Ion-molecule reactions of O,S-dimethyl methylphosphonothioate: evidence for intramolecular sulfur oxidation during VX perhydrolysis.

Abstract

The alkaline perhydrolysis of the nerve agent O-ethyl S-[2-(diisopropylamino)ethyl] methylphosphonothioate (VX) was investigated by studying the ion-molecule reactions of HOO(-) with O,S-dimethyl methylphosphonothioate in a modified linear ion-trap mass spectrometer. In addition to simple proton transfer, two other abundant product ions are observed at m/z 125 and 109 corresponding to the S-methyl methylphosphonothioate and methyl methylphosphonate anions, respectively. The structure of these product ions is demonstrated by a combination of collision-induced dissociation and isotope-labeling experiments that also provide evidence for their formation by nucleophilic reaction pathways, namely, (i) S(N)2 at carbon to yield the S-methyl methylphosphonothioate anion and (ii) nucleophilic addition at phosphorus affording a reactive pentavalent intermediate that readily undergoes internal sulfur oxidation and concomitant elimination of CH(3)SOH to yield the methyl methylphosphonate anion. Consistent with previous solution phase observations of VX perhydrolysis, the toxic P-O cleavage product is not observed in this VX model system and theoretical calculations identify P-O cleavage to be energetically uncompetitive. Conversely, intramolecular sulfur oxidation is calculated to be extremely exothermic and kinetically accessible explaining its competitiveness with the facile gas phase proton transfer process. Elimination of a sulfur moiety deactivates the nerve agent VX and thus the intramolecular sulfur oxidation process reported here is also able to explain the selective perhydrolysis of the nerve agent to relatively nontoxic products.

Full text

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University of Wollongong
Research Online
Faculty of Science - Papers Faculty of Science
2009
Ion-Molecule Reactions of O,S-Dimethyl
Methylphosphonothioate: Evidence for
Intramolecular Sulfur Oxidation during VX
Perhydrolysis
J. Williams
Martin Paine
University of Wollongong, mrlp93@uow.edu.au
Stephen J. Blanksby
University of Wollongong, blanksby@uow.edu.au
Michael L. Rogers
Defence Sci & Technology Org
Andrew M. McAnoy
Research Online is the open access institutional repository for the
University of Wollongong. For further information contact Manager
Repository Services: morgan@uow.edu.au.
Recommended Citation
Williams, J.; Paine, Martin; Blanksby, Stephen J.; Rogers, Michael L.; and McAnoy, Andrew M.: Ion-Molecule Reactions of O,S-
Dimethyl Methylphosphonothioate: Evidence for Intramolecular Sulfur Oxidation during VX Perhydrolysis 2009, 9319-9327.
http://ro.uow.edu.au/scipapers/281

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Ion-Molecule Reactions of O,S-Dimethyl Methylphosphonothioate:
Evidence for Intramolecular Sulfur Oxidation during VX Perhydrolysis
Abstract
The alkaline perhydrolysis of the nerve agent O-ethyl S-[2-(diisopropylamino)ethyl]
methylphosphonothioate (VX) was investigated by studying the ion-molecule reactions of HOO- with O,S-
dimethyl methylphosphonothioate in a modified linear ion-trap mass spectrometer. In addition to simple
proton transfer, two other abundant product ions are observed at m/z 125 and 109 corresponding to the S-
methyl methylphosphonothioate and methyl methylphosphonate anions, respectively. The structure of these
product ions is demonstrated by a combination of collision-induced dissociation and isotope-labeling
experiments that also provide evidence for their formation by nucleophilic reaction pathways, namely, (i)
S(N)2 at carbon to yield the S-methyl methylphosphonothioate anion and (ii) nucleophilic addition at
phosphorus affording a reactive pentavalent intermediate that readily undergoes internal sulfur oxidation and
concomitant elimination of CH3SOH to yield the methyl methylphosphonate anion. Consistent with
previous Solution phase observations of VX perhydrolysis, the toxic P-O cleavage product is not observed in
this VX model system and theoretical calculations identify P-O cleavage to be energetically uncompetitive.
Conversely, intramolecular sulfur oxidation is calculated to be extremely exothermic and kinetically accessible
explaining its competitiveness with the facile gas phase proton transfer process. Elimination of a sulfur moiety
deactivates the nerve agent VX and thus the intramolecular sulfur oxidation process reported here is also able
to explain the selective perhydrolysis of the nerve agent to relatively nontoxic products.
Keywords
intramolecular, sulfur, oxidation, during, vx, perhydrolysis, ion, molecule, reactions, o, dimethyl,
methylphosphonothioate, evidence
This journal article is available at Research Online:http://ro.uow.edu.au/scipapers/281

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DOI: 10.1021/jo901944p
r2009 American Chemical Society
Published on Web 11/17/2009
J. Org. Chem. 2009, 74, 9319–93279319
pubs.acs.org/joc
Ion-Molecule Reactions of O,S-Dimethyl Methylphosphonothioate:
Evidence for Intramolecular Sulfur Oxidation during VX Perhydrolysis
Andrew M. McAnoy,*,†Jilliarne Williams,†Martin R. L. Paine,‡Michael L. Rogers,†and
Stephen J. Blanksby*,‡
†Human Protection and Performance Division, Defence Science and Technology Organisation,
506 Lorimer St., Fishermans Bend, Victoria 3207, Australia, and‡School of Chemistry, University of
Wollongong, Wollongong, New South Wales 2522, Australia
andrew.mcanoy@dsto.defence.gov.au; blanksby@uow.edu.au
Received September 8, 2009
The alkaline perhydrolysis of the nerve agent O-ethyl S-[2-(diisopropylamino)ethyl] methylphos-
phonothioate (VX) was investigated by studying the ion-molecule reactions of HOO-with O,S-
dimethyl methylphosphonothioate in a modified linear ion-trap mass spectrometer. In addition to
simple proton transfer, two other abundant product ions are observed at m/z 125 and 109 cor-
responding to the S-methyl methylphosphonothioate and methyl methylphosphonate anions,
respectively. The structure of these product ions is demonstrated by a combination of collision-
induceddissociationandisotope-labeling experiments thatalso provide evidencefortheir formation
by nucleophilic reaction pathways, namely, (i) SN2 at carbon to yield the S-methyl methylphos-
phonothioate anion and (ii) nucleophilic addition at phosphorus affording a reactive pentavalent
intermediate that readily undergoes internal sulfur oxidation and concomitant elimination of
CH3SOH to yield the methyl methylphosphonate anion. Consistent with previous solution phase
observations of VX perhydrolysis, the toxic P-O cleavage product is not observed in this VX model
system and theoretical calculations identify P-O cleavage to be energetically uncompetitive.
