Nucleophilic reactivity of a copper(ii)-hydroperoxo complex

ABSTRACT Copper(II)-hydroperoxo species are often detected as key intermediates in metalloenzymes and biomimetic compounds containing copper. However, the only reactivity has previously been

observed for the copper(II)-hydroperoxo complexes is electrophilic, occurring through O-O bond cleavage. Here we report that a mononuclear end-on copper(II)-hydroperoxo complex, which has

been successfully characterized by various physicochemical methods including UV-vis, rRaman, CSI-MS and EPR, is a reactive oxidant that utilizes a nucleophilic mechanism. In addition, DFT

calculations fully support the electronic structure of this complex as a copper(II)-hydroperoxo complex with trigonal bipyramidal coordination geometry. A positive Hammett _ρ_ value (2.0(3))

is observed in the reaction of copper(II)-hydroperoxo complex with _para_-substituted acyl chlorides, which clearly indicates nucleophilic character for the copper(II)-hydroperoxo complex.

The copper(II)-hydroperoxo complex is an especially reactive oxidant in aldehyde deformylation with 2-PPA and CCA relative to the other metal-bound reactive oxygen species reported so far.

The observation of nucleophilic reactivity for a copper(II)-hydroperoxo species expands the known chemistry of metal-reactive oxygen species. SIMILAR CONTENT BEING VIEWED BY OTHERS TRAPPING

OF A PHENOXYL RADICAL AT A NON-HAEM HIGH-SPIN IRON(II) CENTRE Article 12 January 2024 COPPER-DEPENDENT HALOGENASE CATALYSES UNACTIVATED C−H BOND FUNCTIONALIZATION Article 29 January 2025

IRON-CATALYZED ALIPHATIC C–H FUNCTIONALIZATION TO CONSTRUCT CARBON–CARBON BONDS Article Open access 20 May 2025 INTRODUCTION Copper-bound reactive oxygen adducts, such as Cu-superoxo,

-peroxo, -hydroperoxo, and -oxyl radical species, have been proposed to be reactive intermediates in biological systems1,2. One such intermediate, specifically a Cu(II)-hydroperoxo complex,

has received much attention since it has been hypothesized to play an important role in the catalytic cycle of certain copper-containing enzymes (Fig. 1). In

peptidylglycine-_α_-hydroxylating monooxygenase (PHM) and dopamine-_β_-monooxygenase (D_β_M), it has been proposed that Cu(II)-hydroperoxo species were converted to Cu(II)-oxyl radicals and

water after electron and proton transfers3,4,5. The reactive species in lytic polysaccharide monooxygenases (LPMOs) has also been proposed to be a Cu(II)-hydroperoxo intermediate that

directly reacts with polysaccharides6,7,8,9. In synthetic chemistry, a number of Cu(II)-OOH species have been prepared and characterized by spectroscopic and crystallographic methods.

Masuda’s group reported the first crystal structure of the Cu(II)-OOH complex bearing a trigonal bipyramidal ligand where the hydroperoxo bound Cu(II) core was stabilized through

intramolecular hydrogen bonding interactions10. Most recently, stabilization of [Cu(biot-et-dpea)(OOH)]+ has been achieved in artificial proteins by using antigen-antibody interaction11. In

general, the reaction of Cu(II)-OOH complexes with substrates occurs through O–O bond cleavage to give putative Cu(II)-oxyl radical or Cu(III)-oxo species. Detailed studies on the ligand

hydroxylation by the putative intermediates have been reported by Karlin and co-workers12. Recently, it was also reported that the cleavage of Cu–O bond in Cu(II)-OOH species results in the

_N_-dealkylation through the Fenton chemistry13. Notably, to our knowledge no reports of direct reactions of Cu(II)-OOH species with external substrates, i.e., prior to O–O bond cleavage,

have yet appeared in the literature, although numerous examples of electrophilic reactivity in Cu(II)-OOH complexes have been shown to occur via O–O bond cleaved intermediates14,15,16. By

contrast the nucleophilic reaction of Cu(II)-alkylperoxo complexes was reported very recently17. Herein, we report the nucleophilic reactivity of the Cu(II)-hydroperoxo complex,

[Cu(_i_Pr3-tren)(OOH)]+ (1, _i_Pr3-tren = tris[2-(isopropylamino)ethyl]amine), which we find is capable of oxidation of organic carbonyl compounds directly. 1 was successfully characterized

by various spectroscopic methods such as UV-vis, resonance Raman (rRaman), and electron paramagnetic resonance (EPR) spectroscopy together with cold spray ionization mass spectrometry

