<p>Homogeneous palladium-catalyzed Heck vinylation of aryl chlorides was investigated under air using Herrmann’s palladacycle and the P(<i>t</i>-Bu)₃-liberating salt [(<i>t</i>-Bu)₃PH]BF₄. Based on the results, controlled microwave heating was utilized to accelerate model Heck reactions with aryl chlorides down to 30 min employing an electron-poor olefin and a mixture of an ionic liquid and 1,4-dioxane as solvent.</p><p>For the first time, a highly regioselective general protocol has been developed for palladium-catalyzed terminal (β-) arylation of acyclic vinyl ethers using inexpensive aryl chlorides as starting materials and the preligand [(<i>t</i>-Bu)₃PH]BF₄ as the key additive. This swift and straightforward protocol exploits non-inert conditions and controlled microwave heating to reduce handling and processing times, and aqueous DMF or environmentally friendly PEG-200 as the reaction medium. Somewhat higher selectivity for the linear β-product was observed in PEG-200. DFT calculations were performed at the B3LYP level of theory for the regioselectivity-determining insertion step in the Heck reaction following the neutral pathway. A series of <i>para</i>-substituted phenylpalladium(II) complexes was investigated in the computational study. The calculations support a ligand-driven selectivity rationale, where the electronic and steric influence of the bulky P(<i>t</i>-Bu)₃ ligand provides improved β-selectivity. The preparative methodology was used to synthesize the β-adrenergic blocking agent Betaxolol.</p><p>Highly stereoselective Pd(0)-catalyzed β-arylation and β-vinylation of a tetra-substituted cyclopentenyl ether have been accomplished using a chiral, pyrrolidine-based and substrate-bound palladium(II)-directing group under neutral reaction conditions. To the best of the author’s knowledge, this P(<i>t</i>-Bu)₃-mediated method represents the first examples of the successful utilization of aryl and vinyl chlorides in asymmetric Heck reactions. The Heck arylation products formed were hydrolyzed and isolated as the corresponding quaternary 2-aryl-2-methyl cyclopentanones in good to moderate two-step yields with excellent stereoselectivity (90-96% ee). Inclusion of vinyl triflates under neutral reaction conditions and one aryl triflate equipped with a strongly electron-withdrawing <i>para</i>-cyano substituent under cationic conditions increased the preparative usefulness of the methodology.</p><p>Furthermore, diastereoselective Heck arylation of both five- and six-membered cyclic vinyl ethers with aryl bromides, using the identical chiral auxiliary and suitable Pd sources, was performed. Arylated products from the tetra-substituted cyclopentenyl ether were also in this case hydrolyzed to the corresponding 2-aryl-2-methyl cyclopentanones with high to excellent enantioselectivity (85-94% ee). Despite low reaction rates and relatively modest yields, arylation reactions with the tri-substituted cyclohexenyl ether were found to be highly diastereoselective (94-98% de).</p><p>Thus, an attractive supplement to direct Pd(0)-catalyzed α-arylation protocols, particularly when the use of organic chlorides, aryl bromides, and milder reaction conditions are of great importance, have been developed.</p>

Gradient surfaces exhibit a variation in functionality along the length of the surface. One method for preparing gradients is controlled-rate infusion (CRI). In Part 1 of this work, CRI was used to prepare gradients for the purpose of separating transition and heavy metals. Initial work on this project was focused on controlling the retention of the metal ions by varying the number of amine groups, aminoalkoxysilane concentration, and the infusion time. The retention factors of four metal ions varied predictably with increasing number of amine groups, increasing aminoalkoxysilane concentration, and increasing infusion time, producing small but useful changes in the retention factors. The continuation of this project involved the preparation of two-dimensional multi-component gradients on TLC plates, which were used to separate six transition and heavy metals. The retention, and thus the separation, was affected by the presence or absence of a gradient and the direction of the gradient. Part 2 of this work focused on understanding the factors that motivated instructors in the early and late stages in the process of change. Instructors who attended the POGIL-PCL (Process-Oriented Guided Inquiry Learning in the Physical Chemistry Laboratory) workshops were asked to complete online surveys. The goals of the first survey were to understand the factors that initially interested instructors in POGIL-PCL, to determine if instructors enter the implementation stage, and to understand the factors that affect how instructors implement POGIL-PCL. Later surveys were designed to explore the development of the POGIL-PCL network and assess whether implementation is sustained over time.

