This thesis is concerned with the development, application and theoretical treatment of the scanning electrochemical microscope (SEeM), with the aim of obtaining new insights into the kinetics and mechanisms of ionic crystal dissolution processes. The ultramicroelectrode (UME) probe of the SEeM, placed at close distances to the surface of an ionic single crystal face in contact with a saturated solution, was used to induce and monitor the dissolution processes of interest. This was achieved by stepping the potential at the UME from a value at which no electrode reaction occurred to one where a component of the saturated solution was electrolysed at a diffusion-controlled rate. The resulting undersaturation induced the dissolution process and dissolving material, after traversing the tip/substrate gap, was subsequently collected at the UME probe. The current-time behaviour provided quantitative information on the local dissolution rate. The SEeM was successfully used to determine the dissolution characteristics of the (010) face of monoclinic potassium ferrocyanide trlhydrate. A second-order dependence on the interfacial undersaturation was found, consistent with the classical Burton, Cabrera and Frank dissolution model. This investigation proved that the SEeM was capable of delivering high mass transport rates under well-defined conditions and demonstrated that the dissolution of an un symmetric salt could be described by classical theories. In addition, through the development of SEeM dissolution rate imaging, it was shown that it was possible to map the dissolution activity across single pits in the crystal surface with micrometre resolution. The kinetics and mechanism controlling the dissolution of silver chloride is a classical system which, despite a number of studies, remains unresolved. SECM studies of the dissolution of pellets and electrochemically grown films of Agel in aqueous solutions, both in the absence and presence of supporting electrolyte (where the supporting electrolyte does not contain a ion common to Agel), were carried out and the corresponding mass transfer theories developed. In the latter case dissolution was found to be diffusion-controlled, due to the build up of electroinactive ions in the tip/substrate gap, suppressing the attainment of high interfacial undersaturations. In contrast, in the absence of supporting electrolyte, where the principle of electroneutrality prevented this process, the dissolution kinetics were determined unequivocally. In order to significantly increase the spatial resolution of electrochemically induced SECM imaging, a new integrated electrochemical-atomic force microscopy (IEAFM) probe was developed, which simultaneously measured the topography of the surface while electrochemically inducing dissolution under conditions which closely mimicked those of SEeM experiments. Using this technique, it was demonstrated, for the first time, that dissolution of an ionic crystal surface (the (100) face of potassium bromide), under conditions of very low interfacial undersaturation, occurred by the dynamic unwinding of steps at the sites of screw dislocations. Through use of the high spatial resolution and well-defined mass transport characteristics of the SEeM, it was possible to determine the dissolution characteristics, in an area of a crystal surface devoid of dislocations and defects, i.e. a 'perfect' surface. Studies on the (100) face of copper sulfate pentahydrate demonstrated that dissolution, in low dislocation density areas, occurred via an oscillatory mechanism. A new hydrodynamic technique, the microjet electrode, was developed and found to be capable of achieving mass transfer coefficients up to 0.82 cm s-l. The ability of the technique to characterise fast surface processes was demonstrated through kinetic studies of the oxidation of ferrocyanide ions at a Pt electrode. Possible modifications to the technique in order to facilitate the characterisation of dissolution processes were considered.

This thesis describes novel catalysts and methods for the synthesis of nitrogen heterocycles using copper (I) mediated atom transfer radical cyclisation (A TRC). It is divided into six chapters. The first chapter provides a short review on the use of copper (I) salts In radical cyclisation chemistry. The second chapter describes the synthesis and copper (I) mediated A TRC of novel a-halo dienamides derived from a,B-unsaturated ketones. A range of multifunctional heterocyclic building blocks were prepared including pyrrolidinones, tetrahydroisoquinolinones and p-Iactams by 5-exo, 6-endo and 4-exo cyclisation. The third chapter extends the methodology discussed in chapter two to the synthesis and cyclisation of further a-halo dienamides derived from a,B-unsaturated aldehydes. This class of radical precursor was found to cyclise exclusively in the 4-exo mode to give B-lactam products. The fourth chapter looks at the copper (I) mediated 5-endo cyclisation of a-halo keto enamides as a potential route to the synthesis of the heterocyclic ring fragment of natural product ZG-1494a. The fifth chapter describes the synthesis of novel solid supported copper (I) catalysts and their application to the atom transfer radical cyclisation of a-halo amides. A comparison of the activity of these catalysts to solution ligand/copper (I) halide mixtures is made. The reusability of polystyrene supported catalysts in the cyclisation of one radical precursor is discussed. The sixth chapter gives the detailed preparative methods and analytical data for the compounds described in chapters two, three, four and five.

