Positron emission tomography (PET) imaging agents that detect amyloid plaques containing amyloid beta (Aβ) peptide aggregates in the brain of Alzheimer’s disease (AD) patients have been successfully developed and recently approved by the FDA for clinical use. However, the short half-lives of the currently used radionuclides 11C (20.4 min) and 18F (109.8 min) may limit the widespread use of these imaging agents. Therefore, we have begun to evaluate novel AD diagnostic agents that can be radiolabeled with 64Cu, a radionuclide with a half-life of 12.7 h, ideal for PET imaging. Described herein are a series of bifunctional chelators (BFCs), L1–L5, that were designed to tightly bind 64Cu and shown to interact with Aβ aggregates both in vitro and in transgenic AD mouse brain sections. Importantly, biodistribution studies show that these compounds exhibit promising brain uptake and rapid clearance in wild-type mice, and initial microPET imaging studies of transgenic AD mice suggest that these compounds could serve as lead compounds for the development of improved diagnostic agents for AD.

Positron emission tomography (PET) is emerging as one of the most important diagnostic tools for brain imaging, yet the most commonly used radioisotopes in PET imaging, 11C and 18F, have short half-lives, and their usage is thus somewhat limited. By comparison, the 64Cu radionuclide has a half-life of 12.7 h, which is ideal for administering and imaging purposes. In spite of appreciable research efforts, high-affinity copper chelators suitable for brain imaging applications are still lacking. Herein, we present the synthesis and characterization of a series of bifunctional compounds (BFCs) based on macrocyclic 1,4,7-triazacyclononane and 2,11-diaza[3.3](2,6)pyridinophane ligand frameworks that exhibit a high affinity for Cu2+ ions. In addition, these BFCs contain a 2-phenylbenzothiazole fragment that is known to interact tightly with amyloid β fibrillar aggregates. Determination of the protonation constants (pKa values) and stability constants (log β values) of these BFCs, as well as characterization of the isolated copper complexes using X-ray crystallography, electron paramagnetic resonance spectroscopy, and electrochemical studies, suggests that these BFCs exhibit desirable properties for the development of novel 64Cu PET imaging agents for Alzheimer’s disease.

JIB-04, a specific inhibitor of the O2-activating, Fe-dependent histone lysine demethylases, is revealed to disrupt the binding of O2 in KDM4A/JMJD2A through a continuous O2-consumption assay, X-ray crystal structure data, and molecular docking.

The N,N′-di(toluenesulfonyl)-2,11-diaza[3,3](2,6)pyridinophane (TsN4) precursor was sought after as a starting point for the preparation of various symmetric and asymmetric pyridinophane-derived ligands. Various procedures to synthesize TsN4 had been published, but the crucial problem had been the purification of TsN4 from the larger 18- and 24-membered azamacrocycles. Most commonly, column chromatography or other laborious methods have been utilized for this separation, yet we have found an alternate selective dissolution method upon protonation which allows for multi-gram scale output of TsN4·HCl. This optimized synthesis of TsN4 also led to the development of symmetric RN4 derivatives as well as the asymmetric derivative N-(tosyl)-2,11-diaza[3,3](2,6)pyridinophane (TsHN4). Using this TsHN4 precursor, different N-substituents can be added to create a library of asymmetric RR′N4 macrocyclic ligands. These asymmetric RR′N4 derivatives expand the utility of the RN4 framework in coordination chemistry and the ability to study the electronic, steric, and denticity effects of these pyridinophane ligands on the metal center.

The use of the tridentate ligand 1,4,7-trimethyl-1,4,7-triazacyclononane (Me3tacn) and the cyclic alkyl/aryl C-donor ligand -CH2CMe2-o-C6H4- (cycloneophyl) allows for the synthesis of isolable organometallic NiII, NiIII, and NiIV complexes. Surprisingly, the five-coordinate NiIII complex is stable both in solution and the solid state, and exhibits limited C-C bond formation reactivity. Oxidation by one electron of this NiIII species generates a six-coordinate NiIV complex, with an acetonitrile molecule bound to Ni. Interestingly, illumination of the NiIV complex with blue LEDs results in rapid formation of the cyclic C-C product at room temperature. This reactivity has important implications for the recently developed dual Ni/photoredox catalytic systems proposed to involve high-valent organometallic Ni intermediates. Additional reactivity studies show the corresponding NiII species undergoes oxidative addition with alkyl halides, as well as rapid oxidation by O2, to generate detectable NiIII and/or NiIV intermediates and followed by C-C bond formation.

