Hydrolysis and oxidation products of the chemical warfare agents 1,2-Bis[(2-chloroethyl)thio]ethane Q and 2,2′-Bis(2-chloroethylthio) diethyl ether T

Article abstract of DOI:10.1080/10426500390228710

Syntheses of diols of structure [HOCH₂CH₂S] ₂(CH₂)_n in 86-95% yield from the sodium salt of 2-mercaptoethanol and Br(CH₂)_nBr (n = 1 to 5) or in 60-90% yield from 2-chloroethanol and NaS(CH₂)_nSNa (n = 2 to 5) are described. The diol [HOCH₂CH₂SCH ₂CH₂]₂O was prepared in 82% yield from the sodium salt of 2-mercaptoethanol and [ClCH₂CH₂] ₂O, and in 88% yield from 2-chloroethanol and [HSCH ₂CH₂]₂O. Mono- and bis-sulfoxides and bis-sulfones of these species were prepared in generally high yield by treatment with an equivalent of KIO₄ in aqueous methanol, two equivalents of NaIO₄ in aqueous methanol, or four equivalents of H₂O₂ in trifluoroacetic acid respectively. The compounds are important analytical standards for investigating the fate of the chemical warfare agents sesquimustard Q and oxygen mustard T in environmental samples.

Full text of DOI:10.1080/10426500390228710

This article was downloaded by: [University of Cambridge]
On: 23 December 2014, At: 15:48
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House,
37-41 Mortimer Street, London W1T 3JH, UK
Phosphorus, Sulfur, and Silicon and the Related
Elements
Publication details, including instructions for authors and subscription information:
http://www.tandfonline.com/loi/gpss20
Hydrolysis and Oxidation Products of the Chemical
Warfare Agents 1,2-Bis[(2-chloroethyl)thio]ethane Q
and 2,2′-Bis(2-chloroethylthio)diethyl Ether T
Christopher M. Timperley a , Robin M. Black a , Michael Bird a , Ian Holden a , Joanna L.
Mundy a & Robert W. Read a
a Defence Science and Technology Laboratory , Wiltshire, United Kingdom
Published online: 23 Aug 2006.
To cite this article: Christopher M. Timperley , Robin M. Black , Michael Bird , Ian Holden , Joanna L. Mundy & Robert W.
Read (2003) Hydrolysis and Oxidation Products of the Chemical Warfare Agents 1,2-Bis[(2-chloroethyl)thio]ethane Q and
2,2′-Bis(2-chloroethylthio)diethyl Ether T, Phosphorus, Sulfur, and Silicon and the Related Elements, 178:9, 2027-2046, DOI:
10.1080/10426500390228710
To link to this article: http://dx.doi.org/10.1080/10426500390228710
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained
in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the
Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and
are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and
should be independently verified with primary sources of information. Taylor and Francis shall not be liable for
any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever
or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of
the Content.
This article may be used for research, teaching, and private study purposes. Any substantial or systematic
reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any
form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http://
www.tandfonline.com/page/terms-and-conditions

Phosphorus, Sulfur, and Silicon, 178:2027–2046, 2003
ꢀC
Copyright Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500390228710
HYDROLYSIS AND OXIDATION PRODUCTS
OF THE CHEMICAL WARFARE AGENTS
1,2-BIS[(2-CHLOROETHYL)THIO]ETHANE Q AND
2,2ꢀ-BIS(2-CHLOROETHYLTHIO)DIETHYL ETHER T
Christopher M. Timperley, Robin M. Black, Michael Bird,
Ian Holden, Joanna L. Mundy, and Robert W. Read
Defence Science and Technology Laboratory, Wiltshire,
United Kingdom
(Received April 1, 2003; accepted May 20, 2003)
Syntheses of diols of structure [HOCH2CH2S]2(CH2)n in 86–95% yield
from the sodium salt of 2-mercaptoethanol and Br(CH2)nBr (n = 1
to 5) or in 60–90% yield from 2-chloroethanol and NaS(CH )nSNa
(n = 2 to 5) are described. The diol [HOCH2CH2SCH2CH2]22O was
prepared in 82% yield from the sodium salt of 2-mercaptoethanol
and [ClCH2CH2]2O, and in 88% yield from 2-chloroethanol and
[HSCH2CH2]2O. Mono- and bis-sulfoxides and bis-sulfones of these
species were prepared in generally high yield by treatment with an
equivalent of KIO4 in aqueous methanol, two equivalents of NaIO4 in
aqueous methanol, or four equivalents of H2O2 in trifluoroacetic acid
respectively. The compounds are important analytical standards for
investigating the fate of the chemical warfare agents sesquimustard Q
and oxygen mustard T in environmental samples.
Keywords: Chemical warfare agent; potassium periodate; sulfone;
sulfoxide; sulfur mustard
Sulfur mustard H is a potent vesicant. It was used as a chemical war-
fare agent in World War I and has been stockpiled by several countries
since. Its use during the Iran–Iraq conflict1 renewed interest in it. Two
analogues often feature in sulfur mustard mixtures: sesquimustard Q
and oxygen mustard T (Scheme 1). They are more vesicant and per-
sistent than sulfur mustard, but do not produce casualties by vapour
action due to their lower volatility.
Address correspondence to Christopher M. Timperley, Defence Science and Technol-
ogy Laboratory, Porton Down, Salisbury, Wiltshire SP4 OJQ, UK. E-mail: cmtimperley@
dstl.gov.uk
2027

