Exclusive Imidazole Ligation to Cu^III₂O₂ and Cu^IIICu^II₂O₂ Cores

Abstract

We disclose herein the synthesis and characterization of L₂Cu(III)₂O₂ and L₃Cu(III)Cu(II)₂O₂ complexes with nitrogen ligation exclusively from imidazoles for the first time. Their accessibility by direct oxygenation of a L-Cu(I) precursor and the resulting Cu(III) formation inform on the kinetic accessibility and thermodynamic superiority of imidazole in stabilizing Cu(III).

Graphical Abstract

Direct oxygenation of imidazole-ligated Cu(I) generates dinuclear and trinuclear Cu(III) species with exclusive imidazole ligation.

In biological systems, copper is one of the two most used metals for activating dioxygen. The resulting copper-dioxygen (Cu_x-O₂) assemblies adopt myriad structures with varied nuclearity and degree of O₂ reduction, with the Cu oxidized to the Cu(I) or Cu(II) oxidation states.^1,2 Despite the diversity of oxidant structures and substrates, these Cu_x-O₂ active sites retain remarkably similar ligation spheres, with dominant ligation from histidine-derived imidazole groups.^3,4 As imidazole ligands present a synthetic challenge,^5–8 synthetic mimics often use Cu(I) complexes with abiological nitrogenous ligation – such as amines,^9,10 pyridines,^11,12 pyrazoles,^13–15 guanidines,^16,17 and anionic chelates^18,19 – that frequently oxygenate to Cu(III)-containing species such as dicopper(III) bis-μ-oxide (O) or trinuclear bis(μ₃-oxide)Cu(III)Cu(II)₂ (T) species at low temperatures.²⁰ While Cu(III) has been proposed to be operative in biological intermediates,^21–25 it has yet to be spectroscopically characterized in any system.³ This apparent disconnect between synthetic and biological systems is attributed frequently to the greater basicity of the common synthetic ligands compared to the predominance of imidazole ligation in biology.^26,27 Recently, we reported that histamine with mixed imidazole and primary amine ligation could stabilize a Cu(III) O species at low temperatures,²⁸ and that direct oxygenation of a histamine-Cu(I) complex forms a Cu(III)-containing T species directly.²⁹ Whether this reactivity is allowed only by the highly basic amine ligation or whether imidazole alone is capable of stabilizing Cu(III) is unknown, as all literature precedents of direct oxygenation of Cu(I) species with exclusive nitrogen ligation from imidazole yield Cu(II) complexes.

Herein we report the direct and indirect synthesis of an O_L species with exclusive imidazole ligation that uses bis(1-n-butylimidazole)methane, L_nBuBIM, a bidentate, bis-imidazole ligand, to create O_nBuBIM. The direct oxygenation of L_nBuBIM-Cu(I) forms Cu(III) species O_nBuBIM and T_nBuBIM at low temperatures. Clean formation of O_nBuBIM is also possible through ligand exchange reactions from other preformed O_L complexes. Optical monitoring of ligand competition experiments among O_L species clearly demonstrates that L_nBuBIM is the most donating and thermodynamically stabilizing ligand for Cu(III) investigated to date, despite being less basic than the majority of other O-stabilizing ligands.

As most Cu_x-O₂ species formed by oxygenation are strong oxidants with limited lifetimes at 25 °C, synthetic L₂Cu(III)₂O₂ complexes (O_L) are assembled generally at low temperatures by direct injection of a L-Cu(I) precursor into an equilibrated O₂ solution.¹⁰ For example, tetramethylpropylenediamine (L_TMPD) forms O_TMPD in 90% yield in 1 min at −125 °C from L_TMPD-Cu(I) and O₂, and near quantitative yields after 5 min. This complex is a convenient synthon for other O_L complexes of greater thermodynamic stability by simple ligand exchange; mixed tertiary amine and imidazole ligation can be achieved by addition of 2 equiv of N_α,N_α,N_τ-trimethyl-histamine (L_Me3His) to O_TMPD, forming O_Me3His in high yields by L_TMPD displacement. As the only difference between these ligands is the substitution of 2 tertiary amines for 2 imidazoles, this ligand exchange evidences thermodynamic stabilization of Cu(III) by partial imidazole ligation over peralkylated amine ligation.²⁸

