Development of a residual solvent test for bulk alpha-phenyl-1-(2-phenylethyl)-piperine methanol using headspace sampling

An automated static headspace gas chromatographic method for the determination of residual solvents in the bulk drug substance alpha-phenyl-1-(2-phenylethyl)-piperine methanol, a serotonin 5-HT2 receptor antagonist, is evaluated. The method includes the use of 1-propanol as an internal standard. The gas chromatographic conditions utilize a dimethylpolysiloxane phase (SPB-1) capillary column and a flame ionization detector. Validation of this test method includes a recovery study of known levels of acetone, ethyl acetate, methanol, and methyl ethyl ketone in the range of 0.05% to 1.0% (weight-per-weight or w/w) to verify the accuracy of this method; these four solvents are the most likely residual volatiles used in the production of the drug substance. These data and other aspects of the development of this test method are discussed.     

Identification of esters by collisional charge inversion of their enolate ions

The collisional charge inversion and neutralization-reionization (^?NR) mass spectra of the enolate ions of m/z 115 derived from the four butyl acetates, the two propyl propionates, ethyl butyrate, ethyl isobutyrate, methyl valerate, methyl 2-methylbutyrate and methyl 3-methylbutyrate were recorded. The major primary fragmentation reactions of the unstable carbenium ion formed by charge inversion involve elimination of an alkoxy radical to form a ketene or alkylketene molecular ion and formation of an alkyl ion consisting of the R¹ group of RCOOR¹. A minor fragmentation reaction involves elimination of an alkyl radical by cleavage of a C? C bond α to the ether oxygen. The alkylketene ions fragment by β-cleavage eliminating an alkyl radical to form an olefinic acylium ion. In most cases the charge inversion mass spectra of the enolate ions allow identification of the ester.     

SYNTHESIS AND CHARACTERIZATION OF NEWLY DESIGNED POLY[DI(ALKYL) VINYLTEREPHTHALATE]S

A series of newly designed monomers of 2-vinylterephthalates (VT) were synthesized. The monomers contain onephenylene group connected with two alkyl groups (carbon number varying from 1 to 6) via ester linkage. Their chemicalstructures were confirmed by mass spectroscopy (MS), ~1-H-NMR, and elemental analysis (EA). The corresponding polymers,poly[di(alkyl) vinylterephthalate]s (PDAVTs), were obtained using convenional free redical polymerization. The polymerswere found to be able to develop inio liquid crystalline phase when the size of the alkyl group in the side-chain increases tobe larger than the ethyl group.     

Determination of collision-induced dissociation mechanisms and cross-sections in organophosphorus compounds by atmospheric pressure ionization tandem mass spectrometry

Nineteen organophosphorus compounds (OPCs) of the generic classes (dialkyl alkyl′-phosphonates (twelve compounds) and tri-alkyl phosphates (seven compounds) were investigated by atmospheric pressure ionization (API) tandem mass spectrometry (MS/MS). All OPCs showed consistent and comparable collision-induced dissociation (CID) pathways allowing for a generalized scheme for dissociation. When the alkyl groups are equal to or larger than ethyl, CID mechanisms are dominated by McLafferty rearrangements and neutral losses are stable molecules in all cases except cleavage of P? C or O? C bonds to form alkyl fragment ions. CID cross-sections for the OPCs were determined with excellent reproducibility and a good correlation was found with a simple model. Inferences with respect to ionic structures were made from observed trends in the cross-section measurements. Limitations in API-MS/MS instruments of this design are found in the energy distribution of the ionization and ion sampling events.     

全二维气相色谱/飞行时间质谱用于柴油组成的研究

将全二维气相色谱法(GC×GC)用于柴油馏分的组成分布研究,建立了两种GC×GC方法,一种用于柴油组成的详细表征,另一种用于柴油族组成的快速分离和定量,两种方法均不需要样品预处理。用前一种方法对柴油馏分中的烃类化合物、主要的含硫化合物与含氮化合物组成进行了研究;对催化裂解柴油中的27种含氮化合物和42种含硫化合物进行了定性;用后一种方法在70 min内即可完成柴油馏分族组成的定量分析,应用所建立的方法测定了4个不同来源的柴油馏分中非芳烃、一环芳烃、二环芳烃、三环芳烃的含量,定量结果与ASTM D2425法     

Mass spectral fragmentation of thioesters. 1—Identification of low energy,slow processes

A variety of thiol and thion esters, including acetates and benzoates with n-butyl and β-phenethyl alkyl groups, have been studied by electron impact mass spectrometry. Several rearrangement ions were documented and their persistence in low voltage and field ion spectra demonstrated. Among the significant ions found in the rich thion spectra, the most general requires O to S rearrangement of the alkyl group and subsequent cleavage to yield acyl ions (CH₃CO or PhCO). This process is more important in longer chain compounds than in the methyl and ethyl homologues studied previously.     

