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  • Synthesis of Fluorescent Phosphorus Ligands

    and their Applications in Medical Imaging and

    Catalysis

    Jennifer Fairbairn Wallis

    Engineering Doctorate in Biopharmaceutical Process Development

    Supervisor of Research: Dr Lee J. Higham

    Industry Sponsor: High Force Research

    School of Chemical Engineering – Newcastle University

    June 2018

  • ii

    Abstract

    This thesis reports the synthesis of novel, air-stable, fluorescent phosphorus-containing

    compounds, based on a Bodipy backbone, and their applications in cell imaging and catalysis. The

    syntheses of all the novel target compounds reported in this thesis are via a primary phosphine, an

    under-utilised class of compound due to a hazardous reputation. Chapter 1 explores the stability of

    primary phosphines, how they can be made user-friendly and the ability to create a library of novel

    phosphorus compounds via the phosphorus-hydrogen bonds. The LJH group synthesised the first,

    air-stable, fluorescent primary phosphine and Chapter 2 explores a second generation of this type

    of ligand with an increased fluorescent quantum yield due to the addition of alkyne groups on the

    boron atom. Chapter 3 details the coordination chemistry of primary phosphines to group 6 and 8

    transition metals. Interestingly, the addition of the metals had different effects on the photophysical

    properties, group 6 metal complexes retained high quantum yields, whereas group 8 metals

    quenched the fluorescence, possibly due to the heavy atom effect.

    Chapter 4 discusses the synthesis of fluorescent phosphonium salts which have the potential to be

    used as trifunctional imaging agents. The three functions within the compounds include i) a

    fluorophore, to provide in vitro fluorescence imaging, ii) a positive charge on the phosphorus atom

    to introduce organelle specificity – in this case, to the mitochondria and iii) the inclusion of an 18F

    radioisotope enables in vivo imaging techniques such as PET imaging. Chapter 5 shows further

    versatility of fluorescent primary phosphines where we report the synthesis of a novel, chiral,

    fluorescent phosphonite ligand that has been tested for its applications as a catalyst in asymmetric

    hydrogenation reactions of a benchmark substrate. The results showed full conversion and an

    enantiomeric excess (ee) of >99%. The final chapter discusses the importance of the aryl linker

    between the Bodipy core and the phosphorus atom. The compounds synthesised in this chapter

    show decreased fluorescence when the phosphorus atom is directly bound to the fluorophore and

    have potential applications as a switch.

  • iii

    List of Publications

    L. H. Davies, J. F. Wallis, M. R. Probert and L. J. Higham, Synthesis, Efficient multigram synthesis

    of air-stable, fluorescent primary phosphines via palladium-catalyzed phosphonylation of aryl

    bromides, 2014, 46, 2622-2628.

    N. Fey, S. Papadouli, P. G. Pringle, A. Ficks, J. T. Fleming, L. J. Higham, J. F. Wallis, D.

    Carmichael, N. Mézailles and C. Müller, Phosphorus, Sulfur, and Silicon and the Related Elements,

    Setting P-Donor Ligands into Context: An Application of the Ligand Knowledge Base (LKB)

    Approach, 2015, 190, 706-714.

    S.Nigam, B. P. Burke, L. H. Davies, J. Domarkas, J. F. Wallis, P. G. Waddell, J. S. Waby, D. M.

    Benoit, A. Seymour, C. Cawthorne, L. J. Higham and S. J. Archibald, Chem.Commun., Structurally

    optimised Bodipy derivatives for imaging of mitochondrial dysfunction in cancer and heart cells,

    2016, 52, 7114-7117.

    L. H. Davies, J. F. Wallis, R. W. Harrington, P. G. Waddell & L. J. Higham, J. Coord. Chem., Air-

    stable fluorescent primary phosphine complexes of molybdenum and tungsten, 2016, 69, 2069-

    2080.

  • iv

    Acknowledgements

    First, I would like to sincerely thank my supervisor Dr Lee J. Higham, for giving me this

    opportunity and taking a chance on me! I have had the best time working with him and his research

    group over the last few years. I have been given the chance to attend several international and

    national conferences which have been quite an experience! Thank you for your patience and

    guidance throughout this EngD course.

    I would like to thank the EPSRC for funding, as well as High Force Research who were my

    industrial sponsor. The team in the BBTC have been amazing throughout the years, so thank you

    for all of your help.

    A special thank you to Dr Laura Davies who taught me everything I know about Bodipy and all of

    the special tricks required to synthesise them!

