The term “click chemistry” was first coined by Sharpless and co-workers in 2001 and encompasses a range of high yielding organic coupling reactions which are rapid, highly selective and proceed with good functional group tolerance. Furthermore the reaction conditions are mild and require minimal workup and product purification. The most prominent example of these reactions is the copper catalysed alkyne/azide cycloaddition (CuAAC) for the formation of 1,4- disubstituted-1,2,3-triazoles. CuACC has been utilised in a variety of chemical disciplines including organic synthesis, the modification of biological macromolecules and in polymer and materials chemistry. More recently this reaction has shown a growing interest from the inorganic community for the design of new ligands for transition metal complexes and their supramolecular assemblies. In this thesis, I present my results on the use of the 'click' chemistry in coordination and supramolecular chemical applications. Described in chapter 3 is the synthesis of 1,4 disubstituted-1,2,3-triazole ligands which can act as either axial monodentate ligands, through the N3 atom of the triazole ring, or as bidentate N^N donor ligands if a pyridyl substituent is incorporated into a chelate ligand framework. The photophysical effects of these ligands were investigated on rhenium tricarbonyl complexes. It was found that replacing the Cl- ligand by the triazole stabilises the energy of the HOMO with respect to the LUMO and results in a blue shift of the emission maximum whilst changing the bidentate ligand by replacing the bipyridyl ligand by pyridinetriazole ligand elevates the LUMO with respect to the HOMO again resulting in a blue shift in luminescence. Described in chater 4 is the synthesis of 4-azido-2,2’-bipyridyl and 4,4’-diazido-2,2’-bipyridyl ligands and the CuAAC modification thereof. 4-azido-2,2’- bipyridyl was incorporated in to [Ru(p-cymene)( 4-azido-2,2’-bipyridyl)Cl]+ type complexes. The CuAAC reaction was utilised to hemically modify the periphery of a metal complex hen an azido substituted ligand is allowed to react with a range of alkynes. Through this approach a second metal binding domain can easily be introduced upon reaction with 2-pyridyl acetylene. [Ru(p-cymene)( 4-azido-2,2’-bipyridyl)Cl]+ and “click” chemistry can be used as a potential tool in building metallo-supramolecular species. We have therefore made some of the first steps towards the goal of the development of a general “click” chemistry-based methodology for the construction of functional supramolecular architectures via azide-functionalised transition metal complexes. Desciribed in chapter 5 is the preperation of 1,2,3-triazole bridged luminescent redox switches. Ruthenium, iridium and rhenium complexes incorporating ferrocenyl-bipyridyl ligand in which the ferrocene unit is tethered to the bipyridyl through a 1,2,3-triazole linkage were prepared. We have developed two potential luminescent switches with ferrocene tagged bipyridyl ligands containing a CuAAC derived triazole linker. The ferrocene moiety quenches the Ru/Ir based luminescent emission, presumably by electron transfer across the triazole bridge. We have demonstrated that the luminescent emission can be switched on by oxidation of the Fc moiety to Fc+. Described in chapter 6 is the synthesis and characterisation of a range of ligands, incorporating the 1,2,3-triazole moiety, which have designed to act as bridging ligands for the construction of supramolecular assemblies. We have subsequently prepared two dinuclear ruthenium and iridium complexes of the 4-pyridyl-1-(2,2’-bipyrid-4-yl)-1,2,3-triazole bridging ligand, and carried photophysical studies. We have shown that the dinuclear species exhibit greater luminescent intensities than mono-nuclear model complexes because the metal centre coordinated to the pyridine-triazole domain acts as a sensitizer for the metal centre coordinated to the bipyridyl domain through a photoinduced energy transfer mechanism. This shows that there is efficient transfer across the bridging ligand.

