Interactions between carbohydrates and proteins are increasingly being recognized as crucial in many biological processes, such as cellular adhesion and communication. In order to investigate the interactions of carbohydrates and proteins, the development of efficient analytic technologies, as well as novel strategies for the synthesis of carbohydrates, have to be explored. To date, several methods have been exploited to analyze interactions of carbohydrates and proteins, for example, biosensors, nuclear magnetic resonance (NMR); enzyme-linked immunosorbent assays (ELISA), X-ray crystallography and array technologies. This thesis describes the development of novel strategies for the synthesis of carbohydrates, as well as new efficient strategies to Quartz Crystal Microbalance- (QCM-) biosensors and carbohydrate microarrays technologies. These methodologies have been used to probe carbohydrate-lectin-interactions for a range of plant and animal lectins. / QC 20100915

This thesis deals mainly with two oxidation reactions: water oxidation and aerobic oxidation, both of which have been applied in a biomimetic fashion. In the former reaction molecular oxygen is generated whereas in the latter it was used as terminal oxidant in oxidation reactions. The first part of this thesis describes the synthesis of different ruthenium and manganese complexes that could potentially act as catalysts for water oxidation. This part includes a discussion of the stability and reactivity of a new manganese(III) amide-type complex, that has been used as a catalyst for both epoxidation of stilbene and alcohol oxidation. The second part of this thesis discusses the synthesis of two new hybrid catalysts consisting of hydroquinone linked cobalt(II) salophen and cobalt(II) salmdpt, which have been used as oxygen-activating catalysts in aerobic oxidation reactions. The former catalyst was applied to the Pd-catalyzed reactions such as 1,4-diacetoxylation of cyclohexadiene whereas the latter was applied to the Ru-catalyzed oxidation of secondary alcohols to ketones. Moreover, these two hybrid catalysts could be used in the Pd-catalyzed carbocyclization of enallenes. In all cases molecular oxygen was used as the stoichiometric oxidant.

According to the famous axiom known as Moore’s Law the number of transistors that can be etched on a given piece of silicon, and therefore the computing power, will double every 18 to 24 months. For the last 40 years Moore’s prediction has held true as computers have grown more and more powerful. However, around 2020 hardware manufac-turers will have reached the physical limits of silicon. A proposed solution to this dilemma is molecular electronics. Within this field researchers are attempting to develop individual organic molecules and metal complexes that can act as molecular equivalents of electronic components such as diodes, transistors and capacitors. By utilizing molecular electronics to construct the next generation of computers processors with 100,000 times as many components on the same surface area could potentially be created. We have synthesized a range of new pyridyl thienopyridine ligands and compared the electrochemical and photophysical properties of their corresponding Ru(II) complexes with that with the Ru(II) complexes of a variety of ligands based on 6-thiophen-2-yl-2,2´-bipyridine and 4-thiophen-2-yl-2,2´-bipyridine. While the electrochemistry of the Ru(II) complexes were similar to that of unsubstituted [Ru(bpy)3]2+, substantial differences in luminescence lifetimes were found. Our findings show that, due to steric interactions with the auxiliary bipy-ridyl ligands, luminescence is quenched in Ru(II) complexes that in-corporate the 6-thiophen-2-yl-2,2´-bipyridine motif, while it is on par with the luminescence of [Ru(bpy)3]2+ in the Ru(II) complexes of the pyridyl thienopyridine ligands. The luminescence of the Ru(II) com-plexes based on the 4-thiophen-2-yl-2,2´-bipyridine motif was en-hanced compared to [Ru(bpy)3]2+ which indicates that complexes of this category are the most favourable for energy/electron-transfer sys-tems. At the core of molecular electronics are the search for molecular ON/OFF switches. We have synthesized a reversible double cyclome-tallated switch based on the Ru(tpy) complex of 3,8-bis-(6-thiophen-2-yl-pyridin-2-yl)-[4,7]phenanthroline. Upon treatment with acid/base the complex can be switched between the cyclometallated and the S-bonded form. This prototype has potentially three different states which opens the path to systems based on ternary computer logic.

