abstract: Monte Carlo methods often used in nuclear physics, such as auxiliary field diffusion Monte Carlo and Green's function Monte Carlo, have typically relied on phenomenological local real-space potentials containing as few derivatives as possible, such as the Argonne-Urbana family of interactions, to make sampling simple and efficient. Basis set methods such as no-core shell model or coupled-cluster techniques typically use softer non-local potentials because of their more rapid convergence with basis set size. These non-local potentials are typically defined in momentum space and are often based on effective field theory. Comparisons of the results of the two types of methods are complicated by the use of different potentials. This thesis discusses progress made in using such non-local potentials in quantum Monte Carlo calculations of light nuclei. In particular, it shows methods for evaluating the real-space, imaginary-time propagators needed to perform quantum Monte Carlo calculations using non-local potentials and universality properties of these propagators, how to formulate a good trial wave function for non-local potentials, and how to perform a "one-step" Green's function Monte Carlo calculation for non-local potentials. / Dissertation/Thesis / Ph.D. Physics 2013

Obtaining enantio pure drug molecules is a long standing challenge in asymmetric synthesis implying that the identification of enantiomers and the determination of enantiomeric purity from a racemic mixture are of profound importance. In achieving this target NMR spectroscopy has proven to be an excellent analytical tool. It is well known that normal achiral NMR solvents do not distinguish the spectra of enantiomers. On the other hand, the conversion of substrates to diastereomers using one of the enantiopure chiral auxiliaries, such as, chiral solvating agent, chiral derivatizing agent and chiral lanthanide shift reagent, circumvents this problem. The imposition of diasteomeric interactions circumvents this problem. There is a pool of chiral auxiliaries available in the literature, each of which is specific to molecules of certain functionalities and has its own advantages and limitations. These classical methods have two limitations as they demand the presence of a targeted functional group in the chiral molecule and utilize only chemical shifts to visualize enantiomers. On the other hand in chiral anisotropic medium, due to differential ordering effect, the order-sensitive NMR observables, viz. chemical shift anisotropies (∆σi), dipolar couplings (Dij) and for nuclei with spin >1/2 the quadrupolar couplings (Qi) have enormous power of exhibiting different spectrum for each enantiomer permitting their discrimination. Numerous weakly ordered chiral aligning media have been reported in the literature. Nevertheless there is a scarcity of water compatible medium. Research work presented in this thesis is focused on various aspects, such as, the discovery of new chiral aligning medium for the enantiodiscrimination of water soluble chiral molecules, potential utility of DNA liquid crystal for discrimination of amino acids, on-the-fly monitoring of enzyme kinetics and the preparation of novel composite liquid crystals, hydrogels and thin films. The derived results are discussed in different chapters. Chapter 1 provides a brief introduction to NMR spectroscopy with special emphasis on the conceptual understanding of the tensorial interaction parameters, such as chemical shifts, scalar and dipolar couplings, quadrupolar couplings, effect of r.f pulses, basic introduction to 2D NMR experiments. Subsequently, a broad overview of the enantiomers, specification of their configurations, chirality without stereogenic carbon, chirality in molecules containing different atoms, are discussed. Following this a brief introduction to liquid crystals and their properties, their classification, their orientation in the magnetic field, order parameter are also discussed. The description on the chiral liquid crystals, the differential ordering effect, employment of the orientation dependent NMR interactions, utility of 2H NMR experiments for the visualization of enantiomers and the measurement of enantiomeric composition has been set out in brief. Chapter 2: As far as the organo soluble chiral molecules is concerned (in solvents such as, chloroform, dioxane, tetrahydrofuran and dimethylformamide), it has been well established that an ideal choice of chiral liquid crystal for enantiodiscrimination is poly-�-benzyl-L-glutamate (PBLG). Nevertheless, there is a scarcity of weak aligning medium for water soluble chiral molecules. This chapter introduces the chiral liquid crystal derived from the polysaccharide xanthan, which has numerous applications. The detailed discussion on the preparation of polysaccharide xanthan mesophase is given. The appearance of the mesophse is established by detecting the quadrupole split doublet of dissolved water. Subsequently enantiodiscrimination power of this new medium has been investigated on deuterated D/L-Alanine and (R/S)-β-butyrolactone. For