Novel approaches for the synthesis of C-5 modified pyrimidine nucleosides

The antiviral or anticancer activities of C-5 modified pyrimidine nucleoside analogues validate the need for the development of their syntheses. In the first half of this dissertation, I explore the Pd-catalyzed cross-coupling reaction of allylphenylgermanes with aryl halides in the presence of SbF 5/TBAF to give various biaryls by transferring multiple phenyl groups, which has also been applied to the 5-halo pyrimidine nucleosides for the synthesis of 5-aryl derivatives. To avoid the use of organometallic reagents, I developed Pd-catalyzed direct arylation of 5-halo pyrimidine nucleosides. It was discovered that 5-aryl pyrimidine nucleosides could be synthesized by Pd-catalyzed direct arylation of N3-free 5-halo uracil and uracil nucleosides with simple arenes or heteroaromatics in the presence of TBAF within 1 h. Both N3-protected and N3-free uracil and uracil nucleosides could undergo base-promoted Pd-catalyzed direct arylation, but only with electron rich heteroaromatics. ^ In the second half of this dissertation, 5-acetylenic uracil and uracil nucleosides have been employed to investigate the hydrogermylation, hydrosulfonylation as well as hydroazidation for the synthesis of various functionalized 5-vinyl pyrimidine nucleosides. Hydrogermylation of 5-alkynyl uracil analogues with trialkylgermane or tris(trimethylsilyl)germane hydride gave the corresponding vinyl trialkylgermane, or tris(trimethylsilyl)germane uracil derivatives. During the hydrogermylation with triphenylgermane, besides the vinyl triphenylgermane uracil derivatives, 5-[2-(triphenylgermyl)acetyl]uracil was also isolated and characterized and the origin of the acetyl oxygen was clarified. Tris(trimethylsilyl)germane uracil derivatives were coupled to aryl halides but with decent yield. Iron-mediated regio- and stereoselective hydrosulfonylation of the 5-ethynyl pyrimidine analogues with sulfonyl chloride or sulfonyl hydrazine to give 5-(1-halo-2-tosyl)vinyluracil nucleoside derivatives has been developed. Nucleophilic substitution of the 5-(β-halovinyl)sulfonyl nucleosides with various nucleophiles have been performed to give highly functionalized 5-vinyl pyrimidine nucleosides via the addition-elimination mechanism. The 5-(β-keto)sulfonyluracil derivative has also been synthesized via the aerobic difunctionalization of 5-ethynyluracil analogue with sulfinic acid in the presence of catalytic amount of pyridine. Silver catalyzed hydroazidation of protected 2'-deoxy-5-ethynyluridine with TMSN3 in the presence of catalytic amount of water to give 5-(α-azidovinyl)uracil nucleoside derivatives was developed. Strain promoted Click reaction of the 5-(α-azidovinyl)uracil with cyclooctyne provide the corresponding fully conjugated triazole product.^

New Organogermanium Substrates for Palladium-Catalyzed Cross-Coupling Reactions. Application of Organogermanes towards the Synthesis of Carbon-5 Modified Uridine Analogues

