Antibiotic resistance is a global threat to public health due to a combination of limited new antibiotic candidates and the dramatic rise in multidrug-resistant bacteria. Antimicrobial peptides (AMPs) are part of the host innate immune system and are potential alternatives to treat infections is increasing. AMPs have multiple modes of action to kill bacteria, mostly involving non-stereo specific interactions which drastically diminishe acquired-resistance pressure. For instance, one of the typical mechanisms is to target the bacterial cell membrane via electrostatic interactions and disrupt the lipid bilayer integrity. Maculatin 1.1 (Mac1, GLFGVLAKVAAHVVPAIAEHF-NH2) is a cationic membrane-active AMP, isolated from the skin of Australian tree frogs and well-known for its antibacterial ability. The molecular mechanism of Mac1 interaction with bacterial membranes has been mainly studied in vitro using model membrane systems. Although providing critical insights into the lipid-peptide interactions, it is unclear if the peptide retains a similar behaviour against bacterial membrane. Indeed, while the details of how Mac1 assembles into a lipid bilayer, and the lipid composition of model membranes have been shown to play a critical role in the peptide activity. Thus, investigating Mac1 structural arrangement in intact bacteria is an important step towards deciphering how AMPs may interact in situ. Solid-state NMR (ssNMR) is able to reveal structural behaviour of AMP in vitro, but its application is limited in vivo, especially due to the short life span of bacteria. Recent developments in dynamic nuclear polarization (DNP) ssNMR has led to the feasibility to conduct in-cell experiments due to higher sensitivity and longer cell survival rates. Spin probes together with isotope enriched peptides are required for DNP ssNMR experiment. In this thesis, the methodology to determine the structural arrangement of Mac1 in live bacteria by DNP-ssNMR is developed and the initial steps in understanding how AMPs self-assemble will be described.

Copper is a vital but potentially toxic element for all living organisms. Therefore, it is necessary to maintain a balance between a deficiency and an excess level of copper. Cu-ATPase proteins are selective for Cu(I) and are crucial for removal of excess copper from cellular cytosols and for supply of essential copper to the required enzymes. Using the energy derived from ATP hydrolysis, the ATPase ATP7A (Menkes' protein, MNK) plays a key role in maturation of copper enzymes by inserting the essential metal cofactor into the nascent apo-forms. It also maintains copper homeostasis by controlling copper levels in cells. Mutations in the ATP7A gene appear to lead to neurodegenerative diseases such as Menkes' disease (MD), Occipital Horn Syndrome (OHS), X-linked Distal Hereditary Motor Neuropathy (dHMNx), and Brachial Amyotrophic Diplegia (BAD). In the past decade, in vivo studies of the human copper pumps ATP7A/ATP7B have improved the understanding of their cellular functions. However, the investigation of the Cu-ATPase pump at the molecular level has fallen behind due to a number of challenges. In general, molecular characterization of transmembrane proteins requires large amounts of highly purified samples plus the challenge of producing a Cu pump in unmodified native form. It has also proven difficult to express and isolate the Cu pumps. This study details methods to address those challenges. This work also aims to undertake molecular characterisation of ATP7A and selected mutants using a 1H-NMR approach as a sensitive probe of ATPase activity. Asp1044 is the primary phosphorylation site that is essential for ATP7A function and the variant D1044E served as a negative control for the functional assay. The two variants P1386S and M1311V are two mutations identified in patients with dHMNx and BAD diseases, respectively. A baculovirus expression system was used to express His-tagged wild-type protein ATP7Awt and the variants in fully functional form. When dissolved in the detergent n-dodecyl-Beta-D-maltopyranoside (DDM) or embedded in Sf21 microsomes, the expressed proteins were each active in acyl-phosphorylation using the BODIPY FL ATP-Gamma-S assay system. Rates varied with Cu(I) availability, ATP concentration, enzyme concentration and temperature, and other conditions were optimized. The effects of competition for Cu(I) by glutathione (GSH), bathocuproine disulfonate anion (BCS), the metal binding site 1 from the E. coli analogue EcCopA (MBS1), metal binding site 6 of human Wilson disease protein (WLN6) and antioxidant protein 1 (ATOX1) were investigated. The ATPase activity assays evaluated by 1H-NMR demonstrated that: ATPase activity is dependent upon Cu(I) availability to the enzyme; the ATP7Awt protein is most active in the presence of its native metallo-chaperone ATOX1. The M1113V mutation does not affect ATPase activity significantly. Consequently, the problem of this mutation in BAD is likely related to the trafficking of Cu(I) rather than to its enzyme activity. The P1386S mutation associated with dHMNx, however, exhibited a reduced ATPase activity.

