Hydrolysis of sesquimustards

Article abstract of DOI:10.1071/CH02181

The hydrolysis of the sesquimustards 1,2-bis(2-chloroethylthio)ethane (QN2) and 1,3-bis(2-chloroethylthio) propane (QN3) has been studied by ¹H and ¹³C nuclear magnetic resonance spectroscopy. For both sesquimustards, stable cyclic sulfonium ions were observed in hydrolysis experiments in a 1 : 1 mixture of [D₆]acetone and D₂O. The cyclic sulfonium ions, which persist in the aqueous solution for up to a week, are likely to retain some toxicity and could possibly be used as markers for sesquimustards in the analysis of mustard-contaminated soil for chemical weapons treaty verification. The formation of a macrocyclic oxadithiaether was also demonstrated for QN2 but not QN3.

Full text of DOI:10.1071/CH02181

CSIRO PUBLISHING
www.publish.csiro.au/journals/ajc
Aust. J. Chem. 2003, 56, 309–313
Hydrolysis of Sesquimustards
A
B
A,C
Timothy D. St Quintin, D. Ralph Leslie and J. Grant Collins
A
School of Chemistry, University College, University of New South Wales,
Australian Defence Force Academy, Canberra 2600, Australia.
Aeronautical and Maritime Research Laboratory, Defence Science and Technology Organisation,
P.O. Box 4331, Melbourne 3001, Australia.
B
C
Author to whom correspondence should be addressed (email: g-collins@adfa.edu.au).
The hydrolysis of the sesquimustards 1,2-bis(2-chloroethylthio)ethane (QN2) and 1,3-bis(2-chloroethylthio)
1
13
propane (QN3) has been studied by H and C nuclear magnetic resonance spectroscopy. For both sesquimustards,
stable cyclic sulfonium ions were observed in hydrolysis experiments in a 1 : 1 mixture of [D6]acetone and D2O.
The cyclic sulfonium ions, which persist in the aqueous solution for up to a week, are likely to retain some toxicity
and could possibly be used as markers for sesquimustards in the analysis of mustard-contaminated soil for chemical
weapons treaty verification. The formation of a macrocyclic oxadithiaether was also demonstrated for QN2 but
not QN3.
Manuscript received: 4 September 2002.
Final version: 13 November 2002.
CH3
Introduction
S
N
Due to its use as a chemical warfare agent, the reac-
Cl
Cl
Cl
Cl
ꢀ
tions of sulfur mustard (2,2 -dichlorodiethylsulfide; HD)
Sulfur Mustard (HD)
Nitrogen Mustard
[1–8]
have been extensively studied.
As a highly lipid-soluble
molecule, sulfur mustard can rapidly penetrate the skin and
alkylate a range of biomolecules. Vesication (blistering of
the skin) results from the cleavage of the basal cell mem-
brane from the basement membrane (the two lower layers
Cl
S
S
S
S
Cl Cl
Cl
Sesquimustard (QN2)
Sesquimustard (QN3)
[9]
of the epidermis). However, the mechanism of vesica-
tion is not well understood. One theory proposes that, via
a sequence of enzymatic processes, DNA alkylation leads to
the reduction in cellular levels of nicotinamide adenine din-
Scheme 1. Structure of sulfur mustard (HD), nitrogen mustard, and
the sesquimustards (QN2 and QN3).
+
ucleotide (NAD ), an important component of glycolysis.
Consequently, as has been the case for HD, it is now important
to develop an understanding of the reactions of sesquimus-
tards with water and various biomolecules in order to develop
antidotes and/or pretreatments.
The mechanism of hydrolysis of HD has been extensively
studied,
shares a common reaction mechanism and also because water
is a major component of biological systems. Kinetic and
mechanistic studies have shown that HD is hydrolyzed by the
initial formation of a transient cyclic sulfonium ion with the
The disruption of glycolysis leads, ultimately, to the activa-
tion of cellular proteases that are thought to cause disruption
to the dermal–epidermal attachments, resulting in blister
[
10,11]
formation.
interstrand cross-linking prevents the unwinding of the DNA
Alternatively, it has been proposed that DNA
[
1–5]
as its substitution by biological nucleophiles
[
11]
helix required for protein, RNA, and DNA synthesis. Con-
sequential cell death results in separation of the epidermis
from the dermis, forming blisters.
