Analysisofchemicalwarfareagent

Automatically generated rough PDF by ProofCheck from River Valley Technologies Ltd hswr slcne ne h raieCmosAtiuinNnomrilNDrvtvs40License. Attribution-NonCommercial-NoDerivatives 4.0 Commons Creative the under licensed is work This Valdez A. Carlos (HD, (vesi- sulfur mustard agents ( as blistering HN2 such the and includes gasses also CWAs mustard of the family by the typified addition, cants) In (GB, 2012). Becker, sarin & (Coughlin as V-series the such agents nerve (VX, (OP)-based (OPCW) phonothioate Weapons organophosphorus Chemical lethal of Prohibition and the that (GD, acting compounds for toxic Organization fast of the repertoire the by broad materials include The erad- 1 2005). to Schedule Szinicz, military as 2010; the designated by (Ganesan, used are threat been a have incapacitate that compounds fully chemical or on toxic icate The based highly 1994). of undeniably Munro, number 2008; is al., a substances et describes CWA (Chauhan toxic destruction term these mass modern and way by power destructive the infused unparalleled for altered fear potential radically collective their have worldwide (CWAs) The agents conducted. warfare chemical is warfare that doubt no exists there Nowadays, Introduction Received: DOI: Lawrence the at Center Science Forensic Keywords: the the as in intact lab arepre- importance species our the much Laboratory.of these from National in examples as Livermore some detection carry methods highlighting derivatization CWA their degradation the available each with their for analysis, dealing ofsented forensic from reports arising field the of products with in discussions themselves as begins agents with section Furthermore, Each along and GC-MS. CWA agents. classes by CWA incapacitating the main form the of lastly, the and of introduction agents three brief blistering on a concentrates the review agents, The nerve products. the detection degradation available includes direct methods their their derivatization of on sample analysis introduction various the broad the for a and with (GC-MS) reader spectrometry chromatography-mass the effi- gas provide their by to on seeks chemistry analytical focused review modern have following by The efforts detection their methods. These and development. their countermeasures mitigate medical their of to with development methods destruction, par cient counter on ability, and CWAsalong immediately destruction warfare modern mass almost modern more their way appeared then, to the impact Since Owing shaped violently WarI. conducted. and are emerged World relations have diplomatic manufacture until breakthrough their realized full for their not methods but was efficient Ages conflicts Middle with the bellic as in back players far central as traced mankind. as by be produced can substances warfare toxic conventional feared in most inception the Their of one unarguably are (CWAs) agents warfare Chemical 1 products degradation their of analysis the for approaches derivatization and detection direct their for methods spectrometry: chromatography-mass gas by agents warfare chemical of Analysis Valdez A. Carlos GRUYTER DE Abstract: hscladLf cecsDrcoae arneLvroeNtoa aoaoy iemr,C 45,UA ula and Nuclear USA; 94550, CA Livermore, Laboratory, National Livermore Lawrence Directorate, Sciences Life and Physical e,Lwec iemr ainlLbrtr,Lvroe A950 S,Emi:[email protected] E-mail: USA, 94550, Cen- CA Science Livermore, Laboratory, Forensic National and Livermore USA; Lawrence ter, 94550, CA Livermore, Laboratory, National Livermore Lawrence Division, Sciences Chemical 10.1515/revac-2017-0007 2 ,ccoai (GF, cyclosarin ), pi ,2017; 1, April 21 adze l,pbihdb eGruyter. De by published al., et Valdez ©2018 hmclwraeaet,fnay,Lwst,nreaet,slu mustard sulfur agents, nerve Lewisite, fentanyl, agents, warfare chemical 8 ] iia otemsad,aohrcmol mlydsto eiat r h arsenic-containing the are vesicants of set employed commonly another mustards, the to Similar )]. stecrepnigauthor. corresponding the is 1 ol .Leif N. Roald / 4 n ( and ) Accepted: 3 eogn oteGsre n ( and G-series the to belonging ) S )-2-(diethylamino)ethyl a 1 2017 31, May 1 ahnHok Saphon / 1 rde .Hart R. Bradley / O iouy ehlhshntiae(VR, methylphosphonothioate -isobutyl S )-2-(diisopropylamino)ethyl 6 n h irgnbsdmsad H1( [HN1 mustards nitrogen-based the and ) 1 eiw nAayia hmsr.21;20170007 2018; Chemistry. 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As to toxic scenarios. at of chosen these samples) employment are soil of concentrations the markers and involving These range. (water direct scenarios matrices represent case various tests that real into proficiency products recreate spiked lines, to degradation these aimed examinations, Along are these 2012). al. OCPW During et the (Mayer by theirfull reasons from provided forensics (PTs) acids produced chemical for the phosphonic of important when Insuchcases, instance, is form. For identification by-products. hydrolysis correct found and the degraded but detection of analysis agents, its intact systematic nerve a in with by it dealing agent the find detect not indirectly may to first necessary attack where is agent instances it presumed exist a However, there of 2005). scene 2004; al. the et to Smith responders 2002; gas chromatography-mass al., deployable et a field [e.g. (Hook unit] means (GC-MS) spectrometry analytical it byvarious analyze subsequently and fiber) 1: Figure of subject the where who products (2003), degradation Muir their and to Black by addition review in detail. CWAs the in over of discussed (Coughlin look available is detection to derivatization are the encouraged them is covering for reviews reader methods excellent the describe as addition, here In discussed 2012). be Becker, not & will these agents, blood and ( fentanyl agents system-acting 13 nervous central the by ( epitomized agents I Lewisite as such Lewisites ehlitaoaie(EDEA, -ethyldiethanolamine n ezlcai (BA, acid benzilic and ) choking the as such exist space CWA the within classes other Although 2012). Becker, & (Coughlin 1) (Figure ) eeto fCA nteritc omhsrle ntcnlge hteetvl rpteaaye(..i a in (e.g. analyte the trap effectively that technologies on relied has form intact their in CWAs of Detection adze al. et Valdez ito hmclwraeaetcassdsusdi hsrve n hi structures. their and review this in discussed classes agent warfare chemical of List 2 htdgae ntal oishl se iaoy ehlhshncai ( acid methylphosphonic pinacolyl ester half its to initially degrades that ) 17 n t ihroiainsaetidgyo ufxd (TDGO, sulfoxide thiodiglycol state oxidation higher its and ) 21 Fgr 2D). (Figure ) 9 ,I ( II ), 19 .Lsl,i h rsneo naaiaigaet sssetd w divergent two suspected, is agents incapacitating of presence the if Lastly, ). 