Radical Reactivity via Transient Carbon Dioxide Radical Anion (CO2•−) Open Access

Abstract

Single electron reduction is a straightforward pathway towards the formation of valuable radical intermediates from electron poor substrates. Visible-light photoredox catalysis has transpired at the forefront of single electron chemistry over the past decade owing to its exceedingly mild energetic requirements and its ability to promote unprecedented carbon-carbon and carbon- heteroatom bond formations. However, a variety of valuable radical precursors extend beyond the energetic limits of traditional photoredox catalysts. We have developed an alternative method towards single electron reduction that relies on the carbon dioxide radical anion (CO2•−) as a powerful single electron reductant (E°1/2= -2.21 V vs SCE). We generate CO2•− through a hydrogen atom transfer (HAT) between formate and a thiol HAT catalyst. In addition to reduction, we found CO2•− undergoes radical conjugate addition with electron deficient olefins that have more negative reductions potentials to form the corresponding carboxylated products. Following these initial discoveries detailed in chapter 2, we exploit the highly reducing nature of CO2•− towards a variety of reductive transformations that enable unique carbon-carbon bond formations. The CO2•− system enabled highly selective 5-exo radical cyclizations from bromopyridines which was demonstrated in conjunction with a method to selectively form the 6-endo product. The selectivity was controlled through the choice of HAT catalyst. Last, we report a method developed for the coupling of difluorobenzylic radicals with N,N-dialkylhydrazones to form unique b-difluorobenzylic hydrazines. 

Table of Contents

Chapter 1: Introduction to Single Electron Reduction and Photoredox Catalysis 1

1.1 Single Electron Reduction in Organic Synthesis 2

1.1.1 Single Electron Reduction 2

1.1.2 Halogen Atom Abstraction (XAT) 3

1.2 Photoredox Catalysis 5

1.2.1 General Principles of Photoredox Catalysis 5

1.2.2 Single Electron Reduction via Photoredox Catalysis 8

1.2.3 Photoredox Catalysis in the Jui Lab 8

1.3 References 13

Chapter 2: Discovery of the Carbon Dioxide Radical Anion (CO2•−) as a Potent Single Electron Reductant and Carboxylating Agent 17

2.1 Introduction 18

2.1.1 Single Electron Reduction 18

2.1.2 Carbon Dioxide Radical Anion (CO2•−) 19

2.2 Results and Discussion 22

2.2.1 Discovery of the CO2•−as a Nucleophilic Carboxylating Reagent 22

2.2.2 Optimization of the Carboxylation of Michael Acceptors 24

2.2.3 Mechanistic Investigations of Carboxylation Reaction 25

2.2.4 Carboxylation of Michael Acceptors Scope 27

2.2.5 Mechanistic Investigations of CO2•− Reduction 29

2.2.6 Scope of Reactivity Enabled by CO2•− Reduction 32

2.2.7 Divergent Reactivity of CO2•− 35

2.3 Conclusions 37

2.4 References 38

2.5 Supporting Information 42

2.5.1 General Information 42

2.5.2 Optimization of Carboxylation of Michael Acceptors 44

2.5.3 Optimization of Hydrodechlorination with CO2•− 44

2.5.4 Preparation of Starting Materials 47

2.5.5 Preparation of Products from Substrate Tables 58

2.5.6 Initial Discovery of Carboxylation of Michael Acceptors 83

2.5.7 Investigation into other Formyl C–H Reagents 84

2.5.8 Alternative Initiators 86

2.5.9 Fluorescence Quenching Experiments 87

2.5.10 Transient Absorption Spectroscopy 88

2.5.11 Quantum Yield Experiment 92

2.5.12 Chain Length Approximation 94

2.5.13 Calculated Reduction Potentials 95

2.5.14 Electrochemical Measurements 96

2.5.15 Supporting Information References 100

Chapter 3: Reagent Controlled Regioselective Formation of 6-endo or 5-exo Reductive Radical Cyclizations 106

3.1 Introduction 107

3.2 Results and Discussion 111

3.2.1 Optimization of 5-exo and 6-endo Radical Cyclizations 111

3.2.2 Scope of 5-exo and 6-endo Radical Cyclizations 113

3.2.3 Mechanistic Investigations 115

3.3 Conclusions 118

3.4 References 119

3.5 Supporting Information 123

3.5.1 General Information 123

3.5.2 General Procedures 125

3.5.3 Optimization Details 126

3.5.4 Preparation of Starting Materials 129

3.5.5 Preparation of Products from Substrate Table 143

3.5.6 Hantzsch Ester Solubility Experiment 161

3.5.7 Investigation of Non-Heteroaryl Substrates 162

3.5.8 Supporting Information References 163

Chapter 4: Defluoroalkylation of Trifluoromethylarenes with N,N- dialkylhydrazones: Rapid Access to Benzylic Difluoroarylethylamines 165

4.1 Introduction 166

4.2 Results and Discussion 171

4.2.1 Optimization of Defluoroalkylation with CF3-arenes 171

4.2.2 Scope of Defluoroalkylation with CF3-arenes 172

4.2.3 Proposed Mechanism 175

4.2.4 N–N Bond Cleavage 177

4.2.5 Carboxylation of N-acyl Hydrazones with CO2•− 177

4.3 Conclusion 179

4.4 References 180

4.5 Supporting Information 183

4.5.1 General Information 183

4.5.2 Optimization Details 184

4.5.3 Preparation of Starting Materials 186

4.5.4 Preparation of Products from Substrate Scope 197

4.5.5 Nitrogen-Nitrogen Bond Cleavage 226

4.5.6 Alternative Initiators 227

4.5.7 Carboxylation of N-Acyl Hydrazone 227

4.5.8 Supporting Information References 228 

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School	Laney Graduate School
Department	Chemistry
Degree	Ph.D.
Submission	Dissertation
Language	English
Research Field	Chemistry, Organic
Keyword	methodology single electron reduction carbon dioxide radical anion visible light catalysis radical reactivity
Committee Chair / Thesis Advisor	Blakey, Simon , Emory University
Committee Members	Liotta, Dennis , Emory University Wuest, William , Emory University

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