Copper Hydride Catalyzed Hydroamination of Alkenes and Alkynes

Over the past few years, CuH‐catalyzed hydroamination has been discovered and developed as a robust and conceptually novel approach for the synthesis of enantioenriched secondary and tertiary amines. The success in this area of research was made possible through the large body of precedent in copper(I) hydride catalysis and the well‐explored use of hydroxylamine esters as electrophilic amine sources in related copper‐catalyzed processes. This Minireview details the background, advances, and mechanistic investigations in CuH‐catalyzed hydroamination.     

A Modified System for the Synthesis of Enantioenriched N‐Arylamines through Copper‐Catalyzed Hydroamination

Despite significant recent progress in copper‐catalyzed enantioselective hydroamination chemistry, the synthesis of chiral N‐arylamines, which are frequently found in natural products and pharmaceuticals, has not been realized. Initial experiments with N‐arylhydroxylamine ester electrophiles were unsuccessful and, instead, their reduction in the presence of copper hydride (CuH) catalysts was observed. Herein, we report key modifications to our previously reported hydroamination methods that lead to broadly applicable conditions for the enantioselective net addition of secondary anilines across the double bond of styrenes, 1,1‐disubstituted olefins, and terminal alkenes. NMR studies suggest that suppression of the undesired reduction pathway is the basis for the dramatic improvements in yield under the reported method.     

Facially Dispersed Polyhydride Cu9 and Cu16 Clusters Comprising Apex‐Truncated Supertetrahedral and Square‐Face‐Capped Cuboctahedral Copper Frameworks

By using a linear tetraphosphine, meso‐bis[(diphenylphosphinomethyl)phenylphosphino]methane (dpmppm), nona‐ and hexadecanuclear copper hydride clusters, [Cu₉H₇(μ‐dpmppm)₃]X₂ (X=Cl ( 1 a ), Br ( 1 b ), I ( 1 c ), PF₆ ( 1 d )) and [Cu₁₆H₁₄(μ‐dpmppm)₄]X₂ (X₂=I₂ ( 2 c ), (4/3) PF₆?(2/3) OH ( 2 d )) were synthesized and characterized. They form copper‐hydride cages of apex‐truncated supertetrahedral {Cu₉H₇}²⁺ and square‐face‐capped cuboctahedral {Cu₁₆H₁₄}²⁺ structures. The hydride positions were estimated by DFT calculations to be facially dispersed around the copper frameworks. A kinetically controlled synthesis gave an unsymmetrical Cu₈H₆ cluster, [Cu₈H₆(μ‐dpmppm)₃]²⁺ ( 3 ), which readily reacted with CO₂ to afford linear Cu₄ complexes with formate bridges, leading to an unprecedented hydrogenation of CO₂ into formate catalyzed by {Cu₄(μ‐dpmppm)₂} platform. The results demonstrate that new motifs of copper hydride clusters could be established by the tetraphosphine ligands, and the structures influence their reactivity.     

The coordination chemistry of two symmetric double‐armed oxadiazole‐bridged organic ligands with copper salts

Two new symmetric double‐armed oxadiazole‐bridged ligands, 4‐methyl‐{5‐[5‐methyl‐2‐(pyridin‐3‐ylcarbonyloxy)phenyl]‐1,3,4‐oxadiazol‐2‐yl}phenyl pyridine‐3‐carboxylate (L1) and 4‐methyl‐{5‐[5‐methyl‐2‐(pyridin‐4‐ylcarbonyloxy)phenyl]‐1,3,4‐oxadiazol‐2‐yl}phenyl pyridine‐4‐carboxylate (L2), were prepared by the reaction of 2,5‐bis(2‐hydroxy‐5‐methylphenyl)‐1,3,4‐oxadiazole with nicotinoyl chloride and isonicotinoyl chloride, respectively. Ligand L1 can be used as an organic clip to bind Cu^II cations and generate a molecular complex, bis(4‐methyl‐{5‐[5‐methyl‐2‐(pyridin‐3‐ylcarbonyloxy)phenyl]‐1,3,4‐oxadiazol‐2‐yl}phenyl pyridine‐3‐carboxylate)bis(perchlorato)copper(II), [Cu(ClO₄)₂(C₂₈H₂₀N₄O₅)₂], (I). In compound (I), the Cu^II cation is located on an inversion centre and is hexacoordinated in a distorted octahedral geometry, with the pyridine N atoms of two L1 ligands in the equatorial positions and two weakly coordinating perchlorate counter‐ions in the axial positions. The two arms of the L1 ligands bend inward and converge at the Cu^II coordination point to give rise to a spirometallocycle. Ligand L2 binds Cu^I cations to generate a supramolecule, diacetonitriledi‐μ₃‐iodido‐di‐μ₂‐iodido‐bis(4‐methyl‐{5‐[5‐methyl‐2‐(pyridin‐4‐ylcarbonyloxy)phenyl]‐1,3,4‐oxadiazol‐2‐yl}phenyl pyridine‐4‐carboxylate)tetracopper(I), [Cu₄I₄(CH₃CN)₂(C₂₈H₂₀N₄O₅)₂], (II). The asymmetric unit of (II) indicates that it contains two Cu^I atoms, one L2 ligand, one acetonitrile ligand and two iodide ligands. Both of the Cu^I atoms are four‐coordinated in an approximately tetrahedral environment. The molecule is centrosymmetric and the four I atoms and four Cu^I atoms form a rope‐ladder‐type [Cu₄I₄] unit. Discrete units are linked into one‐dimensional chains through π–π interactions.     

