Дисертації з теми "Organic development strategies"

L'objectiu principal d'aquesta tesi és el desenvolupament de noves estratègies sintètiques que aprofitin la irradiació amb llum visible. La catàlisi fotoredox en combinació amb catalitzadors orgànics i metàl·lics, així com la fotoquímica dels complexos pi-aniò, seran els principals conceptes emprats per explorar noves vies de reacció. Després d’una introducció general, es recullen tres projectes de recerca en aquesta tesi. El primer projecte de recerca, inclòs al capítol II, mostra el desenvolupament d’una metodologia per a l’acoblament asimètric deshidrogenatiu creuat d’aldehids i xantens. La característica clau d’aquest enfocament es troba en el procés de dos passos emprat per oxidar els xantens als carbocations corresponents, que seran atrapats per una enamina formada in situ. La suavitat i selectivitat que permet la catàlisi fotoredox permet assolir alts nivells d’estereocontrol, bons rendiments i una àmplia tolerància de grup funcionals. El segon projecte, que es mostra al capítol III, il·lustra una nova estratègia fotoredox per a la síntesi d’una àmplia gamma d’amines i èters al·lílics a partir d’àcids i alquins carboxílics. Aquesta aproximació es basa en l’activació d’alquins terminals mitjançant la fotoexcitació d’intermedis d’acetilur de coure formats in situ. Aquest procés té lloc mitjançant catàlisi cooperativa de coure i fotoredox orgànica i es pot dur a terme de manera estereodivergent. La metodologia desenvolupada s’ha aplicat a l’acoblament estereoselectiu de radicals alquils primaris, secundaris i terciaris amb alquins terminals (hetero)aromàtics. Finalment, les interaccions anió-pi s’han identificat com el pas habilitant per a l’amidació de sistemes aromàtics promoguda per llum. Les proves disponibles indiquen que es produeix un complex anió entre un carbonat i una ariloxi amida pobra en electrons, permetent l'absorció de llum visible. Després de la irradiació, es produeix una transferència espontània d’electrons intracomplex, que condueix finalment a la generació de radicals amidil. Aquests radicals han estat atrapats eficientment per (hetero)arens rics en electrons o de manera intramolecular, proporcionant els corresponents productes amidats.
El principal objetivo de esta tesis es el desarrollo de nuevas estrategias sintéticas que aprovechen la irradiación con luz visible. La catálisis fotoredox en combinación con catalizadores órganicos y metálicos, así como la fotoquímica de complejos pi-anión, serán los conceptos principales que permitirán explorar nuevas vías de reacción. Tras una introducción general, en esta tesis se recogen tres proyectos de investigación. El primer proyecto de investigación, incluido en el Capítulo II, muestra el desarrollo de una metodología para el acoplamiento cruzado deshidrogenativo asimétrico de aldehídos y xantenos. La característica clave de esta aproximación se encuentra en el proceso de dos pasos empleado para oxidar los xantenos a sus correspondientes carbocationes, posteriormente atrapados por una enamina formada in situ. La suavidad y selectividad que permite la catálisis fotoredox permite alcanzar altos niveles de estereocontrol, buenos rendimientos y una amplia tolerancia de grupos funcionales. El segundo proyecto, que se muestra en el Capítulo III, ilustra una nueva estrategia fotoredox para la síntesis de una amplia gama de aminas alílicas y éteres a partir de ácidos carboxílicos y alquinos. Este enfoque se basa en la activación de alquinos terminales a través de la fotoexcitación de intermedios de acetiluro de cobre formados transitoriamente. Este proceso se lleva a cabo mediante catálisis cooperativa de cobre y un catalizador orgánico fotoredox y se puede realizar de manera estereodivergente. La metodología desarrollada se ha aplicado al acoplamiento estereoselectivo de radicales alquilo primarios, secundarios y terciarios con alquinos terminales (hetero)aromáticos. Finalmente, las interacciones anión-pi se han identificado como el paso habilitador en la amidación de sistemas aromáticos promovida por la luz. La evidencia disponible indica que se produce un complejo anión-pi entre el carbonato y una ariloxi amida pobre en electrones, lo que facilita la absorción de la luz visible. Tras la irradiación, tiene lugar una transferencia de electrones intracomplejo espontánea, que conduce finalmente a la generación de radicales amidilo. Estos radicales han sido atrapados eficazmente por (hetero)arenos ricos en electrones o de forma intramolecular, proporcionando los correspondientes productos amidados.
The main goal of this thesis is the development of new synthetic strategies harnessing visible light irradiation. Cooperative organo- and metal photoredox catalysis, as well as anion-pi complexes photochemistry, will be the main concepts exploited to explore new reaction pathways. After a general introduction, three research projects are collected in this thesis. The first research project, included in Chapter II, shows the development of a methodology for the asymmetric cross-dehydrogenative coupling of aldehydes and xanthenes. The key feature of this approach stands in the two-step process employed to oxidize xanthenes to their corresponding carbocations, subsequently trapped by an in situ formed enamine. The mildness and selectivity enabled by photoredox catalysis allows to reach high levels of stereocontrol, good yields and wide functional group tolerance. The second project, shown in Chapter III, illustrates a novel photoredox strategy for the synthesis of a wide range of allylic amines and ethers from carboxylic acids and alkynes. This approach relies on the activation of terminal alkynes through the photoexcitation of transiently formed copper acetylide intermediates. This process takes place through cooperative copper and organic photoredox catalysis and can be carried out in stereodivergent manner. The developed methodology has been applied to the stereoselective coupling of primary, secondary and tertiary alkyl radicals with (hetero)aromatic terminal alkynes. Finally, anion–pi interactions have been identified as the enabling step in the light-promoted amidation of aromatic systems. The available evidence indicates that an anion pi-complex between carbonate and an electron-poor aryloxy amide is elicited, facilitating the absorption of visible light. Upon irradiation, a spontaneous intracomplex electron transfer takes place, leading ultimately to the generation of amidyl radicals. These radicals have been efficiently trapped by electron-rich (hetero)arenes or in an intramolecular fashion, affording the corresponding amidated products.

