Tesi sul tema "Organophosphorus compounds"

A radioisotope of rubidium, 82Rb is used in positron emission tomography. Neutral crown ethers and cryptands have been studied as carrier ligands for Rb+ but exhibit low ion carrying capacity and high toxicity. The present study involved investigating a lariat ether containing an ionizable phosphoryl moiety and a lipophilic sidearm. This kind of molecule is expected to be ionized at physiological pH. It should be able to form neutral complexes with Rb+ and may be able to cross the blood-brain barrier. Molecular modeling of crown ether-alkali metal cation complexes indicates that a macrocycle containing more than 18 but less than 21 atoms can incorporate Rb+ ion in its cavity. Molecular modeling of some of the complexes of phospho-lariat ethers with rubidium using the Spartan'02 software package revealed that a lariat ether containing 20 member macrocycle will probably form the most stable complex with Rb+ion. Also, it was thought that more flexibility could be imparted to the macrocycle if it contains propyleneoxy units instead of ethyleneoxy units which form most crown ethers. Molecular modeling of two phospho-lariat ethers with 16 and 20 membered rings revealed that 20 membered macrocycle may be a better choice due to the side arm's participation in the complexation with Rb+ to a greater extent. Molecular modeling was used to find the bond angles and bond distances in this molecule. The synthesis to obtain ionizable phospho-bipodands was performed using subsequent benzylation, phosphorylation and hydrogenation steps. The characterization of products was done using HPLC, NMR and ESI-MS techniques. The synthetic scheme used was demonstrated to be plausible and could be used to obtain ionizable phoshobipodands. Extraction using solid phase anion exchange columns proved to be a good clean up procedure for obtaining pure bipodand. This bipodand could be used as a precursor for synthesizing an ionizable 20 membered lariat ether.

Thesis (M. Phil.)--Hong Kong University of Science and Technology, 2003.
Includes bibliographical references (leaves 135-142). Also available in electronic version. Access restricted to campus users.

The majority of this project is to discover novel mechanistic pathways for a wide range of organic reactions involving different carbonyl compounds with trivalent phosphorus compounds. The first part of our research involved the one-pot intra-molecular cyclisation reaction of the different 2-substituted benzoylphosphonates in the presence of triniethyl phosphite. The mechanistic pathway of these reactions was found to intra-molecular insert to the electrophilic carbonyl centre in the substituent via the initially formed carbanionic intermediate. The subsequently formed tricyclic phospholane intermediate [δp ~ -48 (d) & +18 (d), Jpp 33 Hz] were observed from the NMR spectra of the crude reaction prior the "formation of the final cyclic benzofuranyl-phosphonate products. Experiments were carried out ,to study the decomposition product of the observed phospholane intermediate in the absence of phosphite, which led to. the formation of the novel ~- ketophosphonates. We have also generated a senes of anionic intermediates in situ usmg different phosphate- phosphonates, and studied their anionic manors inter- and intra- molecularly toward the electrophilic carbonyl reacting sites. The second part of our project involved the reactions of various halogeno-substituted 2,5-cyclic- diones with different trivalent phosphorus compounds. Under the treatment of trialkyl phosphites, many of the, related non-halogenated substituted cyclic diones were report to process deoxygenations reaction followed .by dimerisations and .rearrangements reactions. , However, in Our practical, a range of unusual stabilised phosphonium ylides were isolated and their structures were studied analytically in. detail by the NMR data. In particular, .ylidic phosphinie oxide and ylidic bisphosphine oxide were successfully crystallised, which allowed us to study the physical properties of these ylides by the X-ray crystallography. The mechanistic pathways of these reactions proceeded differently, depending on the number of substituents on the cyclic diones.