Neste trabalho estudou-se a complexação do poli(acrilato de sódio), PAS, com aminpentacianoferrato de sódio,APCF. As reações de complexação ocorreram imediatamente com a formação de uma coloração amarela com total solubilização do polímero na solução 0,032 M molar do complexo. As soluções mostraram-se estáveis por 48 h e após esse período observou-se alterações na natureza do complexo polimérico com a formação de precipitado. O UV foi usado como ferramenta de caracterização do complexo. O máximo de absorção obtido após dissolução imediata foi de 405 nm com desvio para o azul (398 nm) e um pequeno efeito hipercrômico. As amostras mantidas à temperatura ambiente por mais de 48 h deram origem a precipitados, que como a solução, absorveram com máximo de 364, 389 e 398 nm. O Complexo PAS-APCF foi também caracterizado através de FTIR por ATR e apresentou pequenas variações no espectro do material de partida (PAS). Um incremento na intensidade da deformação axial assimétrica do grupo carboxilato (1651 cm-1) e a presença do estiramento em 2055 cm-1 do grupo cianeto, diferentemente do APCF (2048 cm-1), confirmaram a formação do complexo PAS-APCF. As freqüências de absorção observadas para o complexo foram compatíveis com a presença de estruturas mono e bidentadas de complexação. As análises de TGA e DSC também foram utilizadas para a caracterização das estruturas. O estudo modelo envolvendo a complexação de sais sódicos de diácidos orgânicos de diferentes tamanhos de cadeia (oxalato, malonato, succinato, glutarato e adipato), diferentemente do PAS, promoveu um desvio para o vermelho na frequência máxima de absorção junto de um pequeno efeito hipercrômico (421 nm). Esta variação pode também ser observada quando do emprego de acetato de sódio, indicando, provavelmente, apenas a formação de estruturas monodentadas / In this work we studied the complexation of poly (sodium acrylate), PAS, with sodium amminepentacyanoferrate, APCF. The complexation reactions occurred immediately with the formation of a yellow color with complete solubility of the polymer solution in 0.032 M molar complex. The solutions were stable for 48 h and after this period saw changes in the nature of the polymeric complex with the formation of precipitate. The spectrophotometry was used as a tool for characterization of the complex. The maximum absorption was obtained immediately after dissolution of 405 nm with a shift to the blue (398 nm) and a small hyperchromic effect. The samples kept at room temperature for more than 48 h resulted in precipitates that as the solution, absorbed with a maximum of 364, 389 and 398 nm. Complex PAS-APCF was also characterized by using FTIR and ATR spectra showed small variations in the starting material (PAS). An increase in the intensity of the asymmetric axial deformation of the carboxylate group (1651 cm-1) and the stretch at 2055 cm-1 group cyanide, unlike APCF (2048 cm-1), confirmed the formation of the PAS-APCF. The absorption frequencies observed for the complex were consistent with the presence of mono and bidentate complexation. The TGA and DSC were also used to characterize the structures. The study model involving the complexation of sodium salts of organic diacids of different chain sizes (oxalate, malonate, succinate, glutarate and adipate), unlike PAS, held a red shift in the frequency of maximum absorption with a small effect hyperchromic (421 nm). This variation may also be observed when employing sodium acetate, indicating probably the formation of only monodentate structures