Quantum mechanics calculations of the thermodynamically controlled coverage and structure of alkyl monolayers on Si(111) surfaces

The heat of formation, Delta E, for silicon (111) surfaces terminated with increasing densities of the alkyl groups CH3- (methyl), C2H5- (ethyl), (CH3)2CH- (isopropyl), (CH3)3C- (tert-butyl), CH3(CH2)5- (hexyl), CH3(CH2)7- (octyl), and C6H5- (phenyl) was calculated using quantum mechanics (QM) methods, with unalkylated sites being H-terminated. The free energy, Delta G, for the formation of both Si-C and Si-H bonds from Si-Cl model compounds was also calculated using QM, with four separate Si-H formation mechanisms proposed, to give overall Delta G(S) values for the formation of alkylated Si(111) surfaces through a two step chlorination/alkylation method. The data are in good agreement with measurements of the packing densities for alkylated surfaces formed through this technique, for Si-H free energies of formation, Delta G(H), corresponding to a reaction mechanism including the elimination of two H atoms and the formation of a C=C double bond in either unreacted alkyl Grignard groups or tetrahydrofuran solvent.     

Synthesis and quantitative structure–activity relationship of a new series of chiral 4‐alkoxycarbonyl‐2‐(alkylamino)‐1,3,2‐oxa or thiazaphospholidine‐2‐ones

Twenty‐one of the chiral 4‐alkoxycarbonyl‐2‐(α‐alkyl‐α‐ethoxycarbonyl methylamino)‐1,3‐2‐thia or oxazaphospholidine‐2‐ones have been synthesized by cyclization of L‐serine or L‐cysteine ethyl or n‐octyl ester with phosphoryl chloride followed by reaction with a suitable L‐amino acid ethyl ester. Proton NMR, IR, and mass spectra of these compounds have been discussed in detail. These compounds inhibited up to 68.52% of acetylcholinesterase (AChE) at the 1 ppm concentration level. Regression analysis showed that AChE inhibition was determined by both the steric and electronic effects of the alkyl groups of the amino acid. The enzyme inhibition correlated directly with the steric bulk of the alkyl groups, indicating a steric requirement for maximizing inhibitor–enzyme interaction and an inverse relationship with the electron‐donating ability of the alkyl groups. This supports the concept of a nucleophilic attack mechanism of a hydroxyl group of a serine amino acid in the enzyme active center on the partially positive phosphorus atom of the oxazaphospholidines and thiazaphospholidines, with correlation coefficients of 0.999 and 0.838, respectively. Results also indicated that the steric requirement was more important than the electronic factor in affecting the inhibition process, which explained the high activity of compounds containing the isoleucine moiety. The high AChE inhibition activity of these compounds and the expected nontoxic products of their in vivo hydrolysis make them eligible for pesticidal application. © 1999 John Wiley & Sons, Inc. Heteroatom Chem 10: 475–480, 1999     

高效液相色谱质谱法分析脂肪醇聚氧乙烯醚中的碳数及环氧乙烷加成数的分布

应用高效液相色谱法将脂肪醇聚氧乙烯醚按碳数和环氧乙烷加成数 (EO数 )分离后 ,在线联用电喷雾离子化质谱 (ESI MS) ,根据其一系列准分子离子峰判断烷基链长和环氧乙烷聚合度。解释了准分子离子峰强度失真的原因。     

Closing one of the last gaps in polyionene compositions: alkyloxyethylammonium ionenes as fast-acting biocides

Alkyloxyethylammonium ionenes are reported as biocompatible biocides with a time of biocidal action within a few minutes. The presence of both ethoxyethyl and aliphatic spacers besides long alkyl chain substituents on the quaternary nitrogen atom differentiates these biocides structurally from the known polyionenes. The influence of alkyl spacer length, counter ion and length of the pendant alkyl groups on the antibacterial properties is studied. E. coli is adopted as a test organism. MIC and MBC values are determined via broth dilution methods; time-dependent tests are accomplished by determining the number of viable cells with the spread-plate method after different contact times. Structural characterization is conducted via NMR and mass spectrometry techniques.     

