Cavity Quantum Electrodynamics Enables para- and ortho-Selective Electrophilic Bromination of Nitrobenzene.

Coupling molecules to a quantized radiation field inside an optical cavity has shown great promise to modify chemical reactivity. In this work, we show that the ground-state selectivity of the electrophilic bromination of nitrobenzene can be fundamentally changed by strongly coupling the reaction to the cavity, generating ortho- or para-substituted products instead of the meta product. Importantly, these are products that are not obtained from the same reaction outside the cavity. A recently developed ab initio approach was used to theoretically compute the relative energies of the cationic Wheland intermediates, which indicate the kinetically preferred bromination site for all products. Performing an analysis of the ground-state electron density for the Wheland intermediates inside and outside the cavity, we demonstrate how strong coupling induces reorganization of the molecular charge distribution, which in turn leads to different bromination sites directly dependent on the cavity conditions. Overall, the results presented here can be used to understand cavity induced changes to ground-state chemical reactivity from a mechanistic perspective as well as to directly connect frontier theoretical simulations to state-of-the-art, but realistic, experimental cavity conditions.

Computationally Guided Ligand Discovery from Compound Libraries and Discovery of a New Class of Ligands for Ni-Catalyzed Cross-Electrophile Coupling of Challenging Quinoline Halides.

Although screening technology has heavily impacted the fields of metal catalysis and drug discovery, its application to the discovery of new catalyst classes has been limited. The diversity of on- and off-cycle pathways, combined with incomplete mechanistic understanding, means that screens of potential new ligands have thus far been guided by intuitive analysis of the metal binding potential. This has resulted in the discovery of new classes of ligands, but the low hit rates have limited the use of this strategy because large screens require considerable cost and effort. Here, we demonstrate a method to identify promising screening directions via simple and scalable computational and linear regression tools that leads to a substantial improvement in hit rate, enabling the use of smaller screens to find new ligands. The application of this approach to a particular example of Ni-catalyzed cross-electrophile coupling of aryl halides with alkyl halides revealed a previously overlooked trend: reactions with more electron-poor amidine ligands result in a higher yield. Focused screens utilizing this trend were more successful than serendipity-based screening and led to the discovery of two new types of ligands, pyridyl oxadiazoles and pyridyl oximes. These ligands are especially effective for couplings of bromo- and chloroquinolines and isoquinolines, where they are now the state of the art. The simplicity of these models with parameters derived from metal-free ligand structures should make this approach scalable and widely accessible.

Computational Methods Enable the Prediction of Improved Catalysts for Nickel-Catalyzed Cross-Electrophile Coupling.

Cross-electrophile coupling has emerged as an attractive and efficient method for the synthesis of C(sp2)-C(sp3) bonds. These reactions are most often catalyzed by nickel complexes of nitrogenous ligands, especially 2,2'-bipyridines. Precise prediction, selection, and design of optimal ligands remains challenging, despite significant increases in reaction scope and mechanistic understanding. Molecular parameterization and statistical modeling provide a path to the development of improved bipyridine ligands that will enhance the selectivity of existing reactions and broaden the scope of electrophiles that can be coupled. Herein, we describe the generation of a computational ligand library, correlation of observed reaction outcomes with features of the ligands, and the in silico design of improved bipyridine ligands for Ni-catalyzed cross-electrophile coupling. The new nitrogen-substituted ligands display a 5-fold increase in selectivity for product formation versus homodimerization when compared to the current state of the art. This increase in selectivity and yield was general for several cross-electrophile couplings, including the challenging coupling of an aryl chloride with an N-alkylpyridinium salt.

The hydrogen-bonding dynamics of water to a nitrile-functionalized electrode is modulated by voltage according to ultrafast 2D IR spectroscopy.

