UCLA

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.