Dissertations / Theses on the topic 'Heterocyclic ions'

Cette thèse porte sur l’étude de la radio-sensibilité de Molécules AromatiquesHétérocycliques (MAH) à basse température exposées à une irradiation avec des ionslourds rapides. La présence de ces molécules dans les météorites carbonées sur Terre estune forte indication pour l’existence de cette catégorie de molécules dans l’espace.L’objectif de ce travail est de simuler l’effet des rayons cosmiques sur des MAH enphase solide et d’estimer leur résistance à l’irradiation. Les lignes de faisceaux deGANIL et de GSI permettent de simuler cet effet. L’évolution des MAH en phase solidea été monitorée par spectroscopie infrarouge à transformée de Fourier. Cela permet dequantifier la destruction des MAH, de déterminer leur section efficace de destruction etde détecter les molécules produites. Les sections efficaces de destruction de l’adénine etde la cytosine suivent une loi puissance en fonction du pouvoir d’arrêt électronique :σd~ Se1.2. Les nouvelles bandes d’absorption observées après l’irradiation des MAH sontprincipalement attribuées à des nitriles (R-C≡N), des isonitriles (R-N≡C) et (R-C≡C).L’évolution de la section efficace en fonction du pouvoir d’arrêt électronique a permisd’estimer la durée de vie de l’adénine dans l’espace : (14×106) années. Ces résultatspermettront de comprendre la stabilité et la chimie de ces molécules complexes dansl’espace
The thesis concerns the study of the radio sensitivity of aromatic heterocyclic molecules(AHMs) at low temperature (12 K) exposed to swift heavy ion radiation. The presenceof aromatic heterocyclic molecules in carbonaceous meteorites on Earth is a strongindication that this class of molecules exists in outer space.The aim of this work was to study the effects of cosmic ray analogues on solid AHMsand to estimate their survival under radiation. The beam lines of GANIL and GSI allowto simulate the effects of cosmic rays in AHMs. The evolution of the solid AHMs underirradiation was monitored by Fourier transformed infrared absorption spectroscopy; thisallows to quantify the disappearance of AHMs, to determine their apparent destructioncross section and to detect their radioproducts. Furthermore, it was found that adenineand cytosine destruction cross sections (σd) follow a power law with the electronicenergy loss: σd~ Se1.2 .New IR absorption peaks arising from the AHMs degradationswere observed; these peaks can be attributed to nitriles (R-C≡N), isonitriles (R-N≡C),and (R-C≡C).The observed power law allowed the estimation of the lifetime of adeninein space exposed to galactic cosmic rays as (14×106) years. These findings may help tounderstand the stability and chemistry related to complex organic molecules in space

This thesis describes our physical organic and mechanistic investigations into N Heterocyclic Carbene (NHC) mediated organocatalytic transformations, through a collaboration with the research group of Dr AnnMarie O'Donoghue and PhD student Richard Massey at Durham University. Initial research focused upon the determination of kinetic acidities and associated pKₐ values for a range of triazolium salts using C(3) H/D exchange, monitored by ¹H NMR spectroscopy. Estimates for pKₐ values in the range 16.6 17.4 were obtained, which are some ~2 and ~3 5 pK units lower than analogous imidazolium and thiazolium species respectively, with modest N substituent (0.3 pK units) effects observed. At lower pD values, an altered pD dependence indicates a dicationic triazolium species is formed (through N(1) protonation) with an estimated pKₐᴺ¹ of -0.2-0.5 and C(3) H pKₐ values at least 2 units lower than their monocationic analogues. This methodology was subsequently extended to mesoionic NHCs, where pKa values of 23.0 27.1 for a range of triazolium and 30.2 31.0 for a range of imidazolium salts were estimated. A detailed study of the NHC catalysed intramolecular Stetter reaction was also undertaken using ¹H NMR spectroscopy. A range of 3 (hydroxybenzyl)azolium salts (adducts), formed from the addition of NHC to aldehyde were isolated, enabling the generation of reaction profiles and the determination of rate constants. The reaction proceeds via rapid and reversible adduct generation, followed by rate limiting Breslow intermediate formation, with electron withdrawing N aryl substituents increasing the rate of product formation. Consistent with rate limiting deprotonation, deuterium exchange studies of O methylated adduct analogues found electron withdrawing N-aryl units gave faster exchange. Examination of the equilibrium constants for adduct formation revealed that both in the case of NHCs bearing 2,6 disubstituted N aryl units and aldehydes bearing a 2 ether substituent, the equilibrium position is significantly shifted towards adduct. Finally, studies at sub-stoichiometric NHC concentrations, monitored by HPLC, imply the reaction is first order with respect to NHC precursor, but zero order in aldehyde, again indicative of rate limiting deprotonation.