Ports are key members in the supply chain, therefore they are expected to provide reliable and efficient services. It has been recognised that one way to improve this is by adopting e-business solutions. Nowadays, a large number of organisations are operating their documents electronically. This research aims to identify the relationship between supply chain operations and e-business models and how e-business facilities the documentation flow within a port context. The research focuses on a case study of Alexandria Port in Egypt, with the emphasis is on its current documentation systems. The principal aim of this research is to evaluate the benefits of using e-business models in ports with respect to the documentation flow and with the purpose of automating the port documentation flow, reducing the process documentation steps and the associated time. It also aims to investigate the documentation flow using the current systems applied in Alexandria Port and to design a generic e-business model that can be applied to ports such as Alexandria to reduce the steps within the documentation flow. This is referred as the GEMA Model, namely, Generic E-Business Model for Alexandria Port. The research investigates the barriers faced by Alexandria Port in operating efficient supply chain operations. It focuses on the barriers to the smooth flow of documentation and the need to transform it into an electronic flow. It addresses the importance of the application of an e-business documentation flow system as a tool to speed up the operational process and is therefore a time saving to the port. The research also evaluates the importance of enhancing the trust between all parties involved in electronic business transactions to create awareness and collaboration. The analysis starts by reviewing the manual documentation system in Alexandria Port through direct and participant observations, process mapping, structured and semi-structured interviews and modelling. This is followed by an analysis of the semi-automated e-business system introduced by the port after one year from the beginning of this research (using the same methods as the manual system and only automate the customs process) and highlights the strengths and weaknesses of these two current systems of the port. Finally, it analyses and evaluates the effectiveness of this GEMA e-business model and discusses how it can affect the efficiency of the documentation flow in the port. The research evaluates the likely effectiveness of the original GEMA model with the focus on the documentation flow steps and time reduction using a before and after scenario. The research highlights the effectiveness of using e-business in ports and it can reduce the documentation flow time and related costs. The research methodology used is multiple methodological approaches including participant observation, process mapping, structured and semi-structured interviews and e-business modelling.

Biopharmaceutical production of protein for therapeutic use is an expanding practice for treatment of numerous diseases in medicine. However the full benefits of this technique have not yet been fully realised due to a number of barriers. The largest of these barriers is that of protein aggregation, where mis-folded protein monomers self associate to form non functional macromolecules; aggregates. Further understanding of protein aggregation may lead to an improvement in the effectiveness and availability of these therapeutic treatments. Here is presented work which utilises novel or under-used techniques to elucidate information on the structure of protein aggregates, their formation mechanisms and the kinetics and thermodynamics of their growth. Results presented in the chapter on aggregate nucleation indicate that the nucleation stage of aggregation in bovine serum albumin has a temperature dependant mechanism, which in the middle of the temperature range follow mechanisms for stable nuclei population postulated in the literature. However at the extremes of this range, it appears that the nucleation mechanisms deviate from this and that there may be clustering of highly reactive nuclei at high temperatures, and continual formation of aggregate nuclei at low temperatures. Possible explanations for this behaviour are discussed. Analysis presented on the growth of particulate aggregates show that the model of monomer addition to the aggregate nuclei appears to be a fitting description of the growth process, which is generic across proteins. Furthermore the detailed analysis from an ultra violet light scattering spectroscopy technique provides a numerical method for examining the efficiency of aggregate preventing additives, and also illustrates the mechanism by which the additives prevent aggregation through stabilising the native state. Finally; results presented in the chapter on aggregation during refolding indicate the use of fluorescence anisotropy to monitor the molten globule state during refolding of proteins. Most strikingly, it is shown there is an obvious relationship between the mobility period of the protein and its propensity to aggregate. It is also shown that the presence of salt and urea can be utilised to moderate the presence of the molten globule state, and therefore the resultant aggregation.

In this thesis I present an investigation on the spin dynamics observed during moment localisation, non-ergodic magnetic phase transitions, and weak itinerant electron magnetism. The pseudo-binary compound Y(Mn1-xAlx)2 has been investigated under the influence of equivalent opposing chemical and mechanical pressures using Muon Spin Relaxation. The results reveal the application of external mechanical pressure (4.5kbar) to destabilise the manganese moment, and produce a ground stte distinctly different to that seen under ambient pressure conditions. Short-range nuclear and spin correlations have been studies via diffuse neutron scattering, and through a combination of analysis techniques I have mapped the temperature dependence of these correlations and their evolution due to the substitution of manganese for aluminium. Applying new methods of hierarchical relaxation and non-extensive entopy I have studied the slow relaxation dynamics of the spin glass phase using Beutron Spin Echo spectroscopy. The results are dveloped further by applying the same analysis to a variety of glassy magnetic phenomena: spin glass freezing ((La1-xEr x)Al )Al2), and superparamagnetic blocking (Cr 1-xFe x). I have shown that within this framework the underlying freezing mechanisms result in distinctly different responses, and that in the case of spin glass relaxation an apparantly universal scaling relationship is present. Finally the results of a Muon Spin Relaxation study on the moment fluctuations in Au4V above the Curie temperature are reported. The temperature dependence of the muon spin relaxation rate is to be similar to that of the archetypal weak itinerant helimagnet, MnSi.