Conversely, intramolecular sulfur oxidation is calculated to be extremely exothermic and kinetically
accessible explaining its competitiveness with the facile gas phase proton transfer process. Elimina-
tion of a sulfur moiety deactivates the nerve agent VX and thus the intramolecular sulfur oxidation
processreportedhereisalsoabletoexplaintheselectiveperhydrolysisofthenerveagenttorelatively
nontoxic products.
Introduction
Over recent years, the threat of a nerve agent release in
a civilian environment by a terrorist group, such as the
1995 nerve agent attack in a Tokyo subway system,1has
provided the impetus for the enhancement of methods
for nerve agent detection and decontamination.2-5
The chemistry of nerve agent degradation by alkaline
hydrolysisiswellestablished;O-isopropylmethylphosphono-
fluoridate (GB) and O-pinacolyl methylphosphonofluori-
date (GD) are known to degrade to their corresponding
phosphonic acids within minutes while, conversely, the alka-
line hydrolysis of O-ethyl S-[2-(diisopropylamino)ethyl]
methylphosphonothioate (VX) occurs slowly.6In addi-
tion, alkaline hydrolysis of VX results in two products
formed via thiolate elimination, to form relatively non-
toxic ethyl methylphosphonic acid (EMPA), or ethoxide
elimination, to form the highly toxic and persistent
S-[2-(diisopropylamino)ethyl]methylphosphonthioicacid
(EA 2192) (Scheme 1).
(1) Suzuki,T.;Morita,H.;Ono,K.;Maekawa,K.;Nagai,R.;Yazaki,Y.;
Nozaki, H.; Aikawa, N.; Shinozawa, Y.; Hori, S.; Fujishima, S.; Takuma,
K.; Sagoh, M. Lancet 1995, 345, 980–981.
(2) Eubanks, L. M.; Dickerson, T. J.; Janda, K. D. Chem. Soc. Rev. 2007,
36, 458–470.
(3) Giordano, B. C.; Collins, G. E. Curr. Org. Chem. 2007, 11, 255–265.
(4) Talmage, S. S.; Watson, A. P.; Hauschild, V.; Munro, N. B.; King, J.
Curr. Org. Chem. 2007, 11, 285–298.
(5) Yang,Y.C.;Baker,J.A.;Ward,J.R.Chem.Rev.1992,92,1729–1743.
(6) Yang, Y. C.; Berg, F. J.; Szafraniec, L. L.; Beaudry, W. T.; Bunton,
C. A.; Kumar, A. J. Chem. Soc., Perkin Trans. 2 1997, 607–613.

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9320J. Org. Chem. Vol. 74, No. 24, 2009
JOCArticle
McAnoy et al.
Peroxide-based decontaminants have also long been
known to effectively degrade nerve agents6-8and an effec-
tive, environmentally benign decontaminant consisting of
hydrogen peroxide and a peroxide activator in solution has
been reported.9Interestingly, hydrogen peroxide alone in
solutiondegradesGBveryslowlywithahalf-lifemeasuredin
the order of days, while the degradation of GB with an
activated hydrogen peroxide solution occurs too rapidly to
measure by NMR.9An additional benefit is that the perhy-
drolysis of VX also occurs rapidly under alkaline conditions
and exclusively yields the nontoxic EMPA product.6-8
The disparity in product distribution between hydrolysis
and perhydrolysis of VX is not fully understood. Addition-
elimination processes at phosphorus are well-known to
proceed via a pentavalent intermediate with nucleophilic
attack and elimination preferentially occurring from the
apical positions.10,11In addition, the more electronegative
grouppreferstobeapicalandso,intheabsenceofcompeting
rearrangement processes, P-O cleavage may be expected to
be favored over P-S cleavage as observed during the hydro-
lysis of cyclic phosphorothioates.12Conversely, the thiolate
moiety is the more stable leaving group compared to the
alkoxide group and should favor P-S over P-O cleavage.
Pseudorotation between pentavalent intermediates, with an
equilibrium favoring the thiol eliminating species, provides
an explanation for the hydrolysis product distribution.
