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Tricyanofuran-type metastable-state photoacids, relative newcomers to the field of photochromism, outperform traditional light-controlled molecular switches in regards to applicability in biological systems. In a preliminary attempt to understand the underlying processes that govern these compounds, this thesis project establishes the isomeric identity of an unsubstituted tricyanofuran-type metastable-state photoacid, referred to as TCF 1 in this work. Two-dimensional nuclear magnetic resonance experiments are employed to experimentally determine the presence and identity of the open-form TCF 1 isomers. Electronic structure calculations are then used to provide quantitative insight into the experimental results. Experiment and theory show that four out of eight possible open-form isomers exist in solution. To validate the information obtained theoretically, the calculation methodologies are tested against experimental chemical shifts. The impressive agreement with the experiments gives credibility to the picture painted by the theoretical models.

This thesis examines the design, synthesis and biological applications of a series of inhibitors which incorporate an azobenzene photoswitch, a peptidyl backbone and a trifluoromethyl ketone warhead. The photoswitch can be isomerised by irradiation with UV or visible light and has been employed to modulate the reactivity of the enzyme. Chapter one gives a brief outline of some of the important areas related to this work. Examples of previously utilised photoswitches as well as some background on serine protease and the uses of fluorine in medicine has been covered. Chapter two outlines the synthesis of the key trifluoromethyl carbinol 2.6 by two different methods. The condensation of a fluorinated aldehyde with a nitroalkane affords an α-nitro trifluoromethyl carbinol which can be reduced to give the desired amine 2.6. Treatment of oxazolones with trifluoroacetic anhydride via a modified Dakin-West reaction gives trifluoromethyl ketones which can be reduced to give trifluoromethyl carbinols. Chapter three investigate the synthesis of substituted stilbenes and phenanthrenes as alternative molecular switches to azobenzenes. Molecular modelling of phenanthrenes suggests they may be suitable mimics of E-azobenzenes. Chapter four outlines the synthesis of a series of mono and disubstituted azobenzenes by direct sulfonation of azobenzene or by condensation of nitroso arenes with aryl amines. The switches incorporate one or two peptidyl residues designed to improve specificity towards the enzyme. Chapter five examines the photoisomerisation of eight potential inhibitors by irradiating with UV or visible light. Irradiation with UV light enriches the sample to give 78-93 % of the Z-isomer. Irradiation with visible light gave photostationary states with 14-21 % Z-isomer. Ambient photostationary states are ca. 22 % Z-isomer. Chapter six looks at the testing of five trifluoromethyl ketones as potential inhibitors ofα-chymotrypsin. The inhibitors vary in substituents, substitution patterns and chain length. The inhibitors were tested at both ambient and Z-enriched photostationary states and were found to exhibit slow binding kinetics. In all cases the Z-enriched inhibitor solution was at least 3-fold more potent than the ambient solution. Chapter seven is an experimental chapter and outlines the synthesis of the compounds prepared in this thesis.

This thesis examines the design, synthesis and biological applications of a series of inhibitors which incorporate an azobenzene photoswitch, a peptidyl backbone and a trifluoromethyl ketone warhead. The photoswitch can be isomerised by irradiation with UV or visible light and has been employed to modulate the reactivity of the enzyme. Chapter one gives a brief outline of some of the important areas related to this work. Examples of previously utilised photoswitches as well as some background on serine protease and the uses of fluorine in medicine has been covered. Chapter two outlines the synthesis of the key trifluoromethyl carbinol 2.6 by two different methods. The condensation of a fluorinated aldehyde with a nitroalkane affords an α-nitro trifluoromethyl carbinol which can be reduced to give the desired amine 2.6. Treatment of oxazolones with trifluoroacetic anhydride via a modified Dakin-West reaction gives trifluoromethyl ketones which can be reduced to give trifluoromethyl carbinols. Chapter three investigate the synthesis of substituted stilbenes and phenanthrenes as alternative molecular switches to azobenzenes. Molecular modelling of phenanthrenes suggests they may be suitable mimics of E-azobenzenes. Chapter four outlines the synthesis of a series of mono and disubstituted azobenzenes by direct sulfonation of azobenzene or by condensation of nitroso arenes with aryl amines. The switches incorporate one or two peptidyl residues designed to improve specificity towards the enzyme. Chapter five examines the photoisomerisation of eight potential inhibitors by irradiating with UV or visible light. Irradiation with UV light enriches the sample to give 78-93 % of the Z-isomer. Irradiation with visible light gave photostationary states with 14-21 % Z-isomer. Ambient photostationary states are ca. 22 % Z-isomer. Chapter six looks at the testing of five trifluoromethyl ketones as potential inhibitors ofα-chymotrypsin. The inhibitors vary in substituents, substitution patterns and chain length. The inhibitors were tested at both ambient and Z-enriched photostationary states and were found to exhibit slow binding kinetics. In all cases the Z-enriched inhibitor solution was at least 3-fold more potent than the ambient solution. Chapter seven is an experimental chapter and outlines the synthesis of the compounds prepared in this thesis.