Chemical oxidation by hydrogen peroxide is used for the treatment of hazardous organic materials present at low concentrations in contaminated soil and water. A knowledge of the oxidation of thiophene and its derivatives, with particular reference to oxidative destruction and the identification of intermediate oxidation products would be useful for a deeper understanding of reaction mechanisms in waste treatment and the optimization of conditions. In this thesis, the oxidation of thiophenes, namely thiophene and 2- and 3-methylthiophene, with hydrogen peroxide and catalyst systems, e.g. Fenton's reagent, Gif systems and titanium dioxide-assisted photocatalytic oxidations, all of which may involve the formation of free radicals, e.g. the hydroxyl radical (HO-), has been studied. Fenton-related catalyst systems, mixtures of iron salts (and sometimes also with copper salts) and hydrogen peroxide, have been suggested in the literature and their reactions with thiophenes have been investigated. Additionally, other catalytic systems that have also been suggested in the literature as having potential have been studied. The oxidation of thiophene derivatives with Fenton-like reagents involving a combinations of hydrogen peroxide with other metal salts including vanadium(IV), titanium(III), copper(I) and copper(II) have been explored, since all of these systems appear to form hydroxyl radicals. Further Fenton-related oxidations of reaction intermediates have been carried out in order to help understand whether the oxidation products described are derived directly from the original compound or from further oxidation of a reaction intermediate. The progress of the oxidation reactions was followed by chromatographic analysis, using Gas Chromatography-Mass Spectrometry and High Performance Liquid Chromatography, so as to establish the nature of the oxidation products and the possible reaction pathways. Components of the mixtures were identified by comparison with commercially available products or synthetic standards. Oxidation reactions were monitored over set time intervals and the amounts of residual thiophenes were determined. In all of the oxidation reactions investigated, Fenton-related and Fenton-like, heteroaromatic ring destruction was observed, together with the formation of small amounts of hydroxylated ring products and dimeric structures. The oxidative destruction of thiophenes was successfully achieved with the above catalyst systems in the presence of excess hydrogen peroxide. Recent literature has questioned the formation of hydroxyl radicals in Fenton-related systems, and in order to contribute to the debate regarding the oxidizing species responsible for the destruction of each of the thiophenes, the oxidation reactions have been carried out in the presence of a complexing agent such as ethylenediaminetetraacetic acid (EDTA), and a radical trapping reagent 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO), respectively. Evidence of radical trapping was observed. Gif chemistry may involve the formation of high oxidation state iron complexes rather than free radicals. The oxidation of thiophenes was carried out using Fenton's reagent under Gif conditions and the results were compared with those from conventional Fenton and related conditions, to determine whether free radical species are involved in the latter. Radical derived products were again observed. Titanium-catalysed photooxidation has also formed part of this study to determine the nature of intermediate products which might be similar to those from Fenton-catalysed systems. For these reasons, the photocatalytic oxidation of 2-methylthiophene was studied in aqueous solution and the reaction was conducted in the presence and absence of titanium dioxide under an oxygen atmosphere. A similar range of radical derived products was found as in the conventional Fenton and related systems.

The aim of this project was to develop new catalytic methods to control asymmetry in electrocyclic reactions, and to apply these methods to generate complex molecules. Initial efforts were directed towards the catalysis of anionic 8π electrocyclizations (Chapter 2 and Figure i). 8π electrocyclization was not achieved due to issues with alkene geometry and anion stability. Our efforts were then directed towards using phase-transfer catalysis to generate complex polycyclic compounds via a cascade electrocyclization-1,4-addition (Chapter 3 and Figure ii). Pyrrolidines and indolizidines were generated in excellent yield from simple starting-materials with high levels of stereocontrol. Finally, we investigated the catalysis of a 6π [1,6] electrocyclization to generate dihydroquinolones (Chapter 4 and Figure iii). A novel BINOL-derived copper(II) catalyst was developed, and afforded dihydroquinolones directly from their amine and aldehyde precursors with good yields and enantioselectivities.

