Hypervalent iodine in synthesis 93. A facile synthesis of 2-substituted imidazo[1,2-a]pyrimidines by cyclocondensation of alkynyl(phenyl)iodonium salts and 2-aminopyrimidine

Simple stirring of a mixture of the alkynyl(phenyl)iodonium salts 1 with 2-aminopyrimidine 2 in chloroform under reflux for two hours in the presence of K2CO3 gave, after workup, the 2-substituted imidazo[1,2-]pyrimidines 3 in moderate to good yields. A possible mechanism for the formation of 3 involves the intramolecular cyclization of the intermediate alkylidenecarbene 6.

Transglutaminase mediated grafting of silk proteins onto wool fabrics leading to improved physical and mechanical properties

Transglutaminases have the ability to incorporate primary amines and to graft peptides (containing glutamine or lysine residues) into proteins. These properties enable transglutaminases to be used in the grafting of a range of compounds including peptides and/or proteins onto wool fibres, altering their functionality. In this paper we investigated the transglutaminase mediated grafting of silk proteins into wool and its effect on wool properties. A commercial hydrolysed silk preparation was compared with silk sericin. The silk sericin protein was labelled with a fluorescent probe which was used to demonstrate the efficiency of the TGase grafting of such proteins into wool fibres. The TGase mediated grafting of these proteins led to a significant effect on the properties of wool yarn and fabric, resulting in increased bursting strength, as well as reduced levels of felting shrinkage and improved fabric softness. Also observed was an accumulation of deposits on the surface of the treated wool fibres when monitored by SEM and alterations in the thermal behaviour of the modified fibres, in particular for mTGase/sericin treated fibres which, with the confocal studies, corroborate the physical changes observed on the treated wool fabric. © 2006 Elsevier Inc. All rights reserved.

Nitrogen cycle of effluent-irrigated energy crop plantations:from wastewater treatment to thermo-chemical conversion processes

This paper reviews nitrogen (N) cycle of effluent-irrigated energy crop plantations, starting from wastewater treatment to thermo-chemical conversion processes. In wastewater, N compounds contribute to eutrophication and toxicity in water cycle. Removal of N via vegetative filters and specifically in short-rotation energy plantations, is a relatively new approach to managing nitrogenous effluents. Though combustion of energy crops is in principle carbon neutral, in practice, N content may contribute to NOx emissions with significant global warming potential. Intermediate pyrolysis produces advanced fuels while reducing such emissions. By operating at intermediate temperature (500°C), it retains most N in char as pyrrolic-N, pyridinic-N, quaternary-N and amines. In addition, biochar provides long-term sequestration of carbon in soils.

Stabilisation of isocyanate cross linked polybutadiene binder

Isocyanate cross-linked hydroxy terminated polybutadiene is used as a binder for solid rocket propellant. Rocket motors containing this propellant require a storage life of at least 20 years. During storage it has been found that the important rubbery properties of the binder can be lost due to oxidative cross-linking of the polybutadiene chains. This could cause catastrophic failure when the rocket motor is required. At present the bis-hindered phenol Calco 2246 is used as a thermal oxidative stabiliser, but it's performance is only adequate. This has led to the search for a more efficient stabiliser system. To hasten the evaluation of new antioxidant systems the use of dynamic thermal analysis was investigated. Results showed that a tentative relationship existed between predictions by thermal analysis and the long term oven ageing for simple single antioxidant systems. But for more complex systems containing either autosynergistic or mixed antioxidants no relationship was observed suggesting that results for such an "accelerated" technique cannot be used for the purpose of extrapolation for long term performance. This was attributed to the short time and more aggressive condition used (hjgher temperature and oxygen rich atmosphere in thermal analysis) altering the mechanism of action of the antioxidants and not allowing time for co-operative effect of the combined antioxidant system to form. One potential problem for the binder system is the use of an diisocyanate as a cross-linking agent. This reacts with the hydroxyl hydrogen on the polymer as well as other active hydrogens such as those contained in a number of antioxidants, affecting both cross-linking and antioxidant effectiveness. Studies in this work showed that only antioxidants containing amine moieties have a significant affect on binder preparation, with the phenolic antioxidants not reacting. This is due to the greater nucleophilicity of the amines. Investigation of a range of antioxidant systems, including potentially homo, hetero and autosynergistic systems, has highlighted a number of systems which show considerably greater effectiveness than the currently used antioxidant Calco 2246. The only single antioxidant which showed improvement was the partially unhindered phenol y-Tocopherol. Of the mixed systems combinations of the sulphur containing antioxidants e.g. DLTP with higher levels of chain-breaking antioxidants, especially Calco 2246, were the most promising. Also the homosynergistic mix of an aromatic amine and a phenol was seen to be very effective but the results were inconsistent. This inconsistency could be explained by the method of sample preparation used. It was shown that the efficiency of a number of antioxidant.s could be dramatically improved by the use of ultrasound during the mixing stage of preparation. The reason for this increase in performance is unclear but in the case of the homosynergistic amine/phenol mix both more efficient mixing and/or the production of a novel mechanism of action are suggested

