Templating Bicarbonate in the Second Coordination Sphere Enhances Electrochemical CO2 Reduction Catalyzed by Iron Porphyrins.

Bicarbonate-based electrolytes are ubiquitous in aqueous electrochemical CO2 reduction, particularly in heterogenous catalysis, where they demonstrate improved catalytic performance relative to other buffers. In contrast, the presence of bicarbonate in organic electrolytes and its roles in homogeneous electrocatalysis remain underexplored. Here, we investigate the influence of bicarbonate on iron porphyrin-catalyzed electrochemical CO2 reduction. We show that bicarbonate is a viable proton donor in organic electrolyte (pKa = 20.8 in dimethyl sulfoxide) and that urea pendants in the second coordination sphere can be used to template bicarbonate in the vicinity of a molecular iron porphyrin catalyst. The templated binding of bicarbonate increases its acidity, resulting in a 1500-fold enhancement in catalytic rates relative to unmodified parent iron porphyrin. This work emphasizes the importance of bicarbonate speciation in wet organic electrolytes and establishes second-sphere bicarbonate templating as a design strategy to harness this adventitious acid and enhance CO2 reduction catalysis.

Deciphering Distinct Overpotential-Dependent Pathways for Electrochemical CO2 Reduction Catalyzed by an Iron-Terpyridine Complex.

[Fe(tpyPY2Me)]2+ ([Fe]2+) is a homogeneous electrocatalyst for converting CO2 into CO featuring low overpotentials of <100 mV, near-unity selectivity, and high activity with turnover frequencies faster than 100 000 s-1. To identify the origins of its exceptional performance and inform future catalyst design, we report a combined computational and experimental study that establishes two distinct mechanistic pathways for electrochemical CO2 reduction catalyzed by [Fe]2+ as a function of applied overpotential. Electrochemical data shows the formation of two catalytic regimes at low (ηTOF/2 of 160 mV) and high (ηTOF/2 of 590 mV) overpotential plateaus. We propose that at low overpotentials [Fe]2+ undergoes a two-electron reduction, two-proton-transfer mechanism (electrochemical-electrochemical-chemical-chemical, EECC), where turnover occurs through the dicationic iron complex, [Fe]2+. Computational analysis supports the importance of the singlet ground-state electronic structure for CO2 binding and that the rate-limiting step is the second protonation in this low-overpotential regime. When more negative potentials are applied, an additional electron-transfer event occurs through either a stepwise or proton-coupled electron-transfer (PCET) pathway, enabling catalytic turnover from the monocationic iron complex ([Fe]+) via an electrochemical-chemical-electrochemical-chemical (ECEC) mechanism. Comparison of experimental kinetic data obtained from variable controlled potential electrolysis (CPE) experiments with direct product detection with calculated rates obtained from the energetic span model supports the PCET pathway as the most likely mechanism. Moreover, we build upon this mechanistic understanding to propose the design of an improved ligand framework that is predicted to stabilize the key transition states identified in our study and explore their electronic structures using an energy decomposition analysis. Taken together, this work highlights the value of synergistic computational/experimental approaches to decipher mechanisms of new electrocatalysts and direct the rational design of improved platforms.

A Combined DFT, Energy Decomposition, and Data Analysis Approach to Investigate the Relationship Between Noncovalent Interactions and Selectivity in a Flexible DABCOnium/Chiral Anion Catalyst System.

Developing strategies to study reactivity and selectivity in flexible catalyst systems has become an important topic of research. Herein, we report a combined experimental and computational study aimed at understanding the mechanistic role of an achiral DABCOnium cofactor in a regio- and enantiodivergent bromocyclization reaction. It was found that electron-deficient aryl substituents enable rigidified transition states via an anion-π interaction with the catalyst, which drives the selectivity of the reaction. In contrast, electron-rich aryl groups on the DABCOnium result in significantly more flexible transition states, where interactions between the catalyst and substrate are more important. An analysis of not only the lowest-energy transition state structures but also an ensemble of low-energy transition state conformers via energy decomposition analysis and machine learning was crucial to revealing the dominant noncovalent interactions responsible for observed changes in selectivity in this flexible system.