10 n I ( III and ) 11 .Lsl,tevs eetieas otisteincapacitating the contains also repertoire vast the Lastly, ). 15 n iaoy loo (PA, alcohol pinacolyl and ) 12 n -unciiy ezlt (BZ, benzilate 3-quinuclidinyl and ) 7 edn otepouto of production the to leading ) 14 18 13 hti unundergoes turn in that ) ilb eylikely very a be will ) ,acmon known compound a ), 6 ,dtcinof detection ), 16 EGRUYTER DE – (Figure ) 0ppm 10 Automatically generated rough PDF by ProofCheck from River Valley Technologies Ltd htd o eyo asseta nlss,tebodaet ilntb oee nti review. this in covered systems be detection not orother will agents spectroscopy blood the fluorescence UV, analysis), spectral (e.g. mass means studies. on other various rely GC-MS by the not for analysis discuss do suitable will and that species we degradation size that these their sub-sections make to of to these their analysis Due analyst in on the the work is with to published It deal available GC-MS. with that methods by sub-sections along derivatization analysis feature given and will is class products CWA class degradation each each their addition, begin incapac- for We In the introduction GC-MS. 1. with brief by Figure concluding detection a in and direct section, agents presented CWAs each blistering the the In by of agents. has followed GC-MS review itating agents, following by nerve The analysis OP-based for. the the searching introducing is with by he/she dealing what mixture, sections beforehand given know in a to in organized analyst impurities) been the (including analytes reac- for the highly vital all employ it modify reactions making purposes, derivatization thus practical all all for general, will, In that agents. agents acylating tive other or anhydride acetic ploying (TMO tetrafluoroborate trimethyloxonium or trimethylsilyldiazomethane zomethane, deriva- employing employed silylation, commonly most are the or For chem- chemistry of volatility. to some analytical non-existent order Among in to volatility. in analysis low suitable their tizations with with to entities prior species performed into for be them blind must convert virtually species ically these is of GC-MS reactions derivatization that reason, One is this technique. ones the How- of important nature laboratories. most the chemistry to the analytical inherent drawbacks of most with in comes GC-MS system with analysis experienced oper- benchtop simplicity low-cost the ubiquitous ever, a a and abil- systems it the deployable offers making for GC-MS adaptability system hand, preparation, ation other minimal the with On analysis cost. sample mainly operation rapid field high of the and ity in portability employment yet-to-be-attained wide its for of modifica- marginalized result chemical heavily a prior is as their approach without the of product of glimpse degradation comprehensive practicality their a the However, with with along tion. chemist mixture analytical a analytes most in other the interest with provides two of along LC-MS analytes analyzed Indeed, the the and form. detected intact constitute directly their be in unarguably can CWA interest the of GC-MS LC-MS, of and case the (LC-MS) In ones. prominent spectrometry chromatography-mass liquid ucts, CWAs. the original of identification the in markers forensic 2: Figure GRUYTER DE N mn nltclmtosta aebe eeoe o W nlssaogwt hi erdto prod- degradation their with along analysis CWA for developed been have that methods analytical Among -methyl- yrlsspout o eetdCA n hi tutrs hs rdcscnb sdrtopcieyas retrospectively used be can products These structures. their and CWAs selected for products Hydrolysis N -(trimethylsilyl)trifluoroacetamide (MSTFA), alkylation in the form of methylation using dia- of methylation the form in alkylation (MSTFA), -(trimethylsilyl)trifluoroacetamide N , O bstiehliy)rfuraeaie(BSTFA) -bis(trimethylsilyl)trifluoroacetamide . BF 4 ,adayainem- acylation and ), adze al. et Valdez 3 Automatically generated rough PDF by ProofCheck from River Valley Technologies Ltd 4 type ofCWAs. of level key higher a lethal play a will particularly methylation attains this of agent and products silylation intact degradation of identification its form the retrospective of the the cases analysis in in has some an primarily role that reactions that in derivatization However, instances technique, end, these units. analytical this in To the GC-MS is importance. of portable it miniaturization of and the found development be with noteworthy the never conjunction is for it in path quality, Thus, acids. the this V-series phosphonic forged is polar- the the of it for namely degree that same products, 300°C the hydrolysis mention displays of exhibit main to not VX point their do while boiling they as G-series, a nature, hydrophilicity in with the and hydrophobic for GC-MS ity extent some by (239°C) to detectability GF and keeping polar and Although still for (198°C) agents. values while GD range value temperature (158°C), the higher GB within much as fall a that such points analysis boiling GC-MS their typical is property a such One means. GC-MS by oximetreat- sis via conventional beregenerated that cannot (Path- enzyme residue adducted serine the modified of a aging to however, leading step); ment. (Adduction possibility agent a the also to is exposure B) way after accomplished be can A) way 3: Figure 2004). (Bajgar, individual affected the this of if demise However, ( the AChE enzyme. in aged this results as and of known accomplished is levels be what normal cannot becoming reactivation the hydrolysis, then restoring partial a residue referred undergoes serine commonly intermediate enzyme, adducted adducted inhibited this the of ( of oximolysis) AChE Treatment (i.e. ACh. adducted of the breakdown AChE as the of to in phosphonylation a nucleophile the to ( efficient agent is due producing an event nerve ACh death as eventually inhibitory the of by and this buildup residue paralysis of a serine muscle step site in in critical results The results that 2004). AChE (Bajgar, junctions of asphyxiation synaptic Inhibition at body. blockade the reversible process slowly in vital is the contraction/relaxation restoring enzyme thereby This muscle (ACh) 2005). acetylcholine of neurotransmitter McDonough, key & the Kan down Shih, breaking structurally 