Copper Species Research Articles

When Metal Complexes Evolve, and a Minor Species is the Most Active: the Case of Bis(Phenanthroline)Copper in the Catalysis of Glutathione Oxidation and Hydroxyl Radical Generation

AbstractSeveral copper‐ligands, including 1,10‐phenanthroline (Phen), have been investigated for anticancer purposes based on their capacity to bind excess copper (Cu) in cancer tissues and form redox active complexes able to catalyse the formation of reactive oxygen species (ROS), ultimately leading to oxidative stress and cell death. Glutathione (GSH) is a critical compound as it is highly concentrated intracellularly and can reduce and dissociate copper(II) from the ligand forming poorly redox‐active copper(I)‐thiolate clusters. Here we report that Cu‐Phen2 speciation evolves in physiologically relevant GSH concentrations. Experimental and computational experiments suggest that at pH 7.4 mostly copper(I)‐GSH clusters are formed, but a minor species of copper(I) bound to one Phen and forming ternary complexes with GSH (GS−Cu‐Phen) is the redox active species, oxidizing quite efficiently GSH to GSSG and forming HO⋅ radicals. This minor active species becomes more populated at lower pH, such as typical lysosomal pH 5, resulting in faster GSH oxidation and HO⋅ production. Consistently, cell culture studies showed lower toxicity of Cu‐Phen2 upon inhibition of lysosomal acidification. Overall, this study underscores that sub‐cellular localisation can considerably influence the speciation of Cu‐based drugs and that minor species can be the most redox‐ and biologically‐active.

When Metal Complexes Evolve, and a Minor Species is the Most Active: the Case of Bis(Phenanthroline)Copper in the Catalysis of Glutathione Oxidation and Hydroxyl Radical Generation.

Several copper-ligands, including 1,10-phenanthroline (Phen), have been investigated for anticancer purposes based on their capacity to bind excess copper (Cu) in cancer tissues and form redox active complexes able to catalyse the formation of reactive oxygen species (ROS), ultimately leading to oxidative stress and cell death. Glutathione (GSH) is a critical compound as it is highly concentrated intracellularly and can reduce and dissociate copper(II) from the ligand forming poorly redox-active copper(I)-thiolate clusters. Here we report that Cu-Phen2 speciation evolves in physiologically relevant GSH concentrations. Experimental and computational experiments suggest that at pH7.4 mostly copper(I)-GSH clusters are formed, but a minor species of copper(I) bound to one Phen and forming ternary complexes with GSH (GS-Cu-Phen) is the redox active species, oxidizing quite efficiently GSH to GSSG and forming HO⋅ radicals. This minor active species becomes more populated at lower pH, such as typical lysosomal pH5, resulting in faster GSH oxidation and HO⋅ production. Consistently, cell culture studies showed lower toxicity of Cu-Phen2 upon inhibition of lysosomal acidification. Overall, this study underscores that sub-cellular localisation can considerably influence the speciation of Cu-based drugs and that minor species can be the most redox- and biologically-active.

Electrochemical Upgrading of Waste Polylactic Acid Plastic for the Coproduction of C2 Chemicals and Green Hydrogen

Tandem alkali-catalyzed hydrolysis and alkaline electrolysis have gradually become appealing avenues for the reformation of polyester plastics into high-value-added chemicals and green hydrogen with remarkable environmental and economic benefits. In this study, an electrochemical upcycling strategy was developed for the electrocatalytic oxidation of polylactic acid (PLA) hydrolysate into valued C2 chemicals (i.e., acetate) and hydrogen fuel using N, P-doped CuOx nanowires (NW) supported on nickel foam (NF) as the electrocatalyst. This 3D well-integrated catalyst was easily prepared from a Cu(OH)2 NW/NF precursor with Saccharomycetes as a green and safe P and N source. The electrocatalyst can efficiently catalyze the lactate monomer derived from the hydrolysis of PLA waste to acetate with high selectivity and exhibits a lower onset potential for the lactate oxidation reaction (LOR) than for water oxidation, saving 224 mV to deliver a current density of 30 mA/cm2. The experimental results reveal that the plausible pathway of the LOR on these CuOx NW involves oxidation and subsequent decarboxylation. Divalent copper species have been verified to be active sites for LOR via in situ Raman spectroscopy.