Controlled Single-Electron Transfer via Metal-Ligand Cooperativity Drives Divergent Nickel-Electrocatalyzed Radical Pathways.

Electrocatalysis enables the construction of C-C bonds under mild conditions via controlled formation of carbon-centered radicals. For sequences initiated by alkyl halide reduction, coordinatively unsaturated Ni complexes commonly serve as single-electron transfer agents, giving rise to the foundational question of whether outer- or inner-sphere electron transfer oxidative addition prevails in redox mediation. Indeed, rational design of electrochemical processes requires the discrimination of these two electron transfer pathways, as they can have outsized effects on the rate of substrate bond activation and thus impact radical generation rates and downstream product selectivities. We present results from combined synthetic, electroanalytical, and computational studies that examine the mechanistic differences of single electron transfer to alkyl halides imparted by Ni metal-ligand cooperativity. Electrogenerated reduced Ni species, stabilized by delocalized spin density onto a redox-active tpyPY2Me polypyridyl ligand, activates alkyl iodides via outer-sphere electron transfer, allowing for the selective activation of alkyl iodide substrates over halogen atom donors and the controlled generation and sequestration of electrogenerated radicals. In contrast, the Ni complex possessing a redox-innocent pentapyridine congener activates the substrates in an inner-sphere fashion owning to a purely metal-localized spin, thereby activating both substrates and halogen atom donors in an indiscriminate fashion, generating a high concentration of radicals and leading to unproductive dimerization. Our data establish that controlled electron transfer via Ni-ligand cooperativity can be used to limit undesired radical recombination products and promote selective radical processes in electrochemical environments, providing a generalizable framework for designing redox mediators with distinct rate and potential requirements.

Metal-Ligand Cooperativity via Exchange Coupling Promotes Iron- Catalyzed Electrochemical CO2 Reduction at Low Overpotentials.

Biological and heterogeneous catalysts for the electrochemical CO2 reduction reaction (CO2RR) often exhibit a high degree of electronic delocalization that serves to minimize overpotential and maximize selectivity over the hydrogen evolution reaction (HER). Here, we report a molecular iron(II) system that captures this design concept in a homogeneous setting through the use of a redox non-innocent terpyridine-based pentapyridine ligand (tpyPY2Me). As a result of strong metal-ligand exchange coupling between the Fe(II) center and ligand, [Fe(tpyPY2Me)]2+ exhibits redox behavior at potentials 640 mV more positive than the isostructural [Zn(tpyPY2Me)]2+ analog containing the redox-inactive Zn(II) ion. This shift in redox potential is attributed to the requirement for both an open-shell metal ion and a redox non-innocent ligand. The metal-ligand cooperativity in [Fe(tpyPY2Me)]2+ drives the electrochemical reduction of CO2 to CO at low overpotentials with high selectivity for CO2RR (>90%) and turnover frequencies of 100 000 s-1 with no degradation over 20 h. The decrease in the thermodynamic barrier engendered by this coupling also enables homogeneous CO2 reduction catalysis in water without compromising selectivity or rates. Synthesis of the two-electron reduction product, [Fe(tpyPY2Me)]0, and characterization by X-ray crystallography, Mössbauer spectroscopy, X-ray absorption spectroscopy (XAS), variable temperature NMR, and density functional theory (DFT) calculations, support assignment of an open-shell singlet electronic structure that maintains a formal Fe(II) oxidation state with a doubly reduced ligand system. This work provides a starting point for the design of systems that exploit metal-ligand cooperativity for electrocatalysis where the electrochemical potential of redox non-innocent ligands can be tuned through secondary metal-dependent interactions.

Regio- and Enantioselective Bromocyclization of Difluoroalkenes as a Strategy to Access Tetrasubstituted Difluoromethylene-Containing Stereocenters.

