Quinone-mediated hydrogen anode for non-aqueous reductive electrosynthesis.

Electrochemical synthesis can provide more sustainable routes to industrial chemicals1-3. Electrosynthetic oxidations may often be performed 'reagent-free', generating hydrogen (H2) derived from the substrate as the sole by-product at the counter electrode. Electrosynthetic reductions, however, require an external source of electrons. Sacrificial metal anodes are commonly used for small-scale applications4, but more sustainable options are needed at larger scale. Anodic water oxidation is an especially appealing option1,5,6, but many reductions require anhydrous, air-free reaction conditions. In such cases, H2 represents an ideal alternative, motivating the growing interest in the electrochemical hydrogen oxidation reaction (HOR) under non-aqueous conditions7-12. Here we report a mediated H2 anode that achieves indirect electrochemical oxidation of H2 by pairing thermal catalytic hydrogenation of an anthraquinone mediator with electrochemical oxidation of the anthrahydroquinone. This quinone-mediated H2 anode is used to support nickel-catalysed cross-electrophile coupling (XEC), a reaction class gaining widespread adoption in the pharmaceutical industry13-15. Initial validation of this method in small-scale batch reactions is followed by adaptation to a recirculating flow reactor that enables hectogram-scale synthesis of a pharmaceutical intermediate. The mediated H2 anode technology disclosed here offers a general strategy to support H2-driven electrosynthetic reductions.

Heterogeneous M-N-C Catalysts for Aerobic Oxidation Reactions: Lessons from Oxygen Reduction Electrocatalysts.

Nonprecious metal heterogeneous catalysts composed of first-row transition metals incorporated into nitrogen-doped carbon matrices (M-N-Cs) have been studied for decades as leading alternatives to Pt for the electrocatalytic O2 reduction reaction (ORR). More recently, similar M-N-C catalysts have been shown to catalyze the aerobic oxidation of organic molecules. This Focus Review highlights mechanistic similarities and distinctions between these two reaction classes and then surveys the aerobic oxidation reactions catalyzed by M-N-Cs. As the active-site structures and kinetic properties of M-N-C aerobic oxidation catalysts have not been extensively studied, the array of tools and methods used to characterize ORR catalysts are presented with the goal of supporting further advances in the field of aerobic oxidation.

Cyclic voltammetry and chronoamperometry: mechanistic tools for organic electrosynthesis.

Electrochemical methods offer unique advantages for chemical synthesis, as the reaction selectivity may be controlled by tuning the applied potential or current. Similarly, measuring the current or potential during the reaction can provide valuable mechanistic insights into these reactions. The aim of this tutorial review is to explain the use of cyclic voltammetry and chronoamperometry to interrogate reaction mechanisms, optimize electrochemical reactions, or design new reactions. Fundamental principles of cyclic voltammetry and chronoamperometry experiments are presented together with the application of these techniques to probe (electro)chemical reactions. Several diagnostic criteria are noted for the use of cyclic voltammetry and chronoamperometry to analyze coupled electrochemical-chemical (EC) reactions, and a series of individual mechanistic studies are presented. Steady state voltammetric and amperometric measurements, using microelectrodes (ME) or rotating disk electrodes (RDE) provide a means to analyze concentrations of redox active species in bulk solution and offer a versatile strategy to conduct kinetic analysis or determine the species present during (electro)synthetic chemical reactions.

Manganese-Mediated Electrochemical Oxidation of Thioethers to Sulfoxides Using Water as the Source of Oxygen Atoms.

