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Efficient Extraction of Sulfur and Nitrogen Mustards from Nonpolar Matrix and an Investigation on Their Sorption Behavior on Silica Kanchan Sinha Roy, D. Raghavender Goud, Buddhadeb Chandra, and Devendra K. Dubey Anal. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.analchem.8b02157 • Publication Date (Web): 16 Jun 2018 Downloaded from http://pubs.acs.org on June 16, 2018
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Analytical Chemistry
Efficient Extraction of Sulfur and Nitrogen Mustards from Nonpolar Matrix and an Investigation on Their Sorption Behavior on Silica Kanchan Sinha Roy, D. Raghavender Goud, Buddhadeb Chandra, Devendra Kumar Dubey* VERTOX Laboratory, Defence Research and Development Establishment Jhansi Road, Gwalior-474002, Madhya Pradesh, India ABSTRACT: Extraction of vesicant class of chemical warfare agents (CWAs) such as sulfur mustard and nitrogen mustards from the environmental matrices is of prime importance; from forensic & verification view point of the Chemical Weapons Convention (CWC). For extraction of Convention Related Compounds from nonpolar organic medium, commercially available silica cartridges are used extensively. But silica cartridges exhibit limited efficiency towards vesicant classes of compounds. It is expected that sulfur mustard being nonpolar do not retain sufficiently on silica surface and nitrogen mustards (being basic) are strongly adsorbed on acidic silica surface, resulting in their poor recoveries. Contrary to expected higher recovery of sulfur mustard over nitrogen mustards, it was observed that the recovery of sulfur mustard was lower than that of nitrogen mustards with silica based sorbent. The reason for this typical behavior of these agents on silica was investigated. This study was aimed to develop an analytical method for efficient extraction and enrichment of sulfur & nitrogen mustards from hydrophobic matrices. In this work, polymeric sorbent was synthesized with polar methacrylic acid (MAA) as monomer and ethylene glycol dimethacrylate (EGDMA) as crosslinker and used for solid phase extraction (SPE) of sulfur mustard and nitrogen mustards. The extraction efficiency of the polymeric sorbent was optimized and compared with that of silica cartridges. Both classes of analytes were recovered in good amounts from the polymeric sorbent compared to silica. The extraction parameters were optimized for the proposed method which included extraction solvent ethyl acetate and washing solvent 1 mL n-hexane. The recoveries of the analytes ranged from 75-87 % with relative standard deviations (RSDs) lower than 9 %. The limit of detection (LOD) was found to be in the range of 0.075-0.150 µg mL-1 and limit of quantification (LOQ) was > 0.25 µg mL-1. Linear dynamic range of optimized method was found to be 0.50 – 20 µg mL-1 (r2 = 0.9994) for sulfur mustard and 0.25 – 20 µg mL-1 (r2 = 0.9897–0.9987) for nitrogen mustards respectively.
