Method for Derivatization and Detection of Chemical Weapons

Jun 8, 2015 - Chromatographic analysis of chemical compounds related to the Chemical Weapons Convention. Zygfryd Witkiewicz , Ewa Sliwka , Slawomir Ne...
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Method for Derivatization and Detection of Chemical Weapons Convention Related Sulfur Chlorides via Electrophilic Addition with 3‑Hexyne D. Raghavender Goud, Deepak Pardasani, Ajay Kumar Purohit, Vijay Tak, and Devendra Kumar Dubey* Vertox Laboratory, Defence Research and Development Establishment, Jhansi Road, Gwalior 474002, India S Supporting Information *

ABSTRACT: Sulfur monochloride (S2Cl2) and sulfur dichloride (SCl2) are important precursors of the extremely toxic chemical warfare agent sulfur mustard and classified, respectively, into schedule 3.B.12 and 3.B.13 of the Chemical Weapons Convention (CWC). Hence, their detection and identification is of vital importance for verification of CWC. These chemicals are difficult to detect directly using chromatographic techniques as they decompose and do not elute. Until now, the use of gas chromatographic approaches to follow the derivatized sulfur chlorides is not reported in the literature. The electrophilic addition reaction of sulfur monochloride and sulfur dichloride toward 3-hexyne was explored for the development of a novel derivatization protocol, and the products were subjected to gas chromatography−mass spectrometric (GC-MS) analysis. Among various unsaturated reagents like alkenes and alkynes, symmetrical alkyne 3-hexyne was optimized to be the suitable derivatizing agent for these analytes. Acetonitrile was found to be the suitable solvent for the derivatization reaction. The sample preparation protocol for the identification of these analytes from hexane spiked with petrol matrix was also optimized. Liquid−liquid extraction followed by derivatization was employed for the identification of these analytes from petrol matrix. Under the established conditions, the detection and quantification limits are 2.6 μg/mL, 8.6 μg/mL for S2Cl2 and 2.3 μg/mL, 7.7 μg/mL for SCl2, respectively, in selected ion monitoring (SIM) mode. The calibration curve had a linear relationship with y = 0.022x − 0.331 and r2 = 0.992 for the working range of 10 to 500 μg/mL for S2Cl2 and y = 0.007x − 0.064 and r2 = 0.991 for the working range of 10 to 100 μg/mL for SCl2, respectively. The intraday RSDs were between 4.80 to 6.41%, 2.73 to 6.44% and interday RSDs were between 2.20 to 7.25% and 2.34 to 5.95% for S2Cl2 and SCl2, respectively.

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very large set of chemicals relevant to CWC.9 The convention related chemicals (CRCs) are annexed in the CWC text as Schedule 1−3 chemicals.5,6 The CRCs are categorized in three schedules on the basis of their potential use as CWAs or their precursors. Even though the threat by chemical weapons has been reduced by the implementation of the CWC, their use in conflict and in acts of terrorism is still reported.10−12 Therefore, the advancement in analytical capabilities of CRCs still is an active area of current research.13−20 An extension of verification is attribution. Chemical profiling of reaction products can be used to link CWAs to the synthetic route used to produce them or precursor chemicals. Sulfur monochloride and sulfur dichloride are, respectively, categorized into schedule 3.B.12 and 3.B.13 chemicals.5 They are the precursors of sulfur mustard, which belongs to the vesicant class of CWAs (Figure 1); however, it can also have legitimate industrial uses and can be used if declared and controlled appropriately. In the Depretz method, sulfur mustard is synthesized by treating sulfur dichloride with ethylene, whereas