Reactions of directly related tellurium and selenium heterocycic compunds with triiron dodecacarbonyl

The reactions of directly related tellurium and selenium heterocyclic compounds with triiron dodecacarbonyl are described. The reaction of 2-telluraphthalide, C8H8OTe with [Fe3(CO)12 gave [Fe{C6H4(CH2)Te}(CO)3]2, (1). An iron atom has inserted into the telluracyclic ring, and it is probable that one co-ordinated CO ligand arises from the initially organic carbonyl group. X-ray analysis of compound (1) showed that the compound has a Fe2Te2 core, which is achieved by dimerisation. The reaction of telluraphthalic anhydride, C8H402Te with [Fe3(CO)12] gave a known, but unexpected, organic phthalide product, C8H602, which was confirmed by X-ray crystallography. Selenaphthalic anhydride,  C8H4O2Se gave intractable products on reaction with [Fe3(CO)12], 2-selenaphthalide, C8H6OSe, on reaction with [Fe3(CO)12] gave a major product [Fe2{C6H4(CH2)Se}(CO)6], (2) and a minor product [Fe3{C6H4(CH2)Se}(CO)8], (3) which is an intermediate in the formation of (2). X-ray analysis of (2) shows that compound (2) is very similar to (1) except that the 18 electron rule is satisfied by co-ordination of a Fe(CO)3 moiety, rather than dimerisation. Compound (3), also studied by X-ray crystallography, differs from (2) mainly in the addition of an Fe(CO)2 moiety. Telluraphtbalic anhydride, C8H402Te, and selenaphthalic anhydride, C8H402Se, are both monoclinic and crystallise in space group P21/n. 2-Selenaphthalide, C8H402Se, is also monoclinic, space group P21/C. The reactions of the following compounds (l,3-dihydrobenzo[c]selenophene, 1,3,7,9-tetrahydrobenzo[1,2c; 4,5c'] ditellurophene, dibenzoselenophene, phenoxselenine, 3, 5-naphtho-1-telluracyclohexane and 3,5-naphtho-1-selenacyclohexane) with [Fe3lCO)12] are reported. It is unfortunate that the above compounds do not react under the conditions employed; this may be due to differing degrees of ring strain. 1,8-bis(bromomethyl)naphthalene, C12H10Br2 is monoclinic and crystallises in space group C2/c. 1,1-diiodo-3,5-naphthotelluracyclohexane, C12H10TeI2 and 3,5-naphtho-l-telluracyclohexane, C12H10Te are monoclinic and crystallise in space group P21/c. 3,5-naphtho-l-selenacyclohexane, C12H10Se and 2,2,8,8-tetraiodo-1,3,7,9-tetrahydrobenzo[1,2c;4,5c']ditellurophene are also monoclinic, space group P21/a. The syntheses of intramolecular stabilised organo-tellurium and selenium compounds are reported, having a general formula of REX (where R = phenylazophenyl; E = Se, Te; X = electronegative group, for example C1, Br or I). The crystal structures of R'TeBr, RTeI, RSeCI, RSeCI/I and RSeI (where R = phenylazophenyl) are reported. The tellurium containing X-ray structures are triclinic and have a space group P-1. The selenium containing X-ray structures are monoclinic with space group P21/n. The inclusion of nitrogen in selenium heterocycles provides access to an entirely new area of organometallic chemistry. The reaction of 2-methylbenzoselenazole with [Fe3(CO)12] gave [Fe2{C6H4(NCH2CH3)Se}(CO)6]. The reactions of 2-(methyltelluro)benzanilide or 2-(methylseleno)benzanilide with [Fe3(CO)12] gave reaction products [Fe2(μTeMe)2(CO)6] and [Fe2 (μ-SeMe)2(CO)6] respectively, which were confmned by X-ray crystallography. The use of Mossbauer spectroscopy on the products obtained from the reactions of heterocyclic compounds with [Fe3(CO)12] can give useful information, for example the number of iron sites and the environments of these iron sites within the products.