We report the hydrogen-bonding dynamics of water to a nitrile-functionalized and plasmonic electrode surface as a function of applied voltage. The surface-enhanced two-dimensional infrared spectra exhibit hydrogen-bonded and non-hydrogen-bonded nitrile features in similar proportions, plus cross peaks between the two. Isotopic dilution experiments show that the cross peaks arise predominantly from chemical exchange between hydrogen-bonded and non-hydrogen-bonded nitriles. The chemical exchange rate depends upon voltage, with the hydrogen bond of the water to the nitriles breaking 2 to 3 times slower (>63 vs. 25 ps) under a positive as compared to a negative potential. Spectral diffusion created by hydrogen-bond fluctuations occurs on a ~1 ps timescale and is moderately potential-dependent. Timescales from molecular dynamics simulations agree qualitatively with the experiment and show that a negative voltage causes a small net displacement of water away from the surface. These results show that the voltage applied to an electrode can alter the timescales of solvent motion at its interface, which has implications for electrochemically driven reactions.

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.

Reductive Arylation of Nitroarenes with Chloroarenes: Reducing Conditions Enable New Reactivity from Palladium Catalysts.

Palladium-catalyzed C-N bond forming reactions are a key tool in modern synthetic organic chemistry. Despite advances in catalyst design enabling the use of a variety of aryl (pseudo)halides, the necessary aniline coupling partner is often synthesized in a discrete reduction step from a nitroarene. An ideal synthetic sequence would avoid the necessity of this step while maintaining the reliable reactivity of palladium catalysis. Herein, we describe how reducing conditions enable new chemical steps and reactivity from well-studied palladium catalysts, resulting in a new, useful transformation: the reductive arylation of nitroarenes with chloroarenes to form diarylamines. Mechanistic experiments suggest that under reducing conditions, BrettPhos-palladium complexes catalyze the dual N-arylation of typically inert azoarenes─generated via the in situ reduction of nitroarenes─via two distinct mechanisms. Initial N-arylation proceeds via a novel association-reductive palladation sequence followed by reductive elimination to yield an intermediate 1,1,2-triarylhydrazine. Arylation of this intermediate by the same catalyst via a traditional amine arylation sequence forms a transient tetraarylhydrazine, unlocking reductive N-N bond cleavage to liberate the desired product. The resulting reaction allows for the synthesis of diarylamines bearing a variety of synthetically valuable functionalities and heteroaryl cores in high yield.

Formation of C(sp2)-C(sp3) Bonds Instead of Amide C-N Bonds from Carboxylic Acid and Amine Substrate Pools by Decarbonylative Cross-Electrophile Coupling.

Carbon-heteroatom bonds, most often amide and ester bonds, are the standard method to link together two complex fragments because carboxylic acids, amines, and alcohols are ubiquitous and the reactions are reliable. However, C-N and C-O linkages are often a metabolic liability because they are prone to hydrolysis. While C(sp2)-C(sp3) linkages are preferable in many cases, methods to make them require different starting materials or are less functional-group-compatible. We show here a new, decarbonylative reaction that forms C(sp2)-C(sp3) bonds from the reaction of activated carboxylic acids (via 2-pyridyl esters) with activated alkyl groups derived from amines (via N-alkyl pyridinium salts) and alcohols (via alkyl halides). Key to this process is a remarkably fast, reversible oxidative addition/decarbonylation sequence enabled by pyridone and bipyridine ligands that, under reaction conditions that purge CO(g), lead to a selective reaction. The conditions are mild enough to allow coupling of more complex fragments, such as those used in drug development, and this is demonstrated in the coupling of a typical Proteolysis Targeting Chimera (PROTAC) anchor with common linkers via C-C linkages.

Protodemetalation of (Bipyridyl)Ni(II)-Aryl Complexes Shows Evidence for Five-, Six-, and Seven-Membered Cyclic Pathways.