The diverse biological properties exhibited by uridine analogues modified at carbon-5 of the uracil base have attracted special interest to the development of efficient methodologies for their synthesis. This study aimed to evaluate the possible application of vinyl tris(trimethylsilyl)germanes in the synthesis of conjugated 5-modified uridine analogues via Pd-catalyzed cross-coupling reactions. The stereoselective synthesis of 5-[(2-tris(trimethylsilyl)germyl)ethenyl]uridine derivatives was achieved by the radical-mediated hydrogermylation of the protected 5-alkynyluridine precursors with tris(trimethylsilyl)germane [(TMS)3GeH]. The hydrogermylation with Ph3GeH afforded in addition to the expected 5-vinylgermane, novel 5-(2-triphenylgermyl)acetyl derivatives. Also, the treatment with Me3GeH provided access to 5-vinylgermane uridine analogues with potential biological applications. Since the Pd-catalyzed cross-coupling of organogermanes has received much less attention than the couplings involving organostannanes and organosilanes, we were prompted to develop novel organogermane precursors suitable for transfer of aryl and/or alkenyl groups. The allyl(phenyl)germanes were found to transfer allyl groups to aryl iodides in the presence of sodium hydroxide or tetrabutylammonium fluoride (TBAF) via a Heck arylation mechanism. On the other hand, the treatment of allyl(phenyl)germanes with tetracyanoethylene (TCNE) effectively cleaved the Ge-C(allyl) bonds and promoted the transfer of the phenyl groups upon fluoride activation in toluene. It was discovered that the trichlorophenyl,- dichlorodiphenyl,- and chlorotriphenylgermanes undergo Pd-catalyzed cross-couplings with aryl bromides and iodides in the presence of TBAF in toluene with addition of the measured amount of water. One chloride ligand on the Ge center allows efficient activation by fluoride to promote transfer of one, two or three phenyl groups from the organogermane precursors. The methodology shows that organogermanes can render a coupling efficiency comparable to the more established stannane and silane counterparts. Our coupling methodology (TBAF/moist toluene) was also found to promote the transfer of multiple phenyl groups from analogous chloro(phenyl)silanes and stannanes.

Pore-water concentration of chloride in sediment cores and equilibrium temperatures and gas bubble analysis at ROV stations from the Vodyanitskii mud volcano

Vodyanitskii mud volcano is located at a depth of about 2070 m in the Sorokin Trough, Black sea. It is a 500-m wide and 20-m high cone surrounded by a depression, which is typical of many mud volcanoes in the Black Sea. 75 kHz sidescan sonar show different generations of mud flows that include mud breccia, authigenic carbonates, and gas hydrates that were sampled by gravity coring. The fluids that flow through or erupt with the mud are enriched in chloride (up to 650 mmol L**-1 at 150-cm sediment depth) suggesting a deep source, which is similar to the fluids of the close-by Dvurechenskii mud volcano. Direct observation with the remotely operated vehicle Quest revealed gas bubbles emanating at two distinct sites at the crest of the mud volcano, which confirms earlier observations of bubble-induced hydroacoustic anomalies in echosounder records. The sediments at the main bubble emission site show a thermal anomaly with temperatures at 60 cm sediment depth that were 0.9 °C warmer than the bottom water. Chemical and isotopic analyses of the emanated gas revealed that it consisted primarily of methane (99.8%) and was of microbial origin (dD-CH4 = -170.8 per mil (SMOW), d13C-CH4 = -61.0 per mil (V-PDB), d13C-C2H6 = -44.0 per mil (V-PDB)). The gas flux was estimated using the video observations of the ROV. Assuming that the flux is constant with time, about 0.9 ± 0.5 x 10**6 mol of methane is released every year. This value is of the same order-of-magnitude as reported fluxes of dissolved methane released with pore water at other mud volcanoes. This suggests that bubble emanation is a significant pathway transporting methane from the sediments into the water column.

Synthesis, crystal structure and spectroscopic characterization of a coordination polymer of copper(II) chloride with ethylenediamine and the 2-hydroxybenzoate ion

Peer reviewed

Synthesis, crystal structure and spectroscopic characterization of a coordination polymer of copper(II) chloride with ethylenediamine and the 2-hydroxybenzoate ion

Peer reviewed

Silver toxicity across salinity gradients: the role of dissolved silver chloride species (AgCl x ) in Atlantic killifish (Fundulus heteroclitus) and medaka (Oryzias latipes) early life-stage toxicity.