Aza-sugars are naturally occurring polyhydroxylated alkaloids in which the ring oxygen is replaced by nitrogen. They are reported to have a wide range of biological properties, most importantly as glycosidase inhibitors; these glycosidases play a key role in various diseases like HIV, cancer and lysosomal storage disorders. This thesis will describe an approach to the synthesis of analogues and precursors of azasugar natural products in the indolizidine (for example castanospermine) and pyrrolizidine (for example hyacinthacine) using cyclopropenones and cyclic imines as key intermediates. This thesis contains work that is an extension of the work pioneered by Eicher and Heimgartner and followed by our group for the reaction of cyclic imines with diphenylcyclopropenone. The methodology was extended towards the synthesis of more complex bicyclic heterocycles like indolizidine and pyrrolizidine aza-sugars and is summarised by the following Scheme. In this thesis, cyclopropenones other than diphenylcyclopropenone were used. This work also extended the range of cyclic imines that can be reacted by using for the first time, the parent aldimines, polyhydroxylated cyclic aldimines synthesised from sugars and other substituted cyclic imines. The reactions gave bicyclic products but always with an extra oxygen at the bridge head postion (X= OH) via aerial oxidation of the initial product (X= H).

This thesis describes the synthesis of different cyclic imines and the exploration of their reactivity with cyclopropenones and 1,3-dipoles,as well as an investigation of the chemistry of the products. The synthesis of biologically and pharmaceutically important heterocyclic natural product analogues, such as the pyrroloazepines, indolizidines and pyrrolizidines has been achieved using a cycloaddition reaction between cyclic imidates and cyclopropenones. A new route to pyridines has been developed using the generation of a proposed 3-azacyclopentadienone as the key step. The 3-azacyclopentadienones are generated by using boiling toluene to induce a [2+2]-cycloreversion in a series of azabicyclo[3.2.0]hept-2-en-4- ones. Regiospecific Diels-Alder reaction of the intermediate 3-azacyclopentadienone with a styrene is followed by chelotropic extrusion of carbon monoxide and loss of hydrogen to give the pyridine. The process is similar to the well-known process by which benzenes are accessed from cyclopentadienones. The azabicyclo[3.2.0]hept-2 en-4-ones were available from the reaction of cyclopropenones with 1-azetines, where cyclopropenones behave as an all carbon 1,3- dipole equivalents. Using the same methodology 1,3-dipolar cycloaddition of nitrile oxides to 4-aryl-2-alkylthio-1-azetines afforded a series of oxadiazabicyclo[3.2.0]heptenes as single diastereoisomers. Heating these cycloadducts in toluene resulted in an overall [2+2]- cycloreversion to give 5-alkylthio-3-aryl-1,2,4 oxadiazoles. Cycloaddition reactions of a series of benzodiazepines were also studied. The benzodiazepines were formed using literature methods and converted to cyclic imines with the help of Meerwein’s reagent. Reactions between such cyclic imines and cyclopropenones and 1,3 dipoles were attempted to produce tricyclic and tetracyclic benzodiazepine analogues. Finally, some multicomponent reactions of aryl aldehydes with cyanides and 1,3-dicarbonyl compounds were investigated to produce fully substituted heterocyclic compounds like dihydropyridines and pyrans with substituents suitable for intramolecular cyclization and imine formation. The main substituent of interest was the azide group as this had been used in section 2.3.3.1.2 & 2.3.3.1.3 in this thesis.