Protonation of C-M bonds and its microscopic reverse, metalation of C-H bonds, are fundamental steps in a variety of metal-catalyzed processes. As such, studies on protonation of C-M bonds can shed light on C-H activation. We present here studies on the rate of protodemetalation (PDM) of a suite of arylnickel(II) complexes with various acids that provide evidence for a concerted, cyclic transition state for the PDM of C-Ni bonds and demonstrate that five-, six-, and seven-membered transition states are particularly favorable. Our data show that while the rate of protodemetalation of arylnickel(II) complexes scales with acidity for many acids, several are faster than predicted by pKa. For example, while acetic acid and acetohydroxamic acid are much less acidic than HCl, they both protodemetalate arylnickel(II) complexes significantly faster than HCl. Our data also show how in the case of acetohydroxamic acid, a seven-membered cyclic transition state (CH3C(O)NHOH) can be more favorable than a six-membered transition state (CH3C(O)NHOH). Similarly, five-membered transition states, such as for pyrazole, are highly favorable as well. Comparison of transition state polarization (from density functional theory) compares these new nickel transition states to better-studied precious-metal systems and demonstrates how the base can change the polarization of the transition state giving rise to opposing electronic preferences. Collectively, these studies suggest several new avenues for study in C-H activation as well as approaches to accelerate or slow protodemetalation in nickel catalysis.

Multimetallic-Catalyzed C-C Bond-Forming Reactions: From Serendipity to Strategy.

The use of two or more metal catalysts in a reaction is a powerful synthetic strategy to access complex targets efficiently and selectively from simple starting materials. While capable of uniting distinct reactivities, the principles governing multimetallic catalysis are not always intuitive, making the discovery and optimization of new reactions challenging. Here, we outline our perspective on the design elements of multimetallic catalysis using precedent from well-documented C-C bond-forming reactions. These strategies provide insight into the synergy of metal catalysts and compatibility of the individual components of a reaction. Advantages and limitations are discussed to promote further development of the field.

Ni- and Ni/Pd-Catalyzed Reductive Coupling of Lignin-Derived Aromatics to Access Biobased Plasticizers.

Lignin-derived aromatic chemicals offer a compelling alternative to petrochemical feedstocks, and new applications are the focus of extensive interest. 4-Hydroxybenzoic acid (H), vanillic acid (G), and syringic acid (S) are readily obtained via oxidative depolymerization of hardwood lignin substrates. Here, we explore the use of these compounds to access biaryl dicarboxylate esters that represent biobased, less toxic alternatives to phthalate plasticizers. Chemical and electrochemical methods are developed for catalytic reductive coupling of sulfonate derivatives of H, G, and S to access all possible homo- and cross-coupling products. A conventional NiCl2/bipyridine catalyst is able to access the H-H and G-G products, but new catalysts are identified to afford the more challenging coupling products, including a NiCl2/bisphosphine catalyst for S-S and a NiCl2/phenanthroline/PdCl2/phosphine cocatalyst system for H-G, H-S, and G-S. High-throughput experimentation methods with a chemical reductant (Zn powder) are shown to provide an efficient screening platform for identification of new catalysts, while electrochemical methods can access improved yields and/or facilitate implementation on larger scale. Plasticizer tests are performed with poly(vinyl chloride), using esters of the 4,4'-biaryl dicarboxylate products. The H-G and G-G derivatives, in particular, exhibit performance advantages relative to an established petroleum-based phthalate ester plasticizer.

CdS Quantum Dots for Metallaphotoredox-Enabled Cross-Electrophile Coupling of Aryl Halides with Alkyl Halides.

Semiconductor quantum dots (QDs) offer many advantages as photocatalysts for synthetic photoredox catalysis, but no reports have explored the use of QDs with nickel catalysts for C-C bond formation. We show here that 5.7 nm CdS QDs are robust photocatalysts for photoredox-promoted cross-electrophile coupling (40 000 TON). These conditions can be utilized on small scale (96-well plate) or adapted to flow. NMR studies show that triethanolamine (TEOA) capped QDs are the active catalyst and that TEOA can displace native phosphonate and carboxylate ligands, demonstrating the importance of QD surface chemistry.

Control of Redox-Active Ester Reactivity Enables a General Cross-Electrophile Approach to Access Arylated Strained Rings.