The aim of this thesis was to study the phenomenon of supramolecular gelation of urea-based gelators and their application as sensors for neutral organophosphorus species such as nerve agents. The work was therefore naturally divided into two major parts. The first part consisted in an investigation of the structure-gelation relationship of a series of urea gelators, in an effort to overcome the serendipitous approach that is widely applied to their discovery. Among the components of the common gelator scaffold that were optimised to deliver the best gelation performance, particular attention was given to the role of the head substituent on its benzene ring. Crystal structure prediction calculations together with liquid- and solid-state NMR were used to understand the molecular reasons behind the observed macroscopic properties of supramolecular gels formed either by nitro- or methoxy-substituted gelators. Remarkably, this approach demonstrated that, rather than electronic effects, it was the nitro substituent’s ability to interfere with the urea hydrogen bond network to cause the differences observed in the gel formation experiments, when compared to the methoxy-analogue. The second part focused on the possible application of bis/tris(urea)-based supramolecular gels as organophosphorus warfare agents’ sensors. After the development of a fast and easily interpretable in-house test, it was possible to observe the effectiveness of different candidates in responding to the presence of either the nerve agent Soman or its simulant dimethyl methyl phosphonate. It was observed that in the presence of the guest molecules gelation could be delayed or even suppressed, suggesting the formation of hydrogen bonds between guest and host that were interfering with the self-assemble of the gelator molecules. Conversely it was also found that, if present in lower amount, dimethyl methyl phosphonate could instead induce a detectable thermo-mechanical reinforcement of the gel network, as confirmed by rheology and calorimetry results, which was ascribed to solvophobic effects.

The clean reaction of 5-lithio-6-diisopropylphosphinoacenaphthene (1') with dichlorophosphines, RPCl₂ (R = Ph, Fc, NMe₂, iPr), led to the formation of peri-substituted phosphino-phosphonium chloride salts 2-5. The synthetic utility of these salts was demonstrated in a range of reactions. Mixed tertiary/secondary bis(phosphines) (6 and 7) were prepared by the LiAlH₄ reduction of phenyl or ferrocenyl phosphino-phosphoniums (2 and 3), and the bis(borane) adduct of 6 was prepared by reduction of 2 with BH₃•SMe₂. Reaction of 2 and 3 with a large excess of MeOTf at elevated temperature gave 1,2-diphosphoniums (11 and 12), which were subjected to reduction and co-ordination to a molybdenum(0) centre. An investigation into the co-ordination chemistry of 2 revealed three distinct modes of reactivity. In the reaction with [(nor)Mo(CO)₄] the Mo(0) complex [(2)Mo(CO)₄Cl] (18) was isolated, in which monodentate co-ordination was observed. [PtCl₂(cod)] reacts with the chloride and triflate salts of 2 to form [(2Cl)PtCl₂] (19) and [((2Cl)PtCl)₂][TfO]₂ (21) respectively, both of which show co-ordination of 2 as a bidentate phosphine/chlorophosphine ligand. A palladium(II) dimer (22) in which 2 forms a chelating phosphine/phosphide ligand was isolated from the oxidative addition of 2 to a palladium(0) complex. The geminally bis(peri-substituted) tridentate phosphine (27) was prepared by reaction of 1' with half an equivalent of iPrPCl₂. 27 has a rather strained geometry, and displays restricted dynamics on an NMR timescale, which leads to anisochronicity of all three phosphorus nuclei at low temperatures. Strained bis and tris(sulfides) 28 and 29 and the bis(selenide) 30 have been isolated from the reaction of 27 with sulfur and selenium, respectively. A series of co-ordination complexes, [(27)Cu(MeCN)][BF₄] (32), [(27)PtCl][Cl] (33), [(27)FeCl₂] (34) and fac-[(27)Mo(CO)₃] (35), with tetrahedral, square planar, trigonal bipyramidal and octahedral geometries, respectively, were synthesised. In all of these complexes the tris(phosphine) backbone is distorted, but to a significantly smaller extent that in the chalcogenides 28-30.

