Green approach to Palladium Cross-Coupling reactions and development of new methodologies based on highly abundant metals

Transition metal catalyzed cross-coupling reactions represent among the most versatile and useful tools in organic synthesis for the carbon-carbon (C-C) bond formation and have a prominent role in both the academic and pharmaceutical segments. Among them, palladium catalyzed cross-coupling reactions are currently the most versatile. In this thesis, the applications, impact and development of green palladium cross-coupling reactions are discussed. Specifically, we discuss the translation of the Twelve Principles of Green Chemistry and their applications in pharmaceutical organometallic chemistry to stimulate the development of cost-effective and sustainable catalytic processes for the synthesis of active pharmaceutical ingredients (API). The Heck-Cassar-Sonogashira (HCS) and the Suzuki-Miyaura (SM) protocols, using HEP/H2O as green mixture and sulfonated phosphine ligands, allowed to recycle and recover the catalyst, always guaranteeing high yields and fast conversion under mild conditions, with aryl iodides, bromides, triflates and chlorides. No catalyst leakage or metal contamination of the final product were observed during the HCS and SM reactions, respecting the very low limits for metal impurities in medicines established by the International Conference of Harmonization Guidelines Q3D (ICH Q3D). In addition, a deep understanding of the reaction mechanism is very important if the final target is to develop efficient protocols that can be applied at industrial level. Experimental and theoretical studies pointed out the presence of two catalytic cycles depending on the counterion, shedding light on the role of base in catalyst reduction and acetylene coordination in the HCS coupling. Finally, the development of a cross-coupling reaction to form aryldifluoronitriles in the presence of copper is discussed, highlighting the importance of inserting fluorine atoms within biological structures and the use of readily available metals such as copper as an alternative to palladium.

Two stroke cycle, novel combustion concepts and electrification for a new generation of internal combustion engines

The pursuit of decarbonization and increased efficiency in internal combustion engines (ICE) is crucial for reducing pollution in the mobility sector. While electrification is a long-term goal, ICE still has a role to play if coupled with innovative technologies. This research project explores various solutions to enhance ICE efficiency and reduce emissions, including Low Temperature Combustion (LTC), Dual fuel combustion with diesel and natural gas, and hydrogen integration. LTC methods like Dual fuel and Reactivity Controlled Compression Ignition (RCCI) show promise in lowering emissions such as NOx, soot, and CO2. Dual fuel Diesel-Natural Gas with hydrogen addition demonstrates improved efficiency, especially at low loads. RCCI Diesel-Gasoline engines offer increased Brake Thermal Efficiency (BTE) compared to standard diesel engines while reducing specific NOx emissions. The study compares 2-Stroke and 4-Stroke engine layouts, optimizing scavenging systems for both aircraft and vehicle applications. CFD analysis enhances specific power output while addressing injection challenges to prevent exhaust short circuits. Additionally, piston bowl shape optimization in Diesel engines running on Dual fuel (Diesel-Biogas) aims to reduce NOx emissions and enhance thermal efficiency. Unconventional 2-Stroke architectures, such as reverse loop scavenged with valves for high-performance cars, opposed piston engines for electricity generation, and small loop scavenged engines for scooters, are also explored. These innovations, alongside ultra-lean hydrogen combustion, offer diverse pathways toward achieving climate neutrality in the transport sector.

Computational design of a new type of sandwich cross-section for a defined solution of a tree-like column produced by wire-and-arc additive manufacturing

When it comes to designing a structure, architects and engineers want to join forces in order to create and build the most beautiful and efficient building. From finding new shapes and forms to optimizing the stability and the resistance, there is a constant link to be made between both professions. In architecture, there has always been a particular interest in creating new shapes and types of a structure inspired by many different fields, one of them being nature itself. In engineering, the selection of optimum has always dictated the way of thinking and designing structures. This mindset led through studies to the current best practices in construction. However, both disciplines were limited by the traditional manufacturing constraints at a certain point. Over the last decades, much progress was made from a technological point of view, allowing to go beyond today's manufacturing constraints. With the emergence of Wire-and-Arc Additive Manufacturing (WAAM) combined with Algorithmic-Aided Design (AAD), architects and engineers are offered new opportunities to merge architectural beauty and structural efficiency. Both technologies allow for exploring and building unusual and complex structural shapes in addition to a reduction of costs and environmental impacts. Through this study, the author wants to make use of previously mentioned technologies and assess their potential, first to design an aesthetically appreciated tree-like column with the idea of secondly proposing a new type of standardized and optimized sandwich cross-section to the construction industry. Parametric algorithms to model the dendriform column and the new sandwich cross-section are developed and presented in detail. A catalog draft of the latter and methods to establish it are then proposed and discussed. Finally, the buckling behavior of this latter is assessed considering standard steel and WAAM material properties.