(CSI-MS). The nucleophilic reactivity of 1 has also been investigated by kinetic studies including a Hammett analysis. RESULTS SYNTHESIS AND CHARACTERIZATION OF COPPER COMPLEXES As a

starting material, the copper(II) complex, [Cu(_i_Pr3-tren)(CH3CN)]2+, was synthesized by combining _i_Pr3-tren and Cu(ClO4)2·H2O in acetonitrile and characterized using UV-vis, electrospray

ionization mass spectrometry (ESI-MS) and X-ray crystallography (see the Supplementary Methods, Supplementary Tables 1 and 2, and Supplementary Figs. 1 and 2). The copper(II)-hydroperoxo

complex, [Cu(_i_Pr3-tren)(OOH)]+ (1), was generated by the addition of 5 equiv of H2O2 and 2 equiv of TEA to [Cu(_i_Pr3-tren)(CH3CN)]2+ in CH3OH at –50 °C (Fig. 2). Spectrophotometric

titration used to monitor the formation of 1 revealed that 5 equiv of H2O2 is required for full formation (Supplementary Fig. 3). The intermediate 1 is observed to be metastable (e.g., ca.

5% decay for 1 h at –50 °C). The color of the solution changed from blue to green, with the final solution showing an intense band at 360 nm (_ε_ = 1300 M–1 cm–1) and two weak bands at 656

(_ε_ = 230 M–1 cm–1) and 830 nm (_ε_ = 270 M–1 cm–1) in the UV-vis spectrum, which are characteristic features of Cu(II)-hydroperoxo complexes (Fig. 3a)18,19,20,21,22,23,24. The former band

has been assigned to a LMCT band of the Cu(II)-OOH species, and the latter bands to the d-d transitions of the Cu(II) ion bearing a trigonal bipyramidal structure. The CSI-MS spectrum of 1

supported the formation of Cu(II)-hydroperoxo species, [Cu(_i_Pr3-tren)(OOH)]+ (1-16O2H) at a mass-to-charge ratio (_m/z_) of 368.2 (calcd _m/z_ 368.2; Fig. 3b, red line), together with some

unidentified species presumably resulting from the thermal instability of 1 (Supplementary Fig. 4). When the reactions were carried out with isotopically labeled H218O2 in CH3OH and 2H2O2

in CH3O2H, mass peaks corresponding to [Cu(_i_Pr3-tren)(18O18OH)]+ (1-18O2H) (Fig. 3b, blue line) and [Cu(_i_Pr3-tren)(OO2H)]+ (1-O22H) (Fig. 3b, green line) were observed at _m/z_ 372.2

(calcd _m/z_ 372.2) and 369.2 (calcd _m/z_ 369.2), respectively. The four-mass unit shift upon substitution of 16O with 18O demonstrates that 1 contains two oxygen atoms. The one-mass unit

shift in a deuterium isotope experiment verifies the existence of a hydroperoxide ligand in 1. The rRaman spectrum of 1 was collected using 405 nm excitation in CH3OH at –30 °C (Fig. 3a,

inset). 1-16O2H exhibits two isotope sensitive bands at 834 and 501 cm−1, which shifted to 790 and 482 cm−1, respectively, in 1-18O2H. The results support the assignments of these features

as O–O and Cu–O stretching vibration on the basis of 16-18Δ value of 44 and 19 cm−1 (16-18Δ (calcd) = 48 and 23 cm−1 for diatomic harmonic oscillator), respectively18,19,20,21,22,23,24. Upon

2H-substitution in 1, the characteristic Cu–O and O–O stretching vibrational features exhibited a 2-cm−1 downshift each (Supplementary Fig. 5), which is comparable to those of a number of

metal-hydroperoxo species (Supplementary Table 3)24,25,26,27,28,29,30. The EPR spectrum of a frozen solution of 1 at 113 K shows a reverse axial signal with g┴ = 2.26 (_A_┴ = 108 G) and g║ =

 2.06 (_A_║ = 70 G), which is typical for trigonal bipyramidal five-coordinate Cu(II) complexes (Fig. 3c; see also Supplementary Fig. 6)2,18,31,32,33,34,35,36,37. Spin quantification finds

that the EPR signal corresponds to 91(6)% of the total copper content in the sample (see Supplementary Methods). All the spectroscopic results clearly show that 1 is assigned to be a