Analysis of rubber vulcanisates

A study has been made, using High Pressure Liquid Chromatography, of the migration of TMQ (a quinoline type) and 6PPD (a paraphenylenediamine type) antidegradants from a tyre sidewall compound into adjacent casing and liner compounds containing no antidegradant. Migration takes place at a rapid rate, even during the vulcanisation of the composite. After 4000 hours ageing in nitrogen at 100oC, there is a higher level of antidegradants in the casing than in the sidewall. An equilibrium distribution is not obtained. After 114 days at 50oC in 95% relative humidity, the level of solvent extractable 6PPD fell to zero, but subsequent ageing for 2 years in 50 pphm ozone showed no evidence of sidewall cracking. It is suggested that the antidegradant is still active but linked to the polymer chain. An analytical method, for the type and amount of sulphenamide accelerators in vulcanised rubber compounds, has been developed. During the vulcanisation process, the accelerators decay, liberating specific amines which have been solvent extracted, derivatised with 1-chloro-2,4-dinitrobenzene and the yellow coloured zwitter ion analysed using High Pressure Liquid Chromatography. The decay of the accelerator and sulphur during the vulcanisation process, has been studied. It has been demonstrated that the sulphur crosslinking with a styrenebutadiene polymer is a first order reaction, after an initial period during which the accelerator content falls to zero. Variations in sulphur to accelerator ratios gave consistent rate constants for the crosslinking, except for a sulphur level of less than 1% by weight and a ratiio of accelerator to sulphur of 1:1.3. The retention time of the reaction product between sulphur and accelerator from an HPLC column changes with cure time, showing that the precurser to crosslinking is an ever changing material. One of these reaction products has been analysed.

The chemistry of British bituminous coals : an assessment of phase transfer catalysed reactions in the determination of coal structure

Three British bituminous coals, (Gedling, Cresswell, and Cortonwood Silkstone) were selected for study. Procedures were developed, using phase transfer catalysts (PTC's), to degrade the solvent insoluble fractions of the coals. PTC's are of interest because they have the potential to bring about selective high conversion reactions, under mild conditions, (often in the past, severe reaction conditions have had to be used to degrade the coals, this in turn resulted in the loss of much of the structural information). We have applied a variety of physical and chemical techniques to maximise the amount of structural information, these include, elemental analysis, 1H-NMR, 13C-CPMAS-NMR, GPC, GC-MS, FTIR spectroscopy, DRIFT spectroscopy, and gas adsorption measurements. The main conclusions from the work are listed below:- ( 1 ) PTC O-methylation; This reaction removes hydrogen bonds within the coal matrix by 'capping' the phenolic groups. It was found that the polymer-like matrix could be made more flexible, but not significantly more soluble, by O-methylation. I.E. the trapped or 'mobile' phase of the coals could be removed at a faster rate after this reaction had been carried out. ( 2 ) PTC Reductive and Acidic Ether Cleavage; The three coals were found to contain insignificant amounts of dialkyl and alkyl aryl ethers. The number of diaryl ethers could not be estimated, by reductive ether cleavage, (even though a high proportion of all three coals was solublised). The majority of the ethers present in the coals were inert to both cleavage methods, and are therefore assumed to be heterocyclic ethers. ( 3 ) Trif!uoroperacetic Acid Oxidation; This oxidant was used to study the aliphatic portions of the polymer-like macromolecular matrix of the coals. Normally this reagent will only solublise low rank coals, we however have developed a method whereby trifluoroperacetic acid can be used to degrade high rank bituminous coals. ( 4 ) PTC/Permanganate Oxidation; This reagent has been found to be much more selective than the traditional alkaline permanganate oxidation, with a lot more structural information being retained within the various fractions. This degradative method therefore has the potential of yielding new information about the molecular structure of coals.