The aim of this thesis was to identify and develop anti-neuroblastoma agents via two strategies. The first involves a targeted therapy approach towards the synthesis of new drug-like PTP inhibitors (Chapter 2 and 3) and the second involved devising a new versatile synthetic route to the recently established anti-tumour natural-product lead, methyl jasmonates and its analogues (Chapter 4). From a unique proprietary screening library of 5000 drug-like compounds targeted towards PTPs, three compounds from two distinct chemical series, tetrahydroquinolines P00104 and P00341, and thiobarbituric acid P00337, were identified as PTPN22 inhibitors (IC50 = 5 μM) with moderate potency in vitro. A synthetic route to each chemical series was established and optimised and the procedure was used to synthesize a series of rationally-designed analogues for detailed structure-activity relationship (SAR) studies. The compounds were tested for PTP inhibitory activity against PTPN22 via two experimentally optimised protein assays and were tested for cytotoxicity in a number of neuroblastoma cell lines. However, none of the compounds including the resynthesized hits displayed any promising biological activity, and further investigation on these chemical series was abandoned and another strategy for developing anti-neuroblastoma agents was pursued. During the last decade, many studies have reported the cytotoxic effects of methyl jasmonate, a plant stress hormone, against various tumours both in vitro and in vivo. As the research on the anti-tumour properties of methyl jasmonate is still at early stages, and also due to the lack of a versatile synthetic procedure for the preparation of its structural derivatives, detailed SAR studies of this compound have not yet been conducted. In the course of this project, a novel versatile synthetic route to methyl jasmonate and its analogues has been developed, which allows substituents to be readily introduced at the α- and β-position of cyclopentenone. This synthetic procedure will facilitate future extensive SAR studies of methyl jasmonate in tumour cells. The cytotoxic activity of the synthesized methyl jasmonate was confirmed against a range of neuroblastoma cell lines including SK-N-SH, SHSY5Y, LAN5 and the Kelly cells, and a further study on the mechanism by which methyl jasmonate induces neuroblastoma cell death is currently underway.

