Reactions of sulfides with S-330, a potential decontaminant of sulfur mustard in formulations

Article abstract of DOI:10.1002/(SICI)1099-1263(199912)19:1+3.0.CO;2-F

Because the vesicant sulfur mustard (HD) remains a major chemical threat from either domestic terrorists or countries in conflict, topical preparations are being evaluated as protectants from HD exposure. The objective of this study was to evaluate the effectiveness of chloroamide S-330 as a potential reactive component in topical formulations. Therefore, the rate, mechanism and by-products of the oxidation reactions of sulfides by S-330 in solvent media or specific formulation vehicles were investigated. Using NMR, LC, LC-MS and GC-MS, the reactions of S-330 with HD, dibutyl sulfide (DBS) and methyl phenyl sulfide (MPS) were studied in acetonitrile, chloroform and perfluoropolyether (PFPE) oil. The oxidation of the three sulfides with S-330 was very rapid and completed in < 4 min in acetonitril-water or PFPE oil, but the rates of reaction in chloroform were significantly slower. In a large excess of S-330, the major products resulted from chlorination of the side chains. At a high HD/S-330 ratio, the major product was HD sulfoxide. Under both conditions, only a trace of HD sulfone, also a blistering agent, was observed. Reactions with DBS and MPS primarily gave sulfoxides and sulfones, with less side-chain chlorination. The chloroamide S-330 appeared to be a rapid and effective decontaminant of HD in either polar media or in a PFPE oil. The two alkyl and aryl sulfides are suitable simulants of HD for the initial screening and evaluation of S-330 or other similar oxidizing agents.

Full text of DOI:10.1002/(SICI)1099-1263(199912)19:1+3.0.CO;2-F

JOURNAL OF APPLIED TOXICOLOGY
J. Appl. Toxicol. 19, S83–S88 (1999)
Reactions of Sulfides with S-330, a Potential
Decontaminant of Sulfur Mustard in
Formulations†‡
Ming L. Shih,1 William D. Korte,2* J. Richard Smith1 and Linda L. Szafraniec3
1US Army Medical Research Institute of Chemical Defense, APG, MD 21010, USA
2Department of Chemistry, California State University, Chico, CA 95929, USA
3US Army Edgewood Chemical and Biological Center, APG, MD 21010, USA
Key words: sulfur mustard; decontamination; S-330; chloroamide; sulfide oxidations.
Because the vesicant sulfur mustard (HD) remains a major chemical threat from either domestic
terrorists or countries in conflict, topical preparations are being evaluated as protectants from HD
exposure. The objective of this study was to evaluate the effectiveness of chloroamide S-330 as a
potential reactive component in topical formulations. Therefore, the rate, mechanism and by-products
of the oxidation reactions of sulfides by S-330 in solvent media or specific formulation vehicles were
investigated. Using NMR, LC, LC–MS and GC–MS, the reactions of S-330 with HD, dibutyl sulfide
(DBS) and methyl phenyl sulfide (MPS) were studied in acetonitrile, chloroform and perfluoropolyether
(PFPE) oil. The oxidation of the three sulfides with S-330 was very rapid and completed in Ͻ4 min in
acetonitrile–water or PFPE oil, but the rates of reaction in chloroform were significantly slower. In a
large excess of S-330, the major products resulted from chlorination of the side chains. At a high
HD/S-330 ratio, the major product was HD sulfoxide. Under both conditions, only a trace of HD
sulfone, also a blistering agent, was observed. Reactions with DBS and MPS primarily gave sulfoxides
and sulfones, with less side-chain chlorination.
The chloroamide S-330 appeared to be a rapid and effective decontaminant of HD in either polar
media or in a PFPE oil. The two alkyl and aryl sulfides are suitable simulants of HD for the initial
screening and evaluation of S-330 or other similar oxidizing agents.
anism with HD and the products generated have been
INTRODUCTION
published. To evaluate S-330 or other haloamides8 as
effective reactants in rTSP, the rate, mechanism and
by-products of the decontamination reaction need to
be elucidated. This paper reports a series of reactions
with S-330 that give insight into the probable reactivity
with HD in a perfluorinated oil-based rTSP. The reac-
tions of two other sulfides—dibutyl sulfide (DBS) and
methyl phenyl sulfide (MPS)—also were studied to
determine whether they could be used as substitutes for
HD oxidation studies. The use of suitable alternative
compounds in rTSP evaluation would enhance the
understanding of sulfide reactions and minimize the
use of the highly toxic HD in future screenings of
other reactive decontaminants.