Etude de l'effet de l'acidite de la lipophilie et effets structuraux des acyl-4 pyrazolones-5 dans l'extraction de cu, co, zu et pb divalents. Extraction de 3 types de complexes metalliques : mononucleaires de type m(l-n-lh)::(2) ou m(l-n-l) et polynucleaires (m(l-n-l))::(j). Meilleures possibilites des bis-acyl-4 pyrazolones-5

Extraction de cd et zn a partir des milieux aqueux, perchlorate, nitrate et sulfate par des melanges de phenyl-1 methyl-3 benzoyl-4 pyrazolone-5 et de sels d'ammonium lipophiles. Le pyrazolonate de nh::(4) est l'agent reel de synergie. Mecanisme de transport de cuivre par des acyl-4 pyrazolones-5 a travers une membrane liquide epaisse

Etude des propriétés d'agent d'extraction des acides di(alkyl)dithiophosphoriques ; ils ne peuvent pas être utilisés industriellement car ils s'hydrolysent rapidement au contact d'une phase aqueuse des 35**(o). En fait il semble que les anions di(alkyl) monothiophosphoriques conviennent, utilises en même temps qu'une oxime. Effet de divers facteurs sur la cinétique d'extraction. On peut séparer à ph1, ni et co par une extraction par acide di(ethyl)monothiophosphorique et quinoleinols-8 substitués.

Caracterisation et quantification des equilibres chimiques qui regissent un nouveau systeme d'extraction dont l'apport est de pouvoir operer a partir du milieux fortement acides avec des cinetiques d'extraction tres rapides. Des substitutions de coordinats sont prealablement operees en phase aqueuse. L'extraction elle-meme est realisee par des echangeurs cationiques formant des micelles inverses dans les diluants utilises. Cas de l'acide dinonylnaphtalenesulfonique

Metallosupramolecular chemistry involves the construction of nanoscale molecular assemblies by reacting metal atoms with bridging organic ligands. The metal atoms act as a type of molecular ‘glue’ binding together the organic ligands in specific orientations. Thus, appropriate combinations of metal ions and ligands lead to the controlled self-assembly of interesting one-, two- and three-dimensional molecular aggregates. This thesis details the preparation of a range of novel flexible bridging heterocyclic ligands using conventional organic synthesis, and then explores their reactions with a variety of transition metal precursors. By varying the nature of the organic ligand and the transition metal precursor, new and exciting supramolecular topologies and architectures can be formed. A total of forty-eight ligands were synthesised in this work, forty-seven of which are new compounds. The majority of the ligands synthesised were based around commercially available bisphenol cores. All forty-eight of the ligands had nitrogen heterocyclic groups as coordinating units. The ligands discussed in this thesis can be divided into three main sections. The first involves the synthesis and coordination chemistry of two-armed ligands based around the Bisphenol A, Bisphenol Z and Bisphenol AP cores. The second section describes the synthesis and coordination chemistry of the larger Bisphenol P and Bisphenol M based two-armed bridging ligands. The third section describes the synthesis and coordination chemistry of various multi-substituted ligands, including tripodal ligands based around a trisphenol core, four-armed ligands and six-armed ligands. The two-armed bisphenol based ligands proved very successful as synthons in metallosupramolecular chemistry and produced many products with a variety of different metal atoms. The complexes characterised included discrete dimeric products, coordination polymers and a number of helicates, including a dinuclear quadruply-stranded helicate. Multi-armed ligands are topical, because they have multiple coordination sites that are capable of binding and bridging multiple metal atoms. Such coordination can lead to the construction of cage-like species and complicated networks. A series of three-armed ligands based around a trisphenol core were synthesised with the intention to use these to form such species on coordination with appropriate metal salts. Indeed, one of the products of self-assembly was an interesting M₃L₂ cage. Various other multi-armed ligands were also investigated. The ligands and complexes in this thesis were characterised by a variety of structural techniques, such as ¹H NMR, ¹³C NMR, mass spectrometry, elemental analysis and X-ray crystallography when crystals were obtained. The crystal structures of twenty-seven ligands and forty-three complexes are described.

Etude de la solvatation des especes resultant de l'inclusion d'un cation metallique dans la cavite d'un coordinat macrobicyclique, par la mesure des parametres thermodynamiques. Specificite des differents complexes du 222

Mono n-alkylation des macrocycles. Synthese de resines par polymerisation ou copolymerisation de tetraazamacrocyles monomeres, par greffage de tetraazamacrocycles n-fonctionnalises sur des polymeres ou par impregnation de tetraazamacrocycles lipophiles sur resine inerte. Aptitude de ces composes a extraire les cations cobalt, nickel, cuivre et zinc