The importance of scientific analyses on artworks has become more and more crucial in the articulate processes of conservation and restoration. Moreover, the complexity of artistic materials, composed by organic and inorganic substances mixed together and often aged, requires extremely sensitive but user-friendly analytical tools. For this reason, the request of effective non-invasive diagnostic techniques is steadily increasing. In particular, a challenging task is represented by organic compounds, which can be found in the artistic field with a wide range of applications: they are binders used to spread pigments in paintings, varnishes, coatings and adhesives applied by the artist himself or during the restoration works, and colouring substances. Among the latter two different typologies can be individuated, namely natural dyes, used from the antiquity to dye textiles and in paintings in form of lakes, and a quite recent family of pigments, the synthetic organic ones. The detection of such materials can be hardly achieved by the non-invasive and in-situ appliable analytical techniques commonly employed in the field of conservation science. Briefly, X-ray fluorescence cannot provide useful information as it detects only elements with medium to high atomic number, while infrared and Raman spectroscopies are affected by the problem of fluorescence emission and of the matrix interference respectively. This Ph.D. thesis work was intended to develop innovative strategies based on molecular spectroscopies, pursuing the objective of non-invasively identifying the most common organic materials which can be found in museum objects, mainly focusing the attention on paintings (binders and synthetic organic pigments) and ancient textiles (natural dyes). In particular, spectrofluorimetry was proposed for the identification of synthetic organic pigments, a quite recent category of colourants since they were introduced by Perkin in the second half of the 19th century. The fluorescence emission upon visible excitation exhibited by several organic pigments used in contemporary artworks was successfully demonstrated and an analytical approach combining visible-induced spectrofluorimetry and visible-reflectance spectroscopy with a multivariate processing of data was established. The effectiveness of the method was finally confirmed by its application to three contemporary paintings. In addition, the possibility of exploiting fluorescence emission induced by UV radiation was considered, as well as the prospect of investigating such materials by ultraviolet fluorescence (UVF), visible and infrared luminescence (VIVF and VIL) images. The use of near-infrared (NIR) spectroscopy was proposed for the detection of organic binders and to understand the complex stratigraphy in paintings. This spectral region, in particular in the range 6500-4000 cm-1, is dominated by combination and overtone bands due to functional groups typical of the lipidic and proteinaceous materials used as binding media, therefore it can be exploited for identification purposes. Moreover, it was demonstrated that the greater penetration depth of the NIR radiation in comparison with the mid-infrared (MIR) one allows the investigation of the preparatory layers possibly applied by the artist on the painting support. In this respect, an exhaustive study was carried out at first on a consistent number of reference mock-up samples, prepared on the basis of ancient recipes, and then on eight paintings, dating from the end of the 15th century to the end of the 18th century and exemplifying different artistic techniques on different supports. Finally, the main part of the work was dedicated to surface-enhanced Raman spectroscopy (SERS) for the identification of natural dyes in textiles. This technique, which exploits the strong intensification by several orders of magnitude of the Raman scattering of organic molecules in the proximity of metal nanoparticles and nanostructured surfaces, is a well-established method for the detection of dyes, but generally requires the extraction of the target analyte from a sample. Many experiments were performed therefore performed to develop SERS-sensors suitable for performing measurements directly from dyed fibres in dry-state condition, i.e without requiring extraction protocols or the placement of a wet substrate in contact with the artefact. In this respect, a general, easy-to-apply protocol involving the deposition of colloidal nanoparticles on glass supports was developed. The importance of hot spots, areas of strong SERS intensification of the Raman signal formed between close nanoparticles or on anisotropic structures rich in tips, leads to experiment different aggregation procedures and nanoparticle shapes, ranging from nanospheres to nanostars and nanorods. The final aim was to create reproducible and homogeneous sensors, able to provide a high SERS enhancement when just put in contact in dry-state conditions with the artistic object under investigation. In this respect silver was demonstrated to be the best metal in comparison with gold and the most effective substrates, allowing the identification of four historical dyes from dyed wool yarn, were those obtained from silver nanostars. Finally, also some related issues are faced, such as the release of metal on the sample and the cleaning of the substrate surface exploiting the photochemical properties of titanium dioxide.

The project reported here took place in Messara plain, Crete, Greece, a semi-arid Mediterranean region. It involved a literature review (Chapter 1), a field survey (Chapter 2), two field experiments (Chapters 3 and Chapter 4) and associated laboratory analyses. The survey took place in three crop years using pairs of neighbouring organic and conventional commercial olive orchards of the cultivar Koroneiki at the valley and the surrounding hills. Both field experiments took place in a 2.4 ha table olive orchard consisted of trees of Kalamon and Manzanila olive cultivars for three crop years. Results from the field survey (Chapter 2) indicate that organic olive oil production systems developed in the Messara plain can produce the same or higher yields of oil than conventional production in the same area. Although olive oil produced from both systems is of similar quality, slightly but significantly higher levels of acidity were detected in organic olive oil. Pesticide contamination was identified as a problem in both organic and conventional production with endosulphan sulphate being the main pesticide residue. This will have to be resolved to preserve the reputation of the region for high quality oil production. Improvement in cover cropping was the main target in the 1st field experiment (Chapter 3). There were few significant effects of cover crops/cover crop mixtures on nutrient availability, invertebrate activity, and yield parameters. Rhizobium inoculation had a negative effect on Vicia sativa establishment but did not affect any of the nodulation parameters assessed. The highest levels of Hymenoptera activity were found in the cover crop mixture consisting of vetch, peas and barley. Also, the non-inoculated vetch and the cover crop mixture reduced the concentrations of olive leaf boron. The development of improved olive fruit fly management strategies was the main target in the 2nd field experiment (Chapter 4). Wind direction, humidity, rainfall and temperature were identified as important potential environmental drivers for olive fly pest pressure in the Messara region. Also, results indicate that soil survival is probably not an important over-wintering mechanism for the olive fly in the Messara plain and other semiarid Mediterranean regions. The two mass trapping systems compared differ significantly with respect to number of non-target invertebrates killed, but caught similar numbers of olive fruit flies. Results also indicated that the dates for placing mass-traps into orchard may need to be revised and related to the drivers of olive fly pressure.

