Simultaneously Enhancing the Redox Potential and Stability of Multi-Redox Organic Catholytes by Incorporating Cyclopropenium Substituents.

High redox potential, two-electron organic catholytes for nonaqueous redox flow batteries were developed by appending diaminocyclopropenium (DAC) substituents to phenazine and phenothiazine cores. The parent heterocycles exhibit two partially reversible oxidations at moderate potentials [both at lower than 0.7 V vs ferrocene/ferrocenium (Fc/Fc+)]. The incorporation of DAC substituents has a dual effect on these systems. The DAC groups increase the redox potential of both couples by ∼300 mV while simultaneously rendering the second oxidation (which occurs at 1.20 V vs Fc/Fc+ in the phenothiazine derivative) reversible. The electron-withdrawing nature of the DAC unit is responsible for the increase in redox potential, while the DAC substituents stabilize oxidized forms of the molecules through resonance delocalization of charge and unpaired spin density. These new catholytes were deployed in two-electron redox flow batteries that exhibit voltages of up to 2.0 V and no detectable crossover over 250 cycles.

Integrating Electrochemical and Statistical Analysis Tools for Molecular Design and Mechanistic Understanding.

Medicinal chemistry campaigns set the foundation for streamlined molecular design strategies through the development of quantitative structure-activity models. Our group's enduring underlying interest in reaction mechanism propelled our adaption of a similar strategy to unite mechanistic interrogation and catalyst optimization by relating reaction outputs to molecular descriptors. Through collaborative opportunities, we have recently expanded these predictive statistical modeling tools to electrocatalysis and the design of redox-active organic molecules for application as electrolytes in nonaqueous redox flow batteries. Utilizing small, strategically designed data sets for a given core structure, we develop predictive statistical models that enable rapid virtual screening campaigns to identify analogues with enhanced properties. This process relates structural parameters to the output of interest, providing insight into the structural features that influence the output under study. Furthermore, the weighting of the coefficients for each parameter in the model can furnish mechanistic insight. Such a synergistic implementation of experimental and computational tools for mechanistic insight provides a means of forecasting properties of analogues without necessitating the synthesis and analysis of each molecule of interest. Through collaborative efforts, we have demonstrated the effectiveness of these tools for predicting diverse outputs such as stability, redox potential, and nonaqueous solubility. In this Account, we outline our entry into the field of organic electrochemistry and the implementation of statistical modeling tools for designing organic electrolytes. Through these projects we were exposed to the power of electrochemical techniques as a mechanistic tool, which has provided access to critical information that would otherwise be difficult to obtain. Utilizing electroanalytical techniques, we have quantified the rates of disproportionation of a variety of cobalt complexes and developed statistical models that provide critical insight into understanding of fundamental processes involved in the disproportionation of organometallic complexes. Electroanalytical tools have also been effective in elucidating the active catalyst oxidation state in different catalytic organometallic systems for C-H functionalization. Thus, our foray into electrolyte design and electrocatalysis, in which the statistical modeling tools developed for mechanistic insight were applied in a new context, came full circle to the core foundation of our group: mechanistic understanding.

Mechanistic Studies Inform Design of Improved Ti(salen) Catalysts for Enantioselective [3 + 2] Cycloaddition.

Ti(salen) complexes catalyze the asymmetric [3 + 2] cycloaddition of cyclopropyl ketones with alkenes. While high enantioselectivities are achieved with electron-rich alkenes, electron-deficient alkenes are less selective. Herein, we describe mechanistic studies to understand the origins of catalyst and substrate trends in an effort to identify a more general catalyst. Density functional theory (DFT) calculations of the selectivity determining transition state revealed the origin of stereochemical control to be catalyst distortion, which is largely influenced by the chiral backbone and adamantyl groups on the salicylaldehyde moieties. While substitution of the adamantyl groups was detrimental to the enantioselectivity, mechanistic information guided the development of a set of eight new Ti(salen) catalysts with modified diamine backbones. These catalysts were evaluated with four electron-deficient alkenes to develop a three-parameter statistical model relating enantioselectivity to physical organic parameters. This statistical model is capable of quantitative prediction of enantioselectivity with structurally diverse alkenes. These mechanistic insights assisted the discovery of a new Ti(salen) catalyst, which substantially expanded the reaction scope and significantly improved the enantioselectivity of synthetically interesting building blocks.