2,6-Disubstituted spiro[3.3]heptanes were synthesized to investigate and develop synthetic methods for preparation of these compounds. Possibilities for introducing different functionalities like nitriles and sulfonamides were also investigated.   Synthetic routes presented describe successive [2+2] cycloadditions between dichloroketene and olefins to give the sought after spiro compounds with low to moderate yields throughout the multi-step synthesis. [2+2] Cycloadditions offered low turnovers and chromatography was required for purification.   A synthetic route with cyclisations through double substitution reactions between di-electrophiles and di-nucleophiles resulting in a 2,6-disubstituted spiro[3.3]heptane is also described. This multi-step synthesis offered higher turnover and yields and often there was no need for purification through chromatography.

The use of enzymes as catalysts in organic synthesis constitutes an attractive alternative to conventional chemical catalysis. Enzymes are non-toxic and biodegradable and they can operate under mild reaction conditions. Furthermore, they often display high chemo-, regio- and stereoselectivity, enabling specific reactions with single product outcome. By the use of protein engineering, enzymes can be altered for the specific needs of the researcher. The major part of this thesis describes engineering of lipase A from Candida antarctica (CalA), for improved enantioselectivity in organic synthetic transformations. The first part of the thesis describes a highly combinatorial method for the introduction of mutation sites in an enzyme library. By the simultaneous introduction of nine mutations, we found an enzyme variant with five out of the nine possible mutations. This quintuple variant had an enlarged active site pocket and was enantioselective and active for our model substrate, an ibuprofen ester. This is a bulky substrate for which the wild-type enzyme shows no enantioselectivity and very poor activity. In the second part of the thesis, we continued our approach of combinatorial, focused enzyme libraries. This time we aimed at decreasing the alcohol pocket of CalA, in order to increase the enantioselectivity for small and medium-sized secondary alcohols. The enzyme library was bound on microtiter plates and screened by a transacylation reaction in organic solvent. This library yielded an enzyme variant with high enantioselectivity for the model substrate 1-phenyl ethanol, and high to excellent selectivity for other alcohols tested. Screening in organic solvent is advantageous since a potential hit is more synthetically useful. In the third part of the thesis, we used manipulated beads of controlled porosity glass (EziG™) for enzyme immobilization, and demonstrated the generality of this carrier for several enzyme classes. EziG™ allowed fast enzyme immobilization with simultaneous purification and yielded active biocatalysts in all cases. The last project describes the function of the proposed active site flap in CalA. In our study, we removed this motif. The engineered variant was compared to the wild-type enzyme by testing the amount of interfacial activation and the selectivity for certain alcohols. We showed that the motif is indeed controlling the entrance to the active site and that the flap is not part of the enantioselectivity determining machinery. / <p>At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 4: Manuscript.</p>