Cu(II)-hydroperoxo complex in trigonal bipyramidal geometry, which is further supported by DFT calculations (vide infra). COMPUTATIONAL STUDY To investigate the geometric structure of 1, DFT

calculations were conducted at the spin-unrestricted B3LYP level of theory (see Supplementary Methods). The optimized structure of 1 reveals the trigonal bipyramidal geometry whose axial

site is occupied by the hydroperoxo group in the manner of end-on replacing an acetonitrile of [Cu(_i_Pr3-tren)(CH3CN)]2+ (Fig. 2, and see also Supplementary Table 4). This result is in

agreement with the result of EPR spectroscopy described above. The calculated O–O bond distance is determined to be 1.46 Å, which is very close to that determined crystallographically for

Masuda’s Cu(II)-hydroperoxo complex (1.460 Å)10 and also that observed for homoprotocatechuate 2,3-dioxygenase (1.5 Å)38. TD-DFT calculations were employed to investigate the electronic

structure of 1. The calculated spectrum exhibits an intense peak at 368 nm and multiple weak peaks in the range from 650 to 850 nm which are seen in experimental UV-Vis spectrum

(Supplementary Fig. 7). The peak at 368 nm was comprised of electron transitions from overlapped orbitals between the ligand and Cu d-orbitals to σ* orbital of the dz2 orbital in Cu and pz

orbital in O2H. The minor peaks in the range from 650 to 850 nm are assigned as electron transitions between π* orbitals of Cu-OOH moieties. The singly occupied molecular orbital (SOMO) for

1 was observed to be σ* orbital whose spin density distribution was calculated indicating that about half a radical belongs to Cu center and the rest is contained in the O2H group and ligand

in doublet state (Supplementary Fig. 8; Supplementary Table 5). Natural population analysis (NPA) depicted atomic charges for 1, which demonstrates that the proximal oxygen atom possesses

more negative charge than the distal oxygen atom (Supplementary Fig. 9)39. Thus, overall calculations are indicative of a trigonal bipyramidal Cu(II)-hydroperoxo intermediate for 1.

REACTIVITY STUDY OF 1 The reactivity of 1 was examined in oxidation reaction with organic substrates. The electrophilic reactivity of 1 was tested in the oxidation of triphenylphosphine

(i.e., oxygen atom transfer) and cyclohexadiene (i.e., hydrogen atom abstraction). Upon addition of the substrates to 1 in CH3OH at –50 °C, 1 remained intact without showing any spectral

changes (Supplementary Fig. 10). Only trace amounts of products were detected in the product analysis of the reaction solutions. These results indicate that 1 is not capable of oxidizing

substrates in electrophilic oxidation under the reaction conditions. NUCLEOPHILIC REACTION WITH ACYL CHLORIDE The nucleophilic character of 1 was established in oxidation of acyl chlorides,

which are electrophile substrates. On the addition of 100 equiv of benzoyl chloride (PhCOCl) to 1 in CH3OH at –50 °C, the characteristic absorption bands of 1 disappeared through a

first-order decay profile (Fig. 4a). After the reaction was completed, product analysis revealed the formation of benzoic acid in a quantitative yield (Supplementary Table 6). Reaction of 1

with a series of _para_-substituted benzoyl chlorides (_para_-X-PhCOCl, X = OCH3, CH3, F, H, Cl) gave a linear correlation of the Hammett plot of the first-order rate constant against _σ_p+

resulting a _ρ_ value of 2.0(3) (Fig. 4b). The positive _ρ_ value indicates nucleophilic character for 1. ALDEHYDE DEFORMYLATION REACTION It is well known that metal-peroxo species are

frequently capable of nucleophilic reactivity. Since it has been reported that the iron-hydroperoxo species is much more reactive than the corresponding iron-peroxo species in aldehyde

deformylation40, the reactivity of 1 was further examined in the oxidation of 2-phenylpropionaldehyde (2-PPA) and cyclohexylcarboxaldehyde (CCA). Kinetic studies of 1 with CCA in CH3OH at

–70 °C exhibit a pseudo-first-order reaction profile (Supplementary Fig. 11). A plot of the first-order rate constants against the concentration of CCA shows a linear correlation, giving a

second-order rate constant (_k_2) of 6.5(3) M–1 s–1 (Fig. 5a). Similarly, the _k_2 value of 1.5(1)×10–1 M–1 s–1 was determined in the reaction of 1 and 2-PPA at –50 °C (Supplementary Fig. 