Oxygen-atom transfer reactions are a prominent class of synthetic redox reactions that often use high-energy oxygen-atom donor reagents. Electrochemical methods can bypass these reagents by using water as the source of oxygen atoms through pathways involving direct or indirect (mediated) electrolysis. Here, manganese porphyrins and related mediators are shown to be effective molecular electrocatalysts for selective oxidation of thioethers to sulfoxides, without overoxidation to the sulfone. The reactions proceed by proton-coupled oxidation of a MnIII-OH2 species to generate a MnIV-OH and MnV═O species. This methodology is compared to direct electrolysis methods initiated by single-electron oxidation of the thioether, and chloride-mediated electrochemical oxidation of thioethers. The Mn-mediated reactions operate at lower applied potential and exhibit improved substrate scope and functional group compatibility relative to direct electrolysis, and the tunability of the Mn-based mediators allows for improved performance relative to chloride-mediated electrolysis. An electrochemical parallel screening platform is developed and applied to a library of pharmaceutically relevant thioethers.

Heterogeneous Fe-N-C Catalyst for Aerobic Dehydrogenation of Hydrazones to Diazo Compounds Used for Carbene Transfer.

Organic diazo compounds are versatile reagents in chemical synthesis and would benefit from improved synthetic accessibility, especially for larger scale applications. Here, we report a mild method for the synthesis of diazo compounds from hydrazones using a heterogeneous Fe-N-C catalyst, which has Fe ions dispersed within a graphitic nitrogen-doped carbon support. The reactions proceed readily at room temperature using O2 (1 atm) as the oxidant. Aryl diazoesters, ketones, and amides are accessible, in addition to less stable diaryl diazo compounds. Initial-rate data show that the Fe-N-C catalyst achieves faster rates than a heterogeneous Pt/C catalyst. The oxidative dehydrogenation of hydrazones may be performed in tandem with Rh-catalyzed enantioselective C-H insertion and cyclopropanation of alkenes, without requiring isolation of the diazo intermediate. This sequence is showcased by using a flow reactor for continuous synthesis of diazo compounds.

Copper-Nitroxyl-Catalyzed α-Oxygenation of Cyclic Secondary Amines Including Application to Late-Stage Functionalization.

Cyclic secondary amines are prominent subunits in pharmaceutical compounds. Methods for direct functionalization of N-unprotected/unsubstituted piperidines and related heterocycles have limited precedent despite their potential to impact medicinal chemistry and organic synthesis. Herein, we report a Cu/nitroxyl co-catalyzed method for direct conversion of cyclic secondary amines to the corresponding lactams via aerobic dehydrogenation and oxidative coupling with water. The mild reaction conditions tolerate diverse functional groups, enabling application to molecules that cover broad chemical space. The method is showcased in selective functionalization of building blocks and complex molecules, including late-stage functionalization of bromodomain inhibitors.

Divergent Bimetallic Mechanisms in Copper(II)-Mediated C-C, N-N, and O-O Oxidative Coupling Reactions.

Copper-catalyzed aerobic oxidative coupling of diaryl imines provides a route for conversion of ammonia to hydrazine. The present study uses experimental and density functional theory computational methods to investigate the mechanism of N-N bond formation, and the data support a mechanism involving bimolecular coupling of Cu-coordinated iminyl radicals. Computational analysis is extended to CuII-mediated C-C, N-N, and O-O coupling reactions involved in the formation of cyanogen (NC-CN) from HCN, 1,3-butadiyne from ethyne (i.e., Glaser coupling), hydrazine from ammonia, and hydrogen peroxide from water. The results reveal two different mechanistic pathways. Heteroatom ligands with an uncoordinated lone pair (iminyl, NH2, OH) undergo charge transfer to CuII, generating ligand-centered radicals that undergo facile bimolecular radical-radical coupling. Ligands lacking a lone pair (CN and CCH) form bridged binuclear diamond-core structures that undergo C-C coupling. This mechanistic bifurcation is rationalized by analysis of spin densities in key intermediates and transition states, as well as multiconfigurational calculations. Radical-radical coupling is especially favorable for N-N coupling owing to energetically favorable charge transfer in the intermediate and thermodynamically favorable product formation.

Copper-Catalyzed Benzylic C-H Cross-Coupling Enabled by Redox Buffers: Expanding Synthetic Access to Three-Dimensional Chemical Space.

