A series of para-substituted acetophenones bearing a furanyl or a thiophenyl moiety show a large Stokes-shift, which is a function of various solvent properties. Photophysical properties such as emission lifetime of the compounds have been determined using time-correlated-single photon counting to secure the intrinsic fluorescence behaviour. The solvent dependent position of the UV/Vis emission band [small nu, Greek, tilde]max,em of the compounds has been measured in 26 various solvents. The influence of the solvent on [small nu, Greek, tilde]max,em is of very complex nature and mathematically analysed by multiple square linear solvation energy (LSE)-correlation analysis using Catalán's four-solvent parameter set. Solvent acidity has a strong influence on the bathochromic shift of 2,5-disubstituted furan derivatives compared to the non-5-substituted furan and thiophene derivatives, which show a contrary behaviour. Therefore, the 5-cyanofuranyl-substituted acetophenone derivative is useful as a probe for measuring environmental properties by fluorescence spectroscopy. / Dieser Beitrag ist aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

The thesis entitled “Design and Development of Synthetic Methods using Metal-mediated and Metal-free Redox Reactions: Novel C-H Activations, Reductions and Oxidative Transformations” is presented in 4 chapters Chapter 1; Iodine catalyzed amination of benzoxazoles: efficient metal free route to 2-aminobenzoxazoles under mild conditions. The Chapter 1 of this thesis describes iodine catalyzed C-H activation of benzoxazole with primary and secondary amines to form oxidative aminated products. Selective C-H oxidation is a frontline area of modern chemical research as it offers the opportunities to new avenues and more direct synthetic strategies for the synthesis of complex organic molecules.1 In this context, transition metals such as palladium copper, nickel etc, are used extensively for the functional group directed C-H activation, and thus provides new, rapid, low-cost, and environmentally benign protocols for the construction of new chemical bonds.2 During the past two decades iodine and hypervalent iodine have been focus of great attention as they provide mild, chemoselective and environmentally benign strategies in contrast to toxic metal oxidants.3 In this chapter, a facile metal-free route of oxidative amination of benzoxazole with secondary or primary amines in the presence of catalytic amount of iodine (5 mol%) in aq tert-butyl hydroperoxide (1equiv) and AcOH (1.1 equiv) at ambient temperature, under the solvent-free reaction condition is presented. This user-friendly method to form C-N bonds produces tert-butanol and water as the by-products, which are environmentally benign. A wide range of benzoxazole derivatives containing electron-donating and electron-withdrawing groups were coupled with both primary and secondary amines (Scheme 1). Application of this methodology is demonstrated by synthesizing therapeutically active benzoxazoles by reacting 5-chloro-7-methylbenzoxazole with N-methylpiperazine and N-ethylhomopiperazine to obtain corresponding N-aminatedbenzaxozoles, which exhibit antidiarrhetic activity (Scheme 2).4 Scheme 2 Chapter 2: NIS catalyzed reactions. amidation of acetophenones and oxidative amination of propiophenones Chapter 2 is divided in to 2 parts. Part 1 describes the synthesis of α-ketoamides by using acetophenone and secondary amine in the presence of N-iodosuccinamide and TBHP in acetonitrile at room temperature, whereas Part 2 reveals the synthesis of 2-aminoketones by reacting aryl alkyl ketones and suitable secondary amine in the presence of NIS and TBHP. Part 1: Oxidative amidation, synthesis of α-ketoamide: Alpha α-ketoamides are important intermediates in organic synthesis that are present in a variety of natural products, and pharmaceutically active compounds. Herein, a mild and efficient conversion of acetophenones to α-ketoamide is documented by using aq.TBHP and N-iodosuccinamide (NIS) as a catalyst, at ambient temperature. This amidation reaction was found to be versatile as several aetophenone derivitives containing electron-withdrawing and electron-donating substituents underwent a facile amidation. It was also found that acetyl derivatives of heterocylic compounds could be easily converted to their corresponding ketoamides (few examples are shown in Scheme 3).5 Scheme3 Part 2 of Chapter 2 narrates a novel amination of propiophenone and its derivatives catalysed by NIS in the presence of TBHP to furnish their corresponding 2-aminoketone derivatives (Scheme 4). These derivatives are ubiquitous scaffolds that are present in a wide variety of therapeutic agents. Some of these compounds are used in the treatment of depression, smoking cessation, as monoamine uptake inhibitors, rugs for cancer. They are photoinitiators, precursors to β-aminoalcohols, such as pseudoephedrine analogues. 