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Simplified Routines for Sample Preparation and Analysis of Chemical Warfare Agent Degradation Products
Umeå University, Faculty of Science and Technology, Department of Chemistry.
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The thesis describes the development of new and improved methods for analyzing degradation markers from organophosphorus Chemical Warfare Agents (CWAs).

Paper I and II describes an innovative and significantly improved method for the enrichment, derivatization (trimethysilylation) and GC-MS analysis of a broad range of organophosphorus CWAs degradation markers, namely the alkylphosphonic acids and a zwitterionic compound. That was achieved using solid phase disc extraction in combination with solid phase derivatization. The new method overcomes most limitations observed with existing techniques: it offers almost 100 % recoveries, requires no elution or evaporation steps, facilitates miniaturization of the solid sorbent and reagent, is compatible with in-vial derivatization, and minimizes the chromatographic background due to the use of a highly selective anion exchange sorbent disc.

Paper III describes the development of new fluorinated diazomethane derivatization reagents and their evaluation for rapid and high sensitivity screening and identification of nerve agent degradation markers. The reagents are water-tolerant to some extent, which simplifies the derivatization step. The best reagent identified was 3,5-bis(trifluoromethyl)benzyl diazomethane, which outperformed the other reagent isomers tested and also the established commercial alternative, pentafluorobenzylbromide, allowing for the rapid (5 min) and direct derivatization of a 25 μL aqueous sample in acetonitrile. The spectra of the formed derivatives (high-energy collision induced fragmentation MS/MS) were used to construct a database (Paper IV) that proved to be superior in terms of match factor and probability compared to EI data gathered for trimethylsilyl derivatives. The study also focused on efforts towards achieving detailed structure information on the alkyl chains of the compounds in question using diagnostic ion interpretation.

The final paper (paper V) describes the first rapid direct derivatization method for analyzing nerve agent metabolites in urine at trace levels. The method is based on the derivative from the paper III and the unambiguous identification was proven using a combination of low resolution and high resolution negative ion chemical ionization selected ion monitoring techniques.

Novel results presented in these papers include: the first in-situ derivatization of alkylphosphonic acids on an SPE disc; the first direct derivatization of nerve agent markers in water and biomedical samples; the first high sensitivity GC-MS screening for these markers; and the first highly reproducible high-energy isomer specific CID MS/MS library. Overall, the results presented in this thesis represent significant contributions to the analysis of nerve agent degradation products.

Place, publisher, year, edition, pages
Umeå: Umeå University , 2012. , 58 p.
Keyword [en]
Nerve agents, Alkyl alkylphosphonic acids, Solid phase derivatization, Fluorinated diazomethane reagent, High-energy collision induced dissociation, CID MS/MS library
National Category
Chemical Sciences
Research subject
Analytical Chemistry
Identifiers
URN: urn:nbn:se:umu:diva-54639ISBN: 978-91-7459-440-9 (print)OAI: oai:DiVA.org:umu-54639DiVA: diva2:524691
Public defence
2012-05-25, KB3B1, KBC-huset, Umeå University, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2012-05-04 Created: 2012-05-03 Last updated: 2012-05-04Bibliographically approved
List of papers
1. Combination of solid phase extraction and in vial solid phase derivatization using a strong anion exchange disk for the determination of nerve agent markers
Open this publication in new window or tab >>Combination of solid phase extraction and in vial solid phase derivatization using a strong anion exchange disk for the determination of nerve agent markers
2009 (English)In: Journal of Chromatography A, Vol. 1216, no 48, 8452-9 p.Article in journal (Refereed) Published
Abstract [en]

Alkylphosphonic acids (APAs) are degradation products and chemical markers of organophosphorous (OP) nerve agents (chemical warfare agents). Anion exchange disk-based solid phase extraction (SPE) has been combined with in vial solid phase derivatization (SPD) and GC-MS analysis for the determination of APAs in aqueous samples. The optimization of critical method parameters, such as the SPD reaction, was achieved using statistical experimental design and multivariate data analysis. The optimized method achieved quantitative recoveries in the range from 83% to 101% (n=13, RSD from 4% to 10%). The method was sensitive, with LODs in SIM mode of 0.14ppb, and demonstrated excellent linearity with an average R(2)>/=0.99 over the concentration range of 0.07-1.4ppm in full scan mode and from 0.14ppb to 14ppb in SIM mode. For forensic applications, aqueous samples containing APAs at concentrations exceeding 14ppb were concentrated and target analytes were successfully identified by spectral library and retention index matching. Method robustness was evaluated using aqueous samples from the official OPCW Proficiency Test (round 19) and all APAs present in the sample were conclusively identified. The SPE disk retained the underivatized APAs in a stable condition for extended periods of time. No significant losses of APAs from the disk were observed over a 36-day period. Overall, the method is well suited to the qualitative and quantitative analysis of degradation markers of OP nerve agents in aqueous matrices with simplicity, a low risk of cross-contamination and trace level sensitivity.