Sulfur mustard1,2 (SM) and nitrogen mustards2,3 (NMs) are the vesicant class of chemical warfare agents4 (CWAs), also known as blister agents. Exposure to sulfur mustard can seriously damage the eyes and respiratory system 5. They are also strong alkylating agents, reacts promptly with various free nucleophilic site present in the biological medium and show mutagenic, carcinogenic and cytotoxic effects6. In 1997, an international treaty known as Chemical Weapon Convention (CWC) came into force to prohibit the development, production, stockpiling, transfer and use of chemical warfare agents 7,8. The Organization for Prohibition of Chemical Weapons (OPCW) located in The Hague, The Netherlands, is responsible for implementation of the multilateral treaty through its strict verification regime 9. Despite the CWC, nonstate actors can use CWAs due to their ease of manufacture and stockpiling. Although there is no known evidence of the use of nitrogen mustards in combat but their deployment has been seriously considered. Nitrogen mustards were rehabilitated and have been captive used in pharmaceutical industries for the treatment of malignant lymphoma and leukaemia 10. The acidic salt of NMs are stable and highly toxic, can be easily prepared and their precursors are easily available. Therefore, it can be potentially misused by non-state actors to poison, sabotage or contaminate various environmental sources and food. In the context of verification of the CWC and the forensic analysis, unambiguous detection and identification of these agents’ in complex samples are of
utmost important. Organic matrices can be used as solvent during synthesis or used as vehicle to spread of the CWAs. Analysis of organic samples from different sources like engine oil, machine fuel, silicon oil, vacuum pump oil, synthetic waste or incineration waste are also essential to identify undeclared facility prohibited by CWC. However, it is very complex and challenging task because most of the organic samples generally contain high hydrocarbon background. Gas chromatography coupled to mass spectrometry (GC-MS) is the most reliable and primary analytical technique used for retrospective detection and identification of CWAs 11,12. Direct analysis of contaminated organic samples leads to false negative results and create difficulties in identification because analyte peaks are masked by the co-eluting background peaks 13 . Therefore, extraction and sample clean-up are essential before analysis. Extraction is an important aid, used mostly to enrich the analytes in presence of complex matrices. Extraction and isolation of vesicant class of CWAs like SM and NMs from the nonpolar environmental matrices is challenging, because these agents are lipophilic in nature and have an inclination towards the nonpolar environmental matrices. Various methods like liquid–liquid extraction (LLE), solid-phase micro extraction (SPME), liquid-phase micro extraction (LPME), and solid-phase extraction (SPE) are reported for the extraction of sulfur mustard and nitrogen mustards from polar
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Analytical Chemistry environmental matrix like water14-16. However, very few reports are available for extraction of SM from nonpolar matrix 17,18. In most of the studies, nitogen mustards were not consider to be primary substrate, perhaps due to their nonweaponization. Many sample preparation methods developed for extraction of SM are assumed to be applicable for NMs, which leaves ambiguity in application of that method for extraction of NMs. According to Recommended Operating Procedures 18,19 (ROP), solid phase extraction using silica cartridges and acetonitrile extraction are most common method used for the extraction of CWAs from organic samples in presence of high nonpolar background 17,20. Moreover, solvent exchange method with acetonitrile extraction requires further clean up of the hydrocarbon background using nhexane, and the reported recovery for SM was low due to low partitioning of nonpolar SM into polar acetonitrile 17. There is no discussion on the extraction of NMs using ACN extract in ROP. ROP recommends use of silica as sorbent, and methanol and ethyl acetate as elution solvent for polar and nonpolar analyes respectively18. But polar protic methanol is not suitable solvent for extraction of mustards due to its nucleophilic nature. In addition, it is also mentioned in ROP that SM does not get efficiently retained on silica cartridge18,19. Further silica exhibits limited extraction efficiency for NMs as they are strongly adsorbed on the acidic surface of silica due to the basic nature of nitrogen atom21,22. Therefore, based on these observations18,19,21,22, we expected that relative recovery of sulfur mustard might be higher than that of nitrogen mustards. But on experimentation, we observed that silica gave relatively good recoveries of nitrogen mustards than that of the sulfur mustard i.e., SM was found to be adsorbed on silica and NMs were extractable. At lower concentration (below 5 µg mL-1) recovery of SM was negligible. This primary observation prompted us to investigate the phenomenon in depth and led to develop a new SPE methodology for efficient extraction of both types of mustard from organic matrix. Thus, this study was aimed to develop an analytical method to overcome the difficulties associated with the silica SPE cartridges for extraction and enrichment of both SM & NMs (Figure 1) from hydrophobic environmental matrices. Development of a better sorbent was desirable to efficiently extract the mustards. Currently, polymeric sorbents have received great attention towards SPE due to their stability and manipulability with various functional characteristics 23. Polymeric adsorbents are more rugged and they have excellent mechanical stress as well as stable in wider pH range than most silica-based materials do. To answer this problem, we contemplated synthesis of polymeric sorbent with moderately polar surface to serve the purpose. A copolymer composed of methacrylic acid (MAA) and ethylene glycol dimethacrylate (EGDMA) is widely used in liquid chromatography24, HN1
SM
100
80 60 40 20 0
CEES
capillary electrochromatography 25 (CEC) and SPE 26. The poly(MAA–co–EGDMA) material is a kind of polymeric sorbent that holds the polar carboxylic acid groups in suspended form over the hydrophobic backbone structure. Therefore, this kind of material would have ideal balance in surface polarity which is optimum for extraction of nonpolar SM and basic NMs from highly nonpolar organic background. In this work, Poly-(MAA-co-EGDMA) was developed using MAA as a functional monomer and EGDMA as a crosslinker. The polymer so developed was used as SPE sorbent to study the recovery of SM and NMs from highly nonpolar organic matrix.
