The effects of additives such as ferric benzoate, cupric benzoate, m-dinitrobenzene and nitrobenzene on the thermal decomposition of benzoyl peroxide in toluene, anisole and t-butylbenzene have been investigated over a wide range of additive concentrations. In the reactions of anisole, the effect of air, oxygen, t-butyl hydroperoxide and nitrosopentafluorobenzene were also examined. The additives exhibited different effects on the product distribution of these substrates. Explanations have been suggested to account for these observations. The effects of these additives on the competitive reactions of toluene, anisole and t-butylbenzene with benzene as a standard solvent have been studied over a wide range of additive concentrations. Relative rates are significantly lowered in the presence of additives, and partial rate factors are also altered. These observations have been interpreted in terms of the formation of some weak complexes between phenyl radicals or their precursors with the substrate molecules in the absence of additives, but such complications are removed in the presence of additives. The mean values of the relative rate and the partial rate factors which are determined in this work in the presence of additives are considered to be the best definitive set now available. The competitive reactions containing various molar concentrations of anisole and benzene, toluene and benzene with or without the presence of additives were also studied. Finally, the cross-checked experiments involving the direct competitive reactions between toluene/anisole, toluene/t-butyibenzene and anisole/t-butylbenzene were carried out. The results substantiated the order of reactivity determined for toluene, anisole and t-butylbenzene towards the phenylation reactions by benzoyl peroxide. To study the silylation reaction on aromatic substrates, attempts were made to generate dimethylphenylsilyl radicals, thermally or photolytically, from dimethylphenylsilane in the presence of radical initiators such as t-butyl peroxide, azo-bisisobutyronitrile and benzoyl peroxide. The formation of dimethyldiphenylsilane anddiphenyltetramethyldisilane in the reaction of the dimethylphenylsilane in benzene indicated the formation of silyl radicals. Benzoyl peroxide was found to be the most efficient initiator in this reaction. Investigation was extended to the study of the reactions of dimethylphenylsilane with toluene, naphthalene and halobenzenes (chlorobenzene, bromobenzene, p-dichlorobenzene and iodobenzene) and anisole. In the reactions with toluene, naphthalene and anisole, nuclear silylated products were detected. However, in the reaction with halobenzene, the main reaction was the displacement or the abstraction of the halogen from the aromatic nucleus by silyl radicals. Mechanisms have been suggested to account for these observations. These results indicated the nucleophilic character of the dimethylphenylsilyl radical.

The reactions of some polybromoanilines with pentyl nitrite in benzene at 80° has been studied. 2,3,4,5,6-Pentabromobiphenyl was prepared by this method and also by the Ullmann reaction between iodobenzene, pentabromoiodobenzene, and copper powder. The yield of biaryl formed from homolytic arylation of benzene decreases as o-bromoaniline, 2,4,6-tribromoaniline or pentabromoaniline are the sources of the aryl radicals. This decrease is paralleled by an increase in the yield of the benzene derivative arising from the formal protodeamination of the parent aniline derivative. Evidence was also found of a heterolytic reaction accompanying the main homolytic arylation reaction which gives hexabromobenzene as a side-product in the reaction of pentabromoaniline and pentyl nitrite in benzene. Photochemical bromination reactions of some benzene derivatives, using molecular bromine as the source of bromine atoms, were performed. Both nuclear addition and nuclear substitution products were formed, the relative amounts of which vary with the benzene derivative since both polar and steric factors influence these reactions. However, it was found that the ratio of nuclear substitution to nuclear addition increased with increase in temperature from ca. 25 to ca. 50°. Evidence (i.e. the photochemical decomposition of benzene hexabromide and of 1,2,3,4,5,6-hexabromochlorocyclohexane to give some di-halo-arenes) was adduced which suggests an addition-elimination mechanism as an interpretation of the formation of bromo-arenes in the photochemical bromination of benzene derivatives. Direct abstraction of hydrogen from a species such as C₆H₆Br· seems unlikely by Br₂ on thermochemical grounds, but possible by Br· or by a photochemically excited species Br₂*. Partial rate factors for free radical bromination of biphenyl have been determined and discussed, although it is unlikely that they are capable of simple interpretation. The isomer distribution of bromo-arenes found here was quite different from the corresponding ratio reported for heterolytic reactions. The meta-positions of certain benzene derivatives, which are deactivated towards electrophiles in ionic reactions, were found to be readily attacked by bromine atoms.

