Encapsulation of tricopper cluster in a synthetic cryptand enables facile redox processes from Cu^ICu^ICu^I to Cu^IICu^IICu^II states

Abstract

One-pot reaction of tris(2-aminoethyl)amine (TREN), [Cu^I(MeCN)₄]PF₆, and paraformaldehyde affords a mixed-valent [TREN₄Cu^IICu^ICu^I(μ₃-OH)](PF₆)₃ complex. The macrocyclic azacryptand TREN₄ contains four TREN motifs, three of which provide a bowl-shape binding pocket for the [Cu₃(μ₃-OH)]³⁺ core. The fourth TREN caps on top of the tricopper cluster to form a cryptand, imposing conformational constraints and preventing solvent interaction. Contrasting the limited redox capability of synthetic tricopper complexes reported so far, [TREN₄Cu^IICu^ICu^I(μ₃-OH)](PF₆)₃ exhibits several reversible single-electron redox events. The distinct electrochemical behaviors of [TREN₄Cu^IICu^ICu^I(μ₃-OH)](PF₆)₃ and its solvent-exposed analog [TREN₃Cu^IICu^IICu^II(μ₃-O)](PF₆)₄ suggest that isolation of tricopper core in a cryptand enables facile electron transfer, allowing potential application of synthetic tricopper complexes as redox catalysts. Indeed, the fully reduced [TREN₄Cu^ICu^ICu^I(μ₃-OH)](PF₆)₂ can reduce O₂ under acidic conditions. The geometric constraints provided by the cryptand are reminiscent of Nature's multicopper oxidases (MCOs). For the first time, a synthetic tricopper cluster was isolated and fully characterized at Cu^ICu^ICu^I (4a), Cu^IICu^ICu^I (4b), and Cu^IICu^IICu^I (4c) states, providing structural and spectroscopic models for many intermediates in MCOs. Fast electron transfer rates (10⁵ to 10⁶ M⁻¹ s⁻¹) were observed for both Cu^ICu^ICu^I/Cu^IICu^ICu^I and Cu^IICu^ICu^I/Cu^IICu^IICu^I redox couples, approaching the rapid electron transfer rates of copper sites in MCO.

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Introduction

Synthetic tricopper clusters have been a prominent synthetic target for the (bio)inorganic community over the past few decades,^1–9 since tricopper centers were identified/proposed as essential active sites for biological reduction of O₂ to H₂O in multicopper oxidase (MCO)^10,11 and aerobic hydroxylation of methane in particulate methane monooxygenase (pMMO).¹² Although a tricopper active site in pMMO has been disputed, the conversion of methane to methanol was demonstrated with small-molecule tricopper complexes.^13,14 In both oxygen reduction and hydrocarbon hydroxylation, the synergy of three Cu^II/Cu^I redox couples in tricopper clusters is essential to harness the oxidative power of O₂. Therefore, understanding factors governing the redox of tricopper clusters as a single unit is fundamental to their development as biomimetic catalysts in fuel cell technology and functionalization of alkanes.

