The Enhanced Permeability and Retention (EPR) effect has seen considerable exploration by many researchers since it’s discovery by Maeda et al in 1985. Polymers and nanoparticles with a long blood residence half-life can accumulate in some tumour tissues, allowing for the delivery of either diagnostic or therapeutic payloads. We have contributed to this field by the development of methodology to prepare radiolabeled dendrimers which are suitable for EPR effect accumulation with a variety of peripheral functionalities. The first of these was a 99mTc-labeled fifth generation dendron which was peripherally functionalized with low molecular weight poly(ethylene glycol) chains, which was observed to accumulate in xenograft mouse tumours over the course of 6 hours. This work led to the development of improved synthetic means for the preparation of high generation dendrimers with complex peripheral functionality, which hinged on the use of the Strain Promoted Alkyne-Azide Cycloaddition reaction to give high generation dendrimers by a convergent approach. This resulted in the facile preparation of dendrimers with challenging peripheral functionality in reaction times as short as 5 minutes. This SPAAC based convergent synthesis approach was used to prepare 99mTc labeled sulfobetaine and carboxybetaine dendrons of the sixth generation, and these compounds were found to have a size greater than the renal clearance threshold of ~ 5 nm, though it was found that labeling with [99mTc(CO)3]+ was not possible without extensive degradation of the zwitterionic dendrimers. Finally, the dendritic architecture explored for imaging was adapted for use in shielding an enzyme from macromolecules while retaining activity against the native small molecule substrate, and we found that conjugation of high-generation bis-MPA dendrons to α-chymotrypsin was an effective way to eliminate enzyme activity against macromolecules while preserving efficacy against small substrates, indicating this approach may be an effective way to shield proteins from the immune system without interfering with their desired function. This work illustrates the ability to radiolabel polyester dendrimers for tumour imaging through the EPR effect. In addition, it has demonstrated that polymer architecture has a large impact on the properties of polymer-protein conjugates and gives evidence of unique properties that are imparted by the conjugation of high-generation dendrimers onto a protein. / Thesis / Doctor of Science (PhD)

Semicrystalline thermoplastic polyimides based upon bis(4-aminophenoxy)benzene and related "triphenyl ether" diamines were synthesized via the classical two step amic acid route. More specifically, polyimides were derived from para linked 1,4-bis(4-aminophenoxy)benzene, or TPEQ (triphenyl ether diamine- hydroquinone) and its meta isomer 1,3-bis(4-aminophenoxy)benzene, or TPER (triphenyl ether diamine-resorcinol). The reaction of these diamines with rigid or semi-rigid dianhydrides such as pyromellitic dianhydride (PMDA), biphenyl dianhydride (BPDA), and oxydiphthalic anhydride (ODPA) yields very thermally stable semi-crystalline polymers which have excellent resistance to organic liquids. Amorphous polyimides could be derived from hexafluoroisopropylidene-linked diphthalic anhydride (6FDA), but these systems were not extensively investigated. Importantly, molecular weight characterization of the semicrystalline systems at the soluble amic acid stage was successful by employing hydrodynamic volume calibrated, viscosity detector size exclusion chromatography (SEC). The experimental values were found to be within the targeted <M_n> range of 20-30,000 g/mole. Polyimide powders derived from these ether diamines were prepared by solution imidization at 180°C, to afford about 70% imidized structures as judged by dynamic thermal gravimetric analysis (TGA), before crystallization/precipitation occurred. Relatively small particle sizes ranging from 2 to 25 μm in size were generated, which would be appropriate for thermoplastic polymer matrix composites prepared by powder processing. All specimens showed excellent thermooxidative stability, consistent with the aromatic imide structure. The molecular design of the aromatic polyetherimide repeat unit was critical for the successful utilization of these semicrystalline high performance materials. The metba-linked TPER system when combined with the thermally stable s-biphenyl dianhydride (BPDA) produced a melting endotherm, T_m, at about 395°C, which was well within the thermal stability limitations of organic materials, i.e., less than or approximately 450°C. It was also demonstrated to be important to quantitatively endcap both ends of the chains at about 20-30,000 <M_n> with non-reactive phthalimide groups to achieve appropriate melt viscosities and good melt stability. This was done by off-setting the stoichiometry in favor of the diamine, reacting with a calculated amount of phthalic anhydride and imidizing in bulk above the Tg (≈210°C) at 300°C. These considerations allowed for remarkable melt stability in nitrogen at 430°C for at least 45 minutes, and importantly, repeated recrystallizations from the melt to afford tough, ductile semicrystalline films with excellent solvent resistance. If the macromolecular chains were not properly endcapped, it was demonstrated that viscosity increased rapidly at 430°C, suggesting reactions such as transimidization involving terminal amine end groups with in-chain imide segments and/or other side reactions, which quickly inhibited recrystallization, probably by reducing molecular transport processes. In contrast, polyimides based upon the more rigid para-linked TPEQ did not demonstrate melt or flow characteristics below 400°C, and degraded around the T_m at about 470°C! The less thermally stable TPEQ-ODPA based polyimide did melt around 409°C, and lower molecular weight samples, e.g., 10,000 M_n, recrystallized from the melt after short melt times, but cast films were brittle. It was hypothesized that the weak link may be the relatively electron rich arylene ether bond derived from the ODPA dianhydride. Several alkylated derivatives of TPER were synthesized in good yield by the reactions of alkylated resorcinol precursors with p-fluoronitrobenzene to produce dinitro compounds, which were subsequently reduced. These model diamines were then used to synthesize polyimides by the classical two step route. As expected, few of the polyimides derived from BPDA and these diamines displayed melting transitions (T_m), probably because of poor chain packing. However, they could have potential as new thermally stable membrane materials. Several amorphous polyimides prepared from 1,3-bis(p-aminophenoxy)-4-hexylbenzene were soluble in selected common organic solvents and could be cast into flexible films. / Ph. D.

Palladium(II) acetate and palladium(II) chloride react with amino acids in acetone/water to yield cis or trans square planar bis-chelated palladium amino acid complexes. The naturally occurring amino acids and some N-alkylated and substituted derivatives and homologs were evaluated as ligands. Thirty-eight amino acids in total were investigated as ligands. The formation of aquo complexes in water was observed and studied by 13C NMR spectroscopy and modeled by DFT calculations. Each class of amino acid ligand is catalytically active with respect to the oxidative coupling of olefins and phenylboronic acids. Some enantioselectivity is observed and the formation of products not reported in other Pd(II) oxidative couplings is seen. Both activated and non-activated alkenes were oxidatively coupled to phenylboronic acids incorporating both electron-donating and electron-withdrawing groups. The crystal structures of nineteen catalyst complexes were obtained. The extended lattice structures arise from N-H..O or O..(HOH)..O hydrogen bonding. NMR, HRMS, FTIR, single crystal XRD, and powder XRD data are evaluated. / Ph. D.

As a part of a continuing search for bioactive compounds with the International Cooperative Biodiversity Group (ICBG), and in collaboration with the Natural Products Discovery Institute of the Institute for Hepatitis and Virus Research (IHVR), twelve plant extracts were investigated for their antiproliferative activity against the A2780 cell line, three plant extracts were investigated for their antimalarial activity against Plasmodium falciparum, and three plant extracts were investigated for their anti-inflammatory activity (PPAR-y inhibition). Bioassay-guided fractionation of extracts led to the identification of four new antiproliferative compounds (2.1-2.3, 3.1), five new anti-inflammatory compounds (6.4a, 6.5a-b, 6.6a, 6.6c), and twenty-eight known compounds from eight of the extracts. In addition, mallotojaponin C, an antimalarial natural product, and derivatives were synthesized and investigated for their antimalarial activity. / Ph. D.

We have synthesized a series of dimers of (+)-(7R,11R)-huprine Y and evaluated their activity against Trypanosoma brucei, Plasmodium falciparum, rat myoblast L6 cells and human acetylcholinesterase (hAChE), and their brain permeability. Most dimers have more potent and selective trypanocidal activity than huprine Y and are brain permeable, but they are devoid of antimalarial activity and remain active against hAChE. Lead optimization will focus on identifying compounds with a more favourable trypanocidal/anticholinesterase activity ratio.

