Comparative study of Li, Na, and K adsorptions on graphite by using ab initio method

A comprehensive study has been conducted to compare the adsorptions of alkali metals (including Li, Na, and K) on the basal plane of graphite by using molecular orbital theory calculations. All three metal atoms prefer to be adsorbed on the middle hollow site above a hexagonal aromatic ring. A novel phenomenon was observed, that is, Na, instead of Li or K, is the weakest among the three types of metal atoms in adsorption. The reason is that the SOMO (single occupied molecular orbital) of the Na atom is exactly at the middle point between the HOMO and the LUMO of the graphite layer in energy level. As a result, the SOMO of Na cannot form a stable interaction with either the HOMO or the LUMO of the graphite. On the other hand, the SOMO of Li and K can form a relatively stable interaction with either the HOMO or the LUMO of graphite. Why Li has a relatively stronger adsorption than K on graphite has also been interpreted on the basis of their molecular-orbital energy levels.

Cyclic and acyclic modifications of 5-aminoimidazole-4-carboxamide

The Introduction gives a brief resume' of the biologically important aspects of 5 -aminoimidazole -4 -carbozamide (1) and explores., in-depth, the synthetic routes to this imidazole. All documented reactions of 5 -aninoimidanole-4 -carboxamide are reviewed in detail, with particular emphasis on the preparation and subsequent coupling reactions of 5 –diazo-imidazole-4 -carboxamide (6). A series of thirteen novel amide 5-amino-2-arylazoimidazole-4-carboxamide derivatives (117-129) were prepared by the coupling of aryldiazonium salts with 5-aminoimidazole-4-carboxamide. Chemical modification of these azo-dyes resulted in the preparation of eight previously unknown acyl derivatives (136-143) Interaction of 5-amino-2-arylazoimidazole-4-carboxides with ethyl formate in sodium ethoxide effected pyrimidine ring closure to the novel 8-arylazohypoxanthines (144 and 145). Several reductive techniques were employed in an effort to obtain the elusive 2,5-diaminoimidazole-4-carboxamide (71),a candidate chemotherapeutic agent, from the arylazoiridazoles. No success can be reported although 5-amino-2-(3-aminoindazol-2-yl) imidazole-4-carboxamide (151) was isolated due to a partial reduction and intramolecular cyclisation of 5-amino72-(2-cyanaphenylazo)imidazole-4-carboxamide (122) .Further possible synthetic approaches to the diaminoimidazole are discussed in Chapter 4. An interesting degradation of a known unstable nitrohydrazone is described in Chapter 5.This resulted in formation of 1, 1-bis(pyrazol--3-ylazo)-1-nitroethane (164) instead of the expected cyclisation to a bicyclic tetrazine N-oxide. An improved preparation of 5-diazoinidazole-4-carboxamide has been achieved, and the diazo-azole formed cycloadducts with isocyanates to yield the hitherto unknown imidazo[5,1-d][1,2,3,5]tetrazin-7(6H)-ones. Eleven derivatives (167-177) of this new ring-system were prepared and characterised. Chemical and spectroscopic investigation showed this ring-system to be unstable under certain conditions, and a comparative study of stability within the group has been made. "Retro-cycloaddition" under protic and photolytic conditions was an unexpected property of 6-substituted imidazo[5,1-d][1,2,3,5]tetrazin--7(0)-ones.Selected examples of the imidazotetrazinone ring-system were tested for antitumour activity. The results of biological evaluation are given in Chapter 7, and have culminated in a Patent application by the collaborating body, May and Baker Ltd. One compound,3-carbamoyl-6-(2-chloro-ethyl)imidazo[5,1-d][1,2,3,5jtetrazin-7(6H)-one (175),shows striking anti-tumour activity in rodent test systems.