Nickel-catalyzed cross-coupling reactions are experiencing a dramatic resurgence in recent years given their ability to employ a wider range of electrophiles as well as promote stereospecific or stereoselective transformations. In contrast to the extensively studied Pd catalysts that generally employ diamagnetic intermediates, Ni systems can more easily access various oxidation states including odd-electron configurations. For example, organometallic NiIII intermediates with aryl and/or alkyl ligands are commonly proposed as the active intermediates in cross-coupling reactions. Herein, we report the first isolated NiIII–dialkyl complex and show that this species is involved in stoichiometric and catalytic C–C bond formation reactions. Interestingly, the rate of C–C bond formation from a NiIII center is enhanced in the presence of an oxidant, suggesting the involvement of transient NiIV species. Indeed, such a NiIV species was observed and characterized spectroscopically for a nickelacycle system. Overall, these studies suggest that both NiIII and NiIV species could play an important role in a range of Ni-catalyzed cross-coupling reactions, especially those involving alkyl substrates.

Herein we report an atom- and step-economic aromatic cyanoalkylation reaction that employs nitriles as building blocks and proceeds through Csp2–H and Csp3–H bond activation steps mediated by NiIII. In addition to cyanomethylation with MeCN, regioselective α-cyanoalkylation was observed with various nitrile substrates to generate secondary and tertiary nitriles. Importantly, to the best of our knowledge these are the first examples of C–H bond activation reactions occurring at a NiIII center, which may exhibit different reactivity and selectivity profiles than those corresponding to analogous NiII centers. These studies provide guiding principles to design catalytic C–H activation and functionalization reactions involving high-valent Ni species.

A Ni(II) complex with two t-butylisocyanide ligands supported by a N3C− type tetradentate ligand was synthesized and characterized. Quantitative generation of the aromatic cyanation product, tBuN3C-CN, is observed by reacting this Ni(II) complex with 1 equiv. of an oxidant. Reactivity studies suggest that this oxidatively-induced cyanation involves a heterolytic cleavage of the N–tBu bond and is mediated by Ni(III).

Herein we report the synthesis and reactivity of several organometallic NiIII complexes stabilized by a modified tetradentate pyridinophane ligand containing one phenyl group. A room temperature stable dicationic NiIII–disolvento complex was also isolated, and the presence of two available cis coordination sites in this complex offers an opportunity to probe the C-heteroatom bond formation reactivity of high-valent Ni centers. Interestingly, the NiIII-dihydroxide and NiIII-dimethoxide species can be synthesized, and they undergo aryl methoxylation and hydroxylation that is favored by addition of oxidant, which also limits the β-hydride elimination side reaction. Overall, these results provide strong evidence for the involvement of high-valent organometallic Ni species, possibly both NiIII and NiIV species, in oxidatively induced C-heteroatom bond formation reactions.

Organometallic Ni(III) intermediates have been proposed in several Nickel-catalyzed cross-coupling reactions, yet no isolated bis(hydrocarbyl)Ni(III) complexes have been reported to date. Herein we report the synthesis and detailed characterization of stable organometallic Ni(III) complexes that contain two trifluoromethyl ligands and are supported by tetradentate N-donor ligands RN4 (R = Me or tBu). Interestingly, the corresponding Ni(II) precursors undergo facile oxidation, including aerobic oxidation, to generate uncommonly stable organometallic Ni(III) complexes that exhibit limited reactivity.

Nickel complexes have been widely employed as catalysts in C–C and C–heteroatom bond formation reactions. In addition to Ni(0) and Ni(II) intermediates, several Ni-catalyzed reactions are proposed to also involve odd-electron Ni(I) and Ni(III) oxidation states. We report herein the isolation, structural and spectroscopic characterization, and organometallic reactivity of Ni(III) complexes containing aryl and alkyl ligands. These Ni(III) species undergo transmetalation and/or reductive elimination reactions to form new C–C or C–heteroatom bonds and are also competent catalysts for Kumada and Negishi cross-coupling reactions. Overall, these results provide strong evidence for the direct involvement of organometallic Ni(III) species in cross-coupling reactions and oxidatively induced C–heteroatom bond formation reactions.