evelopment of analytical methods of chemical warfare agents (CWAs) and their related chemicals has gained importance in light of verification program of Chemical Weapons Convention (CWC).1−4 Other than those permitted provisions, the CWC prohibits production, storage, and usage of CWAs.5 The Organization for the Prohibition of Chemical Weapons (OPCW), situated in The Netherlands, ensures implementation of CWC through its verification program.6 The verification process of CWC involves unequivocal detection and identification of CWAs, their precursors, and degradation products in the samples collected by the OPCW inspection team during inspections.2,7 The inspection team performs the analysis of collected samples on-site using approved equipment. In the case of any unresolved ambiguity, the samples are sent for off-site analysis to at least two “designated laboratories” selected by the OPCW.8 The OPCW designated laboratory network is an important element of the verification regime of the CWC. The OPCW has been conducting official proficiency tests (OPTs) since 1996 to designate laboratories for the analysis of authentic samples. During the OPTs conducted by the OPCW, to attain the status of designated laboratory, a laboratory must prove its analytical capability for the identification of chemicals out of a © 2015 American Chemical Society

Received: April 5, 2015 Accepted: June 8, 2015 Published: June 8, 2015 6875

DOI: 10.1021/acs.analchem.5b01283 Anal. Chem. 2015, 87, 6875−6880

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EXPERIMENTAL SECTION Chemicals. Sulfur monochloride (96%) and sulfur dichloride (94%) were synthesized as per the reported procedures.28 PCl3 (2%) was used as a stabilizer for both the chemicals. Sulfur dichloride was sealed in a glass tube under chlorine atmosphere, and both the chemicals were stored at −10 °C. At frequent intervals, the purity of both the chemicals were determined by derivatizing them with 3-hexyne and analyzing using GC-MS. HPLC grade solvents n-hexane, dichloromethane, acetone, methanol, ethyl acetate, carbon tetrachloride, and acetonitrile were obtained from E-merk (Mumbai, India) and dried before use.29 Standard stock solutions of SCl2 and S2Cl2 in hexane (1000 μg/mL) were freshly prepared before each experiment. All the reagents including 3-hexyne and chromatographic standard diphenyl sulfide (DPS) were obtained from Sigma-Aldrich (Mumbai, India). Sulfur mustard (99%) was synthesized in OPCW declared facility of DRDE as per the reported procedure.30 Petrol (gasoline with octane rating 93) was obtained from local filling station of Bharat petroleum, India and stored at 4 °C. Spiking of Organic Liquid. A stock solution (1000 μg/ mL) of spiking chemicals was prepared in hexane. Hexane (40 mL) was mixed with 1.25 mL of this solution and 150 mg of petrol; finally, it was made up to 50 mL with n-hexane to get 25 μg/mL analytes and 3000 μg/mL petrol. Extraction and Derivatization. One milliliter of spiked matrix was extracted by agitating for 10 min with 250 μL of acetonitrile. The acetonitrile layer was separated after it was kept for 5 min, and 100 μL of 3-hexyne was added. The organic matrix was further extracted with 2 × 250 μL of acetonitrile, and each extracted acetonitrile fraction was combined with acetonitrile fraction containing 3-hexyne. After the layer was kept for 20 min at room temperature, 10 μL of chromatographic standard (1000 μg/mL DPS in acetonitrile) was added to acetonitrile layer. The total volume of the sample was increased to 1 mL with acetonitrile. Extraction and derivatization protocols were run in triplicate and analyzed by GC-MS in both full scan and selected ion monitoring (SIM) modes. Retention time and ions selected to monitor the derivatized analytes are given in Table 1. To

Figure 1. Structures of convention related sulfur chlorides and sulfur mustard.

in the Levinstein process, sulfur monochloride is used as a precursor21 (Scheme 1). Hence, their detection and identification in a sample submitted for off-site analysis is very important from a verification point of view of CWC. Scheme 1. Synthesis of Sulfur Mustard from Sulfur Dichloride and Sulfur Monochloride

