Mononuclear Cu/O₂ Complexes

Abstract

Using interwoven experimental and theoretical methods, detailed studies of several structurally defined 1:1 Cu/O₂ complexes have provided important fundamental chemical information useful for understanding the nature of intermediates involved in aerobic oxidations in synthetic and enzymatic copper-mediated catalysis. In particular, these studies have shed new light onto the factors that influence the mode of O₂ coordination (end-on vs. side-on) and the electronic structure, which can vary between Cu(II)-superoxo and Cu(III)-peroxo extremes.

Introduction

Numerous aerobic oxidations performed by biological¹ and synthetic² metal catalysts use copper, which is particularly well-suited for this purpose because of a favorable combination of redox and coordination chemistry properties. A common, fundamentally important reaction step is the seemingly simple interaction of O₂ with a Cu(I) site to yield a Cu/O₂ species that is activated toward O-O bond scission or attack at an organic substrate. Understanding the nature of Cu/O₂ species and the mechanisms of their generation thus represents a significant research goal, towards which extensive studies of the reactions of Cu(I) complexes with O₂ have been aimed.³ For the most part, these studies have focused on (μ-peroxo)- or bis(μ-oxo)dicopper complexes that result from trapping of initially formed 1:1 Cu/O₂ adducts by a second equivalent of the Cu(I) reagent (Scheme 1). Because of the rapidity of this trapping reaction and/or the thermodynamic stability of the resulting dicopper species, the 1:1 adducts generally have only been observed as fleeting intermediates in low temperature stopped-flow kinetic studies of Cu(I)-complex oxygenations.^3,4 Recently, however, several examples of such 1:1 adducts have been isolated as crystalline solids and characterized in detail via experiment and theory, thus providing new insights into geometric, spectroscopic, electronic structural, and reactivity properties. We summarize this work herein, with a specific view toward comparing and contrasting the properties of structurally defined CuO₂ moieties and evaluating how these properties depend on the nature of the ancillary supporting ligands (for complementary perspectives, see refs. ³ and ⁵). Possible implications for understanding copper-promoted aerobic oxidations in biology and catalysis are then discussed.

Scheme 1.

Synthesis and Structures

Use of low temperatures and suitably sterically hindered supporting ligands to inhibit decomposition and dicopper complex formation were key to the successful isolation and structural characterization of the 1:1 Cu/O₂ adducts shown in Figure 1. Complexes 1,⁶ 3,^7,8 and 4⁹ feature side-on (η²) coordination of the O₂ fragment, whereas it is bound end-on (η¹) in 2.¹⁰ Comparison of the core geometries of 1a, 2, and 4 (Figure 2) reveals significant differences in metal-ligand and O-O bond distances that are indicative of different oxidation levels for the Cu ion and the O₂ moiety. In 1a and 2, the Cu-N,O distances and geometries are typical for Cu(II) compounds. The O-O distances fall in the range characteristic of superoxide complexes (∼1.2-1.3 Å),¹¹ the value of 1.22(3) Å for 1a being so short as to be similar to that of free O₂ (1.21 Å). Indeed, vibrational spectroscopic data and results from theory (see below)^12,13 suggest that this distance is underestimated in the X-ray structure of 1a, perhaps due to librational disorder of the O₂ moiety like that identified in an analogous cobalt complex.^12,14 In 4, an O-O distance of 1.392(3) Å, which is significantly longer than those in 1a and 2, is consistent with a peroxide assignment (typical O-O = ∼1.4 Å).¹¹ In addition, a comparison of the Cu-N distances in 4 to those of a range of 4-coordinate (β-diketiminate)Cu(II) complexes revealed those in 4 to be generally shorter, supporting a Cu(III) formulation.⁸ The CuO₂ core parameters of 3a from EXAFS experiments¹³ and 3b from X-ray crystallography are similar to those of 4 (e.g. for 3b, O-O = 1.39(1) Å), but detailed interpretation of the data for 3b was limited by disorder problems. In sum, the X-ray crystal structures clearly differentiate between the end-on and side-on O₂ binding modes and suggest, at least to first order, that 1a and 2 may be considered as Cu(II)-superoxides, whereas 3 and 4 may be formulated as Cu(III)-peroxides. To further evaluate these oxidation level assignments and CuO₂ core bonding, detailed spectroscopic and theoretical studies were required, the results of which are described below.

