Rearrangement of 2-quinolyl- and 1-isoquinolylcarbenes to naphthylnitrenes

2-Quinolylcarbene 23 and 1-isoquinolylcarbene 33 are generated by flash vacuum thermolysis (FVT) of the corresponding triazolo[1,5-a]quinoline and triazolo[5,1-a]isoquinoline 19 and 29, as well as 2-(5-tetrazolyl)quinoline and 1-(5-tetrazolyl)isoquinoline 20 and 30, respectively. These carbenes rearrange to 1- and 2-naphthylnitrene 21 and 31, respectively, and the nitrenes are also generated by FVT of 1- and 2-naphthyl azides 18 and 28. The products of FVT of both the nitrene and carbene precursors are the 2- and 3-cyanoindenes 26 and 27 together with the nitrene dimers, viz. azonaphthalenes 25 and 35, and the H-abstraction products, aminonaphthalenes 24 and 34. All the azide, triazole, and tetrazole precursors yield 3-cyanoindene 26 as the principal ring contraction product under conditions of low FVT temperature (340-400 degreesC) and high pressure (1 Torr N-2 as carrier gas for the purpose of collisional deactivation). This ring contraction reaction is strongly subject to chemical activation, which caused extensive isomerization of 3-cyanoindene to 2-cyanoindene under conditions of low pressure (10(-3) Torr). 2-Cyanoindene is calculated to be ca. 1.7 kcal/mol below 3-cyanoindene in energy; accordingly, high-temperature FVT of these cyanoindenes always gives mixtures of the two compounds with the 2-cyano isomer dominating. Photolysis of trizolo[1,5-a]quinoline 19 and triazolo[5,1-a]isoquinoline 29 in Ar matrixes causes partial ring opening to the corresponding 2-diazomethylquinoline 19' and 1-diazomethylisoquinoline 29'. The photolysis of the former gives rise to a small amount of the cyclic ketenimine 22, the intermediate connecting 2-quinolylcarbene and 1-naphthylnitrene.

The rearrangements of naphthyinitrenes: UV/Vis and IR spectra of azirines, cyclic ketenimines, and cyclic nitrile ylides

Ar matrix photolysis of 1- and 2-naphthyl azides 3 and 4 at 313 nm initially affords the singlet naphthyl nitrenes, (1)1 and (1)2. Relaxation to the corresponding lower energy, persistent triplet nitrenes (3)1 and (3)2 competes with cyclization to the azirines 15 and 18, which can also be formed photochemically from the triplet nitrenes. On prolonged irradiation, the azirines can be converted to the seven-membered cyclic ketenimines 10 and 13, respectively, as described earlier by Dunkin and Thomson. However, instead of the o-quinoid ketenimines 16 and 19, which are the expected primary ring-opening products of azirines 15 and 18, respectively, we observed their novel bond-shift isomers 17 and 20, which may be formally regarded as cyclic nitrile ylides. The existence of such ylidic heterocumulenes has been predicted previously, but this work provides the first experimental observation of such species. The factors which are responsible for the special stability of the ylidic species 17 and 20 are discussed.

Comparison of specificity of quantitative myocardial contrast echocardiography for diagnosis of coronary artery disease in patients with versus without diabetes mellitus

Impaired coronary flow reserve is widely reported in diabetes mellitus (DM) but its effect on myocardial contrast echocardiography (MCE) is unclear. We sought to identify whether DM influences the accuracy of qualitative and quantitative assessment of coronary artery disease (CAD) using MCE in 83 patients who underwent coronary angiography (60 men, 27 with DM; 56 +/- 11 years;). Destruction replenishment imaging was performed at rest and after combined dipyridamole-exercise stress testing. Ischemia was identified by the development of new wall motion abnormalities, qualitative MCE (new perfusion defects apparent 1 second after flash during hyperemia), and quantitative MCE (myocardial blood flow reserve < 2.0 in the anterior circulation). Qualitative and quantitative assessment of perfusion was feasible in 100% and 92% of patients, respectively. Significant left anterior descending coronary stenosis (> 50% by quantitative angiography) was present in 28 patients (including 8 with DM); 55 patients had no CAD (including 19 with DM). The myocardial blood flow reserve was reduced in patients with coronary stenosis compared with those with no CAD (1.6 +/- 1.1 vs 3.8 +/- 2.5, p < 0.001). Among patients with no CAD, those with DM had an impaired flow reserve compared with control patients without DM (2.4 +/- 1.0 vs 4.5 +/- 2.8, p = 0.003). In conclusion, DM significantly influenced the quantitative, but not the qualitative, assessment of MCE, with a marked reduction in specificity in patients with DM. (c) 2005 Elsevier Inc. All rights reserved.