Ce memoire est consacre a la synthese, la caracterisation et l'etude electrochimique de nouveaux tensioactifs derives du pyrrole, analogues du dodecyltrimethylammonium et associes aux contre-ions br#-, no#-#3, tso#-, bf#-#4. La plupart forment des micelles en solution aqueuse. Une electrode selective du cation dodecyltrimethylammonium a ete utilisee pour determiner leurs concentrations micellaires critiques (cmc). Nous avons aussi montre que la voltammetrie cyclique permet dans certains cas de determiner la cmc en milieu electrolytique, en depit du caractere irreversible de l'oxydation de la sonde redox que constitue le pyrrole. On constate que l'introduction d'un motif pyrrole a l'extremite de la chaine hydrocarbonee (series a1 et a2) ne modifie pas la cmc de ces tensioactifs par rapport a leurs analogues sans pyrrole. Par contre si le pyrrole est situe sur la tete polaire (serie b1), leur cmc est plus basse. L'etude par rmn#1h a eclaire ces constatations, en precisant la localisation des divers groupements dans la micelle : le pyrrole se place dans le cur hydrophobe dans le cas des a1 et a2, alors qu'il se replie vers l'interieur de la micelle pres de la tete polaire pour les b1. Dans le cas particulier des tensioactifs associes a l'anion tosylate, nous avons constate que le tosylate penetre dans la micelle et s'intercale entre les groupes ammonium. L'etude electroanalytique a montre que ces composes s'adsorbent fortement sur carbone et que des films de polypyrrole peuvent croitre sur ces electrodes par electrooxydation de solutions micellaires. Ces films sont electroinactifs, mais d'epaisseurs significatives (20 a 1000 couches monomoleculaires). Les rendements de depots sont faibles (5 a 10%) dans le cas des a1 et a2, mais nettement plus importants (50%) dans le cas des b1. L'electropolymerisation de solutions micellaires des series a1 et a2 conduit majoritairement a la formation d'oligomeres solubles, de type polypyrrole suroxyde.

碩士
國立臺灣大學
化學研究所
94
This thesis consists of two parts. The first part is to prepare water soluble bispyrrole-bipyridine derivatives for recognition of metal ions in water; the second part is to synthesize water soluble bispyrrole-naphthyridine derivatives, and the binding study in two-phase system is also attempted. Part I: Preparation of water soluble bispyrrole-bipyridine derivatives for recognition of metal ions in water By introduction of ethylene glycol moiety to the pyrrole ring of BPBP molecule, the solubility of such BPBP derivative in water is enhanced, thus sensing metal ions in water becomes possible. The synthesis of a water-soluble BPBP derivative is carried out, and the BPBP compound showed binding affinity toward silver(I), copper(II), and mercury(II) ions in aqueous solution ( CH3CN/H2O = 1: 99 ). The BPBP receptor shows shifts in the UV-Vis spectra on binding with appropriate metal ions. Part II: Synthesis of water soluble bispyrrole-naphthyridine derivatives and the binding study in two-phase system Bispyrrole-naphthyridine molecule BPN (2,7-bis(1H-pyrrol-2-yl)ethynyl-1,8-naphthyridine) is a fluorescent molecule designed to bind selectively with octyl glucopyranoside in our lab. The excellent photophysical properties make BPN a highly sensitive probe for monitoring glucopyranoside to a detection limit of 100 pM. However, BPN has poor water solubility, thus we have to use alkyl glucopyranoside for the binding study in organic solvents. We thus attempted to incorporate ethylene glycol group to BPN to render an enhanced solubility in water. We also attempted to examine the binding of BPN with sugar in two-phase system. However, the blank tests showed that even little water extracted in dichloromethane would interfere with the fluorescence intensity of BPN.

碩士
國立成功大學
化學系碩博士班
100
Free-radical reaction has been applied to formation of carbon-carbon bond for decades and it plays an important role for synthesis of heterocyclic compounds. Manganese (Ⅲ) acetate and Silver (Ⅱ) are the most common reagents for the oxidative free-radical reaction. The study was initiated by the methodology. There are two parts in this thesis: (1)The oxidative free radical reactions of 2-anilino-1,4-naphthoquinones 62 with Silver (Ⅱ) produce benzo[b]acridines 63 effectively. (2)The oxidative free radical reactions of 2-(Allylsulfonyl)-N-benzyl-N-(4’-methoxybiphenyl-2-yl)acetamide 76 with manganese (III) acetate produce spiro compound 77 and azepine compound 78 effectively.