Difluoromethylene-containing compounds have attracted substantial research interest over the past decades for their ability to mimic biological functions of traditional functional groups while providing a wide variety of pharmacological benefits bestowed by the C-F bond. We report a novel strategy to access RCF2Br-containing heterocycles by regio- and enantioselective bromocyclization of difluoroalkenes enabled by chiral anion phase-transfer catalysis. The utility of this methodology was highlighted through a synthesis of an analogue of efavirenz, a drug used for treating HIV. Additionally, the synthetic versatility of the CF2Br intermediates was showcased through functionalization to a variety of enantioenriched α,α-difluoromethylene-containing products.

Consistent inclusion of continuum solvation in energy decomposition analysis: theory and application to molecular CO2 reduction catalysts.

To facilitate computational investigation of intermolecular interactions in the solution phase, we report the development of ALMO-EDA(solv), a scheme that allows the application of continuum solvent models within the framework of energy decomposition analysis (EDA) based on absolutely localized molecular orbitals (ALMOs). In this scheme, all the quantum mechanical states involved in the variational EDA procedure are computed with the presence of solvent environment so that solvation effects are incorporated in the evaluation of all its energy components. After validation on several model complexes, we employ ALMO-EDA(solv) to investigate substituent effects on two classes of complexes that are related to molecular CO2 reduction catalysis. For [FeTPP(CO2-κC)]2- (TPP = tetraphenylporphyrin), we reveal that two ortho substituents which yield most favorable CO2 binding, -N(CH3)3 + (TMA) and -OH, stabilize the complex via through-structure and through-space mechanisms, respectively. The coulombic interaction between the positively charged TMA group and activated CO2 is found to be largely attenuated by the polar solvent. Furthermore, we also provide computational support for the design strategy of utilizing bulky, flexible ligands to stabilize activated CO2 via long-range Coulomb interactions, which creates biomimetic solvent-inaccessible "pockets" in that electrostatics is unscreened. For the reactant and product complexes associated with the electron transfer from the p-terphenyl radical anion to CO2, we demonstrate that the double terminal substitution of p-terphenyl by electron-withdrawing groups considerably strengthens the binding in the product state while moderately weakens that in the reactant state, which are both dominated by the substituent tuning of the electrostatics component. These applications illustrate that this new extension of ALMO-EDA provides a valuable means to unravel the nature of intermolecular interactions and quantify their impacts on chemical reactivity in solution.

Advanced Electron Paramagnetic Resonance Studies of a Ternary Complex of Copper, Amyloid-ß, and a Chemical Regulator.

Although there has been extensive effort to develop chemical regulators, progress has been static, in part because of these regulators' unclear mechanisms. Here, we report using advanced electron paramagnetic resonance (EPR) spectroscopy to obtain the first molecular-level structural information regarding a ternary complex of CuII-amyloid-ß (Aß) with a chemical regulator that can specifically modulate Cu-induced Aß aggregation. Our advanced EPR spectroscopic results revealed that a chemical regulator (1) for CuII-Aß1-16 disrupted the coordination environment of CuII in Aß, resulting in the detachment of the primary amine at the N-terminal and a carbonyl group between Asp1 and Ala2 from the CuII center and the subsequent formation of a ternary complex, chemical regulator-CuII-Aß1-16. Therefore, our results demonstrate how a chemical regulator interacts with metal-Aß at the molecular level. These findings provide novel insight into working mechanisms and thereby contribute to the establishment of a rational design for chemical regulators of metal-Aß complexes.

Regulatory Activities of Dopamine and Its Derivatives toward Metal-Free and Metal-Induced Amyloid-ß Aggregation, Oxidative Stress, and Inflammation in Alzheimer's Disease.