The complex (Me3tacn)PdII(CH2CMe2C6H4) is readily oxidized by O2 or H2O2 to yield the PdIV–OH complex [(Me3tacn)PdIV(OH)(CH2CMe2C6H4)]+. Thermolysis of this product leads to the selective C(sp2)–O reductive elimination of 2-tert-butylphenol, no C(sp3)–O elimination product being detected. This system represents a rare example of selective C(sp2)–O bond formation that is relevant to Pd-catalyzed aerobic C–H hydroxylation reactions.

The conformationally flexible tetradentate pyridinophane ligand tBuN4 effectively lowers the oxidation potential of (tBuN4)PdII complexes and promotes their facile chemical and electrochemical oxidation, including unpredecented aerobic oxidation reactivity. While the low potential of a number of PdII (and PtII) complexes supported by various fac-chelating polydentate ligands is often attributed to the presence of a coordinating group in the axial position of the metal center, no detailed electrochemical studies have been reported for such systems. Described herein is the detailed electrochemical investigation of the effect of ligand conformation on the redox properties of the corresponding PdII complexes. These Pd complexes adopt different conformations in solution, as supported by studies using variable scan rate, variable-temperature cyclic voltammetry (CV), differential pulse voltammety, and digital CV simulations at variable scan rates. The effect of the axial amine protonation on the spectroscopic and electrochemical properties of the complexes was also investigated. A number of new PdIII complexes were characterized by electron paramagnetic resonance, UV–vis spectroscopy, and X-ray diffraction including [(tBuN4)PdIIICl2]ClO4, a dicationic [(tBuN4)PdIIIMe(MeCN)](OTf)2, and an unstable tricationic [(tBuN4)PdIII(EtCN)2]3+ species. Although the electron-rich neutral complexes (tBuN4)PdMeCl and (tBuN4)PdMe2 are present in solution as a single isomer with the axial amines not interacting with the metal center, their low oxidation potentials are due to the presence of a minor conformer in which the tBuN4 ligand adopts a tridentade (κ3) conformation. In addition, the redox properties of the (tBuN4)Pd complexes show a significant temperature dependence, as the low-temperature behavior is mainly due to the contribution from the major, most stable conformer, while the room-temperature redox properties are due to the formation of the minor, more easily oxidized conformer(s) with the tBuN4 ligand acting as a tridentate (κ3) or tetradentate (κ4) ligand. Overall, the coordination to the metal center of each axial amine donor of the tBuN4 ligand leads to a lowering of the PdII/III oxidation potential by ∼0.6 V. These detailed electrochemical studies can thus provide important insights into the design of new ligands that can promote Pd-catalyzed oxidation reactions employing mild oxidants such as O2.

Despite the rich chemistry of palladium in oxidation states of 0, +2, and +4, no PdIII coordination compounds have been reported until the 1980s. Moreover, while Pd complexes are among the most commonly used catalysts in organometallic chemistry, the first organometallic PdIII complexes have only been reported in 2006. Since then, a significant number of PdIII complexes have been isolated, characterized, and proposed as active catalytic intermediates in the functionalization of CH bonds, oxidatively induced CC bond formation reactions, as well as radical insertion and addition reactions. This review provides an overview of the synthesis and spectroscopic characterization of mononuclear and dinuclear PdIII complexes. A detailed understanding of the steric and electronic properties of PdIII complexes should provide insight for the development of novel catalysts for multi-electron redox reactions and various organometallic transformations.Highlights► Despite the rich chemistry of palladium in the 0, +2, and +4 oxidation states, Pd(III) complexes are less common. ► Pd complexes are among the most widely used catalysts in organic chemistry, yet organometallic Pd(III) complexes have only been reported starting in 2006. ► A number of Pd(III) complexes have been proposed recently as catalytic intermediates in CH functionalization, CC bond formation, and radical reactions. ► This review provides an overview of the synthesis and spectroscopic characterization of mononuclear and dinuclear Pd(III) complexes. ► A detailed understanding of the steric and electronic properties of Pd(III) complexes should provide insight for the development of novel catalysts for various redox reactions.

