This dissertation covers a range of computational studies on noncovalent interactions in biological systems and mechanistic investigations of synthetically and biosynthetically relevant reactions. Chapter 1 introduces the main concepts (i.e., basics of quantum mechanics, analysis of noncovalent interactions, and modeling organic reactions) behind quantum chemical calculations discussed (in the order they appear) in this report.Chapter 2 details the roles of noncovalent interactions involving sulfur atoms in biological systems, where computational approaches for modeling noncovalent interactions were described and examples of their applications were provided. Chapter 3 homes elucidation of organic reaction mechanisms involving sulfur atoms: (1) a collaborative effort with the research groups of Prof. John P. Toscano, Prof. Adrian J. Hobbs, and Prof. Jon M. Fukuto which explored the reaction mechanism of hydropersulfides with S-nitrosothiols, and revealed that S-nitrosothiols can be degraded by hydropersulfides to release nitric oxide which results in the regulation of vascular tone; (2) mechanistic investigation of the formation of zwiebelanes which are bioactive natural products isolated from onion extracts (ongoing). Chapter 4 details a collaboration with Prof. Uttam K. Tambar’s group. Our study discussed the catalyst-controlled regiodivergence in rearrangements of indole-based onium ylides and the mechanistic investigation of rhodium- and copper-catalyzed reactions showed divergent pathways favoring [2,3]-rearrangement involving a metal-free ylide and [1,2]-rearrangement involving a metal-coordinated ion pair in a solvent-cage. Lastly, Chapter 5 of this dissertation (in collaboration with the groups of Prof. Ikuro Abe, Prof. John A. Porco Jr., and Prof. Makoto Fujita) focuses on the evaluation of the potential of meroterpenoid cyclases to expand the chemical space of fungal meroterpenoids. Our study shed light on their catalytic activity and could pave the way to create unnatural pathways towards second generation meroterpenoids.

This dissertation is a collection of computational chemistry works on chemical and photochemical reaction mechanisms. Multiple theoretical tools have been utilized to tackle mechanistic questions in organic chemistry and photochemistry. They include density functional theory, machine learning and ab initio molecular dynamics and they are briefly discussed in chapter 1.Chapter 2 is about the migratory aptitude of carbocation rearrangement from the perspective of dynamic effects. Carbocation rearrangement reactions are of great significance to synthetic and biosynthetic chemistry. In pursuit of a scale of inherent migratory aptitude that takes into account dynamic effects, both uphill and downhill ab initio molecular dynamics (AIMD) simulations were used to examine competing migration events in a model system designed to remove steric and electronic biases. The results of these simulations were combined with detailed investigations of potential energy surface topography and variational transition state theory calculations to reveal the importance of non-statistical dynamic effects on migratory aptitude. Chapter 2 formulates a selectivity model based on the widths of pathways to competing products, rather than barrier heights, for a butadiene + allyl cation reaction. This model was arrived at via analysis of stationary points, intrinsic reaction coordinates, potential energy surface shapes and direct dynamics trajectories, all determined using quantum chemical methods. Chapter 3 is on photochemistry. Selectivity for photochemical reactions where crossing between excited state and ground state surfaces occurs near ground state transition structures that interconvert competing products should be controlled by the momentum of the reacting molecules as they return to the ground state and the shape of the potential energy surfaces involved. The roles of these factors are revealed here for a classic photochemical reaction: deazetization of 2,3-diazabicyclo[2.2.2]oct-2-ene. The utility of analogies between such photochemical reactions and ground state reactions with post-transition state bifurcations for forward design is suggested. Chapter 4 is a collaborative project with the Sarpong group at UC Berkley. They have made synthetic efforts towards the pupukeanane natural products. The 10-step enantiospecific synthetic route to 2-isocyanoallopupukeanane facilitates an unprecedented bio-inspired ‘contra-biosynthetic’ rearrangement, providing divergent access to the pupukeanane core. The computational studies provide insights into the nature of this novel rearrangement. Chapter 5 is a collaborative project with the Zheng group at the University of Arkansas. Distonic radical cations generated from the ring-opening of cyclopropylamines have shown distinct reactivities and TMSCN has been shown to be able to make the ring-opening happen. Our computational study has pointed out that the change in the photoredox potential and the quenching of the distonic radical cations by TMSCN are critical to the reactivities. Chapter 6 is a collaborative project with the Lectka group at Johns Hopkins University on a through-space arene activations with halogens, tetrazoles and achiral esters and amides. Contrary to previously assumed direct activation through σ-complex stabilization, computational and experimental results suggest that these reactions proceed by a relay mechanism wherein the lone pair-containing activators form exothermic π-complexes with electrophilic nitronium ion before transferring it to the probe ring through low barrier transition states.