An ideal tricopper redox catalyst should be able to engage all three Cu^II/Cu^I couple and accommodate four redox states from Cu^ICu^ICu^I to Cu^IICu^IICu^II. However, the majority of synthetic tricopper clusters reported to date have limited redox capability, and only isolated at a single oxidation state (primarily Cu^IICu^IICu^II or Cu^ICu^ICu^I).^15,16 Copper(I) center (d¹⁰) and copper(II) center (d⁹) prefer distinct geometry due to the Jahn–Teller effect. The redox of Cu^II/Cu^I, in an unconstrained solvent-exposed environment, often results in significant geometric rearrangement associated with high reorganization energy.¹⁷ Notably, among ca. 186 crystallographically characterized molecular tricopper μ₃-E, (E = O, OH, S) clusters, 1 and 2 (Fig. 1A and B) represents the only two redox-active examples.^18,19 Even 1 and 2, however, cannot be further reduced to the Cu^ICu^ICu^I state,¹⁶ which is crucial for the activation of O₂ during catalytic oxygen reduction reaction (ORR) and hydrocarbon hydroxylation. In sharp contrast, Nature's trinuclear copper cluster (TNC) in MCOs has been observed in three different oxidation states: fully reduced (Cu^ICu^ICu^I, FR), alternative resting (Cu^IICu^ICu^I, AR), and native intermediate (Cu^IICu^IICu^II, NI). Unlike synthetic tricopper complexes, TNC is embedded in a protein matrix, which provides conformational strains and site isolation that reduce reorganization energy during electron transfer (ET).^20,21 According to Marcus theory, electron transfer in solution is strongly influenced by both inner sphere ligand interactions and outer sphere solvent environments.¹⁷ We posited that the encapsulation of a synthetic tricopper cluster in a cryptand could constrain the coordination environment, hence lowing the barriers for reorganization and allowing access to different redox states of tricopper clusters. Instead of using bulky ligands to simulate the protein environment, we leveraged a multicyclic azacryptand ligand to restrict the conformational freedom and limit solvent interactions. The electrochemical property of 4 was compared to its solvent-exposed analog [TREN₃Cu^IICu^IICu^II(μ₃-O)]Cl₄, 3²² to understand how compartmentalization of tricopper center impacts the redox behavior of Cu^II/Cu^I.

Fig. 1 Redox-active tricopper clusters and their corresponding oxidation states demonstrated by CV study. 1–3 were isolated at one oxidation state. 4 reported in this work is isolated and characterized at three different oxidation states, denoted as 4a, 4b, and 4c.

Results and discussion

The tricopper complex [TREN₃Cu^IICu^IICu^II(μ₃-O)](PF₆)₄, 3 (Fig. 1C) has been considered as a structural²² and spectroscopic model^23,24 for TNC. However, 3 does not exhibit the multi-electron redox function of TNC. The ca. 550 mV separation of the redox couple (Fig. 4C), which is typical for synthetic tricopper complexes, indicates a substantial barrier for reorganization during ET. Notably, the reduction of Cu^IICu^ICu^I to Cu^ICu^ICu^I was not observed within the voltage window of water, suggesting 3 is not suitable to activate dioxygen. To construct an isolated microenvironment, we sought to install an additional TREN cap on 3 to afford 4 (Fig. 1D). The desired azacryptand TREN₄ has been synthesized previously,²⁵ however, no transition metal complex has been reported thus far. We found that metalation of TREN₄ with Cu(I) and Cu(II) salts only afforded complicated mixtures in low yields. Inspired by the metal-templated synthesis reported by Suh et al.,²² we explored the one-pot reaction of copper salts, TREN, and paraformaldehyde. Reaction of [Cu^I(MeCN)₄]PF₆, TREN (3.3 equivalents), and paraformaldehyde (20 equivalents based on CH₂O units) resulted in the formation of a blue solid (Fig. 2A). Workup and recrystallization under our optimized conditions afforded complex 4b in 18% yield (see ESI†).

Fig. 2 (A) Synthesis of [TREN₄Cu^IICu^ICu^I(μ₃-OH)](PF₆)₃ (4b). (B) ESI-MS (positive mode) of 4b, (C) X-band EPR spectrum (frozen MeCN, 0.5 mM) of 4b, g_x = 2.25 g_y = 2.14, g_z = 2.01, A_z(Cu) = 146 MHz.