such a purpose the selective 2D-SERF (SElective ReFocussing) experiment has been employed. It has been convincingly demonstrated that the medium has wide applicability for the discrimination of enantiomers, enantiotopic directions in prochiral molecules, measurement of enantiomeric excess and the RDCs in medium sized molecules. The new medium is sustainable over a wide range of temperature and concentration of ingredients, the mesophase is reversible, reproducible, easy to prepare besides being cost effective. It is possible to have the controlled tuning of the degree of order for specific application. Chapter 3: In this chapter the real discriminatory potential of DNA liquid crystalline phase has been explored. It is unambiguously established that; i) the fragmented DNA liquid crystal is able to differentiate between enantiomers of structurally different chiral amino acids; ii) the T1 (2H) values for L/D (alanine) is nearly equal indicating the similar dynamics for both the enantiomers, thus permitting the measurement of ee from the integral areas of the peaks of the contours of 2D spectrum; iii) the enantiotopic discrimination in prochiral compounds has also been successfully explored. Furthermore the analyses of NMR results yielded fruitful information on the analytical potential of DNA chiral liquid crystal, such as, (a) the chiral discrimination is effective on a large range of amino acids with spectral differences ΔΔʋQ‘s and ΔʋQ‘s varying from 80 to 338 Hz, and 50 to 900 Hz respectively; (b) the discrimination phenomenon remain active irrespective of the structure and the electronic nature (polarity) of the fourth substituent around the stereogenic center; (c) compared to an alkyl moiety, the presence of a terminal –OH or –SH group seems to slightly increase both the degree of alignment of the solute and the enantiodiscrimination efficiency compared to alanine; (d) The enantiodiscrimination can be detected easily not only on CD3 and CD groups, but also on CD2 sites exhibiting inequivalent diastereotopic directions; (e) discriminations with rather large differential ordering effect were obtained even for the sites that are situated far away from the asymmetric center; (f) The relative position of quadrupolar doublets from one 2H site to another can be reversed with regard to the absolute configuration (L/D). Chapter 4: Racemases recognize a chiral substrate such as (L-Alanine) and convert it into its enantiomer, i.e., (D-Alanine) and vice versa. Alanine racemase plays a vital role for certain bacteria, providing D-Alanine for peptidoglycan cell-wall biosynthesis. Elucidating the mechanism of enzymatic racemization is crucial for designing new inhibitors that may be useful as a novel class of antibiotics. This requires techniques to discriminate L-and D-Alanine and follow their concentrations as a function of time, so that one can determine the kinetic parameters and study the effect of inhibitors. In this chapter the utility of DNA liquid crystal media for in situ and real-time monitoring of the interconversion of L-and D-alanine-d3 by alanine racemase from Bacillus stearothermophilus has been demonstrated. The enantiomeric excess has been measured at different time intervals to monitor the enzymatic racemization at different time intervals in pseudo 2D NMR. The study unambiguously ascertains the reliability and robustness of utility of NMR in chiral anisotropic phase for monitoring the enzymatic racemization. The method thus provides new mechanistic insight and a better understanding of enzymatic reactions, in particular for alanine racemase. Chapter 5: In continuation with the development of weakly ordered liquid crystals, this chapter reports the spontaneous formation of composite graphene oxide (GO)/double stranded DNA (dsDNA) liquid crystals at higher concentrations of ingredients, and hydrogels at lower concentrations of ingredients, the process of which involves simple mixing in an aqueous phase has been demonstrated. The liquid crystalline phases and hydrogels have been characterized using optical polarized microscopy (OPM), scanning electron microscopy (SEM), Raman spectroscopy and 2H NMR spectroscopy. The observation of strong birefringence in the optical polarized microscope gives evidence for the formation of GO/dsDNA liquid crystals. The strong interaction between the dsDNA and GO was confirmed using Raman spectroscopic analysis. Furthermore, GO/dsDNA thin films have also been prepared and characterized using SEM and OPM. The GO/dsDNA thin film was prepared and its liquid crystal nature was established using OPM and 2H NMR. Importantly, the GO/dsDNA hydrogels were formed without any heat treatment to unwind dsDNA molecules and the porosity of hydrogels can be controlled by changing concentration of the dsDNA. This novel multifunctional composite liquid crystals and hydrogels of GO/dsDNA thus opens up new avenues for many applications like security papers, optical devices such as circular polarizers, reflective displays and drug delivery as well as tissue engineering using GO composite hydrogels.

