ConspectusTransition-metal catalyzed cross-coupling reactions are fundamental reactions in organic chemistry, facilitating strategic bond formations for accessing natural products, organic materials, agrochemicals, and pharmaceuticals. Redox chemistry enables access to elusive cross-coupling mechanisms through single-electron processes as an alternative to classical two-electron strategies predominated by palladium catalysis. The seminal reports of Baran, MacMillan, Doyle, Molander, Weix, Lin, Fu, Reisman, and others in merging redox perturbation (photochemical, electrochemical, and purely chemical) with catalysis are pivotal to the current resurgence and mechanistic understanding of first-row transition metal-based catalysis. The hallmark of this redox platform is the systematic modulation of transition-metal oxidation states by a photoredox catalyst or at a heterogeneous electrode surface. Electrocatalysis and photocatalysis enhance transition metal catalysis' capacity for bond formation through electron- or energy-transfer processes that promote otherwise challenging elementary steps or elusive mechanisms. Cross-coupling conditions promoted by electrocatalysis and photocatalysis are mild, and bond formation proceeds with exceptionally high chemoselectivity and wide functional group tolerance. The interfacing of abundant first-row transition-metal catalysis with electrocatalysis and photocatalysis has brought about a paradigm shift in cross-coupling technology as practitioners are quickly applying these tools in synthesizing fine chemicals and pharmaceutically relevant motifs. In particular, the merger of Ni catalysis with electro- and photochemistry ushered in a new era for carbon-carbon and carbon-heteroatom cross-couplings with expanded generality compared to their thermally driven counterparts. Over the past decade, we have developed enabling photo- and electrochemical methods throughout our combined research experience in industry (BMS, AstraZeneca) and academia (Professor Baran, Scripps Research) in cross-disciplinary collaborative environments. In this Account, we will outline recent progress from our past and present laboratories in photo- and electrochemically mediated Ni-catalyzed cross-couplings. By highlighting these cross-coupling methodologies, we will also compare mechanistic features of both electro- and photochemical strategies for forging C(sp2)-C(sp3), C(sp3)-C(sp3), C-O, C-N, and C-S bonds. Through these side-by-side comparisons, we hope to demystify the subtle differences between the two complementary tools to enact redox control over transition metal catalysis. Finally, building off the collective experience of ourselves and the rest of the community, we propose a tactical user guide to photo- and electrochemically driven cross-coupling reactions to aid the practitioner in rapidly applying such tools in their synthetic designs. 

A Paradigm Shift in Catalysis: Electro- and Photomediated Nickel-Catalyzed Cross-Coupling Reactions.

Easy, efficient, and economic synthesis of anilines remains an important challenge in synthetic chemistry. In this study, a Ni(OAc)2-bipyridine complex is shown to readily catalyze the amination of aryl halides with ammonium salts under direct excitation of light, allowing a broad array of aryl chlorides and bromides to be converted into the corresponding primary (hetero)arylamines in the absence of an external photosensitizer. Late-stage modification of drug molecules and 15N-labeling of primary aryl amines are also demonstrated with a number of examples. Photoinduced generation of Ni(I)-bipyridine species is believed to be the key step in the reaction, enabling a Ni(I)/Ni(III) cycle for catalytic turnover. 

Photochemical Synthesis of Anilines via Ni-Catalyzed Coupling of Aryl Halides with Ammonium Salts

We have developed an electrochemical method for phosphorothiolation of 2H-indazoles using S-hydrogen phosphorothioates via cross dehydrogenative coupling reaction under metal-free and electrolyte-free conditions. This protocol is compatible with electron donating groups like −Me, −OMe, halogen and elctron withdrawing groups such as −COOEt, affording respective indazolyl phosphorothioates in 62%-91% yields. Comprehensive mechanistic studies indicate that the reaction proceeds through a radical pathway. 

Electrochemically Enabled Dehydrogenative Phosphorothiolation of 2H‐Indazoles under Electrolyte‐Free Conditions