1990; for Though al., responsible agents. et nerve (Friboulet (AChE) OP-based acetylcholinesterase the enzyme are the individual realm their this 1), of (Figure members different feared most the CWAs, the Within agents Nerve ev gnsehbtpyia rprista aete utbecniae o ietdtcinadanaly- and detection direct for candidates suitable them make that properties physical exhibit agents Nerve adze al. et Valdez rpsdmcaimo cinfrteihbto fAh ynreaet.Nra eeeaino CE(Path- AChE of regeneration Normal agents. nerve by AChE of inhibition the for action of mechanism Proposed 23 iue3,wt ihyncepii xm nioe eut ntebreakdown the in results antidotes oxime nucleophilic highly with 3), Figure , oioperandi modi 22 iue3.Oc hsmdfcto ae lc,tesrn antact cannot theserine place, takes modification this Once 3). Figure , hr iia hrceitcta novsteihbto of inhibition the involves that characteristic similar a share 24 EGRUYTER DE iue3), Figure , ’ active s Automatically generated rough PDF by ProofCheck from River Valley Technologies Ltd ihyratv pce htrqie t rs rprto eoeuei neiin n ihyedn deriva- high-yielding and efficient is an Diazomethane if itself. use reagent before the preparation of fresh its nature requires the that in species lies reactive actually analysis. highly final methodology a the this in by-products derivatiza- in interfering the of drawback which An absence the at the However, interest. and conditions temperature) yielding mild of ambient the thus (normally analytes method namely place excess, silylated This silylation, takes to tion diazomethane. in other relative reagent, attributions or obscure known superior may universally neat) two the from that (i.e. enjoys employing chromatograph medium methylation GC is reaction silylation the a to in as alternative employed signal often interfering large is a itself reagent the (typically Lastly, necessary 2007). is in tized. 1 Caruso, improvement heating usually for & for protocol, silylation 80°C) room (Richardson and the exists GC-ICPMS 65 during there between example using technique, For pg practicality. derivatization and 5 reliable execution and than overall simple its and less water a detection theoptimal in is detection of silylation their determining After limit though for (GA). applied Even reported was tabun a method the with ACN), agent in samples nerve the min soil of agents. 45 for nerve (80°C hydrolysis silylation G-series pass their and for first V- conditions the to from related product acids main silylat- seven the same of the derivatization CWAs, included efficient to acids related the These acids in phosphonic employed involving was report agent relevant ing more a to attention 0.1 our Turning of acetoni- range with co-evaporation the copious after in samples, (ACN), water trile in detected was ethephon to approach, bis- demonstrated this Using was its STFA. silyla- Ethephon to the conversion acid). by (2-chloroethylphosphonic smooth highlighted ethephon a as regulator undergo efficient hormone and rapid plant is the acids of the tion of derivatization the the employing times, Often by BSTFA. employing general, In deriva- analysis. initial for their their N requirement means, to GC-MS modified necessary been by have a acids species phosphonic is these technique, silylation methylation of or detection silylation important direct yielding nature of using thus the lack presence tization into past the insight their to key for testament a Due provides provides information. CWAs and it of forensic in context present the agents within nerve potential mixture the a of in ( species MPA namely these product, of ultimate Detection common, 2012). a to leads conditions oxidative or are basic agents (Compounds nerve esters OP-based half the of acid hydrolysis) phosphonic oxidative the (and hydrolysis the from products degradation main The acids Phosphonic Joseph by book assembled superbly analy- the CWA read for to others, encouraged by 2011). and is analysis al. GC-MS reader subsequent et by the (Kroening and methods, Caruso products, analytical modifications degradation on high- their their and review for and extensive nature, sis applied their and and excellent been collected species an have a the For in that to GC-MS. found methods introduction when concise derivatization purposes a degradation forensic the with various for light experienced sections markers the have key the introduce agents organized as will have nerve serve we We from below that sample. arising sections agents nerve the products in from of Thus, arising detection attention. products the of at level aimed important equally methods an that surprise expensive no of is it decontamination agents when nerve use of their degradation needed. the limits is in materials nature sensitive result oxidative or emerged methods their equipment these by-products, also Though non-toxic have 1993). yield agents al., and nerve et of (Yang Oxone as peroxide) destruction such hydrogen ultimately oxidants the (e.g. to of employment for manner the regioselective methods include the a these Oxidative highlights and VX in products. of proceeds non-toxic hydrolysis that basic only process the a furnish for decontamination of distribution a production product developing the observed for in The importance only 1999). Yang, not 1993; result when al., conditions However, to et basic agents. (Yang 12) VX) G-series above earliest (e.g. the values the V-series ( hydrolyze pH of the product rapidly non-toxic with One to and (typically 1992). belonging efficiently Ward, media agents & conditions alcoholic with Baker These or dealing Yang, agent. aqueous 2011; the basic, al., highly of et of Kim dispose 2013; use and Rebek, safely the & to includes with technologies (Ajami explored methods on results been focused have of has approaches range agents decontamination wide agent nerve nerve of a several mitigation end, global this To the them. in destroy areas efficiently thrust main the of One -( tert ihtevreyo ehd o h yrlssi diint hi aua erdto nteenvironment, the in degradation natural their to addition in hydrolysis the for methods of variety the With -butyldimethylsilyl)- ∼ 7)bti lorslsi h rdcino A29 ( EA-2192 of production the in results also it but 77%) 14 , 15 N , 25 mtytilooctmd MBTA n otertiehliy TS ethers (TMS) trimethylsilyl totheir and (MTBSTFA) -methyltrifluoroacetamide – – gl ng 1 28 – nadto otesdu ato ty yrgndimethylaminophosphate, hydrogen ethyl of salt sodium the to addition in nodrt nueta o ocnrto nlt saeutl deriva- adequately is