12b). Cyclohexene (84(9)%) and acetophenone (93(7)%) were obtained in the oxidation of CCA and 2-PPA, respectively, as final products. Also 1 changed back to the Cu(II) precursor after

completion of aldehyde deformylation reaction (Supplementary Fig. 13). The _k_2 values were dependent on the reaction temperature where the activation parameters for oxidation of aldehydes

by 1 were determined to be _ΔH_‡ = 23(1) kJ mol–1 and _ΔS_‡ = −112(2) J mol–1 K–1 in the range of 193–223 K for CCA (Fig. 5b), and _ΔH_‡ = 31(1) kJ mol–1 and _ΔS_‡ = −118(7) J mol–1 K–1 in

the range of 213–243 K for 2-PPA (Supplementary Fig. 12c). A bimolecular mechanism for the nucleophilic oxidative reaction by 1 is suggested by the observed negative entropy and the

second-order kinetics. Compared with the reactivity of a previously reported iron(III)-hydroperoxo complex40 and copper(II)-alkylperoxo adducts17, the reactivity of 1 (_k_2 = 3.6 × 10–1 M–1 

s–1 at –40 °C) is higher than that of the iron(III)-hydroperoxo species (_k_2 = 1.3 × 10–1 M–1 s–1 at –40 °C) and those of copper(II)-alkylperoxo complexes (_k_2 = 1.2–1.8 × 10–1 M–1 s–1 at

–40 °C) in aldehyde deformylation of 2-PPA (Supplementary Table 7). It should be noted that the reactivity of 1 (_k_2 = 3.4 M–1 s–1 at –80 °C) with CCA is also higher than that of a

Cu(II)-superoxo complex, [Cu(_β_DK)(O2)]– (_k_2 = 1.4 M–1 s–1 at –80 °C), which was a highly reactive oxidant in aldehyde deformylation reported so far (Supplementary Table 8)41. Very

recently, it has been reported that an anionic copper(II)-superoxo complex acts as a base than a nucleophile in the aldehyde deformylation of wet 2-PPA42. Furthermore, nucleophilic

reactivity has been observed for an Fe(III) porphyrin peroxo complex in the epoxidation of electron-deficient olefins43,44. Thus, we also explored epoxidation of olefins such as cyclohexene

and 2-cyclohexene-1-one, which is an electron-deficient olefin, by 1 in CH3OH at –50 °C (Supplementary Figs. 14 and 15). Product analyses of the reaction solutions with olefins did not show

oxidized products. These results suggest that 1 lacked reactivity in the epoxidation of electron-deficient olefins. DISCUSSION Based on the results of kinetic and product analyses, there are

two possible initial steps for the nucleophilic reaction, a proximal oxygen attack and a distal oxygen attack by 1 (Fig. 6). The formation of a peroxyhemiacetal intermediate initially

proceeds via an attack of the proximal oxygen to the carbonyl center of aldehydes, while the formation of a [Cu(_i_Pr3-tren)]2+ bound peroxyhemiacetal-like species occurs through a proton

transfer and a distal oxygen attack to the aldehydes. The calculated atomic charge distribution of the proximal oxygen (–0.60) from NPA is more negative than that of the distal oxygen

(–0.49) (Supplementary Fig. 8), supporting the proximal oxygen attack mechanism. However, the negative charge difference is small. Thus, further detailed DFT studies such as reaction

coordinate calculations are under investigation. In this study, we have demonstrated the oxidation of organic carbonyl compounds by 1, giving the first, to our knowledge, example of

nucleophilic reactivity of a copper(II)-hydroperoxo complex. 1 was characterized by various methods such as UV-vis, CSI-MS, rRaman and EPR. These results clearly indicate that 1 is an end-on

Cu(II)-hydroperoxo complex with trigonal bipyramidal coordination geometry, which is also supported by isotope labeling experiments and DFT calculations. The nucleophilic character of 1 was

confirmed by a positive slop in the Hammett plot for the reaction of 1 and _para_-substituted acyl chlorides. Kinetic studies represent that 1 is a very reactive nucleophilic oxidant in

aldehyde deformylation. We believe the observed oxidative nucleophilic reactivity of 1 demonstrates a new class of reactivity for Cu(II)-hydroperoxo intermediates. METHODS PREPARATION OF

