This work aimed to investigate and exploit the hydrogen bonds generated between heterocyclic aromatic compounds, namely benzimidazole and imidazole, and the carboxylic acid group. The flexible but robust hydrogen bonds generated have been used to create molecular complexes, using practical and relevant co-molecules. A systematic approach has been used in the selection of co-molecules on the basis of crystal engineering principles. A library of robust hydrogen bonds and primary structural motifs has been generated, which has been used to explain the solid-state assembly of the collection of molecular complexes produced in this work and in related published structures. The similarities in hydrogen bond strength, bonding motifs and proton transfer behaviour between very dissimilar molecular complexes have been remarkable. The opposite is also true in other examples, with very similar molecular complexes showing remarkable differences, but overall, a picture is built up of predictable use of crystal engineering principles in designing molecular complexes with anticipated structural and packing features. The phenomenon of polymorphism, widely known but poorly understood, is essential to many industrial processes. A primary aim of this work was to promote and control the formation of molecular complex polymorphs through varying crystallisation conditions. Co-crystallisations involving benzimidazole with the whole series of halo-benzoic acid molecules were scrutinised and polymorphism found to be prominent throughout. Selective growth for individual forms has been achieved, offering the potential for polymorph selection, but not fully understood. The behaviour of the protons was investigated in the molecular complexes generated; proton transfer was prevalent. This was achieved through three methods; firstly with the use of variable temperature X-ray and neutron diffraction experiments on the product, by altering the levels of pH during the crystallisation process and lastly by introducing competing acceptor sites through co-molecule selection. A feasibility study into the use of the relatively new solvent-free crystallisation processes was undertaken. It was shown to be a successful technique in screening for polymorphs and molecular complexes.

This thesis represents computational studies of the mechanisms of chlorination in the FAD-dependent enzyme PrnA using QM, MD and QM/MM methods. It also contains Time-Dependent Density Functional Theory (TDDFT) spectra and conformational analysis of the fluoro-imine derivatives of pyridoxal 5’-phosphate (PLP). Chapter 1 gives a brief introduction of the theoretical methods used in the thesis and an explanation of their implementation in Computational Chemistry. Chapter 2 presents an overview of the variety of halogenated natural products and halogenating enzymes. This chapter takes a closer look at the group of the FAD-dependent enzymes and in particular at PrnA. All the feasible mechanisms of regioselective chlorination of tryptophan in PrnA are thoroughly discussed. In Chapter 3 model reactions for the chlorination of the substrate tryptophan at the DFT level are investigated. Two different chlorinating agents are proposed and the reaction energies and barriers for the halogenating reactions are calculated. A simple comparison of the chlorinating agents at the QM level without the enzyme is given. Chapters 4 and 5 are devoted to MD simulations on PrnA for equilibration of the solvated protein and QM/MM modelling with the AM1/AMBER03 and the DFT/AMBER03 methods. The QM/MM methods gave the opportunity of studying the reaction mechanisms with the account of the environment of the enzyme. All the steps along the mechanisms of chlorination with the possible chlorinating agents were investigated. In chapter 6 TDDFT has been used to calculate the electronic spectra of PLP and its derivatives. PLP is co-factor in a diversity of enzymes with different biological function. In the alanine racemase it takes part in the racemisation of L-alanine to D-alanine. The latter is a building block of the bacterial cell wall. A novel method of blocking the function of the enzyme is the use of the β,β,β-trifluoroalanine inhibitor which forms an external aldimine with PLP. A mechanism of the β,β,β-trifluoroalanine inhibitor activity was proposed by Faraci and Walsh. The spectra at all the steps along the proposed mechanism with intermediates in different protonation states were calculated. Chapter 7 focusses on the examination of the conformations of the PLP derivatives and the energetics of these compounds. The preference of gauche conformation in β- fluoroimines was studied. In this chapter are presented empirical (X-ray) and theoretical (DFT) evidence for the gauche effect in β-fluoroimines. NCCF bond rotational profiles of acetaldehyde-derived imines and β-fluoropyridoximine at the DFT level were analysed. NBO analysis of the investigated compounds proved the Dunathan’s stereoelectronic hypothesis.