Different behavior of nitrenes and carbenes on photolysis and thermolysis: Formation of azirine, ylidic cumulene, and cyclic ketenimine and the rearrangement of 6-phenanthridylcarbene to 9-phenanthrylnitrene

Flash vacuum thermolysis (FVT) of 9-azidophenanthrene 8, 6-(5-tetrazolyl)phenanthridine 18, and [1,2,3]triazolo[1,5-f]phenanthridine 19 yields 9-cyanofluorene 12 as the principal product and 4-cyanofluorene as a minor product. In all cases, when the product is condensed at or below 77 K, the seven-membered ring ketenimine 24 is detectable by IR spectroscopy (1932 cm(-1)) up to 200 K. Photolysis of Ar matrix isolated 8 at lambda = 308 or 313 nm generates at first the azirine 26, rapidly followed by the ylidic cumulene 27. The latter reverts to azirine 26 at lambda > 405 nm, and the azirine reverts to the ylidic cumulene at 313 nm. Nitrene 9 is observed by ESR spectroscopy following FVT of either azide 8, tetrazole 18, or triazole 19 with Ar matrix isolation of the products. Nitrene 9 and carbene 21 are observed by ESR spectroscopy in the Ar matrix photolyses of azide 8 and triazole 19, respectively.

A cyclopropabenzenylidenethenone (Propadienone) via a new route to alkylidenecycloproparenes

Reaction of 1,1-dichloro-2,5-diphenylcyclopropabenzene 6 with Meldrum's acid 8 in the presence of pyridine leads to coupling of the cycloproparenyl cation 7 with the stabilized diketo anion 9. Subsequent, spontaneous, base-induced dehydrochlorination gives the alkylidenecyclopropabenzene 11 in a one-pot reaction. Flash vacuum thermolysis of 11 at 650 degreesC ejects acetone and carbon dioxide, giving cyclopropabenzenylldenethenone 12 that is isolated in an Ar matrix at 20 K and characterized by a strong ketene band at 2107 cm(-1) in the IR spectrum.

Kinetic and structural evidence for the importance of Tyr236 for the integrity of the Mo active site in a bacterial sulfite dehydrogenase

The sulfite dehydrogenase from Starkeya novella is the only known sulfite-oxidizing enzyme that forms a permanent heterodimeric complex between a molybdenum and a heme c-containing subunit and can be crystallized in an electron transfer competent conformation. Tyr236 is a highly conserved active site residue in sulfite oxidoreductases and has been shown to interact with a nearby arginine and a molybdenum-oxo ligand that is involved in catalysis. We have created a Tyr236 to Phe substitution in the SorAB sulfite dehydrogenase. The purified SDHY236F protein has been characterized in terms of activity, structure, intramolecular electron transfer, and EPR properties. The substituted protein exhibited reduced turnover rates and substrate affinity as well as an altered reactivity toward molecular oxygen as an electron acceptor. Following reduction by sulfite and unlike SDHWT, the substituted enzyme was reoxidized quickly in the presence of molecular oxygen, a process reminiscent of the reactions of the sulfite oxidases. SDHY236F also exhibited the pH-dependent CW-EPR signals that are typically observed in vertebrate sulfite oxidases, allowing a direct link of CW-EPR properties to changes caused by a single-amino acid substitution. No quantifiable electron transfer was seen in laser flash photolysis experiments with SDHY236F. The crystal structure of SDHY236F clearly shows that as a result of the substitution the hydrogen bonding network surrounding the active site is disturbed, resulting in an increased mobility of the nearby arginine. These disruptions underline the importance of Tyr236 for the integrity of the substrate binding site and the optimal alignment of Arg55, which appears to be necessary for efficient electron transfer.