Sesquimustards, Scheme 1, were first described in the
[
12]
[3]
literature in 1921.
chloroethylthio)ethane (QN2) and 1,3-bis(2-chloroethylthio)
Of the sesquimustards, 1,2-bis(2-
loss of a chloride ion. The sulfonium ion then rapidly reacts
with water, forming 2-chloroethyl-2-hydroxyethylsulfide and
a hydrogen ion. The second chloroethyl group is hydrolyzed
by the same mechanism to give thiodiglycol. However, for
the sesquimustards, there is the possibility for the formation
of larger-ringed cyclic sulfonium ions through the nucleo-
philic attack of the sulfur atom distal to the carbon bearing
the chloro group. These larger ringed cyclic sulfonium ions
[13]
propane (QN3) have the greatest vesicant power. Although
QN2 and QN3 have significantly greater vesicant properties
than HD, sesquimustards have to date not been stockpiled
or used as chemical warfare agents, primarily due to their
very low vapour pressures. However, dissemination of these
agents will produce a highly persistent liquid contact hazard.
©
CSIRO 2003
10.1071/CH02181
0004-9425/03/04309

3
10
T. D. St Quintin, D. R. Leslie and J. G. Collins
should be considerably more stable than the 3-membered
ring formed by HD. Indeed, 2-chloroethyl-1,4-dithianium has
been recently identified, and a pathway for its formation pro-
posed (Scheme 2), as the major decomposition product of HD
(3.73 ppm). The structure of QN3–OD was confirmed by gas
chromatography–mass spectroscopy (GCMS). During the
course of the reaction, small but significant additional peaks
1
are also observed in the H NMR spectra, e.g. 4.16, 3.18, and
[
14]
in storage containers.
It is important to confirm the for-
2.27 ppm.As the purity of the QN3 sample was determined to
be >99% by GC analysis, these peaks must represent inter-
mediates in the hydrolysis reaction (see Scheme 3). These
peaks are not consistent with QN3–III, the expected product
of the first step of the hydrolysis.
mation and stability of the cyclic sulfonium ions formed by
sesquimustards, and subsequently, their physiological effects
and toxicities. In this paper we present the results of an NMR
study of the hydrolysis of QN2 and QN3.
In the 13C NMR spectrum of the mixture after 7 days (see
Fig. 3), resonances from QN3 and the QN3–OH product are
observed along with one apparent set of six resonances of
Results and Discussion
Hydrolysis of QN3
1
Figure 1 shows the H NMR spectra of QN3 at various
times after it was dissolved in a 1 : 1 solution of D2O and
6
β
2
β
7
S
S
5
[
D6]acetone. At 10 minutes the major peaks are assigned,
+
S
9
Cl
Cl
α
1
3
α
S
X
using the nomenclature shown in Figure 2, to the H1 (2.75),
8
H2 (1.90), Hα (2.93), and Hβ (3.77 ppm) of QN3. After
3
2
3
0 days, the reaction has proceeded to one dominant prod-
βЈ
β
2
ꢀ
ꢀ
ꢀ
ꢀ
uct, QN3–OH: H1 (2.70), H2 (1.88), Hα (2.72), and Hβ
S
S
S
X = Cl or OH
9
Cl
OH
OH
3Ј
αЈ
α
1
+
S
8
S
Cl-
βЈ
βЈ
O
2Ј
+
Cl
Cl
Cl
S
2
S
HO
αЈ
1Ј
3Ј
αЈ
HD
3
6
S
5
Cl
Cl
Cl
Cl
Fig. 2. StructureandatomnumberingofQN3, QN3–III, andQN3–OH
(top to bottom on left), the cyclic sulfonium ions QN3–II (X = Cl) and
QN3–VI (X = OH), and 1-oxa-4,7-dithiacyclononane.