This thesis focuses on the development of methods for the activation of the hydroxyl group in non-derivatized alcohols in substitution reactions. The thesis is divided into two parts, describing three different catalytic systems. The first part of the thesis (Chapter 2) describes nucleophilic allylation of amines with allylic alcohols, using a palladium catalyst to generate unsymmetrical diallylated amines. The corresponding amines were further transformed by a one-pot ring-closing metathesis and aromatization reaction to afford β-substituted pyrroles with linear and branched alkyl, benzyl, and aryl groups in overall moderate to good yields. The second part (Chapters 3 and 4) describes the direct intramolecular stereospecific nucleophilic substitution of the hydroxyl group in enantioenriched alcohols by Lewis acid and Brønsted acid/base catalysis. In Chapter 3, the direct intramolecular substitution of non-derivatized alcohols has been developed using Fe(OTf)3 as catalyst. The hydroxyl groups of aryl, allyl, and alkyl alcohols were substituted by the attack of O- and N-centered nucleophiles, to provide five- and six-membered heterocycles in up to excellent yields with high enantiospecificities. Experimental studies showed that the reaction follows first-order dependence with respect to the catalyst, the internal nucleophile, and the internal electrophile of the substrate. Competition and catalyst-substrate interaction experiments demonstrated that this transformation proceeds via an SN2-type reaction pathway. In Chapter 4, a Brønsted acid/base catalyzed intramolecular substitution of non-derivatized alcohols was developed. The direct intramolecular and stereospecific substitution of different alcohols was successfully catalyzed by phosphinic acid (H3PO2). The hydroxyl groups of aryl, allyl, propargyl, and alkyl alcohols were substituted by O-, N-, and S-centered nucleophiles to generate five- and six-membered heterocycles in good to excellent yields with high enantiospecificities. Mechanistic studies (both experiments and density functional theory calculations) have been performed on the reaction forming five-membered heterocyclic compounds. Experimental studies showed that phosphinic acid does not promote SN1 reactivity. Rate-order determination indicated that the reaction follows first-order dependence with respect to the catalyst, the internal nucleophile, and the internal electrophile. DFT calculations corroborated with a reaction pathway in which the phosphinic acid has a dual activation mode and operates as a bifunctional Brønsted acid/Brønsted base to simultaneously activate both the nucleophile and nucleofuge, resulting in a unique bridging transition state in an SN2-type reaction mechanism. / <p>At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 2: Manuscript. Paper 4: Manuscript.</p>

Antioxidants are widely used to protect organic materials from damages caused by autoxidation, an oxidation process that occurs under normal aerobic conditions. In this thesis, novel multifunctional organoselenium and organotellurium antioxidants were designed, synthesized, and evaluated in search for compounds with better radical-trapping capacity, regenerability, and hydroperoxide-decomposing ability. Selenium was incorporated into ebselenols and hydroxy-2,3-dihydrobenzo[b]selenophenes and tellurium into diaryl disulfides and aryltellurophenols. All newly developed antioxidants were evaluated in a chlorobenzene/water two-phase lipid peroxidation system containing suitable co-antioxidants in the aqueous phase. Ebselenol carrying a hydroxyl group (OH) ortho to selenium showed a two-fold longer inhibition time than the reference α-tocopherol in the presence of aqueous-phase ascorbic acid. 2,3-Dihydrobenzo[b]selenophenes carrying a 5- or 7-OH outperformed α-tocopherol both when it comes to radical-trapping capacity and regenerability. Alkyltellurothiophenols, in situ formed from their corresponding disulfides by tris(2-carboxyethyl)phosphine, were also efficient regenerable radical-trapping antioxidants. The consumption of N-acetylcysteine in the water phase was followed and found to be limiting for the duration of the inhibition. The hydroperoxide-decomposing ability of all organoselenium antioxidants was evaluated. Ebselenols were often better glutathione peroxidase mimics than the parent. In an effort to find out more about antioxidant mechanisms, aryltellurophenols carrying electron donating and electron withdrawing groups in the phenolic or aryltelluro parts were synthesized and OH bond dissociation enthalpies, BDEO-Hs, were calculated. Compounds carrying electron donating groups in the phenolic or aryltelluro part of the molecule showed the best radical-trapping capacity. Deuterium labelling experiments suggested that hydrogen atom transfer could be the rate-limiting step in the antioxidant mechanism.