The goal of our research endeavor was to successfully employ modern lead discovery and optimization strategies towards the development and identification of compounds possessing antimalarial activity. Preliminary data from in vitro screening at the Walter Reed Army Institute of Research identified several chemotypes including 4(1H)-quinolones and 1,2,3,4-tetrahydroacridones to have potent antimalarial activities. Multiple synthetic routes were devised and implemented which enabled the rapid preparation and isolation of over 400 structurally diverse 4(1H)-quinolones and 1,2,3,4-tetrahydroacridones. Our research towards discovering and optimizing antimalarials was inspired from the severe impact malaria has had on our planet especially on impoverished countries. There are over 300 million cases annually and over one million deaths. The staggering mortality rates combined with the global emergence of chemical resistance that the parasite Plasmodium falciparum has developed towards many of the common antimalarials compelled us to extend our research efforts to this growing problem. The need for identifying and developing new antimalarial drugs is very important. However, our approach focuses on the optimization of historic antimalarials such as endochin, floxacrine, or ICI 56,780 which possess liabilities such as lack of poor solubility, poor in vivo activity or lingering toxicity issues. Through these optimization efforts using both SAR and structure-property relationship (SPR) studies, a more suitable candidate was developed that had superior physicochemical properties. Our drug design approach included not only the identification of liabilities of historic compounds but also the synthesis and optimization of numerous analogs guided by SAR. All compounds were tested in vitro for antimalarial activity and characterized in parallel for physicochemical properties such as solubility, permeability, and logD7.4. Insights from both the antimalarial activity as well as the physicochemical properties determined which analogs would be advanced in the design process. Based on our early investigations, 6-chloro-7-methoxy-3-phenyl-4(1H)-quinolone emerged as a promising hit. Compared to endochin, which possesses EC50s of 8.6 nM and 46.6 nM against drug resistant strains W2 and TM90C2B, and a solubility of less than 2 µM, 6-chloro-7-methoxy-3-pheny-4(1H)-quinolone was superior with a 4-fold improvement in solubility (6 µM) as well as slightly improved antimalarial activity (EC50s of 26.2 nM and 15.3 nM against W2 and TM90C2B, respectively). Unfortunately, this compound failed to reduce parasitemia levels in P. berghei infected mice. Hit-to-lead optimization lead to the discovery of 6-chloro-7-methoxy-2-methyl-3-o-tolyl-4(1H)-quinolone which was shown to reduce parasitemia levels by 41% at day 6 post-exposure (PE) in P. berghei infected mice at a 50 mg/kg dose. The observed in vivo activity of 6-chloro-7-methoxy-2-methyl-3-o-tolyl-4(1H)-quinolone was believed to relate to the 3-fold increase in solubility (19 µM) over the 3-phenyl-susbtituted analogue. Continuation of SAR and SPR studies identified additional 4(1H)-quinolones suggesting that the microsomal stability of the compounds is as important for in vivo efficacy as the aqueous solubility. Several of the analogs that showed minimal degradation in human microsomal stability studies demonstrated increased in vivo activity in the ranges of 72-98% parasitemia reductions on day 6PE in P. berghei infected mice at 50 mg/kg. These results helped refine the final SAR and SPR optimization identifying a compound with radical curative activity in mice (99% parasitemia reductions on day 6PE in P. berghei infected mice at 50 mg/kg with five out of five mice surviving beyond 30 days). Theses studies not only highlight the effectiveness of detailed SAR and SPR strategies used in drug discovery programs, but they also showcase the importance of re-evaluating historic antimalarials and exploiting their shortcomings. These studies have opened the doors to several possibilities regarding the 4(1H)-quinolone scaffold optimization for future antimalarial development. Several of the compounds described in this work are currently being subjected to stringent head-to-head comparative studies to determine the analog best suited for pre-clinical trials.