2-Aminoacetophenone analogues are also important intermediates for the formation of several heterocyclic compounds and are active moieties in several important drugs such as ifenprodil, Scheme 4. Chapter 3: Efficient oxidation of primary azides to nitriles This Chapter is divided in to 2 parts, which presents the oxidation of primary azides to their corresponding nitriles. Part 1: An Efficient oxidation of primary azides catalyzed by copper iodide: a convenient method for the synthesis of nitriles In Part 1, an efficient oxidation of primary azides catalyzed by copper iodide to their corresponding nitriles is reported. Herein, the oxidation of primary azide to nitrile is performed using catalytic amount of copper iodide, and aq TBHP in water at 100 ° C. This methodology is compatible with a wide range of primary benzylic azides that contain electron-donating and electron-withdrawing functional groups. The oxidation was found to be selective and a number of oxidizable functional groups were well-tolerated during the reaction conditions (few examples are shown in Scheme 5).6 Scheme 6 Furthermore, oxidation of secondary azides furnished the corresponding ketones in excellent yields (Scheme 6).6 In the Part 2 of Chapter 3, a non-metal catalysed oxidation of primary azides to nitriles at ambient temperature is reported. This part reveals the oxidation of primary azides to nitriles by employing catalytic amounts of KI (25 mol%), DABCO (25 mol%) and aq. TBHP (3 equiv., 70% solution in water). This reaction provides a good selectivity, as double and triple bonds were not oxidized under the reaction conditions. Additionally, chemoselective oxidation of benzylicazides against aliphatic azides increases the potential application of the present method (Scheme 7).7 Chapter 4: Chemoeselective reduction of olefins Part 1: Iron chloride catalysed aerobic reduction of olefins using aqueous hydrazine at ambient temperature Chapter 4 describes the reduction olefins and acetylenes, which is presented in two Parts. Part 1 documents utility of hydrazine (1.5 equiv) for the chemoselective reduction of nonpolarised carbon-carbon bond using iron catalysts. In this part, a chemoselective reduction of alkenes and alkynes in the presence of a variety of reducible functional groups is demonstrated (Scheme 8). The highlight of the present method is that the reduction proceeds well at room temperature and requires only 1.5 equiv of hydrazine hydrate. The olefin reduction by hydrazine depends upon the controlled release of diimide during the reduction. Generally, metal catalyzed reduction of olefins employ a large excess of hydrazine (10-20 equiv), which might be attributed to uncontrolled release of diimide during the reduction.8 Scheme 8 Part 2: Guanidine catalyzed aerobic reduction: a selective aerobic hydrogenation of olefins using aqueous hydrazine In Chapter 4, part 2, organocatalytic generation of diimide and its utility to reduce the double bonds is presented. Generation of diimide in situ by using organo catalysts and its use for the reduction of carbon-carbon double bond is one of the interesting topics in organic chemistry. It has been shown in this part of the thesis that the reduction of olefin at room temperature can be efficiently performed by using 10 mol% of guanidine nitrate, 2 equiv of aqueous hydrazine in oxygen atmosphere. This method tolerates a variety of reducible functional groups such as nitro, azido, and bromo and protective groups such as methyl ethers, benzyl ethers, and Cbz groups. It is also shown that terminal olefin can be selectively reduced in the presence of internal olefin (Scheme 9). Unlike other methods that employ diimide strategy, the present method is shown to be efficient in reducing substrates those contain internal double bonds such as cinnamyl alcohol and its derivatives

