This dissertation focuses on the discovery and developments of novel carbon–carbon (C–C) bond forming reactions through dicoordinate carbocation intermediates. Chapter one provides a brief introduction into the known reactivity of relevant aryl and vinyl carbocations. In particular, C–C bond forming transformations will be the main focus of this discussion.

Our experimental work begins with the account of serendipitous discovery of intermolecular C–H insertion reactions of an aryl cation intermediate. We detail the reactivity-driven nature of our initial hypothesis and its development into a novel hydrocarbon arylation methodology. It was demonstrated that ortho-silylated aryl fluorides can be used as precursors for generating aryl cations capable of C–H insertion. The insertion chemistry exhibits inherent terminal selectivity in linear alkanes and is capable of activating one of the most challenges C–H bonds in methane.

Subsequently, we followed the reactivity of our aryl cations to other dicoordinate carbocations as in vinyl cations. Utilizing a similar strategy hinged upon the use of silylium–weakly coordinating anion catalysis, vinyl cations were found to also undergo intermolecular insertion into sp3 C–H bonds. Here, we establish a reductive coupling process between vinyl triflates and various hydrocarbons. Extensive deuterium labeling studies also helped to uncover key features of the dicoordinate carbocation insertion mechanism. A detailed account of our hypotheses in establishing our mechanistic probe experiments is reported.

In efforts to bring our new methodology to a more broadly applicable chemical space, we were determined to further develop our system for heteroatom compatibility. Our progress has culminated in a new mode of generation for vinyl cations under highly basic conditions, and results in the C–H insertion reactions in the presence of a wide variety of heteroatom-containing substrates. In these studies, 3-substitued cyclooctenyl vinyl triflates was a substrate class used to highlight the increased functional group tolerance of our new method. Utilization of lithium-weakly coordinating anions has allowed entry for our dicoordinate carbocation insertion chemistry into applications such as fine chemical syntheses.

This dissertation describes the development of Lewis acid-based methodology togenerate dicoordinated carbocations catalytically. These reactive intermediates were once sparingly accessible synthetically and were mostly the focus of theoretical studies. This dissertation highlights new, mild conditions that can generate these species in a kinetically persistent fashion through the use of weakly coordinating anions in non-polar media. These conditions also enable new carbon–carbon bond forming reactions of these intermediates to take place; either through Friedel-Crafts or C–H insertion. Additionally mechanistic nuances and the key advantages and disadvantages of each developed system will be highlighted. Overall, this work features the development of this chemistry from a fundamental study to a more broadly applicable reaction. Chapter One is a brief overview of the current state of research on aryl and vinyl cations. This chapter serves as a prelude to the remaining chapters and will be referenced throughout this dissertation. Strategies to generate these reactive species, specifically ones that inspired our own research in this area are presented. Furthermore, some reactivity of these cations is also highlighted, again focusing on mechanistically similar reactions to our own. Chapter Two describes our efforts in the development of a silylium-carborane catalyzed reaction to generate aryl and vinyl cations catalytically from aryl fluorides and vinyl triflates respectively. These species were then able to be engaged in intermolecular reactions with inert C–H bonds of both alkanes and arenes resulting in a mild C–H functionalization reaction. Chapter Three discusses our investigations of lithium-based Lewis acids to generate reaction vinyl cations under highly basic conditions and their ensuing reactivity. Notably, this work also overcomes some of the challenges presented in chapter Two with regards to the functional group compatibility of these systems. This work represents an important advancement of our chemistry towards a more robust, practical reaction. Chapter Four highlights an ongoing effort in our research group to utilize different vinyl sulfonate precursors in order to access a broader class of vinyl cation intermediates. With these precursors in hand, we utilize similar conditions to Chapter Three to develop some new vinyl cation reactivity. These reactions involve trapping of vinyl cations with allylsilanes, silyl ketene acetals, and methyl ethers. Chapter Five discusses our ongoing effort to develop a “field guide” for the practicing organic chemist in order to disseminate some of our groups in-house knowledge in developing these cation methodologies over the past few years. Here, mechanistic nuances, substrate design, and choice of catalytic system are discussed.

