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Biogenic monoamines such as dopamine play an important role as major neurotransmitters. Simultaneous determination of the concentration changes is thus crucial to understand brain function. Additionally, quantification of pharmaceutically active compounds (PhACs) and their metabolites in biological fluids is an important issue for forensic tests, clinical toxicology and pharmaceutical analysis. We have developed two postcolumn luminescence detection methods coupled to a 2-dimensional-solid phase extraction (2D-SPE) system. The postcolumn reaction methods used in this study are the redox-dependent photoluminescence-following electron-transfer (PFET) and Fenton-based chemiluminescence techniques, for the determination of certain neurotransmitter and nonsteroidal anti-inflammatory drugs (NSAIDs). A stable [Os(tmphen)3]3+ (tmphen = 3,4,7,8-tetramethyl-1,10-phenanthroline) reagent was prepared in neutral aqueous solution by oxidation of [Os(tmphen)3]2+ with lead(IV) oxide. [Os(tmphen)3]2+ and [Os(tmphen)3]3+ are characterized by absorption spectroscopy. [Os(tmphen)3]3+ stability is compared with [Ru(tmphen)3]3+ in the same pH 7 environment. The properties of Os(III) and Ru(III) complexes were investigated for use as the oxidant in a PFET system. Studies of photophysical and electrochemical properties, the stability of the Os(III) and Ru(III) complexes, and analytical application in PFET detection of oxidizable analytes are presented. The spectroscopic properties of the complexes were not very advantageous, but careful control of the detection system and reaction conditions enabled sensitive detection of the analytes. The method was fully validated and the optimized system was capable of detecting dopamine and acetaminophen at about 30.2 µg L-1 and 33.5 µg L-1, respectively. The limit of detection (LOD) was 1.5 µg L-1 for acetaminophen and 4.3 µg L-1 for dopamine. The accuracy and precision were within bioanalytical method validation limits (90.9 to 101.5 % and RSD < 12.0 %, respectively). Typical analysis time was less than 15 minutes. Two Fenton-based flow-injection chemiluminescence (CL) methods were developed and validated for the determination of naproxen. Under the optimal experimental conditions the proposed methods exhibited advantages in a larger linear range from 2,760 ng mL-1 to 207,000 ng mL-1 for the first CL method and 41.4 ng mL-1 to 700.0 ng mL-1 for the second CL method. The LOD was 13.8 ng mL-1 for naproxen. The CL mechanisms for the system, H2O2-FeIIEDTA-naproxen was further studied by batch experiments, chemiluminescence spectroscopy, fluorometry, high pressure liquid chromatography (HPLC) and Fourier transform infrared spectroscopy (FTIR). The effects of various interferences commonly found in biological and wastewater systems on the chemiluminescence intensity were also investigated. We used these methods to determine NSAIDs in commercial pharmaceutical formulations. Another application of these method was for detecting NSAIDs in biological samples. A 2x-1-Dimensional Solid Phase Extraction (2x-1D SPE) method was developed for determination of acetaminophen and naproxen in urine. This method uses both the methanol concentration and the pH advantageously to preferentially isolate analytes of interest from complex sample matrix. These methods were fully validated and had sufficient sensitivity (limit of quantification: acetaminophen; 40.41 mg L-1 - 360.0 mg L-1 and naproxen; 23.03 mg L-1 - 214.8 mg L-1) for biological matrices and applications. / Chemistry

京都大学 / 新制・課程博士 / 博士(農学) / 甲第24664号 / 農博第2547号 / 新制||農||1098(附属図書館) / 学位論文||R5||N5445(農学部図書室) / 京都大学大学院農学研究科応用生命科学専攻 / (主査)教授 白井 理, 教授 菅瀬 謙治, 教授 三芳 秀人 / 学位規則第4条第1項該当 / Doctor of Agricultural Science / Kyoto University / DGAM

