Electronic energy-transfer rate constants for geometrical isomers of a bichromophoric macrocyclic complex

The rate of electronic energy transfer (EET) between a naphthalene donor and an anthracene acceptor in [ZnL3]-(ClO4)(2) and [ZnL4](ClO4)(2) was determined by time-resolved fluorescence measurements, where L 3 and L 4 are the geometrical isomers of 6-[(anthracen-9-ylmethyl)amino]-trans-6,13-dimethyl-1,4,8,11-tetraazacyclotetradecane-13-amine (L-2), substituted with either a naphthalen-1-ylmethyl or naphthalen-2-ylmethyl donor, respectively. The energy transfer rate constant, k(EET), was determined to be (0.92 +/- 0.02) x 10(9) s(-1) for the naphthalen-1-ylmethyl-substituted isomer, while that for the naphthalen-2-ylmethyl-substituted isomer is somewhat faster, with k(EET) = (1.31 +/- 0.01) x 10(9) s(-1). The solid-state structure of [(ZnLCl)-Cl-3]ClO4 has been determined, and using molecular modeling calculations, the likely distributions of solution conformations in CH3CN have been evaluated for both complexes. The calculated conformational distributions in the common trans-III N-based isomeric form gave Forster EET rate constants that account for the differences observed and are in excellent agreement with the experimental values. It is shown that the full range of conformers must be considered to accurately reproduce the observed EET kinetics.

Photodegradation of polyaromatic hydrocarbons in passive air samplers: Field testing different deployment chambers

Semi-permeable membrane devices (SPMDs) were loaded with deuterated anthracene and pyrene as performance reference compounds (PRCs) and deployed at a test site in four different chambers (open and closed box chamber, bowl chamber and cage chamber) for 29 days. The losses of PRCs and the uptake of polyaromatic hydrocarbons (PAHs) from the ambient air were quantified. UV-B levels measured in each deployment chamber indicated that SPMDs would be exposed to the most UV-B in the cage chamber and open box chamber. Significantly less PAHs were quantified in SPMDs deployed in the cage chamber and open box chamber compared to samplers from the other two chambers, suggesting that photodegradation of PAHs had occurred. The loss of PRCs confirmed these results but also showed that photodegradation was occurring in the closed box chamber. The bowl chamber appears to provide the best protection from the influence of direct photodegradation. (c) 2006 Elsevier Ltd. All rights reserved.

Organochlorine and heavy metal concentrations in blubber and liver tissue collected from Queensland (Australia) dugong (Dugong dugon)

Tissue samples of liver and blubber were salvaged from fifty-three dugong (Dugong dugon) carcasses stranded along the Queensland coast between 1996 and 2000. Liver tissue was analysed for a range of heavy metals and blubber samples were analysed for organochlorine compounds. Metal concentrations were similar in male and female animals and were generally highest in mature animals. Liver concentrations of arsenic, chromium, iron, lead, manganese, mercury and nickel in a number of individual animals were elevated in comparison to concentrations previously reported in Australian dugong. Dieldrin, DDT (and its breakdown products) and/or heptachlor epoxide were detected in 59% of dugong blubber samples. In general, concentrations of organochlorines were similar to those reported in dugong 20 years earlier, and were low in comparison to concentrations recorded from marine mammal tissue collected elsewhere in the world. With the exception of lead, the extent of carcass decomposition, the presence of disease or evidence of animal starvation prior to death did not significantly affect dugong tissue concentrations of metals or organochlorines. The results of the study suggest that bioaccumulation of metals and organochlorine compounds (other than dioxins) does not represent a significant risk to Great Barrier Reef dugong populations, particularly in the context of other pressures associated with coastal development and other anthropogenic activities. (c) 2004 Elsevier Ltd. All rights reserved.