Innate immunity is provided by a complex network of cells, soluble factors, and organs that respond immediately or within hours of the appearance of a stimulus in the body. Innate immune processes can involve recognition of metabolites, including those of self or microbial pathogens, by endogenously-expressed pattern recognition receptors. In this thesis, I explored the structure of different antigens that can be recognized by the innate immunity macrophage inducible C-type lectin receptor (Mincle), innate-like natural killer T (NKT) cell, and mucosal-associated invariant T (MAIT) cells. Chapter 2 describes the synthesis of acyl variants of cholesteryl and ergosteryl alpha-mannoside (CAMs and EAMs), proposed structures for glycolipids from Candida albicans. These glycolipids were synthesized by mannosylation of cholesterol or ergosterol, followed by the introduction of the acyl groups by esterification of the sugar primary alcohol. The synthetic glycolipids were assessed for their ability to agonize signaling by mouse and human Mincle. We showed that both CAMs and EAMs elicited strong signaling through both mouse and human Mincle. Chapter 3 discloses the total synthesis of an alpha-galactosylceramide originally reported from Bacteroides fragilis: GalCerBf-716, as well as analogs bearing modified lipid side chains to allow exploration of structure-activity relationships for activation of CD1d-restricted iNKT cells. GalCerBf-716 was synthesized by galactosylation of a sphinganine acceptor, followed by an amide coupling with different acid side chains. All synthesized GalCerBf-716 analogs stimulated mouse and human iNKT cells. In Chapter 4 we proposed a structure for an undefined antigen (5-F-7-RdX) arising from the reaction of 5-A-RU with a dicarbonyl compound. We synthesized a simpler analog, 7-RdX. 7-RdX was shown to act as a weak and selective agonist for MAIT TCR-Tyr94 cell lines, over Tyr95 cell lines. The electron density of 7-RdX from an X-ray structure in complex with the antigen-presenting molecule MR1 is a close match to that for unknown antigen.

Ammonia is commonly used as an indicator of water quality, to assess the impacts of anthropogenic activity on ecosystem function and health. Water quality assessment often relies on the use of expensive equipment requiring a high degree of operator skill, or periodic, discrete, manual sampling and laboratory-based analysis, which is laborious, costly and without the guarantee that episodic pollution events will be detected. Low-cost, portable and/or field-deployable analytical tools are required to overcome this challenge. Hence, research conducted in the context of this thesis involves the development of novel analytical tools for the monitoring of ammonia in marine waters, covering both active and passive sampling. A flow-based analytical method was designed and developed for the determination of total ammonia over a wide concentration range in marine waters using the gas-diffusion spectrophotometric method. Limits of detection similar to that of highly sensitive fluorometric methods was achieved. A novel flow approach was adopted whereby a continuous stream of sample was merged with the sodium hydroxide reagent stream and delivered to a gas-diffusion ammonia separation unit, allowing large sample volumes to be used, rather than being limited by the use of discrete samples. The working range and sensitivity of the method could be tailored by simple modification of the sample volumes used, and by minor adjustments to the program used to control the instrument, without the need to make changes to the manifold. Three working ranges were obtained, and the analytical figures of merit are described. This project was an enabling step in the development of an ammonia gas-diffusion passive sampling device, as it allowed the measurement of low concentrations often found in field samples, as well as high concentrations accumulated in the passive sampler’s receiving solution, using the same instrumentation and reagents. A passive sampling device based on gas-diffusion across a hydrophobic membrane was developed and successfully applied for the determination of the time-weighted average concentration (Ctwa) of ammonia in marine waters for a period of 3 to 7 days. Molecular ammonia (NH3) present in the sampled source solution (SS) diffuses through a hydrophobic membrane into an acidic receiving solution where it is ionised and accumulated as NH4+ which is directly proportional to the NH3 concentration in the SS. Biofouling limited the application of the first gas-diffusion-based passive sampler (GD-PS) prototype to 3 days, and a number of antifouling strategies were therefore assessed, with a copper mesh enabling the sampling period to be extended to 7 days. The effects of environmental variables (temperature, pH and salinity) on NH3 accumulation were also investigated, and the Group Method of Data Handling (GMDH) Algorithm was used to develop a single calibration model for a range of environmental conditions (10 to 30 degrees C, pH 7.8 to 8.2, salinity 20 to 35). PSDs were deployed at four estuarine and marine sites in Nerm (Port Phillip Bay), south eastern Australia, achieving good agreement between passive and automated discrete sampling methods (maximum relative error between -12 % to -19 %). The GD-PS covers the revised water quality trigger value (160 ug L-1 NH3-N) and allows for episodic pollution events to be successfully detected, highlighting this as an exciting new tool for water quality assessment.