[CU(_I_PR3-TREN)(CH3CN)](CLO4)2 [Cu(_i_Pr3-tren)(CH3CN)](ClO4)2 was prepared by reacting Cu(ClO4)2·6H2O (0.185 g, 0.50 mmol) and tris[2-(isopropylamino)ethyl]amine (_i_Pr3-tren) (176.42 

_μ_L, 0.50 mmol) in CH3CN (3.0 mL). The mixture was stirred for 12 h, giving a blue solution. Et2O (40 mL) was added to the resulting solution to yield a blue powder, which was collected by

filtration, washed with Et2O, and dried in a vacuo. Yield: 97% (0.2799 g). X-ray crystallographically suitable crystals were obtained by slow diffusion of Et2O into a solution of the complex

in CH3CN (Supplementary Table 1 and 2; Supplementary Fig. 1). ESI-MS in CH3CN (Supplementary Fig. 2): _m/z_ 167.6 for [Cu(_i_Pr3-tren)]2+, _m/z_ 188.2 for [Cu(_i_Pr3-tren)(CH3CN)]2+, _m/z_

208.7 for [Cu(_i_Pr3-tren)(CH3CN)2]2+, and _m/z_ 434.3 for [Cu(_i_Pr3-tren)](ClO4)+. Anal. Calcd for C17H39CuN5O8: C, 35.45; H, 6.82; N, 12.16. Found: C, 35.54; H, 7.05; N, 12.16. The

effective magnetic moment of _μ_eff = 1.8 B.M. was determined by 1H NMR Evans method in CD3CN at 25 °C. GENERATION OF [CU(_I_PR3-TREN)(OOH)]+ (1) Treatment of [Cu(_i_Pr3-tren)(CH3CN)](ClO4)2

(1 mM) with 5 equiv of H2O2 in the presence of 2 equiv of triethylamine (TEA) in CH3OH at −50 °C afforded a green solution. [Cu(_i_Pr3-tren)(18O18OH)]+ and [Cu(_i_Pr3-tren)(OO2H)]+ were

prepared by adding 5 equiv of H218O2 (36 μL, 95% 18O-enriched, 2.2% H218O2 in water) and 5 equiv of 2H2O2 (30% in 2H2O), respectively, to a solution containing

[Cu(_i_Pr3-tren)(CH3CN)](ClO4)2 (1 mM) and 2 equiv of TEA in CH3OH at −50 °C. UV-vis in CH3OH: _λ_max (_ε_) = 360 nm (1300 M−1 cm−1), 656 nm (230 M−1 cm−1) and 830 nm (270 M−1 cm−1). X-RAY

CRYSTALLOGRAPHY See Supplementary Methods, Supplementary Fig. 1, and Supplementary Tables 1 and 2. COMPUTATIONAL DETAILS See Supplementary Methods, Supplementary Figs. 6, 7, and 8, and

Supplementary Tables 4 and 5. REACTIVITY STUDIES See Supplementary Methods, Supplementary Figs. 9–14, and Supplementary Tables 6–8. DATA AVAILABILITY The X-ray crystallographic coordinates

for the structures reported in this Article have been deposited at the Cambridge Crystallographic Data Centre (CCDC), under deposition number CCDC-1879280. These data can be obtained free of

charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/ data_request/cif. All other data are available from the corresponding author upon reasonable request.

REFERENCES * Elwell, C. E. et al. Copper−oxygen complexes revisited: structures, spectroscopy, and reactivity. _Chem. Rev._ 117, 2059–2107 (2017). Article  CAS  Google Scholar  * Solomon, E.

I. et al. Copper active sites in biology. _Chem. Rev._ 114, 3659–3853 (2014). Article  CAS  Google Scholar  * Pettingill, T. M., Strange, R. W. & Blackburn, N. J. Carbonmonoxy dopamine

_β_ -hydroxylase. _J. Biol. Chem._ 266, 16996–17003 (1991). CAS  PubMed  Google Scholar  * Prigge, S. T., Kolhekar, A. S., Eipper, B. A., Mains, R. E. & Amzel, L. M. Amidation of

bioactive peptides: the structure of peptidylglycine _α_-hydroxylating monooxygenase. _Science_ 278, 1300–1305 (1997). Article  CAS  Google Scholar  * Klinman, J. P. The copper-enzyme family

of dopamine _β_-monooxygenase and peptidylglycine _α_-hydroxylating monooxygenase: resolving the chemical pathway for substrate hydroxylation. _J. Biol. Chem._ 281, 3013–3016 (2006).