Synthetic Approaches to Flexible Fluorescent Conjugated Polymers

Conjugated polymers (CPs) are intrinsically fluorescent materials that have been used for various biological applications including imaging, sensing, and delivery of biologically active substances. The synthetic control over flexibility and biodegradability of these materials aids the understanding of the structure-function relationships among the photophysical properties, the self-assembly behaviors of the corresponding conjugated polymer nanoparticles (CPNs), and the cellular behaviors of CPNs, such as toxicity, cellular uptake mechanisms, and sub-cellular localization patterns. Synthetic approaches towards two classes of flexible CPs with well-preserved fluorescent properties are described. The synthesis of flexible poly(p-phenylenebutadiynylene)s (PPBs) uses competing Sonogashira and Glaser coupling reactions and the differences in monomer reactivity to incorporate a small amount (~10%) of flexible, non-conjugated linkers into the backbone. The reaction conditions provide limited control over the proportion of flexible monomer incorporation. Improved synthetic control was achieved in a series of flexible poly(p-phenyleneethynylene)s (PPEs) using modified Sonogashira conditions. In addition to controlling the degree of flexibility, the linker provides disruption of backbone conjugation that offers control of the length of conjugated segments within the polymer chain. Therefore, such control also results in the modulation of the photophysical properties of the materials. CPNs fabricated from flexible PPBs are non-toxic to cells, and exhibit subcellular localization patterns clearly different from those observed with non-flexible PPE CPNs. The subcellular localization patterns of the flexible PPEs have not yet been determined, due to the toxicity of the materials, most likely related to the side-chain structure used in this series. The study of the effect of CP flexibility on self-assembly reorganization upon polyanion complexation is presented. Owing to its high rigidity and hydrophobicity, the PPB backbone undergoes reorganization more readily than PPE. The effects are enhanced in the presence of the flexible linker, which enables more efficient π-π stacking of the aromatic backbone segments. Flexibility has minimal effects on the self-assembly of PPEs. Understanding the role of flexibility on the biophysical behaviors of CPNs is key to the successful development of novel efficient fluorescent therapeutic delivery vehicles.

New methods for the asymmetric synthesis of α-alkylated ketones and 1,3-amino alcohols

A large number of optically active drugs and natural products contain α-functionalised ketones or simple derivatives thereof. Furthermore, chiral α-alkylated ketones are useful synthons and have found widespread use in total synthesis. The asymmetric alkylation of ketones represents one of the most powerful and longstanding procedures in organic chemistry. Surprisingly, however, only one effective methodology is available, and this involves the use of chiral auxiliaries. This is discussed in Chapter 1, which also provides a background of other key topics discussed throughout the thesis. Expanding on the existing methodology of chiral auxiliaries, Chapter 2 details the synthesis of a novel chiral auxiliary containing a pyrrolidine ring and its use in the asymmetric preparation of α-alkylated ketones with good enantioselectivity. The synthesis of racemic α-alkylated ketones as reference standards for GC chromatography is also reported in this chapter. Chapter 3 details a new approach to chiral α-alkylated ketones using an intermolecular chirality transfer methodology. This approach employs the use of simple non-chiral dimethylhydrazones and their asymmetric alkylation using the chiral diamine ligands, (+)- and (-)-sparteine. The methodology described represents the first example of an asymmetric alkylation of non-chiral azaenolates. Enantiomeric ratios up to 83 : 17 are observed. Chapter 4 introduces the first aldol-Tishchenko reaction of an imine derivative for the preparation of 1,3-aminoalcohol precursors. 1,3-Aminoalcohols can be synthesised via indirect routes involving various permutations of stepwise construction with asymmetric induction. Our approach offers an alternative highly diastereomeric route to the synthesis of this important moiety utilising N-tert-butanesulfinyl imines in an aldol-Tishchenko-type reaction. Chapter 5 details the experimental procedures for all of the above work. Chapter 6 discusses the results of a separate research project undertaken during this PhD. 2-alkyl-quinolin-4-ones and their N-substituted derivatives have several important biological functions such as the role of Pseudomonas quinolone signal (PQS) in quorum sensing. Herein, we report the synthesis of its biological precursor, 2-heptyl-4-hydroxy-quinoline (HHQ) and possible isosteres of PQS; the C-3 Cl, Br and I analogues. N-Methylation of the iodide was also feasible and the usefulness of this compound showcased in Pd-catalysed cross-coupling reactions, thus allowing access to a diverse set of biologically important molecules.