Oxidation of organic compounds in molten salts

The objective of this research was to investigate the oxidation of organic compounds in molten alkali metal hydroxides containing manganates. It has been shown that controlled oxidation can be readily achieved with high specificity to give products in high yield with very short reaction times. The concurrent changes in the melt were monitored using a vibrating platinum indicator electrode with a quazi-reference electrode which was successfully developed for use in molten (Na-K)OH eutectic at 523K. Henry's Law constants for water in the molten eutectic system (Na-K)OH have been measured and used to calculate the water concentration in the melt. The electrochemistry of manganates in molten (Na-K)OH eutectic at 523K has been studied using the vibrating platinum electrode, and the existence of the species Mn(II), Mn(II!), Mn(IV), Mn(V) and Mn(VI) in such melts has been investigated at various water concentrations. The half-wave potentials of the voltammetric waves were measured versus the cathodic limit of the melt. The stability of Mn(V) or Mn(VI) in the melt was achieved by varying the water concentration. A range of organic chemicals has been passed through molten (Na-K)OH at 523K and the reactions of these chemicals with the melt have been studied. The same organics were then passed through molten (Na-K)OH containing stabilized Mn(V) or Mn{VI) without violent reaction. Methanol, allyl alcohol, propane 1, 2 diol, I-heptene and acetone were oxidized by Mn(V) and Mn(VI). Ethanol was only oxidized by Mn(VI), isopropanol and benzyl alcohol were only oxidized by Mn(V). Npropanol, butanol, 2 methyl propan-2-ol, n-hexane, n-heptane toluene and cyclohexane were unchanged by both Mn(V) and Mn(VI). Detailed experiments have been performed on the reactions of ethanol, iso-propanol and methanol in molten (Na-K)OH containing stabilized Mrt(V) or Mn(VI), and reaction mechanisms have been postulated. Ethanol and iso-propanol were oxidized to acetaldehyde and acetone respectively with a potential for useful chemical process. The oxidation of methanol could be developed as a basis for an industrial methanol disposal process.

Cytotoxicity of 3,4-dihalogenated 2(5H)-furanones

Mucohalogen acids have been used for the preparation of a variety of 3,4-clihalogenated 2(5H)-furanones. In one synthetic step the carbarnates 2a-c and the pseudoanhydrides 4a-e were prepared using isocyanates and acid anhydrides. A series of 5-alkoxylated 3,4-dichloro-2(5H)-furanones 5a-o have been synthesized with a wide range of lipophilicity, using the hydroxy-form of mucohalogen acids 1a and 1b. The 5-allyl-3,4-dichloro-2(5H)-furanone 5f was derived into the dihydro-isoxazol 6 and the oxirane 7. The methyl ester 5a was converted with ammonia into the tetramic acid chloride 11. The pseudo acid chloride 3 was reacted further into the bis aziricline 8. Reduction of the mucochloric acid 1a furnished the trichlorofuranone 3. The cytotoxicity of these simple and bis-cyclic butenolides have been evaluated in tissue culture on MAC13 and MAC16 cancer cell lines using the MTT cytotoxicity assay. The ester 5g, the acetate 4b and the carbamate 2b displayed a cytotoxicity in the low micromolar range. Further, an IC50 (50% inhibitory concentration) of 50 nM and 30 nm was determined forthe epoxide 7 and the aziridine 18. © 2004 The Authors Recieved.

Enzyme catalysed modification of polymers

The aim of this project was to investigate the enzyme catalysed modification of synthetic polymers. It was found that an immobilised lipase from Candida antartica (Novozyme 435) catalysed the selective epoxidation of poly(butadiene) in the presence of hydrogen peroxide and catalytic quantities of acetic acid. The cis and trans double bonds of the backbone were epoxidised in yields of up to 60 % whilst the pendent vinyl groups were untouched. The effect of varying a number of reaction parameters was investigated. These studies suggested that higher yields of epoxide could not be obtained because of the conformational properties of the partially epoxidised polymer. Application of this process to the Baeyer-Villiger reaction of poly(vinyl phenyl ketone) and poly(vinyl methyl ketone) were unsuccessful. The lack of reactivity was found to be a property of the polymer rather than the enzymatic system employed. Attempts to modify hydroxyl containing polymers and polymers bearing active esters close to the polymer backbone were unsuccessful. Steric factors appear to be the most important influence on the outcome of the reactions.