Yes / Exploring the detailed structural features of synthetic molecules in the membrane phase requires sensitive probes of conformation. Here we describe the design, synthesis and characterization of bis(pyrene) probes that report conformational changes in membrane-active dynamic foldamers. The probes were designed to distinguish between left-handed (M) and right-handed (P) screw-sense conformers of 310-helical α-aminoisobutyric acid (Aib) peptide foldamers, both in solution and in bilayer membranes. Several different bis(pyrene) probes were synthesized and ligated to the C-terminus of Aib tetramers that had different chiral residues at the N-terminus, residues that favored either an M or a P screw-sense in the 310-helix. The readily synthesized and conveniently incorporated N-acetyl-1,2-bis(pyren-1′-yl)ethylenediamine probe proved to have the best properties. In solution, changes in foldamer screw-sense induced substantial changes in the ratio of excimer/monomer fluorescence emission (E/M) for this reporter of conformation, with X-ray crystallography revealing that opposite screw-senses produce very different interpyrene distances in the reporter. In bilayers, this convenient and sensitive fluorescent reporter allowed, for the first time, an investigation of how the chirality of natural phospholipids affects foldamer conformation. / European Research Council (Advanced Grant ROCOCO), the BBSRC (DTP studentship and grant BB/I007962) and the EPRSC (grants EP/N009134/1 and EP/ K039547).

Résumé: Dans le but de préparer des complexes de Zr pour la catalyse homogène de la polymérisation des lactides et de l’hydroamination des olefines, l’elaboration et l’optimisation d’une méthode systématique et efficace de synthèse des ligands dikétimines ayant différents substituants alkyles (R) à la position N,N’ a été realisée. Des dikétimines (nacnacRH) symétriques ont été obtenus avec une pureté de plus de 95 % et un rendement de 65 % lorsque R = Me et des rendements allant de 80 à 95 % lorsque le groupe R = n-Pr, i-Pr, i-Bu, Bu, Cy et (+)-CH(Me)Ph. La synthèse des dikétimines ayant des substituants N-alkyls différents, dite asymétriques, donne toujours un mélange statistique de trois ligands: nacnacR,R’H, nacnacR,RH et nacnacR’,R’H qui n’ont pu être separés. Seuls les dikétimines asymétriques avec un substituant N-alkyl et un autre N-aryl (nacnacR,ArH) ont été obtenus avec des rendements plus élevés que celui du mélange statistique. Par la suite, la complexation de ces ligands bidentés au Zr, la caractérisation de ces complexes et l’investigation de la réactivité ont été étudiés. Les complexes de Zr de type (nacnacR)2ZrCl2 ont été obtenus par deux voies de synthèse principales: la première consiste à traiter le sel de lithium du ligand avec le ZrCl4. La seconde est la réaction du ligand avec les complexes neutres d’alkyl-zirconium(IV) par protonation de l'alkyle coordonné. En solution, les complexes obtenus de (nacnacR)2ZrX2 possèdent un comportement dynamique via un « Bailar-twist » et les paramètres d'activation de cette isomérisation ont été calculés. Le complexe octaèdrique (nacnacBn)2ZrCl2 n'est pas réactif dans la carbozirconation et son alkylation n'était pas possible par l’échange des chlorures avec les alkyles. L’analogue diméthylé (nacnacBn)2ZrMe2 peut être préparé par alkylation du ZrCl4 avant la complexation du ligand. On a également observé que ce dernier n’est pas réactif dans la carbozirconation. L‘analogue diéthoxyde (nacnacBn)2Zr(OEt)2 est obtenu par échange des diméthyles avec les éthoxydes. La polymérisation du lactide avec celui-ci en tant que précurseur est relativement lente et ne peut être effectuée que dans le monomère fondu. Par conséquent, pour résoudre les problèmes rencontrés avec les complexes de zirconium (dikétiminates non-pontés), un ligand dikétimines pontés par le diaminocyclohexane, (±)-C6H10(nacnacXylH)2, LH2, (Xyl = 2,6-diméthylphényle) a été préparé. La complexation de ce ligand tetradenté au metal a été réalisée par deux voies de synthèse; la première est la réaction du sel de lithium de ce ligand avec le ZrCl4(THF)2. La deuxième est la déprotonation du ligand neutre avec le Zr(NMe2)4 et l’élimination du diméthylamine. Des complexes du type: (±)-C6H10(nacnacXylH)2ZrX2 avec X = Cl, NMe2 ont été obtenus. Les