Among various chromatographic and spectroscopic techniques that can be employed for the analysis of CRCs, gas chromatography coupled with mass spectrometry (GC-MS) is widely employed, because it provides both characteristic spectra and molecular weight information.22−24 Recommended operating procedures (ROPs) have been developed for the gas chromatographic analysis of polar precursors/degradation products of toxic chemicals.25,26 Prior to GC-MS analysis, these compounds are converted to their respective volatile derivatives. Unlike other schedule 3.B. chemicals, conventionrelated sulfur chlorides like sulfur monochloride and sulfur dichloride cannot be detected by NMR as they do not contain NMR active nuclei. These chemicals cannot be directly analyzed by GC-MS because they tend to interact with the GC column and do not elute. However, these chemicals can be detected using FTIR,27 but may lack sufficient sensitivity for the identification of trace residues of these chemicals from sulfur mustard products and the environmental matrices. Identification of these analytes from complex mixtures is another drawback of this method. Thus, there is dire need to develop an analytical method that can detect and identify these inorganic compounds at required sensitivity for verification analysis of CWC. However, to the best of our knowledge until now no report is available for the derivatization and identification of sulfur monochloride and sulfur dichloride using GC-MS. Moreover, the designated laboratories of OPCW are supposed to maintain a quality system (e.g., ISO 17025:2005), and as per the requirement of such a system, the laboratory must put forward the analytical methods to accreditation body for chemicals that fall within its scope. These reasons emphasize the urgent need for the development of derivatization and identification methods for sulfur monochloride and sulfur dichloride. Present study deals with the development of a novel derivatization method for both sulfur monochloride and sulfur dichloride using 3-hexyne via an electrophilic addition reaction. The sample preparation protocol is also developed for extraction of target analytes from hexane spiked with petrol matrix, which has been used to mask the presence of scheduled chemicals in the proficiency tests.

Table 1. Retention Time and Ions Selected to Monitor the Derivatized Analytes

a

Qualifier ion. bQuantifier ion.

calculate the recoveries of analytes, ratios of peak areas of analytes versus chromatographic standard (in prepared samples) were compared with ratios of peak areas of analytes versus chromatographic standard of control solution. Control Solution. One milliliter of 3000 μg/mL solution of petrol in hexane was extracted by agitating for 10 min with 250 μL of acetonitrile. Acetonitrile layer was separated after keeping 6876

DOI: 10.1021/acs.analchem.5b01283 Anal. Chem. 2015, 87, 6875−6880

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Analytical Chemistry for 5 min. The hexane layer was further extracted with 2 × 250 μL of acetonitrile, and all the acetonitrile fractions were combined. Control solution (25 μg/mL) was prepared by diluting the stock solution of analytes with extracted acetonitrile fraction and derivatizing with 100 μL of 3-hexyne. Ten microliters of chromatographic standard (1000 μg/mL DPS in acetonitrile) was added, and total volume of the sample was increased to 1 mL with acetonitrile and analyzed. GC-MS Analysis. The GC-MS analyses were performed in EI mode (70 eV) on an Agilent 6890 GC system, equipped with model 5973 mass selective detector (Agilent Technologies, U.S.A.). A DB-5MS (Agilent technologies) capillary column (30 m × 0.25 mm I.D., 0.25 μm film thickness) was used as stationary phase. The flow rate of helium as carrier gas was 1.0 mL/min. The oven temperature program began at 50 °C (held for 2 min) and increased to 300 °C (held for 2 min) at a rate of 20 °C/min. The samples were analyzed in splitless mode at an injection temperature of 250 °C, EI source temperature 230 °C, and quadrupole analyzer at 150 °C. Quantitation studies were performed in the selected ion monitoring (SIM) mode.

strategy for the derivatization and identification of sulfur chlorides. Screening of Reagents. Initially, for the optimization of a derivatizing reagent, various alkenes were screened. As shown in Figure 2, symmetric, asymmetric, and dialkenes were reacted

Figure 2. Reagents screened for the derivatization of sulfur dichloride.