La maladie d'Alzheimer est une maladie neurodégénérative, touchant plus de 30 millions de personnes dans le monde. A ce jour, seules des thérapies symptomatiques sont disponibles ; aucun traitement curatif n'existe. Une des hypothèses concernant cette maladie propose une mauvaise régulation des quantités en ions métalliques, notamment les ions Cu et Zn, dans certaines zones du cerveau. Ils favoriseraient une accumulation de peptides appelés Amyloïdes-ß (Aß) dans les fentes synaptiques. Ces dépôts empêcheraient les connexions neuronales, entrainant les symptômes connus de la maladie, tels que la perte de mémoire ou les déficiences intellectuelles. Les ions Cu seraient également responsables d'un stress oxydant incontrôlé, dégradant entre autres les membranes neuronales. Les ions Cu sont donc une cible thérapeutique à privilégier. Les recherches se dirigent vers le développement de nouvelles molécules, dites chélateurs, en vue d'extraire sélectivement ces ions Cu (par rapport aux ions Zn), pour réguler leur quantité et limiter voire empêcher cette accumulation de peptides. Mon projet de recherche se place précisément dans ce contexte. Différents chélateurs des ions Cu(II) et Cu(I) sont étudiés, en présence ou non de Zn(II), pour comprendre les paramètres à prendre en compte pour le développement de chélateurs efficaces. La première partie de cette étude regroupe différentes preuves de concept concernant les chélateurs des ions Cu. L'aspect cinétique du retrait du Cu(II) du peptide Aß par un chélateur est étudié grâce à des ligands macrocycliques. Ensuite, l'état d'oxydation des ions Cu dans les fentes synaptique n'étant pas connu à ce jour, deux chélateurs du Cu(I) ou du Cu(I/II) sont proposés. La seconde partie de l'étude prend en compte l'impact du Zn(II) dans la chélation des ions Cu. Le côté thermodynamique de la chélation du Cu en présence de Zn(II) est mis en évidence grâce à différents chélateurs aux caractéristiques différentes. / Alzheimer's disease is a neurodegenerative disease, affecting more than 30 million people all over the world. Nowadays, only symptomatic therapies exist, there is no cure yet. A dyshomeostasis of metal ions such as Cu and Zn ions in some areas of the brain is one of the different hypothesis about this disease. They would promote an accumulation of peptides, the Amyloid-ß (Aß) peptides, in the synaptic cleft. These aggregates would prevent the neuronal connections, triggering known symptoms of the disease, such as memory loss or cognitive impairments. Cu ions would also be responsible for an important oxidative stress, destroying the neuronal membranes for example. Cu ions are an important therapeutic target to cure the disease. Investigations are currently focusing on the development of new molecules, called chelators, in order to remove selectively Cu ions (over Zn ions), to regulate their concentrations and avoid the accumulation of the peptides. My research project focuses precisely on such kind of investigations. Different Cu(II) and Cu(I) chelators are studied, in the presence or not of Zn(II), in order to understand the different criteria to take into account for the development of good chelators. Different proof-of-concepts are developed in the first part. The kinetic aspect of the removal of Cu(II) from the Aß peptide by a chelator is studied with macrocyclic ligands Then, the redox state of Cu ions in the synaptic cleft staying unknown, two Cu(I) or Cu(I/II) chelators are proposed. The second part of the study takes into account the impact of Zn(II) in the Cu chelation. The thermodynamic part of the Cu(II) chelation in the presence of Zn(II) is evidenced with different chelators.

Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Botany Candidate: Hana Němcová Supervisor: PharmDr. Jana Karlíčková, Ph.D. Title of Thesis: Comparison of interactions of equol and desmethylangolensin with iron and copper Iron and copper are essential trace elements, which are important for our body. Both elements have a significant effect on the correct function of organs and make part of many enzymes. They are able to accept or donate electrons - conversion between oxidized (Fe3+, Cu2+) and reduced (Fe2+, Cu+) forms. If these metals are excess in organism, they are accumulated in the cells and mediate the creation of free radicals, that destroy cell structures. This deficiency is treated with chelators, which facilitate the excretion of metals from the body. Isoflavonoids are polyfenolic substances, which can have antioxidant effects and they are involved in the scavening of free radicals. Isoflavonoids can have also a pro-oxidative effect, because they are able to reduce metal ions. In this study were tested interactions (chelation and reduction) between the metabolites of isoflavonoids (equol and desmethylangolensin) and ions of iron and copper. Both metabolites only weakly chelate metal ions, but they significantly reduce cupric ions. KEYWORDS: Iron,...

Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Botany Candidate: Zuzana Lomozová Supervisor: PharmDr. Jana Karlíčková, Ph.D. Title of Thesis: Interactions of tamarixetin and isorhamnetin with copper Keywords: tamarixetin, isorhamnetin, chelation, reduction, copper, bathocuproine, hematoxylin Copper is a biogenic trace element important for proper function of human organism. It is an essential part of several enzymes and is involved in metabolic processes in the body. Excess or lack of serum copper can lead to pathological conditions. Copper chelating agents are used to treat copper toxic effects. Flavonoids are polyphenolic substances belonging to secondary metabolites of various plants. They are part of the human diet and have a positive impact on our health. They exhibit antioxidant and anti-inflammatory effects and are able to chelate transient metals, especially iron and copper. Chelation therapy is currently used in Wilson's disease in which copper is overloaded. In the future, the chelating effects of flavonoids could be used to treat neurodegenerative diseases, cardiovascular diseases or cancer. In this diploma thesis, interactions of two flavonoids (namely tamarixetin and isorhamnetin) with copper ions in different buffers were tested....