ligands de chlorure sont dans ce cas facilement remplaçables par des éthoxydes ou des méthyles. On a observé l’activité la plus élevée jamais observée pour un complexe d’un métal du groupe 4 avec le complexe de (±)-C6H10(nacnacXylH)2Zr(OEt)2 dans la polymérisation de lactide. L'étude cinétique a montré que la loi de vitesse est du premier ordre en catalyseur et en monomère et la constante de vitesse est k = 14 (1) L mol-1 s-1. L'analyse des polymères a montré l’obtention de masses moléculaires faibles et l’abscence de stéréocontrôle. La réaction de (±)-C6H10(nacnacXylH)2ZrCl2 avec le triflate d’argent donne le (±)-C6H10(nacnacXylH)2Zr(OTf)2. Le complexe bis-triflate obtenu possède une activité catalytique elevée pour les additions du type aza-Michael. L’utilisation du R,R-C6H10(nacnacXylH)2Zr(OTf)2 énantiopur comme catalyseur, dans les additions du type aza-Michael asymétriques donne le produit desiré avec un excès énantiomérique de 19%. / Abstract: In order to prepare the complexes of Zr targeted for homogeneous catalysis in polymerization of lactides and hydroamination of activated olefins, we focused on the elaboration and the optimization of a systematic and efficient method for the synthesis of diketimines ligands with a variety of substituted alkyl (R) on their position N,N'. Symmetrical diketimines (nacnacRH) were obtained with a greater than 95% purity and a yield of 65% when R = Me and yields ranging from 80 to 95% when R = nPr, iPr, iBu, Bn, and Cy (+)-CH (Me) Ph. The Synthesis of diketimines with different N-alkyl substituents, called asymmetric, always gives a statistical mixture of three ligands: nacnacR,R'H nacnacR,RH and nacnacR',R'H that made their isolation problematic. Yields greater than statistical mixtures were obtained only with asymmetric diketimines bearing N-alky and N-aryl substituents (nacnacR,ArH). Subsequently, we studied the complexation of these bidentate ligands with Zr, the characterization of these complexes and investigation of their reactivity. Zr complexes of type (nacnacRH)2ZrCl2 were obtained via two main synthetic routes: the first consists in treatment of the lithium salt of the ligand with ZrCl4. The second is the reaction of the ligand with neutral complexes of alkyl-zirconium (IV) by protonation of the alkyl coordinated. In solution, the obtained complexes (nacnacR)2ZrX2 showed dynamic behavior via a "Bailar-twist" isomerization and the activation parameters of the isomerization were calculated. Octahedral complex (nacnacBn)2ZrCl2, showed no reactivity in alkylation and carbozirconation was not possible by the exchange of alkyl with chlorides. The dimethyl analogue (nacnacBn)2ZrMe2, can be prepared by alkylation of ZrCl4 before ligand complexing. The diethoxide analogue (nacnacBn)2Zr(OEt)2 is obtained by exchange of dimethyls with ethoxides. The latter had slow reactivity in lactide polymerization under melt conditions. Consequently, to address the problems encountered with unbridged (diketiminate) zirconium complexes, a cyclohexanediyl-bridged diketiminate ligand, (±)-C6H10(nacnacXylH)2, LH2, (Xyl = 2,6-dimethylphenyl) is prepared. Complexation of the tetradentate ligand is realized via two synthetic routes; The first is reaction of the lithium salt of the ligand with ZrCl4(THF)2. The second is deprotonation of the neutral ligand with Zr(NMe2)4 and elimination of dimethylamine. Complexes of the type: (±)-C6H10(nacnacXylH)2ZrX2 with X = Cl, NMe2 are obtained. The chloride ligands are in this case readily replaceable with ethoxides or methyls. The (±)-C6H10(nacnacXylH)2Zr(OEt)2 complex showed the highest activity ever observed for any group 4 metal complex in lactide polymerization. The kinetic study showed that the rate law is first order in catalyst and monomer and the rate constant is k = 14(1) L mol−1 s−1. Analysis of the obtained polymer showed low molecular weight with no-stereocontrol. Reaction of the (±)-C6H10(nacnacXylH)2ZrCl2 with silver triflates yielded the (±)-C6H10(nacnacXylH)2Zr(OTf)2. The obtained bis-triflate complex showed to be a highly active catalyst for aza-Michael additions. The use of the enatiopure R,R-C6H10(nacnacXyl)2Zr(OTf)2 as catalyst for asymmetric aza-Michael additions of activated olefines gave the desired product with an enantiomeric excess of 19%.