This thesis describes the synthesis and characterisation of group I and group II nitride materials as potential hydrogen stores. New synthetic routes as well as the development of conventional methods were employed to synthesise binary and ternary nitrides. Ball milling of single phase α-Li3N and of commercial Li3N was performed to induce a phase transformation in order to synthesise β-Li3N which adopts a hexagonal crystal structure (space group P63/mmc). The beta polymorph was initially characterised by PXD and subsequently by a variable temperature PND experiment, which demonstrated that the phase transformation to α-Li3N began at 600 K. Due to the fact that β-Li3N exhibits the same magnitude of Li+ conductivity as α-Li3N and that lithium ion diffusion is thought to be an important factor in the hydrogen storage potential of the solid, a further PND investigation to study the interaction of D2 gas with β-Li3N was performed. At lower temperatures, negative thermal expansion can be observed; this expands following similar trends known for α-Li3N and commercial Li3N. In agreement with the behaviour of Li3N reported in the literature, Li3N reacts with D2 at higher temperatures resulting in the formation of LiND2 and LiD. The phase behaviour in the complex Li-N-H system is still being debated despite significant research in this area. This work has focussed on lithium nitride hydride, which has been reported as a minority phase during the hydrogenation of Li3N. Li4ND was prepared by both conventional means and by a novel synthesis using microwaves; the product was characterised by PXD and PND. During both conventional and microwave syntheses, tetragonal Li4ND (space group I-4) and a new high temperature cubic polymorph formed (space group Fm-3m) where N3-, D- and (ND)2- are disordered across the anti-fluorite anion sites. With regard to providing further evidence for the proposition of a new reaction pathway upon hydrogenation of Li3N, Li4ND and Li2ND were reacted in-situ during a PND investigation forming a solid solution and resulting in synthesis of a cubic ‘quasi-imide’ phase. The ‘quasi-imide’ phase was refined against a modified cubic Li2ND starting model. The presence of D+ and D- ensured that charge balance was maintained. As the stoichiometry increases, the anion distribution changes; the occupancy of N3- and N from (ND)2- on the 4a site increases as does the occupancy of protonic D from (ND)2- on the 192l site. A ternary nitride, LiCaN (space group Pnma), was prepared by both conventional and novel (via microwaves) means. Optimization of the reaction parameters was the initial focus of the investigation in order to synthesise single phase LiCaN. Firstly, a PND study was performed in order to ascertain accurate Li positions and ensure the material was perfectly stoichiometric as made. In order to compare the Li-Ca-N system with reports on the Li-Mg-N system in which both Mg-rich and Li-rich phases as well as stoichiometric LiMgN have been synthesised, attempts were made to synthesise nonstoichiometric Li-Ca-N compounds. This system was investigated by PND.

Nakadomarin A is a polycyclic marine alkaloid of the manzamine family. It was first isolated from the marine sponge Haliclona sp. collected off Manzamo, (Okinawa, Japan) and was characterised by Kobayashi and co-workers in 1997. The structure of this unprecedented compound was elucidated by exhaustive spectroscopic studies which showed that the natural product has a unique hexacyclic skeleton. In terms of biological activity, this natural product displays cytotoxicity against murine lymphoma L1210 cells (IC50 1.3 μg/mL), inhibitory activity against cyclin-dependent kinase 4 (IC50 9.9 μg/mL), anti-microbial activity against the fungus Trichophyton mentagrophytes (MIC 23 μg/mL) and anti-bacterial activity against the Gram-positive bacterium Corynebacterium xerosis. The complex structure of nakadomarin A combined with its biological activities has made it a highly attractive synthetic target. The work described herein displays the most recent contribution to this field from our research group.

A novel tandem process has been developed for the stereoselective synthesis of bicyclic γ-lactams. Treatment of an allylic alcohol with trichloroacetonitrile, in the presence of DBU, affords the corresponding allylic trichloroacetimidate. This is then subjected to a tandem Overman rearrangement/RCM/Kharasch cyclisation, forming the desired bicyclic lactam in high yield and high enantiomeric excess. Overall, the one-pot tandem process involves three mechanistically distinct processes catalysed by palladium(II) (step 1) and Grubbs 1st generation catalyst (steps 2 and 3). The use of a thermal Overman rearrangement in tandem with the Grubbs catalysed RCM/Kharasch cyclisation was also investigated. Furthermore, a microwave-assisted tandem process was developed which resulted in the accelerated synthesis of the desired bicyclic γ-lactams. A two-step tandem process was then developed for the synthesis of bicyclic allylic amides, a closely related core unit to that found in a number of important commercially available drugs. Finally, progress has been made towards the total synthesis of (±)-deethylibophyllidine, which will utilise a tandem RCM/Kharasch cyclisation to construct the C and D rings of the natural product.