Sulfur mustard (HD; 2, 2′-dichlorodiethylsulfide), a
vesicant or blistering agent, remains a major threat as
a chemical warfare agent to both civilians and military
personnel in hostile actions.1,2 Special clothing, gas
masks and topical skin protectants (TSPs) can facilitate
protection against HD exposure. The major role of the
TSP is to provide a physical barrier that will prevent
the contact of HD with the skin. However, it would
be more desirable to add to the TSP reactive compo-
nents that chemically decontaminate any HD adhered
to the formulation.
Chloroamide-class compounds have been investi-
gated as decontaminants of HD.4,5 The chloroamide
1,3,4,6-tetrachloro-7, 8-diphenyl-2, 5-diimino glycoluril
(S-330)6 has been reported to be a relatively non-
irritating and effective decontaminating agent that could
be used as the active component in a reactive TSP
(rTSP).3,4,7 However, few reports on its reaction mech-
The effectiveness of S-330 to decontaminate HD under
different conditions was determined by monitoring the
time required for the conversion of HD to non-vesicating
products and the characterization of the major products
of the reactions. There are five common types of reactions
between chloroamides and sulfides and sulfoxides,9 which
could lead to more than 20 different products in the
reaction between HD and S-330, depending on the
specific conditions of the reactions:
* Correspondence to: W. D. Korte, Department of Chemistry, Califor-
nia State University, Chico, CA 95929, USA.
†The views, opinions and/or findings contained in this report are
those of the authors and should not be construed as an official
Department of the Army position, policy or decision, unless so
designated by other documentation.
‡ This article is a US Government work and is in the public domain
in the United States.
(i) Reaction I, the oxidation of the sulfide to sul-
foxide:
R2S + ϾNCl + H2O = R2SO + ϾNH + HCl
Received 1 July 1999
Revised 15 July 1999
Accepted 19 July 1999
Published in 1999 by John Wiley & Sons, Ltd.

S84
M. L. SHIH ET AL.
(ii) Reaction II, the oxidation of sulfoxide to sulfone:
program set at 75°C for 2 min, a 30°C min−1 ramp to
250°C and then 5 min at 250°C.
R2SO + ϾNCl + H2O = R2SO2 + ϾNH + HCl
The NMR spectra were obtained on a Varian
UnityPlus 400 MHz NMR spectrometer. The proton
spectra were acquired at 400 MHz, and the carbon-13
spectra were acquired at 100 MHz. Quantitative data
were obtained by digital integration of the peak areas
of interest.
(iii) Reaction III, the chlorination of the carbon side
chain in a sulfide:
RSR′H + ϾNCl = RSR′Cl + ϾNH
(iv) Reaction IV, the chlorination of the carbon side
chain in a sulfoxide:
RSOR′H + ϾNCl = RSOR’Cl + ϾNH
Reaction procedures
(v) Reaction V, the cleavage of a sulfur–carbon bond:
All reactions were performed either in NMR tubes or
reaction vials and carried out at 20 Ϯ 1°C except reac-
tion J. Reactions A, B and C in Table 1 were monitored
directly in NMR tubes. Reactions D–J were performed
in 5-ml reaction vials. Reaction K in the oil was
attempted in an NMR tube, but the oil was too viscous
for rapid mixing and the NMR spectra were un-
interpretable. Large 20-ml vials were used for reactions
K–M to allow for a magnetic stirring bar to mix the
viscous material. In all the reactions in Table 1, the
molar ratio of sulfide to S-330 was 0.5:1, 2:1, 3:1 or
3.4:1, and theoretically there was an excess of active
chlorine from the S-330 reagent.