Figure 1.

1:1 Cu/O₂ complexes, of which all except 1b and 3a have been structurally defined by X-ray crystallography.

Figure 2.

Cores of 1:1 Cu/O₂ adducts determined by X-ray crystallography, with atoms as arbitrary spheres (1a) or 50% thermal ellipsoids (2 and 4) and selected bond distances (Å) and angles (deg) indicated. Atom color scheme: Cu, green; N, blue; O, red.

Electronic Structure and Bonding

(a) Cu and O₂ fragment oxidation states

Among the various experimental data that may be used to understand the electronic structure of the 1:1 Cu/O₂ adducts, the O-O stretching frequency (ν(O-O)) and the edge features in X-ray absorption spectra (XAS)^13,15 are especially informative for ascertaining the O-O bond order and the Cu oxidation state, respectively (Table 1). The ν(O-O) values for 1a,b¹⁶ and 2¹⁷ are similar to those usual for superoxide complexes (∼1075-1295 cm^-1),^11,18 whereas the values for 3a,b^7,19 and 4⁹ are significantly lower, albeit above the region typical for peroxides (∼750-930 cm^-1). Such intermediate values have been noted previously for metal/O₂ adducts,^11,18 and the existence of a “more or less continuous range of values”^11c that span 700-1300 cm^-1 for such species has been noted.²⁰ To better place the ν(O-O) data for 1-4 into perspective, we previously presented a correlation between these values and the associated O-O distances that was applicable to a range of side-on metal/O₂ adducts characterized both via theory and experiment, and included simple oxygen species such as O₂, O₂^-, and O₂^2-.¹² This correlation is better expressed by recourse to Badger’s rule (eq. 1),²¹ an

$$r_e=\frac{C_{ij}}{{\nu }_e^{2∕3}}+d_{ij}$$ (1)

empirical relation between an equilibrium internuclear distance (r_e) and the associated stretching frequency (ν) that has been applied with success recently in analyses of Fe-O and S-S bonding.^22,23 Here we apply it to a greater range of compounds than analyzed in ref. 12, yet limited to side-on metal/O₂ adducts excepting 2 and some simple oxygen species uncoordinated to any metal. The data (listed in supporting information Table S1) are plotted as O-O distance vs. 1/ν^2/3 in Figure 3, and are in good agreement with a linear fit to eq. 1 giving C = 70.7 and d = 0.671 with R² = 0.96. This fit excludes the experimental data point for 1a, which is deemed an outlier due to its unreasonably short O-O distance equivalent to that of free O₂.

Table 1.

Selected structural and spectroscopic data

Compound	O-O distance, Å	ν(O-O), cm-1 (Δ18O)	K-edge 1s → 3d, eV	L3-edge 2p→ 3d, eV	Ref
1a	1.22(3)	1112 (52)	-	-	6,16
1b	-	1043 (59)	8978.6	930.8	13,16
2	1.280(3)	1117 (58)	-	-	10,17
3a	-	968 (51)	8980.7	932.7	13,19
3b	1.39 (1)	961 (49)	-	-	7
4	1.392(3)	974 (66)	-	-	9
La2Li1/2Cu1/2O4	-	-	-	932.8	13
[(TMPA)Cu(OH2)]2+	-	-	-	930.8	9
[(Me3tacn)2Cu2(μ-OH)2]2+			8978.7		15
[(Me3tacn)2Cu2(μ-O)2]2+	-	-	8980.5	-	15

Figure 3.

Plot of O-O distance (Å) vs. 1/ν^2/3 (cm^2/3) for a range of side-on MO₂ complexes and H₂O₂, O₂^-, O₂, and O₂⁺. Experimental and calculated data are shown as blue circles and black squares, respectively, and are listed in Table S1. The data for complexes 1a, 2, 3b, and 4 are labeled, with a parenthetical “t” denoting values calculated via theory. The line is a fit to eq. 1 (see text).

