UC Davis

The work described in this dissertation builds upon a vast body of work in applied theoretical organic chemistry and spans various sub-disciplines within chemistry. Organic chemistry, organometallic chemistry, and organic chemistry relevant to biological systems—sub-topics of these areas are discussed in this dissertation. A common theme threads through all chapters: computational tools were used to investigate mechanisms of synthetically relevant—and theoretical—reactions to derive general, predictive, and portable models to inform future studies. Chapter 1 outlines the state of modern, applied theoretical organic chemistry. One role of an applied theoretical organic chemist is to make sense of the complex patterns that emerge out of experimental synthetic organic laboratories. This includes, but is not limited to, deducing mechanistic models that experimentalists can arm themselves with in exploring new reactions. Theoretical chemists use computational methods, in the form of quantum chemistry calculations, to probe the nuances of organic reaction mechanisms. Chapter 1 discusses these methods along with caveats that inevitably come with limited scientific tools (such as ours). Part I of this dissertation (which includes Chapters 2-6) homes in on dirhodium(II)-catalyzed reactions and provides examples for which mechanistic details, up until our theoretical investigations, were left in the dark: specifically, mechanistic nuances of ylide-formation/sigmatropic rearrangements (Chapters 2 and 3), donor/donor carbene C-H insertion reactions (Chapters 4 and 5) are described. Specifically for metal-catalyzed ylide-forming reactions, whether dirhodium catalysts are explicitly bound to the ylide intermediate upon subsequent sigmatropic rearrangement (e.g., [1,2]- or [2,3]-shift) remained unknown. A “breadcrumb trail” of evidence in the literature, however, provided ample control experiments for a systematic and comparative theoretical analysis. Reactants, intermediates, and products of synthetically-relevant ylide-formation [1,2]- and [2,3]-rearrangements—and the transition state structures that connect them—were computed with density functional theory. It was found that whether the metal catalyst dissociates before rearrangement depends on the system—the most significant factor that directs catalyst dissociation before rearrangement, however, is the steric bulk of the group adjacent to the carbene center. Additionally, computational studies were done in collaboration with the group of Prof. Jared T. Shaw on dirhodium-catalyzed C-H insertion reactions of donor/donor carbenes (Chapter 5). A stepwise mechanism with an SE2 C-C bond formation was discovered in the C-H insertion reaction. Finally, dirhodium-catalyzed cyclopropanations of cycloheptatriene diazo compounds to semibullvalenes, described in Chapter 6, showcases one example of a theoretical prediction encouraging a synthetic collaboration to test predictions sparked by theory (ongoing). Part II of this dissertation describes a foray into heterolytic fragmentation reactions. In Chapter 7, computational studies of a designed 1-aza-adamantane model system—by density functional theory, natural bond orbital, ab initio molecular dynamics simulations, and external electric field calculations—revealed a divergent fragmentation, one in which a substrate can fragment to two unique products via different mechanistic pathways. Substituents, electrostatic environment, and dynamic effects were found to all influence pathways to competing products. Chapter 8 provides a portrait of through-bond stereoelectronic effects in products that emerge from a fragmentation reaction, 3-azabicyclo[3.3.1]nonanes. Computational studies of substituent effects, noncovalent interactions, natural bond orbitals, isodesmic reactions, and hydration propensities demonstrated that hyperconjugation/conjugation through-bond effects dominated the different reactivity between two similar compounds—a vinylogous chloride and a vinylogous ester. Finally, Part III of this dissertation describes an isolated project which benefitted from close collaboration between our group (theory) and the groups of Prof. Reuben Peters (Iowa State University), Prof. Qiang Wang (Sichuan Agricultural University) and Prof. Jeroen Dickschat (University of Bonn), all experimental groups in terpene chemistry. Collaboration between theoretical and experimental groups achieve a depth of mechanistic insight that is potentially missed in the absence of collaboration. This synergy is demonstrated in a collaborative project with all three groups, with whom a plausible mechanism was elucidated for the formation of a natural product, (14S)-cleistantha-8,12-diene, from barley diterpene synthase, HvKSL4 (Chapter 9).