The use of enzymes in organic solvents in polytransesterification reactions

The aim of this research project was to identify the factors affecting the porcine pancreatic lipase (PPL.)-catalysed polytransesterification of a diester and a diol in organic solvents. It was hoped that by modifying reaction conditions a commercially acceptable polymer molecular weight (Mn) of 20,000 daltons might be attained. Exploratory investigations were carried out using 1,4-butanediolibis(2,2,2- trichloroethyl) adipate and glutarate systems in diethyl ether, with and without molecular sieves. It was found that molecular sieves promoted the reaction by reducing hydrolysis of the ester end-groups, resulting in polymer molecular weights between 1.2 and 2.2 times greater than those obtainable without molecular sieves. Investigations were then concentrated on the PPL-catalysed polytransesterification of 1,4-butanediol with divinyl adipate. The particular advantage of this system is that the reaction is irreversible. The effects of varying substrate concentration, mass of drying agent, reaction solvent, reaction temperature, mass of enzyme and also enzyme immobilisation on the 1,4-butanediolidivinyl adipate system were investigated. The highest molecular weight polymer obtained for the PPL-catalysed polytransesterification of 1,4-butanedial with divinyl adipate in diethyl ether was Mn -8,000. In higher boiling ether solvents molecular weights as high as Mn -9,200 were obtained for this system at elevated temperatures. It was found that the major factor limiting polymerisation was the low solubility of the polymer in the solvent which resulted in precipitation of the polymer onto the surface of the enzyme.

The development and applications of the combined use of NMR and ultrasound

The objective of the research carried out in this report was to observe the first ever in-situ sonochemical reaction in the NMR Spectrometer in the megahertz region of ultrasound. Several reactions were investigated as potential systems for a sonochemical reaction followed by NMR spectroscopy. The primary problem to resolve when applying ultrasound to a chemical reaction is that of heating. Ultrasound causes the liquid to move and produces 'hot spots' resulting in an increase in sample temperature. The problem was confronted by producing a device that would counteract this effect and so remove the need to account for heating. However, the design of the device limited the length of time during which it would function. Longer reaction times were required to enable observations to be carried out in the NMR spectrometer. The fIrst and most obvious reactions attempted were those of the well-known ultrasonic dosimeter. Such a reaction would, theoretically, enable the author to simultaneously observe a reaction and determine the exact power entering the system for direct comparison of results. Unfortunately, in order to monitor the reactions in the NMR spectrometer the reactant concentrations had to be signifIcantly increased, which resulted in a notable increase in reaction time, making the experiment too lengthy to follow in the time allocated. The Diels-Alder Reaction is probably one of the most highly investigated reaction systems in the field of chemistry and it was this to which the author turned her attention. Previous authors have carried out ultrasonic investigations, with considerable success, for the reaction of anthracene with maleic anhydride. It was this reaction in particular that was next attempted. The first ever sonochemically enhanced reaction using a frequency of ultrasound in the megahertz (MHz) region was successfully carried out as bench experiments. Due to the complexity of the component reactants the product would precipitate from the solution and because the reaction could only be monitored by its formation, it was not possible to observe the reaction in the NMR spectrometer. The solvolysis of 2-chloro-2-methylpropane was examined in various solvent systems; the most suitable of which was determined to be aqueous 2-methylpropan-2-ol. The experiment was successfully enhanced by the application of ultrasound and monitored in-situ in the NMR spectrometer. The increase in product formation of an ultrasonic reaction over that of a traditional thermal reaction occurred. A range of 1.4 to 2.9 fold improvement was noted, dependent upon the reaction conditions investigated. An investigation into the effect of sonication upon a large biological molecule, in this case aqueous lysozyme, was carried out. An easily observed effect upon the sample was noted but no explanation for the observed effects could be established.

