Dissertations / Theses on the topic 'Hydroxybenzoic'

No<br>A microemulsion electrokinetic chromatography (MEEKC) method has been developed and validated for the determination of 4-hydroxybenzoates and their impurities. These materials are commonly known as parabens and are widely used as preservatives in foods, cosmetics and pharmaceuticals. The method was shown to be selective and quantitative for the methyl, ethyl, propyl and butyl esters of 4-hydroxybenzoic acid. An internal standard, 4-hydroxyacetophenone, was employed to improve injection precision and detector linearity. In addition, 4-hydroxybenzoic acid, the major degradent, could also be monitored at the 0.1% (m/m) level. The method was successfully validated for assay and detection of the impurities in 4-hydroxybenzoic acid methyl ester and 4-hydroxybenzoic acid propyl ester samples and for the determination of 4-hydroxybenzoic acid methyl ester in a liquid pharmaceutical formulation. The determination of paraben content by MEEKC in a liquid sample was consistent with HPLC analysis. This work is the first reported validated MEEKC method and shows that the methodology can be successfully implemented into routine quality control testing.

It is generally agreed that the high physical properties arising in as-processed liquid crystalline materials are due to the high degree of molecular orientation which develops during the processing step. In order to more fully understand and predict such behavior, a constitutive equation describing the flow behavior of these materials would be useful. It has been suggested that in order to describe the rheology of liquid crystalline fluids such a constitutive equation would need to include molecular orientation effects. The purpose of part of this study has been to examine the usefulness of several constitutive equations for describing the steady and transient behavior of several liquid crystalline polymers. These include a copolyester of para-hydroxybenzoic acid and polyethylene terephthalate, and an anisotropic solution of 12 weight% Kevlar in 100% sulfuric acid. It was found that in the case of the copolyester system, the steady shear and dynamic viscosities were equal over certain temperature ranges. For this reason, the constitutive equation of Zaremba, Fromm, and DeWhitt (ZFD model) was used to predict the steady state behavior of the system studied. From knowledge of either the steady shear or dynamic viscosity it was possible to predict both the steady state normal stresses (N1) and the storage modulus (G'). The model could not, however, predict the transient behavior of the systems studied. Ericksen’s anisotropic fluid theory has been investigated in detail as it takes molecular orientation effects into account. Ericksen’s theory can partially explain the transient behavior of the systems studied in terms of molecular orientation which develops during shear flow. However, wide angle x-ray scattering (WAXS) and scanning electron microscope (SEM) studies reveal that shear flow has little effect on the development of molecular orientation during flow. In addition, any orientation produced during flow may be lost within thirty seconds at the melt temperature. It appears that a disruption of texture is occurring during flow which may need to be incorporated into the theory of Ericksen.<br>Ph. D.<br>incomplete_metadata

The Ph.D. project compiled in this thesis has focused on the role of the solvent in solid-liquid phase equilibria and in nucleation kinetics. Six organic substances have been selected as model compounds, viz. ortho-, meta- and para-hydroxybenzoic acid, salicylamide, meta- and para-aminobenzoic acid. The different types of crystal phases of these compounds have been explored, and their respective solid-state properties have been determined experimentally. The solubility of these crystal phases has been determined in various solvents between 10 and 50 oC. The kinetics of nucleation has been investigated for salicylamide by measuring the metastable zone width, in five different solvents under different experimental conditions. A total of 15 different crystal phases were identified among the six model compounds. Only one crystal form was found for the ortho-substituted compounds, whereas the meta-isomeric compounds crystallized as two unsolvated polymorphs. The para-substituted isomers crystallized as two unsolvated polymorphs and as several solvates in different solvents. It was discovered that the molar solubility of the different crystal phases was linked to the temperature dependence of solubility. In general, a greater molar solubility corresponds to a smaller temperature dependence of solubility. The generality of this relation for organic compounds was investigated using a test set of 41 organic solutes comprising a total of 115 solubility curves. A semi-empirical solubility model was developed based on how thermodynamic properties relate to concentration and temperature. The model was fitted to the 115 solubility curves and used to predict the temperature dependence of solubility. The model allows for entire solubility curves to be constructed in new solvents based on the melting properties of the solute and the solubility in that solvent at a single temperature. Based on the test set comprising the 115 solubility curves it was also found that the melting temperature of the solute can readily be predicted from solubility data in organic solvents. The activity of the solid phase (or ideal solubility) of four of the investigated crystal phases was determined within a rigorous thermodynamic framework, by combining experimental data at the melting temperature and solubility in different solvents and temperatures. The results show that the assumptions normally used in the literature to determine the activity of the solid phase may give rise to errors up to a factor of 12. An extensive variation in the metastable zone width of salicylamide was obtained during repeated experiments performed under identical experimental conditions. Only small or negligible effects on the onset of nucleation were observed by changing the saturation temperature or increasing the solution volume. The onset of nucleation was instead considerably influenced by different cooling rates and different solvents. A correlation was found between the supersaturation ratio at the average onset of nucleation and the viscosity of the solvent divided by the solubility of the solute. The trends suggest that an increased molecular mobility and a higher concentration of the solute reduce the metastable zone width of salicylamide.<br>QC 20100831

Fundação de Amparo a Pesquisa do Estado de Minas Gerais<br>The biossensores constitute analytical important devices for the clinical diagnosis of many diseases, enabling real-time analysis, with high specificity and sensitivity. Accordingly, the aim of this study was to develop a platform functionalized with the poly (3- hydroxybenzoic acid), to detection of nitrogenous bases, oligonucleotides and antibodies against the surface protein (Am1) of Anaplasma marginale.These biological recognition elements were immobilized on the functionalized platform and the biosensor was characterized by electrochemical and spectroscopic techniques. The detections of the antigen-antibody interaction were conducted using the signal obtained from the oxidation of protein interleaver, 4- aminoantipyrine (4 -AAP), using voltammetry technique of differential pulse.Theoretical chemistry studies were employed to analyze the Am1 interactions with the sensor platform and the web server model RaptorX to infer three-dimensional structure of the membrane proteins of A. marginale.The molecular modeling was conducted from methods semi- empirical, DFT and molecular mechanics.The transitions redoxes of polymer were classified as almost reversible, with band gap of 1.2 V, characteristic of semiconductor materials.The detections of poly CT and antibodies of A. marginale, using the graphite electrode functionalized with the probes, poly GA and Am1 respectivamente, were 66% higher than the graphite electrode not functionalized.The protein of superfice Am1 presented a structure stable in beta-sheet, while Am2 presented an unstable structure in &#945; -helix.In electrochemical impedance spectroscopy was possible qualitatively differentiate the functionalized platform with: Am1, IgG+, IgG- and interfering. The time of storage of the immunosensor was satisfactory, with reduced peak current by 35%, after 90 days. These results demonstrate the excelent applicability of functionalized platform for the development of immunosensor for diagnosis of bovine anaplasmosis, leaving only the economic feasibility studies for commercial deployment of the said immunosensor.<br>Os biossensores constituem-se como dispositivos analíticos importantes para o diagnóstico clínico de inúmeras doenças, por permitirem uma análise em tempo real, além de suas altas especificidades e sensibilidades. Nesse sentido, o objetivo desse estudo foi desenvolver uma plataforma funcionalizada com o poli (ácido 3-hidroxibenzóico), para a detecção de bases nitrogenadas, oligonucleotídeos e anticorpos contra a proteína de superfície (Am1) da Anaplasma marginale. Esses elementos de reconhecimento biológico foram imobilizados na plataforma funcionalizada e o biossensor foi caracterizado por técnicas eletroquímicas e espectroscópicas. As detecções da interação antígeno-anticorpo foram realizadas através do sinal obtido da oxidação do intercalador de proteína, 4-aminoantipirina (4-AAP), utilizando a técnica de voltametria de pulso diferencial. Estudos de química teórica foram empregados para análise das interações da Am1 com a plataforma sensora e o modelo web server RaptorX para inferência da estrutura tridimensional das proteínas de membrana da A. marginale. A modelagem molecular foi realizada a partir de métodos semi-empíricos, DFT e mecânica molecular. As transições redoxes do polímero foram classificadas como quase reversíveis, com band gap de 1,2 V característico de materiais semicondutores. As detecções de poli CT e anticorpos da A. marginale, empregando o eletrodo de grafite funcionalizado com as sondas, poli GA e Am1 respectivamente, foram 66 % superior a do eletrodo de grafite não funcionalizado. A proteína de superfície Am1 apresentou uma estrutura estável em folha-beta e a Am2 uma estrutura instável em &#945;-hélice. Na espectroscopia de impedância eletroquímica foi possível diferenciar qualitativamente a plataforma funcionalizada com: Am1, IgG+, IgG- e interferente. O tempo de estocagem do imunossensor mostrou-se satisfatório, com redução do pico de corrente em 35 %, após 90 dias. Esses resultados demonstraram a excelente aplicabilidade da plataforma funcionalizada para o desenvolvimento de imunossensor para diagnóstico da anaplasmose bovina, restando apenas os estudos de viabilidade econômica para implantação comercial do referido imunossensor.<br>Doutor em Química