The synthesis and structural comparison are reported herein for a series of late first-row transition metal complexes using a macrocyclic pyridinophane ligand, N,N′-di-tert-butyl-2,11-diaza[3.3](2,6)pyridinophane (tBuN4). The tBuN4 ligand enforces a distorted octahedral geometry in complexes [(tBuN4)MII(MeCN)2](OTf)2 (M = FeII, CoII, NiII, CuII), [(tBuN4)ZnII(MeCN)(OTf)](OTf), and [(tBuN4)FeIII(OMe)2](OTf), with elongated axial M–Namine distances compared to the equatorial M–Npy distances. The geometry of [(tBuN4)CuI(MeCN)](OTf) is pentacoordinate with weak axial interactions with the amine N-donors of tBuN4. Complexes [(tBuN4)M(MeCN)2](OTf)2 (M = Fe, Co) exhibit magnetic properties that are intermediate between those expected for high spin and low spin complexes. Electrochemical studies of (tBuN4)M complexes suggest that tBuN4 is suitable to stabilize CoI, NiI, CoIII, FeIII solvato-complexes, while the electrochemical oxidation of (tBuN4)NiCl2 complex leads to formation of a NiIII species, supporting the ability of the tBuN4 ligand to stabilize first row transition metal complexes in various oxidation states. Importantly, the [(tBuN4)MII(MeCN)2]2+ complexes exhibit two available cis coordination sites and thus can mediate reactions involving exogenous ligands. For example, the [(tBuN4)CuII(MeCN)2]2+ species acts as an efficient Lewis acid and promotes an uncommon hydrolytic coupling of nitriles. In addition, initial UV–vis and electron paramagnetic resonance (EPR) studies show that the [(tBuN4)FeII(MeCN)2]2+ complex reacts with oxidants such as H2O2 and peracetic acid to form high-valent Fe transient species. Overall, these results suggest that the (tBuN4)MII systems should be able to promote redox transformations involving exogenous substrates.

The coordination chemistry of Cu and Zn metal ions with the amyloid β (Aβ) peptides has attracted a lot of attention in recent years due to its implications in Alzheimer's disease. A number of reports indicate that Cu and Zn have profound effects on Aβ aggregation. However, the impact of these metal ions on Aβ oligomerization and fibrillization is still not well understood, especially for the more rapidly aggregating and more neurotoxic Aβ42 peptide. Here we report the effect of Cu2+ and Zn2+ on Aβ42 oligomerization and aggregation using a series of methods such as Thioflavin T (ThT) fluorescence, native gel and Western blotting, transmission electron microscopy (TEM), and cellular toxicity studies. Our studies suggest that both Cu2+ and Zn2+ ions inhibit Aβ42 fibrillization. While presence of Cu2+ stabilizes Aβ42 oligomers, Zn2+ leads to formation of amorphous, non-fibrillar aggregates. The effects of temperature, buffer, and metal ion concentration and stoichiometry were also studied. Interestingly, while Cu2+ increases the Aβ42-induced cell toxicity, Zn2+ causes a significant decrease in Aβ42 neurotoxicity. While previous reports have indicated that Cu2+ can disrupt β-sheets and lead to non-fibrillar Aβ aggregates, the neurotoxic consequences were not investigated in detail. The data presented herein including cellular toxicity studies strongly suggest that Cu2+ increases the neurotoxicity of Aβ42 due to stabilization of soluble Aβ42 oligomers.

A series of (N2S2)PdRX complexes (N2S2 = 2,11-dithia[3.3](2,6)pyridinophane; R = X = Me, 1; R = Me, X = Cl, 2; R = Me, X = Br, 3; R = X = Cl, 4) were synthesized, and their structural and electronic properties were investigated. X-ray crystal structures show that for the corresponding Pd(II) complexes the N2S2 ligand adopts a κ2 conformation, with the pyridine N donors binding in the equatorial plane. Cyclic voltammetry (CV) studies suggest that the Pd(III) oxidation state is accessible at moderate redox potentials. In situ EPR, ESI-MS, UV–vis, and low-temperature electrochemical studies were employed to detect the formation of Pd(III) species during the oxidation of Pd(II) precursors. In addition, the [(N2S2)PdIVMe2](PF6)2 ([12+](PF6)2) complex was isolated by oxidation of 1 with 2 equiv of FcPF6, and its structural characterization reveals an octahedral Pd(IV) center. The reversible PdIV/III redox couple for the Pd(IV) species supports the observed formation of the Pd(III)–dimethyl species upon chemical reduction of 12+. In addition, reactivity studies reveal ethane, MeCl, and MeBr elimination upon one-electron oxidation of 1 (as well as the one-electron reduction of 12+), 2, and 3, respectively. Mechanistic studies suggest the initial formation of a Pd(III) species, followed by methyl group transfer/disproportionation and subsequent reductive elimination from a Pd(IV) intermediate, although a halogen radical pathway cannot be completely excluded during C–halide bond formation. Interestingly, computational results suggest that the N2S2 ligand stabilizes to a greater extent the Pd(IV) vs the Pd(III) oxidation state, likely due to steric rather than electronic effects.

