The three-dimensional structure of proteins and receptor binding sites requires small molecule drug candidates with complex molecular shapes, to enable greater receptor specificity and potency. A logical strategy to increase conformational complexity in small molecule drug candidates is to incorporate sp3 hybridised centres into the carbon structural framework. However, the reliance on sp2-sp2 cross coupling methodologies in medicinal and high throughput combinatorial chemistry has resulted in chemical libraries that are dominated by planar molecules. Consequently, the development of new methods to forge new C(sp3)-C bonds and rapidly access conformationally complex molecules is vital to accelerating contemporary drug discovery. This thesis aims to address this challenge in the chemical and medical sciences, by focussing on the development of novel methodologies to access C(sp3)-C bonds. To achieve this, attention is placed on two possible approaches to synthesise saturated carbon skeletons; namely, transition metal catalysed cross coupling and alkene hydrofunctionalisation (including hydrogenation) reactions enabled by visible light mediated catalysis. In chapter one, transition metal catalysed cross coupling of sp3 fragments and alkene hydrofunctionalisation is introduced and their key limitations identified. Next, strategies that have been employed to overcome these limitations are discussed. Specifically, the use of visible light photoredox catalysis has shown to be effective in affording distinct reactivity and selectivity in these reactions, compared to thermal approaches. Finally, the research focus and aims of this thesis are elaborated. Chapter 2 builds on a recent discovery by the Polyzos laboratory, which established that cyclopalladated complex consisting of 8-aminoquinoline auxiliary exhibits a long-lived excited state capable of undergoing light induced single electron transfer with alkyl halides and providing access to Pd(II)/Pd(III)/Pd(IV) redox couples. The use of this complex to achieve light induced C(sp3)-H cross coupling is investigated. Furthermore, an investigation is conducted to establish whether other cyclopalladated complexes similarly display long-lived excited states that can be harnessed for C-C cross coupling. During reaction optimisation, it was found that extensive decomposition of cyclopalladated complex occurs, following single electron transfer to aryl halides, likely due to the formation of hybrid aryl palladium(III) radical pairs. Chapter 3 describes the development of a novel C(sp3)-C cross coupling methodology using energy transfer catalysis. Specifically, the energy of excited state cyclopalladated complex consisting of 8-aminoquinoline auxiliary is transferred to polyaromatic hydrocarbons, to enable the reduction of energy demanding aryl bromides and prevent the decomposition pathways observed in chapter 2. The resulting aryl radical is trapped by ground state cyclopalladated complex with subsequent reductive elimination affording a C(sp3)-arylated product in excellent yield. In chapter 4, a novel mode of alkene activation is developed via photoredox catalysed single electron reduction. This is achieved using the multiphoton, tandem catalytic mechanism of heteroleptic iridium photocatalyst, [Ir(ppy)2dtbbpy]PF6, discovered in the Polyzos group. The reactivity of the resulting olefinic radical anion is effectively controlled to achieve a formal hydrogenation of 1,1-diarylethylenes and substituted styrenes. Mechanistic studies including luminescence quenching, deuterium labelling and radical clock experiments indicate a Birch-type reduction as the major reaction pathway. In chapter 5, an unexpected aminomethylated by-product observed in chapter 4 is optimised to establish the first photoredox catalysed aminomethylation of electron rich alkenes (1,1-diarylethylenes). During this, the ability of other heteroleptic iridium photocatalysts to engage in the tandem catalytic paradigm is investigated, to expand the reaction scope to include unprotected secondary amines. Mechanistic studies indicate that the single electron activation of both alkene and amine coupling partners, via the multiphoton tandem catalytic system, is vital for aminomethylation to occur. Chapter 6 details the experimental procedures used throughout this thesis, including spectroscopic data of all isolated compounds.

Regular monitoring of heavy metal ions concentrations in aquatic systems is essential to determine their availability to the environment and evaluate their potential risk due to their toxicity to aquatic organisms. The passive sampling based on the use of a polymer inclusion membrane (PIM) as the semipermeable membrane barrier between the sampled medium and a liquid receiving phase has been recently introduced as a promising analytical tool, not only due to the superior stability of PIMs compared to supported liquid membranes, but also because it contains a liquid receiving phase which can be analysed directly, thus simplifying its processing prior to analysis. However, passive sampling based on PIMs is relatively new and limited research has been directed towards overcoming the issues associated with the effect of environmental variables on the performance of such passive samplers. Hence, the research described in this thesis aims at further developing PIM-based passive sampling devices for Zn2+ as the model analyte. This research includes the development of a 3D-printed flow-through passive sampling device (PSD), and the study of the influence of several environmental factors (i.e., flow pattern, water matrix, and temperature) on the accumulation of Zn2+ ions, and the assessment of strategies to either minimize or eliminate their effects on the estimated time-weighted average (TWA) Zn2+ concentration.

