DEVELOPMENT OF PHOTOREDOX CATALYSIS-MEDIATED FUNCTIONALIZATION METHODS FOR ARENES AND OLEFINS Megan Elizabeth Schutzbach-Horton 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 2020 Approved by: David A. Nicewicz Jeffrey S. Johnson Abigail S. Knight Frank A. Leibfarth Marcey L. Waters © 2020 Megan Elizabeth Schutzbach-Horton ALL RIGHTS RESERVED ii ABSTRACT Megan Elizabeth Schutzbach-Horton: DEVELOPMENT OF PHOTOREDOX CATALYSIS- MEDIATED FUNCTIONALIZATION METHODS FOR ARENES AND OLEFINS (Under the direction of David A. Nicewicz) I. Introduction to Organic Photoredox Catalysis This chapter provides a brief discussion of relevant photophysical properties and the thermodynamics of photoinduced electron transfer. The development of acridinium ion catalysts and their use by our lab is also included. II. Development of Photoredox Catalysis-Mediated Methods for the Hydrofunctionalization of Glycals Efforts to-date on the development of glycal hydrofunctionalization methods using acridinium-mediated photoredox catalysis are summarized. This work includes data obtained by Heqing Sun on the use of exo-glycals as substrates in a hydroalkoxylation reaction. The latter portion of the chapter summarizes efforts towards the use of endo-glycals as substrates in a variety of hydrofunctionalization methods, including hydroamination and hydroalkoxylation reactions. III. Development of a Photoredox-Mediated Method for the Anti-Markovnikov Hydroazidation of Activated Olefins This chapter discusses the use of acridinium-mediated photoredox catalysis in the development of an anti-Markovnikov hydroazidation method that is complementary to existing work. Using mild conditions that feature the use of TMSN3 and TFE, we report the synthesis of 31 organic azides in yields ranging from 22 – 98%. iii IV. Development of a Method for the Nucleophilic Defluorination of Electron-Neutral and Electron-Rich Fluoroarenes In this chapter, the development of a general method for the use of electron-neutral and electron-rich fluoro(hetero)arenes as substrates in a CRA-SNAr reaction is discussed. Using both an acridinium catalyst, as well as a novel xanthylium catalyst, conditions were developed for 78 examples of nucleophilic defluorination in a manner that is complementary to existing SNAr chemistry. iv ACKNOWLEDGEMENTS The success of my graduate studies is the result of so many individuals beyond myself. I have had the privilege of interacting with so many incredible human beings over the course of my undergraduate/graduate studies and would be remiss if I didn’t acknowledge that support. First, I would like to thank my advisor, Dave Nicewicz, for the opportunity to work in his lab for the last five years. Dave: I cannot tell you how much I appreciate the opportunity to learn and grow as a scientist under your guidance. I appreciate your commitment to ensuring that I succeed and your support of my professional goals. To my committee: Thank you for your willingness to support me over the course of my graduate studies. I appreciate the guidance in terms of research, as well as professional matters. I am so incredibly thankful to find myself in a department that values graduate students as much as the Chemistry Department at UNC does. I can’t tell you how grateful I am for the greetings in the hallways, conversations in passing, and general interest in my well-being. Knowing that I have the support of so many incredible faculty members has made graduate school so much more bearable. To my coworkers: I am so grateful to have surrounded myself with all of you incredible scientists. When I first joined the lab, I was afraid that I wouldn’t fit in because everyone was so “normal”. That fear was soon put to rest when Cole Cruz convinced Cortney Cavanaugh to show me her velociraptor impersonation. Turns out, “normal” is vastly overrated. Everyone that I’ve interacted with over the years has brightened my world in so many ways. I am constantly in awe of the insane amount of talent that is possessed by the v members of the group, and I have appreciated all of the fruitful discussions I’ve had with colleagues over the years. I am so grateful for the love and support that you all have shown me over the last five years. Thank you for eating all of my gluten free baked goods and being good sports about being forced to draw for Secret Santa on November 1st. To my friends: There is no way that I would have made it through graduate school without your fierce friendship and support. You have been such incredible supporters along this crazy, bumpy road. To keep things short, I will simply say thank you again. Know that this accomplishment is as much yours as it is mine because each and