In further studies aimed at defining the electronic structures of the similarly side-on bound adducts 1b and 3a, a direct experimental comparison of their Cu oxidation states was accomplished through X-ray absorption spectroscopy (Table 1).¹³ Both the K- and L₃-pre-edges for 1b were ∼2 eV lower than those for 3a, supporting their respective assignments as Cu(II) and Cu(III) complexes. Accentuating this point, the pre-edge 1s → 3d energy for 1b falls into the range observed for a set of bona fide Cu(II) complexes (8978.8 × 0.4 eV),^15,24 whereas that for 3a is similar to those of other Cu(III) compounds (8981 ± 0.5 eV; cf. data for [(Me₃tacn)₂Cu₂(μ-OH)₂]²⁺ and [(Me₃tacn)₂Cu₂(μ-O)₂]²⁺ in Table 1).¹⁵ Similar comparisons of L₃-edges (2p→ 3d transitions) are even more striking due to the high resolution of L-edge data (Figure 4).²⁵ In general, differences in XAS edge energies may be traced to different charges at the absorbing atom (Q) and/or ligand fields (LF).²⁶ On the basis of calculations and correlations to XPS data, LF contributions were deemed to dominate the XAS edge energy disparities between 1b and 3a, with the Q for the Cu(III) site in 3a being essentially the same as the Cu(II) center in 1b because of compensation by the strongly electron donating β-diketiminate ligand.¹³

Figure 4.

Normalized Cu XAS data showing the ∼2 eV difference between the L₃-edge transition energies for 1b and the Cu(II) complex [(TMPA)Cu(OH₂)]²⁺ vs. those for 3b and the Cu(III) compound La₂Li_1/2Cu_1/2O₄. Adapted from ref. 13.

Computational studies on Cu- and other metal-O₂ complexes have been particularly useful in defining geometrical and electronic structural features having a bearing on oxidation state. As depicted in Figure 3, the theoretical data (all of which derive from density functional calculations with the mPWPW91 functional²⁷ and basis sets of polarized double- to triple-ζ quality) follow Badger’s rule particularly well and are in excellent agreement with experiment in most instances. In cases of disagreement, challenges associated with librational motion and structural disorder may render the experimental data less reliable than the theoretical (cf. 1a, as noted above).¹² The theoretical and experimental data taken together comprise a collection of bond lengths and vibrational frequencies that smoothly span the range from superoxide-like to peroxide-like, and this smooth progression suggests that the assignment of standard “integer” metal and O₂-fragment oxidation states is not necessarily a straightforward procedure—covalent character in the metal-O₂ bonding leads to species that may be regarded as valence-bond hybrids of the limiting superoxide and peroxide extremes.

The covalent communication between the metal and O₂ fragment and its impact on apparent oxidation state has been analyzed in detail for a simplified model of 3 as illustrated in Figure 5.²⁸ The 11b₂ and 12b₂ orbitals are bonding and antibonding combinations of the in-plane O₂ π* orbital and the Cu d_xz orbital (taking the z axis as the C_2v symmetry axis and the x axis as parallel to the O-O bond vector). In the singlet state, the 3a₂ out-of-plane O₂ π* orbital is empty (it is singly occupied in the higher energy triplet state), and multiconfigurational treatments predict that the singlet ground state is well represented by

$${}^1\mathrm{A}_1=c_1\mid \mathrm{L}11b_2^2\rangle -c_2\mid \mathrm{L}12b_2^2\rangle$$ (2)

where c₁ and c₂ are configuration weights that indicate the relative importance of each determinant and ensure normalization. When the diketiminate ligand is rendered poorly electron donating by fractionally increasing the atomic charge of the nitrogen atoms (or by changing a backbone carbon nucleus to nitrogen; data not shown), c₁ and c₂ are found to be roughly equal in magnitude such that the 11b₂ and 12b₂ orbitals may be considered to be similarly populated. Algebraically, this situation is equivalent to a 2-electron in 2-orbital open-shell singlet, where the 2 orbitals are formed from positive and negative linear combinations of 11b₂ and 12b₂. In this case, those linear combinations correspond to an isolated Cu d_xz orbital and an isolated O₂ π* orbital, which would be the ionic valence bond picture associated with a classic Cu(II) superoxide species. Consistent with this analysis, the O₂ bond length is predicted to be in the shorter range typical of a superoxide. As the electron donating character of the ligand is increased by fractionally decreasing the nitrogen nuclear charge (or changing a backbone carbon nucleus to boron; data not shown), the opposite effect is observed. The ratio of c₁ to c₂ becomes large and the 11b₂ orbital simultaneously localizes more heavily on the O₂ fragment. The resulting closed-shell wave function corresponds to a Cu(III)-peroxide species and consistent with this picture the O₂ bond length is predicted to be correspondingly long. Variation between these two extremes proceeds smoothly with variation in nitrogen nuclear charge (Figure 5), illustrating the degree to which covalent communication mediates charge flow and the ligand influences the Cu-O₂ interaction. It is noteworthy that the distance between the Cu and O₂ fragment is not particularly sensitive to variation in the ligand’s electron donating capabilities, in contrast to a prior suggestion.²⁹

Figure 5.