The influence of salinity on Ag toxicity was investigated in Atlantic killifish (Fundulus heteroclitus) early life-stages. Embryo mortality was significantly reduced as salinity increased and Ag(+) was converted to AgCl(solid). However, as salinity continued to rise (>5 ‰), toxicity increased to a level at least as high as observed for Ag(+) in deionized water. Rather than correlating with Ag(+), Fundulus embryo toxicity was better explained (R(2) = 0.96) by total dissolved Ag (Ag(+), AgCl2 (-), AgCl3 (2-), AgCl4 (3-)). Complementary experiments were conducted with medaka (Oryzias latipes) embryos to determine if this pattern was consistent among evolutionarily divergent euryhaline species. Contrary to Fundulus data, medaka toxicity data were best explained by Ag(+) concentrations (R(2) = 0.94), suggesting that differing ionoregulatory physiology may drive observed differences. Fundulus larvae were also tested, and toxicity did increase at higher salinities, but did not track predicted silver speciation. Alternatively, toxicity began to increase only at salinities above the isosmotic point, suggesting that shifts in osmoregulatory strategy at higher salinities might be an important factor. Na(+) dysregulation was confirmed as the mechanism of toxicity in Ag-exposed Fundulus larvae at both low and high salinities. While Ag uptake was highest at low salinities for both Fundulus embryos and larvae, uptake was not predictive of toxicity.

Novel Approaches for the Synthesis of C-5 Modified Pyrimidine Nucleosides

The antiviral or anticancer activities of C-5 modified pyrimidine nucleoside analogues validate the need for the development of their syntheses. In the first half of this dissertation, I explore the Pd-catalyzed cross-coupling reaction of allylphenylgermanes with aryl halides in the presence of SbF5/TBAF to give various biaryls by transferring multiple phenyl groups, which has also been applied to the 5-halo pyrimidine nucleosides for the synthesis of 5-aryl derivatives. To avoid the use of organometallic reagents, I developed Pd-catalyzed direct arylation of 5-halo pyrimidine nucleosides. It was discovered that 5-aryl pyrimidine nucleosides could be synthesized by Pd-catalyzed direct arylation of N3-free 5-halo uracil and uracil nucleosides with simple arenes or heteroaromatics in the presence of TBAF within 1 h. Both N3-protected and N3-free uracil and uracil nucleosides could undergo base-promoted Pd-catalyzed direct arylation, but only with electron rich heteroaromatics. In the second half of this dissertation, 5-acetylenic uracil and uracil nucleosides have been employed to investigate the hydrogermylation, hydrosulfonylation as well as hydroazidation for the synthesis of various functionalized 5-vinyl pyrimidine nucleosides. Hydrogermylation of 5-alkynyl uracil analogues with trialkylgermane or tris(trimethylsilyl)germane hydride gave the corresponding vinyl trialkylgermane, or tris(trimethylsilyl)germane uracil derivatives. During the hydrogermylation with triphenylgermane, besides the vinyl triphenylgermane uracil derivatives, 5-[2-(triphenylgermyl)acetyl]uracil was also isolated and characterized and the origin of the acetyl oxygen was clarified. Tris(trimethylsilyl)germane uracil derivatives were coupled to aryl halides but with decent yield. Iron-mediated regio- and stereoselective hydrosulfonylation of the 5-ethynyl pyrimidine analogues with sulfonyl chloride or sulfonyl hydrazine to give 5-(1-halo-2-tosyl)vinyluracil nucleoside derivatives has been developed. Nucleophilic substitution of the 5-(β-halovinyl)sulfonyl nucleosides with various nucleophiles have been performed to give highly functionalized 5-vinyl pyrimidine nucleosides via the addition-elimination mechanism. The 5-(β-keto)sulfonyluracil derivative has also been synthesized via the aerobic difunctionalization of 5-ethynyluracil analogue with sulfinic acid in the presence of catalytic amount of pyridine. Silver catalyzed hydroazidation of protected 2'-deoxy-5-ethynyluridine with TMSN3 in the presence of catalytic amount of water to give 5-(α-azidovinyl)uracil nucleoside derivatives was developed. Strain promoted Click reaction of the 5-(α-azidovinyl)uracil with cyclooctyne provide the corresponding fully conjugated triazole product.

