Electro-Mechanochemical Atom Transfer Radical Cyclizations using Piezoelectric BaTiO3

The formation and regeneration of active Cu^I species is a fundamental mechanistic step in copper-catalyzed atom transfer radical cyclizations (ATRC). Typically, the presence of the catalytically active Cu^I species in the reaction mixture is secured by using high Cu^I catalyst loadings or the addition of complementary reducing agents. In this study it is demonstrated how the piezoelectric properties of barium titanate (BaTiO₃) can be harnessed by mechanical ball milling to induce electrical polarization in the strained piezomaterial. This strategy enables the conversion of mechanical energy into electrical energy, leading to the reduction of a Cu^II precatalyst into the active Cu^I species in copper-catalyzed mechanochemical solvent-free ATRC reactions.     

The Development of Copper‐Catalyzed Aerobic Oxidative Coupling of H‐Tetrazoles with Boronic Acids and an Insight into the Reaction Mechanism

The development of a highly efficient and practical protocol for the direct C?N coupling of H‐tetrazole and boronic acid was presented. A careful and patient optimization of a variety of reaction parameters revealed that this conventionally challenge reaction could indeed proceed efficiently in a very simple system, that is, just by stirring the tetrazoles and boronic acids under oxygen in the presence of different Cu^I or Cu^II salts with only 5 mol % loading in DMSO at 100 °C. Most significantly, the reaction could proceed very smoothly in a regiospecific manner to afford the 2,5‐disubstituted tetrazoles in high to excellent yields. A mechanistic study revealed that both tetrazole and DMSO are crucial for the generation of catalytically active copper species in the reaction process in addition to their role as reactant and solvent, respectively. It is demonstrated that in the reaction cycle, the Cu^I catalyst could be oxidized to Cu^II by oxygen to form a [CuT₂D] complex (T=tetrazole anion; D=DMSO) through an oxidative copper amination reaction. The Cu^II complex thus formed was confirmed to be the real catalytically active copper species. Namely, the Cu^II complex disproportionates to aryl Cu^III and Cu^I in the presence of boronic acid. Facile elimination of the Cu^III species delivers the C?N‐coupled product. The results presented herein not only provide a reliable and efficient protocol for the synthesis of 2,5‐disubstituted tetrazoles, but most importantly, the mechanistic results would have broad implications for the de novo design and development of new methods for Cu‐catalyzed coupling reactions.     

Harnessing the Dual Properties of Thiol‐Grafted Cellulose Paper for Click Reactions: A Powerful Reducing Agent and Adsorbent for Cu

A new approach exploiting the dual properties of thiol‐grafted cellulose paper for promoting copper‐catalyzed [3+2]‐cycloadditions of organic azides with alkynes and adsorbing residual copper species in solution was developed. The thiol‐grafted cellulose paper, used as a paper strip, effects the reduction of Cu^II to catalytically active Cu^I and acts as a powerful adsorbent for copper, thereby facilitating the work‐up process and leaving the crude mixture almost free of copper residues after a single filtration.     

Evidence of CuI/CuII Redox Process by X‐ray Absorption and EPR Spectroscopy: Direct Synthesis of Dihydrofurans from β‐Ketocarbonyl Derivatives and Olefins

The Cu^I/Cu^II and Cu^I/Cu^III catalytic cycles have been subject to intense debate in the field of copper‐catalyzed oxidative coupling reactions. A mechanistic study on the Cu^I/Cu^II redox process, by X‐ray absorption (XAS) and electron paramagnetic resonance (EPR) spectroscopies, has elucidated the reduction mechanism of Cu^II to Cu^I by 1,3‐diketone and detailed investigation revealed that the halide ion is important for the reduction process. The oxidative nature of the thereby‐formed Cu^I has also been studied by XAS and EPR spectroscopy. This mechanistic information is applicable to the copper‐catalyzed oxidative cyclization of β‐ketocarbonyl derivatives to dihydrofurans. This protocol provides an ideal route to highly substituted dihydrofuran rings from easily available 1,3‐dicarbonyls and olefins.     