L'acétylation des lysines est une modification post-traductionnelle des protéines dont l’ajout et l’élimination sont catalysés respectivement par les histones acétyltransférases (HAT) et les désacétylases d'histones (HDAC). Cette modification joue un rôle majeur dans la régulation de processus cellulaires tels que l'expression génique, la mobilité cellulaire et le métabolisme. Il est maintenant bien établi qu'une altération de l'activité des désacétylases, entrainant ainsi une dérégulation de l'acétylome, est associée au développement tumoral. Par conséquent, les HDAC sont considérées comme des cibles prometteuses en thérapie anti-cancéreuse ce qui a conduit au développement de nombreux inhibiteurs de HDAC. Cependant, la recherche de nouvelles molécules avec un potentiel anti-cancéreux accru et moins d’effets secondaires est indispensable. Nous avons identifié cinq acides 4-hydroxybenzoïques comme nouveaux inhibiteurs de HDAC, trois inhibiteurs qui ciblent plusieurs HDAC et deux inhibiteurs spécifiques de HDAC6. Les inhibiteurs qui ciblent plusieurs HDAC induisent l'acétylation de certaines lysines des histones H3 et H4 dans les cellules de leucémie myéloïde chronique humaine K-562. Le traitement des cellules induit un arrêt de la progression du cycle cellulaire associé à la modulation de l'expression des cyclines et l'activation de la transcription du gène codant p21. Enfin, les trois composés qui inhibent plusieurs HDAC induisent une mort par apoptose qui est confirmée par l'observation du clivage et de l'activation des caspases. Les inhibiteurs spécifiques de HDAC6 induisent une hyperacétylation importante de la tubuline-α corrélée à une condensation des microtubules dans les cellules cancéreuses adhérentes de prostate (cellules PC-3 et LNCaP). Ces composés induisent une mort par apoptose des cellules cancéreuses en suspension K-562 accompagnée du clivage des caspases et de l'activation de la protéine pro-apoptotique BAX. Enfin, les molécules altèrent la fonction de la protéine chaperonne HSP90α observée par une forte diminution de l'expression de ses protéines clientes: Bcr-Abl et le récepteur aux androgènes. Par ailleurs, les cinq composés n'affectent pas la viabilité des cellules saines. L'ensemble de ce travail révèle que les acides 4-hydroxybenzoïques sont des molécules prometteuses pour le développement de nouveaux composés ayant des propriétés anti-tumorales intéressantes<br>Lysine acetylation is a post-translational modification characterized by addition and removal acetyl group by histone acetyltransferases (HATs) and histone deacetylases (HDACs), respectively. This modification plays a crucial role in multiple cellular processes including gene expression, cell motility and metabolism. It is now well established that disruption of deacetylase activity, leading to a pathological acetylation profile, is associated to cancer development. Consequently, HDACs are considered as promising targets for anticancer therapy, which led to the development of novel HDAC inhibitors. However, discovery and synthesis of new molecules is essential to increase anticancer potential and decrease adverse health effects of already known compounds. We identified five 4-hydroxybenzoic acids as new HDAC inhibitors: three pan-HDAC inhibitors and two HDAC6-specific inhibitors. Pan-HDAC inhibitors induce acetylation of selected lysines within histones H3 and H4 in human chronic myeloid leukemia K-562 cells. Treatment of cells induces cell cycle arrest associated with increased cyclin expression and the transcriptional activation of p21. Finally, these pan-HDAC inhibitors induce apoptotic cell death further confirmed by the cleavage and activation of caspases. HDAC6-specific inhibitors induce hyperacetylation of α-tubulin in correlation with microtubule condensation in adherent prostate cancer cells (PC-3 and LNCaP cells). These compounds induce apoptotic cell death in K-562 cells accompanied by caspase cleavage and the activation of the pro-apoptotic protein BAX. Furthermore, these molecules alter the chaperon function of HSP90α, which is observed through the robust decrease of the expression of its client proteins (i.e. Bcr-Abl and androgen receptor). Noteworthy, the five compounds did not affect healthy cell viability. Taken together these results revealed that 4-hydroxybenzoic acids are attractive molecules for the development of new compounds with promising anticancer properties

CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior<br>CNPq - Conselho Nacional de Desenvolvimento Científico e Tecnológico<br>FAPEMIG - Fundação de Amparo a Pesquisa do Estado de Minas Gerais<br>Neste trabalho foi desenvolvido um nanocompósito polimérico de óxido de grafeno reduzido e poli(ácido 3 hidroxibenzóico) para a modificação de eletrodos de grafite, visando o desenvolvimento de um genossensor para a detecção do DNA genômico de Alicyclobacillus acidoterrestris. Esta é uma bactéria associada à deterioração de sucos ácidos, como o suco de laranja, do qual o Brasil é o maior produtor mundial. Neste contexto, os biossensores aparecem como dispositivos de detecção rápidos e fáceis de manusear, com grande potencial para serem utilizados em toda a cadeia produtiva do suco. Para a construção do genossensor, óxido de grafeno foi produzido pelo método de Hummers modificado, gotejado sobre a superfície do eletrodo de grafite e reduzido eletroquimicamente. O ácido 3-hidroxibenzóico foi eletropolimerizado sobre esta superfície contendo o nanomaterial. Análises por espectroscopia no infravermelho e voltametria cíclica comprovaram a redução do óxido de grafeno. Além disso, as análises eletroquímicas evidenciaram que o nanocompósito produzido apresenta propriedades eletrônicas superiores às do filme polimérico. Sobre este nanocompósito foi imobilizado um oligonucleotídeo sonda ALIC1, específico para A. acidoterrestris, o qual foi utilizado para detecção de um oligonucleotídeo alvo complementar ALIC2 pela técnica de voltametria de pulso diferencial (VPD), tanto direta quanto indiretamente, esta última utilizando-se o intercalante da dupla fita de DNA Hoechst 33258. Um lisado celular obtido a partir de uma cultura de A. acidoterrestris também foi detectado de maneira indireta pela técnica de VPD, e uma curva de calibração foi construída. O genossensor proposto apresentou um limite de detecção de 174 ng mL-1 e limite de quantificação de 581 ng mL-1, sendo capaz de detectar o DNA genômico em uma amostra real de suco de laranja e de discernir entre amostras de A. acidoterrestris e Escherichia coli. Deste modo, este bioeletrodo apresenta-se como a primeira plataforma de detecção eletroquímica do DNA genômico de A. acidoterrestris na literatura científica.<br>In this work a polymeric nanocomposite of reduced graphene oxide and poly (3- hydroxybenzoic acid) was developed for the modification of graphite electrodes, aiming the development of a genossensor for the detection of the Alicyclobacillus acidoterrestris genomic DNA. This bacterium is associated with the spoilage of acidic juices, such as orange juice, of which Brazil is the largest producer in the world. In this context, biosensors appear as fast and easy to handle detection devices, with great potential for use throughout the juice production chain. For the construction of the genosensor, graphene oxide was produced by the modified Hummers method, dripped onto the surface of the graphite electrode and reduced electrochemically. The 3-hydroxybenzoic acid was electropolymerized on this surface containing the nanomaterial. Analyzes by infrared spectroscopy and cyclic voltammetry proved the reduction of graphene oxide. In addition, the electrochemical analysis showed that the nanocomposite produced has higher electronic properties than the polymeric film. On this nanocomposite, an oligonucleotide probe ALIC1, specific for A. acidoterrestris, was immobilized, and was used to detect a complementary target oligonucleotide ALIC2, both directly and indirectly, the latter using the Hoechst 33258 double strand DNA intercalator, by the differential pulse voltammetry (DPV) technique. A cell lysate obtained from an A. acidoterrestris culture was also indirectly detected by DPV, and a calibration curve was constructed. The proposed genosensor presented a limit of detection of 174 ng mL-1 and limit of quantification of 581 ng mL-1, being able to detect the genomic DNA in a real sample of orange juice and to distinguish between the samples of A acidoterrestris and Escherichia coli. Thus, this bioelectrode presents as the first platform of electrochemical detection of the genomic DNA of A. acidoterrestris in the scientific literature.<br>Dissertação (Mestrado)

Ce travail, sur la dépollution de l’eau par OVHC sur charbon actif (CA), étudie l'interaction oxydation - adsorption : comment l'oxydation sur charbon de produits aromatiques modifie ses propriétés et en particulier sa capacité d'adsorption et d'oxydation (désactivation). Divers charbons commerciaux, mais aussi issus de boues activées, ont été caractérisés avant et après oxydation : propriétés texturales, composition élémentaire (CHNSO), fonctions de surface, pH au point de charge nulle et allure des courbes ATG. Seule leur teneur en cendres semble différer notablement. Les charbons actifs de boues ont une surface spécifique bien moindre (de 90 à 265 m².g-1) et un taux de cendres supérieur à 50% qui en font de moins bons adsorbants. Cependant la présence de métal, notamment le fer, a un effet positif sur l'oxydation catalytique. L'étude comparative en oxydation catalytique de 4 CA commerciaux en grains montre une désactivation intense (qui augmente avec la concentration de polluant) sur les 3-4 premières utilisations, puis une stabilisation. Le charbon résultant est nettement moins adsorbant. Les CA S23 et F22 ainsi stabilisés ont ensuite été utilisés pour déterminer la cinétique d'oxydation catalytique apparente et intrinsèque du phénol, grâce à un modèle incluant la diffusion. La comparaison de l'OVHC de 4 polluants aromatiques seuls et en divers mélanges synthétiques met en évidence des effets de mélange significatifs: les polluants les plus réfractaires en oxydation catalytique se dégradent beaucoup plus vite en mélange (ex 4NP) et inversement, les polluants les plus oxydés, lorsqu'ils sont seuls en solution, voient leur cinétique diminuer lorsqu'ils sont mélangés aux autres polluants (ex phénol, 4chlorophénol). Le mélange tend donc à uniformiser les comportements particuliers. Enfin, les essais de faisabilité du procédé de régénération oxydante AD-OX ont été effectués sur des effluents industriels. La régénération du charbon actif comme adsorbant est moins limitée qu'avec des mélanges de phénols substitués<br>This work, on water treatment by catalytic Wet Air Oxidation (CWAO) using activated carbon (AC), aimed to study the interaction between oxidation-adsorption phenomena: how the oxidation of aromatic compounds on AC can modify its properties and specially its adsorption and oxidation characteristics (deactivation). Various commercials AC, and AC produced from activated sludge, have been characterized before and after oxidation by according methods such as textural characterization, elemental analysis (CHNSO), functional groups on carbon surfaces analysis, pH of the point of zero charge (pHpzc) analysis and thermogravimetric analysis (TGA); however, only their ash level was significantly different. In addition, the sludge based AC (SBAC) have a specific surface range of 90 to 265 m².g-1, which is lower than commercial AC, and with an ash level over 50%. Consequently they are less good adsorbents. However, the presence of metal, e.g. iron, has a positive affect on catalytic oxidation. The comparative study of catalytic oxidation with 4 commercial AC, show a severe deactivation (which increase with the pollutant concentration) on the first 3-4 utilizations before stabilization. The residual AC is clearly poor adsorbent. After stabilization, 2 commercials AC, only S23 and F22 CA, were studied on catalytic oxidation of phenol in term of apparent and intrinsic kinetics with including the diffusion effect in the model. The CWAO of 4 pure aromatic pollutants, and their various synthetic mixtures, showed mixing effects significantly: the most oxidation catalytic refractory pollutants were degraded rapidly when they mixed (e.g. 4-nitrophenol) but the kinetic was slow down for the pure pollutant whereas, the most oxidised pollutants, for pure solution, have an oxidation kinetic slower than when they mixed with others pollutants (e.g. Phenol, 4-chlorophenol). Therefore, the mixture tends to standardize from the individual behaviour. In conclude, the feasibility study of the oxidative regeneration process (AD-OX) was performed on industrial waste water. The regeneration AC as adsorbent is less limited than with mixtures of substituted phenols

Thesis (MTech(Chemistry))--Cape Technikon, Cape Town, 2001<br>Many naturally occurring antibiotics have been identified and their synthesis successfully carried out in laboratories. It was envisaged by our group that by preparing a variety of, for example, quinoid compounds and then comparing their biological properties and activities, a better insight would be gained into a molecular structure - activity relationship. Chapter 1 deals with the attempted synthesis of 2-(1 '-hydroxyethyl)-3-(prop-2'enyl)- 1,4-benzoquinone (17) which may be converted by known methods into benzopyran derivatives. The second chapter describes a synthetic route to (±)(3R, 4R)-3,4-dihydro-3methyl- 4-hydroxy-l H-benzo[c]pyran-5,8-dione (42) and its (±)(45) diastereomer (43), both of which were found to be active against Gram negative and Gram positive organisms. The trans-l,3-dimethyl-4-hydroxypyranquinones (45) and (46) were also successfully synthesised. A different route of synthesis for the compounds (53), (54), (55) and (56) was also investigated. Several compounds were evaluated for biological activity. It was found that the quinones synthesised during this study were active against Gram negative and Gram positive bacteria, with the exception of compound (25) which had an acetate group in place of a hydroxy group. It was found that this trend was carried through all of the quinone derivatives tested.