The aqueous interface between biomolecules and inorganic substrates is of interest to many cross-disciplinary areas of science, ranging from fundamental biological research into biomineralisation processes, to the more application-driven fields of nanotechnology and biomimetic materials synthesis. In particular, by harnessing the selectivity observed in Nature, proteins and peptides make ideal candidates for directing the assembly of nanoparticles into nanostructured, multifunctional materials with pre-defined physical properties. The rational design of peptide sequences with tunable affinities either for a substrate of a specific composition, or for a specific crystallographic plane of a given material, would mark an important step towards realising these goals. Before this is possible, however, the fundamental mechanisms involved in peptide substrate binding under aqueous conditions must be understood. Molecular simulation, used throughout this thesis, is well suited for studying biointerfacial systems at the level of detail needed to advance research. The work presented herein is primarily focused on answering the question of whether facet-selective peptide adsorption is indeed possible at the aqueous quartz and gold interfaces. A range of different simulation techniques, all based on atomistic molecular dynamics, are employed. As part of the study, two of the ‘grand challenges’ currently facing biointerfacial simulation–the deviation of force-fields suitable for the interfacial environment, and enhancing conformational sampling of an adsorbed biomolecule–are addressed. Potential of Mean constraint Force free energy of adsorption calculations show that, out of the amino-acid analogues tested, all display energetic and/or spatial selectivity between the (100), (001) and (011) surfaces, on adsorption to Quartz. Facet specificity in binding, for the building blocks from which peptides are comprised, is highly suggestive of the biomolecules themselves displaying similar characteristics. The general trend in small molecule adsorption strength–non-polar aromatic > negatively-charged > non-polar aliphatic > positively-charged–is common to all three aqueous Quartz interfaces. The propensity for negatively-charged ethanoate to bind more strongly to the aqueous, fully hydroxylated (100) a-Quartz surface than positively-charged ammonium is confirmed by first-principles simulations. Selectivity between the Au(111), Au(100)(1×1) and Au(100)(5×1) surfaces is also observed when the gold-binding peptide AuBP-1 [Hnilova et al. [2008]] adsorbs to gold under aqueous conditions. Metadynamics, in combination with the advanced sampling technique Replica Exchange with Solute Tempering, is used to study this system. The impact of Au(100) reconstruction on peptide binding is considered here for the first time. This aspect of gold binding was made possible by a suite of force-fields derived within this work, GolP-CHARMM, for modelling the interactions between proteins and peptides and gold.

The general concepts of the thesis have been introduced in Chapter 1. These include the polymerization techniques that have been utilized and a background to each of the applications that have been targeted. In Chapter 2 the synthesis of poly(tryptophan) though a polymeric scaffold synthesized via RAFT polymerization is investigated. Once synthesized, the monomer and polymer, along with previously synthesized poly(phenylalanine), are used for in the chiral resolution experiments of 1,1’-bi-2-napthol. Chapter 3 focuses on the synthesis of a novel monomer that contains the catalytically active MacMillan catalyst synthesized from L-tyrosine. This enabled immobilization of the MacMillan catalyst into polymers prepared via RAFT polymerization. The monomeric catalyst could then be incorporated into co-polymers at pre-determined specific loadings. These polymers were then used to catalyze the Diels-Alder reaction with great effect and had the ability to be used in a pseudo-continuous process. Chapter 4 places the monomeric MacMillan catalyst into nanogels synthesized through emulsion polymerization. The effect of having the catalyst within this unique environment was studied both through conversion and selectivity. The relatively simple synthesis allowed for the bespoke environment to be readily changed altering the amount of catalyst and co-monomer of the nanogel. In Chapter 5 a new polymerizable L-tryptophan monomer has been synthesized and incorporated into RAFT synthesized polymers and nanogels which were synthesized through emulsion polymerization. Both of these structures fluorescent properties have been investigated; in particular the nanogels ability to function as a FRET pair to the small molecule dansyl amide has been examined. This has allowed for the effect of the structure of the nanogel on small molecule diffusion to be probed.