Nitrenes, diradicals, and ylides. Ring expansion and ring opening in 2-quinazolylnitrenes

Tetrazolo[1,5-a] quinazoline (9) is converted to 2-azidoquinazoline (10) on sublimation at 200 degrees C and above, and the azide-tetrazole equilibrium is governed by entropy. 2-Quinazolylnitrenes 11 and 27 and/ or their ring expansion products 14 and 29 can undergo type I (ylidic) and type II (diradicaloid) ring opening. Argon matrix photolysis of 9/10 affords 2-quinazolylnitrene (11), which has been characterized by ESR, UV, and IR spectroscopy. A minor amount of a second nitrene, formed by rearrangement or ring opening, is also observed. A diradical (19) is formed rapidly by type II ring opening and characterized by ESR spectroscopy; it decays thermally at 15 K with a half-life of ca. 47 min, in agreement with its calculated facile intersystem crossing (19T -> 19OSS) followed by facile cyclization/rearrangement to 1-cyanoindazole (21) (calculated activation barrier 1- 2 kcal/mol) and N-cyanoanthranilonitrile (22). 21 and 22 are the isolated end products of photolysis. 21 is also the end product of flash vacuum thermolysis. An excellent linear correlation between the zero-field splitting parameter D (cm(-1)) and the spin density F on the nitrene N calculated at the B3LYP/EPRIII level is reported (R-2 = 0.993 for over 100 nitrenes). Matrix photolysis of 3-phenyltetrazolo[1,5-a] quinazoline (25) affords the benzotriazacycloheptatetraene 29, which can be photochemically interconverted with the type I ring opening product 2-isocyano-alpha-diazo-alpha- phenyltoluene (33) as determined by IR and UV spectroscopy. The corresponding carbene 37, obtained by photolysis of 33, was detected by matrix ESR spectroscopy.

Oxoketene-oxoketene, imidoylketene-imidoylketene and oxoketenimine-imidoylketene rearrangements. 1,3-shifts of phenyl groups

Dibenzoylketene 5 undergoes degenerate 1,3-shifts of the phenyl group between acyl and ketene carbon atoms, thus interconverting it with 6 and 7. This 1,3-shift takes place in the gas phase under flash vacuum thermolysis (FVT) conditions, but not in solution at 110-145 degrees C. Imidoyl(benzoyl)ketene 13 undergoes degenerate 1,3-shift of the phenyl group on FVT, thus interconverting it with 14, but the ketenimine isomer 15 is not formed, and none of these shifts take place in the solid state at 250 degrees C. Imidoyl(p-toluoyl)ketene 21 undergoes a 1,3-p-tolyl shift, interconverting it with ketene 22 but not with ketenimine 23. The imidoyl(p-toluoyl)ketene rotamer 25 cyclizes to 4-toluoyloxyquinoline 28 and 4-quinolone 29. The cyclization of imidoyl(benzoyl)ketene 13 to 4-benzoyloxyquinoline 18, and of 25 to 28 involves 1,3-C-to-O shifts of benzoyl (toluoyl) groups. Calculations of the transition states for the transformations at the B3LYP/6-31G** level of theory are in agreement with the observed reaction preferences.

Aryliminopropadienone-C-amidoketenimine-amidinoketene-2-aminoquinolone cascades and the ynamine-isocyanate reaction

Imidoylketenes 11 and oxoketenimines 12 are generated by flash vacuum thermolysis of Meldrum's acid derivatives 9, pyrrolediones 17 and 18, and triazole 19 and are observed by IR spectroscopy. Ketenimine-3-carboxylic acid esters 12a are isolable at room temperature. Ketenes 11 and ketenimines 12 undergo rapid interconversion in the gas phase, and the ketenes cyclize to 4-quinolones 13. When using an amine leaving group in Meldrum's acid derivatives 9c, the major reaction products are aryliminopropadienones, ArN=C=C=C=O (15). The latter react with 1 equiv of nucleophile to produce ketenimines 12 and with 2 equiv to afford maIonic acid imide derivatives 16. N-Arylketenimine-C-carboxamides 12c cyclize to quinolones 13c via the transient amidinoketenes 11c at temperatures of 25-40 degrees C. This implies rapid interconversion of ketenes and ketenimines by a 1,3-shift of the dimethylamino group, even at room temperature. This interconversion explains previously poorly understood outcomes of the ynamine-isocyanate reaction. The solvent dependence of the tautomerism of 4-quinolones/4-quinolinols is discussed. Rotational barriers of NMe2 groups in amidoketenimines 12c and malonioc amides and amidines 16 (24) are reported.