However, it is difficult to account for the complete absence
ofP-OcleavageobservedduringVXperhydrolysisbasedon
preferential pseudorotation alone.Onthebasisoftheirearly
experimental work, Yang et al. explained the preference for
P-S cleavage by intramolecular oxygen transfer to sulfur,
via a cyclic sulfonium ion, to yield a labile mixed anhydride
that is readily hydrolyzed.7However, later work by Yang
et al. on the alkaline perhydrolysis of O,S-diethyl methyl-
phosphonothioate in H218O found no evidence for isotopic
label incorporationintoanyreaction productsandledtothe
proposition of an SN2(phosphorus) mechanism for VX
perhydrolysis with product selectivity due to relative basi-
cities of the anionic nucleophile and leaving anions.6More
recently, a theoretical study compared the alkaline hydro-
lysis and perhydrolysis of a VX model system and deter-
minedthatbothprocessesinvolveaddition-eliminationand
proceed via respective phosphorus-centered pentavalent in-
termediates.13However, while reactions resulting in the
direct cleavage of P-O and P-S bonds of the intermediates
were calculated to be kinetically competitive during hydro-
lysis, only P-S bond cleavage was calculated to be kineti-
cally favored during alkaline perhydrolysis and may explain
the absence of the toxic product.13
Wagner et al. previously obtained31P NMR evidence for
the elusive peroxyphosphonate intermediate in support of
the GB and GD perhydrolysis mechanism in alkaline solu-
tion.9However, an analogous peroxy intermediate during
VX perhydrolysis was not observed by31P NMR indicative
ofeitherarapidreactionconsumingtheperoxyintermediate
or an alternative mechanism for VX perhydrolysis. Interest-
ingly, an alternative mechanism involving intramolecular
sulfur oxidation within the pentavalent intermediate, with
concomitant loss of the oxidized sulfur moiety, cannot be
ruled out based on previous experimental data. Theoretical
investigations into the perhydrolysis of VX and a model
systemindicatethattheincipienthydroperoxidecantransfer
its nucleophilic oxygen to sulfur with the remaining hydro-
xide retained by the phosphorus atom.13,14These studies
subdue concerns raised by the absence of18O incorporation
during labeling studies that led to the proposal of an SN2-
(phosphorus) mechanism.6Here we investigate the reactions
of the putative perhydrolysis reagent HOO-with O,S-
dimethyl methylphosphonothioate (1), a VX model com-
pound,toprovideinsightintothemechanismforthealkaline
perhydrolysisofVX.Inparticular,ouraimsaretodetermine
the effect of the methylthiolate on the gas phase reactivity at
phosphorus as compared to analogous reactivity observed
for dimethyl methylphosphonate (DMMP)15and to search
forevidence,orotherwise,fortheinternalsulfuroxidationof
the pentavalent intermediate.
Results and Discussion
Intheabsenceofsolventeffects,gasphasereactionsofthe
hydroperoxide ion may provide insight into the efficacy and
selectivity of nerve agent degradation by alkaline perhydro-
lysis. For example, the gas phase reactions of HOO-with
neutral DMMP are reported to undergo either an SN2-
(carbon) process (89%) or proton transfer (11%).15These
resultscontrastthetrendwhereprotontransferdominatesall
other reported analogous reactions of anions of similar basi-
city to HOO-(ΔacidH300[HOOH]=376.5 ( 0.4 kcal mol-1)16
demonstrating the intrinsic nucleophilicity of the HOO-
SCHEME 1.
Products of VX Hydrolysis and Perhydrolysis
(7) Yang, Y. C.; Szafraniec, L. L.; Beaudry, W. T.; Bunton, C. A. J. Org.
Chem. 1993, 58, 6964–6965.
(8) Yang, Y. C.; Szafraniec, L. L.; Beaudry, W. T.; Rohrbaugh, D. K.
J. Am. Chem. Soc. 1990, 112, 6621–6627.
(9) Wagner, G. W.; Yang, Y. C. Ind. Eng. Chem. Res. 2002, 41, 1925–
1928.
(10) Thatcher, G. R. J.; Kluger, R. Adv. Phys. Org. Chem. 1989, 25, 99–
265.
(11) Westheimer, F. H. Acc. Chem. Res. 2002, 1, 70–78.
(12) Dantzman, C. L.; Kiessling, L. L. J. Am. Chem. Soc. 1996, 118,
11715–11719.
(13) Seckute, J.; Menke, J. L.; Emnett, R. J.; Patterson, E. V.; Cramer,
C. J. J. Org. Chem. 2005, 70, 8649–8660.
(14) Daniel, K. A.; Kopff, L. A.; Patterson, E. V. J. Phys. Org. Chem.
2008, 21, 321–328.
(15) McAnoy,A.M.;Paine,M.R.L.;Blanksby,S.J.Org.Biomol.Chem.
2008, 6, 2316–2326.
(16) Ramond, T. M.; Blanksby, S. J.;Kato, S.; Bierbaum, V. M.; Davico,
G. E.; Schwartz, R. L.; Lineberger, W. C.; Ellison, G. B. J. Phys. Chem. A
2002, 106, 9641–9647.

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J. Org. Chem. Vol. 74, No. 24, 20099321
McAnoy et al.
JOCArticle
ion pertinent to nerve agent degradation. However, the
absence of an addition-elimination pathway in the gas
phase reactions of HOO-with DMMP indicates that this
compound, which differs from nerve agents by the absence
of P-F or P-S bonds and larger alkyl groups, is not an
appropriate model to fully probe nerve agent perhydroly-
sis. The structure of 1 is similar to that of DMMP except
that methylthiolate is substituted for a methoxide and is
therefore a more appropriate model compound for VX.
Possibleproductionswhichmayformduringthegasphase
reactions of 1 with HOO-are shown in Scheme 2 and
include products of proton transfer (2), nucleophilic sub-
stitution at carbon (3a/3b), and nucleophilic addition-
elimination at phosphorus involving direct P-S cleavage
(4a), P-O cleavage (5a), or internal sulfur oxidation (6a).
Significantly, many of these possibilities are distinguish-
able based on nominal m/z values asserting ion-trap mass
spectrometry as an ideal tool to probe these reaction
pathways.
Ion-Molecule Reactions of O,S-Dimethyl Methylphos-
phonothioate (1). The ion-molecule reactions of 1 with
isolated CH3O-, CH3CH2O-, and HOO-were conducted
with use of a modified linear ion-trap mass spectrometer.