Strained rings are increasingly important for the design of pharmaceutical candidates, but cross-coupling of strained rings remains challenging. An attractive, but underdeveloped, approach to diverse functionalized carbocyclic and heterocyclic frameworks containing all-carbon quaternary centers is the coupling of abundant strained-ring carboxylic acids with abundant aryl halides. Herein we disclose the development of a nickel-catalyzed cross-electrophile approach that couples a variety of strained ring N-hydroxyphthalimide (NHP) esters, derived from the carboxylic acid in one step, with various aryl and heteroaryl halides under reductive conditions. The chemistry is enabled by the discovery of methods to control NHP ester reactivity, by tuning the solvent or using modified NHP esters, and the discovery that t-Bu BpyCamCN , an L2X ligand, avoids problematic side reactions. This method can be run in flow and in 96-well plates.

CdS Quantum Dots as Potent Photoreductants for Organic Chemistry Enabled by Auger Processes.

Strong reducing agents (<-2.0 V vs saturated calomel electrode (SCE)) enable a wide array of useful organic chemistry, but suffer from a variety of limitations. Stoichiometric metallic reductants such as alkali metals and SmI2 are commonly employed for these reactions; however, considerations including expense, ease of use, safety, and waste generation limit the practicality of these methods. Recent approaches utilizing energy from multiple photons or electron-primed photoredox catalysis have accessed reduction potentials equivalent to Li0 and shown how this enables selective transformations of aryl chlorides via aryl radicals. However, in some cases, low stability of catalytic intermediates can limit turnover numbers. Herein, we report the ability of CdS nanocrystal quantum dots (QDs) to function as strong photoreductants and present evidence that a highly reducing electron is generated from two consecutive photoexcitations of CdS QDs with intermediate reductive quenching. Mechanistic experiments suggest that Auger recombination, a photophysical phenomenon known to occur in photoexcited anionic QDs, generates transient thermally excited electrons to enable the observed reductions. Using blue light-emitting diodes (LEDs) and sacrificial amine reductants, aryl chlorides and phosphate esters with reduction potentials up to -3.4 V vs SCE are photoreductively cleaved to afford hydrodefunctionalized or functionalized products. In contrast to small-molecule catalysts, QDs are stable under these conditions and turnover numbers up to 47 500 have been achieved. These conditions can also effect other challenging reductions, such as tosylate protecting group removal from amines, debenzylation of benzyl-protected alcohols, and reductive ring opening of cyclopropane carboxylic acid derivatives.

Nickel-Catalyzed C(sp3)-C(sp3) Cross-Electrophile Coupling of In Situ Generated NHP Esters with Unactivated Alkyl Bromides.

The formation of C(sp3)-C(sp3) bonds by cross-coupling remains a challenge in synthesis. Here, we demonstrate a two-step, one-pot protocol for the in situ generation of N-hydroxyphthalimide esters and their nickel-catalyzed cross-electrophile coupling with unactivated alkyl bromides for the construction of 1°/1 ° C(sp3)-C(sp3) bonds. The conditions tolerate an array of functional groups, and mechanistic studies indicate that both substrates are converted to alkyl radicals during the reaction.

In-Situ Bromination Enables Formal Cross-Electrophile Coupling of Alcohols with Aryl and Alkenyl Halides.

Although alcohols are one of the largest pools of alkyl substrates, approaches to utilize them in cross-coupling and cross-electrophile coupling are limited. We report the use of 1° and 2° alcohols in cross-electrophile coupling with aryl and vinyl halides to form C(sp3)-C(sp2) bonds in a one-pot strategy utilizing a very fast (<1 min) bromination. The reaction's simple benchtop setup and broad scope (42 examples, 56% ± 15% ave yield) facilitates use at all scales. The potential in parallel synthesis applications was demonstrated by successfully coupling all combinations of 8 alcohols with 12 aryl cores in a 96-well plate.

Zinc-Free, Scalable Reductive Cross-Electrophile Coupling Driven by Electrochemistry in an Undivided Cell.

