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Inhibition of amyloid β (Aβ) aggregation and cholinesterase activity are two major therapeutic targets for Alzheimer's disease (AD). Multifunctional Molecules (MFMs) specifically designed to address other contributing factors, such as metal ion induced abnormalities, oxidative stress, toxic Aβ aggregates etc. are very much required. Several multifunctional molecules have been developed using different molecular scaffolds. Reported herein is a new series of four MFMs based on ThT, Azo-stilbene and metal ion chelating pockets. The synthesis, characterization, and metal chelation ability for [Cu 2+ and Zn 2+ ] are presented herein. Furthermore, we explored their multifunctionality w.r.t. to their (i) recognition of Aβ aggregates and monomeric form, (ii) utility in modulating the aggregation pathways of both metal-free and metal-bound amyloid-β, (iii) ex-vivo staining of amyloid plaques in 5xFAD mice brain sections, (iv) ability to scavenge free radicals and (v) ability to inhibit cholinesterase activity. Molecular docking studies were also performed with Aβ peptides and acetylcholinesterase enzyme to understand the observed inhibitory effect on activity. Overall, the studies presented here establish the multifunctional nature of these molecules and qualify them as promising candidates for furthermore investigation in the quest for finding Alzheimer's disease treatment., (© 2024 Wiley-VCH GmbH.)

The aggregation of amyloid β (Aβ) peptides is a significant hallmark of Alzheimer's disease (AD), and the detection of Aβ aggregates and the inhibition of their formation are important for the diagnosis and treatment of AD, respectively. Herein, we report a series of benzothiazole-based Ir(III) complexes HN-1 to HN-8 that exhibit appreciable inhibition of Aβ aggregation in vitro and in living cells. These Ir(III) complexes can induce a significant fluorescence increase when binding to Aβ fibrils and Aβ oligomers, while their measured log  D values suggest these compounds could have enhanced blood-brain barrier (BBB) permeability. In vivo studies show that HN-1, HN-2, HN-3, and HN-8 successfully penetrate the BBB and stain the amyloid plaques in AD mouse brains after a 10-day treatment, suggesting that these Ir(III) complexes could act as lead compounds for AD therapeutic and diagnostic agent development.

Ferrocene is one of the most common electron donors, and mapping its ligand-field excited states is critical to designing donor-acceptor (D-A) molecules with long-lived charge transfer states. Although 3 (d-d) states are commonly invoked in the photophysics of ferrocene complexes, mention of the high-spin 5 (d-d) state is scarce. Here, we provide clear evidence of 5 (d-d) formation in a bimetallic D-A molecule, ferrocenyl cobaltocenium hexafluorophosphate ([FcCc]PF 6 ). Femtosecond optical transient absorption (OTA) spectroscopy reveals two distinct electronic excited states with 30 and 500 ps lifetimes. Using a combination of ultraviolet, visible, near-infrared, and short-wave infrared probe pulses, we capture the spectral features of these states over an ultrabroadband range spanning 320 to 2200 nm. Time-dependent density functional theory (DFT) calculations of the lowest triplet and quintet states, both primarily Fe(II) (d-d) in character, qualitatively agree with the experimental OTA spectra, allowing us to assign the 30 ps state as the 3 (d-d) state and the 500 ps state as the high-spin 5 (d-d) state. To confirm the ferrocene-centered high-spin character of the 500 ps state, we performed X-ray transient absorption (XTA) spectroscopy at the Fe and Co K edges. The Fe K-edge XTA spectrum at 150 ps shows a red shift of the absorption edge that is consistent with an Fe(II) high-spin state, as supported by ab initio calculations. The transient signal detected at the Co K-edge is 50× weaker, confirming the ferrocene-centered character of the excited state. Fitting of the transient extended X-ray absorption fine structure region yields an Fe-C bond length increase of 0.25 ± 0.1 Å in the excited state, as expected for the high-spin state based on DFT. Altogether, these results demonstrate that the high-spin state of ferrocene should be considered when designing donor-acceptor assemblies for photocatalysis and photovoltaics.

Photoassisted catalysis using Ni complexes is an emerging field for cross-coupling reactions in organic synthesis. However, the mechanism by which light enables and enhances the reactivity of these complexes often remains elusive. Although optical techniques have been widely used to study the ground and excited states of photocatalysts, they lack the specificity to interrogate the electronic and structural changes at specific atoms. Herein, we report metal-specific studies using transient Ni L- and K-edge X-ray absorption spectroscopy of a prototypical Ni photocatalyst, (dtbbpy)Ni( o -tol)Cl (dtb = 4,4'-di- tert -butyl, bpy = bipyridine, o -tol = ortho -tolyl), in solution. We unambiguously confirm via direct experimental evidence that the long-lived (∼5 ns) excited state is a tetrahedral metal-centered triplet state. These results demonstrate the power of ultrafast X-ray spectroscopies to unambiguously elucidate the nature of excited states in important transition-metal-based photocatalytic systems.

X-ray absorption spectroscopy (XAS) is widely used across the life and physical sciences to identify the electronic properties and structure surrounding a specific element. XAS is less often used for the characterization of organometallic compounds, especially for sensitive and highly reactive species. In this study, we used solid- and solution-phase XAS to compare a series of 25 palladium complexes in controlled ligand environments. The compounds include palladium centers in the formal I, II, III, and IV oxidation states, supported by tridentate and tetradentate macrocyclic ligands, with different halide and methyl ligand combinations. The Pd K-edge energies increased not only upon oxidizing the metal center but also upon increasing the denticity of the ligand framework, substituting sigma-donating methyl groups with chlorides, and increasing the charge of the overall metal complex by replacing charged ligands with neutral ligands. These trends were then applied to characterize compounds whose oxidation states were otherwise unconfirmed.