S
S
+
S
S+
S
S
Cl-
Cl
Cl
+
Cl-
+
H2
C
H2
C
H2
C
S
S
Cl
Cl
C
H
C
H
C
H
C
H
Cl
Cl
2
2
2
2
QN3
Scheme 2. Proposed pathway by which 2-chloroethyl-1,4-dithianium
is formed from HD.
[14]
H
C
2
H
C
2
+
S
S
CH
2
+
S
Cl
C
H
C
H
C
H
S
Hβ'
2
2
2
Cl
CH
2
Hα' H1'
30 days
acetone H2'
QN3-I
QN3-II
+
H2O
- H
C
H
C
2
H
C
2
H
2
C
7
days
S
S
H
C
2
H
C
2
H
C
2
H
C
2
Cl
C
H
C
C
H
OH
S
2
H
2
H
2
2
Cl
C
H
C
2
S
C
H
OH
2
H
2
18 hrs
QN3-III
QN3-IV
H9*
3
10 min
30 min
+
H
C
2
H
C
2
H
2
C
S
S
+
S
C
H
C
H
C
H
OH
S
1
CH
2
2
2
2
OH
QN3-V
QN3-VI
5
0 min
0 min
H2O - H+
1
Hβ
Hα H1
H2
H2
C
H2
C
H2
C
H
C
2
H
C
2
H
C
2
H
C
2
4
.0 3.8 3.6 3.4 3.2 3.0 2.8 2.6 2.4 2.2 2.0 ppm
S
S
S
HO
C
H
C
H
C
H
C
H
OH
HO
C
H
C
S
C
H
OH
2
2
2
2
2
H
2
2
1
◦
Fig. 1. H NMR spectra of QN3 in 1 : 1 [D6]acetone/D2O at 25 C as
a function of time after the addition of QN3 to the [D6]acetone/D2O
mixture. H9 indicates the H9 resonance assigned to QN3–VI at
QN3-OH
QN3-VII
∗
4
.16 ppm.
Scheme 3. Proposed reaction pathway for the hydrolysis of QN3.

Hydrolysis of Sesquimustards
311
similar significant intensity that do not belong to the QN3.
The three resonances in the 39–45 ppm region are consis-
tent with carbon atoms adjacent to either chlorine atoms
result in the observation of a significant amount of QN3–
VII. This suggests that the mechanism of hydrolysis for the
stable sulfonium ion QN3–VI, and hence QN3–II (should it
form), through QN3–V and QN3–I, respectively, is strongly
favoured over direct hydrolysis of QN3–VI and QN3–II.
While QN3–VI builds up to a significant extent in the 7th
[4]
or a positively charged sulfur atom. The resonances from
carbon atoms next to an oxygen atom occur significantly fur-
ther downfield (50–65 ppm). QN3–VI is the only possible
intermediate that would be expected to give three, and only
three, resonances in the 39–45 ppm region. The assignment
13
day C NMR spectrum, QN3–II does not accumulate to any
extent throughout the hydrolysis experiment. This could be
due to the ability of QN3–II to undergo an SN2-type reaction
with water to form QN3–VI, which in turn can only undergo
hydrolysis. However, this seems unlikely given that the half-
life for the hydrolysis of the first 2-chloroethylsulfide group
1
3
of the six C resonances to QN3–VI (see Table 1) was con-
1
firmed by the ability to assign corresponding H resonances
1
3
to the C resonances in a GHSQC (pulsed field gradient,
heteronuclear single-quantum correlation) spectrum, and the
subsequent confirmation of the H2–H3, H5–H6–H7, and
[
5]
in HD is approximately 12 min, and the rate of hydrolysis
1
1
6
H8–H9 J-coupled spin systems in a H– H DQFCOSY
double-quantum filtered correlated spectroscopy) spectrum.
of 2-chloroethyl methyl sulfide is 10 times that of n-butyl
[
15]
(
chloride.
A more likely explanation is that while the for-
The seventh carbon resonance (C5) of QN3–VI was identified
under the acetone peaks.
mation of QN3–I is greatly favoured over the formation of
QN3–II, QN3–VI can build up because there is no competing
reaction for the sulfur atom on the β-carbon to the hydroxyl
group in QN3–III.