A Photoreducible Copper(II)‐Tren Complex of Practical Value: Generation of a Highly Reactive Click Catalyst

A detailed study on the photoreduction of the copper(II) precatalyst 1 to generate a highly reactive cuprous species for the copper(I)‐catalyzed alkyne‐azide cycloaddition (CuAAC) click reaction is presented. For the photoactive catalyst described herein, the activation is driven by a photoinduced electron transfer (PET) process harnessing a benzophenone‐like ketoprofenate chromophore as a photosensitizer, which is equally the counterion. The solvent is shown to play a major role in the Cu^II to Cu^I reduction process as the final electron source, and the influence of the solvent nature on the photoreduction efficiency has been studied. Particular attention was paid to the use of water as a potential solvent, aqueous media being particularly appealing for CuAAC processes. The ability to solubilize the copper‐tren complexes in water through the formation of inclusion complexes with β‐CDs is demonstrated. Data is also provided on the fate of the copper(I)‐tren catalytic species when reacting with O₂, O₂ being used to switch off the catalysis. These data show that partial oxidation of the secondary benzylamine groups of the ligand to benzylimines occurs. Preliminary results show that when prolonged irradiation times are employed a Cu^I to Cu⁰ over‐reduction process takes place, leading to the formation of copper nanoparticles (NPs). Finally, the main objective of this work being the development of photoactivable catalysts of practical value for the CuAAC, the catalytic, photolatent, and recycling properties of 1 in water and organic solvents are reported.     

Visible‐Light‐Accelerated Copper(II)‐Catalyzed Regio‐ and Chemoselective Oxo‐Azidation of Vinyl Arenes

The visible‐light‐accelerated oxo‐azidation of vinyl arenes with trimethylsilylazide and molecular oxygen as stoichiometric oxidant was achieved. In contrast to photocatalysts based on iridium, ruthenium, or organic dyes, [Cu(dap)₂]Cl or [Cu(dap)Cl₂] were found to be unique for this transformation, which is attributed to their ability to interact with the substrates through ligand exchange and rebound mechanisms. Cu^II is proposed as the catalytically active species, which upon coordinating azide will undergo light‐accelerated homolysis to form Cu^I and azide radicals. This activation principle (Cu^II‐X→Cu^I+X^.) opens up new avenues for copper‐based photocatalysis.     

Selective Alcohol Oxidation by a Copper TEMPO Catalyst: Mechanistic Insights by Simultaneously Coupled Operando EPR/UV‐Vis/ATR‐IR Spectroscopy

The first coupled operando EPR/UV‐Vis/ATR‐IR spectroscopy setup for mechanistic studies of gas‐liquid phase reactions is presented and exemplarily applied to the well‐known copper/TEMPO‐catalyzed (TEMPO=(2,2,6,6‐tetramethylpiperidin‐1‐yl)oxyl) oxidation of benzyl alcohol. In contrast to previous proposals, no direct redox reaction between TEMPO and Cu^I/Cu^II has been detected. Instead, the role of TEMPO is postulated to be the stabilization of a (bpy)(NMI)Cu^II‐O₂^??‐TEMPO (bpy=2,2′‐bipyridine, NMI=N‐methylimidazole) intermediate formed by electron transfer from Cu^I to molecular O₂.     

Molecular CuII‐O‐CuII Complexes: Still Waters Run Deep

Research on O₂ activation at ligated Cu^I is fueled by its biological relevance and the quest for efficient oxidation catalysts. A rarely observed reaction is the formation of a Cu^II‐O‐Cu^II species, which is more special than it appears at first sight: a single oxo ligand between two Cu^II centers experiences considerable electron density, and this makes the corresponding complexes reactive and difficult to access. Hence, only a small number of these compounds have been synthesized and characterized unequivocally to date, and as biological relevance was not apparent, they remained unappreciated. However, recently they moved into the spotlight, when Cu^II‐O‐Cu^II cores were proposed as the active species in the challenging oxidation of methane to methanol at the surface of a Cu‐grafted zeolite and in the active center of the copper enzyme particulate methane monooxygenase. This Minireview provides an overview of these systems with a special focus on their reactivity and spectroscopic features.     