analyte concentration low a that ensure to order in h 2 − 1 tert iharpre ii fqatfcto f01ngl 0.1 of quantification of limit reported a with btliehliy te hnhae t4° o nna MTB- neat in h 1 for 45°C at heated when ether -butyldimethylsilyl 4 25 14, – 28 iue4.Frhrhdoyi fteeetr ihrunder either esters these of hydrolysis Further 4). Figure , ® (2KHSO tert btliehliy TDS tesusing ethers (TBDMS) -butyldimethylsilyl 5 ·KHSO ∼ 2)wihi tefi stxca VX as toxic as is itself in which 22%) 4 ·K 15 2 nFgr )(izgtie al. et (Bizzigotti 4) Figure in SO 4 ,bec n peroxides and bleach ), − 1 Ryre l,2006). al., et (Royer adze al. et Valdez 5 Automatically generated rough PDF by ProofCheck from River Valley Technologies Ltd 6 (Figure bicarbonate sodium aqueous with is out conve- carried that is acid mixture tetrafluoroboric the 5). and of salt trimethyloxonium proceeds ether neutralization the likely dimethyl of when volatile methylation groups removed highly methyl the niently the the for of product, mechanism one methylated to The oxygen the acid in. generating phosphonic participated the of laboratory attack our nucleophilic via that Test OPCW C various 38th of the 10 composed a 2016) at matrix & Alcaraz, spiked complex when methylation a Leif acids their (Valdez, in phosphonic for GC-MS workin applied of by was when panel identification method a this unambiguous Interestingly, very recently, of 5). their TMO methylation (Figure until by clean of followed and agents use dormant efficient nerve effective, the remained to the related then, chemistry for various of analytical use Since of its 1998). demonstrated detection Woll, field group qualitative & our the Gessele and realm in the (Liebich, derivatization agent in methylating samples the use a urine experienced in in salts employed these present were that acids they 1998 carboxylic until when not chemistry was it analytical However, Burrow sub- 1937). Diem, of and (Jo al., alkylating acids synthesis et carboxylic as their Meerwein including salts 1977; described groups Fry, oxonium functional who & various of group of Meerwein use alkylation the the The in of literature. applications work the sequent pioneering in the re-appearance by a introduced was make slowly agents to started have 5) Figure ( acid methylphosphonic and 4: Figure & (Crenshaw time of use trimethylsilyldiazomethane the this as at 2011). Kemsley, that such 2004; into preparation Cummings, methylations community the toconduct scientific the Furthermore, alternatives pressured have 2012). other that Wahl, finding hazards explosive & possesses lifetime, Harvey endeavor its recurring 2012; a extend al., constitutes to et refrigeration Ghassabian and 2011; 4 atmosphere Mallard, after inert that an recommended under is storage it careful Despite desired. is tization oti n,rprsivligtemtyaino hshncaisepoigtesal atTMO salt stable the employing acids phosphonic of methylation the involving reports end, this To adze al. et Valdez erdto ahaso ev gnslaigt h omto fhgl igotchl hshncai esters acid phosphonic half diagnostic highly of formation the to leading agents nerve of pathways Degradation 15 ). – as e ac fdaoehn hudb rprd(mhir,Plt& Palit (Amphaisri, prepared be should diazomethane of batch new a days, 5 16 – C 18 at cdmty sesfaue nogncsmlsduring samples organic in featured esters methyl acid fatty μ g g − 1 concentration EGRUYTER DE . BF . BF 4 4 ( 31 as , Automatically generated rough PDF by ProofCheck from River Valley Technologies Ltd ehltn gnshv endvlpd sa lentv odaoehn,orgopepoe TMO employed other 4°C, group at our and diazomethane, atmosphere to inert an alternative under an explosive stored potentially As when ( the developed. even to life been Due shelf have short 2003). agents Ley, its methylating & and Yamanoi taurospon- preparation of Hollowood, its synthesis 2002; of total Yamanoi, their nature & to route Ley en (Hollowood, group A Ley usedtoefficiently the gin be by can demonstrated elegantly as 2005). acids diazomethane (Kuitunen, chemical these using acid Methylations derivatize this this GC-MS. report by for to identification methylation and failed than detection labs rather subsequent 19 silylation of on when relying out fractions of 6 silylated result that the a found in as was found report it not end, their was in the it In reaction, employed. methylation were MSTFA the dismiss and underwent BSTFA rapidly that PT, to OPCW sample not water 12th careful the the be in in must example, For one found. species, ( not these acid is of sulfonic product made silylated presence not the the have may if silylation for results presence as reaction powerful those their screening as However, but simplicity. initial tool, expected an derivatization their as enjoy for main been be perhaps conditions likely the literature has as the the acids silylation in as 2-aminoethylsulfonic appearance BSTFA using of their basis as asso- analysis routine well the acids detection a as 2-aminoethylsulfonic that MTBSTFA in for believed of employing performed is h silylation accomplished it 1 fashion, be Indeed similarity. similar after can unparalleled a occurred VR an in had and derivative that VX silylated expect with the can ciated to one ( conversion Therefore, acids enough GC-MS. sulfonic However by the h. of of 24 conditions mixture The for 70°C) excess 1990). an mmol) (at Hupé, of temperature presence & L-cysteic heating the (Ng lower again in derivatives and a TBDMS once involve their 2-aminoethylsulfonic and silylation provide to acid to the MSTFA relationship 2-amino-5-chlorotoluenesulfonic for employing structural of time has in silylation treatment this close where but the are report acid describes one that only report species exists This acid there sulfonic acids. report, degrada- derivatize early the to to this led from acids used cysteic Aside been and that derivatives. taurine found silylated the authors involving the The h) 2 1978). of to Helland, tion (up & mixtures (Stokke with reaction GC-MS silylated the by efficiently of analyzed were heating subsequently that prolonged and acid h L-cysteic 1 and for of taurine 110°C One as at acids. BSTFA such 2-aminoethylsulfonic acids to applied sulfonic involved similarly em- reports be reactions earliest can derivatization acids the sulfonic the plain that common, expected more highly the for is ployed it Nevertheless, acids. 