Novel materials for membrane separation processes

The aim of this work was to synthesise a series of hydrophilic derivatives of cis-1,2-dihydroxy-3,5-cyclohexadiene (cis-DHCD) and copolymerise them with 2-hydroxyethyl methacrylate (HEMA), to produce a completely new range of hydrogel materials. It is theorised that hydrogels incorporating such derivatives of cis-DHCD will exhibit good strength and elasticity in addition to good water binding ability. The synthesis of derivatives was attempted by both enzymatic and chemical methods. Enzyme synthesis involved the transesterification of cis-DHCD with a number of trichloro and trifluoroethyl esters using the enzyme lipase porcine pancreas to catalyse the reaction in organic solvent. Cyclohexanol was used in initial studies to assess the viability of enzyme catalysed reactions. Chemical synthesis involved the epoxidation of a number of unsaturated carboxylic acids and the subsequent reaction of these epoxy acids with cis-DHCD in DCC/DMAP catalysed esterifications. The silylation of cis-DHCD using TBDCS and BSA was also studied. The rate of aromatisation of cis-DHCD at room temperature was studied in order to assess its stability and 1H NMR studies were also undertaken to determine the conformations adopted by derivatives of cis-DHCD. The copolymerisation of diepoxybutanoate, diepoxyundecanoate, dibutenoate and silyl protected derivatives of cis-DHCD with HEMA, to produce a new group of hydrogels was investigated. The EWC and mechanical properties of these hydrogels were measured and DSC was used to determine the amount of freezing and non-freezing water in the membranes. The effect on EWC of opening the epoxide rings of the comonomers was also investigated

The use of enzyme catalysts in organic media for the synthesis of biodegradable polyesters

The enzyme catalysed polytransesterification of diesters with diols was investigated under various conditions. The most consistent results were obtained using crude porcine pancreatic lipase (PPL) suspended in anhydrous diethyl ether. Addition of molecular sieve to the above system gave higher molecular weight products. The PPL catalysed reaction of bis(2,2,2-trichlorethyl) adipate and glutarate with butane-1,4-diol in anhydrous ether with and without molecular sieve was investigated over a range of times from 8 to 240 hours. The 72 hour adipate reaction with molecular sieve gave the highest molecular weight polymer (Mn 6,500 and Mw 9,400). The glutarate gave the maximum molecular weight polyester after 24 hours (Mn 5,700 and Mw 9,500). Occasionally the glutarate reaction produced very high molecular weight polyester-enzyme complexes. Toluene generally gave lower molecular weight products than diethyl ether. Dichloromethane and tetrahydrofuran gave mainly dimers and trimers. Alternative enzyme and diol systems were also investigated. These yielded no polymeric products. The molecular weights of the polyesters were determined by 1H NMR end-group analysis and by GPC. The molecular weights determined by NMR were on average about twice as great as those determined by GPC. The synthesis of the following diesters is described: i)Bis(2,2,2-trichloroethyl) succinate, glutarate, adipate, trans-3-hexenedioate, and trans-3,4-epoxyadipate. ii) Diphenyl glutarate and adipate.iii)Bis(2,2,2-fluoroethyl) glutarate and trans-3-hexendioate.iv) Divinyl glutarate. v) N,N'Glutaryl dicyclohexanone oxime.The polytransesterification of all the above esters with diols was investigated. The easily synthesised bis(2,2,2-trichloroethyl) glutarate and adipate gave the best results and the work was concentrated on these two esters.