A necessidade de metodologias adequadas para análise de fármacos e seus metabólitos em matrizes biológicas complexas levaram a um crescente interesse no desenvolvimento de novas técnicas de preparação de amostras, particularmente as técnicas de microextração, por serem altamente seletivas e requererem o consumo mínimo de solventes orgânicos. Aliado a esses avanços, o emprego de modernas e eficientes tecnologias analíticas, como a eletroforese capilar (CE) e a cromatografia líquida de alta eficiência acoplada à espectrometria de massas (LC-MS-MS), tem resultado em um considerável avanço em qualidade nas metodologias analíticas disponíveis para bioanálises. Dentro desse cenário, destaca-se a utilização dessas técnicas para o desenvolvimento de metodologias enantiosseletivas, permitindo quantificar os enantiômeros de fármacos administrados como racematos. Sendo assim, propusemos o desenvolvimento e a validação de metodologias enantiosseletivas para a análise dos enantiômeros da mirtazapina (MRT) e de seus principais metabólitos em plasma e urina, utilizando a CE e a LC-MS-MS. Para a preparação das amostras foram empregadas a microextração em fase sólida (SPME) e a microextração em fase líquida (LPME). No primeiro método desenvolvido, a LPME foi utilizada para extrair os analitos das amostras de plasma (1 mL), previamente diluídas, alcalinizadas com 3,0 mL de uma solução tampão fosfato 0,5 mol L-1 (pH 8) e adicionadas de 15% (m/v) de cloreto de sódio. Éter n-hexílico e uma solução de ácido acético 0,01 moL L-1 foram utilizados como solvente extrator e fase aceptora, respectivamente. As análises cromatográficas foram feitas em uma coluna Chiralpak AD-RH, empregando acetonitrila:metanol:etanol (98:1:1, v/v/v) mais 0,2% de dietilamina como fase móvel, na vazão de 1 mL min-1. A detecção dos analitos foi conduzida por LC-MS-MS usando um analisador triplo-quadrupolo e ionização por eletrospray positivo. Nessas condições, foram obtidas recuperações de 18,3 a 45,5%, resposta linear na faixa de concentração de 1,25-125 ng mL-1 e limite de quantificação (LQ) de 1,25 ng mL-1 para todos os enantiômeros avaliados. Posteriormente, a CE e a LPME foram utilizadas para a análise da MRT e seus principais metabólitos em urina. Antes da extração, amostras de urina (1 mL) foram submetidas a hidrólise enzimática a 37 ºC por 16 horas. Então, a enzima foi precipitada com ácido tricloroacético, o pH foi ajustado para 8 com uma solução tampão fosfato 0,5 mol L-1 (pH 11) e 10% de NaCl também foi adicionado. Em seguida as amostras foram submetidas a extração de forma similar aquela realizada para as amostras de plasma. As análises eletroforéticas foram obtidas em uma solução tampão fosfato 50 mmol L-1 (pH 2,5) contendo 0,55% (m/v) de carboximetil-b-ciclodextrina (CM-b-CD). O método foi linear na faixa de concentração de 62,5-2500 ng mL-1 para cada enantiômero da MRT e 8-hidroximirtazapina (8-OHM) e 62,5-1250 ng mL-1 para cada enantiômero da desmetilmirtazapina (DMR). O LQ foi 62,5 ng mL-1 para todos os enantiômeros. A SPME também foi utilizada no desenvolvimento de um método para a determinação simultânea do fármaco e seus metabólitos em urina usando CE e LC-MS-MS. Os analitos de interesse foram transferidos da solução aquosa hidrolisada para uma fibra de polidimetilsiloxano-divinilbenzeno (PMDS-DVB) e então foram desorvidos em metanol. As recuperações médias foram de 12 % para os enantiômeros da MRT, 3,8 % para a DMR e 0,72 % para a 8-OHM. O método foi linear na faixa de concentração de 62,5-2500 ng mL-1 com adequado LQ (62,5 ng mL-1) para todos os enantiômeros. A precisão e exatidão foram menores que 15% para todos os métodos desenvolvidos. Além disso, os métodos foram adequadamente aplicados em estudos preliminares de determinação dos enantiômeros da MRT, 8-OHM e DMR em amostras de plasma