2-aminoethylsulfonic acid analysis. of sulfonic GC-MS analysis nature successful the crystalline a of their out derivatization ACN, to carry or to due chloride order and methylene in agents, as mandated nerve such is V-type solvents group these organic in of solubility presence poor latent and the at hints strongly mixture low ( feature acid both they are as degradation counterparts oxidative phosphorus-based undergo their environment of electrophilic and oxidative that toward to VX an reactivity p comparable agents in be acid in to nerve Sulfonic present also expected the acids. is when but 2-aminoethylsulfonic reagents of process, that corresponding hydrolysis overall species their oxidative the 2-aminoethanethiol into example, in conversion the For present hydrogen water yields products. or the initially these bleach of VR of as virtue oxidation such by oxidants subsequent hydrolysis various their the by in caused results agents initially nerve peroxide OP-based of degradation oxidative The acids Sulfonic GC-MS. by detection for amenable now is that ester methyl a yields derivatization ent 5: Figure GRUYTER DE 31 K a ntemtyainof methylation the in ) ned ehlto a ena diinl eibewyo eiaiigsloi cd fti idfrtheir for kind this of acids sulfonic derivatizing of way reliable additional, an been has methylation Indeed, the on reports of number scarce a are there exist, acids sulfonic of analysis GC-MS for methods Although aus(sal ntevcnt f2 of vicinity the in (usually values 30 htoiiaefo h gnsV n R epciey( respectively VR, and VX agents the from originate that ) rpsdmcaimfrtemtyaino iaoy ehlhshncai ( acid methylphosphonic pinacolyl of methylation the for mechanism Proposed 30 asdmjrpolm osvrlpriiaiglbrtre.Atog twsdtce easily detected was it Although laboratories. participating several to problems major caused ) N,N N,N diorplmnehlsloi cd( acid sulfonic -diisopropylaminoethyl diorplmnehlsloi cd( acid sulfonic -diisopropylaminoethyl – ) w ftems motn ufncaisaiigfo ev agent nerve from arising acids sulfonic important most the of Two 3). tert btliehliy hoie( chloride -butyldimethylsilyl iesupra vide 29 29 and ) and ) iue4.Terpeec nagiven a in presence Their 4). Figure , ∼ .5mo)adMBTA( MTBSTFA and mmol) 0.15 N,N N,N 14 yTMO by ) dehlmnehlsulfonic -diethylaminoethyl dehlmnehlsulfonic -diethylaminoethyl N,N ∼ .1 ml nACN in mmol) 0.015 . -diethylaminoethyl BF 4 adze al. et Valdez ( 31 .Teexpedi- The ). ∼ . BF 0.5 7 4 Automatically generated rough PDF by ProofCheck from River Valley Technologies Ltd M)i mlydt euetetm o h eiaiainadbcueprin fteNIaenee to needed are NMI the and of (PDMSCl portions reagents because both 8 and of derivatization excess the process, appear for the may time in it reactivator the though catalytic Even reduce activation. a to chloride employed of silyl role is of the NMI) round plays another solely for NMI NMI that the regenerates Kiessling, process & the (Marlow in ( galactofuranose PA for between activator diphosphate reaction suitable uridine a the of as Thus, NMI 2001). synthesis (Corey introduced their and pyridine) group Kiessling during (i.e. TBDMSCl the monophosphate report, uridine recent usedcondition more a widely In the most 1972). 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Due interfering PAhas when several compound. specifically recognized, 2 is well means Schedule GC-MS a field by as this OPCW in by importance its labeled As been information. forensics chemical important providing ( GD (3,3-dimethyl-2-butanol, PA (3,3-dimethyl-2-butanol) alcohol Pinacolyl methylation. fact the the undergo is still methodology they this DCM, of in feature soluble important not An are temperature. acids ambient sulfonic at the and if h) even (<1 that rapid is esters methyl their to 6: Figure (Phelam, analogs acid-bearing 2-aminosulfonic similar derivatization structurally the of 2014). in methylation Ellman, solely safer & use Patel and its mild for the exist in reports fully no although agent, methylating effective of an as used be ( derivatizations can acid phosphonic discussing section the in instrument (TMO of chloride itself methylation ( matrix methylene efficient products the in the of soluble insoluble), exception virtually were the are with esters, reaction, acids methyl the acid in fatty components the of of composed none Although 6). (Figure 2016) caraz, ( acid 29 N 2 and 30 .Ispeec nagvnsml inl h rvoso aetpeec fti ev gn nadto to addition in agent nerve this of presence latent or previous the signals sample given a in presence Its ). mtyiiaoe(NMI, -methylimidazole adze al. et Valdez nmtyeeclrd ofrihsloi cdmty esters methyl acid sulfonic furnish to chloride methylene in ) ehlto of Methylation 30 32 ’ nenlNS aaae oei-et icsino hsueu ehltn atcnb found be can salt methylating useful this on discussion in-depth more A database. NIST internal s o usqetG-Saayi.Nvrhls,tiehliydaoehn a enue success- used been has trimethylsilyldiazomethane Nevertheless, analysis. GC-MS subsequent for and 33 fteetoipratVsre gn akr eedtce yG-Sadvrfe ythe by verified and GC-MS by detected were markers agent V-series important two these of ) N,N nsitu in sbtttdaioty ufncaisuigTMO using acids sulfonic aminoethyl -substituted 16 ,i diint P ( MPA to addition in ), ciain Fgr ) h ocp a nrdcdb h oe ru akin back group Corey the by introduced was concept The 7). (Figure activation) 35 Ab ta.21) h ecino Awt DSli h rsneo NMI of presence the in PDMSCl with PA of reaction The 2014). al. et (Albo ) 16 n hsitreit ilstepeydmtyslltdP ( PA phenyldimethylsilylated the yields intermediate this and ) ∼ – sncsayt ffc h opeedrvtzto.Ti may This derivatization. complete the effect to necessary is h 3 )o ai odtos(pH conditions basic or 4) 14 tert ,i h te ao yrlsspouto h ev agent nerve the of product hydrolysis major other the is ), btliehliyaino eea loosta show that alcohols several of -butyldimethylsilylation 29 ieinfra vide and 30 .Atraiey trimethylsilyldiazomethane Alternatively, ). a edl copihd h methylated The accomplished. readily was 32 and . BF ∼ 1 4 – nmtyeeclrd.Teconversion The chloride. methylene in

33 > 5 36