This thesis covers the development of catalytic methodologies for the mild and chemoselective hydrosilylation of amides. The first part describes the investigation of the Mo(CO)6-catalyzed reduction of carboxamides. It was found that the reduction could be controlled by tuning the reaction temperature and either amines or aldehydes could be obtained selectively. The system showed an unprecedented chemoselectivity and the amide reduction could take place in the presence of other reducible functional groups such as ketones, aldehydes, and imines. Moreover, the transformation could be performed on a preparative scale and was further employed in the synthesis of Donepezil, a pharmaceutical drug used in the treatment of Alzheimer´s disease. The third chapter concerns the development of the Mo(CO)6-mediated hydrosilylation protocol for the reduction of carboxamides containing acidic α-hydrogens. In this case, enamines were formed and a high level of chemoselectivity was observed. Enamines containing sensitive functional groups such as ketones, aldehydes and imines were generated. The enamines were not isolated but used in subsequent catalytic reductive functionalization of amides, which is described in the last part of the thesis (Chapters 4 – 7). The in situ formed enamines were reacted with a wide variety of electrophiles, generating heterocyclic compounds as triazolines, triazoles, 4,5-dihydroisoxazoles and pyrimidinediones. N-sulfonylformamidines as well as thioacrylamides could also be prepared with this approach. The protocols for the synthesis of triazolines, triazoles and N-sulfonylformamidines could additionally be performed on a preparative scale, showing the practicality of the methodology.

New and more efficient magnetic materials for energy applications are a big necessity for sustainable future. Whether the application is energy conversion or refrigeration, materials based on sustainable elements should be used, which discards all rare earth elements. For energy conversion, permanent magnets with high magnetisation and working temperature are needed whereas for refrigeration, the entropy difference between the non-magnetised and magnetised states should be large. For this reason, magnetic materials have been synthesised with high temperature methods and structurally and magnetically characterised with the aim of making a material with potential for large scale applications. To really determine the cause of the physical properties the connections between structure (crystalline and magnetic) and, mainly, the magnetic properties have been studied thoroughly. The materials that have been studied have all been iron based and exhibit properties with potential for the applications in mind. The first system, for permanent magnet applications, was Fe5SiB2. It was found to be unsuitable for a permanent magnet, however, an interesting magnetic behaviour was studied at low temperatures. The magnetic behaviour arose from a change in the magnetic structure which was solved by using neutron diffraction. Substitutions with phosphorus (Fe5Si1-xPxB2) and cobalt (Fe1-xCox)5PB2 were then performed to improve the permanent magnet potential. While the permanent magnetic potential was not improved with cobalt substitutions the magnetic transition temperature could be greatly controlled, a real benefit for magnetic refrigeration. For this purpose AlFe2B2 was also studied, and there it was found, conclusively, that the material undergoes a second order transition, making it unsuitable for magnetic cooling. However, the magnetic structure was solved with two different methods and was found to be ferromagnetic with all magnetic moments aligned along the crystallographic a-direction. Lastly, the origin of magnetic cooling was studied in Fe2P, and can be linked to the interactions between the magnetic and atomic vibrations.

This thesis discusses methods for the comparatively mild covalent functionalization of graphene. Several graphene models were investigated: polycyclic aromatic hydrocarbons (PAHs), chemical vapor deposition (CVD)-graphene on SiO2/Si substrate, graphite foil, graphite flakes, kish graphite and highly oriented pyrolytic graphite. The PAHs were viewed as graphene edge analogs with the following molecules representing different edge motifs: pyrene, perylene, benzo[a]pyrene, benzo[e]pyrene, triphenylene, acenapthylene, and anthracene. Ozone was used in combination with different solvents to functionalize PAHs, graphite, and CVD-graphene on SiO2/Si. Ozonation in water or methanol resulted in trapping of the carbonyl oxide intermediate that was formed in the reaction, producing a variety of functional groups. Ozonation in hydrogen peroxide solution with sonication promoted radical formation, possibly resulting in edge-oxidation of graphite. The regioselectivity for addition reactions (ozonolysis) and electrophilic aromatic substitution reactions with graphene edges is discussed. To achieve functionalization of the basal plane of graphite or graphene, white light irradiation was used in combination with several transfer hydrogenation reagents. Formic acid treatment under irradiation resulted in the expected hydrogenation, whereas iso-propanol treatment resulted in iso-propanol attachment to the graphene. The developed methods provide opportunities for graphene functionalization without the need for metal based reagents or harsh conditions.