The broader utilization of 64 Cu positron emission tomography (PET) imaging agents has been hindered by the unproductive demetalation induced by bioreductants. To advance the development of 64 Cu-based PET imaging tracers for Alzheimer's Disease (AD), there is a need for novel ligand design strategies. In this study, we developed sulfur-containing dithiapyridinophane (N2S2) bifunctional chelators (BFCs) as well as all nitrogen-based diazapyridinophane (N4) BFCs to compare their abilities to chelate Cu and target Aβ aggregates. Through spectrophotometric titrations and electrochemical measurements, we have demonstrated that the N2S2-based BFCs exhibit >10 orders of magnitude higher binding affinity toward Cu(I) compared to their N4-based counterparts, while both types of BFCs exhibit high stability constants toward Cu(II). Notably, solid state structures for both Cu(II) and Cu(I) complexes supported by the two ligand frameworks were obtained, providing molecular insights into their copper chelating abilities. Aβ binding experiments were conducted to study the structure-affinity relationship, and fluorescence microscopy imaging studies confirmed the selective labeling of the BFCs and their copper complexes. Furthermore, we investigated the potential of these ligands for the 64 Cu-based PET imaging of AD through radiolabeling and autoradiography studies. We believe our findings provide molecular insights into the design of bifunctional Cu chelators that can effectively stabilize both Cu(II) and Cu(I) and, thus, can have significant implications for the development of 64 Cu PET imaging as a diagnostic tool for AD.

Chromophores with zwitterionic excited-state intramolecular proton transfer (ESIPT) have been shown to have larger Stock shifts and red-shifted emission wavelengths compared to the conventional π-delocalized ESIPT molecules. However, there is still a dearth of design strategies to expand the current library of zwitterionic ESIPT compounds. Herein, a novel zwitterionic excited-state intramolecular proton transfer system is reported, enabled by addition of 1,4,7-triazacyclononane (TACN) fragments on a dicyanomethylene-4H-pyran (DCM) scaffold. The solvent-dependent steady-state photophysical studies, pKa measurements, and computational analysis strongly support that the ESIPT process is more efficient with two TACN groups attached to the DCM scaffold and not affected by polar protic solvents. Impressively, compound DCM-OH-2-DT exhibits a near-infrared (NIR) emission at 740 nm along with an uncommonly large Stokes shift. Moreover, DCM-OH-2-DT shows high affinity towards soluble amyloid β (Aβ) oligomers in vitro and in 5xFAD mouse brain sections, and we have successfully applied DCM-OH-2-DT for the in vivo imaging of Aβ aggregates and demonstrated its potential use as an early diagnostic agent for AD. Overall, this study can provide a general molecular design strategy for developing new zwitterionic ESIPT compounds with NIR emission in vivo imaging applications., (© 2023 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

Two new ligands were synthesized with the goal of copper stabilization, N,N'-(2-methylpyridine)-2,11-diaza[3,3](2,6)pyridinophane ( Pic N4) and N-(methyl),N'-(2-methylpyridine)-2,11-diaza[3,3](2,6)pyridinophane ( PicMe N4), by selective functionalization of H N4 and TsH N4. These two ligands, when reacted with various copper salts, generated both Cu(II) and Cu(I) complexes. These ligands and Cu complexes were characterized by various methods, such as NMR, UV-Vis, MS, and EA. Each compound was also examined electrochemically, and each revealed reversible Cu(II)/Cu(I) redox couples. Additionally, stability constants were determined via spectrophotometric titrations, and radiolabeling and cytotoxicity experiments were performed to assess the chelators relevance to their potential use in vivo as 64 Cu PET imaging agents., Competing Interests: Conflicts of Interest: The authors declare no competing financial interest.

Herein, we report the synthesis, characterization, and electrocatalytic CO 2 reduction activity of a series of Pd(II) complexes supported by tetradentate pyridinophane ligands. In particular, we focus on the electrocatalytic CO 2 reduction activity of a Pd(II) complex supported by the mixed hard--soft donor ligand 2,11-dithia[3.3](2,6)pyridinophane (N2S2). We also provide spectroscopic evidence of a CO-induced decomposition pathway for the same catalyst, which provides insights into catalyst poisoning for molecular Pd CO 2 reduction electrocatalysts.

Nickel K- and L 2,3 -edge X-ray absorption spectra (XAS) are discussed for 16 complexes and complex ions with nickel centers spanning a range of formal oxidation states from II to IV. K-edge XAS alone is shown to be an ambiguous metric of physical oxidation state for these Ni complexes. Meanwhile, L 2,3 -edge XAS reveals that the physical d-counts of the formally Ni IV compounds measured lie well above the d 6 count implied by the oxidation state formalism. The generality of this phenomenon is explored computationally by scrutinizing 8 additional complexes. The extreme case of NiF 6 2- is considered using high-level molecular orbital approaches as well as advanced valence bond methods. The emergent electronic structure picture reveals that even highly electronegative F-donors are incapable of supporting a physical d 6 Ni IV center. The reactivity of Ni IV complexes is then discussed, highlighting the dominant role of the ligands in this chemistry over that of the metal centers., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Described herein is the synthesis of the Ni II complex ( t BuMe 2 tacn)Ni II (cycloneophyl) ( t BuMe 2 tacn = 1- tert -butyl-4,7-dimethyl-1,4,7-triazacyclononane, cycloneophyl = -CH 2 CMe 2 - o -C 6 H 4 -) and its reactivity with dioxygen and peroxides. The new t BuMe 2 tacn ligand is designed to enhance the oxidatively induced bond-forming reactivity of high-valent Ni intermediates. Tunable chemoselectivity for Csp 2 -O vs Csp 2 -Csp 3 bond formation was achieved by selecting the appropriate solvent and reaction conditions. Importantly, the use of cumene hydroperoxide and meta -chloroperbenzoic acid suggests a heterolytic O-O bond cleavage upon reaction with ( t BuMe 2 tacn)Ni II (cycloneophyl). Mechanistic studies using isotopically labeled H 2 O 2 support the generation of a high-valent Ni-oxygen species via an inner-sphere mechanism and subsequent reductive elimination to form the Csp 2 -O bond. Kinetic studies of the exceptionally fast Csp 2 -O bond-forming reaction reveal a first-order dependence on both ( t BuMe 2 tacn)Ni II (cycloneophyl) and H 2 O 2 , and thus an overall second-order reaction. Eyring analysis further suggests that the oxidation of the Ni II complex by H 2 O 2 is the rate-determining step, which can be modulated by the presence of coordinating solvents. Moreover, computational studies fully support the conclusions drawn from experimental results. Overall, this study reveals for the first time the ability to control the oxidatively induced C-C vs C-O bond formation reactions at a Ni center. Importantly, the described system merges the known organometallic reactivity of Ni with the biomimetic oxidative transformations resembling oxygenases and peroxidases, and involving high-valent metal-oxygen intermediates, which is a novel approach that should lead to unprecedented oxidative catalytic transformations.