Mechanism-Based Design of a High-Potential Catholyte Enables a 3.2 V All-Organic Nonaqueous Redox Flow Battery.

Nonaqueous redox flow batteries (RFBs) represent a promising technology for grid-scale energy storage. A key challenge for the field is identifying molecules that undergo reversible redox reactions at the extreme potentials required to leverage the large potential window of organic solvents. In this Article, we use a combination of computations, chemical synthesis, and mechanistic analysis to develop thioether-substituted cyclopropenium derivatives as high potential electrolytes for nonaqueous RFBs. These molecules exhibit redox potentials that are 470-500 mV higher than those of known electrolytes. Strategic variation of the alkyl substituent on sulfur afforded a derivative that undergoes charge-discharge cycling at +1.33 V vs ferrocene/ferrocenium in acetonitrile/tetrabutylammonium hexafluorophosphate. This electrolyte was paired with a phthalimide derivative to achieve a proof-of-principle 3.2 V all-organic RFB.

Developing a Predictive Solubility Model for Monomeric and Oligomeric Cyclopropenium-Based Flow Battery Catholytes.

The implementation of redox active organics in nonaqueous redox flow batteries requires the design of molecules that exhibit high solubility (>1 M) in all battery-relevant redox states. Methods for forecasting nonaqueous solubility would be valuable for streamlining the identification of promising structures. Herein we report the development of a workflow to parametrize and predict the solubility of conformationally flexible tris(dialkylamino)cyclopropenium (CP) radical dications. A statistical model is developed through training on monomer species. Ultimately, this model is used to predict new monomeric and dimeric CP derivatives with solubilities of >1 M in acetonitrile in all oxidation states. The most soluble CP monomer exhibits high stability to electrochemical cycling at 1 M in acetonitrile without a supporting electrolyte in a symmetrical flow cell.

Mechanistic Study of Ruthenium-Catalyzed C-H Hydroxylation Reveals an Unexpected Pathway for Catalyst Arrest.

We have recently disclosed [(dtbpy)2RuCl2] as an effective precatalyst for chemoselective C-H hydroxylation of C(sp3)-H bonds and have noted a marked disparity in reaction performance between 4,4'-di- tert-butyl-2,2'-bipyridine (dtbpy)- and 2,2'-bipyridine (bpy)-derived complexes. A desire to understand the origin of this difference and to further advance this catalytic method has motivated the comprehensive mechanistic investigation described herein. Details of this reaction have been unveiled through evaluation of ligand structure-activity relationships, electrochemical and kinetic studies, and pressurized sample infusion high-resolution mass spectrometry (PSI-MS). Salient findings from this investigation include the identification of more than one active oxidant and three disparate mechanisms for catalyst decomposition/arrest. Catalyst efficiency, as measured by turnover number, has a strong inverse correlation with the rate and extent of ligand dissociation, which is dependent on the identity of bipyridyl 4,4'-substituent groups. Dissociated bipyridyl ligand is oxidized to mono- and bis- N-oxide species under the reaction conditions, the former of which is found to act as a potent catalyst poison, yielding a catalytically inactive tris-ligated [Ru(dtbpy)2(dtbpy N-oxide)]2+ complex. Insights gained through this work highlight the power of PSI-MS for studies of complex reaction processes and are guiding ongoing efforts to develop high-performance, next-generation catalyst systems for C-H hydroxylation.

Physical Organic Approach to Persistent, Cyclable, Low-Potential Electrolytes for Flow Battery Applications.

The deployment of nonaqueous redox flow batteries for grid-scale energy storage has been impeded by a lack of electrolytes that undergo redox events at as low (anolyte) or high (catholyte) potentials as possible while exhibiting the stability and cycling lifetimes necessary for a battery device. Herein, we report a new approach to electrolyte design that uses physical organic tools for the predictive targeting of electrolytes that possess this combination of properties. We apply this approach to the identification of a new pyridinium-based anolyte that undergoes 1e- electrochemical charge-discharge cycling at low potential (-1.21 V vs Fc/Fc+) to a 95% state-of-charge without detectable capacity loss after 200 cycles.

