Development of Well-Defined, Bench-Stable Ni-NHC Precatalysts for Challenging C-N Bond Formation Reactions

Abstract

Transition-metal-catalyzed C-N bond formation represents one of the most powerful synthetic methods for constructing aromatic amines and nitrogen-containing heterocycles. While palladium has historically dominated this field, nickel has recently emerged as a sustainable and cost-effective alternative due to its earth abundance, unique redox flexibility, and capacity to engage in both two-electron and single-electron processes. However, despite its potential, the development of well-defined, air- and moisture-stable nickel complexes capable of promoting challenging amination reactions remains limited. This thesis describes the systematic design, synthesis, and catalytic evaluation of new generations of bench-stable Ni-NHC precatalysts that overcome longstanding challenges in nickel-catalyzed C-N cross-coupling. The work focused on enhancing catalyst stability and reactivity through rational modification of the NHC ligand's steric and electronic properties.

A first-generation Ni-NHC-IPr complex synthesized by Organ group shown to promote the amination of aryl chlorides under mild conditions while maintaining excellent air and moisture stability. The reactivity is consistent with in-situ reduction of Ni(II) to a catalytically active Ni(0) species operating through a conventional Ni(0)/Ni(II) cycle. Although its activity diminished with sterically hindered or electronically deactivated substrates, the results confirmed that well-defined Ni-NHC complexes can serve as reliable precatalysts for cross-coupling applications. Interestingly, an unusual halide reactivity trend was observed: aryl chlorides afforded higher yields than their bromide or iodide analogues. This behavior was attributed to catalyst poisoning by bromide and iodide species, which divert the Ni complex off-cycle and terminate productive catalysis. These findings emphasize the distinctive oxidative-addition behavior of the Ni-NHC system and the critical role of halide identity in determining catalytic efficiency and stability.

Building on these results, the Ni-NHC-IPr complex was further explored under visible-light irradiation in combination with an iridium-based photoredox co-catalyst. The resulting dual [Ni]/[Ir] system enabled cross-coupling under milder conditions via high-valent Ni(I)/Ni(III) intermediates, accelerating reductive elimination. This photochemically assisted platform demonstrated enhanced performance with select substrates, highlighting the potential of redox modulation to extend nickel's reactivity window. However, the need for an external photosensitizer and diminished performance with demanding substrates underscore the need for further refinement. To advance catalyst performance, a range of sterically and electronically tuned NHC ligands, including IPent, IHept, IPr^*OMe, IPr^Cl, IPent^Cl, and IHept^Cl, were developed and incorporated into new generations of Ni-NHC complexes. Comparative catalytic studies revealed that increasing ligand bulk accelerates reductive elimination against B-hydride elimination but can also hinder substrate coordination, highlighting the need for fine steric balance. Backbone chlorination enhanced reactivity and selectivity in certain reactions but did not universally improve yields. The introduction of π-allyl ligands replaced the bulky stabilizing ligand with a more compact π-allyl group, opening greater coordination flexibility to accommodate bulkier NHC ligands on nickel; however, this modification came at the expense of reduced air stability.

Collectively, this work establishes a comprehensive framework for the development of well-defined Ni-NHC precatalysts that are not only bench-stable but also tunable across electronic and steric dimensions to meet diverse synthetic challenges. Through rational ligand design and systematic evaluation, it delivers a versatile platform for promoting challenging C-N bond formation with reliable performance under mild conditions, advancing both mechanistic understanding and practical applicability, and ultimately bridging the gap between academic discovery and industrial application.