博士
國立成功大學
化學系碩博士班
96
The use of radicals in organic synthesis has increased dramatically within the last decades. Radical carbon-carbon bond-forming reactions have grown in importance to the point where chemists are now routinely considered in strategy planning of complex targets. A typical, widely used radical cyclization involves the reduction of a halide or other functional group to a radical with R3SnH, followed by cyclization and reduction of the resulting radical to a hydrocarbon in the chain propagation steps. While this sequence often gives high yields of products, this approach is limited, leading to relatively unfunctionalized products. Oxidative free-radical reaction in which the initial radical is generated oxidatively or the cyclic radical is terminated oxidatively, has considerable synthetic potential, since more highly functionalized products can be prepared from simple precursors. In this report, we describe our results on: (1) Oxidative free radical reactions between 1,4-quinone derivatives and ketones, benzoylacetonitriles, β-enamino ketones, carboxylic acids, β- dicarbonyl compounds. Carbon radicals which can be generated effectively by metal ion oxidation of ketones,β-enamino ketones orβ-dicarbonyl compounds undergo inter- molecular free radical additions with 1,4-quinones to produce spirolactam, indole-4,7-dione or isobenzofuran-4,7-dione. (2) Oxidative free radical reactions between indole derivatives and β- dicarbonyl compounds. Radical generated by the manganese(III) oxidation ofβ-dicarbonyl compounds undergoes efficient addition to the 2-position of 3-unsubstituted indoles and 2-(3-oxo-2-indolylidene)malonates or furo[3,2-b] indoles was produced. (3) Oxidative free radical reactions of β-aminocinnamates. We describe an effective method for the synthesis of highly substituted pyrroles via oxidative free radical reaction betweenβ-aminocinnamates and enamines.

碩士
國立中山大學
材料科學研究所
91
Abstract Two novel conjugated polymers (PTP-SiO) and (PTP-P-SiO) with alternating N-containing heterocycles and siloxane (-Si-O-) units were synthesized using the Heck reaction. The incorporation of siloxane units in the polymers improves their thermal stability and processability. The polymers can be dissolved in organic solvent and exhibited good thermal stability with 5％ weight loss temperature above 370℃ under nitrogen atmosphere. The photoluminescence (PL) spectra of PTP-SiO and PTP-P-SiO in solution show maximum peaks at 491 and 520 nm respectively. The heterocycles in the two polymers contain N- atoms, which can coordinate with transition or lanthanides metal ions to form complexes. The absorption spectra show peaks at around 275~290 nm and 320~330 nm, which are attributed to π-π* and n-π* transitions, respectively. On the other hand, the emission spectra consist of peaks at around 408~420 nm and 491~520 nm. These two emission peaks belong to π-π* and n-π* transitions of the ligands, respectively. With pyridazine ( heterocycle with –N=N- group) ring, PTP-P-SiO shows more significant variation upon coordination with metals ions as compared to PTP-SiO. These variations of optical property offer a possibility for application in chemosensors for detection of metal ions.

碩士
國立交通大學
應用化學系所
96
Based on our design, 7-methoxycoumarin was chosen as the fluorophore, and heterocyclic building blocks, such as 1,4-triazole and di-2-picolylamino (DPA) groups, were ultilized as the ionophores for metal ions. These two units were jointed with methylene, acetyl, and amide bridges respectively to afford a series of novel coumarin-based fluoroionophores 13, 14, 15, and 17. The photophysical and metal ion-sensing properties of these products were examined in acetonitrile. The changes in fluorescence and ion selectivity of each product were found to be different from one another. 15 and 17 were capable of detecting specific metal ions by showing dramatic enhancement of fluorescence. In contrast with 15 and 17, the fluorescence signals of 13 and 14 were inefficiently altered by metal ions. Hence, 15 and 17 were further investigated with detailed 1H-NMR, UV-vis, and fluorescence titrations. In our research, methylene-bridged 15 is prone to form 1:1 complexes with Ca2+, Cd2+, Mg2+, and Zn2+, and amide-bridged 17 is probably chelated with multiple equivalences of Cd2+ and Zn2+. The complexation stoichiometries of 17 with Cd2+ and Zn2+ were calculated to be 1:2 with Hill plots, but Job plots indicated 2:3 complexes were formed between 17 and those metal ions. Because of the inconsistent results, other analytical methods will be required to obtain the actual binding ratios and complexation models.

碩士
靜宜大學
應用化學系
107
This work describes catalytic behaviors of a series of N-heterocyclic carbene (NHC) ion pair complexes and a comparison for catalytic studies in water mediated Suzuki–Miyaura cross coupling reaction were also investigated. All prepared complexes were full characterized by 1H and 13C NMR spectroscopy and elemental analyses as well as their structures determined by the single-crystal X-ray diffraction. The synthesis palladium complexes applied as catalysts for Suzuki-Miyaura coupling reactions of aryl chlorides with arylboronic acids under mild conditions. Under the optimum conditions, the expected biaryl products afforded in good to quantitative yields. Compared with literature reports, our Pd complexes show the better performance for Suzuki-Miyaura coupling reaction in the aqueous phase in reaction time and temperature.