Large diameter optic nerve axon fibres in Alzheimer's disease

A variety of visual symptoms have been associated with Alzheimer's disease (AD). These include delays in flash visual evoked potentials which indicate a disruption of the integrity of the visual pathway. Examination of the visual cortex has revealed the presence of both senile plaques and neurofibrillary tangles. The purpose of this study was to determine whether there were differences in the number and/or size of optic nerve axons between AD patients and non-demented age-matched controls. Five optic nerves from AD patients and five from age-matched controls were embedded in epon resin and 1 micron sections prepared on a Reichert ultramicrotome. The sections were then stained in toluidine blue and examined at x400 magnification. The numbers of axons were counted in photographs of three fields taken at random from each section. To evaluate the axon diameters, 70 axons were chosen at random from each patient and measured using a calibrated eyepiece graticule. The total axon counts revealed no significant differences between the AD optic nerves and the age-matched controls. However, the frequency distribution of axon diameters was significantly different in the two groups. In particular, there were fewer larger diameter axons in patients with AD as previously reported. Degeneration of the large diameter axons suggests involvement of the magnocellular as opposed to the parvocellular pathways. Hence, there could be differences in visual performance of AD patients compared with normals which could be important in clinical diagnosis.

The case for aluminium as the neurotoxin in sporadic Alzheimer's disease

The flash-pattern evoked potential difference (F - P) in man increases with age (93 subjects), correlates with decreasing cognitive ability and when it exceeds a unique critical level the subject is clinically diagnosed as having Alzheimer's disease. Aluminium accumulates in the human brain with age, increases the F - P value close to the critical value in a dose dependent manner, and at such a rate that normal environmental exposure to aluminium accounts for all or nearly all the F - P increases in man. Aluminium neurotoxicity is therefore a major cause of sporadic Alzheimer's disease.

Technical and economic simulation of biomass pyrolysis processes for fuels and electricity

There is considerable concern over the increased effect of fossil fuel usage on the environment and this concern has resulted in an effort to find alternative, environmentally friendly energy sources. Biomass is an available alternative resource which may be converted by flash pyrolysis to produce a crude liquid product that can be used directly to substitute for conventional fossil fuels or upgraded to a higher quality fuel. Both the crude and upgraded products may be utilised for power generation. A computer program, BLUNT, has been developed to model the flash pyrolysis of biomass with subsequent upgrading, refining or power production. The program assesses and compares the economic and technical opportunities for biomass thermochemical conversion on the same basis. BLUNT works by building up a selected processing route from a number of process steps through which the material passes sequentially. Each process step has a step model that calculates the mass and energy balances, the utilities usage and the capital cost for that step of the process. The results of the step models are combined to determine the performance of the whole conversion route. Sample results from the modelling are presented in this thesis. Due to the large number of possible combinations of feeds, conversion processes, products and sensitivity analyses a complete set of results is impractical to present in a single publication. Variation of the production costs for the available products have been illustrated based on the cost of a wood feedstock. The effect of selected macroeconomic factors on the production costs of bio-diesel and gasoline are also given.

The effects of vigabatrin of the visual system

This thesis considers the visual electrophysiological effects of vigabatrin (an anti-epileptic drug, which acts by increasing the levels of the inhibitory neurotransmitter GABA on the retina of the eye compared to the concentric visual field defects which have been found associated with the drug. Flash and pattern ERG's, EOG's multifocal ERG's (VERIS), flash and pattern VEP's and visual fields were tested. Although VEP's have been shown not to be affected by vigabatrin, these were recorded to complete the testing. Initially, of the eight vigabatrin patients with known visual field defects, 7 showed abnormally delayed 30Hz flicker a-wave latencies, 5 abnormally delayed 30Hz b-wave latencies and 6 abnormally low 30Hz amplitudes. Also 7 showed an abnormally prolonged latency of oscillatory potential 1 (OP1). The two patients taking vigabatrin at the time of testing showed low EOG Arden index values. The VERIS results correlated well with the severity of the visual field defects. Following this finding, eleven healthy subjects received vigabatrin over a 10-day period. No changes were seen in the visual fields, however, the photopic ERG b-wave latency significantly increased (although not to abnormal values). A matched pairs study with eleven vigabatrin, patients and eleven epileptic patients, who had never taken vigabatrin supported the findings of abnormal 30Hz flicker b-wave and OP latencies associated with vigabatrin, again with the VERIS results correlating to the severity of the visual field defect. The abnormal 30Hz flicker and VERIS responses indicate involvement of the cone photoreceptors and the OP's show an effect on the amacrine cells. The ERG increase in the photopic b-wave latency also suggests involvement of the bipolar cells, however, this effect and the reversible effect on the Arden index after cessation of the drug may be unrelated to the visual field defect. To conclude this thesis, a field specific VEP stimulus was developed to assess the retinal function in the peripheral field of paediatric patients. It comprises of a dartboard stimulus with a central 0-5 degree black and white chequered stimulus, a blank 5-30 degree annulus and a 30-60 degree peripheral chequered stimulus. When optimised on four vigabatrin patients it was found that no peripheral response can be evoked with a field loss exceeding 30-35 degrees. Co-operation was found to be successful in children as young as four years old.