This dissertation describes the application and development of electron crystallography in the realm of small molecules and, in particular, natural products (NPs). Natural products serve as a major inspiration for drug discovery, but the rate of discovering novel NPs is hindered by limitations in existing characterization techniques. This dissertation highlights microcrystal electron diffraction (MicroED) as a powerful approach to overcome these limitations and structurally characterize NPs and other small molecules. Overall, this work demonstrates the general applicability of MicroED in natural product and small molecule characterization. Moreover, using MicroED as a platform, an efficient workflow for NP identification is developed, with the goal of accelerating the rate of novel natural product discovery as well as drug discovery. Chapter One is a brief overview of the current state of research on using electron diffraction to elucidate structures of natural products. This chapter serves as both a prelude to and a summary of the remaining chapters, and will be referenced throughout this dissertation. Brief history of electron diffraction and background of MicroED is provided, focusing on the scope of MicroED in small molecule regime. Furthermore, the application of MicroED in natural products and currently remaining challenges are highlighted, drawing on our experiences as well as others’. Chapters Two through Five describe the applications of MicroED in NP characterization. Chapter Two highlights the structural elucidation of a glucosyluric metabolite in C. elegans, whose MicroED structure was used to complement the NMR data that was ambiguous due to poor line shapes. Chapter Three showcases the structure determination of a biosynthetic intermediate to a fungal metabolite (–)-sambutoxin, whose relative stereochemistry was validated using MicroED. Chapter Four discusses the synergy between MicroED and genome mining by rediscovering the biosynthetic pathway to fischerin and revising its relative stereochemistry that was incorrectly assigned using computational studies. In this chapter, a novel compound is isolated and characterized using MicroED, demonstrating the first example of a novel, non-peptidyl NP structurally elucidated via MicroED. Additionally, this study highlights MicroED’s impressive sensitivity by detecting structural information from only 3 ng of material. Chapter Five reports the structural revision of the lomaiviticins enabled by MicroED analysis. The lomaiviticins are highly cytotoxic bacterial metabolites that have been extensively studied for decades, with multiple total synthesis efforts that failed. This structural revision, supported by high-field NMR as well as DFT calculations, enables scientists to embark on future synthetic efforts and studies on mechanisms of action with more confidence. Chapter Six highlights the development of a MicroED platform to enable highthroughput screening for crystalline NPs. Initial studies demonstrate MicroED’s ability to obtain crystal structures in complex mixtures of natural products. These preliminary experiments are used to envision a workflow coupling liquid chromatography and MicroED, which is further developed into a high-throughput strategy. Using this platform, NPs produced in insufficient amounts for other analytical techniques can be detected and characterized, accelerating the rate of NP discovery. Chapter Seven describes the expansion of the scope of MicroED further in the small molecule regime by solving structures of reactive organometallic species and synthetic reaction products. These examples showcase the ability of MicroED in obtaining crystal structures that were previously unattainable, and demonstrate the structural integrity of MicroED structures when compared with structures obtained by X-ray crystallography. Notably, we discuss the utility of room temperature MicroED experiments, which provide a facile and quick method of screening for diffraction and become an integral part of the workflow in structural elucidation of small molecules.

This dissertation describes the development of Lewis acid-based methodology to access polycyclized sesquiterpenes and diterpenes through simple catalytic methods. This challenging biomimetic reaction is difficult to replicate in synthesis and remains understudied. In addition, this dissertation explores the application and development of an electron diffraction technique for the elucidation of small molecules in an efficient manner. Overall, this work seeks to push the boundaries of synthesis and analysis of complex structures through development of synthetic and analytical methods described herein. Chapter One is a brief overview of the current state of research on biomimetic terpene cyclization reactions and history of transmission electron microscopy techniques leading up to the development of microcrystal electron diffraction. This chapter serves as a prelude to the remaining chapters and will be referenced throughout this dissertation. Chapter Two describes our efforts in the development of a lithium-weakly coordinating anion-mediated polycyclization reaction to generate polycyclic terpenes from acyclic fluorides precursors. The analysis of complex mixtures and early efforts to characterize these species utilizing microcrystal electron diffraction is discussed. Chapter Three discusses our investigations into development and application of microcrystal electron diffraction to solve small molecule structural problems in chemistry. The analysis of pharmaceuticals and natural products is described, and the application of an automated data processing procedure is explored. Chapter Four highlights an ongoing effort in our research group to create automated tools to make microcrystal electron diffraction a more practical and efficient tool for the elucidation of small molecule structures. The development of Python automation scripts for data collection and processing is discussed.

