The synthesis of ligand systems and complexes thereof suitable for use as positron emission tomography (PET) agents is studied herein. The ligands 6,6’-(1,4-diazepane- 1,4-diyl)bis(3-aminobenzoate) (HPR), 6,6’-(piperazine-1,4-diyl)bis(3-aminobenzoate) (PipR.2HCl), 6,6’,6”-(1,4,7-triazonane-1,4,7-triyl)tris(3-aminobenzoate) (TACNR), 1,4-bis(2-amino-4-tolyl)- 1,4-diazepane (HPTol), 1,4-bis(2-amino-4-trifluoromethylphenyl)-1,4-diazepane (HPCF3 ), di-tert-butyl 4,4’-(1,4-diazepane-1,4-diyl)bis(3-aminobenzoate) (HPtButyl), 1,3-bis(2-amino- 4-tolyl)-1,3-diazacyclohexane (PipTol), 1,4,7-tris(2-amino-4-trifluoromethylphenyl)-1,4,7- triazacyclononane (TACNCF3), have been studied. Ni(II), Cu(II), and Zn(II) complexes of these ligands have been synthesised, DFT calculations have elucidated structural configuration, whilst x-ray crystal structures of NiHPtButyl, and CuTACNCF3 have been determined. EPR measurements of CuHPR have been taken. A series of triazine core compounds have been prepared for use as model compounds for targeting molecules. The compound Tz(EtGly)(BocGuan)Cl has been synthesised with the required arms to selectively bind to the integrin αvβ3. DO3A moieties have been added to these ligands, and mass spectra analysis of the coordination products with a series of metals has been determined. NO2A derived compounds 2,2’-(7-tosyl-1,4,7-triazonane-1,4-diyl)diaceticacid (TsTACNA2) and 2,2’-(7-(4-nitrophenyl)-1,4,7-triazonane-1,4-diyl)diacetic acid (NPhTACNA2) have been studied,with the x-ray crystallography of the copper complexes completed. Positron emmision tomography (PET) studies of the complexes have also been undertaken and show high levels of complexation at ng scales, with moderate stability in human serum. Glutaric acid functionalised compounds (2S,2’S)-2,2’-(1,4-diazepane-1,4-diyl)dipentanedioic acid (HPGlut), 2,2’,2”-(1,4,7-triazonane-1,4,7-triyl)tripentanedioic acid (TACNGlut), and 2,2’-(4,11-dimethyl-1,4,8,11-tetraazacyclotetradecane-1,8-diyl)dipentanedioic acid (DMiii iv CGlut) have been synthesised, with the copper complex of DMCGlut affording structural determination. The Mn(II) and Gd(III) complexes of the DMCGlut ligand system have been studied by xylenol orange UV titration for their metal-ligand binding ratio, with the Mn(II) system showing a 1:1 binding ratio, whilst the Gd(III) complex showed no binding at all. Synthesis of the trispyrazylborate analogue, tris(4-methyl-2-(2-pyridine)pyrazyl)borate (MeTpPy), was unsuccessful, however, the bis- (MeDpPy) and tetra- (MeQpPy) substituted analogues were successfully synthesised.

Methanol oxidation to formaldehyde is one of the most important industries in our lives; the reaction occurs on catalyst surface in heterogeneous catalysis. Iron molybdate is the current selective catalyst. However, molybdenum volatilises during methanol oxidation and leaving the catalyst with a low molybdenum ratio, which deactivates the catalyst, a 2.2 Mo: 1Fe iron molybdate catalyst was used instead the stoichiometric catalyst, while yield of formaldehyde cannot be 100%. The goal of this study is to find more selective and more productive catalyst than iron molybdate catalyst, the first step is to find another transition element as selective as molybdenum, because molybdenum is the selective part, and iron is the active part, the resulting iron molybdate catalyst is a selective catalyst to formaldehyde near molybdenum and active near iron. Experimentally, catalysts were prepared using co-precipitation method, however, some doped catalysts were papered by incipient wetness impregnation, also sol-immobilization was used to prepare nano-gold particles on the surfaces of few supports. Catalysts characterizations were carried out within several techniques for the surface analysis (XPS) and bulk analysis (XRD), also the surface area was measured by BET equipment. Raman too was used in this study, while micro-reactor was the reactor to determine selectivity and activity of each catalyst. When molybdenum replaced by vanadium, the catalyst yielded 100% formaldehyde at 200 oC; moreover, tungsten was selective. Likewise, iron was replaced by other active metals such as manganese, copper and bismuth, which are active. Nano-gold improved activity when doped on molybdenum oxide and iron molybdate supports.