Visualizing redox-active metal ions, such as Fe 2+ and Fe 3+ ions, are essential for understanding their roles in biological processes and human diseases. Despite the development of imaging probes and techniques, imaging both Fe 2+ and Fe 3+ simultaneously in living cells with high selectivity and sensitivity has not been reported. Here, we selected and developed DNAzyme-based fluorescent turn-on sensors that are selective for either Fe 2+ or Fe 3+ , revealing a decreased Fe 3+ /Fe 2+ ratio during ferroptosis and an increased Fe 3+ /Fe 2+ ratio in Alzheimer's disease mouse brain. The elevated Fe 3+ /Fe 2+ ratio was mainly observed in amyloid plaque regions, suggesting a correlation between amyloid plaques and the accumulation of Fe 3+ and/or conversion of Fe 2+ to Fe 3+ . Our sensors can provide deep insights into the biological roles of labile iron redox cycling.

Herein we report the direct observation of C-H bond activation at an isolated mononuclear Pd(iii) center. The oxidation of the Pd(ii) complex ( Me N4)Pd II (neophyl)Cl (neophyl = -CH 2 C(CH 3 ) 2 Ph; Me N4 = N , N '-dimethyl-2,11-diaza[3.3](2,6)pyridinophane) using the mild oxidant ferrocenium hexafluorophosphate (FcPF 6 ) yields the stable Pd(iii) complex [( Me N4)Pd III (neophyl)Cl]PF 6 . Upon the addition of an acetate source, [( Me N4)Pd III (neophyl)Cl]PF 6 undergoes Csp 2 -H bond activation to yield the cyclometalated product [( Me N4)Pd III (cycloneophyl)]PF 6 . This metalacycle can be independently prepared, allowing for a complete characterization of both the starting and final Pd(iii) complexes. The C-H activation step can be monitored directly by EPR and UV-Vis spectroscopies, and kinetic isotope effect (KIE) studies suggest that either a pre-association step such as an agostic interaction may be rate limiting, or that the C-H activation is partially rate-limiting in conjunction with ligand rearrangement. Density functional theory calculations support that the reaction proceeds through a κ 3 ligand coordination and that the flexible ligand structure is important for this transformation. Overall, this study represents the first example of discrete C-H bond activation occurring at a Pd(iii) center through a concerted metalation-deprotonation mechanism, akin to that observed for Pd(ii) and Pd(iv) centers., Competing Interests: The authors declare no competing financial interest., (This journal is © The Royal Society of Chemistry.)

Significant progress has been made in the bioinorganic modeling of the paramagnetic states believed to be involved in the hydrogen redox chemistry catalyzed by [NiFe] hydrogenase. However, the characterization and isolation of intermediates involved in mononuclear Ni electrocatalysts which are reported to operate through a Ni I/III cycle have largely remained elusive. Herein, we report a Ni II complex (NCHS2)Ni(OTf)2, where NCHS2 is 3,7-dithia-1(2,6)-pyridina-5(1,3)-benzenacyclooctaphane, that is an efficient electrocatalyst for the hydrogen evolution reaction (HER) with turnover frequencies of ~3,000 s -1 and a overpotential of 670 mV in the presence of trifluoroacetic acid. This electrocatalyst follows a hitherto unobserved HER mechanism involving C-H activation, which manifests as an inverse kinetic isotope effect for the overall hydrogen evolution reaction, and Ni I /Ni III intermediates, which have been characterized by EPR spectroscopy. We further validate the possibility of the involvement of Ni III intermediates by the independent synthesis and characterization of organometallic Ni III complexes., (© 2023. The Author(s).)

Herein, we report a new series of divalent 2-(4-hydroxyphenyl)benzothiazole bifunctional chelators (BFCs) with high affinity for amyloid β aggregates and favorable lipophilicity for blood-brain barrier penetration. The addition of an alkyl carboxylate ester pendant arm offers high binding affinity toward Cu(II). The novel BFCs form stable 64 Cu-radiolabeled complexes and exhibit promising partition coefficient (log D ) values of 1.05-1.85. Among the five compounds tested, the 64 Cu-YW-15 complex exhibits significant staining of amyloid β plaques in ex vivo autoradiography studies. In addition, biodistribution studies show that 64 Cu-YW-15-Me exhibits moderate brain uptake (0.69 ± 0.08 %ID/g) in wild type mice.

Catalytic transformations involving Pd(0)/Pd(II) catalytic cycles are very well known, and processes involving high-valent Pd(III) and Pd(IV) and low-valent Pd(I) intermediates have also gained interest in recent years. Although low-valent Pd(I) intermediates are proposed in these catalytic cycles, isolated and characterized mononuclear Pd(I) species are very rare. Herein, we report the isolation of two heteroleptic mononuclear Pd(I) complexes stabilized by dithiapyridinophane ligands that were fully characterized by single-crystal X-ray diffraction; EPR, IR, UV-vis spectroscopies; and computational studies. Excitingly, one of these Pd(I) complexes shows Kumada Csp 3 -Csp 2 cross-coupling competency, and initial studies of the other shows direct evidence for Csp 3 -H bond activation proposed to occur at the Pd(I) center.

The misfolded proteins or polypeptides commonly observed in neurodegenerative diseases, including Alzheimer's disease (AD), are promising drug targets for developing therapeutic agents. To target the amyloid-β (Aβ) peptide plaques and oligomers, the hallmarks of AD, we have developed twelve amphiphilic small molecules with different hydrophobic and hydrophilic fragments. In vitro fluorescence binding assays demonstrate that these amphiphilic compounds show high binding affinity to both Aβ plaques and oligomers, and six of them exhibit selective binding toward Aβ oligomers. These amphiphilic compounds can also label the Aβ species in the brain sections of transgenic AD mice, as shown by immunostaining with an Aβ antibody. Molecular docking studies were performed to obtain structure-affinity relationships. To our delight, four amphiphilic compounds can alleviate the Cu 2+ -Aβ induced toxicity in cell viability assays. In addition, confocal fluorescence imaging studies provide evidence that two compounds, ZY-15-MT and ZY-15-OMe, can disrupt the interactions between Aβ oligomers and human neuroblastoma SH-SY5Y cell membranes. Overall, these studies strongly suggest that developing compounds with amphiphilic properties that target Aβ oligomers and modulate the Aβ oligomer-cell membrane interactions can be an effective strategy for the development of small molecule AD therapeutics., Competing Interests: The authors declare no competing financial interest., (This journal is © The Royal Society of Chemistry.)

