<p>In this thesis, the preparation of new photoactive substances containing mono- and bipyridines coordinated to ruthenium is presented together with initial evaluations of their photoelectrochemical and photophysical properties. </p><p>Complexes of the type Ru(bpy)₂(4-X-py)₂ (X = SH, COOH) were prepared and used in Grätzel-type solar cells based on ZnO. The results show that the thiol complex binds to the surface but give rather low solar cell efficiencies. Different routes to obtain Ru(bpy)₂(4,4´-dithio-2,2´-bipyridine) were evaluated, among them substitution reactions on 4,4´-dichloro-2,2´-bipyridine coordinated to ruthenium. Due to reactivity issues, the target sulphur-containing complex has not yet been obtained.</p><p>The synthesis of methanofullerenes, fulleropyrrolidines and –pyrazolines are presented, among them dyads containing Ru(bpy)_n-units. A common feature for the dyads is the unusually short linkers between the fullerene and the ruthenium complex. Dyad preparations were in some cases simplified by carrying out the reactions in the presence of silver salts.</p><p>A preliminary evaluation of the emission of the dyads showed almost complete quenching of the excited state of a pyrrolidine-based dyad, whereas emission remained from the pyrazoline-based ones. Whether this was due to incomplete quenching of the excited states of the ruthenium complex, or induced by the presence of hydrazones has yet to be revealed.</p><p>The use of fullerene-substituted malonic acid and its ethyl ester as dyes in Grätzel-type solar cells resulted in even lower efficiencies (IPCE) than for bare TiO₂. This could be due to electron transfer in the reverse direction compared to what is observed for ruthenium complexes. Thus, these fullerene derivatives are not suitable as sensitisers for Grätzel-type solar cells.</p>

This thesis describes the design, synthesis and structure-activity relationships analysis of potential inhibitors targeting the hepatitis C virus (HCV) NS3 protease. Also discussed is the disease caused by HCV infection and the class of enzymes known as proteases. Furthermore are explained why such enzymes can be considered to be suitable targets for developing drugs to combat diseases in general and in particular HCV, focusing on the NS3 protease. Moreover, some strategies used to design protease inhibitors and the desired properties of potential drug candidates are briefly examined. Synthesis of linear and macrocyclic NS3 protease inhibitors comprising a designed trisubstituted cyclopentane moiety as an N-acyl-(4R)-hydroxyproline bioisostere is also addressed, and several very potent and promising compounds are evaluated. / Report code: LIU-TEK-LIC-2006:46.

In this thesis, the preparation of new photoactive substances containing mono- and bipyridines coordinated to ruthenium is presented together with initial evaluations of their photoelectrochemical and photophysical properties. Complexes of the type Ru(bpy)2(4-X-py)2 (X = SH, COOH) were prepared and used in Grätzel-type solar cells based on ZnO. The results show that the thiol complex binds to the surface but give rather low solar cell efficiencies. Different routes to obtain Ru(bpy)2(4,4´-dithio-2,2´-bipyridine) were evaluated, among them substitution reactions on 4,4´-dichloro-2,2´-bipyridine coordinated to ruthenium. Due to reactivity issues, the target sulphur-containing complex has not yet been obtained. The synthesis of methanofullerenes, fulleropyrrolidines and –pyrazolines are presented, among them dyads containing Ru(bpy)n-units. A common feature for the dyads is the unusually short linkers between the fullerene and the ruthenium complex. Dyad preparations were in some cases simplified by carrying out the reactions in the presence of silver salts. A preliminary evaluation of the emission of the dyads showed almost complete quenching of the excited state of a pyrrolidine-based dyad, whereas emission remained from the pyrazoline-based ones. Whether this was due to incomplete quenching of the excited states of the ruthenium complex, or induced by the presence of hydrazones has yet to be revealed. The use of fullerene-substituted malonic acid and its ethyl ester as dyes in Grätzel-type solar cells resulted in even lower efficiencies (IPCE) than for bare TiO2. This could be due to electron transfer in the reverse direction compared to what is observed for ruthenium complexes. Thus, these fullerene derivatives are not suitable as sensitisers for Grätzel-type solar cells.