Figure1: Structures of SM, its reactive intermediate, simulants, hydrolysis product, NMs and its reactive intermediate.
RESULT AND DISCUSSION: Sorption behaviour of SM and NMs on silica cartridges: Generally, nitrogenious componds are strongly adsorbed on the acidic silica surface. So, it is expected that silica will show restriction to extraction of NMs compare to SM. Therefore, to check the adsorption and desorption behaviour of the SM and NMs on the silica surface at low concentration (below 5 µg mL-1), silica SPE cartridge was tested at a spiked concentration of 3µg mL-1 of each analytes in n-hexane using ethyl acetate as the eluting solvent. Interestingly, on experimentation, we observed that, recovery of SM was found to be lower from silica in comparison to those of NMs as shown in Figure 2. In order to understand the reasons of this observation, same investigation was extended with the simulants 2-chloroethyl ethyl sulfide (CEES), 2-chloroethyl phenyl sulfide (CEPS) and hydrolysed product thiodiglycol (TDG) of SM (Figure 1). The results depicted in Figure 3 show that the recoveries of simulants of SM (i.e. CEES and CEPS) were also low like that of SM. The hydrolysed product TDG acted differently (~80% recovery). The recoveries of analytes shown in Figure 3 indicate that SM and its simulants (CEES, CEPS) have high retentivity towards the silica than hydrolysed product TDG. This behaviour could be attributed to the reactivity of sulfur mustards towards silica arising from
CEPS
SM
TDG
80 60 40 20
HN1
SM
Figure 2: Recovery (%) of SM and NMs in ethyl acetate from silica surface.
HN2
HN1
SM
80 60 40 20 0
0 HN2
100
Recovery (%)
HN2
Recovery (%)
100
Recovery (%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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Effluent
Washing
Elution
Figure 3: Recovery (%) of SM and its simulants and hydrolysed product from silica in ethyl acetate
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DCM
CHCl3
EtOAc Acetone
Figure 4: Recoveries (%) of SM and NMs from silica cartridges with different elution solvents.
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formation of epi-sulfonium ion intermediate via intramolecular SN2 mediated knockout of chlorine as nucleofuge (shown in electronic supporting information: ESI Scheme-S1). However, similar mechanism does not take place with TDG.
recover NMs by disrupting the H-bonds. Results enumerated in Figure 4 further illustrate the fact, because the recoveries of NMs from silica were relatively inferior with acetone than those obtained with EtOAc as acetone has less H-bond accepting properties than EtOAc.
The recovery of the SM and their simulants were found to have direct correlation with the ease of formation of episulfonium ion intermidiate which in turn is responsible for their reactivity. Among sulfur mustard (SM) and its simulants (CEES, CEPS), SM is more reactive due to two reactive sites and comparatively less non-polar. Therefore, SM was retained maximum on silica surface. Amounts of CEPS found in effluent as well as in washing were higher than others due to its high non-polar nature (Figure 3). On the other hand, in elution, recovery of CEES was considerably higher than SM and CEPS, due to the stability of its corresponding episulfonium ion intermediate compare to the epi-sulfonium ion intermediates of CEPS and SM (Scheme S1). SM already has two electron withdrawing chlorine for reactive epi-sulfonium ion intermediate formation. In the case of CEPS electron withdrawing phenyl ring enhanced the reactivity of its episulfonium ion intermediate. Further no other compounds were observed related to degradation, elimination or hydrolysis of SM or its simulants, proposed that the rest of percentage of all analytes were permanently adsorbed on the silica surface (chemisorption) (Scheme 2). However, TDG effectively came out in elution indicating its physisorption on silica surface. Excitingly, NMs were recovered easily with ethyl acetate from silica surface as shown in Figure 2. This was conceived that NMs may physisorb on silica surface either through protonation of basic ‘N’ atom or through H-bond formation between NMs and silica surface as shown in Scheme-1. Therefore, lone pair of electrons were not available on ‘N’ atom of NMs to form reactive aziridinium ion intermediate by intramolecular SN2 nucleophilic attack on the carbon of C—Cl bond through anchimeric assistance, hence formation of aziridinium ion intermediate (shown in ESI Scheme S2) was also prevented which in turn prevent the chemisorption.