The work presented in this thesis is concerned with the synthesis, characterisation, and application in catalysis of mono- and bis-expanded ring (including bicyclics) Nheterocyclic carbenes (NHCs) with emphasis on their coordination to palladium, silver, rhodium, gold, copper, and nickel. Chapter two provides the synthesis and characterisation of a series of bis-expanded ring NHC precursors along with the attempted synthesis of mixed 5- and 6-membered types. The attempted coordination of the bis-NHC precursors to palladium did not produce the desired complexes rather a rearrangement occurred to give nitrogen coordinated species through elimination of the linking group between the two heterocycles. Chapter three explores the synthesis and characterisation of a range of novel alkylated bicyclic NHC precursors including the dimethyl, diethyl, and diisopropyl derivatives, and their coordination to rhodium(I). The increased steric demand (iPr > Et > Me) of the exocyclic substituent leads to a larger NCN angle across the series. The rhodium complexes exist as a mixture of two isomers (syn-alkene and syn-chloride) in a 2:1 ratio resulting from restricted rotation about the Rh-CNHC bond. The complexes are active for the transfer hydrogenation of ketones with conversions up to 37 %. Chapter four discusses the coordination chemistry of monocyclic expanded-ring and bicyclic NHCs with copper(I). The expanded ring NHC copper(I) complexes of the type [Cu(NHC)X] show typical Ccarbene-Cu-X bond angles of around 180 °. However, the related complex of the mesityl bicyclic NHC shows an apparent non covalent interaction between the metal and the mesityl ring causing a deviation of the Ccarbene-Cu-X bond away from linearity. The catalytic activity of the expanded ring copper(I) halide complexes for hydrosilylation was explored but were shown to be inactive. Chapter five concerns gold(I) complexes of expanded-ring and bicyclic NHCs. A small crystallographic library of complexes enabled the percentage buried volumes to be determined. As expected, these were large for the aromatic substituted expanded ring complexes of type [Au(NHC)X] but appreciably smaller (more akin to the common 5- membered NHCs) for the bicyclic systems and the alkylated expanded ring systems. The catalytic activity of the complexes in the hydration of alkynes was explored with iv conversions of up to 100 % being observed. Selectivities were noticeably better than those reported for the [Au(6-DIPP)Cl] and [Au(7-DIPP)Cl] with values of around 30:70. Chapter six moves into the coordination and characterisation of a series of highly sensitive expanded ring nickel(I) complexes. Due to the paramagnetic nature of these compounds analysis using EPR was achieved. This showed that the nickel(I) complexes all exhibited orthorhombic g values.

The direct, gas-phase hydrochlorination of acetylene is a method by which vinyl chloride monomer (VCM) is produced industrially. VCM is polymerised to produce poly-vinyl chloride (PVC), one of the world’s most widely used plastics. Although other methods, using oil-derived ethene, are now more widely used, hydrochlorination of acetylene, which is coal-derived, is still the preferred method in areas where coal is a cheap and widely available resource. However, there are numerous problems associated with the mercury based catalysts which are traditionally used for this process, largely for environmental reasons, and therefore a new catalyst is desirable. Gold based catalysts have been shown to be active and particularly selective for this reaction, but deactivation with use is still an issue restricting commercial application. Previously it has been demonstrated that Au3+ is likely to be the active site for acetylene hydrochlorination by Au/C catalysts, and that deactivation of the catalysts during reaction above 120°C is due to reduction of this species to Au0. Therefore Au/C catalysts have been investigated in detail, in order to investigate the true importance of the Au3+ species. Catalysts were prepared with numerous variations in the method used, including the acid used for impregnation and the drying temperature, and subjected to oxidation and reduction treatments. Characterisation was carried out by temperature programmed reduction (TPR) in addition to XPS which has been typically used to identify the surface species of such catalysts. TPR was found to be a technique which is able to provide an extensive amount of information about both the gold and the carbon support and enabled it to be shown that whilst Au3+ is important for catalytic activity, its presence alone is not sufficient and the reducibility of this species is a key factor.