A recent theranostic approach to address Alzheimer's disease (AD) utilizes multifunctional targets that both tag and negate the toxicity of AD biomarkers. These compounds, which emit fluorescence with both an activation and a spectral shift in the presence of Aβ, were previously characterized with traditional fluorescence imaging for binary characterization. However, these multifunctional compounds have broad and dynamic emission spectra that are dependent on factors such as the local environment, presence of Aβ deposits, etc. Since quantitative multiphoton microscopy is sensitive to the binding dynamics of molecules, we characterized the performance of two such compounds, LS-4 and ZY-12-OMe, using Simultaneous Label-free Autofluorescence Multi-harmonic (SLAM) microscopy and Fast Optical Coherence, Autofluorescence Lifetime imaging and Second harmonic generation (FOCALS) microscopy. This study shows that the combination of quantitative multiphoton imaging with multifunctional tags for AD offers new insights into the interaction of these tags with AD biomarkers and the theranostic mechanisms., (© 2022 The Authors. Journal of Biophotonics published by Wiley-VCH GmbH.)

Neurodegenerative diseases such as Alzheimer's disease (AD) are associated with progressive neuronal cell death, and they are commonly correlated with aberrant protein misfolding and aggregation of Aβ peptides. Transition metal ions (Cu, Fe, and Zn) have been shown to promote aggregation and oxidative stress through formation of Aβ-metal complexes. In this context, integrating molecular scaffolds rationally is used here to generate multifunctional molecules as modulators for metal-induced abnormalities. This work encompasses two azo-stilbene ( AS )-derived compounds ( AS-HL1 and AS-HL2 ), the rationale behind the design, their synthesis, characterization, and metal chelation ability [Cu(II) and Zn(II)]. The molecular frameworks of the designed compounds consist of stilbene as an Aβ-interacting moiety, whereas N,N,O and N,N,N,O donor atoms are linked to generate the metal chelation moiety. Furthermore, we went on exploring their multifunctionality with respect to (w.r.t.) (i) their metal chelating capacities and (ii) their utility to modulate the aggregation pathways of both metal-free and metal-bound amyloid-β, (iii) scavenge free radicals, and (iv) inhibit the activity of acetylcholinesterase and (v) cytotoxicity. Moreover, the compounds were able to sequester Cu 2+ from the Aβ-Cu complex as studied by the UV-visible spectroscopic assay. Molecular docking studies were also performed with Aβ and acetylcholinesterase enzyme. Overall, the studies presented here qualify these molecules as promising candidates for further investigation in the quest for finding a treatment for Alzheimer's disease.

An isolated Ni(II)-nitrosyl complex supported by the bulky tridentate 1,4,7-triisopropyl-1,4,7-triazacyclononane (iPr 3 TACN) ligand was obtained from the reaction of a Ni(II) dimethyl complex with NOPF 6 , suggesting the in situ formation of a Ni(I) species that reacts with the resulting NO product. Use of a π-acceptor ancillary isocyanide ligand led to the isolation and characterization of an uncommon 5-coordinate Ni(I) complex supported by the iPr 3 TACN ligand and tert -butylisocyanide.

Timely diagnostic imaging plays a crucial role in managing cerebral amyloid angiopathy (CAA)-the condition in which amyloid β is deposited on blood vessels. To selectively map these amyloid plaques, we have designed amyloid-targeting ligands that can effectively complex with 68 Ga 3+ while maintaining good affinity for amyloid β. In this study, we introduced novel 1,4,7-triazacyclononane-based bifunctional chelators (BFCs) that incorporate a benzothiazole moiety as the Aβ-binding fragment and form charged and neutral species with 68 Ga 3+ . In vitro autoradiography using 5xFAD and WT mouse brain sections (11-month-old) suggested strong and specific binding of the 68 Ga complexes to amyloid β. Biodistribution studies in CD-1 mice revealed a low brain uptake of 0.10-0.33% ID/g, thus suggesting 68 Ga-labeled novel BFCs as promising candidates for detecting CAA., Competing Interests: The authors declare no competing financial interest., (© 2022 The Authors. Published by American Chemical Society.)

Protein misfolding and metal dishomeostasis are two key pathological factors of Alzheimer's disease. Previous studies have shown that Cu-mediated amyloid β (Aβ) peptide aggregation leads to the formation of neurotoxic Aβ oligomers. Herein, we report a series of picolinic acid-based Cu-activatable sensors, which can be used for the fluorescence imaging of Cu-rich Aβ aggregates., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Positron emission tomography (PET), which uses positron-emitting radionuclides to visualize and measure processes in the human body, is a useful noninvasive diagnostic tool for Alzheimer's disease (AD). The development of longer-lived radiolabeled compounds is essential for further expansion of the use of PET imaging in healthcare, and diagnostic agents employing longer-lived radionuclides such as 64 Cu ( t 1/2 = 12.7 h, β + = 17%, β - = 39%, electron capture EC = 43%, and E max = 0.656 MeV) can accomplish this task. One limitation of 64 Cu PET agents for neuroimaging applications is their limited lipophilicity due to the presence of several anionic groups needed to ensure strong Cu chelation. Herein, we evaluate a series of neutral chelators containing the 1,4,7-triazacyclononane or 2,11-diaza[3.3](2,6)pyridinophane macrocycles that have pyridyl-containing arms incorporating Aβ-peptide-interacting fragments. The crystal structures of the corresponding Cu complexes confirm that the pyridyl N atoms are involved in binding to Cu. Radiolabeling and autoradiography studies show that the compounds efficiently chelate 64 Cu, and the resulting complexes exhibit specific binding to the amyloid plaques in the AD mouse brain sections versus wild-type controls.

