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Marcos N. Eberlin - One of the best experts on this subject based on the ideXlab platform.
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Meerwein Reaction of phosphonium ions with epoxides and thioepoxides in the gas phase
Journal of the American Society for Mass Spectrometry, 2004Co-Authors: Eduardo C. Meurer, Ls Riter, Hao Chen, R. Graham Cooks, Marcos N. EberlinAbstract:Phosphonium ions are shown to undergo a gas-phase Meerwein Reaction in which epoxides (or thioepoxides) undergo three-to-five-membered ring expansion to yield dioxaphospholanium (or oxathiophospholanium) ion products. When the association Reaction is followed by collision-induced dissociation (CID), the oxirane (or thiirane) is eliminated, making this ion molecule Reaction/CID sequence a good method of net oxygen-by-sulfur replacement in the phosphonium ions. This replacement results in a characteristic mass shift of 16 units and provides evidence for the cyclic nature of the gas-phase Meerwein product ions, while improving selectivity for phosphonium ion detection. This Reaction sequence also constitutes a gas-phase route to convert phosphonium ions into their sulfur analogs. Phosphonium and related ions are important targets since they are commonly and readily formed in mass spectrometric analysis upon dissociative electron ionization of organophosphorous esters. The Meerwein Reaction should provide a new and very useful method of recognizing compounds that yield these ions, which includes a number of chemical warfare agents. The Meerwein Reaction proceeds by phosphonium ion addition to the sulfur or oxygen center, followed by intramolecular nucleophilic attack with ring expansion to yield the 1,3,2-dioxaphospholanium or 1,3,2-oxathiophospholanium ion. Product ion structures were investigated by CID tandem mass spectrometry (MS^2) experiments and corroborated by DFT/HF calculations.
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the gas phase Meerwein Reaction
Chemistry: A European Journal, 2000Co-Authors: Luiz Alberto Beraldo De Moraes, Marcos N. EberlinAbstract:A systematic investigation of a novel epoxide and thioepoxide ring expansion Reaction promoted by gaseous acylium and thioacylium ions is reported. As ab initio calculations predict, and 18O-labeling and MS3 pentaquadrupole experiments demonstrate, the Reaction proceeds by initial O(S)-acylation of the (thio)epoxides followed by rapid intramolecular nucleophilic attack that results in three-to-five-membered ring expansion, and forms cyclic 1,3-dioxolanylium, 1,3-oxathiolanylium, or 1,3-dithiolanylium ions. This gas-phase Reaction is analogous to a condensed-phase Reaction long since described by H. Meerwein (Chem. Ber. 1955, 67, 374), and is termed as "the gas-phase Meerwein Reaction"; it occurs often to great extents or even exclusively, but in some cases, particularly for the most basic (thio)epoxides and the most acidic (thio)acylium ions, proton transfer (eventually hydride abstraction) competes efficiently, or even dominates. When (thio)epoxides react with (thio)-acylium ions, the Reaction promotes O(S)-scrambling; when epoxides react with thioacylium ions and the adducts are dissociated, it promotes S/O replacement. An analogous four-to-six-membered ring expansion also occurs predominantly in Reactions of trimethylene oxide with acylium and thioacylium ions.
Luiz Alberto Beraldo De Moraes - One of the best experts on this subject based on the ideXlab platform.