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(Figure time reaction the extending after improvement yield product little with p lower the in was moieties in reactivity heterocycle observed benzimidazole the and for imidazole explanation alco- the Their thio-containing by HD. homologous the other to and trifluoroacety- TDG related superior of closely be derivatization to hols the found running were TFABI when TFABT and TFAI than work, agents their of lating During 9E). reactivity (Figure the 2004) al. compare et (Pardasani to additional designed an of As set (TFABT, toproduce 9D). oroacetylbenzotriazole than a TFAI (Figure better performed including 2014) agents magnitude laboratories trifluoroacetylating al., Vertox ml of different et from ng three orders (Popiel group employed 0.01 two to is chemistry is BSTFA) down paper the (with value note, their silylation LOD in when the obtained described reported one studies authors the additional the to methodology, compared this when Using which 30°C). at h imidazole (1 (TFAI, conditions trifluoroacetyl (2014) employed etal. to it example convert another TDG, Popiel yet to In 9C). into (Figure introduction 1988) tag Read, & fluorine involving (Black GC-MS values ionization chemical LOD ion negative low using extremely analysis report, early another ana- In (PFBC, immediately (SIM). ml and ng monitoring acetate 1 ethyl ion After to 9B). in selected (down further (Figure re-suspended to using 1990) sieves dried, al., EI-GC-MS et molecular was by (Jakubowski Å sample h lyzed 5 the 1 of completed, for after presence 60°C was samples to the derivatization urine mixture in the rat the acetate, heating in ethyl and present water, dry residual TDG in any HFBA of scavenge with derivatization of reaction the derivatization and to removal report applied water early successfully an was in method Thus, The developed. scribed. (HFBA,earlier, been anhydride noted have heptafluorobutyl briefly duetothe electron-capturing TDG with As into TDG analyte samples. reporters aqueous chemical the ( in powerful fordetecting atom product these fluorine HD thesensitivity ml the this ng of increases 100 of aids ability and analysis tags 7 the fluorinated be of for to use reported found method The the were h. viable 1 urine, for a and 60°C of it serum at heating limit matrices, making by followed impressive remaining (1:1) two ACN an with the featured co-solvent for a also LOD of form that the method in TBDMSCl) the after 1% for (with urine ml material and ng derivatized 5.4 serum of the water, (LOD) detection of in recovery detection 55% its a by reported demonstrated ( ( as MTBSTFA TDG derivatization with is conversion HD prior its of its hydrolysis requires basic complete, GC-MS the by from arising product main The Thiodiglycol hydrolysis. idative 8: Figure ( HD employed commonly most the a on derivatizations focus their will making products. section thus following degradation compounds, The its of analysis. kinds their these in for step typical necessary is peaks the of broadening however, adze al. et Valdez 47 oeo lyainb h ufrmsad sonfrH)adtermi erdto rdcsfo hi ox- their from products degradation main their and HD) for (shown mustards sulfur the by alkylation of Mode nprdn tabettmeauefr5mnt uns loiae D derivative TDG fluorinated furnish to min 5 for temperature ambient at pyridine in ) 51 bis − tilooctltdTG( TDG -trifluoroacetylated ( 1 ∼ p)i rn ape eedslsdb ecigTGwt etfurbnolchloride pentafluorobenzoyl with TDG reacting by disclosed were samples urine in ppb) 1 , .) h ecinwsfudt rce mohya min eprtr n ut5min, 5 just and temperature ambient at smoothly proceed to found was reaction The 8.3). − iesupra vide 1 o h ae ape h ehdivle h ramn fTGwt MTBSTFA with TDG of treatment the involves method The sample. water the for 43 51 to ) n hi hnnwydvlpdtilooctlezmdzl (TFABI, trifluoroacetylbenzimidazole developed newly then their and ) bis .Tu,i sntsrrsn htdrvtzto ehd htintroduce that methods derivatization that surprising not is it Thus, ). - tert 50 btliehliyae D ( TDG -butyldimethylsilylated .Terato a are u nmtyeeclrd ne mild under chloride methylene in out carried was reaction The ). 45 49 opoiethe provide to ) and 52 ( ∼ .)rltv oteoeehbtdb h triazole the by exhibited one the to relative 7.0) bis 50 hpaloouy eiaie( derivative -heptafluorobutyl h he gnswr FI( TFAI were agents three The . 44 Fgr A.Osw ta.(2004) al. et Ohsawa 9A). (Figure ) 17 Fgr ) eeto fTDG of Detection 8). 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(Figure 2007) Black, & Read (Riches, 18 .I hsrpr,tepooo novstehaigo h re apecnann h TDGO the containing sample dried the of heating the involves protocol the report, this In ). .Det h iiaiyntol nsrcuebtratvt swl oTG ti o surprising not is it TDG, to well as reactivity but structure in only not similarity the to Due ). bis hpaloouyyae DO( TDGO -heptafluorobutyrylated 55 .Terato a on opoedi ubro rai solvents organic of number a in proceed to found was reaction The ). 49 okdecpinlywl ncnetn it converting in well exceptionally worked ) 53 a sdadaaye nuiesamples urine in analyzed and used was ) ∼ i t3°)o DOto TDGO of 30°C) at min 1 53 usqetdetection Subsequent . adze al. et Valdez – E). 11 55 Automatically generated rough PDF by ProofCheck from River Valley Technologies Ltd 12 use. their involving attention scenario the real-case a of in bulk species the encountered received likely have most fortheintact that their the oxidative) is are and it or readouts water, these volatility (basic including as their hydrolysis nucleophiles and sensitive of various from towards result arising reactivity accurate direct products high however, can provide a degradation their possible; of that is result is detection a form of detectors as Interestingly, intact ease nitrogen agents. Their their specific HD. in with the species equipped than these GC 2-aminoethyl attention of or less analysis ethanolamines received and have as known detection these products GC-MS alcohol-containing 11). their Degradation (Figure hydrolysis. oxidative to alcohols and leads basic been mustards namely have CWAs, nitrogen mustards most such and nitrogen the HD as at of the aimed and for undertaken approaches character ones Decontamination electrophilic the nucleophiles. to highly of similar displays range intermediate large This a ion. with reacts aziridinium (S similar to isvery displacement an sequential of action the involves intermediacy of that which mode agents the HD, alkylating the Their powerful by agents. are displayed crosslinking They one non-specific vesicants. the as powerful acting by are damage mustards DNA nitrogen severe cause the family, HD the as Just mustards Nitrogen 10: Figure theimidazole- when unlikely is highly are employed. that TFAI as pathway a such acid), agents trifluoroacetylating trifluoroacetic based (i.e. acid generated the of presence adze al. et Valdez eiaiaino DO( TDGO of Derivatization 18 ihfurn-ern asfrisaayi byGC-MS. its analysis for tags fluorine-bearing with ) N -ie fterclrn tm via atoms chlorine their of 2-like) EGRUYTER DE Automatically generated rough PDF