Molecular photoswitches are attracting much attention lately mostly because of their possible applications in nano technology, and their role in biology. One of the widely studied representatives of photochromic molecules is azobenzene (AB). With light, by a static electric field, or with tunneling electrons this specie can be "switched" from the flat and energetically more stable trans form, into the compact cis form. The back reaction can be induced optically or thermally. Quantum chemical calculations, mostly based on density functional theory, on the AB molecule, AB derivatives and related systems are presented. All the calculations were done for isolated species, however, with implications for latest experimental results aiming at the switching of surface mounted ABs. In some of these experiments, it is assumed that the switching process is substrate mediated, by attaching an electron or a hole to the adsorbate forming short-lived anion or cation resonances. Therefore, we calculated also cationic and anionic ABs in this work. An influence of external electric fields on the potential energy surfaces, was also studied. Further, by the type, number and positioning of various substituent groups, systematic changes on activation energies and rates for the thermal cis-to-trans isomerization can be enforced. The nature of the transition state for ground state isomerization was investigated. Applying Eyring's transition state theory, trends in activation energies and rates were predicted and are, where a comparison was possible, in good agreement with experimental data. Further, thermal isomerization was studied in solution, for which a polarizable continuum model was employed. The influence of substitution and an environment leaves its traces on structural properties of molecules and quantitative appearance of calculated UV/Vis spectra, as well. Finally, an explicit treatment of a solid substrate was demonstrated for the conformational switching, by scanning tunneling microscope, of a 1,5-cyclooctadiene (COD) molecule at a Si(001) surface, treated by a cluster model. At first, we studied energetics and potential energy surfaces along relevant switching coordinates by quantum chemical calculations, followed by the switching dynamics using wave packet methods. We show that, in spite the simplicity of the model, our calculations support the switching of adsorbed COD, by inelastic electron tunneling at low temperatures. / Um den technologischen Fortschritt zu gewährleisten, ist man in vielen technischen Gebieten auf der Suche nach neuen und leistungsfähigeren Materialien. In der Computer- und Informationstechnologie folgte daraus die stetige Miniaturisierung von Bauelementen. Molekulare Photoschalter sind häufig an biologischen Prozessen beteiligt und äußerst vielversprechend, auf diesem Gebiet Anwendung zu finden. Ein sehr umfangreich studiertes photochromes Molekül ist Azobenzol (AB). Diese Spezien können durch Licht, statische elektrische Felder oder elektronisches Tunneln von der energetisch stabilen trans Form zur geometrisch kompakten cis Form "geschaltet" werden. Die Rückreaktion kann optisch oder thermisch erfolgen. In dieser Arbeit werden vorwiegend auf der Dichtefunktionaltheorie beruhende quantenchemische Rechnungen von AB, AB-Derivaten und verwandten Systemen vorgestellt. Alle Rechnungen betrachten isolierte Moleküle, werden jedoch in Zusammenhang mit neuesten experimentellen Ergebnissen zu oberflächengebundenen AB-Schaltern gestellt. In einigen dieser Experimente wird angenommen, dass der Schaltprozess substratvermittelt erfolgt, indem dem Adsorbat ein Elektron zugeführt oder entzogen und so eine kurzlebige anionische oder kationische Resonanz erzeugt wird. Daher werden sowohl ionische AB