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Ions acilio : estrutura e reatividade na fase gasosa
2017Co-Authors: Luiz Alberto Beraldo De MoraesAbstract:Resumo: Aspectos estruturais e de reatividade na fase gasosa de vários íons acílios (R-CO) e seus análogos de enxofre (R-CS) foram estudados através da espectrometria de massas pentaquadrupolar. A reação de cetalização de íons acílios com dióis e análogos formou cetais iônicos, os quais foram caracterizados empregando-se espectros sequênciais MS e marcação isotópica com o íon R-C=O. A dissociação dos cetais iônicos com marcação isotópica levou à recuperação do íon acílio reagente isotopicamente marcado e isotopicamente puro, em iguais proporções. Este padrão de dissociação caracterizou a estrutura do produto formado como cíclica e simétrica. Íons acílios e tioacílios reagiram também com cetais e acetais neutro cíclicos, através da reação de transacetalização, onde o composto carbonílico protegido no cetal neutro foi substituído pelo íon acílio de partida. Para cetais contendo oxigênio e enxofre, observou-se preferência do íon acílio ao enxofre. Íons acílios promoveram também reações de expansão de anéis de epóxidos (reação de Meerwein em fase condensada), levando a formação de cetais iônicos cíclicos. Porém, anéis heterocíclicos de 5 e 6 membros não sofrem expansão de anel pelo ataque do íon acílios, devido a pequena tensão angular desses anéis. A caracterização estrutural dos produtos foi também realizada empregando-se o íon R-C=O. As reações de cetalização, transacetalização e expansão de anel foram empregadas na caracterização de sítios acílio em íons acílio distônicos, íons 'diacílios' e na diferenciação de isômeros orto, meta e para de cátions benzoíla, funcionando assim como diagnóstico na caracterização de íons acílios na fase gasosa. Cálculos ab initio e DFT mostraram que as novas reações observadas para íons acílio são favoreci-das termodinamicamente na fase gasosa, fornecendo portanto suporte teórico para os resultados experimentais obtidos.Abstract: The structure and reactivity in the gas phase of several acylium ions ( R-CO ) and their sulfur analogues were studied using pentaquadrupole mass spectrometry. Cyclic ionic ketal were formed via ketalization Reactions of acylium ions with diols and analogues; the products were characterized via sequential MS spectra and isotopic labeling with R-C=O. The dissociation of O-labeled ionic ketal occurred via re-generation of both the labeled and unlabeled reactant acylium ion in equal abundance's, and this dissociation pattern characterized cyclic and O/O-scrambled structures. Acylium and thioacylium ions also reacted with cyclic ketals and acetals via transacetalization, by which the protected carbonyl compound is replaced by the reactant acylium ion. For O/S-cyclic ketals, the sulfur site is the most reactive. Acylium ions were also found to promote ring expansion of epoxide rings (the gas-phase "Meerwein Reaction") forming cyclic ionic ketals. However, heterocyclic rings of five and six members failed to undergo similar Reactions with acylium ions, likely owing to reduced ring strain. Structural characterization of the ionic products as cyclic ionic ketals were also performed by using R-C=O. The gas-phase ketalization, transacetalization and epoxide ring expansion Reactions were used to characterize the acylium site in distonic acylium ions, diacylium ions and isomers differentiation of the benzoyl cations; they provide structurally diagnostic tests for gaseous acylium ions. Ab initio and DFT calculations showed that the novel Reactions observed for acylium ions in the gas phase are thermodynamically favored, providing therefore theoretical support for the experimental results
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the gas phase Meerwein Reaction
Chemistry: A European Journal, 2000Co-Authors: Luiz Alberto Beraldo De Moraes, Marcos N. EberlinAbstract:A systematic investigation of a novel epoxide and thioepoxide ring expansion Reaction promoted by gaseous acylium and thioacylium ions is reported. As ab initio calculations predict, and 18O-labeling and MS3 pentaquadrupole experiments demonstrate, the Reaction proceeds by initial O(S)-acylation of the (thio)epoxides followed by rapid intramolecular nucleophilic attack that results in three-to-five-membered ring expansion, and forms cyclic 1,3-dioxolanylium, 1,3-oxathiolanylium, or 1,3-dithiolanylium ions. This gas-phase Reaction is analogous to a condensed-phase Reaction long since described by H. Meerwein (Chem. Ber. 1955, 67, 374), and is termed as "the gas-phase Meerwein Reaction"; it occurs often to great extents or even exclusively, but in some cases, particularly for the most basic (thio)epoxides and the most acidic (thio)acylium ions, proton transfer (eventually hydride abstraction) competes efficiently, or even dominates. When (thio)epoxides react with (thio)-acylium ions, the Reaction promotes O(S)-scrambling; when epoxides react with thioacylium ions and the adducts are dissociated, it promotes S/O replacement. An analogous four-to-six-membered ring expansion also occurs predominantly in Reactions of trimethylene oxide with acylium and thioacylium ions.
