Novel Magnetic Materials Based on Macrocyclic Ligands: Towards High Relaxivity Contrast Agents and Mononuclear Single-Molecule Magnets Emma Stares A thesis submitted to the Department of Chemistry in partial fulfillment of the requirements for the Degree of Doctor of Philosophy Supervised by Professor Melanie Pilkington Brock University St. Catharines Ontario, Canada August 2015 © Emma Stares, 2015 Abstract The preparation and characterization of coordination complexes of Schiff-base and crown ether macrocycles is presented, for application as contrast agents for magnetic resonance imaging, Project 1; and single-molecule magnets (SMMs), Projects 2 and 3. II III In Project 1, a family of eight Mn and Gd complexes of N3X2 (X = NH, O) and N3O3 Schiff-base macrocycles were synthesized, characterized, and evaluated as potential contrast agents for MRI. In vitro and in vivo (rodent) studies indicate that the studied complexes display efficient contrast behaviour, negligible toxicity, and rapid excretion. III In Project 2, Dy complexes of Schiff-base macrocycles were prepared with a view to developing a new family of mononuclear Ln-SMMs with pseudo-D5h geometries. Each complex displayed slow relaxation of magnetization, with magnetically-derived energy barriers in the range Ueff = 4 – 24 K. In Project 3, coordination complexes of selected later lanthanides with various crown ether ligands were synthesized. Two families of complexes were structurally and magnetically analyzed: ‘axial’ or sandwich-type complexes based on 12-crown-4 and 15- crown-5; and ‘equatorial’ complexes based on 18-crown-6. Magnetic data are supported by ab initio calculations and luminescence measurements. Significantly, the first mononuclear Ln-SMM prepared from a crown ether ligand is described. i Acknowledgments First and foremost, thank you to Dr. Melanie Pilkington for her patient guidance over the past four-and-a-half years. Thank you for having great ideas, for turning us all into independent researchers (whether we like it or not!), and for being a kind, funny and supportive boss. A huge thank you to all the members the Pilkington Group, past and present, for the fun, friendship and support; with a special shout-out to the ‘originals:’ Shari, Roger, Roland, Peter, and Nick H who showed me all their wise lab ways; to Majeda, Marnie, Jeff, Kevan and John for all the great chats; and to our Cairns neighbours Terry, Nick M, and Kseniya for the coffee runs, Lester Ds and movie nights, and general good times. Thank you to my committee members, Dr. Travis Dudding and Dr. Theocharis Stamatatos, for their ongoing help and advice. A special thank you to Dr. Stamatatos and Dr. Jeremy Rawson (University of Windsor) for teaching me to interpret magnetic data and answering a lot of questions along the way; also to Dr. Fereidoon Razavi for allowing us so much time on the MPMS and PPMS, and to Jory Korobanik, for showing me how to use them. A great big hug goes to Majeda Al Hareri for her summer of dedicated synthetic work on the crown project; and an ‘air high five’ to Jeffery Regier, for figuring out the mystery that is MOLCAS and performing calculations on the crown complexes. Thanks to the wonderful Tim Jones for his mass spectrometry measurements, especially on our finicky Schiff-base macrocyclic complexes; and to Razvan Simonescu, for his help gathering high-field relaxivity measurements on the NMR machines. ii Thank you to Dr. Warren Foltz and Dr. Deborah Scollard (STTARR), and the staff at the Animal Resource Center, for their guidance and help with designing and performing the animal studies; and to Dr. Meegan Larsen (Mbed Pathology) for her work performing necropsies and histopathology. Special thanks also to our collaborators for their important contributions to this thesis: Yassine Beldjoudi (University of Windsor) and Dr. John Wallis (Nottingham Trent University) for performing TGA and powder diffraction measurements; Dr. Fereidoon Razavi (Brock University) for the heat capacity measurements; Dr. Ian Brindle and Yong Wang (Brock University) for ICP-MS measurements; Dr. Steve Kornic (McMaster University) for far-IR and Raman measurements; and Dr. Rute Ferreira (University of Aveiro) for gathering and modelling the luminescence data. Finally, thank you to my family and friends; and especially my amazing husband Dave, for his unfailing encouragement and support. iii Table of Contents Abstract ......................................................................................................................................... i Acknowledgments ....................................................................................................................... ii Table of Contents ........................................................................................................................ iv List of Tables ............................................................................................................................. vii List of Figures ............................................................................................................................. xi List of Schemes ......................................................................................................................... xxi List of Abbreviations ............................................................................................................... xxii 1 INTRODUCTION ........................................................................................................................ 1 1.1 MRI contrast agents ............................................................................................................... 2 1.1.1 MRI theory ...................................................................................................................... 2 1.1.2 Development of contrast agent theory: ........................................................................... 5 1.1.3 Advances in small molecule agents: ............................................................................. 16 1.2 Molecule-based magnetism ................................................................................................. 30 1.2.1 Origins of magnetic behaviour ...................................................................................... 30 1.2.2 Classical magnets vs. molecule-based magnets ............................................................ 38 1.2.3 Single-molecule magnets .............................................................................................. 41 1.2.4 Lanthanide single-molecule magnets (Ln-SMMs) ........................................................ 48 1.3 Schiff-base macrocycles: ..................................................................................................... 59 1.3.1 Mononuclear complexes ............................................................................................... 60 1.3.2 Polynuclear complexes ................................................................................................. 66 1.4 Crown ethers: A brief background ....................................................................................... 76 1.4.1 Historical perspective .................................................................................................... 76 1.4.2 Lanthanide complexes of crown ethers ......................................................................... 78 1.4.3 Luminescence of lanthanide-crown ether complexes ................................................... 81 1.4.4 Crown ethers in molecular magnetism .......................................................................... 88 2 RESULTS AND DISCUSSION FOR PROJECT 1: .................................................................. 90 2.1 Introduction .......................................................................................................................... 90 2.1.1 Target family of macrocycles ....................................................................................... 93 2.2 Organic synthesis: macrocyclic building blocks .................................................................. 95 iv 2.3 Inorganic synthesis: MnII and GdIII complexes .................................................................. 103 2.3.1 MnII complexes ........................................................................................................... 104 2.3.2 GdIII complexes ........................................................................................................... 117 2.4 Relaxivity studies ............................................................................................................... 126 2.5 In vitro toxicity study ......................................................................................................... 129 2.6 In vivo study ....................................................................................................................... 134 2.6.1 Acute toxicity .............................................................................................................. 134 2.6.2 Imaging ....................................................................................................................... 138 2.7 Ongoing and future work ................................................................................................... 147 2.7.1 In vivo stability studies ................................................................................................ 147 2.7.2 Bio-targeting: development of a model targeted