Novel Ruthenium Complexes and Their Applications as Catalysts and Anticancer Agents Andrea Rodríguez Bárzano Submitted in accordance with the requirements for the degree of Doctor of Philosophy The University of Leeds School of Chemistry May 2013 The candidate confirms that the work submitted is her own and that appropriate credit has been given where reference has been made to the work of others. This copy has been supplied on the understanding that it is copyright material and that no quotation from the thesis may be published without proper acknowledgement. The right of Andrea Rodríguez Bárzano to be identified as Author of this work has been asserted by her in accordance with the Copyright, Designs and Patents Act 1988. © 2013 The University of Leeds and Andrea Rodríguez Bárzano I Acknowledgements Firstly, I thank Patrick for giving me the opportunity of spending these years in his lab, for sharing his knowledge, for his invaluable guidance, help and support and, no less importantly, for making my time with the McGowan group such an enjoyable experience. Thank you to TSB for the funding and to all the members of the Cp* project. Particularly, thank you to John, for all the meetings and advice and to Tom and Ben for their help with the hydrogenations. Many thanks to Christopher Pask for basically everything, from very constructive discussions to disgusting pump-oil changing. We miss you upstairs. Special thanks go to the technical staff at Leeds, including Colin Kilner, Simon Barrett, Tanya Marinko-Covell and Ian Blakeley, who provided analyses and characterisation data. Chapter 6 would not have been possible without the efforts of our “Bradford team”: Rianne and Aida, I cannot thank you enough. Thank you also to the iPRD members, mainly Peter Baldwin for testing some of my compounds against racemisations and James Tunstall for his patience with the “delicate” GC machine. Thanks to all the people in the McGowan and Halcrow groups (past and present) for the fun. I will probably forget someone, but I have to mention Joel and Alun (for sharing the “ruthenium joy”), Chris, Felix (endless knowledge of everything technology-related), Steph, Rianne, Aida, Carlo, Andrew, Zary, Ben, Jonathan, Laurence, Amedeo, Rufeida, Tom, and many masters students. Outside the lab, for their help with X-ray crystallography, I would like to thank James and Ben, and all the people involved in the McGowan-Willans-Kee group meetings for listening and sharing ideas. Leo, thank you for your affection, for your constant encouragement and for many beautiful moments. You have given these years the best possible soundtrack. Finally, I have to thank my family and, above all, my parents for their unconditional support and for being always present despite the distance. For so much effort... Gracias. II Abstract This thesis concerns the synthesis and characterisation of arene, Cp* and functionalised Cp* complexes of ruthenium for their use as transfer hydrogenation catalysts and anticancer agents. As catalysts, the compounds have been tested, principally, against the redox neutral alkylation of tert-butylamine with phenethyl alcohol and the reduction of benzaldehyde. As anticancer agents, the compounds have been tested in vitro against the cell lines HT-29 and A2780. Chapter 1 is a review of transfer hydrogenations using ruthenium, iridium and rhodium complexes, immobilisation alternatives and research into metal-containing anticancer drugs. Chapter 2 describes the synthesis and characterisation of functionalised η6-arene complexes of ruthenium and a brief investigation into their immobilisation possibilities. Chapter 3 describes the synthesis and characterisation of pyridine-containing p- cymene complexes of ruthenium. Chapter 4 describes the synthesis and characterisation of Cp*, functionalised Cp* and tetramethylfulvene complexes of ruthenium. Chapter 5 describes the homogeneous catalytic testing of the compounds discussed in Chapters 2-4 for transfer hydrogenations. Chapter 6 describes the in vitro IC50 results obtained for compounds selected among those discussed in Chapter 4 against two cell lines. Chapter 7 gives the experimental details and the characterisation data for the processes and compounds discussed in Chapters 2-6. III Table of Contents Acknowledgements ..................................................................................................... II Abstract ...................................................................................................................... III Table of Contents ....................................................................................................... IV Glossary of Terms ...................................................................................................... IX Chapter 1 Introduction ........................................................................... 1 1.1 Introduction ............................................................................................................ 2 1.2 Transfer Hydrogenation Reactions ........................................................................ 2 1.2.1 Introduction .................................................................................................... 2 1.2.2 Redox Neutral Alkylations ............................................................................. 3 1.2.3 Hydrogenations and Dehydrogenations ......................................................... 9 1.2.4 Racemisations and Dynamic Kinetic Resolutions........................................ 20 1.2.5 Other Transfer Hydrogenation Reactions ..................................................... 22 1.2.6 Reactions Involving H2 ................................................................................ 25 1.3 Mechanistic Investigations ................................................................................... 27 1.3.1 Inner Sphere Mechanisms ............................................................................ 29 1.3.2 Outer Sphere Mechanisms ............................................................................ 30 1.4 Immobilisation Techniques .................................................................................. 34 1.4.1 Introduction .................................................................................................. 34 1.4.2 Covalent Immobilisation .............................................................................. 34 1.4.3 Non-Covalent Immobilisation ...................................................................... 36 1.4.4 Examples of Immobilised Ruthenium Complexes ....................................... 41 1.5 Cancer .................................................................................................................. 46 1.6 Platinum-Based Anticancer Drugs ....................................................................... 47 1.6.1 Cisplatin ........................................................................................................ 47 1.6.2 Carboplatin ................................................................................................... 49 1.6.3 Oxaliplatin .................................................................................................... 50 1.7 Metallocenes ........................................................................................................ 50 1.8 Ruthenium Complexes ......................................................................................... 53 1.8.1 NAMI-A ....................................................................................................... 53 1.8.2 KP1019 ......................................................................................................... 54 1.9 Project Aims ......................................................................................................... 55 1.10 References .......................................................................................................... 56 IV Chapter 2 2,5-Dihydrophenyl Carboxy Ligands and Functionalised 6 η -Arene Ruthenium Complexes ......................................................... 66 2.1 Introduction .......................................................................................................... 67 2.2 2,5-Dihydrophenyl Carboxy Ligands .................................................................. 68 6 2.3 Functionalised η -Arene Ruthenium Complexes ................................................. 69 2.3.1 Synthesis of [RuX2C6H5(CH2)nCOOR]2 (X = Cl, Br) (2.3−2.8) .................. 69 2.3.2 Synthesis of [RuI2C6H5CH2COOCH2CH3]2 (2.9) ........................................ 73 2.3.3 Synthesis of [RuCl2(C6H5CH2COOCH2CH3)(NC5H5)] (2.10) .................... 76 2.4 General Observations and Comments .................................................................. 80 2.5 Immobilisation Attempts ...................................................................................... 82 2.6 Conclusions .......................................................................................................... 83 2.7 References ............................................................................................................ 84 6 Chapter 3 η -p-Cymene Ruthenium Complexes ................................ 86 3.1 Introduction .......................................................................................................... 87 6 3.2 η -p-Cymene Ruthenium Dimers ......................................................................... 88 3.2.1 Synthesis of [RuCl2(C10H14)]2