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Ions acilio : estrutura e reatividade na fase gasosa
Universidade Estadual de Campinas. Instituto de Quimica, 1999Co-Authors: Luiz Alberto Beraldo De MoraesAbstract:Aspectos estruturais e de reatividade na fase gasosa de vários íons acílios (R-CO) e seus análogos de enxofre (R-CS) foram estudados através da espectrometria de massas pentaquadrupolar. A reação de cetalização de íons acílios com dióis e análogos formou cetais iônicos, os quais foram caracterizados empregando-se espectros sequênciais MS e marcação isotópica com o íon R-C=O. A dissociação dos cetais iônicos com marcação isotópica levou à recuperação do íon acílio reagente isotopicamente marcado e isotopicamente puro, em iguais proporções. Este padrão de dissociação caracterizou a estrutura do produto formado como cíclica e simétrica. Íons acílios e tioacílios reagiram também com cetais e acetais neutro cíclicos, através da reação de transacetalização, onde o composto carbonílico protegido no cetal neutro foi substituído pelo íon acílio de partida. Para cetais contendo oxigênio e enxofre, observou-se preferência do íon acílio ao enxofre. Íons acílios promoveram também reações de expansão de anéis de epóxidos (reação de Meerwein em fase condensada), levando a formação de cetais iônicos cíclicos. Porém, anéis heterocíclicos de 5 e 6 membros não sofrem expansão de anel pelo ataque do íon acílios, devido a pequena tensão angular desses anéis. A caracterização estrutural dos produtos foi também realizada empregando-se o íon R-C=O. As reações de cetalização, transacetalização e expansão de anel foram empregadas na caracterização de sítios acílio em íons acílio distônicos, íons 'diacílios' e na diferenciação de isômeros orto, meta e para de cátions benzoíla, funcionando assim como diagnóstico na caracterização de íons acílios na fase gasosa. Cálculos ab initio e DFT mostraram que as novas reações observadas para íons acílio são favoreci-das termodinamicamente na fase gasosa, fornecendo portanto suporte teórico para os resultados experimentais obtidos.The structure and reactivity in the gas phase of several acylium ions ( R-CO ) and their sulfur analogues were studied using pentaquadrupole mass spectrometry. Cyclic ionic ketal were formed via ketalization Reactions of acylium ions with diols and analogues; the products were characterized via sequential MS spectra and isotopic labeling with R-C=O. The dissociation of O-labeled ionic ketal occurred via re-generation of both the labeled and unlabeled reactant acylium ion in equal abundance's, and this dissociation pattern characterized cyclic and O/O-scrambled structures. Acylium and thioacylium ions also reacted with cyclic ketals and acetals via transacetalization, by which the protected carbonyl compound is replaced by the reactant acylium ion. For O/S-cyclic ketals, the sulfur site is the most reactive. Acylium ions were also found to promote ring expansion of epoxide rings (the gas-phase "Meerwein Reaction") forming cyclic ionic ketals. However, heterocyclic rings of five and six members failed to undergo similar Reactions with acylium ions, likely owing to reduced ring strain. Structural characterization of the ionic products as cyclic ionic ketals were also performed by using R-C=O. The gas-phase ketalization, transacetalization and epoxide ring expansion Reactions were used to characterize the acylium site in distonic acylium ions, diacylium ions and isomers differentiation of the benzoyl cations; they provide structurally diagnostic tests for gaseous acylium ions. Ab initio and DFT calculations showed that the novel Reactions observed for acylium ions in the gas phase are thermodynamically favored, providing therefore theoretical support for the experimental results
Alireza S Kord - One of the best experts on this subject based on the ideXlab platform.
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gas phase derivatization via the Meerwein Reaction for selective and sensitive lc ms analysis of epoxides in active pharmaceutical ingredients
Journal of Pharmaceutical and Biomedical Analysis, 2011Co-Authors: David Q Liu, Frederick G Vogt, Alireza S KordAbstract:A gas-phase derivatization strategy is reported by using the gas-phase Meerwein Reaction for rapid and direct LC-MS analysis of epoxides, which are potential genotoxic impurities (GTIs) in active pharmaceutical ingredients (APIs). This class-selective ion/molecule Reaction occurs between epoxides and the ethylnitrilium ion (CH(3)-C≡NH↔CH(3)-C=NH) that is generated by atmospheric pressure ionizations (when acetonitrile is used as the mobile phase). Density functional theory (DFT) calculations at the B3LYP/6-311+G(d,p) level show that the gas-phase Meerwein Reaction is thermodynamically favorable. Commonly used atmospheric pressure ionization techniques including ESI, APCI and APPI were evaluated for optimal formation of the Meerwein Reaction products. APCI appears to be the method of choice since it offers better sensitivity and more robust detection under typical LC-MS instrumentation conditions. Quantitative analysis of epoxides can be achieved by either single ion monitoring (SIM) or multiple Reaction monitoring (MRM) of the Meerwein Reaction products. We demonstrate herein quantitative analysis of two potential GTIs of SB797313 and SB719133 in APIs. The validated methods afford excellent linearity (r(2)≥0.999), sensitivity (LOD≤1 ppm by w/w in 10 mg/mL APIs) and recovery (ranging from 92% to 102%), as well as accuracy (≤2.8% difference) and precision (≤2.2% RSD) based on injections of six prepared standards. This novel strategy is particularly useful when a target analyte is difficult to be directly analyzed by LC-MS (e.g. due to poor ionization) or unstable in the course of solution-phase derivatization.
