Novel aspects of benzyne chemistry

Chapter One describes attempts at utilising ortho-quinodimethanes in the synthesis of polycyclic ring systems, where construction of the the 1,4-elimination precursor could not be achieved. Additionally, several attempts were made to utilise the diradical behaviour which ortho-quinodimethanes are thought to possess, in similar annulative reactions. Unsuccessful attempts at generating furanyl- ,benzofuranyl- and benzenoid- derived diradical species, however, brought these particular studies to an end. The remainder of this thesis is devoted to studies that were made into developing new uses for benzynes in organic synthesis. Their discovery, general history and subsequent application is divided for convenience into three chapters; Chapter Two covers the discovery of these classic species, and approaches to these species which have been improved from the highly impractical methods which were originally developed. Chapters Three and Four give an overall review of the past and recently reported applications of benzynes in organic synthesis; Chapter Three covers the use of benzynes in nucleophilic couplings, whilst Chapter Four covers their application in cycloaddition reactions. Chapter Five describes preliminary studies that were made into developing new routes to polycyclic ring systems via the intramolecular Diels-Alder trapping of benzynes. After unsuccessful attempts at utilising the anthranilic acid route to benzynes, the remainder of the studies were concentrated on utilising the 1-aminobenzotriazole route to benzynes, a mild, efficient, yet relatively underexploited route. An improved synthesis of 7-methyl-1-aminobenzotriazole is described, as is the functionalisation of the methyl substitutent in the BOC-derivative via the formation of the dianion. However, 1,3-diene incorporation via this route was unsuccessful, due to difficulties in preparing suitable l,3-dienes. Chapter Six describes attempts at applying the metallation chemistry of BOC-protected 7-methyl-l-aminobenzotriazole to the synthesis of 2-substituted dihydrobenzofurans (n = 0) and chromans (n = 1) via the intramolecular trapping of benzynes by flanking hydroxyl functions, which were incorporated via the condensation of the dianion with aldehydes and epoxides respectively. Using H-bromosuccinimide as the reagent for benzyne generation, benzo-fused heterocycles were successfully generated in moderate yields, with bromine incorporation also being achieved (X =Br). Using lead (1V) acetate, simple dihydrobenzofurans (X=H) were obtaine4 in better yields. Excellent yields, in some cases virtually quantitative, were obtained using N-iodosuccinimide as the reagent, with the iodine substituent (X = I) being incorporated. The additional bonus of having the iodine substituent was highlighted by utilising iododihydrobenzofurans and chromans in subsequent coupling reactions. Overall, this thesis describes the advances made in increasing the role of benzynes in synthetic organic chemistry, providing novel metalation chemistry on the aminobenzotriazole ring system, and a novel annulative approach to valuable synthetic and potentially active species such as dihydrobenzofurans and chromans. Above all, this work illustrates that under certain suitable conditions, benzynes can serve as extremely efficient reactive intermediates in heterocyclic annulations