Les Hydrocarbures Aromatiques Polycycliques (HAP) sont responsables de cancers du poumon, de la vessie et de la peau. Parmi eux, seul le benzo(a)pyrène (BaP) est classé cancérogène certain pour l'homme. La surveillance biologique de leur exposition passe par le dosage du 1-hydroxypyrène urinaire (1-OHP), métabolite du pyrène non cancérogène. L'objectif de cette thèse était de développer un nouveau biomarqueur plus proche du risque cancérogène. Le 3-hydroxybenzo(a)pyrène (3-OHBaP) est apparu comme le meilleur candidat car c'est le métabolite majoritaire du BaP, car ses concentrations sont liées aux taux d'adduits à l'ADN mesurés dans le poumon de rat et car son dosage est réalisable dans les urines de sujets exposés. Nous avons développé une méthode analytique de routine associant l'extraction en phase solide à la chromatographie liquide avec une détection en fluorescence, qui nous a permis d'atteindre une limite de détection 0,02 ng/L. La médiane des concentrations de 3-OHBaP dans les urines de sujets fumeurs atteignait 0,02 nmole/mole de créatinine et était deux fois plus élevée que chez les non-fumeurs. Dans les secteurs de production du silicium, des cathodes et des anodes, de 30 à 70% des niveaux étaient supérieurs à la valeur recommandée en France, ce qui confirme le risque sanitaire lié à ces activités professionnelles. Lors d'une exposition répétée aux HAP pendant une semaine de travail, le prélèvement des urines doit être réalisé en fin de semaine fin de poste, du fait de l'atteinte d'un équilibre entre les doses de BaP absorbées et celles de 3-OHBaP éliminées. La corrélation entre les niveaux urinaires de 3-OHBaP et de 1-OHP est variable en fonction du secteur et des activités professionnelles. Ceci démontre la difficulté d'établir une seule valeur limite professionnelle en lien avec le risque cancérogène des HAP pour le 1-OHP et souligne tout l'intérêt de doser le 3-OHBaP.

This work concerns the interrelationship between thermodynamic, kinetic and structural aspects of crystal polymorphism. It is both experimental and theoretical, and limited with respect to compounds to substituted monocyclic aromatics. Two polymorphs of the compound m-aminobenzoic acid have been experimentally isolated and characterized by ATR-FTIR spectroscopy, X-ray powder diffraction and optical microscopy. In addition, two polymorphs of the compound m-hydroxybenzoic acid have been isolated and characterized by ATR-FTIR spectroscopy, high-temperature XRPD, confocal Raman, hot-stage and scanning electron microscopy. For all polymorphs, melting properties and specific heat capacity have been determined calorimetrically, and the solubility in several pure solvents measured at different temperatures with a gravimetric method. The solid-state activity (ideal solubility), and the free energy, enthalpy and entropy of fusion have been determined as functions of temperature for all solid phases through a thermodynamic analysis of multiple experimental data. It is shown that m-aminobenzoic acid is an enantiotropic system, with a stability transition point determined to be located at approximately 156°C, and that the difference in free energy at room temperature between the polymorphs is considerable. It is further shown that m-hydroxybenzoic acid is a monotropic system, with minor differences in free energy, enthalpy and entropy. 1393 primary nucleation experiments have been carried out for both compounds in different series of repeatability experiments, differing with respect to solvent, cooling rate, saturation temperature and solution preparation and pre-treatment. It is found that in the vast majority of experiments, either the stable or the metastable polymorph is obtained in the pure form, and only for a few evaluated experimental conditions does one polymorph crystallize in all experiments. The fact that the polymorphic outcome of a crystallization is the result of the interplay between relative thermodynamic stability and nucleation kinetics, and that it is vital to perform multiple experiments under identical conditions when studying nucleation of polymorphic compounds, is strongly emphasized by the results of this work. The main experimental variable which in this work has been found to affect which polymorph will preferentially crystallize is the solvent. For m-aminobenzoic acid, it is shown how a significantly metastable polymorph can be obtained by choosing a solvent in which nucleation of the stable form is sufficiently obstructed. For m-hydroxybenzoic acid, nucleation of the stable polymorph is promoted in solvents where the solubility is high. It is shown how this partly can be rationalized by analysing solubility data with respect to temperature dependence. By crystallizing solutions differing only with respect to pre-treatment and which polymorph was dissolved, it is found that the immediate thermal and structural history of a solution can have a significant effect on nucleation, affecting the predisposition for overall nucleation as well as which polymorph will preferentially crystallize. A set of polymorphic crystal structures has been compiled from the Cambridge Structural Database. It is found that statistically, about 50% crystallize in the crystallographic space group P21/c. Furthermore, it is found that crystal structures of polymorphs tend to differ significantly with respect to either hydrogen bond network or molecular conformation. Molecular mechanics based Monte Carlo simulated annealing has been used to sample different potential crystal structures corresponding to minima in potential energy with respect to structural degrees of freedom, restricted to one space group, for each of the polymorphic compounds. It is found that all simulations result in very large numbers of predicted structures. About 15% of the predicted structures have excess relative lattice energies of &lt;=10% compared to the most stable predicted structure; a limit verified to reflect maximum lattice energy differences between experimentally observed polymorphs of similar compounds. The number of predicted structures is found to correlate to molecular weight and to the number of rotatable covalent bonds. A close study of two compounds has shown that predicted structures tend to belong to different groups defined by unique hydrogen bond networks, located in well-defined regions in energy/packing space according to the close-packing principle. It is hypothesized that kinetic effects in combination with this structural segregation might affect the number of potential structures that can be realized experimentally. The experimentally determined crystal structures of several compounds have been geometry-optimized (relaxed) to the nearest potential energy minimum using ten different combinations of common potential energy functions (force fields) and techniques for assigning nucleus-centred point charges used in the electrostatic description of the energy. Changes in structural coordinates upon relaxation have been quantified, crystal lattice energies calculated and compared with experimentally determined enthalpies of sublimation, and the energy difference before and after relaxation computed and analysed. It is found that certain combinations of force fields and charge assignment techniques work reasonably well for modelling crystal structures of small aromatics, provided that proper attention is paid to electrostatic description and to how the force field was parameterized. A comparison of energy differences for randomly packed as well as experimentally determined crystal structures before and after relaxation suggests that the potential energy function for the solid state of a small organic molecule is highly undulating with many deep, narrow and steep minima.<br>QC 20110527

碩士<br>臺灣大學<br>化學研究所<br>98<br>Phenol is a chromophore of amino acid tyrosine. The photostability of amino acids is very important to life. According to the experimental results and theoretical calculations, phenol absorb an UV photon are excited to ππ* electronic excited state. The ππ* state couples with a πσ* repulsive state. Then the H atom of O-H bond eliminates from the repulsive state. The photodissociation produce the radicals which cause further reaction. That is opposite to the photostability of amino acids. To go a step further to study the effect of the different side chains on H elimination channel, 2-,3-,4-hydroxybenzoic acid and 2-,3-,4-hydroxyacetophenone are chosen in this experiment. We study the photodissociation of each compound by using multimass ion imaging technique. For hydroxybenzoic acid, H elimination is the major channel for 3-,4-hydroxybenzoic acid and H2O elimination is the major channel for 2-hydroxybenzoic acid. On the other hand, COCH3 elimination is the major channel for 2-, 3-, 4-hydroxyacetophenone. H elimination is observed for 3-, 4-hydroxyacetophenone but it is not observed for 2-hydroxyacetophenone. In comparison with photodissociation channels and molecular structures, H elimination from the repulsive excited state is quenched for the molecules with intramolecular hydrogen bond.

碩士<br>逢甲大學<br>光電研究所<br>99<br>In this work, we studied the surface enhanced Raman scattering (SERS) of carboxyl and benzene ring’s vibrational modes of benzoic acid (BA) and p-hydroxybenzoic acid (PHBA) dissolved, respectively, in the methanol at the concentration range from 0.008M to 0.6M. All three vibrational modes’ SERS of BA have similar concentration dependence, with the maximum at around 0.05M. However, those of PHBA only monotonically increase with its concentration. These results are interpreted as the different surface orientation. These phenomena were interpreted as the result of different adsorption orientation of BA and PHBA on the silver nanoparticles, with the former to be vertically adhered on the Ag surface, and the latter tends to lie flat on the surface. The BA’s SERS was expected to increase as its concentration is increasing initially. However, at higher concentrations, its SERS will start to decline due to the impact in between the overcrowded adsorbed BA molecules. Based on this peculiar SERS dependence on the BA concentration, we can probably estimate the nanoparticle’s coverage for the best SERS (? 63%) and even design a Raman spectral method in determining the size of nanoparticles.

碩士<br>國立高雄師範大學<br>化學類<br>86<br>Abstract The study was two investigate the reaction of 4-hydroxybenzoic acid(4-HBA) with Fenton''s reagent. By varying the condition of pH, ferrous ion concentration, and reaction time, the reation was examined by product analysis with HPLC- photodiode array. The study found that the reation products are 3,4-hydroxybenzoic acid, 2,3,4-hydroxybenzoic acid, 3,4,5-hydroxybenzoic acid, hydroquinone and 1,4-benzoquinone, but hydroquinone were not found at pH=2.8 conditions; 1,4-benzoquinone were not found at pH=5.8 conditions. The rate of the reaction is faster with the decreasing of pH values and increasing the ratio of Fe2+ to 4-hydroxybenzoic acid. At the ratio of Fe2+ to 4-hydroxybenzoic acid is 22.99, the reactions are trending toward decarboxylation reaction. At the ratio of Fe2+ to 4-hydroxybenzoic acid is 0.2299 and pH=5.8 conditions, the products of the reactions are only hydroxylated products. At the higher ratio of Fe2+ to 4-hydroxybenzoic acid and the lower pH values conditions, the total concentration of the decarboxylated products are no significant change with time, when it reach the maximum total concentration. The results of this study can be explained by the hydroxyl radical oxidation with 4-HBA, that hydroxyl radical is generated by Fenton''s reagent.