Alternate polymeric sorbent for efficient extraction of NMs and SM and NMs : Limited applicability of silica sorbent prompted us to look for alternative material that can extract both the kind of mustards from organic sample. Polymeric sorbent composed of MAA and EGDMA, was synthesized. (See in supporting information). The presence of polar -COOH groups over the hydrophobic backbone provides an optimum balance in surface polarity that favor the partition of SM and NMs over the nonpolar background. Therefore, this polymeric sorbent was used for extraction of SM and NMs. Optimization of elution solvent and its volume: To find the best recoveries of SM and NMs from polymeric sorbent, various solvents (dichloromethane, chloroform, acetone, and ethyl acetate) were empolyed, considering not only their eluting ability, but also the chromatographic profile. Results depicted in Figure 5 showed that all extracting solvents were able to recover both types of mustard from polymer surface. These observations indicate that both SM and NMs were physisorb on the polymer surface, mainly through the hydrophobic interaction with the hydrophobic backbone of polymer. In addition, weak dipolar interaction and H-bonding between the analytes and –COOH groups of polymer are also likely to play a role (ESI Scheme S3). However, ethyl acetate was selected as eluting solvent owing to its higher elution capability than others and better chromatographic profile in nonpolar GC column. Extraction with 1 mL ethyl acetate, used in two portion of 0.5 mL each (2 × 0.5 mL), was sufficient to recover 75-87 % of analytes from the polymeric surface.
Scheme 1: Physisorption of NMs on silica surface (a) through protonation of basic ‘N’ atom and (b) through H-bonding between NMs and silica surface.
(a)
Cl Cl
R
+ 2 NR
Cl Cl
-
Cl Basic Nature Acidic Nature
(b)
Cl
- NH
Cl
2 Cl
R N
N Cl
N
Cl
To investigate the sorption mechanism of SM and NMs in depth, different solvents were employed for elution of SM and NMs from silica surface. Results depicted in Figure 4 show that none of the solvents was able to extract the SM from silica, which further support the chemisorption of SM on silica surface via. intermolecular SN2 mechanism as shown in Scheme-2. It is important to note that recoveries of NMs from silica were almost zero with DCM and CHCl3 because of the protonation or H-bonding of basic ‘N’ atom of NMs (Scheme1). Only with EtOAc and acetone, the recoveries were good enough. These observations are suggestive of the formation of H-bond between NMs with ‘–OH’ group present on silica surface over the protonation of basic ‘N’ atom of NMs. DCM and CHCl3 were unable to break the H-bond whereas EtOAc and acetone, owing to their H-bond acceptor property, could
Scheme 2: Chemisorption mechanism of SM on silica surface. R
S S
H-bondingCl Cl
NH R
S
HN2
HN1
SM
80 60 40 20 0 DCM
CHCl3
EtOAc
Acetone
Figure 5: Recovery of SM and NMs from poly(MAA-co-EGDMA) SPE sorbent in different solvents.