Place, publisher, year, edition, pages
Elsevier, 2009
Keyword
Chemical warfare agents, Alkylphosphonic acids, Disk solid phase extraction, Solid phase derivatization, Anion exchange disk, Statistical experimental design
National Category
Chemical Sciences
Identifiers
urn:nbn:se:umu:diva-26845 (URN)10.1016/j.chroma.2009.10.017 (DOI)
Available from: 2009-10-28 Created: 2009-10-28 Last updated: 2012-05-04Bibliographically approved
2. Determination of S-2-(N,N-diisopropylaminoethyl)- and S-2-(N,N-diethylaminoethyl) methylphosphonothiolate, nerve agent markers, in water samples using strong anion-exchange disk extraction, in vial trimethylsilylation, and gas chromatography-mass spectrometry analysis
Open this publication in new window or tab >>Determination of S-2-(N,N-diisopropylaminoethyl)- and S-2-(N,N-diethylaminoethyl) methylphosphonothiolate, nerve agent markers, in water samples using strong anion-exchange disk extraction, in vial trimethylsilylation, and gas chromatography-mass spectrometry analysis
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2012 (English)In: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1229, 86-94 p.Article in journal (Refereed) Published
Abstract [en]

Since the establishment of the Chemical Weapons Convention in 1997, the development of analytical methods for unambiguous identification of large numbers of chemicals related to chemical warfare agents has attracted increased interest. The analytically challenging, zwitterionic S-2-(N,N-diisopropylaminoethyl) methylphosphonothiolate (EA-2192), a highly toxic degradation marker of the nerve agent VX, has been reported to resist trimethylsilylation or to result in an unacceptably high limit of detection in GC-MS analysis. In the present study, the problem is demonstrated to be associated with the presence of salt, which hinders trimethysilylation. EA-2192 was extracted from aqueous samples by use of a strong anion-exchange disk, derivatized as a trimethylsilyl derivative via in vial solid-phase trimethylsilylation and identified by GC-MS. The limits of detection were 10ng/mL and 100ng/mL (in a water sample) for SIM and SCAN mode respectively. The analytical method was found to be repeatable with relative standard deviation <10%. The performance of the method was evaluated using a proficiency test sample and environmental samples (spiked river water and Baltic Bay water) and compared with the commonly used evaporation-silylation method. The disk method displayed good tolerance to the presence of salt and the spiked EA-2192 was conclusively identified in all matrices. In addition, the applicability of the method was further demonstrated for other selected hydrolysis products of VX and Russian VX, namely S-2-(N,N-diethylaminoethyl) methylphosphonothiolate, ethyl methylphosphonic acid, methylphosphonic acid, and isobutyl methylphosphonic acid. For the synthesis of reference compounds, EA-2192 and its analog from degradation of the Russian VX isomer, the present methods were improved by using a polymer-bound base, resulting in >90% purity based on (1)H NMR. Based on the current results and earlier work on alkylphosphonic acids using the same method, we conclude that the method is a viable choice for the simultaneous determination of a wide range of degradation products of nerve agents - zwitterionic, monoacid, diacid, and monothioacid chemicals - with excellent performance.

Place, publisher, year, edition, pages
Amsterdam: Elsevier, 2012
Keyword
Chemical warfare agents, EA-2192, Silylation, Alkylphosphonic acid, Solid-phase derivatization, Anion-exchange disk
National Category
Chemical Sciences
Identifiers
urn:nbn:se:umu:diva-52430 (URN)10.1016/j.chroma.2012.01.068 (DOI)22326187 (PubMedID)
Available from: 2012-02-21 Created: 2012-02-21 Last updated: 2017-12-07Bibliographically approved
3. Direct derivatization and rapid GC-MS screening of nerve agent markers in aqueous samples
Open this publication in new window or tab >>Direct derivatization and rapid GC-MS screening of nerve agent markers in aqueous samples
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2010 (English)In: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 82, no 17, 7452-7459 p.Article in journal (Refereed) Published
Abstract [en]

A rapid screening and identification method based on derivatization and gas chromatography mass spectrometry (GC-MS) has been developed for the detection of alkylphosphonic acids (APAs), the degradation products of organophosphorus nerve agents. The novel method described involves rapid (5 min) and direct derivatization of 25 muL aqueous sample using highly fluorinated phenyldiazomethane reagents (e.g., 1-(diazomethyl)-3,5-bis(trifluoromethyl)benzene). The APA derivatives are then screened by GC-MS negative ion chemical ionization (NICI) and identified by electron ionization (EI) mode. The conditions for the derivatization were optimized using statistical experimental design and multivariate data analysis. Method robustness was evaluated using aqueous samples from an official OPCW Proficiency Test and all APAs present in the sample were conclusively identified. Limits of detection for rapid screening using SIM NICI were between 5 and 10 ng/mL APA in aqueous sample, and for identification using full scan EI 100 ng/mL.