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gas phase Meerwein Reaction of epoxides with protonated acetonitrile generated by atmospheric pressure ionizations
Journal of the American Society for Mass Spectrometry, 2010Co-Authors: David Q Liu, Alireza S KordAbstract:Ethylnitrilium ion can be generated by protonation of acetonitrile (when used as the LC-MS mobile phase) under the conditions of atmospheric pressure ionizations, including electrospray ionization (ESI) and atmospheric pressure chemical ionization (APCI) as well as atmospheric pressure photoionization (APPI). Ethylnitrilium ion (CH3 C N H and its canonical form CH3 C NH) is shown to efficiently undergo the gas-phase Meerwein Reaction with epoxides. This Reaction proceeds by the initial formation of an oxonium ion followed by three-to-five-membered ring expansion via an intramolecular nucleophilic attack to yield the Meerwein Reaction products. The density functional theory (DFT) calculations at the B3LYP/6-311G(d,p) level show that the gas-phase Meerwein Reaction is thermodynamically favorable. Collision-induced dissociation (CID) of the Meerwein Reaction products yields the net oxygen-by-nitrogen replacement of epoxides with a characteristic mass shift of 1 Da, providing evidence for the cyclic nature of the gas-phase Meerwein Reaction products. The gas-phase Meerwein Reaction offers a novel and fast LC-MS approach for the direct analysis of epoxides that might be of genotoxic concern during drug development. Understanding and utilizing this unique gas-phase ion/molecule Reaction, the sensitivity and selectivity for quantitation of epoxides can be enhanced. (J Am Soc Mass Spectrom 2010, 21, 1802–1813) © 2010 American Society for Mass Spectrometry
Mn Eberlin - One of the best experts on this subject based on the ideXlab platform.
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Acyclic distonic acylium ions: Dual free radical and acylium ion reactivity in a single molecule
EUA, 2015Co-Authors: Moraes Lab, Mn EberlinAbstract:Three gaseous acyclic distonic acylium ions: . CH2-CH2-C+=O, . CH2-CH2-CH2-C+=O, and . CH2=C(CH2)-C+=O, are found to display dual free radical and acylium ion reactivity; with appropriate neutrals, they react selectively either as free radicals with inert charge sites, or (and more pronouncedly) as acylium ions with inert radical sites. The free radical reactivity of the ions is demonstrated via the Kenttamaa Reaction: CH3S. abstraction with the spin trap dimethyl disulfide; their ion reactivity by two Reactions most characteristic of acylium ions: transacetalization with 2-methyl-1,3-dioxolane and the gas-phase Meerwein Reaction, that is, expansion of the three-membered epoxide ring of epichlorohydrin to the five-membered 19-dioxolanylium ion ring. In "one-pot" Reactions with gaseous mixtures of epichlorohydrin and dimethyl disulfide, the ions react selectively at either site, bur more readily at the acylium charge site, to form the two mono-derivatized ions. Further Reaction at either the remaining free radical or acylium charge site forms a single bi-derivatized ion as the final product. Becke3LYP/6-31G(d) calculations predict the Reactions at the acylium charge sites of the three distonic ions to be highly exothermic, and both the "hot" transacetalization and epoxide ring expansion products of . CH2-CH2-CH2-C+=O to dissociate rapidly by H2C=CH2 loss in overall exothermic processes. The calculations also predict highly spatially separate odd spin and charge sites for the novel cyclic distonic ketal ions formed by the Reactions at the acylium charge sites. (J Am Soc Mass Spectrom 2000, 11, 697-704) (C) 2000 American Society for Mass Spectrometry.11869770
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Meerwein Reaction of phosphonium ions with epoxides and thioepoxides in the gas phase
EUA, 2015Co-Authors: Ec Meurer, Chen H, Ls Riter, Rg Cooks, Mn EberlinAbstract:Phosphonium. ions are shown to undergo a gas-phase Meerwein Reaction in which epoxides (or thioepoxides) undergo three-to-five-membered ring expansion to yield dioxaphospholanium. (or oxathiophospholanium) ion products. When the association Reaction is followed by collision-induced dissociation (CID), the oxirane (or thiirane) is eliminated, making this ion molecule Reaction/CID sequence a good method of net oxygen-by-sulfur replacement in the phosphonium. ions. This replacement results in a characteristic mass shift of 16 units and provides evidence for the cyclic nature of the gas-phase Meerwein product ions, while improving selectivity for phosphonium ion detection. This Reaction sequence also. constitutes a gas-phase route to convert phosphonium ions into their sulfur analogs. Phosphonium and related ions are important targets since they are commonly and readily formed in mass spectrometric analysis upon dissociative electron ionization of organophosphorous esters. The Meerwein Reaction should provide a new and very useful method of recognizing compounds that yield these ions, which includes a number of chemical warfare agents. The Meerwein Reaction proceeds by phosphonium ion addition to the sulfur or oxygen center, followed by intramolecular nucleophilic attack with ring expansion to yield the 1,3,2-dioxaphospholanium or 1,3,2-oxathiophospholanium ion. Product ion structures were investigated by CID tandem mass spectrometry (MS2) experiments and corroborated by DFT/HF calculations. (C) 2004 American Society for Mass Spectrometry.15339840