A presente tese trata da análise conformacional e estudo das interações eletrônicas de algumas 2-(fenilselanil)-2-(metoxi)-4\'-substituídas-acetofenonas (série I) e das 2-(4-substituídasfenilsulfanil)-2-(metoxi)-4\'-substituídas-acetofenonas (série II) contendo grupos doadores, hidrogênio e atraentes de elétrons na posição para dos anéis fenacílico [4\'-Y-PhC(O)] e fenilsulfanílico (S-Ph-4-X). Através da resolução das bandas de νCO, foi constatada a ocorrência de isomerismo conformacional nos solventes de constante dielétrica crescente (n-C6H14, CCl4, CHCl3, CH2Cl2, CH3CN) em ambas as séries. Cinco compostos da série II apresentaram ressonância de Fermi (RF) no infravermelho e precisaram ser deuterados. Os dados espectroscópicos são concordantes tanto com os resultados dos cálculos de otimização e frequência em fase gasosa quanto com a simulação do efeito do solvente (PCM), no nível de teoria B3LYP/6-31+G(d,p). Em ambas as séries, foram encontradas três conformações estáveis c1, c2 e c3, sendo que c2 é significativamente mais estável que c1 e c3. O confôrmero c1 possui o oxigênio metoxílico e o carbonílico em sinperiplanar enquanto os grupos -SePh/- SPh estão em anticlinal. Os confôrmeros c2 e c3 possuem o hidrogênio metínico em sinperiplanar com a carbonila enquanto os grupos -OMe e -SePh/-SPh estão na anticlinal. O confôrmero c1 pode ser atribuído ao componente de banda (IR) de maior frequência νCO. Da mesma forma, c2 e c3 são o componente de frequência intermediária e de menor frequência, respectivamente, na série I enquanto que na série II eles coalescem em apenas um componente de menor frequência. Os cálculos de PCM mimetizam os dados espectroscópicos, i.e. é possível constatar a inversão populacional entre c1 e c2, conforme a polaridade do solvente aumenta. Através do cálculo de frequências anarmônicas e construção da PED, foram encontrados dois modos vibracionais que combinados interagem com νCO originando a RF (série II). Um modo é de alta frequência e envolve uma porcentagem considerável de &#948C-H(metínico), o outro modo é esqueletal. A análise das interações orbitalares (NBO) mostrou que os confôrmeros c1 e c2 são estabilizados pela transferência de cargas entre LpO5→σ*CS/Se (ca. 18 kcal mol-1) enquanto c3 é estabilizado pela interação menos intensa LpO5→σ*C-C (ca. 9,5 kcal mol-1). As interações eletrônicas foram investigadas a partir dos contatos interatômicoscurtos com apoio das cargas atômicas parciais. Apesar de c1 e c2 apresentarem praticamente a mesma estabilidade em termos de interações orbitalares, o primeiro é fortemente desestabilizado pela repulsão eletrostática entre os átomos O&#948-CO...O&#948-OMe negativamente carregados separados por uma distância menor que a soma dos raios de van der Waals. Este contato curto entre os dipolos C&#948+=O&#948- e C&#948+−O&#948- é responsável pela maior frequência de νCO de c1 frente c2 e c3. A maior estabilidade de c1 nos solventes mais polares, porém, deve-se à melhor solvatação local destes dipolos. As análises dos monocristais (raios-X) indicou que os compostos assumem, no estado sólido, a conformação menos estável c1, obtida em fase gasosa. Não foram encontradas diferenças significativas no que se refere aos substituintes Y e X. Conclui-se que a estabilidade global das conformações é determinada pelo balanço energético entre as interações orbitalares e eletrostáticas, nas duas séries estudadas. / This thesis reports the conformational analysis and the electronic interactions study of some 2-(phenylselanyl)-2-(methoxy)-4\'-substituted-acetophenones (series I) and 2-(4-substitutedphenylsulphanyl)-2-(methoxy)-4\'-substituted-acetophenones (series II) bearing electron donating, hydrogen and electron attracting substituents in the para position of the phenacyl [4\'-Y-PhC(O)] and phenylsulphanyl (S-Ph-4-X). The occurrence of conformational isomerism in crescent dielectric constant solvents (n-C6H14, CCl4, CHCl3, CH2Cl2, CH3CN) in the two series was studied through the νCO infrared band decomposition. From the series II compounds, five presented Fermi resonance (FR) and had to be deuterated. The spectroscopic data are in line with theoretical calculations results for optimization and frequency in gas phase as well as for solvent effect simulation (PCM), both in B3LYP/6-31+G(d,p) level. Three stable conformers (c1, c2 and c3) were found for both series being the c2 significantly more stable than c1 and c3. Particularly in the c1 conformer, the methoxyl and the carbonyl oxygens are in sinperiplanar orientation while the -SePh/-SPh groups are in anticlinal. In the c2 and c3 conformers the methyne hydrogen