berechnet als auch der Einfluss eines externen elektrischen Feldes auf die Potentialhyperfläche studiert. Weiterhin können Aktivierungsenergie und Reaktionsrate der thermischen cis-trans-Isomerisierung durch Art, Anzahl und Position verschiedener Substituenten variieren. Die Natur des Übergangszustandes wird daher intensiv erforscht. Mit Hilfe der Theorie des Übergangszustandes nach Eyring werden Reaktionsraten prognostiziert, welche gut mit experimentellen Daten übereinstimmen. Daneben wird die thermische Isomerisierung in einem Lösungsmittel unter Verwendung des polarizable continuum model untersucht, da der Einfluss des Substituenten und die Anwesenheit einer Umgebung zu Veränderungen der strukturellen Eigenschaften der Moleküle und dem quantitativen Verlauf der berechneten UV/Vis-Spektren führen. Abschließend wird unter expliziter Einbeziehung eines festen Substrates das elektronisch getriebene konformale Schalten von 1,5-Cyclooctadien (COD) an einer Si(001)-Oberfläche demonstriert. Zunächst wird die Energetik und die Potentialhyperfläche entlang der relevanten Schaltkoordinaten durch quantenchemische Rechnungen ermittelt und das Schaltverhalten durch Wellenpaketmethoden beschrieben. Trotz der Einfachheit wird gezeigt, dass ein derartiges Modell das elektronische Schalten von adsorbiertem COD bei niedrigen Temperaturen gut beschreibt.

In this thesis, a combination of density functional theory (DFT) based calculations and nonequilibrium Green’s functions are employed to investigate electron transport in molecular switches, molecular cords and nanoscale devices.   Molecular electronic devices have been proposed as an approach to complement today’s silicon based electronic devices. However, engineering of such miniature devices and design of functional molecular components still present significant challenges.   First, the way to connect a molecule to conductive electrodes has to be controlled. We study, in a nanoelectrode-nanoparticle platform, how structural changes affect the measured conductance and how current fluctuations due to these structural changes can be decreased. We find that, for reproducible measurements, it is important to have the molecules chemically bonded to the surfaces of adjacent nanoparticles. Furthermore, we show by a combination of DFT and theoretical modeling that we can identify signals from single-molecules in inelastic electron spectroscopy measurements on these devices.   Second, active elements based on molecules, some examples being switches, rectifiers or memory devices, have to be designed. We study molecular conductance switches that can be operated by light and/or temperature. By tuning the substituents on the molecules, we can optimize the shift of the most conducting molecular orbital and increase the effective coupling between the molecule and the electrodes when going from the OFF to the ON-state of the switches, giving high switching ratio (up to three orders of magnitude). We also study so called mechanoswitches that are activated by a mechanical force elongating the molecules, which means that these switches could operate as sensors.   Furthermore, we have studied two different classes of compounds that may function either as rigid molecular spacers with a well-defined conductance or as molecular cords. In both cases, we find that it is of great importance to match the conjugation of the anchoring groups with the molecular backbone for high conductance.   The last part of the thesis is devoted to another interesting semiconductor material, diamond. We have accurately calculated the band structure and effective masses for this material. Furthermore, these results have been used to calculate the Hall coefficient, the resistivity and the Seebeck coefficient.

