Specificity enhancement by electrospray ionization multistage mass spectrometry – a valuable tool for differentiation and identification of ‘V’‐type chemical warfare agents

The use of chemical warfare agents has become an issue of emerging concern. One of the challenges in analytical monitoring of the extremely toxic ‘V’‐type chemical weapons [O‐alkyl S‐(2‐dialkylamino)ethyl alkylphosphonothiolates] is to distinguish and identify compounds of similar structure. MS analysis of these compounds reveals mostly fragment/product ions representing the amine‐containing residue. Hence, isomers or derivatives with the same amine residue exhibit similar mass spectral patterns in both classical EI/MS and electrospray ionization‐MS, leading to unavoidable ambiguity in the identification of the phosphonate moiety. A set of five ‘V’‐type agents, including O‐ethyl S‐(2‐diisopropylamino)ethyl methylphosphonothiolate (VX), O‐isobutyl S‐(2‐diethylamino)ethyl methylphosphonothiolate (RVX) and O‐ethyl S‐(2‐diethylamino)ethyl methylphosphonothiolate (VM) were studied by liquid chromatography/electrospray ionization/MS, utilizing a QTRAP mass detector. MS/MS enhanced product ion scans and multistage MS³ experiments were carried out. Based on the results, possible fragmentation pathways were proposed, and a method for the differentiation and identification of structural isomers and derivatives of ‘V’‐type chemical warfare agents was obtained. MS/MS enhanced product ion scans at various collision energies provided information‐rich spectra, although many of the product ions obtained were at low abundance. Employing MS³ experiments enhanced the selectivity for those low abundance product ions and provided spectra indicative of the different phosphonate groups. Study of the fragmentation pathways, revealing some less expected structures, was carried out and allowed the formulation of mechanistic rules and the determination of sets of ions typical of specific groups, for example, methylphosphonothiolates versus ethylphosphonothiolates. The new group‐specific ions elucidated in this work are also useful for screening unknown ‘V’‐type agents and related compounds, utilizing precursor ion scan experiments. Copyright © 2013 John Wiley & Sons, Ltd.     

Identification of V‐type nerve agents in vapor samples using a field‐portable capillary gas chromatography/membrane‐interfaced electron ionization quadrupole mass spectrometry instrument with Tri‐Bed concentrator and fluoridating conversion tube

A field‐portable gas chromatography–mass spectrometry (GC–MS) system (Hapsite ER) was evaluated for the detection of nonvolatile V‐type nerve agents (VX and Russian VX (RVX)) in the vapor phase. The Hapsite ER system consists of a Tri‐Bed concentrator gas sampler, a nonpolar low thermal‐mass capillary GC column and a hydrophobic membrane‐interfaced electron ionization quadrupole mass spectrometer evacuated by a non‐evaporative getter pump. The GC–MS system was attached to a VX‐G fluoridating conversion tube containing silver nitrate and potassium fluoride. Sample vapors of VX and RVX were converted into O‐ethyl methylphosphonofluoridate (EtGB) and O‐isobutyl methylphosphonofluoridate (iBuGB), respectively. These fluoridated derivatives were detected within 10 min. No compounds were detected when the VX and RVX samples were analyzed without the conversion tube. A vapor sample of tabun (GA) was analyzed, in which GA and O‐ethyl N,N‐dimethylphosphoramidofluoridate were detected. The molar recovery percentages of EtGB and iBuGB from VX and RVX vapors varied from 0.3 to 17%, which was attributed to variations in the vaporization efficiency of the glass vapor container. The conversion efficiencies of the VX‐G conversion tube for VX and RVX to their phosphonate derivatives were estimated to be 40%. VX and RVX vapors were detected at concentrations as low as 0.3 mg m⁻³. Gasoline vapor was found to interfere with the analyses of VX and RVX. In the presence of 160 mg m⁻³ gasoline, the detection limits of VX and RVX vapor were increased to 20 mg m⁻³. Copyright © 2017 John Wiley & Sons, Ltd.     