Further studies of the visually evoked subcortical potential in man

The Visually Evoked Subcortical Potential, a far-field signal, was originally defined to flash stimulation as a triphasic positive-negative-positive complex with mean latencies of P21 N26.2 P33.6 (Harding and Rubinstein 1980). Inconsistent with its subcortical source however, the signal was found to be tightly localised to the mastoid. This thesis re-examines the earlier protocols using flash stimulation and with auditory masking establishes by topographic studies that the VESP has a widespread scalp distribution, consistent with a far-field source of the signal, and is not a volume-conducted electroretinogram (ERG). Furthermore, mastoid localisation indicates auditory contamination from the click, on discharge of the photostimulator. The use of flash stimulation could not precisely identify the origin of the response. Possible sources of the VESP are the lateral geniculate body (LGB) and the superior colliculus. The LGB received 80% of the nerve fibres from the retina, and responds to high contrast achromatic stimulation in the form of drifting gratings of high spatial frequencies. At low spatial frequencies, it is more sensitive to colour. The superior colliculus is insensitive to colour and suppressed by contrast and responds to transitory rapid movements, and receives about 20% of the optic nerve fibres. A pattern VESP was obtained to black and white checks as a P23.5 N29.2 P34 complex in 93% of normal subjects at an optimal check size of 12'. It was also present as a P23.0 N28.29 P32.23 complex to red and green luminance balanced checks at 2o check size in 73% of subjects. These results were not volume-conducted pattern electroretinogram responses. These findings are consistent with the spatial frequency properties of the lateral geniculate body which is the considered source of the signal. With further work, the VESP may supplement electrodiagnosis of post-chiasmal lesions.

Clinical studies of spatial and temporal aspects of vision: an investigation using psychophysical and electrophysiological techniques

Separate physiological mechanisms which respond to spatial and temporal stimulation have been identified in the visual system. Some pathological conditions may selectively affect these mechanisms, offering a unique opportunity to investigate how psychophysical and electrophysiological tests reflect these visual processes, and thus enhance the use of the tests in clinical diagnosis. Amblyopia and optical blur were studied, representing spatial visual defects of neural and optical origin, respectively. Selective defects of the visual pathways were also studied - optic neuritis which affects the optic nerve, and dementia of the Alzheimer type in which the higher association areas are believed to be affected, but the primary projections spared. Seventy control subjects from 10 to 79 years of age were investigated. This provided material for an additional study of the effect of age on the psychophysical and electrophysiological responses. Spatial processing was measured by visual acuity, the contrast sensitivity function, or spatial modulation transfer function (MTF), and the pattern reversal and pattern onset-offset visual evoked potential (VEP). Temporal, or luminance, processing was measured by the de Lange curve, or temporal MTF, and the flash VEP. The pattern VEP was shown to reflect the integrity of the optic nerve, geniculo striate pathway and primary projections, and was related to high temporal frequency processing. The individual components of the flash VEP differed in their characteristics. The results suggested that the P2 component reflects the function of the higher association areas and is related to low temporal frequency processing, while the Pl component reflects the primary projection areas. The combination of a delayed flash P2 component and a normal latency pattern VEP appears to be specific to dementia of the Alzheimer type and represents an important diagnostic test for this condition.