Photoswitchable Sol–Gel Transitions and Catalysis Mediated by Polymer Networks with Coumarin‐Decorated Cu24L24 Metal–Organic Cages as Junctions

Photoresponsive materials that change in response to light have been studied for a range of applications. These materials are often metastable during irradiation, returning to their pre‐irradiated state after removal of the light source. Herein, we report a polymer gel comprising poly(ethylene glycol) star polymers linked by Cu₂₄L₂₄ metal–organic cages/polyhedra (MOCs) with coumarin ligands. In the presence of UV light, a photosensitizer, and a hydrogen donor, this “polyMOC” material can be reversibly switched between Cu^II, Cu^I, and Cu⁰. The instability of the MOC junctions in the Cu^I and Cu⁰ states leads to network disassembly, forming Cu^I/Cu⁰ solutions, respectively, that are stable until re‐oxidation to Cu^II and supramolecular gelation. This reversible disassembly of the polyMOC network can occur in the presence of a fixed covalent second network generated in situ by copper‐catalyzed azide‐alkyne cycloaddition (CuAAC), providing interpenetrating supramolecular and covalent networks.     

The Glutathione/Metallothionein System Challenges the Design of Efficient O2‐Activating Copper Complexes

Copper complexes are of medicinal and biological interest, including as anticancer drugs designed to cleave intracellular biomolecules by O₂ activation. To exhibit such activity, the copper complex must be redox active and resistant to dissociation. Metallothioneins (MTs) and glutathione (GSH) are abundant in the cytosol and nucleus. Because they are thiol‐rich reducing molecules with high Cu^I affinity, they are potential competitors for a copper ion bound in a copper drug. Herein, we report the investigation of a panel of Cu^I/Cu^II complexes often used as drugs, with diverse coordination chemistries and redox potentials. We evaluated their catalytic activity in ascorbate oxidation based on redox cycling between Cu^I and Cu^II, as well as their resistance to dissociation or inactivation under cytosolically relevant concentrations of GSH and MT. O₂‐activating Cu^I/Cu^II complexes for cytosolic/nuclear targets are generally not stable against the GSH/MT system, which creates a challenge for their future design.     

Palladium Catalysis for Aerobic Oxidation Systems Using Robust Metal–Organic Framework

Described here is a new and viable approach to achieve Pd catalysis for aerobic oxidation systems (AOSs) by circumventing problems associated with both the oxidation and the catalysis through an all‐in‐one strategy, employing a robust metal–organic framework (MOF). The rational assembly of a Pd^II catalyst, phenanthroline ligand, and Cu^II species (electron‐transfer mediator) into a MOF facilitates the fast regeneration of the Pd^II active species, through an enhanced electron transfer from in situ generated Pd⁰ to Cu^II, and then Cu^I to O₂, trapped in the framework, thus leading to a 10 times higher turnover number than that of the homogeneous counterpart for Pd‐catalyzed desulfitative oxidative coupling reactions. Moreover, the MOF catalyst can be reused five times without losing activity. This work provides the first exploration of using a MOF as a promising platform for the development of Pd catalysis for AOSs with high efficiency, low catalyst loading, and reusability.     

A mixed‐valence chair‐like tetranuclear copper(I,II) cluster with three linking modes of the 3,5‐bis(2‐pyridyl)‐1,2,4‐triazole ligand

In the tetranuclear copper complex tetrakis[μ‐3,5‐bis(2‐pyridyl)‐1,2,4‐triazolido]bis[3,5‐bis(2‐pyridyl)‐1,2,4‐triazolido]dicopper(I)dicopper(II) dihydrate, [Cu^I₂Cu^II₂(C₁₂H₈N₅)₆]·2H₂O, the asymmetric unit is composed of one Cu^I center, one Cu^II center, three anionic 3,5‐bis(2‐pyridyl)‐1,2,4‐triazole (2‐BPT) ligands and one solvent water molecule. The Cu^I and Cu^II centers exhibit [Cu^IN₄] tetrahedral and [Cu^IIN₆] octahedral coordination environments, respectively. The three independent 2‐BPT ligands adopt different chelating modes, which link the copper centers to generate a chair‐like tetranuclear metallomacrocycle with metal–metal distances of about 4.4 × 6.2 Å disposed about a crystallographic inversion center. Furthermore, strong π–π stacking interactions and O—H...N hydrogen‐bonding systems link the tetracopper clusters into a two‐dimensional supramolecular network.     