Although the formation of QN3–VI was established, there
was no evidence of QN3–VII in the 43rd day 13C NMR
spectrum. Therefore, QN3–VI must only lead to QN3–OH,
and without the formation of another stable intermediate,
1
In the H NMR spectra of the QN3 hydrolysis, several
additional sets of resonances are also observed near the reso-
nances from QN3–VI. These resonances, which appear after
about 10 min but then decrease in relative proportion to those
of QN3–VI, are most likely due to acyclic sulfonium ions,
such as that formed from the reaction of QN3–I with QN3–III
+
since attack on the carbons positioned α to the S should
Cβ'
C1'
(see Scheme 4). The chemical shift for most of the reso-
Cα'
QN2
nances in suchions wouldbe similar to those from QN3–VI or
QN3. For example, as shown in Figure 1, either of the triplets
24-40 hrs
(
4.25 and 4.11 ppm) near the triplet assigned to H9 of QN3–
+
VI (4.16 ppm) could be assigned to the S CH2CH2–OH of
the ion in Scheme 4. The formation of other acyclic sulfo-
nium ions cannot be excluded. Hydrolysis of these potential
dimericsulfoniumionswouldbethroughthereversereaction,
to give the episulfonium ion, analogously to the proposed
hydrolysis pathway for QN3–VI.
QN2
28 days
QN3
7
days
QN3
Cβ'
C1'
Hydrolysis of QN2
Cα'
1
Figure 4 shows the H NMR spectra of QN2 at various
times after it was dissolved in a 1 : 1 solution of D2O and
43 days
[
D6]acetone. After 10 min the major peaks observed are
6
0
55
50
45
40
35
30
25 ppm
assigned to QN2, while after 7 h the major peaks are assigned
to the product QN2–OH (see Scheme 5). Similar to the
hydrolysis of QN3, the H and C NMR (see Fig. 3) spectra
showed evidence of long-lived intermediates consistent with
Figure 3. 13C NMR spectra of QN3 and QN2 in 1 : 1 [D6]acetone/D2O
at 25 C at several time points after the addition of QN3 or QN2 to the
D6]acetone/D2O mixture.
1
13
◦
[
1
cyclic sulfonium ions. The assignment of the H resonances
and the 13C resonances in a GHSQC spectrum, and the sub-
Table 1. 1H and 13C NMR assignments (ppm) of the resonances
observed in the hydrolysis of QN3 at 25 C in 1 :1 [D6]acetone/D2O
◦
A
1
1
sequent confirmation of the H– H J-coupled spin systems
QN3
1H
QN3–OH
1H
13C
QN3–VI
1H
13C
ꢀ
2
ꢀ
S+
1
2
α
β
/3
2.75
1.90
2.93
3.77
1 /3
2.70 31.0
1.88 30.5
2.72 34.3
3.73 61.5
2
3
5
6
7
8
9
3.89 42.2
3.18 26.6
2.84 30.9
2.27 24.8
3.70 40.0
3.76 44.4
4.16 57.0
S
S
S
ꢀ
Cl
Cl
Cl
αꢀ
.
.
ꢀ
β
S
S
S
S
S
Cl
Cl
Cl
OH
S
+
OH
A
Positional numbering refers to the numbering scheme given in
Scheme 4. Potential acyclic sulfonium ion formed between QN3–I
Figure 2.
and QN3–III.

3
12
T. D. St Quintin, D. R. Leslie and J. G. Collins
in a DQFCOSY spectrum, confirmed the assignment of these
resonances to QN2–V. In addition, spin–lattice relaxation
time (T1) experiments recorded after 3 d showed that the res-
onances assigned to QN2–V have significantly shorter T1
values (H2 1.1, H3 0.7, H7 1.9, and H8 1.1 s) than those res-
Relevance
This paper constitutes the first detailed study of sesquimus-
tard hydrolysis since the Second World War. Such studies
are valuable, not only because they yield information about
the sesquimustards themselves but, by contrasting the results
with those of sulfur and nitrogen mustards, they may also
provide insights into the differences in vesicatory action, and
hence leadto a better understandingof mustard vesicantprop-
erties in general. In this study the formation of long-lived
cyclic sulfonium ions has been demonstrated. The sulfonium
ions are likely to retain some toxicity, via the reformation
of the powerful alkylating agents QN3–V and QN2–IV, and
could possibly be used as markers for sesquimustard in the
analysis of mustard-contaminated soil for chemical weapons
ꢀ
ꢀ
ꢀ
onances from QN2–OH (H1 1.5, Hα 2.0, Hβ 2.3 s). This is
consistent with QN–V being a less flexible cyclic structure.