Nucleic acid biosensors represent a powerful tool for clinical and environmental pathogens detection. For applications such as point-of-care biosensing, it is fundamental to develop sensors that should be automatic, inexpensive, portable and require a professional skill of the user that should be as low as possible. With the goal of determining the presence of pathogens when present in very small amount, such as for the screening of pathogens in drinking water, an amplification step must be implemented. Often this type of determinations should be performed with simple, automatic and inexpensive hardware: the use of a chemical (or nanotechnological) isothermal solution would be desirable. My Ph.D. project focused on the study and on the testing of four isothermal reactions which can be used to amplify the nucleic acid analyte before the binding event on the surface sensor or to amplify the signal after that the hybridization event with the probe. Recombinase polymerase amplification (RPA) and ligation-mediated rolling circle amplification (L-RCA) were investigated as methods for DNA and RNA amplification. Hybridization chain reaction (HCR) and Terminal deoxynucleotidil transferase-mediated amplification were investigated as strategies to achieve the enhancement of the signal after the surface hybridization event between target and probe. In conclusion, it can be said that only a small subset of the biochemical strategies that are proved to work in solution towards the amplification of nucleic acids does truly work in the context of amplifying the signal of a detection system for pathogens. Amongst those tested during my Ph.D. activity, recombinase polymerase amplification seems the best candidate for a useful implementation in diagnostic or environmental applications.

Nucleic acid biosensors represent a powerful tool for clinical and environmental pathogens detection. For applications such as point-of-care biosensing, it is fundamental to develop sensors that should be automatic, inexpensive, portable and require a professional skill of the user that should be as low as possible. With the goal of determining the presence of pathogens when present in very small amount, such as for the screening of pathogens in drinking water, an amplification step must be implemented. Often this type of determinations should be performed with simple, automatic and inexpensive hardware: the use of a chemical (or nanotechnological) isothermal solution would be desirable. My Ph.D. project focused on the study and on the testing of four isothermal reactions which can be used to amplify the nucleic acid analyte before the binding event on the surface sensor or to amplify the signal after that the hybridization event with the probe. Recombinase polymerase amplification (RPA) and ligation-mediated rolling circle amplification (L-RCA) were investigated as methods for DNA and RNA amplification. Hybridization chain reaction (HCR) and Terminal deoxynucleotidil transferase-mediated amplification were investigated as strategies to achieve the enhancement of the signal after the surface hybridization event between target and probe. In conclusion, it can be said that only a small subset of the biochemical strategies that are proved to work in solution towards the amplification of nucleic acids does truly work in the context of amplifying the signal of a detection system for pathogens. Amongst those tested during my Ph.D. activity, recombinase polymerase amplification seems the best candidate for a useful implementation in diagnostic or environmental applications.

Organic chemistry has seen a tremendous growth over the past decades and nowadays it is routinely used for a variety of applications in countless fields. Nevertheless, a major concern that is hindering its development is the negative impact that organic synthetic methodologies may have on the environment. Therefore, great effort has been devoted to the development of novel efficient and sustainable synthetic approaches. In this scenario, catalysis has played a crucial role in the preparation of organic molecules as drugs, natural products, and agrochemicals to improve the greenness of a synthetic process. Although it moved its first steps in organic chemistry in the 18th century, catalysis is still considered a hot topic, especially because it stood out as a valuable and efficient tool to access economical, energy-saving, and sustainable chemical processes. The aim of this doctoral thesis is to devise and employ a variety of novel catalytic approaches as means to efficiently access relevant pharmacologically active molecules. With this aim in mind, we developed different methodologies to improve the sustainability of the proposed synthetic processes without sacrificing efficiency. A cascade cyclocarbopalladation of the readily available aryl/alkyl-substituted propargylic amides followed by Suzuki–Miyaura coupling with arylboronic acids or aminopalladation reacting with 2-alkynyltrifluoroacetanilides allowed an efficient regio- and stereoselective synthesis of dihydroisoquinolinones differently substituted. The usefulness of this cascade approach is determined by the high number of bonds formed in a single synthetic step, that leads to the increased structural complexity of desired products and to the improvement of the greenness of the whole process, avoiding numerous subsequent purification steps and reducing wastes. Then, a novel metal-free protocol to perform N-alkylation reactions of a wide variety of amine substrates was developed. This mild boron Lewis acid-catalysed synthetic methodology gives access to a broad range of pharmacologically appealing N-alkylated products in good to excellent yields. Moreover, a fruitful collaboration between Dr Melen’s and Prof. Dr Carlone’s groups was established to develop convenient methods for the quick construction of chiral boron Lewis acids. With this purpose, the synthesis of several chiral ligands was carried out to pave the way to a novel asymmetric metal-free approach. Exploiting organocatalysis as greener catalytic strategy, a novel and safe reaction protocol for the enantioselective enamine-catalysed addition of acetaldehyde to nitroalkenes was performed. This protocol makes use of a safe masked acetaldehyde to access important intermediates to Active Pharmaceutical Ingredients (APIs) improving the industrial feasibility of the entire process. Using water as a reaction medium allows us to further improve this synthetic protocol. Crucial to the success of this approach was the application of chemometrics-assisted ‘Design of Experiments’ (DoE) optimisation during the development of the presented approach. DoE allows to investigate the chemical space in a rational way, reducing the number of the experiments. Moreover, a library of phosphoric acids was synthesised to develop an organocatalysed eco-friendly approach to the enantioselective cyclobutane-containing molecules preparation. An efficient alternative protocol for the synthesis of a valuable API precursor developed in collaboration with the pharmaceutical industry Dipharma is also reported. We designed and developed an alternative approach to improve the well-established methodology by limiting the waste production as much as possible exploiting immobilised catalysts. The last catalytic methodology investigated is a combination of the previous ones, known as synergistic catalysis. A critical review about current and past literature is reported.