Studies in asymmetric and heterocyclic synthesis: I. chiral ketones II. Quinolones III. Trifluoromethylated pyrones

This thesis is split into three sections based on three different areas of research. In the first section, investigations into the α-alkylation of ketones using a novel chiral auxiliary is reported. This chiral auxiliary was synthesised containing a pyrrolidine ring in the chiral arm and was applied in the preparation of α-alkylated ketones which were obtained in up to 92% ee and up to 63% yield over two steps. Both 3-pentanone and propiophenone based ketones were used in the investigation with a variety of both alkyl and benzyl based electrophiles. The novel chiral auxiliary was also successful when applied to Michael and aldol reactions. A diamine precursor en route to the chiral auxiliary was also applied as an organocatalyst in a Michael reaction, with the product obtained in excellent enantioselectivity. In the second section, investigations into potential anti-quorum sensing molecules are reported. The bacteria Pseudomonas aeruginosa is an antibiotic-resistant pathogen that demonstrates cooperative behaviours and communicates using small chemical molecules in a process termed quorum sensing. A variety of C-3 analogues of the quorum sensing molecules used by P. aeruginosa were synthesised. Expanding upon previous research within the group, investigations were carried out into alternative protecting group strategies of 2-heptyl-4-(1H)- quinolone with the aim of improving the yields of products of cross-coupling reactions. In the third section, investigations into fluorination and trifluoromethylation of 2-pyrones, pyridones and quinolones is reported. The incorporation of a fluorine atom or a trifluoromethyl group into a molecule is important in pharmaceutical drug discovery programmes as it can lead to increased lipophilicity and bioavailability, however late-stage incorporation is rarely reported. Both direct fluorination and trifluoromethylation were attempted. Eight trifluoromethylated 2-pyrones, five trifluoromethylated 2-pyridones and a trifluoromethylated 2-quinolone were obtained in a late-stage synthesis from their respective iodinated precursors using methyl fluorosulfonyldifluoroacetate as a trifluoromethylating reagent.

Synthesis and evaluation of novel ellipticines as potential anti-cancer agents

Ellipticine is a natural product which possesses multimodal anti-cancer activity. This thesis encompasses the synthesis and biological evaluation of novel ellipticine and isoellipticine derivatives as anti-cancer agents. Expanding on previous work within the group utilising vinylmagnesium bromide, derivatisation of the C5 position of ellipticine was accomplished by reaction of a key ketolactam intermediate with Grignard reagents. Corresponding attempts to introduce diverse substitution at the C11 position were unsuccessful, although one novel C11 derivative was produced using an alkyllithium reagent. A panel of novel ellipticinium salts encompassing a range of substitutions at the N2, C9 and N6 positions were prepared. Extensive derivatisation of the N10 position of isoellipticine was undertaken for the first time. Novel substitution in the form of acid and methyl ester functionalities were introduced at the C7 position of isoellipticine while novel C7 aldehyde and alcohol derivatives were synthesised. A large panel of isoellipticinium salts were prepared with conditions adjusted for the reactivity of the alkyl halide. Novel coupling reactions to increase the yield of isoellipticine were attempted but proved unsuccessful. A panel of 54 novel derivatives was prepared and a multimodal analysis of their anti-cancer activity was conducted. The NCI 60-human tumour cell lines screen was a primary source of information on the in vitro activity of compounds with derivatives found to exert potent anticancer effects, with mean GI50 values as low as 1.01 μM across the full range of cancer types and as low as 16 nM in individual cell lines. A second in vitro screen in collaboration with researchers in the University of Nantes identified derivatives which could potently inhibit growth in a p53 mutant NSCLC cell line. The cell cycle effects of a selected panel of isoellipticines were studied in leukaemia cell lines by researchers in the Department of Biochemistry and Cell Biology, UCC. Emerging from this, the therapeutic potential of one of the derivatives in AML was then assessed in vivo in an AML xenograft mouse model, with tumour weight reduced by a factor of 7 in treated mice relative to control.