For the reactions D–J an aliquot was removed after
1 or 2 min, diluted in chloroform, filtered and analyzed
by GC (HD and DBS) or LC (MPS). In 1% water–
acetonitrile, a precipitate formed immediately on mix-
ing. Analysis of the solid by LC–MS indicated that it
was mostly a protonated form of the non-chlorinated
starting material, 7,8-diphenyl-2,5-diimino glycoluril,
with traces of the protonated monochloro and dichloro
glycourils. With 5% and 10% water–acetonitrile as the
solvents, all compounds remained soluble during the
reaction. Reactions in chloroform were relatively slow.
Therefore, after the initial 2-min sample, additional
samplings were drawn periodically from the mixture
for 24 h. Higher temperature was applied to hasten the
reaction of MPS.
R2S + 2 ϾNCl + 2 H2O = RSO2H + 2
ϾNH + RCl + HCl
MATERIALS AND METHODS
Reagents
The chloroamide S-330 was obtained from Ash Stevens
Inc. and analyzed in detail.6 A perfluorinated polyether
polymer oil (Fomblin ), acetonitrile and MPS were
purchased from Ausimont USA, Inc., Burdick and
Jackson and ACROS, respectively. Dibutyl sulfide,
methyl phenyl sulfone and methyl phenyl sulfoxide
were from Fluka. Hydrogen peroxide (30%) and
chloroform (0.02% water content) were acquired from
Fisher. Dibutyl sulfone and sulfoxide were prepared
from the hydrogen peroxide reaction with DBS.10 Sul-
fur mustard was supplied by the US Army Edgewood
Chemical and Biological Center.
Equipment and chromatographic conditions
The LC system consists of a Waters 510 pump, Waters
712 Wisp autoinjector and an HP Series 1100 diode-
array detector with HP Chem Station software for data
analysis. A Waters NovaPak column (3.9 × 150 mm)
and acetonitrile–water (60:40, v/v) solvent mixture
were used for LC separations. The detector was set
at 215 nm.
The LC–MS analyses were performed using a
Micromass Quattro triple quadrupole mass spectrometer
fitted with an electrospray interface. Samples were
injected using flow injection analysis with a 20-␮l
sample loop. The mobile phase was a mixture of
acetonitrile and water (50:50, v/v) delivered iso-
cratically at 5 ␮l min−1. The MS conditions were as
follows: positive ion full scan, variable sample cone
voltage and source temperature at 100° C; nitrogen was
used for both the drying and nebulization gas at flow
rates of 5 and 0.3 l min−1, respectively. Tandem MS
experiments were based on collision-induced dis-
sociations (CID) occurring in the r.f.-only hexapole
collision cell of the triple quadrupole at a collision
energy of 20 eV. The pressure of the argon in the
collision cell was controlled to give a 50% attenuation
of the selected ion beam.
Reactions in the viscous PFPE oil were stirred vigor-
ously for 2 or 4 min and then extracted with chloroform
and filtered. An aliquot was taken from the filtrate,
diluted with the appropriate solvent and analyzed by
NMR (HD), GC (DBS) or LC (MPS). Because the
reactions were slow in chloroform, it was assumed that
any reaction after extraction and dilution with chloro-
form was very slow and would not change significantly
the ratio of products.
RESULTS AND DISCUSSION
Reactions in water–acetonitrile mixture
As indicated in Table 1 (reactions A–F), all three sul-
fides HD, DBS and MPS, dissolved in mixtures of
acetonitrile and water, reacted rapidly with S-330
during the initial 2–4 min. Most of the active chlorine
of S-330 was found to be consumed during the initial
mixing time in reactions B–F. Spectrophotometric stud-
ies based on the disappearance of the UV absorbance
of the N-Cl bond indicated that the reactions are
complete in Ͻ 1 min after mixing. This extremely
rapid rate of reaction was consistent with reported
The GC–MS system consists of an HP 5890 gas
chromatograph fitted with a J&W DB17 (30 m ×
250 ␮m) capillary column and a 5972 Mass Selective
Detector using HP Chem Station software. The GC–
MS analyses were performed with the temperature
Published in 1999 by John Wiley & Sons, Ltd.
