Verdazyl Radicals As Mediators in Living Radical Polymerizations and As Novel Substrates for Heterocyclic Syntheses
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VERDAZYL RADICALS AS MEDIATORS IN LIVING RADICAL POLYMERIZATIONS AND AS NOVEL SUBSTRATES FOR HETEROCYCLIC SYNTHESES By Eric Kuan Yu Chen A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy Graduate Department of Chemistry University of Toronto © Copyright by Eric Kuan Yu Chen 2010 VERDAZYL RADICALS AS MEDIATORS IN LIVING RADICAL POLYMERIZATIONS AND AS NOVEL SUBSTRATES FOR HETEROCYCLIC SYNTHESES Degree of Doctor of Philosophy, 2010 Eric Kuan Yu Chen Department of Chemistry, University of Toronto Abstract Verdazyl radicals are a family of multicoloured stable free radicals. Aside from the defining backbone of four nitrogen atoms, these radicals contain multiple highly modifiable sites that grant them a high degree of derivatization. Despite having been discovered more than half a century ago, limited applications have been found for the verdazyl radicals and little is known about their chemistry. This thesis begins with an investigation to determine whether verdazyl radicals have a future as mediating agents in living radical polymerizations and progresses to their application as substrates for organic synthesis, an application that to date has not been pursued either with verdazyl or nitroxide stable radicals. The first part of this thesis describes the successful use of the 1,5-dimethyl-3-phenyl-6- oxoverdazyl radical as a mediating agent for styrene and n-butyl acrylate stable free radical polymerizations. The study of other verdazyl derivatives demonstrated the impact of steric and electronic properties of the verdazyl radicals on their ability to mediate polymerizations. ii The second part of this thesis outlines the initial discovery and the mechanistic elucidation of the transformation of the 1,5-dimethyl-3-phenyl-6-oxoverdazyl radical into an azomethine imine, which in the presence of dipolarophiles, undergoes a [3+2] 1,3-dipolar cycloaddition reaction to yield unique pyrazolotetrazinone structures. The reactivity of the azomethine imine and the scope of the reaction were also examined. The third part of this thesis describes the discovery and mechanistic determination of a base- induced rearrangement reaction that transforms the verdazyl-derived pyrazolotetrazinone cycloadducts into corresponding pyrazolotriazinones or triazole structures. The nucleophilicity, or the lack thereof, of the base employed leading to various rearrangement products was examined in detail. The final part of this thesis demonstrates the compatibility of the verdazyl-initiated cycloaddition and rearrangement reactions with the philosophy of diversity-oriented synthesis in generating libraries of heterocycles. A library of verdazyl-derived heterocycles was generated in a short amount of time and was tested non-specifically for biological activity against acute myeloid leukemia and multiple myeloma cell lines. One particular compound showed cell-killing activity at the 250 µM range, indicating future potential for this chemistry in the field of drug discovery. iii Acknowledgements First and foremost, I would like to thank my supervisor Professor Michael Georges. Words cannot express my gratitude for all you have done for me over the years. The invaluable lessons you have taught me in chemistry, life, or otherwise, will take me long ways from here. Thank you for unselfishly sharing your knowledge and experience, and thank you for being an excellent scientist, supervisor, teacher and friend. I would like to thank Dr. Gord Hamer not only for sharing his NMR and DFT expertise, but also for his support through all stages of my degree. I would also like to thank my fellow graduate students Andrea, Joanne, Delphine, Julie, Taka, Matthew, Jeremy and Anna; you have all made my learning and working experience more enjoyable. A special thanks to Julie for paving the path and guiding me through graduate student life. To the postdoctoral fellows Antoine, Steve and Angela: thank you for enriching and expanding my learning horizons. To the members of my supervisory committee Professor Winnik and Professor Kumacheva, along with the members of my thesis committee Professor Gunning and Professor Chong: thank you for the effort and guidance. I would like to thank my friends who have stuck by me through times good and bad: Jon, Sco, Jeff, Selene, Ashley, Lin, Nat, Julie, Richard, Adrienne, Couch, Saad, Ping, Ryan, George and all of you others; thanks for the support and company. Last but definitely not least I would like to thank my family for the support through it all: my parents Julia and Kevin; my sister Christina. Thank you for being patient and having faith in me. I could not have done this without you guys. iv Table of Contents 1 Chapter 1 - Introduction 1.1 Verdazyl Radicals ............................................................................................................ 