Degradation and stabilisation of diisocyanate cured polybutadiene

Hydroxyl terminated polybutadiene (HTPB) has been used as a rocket propellant binder which is required to be stored for at least twenty years. It is found that the excellent stress-strain characteristics of this propellant can be totally lost, during this long storage, due to the deterioration of the polybutadiene chains. As a result, the propellant can not stand the service loads, which may lead to a catastrophe. The study of the HTPB binder degradation, below 80°C, has been carried out by investigating the environmental factors and the changes which occur along the macromolecular chains. Results have shown that oxygen is the main factor which causes the crosslinking and chain scission reactions. The former is the predominant reaction and proceeds rapidly under oxygen sufficient environment. The unsaturation of polymer chain, which provides the desired physical properties to the binder, was lost with the increase in crosslink density. At the same time hydroperoxides were found to form and decompose along the polymer chains. Therefore, the deterioration of the binder results from the oxidation of polymer chains. Since the oxidation reaction occurred at higher rate than oxygen diffusion rate and oxygen diffusion rate is inversely proportional to the crosslink density, the binder, below the surface layer in a thick section container, could be naturally protected under an oxygen deficient condition for a long time. Investigation of the effectiveness of antioxidants in HTPB binder has shown that the efficiency of an antioxidant depends on its ability to scavenge radicals. Generally, aromatic amines are the most effective binder antioxidants. But when a peroxide decomposer is combined with an aromatic amine at the appropriate ratio, a synergistic effect is obtained, which gives the lowest binder gel increase rate.

Non-classical inhibitors of dihydrofolate reductase

This thesis comprises two main objectives. The first objective involved the stereochemical studies of chiral 4,6-diamino-1-aryl-1,2-dihydro-s-triazines and an investigation on how the different conformations of these stereoisomers may affect their binding affinity to the enzyme dihydrofolate reductase (DHFR). The ortho-substituted 1-aryl-1,2-dihydro-s-triazines were synthesised by the three component method. An ortho-substitution at the C6' position was observed when meta-azidocycloguanil was decomposed in acid. The ortho-substituent restricts free rotation and this gives rise to atropisomerism. Ortho-substituted 4,6-diamino-1-aryl-2-ethyl-1,2-dihydro-2-methyl-s-triazine contains two elements of chirality and therefore exists as four stereoisomers: (S,aR), (R,aS), (R,aR) and (S,aS). The energy barriers to rotation of these compounds were calculated by a semi-empirical molecular orbital program called MOPAC and they were found to be in excess of 23 kcal/mol. The diastereoisomers were resolved and enriched by C18 reversed phase h.p.l.c. Nuclear overhauser effect experiments revealed that (S,aR) and (R,aS) were the more stable pair of stereoisomers and therefore existed as the major component. The minor diastereoisomers showed greater binding affinity for the rat liver DHFR in in vitro assay. The second objective entailed the investigation into the possibility of retaining DHFR inhibitory activity by replacing the classical diamino heterocyclic moiety with an amidinyl group. 4-Benzylamino-3-nitro-N,N-dimethyl-phenylamidine was synthesised in two steps. One of the two phenylamidines indicated weak inhibition against the rat liver DHFR. This weak activity may be due to the failure of the inhibitor molecule to form strong hydrogen bonds with residue Glu-30 at the active site of the enzyme.

Design, synthesis and development of PDE5 inhibitors

This research project is concerned with the design, synthesis and development of new phosphodiesterase 5 (PDE5) inhibitors with improved selectivities and lower toxicities. Two series of a 5 member and a 6 member ring fused heterocyclic compounds were designed, and synthesized. By alteration of starting materials and fragments, two virtual libraries, each is consisted of close to hundred compounds, were obtained successfully. The screening of sexual stimulation activity with rabbits demonstrated both groups of compounds were able to stimulate rabbit penile erection significantly. The following toxicity studies revealed 2-(substituted-sulfonylphenyl)-imidazo [1,5-a]-1,3,5-triazine-4-(3H)-one group possessed an unacceptable toxicity with oral LD50 about 200mg/kg; while 2-(substituted-sulfonylphenyl)-pyrrolo[2,3-d]pyrimidin-4-one group showed an acceptable toxicity with oral LD50 over 2000mg/kg. The continued bioactivity studies showed yonkenafil, the representative of 2-(substituted-sulfonylphenyl)-pyrrolo[2,3-d]pyrimidin-4-one group, has a better selectivity towards PDE5 and PDE6 than sildenafil and a better overall profile of sexual stimulation on animals than sildenafil. Chronic toxicity studies of yonkenafil further confirmed yonkenafil did not cause any serious side effect and damage on animal models and most actions were explainable. Based on evidences of the above studies, yonkenafil were recommended to enter clinical trials by the regulation authority of China, SFDA. Currently yonkenafil has been through the Phase I clinical trials and ready to progress into Phase II. Hopefully, yonkenafil will provide an alternative to the ED patients in the future.

