Reductive alkyl-alkyl coupling from isolable nickel-alkyl complexes.

The selective cross-coupling of two alkyl electrophiles to construct complex molecules remains a challenge in organic synthesis. Known reactions are optimized for specific electrophiles and are not amenable to interchangeably varying electrophilic substrates that are sourced from common alkyl building blocks, such as amines, carboxylic acids and halides. These limitations restrict the types of alkyl substrate that can be modified and, ultimately, the chemical space that can be explored.

Persistent organonickel complexes as general platforms for Csp-Csp coupling reactions.

The importance of constructing Csp-Csp bonds has motivated the development of electrochemical, photochemical and thermal activation methods to reductively couple abundant aryl and alkyl electrophiles. However, these methodologies are limited to couplings of very specific substrate classes and require specialized sets of catalysts and reaction set-ups. Here we show a consolidation of these myriad strategies into a single set of conditions that enable reliable alkyl-aryl couplings, including those that were previously unknown.

Nickel-Catalyzed Electroreductive Coupling of Alkylpyridinium Salts and Aryl Halides.

An electrochemical, nickel-catalyzed reductive coupling of alkylpyridinium salts and aryl halides is reported. High-throughput experimentation (HTE) was employed for rapid reaction optimization and evaluation of a broad scope of pharmaceutically relevant structurally diverse aryl halides, including complex drug-like substrates. In addition, the transformation is compatible with both primary and secondary alkylpyridinium salts with distinct conditions.

Cobalt-Catalyzed Electroreductive Alkylation of Unactivated Alkyl Chlorides with Conjugated Olefins.

Reactions of unactivated alkyl chlorides under mild and sustainable conditions are rare compared to those of alkyl bromides or iodides. As a result, synthetic methods capable of modifying the vast chemical space of chloroalkane reagents, wastes, and materials are limited. We report the cobalt-catalyzed reductive addition of unactivated alkyl chlorides to conjugated alkenes.

Copper-Catalyzed Electrochemical C-H Fluorination.

We report the systematic development of an electrooxidative methodology that translates stoichiometric C-H fluorination reactivity of an isolable Cu fluoride complex into a catalytic process. The critical challenges of electrocatalysis with a highly reactive Cu species were addressed by the judicious selection of electrolyte, F source, and sacrificial electron acceptor. Catalyst-controlled C-H fluorination occurs with a preference for hydridic C-H bonds with high bond dissociation energies over weaker but less hydridic C-H bonds.

Synergistic Catalyst-Mediator Pairings for Electroreductive Cross-Electrophile Coupling Reactions.

Electroreductive cross-electrophile coupling (eXEC) represents an attractive approach for the direct C-C coupling of two electrophiles but generally suffers from limited scope compared to reactions with chemical reductants. This work demonstrates that mediator-assisted electrocatalysis is a general strategy for the enhancement of eXEC reactions. While eXEC reactions catalyzed by a variety of widely available ligand-nickel complexes are low yielding when applied to reductive couplings of challenging substrates, reactions with the same complexes generate products in near-quantitative yield when a redox-matched mediator is included.

Closed Aromatic Tubes-Capsularenes.

In this study, we describe a synthetic method for incorporating arenes into closed tubes that we name capsularenes. First, we prepared vase-shaped molecular baskets 4-7. The baskets comprise a benzene base fused to three bicycle[2.

Controlling Ni redox states by dynamic ligand exchange for electroreductive Csp3-Csp2 coupling.

Cross-electrophile coupling (XEC) reactions of aryl and alkyl electrophiles are appealing but limited to specific substrate classes. Here, we report electroreductive XEC of previously incompatible electrophiles including tertiary alkyl bromides, aryl chlorides, and aryl/vinyl triflates. Reactions rely on the merger of an electrochemically active complex that selectively reacts with alkyl bromides through 1e processes and an electrochemically inactive Ni(phosphine) complex that selectively reacts with aryl electrophiles through 2e processes.

