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Flow chemistry, the basis of petrochemical and bulk chemicals industry, has recently found various applications in fine chemicals production and discovery chemistry with the development of commercially available laboratory equipment. Due to the precise control of the reaction parameters, the potential for automation and sequencing of reactions, the in situ analysis and for safety reasons the development of this novel technology has proven to make significant impact within organic chemistry. By taking advantage of the potential of flow chemistry, the optimisation of difficult batch reactions involved in the total synthesis of epicocconone analogues, and the in situ generation of isocyanides were attempted. However, some limitations such as solubility issues and formation of insoluble species made the optimisations complicated. Then, activation energies and reaction rate constants were determined from the thermolysis of 1,3-dioxin-4-ones by means of in situ analysis (UV and IR) and by using conventional and novel kinetic study methods. Good consistency was observed between both procedures. The significant gain in time and the lower consumption of material were the main advantages of this novel methodology which can be used as a reliable tool to accelerate reaction study and process development. Finally, the flow platform was employed to develop optimisation of reaction methodologies by using the dispersion effect and the “turn off” light concept. Thermolysis of 1,3-dioxin-4-one, Diels-Alder reaction, [2+2] photocycloaddition, photocyclisation and SRN1 reactions were used as models for the development of these two methodologies. The determination of the rate constant of both 1st and 2nd order reactions, the determination of the optimum amount of reagent and the determination of the optimum concentration of starting material were achieved with the dispersion effect methodology. Then, the “turn off” light procedure was developed to rapidly determine the optimum reaction time. Consistent results were obtained for both new methodologies.

El éxito de una separación cromatográfica radica en alcanzar una interacción diferencial de los solutos con la fase estacionaria, lo que se consigue controlando las variables o factores experimentales más accesibles. Generalmente, los requisitos para resolver cada soluto son específicos y, con frecuencia, la mejora en la separación de unos conlleva el empeoramiento en otros. Por lo tanto, lograr un compromiso que permita resolver todos los solutos en una mezcla compleja puede llegar a ser un problema arduo, que generalmente se resuelve mediante estrategias de prueba y error basadas en la experiencia del cromatografista. Desafortunadamente, la aplicación de estas estrategias requiere mucho tiempo y suelen fracasar con muestras que contienen un gran número de compuestos, o cuando existen múltiples factores involucrados con efectos difíciles de predecir. La situación empeora cuando el poder de resolución en el orden cromatográfico es insuficiente y no puede completarse con la riqueza de la señal proporcionada por el detector o mediante una segunda separación. El modo más eficiente de abordar una optimización en cromatografía líquida es el uso de estrategias basadas en modelos predictores de la resolución. Por otro lado, los estudios de tipo fundamental en cromatografía son esenciales para mejorar el conocimiento sobre las posibilidades de los sistemas separadores. A pesar del interés que muchos investigadores han mostrado por estos estudios, existen varios aspectos esenciales que es necesario todavía revisar o desarrollar. A lo largo de esta Tesis, se estudiaron las ventajas aportadas por el uso de modelos predictores del comportamiento de retención y perfil de los picos cromatográficos, para conocer en profundidad las posibilidades de los sistemas separadores. Las investigaciones se centraron en diversas variables cromatográficas, algunas relacionadas con la composición de la fase móvil (disolvente orgánico y pH), y otras de carácter ambiental (temperatura) o instrumental (caudal). Se consideraron situaciones en las que se optimizaba una sola variable, o dos o tres variables simultáneamente. En cada caso, se comprobó la idoneidad de las predicciones mediante su comparación con experiencias reales, con resultados muy satisfactorios. Además, se revisó la estimación de algunos parámetros fundamentales, como el tiempo muerto, la capacidad de pico, el coeficiente de reparto octanol-agua y la eficacia, y se propusieron modificaciones de métodos publicados, junto con nuevos métodos. Se propuso también un método exhaustivo de comparación de columnas cromatográficas en intervalos amplios de composición de fase móvil, que considera el tiempo de análisis, la selectividad, la forma de los picos cromatográficos y la resolución, así como la posibilidad de transferir resultados entre columnas. Se trabajó en cromatografía líquida convencional y cromatografía líquida rápida, utilizando una amplia variedad de columnas de fase inversa (microparticuladas y monolítica) y numerosos solutos con diversas características, incluyendo beta-bloqueantes, diuréticos, fenoles y series homólogas. / The success in a chromatographic separation relies on the achievement of a differential