e urina obtidos após a administração oral de uma dose única de rac-MRT a voluntários sadios. / The need for appropriate methodology for the analysis of drugs and their metabolites in complex biological matrices led to a growing interest in developing new techniques for sample preparation, particularly microextraction techniques because they are highly selective and require a minimum consumption of organic solvents. Allied to these developments, the employment of modern and efficient analytical technologies, such as capillary electrophoresis (CE) and high-performance liquid chromatography coupled to mass spectrometry (LC-MS-MS), has resulted in a considerable improvement in quality in the analytical methodologies available for bioanalysis. In this context, it is worth to mention the use of such techniques to develop enantioselective methodologies, allowing the quantification of the enantiomers of drugs administered as racemates. Therefore, we proposed the development and validation of enantioselective methodologies for the analysis of the enantiomers of mirtazapine (MRT) and of its main metabolites in plasma and urine, using the CE and LC-MS-MS. Solid phase microextraction (SPME) and liquid phase microextraction (LPME) were used for sample preparation. In the first method, LPME was used to extract the analytes from plasma samples (1 ml), previously diluted, alkalinized with 3.0 mL 0.5 mol L-1 pH 8 phosphate buffer solution and supplemented with 15% (w/v) sodium chloride. N-hexyl ether and 0.01 mol L-1 acetic acid solution were used as solvent extractor and acceptor phase, respectively. The analyses were carried out on a CHIRALPAK AD-RH column and acetonitrile: methanol: ethanol (98:1:1, v / v / v) plus 0.2% of diethylamine was used as mobile phase, at a flow rate of 1 mL min-1. The detection was performed by LC-MS-MS equipped with a triple-quadrupole analyzer and ionization by eletrospray positive. Under these conditions, recoveries were from 18.3 to 45.5%; linear response over the 1,25-125 ng ml-1 concentration range and limit of quantification (LOQ) of 1.25 ng ml-1 for all enantiomers evaluated were obtained. CE and LPME were also used for the analysis of MRT and its main metabolites in urine. Before the extraction, urine samples (1 mL) were submitted to enzymatic hydrolysis at 37 ºC for 16 hours, the enzyme was precipitated with trichloroacetic acid, the pH was adjusted to 8 with 0.5 mol L-1 phosphate buffer solution (pH 11) and 10% (w/v) sodium chloride was further added. Then, the LPME extraction was performed according to the procedure previously developed. The electrophoretic analyses were carried out in 50 mmol L-1 phosphate buffer solution (pH 2.5) containing 0.55% (w/v) carboxymethyl-b-cyclodextrin (CM-b-CD). The method was linear over the concentration range of 62.5-2500 ng mL-1 for each MRT and 8-OHM enantiomer and 62.5-1250 ng mL-1 for each DMR enantiomer. The quantification limit (LOQ) was 62.5 ng mL-1 for all the enantiomers. A SPME method was also developed for the simultaneous enantioselective determination of MRT and its metabolites in urine using CE and LC-MS-MS. The target analytes were transferred from the hydrolyzed aqueous solution to the polydimetylsiloxane-divinylbenzene (PMDS-DVB) fiber coating and then desorbed in methanol. The means recoveries were 12 % for the enantiomers of MRT, 3.8 % for DMR and 0.72 % for 8-OHM. The method was linear over the concentration range of 62.5-2500 ng mL-1 with suitable LOQ (62.5 ng mL-1) for all the enantiomers. The precision and accuracy were lower than 15% for all developed methods. Moreover, the methods were successfully employed for the determination of MRT, 8-OHM and DMR enantiomers in plasma and urine samples obtained after oral administration of a single dose of rac-MRT to healthy volunteers.

