This thesis describes the determination of the pKa values of a number of carbon acids in 020 at 25 oc and fixed ionic strength (KCl). Second-order rate constants for the deprotonation of these carbon acids by deuteroxide ion k00 (M-1s- 1), in 0 20 at 25 oc were determined by 1H NMR spectroscopy. These k00 values could be used to calculate values for kHo (M-1s- 1), the second-order rate constant for deprotonation of the carbon acid by hydroxide ion to give the corresponding conjugate base in water. This thesis deals with three different groups of carbon acids: the conjugate acids of N-heterocyclic carbenes, diketopiperazines, and thalidomide and thalidomide analogues. Oiaminocarbenes are of significant interest as ligands in organometallic catalysis and in medicinal chemistry. The syntheses and determination of the pKa values of a series of the azolium ions including 1,3-disubstituted imidazolium ions, 4,5~dihydroimidazolium ions, and 3,4,5-trihydropyrimidinium ions are described. Values for kHo (M-ls- 1), the second order-rate constant for deprotonation at C2 of each azolium ion, were determined as described above. Evidence is presented that the reverse rate constant for carbine protonation by solvent water is limited by solvent reorganization and occurs with a rateconstant of kHoH = kreorg =1011 s- 1. Values for kHo and kHoH permitted the calculation ofreliable carbon acid pKas for ionization of the azolium ions in water. The effects of the N-substituents and ring size of the heterocycle on kHo and pKa values are discussed. The relative hydrolytic stabilities of the azolium ions is also discussed. Oiketopiperazines (DKPs) are an important class of biological compound. The synthesis and determination of the pKa values of bis-0-proline and bis-L-proline diketopiperazine are described. Values for kHo (M- 1s- 1), the second order-rate constant for deprotonation at the a-carbon of the OKP were determined as described above. Evidence is presented that the reverse rate of protonation of the OKP enolates by solvent water is likely to be less than diffusion controlled. Hence, the pKa values were determined by extrapolation from a Bremsted plot of log kHo values against pKa values of other neutral simple carbon acids. The OKP kHo and pKa values are compared with analogous values for acyclic peptide analogues. Thalidomide and analogues such as the chemokine inhibitors, N-(2-0xo-piperidine-3yl)propionamide and N-(2-0xo-azapan-3-yl)propionamide, have been of considerable interest to the pharmaceutical industry for some time. Determination of the rates of hydrolysis and the pKa values for thalidomide and the analogues in 0 20 at 25oC and fixed ionic strength (KCl) are described. The pKa values were determined from a Bronsted plot of log kHo values against pKa of other neutral simple carbon acids in a similar manner to that performed for the diketopiperazines. The rates of hydrolysis and the relative stereo integrity of the species are discussed.

The investigation is concerned with the effect of electrolytes on the rates of reaction of p-methoxybenzyl chloride and benzbydryl chloride in 70% acetone, where both compounds hydrolyse entirely by mechanism S(_N)1. The work was designed to test the possibility that better nucleophilic reagents than water could react with p-mothoxybenzyl chloride by the concurrent operation of mechanisms S(_N)1 and S(_N)2. Since electrolytes had been previously demonstrated to have specific effects on the rates of ionlsation of organic compounds(^29,86,87,) it was also necessary to measure their effect on an Ionization process before the quantitative treatment of the first problem was possible. Benzhydryl chloride, which is not susceptible to bimolecular attack(^61b), was chosen for this purpose because its rate of ionisation was known to have the same sensitivity as that of p-methosybenzyl chloride to changes in the solvent composition and to additions of sodium perchlorate(^29). The studies have shorn that the specific effects of electrolytes on the rate of reaction of benzhydryl chloride in the present solvent are consistent with the operation of two effects 1) a non-specific acceleration of the rate of reaction duo to ion-atmosphere stabilisation of the transition state for ionisation(^80), ii) a specific change in the “effective” solvent composition due to solvent of the electrolytes(^87). The effect is greater for p-methoxybenzyl chloride than for benzhydryl chloride by a constant small amount. The application of these principles to the effects of electrolytes on the rate of reaction of p-methoxybenzyl chloride, has confirmed that azlde ions and chloride ions react with this compound by the simultaneous operation of the S(_N)1 and S(_N)2 processes. This is probably also the case for the substitutions by bromide, nitrate and fluoride ions. The non-electrolyte, pyridine, has also been shown to react with p-methoxybenzyl chloride by concurrent operation of the two S(_N) mechanisms, but no allowance for the medium effect could be made in tills case, because other inert non-electrolytes were found to affect the rates of ionisation of beazhydryl chloride and p-methoxybenzyl chloride in different ways. Additional evidence is provided for the validity of the criterion(^61)of mechanism on which it was concluded(^29) that p-methoxybenzyl chloride hydrolyses by mechanism S(_N)1 70% aqueous acetone. This mechanistic criterion requires that the value of the ratio ΔC*/∆S* should be independent of the nature of the substrate for S(_N)1 reactions. The value of this ratio for the hydrolysis of p-nitrobenzhydryl chloride in 50% aqueous acetone is shown to be the same as the corresponding values for the structurally different compounds tert-butyl chloride, benzylidene chloride, p-methylbenzylidene chloride and benzotrichloride in the same solvent(^62), where the reactions all follow the S(_N)1 path.