The reagent ions were generated in the ion source via
negative ion electrospray ionization and 1 was introduced
into the ion-trapping region as a gaseous neutral with the
helium buffer gas and allowed to react with the isolated
reactant ion. The product ions and remaining reagent ions
werescannedoutofthetrapanddetectedtoproduceproduct
ion spectra (Figure 1). The alkoxide ions react as gas phase
bases and only undergo proton transfer to yield the product
ion 2 at m/z 139. The basicities of CH3O-(ΔacidH300[CH3-
OH]=382.4(0.5kcalmol-1),CH3CH2O-(ΔacidH300[CH3-
CH2OH]=379.1(0.5kcalmol-1),17andHOO-(ΔacidH300-
[HOOH]=376.5 (0.4 kcalmol-1)16are similar andtherefore
reactionsofHOO-with1maybeexpectedtoonlyundergo
proton transfer. However, the reactions of HOO-with 1
undergo a proton transfer yielding 2 (m/z 139), with a
branching ratio of 74%, and minor nucleophilic processes
yielding product ions at m/z 125 and 109 with branching
ratios of 11% and 15%, respectively. The branching ratios
were determined with use of the Grawbowski method18
(Supporting Information) and this analysis shows a down-
ward deviation from linearity of the m/z 139 data and
upward deviation of the m/z 125 data at high (>80%)
reagent ion consumption. This indicates an onset of sec-
ondary processes where m/z 139 product ions react with 1
to yield additional m/z 125 product ions. Conversely, the
m/z 109 product ion intensity scales linearly with HOO-
consumption indicating that the m/z 109 ion is a primary
product of the reaction between HOO-and 1 under
pseudo-first-order conditions.
The product ions observed at m/z 139, 109, and 125,
formedbyreactionofHOO-with1,werefurthercharacteri-
zed with MSnexperiments (Figure 2). Collision-induced
dissociation (CID) of the m/z 139 product ion yields a
fragment ion at m/z 93 (Figure 2a). A nominal loss of 46
Daforthisfragmentationprocessisattributedtoneutralloss
of thioformaldehyde from 2, presumably eliminated via a
5-centeredrearrangementinvolvingprotontransferfromthe
methylthiolate to the charged center. This assignment is
confirmed by CID of the34S-isotopologue ion at m/z 141
(Supporting Information) that undergoes loss of34S-thio-
formaldehyde (48 Da). Interestingly, loss of formaldehyde
(30 Da) via a similar rearrangement process involving the
SCHEME 2.
ProposedIon-MoleculeReactionsofHOO-with1
FIGURE 1. Product ion spectra resulting from the gas phase reac-
tion of (a) CH3O-(m/z 31), (b) CH3CH2O-(m/z 45), (c) HOO-
(m/z 33), and (d) H18O2-(m/z 37) with 1. In each case, proton
transfer yields 2 at m/z 139, while product ions of nucleophilic
reactions at m/z 109/111 and 125 are only observed in the reactions
of HOO-/H18O2-.
(17) Ramond, T. M.; Davico, G. E.; Schwartz, R. L.; Lineberger, W. C.
J. Chem. Phys. 2000, 112, 1158–1169.
(18) Grabowski, J. J.; Lum, R. C. J. Am. Chem. Soc. 1990, 112, 607–620.

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9322J. Org. Chem. Vol. 74, No. 24, 2009
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McAnoy et al.
methoxideisnotobservedindicatingthecleavageoftheP-S
bond to lose thioformaldehyde is significantly favored over
cleavage of the P-O to lose formaldehyde. The CID spec-
trumoftheresultingm/z93fragmention(Figure2b)showsa
majorfragmentionatm/z78andminorfragmentionsatm/z
77 and 63. These can be attributed to the respective losses of
CH3, CH4, and 2 ? CH3(or CH2O) and are in agreement
with previously reported MSnexperiments.15
Interestingly, the m/z 109 product ion can be attributed to
6a formed as a result of the proposed sulfur oxidation
mechanism. The pathway for m/z 109 formation was further
investigated by comparison of CID data of the m/z 109
product ion with CID data of an authentic 6a ion and,
ultimately, with18O-isotope labeling experiments that, by
tracking oxygen atoms originating from the incipient
H18O2-ion,allowdifferentiationofthecompetingpathways
described in Scheme 2. The CID spectrum of the m/z 109
product ion (Figure 2c) shows only one fragment ion at
m/z 77 due to neutral loss of methanol (32 Da) and is con-
sistent with a product ion structure of 6a. An ion of known
structure 6a was generated by negative electrospray ioniza-
tion of methyl hydrogen methylphosphonate (9). The CID
data of the m/z 109 product ion are in agreement with the
CID data of the authentic 6a ion produced under similar
experimental conditions (Supporting Information) indicat-
ing the ions have the same structure. Finally, the18O-labeled
HOO-ion(m/z37)wasgeneratedbyelectrosprayionization
of an infused 3% solution of H218O2and allowed to react
with 1 in the ion-trap. A mass shift from m/z 109 to 111 was
observed in the resulting product ion spectrum (Figure 1d)
indicating incorporation of an18O atom into the product
ion. These data unequivocally identify the m/z 109 product
ion as 6a and provide the first experimental evidence of
intramolecular sulfur oxidation occurring in this VX model
system.
Theobservedproductionintensityatm/z125isconsistent
with the formation of three distinct product ions from two
reaction processes, namely SN2 at carbon forming product
ions 3a/3b and addition-elimination with P-S cleavage
forming product ion 4a. The CID of the m/z 125 product
ion results in the exclusive formation of a fragment ion at
m/z77(Figure2d)andcanbeattributedtotheneutrallossof
thiomethanol (48 Da) from 3a/3b. This assignment was
confirmed by CID of the34S-isotopologue ion at m/z 127
(Supporting Information) that undergoes loss of34S-thio-
methanol (50 Da). Interestingly, the m/z 125 product ion(s)
do not undergo loss of methanol suggesting that the decom-
posing ion is 3a. This may be explained in terms of the initial
SN2reactionofHOO-favoringattackatthemethoxideover
the thiolate and/or facile rearrangement from 3b to 3a upon
collisional activation immediately prior to decomposition.
The addition-elimination product ion 4a could conceivably
undergo neutral loss of CH3OOH (48 Da) upon collisional
activation and therefore may also contribute to the m/z 125
product ion. However, 4a may be expected to undergo some
loss of methanol, which is not observed. Further,18O-label-
ing would result in a mass shift of 4a, from m/z 125 to 129,
due to the incorporation of two18O atoms. No mass shift is
observed during the18O-labeled experiments consistent with
the m/z 125 product ion being formed by an SN2(carbon)
process, indicating that the addition-elimination with P-S
cleavage does not occur in this system.