This thesis explores the use of bromo and thio maleimide functional groups in polymer chemistry. The reactivity of bromomaleimide groups towards thiols is exploited as a new and efficient post-polymerisation modification reaction, while the fluorescence of the dithiomaleimide (DTM) products is utilised for labelling of polymers and polymer nanoparticles. Chapter 1 gives an introduction to ways in which control over free radical polymerisation can be achieved using reversible-deactivation mechanisms. The incorporation of functionality into polymers, and the synthesis of polymer nanoparticles is also discussed, leading to a review of the different strategies for fabrication of fluorescent polymer nanoparticles. In Chapter 2 novel reversible addition-fragmentation chain transfer (RAFT) agents are developed with the aim of introducing monobromomaleimide (MBM) or dibromomaleimide (DBM) as a polymer end-group via RAFT. In Chapter 3 the fluorescent properties of the DTM group are first explored, then a novel RAFT agent/ring-opening polymerisation initiator is used for site-specific introduction of DTM fluorophores into linear polymers. Site-specific introduction of DTM groups by post-polymerisation functionalisation reaction of DBM-terminated polymers (synthesised in Chapter 2) with thiols is also developed. In Chapter 4 novel DTM and DBM-functional vinyl monomers are synthesised, and their RAFT polymerisation with non-functional comonomers is used to incorporate DTM and DBM functionality along polymer backbones. Post-polymerisation functionalisation of these DBM-functional polymers with thiols is also demonstrated. In Chapter 5 fluorescently-labelled polymer nanoparticles containing DTM fluorophores are synthesised, using the DTM-functional RAFT agent developed in Chapter 3, and DTM-functional monomers developed in Chapter 4. Nanoparticles are fabricated by block copolymer self-assembly and emulsion polymerisation. These fluorescent nanoparticles are analysed by steady-state and time-resolved fluorescence spectroscopy to assess their utility as contrast agents. Chapter 6 summarises RAFT polymerisation data from Chapters 2, 3 and 4 to assess the extent to which the DBM and DTM groups interfere in RAFT polymerisation, and the mechanism by which this may occur.

Prodiginines are a large family of red-pigmented antibiotics produced by a range of actinomycetes and other eubacteria that contain the highly-conjugated 4-methoxypyrrolyldipyrromethene core. It has recently been shown that the Rieske oxygenase-like non-haem iron-dependent enzyme RedG is responsible for catalysing the oxidative carbocyclisation of undecylprodigiosin to form the carbocyclic derivative streptorubin B, via functionalisation of an unactivated C-H bond. The mechanism of this chemically challenging reaction has been investigated using a mutasynthesis approach, employing analogues of key biosynthetic intermediates that bear specific functional groups, designed to probe different aspects of the proposed catalytic mechanism. Analogues of the biosynthetic intermediate 2-undecylpyrrole bearing sulphides, ethers, cyclopropanes, methyl substituents and deuterium labels in the undecyl chain have been synthesised and fed to Streptomyces coelicolor mutants blocked in the biosynthesis of 2-undecylpyrrole. These 2-undecylpyrrole analogues have also been fed along with synthetic 4-methoxy-2,2’-bipyrrole carboxaldehyde to Streptomyces albus expressing redH and redG. The results of these feeding experiments have confirmed that RedG utilises molecular oxygen, is capable of catalysing dealkylation of an ether and revealed that the pro-R hydrogen atom from C-7’ of the undecyl chain is specifically abstracted during the oxidative carbocyclisation. The results also showed that RedG is not able to tolerate substrate analogues with increase steric bulk close to the site of cyclisation.

The objective of this thesis was to investigate Cu(0)-mediated living radical polymerisation and explore the potential and the limitations of this system with the ultimate goal to maximise the end-group fidelity and enable the synthesis of multiblock copolymers. Careful optimisation of the ligand and catalyst concentration was shown to be vital for preservation of end-group functionality, which can be exploited for post-polymerisation modifications. High molecular weight multiblock copolymers were obtained for the first time, although the weaknesses and limitations of the technique were also revealed and discussed. At the same time, a new, novel polymerisation protocol was discovered, exploiting photo-activation in the presence of a cupric precursor CuII(Me6-Tren)Br2 and an excess of an aliphatic tertiary amine ligand Me6-Tren. For the first time under UV irradiation (λ ~ 360 nm) near-quantitative conversions and narrow dispersities for a range of targeted molecular weights were achieved while the scope of this technique was expanded to a range solvents and monomers. Significantly, temporal control is also observed during intermittent light and dark reactions and excellent end-group fidelity can be attained. This remarkable degree of control obtained during both homo and block copolymerisations motivated further investigation into the scope of the system in pursuit of acrylic multiblock copolymers with good sequential control over discrete block compositions, synthesised via a photo-mediated approach in a one-pot process without intermediate purification steps and in the absence of potentially costly additives such as photo-redox catalysts, initiators and dye sensitisers. Both techniques utilised the multiblock copolymer synthesis as a tool not only to synthesise functional well-controlled materials but more importantly to enable polymerisations with high end-group fidelity, whereby termination has been significantly suppressed.