2028
C. M. Timperley et al.
SCHEME 1
Sesquimustard2,3 is five times more vesicant than sulfur mustard.4
The HQ process, developed in the United Kingdom during World War II,
involved treating a 15:85 mixture of 2-mercaptoethanol and thiodiglycol
with hydrogen chloride. A 70:30 mixture of HQ resulted, having better
vesicant properties than H alone. The skin damaging effect of bis(2-
chloroethylsulfanyl)alkanes with one to ten methylene groups between
the two sulfur atoms was also examined.4 Vesicancy was maximal with
an ethylene bridge (i.e., Q itself) and diminished with increasing bridge
length. Compounds with one to five methylene groups in the bridge are
more vesicant than sulfur mustard4 and are important from the stand-
point of chemical defence. Oxygen mustard5 is 3.5 times more vesicant
than sulfur mustard.4 Thiodiglycol and gaseous hydrogen chloride at
high temperature give a 60:40 mixture of sulfur mustard and a residue
that contains T and related homologues.6−8 The resulting HT mixture
is a standard weapon fill.
The Chemical Weapons Convention9 specifically lists a number
of sulfur mustard homologues under Schedule 1 in the Annex of
Chemicals considered a threat. These include Q, T, and analogues of
structure [ClCH2CH2S]2(CH2)n where n= 1–5. Our laboratory, which
supports the Organisation for the Prohibition of Chemical Weapons
(OPCW), is required to be able to detect and identify the com-
pounds and their degradation products in environmental samples.
The Q analogue [ClCH2CH2S]2(CH2)5 and its degradation product
[HOCH2CH2SO]2(CH2)5 were used as spiking compounds in the Sixth
Official OPCW Proficiency Test. They were detected in soil and water
samples respectively and their structures confirmed by the synthesis
of analytical standards.
Degradation of sulfur mustard and its analogues occurs through
hydrolysis and oxidation. Hydrolysis occurs through a cyclic episulfo-
nium ion and results in stepwise replacement of the chlorine atoms by

Chemical Warfare Agents
2029
hydroxy groups. Oxidation of sulfur gives the sulfoxide and then the sul-
fone. These are stable and important forensic markers. Sulfur mustard
has been studied for over a century and its degradation chemistry10 is
well characterized. Little is known about the fate of Q and T except
that they behave like sulfur mustard in stagnant water,11 sinking to
the bottom and remaining hazardous for years. Hydrolysis pathways
have not been elucidated in detail but appear to parallel those of sulfur
mustard, the major products being the corresponding diols.12,13
Previous work from this laboratory described the preparation of
various derivatives of sulfur mustard14,15 for use in studies involving
analysis16,17 and metabolism.18−20 This article describes the synthe-
sis of Q and T diols and their sulfoxide and sulfone derivatives. Such
compounds are likely to be present in contaminated soil samples or bi-
ological fluids, and are important reference compounds in support of
the resolutions of the Chemical Weapons Convention. Although some
of the diols have been reported before, their purity was dubious as they
were made without the aid of modern chromatographic or analytical
techniques. Syntheses of oxidation products have not been described.
All products were prepared in over 98% purity and their structures
confirmed by NMR and IR spectroscopy, and LC-MS.
RESULTS AND DISCUSSION
The Synthesis of Q Diols
Diglycols 1a–e having one to five methylene groups bridging the sulfur
atoms were prepared in high yield by interaction of dibromoalkanes
with two molar equivalents of 2-mercaptoethanol in alcoholic sodium
ethoxide (Scheme 2). The method followed the early literature2 al-
though 1a was obtained from dibromomethane (not dichloromethane)4
and purification of the series was achieved by chromatography on silica
gel (not distillation,4 which gave impure specimens).
SCHEME 2