The Electrospray Ionization Mass Spectrum (ESI-MS, Fig. 2B) of 4b exhibited a prominent peak at 312.2 m/z, and the isotope distribution pattern matches that of [TREN₄Cu^IICu^ICu^I(μ₃-OH)]³⁺ (molecular mass = 938.75 g mol⁻¹, C₃₆H₇₅Cu₃N₁₆O), supporting the presence of a [Cu₃(μ₃-OH)]³⁺ core. The frozen solution electron paramagnetic resonance (EPR) spectrum of 4b (Fig. 2C) displayed a rhombic signal (g_x = 2.25, g_y = 2.14, g_z = 2.01) with hyperfine couplings to one ^63/65Cu (I = 3/2) nucleus (A_z(Cu) = 146 MHz), suggesting a valence-localized one-hole Cu^IICu^ICu^I electronic structure. The high g_x and g_y values indicated that the unpaired electron resides in the d_z² orbital, consistent with a trigonal bipyramidal geometry.²⁶

Single crystal X-ray diffraction analysis of 4b confirmed its assignment as mixed-valent [TREN₄Cu^IICu^ICu^I(μ₃-OH)](PF₆)₃ (Fig. 3). Cryptate 4b shares the macrocyclic tricopper assembly of 3 but features a fully encapsulated tricopper core. Three of four TREN moieties in TREN₄ serve as bowl-shape binding sites for the tricopper core, while the remaining one forms a cryptand that isolates the Cu₃(μ₃-OH) core in a capsule. With its one-hole Cu^IICu^ICu^I oxidation state, complex 4b is the first synthetic model for the alternative resting (AR) state in MCO (Cu^IICu^ICu^I).^27,28 The Cu⋯Cu and Cu–O bond metrics within 4b (Cu⋯Cu: 2.973–3.260 Å; Cu–O: 1.878–1.971 Å) are similar to those in 3 (Cu⋯Cu: 3.095 Å; Cu–O: 1.863 Å) but vary greater from each other, perhaps as a result of its localized electronic structure.

Fig. 3 Solid-state structure of 4b (100 K) with thermal ellipsoids shown at 35% probability level. All PF₆ anions, the minor components of disorder, and all C–H hydrogen atoms are omitted for clarity.

To evaluate the impact of tricopper encapsulation on the redox capability, we performed cyclic voltammetry (CV) studies of 3 and 4 in aqueous environments with pH values range from 5.6 to 13. Dissolution of 3 in water produces an equilibrium mixture of 3 and its conjugate acid (pK_a = 4.6).²² Cyclic voltammogram of 3 at pH = 5.6 showed an irreversible reduction at −0.18 V (vs. NHE), which gradually shifts to −0.30 V (vs. NHE) at pH = 13. This cathodic peak is assigned to the two-electron reduction of [Cu^IICu^IICu^II(μ₃-OH)]⁵⁺ to [Cu^IICu^ICu^I(μ₃-OH)]³⁺ based on variable scan rate CV study (see ESI, Fig. S19†). During the reverse scan, an anodic peak was observed at 0.37 V (vs. NHE, pH = 5.8), which is attributed to the oxidation of [Cu^IICu^ICu^I(μ₃-OH)]³⁺ back to [Cu^IICu^IICu^II(μ³-OH)]⁵⁺ (Fig. 4A). The ca. 550 mV separation of the redox couple indicates a substantial geometric difference at Cu^IICu^IICu^II and Cu^IICu^ICu^I states. As the tricopper center in 3 is exposed to bulk exterior, it can lose/gain interactions with solvents during redox processes, further raising the reorganization energy. Notably, further reduction of [Cu^IICu^ICu^I(μ₃-OH)]³⁺ to [Cu^ICu^ICu^I(μ₃-OH)]²⁺ was not observed within the voltage window of water. The CV of 3 becomes more reversible as the pH increases from 5.6 to 13, perhaps due to the deprotonation of central μ₃-OH to μ₃-O, a stronger ligand that rigidifies the coordination environment (see ESI, Scheme S2†).

Fig. 4 Cyclic voltammogram of (A) 3 and (B) 4, in an aqueous environment with various pH from 5.8 to 13 (phosphate buffer solution). (C) Overlay of the CV of 3 and 4 in an aqueous environment with pH = 5.8 (phosphate buffer solution). Scan rate of 0.1 V s⁻¹. Working electrode: glassy carbon; counter electrode: Pt wire; reference electrode: Ag/AgCl.

