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View/Open: Melzer Georgetown 0076D 10282 NEW INSIGHTS INTO THE ROLES OF METALS IN NITRIC OXIDE DELIVERY A Dissertation submitted to the Faculty of the Graduate School of Arts and Sciences of Georgetown University in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Chemistry By Marie M. Melzer, B.S. University of North Carolina at Charlotte Washington , DC April 29, 2009 NEW INSIGHTS INTO THE ROLES OF METALS IN NITRIC OXIDE DELIVERY Marie M. Melzer, B.S. Thesis Advisor: Timothy H. Warren, Ph.D. Abstract The biochemistry of organic nitroso compounds (E-NO, E = RS, RO, R2N, R) is connected to that of nitric oxide. These organic derivatives can serve either as sources of NO in vivo or produce similar effects as NO such as vasodilation. In contrast to free NO, these organic derivatives are stable towards dioxygen. Release of NO from many organonitroso compounds requires a reducing equivalent, implicating redox active metalloenzymes. Thus in many cases the “stored” NO in its carrier molecules has to go through certain release-and-capture cycles to execute its various biological functions. The transport of NO in biological systems is via S-nitrosothiols, part of sulfur-containing proteins. Employing monovalent nickel and copper beta-diketiminates and tris(pyrazolyl)- borates as models for these metal ions in metalloenzymes, we find that the E-NO bonds of O-nitroso (RO-NO), N-nitroso compounds (R2N-NO), and S-nitroso (RS-NO) are readily cleaved to form well defined metal complexes [Ni](II)-E. In the case of the most biologically relevant Cu complexes, we observe an important contrast to all previously studied systems in which [Cu](II)-E species are reductively cleaved by NO to give the organonitroso compounds E-NO. The NO released in the nickel system binds with an extra equivalent of Ni(I) to form [Ni]-NO. For copper chemistry the fate of the NO ii depends on the ligand system used. Copper beta-diketiminate products are decomposed and copper tris(pyrazolyl)borate nitrosyls [Cu](NO) are observed. Copper(I) N-heterocylic carbene complexes are less electron-rich and do not activate the S-NO bond. Rather, we have shown that copper can have a role in the formation of the S-NO bond through trans-s-nitrosation as well as nitrosonium addition to the copper(I) thiolate [Cu]-SR. This work has provided of insight into the biochemistry of NO and the role of metals in E-NO bond cleavage and formation. iii Acknowledgments My experience in graduate school has been one of intense learning and growth. Not only have I gained a wide array of scientific skills, I walk away with analytical and problem solving skills that can only come through many years of scientific research. There are many people who have walked alongside me through this journey. I am forever thankful and in debt to their support (and too often patience!). It was an honor and privilege to work for Professor Timothy Warren the past five years. Not only is he a brilliant scientist, gifted teacher, and probably the most patient man I have ever met, he genuinely cares about the well-being and success of each of his students on a personal level. As a person who values family, I could not have asked to work for a more supportive boss when it came to time with family. Over the past five years, I have had several family commitments and emergencies, and Tim always gave me his full support in dealing with these issues. I aspire to be the kind of leader and mentor that Tim was to me. I would like to thank the members of my committee, Professor Bahram Moasser, Professor Steven Metallo, and Professor Toshiko Ichiye for their assistance and dedication to my Ph.D. journey. Your thoughts, comments, questions, and suggestions during my Phase 2A and Phase 2B were most appreciated and helpful in my graduate school experience. I would especially like to thank Bahram for his assistance with my kinetic questions.Kim Yearick Spangler, Dr. Yosra Badiei, and Matthew Varonka were my daily sanity throughout these past five years. The company of good friends and laughter helped me not to take life and chemistry too seriously. I could not have made iv this journey without you there and I will miss each of you tremendously. To Stefan Wiese, thank you for being a patient glovebox mate with my mess and vials everywhere. You were truly someone enjoyable to work alongside. To my undergraduate student Ashley Bartell and Project SEED student Corwin Ward, thank you for your enthusiasm and assistance on the nitrosamine project. I appreciate assistance from Professor K. Travis Holman (X-ray structures) and Dr. Ercheng Li (VT 1H and 15N high field NMR studies). The office staff: Kay Bayne, Inez Traylor and Travis Hall have made the business side of graduate school much more amenable. Finally, I would like to thank