This dissertation discloses the work of several research projects involving stereoelectronic effects as a tool to control chemical reactivity. In particular, three areas have been discussed in details: 1. Taming oxygen-rich systems with stereoelectronic effects; 2. Au(I)-Catalyzed Bergman-Cyclization; 3. Isonitriles as stereoelectronic chameleons. Chapter One starts by introducing stereoelectronic effects. In this chapter, I explain how stereoelectronic effects can be studied computationally by defining the tools used throughout this dissertation with definitions and providing examples of their utility. The main quantitative tools for stereoelectronic effects are introduced: conformational changes, reaction equations (such as isodesmic equations), and Natural Bond Orbital (NBO) analysis. The concept of hyperconjugation is explained, with special attention to the role of polarity on the magnitude of these interactions. Chapter Two expands on the role of stereoelectronic effects as a tool to control chemical reactivity by showing examples of how oxygen-rich systems can be tamed. The unusual stability of bis-peroxides contradicts conventional wisdom – some of them can melt without decomposition at temperatures exceeding 100 oC. In this chapter, we disclose a stabilizing stereoelectronic effect that two peroxide groups can exert on each other. This stabilization originates from strong anomeric n_O→σ_(C-O)^* interactions that are absent in mono-peroxides, but reintroduced in molecules where two peroxide moieties are separated by a CH2 group. The two unstable peroxides are transformed into two acetals. The value of stereoelectronic guidelines is illustrated by the discovery of a convenient, ozone-free synthesis of bridged secondary ozonides from 1,5-dicarbonyl compounds and H2O2. The expected tetraoxanes are not formed when the structural distortions imposed on the tetraoxacyclohexane subunit by a three-carbon bridge partially deactivate the anomeric effects, a design projected from our computational endeavors. Finally, we have employed stereoelectronic effects to design a trap for the Criegee Intermediate (CI), the elusive intermediary for the Baeyer-Villiger reaction. Our strategy involved the deactivation of transition-state stabilizing effects for the migratory step via precise cyclic constraints and the usage of the newly-found reverse α-effect. Chapter Three explores the stereoelectronic and zwitterionic assistance in the Au(I)-Catalyzed Bergman Cyclization. With 90% of chemically individual molecules in nature containing a carbo- or heterocyclic subunit, the ability to make cyclic structures in an efficient and selective manner can be paramount to the success of a synthesis. Out of the three main approaches to the formation of cyclic structures (i.e., cyclizations, pericyclic reactions, and cycloaromatizations), cycloaromatization reactions are by far the most unusual and difficult to control. A typical cyclization reaction generally involves a "preformed" high energy reactive center (e.g., a cation, a radical, or an anion) that attacks a weak functionality (e.g., a π-bond) in a process where one bond is formed and the other is broken. In a similar way, the number of bonds is conserved in the classic pericyclic reactions which avoid the formation of unstable intermediates by coordinating the bond-breaking and the bond-forming processes. However, the synergy between bond formation and bond breaking that is typical for pericyclic reactions is lost in their mechanistic cousins, cycloaromatization reactions. In these reactions, exemplified by the Bergman cyclization (BC), two bonds are sacrificed to form a single bond and the reaction progress is interrupted at the stage of a cyclic diradical intermediate. Intrigued by a recent discovery of an unusually fast Au-catalyzed BC, we developed two key tools that allowed us to understand the nature of the catalytic effect: First, we developed a strategy to analyzed the intricate bonding aspects (via NBO analysis) of the two perpendicular π-systems through the course of the reaction; In parallel, we advanced a new theoretical framework for understanding the nature of the catalytic effect by applying the distortion-interaction (DI) analysis to metal-catalyzed reactions. Until then, the widely used DI model was only applied for bimolecular processes. We have shown that our model can provide useful information regarding unimolecular reactions promoted by coordination with a catalyst. Chapter Four dives into the chameleonic behavior of isonitriles facing reactions with radicals. Radical addition to isonitriles (isocyanides) starts and continues all the way to the TS mostly as a simple addition to a polarized pi-bond. Only after the TS has been passed, the spin density moves to the alpha-carbon to form the imidoyl radical, the hallmark intermediate of the 1,1-addition-mediated cascades. Addition of alkyl, aryl, heteroatom-substituted and heteroatom-centered radicals reveals a number of electronic, supramolecular, and conformational effects potentially useful for the practical control of isonitrile-mediated radical cascade transformations. Addition of alkyl radicals reveals two stereoelectronic preferences. First, the radical attack aligns the incipient C⋯C bond with the aromatic pi-system. Second, one of the C-H/C-C bonds at the radical carbon eclipses the isonitrile N-C bond. Combination of these stereoelectronic preferences with entropic penalty explains why the least exergonic reaction (addition of the t-Bu radical) is also the fastest. Heteroatomic radicals reveal further unusual trends. In particular, the Sn radical addition to the PhNC is much faster than addition of the other group IV radicals, despite forming the weakest bond. This combination of kinetic and thermodynamic properties is ideal for applications in control of radical reactivity via dynamic covalent chemistry and may be responsible for the historically broad utility of Sn-radicals ("the tyranny of tin"). In addition to polarity and low steric hindrance, radical attack at the relatively strong pi-bond of isonitriles is assisted by "chameleonic" supramolecular interactions of the radical center with both the isonitrile pi*-system and lone pair. These interactions are yet another manifestation of supramolecular control of radical chemistry. / A Dissertation submitted to the Department of Chemistry and Biochemistry in partial fulfillment of the requirements for the degree of Doctor of Philosophy. / Fall Semester 2018. / November 6, 2018. / computational chemistry, Gold-catalyzed Bergman cyclization, isonitriles, organic chemistry, oxygen-rich systems, stereoelectronic effects / Includes bibliographical references. / Igor V. Alabugin, Professor Directing Dissertation; Bruce Locke, University Representative; Kenneth Hanson, Committee Member; James H. Frederich, Committee Member.

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