with sulfur dichloride in dichloromethane, and the products were analyzed using GC-MS. Among them, acrylonitrile, perchloroethene did not react with sulfur dichloride. Remaining alkenes underwent addition reaction with sulfur dichloride but resulted in the formation of mixture of diastereomers and multiple products (resulted from elimination of HCl) (Figure S1). In search of better derivatizing agent, symmetric as well as asymmetric alkynes like ethyl propiolate, 1-hexyne, and 3hexyne were screened. Among the alkynes, asymmetric alkyne 1-hexyne resulted in the formation of two diastereomeric addition products (Figure S2a), corresponding to the m/z value of molecular ion 266 at 10.06 and 10.32 min. Whereas symmetric alkyne 3-hexyne gave only a single isomeric peak with high response without formation of multiple products and diastereomers (Figure S2b) with the m/z value of molecular ion 266. Therefore, the reagent 3-hexyne was selected for further study for the derivatization of sulfur chlorides. Mass spectral patterns are displayed in Figures S3 and S4 for SCl2 and S2Cl2 derivatives. The mass to charge ratio m/z 266 and m/z 298 correspond to the molecular ions of both the derivatives of SCl2 and S2Cl2 (Scheme 3).

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RESULTS AND DISCUSSION Reagent Selection Strategy. For the development of a derivatization reaction for sulfur chlorides, possible reactions such as nucleophilic substitution and electrophilic addition were investigated. Sulfur dichloride undergoes nucleophilic substitution reaction with alcohols to give sulfoxylate esters31 (Scheme 2a). However, the main drawbacks of using Scheme 2. Nucleophilic Substitution and Electrophilic Addition Reactions of Sulfur Dichloride with Alcohols and Alkenes

Scheme 3. Reaction of Sulfur Monochloride and Sulfur Dichloride with 3-Hexyne nucleophilic substitution reaction with alcohols for the derivatization of sulfur halides are harsh reaction conditions (−75 to −95 °C), use of organic base as acid acceptor, and formation of multiple products which make the quantification difficult. In addition, no substituted products were identified by the reaction of sulfur chlorides with alcohols at room temperature. Alternative reaction for the derivatization of sulfur chlorides is electrophilic addition to the unsaturated compounds (Scheme 2b). The advantages of electrophilic addition reaction of sulfur chlorides to the unsaturated compounds over nucleophilic substitution reaction at sulfur center of sulfur chlorides include mild reaction conditions and no requirement of acid acceptor. In addition, because the reaction is an addition reaction, the products formed can be easily detected, and furthermore, the presence of isotopic peaks due to the presence of chlorine and sulfur atoms support unambiguous identification of molecular ion peak in mass spectrum. On the basis of the above considerations, we adopted electrophilic addition

Optimization of Reaction Conditions. Initially, solvents with varying polarity were screened to derivatize the sulfur chlorides. Sulfur monochloride and sulfur dichloride were taken in solvent at an arbitrary concentration of 25 μg/mL and reacted with 100 μL of 3-hexyne at room temperature for 1 h. Using DPS as chromatographic standard, the relative response (ratio of peak area of derivative to that of DPS) of derivatives of both the analytes were compared in different solvents as shown 6877

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Under the optimized reaction conditions in acetonitrile, the limit of detection (LOD), limit of quantification (LOQ) for SCl2 and S2Cl2 were found to be 0.5 μg/mL, 2.5 μg/mL and 0.75 μg/mL, 3.7 μg/mL, respectively, in SIM mode. Sample Preparation for Organic Liquid. Sulfur chlorides, being reactive toward a protic environment, are likely to be detected and identified in aprotic solvents during OPTs or in scenarios of contamination by CWAs. Therefore, an organic liquid sample is prepared by spiking the SCl2 and S2Cl2 in hexane containing a fuel like petrol. Petrol contains lower hydrocarbons as well as aromatic hydrocarbons. In addition to providing high hydrocarbon background, these aromatic compounds in petrol have the tendency to participate in electrophilic substitution reactions with strong electrophiles. SCl2 and S2Cl2 are also strong electrophiles, and therefore, extraction of these analytes from this complex matrix is studied. However, no reaction products of SCl2 and S2Cl2 with these aromatic compounds were identified (sulfur chlorides undergo electrophilic substitution reactions with aromatic compounds in the presence of Lewis acid catalysts like AlCl3 only33). Initially, for the identification of analytes, derivatizing agent 3-hexyne was added at room temperature and analyzed as such after 1 h. A weak signal corresponding to the derivative of sulfur dichloride was observed, but no signal of derivative of sulfur monochloride was observed (Figures 5a and 6a), which could

in Figure 3. It is clearly evident from Figure 3 that the reaction was prominent in a polar aprotic solvent like acetonitrile, which