The Investigation is concerned with the effect of p-substituents on the rates and activation parameters in the ionisation (S(_N)1 reaction) of phenylmethyl halides. In these systems, substituents exert their effect on the rate almost entirely by altering the electron density at the reaction centre(^1). The work was designed to yield information about the effect of changing electron demand at the site of p-substitution in the transition state. The reaction of p-substituted benzyl halides with slightly moist formic acid was studied initially. In this system, the electron demand at the site of p-substitution can be expected to be large but the results were unsuitable for discussion of substituent effects in S(_N)l reactions since this mechanism did not operate throughout the series. Completely S(_N)l solvolysis appears to require the presence of an electron donating substituent and may not be attained by the p-methyl derivative. An extension to aqueous organic solvents showed that completely S(_N)l hydrolysis requires the presence of a p-phenoxy, or better electron releasing substituent. The hydrolysis of p-substituted p'-nitro-, p'-hydrogen-, and p'-raethoxy-benzhydryl chlorides undoubtedly occurs by the ionisation mechanism. The electron demand at the site of p-substitution was expected to decrease in the order, p'-nitro > p'-hydrogen > p'-methoxy and it is consistent with this view that the effect of any one p-substituent on the rate follows the same sequence. The kinetic effect of these p-substituents arises almost entirely from changes in the activation energy although the entropy of activation is significantly reduced by the introduction of p-phenoxy and p-methoxy substituents. In all three series, reaction is facilitated by electron releasing p-substituents, particularly by those which are polarisable with respect to electron demand at the reaction centre. There is, however, no simple relation between the magnitude of these polarisabllity effects and the electron demand at the site of p-substitution. As a result, simple free-energy relations of the Hammett type(^2) are inadequate in accounting for the effect of p-substituents on the rates, even in the present three similar series. The Tsuno-Yukawa equation(^3), which attempts to allow for polarisation and polarisabllity effects separately, describes the present rates more satisfactorily, if the reaction constants are derived from the results for the two p-substltuents with extreme polar properties. However, this equation assumes a linear relation for the response of substituents to a demand for electrons. It is concluded that the effects of p-substituents are more profitably discussed by using Ingold's approach(^4) of considering the polarisation and polarisability effects, and the reaction mechanism.

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No description available.

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Part I. A study has been carried out on the effect of a pentafluorophenyl substituent in promoting carbanion rearrangements in a simple ethyl system. Analogous non-fluorinated systems are reported to have produced rearrangement only with caesium or alkali metal alloys. The reactions of 1-bromo-2-pentafluorophenylethane with magnesium and lithium have been studied under various conditions. The major product in the case of lithium was the corresponding ethene, formed by decomposition of the lithium compound. With magnesium the expected ethane was formed on hydrolysis. Isotopic labelling studies indicated that no rearrangement occurred in this system. The evidence suggests that a single pentafluoro- phenyl group is insufficiently activating to cause rearrangement to occur with the less active alkali metals. Part II. The reactions of an "internal" fluoroalkene (perfluoro-3,4-dimethyl- 3-hexene) with various carbon and nitrogen nucleophiles have been investigated. Unusually, a terminal elkene has been produced as the major product with a carbon nucleophile, rather than the more highly substituted Isomer. The reactions with nitrogen nucleophiles have resulted in products being formed from each of the three isomers of perfluoro-3,4-dime thyl-3-hexene.An interesting series of fluorinated furans has been prepared, with a variety of substituents at the 2-position. These are related to the internal fluoroalkene discussed above. This series has provided a useful probe for the investigation of the photochemistry of fluorinated furans. The expected products (cyclopropenylketones) were obtained in all cases except where the substituent was perfluoro-1-H-T-H-propyl, where the only observed products resulted from loss of HP from the side chain. Specificity in ring opening was only observed for one furan - perfluoro-3,4,5-triraethylfuran.Perfluorotetramethylfuran has proved to be largely inert to nucleophilic attack and reaction with addition reagents.