This thesis describes investigations of gas-phase molecular cations --- protonated azobenzenes, ruthenium sulfoxide coordination complexes, and the ferrocenium and tropylium cations --- using electronic action spectroscopy. Protonated azobenzenes and ruthenium sulfoxide complexes are prototypical molecular photoswitches, which reversibly change isomeric form in response to light, and are building blocks of light-activated molecular machines. The ferrocenium cation is, along with its reduced form ferrocene, a common redox standard and an archetypal organometallic complex. Tropylium is a 6 pi-aromatic molecule with rare sevenfold symmetry and is involved in the combustion of aromatic hydrocarbons. The electronic spectra of these molecular cations, recorded by measuring photoisomerisation or photodissociation yields as a function of wavelength, provide insight into their electronic and molecular structures. Action spectra of the protonated azobenzene and 4-aminoazobenzene cations are obtained by measuring the trans-to-cis photoisomerisation yield over the 350--600 nm range. One band corresponding to the S1 <- S0 pi-pi* transition is observed for each species with maxima at 435 and 525 nm for protonated azobenzene and 4-aminoazobenzene, respectively. The transitions are assigned based on density functional theory and coupled cluster calculations. The experimental and computational results indicate that photoisomerisation occurs following pi-pi* excitation in protonated azobenzenes and that the lowest-energy pi-pi* transitions are significantly red-shifted compared to their neutral azobenzene counterparts. Ruthenium bis-sulfoxide bipyridyl coordination complexes undergo linkage photoisomerisation, where the binding modes of two sulfoxide groups in a chelating ligand change from S- to O-bound following electronic excitation. Photoisomerisation is observed over the 295--515 nm range following excitation of distinct metal-to-ligand charge transfer and ligand-centred pi-pi* transitions. Concerted isomerisation of both sulfoxide groups from S- to O-bound following single-photon absorption is the predominant gas-phase pathway, whereas sequential isomerisation of each sulfoxide group, requiring two photons of two different wavelengths, is the only process observed in solution. Comparison of the gas-phase results with time-resolved experiments in solution suggest the apparent change in dynamics upon solvation is caused by rapid quenching of vibrational energy in the electronically-excited state associated with isomerisation. Electronic spectra of the ferrocenium cation, Fe(C5H5)2+, are measured over the 560--640 nm range through photodissociation of its weakly-bound complexes with neon and argon. Band systems with origin transitions at 15830 cm-1 and 15809 cm-1 for the neon and argon complexes, respectively, are assigned to the B 2E1' <- X 2E2' ligand-to-metal charge transfer transition, on the basis of multireference electronic structure calculations. The dominant vibrational progression corresponds to the totally-symmetric ligand-metal-ligand stretching mode v4 with a spacing of ~285 cm-1. Several non-Franck-Condon bands likely arise from a weak Jahn-Teller effect or from spin-orbit coupling. The vibronic bands measured for the neon complexes are sharp, whereas those for the argon complexes are broad and show substructure. Vibronic coupling in the S1 1E3' state of the tropylium cation, C7H7+, is characterised using density functional theory, coupled cluster, and multiconfigurational self-consistent field electronic structure calculations. The weak, forbidden A 1E3' <- X 1A1' transition, recorded over the 250--285 nm range through photodissociation of tropylium-argon complexes, is found to gain intensity through Herzberg-Teller coupling to the bright B 1E1' state mediated by vibrational modes with e2' and e3' symmetries. A weak Jahn-Teller effect occurs in the A 1E3' state associated with the v7 (e1') mode, although its influence on the electronic spectrum is predicted to be small. The spectroscopic investigations of these molecular cations lay the foundations for further exploration of their photoisomerisation dynamics and vibronic interactions. Time-resolved experiments should complement the photoisomerisation action spectra by following the excited-state dynamics of these photoswitches in real time. The vibrationally-resolved spectra of ferrocenium and tropylium should provide starting points for high-resolution spectroscopic investigations of these cations. The reported spectra should serve as benchmarks for accurate electronic structure theories, which may help to guide future experiments.