Figure 3. Solvent optimization for derivatization of SCl2 and S2Cl2 using 3-hexyne. (Error bars represent standard deviation of the three results.)

could be attributed to the stabilization of episulfonium ion32 in polar solvents. Whereas nonpolar solvents like hexane and carbon tetrachloride gave less response for a derivative of sulfur monochloride, it could be due to less electrophilicity of sulfur monochloride in comparison to that of sulfur dichloride. A protic solvent like methanol is reactive toward both the analytes, and no response was obtained. In acetone, no derivatized products corresponding to either of the analytes were identified. In dichloromethane, reaction of sulfur dichloride with 3-hexyne resulted in the formation of an intricate reaction mixture that was not suitable for chromatographic analysis of the desired derivative. Hence, for further optimization of reaction conditions, acetonitrile was taken as solvent. For optimization of reaction time and temperature, reactions were carried out in acetonitrile at varying temperatures of 0−50 °C and at time intervals of 5−60 min. The electrophilic addition reaction of these analytes to 3hexyne in an aprotic polar solvent like acetonitrile is a fast reaction even at low temperatures. There is a slight increase in relative response of both the derivatives with increase in temperature, as shown in Figure 4a,b. At a temperature above

Figure 5. GC-MS total ion chromatograms of (a) n-hexane with 3000 μg/mL petrol spiked with 25 μg/mL SCl2 and S2Cl2 and derivatized with 3-hexyne; (b) derivatization with 3-hexyne followed by liquid− liquid extraction with acetonitile; (c) liquid−liquid extraction with acetonitrile followed by derivatization with 3-hexyne.

be ascribed to its poor reactivity in nonpolar hexane matrix. Efforts were made to increase the response of the derivatized analytes by sample preparation. For this, the liquid−liquid extraction with acetonitrile was selected.34 Thus, liquid−liquid extraction of spiked samples with acetonitrile was performed in two ways. First, the derivatization was performed before the extraction, and second, the derivatization was performed after extraction. Results are depicted in Figures 5 and 6. It is evident that best response for derivatives of both the analytes was observed when the derivatization was performed after extraction (Figures 5c and 6c). As the analytes reactivity was prominent in acetonitrile, this strategy was adopted which not only gave better response of both the derivatives but also

Figure 4. Reaction time and temperature optimization for derivatization reaction of 3-hexyne with (a) SCl2, (b) S2Cl2.

room temperature (25 °C), that is, at 50 °C, the relative response of sulfur monochloride derivative decreased (Figure 4b), which may be due to decomposition of sulfur monochloride at higher temperatures. On the basis of the observations shown in Figure 4, reaction conditions were optimized to be at room temperature (25 °C) for 20 min. 6878

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In addition to OPTs, the laboratories involved in forensic analysis of samples collected from a chemical weapon contamination or a plant reactor are also required to unambiguously identify the CWAs and their related chemicals. Therefore, to mimic the real field sample, sulfur chlorides (10 μg/mL each) were spiked along with sulfur mustard (100 μg/ mL) in acetonitrile, derivatized by 3-hexyne under above optimized conditions, and analyzed using GC-MS (Figure S11). Both the analytes were successfully identified, and no effect of sulfur mustard was found on derivatization reaction of sulfur chlorides with 3-hexyne. This further justifies the application of selective elcetrophilic addition strategy for the derivatization and identification of sulfur chlorides for real field applications.

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Figure 6. Optimization for extraction parameters for sulfur chlorides: Relative response of derivatives of the analytes in (a) n-hexane with 3000 μg/mL petrol; (b) derivatization with 3-hexyne followed by liquid−liquid extraction with acetonitile; (c) liquid−liquid extraction with acetonitrile followed by derivatization with 3-hexyne.

