmetry (2^syn) both νCu—O_sym and νCu—O_antisym transform as A leading to a total of three expected features in the metal ligand stretching region. For the Cu–O region, two transitions with comparable intensity are observed (Figure 4). In other end-on peroxo complexes, two metal-ligand features are observed and are assigned as dimer νCu—O_sym and dimer νCu—O_antisym bands at higher and lower energy respectively, with the symmetric stretch enhanced relative to the weaker antisymmetric stretch.^{[6a, 13]} In the rR spectrum of 2, the lower energy metal-ligand feature is more intense than the higher energy feature, inconsistent with a simple assignment as the νCu—O_antisym stretch. Bandshape analysis of the oxygen isotope sensitive features in the metal ligand stretching region are best fit by three bands with the same bandwidth at 542 cm⁻¹, 512 cm⁻¹ and 491 cm⁻¹ giving an intensity ratio of 1.0:1.0:0.8. Analytical frequency calculations from the DFT structures (see Supporting Information) indicate that the 835 cm⁻¹ and 542 cm⁻¹ features correspond to 2^anti (the νO—O and νCu—O_sym, respectively) while the 821 cm⁻¹, 512 cm⁻¹, and 491 cm⁻¹ features arise from 2^syn (the νO—O, νCu—O_sym, and νCu—O_antisym, respectively).

Additional quantitative information on the nature of the end-on peroxo/bis-μ-oxo equilibrium was determined from modeling stopped-flow kinetics data of the reaction of [(BQPA)Cu^I]B(C₆F₅)₄ with dioxygen.^[14] Fitting the observed spectral changes (Figure 1) to the simplest, sequential model of 1 ⇌ 2 ⇌ 3 (Scheme S1) yields spectra that are inconsistent with the absorption spectra of a pure trans-peroxo or bis-μ-oxo species (Figure S1). Inclusion of an additional pathway where 1 can also convert directly to 3 in a parallel kinetic model (Scheme 1) remedies the kinetically derived spectra (Figure S1). While both species form simultaneously at the very early stages of the reaction, the formation of the trans-peroxo is preferred by an order of magnitude (i.e., k₁ > k₂) and at equilibrium roughly 85% of 3 is formed from 2. As indicated in Scheme 1 and substantiated by the corresponding Eyring plots with varying initial concentrations of [(BQPA)Cu^I]⁺ (1) and O₂ (Figures S2), these initial reactions are second order in 1 and first order in O₂ for both the formation of 2 and 3. Subsequently, 2 is converted in a first order reaction (k₃) to the more thermodynamically stable bis-μ-oxo species 3; this transformation is zero order in [(BQPA)Cu^I]⁺. The same is true for the back reaction k_-3 from 3 to 2 (K_EQ = k₃/k_-3 = 3.2 at –90 °C; Table 1). Further, thermodynamic parameters for the parallel kinetic model (Scheme 1) were determined indicating that the formation of the bis-μ-oxo from the trans-peroxo is slightly exergonic (ΔH = −0.64 ± 0.07 kcal/mol, ΔS = 5.7 ± 0.3 cal/mol·K).

Scheme 1.

Parallel kinetic model.

Table 1.

Rates and thermodynamic parameters for the reactions in Scheme 1.

	k (−90 °C)	ΔH‡ (kcal/mol)	ΔS‡ (cal/mol·K)
k1 (M−2s−1)	(4.3 ± 0.4) × 105	−1.4 ± 0.1	−39.4 ± 0.5
k2 (M−2s−1)	(5.9 ± 0.2) × 104	−1.9 ± 0.2	−46 ± 1
k−2 (s−1)	(3 ± 2) × 10−5	17.0 ± 0.5	15 ± 3
k3 (s−1)	(1.6 ± 0.1) × 10−1	10.94 ± 0.05	−1.4 ± 0.2
k−3 (s−1)	(5.0 ± 0.2) × 10−2	10.29 ± 0.05	−7.2 ± 0.2

We sought to computationally model these thermodynamic results by surveying the functional dependence of the end-on peroxo/bis-μ-oxo equilibrium. We also included a series of related copper-dioxygen adducts in the modeling, since TMPA and BPQA yield trans-peroxo species as the thermodynamic product while Me₂tpa (like BQPA) yields a bis-μ-oxo as the thermodynamic product (Figure 2).^{[8–9, 11]} Of the tested methods, BLYP, BP86, mPWPW91, PBE, and TPSSh correctly predicted Me₂tpa and BQPA to form bis-μ-oxo species and for BPQA and TMPA, end-on peroxo adducts were energetically favored.