2030
C. M. Timperley et al.
Another route, reported only for the synthesis of 1b,15 involves treat-
ing the disodium salt of alkanedithiols with two molar equivalents of
2-chloroethanol in ethanol. This approach cannot be used for the sim-
plest homologue as HSCH2SH is unavailable. We prepared diols 1b–e
from commercial dithiols in good yield (Scheme 3).
SCHEME 3
An attempt to obtain compound 1a by condensing 2-mercaptoethanol
with formaldehyde, in the presence of concentrated sulfuric acid,
did not give the desired product, but yielded a pale yellow liquid
whose structure could not be resolved. Its LC-MS spectrum was
consistent with the formula HOC2H4SC2H4SCH2SC2H4OH, but con-
flicted with NMR data, which suggested extra hydrocarbon frag-
ments. Diols 1a–e are pale yellow liquids or low-melting white
crystalline solids. 1,2-Bis(2-hydroxyethylsulfanyl)ethane 1b, a major
hydrolysis product of Q,21 is a waxy white solid, soluble in water,
ethanol, chloroform, and acetone, slightly soluble in ether, and insol-
uble in benzene or carbon tetrachloride. Analytical data appear in
Table I.
The Synthesis of Q Diol Mono-Sulfoxides
Diols 1a-e have two sulfur atoms and methods for obtaining the prod-
ucts of selective oxidation were sought. Conversion of sulfides to sul-
foxides can be effected using an equimolar amount of aqueous sodium
periodate at 0◦C or at room temperature in a suitable cosolvent (e.g.,
methanol, ethanol, acetone, acetonitrile).22,23 Sodium iodate forms as
the byproduct. The system is mild and rarely results in overoxidation
unless high temperatures are employed. In contrast, potassium pe-
riodate has not found much, if any, application in organic synthesis,
which is surprising given its appreciably lower cost. This might arise
partly from its lower aqueous solubility, which limits its use to het-
erogeneous systems (it is 25 times less soluble in water than sodium

2031

2032

Chemical Warfare Agents
2033
periodate: solubilities at 25◦C are 0.51 g KIO4 and 12.62 g NaIO4 per
100 g water).24
We found that a potassium periodate slurry in aqueous methanol
oxidised diglycols 1a–e to monosulfoxides 2a–e at room temperature
(Scheme 4). Thin-layer chromatograms of reaction mixtures suggested
only trace amounts of the unwanted bis-sulfoxides. Work up was facile
and involved removal of the inorganic material by filtration, removal of
solvent and chromatography on silica gel. Mono-sulfoxides 2a–e are
viscous liquids or crystalline solids that exist as racemates. No at-
tempt was made to resolve the enantiomers. Analytical details appear
in Table II.
SCHEME 4
The lower reactivity of potassium periodate versus sodium periodate
was demonstrated by treating 1,1-bis(2-hydroxyethylsulfanyl)methane
1a with two molar equivalents of each and comparing the reaction rate.
After 12 h, the former yielded mainly mono-sulfoxide, the latter mainly
bis-sulfoxide. Oxidation of 1,3-bis(2-hydroxyethylsulfanyl)propane 1c
with a molar equivalent of potassium periodate or sodium periodate
was also carried out under comparable conditions. The isolated yield
of mono-sulfoxide 2c was better from KIO4 (52%) than from NaIO4
(46%).
The Synthesis of Q Diol Bis-Sulfoxides
Treatment of diols 1a–e with two molar equivalents of sodium periodate
in aqueous methanol resulted in selective oxidation of both sulfur atoms
and allowed the isolation of bis-sulfoxides 3a–e (Scheme 5). They are
white crystalline solids that exist as an enantiomeric pair and an achi-
ral meso form; individual components were not separated. Analytical
details appear in Table III.

2034
C. M. Timperley et al.
SCHEME 5
The synthesis of Q Diol Bis-Sulfones
The synthesis of sulfone derivatives of sulfur mustard and analogues of-
ten involves oxidation with hydrogen peroxide in glacial acetic acid.25−27
This suffers the drawback that acetic acid can be difficult to remove
from the product: prolonged drying under high vacuum is required.
Replacement of glacial acetic acid (b.p. 118◦C) with the more volatile
trifluoroacetic acid (b.p. 72◦C) overcomes this problem.
Treatment of diols 1a–e with four molar equivalents of hydro-
gen peroxide in trifluoroacetic acid oxidised both sulfur atoms, when
bridged by two or more methylene units, to the sulfone. 1,1-Bis(2-
hydroxyethylsulfonyl)methane 4a could not be obtained and gave a
complex mixture of products arising from cleavage of the methylene
bridge; the synthesis of geminal sulfones is known to be difficult.28
Bis-sulfones 4b–e were isolated in variable yield after chromatogra-
phy as white solids (Scheme 6). Analytical details appear in Table IV.
Our inability to prepare 4a implies that it is unlikely to be found in
environmental samples contaminated by sulfur mustard mixtures. Its
synthesis was not pursued further.
SCHEME 6