The addition-elimination pathway resulting in P-O
cleavage would be expected to yield product ion 5a at m/z
141. However, CID of the m/z 141 ion is consistent with the
34S-isotopologueof2 (asdiscussedabove)andnosignificant
ion intensity is observed at m/z 143 for the34S-isotopologue
of 5a. Further, incorporation of two18O atoms during the
18O-labeled experiments would mass shift the P-O cleavage
product ion by 4 Da. Therefore, the absence of an m/z 145
product ion in the reactions of H18O2-with 1 (Figure 1d)
indicates that the P-O cleavage pathway does not occur in
this system.
Calculated Reaction Pathways. Gas phase proton transfer
reactions are thermodynamically controlled and the inten-
sity of facile proton transfer from 1 to HOO-indicates 1 has
a significantly lower enthalpy of deprotonation relative to
hydrogen peroxide (ΔacidH300[HOOH] = 376.5 ( 0.4 kcal
mol-1).16The acidity of 1 has not been reported, but
comparison of zero point energy corrected electronic ener-
gies of 1 and 2, at the B3LYP/aug-cc-pVTZ//B3LYP/
6-31þG(d) level of theory, estimates this to be 364.8 kcal
mol-1(Table 1). On the basis of calculations at the same
level of theory,15the acidity of DMMP is calculated to be
371.9 kcal mol-1and is in close agreement with the experi-
mental value of ΔacidH300[CH3PO(OCH3)2]=373 ( 3 kcal
mol-1.19The low acidity value of 1 compared to that of
hydrogen peroxide explains the dominance of 2 in the
product ion spectrum. The pathways of the nucleophilic
reactions between HOO-and 1 (Scheme 2) were similarly
investigated at the same level of theory to explain the
observation,orabsence,ofionsintheproductionspectrum.
FIGURE 2. MSnspectra of product ions formed by the reaction
ofHOO-with1:(a)CIDof2(MS3ofm/z33f139),(b)CIDofthe
m/z93fragmention(MS4ofm/z33f139f93),(c)CIDof6a(MS3
of m/z 33 f 109), and (d) CID of 3a/b (MS3of m/z 33 f 125).
(19) Lum, R. C.; Grabowski, J. J. J. Am. Chem. Soc. 1993, 115, 7823–
7832.

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Theinitialpathwaysinvestigatedinvolvedtheapproachof
HOO-toward the phosphorus center directly opposite
SCH3, as would be expected for an addition-elimination
process resulting in cleavage of the P-S bond. Relevant
energiesforthestationarypointsidentifiedfromthisstarting
point are provided in Table 1 and the structures of pertinent
stationary points are shown in Figure 3. The reactant ion-
neutral complex a1 is stabilized with respect to the separated
reactants by 22.2 kcal mol-1, providing significant com-
plexationenergyforfurtherreaction.Theapproachopposite
CH3S may undergo SN2(carbon) at methoxide through a
calculated barrier of 10.5 kcal mol-1(relative to a1) to
separated products 3a and CH3OOH that are stabilized by
an additional 29.9 kcal mol-1. Overall, this simple SN2-
(carbon)processissignificantlyexothermic(52.1kcalmol-1)
and, combined with a negative activation barrier relative to
separated reagents, explains the observation of the m/z 125
product ion.
Nucleophilicadditionatphosphorusfroma1is calculated
to have a barrier of 3.2 kcal mol-1and results in a lower
energy pentavalent intermediate (a2) with HOO-and SCH3
groups in the apical positions. The rotation of the equatorial
methoxide from the initially formed pentavalent intermedi-
ate has a barrier of only 1.2 kcal mol-1and coincides with a
significant 0.2 A˚ increase in the P-S bond. The resulting
intermediate (a3) has a negative barrier of 0.5 kcal mol-1to
P-S bond cleavage and continued methoxide rotation to
forma4.AttheB3LYP/6-31þG(d)levelusedtooptimizethe
structures the barrier is 0.04 kcal mol-1indicating this is an
effectively barrierless process. The resulting ion-neutral
complex a4 is 42.3 kcal mol-1lower than the entrance
channelandhassufficientinternalenergyforprotontransfer
and subsequent elimination of thiomethanol to yield the
productionatm/z125.Directdissociationoftheion-neutral
complex to 7 and CH3S-requires 15.1 kcal mol-1while
proton transfer and dissociation to the more stable product
ion 4b and CH3SH requires 9.6 kcal mol-1. However,18O-
labelingdatashowthat4bdoesnotcontributetotheproduct
ion observed at m/z 125 suggesting there are lower energy
and/or more accessible pathways that are more competitive
than the P-S cleavage pathway.
Alternative pathways that involved the approach of
HOO-opposite OCH3were similarly investigated with rele-
vant energies and structures of stationary points from this
TABLE 1.
ing Opposite SCH3
Calculated Data for Reactions of 1 with HOO-Approach-
electronic
energya
-1009.853082
-1009.271696
-150.997306
zero point
correctiona
relative
energyb
1
2
HOO-
1 þ HOO-
a1
TS 1-3a
3a
CH3OOH
3a þ CH3OOH
TSa1a2
a2
TSa2a3
a3
TSa3a4
a4
4a
4b
CH3SH
4a þ CH3SH
4b þ CH3SH
7
CH3S-
7 þ CH3S-
aEnergies (hartrees) calculated at the B3LYP/aug-cc-pVTZ//
B3LYP/6-31þG(d) level of theory and include zero point correction.
bRelative energies (kcal mol-1) are relative to a1, except for that of 2,
which is relative to 1.