Strategy on rapid selection of woody species for phytoremediation in soils contaminated with copper, lead and zinc in Shanghai

The use of woody species for the remediation of heavy metal-contaminated soils is an environmentally friendly and economically viable strategy. This study investigates the phytoextraction abilities of 15 woody species for copper, lead and zinc in contaminated soil. The results indicated that all species showed phytoextraction ability, with metal concentrations varying from 5.59 to 27.45 mg·kg−1 for Cu, 2.79 to 16.75 mg·kg−1 for Pb and 22.13 to 185.72 mg·kg−1 for Zn in the stem tissues depending on the species. Pterocarya stenoptera, Paulownia fortunei and Salix matsudana were identified as the top performers in terms of overall phytoextraction capacity. Notably, their capacity to transport zinc exceeded that of copper and lead. The enrichment of copper, lead and zinc in the soil showed a synergistic effect in the presence of heavy metal. The distribution of heavy metals within plant tissues was affected by water content and the inherent toxicity of metals. The study highlights that the accumulation of tree biomass and water content in the stem play a significant role in determining the amount of heavy metals phytoextracted. This insight offers a quick method for the rapid selection of woody species for phytoremediation in urban soils contaminated with heavy metals.

Overcoming Copper Reduction Limitation in Asymmetric Substitution: Aryl-Radical-Enabled Enantioconvergent Cyanation of Alkyl Iodides.

Cu-catalyzed enantioconvergent cross-coupling of alkyl halides has emerged as a powerful strategy for synthesizing enantioenriched molecules. However, this approach is intrinsically limited by the weak reducing power of copper(I) species, which restricts the scope of compatible nucleophiles and necessitates extensive ligand optimization or the use of complex chiral scaffolds. To overcome these challenges, we introduce an aryl-radical-enabled strategy that decouples the alkyl halide activation step from the chiral Cu center. We demonstrate that merging aryl-radical-enabled iodine abstraction with Cu-catalyzed asymmetric radical functionalization enables the conversion of racemic α-iodoamides to enantioenriched alkyl nitrile products with good yield and enantioselectivity. The rational design of chiral ligands identified a new class of carboxamide-containing BOX ligands. Mechanistic studies support an aryl-radical-enabled pathway and the unique hydrogen-bonding ability in the newly designed BOX ligands. This aryl-radical-enabled asymmetric substitution reaction has the potential to significantly expand the scope of Cu-catalyzed enantioconvergent cross-coupling reactions.

Identifying Active Oxygen and Copper Species in Cu/CeO2 Catalysts Using Raman and UV–Vis Modulation Excitation Spectroscopy

Identifying Active Oxygen and Copper Species in Cu/CeO₂ Catalysts Using Raman and UV–Vis Modulation Excitation Spectroscopy

Effect of Alkaline Etching on Formation Behavior and Corrosion Resistance of a Cr-Zr-Ti TCP Conversion Coating on AA2024 Aluminum Alloy

Abstract Trivalent chromium process conversion coating is considered to be the ideal alternative to traditional chromate conversion coating due to its high corrosion resistance and low toxicity. However, achieving a high corrosion resistance trivalent chromium conversion coating on 2xxx aluminum alloys has been a great challenge. Herein, based on a newly developed trivalent chromium conversion solution (CN patent, ZL 202210804263.2), the effect of alkaline etching on the formation behavior and corrosion resistance of the coating on AA2024-T351 aluminum alloy was investigated. It was found that under the same conditions, the mechanically polished sample and the sample alkaline etched for 30 s showed the highest corrosion resistance. When the alkaline etching time was too short or too long, the corrosion resistance of the coating deteriorated. This is ascribed to changes in the surface microstructure of the alloy during alkaline etching, i.e., reduced number of intermetallic particles and formation of a copper enrichment layer. Reducing the number of intermetallic particles on the alloy surface is beneficial for uniform growth of the coating. However, the copper enrichment layer participated in formation of the coating, resulting in doping of copper species in the coating, which is detrimental to the corrosion resistance of the coating.