Résumé: Dans le but de préparer des complexes de Zr pour la catalyse homogène de la polymérisation des lactides et de l’hydroamination des olefines, l’elaboration et l’optimisation d’une méthode systématique et efficace de synthèse des ligands dikétimines ayant différents substituants alkyles (R) à la position N,N’ a été realisée. Des dikétimines (nacnacRH) symétriques ont été obtenus avec une pureté de plus de 95 % et un rendement de 65 % lorsque R = Me et des rendements allant de 80 à 95 % lorsque le groupe R = n-Pr, i-Pr, i-Bu, Bu, Cy et (+)-CH(Me)Ph. La synthèse des dikétimines ayant des substituants N-alkyls différents, dite asymétriques, donne toujours un mélange statistique de trois ligands: nacnacR,R’H, nacnacR,RH et nacnacR’,R’H qui n’ont pu être separés. Seuls les dikétimines asymétriques avec un substituant N-alkyl et un autre N-aryl (nacnacR,ArH) ont été obtenus avec des rendements plus élevés que celui du mélange statistique. Par la suite, la complexation de ces ligands bidentés au Zr, la caractérisation de ces complexes et l’investigation de la réactivité ont été étudiés. Les complexes de Zr de type (nacnacR)2ZrCl2 ont été obtenus par deux voies de synthèse principales: la première consiste à traiter le sel de lithium du ligand avec le ZrCl4. La seconde est la réaction du ligand avec les complexes neutres d’alkyl-zirconium(IV) par protonation de l'alkyle coordonné. En solution, les complexes obtenus de (nacnacR)2ZrX2 possèdent un comportement dynamique via un « Bailar-twist » et les paramètres d'activation de cette isomérisation ont été calculés. Le complexe octaèdrique (nacnacBn)2ZrCl2 n'est pas réactif dans la carbozirconation et son alkylation n'était pas possible par l’échange des chlorures avec les alkyles. L’analogue diméthylé (nacnacBn)2ZrMe2 peut être préparé par alkylation du ZrCl4 avant la complexation du ligand. On a également observé que ce dernier n’est pas réactif dans la carbozirconation. L‘analogue diéthoxyde (nacnacBn)2Zr(OEt)2 est obtenu par échange des diméthyles avec les éthoxydes. La polymérisation du lactide avec celui-ci en tant que précurseur est relativement lente et ne peut être effectuée que dans le monomère fondu. Par conséquent, pour résoudre les problèmes rencontrés avec les complexes de zirconium (dikétiminates non-pontés), un ligand dikétimines pontés par le diaminocyclohexane, (±)-C6H10(nacnacXylH)2, LH2, (Xyl = 2,6-diméthylphényle) a été préparé. La complexation de ce ligand tetradenté au metal a été réalisée par deux voies de synthèse; la première est la réaction du sel de lithium de ce ligand avec le ZrCl4(THF)2. La deuxième est la déprotonation du ligand neutre avec le Zr(NMe2)4 et l’élimination du diméthylamine. Des complexes du type: (±)-C6H10(nacnacXylH)2ZrX2 avec X = Cl, NMe2 ont été obtenus. Les ligands de chlorure sont dans ce cas facilement remplaçables par des éthoxydes ou des méthyles. On a observé l’activité la plus élevée jamais observée pour un complexe d’un métal du groupe 4 avec le complexe de (±)-C6H10(nacnacXylH)2Zr(OEt)2 dans la polymérisation de lactide. L'étude cinétique a montré que la loi de vitesse est du premier ordre en catalyseur et en monomère et la constante de vitesse est k = 14 (1) L mol-1 s-1. L'analyse des polymères a montré l’obtention de masses moléculaires faibles et l’abscence de stéréocontrôle. La réaction de (±)-C6H10(nacnacXylH)2ZrCl2 avec le triflate d’argent donne le (±)-C6H10(nacnacXylH)2Zr(OTf)2. Le complexe bis-triflate obtenu possède une activité catalytique elevée pour les additions du type