National Category
Chemical Sciences
Identifiers
urn:nbn:se:umu:diva-35700 (URN)10.1021/ac101604n (DOI)000281306000055 ()20701266 (PubMedID)
Available from: 2010-08-31 Created: 2010-08-31 Last updated: 2017-12-12Bibliographically approved
4. An isomer-specific high-energy collision-induced dissociation MS/MS database for forensic applications: a proof-of-concept on chemical warfare agent markers
Open this publication in new window or tab >>An isomer-specific high-energy collision-induced dissociation MS/MS database for forensic applications: a proof-of-concept on chemical warfare agent markers
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2011 (English)In: Journal of Mass Spectrometry, ISSN 1076-5174, E-ISSN 1096-9888, Vol. 46, no 9, 917-924 p.Article in journal (Refereed) Published
Abstract [en]

Spectra database search has become the most popular technique for the identification of unknown chemicals, minimizing the need for authentic reference chemicals. In the present study, an isomer-specific high-energy collision-induced dissociation (CID) MS/MS spectra database of 12 isomeric O-hexyl methylphosphonic acids (degradation markers of nerve agents) was created. Phosphonate anions were produced by the electrospray ionization of phosphonic acids or negative-ion chemical ionization of their fluorinated derivatives and were analysed in a hybrid magnetic-sector–time-of-flight tandem massspectrometer. A centre-of-mass energy (Ecom) of 65eV led to an optimal sequential carbon–carbon bond breakage, which was interpreted in terms of charge remote fragmentation. The proposed mechanism is discussed in comparison with the routinely used low-energy CID MS/MS. Even-mass (odd-electron) charge remote fragmentation ion series were diagnostic of the O-alkyl chain structure and can be used to interpret unknown spectra. Together with the odd-mass ion series, they formed highly reproducible, isomer-specific spectra that gave significantly higher database matches and probability factors (by 1.5 times) than did the EI MS spectra of the trimethylsilyl derivatives of the same isomers. In addition, ionization by negative-ion chemical ionization and electrospray ionization resulted in similar spectra, which further highlights the general potential of the high-energy CID MS/MS technique.  

Place, publisher, year, edition, pages
Wiley, 2011
Keyword
HE CID, MS/MS database, nerve agents, alkylphosphonic acids, charge remote fragmentation
National Category
Chemical Sciences
Identifiers
urn:nbn:se:umu:diva-46524 (URN)10.1002/jms.1970 (DOI)
Available from: 2011-09-05 Created: 2011-09-05 Last updated: 2017-12-08Bibliographically approved
5. Direct derivatization and trace determination of nerve agent biomarkers in urine samples
Open this publication in new window or tab >>Direct derivatization and trace determination of nerve agent biomarkers in urine samples
(English)Manuscript (preprint) (Other (popular science, discussion, etc.))
Abstract [en]

A rapid direct derivatization and gas chromatography mass spectrometry (GC-MS) method has been developed for the determination of alkylphosphonic acids (APAs) in urine, which act as biomarkers of organophosphorus nerve agents. The method involves rapid (5 min) and direct derivatization of acidified urine samples (25 μL) using the highly fluorinated phenyldiazomethane reagent [1-(diazomethyl)-3,5-bis(trifluoromethyl)benzene]. The APA derivatives are then trapped on reversed-phase C18 bonded silica to remove any underivatized APAs and HCl in the sample solution. After elution, the APA derivatives are then determined by low resolution mass spectrometry using negative ion chemical ionization single ion monitoring.The selectivity of the method was further improved by using high resolution negative ion chemical ionization selected ion monitoring on a double focusing magnetic sector mass spectrometer. High sensitivity was obtained with limits of detection ranging from 0.1 to 10 ng/mL of the APAs (in urine) for both techniques. The conditions for the derivatization were optimized using statistical experimental design and multivariate data analysis. Based on the current results and earlier work on APAs in water using the direct derivatization approach, we conclude that the method offers excellent performance and is viable for the simultaneous trace determination of a wide range of nerve agent markers.

Keyword
Biomarkers, nerve agents
National Category
Chemical Sciences
Research subject
Analytical Chemistry
Identifiers
urn:nbn:se:umu:diva-54641 (URN)
Available from: 2012-05-03 Created: 2012-05-03 Last updated: 2012-05-04Bibliographically approved

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  • modern-language-association-8th-edition
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  • nn-NO
  • nn-NB
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