Probing the conformational changes of amyloid beta (Aβ) peptide aggregation is challenging owing to the vast heterogeneity of the resulting soluble aggregates. To investigate the formation of these aggregates in solution, we designed an MS-based biophysical approach and applied it to the formation of soluble aggregates of the Aβ42 peptide, the proposed causative agent in Alzheimer’s disease. The approach incorporates pulsed hydrogen–deuterium exchange coupled with MS analysis. The combined approach provides evidence for a self-catalyzed aggregation with a lag phase, as observed previously by fluorescence methods. Unlike those approaches, pulsed hydrogen–deuterium exchange does not require modified Aβ42 (e.g., labeling with a fluorophore). Furthermore, the approach reveals that the center region of Aβ42 is first to aggregate, followed by the C and N termini. We also found that the lag phase in the aggregation of soluble species is affected by temperature and Cu2+ ions. This MS approach has sufficient structural resolution to allow interrogation of Aβ aggregation in physiologically relevant environments. This platform should be generally useful for investigating the aggregation of other amyloid-forming proteins and neurotoxic soluble peptide aggregates.

Abnormal interactions of Cu and Zn ions with the amyloid β (Aβ) peptide are proposed to play an important role in the pathogenesis of Alzheimer’s disease (AD). Disruption of these metal–peptide interactions using chemical agents holds considerable promise as a therapeutic strategy to combat this incurable disease. Reported herein are two bifunctional compounds (BFCs) L1 and L2 that contain both amyloid-binding and metal-chelating molecular motifs. Both L1 and L2 exhibit high stability constants for Cu2+ and Zn2+ and thus are good chelators for these metal ions. In addition, L1 and L2 show strong affinity toward Aβ species. Both compounds are efficient inhibitors of the metal-mediated aggregation of the Aβ42 peptide and promote disaggregation of amyloid fibrils, as observed by ThT fluorescence, native gel electrophoresis/Western blotting, and transmission electron microscopy (TEM). Interestingly, the formation of soluble Aβ42 oligomers in the presence of metal ions and BFCs leads to an increased cellular toxicity. These results suggest that for the Aβ42 peptide—in contrast to the Aβ40 peptide—the previously employed strategy of inhibiting Aβ aggregation and promoting amyloid fibril dissagregation may not be optimal for the development of potential AD therapeutics, due to formation of neurotoxic soluble Aβ42 oligomers.

Isostructural dinuclear Pd and Pt complexes that exhibit unique d8–d8 interactions between dicationic metal centers are reported. These metal–metal interactions are not supported by any bridging ligands and suggest a significant metal–metal bonding character for both Pd and Pt systems.

The tetradentate ligands RN4 (RN4 = N,N′-di-alkyl-2,11-diaza[3,3](2,6)pyridinophane, R = Me or iPr) were found to stabilize cationic (RN4)PdMe2 and (RN4)PdMeCl complexes in both PdIII and PdIV oxidation states. This allows for the first time a direct structural and reactivity comparison of the two Pd oxidation states in an identical ligand environment. The PdIII complexes exhibit a distorted octahedral geometry, as expected for a d7 metal center, and display unselective C–C and C–Cl bond formation reactivity. By contrast, the PdIV complexes have a pseudo-octahedral geometry and undergo selective non-radical C–C or C–Cl bond formation that is controlled by the ability of the complex to access a five-coordinate intermediate.