A catecholamine neurotransmitter, dopamine (DA), is suggested to be linked to the pathology of dementia; however, the involvement of DA and its structural analogues in the pathogenesis of Alzheimer's disease (AD), the most common form of dementia, composed of multiple pathogenic factors has not been clear. Herein, we report that DA and its rationally designed structural derivatives (1-6) based on DA's oxidative transformation are able to modulate multiple pathological elements found in AD [i.e., metal ions, metal-free amyloid-ß (Aß), metal-bound Aß (metal-Aß), and reactive oxygen species (ROS)], with demonstration of detailed molecular-level mechanisms. Our multidisciplinary studies validate that the protective effects of DA and its derivatives on Aß aggregation and Aß-mediated toxicity are induced by their oxidative transformation with concomitant ROS generation under aerobic conditions. In particular, DA and the derivatives (i.e., 3 and 4) show their noticeable anti-amyloidogenic ability toward metal-free Aß and/or metal-Aß, verified to occur via their oxidative transformation that facilitates Aß oxidation. Moreover, in primary pan-microglial marker (CD11b)-positive cells, the major producers of inflammatory mediators in the brain, DA and its derivatives significantly diminish inflammation and oxidative stress triggered by lipopolysaccharides and Aß through the reduced induction of inflammatory mediators as well as upregulated expression of heme oxygenase-1, the enzyme responsible for production of antioxidants. Collectively, we illuminate how DA and its derivatives could prevent multiple pathological features found in AD. The overall studies could advance our understanding regarding distinct roles of neurotransmitters in AD and identify key interactions for alleviation of AD pathology.

Positional effects of second-sphere amide pendants on electrochemical CO2 reduction catalyzed by iron porphyrins.

The development of catalysts for electrochemical reduction of carbon dioxide offers an attractive approach to transforming this greenhouse gas into value-added carbon products with sustainable energy input. Inspired by natural bioinorganic systems that feature precisely positioned hydrogen-bond donors in the secondary coordination sphere to direct chemical transformations occurring at redox-active metal centers, we now report the design, synthesis, and characterization of a series of iron tetraphenylporphyrin (Fe-TPP) derivatives bearing amide pendants at various positions at the periphery of the metal core. Proper positioning of the amide pendants greatly affects the electrocatalytic activity for carbon dioxide reduction to carbon monoxide. In particular, derivatives bearing proximal and distal amide pendants on the ortho position of the phenyl ring exhibit significantly larger turnover frequencies (TOF) compared to the analogous para-functionalized amide isomers or unfunctionalized Fe-TPP. Analysis of TOF as a function of catalyst standard reduction potential enables first-sphere electronic effects to be disentangled from second-sphere through-space interactions, suggesting that the ortho-functionalized porphyrins can utilize the latter second-sphere property to promote CO2 reduction. Indeed, the distally-functionalized ortho-amide isomer shows a significantly larger through-space interaction than its proximal ortho-amide analogue. These data establish that proper positioning of secondary coordination sphere groups is an effective design element for breaking electronic scaling relationships that are often observed in electrochemical CO2 reduction.

Chelating N-Heterocyclic Carbene Ligands Enable Tuning of Electrocatalytic CO2 Reduction to Formate and Carbon Monoxide: Surface Organometallic Chemistry.

Reported here is the chelate effect as a design principle for tuning heterogeneous catalysts for electrochemical CO2 reduction. Palladium functionalized with a chelating tris-N-heterocyclic carbene (NHC) ligand (Pd-timtmbMe ) exhibits a 32-fold increase in activity for electrochemical reduction of CO2 to C1 products with high Faradaic efficiency (FEC1 =86 %) compared to the parent unfunctionalized Pd foil (FE=23 %), and with sustained activity relative to a monodentate NHC-ligated Pd electrode (Pd-mimtmbMe ). The results highlight the contributions of the chelate effect for tailoring and maintaining reactivity at molecular-materials interfaces enabled by surface organometallic chemistry.

Supramolecular Porphyrin Cages Assembled at Molecular-Materials Interfaces for Electrocatalytic CO Reduction.

Conversion of carbon monoxide (CO), a major one-carbon product of carbon dioxide (CO2) reduction, into value-added multicarbon species is a challenge to addressing global energy demands and climate change. Here we report a modular synthetic approach for aqueous electrochemical CO reduction to carbon-carbon coupled products via self-assembly of supramolecular cages at molecular-materials interfaces. Heterobimetallic cavities formed by face-to-face coordination of thiol-terminated metalloporphyrins to copper electrodes through varying organic struts convert CO to C2 products with high faradaic efficiency (FE = 83% total with 57% to ethanol) and current density (1.34 mA/cm2) at a potential of -0.40 V vs RHE. The cage-functionalized electrodes offer an order of magnitude improvement in both selectivity and activity for electrocatalytic carbon fixation compared to parent copper surfaces or copper functionalized with porphyrins in an edge-on orientation.