NOUVEAUX DÉCONTAMINANTS. ACTION DU MONOPERPHTALATE DE MAGNÉSIUM (MPPM) SUR QUELQUES INSECTICIDES ET TOXIQUES DE GUERRE ORGANOPHOSPHORÉES OU ORGANOSOUFRÉS

Abstract

Magnesium monoperoxyphthalate (MMPP) is a good decontaminant reagent when it is used in alcoholic solvent. Paraoxon (O,O-diethyl O-paranitrophenyl phosphate) but specially VX [O-ethyl S-(2-diiso-propylaminoethyl)] methylphosphonothiolate and HD (2,2′-dichlorodiethyIsulfide) react with MMPP completely in a very short time.

Le monoperphtalate de magnesium (MPPM) est un bon agent de décontamination lorsqu'il est utilisé en milieu alcoolique. Le Paraoxon (O.O-diéthyl O-paranitrophenyl phosphate) mais surtout le VX [O-éthyl S-(diisopropylaminoéthyl-2)] méthylphosphonothiolate et l'ypérite (HD) (dichloro-2.2′diéthyl-sulfure) réagissent de faFon totale avec le MPPM en un temps très court.     

Two succinic acid derivatives of 2‐ethyl‐6‐methylpyridin‐3‐ol

Crystals of bis(2‐ethyl‐3‐hydroxy‐6‐methylpyridinium) succinate–succinic acid (1/1), C₈H₁₂NO⁺·0.5C₄H₄O₄²⁻·0.5C₄H₆O₄, (I), and 2‐ethyl‐3‐hydroxy‐6‐methylpyridinium hydrogen succinate, C₈H₁₂NO⁺·C₄H₅O₄⁻, (II), were obtained by reaction of 2‐ethyl‐6‐methylpyridin‐3‐ol with succinic acid. The succinate anion and succinic acid molecule in (I) are located about centres of inversion. Intermolecular O—H...O, N—H...O and C—H...O hydrogen bonds are responsible for the formation of a three‐dimensional network in the crystal structure of (I) and a two‐dimensional network in the crystal structure of (II). Both structures are additionally stabilized by π–π interactions between symmetry‐related pyridine rings, forming a rod‐like cationic arrangement for (I) and cationic dimers for (II).     

A zinc–lithium complex of 4,7‐bis(2‐aminoethyl)‐1,4,7‐triazacyclononane‐1‐acetate

The asymmetric unit of {[4,7‐bis(2‐amino­ethyl)‐1,4,7‐tri­aza­cyclo­nonan‐1‐yl]acetato}zinc(II) triaqua{μ‐[4,7‐bis(2‐amino­ethyl)‐1,4,7‐tri­aza­cyclo­nonan‐1‐yl]acetato}lithium(I)zinc(II) chloride diperchlorate, [Zn(C₁₂H₂₆N₅O₂)][LiZn(C₁₂H₂₆N₅O₂)(H₂O)₃]Cl(ClO₄)₂, obtained from the reaction between the lithium salt of 4,7‐bis(2‐amino­ethyl)‐1,4,7‐tri­aza­cyclo­nonane‐1‐acetate and Zn(ClO₄)₂, contains two Zn^II complexes in which each Zn^II ion is six‐coordinated by five N‐atom donors and one O‐­atom donor from the ligand. One carboxyl­ate O‐atom donor is not involved in coordination to a Zn^II atom, but coordinates to an Li⁺ ion, the tetrahedral geometry of Li⁺ being completed by three water mol­ecules. The two complexes are linked via a hydrogen bond between a primary amine N—H group and the carboxyl­ate‐O atom not involved in coordination to a metal.     

Fused quinoline heterocycles VI: Synthesis of 5H‐1‐thia‐3,5,6‐triazaaceanthrylenes and 5H‐1‐thia‐3,4,5,6‐tetraazaaceanthrylenes