The studies described herein focus on the 1,3-dipolar cycloaddition reaction between first-row transition metal–azide complexes and alkyne reagents, i.e. an inorganic variant of the extensively used “click reaction”. The reaction between the azide complexes of biologically-relevant metals (e.g., Fe, Co and Ni) found in metalloenzyme active sites and alkyne reagents has been investigated as a proof-of-principle for a novel method of developing metalloenzyme triazole-based inhibitors. Six Fe, Co and Ni mono-azide complexes employing salen- and cyclam-type ligands have been synthesized and characterized. The scope of the targeted inorganic azide–alkyne click reaction was investigated using the electron-deficient alkyne dimethyl acetylenedicarboxylate. Of the six metal–azide complexes tested, the Co and Ni complexes of the 1,4,8,11-tetrametyl-1,4,8,11-tetraazacyclotetradecane (Me4cyclam) ligand showed a successful cycloaddition reaction and formation of the corresponding metal–triazolate products, which were crystallographically characterized. Moreover, use of less electron deficient alkynes resulted in a loss of cycloaddition reactivity. Analysis of the structural parameters of the investigated metal–azide complexes suggests that a more symmetric structure and charge distribution within the azide moiety is needed for the formation of a metal–triazolate product. Overall, these results suggest that a successful cycloaddition reaction between a metal–azide complex and an alkyne substrate is dependent both on the ligand and metal oxidation state, that determine the electronic properties of the bound azide, as well as the electron deficient nature of the alkyne employed.

The Jumonji C domain-containing histone demethylases (JmjC-HDMs) are α-ketoglutarate (αKG)-dependent, O2-activating, non-heme iron enzymes that play an important role in epigenetics. Reported herein is a detailed kinetic analysis of three JmjC-HDMs, including the cancer-relevant JMJD2C, that was achieved by employing three enzyme activity assays. A continuous O2 consumption assay reveals that HDMs have low affinities for O2, suggesting that these enzymes can act as oxygen sensors in vivo. An interesting case of αKG substrate inhibition was found, and the kinetic data suggest that αKG inhibits JMJD2C competitively with respect to O2. JMJD2C displays an optimal activity in vitro at αKG concentrations similar to those found in cancer cells, with implications for the regulation of histone demethylation activity in cancer versus normal cells.

The dimethyl PdII complex (MeN4)PdIIMe2 (MeN4 = N,N′-dimethyl-2,11-diaza[3,3](2,6)pyridinophane) is readily oxidized by dioxygen in the presence of protic solvents to selectively eliminate ethane. UV–vis, EPR, ESI-MS, and NMR studies reveal the formation of several PdIII and PdIV intermediates during the aerobically induced C–C bond formation reaction, including the key intermediate [(κ3-MeN4)PdIVMe3]+, which leads to ethane elimination. The latter complex was also synthesized independently and structurally characterized to reveal a distorted octahedral geometry that is proposed to promote facile reductive elimination. Overall, this study represents a rare example of aerobic oxidation of an organometallic PdII precursor that leads to a well-defined PdIV species, which undergoes selective C–C bond formation under ambient conditions.

The dimethyl PdII complex (Me3tacn)PdIIMe2 (Me3tacn = N,N′,N″-trimethyl-1,4,7-triazacyclononane) undergoes facile aerobic oxidation to yield the stable species [(Me3tacn)PdIVMe3]+. EPR, UV–vis, and ESI-MS studies suggest an inner-sphere mechanism for the oxidation of (Me3tacn)PdMe2 by O2 and formation of PdIV species. In addition, the structurally characterized complex [(Me3tacn)PdIVMe3]I undergoes selective elimination of ethane at elevated temperatures. Overall, this system represents one of the first examples of aerobic oxidation of a PdII organometallic precursor to yield a well-defined PdIV product, supporting the role of PdIV species as viable intermediates in Pd-mediated catalytic or stoichiometric aerobic oxidative transformations.