Minor Structural Variations of Small Molecules Tune Regulatory Activities toward Pathological Factors in Alzheimer's Disease.

Chemical tools have been valuable for establishing a better understanding of the relationships between metal ion dyshomeostasis, the abnormal aggregation and accumulation of amyloid-ß (Aß), and oxidative stress in Alzheimer's disease (AD). Still, very little information is available to correlate the structures of chemical tools with specific reactivities used to uncover such relationships. Recently, slight structural variations to the framework of a chemical tool were found to drastically determine the tool's reactivities toward multiple pathological facets to various extents. Herein, we report our rational design and characterization of a structural series to illustrate the extent to which the reactivities of small molecules vary toward different targets as a result of minor structural modifications. These compounds were rationally and systematically modified based on consideration of properties, including ionization potentials and metal binding, to afford their desired reactivities with metal-free or metal-bound Aß, reactive oxygen species (ROS), and free organic radicals. Our results show that although small molecules are structurally similar, they can interact with multiple factors associated with AD pathogenesis and alleviate their reactivities to different degrees. Together, our studies demonstrate the rational structure-directed design that can be used to develop chemical tools capable of regulating individual or interrelated pathological features in AD.

Stereochemistry of metal tetramethylcyclam complexes directed by an unexpected anion effect.

Metal(TMC) complexes (TMC = tetramethylcyclam) exclusively form trans-I diastereoisomers; thus, little is known about the trans-III isomers. Herein, we report a new method to prepare the trans-III-[Cu(TMC)]2+ complex via an anion effect. Our crystallographic, spectroscopic, and computational analyses validated that [Cu(TMC)](NO3)2 produced the trans-III complex, different from the trans-I structure of [Cu(TMC)](ClO4)2.

Mechanistic Insights into Tunable Metal-Mediated Hydrolysis of Amyloid-ß Peptides.

An amyloidogenic peptide, amyloid-ß (Aß), has been implicated as a contributor to the neurotoxicity of Alzheimer's disease (AD) that continues to present a major socioeconomic burden for our society. Recently, the use of metal complexes capable of cleaving peptides has arisen as an efficient tactic for amyloid management; unfortunately, little has been reported to pursue this strategy. Herein, we report a novel approach to validate the hydrolytic cleavage of divalent metal complexes toward two major isoforms of Aß (Aß40 and Aß42) and tune their proteolytic activity based on the choice of metal centers (M = Co, Ni, Cu, and Zn) which could be correlated to their anti-amyloidogenic properties. Such metal-dependent tunability was facilitated employing a tetra-N-methylated cyclam (TMC) ligand that imparts unique geometric and stereochemical control, which has not been available in previous systems. Co(II)(TMC) was identified to noticeably cleave Aß peptides and control their aggregation, reporting the first Co(II) complex for such reactivities to the best of our knowledge. Through detailed mechanistic investigations by biochemical, spectroscopic, mass spectrometric, and computational studies, the critical importance of the coordination environment and acidity of the aqua-bound complexes in promoting amide hydrolysis was verified. The biological applicability of Co(II)(TMC) was also illustrated via its potential blood-brain barrier permeability, relatively low cytotoxicity, regulatory capability against toxicity induced by both Aß40 and Aß42 in living cells, proteolytic activity with Aß peptides under biologically relevant conditions, and inertness toward cleavage of structured proteins. Overall, our approaches and findings on reactivities of divalent metal complexes toward Aß, along with the mechanistic insights, demonstrate the feasibility of utilizing such metal complexes for amyloid control.

Structure-mechanism-based engineering of chemical regulators targeting distinct pathological factors in Alzheimer's disease.