Catalyst-controlled functionalization of carboxylic acids by electrooxidation of self-assembled carboxyl monolayers.

While the electrooxidative activation of carboxylic acids is an attractive synthetic methodology, the resulting transformations are generally limited to either homocoupling or further oxidation followed by solvent capture. These reactions require extensive electrolysis at high potentials, which ultimately renders the methodology incompatible with metal catalysts that could possibly provide new and complementary product distributions. This work establishes a proof-of-concept for a rare and synthetically-underutilized strategy for selective electrooxidation of carboxylic acids in the presence of oxidatively-sensitive catalysts that control reaction selectivity.

Mediator-Enabled Electrocatalysis with Ligandless Copper for Anaerobic Chan-Lam Coupling Reactions.

Simple copper salts serve as catalysts to effect C-X bond-forming reactions in some of the most utilized transformations in synthesis, including the oxidative coupling of aryl boronic acids and amines. However, these Chan-Lam coupling reactions have historically relied on chemical oxidants that limit their applicability beyond small-scale synthesis. Despite the success of replacing strong chemical oxidants with electrochemistry for a variety of metal-catalyzed processes, electrooxidative reactions with ligandless copper catalysts are plagued by slow electron-transfer kinetics, irreversible copper plating, and competitive substrate oxidation.

General C(sp)-C(sp) Cross-Electrophile Coupling Reactions Enabled by Overcharge Protection of Homogeneous Electrocatalysts.

Cross-electrophile coupling (XEC) of alkyl and aryl halides promoted by electrochemistry represents an attractive alternative to conventional methods that require stoichiometric quantities of high-energy reductants. Most importantly, electroreduction can readily exceed the reducing potentials of chemical reductants to activate catalysts with improved reactivities and selectivities over conventional systems. This work details the mechanistically-driven development of an electrochemical methodology for XEC that utilizes redox-active shuttles developed by the energy-storage community to protect reactive coupling catalysts from overreduction.

Direct and Scalable Electroreduction of Triphenylphosphine Oxide to Triphenylphosphine.

The direct and scalable electroreduction of triphenylphosphine oxide (TPPO)-the stoichiometric byproduct of some of the most common synthetic organic reactions-to triphenylphosphine (TPP) remains an unmet challenge that would dramatically reduce the cost and waste associated with performing desirable reactions that are mediated by TPP on a large scale. This report details an electrochemical methodology for the single-step reduction of TPPO to TPP using an aluminum anode in combination with a supporting electrolyte that continuously regenerates a Lewis acid from the products of anodic oxidation. The resulting Lewis acid activates TPPO for reduction at mild potentials and promotes P-O over P-C bond cleavage to selectively form TPP over other byproducts.

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.

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.

Macromolecular Design Strategies for Preventing Active-Material Crossover in Non-Aqueous All-Organic Redox-Flow Batteries.

Intermittent energy sources, including solar and wind, require scalable, low-cost, multi-hour energy storage solutions in order to be effectively incorporated into the grid. All-Organic non-aqueous redox-flow batteries offer a solution, but suffer from rapid capacity fade and low Coulombic efficiency due to the high permeability of redox-active species across the battery's membrane. Here we show that active-species crossover is arrested by scaling the membrane's pore size to molecular dimensions and in turn increasing the size of the active material above the membrane's pore-size exclusion limit.

Mechanism-Based Development of a Low-Potential, Soluble, and Cyclable Multielectron Anolyte for Nonaqueous Redox Flow Batteries.

The development of nonaqueous redox flow batteries (NRFBs) has been impeded by a lack of electroactive compounds (anolytes and catholytes) with the necessary combination of (1) redox potentials that exceed the potential limits of water, (2) high solubility in nonaqueous media, and (3) high stability toward electrochemical cycling. In addition, ideal materials would maintain all three of these properties over multiple electron transfer events, thereby providing a proportional increase in storage capacity. This paper describes the mechanism-based design of a new class of metal-coordination complexes (MCCs) as anolytes for NRFBs.