In this thesis the direct synthesis of hydrogen peroxide from hydrogen and oxygen using gold-palladium supported catalysts is described. The direct route presents a greener and sustainable alternative to the current industrial manufacture process. This work aims to meet industrial requirements set by Solvay® which would make the direct process industrially viable. The drawback preventing the requirements being met is the reaction of hydrogen and oxygen over a catalyst can yield water as well as hydrogen peroxide. Once H2O2 is formed, it can be consumed by either reduction or decomposition. Thus, the rates of the subsequent reactions must be minimized to increase the selectivity and therefore H2O2 concentration to a desirable level. Aspects of the catalyst design and reaction variables have been studied over three results chapters. Firstly, the thermal treatment conditions have been altered, ultimately producing a catalyst with no activity to the H2O2 consumption under standard conditions. Switching off H2O2 hydrogenation was concluded to be due to an increase in Pd2+, isolating active Pd0 species. Secondly, active catalysts to both the synthesis and hydrogenation of H2O2 have been produced with no halide; the addition of halide has been shown to decrease hydrogenation activity while maintaining synthesis activity. Finally, a biphasic solvent system and a constant flow of gases through the reaction medium have been examined in order to produce higher H2O2 concentrations. In the former case H2O2 is extracted in-situ from an immiscible organic phase. The production of a 3 wt% H2O2 solution highlights the potential of such a system. In the latter case a semi-continuous flow reactor is utilised increasing the H2O2 concentration up to ca. 1 wt% (from ca. 0.2 wt%). The reactor allowed H2 selectivity and H2O concentration to be measured as a function of time, thus providing greater insight into catalyst activity.

A variety of mass spectrometry experiments have been performed with the aim of further understanding of the ionisation processes involved and the gas-phase behaviour of various organic molecules within two ionisation techniques: Matrix-Assisted Laser Desorption Ionisation (MALDI) and Electrospray Ionisation (ESI). The majority of the studied compounds were C60 derivatised in various ways, either with addition of a ligand, or by the creation of an orifice within the cage structure with heteroatoms – Open-Cage Fullerenes (OCFs). The DCTB-MALDI investigations into the OCFs revealed a possible correlation between orifice size and the heteroatoms present in the orifice, to how the OCF behaved under elevated laser fluence. An extended investigation into the smallest hydrofullerene, C60H2, established for the first time decomposition-free conditions for its analysis, so that its oxidation over time, which has been controversial in the literature, could be studied. The use of pencil lead as a matrix was compared to the traditional matrix for fullerenes, DCTB. Pencil lead was found to be inferior as a matrix, however, proved an exceptionally easy way of creating sodium and potassium adducts, which was found to be useful in the differentiation of isomers of some of the OCFs. The formation of polyaromatic hydrocarbons adducts to C60 were synthesized and analysed with both MALDI and ESI-MS. These complexes are notoriously labile, yet a larger C60PAH:C60 peak intensity ratio was achieved than had been previously reported. The use of silver in ESI experiments was explored in depth. Initially, heterodimers of amino acids bound by silver (I) ions were created and fragmented in order to ascertain relative silver binding affinities, by use of the kinetic method. The same technique was applied to compounds that have been traditionally difficult to ionise with ESI-MS. These included pure fullerenes, fullerene derivatives, and various fullerene precursors. These compounds have been successfully arranged into order of their silver-ion affinities.

The aim of this project lied in the development of an Evolvable Process Design (EPD) reactor platform such that 'evolved' chemical reactions could be investigated for the first time. The development of this 'machine' would allow us to take small organic / inorganic building blocks and use them to prepare any theoretical compound with any theoretical property that is determined by the 'machine'. One of the essential components required were building blocks that can reversibly react under various conditions until a product with a desired property has been evolved. As we were developing a proof-of-principle EPD, we at Warwick concentrated on synthesizing a library of uniquely coloured imine products to prove a desired coloured imine could be evolved in the 'machine'. For this we first required a suitable analytical method that could accurately detect multiple components in a mixture (three aldehydes, three amines resulting in nine imine products) so we could understand the reaction before placing into the 'machine'. In chapter 2, we demonstrated that 19F NMR spectroscopy was sufficient to monitor in real time the equilibrium of a 3 x 3 matrix of fluorinated amine + aldehyde building blocks (nine imines). We also demonstrated that the system of our study was under a dynamic equilibrium and that by altering the acid or base concentrations, we can affect the dynamics of the reaction and monitor it quantitatively. In chapter 3, we synthesized a library of highly conjugated aromatic imines from fluorinated aldehydes and non-fluorinated amines. These imines possessed unique UV / Vis profiles (and unique 19F NMR data) therefore could be monitored in our 'machine' equipped with a UV / Vis sensor. In chapter 4, a reaction was ready to be trailed on the 'machine' as previously synthesized in chapter three but no such 'machine' had been developed by our collaborators and therefore we created our own mini-flow system to test in situ UV / Vis absorbance measurements of our library of imines. In chapter 5 we focused on synthesizing imine ligands for metal mediated atom transfer radical cyclization reactions (ATRC) (extensively studied by the Clark group) as this 'machine' was still under development by our collaborators. We knew that once the 'machine' was developed, we could tweak the system in a way which would allow us to develop optimised imine catalysts for ATRC reactions. In chapter 6 we demonstrated KBH4 to be the most efficient reducing agent for copper mediated AGET / ARGET – ATRC and by increasing the concentration of the reaction mixtures we significantly improved the efficiency of copper mediated AGET–ATRC of previously investigated reactions by the Clark group. We also demonstrated copper mediated AGET-ATRC in water at good conversions using ultrasound, replacing a toxic solvent and may now be considered as 'green' chemistry. In chapter 7, we were able to demonstrate an alternative procedure to oxindoles via copper meditated cyclisation reaction. In the presence of 1.1 equiv. of CuBr / TPA in methanol at 50 oC we were able to show 100% conversions of substrates 2-Bromo-N-butyl-2-methyl-N-(p-tolyl)propanamide and 2-Bromo-Nbutyl- 2-methyl-N-(m-tolyl)propanamide. We then performed a series of reactions to reduce the transition metal and ligand loadings by using borohydride reducing agents but unfortunately, these reactions were not that efficient.