Synthesis of α-fluoro-β-hydroxy esters by an enantioselective Reformatsky-type reaction

The first enantioselective Reformatsky-type reaction of ethyl iodofluoroacetate has been accomplished with alkyl aryl ketones. High diastereoselectivities and excellent enantioselectivities for the major diastereomer (93-95% ee) were achieved with large alkyl groups. For smaller alkyl groups the diastereoselectivities were moderate, but excellent enantioselectivities were obtained for both diastereomers (79-94% ee).     

Capillary electrophoresis/mass spectrometry: a promising tool for the control of some physiologically hazardous compounds. I-derivatives of 3-quinuclidinol

A method based on the coupling of capillary electrophoresis with mass spectrometry (CE/MS) was developed for the monitoring of 3-quinuclidinol and its four N-alkyl derivatives (methyl, ethyl, propyl and isopropyl derivatives). A fragmentation study (collision-induced dissociation of ions in an ion trap) and optimization of the ion optics set-up for CE/MS experiments using direct infusion of a methanolic solution of the standards into the mass spectrometer were carried out in advance. Molecular ions of all quaternary compounds and the quasi-molecular ion [M + H]+ of free 3-quinuclidinol prevail in the mass spectra. In the MS/MS of propyl and isopropyl derivatives, the elimination of the alkyl chain dominates, leading to the ion at m/z 128. The fragmentation of the other compounds is more complex. Previous CE separation of the mixture of isobaric propyl and isopropyl derivatives is necessary for their unambiguous identification. A 10 mM ammonium acetate buffer (pH 4.0) is the optimum running electrolyte, allowing the CE separation of methyl, ethyl, propyl and isopropyl derivatives. A 0.5% (v/v) solution of acetic acid in methanol provides sufficient detection sensitivity when used as the sheath liquid. Limits of detection of 0.1 ppm for 3-quinuclidinol and 0.05 ppm for quaternary derivatives were achieved under the optimum conditions. The optimized method was applied to the determination of 3-quinuclidinol and related quaternary derivatives spiked into a sample of pond water. The experimental set-up for CE/MS/MS was investigated, which strongly increases the identification capability of the technique.     

The 5-HT(1A) agonism potential of substituted piperazine-ethyl-amide derivatives is conserved in the hexyl homologues: molecular modeling and pharmacological evaluation

In a series of carboxamide and sulphonamide alkyl (ethyl to hexyl) piperazine analogues, although the size of the linker is very different, ethyl and hexyl derivatives possess a high affinity for 5-HT(1A) receptors. Docking studies clearly show that hexyl and ethyl compounds favorably interact with the binding site of the active conformation of 5-HT(1A) receptors, thus confirming a possible agonist profile. This activity is effectively detected in electrophysiological experiments in which all four compounds inhibit the activity of rat dorsal raphe serotonergic neurons.     

高效液相色谱质谱法分析脂肪醇聚氧乙烯醚中的碳数及环氧乙烷加成数的分布

 应用高效液相色谱法将脂肪醇聚氧乙烯醚按碳数和环氧乙烷加成数 (EO数 )分离后 ,在线联用电喷雾离子化质谱 (ESI MS) ,根据其一系列准分子离子峰判断烷基链长和环氧乙烷聚合度。解释了准分子离子峰强度失真的原因。     

Determination of Anionic Surfactants in Water

The use of ternary complexes in the determination of anionic surfactants has been investigated and an analytical method using linear alkyl sulfonates as a test substance has been developed. The method involves the formation of the chloroform-extractable bisphenanthroline Cu(II)-linear alkyl sulfonate (LAS) complex and the subsequent equilibration of the extract with erythrosine to form the extractable bisphenanthroline Cu(II)-erythrosine complex. In the equilibration step erythrosine displaces LAS quantitatively, allowing the determination of the LAS originally present by measuring the absorbance of the extracted bisphenanthroline-Cu(II)-erythrosine complex. Results are reported of studies made to determine the optimum analytical conditions, the sensitivity, and the precision for the method described.     