Evolutionary Design of Low Molecular Weight Organic Anolyte Materials for Applications in Nonaqueous Redox Flow Batteries.

The integration of renewable energy sources into the electric grid requires low-cost energy storage systems that mediate the variable and intermittent flux of energy associated with most renewables. Nonaqueous redox-flow batteries have emerged as a promising technology for grid-scale energy storage applications. Because the cost of the system scales with mass, the electroactive materials must have a low equivalent weight (ideally 150 g/(mol·e(-)) or less), and must function with low molecular weight supporting electrolytes such as LiBF4.

Iridium-catalyzed oxidative olefination of furans with unactivated alkenes.

The oxidative coupling of arenes and alkenes is an attractive strategy for the synthesis of vinylarenes, but reactions with unactivated alkenes have typically occurred in low yield. We report an Ir-catalyzed oxidative coupling of furans with unactivated olefins to generate branched vinylfuran products in high yields and with high selectivities with a second alkene as the hydrogen acceptor. Detailed mechanistic experiments revealed catalyst decomposition pathways that were alleviated by the judicious selection of reaction conditions and application of new ligands.

Iridium-catalyzed, intermolecular hydroamination of unactivated alkenes with indoles.

The addition of an N-H bond to an olefin is the most direct route for the synthesis of alkylamines. Currently, intermolecular hydroamination is limited to reactions of a narrow range of reagents containing N-H bonds or activated alkenes, and all the examples of additions to unactivated alkenes require large excesses of alkene. We report intermolecular hydroamination reactions of indoles with unactivated olefins.

Iridium-catalyzed, intermolecular hydroetherification of unactivated aliphatic alkenes with phenols.

Metal-catalyzed addition of an O-H bond to an alkene is a desirable process because it allows for rapid access to ethers from abundant starting materials without the formation of waste, without rearrangements, and with the possibility to control the stereoselectivity. We report the intermolecular, metal-catalyzed addition of phenols to unactivated α-olefins. Mechanistic studies of this rare catalytic reaction revealed a dynamic mixture of resting states that undergo O-H bond oxidative addition and subsequent olefin insertion to form ether products.

Iridium-catalyzed intermolecular asymmetric hydroheteroarylation of bicycloalkenes.

Catalytic hydroarylation of alkenes is a desirable process because it can occur under neutral conditions with regioselectivity complementary to that of acid-catalyzed reactions and stereoselectivity derived from the catalyst. We report an intermolecular asymmetric addition of the C-H bonds of indoles, thiophenes, pyrroles, and furans to bicycloalkenes in high yield with high enantiomeric excess. These heteroarene alkylations occur ortho to the heteroatom.

Iridium-catalyzed intermolecular hydroamination of unactivated aliphatic alkenes with amides and sulfonamides.

The intermolecular addition of N-H bonds to unactivated alkenes remains a challenging, but desirable, strategy for the synthesis of N-alkylamines. We report the intermolecular amination of unactivated α-olefins and bicycloalkenes with arylamides and sulfonamides to generate synthetically useful protected amine products in high yield. Mechanistic studies on this rare catalytic reaction revealed a resting state that is the product of N-H bond oxidative addition and coordination of the amide.

Selectivity in the electron transfer catalyzed Diels-Alder reaction of (R)-alpha-phellandrene and 4-methoxystyrene.

Electron transfer catalysis is an effective method for the acceleration of Diels-Alder reactions between two substrates of similar electron density. The dependence of the selectivity of the Diels-Alder reaction between (R)-alpha-phellandrene and 4-methoxystyrene catalyzed by photoinduced electron transfer with tris(4-methoxyphenyl) pyrylium tetrafluoroborate is studied. Despite the fact that the radical ions involved are highly reactive species, complete regioselectivity favoring attack on the more highly substituted double bond is observed.