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SELECTIVE C–H and ALKENE FUNCTIONALIZATION VIA ORGANIC PHOTOREDOX CATALYSIS Nicholas Paul Ralph Onuska a Dissertation Submitte

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SELECTIVE C–H and ALKENE FUNCTIONALIZATION VIA ORGANIC PHOTOREDOX CATALYSIS Nicholas Paul Ralph Onuska a Dissertation Submitte SELECTIVE C–H AND ALKENE FUNCTIONALIZATION VIA ORGANIC PHOTOREDOX CATALYSIS Nicholas Paul Ralph Onuska A dissertation submitted to the faculty at the University of North Carolina at Chapel Hill in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Chemistry Chapel Hill 2021 Approved by: David Nicewicz Erik Alexanian Jeffrey Aubé Alexander Miller Andrew Moran © 2021 Nicholas Paul Ralph Onuska ALL RIGHTS RESERVED ii ABSTRACT Nicholas Paul Ralph Onuska: Selective C–H and Alkene Functionalization Via Organic Photoredox Catalysis (Under the direction of David A. Nicewicz) Photoinduced electron transfer (PET) can be defined as the promotion of an electron transfer reaction through absorption of a photon by a reactive species in solution. Photoredox catalysis has leveraged previous knowledge of PET processes to enable a wide variety of high value chemical transformations. Most early work in the field of photoredox catalysis centered around the use of visible-light absorbing transition metal catalyst systems based on ruthenium or iridium polypyridyl scaffolds, organic redox chromophores offer a more sustainable, accessible, and versatile alternative to these complexes. Organic photoredox catalysts are often less expensive, easier to prepare, and have expanded redox windows relative to many known transition-metal photoredox catalysts, enabling the generation of a wider variety of single electron reduced/oxidized species. This ultimately translates into the development of previously undiscovered modes of reactivity. Herein is described the development and mechanistic study of a several C–H and alkene functionalization reactions facilitated by visible light-absorbing acridinium salts, as well as the discovery and characterization of a neutral organic radical which possess one of the most negative excited state oxidation potentials observed to date. Through single electron oxidation of protected secondary amines, the corresponding neutral alpha-carbamyl radical species may be generated and utilized in a formal carbon-carbon bond forming C–H functionalization reaction. Electron rich arenes are amenable to functionalization via net oxidative or redox neutral pathways using similar catalytic systems. iii Upon generation of an electrophilic arene cation radical through PET, diazoacetate derivatives undergo nucleophilic addition to these intermediates, affording formal C–H functionalization products containing a new sp3-sp2 carbon-carbon bond. Methods for the anti-Markovnikov functionalization of activated olefins are also accessible via photoredox catalysis. Acridinium salts are shown to serve as competent catalysts in electrophilic hydroazidation reactions of activated olefins in combination with a sterically hindered thiol hydrogen atom transfer catalyst. An investigation of the photophysical behavior of a neutral acridine is presented. A combined spectroscopic, computational, and experimental study suggests excitation of this species leads to the population of several extremely reducing doublet excited states. The in situ generation and excitation of this species enables a variety of catalytic reductive photoredox transformations. iv TABLE OF CONTENTS LIST OF FIGURES ....................................................................................................................... ix LIST OF ABBREVIATIONS ...................................................................................................... xiv Chapter 1 : ORGANIC PHOTOREDOX CATALYSIS ................................................................ 1 1.1: Introduction .......................................................................................................................... 1 1.2: Photoinduced Electron Transfer ........................................................................................... 2 1.3: Organic Photoredox Catalysts .............................................................................................. 4 Chapter 2 : GENERATION AND TRAPPING OF α-CARBAMYL RADICALS VIA ORGANIC PHOTOREDOX CATALYSIS ................................................................................... 6 2.1: Introduction .......................................................................................................................... 6 2.1: Reaction Discovery and Optimization ............................................................................... 13 2.3: Scope of Photoredox C–H Alkylation Reaction ................................................................ 18 2.4: Mechanistic Studies and Application to Natural Product Synthesis .................................. 21 Chapter 3 : ANTI-MARKOVNIKOV HYDROAZIDATION OF ACTIVATED OLEFINS VIA ORGANIC PHOTOREDOX CATALYSIS ........................................................ 26 3.1: Markovnikov and Anti-Markovnikov Alkene Functionalization ...................................... 26 3.2: Introduction to Organic Azides .......................................................................................... 29 3.3: Reaction Discovery and Optimization ............................................................................... 31 3.4: Scope of Photoredox anti-Markovnikov Hydroazidation Reaction ................................... 34 3.5: Results and Discussion ....................................................................................................... 37 Chapter 4 : REGIOSELECTIVE ARENE C–H ALKYLATION VIA ORGANIC PHOTOREDOX CATALYSIS .................................................................................................... 38 4.1: Introduction to Arene C–H Functionalization .................................................................... 38 v 4.2: Introduction to C–H Alkylation Reactions Involving Diazoacetate and Diazoacetate Derived Intermediates ............................................................................................................... 46 4.3: Photoredox Catalysis and Diazoalkanes ............................................................................ 47 4.4: Reaction Discovery and Optimization ............................................................................... 49 4.5: Scope of Photoredox C–H Alkylation Reaction ................................................................ 50 4.5: Mechanistic and Computational Studies ............................................................................ 52 Chapter 5 : DISCOVERY AND CHARACTERIZATION OF ACRIDINE RADICAL PHOTOREDUCTANTS ............................................................................................................... 58 5.1: Introduction ........................................................................................................................ 58 5.2: Approaches Towards Net Reductive Photoredox Catalysis ............................................... 59 5.3: Neutral Organic Radicals as Excited State Reducing Agents ............................................ 63 5.4: Acridine Radicals as Potent Excited State Reducing Agents ............................................. 66 5.5: Computational Investigation of Mes-Acr• Photophysics ................................................... 67 5.6: Transient Absorption Study of Mes-Acr• Photophysics .................................................... 70 5.6: Development of Reductive Transformations Facilitated by Mes-Acr• .............................. 72 5.7: Scope of Reductive Reactions Facilitated by Photoexcited Mes-Acr• .............................. 74 APPENDIX A: SUPPORTING INFORMATION FOR “GENERATION AND TRAPPING OF α-CARBAMYL RADICALS VIA ORGANIC PHOTOREDOX CATALYSIS” ............................................................................................................................... 80 A.1: General Information .......................................................................................................... 80 A.2: Electrochemical Data ........................................................................................................ 81 A.3: Synthesis and Characterization of Catalyst and Substrates: .............................................. 84 A.4: Reaction Optimization ....................................................................................................... 92 A.5: Procedure and Data for Product Synthesis ........................................................................ 93 A.6: Stern Volmer Analysis .................................................................................................... 112 A.7: Photochemical Quantum Yield (Φr) Determination: ...................................................... 115 vi A.8: Large Scale Flow Synthesis of tert-butyl (R)-(3,3-dicyano-2- phenylpropyl)(phenyl)carbamate ............................................................................................ 117 A.9: Computational Details: .................................................................................................... 118 A.10: NMR Spectra for New Compounds .............................................................................. 121 APPENDIX B: SUPPORTING INFORMATION FOR “ANTI-MARKOVNIKOV HYDROAZIDATION OF ACTIVATED OLEFINS VIA ORGANIC PHOTOREDOX CATALYSIS” ............................................................................................................................. 122 B.1: General Information ........................................................................................................ 122 B.2: Catalyst and Substrate Synthesis: ...................................................................................
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