David A. Cagan

The construction of stereogenic C(sp ³ )–C(sp ³ ) bonds through cross-coupling remains a formidable challenge owing to competing β-hydride elimination and homocoupling as well as the poor inherent stereocontrol of radical pathways. In this work, we report a scalable stereoretentive radical-radical cross-coupling of two distinct, transient alkyl radicals, derived from enantioenriched sulfonylhydrazides and achiral primary and secondary alkyl halides, achieved without chiral ligands, directing groups, or exogenous redox agents. This substrate-controlled approach leverages a nickel-catalyzed, redox-neutral manifold, which enables precise kinetic matching of diazene-mediated radical generation and halogen atom transfer. The reaction produced enantiospecificities of 80 to 96% and synthetically useful yields (up to 90%) across diverse piperidine and pyrrolidine scaffolds while tolerating ethers, free amines, aryl halides, heterocycles, olefins, and other sensitive motifs. Mechanistic studies support caged radical rebound at nickel to preserve chirality, followed by nickel(I)-nickel(III)–mediated radical capture and reductive elimination.

Reductive cross‐couplings have emerged as a powerful strategy for forging C–C bonds directly from electrophiles, circumventing the need for preformed organometallic reagents, yet they often suffer from limitations associated with heterogeneous reductants like Zn (e.g., poor reproducibility and scalability) or costly homogeneous alternatives such as TDAE. Inspired by prior explorations of hydrazide chemistry, we disclose arylhydrazines as inexpensive, readily available homogeneous sacrificial reductants that enable Ni‐catalyzed sp ² ‐sp ³ cross‐coupling of aryl halides with secondary alkyl iodides under mild, operationally simple conditions using a Ni ^II precursor, bipyridine ligand, and hindered amine base. Optimization, substrate scope studies, and direct comparisons reveal superior yields and selectivity relative to Zn‐based methods, particularly for heterocyclic and electron‐rich partners, while calorimetry‐guided safety assessments and decagram‐scale demonstrations highlight enhanced thermal control, reproducibility, and practicality. Mechanistic investigations via UV–vis spectroscopy, ¹⁹ F NMR, and reaction calorimetry support a pathway involving hydrazine‐mediated Ni ^II reduction to initiate a Ni ^I /Ni ^III cycle, with benign byproducts (N ₂ and arene), positioning arylhydrazines as versatile reagents for executing reductive coupling on scale.

Reductive cross‐couplings have emerged as a powerful strategy for forging C–C bonds directly from electrophiles, circumventing the need for preformed organometallic reagents, yet they often suffer from limitations associated with heterogeneous reductants like Zn (e.g., poor reproducibility and scalability) or costly homogeneous alternatives such as TDAE. Inspired by prior explorations of hydrazide chemistry, we disclose arylhydrazines as inexpensive, readily available homogeneous sacrificial reductants that enable Ni‐catalyzed sp ² ‐sp ³ cross‐coupling of aryl halides with secondary alkyl iodides under mild, operationally simple conditions using a Ni ^II precursor, bipyridine ligand, and hindered amine base. Optimization, substrate scope studies, and direct comparisons reveal superior yields and selectivity relative to Zn‐based methods, particularly for heterocyclic and electron‐rich partners, while calorimetry‐guided safety assessments and decagram‐scale demonstrations highlight enhanced thermal control, reproducibility, and practicality. Mechanistic investigations via UV–vis spectroscopy, ¹⁹ F NMR, and reaction calorimetry support a pathway involving hydrazine‐mediated Ni ^II reduction to initiate a Ni ^I /Ni ^III cycle, with benign byproducts (N ₂ and arene), positioning arylhydrazines as versatile reagents for executing reductive coupling on scale.

The ultrafast excited state pathways and dynamics of Ni^II-bipyridine complexes influence the yield of photochemical processes involved in their catalytic cross-coupling reactions. Here we present ultrafast Ni Kβ X-ray emission spectroscopy (XES) and X-ray solution scattering (XSS) of a Ni^II-bipyridine aryl halide complex, [Ni(^t-Bubpy)(o-tol)Br], to quantify the excited state population dynamics and structural changes of the precatalyst. Due to the local spin-sensitivity of XES, the population dynamics of metal-to-ligand charge transfer (MLCT) and metal-centered (MC) excited states is established. A rapid ground state recovery pathway is newly identified, representing a significant deactivation pathway during photocatalysis. Furthermore, the pseudotetrahedral structure of the long-lived MC excited state is unambiguously identified and refined by XSS. The results advance our understanding of the ultrafast relaxation mechanisms that impact the photocatalytic mechanism and yield for Ni^II-bipyridine aryl halide cross-coupling catalysts.