Nucleophilic addition of Nitrones to Electron deficient acetylenes and related studies

Nitrones or azomethine-N-oxides are important precursors for the synthesis of several heterocyclic systems. They belong to the allyl anion type 1,3-dipoles and possess unique structural features which make them extraordinarily useful synthons. They behave as 1,3-dipoles in 1,3-dipolar cycloaddition reactions and as electrophiles in reactions with organometallic reagents. These are the two basic reactions given by nitrones. Nitrones also act as ‘spin traps’ in which they react with short-lived radicals to furnish stable nitroxide radicals which can be detected and identified by electron paramagnetic resonance (EPR) spectroscopy. Recently SmI2 catalysed reductive cross-coupling reactions of nitrones have gained significant interest in which the reactions are initiated by single electron transfer (SET) to nitrones. Apart from these reactions, nitrones are also known to participate in reactions which are initiated by the nucleophilic attack of nitrone-oxygen. In our group, we have also explored the nucleophilic character of nitrones through various reactions. The results obtained enabled us to develop a novel two-step one-pot strategy for quinolines and indoles - the heterocycles renowned for their pharmacological applications, from nitrones and electron deficient acetylenes. Using dibenzoylacetylene and phenylbenzoylacetylene as dipolarophiles, we could introduce a desired functional group at a predetermined position of the quinolines or indoles to be synthesised. In this context, the thesis entitled “NUCLEOPHILIC ADDITION OF NITRONES TO ELECTRON DEFICIENT ACETYLENES AND RELATED STUDIES” portrays our attempt to expand the scope of our x novel synthetic protocol using ester functionalised acetylenes: dimethyl acetylenedicarboxylate (DMAD) and methyl propiolate. The thesis is organised in to five chapters. The first chapter briefly describes the different classes of reactions that nitrone functionality can tolerate. The research problem is defined at the end of this chapter. The second chapter describes the synthesis of different nitrones used for the present study. The optimisation and expansion of scope of the novel strategy towards quinoline synthesis is discussed in the third chapter. The fourth chapter portrays the synthesis of indole-3-carboxylates using the novel strategy. In the fifth chapter, the reaction of N-(2,6-dimethylphenyl) and N-(2,4,6-trimethylphenyl)nitrones are discussed. Here we also discuss the mechanistic reinvestigation of Baldwin’s proposal in the isoxazoline-oxazoline rearrangement. The major outcome of the work is given at the end of the thesis. The structural formulae, schemes, tables and figures are numbered chapter-wise since each chapter of the thesis is organized as an independent unit. All new compounds (except two compounds reported in fourth chapter) are fully characterised on the basis of spectral and analytical data and single crystal X-ray analysis on representative examples. Relevant references are included at the end of individual chapters.

Synthetic approaches to flexible fluorescent conjugated polymers

Conjugated polymers (CPs) are intrinsically fluorescent materials that have been used for various biological applications including imaging, sensing, and delivery of biologically active substances. The synthetic control over flexibility and biodegradability of these materials aids the understanding of the structure-function relationships among the photophysical properties, the self-assembly behaviors of the corresponding conjugated polymer nanoparticles (CPNs), and the cellular behaviors of CPNs, such as toxicity, cellular uptake mechanisms, and sub-cellular localization patterns. ^ Synthetic approaches towards two classes of flexible CPs with well-preserved fluorescent properties are described. The synthesis of flexible poly( p-phenylenebutadiynylene)s (PPBs) uses competing Sonogashira and Glaser coupling reactions and the differences in monomer reactivity to incorporate a small amount (∼10%) of flexible, non-conjugated linkers into the backbone. The reaction conditions provide limited control over the proportion of flexible monomer incorporation. Improved synthetic control was achieved in a series of flexible poly(p-phenyleneethynylene)s (PPEs) using modified Sonogashira conditions. In addition to controlling the degree of flexibility, the linker provides disruption of backbone conjugation that offers control of the length of conjugated segments within the polymer chain. Therefore, such control also results in the modulation of the photophysical properties of the materials. ^ CPNs fabricated from flexible PPBs are non-toxic to cells, and exhibit subcellular localization patterns clearly different from those observed with non-flexible PPE CPNs. The subcellular localization patterns of the flexible PPEs have not yet been determined, due to the toxicity of the materials, most likely related to the side-chain structure used in this series. ^ The study of the effect of CP flexibility on self-assembly reorganization upon polyanion complexation is presented. Owing to its high rigidity and hydrophobicity, the PPB backbone undergoes reorganization more readily than PPE. The effects are enhanced in the presence of the flexible linker, which enables more efficient π-π stacking of the aromatic backbone segments. Flexibility has minimal effects on the self-assembly of PPEs. Understanding the role of flexibility on the biophysical behaviors of CPNs is key to the successful development of novel efficient fluorescent therapeutic delivery vehicles.^

