Functionalization of Arenes, Amines, Alkenes, and Alkynes Mediated by Radical Pathways Dissertation Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Stacy C. Fosu Graduate Program in Chemistry The Ohio State University 2019 Dissertation Committee Prof. David Nagib, Advisor Prof. Dehua Pei Prof. Christo Sevov Copyrighted by Stacy C. Fosu 2019 2 Abstract Efficiently building molecular complexity has always been a long-standing problem in organic synthesis. To intricately stitch organic fragments together to construct valuable cores necessitates the appropriate handles. Classically, the synthesis of complex molecules such as natural products or pharmaceuticals usually requires utilizing pre-functionalized building blocks at the beginning of the synthesis to allow for later functional group manipulation to achieve the construction of the desired product. Diversifying complex organic molecules, such as natural products, becomes a slow and iterative process as the synthesis of new compounds relies heavily on functional group interconversion. Although carbon-hydrogen bonds are ubiquitous in organic molecules, due to their inert nature, these bonds are often not utilized as handles for functional group installation. With C-H bond functionalization, an otherwise inert C-H bond can be transformed into a C-X bond (where X is a non-hydrogen atom). C-H bond functionalization strategies allows otherwise lengthy synthetic processes to be streamlined. Inspired by one of the earliest approaches to C- H bond functionalization, we sought to improve upon and develop other functionalization protocols which utilize the powerful nature of radicals. The research herein describes four novel methods to construct valuable cores through the functionalization of arenes, amines, alkenes, and alkynes using open-shell intermediates. The first method describes a convenient C-H functionalization methodology to install halides and pseudohalides on arenes and heteroarenes. The synthetic utility of nitrogen-centered radicals to afford selective amination and amino-functionalization will be outlined further. Coupling of aldehydes to π-systems to build unique atom-transfer products will also be discussed. i Dedication I dedicate this to all who have helped me along the way. ii Acknowledgments I would like to acknowledge my family, friends, and labmates. I could not have done this without your continual support. First and foremost, I would like to thank my parents, Joseph and Regina for all the sacrifices that they have made for me. I know at times there were struggles, but you both always did what you thought was the best for your children, and what you thought was best for me. Thank you for making the trek all the way to America to give me the chance to have an education that might not have otherwise been possible. Thank you for leaving behind everything that you knew to give your children the opportunity to have a successful life. For all the sacrifices that you two have made that I cannot even imagine, I will always be forever grateful and will never take my degree for granted. I would also like to extend my gratitude to my Father Uncle Philip for always caring so much about me, for all the words of encouragement throughout the years, and for truly being a second father to me. I’m also appreciative of all my sisters and brothers, Getty, Joseph, Ronald, and Linda, for always looking out for their baby sister. Thank you to Christina for letting me call you at odd hours of the night and for the countless voicemail messages. Thank you, Abby, for letting me unleash my frustrations to you and for all your impromptu weekend visits to Columbus to cheer me up. Thank you, George, Hannah, and the kids for always making me feel at home. I can never get enough of your homecooked meals, Hannah. Thank you, Anthony, for always being a shoulder to lean on and for absolutely everything. I wish to acknowledge financial support that I have received throughout my PhD program. I am grateful for The Ohio State University Graduate School for my Graduate Enrichment Fellowship during my first year and for the Chemistry-Biology Interface Training Program for my fellowship during my second year. I am very grateful to the iii Howard Hughes Medical Institute for funding me for the last three years of my program through the Gilliam Fellowship. I am grateful for all the people that I have met through HHMI, all the places I have been able to go, and all the opportunities that HHMI has opened up for me. I would also like to take the opportunity to thank everyone that I had the pleasure of working with involving outreach activities. Thanks to Michelle for all her hard work with Scientific Thinkers. Thanks to all the kids at Innis and Mansion Day for making my Tuesdays and