Palladium- and Nickel-Catalyzed Cross-Coupling: Reaction Development and Mechanistic Investigations

Abstract

Transition metal-catalyzed cross-coupling has revolutionized the field of synthetic organic chemistry through the development of C–C and C–heteroatom bond-forming transformations. Palladium complexes are the most commonly used metal catalysts in cross-coupling due to their high reactivity and stability, whereas catalysis based on the more abundant nickel metal has recently witnessed tremendous advances because of its similar yet unique reactivity. The following dissertation highlights the reaction development and mechanistic investigations of Pd- and Ni-catalyzed cross-coupling reactions.Chapter 1 chronicles the history of synthetic organic chemistry and the development of cross-coupling reactions. The differences between Pd and Ni in terms of physical properties and reactivity are illustrated. The challenges associated with each metal are also discussed in the context of cross-coupling reactions. Chapter 2 describes the development of a Pd-catalyzed C–N coupling reaction using triethylamine as a weak soluble base. This strategy circumvented the use of ionic and inorganic bases which can be incompatible with base-sensitive functional groups and technologies such as continuous flow and robotic high-throughput screening. Mechanistic investigations established a unique water-assisted mechanism that is distinct from the conventional pathways proposed for Buchwald-Hartwig amination. Chapter 3 discusses our efforts in synthesizing and characterizing the coordinatively-unsaturated active state of zerovalent Pd catalysts bound by a single ancillary ligand, which has long eluded direct observation in solution. The synthesis and unambiguous solution- and solid-state characterization of such highly reactive species were accomplished by leveraging exceptionally facile B-to-Pd transmetalation reactions at cryogenic temperature. In chapter 4, we demonstrate a Ni/photoredox-catalyzed enantioselective cross-electrophile coupling of styrene oxides with aryl iodides using a chiral biimidazoline ligand. This transformation allows facile access to enantioenriched 2,2-diarylalcohols from racemic epoxides via a stereoconvergent mechanism. This study highlighted the use of statistical modeling as a complementary tool to experimental and computational mechanistic studies for elucidating a nonintuitive structure-selectivity relationship in a complex catalytic system. In chapter 5, we describe the development of EDBO+, a multi-objective active-learning platform for Bayesian reaction optimization. We showcased its applications in real-word test scenarios, and developed a web application to allow for broad adoption of Bayesian optimization into everyday laboratory practices.