Reactions of copper macrocycles with antioxidants and HOCl:potential for biological redox sensing

A series of simple copper N(2)S(2) macrocycles were examined for their potential as biological redox sensors, following previous characterization of their redox potentials and crystal structures. The divalent species were reduced by glutathione or ascorbate at a biologically relevant pH in aqueous buffer. A less efficient reduction was also achieved by vitamin E in DMSO. Oxidation of the corresponding univalent copper species by sodium hypochlorite resulted in only partial (~65 %) recovery of the divalent form. This was concluded to be due to competition between metal oxidation and ligand oxidation, which is believed to contribute to macrocycle demetallation. Electrospray mass spectrometry confirmed that ligand oxidation had occurred. Moreover, the macrocyclic complexes could be demetallated by incubation with EDTA and bovine serum albumin, demonstrating that they would be inappropriate for use in biological systems. The susceptibility to oxidation and demetallation was hypothesized to be due to oxidation of the secondary amines. Consequently these were modified to incorporate additional oxygen donor atoms. This modification led to greater resistance to demetallation and ligand oxidation, providing a better platform for further development of copper macrocycles as redox sensors for use in biological systems.

Preparation of 9-substituted pyridine-stretched adenines and hypoxanthines

9-Methylsulfanyl pyridine-stretched adenine and hypoxanthine derivatives have been prepared via regioselective reaction of a 5-aminoimidazole with 2-(bis-methylsulfanylmethylene)malononitrile [(NC)C=C(SMe) ]. The 9-methylsulfanyl substituent can be replaced by sequential oxidation and substitution by nucleophiles including amines.

Chapter 1 : nucleobases with designed patterns of hydrogen bonding

The chemistry used in key bond-forming steps to prepare nucleobases with designed patterns of hydrogen bonding is surveyed. Incorporation of the nucleobases into DNA and RNA oligomers is achieved either chemically using building blocks such as nucleoside phosphoramidites or enzymatically using nucleotide triphosphates. By varying the hydrogen bonding pattern within nucleobases, and by incorporating additional substituents, new structures have been designed that "reach over" so that contacts with both strands in targeted duplex DNA can be made in antigene strategies to control gene expression. Various new base-pairing systems have been evaluated that expand the genetic alphabet beyond Watson-Crick base pairs A.T and G.C. For example, benzo-homologated analogs of the natural DNA bases represent a new genetic set of orthogonal, size-expanded derivatives that have been shown to encode amino acids of a protein in a living organism.

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.

Novel anti-bacterials against MRSA:Synthesis of focussed combinatorial libraries of tri-substituted 2(5H)-furanones

Mucobromic and mucochloric acid were used as building blocks for the construction of a chemical combinatorial library of 3,4,5-trisubstituted 2(5H)-furanones. With these 2 butenolide building blocks, and eight alcohols a sublibrary of 16 dihalogenated 5-alkoxy-2(5H)-furanones was prepared. This sublibrary of 5-alkoxylated furanones was reacted with 16 amines generating a full size focussed combinatorial library of 256 individual compounds. This three dimensional combinatorial library of 3-halogen-4-amino-5-alkoxy-2(5H)-furanones was prepared around the benzimidazolyl furanone lead structure by applying a solution phase combinatorial chemistry concept. Typical representatives of the library were purified and fully characterized and one x-ray structures was recorded, additionally. The 3-bromo-4-benzimizazolyl-5-methoxy-2(5H)furanone, Br-A-l, showed an MIC of 8 μg/ml against the multiresistant Staphylococcus aureus ( MRSA). © 2006 Bentham Science Publishers Ltd.