This report describes two methodology studies dedicated towards development of metal catalysed crosscoupling reactions in the synthesis of novel heterocyclic compounds. Firstly, a Heck-Mizoroki arylation reaction is reported for the direct functionalisation of tetrahydropyridines, towards the synthesis of kainoid analogues. Kainoids are a group of non-proteinogenic pyrrolidine dicarboxylic acids, which have attracted considerable interest because of their potent biological activity, including insecticidal, anthelmintic and neuroexcitatory properties. The ideal synthesis of kainoids would allow the ability to introduce various side chains at the C-4 position to access diverse pharmacologically active kainoid analogues. Tandem asymmetric Heck-Mizoroki arylation reaction and [2,3]-sigmatropic rearrangement provides a quick and efficient way to access these molecules. The Heck-Mizoroki arylation of 1-methyl-1,2,5,6-tetrahydropyridine and its hydrochloride salt is reported, with the arylation in the 3- position of the tetrahydropyridine as the major product. The reaction has been applied to a variety of substituted aryliodides, with promising results, demonstrating functional group tolerance of the method, however isolation and purification of the resulting compounds has remained challengeing. Diarylation of tetrahydropyridines has also been achieved. Secondly, a new catalytic method for arylative spirocyclisation is reported, using stoichiometric Grignard reagents and iron(III) catalysts, to induce cyclisation of 2-iodo benzyl ethers of furan in a highly stereoselective manner to produce novel functionalised spirocyclic compounds. Method optimisation and application of a variety of Grignard reagents is reported with aryl cross-coupling achieved in high yields. Alkyl- cross coupling has also been achieved with ethylmagnesium bromide Grignard reagent.

Although considered Gram-negative the outer membrane (OM) of Borrelia is unique, consisting of a variety of glycolipids, a significant number of surface exposed lipoproteins and a smaller number of integral membrane-spanning β-barrels. Many of these proteins are known to act as adhesins and invasins binding to regulators of the host immune response and extracellular matrix proteins. Many Gram-negative bacteria have the evolutionary conserved OmpA-like transmembrane domain consisting of an eight-stranded membrane spanning β- barrel. The prototypical example is E. coli OmpA; a multifunctional protein involved in a wide variety of physiological and pathological functions. To date the OmpA-like transmembrane domain has not been identified in the Spirochaete phylum. An approach based on hidden Markov models and topology and fold prediction identified a group of homologous genes in the genus Borrelia (BAPKO_0026, BAPKO_0422, BAPKO_0423 and BAPKO_0571), which are predicted to form an eight stranded OM-spanning β-barrel structure with similar structure to E. coli OmpA/W. One of these orthologues in B. afzelii (BAPKO_0422) has been expressed, purified and characterised in vitro; circular dichroism studies show a large percentage of β-strand. A low resolution molecular envelope generated from small-angle X-ray scattering data is consistent with an eight-stranded β-barrel.

No description available.

The method of understanding and managing diversity within a business is at the heart of the reasoning behind the concept of „supply chain segmentation‟. The overarching principle is to find economic segments within the diverse product and customer mix and to match differentiated strategies accordingly. The aim is to prioritise resource to the products and customers which contribute the highest proportion of sales and to reduce operational costs to those that contribute the lowest proportion of sales, whilst matching service level requirements. In essence this strategy balances supply chain costs for individual products against their value to the business. As a result overall costs are reduced and subsequently profits are increased. This research study pulls together the extensive documentation which is available regarding many supply chain concepts and principles into a single approach. A critical evaluation of the current research is undertaken which concludes that the majority of supply chain segmentation is currently focused within the area of supply chain design and has parallels with the established lean and agile concepts. It is shown that supply chain segmentation can be considered a holistic supply chain strategy and by following a structured framework can be applied to all planning levels, strategic, tactical and operational. The drive of the research was to consider which factors can be used to segment both products and customers. This was tested within an operational environment and it is shown how different strategies can be applied accordingly to each segment. It is proposed by Smith and Slater (2001) that products can be assigned inventory strategies depending on which one of six segments they fall within. The results of a variability index and volume calculations are the determining factors for the segmentation process. It is proposed within this study that an added dimension of lead time variability and a coefficient correlation calculation to determine the level of variability will produce a more accurate inventory model. A segmentation strategy, which combines different supply chain and research methodologies, was applied to a company called Newey and Eyre, which operates within the electrical industry. This is presented within the case study chapter. The practical research programme was designed as three separate research projects and these represent the different planning levels of the business. The first and second research project was carried out within the South West region of the business, where changes were made to the design of the supply chain and to the design and layout of a regional distribution centre (RDC) based at Avonmouth respectively. The third research project is based upon analysis which was undertaken of the company‟s purchasing and inventory system. A discrete event simulation (DES) model of this system was created and this provided the platform to test a number of segmentation strategies against the current system of operation.