Ethyl 3‐amino‐4‐chlorothieno[3,2‐c]quinoline‐2‐carboxylate ( 4 ) is a versatile synthon, prepared by reacting an equimolar amount of 2,4‐dichloroquinoline‐3‐carbonitrile ( 1 ) with ethyl mercaptoacetate ( 2 ). Ethyl 5‐alkyl‐5H‐1‐thia‐3,5,6‐triazaaceanfhrylene‐2‐carboxylates 9a‐c , novel perianellated tetracyclic heteroaro‐matics, were prepared by refluxing 4 with excess of primary amines 7a‐c to yield the corresponding amino‐thieno[3,2‐c]quinolines 8a‐c . Subsequent reaction with an excess of triethyl orthoformate (TEO) furnished 9a‐c . Reaction of 4 with TEO in Ac₂O at reflux, gave the simple acetylated compounds, thieno[3,2‐c]‐quinolines 12 and 13 . Refluxing 4 with benzylamine ( 7d ) gave 10 , and subsequent treatment with TEO gave the tetracyclic compound 11 . Refluxing 13 with an excess of alkylamines 7a‐d gave the fhieno[3,2‐c]quino‐lines 15 . Refluxing the aminothienoquinolines 8b with an excess of triethyl orthoacetate gave thieno[3,2‐c]quinoline 17 , while heating with Ac₂O gave 18 and 19 , with small amounts of 16 . Reaction of 8a,b with ethyl chloroformate and phenylisothiocyanate generated the new 1‐thia‐3,5,6‐triazaaceanthrylenes 20a,b and 21a,b , respectively. Diazotization of 8a‐c afforded the novel tetracyclic ethyl 5‐alkyl‐5H‐1‐fhia‐3,4,5,6‐tetraazaaceanthrylene‐2‐carboxylates 22a‐c in good yields.     

Reaction of 2‐amino‐3‐cyano‐4,5,6,7‐tetrahydrobenzo‐[b]thiophene with ethyl acetoacetate: Novel syntheses of pyridines,pyrazoles, and their fused derivatives

The reaction of 2‐amino‐3‐cyano‐4,5,6,7‐tetrahydrobenzo[b]thiophene 1 with ethyl acetoacetate 2 gave compound 3 . The reactivity of the latter product toward a variety of chemical reagents was studied to give fused thiophene derivatives of potential pharmaceutical interest. © 2001 John Wiley & Sons, Inc. Heteroatom Chem 12:518–527, 2001     

1‐Methyl‐1‐phenyl‐3‐[1‐hydroxy­imino‐2‐(succinimido)­ethyl]­cyclo­butane

In the title compound, C₁₇H₂₀N₂O₃, the cyclo­butane ring is puckered, with a dihedral angle of 19.11 (15)°. The 1‐phenyl and 3‐[1‐hydroxy­imino‐2‐(succinimido)­ethyl] groups are in cis positions. The mol­ecules are linked by O—H⋯O and C—H⋯π(benzene) interactions, forming a two‐dimensional network.     

Structural comparison of group 7 tricarbonyl complexes of 2‐{[2‐(1H‐imidazol‐4‐yl)ethyl]iminomethyl}‐5‐methylphenolate

Two tricarbonyl complexes of rhenium(I) and manganese(I) coordinated by the ligand 2‐{[2‐(1H‐imidazol‐4‐yl)ethyl]iminomethyl}‐5‐methylphenolate are reported, viz. fac‐tricarbonyl(2‐{[2‐(1H‐imidazol‐4‐yl‐κN³)ethyl]iminomethyl‐κN}‐5‐methylphenolato‐κO)rhenium(I) methanol monosolvate, [Re(C₁₆H₁₄N₃O₄)(CO)₃]·CH₃OH, (I), and fac‐tricarbonyl(2‐{[2‐(1H‐imidazol‐4‐yl‐κN³)ethyl]iminomethyl‐κN}‐5‐methylphenolato‐κO)manganese(I), fac‐[Mn(C₁₆H₁₄N₃O₄)(CO)₃], (II), display facial coordination in a distorted octahedral environment. The crystal structure of (I) is stabilized by O—H...O, N—H...O and C—H...O hydrogen‐bond interactions, while that of (II) is stabilized by N—H...O hydrogen‐bond interactions only. These interactions result in two‐dimensional networks and π–π stacking for both structures.     