    My time in the lab has been made significantly more entertaining and memorable by a number of

    people: the old school LJH group members: Dr Arne Ficks, Dr Manuel Abelairas-Edesa, Dr Connor

    Sibbald, Dr James Fleming, Dr Ana Cioran, the more recent LJH members: Charlotte Hepples,

    Antonio Sanchez-Cid and Graeme Bowling (not forgetting adopted member Dr Tommy

    Winstanley) and all of the other students within the Johnston Lab. A special mention to Manuel,

    (we were the original Boss-Monkey team and he introduced me to Estrella Galicia and Faustino I),

    James and Charlotte who have all assisted me with research in the lab, but have also created the

    best memories outside of the lab, and hope that we will continue to meet up at our annual beer and

    gin festivals throughout the year!

    I could not have completed this work without the help of our fantastic crystallographer Dr Paul

    Waddell, and NMR experts Dr Corinne Wills and Prof. William Mcfarlane, they have undoubtedly

    helped me complete and understand this work.

    Another special thank you to all of the academic research collaborators involved with this research,

    especially Prof Steve Archibald and Dr Amy Reeve who both helped out with cell studies.

    I have been lucky enough to work with several Erasmus and Masters Students and I’d especially

    like to thank Francesca, Anna, Giorgia, Vince, Sophie, Tom and everyone else who contributed

    towards the Bodipy research!

    Finally I’d like to thank my amazing Dad for always believing in me and helping me get to where

    I am today, even when I doubted myself he would always guide me and tell me I could do it - my

    Mam would be so proud of what I have achieved. My sisters Katie and Rachael and my boyfriend

    Chris have also been exceptionally patient during the last 5 years. I love you all!

  • v

    Abbreviations

    General:

    β Beta particle

    B3LYP Becke Parameter Lee-Yang-Parr

    CT Computed Tomography

    DFT Density Functional Theory

    γ Gamma ray

    HOMO Highest Occupied Molecular Orbital

    HPLC High-Performance Liquid Chromatography

    LMCT Ligand-to-Metal Charge Transfer

    LUMO Lowest Unoccupied Molecular Orbital

    99m Metastable isotope

    MLCT Metal-to-Ligand Charge Transfer

    MMCT Metal-to Metal Charge Transfer

    MRI Magnetic Resonance Imaging

    PET Positron Emission Tomography

    PeT Photoinduced electron Transfer

    RT Room Temperature

    SOMO Singly Occupied Molecular Orbital

    SPECT Single Photon Emission Computed Tomography

    TLC Thin Layer Chromatography

    t1/2 Half-life

    Chemicals:

    Bodipy 4,4-difluoro-4-borata-3a-azonia-4a-aza-s-indacene

    CDCl3 Deuterated chloroform

    DCM Dichloromethane

    DDQ 2,3-Dicyano-5,6-dichloroparabenzoquinone

    DMSO Dimethyl sulfoxide

    DPPB 1,4-Bis-(diphenylphosphino)-butane

    Et2O Diethyl ether

  • vi

    HP(O)(OEt)2 Diethyl phosphite

    LiAlH4 Lithium aluminium hydride

    MgSO4 Magnesium sulphate

    NEt3 Triethylamine

    Pd(OAc)2 Palladium(II) acetate

    POBr3 Phosphoryl oxybromide

    POCl3 Phosphoryl oxychloride

    TFA Trifluoroacetic acid

    THF Tetrahydrofuran

    TMSCl Chlorotrimethylsilane

    Units:

    Å Angstroms

    cm Centimetres

    ° Degrees

    °C Degrees Celsius

    eq Equivalents

    eV Electron Volts

    Hz Hertz

    h Hours

    L Litres

    mg Milligrams

    MHz Megahertz

    mmol Millimolar

    mins Minutes

    M Molar

    nm Nanometres

    ppm Parts per million

    s Seconds

  • vii

    Experimental techniques terms:

    APCI Atmospheric-Pressure Chemical Ionisation

    br Broad

    δ Chemical shift

    d Doublet

    ε Molar Absorption Coefficient

    EI Electron Ionisation

    ESI Electrospray Ionisation

    FTIR Fourier Transform Infrared Spectroscopy

    HRMS High Resolution Mass Spectrometry

    I Nuclear Spin

    J Coupling Constant

    LRMS Low Resolution Mass Spectrometry

    NIR Near-Infrared

    NSI Nanospray Ionisation

    m Multiplet

    NMR Nuclear Magnetic Resonance

    ΦF Quantum yield

    q Quartet

    s Singlet

    t Triplet

  • viii

    Table of Contents

    Abstract ..............

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