Elemental composition and petroleum-generating potential of the methylene chloride extracts from DSDP Leg 66 Holes

Organic geochemical studies on samples from Holes 487, 488, and 490 in the southern Mexico Middle America Trench provided an opportunity to characterize the organic fraction of the sedimentary section in an active trench environment and to project the petroleum-producing potential of the extracted lipid fractions. The samples were geologically young and of shallow burial history. Samples from Hole 487, located on the oceanic plate, range in age from late Miocene to middlelate Pleistocene. Samples from Hole 488, representing undifferentiated Quaternary sediment, were collected on the landward side of the lower trench slope. Miocene(?) to Quaternary sediments from Hole 490 were obtained from the upper slope immediately seaward of the inferred location of the continental crust.

Chloride ingress into marine exposed concrete: A comparison of empirical- and physically- based models

In establishing the reliability of performance-related design methods for concrete – which are relevant for resistance against chloride-induced corrosion - long-term experience of local materials and practices and detailed knowledge of the ambient and local micro-climate are critical. Furthermore, in the development of analytical models for performance-based design, calibration against test data representative of actual conditions in practice is required. To this end, the current study presents results from full-scale, concrete pier-stems under long-term exposure to a marine environment with work focussing on XS2 (below mid-tide level) in which the concrete is regarded as fully saturated and XS3 (tidal, splash and spray) in which the concrete is in an unsaturated condition. These exposures represent zones where concrete structures are most susceptible to ionic ingress and deterioration. Chloride profiles and chloride transport behaviour are studied using both an empirical model (erfc function) and a physical model (ClinConc). The time dependency of surface chloride concentration (Cs) and apparent diffusivity (Da) were established for the empirical model whereas, in the ClinConc model (originally based on saturated concrete), two new environmental factors were introduced for the XS3 environmental exposure zone. Although the XS3 is considered as one environmental exposure zone according to BS EN 206-1:2013, the work has highlighted that even within this zone, significant changes in chloride ingress are evident. This study aims to update the parameters of both models for predicting the long term transport behaviour of concrete subjected to environmental exposure classes XS2 and XS3.

Exceptional activity of gallium(III) chloride and chlorogallate(III) ionic liquids for Baeyer–Villiger oxidation

Baeyer–Villiger oxidation of cyclic ketones, using H2O2 as the oxidising agent, was systematically studied using a range of metal chlorides in different solvents, and in neat chlorogallate(III) ionic liquids. The extremely high activity of GaCl3 in promoting oxidation with H2O2, irrespective of solvent, was reported for the first time. The activity of all other metal chlorides was strongly solvent-dependent. In particular, AlCl3 was very active in a protic solvent (ethanol), and tin chlorides, SnCl4 and SnCl2, were active in aprotic solvents (toluene and dioxane). In order to eliminate the need for volatile organic solvent, a Lewis acidic chlorogallate(III) ionic liquid was used in the place of GaCl3, which afforded typically 89–94% yields of lactones in 1–120 min, at ambient conditions. Raman and 71Ga NMR spectroscopic studies suggest that the active species, in both GaCl3 and chlorogallate(III) ionic liquid systems, are chlorohydroxygallate(III) anions, [GaCl3OH]−, which are the products of partial hydrolysis of GaCl3 and chlorogallate(III) anions; therefore, the presence of water is crucial.

Avoiding Overfitting in Inverse Modeling of Chloride Migration in Concrete

Inverse analysis for reactive transport of chlorides through concrete in the presence of electric field is presented. The model is solved using MATLAB’s built-in solvers “pdepe.m” and “ode15s.m”. The results from the model are compared with experimental measurements from accelerated migration test and a function representing the lack of fit is formed. This function is optimised with respect to varying amount of key parameters defining the model. Levenberg-Marquardt trust-region optimisation approach is employed. The paper presents a method by which the degree of inter-dependency between parameters and sensitivity (significance) of each parameter towards model predictions can be studied on models with or without clearly defined governing equations. Eigen value analysis of the Hessian matrix was employed to investigate and avoid over-parametrisation in inverse analysis. We investigated simultaneous fitting of parameters for diffusivity, chloride binding as defined by Freundlich isotherm (thermodynamic) and binding rate (kinetic parameter). Fitting of more than 2 parameters, simultaneously, demonstrates a high degree of parameter inter-dependency. This finding is significant as mathematical models for representing chloride transport rely on several parameters for each mode of transport (i.e., diffusivity, binding, etc.), which combined may lead to unreliable simultaneous estimation of parameters.