The absence of effective therapeutics against Alzheimer's disease (AD) is a result of the limited understanding of its multifaceted aetiology. Because of the lack of chemical tools to identify pathological factors, investigations into AD pathogenesis have also been insubstantial. Here we report chemical regulators that demonstrate distinct specificity towards targets linked to AD pathology, including metals, amyloid-ß (Aß), metal-Aß, reactive oxygen species, and free organic radicals. We obtained these chemical regulators through a rational structure-mechanism-based design strategy. We performed structural variations of small molecules for fine-tuning their electronic properties, such as ionization potentials and mechanistic pathways for reactivity towards different targets. We established in vitro and/or in vivo efficacies of the regulators for modulating their targets' reactivities, ameliorating toxicity, reducing amyloid pathology, and improving cognitive deficits. Our chemical tools show promise for deciphering AD pathogenesis and discovering effective drugs.

Importance of the Dimethylamino Functionality on a Multifunctional Framework for Regulating Metals, Amyloid-ß, and Oxidative Stress in Alzheimer's Disease.

The complex and multifaceted pathology of Alzheimer's disease (AD) continues to present a formidable challenge to the establishment of long-term treatment strategies. Multifunctional compounds able to modulate the reactivities of various pathological features, such as amyloid-ß (Aß) aggregation, metal ion dyshomeostasis, and oxidative stress, have emerged as a useful tactic. Recently, an incorporation approach to the rational design of multipurpose small molecules has been validated through the production of a multifunctional ligand (ML) as a potential chemical tool for AD. In order to further the development of more diverse and improved multifunctional reagents, essential pharmacophores must be identified. Herein, we report a series of aminoquinoline derivatives (AQ1-4, AQP1-4, and AQDA1-3) based on ML's framework, prepared to gain a structure-reactivity understanding of ML's multifunctionality in addition to tuning its metal binding affinity. Our structure-reactivity investigations have implicated the dimethylamino group as a key component for supplying the antiamyloidogenic characteristics of ML in both the absence and presence of metal ions. Two-dimensional NMR studies indicate that structural variations of ML could tune its interaction sites along the Aß sequence. In addition, mass spectrometric analyses suggest that the ability of our aminoquinoline derivatives to regulate metal-induced Aß aggregation may be influenced by their metal binding properties. Moreover, structural modifications to ML were also observed to noticeably change its metal binding affinities and metal-to-ligand stoichiometries that were shown to be linked to their antiamyloidogenic and antioxidant activities. Overall, our studies provide new insights into rational design strategies for multifunctional ligands directed at regulating metal ions, Aß, and oxidative stress in AD and could advance the development of improved next-generation multifunctional reagents.

A Redox-Active, Compact Molecule for Cross-Linking Amyloidogenic Peptides into Nontoxic, Off-Pathway Aggregates: In Vitro and In Vivo Efficacy and Molecular Mechanisms.

Chemical reagents targeting and controlling amyloidogenic peptides have received much attention for helping identify their roles in the pathogenesis of protein-misfolding disorders. Herein, we report a novel strategy for redirecting amyloidogenic peptides into nontoxic, off-pathway aggregates, which utilizes redox properties of a small molecule (DMPD, N,N-dimethyl-p-phenylenediamine) to trigger covalent adduct formation with the peptide. In addition, for the first time, biochemical, biophysical, and molecular dynamics simulation studies have been performed to demonstrate a mechanistic understanding for such an interaction between a small molecule (DMPD) and amyloid-ß (Aß) and its subsequent anti-amyloidogenic activity, which, upon its transformation, generates ligand-peptide adducts via primary amine-dependent intramolecular cross-linking correlated with structural compaction. Furthermore, in vivo efficacy of DMPD toward amyloid pathology and cognitive impairment was evaluated employing 5xFAD mice of Alzheimer's disease (AD). Such a small molecule (DMPD) is indicated to noticeably reduce the overall cerebral amyloid load of soluble Aß forms and amyloid deposits as well as significantly improve cognitive defects in the AD mouse model. Overall, our in vitro and in vivo studies of DMPD toward Aß with the first molecular-level mechanistic investigations present the feasibility of developing new, innovative approaches that employ redox-active compounds without the structural complexity as next-generation chemical tools for amyloid management.