every one of you believed in me when I couldn’t believe in myself. To my family: Mom and Dad, this is for you. Thank you for believing in me from the beginning and seeing me through the rough patches. Everyone thinks that you have to be a genius to go to graduate school, but the truth is that hard work and dedication get you so much farther than sheer intelligence. Thank you for teaching me how to work hard and see things through to the end. There is no doubt in my mind that all of my strengths and abilities were inherited from you, and I am so grateful for your love and support. Ben: Thank you for reminding me to laugh and that I will never be as smart as you. I find that I am constantly in need of your reminders to take myself less seriously and enjoy life. Matthew Charles: Thank you for finding me. I am so incredibly grateful for the opportunity to experience life with you. Your endless optimism and huge heart are a constant joy. Thank you for supporting me and giving me strength to tackle life’s challenges. There is no one else that I would rather be on this crazy adventure with. I love you endlessly. Graduate school has undoubtedly been the most challenging experience of my life thus far. If you had asked me during the early days (okay, pretty much any day), I would vi have sworn to you that I was always on the verge of failing out. But thanks to the support of my colleagues, friends, family, etc., I found the strength to push through. Special shout out to SSRI’s, buckets of coffee, and murder-related podcasts for helping me get by as well. SSDGM. vii PREFACE A portion of the work discussed in Chapter 2 was carried out by Heqing Sun, an alumnus of the Nicewicz group. Heqing carried out initial work on the functionalization of glycals with external olefins and preliminary investigations on substrates with internal olefins. His work provided extensive insight into the behavior of glycals in our acridinium- mediated hydrofunctionalization systems. I am grateful for all of the support he provided while at UNC and beyond. The work discussed in Chapter 3 was performed in collaboration with Nicholas Onuska and José Rosario Collazo. Nicholas and I worked on initial reaction optimization, and the three of us explored the substrate scope for this transformation. Chapter 4 was a collaboration with Vincent Pistritto. Vincent worked on the defluorination of electron-neutral fluoroarenes using pyrazole as a nucleophile, as well as the defluorination of electron-rich fluoro(hetero)arenes using nitrogenous nucleophiles. I had the privilege of exploring the scope of azole nucleophiles for the defluorination of electron- neutral fluoroarenes, as well as the defluorination of electron-rich fluoro(hetero)arenes using carboxylic acid nucleophiles. I dedicate this dissertation to every woman who was ever told that she would never succeed. “Nevertheless, she persisted” TABLE OF CONTENTS CHAPTER 1: INTRODUCTION TO ORGANIC PHOTOREDOX CATALYSIS ................ 1 1.1 Introduction ..................................................................................................................... 1 1.2 Organic Photoredox Catalysis Background .................................................................... 2 1.2.1 Photophysics of Organic Photoredox Catalysis ....................................................... 2 1.2.2 Exploring the Thermodynamics of Photoinduced Electron Transfer (PET) ............ 8 1.2.3 Use of Acridinium Salts as Organic Photoredox Catalysts.................................... 12 1.3 Prior Nicewicz Lab Work ............................................................................................. 20 1.3.1 Development of Olefin Hydrofunctionalization Reactions ................................... 20 1.3.2 Development of Cation-Radical-Accelerated Nucleophilic Aromatic Substitution Reactions ......................................................................................................................... 24 1.4 Conclusions ................................................................................................................... 26 CHAPTER 2: DEVELOPMENT OF PHOTOREDOX CATALYSIS-MEDIATED METHODS FOR THE HYDROFUNCTIONALIZATION OF GLYCALS ......................... 28 2.1 Introduction ................................................................................................................... 28 2.1.1 Glycosides and Their Importance .......................................................................... 28 2.1.2 Synthesis of Aminoglycosides via Polar Chemistry .............................................. 32 2.1.3 Synthesis of Deoxyglycosides via Polar Chemistry .............................................