Despite the privileged position of Hamilton’s barbiturate binding system in supramolecular chemistry, this motif has never been used in generating interlocked structures, such as rotaxanes or catenanes. This thesis demonstrates the feasibility of such structures. A series of Hamilton-like receptors has been synthesised. Their conversion from “open” to “closed” forms by metathesis and their binding with barbital was studied, demonstrating the importance of the macrocycle size. Barbiturates disubstituted with flexible chains terminated either by reacting groups (anthracenes, olefins) or stoppers (trityl) were also synthesised. The fluorescence properties of anthracene-tagged barbiturates and their kinetics of intramolecular anthracene photodimerisation and thermal return were studied, demonstrating remarkable differences depending on the chain length. Binding studies of these barbiturates with the receptors were then undertaken, revealing smaller binding constants compared with barbital. A series of ring-closing experiments involving the barbiturate complexes was then undertaken, either by anthracene photodimerisation or olefin metathesis. In one metathesis experiment, indirect evidence for the formation of a low amount of catenane was obtained by mass spectrometry, where the smallest ring is formed by a chain of only 19 carbon atoms, which is unprecedented. Finally, different synthetic pathways for the synthesis of barbiturates substituted with large rigid substituents were investigated. Models of their complexes with the receptors and IR studies are presented that suggest that their structure would facilitate the formation of interlocked complexes.

A [5:5] ligand based on the bicyclic guanidine 1,4,6-triazabicyclo[3.3.0]oct-4-ene [Htbo] has been synthesised. Two of these tbo units have been linked via a carbon bridgehead to form a novel bidentate ligand. Based on the knowledge that the electronic properties and specific steric interactions at a metal can lead to new insights into the relationship between crystal structure and ligand activity, the synthesised compounds have been investigated as polydentate ligands on the assumption that that they could be used to precisely control coordination environment. The corresponding [6:6] system which is based on the bicyclic guanidine 1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine) [hppH] has also been synthesised and its coordination to silyl groups investigated. 1,4,6-triazabicyclo[3.3.0]oct-4-ene (Htbo) has been deprotonated to form the [tbo]- anion, which has been assessed as a ligand at Li, Al and Zn centres, allowing direct structural comparison to be made with the [hpp]- analogues. The coordination chemistry of Htbo and its derivatives has been explored through formation of a variety of transition metal complexes. Additionally, crystal structures showed that Htbo coordinates to the metal through the N-imine atom as a monodentate ligand to form trigonal planar, tetrahedral, square planar and octahedral complexes. The bis (tbo) methane H2C{tbo}2 ligand was found to support a range of coordination geometries and upon coordination, ionic structures such as [Pd(H2C{tbo}2)2][Cl]2 were formed. The synthesis of the monosubstituted compound hppSiCl3 afforded a series of (hpp) silanes which were isolated and reacted with LiOAr (Ar= 2,6-tBu2C6H3), providing a proof of N-Si bond stabilisation using a metal. Five examples of pentacoordinated silicon species have been synthesised via the reaction of [hpp]- and R2SiCl2 (R= Ph, Me).

The primary goal of this research project was to investigate the mechanism of a novel thermally activated cyclisation reaction discovered by Parsons et al. During these studies two novel reactions were discovered: For reaction see Abstract in pdf Reagents and Conditions: (i) Toluene 0.1M, reflux, 4h, 32%. For reaction see Abstract in pdf Reagents and Conditions: (i) Toluene, 0.01M, reflux, 4h, 53% Radical and ene pathways for the generation of these products were proposed. However, despite extensive empirical studies, no definitive proof for either mechanism was found. The breadth of the synthetic utility of the above reactions was also investigated by synthesizing various analogues. The general application of the Parsons' cyclisation to the synthesis of steroid cored and the complex natural product Jiadifenin was also investigated. Advanced intermediates were synthesised and invaluable information on reactivity was gained, however these investigations could not be completed due to time constraints