Calculated frontier molecular orbitals for the simplified (b-diketiminate)CuO₂ complex shown, with a plot of Cu-O (red) and O-O (blue) distances as a function of the charge on the N-donor atoms. Adapted from ref. 28.

(b) End-on vs. Side-on Coordination

In addition to the assignment of the Cu and O₂ fragment oxidation states, a separate structural feature of key interest is the mode of O₂ binding to Cu. While side-on coordination dominates among the complexes shown in Figure 1, end-on bonding has been identified by X-ray crystallography in the active site of peptidyl α-hydroxylating monooxygenase (PHM)³⁰ and in 2, and it has been suggested on the basis of spectroscopic data for several complexes that have not been structurally characterized.^31,32 Determining the factors that influence the O₂ binding mode is an important research objective, especially in view of the potential relationship between the O₂ coordination geometry and reactivity with substrates.

Theory can provide key insights into these questions, but it proves technically extremely challenging to model end-on vs. side-on coordination because the varying degrees of multideterminantal character associated with these different binding modes can lead to significant errors in DFT predictions of singlet state energies relative to one another or to corresponding triplet states.^33,34 A protocol that we have found particularly effective is to use DFT to obtain molecular structures, and then to correct singlet energies relative to those of triplets (which as single determinants are well treated by DFT) based on multireference second-order perturbation theory (CASPT2),³⁵ the latter being designed to handle multideterminantal character in a rigorous fashion. The utility of this approach was first demonstrated in a mechanistic study of the activation of molecular oxygen to generate 3a.⁸ Temperature-dependent stopped-flow kinetics data in varying nitrile/THF mixtures indicated that the oxygenation reaction follows a two-term rate law (eq. 3), and a Hammet study using para-substituted benzonitriles revealed substituent effects on the bimolecular rate constant (k₂). These and other results were interpreted to indicate that there are two competing pathways in the reaction (Scheme 2). The rate-determining step for one is exchange of THF solvent for nitrile prior to oxygenation, while for the other pathway coordination of O₂ to the Cu(I)-nitrile complex is rate-controlling. CASPT2-corrected DFT calculations (including continuum solvation) provided insight into the structures of the rate-determining transition states and predicted activation enthalpies and entropies within experimental error for both pathways, although raw, i.e., uncorrected, DFT predictions were substantially in error.⁸

$$\text{Rate}=k_1\left[\mathrm{Cu}\left(\mathrm{I}\right)\right]+k_2\left[O_2\right]\left[\mathrm{Cu}\left(\mathrm{I}\right)\right]$$ (3)

Scheme 2.

Proposed dual pathway mechanism for the oxygenation yielding 3a.

Interestingly, in the pathway involving rate-determining solvent exchange the initial coordination of O₂ is calculated to be end-on. While this structure is predicted to be a local minimum, it is separated by a rather low barrier (1.8 kcal mol^-1) from the more stable side-on product that is isolated, and the free energy difference (4.7 kcal mol^-1) is such that no observation of the end-on isomer would be expected at equilibrium. Nonetheless, the relatively small energy differences between the end-on and side-on structures suggested that it might be possible to access the former by suitably modifying the β-diketiminate ligand. One β-diketiminate modification involved incorporation of a thioether arm, so as to model the N₂S(thioether) donor set in the active site of PHM. However, only side-on coordination upon oxygenation of a Cu(I) precursor was indicated by the spectroscopic data (ν(O-O) = 994 cm^-1) and by theoretical calculations, which predicted only weak binding of the thioether sulfur atom to copper (Figure 6).³⁶ Further ligand perturbations considered with computational modeling involved the introduction of an ancillary ligand whose steric and/or electronic requirements might bias the binding of O₂ in 3 to favor end-on coordination; again, however, no simple, solvent-like ligand could be identified that led to the prediction of a thermodynamically stable end-on oxygenated product.³⁷ Finally, given that the end-on geometry is likely to have more Cu(II)-superoxide character that would be stabilized relative to the Cu(III)-peroxide alternative by a less electron donating supporting ligand, we examined versions of the β-diketiminate in 3 with one or two CF₃ replacements for the methyl groups on the backbone.³⁸ CASPT2-corrected DFT calculations predict that each CF₃ group does indeed perturb the end-on/side-on equilibrium such that with two such groups it is reversed, i.e., end-on coordination is favored. Unfortunately, theory also predicts that each CF₃ group reduces the standard-state binding free energy such that it becomes positive with two CF₃ substituents. Experimental studies appeared to confirm that prediction: with a single CF₃ group O₂ coordination was observed to be side-on (ν(O-O) = 977 cm^-1) while with two CF₃ groups it did not prove possible to isolate a 1:1 Cu/O₂ adduct.³⁸