O termo sigma do núcleon, $sigma_N$, pode ser extraído dos dados experimentais e permite testar teorias e modelos que buscam descrever os efeitos da quebra explícita de simetria quiral sobre o núcleon. A teoria de perturbação quiral é considerada atualmente a teoria efetiva da cromodinâmica quântica, sendo destinada a descrever o regime de baixas energias das interações fortes. Neste contexto, a expansão do termo sigma do núcleon em função da massa do píon depende das chamadas constantes de baixa energia, que devem ser extraídas da experiência. Neste trabalho apresentamos um modelo em que se elimina este tipo de dependência e fornece valores para $sigma_N$ e o termo sigma da delta, $sigma_Delta$, a partir de parâmetros conhecidos. No caso deste último, este procedimento é particularmente importante, porque não é possível extrair $sigma_Delta$ a partir da experiência, apesar desta grandeza ser fundamental para a obtenção de amplitudes na teoria de perturbação quiral, quando a delta aparece como grau de liberdade explícito. Variando as constantes de acoplamento entre os bárions e o píon, obtivemos resultados nos intervalos 43~MeV~$leq sigma_N leq$~49~MeV e 28~MeV~$leq sigma^R_Delta leq$~32~MeV, compatíveis com resultados de outros grupos. Pela possibilidade da delta decair, o seu termo sigma possui uma parte imaginária, a qual usamos para testar a consistência dos nossos resultados. Analisamos também a contagem de potências e o limite quiral, que mostraram o acordo entre a nossa expansão e a tirada da teoria de perturbação quiral. / The nucleon sigma term, $sigma_N$, may be extracted from experimental data and allows theories and models aimed at describing chiral symmetry breaking effects to be tested. At present, chiral perturbation theory is considered the effective theory of quantum chromodynamics at low energies. With this theory, one can obtain an expansion of $sigma_N$ in terms of the pion mass, involving low energy constants, which must be obtained from experiment. In this work we present a model that yields values for both $sigma_N$ and the delta sigma term, $sigma_Delta$, as functions of known parameters only. In the case of $sigma_Delta$, this procedure is particularly relevant, because $sigma_Delta$ is an important quantity in the evaluation of theoretical amplitudes and it is impossible to take it from experimental data. Several choices for pion-baryon coupling constants were used and our results lie in the intervals 43~MeV~$leq sigma_N leq$~49~MeV e 28~MeV~$leq sigma^R_Delta leq$~32~MeV, which are compatible with values produced by other groups. As the delta can decay, its sigma term has an imaginary part that we used to test the consistency of our calculations. The power counting in the chiral limit of our results is consistent with chiral perturbation theory.

O presente trabalho teve como foco principal, a preparação one pot de compostos orgânicos alquílicos e vinílicos contendo o grupamento butiltelurenila em sua estrutura, e o estudo do comportamento desses em variados tipos de reações. Uma delas foi a reação de troca Te/Li. Assim, teluretos foram utilizados como equivalentes sintéticos de vários reagentes organometálicos. Os teluretos foram submetidos à reação de troca Te/Li, e os respectivos compostos organolítio gerados, transformados em reagentes organometálicos de zinco, cobre e cério através de reações de transmetalação. Esses reagentes gerados in situ foram submetidos à reação com variados eletrófilos. Os reagentes organometálicos de zinco e cobre gerados foram submetidos à reação de acilação frente a cloreto de ácidos, resultando em 1,4-hidroxicetonas. Um exemplo dessas hidroxicetonas foi obtido em sua forma enantiopura utilizando um telureto quiral, e esse utilizado na síntese formal e enantiosseletiva da (-)-Pirenoforina. Diferentes estequiometrias de cupratos e outros reagentes organometálicos oriundos de um telureto também foram preparados, e esses testados em reações de substituição de tosilatos e abertura de epóxidos. Os substratos gerados dessas reações foram empregados na síntese das moléculas bioativas Endo-Brevicomina e Frontalina. Apresentaremos também, o resultado obtido na reação direta entre uma espécie di-litiada quiral na presença de benzonitrila. A hidroxicetona assim produzida é um análogo do Ipomeanol, um composto com atividade contra câncer de pulmão. Será apresentado também, o comportamento de entidades di-aniônicas contendo grupamentos silila em reações catalisadas por CeCl3, em que a captura desses com eletrófilos como aldeídos, forneceram 1,4-enedióis em bons rendimentos químicos e alta