This thesis described investigations into the synthesis and reactions of chiral monophosphines, in five chapters. Chapter 1 introduces asymmetric catalysis, Chapter 2 and 3 describe the synthesis of enantiomerically pure monophosphine via an oxide and borane route respectively. Chapter 4 describes the organometallic reactions of these monophosphines and Chapter 5 contains experimental details of the reactions. Chapter 1 describes the importance of chirality and significant asymmetric processes. The literature methods of producing homochiral monophosphines are detailed. Chapter 2 describes the synthesis of enantiomerically enriched monophosphine oxides. Diastereomerically pure (2R, 4S, 5R)-2-chloro-5-phenyl-3,4-dimethyl-1,3,2-oxazaphospholidine was prepared from PCl₃ and (-)-ephedrine. This compound was reacted with 2-adamantyl magnesium bromide to afford (2R, 4S, 5R) and (2S, 4S, 5R)-3,4-dimethyl-2-2-adamantyl-5-phenyl-1,3,2-oxazaphospholidin-2-oxide after oxidation with ^tBuOOH. An X-ray crystal structure was obtained of the R_P diastereoisomer and a detailed NMR study carried out on the S_P diastereoisomer. The R_P diastereoisomer was reacted with 2-methoxyphenylmagnesium bromide to give R_P-N-methyl-N-(1S,2S)-(1-methyl-2-hydroxy-2-phenyl)-ethyl-P-(2-methoxyphenyl)-P-(2-adamantyl)phosphinamide in 68% yield and 95% d.e. The ephedrinyl residue was replaced by O-methyl under acid catalysis with inversion of configuration and with >85% e.e. Displacement of the methoxy group using phenyl lithium occurred with inversion of configuration to give the corresponding phosphine oxide in 65% e.e., which could be reduced under forcing conditions using polymethylhydrosiloxane in the presence of Ti(OⁱPr)₄. Chapter 3 describes the synthesis of enantiomerically enriched monophosphines via phosphine borane complexes. Diastereomerically pure (2R, 4S, 5R)-2,5-diphenyl-3,4-dimethyl-1,3,2-oxazaphospholidine borane was prepared directly from PhPCl₂ and (-)-ephedrine, followed by oxidation with BH₃.Me₂S. This compound reacted regiospecifically with ortho-anisyl lithium to afford the product formed by P-O cleavage with >96% d.e. and with retention of configuration at phosphorus. The ephedrinyl residue was replaced by O-methyl under acid conditions with inversion of configuration and with >98% e.e. Ferrocenyl, 1-adamantyl and tert-butyl lithium reagents displaced the methoxy group with inversion of configuration and with >92% e.e., as determined by ¹H NMR methods. The phosphine borane complexes were then reduced quantitatively with Et₂NH with retention of configuration and with >98% e.e. Chapter 4 describes the synthesis of indium and rhodium complexes of (S)-t-butyl-(2-methoxyphenyl)-phenyl phosphine and (S)-ferrocenyl-(2-methoxyphenyl)-phenyl phosphine. The iridium complexes are shown to reduce a range of prochiral olefins, including Z-methyl-2-acetylamino-3-phenylpropenoate (MAC) in up to 19% e.e. The di-(R,R)-(ferrocenyl-(2-methoxyphenyl)-phenyl phosphine) rhodium complex is more selective, reducing MAC in 54% e.e., while the rhodium complex of (S)-t-butyl-(2-methoxyphenyl)-phenyl phosphine reduces MAC in 24% e.e.

Thesis (M. Phil.)--Hong Kong University of Science and Technology, 2003.
Includes bibliographical references (leaves 107-111). Also available in electronic version. Access restricted to campus users.

Thesis (MSc)--University of Stellenbosch, 2005.