ConspectusCross-coupling methods are the most widely used synthetic methods in medicinal chemistry. Existing reactions are dominated by methods such as amide coupling and arylation reactions that form bonds to sp2-hybridized carbon atoms and contribute to the formation of "flat" molecules. Evidence that three-dimensional structures often have improved physicochemical properties for pharmaceutical applications has contributed to growing demand for cross-coupling methods with sp3-hybridized reaction partners. Substituents attached to sp3 carbon atoms are intrinsically displayed in three dimensions. These considerations have led to efforts to establish reactions with sp3 cross-coupling partners, including alkyl halides, amines, alcohols, and carboxylic acids. As C(sp3)-H bonds are much more abundant that these more conventional coupling partners, we have been pursuing C(sp3)-H cross-coupling reactions that achieve site-selectivity, synthetic utility, and scope competitive with conventional coupling reactions.In this Account, we outline Cu-catalyzed oxidative cross-coupling reactions of benzylic C(sp3)-H bonds with diverse nucleophilic partners. These reactions commonly use N-fluorobenzenesulfonimide (NFSI) as the oxidant. The scope of reactivity is greatly improved by using a "redox buffer" that ensures that the Cu catalyst is available in the proper redox state to promote the reaction. Early precedents of catalytic Cu/NFSI oxidative coupling reactions, including C-H cyanation and arylation, did not require a redox buffer, but reactions with other nucleophiles, such as alcohols and azoles, were much less effective under similar conditions. Mechanistic studies show that some nucleophiles, such as cyanide and arylboronic acids, promote in situ reduction of CuII to CuI, contributing to successful catalytic turnover. Poor reactivity was observed with nucleophiles, such as alcohols, that do not promote CuII reduction in the same manner. This insight led to the identification of sacrificial reductants, termed "redox buffers", that support controlled generation of CuI during the reactions and enable successful benzylic C(sp3)-H cross-coupling with diverse nucleophiles. Successful reactions include those that feature direct coupling of (hetero)benzylic C-H substrates with coupling partners (alcohols, azoles) and sequential C(sp3)-H functionalization/coupling reactions. The latter methods feature generation of a synthetic linchpin that can undergo subsequent reaction with a broad array of nucleophiles. For example, halogenation/substitution cascades afford benzylic amines, (thio)ethers, and heterodiarylmethane derivatives, and an isocyanation/amine-addition sequence generates diverse benzylic ureas.Collectively, these Cu-catalyzed (hetero)benzylic C(sp3)-H cross-coupling reactions rapidly access diverse molecules. Analysis of their physicochemical and topological properties highlights the "drug-likeness" and enhanced three-dimensionality of these products relative to existing bioactive molecules. This consideration, together with the high benzylic C-H site-selectivity and the broad scope of reactivity enabled by the redox buffering strategy, makes these C(sp3)-H cross-coupling methods ideally suited for implementation in high-throughput experimentation platforms to explore novel chemical space for drug discovery and related applications.

Impact of C-H Cross-Coupling Reactions in the One-Step Retrosynthesis of Drug Molecules.

Pharmaceutical synthesis requires a diversity of chemical reactions. The discovery of new reactions enable novel retrosynthetic disconnections, potentially expediting access to complex molecules. This Synopsis demonstrates the use of enumerative combinatorics to find impactful underdeveloped reactions for drug synthesis. By mapping pharmaceutical target molecules onto available building blocks using just one retrosynthetic disconnection even if the requisite reaction is not yet known, we highlight the importance of site-selective C-H cross-coupling methods. This cheminformatics-driven retrosynthetic analysis identifies novel reaction methods of value to the synthesis toolbox.

The Aqueous and Acetonitrile Bond Dissociation Free Energies of N-Hydroxyphthalimide.

Widely cited values of 89 and 90.9 kcal/mol for the bond-dissociation free energy of N-hydroxyphthalimide (NHPI) in water and acetonitrile, respectively, are in error. The sources of the errors leading to these values have been explored and corrected. The corrected values are confirmed through new experiments in aqueous and acetonitrile media and are found to be 84.4 ± 0.1 and 80.04 ± 0.06 kcal/mol, respectively.