Myoglobin (Mb) oxidation, and the subsequent browning, is the primary basis for consumer rejection of fresh retail beef. Considerable effort has been directed by the industry towards the development of techniques that can enhance color stability. However, the underlying mechanism of Mb oxidation has been studied extensively, but is still not entirely understood. It is known that chelation of iron and copper delays Mb oxidation and browning, but a clear role for these metals has not been established in any current Mb oxidation mechanism. The objective of the current study was to examine the possibility that iron plays a more direct role in Mb oxidation, and that metal chelators such as milk mineral (MM) and sodium tripolyphosphate can inhibit this action. MM, a colloidal calcium phosphate of large molecular weight and undetermined structure, was demonstrated to be a high-affinity iron chelator. Non-heme iron was found to stimulate Mb oxidation even in the absence of lipid, showing for the first time that the role of ferrous iron was not limited to promoting lipid oxidation, but instead has a yet-to-be determined role as a pro-oxidant factor in Mb oxidation. Ferrous iron was found to promote Mb oxidation under standard atmospheric conditions, while in high oxygen systems this effect was not seen. Addition of catalase did not affect Mb oxidation. However, in iron-containing systems, catalase significantly slowed Mb oxidation, while MM addition completely reversed the stimulatory effect of added iron. Type I radical-quenching antioxidants were found to rapidly reduce ferric iron to the ferrous form. This strong reducing ability accounted for the pro-oxidant effects of rosmarinic acid and eugenol in the lipid-free Mb model system. In raw ground beef, Type I antioxidants were highly effective at preventing Mb oxidation in the presence of lipid. Of the Type II chelators examined, only MM was able to delay Mb oxidation as well as the Type I antioxidants, possibly because it is not as susceptible to enzymatic hydrolysis.

A sobrecarga de ferro é uma condição prejudicial para os pacientes, que apresentam uma diminuição significativa na qualidade de vida. Os fármacos quelantes são moléculas que têm capacidade de uso clínico para atuar como atenuadores da sobrecarga de metais. Neste trabalho apresentamos uma análise de sideróforos do tipo hidroxamato e quinona, com o objetivo de ampliar a gama de terapia de sobrecarga de ferro. Para cada composto foi realizado um ensaio competitivo com a sonda calce- ína para verificar a capacidade de ligação do ferro, e um ensaio antioxidante baseado na supressão da oxidação dependente de ferro da dihidrorrodamina (DHR) sob ascorbato. Foi observado que o hidroxamato cíclico piridoxatina apresentou capacidade de sequestrar ferro de substratos de alta afinidade, tanto em meio tamponado quanto em meio intracelular. Em ambas as situações também se mostrou um antioxidante eficiente. Entretanto, parece ser o mais tóxico do grupo dos hidroxamatos (que ainda continha o hidroxamato linear desferricoprogênio e o aromático desferriastercromo). Outros compostos naturais também foram estudados como possíveis candidatos a fármacos para sobrecarga de ferro. Complexos de ferro foram caracterizados por espectrofotometria para avaliar a estequiometria possível, considerando os sítios de ligação para cada composto. Ensaios de fluorescência revelaram que entre os quatro compostos em estudo (ácido clorogênico, lapachol, hemateína e hematoxilina), o complexo entre ferro e hemateína apresenta maior estabilidade relativa do que outros. / Iron overload is a harmful condition for patients, who have a significant decrease in life quality. Chelating drugs are molecules that have the capacity for clinical use to act as attenuators of metal overload. In this work we present an analysis of hydroxamate and quinone-type siderophores, intending to broaden the range of iron overload therapy. For each compound it was conducted a competitive assay with the fluorescent probe calcein to verify the iron binding ability, and an antioxidant assay based on suppression of the iron-dependent oxidation of dihydrorhodamine (DHR) under ascorbate. It was observed that cyclic hydroxamate pyridoxatin displayed good ability to scavenge iron from high affinity substrates both in buffer and in intracellular medium. It was also an efficient antioxidant in both setups. However, pyridoxatin seems to be the most toxic from the hydroxamate group (composed also by the linear desferricoprogen and the aromatic desferriasterchrome). Other natural compounds have also been studied as possible candidates for iron-overload drug therapy. Iron complexes were characterized by spectrophotometry to assess the possible stoichiometry considering the binding sites for each compound. Fluorescence assays revealed that among the four compounds in study (chlorogenic acid, lapachol, hematein and hematoxylin), the complex between iron and hematein has higher relative stability than others.