Photoactive platinum compounds have the potential to reduce some of the debilitating side-effects associated with conventional chemotherapeutics, such as cisplatin. Stable platinum(IV) complexes which are reduced to active platinum(II) species only on irradiation, could provide a site-specific treatment. The photodegradation pathways of the photoactive platinum(IV) diazido complex cis,trans,cis-[Pt(N3)2(OH)2(NH3)2] have been extensively studied. Various photoisomerisation, trans-labilisation and photoreduction pathways were observed, with several unexpected photoproducts including ammonia, oxygen and free azide. The photoreactions of cis,trans,cis-[Pt(N3)2(OH)2(NH3)2] in the presence of two amino acid derivatives, N-acetyl-L-histidine and N-acetyl-L-methionine, and the nitrogen-heterocycle 1-methylimidazole, have also been investigated. In the presence of 1-methylimidazole, surprisingly the major photoproduct was the tetra-substituted PtII complex [PtII(1-MeIm-N3)4]2+, even at a Pt/1-MeIm molar ratio of 1:1. Reactions with the amino acid derivatives identified some unusual di- and tri-substituted platinum(II) photoproducts. This work has involved using a variety of techniques including multinuclear NMR spectroscopy, DFT/TD-DFT calculations and electrospray ionisation-mass spectrometry (ESI-MS). The reaction of cisplatin (cis-[PtCl2(NH3)2]) with the protein ubiquitin was investigated using ion mobility-mass spectrometry (IM-MS), revealing multiple induced protein conformations upon platination. The preferred binding site of cisplatin on the amino acid Met1 was also directly identified for the first time. The primary platination site of cis,trans,cis-[Pt(N3)2(OH)2(NH3)2] and trans,trans,trans-[Pt(N3)2(OH)2(NH3)2] on ubiquitin was also investigated, and found to be Met1. The ESI-MS studies highlight the rapid generation and diverse nature of the photoinduced reactive platinum(II) species after short UVA irradiation times. Insights into the reaction of cis,trans,cis-[Pt(N3)2(OH)2(NH3)2] with cytochrome c are also reported. The antiviral properties of cisplatin (cis-[PtCl2(NH3)2] and the photoinduced activity of cis,trans,cis-[Pt(N3)2(OH)2(NH3)2] and trans,trans,trans-[Pt(N3)2(OH)-2(NH3)2] were assessed against the bacterial virus bacteriophage P1. This work has highlighted the complex and novel speciation of such platinum(IV) complexes upon irradiation, which may lead to new cytotoxic mechanisms in cancer cells.

This thesis begins with an introduction to inflammation and current antiinflammatory drugs in general, and the new small molecule somatotaxins developed by Fox and colleagues in particular. Chapter 1 describes the evidence used to propose the existence of structurally similar C-terminal lactam peptides that could potentially provide a novel anti-inflammatory pathway in vitro. Chapter 2 describes the synthesis of some C-terminal lactam peptides using solution phase peptide synthesis. Both linear and block syntheses were used. This chapter also describes some of the problems encountered using peptide coupling agents and our attempts to overcome them. Chapter 3 describes our investigations into thioacids for the block synthesis of peptides. The use of isoleucine in model peptides for the quantification of epimerization at the C-terminal amino-acid is also illustrated, and a series of NMR experiments were performed to allow us to differentiate between the relative stereoisomers of isoleucine residues in compounds. Chapter 4 describes the use of these 1H NMR experiments to predict the relative stereochemistry of a C-terminal isoleucine residue in the natural product, azolemycin A. The first total synthesis of azolemycins A and B, and a number of analogues, is then described.

No description available.