my family, Mom, Dad, Suzi and Rich Melzer, my sisters Jessica, Jocelyn, Allie, Gabrielle, and Miriam, my brother Chuck, my sister in- laws Sarah and Joanna, my brother in-law Tom, my nephews Brent and Michael, and my precious nieces Chloe and Montana. The experience of graduate school is not one walked alone. I appreciate everything that you have done for me along the way to encourage me to reach my goals. Last, but most importantly, I would like to thank my husband Jonathan Melzer for his unconditional love and friendship. You are the most important thing in my life and I could not have made it without you. Thank you for being there for me when I was sad and frustrated, thank you for your support during the busy final months of completion, and thank you for making me feel like the most loved woman in the world. I hope to have many more life experiences with you by my side. v Respective Contributions Dr. Susanne Meyer from Professor Karsten Meyer’s research at the University of Erlangen-Nürnberg performed in depth EPR analyses and simulation studies for several II I compounds, [Me2NN]Cu (ON-Me2NN)2Cu (1), [Me2NN]Cu-NPh2 (2), [Me2NN]Cu- 15 NPh2 (2'), [Me2NN]Cu-I (3) (Figures 2.8, 2.13, and 2.14). vi Table of Contents Title……………………………………………………………..…………………………i Abstract…………………………………..……….………………………………....…...ii Acknowledgements……………………………………………..…………………….....iv Respective Contributions…………………………………………….…………………vi Table of Contents……………...………………………………..……………………....vii General Introduction Organonitroso Compounds: N-nitrosoamines, O-nitrosoalcohols, S-nitrosothiols; Biological Activities, Chemical Properties, and Interactions with Metals…………………………………………………………………………...…………1 Abstract….………...........................................…………….....……………..…..……1 Introduction….................................................…………….....……………….....……1 I.1.a. N-Nitrosamines (R2NNOs) - biological applications..…...……..…......….... 3 I.1.b. N-Nitrosamines – syntheses….………………….....…………..…........……4 I.1.c. N-Nitrosamines - chemical properties….……………………....…….…..…5 I.2.a. O-Nitrosoalcohols (RONOs) - biological applications….…...……..…..…...6 I.2.b. O-Nitrosoalcohols – syntheses….…………….…….....…….......…..……...8 I.2.c. O-Nitrosoalcohols – chemical properties….………..….……...……..……..8 I.3.a. S-Nitrosothiols (RSNOs) - biological applications……………......…..…...11 I.3.b. S-Nitrosothiols – syntheses….…...………….......……………...…..……...13 I.3.c. S-Nitrosothiols - chemical properties….….…………….....………..……..13 I.4.a. N-nitrosamines - complexes with metals….…...…….…...……...…..…….19 vii I.4.b. O-Nitrosoalcohols and S-Nitrosothiols - complexes with metals……...…..21 Chapter 1 Reductive Cleavage of O-, S-, N-Organonitroso Compounds by Nickel(I) β- Dketiminates...…………………………………………………………………………...30 Abstract………………….……….…………………………………….……......…..30 Introduction………………..…………………………………..……….……............30 Results and Discussion……………...……………………………….……………...33 1.1. Reaction of [Me3NN]Ni(2,4-lutidine) with CyONO or AdSNO…..…..........33 1.2. Reaction of [Me3NN]Ni(2,4-lutidine) with Ph2NNO……………...…..……34 1.3. Independent synthesis of [Me3NN]Ni-NPh2 and reactivity with 2,4- lutidine………………..…………………………………..……….……..............35 1.4. Electronic properties of [Me3NN]Ni-NPh2. …………...……………............40 1.5. Mechanistic considerations…………………………………….……............44 Summary…………………………………………………………………...….……..46 Experimental Procedures…………………………………………………..………...53 References…………………………………………………………………...….........66 Chapter 2 A Three Coordinate Copper(II)-Amide from Reductive Cleavage of a Nitrosamine……………….……………...………………………………………………69 Abstract..………………………………………………………….……………........69 Introduction………………..…………………………………..……….……............69 Results and Discussion……………...……………………………….……………...74 II I 2.1. Synthesis and characterization of [Me2NN]Cu (ON-Me2NN)2Cu .........…...74 2.2. Isolation of [Me2NN]Cu-NPh2 from reaction mixture………………............78 viii 2.3. Independent synthesis of [Me2NN]Cu-NPh2..………………......…………..79 2.4. Electronic properties of [Me2NN]Cu-NPh2.……...…………......…………..86 2.5. Reaction of {[Me2AI]Cu}2 + Ph2NNO..……...…………......……………….88 t 2.6. Reaction of {[Me2AI]Cu}2 + xs BuONO..……...…………......……………89 2.7. Electronic differences between {[Me2NN]Cu}2 and {[Me2AI]Cu}2….…….92 Summary…………………………………………………………………...….……..94 Experimental Procedures…………………………………………………..………...97 References…………………………………………………………………...….......114 Chapter 3 Release of NO from S-nitrosothiols and Organic Nitrites at a β-Diketiminato Copper(I) Complex ………….……………...……………………………………….....118 Abstract..………………………………………………………….……………......118 Introduction..………………………………………………………………..….......118 Results and Discussion……………...……………………………….………….....125 t 3.1. Reaction of BuONO with {[Me2NN]Cu}2. …..…………….…………......125 t
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