J. Appl. Toxicol. 19, S83–S88 (1999)

REACTIONS OF SULFIDES WITH S-330
S85
Table 1. Reactions of S-330 with sulfides
Reaction Sulfide
Conditions
Major products
Reaction timea
(% sulfide
reacted)
(molar ratio, sulfide/S- (% of total product)
330)
Reactions in acetonitrile
A. (CIC2H4)2S
1% H2O
(0.5: l)c
(CIC2H4)2SOb + Chlorinated HD
(19%) (40%)
4 min
(Ͼ99%)
B. (CIC2H4)2S
C. (C4H9)2S
10% H2O
3.4: l)c
(ClC2H4)2SO + ClCH2CH2SCH(Cl)CH2Cl
(48%) (21%)
4 min
(72%)
1% H2O
(2: 1)c
(C4H9)2SO + (C4H9)2SO2
Monochlorinated sulfoxided
(53%) (18%) (21%)
+
4 min
(Ͼ95%)
D. (C4H9)2S
5% H2O
(2: 1)f
(C4H9)2SO + (C4H9)2SO2
+
2 min
(Ͼ85%)
Monochlorinated sulfoxided
(50–60%)c
(25–35%)
(3–5%)
E. C6H5SCH3
F. C6H5SCH3
1% H2O
(3: 1)f
C6H5SOCH3 + C6H5SO2CH3
2 min
(Ͼ98%)
1 min
(76%)
C6H5SOCH3 + C6H5SO2CH3
(52%) (42%)
(20%)
5% H2)
(3: 1)f)
(Ͼ96%)
Reactions in chloroform
G. (ClC2H4)2S
(2: 1)g
(2: 1)g
(ClC2H4)SO
24 h
(Ͻ50%)
h
H. (C4H9)2S
(C4H9)2SO
(85–90%)c
25 h
(Ͼ90%)
J. C6H5SCH3
60°C
C6H5SOCH3 + C6H5SO2CH3 + C6H5SCH2Cl
1 h
(Ͼ92%)
(3: 1)f
(15%)
(27%)
(38%)
Reactions in PFPE oil
K. (ClC2H4)2S
(2: 1)f
(2: 1)g
(3: 1)g
(ClC2H4)2SO
i
4 min
(Ͼ99%)
L. (C4H9)2S
(C4H9)2SO + (C2H4)2SO2 + Chlorinated Sulfoxide
(60–70%)e (10–20%)e
(3–6%)
4 min
(Ͼ96%)
M. C6H5SCH3
C6H5SOCH3 + C6H5SO2CH3 + C6H5SCH2Cl
(33%) (50%) (4%)
2 min
(Ͼ96%)
aThe reaction time was the time when the reaction was quenched by dilution or extraction.
bComposition analysis was performed by integrating proton NMR signals. Both the proton and carbon signals were very
complex and detailed analysis indicated that numerous compounds were present, including a significant amount of 2,2,2′,2′-
tetrachlorodiethylsulfide. However, Ͻ1% HD and HD sulfone were also observed.
cThe solution was 7 × l0−2 M in S-330.
dAnalysis by GC–MS confirmed the chlorination of the sulfoxide, but the structure of the particular isomer was not proven.
eOverlapping and broad peaks for dibutyl sulfoxide and dibutyl sulfone in the GC–MS analysis led to variations in attempted
integrations and a lack of precision in the determination of concentrations.
fThe solution was 1.3 × 10−2 M in S-330.
gThe solution was 5 × 10−4 M in S-330.
hThe broad and weak signal for HD sulfoxide by GC–MS did not allow for quantitation of the product, but the disappearance of
the HD starting material could be determined easily.
iAn NMR analysis of the sample was not possible because of the viscosity of the sample. Extraction with chloroform gave a
trace of HD. A GC–MS analysis of an identical sample after extraction with chloroform indicated numerous small peaks, a weak
broad signal for HD sulfoxide and only a trace of HD.
observations of the reactions of sulfides with halo-
amides11–13 and an N-sulfonyloxaziridine.14
of active chlorine to sulfur atoms and 1% added water
led to a very complex mixture of compounds observed
in NMR spectra. Compounds identified were 19% HD
sulfoxide and 40% side-chain-chlorinated HD. Other
components in the mixture were not clearly identified,
including halogenated HD sulfoxides, small quantities
of vinyl sulfides and thiodiglycol. Sulfur mustard and
the relatively toxic HD sulfone15 were found only in
trace quantities in the NMR analysis, indicating a
satisfactory decontamination of HD by S-330.
