Bifunctional Ligands Discerning and Medicinal Chemistry of ... Bifunctional Ligands in Discerning and

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  • Bifunctional Ligands in Discerning and Developing the Fundamental

    and Medicinal Chemistry of B i s m u t h o

    Glen G. Briand

    Submitted in partial filfiliment of the requirrments

    for the degree of Doctor of Philosophy

    Dalhousie University

    Halifax, Nova Scotia

    Juiy 1999

    @ Copyright by Glen G. Briand, 1999

  • National Library of Canada

    Bibliothèque nationale du Canada

    Acquisitions and Acquisitions et Bibliographie Services services bibliographiques 395 Wellington Stræt 395, nm Wdlingtori OttawaON K l A W OtiawsON K l A W Canada canada

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  • For Janice

  • Table of Contents

    Table of Contents ...................................................................................... v

    List of Figures ........................................................................................... ix

    List of Tables .......................................................................................... x

    Abstract ................................................................................................... xii ... ............................................................. List of Abbreviations aad Symbols xiii

    Acknowledgrnents ......................................................................... xvii

    . ......................................................................... Chapter 1 Introduction 1

    1 . 1 Bifunctional Ligands as a Means to Denning the Coordination

    Chemistry of Bismuth ............................................................... 1

    1.2 Structurai Divmity in Bismuth Chemistry ....................................... 5

    1 . 3 Characterization Techniques ......................................................... 6

    .......................................... 1.4 Scope of Thesis and General Comments 8

    1.5 Conclusions . Industry and the Scientific Method ............................... 9

    Chapter 2 . The Chemistry of Medicina1 Bismuth Compounds: Hydroxy-/

    Alkoxycarbox ylates and Inorganic Salts .................................................... 12

    Introduction .......................................................................... 12

    Inorganic Compounds ........................................................... 13

    Carboxylates and Dexivatives ....................................................... 20

    2 . 3 . Poiyhydroxycarboayfic Acid Complexes ............................... 20

    ................... 2.3.2 PoIyuminocarboxyJates and ~ioIatoc(~rboxyJutes 26

  • 2.4 'ColloidaI Bismuth Subcitrate' (CBS). 'Bismuth Subsalicylate' (BSS)

    and 'Ranitidine Bismuth Citrate' (RBC) ................................................ 27

    2.5 Models and Alternatives for Bioactive Bismuth Compounds ................ 32

    2.6 Interactions with Biomolecules and Phmaceutical Agents .................. 35

    2.7

    Chapter 3 .

    3.3

    3.4

    Chapter 4 .

    ................................................................ 2.6.2 Amino Aci'ds 35

    ...................................................... 2.6.2 Pqptides und Proteins 36

    2.6.3 Xnzeruc~ion of Bismuth Compun& witA Other Dmgs and

    ............................................................... Food Camponents 38

    ................................................................... 2.6.4 Antidotes 39

    Conclusions ........................................................................... 40

    Toward the General Synthesis of Dicarboxylates and the Structural

    Characterization of Bismuth Oxdate .................................. .., .................. 42

    Introduction .............................................................................. 42

    Synthesis and Structure of Bismuth Carboxylates ................................... 43

    ............................................................... 3.2. I Carhxylates 45

    .............................................................. 3.2.2 DicnrbaxyIates 49

    ................................................................ Results and Discussion 51

    ................................................. Conclusions and Future Directions 54

    Aminocarboxylates: New Investigations into the Bi- System

    .................................. Including Isolation of the First CatioNc Complex 58

    Introduction ............................................................................. 58 ......................... S ynthesis and Structure of Bismuth-Aniin&xy lates 58

    ............................................................... Results and Discussion 69

  • .......................................................... 4.3.1 Synthetic Shrdies 69

    4.3.2 Prefiminary Electrosproy Mass Spectrometry Snidies of the

    ...................................................................................... Bi-&fa System 74

    ................................................. 4.4 Conclusions and Future Directions 75

    ......................................... Chapter 5 . Introduction to Bismuth Thiolate Chcmistry 78

    ........................................................................... 5.1 Introduction 78

    ......................................................................... 5.2 Monothiolates 78

    ............................................................... 5.3 Bifiinctional Thiolates 84

    .................................................................. 5.3.1 Dithiolates 84

    5.3.2 TIriuiatocarboxylates ...................................................... 89

    ..................................... 5.3.3 Hydroxy-/Alkoxy- and Ketothiolates 91

    ....................................... 5.3.4 Amino-, Imino- and Ara-Thiolates 95

    ....................................................... 5.4 Thio- and Dithiocarboxylates 101

    .......................................................... 5.4.1 ThiocarboxyIates 102

    5.4.2 Dithiocarboqdates (Dithiocarbamates. Dithioxanthates) ......... 103

    .......................................................... 5.5 Summary and Conclusions 113

    Chapter 6 . Definhg and Controlling the Arninoethanethiolate Chemistry of

    Bismuth(III): Synthesis and Comprehemive Characterization of

    ..................................................... Homologous Thiolatobismutth Series 116

    .......................................................................... 6.1 Introduction 116 ............................................................. 6.2 Results and Discussion 118

    .............................................. 6.3 Conclusions and Future Directions 130

  • Chapter 7 . (Methy1estei)methanethiolates: The First Ester Complexes of

    Bismuîh(m) as a Step Toward Modeling 'Colloidal Bismuth

    Subcitrate' ............................................................................................. 135

    7.1 Introduction .................................................................... 135

    7.2 Synthesis and Structure of Bismuth-Organocarbonyl Complexes .......... 135

    7.3 Secondary Bonding and the tram ERect: the Role of a* Orbitals .......... 139

    7.4 Results and Discussion ........................................................ 140

    7.5 Conclusions and Future Direction ................................................. 147

    Chapter 8 . Experimental ...................................................................... 151

    8.1 General Procedures ................................................................... 151

    8.2 Synthetic Procedures ............................................................... 151

    8.3 Physical and Spectroscopie Data .................................................................... -160

    8.4 X-ray Cxystallogcaphic Data ...................................................................... 168

    References .......................................................................................... -173

    viii

  • List of Figures

    Figure 1.1 Bismuth bonding arrangements witb organic functional groups and their

    heavier group 1 5 and 16 analogues ........................................................ 2

    Figure 1.2 Bifunctional combinations for developing the chemistry of bismuth .......... 4

    Figure 1.3 APCI-mass spectnun of bis(hydroxethane~olato)bi~~nuth(III) nitrate

    550 in acetonitrile ............. .........-.... .......................-.....-................................. 7