The ring opening polymerization of ring strained cyclic ethers

The kinetics and mechanisms of the ring-opening polymerization of oxetane were studied using cationic and coordinated anionic catalysts. The cationic initiators used were BF30Et2!/ethanol, BF30Et2!/ethanediol and BF30Et2/propantriol. Kinetic determinations with the BF30Et2/diol system indicated that a 1: 1 BF3:0H ratio gave the maximum rate of polymerization and this ratio was employed to detenmne the overall rates of polymerization. An overall second-order dependence was obtained when the system involved ethanediol or propantriol as co-catalyst and a 3/2-order dependence with ethanol, in each case the monomer gave a first-order relationship. This suggested that two mechanisms accounted for the cationic polymerization. These mechanisms were investigated and further evidence for these was obtained from the study of the complex formation of BF30Et2 and the co-catalysts by 1H NMR. Molecular weight studies (using size-exclusion chromatography) indicated that the hydroxyl ion acted as a chain transfer reagent when the [OH] > [BF3]. A linear relationship was observed when the number average molecular weight was plotted against [oxetane] at constant [BF3:0H], and similarly a linear dependency was observed on the BF3:0H 1:1 adduct at constant oxetane concentration. Copolymerization of oxetane and THF was carried out using BF30Et2/ethanol system. The reactivity ratios were calculated as rOXT = 1.2 ± 0.30 and rTHF = 0.14 ± 0.03. These copolymers were random copolymers with no evidence of oligomer formation. The coordinated anionic catalyst, porphinato-aluminium chloride [(TPP)AICl], was used to produce a living polymerization of oxetane. An overall third-order kinetics was obtained, with a second-order with respect to the [(TPP)AICl] and a first-order with respect to the [oxetane] and a mechanism was postulated using these results. The stereochemistry of [(TPP)AlCl] catalyst was investigated using cyclohexene and cyclopentene oxide monomers, using extensive 1H NMR, 2-D COSY and decoupling NMR techniques it was concluded that [(TPP)AlCl] gave rise to stereoregular polymers.

Synthesis and cytotoxity of oxysterols:studies on the A,B ring polyoxygenated sterols

Oxysterols (OS), the polyoxygenated sterols, represent a class of potent regulatory molecules for important biological actions. Cytotoxicity of OS is one of the most important aspects in studies of OS bioactivities. However, studies, the structure-activity relationship (SAR) study in particular, have been hampered by the limited availability of structurally diverse OS in numbers and amounts. The aim of this project was to develop robust synthetic methods for the preparation of polyhydroxyl sterols, thereof, evaluate their cytotoxicity and establish structure-activity relationship. First, we found hydrophobicity of the side chain is essential for 7-HC's cytotoxicity, and a limited number of hydroxyl groups and a desired configuration on the A, B ring are required for a potent cytotoxicity of an OS, after syntheses and tests of a number of 7-HC's analogues against cancer cell lines. Then polyoxygenation of cholesterol A, B rings was explored. A preparative method for the synthesis of four diastereomerically pure cholest-4-en-3,6-diols was developed. Epoxidation on these cholest-4-en-3,6-diols showed that an allyl group exerts an auxiliary role in producing products with desired configuration in syntheses of the eight diastereomerically pure 45-epoxycholestane-3,6-diols. Reduction of the eight 45-epoxycholestane-3,6-diols produced all eight isomers of the cytotoxic 5α-acholestane 3β,5,6β-triol (CT) for the first time. Epoxide ring opening with protic or Lewis acids on the eight 45-epoxycholestane-3,6-diols are carefully studied. The results demonstrated a combination of an acid and a solvent affected the outcomes of a reaction dramatically. Acyl group participation and migration play an important role with numbers of substrates under certain conditions. All the eight 4,5-trans cholestane- 3,4,5,6-tetrols were synthesised through manipulation of acyl participation. Furthermore these reaction conditions were tested when a number of cholestane-3,4, 5,6,7-pentols and other C3-C7 oxygenated sterols were synthesised for the first time. Introduction of an oxygenated functional group through cholest-2-ene derivatives was studied. The elimination of 3-(4-toluenesulfonate) esters showed the interaction between the existing hydroxyls or acyls with the reaction centre often resulted in different products. The allyl oxidation, epoxidation and Epoxide ring opening reactions are investigated with these cholest-2-enes.