The union of transition metal catalysis with native biochemistry presents a powerful opportunity to perform abiotic reactions within complex biological systems. However, several chemical compatibility challenges associated with incorporating reactive metal centers into complex biological environments have hindered efforts in this area, despite the many opportunities it may present. More challenging than chemical compatibility is biocommunicative transition metal catalysis, where the reactivity of the metal species is regulated by native biological stimuli, akin to natural biocatalytic processes. This dissertation describes the discovery of Au(I)-bound metal-mediated base pairs (MMBPs) in pyrimidine mismatches. Additionally, the application of these Au(I)-DNA complexes as catalysts that are dependent on genetic information was shown. These Au(I)-DNA catalysts form fluorescent product in response to nucleic acid fragments and can be used to detect nucleic acids in complex biological matrices. Chapter One is a perspective on transition metal bound to RNA and DNA sequences. These complexes often possess nuclease-type activity in natural biological systems. However, there are some examples of researchers creating abiotic metalallo-nucleic acid complexes that are asymmetric catalysts, that exhibit sequence rate enhancing ligands, or in a few rare examples, are activated through addition of a specific sequence. Chapter Two details experimental and computational studies of Au(I) metal-mediated base pairs with all three pyrimidine mismatches. Au(I) is incorporated into DNA duplex and hairpin structures containing a C–C, C–T, and T–T mismatch leading increases in thermal stability, changes in circular dichroism, and mass adducts through mass spectrometry. The stable complexes formed through the addition of (Me2S)AuCl to these mismatches can be used in further applications in nanotechnology and biocatalysis. Chapter Three describes the activity of a Au(I)-DNA catalyst formed through a C–Au(I)–T metal-mediated base pair. This catalyst is composed of a DNA hairpin structure with a toehold sequence, to aid in hybridization, and a C–T mismatch in the stem. Once the Au(I) precursor is added, an inactive catalyst is formed. Only through hybridization does this catalyst become active, catalyzing the formation of a fluorescent BODIPY molecule through a Au(I)-catalyzed hydroamination reaction. This catalyst become active when hybridized to DNA or RNA complement and exhibits sequence selectivity for the nucleic acid analyte. Chapter Four outline the development of a Au(I)-DNA catalyst that exhibits turnover, unlike the previous catalyst system (Chapter Three). This catalyst, formed through a C–Au(I)–C metal-mediated base pair, catalyzes the formation of a fluorescent coumarin derivative through a Au(I)-catalyzed hydroarylation. The Au(I)-DNA catalyst or Au(I)-CAP (chemocatalytic amplification probe) with substrate, leads to significant increases in fluorescence, even at low nM concentrations of catalyst. This Au(I)-CAP system outperforms standard molecular beacon technology and works in complex biological systems, such as cell lysates and E. coli whole cells, leading to a fluorescent response. Chapter Five describes the use of a Au(I)-CAP that hybridizes to SARS-CoV-2 related nucleic acid fragments. Hairpins were designed such that they hybridize to either the viral RNA or viral cDNA of the N gene of the SARS-CoV-2 genome. These catalysts form a fluorescent coumarin product in response to the viral genetic information leading to detection levels in the low fM range. In addition, this can be paired with a nucleic acid amplification technique to detect less than 1 copy/ul of viral RNA or DNA. Finally, direct detection of viral RNA from heat-inactived virus in human saliva was achievable in this system.

This dissertation focuses on the development of catalytic Carbon to Carbon (C–C) bond forming reactions of dicoordinate carbocations. The unique reactivity described herein focuses on the use of ionizable groups and appropriate counter anions to facilitate productive reactions of high-energy cationic intermediates. The first chapter discusses the exploration of phenyl carbocations, generated from aryl fluorides under silylium-weakly coordinating anion (WCA) catalysis, in the context of hydrocarbon functionalization. Chapter two describes the discovery of C–H insertion and reductive Friedel-Crafts reactions of vinyl carbocations generated from vinyl triflates and silylium-WCA salts. Chapter three describes a novel approach to generating vinyl cations using Lithium Lewis acids. Interestingly, these vinyl carbocations are formed under basic conditions, with lithium hexamethyldisilazide (LiHMDS) as the Lewis acid precursor. Chapter four describes two new catalytic manifolds using urea-based organocatalysts. In one instance, the urea catalyst directly ionizes the vinyl triflate through a hydrogen-bonding interaction to promote intra molecular C–H insertion reactions. In another case, urea organocatalysts combined with LiHMDS, result in novel lithium-urea catalyst that promote Friedel-Crafts reactions of vinyl triflates. In summary, these studies have resulted in the development of new catalytic methods using main-group catalysis for the formation of C–C bonds.