Novel aspects of benzyne chemistry

Chapter One describes attempts at utilising ortho-quinodimethanes in the synthesis of polycyclic ring systems, where construction of the the 1,4-elimination precursor could not be achieved. Additionally, several attempts were made to utilise the diradical behaviour which ortho-quinodimethanes are thought to possess, in similar annulative reactions. Unsuccessful attempts at generating furanyl- ,benzofuranyl- and benzenoid- derived diradical species, however, brought these particular studies to an end. The remainder of this thesis is devoted to studies that were made into developing new uses for benzynes in organic synthesis. Their discovery, general history and subsequent application is divided for convenience into three chapters; Chapter Two covers the discovery of these classic species, and approaches to these species which have been improved from the highly impractical methods which were originally developed. Chapters Three and Four give an overall review of the past and recently reported applications of benzynes in organic synthesis; Chapter Three covers the use of benzynes in nucleophilic couplings, whilst Chapter Four covers their application in cycloaddition reactions. Chapter Five describes preliminary studies that were made into developing new routes to polycyclic ring systems via the intramolecular Diels-Alder trapping of benzynes. After unsuccessful attempts at utilising the anthranilic acid route to benzynes, the remainder of the studies were concentrated on utilising the 1-aminobenzotriazole route to benzynes, a mild, efficient, yet relatively underexploited route. An improved synthesis of 7-methyl-1-aminobenzotriazole is described, as is the functionalisation of the methyl substitutent in the BOC-derivative via the formation of the dianion. However, 1,3-diene incorporation via this route was unsuccessful, due to difficulties in preparing suitable l,3-dienes. Chapter Six describes attempts at applying the metallation chemistry of BOC-protected 7-methyl-l-aminobenzotriazole to the synthesis of 2-substituted dihydrobenzofurans (n = 0) and chromans (n = 1) via the intramolecular trapping of benzynes by flanking hydroxyl functions, which were incorporated via the condensation of the dianion with aldehydes and epoxides respectively. Using H-bromosuccinimide as the reagent for benzyne generation, benzo-fused heterocycles were successfully generated in moderate yields, with bromine incorporation also being achieved (X =Br). Using lead (1V) acetate, simple dihydrobenzofurans (X=H) were obtaine4 in better yields. Excellent yields, in some cases virtually quantitative, were obtained using N-iodosuccinimide as the reagent, with the iodine substituent (X = I) being incorporated. The additional bonus of having the iodine substituent was highlighted by utilising iododihydrobenzofurans and chromans in subsequent coupling reactions. Overall, this thesis describes the advances made in increasing the role of benzynes in synthetic organic chemistry, providing novel metalation chemistry on the aminobenzotriazole ring system, and a novel annulative approach to valuable synthetic and potentially active species such as dihydrobenzofurans and chromans. Above all, this work illustrates that under certain suitable conditions, benzynes can serve as extremely efficient reactive intermediates in heterocyclic annulations

Novel use of stir bar sorptive extraction (SBSE) as a tool for isolation of oviposition site attractants for gravid Culex quinquefasciatus

Mosquitoes such as Culex quinquefasciatus Say (Diptera: Culicidae) are important vectors of organisms that cause disease in humans. Research into the development of effective standardized odour baits for blood-fed females (oviposition attractants), to enable entomological monitoring of vector populations, is hampered by complex protocols for extraction of physiologically active volatile chemicals from natural breeding site water samples, which have produced inconsistent results. Air entrainment and solvent extraction are technically demanding methods and are impractical for use in resource poor environments where mosquito-borne disease is most prevalent. This study reports the first use of a simple, robust extraction technique, stir bar sorptive extraction (SBSE), to extract behaviourally active small lipophilic molecules (SLMs) present in water samples collected from Cx. quinquefasciatus breeding sites in Tanzania. Extracts from a pit latrine and from a cess pool breeding site attracted more gravid Cx. quinquefasciatus in pair choice bioassays than control extracts, and coupled gas chromatography-electroantennography (GC-EAG) allowed tentative identification of 15 electrophysiologically active chemicals, including the known oviposition attractant, skatole (3-methylindole). Here, we have demonstrated, using simple pair choice bioassays in controlled laboratory conditions, that SBSE is effective for the extraction of behaviourally and electrophysiologically active semiochemicals from mosquito breeding site waters. Further research is required to confirm that SBSE is an appropriate technique for use in field surveys in the search for oviposition cues for Cx. quinquefasciatus

Is It Really Home-Based?:A Commentary on the Necessity for Accurate Definitions across Exercise and Physical Activity Programmes

Background: There is wide discrepancy in how published research defines and reports home-based exercise programmes. Studies consisting of fundamentally different designs have been labelled as home-based, making searching for relevant literature challenging and time consuming. This issue has been further highlighted by an increased demand for these programmes following the COVID-19 pandemic and associated government-imposed lockdowns. Purpose: To examine what specifically constitutes home-based exercise by: 1) developing definitions for a range of terms used when reporting exercise and physical activity programmes and 2) providing examples to contextualise these definitions for use when reporting exercise and physical activity programmes. Methods: A literature search was undertaken to identify previous attempts to define home-based exercise programmes. A working document, including initial definitions and examples were developed, which were then discussed between six experts for further refinement. Results: We generated definitions for universal key terms within three domains (and subdomains) of programme design: location (home-based, community/centre-based, or clinical setting), prescription (structured or unstructured) and delivery (supervised, facilitated, or unsupervised). Examples for possible combinations of design terms were produced. Conclusions: Definitions will provide consistency when using reporting tools and the intention is to discuss the issues presented as part of a Delphi study. This is of paramount importance due to the predicted increase in emerging research regarding home-based exercise