The aim of this thesis is the quantum dynamical study of two examples of scanning tunneling microscope (STM)-controllable, Si(100)(2x1) surface-mounted switches of atomic and molecular scale. The first example considers the switching of single H-atoms between two dangling-bond chemisorption sites on a Si-dimer of the Si(100) surface (Grey et al., 1996). The second system examines the conformational switching of single 1,5-cyclooctadiene molecules chemisorbed on the Si(100) surface (Nacci et al., 2008). The temporal dynamics are provided by the propagation of the density matrix in time via an according set of equations of motion (EQM). The latter are based on the open-system density matrix theory in Lindblad form. First order perturbation theory is used to evaluate those transition rates between vibrational levels of the system part. In order to account for interactions with the surface phonons, two different dissipative models are used, namely the bilinear, harmonic and the Ohmic bath model. IET-induced vibrational transitions in the system are due to the dipole- and the resonance-mechanism. A single surface approach is used to study the influence of dipole scattering and resonance scattering in the below-threshold regime. Further, a second electronic surface was included to study the resonance-induced switching in the above-threshold regime. Static properties of the adsorbate, e.g., potentials and dipole function and potentials, are obtained from quantum chemistry and used within the established quantum dynamical models. / Die vorliegende Doktorarbeit befasst sich mit kleinsten schaltbaren Einheiten in Form des Moleküls Cyclooctadien (COD) und dem Wasserstoff-Atom, die chemisch fest mit einer Oberfläche aus kristallinem Silizium verbunden sind. Jeder dieser Schalter kann mittels einer winzigen Spitze, eines so genannten Rastertunnelmikroskops (RTM), von atomarem Durchmesser in zwei unterscheidbare und stabile Schaltpositionen gebracht werden. Dabei besteht das Schalten entweder in einer Änderung der Geometrie des molekularen Schalters oder im Brechen und Neu-knüpfen chemischer Bindungen. Dabei ist es entscheidend, dass durch die geringe Grösse dieser Schalter eine hohe Anzahl dieser Schalter auf einer Oberfläche deponiert werden können. Mit der in den Schaltern speicherbaren Informationen an oder aus, 0 oder 1 ließen sich sehr hohe Speicherkapazitäten erreichen. Vor einer Anwendung dieser Art ist es wichtig zunächst ein grundlegendes Verständnis der Schaltprozesse auf der Oberfläche zu gewinnen. Wenn alle wesentlichen Faktoren berücksichtigt wurden und der Mechanismus des Schaltens verstanden ist, kann das Ergebnis des Experiments mit Hilfe eines theoretischen Modells vorhergesagt werden. Für die Handhabbarkeit muss sich das theoretisches Modell auf wesentliche Einflüsse beschränken und diese so einfach wie möglich beschreiben. So wurde die simultane Bewegung der 12 Atome des COD in die Bewegung eines gemittelten Massenpunktes entlang von einer oder von zwei räumlichen Freiheitsgraden übersetzt. Dabei kann der Massenpunkt im klassischen Bild anschaulich als eine rollende Kugel beschrieben werden, die in einer Seite einer Doppelmulde gefangen ist. Die Kugel kann durch äußere Anregung zum Schwingen gebracht werden und schließlich über eine Barriere in die benachbarte Mulde schalten. Nun muss die Schwingung der Kugel gebremst werden, um ein Zurück-Schwingen der Kugel zu verhindern. Die Anregung erfolgt durch elektrische Ladungen die von der Spitze des RTM zur Oberfläche wandern oder durch eine schwingende, d.h. warme Oberfläche. Das Bremsen wird über die elastische Bindung zu einer kalten Oberfläche vermittelt. Um Quanteneffekte wie das Tunneln der Kugel durch die Barriere zu beschreiben wurde die Kugel durch ein Wellenpaket beschrieben und dessen Aufenthaltswahrscheinlichkeit in der Doppelmulde untersucht. Im Fall des Wasserstoffatoms war die experimentelle Prüfung des entworfenen Modells für ein Schalten bei starkem Strom leider nicht möglich. Für das COD Molekül konnte jedoch nicht nur die Übereinstimmung mit den experimentellen Befunden, sondern im Fall des Schaltens in Abhängigkeit der Oberflächentemperatur auch die Vorhersagefähigkeit des Modells unter Beweis gestellt werden.