assume a sinperiplanar geometry with respect to the carbonyl whereas both -OMe and -SePh/-SPh are in anticlinal. The c1 conformer can be ascribed to the highest frequency νCO band component (IR). So, c2 and c3 ones can be ascribed to the medium and the lowest frequency νCO component, respectively, in the series I whereas in the series II they come together (coalescence) in one single band component. The PCM calculations are in good agreement with spectroscopic data i.e. it is possible to observe a populational inversion between c1 and c2 conformers as the solvent polarity increases. The anharmonic frequencies and PED theoretical treatment revealed that the combination of two vibrational modes interact with the νCO giving rise to the FR (series II): the high frequency one involves a considerable δC-H(methyne) percentage; whilst the other is skeletal. The orbital interactions analysis (NBO) showed that the c1 and c2 conformers are mainly stabilized by charge transfer LpO5→σ*CS/Se (ca. 18 kcal mol-1) while c3 is stabilized by the less intense interaction LpO5→σ*C-C (ca. 9,5 kcal mol-1). The electronic interactions were investigated by means of interatomic short contacts supported by partial atomic charges calculations. In contrast with the almost similar orbital interactions stability of c1 and c2, the former is strongly destabilized by the electrostatic repulsion between Oδ-CO...Oδ-OMe atoms which are negatively charged separated by a distance shorter than the van der Waals radius sum. This short contact between Cδ+=Oδ- and Cδ+−Oδ- dipoles is responsible for the highest νCO frequency of c1 compared to c2 and c3. In the other hand, the greater stabilization of c1 in the more polar solvents is due to the better solvation of those local dipoles. Last, but not least, the X-ray analysis showed that the compounds in the solid state assume the less stable conformation c1, obtained in gas phase. No significative differences were found in terms of the Y and X substituents. It is suggestive that an energetic balance between orbital and electrostatic interactions determines the global stability of conformations in both studied series.

A presente tese trata da análise conformacional e estudo das interações eletrônicas de algumas 2-(fenilselanil)-2-(metoxi)-4\'-substituídas-acetofenonas (série I) e das 2-(4-substituídasfenilsulfanil)-2-(metoxi)-4\'-substituídas-acetofenonas (série II) contendo grupos doadores, hidrogênio e atraentes de elétrons na posição para dos anéis fenacílico [4\'-Y-PhC(O)] e fenilsulfanílico (S-Ph-4-X). Através da resolução das bandas de νCO, foi constatada a ocorrência de isomerismo conformacional nos solventes de constante dielétrica crescente (n-C6H14, CCl4, CHCl3, CH2Cl2, CH3CN) em ambas as séries. Cinco compostos da série II apresentaram ressonância de Fermi (RF) no infravermelho e precisaram ser deuterados. Os dados espectroscópicos são concordantes tanto com os resultados dos cálculos de otimização e frequência em fase gasosa quanto com a simulação do efeito do solvente (PCM), no nível de teoria B3LYP/6-31+G(d,p). Em ambas as séries, foram encontradas três conformações estáveis c1, c2 e c3, sendo que c2 é significativamente mais estável que c1 e c3. O confôrmero c1 possui o oxigênio metoxílico e o carbonílico em sinperiplanar enquanto os grupos -SePh/- SPh estão em anticlinal. Os confôrmeros c2 e c3 possuem o hidrogênio metínico em sinperiplanar com a carbonila enquanto os grupos -OMe e -SePh/-SPh estão na anticlinal. O confôrmero c1 pode ser atribuído ao componente de banda (IR) de maior frequência νCO. Da mesma forma, c2 e c3 são o componente de frequência intermediária e de menor frequência, respectivamente, na série I enquanto que na série II eles coalescem em apenas um componente de menor frequência. Os cálculos de PCM mimetizam os dados espectroscópicos, i.e. é possível constatar a inversão populacional entre c1 e c2, conforme a polaridade do solvente aumenta. Através do cálculo de frequências anarmônicas e construção da PED, foram encontrados dois modos vibracionais que combinados interagem com νCO originando a RF (série II). Um modo é de alta frequência e envolve uma porcentagem considerável de &#948C-H(metínico), o outro modo é esqueletal. A análise das interações orbitalares (NBO) mostrou que os confôrmeros c1 e c2 são estabilizados pela transferência de cargas entre LpO5→σ*CS/Se (ca. 18 kcal mol-1) enquanto c3 é estabilizado pela interação menos intensa LpO5→σ*C-C (ca. 9,5 