Photoredox nickel catalysis has emerged as a powerful strategy for cross-coupling reactions. Although the involvement of paramagnetic Ni(I)/Ni(III) species as active intermediates in the catalytic cycle has been proposed, a thorough spectroscopic investigation of these species is lacking. Herein, we report the tridentate pyridinophane ligands R N3 that allow for detailed mechanistic studies of the photocatalytic C-O coupling reaction. The derived ( R N3)Ni complexes are active catalysts under mild conditions and without an additional photocatalyst. We also provide direct evidence for the key steps involving paramagnetic Ni species in the proposed catalytic cycle: the oxidative addition of an aryl halide to a Ni(I) species, the ligand exchange/transmetalation at a Ni(III) center, and the C-O reductive elimination from a Ni(III) species. Overall, the present work suggests the R N3 ligands are a practical platform for mechanistic studies of Ni-catalyzed reactions and for the development of new catalytic applications., (© 2022. The Author(s).)

A bioinspired (N2S2)Ni(II) electrocatalyst is reported that produces H 2 from CF 3 CO 2 H with a turnover frequency (TOF) of ∼1250 s -1 at low acid concentration (<0.043 M) in MeCN. A mechanism for the H 2 production by this electrocatalyst is proposed and its activity is benchmarked against those of other reported molecular Ni H 2 evolution electrocatalysts. The involvement of a hemilabile pyridyl group of the N2S2 ligand is proposed to mimic the role of a cysteine residue involved in the biological proton reduction performed by [NiFe] hydrogenases.

Herein we report a new series of bifunctional chelators (BFCs) with high affinity for amyloid β aggregates, strong binding affinity towards Cu(II), and favorable lipophilicity for potential blood-brain barrier (BBB) penetration. The alkyl carboxylate ester pendant arms show high binding affinity towards Cu(II). The BFCs form stable 64 Cu-radiolabeled complexes and exhibit favorable partition coefficient (log  D ) values of 0.75-0.95. Among the five compounds tested, 64Cu-YW-1 and 64Cu-YW-13 complexes exhibit significant staining of amyloid plaques in ex vivo autoradiography studies.

Herein, we report a new series of bifunctional chelators (BFCs) with a high affinity for amyloid aggregates, a strong binding affinity toward Cu(II), and favorable lipophilicity for potential blood-brain barrier penetration. The alkyl carboxylate ester pendant arms offer up to 3 orders of magnitude higher binding affinity toward Cu(II) and enable the BFCs to form stable 64 Cu-radiolabeled complexes. Among the five compounds tested, the 64 Cu-YW-7 and 64 Cu-YW-10 complexes exhibit strong and specific staining of amyloid plaques in ex vivo autoradiography studies. Importantly, these BFCs have promising partition coefficient (log D oct ) values of 0.91-1.26 and show some brain uptake in biodistribution studies using CD-1 mice. Overall, these BFCs could serve as lead compounds for the development of positron emission tomography imaging agents for AD diagnosis.

Most photoacoustic (PA) imaging agents are based on the repurposing of existing fluorescent dye platforms that exhibit non-optimal properties for PA applications. Herein, we introduce PA-HD, a new dye scaffold optimized for PA probe development that features a 4.8-fold increase in sensitivity and a red-shift of the λ abs from 690 nm to 745 nm to enable ratiometric imaging. Computational modeling was used to elucidate the origin of these enhanced properties. To demonstrate the generalizability of our remodeling efforts, we developed three probes for β-galactosidase activity (PA-HD-Gal), nitroreductase activity (PA-HD-NTR), and H 2 O 2 (PA-HD-H 2 O 2 ). We generated two cancer models to evaluate PA-HD-Gal and PA-HD-NTR. We employed a murine model of Alzheimer's disease to test PA-HD-H 2 O 2 . There, we observed a PA signal increase at 735 nm of 1.79±0.20-fold relative to background, indicating the presence of oxidative stress. These results were confirmed via ratiometric calibration, which was not possible using the parent HD platform., (© 2021 Wiley-VCH GmbH.)

Herein we report the isolation, characterization, and photoreactivity of a stable Ni III dichloride complex supported by a tetradentate pyridinophane N-donor ligand. Upon irradiation, this complex undergoes an efficient photoreductive chlorine elimination reaction, both in solution and the solid-state. Subsequently, the Ni III Cl 2 species can be regenerated via a reaction with PhICl 2 .

Alzheimer's Disease (AD) is the most common neurodegenerative disease, and efficient therapeutic and early diagnostic agents for AD are still lacking. Herein, we report the development of a novel amphiphilic compound, LS-4, generated by linking a hydrophobic amyloid-binding distyrylbenzene fragment with a hydrophilic triazamacrocycle, which dramatically increases the binding affinity toward various amyloid β (Aβ) peptide aggregates, especially for soluble Aβ oligomers. Moreover, upon the administration of LS-4 to 5xFAD mice, fluorescence imaging of LS-4-treated brain sections reveals that LS-4 can penetrate the blood-brain barrier and bind to the Aβ oligomers in vivo . In addition, the treatment of 5xFAD mice with LS-4 reduces the amount of both amyloid plaques and associated phosphorylated tau aggregates vs the vehicle-treated 5xFAD mice, while microglia activation is also reduced. Molecular dynamics simulations corroborate the observation that introducing a hydrophilic moiety into the molecular structure of LS-4 can enhance the electrostatic interactions with the polar residues of the Aβ species. Finally, exploiting the Cu 2+ -chelating property of the triazamacrocycle, we performed a series of imaging and biodistribution studies that show the 64 Cu-LS-4 complex binds to the amyloid plaques and can accumulate to a significantly larger extent in the 5xFAD mouse brains vs the wild-type controls. Overall, these results illustrate that the novel strategy, to employ an amphiphilic molecule containing a hydrophilic moiety attached to a hydrophobic amyloid-binding fragment, can increase the binding affinity for both soluble and insoluble Aβ aggregates and can thus be used to detect and regulate various Aβ species in AD.