diastereosseletividade. Será apresentado também o estudo do comportamento de teluretos com hibridização sp2 em reações pericíclicas. A reação pericíclica estudada compreende compostos contendo telúrio (II) e (IV) em reações de Diels-Alder. / One of the main purposes of this work was to develop a new direct methodology to prepare functionalized organic tellurides, to be submitted to a series of different reactions, as for example the Te/Li exchange reaction, aimed to afford synthetic equivalents of several organometallic reagents. Zinc, copper and cerium organometallic compounds were generated via a transmetalation reaction of the lithium species, and were reacted with several electrophiles. As a result, 1,4-hydroxyketones could be successfully prepared. According to this methodology, an enantioenriched 1,4-hydroxyketone could be obtained, using a chiral telluride as starting material. This chiral nonracemic intermediate was employed in an enantioselective formal synthesis of (-)-Pyrenophorin. Cuprates and other organometallic reagents, prepared from a specific telluride and using the above described methodology, were the choosen nucleophiles for performing some aliphatic substitution reactions and, in particular, for the ring opening of epoxides. The resulting products were employed as building blocks for the synthesis of the bioactive cyclic compounds Endo-Brevicomin and Frontalin. The direct reaction of the chiral dilithiated specie with benzonitrile afforded a 1,4-hydroxyketone as an analogue of Ipomeanol, a bioactive compound for cancer therapy. Bis-anionic sililated species, prepared from a telluride, were submitted to reaction with a series of aldehydes. Such reactions, in which CeCl3 was employed as catalyst, showed to be highly diastereoselectives, affording (E)-1,4-enediols in good yields. The pericyclic reaction of insaturated tellurides was also investigated. It is worth mentioning that the same Diels-Alder reaction could be performed either with tellurium II or tellurium IV species.

The potential of countercurrent chromatography (CCC) as a small footprint bioreactor/separator for manufacture of enantiopure chiral molecules was explored, using as a model reaction the isolation of L-amino butyric acid (L-ABA) from a DL-ABA racemate and the enantioselectivity of D-amino acid oxidase (DAAO). Bioconversion of D-ABA to ketobutyric acid (KBA) by DAAO, immobilised by selective partitioning in the stationary phase of the CCC centrifuge, was accompanied by separation of unreacted L-ABA from KBA by the countercurrent action of the centrifuge. For effective bioreactor/separator action, a high partition of the biocatalyst to the stationary phase was required in order to retain the biocatalyst in the coil, with differing partitions of substrates and products between the stationary phase (SP) and mobile phase (MP) so that these could be separated. Aqueous two-phase systems (ATPS) were the major two-phase systems used to provide SP and MP, as these are well reported to be effective in preserving enzyme activity. The distribution ratios of DL-ABA, KBA and DAAO were measured in a range of phases with polyethylene glycols (PEGs) of different molecular weights, different salts, and different compositions of PEG and salt, using an automated robotic method, developed for the purpose. A system of 14% w/w PEG 1000/ 14% w/w potassium phosphate, pH 7.6, gave the best combination of distributions ratios (CPEG phase/Csalt phase = CSP/CMP) for ABA, KBA and biocatalyst (DAAO) of 0.6, 2.4 and 19.6 respectively. A limited number of aqueous-organic and ionic liquid two-phase systems were also reviewed, but found unsatisfactory. CCC operating conditions such as substrate concentration, biocatalyst concentration, the mobile phase flow rate (residence time in the CCC coil), temperature, rotational speed and operational modes (single flow and multiple-dual flow) and types of mixing (cascade and wave-like) were optimised to produce total conversion of D-ABA to KBA, which was then completely separated from unreacted, enantiomerically pure (>99% ee), LABA. Advantages of the CCC bioreactor over conventional technology include reduced equipment footprint, cheaper running costs, and faster purifications. However, in its current format the drawbacks, such as enzyme instability and excessive optimisation time, reduce its commercial appeal. Additional investigations into the use of whole cell preparations of biocatalyst in the CCC bioreactor showed potential to overcome the problem of enzyme instability and this may in the future give the CCC bioreactor a place in the enantioseparation field.