Cu (ii) Immobilized on Mesoporous Poly (Guanidine–Triazine–Sulfonamide) (PGTSA/Cu): A New Catalyst for the Synthesis of Tetrazolo[1,5‐a]pyrimidines

ABSTRACTThe study focuses on the synthesis and characterization of a new mesoporous polysulfonamide stabilizer using condensation polymerization and the nanocasting technique. The resulting material, PGTSA, was modified with copper ions and used as a nanocatalyst in the reaction of benzaldehydes, 1H‐tetrazole‐5‐amine, and malononitrile. The performance of the mesoporous PGTSA/Cu (II) was compared with non‐porous PGTSA/Cu (II), highlighting the significance of support porosity in catalytic activity and loading of copper species. Based on the analysis of the ICP and catalytic performance, it was observed that mesoporous PGTSA/Cu (II) exhibited a higher level of catalytic activity compared to PGTSA/Fe3O4/Cu (II) and non‐porous PGTSA/Cu (II). Also, the catalytic activity of the aryl aldehyde was significantly influenced by its electrical characteristics. The recovery and reusability of the PGTSA/Cu (II) catalyst are noteworthy aspects, highlighting the practicality and sustainability of the catalytic system. The amount of copper in fresh catalyst and the recycled catalyst after six times recycling is 1.57% and 1.52%, respectively. Therefore, ICP‐OEIS analysis indicated that copper leaching of this catalyst is very low. The procedure offered high product yields, easy recovery of the nanocatalyst, remarkable reusability, short reaction times, and compatibility with various substrates.

Axially chiral α-boryl-homoallenyl boronic esters as versatile toolbox for accessing centrally and axially chiral molecules

Axially chiral allenes bearing organoboron groups are highly sought-after building blocks in organic synthesis due to their potential for generating a wide range of axially and centrally chiral molecules. However, the existing methods for preparing axially chiral allenes containing boron group are primarily limited to the synthesis of allenyl boronic esters, and strategies for accessing axially chiral homoallenyl boronic esters are still scarce. Here, we report the general method for synthesizing axially chiral α-boryl-homoallenyl boronic esters through a highly regio- and stereoselective copper-mediated SN2’-addition of newly prepared (diborylalkyl)copper species to chiral propargyl electrophiles. The reaction conditions were optimized to achieve high yields and excellent stereospecificity. The obtained products were successfully transformed into various axially chiral allenes and other chiral molecules by transforming diboron units. The potential for axial-to-central chirality transfer of axially chiral α-boryl-homoallenyl boronic esters is also demonstrated through the stereospecific addition to aldehydes and N-H aldimines, yielding enantioenriched 1,2-oxaborinin-3,5-dienes and 2-aminomethyl-1,3-dienes.

Exploring complete catalytic cycle of methane oxidation to methanol on Cu2O2 stabilized within MIL-53(Al) framework: A combined DFT and microkinetic study

Although inspiration from copper-based natural enzymes has shown promise in improving catalyst design for methane-to-methanol (MTM) oxidation, high productivity, and selectivity under mild conditions remain a significant challenge. This study constructs the dinuclear copper (Cu2) species stabilized within the metal-organic framework (MOF), MIL-53(Al), containing Cu as efficient catalytic sites and explores the ability of different oxidants (O2, N2O, and H2O2) to oxidize Cu2 into the dicopper-oxo (Cu2O2) species using density functional theory (DFT) calculations. Our results indicate the kinetic and thermodynamic favorability of Cu2O2 species formation using O2 as an oxidant within the MIL-53(Al) framework. Furthermore, the thermal stability of Cu2O2/MIL-53(Al) has been verified via ab initio molecular dynamics (AIMD) calculations. The kinetics of the complete MTM oxidation cycle over Cu2O2/MIL-53(Al) have been studied using both DFT and microkinetic simulation methods. The present study predicts that the C-H activation on the Cu2O2/MIL-53(Al) has a low free energy barrier (0.77 eV) and that the high stability of CH3 and its very low free energy barrier in the C-O coupling step favors the methanol formation over the formaldehyde. More importantly, Cu2O2/MIL-53(Al) exhibits high methanol selectivity owing to the inhibition of CH3 dehydrogenation and low methanol desorption energy (0.21 eV). Microkinetic simulations confirm the methanol production under relatively mild reaction conditions (200–280 K and 1 bar). This work provides insights into the feasibility of selective MTM oxidation over this family of MOF under mild conditions.