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The atmospheric pressure Meerwein Reaction
Inglaterra, 2015Co-Authors: Ec Meurer, Mn EberlinAbstract:We have already shown that the in-vacuum gas-phase Meerwein Reaction of (thio)acylium ions is general in nature and useful for class-selective screening of cyclic (thio)epoxides. Herein we report that this gas-phase Reaction can also be performed efficiently at atmospheric pressure under both electrospray ionization (ESI) and atmospheric pressure chemical ionization (APCI) conditions. This alternative expands the range of molecules that can be reacted by gas-phase Meerwein Reaction. Phenyl epoxide, thiirane, 3-methoxy-2,2-dimethyloxirane, propylene oxide, 2,2'-bioxirane, trans-1,3-diphenyl-2,3-epoxypropan-1-one, epichloridrine and propylene oxide are shown to react efficiently in both ESI and APCI conditions. Tetramethylurea (TMU) and (thio)TMU were both used as dopants, being co-injected with either toluene, acetonitrile or methanol solutions of the (thio)epoxides, with similar results. In both ESI and APCI, (thio)TMU is protonated preferentially, and these labile species dissociate promptly to yield (CH3)(2)N-C+=O and (CH3)(2)NCS+, which are the least acidic and most reactive (thio)acylium ions so far tested in the gas-phase Meerwein Reaction. Under the low-energy ESI conditions set to favor both the formation of the (thio)acylium ion and ion/molecule Reactions, (CH3)(2)NCO(S)(+) react competitively with (thio)TMU to form acylated (thio)TMU and with the (thio)epoxide to form the characteristic Meerwein products. Enhanced selectivity in structural characterization or for the screening of (thio)epoxides is achieved by performing on-line collision-induced dissociation of Meerwein products, particularly for the more structurally complex (thio)epoxides. Copyright (c) 2006 John Wiley & Sons, Ltd.41447047
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Ion/molecule Reactions performed in a miniature cylindrical ion trap mass spectrometer
Inglaterra, 2015Co-Authors: Ls Riter, Mn Eberlin, Ec Meurer, Chen H, Es Handberg, Bc Laughlin, Ge Patterson, Rg CooksAbstract:A recently constructed miniature mass spectrometer, based on a cylindrical ion trap (CIT) mass analyzer, is used to perform ion/molecule Reactions in order to improve selectivity for in situ analysis of explosives and chemical warfare agent simulants. Six different Reactions are explored, including several of the Eberlin Reaction type (M. N. Eberlin and R. G. Cooks, Org. Mass Spectrom., 1993, 28, 679-687) as well as novel gas-phase Meerwein Reactions. The Reactions include ( 1) Eberlin transacetalization of the benzoyl, 2,2-dimethyloximinium, and 2,2-dimethylthiooximinium cations with 2,2-dimethyl-1,3-dioxolane to form 2-phenyl-1,3-dioxolanylium cations, 2,2-dimethylamine-1,3-dioxolanylium cations and the 2,2-dimethylamin-1,3-oxathiolanylium cations, respectively; (2) Eberlin Reaction of the phosphonium ion CH3P(O)OCH3+, formed from the chemical warfare agent simulant dimethyl methylphosphonate (DMMP), with 1,4-dioxane to yield the 1,3,2-dioxaphospholanium ion, a new characteristic Reaction for phosphate ester detection; (3) the novel Meerwein Reaction of the ion CH3P(O)OCH3+ with propylene sulfide forming 1,3,2-oxathionylphospholanium ion; (4) the Meerwein Reaction of the benzoyl cation with propylene oxide and propylene sulfide to form 4-methyl-2-phenyl-1,3-dioxolane and its thio analog, respectively; (5) ketalization of the benzoyl cation with ethylene glycol to form the 2-phenyl-1,3-dioxolanylium cation; (6) addition/NO2 elimination involving benzonitrile radical cation in Reaction with nitrobenzene to form an arylated nitrile, a diagnostic Reaction for explosives detection and (7) simple methanol addition to the C7H7+ ion, formed by NO2 loss from the molecular ion of p-nitrotoluene to form an intact adduct. Evidence is provided that these Reactions occur to give the products described and their potential analytical utility is discussed.12891112111
David Q Liu - One of the best experts on this subject based on the ideXlab platform.