The objective of this project is to explore the potential for enantiomer separation by preferential crystallization using tailor-made emulsions. Preferential crystallization is widely used as a means of separating pure enantiomers from racemic solutions. This is usually assisted by the addition of seed crystals of one enantiomer for which crystallization yields a conglomerate rather than a racemic compound. Three racemic materials, DL-threonine (stable conglomerate), R,S-2-chloromandelic acid (racemic compound with the occurrence of a metastable conglomerate) and R,S-clopidogrel hydrogen sulphate (stable racemic compound) were chosen based on their different racemic properties to both develop and test the limitations of an emulsion crystallization process. Since threonine is reported to form only a stable conglomerate it seemed an ideal material to use for the development of an emulsion crystallization process. Indeed this was successful with enantiomer enrichments of up to 88 % of the D-enantiomer being achievable. 2-Chloromandelic acid is reported to crystallize as a stable racemic compound but with both metastable (polymorphic) compound and conglomerate known. An investigation into solution crystallization was performed as a means of preparing the metastable conglomerate and also to explore the possibility of developing an emulsion crystallization process in this system. Crystallization of 2-chloromandelic acid yielded both stable and metastable racemic compounds and the metastable conglomerate. Solubility data of the pure enantiomer, stable racemic compound and metastable conglomerate have been determined in acetonitrile and a robust drown-out method developed for consistent preparation of the conglomerate in diethyl ether. In situ UV-Vis spectroscopy studies revealed that in a stirred slurry, the metastable conglomerate converts to the stable racemic compound in approximately 10 minutes at 15 °C. This time scale defined the subsequent process of preferential crystallization from a seeded, tailor-made, non-aqueous emulsion which was successful in providing a route to a product with significant chiral enrichment of the R-enantiomer. R,S-Clopidogrel hydrogen sulphate is a stable compound forming system, which has been reported in patents to form six different polymorphs. The possibility of conglomerate formation is not known. During the course of this work, attempts were made to preferentially crystallize one enantiomer from an already enriched racemic solution. This was unsuccessful, largely due to the fact that the pure enantiomer was found to be more soluble that the enriched starting material. No evidence of a conglomerate was found, but an amorphous form and four crystalline forms of S-clopidogrel hydrogen sulphate (S-I, S-II, S-III and S-IV) have been crystallized from various solvents via different crystallization conditions. Forms III and IV are believed to be present as hydrates which are not currently reported in the literature. The amorphous form and crystalline polymorphs have been characterized using DSC, pXRD and FTIR, of which data for the latter technique is lacking in the literature. Overall this thesis demonstrates the development of both aqueous and non-aqueous emulsion crystallisation processes for enantiomer separations, highlighting the importance of the phase behaviour of the solute as a major determinant for success.

This thesis comprises an account of research carried out into the flexoelectro-optic effect, as observed in chiral nematic liquid crystals, and its potential for application in fibre optic communications components. The flexoelectro-optic effect provides a mechanism of fast, analogue rotation of the optic axis in chiral nematic materials via the application of an electric field to the sample. In particular, bimesogenic liquid crystal materials exhibit very large flexoelectro-optic tilt angles, and a large tilt angle per unit field in comparison to other mesogenic materials. In this work a new geometry for the flexoelectro-optic effect is developed in which the chiral nematic liquid crystal is aligned with its helical axis along the normal to the cell walls and the electric field is applied in the plane of the cell. It is shown that polymer stabilization of this device by the addition of a small percentage of reactive mesogen to mixture increases greatly the ability of the device to withstand high amplitude a.c. electric fields. Applied fields of up to 6.8 V/μm are shown to induce a maximum birefringence of ∆n=0.037, due to both flexoelectric and dielectric coupling, and ∆n=0.012 due to flexoelectric coupling only in a sample based on symmetric difluorinated bimesogens. This induced birefringence is shown to consistently respond to field application and removal on the sub millisecond timescale. Polymer stabilization of the same mixtures in the uniform lying helix texture is shown to affect the electro-optic response of the samples in a manner which is dependent on the concentration of reactive mesogen used, and the temperature at which the reactive mesogen is cured. A concentration of approximately 3% weight/weight, however, has little detrimental impact on the device characteristics, and curing of the sample at the lower end of the chiral nematic temperature range is shown to allow optimization of both tilt angle and response time of the samples. The effect is also employed to demonstrate a new method of fast electrical tuning of the output wavelength from chiral nematic photonic band edge lasers. An 8nm shift was induced in these devices by a 3.5 V/μm applied field.