The polycyclic polyprenylated acylphloroglucinols (PPAPs) are a class of naturally occurring compounds with a characteristic bicyclo core system (either [3.3.1]nonane or [3.2.1]octane). This class of compounds have been shown to have significant biological activity, including activity against cancer, HIV, bacterial infection and depression. The biological activity and the structural challenges that these compounds pose have led to significant interest from the synthetic chemists. A review of the previous synthetic work and the biological activity of the PPAPs is contained within Chapter 1. A total synthesis of the type A PPAP nemorosone (4) is described, using a modified Effenberger cyclisation as the key bicyclo[3.3.1]nonane forming step. Further functionalisation was performed through a difficult bridgehead iodination, followed by halogen-metal exchange and benzoylation. Chapter 2 describes our total synthesisof nemorosone (4) in 13 synthetic steps and 6% overall yield. Chapter 3 describes the first total synthesis of the type C PPAP nemorosone II (150) in 10 synthetic steps and 1.5% overall yield. Once more the key bicyclo[3.3.1]nonane core was formed using the modified Effenberger cyclisation. Alongside the synthesis, biological studies have been performed on the final compounds and a range of intermediates (Chapter 4). Investigations into the difficult bridgehead substitution and resulting halogen-metal exchange reactions are discussed in Chapter 5. Preliminary studies were undertaken into a new shorterroute to nemorosone (4) using a Dieckmann condensation as the keybicyclo[3.3.1]nonane forming step. (Chapter 6).

The work reported in this thesis concerns the development of Cryorelaxors having potential applications in very low temperature NMR studies of biological materials. Two approaches have been explored, namely calixarene host-guest complexes incorporating rotationally labile methyl groups, and endohedral fullerene complexes. The first chapter provides an overview of the background of the project and of potential approaches to the problem of low temperature relaxation agents, particularly those based on supramolecular systems. The next chapter describes the preparation, characterization, and studies of the behaviour of calixarene complexes incorporating potentially freely rotating guests. Ten calixarene complexes have been prepared and characterised by X-ray structural studies and their relaxation behaviour has been investigated using a variety of techniques including MAS and Field Cycling NMR experiments and Inelastic Neutron Scattering spectroscopy. Crystallographically disordered methyl-group environments have been identified in a number of cases and their proton spin-lattice relaxation behaviour has been shown to be strongly dependent on the thermal history of the sample. NMR studies of samples of partially deuterated calixarene complexes reveal a systematic reduction in T1 at low temperatures with higher levels of deuteration of the system studied, the p-iso-propylcalix[4]arene (2:1) p-xylene complex has been shown to have the best relaxation properties. Synthetic strategies towards calixarene and fullerenes complexes bearing active biological anchors are also discussed. The third chapter describes an investigation of the Komatsu route to the endohedral fullerene complex H2@C60 and the structural characterization of one of the key intermediates in this process. The fourth chapter give a brief overview the results obtained and the final chapter details of the experimental work undertaken. Appendices are also included containing full details of the X-ray structural studies and mathematical models

Crystal structure assembly is a subtle compromise between geometrical features, a natural tendency to minimize the free, empty, volume, linked to the involvement of classical van der Waals forces, and the ability of particular complementary functional groups to form additional cohesive directional interactions. Depending on the system considered, each of these factors can have a more pronounced influence in determining the crystal packing. In order to develop a successful strategy to design new solid forms by a crystal engineering approach a complete understanding of crystal structure is required. It involves the so called “retrosynthetic” approach which allows the identification of robust assemblies. However, this procedure is worthless without a systematic approach able to define the structural consequences deriving from small changes in the molecular skeleton of a given target molecule. In this thesis three families of substituted salicylic acid derivatives have been prepared and separately studied in order to compare the crystal structures and determine whether the substitution and the associated changes in shape and electrostatic of the parent molecule introduce alternative intermolecular interactions or molecular patterns. The first family is based on acetylsalicylic acid derivatives (aspirins) and contains 15 novel structures together with some substituted derivatives already present on the CSD. The second family contains 13 new structures of substituted salicylic acid and, as for aspirin derivatives, some already reported in CSD. The last family contains 13 new crystal structures of molecular salts based on the pair 4-aminopyridine-salicylic acid derivatives. The families of compounds are those in which the parent molecules are substituted with small groups (Cl, Br, I, Me, NO2, MeO etc.) and in different positions. The only exception is given by the acetylamino derivatives, which were included in the analysis in order to verify if they can compete with the carboxylic group in forming particular intermolecular interactions and consequently different supramolecular synthons. The results in this work clearly showed that the substituent groups have an important role in generating similarities but, also, differences within the family under study. Furthermore the analysis has shown the significant involvement of both weak intermolecular interactions and shape-related packing features in the crystal structure assembly. In the other hand, the analysis showed the importance of particular functional group in defining robust supramolecular synthons. The three families studied showed, apart from a small number of exceptions, predictable synthons (carboxylic dimers for the aspirins and the salicylic acids and the well known pyridine-carboxylate synthon for the salts) observed in the majority of the structures