by ProofCheck from River Valley Technologies Ltd in h opsto fmnto-rd eiie swl sLwst tnad yteie nalaboratory a in synthesized standards Lewisite purifica- as for well distillations as fractional Lewisites of munition-grade rounds several of of Jones, composition 1949a; use Woodward, the & the Rosser chlo- tion, despite Jones, (III) 1959; Thus, antimony (Jarman, 1949b). chloride, media Woodward, HCl (II) in & aqueous mercury Vallender in gas chloride, these acetylene of aluminum with combination as reacts the such or trichloride catalysts ride, arsenic chloride when metal results of that presence mixture the organoarsenical the describe to used most The class. agent one ( ( least blistering I at the Lewisite to to are bonded belong class lently also this nitrogen/HD of like members common that CWAs arsenic-based are Lewisites Lewisites the in 2005). centers al., nucleophilic et sodium most Cacciapaglia (e.g. 1994; the al., conditions are et basic groups (Corda hydroxyl groups under the amine strongly other that over conducted assuring even are molecule thus GC-MS. these iodide), by methyl detection but subsequent and exists the and hydride converts volatility alcohols not ultimately its amino of that handicapping derivatization center severely of nitrogen the when thus Methylation to tertiary salt it leading nucleophilic quaternary against highly excess works a of large the into inherently introduction in also molecule that used the but electrophilicity is groups for of hydroxyl Diazomethane reagent the degree substrates. employed only high of most class its the this is is with it dealing analytes, diazomethane into As moiety practice. methyl widespread the a been not has The 2014a). Hart, ( PA & of Leif silylation (Valdez, the involving PDMSCl laboratory the our and activate temperature from to (ambient conditions base same nucleophilic the involves powerful protocol a as pyridine over products silylated NMI furnish to respectively, VR, alcohols and of derivatization efficient the ( in mustards utilized nitrogen was in- the alcohols to 2-aminoethyl linked of ones panel silylat- the a well-established cluding of the silylation the with efficient with to The conditions alcohols NMI. mild procedure and 2-aminoethyl phenyldimethylchlorosilane under several alternate employing accomplished of an be derivatization As can that moiety derivatization. found phenyldimethylsilyl conducted their laboratory the was ACN our out in above, BSTFA carry mentioned of to methods presence ml min ing the ng in 30 2.5 alcohols for the of 60°C of values heating at Similarly, LOD 2011). reported Alp, was with & treatment (Kenar samples to acidic MDEA urine evaporation same rat to This prior in ( step. mixture EDEA analysis derivatization derivatizing aqueous GC-MS when the the group during to Alp alcohols the HCl by the employed of subsequently of addition recovery the the that suggest increases Seto dryness and Ohsawa that 7% note low highest to the the in be lying to serum found were from recoveries samples for water and 79% for the 60°C for and recovery to 88% sample residue The 88%, the MTBSTFA. ml of excess at of heating ng presence the 10 by the followed and in mixture silylate h 2.5 aqueous 1 the to 2.5, of at used drying complete be was the MTBSTFA involved to reaction example, found sample For water needed. the is in silylation, via example for alcohols analytes, these the of in task tization important an remains sample given species. a toxic in these species of these study detecting overall why clear becomes it CWAs, tioned complete the ( from originating alcohol products the ( in VX present be of to hydrolysis found be can functionality ( alcohol EDEA 2-aminoethyl are the HN3 and HN2 HN1, mustards nitrogen the N of hydrolysis the from arising alcohols 2-aminoethyl ( (HN1 mustards nitrogen the of ( hydrolysis HN3 the from arising products degradation various the Of alcohols) (2-aminoethyl Ethanolamines GC-MS. by analysis their for used strategies silylation undertaken the and agents V-series the of hydrolysis basic or tive 11: Figure GRUYTER DE 11 mtydehnlmn (MDEA, -methyldiethanolamine ,altresbttet nteasncae2clrvnluis neetnl,tetr eiiei commonly is Lewisite term the Interestingly, units. 2-chlorovinyl are arsenic the on substituents three all ), ehlto samaueo omltn utbedrvtvso -mnehlachl o CM analysis GC-MS for alcohols 2-aminoethyl of derivatives suitable formulating of measure a as Methylation deriva- initial the cases these in and reported well is means GC-MS by products hydrolysis these of Detection 56 ) h nsbaigte2aioty loo ucinlt tn u stems rmnn ns The ones. prominent most the as out stand functionality alcohol 2-aminoethyl the bearing ones the )), 60 19 -mnehlachlcnann rdcsaiigfo h yrlsso h irgnmsad n h oxida- the and mustards nitrogen the of hydrolysis the from arising products alcohol-containing 2-Aminoethyl Fgr 1.Cneunl,atrraiaino hsln ewe hs rdcst h aforemen- the to products these between link this of realization after Consequently, 11). 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Figure , 58 h okdmntae h datg fusing of advantage the demonstrated work The . htaeteoiaiehdoyi rdcso VX of products hydrolysis oxidative the are that ,rsetvl Fgr 1.As simportantly, as Also 11). (Figure respectively ), ∼ 11 0mn steoedsrbdi ale work earlier in described one the as min) 30 ,alfauiga rei II etrcova- center (III) arsenic an featuring all ), 19 n DA( MDEA and ) − 1 59 o DAad16n ml ng 1.6 and EDEA for and ) 57 nsitu in ,uigBTA o their for BSTFA, using ), N,N -diethylaminoethyl ciainmethod activation adze al. et Valdez 7 ,H2( HN2 ), – 8 − 100% and ) 1 57 for 13 ), Automatically generated rough PDF by ProofCheck from River Valley Technologies Ltd 14 (BCVAOA, product dimer oxidation arsenic its while produce derivatization, to after reaction condensation (BCVAOA, a acid chlorovinylarsonic via process degradation the 67 in participates oxi- further of which order higher ( a II exhibiting Lewisite counterpart Similarly, their contrast, In GC-MS. (e.g. by dation analysis their to prior derivatization (CVAOA, acid chlorovinylarsonic (CVAO, oxide 2-chlorovinylarsonous ( I Lewisite oxides their and acids arsinic Arsonous, (Black derivatizations higher for At need derivatization. the without without 2010). GC-MS GC-MS Filipescu, by by & analyzed analyzed Grigoriu be directly Epure, also 2003; be Muir, can can & II it and why I reason Lewisites the concentrations, is which ( to III media, direct unreactive Lewisite ous species and to Interestingly, a non-electrophilic intact inability concentrations. is is the the low center of that to in arsenic quantitation themselves its leading present irreproducible samples problem are the major the in these resulting a when of analysis particularly represents corrosiveness deterioration their This the and during moisture. by responses acidity complicated to linear aided further the sensitivity achieve is instrument high to form the their due intact in of the phases adducts consequence in stationary unwanted detection GC their form Lastly, conditions the to possess port. under which GC react of compounds thiols the may of matter center, these heat that arsenic of the for their instability by or for alcohols, the affinity of to presence unmatched due the an difficult Furthermore, extremely exists. moisture is minimal GC-MS where by form intact the of consists generally Ppe akwk,21)(iue1) si h aeo eiieI CA ( BCVAA I, Lewisite of case the in As 12). 