1 1.1.1 Introduction ............................................................................................................... 1 1.1.2 History, Synthesis, and Characterization of Verdazyl Radicals ............................... 2 1.1.3 History of Verdazyl Radical Chemistry .................................................................... 7 1.1.4 History of Verdazyl Radical Applications ................................................................ 8 1.1.5 Concluding Remarks ................................................................................................. 9 1.2 Stable Free Radical Polymerization ................................................................................. 9 1.2.1 Conventional vs. Living Polymerization .................................................................. 9 1.2.2 Introduction to Living Radical Polymerization Systems ........................................ 14 1.2.3 Nitrogen-Centered Radicals in Stable Free Radical Polymerizations .................... 27 1.2.4 Concluding remarks ................................................................................................ 33 1.3 1,3-Dipolar Cycloadditions Involving Azomethine Imines ........................................... 34 1.3.1 Introduction to 1,3-Dipolar Cycloadditions ............................................................ 34 1.3.2 Azomethine Imines as Dipoles ............................................................................... 37 1.3.3 History of Azomethine Imines ................................................................................ 39 1.3.4 Recent Developments in Azomethine Imine Cycloadditions ................................. 41 1.3.5 Concluding Remarks ............................................................................................... 44 1.4 Heterocyclic Rearrangements ........................................................................................ 45 1.4.1 General Considerations ........................................................................................... 45 1.4.2 Dimroth Rearrangements ........................................................................................ 45 1.5 References ...................................................................................................................... 54 2 Chapter 2 - Verdazyl-Mediated Living Radical Polymerization of Styrene and n-Butyl Acrylate 2.1 Introduction and Objective ............................................................................................. 62 2.2 Experimental Section ..................................................................................................... 65 v 2.2.1 Materials and Equipment ........................................................................................ 65 2.2.2 Styrene Polymerization Initiated with 1,1’-Azobis(cyclohexanecarbonitrile) (Vazo® 88) in the Presence of 1,5-Dimethyl-3-phenyl-6-oxoverdazyl Radical 16 ............. 67 2.2.3 Styrene Polymerization Initiated with BPO in the Presence of 1,3,5-Triphenyl-6- oxoverdazyl Radical 17 ......................................................................................................... 67 2.2.4 Synthesis of 2-(3-Oxo-2,4,6-triphenyl-3,4-dihydro-1,2,4,5-tetrazin-1(2H)-yl)-2- phenylethyl benzoate ( 18 ) ..................................................................................................... 68 2.2.5 Styrene Polymerization Initiated with Unimolecular Initiator 18 ........................... 68 2.2.6 Synthesis of 2-(2,4-Dimethyl-3-oxo-6-phenyl-3,4-dihydro-1,2,4,5-tetrazin-1(2H)- yl)-2-phenylethyl benzoate ( 19 ) ............................................................................................ 69 2.2.7 Styrene Polymerization Initiated with Unimolecular Initiator 19 ........................... 69 2.2.8 n-Butyl Acrylate Polymerization Initiated with Unimolecular Initiator 19 ............ 69 2.2.9 Reaction of 1,5-Dimethyl-3-phenyl-6-oxoverdazyl Radical 16 with BPO and Styrene ................................................................................................................................. 70 2.2.10 Preparation of Poly( n-butyl acrylate-b-polystyrene) from a Poly( n-butyl acrylate) Macroinitiator ........................................................................................................................ 70 2.2.11 Preparation of Poly(styrene-b-n-butyl acrylate) from a Polystyrene Macroinitiator .. ................................................................................................................................. 71 2.2.12 Synthesis of 2-(6-(4-Cyanophenyl)-2,4-dimethyl-3-oxo-3,4-dihydro-1,2,4,5- tetrazin-1(2H)-yl)-2-phenylethyl