In contrast to the irreversible redox behavior of 3, the cyclic voltammogram of 4 shows two reversible (E_1/2 = −0.55 V and −0.13 V vs. NHE) and one irreversible (E_ox = 0.33 V vs. NHE) redox events, allowing access to all four oxidation states of the tricopper cluster electrochemically (Fig. 4B). The three redox events of complex 4 are insensitive to the pH of the buffer (Fig. 4B), implicating that the cryptand of TREN₄ isolates the tricopper core from direct solvent interactions. Additionally, the CVs of 4 in aqueous and non-aqueous environments, e.g. dimethylformamide (DMF) or acetonitrile, are essentially the same (Fig. S17†), further supporting that the redox of tricopper center in 4 is unaffected by the bulk exterior. As shown in the Fig. 4C, the reduction potentials required to reach Cu^IICu^ICu^I state (−0.17 V for 3, −0.17 V for 4) and the oxidation potentials required for Cu^IICu^IICu^II state (0.38 V for 3, 0.32 V for 4) are similar for 3 and 4. Given the less electron-donating nature of TREN₃vs.TREN₄, the reduction and oxidation peaks of 3 should be more anodic than those of 4. The fact that 3 and 4 share the similar redox potentials suggests that the high solvent accessibility of 3 has shifted its redox potentials cathodically. Solvent molecules may serve as ligands to tricopper core and make 3 more electron-rich, while the tricopper core in 4 is completely shielded from such solvent coordination. This is also consistent with the cathodic shift of the reduction and oxidation peak of 3 when the pH of the solvent increases (Fig. 4A).

The highly reversible oxidation and reduction couples of 4b prompted us to pursue the isolation of fully reduced [TREN₄Cu^ICu^ICu^I(μ₃-OH)]²⁺ (4a, Fig. 5A) and two-hole [TREN₄Cu^IICu^IICu^I(μ₃-OH)]⁴⁺ (4c, Fig. 5A). Consistent with its electrochemical behavior, chemical oxidation of 4b with decamethylferrocenium hexafluorophosphate (Me₁₀FcPF₆, E_1/2 = −0.49 V vs. Fc⁺/Fc) afforded a dark blue compound [TREN₄Cu^IICu^IICu^I(μ₃-OH)](PF₆)₄ (4c) in 50% yield (Fig. 5A). ¹H NMR spectrum of 4c shows nineteen broad resonances from 0.13 to 122.5 ppm (see ESI, Fig. S8†), indicating an S = 1 ground state. Complex 4c is a rare example of a tricopper cluster with a Cu^IICu^IICu^I oxidation state with the only other example being 2 reported by Murray et al.¹⁹ Chemical reduction of 4b with cobaltocene (Cp₂Co, E_1/2 = −1.3 V vs. Fc⁺/Fc) led to a rapid color change from blue to yellow (Fig. 5B), and colorless crystals of fully reduced [TREN₄Cu^ICu^ICu^I(μ₃-OH)](PF₆)₂ (4a) were obtained by recrystallization. ¹H NMR characterization of 4a was hampered by its low solubility. Therefore, we synthesized an analog of 4a with (3,5-bis(trifluoromethyl)phenyl)borate (BAr^F₄) counter anions (4a-BAr^F₄) by treating 4b-BAr^F₄ with Cp₂Co. All five ¹H NMR resonances of 4a-BAr^F₄ between 2 to 4.5 ppm are quite broad, perhaps because of the dynamic behavior of CH₂ groups on TREN₄ (see ESI, Fig. S6†).

Fig. 5 (A) Synthesis of 4a and 4c from 4b. (B) Geometric comparison of the Cu₃[μ₃-O(H)] core in 4a, 4b, and 4c. All bond metrics (Å) were determined based on X-ray single-crystal diffraction.