Palladium-catalysed alkoxy- and aminocarbonylation of aryl (pseudo)halides provides efficient access to aromatic esters and amides. The broad application of this approach has been restricted by functional group tolerance, high reaction temperatures and moderate catalyst efficiency. Free-radical carbonylation is a complementary approach not confined by the same inherent limitations of palladium-catalysed carbonylative cross-coupling methodology. The development of free-radical carbonylation has been hindered by the ability to selectively generate the carbon-centred radical species and the high pressures of carbon monoxide required to drive the carbonylation step. This thesis describes the development of visible light photoredox-catalysed alkoxy- and aminocarbonylation of aryl (pseudo)halides. Visible light photoredox-catalysis is a potent method to generate carbon-centred radicals selectively under mild reaction conditions. Aryl radicals can be trapped by carbon monoxide to afford carbonyl compounds. Continuous flow chemistry is utilised throughout, employing tube-in-tube semipermeable membrane reactor technology, to enable precise control over reactions conditions and safe use of carbon monoxide. Chapter 1 introduces carbonylation and elaborates on carbonylative cross-coupling of aryl (pseudo)halides. It further introduces continuous flow processing in synthetic chemistry (flow chemistry) and details the application of flow chemistry to carbonylative cross-coupling and photochemical reactions. Chapter 2 established a continuous flow platform for high pressure gas-liquid photochemistry. The flow system consisted of a pumping module, a reagent delivery module, a Teflon AF-2400 tube-in-tube reactor for saturation of the reaction stream with carbon monoxide, a photoreactor and pressure regulation devices. The photoredox-catalysed alkoxycarbonylation of aryl diazonium salts was selected to evaluate the performance of the flow system. It was determined that excellent yields of the benzoate ester could be achieved at significantly lower partial pressures of carbon monoxide and processing time than in batch. Chapter 3 details the development of a free-radical annulative addition/alkoxycarbonylation cascade reaction. The developed methodology was applied to the synthesis of a diverse library of novel 3-acetate functionalized 2,3-dihydrobenzofurans from widely accessible allyl aryl diazonium ethers. Application of the previously established continuous flow system enabled dilute reaction conditions to effectively control the propagation of competitive intermolecular radical addition side reactions without compromising on reaction throughput or space-time yield. Chapter 4 describes the development of photoredox-catalysed aminocarbonylation of aryl halides. The developed methodology was applied to the synthesis of both electron rich and electron deficient benzamides at room temperature. Spectroscopic and theoretical computational studies were conducted to elucidate the reaction mechanism. A novel tandem photoredox catalytic manifold was proposed that features the transformation of Ir(dtbbpy)(ppy)2]PF6 in the presence of DIPEA to generate a distinct highly reducing Ir-complex capable of engaging energy demanding aryl halides. Chapter 5 provides a summary of the work described in this thesis. Supplementary data is included in the appendix.