Radicals, like other functional groups, may be classed as nucleophiles or electrophiles depending upon their character. Much has been done in the past to determine the· nucleophilicity or electrophilicity of a wide ra~ge of radicals, but it .. does not appear that the philicity ofthe aryl radical has yet been determined. A competitive cyclisation of an aryl radical to one of two alkyl chains containing olefins ofdiffering electron density was undertaken to determine aryl radical philicity. Prior to cyclisation, synthesis of the precursors was required, starting from simple commercially available aromatic compounds. A wide range of allyloxy aromatic compounds with different substituents on the two olefins was synthesised. In the course of the required multi-step synthesis many previously unreported compounds were isolated and fully characterised, including crystal X-ray diffraction studies where crystals were obtained. To investigate the effects of different electron density in the aryl ring a further range of competitive cyclisation precursors were synthesised with an ester group para to the site where the aryl radical is formed. Studies into the synthesis of a competitive cyclisation precursor with olefin bearing side chains with no heteroatom were also undertaken. The procedure for the cyclisation reactions and subsequent work-up was optimised under both conventional and microwave methodology. Analysis of the products was performed using both quantitative and qualitative analytical techniques. Quantitative analysis was performed using gas chromatography, IH NMR spectroscopy with an internal standard and isolation of products. Qualitative analysis was performed using both ID and 2D NMR spectroscopy. Analysis of the results of the competitive cyclisation reactions show beyond reasonable doubt that the aryl radical is nucleophilic in character.

6-Methylsalicylic acid (6-MSA) is one of the oldest known polyketides. It is synthesised in vivo by the polyketide synthase 6-methylsalicylic acid synthase (6-MSAS), a multifunctional enzyme which uses its active sites iteratively. The stereochemistry of the hydroxyl produced from the single ketoreduction, as well as the order of dehydration, cyclisation and aromatisation steps, remain cryptic, despite extensive study. Holo 6-MSAS was heterologously expressed in E. coli and purified in two steps. A non-hydrolysable carba(dethia)malonyl-N-acetylcysteamine analogue was synthesised and used to off-load enzyme-bound intermediates from 6-MSAS. In assays with acetyl-CoA and acetoacetyl-CoA alone, diketide and triketide intermediates were off-loaded and detected by HPLC-HR-ESI-MS. In the presence of NADPH, the off-loaded triketide was reduced by the ketoreductase domain of 6-MSAS. A potential dehydrated intermediate was also observed. The dehydratase domain of 6-MSAS has recently been reassigned as a thioester hydrolase. To test this theory, the catalytic histidine residue in 6-MSAS was mutated to an alanine and the abolition of production of 6-MSA in vivo was observed. Mutated 6-MSAS was still able to produce the shunt product triacetic acid lactone. Incubation of mutated 6-MSAS with acetyl-CoA, malonyl-CoA, NADPH and carba(dethia)malonyl-N-acetylcysteamine saw only the off-loading of diketide and triketide analogues. To investigate the stereochemistry of ketoreduction in 6-MSA biosynthesis, steps were made to synthesise the resolved diastereomeric reduced-triketide CoAs which would be the substrates for the ketoreductase domain. Attempts to phosphopantetheinylate apo 6-MSAS in vitro with three different phosphopantetheinyltransferases were unsuccessful. Limited proteolysis of both holo and apo 6-MSAS found that the apo synthase rapidly lost a C-terminal fragment while holo 6-MSAS was much more stable under the same conditions. Attempts were made to express the acyl carrier protein domain from 6-MSAS to overcome these problems. These experiments represent the first use of the non-hydrolysable analogue methodology in a Type I iterative polyketide synthase and provide a framework for future experiments investigating intermediates in the biosynthesis of 6-MSA.