碩士<br>萬能科技大學<br>化妝品應用與管理研究所<br>104<br>Cosmetics may are contaminated with spoilage microorganisms. The necessary of add preservative in cosmetic, to preserve the pollution caused by bacteria and mould, but preservatives must not be added to products in amounts which may jeopardize the safety of human beings, and that consideration must be given to minimizing the amount of preservatives used. Their activity would be influenced by other cosmetic ingredients such as surfactants. The purpose of this study is evaluating the minimum inhibitory concentration (MIC) of methyl paraben and butyl paraben and the interaction with Tween nonionic surfactants. The methyl paraben and Butyl paraben and Phenoxyethanol and Methylisothiazolinone and Imidazolidinyl urea are widely used in cosmetics as preservatives. The minimum inhibitory concentration of methyl paraben and Butyl paraben and Phenoxyethanol and Methylisothiazolinone and Imidazolidinyl urea against Pseudomonas aeruginosa and Staphylococcus aureus can be to reduce the amount of preservatives used. Furthermore, explore the interaction of nonionic surfactants and preservative, the results found Tween 20 and methyl paraben exhibited synergistic effect that against S. aureus. The above results show, the synergistic effect of Tween 20 and methyl paraben is useful for cosmetic modulation that can diminish preservatives concentration. But mechanism of action of this phenomenon is not clear. The mechanism of parabens as antimicrobial agents the phenomenon is reversible. Our result suggested Tween 20 disrupts cell membrane structure and enhances the bactericide effect of methyl paraben.

碩士<br>國立中興大學<br>土壤環境科學系<br>89<br>Recently, the biotechnology is applied to screen microorganism of phenolic compounds of degradation for decreasing allelopathy and increasing crop production. In this study, we approach phosphate-solubilizing bacteria which able to degrade phenolic compounds. Four typical phosphate-solubilizing bacteria strains (A5、C3、Rhodococcus erythroplis and Gordonia sp.) isolated from rhizosphere, were selected from liquid tricalcium phosphate medium with 5000 µg mL-1 ferulic acid and p-hydroxybenzoic acid , respectively. Then, four strains were inoculated to four treatments of two phenolic acid for 240 hours. In this period, we measured C.F.U., pH, water-soluble phosphorus, the degradation of phenolic acids and bioassay. The results showed that pH were all decreased by four strains, especially at Rhodococcus erythroplis and Gordonia sp. strain down to 4.8 in tricalcium phosphate medium with 5000 µg mL-1 p-hydroxybenzoic acid. In opposite, the water-soluble phosphate was increased to 220 and 305 µg mL-1, respectively; however, C.F.U. of four strains were not significantly increased during 240 hours. Beside, only phosphate-solubilizing bacteria Rhodococcus erythroplis strain is able to degrade p-hydroxybenzoic acid. The rate of degradation was 98﹪and the amount of p-hydroxybenzoic acid was down from 3800 to 80 µg mL-1 (0 to 240 hours) and the other three strains were not. In mixed two phenolic acid treatment, the degradation were inhibited showed phenolic acid degradation of phosphate-solubilizing bacteria has specificity. The result of bioassay showed that the seedling of lettuce all inhibited in 5000 µg mL-1 phenolic acid. In conclusion, all results showed phosphate- solubilizing bacteria strains have specificity in degradation of different phenolic compounds.

碩士<br>國立中興大學<br>化學工程學系<br>90<br>- III - In the present study, the kinetics of synthesizing benzyl salicylate, which is used in perfume fixative, solvent for synthetic musk, sun-screening lotions, and soap odorant, etc., from the carboxylation of benzyl bromide via solid-liquid phase-transfer catalysis was investigated. The operating conditions for investigation include agitation speeds 、reaction temperatures 、catalyst amounts 、types of solvents 、molar ratio of reactants 、 type of phase-transfer catalysts 、volume ratio of aqueous to solvent, and so on. The reaction mechanism and apparent reaction rate constants were obtained from the experimental results. In quaternary ammonium salts system, the product selectivity and kinetics of sodium salicylate with benzyl bromide to produce benzyl salicylate via solid-liquid phase-transfer catalysis were investigated. The behavior of phase-transfer catalytic intermediate in the solid-liquid system was explored.The concentraction of catalytic intermediate (Ph(OH)COOQ) increased as increasing molar quantity of catalyst used after induction period and has greater solubility in organic solvent and mostly exists as the ion-pair, thus enhancing the intrinsic organic reaction effectively. When the agitation speed exceeds 250 rpm, the mass transfer resistance at the solid-liquid interface can be ignored. Different phase-transfer catalysts were employed to compare their catalytic efficiency ： TBAB @ TBAI ＞ BTBAB @ PBPB ＞Aliquat 336 ＞TBAHS ＞PEG1500.

Parabens have been used as antimicrobial preservatives in multiple different types of products for decades, however relatively recent studies have caused concern as to whether their wide-use could be potentially harmful. The following paper reviews the extensive areas of human exposure, from mother to fetus, infants via breast milk, baby and child care products through adult personal care products, and other environmental sources. The potential impacts on human health are also discussed. Parabens predominantly impact biological systems as an endocrine disruptor not only by binding to the human Estrogen Receptor directly, but increasing the availability of naturally occurring 17β-estradiol, further potentiating the effect. Alternative antimicrobial preservatives are also discussed, along with their efficacies and potential health concerns. Common alternatives found in personal care products include phenoxyethanol, methylisothiazolinone, and formaldehyde releasers. Additionally, weak organic acids and plant-derived essential oils are also used in personal care products, but tend to be added more so to food products to prevent the growth of spoilage bacteria, fungi and mold. The potential for these alternatives to replace the use of parabens in personal care products, our greatest area of exposure, is very promising. If parabens in personal care products were replaced with a safe and effective alternative, then the other areas of environmental exposure would likely be negligible to produce any harm on society. Future investigation into the nuances of the various plant-derived essential oils and effective formulations for preservation, is likely the most promising solution, due to their mostly harmless nature. Lastly, the discussion of proposed future research in order to lead to a more definitive connection between paraben exposure and adverse health effects is presented.

碩士<br>國立中興大學<br>化學工程學系所<br>95<br>The kinetics of esterification of sodiume salicylate with butyl bromide to produce salicylic acid n-butyl ester were investigated via ultrasound-assisted tri-liquid phase-transfer catalysis. Third-liquid phase was formed with high catalytic intermediates to increase reaction rate. Sonochemistry is a technique to increase chemical reaction rate by ultrasounic irradiation. Ultrasonic irradiation can provide energy to promote the reaction. The subject of this research involves kinetics for synthesizing o-hydroxybenzoic acid butyl ester, the optimum condition of the reaction system, comparisons between ultrasound-assisted, stirring mixing and both operations. Only tetrabutylphosphonium bromide(TBPB) and tetrabutylammonium bromide(TBAB) can form third-liquid phase among the four catalysts tested in this study. Reaction activity increases with increasing organic reactant concentration as butyl bromide added but keeps constant with largely excess amounts. Activity increases with decreasing ultrasonic frequency. Using ultrasonic frequency 28 kHz the production yield was 82.3 % within 3 hours. Correlating the experimental data, the relation of the enhancement ratio (η) of ArCOOQ in third-liquid phase, and the product yield in organic phase is . The pseudo-first-order kinetic model was used to well describe the overall reaction, by the equation , and the apparent reaction rate constants (kapp) were obtained for with different conditions. We can obtain the activation energy of 31.5 kJ/mol by Arrehenius equation during 50~80 ℃. For high product yield, cost, easy analysis, the production yield was 97.3% as ultrasonic frequency 28kHz, power 300W, and 70℃. With ultrasound alone, the activity becomes lower the energy of higher frequency decreases quickly. Molecule collision raised by agitation can overcome mass transfer resistance. Combining two operations of ultrasound and agitaion make the activity better than with each single operation. Mass transfer resistance can be neglected by stirring speed more than 100 rpm, the yield increases and kapp increases 53.3 % as ultrasound assisted extra.

碩士<br>國立中興大學<br>化學工程學系<br>93<br>The present study is to investigate the kinetics of synthesizing o-hydroxybenzoic acid benzyl ester in a continuous flow reactor via third-liquid phase transfer catalysis. This reactor was designed in such a way that the third-liquid phase was kept in middle part of the reactor with both aqueous phase and organic phase flowing through. The conditions of forming the third-liquid phase include different concentrations of aqueous reactants, inorganic salts, and catalysts, and the optimal condition to form the catalytic intermediate in the third-liquid phase was found. Adding an excess of water the volume of third-liquid will disappear. The operating parameters include aqueous reactants, inorganic slats, agaitation speed organic reactans, phase transfer catalyst, and different of temperature on the reaction, and space time. In this system, the reaction conditions of agaitation speed at 300 rpm, catalyst tetrabutylphosphonium bromide ( TBPB ) at 0.025 mol and at 70℃, the product yield greater than 82.43% was obtained. The apparent activation energy in heptane was obtained 8.91 kcal/mol using tetrabutylphosphoium bromide as the catalyst and a higher temperature is to facilitating to form the third-liquid phase. The yield of o-hydroxybenzoic acid benzyl ester increases with the space time for the aqueous phase and organic phase both controlling at 0.3 ml/min. It is found that the minimum quantity of TBPB required to form the third –liquid is dependent on the amounts of NaBr added, and the volume of third-liquid generated increases with increasing catalyst used. The reaction rate will be decreased in an excess of catalyst at 0.025mol. The experimental data were well described by the proposed kinetic model. Adding trialkylamines are also investigated at different reaction conditions in the continuous flow reactor. Trialkyamines first reacted to form tetraalkylammonium salts with benzyl bromide in organic phase and then transferred into the third liquid phase. Adding tralkylamies well effects volume of third liquid phase, reaction rate and changing properties of the third-liquid phase. By increasing temperature, the reaction rate will be faster and get a higher product yield for tri-ethylamine, due to its easy reaction with the aqueous reactant to form the catalytic intermediate and good for this esterification reacation.