Herein, we report a 64 Cu positron emission tomography (PET) imaging agent that shows appreciable in vivo brain uptake and exhibits high specific affinity for beta-amyloid (Aβ) aggregates, leading to the successful PET imaging of amyloid plaques in the brains of 5xFAD mice versus those of wild-type mice. The employed approach uses a bifunctional chelator with two Aβ-interacting fragments that dramatically improves the Aβ-binding affinity and lipophilicity for favorable blood-brain barrier penetration, while the use of optimized-length spacers between the Cu-chelating group and the Aβ-interacting fragments further improves the in vivo Aβ-binding specificity and brain uptake of the corresponding 64 Cu PET imaging agent., Competing Interests: The authors declare no competing interest.

Palladium is a versatile transition metal used to catalyze a large number of chemical transformations, largely due to its ability to access various oxidation states (0, I, II, III, and IV). Among these oxidation states, Pd(I) is arguably the least studied, and while dinuclear Pd(I) complexes are more common, mononuclear Pd(I) species are very rare. Reported herein are spectroscopic studies of a series of Pd(I) intermediates generated by the chemical reduction at low temperatures of Pd(II) precursors supported by the tetradentate ligands 2,11-dithia[3.3](2,6)pyridinophane (N2S2) and N , N '-di- tert -butyl-2,11-diaza[3.3](2,6)pyridinophane ( tBu N4): [(N2S2)Pd II (MeCN)] 2 (OTf) 4 ( 1 ), [(N2S2)Pd II Me] 2 (OTf) 2 ( 2 ), [(N2S2)Pd II Cl](OTf) ( 3 ), [(N2S2)Pd II X](OTf) 2 (X = tBuNC 4 , PPh 3 5 ), [(N2S2)Pd II Me(PPh 3 )](OTf) ( 6 ), and [( tBu N4)Pd II X 2 ](OTf) 2 (X = MeCN 8 , tBuNC 9 ). In addition, a stable Pd(I) dinuclear species, [(N2S2)Pd I (μ-tBuNC)] 2 (ClO 4 ) 2 ( 7 ), was isolated upon the electrochemical reduction of 4 and structurally characterized. Moreover, the ( tBu N4)Pd I intermediates, formed from the chemical reduction of [( tBu N4)Pd II X 2 ](OTf) 2 (X = MeCN 8 , tBuNC 9 ) complexes, were investigated by EPR spectroscopy, X-ray absorption spectroscopy (XAS), and DFT calculations and compared with the analogous (N2S2)Pd I systems. Upon probing the stability of Pd(I) species under different ligand environments, it is apparent that the presence of soft ligands such as tBuNC and PPh 3 significantly improves the stability of Pd(I) species, which should make the isolation of mononuclear Pd(I) species possible.

Alzheimer's disease (AD) is the most common neurodegenerative disorder, yet the cause and progression of this disorder are not completely understood. While the main hallmark of AD is the deposition of amyloid plaques consisting of the β-amyloid (Aβ) peptide, transition metal ions are also known to play a significant role in disease pathology by expediting the formation of neurotoxic soluble β-amyloid (Aβ) oligomers, reactive oxygen species (ROS), and oxidative stress. Thus, bifunctional metal chelators that can control these deleterious properties are highly desirable. Herein, we show that amentoflavone (AMF), a natural biflavonoid compound, exhibits good metal-chelating properties, especially for chelating Cu 2+ with very high affinity (pCu 7.4 = 10.44). In addition, AMF binds to Aβ fibrils with a high affinity ( K i = 287 ± 20 nM), as revealed by a competition thioflavin T (ThT) assay, and specifically labels the amyloid plaques ex vivo in the brain sections of transgenic AD mice, as confirmed via immunostaining with an Aβ antibody. The effect of AMF on Aβ 42 aggregation and disaggregation of Aβ 42 fibrils was also investigated and revealed that AMF can control the formation of neurotoxic soluble Aβ 42 oligomers, both in the absence and presence of metal ions, as confirmed via cell toxicity studies. Furthermore, an ascorbate consumption assay shows that AMF exhibits potent antioxidant properties and can chelate Cu 2+ and significantly diminish the Cu 2+ -ascorbate redox cycling and reactive oxygen species (ROS) formation. Overall, these studies strongly suggest that AMF acts as a bifunctional chelator that can interact with various Aβ aggregates and reduce their neurotoxicity and can also bind Cu 2+ and mediate its deleterious redox properties. Thus AMF has the potential to be a lead compound for further therapeutic agent development for AD.

There is a large interest in developing oxidative transformations catalyzed by palladium complexes that employ environmentally friendly and economical oxidizing reagents such as dioxygen. Recently, we have reported the isolation and characterization of various mononuclear Pd III and Pd IV complexes supported by the tetradentate ligands N , N '-dialkyl-2,11-diaza[3.3](2,6)pyridinophane ( R N4, R = t Bu, i Pr, Me), and the aerobically induced C-C and C-heteroatom bond formation reactivity was investigated in detail. Given that the steric and electronic properties of the multidentate ligands were shown to tune the stability and reactivity of the corresponding high-valent Pd complexes, herein we report the use of an asymmetric N4 ligand, N- mehtyl- N '-tosyl-2,11-diaza[3.3](2,6)pyridinophane ( TsMe N4), in which one amine N atom contains a tosyl group. The N-Ts donor atom exhibits a markedly reduced donating ability, which led to the formation of transiently stable Pd III and Pd IV complexes, and consequently the corresponding O 2 oxidation reactivity and the subsequent C-C bond formation were improved significantly.