Nickel-catalyzed reductive cross-electrophile coupling reactions are becoming increasingly important in organic synthesis, but application at scale is limited by three interconnected challenges: a reliance on amide solvents (complicated workup, regulated), the generation of stoichiometric Zn salts (complicated isolation, waste disposal issue), and mixing/activation challenges of zinc powder. We show here an electrochemical approach that addresses these three issues: the reaction works in acetonitrile with diisopropylethylamine as the terminal reductant in a simple undivided cell (graphite(+)/nickel foam(-)). The reaction utilizes a combination of two ligands, 4,4'-di-tert-butyl-2,2'-bipyridine and 4,4',4''-tri-tert-butyl-2,2':6',2''-terpyridine. Studies show that, alone, the bipyridine nickel catalyst predominantly forms protodehalogenated aryl and aryl dimer, whereas the terpyridine nickel catalyst predominantly forms bialkyl and product. By combining these two unselective catalysts, a tunable, general system results because excess radical formed by the terpyridine catalyst can be converted to product by the bipyridine catalyst. As the aryl bromide becomes more electron rich, the optimal ratio shifts to have more of the bipyridine nickel catalyst. Lastly, examination of a variety of flow-cell configurations establishes that batch recirculation can achieve higher productivity (mmol product/time/electrode area) than single-pass, that high flow rates are essential to maximizing current, and that two flow cells in parallel can nearly halve the reaction time. The resulting reaction is demonstrated on gram scale and should be scalable to kilogram scale.

A General, Multimetallic Cross-Ullmann Biheteroaryl Synthesis from Heteroaryl Halides and Heteroaryl Triflates.

Despite their importance to medicine and materials science, the synthesis of biheteroaryls by cross-coupling remains challenging. We describe here a new, general approach to biheteroaryls: the Ni- and Pd-catalyzed multimetallic cross-Ullmann coupling of heteroaryl halides with triflates. An array of 5-membered, 6-membered, and fused heteroaryl bromides and chlorides, as well as aryl triflates derived from heterocyclic phenols, proved to be viable substrates in this reaction (62 examples, 63 ± 17% average yield). The generality of this approach to biheteroaryls was further demonstrated in 96-well plate format at 10 µmol scale. An array of 96 possible products provided >90% hit rate under a single set of conditions. Further, low-yielding combinations could be rapidly optimized with a single "Toolbox Plate" of ligands, additives, and reductants.

ChemBead Enabled High-Throughput Cross-Electrophile Coupling Reveals a New Complementary Ligand.

High-throughput experimentation (HTE) methods are central to modern medicinal chemistry. While many HTE approaches to C-N and Csp2 -Csp2 bonds are available, options for Csp2 -Csp3 bonds are limited. We report here how the adaptation of nickel-catalyzed cross-electrophile coupling of aryl bromides with alkyl halides to HTE is enabled by AbbVie ChemBeads technology. By using this approach, we were able to quickly map out the reactivity space at a global level with a challenging array of 3×222 micromolar reactions. The observed hit rate (56 %) is competitive with other often-used HTE reactions and the results are scalable. A key to this level of success was the finding that bipyridine 6-carboxamidine (BpyCam), a ligand that had not previously been shown to be optimal in any reaction, is as general as the best-known ligands with complementary reactivity. Such "cryptic" catalysts may be common and modern HTE methods should facilitate the process of finding these catalysts.

Sulfonate Versus Sulfonate: Nickel and Palladium Multimetallic Cross-Electrophile Coupling of Aryl Triflates with Aryl Tosylates.

While phenols are frequent and convenient aryl sources in cross-coupling, typically as sulfonate esters, the direct cross-Ullmann coupling of two different sulfonate esters is unknown. We report here a general solution to this challenge catalyzed by a combination of Ni and Pd with Zn reductant and LiBr as an additive. The reaction has broad scope, as demonstrated in 33 examples (65% ± 11% average yield). Mechanistic studies show that Pd strongly prefers the aryl triflate, the Ni catalyst has a small preference for the aryl tosylate, aryl transfer between catalysts is mediated by Zn, and Pd improves yields by consuming arylzinc intermediates.