2035

2036

Chemical Warfare Agents
2037
The Synthesis of T Diol and Oxidation Products
T diol 5, from 2-chloroethyl ether and 2-mercaptoethanol in sodium
ethoxide solution, was first reported in 1948 by Woodward29 but no
yield was given. This reaction was reinvestigated and we obtained the
desired diol in 30% yield. The use of aqueous sodium hydroxide as base
increased the yield to 82%. Diol 5 was isolated by chromatography on
silica gel as a waxy white solid that melted between 31–32◦C (in agree-
ment with Woodward).29 An alternative route from 2-mercaptoethyl
ether gave the same compound in 88% yield (Scheme 7).
SCHEME 7
Mono-sulfoxide 6, bis-sulfoxide 7, and bis-sulfone 8 were prepared
in 45%, 86%, and 58% yield, respectively, by employing the oxidising
systems used for the Q derivatives (Figure 1). Analytical details appear
in Table V.
In summary, the synthesis of six diols by two routes, from dihaloalka-
nes or alkanedithiols, has been studied. With the exception of 1,1-bis(2-
hydroxyethylsulfanyl)methane, for which the former route is the only
option, there is little advantage between the two routes in terms of
yield. In the case of the Q derivatives, the former is more economical
than the latter, as the starting dibromoalkanes are less expensive than
FIGURE 1 T diol oxidation products.

2038

Chemical Warfare Agents
2039
the corresponding alkanedithiols. Syntheses of pure compounds are de-
scribed, updating those of 50 years ago. Selective methods to oxidation
products also are outlined. These products are relevant to investiga-
tions involving the chemical warfare agents Q and T, and to analytical
support for the Chemical Weapons Convention.
EXPERIMENTAL
Warning: 2-Chloroethyl ether is a potent alkylating agent and carcino-
gen and should only be used by trained personnel in an efficient fume
cupboard. Reagents were purchased from Aldrich Ltd. (Gillingham,
UK) and used as received. Anhydrous solvents were employed in all
˚
experiments. Thin layer chromatography plates, MK6F silica gel 60 A
(2.5 × 7.5 cm, layer thickness 250 µm), were obtained from Whatman
(Maidstone, UK). Product spots were visualised with iodine vapor un-
less stated otherwise. Silica gel for flash chromatography was from
BDH Laboratory Supplies (Poole, UK). NMR spectra were obtained on
1
a JEOL Lambda 500 instrument (operating at 500 MHz for H and
125 MHz for 13C spectra) or Lambda 300 instrument (operating at
300 MHz for 1H and 75 MHz for 13C spectra) as solutions in CDCl3 un-
less stated otherwise, with internal reference SiMe4. Data are recorded
as follows: chemical shifts in ppm from reference on the δ scale, integra-
tion, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, and
m = multiplet; br = broad), coupling constant (J/Hz) and assignment.
IR spectra were recorded as liquid films on a Nicolet SP210 instrument
using Omnic software.
LC-MS of T and Q Hydrolysis and Oxidation Products
Compounds were analyzed as 10 µg/mL solutions in water. LC-MS was
performed using a published method.30 Brief details are as follows: A
Hewlett-Packard LC system consisting of a model 1050 pump plus sol-
vent conditioner was used. The system was fitted with a 150 × 2 mm
internal diameter Columbus C18 column (Phenomenex). The mobile
phase comprised 0.02 M ammonium formate in H2O (solvent A) and
0.02 M ammonium formate in MeOH (solvent B). The elution gradi-
ent was 5% B (0–5 min) to 90% B (15–20 min) at a flow rate of 0.2
mL/min. Injections (10 µL) were made using a Rheodyne 9125 in-
jector fitted with a 20 µL PEEK loop. The effluent was introduced
into a Finnigan TSQ700 mass spectrometer operated in atmospheric
pressure chemical ionisation mode. Source conditions: corona cur-
rent 2 µA, vaporizer temperature 400◦C, capillary temperature 150◦C,