Palladium‐Catalyzed Aerobic Intermolecular Cyclization of Acrylic Acid with 1‐Octene to Afford α‐Methylene‐γ‐butyrolactones: The Remarkable Effect of Continuous Water Removal from the Reaction Mixture and Analysis of the Reaction by Kinetic,ESI‐MS,and XAFS Measurements

Further study of our aerobic intermolecular cyclization of acrylic acid with 1‐octene to afford α‐methylene‐γ‐butyrolactones, catalyzed by the Pd(OCOCF₃)₂/Cu(OAc)₂ ? H₂O system, has clarified that the accumulation of water generated from oxygen during the reaction causes deactivation of the Cu cocatalyst. This prevents regeneration of the active Pd catalyst and, thus, has a harmful influence on the progress of the cyclization. As a result, both the substrate conversion and product yield are efficiently improved by continuous removal of water from the reaction mixture. Detailed analysis of the kinetic and spectroscopic measurements performed under the condition of continuous water removal demonstrates that the cyclization proceeds in four steps: 1) equilibrium coordination of 1‐octene to the Pd acrylate species, 2) Markovnikov‐type acryloxy palladation of 1‐octene (1,2‐addition), 3) intramolecular carbopalladation, and 4) β‐hydride elimination. Byproduct 2‐acryloxy‐1‐octene is formed by β‐hydride elimination after step 2). These cyclization steps fit the Michaelis–Menten equation well and β‐hydride elimination is considered to be a rate‐limiting step in the formation of the products. Spectroscopic data agree sufficiently with the existence of the intermediates bearing acrylate (Pd? O bond), η³‐C₈H₁₅ (Pd? C bond), or C₁₁H₁₉O₂ (Pd? C bond) moieties on the Pd center as the resting‐state compounds. Furthermore, not only Cu^II, but also Cu^I, species are observed during the reaction time of 2–8 h when the reaction proceeds efficiently. This result suggests that the Cu^II species is partially reduced to the Cu^I species when the active Pd catalytic species are regenerated.     

Syntheses and crystal structures of two heterometallic iodoplumbates containing mixed‐valence copper(I/II)

Mixed‐valence copper(I/II) atoms have been introduced successfully into a Pb/I skeleton to obtain two heterometallic iodoplumbates, namely poly[bis(tetra‐n‐butylammonium) [bis(μ₃‐dimethyldithiocarbamato)dodeca‐μ₃‐iodido‐hexa‐μ₂‐iodido‐tetracopper(I)copper(II)hexalead(II)]], {(C₁₆H₃₆N)₂[Cu₄^ICu^IIPb₆(C₃H₆NS₂)₂I₁₈]}_n , (I), and poly[[μ₃‐iodido‐tri‐μ₂‐iodido‐iodido[bis(1,10‐phenanthroline)copper(I)]copper(I)copper(II)lead(II)] hemiiodine], {[Cu^ICu^IIPbI₅(C₁₂H₈N₂)₂]·0.5I₂}_n , (II), under solution and solvothermal conditions, respectively. Compound (I) contains two‐dimensional anionic layers, which are built upon the linkages of Cu^II(S₂CNMe₂)₂ units and one‐dimensional anionic Pb/I/Cu^I chains. Tetra‐n‐butylammonium cations are located between the anionic layers and connected to them via C—H…I hydrogen‐bonding interactions. Compound (II) exhibits a one‐dimensional neutral structure, which is composed of [PbI₅] square pyramids, [Cu^II₄] tetrahedra and [Cu^IIN₄I] trigonal bipyramids. Face‐to‐face aromatic π–π stacking interactions between adjacent 1,10‐phenanthroline ligands stabilize the structure and assemble compound (II) into a three‐dimensional supramolecular structure. I₂ molecules lie in the voids of the structure.     