In recent years, molecular analogues to electronic devices have been sought after to remedy the practical limitations imposed on classical circuits by Moore's law leading to the inception of the multidisciplinary research field of molecular electronics. In addition to the miniaturisation of current electronic technologies, researchers have sought also to exploit the interplay between the spin degree of freedom inherent to magnetic molecules embedded in devices and to the local electronic currents to which they are coupled. Single-molecule magnets (SMMs), metal complexes with large magnetically anisotropic spin moments that exhibit slow relaxation effects, have enjoyed a position in the subfield of molecular spin-electronics (spintronics) as magnetic units that may act as elements in new molecular-scale spintronic technologies. In this thesis, three projects composed of theoretical models of spin transport through single-molecule magnet-based spintronic devices are presented which serve to predict and explain the quantum spin dynamics exhibited by novel device set-ups that are based on current state-of-the-art experimental systems. In the first project, I have contributed to the development of two models of spin-polarised transport through a general molecular nanomagnet device that is perturbed either by some time dependent, resonant perturbation or by a static perturbation. In the former case, a study of the time evolution of the quantum states of the nanomagnet revealed Rabi oscillations between spin states that are resonantly coupled by the perturbation, suggesting that these states could behave as a molecular qubit for quantum computation that is addressed with a spin-polarised current. In the steady-state limit of the time-dependent model the device functions as a spin current pump, amplifier and inverter which could be potentially useful for logic gates in novel circuitry based on the spin degree of freedom of an electronic current rather than on the charge; these effects are preserved in time-averaged current measurements of the device operating under a pulsed radiation regimen. In the second model, the spin inversion property of the device is preserved even when using a static rather than a time-dependent perturbation owing to a mixing between electric current blockaded and non-blockaded states. In the second project, I have contributed to the theoretical description of electron transport through a molecular break junction device housing a single terbium \begin{em}bis\end{em}-phthalocyaninato (TbPc$_2$) nanomagnet. The model developed in this project is shown to capture all experimental properties measured for the single-molecule device, in particular, its magneto-conductance dependence on the applied magnetic field, gate and bias voltage. Crucially, using the model it was possible to confirm that different states of the molecular magnet give rise to disparate signals in the magneto-conductance which may be used to perform an electrical read-out of the molecular states of the device. At variance with previous interpretations that advocated for a strongly coherent regime of electron transport through the device, the behaviour of the experimentally observed magneto-conductance is shown here to be fully captured within the incoherent sequential tunnelling regime. In the third project, I have contributed to the understanding of an experimentally realised molecular spin valve by providing the first simulations of the hysteresis of the differential magneto-conductance for a hybrid molecular-quantum point contact three-terminal device, triggered by the slow relaxation of the SMMs grafted to the device in a time-dependent sweeping magnetic field. The transport dynamics were modelled here in a completely incoherent transport regime without necessitating the tenuous assumption of spin dependent Fano-resonance interference that were invoked in previous theoretical studies of the devices. The signature of the slow relaxation of two or more TbPc$_2$ single-molecule magnets manifests in magneto-conductance measurements owing to a phonon-mediated direct relaxation process between the Tb electronic states leading to the transient population of non-conducting anti-parallel configurations of the TbPc$_2$ magnetic moments. The model developed here was also able to capture well the temperature dependence of the experimentally measured molecular spin valve magneto-conductance as well as its dependence on bias voltage in the static field regime.

Porphyrins are tetrapyrrolic macrocycles which form highly stable metal complexes crucial to many biological processes. These complexes are characterised by a high kinetic barrier to decomplexation, which is a desirable quality in the design of new radiopharmaceuticals. Positron Emission Tomography (PET) imaging makes use of radionuclides such as copper-64 (half life of 12.7 hours) to aid in the diagnosis of disease. Current reports of porphyrin ligands radiolabelled with copper-64 are limited, due to the typically forcing conditions required to achieve sufficient radiolabelling for application. 2,2’-Bisdipyrrins are acyclic tetrapyrroles that form charge-neutral square-planar complexes with divalent metal cations. They are structurally analogous to porphyrins, although they are suggested to offer superior complexation kinetics under milder conditions. Accordingly, they hold promise as an alternative to porphyrins as potential radiotherapeutics. To date, there have been no reported attempts to translate these ligands into biological applications. This thesis presents the synthesis and characterisation of new (2,2’-bisdipyrrinato) metal(II) complexes and attempts to assess their efficacy for applications in the diagnostic imaging of disease. A number of (2,2’-bisdipyrrinato) copper(II) complexes have been synthesised and shown to be charge-neutral and approximately square-planar in structure based on crystallography. Cyclic voltammetry has elucidated a one-electron transfer process at ca. –1.1 V in all copper(II) complexes, and retention of this process with slight variations in potential for the corresponding Pd(II) and Ni(II) complexes evidences that this process is largely ligand-based in character. Slight shifts between the free base ligand and complexes are associated with structural variations following metal ion coordination. A (2,2’-bisdipyrrinato) copper(II) complex was determined to have a KD of 6 x 10-15 M at pH 7.4 and 25 degrees celcius, and is resistant to copper(II) removal following administration of a high affinity copper(II) chelator at up to 80 degrees Celcius with 50 equivalents of competitor. Interactions of the model ligand with bovine serum albumin (BSA) were demonstrated using fluorescence spectroscopy, and the protective effects of BSA following administration of a reducing agent on the complex supports the formation of BSA-complex interactions in situ. Preliminary work has also shown the aforementioned ligand based electrochemistry is potentially sufficient to mediate some decomplexation. Cell studies involving four different cell lines have shown that membrane permeability is significantly affected by the peripheral substitution of the 2,2’-bisdipyrrin. Oligo(ethylene glycol) substituents and negative charges limit the membrane permeability, while charge neutral or positively charged derivatives with comparatively small substituents were shown to cross membranes with the highest efficacy. Preliminary radiolabelling of the 2,2’-bisdipyrrins is efficient under mild conditions, although the presence of the oligo(ethylene glycol) substituents inhibits this. Biodistribution of a representative complex labelled with copper-64 in mice is distinct from the biodistribution of the unchelated [64Cu]Cu(OAc)2, indicating in vivo stability following administration. The stability studies in conjunction with the membrane permeability and biodistribution of selected (2,2’-bisdipyrrinato) copper(II) complexes suggest this new family of complexes are superior to porphyrins for applications in diagnostic imaging.