The merger of photoredox and nickel catalysis for the decarboxylative arylation of carboxylic acids has evolved into an effective strategy to forge C–C bonds from readily available feedstock. Despite its rapid industrial adoption, the mechanism of this dual-catalyzed cross-coupling reaction has remained unclear and under-studied. Here, we propose an alternative mechanism for the photoredox–Ni dual-catalyzed decarboxylative arylation of α-amino acids based on control experiments with NiIIArBr complexes, cyclic voltammetry (CV), and computational studies. Our mechanistic studies revealed that a Ni0–NiII–NiI–NiII–Ni0 cycle is feasible in the dual-catalyzed Csp2–Csp3 cross-coupling. Distinct from previous mechanism proposals, we show with a series of CV studies and density functional theory (DFT) calculations that a single electron transfer reduction of NiIIArBr to NiIAr by IrII is thermodynamically favorable. Reductive elimination via a NiII-species rather than via a NiIII-species is also supported by DFT calculations. Those mechanistic insights allowed for the reaction scope to be extended to encompass α-amino acids bearing pharmacophoric elements, which were previously unexplored coupling partners. α-Amino acids bearing broad functional groups, including heterocycles, successfully underwent decarboxylative arylation with a diverse set of aryl bromides. This strategy represents an advance in photoredox and Ni-catalysis and broadens its industrial applicability as well as mechanistic understanding. 

Metallaphotoredox Decarboxylative Arylation of Natural Amino Acids via an Elusive Mechanistic Pathway

Metallaphotoredox catalysis can unlock useful pathways for transforming organic reactants into desirable products, largely due to the conversion of photon energy into chemical potential to drive redox and bond transformation processes. Despite the importance of these processes for cross-coupling reactions and other transformations, their mechanistic details are only superficially understood. In this review, we have provided a detailed summary of various photoredox mechanisms that have been proposed to date for Ni-bipyridine (bpy) complexes, focusing separately on photosensitized and direct excitation reaction processes. By highlighting multiple bond transformation pathways and key findings, we depict how photoredox reaction mechanisms, which ultimately define substrate scope, are themselves defined by the ground- and excited-state geometric and electronic structures of key Ni-based intermediates. We further identify knowledge gaps to motivate future mechanistic studies and the development of synergistic research approaches spanning the physical, organic, and inorganic chemistry communities. 

Mechanisms of Photoredox Catalysis Featuring Nickel–Bipyridine Complexes

A photoredox and copper-catalyzed sulfonylphosphorothiolation of alkenes has been developed. With the use of readily available aryl or alkyl sulfonyl chlorides as radical precursors and (RO)2P(O)SH as coupling partners, a wide range of decorated β-sulfonyl phosphorothioates could be obtained in 37–98% yields with good functional group tolerance. Importantly, this three-component reaction can be conveniently extended to late-stage modification of bioactive molecules and gram-scale synthesis. 

Photoredox and Copper‐Catalyzed Sulfonylphosphorothiolation of Alkenes toward β‐Sulfonyl Phosphorothioates

Nickel catalysis has garnered interest in mainstream organic synthesis for constructing chemical bonds and has been merged with photoredox catalysis and electrocatalysis. Despite its success and increasing adoption by academia and industry, the mechanism by which Ni catalyzes C–C cross-coupling reactions and how the precatalyst is activated remains unclear. An exploration of stabilized dimethylNiII complexes, [(dtbbpy)Ni(Me)2] (dtbbpy = 4,4′-di-tert-butyl-2,2′-bipyridine, 1) and [(bpy)Ni(Me)2] (bpy = 2,2′-bipyridine, 2), as Ni-precatalysts for promoting Csp2–Csp3 cross-coupling revealed that they readily undergo photo-induced Ni–C bond homolysis upon exposure to visible light and are a source of Ni0 species. Photo-initiation of dimethylNiII complexes 1 and 2 produced active Ni0 and reactive methyl radicals, which were harnessed to promote methylative and other Csp2–Csp3 cross-coupling reactions. The mechanistic studies conducted to illuminate aspects of the process include a competition reaction, NiIIArBr-complex synthesis, light-on and light-off studies, density functional theory (DFT) calculations of the bond dissociation free energies (BDFE), as well as control experiments with a Ni0-precursor. We further demonstrated the robustness and utility of dimethylNiII as a Ni0-precursor in the late-stage installation of methyl, CD3, alkyl, and benzyl groups on aryl bromides that have potential value in drug design and optimization. This work sheds light on the activation mechanism of Ni-catalyzed cross-coupling of aryl halides with organozinc reagents when a NiII-precatalyst is employed and the critical role that visible light plays in the process. 

Photo-Initiated Nickel Catalysis (PiNiC): Unmasking Dimethylnickel with Light

High proton conduction in two highly stable phenyl imidazole dicarboxylate-based Cd(II)-MOFs

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Photoredox and Copper‐Catalyzed Sulfonylphosphorothiolation of Alkenes toward β‐Sulfonyl Phosphorothioates

Photo-Initiated Nickel Catalysis (PiNiC): Unmasking Dimethylnickel with Light

High proton conduction in two highly stable phenyl imidazole dicarboxylate-based Cd(II)-MOFs