No description available.

This thesis is divided into three key chapters. Chapter 1 focuses on the metal-catalysed higher-order carbocyclisation reaction whilst Chapter 2 describes metal-catalysed ene- cycloisomerisation reactions. The final section, Chapter 3, will delineate the key features of the mechanism of each transformation through kinetic and computational analysis. Chapter 1 commences with an introduction to ['m+2+2'] carbocyclisation reactions (Section 1.1). This is segregated into the following sections: metal-catalysed ['2+2+2'] (Section 1.1.1), metal-catalysed ['3+2+2'] (Section 1.1.2) and metal-catalysed ['4+2+2'] (Section 1.1.3) carbocyclisation reactions. Each section is divided into sub-sections, which correspond to their molecularity. Each sub-section begins with the intermolecular variant ([m+2+2]), followed by semi-intermolecular reactions ([(m+2)+2] and [m+(2+2)]), and conclude with the fully intramolecular molecular reaction ([(m+2+2)]). Each sub-section is partitioned depending on the degree of saturation. For example, alkyne trimerisation (Section l. 1.1. 1.1) precedes the reaction of two alkynes with one alkene (Section 1.1.1.1.2), which in turn precedes the reaction of one alkyne with two alkenes (Section 1.1.l.l.3). Section 1.2 describes our development of a regiodivergent [(2+2)+2] carbocyclisation reaction. This highlights the optimal reaction conditions as well as the scope and generality of the reaction. A hypothesis for the observed results is also discussed. The development of a regio- and diastereoselective [(3+2)+2] carbocyclisation will be discussed in Section 1.3. The section commences with an overview of three-carbon synthons in carbocyclisation reactions (Section 1.3.1.1) and highlights a plausible rationale for the potential of alkenylidenecyclopropanes in the context of a rhodium-catalysed [(3+2)+2] carbocyclisation reaction (Section 1.3.1.2). A detailed study into the optimisation and scope of the reaction is described in Section 1.3.2 and 1.3.3, respectively, which includes a plausible mechanism which accounts for the oberserved selectivities.

The aim of this project was to generate a new type of therapeutic delivery system and immunogenic vector, based on calixarenes, that is able to not only deliver immunogenic peptide but also act as a potential cancer vaccine. The introduction presents calixarenes derivatives in the context of supramolecular chemistry. Their properties on the nanoscale allow them to be potential adjuvants for cancer immunotherapeutics. The synthetic study of these materials presented in Chapter II compares traditional synthetic protocols and a new greener approach utilising microwave irradiation. Initial studies in this area concentrate on alkyl-footed derivatives of both the resorcin[4]arene and pyrogallol[4]arene macrocycles but have also been expanded to the previously problematic aromatic derivatives. This microwave method has been optimised to produce the rccc diastereoisomer for both the alkyl and aromatic derivatives, showing that the nature of the substituent on the pendant chains does not have a great effect on the conformation using this green protocol. The solution and solid state studies of these new aromatic pyrogallol[4]arene macrocycles, in the rccc cone conformation, have been investigated and demonstrate their future potential application in hydrogen storage. The synthesis of polar analogues, described in Chapter III, was achieved by functionalising the pendant chains with polar groups, including amines, alcohols and carboxylic acids. The importance of the solvent in the crystallisation process is highlighted by single crystal X-ray diffraction study, showing that it can act as templating agent or guest. Access to polar footed calixarenes has enabled the project to investigate their potential to link bioactive therapeutics including amino acids and peptides, towards nano-vectors exposed in Chapter IV. The traditional synthesis in solution was challenging due to purification issues, and only succeeded in the attachment of three trialanines. The method was therefore tuned towards solid phase synthesis, which opened up to the new development of Merrifield resin functionalised with calixarenes. As the macrocycle will be considered for immunisation in the future, the lead macrocycle from this study have been screened for potential downstream biological applications. Preliminary studies, including haemolytic properties and cytotoxicity studies did not show any toxicity at the workable concentrations.