This work focuses on the measurement and analysis of gas-phase electronic spectra of C4H2+, C4H4+, C4H5+, and C6H4+ cations. The spectra are recorded by photodissociating the cations, or their messenger tagged complexes, in a tandem mass spectrometer and monitoring the photofragment signal as a function of laser wavelength. Ultimately, structural and energetic information extracted from these spectra, complemented by quantum chemical calculations, may provide insights into the roles of cations in the chemistry of flames, plasmas, and extraterrestrial environments. Understanding the vibronic structures of the cations is also fundamental for facilitating their possible detection in remote environments. Electronic spectra of C4H2+-Ar_n (n = 1-3) and C4H2+-(N2)_n (n = 1-2) complexes are recorded over the 290-530 nm range by monitoring C4H2+ photofragments. Intense narrow bands in the visible region arise from the A2(Pi)u<--X2(Pi)g electronic transition of the diacetylene cation, HC4H+. Vibronic transitions are compared with previous results and theoretical predictions for the A2(Pi)u<--X2(Pi)g band system based on calculations at the CCSD/cc-pCVTZ and EOM-CCSD/cc-pCVTZ levels of theory. Hole burning experiments confirm that the weak, broad bands in the ultraviolet region also correspond to excitations of HC4H+. These bands are assigned to the 22(Pi)u<--X2(Pi)g electronic transition based on calculated energies and oscillator strengths, previous experiments, and spectra of isoelectronic molecules. The origin transition is observed at 29723 cm-1 (336.44 nm) for HC4H+-Ar, followed by a progression in the symmetric C-C stretch vibration, spaced by 906 cm-1. Spectral congestion observed toward shorter wavelengths is possibly due to the presence of close-lying electronic states, vibronic coupling effects, and HC4H+ being bent in the 22(Pi)u electronic state. Electronic spectra of Ar- and N2-tagged C4H4+ cations, generated from acetylene ion-molecule reactions, are recorded over the 296-550 nm range by monitoring C4H4+ and C4H3+/C4H2+ photofragments. The spectra exhibit a clearly resolved band system commencing at 511 nm, a set of weak bands around 410 nm, and an intense broad band in the UV. Band assignments are based on previous spectroscopic studies and calculations for the four lowest energy C4H4+ isomers. The visible region of the spectrum is dominated by the B2A’’<--X2A’’ electronic transition of the vinylacetylene cation (VA+) whose origin transition occurs 19558 cm-1 (511.30 nm) for VA+-Ar and at 19551 cm-1 (511.48 nm) for VA+-N2. The spectrum features a strong progression in the central C-C stretching vibration spaced by approximately 806 cm-1 and well defined vibronic transitions associated with two bending vibrational modes. The weaker 410 nm system is assigned to the D2B3<--X2B2 electronic transition of the butatriene cation (BT+). Two broad bands, following the origin transition at 24399 cm-1 (409.85 nm) in the C4H4+-Ar spectrum, arise from excitation of a symmetric C=C stretching vibration and possibly the CH2 twisting vibration. The observation of C4H4+ and C4H3+ /C4H2+ photofragments following excitation of BT+-Ar complexes over the 380-410 nm range accords with calculated dissociation pathways on the ground state C4H4+ potential energy surface. The broad band appearing at wavelengths below 320 nm is predicted to be due to electronic transitions of all four of the lowest energy C4H4 + isomers, including the VA+ and BT+ cations. The B2A’<--X2A’ electronic spectrum of the 1-butyn-3-yl cation (H3CCHCCH+) is recorded over the 245-285 nm range by photodissociating the bare cation and its Ne and Ar-tagged complexes. Origin transitions for H3CCHCCH+ and H3CCHCCH+-Ne are observed at 35936 cm-1 (278.27 nm) and 35930 cm-1 (278.32 nm), respectively. Additional bands in the spectra are assigned to vibronic transitions of H3CCHCCH+ through quantum chemical calculations and comparison of the spectra with those of similar molecules, the propargyl (C3H3+) and methyl propargyl (H3C4H2+) cations. Excitation of H3CCHCCH+ produces C2H3+ +C2H2 (protonated acetylene + acetylene) and C4H3+ +H2 (protonated diacetylene + hydrogen molecule) photofragments. The preferred formation of C2H3+ +C2H2 photofragments is correctly predicted by master equation simulations, generated from calculated dissociation pathways on the ground state C4H5+ potential energy surface. Electronic spectra of Ar- and N2-tagged C6H4+ cations, generated from acetylene ion-molecule reactions, are recorded over the 265-700 nm range by monitoring C6H4+ and C4H2+ photofragments. Bands are assigned to transitions of five isomers based on previous spectroscopic studies, calculated stationary points on the ground state C6H4+ potential energy surface, hole burning experiments, and spectral simulations generated from TD-DFT calculations. In the C6H4+-Ar spectrum, bands over the 526-700 nm range arise from the B2A’’<-- X2A’’ electronic transition of the 1-hexene-1,3-diyne cation (CH2CHCCCCH+) and the C2Bg <-- X2Au electronic transition