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Title: Applications of Catalytically Generated Alkoxy Radicals in the Development of Novel Synthetic Methods
Authors: Tsui, Elaine
Advisors: Knowles, Robert R
Contributors: Chemistry Department
Keywords: alkoxy radical
methodology development
nucleophilic aromatic substitution
phenoxy radical
Subjects: Chemistry
Organic chemistry
Issue Date: 2022
Publisher: Princeton, NJ : Princeton University
Abstract: Alkoxy radicals have long been recognized as powerful synthetic intermediates with well-established reactivity patterns. Despite their versatility, these electrophilic oxygen-centered radicals are not always trivial to generate. Due to the high bond dissociation free energy of aliphatic alcohol O–H bonds, these radicals are difficult to access through direct homolysis, and conventional methods have instead relied on activation of O-functionalized precursors through thermolysis or UV photolysis. Over the past decade, however, numerous catalytic methods for the direct generation of alkoxy radicals from simple alcohol starting materials have emerged and created opportunities for the development of new transformations under mild reaction conditions.This dissertation discusses our group’s recent contributions in catalytic alkoxy radical generation, with particular emphasis on the use of proton-coupled electron transfer (PCET) for the direct activation of unfunctionalized alcohols, and describes three distinct applications of catalytically generated alkoxy radicals in organic synthesis. In Chapter 2, I describe the development of a catalytic, light-driven protocol for the intramolecular hydroetherification of unactivated alkenols to furnish cyclic ether products. This method relies on concerted PCET activation of the alkenol O–H bond in the presence of an Ir(III)-based photoredox catalyst, a Brønsted base catalyst, and a hydrogen atom transfer co-catalyst to generate the key alkoxy radical intermediate. Results demonstrating the extension of this catalytic system to carboetherification reactions are also presented. In Chapter 3, I highlight progress toward the intermolecular hydroetherification of unactivated alkenes. A proof-of-concept demonstration validates our hypothesis that PCET-activation of O–H bonds can be leveraged for the synthesis of anti-Markovnikov linear ethers, a class of products that remains challenging to access. Finally, in Chapter 4, I report a strategy for the remote activation of inert electrophiles, wherein generation of a transient phenoxy radical via stepwise PCET enhances the electrophilicity at a distal reaction site. This mode of activation was used to design a protocol for the nucleophilic aromatic substitution of halophenols. Taken together, these successful applications of alkoxy radicals in synthesis suggest that these radicals, and the methods for generating them, will continue to play consequential roles in organic chemistry.
Alternate format: The Mudd Manuscript Library retains one bound copy of each dissertation. Search for these copies in the library's main catalog:
Type of Material: Academic dissertations (Ph.D.)
Language: en
Appears in Collections:Chemistry

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