Ligand‐forced dimerization of copper(I)–olefin complexes bearing a 1,3,4‐thiadiazole core

As an important class of heterocyclic compounds, 1,3,4‐thiadiazoles have a broad range of potential applications in medicine, agriculture and materials chemistry, and were found to be excellent precursors for the crystal engineering of organometallic materials. The coordinating behaviour of allyl derivatives of 1,3,4‐thiadiazoles with respect to transition metal ions has been little studied. Five new crystalline copper(I) π‐complexes have been obtained by means of an alternating current electrochemical technique and have been characterized by single‐crystal X‐ray diffraction and IR spectroscopy. The compounds are bis[μ‐5‐methyl‐N‐(prop‐2‐en‐1‐yl)‐1,3,4‐thiadiazol‐2‐amine]bis[nitratocopper(I)], [Cu₂(NO₃)₂(C₆H₉N₃S)₂], (1), bis[μ‐5‐methyl‐N‐(prop‐2‐en‐1‐yl)‐1,3,4‐thiadiazol‐2‐amine]bis[(tetrafluoroborato)copper(I)], [Cu₂(BF₄)₂(C₆H₉N₃S)₂], (2), μ‐aqua‐bis{μ‐5‐[(prop‐2‐en‐1‐yl)sulfanyl]‐1,3,4‐thiadiazol‐2‐amine}bis[nitratocopper(I)], [Cu₂(NO₃)₂(C₅H₇N₃S₂)₂(H₂O)], (3), μ‐aqua‐(hexafluorosilicato)bis{μ‐5‐[(prop‐2‐en‐1‐yl)sulfanyl]‐1,3,4‐thiadiazol‐2‐amine}dicopper(I)–acetonitrile–water (2/1/4), [Cu₂(SiF₆)(C₅H₇N₃S₂)₂(H₂O)]·0.5CH₃CN·2H₂O, (4), and μ‐benzenesulfonato‐bis{μ‐5‐[(prop‐2‐en‐1‐yl)sulfanyl]‐1,3,4‐thiadiazol‐2‐amine}dicopper(I) benzenesulfonate–methanol–water (1/1/1), [Cu₂(C₆H₅O₃S)(C₅H₇N₃S₂)₂](C₆H₅O₃S)·CH₃OH·H₂O, (5). The structure of the ligand 5‐methyl‐N‐(prop‐2‐en‐1‐yl)‐1,3,4‐thiadiazol‐2‐amine (Mepeta ), C₆H₉N₃S, was also structurally characterized. Both Mepeta and 5‐[(prop‐2‐en‐1‐yl)sulfanyl]‐1,3,4‐thiadiazol‐2‐amine (Pesta ) (denoted L ) reveal a strong tendency to form dimeric {Cu₂L ₂}²⁺ fragments, being attached to the metal atom in a chelating–bridging mode via two thiadiazole N atoms and an allylic C=C bond. Flexibility of the {Cu₂(Pesta )₂}²⁺ unit allows the Cu^I atom site to be split into two positions with different metal‐coordination environments, thus enabling the competitive participation of different molecules in bonding to the metal centre. The Pesta ligand in (4) allows the Cu^I atom to vary between water O‐atom and hexafluorosilicate F‐atom coordination, resulting in the rare case of a direct Cu^I…FSiF₅²⁻ interaction. Extensive three‐dimensional hydrogen‐bonding patterns are formed in the reported crystal structures. Complex (5) should be considered as the first known example of a Cu^I(C₆H₅SO₃) coordination compound. To determine the hydrogen‐bond interactions in the structures of (1) and (2), a Hirshfeld surface analysis has been performed.     