of the trans-3-hexene-1,5-diyne cation (HCCCHCHCCH+), with origin transitions occurring at 604 and 581 nm, respectively. Over the 375-460 nm range, broad bands at 440, 425, and 423 nm are assigned to vibronic transitions within the C2A’’<-- X2A’’ band system of the 1-ethynyl-3-methylene-cyclopropa-1,2-diene cation (H2C[c –C3H]CCH+). Sharper bands at 416, 407, and 400 nm are ascribed to the B2A’’<-- X2A’’ electronic transition of the propargyl cyclopropene cation ([c –C3H2]CHCCH+). Between 265 and 375 nm, several bands appear, superimposed on a broad band that extends for several thousand wavenumbers. The 371 nm band is assigned to the B2A’’<-- X2A’’ origin transition of the 1-hexene-1,3-diyne cation (CH2CHCCCCH+), agreeing with previous assignments. In light of the TD-DFT calculations, the bands at 365 and 357 nm are tentatively reassigned to the C2B<--X2B electronic transition of the propadienylidene cyclopropene ([c –C3H2]CCCH2+) isomer. The underlying band possibly arises from the C2Bg <-- X2Au electronic transition of the trans-3-hexene-1,5-diyne (HCCCHCHCCH+) cation, which undergoes a reduction in symmetry upon photoexcitation. Formation of C4H2+ photofragments at wavelengths below 426 nm (2.91 eV) agrees with calculated C6H4+ dissociation pathways on the ground state C6H4+ potential energy surface.

The ubiquity of amines in pharmaceutical, agrochemical and advanced materials has incentivised modern synthetic chemists to develop novel and innovative methods for their synthesis and functionalisation. Specifically, the direct alpha-C-H functionalisation of aliphatic amines represents one such transformation which demands further development and improvement of current methodology. Visible-light mediated catalysis has presented a powerful platform to facilitate this transformation, with several pathways established to achieve the alpha-functionalisation of amines. This thesis is an exploration of the visible-light mediated functionalisation of aliphatic amines. Specifically, it explores the formal alpha-functionalisation of amines via the generation of alpha-amino radicals as key intermediates and investigates subsequent pathways of reactivity. The methodologies developed have been applied to the synthesis of biologically relevant amine scaffolds. Upon optimisation, continuous flow protocols were established to enhance the photochemical reaction conditions. Chapter 1 summarises the protocols for the alpha-functionalisation of amines. A brief history of this transformation is explored, highlighting several methodologies and is accompanied by a critical evaluation of their benefits and limitations. The concept and principles of photoredox catalysis are introduced and notable examples examined within the context of photocatalytic protocols for amine alpha-functionalisation. Finally, flow chemistry is presented detailing its advantages with emphasis towards photoredox catalysis. Chapter 2 establishes a visible-light mediated transfer hydrogenation of diarylmethimines. This process makes use of the single electron reduction of imines to engender alpha-amino radicals with triethylamine functioning as both a sacrificial reductant and hydrogen source. The developed conditions enabled the synthesis of a series of diarylmethamines to be synthesised with excellent chemoselectivity. A plausible mechanism was established, highlighting the dual role of triethylamine. Flow engineering enabled this procedure to be efficiently scaled to synthetically useful quantities with retention of the chemoselectivity established in batch. Chapter 3 details the development of the decarboxylative alpha-alkylation of fused heterocyclic amines. This process engages fused heterocyclic amines and N-hydroxy phthalimide esters as radical surrogates to simultaneously establish both alpha-amino and alkyl radicals. Upon in situ generation of alpha-amino and alkyl radicals, radical-radical coupling produces the desired alpha-alkylated amine. The addition of co-reductant, diphenylamine is believed to facilitate a second mechanistic pathway that proceeds concurrently and improves the efficiency of this transformation. A flow protocol established more favourable reaction conditions, enabling conjugation of a variety of biologically active derivatives in typically good yields. Chapter 4 introduces the concept of the tandem photocatalytic cycle revealing that in situ generation of a highly reducing iridium species establishes an effective pathway for single electron reduction of energy demanding substrates. This chapter further extends the knowledge of the tandem photoredox cycle, applying this mechanism towards the radical-radical coupling of alpha-amino and alkyl radicals. Accessing a highly reducing species enabled the single electron reduction of energy demanding alkyl halides; substrates previously difficult to access. This chapter further investigates the tandem photocatalytic cycle and establishes an alternative protocol for alpha-amino sp3 C-C bond formation.

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.