CONCLUSIONS This work represents a first and novel derivatization method for the detection of Chemical Weapons Convention related sulfur chlorides utilizing electrophilic addition reaction of 3-hexyne with sulfur monochloride as well as sulfur dichloride. Both the analytes were efficiently derivatized by the reagent 3-hexyne, and the products were subjected to gas chromatographic-mass spectrometric analysis. Single product formation, mild reaction conditions, fast reaction, unambiguous identification, and clean TIC are the major advantages of this method. EI-Mass Spectra of these derivatives were simple and showed molecular ions and isotopic peaks. The limited reactivity and identification of analytes in petrol-spiked hexane matrix can be overcome by sample preparation method extraction with acetonitrile followed by derivatization. This derivatization and sample preparation protocol can be successfully employed for the detection and identification of convention related sulfur chlorides like sulfur monochloride and sulfur dichloride during OPCW official proficiency tests as well as off-site analysis. This method can also be used to verify synthetic route used for the production of sulfur mustard. This derivatization reaction can also be used for the development of novel sample preparation protocols for the trace level identification of convention related sulfur chlorides.

reduced hydrocarbon background to a great extent. Recoveries of analytes from spiked matrices was determined by taking DPS (10 μg/mL) as chromatographic standard (see Experimental Section for details); the recoveries of both the analytes SCl2 and S2Cl2 were 31.41 ± 3.66%, 20.04 ± 2.72% respectively. To check the storage stability, these derivatives were stored in refrigerator at 4 °C. No reduction in the recovery was observed even after 3 months for both the derivatives. Verification of Method Performance. The extraction followed by derivatization protocol for the identification of SCl2 and S2Cl2 from hexane with petrol matrix showed good linearity with least-squares linear regression analysis. Calibration curves were obtained from the results of the extraction and derivatization of SCl2 and S2Cl2 from hexane with petrol background. The regression line of peak area ratios of sulfur dichloride derivative to the chromatographic standard on concentration had a linear relationship with y = 0.007x − 0.064 (r2 = 0.991) and linear range was 10 to 100 μg/mL (Figure S5). For sulfur monochloride the equation for regression line was y = 0.022x − 0.331 (r2 = 0.992), linear range was 10 to 500 μg/mL (Figure S6). For SCl2 and S2Cl2, LOD (at S/N ratio 3/1) and LOQ (at S/N ratio 10/1) were determined to be 2.3 μg/mL, 7.7 μg/mL and 2.6 μg/mL, 8.6 μg/mL, respectively, in SIM mode. The RSDs for intraday repeatability were evaluated by three spiked samples at concentrations of 10, 50, 100 μg/mL for SCl2 and 10, 100, 250 μg/mL for S2Cl2, respectively, by triplicate analysis. The RSDs for interday intermediate precision were determined by their recovery in spiked samples on three consecutive days. The intraday repeatability (Table 2) for SCl2 and S2Cl2 were between 2.73 to 6.44% and 4.80 to 6.41%, respectively. The interday precision (Table 2) for SCl2 and S2Cl2 were between 2.34 to 7.25% and 2.20 to 7.26%, respectively.

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ASSOCIATED CONTENT

S Supporting Information *

Additional content as noted in text. The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.analchem.5b01283.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: dkdubey@rediffmail.com Notes

The authors declare no competing financial interest.

Table 2. Intra and inter-day precession results for the analysis of sulfur chlorides in petrol spiked hexane samples sample no.

1 2 3

SCl2 samples

S2Cl2 samples

spiked concn (μg/mL)

repeatability (RSD %)

intermediate precision (RSD %)

spiked concn (μg/mL)

repeatability (RSD %)

intermediate precision (RSD %)

10 50 100

2.73 6.44 6.09

5.95 7.25 2.34

10 100 250

4.80 6.41 6.23

2.20 7.26 6.08

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ACKNOWLEDGMENTS We thank Dr. Lokendra Singh, Director, DRDE, Gwalior for his keen interest and encouragement.

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DOI: 10.1021/acs.analchem.5b01283 Anal. Chem. 2015, 87, 6875−6880