Complete monodentate imidazole ligation of an O_L species is thermodynamically precluded as addition of 4 equiv. of 1-methylimidazole (L_1MeImd) to O_TMPD at −145 °C results in a mixture of the dicopper(II) μ-η²:η²-side-on peroxide, ^SP_1MeImd, species³⁰ and O_TMPD starting material under all reaction conditions examined (Figure S1). To encourage coordination of only two imidazoles to an O species, L_nBuBIM, a bidentate, bis-imidazole chelating ligand (Scheme S1/S2) was used in a similar core-capture experiment; 2 equiv of L_nBuBIM added to O_TMPD at −125 °C in 2-methyltetrahydrofuran (2-MeTHF) produces O_nBuBIM in ca. 5 min (Figures 1 and 2), evidenced by two new intense ligand-to-metal charge transfer (LMCT) transitions at 349 and 251 nm (Figure 2).^31,32 O_nBuBIM is formed in greater than 80% yield established through independent redox titrations with 5,6-isopropylidene ascorbic acid (Figure 2 inset, Figure S7) and ferrocenecarboxylic acid and exhibits a half-life of ca. 60 min at −125 °C. Cu K-edge X-ray absorption spectra (XAS) show a clean pre-edge transition at 8980.7 eV suggestive of Cu(III) (Figure S9).³³ Extended X-ray absorption fine structure (EXAFS) analysis reveals a Cu-Cu distance of 2.78 Å and a Cu-N_avg. of 1.94 Å, both distances the shortest known for O_L compounds, consistent with sterically undemanding ligation (Table 1, Figure S10). Significantly improved EXAFS fits result from incorporation of Cu-imidazole multiple scattering, supporting direct imidazole ligation to Cu(III) centers. The metrical trends and optical spectra are recapitulated in the DFT optimized structures (Table 1) and their corresponding TD-DFT spectra (Figure S5).^34,35

Figure 1.

Templated core capture synthetic methodology to generate O_nBuBIM.

Figure 2.

UV-Vis absorption spectra of O_nBuBIM (λ_max = 349, 251 nm, red trace) generated from O_TMPD (black trace) at −125 °C. [Cu] = 0.9 mM, 0.1 cm path, 2-MeTHF. Inset: titration of the 349 nm feature of O_nBuBIM by ascorbic acid.

Table 1.

Physical Properties of Relevant O_L Complexes.

Entry	Compound[a]	UV-Vis: λmax, nm; (ε, mM−1 cm−1)[a,b,c,d]	Metrical parameters: EXAFS, Å[d]; (DFT, Å[e])
			Cu-Cu	Cu-O	Cu-N
A	OTMPD[b]	403 (29.4), 302 (18.7)	2.85 (2.77)	1.84 (1.77)	2.02 (1.97)
B	OPD[b]	375 (22.6), 278 (21.0)	2.77 (2.66)	1.86 (1.76)	2.00 (1.91)
C	OMe3His[c]	380 (30.2), 280 (24.5)	2.80 (2.72)	1.82 (1.77)	1.97 (1.95, 1.89)
D	OnBuHis[c]	363 (27.8), 262 (34.2)	2.78 (2.69)	1.82 (1.77)	1.96 (1.91, 1.88)
E	OnBuBIM	349 (24.1), 251 (35.1)	2.78 (2.69)	1.84 (1.76)	1.94 (1.89)

^[a]SbF₆⁻, 2-MeTHF, −125 °C, yield corrected extinction coefficients.

^[b]See reference 10 for further characterization.

^[c]See reference 28 for further characterization.

^[d]Resolution ≈ ±0.01 Å.

^[e]Optimized at the CAM-B3LYP/6–31g*/SMD(THF) level. Def2TZVP basis sets recapitulate the same trend.

The systematic blue-shifting in optical transitions between the O_L species listed in Table 1 is suggestive of stronger donation and bonding from the nitrogenous ligands, the only varying parameter between all the complexes. The accepting orbital of the LMCT is predominantly a Cu-N antibonding orbital. An increase in donation from the nitrogenous ligand increases the energy of this antibonding orbital resulting in a higher energy transition. For example, O_Me3His (Table 1 entry C: λ_max = 380 nm, Cu-N (EXAFS) = 1.97 Å) absorbs at higher energies than O_TMPD (Table 1 entry A: λ_max = 403 nm, Cu-N (EXAFS) = 2.02 Å) as the imidazole bonds closer to the Cu center in comparison to tertiary amines. Similarly, O_nBuHis (Table 1 entry D: λ_max = 363 nm, Cu-N (EXAFS) = 1.96 Å) exhibits blue-shifting and contraction from the propylene diamine (L_PD) ligated O species, O_PD (Table 1 entry B: λ_max = 375 nm, Cu-N (EXAFS) = 2.00 Å), supporting that imidazoles form stronger interactions, presumably through increased σ-donation, than do primary amines to the Cu center.³¹ The optical and structural features of O_nBuBIM (Table 1 entry E: λ_max = 349 nm, Cu-N (EXAFS) = 1.94 Å) are consistent with these findings, as O_nBuBIM exhibits the most blue-shifted optical transition (Figure S4) and shortest Cu-N bond distances of any O species. These observations are further corroborated by DFT and TD-DFT calculations (Figure S5).