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(Figure 1987) al., et (Stotter yields good in 103 Lee l,20)(iue1) neetnl,it Interestingly, 19). (Figure 2008) al., et (Lee ) nsitu in eiaiaino h nlt when analyte the of derivatization p tllscaae(PTI, -tolylisocyanate 106 hti amenable is that ) 101 adze al. et Valdez Fgr 19). (Figure 105 .The ). 21 Automatically generated rough PDF by ProofCheck from River Valley Technologies Ltd 22 chemical of acids scheduled of silylation subsequent and methylation assisted Thermally (2011). G. Mallard, & M. Palit, K., Amphaisri, determi- fentanyl for development method HPLC-UV (2011). K. Nakashima, & K. R. Hanajiri, N., Kuroda, M., Wada, R., Ikeda, A., phenyldimethylchlorosilane A. with Almoussa, alcohol pinacolyl of Derivatization (2014). C. Koester, & A. H. Mulcahy, N., R. Leif, A., C. Valdez, F., L. R. Albo, agents. nerve of destruction and detection for approaches Chemical (2013). J. Rebek, & D. Ajami, References National Livermore Lawrence by Energy of DE-AC52-07NA27344. Department Contract US the under of Laboratory auspices the under performed was work This shallnotbe Funding and LLC, National Security, Livermore orLawrence purposes. necessarily endorsement US not government product do the or herein advertising of Lawrence expressed for or used authors con- government those the necessarily States of reflect United opinions not or and the does state views by otherwise The favoring LLC. or or commercial Security, recommendation National manufacturer specific Livermore any trademark, endorsement, to its name, or herein imply trade Reference or disclosed, by rights. stitute process service owned or privately or product infringe process apparatus, not product, would information, use any responsibility its or of liability that usefulness legal represent any or assume completeness or accuracy, implied, the or expressed nor for warranty, LLC, any Security, make National employees Livermore United their Lawrence the of nor of any government agency States an United by sponsored the work Neither of government. account States an as prepared was (LLNL-JRNL-727114) document This Acknowledgments are techniques milder derivatization and rapid materials. more toxic chemist these as analytical newer, of the into this expansion anal- non-toxic way GC produce overall their that the is experiencing making with also interfere but not field interest do of The that analyte extraction) ysis. or the evaporation development for (via the by-products efficient removable demanded only of easily has not and identification transition are qualitative passed,CWAanal- This that rapid, products. protocols yearshave the degradation derivatization As toward associated of analysis their quantitative and chemistry. the species in analytical toxic from these transition position silylation a established like experienced their to methods has Derivatization ysis mostly due nature. are field CWAs early the polar positive from enormous in highly an impact arising made or certainly respectively, products salt-like diazomethane, and degradation BSTFA their employing methylation, as anal- to and important GC-MS due research particularly routine parallel GC-MS is for the ascene by vital research in to imperceptible are resulted of that has area responders protocols fact This first derivatization this of the overall well-established or yses. of improve combatants Recognition or by suspected. discover one facet tool highly to is analytical efforts CWAs preferred only of represents the presence this become the the to field, where Despite technique the transition. the in unit of portability its field-deployable on growth are GC-MS effort to CWAs achieving focused of benchtop toward analysis concerted, much-needed advances quantitative the its and great behind qualitative and reasons the swift nature for a the inexpensive in technique of relatively detect mainstream form Some can a the that entities. as tools in and derivatization toxic analytical GC-MS technique develop highly consolidating to the sample preparation these need of urgent manner miniaturization an moreefficient efficient is the new, there and history, in of in advances revitaliza- ever great than strong the development More of a and methods. result experienced a has units as products field-deployable decades degradation of two their past and the CWAs in of tion means GC-MS by analysis The Conclusions epncneto o nst nlssadiscmaio ihteohrmtoso methylation. of methods other the with 972 comparison its and analysis on-site for convention weapon rats. Sciences Life to and administration i.p. Biomedical after the behavior in Technologies pharmacokinetic elucidate B,Analytical to application its and plasma rat in nation spectrometry. chromatography-mass gas by detection enhanced for 3936 – adze al. et Valdez – 980. 3942. ’ olo rvdn i/e ihapecocsfrteanalysis the for choices ample with him/her providing toolbox s 7,2941 879, , – 2944. nltcladBonltclChemistry Bioanalytical and Analytical rai imlclrChemistry Biomolecular & Organic ora fCrmtgah A Chromatography of Journal 0,5231 406, , ora fChromatography. of Journal – 5234. EGRUYTER DE 11, , 1218, , Automatically generated rough PDF by ProofCheck from River Valley Technologies Ltd re,T .&Wt,P .M (2007). outcome. M. postoperative P. G. Wuts, in & analgesia W. T. and Green, anesthesia epidural of role The (2000). A. J. Grass, route. epidural/intrathecal analgesic: postoperative as use clinical Fentanyl: (1992b). A. J. 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