Part I: The Synthesis and Characterization of Scorpionate Ligands for Lanthanide Complexation for Potential PARACEST Applications Part II: The Synthesis and the Characterization of New and Old Organic Dyes by Emma Nicholls-Allison BSc., University of Victoria, 2010 A Dissertation Submitted in Partial Fulfillment of the Requirements for the Degree of DOCTOR OF PHILOSOPHY in the Department of Chemistry Emma Nicholls-Allison, 2015 University of Victoria All rights reserved. This dissertation may not be reproduced in whole or in part, by photocopy or other means, without the permission of the author. ii Supervisory Committee Part I: The Synthesis and Characterization of Scorpionate Ligands for Lanthanide Complexation for Potential PARACEST Applications Part II: The Synthesis and the Characterization of New and Old Organic Dyes by Emma Nicholls-Allison BSc., University of Victoria, 2010 Supervisory Committee Dr. David J. Berg, (Department of Chemistry) Co-Supervisor Dr. Robin G. Hicks, (Department of Chemistry) Co-Supervisor Dr. Cornelia Bohne, (Department of Chemistry) Departmental Member Dr. Michel Lefebvre, (Department of Physics) Outside Member iii Abstract Supervisory Committee Dr. David J. Berg, (Department of Chemistry) Co-Supervisor Dr. Robin G. Hicks, (Department of Chemistry) Co-Supervisor Dr. Cornelia Bohne, (Department of Chemistry) Departmental Member Dr. Michel Lefebvre, (Department of Physics) Outside Member Reported in Chapter 2 of this thesis is the reliable and tolerant synthesis of a small library of pyrazole and triazole heterocycles. This synthesis was achieved in two steps in good yields from the reaction of acetophenone and benzamide derivatives with dimethyl formamide-dimethyl acetal followed by a cyclization with hydrazine. Also reported is the synthesis and characterization of their corresponding scorpionate ligands. Preliminary co- ordination chemistry was done with a variety of lanthanide metals and was studied by standard spectroscopic methods as well as variable temperature 1H NMR, which revealed that Curie-Weiss behaviour was followed for these complexes in solution. An X-ray crystal structure of a nine co-ordinate ytterbium metal centre with eight nitrogen atom (four pyrazole, four pyridine) donors and one chloride atom was obtained, which may have been a product of decomposition during crystal growth. The bond lengths of this structure were compared with other lanthanide complexes of similar structural motifs. This comparison supported the theory of decomposition as the pyridine nitrogen atom-ytterbium bond lengths were longer than the average ytterbium-nitrogen atom bond length. Reported in Chapter 4 of this thesis is the synthesis and partial characterization of a new organic dye named perinaphthindigo. Perinaphthindigo was synthesized with adapted iv Baeyer-Drewson reaction conditions for the synthesis of indigo which involved the treatment of 1,8-nitronaphthaldehyde with acetone under basic conditions, and was found to be an intense green colour in solution. Perinaphthindigo was produced in poor yields, so efforts were undertaken to improve the yields through an alternative two-step synthesis, first between 1,8-nitronaphthaldehyde and nitromethane in a Henry reaction followed by oxidative coupling. The synthesis of perinaphindigo was adapted so as to structurally modify the final compound, either through incorporation of solubilizing tert-butyl groups or bromine atoms for future cross-coupling chemistry. The brominated derivatives of perinaphthindigo were also synthesized in low yields so cross-coupling conditions were scanned on model precursor compounds. The brominated perinaphthindigo compounds were found to have a bathochromically shifted absorbance maximum from the parent perinaphthindigo. This bathochromic shift was more pronounced in our compounds than in the comparison of indigo and 6.6’-dibromoindigo which indicates our compounds are more sensitive to perturbation by substitution. Reported in Chapter 5 of this thesis is the study of the acid and base chemistry of Nindigo, a previously reported compound. The treatment of Nindigo with a series of strong acids led to an interesting “protoisomerization”, or trans to cis isomerization of the central olefin, with ultimate structural determination through X-ray crystallographic methods. This isomerization was studied through absorbance stopped-flow methods which identified a probable pathway of the isomerization through a neutral, cis species. The investigation of neutral Nindigo was undertaken to attempt to identify two peaks which are red-shifted from the π-to-π transition at 586 nm. These two peaks appear at 657 nm and 741 nm and are present in all solvents. The preparative acid chemistry allowed us to assign the first red v shifted peak at 657 nm to the cationic species. Aggregation studies showed concentration dependent behaviour of the ratio between the peaks at 586 nm and 657 nm with little effect on the species at 741 nm. In order to probe whether an autoionization process was occurring, variable temperature NMR and UV-Vis experiments were performed which did not provide a definitive answer to the species at 741 nm. vi Table of Contents Supervisory Committee ...................................................................................................... ii Abstract .............................................................................................................................. iii Table of Contents ............................................................................................................... vi List of Tables ..................................................................................................................... ix List of Schemes ................................................................................................................... x List of Figures ................................................................................................................... xii List of Equations .............................................................................................................. xiv List of Abbreviations ........................................................................................................ xv List of Numbered Compounds ......................................................................................... xix Acknowledgments........................................................................................................... xxv Dedication ..................................................................................................................... xxvii Chapter 1: Introduction to Part 1 ........................................................................................ 1 1.1 Metals in medicine .............................................................................................. 1 1.2 Other diagnostic medicine techniques ................................................................ 2 1.3 Magnetic Resonance Imaging (MRI) in diagnostic medicine .................................. 4 1.3.1 MRI and traditional T1 relaxation agents ........................................................... 4 1.3.2 CEST and PARACEST agents for imaging....................................................... 6 1.4 Bioinorganic ligand design for MRI contrast agents ........................................ 10 1.5 Objectives of this work ..................................................................................... 11 Chapter 2: Ligand Design for Lanthanide Co-ordination Chemistry for PARACEST Applications ...................................................................................................................... 14 2.0 Introduction ............................................................................................................. 14 2.1 Results of the phosphinimine chemistry ................................................................. 15 2.2 Introduction to scorpionate chemistry .................................................................... 19 2.3 Triazole synthesis by Suzuki cross coupling .......................................................... 20 2.4 Triazole synthesis using the Ferrence method ........................................................ 23 2.5 Successful and highly tolerant scorpionate synthesis ............................................. 24 2.5.1 Pyrazole and triazole synthesis ........................................................................ 25 2.5.2 Synthesis of the scorpionate ligands ................................................................ 28 2.5.3 Characterization of the Scorpionate Complexes .............................................. 28 2.6 Continued work towards novel ligand systems with oxygen donors ...................... 31 2.7 Continued work towards a novel ligand systems with nitrogen donors ................. 35 2.8 Synthesis and Characterization of the Lanthanide Metal-Scorpionate Complexes 36 2.9 Summary ................................................................................................................. 45 2.10 Experimental Section ............................................................................................ 47 2.10.1 Methods and Materials ................................................................................... 47 2.10.2 Experimental Data ......................................................................................... 48 Chapter 3: Introduction to Part II .....................................................................................