0.125293
0.110303
0.012921
364.8
22.2
0.0
10.5
-1160.885788
-1160.868994
-970.049369
-190.884064
0.139191
0.139060
0.084721
0.054687
-29.9
-1160.880684
-1160.903059
-1160.901010
-1160.905426
-1160.906140
-1160.917754
-722.191900
-722.175495
-438.710632
0.140438
0.142195
0.141799
0.141968
0.141682
0.140528
0.090517
0.089062
0.046301
3.2
-10.8
-9.6
-12.3
-12.8
-20.1
-10.5
-0.2
-722.749535
-438.144250
0.103788
0.036149
-5.0
FIGURE 3. Optimized B3LYP/6-31þG(d) geometries of pertinent
stationary points on addition-elimination pathways resulting in
(a) P-S cleavage and (b) P-O cleavage. P-S or P-O bond distan-
ces (A˚) are indicated in parentheses.

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9324J. Org. Chem. Vol. 74, No. 24, 2009
JOCArticle
McAnoy et al.
startingpointprovidedinTable2andFigure3.Thereactant
ion-neutral complex b1 is stabilized with respect to the
separated reactants by 22.1 kcal mol-1. As HOO-ap-
proaches 1 opposite the OCH3 it can also react at the
methylthiolate moiety via an SN2(carbon) process with a
barrier of 8.3 kcal mol-1from b1 to 3b and CH3OOH.
Similar to the SN2(carbon) at the methoxide group, this
simple SN2(carbon) process is overall significantly exother-
mic (47.6 kcal mol-1) explaining the observation of the
m/z 125 product ion. Interestingly, 3b is slightly higher in
energy than 3a consistent with the experimental results sug-
gesting that the decomposing m/z 125 ion has structure 3a.
Nucleophilic addition at phosphorus yielding a pentava-
lentintermediatewithHOO-andOCH3groupsintheapical
positions (b2) is calculated to have a barrier of 1.1 kcal
mol-1. Similar to the P-S cleavage pathway, rotation of the
equatorial group is needed to facilitate elimination of the
apicalleavinggroup.However,thebarrierforrotationofthe
CH3S group through TSb2b3 is calculated to be 8.3 kcal
mol-1and results in a relatively stable, albeit slightly higher
in energy, pentavalent intermediate, b3, with no significant
effect on the P-O bond. The following step in the process
involves cleavage of the P-O bond through TSb3b4 to yield
an ion-neutral complex and is calculated to have a barrier of
15.6 kcal mol-1. The resulting complex b4 is 19.3 kcal mol-1
lower than the entrance channel and, if formed, should have
sufficientinternalenergyforprotontransferandelimination
of methanol to yield 5a,b (m/z 141). Direct dissociation of b4
to 8 and CH3O-requires 25.7 kcal mol-1and is not
competitive with respect to proton transfer and elimination
of methanol to yield 5a or 5b that only requires 3.5 kcal
mol-1or releases 4.5 kcal mol-1, respectively.
Interestingly, initial nucleophilic attack opposite the
OCH3group is considered to be significantly more favored
as compared to attack opposite SCH3, in part, due to the
preference for the most electronegative group to occupy the
apical position.10,11However, no experimental evidence for
P-Ocleavagehasbeenobservedduringtheperhydrolysisof
VXandrelatedcompoundsindicatinganalternatefateofthe
apparently favored pentavalent intermediate b1. It has been
proposed that the intermediate leading to P-O cleavage
could be a dead end species and always reverts back to
reactants.6This is consistent with the reverse activation
energy for b3 formation (5.6 kcal mol-1) being significantly
lower than the forward barrier for P-O cleavage (15.6 kcal
mol-1). However, in the gas phase the initial complexation
energy imparted on the system is significantly large that the
barrier toP-Ocleavagemaynotfullyexplaintheabsenceof
thispathway.Otherpathwaysproposedforthealternatefate
of b1 involve pseudorotation to an intermediate with apical
thiolate and subsequent P-S cleavage or an intramolecular
transfer of a hydroperoxy oxygen to the sulfur atom and
subsequent elimination of an oxidized sulfur moiety.7,13We
have calculated a pseudorotation transition state (TSb2a3)
for conversion of the intermediate b2 to a3 that has
methylthiolate in the apical position to eliminate thiometha-
nol as described above (Figure 4). This pseudorotation
process has a barrier of 9.3 kcal mol-1and compares to an
energyrequirementof18.3kcalmol-1toinvoketherequired
CH3S rotation andsubsequent P-O bond cleavage from the
same intermediate (Table 2). In addition, intermolecular
oxygen transfer to sulfur is calculated to have a barrier of
TABLE 2.
ing Opposite OCH3
Calculated Data for Reactions of 1 with HOO-Approach-
electronic
energya
-1160.885597
-1160.872354
-970.042277
zero point
correctiona
relative
energyb
b1
TS 1-3b
3b
3b þ CH3OOH
TSb1b2
b2
TSb2b3
b3
TSb3b4
b4
5a
5b
CH3OH
5a þ CH3OH
5b þ CH3OH
8
CH3O-
8 þ CH3O-
TSb2a3
TSb2c3
c3
TSc3c4
c4
TSc4c5
c5
TSc5c6
c6
6a
6b
CH3SOH
6a þ CH3SOH
6b þ CH3SOH
9
CH3SO-
9 þ CH3SO-
aEnergies (hartrees) calculated at the B3LYP/aug-cc-pVTZ//
B3LYP/6-31þG(d) level of theory and include zero point correction.
bRelative energies (kcal mol-1) are relative to a1.
0.140116
0.138571
0.086229
0.1
8.4
-25.4
-1160.883926
-1160.904214
-1160.889465
-1160.900006
-1160.891066
-1160.881234
-1045.163022
-1045.150267
-115.725354
0.140570
0.142108
0.141995
0.142010
0.141335
0.137350
0.087037
0.085758
0.051291
1.2
-11.6
-3.3
-8.9
6.7
2.9
-1.6
6.4
-1045.717062
-115.123162
0.100217
0.035142
28.6
-2.3
-4.9
-53.3
-46.6
-60.9
-58.3
-59.9
-60.7
-70.3
-1160.889465
-1160.893549
-1160.970755
-1160.960086
-1160.982849
-1160.978654
-1160.981246
-1160.982483
-1160.997888
-647.071877
-647.012598
-513.939344
0.141995
0.140661
0.141038
0.142138
0.141783
0.141235
0.141787
0.141079
0.140441
0.087779
0.084979
0.052025
-78.7
-41.5
-647.604383
-513.368510
0.099950
0.039039
-54.7
FIGURE 4. Optimized B3LYP/6-31þG(d) geometries of pertinent
stationary points for the intramolecular oxygen transfer to sulfur
and rearrangement to c6 that subsequently eliminates CH3SOH to
yield product ion 6a (m/z 109).