While Alzheimer's Disease (AD) is the most common neurodegenerative disease, there is still a dearth of efficient therapeutic and diagnostic agents for this disorder. Reported herein are a series of new multifunctional compounds (MFCs) with appreciable affinity for amyloid aggregates that can be potentially used for both the modulation of Aβ aggregation and its toxicity, as well as positron emission tomography (PET) imaging of Aβ aggregates. Firstly, among the six compounds tested HYR-16 is shown to be capable to reroute the toxic Cu-mediated Aβ oligomerization into the formation of less toxic amyloid fibrils. In addition, HYR-16 can also alleviate the formation of reactive oxygen species (ROS) caused by Cu 2+ ions through Fenton-like reactions. Secondly, these MFCs can be easily converted to PET imaging agents by pre-chelation with the 64 Cu radioisotope, and the Cu complexes of HYR-4 and HYR-17 exhibit good fluorescent staining and radiolabeling of amyloid plaques both in vitro and ex vivo . Importantly, the 64 Cu-labeled HYR-17 is shown to have a significant brain uptake of up to 0.99 ± 0.04 %ID per g. Overall, by evaluating the various properties of these MFCs valuable structure-activity relationships were obtained that should aid the design of improved therapeutic and diagnostic agents for AD., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Alzheimer's disease (AD) is the most common neurodegenerative disease, and its main hallmark is the deposition of amyloid beta (Aβ) peptides. However, several clinical trials focusing on Aβ-targeting agents have failed recently, and thus new therapeutic leads are focusing on alternate targets such as tau protein pathology, Aβ-metal induced oxidative stress, and neuroinflammation. To address these different pathological aspects of AD, we have employed a multifunctional compound, L1 [4-(benzo[ d ]thiazol-2-yl)-2-((4,7-dimethyl-1,4,7-triazonan-1-yl)methyl)-6-methoxyphenol], that integrates Aβ-interacting and metal-binding fragments in a single molecular framework, exhibits significant antioxidant activity and metal chelating ability, and also rescues neuroblastoma N2A cells from Cu 2+ -induced Aβ neurotoxicity. Along with demonstrating in vivo Aβ-binding and favorable brain uptake properties, L1 treatment of transgenic 5xFAD mice significantly reduces the amount of both amyloid plaques and associated phosphorylated tau (p-tau) aggregates in the brain by 40-50% versus the vehicle-treated 5xFAD mice. Moreover, L1 mitigates the neuroinflammatory response of the activated microglia during the Aβ-induced inflammation process. Overall, these multifunctional properties of L1 to attenuate the formation of amyloid plaques and associated p-tau aggregates while also reducing the microglia-mediated neuroinflammatory response are quite uncommon among the previously reported amyloid-targeting chemical agents, and thus L1 could be envisioned as a lead compound for the development of novel AD therapeutics.

Nickel complexes have been widely employed as catalysts in C-C and C-heteroatom bond formation reactions. While Ni(0), Ni(i), and Ni(ii) intermediates are most relevant in these transformations, recently Ni(iii) and Ni(iv) species have also been proposed to play a role in catalysis. Reported herein is the synthesis, detailed characterization, and reactivity of a series of Ni(ii) and Ni(iii) metallacycle complexes stabilized by tetradentate pyridinophane ligands with various N-substituents. Interestingly, while the oxidation of the Ni(ii) complexes with various other oxidants led to exclusive C-C bond formation in very good yields, the use of O 2 or H 2 O 2 as oxidants led to formation of appreciable amounts of C-O bond formation products, especially for the Ni(ii) complex supported by an asymmetric pyridinophane ligand containing one tosyl N-substituent. Moreover, cryo-ESI-MS studies support the formation of several high-valent Ni species as key intermediates in this uncommon Ni-mediated oxygenase-type chemistry., (This journal is © The Royal Society of Chemistry 2019.)

Chemical tools are needed to discover new effective drugs for tackling multifaceted complex neurodegenerative diseases like Alzheimer's disease (AD). Multifunctional nature of two compounds, 5-((4-nitro-phenyl)diazenyl)quinolin-8-ol (HL1) and 4-((4-nitrophenyl)diazenyl)benzene-1,3-diol (HL2) is reported w.r.t. their ability to bind Cu 2+ ions and amyloid aggregates related to AD. HL1 and HL2 have half congo-red type azo-stilbene structural framework incorporated with metal chelating groups, designed to chelate metal ions from metal-amyloid species. Metal binding studies of HL1 and HL2 are established by the methods of Job's Plot, UV-vis spectra with metal ions and stability constant determination. In addition, their metal complexes are isolated, purity checked by elemental analysis, spectroscopically characterized and their structural analyses were obtained from DFT based calculations including binding energy determination. Chicken egg white Lysozyme (CEWL) was used as a model peptide for fibrillation studies. HL1 is found as an excellent colorimetric sensor for amyloid fibrils. Inhibitory effect of HL1 and HL2 and their isolated metal complexes L1-Cu and L2-Cu on CEWL fibrillation was studied using ThT and ANS fluorescence assay along with TEM imaging. In addition, the cell toxicity studies on these compounds suggest that although azo dyes may be non-toxic but having a nitro-substitution lead to significant cell toxicity. Overall, these results suggest that this new class of multifunctional small molecules can interact with amyloids as well as metal ions and could be potential anti-aggregation metal chelating agents.

Several new Pd II and Pd III complexes supported by electronically and sterically tuned tetradentate pyridinophane ligands Me N4 OMe , Me N4, and tBu N4 were isolated and fully characterized ( Me N4 OMe : N,N'-dimethyl-2,11-diaza[3,3](2,6)-para-methoxypyridinophane; Me N4: N,N'-dimethyl-2,11-diaza[3,3](2,6)pyridinophane; tBu N4: N,N'-di-tert-butyl-2,11-diaza[3,3](2,6)pyridinophane). Cyclic voltammetry studies, UV-vis and EPR spectroscopy, and X-ray crystallography were employed to reveal that the steric properties of the N-substituents of the R N4 ligands have a pronounced effect on the electronic properties of the corresponding Pd III complexes, while the electronic tuning of the ligand pyridyl groups has a surprisingly minimal effect. An explanation for these observations was provided by DFT and TD-DFT calculations which suggest that the electronic properties of the Pd III complexes are mainly dictated by their frontier molecular orbitals that have major atomic contributions from the Pd center (mainly the Pd d z 2 atomic orbital) and the axial N atom donors.

The N,N'-di(toluenesulfonyl)-2,11-diaza[3,3](2,6)pyridinophane ( Ts N4) precursor was sought after as a starting point for the preparation of various symmetric and asymmetric pyridinophane-derived ligands. Various procedures to synthesize Ts N4 had been published, but the crucial problem had been the purification of Ts N4 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 Ts N4·HCl. This optimized synthesis of Ts N4 also led to the development of symmetric R N4 derivatives as well as the asymmetric derivative N-(tosyl)-2,11-diaza[3,3](2,6)pyridinophane ( TsH N4). Using this TsH N4 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 R N4 framework in coordination chemistry and the ability to study the electronic, steric, and denticity effects of these pyridinophane ligands on the metal center.