Thursdays a little bit brighter for the past four years. Thanks Angie, for being ‘the guy’ with all the stuff that I could ever need for outreach events. Thanks Marcela for being a champion for minorities in STEM. Thanks Jennifer for always having an answer or being able to point me in the right direction whenever I had a question. Thanks Susan for letting me knock on your door countless times and always having your chocolate dish stocked with goodies. I truly appreciate all the advice and support from Prof. Timothy Lash and for really being the first one to give me the opportunity to do organic chemistry research and showing me what it is like to truly love your career. Thank you, David for teaching me that it is okay to take chances sometimes. Thanks for your guidance and critiques to make me a better scientist. I would also like to thank all my labmates past and present. All of this work would not have been possible without the never-ending encouragement and advice of my labmates. Thanks Deyaa for being there with me from the beginning through the whole graduate school application process. Even though we went to different schools, it was still comforting to know we were going through the same obstacles even if we were in different locations. Mathieu, I will always appreciate ‘the wheel.’ May everyone always spin 100%. My dearest Avassaya, my TLC chamber is always waiting for you. Thank you for being my column conversation partner. Thank you Zuxiao for being a great example of working efficiently. Thanks Leah for being an awesome lifetime labmate. I have thoroughly enjoyed working alongside you teaching kiddos and starting organizations. I’m grateful to Q for being a great hood neighbor. You were always there with a good movie recommendation iv or some aqua regia. Thanks Joy for revealing your secret ability to sell anything, now I know who to call. I appreciate all our little talks Ray and will always treasure them. Thanks for being a trooper whenever we gave you a hard time. My dear Prusinowski, you may use my balance once I’m gone. James, I don’t care what other people say, you’re not a traitor to me. Melissa, thank you for being the best story-teller ever and making my first-year so enjoyable. Alyson, Ross, and Shania it was a pleasure to work with you all during my last year. I wish to thank various colleagues who I like to call dear friends that have worked tirelessly on multiple projects with me. Ethan, you were a great person to work with on our lab’s first paper. And thanks for being an awesome hood and desk neighbor in Evans and CBEC. Thanks for always being willing to talk through chemistry problems with me and your creative solutions. Thank you Kohki for your perseverance, hard work, and dedication. I’m always amazed by how hard and efficiently you work. And bless you. Thanks to Chido for her unwavering persistence and willpower. I appreciate your never- ending work ethic and determination to finish things. Thanks Andrew for all the computational work that you have done as well as our late-night “pep-talks.” To Lu, it has been truly incredible to know you, and thank you for all the hard work that you have done. I am truly privileged to have worked alongside you. In the same vein, I will always be grateful to Jeremy and Sean for all the hard work that they put into team ketyl. Jeremy, I will always treasure our Rhode Island Gordon and getting lost in San Francisco. Sean, I will always truly appreciate your honesty. Thank you for always having my back. I absolutely would not have been able to get through this all without the three remarkable scientists that I began this journey with. We have all been through a lot together and I could not imagine going through all five years of grad school with any other guys. Ethan, Kohki, and Jeremy-thank you. Once again, I am truly indebted to all who have supported me in one way or another throughout this process. v Vita 2011………………......……B.S. Chemistry, University of Illinois at Urbana-Champaign 2014…................……………………………….M.S. Chemistry, Illinois State University Thesis: “Synthesis of Benziporphyrin Analogs and Carbaporphyrinoid Systems” 2014 – 2015.……...…….………….……...…………………Graduate Enrichment Fellow Department of Chemistry and Biochemistry, The Ohio State University 2015 – 2016…………..…………….… Chemistry and Biology Interface Program Fellow Department of Chemistry and Biochemistry, The Ohio State University 2016 – present……..……….…….……Howard Hughes Medical Institute Gilliam Fellow Department of Chemistry and Biochemistry, The Ohio State University Publications Fosu, S. C.†; Hambira, C. M.†; Chen, A. D.; Fuchs, J. R.; Nagib, D. A. “In situ Iodane Activation Enables Site-Selective C-H Functionalization of (Hetero)arenes.” Chem, 2019, 5, 417 – 428 Fosu, S.