Article  CAS  Google Scholar  * Luisa, C., Gideon, J. D., William, B. T. & Paul, H. W. Bracing copper for the catalytic oxidation of C–H bonds. _Nat. Catal._ 1, 571–577 (2018). Article 

Google Scholar  * Hemsworth, G. R., Henrissat, B., Davies, G. J. & Walton, P. H. Discovery and characterization of a new family of lytic polysaccharide monooxygenases. _Nat. Chem. Biol._

10, 122–126 (2014). Article  CAS  Google Scholar  * Kim, S., Stahlberg, J., Sandgren, M., Paton, R. S. & Beckham, G. T. Quantum mechanical calculations suggest that lytic polysaccharide

monooxygenases use a copper-oxyl, oxygen-rebound mechanism. _Proc. Natl Acad. Sci. USA_ 111, 149–154 (2014). Article  CAS  Google Scholar  * Hedegård, E. D. & Ryde, U. Molecular

mechanism of lytic polysaccharide monooxygenases. _Chem. Sci._ 9, 3866–3880 (2018). Article  Google Scholar  * Wada, A. et al. Structural and spectroscopic characterization of a mononuclear

hydroperoxo - copper(II) complex with tripodal pyridylamine ligands. _Angew. Chem. Int. Ed._ 37, 798–799 (1998). Article  CAS  Google Scholar  * Mann, S. I., Heinisch, T., Ward, T. R. &

Borovik, A. S. Peroxide activation Regulated by hydrogen bonds within artificial Cu proteins. _J. Am. Chem. Soc._ 139, 17289–17292 (2017). Article  CAS  Google Scholar  * Maiti, D., Lucas,

H. R., Narducci Sarjeant, A. A. & Karlin, K. D. Aryl hydroxylation from a mononuclear copper-hydroperoxo species. _J. Am. Chem. Soc._ 129, 6998–6999 (2007). Article  CAS  Google Scholar

  * Kim, S. et al. Amine oxidative N-dealkylation via cupric hydroperoxide Cu–OOH homolytic cleavage followed by site-specifc fenton chemistry. _J. Am. Chem. Soc._ 137, 2867–2874 (2015).

Article  CAS  Google Scholar  * Maiti, D., Sarjeant, A. A. N. & Karlin, K. D. Copper-hydroperoxo-mediated N-debenzylation chemistry mimicking aspects of copper monooxygenases. _Inorg.

Chem._ 47, 8736–8747 (2008). Article  CAS  Google Scholar  * Li, L., Sarjeant, A. A. N. & Karlin, K. D. Reactivity study of a hydroperoxodicopper(II) complex: hydroxylation,

dehydrogenation, and ligand cross-link reactions. _Inorg. Chem._ 45, 7160–7172 (2006). Article  CAS  Google Scholar  * Li, L. et al. Exogenous nitrile substrate hydroxylation by a new

dicopper-hydroperoxide complex. _J. Am. Chem. Soc._ 127, 15360–15361 (2005). Article  CAS  Google Scholar  * Kim, B., Jeong, D. & Cho, J. Nucleophilic reactivity of

copper(II)–alkylperoxo complexes. _Chem. Commun._ 53, 9328–9331 (2017). Article  CAS  Google Scholar  * Choi, Y. J. et al. Spectroscopic and computational characterization of CuII–OOR (R = H

or cumyl) complexes bearing a Me6-tren ligand. _Dalton Trans._ 40, 2234–2241 (2011). Article  CAS  Google Scholar  * Yamaguchi, S. et al. Synthesis, characterization, and thermal stability

of new mononuclear hydrogenperoxocopper(II) complexes with N3O-type tripodal ligands bearing hydrogen-bonding interaction sites. _Bull. Chem. Soc. Jpn_ 78, 116–124 (2005). Article  CAS 

Google Scholar  * Yamaguchi, S. et al. Thermal stability of mononuclear hydroperoxocopper(II) species. Effects of hydrogen bonding and hydrophobic field. _Chem. Lett._ 33, 1556–1557 (2004).