Rhodium(I) catalyzed [2+2+2] cycloaddition reactions: experimental and theoretical studies

The [2+2+2] cycloaddition reaction involves the formation of three carbon-carbon bonds in one single step using alkynes, alkenes, nitriles, carbonyls and other unsaturated reagents as reactants. This is one of the most elegant methods for the construction of polycyclic aromatic compounds and heteroaromatic, which have important academic and industrial uses. The thesis is divided into ten chapters including six related publications. The first study based on the Wilkinson’s catalyst, RhCl(PPh3)3, compares the reaction mechanism of the [2+2+2] cycloaddition process of acetylene with the cycloaddition obtained for the model of the complex, RhCl(PH3)3. In an attempt to reduce computational costs in DFT studies, this research project aimed to substitute PPh3 ligands for PH3, despite the electronic and steric effects produced by PPh3 ligands being significantly different to those created by PH3 ones. In this first study, detailed theoretical calculations were performed to determine the reaction mechanism of the two complexes. Despite some differences being detected, it was found that modelling PPh3 by PH3 in the catalyst helps to reduce the computational cost significantly while at the same time providing qualitatively acceptable results. Taking into account the results obtained in this earlier study, the model of the Wilkinson’s catalyst, RhCl(PH3)3, was applied to study different [2+2+2] cycloaddition reactions with unsaturated systems conducted in the laboratory. Our research group found that in the case of totally closed systems, specifically 15- and 25-membered azamacrocycles can afford benzenic compounds, except in the case of 20-membered azamacrocycle (20-MAA) which was inactive with the Wilkinson’s catalyst. In this study, theoretical calculations allowed to determine the origin of the different reactivity of the 20-MAA, where it was found that the activation barrier of the oxidative addition of two alkynes is higher than those obtained for the 15- and 25-membered macrocycles. This barrier was attributed primarily to the interaction energy, which corresponds to the energy that is released when the two deformed reagents interact in the transition state. The main factor that helped to provide an explanation to the different reactivity observed was that the 20-MAA had a more stable and delocalized HOMO orbital in the oxidative addition step. Moreover, we observed that the formation of a strained ten-membered ring during the cycloaddition of 20-MAA presents significant steric hindrance. Furthermore, in Chapter 5, an electrochemical study is presented in collaboration with Prof. Anny Jutand from Paris. This work allowed studying the main steps of the catalytic cycle of the [2+2+2] cycloaddition reaction between diynes with a monoalkyne. First kinetic data were obtained of the [2+2+2] cycloaddition process catalyzed by the Wilkinson’s catalyst, where it was observed that the rate-determining step of the reaction can change depending on the structure of the starting reagents. In the case of the [2+2+2] cycloaddition reaction involving two alkynes and one alkene in the same molecule (enediynes), it is well known that the oxidative coupling may occur between two alkynes giving the corresponding metallacyclopentadiene, or between one alkyne and the alkene affording the metallacyclopentene complex. Wilkinson’s model was used in DFT calculations to analyze the different factors that may influence in the reaction mechanism. Here it was observed that the cyclic enediynes always prefer the oxidative coupling between two alkynes moieties, while the acyclic cases have different preferences depending on the linker and the substituents used in the alkynes. Moreover, the Wilkinson’s model was used to explain the experimental results achieved in Chapter 7 where the [2+2+2] cycloaddition reaction of enediynes is studied varying the position of the double bond in the starting reagent. It was observed that enediynes type yne-ene-yne preferred the standard [2+2+2] cycloaddition reaction, while enediynes type yne-yne-ene suffered β-hydride elimination followed a reductive elimination of Wilkinson’s catalyst giving cyclohexadiene compounds, which are isomers from those that would be obtained through standard [2+2+2] cycloaddition reactions. Finally, the last chapter of this thesis is based on the use of DFT calculations to determine the reaction mechanism when the macrocycles are treated with transition metals that are inactive to the [2+2+2] cycloaddition reaction, but which are thermally active leading to new polycyclic compounds. Thus, a domino process was described combining an ene reaction and a Diels-Alder cycloaddition.