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gas phase derivatization via the Meerwein Reaction for selective and sensitive lc ms analysis of epoxides in active pharmaceutical ingredients
Journal of Pharmaceutical and Biomedical Analysis, 2011Co-Authors: David Q Liu, Frederick G Vogt, Alireza S KordAbstract:A gas-phase derivatization strategy is reported by using the gas-phase Meerwein Reaction for rapid and direct LC-MS analysis of epoxides, which are potential genotoxic impurities (GTIs) in active pharmaceutical ingredients (APIs). This class-selective ion/molecule Reaction occurs between epoxides and the ethylnitrilium ion (CH(3)-C≡NH↔CH(3)-C=NH) that is generated by atmospheric pressure ionizations (when acetonitrile is used as the mobile phase). Density functional theory (DFT) calculations at the B3LYP/6-311+G(d,p) level show that the gas-phase Meerwein Reaction is thermodynamically favorable. Commonly used atmospheric pressure ionization techniques including ESI, APCI and APPI were evaluated for optimal formation of the Meerwein Reaction products. APCI appears to be the method of choice since it offers better sensitivity and more robust detection under typical LC-MS instrumentation conditions. Quantitative analysis of epoxides can be achieved by either single ion monitoring (SIM) or multiple Reaction monitoring (MRM) of the Meerwein Reaction products. We demonstrate herein quantitative analysis of two potential GTIs of SB797313 and SB719133 in APIs. The validated methods afford excellent linearity (r(2)≥0.999), sensitivity (LOD≤1 ppm by w/w in 10 mg/mL APIs) and recovery (ranging from 92% to 102%), as well as accuracy (≤2.8% difference) and precision (≤2.2% RSD) based on injections of six prepared standards. This novel strategy is particularly useful when a target analyte is difficult to be directly analyzed by LC-MS (e.g. due to poor ionization) or unstable in the course of solution-phase derivatization.
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gas phase Meerwein Reaction of epoxides with protonated acetonitrile generated by atmospheric pressure ionizations
Journal of the American Society for Mass Spectrometry, 2010Co-Authors: David Q Liu, Alireza S KordAbstract:Ethylnitrilium ion can be generated by protonation of acetonitrile (when used as the LC-MS mobile phase) under the conditions of atmospheric pressure ionizations, including electrospray ionization (ESI) and atmospheric pressure chemical ionization (APCI) as well as atmospheric pressure photoionization (APPI). Ethylnitrilium ion (CH3 C N H and its canonical form CH3 C NH) is shown to efficiently undergo the gas-phase Meerwein Reaction with epoxides. This Reaction proceeds by the initial formation of an oxonium ion followed by three-to-five-membered ring expansion via an intramolecular nucleophilic attack to yield the Meerwein Reaction products. The density functional theory (DFT) calculations at the B3LYP/6-311G(d,p) level show that the gas-phase Meerwein Reaction is thermodynamically favorable. Collision-induced dissociation (CID) of the Meerwein Reaction products yields the net oxygen-by-nitrogen replacement of epoxides with a characteristic mass shift of 1 Da, providing evidence for the cyclic nature of the gas-phase Meerwein Reaction products. The gas-phase Meerwein Reaction offers a novel and fast LC-MS approach for the direct analysis of epoxides that might be of genotoxic concern during drug development. Understanding and utilizing this unique gas-phase ion/molecule Reaction, the sensitivity and selectivity for quantitation of epoxides can be enhanced. (J Am Soc Mass Spectrom 2010, 21, 1802–1813) © 2010 American Society for Mass Spectrometry