ENGLISH ABSTRACT: This investigation comprised the synthesis and characterisation of new Au(I) phosphonium ylide complexes and other compounds formed during coordination reactions. These complexes could exploit the synergism between two pharmacologically active substances (gold complex unit and phosphorus ylide) to furnish an even more active substance. Four phosphonium salts were prepared, [C6H5CH2PPh3]Br (1), [Ph3P(CH2)3PPh3]Br2 (2a), p-[{Ph3PCH2}2C6H4]Br2 (3a) and m- [{Ph3PCH2}2C6H4]Br2 (4a), by reacting PPh3 with the corresponding alkylbromides. The 13C and 1H NMR spectra of the compounds 1 – 4a indicated that many of the nuclei are magnetically inequivalent. The aromatic units in PPh3 are normally identical, but multiple, overlapping signals proved that the corresponding ortho, meta and para carbon and proton nuclei are in magnetically different environments from each other. Single crystal structures of salts 3a and 4a were determined. Different methods were followed to deprotonate the phosphonium salts to afford the corresponding ylides and to coordinate the ylides to gold precursor compounds. Most of the reactions yielded inseparable mixtures of products and pure compounds could not be isolated in large enough quantities for characterisation by all physical methods. Sufficient crystals for structure determination by X-ray diffraction were obtained. The product mixtures were characterised by 1H, 13C and 31P NMR spectroscopy and mass spectrometry. Characteristic downfield chemical shift changes after coordination of the ylides to Au(I) were observed for the carbon and phosphorus nuclei, while the protons displayed upfield shifts. Reaction of (C6F5)Au(tht) with the salts 1 – 4a, and subsequent deprotonation yielded the gold(I) ylide complexes [C6H5CH(AuC6F5)PPh3] (5), [{Ph3PCH(AuC6F5)}2CH2] (6), p-[{Ph3PCH(AuC6F5)}2C6H4] (8), and m- [{Ph3PCH(AuC6F5)}2C6H4] (9). The crystal and molecular structures of compounds 5 and 9 were determined. Deprotonation of 4a with n-BuLi, followed by reaction with (C6F5)Au(tht) yielded complexes 9 and [{Ph3PCH2}2C6H4][BrAuC6F5]2 (10). The crystal structure of compound 10 was determined. Two aurocyclic compounds, [μ- {(Ph3PCH)2CH2}2Au2][BF4]2 (12) and [μ–{(Ph3PCH)2C6H4}2Au2][BF4]2 (13) were synthesised by deprotonating salts 2b and 3b with n-BuLi and subsequently reacting the corresponding bisylides with ClAu(tht). Reaction procedures in which Ag2O was used as deprotonating agent for the phosphonium salts 2a, 3a and 4a, yielded mixtures of products. Single crystals of complexes m-[Ph3PCH(AuC6F5)C6H4CH3] (14), [C6F5Au(tht)] (15) and [(C6F5)2Au][(Ph3PCH2)2C6H4] (16) were isolated from the reaction mixtures and subjected to X-ray crystal structure determination. The molecular structure of 15 exhibited unusual aurophilic interactions and represents the first example of a linear gold chain in which the gold···gold distances systematically alternate between 3.13Å, 3.31Å and 3.20Å. Salt 2b was reacted with Ph3PAu(acac) to afford the desired compound, [{Ph3PCH(AuPPh3)}2CH2](BF4)2 (19), along with [CH3C(O)C(AuPPh3)2C(O)CH3] (17) and some byproducts. Compound 17 was characterised by single crystal Xray diffraction. The fluorobiphenylgold(I) complexes, 4,4’-[(AuPPh3)2C12F8] (21) and 2,2’- [(AuPPh3)2C12F8] (22) were synthesised by reaction of ClAuPPh3 with the lithiated 2,2’-dibromooctafluorobiphenyl and 4,4’-dibromooctafluorobiphenyl respectively. The molecular structure of 21 revealed that one of the C–Au–P bond angles deviates from linearity by 12.5°, probably as a result of π-stacking of the tetrafluorophenyl rings and steric requirements of the bulky PPh3 units. The other C–Au–P bond angle is linear [177.9(3)°].