Many chemically important nuclei are quadrupolar with half-integer spin (i.e., spin I = 1.5, 2.5, etc.) The presence of quadrupolar broadening for such nuclei can limit the information that may be extracted using NMR. MAS is able to remove first-order quadrupolar broadening but can only reduce the second-order contribution to the linewidth. The MQMAS and STMAS techniques have enabled high-resolution NMR spectra of half-integer quadrupolar nuclei in the solid state to be obtained by two-dimensional correlation under MAS conditions. Both of these experiments have several well-known limitations. One is that the conversion pulses in particular are very inefficient and the other is that the longer acquisition times required for two-dimensional experiments can be a limiting factor. Both of these disadvantages are addressed in this thesis. For the former case, existing composite pulse schemes designed to improve the efficiency of the conversion of multiple-quantum coherences are compared using 27Al and 87Rb MQMAS NMR of a series of crystalline and amorphous materials. In the latter case, a new experiment, named STARTMAS, is introduced that enables isotropic spectra of spin I = 1.5 spectra to be acquired in real time. The theoretical basis of the technique is explained and its applicability demonstrated using 23Na and 87Rb NMR of a wide range of solids. The nuclear Overhauser effect (NOE) is one of the most widely exploited phenomena in NMR and is now widely used for molecular structure determination in solution. NOEs in the solid state are rare and those to quadrupolar nuclei rarer still, this being due to the general absence of motion on the correct timescale and the usual efficiency of quadrupolar T1 relaxation, respectively. In this thesis, 11B{1H} transient NOE results are presented for a range of solid borane adducts. A comparison is made of the 11B NMR enhancements observed under MAS and static conditions and a rationale is proposed for the behaviour in the latter case.

This thesis presents computational investigations of problems related to redox processes and structural rearrangement in inorganic systems. Density functional theory has been used to gain insight into the origin and nature of such reactions. The work presented concerns two main topics: hydrogenase-like systems containing an Fe2 core and carbonphosphorus cluster compounds. In chapters II and III, we describe the impact of reduction, an important phenomenon in the H2 production catalytic cycle, on a hydrogenase-like model. In collaboration with Talarmin and co-workers who have conducted careful electrochemical studies, we have used DFT to identify structures of species observed in cyclic voltammetry. We have also studied the binding of a proton to similar systems and, through the calculation of chemical shifts and coupling constants, confirmed the structures of iron hydrides observed by 1H NMR spectroscopy. In chapter V we focus on carbon-phosphorus systems that can exist in 2 or more isomeric forms. We address first the case of a system of formula C6H4P3 which has the right valence configuration to exist either as a planar structure or as a 3-dimensional cluster (nido according to Wade’s rules). We then examine whether it is possible to control the preferred conformation by the addition of substituents on the phenyl ring. Finally, we look at the rearrangement of a planar diphosphene into a cage isomer and try to understand the mechanism and in particular the role of the protonation in the conversion from planar to 3-dimensional structure.

The Cambridge structural database (CSD) is a vast resource for crystallographic information. As of 1st January 2009 there are more than 469,611 crystal structures available in the CSD. This work is centred on a program dSNAP which has been developed at the University of Glasgow. dSNAP is a program that uses statistical methods to group fragments of molecules into groups that have a similar conformation. This work is aimed at applying methods to reduce the number of variables required to describe the geometry of the fragments mined from the CSD. To this end, the geometric definition employed by dSNAP was investigated. The default definition is total geometries which are made up of all angles and all distances, including all non-bonded distances and angles. This geometric definition was investigated in a comparative manner with four other definitions. There were all angles, all distances, bonded angles and distances and bonded angles, distances and torsion angles. These comparisons show that non-bonded information is critical to the formation of groups of fragments with similar conformations. The remainder of this work was focused in reducing the number of variables required to group fragments having similar conformations into distinct groups. Initially a method was developed to calculate the area of triangles between three atoms making up the fragment. This was employed systematically as a means of reducing the total number of variables required to describe the geometry of the fragments. Multivariate statistical methods were also applied with the aim of reducing the number of variables required to describe the geometry of the fragment in a systematic manner. The methods employed were factor analysis and sparse principal components analysis. Both of these methods were used to extract important variables from the original default geometric definition, total geometries. The extracted variables were then used as input for dSNAP and were compared with the original output. Biplots were used to visualise the variables describing the fragments. Biplots are multivariate analogues to scatter plots and are used to visualise how the fragments are related to the variables describing them. Owing to the large number of variables that make up the definition factor analysis was applied to extract the important variables before the biplot was calculated. The biplots give an overview of the correlation matrix and using these plots it is possible to select variables that are influencing the formation of clusters in dSNAP .