Rate Equations for Reversible Disproportionation Reactions and Fitting to Time-Course Data.

Integrated rate equations are straightforward to fit to experimental data to verify a proposed mechanism and to extract kinetic parameters. Such equations are derived for reversible disproportionation/comproportionation reactions with any set of initial concentrations. Extraction of forward and reverse rate constants from experimental data by fitting the rate law to the data is demonstrated for the disproportionation of 2,2,6,6-tetramethyl-1-piperidinyl-N-oxyl (TEMPO) under acidic conditions where the approach to equilibrium is observed.

Optimizing the Synthetic Potential of O2: Implications of Overpotential in Homogeneous Aerobic Oxidation Catalysis.

Molecular oxygen is the quintessential oxidant for organic chemical synthesis, but many challenges continue to limit its utility and breadth of applications. Extensive historical research has focused on overcoming kinetic challenges presented by the ground-state triplet electronic structure of O2 and the various reactivity and selectivity challenges associated with reactive oxygen species derived from O2 reduction. This Perspective will analyze thermodynamic principles underlying catalytic aerobic oxidation reactions, borrowing concepts from the study of the oxygen reduction reaction (ORR) in fuel cells. This analysis is especially important for "oxidase"-type liquid-phase catalytic aerobic oxidation reactions, which proceed by a mechanism that couples two sequential redox half-reactions: (1) substrate oxidation and (2) oxygen reduction, typically affording H2O2 or H2O. The catalysts for these reactions feature redox potentials that lie between the potentials associated with the substrate oxidation and oxygen reduction reactions, and changes in the catalyst potential lead to variations in effective overpotentials for the two half reactions. Catalysts that operate at low ORR overpotential retain a more thermodynamic driving force for the substrate oxidation step, enabling O2 to be used in more challenging oxidations. While catalysts that operate at high ORR overpotential have less driving force available for substrate oxidation, they often exhibit different or improved chemoselectivity relative to the high-potential catalysts. The concepts are elaborated in a series of case studies to highlight their implications for chemical synthesis. Examples include comparisons of (a) NOx/oxoammonium and Cu/nitroxyl catalysts, (b) high-potential quinones and amine oxidase biomimetic quinones, and (c) Pd aerobic oxidation catalysts with or without NOx cocatalysts. In addition, we show how the reductive activation of O2 provides a means to access potentials not accessible with conventional oxidase-type mechanisms. Overall, this analysis highlights the central role of catalyst overpotential in guiding the development of aerobic oxidation reactions.

Polar Heterobenzylic C(sp3)-H Chlorination Pathway Enabling Efficient Diversification of Aromatic Nitrogen Heterocycles.

Site-selective radical reactions of benzylic C-H bonds are now highly effective methods for C(sp3-H) functionalization and cross-coupling. The existing methods, however, are often ineffective with heterobenzylic C-H bonds in alkyl-substituted pyridines and related aromatic heterocycles that are prominently featured in pharmaceuticals and agrochemicals. Here, we report new synthetic methods that leverage polar, rather than radical, reaction pathways to enable the selective heterobenzylic C-H chlorination of 2- and 4-alkyl-substituted pyridines and other heterocycles. Catalytic activation of the substrate with trifluoromethanesulfonyl chloride promotes the formation of enamine tautomers that react readily with electrophilic chlorination reagents. The resulting heterobenzyl chlorides can be used without isolation or purification in nucleophilic coupling reactions. This chlorination-diversification sequence provides an efficient strategy to achieve heterobenzylic C-H cross-coupling with aliphatic amines and a diverse collection of azoles, among other coupling partners.

Benzylic C-H Esterification with Limiting C-H Substrate Enabled by Photochemical Redox Buffering of the Cu Catalyst.