Two 2,2‐dihalo‐N‐(1‐phenyl­ethyl)­cyclo­propane‐1‐carbox­amides

The crystal structures of (1R,1′S)‐2′,2′‐di­chloro‐N‐(1‐phenyl­ethyl)­cyclo­propane‐1′‐carbox­amide, C₁₂H₁₃Cl₂NO, (I), and (1R,1′R)‐2′,2′‐di­fluoro‐N‐(1‐phenyl­ethyl)­cyclo­propane‐1′‐car­box­amide, C₁₂H₁₃F₂NO, (II), have been determined. Both crystals contain two independent mol­ecules with different conformations of the phenyl­ethyl groups. In the crystals of both compounds, the mol­ecules are linked together by N—H⃛O hydrogen bonds, thus forming chains in the a direction.     

Synthesis and bioactivities of 1,3,2‐benzodiazaphosphorin‐2‐carboxamide 2‐oxides containing α‐aminophosphonate groups

In order to search for novel antitumor and antiviral agents with high activity and low toxicity, a series of 1‐ethoxycarbonylmethyl‐3‐ethyl‐1,2,3,4‐tetrahydro‐4‐oxo‐1,3,2‐benzodiazaphosphorin‐2‐carboxamide 2‐oxides containing α‐aminophosphonate groups have been designed and synthesized by a convenient one‐pot procedure in good yields. The structures of products were confirmed by ¹H NMR, ³¹P NMR, IR spectra, and elemental analyses. The bioassay results showed that some of them possess excellent anti–tobacco mosaic virus activities and exhibit higher inhibitory effects compared with that of the contrast drug 2,4‐dioxyhexahydro‐1,3,5‐triazine. © 2001 John Wiley & Sons, Inc. Heteroatom Chem 12:97–101, 2001     

Crystal Structure and Ethylene Oligomerization Catalytic Activity of {2-Carbethoxy-6-[1-[（2,6-diethylphenyl）imino]ethyl]pyridine}CoCl2

The unsymmetric precursor ethyl 6-acetylpyridine-2-carboxylate （4） was synthesized from 2,6-dimethylpyridine （1）. On the basis of this precursor, a new mono（imino）pyridine ligand （5） and the corresponding Co（Ⅱ） complex {2-carbethoxy-6-[1-[（2,6-diethylphenyl）imino]ethyl]pyridine}CoCl2 （6） were prepared. The crystal structure of complex indicates that the 2-carbethoxy-6-iminopyridine is coordinated to the cobalt as a tridentate ligand using [N, N, O] atoms, and the coordination geometry of the central cobalt is a distorted trigonal bipyramid, with the pyridyl nitrogen atom and the two chlorine atoms forming the equatorial plane. Being applied to the ethylene oligomedzation, this cobalt complex shows catalytic activity of 1.820× 10^4 g/mol-Cooh at 101325 Pa of ethylene at 15.5℃ for 1 h, when 1000 equiv, of methylaluminoxane （MAO） is employed as the cocatalyst.     

4‐Ethoxycarbonyl‐3‐hydroxy‐3‐phenylcyclohexanone

The title compound, ethyl 2‐hydroxy‐4‐oxo‐2‐phenyl­cyclo­hexane­carboxyl­ate, C₁₅H₁₈O₄, was obtained by a Michael–Aldol condensation and has the cyclo­hexanone in a chair conformation. The attached hydroxy, ethoxy­carbonyl and phenyl groups are disposed in β‐axial, β‐equatorial and α‐­equatorial configurations, respectively. An intermolecular hydrogen bond, with an O?O distance of 2.874 (2) Å, links the OH group and the ring carbonyl. Weak intermolecular C—H?O=C (ester and ketone), O—H?O=C (ketone) and C—H?OH hydrogen bonds exist.     

2‐[(Acetyloxy)methyl]‐4‐(acetylsulfanyl)‐2‐(ethoxycarbonyl)‐3‐oxobutyl Group: A Thermolabile Protecting Group for Phosphodiesters