The development of a synthetic method of radiolabelled methylphosphono-fluoridates on a milligram scale is presented. The aim of this method is, besides affording high yield, to choose reaction pathways and reagents so that handling and transfer of labelled toxic substances is minimised, thereby reducing the risk of exposure as much as possible. The only substituent that is stable enough to be labelled is the methyl group, directly bonded to phosphorus. A drawback when labelling the methyl group is that it requires the label to be introduced early in the synthesis since the carbon-phosphorus bond of the methyl substituent usually has to be synthesized a few steps ahead of the final product. Two new classes of reagents for halogenation of phosphorus oxyacids have been developed. Firstly, four different analogues of α-chloroenamines and α-fluoroenamines were evaluated. Secondly, cyanuric fluoride was assessed in solution, but more importantly, as a resin-bound reagent. The reagents are evaluated for halogenation of phosphinic, phosphonic and phosphoric acids. Cyanuric fluoride is also successfully loaded on a polystyrene resin and used as a solid-phase reagent. The reagents produce high yields and low levels of impurities on a milligram scale. Furthermore, a new method for the preparation of mono-alkylated phosphonic acids on a small scale has been developed. The new method utilises the crystal water bound to certain salts to liberate limited amounts of water in a controlled manner. Phosphonic dichlorides are in this way reacted with water to form anhydrides. The anhydride is then cleaved with an appropriate alcohol to produce mono-alkylated phosphonic acids. / Rikard Norlin = Rikard Wärme

According to the famous axiom known as Moore’s Law the number of transistors that can be etched on a given piece of ultra-pure silicon, and therefore the computing power, will double every 18 to 24 months. However, around 2020 hardware manufacturers 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 wires, diodes, transistors and capacitors. In this work we have synthesized a number of new bi- and terdentate thiophenyl pyridine and pyridyl thienopyridine ligands and compared the electrochemical, structural and photophysical properties of their corresponding Ru(II) complexes with 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 motifs. While the electrochemistry of the Ru(II) complexes were similar to that of unsubstituted [Ru(bpy)3]2+ and [Ru(tpy)2]2+, substantial differences in luminescence lifetimes were found. Our findings show that, due to steric interactions with the auxiliary bipyridyl ligands, luminescence is quenched in Ru(II) complexes that incorporate the 6-thiophen-2-yl-2,2'-bipyridine motif, while it was comparable with the luminescence of [Ru(bpy)3]2+ in the Ru(II) complexes of bidentate pyridyl thienopyridine ligands. The luminescence of the Ru(II) complexes based on the 4-thiophen-2-yl-2,2'-bipyridine motif was enhanced compared to [Ru(bpy)3]2+ which indicates that complexes of this category may be applicable for energy/electron-transfer systems. At the core of molecular electronics is the search for molecular ON/OFF switches. Based on the ability of the ligand 6-thiophen-2-yl-2,2'-bipyridine to switch reversibly between cyclometallated and non-cyclometallated modes when complexed with Ru(tpy) we have synthesized a number of complexes, among them a bis-cyclometallated switch based on the ligand 3,8-bis-(6-thiophen-2-yl-pyridin-2-yl)-[4,7]phenanthroline, and examined their electrochemical properties. Only very weak electronic coupling could be detected, suggesting only little, if any, interaction between the ruthenium cores.