碩士<br>國立中興大學<br>化學工程學系所<br>96<br>The present study is to investigate the kinetics of synthesizing o-hydroxybenzoic acid n-butyl ester in a continuous flow reactor via ultrasound-assisted tri-liquid phase-transfer catalysis. The operating parameters including agitation speeds, types of catalyst, amount of catalyst, types of solvent, reaction temperature, types of inorganic salt, amount of reactant, space time, ultrasonic frequency and power, were all performed to find the optimal reaction conditions. Sonochemistry is a technique to increase chemical reaction rate by ultrasounic irradiation. Ultrasound assisted effect can energize to promote the chemical reaction. The reactor was designed by keeping the third-liquid phase in middle part of the reactor, and both of the aqueous phase and organic phase flowing through the third-liquid phase for reaction. The yield of o-hydroxybenzoic acid n-butyl ester increases with the space time, so the flow rates of aqueous phase and organic phase were both controlled at 0.3 ml/min. Increasing the organic reactant concentration butylbromide can increae the reaction activity. The lower ultrasonic frequency makes the yield of product higher. Mass transfer resistance can be neglected by agitation speed more than 150 rpm. The mechanism and kinetics in a continuous-flow reaction were proposed, and we can calculate the kapp by the model. For high product yield and cost effective, the system condition of agitation speed at 150 rpm, catalyst tetrabutylphosphonium bromide (TBPB) at 0.0125 mol, ultrasonic frequency at 28 kHz and power 300 W, the reaction temperature at 70 ℃, the product in the organic phase was 78.8 %. The apparent activation energy can be obtained as 14.5 kcal/mol in the range of 50~80 ℃. Combining agitation and ultrasound irradiation makes the reaction activity advance a lot. The yield of product was 49.7 % without any agitation and ultrasound assisted. Under the agitation, the yield of product was 65.1% without any ultrasound assisted. The yield of product raised to 58.2 % with ultrasound promoting the reaction. Using agitation and ultrasound at the same time, the product yield was obtained 78.2 %, raising the product yield by 57.3% higher than that without any assistance of agitation and ultrasound.

碩士<br>國立中興大學<br>化學工程學系所<br>104<br>In this study, o-hydroxybenzoic acid butyl ester was synthesized from the reaction of sodium salicylate and 1-bromobutane via a phase-transfer catalyst,under ultrasound irradiation in a solid-liquid batch system with ionic liquid. The explored operating parameters included ultrasound, types of catalyst, addition catalyst, ionic liquid , agitation speed, temperature,etc.. 　　For the reaction mechanism, the reactions dominated to conduct in the interface between the organic and solid phases. As adding ionic liquid in the system, the reaction of catalytic intermediate was promoted. Using ionic liquid would be beneficial to the present esterification, especially for phosphonium-based ionic liquid. The product yield was 0% without adding both ionic liquid and catalyst. The yield raised to 21.08% when adding catalyst but without ionic liquid in 150 minutes; The yield was 37.47% with adding ionic liquid but without catalyst in 150 minutes, and further increased to 75.51% with both catalyst and ionic liquid. By using ultrasonic irradiation, the overall reaction rate was higher than without ultrasound. When using ionic liquid trihexyltetradecylphosphonium bis(2,4,4-trimethylpentyl)phosphinate combined with the catayst, there would be the best catalytic efficiency among the tested ionic liquids. 　　In this solid-liquid system, the yield was75.51 % in 150 minutes without adding water; by adding water, the system became a liquid-liquid type and the yield declined to 20.09% When using highly polar solvents such as methyl isobutyl ketone, there would be a high catalytic effect. To use the low-polar or non-polar solvents such as toluene and heptane, the yield would be lowered, indicating the level of solvent polarity influencing the yield. Due to the requirement of green reaction , heptane was selected as the solvent. 　　Pesudo-zero-order kinetic equation was applied to describe experimental results. Using heptane as solvent, the kinetic results were correlated by using Y=kappt (Y<1) equation successfully , where Y was product yield and kapp was modified apparent-zero-order rate constant. With ultrasound (28 kHz/300 W) in this reaction system, kapp was raised to a value 2.7 times of that without ultrasound, showing a great enhancement in reaction rate by applying ultrasound. Using Arrhenius'' equation to estimate the apparent activation energy, the apparent activation energy was 16.75 kcal/mol with ultrasound,and was 16.52 kcal/mol without ultrasound.

碩士<br>國立中興大學<br>化學工程學系所<br>100<br>In this study, o-hydroxybenzoic acid butyl ester was synthesized from the reaction of sodium salicylate and 1-bromobutane via a dual-site phase-transfer catalyst, 1,4-bis(trihexylammoniomethyl)benzenedibromide(BTHAMBB), under ultrasound irradiation in a tri-liquid batch system with ionic liquid. The catalyst BTHAMBB was synthesized from the reaction of p-xylylene dibromide and excess trihexylamine in acetonitrile at 70 oC. In this study, the investigation included the forming condition of the tri-liquid phase by BTHAMBB and kinetics of synthesizing sodium salicylate. The operating parameters of forming the third-liquid phase including the type of organic solvent, the amounts of ionic liquid and catalyst, the reaction temperature, and the ultrasound. In the conditions of 3mmol of sodium salicylate, 0.375 mmol of BTHAMBB, 10 ml of de-ionized water, 10 ml of heptane, temperature at 70 oC and stirring speed at 250 rpm, the volume 1 cm3 of the third-liquid phase was formed after 20 minutes of reaction without adding any extra inorganic salts in the reaction system. It is because the structure of the catalytic intermediate that made the third-liquid phase having low solubility in both water and heptane. The catalytic intermediate had the highest ratio in the third-liquid phase when the amount of BTHAMBB is 0.375 mmol. An excess addition of BTHAMBB might transfer more catalyst into the third-liquid phase and reduced the effective concentration of the catalytic intermediate for reaction. In this study, the third-liquid phase could be formed by using toluene or heptane as organic solvent. But the high-polarity solvent of methyl isobutyl ketone (MIBK) can not be used to form the third-liquid phase, because the catalyst and the catalytic intermediate can be dissolved by methyl isobutyl ketone. In the kinetic part, the result indicated the reactions dominate to conduct in the third-liquid phase. The rate of apparent reaction could be described by pseudo-first-order kinetic equation. The yield of the product of o-hydroxybenzoic acid butyl ester in the organic phase was obtained 69.7% by using BTHAMBB as phase-transfer catalyst in 4 hours in the condition of temperature at 70 oC, agitation speeg at 250 rpm, ultrasonic frequency and power at 28 kHz and 300 W, while the yield of the product was 0 % at the same condition without using BTHAMBB as phase-transfer catalyst. The yield of the product will raise to 94.1% by adding the ionic liquid to the reaction system. By using ultrasonic irradiation, the yield of the product will increase 4%~12%, and the kapp will be higher than without ultrasonic.

碩士<br>國立宜蘭大學<br>園藝學系碩士班<br>105<br>The lack of water resources in Taiwan during the dry season results in water shortages, whereas during the East Asian rainy season, heavy rains frequently lead to floods. In addition to the substantial use of chemical fertilizers that accelerate soil salinization, the aforementioned stress factors have reduced the quality and yield of vegetable cultivation. Therefore, this study was conducted to pretreat plants using 4-hydroxybenzoic acid (PHBA) and cinnamic acid (CA), and investigate changes in the growth, oxidative stress, and antioxidant defense systems of the plants under various stress conditions. The findings can contribute to reducing the negative effects of stress on crop growing. Either PHBA or CA was applied to the plants of sweet pepper “Emerald Star” and tomato “Golden Gem” that contain five to six true leaves. Specifically, a PHBA or CA solution was poured into the growth medium 2 and 4 days before applying the draught stress. After 5 days of draught treatment, watering was recovered for 7 days. The results showed that the plants pretreated with PHBA or CA demonstrated increased superoxide dismutase, catalase, ascorbate peroxidase, and glutathione reductase activities as well as reduced concentrations of MDA, superoxide anions, and hydrogen peroxide in the leaves. Three different concentrations of PHBA and CA were adopted, revealing that the bell pepper plants attained the most favorable antioxidant capability under 0.1 mM PHBA or 0.025 mM CA, whereas the optimal concentration for the tomato plants was 0.15 mM PHBA or 0.05 mM CA. Another experiment was conducted, in which PHBA or CA was respectively added to the growth medium 2 and 4 days before applying a flood treatment for 7 days, after which the plants were removed from the flooded medium and recovered for another 7 days. The results showed that the sweet pepper plants most effectively reduced lipid peroxidation and ROS content under 0.15 mM PHBA or 0.05 mM CA, demonstrating enhanced antioxidant activities in the leaves. The tomato plants were most resistant to flooding under 0.1 mM PHBA or 0.05 mM CA. A salinization experiment was also conducted, in which sweet pepper and tomato plants were subjected to seven salinization treatments using 150 mM NaCl. Specifically, after pretreatment of two salinization treatments, PHBA or CA was added to the growth medium during the third and fourth treatments, respectively. After 14 days of salinization treatments and 7 days of recovery, the results showed that applying either PHBA or CA was effective against the saline damage; the plant growth was less inhibited, and the internal antioxidation capability was enhanced. Particularly, the sweet pepper plants attained the most favorable salt resistance capability under 0.15 mM PHBA or 0.05 mM CA, whereas the optimal treatment concentration of the tomato was 0.25 mM PHBA.