Novel three-component blends based on poly(L-lactide)

A significant number of poly a-ester homologues of poly(L-lactide) (PLLA) have been synthesized and used in miscibility studies together with conventional isomeric diacid-diol polyester variants, poly ß-esters (based on ß-hydroxybutyrate (HB) and ß-hydroxyvalerate (HV)), poly e-caprolactone (PCL), poly e-caprolactone copolymers (e.g. poly(L-lactide-co-caprolactone), and a series of cellulose-based polymers (e.g. cellulose acetate butyrate (CAB), cellulose acetate propionate (CAP)). A combinatorial approach to rapid miscibility screening using 96-well plates and a uv-visible multi-wavelength plate reader has been developed enabling the clarity of PLLA-based multi-component blend films to be observed. Using these techniques and materials, the ternary phase compatibility diagrams of a range of three-component blend films was prepared, illustrating ranges of behavior varying from miscible blends giving rise to clear films to immiscible blends which are opaque. In this way, novel three-component blends of PLLA/CAB/PCL were developed which are miscible when the CAB content is more than 30%, PLLA less than 80% and PCL less than 60%.

Impact of the counterion on the solubility and physicochemical properties of salts of carboxylic acid drugs

Aim: Salt formation is a widely used approach to improve the physicochemical and solid state properties of an active pharmaceutical ingredient. In order to better understand the relationships between the active drug, the selected counterion and the resultant salt form, crystalline salts were formed using four different carboxylic acid drugs and a closely related series of amine counterions. Thirty-six related crystalline salts were prepared, characterized and the relationship between solubility and dissolution behaviour and other properties of the salt and the counterion studied. Methods: Salts of four model acid drugs, gemfibrozil, flurbiprofen, ibuprofen and etodolac were prepared using the counterions butylamine, hexylamine, octylamine, benzylamine, cyclohexylamine, tert-butylamine, 2-amino-2-methylpropan-1-ol, 2-amino-2-methylpropan-1,3-diol andtris(hydroxymethyl)aminomethane. Salt formation was confirmed, the salts were characterized and their corresponding solubilities determined and rationalized with respect to the counterions' properties. Results and conclusion: The properties of the salt highly dependent on the nature of the counterion and, although there is considerable variation, some general conclusion can be drawn. For the alkyl amines series, increasing chain length leads to a reduction in solubility across all the acidic drugs studied and a reduction in melting point, thus contradicting simplistic relationships between solubility and melting point. Small, compact counterions consistently produce crystalline salts with high melting point accompanied with a modest improvement in solubility and the nature of hydrogen bonding between the ions has a major impact on the solubility. © 2012 Informa Healthcare USA, Inc.

A simple bioanalytical method for the quantification of antiepileptic drugs in dried blood spots

An increasing number of publications on the dried blood spot (DBS) sampling approach for the quantification of drugs and metabolites have been spurred on by the inherent advantages of this sampling technique. In the present research, a selective and sensitive high-performance liquid chromatography method for the concurrent determination of multiple antiepileptic drugs (AEDs) [levetiracetam (LVT), lamotrigine (LTG), phenobarbital (PHB)], carbamazepine (CBZ) and its active metabolite carbamazepine-10,11 epoxide (CBZE)] in a single DBS has been developed and validated. Whole blood was spotted onto Guthrie cards and dried. Using a standard punch (6 mm diameter), a circular disc was punched from the card and extracted with methanol: acetonitrile (3:1, v/v) containing hexobarbital (Internal Standard) and sonicated prior to evaporation. The extract was then dissolved in water and vortex mixed before undergoing solid phase extraction using HLB cartridges. Chromatographic separation of the AEDs was achieved using Waters XBridge™ C18 column with a gradient system. The developed method was linear over the concentration ranges studied with r ≥ 0.995 for all compounds. The lower limits of quantification (LLOQs) were 2, 1, 2, 0.5 and 1 μg/mL for LVT, LTG, PHB, CBZE and CBZ, respectively. Accuracy (%RE) and precision (%CV) values for within and between day were <20% at the LLOQs and <15% at all other concentrations tested. This method was successfully applied to the analysis of the AEDs in DBS samples taken from children with epilepsy for the assessment of their adherence to prescribed treatments.