Both 4a and 4c were characterized by X-ray single crystallography (Fig. 5B, S12 and S13†). The geometric features of Cu₃(μ₃-OH) are maintained throughout the redox processes. Complex 4a has a slightly contracted [Cu^ICu^ICu^I(μ₃-OH)]²⁺ core as evidenced by the shortened Cu⋯Cu distance (average 3.098 Å in 4a comparing to 3.112 Å in 4b) and Cu–O distances (average 1.885 Å in 4a comparing to 1.913 Å in 4b). In contrast, the [Cu^IICu^IICu^I(μ₃-OH)]⁴⁺ core in 4c expanded (average Cu⋯Cu distance 3.181 Å, average Cu–O distance 1.937 Å) because of the increased coulombic repulsion. The minimal geometric differences of complex 4a, 4b, and 4c agree with their highly reversible redox behaviors. Importantly, the trigonal bipyramidal geometry of the Cu centers is preserved, even at the Cu^ICu^ICu^I state, highlighting the extraordinary constraints imposed by the multicyclic ligand TREN₄, a feature not shared by TREN₃.

Infrared spectra of complexes 4a, 4b, 4c reveal that the O–H stretches of μ₃-OH progressively blueshifts from 3372 cm⁻¹ (Cu^IICu^IICu^I) to 3440 cm⁻¹ (Cu^IICu^ICu^I) to 3516 cm⁻¹ (Cu^ICu^ICu^I), indicating increasing O–H bond strength as Cu oxidation state decreases (Fig. 6A). The UV-vis spectra of 4b and 4c both exhibit two broad intervalence charge-transfer bands (4b: 655 nm (800 M⁻¹ cm⁻¹) and 790 nm (870 M⁻¹ cm⁻¹), 4c: 680 nm (1000 M⁻¹ cm⁻¹) and 850 nm (1300 M⁻¹ cm⁻¹), Fig. 6B). Time-dependent density functional theory (TD-DFT) calculations at the TPSSh/TZVP level showed that these absorptions originate from charge transfers from combinations of copper d orbitals to the LUMO, which features the σ* interaction of copper d_z² and the μ₃-O p_z (see ESI, Tables S5 and S6†). Moreover, the calculated UV-vis spectra reflected the red-shifting trend from 4b to 4c (see ESI, Fig. S22†).

Fig. 6 (A) Infrared and (B) UV-vis spectra of 4a (Cu^ICu^ICu^I, black), 4b (Cu^IICu^ICu^I, red), and 4c (Cu^IICu^IICu^I, blue).

The reorganization energies (λ) of tricopper clusters during ET have important implications in oxygen reduction reaction catalyzed by MCO.²⁹ The reorganization energies of TNC have been used to rationalize the various rates of intermolecular ET between type 1 Cu sites and TNC²¹ as well as the inhibition³⁰ or acceleration³¹ of ORR by halides. To further understand the kinetic factors that govern the redox of 4, we evaluated the self-exchange rates (k₁₁) and reorganization energy (λ) of Cu^ICu^ICu^I/Cu^IICu^ICu^I and Cu^IICu^ICu^I/Cu^IICu^IICu^I redox couples. Determine of k₁₁ using ¹H NMR line broadening experiment³² was not feasible due to the dynamic behavior of CH₂ resonances in 4a and paramagnetic nature of 4c. As an alternative, we employed an electrochemical method reported by Nicholson;^33,34 the self-exchange rates of 4a/4b and 4b/4c were determined to be 7.4(2) × 10⁵ M⁻¹ s⁻¹ and 7.2(2) × 10⁵ M⁻¹ s⁻¹, respectively (see ESI, Fig. S20†). These fast ET rates approach the fastest synthetic mono- and dicopper system (10⁵ to 10⁶ M⁻¹ s⁻¹)^33,35–43 as well as Nature's blue copper ET protein 10⁵ to 10⁶ M⁻¹ s⁻¹.^44,45 The corresponding reorganization energies for 4a/4b and 4b/4c were calculated to be 1.21(1) eV and 1.21(1) eV using eqn (1) (Z = 10¹¹ M⁻¹ s⁻¹, T = 298 K).^39,46