Products Reactions I–IV were observed in different
quantities, depending on the particular sulfide used and
the amount of water in the solvent. Water (1:10 vol. %)
was added to the acetonitrile to reflect possible water
concentrations in formulations using S-330. The presence
of added water has been shown to increase the relative
quantity of sulfur oxidation11 and the rate of carbon–
chlorine bond hydrolysis, an additional but usually rela-
tively slow process that could also enhance the rate of
detoxifying HD.1 Reaction A of HD with an 8:1 ratio
In Reaction B, a greater ratio of HD to S-330 (3.4:1)
and an increased water concentration (10%) led to the
Published in 1999 by John Wiley & Sons, Ltd.
J. Appl. Toxicol. 19, S83–S88 (1999)

S86
M. L. SHIH ET AL.
formation of a less complex mixture (Fig. 1). Sulfur
mustard sulfoxide and 1,2,2′-trichlorodiethylsulfide
comprised 48% and 21% of the sulfur compounds,
respectively. The remaining 30% HD stayed unchanged
even after 24 h. The higher percentage of sulfoxide
than chlorinated HD in Reaction B compared with
Reaction A was consistent with the reported greater
rate of oxidation of the sulfur than chlorination of the
side chain in the higher concentration of water,11 and
with observations for Reactions C and D discussed
below. Even in the presence of 10% water, only 1%
of HD was hydrolyzed to thiodiglycol in acetonitrile.
Reactions C and D between DBS and S-330 gave
higher yields of sulfoxide formation and significant
further oxidation of the sulfoxide to sulfone compared
with the reactions of HD. This observation was consist-
ent with the reported observation that DBS reacted
nine times faster than HD in the oxidation of sulfide.14
An exact ratio of rates for this study could not be
determined because of the complexity of the reaction.
Even though the reaction with DBS is more rapid than
the reaction with HD, almost 5% of the sulfide
remained unreacted in Reaction C. This lack of com-
plete reaction even with excess S-330 was also noted
in Reaction D. Side-chain chlorination appears to occur
after the formation of sulfoxide because there was no
clear indication of side-chain chlorination of the parent
sulfide in the NMR spectrum and only a trace seen in
GC–MS analysis. Reactions E and F between MPS
and S-330 were similar to, but faster than, those with
DBS and a trace (Ͻ1%) of side-chain halogenation
was observed. Unreacted residues of MPS were lower
than the DBS reactions even though the ratio of sulfide
to S-330 was higher. The major advantages of using
MPS were that all reactants and products could be
monitored on the LC with a UV detector (Fig. 2), and
the reproducibility of quantitative determinations for
the products by LC was greater than similar determi-
nations from GC–MS analysis
Reactions in chloroform
Reactions of S-330 in chloroform (G–J in Table 1)
were dramatically slower than those in acetonitrile–
water. In reaction G, HD showed a gradual decrease
to ca. 50% after 24 h when monitored by GC–MS.
The HD sulfoxide signal was very weak and broad,
but it appeared to be the only new signal observed
during the course of the reaction. Because of the lack
of HD sulfoxide standard and the instability of the
signal in the GC–MS, a quantitative value was not
assigned to it. Reaction H with DBS was much easier
to monitor and clearly showed the increase in the
sulfoxide signal over a 25-h time period (Fig. 3). Pre-
sumably the source of oxygen for these reactions was
the trace of water (ca. 0.02%) in the chloroform and
water or ethanol left from recrystallization of S-330.
When the reaction temperature was raised to 60°C to
accelerate the reaction rate of MPS in reaction J,
the reaction time was shortened to ca. 1 h. Carbon
chlorination, giving chloromethyl phenyl sulfide,
became the principal mode of reaction.
Figure 1. Carbon 13 NMR spectrum of HD with S-330 reaction in acetonitrile (10% H2O): (A) chlorinated HD; (B) HD sulfoxide; (C) HD.