The impact of monoclonal antibodies (mAbs) in current pharmaceutical research is due to their unique ability to bind biological targets with very high affinity. On the other hand, there is a considerable interest in the development of small molecule ligands with antibody-like affinities, which may overcome some limitations of mAbs. This PhD work describes the development of general strategies to increase the binding affinity of peptide ligands bearing the Arg-Gly-Asp motif, i.e. the well-known recognition sequence of specific tumor-associated integrin receptors. In our first approach, we designed a bicyclic peptide bearing two RGD motifs that displayed an enhanced inhibition of ECM protein binding to integrin receptors αvβ3 and α5β1 and marked biological effects in U-373 MG glioblastoma cells. Later on, we focused on the 2-hydroxybenzaldehyde tag (2HB), which can engage ϵ‐amino groups of Lys residues in stable imines. After investigating the 2HB installation to different types of reactive handles, we conjugated the 2HB tag to the N-side and on the C-side of a cyclic RGD peptide. The resulting conjugates have been investigated as novel αvβ3 integrin ligands and the nature of the ligand-protein interaction has been investigated performing in silico experiments. For both the 2HB-RGD conjugates, the biological results and the computational outcomes demonstrated to be coherent with each other, proving the feasibility of the reversible covalent engagement of Lys residues with the 2HB tag to enhance the affinity of a well-known small ligand.

The amount of organic micropollutants (OMP) currently being released to the aquatic environment is incommensurable. Thus, different analytical strategies were developed over the recent years to monitor the occurrence of OMP in environmental samples. In this thesis, different tools have been applied to refine target, suspect and non-target screening strategies for the monitoring of the aquatic environment with special emphasis on the hyphenation of ion mobility separation (IMS) to high resolution mass spectrometry. Additionally, the development of refinement tools for suspect screening strategies such as retention time indexing or in silico prediction of IMS data, as well as the implementation of effect-directed analysis for a comprehensive overview of the quality of water bodies have also been explored. Finally, the monitoring of new psychoactive substances in complex matrices such as influent wastewater and pooled urine samples is evaluated, with special aid of the previously developed tools.
La cantidad de microcontaminantes orgánicos (OMP) emitidos al medio ambiente acuático en la actualidad es incalculable. Por ello, se han desarrollado distintas estrategias analíticas para monitorizar la incidencia de OMP en muestras ambientales. En esta tesis se han aplicado diferentes herramientas para refinar estrategias de cribado dirigidas, de sospechosos y no dirigidas para la monitorización del medio ambiente acuático con especial énfasis en el acoplamiento de la separación por movilidad iónica (IMS) con espectrometría de masas de alta resolución. Adicionalmente, se ha explorado el desarrollo de herramientas de mejora para los cribados de sospechosos como, por ejemplo, indexación de tiempo de retención o predicción computacional de datos de IMS, así como la implementación de análisis basados en efecto (EDA) para una visión completa de la calidad de los cuerpos acuáticos. Finalmente, se ha evaluado la monitorización de Nuevas Sustancias Psicoactivas (NPS) en muestras complejas tales como aguas residuales y orina.
Programa de Doctorat en Ciències