1
13
The Hand CNMRchemicalshiftsforQN2, QN2–OH, and
QN2–V are given inTable 2. Similar to the QN3 hydrolysis, a
significant build up of QN2–V was observed compared with
QN2–II, which did not accumulate to any extent throughout
the experiment.
Interestingly, an additional set of peaks is also clearly
observed after 6 d that have very similar chemical shifts
to the major product QN2–OH (see Fig. 4 and Table 2). In
addition, a white precipitate was also observed in the NMR
tube after 6 d, which after isolation was shown to account for
the additional product peaks in the spectra of the hydrolysis
mixture. From the combined NMR data, this additional prod-
uct was determined to be 1-oxa-4,7-dithiacyclononane (see
Figure 2). A satisfactory elemental analysis was obtained for
the isolated 1-oxa-4,7-dithiacyclononane. The formation of
this macrocycle could result from the intramolecular ring-
opening attack by the oxygen of QN2–V, or more likely (given
that no evidence of nucleophilic attack at the carbon adjacent
H2
C
H2
C
H2
C
S
Cl
Cl
C
2
C
2
S
C
H
H
H
2
QN2
H2
C
H2
C
Cl
+
+
Cl
S
CH2
S
S
C
H
S
C
H
2
2
CH
2
QN2-II
QN2-I
+
to a S has been observed) of QN2–IV.
H2O
-H+
H2
C
H2
C
H2
C
Cl
S
C
2
S
C
2
C
OH
H1'
H
H
H
Hβ'
2
Hα'
QN2-III
6
days
1
7
3
6
1
6.5 hrs
hrs
+
H
C
2
H
C
2
HO
+
H C
S
OH
2
S
S
C
2
S
C
H
H
2
hrs
CH2
QN2-V
QN2-IV
0 min
0 min
H O - H +
2
Hβ
Hα
H1
acetone
H2
H2
H2
C
S
C
C
OH
HO
C
H
C
S
C
H
4.2
4.0
3.8
3.6
3.4
3.2
3.0
ppm
H
2
2
2
1
◦
Figure 4. H NMR spectra of QN2 in 1 : 1 [D6]acetone/D2O at 25 C
as a function of time after the addition of QN2 to the [D6]acetone/D2O
mixture.
QN2-OH
Scheme 5. Proposed reaction pathway for the hydrolysis of QN2.
Table 2. 1H and 13C NMR assignments (ppm) of the resonances observed in the hydrolysis of QN2 at 25 C
◦
in 1 :1 [D6]acetone/D2OA
QN2
/2
1H
QN2–OH
1H
13C
QN2–V
1H
13C
QN2-mcB
1H
13C
ꢀ
α
ꢀ
1
2.89
2.98
3.78
1 /2
2.83
2.76
3.74
32.5
34.3
61.6
2/6
3/5
7
3.91
3.23
3.82
4.16
42.5
27.1/26.9
44.5
2/9
3/8
5/6
3.74
2.75
2.84
61.6
34.5
32.4
ꢀ
α
ꢀ
β
β
8
57.0
A
B
Positional numbering is analogous to the numbering scheme given in Figure 2.
QN2-mc = 1-oxa-4,7-dithiacyclononane.

Hydrolysis of Sesquimustards
313
treaty verification.The formation of a macrocyclic oxadithia-
ether was demonstrated for QN2, but not QN3. Whilst the
acetone/water solvent used in these studies does not accu-
rately reflect physiological conditions, it remains likely that
this macrocycle could still form in vivo.
(t, J 7.7), 2.81 (s); QN3: 3.65 (t, J 7.8), 2.87 (t, J 7.8), 2.69 (t, J 7.1),
1
.89 (m, J 7.1).