The phosphodiester linkage of 3′‐O‐levulinoylthymidine 5′‐methylphosphate ( 5 ) has been protected with 2‐[(acetyloxy)methyl]‐4‐(acetylsulfanyl)‐2‐(ethoxycarbonyl)‐3‐oxobutyl group (to give 1 ) to study the potential of this group as an esterase‐ and thermolabile protecting group. The group turned out to be unexpectedly thermolabile, being removed as ethyl 3‐(acetyloxy)‐4‐(acetylsulfanyl)‐2‐methylidenebut‐3‐enoate ( 10 ) without accumulation of any intermediates. The half‐life of this reaction at pH 7.5 and 37° is 14 min. Hog liver esterase (HLE), in turn, removes the protecting group as ethyl 4‐(acetylsulfanyl)‐2‐methylidene‐3‐oxobutanoate ( 12 ). On using 2.6 units of HLE in 1 ml, the rate of the enzymatic deprotection was still only one third of that of the nonenzymatic reaction. The mechanisms of both reactions have been studied and discussed. The crucial step seems to be removal of the O‐bound Ac group, either by esterase or by migration to the neighboring 3‐oxo group (nonenzymatic removal). This triggers the removal by retro‐aldol condensation/elimination mechanism. No alkylation of glutathione (GSH) upon the deprotection of 1 could be detected.     

Studies on [PtCl2]‐ or [AuCl]‐Catalyzed Cyclization of 1‐(Indol‐2‐yl)‐2,3‐Allenols: The Effects of Water/Steric Hindrance and 1,2‐Migration Selectivity

The [PtCl₂]‐ or [AuCl]‐catalyzed reaction of 1‐(indol‐2‐yl)‐2,3‐allenols occurred smoothly at room temperature to afford a series of poly‐substituted carbazoles efficiently. Compared with the [PtCl₂]‐catalyzed process, the [AuCl]‐catalyzed reaction represents a significant advance in terms of the scope and the selectivity. Selective 1,2‐alkyl or aryl migration of the gold carbene intermediate was observed: compared with the methyl group, the isopropyl, cyclopropyl, cyclobutyl, and cyclohexyl groups migrate exclusively; the cyclopropyl group shifts selectively over the ethyl group; the 1,2‐migration of a non‐methyl linear alkyl is faster than methyl group; the phenyl group migrates exclusively over methyl or ethyl group. DFT calculations show that water makes the elimination of H₂O facile requiring a much lower energy and validates the migratory preferences of different alkyl or phenyl groups observed.     

Synthesis of optically active af‐(1‐Ethyl‐3‐methylhexahydro‐1,3‐diazin‐5‐yl)‐ and N‐(1‐Ethyl‐5‐methyloctahydro‐1,5‐diazocin‐3‐yl)pyridine‐3‐carboxamides

As part of the structure‐activity relationship of the dopamine D₂ and serotonin 5‐HT₃ receptors antagonist 1, which is a clinical candidate with a broad antiemetic activity, the synthesis and dopamine D₂ and serotonin 5‐HT₃ receptors binding affinity of (R)‐5‐bromo‐N‐(1‐ethyl‐3‐methylhexahydro‐1,3‐diazin‐5‐yl)‐ and (R)‐5‐bromo‐N‐(1‐ethyl‐5‐methyloctahydro‐1,5‐diazocin‐3‐yl)‐2‐methoxy‐6‐methylaminopyridine‐3‐carboxam‐ides ( 2 and 3 ) are described. Treatment of 1‐ethyl‐2‐(p‐toluenesulfonyl)amino‐3‐methylaminopropane dihy‐drochloride ( 4a ) with paraformaldehyde and successive deprotection gave the 5‐aminohexahydro‐1,3‐diazine 6 in excellent yield. 3‐Amino‐1‐ethyl‐5‐methyloctahydro‐1,5‐diazocine ( 15 ) was prepared from 2‐(benzyloxycarbonyl)amino‐3‐[[N‐(tert‐butoxycarbonyl)‐N‐methyl]amino]‐1‐ethylaminopropane ( 9 ) through the intramolecular amidation of (R)‐3‐[N‐[(2‐benzyloxycarbonylamino‐3‐methylamino)propyl]‐N‐ethyl]aminopropionic acid trifluoroacetate ( 12 ), followed by lithium aluminum hydride reduction of the resulting 6‐oxo‐1‐ethyl‐5‐methyloctahydrodiazocine ( 13 ) in 41% yield. Reaction of the amines 6 and 15 with 5‐bromo‐2‐methoxy‐6‐methylaminopyridine‐3‐carboxylic acid furnished the desired 2 and 3 , which showed much less potent affinity for dopamine D₂ receptors than 1 .     