碩士<br>國立中興大學<br>化學工程學系所<br>104<br>In this study, the esterification of sodium salicylate and 2-phenoxyethyl bromide to synthesize o-hydroxybenzoic acid 2-phenoxyethyl ester with dual-site phase-transfer catalyst under ultrasonic irradiation in solid-liquid system was investigated. The dual-site phase-transfer catalyst, 1,4-bis(trihexylammoniomethyl) benzene dibromide (BTHAMBB, QBr2), was synthesized from the reaction of p-xylene dibromide and trihexylamine. This catalyst was applied in this study to investigate the effect of operating parameters and kinetics of synthesizing o-hydroxybenzoic acid 2-phenoxyethyl ester. The operating parameters included catalyst effect, ionic liquid effect, types of organic solvent, quantities of organic reactants, agitation speed, temperature effect, quantities of water, types of salt and sodium hydroxide effect. From the experimental results, the catalytic activity of dual-site phase-transfer catalyst was better than commercial catalysts. When the high-polar solvent, methyl isobutyl ketone, was used, there was the best catalytic effect among the tested solvents; while using the low-polar or non-polar solvents toluene and n-heptane, the yields both decreased. It indicated that the solvent polarity would influence the yield much. To meet the requirement of green chemistry, n-heptane was selected as the solvent. Ultrasound was applied to enhance the solid-liquid reaction. Under the conditions of ultrasound irradiation at frequency 28 kHz and power 100 W, stirring speed 300 rpm, temperature 70℃ and n-heptane as an organic solvent, the reaction can not be carried out after 90 minutes without adding catalyst. The yield of product was raised to 71.27% with 1 mmol BTHAMBB catalyst but without ionic liquid. Adding 1 mmol catalyst and 0.1 mmol ionic liquid promoted the yield to 77.51%. In this system, the yield could reach a maximum when the agitation speed was set at 300 rpm. The product yield was increased when a small amount of NaI was added. But adding NaOH could destroy some parts of the catalyst, leading to the reduction of catalytic efficiency. In this solid-liquid system, the yield was 71.27% in 90 minutes without adding water. However, the system changed to a liquid-liquid type by adding water, resulting in the yield to be declined. Without ultrasound and agitation, the yield was only 4.54%. With both ultrasonication and agitation in the system, the best catalytic efficiency was achieved. For the reaction mechanism, the reactions dominated to conduct in the interface between the solid and organic phase. The kinetic results were successfully correlated by using pseudo-zero-order kinetic equation (Y<1), where Y was product yield, and was the modified apparent-zero-order rate constant. The with ultrasound was about 1.2 times of that without ultrasound. The activation energy with ultrasound-assisted was "24.49 kcal/mol" . In this study, the green method for synthesizing ether-ester compounds by dual-site phase-transfer catalyst in a solid-liquid system was developed.

The rapidly growing world population, increasing severity of climate change, and constantly evolving environmental pressures have drawn into question whether current agricultural practices can meet the growing food demands healthily, equitably and sustainably. This has resulted in the rising popularity of natural biostimulants, particularly seaweed extracts, to increase crop productivity in an eco-friendly and safe manner. To better understand the complex modes of action underpinning the well-reported benefits of seaweed biostimulants to crops, their phytochemical composition requires further characterisation. Hydroxybenzoic acids, a subclass of phenolic acids, are an important class of phytochemicals and the aim of this study was to characterise their profile in commercial seaweed biostimulants. This work used modern analytical technologies to investigate salicylic acid and other benzoic acid derivatives in a commercial seaweed biostimulant, and then assessed the biological activity of the monohydroxybenzoic acids using plant growth assays. Qualitative HPLC-ESI-MS/MS methods were developed for the analysis of hydroxybenzoic acids and related derivatives. The various benzoic acid derivatives investigated include monohydroxybenzoic acids, dihydroxybenzoic acids, trihydroxybenzoic acids, methoxylated hydroxybenzoic acids, methoxylated benzoic acids, and an amino substituted benzoic acid. The HPLC-ESI-MS/MS methods for the analysis of the various derivatives were then employed to investigate the presence of these compounds in the commercial seaweed biostimulant. The compounds found to be present were the monohydroxybenzoic acids, 2,3- and 3,4-dihydroxybenzoic acid, syringic acid, and anthranilic acid. A HPLC-ESI-MS/MS method for the analysis of the monohydroxybenzoic acids was optimised and partially validated for the quantification of salicylic acid and its isomers in a commercial seaweed biostimulant. Sample preparation employed acidified acetonitrile partitioning of the seaweed biostimulant before mixed-mode solid-phase extraction. The three isomers were successfully separated using a reversed-phase biphenyl stationary phase with a methanol/water mobile phase acidified with formic acid. The MS/MS detection employed the characteristic MRM transition of m/z 137  93 of the monohydroxybenzoic acids. The concentrations of 2-, 3- and 4-hydroxybenzoic acid in a commercial seaweed biostimulant were found to be 137, 3409, and 1748 μg/L, respectively. Tomato seedling plant growth bioassays were conducted to investigate the biological effects of salicylic acid and its isomers on plant growth. Fresh and dry root and shoot weight data along with longest root length data were assessed to evaluate the biological effects of the various treatments on tomato seedling growth. It was found that a significant increase in root growth was observed when the commercial seaweed biostimulant was fortified with a combination of the three monohydroxybenzoic acids, using dosages that correlate to the concentrations determined in the seaweed biostimulant in this study.

Yes<br>Cocrystallization is an attractive approach to improving the physicochemical properties of active pharmaceutical ingredients (APIs), which have great potential in drug development. Accordingly, there is a growing need to understand the physicochemical changes that occur upon co-crystallisation. This work focuses on the combined use of spectroscopy and density functional theory (DFT) calculations to understand the molecular structure, hydrogen bond interactions and physicochemical properties of a pharmaceutical cocrystal. Solid-state NMR (ssNMR) spectroscopy can provide detailed molecular structure information on pharmaceutical cocrystals and complexes. It is non-destructive and usually provides deep structural insights that complement well with vibrational spectroscopy. In this work, a cocrystal of an antibiotic drug, nitrofurantoin (NF), with 4-hydroxybenzoic acid (4HBA) is examined to understand the capability of multiple spectroscopic techniques such as infrared (IR), Raman and solid-state NMR spectroscopies, and to confirm the molecular structure and hydrogen bonding of cocrystal systems. The results of IR and Raman spectroscopy showed that for the cocrystal formation, NF and 4HBA molecules interact through N–H⋯O–H interactions between the imide N–H of nitrofurantoin and the phenolic –OH of 4-hydroxybenzoic acid, and these interactions are also confirmed by natural bond orbital (NBO) and quantum theory of atoms in molecules (QTAIM) analyses. It is critical to understand whether a given cocrystal, upon conceiving a modified crystalline structure compared to that of its API, shows enhanced physical and chemical properties or not. Computationally, it is found that the NF–4HBA cocrystal shows softer (more reactive) behaviour in comparison to NF as its cocrystal, NF–4HBA, has a low band gap in comparison to the API, NF. These results demonstrate that the quantum chemical approach predicts accurately how to relate cocrystal with its physical and chemical properties.<br>BSR meritorious fellowship scheme. The Newton-Bhabha PhD placement award (2017). The Royal Society Seed Corn Research Grant (2018-19)