In this work, we calculate the density of photon states (DOS) of the normal modes in dye-doped chiral nematic liquid crystal (LC) cells in the presence of various loss mechanisms. Losses and gain are incorporated into the transmission characteristics through the introduction of a small imaginary part in the dielectric constant perpendicular and along the director, for which we assume no frequency dispersion. Theoretical results are presented on the DOS in the region of the photonic band gap for a range of values of the loss coefficient and different values of the optical anisotropy. The obtained values of the DOS at the photonic band gap edges predict a reversal of the dominant modes in the structure. Our results are found to be in good agreement with the experimentally obtained excitation thresholds in chiral nematic LC lasers. The behaviour of the DOS is also discussed for amplifying LC cells providing an additional insight to the lasing mechanism of these structures. We subsequently investigate the spontaneous emission properties, under the assumption that the electronic transition frequency is close to the photonic edge mode of the structure (resonance). We take into account the transition broadening and the decay of electromagnetic field modes supported by the so-called 'mirror-less' cavity. We employ the Jaynes-Cummings Hamiltonian to describe the electron interaction with the electromagnetic field, focusing on the mode with the diffracting polarization in the chiral nematic layer. As known in these structures, the density of photon states, calculated via the Wigner method, has distinct peaks on either side of the photonic band gap, which manifests itself as a considerable modification of the emission spectrum. We demonstrate that, near resonance, there are notable differences between the behaviour of the density of states and the spontaneous emission profile of these structures. In addition, we examine in some detail the case of the logarithmic peak exhibited in the density of states in 2D photonic structures and obtain analytic relations for the Lamb shift and the broadening of the atomic transition in the emission spectrum. The dynamical behaviour of the atom-field system is described by a system of two first order differential equations, solved using the Green's function method and the Fourier transform. The emission spectra are then calculated and compared with experimental data. Finally, we detail a new technique for the pumping of dye lasers which requires no moving parts or flushing mechanisms and is applicable to both solid state and liquid based devices. A reconfigurable hologram is used to control the position of incidence of a pump beam onto a dye laser and significant increases in device lifetimes are achieved. The technique is also applied to wavelength tune a dye laser. This offers access to higher repetition rates and larger average output powers. With higher repetition rate pump lasers it is feasible that the approach could allow such organic lasers to reach operating frequencies on the order of MHz. The unique nature of the adaptive pumping method also allows precise control of the spatial wave-front and configuration of the pumping wave which allows greater versatility and functionality to be realised. It is possible to envisage that novel pump beam profiles that optimise propagation through the medium could also be demonstrated.

Since its discovery in 1912, the Mannich reaction has been widely utilized in organic chemistry to form C-C bonds. Reactivity of an enol with an imine allows for easy formation of a [beta]-aminoketone. Enamines have also been widely utilized as convenient nucleophiles. In our work, unexpected reactivity of the [gamma] position of [beta]-enamidoesters in a Brønsted acid environment and high enantioselectivity of a Mannich reaction were achieved through chiral phosphoramidic acid catalysis. A novel class of chiral phosphoramidic acids was designed, synthesized from the corresponding diamines, with several sulfonyl N-protecting groups, and characterized. Their unique properties arise from their Brønsted acid nature, atropisomerism and ability to form complexes via H-bond. Once prepared, such catalysts were successfully used as organocatalysts for the regio- and enantioselective Mannich reaction of [beta]-enamidoesters and imines. Their activity is described as a method to reverse the regioselectivity of the nucleophile while achieving high enantioselectivities in the formation of chiral benzhydrils. A diverse range of imines has been tested, obtaining yields of up to 93% and enantioselectivities of up to 99:1. A few substituted enamines were also tested to study the influence of substituents on the regioselectivity. A mechanism for this reaction is proposed and kinetic studies confirmed that the reaction is first order in catalyst. The ozonolysis of the product of this Mannich reaction was performed to prove the absolute stereochemistry of the product; and a new efficient methodology for the asymmetric preparation of aminoacid [beta]-phenyl-[beta]-alanine benzyl ester is described. The reduction of the enamide moiety of the Mannich product was attempted via asymmetric hydrogenation and via hydride reduction to diastereomerically obtain 1,3-diamines, which are compounds of major synthetic interest. Unfortunately our attempts in this direction were not successful. Finally, a multicomponent reaction between an aldehyde, a substituted phenol, and a styrylboronate was developed as an alternative method for the preparation of chiral benzhydrils. This process is also organocatalytic and the methodology was optimized in the presence of 3-3'-disubstituted BINOLs. Yields up to 71% and enantioselectivities up to 96:4 were achieved. A mechanism for this organocatalytic reaction is also proposed.