kcal mol-1). As interações eletrônicas foram investigadas a partir dos contatos interatômicoscurtos com apoio das cargas atômicas parciais. Apesar de c1 e c2 apresentarem praticamente a mesma estabilidade em termos de interações orbitalares, o primeiro é fortemente desestabilizado pela repulsão eletrostática entre os átomos O&#948-CO...O&#948-OMe negativamente carregados separados por uma distância menor que a soma dos raios de van der Waals. Este contato curto entre os dipolos C&#948+=O&#948- e C&#948+−O&#948- é responsável pela maior frequência de νCO de c1 frente c2 e c3. A maior estabilidade de c1 nos solventes mais polares, porém, deve-se à melhor solvatação local destes dipolos. As análises dos monocristais (raios-X) indicou que os compostos assumem, no estado sólido, a conformação menos estável c1, obtida em fase gasosa. Não foram encontradas diferenças significativas no que se refere aos substituintes Y e X. Conclui-se que a estabilidade global das conformações é determinada pelo balanço energético entre as interações orbitalares e eletrostáticas, nas duas séries estudadas. / This thesis reports the conformational analysis and the electronic interactions study of some 2-(phenylselanyl)-2-(methoxy)-4\'-substituted-acetophenones (series I) and 2-(4-substitutedphenylsulphanyl)-2-(methoxy)-4\'-substituted-acetophenones (series II) bearing electron donating, hydrogen and electron attracting substituents in the para position of the phenacyl [4\'-Y-PhC(O)] and phenylsulphanyl (S-Ph-4-X). The occurrence of conformational isomerism in crescent dielectric constant solvents (n-C6H14, CCl4, CHCl3, CH2Cl2, CH3CN) in the two series was studied through the νCO infrared band decomposition. From the series II compounds, five presented Fermi resonance (FR) and had to be deuterated. The spectroscopic data are in line with theoretical calculations results for optimization and frequency in gas phase as well as for solvent effect simulation (PCM), both in B3LYP/6-31+G(d,p) level. Three stable conformers (c1, c2 and c3) were found for both series being the c2 significantly more stable than c1 and c3. Particularly in the c1 conformer, the methoxyl and the carbonyl oxygens are in sinperiplanar orientation while the -SePh/-SPh groups are in anticlinal. In the c2 and c3 conformers the methyne hydrogen assume a sinperiplanar geometry with respect to the carbonyl whereas both -OMe and -SePh/-SPh are in anticlinal. The c1 conformer can be ascribed to the highest frequency νCO band component (IR). So, c2 and c3 ones can be ascribed to the medium and the lowest frequency νCO component, respectively, in the series I whereas in the series II they come together (coalescence) in one single band component. The PCM calculations are in good agreement with spectroscopic data i.e. it is possible to observe a populational inversion between c1 and c2 conformers as the solvent polarity increases. The anharmonic frequencies and PED theoretical treatment revealed that the combination of two vibrational modes interact with the νCO giving rise to the FR (series II): the high frequency one involves a considerable δC-H(methyne) percentage; whilst the other is skeletal. The orbital interactions analysis (NBO) showed that the c1 and c2 conformers are mainly stabilized by charge transfer LpO5→σ*CS/Se (ca. 18 kcal mol-1) while c3 is stabilized by the less intense interaction LpO5→σ*C-C (ca. 9,5 kcal mol-1). The electronic interactions were investigated by means of interatomic short contacts supported by partial atomic charges calculations. In contrast with the almost similar orbital interactions stability of c1 and c2, the former is strongly destabilized by the electrostatic repulsion between Oδ-CO...Oδ-OMe atoms which are negatively charged separated by a distance shorter than the van der Waals radius sum. This short contact between Cδ+=Oδ- and Cδ+−Oδ- dipoles is responsible for the highest νCO frequency of c1 compared to c2 and c3. In the other hand, the greater stabilization of c1 in the more polar solvents is due to the better solvation of those local dipoles. Last, but not least, the X-ray analysis showed that the compounds in the solid state assume the less stable conformation c1, obtained in gas phase. No significative differences were found in terms of the Y and X substituents. It is suggestive that an energetic balance between orbital and electrostatic interactions determines the global stability of conformations in both studied series.