Despite significant advances over the past few decades, most free radical reactions are traditionally carried out in organic solvents that are often toxic, flammable, and difficult to recycle. It is therefore timely to explore whether and how free radical chemistry can be moved away from "conventional" solvents into ionic liquids. Ionic liquids are green alternatives to traditional organic solvents, being recyclable, non-volatile, non-flammable and air resistance. Ionic liquids are composed entirely of ions, and they can be designed for specific applications by the variation of either the anions, cations or by modification on the substituents on the anion and cation. Therefore, a wide variety of ILs structure is available for various requirements. For example, the physical properties of the ILs including density, viscosity, melting point, hydrophobicity and solubility of the ILs can be tuned. While chemistry involving ionic liquids has dramatically increased in the last decade, their impact upon chemical kinetics is still unclear. Further, very little traditional radical chemistry has been performed in ionic liquids, and it is essential to understand how critical rate constants for hydrogen atom transfer and radical rearrangements are impacted by these alternative solvents. Although ionic liquids are often considered as ‘green solvents’, it is their ionic nature in particular that may influence reactivity and selectivity of radical reactions. In this work the first kinetic parameters for the intramolecular homolytic cyclisation of a series of alkyl and alkoxyl radicals, intramolecular homolytic substitution at selenium and intermolecular homolytic addition at double bond in the [EMIm][NTf2], an imidazolium-based ionic liquid, as well as in organic solvents such as benzene, n-hexane or t-butylbenzene have been reported. Through the combination of laser flash photolysis and competition kinetic studies we obtained the absolute rate coefficient for the hydrogen abstraction from t-BuSH by primary alkyl radicals in [EMIm][NTf2], which was about five times higher than kH in conventional organic solvents. Competition kinetic studies were used to determine kC for a number of 5-exo radical cyclisations and an intramolecular homolytic substitution on Se, which are up to one order of magnitude higher in the ionic liquid than in organic solvents. Generally, the rate of the 5-exo cyclisation at room temperature is up to 50% more facile in the ionic liquid, depending on the nature of the radical, without any impact on the stereochemical outcome. The faster cyclisations observed for all studied radicals in [EMIm][NTf2] is ascribable to the favourable activation entropies for all radicals that are suggestive of less-organised transition states for the 5-exo cyclisation, compared to the corresponding reactions in conventional organic solvents. Lowering the viscosity of ionic liquid by performing the reaction at elevated temperatures led to a significant acceleration in the cyclisation rate. No interfering reaction involving the ionic liquid constituents were observed and all products can be quantitatively extracted from the ionic liquid phase, which can be reused without purification. On the whole, our results highlight the potential of ionic liquids as alternatives to conventional organic solvents for radical cyclisations, intramolecular homolytic substitutions with neutral radicals and intermolecular radical addition to the alkene.