One of the largest problems in current medicine is the shortage of organs for transplant due to technological limitations in the storage of organs for any length of time. A possible solution to this problem would involve cryopreservation. However, current cryopreservatives such as sucrose or DMSO have concerning cytotoxic issues that limit their possible applications. A major cause of cryoinjury is the uncontrolled recrystallization of inter and intra-cellular ice crystals that occurs during the thawing process leading to mechanical damage and dehydration. The Ben lab has thus been interested in the design of compounds that are capable of inhibiting this process but do not possess other undesirable properties found in the native compounds. These synthetic analogues have been shown to increase cellular viability post-thaw. A series of mixed α/β glycopeptides are prepared and analyzed for antifreeze properties. The results of this study imply that it is not the gross conformation of the glycopeptide that is responsible for activity, but rather that intramolecular relationships may be responsible for disrupting the reorganization of ice. A technique was devised for the incorporation of triazoles into the analogues to investigate the importance of the linker and to greatly simplify the synthesis of a library of glycoconjugates. It was found that the IRI activity of glycopeptides is very sensitive to the distance between carbohydrate and peptide backbone. The electron density at the anomeric oxygen is an important parameter with respect to intramolecular networks. A series of substituted galactosides is presented that modify the electronics of the anomeric oxygen. The results demonstrate that decreasing electron density at this position appears to improve IRI activity in a predictable manner. To better understand the remarkable IRI activity of a key analogue, it was systematically truncated. This study led to the serendipitous discovery of a series of very highly IRI active analogues that do not contain a peptide backbone. These compounds represent the first non-glycopeptides that can show very significant IRI activity even at very low concentrations. The final portion of the thesis reports the efforts towards the preparation of a carbasugar analogue of AFGP-8.

Siphonaria zelandica, a pulmonate mollusk, has been the subject of many natural product isolation studies by several, independent research groups. These studies have yielded several polypropionate structures (e.g. 4, 6, 8, and 10), which, upon careful inspection, were proposed to be related. There has been speculation that none of these isolated structures (4, 6, 8, and 10) are biosynthetic products, but are artifacts of isolation. Instead, it has been proposed that an unstable, acyclic precursor, such as 14/15 is the biosynthetic product produced by this mollusk; the putative acyclic precursor has not been isolated or synthesized. None of the synthetic studies on this series of compounds have attempted to address the potential relationships between these structures or speak to their status as natural products.<p> This work describes the enantioselective synthesis of the putative acyclic precursor 14/15 and its isomerization to siphonarin B (4). This was the first enantioselective synthesis of siphonarin B (4). Siphonarin B (4) was shown to readily undergo a retro-Claisen rearrangement to afford baconipyrone C (6) and concurrently undergo a retro-Claisen rearrangement/aldol cascade to provide baconipyrone A (6). This was the first total synthesis of baconipyrone A (6) through an unprecedented retro-Claisen rearrangement/aldol cascade and the first total synthesis of baconipyone C (8) by a biomimetic route versus the classical esterification route. The fourth compound in this series of potentially related compounds, caloundrin B (10), was never observed despite a careful search of each reaction crude where it may have been present.<p> The relationships between these compounds were probed and it was found, that under the conditions examined, the putative acyclic precursor 14/15 is not a biosynthetic product. Instead, siphonarin B (4) or perhaps caloundrin B (10), are the most likely biosynthetic products of the mollusk. Baconipyrone C (8) is not a precursor of baconipyrone A (6). The processes responsible for baconipyrones A (6) and C (8) are irreversible. As had been previously hypothesized, baconipyrones A (6) and C (8) are most likely artifacts of isolation (i.e., not natural products). The missing link in this series of compounds is caloundrin B (10) and its isomerization and rearrangement behavior.

One of the largest problems in current medicine is the shortage of organs for transplant due to technological limitations in the storage of organs for any length of time. A possible solution to this problem would involve cryopreservation. However, current cryopreservatives such as sucrose or DMSO have concerning cytotoxic issues that limit their possible applications. A major cause of cryoinjury is the uncontrolled recrystallization of inter and intra-cellular ice crystals that occurs during the thawing process leading to mechanical damage and dehydration. The Ben lab has thus been interested in the design of compounds that are capable of inhibiting this process but do not possess other undesirable properties found in the native compounds. These synthetic analogues have been shown to increase cellular viability post-thaw. A series of mixed α/β glycopeptides are prepared and analyzed for antifreeze properties. The results of this study imply that it is not the gross conformation of the glycopeptide that is responsible for activity, but rather that intramolecular relationships may be responsible for disrupting the reorganization of ice. A technique was devised for the incorporation of triazoles into the analogues to investigate the importance of the linker and to greatly simplify the synthesis of a library of glycoconjugates. It was found that the IRI activity of glycopeptides is very sensitive to the distance between carbohydrate and peptide backbone. The electron density at the anomeric oxygen is an important parameter with respect to intramolecular networks. A series of substituted galactosides is presented that modify the electronics of the anomeric oxygen. The results demonstrate that decreasing electron density at this position appears to improve IRI activity in a predictable manner. To better understand the remarkable IRI activity of a key analogue, it was systematically truncated. This study led to the serendipitous discovery of a series of very highly IRI active analogues that do not contain a peptide backbone. These compounds represent the first non-glycopeptides that can show very significant IRI activity even at very low concentrations. The final portion of the thesis reports the efforts towards the preparation of a carbasugar analogue of AFGP-8.