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J. Org. Chem. Vol. 74, No. 24, 20099325
McAnoy et al.
JOCArticle
6.7kcalmol-1andtheresultingintermediatec3hasareverse
activation energy of 48.4 kcal mol-1indicating a major
exothermic drive for this reactive pathway (Table 2, Figure 4).
Further, the substantial amount of excess energy of c3 is
sufficient for the subsequent rearrangement processes to
yield the lower energy ion-neutral complex c6. Direct
dissociation of c6 to 9 and CH3SO-requires 15.6 kcal
mol-1and compares to the elimination of CH3SOH from
c6 to yield the more stable product ion 6a that releases an
additional 8.4 kcal mol-1. It should also be noted that the
above pseudorotation process also provides a channel
from the P-S cleavage pathway to intermediate b2 that
can undergo intermolecular oxygen transfer to sulfur.
Therefore, all calculated pentavalent intermediates can
proceed via the intramolecular sulfur oxidation pathway
to CH3SOH and yield 6a in a process that is overall
exothermic by 100.9 kcal mol-1.
The above calculations explain the observation, abun-
dance, and absence of reaction products of the proposed
reaction pathways in the gas phase reactions of HOO-with
1. The nucleophilic pathways are summarized in Figure 5,
whichclearlyshows(i)P-Ocleavageisnotcompetitivewith
several lower energy alternative pathways and (ii) internal
oxygen transfer is energetically viable and explains the
abundance of 6a in the product ion spectrum. Interestingly,
the formation of b2 is essentially barrierless and would
proceed irrespective of the gas phase complexation energy
imparted on the system. It follows that b2 should readily
form in solution under ambient conditions and proceed to
the exothermic products 4a and/or 6a, while the relatively
high barrier to P-O cleavage would still prohibit formation
of 5a in solution.
Conclusions
The ion-molecule reactions of HOO-with 1 have been
investigated with a modified linear ion-trap mass spectro-
meter.Themajorabundanceof2intheresultingproduction
spectrum isexplained bythesignificantly loweracidity value
of 1 relative to that of hydrogen peroxide leading to an
extremely efficient proton transfer process. Significant pro-
duct ions also appearing in the spectrum correspond to the
nucleophilic reaction products 3a/3b and 6a. Simple SN2 at
carbonprocessesyield3a/3b,while6aisformedasaresultof
nucleophilic addition at phosphorus affording a reactive
pentavalent intermediate that readily undergoes internal
sulfur oxidation and concomitant elimination of CH3SOH.
The addition-elimination reaction resulting in cleavage of
the P-O bond is not observed in the gas phase and is
consistent with its absence in all previous investigations into
the alkaline perhydrolysis of VX and related compounds.
The elimination of a sulfur moiety deactivates the nerve
agent VX and therefore the intramolecular sulfur oxidation
processreportedheremayexplaintheselectiveperhydrolysis
of the nerve agent to relatively nontoxic products.
FIGURE 5. Summary of nucleophilic addition pathways for reactions of HOO-with 1: addition-elimination with P-S cleavage (a1 to a4),
addition-eliminationwithP-Ocleavage(b1tob4),andsulfuroxidationwitheliminationofCH3OSH(c5toc6,nottoscale).Relativeenergies
(kcalmol-1)arecalculated attheB3LYP/aug-cc-pVTZ//B3LYP/6-31þG(d) level oftheory. (Note:TSa3a4andTSc5c6 are0.04and0.49kcal
mol-1higher than a3 and c5 at B3LYP/6-31þG(d), respectively, and indicate small or insignificant barriers for these steps.)

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9326J. Org. Chem. Vol. 74, No. 24, 2009
JOCArticle
McAnoy et al.
Finally, it is of interest that nucleophilic products are not
observed in the reactions of CH3O-and CH3CH2O-with 1
whereonlyprotontransferisobserved.Therelativebasicitiesof
CH3O-,CH3CH2O-,andHOO-aresimilarandthereforethe
observation of significant nucleophilic processes in the reac-
tions of HOO-with 1 may be considered indicative of an
enhanced nucleophilicity of HOO-. We recently detailed
dominant nucleophilic processes in the reactions of HOO-
with DMMP, compared to dominant proton transfer for
reactions of CH3O-with DMMP, as evidence supporting a
gas phase R-effect.15Meanwhile, an investigation into the SN2
reactions of R-nucleophiles with alkyl chlorides reported no
influence on gas phase reactivity.20These experimental studies
follow theoretical investigations reporting the existence of gas
phase R-effects21-23and highlight the complexities of these
phenomena are yet to be fully understood.
Experimental Section
Mass Spectrometry. Experiments were performed on a mod-
ified linear quadrupole ion-trap mass spectrometer fitted with a
conventional electrospray ionization source.24Ions were gene-
ratedbyinfusionat3-5μLmin-1ofneatCH3OH,CH3CH2OH,
or 3% aqueous solutions of H2O2, H218O2into the electrospray
ion source. Typical instrumental settings were as follows: spray
voltage -5.0 kV, capillary temperature 200 ?C, sheath gas flow
between 10 and 30 (arbitrary units), sweep and auxiliary gas flow
set at between 0 and 10 (arbitrary units). For collision-induced
dissociation (CID) experiments, ions were mass-selected with a
window of 1-4 Da, using a Q-parameter of 0.250, and the frag-
mentation energy applied was typically 10-45 (arbitrary units)
with an excitation time of 30 ms. Modifications to the mass
spectrometer to allow the introduction of neutral gases into the
ion-trap region of the instrument have been previously de-
scribed.25Briefly, neutral liquids and gases are introduced into a
flow of Ultra High Purity (UHP) helium (3-5 psi) supplied via a
variableleak valve toprovide a total ion gauge reading of ∼0.9?