Resistance of alkali activated slag concretes to chloride environments based on chloride penetration measurements

Comparing the chloride ingress between tradition concretes and AASCs is worthwhile to prove the possibility of increasing concrete lifetime in proximity to sea and deciding while such concretes are practical for use. Findings show that compared to the PC concretes, the AAS concretes have lower rate of chloride ingress.

Resistance of alkali activated slag concretes to chloride environments based on chloride penetration measurements

ABSTRACT

One of the binder systems with low environmental footprint is alkali activated slag concretes (AASC), made by adding alkalis such as sodium hydroxide and sodium silicate to industrial by-products such as ground granulated blast furnace slag (GGBS). Whilst they have the similar behaviour as that of traditional cement systems in terms of strength and structural behaviour, AASC do exhibit superior performance in terms of abrasion and acid resistance and fire protection.
In this article, the authors focus their attention on chloride ingress into different grades of AASC. The mix variables in AASC included water-to-binder, binder to aggregate ratio, percentage of alkali and the SiO2/Na2O ratio (silica modulus, Ms). The first challenge is to get mixes for different range of workability (with slump values from 40mm to 240mm) and reasonable early age and long term compressive strength according to each one. Then the chloride diffusion and migration in those mixes were measured and compared with same normal concretes in the existed literature based on chloride penetration depth. Comparing the chloride ingress between tradition concretes and AASCs is worthwhile to prove the possibility of increasing concrete lifetime in proximity to sea and deciding while such concretes are practical for use. Findings show that compared to the PC concretes, the AAS concretes have lower rate of chloride ingress.

Resistance of alkali activated slag concretes to chloride environments

ABSTRACT: Researchers are focusing their attention on alternative binder systems using 100% supplementary cementitious materials as it allows better control over the microstructure formation and low to moderate environmental footprint. One such system being considered is alkali activated slag concretes (AASC), made by adding alkalis such as sodium hydroxide and sodium silicate to ground granulated blast furnace slag (GGBS). Whilst they have a similar behaviour as that of traditional cement systems in terms of strength and structural behaviour, AASC are reported to exhibit superior performance in terms of abrasion,acid resistance and fire protection.
In this article, the authors investigate chloride ingress into different grades of AASC. The mix variables in AASC included water to binder, and binder to aggregate ratio, percentage of alkali and the SiO2/Na2O ratio (silica modulus, Ms). The first challenge was to develop mixes for different range of workability (with slump values from 40mm to 240mm) and reasonable early age and long term compressive strength. Further chloride ingress into those mixes were assessed and compared with the data from normal concretes based on literature. Findings show that compared to the PC concretes, the AAS concretes have lower rate of chloride ingress.

Oxygen and Chloride Permeability of Alkali-Activated Natural Pozzolan Concrete

One of the important factors in the use of portland cement concrete is its durability, and most of the situations where durability is lacking have been identifi ed and strategies to manage durability have been implemented. Geopolymer concrete, made from an alkali-activated natural pozzolan (AANP), provides an important opportunity for the reduction of carbon dioxide (CO2) emissions associated with the manufacture of concrete but has a limited history of durability studies. Until its different properties are well understood there is no desire to adopt this new technology of unknown provenance by the concrete industry. This paper presents an experimental study of oxygen and chloride permeability of AANP concrete prepared by activating Taftan andesite and Shahindej dacite (Iranian natural pozzolans), with and without calcining, and the correlations between these properties and compressive strength. The results show that compared to ordinary portland cement (OPC) concrete, AANP concrete has lower oxygen permeability at later ages; but it shows moderate to high chloride ion penetrability.