Cu/N-doped carbon spheres derived from soybean flour as an active green nanocomposite for the synthesis of 1,4-disubstituted 1H-1,2,3-triazole derivatives

Cu immobilized onto N-doped carbon spheres (Cu/N-doped CS) derived from soybean flour was synthesized via the hydrothermal method and certified as a green high-efficiency catalyst for the regioselective synthesis of 1,4-disubstituted 1H-1,2,3-triazoles. The obtained N-doped carbon spheres from a combination of glucose and soy flour have a larger size and suitable affinity for load copper species. The morphology and structure of the as-prepared catalyst have been confirmed based on FT-IR, XRD, FE-SEM, EDX, BET, and ICP-OES characterizations. The catalytic performance of the Cu/N-doped carbon spheroids was investigated experimentally. It was found that the Cu/N-doped CS nanocomposite has a high efficiency and recyclability for 5 cycles without any appreciable loss in its catalytic activity in the synthesis of 1,4-disubstituted 1H-1,2,3-triazoles via the three-component condensation reaction of various epoxide/alkyl or aryl halides, sodium azide, and phenylacetylene in a water medium. Furthermore, significant advantages such as stability, ease of preparation, low cost of the carbon resource, high regioselectivity, and good product yield have been achieved in the heterogeneous catalyst system attractive for large-scale in many industrial products.

Boosting selectivity for multi-carbon products in electrochemical CO2 reduction via enhanced hydroxide adsorption in ultrafine CuOx/CeOx nanoparticles

The electricity-driven reduction of CO2 presents a unique prospect of mitigating atmospheric CO2 levels and converting renewable energy into chemical fuels. However, the lack of an efficient catalyst that can transform CO2 into desired products with appreciable selectivity at commercially relevant current densities (ID) impedes the practical implications of this technology. This work describes a scalable approach for producing ultrafine nanoparticles of CuOx-CeOx (CuCe) composites via rapid coprecipitation under oxygen-deprived conditions. In this process, Ce(OH)3 acts as a reducing agent converting Cu(OH)2 into ultrafine Cu2O nanoparticles. Thus, the Ce: Cu ratio in composite effectively controls the particle size and bulk structural fixture of the CuCe composites. Despite having lower ECSA, The CuCe composites exhibit superior catalytic performance compared to CuO, with significantly higher selectivity for ethanol production and lower selectivity for CO and H2. The Cu1.5Ce prepared using a Cu: Ce ratio of 1.5:1, demonstrated remarkable catalytic activity with Faradaic efficiencies (F. E.) of 34.2 % for ethanol, 44.1 % for ethylene, and 81.08 % for multi-carbon (C2+) products. Moreover, while operating at the ID of 500 mA cm−2, Cu1.5Ce achieves a single pass CO2 conversion (SPCC) of 19.9 %, and a half-cell energy efficiency (E. E. half-cell) of 31.5 % for the C2+ products. It produces the C2+ products at the partial current density (pID) of 405.4 mA cm−2. The superior performance of Cu1.5Ce can be attributed to the improved hydroxide adsorption and partial retention of oxidized copper species under cathodic bias.

Catalytic functionalization of MCM-41 and MCM-48 with copper by modified template ion-exchange method for low-temperature NH3-SCR process: the role of complexing agents for copper dispersion

Mesoporous silicas of MCM-41 and MCM-48 types were synthesized and modified with copper by template ion-exchange (TIE) technique. A high dispersion of deposited copper species was managed by subsequent treatment of the samples with ammonia, urea, or acetonitrile solution. Copper-modified silicas were analysed in terms of their chemical composition (ICP-OES), ordering of porous structure (XRD), textural parameters (low-temperature N2 sorption), dispersion and form of introduced copper species (UV–vis-DR, XRD, H2-TPR, NH3-TPD). Mesoporous silicas modified with copper exhibited promising catalytic efficiency in selective catalytic reduction of NO with ammonia (NH3-SCR). The samples containing dispersed copper species (predominantly monomeric copper cations) presented enhanced catalytic activity compared to catalysts containing CuO aggregates. On the other hand, CuO aggregates showed greater catalytic activity in the side process of direct ammonia oxidation by oxygen present in the reaction mixture. It was demonstrated that TIE post-treatment of the samples with urea resulted in most effective improving dispersion of deposited copper and is less destructive for ordered porous structures of mesoporous silica comparing to treatment with ammonia solution.Graphical abstract

Revealing the Intrinsic Correlation between Cu Scales and Free Radical Chain Reactions in the Regulation of Catalytic Behaviour.