Transfer of Copper from an Amyloid to a Natural Copper‐Carrier Peptide with a Specific Mediating Ligand

The oxidative stress that arises from the catalytic reduction of dioxygen by Cu^II/I‐loaded amyloids is the major pathway for neuron death that occurs in Alzheimer’s disease. In this work, we show that bis‐8(aminoquinoline) ligands, copper(II) specific chelators, are able to catalytically extract Cu^II from Cu–Aβ_1–16 and then completely release Cu^I in the presence of glutathione to provide a Cu^I–glutathione complex, a biological intermediate that is able to deliver copper to apo forms of copper–protein complexes. These data demonstrate that bis‐8(aminoquinolines) can perform the transfer of copper ions from the pathological Cu–amyloid complexes to regular copper–protein complexes. These copper‐specific ligands assist GSH to recycle Cu^I in an AD brain and consequently slow down oxidative damage that is due to copper dysregulation in Alzheimer’s disease. Under the same conditions, we have shown that the copper complex of PBT2, a mono(8‐hydroxyquinoline) previously used as a drug candidate, does not efficiently release copper in the presence of GSH. In addition, we report that GSH itself was unable to fully abstract copper ions from Cu–β‐amyloid complexes.     

Improved Photostability of a CuI Complex by Macrocyclization of the Phenanthroline Ligands

The development of molecular materials for conversion of solar energy into electricity and fuels is one of the most active research areas, in which the light absorber plays a key role. While copper(I)-bis(diimine) complexes [Cu^I(L)₂]⁺ are considered as potent substitutes for [Ru^II(bpy)₃]²⁺, they exhibit limited structural integrity as ligand loss by substitution can occur. In this article, we present a new concept to stabilize copper bis(phenanthroline) complexes by macrocyclization of the ligands which are preorganized around the Cu^I ion. Using oxidative Hay acetylene homocoupling conditions, several Cu^I complexes with varying bridge length were prepared and analyzed. Absorption and emission properties are assessed; rewardingly, the envisioned approach was successful since the flexible 1,4-butadiyl-bridged complex does show enhanced MLCT absorption and emission, as well as improved photostability upon irradiation with a blue LED compared to a reference complex.     

Protonation of a Biologically Relevant CuII μ‐Thiolate Complex: Ligand Dissociation or Formation of a Protonated CuI Disulfide Species?

The proton‐induced electron‐transfer reaction of a Cu^II μ‐thiolate complex to a Cu^I‐containing species has been investigated, both experimentally and computationally. The Cu^II μ‐thiolate complex [Cu^II₂( L^MeS )₂]²⁺ is isolated with the new pyridyl‐containing ligand L^MeSSL^Me , which can form both Cu^II thiolate and Cu^I disulfide complexes, depending on the solvent. Both the Cu^II and the Cu^I complexes show reactivity upon addition of protons. The multivalent tetranuclear complex [Cu^I₂Cu^II₂( LS )₂(CH₃CN)₆]⁴⁺ crystallizes after addition of two equivalents of strong acid to a solution containing the μ‐thiolate complex [Cu^II₂( LS )₂]²⁺ and is further analyzed in solution. This study shows that, upon addition of protons to the Cu^II thiolate compound, the ligand dissociates from the copper centers, in contrast to an earlier report describing redox isomerization to a Cu^I disulfide species that is protonated at the pyridyl moieties. Computational studies of the protonated Cu^II μ‐thiolate and Cu^I disulfide species with LSSL show that already upon addition of two equivalents of protons, ligand dissociation forming [Cu^I(CH₃CN)₄]⁺ and protonated ligand is energetically favored over conversion to a protonated Cu^I disulfide complex.     

Visualizing Biological Copper Storage: The Importance of Thiolate‐Coordinated Tetranuclear Clusters

Bacteria possess cytosolic proteins (Csp3s) capable of binding large quantities of copper and preventing toxicity. Crystal structures of a Csp3 plus increasing amounts of Cu^I provide atomic‐level information about how a storage protein loads with metal ions. Many more sites are occupied than Cu^I equiv added, with binding by twelve central sites dominating. These can form [Cu₄(S‐Cys)₄] intermediates leading to [Cu₄(S‐Cys)₅]⁻, [Cu₄(S‐Cys)₆]²⁻, and [Cu₄(S‐Cys)₅(O‐Asn)]⁻ clusters. Construction of the five Cu^I sites at the opening of the bundle lags behind the main core, and the two least accessible sites at the opposite end of the bundle are occupied last. Facile Cu^I cluster formation, reminiscent of that for inorganic complexes with organothiolate ligands, is largely avoided in biology but is used by proteins that store copper in the cytosol of prokaryotes and eukaryotes, where this reactivity is also key to toxicity.     