Resorcyclic acid lactones (RALs) are natural products, with some having been shown to be potent inhibitors of several protein kinases and mammalian cell proliferation and tumour growth in animals. LL-Z1640-2 (also known as 5Z-7-oxo-zeanol or C292) is a cis-enone RAL, isolated in 1978 from fungal broth and classified as an anti-protozoal agent. Later, in 1999, its cytokine releasing inhibiting activity was discovered, with subsequent data showing it could selectively and irreversibly inhibit transforming growth factor activating kinase-1 (TAK1) activity at low concentrations. It is also reported as having significant activity versus tumour necrosis factor-alpha (TNF-α) production in cells. This thesis documents and describes the work undertaken towards a total synthesis of the 14-membered macrocycle, LL-Z1640-2. The presence of two internal bonds and three stereogenic centres poses a challenge synthetically, but this has been effectively overcome with the development of a flexible, economic and efficient synthesis, beginning from the commercially available starting materials, methyl 2,4,6-trihydroxybenzoate and 2-deoxy-D-ribose. The original route relied on a Wittig olefination to introduce the E-double bond, with moderate selectivity and success. Later, an improved method was built upon, which utilised Grubbs mediated cross-metathesis to form the desired E-olefin in good yield and selectivity. Once the entire carbon framework had been established via a one-pot oxidation-Grignard adition of the appropriate alkyne unit, subsequent transformations enabled the formation of the seco-acid. This very successfully underwent Mitsunobu macrolactonisation, with complete inversion of the stereocentre, to afford the macrocyclic lactone. From this intermediate, the desired natural product LL-Z1640-2 could be generated in three steps. A number of natural products and biologically important compounds contain spirocyclic pyran and piperidines ring systems as part of their overall structures. In 1996, pinnaic acid and halichlorine were isolated from their respective marine natural sources. It was subsequently shown that they exhibited inhibitory activity towards certain biological substances and for this reason they became targets for total synthesis. Characterised by an azaspiro[4.5]decane ring system, the difficulty in achieving total syntheses of such compounds is immense. The aim of the project was to develop a concise method towards the generation of highly functionalised spirocyclic piperidine units. The regioselective aza-Achmatowicz oxidative rearrangement was used as the key step to rearrange α-amino furan building blocks into their respective enones. Importantly, this rearrangement was proven to be viable and to proceed with compounds possessing a terminal olefin, with no over-oxidation observed. This thesis also describes the investigation and efforts made into the production of more functionalised units, as well as studies into the synthesis of the cores of halichlorine and polymaxenolide, again using the aza-Achmatowicz and Achmatowicz rearrangement respectively.

This thesis details the development of methods for the preparation and the functionalisation of cyclic enones, which may be utilised for the synthesis of marine polycyclic ether natural products. These metabolites are among the most complex and challenging toxins isolated so far. The first chapter serves as an introduction to such complex natural products and describes their toxicology and biogenetic origins. A literature review of the advances made within the Clark group as well as in other laboratories toward the iterative and biomimetic synthesis of polycyclic ethers is also included with particular emphasis on the ciguatoxins. This is followed by a review of olefin metathesis and the use of ring-closing and ring-rearrangement metathesis reactions for the preparation of cyclic ethers. Chapter 2 describes efforts towards the synthesis of seven- and eight-membered cyclic enones from commercially available carbohydrate derivatives. Cyclic ethers are prepared by ring closing metathesis of dienone precursors. The functionalisation of seven-membered system involves the utilisation of highly enantioselective reactions, such as copper-catalysed conjugate addition of dialkylzinc reagent and Tsuji-Trost allylation. The cyclisation of the dienone precursor of the eight-membered ring system proved to be problematic. In this case, the importance of the allylic substituent on the RCM reaction was demonstrated. Also, a two-directional approach to the IJK fragment of the marine polycyclic ether CTX3C was proposed. A reliable and relatively inexpensive synthetic pathway has been established to the first key intermediate. This latter was prepared in 1.6% overall yield over fourteen steps. Finally, the different options for the future work are discussed.