Florida State University Libraries Electronic Theses, Treatises and Dissertations The Graduate School 2012 Development of Copper(II)-Mediated Azide-Alkyne Cycloaddition Reactions Using Chelating Azides Wendy S. Brotherton Follow this and additional works at the FSU Digital Library. For more information, please contact [email protected] THE FLORIDA STATE UNIVERSITY COLLEGE OF ARTS AND SCIENCES DEVELOPMENT OF COPPER(II)-MEDIATED AZIDE-ALKYNE CYCLOADDITION REACTIONS USING CHELATING AZIDES By WENDY S. BROTHERTON A Dissertation submitted to the Department of Chemistry and Biochemistry in partial fulfillment of the requirements for the degree of Doctor of Philosophy Degree Awarded: Spring Semester, 2012 Wendy S. Brotherton defended this dissertation on December 8, 2011. The members of the supervisory committee were: Lei Zhu Professor Directing Dissertation P. Bryant Chase University Representative Gregory B. Dudley Committee Member Igor V. Alabugin Committee Member Michael G. Roper Committee Member The Graduate School has verified and approved the above-named committee members, and certifies that the dissertation has been approved in accordance with university requirements. ii This manuscript is dedicated to my mother for all of her encouragement and sacrifices over the many years of my education. I would also like to dedicate this to my fiancé, Travis Ambrose, who has been so supportive and encouraging throughout this entire process. iii ACKNOWLEDGEMENTS I would like to thank Professor Lei Zhu for his guidance, support and assistance over the course of my graduate studies. I would like to express my gratitude to the past and present members of the Zhu group for their support and friendship over the years: Dr. Lu Zhang, Dr. Guichao Kuang, Dr. Pampa Guha, Dr. Sreenath Kesavapillai, Heather Michaels, Ali Younes, and Tyler Simmons. I also would like to thank a very talented undergraduate student, Lisa Stankee, for her assistance. I owe significant thanks to Dr. Clark and his excellent crystallography skills. I would also like to thank him for his guidance/advice regarding crystals and their growth. Thank you to Dr. Dalal and Dr. Shatruk for your roles in understanding the properties of the generated compounds and for the helpful advice and discussions. I would like to thank various people within the chemistry department that have provided training and guidance on different machines/techniques: Hank Hendricks, Umesh Goli, Steve Freitag and Doris Terry. Thank you to my friends and colleagues for their support and advice, specifically Kerry Gilmore, Mioara Larion, Supriya Mathur, and Amy McKenna. Lastly, thank you to my family and Travis for providing constant support and encouragement. iv TABLE OF CONTENTS List of Tables ................................................................................................................ ix List of Figures .............................................................................................................. xi List of Abbreviations ................................................................................................. xxii Abstract ...................................................................................................................... xxv 1. CHAPTER ONE. INTRODUCTION TO THE COPPER(I)-CATALYZED AZIDE- ALKYNE CYCLOADDITION REACTION ............................................................ 1 1.1 Click Chemistry .................................................................................................. 1 1.2 The Philosophy of Click Chemistry .................................................................. 2 1.3 Click Reactions ................................................................................................... 3 1.3.1 Cycloaddition Reactions ....................................................................................... 4 1.4 Copper(I)-Catalyzed Azide-Alkyne Cycloaddition (CuAAC) ............................ 5 1.4.1 εeldal’s Copper(I)-Catalyzed Synthesis of Peptidotriazoles ................................ 5 1.4.2 Sharpless’ Work on Cu(I) Catalyzed Azide-Alkyne Cycloaddition ........................ 7 1.5 Mechanism of CuAAC Reaction ........................................................................ 9 1.6 Assisting Ligands with the CuAAC ................................................................. 10 1.7 Selected Applications of CuAAC .................................................................... 11 1.7.1 Synthesis of Small-Molecule Libraries for Drug Discovery ................................. 12 1.7.2 Bioconjugation .................................................................................................... 13 1.7.3 Materials Chemistry ............................................................................................ 15 1.7.4 Coordination Chemistry ...................................................................................... 16 1.8 Origin of Present Work .................................................................................... 18 2. CHAPTER TWO. APPARENT COPPER(II)-ACCELERATED AZIDE-ALKYNE CYCLOADDITION (AAC) .................................................................................. 20 v 2.1 Summary ........................................................................................................... 20 2.2 Common Copper(I) Source .............................................................................. 20 2.2.1 Other Copper Sources ........................................................................................ 21 Cu(I)-halide salts ................................................................................................ 21 Cu(0) and Cu(0)/Cu(II) combinations .................................................................. 21 Copper nanoparticles ......................................................................................... 22 Copper on immobile phases ............................................................................... 22 Direct Cu(II) catalysis ......................................................................................... 23 2.3 Cu(II) Reduction in Alcoholic Solvents ........................................................... 23 2.4 Results and Discussion ................................................................................... 24 2.4.1 Preliminary Results ............................................................................................. 24 2.4.2 Initial Azide and Alkyne Screening ..................................................................... 26 2.4.3 Evidence of Copper(II) Reduction ....................................................................... 29 2.4.4 Chelating Azides and Triazoles .......................................................................... 33 2.5 Conclusions ...................................................................................................... 37 2.6 Experimental Information ............................................................................... 37 2.6.1 Materials and General Methods.......................................................................... 37 2.6.2 Representative Procedures for Table 2.2 ........................................................... 38 2.6.3 Absorption Spectroscopy .................................................................................... 38 2.6.4 Electron Paramagnetic Resonance .................................................................... 39 2.6.5 Synthesis of Complex [Cu(2)2(ClO4)CH3CN](ClO4) ............................................ 40 2.6.6 Characterization of Compounds ......................................................................... 40 2.6.7 1H and 13C NMR Spectra .................................................................................... 43 3. CHAPTER THREE. STRUCTURAL AND MECHANISTIC ASPECTS OF THE COPPER(II)-ACCELERATED AZIDE-ALKYNE CYCLOADDITION ................. 50 3.1 Summary ........................................................................................................... 50 3.2 Additional Information Leading to Mechanistic Investigation ..................... 50 3.2.1 Chelating Azides ................................................................................................. 51 3.2.2 Assisting Ligand Effect ....................................................................................... 52 3.2.3 Motivation for Mechanistic Investigation ............................................................. 54 3.3 Results and Discussion ................................................................................... 54 3.3.1 Solvent Screening .............................................................................................. 54 vi 3.3.2 Alkyne Screening ................................................................................................ 59 3.3.3 Reorganization of Copper Catalyst ..................................................................... 62 3.4 Conclusions ...................................................................................................... 63 3.5 Experimental Information ................................................................................ 64 3.5.1 Materials and General Methods.......................................................................... 64 3.5.2 TLC Monitoring Conditions for Tables 3.2 and 3.3 ............................................. 65 3.5.3 Generation of [Cu4(OAc)4(OCH3)4] Complex ...................................................... 65 3.5.4 Characterization