Several zinc porphyrin small molecules and pendant polymers were synthesized in order to assess their ability to act as dual absorber-upconverters in both solution and solid-state triplet-triplet annihilation mediated non-coherent photon upconversion (NCPU-TTA) systems. Control over the proximity, relative orientation and degree of orbital overlap between zinc porphyrin chromophores was exercised through covalent structural design in each set of studied zinc porphyrin derivatives. Structure-property relationships were determined through photophysical analyses of the zinc porphyrin compounds. Photophysical analyses were able to provide the basis for mechanistic models that detailed excitonic decay processes in the zinc porphyrin compounds. Meso-diaryl- and meso-tetraaryl-substituted zinc porphyrin derivatives were synthesized with varying steric bulk at the meso-aryl-substituents. The absorption and S1 emission properties of all compounds were able to be interpreted through established porphyrin orbital theory. The lower delta OD values observed in the transient absorption spectra of the di-substituted compounds were consistent with the relative solution-state NCPU-TTA S2 fluorescence yields obtained for the di-substituted compounds compared to the tetra-substituted compounds. The NCPU-TTA S2 fluorescence yields generally increased with increasing steric bulk in in both the di- and tetra-substituted series in solution. NCPU-TTA S2 fluorescence was not observable in the solid state for the di-substituted series, however the NCPU-TTA S2 fluorescence yields increased approximately 20 fold in the solid-state for zinc(II) tetramesitylporphyrin 2.6 compared to zinc(II) tetraphenylporphyrin 2.4. Computational analyses provided insight into the observed NCPU-TTA S2 fluorescence trends. A series of polymers with pendant zinc porphyrin units containing beta-oligo-para-phenylene vinylene (beta-oligo-p-PV) substitutents were synthesized via post-polymerization functionalization methods and Horner-Wadsworth-Emmons olefination. The beta-oligo-p-PV substituents on the zinc porphyrin pendants were designed to act as pendant-to-backbone linking moieties in the pendant polymers. Monomeric analogues of the pendant polymers were synthesized for photophysical comparison. The absorption spectra of the pendant polymers demonstrated reduced extinction coefficients with respect to their monomeric analogues and Soret broadening characteristic of chromophores in close proximity, however no exciton coupling was observed. The fluorescence quantum yields of the polymers remained almost unchanged with increasing beta-conjugation length with the exception of a minor increase in emission intensity from the Q(0,0) vibronic band. The fluorescence quantum yields of the polymers were reduced more than 50% in comparison to the monomers. The dominant triplet absorption bands in the monomers were approximately 5 – 9% as intense in their respective polymer spectra. Pendant zinc porphyrin polymers with rotatable stilbene and benzyl ether pendant-to-backbone linking groups were synthesized by post-polymerization functionalization. Red-shifting and broadening of absorption maxima were observed upon inclusion of porphyrins into the pendant polymer structure. Bi-exponential fits to the polymer fluorescence decay profiles were attributed to rotation-induced excimer-type quenching between pendant porphyrin units in the S1 excited state. The polymer NCPU-TTA S2 fluorescence quantum yields in toluene were 2 orders of magnitude lower than their respective monomer analogues, being of the order of 10-7. The NCPU-TTA S2 fluorescence intensity of the polymer 4.6 in the coordinating solvent THF was reduced less than for the analogous monomer 4.3 due to restricted access of THF molecules to the metal centre in the crowded pendant environment. Triplet absorption intensities of the polymers were approximately 10% of that observed for their respective monomeric analogues. Triplet decay profiles of the monomeric compounds were able to be fit to first-plus-second order kinetic equations that account for TTA occurring in the monomers. The polymers displayed a region of rapid decay at the beginning of their triplet decay profiles that could not be accounted for by TTA due to the very low polymer NCPU-TTA S2 fluorescence quantum yields. The polymer triplet decay profiles were able to be adequately modeled by three competing first- and pseudo-first order decay processes which were attributed to intersystem crossing to the ground state in addition to both intra- and intermolecular quenching of pendant porphyrins by neighbouring porphyrins in the ground state. Rapid excited state decay and exciton quenching in both the singlet and triplet states of the pendant zinc porphyrin polymers studied in this thesis likely render them as poor dual absorber-upconverter compounds for NCPU-TTA systems.