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, 11 C and 18 F, have short half-lives, and their usage is thus somewhat limited. By comparison, the 64 Cu 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 Cu 2+ 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 (pK a 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 64 Cu PET imaging agents for Alzheimer's disease.

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 11 C (20.4 min) and 18 F (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 64 Cu, a radionuclide with a half-life of 12.7 h, ideal for PET imaging. Described herein are a series of bifunctional chelators (BFCs), L 1 -L 5 , that were designed to tightly bind 64 Cu 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.

The tetradentate ligands N,N'-dialkyl-2,11-diaza[3,3](2,6)pyridinophane ( R N4, where R = Me or tBu) were employed to synthesize and fully characterize [( R N4)M I (COD)] + complexes (M = Rh or Ir; COD = cyclooctadiene). Interestingly, these complexes exhibit accessible oxidation potentials and can generate detectable [( R N4)M II (COD)] 2+ complexes, which were characterized by electron paramagnetic resonance and high-resolution electrospray ionization mass spectrometry. Moreover, a rare mononuclear [( Me N4)Rh II (COD)] 2+ complex was isolated and crystallographically characterized, allowing for a direct comparison with its rhodium(I) analogue. The detailed characterization of such paramagnetic rhodium(II) and iridium(II) complexes enables further investigation of their redox reactivity.

Cytochrome c (cyt c ), required for electron transport in mitochondria, possesses a covalently attached heme cofactor. Attachment is catalyzed by holocytochrome c synthase (HCCS), leading to two thioether bonds between heme and a conserved CXXCH motif of cyt c In cyt c , histidine (His19) of CXXCH acts as an axial ligand to heme iron and upon release of holocytochrome c from HCCS, folding leads to formation of a second axial interaction with methionine (Met81). We previously discovered mutations in human HCCS that facilitate increased biosynthesis of cyt c in recombinant Escherichia coli Focusing on HCCS E159A, novel cyt c variants in quantities that are sufficient for biophysical analysis are biosynthesized. Cyt c H19M, the first bis-Met liganded cyt c , is compared with other axial ligand variants (M81A, M81H) and single thioether cyt c variants. For variants with axial ligand substitutions, electronic absorption, near-UV circular dichroism, and electron paramagnetic resonance spectroscopy provide evidence that axial ligands are changed and the heme environment is altered. Circular dichroism spectra in far UV and thermal denaturation analyses demonstrate that axial ligand changes do not affect secondary structures and stability. Redox potentials span a 400-mV range (+349 mV vs. standard hydrogen electrode, H19M; +252 mV, WT; -19 mV, M81A; -69 mV, M81H). We discuss the results in the context of a four-step mechanism for HCCS, whereby HCCS mutants such as E159A are enhanced in release (step 4) of cyt c from the HCCS active site; thus, we term these "release mutants."

JIB-04, a specific inhibitor of the O 2 -activating, Fe-dependent histone lysine demethylases, is revealed to disrupt the binding of O 2 in KDM4A/JMJD2A through a continuous O 2 -consumption assay, X-ray crystal structure data, and molecular docking.

The use of the tridentate ligand 1,4,7-trimethyl-1,4,7-triazacyclononane (Me 3 tacn) and the cyclic alkyl/aryl C-donor ligand -CH 2 CMe 2 -o-C 6 H 4 - (cycloneophyl) allows for the synthesis of isolable organometallic Ni II , Ni III , and Ni IV complexes. Surprisingly, the five-coordinate Ni III complex is stable both in solution and the solid state, and exhibits limited C-C bond formation reactivity. Oxidation by one electron of this Ni III species generates a six-coordinate Ni IV complex, with an acetonitrile molecule bound to Ni. Interestingly, illumination of the Ni IV 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 Ni II species undergoes oxidative addition with alkyl halides, as well as rapid oxidation by O 2 , to generate detectable Ni III and/or Ni IV intermediates and followed by C-C bond formation.

A series of organometallic Ni II and Ni III complexes supported by tertadendate R N3C - 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 Ni III 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 R N3C - ligand leads to a more accessible Ni III center. These results also suggest that the ( Np N3C)Ni system should be more reactive toward oxidation than the corresponding ( tBu N3C)Ni and ( pOMe N3C)Ni systems. Indeed, aerobic oxidative aromatic cyanation was achieved with the ( Np N3C)Ni system at room temperature.

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 Ni III intermediates with aryl and/or alkyl ligands are commonly proposed as the active intermediates in cross-coupling reactions. Herein, we report the first isolated Ni III -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 Ni III center is enhanced in the presence of an oxidant, suggesting the involvement of transient Ni IV species. Indeed, such a Ni IV species was observed and characterized spectroscopically for a nickelacycle system. Overall, these studies suggest that both Ni III and Ni IV species could play an important role in a range of Ni-catalyzed cross-coupling reactions, especially those involving alkyl substrates.

Light-harvesting antenna complexes not only aid in the capture of solar energy for photosynthesis, but regulate the quantity of transferred energy as well. Light-harvesting regulation is important for protecting reaction center complexes from overexcitation, generation of reactive oxygen species, and metabolic overload. Usually, this regulation is controlled by the association of light-harvesting antennas with accessory quenchers such as carotenoids. One antenna complex, the Fenna-Matthews-Olson (FMO) antenna protein from green sulfur bacteria, completely lacks carotenoids and other known accessory quenchers. Nonetheless, the FMO protein is able to quench energy transfer in aerobic conditions effectively, indicating a previously unidentified type of regulatory mechanism. Through de novo sequencing MS, chemical modification, and mutagenesis, we have pinpointed the source of the quenching action to cysteine residues (Cys49 and Cys353) situated near two low-energy bacteriochlorophylls in the FMO protein from Chlorobaculum tepidum Removal of these cysteines (particularly removal of the completely conserved Cys353) through N-ethylmaleimide modification or mutagenesis to alanine abolishes the aerobic quenching effect. Electrochemical analysis and electron paramagnetic resonance spectra suggest that in aerobic conditions the cysteine thiols are converted to thiyl radicals which then are capable of quenching bacteriochlorophyll excited states through electron transfer photochemistry. This simple mechanism has implications for the design of bio-inspired light-harvesting antennas and the redesign of natural photosynthetic 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, (tBu)N3C-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-(t)Bu bond and is mediated by Ni(iii).