10-5Torr representing an estimated trap pressure of 2.5 mTorr.
The temperature of the vacuum manifold surrounding the ion-
trap was measured at 307 ( 1 K, which is taken as being the
effective temperature for ion-molecule reactions observed here-
in.26For ion-molecule reactions herein, the instrument was
operated in low mass mode, the mass cutoff set to m/z 20, and
the isolation window varied (8-12 Da) to maximize reagent ion
transmission and isolation.Typicalreaction times of 10 to 200 ms
were set, using the excitation time parameter within the control
software using a fragmentation energy of 0 (arbitrary units). All
spectra presented represent an average of at least 50 scans.
Synthesis. The phosphonothioate 1 was prepared by a mod-
ifiedprocedureandcharacterizationisprovidedwhereliterature
data are absent.27-29The phosphonate 9 was prepared accord-
ing toaliterature procedure andhadNMRdata consistentwith
those reported previously.30Both compounds were obtained to
a purity of >95% as determined by1H and31P NMR. EI MS
analysiswascoupledwithgaschromatographyandHRMSdata
were obtained with a FT MS instrument. CAUTION: Organo-
phosphorus compounds can be hazardous and should only be
handled in controlled environments.
O,S-Dimethyl Methylphosphonothioate (1).28,29Oxalyl chlo-
ride (2.03 g, 160 mmol) was added in one portion to dimethyl
methylphosphonate (2.00 g, 160 mmol) in CH2Cl2(15 mL) and
the mixture was refluxed for 8 h. The solvent was evaporated
under reduced pressure to yield methyl methylphosphonyl
chloride31(2.00 g, 97%). A mixture of methyl methylphospho-
nyl chloride (2.00 g, 160 mmol) in anhydrous THF (15 mL) and
sodium methanethiolate (1.12 g, 160 mmol) was stirred for 1.5 h
underanitrogenatmosphere.Themixturewasfiltered,thesolid
waswashedwithCH2Cl2,andthesolventwasremovedfromthe
filtrate under reduced pressure. Flash chromatography (30%
acetone/70% hexane on silica) of the residue afforded the O,S-
dimethyl ester, 128,29(0.560 g, 29%):
DMSO-d6) δ 56.24 (s);1H NMR (500 MHz, DMSO-d6) δ 1.78
(3H, d, J = 15.5 Hz), 2.23 (3H, d, J = 12.9 Hz), 3.64 (3H, d,
J=12.6 Hz);13C (126 MHz, DMSO-d6) δ 12.0 (d, J=3.5 Hz),
17.8 (d, J = 108.1 Hz), 51.5 (d, J = 7.0 Hz); MS (EI) m/z (rel
intensity, %) 140 (70), 125 (14), 110 (13), 93 (100), 79 (37), 63
(31), 47 (24); HRMS (ESI) m/z 141.01334 (MHþ), calcd for
C3H10PO2S 141.01336.
Electronic Structure Calculations. Geometry optimizations
were carried out with the Becke 3LYP (B3LYP) method,32using
the 6-31þG(d) basis set within Gaussian 03W suite of pro-
grams.33All stationary points were characterized as either a
minima (no imaginary frequencies) or transition states (one
imaginary frequency) by calculation of the frequencies, using
analytical gradient procedures. Frequency calculations also pro-
vided zero point energies, which were used to correct electronic
energies calculated with the larger and correlation consistent
Dunnings basis set aug-cc-pVTZ.34The minima connected by a
given transition state were confirmed by inspection of the ani-
mated imaginary frequency, using the GaussView package35and
by intrinsic reaction coordinate (IRC) calculation.36,37
31P NMR (202 MHz,
Acknowledgment. The authors would like to thank
Mr. Alex Theo and Dr. Craig Brinkworth (DSTO) for techni-
cal assistance and the Australian Partnership for Advanced
(20) Villano, S. M.; Eyet, N.; Lineberger, W. C.; Bierbaum, V. M. J. Am.
Chem. Soc. 2009, 131, 8227–8233.
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1985, 41, 4909–4917.
(28) Hall, C. R.; Inch, T. D. J. Chem. Soc., Perkin Trans. 1 1981, 2368–
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(29) Barr, J. D.; Bell, A. J.; Ferrante, F.; La Manna, G.; Mundy, J. L.;
Timperley, C. M.; Waters, M. J.; Watts, P. Int. J. Mass Spectrom. 2005, 244,
29–40.
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G. A.; Trucks, G. W.; Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.;
Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.;
Schlegel, H. B.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.;
Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Scuseria,
G. E.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.;
Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.; Salvador, P.;
Robb, M. A.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels,
A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.;
Raghavachari, K.; Foresman, J. B.; Cheeseman, J. R.; Ortiz, J. V.; Cui, Q.;
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Liashenko, A.; Piskorz, P.; Komaromi, I.; Montgomery, J. A., Jr.; Martin,
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McAnoy et al.
JOCArticle
Computing for a generous allocation of supercomputing time.
A.M.M. acknowledges a DSTO Fellowship Award that sup-
ported this project. S.J.B. acknowledges an ARC grant
(DP0986738) and thanks UoW and DSTO for their support.
Supporting Information Available:
spectra for 1,31P and1H NMR spectra for 9, CID spectra of
31P,1H, and13C NMR
34S-isotopologue ions of 2 and 3a/3b, CID comparison data for
authentic 6a and the m/z 109 product ion, additional structures
of selected stationary points as well as electronic energies,
zero point energies, and molecular geometries (as Cartesian
coordinates) for all stationary points discussed in the text. This
material is available free of charge via the Internet at http://
pubs.acs.org.