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Cl
Cl
R
100
Recovery (%)
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Analytical Chemistry
Cl
Analytical Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
Background elimination: A highly hydrocarbon background such as diesel fuel has been commonly encountered in organic matrix. Identification of analytes is very difficult in the presence of such complex hydrocarbon background, as they can mask the analyte peaks in the chromatogram of GC-MS analysis. (Figure 6a). That is why, the choice of the washing solvent and its volume must be optimized in such a way that it causes minimum loss of the desired analytes with maximum elimination of the background. In the solid phase extraction, hydrocarbon background also get adsorbed on the hydrophobic backbone of poly-(MAA-co-EGDMA) sorbent due to hydrophobic interactions along with the analytes of interest. Hence, nhexane was considered as washing solvent to eliminate such hydrocarbon background due to its affinity towards hydrocarbon. It is quite evident from the results depicted in Figure 6b that 1 mL of n-hexane efficiently washed out the hydrocarbon background without losing SM and NMs. Further increase in the amount of n-hexane to 2 and 3 mL, caused analytes loss with no further appreciable removal of background. Hence, 1 mL n-hexane was prefered for washing .
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concentration levels of analytes. The method was found to be linear in the concentration range of 0.25-20.0 µg mL-1 for both types of mustard with correlation coefficients (r2) between 0.9887–0.9994 as shown in Table-1. The LODs and LOQs for selected mustards (SM & NMs) were determined based on signal to noise (S:N) ratio of 3:1 and 10:1 respectively and illustrate in Table-1. Observed LODs of each mustards were re-evaluated by analysis of the identical spiked concentration in n-hexane. It was also observed that S:N ratio in LOD of each mustard was greater than 3. The intraday/inter-day precision and accuracy were determined by relative standard deviation (RSD) for selected analytes at three quantification levels in triplicate for three consecutive days for three weeks. The intraday precision and the corresponding interday mean precision for selected mustards were found in the range of 1.49–5.60% and 2.64–8.21% respectively.
CONCLUSION: To the best of our knowledge this is the first study on sorption behaviour of SM and NMs on silica surface. Detailed investigation proposed that SM was strongly adsorbed on silica surface though chemisorption, where NMs undergoes physisorption through H-bonding. As a result, desorption of NMs is easy but SM is not efficient from silica surface. This result is contrary to our general expectation. Therefore, poly(MAA-co-EGDMA) was employed as an alternative SPE sorbent for efficient extraction of SM and NMs from highly nonpolar samples. This study has overcome the difficulties associated with silica for extraction of SM and NMs from hydrocarbon backgrounds. The results of the study indicate that this method can be successfully empolyed during the offsite analysis of CWAs for the extraction of SM and NMs.
ASSOCIATED CONTENT Supporting Information: Experimental Section: All detailed and experimental methods are presented in the electronic supporting information.
AUTHOR INFORMATION Corresponding Author * E-mail:
[email protected] Fax: (+) 0751-2341148
Author Contributions The manuscript was written through contributions of all authors.
Notes The authors declare no competing financial interest. Figure 6: Total ion chromatogram obtained from GC-EI-MS analyses of (a) spiked SM and NMs in n-hexane matrix containing diesel background (b) after solid phase extraction with poly-(MAA-co-EGDMA) sorbent (expanded Y scale).
Sensitivity and Method Validation: Limits of detection (LODs), limits of quantification (LOQs) and linearity range were determined under the optimized SPE conditions. Calibration curves were established with different
ACKNOWLEDGMENT Kanchan Sinha Roy is thankful to DRDE, Gwalior and DRDO, New Delhi for funding and fellowship. We are thankful to Dr. Meehir Palit for his scientific inputs. This article is assigned the DRDE accession no. DRDE/VTX/010/2018.
Table-1: Analytical figures of merit for SM and NMs under the optimized SPE conditions Analytes
Linearity Range (µg mL-1)
HN1 HN2 HN3 SM
0.30-20 0.40-20
Coefficient of determination (r2) 0.9987 0.9897
Intraday repeatability (RSD %) 1.49 1.69
Inter-day reproducibility (RSD %) 2.64 6.41
LOD in SIM (µg mL-1) 0.100 0.125
LOQ in SIM (µg mL-1) 0.30 0.40
0.25-20 0.50-20
0.9950 0.9994
2.32 5.60
8.21 7.31
0.075 0.150
0.25 0.50
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Analytical Chemistry
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