The relative thermodynamic stability between imidazole-containing O species such as O_Me3His, O_nBuHis and O_nBuBIM is established by ligand competition core capture experiments. Two equiv of L_nBuBIM sequesters the Cu₂O₂ core from O_Me3His, with a blue-shift in the optical spectrum (Figure S6), while the reverse ligand exchange reaction between L_Me3His and O_nBuBIM is not observed. DFT calculations support these thermodynamic rankings through a computed isodesmic ligand exchange reaction, where O_nBuBIM is favored over O_Me3His by ca. 8 kcal•mol⁻¹ (Figure 3). Likewise, addition of 2 equiv L_nBuHis to O_nBuBIM leads to no significant optical shift, whereas addition of 2 equiv L_nBuBIM to O_nBuHis leads to a rapid initial blue-shift of the characteristic LMCT bands, followed by a rapid decay, attributed to concomitant Cu₂O₂ core capture and oxidation of the free primary amine. Overall, this suggests that O_nBuBIM is more thermodynamically stable than O_nBuHis, the most stable O species previously identified, and further supports the energetic preference of imidazole ligation to Cu(III). Combined with the observation of O_nBuBIM having the most blue-shifted λ_max, these results suggest that exclusive imidazole ligation donates more strongly into the Cu(III) centers than any other combination of neutral, nitrogenous ligation studied and produces the most thermodynamically stable O_L species to date.

Figure 3.

DFT calculated isodesmic ligand exchange reactions. Optimized at the CAM-B3LYP/6–31g*/SMD(THF) level with def2tzvp and DKH2 relativistic corrections for single point energy calculations. Red X over the reverse reaction indicates that reversibility was not observed experimentally even in presence of excess ligand.

Direct oxygenation of L_nBuBIM-Cu(I) at −125 °C results in a new optical spectrum inconsistent with O_nBuBIM, but reminiscent of a L₃Cu(III)Cu(II)₂O₂ trinuclear, T_L, cluster with an intense feature at 310 nm and two lesser intensity visible features at 495 and 630 nm (Figure 4).^11,29,36 The EXAFS data show a characteristically short Cu-Cu_avg. distance of 2.66 Å as well as both Cu(III) and Cu(II) pre-edges at 8980.4 and 8979.1 eV, respectively, consistent with the compact Cu₃O₂ bis-oxide species, T_nBuBIM (Figures 4A, S3, S11, and S12).³⁷ Altering the oxygenation reaction conditions to afford high [O₂]–[Cu(I)] ratios at low overall concentrations, the characteristic 349 nm LMCT of O_nBuBIM is observed initially at −145 °C.²⁹ Using its known extinction coefficient from the synthesis by ligand exchange described above, formation by oxygenation is estimated at 15% (Figure S2). T_nBuBIM forms subsequently over 2 min, resulting in a mixture of two different Cu(III)-containing species formed directly from the oxygenation of a Cu(I)-imidazole precursor (Figure 4B). Taken together, these experiments suggest that exclusive imidazole ligation of Cu(III) is not only thermodynamically favorable, but also kinetically accessible from imidazole-ligated Cu(I) and O_2.^31,38

Figure 4.

A) Oxygenation of L_nBuBIM-Cu(I) ([Cu] = 0.9 mM, 0.1 cm, 2-MeTHF, −125 °C). Inset: Titration of the 310 nm feature of T_nBuBIM by incremental addition of cobaltocene (Figure S8). B) Oxygenation of L_nBuBIM-Cu(I) ([Cu] = 0.1 mM, 1 cm, 4:1 2-MeTHF:T THF, −145 °C). Beginning O_nBuBIM formation is shown in red with subsequent T_nBuBIM formation in grey/black.

The characterization of O_nBuBIM demonstrates that the Cu(III) oxidation state in a Cu_X-O₂ core is viable in an exclusive imidazole ligation environment as found in biological systems. What is most surprising is that – despite the greater basicity of synthetic ligand substitutes – the observation of short Cu-N_imidazole bond distances, the most blue-shifted λ_max for an O species to date, and the isodesmic ligand exchange calculations all suggest that, among bidentate ligands, imidazoles are in fact the most stabilizing neutral, nitrogenous ligation moiety for these high-valent Cu(III) O species. The blue-shift in λ_max for O_nBuBIM relative to previously reported O species is especially noteworthy as the energy ranges for O and ^SP LMCT features now overlap such that characterization of Cu(III) vs Cu(II) oxidation states should not be determined by optical transition energies alone. A detailed study of the stereoelectronic compositions of these complexes and how ligation affects their thermodynamic stabilities and optical properties is underway currently.