The reorganization energy (λ) can be further partitioned into inner-sphere reorganization energy (λ_i, ligands and coordinated/hydrogen-bonded solvent molecules) and outersphere reorganization energy (λ_o, free solvent molecules, eqn (2)). The outer sphere reorganization energy can be estimated with eqn (3), which is based on a spherical model that separates the inner sphere and the outer sphere contribution. Solvent molecules association and dissociation with the inner sphere during the electron transfer will affect the accuracy in the reorganization energy calculation. In order to minimize the inaccuracy in determining the reorganization energy caused by direct hydrogen bonding of solvent with 3 and 4, acetonitrile was utilized, instead of water, in the electrochemical study and the following calculations. The outersphere reorganization energy was calculated to be 0.68 eV for 4a/4b and 4b/4c using eqn (3), where Δe is the elementary charge, a₁ and a₂ are the radii of redox partners, and D_opt and D_stat are optical- and static-dielectric constants of acetonitrile⁴⁷ at 298.15 K. Thus, the inner-sphere reorganization energy for 4a/4b and 4b/4c are estimated to be 0.53(1) eV and 0.53(1) eV using eqn (2).

λ = λ_i + λ_o (2)

λ_i = λ_ox + λ_red (4)

Determination of k₁₁ of 3 was not viable, since the redox of Cu^IICu^IICu^II/Cu^IICu^ICu^I was not reversible, and Cu^IICu^ICu^I/Cu^ICu^ICu^I was not observed experimentally. Therefore, we turned to computational study to compare the reorganization energies of 3 and 4. The inner-sphere reorganization energy λ_i can be calculated by eqn (4), where λ_ox and λ_red are the reorganization energy of the reduced and oxidized complexes. λ_ox and λ_red can be computationally estimated by the energy required to distort the equilibrium geometries to their redox-partners' geometries (see ESI, Fig. S21 and Scheme S3†).^29,30,48

Single-point energies of 3 and 4 at all four redox states were calculated at TPSSh/def2-TZVP(Cu)/def2-SVP(C, N, O, H) level with a continuum solvation model⁴⁹ and dispersion corrections.^50,51 The Gibbs free energy of each species was determined by adding the solvated single point SCF energy to the thermal correction from the respective frequency calculation.⁵² The frequency calculations were conducted with BP86 functional due to the conversion issues of a few species in high spin states with other hybrid functionals. There are several competing spin states for the Cu^IICu^IICu^II and Cu^IICu^IICu^I oxidation states. Since our goal is to compare the reorganization energies of 3 and 4, we have only studied the electronic states with the lowest energies, that is quartet states for Cu^IICu^IICu^II with three ferromagnetically coupled Cu(II) centers and triplet states for Cu^IICu^IICu^I with two ferromagnetically coupled Cu(II) centers (see ESI, Table S3†). We compared the optimized geometry of 3 and 4 at different redox states (Table S7 and Fig. S23†). Consistent with their solid-state structure, no significant geometric distortion was observed for 4 at all four oxidation states. In contrast, there was substantial geometric changes of 3 from Cu^IICu^ICu^I to Cu^ICu^ICu^I state, which may results in large reorganization energy for Cu^IICu^ICu^I/Cu^ICu^ICu^I couple (Fig. S23†).

The inner-sphere reorganization energies (λ_i) of 3 and 4 were summarized in Table 1 and Scheme S3.† The λ_i values of 3 for each redox couple are generally greater than those of 4. The especially high λ_i value for Cu^IICu^ICu^I/Cu^ICu^ICu^I redox couple of 3 (2.1 eV) agrees with the large degree of geometry distortion. Consequently, a large separation between the reduction and oxidation peak may be expected, which explains why the fully reduced Cu^ICu^ICu^I state for 3 cannot be achieved within the chemical window of water.⁵³ The large inner-sphere reorganization energy for [TREN₃Cu^IICu^ICu^I(μ₃-O)]²⁺/[TREN₃Cu^ICu^ICu^I(μ₃-O)]⁺ (2.1 eV) may be rationalized by its trigonal bipyramidal Cu centers, a geometry highly preferred by Cu(II). As a result, the reduction of Cu^IICu^ICu^I to Cu^ICu^ICu^I, in an unconstrained environment, could be coupled with chemical reactions, e.g. ligand dissociation/reorganization. In contrast, multicyclic ligand TREN₄ prevents such ligand dissociation and restrict solvent access to the tricopper centers, synergistically yielding small reorganization energy and fast ET rates.