This dissertation summarizes a number of computational chemistry strategies used to study organic reactions, specifically pericyclic reactions and non-classical carbocations. Chapter 1 briefly touches on some of these methods, and they include density functional theory, ab initio molecular dynamics, and machine learning.Chapter 2 is focused on the Woodward-Hoffmann rules, which dictate "allowed" and "forbidden" stereochemical outcomes in pericyclic reactions. DFT is used to investigate how the use of a transition metal catalyst and stereoelectronic effects can not only allow for a "forbidden" product, but also favor it over the "allowed" product. Chapter 3 then moves to investigate pericyclic reactions in nature as opposed to a lab. DFT is still used as the primary quantum chemistry tool. Chapter 4 involves a change in methods. This chapter still investigates a similar class of reactions, pericyclic reactions, but now the focus is on non-statistical dynamic effects. This dissertation then implements the use of molecular dynamics as a strategy to investigate pericyclic reactions. Specifically, post-transition state bifurcations are investigated in cycloadditions. Finally, chapter 5 uses a similar set of tools as those used in chapter 4, but to tackle a much more complicated (in my opinion) and intensive problem on a different class of molecules. Molecular dynamics are used, but the focus is on non-classical carbocations. This chapter investigates what the relationship is between a different flavor of non-statistical dynamics effects, dynamic matching specifically, and quantum mechanical tunneling. Quasiclassical trajectories are used to gain insight about dynamic matching, but ring-polymer molecular dynamics (RPMD) trajectories are needed to address tunneling questions. RPMD is an expensive method, thus, a machine learning potential was added to the set of tools used.

This dissertation explores a broad spectrum of modern computational chemistry techniques to address mechanistic questions in organic reactions. It delves into the thermodynamic and kinetic aspects of these reactions while also examining the roles of dynamic effects and tunneling in influencing organometallic reaction outcomes. Key areas of focus include elucidating reaction mechanisms from kinetic, thermodynamic, and dynamic perspectives, understanding reaction pathways and the origins of selectivity, investigating byproduct formation in catalytic reactions, and developing strategies to mitigate these byproducts.

Chapter 1 introduces the physical chemistry methods used to tackle these questions, providing a concise overview of the fundamentals of computational chemistry, physical organic chemistry, and the theoretical assumptions applied to the following chapters.

The next three chapters concentrate on dirhodium-catalyzed reactions from various systems and perspectives. In Chapter 2, the project examines a previously reported lactonization reaction complicated by post-transition state bifurcation (PTSB). Here, traditional transition state theory (TST) falls short in accurately predicting product yield and selectivity. Ab initio molecular dynamics (AIMD) simulations offer a framework to rationalize selectivity origins, revealing the interplay between thermodynamic and dynamic preferences. The study of larger catalysts illustrates how a lowered barrier for byproduct recombination can lead to the formation of β-lactones.

Chapter 3 investigates another C-H insertion reaction that is combined with a Cope rearrangement (CHCR). A PTSB effect is proposed to be at play, leading to competing C-H insertion and CHCR products. However, further AIMD simulations reveal multiple accessible channels after the transition state, resulting in byproducts that cannot revert to either CH or CHCR products. An analysis of vibrational modes uncovers a “dynamic mismatching” effect, where the reaction is driven away from producing a downhill product and instead becomes trapped in flat energy regions, ultimately leading to byproduct formation.

Chapter 4 presents a study on a C-C activation reaction forming cyclopropanation products and dimerized byproducts. This chapter specifically focuses on a mixed-ligand dirhodium catalyst where one acetate ligand is replaced with a PhTCB group. This tethered, axially coordinated ligand system (TACLS) has been reported to enhance selectivity toward the desired product but lacks a detailed mechanistic study. The mixed-ligand design allows for the dissociation of the PhTCB ligand to form either a stabilizing π-π stacking interaction with the substrate in a unique three-benzene sandwich structure, or a free ylide as a key intermediate. A comprehensive DFT study was employed to uncover and formulate the reaction mechanism.

Chapter 5 explores the formation and rearrangement of a non-classical carbonation -- barbaralyl cation (C9H9+). Computational studies on proposed stationary structures reveal two highly delocalized minima, one of Cs symmetry and the other of D3h symmetry, affirmed by quantum chemistry-based NMR predictions. Partial and total rearrangement cycle was found to proceed through a C2 and C2v symmetric transition structure. AIMD simulations initiated from the D3h C9H9+ structure revealed its connection to six minima, due to the six-fold symmetry of the PES. The effects of tunneling and boron substitution on this complex reaction network were also examined.

Chapter 6 discusses heavy atom tunneling in organic synthesis. The contribution of quantum mechanical tunneling to the rates of several radical coupling reactions, which are key steps in natural product total syntheses, was computed using density functional theory. The results indicate that tunneling plays a significant role in the rates and should be considered when designing complex synthetic schemes.