碩士
國立臺北科技大學
化學工程研究所
102
The purpose of this study is to synthesize four kinds of trifluoroacetyl ketones by the acylation reaction using four different aromatic five-membered heterocyclic rings and trifluoroacetic anhydride, their structures were identified by Frustrated Total Internal Reflection and Nuclear Magnetic Resonance spectrometer, the unacylated five-membered heterocyclic rings(0.03wt.%) and acylated products(0.03wt.% and 0.05wt.%) were added as an additive into the liquid electrolyte(1M LiPF6 in EC:DEC(1:1)), and assembled these into the coin cells, electrochemical properties were measured by charge-discharge tests. In the constant current discharge-charge test shows that the addition of 3% five-membered heterocyclic rings additive is able to increase battery cycle life and reducing decay rate at most to 2.01% from 3.11%. The increase of first cycle discharge capacity by 4-6 mAh/g, poor battery cycle life and larger decay rate are showed in the addition of 3% acylated products. Decrease of battery capacity and cycle life with addition of 5% acylated products additive.

The development of artificial receptors for the recognition of ionic species involved in biological pathways is a topic of great interest as highly selective anion or cation sensing is imperative for many biological and clinical applications. Chemical sensors based on heterocyclic units are unique and useful for molecular recognition because they can act both as recognition and signaling unit, and as these systems are usually highly fluorescent they present advantages like increased sensitivity, lower detection limits and spatial and temporal resolution. In natural amino acids, metallic cations can be complexed through N, O and S donor atoms, at the main and side chains, whereas anion coordination, based on hydrogen bonding and electrostatic interactions, can arise from amino acid side and main chain OH and NH groups. This complexation ability can be enhanced by modifying amino acids with an ion chelating site for stable complex formation with extra heteroatoms in order to exert a cooperative effect for a more efficient binding process. The work presented in this thesis reports the synthesis and characterisation of heterocyclicbased amino acids as well as the evaluation of their photophysical properties having in mind their potential application as fluorescent probes and colorimetric and/or fluorimetric chemosensors for anions and cations, since there is practical interest on the expansion of the body of work published in recent years in the area of unnatural functional amino acids. Therefore, novel unnatural amino acids with enhanced functionalities, such as fluorescence and metal cation and anion recognition ability, were obtained by synthetic manipulation at the side chain of the natural amino acids like phenylalanine, tyrosine, asparagine and glutamine, with the incorporation of sulphur, oxygen and nitrogen heterocycles. The heterocycles used in the present work were (bi)thiophene, furan, pyrrole, imidazole, thiazole, 1,3,4-thiadiazole, 1,2,4-triazole, benzocrown ethers, benzoxazole and benzimidazole, and with these pi-conjugated bridges of heterocyclic nature it was intended to improve the photophysical properties of the resulting systems, and to optimize the recognition of the target analytes by introducing additional binding sites in the overall structure. The novel heterocyclic amino acids were completely characterised by the usual characterisation techniques (proton and carbon nuclear magnetic resonance spectroscopy, UV-Vis absorption and fluorescence spectroscopy, infrared spectroscopy mass spectrometry and/or elemental analysis). The photophysical properties of the synthesised compounds were evaluated in organic solvents of different character and aqueous mixtures, and in some cases related with p* values by Kamlet and Taft. In most cases, the novel compounds displayed very high fluorescence quantum yields, making them good candidates for application as intrinsic fluorescent probes for incorporation in peptidic frameworks, as well as fluorimetric chemosensors. The evaluation of the chemosensory ability of the unnatural amino acids towards organic and inorganic anions, (such as AcO-, F-, Cl-, Br-, I-, ClO4 -, CN-, NO3 -, BzO-, OH-, H2PO4 - and HSO4 -) and alkaline, alkaline-earth, and transition metal cations, (such as Na+, K+, Cs+, Ag+, Cu+, Cu2+, Ca2+, Cd2+, Co2+, Pb2+, Pd2+, Ni2+, Hg2+, Zn2+, Fe2+, Fe3+ and Cr3+) was carried out by spectrophotometric and spectrofluorimetric titration in acetonitrile and aqueous mixtures. The chemosensing studies revealed that the new amino acids could be used as highly sensitive fluorimetric sensors for Cu2+, Fe3+ and Pd2+. The association constants and the stoichiometry of the formed complexes were calculated by HypSpec software and the stoichiometry was confirmed by Job’s plots. The binding process of the ions was also studied using 1H NMR spectroscopy. Finally, some of the synthesised amino acids were used in the synthesis of short peptide sequences, in order to obtain “proof of concept” regarding the appearance of these amino acids’ intrinsic functionalities (fluorescence and ion recognition ability) in the resulting peptides, as suggested by previous results published within the research group where this work was conducted. Short sequences belonging to the C-terminal of bombesin and melanocortin, as model peptides, were modified by the introduction of some synthesised thiosemicarbazone- and hydrazine-phenylalanines, benzoxazol-alanines and asparagines by substitution of a selected native residue in each peptide model. However, this work on peptide synthesis was not in publishable form at the time of submission of the present thesis but the work is in progress and it is expected that it will be completed in the near future.