Dispersed niobia catalysts were prepared via a non-aqueous synthesis route. The effects of the type of oxide support, the support thermal pre-treatment, the calcination temperature and the niobia loading on the activity and selectivity for mesityl oxide (MO) synthesis at 160C were investigated in an autoclave reactor. The morphological and chemical properties of the catalysts were characterized via EDXRF, XRD, BET and Raman spectroscopy. The strength and nature of the acid sites were elucidated via in situ DRIFT spectra of the adsorption of pyridine as well as the temperature programmed desorption of NH3 interacting with the surface oxide phase. All four catalyst parameters had significant effects on the catalytic properties. Significantly, the nature of the acidity was clearly linked to the catalyst activity and particularly the catalyst stability. Catalysts exhibiting predominantly Lewis acidity invariably deactivated despite good initial activity, with the final acetone conversion dependent on the catalyst formulation. In contrast, catalysts exhibiting Bronsted acidity showed no evidence of catalyst deactivation after 8 hours of reaction. A plausible mechanism which explains these observations is proposed. Catalysts exhibiting Lewis acidity were more active when the supports were first activated at elevated temperature, likely due to a stronger support-surface oxide interaction as a consequence of increased surface coordinative unsaturation of the support. SiO¬2 supported catalysts exhibiting Bronsted acidity were more active if the supports were initially activated at 100C. Evidently, the hydroxyl groups on the oxide support contribute to the generation of Bronsted acidity. Different oxide supports gave rise to distinct acidic and catalytic properties in the niobia overlayer. The most striking example of this was the direct comparison of niobia dispersed onto two kinds of silica supports following the same preparative method. Unique and very strong acid sites were observed in niobia dispersed onto a commercial SiO¬2 catalyst carrier that were not observed in niobia dispersed onto fumed SiO¬2. For SiO2 catalysts, the activity increased linearly with niobia loading regardless of calcination temperature. In contrast, Al2O3 catalysts exhibited an initial increase in activity for MO synthesis with niobia loading followed by a decrease in activity after reaching a maximum activity below 1/3 monolayer coverage. The effect was more pronounced for catalysts exhibiting Bronsted acidity. It is proposed that adlineation sites are primarily responsible for catalytic activity in Nb2O5/-Al2O3 catalysts exhibiting Bronsted acidity. Niobia catalysts were developed using commercially available catalyst carriers as supports. The macrokinetics of MO and MIBK syntheses were investigated in a benchtop fixed bed flow reactor. The catalysts showed excellent activity for MO and MIBK syntheses at 160°C, typically 0.9 to 1.3 [g/hr*gcat]. However, the MIBK selectivity was constrained from 82 to 85% due to the coproduction of 2-propanol and diisobutyl ketone. The productivity for MO synthesis was found to be strongly dependent on the space velocity suggesting product inhibition. The intrinsic kinetics of the one-step synthesis of MIBK over a 15.2 wt% Pd/Nb2O5/SiO2 catalyst was investigated in an autoclave reactor. A kinetic model was developed and is reported. The one step synthesis of MIBK was investigated at the pilot plant scale via catalytic distillation (CD). An important finding was that while operating at 100% reflux, the accumulation of water in the reactive section resulted in the suppression of the DAA dehydration reaction. The in situ removal of water from the reactive section via an overhead distillate stream operating at 83 to 97% reflux directly resulted in an increase in MIBK productivity and hydrogen uptake efficiency by factors of about 20 yielding a moisture free reboiler product stream with as high as 53 wt% MIBK. The process was found to be controlled by the external mass transfer of hydrogen. Interestingly, the results suggest that the catalyst wetting efficiency affects the transport of hydrogen to the active sites as evidenced by the dependence of MO conversion on the reflux flow rate. The condition of minimum reflux flow rate and maximum hydrogen flow rate resulted in 97% MO conversion and 90 wt% MIBK selectivity.