AFRIKAANSE OPSOMMING: Hierdie studie behels die sintese en karakterisering van nuwe fosfoniumylied goud(I)-komplekse en ander verbindings wat gedurende koördinasiereaksies vorm. Sulke komplekse kan sinergisme tussen twee farmakologies-aktiewe entiteite (goud(I) en fosfoniumylied) om ʼn meer aktiewe verbinding te vorm meebring. Vier fosfoniumsoute is berei, [C6H5CH2PPh3]Br (1), [Ph3P(CH2)3PPh3]Br2 (2a), p- [{Ph3PCH2}2C6H4]Br2 (3a) en m-[{Ph3PCH2}2C6H4]Br2 (4a), deur PPh3 met die ooreenstemmende alkielbromiedes te reageer. Die 13C- en 1H- KMR-spektra van dié verbindings toon dat ʼn aantal kerne in aromatiese ringe magneties onekwivalent is. Normaalweg is die koolstowwe in PPh3-eenhede ekwivalent, maar meervoudige, oorvleuelende pieke het nou getoon dat die ooreenstemmende orto-, meta- en para-koolstof sowel as die ooreenstemmende protonkerne in verskillende magnetiese omgewings voorkom. Die kristalstrukture van die soute 3a en 4a hierbo is met behulp van X-straal tegnieke bepaal. Verskillende metodes is gevolg om die fosfoniumsoute te deprotoneer na die ooreenstemmende yliede en om die yliede dan aan goud-bevattende uitgangstowwe te probeer koördineer. Die meeste reaksies het nie-skeibare mengsels gevorm en enkelprodukte kon nie in groot genoeg konsentrasies geïsoleer word om hulle afsonderlik te karakteriseer nie. Kristalle vir X-straal kristalstruktuur bepalings is verkry. Die produkmengsels is gekarakteriseer met behulp van 1H-, 13C- en 31P- KMR-spektroskopie en massaspektrometrie. Karakteristieke veranderinge in chemiese verskuiwings na laer veldsterktes vir die koolstof en fosfor kerne is waargeneem na koördinasie van die yliede aan Au(I), terwyl die protone na höer veldsterktes verskuif het. Die reaksie tussen (C6F5)Au(tht) (tetrahidrotiofeen) en soute 1 – 4a gevolg deur deprotonering, vorm die goud-yliedkomplekse [C6H5CH(AuC6F5)PPh3] (5), [{Ph3PCH(AuC6F5)}2CH2] (6), p-[{Ph3PCH(AuC6F5)}2C6H4] (8), en m- [{Ph3PCH(AuC6F5)}2C6H4] (9). Die kristalstrukture van komplekse 5 en 9 het al die molekulêre interaksies daarin blootgelê. Deprotonering van 4a met n-BuLi, gevolg deur reaksie met (C6F5)Au(tht) lewer komplekse 9 en [{Ph3PCH2}2C6H4][BrAuC6F5]2 (10). Die kristal- en molekulêre struktuuur van kompleks 10 is bepaal. Twee aurosikliese verbindings, [μ- {(Ph3PCH)2CH2}2Au2][BF4]2 (12) en [μ–{(Ph3PCH)2C6H4}2Au2][BF4]2 (13) is gesintetiseer deur gedeprotoneerde bisyliede verkry van 2b en 3b met substitusie van tht aan die ClAu-eenheid te koördineer. Reaksieprosedures waarin Ag2O vir deprotonering van die fosfoniumsoute 2a, 3a en 4a gebruik is, het tot mengsels van produkte aanleiding gegee. Enkelkristalle van komplekse [Ph3PCH(AuC6F5)C6H4CH3] (14), [C6F5Au(tht)] (15) en [(C6F5)2Au][(Ph3PCH2)2C6H4] (16) is geïsoleer uit die reaksies en kristalstruktuurbepalings is uitgevoer. Die molekulere struktuur van 15 toon ongewone aurofiliese interaksies en verteenwoordig die eerste voorbeeld van ʼn linieêre goudketting; met goud···goud afstande wat sistematies varieër tussen 3.13Å, 3.31Å en 3.20Å. Sout 2b is met Ph3PAu(acac) gereageer om die gewenste produk, [{Ph3PCH(AuPPh3)}2CH2](BF4)2 (19), saam met [CH3C(O)C(AuPPh3)2C(O)CH3] (17) en ander byprodukte te vorm. Verbinding 17 is as enkelkristalle Xstraalkristallografies gekarakteriseer. Die fluorobifeniel goud(I)-komplekse, 4,4’-[(AuPPh3)2C12F8] (21) en 2,2’- [(AuPPh3)2C12F8] (22), is gesintetiseer deur koördinasie van AuPPh3 aan die gelitieërde 2,2’-dibromooktafluorobifeniel en 4,4’-dibromooktafluorobifeniel respektiewelik. Die molekulere struktuur van 21 het getoon dat een van die C-Au- P bindingshoeke met 12.5º afwyk van 180º, waarskynlik as gevolg van π- interaksie van die tetrafluorofenielringe en die steriese vereistes van die groot PPh3-eenhede. Die ander C-Au-P bindingshoek is linieêr [177.9(3)°].