Urban stormwater runoff is recognised as a substantial source of heavy metal contamination, which adversely impacts on water quality of regional receiving waterways. Conventional treatment of urban runoff mostly involves a filtration system using sand to retain particulate matters. Sand provides limited sorption of dissolved metals and the inclusion of commercial sorbents to these treatment systems is not cost effective due to the concentration of dissolved metals in the runoff. Recycled organic materials are by-products or waste from industrial or agricultural operations, and could be alternative low cost sorbents for stormwater treatment systems. The use of recycled sorbents also provides added value to the waste materials and reduces landfill disposal. The research explores the application of compost, zeolite, ash, and recyclable waste in urban runoff treatment, especially for dissolved metal removal. The research combines the two aspects of experimental studies and management analysis to develop a holistic approach to heavy metal control in urban stormwater systems. Experimental results of batch sorption test show that compost is suitable for removing dissolve copper in stormwater treatment. The comparison of the different mixing ratios between compost and glass beads in column test evaluates the optimum mixing sorbent and performance over a long period for copper removal. Substance Flow Analysis (SFA) of copper has been performed in the Upper Parramatta River Catchment, Sydney to identify the sources of copper associated with runoff, effect of using waste material such as compost in urban stormwater treatment and the copper load in urban stormwater runoff. This case study shows the relationship between copper input, copper stock, sorbent type and urban stormwater quality control in the system boundary of the catchment. Different scenarios of source control are evaluated to control copper load from the different sources. Source control focusing on roads and vehicles is the most effective copper control strategy. The combination of source control and stormwater treatment reduces copper in stormwater and receiving water. The thesis applies the analysis from SFA and experimental results to derive both a regional system-wide solution with source control, and an improved design of stormwater treatment for heavy metal removal using recycled organics.

This thesis explores how to overcome barriers to growing food in yards in cities of North America’s Pacific Northwest Coastal Region, to help build towards a more sustainable society. We used a survey and interviews to investigate what barriers prevent people with access to yards from growing food, or prevent them from increasing the amount of food grown in their yards, and how these barriers can be overcome. We also collected data to determine the resource inputs and production and/or financial outputs for three groups of people involved with growing food in yards: Do-it-yourself gardeners, Consultants involved with designing and implementing food gardens, and Commercial Urban Farmers. This allowed us to gain a better understanding of the current reality and identify what role these groups can play in helping to overcome the barriers. Based on our results, we made a list of recommended actions that are tangible, move in the right direction towards sustainability, can act as stepping stones for future improvements, and could provide a positive return on investment, in order to help individuals with access to yards who are interested in growing food overcome the barriers facing them.

Environmental protection is one of the greatest themes of the XXI century. For what concerns chemistry, in the early 1990’s, even before its current formal and exhaustive definition, given by Paul T. Anastas and John C. Warner in 1998, the term "green chemistry" starts to appear in the literature. Anastas and Warner formulated a list of 12 principles, that constitute the most complete definition of green chemistry. Herein, an effort towards the fulfillment of these principles is presented with respect to: 1) the development of a catalytic system based on hydrate ferric sulfate for the hydration of internal alkynes; 2) an approach to the synthesis of a new family of chiral phosphates for organocatalysis.

Wine With a View is a Portuguese startup company, which sells wine by the glass at tourist attractions in the metropolitan area of Lisbon. Due to the local popularity and estimated potential of other locations, the management is striving to grow the business. For this purpose, an individual framework of growth strategies was developed. A scoring model, based on carefully selected criteria to determine the fit of strategies with company resources, concluded in the recommendation of a product line extension and an organic, domestic expansion strategy, while franchising was determined not to be a feasible option in the near future.

碩士
國立交通大學
經營管理研究所
90
OLED is the organic light-emitting diode. It is a new generation display. The OLED display needs no backlight, thus, can be thinner and lighter than a liquid-crystal display, and has a wider viewing angle and temperature range and a speedier response to boot. Therefore, OLEDs have lower materials content, less capital-cost potential and fewer process steps than an LCD. After an amazing short period of applied research and development, commercial activity in the OLED display world is now exploding. Nowadays, there are many technology companies targeting the same market segment with OLEDs and are poised to do quite a strong battle in taiwan. However, the organic light-emitting diode forms of display still have obstacles to overcome before it’s popularity and even more importantly, its reliability are up to par with standards expected by consumers. Besides, OLED’s marketing strategic analysis of the emerging OLED industry in Taiwan should be analyzed and researched. By visiting companies, interviewing experts and collecting industry reports, applying Michael E. Porter’s「Diamond model」and「SWOT analysis」, this paper idendified key success Factors of OLED epi-wafer manufacturers in taiwan. According to these factors, the competitiveness of OLED’s industry is comparing Taiwan with Korea and Japan. Finally, this paper provide suggestions for the future direction of epi-wafer manufactures in taiwan.