Small molecule dependent molecular switches that control gene expression are important tool in understanding biological cellular processes and for regulating gene therapy. Nuclear receptors are ligand activated transcription factors that have been engineered to selectively respond to synthetic ligands and used as regulators of gene expression. In this work the retinoid X receptor (RXR), has been used to develop an inducible molecular switch with a near drug like compound LG335. Three RXR variants (Q275C; I310M; F313I), (I268A; I310A; F313A; L436F), (I268V; A272V; I310M; F313S; L436M) were created via site-directed mutagenesis and a structure based approach, such that they preferentially bind to the synthetic ligand LG335 and not its natural ligand, 9-cis retinoic acid. These variants show reverse ligand specificity as designed and have an EC50 for LG335 of 80 nM, 30 nM, 180 nM, respectively. The ligand binding domains of the RXR variants were fused to a yeast transcription factor Gal4 DNA binding domain. This modified chimeric fusion protein showed reverse response element specificity as designed and recognized the Gal4 response element instead of the RXR response element. The modified RXR protein did not heterodimerize with wild type RXR or with other nuclear receptor such as retinoic acid receptor. These RXR-based molecular switches were tested in retroviral vectors using firefly luciferase and green fluorescence protein and they maintain their inducible behavior with LG335. These experiments demonstrate the orthogonality of RXR variants and their possible use in regulating gene therapy.

Several photochromic dihydropyrenes were designed to test whether the DHP molecule retains its response to light when it is bound to the first row transition metals. DAP 26, NDAP 22 and BDAP 21 were composed of the parent DHP 11, naphthoyl-DHP 38 and the BDHP 12 fragments respectively that were bound via a Sonogashira coupling to the phenanthroline unit through an acetylene linker. A condensation reaction between DHP-imid 29 and BDHP-imid 50 with phenanthroline diketone 28 in the presence of an excess of NH4+OAc- yielded the imidazole functionalized dihydropyrenes DHP-imid 23 and BDHP-imid 24 respectively. PDD 25 which is a [e]pyrazino annelated DHP 11 was obtained from condensation of the DHP-diamine, generated in situ from its dinitro precursor 45, with phenanthroline diketone 28. Compounds 21, 24 and 25 responded reversibly to UV and visible irradiation while also undergoing thermal return. NDAP 22 decomposed upon exposure to UV while being converted from its open to the closed state. Acac and hfac complexes of BDAP 52-55 and of PDD 60-61 were synthesized by reacting Co(acac)2(H2O)2 51 and M(hfac)2 59 (where M = Co2+, Mn2+, Ni2+) with one equivalent of either BDAP 21 or PDD 25 photochrome respectively. Co(acac)2(BDAP) 52 and Co(acac)2(PDD) 60 complexes showed reversible opening and closing under alternative UV and visible irradiation for at least 10 cycles. Mn(hfac)2(BDAP) 53, Ni(hfac)2(BDAP) 54 and Co(hfac)2(BDAP) 55 complexes opened upon exposure to visible light and then closed with heating in the dark. Thermodynamic parameters ΔEact, ΔH‡ and ΔS‡ were determined after fitting the closing rate constant data for each species at 54, 64 and 74 °C (unless stated otherwise) to Arrhenius and Eyring equations.

Part I . We explored the synthesis of a C -glycoside synthesis from L-fucose and malononitrile in the presence of a base catalyst. The reaction was much faster than the previously studied Henry condensation, and went further---to a double cyclization of 2:1 adduct with a novel dioxabicyclic structure. It provides a new route for the synthesis of chiral polysubstituted dihydropyrans and dihydropurans. A series of carbasugars was synthesized and tested for inhibitory activity towards fungal glycosidases from Aspergillus oryzae and Penicillium canescens . In order to reveal the dependence of inhibition on the alkyl group R, several derivatives with variable alkyl chain lengths were prepared and screened. Part II . Cyclohexane-based conformationally controlled ionophores, an emerging new class of molecular switches, provide a new and promising approach to allosteric systems with negative cooperativity. Protonation of trans -2-aminocyclohexanols was observed to cause dramatic conformational changes: due to an intramolecular hydrogen bond, a conformer with equatorial position of ammonio- and hydroxy-groups becomes predominant. This signal is mechanically transmitted by the structure of the molecule, inducing a conformational change in the second site and decreasing its affinity for an appropriate guest. Thus, these structures can serve as powerful conformational pH-triggers. The trans -2-aminocyclohexanol moiety has been used for pH-triggered conformational switching of crown ethers and podands, and their complexes with metal ions. The variation of the NR 2 group allows broad tuning of the conformational equilibrium, and thus tuning of the complexing ability of these allosteric ionophores. Heterotropic allosteric systems with high negative cooperativity may find many applications, such as membrane transport and drug delivery.