Les plantes médicinales constituent une source inexhaustible de composés (des produits naturels - PN) utilisé en médecine pour la prévention et le traitement de diverses maladies. L'introduction de nouvelles technologies et méthodes dans le domaine de la chimie des produits naturels a permis le développement de méthodes ‘high throughput’ pour la détermination de la composition chimique des extraits de plantes, l'évaluation de leurs propriétés et l'exploration de leur potentiel en tant que candidats médicaments. Dernièrement, la métabolomique, une approche intégrée incorporant les avantages des technologies d'analyse moderne et la puissance de la bioinformatique s’est révélé un outil efficace dans la biologie des systèmes. En particulier, l'application de la métabolomique pour la découverte de nouveaux composés bioactifs constitue un domaine émergent dans la chimie des produits naturels. Dans ce contexte, le genre Acronychia de la famille des Rutaceae a été choisi sur la base de son usage en médecine traditionnelle pour ses propriétés antimicrobienne, antipyrétique, antispasmodique et anti-inflammatoire. Nombre de méthodes chromatographiques modernes, spectrométriques et spectroscopiques sont utilisées pour l'exploration de leur contenu en métabolites suivant trois axes principaux constituant les trois chapitres de cette thèse. En bref, le premier chapitre décrit l’étude phytochimique d’Acronychia pedunculata, l’identification des métabolites secondaires contenus dans cette espèce et l'évaluation de leurs propriétés biologiques. Le deuxième chapitre vise au développement de méthodes analytiques pour l'identification des dimères d’acétophénones (marqueurs chimiotaxonomiques du genre) et aux stratégies utilisées pour la déréplication de ces différents extraits et la caractérisation chimique des composés par UHPLC-HRMSn. Le troisième chapitre se concentre sur l'application de méthodologies métabolomique (RMN et LC-MS) pour l'analyse comparative (entre les différentes espèces, origines, organes), pour des études chimiotaxonomiques (entre les espèces) et pour la corrélation des composés contenus avec une activité pharmacologique. / Medicinal plants constitute an unfailing source of compounds (natural products – NPs) utilised in medicine for the prevention and treatment of various deceases. The introduction of new technologies and methods in the field of natural products chemistry enabled the development of high throughput methodologies for the chemical composition determination of plant extracts, evaluation of their properties and the exploration of their potentials as drug candidates. Lately, metabolomics, an integrated approach incorporating the advantages of modern analytical technologies and the power of bioinformatics has been proven an efficient tool in systems biology. In particular, the application of metabolomics for the discovery of new bioactive compounds constitutes an emerging field in natural products chemistry. In this context, Acronychia genus of Rutaceae family was selected based on its well-known traditional use as antimicrobial, antipyretic, antispasmodic and anti-inflammatory therapeutic agent. Modern chromatographic, spectrometric and spectroscopic methods were utilised for the exploration of their metabolite content following three basic axes constituting the three chapters of this thesis. Briefly, the first chapter describes the phytochemical investigation of Acronychia pedunculata, the identification of secondary metabolites contained in this species and evaluation of their biological properties. The second chapter refers to the development of analytical methods for the identification of acetophenones (chemotaxonomic markers of the genus) and to the dereplication strategies for the chemical characterisation of extracts by UHPLC-HRMSn. The third chapter focuses on the application of metabolomic methodologies (LC-MS & NMR) for comparative analysis (between different species, origins, organs), chemotaxonomic studies (between species) and compound-activity correlations.