Tese de mestrado em Química, apresentada à Universidade de Lisboa, através da Faculdade de Ciências, 2016<br>O trabalho apresentado nesta tese foi realizado no Grupo de Energética Molecular (GEM), do Centro de Química e Bioquímica da Faculdade de Ciências da Universidade de Lisboa. Um dos temas principais desenvolvidos ao longo dos anos no GEM, prende-se com o estudo da relação entre a energética e a estrutura das moléculas, nomeadamente em sólidos moleculares orgânicos. A abordagem deste tema tem seguido duas linhas de investigação ligeiramente distintas. Na primeira, são estudados sistemas modelo, normalmente constituídos por pequenas moléculas (poucas dezenas de átomos), pouco dispendiosos e que podem ser facilmente manipulados. Estes estudos têm como objetivo estabelecer relações causa-efeito como, por exemplo, averiguar como uma determinada alteração na estrutura de uma molécula, implica mudanças no empacotamento em estado sólido e, consequentemente, nas propriedades físicas. Na segunda linha, os conhecimentos retirados do estudo dos sistemas modelo, são aplicados diretamente ao estudo de compostos com interesse comercial. De facto, este tipo de estudo é de extrema importância para as indústrias que usam formulações orgânicas no estado sólido, onde a indústria farmacêutica se destaca, devido à grande variedade de princípios ativos farmacêuticos que são utilizados em estado sólido. Quando se trabalha com sólidos moleculares cristalinos por vezes, uma mesma molécula pode organizar-se com diferentes arranjos tridimensionais. A este fenómeno dá-se o nome de polimorfismo. Dado que cada forma cristalina pode apresentar diferentes propriedades físicas (e.g. cor, temperatura de fusão e solubilidade), o controlo e previsão deste fenómeno é hoje em dia crucial para a indústria. Por exemplo, para a indústria farmacêutica, se duas formas cristalinas do mesmo composto apresentarem solubilidades distintas, podem conduzir a uma biodisponibilidade diferente do medicamento no organismo do paciente. Apesar de poderem existir vários polimorfos para uma molécula em determinadas condições de pressão e temperatura, apenas uma dessas formas é termodinamicamente estável. Assim, caso não existam barreiras cinéticas, todas as formas metastáveis tendem a evoluir para a fase mais estável. Neste sentido, torna-se importante conhecer a relação energética entre as fases, a fim de evitar problemas durante, e.g. processos de armazenamento. Estes tipos de problemas podem, por esse motivo, levar a uma eventual recolha dos medicamentos baseados num dado principio ativo, e assim levar a perdas monetárias muito elevadas para a indústria. É de realçar, no entanto, que se o polimorfismo for bem compreendido e controlado, pode levar ao desenvolvimento de novos materiais, que possuem características físicas diferentes do material de partida, que podem ser ajustadas para uma determinada aplicação sem alterar a molécula inicial. Este facto, mostra que é de todo o interesse conhecer quais os vários polimorfos existentes para cada molécula, e estudar a maneira mais adequada para os preparar e controlar. É neste âmbito que surge o trabalho que foi desenvolvido nesta tese. Este foi realizado como continuação dos estudos iniciados no GEM para os compostos 4’-hidroxiacetofenona e 4-hidroxibenzaldeído. Ambos podem ser considerados sistemas modelo que pertencem à família de compostos do tipo 4-hidroxibenzoílos (HOC6H4COR). Estes revelaram-se ser compostos com a capacidade para gerar polimorfos, pois tanto para a 4’-hidroxiacetofenona (R = CH3) como para o 4-hidroxibenzaldeído (R = H) já foram identificadas duas formas cristalinas diferentes. Para além destas, no caso da 4’-hidroxiacetofenona, foram também identificados três hidratos. A razão principal que leva a esta diversidade parece estar relacionada com a capacidade destas moléculas poderem formar diferentes tipos de ligações de hidrogénio como OH∙∙∙O, CH∙∙∙Ocarbonilo e CH∙∙∙Ohidroxilo, permitindo diferentes empacotamentos cristalinos. Para além disso, do ponto de vista conformacional, nesta família de compostos, as moléculas podem ainda adotar duas conformações distintas, que diferem na orientação do átomo de hidrogénio do grupo hidroxilo relativamente ao grupo carbonilo. Assim, um dos objetivos principais deste trabalho foi verificar de que forma um aumento do tamanho da cadeia alquilo, i.e. a introdução de um grupo apolar R progressivamente maior, influencia a formação de diferentes estruturas cristalinas. Para isto foram selecionadas quatro moléculas, em adição à 4’-hidroxiacetofenona e 4-hidroxibenzaldeído, aumentando a cadeia carbonada consecutivamente, através da adição de grupos CH2. Neste sentido, foi realizado um estudo sistemático da energética e das estruturas cristalinas da 4’-hidroxipropiofenona (R = C2H5), da 4’-hidroxibutirofenona (R = C3H7), da 4’-hidroxivalerofenona (R = C4H9) e da 4’-hidroxiheptanofenona (R = C6H13). O ponto de partida para o desenvolvimento deste trabalho, foi a caracterização energética para os compostos selecionados, dada a ausência na literatura de dados fiáveis para estes compostos. Este estudo envolveu várias etapas: i) a determinação das temperaturas de fusão e respetivas entalpias de fusão molares padrão (po = 1 bar) , ΔfusHmo, por calorimetria diferencial de varrimento; ii) a avaliação da entalpia de vaporização molar padrão, Δvap𝐻mo, da 4’-hidroxivalerofenona e 4’-hidroxiheptanofenona, e de sublimação molar padrão, Δsub𝐻mo, da 4’-hidroxipropiofenona e 4’-hidroxibutirofenona, por microcalorimetria Calvet; iii) a determinação das capacidades caloríficas molares padrão dos compostos por calorimetria diferencial de varrimento, de forma a possibilitar a correção dos valores de Δvap𝐻mo e Δsub𝐻mo obtidos nas condições experimentais, para entalpias de sublimação molares padrão à temperatura de referência de 298,15 K, ΔsubHmo(298,15) iv) o cálculo das entalpias de formação molar padrão em estado sólido, ΔfHmo(cr), a partir dos valores de ΔsubHmo(298,15) e das entalpias de formação molar padrão em fase gasosa, ΔfHmo (g), à temperatura de 298,15 K. Este trabalho foi recentemente publicado (C. S. D. Lopes, F. Agapito, C. E. S. Bernardes, M. E. Minas da Piedade Thermochemistry of 4-HOC6H4COR (R = H, CH3, C2H5, n-C3H7, n-C4H9, n-C5H11, and n-C6H13) Compounds; J. Chem. Thermodyn. 2016, DOI: 10.1016/j.jct.2016.09.026). Foi realizada uma correlação linear entre as entalpias de sublimação molares padrão a 298,15 K dos compostos com o número de átomos de carbono (R2 = 0,986). Este resultado sugere que apesar dos diferentes empacotamentos cristalinos existentes entre as várias formas a energia de coesão é aditiva, com um aumento por cada CH2 de 6,6±0,6 kJ∙mol-1. A procura de novos polimorfos nos compostos estudados foi realizada, numa primeira etapa, pela verificação da existência de transições de fase e avaliando as temperaturas de fusão dos materiais, por calorimetria diferencial de varrimento. De uma forma geral, os ensaios realizados com os materiais de partida, não revelaram a existência de transições de fase entre a temperatura ambiente e de fusão. No caso da 4’-hidroxivalerofenona (HVP), após avaliar a fusão da amostra, esta foi ainda submetida a ciclos de aquecimento/arrefecimento. Este estudo revelou que o material que precipita a partir do líquido isotrópico da HVP, não apresenta transições de fase na gama de temperaturas estudada (153 K a 453 K). No entanto, a temperatura e entalpia de fusão são significativamente diferentes em relação à amostra inicial: enquanto o composto de partida (forma I), que é preparado por cristalização em etanol, apresenta uma temperatura de fusão de 334,2±0,7 K, e uma entalpia de fusão molar padrão de 25,75±0,26 kJ·mol-1, a que precipita a partir do líquido isotrópico (forma II), funde a 324,0±0,2 K e tem uma entalpia de fusão molar padrão de 18,14±0,18 kJ∙mol-1. Utilizando os valores de entalpia e temperatura de fusão, foi possível concluir que a forma I é termodinamicamente mais estável que a forma II, e que estas se encontram relacionadas monotropicamente. Os resultados destes estudos termoanalíticos sobre o polimorfismo na HVP foram já submetidos para publicação estando a aguardar o resultado da avaliação (C. S. D. Lopes, C. E. S. Bernardes, M. F. M. Piedade, H. P. Diogo, M. E. Minas da Piedade; A New Polymorph of 4′-Hydroxyvalerophenone Revealed by Thermoanalytical and X-ray Diffraction Studies; Eur. Phys. J.). A identificação deste novo polimorfo da HVP foi ainda verificada através de estudos de difração de raios-X de cristal único, os quais permitiram determinar a organização molecular desta nova fase em estado sólido. Para além destes resultados para a 4’-hidroxiheptanofenona (HHP), recorrendo a dados de difração de raios-X de cristal único, foram resolvidas quatro estruturas a diferentes temperaturas (150 K, 190 K, 220 K e 293 K) e identificada uma transição de fase entre 190 K e 220 K. Verificou-se que todas estas estruturas são ortorrômbicas, sendo que a transição de fase que ocorre, leva à alteração do grupo espacial, de P212121 para Pnma, confirmando assim a existência de polimorfismo na molécula. Esta transição também foi identificada por calorimetria diferencial de varrimento. Finalmente, a partir da análise dos dados de difração de raios-X de cristal único das diferentes formas, foi possível verificar que as transições de fase sólido-sólido envolvem modificações conformacionais da cadeia alquilo nas moléculas de HHP, sem que existam alterações significativas da estrutura a nível tridimensional.<br>During the recent years, in the Molecular Energetics Group, Faculdade de Ciências da Universidade de Lisboa, an effort to systematically investigate the structure/energetic relation in molecular crystalline materials has been undertaken. One of the studies performed in this scope, involved the investigation of the 4’-hydroxybenzoyl family (HOC6H4CO-R), by searching for the existence of polymorphs (crystal phases with different molecular arrangements) of 4-hydroxybenzaldeheyde (R = H) and 4’-hydroxyacetophenone (R = CH3), and relating this information with energetic data. In this work, the previous existing results were expanded for compounds with R = C2H5, n-C3H7, n-C4H9 and n-C6H13. The thermochemistry of the compounds was investigated by determining their enthalpies of formation, fusion, vaporization and/or sublimation. These measurements were performed by Calvet-drop microcalorimetry and W1-F12 and CCSD(T)-F12 level of theory. Standard (po = 1 bar) molar enthalpies of formation in the solid, ΔfHmo (cr), and gaseous, ΔfHmo (g), states at 298.15 K were determined for the complete family of compounds studied in this work. A linear correlation was found when the ΔsubHmo (298.15 K) values were plotted as a function of the number of carbon atoms in the alkyl side chain (nc), with a CH2 increment of 6.6±0.6 kJ∙mol-1. Despite the differences in the molecular packing between the crystalline compounds their cohesive energies are approximate additivity. Regarding the polymorphism studies, a new phase of 4’-hydroxyvalerophenone was discovered from differential scanning calorimetry, X-ray powder diffraction and single crystal X-ray diffraction. This novel form (form II) was obtained by crystallization from the melt. It presents a fusion temperature of Tfus = 324.3±0.2 K and an enthalpy of fusion ΔfusHmo = 18.14±0.18 kJ·mol-1. These values are much lower than those obtained for the previously known phase (form I, Tfus = 334.6±0.7 K; ΔfusHmo = 25.7±5.26 kJ·mol-1), which can be prepared by crystallization from ethanol. These results suggest that form I is thermodynamically more stable than form II and both are monotropically related. Finally, for 4’-hydroxyhepatnophenone, four different structures at different temperatures (T = 150 K; 190 K; 220 K and 298 K) were solved by single crystal X-ray diffraction. A phase transition at 203 K was detected by DSC which corresponds to a new polymorph. The two forms are enantiotropicly related.

碩士<br>國立高雄師範大學<br>化學系<br>87<br>Ozonation of 4-hydroxybenzoic acid (4-HBA) by varying pH conditions and mole ratios ([4-HBA]/[O"]) were studied. The ozonation products of the reactions were analyzed by HPLC and the initial reaction path is proposed. Under the experimental conditions (pH = 2.5-6.0 and [4-HBA]/[O"] = 1.48-144.80), 3,4-dihydroxybenzoic acid(3,4-DHBA), benzoquinone(BQ), and hydroquinone(HQ) were found. Under the lower pH conditions, the reactions tend to eliminate carboxylic acid from 4-HBA, and BQ were formed. As the pH increased, the OH addition reaction were turned on, and 3,4-DHBA, BQ, and HQ were found. At fixed pH and varying mole ratios, as [4-HBA]/[O"] ratios increased, the products concentrations increased and stayed at the maximum concentrations even when the [4-HBA]/[O"] ratios further increased. A dual reaction paths that ozone direct reaction and hydroxyl radical reaction is used to explain the results for all the experimental conditions.

博士<br>國立中正大學<br>化學研究所<br>88<br>Abstract The dynamics of excited state intramolecular proton transfer (ESIPT) in 10-hydroxybenzoquinoline (HBQ) and its deuterated analogue (DBQ) have been investigated by steady-state fluorescence spectroscopy, femtosecond fluorescence upconversion in combination with pump-probe transient absorption experiments. In cyclohexane the time scale for both proton and deuterium transfer in the excited state cannot be resolved under the response limit of the upconversion signal of ca.180 fs. Conversely, the proton-transfer rate is estimated to be ca. 150 fs-1 in DBQ through the transient absorption experiment. The results in combination with a steady-state deuterium isotope steady-state measurement lead us to conclude an ESIPT rate of ~100fs-1 for HBQ in cyclohexane. The initially prepared keto-tautomer is in a highly vibronically (and possibly electronically coupled) excited state of which the time-dependent spectral evolution is both excitation and probe wavelength dependent. It then undergoes vibrational relaxation (and/or internal conversion) in a time scale of several picoseconds, followed by a relatively much longer S1’ S0’ (prime indicates the keto tautomer) decay of 250 ps-1 in cyclohexane. Similar time scales of the proton transfer rate and relaxation dynamics were observed in aprotic solvents. The results lead to a conclusion that ESIPT in HBQ is essentially barrierless and the rate of reaction may be determined within the period of low-frequency, large-amplitude vibrations.