Tools of the trade: investigations into design strategies of small molecules to target components in Alzheimer's disease.

The growing prevalence of Alzheimer's disease (AD) has warranted the development of effective therapeutic methods. Current available drugs for AD (i.e., acetylcholinesterase (AChE) inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonists) have only offered brief symptomatic relief. Considering that the numbers affected by AD are projected to substantially rise, long-term strategies are urgently needed. The multiple series of small molecules to combat AD have been expanded, with current methods taking aim at factors, such as misfolded protein accumulation, metal ion dyshomeostasis, and oxidative stress. This concept article focuses on describing the design of compounds to target various components of AD and underlining recent advances that have been made.

The ongoing search for small molecules to study metal-associated amyloid-ß species in Alzheimer's disease.

The development of a cure for Alzheimer's disease (AD) has been impeded by an inability to pinpoint the root cause of this disorder. Although numerous potential pathological factors have been indicated, acting either individually or mutually, the molecular mechanisms leading to disease onset and progression have not been clear. Amyloid-ß (Aß), generated from proteolytic processing of the amyloid precursor protein (APP), and its aggregated forms, particularly oligomers, are suggested as key pathological features in AD-affected brains. Historically, highly concentrated metals are found colocalized within Aß plaques. Metal binding to Aß (metal-Aß) generates/stabilizes potentially toxic Aß oligomers, and produces reactive oxygen species (ROS) in vitro (redox active metal ions; plausible contribution to oxidative stress). Consequently, clarification of the relationship between Aß, metal ions, and toxicity, including oxidative stress via metal-Aß, can lead to a deeper understanding of AD development. To probe the involvement of metal-Aß in AD pathogenesis, rationally designed and naturally occurring molecules have been examined as chemical tools to target metal-Aß species, modulate the interaction between the metal and Aß, and subsequently redirect their aggregation into nontoxic, off-pathway unstructured aggregates. These ligands are also capable of attenuating the generation of redox active metal-Aß-induced ROS to mitigate oxidative stress. One rational design concept, the incorporation approach, installs a metal binding site into a framework known to interact with Aß. This approach affords compounds with the simultaneous ability to chelate metal ions and interact with Aß. Natural products capable of Aß interaction have been investigated for their influence on metal-induced Aß aggregation and have inspired the construction of synthetic analogues. Systematic studies of these synthetic or natural molecules could uncover relationships between chemical structures, metal/Aß/metal-Aß interactions, and inhibition of Aß/metal-Aß reactivity (i.e., aggregation modes of Aß/metal-Aß; associated ROS production), suggesting mechanisms to refine the design strategy. Interdisciplinary investigations have demonstrated that the designed molecules and natural products control the aggregation pathways of metal-Aß species transforming their size/conformation distribution. The aptitude of these molecules to impact metal-Aß aggregation pathways, either via inhibition of Aß aggregate formation, most importantly of oligomers, or disaggregation of preformed fibrils, could originate from their formation of complexes with metal-Aß. Potentially, these molecules could direct metal-Aß size/conformational states into alternative nontoxic unstructured oligomers, and control the geometry at the Aß-ligated metal center for limited ROS formation to lessen the overall toxicity induced by metal-Aß. Complexation between small molecules and Aß/metal-Aß has been observed by nuclear magnetic resonance spectroscopy (NMR) and ion mobility-mass spectrometry (IM-MS) pointing to molecular level interactions, validating the design strategy. In addition, these molecules exhibit other attractive properties, such as antioxidant capacity, prevention of ROS production, potential blood-brain barrier (BBB) permeability, and reduction of Aß-/metal-Aß-induced cytotoxicity, making them desirable tools for unraveling AD complexity. In this Account, we summarize the recent development of small molecules, via both rational design and the selection and modification of natural products, as tools for investigating metal-Aß complexes, to advance our understanding of their relation to AD pathology.