Two areas of study are presented in this thesis: photostability of biomolecules and photoactivation of transition metal complexes. The implementation of a newly constructed transient absorption spectrometer, to investigate relevant photodissociation reactions in solution, is documented and includes a description of a gravity driven thin-film liquid jet, which may prove useful to spectroscopists seeking to remove sample/glass interaction or maximise their temporal resolution. Toward the subject of photostability of biomolecules, solvent induced conformer-specific photodissociation dynamics of guaiacol are elucidated. A particular photodissociation channel is observed to effectively be switched on or off depending on the solvent (cyclohexane or methanol) used. This is attributed to the interchangeable solvent specific conformers of guaiacol; an intramolecular H-bond between OH and OMe moieties is formed in cyclohexane whereas an intermolecular H-bond between OH and solvent is formed in methanol. The latter is thought to lower a barrier to O–H dissociation and facilitates H-atom loss via tunnelling. The photoactivation mechanism of cis-[Ru(bipyridine)2(nicotinamide)2]2+, a photoactive species designed to display high cytotoxicity following irradiation, for potential use in photodynamic therapy (photochemotherapy), is investigated. The photoactivation process is shown to occur with a high quantum yield and on an ultrafast timescale. Importantly, the conclusions here provide a detailed understanding of the initial stages involved in this photoactivation and the foundation required for designing more efficacious photochemotherapy drugs of this type.

Jocic reactions involve the reaction of trihalocarbinols with nucleophiles via 2,2-dichloroepoxides. Stereospecific versions with enantiomerically enriched trihalocarbinols are however rather uncommon. This is probably due to the very few methods of synthesising enantiomerically enriched trihalocarbinols. This thesis describes the development of a general route for synthesis of enantiomerically enriched trichlorocarbinols and their subsequent use in stereoselective Jocic reactions. Chapter 1 discusses the work towards developing a general route for the asymmetric transfer hydrogenation of trichloromethyl ketones. Initially a brief overview of stereoselective hydrogenation and the required forms of chelation is given. Following this, a detailed review of the known directing groups for asymmetric transfer hydrogenation reactions is provided before the report of the discovery that the trichloromethyl moiety may also be a strong directing group. Finally, the ability of trichloromethyl as a directing group for transfer hydrogenation reactions is explored. Chapter 2 opens with a summary of the reported mechanistic investigations into the Jocic reaction. Following this, a detailed review of the different nucleophiles used in both racemic and stereospecific Jocic-type reactions is given. Then, the current reported syntheses of enantiomerically enriched piperazin-2-ones, and related compounds, is discussed. Finally, the development of a general synthesis for these compounds is explored using amine nucleophiles in stereospecific Jocic-type reactions. Chapter 3 opens with a discussion of a publication which reports the enzymatic resolution of an allylic trichloromethyl acetate for the synthesis of its corresponding alcohol in high enantiomeric excess. Following this, the use of porcine liver esterase and Candida rugosa lipase are investigated for enzymatic resolutions with acetate derivatives of some of the trichlorocarbinols from in Chapter 1.

This thesis describes work focused on the use of oxetane rings as isosteres and incorporation of this functional group into pharmaceutically relevant scaffolds. Chapter 1 describes work directed towards the synthesis of 1,5-dioxaspiro[2.3]hexanes via three different strategies, namely ring-closure to form the oxetane ring, Corey epoxidation of the corresponding 3-oxetanones, and epoxidation of the corresponding 3-methylene oxetane. Nucleophilic ring-opening of substituted 1,5-dioxaspiro[2.3]hexanes to give amino acid type isosteres is also investigated. Chapter 2 details the synthesis of novel oxetane-containing peptidomimetics. A ‘one-pot’ conjugate addition process from commercially available 3-oxetanone to give nitro dipeptide precursors in good yields was developed. Various methods for the reduction of the nitro group were explored to optimise the synthesis of the corresponding amine. Amide coupling, followed by deprotection, gave peptidomimetics containing the oxetane at the C-terminus and mid-chain in good yields over the 3 steps, whilst an N-terminus oxetane peptidomimetic was obtained in 45% yield through hydrogenation of the conjugate addition product. X-ray diffraction studies, alongside molecular dynamics simulations, provided structural insights into these new oxetane-containing peptidomimetics. Detailed experimental procedures for the synthesis of all novel compounds are described in Chapter 3.