interaction of the components in the mixture with the column, which is done by tuning carefully the environmental variables with a main impact on selectivity to precise levels. In order to optimise the selectivity, trial-and-error approaches based on the chromatographer experience are commonly used. Unfortunately, these strategies can be time-consuming and prone to fail, which happens especially in problems with a large number of compounds, or involving multiple variables whose effects are difficult to predict. The situation worsens when the resolution power in the chromatographic order is insufficient and cannot be completed by the richness of the signal provided by the detector or by a second separation. The best efficient way to tackle a liquid chromatographic optimization is the use of strategies based on resolution prediction models. Fundamental studies in chromatography are essential for improving the knowledge of the possibilities of the separation system. Despite the interest that many researchers have shown for these studies, there are still several essential aspects that need some revision or development. In this Thesis, the advantage provided by the use of prediction models to optimize chromatographic systems was studied. The research work was based on diverse chromatographic factors, some of them related to the mobile phase composition (organic solvent content and pH), and other factors of environmental (temperature) or instrumental (flow-rate) nature. Moreover, the estimation of some fundamental parameters was revised, such as the dead time, peak capacity, octanol-water partition coefficient and efficiency, and some modifications of published methods were proposed together with new methods. A methodology was also proposed that allows an exhaustive comparison of chromatographic columns, in wide mobile phase composition ranges, which considers the analysis time, selectivity, peak shape and resolution, as well as the possibility of transferring the results among columns.The studies were achieved using conventional liquid chromatography and rapid liquid chromatography, using a wide variety of reversed-phase columns of different nature and a wide range of solutes.

The development of a Microsoft® Excel® spreadsheet is described, for the accurate calculation of CIE (Commission Internationale de l'Eclairage) 1931 xy chromaticity coordinates and luminance data from visible region absorption spectra recorded in transmission mode. Using firmly established CIE principles, absorbance-wavelength data from visible spectra are taken as input, with chromaticity coordinates being generated as output. Colour stimulus measurement example calculation results are firstly presented for aqueous solutions of the dyes, Erythrosin B (red, x, y = 0.608, 0.365), Acid Green 25 (x, y = 0.086, 0.298) and Remaxol Brilliant Blue R (x, y = 0.153, 0.045), and then for tracking electrochromic in situ colour stimulus changes in the methyl viologen and di-n-heptyl viologen systems. The quantification of colour during each viologen dication to cationradical reduction process, and each reverse (oxidation) process, showed that subtle changes in both hue and luminance could be detected, with evidence of colour contributions from both the cation radical and the cation radical dimer. Ruthenium purple (RP) films on transmissive tin-doped indium oxide (ITO)/glass substrates have been synthesised by a novel electrochemical coagulation technique. Using the CIE system of colorimetry, the colour stimulus of the electrochromic RP films and the changes that take place on reversibly switching to the colourless form have been calculated from in situ visible spectra recorded under electrochemical control. (Continues...).

There is an increasing commercial interest in finding alternative ways to produce phenol that overcome the disadvantages of the current cumene process used to synthesize phenol. The drivers for the change are both economic and environmental. A direct oxidation route for producing phenol from benzene is based on using N2O as an oxidizing agent in the gas phase in the presence of modified Fe-ZSM5 zeolite. One of the main objectives was to examine the effect of different Si/Al ratios, temperatures and iron content on the selective conversion of benzene to phenol with a desire to achieve high selectivity and minimise catalyst deactivation. Also one of the research objectives was to identify the active sites in the catalyst and design the catalyst which is able to delay coke formation. The methodology was to incorporate iron directly at extra-framework positions via liquid ion-exchange. In this project, a series of selective Fe-ZSM5 catalysts with different Si/Al ratios have been prepared and evaluated for selective formation of phenol. The catalyst samples were characterized (by Atomic Absorption Spectroscopy (AAS), Malvern mastersizer and Nitrogen adsorption using N2 at 77 K via Micromeritics to determine the elemental composition, average particle size, BET surface area and pore size distribution) and their catalytic activities compared. A quantitative comparison between the number of active sites using isopropylamine decomposition method shows that active sites increase as the Si/Al ratio increased and also as the iron content increased. (Continues...).