Published in 1999 by John Wiley & Sons, Ltd. J. Appl. Toxicol. 19, S83–S88 (1999)

REACTIONS OF SULFIDES WITH S-330
S87
Figure 2. The LC–UV chromatogram of the products from the reaction of MPS with S-330 in PFPE oil after extraction with
chloroform: (A) methy phenyl sulfone; (B) methyl phenyl sulfoxide; (C) MPS; (D) chloromethyl phenyl sulfide.
Figure 3. The GC–MS chromatogram of the reaction of DBS with S-330 in chloroform: (A) DBS; (B) DBS sulfoxide.
Reactions in PFPE oil
was the fastest reacting of the three sulfides under
these conditions.
Reactions in PFPE oil gave results similar to those
observed in the acetonitrile–water mixture. Extraction
of the reaction mixture of HD and S-330 with chloro-
form after 4 min gave only a trace of HD by both
NMR and GC–MS analyses. In GC–MS analysis, the
chloroform extract gave a small HD sulfoxide peak
and showed Ͻ1% of the original HD. Aqueous extrac-
tion and LC analysis of the dechlorinated S-330 that
formed immediately on mixing indicated very little
S-330 remaining in the sample.
Chloroform extraction of the reaction products in
reaction L with DBS also gave products in ratios
similar to that observed in reaction C in acetonitrile
and water. In both cases, the sulfoxides and sulfones
were the major products, with small amounts of side-
chain-chlorinated species. Sufficient moisture content
in the oil or S-330 might be present to supply the
necessary oxygen atoms to complete the oxidation. An
alternative source of the oxygen could be the terminal
hydroxyl ends of the polymer. The reaction with MPS
gave a higher yield of sulfone than sulfoxide and
Stoichiometry and mechanisms of reactions
Reactions A, B and K in Table 1 suggested that at
various concentration ratios of HD to S-330 the
decontamination reaction of S-330 would be rapid and
produce non-toxic HD sulfoxide in either water–
acetonitrile or the PFPE oil. Analysis of the stoichio-
metric relationships in reactions B, C and D indicated
that HD and DBS consumed approximately two and
three of the four possible active chlorines of S-330,
respectively, which suggested some lack of reactivity
of the monochlorinated and dichlorinated residues of
S-330. However, reactions E and F with MPS led to
almost complete consumption of active chlorine, an
observation supported by LC analysis of the dechlori-
nated glycouril after the reaction.
The mechanism of the oxidation of sulfur by haloim-
ides has been described previously12 as a nucleophilic-
type attack by the sulfide on the highly positive active
Published in 1999 by John Wiley & Sons, Ltd.
J. Appl. Toxicol. 19, S83–S88 (1999)

S88
M. L. SHIH ET AL.
chlorine followed by hydrolysis of the chlorosulfonium
ion. Our results were consistent with that mechanism,
because the weakest nucleophile of the three sulfides,
HD, gave the lowest yields of sulfoxide under similar
conditions (reactions B, D and F). The mechanism of
side-chain halogenation8 is less clear and clarification
awaits further study.
70% of the HD. The study of reaction rate and products
in the viscous and non-volatile perfluorinated polymer
oil could be difficult. The water–acetonitrile mixture
provided a suitable alternative medium for monitoring
the reaction rates and products between HD and other
chloroamide oxidizing decontaminants. The slower
reactions with S-330 in the less polar solvent chloro-
form did not reflect the rate of reaction or product
distribution of HD and other sulfides in the PFPE oil.
The two sulfides, DBS and MPS, reacted with S-330
similarly to HD and could serve as good substitute
compounds in the screening of other decontaminants.
CONCLUSIONS
Sulfur mustard could be decontaminated rapidly in
a hydrophilic or PFPE oil-based formulation oil with
a sufficient stoichiometric excess of S-330. Molar
ratios 0.5:1 and 2:1 of HD to S-330 led to the
complete conversion of HD to presumably non-vesicat-
ing materials, whereas a ratio of 3.4:1 only converted
Acknowledgements
W. D. K. greatly appreciates support from the National Research
Council and the US Army Medical Research Institute of Chemical
Defense.
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