Copper-catalyzed radical-relay reactions provide a versatile strategy for selective C-H functionalization; however, reactions with peroxide-based oxidants often require excess C-H substrate. Here, we report a photochemical strategy to overcome this limitation by using a Cu/2,2'-biquinoline catalyst that supports benzylic C-H esterification with limiting C-H substrate. Mechanistic studies indicate that blue-light irradiation promotes carboxylate-to-copper charge transfer, reducing resting-state CuII to CuI, which activates the peroxide to generate an alkoxyl radical hydrogen-atom-transfer species. This "photochemical redox buffering" introduces a unique strategy to sustain the activity of Cu catalysts in radical-relay reactions.

Chemical Kinetic Method for Active-Site Quantification in Fe-N-C Catalysts and Correlation with Molecular Probe and Spectroscopic Site-Counting Methods.

Mononuclear Fe ions ligated by nitrogen (FeNx) dispersed on nitrogen-doped carbon (Fe-N-C) serve as active centers for electrocatalytic O2 reduction and thermocatalytic aerobic oxidations. Despite their promise as replacements for precious metals in a variety of practical applications, such as fuel cells, the discovery of new Fe-N-C catalysts has relied primarily on empirical approaches. In this context, the development of quantitative structure-reactivity relationships and benchmarking of catalysts prepared by different synthetic routes and by different laboratories would be facilitated by the broader adoption of methods to quantify atomically dispersed FeNx active centers. In this study, we develop a kinetic probe reaction method that uses the aerobic oxidation of a model hydroquinone substrate to quantify the density of FeNx centers in Fe-N-C catalysts. The kinetic method is compared with low-temperature Mössbauer spectroscopy, CO pulse chemisorption, and electrochemical reductive stripping of NO derived from NO2- on a suite of Fe-N-C catalysts prepared by diverse routes and featuring either the exclusive presence of Fe as FeNx sites or the coexistence of aggregated Fe species in addition to FeNx. The FeNx site densities derived from the kinetic method correlate well with those obtained from CO pulse chemisorption and Mössbauer spectroscopy. The broad survey of Fe-N-C materials also reveals the presence of outliers and challenges associated with each site quantification approach. The kinetic method developed here does not require pretreatments that may alter active-site distributions or specialized equipment beyond reaction vessels and standard analytical instrumentation.

Thermal Hydroquinone Oxidation on Co/N-doped Carbon Proceeds by a Band-Mediated Electrochemical Mechanism.

Molecular metal complexes catalyze aerobic oxidation reactions via redox cycling at the metal center to effect sequential activation of O2 and the substrate. Metal surfaces can catalyze the same transformations by coupling independent half-reactions for oxygen reduction and substrate oxidation mediated via the exchange of band-electrons. Metal- and nitrogen-doped carbons (MNCs) are promising catalysts for aerobic oxidation that consist of molecule-like active sites embedded in conductive carbon hosts. Owing to their combined molecular and metallic features, it remains unclear whether they catalyze aerobic oxidation via the sequential redox cycling pathways of molecules or band-mediated pathways of metals. Herein, we simultaneously track the potential of the catalyst and the rate of turnover of aerobic hydroquinone oxidation on a cobalt-based MNC catalyst in contact with a carbon electrode. By comparing operando measurements of rate and potential with the current-voltage behavior of each constituent half-reaction under identical conditions, we show that these molecular materials can display the band-mediated reaction mechanisms of extended metallic solids. We show that the action of these band-mediated mechanisms explains the fractional reaction orders in both oxygen and hydroquinone, the time evolution of catalyst potential and rate, and the dependence of rate on the overall reaction free energy. Selective poisoning experiments suggest that oxygen reduction proceeds at cobalt sites, whereas hydroquinone oxidation proceeds at native carbon-oxide defects on the MNC catalyst. These findings highlight that molecule-like active sites can take advantage of band-mediated mechanisms when coupled to conductive hosts.

Chemical and Electrochemical O2 Reduction on Earth-Abundant M-N-C Catalysts and Implications for Mediated Electrolysis.