De nombreux travailleurs sont exposés aux hydrocarbures aromatiques polycycliques (HAP). Le benzo(a)pyrène (BaP) fait partie de ce groupe de polluants. Cette substance a été classée cancérogène reconnu chez l’humain. Pour évaluer l'exposition aux HAP cancérogènes, plusieurs chercheurs ont proposé d’utiliser la mesure du 3-hydroxybenzo(a)pyrène (3-OHBaP) dans l’urine des travailleurs exposés. Dans le cadre du présent projet, deux approches de modélisation ont été développées et appliquées pour permettre une meilleure compréhension de la toxicocinétique du BaP et son biomarqueur d’intérêt actuel, le 3-OHBaP, et pour aider à interpréter les résultats de surveillance biologique. Un modèle toxicocinétique à plusieurs compartiments a été développé sur la base des données préalablement obtenues sur le rat par notre groupe. Selon le modèle, le BaP injecté par voie intraveineuse est rapidement distribué du sang vers les tissus (t½ ≈ 4 h), avec une affinité particulière pour les poumons et les composantes lipidiques des tissus. Le BaP est ensuite distribué vers la peau et le foie. Au foie, le BaP est promptement métabolisé et le 3-OHBaP est formé avec une demi-vie de ≈ 3 h. Le métabolisme pulmonaire du BaP a également été pris en compte, mais sa contribution à la cinétique globale du BaP a été jugée négligeable. Une fois formé, le 3-OHBaP est distribué vers les différents organes presque aussi rapidement que la molécule mère (t½ ≈ 2 h). Le profil temporel du 3-OHBaP dans le rein montre une accumulation transitoire en raison de la différence observée entre le taux d’entrée (t½ = 28 min) et le taux de sortie (t½ = 4,5 h). La clairance totale de 3-OHBaP du corps est principalement gouvernée par le taux de transfert de la bile vers le tractus gastro-intestinal (t½ ≈ 4 h). Le modèle toxicocinétique à plusieurs compartiments a réussi à simuler un ensemble indépendant de profils urinaires publiés sur le 3-OHBaP. Ce modèle toxicocinétique à compartiments s'est avéré utile pour la determination des facteurs biologiques déterminants de la cinétique du BaP et du 3-OHBaP. Par la suite, un modèle pharmacocinétique à base physiologique (PCBP) reproduisant le devenir du BaP et du 3-OHBaP chez le rat a été construit. Les organes (ou tissus) représentés comme des compartiments ont été choisis en fonction de données expérimentales obtenues in vivo chez le rat. Les coefficients de partition, les coefficients de perméabilité, les taux de métabolisation, les paramètres d'excrétion, les fractions absorbées et les taux d'absorption pour différentes voies d’exposition ont été obtenus directement à partir des profils sanguins, tissulaires, urinaires et fécaux du BaP et du 3-OHBaP. Les valeurs de ces derniers paramètres ont été calculées par des procédures Monte-Carlo. Des analyses de sensibilité ont ensuite été réalisées pour s’assurer de la stabilité du modèle et pour établir les paramètres les plus sensibles de la cinétique globale. Cette modélisation a permis d’identifier les facteurs déterminants de la cinétique: 1) la sensibilité élevée des paramètres de la métabolisation hépatique du BaP et du 3-OHBaP ainsi que du taux d'élimination; 2) la forte distribution du BaP dans les poumons par rapport à d'autres tissus; 3) la distribution considérable du BaP dans les tissus adipeux et le foie; 4) la forte distribution du 3-OHBaP dans les reins; 5) le transfert limité du BaP par la diffusion tissulaire dans les poumons; 6) le transfert limité du 3-OHBaP par la diffusion tissulaire dans les poumons, les tissus adipeux et les reins; 7) la recirculation entéro-hépatique significative du 3-OHBaP. Suite à des analyses de qualité des ajustements des équations du modèle aux données observées, les probabilités que les simulations reproduisent les données expérimentales par pur hasard se sont avérées toujours inférieures à 10% pour les quatre voies d’exposition : intraveineuse, orale, cutanée et respiratoire. Nous avons extrapolé les modèles cinétiques du rat à l’humain afin de se doter d’un outil permettant de reconstituer les doses absorbées chez des travailleurs exposés dans diverses industries à partir de mesures de l'évolution temporelle du 3-OHBaP dans leur urine. Les résultats de ces modélisations ont ensuite été comparés à ceux de simulations obtenues avec un modèle toxicocinétique à compartiment unique pour vérifier l’utilité comparative d’un modèle simple et complexe. Les deux types de modèle ont ainsi été construits à partir de profils sanguins, tissulaires, urinaires et fécaux du BaP et du 3-OHBaP sur des rats exposés. Ces données ont été obtenues in vivo par voie intraveineuse, cutanée, respiratoire et orale. Ensuite, les modèles ont été extrapolés à l’humain en tenant compte des déterminants biologiques essentiels des différences cinétiques entre le rat et l’humain. Les résultats ont montré que l'inhalation n'était pas la principale voie d'exposition pour plusieurs travailleurs étudiés. Les valeurs de concentrations de BaP dans l’air utilisées afin de simuler les profils d’excrétion urinaire chez les travailleurs étaient différentes des valeurs de concentrations de BaP mesurées dans l’air. Une exposition au BaP par voie cutanée semblait mieux prédire les profils temporels observés. Finalement, les deux types de modélisation se sont avérés utiles pour reproduire et pour interpréter les données disponibles chez des travailleurs.<br>Many workers are exposed to polycyclic aromatic hydrocarbons (PAHs). Benzo(a) pyrene (BaP) is part of this group of pollutants. This substance has been classified as a known carcinogen in humans. To assess exposure to carcinogenic PAHs, several researchers have proposed using the measurement of 3-hydroxybenzo(a)pyrene (3-OHBaP) in the urine of exposed workers. In this project, two modeling approaches were developed and applied to enable a better understanding of the toxicokinetics of BaP and its biomarker of current interest, 3-OHBaP, to help interpret the results of biological monitoring. A multi-compartment toxicokinetic model was developed based on the data previously obtained in rats by our group of research. According to the model, BaP injected intravenously is rapidly distributed from blood to tissues (t½ ≈ 4 h), with a particular affinity for lungs and lipid components of tissues. Subsequently, BaP is distributed to the liver and the skin. Once in the liver, BaP is promptly metabolized and 3-OHBaP is formed with a half-life of about 3 h. Pulmonary biotransformation of BaP was also taken into account, but its contribution to the overall kinetics of BaP was considered negligible. Once formed, 3-OHBaP is distributed to various organs almost as fast as the parent compound (t½ ≈ 2 h). An accumulation of 3-OHBaP profile is present in the kidneys because of the difference between the uptake rate (t½ = 28 min) and the ouput rate (t½ = 4.5 h). Total clearance of 3-OHBaP from the blood stream is primarily governed by the rate of transfer of the bile to the gastrointestinal tract (t ½ ≈ 4 h). The multi-compartment toxicokinetic model was able to simulate an independent set of published 3-OHBaP urinary profiles. This toxicokinetic compartmental model has proved useful for the determination of the main biological features of the kinetics of BaP and 3-OHBaP. Thereafter, a physiological pharmacokinetic model (PBPK) reproducing the fate of BaP and 3-OHBaP rats was built. Organs (or tissues) represented as compartments were selected based on experimental data obtained in vivo in rats. Partition coefficients, coefficients of permeability, biotransformation rates, excretion parameters, and absorption fraction for different exposure routes were obtained directly from the profiles of BaP and 3-OHBaP in blood, various tissues and excreta. The values of these parameters were calculated by Monte Carlo procedures. Sensitivity analyses were then performed to ensure the stability of the model and to determine the most sensitive parameters. This modeling has identified the following features: 1) a high sensitivity of hepatic metabolism and elimination rates of BaP and 3-OHBaP; 2) a large distribution of BaP in the lungs compared to other tissues; 3) a considerable distribution of BaP in adipose tissues and liver; 4) a significant distribution of 3-OHBaP in the kidneys; 5) a diffusion-limited transfer of BaP in the lungs, 6) a diffusion-limited transfer of 3-OHBaP in lungs, adipose tissues and kidneys; and 7) a significant entero-hepatic recycling of 3-OHBaP. Following a series of analysis of goodness of fit, the probabilites that the model simulations reproduced the experimental data due to pure chance were always below 10%, for the four routes of exposure: intravenous, oral, dermal and respiratory. Subsequently, we have extrapolated the kinetic models from rats to humans in order reproduce the temporal evolution of 3-OHBaP biomarker of exposure in the urine of workers occupationally expose. Results of these models were then compared to simulations obtained with a single compartment toxicokinetic model to verify the comparative usefulness of simple and complex model. Both types of models have been constructed from blood, tissue, urinary and faecal profiles of BaP and 3-OHBaP in rats. These data were obtained in vivo by intravenous, subcutaneous, oral and respiratory exposure. The models were extrapolated to humans taking into account the essential biological determinants of kinetic differences between rats and humans. Results showed that inhalation was not the primary route of exposure for many workers studied. The values of air concentrations of BaP used to simulate the urinary excretion profiles were different from those measured in the air. Dermal exposure to BaP seemed to better predict the temporal patterns observed. Finally, the two types of modeling have been proved useful to reproduce and to interpret experimental data obtained in workers.

碩士<br>國立中正大學<br>化學研究所<br>90<br>The low-lying triplet states of 10-hydroxybenzo[h]quinoline (HBQ) and its halogenated derivatives 7,9-diiodo-10-hydroxybenzo[h]quinoline (DIHBQ) in an excited-state intramolecular proton transfer (ESIPT) process have been investigated. For DIHBQ, enhanced by the intramolecular heavy atom effect, the proton-transfer tautomer (i.e. the keto form) phosphorescence maximized at 735 nm (p = 1.75 s) was resolved in a 77 K methylcyclohexane (MCH) glass. Further transient absorption and 1O2 sensitization experiments deduce the population yield and radiative decay rate of the keto triplet-state to be 0.85 and 8.8 s-1, respectively. Upon increasing the excitation intensity, photolysis reactions were observed for both HBQ and DIHBQ in the MCH glass. The reversibility of the photolysis reaction throughout a thawing-and-freezing cycle led us to conclude the rupture of an intramolecular hydrogen bond through the excessive energy dissipated. The product exhibits a non-hydrogen-bonding type of enol emission that would otherwise be inaccessible in the hydrogen-bonded enol form due to the ultrafast ESIPT. Accordingly, relative energy levels in different spin manifolds are established during a proton-transfer cycle. The keto  enol reverse proton transfer in the lowest triplet manifold was estimated to be endergonic by ~ 7.42 kcal/mol. Photothermal methods, e.g. time-resolved thermal lensing (TRTL) and photoacoustic methods, are powerful techniques to study nonradiative but also radiative process, and are exactly complementary to conventional optical methods. The TRTL method enables us to instantaneously measure the heat released by nonradiative deactivation processes of photoexcited transient species such as excited singlets ,tripets,isomers, and radicals,providing energetic and kinetic information with hight sensitivity and accuracy of calorimetry. In the work,we had used time-resolved thermal lensing successfully to determine the lifetime of singlet oxygen (1Δg) and Φisc in the various solvents produced by energy transfer from 1-H-phenalen-1-one (PH).