Homogeneous palladium-catalyzed Heck vinylation of aryl chlorides was investigated under air using Herrmann’s palladacycle and the P(t-Bu)3-liberating salt [(t-Bu)3PH]BF4. Based on the results, controlled microwave heating was utilized to accelerate model Heck reactions with aryl chlorides down to 30 min employing an electron-poor olefin and a mixture of an ionic liquid and 1,4-dioxane as solvent. For the first time, a highly regioselective general protocol has been developed for palladium-catalyzed terminal (β-) arylation of acyclic vinyl ethers using inexpensive aryl chlorides as starting materials and the preligand [(t-Bu)3PH]BF4 as the key additive. This swift and straightforward protocol exploits non-inert conditions and controlled microwave heating to reduce handling and processing times, and aqueous DMF or environmentally friendly PEG-200 as the reaction medium. Somewhat higher selectivity for the linear β-product was observed in PEG-200. DFT calculations were performed at the B3LYP level of theory for the regioselectivity-determining insertion step in the Heck reaction following the neutral pathway. A series of para-substituted phenylpalladium(II) complexes was investigated in the computational study. The calculations support a ligand-driven selectivity rationale, where the electronic and steric influence of the bulky P(t-Bu)3 ligand provides improved β-selectivity. The preparative methodology was used to synthesize the β-adrenergic blocking agent Betaxolol. Highly stereoselective Pd(0)-catalyzed β-arylation and β-vinylation of a tetra-substituted cyclopentenyl ether have been accomplished using a chiral, pyrrolidine-based and substrate-bound palladium(II)-directing group under neutral reaction conditions. To the best of the author’s knowledge, this P(t-Bu)3-mediated method represents the first examples of the successful utilization of aryl and vinyl chlorides in asymmetric Heck reactions. The Heck arylation products formed were hydrolyzed and isolated as the corresponding quaternary 2-aryl-2-methyl cyclopentanones in good to moderate two-step yields with excellent stereoselectivity (90-96% ee). Inclusion of vinyl triflates under neutral reaction conditions and one aryl triflate equipped with a strongly electron-withdrawing para-cyano substituent under cationic conditions increased the preparative usefulness of the methodology. Furthermore, diastereoselective Heck arylation of both five- and six-membered cyclic vinyl ethers with aryl bromides, using the identical chiral auxiliary and suitable Pd sources, was performed. Arylated products from the tetra-substituted cyclopentenyl ether were also in this case hydrolyzed to the corresponding 2-aryl-2-methyl cyclopentanones with high to excellent enantioselectivity (85-94% ee). Despite low reaction rates and relatively modest yields, arylation reactions with the tri-substituted cyclohexenyl ether were found to be highly diastereoselective (94-98% de). Thus, an attractive supplement to direct Pd(0)-catalyzed α-arylation protocols, particularly when the use of organic chlorides, aryl bromides, and milder reaction conditions are of great importance, have been developed.

Alkali Silica Reaction (ASR) is a deleterious, expansive reaction in concrete. Several ASTM methods test potential aggregates for ASR risk. One method uses NaOH digestion, followed by spectroscopic methods, to estimate the amount of reactive silica present in an aggregate. NaOH, however, can digest both crystalline (i.e. quartz) and non-crystalline (e.g. opal), or poorly crystalline silica, potentially yielding falsely high estimates of reactive silica. Studies in soil and plant sciences have used Tiron, an alkaline chelating agent (C6H4S2O8Na2), as a method of digesting opaline silica for spectroscopic analysis. Here we test this approach by analyzing reactive silica in road aggregate. Tiron extraction of reactive silica is more selective, in some cases extracting only ~ 30% of the silica compared to the harsher NaOH extraction: variation is due to differences in aggregate mineralogy, specifically SiO2. In conducting chelation analyses, UV/VIS seems to be a better approach than AA.