Table 1 Inner-sphere reorganization energy (λ_i, eV) of 4 and 3

	Cu^IICu^ICu^I/Cu^ICu^ICu^I	Cu^IICu^IICu^I/Cu^IICu^ICu^I	Cu^IICu^IICu^II/Cu^IICu^IICu^I
a Experimental reorganization energies determined by electrochemical measurements. b Calculated reorganization energies by DFT.
4	0.53(1)^a	0.53(1)^a	0.18^b
	0.70^b	0.42^b
3	2.1^b	0.68^b	0.34^b

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The generation of the fully reduced Cu^ICu^ICu^I state is crucial for oxygen reduction reaction at MCO. Encouraged by the redox capability of 4, we studied its ability to reduce O₂. As followed by UV-vis spectroscopy (see ESI, Fig. S10†), fully reduced 4a slowly reduced O₂, while 4b and 4c did not react with O₂, consistent with the fact that generation of Cu^ICu^ICu^I state is required to harness the oxidative power of O₂. Addition of proton sources, e.g. acetic acid, significantly accelerated the rate of ORR. Complex 4b was regenerated in 96(2)% spectroscopic yield. The product of the O₂ reduction was assigned as H₂O₂ in 97(2)% yield based on iodometric titration (see ESI, Table S1†).⁵⁴ To elucidate the mechanism of ORR, we performed the reaction 4a with ¹⁸O₂ in the presence of acetic acid. The resulting solution of 4b was analyzed by ESI-MS for ¹⁸O incorporation. Spectrum simulations show 10% of ¹⁸O incorporation (Fig. S15†), indicating that the ORR most likely proceeds through an outer-sphere mechanism,⁵⁵ consistent with the predominant H₂O₂ selectivity.

Conclusions

In conclusion, we report that the encapsulation of tricopper core in a cryptand allows the redox of three Cu^II/Cu^I to be harnessed effectively in a homogeneous synthetic system. The tricopper complex was isolated and characterized in three of four oxidation states, showing that the redox-induced geometric changes were minimal. The encapsulated tricopper complex has self-exchange ET rates of 10⁵ to 10⁶ M⁻¹ s⁻¹, approaching Nature's copper electron transfer sites (blue copper protein 10⁵ to 10⁶ M⁻¹ s⁻¹). Marcus analysis indicates that the reorganization energy required for the reduction of 4b to 4a was 0.70 eV, much smaller than that for solvent-exposed 3 (2.1 eV). These results are particularly consistent with the minimal structural difference of 4 at Cu^ICu^ICu^I, Cu^IICu^ICu^I, and Cu^IICu^IICu^I state and suggest that multicyclic cryptands TREN₄ is effective at providing an isolated microenvironment. The geometric constraints and exclusion of solvent interactions synergistically reduce the reorganization energy of electron transfer. At last, we show that the fully reduced Cu^ICu^ICu^I cryptate can participate in oxygen reduction reaction. Taken together, our work provides insights into Nature strategy in leveraging the cooperativity of multimetallic sties in multielectron transformation. Our results show that redox processes not operational in bulk solution could potentially be accomplished by full encapsulation of the active site in an isolated environment.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

We are grateful for financial supports from OSU, ACS-PRF (59036-DNI3), and National Science Foundation (CHE-1904560). The authors thank The Ohio State University Department of Chemistry and Biochemistry for additional financial support. High-performance computing resources were provided by the Ohio Supercomputer Center.

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Footnote

† Electronic supplementary information (ESI) available: Experimental details, theoretical calculations, and supporting figures. CCDC 1987932 and 1984893–1984895. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/d0sc05441k

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