Electrochemical Ruthenium-Catalyzed C-H Hydroxylation of Amine Derivatives in Aqueous Acid.

The development of an electrochemically driven, ruthenium-catalyzed C-H hydroxylation reaction of amine-derived substrates bearing tertiary C-H bonds is described. The reaction is performed under constant current electrolysis in a divided cell to afford alcohol products in yields comparable to those of our previously reported process, which requires the use of stoichiometric H5IO6 for catalytic turnover. With aqueous acid as solvent, the cathodic electrode reaction simply involves the reduction of protons to evolve hydrogen gas. The optimized protocol offers a convenient, efficient, and atom-economical method for sp3-C-H bond oxidation.

High-Performance Oligomeric Catholytes for Effective Macromolecular Separation in Nonaqueous Redox Flow Batteries.

Nonaqueous redox flow batteries (NRFBs) represent an attractive technology for energy storage from intermittent renewable sources. In these batteries, electrical energy is stored in and extracted from electrolyte solutions of redox-active molecules (termed catholytes and anolytes) that are passed through an electrochemical flow cell. To avoid battery self-discharge, the anolyte and catholyte solutions must be separated by a membrane in the flow cell. This membrane prevents crossover of the redox active molecules, while simultaneously allowing facile transport of charge-balancing ions. A key unmet challenge for the field is the design of redox-active molecule/membrane pairs that enable effective electrolyte separation while maintaining optimal battery properties. Herein, we demonstrate the development of oligomeric catholytes based on tris(dialkylamino)cyclopropenium (CP) salts that are specifically tailored for pairing with size-exclusion membranes composed of polymers of intrinsic microporosity (PIMs). Systematic studies were conducted to evaluate the impact of oligomer size/structure on properties that are crucial for flow battery performance, including cycling stability, charge capacity, solubility, electron transfer kinetics, and crossover rates. These studies have led to the identification of a CP-derived tetramer in which these properties are all comparable, or significantly improved, relative to the monomeric counterpart. Finally, a proof-of-concept flow battery is demonstrated by pairing this tetrameric catholyte with a PIM membrane. After 6 days of cycling, no crossover is detected, demonstrating the promise of this approach. These studies provide a template for the future design of other redox-active oligomers for this application.

Calorimetric studies of the interactions of metalloenzyme active site mimetics with zinc-binding inhibitors.

The binding of drugs to metalloenzymes is an intricate process that involves several interactions, including binding of the drug to the enzyme active site metal, as well as multiple interactions between the drug and the enzyme residues. In order to determine the free energy contribution of Zn(2+) binding by known metalloenzyme inhibitors without the other interactions, valid active site zinc structural mimetics must be formed and binding studies need to be performed in biologically relevant conditions. The potential of each of five ligands to form a structural mimetic with Zn(2+) was investigated in buffer using Isothermal Titration Calorimetry (ITC). All five ligands formed strong 1 : 1 (ligand : Zn(2+)) binary complexes. The complexes were used in further ITC experiments to study their interaction with 8-hydroxyquinoline (8-HQ) and/or acetohydroxamic acid (AHA), two bidentate anionic zinc-chelating enzyme inhibitors. It was found that tetradentate ligands were not suitable for creating zinc structural mimetics for inhibitor binding in solution due to insufficient coordination sites remaining on Zn(2+). A stable binary complex, [Zn(BPA)](2+), which was formed by a tridentate ligand, bis(2-pyridylmethyl)amine (BPA), was found to bind one AHA in buffer or a methanol : buffer mixture (60 : 40 by volume) at pH 7.25 or one 8-HQ in the methanol : buffer mixture at pH 6.80, making it an effective structural mimetic for the active site of zinc metalloenzymes. These results are consistent with the observation that metalloenzyme active site zinc ions have three residues coordinated to them, leaving one or two sites open for inhibitors to bind. Our findings indicate that Zn(BPA)X2 can be used as an active site structural mimetic for zinc metalloenzymes for estimating the free energy contribution of zinc binding to the overall inhibitor active site interactions. Such use will help aid in the rational design of inhibitors to a variety of zinc metalloenzymes.