2040
C. M. Timperley et al.
TABLE VI LC-MS Data for Q and T Hydrolysis and Oxidation Products
MH+ M + NH+4
Compound
Q diols
Structure
n
Number (m/z)
(m/z)
(CH2)n(SCH2CH2OH)2
1
2
3
4
5
1
2
3
4
5
1
2
3
4
5
2
3
4
5
—
1a
1b
1c
1d
1e
2a
2b
2c
2d
2e
3a
3b
3c
3d
3e
4b
4c
4d
4e
5
169
183
197
211
225
185
199
213
227
241
201
215
229
243
257
247
261
275
289
227
243
259
291
186
200
214
228
242
—
—
—
—
—
218
—
—
—
—
264
278
292
306
244
—
Q mono-sulfoxides HOC2H4S(CH2)nSOC2H4OH
Q bis-sulfoxides
(CH2)n(SOCH2CH2OH)2
Q bis-sulfones
T derivatives
(CH2)n(SO2CH2CH2OH)2
O(CH2CH2SCH2CH2OH)2
HOC2H4S(CH2)2O(CH2)2SOC2H4OH —
O(CH2CH2SOCH2CH2OH)2
O(CH2CH2SO2CH2CH2OH)2
6
7
8
—
—
—
308
sheath gas (nitrogen) 60 psi and auxiliary gas (nitrogen) flow me-
ter reading 20. The source octapole (Q0) was operated at an offset of
−5 V.
Compounds gave a single major peak in the total ion chromatogram
(Table VI). All produced protonated molecular ions (MH+) and some
the ammoniated ion (M + NH4+). The ion M + NH+4 constituted the base
peak of the spectra obtained for sulfones.
The Synthesis of Bis(2-hydroxyethylsulfanyl)alkanes
1 a --- e
Procedures for 1,2-bis(2-hydroxyethylsulfanyl)ethane 1b are given. Ho-
mologues were prepared on the same molar scale and purified by
chromatography on silica gel eluting with 19:1 chloroform-methanol.
Retention factors (Rf values) are given in Table I.
From 1,2-dibromoethane: Absolute ethanol (100 mL) and a magnetic
flea were added to a 250 mL three-neck round-bottomed flask. The

Chemical Warfare Agents
2041
centre neck was fitted with a double-surface water condenser and the
side necks with stoppers. Sodium (4.6 g, 0.2 mol) in small pieces was
added in portions to the stirred ethanol until all the metal had dis-
solved. 2-Mercaptoethanol (15.6 g, 0.2 mol) was added quickly. The reac-
tion mixture warmed appreciably. 1,2-Dibromoethane (18.8 g, 0.1 mol)
was added dropwise over 15 min from a pressure-equalising funnel.
The mixture heated almost to the point of reflux and a white pre-
cipitate formed. After addition, the mixture was maintained at re-
flux for 1 h. After cooling, the precipitate was filtered through Celite
and the solvent removed. Chromatography of the crude product, elut-
ing with 19:1 chloroform-methanol, gave 1b as a white solid (15.73 g,
86%).
From 1,2-ethanedithiol: Absolute ethanol (100 mL) and a magnetic
flea were added to a 250 mL three-neck round-bottomed flask. The
center neck was fitted with a double-surface water condenser and
the side necks with stoppers. Sodium (4.6 g, 0.2 mol) in small pieces
was added in portions to the stirred ethanol until all the metal had
dissolved. Ethane-1,2-dithiol (9.4 g, 0.1 mol) was added in one por-
tion. The mixture warmed slightly. 2-Chloroethanol (16.1 g, 0.2 mol)
was added dropwise over 20 min from a pressure-equalizing funnel.
The mixture heated almost to the point of reflux and a white pre-
cipitate formed. After addition, the mixture was maintained at re-
flux for 1 h. After cooling, the precipitate was filtered through Celite
and the solvent removed. Chromatography of the crude product, elut-
ing with 19:1 chloroform-methanol, gave 1b as a white solid (14.66 g,
81%).
Attempted Synthesis of 1,1-Bis(2-hydroxyethylsulfanyl)-
methane 1a Using Formaldehyde
A few drops of concentrated sulfuric acid (0.3–0.5 mL) were added to
a stirred solution of 2-mercaptoethanol (15.6 g, 0.2 mol) and formalde-
hyde (8.11 g of 37% w/w formaldehyde in water, 0.1 mol). The mixture
became very hot and almost boiled, and on standing gradually became
cloudy. It was left to stand at room temperature for 24 h, made into
a paste with anhydrous sodium sulfate and heated to 100◦C for 2 h.
After cooling to room temperature, water (150 mL) was added to dis-
solve most of the solid. The mixture was extracted with ether (4 × 50
mL) and the combined extracts dried (Na2SO4). Analysis by TLC us-
ing 19:1 chloroform-methanol showed a main spot (Rf 0.15) and some
fainter faster-running spots. The drying agent was filtered off and the
filtrate concentrated to a colorless liquid (11.74 g). Chromatography