A dissertation is presented on the bioreduction of hematite (α-Fe2O3) nanoparticles. The study shows that an alternative extracellular electron transfer mechanism other than the classical 'direct-contact' mechanism may be simultaneously employed by Shewanella oneidensis MR-1 during solid-phase metal reduction. This conclusion is supported by analysis of the bioreduction kinetics of hematite nanoparticles coupled with microscopic investigations of cell-mineral interactions. The reduction kinetics of metal-oxide nanoparticles were examined to determine how S. oneidensis utilizes these environmentally-relevant solid-phase electron acceptors. Nanoparticles involved in geochemical reactions show different properties relative to larger particles of the same phase, and their reactivity is predicted to change as a function of size. To demonstrate these size-dependent effects, the surface area normalized reduction rates of hematite nanoparticles by S. oneidensis MR-1 with lactate as the sole electron donor were measured. As evident from whole cell TEM analysis, the mode of nanoparticle adhesion to cells is different between the more aggregated, pseudo-hexagonal to irregular shaped 11 nm, 12 nm, 99 nm and the less aggregated 30 nm and 43 nm rhombohedral particles. The 11 nm, 12 nm and 99 nm particles show less cell contact and coverage than the 30 nm and 43 nm particles but still show significant rates of reduction. This leads to the provisional speculation that S. oneidensis MR-1 employs a pathway of indirect electron transfer in conjunction with the direct-contact pathway, and the relative importance of the mechanism employed depends upon aggregation level and the shape of the particles or crystal faces exposed. In accord with the proposed increase in electronic band-gap for hematite nanoparticles, the smallest particles (11 nm) exhibit one order of magnitude decrease in reduction when compared with larger (99 nm) particles, and the 12 nm rates fall in between these two. This effect may also be due to the passivation of the mineral and cell surfaces by Fe(II), or decreasing solubility due to decrease in size. / Ph. D.

Since their discovery, fullerenes and metallofullerenes have been investigated regarding their structures, synthesis, isolations, and applications. The highly symmetric structures of fullerenes and metallofullerenes lead to extraordinary physical properties, such as electron transfers, and attract major attention from the science community. It has been well established that the stabilities of fullerenes and metallofullerenes can be estimated by recognizing structural patterns. Recently, we developed a generalized spiral program and additional codes and believe they are useful for fullerene/metallofullerene researchers. The higher fullerenes, those with more than 90 carbon atoms, also follow certain structural patterns. In our studies, we have shown that the higher fullerenes with tubular structures are stable in thermodynamics and can survive the aminopropanol reaction, but other spherical fullerenes cannot. For the past three decades, great efforts have been devoted to applying fullerenes and metallofullerenes as electronic materials. In our studies, we find the ground state electron transfer properties endow metallofullerenes as an ideal material for perovskite solar cells to enhance the stabilities. It has been shown in our investigations that common metallofullerenes, such as Sc3N@C80, are capable to be as the electron transfer layers in perovskite solar cells, and the test demonstrates that our novel perovskite solar cells may achieve high stability and high efficiency. The electron transfer abilities of metallofullerenes are studied with the M2@C79N since electron densities located in between the two metal atoms convert between a single electron bond and a double electron bond. The huge spherical electron delocalized structures of fullerenes and metallofullerenes lead to strong interactions with other delocalized systems, such as graphene. Previous studies have shown that graphene has a unique ability in molecular adsorptions. However, the graphene surface is not always flat and the rippled areas have effects on the packing styles. Therefore, we examined the behavior of fullerenes on the rippled graphene surface and then compared with another flat molecule, PTCDA. The results show that the effect of rippled areas varies due to molecular structures. This study gives instructions for electronic device manufacturing using graphene and fullerenes. In our studies, polarizability is a key factor of fullerenes and metallofullerenes. It has been shown that the chromatographic retention behavior has a strong relationship with the average polarizability of a molecule. Based on the experimental data, we built a model for the prediction of chromatographic retention times using computational polarizabilities. After that, we validated the model by