Defining the copper-based catalysts that are responsible for the catalytic behaviour of oil-paper insulation systems and implementing effective regulation are of great significance. Accelerated ageing experiments were conducted to reveal variations in copper scales and deterioration in insulation properties. As ageing progressed, TEM images demonstrated that copper species were adsorbed and aggregated on the fibre surface in the form of nanoparticles (NPs). The scale of NPs exhibited a continuous increase, from 27.06 nm to 94.19 nm. Cu(I) and Cu(II) species were identified as the active sites for inducing intense free radical reactions, which significantly reduced the activation energy, making the insulating oil more susceptible to oxidation. The role of the antioxidant di-tert-butyl-p-cresol (DBPC) in extending the insulation life was regulated by determining the optimal addition time based on variations in the interfacial tension. After the second addition of DBPC, the ageing rates of the dissipation factor, acidity, micro-water and breakdown voltage in the Cu+DBPC group decreased by 28.8%, 43.2%, 52.9% and 46.7%, respectively, compared to the Cu group. This finding not only demonstrates the crucial role of DBPC in preventing the copper-based catalyst-induced oxidation of insulating oil, but also furnishes a vital foundation for enhancing the long-term stability of transformer insulation systems.

TiO2 Films with Macroscopic Chiral Nematic-Like Structure Stabilized by Copper Promoting Light-Harvesting Capability for Hydrogen Generation.

Cellulose nanocrystals (CNCs) have inspired the synthesis of various advanced nanomaterials, opening opportunities for different applications. However, a simple and robust approach for transferring the long-range chiral nematic nanostructures into TiO2 photocatalyst is still fancy. Herein, a successful fabrication of freestanding TiO2 films maintaining their macroscopic chiral nematic structures after removing the CNCs biotemplate is reported. It is demonstrated that including copper acetate in the sol avoids the epitaxial growth of the lamellar-like structure of TiO2 and stabilizes the chiral nematic structure instead. The experimental results and optical simulation demonstrate an enhancement at the blue and red edges of the Fabry-Pérot reflectance peak located in the visible range. This enhancement arises from the light scattering effect induced by the formation of the chiral nematic structure. The nanostructured films showed 5.3 times higher performance in the photocatalytic hydrogen generation, compared to lamellar TiO2, and benefited from the presence of copper species for charge carriers' separation. This work is therefore anticipated to provide a simple approach for the design of chiral nematic photocatalysts and also offers insights into the electron transfer mechanisms on TiO2/CuxO with variable oxidation states for photocatalytic hydrogen generation.

Size-dependent Copper Nanoparticles Supported on Carbon Nanotubes with Balanced Cu+ and Cu0 Dual Sites for the Selective Hydrogenation of Ethylene Carbonate.

Cyclic carbonate hydrogenation offers an alternative for the efficient indirect CO2 utilization. In this study, a series of carbon nanotubes (CNTs) supported xCu/CNTs catalysts with different Cu loadings were fabricated using a convenient impregnation method, and exhibited excellent catalytic activity for the hydrogenation of ethylene carbonate to methanol and ethylene glycol. The structural and physicochemical properties revealed that acid treatment of CNTs resulted in plentiful oxygen-containing functional groups, providing sufficient anchoring sites for copper species. The calcination process conducted under an inert atmosphere resulted in the formation of ternary CuO, Cu2O, and Cu composites, enhancing the metal-support interaction and facilitating the formation of balanced Cu0 and Cu+ dual sites as well as high active surface area after reduction. Contributed to the synergetic effect of balanced Cu+ and Cu0 species proved by density functional theory calculation and the electron-rich CNTs surface, the 40Cu/CNTs catalyst achieved strengthened catalytic performance with methanol yield of 83%, ethylene glycol yield of 99% at ethylene carbonate conversion of >99%, and 150 h of long-term running stability. Consequently, CNTs supported Cu serve as efficient non-silica based catalyst for ester hydrogenation.

Synergistic catalysis of dual-sites promoted cycloaddition of CO2 with epoxides

This study explores the catalytic efficacy of fluorine-modified 1 wt% copper oxide on MCM-41 (F-1Cu/MCM-41) in carbon dioxide cycloaddition reactions. It delves into reaction mechanisms, active sites, and the practical applicability of the catalyst. Comprehensive examination through in situ diffuse reflectance infrared Fourier transform spectroscopy and other analytical methods substantiated the role of halogen-modified mono-dispersed copper species in carbon dioxide activation and silicon hydroxide sites in epoxide activation, while underscoring the role of Lewis bases and Brønsted acids. Kinetic studies and density functional theory calculations pinpointed carbon dioxide activation as the pivotal step. Furthermore, the catalyst exhibited robust stability and efficiency in continuous flow experiments, sustaining a 99% selectivity towards cyclic carbonate over 150 h. An eco-friendly evaluation confirmed the sustainability of the process, emphasizing its minimal environmental footprint and high efficiency. These results establish fluorine-modified 1 wt% copper oxide on MCM-41 as a formidable candidate for industrial-scale cyclic carbonate production, due to its promising performance and sustainability.

