THE DEVELOPMENT OF A METAL-FREE CATALYTIC METHOD FOR THE SELECTIVE HYDROXYLATION OF ALIPHATIC C–H BONDS A DISSERTATION SUBMITTED TO THE DEPARTMENT OF CHEMISTRY AND THE COMMITTEE ON GRADUATE STUDIES OF STANFORD UNIVERSITY IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY Nichole Danielle Litvinas April 2010 © 2010 by Nichole Danielle Litvinas. All Rights Reserved. Re-distributed by Stanford University under license with the author. This work is licensed under a Creative Commons Attribution- Noncommercial 3.0 United States License. http://creativecommons.org/licenses/by-nc/3.0/us/ This dissertation is online at: http://purl.stanford.edu/qr271bk1476 ii I certify that I have read this dissertation and that, in my opinion, it is fully adequate in scope and quality as a dissertation for the degree of Doctor of Philosophy. Justin Du Bois, Primary Adviser I certify that I have read this dissertation and that, in my opinion, it is fully adequate in scope and quality as a dissertation for the degree of Doctor of Philosophy. Robert Waymouth I certify that I have read this dissertation and that, in my opinion, it is fully adequate in scope and quality as a dissertation for the degree of Doctor of Philosophy. Paul Wender Approved for the Stanford University Committee on Graduate Studies. Patricia J. Gumport, Vice Provost Graduate Education This signature page was generated electronically upon submission of this dissertation in electronic format. An original signed hard copy of the signature page is on file in University Archives. iii Dissertation Abstract The diversity and structural intricacies of molecules needed for pharmaceutical, biological, and materials applications have challenged chemists to develop transformative chemical processes that greatly facilitate small molecule synthesis. C–H Bond functionalization represents one such class of reaction types, and is a general problem for reaction discovery that has witnessed an explosion of interest within the past 10 years. Inspired largely by Nature’s ability to conduct site- and stereoselective C–H bond oxidation reactions, we have been driven to design small molecule catalysts that can emulate such processes. Our focus has taken aim at the problem of C–H bond hydroxylation, efforts that have yielded a novel, non-metal-based catalytic system for the selective oxidation of 3° C–H bonds. These findings contrast the large body of literature detailing C–H hydroxylation reactions through transition-metal mediated catalysis. 1,2,3-Benzoxathiazine-2,2-dioxide-based heterocycles have been shown to function as catalysts for C–H hydroxylation with H2O2 operating as the terminal oxidant. The evolution of this catalytic process, which capitalizes on the unique reactivity of an oxaziridine intermediate, was made possible using density functional theory to help guide reagent design. In addition, kinetic analysis of the stoichiometric oxygen-atom transfer reaction has provided insight into the principal features that influence oxaziridine reactivity. This information coupled with the discovery that reactions could be conducted under aqueous reaction conditions with H2O2 has resulted in a markedly improved process for 3° C–H hydroxylation. The reaction occurs stereospecifically and with predictable chemoselectivity in substrates possessing more than one 3° C–H center. The enhanced performance of this catalytic process has been ascribed to the hydrophobic aggregation of the benzoxathiazinane catalyst and hydrocarbon substrate, which serves to accelerate the kinetically slow hydroxylation event. iv Acknowledgements The production of this document is due in no small part to my family, friends, and coworkers at Stanford. I need to express my greatest gratitude to my advisor, Justin Du Bois, for patiently teaching me how to be a scientist. He taught me many things but most importantly to trust myself—a characteristic I never knew I was missing but that I had to develop to successfully complete this dissertation. My colleagues in the Du Bois group have been truly invaluable. Rose Conrad was a wonderful friend and mentor to me; she patiently guided through a rough first few years with lots of encouraging words. I am greatly indebted to Scott Wolckenhauer who was an excellent teacher and even better friend. I relied upon my classmates, Brian Andresen, John Mulcahy, and David Zalatan, for support and comfort as we tackled the many challenges of graduate school—I truly couldn’t have done it without them. The months spent writing this document would have been unbearable without Brian’s companionship. My most recent set of podmates, Dave Olson, Arun Thottumkara, and Mark Harvey, have been wonderful to work with. Research proposal writing was actually fun when they were around to brainstorm with me. I am lucky to have had many excellent mentors in the lab, particularly Alan Whitehead and Ben Brodsky. The Du Bois lab has always been a wonderful place to work. My friends at Stanford have been the best I have ever had and I am grateful to them for their support and companionship. Alicia Gutierrez, Ashley Jaworski, Brian Trantow, Mark Harvey, and Jay Fitzgerald can make me laugh like no one else. Finally, I am extremely grateful to my family, who has cautiously watched me go through tough times. My parents have done everything imaginable to support me and I can’t thank them enough. They have taught me what it means to be selfless and I hope I can pass that trait along someday. v Table of Contents Chapter 1. Catalytic Hydroxylation of C–H Bonds.........................................................1 1.1 Introduction .............................................................................................................1 1.2 Challenges and Goals in Developing C–H Hydroxylation Catalysts..................3 1.3 Hydroxylation Reactions in Nature .......................................................................4 1.4 Cytochrome P450 and Metalloenzyme Mimics ....................................................5 1.4.1 Cytochrome P450s ............................................................................................5 1.4.2 A Survey of “Outer-Sphere” Transition-Metal Catalyzed C–H Hydroxylation Methods ......................................................................................................................9 1.4.3 Summary of outer-sphere transition-metal catalyzed C–H hydroxylation methods ....................................................................................................................15 1.5 Flavin-Containing Monooxygnease and Organocatalytic C–H Hydroxylation16 1.5.1 Flavin-Containing Monooxygenase .................................................................16 1.5.2 A Survey of Potentially-Catalytic Organic Oxidation Methods .........................18 1.6 Conclusion ............................................................................................................33 Chapter 2. Benzoxathiazines for Selective O-Atom Transfer .....................................34 2.1 Introduction ...........................................................................................................34 2.1a Background.......................................................................................................34 2.1b Project Goals and Methods ..............................................................................37 2.2 Oxaziridine Synthesis...........................................................................................39 2.2a Heterocycle synthesis.......................................................................................40 2.2b Synthesis of expanded-ring benzoxathiazine-derived oxaziridines ..................42 2.2c Incorporation of aromatic substituents ..............................................................43 2.3 Overview of Computational Studies and Kinetics Analysis of Oxaziridines for Stoichiometric Epoxidation .......................................................................................46 2.3a DFT Calculations ..............................................................................................46 2.3b Kinetics method ................................................................................................48 2.4 Evaluation of benzoxathiazine-derived oxaziridines as stoichiometric oxidants .......................................................................................................................50 2.4a Heteroatom and the Heterocycle ......................................................................50 2.4b Heterocycle ring size ........................................................................................52 2.4c Halogenation of aromatic ring ...........................................................................54 vi 2.4d Hammett analysis .............................................................................................56 2.4e C5 modification .................................................................................................57 2.4 Conclusions ..........................................................................................................58 Chapter 3. A Catalytic Method for the Hydroxylation of C–H Bonds .......................100 3.1 Introduction .........................................................................................................100 3.2 Protocol A: Diaryldiselenide and Urea Hydrogen Peroxide............................101 3.2a Diaryldiselenides: background and synthesis.................................................101