two series of chromatographic data. The characterization of carbon-based materials has been long investigated. In the last chapter, we introduce a dynamic nuclear polarization-based method to characterize the structures of chars and studied the adsorption of oxygen on the activated radical sites. Overall, the dissertation reports my Ph. D. studies in the areas including theoretical studies of fullerene geometries, chromatographic models, applications and also experimental studies of the applications of fullerenes/metallofullerenes and characterization. / Doctor of Philosophy / Fullerenes and metallofullerenes are important materials for engineering and science. In general, a fullerene cage contains only carbon atoms and has a closed spherical structure. Theoretically, for a given number of carbon atoms, there are thousands of different ways to assemble a fullerene structure, just like assembling Lego. However, just a limited number of fullerene molecules have been discovered. In the past four decades, several theories have been proposed to explain the fact. For example, an isolated pentagon rule shows that the fullerene structures should not have any conjugated pentagons, which will decrease the stabilities of fullerene molecules. In this dissertation, I would like to show our results, which demonstrate fullerenes that can be synthesized follow certain patterns. We apply experimental and theoretical methods to discover the patterns and explain the reason. The application of fullerenes/metallofullerenes is another hot topic. We consider the structures of fullerenes endow them extraordinary abilities of electron transfers. Therefore, we use metallofullerenes as electron transfer material in a solar cell, and we have a good solar cell with high efficiency. We also inspect the interactions between fullerenes and rippled graphene surface. The results are also extended to understand the chromatographic behavior of fullerenes. By considering the physical properties of fullerenes, we build up simple models to simulate the chromatographic retention behaviors of fullerene inside the chromatographic column. The characterization of carbon-based material is a big challenge and in this dissertation, we demonstrate our contributions of a novel method for characterization, which can detect activated carbons.

The chemistry of the radical anion generated from 1,I-dimethyl-5,7-di-tbutylspiro[ 2,5]octa-4,7-dien-6-one (<b>20</b>) was studied electrochemically using cyclic and linear sweep voltammetry (CV, LSV). The reduction potential of <b>20</b> was estimated to be -2.5 V VS. 0.1 M Ag⁺/Ag, similar to the reduction potentials observed for aryl ketones and enones. LSV results for the reduction of <b>20</b> are consistent with the occurrence of substrate reduction followed by a subsequent chemical step (an EC mechanism). The broadness of the reduction wave and variation of peak potential with sweep rate suggest that the rate limiting step is heterogeneous electron transfer. Ring opening of the radical anion generated from <b>20</b> results in a 9:1 ratio of the 3° and 1° distonic radical anions. The rate constant for ring opening has been estimated to be k ≥ 10⁷s⁻¹ with a calculated (AM1) enthalpy of ring opening of ΔH° > -15 kcal/mol. The facile nature of radical anion ring opening can be ascribed to the relief of cyclopropyl ring strain in conjunction with the establishment of aromaticity. On this basis, the regiochemistry of the ring opening of the radical anion derived from <b>20</b> suggests that polar and SET pathways can be differentiated based upon the regiospecificity of cyclopropyl ring opening. In reactions between <b>20</b> and nucleophiles known to react via SET with carbonyl compounds, 20 successfully produced products characteristic of SET pathways. However, subsequent studies of the reaction between <b>20</b> and thiophenoxide, a nucleophile purported to undergo SET, produced no evidence for a SET pathway. It was discovered that ring opened products may also be formed by competing polar pathways involving a carbocationic intermediate, especially in protic solvents. In dipolar aprotic solvents, ring opening occurs primarily via an S_N2 process, with nucleophilic attack occurring preferentially at the least hindered carbon. The strengths and weaknesses of <b>20</b> as a SET probe are discussed / Ph. D.