First Dinuclear Copper/Gallium Complexes: Supporting Cu0 and CuI Centres by Low‐Valent Organogallium Ligands

The synthesis and structural characterisation of low‐valent dinuclear copper(I) and copper(0) complexes supported by organogallium ligands has been accomplished for the first time by the reductive coordination reaction of [GaCp*] (Cp*=pentamethylcyclopentadienyl) and [Ga(ddp)] (ddp=HC(CMeNC₆H₃‐2,6‐iPr₂)₂ 2‐diisopropylphenylamino‐4‐diisopropylphenylimino‐2‐pentene) with readily available copper(II) and copper(I) precursors. The treatment of CuBr₂ and Cu(OTf)₂ (OTf=CF₃SO₃) with [Ga(ddp)] under mild conditions resulted in elimination of [Ga(L)₂(ddp)] (L=Br, OTf) and afforded the novel gallium(I)/copper(I) compounds [{(ddp)GaCu(L)}₂] (L=Br ( 1 ), OTf ( 2 )). The single‐crystal X‐ray structure determinations of 1 and 2 reveal that these molecules are composed of {(ddp)GaCu(L)} dimeric units, with planar Cu^I? Ga^I four‐membered rings and short Cu^I???Cu^I distances, with 2 exhibiting the shortest Cu^I???Cu^I contact reported to date of 2.277(3) Å. The all‐gallium coordinated dinuclear [Cu₂(GaCp*)(μ‐GaCp*)₃Ga(OTf)₃] ( 3 ) is formed when Cu(OTf)₂ is combined with [GaCp*] instead of [Ga(ddp)]. Notably, in the course of this redox reaction Lewis acidic Ga(OTf)₃ is formed, which coordinates to one of the electron‐rich copper(0) centres. Compound 3 is suggested as the first case of a structurally characterised complex of copper(0). By changing the copper(II) to a copper(I) source, that is, [Cu(cod)₂][OTf] (cod=1,5‐cyclooctadiene), the salt [Cu₂(GaCp*)₃(μ‐GaCp*)₂][OTf]₂ ( 4 ) is formed, the cationic part of which is related to previously described isoelectronic dinuclear d¹⁰ complexes of the type [M₂(GaCp*)₅] (M=Pd, Pt).     

UV/Vis Spectroscopy of Copper Formate Clusters: Insight into Metal-Ligand Photochemistry

The electronic structure and photochemistry of copper formate clusters, Cu^I₂(HCO₂)₃⁻ and Cu^II_n(HCO₂)_2n+1⁻, n≤8, are investigated in the gas phase by using UV/Vis spectroscopy in combination with quantum chemical calculations. A clear difference in the spectra of clusters with Cu^I and Cu^II copper ions is observed. For the Cu^I species, transitions between copper d and s/p orbitals are recorded. For stoichiometric Cu^II formate clusters, the spectra are dominated by copper d–d transitions and charge-transfer excitations from formate to the vacant copper d orbital. Calculations reveal the existence of several energetically low-lying isomers, and the energetic position of the electronic transitions depends strongly on the specific isomer. The oxidation state of the copper centers governs the photochemistry. In Cu^II(HCO₂)₃⁻, fast internal conversion into the electronic ground state is observed, leading to statistical dissociation; for charge-transfer excitations, specific excited-state reaction channels are observed in addition, such as formyloxyl radical loss. In Cu^I₂(HCO₂)₃⁻, the system relaxes to a local minimum on an excited-state potential-energy surface and might undergo fluorescence or reach a conical intersection to the ground state; in both cases, this provides substantial energy for statistical decomposition. Alternatively, a Cu^II(HCO₂)₃Cu⁰⁻ biradical structure is formed in the excited state, which gives rise to the photochemical loss of a neutral copper atom.