Organophosphorus (OP) compounds are found in household pest control products, plastics, and petroleum. Due to the neurotoxic nature of OP compounds, exposure can cause both acute and delayed symptoms, including organophosphate-induced delayed neuropathy (OPIDN). This syndrome is characterized by Wallerian-like degeneration of nerves in the central and peripheral nervous system after exposure to neuropathic OP compounds. There are many questions surrounding the mechanisms of the onset of OPIDN, including possible alterations in proteins associated with neuronal maintenance and repair. This dissertation investigated the changes in levels of neurotrophins in vivo and how in vitro levels of neurotrophin receptors and their downstream signaling cascades are affected after exposure to OP compounds. We also characterized the molecular weight of a soluble factor responsible for inducing neurite outgrowth in vitro after in vivo exposure to a neuropathic OP compound. We evaluated in vivo endpoints using enzyme-linked immunosorbant assays. Results indicated that nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3) are found in chicken spinal cord but do not increase as a result of exposure to neuropathic OP compounds. This study also noted that NGF, BDNF, and NT-3 concentrations were not altered after exposure to a non-neuropathic OP compound. We evaluated in vitro endpoints using Western blots, ultrafiltration, and digital morphometry. These studies revealed that activated forms of high-affinity and low-affinity neurotrophin receptors are present after OP compound exposure, that the ratio of these two receptors to each other is stable after OP compound exposure, and that the activated form of the low-affinity receptor, which can lead to apoptosis, was present in greater levels than the activated form of the high-affinity receptor. Furthermore, OP compound exposure resulted in time-dependent changes of protein levels central to the mitogen-activated kinase and phosopholipase C-gamma intracellular pathways. Changes in a third pathway, the protein kinase C pathway, were dependent on the concentration and type of OP compound. Finally, in vitro neurite length was not affected by the type of OP compound administered in vivo or when a whole protein fraction was separated by molecular weight. This research has revealed in vivo consequences and early effects on intracellular protein and activated neurotrophin receptor levels after OP compound exposure. These early effects may contribute to the delayed development of neurotoxic effects associated with OP compound exposure.
Ph. D.

Organophosphorus compounds are widely used in agriculture as pesticides and in industry as petroleum additives and modifiers of plastics. Some of these compounds are capable of inducing an irreversible neuropathy developing weeks to months after exposure, yet there is no effective treatment. This may be due in part to the lack of knowledge of how this neuropathy develops. In this dissertation, it is proposed that as a consequence of a triggering event, peripheral nerves may be predisposed to an increase in calcium (Ca⁺⁺) mobilization and the neuronal accumulation of this cation. This increase in Ca could thereby initiate a cascade of events, in both nerve and muscle, that may account for some of the detrimental changes occurring during organophosphorus-induced delayed neuropathy (OPIDN). The involvement of Ca⁺⁺ in the pathogenesis of OPIDN was tested using functional, morphological, and biochemical techniques in the domestic hen, the recognized animal model of OPIDN. The isolated biventer cervicis nerve-muscle preparation was developed for quick assessment of the time course of OPIDN deficits and validated by comparison to in vivo preparations. This preparation proved more sensitive by functional and morphological evaluation indicating early damage at 4 days following exposure and before appearance of clinical signs. Regeneration was detected after 21 days. OPIDN was modified by using Ca⁺⁺ channel blockers, nifedipine, and verapamil, in the presence of phenyl saligenin phosphate, an active neurotoxicant. Attenuation of OPIDN by these compounds was revealed by clinical assessment, by changes in nerve excitability denoted by strength-duration relationships in response to electrical stimulation, by denervation hypersensitivity to neurotransmitter, and by morphology. These modifiers attenuated all degenerative responses. Furthermore, it was revealed that the activity of Ca⁺⁺-activated neutral protease (CANP), an enzyme responsible for neurofilament degradation, was increased in OPIDN. Such increases were ameliorated by modifiers of Ca movement. This study strongly suggests that Ca⁺⁺, possibly through activation of CANP, may contribute to functional and morphological deficits of OPIDN.
Ph. D.