M-N-C catalysts, incorporating non-precious-metal ions (e.g. M = Fe, Co) within a nitrogen-doped carbon support, have been the focus of broad interest for electrochemical O2 reduction and aerobic oxidation reactions. The present study explores the mechanistic relationship between the O2 reduction mechanism under electrochemical and chemical conditions. Chemical O2 reduction is investigated via the aerobic oxidation of a hydroquinone, in which the O-H bonds supply the protons and electrons needed for O2 reduction to water. Mechanistic studies have been conducted to elucidate whether the M-N-C catalyst couples two independent half-reactions (IHR), similar to electrode-mediated processes, or mediates a direct inner-sphere reaction (ISR) between O2 and the organic molecule. Kinetic data support the latter ISR pathway. This conclusion is reinforced by rate/potential correlations that reveal significantly different Tafel slopes, implicating different mechanisms for chemical and electrochemical O2 reduction.

Electrochemical PINOylation of Methylarenes: Improving the Scope and Utility of Benzylic Oxidation through Mediated Electrolysis.

A mediated electrosynthetic method has been developed for selective benzylic oxidation of methylarenes. Phthalimide-N-oxyl (PINO) radical generated by proton-coupled electrochemical oxidation of N-hydroxypthalimide serves as a hydrogen atom-transfer (HAT) mediator and as a radical trap for the benzylic radicals generated in situ. This mediated electrolysis method operates at much lower anode potentials relative to direct electrolysis methods for benzylic oxidation initiated by single-electron transfer (SET). A direct comparison of SET and mediated-HAT electrolysis methods with a common set of substrates shows that the HAT reaction exhibits a significantly improved substrate scope and functional group compatibility. The PINOylated products are readily converted into the corresponding benzylic alcohol or benzaldehyde derivative under photochemical conditions, and the synthetic utility of this method is highlighted by the late-stage functionalization of the non-steroidal anti-inflammatory drug celecoxib.

Pairing of Aqueous and Nonaqueous Electrosynthetic Reactions Enabled by a Redox Reservoir Electrode.

Paired electrolysis methods are appealing for chemical synthesis because they generate valuable products at both electrodes; however, development of such reactions is complicated by the need for both half-reactions to proceed under mutually compatible conditions. Here, a modular electrochemical synthesis (ModES) strategy bypasses these constraints using a "redox reservoir" (RR) to pair electrochemical half-reactions across aqueous and nonaqueous solvents. Electrochemical oxidation reactions in organic solvents, the conversion of 4-t-butyltoluene to benzylic dimethyl acetal and aldehyde in methanol or the oxidative C-H amination of naphthalene in acetonitrile, and the reduction of oxygen to hydrogen peroxide in water were paired using nickel hexacyanoferrate as an RR that can selectively store and release protons (and electrons) while serving as the counter electrode for these reactions. Selective proton transport through the RR is optimized and confirmed to enable the ion balance, and thus the successful pairing, between redox half-reactions that proceed with different rates, on different scales, and in different solvents (methanol, acetonitrile, and water).

Molecular Catalyst Synthesis Strategies to Prepare Atomically Dispersed Fe-N-C Heterogeneous Catalysts.

We report a strategy to integrate atomically dispersed iron within a heterogeneous nitrogen-doped carbon (N-C) support, inspired by routes for metalation of molecular macrocyclic iron complexes. The N-C support, derived from pyrolysis of a ZIF-8 metal-organic framework, is metalated via solution-phase reaction with FeCl2 and tributyl amine, as a Brønsted base, at 150 °C. Fe active sites are characterized by 57Fe Mössbauer spectroscopy and aberration-corrected scanning transmission electron microscopy. The site density can be increased by selective removal of Zn2+ ions from the N-C support prior to metalation, resembling the transmetalation strategy commonly employed for the preparation of molecular Fe-macrocycles. The utility of this approach is validated by the higher catalytic rates (per total Fe) of these materials relative to established Fe-N-C catalysts, benchmarked using an aerobic oxidation reaction.