Figure 6.

Calculated structure of the CuO₂ adduct with a thioether-modified b-diketiminate ligand (selected interatomic distances shown; colors: blue, N; red, O; green, Cu; yellow. S).

Reactivity

Studies of the reactivity of Cu(II)-superoxos 1 and 2 have yet to be reported, but some investigations of 3a have been performed (Scheme 3). The observation that the oxygenation leading to 3a is irreversible at low temperature has been key to these studies, as this allowed the reactivity of 3a to be assessed in the absence of any free O₂ or precursor Cu(I) complex. The complex is a poor oxidant, as revealed by (a) its lack of reactivity with a range of potential H-atom donors, including phenols, and (b) no phosphine oxide produced upon addition of phosphines and, instead, loss of O₂ and formation of a Cu(I)-phosphine adduct.³⁹ Addition of Cu(I) complexes resulted in the production of bis(μ-oxo)dicopper complexes 5 that feature disparate supporting N-donor ligands,⁷ while reaction of the germylene Ge[N(TMS)₂]₂ yielded a novel heterobimetallic [Cu(μ-O)₂Ge]³⁺ core (6).⁴⁰ In an unusual transformation, reaction of 3a with [Cu(MeCN)₄]⁺ in the presence of 3,5-diphenylpyrazole led to 7,³⁹ which features a Cu(II)-semiquinonato unit resulting from hydroxylation⁴¹ and rearrangement of a ligand aryl group (possibly via an NIH shift similar to ones observed for dicopper compounds).⁴² Since 7 does not form in the absence of added Cu(I) reagent, it appears that a peroxo- or bis(μ-oxo)dicopper intermediate is involved in the aryl oxidation process, although mechanistic information is lacking.

Scheme 3.

Summary of the reactivity of 3a. S-H = phenols, thioanisole, cyclohexene, ferrocene, HBF₄. pzH = 3,5-diphenylpyrazole. PR₃ = PPh₃ or PMePh₂. TMS = trimethylsilyl. L = tetramethylpropanediamine, 1,4,7-trimethylcyclononane, or a β-diketiminate with orthomethylsubstituents.

The basis for the poor oxidizing power of 3a and 4 was examined theoretically in studies that also evaluated Cu(III)-oxo species that would result from cleavage of the O-O bonds.⁴³ Predicted reduction potentials and pK_b values of 3a and 4 showed them to be difficult both to reduce and to protonate compared to the corresponding Cu(III)-oxo alternative. As a result, new O-H bonds formed when these species abstract hydrogen atoms from substrates were predicted to be quite weak and the transition states for these abstractions were predicted to have large activation enthalpies. The Cu(III)-oxo species were predicted to be much more reactive owing to a more favorable combination of reduction potential and basicity.

The lack of oxidizing power exhibited by 3a and 4 is associated with the strongly electron donating character of the β-diketiminate and anilido-imine ligands. While this character does promote binding of dioxygen to the Cu(I) precursors, it renders the subsequent adducts relatively unreactive towards reduction and protonation, and thus reaction with hydrocarbon substrates is thermodynamically unfavorable. Theory suggests that C-H bond activation reactivity will thus be enhanced by ligands (a) having less donating power, so as to increase Cu(II)-superoxide character at the expense of Cu(III)-peroxo character, and (b) designed to favor end-on coordination over side-on, since the former motif is also predicted to be somewhat more oxidizing than the latter for otherwise equivalent ligands. In addition, Cu(III)-oxo species should prove quite reactive if they can be synthetically accessed.