2042
C. M. Timperley et al.
on silica gel, eluting with the solvent system mentioned above, gave a
yellow liquid (5.7 g). Its structure could not be determined with any
confidence.
The Synthesis of 2-(Hydroxyethylsulfanyl)
2ꢀ -(Hydroxyethylsulfinyl) Alkanes 2a---e
Comparable procedures for mono-oxidation of 1,3-bis(2-hydroxyethyl-
sulfanyl)propane 1c with potassium periodate and sodium periodate
are given. Homologues were prepared on the same molar scale using
potassium periodate and purified by chromatography on silica gel, elut-
ing with 9:1 dichloromethane-methanol. Retention factors are given in
Table II.
Using potassium periodate: A solution of 1,3-bis(2-hydroxyethyl-
sulfanyl)propane 1c (3.92 g, 0.02 mol) in methanol (100 mL) and a
magnetic flea were added to a 250 mL three-neck round-bottomed flask.
The center neck was fitted with a double-surface water condenser, one
of the side necks with a dropping funnel and the other with a stop-
per. A slurry of potassium periodate (4.6 g, 0.02 mol) in water (50 mL)
was added dropwise over 5 min. The mixture warmed. After addi-
tion, stirring was continued for 2 h and the mixture left to stand for
12 h. Analysis by TLC, eluting with 9:1 dichloromethane-methanol,
showed three compounds: starting material (Rf 0.6), an unidentified
minor component (Rf 0.5, visualized poorly by iodine vapor), the de-
sired mono-sulfoxide (Rf 0.2) and a minor spot for the bis-sulfoxide (Rf
0.05). The inorganic material was removed by filtration and the solvent
removed from the filtrate to give a colorless liquid containing a little
white solid (4.8 g). Chromatography of this on silica gel, eluting with
9:1 dichloromethane-methanol, gave 2c as a viscous pale yellow liquid
(2.2 g, 52%).
Using sodium periodate: A solution of 1,3-bis(2-hydroxyethyl-
sulfanyl)propane 1c (3.92 g, 0.02 mol) in methanol (100 mL) and a
magnetic flea were added to a 250 mL three-neck round-bottomed flask.
The center neck was fitted with a double-surface water condenser, one
of the side necks with a dropping funnel and the other with a stop-
per. A solution of sodium periodate (4.28 g, 0.02 mol) in water (40 mL)
was added dropwise over 40 min. The mixture became warm and a
thick white precipitate was produced. After addition, stirring was con-
tinued for a further 3.5 h. Analysis of the reaction mixture by TLC,
eluting with 9:1 dichloromethane-methanol, showed the presence of
three compounds: starting material (Rf 0.5), the desired mono-sulfoxide
(Rf 0.1) and a faint spot for the bis-sulfoxide (on the baseline). The in-
organic material was removed by filtration and the solvent removed to

Chemical Warfare Agents
2043
give a sticky white solid (4.6 g). Chromatography of this on silica gel,
eluting with the solvent system mentioned before, gave pure 2c (1.9 g,
46%).
The Synthesis of Bis(2-hydroxyethylsulfinyl)alkanes 3a---e
This general procedure is illustrated for the synthesis of 1,2-bis(2-
hydroxyethylsulfinyl)ethane 3b. A solution of sodium periodate (8.56 g,
0.04 mol) in water (40 mL) was added dropwise to a stirred solution of
1,2-bis(2-hydroxyethylsulfanyl)ethane 1b (3.64 g, 0.02 mol) in methanol
(100 mL). A white precipitate formed. After addition, the mixture was
stirred at room temperature for 1 h. The precipitate was filtered off
and the solvent removed. Chromatography of the residue on silica gel,
eluting with 3:1 chloroform-methanol, gave 3b as a white solid (3.52 g,
82%). M.p. 113–115◦C.
The Synthesis of Bis(2-hydroxyethylsulfonyl)alkanes
4b---e
This general procedure is illustrated for the synthesis of 1,2-bis(2-
hydroxyethylsulfonyl)ethane 4b. A 100 mL two-neck round-bottomed
flask was equipped with a magnetic flea, a double-surface water con-
denser and a dropping funnel. The flask was charged with a solution
of 1,2-bis(2-hydroxyethylsulfanyl)ethane 1b (3.64 g, 0.02 mol) in triflu-
oroacetic acid (20 mL). Hydrogen peroxide (10 mL of a 27.5% aqueous
solution, 10% molar excess) was added in portions over 40 min. The
temperature rose quickly, almost causing the solution to reflux. After
addition, the mixture was heated under reflux for 90 min. The trifluo-
roacetic acid and water were removed using a rotary evaporator then an
oil pump. Analysis of the residue by TLC in 12:1 chloroform-methanol,
using a dilute solution of potassium permanganate in acetone as visu-
alizing agent, showed the desired product (Rf 0.1) as a white spot on a
pink background. Chromatography on silica gel, using the same solvent
system, gave 4b as a white solid (3.1 g, 63%).
2,2ꢀ -Bis(2-hydroxyethylsulfanyl)diethyl Ether 5
From 2-chloroethyl ether and NaOEt: 2-Mercaptoethanol (7.8 g, 0.1 mol)
was added to a solution of sodium ethoxide prepared from sodium metal
(2.3 g, 0.1 mol) and absolute ethanol (40 mL). 2-Chloroethyl ether (7.2 g,
0.05 mol) was added dropwise over 10 min. The mixture warmed up and
turned cloudy. After addition, it was heated under reflux for 1 h. A thick
precipitate of sodium chloride formed. The reaction mixture was filtered