This calibrated computational methodology was then applied to the binuclear “end-on” copper-dioxygen complex [Cu₂(O₂)(m-Xyl^N3N4]²⁺ (4) (Figure 2) that was recently reported to perform the ortho-hydroxylation of 4-methyl-phenolate.^[5] Attribution of this electrophilic reactivity to an end-on peroxo core is significant because it contradicts a sizeable pool of literature that suggests this structural type displays nucleophilic reactivity.^{[2d, 4]} These calibrated computational methods indicate that a bis-μ-oxo isomer of 4 is in fact energetically accessible. This is in contrast to the DFT calculations reported in reference [5] which suggested that a bis-μ-oxo isomer was ~40 kcal higher in energy. Our calculations differed from the previous report in two major respects. First, using the computational methodology reported in reference [5], we found an alternative structure of the putative bis-μ-oxo species that was ~15 kcal more favorable due to equatorial coordination of the amine ligand (Table S10). Second, the experimentally calibrated methodology developed in this report indicates that the bis-μ-oxo isomer of 4 is within ~2 kcal/mol of the end-on peroxo isomer (Table S12). This is in contrast to the DFT methodology in reference [5] that predicts that the bis-μ-oxo is 25 kcal/mol higher than the end-on peroxo. Thus while experimental data in reference [5] indicate that 4 is an end-on peroxo, the calibrated DFT calculations presented here indicate that a bis-μ-oxo isomer is energetically accessible.^[15] The reaction coordinate for electrophilic aromatic substitution of 4-methyl-phenolate was thus revaluated using the improved ligand geometries and calibrated method (TPSSh is shown in Figure 7). The bis-μ-oxo was found to have both a larger driving force and a lower barrier to ortho-hydroxylation than the end-on peroxo despite being slightly higher in energy in the absence of an interaction with 4-methylphenolate (2 kcal/mol). Our present experimental findings with BQPA provide precedent that the end-on species 4 can convert to a bis-μ-oxo species, which is computationally capable of performing the electrophilic aromatic substitution observed experimentally for the m-Xyl^N3N4 system.

Figure 7.

Computational evaluation of electrophilic aromatic substitution by a end-on peroxo (—) and bis-μ-oxo (—) of 4.

In conclusion, analysis of the oxygenation of [(BQPA)Cu^I]⁺, utilizing rR spectroscopy, kinetics analyses, and DFT calculations has led to the observation of an end-on peroxo/bis-μ-oxo equilibrium, featuring formation of the end-on peroxo isomer followed by its conversion to the thermodynamically more stable bis-μ-oxo species (Scheme 1, K_eq = 3.2 at −90 °C); a first in transition metal-dioxygen chemistry. This equilibrium sheds light into the reactivity patterns in Cu₂O₂ chemistry, and strongly suggests that the nucleophilic reactivity pattern of end-on peroxo species holds, in contrast to the recent literature wherein electrophilic reactivity has been proposed.

Experimental Section

BQPA was synthesized as previously reported^[7] and metalated with [Cu^I(CH₃CN)₄]B(C₆F₅)₄ to form [Cu^I(BQPA)](BC₆F₅)₄ (See Supporting Information). Low temperature stopped-flow kinetics were carried out as previously described and for numerical analysis, all data were pretreated by factor analysis and concentration profiles were calculated by numerical integration.^{[8, 16]} rR samples were prepared by adding dioxygen to solutions of [Cu^I(BQPA)](BC₆F₅)₄ in dry, degassed THF (See Supporting Information for details). DFT calculations were performed using Gaussian03.^[17] Molecular structures were optimized using the B3LYP functional within the spin-unrestricted formalism on an ultrafine integration grid. The basis sets employed on Cu, O, and N were of triple-ζ quality with polarization (6–311g*). A double-ζ quality, split-valence basis was used on all other atoms (6–31g*). The functional dependence of the end-on peroxo/bis-μ-oxo equilibrium was determined from solvated single point energies (PCM model in THF) for the tested functionals (BLYP, BP86, mPWPW91, PBE, TPSSh, B3LYP, BMK, M06, M06-L, mPW1PW91, τHCTH, TPSS, VSXC) with the same basis set and B3LYP thermal correction at −80 °C.