O desenvolvimento de recetores artificiais para o reconhecimento de espécies iónicas envolvidas nas vias biológicas é um assunto de grande interesse uma vez que a deteção altamente seletiva de aniões ou catiões é imperativa para muitas aplicações biológicas e clínicas. Os sensores químicos baseados em unidades heterocíclicas são únicos e muito úteis para o reconhecimento molecular, porque podem atuar tanto como a unidade de reconhecimento como a unidade de sinalização, e como esses sistemas são geralmente altamente fluorescentes apresentam vantagens como aumento da sensibilidade, limites de deteção mais baixos e resolução espacial e temporal. Nos aminoácidos naturais, os catiões metálicos podem ser complexados através dos átomos dadores de eletrões como N, O e S, nas cadeias principal e lateral, enquanto que a coordenação de aniões, com base em ligações de hidrogénio e interacções eletrostáticas, pode surgir a partir dos grupos OH e NH nas cadeias principal e lateral. Esta capacidade de complexação pode ser melhorada através da modificação de aminoácidos com uma unidade quelante de iões com heteroátomos adicionais para a formação de um complexo estável, a fim de exercer um efeito cooperativo para um processo de ligação mais eficiente. O trabalho apresentado nesta tese descreve a síntese e caracterização de aminoácidos baseados em heterociclos, bem como a avaliação das suas propriedades fotofísicas tendo em mente a sua potencial aplicação como sondas fluorescentes e sensores químicos colorimétricos e/ou fluorimétricos para aniões e catiões, uma vez que há interesse prático na expansão do corpo de trabalhos publicados nos últimos anos na área dos aminoácidos funcionais não naturais. Assim sendo, novos aminoácidos não naturais com funcionalidades melhoradas, tais como fluorescência e a capacidade de reconhecimento de aniões e catiões, foram obtidos por manipulação sintética na cadeia lateral de aminoácidos naturais como fenilalanina, tirosina, asparagina e glutamina, com a incorporação de heterociclos de enxofre, oxigénio e nitrogénio. Os heterociclos utilizados no presente trabalho foram (bi)tiofeno, furano, pirrole, imidazole, tiazole, 1,3,4-tiadiazole, 1,2,4-triazole, benzoéteres de coroa, benzoxazole e benzimidazole, e com estas pontes pi conjugadas de natureza heterocíclica pretendeu-se melhorar as propriedades fotofísicas dos sistemas resultantes, e optimizar o reconhecimento dos analitos alvo através da introdução de locais de ligação adicionais na estrutura global. Os novos aminoácidos heterocíclicos foram completamente caracterizados pelas técnicas usuais de caracterização (espetroscopia de ressonância magnética nuclear de protão e carbono, espetroscopia de absorção no UV-Vis e de fluorescência, espetroscopia de infravermelho e espetrometria de massa e/ou análise elementar). As propriedades fotofísicas dos compostos sintetizados foi avaliada em solventes orgânicos de diferentes carácter e em misturas aquosas, e em alguns casos, relacionadas com os valores de p* propostos por Kamlet e Taft. Na maioria dos casos, os novos compostos possuem rendimentos quânticos de fluorescência muito elevados, o que os torna bons candidatos para aplicação como sondas fluorescentes intrínsecas para incorporação em sistemas peptídicos assim como sensores químicos fluorimétricos. A avaliação da capacidade quimiossensora dos aminoácidos não naturais face a aniões orgânicos e inorgânicos (tais como AcO-, F-, Cl-, Br-, I-, ClO4 -, CN-, NO3 -, BzO-, OH-, H2PO4 - and HSO4 -) e catiões de metais alcalinos, alcalino-terrosos e de transição (tais como Na+, K+, Cs+, Ag+, Cu+, Cu2+, Ca2+, Cd2+, Co2+, Pb2+, Pd2+, Ni2+, Hg2+, Zn2+, Fe2+, Fe3+ and Cr3+) foi realizada por titulação espetrofotométrica/fluorimétrica em acetonitrilo e misturas aquosas. Os estudos revelaram que os novos aminoácidos podem ser usados como sensores fluorimétricos altamente sensíveis para Cu2+, Fe3+ and Pd2+. As constantes de associação e a estequiometria dos complexos formados foram calculadas pelo software HypSpec e confirmada por gráficos de Job’s. O processo de ligação dos iões também foi estudado por espetroscopia de 1H RMN. Por último, alguns aminoácidos foram usados na síntese de sequências peptídicas curtas como “prova de conceito” relativamente ao aparecimento das propriedades intrínsecas dos aminoácidos (fluorescência e capacidade de reconhecimento de iões) nos péptidos resultantes. Sequências pertencentes ao C-terminal da bombesina e melanocortina, como péptidos modelo, foram modificadas com algumas tiosemicarbazono- e hidrazono-fenilalaninas, benzoxazolil-alaninas e asparaginas por substituição de um resíduo nativo selecionado em cada um dos péptidos modelo. Não obstante, este trabalho de síntese peptídica não estava em forma publicável na altura de submissão da presente tese mas o trabalho está a decorrer e espera-se que seja concluído num futuro próximo.