2044
C. M. Timperley et al.
through Celite, the precipitate rinsed with ethanol, and the solvent re-
moved from the filtrate to leave a viscous yellow liquid. Anhydrous ace-
tone (30 mL) was added to precipitate residual sodium chloride, which
was removed by a second filtration through Celite. The filtrate was con-
centrated and the crude product distilled using a Kugelrohr apparatus
to yield a yellow liquid that solidified on standing overnight (9.9 g). B.p.
∼100◦C/0.02 mmHg. The product was not pure by TLC analysis. Chro-
matography on silica gel, eluting with 19:1 chloroform-methanol, gave
in order of elution: a small amount of an unidentified product (Rf 0.5),
possibly a mono-dehydration product, the title compound (Rf 0.1), and
2-chloroethanol (Rf 0.05). Compound 5 was obtained as a white solid
(3.44 g, 30%).
From 2-chloroethyl ether and NaOH: Sodium hydroxide pellets (8 g,
0.2 mol) were dissolved in water (8 mL) and absolute ethanol (65 mL).
2-Mercaptethanol (15.6 g, 0.2 mol) was added and the mixture stirred
and heated to 45◦C. 2-Chloroethyl ether (14.3 g, 0.1 mol) was added
dropwise over 20 min. A white precipitate formed. After addition, the
mixture was heated under reflux for 20 min, allowed to cool to room
temperature and left for 12 h. Filtration through Celite and removal
of solvent gave a yellow liquid (23.5 g). Chromatography on silica gel,
eluting with 19:1 chloroform-methanol, gave pure compound 5 (18.58 g,
82%).
From 2-mercaptoethyl ether and NaOEt: A solution of sodium
ethoxide was prepared by the addition of sodium metal (4.6 g,
0.2 mol) in small pieces to absolute ethanol (100 mL) with stirring.
2-Mercaptoethyl ether (13.8 g, 0.1 mol) was added. The mixture turned
light yellow. 2-Chloroethanol (16.1 g, 0.2 mol) was added dropwise over
15 min. The mixture warmed up and sodium chloride precipitated. After
addition, the mixture was heated under reflux for 1 h. The precipitate
thickened. Filtration of the mixture through Celite and removal of sol-
vent from the filtrate gave a pale yellow liquid. Chromatography on
silica gel, eluting with 19:1 chloroform-methanol, gave pure compound
5 (19.89 g, 88%). Rf 0.1.
2-(Hydroxyethylsulfanyl) 2ꢀ -(hydroxyethylsulfinyl)diethyl
Ether 6
A
slurry of potassium periodate (2.3 g, 0.01 mol) in water
(25 mL) was added over 5 min to a stirred solution of bis(2-
hydroxyethylsulfanyl)ethyl ether 5 (2.26 g, 0.01 mol) in methanol
(50 mL). The mixture warmed slightly. After addition, stirring was con-
tinued for a further 4 h with monitoring by TLC after 30, 90, 150, and
240 min. All TLC plates were similar and showed, after staining with

Chemical Warfare Agents
2045
iodine vapor, significant starting material and mono-sulfoxide spots (Rf
values 0.45 and 0.15), and a faint bis-sulfoxide spot (Rf 0.05). The in-
tensity of the first two spots appeared to change in favor of the mono-
sulfoxide as time elapsed. The mixture was filtered to remove inorganic
material and the solvent removed from the filtrate to leave a viscous
liquid containing some white solid (2.66 g). Chromatography on silica
gel, eluting with 9:1 dichloromethane-methanol, gave compound 6 as a
pale yellow liquid (1.09 g, 45%).
2,2ꢀ -Bis(2-hydroxyethylsulfinyl)diethyl Ether 7
A solution of sodium periodate (4.28 g, 0.02 mol) in water (40 mL)
was added over 15 min to a stirred solution of bis(2-hydroxyethyl-
sulfanyl)ethyl ether 5 (2.26 g, 0.01 mol) in methanol (80 mL). The mix-
ture warmed up and a thick white precipitate formed. After stirring for
a further 2 h, the mixture was analyzed by TLC using 3:1 chloroform-
methanol. A very faint spot (Rf 0.8) for an unknown minor product, a
faint spot for the starting material (Rf 0.5), and a spot of moderate in-
tensity corresponding to the bis-sulfoxide (Rf 0.15) was observed. The
mixture was left for 12 h at room temperature. Futher TLC analysis
indicated no change. The precipitate was removed by filtration and the
solvent removed to leave a white solid (3.1 g). Chromatography on silica
gel, eluting with the solvent system mentioned before, gave compound
7 as a very viscous colourless liquid (2.22 g, 86%).
2,2ꢀ -Bis(2-hydroxyethylsulfonyl)diethyl Ether 8
A 50 mL two-neck round-bottomed flask was equipped with a magnetic
flea, a double-surface water condenser and a dropping funnel. The flask
was charged with a solution of bis(2-hydroxyethylsulfanyl)ethyl ether
5 (2.26 g, 0.01 mol) in trifluoroacetic acid (10 mL). Hydrogen peroxide
(5 mL of a 27.5% aqueous solution, 1.1 molar equivalents) was added
in six portions over 10 min. The oxidation is exothermic: the mixture
heated to the point of reflux after half the peroxide had been added.
After addition, the mixture was maintained under reflux for 60 min.
Analysis by TLC was inconclusive. The trifluoroacetic acid and water
were removed by rotary evaporation to give a syrup (3.67 g). Chro-
matography on silica gel, eluting with 9:1 dichloromethane-methanol,
gave compound 8 as a very viscous colourless liquid (1.68 g, 58%).
REFERENCES
[1] R. M. Black, R. J. Clarke, R. W. Read, and M. T. J. Reid, J. Chromatogr. A, 662, 301
(1994).