Discovery Of A Rare Pterosaur Bone Bed In A Cretaceous Desert With Insights On Ontogeny And Behavior Of Flying Reptiles.

A pterosaur bone bed with at least 47 individuals (wing spans: 0.65-2.35 m) of a new species is reported from southern Brazil from an interdunal lake deposit of a Cretaceous desert, shedding new light on several biological aspects of those flying reptiles. The material represents a new pterosaur, Caiuajara dobruskii gen. et sp. nov., that is the southermost occurrence of the edentulous clade Tapejaridae (Tapejarinae, Pterodactyloidea) recovered so far. Caiuajara dobruskii differs from all other members of this clade in several cranial features, including the presence of a ventral sagittal bony expansion projected inside the nasoantorbital fenestra, which is formed by the premaxillae; and features of the lower jaw, like a marked rounded depression in the occlusal concavity of the dentary. Ontogenetic variation of Caiuajara dobruskii is mainly reflected in the size and inclination of the premaxillary crest, changing from small and inclined (∼ 115°) in juveniles to large and steep (∼ 90°) in adults. No particular ontogenetic features are observed in postcranial elements. The available information suggests that this species was gregarious, living in colonies, and most likely precocial, being able to fly at a very young age, which might have been a general trend for at least derived pterosaurs.

Pyrimidine-5'-nucleotidase Campinas, A New Mutation (p.r56g) In The Nt5c3 Gene Associated With Pyrimidine-5'-nucleotidase Type I Deficiency And Influence Of Gilbert's Syndrome On Clinical Expression.

Pyrimidine-5'-nucleotidase type I (P5'NI) deficiency is an autosomal recessive condition that causes nonspherocytic hemolytic anemia, characterized by marked basophilic stippling and pyrimidine nucleotide accumulation in erythrocytes. We herein present two African descendant patients, father and daughter, with P5'N deficiency, both born from first cousins. Investigation of the promoter polymorphism of the uridine diphospho glucuronosyl transferase 1A (UGT1A) gene revealed that the father was homozygous for the allele (TA7) and the daughter heterozygous (TA6/TA7). P5'NI gene (NT5C3) gene sequencing revealed a further change in homozygosity at amino acid position 56 (p.R56G), located in a highly conserved region. Both patients developed gallstones; however the father, who had undergone surgery for the removal of stones, had extremely severe intrahepatic cholestasis and, liver biopsy revealed fibrosis and siderosis grade III, leading us to believe that the homozygosity of the UGT1A polymorphism was responsible for the more severe clinical features in the father. Moreover, our results show how the clinical expression of hemolytic anemia is influenced by epistatic factors and we describe a new mutation in the P5'N gene associated with enzyme deficiency, iron overload, and severe gallstone formation. To our knowledge, this is the first description of P5'N deficiency in South Americans.

Bp-13 Pla2: Purification And Neuromuscular Activity Of A New Asp49 Toxin Isolated From Bothrops Pauloensis Snake Venom.

A new PLA2 (Bp-13) was purified from Bothrops pauloensis snake venom after a single chromatographic step of RP-HPLC on μ-Bondapak C-18. Amino acid analysis showed a high content of hydrophobic and basic amino acids and 14 half-cysteine residues. The N-terminal sequence showed a high degree of homology with basic Asp49 PLA2 myotoxins from other Bothrops venoms. Bp-13 showed allosteric enzymatic behavior and maximal activity at pH 8.1, 36°-45°C. Full Bp-13 PLA2 activity required Ca(2+); its PLA2 activity was inhibited by Mg(2+), Mn(2+), Sr(2+), and Cd(2+) in the presence and absence of 1 mM Ca(2+). In the mouse phrenic nerve-diaphragm (PND) preparation, the time for 50% paralysis was concentration-dependent (P < 0.05). Both the replacement of Ca(2+) by Sr(2+) and temperature lowering (24°C) inhibited the Bp-13 PLA2-induced twitch-tension blockade. Bp-13 PLA2 inhibited the contractile response to direct electrical stimulation in curarized mouse PND preparation corroborating its contracture effect. In biventer cervicis preparations, Bp-13 induced irreversible twitch-tension blockade and the KCl evoked contracture was partially, but significantly, inhibited (P > 0.05). The main effect of this new Asp49 PLA2 of Bothrops pauloensis venom is on muscle fiber sarcolemma, with avian preparation being less responsive than rodent preparation. The study enhances biochemical and pharmacological characterization of B. pauloensis venom.

Comparative analysis of the new guidelines and consensuses for the management of hypothyroidism, thyroid nodules, and differentiated thyroid cancer

233