The recent upsurge of degenerative diseases believed to be the result of oxidative stress has sparked an increased interest in utilizing the fundamental principles of physical organic chemistry to understand biological problems. Enzyme pathways can pose several experimental complications due to their complexity, therefore the small molecule probe approach can be utilized in an attempt understand the more complex enzyme mechanisms. The work described in this dissertation focuses on the use of N-cyclopropyl amines that have been used as probes to study the mechanism of monoamine oxidase (MAO) and cytochrome P-450 (cP-450). A photochemical model study of benzophenone triplet (3BP) with the MAO-B substrate 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and two of its derivatives, 1-cyclopropyl-4-phenyl-1,2,3,6-tetrahydropyridine and (+/-)-[trans-2-phenylcyclopropyl-4-phenyl-1,2,3,6-tetrahydropyridine is presented in Chapter 2. The barrier for ring opening of aminyl radical cations derived from N-cyclopropyl derivatives of tertiary amines (such as MPTP) is expected to be low. Reactions of 3BP with all three compounds are very similar. The results suggest that the reaction between benzophenone triplet and tertiary aliphatic amines proceed via a simple hydrogen atom transfer reaction. Additionally these model examinations provide evidence that oxidations of N-cyclopropyl derivatives of MPTP catalyzed by MAO-B may not be consistent with a pure SET pathway. The chemistry of N-cyclopropyl amines has been used to study the mechanism of amine oxidations by cP-450. Until recently, the rate constant for these ring opening reactions has not been reported. Direct electrochemical examinations of N-cyclopropyl-N-methylaniline showed that the radical cation undergoes a unimolecular rearrangement consistent with a cyclopropyl ring opening reaction. Examination of both the direct and indirect electrochemical data showed that the oxidation potential N-cyclopropyl-N-methylaniline to be +0.528 V (0.1 M Ag⁺/Ag), and rate constant for ring opening of 4.1 x 10⁴ s⁻¹. These results are best explained by two phenomena: (i) a resonance effect in which the spin and charge of the radical cation in the ring closed form is delocalized into the benzene ring hindering the overall rate of the ring opening reaction, and/or (ii) the lowest energy conformation of the molecule does not meet the stereoelectronic requirements for a ring opening pathway. Therefore a new series of spiro cyclopropanes were designed to lock the cyclopropyl group into the appropriate bisected conformation. The electrochemical results reported herein show that the rate constant for ring opening of 1'-methyl-3',4'-dihydro-1'H-spiro[cyclopropane-1,2'-quinoline] and 6'-chloro-1'-methyl-3',4'-dihydro-1'H-spiro[cyclopropane-1,2'-quinoline] are 3.5 x 10² s⁻¹ and 4.1 x 10² s⁻¹ with redox potentials of 0.3 V and 0.366 V respectively. In order to examine a potential resonance effect a derivative of N-methyl-N-cyclopropylaniline was synthesized to provide a driving force for the ring opening reaction thereby accelerating the overall rate of the ring opening pathway. The electrochemical results show that the rate constant for ring opening of 4-chloro-N-methyl-N-(2-phenylcyclopropyl)aniline to be 1.7 x 10⁸ s⁻¹ . The formal oxidation potential (E°OX) of this substrate was determined to be 0.53 V. The lowered redox potentials of 1'-methyl-3',4'-dihydro-1'H-spiro[cyclopropane-1,2'-quinoline] and 6'-chloro-1'-methyl-3',4'-dihydro-1'H-spiro[cyclopropane-1,2'-quinoline] can be directly attributed to the electron donating character of the ortho alkyl group of the quinoline base structure of these spiro derivatives, and therefore the relative energy of the ring closed radical cations directly affects the rate of ring opening reactions. The relief of ring strain coupled with the formation of the highly resonance stabilized benzylic radical explains the rate increase for the ring opening reaction of 4-chloro-N-methyl-N-(2-phenylcyclopropyl)aniline. / Ph. D.