Exploring the nature of copper species: CeO2 support shape effect and its influence on CO2 hydrogenation to methanol

A series of CuO catalysts supported on CeO2 with different morphologies (nanorod, nanocube and hydrangea-like) were tested for the CO2 hydrogenation into methanol. Remarkable morphology-dependent CuO-CeO2 interaction was observed, which was associated with the types and concentrations of copper species. The best performance was obtained over the CuO/hydrangea-like-CeO2 catalyst, giving CO2 conversion of 15.6 % and methanol selectivity of 92.4 % at 260 °C and 3 MPa. The enhanced activity was due to the largest amount of small particle size of copper species, which was responsible for the facile activation of H2. Additionally, the Cu2+-Ov-Cex species facilitated the generation of oxygen vacancies and hydroxyl groups, these two species favored formate production and further hydrogenation to methanol. Moreover, in situ diffuse reflectance infrared fourier transform spectroscopy (in situ DRIFTS) results revealed that the both monodentate formate (m-HCOO*) and bidentate formate (bi-HCOO*) were key and necessary intermediate of CO2 hydrogenation to methanol. The proposed predominate reaction pathway was m-HCOO*→ b-*OCH3 → CH3OH and the minor one was bi-HCOO* → t-*OCH3 → CH3OH.

Amorphous Strategy and Doping Copper on Metal-Organic Framework Surface for Enhanced Photocatalytic CO2 Reduction to C2H4.

Amorphous photocatalysts are characterized by numerous grain boundaries and abundant unsaturated sites, which enhance reaction efficiency from both kinetic and thermodynamic perspectives. However, amorphization strategies have rarely been used for photocatalytic CO2 reduction. Doping copper onto a metal-organic framework (MOF) surface can regulate the electronic structure of photocatalysts, promote electron transfer from the MOF to Cu, and improve the separation efficiency of electron-hole pairs. In this study, an amorphous photocatalyst MOFw-p/Cu containing highly dispersed Cu (0, I, II) sites was designed and synthesized by introducing a regulator and in situ copper species during the nucleation process of MOF (UiO-66-NH2). Various characterizations confirmed that the Cu species were anchored to the organometallic skeleton of the surface amorphization MOF structure. The synergistic effect of Cu doping and surface amorphization in MOFw-p/Cu can significantly enhance the CO and CH4 yields while promoting the formation of the multicarbon product C2H4. The approach holds promise for developing novel, highly efficient MOFs as photocatalysts for CO2 photoreduction, enabling the production of high-value-added C2 products.

Bis(amino acidato)copper(II) compounds in blood plasma: a review of computed structural properties and amino acid affinities for Cu2+ informing further pharmacological research.

Neutral bis(amino acidato)copper(II) [Cu(aa)2] coordination compounds are the physiological species of copper(II) amino acid compounds in blood plasma taking the form of bis(l-histidinato)copper(II) and mixed ternary copper(II)-l-histidine complexes, preferably with l-glutamine, l-threonine, l-asparagine, and l-cysteine. These amino acids have three functional groups that can bind metal ions: the common α-amino and carboxylate groups and a side-chain polar group. In Cu(aa)2, two coordinating groups per amino acid bind to copper(II) in-plane, while the third group can bind apically, which yields many possibilities for axial and planar bonds, that is, for bidentate and tridentate binding. So far, the experimental studies of physiological Cu(aa)2 compounds in solutions have not specified their complete geometries. This paper provides a brief review of my group's research on structural properties of physiological Cu(aa)2 calculated using the density functional theory (DFT) to locate low-energy conformers that can coexist in aqueous solutions. These DFT investigations have revealed high conformational flexibility of ternary Cu(aa)2 compounds for tridentate or bidentate chelation, which may explain copper(II) exchange reactions in the plasma and inform the development of small multifunctional copper(II)-binding drugs with several possible copper(II)-binding groups. Furthermore, our prediction of metal ion affinities for Cu2+ binding with amino-acid ligands in low-energy conformers with different coordination modes of five physiological Cu(aa)2 in aqueous solution supports the findings of their abundance in human plasma obtained with chemical speciation modelling.