Dispersion‐Force‐Assisted Disproportionation: A Stable Two‐Coordinate Copper(II) Complex

The synthesis of the first linear coordinated Cu^II complex Cu{N(SiMe₃)Dipp}₂ ( 1 Dipp=C₆H₅‐2,6Prⁱ₂) and its Cu^I counterpart [Cu{N(SiMe₃)Dipp}₂]^? ( 2 ) is described. The formation of 1 proceeds through a dispersion force‐driven disproportionation, and is the reaction product of a Cu^I halide and LiN(SiMe₃)Dipp in a non‐donor solvent. The synthesis of 2 is accomplished by preventing the disproportionation into 1 by using the complexing agent 15‐crown‐5. EPR spectroscopy of 1 provides the first detailed study of a two‐coordinate transition‐metal complex indicating strong covalency in the Cu?N bonds.     

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.     

Intermolecular Hydroamination of Vinylarenes by Iminoanilide Alkaline‐Earth Catalysts: A Computational Scrutiny of Mechanistic Pathways

A thorough computational exploration of the mechanistic intricacies of the intermolecular hydroamination (HA) of vinylarenes by a recently reported class of kinetically stabilised iminoanilide [{N^N}Ae{N(SiMe₃)₂} ? (THF)_n] alkaline‐earth amido compounds (Ae=Ca, Sr, Ba) is presented. Two distinct mechanistic pathways for catalytic HA mediated by alkaline‐earth and rare‐earth compounds have emerged over the years that account equally well for the specific features of the process. On one hand, a concerted proton‐assisted pathway to deliver the amine product in a single step can be invoked and, on the other, a stepwise σ‐insertive pathway that comprises a rapid, reversible migratory olefin insertion step linked to a less facile, irreversible Ae?C alkyl bond aminolysis. The results of the study presented herein, which employed a heavily benchmarked and reliable DFT methodology, supports a stepwise σ‐insertive pathway that involves fast and reversible migratory C?C bond insertion into the polar Ae?N pyrrolido σ bond. This proceeds with strict 2,1 regioselectivity via a highly polarised four‐centre transition state (TS) structure, linked to irreversible intramolecular Ae?C bond aminolysis of the alkaline‐earth alkyl intermediate as the energetically favourable mechanism. Turnover‐limiting aminolysis is consistent with the significant KIE measured; the DFT‐derived effective barrier matches the Eyring parameter empirically determined for the best‐performing {N^N}Ba(NR₂) catalyst gratifyingly well. It also predicts the observed trend in reactivity (Ca<Sr<Ba) correctly and the computationally estimated primary KIE is close to the observed values. Non‐competitive kinetic demands militate against the operation of the alternative concerted proton‐assisted pathway, which describes N?C bond formation triggered by concomitant amino proton transfer at the C?C linkage via a multi‐centre TS structure. A detailed comparison of {N^N}Ae(NR₂) catalysts revealed that the variation in the Ae?pyrrolido bond strength together with the degree of protection of the alkaline earth by a sterically encumbering iminoanilide ligand scaffold not only profoundly influences the performance in HA catalysis, but also the likelihood of traversing rival mechanistic pathways.     