Synthesis of 5‐[2‐(guanin‐9‐yl)‐ and 5‐[2‐(2‐aminopurin‐9‐yl)ethyl]‐2‐D‐ribo‐(1,2′,3′,4′‐tetrahydroxybutyl)‐1,3‐dioxane

Stereoselective synthesis of 5‐[2‐(guanin‐9‐yl)‐ and 5‐[2‐(2‐aminopurin‐9‐yl)ethyl]‐2‐D‐ribo‐(1′,2′,3′,4′‐tetrahydroxybutyl)‐1,3‐dioxane, 2‐5, as potential prodrugs of penciclovir, has been accomplished in six steps from readily available 2,3,4,5‐tetra‐O‐acetyl‐aldehydo‐D‐ribose ( 6 ) and the 1,3‐diol 7 . It has been demonstrated that the use of boron trifluoride diethyl etherate (BF₃·Et₂O) in dichloromethane along with excess anhydrous copper(II) sulfate was crucial for the efficient formation of cyclic acetal 8 . In addition, the chromatographic separation of cis and trans isomers of the cyclic acetal at the bromide stage 10 was feasible, which was requisite for the successful stereoselective synthesis of the ribosyl derivatives 2–5 .     

Silica‐Bound 3‐{2‐[Poly(ethylene Glycol)]ethyl}‐Substituted 1‐Methyl‐1H‐imidazol‐3‐ium Bromide: A Recoverable Phase‐Transfer Catalyst for Smooth and Regioselective Conversion of Oxiranes to β‐Hydroxynitriles in Water

A series of β‐hydroxynitriles were efficiently synthesized from the regioselective ring opening of oxiranes by cyanide anion in the presence of silica‐bound 3‐{2‐[poly(ethylene glycol)]ethyl}‐substituted 1‐methyl‐1H‐imidazol‐3‐ium bromide (SiO₂? PEG? ImBr) as a novel recoverable phase‐transfer catalyst in H₂O (Scheme 1 and Table 2). The workup procedure was straightforward, and the catalyst could be reused over four times with almost no loss of catalytic activity and selectivity.     

Liquid‐phase oxidation of 1‐isopropyl‐ and 1‐ethyl‐4‐methoxybenzenes with oxygen to hydroperoxides

A study was carried out on the kinetics of free‐radical chain oxidation of 1‐isopropyl‐4‐methoxybenzene ( 1a ) and 1‐ethyl‐4‐methoxybenzene ( 1b ) with oxygen in the liquid phase to yield 1‐methyl‐1‐(4‐methoxyphenyl)ethyl hydroperoxide ( 2a ) and 1‐(4‐methoxyphenyl)ethyl hydroperoxide ( 2b ). The oxidizability of 1a and 1b was studied over the temperature range 50–100°C. Long‐term oxidations of 1a and 1b to the corresponding hydroperoxides were carried out and the properties and thermal stability of 2a were established. © 2002 Wiley Periodicals, Inc. Int J Chem Kinet 35: 89–94, 2003     

Polymeric μ‐cyano‐di­cyano­nickelate(II)‐μ‐cyano‐trans‐bis­[N‐(2‐hydroxyethyl)ethyl­enedi­amine]­cadmium(II)

The title compound, catena‐poly­[[μ‐cyano‐1:2κ²C:N‐di­cyano‐1κ²C‐trans‐bis­[N‐(2‐hydroxy­ethyl)­ethane‐1,2‐di­amine‐2κ²N,N′]­cadmium(II)­nickel(II)]‐μ‐cyano‐1:2′κ²C:N], [CdNi(CN)₄(C₄H₁₂N₂O)₂], consists of alternating square‐planar Ni(CN)₄ fragments, formally dianionic, and Cd(hydet‐en)₂ moieties [hydet‐en is N‐(2‐hydroxy­ethyl)­ethyl­ene­di­amine], with the two bridging cyanide ligands in a mutually trans disposition at the Ni atom and cis at the Cd atom. The resulting one‐dimensional zigzag chain structure has the Ni atom on an inversion center, while the distorted octahedron centered on the Cd atom lies on a twofold axis. The polymer chains are connected into undulating sheets by weak interchain N—H⋯N, N—H⋯O and O—H⋯N hydrogen bonds, which are also present between successive sheets.