Article  CAS  Google Scholar  * Fujii, T. et al. Mononuclear copper(II)–hydroperoxo complex derived from reaction of copper(I) complex with dioxygen as a model of D_β_M and PHM. _Chem.

Commun._ 0, 4428–4430 (2006). Article  CAS  Google Scholar  * Yamaguchi, S. et al. Copper hydroperoxo species activated by hydrogen-bonding interaction with its distal oxygen. _Inorg. Chem._

42, 6968–6970 (2003). Article  CAS  Google Scholar  * Kim, S., Saracini, C., Siegler, M. A., Drichko, N. & Karlin, K. D. Coordination chemistry and reactivity of a cupric hydroperoxide

species featuring a proximal H‑bonding substituent. _Inorg. Chem._ 51, 12603–12605 (2012). Article  CAS  Google Scholar  * Chen, P., Fujisawa, K. & Solomon, E. I. Spectroscopic and

theoretical studies of mononuclear copper(II) alkyl- and hydroperoxo complexes: electronic structure contributions to reactivity. _J. Am. Chem. Soc._ 122, 10177–10193 (2000). Article  CAS 

Google Scholar  * Denisov, I. G., Mak, P. J., Makris, T. M., Sligar, S. G. & Kincaid, J. R. Resonance raman characterization of the peroxo and hydroperoxo intermediates in cytochrome

P450. _J. Phys. Chem. A_ 112, 13172–13179 (2008). Article  CAS  Google Scholar  * Mak, P. J., Thammawichai, W., Wiedenhoeft, D. & Kincaid, J. R. Resonance Raman spectroscopy reveals

pH-dependent active site structural changes of lactoperoxidase compound 0 and its ferryl heme O–O bond cleavage products. _J. Am. Chem. Soc._ 137, 349–361 (2015). Article  CAS  Google

Scholar  * Ibrahim, M., Denisov, I. G., Makris, T. M., Kincaid, J. R. & Sligar, S. G. Resonance raman spectroscopic studies of hydroperoxo-myoglobin at cryogenic temperatures. _J. Am.

Chem. Soc._ 125, 13714–13718 (2003). Article  CAS  Google Scholar  * Mak, P. J. et al. Resonance Raman detection of the hydroperoxo intermediate in the cytochrome P450 enzymatic cycle. _J.

Am. Chem. Soc._ 129, 6382–6383 (2007). Article  CAS  Google Scholar  * He, C. et al. Diiron complexes of 1,8-naphthyridine-based dinucleating ligands as models for hemerythrin. _J. Am. Chem.

Soc._ 122, 12683–12690 (2000). Article  CAS  Google Scholar  * Mak, P. J. & Kincaid, J. R. Resonance Raman spectroscopic studies of hydroperoxo derivatives of cobalt-substituted

myoglobin. _J. Inorg. Biochem._ 102, 1952–1957 (2008). Article  CAS  Google Scholar  * Lucchese, B. et al. Mono-, bi-, and trinuclear CuII-Cl containing products based on the

tris(2-pyridylmethyl)amine chelate derived from copper(I) complex dechlorination reactions of chloroform. _Inorg. Chem._ 43, 5987–5998 (2004). Article  CAS  Google Scholar  * Barbucci, R.,

Bencini, A. & Gatteschi, D. Electron spin resonance spectra and spin-hamiltonian parameters for trigonal-bipyramidal nickel(I) and copper(II) complexes. _Inorg. Chem._ 16, 2117–2120

(1977). Article  CAS  Google Scholar  * Kooter, I. M. et al. EPR characterization of the mononuclear Cu-containing _aspergillus japonicus_ quercetin 2,3-dioxygenase reveals dramatic changes

upon anaerobic binding of substrates. _Eur. J. Biochem._ 269, 2971–2979 (2002). Article  CAS  Google Scholar  * Addison, A. W., Hendriks, H. M. J., Reedijk, J. & Thompson, L. K. Copper

complexes of the “tripod” ligand tris(2-benzimidazolylmethyl)amine: five- and six-coordinate copper(II) derivatives and some copper(I) derivatives. _Inorg. Chem._ 20, 103–110 (1981). Article

  CAS  Google Scholar  * Thompson, L. K., Ramaswamy, B. S. & Dawe, R. D. Nickel(II) and copper(II) complexes of the ‘tripod’ ligand tris(2-benzimidazylmethy1)amine. _Can. J. Chem._ 56,