Catalytic reactions involving multiple cycles are common in many key organic transformations. We report a detailed mechanistic analysis of one such network of "nested" cycles, the Ni-catalyzed cross-coupling of alkyl sulfonyl hydrazides with (hetero)aryl halides, employing a battery of techniques, including Temperature Scanning Reaction (TSR) calorimetry coupled with Reaction Progress Kinetic Analysis (RPKA), quantitative NMR time-course analysis, kinetic modeling, linear free energy analysis, and density functional theory (DFT) quantum chemical calculations. TSR/RPKA studies yield the simultaneous determination of the thermodynamic enthalpy of the reaction, the kinetic rate law, and the activation parameters (ΔH^‡, ΔS^‡, ΔG^‡), for the rate-determining step. Expanding the analysis to the coupling of an array of electron-poor and electron-rich sulfonyl hydrazides (each readily accessible on the decagram scale) with a range of (hetero)aryl halide coupling partners introduces the concept of "kinetics matching," and demonstrates that optimal yields may be obtained when the reactivities of the separate cycles are tuned to work in unison. These requirements for reaction networks involving nested catalytic cycles are showcased by several real-world examples. Our work highlights the predictive power of this kinetics-focused mechanistic approach, which may be extended to other nested catalytic networks to select appropriate catalyst and substrate combinations for optimal outcomes.

Reductive cross-couplings have emerged as a powerful strategy for forging C–C bonds directly from electrophiles, circumventing the need for preformed organometallic reagents, yet they often suffer from limitations associated with heterogeneous reductants like Zn (e.g., poor reproducibility and scalability) or costly homogeneous alternatives such as TDAE. Inspired by prior explorations of hydrazide chemistry, we disclose arylhydrazines as inexpensive, readily available homogeneous sacrificial reductants that enable Ni-catalyzed sp²-sp³ cross-coupling of aryl halides with secondary alkyl iodides under mild, operationally simple conditions using a NiII precursor, bipyridine ligand, and hindered amine base. Optimization, substrate scope studies, and direct comparisons reveal superior yields and selectivity relative to Zn-based methods, particularly for heterocyclic and electron-rich partners, while calorimetry-guided safety assessments and decagram-scale demonstrations highlight enhanced thermal control, reproducibility, and practicality. Mechanistic investigations via UV-vis spectroscopy, 19F NMR, and reaction calorimetry support a pathway involving hydrazine-mediated NiII reduction to initiate a NiI/NiIII cycle, with benign byproducts (N₂ and arene), positioning arylhydrazines as versatile reagents for executing reductive coupling on scale.

Catalytic reactions involving multiple cycles are common in many key organic transformations. We report a detailed mechanistic analysis of one such network of “nested” cycles, the Ni-catalyzed cross-coupling of alkyl sulfonyl hydrazides with (hetero)aryl halides, employing a battery of techniques including temperature scanning reaction (TSR) calorimetry coupled with Reaction Progress Kinetic Analysis (RPKA), quantitative NMR time-course analysis, kinetic modeling, and density functional theory (DFT) quantum chemical calculations. TSR/RPKA studies yield the simultaneous determination of the thermodynamic enthalpy of the reaction, the kinetic rate law, and the activation parameters (Δ𝐻‡,Δ𝑆‡,Δ𝐺‡), for the rate-determining step. Expanding the analysis to the coupling of an array of electron-poor and electron-rich sulfonyl hydrazides (each readily accessible on the decagram scale) with a range of (hetero)aryl halide coupling partners introduces the concept of “kinetic matching,” and demonstrates that optimal yields may be obtained when the reactivities of the separate cycles are tuned to work in unison. These requirements for reaction networks involving nested catalytic cycles are showcased by several real-world examples. Our work highlights the predictive power of this kinetics-focused mechanistic approach, which may be extended to other nested catalytic networks to select appropriate catalyst and substrate combinations for high productivity.

Ni-catalyzed cross-coupling is a powerful strategy to forge C(sp³)-C(sp³) bonds. Typically, to do so requires overcoming a challenging C-C bond-forming reductive elimination, often enabled by the intermediacy of highly oxidized Ni species or outer-sphere processes. While direct C(sp³)-C(sp³) reductive elimination from the Ni^II base oxidation state is normally thermally inaccessible, light-activation provides an avenue to affect such transformations. Here, we investigate the mechanism of light-induced C(sp³)-C(sp³) bond formation from dialkyl bipyridine Ni^II complexes through a variety of organometallic, spectroscopic, and computational studies. Wavelength-dependent quantum yields, ligand electronics-reactivity relationships, excited-state lifetimes, computed barriers, and product distributions from crossover studies support a photolysis/radical rebound mechanism. This reactivity paradigm complements existing strategies in the literature to promote reductive elimination from Ni^II, such as the use of destabilizing, sterically hindered ligands and reduction of electron density at Ni through the binding of electron-deficient olefins. Hence, we envision that light-induced reductive elimination may enable the development of challenging C(sp³)-C(sp³) couplings.