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.     

Electric dipole moment studies of carboxylic ester conformations: alkyl acetates,benzoates, 2,4,6-trimethyl-benzoates and 2,3,5,6-tetramethylbenzoates

Electric dipole moments μ in benzene at 30 °C have been determined (Table 3) on methyl, ethyl, isopropyl and t-butyl esters of the title compounds to determine steric effects on conformation in solution. Experimental moments were compared with those calculated for various possible conformations by a 3-dimensional vectorial addition method using bond moments and bond angles. The experimental moments for the alkyl acetates were best interpreted in terms of an out-of-plane deviation of the alkyl group from an s-trans conformation caused by steric interference between the alkyl group and the carbonyl oxygen and increasing in the series from methyl to t-butyl. The dihedral angles 0 (deviations) were calculated using a vector addition method. An increase in the moments of the benzoate series over the acetates was interpreted in terms of conjugative interaction between phenyl and carbonyl groups. Angles of twist φ for the benzoates and trimethylbenzoates were calculated using the Braude-Sondheimer equation. A decrease in the moments of the methyl, ethyl, and isopropyl trimethyl-benzoates as compared with the benzoates was interpreted in terms of steric interference between ortho methyls and both oxygens. The decrease in the angles of twist from methyl to t-butyl for the trimethylbenzoates was tentatively explained by greater steric interaction of the alkyl group with both carbonyl oxygen and ortho methyls, which forces adoption of a more coplanar arrangement between the ring and the carbonyl group than for the other alkyl derivatives, this interaction increasing with the size of the alkyl group. Dipole moments for 2,3,5,6-tetramethylbenzoates were nearly the same as for corresponding trimethyl-benzoates, thus showing no conclusive evidence for operation of a “buttressing” effect.     

Measurement of fuel oxygenates in tap water using solid-phase microextraction gas chromatography-mass spectrometry

The presence of alkyl ether fuel oxygenates in drinking water supplies has raised public health concerns because of possible adverse health effects from chronic exposure to these compounds. To enable large exposure studies exploring possible relationships between chronic exposure to alkyl ether fuel oxygenates and health effects, we developed an improved analytical method, using headspace solid-phase microextraction coupled with capillary gas chromatography and mass spectrometry. This method quantifies trace levels of methyl tertiary-butyl ether, ethyl tertiary-butyl ether, di-isopropyl ether, and tertiary-amyl methyl ether in tap water. The method achieves detection limits of less than 0.025 microg/L for all analytes and linear ranges of three orders of magnitude in the measurement of the alkyl ether fuel oxygenates in 5-mL tap water samples. The relative percentage of recoveries of the alkyl ether fuel oxygenates ranged from 97% to 105%. The relative standard deviation ranged from 2% to 6%. Methyl tertiary-butyl ether was detected in samples of tap water taken from geographically diverse regions of the United States. The improved throughput and sensitivity of this method will enable large epidemiologic field studies of the prevalence and magnitude of exposure to alkyl ether fuel oxygenates in the general population.     

Determination of nerve agent metabolites in human urine by isotope-dilution gas chromatography-tandem mass spectrometry after solid phase supported derivatization

A simple and sensitive method has been developed and validated for determining ethyl methylphosphonic acid (EMPA), isopropyl methylphosphonic acid (IMPA), isobutyl methylphosphonic acid (iBuMPA), and pinacolyl methylphosphonic acid (PMPA) in human urine using gas chromatography-tandem mass spectrometry (GC-MS/MS) coupled with solid phase derivatization (SPD). These four alkyl methylphosphonic acids (AMPAs) are specific hydrolysis products and biomarkers of exposure to classic organophosphorus (OP) nerve agents VX, sarin, RVX, and soman. The AMPAs in urine samples were directly derivatized with pentafluorobenzyl bromide on a solid support and then extracted by liquid–liquid extraction. The analytes were quantified with isotope-dilution by negative chemical ionization (NCI) GC-MS/MS in a selected reaction monitoring (SRM) mode. This method is highly sensitive, with the limits of detection of 0.02 ng/mL for each compound in a 0.2 mL sample of human urine, and an excellent linearity from 0.1 to 50 ng/mL. It is proven to be very suitable for the qualitative and quantitative analyses of degradation markers of OP nerve agents in biomedical samples.     

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.