Implications for Oxidation Catalysis

Evidence has been accumulating to support the notion that 1:1 CuO₂ species participate in biological oxidations,¹ such as those catalyzed by the enzymes PHM,^30,44 amine oxidase,^45,46 quercetinase,⁴⁷ and superoxide dismutase.⁴⁸ Lessons learned in the studies of synthetic models like 1-4 can inform those focused on the metalloproteins. For example, the CASPT2-corrected DFT method shown to be applicable to the model compounds discussed above was used to examine in detail the preference for end-on vs. side-on coordination with various combinations of biologically relevant N-, O-, and S-containing ligands.⁴³ The (N)₂(S) combination found in PHM was predicted to lead most preferentially to end-on coordination with a singlet ground state, while other combinations that increased the donating ability of the ligand environment (e.g., by deprotonating an acidic ligand) changed the preference to side-on. To further appreciate the utility of the CASPT2-corrected DFT method it is instructive to compare these results to prior work on PHM active site models using more conventional DFT protocols. Prior to the appearance of the activated PHM crystal structure, side-on binding was predicted to be preferred with biologically relevant ligands based on restricted DFT results,⁴⁹ the latter theoretical formalism tending to be heavily and inaccurately biased in favor of side-on coordination.³³ In a more recent study,⁵⁰ unrestricted DFT was employed together with molecular mechanics to model the PHM active site and the end-on binding mode was found to be preferred, but with the triplet state significantly lower in energy than the singlet, reflecting the problems of unrestricted Kohn-Sham DFT applied to multideterminantal singlets.^33,34,51 Finally, we note that if one does not care about the relative energetics of the singlet and triplet states, unrestricted DFT can certainly still be useful for the prediction of various structural and vibrational properties, as demonstrated, for example, in reported observations similar to those described above for the factors influencing end-on vs. side-on O₂ coordination to Cu(I) supported by various tripodal and tetrapodal ligand sets.⁵²

In conclusion, our understanding of putative CuO₂ intermediates in catalytic reactions has been deepened through the detailed investigations of the structurally defined complexes 1-4. Identification of a previously unforeseen Cu(III)-peroxo moiety provides precedence for the notion that such a species may be involved in catalysis, although in 3 and 4 poor oxidative reactivity derives from low reduction potentials and basicities. Such an electronic structure may be differentiated experimentally and by theory from an alternative Cu(II)-superoxo formulation as seen in 1 and 2, and we are beginning to understand how supporting ligands influence where a CuO₂ unit may lie on the continuum between these extremes. Unambiguous evidence now shows that end-on and side-on CuO₂ adducts are possible and may be energetically similar, although knowledge of how binding mode differences relate to oxidative reactivity is rudimentary;⁴³ this presents a challenge for future research.⁵³

Biography

Christopher J. Cramer was born in Freeport, Illinois in 1961. He holds an A.B. summa cum laude in mathematics and chemistry from Washington University in St. Louis, where he worked with C. David Gutsche, and a Ph.D. in chemistry from the University of Illinois, where he worked with Scott E. Denmark. He joined the faculty of the University of Minnesota in 1992 after postdoctoral work as an active-duty officer in the United States Army and presently holds the title Distinguished McKnight and University Teaching Professor of Chemistry, Chemical Physics, and Scientific Computation. His research interests are in the area of theoretical chemical modeling.

William B. Tolman grew up in Chelmsford, MA, and obtained a B.A. in chemistry from Wesleyan University in Middletown, CT (1983, research with A. Cutler) and a Ph.D. in chemistry from the University of California, Berkeley (1987, with K.P.C. Vollhardt). After a postdoctoral period with S.J. Lippard at the Massachusetts Institute of Technology, he joined the faculty at the University of Minnesota in 1990, where he is now a Distinguished McKnight University and Lee Irvin Smith Professor of Chemistry. His research encompasses synthetic bioinorganic chemistry focused on modeling Cu and Fe metalloprotein active sites and polymerization catalysis focused on the synthesis of biodegradable materials derived from renewable resources.