Chapter 1: Introduction An introduction into the studies of the pharmaceutical materials and FTiR of biological materials are presented. Chapter 2: Quantification of amorphous lactose using HID exchange coupled with Raman, FTIR and ss-NMR spectroscopies Three analytical techniques coupled with HID exchange are used for quantification of the amorphous content in blends of amorphous and crystalline lactose. Firstly, Raman spectroscopy was used to quantify mixtures pre- and post-deuteration. Prior to deuteration, a known method was utilised using peak height ratios and this showed linearity across the entire percentage amorphous content range with a detection limit of 2.2 %. Post-deuteration, a similar linear trend was observed with the limit of detection found to be 1.5 %. The second technique presented is FTIR where a similar approach was adopted. Before deuteration, bands indicative of either the amorphous or crystalline phase were selected and then used to create a calibration with a limit of detection of 1.47 %. Following deuteration of the blends, the v(O-D) band was integrated and used to construct a further calibration with detection limit equal to 0.7%. Finally 2H solid-state NMR was used and following initial calibration experiments, blends of amorphous and crystalline lactose were collected and the calibration plot had limit of detection of 0.4 %. To extend the data analysis, Principal Component Analysis, a multivariate technique, was employed to the post deuteration FTIR dataset. This gave a new calibration with the detection limit 0.44 %. Chapter 3: Quantification of amorphous cimetidine using HID exchange coupled with Raman, FTIR and ss-NMR spectroscopies A brief recap of previous work complete in the group is presented here, using FT-Raman for the quantification of amorphous cimetidine. The FT-Raman work is then repeated using a dispersive Raman system with a different excitation wavelength. The 785 nm system gave improved limits of detection for both undeuterated cimetidine and deuterated cimetidine compared with the FTRaman work, with the limits of detection 1.95 % and 4.1 % respectively. Cimetidine was further investigated using FTIR. It was found that quantification of amorphous cimetidine could not be performed as incomplete deuteration was observed. A solution casting method was developed, which did allow for the complete deuteration of amorphous cimetidine, however, this was not suitable for quantification purposes. 2H solid-state NMR experiments were performed on blends of deuterated amorphous and crystalline cimetidine and following data processing, a calibration plot was constructed. The limit of detection was 1.6 %. Principal component analysis was applied to the deuterated Raman spectra, this gave an improvement in the limit of detection equal to 1.4 %, bring the detection limit down to 2.7 % amorphous content. Chapter 4: Investigation using FTIR for the prognosis of Breast Cancer using FTIR instrumentation with 25 JIm spatial resolution FTIR images were collected from 8 breast cancer tissue sections (2 Grade 1, 3 Grade 2 and 3 Grade3). Each of the FTIR datasets was subjected to Principal Component Analysis for explore the patterns in the data. Two methods have been presented to construct false colour images, PCA- Fuzzy c-means clustering and Multivariate Curve Resolution and the ability of each multivariate technique to discriminate different tissue types is discussed. Spectra were extracted from regions of tumour and normal cells and then analysed to investigate the possibility of differentiating between the two cell types. It was found that it was possible to discriminate between the two. Finally spectra were extracted from the tumour regions of the different tissues in order to study whether grading of the breast cancer was possible using FTIR imaging. However, no clear relationship was observed between the different grades . . Chapter 5: Investigation using FTIR for the prognosis of Breast Cancer with 5.5 ~m pixel size A similar approach to Chapter 5 was adopted but imaging the tissue sections with a focal plane array detector with pixel size 5.5 ~m. The increased spatial resolution allowed for false colour images with increased similarity to the H&E to be constructed . Finally FTIR imaging was used to successfully grade the breast cancer tissues in a non-subjective way, using PCA. . Chapter 6: Experimental The methods used to perform the experiments presented in this Thesis are outlined, as well as an introduction to the chemometric techniques that have been utilised.