A Kinetic and Mechanistic Study of Cyclic Amine Functionalized Platinum(II) Complexes with Bio-Relevant Nitrogen Nucleophiles By Mthobisi Ian Nxumalo BSc. (Hons.) (University of KwaZulu-Natal) School of Chemistry and Physics University of KwaZulu-Natal Pietermaritzburg 3209 i A Kinetic and Mechanistic Study of Cyclic Amine Functionalized Platinum(II) Complexes with Bio-Relevant Nitrogen Nucleophiles By Mthobisi Ian Nxumalo A thesis submitted in fulfilment of the requirements for the degree of Master of Science School of Chemistry and Physics University of KwaZulu-Natal Pietermaritzburg 3209 Table of Contents Declaration.......................................................................................................................................................... i Abstract ............................................................................................................................................................. iii Acknowledgements .......................................................................................................................................... v Abbreviations .................................................................................................................................................. vi Ligands .......................................................................................................................................................... vi Other Abbreviations ................................................................................................................................. vi List of Figures ................................................................................................................................................ viii List of Tables ...................................................................................................................................................... x List of Schemes ................................................................................................................................................ xi Chapter 1 - Introduction ........................................................................................................ 1 1.1 Platinum Chemistry .................................................................................................................. 1 1.2 Properties Displayed By Recent Complexes Of Interest ....................................... 2 1.3 Current Findings on Anticancer Platinum(II) Drugs .............................................. 3 1.4 Aim Of This Study ..................................................................................................................... 11 1.5 References ................................................................................................................................... 16 Chapter 2 – Substitution Reactions ......................................................................... 22 2.1 Introduction .................................................................................................................................... 22 2.2 Mechanism of Ligand Substitution of Square-Planar Complexes ....................... 24 2.2.1 Stoichiometric and Intimate mechanisms ................................................................... 24 2.2.2 The Dissociative Mechanism (D) ..................................................................................... 26 2.2.3 The Associative Mechanism (A) ...................................................................................... 27 2.2.4 The Interchange Mechanism (I) ...................................................................................... 28 2.3 Substitution Reactions of Square-Planar Complexes ................................................ 29 2.3.1 Kinetics and Mechanism of Ligand Substitution at Square-Planar Centres .... 30 2.4 Factors Influencing the Rate of Substitution Reactions ........................................... 34 2.4.1 The Effect of the Non-Labile Ligand ............................................................................... 34 2.4.1.1 The trans Effect .............................................................................................................. 35 2.4.2 The Molecular Orbital Theory .......................................................................................... 41 2.4.2.1 σ-trans effect ................................................................................................................... 41 2.4.2.2 π-trans effect ................................................................................................................... 43 2.4.2.3 The Cis Effect ........................................................................................................................... 44 2.4.2.4 The Steric Effect ..................................................................................................................... 45 2.4.3 The Effect of the Entering Nucleophile ......................................................................... 47 2.4.4 The Effect of the Leaving Group ...................................................................................... 51 2.4.5 The Effect of the Solvent ..................................................................................................... 52 2.5 References ........................................................................................................................................ 54 Chapter 3 - Reaction Kinetics ......................................................................................... 58 3.1 Introduction ................................................................................................................................... 58 3.2 The Rate Law ................................................................................................................................. 60 3.3 Integrated Rate Expressions ................................................................................................. 61 3.3.1 Irreversible First-Order Reactions ................................................................................. 61 3.3.2 Reversible First-Order Reactions ................................................................................... 62 3.3.3 Irreversible Second-Order Reactions ............................................................................ 63 3.3.4 Reversible Second-Order Reactions .............................................................................. 65 3.4 Activation Parameters and Temperature Dependence ........................................... 67 3.4.1 The Arrhenius Equation ..................................................................................................... 67 3.4.2 Transition-State Theory ..................................................................................................... 68 3.4.3 Effect of Pressure on the Rate Constant ....................................................................... 68 3.5 Instrumental Techniques Associated with the Study of Chemical Kinetics .. 69 3.5.1 UV/Visible Spectrophotometry ....................................................................................... 71 3.5.2 Flow Methods ......................................................................................................................... 73 3.6 References....................................................................................................................................... 75 Chapter 4: Experimental .................................................................................................... 78 4.1 Materials and Procedures ................................................................................................... 78 4.2 Instrumentation and Physical Measurements ......................................................... 79 4.2.1 Characterization ................................................................................................................ 79 4.2.2 Computational Modelling .............................................................................................. 79 4.2.3 Kinetic Analyses ................................................................................................................ 80 4.3 Synthesis of the Ligand Systems (L1 – L4) .................................................................. 81 4.3.1 Synthesis of ligands (4′-[2-(1-Piperidinyl)ethoxy]-2,2′:6′,2′′-terpyridine (L1S1), (4′-[2-(1-Pyrrolidino)ethoxy]-2,2′:6′,2′′-terpyridine (L2S1) and (4′- [2-(1-Morpholino)ethoxy]-2,2′:6′,2′′-terpyridine (L3S1). ................................ 81 4.3.2 Synthesis of 2,6-Di(2-pyridyl)-β-(aminoethoxy)pyridine (L4S1). ................. 83 4.4 Synthesis of Platinum(II) Complexes ............................................................................ 85 4.4.1 Synthesis of [Pt(L1S1)Cl].BF4 (C1S1). ...................................................................... 85 4.4.2 Synthesis of Dichloro(1,5-cyclooctadiene)platinum(II), [Pt(COD)Cl2]. ...... 86 4.4.3 Platination of L1S1, L2S1, L3S1 and L4S1. ............................................................. 87 4.5 Kinetic Measurements .......................................................................................................... 89 4.5.1 Preparation of Platinum Complexes for Kinetic Analyses ............................. 89 4.5.2 Preparation of Nucleophile Solutions for Kinetic Analysis ........................... 89 4.6 References .......................................................................................................................................