This dissertation describes efforts to generate vinyl carbocation intermediates to leveragetheir high–reactivity, with a particular focus on subsequent C–H insertion reactions to forge new C–C bonds. These intermediates have historically been difficult to generate using catalytic regimes, but in doing so their reactivity can be controlled to give high-yielding methodologies. Additionally, efforts to search for new means to generate these intermediates often leads to discovery of novel reactivity. A variety of conditions have been developed to generate these intermediates that will be highlighted in five chapters of this thesis. An initial overview will be given to demonstrate how access to vinyl carbocations has steadily increased in the past decades, allowing for discovery of novel reactivity particularly highlighted by C–H functionalization. Then, efforts of my colleagues and myself are partitioned into four main categories related to the generation of vinyl carbocations and their subsequent reactivity. In the first chapter current state-of-the-art and previous methods of vinyl carbocation generation are reviewed to shed light on the massive amount of work already dedicated to producing these reactive intermediates. The second and third chapters cover the development of Br�nsted basic conditions to generate these intermediates. These chapters detail the surprising discovery of utilizing lithium hexamethyl disilazide, a strong base, to generate vinyl carbocations that subsequently undergo C–H insertion reactions to yield olefinic products. These chapters will describe how these new basic conditions allowed for heteroatom containing substrates and additionally allowed for the use of much more easily accessible urea catalysts. The fourth chapter describes electrochemical means to gain access to these intermediates primarily for nucleophilic fluorination to produce fluoro-olefins. This work was a direct result of the annoyance in needing to use strong Lewis acids; while still allowing fairly diverse substrates, these conditions drastically limited the types of reagents that could be utilized and overall limited the methodology. Instead, Lewis-acid free conditions utilizing electrodes to oxidize substrates to the vinyl carbocation intermediate were developed. Finally, the fifth chapter details ongoing efforts to generate vinyl carbocations paired with chiral counterions to yield enantioselective C–H insertion reactions as well as the future outlook on other issues to tackle in developing new methodology. This work required small incremental discoveries in both catalyst and substrate design, and in all it took four PhD students almost two years to gain high levels of enantio- and regio- selectivity.

This dissertation describes the investigation of reaction mechanisms involving short-lived carbocation and radical intermediates through the synergetic application of modern computational techniques and experimental validation. Density Functional Theory (DFT) and Molecular Dynamics (MD) simulations are employed as the primary computational methods to predict the behavior of those reactive intermediates and to gain insights into their various reaction pathways. Collaborative experiments with experimental groups are conducted to validate the computational results, enhancing the reliability and robustness of the computational findings. The dissertation is organized into two main sections. Chapters 1–6 mainly explore mechanistic investigations of nonclassical and vinyl carbocations, providing a comprehensive understanding of their properties and reactions. Chapters 7–8 focus on research involving radicals, analyzing their roles in site- and stereo-selective reactions.

Chapter 1 delves into Winstein-Trifan solvolysis using modern molecular dynamics techniques under the guidance of Professor Kendall N. Houk. The studies found that the solvolysis of exo-norbornyl brosylate accompanied by σ-bridging occurs in a dynamically concerted process, while endo-solvolysis happens in a dynamically stepwise fashion.

Chapters 2–5 provide comprehensive studies of C–H insertion and Friedel-Crafts reactions of vinyl carbocations. The collaborative mentorship of Professor Kendall N. Houk and Professor Hosea M. Nelson shaped these chapters. Chapters 2 and 3 describe the development of Li+-Ureide catalysis in the generation of vinyl carbocations from vinyl triflates and its impact on vinyl cation C–H insertion reactions. Chapter 4 discusses the formation of medium-sized rings through vinyl carbocation intermediates. Both computational and experimental studies revealed that canonical Friedel-Crafts reactions were involved in the process. Chapter 5 describes the electrochemical fluorination of vinyl boronates via donor-stabilized vinyl carbocation intermediates. DFT calculations were utilized to determine the oxidation potential of vinyl boronates, providing support for further experimental mechanistic studies.

Chapter 6 summarizes a collaborative work between the laboratories of Professor Kendall N. Houk and Professor Isaac J. Krauss. The Krauss lab observed an unusual mechanistic switch from homoallylation to cyclopropylcarbinylation of aldehydes. DFT calculations suggested that the origin of the mechanistic change was associated with carbocation stabilization by substituents. Experimental mechanistic studies were subsequently employed to corroborate the predicted reaction pathway.

Chapter 7 presents a joint research project between the laboratories of Professor Kendall N. Houk and Professor Jiannan Zhao. The Zhao group discovered a diastereoselective radical aminoacylation of olefins facilitated by N-heterocyclic carbene catalysis. Computations were performed to elucidate the full reaction pathway, revealing that the radical coupling step is the diastereoselectivity- and rate-determining step. Additionally, π–π interactions were found to be the origin of the selectivity. The computational findings were further validated by experimental studies.

Chapter 8 details a collaborative project between the laboratories of Professor Kendall N. Houk and Professor Massimo Bietti. The Bietti group carried out the site- and diastereo-selective oxygenation of unactivated C–H bonds in bicyclic and spirocyclic hydrocarbons containing cyclopropyl moieties using 3-ethyl-3-(trifluoromethyl)dioxiranes (ETFDO). DFT calculations were conducted to understand the underlying factors responsible for the selectivities. The calculations found that hyperconjugation effects originating from the Walsh orbital of the cyclopropane ring play a crucial role in the selective α-C−H bond oxidations. Additionally, the computational studies provided evidence of divergent radical and cationic pathways in the ETFDO oxygenations.