Oxidation of the PdII complex (N4)PdIIMe2 (N4 = N,N′-di-tert-butyl-2,11-diaza[3.3](2,6)pyridinophane) with O2 or ROOH (R = H, tert-butyl, cumyl) produces the PdIII species [(N4)PdIIIMe2]+, followed by selective formation of ethane and the monomethyl complex (N4)PdIIMe(OH). Cyclic voltammetry studies and use of 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) as a spin trap suggest an inner-sphere mechanism for (N4)PdIIMe2 oxidation by O2 to generate a PdIII-superoxide intermediate. In addition, reaction of (N4)PdIIMe2 with cumene hydroperoxide involves a heterolytic O–O bond cleavage, implying a two-electron oxidation of the PdII precursor and formation of a transient PdIV intermediate. Mechanistic studies of the C–C bond formation steps and crossover experiments are consistent with a nonradical mechanism that involves methyl group transfer and transient formation of a PdIV species. Moreover, the (N4)PdIIMe(OH) complex formed upon ethane elimination reacts with weakly acidic C–H bonds of acetone and terminal alkynes, leading to formation of a new PdII–C bond. Overall, this study represents the first example of C–C bond formation upon aerobic oxidation of a PdII dimethyl complex, with implications in the development of Pd catalysts for aerobic oxidative coupling of C–H bonds.

The tridentate ligand N-methyl-N,N-bis(2-pyridylmethyl)amine (L) has been employed to synthesize a dinuclear Co(II)Co(III) mixed-valence complex containing μ-methoxo and μ-carboxylato bridging ligands, [LCoII(μ-carboxylato)bis(μ-methoxo)CoIIIL](ClO4)2. In this complex, the two pseudo-octahedral Co centers have an identical ligand environment, yet the average Co–N and Co–O bond distances at the two Co ions differ significantly. Electrochemical, spectroscopic, and magnetic susceptibility measurements confirm that it belongs to a localized Class II mixed-valence system, despite the presence of a short Co···Co distance of 3.021 Å. Oxidation of this Co(II)Co(III) complex leads to formation of the corresponding Co(III)Co(III) complex that was characterized structurally and spectroscopically. In addition, dinuclear and trinuclear μ-hydroxo Co(III) complexes have been obtained in the presence of phosphate anions and absence of methanol, respectively, suggesting that an additional bridging ligand is needed to stabilize the CoIIIbis(μ-hydroxo)CoIII fragment. Moreover, the ability of the mixed-valence Co(II)Co(III) complex and the three related Co(III) complexes to electrocatalytically oxidize water was also investigated. The observed limited water oxidation catalytic ability for these systems suggests that a multinuclear Co cluster and/or presence of O-rich ligands may be needed for the generation of efficient molecular Co-based water oxidation catalysts.

Organometallic Pd(III) complexes have been implicated as intermediates in a number of catalytic and stoichiometric transformations. While a few dinuclear organometallic Pd(III) complexes have been characterized, no mononuclear organometallic Pd(III) complexes have been isolated to date. Reported herein is the synthesis and characterization of a series of Pd(III) complexes supported by the tetradentate ligand N,N′-di-tert-butyl-2,11-diaza[3.3](2,6)pyridinophane (N4). Chemical or electrochemical oxidation of the Pd(II) complexes (N4)PdII(R)(X) (R = Me, X = Cl: 1; R = Ph, X = Cl: 2; R = X = Me: 3) generates [(N4)PdIIIMeCl]+ (1+), [(N4)PdIIIPhCl]+ (2+), and [(N4)PdIIIMe2]+ (3+). These stable Pd(III) complexes were isolated and characterized by X-ray diffraction, cyclic voltammetry, UV−vis, EPR, magnetic moment measurements, and DFT to confirm the presence of paramagnetic d7 Pd(III) centers. Moreover, these Pd(III) complexes undergo light-induced C−C bond formation to give the corresponding homocoupled products ethane or biphenyl. Particularly remarkable is the observation for the first time of ethane formation from monomethyl Pd complexes.

JIB-04, a specific inhibitor of the O2-activating, Fe-dependent histone lysine demethylases, is revealed to disrupt the binding of O2 in KDM4A/JMJD2A through a continuous O2-consumption assay, X-ray crystal structure data, and molecular docking.

A series of organometallic NiII and NiIII complexes supported by tertadendate RN3C− ligands were synthesized and fully characterized using X-ray crystallography, CV, and EPR. Based on the solid state structures, the substituents on the two amine N-donors significantly affect the coordination of the NiIII centers, while the para substituents of the phenyl C-donor have a reduced effect. This is further supported by electrochemical and spectroscopic measurements that suggest the presence of a less bulky N-substituent of the RN3C− ligand leads to a more accessible NiIII center. These results also suggest that the (NpN3C)Ni system should be more reactive toward oxidation than the corresponding (tBuN3C)Ni and (pOMeN3C)Ni systems. Indeed, aerobic oxidative aromatic cyanation was achieved with the (NpN3C)Ni system at room temperature.