σ‐Insertive Mechanism versus Concerted Non‐insertive Mechanism in the Intramolecular Hydroamination of Aminoalkenes Catalyzed by Phenoxyamine Magnesium Complexes: A Synthetic and Computational Study

The phenoxyamine magnesium complexes [{ONN}MgCH₂Ph] ( 4 a : {ONN}=2,4‐tBu₂‐6‐(CH₂NMeCH₂CH₂NMe₂)C₆H₂O^?; 4 b : {ONN}=4‐tBu‐2‐(CH₂NMeCH₂CH₂NMe₂)‐6‐(SiPh₃)C₆H₂O^?) have been prepared and investigated with respect to their catalytic activity in the intramolecular hydroamination of aminoalkenes. The sterically more shielded triphenylsilyl‐substituted complex 4 b exhibits better thermal stability and higher catalytic activity. Kinetic investigations using complex 4 b in the cyclisation of 1‐allylcyclohexyl)methylamine ( 5 b ), respectively, 2,2‐dimethylpent‐4‐en‐1‐amine ( 5 c ), reveal a first‐order rate dependence on substrate and catalyst concentration. A significant primary kinetic isotope effect of 3.9±0.2 in the cyclisation of 5 b suggests significant N?H bond disruption in the rate‐determining transition state. The stoichiometric reaction of 4 b with 5 c revealed that at least two substrate molecules are required per magnesium centre to facilitate cyclisation. The reaction mechanism was further scrutinized computationally by examination of two rivalling mechanistic pathways. One scenario involves a coordinated amine molecule assisting in a concerted non‐insertive N?C ring closure with concurrent amino proton transfer from the amine onto the olefin, effectively combining the insertion and protonolysis step to a single step. The alternative mechanistic scenario involves a reversible olefin insertion step followed by rate‐determining protonolysis. DFT reveals that a proton‐assisted concerted N?C/C?H bond‐forming pathway is energetically prohibitive in comparison to the kinetically less demanding σ‐insertive pathway (ΔΔG^≠=5.6 kcal mol^?1). Thus, the σ‐insertive pathway is likely traversed exclusively. The DFT predicted total barrier of 23.1 kcal mol^?1 (relative to the {ONN}Mg pyrrolide catalyst resting state) for magnesium?alkyl bond aminolysis matches the experimentally determined Eyring parameter (ΔG^≠=24.1(±0.6) kcal mol^?1 (298 K)) gratifyingly well.     

Three AgI,CuI and CdII coordination polymers based on the new asymmetrical ligand 2‐{4‐[(1H‐imidazol‐1‐yl)methyl]phenyl}‐5‐(pyridin‐4‐yl)‐1,3,4‐oxadiazole: syntheses,characterization and emission properties

The new asymmetrical organic ligand 2‐{4‐[(1H‐imidazol‐1‐yl)methyl]phenyl}‐5‐(pyridin‐4‐yl)‐1,3,4‐oxadiazole ( L , C₁₇H₁₃N₅O), containing pyridine and imidazole terminal groups, as well as potential oxdiazole coordination sites, was designed and synthesized. The coordination chemistry of L with soft Ag^I, Cu^I and Cd^II metal ions was investigated and three new coordination polymers (CPs), namely, catena‐poly[[silver(I)‐μ‐2‐{4‐[(1H‐imidazol‐1‐yl)methyl]phenyl}‐5‐(pyridin‐4‐yl)‐1,3,4‐oxadiazole] hexafluoridophosphate], {[Ag( L )]PF₆}_n, catena‐poly[[copper(I)‐di‐μ‐iodido‐copper(I)‐bis(μ‐2‐{4‐[(1H‐imidazol‐1‐yl)methyl]phenyl}‐5‐(pyridin‐4‐yl)‐1,3,4‐oxadiazole)] 1,4‐dioxane monosolvate], {[Cu₂I₂( L )₂]·C₄H₈O₂}_n, and catena‐poly[[[dinitratocopper(II)]‐bis(μ‐2‐{4‐[(1H‐imidazol‐1‐yl)methyl]phenyl}‐5‐(pyridin‐4‐yl)‐1,3,4‐oxadiazole)]–methanol–water (1/1/0.65)], {[Cd( L )₂(NO₃)₂]·2CH₄O·0.65H₂O}_n, were obtained. The experimental results show that ligand L coordinates easily with linear Ag^I, tetrahedral Cu^I and octahedral Cd^II metal atoms to form one‐dimensional polymeric structures. The intermediate oxadiazole ring does not participate in the coordination interactions with the metal ions. In all three CPs, weak π–π interactions between the nearly coplanar pyridine, oxadiazole and benzene rings play an important role in the packing of the polymeric chains.     