aza-Michael. L’utilisation du R,R-C6H10(nacnacXylH)2Zr(OTf)2 énantiopur comme catalyseur, dans les additions du type aza-Michael asymétriques donne le produit desiré avec un excès énantiomérique de 19%. / Abstract: In order to prepare the complexes of Zr targeted for homogeneous catalysis in polymerization of lactides and hydroamination of activated olefins, we focused on the elaboration and the optimization of a systematic and efficient method for the synthesis of diketimines ligands with a variety of substituted alkyl (R) on their position N,N'. Symmetrical diketimines (nacnacRH) were obtained with a greater than 95% purity and a yield of 65% when R = Me and yields ranging from 80 to 95% when R = nPr, iPr, iBu, Bn, and Cy (+)-CH (Me) Ph. The Synthesis of diketimines with different N-alkyl substituents, called asymmetric, always gives a statistical mixture of three ligands: nacnacR,R'H nacnacR,RH and nacnacR',R'H that made their isolation problematic. Yields greater than statistical mixtures were obtained only with asymmetric diketimines bearing N-alky and N-aryl substituents (nacnacR,ArH). Subsequently, we studied the complexation of these bidentate ligands with Zr, the characterization of these complexes and investigation of their reactivity. Zr complexes of type (nacnacRH)2ZrCl2 were obtained via two main synthetic routes: the first consists in treatment of the lithium salt of the ligand with ZrCl4. The second is the reaction of the ligand with neutral complexes of alkyl-zirconium (IV) by protonation of the alkyl coordinated. In solution, the obtained complexes (nacnacR)2ZrX2 showed dynamic behavior via a "Bailar-twist" isomerization and the activation parameters of the isomerization were calculated. Octahedral complex (nacnacBn)2ZrCl2, showed no reactivity in alkylation and carbozirconation was not possible by the exchange of alkyl with chlorides. The dimethyl analogue (nacnacBn)2ZrMe2, can be prepared by alkylation of ZrCl4 before ligand complexing. The diethoxide analogue (nacnacBn)2Zr(OEt)2 is obtained by exchange of dimethyls with ethoxides. The latter had slow reactivity in lactide polymerization under melt conditions. Consequently, to address the problems encountered with unbridged (diketiminate) zirconium complexes, a cyclohexanediyl-bridged diketiminate ligand, (±)-C6H10(nacnacXylH)2, LH2, (Xyl = 2,6-dimethylphenyl) is prepared. Complexation of the tetradentate ligand is realized via two synthetic routes; The first is reaction of the lithium salt of the ligand with ZrCl4(THF)2. The second is deprotonation of the neutral ligand with Zr(NMe2)4 and elimination of dimethylamine. Complexes of the type: (±)-C6H10(nacnacXylH)2ZrX2 with X = Cl, NMe2 are obtained. The chloride ligands are in this case readily replaceable with ethoxides or methyls. The (±)-C6H10(nacnacXylH)2Zr(OEt)2 complex showed the highest activity ever observed for any group 4 metal complex in lactide polymerization. The kinetic study showed that the rate law is first order in catalyst and monomer and the rate constant is k = 14(1) L mol−1 s−1. Analysis of the obtained polymer showed low molecular weight with no-stereocontrol. Reaction of the (±)-C6H10(nacnacXylH)2ZrCl2 with silver triflates yielded the (±)-C6H10(nacnacXylH)2Zr(OTf)2. The obtained bis-triflate complex showed to be a highly active catalyst for aza-Michael additions. The use of the enatiopure R,R-C6H10(nacnacXyl)2Zr(OTf)2 as catalyst for asymmetric aza-Michael additions of activated olefines gave the desired product with an enantiomeric excess of 19%.