Reactions catalyzed by bacterial cytochromes P450

The cytochromes P450 are a large family of oxidative haemoproteins that are responsible for a wide variety of oxidative transformations in a variety of organisms. This review focuses upon the reactions catalyzed specifically by bacterial enzymes, which includes aliphatic hydroxylation, alkene epoxidation, aromatic hydroxylation, oxidative phenolic coupling, heteroatom oxidation and dealkylation, and multiple oxidations including C-C bond cleavage. The potential for the practical application of the oxidizing power of these enzymes is briefly discussed.

Copper salt-catalyzed homo-coupling reaction of potassium alkynyltrifluoroborates: a simple and efficient synthesis of symmetrical 1,3-diynes

The copper-catalyzed dimerization of alkynyltrifluoroborates proceeds readily with good yields. The homo-coupling reaction can be effected in DMSO, in the open air, using Cu(OAc)(2) as catalyst in the absence of any other additives. A variety of functional groups are tolerated. (C) 2008 Elsevier Ltd. All rights reserved.

Ultrasound-assisted synthesis of functionalized 1,3-enynes by palladium-catalyzed cross-coupling reaction of alpha-styrylbutyltelluride with alkynyltrifluoroborate salts

An ultrasound-assisted synthesis of functionalized 1,3-enyne scaffolds is described and illustrated by palladium-catalyzed cross-coupling of potassium alkynyltrifluoroborate salts and alpha-styrylbutyltellurides. This procedure offers easy access to 1,3-enyne architecture that contains aliphatic and aromatic groups in good to excellent yields.

Quantitative analysis of the time courses of enzyme-catalyzed reactions

The catalytic properties of enzymes are usually evaluated by measuring and analyzing reaction rates. However, analyzing the complete time course can be advantageous because it contains additional information about the properties of the enzyme. Moreover, for systems that are not at steady state, the analysis of time courses is the preferred method. One of the major barriers to the wide application of time courses is that it may be computationally more difficult to extract information from these experiments. Here the basic approach to analyzing time courses is described, together with some examples of the essential computer code to implement these analyses. A general method that can be applied to both steady state and non-steady-state systems is recommended. (C) 2001 academic Press.

Analysis of heterogeneously catalyzed ester hydrolysis reactions in a fixed-bed chromatographic reactor

Reactive Chromatography, Fixed-Bed Reactor, Heterogeneous, Hydrolysis, Ester, Catalyst, Adsorption, Ion-Exchange Resin

HPLC-ESI-MS/MS analysis of oxidized di-caffeoylquinic acids generated by metalloporphyrin-catalyzed reactions

This paper reports an HPLC-ESI-MS/MS investigation on the oxidation of 3,5- and 4,5- dicaffeoylquinic acid using iron(III) tetraphenylporphyrin chloride as catalyst. Two major mono-oxidised products of the quinic acid moiety have been identified for both compounds. However, only the 4,5-derivative afforded two different tri-oxo products. Thus, it seems that the oxidation pattern depends on the number and positions of the caffeic acid moieties present in caffeoylquinic acid molecules.