Mechanistic Insights into the Oxidative Coupling of N‐Heterocyclic Carbenes within the Coordination Sphere of Copper Complexes

The behavior of N‐heterocyclic carbene (NHC) ligands in organometallic chemistry is hugely important for catalysis, due to the effect of these ligands on catalytic pathways and their involvement in catalyst decomposition. In this report, a combined experimental and computational study is presented, which provides mechanistic understanding of the unprecedented oxidative coupling of NHCs at Cu. The presence of Cu^I–, Cu^II–, and Cu^III–NHC complexes during the process is postulated, with the unusual C_carbene–C_carbene oxidative coupling reaction occurring under extremely mild reaction conditions. This process may represent a novel pathway for the decomposition of Cu–NHC complexes.     

Visible Light Induced Rhodium(I)‐Catalyzed C−H Borylation

An efficient visible light induced rhodium(I)‐catalyzed regioselective borylation of aromatic C?H bonds is reported. The photocatalytic system is based on a single NHC?Rh^I complex capable of both harvesting visible light and enabling the bond breaking/forming at room temperature. The chelating nature of the NHC‐carboxylate ligand was critical to ensure the stability of the Rh^I complex and to provide excellent photocatalytic activities. Experimental mechanistic studies evidenced a photooxidative ortho C?H bond addition upon irradiation with blue LEDs, leading to a cyclometalated Rh^III‐hydride intermediate.     

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.     

Computational Mechanistic Elucidation of the Intramolecular Aminoalkene Hydroamination Catalysed by Iminoanilide Alkaline‐Earth Compounds

A comprehensive computational exploration of plausible alternative mechanistic pathways for the intramolecular hydroamination (HA) of aminoalkenes by a recently reported class of kinetically stabilised iminoanilide alkaline‐earth silylamido compounds [{N^N}Ae{N(SiMe₃)₂} ? (thf)_n] ({N^N}=iminoanilide; Ae=Ca, Sr, Ba) is presented. On the one hand, a proton‐assisted concerted N?C/C?H bond‐forming pathway to afford the cycloamine in a single step can be invoked and on the other hand, a stepwise σ‐insertive pathway that involves a fast, reversible migratory olefin 1,2‐insertion step linked to a less rapid, irreversible metal?C azacycle tether σ‐bond aminolysis. Notably, these alternative mechanistic avenues are equally consistent with reported key experimental features. The present study, which employs a thoroughly benchmarked and reliable DFT methodology, supports the prevailing mechanism to be a stepwise σ‐insertive pathway that sees an initial conversion of the {N^N}Ae silylamido into the catalytically competent {N^N}Ae amidoalkene compound and involves thereafter facile and reversible insertive N?C bond‐forming ring closure, linked to irreversible intramolecular Ae?C tether σ‐bond aminolysis at the transient {N^N}Ae alkyl intermediate. Turnover‐limiting protonolysis accounts for the substantial primary kinetic isotope effect observed; its DFT‐derived barrier satisfactorily matches the empirically determined Eyring parameter and predicts the decrease in rate observed across the series Ca>Sr>Ba correctly. Non‐competitive kinetic demands militate against the operation of the concerted proton‐assisted pathway, which describes N?C bond‐forming ring closure triggered by concomitant amino proton delivery at the C?C linkage evolving through a multi‐centre TS structure. Valuable insights into the catalytic structure–activity relationships are unveiled by a detailed comparison of [{N^N}Ae(NHR)] catalysts. Moreover, the intriguingly opposite trends in reactivity observed in intramolecular (Ca>Sr>Ba) and intermolecular (Ca<Sr<Ba) HA catalysis for the studied family of iminoanilide alkaline‐earth amido catalysts are rationalised.     

Metal–Ligand Cooperation in Catalytic Intramolecular Hydroamination: A Computational Study of Iridium–Pyrazolato Cooperative Activation of Aminoalkenes