La Théorie de la Fonctionnelle de la Densité (DFT) combinée avec le formalisme de la Symétrie Brisée (BS) est aujourd'hui très utilisée dans le domaine du magnétisme moléculaire pour le calcul des constantes d'échange magnétique. Dans le but d'améliorer la compréhension des contributions qui participe à l'interaction d'échange caractérisant les systèmes magnétiques, nous avons mené une étude théorique systématique basée sur l'étude de deux types de modèles. Ces complexes binucléaires de cuivre(II) reliés par divers groupements pontant de type hydroxo, azoture, et chloro, ainsi que des bis-nitroxydes modèles constitués de deux groupements nitroxydes reliés par un système conjugué sont caractérisés par des couplages ferro- et anti-ferromagnétiques variés. Nous avons développé une approche théorique basée sur l'utilisation d'orbitales gelées permettant d'étudier la décomposition de l'interaction d'échange magnétique en différentes contributions telles que l'échange direct, l'échange cinétique et le mécanisme de polarisation de spin. Dans un second temps, nous avons étendu ce travail de rationalisation aux effets de solvant à l'aide de modèles implicites ou explicites. Grâce à une analyse basée sur l'approche de Hoffmann, nous avons pu déterminer les paramètres caractérisant dans les mécanismes d'échange direct et d'échange cinétique. / Density Functional Theory (DFT) combined with the Broken Symmetry (BS) method is today widely used in the field of molecular magnetism for the computation of magnetic exchange coupling constants. In order to improve the understanding of the contributions involved in the exchange phenomena characterizing some magnetic systems, we propose a study based on two types of models. Copper(II) binuclear complexes connected with various bridging groups like hydroxo, azide, and chlorine, as well as small bis-nitroxide composed of two nitroxide moieties linked by a conjugated system show various ferro- and anti-ferromagnetic couplings. We have developed a theoretical approach based on the use of frozen orbitals to decompose the magnetic exchange interaction in different contributions such as the direct exchange, the kinetic exchange and mechanism of spin polarization. In a second part, we have extended this work to rationalize the solvent effects using implicit or explicit models. Through an analysis based on the Hoffmann's approach, we have determined some parameters characterizing the mechanisms of direct exchange and kinetic exchange.

Tax crimes Abstract This thesis deals with the topic of tax crimes. Its goal is to analyze the current legislation regarding tax offences in the Czech Republic, that is both from a general perspective and from the perspective of specific types of tax crimes, and identify the weaknesses of the legislation. These weaknesses were found mostly in the rigid reaction of the legislator to legislative changes in the law, which causes these changes not to be reflected in the penal code. Some sections are dedicated to general topics about taxes and tax offences, such as the reporting of tax crimes and their preparation and attempt. Furthermore, sections of the penal code were interpreted with a focus on parts that might pose a problem during interpretation. Such problems are for example the extent of a committed tax fraud, the recent extension of the crime in Section 227 of the penal code to include duties during tax governance or the examination of the connections that the penal code has to tax legislation. The following part compared the Czech legislation regarding tax crimes to those in Slovakia and in Austria. Then it focuses on the examination of current problems in the field of tax crimes, mainly the principle of ne bis in idem, the principle of nemo tenetur se ipsum accusare and the problem connected to...