2046
C. M. Timperley et al.
[2] G. M. Bennett and E. M. Whincop, J. Chem. Soc., 119, 1860 (1921).
[3] G. M. Bennett, J. Chem. Soc., 121, 2139 (1922).
[4] E. J. Gasson, H. McCombie, A. H. Williams, and F. N. Woodward, J. Chem. Soc., 44
(1948).
[5] J. S. H. Davies and A. E. Oxford, J. Chem. Soc., 119, 224 (1931).
[6] E. M. Meade and R. C. G. Moggridge, J. Chem. Soc., 813 (1946).
[7] R. J. Charnock and R. C. G. Moggridge, J. Chem. Soc., 815 (1946).
[8] R. Brown and R. C. G. Moggridge, J. Chem. Soc., 816 (1946).
[9] Convention on the Prohibition of the Development, Production, Stockpiling and Use
of Chemical Weapons and on their Destruction, Organisation for the Prohibition of
Chemical Weapons (OPCW), The Hague (1994).
[10] N. B. Munro, S. S. Talmage, G. D. Griffin, et al., Environ. Health Perspect., 107, 933
(1999).
[11] M. Mazurek, Z. Witkiewicz, S. Popiel, and M. Sliwakowski, J. Chromatogr. A, 919,
133 (2001).
[12] P. A. D’Agostino and L. R. Provost, J. Chromatogr., 645, 283 (1993).
[13] P. A. D’Agostino, L. R. Provost, and J. R. Hancock, J. Chromatogr. A, 808, 177 (1998).
[14] J. M. Harrison, J. Labelled Comps. and Radiopharm., 29, 1175 (1991).
[15] R. M. Black, K. Brewster, J. M. Harrison, and N. Stansfield, Phosphorus, Sulfur,
and Silicon, 71, 31 (1992).
[16] R. M. Black, K. Brewster, R. J. Clarke, and J. M. Harrison, Phosphorus, Sulfur, and
Silicon, 71, 49 (1992).
[17] R. M. Black and R. W. Read, J. Chromatogr. A, 759, 79 (1997).
[18] J. L. Hambrook, J. M. Harrison, D. J. Howells, and C. Schock, Xenobiotica, 22, 65
(1992).
[19] R. M. Black, J. M. Harrison, and R. W. Read, Xenobiotica, 27, 11 (1997).
[20] R. M. Black, R. J. Clarke, J. M. Harrison, and R. W. Read, Xenobiotica, 27, 499
(1997).
[21] W. H. Stein, J. S. Fruton, and M. Bergmann, J. Org. Chem., 11, 692 (1946).
[22] L. A. Paquette (ed.), Encyclopedia of Reagents for Organic Synthesis (John Wiley &
Sons, Chichester, UK, 1995), vol. 7, p. 4613.
[23] G. H. Whitham, Organosulfur Chemistry (Oxford Chemistry Primers, Oxford
University Press, 1995), number 33.
[24] A. E. Hill, J. Am. Chem. Soc., 50, 2678 (1928).
[25] A. H. Ford-Moore, R. A. Peters, and R. W. Wakelin, J. Chem. Soc., 1754 (1949).
[26] A. H. Ford-Moore, J. Chem. Soc., 2126 (1949).
[27] A. H. Ford-Moore, J. Chem. Soc., 2433 (1949).
[28] Y. Zhu and D. G. Drueckhammer, Tetrahedron Lett., 43, 1377 (2002).
[29] F. N. Woodward, J. Chem. Soc., 35 (1948).
[30] R. W. Read and R. M. Black, J. Chromatogr. A, 862, 169 (1999).