Organometallic Ni(III) intermediates have been proposed in several Nickel-catalyzed cross-coupling reactions, yet no isolated bis(hydrocarbyl)Ni(III) complexes have been reported to date. Herein we report the synthesis and detailed characterization of stable organometallic Ni(III) complexes that contain two trifluoromethyl ligands and are supported by tetradentate N-donor ligands RN4 (R = Me or tBu). Interestingly, the corresponding Ni(II) precursors undergo facile oxidation, including aerobic oxidation, to generate uncommonly stable organometallic Ni(III) complexes that exhibit limited reactivity.

The complex (Me3tacn)PdII(CH2CMe2C6H4) is readily oxidized by O2 or H2O2 to yield the PdIV–OH complex [(Me3tacn)PdIV(OH)(CH2CMe2C6H4)]+. Thermolysis of this product leads to the selective C(sp2)–O reductive elimination of 2-tert-butylphenol, no C(sp3)–O elimination product being detected. This system represents a rare example of selective C(sp2)–O bond formation that is relevant to Pd-catalyzed aerobic C–H hydroxylation reactions.

Isostructural dinuclear Pd and Pt complexes that exhibit unique d8–d8 interactions between dicationic metal centers are reported. These metal–metal interactions are not supported by any bridging ligands and suggest a significant metal–metal bonding character for both Pd and Pt systems.

A Ni(II) complex with two t-butylisocyanide ligands supported by a N3C− type tetradentate ligand was synthesized and characterized. Quantitative generation of the aromatic cyanation product, tBuN3C-CN, is observed by reacting this Ni(II) complex with 1 equiv. of an oxidant. Reactivity studies suggest that this oxidatively-induced cyanation involves a heterolytic cleavage of the N–tBu bond and is mediated by Ni(III).

The studies described herein focus on the 1,3-dipolar cycloaddition reaction between first-row transition metal–azide complexes and alkyne reagents, i.e. an inorganic variant of the extensively used “click reaction”. The reaction between the azide complexes of biologically-relevant metals (e.g., Fe, Co and Ni) found in metalloenzyme active sites and alkyne reagents has been investigated as a proof-of-principle for a novel method of developing metalloenzyme triazole-based inhibitors. Six Fe, Co and Ni mono-azide complexes employing salen- and cyclam-type ligands have been synthesized and characterized. The scope of the targeted inorganic azide–alkyne click reaction was investigated using the electron-deficient alkyne dimethyl acetylenedicarboxylate. Of the six metal–azide complexes tested, the Co and Ni complexes of the 1,4,8,11-tetrametyl-1,4,8,11-tetraazacyclotetradecane (Me4cyclam) ligand showed a successful cycloaddition reaction and formation of the corresponding metal–triazolate products, which were crystallographically characterized. Moreover, use of less electron deficient alkynes resulted in a loss of cycloaddition reactivity. Analysis of the structural parameters of the investigated metal–azide complexes suggests that a more symmetric structure and charge distribution within the azide moiety is needed for the formation of a metal–triazolate product. Overall, these results suggest that a successful cycloaddition reaction between a metal–azide complex and an alkyne substrate is dependent both on the ligand and metal oxidation state, that determine the electronic properties of the bound azide, as well as the electron deficient nature of the alkyne employed.

The tetradentate ligands RN4 (RN4 = N,N′-di-alkyl-2,11-diaza[3,3](2,6)pyridinophane, R = Me or iPr) were found to stabilize cationic (RN4)PdMe2 and (RN4)PdMeCl complexes in both PdIII and PdIV oxidation states. This allows for the first time a direct structural and reactivity comparison of the two Pd oxidation states in an identical ligand environment. The PdIII complexes exhibit a distorted octahedral geometry, as expected for a d7 metal center, and display unselective C–C and C–Cl bond formation reactivity. By contrast, the PdIV complexes have a pseudo-octahedral geometry and undergo selective non-radical C–C or C–Cl bond formation that is controlled by the ability of the complex to access a five-coordinate intermediate.