Several novel multicomponent assembly processes have been developed for the preparation of a diverse array of complex heterocyclic systems from relatively simple starting materials. These studies resulted in the discovery of a new quinazolone forming reaction, which was applied to the one-step synthesis of the quinazolinocarboline alkaloid rutaecarpine. Biological screening of these complex heterocycles culminated in the identification of a potent sigma-2 receptor ligand. A novel N-acyliminium ion mediated cascade reaction was employed for the concise synthesis of (±)-actinophyllic acid. The completion of the synthesis relied on the development of a reaction sequence that avoided a potentially detrimental fragmentation process. Furthermore, several anti-cancer compounds were identified through a diverted total synthesis approach.
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博士
國立臺灣大學
化學研究所
92
Abstract This thesis consists of three parts. The first part is to develop metal ion chemosensors containing naphthyridine moiety; the second part is to design and synthesize water soluble carbohydrate receptors; the last part is to characterize the second-order nonlinear optical properties of thiophene conjugated heterocycles. Part I: Development of metal ion chemosensors containing naphthyridine moiety Up to now only a few chemosensors of heavy (transition) metal ions utilize fluorescence enhancement as the detection mechanism. Our research objective is to develop efficient fluorescent chemosensors and colorimetric chemosensors for transition metal ions (e.g. Hg2+ and Cu2+) with high sensitivity and selectivity. A series of intrinsic chemosensors p-CHEAN (1), p-BHEAN (2), m-CHEAN (3) and m-BHEAN (4) were thus designed and synthesized by the linkage of 1,8-naphthyridines as donors and bis(hydroxyethyl)aminophenyls as acceptors through triple bonds. The para-substituted chemosensors p-CHEAN and p-BHEAN displayed drastic color changes on addition of mercuric ion in an excellent selectivity in DMSO/H2O (1:1) solution. When these chemosensors bound with mercury ion, an intramolecular charge transfer occurred to account for the color changes. These colorimetric sensors provide a fast and easy method for the direct naked-eye sensing for mercuric ion. In comparison with p-CHEAN, the molecular sensor p-BHEAN of DAD type containing two arms with the bis(hydroxyethyl)amino donor groups at the para position exhibited the absorption band in the visible region, and offered two-stage changes p-BHEAN sensor to detect mercuric ion. On the other hand, the meta-substituted chemosensors m-CHEAN and m-BHEAN showed profound fluorescence enhancements on complexation with cupric ion in CH3CN. These fluorescence sensors were highly selective for Cu2+ ion in the presence of other metal ions (Ni2+, Co2+, Mg2+, Ca2+, Ba2+, Cd2+, Mn2+, and Pb2+). Part II: Design and synthesis of water soluble carbohydrate receptors The saccharide receptor contained the core structure of 1,8-naphthyridine which was linked via ethynyl bridges to two end groups of phenols. The BHPN molecule was synthesized,and found to bind strongly with various octyl glycosides via multiple hydrogen bondings in CH2Cl2. In order to develop effective chemosensors for saccharides in aqueous medium, we attempted to incorporate water-soluble moieties, derivatives with functional groups such as nitro group, carboxylic acid and sulfonic acid, to obtain the BHPN enhanced solubility in water. We have synthesized p-NO2-BHPN and m-CO2CH3-BHPN compounds successfully. However we encountered some problems in separation of the desired products due to their water-soluble properties. Part III: The second-order nonlinear optical properties of thiophene conjugated heterocycles The nonlinear optical properties of bicyclic thiophenes Y1-Y4 with ��-conjugation are described in this part. The aim is to realize whether the lost aromatic resonance energy during the process of polarization can be totally compensated by the newly formed aromatic resonance stabilization of bicyclic thiophene. We thus synthesized the control molecules 89, 90 and 91 which with the same donor and acceptor but without bicyclic structure to compare their nonlinear optics. From the results of ��0 measurements by EFISH we found there were no apparent relationship between ��0 value and the molecular structure.