The objective of this research was to develop fluorescence-based tools that are suitable for performing rapid, accurate and direct characterization of natural organic matter (NOM) and colloidal/particulate substances present in natural water. Most available characterization methods are neither suitable for characterizing all the major NOM fractions such as protein-, humic acid-, fulvic acid- and polysaccharide-like substances as well as colloidal/particulate matter present in natural water nor are they suitable for rapid analyses. The individual and combined contributions of these NOM fractions and colloidal/particulate matter present in natural water contribute to membrane fouling, disinfection by-products formation and undesirable biological growth in drinking water treatment processes and distribution systems. The novel techniques developed in this research therefore, provide an avenue for improved understanding of these negative effects and proactive implementation of control and/or optimization strategies. The fluorescence excitation-emission matrix (EEM) method was used for characterization of NOM and colloidal/particulate matter present in water. Unlike most NOM and colloidal/particulate matter characterization techniques, this method can provide fast and consistent analyses with high instrumental sensitivity. The feasibility of using this method for monitoring NOM at very low concentration levels was also demonstrated with an emphasis on optimizing the instrument parameters necessary to obtain reproducible fluorescence signals. Partial least squares regression (PLS) was used to develop calibration models by correlating the fluorescence EEM intensities of water samples that contained surrogate NOM fractions with their corresponding dissolved organic carbon (DOC) concentrations. These fluorescence-based calibration models were found to be suitable for identifying/monitoring the extent of the relative changes that occur in different NOM fractions and the interactions between polysaccharide- and protein-like NOM in water treatment processes and distribution systems. Principal component analysis (PCA) of fluorescence EEMs was identified as a viable tool for monitoring the performance of biological filtration as a pre-treatment step, as well as ultrafiltration (UF) and nanofiltration (NF) membrane systems. The principal components (PCs) extracted in this approach were related to the major membrane foulant groups such as humic substances (HS), protein-like and colloidal/particulate matter in natural water. The PC score plots generated using the fluorescence EEMs obtained after just one hour of UF or NF operation could be related to high fouling events likely caused by elevated levels of colloidal/particulate-like material in the biofilter effluents. This fluorescence EEM-based PCA approach was sensitive enough to be used at low organic carbon levels present in NF permeate and has potential as an early detection method to identify high fouling events, allowing appropriate operational countermeasures to be taken. This fluorescence EEM-based PCA approach was also used to extract information relevant to reversible and irreversible membrane fouling behaviour in a bench-scale flat sheet cross flow UF process consisting of cycles of permeation and back-washing. PC score-based analysis revealed that colloidal/particulate matter mostly contributed to reversible fouling, while HS and protein-like matter were largely responsible for irreversible fouling. This method therefore has potential for monitoring modes of membrane fouling in drinking water treatment applications. The above approach was further improved by utilizing the evolution of the PC scores over the filtration time and relating these to membrane fouling by the use of PC scores??? balanced-based differential equations. Using these equations the proposed fluorescence-based modeling approach was capable of forecasting UF fouling behaviours with good accuracy based solely on fluorescence data obtained at time = 15 min from the initiation of the filtration process. In addition, this approach was tested experimentally as a basis for optimization by modifying the UF back-washing times with the objective of minimizing energy consumption and maximizing water production. Preliminary optimization results demonstrated the potential of this approach to reduce power consumption by significant percentages. This approach was also useful for identifying the fouling components of the NOM that were contributing to reversible and irreversible membrane fouling. Grand River water (Southwestern Ontario, Canada) was used as the natural water source for developing the techniques presented in this thesis. Future research focusing on testing these methods for monitoring of membrane fouling and treatment processes in large-scale drinking water treatment facilities that experience different sources of raw water would be useful for identifying the limitation of these techniques and areas for improvements.

Il tema di ricerca dottorale è incentrato sullo studio della città "spontanea" e intende inserirsi nel filone di studi che, interpretando la città come un organismo complesso, impiegano il concetto di auto-organizzazione per spiegare le dinamiche dei processi socio-spaziali. L’oggetto dell'analisi è quindi lo studio dei contributi spontanei – ovvero svincolati da decisioni centralizzate – alla trasformazioni urbana. L'analisi è stata svolta approfondendo due casi studio: il quartiere innovativo di Oosterwold, Almere (Paesi Bassi) e l'area "site and service" di Charkop, Mumbai (India). The research topic is focused on the investigation of the “spontaneous” city. The thesis aims to give a contribution in the field of studies that lean on the concept of self-organization for the analysis and the interpretation and socio-spatial dynamics. The analysis of spontaneous contribution – i.e. actions that do not stem from centralized decisional processes – has been carried out in two case studies: the innovative neighborhood of Oosterwold, Almere (The Netherlands), and the site and service area in Charkop, Mumbai (India).