Growth and properties of GaSbBi alloys

Molecular-beam epitaxy has been used to grow GaSb 1− x Bi x alloys with x up to 0.05. The Bi content, lattice expansion, and film thickness were determined by Rutherford backscattering and x-ray diffraction, which also indicate high crystallinity and that >98% of the Bi atoms are substitutional. The observed Bi-induced lattice dilation is consistent with density functional theory calculations. Optical absorption measurements and valence band anticrossing modeling indicate that the room temperature band gap varies from 720 meV for GaSb to 540 meV for GaSb 0.95Bi0.05, corresponding to a reduction of 36 meV/%Bi or 210 meV per 0.01 Å change in lattice constant

High Bi content GaSbBi alloys

The epitaxial growth, structural, and optical properties of GaSb 1– x Bi x alloys have been investigated. The Bi incorporation into GaSb is varied in the range 0 < x ≤ 9.6% by varying the growth rate (0.31–1.33 μm h−1) at two growth temperatures (250 and 275 °C). The Bi content is inversely proportional to the growth rate, but with higher Bi contents achieved at 250 than at 275 °C. A maximum Bi content of x = 9.6% is achieved with the Bi greater than 99% substitutional. Extrapolating the linear variation of lattice parameter with Bi content in the GaSbBi films enabled a zinc blende GaBi lattice parameter to be estimated of 6.272 Å. The band gap at 300 K of the GaSbBi epitaxial layers decreases linearly with increasing Bi content down to 410 ± 40 meV (3 μm) for x = 9.6%, corresponding to a reduction of ∼35 meV/%Bi. Photoluminescence indicates a band gap of 490 ± 5 meV at 15 K for x = 9.6%

Phenotyping of N-acetyltransferase type 2 and xanthine oxidase with caffeine: when should urine samples be collected?

OBJECTIVES: Individual activities of N-acetyltransferase 2 (NAT2) and of xanthine oxidase (XO) can be assessed using ratios of urinary caffeine metabolites. We investigated how ratios changed over time and which urine collection interval would be the best for NAT2 and XO activity assessments. METHODS: On two occasions separated by 14 days, 16 healthy male Caucasians collected urine before and 0-2, 2-4, 4-6, 6-8, 8-12, 12-16 and 16-24 h after a dose of 150 mg caffeine given in the framework of a phenotyping cocktail study. The metabolites 5-acetylamino-6-formylamino-3-methyluracil (AFMU), 5-acetylamino-6-amino-3-methyluracil (AAMU), 1-methylxanthine (1X), and 1-methylurate (1U) were quantified with LC-MS/MS. The molar ratio (AFMU + AAMU)/(1X + 1U + AFMU + AAMU) was used as a NAT2 metric, while the ratio 1U/(1X + 1U) served as XO metric. RESULTS: The NAT2 ratios were stable in the intervals 4-24 h after caffeine dosing. Mean intra-individual coefficients of variation were 11-23% starting 4 h post-dose, while inter-individual variability reached 37-75%. The XO ratios increased gradually by 14% from the 2-4 to the 16-24 h interval. The mean intra- and inter-individual coefficients of variation of XO activity were 3-18 and 7-10% respectively. No significant differences between study occasions were observed. CONCLUSIONS: Any sampling interval at least 4 h after caffeine dosing is suitable for NAT2 and XO activity assessments. XO activities can only be compared between volunteers and studies if the same urine collection schedule has been respected. The low intraindividual variability allows for sample sizes of 16 and 6 participants in crossover interaction studies of NAT2 and XO activity respectively