The present study comprehensively explores diverse mechanistic pathways for intramolecular hydroamination of prototype 2,2‐dimethyl‐4‐penten‐1‐amine by Cp*Ir chloropyrazole ( 1 ; Cp*=pentamethylcyclopentadienyl) in the presence of KOtBu base with the aid of density functional theory (DFT) calculations. The most accessible mechanistic pathway for catalytic turnover commences from Cp*Ir pyrazolato (Pz) substrate adduct 2 ?S, representing the catalytically competent compound and proceeds via initial electrophilic activation of the olefin C?C bond by the metal centre. It entails 1) facile and reversible anti nucleophilic amine attack on the iridium–olefin linkage; 2) Ir? C bond protonolysis via stepwise transfer of the ammonium N? H proton at the zwitterionic [Cp*IrPz–alkyl] intermediate onto the metal that is linked to turnover‐limiting, reductive, cycloamine elimination commencing from a high‐energy, metastable [Cp*IrPz–hydrido–alkyl] species; and 3) subsequent facile cycloamine liberation to regenerate the active catalyst species. The amine–iridium bound 2 a ?S likely corresponds to the catalyst resting state and the catalytic reaction is expected to proceed with a significant primary kinetic isotope. This study unveils the vital role of a supportive hydrogen‐bonded network involving suitably aligned β‐basic pyrazolato and cycloamido moieties together with an external amine molecule in facilitating metal protonation and reductive elimination. Cooperative hydrogen bonding thus appears pivotal for effective catalysis. The mechanistic scenario is consonant with catalyst performance data and furthermore accounts for the variation in performance for [Cp*IrPz] compounds featuring a β‐ or γ‐basic pyrazolato unit. As far as the route that involves amine N? H bond activation is concerned, a thus far undocumented pathway for concerted amidoalkene → cycloamine conversion through olefin protonation by the pyrazole N? H concurrent with N? C ring closure is disclosed as a favourable scenario. Although not practicable in the present system, this pathway describes a novel mechanistic variant in late transition metal–ligand bifunctional hydroamination catalysis that can perhaps be viable for tailored catalyst designs. The insights revealed herein concerning the operative mechanism and the structure–reactivity relationships will likely govern the rational design of late transition metal–ligand bifunctional catalysts and facilitate further conceptual advances in the area.     

Harnessing the Flexibility of Peptidic Scaffolds to Control their Copper(II)‐Coordination Properties: A Potentiometric and Spectroscopic Study

Designing small peptides that are capable of binding Cu²⁺ ions mainly through the side‐chain functionalities is a hard task because the amide nitrogen atoms strongly compete for Cu²⁺ ion coordination. However, the design of such peptides is important for obtaining biomimetic small systems of metalloenyzmes as well as for the development of artificial systems. With this in mind, a cyclic decapeptide, C‐Asp, which contained three His residues and one Asp residue, and its linear derivative, O‐Asp, were synthesized. The C‐Asp peptide has two Pro? Gly β‐turn‐inducer units and, as a result of cyclization, and as shown by CD spectroscopy, its backbone is constrained into a more defined conformation than O‐Asp, which is linear and contains a single Pro? Gly unit. A detailed potentiometric, mass spectrometric, and spectroscopic study (UV/Vis, CD, and EPR spectroscopy) showed that at a 1:1 Cu²⁺/peptide ratio, both peptides formed a major [CuHL]²⁺ species in the pH range 5.0–7.5 (C‐Asp) and 5.5–7.0 (O‐Asp). The corrected stability constants of the protonated species (log K*_CuH(O?Asp)=9.28 and log K*_CuH(C?Asp)=10.79) indicate that the cyclic peptide binds Cu²⁺ ions with higher affinity. In addition, the calculated value of K_eff shows that this higher affinity for Cu²⁺ ions prevails at all pH values, not only for a 1:1 ratio but even for a 2:1 ratio. The spectroscopic data of both [CuHL]²⁺ species are consistent with the exclusive coordination of Cu²⁺ ions by the side‐chain functionalities of the three His residues and the Asp residue in a square‐planar or square‐pyramidal geometry. Nonetheless, although these data show that, upon metal coordination, both peptides adopt a similar fold, the larger conformational constraints that are present in the cyclic scaffold results in different behaviour for both [CuHL]²⁺ species. CD and NMR analysis revealed the formation of a more rigid structure and a slower Cu²⁺‐exchange rate for [CuH(C‐Asp)]²⁺ compared to [CuH(O‐Asp]²⁺. This detailed comparative study shows that cyclization has a remarkable effect on the Cu²⁺‐coordination properties of the C‐Asp peptide, which binds Cu²⁺ ions with higher affinity at all pH values, stabilizes the [CuHL]²⁺ species in a wider pH range, and has a slower Cu²⁺‐exchange rate compared to O‐Asp.     