Dispersed niobia catalysts were prepared via a non-aqueous synthesis route. The effects of the type of oxide support, the support thermal pre-treatment, the calcination temperature and the niobia loading on the activity and selectivity for mesityl oxide (MO) synthesis at 160C were investigated in an autoclave reactor. The morphological and chemical properties of the catalysts were characterized via EDXRF, XRD, BET and Raman spectroscopy. The strength and nature of the acid sites were elucidated via in situ DRIFT spectra of the adsorption of pyridine as well as the temperature programmed desorption of NH3 interacting with the surface oxide phase. All four catalyst parameters had significant effects on the catalytic properties. Significantly, the nature of the acidity was clearly linked to the catalyst activity and particularly the catalyst stability. Catalysts exhibiting predominantly Lewis acidity invariably deactivated despite good initial activity, with the final acetone conversion dependent on the catalyst formulation. In contrast, catalysts exhibiting Bronsted acidity showed no evidence of catalyst deactivation after 8 hours of reaction. A plausible mechanism which explains these observations is proposed. Catalysts exhibiting Lewis acidity were more active when the supports were first activated at elevated temperature, likely due to a stronger support-surface oxide interaction as a consequence of increased surface coordinative unsaturation of the support. SiO¬2 supported catalysts exhibiting Bronsted acidity were more active if the supports were initially activated at 100C. Evidently, the hydroxyl groups on the oxide support contribute to the generation of Bronsted acidity. Different oxide supports gave rise to distinct acidic and catalytic properties in the niobia overlayer. The most striking example of this was the direct comparison of niobia dispersed onto two kinds of silica supports following the same preparative method. Unique and very strong acid sites were observed in niobia dispersed onto a commercial SiO¬2 catalyst carrier that were not observed in niobia dispersed onto fumed SiO¬2. For SiO2 catalysts, the activity increased linearly with niobia loading regardless of calcination temperature. In contrast, Al2O3 catalysts exhibited an initial increase in activity for MO synthesis with niobia loading followed by a decrease in activity after reaching a maximum activity below 1/3 monolayer coverage. The effect was more pronounced for catalysts exhibiting Bronsted acidity. It is proposed that adlineation sites are primarily responsible for catalytic activity in Nb2O5/-Al2O3 catalysts exhibiting Bronsted acidity. Niobia catalysts were developed using commercially available catalyst carriers as supports. The macrokinetics of MO and MIBK syntheses were investigated in a benchtop fixed bed flow reactor. The catalysts showed excellent activity for MO and MIBK syntheses at 160°C, typically 0.9 to 1.3 [g/hr*gcat]. However, the MIBK selectivity was constrained from 82 to 85% due to the coproduction of 2-propanol and diisobutyl ketone. The productivity for MO synthesis was found to be strongly dependent on the space velocity suggesting product inhibition. The intrinsic kinetics of the one-step synthesis of MIBK over a 15.2 wt% Pd/Nb2O5/SiO2 catalyst was investigated in an autoclave reactor. A kinetic model was developed and is reported. The one step synthesis of MIBK was investigated at the pilot plant scale via catalytic distillation (CD). An important finding was that while operating at 100% reflux, the accumulation of water in the reactive section resulted in the suppression of the DAA dehydration reaction. The in situ removal of water from the reactive section via an overhead distillate stream operating at 83 to 97% reflux directly resulted in an increase in MIBK productivity and hydrogen uptake efficiency by factors of about 20 yielding a moisture free reboiler product stream with as high as 53 wt% MIBK. The process was found to be controlled by the external mass transfer of hydrogen. Interestingly, the results suggest that the catalyst wetting efficiency affects the transport of hydrogen to the active sites as evidenced by the dependence of MO conversion on the reflux flow rate. The condition of minimum reflux flow rate and maximum hydrogen flow rate resulted in 97% MO conversion and 90 wt% MIBK selectivity.