Nickel-Catalyzed Radical Mechanisms: Informing Cross-Coupling for Synthesizing Non-Canonical Biomolecules.

ConspectusNickel excels at facilitating selective radical chemistry, playing a pivotal role in metalloenzyme catalysis and modern cross-coupling reactions. Radicals, being nonpolar and neutral, exhibit orthogonal reactivity to nucleophilic and basic functional groups commonly present in biomolecules. Harnessing this compatibility, we delve into the application of nickel-catalyzed radical pathways in the synthesis of noncanonical peptides and carbohydrates, critical for chemical biology studies and drug discovery.We previously characterized a sequential reduction mechanism that accounts for chemoselectivity in cross-electrophile coupling reactions. This catalytic cycle begins with nickel(I)-mediated radical generation from alkyl halides, followed by carbon radical capture by nickel(II) complexes, and concludes with reductive elimination. These steps resonate with mechanistic proposals in nickel-catalyzed cross-coupling, photoredox, and electrocatalytic reactions. Herein, we present our insights into each step involving radicals, including initiation, propagation, termination, and the nuances of kinetics, origins of selectivity, and ligand effects.Radical generation from C(sp3) electrophiles via one-electron oxidative addition with low-valent nickel radical intermediates provides the basis for stereoconvergent and cross-electrophile couplings. Our electroanalytical studies elucidate a concerted halogen atom abstraction mechanism, where electron transfer is coupled with halide dissociation. Using this pathway, we have developed a nickel-catalyzed stereoselective radical addition to dehydroalanine, facilitating the synthesis of noncanonical peptides. In this application, chiral ligands modulate the stereochemical outcome through the asymmetric protonation of a nickel-enolate intermediate.The capture of the alkyl radical by nickel(II) expands the scope of cross-coupling, promotes reductive elimination through the formation of high-valent nickel(III) species, and governs chemo- and stereoselectivity. We discovered that nickel(II)-aryl efficiently traps radicals with a barrier ranging from 7 to 9 kcal/mol, followed by fast reductive elimination. In contrast, nickel(II)-alkyl captures radicals to form a nickel(III) species, which was characterized by EPR spectroscopy. However, the subsequent slow reductive elimination resulted in minimal product formation. The observed high diastereoselectivity of radical capture inspired investigations into C-aryl and C-acyl glycosylation reactions. We developed a redox auxiliary that readily couples with natural carbohydrates and produces glycosyl radicals upon photoredox activation. Nickel-catalyzed cross-coupling of the glycosyl radical with bromoarenes and carboxylic acids leads to diverse non-natural glycosides that can facilitate drug discovery.Stoichiometric studies on well-defined d8-nickel complexes have showcased means to promote reductive elimination, including ligand association, oxidation, and oxidative addition.In the final section, we address the influence of auxiliary ligands on the electronic structure and redox activity of organonickel intermediates. Synthesis of a series of low-valent nickel radical complexes and characterization of their electronic structures led us to a postulate that ligand redox activity correlates with coordination geometry. Our data reveal that a change in ligand redox activity can shift the redox potentials of reaction intermediates, potentially altering the mechanism of catalytic reactions. Moreover, coordinating additives and solvents may stabilize nickel radicals during catalysis by adjusting ligand redox activity, which is consistent with known catalytic conditions.

Insights into the Mechanism of an Allylic Arylation Reaction via Photoredox-Coupled Hydrogen Atom Transfer.

Despite widespread use as a synthetic method, the precise mechanism and kinetics of photoredox coupled hydrogen atom transfer (HAT) reactions remain poorly understood. This results from a lack of detailed kinetic information as well as the identification of side reactions and products. In this report, a mechanistic study of a prototypical tandem photoredox/HAT reaction coupling cyclohexene and 1,4-dicyanobenzene (DCB) using an Ir(ppy)3 photocatalyst and thiol HAT catalyst is reported. Through a combination of electrochemical, photochemical, and spectroscopic measurements, key unproductive pathways and side products are identified and rate constants for the main chemical steps are extracted. The reaction quantum yield was found to decline rapidly over the course of the reaction. An unreported cyanohydrin side product was identified and thought to play a key role as a proton acceptor in the reaction. Transient absorption spectroscopy (TAS) and quantum chemical calculations suggested a reaction mechanism that involves radical addition of the nucleophilic DCB radical anion to cyclohexene, with cooperative HAT occurring as the final step to regenerate the alkene. Kinetic modeling of the reaction, using rate constants derived from TAS, demonstrates that the efficiency of the reaction is limited by parasitic absorption and unproductive quenching between excited Ir(ppy)3 and the cyanohydrin photoproduct.

Mechanistic Investigations of an α-Aminoarylation Photoredox Reaction.

While photoredox catalysis continues to transform modern synthetic chemistry, detailed mechanistic studies involving direct observation of reaction intermediates and rate constants are rare. By use of a combination of steady state photochemical measurements, transient laser spectroscopy, and electrochemical methods, an α-aminoarylation mechanism that is the inspiration for a large number of photoredox reactions was rigorously characterized. Despite high product yields, the external quantum yield (QY) of the reaction remained low (15-30%). By use of transient absorption spectroscopy, productive and unproductive reaction pathways were identified and rate constants assigned to develop a comprehensive mechanistic picture of the reaction. The role of the cyanoarene, 1,4-dicyanobenzne, was found to be unexpectedly complex, functioning both as initial proton acceptor in the reaction and as a neutral stabilizer for the 1,4-dicyanobenzene radical anion. Finally, kinetic modeling was utilized to analyze the reaction at an unprecedented level of understanding. This modeling demonstrated that the reaction is limited not by the kinetics of the individual steps but instead by scattering losses and parasitic absorption by a photochemically inactive donor-acceptor complex.