Abstract We have developed new synthetic methods for the modification of peptides, exploiting acyl transfer reactions of isoimides. We have developed a new approach for the chemoselective synthesis of N-glycopeptides, using a Ag(I)-promoted coupling. We have successfully applied the Ag(I)-promoted coupling of aspartic acid containing peptide thioamides and glycosyl amines to the chemoselective synthesis of N glycosylated asparaginyl motifs. The methodology employs peptides possessing a thioamide group adjacent to the aspartic acid residue. Intramolecular Ag(I)-promoted coupling of the aspartic acid side-chain carboxylate with the thioamide generates an isoimide intermediate that is trapped by an external glycosyl amine to form an amide bond and generate an N-glycoasparagine. A range of thiopeptides containing unprotected carboxylates undergo Ag(I)-promoted coupling with glycosyl amine derivatives, leading to the preparation of N-glycosylated asparaginyl peptides. Moreover, this method enables the site-selective generation of N-glycosyl asparagines in peptides possessing multiple unprotected carboxylate side chains groups. We have also investigated analogous reactions of peptide thioamides possessing a lysine residue, wherein coupling of the aspartate and lysine side chains generates Lys–Asp side-chain lactam-linked peptides. Thiopeptides with i,i+2, i,i+3, and i,i+4-spaced Lys and Asp residues undergo intramolecular Ag(I)-promoted coupling to give lactam bridged peptides. The final chapter describes initial investigations towards elaborating the Ag(I)-promoted reaction to the synthesis of 18F-radiolabelled peptides. The Ag(I)-promoted method was shown to be effective for the coupling of [18F]-fluorobenzoic acid with thiopeptides, generating18F-fluorobenzoylated peptides.

Positron emission tomography (PET) is a molecular imaging technique that produces three-dimensional images in high resolution and is used to assist in the diagnosis and monitoring of disease. The technique relies on molecules radiolabelled with a positron-emitting radionuclide called ‘tracers’ injected into patient at ‘trace’ concentrations. The most used radionuclide for PET is fluorine-18. Conventional approaches to fluorine-18 radiolabelling rely on the formation of a covalent C-18F bond and such synthetic chemistry can be challenging. It has been suggested that coordinate bond formation between Al3+/Ga3+ and F- may lead to complexes of sufficient stability due to the high metal fluoride bond energy. The work presented in this thesis investigates the potential of the formation of Ga3+-F- complexes as alternative method for rapid incorporation of fluorine-18 into molecules. A series of pentadentate acyclic ligands based on the dipicolinic acid scaffold (H2L3-5) that coordinate to Ga3+ were prepared. Characterisation of [GaL3(OH)], [GaL3Cl] and [GaL3F] by X-ray crystallography revealed that in each case the ligand acted as tetradentate donor with a weak interaction with a sixth nitrogen donor. Treatment of [GaL3(OH)] / [GaL3Cl] with [18F]/H2O at room temperature readily formed [GaL3F]. Although the synthesis of [GaL3F] was straightforward, it was only possible to form [18F][GaL3F] in very low radiochemical yields. In a second approach a family of macrocyclic ligands was adopted to develop a single chelate system that has the potential to be radiolabelled with three radionuclides; fluorine-18, copper-64 and gallium-68. A stilbene derivative attached to the NODA chelator, H2L12 was designed to bind to amyloid b (Ab) plaques associated with Alzheimer’s disease (AD). The ability to identify the burden of insoluble aggregates in the brain in a non-invasive manner may assist our understanding of AD. The new ligand, H2L12 binds to extracellular Ab plaques present in human brain tissue, but there was no evidence that [GaL12F] and [CuL12] bound to Ab plaques. The radiolabelled [18F][GaL12F], [68Ga][GaL12F] and [64Cu][CuL12] formed in high radiochemical purity at pH 4-5.5. The biodistribution and PET imaging potential of [18F][GaL12F] and [64Cu][CuL12] was evaluated in mice and this revealed the initial uptake in brain of [18F][GaL12F] and [64Cu][CuL12] were 0.85 +- 0.13% IA/g and 0.71 +- 0.03% IA/g respectively. An increase in uptake in bone suggested that the [18F]Ga3+-F- system is unstable in vivo. A tetradentate azamacrocyclic ligand with N4 donor set, tetramethyltetraaza[14]annulene (tmtaa) was investigated to replace the carboxylate donor groups in [GaL3F] and [GaL12F]. A five coordinate Ga3+-F- complex of tmtaa was prepared. [Ga(tmtaa)F] was characterised by X-ray crystallography revealing the complex has a saddle-shaped geometry. The radioactive complex, [18F][Ga(tmtaa)F] can be prepared by a halogen exchange reaction starting with [Ga(tmtaa)Cl]. Functionalisation at the methine carbon atoms of H2tmtaa could see future development to include biomolecules. Translation of the non-radioactive Ga3+-F- chemistry to systems containing fluorine-18 remains challenging. The work presented here demonstrated that the [18F]Ga3+-F- complexes are less stable than the Al3+ analogues. It would be of great interest to investigate the potential of the [18F]Al3+-F- complexes of these families of ligands as PET imaging agents.