Copper‐Mediated Controlled/“Living” Radical Polymerization in Polar Solvents: Insights into Some Relevant Mechanistic Aspects

The field of transition‐metal‐mediated controlled/“living” radical polymerization (CLRP) has become the subject of intense discussion regarding the mechanism of this widely‐used and versatile process. Most mechanistic analyses (atom transfer radical polymerization (ATRP) vs. single‐electron transfer living radical polymerization (SET‐LRP)) have been based on model experiments, which cannot correctly mimic the true reaction conditions. We present, for the first time, a determination of the [Cu^IBr]/[L] (L=nitrogen‐based chelating ligand) ratio and the extent of Cu^IBr/L disproportionation during CLRP of methyl acrylate (MA) in dimethylsulfoxide (DMSO) with Cu⁰ wire as a transition‐metal catalyst source. The results suggest that Cu⁰ acts as a supplemental activator and reducing agent of Cu^IIBr₂/L to Cu^IBr/L. More importantly, the Cu^IBr/L species seem to be responsible for the activation of SET‐LRP.     

Amine‐Responsive Disassembly of AuI–CuI Double Salts for Oxidative Carbonylation

A sensitive amine‐responsive disassembly of self‐assembled Au^I‐Cu^I double salts was observed and its utilization for the synergistic catalysis was enlightened. Investigation of the disassembly of [Au(NHC)₂][CuI₂] revealed the contribution of Cu‐assisted ligand exchange of N‐heterocyclic carbene (NHC) by amine in [Au(NHC)₂]⁺ and the capacity of [CuI₂]^? on the oxidative step. By integrating the implicative information coded in the responsive behavior and inherent catalytic functions of d¹⁰ metal complexes, a catalyst for the oxidative carbonylation of amines was developed. The advantages of this method were clearly reflected on mild reaction conditions and the significantly expanded scope (51 examples); both primary and steric secondary amines can be employed as substrates. The cooperative reactivity from Au and Cu centers, as an indispensable prerequisite for the excellent catalytic performance, was validated in the synthesis of (un)symmetric ureas and carbamates.     

In Situ Generation of ArCu from CuF2 Makes Coupling of Bulky Aryl Silanes Feasible and Highly Efficient

A bimetallic system of Pd/CuF₂, catalytic in Pd and stoichiometric in Cu, is very efficient and selective for the coupling of fairly hindered aryl silanes with aryl, anisyl, phenylaldehyde, p‐cyanophenyl, p‐nitrophenyl, or pyridyl iodides of conventional size. The reaction involves the activation of the silane by Cu^II, followed by disproportionation and transmetalation from the Cu^I(aryl) to Pd^II, upon which coupling takes place. Cu^III formed during disproportionation is reduced to Cu^I(aryl) by excess aryl silane, so that the CuF₂ system is fully converted into Cu^I(aryl) and used in the coupling. Moreover, no extra source of fluoride is needed. Interesting size selectivity towards coupling is found in competitive reactions of hindered aryl silanes. Easily accessible [PdCl₂(IDM)(AsPh₃)] (IDM = 1,3‐dimethylimidazol‐2‐ylidene) is by far the best catalyst, and the isolated products are essentially free from As or Pd (<1 ppm). The mechanistic aspects of the process have been experimentally examined and discussed.     

Stabilization of Aliphatic Phosphines by Auxiliary Phosphine Sulfides Offers Zeptomolar Affinity and Unprecedented Selectivity for Probing Biological CuI

Full elucidation of the functions and homeostatic pathways of biological copper requires tools that can selectively recognize and manipulate this trace nutrient within living cells and tissues, where it exists primarily as Cu^I. Buffered at attomolar concentrations, intracellular Cu^I is, however, not readily accessible to commonly employed amine and thioether‐based chelators. Herein, we reveal a chelator design strategy in which phosphine sulfides aid in Cu^I coordination while simultaneously stabilizing aliphatic phosphine donors, producing a charge‐neutral ligand with low‐zeptomolar dissociation constant and 10¹⁷‐fold selectivity for Cu^I over Zn^II, Fe^II, and Mn^II. As illustrated by reversing ATP7A trafficking in cells and blocking long‐term potentiation of neurons in mouse hippocampal brain tissue, the ligand is capable of intercepting copper‐dependent processes. The phosphine sulfide‐stabilized phosphine (PSP) design approach, which confers resistance towards protonation, dioxygen, and disulfides, could be readily expanded towards ligands and probes with tailored properties for exploring Cu^I in a broad range of biological systems.