Au cours des années, l'utilisation de composés nocifs a augmenté de façon exponentielle, et c'est la raison pour laquelle développer des méthodes pour l'identification de composés dangereux, tels que les composés organophosphorés (OP) et les explosifs organiques nitroaromatiques, est indispensable. L'analyse des composés organophosphorés et des explosifs est un enjeu important dans la sécurité intérieure, la médecine légale et les sciences de l'environnement. Il est crucial de développer des méthodes analytiques fiables, sensibles et efficaces pour identifier précisément les composés organophosphorés et les explosifs. Dans ce contexte, le but de ce travail de recherche était de développer des méthodes basées sur la spectrométrie de masse pour l'identification précise et sans ambiguïté de ces composés. Un arbre d'identification a été développé pour l'élucidation structurale de composés organophosphorés. Cette approche a été évaluée à l'aide d'une matrice biologique. D'autre part, les explosifs nitroaromatiques ont été étudiés et plusieurs nouveaux résultats ont été trouvés et reportés. L'application de l'analyse directe en temps réel (DART) couplée à la spectrométrie de masse Orbitrap (DART-FTMS) est décrite ici pour le screening rapide et la caractérisation des échantillons de frottis sur coton obtenus à partir d'armes militaires
Over the years, the widespread use of harmful compounds has increased exponentially, and this is the main reason to develop methods for the identification of dangerous compounds, such as organophosphorus (OP) compounds and organic nitroaromatic explosives. The analysis of OP compounds and explosives is an important issue in homeland security, forensic and environmental sciences. To this aim, it is crucial to develop reliable, sensitive and efficient analytical methods to accurately identify OP compounds and explosives. In this context, the goal of this research work was to develop accurate mass spectrometric-based methods for the unambiguous identification of these compounds. An identification tree was developed for the structural elucidation of OP compounds. This approach was assessed using a biological matrix. On the other hand, nitroaromatic explosives have been investigated and several new findings were found and reported. Furthermore, the application of Direct Analysis in Real Time (DART) coupled to the Orbitrap mass spectrometer (DART-FTMS) is discussed herein for the fast screening and characterization of cotton swab samples obtained from military weapons

Synthesis and flash vacuum pyrolysis (FVP) of stabilised phosphorus ylides containing an o-amino functionalised benzene ring has been examined for the first time. Model studies using N-methyl-N-tosyl and N-mesyl-N-methyl ylides showed that the ylides could be prepared, although yields were variable, and had the expected spectroscopic properties. Upon FVP, however, the expected loss of Ph₃PO and the sulfonyl group was accompanied by unexpected transfer of the reactive site from nitrogen to carbon giving 3- substituted quinolines rather than the expected indole products. Moving to ylides with an α-cinnamoyl group (or heterocyclic analogue) did, however, result in the originally planned tandem cyclisation leading to ring-fused carbazole products. N-Benzyl was also found to be a suitable thermally labile group and a series of α-cinnamoyl N-benzyl-N-methyl ylides were prepared and characterised. For their synthesis, use of N-cinnamoylbenzotriazoles was found to be preferable to cinnamoyl chloride, requiring only half the amount of amino-functionalised phosphonium salt. While FVP of some of these ylides led to benzo-, furo- and thienocarbazoles in good yield, others again gave quinoline-type products pointing to a fine balance between the two alternative modes of cyclisation. It was noted that one of the furocarbazole products was very similar to a natural product, Eustifoline D, isolated from the medicinally active shrub Murraya euchrestifolia from Taiwan and its synthesis was planned. With a view to producing the required N-H carbazole, N,N-dibenzylamino amino ylides were prepared and were found to exhibit restricted rotation leading to broad NMR signals. Their FVP again led to both quinoline and carbazole products, with the former having usually, but not always, lost a phenyl group. Mechanistic pathways for the formation of the various products are proposed. Complete assignment of the complex ¹H NMR spectra of the various fused-ring heterocyclic products was achieved, assisted by simulations in many cases. The ylide precursor required for Eustifoline D was prepared in five steps and 10% overall yield from 5-methylanthranilic acid. The final FVP step gave a quinoline as the major product, but the minor product was Eustifoline D, spectroscopically identical to the natural product.