1311–1318 (1978). Article  CAS  Google Scholar  * Senyukova, G. A., Mikheikin, I. D. & Zamaraev, K. I. EPR spectra of the complex [Cu(tren)OH]+ which has a trigonal bipyramidal

structure. _J. Struct. Chem._ 11, 18–21 (1970). Article  Google Scholar  * Jiang, F., Karlin, K. D. & Peisach, J. An electron spin echo envelope modulation (ESEEM) study of

electron-nuclear hyperfine and nuclear quadrupole interactions of dz 2 ground state copper(II) complexes with substituted imidazoles. _Inorg. Chem._ 32, 2576–2582 (1993). Article  CAS 

Google Scholar  * Kovaleva, E. G. & Lipscomb, J. D. Crystal structures of Fe2+ dioxygenase superoxo, alkylperoxo, and bound product intermediates. _Science_ 316, 453–457 (2007). Article

  CAS  Google Scholar  * Panda, C. et al. Nucleophilic versus electrophilic reactivity of bioinspired superoxido nickel(II) complexes. _Angew. Chem. Int. Ed._ 57, 14883–14887 (2018). Article

  CAS  Google Scholar  * Cho, J. et al. Structure and reactivity of a mononuclear non-haem iron(III)-peroxo complex. _Nature_ 478, 502–505 (2011). Article  CAS  Google Scholar  * Pirovano,

P. et al. Nucleophilic reactivity of a copper(II)–superoxide complex. _Angew. Chem. Int. Ed._ 53, 5946–5950 (2014). Article  CAS  Google Scholar  * Bailey, W. D. et al. Revisiting the

synthesis and nucleophilic reactivity of an anionic copper-superoxide complex. _Inorg. Chem._ 58, 4706–4711 (2019). Article  CAS  Google Scholar  * Sisemore, M. F., Burstyn, J. N. &

Valentine, J. S. Epoxidation of electron-deficient olefins by a nucleophilic iron(III) peroxo porphyrinato complex, peroxo(tetramesitylporphyrinato)ferrate(1-). _Angew. Chem. Int. Ed. Engl._

35, 206–208 (1996). Article  CAS  Google Scholar  * Selke, M. & Valentine, J. S. Switching on the nucleophilic reactivity of a ferric porphyrin peroxo complex. _J. Am. Chem. Soc._ 120,

2652–2653 (1998). Article  CAS  Google Scholar  Download references ACKNOWLEDGEMENTS The research was supported by NRF (2017R1A2B4005441 and 2018R1A5A1025511 to J.C.) and the Ministry of

Science, ICT and Future Planning (CGRC 2016M3D3A01913243 to J.C.) of Korea, and the Ministry of Education, Culture, Sports, Science and Technology of Japan through the “Strategic Young

Researcher Overseas Visits Program for Accelerating Brain Circulation to T.O.”. We thank Profs. Sachiko Yanagisawa and Minoru Kubo for assistance in acquiring rRaman spectra. AUTHOR

INFORMATION Author notes * Takehiro Ohta Present address: Faculty of Engineering, Department of Applied Chemistry, Sanyo-Onoda City University, 756-0884, Sanyo-Onoda, Yamaguchi, Japan

AUTHORS AND AFFILIATIONS * Department of Emerging Materials Science, DGIST, 42988, Daegu, Korea Bohee Kim, Donghyun Jeong & Jaeheung Cho * Picobiology Institute, Graduate School of Life

Science, University of Hyogo, RSC-LP Center, 679-5148, Hyogo, Japan Takehiro Ohta Authors * Bohee Kim View author publications You can also search for this author inPubMed Google Scholar *

Donghyun Jeong View author publications You can also search for this author inPubMed Google Scholar * Takehiro Ohta View author publications You can also search for this author inPubMed 

Google Scholar * Jaeheung Cho View author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS B.K. and J.C. conceived and designed the experiments; B.K.,

D.J., and T.O. performed the experiments; B.K., D.J., and J.C. analyzed the data; B.K., D.J., and J.C. co-wrote the paper. CORRESPONDING AUTHOR Correspondence to Jaeheung Cho. ETHICS

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T. _et al._ Nucleophilic reactivity of a copper(II)-hydroperoxo complex. _Commun Chem_ 2, 81 (2019). https://doi.org/10.1038/s42004-019-0187-3 Download citation * Received: 22 April 2019 *

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