Hydrolysis Experiments
The sesquimustard hydrolysis experiments were carried out in a NMR
◦
tube at 25 C in a solvent of 1 : 1 D2O/[D6]acetone. For QN3, a liquid
The biological consequences of the long-lived cyclic sul-
fonium ions are not known, however, it is possible that they
could lead to a greater degree of DNA alkylation for the
sesquimustards. As they are cationic they will be electro-
statically attracted to polyanionic DNA, thereby leading to an
increased sesquimustard concentration within the grooves of
DNA. In contrast, the highly reactive three-membered cyclic
sulfonium ion formed from sulfur mustard will not be able to
effectively concentrate near DNA, as it will rapidly react with
the numerous nucleophiles available within human cells. As
DNA alkylation is thought to be responsible for the vesicant
at room temperature, approximately 10 µL of the sesquimustard was
added to the NMR tube containing the mixed solvent, just prior to the
commencent of the NMR spectra being recorded. For QN2, a solid at
room temperature, a small quantity was dissolved in acetone prior to
being added to the D2O in the NMR tube. The final concentration of the
sesquimustard in the NMR tube was 40–45 mM.
Instrumentation
The purity of the sesquimustards was determined using a HP6890 GC
coupled to a HP5973 mass-selective detector with a 30 m HP-5MS
column. NMR spectra were recorded on aVarian UnityPlus-400 spectro-
1
meter, operating at 400 MHz for the H nucleus, and analyzed using the
[10,11]
suppliedVarian softwareVNMR.All NMR experiments were conducted
action of mustards,
any increase in the relative amount
◦
at 25 C. One-dimensional proton spectra were accumulated using a
of DNA alkylation may result in greater vesicant properties.
spectral width of 5000 Hz with 16 000 data points and a pulse repetition
delay of 2 s. Carbon spectra were accumulated using a spectral width
of 25 000 Hz with 32 000 data points and a 1.7 s pulse repetition delay.
DQFCOSY experiments were accumulated using 2048 data points in t2
for 256 t1 values with a pulse repetition delay of 1.7 s with 64 scans per
FID. GHSQC experiments were accumulated with spectral widths of
Conclusion
1H and 13C NMR experiments have confirmed that stable
cyclic sulfonium ions are formed in the hydrolysis reactions
of the sesquimustards 1,2-bis(2-chloroethylthio)ethane and
5
000 Hz in the proton dimension and 6500 Hz in the carbon dimension,
using 2048 data points in t2 for 128 t1 values with a pulse repetition
delay of 2.8 s.
1
,3-bis(2-chloroethylthio)propane.Thecyclicsulfoniumions
could possibly be used as markers for sesquimustard in the
analysis of mustard-contaminated soil for chemical weapons
treaty verification.
References
[
1] W. H. Stein, J. S. Fruton, M. Bergmann, J. Org. Chem. 1946,
1, 692.
1
Experimental
[
[
2] C. C Price, R. M. Roberts, J. Org. Chem. 1947, 12, 255.
3] Y.-C. Yang, J. R. Ward, T. Luteran, J. Org. Chem. 1986, 51,
Materials
2
756.
The 1,n-bis(2-hydroxyethylthio) n-alkanes (n = 2, 3) were provided
by Ms S. Pantleidis (Defence Science and Technology Organisation,
Melbourne). The deuterated solvents were obtained from Cambridge
Isotope Laboratories (Cambridge, MA).
[
4] Y.-C. Yang, L. L. Szafraniec, W. T. Beaudry, J. R. Ward, J. Org.
Chem. 1988, 53, 3293.
[
[
5] R. I. Tilley, Aust. J. Chem. 1993, 46, 293.
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Synthesis of Sesquimustards
[
7] M. Osborne, D. Wilman, P. Lawley, Chem. Res. Toxicol. 1995,
2, 316.
Due to the powerful vesicant properties of the sesquimustards extreme
caution must be taken in their synthesis and then subsequent handling.
Nitrile gloves were worn in addition to the usual protective clothing.
Approximately 120 mg of the corresponding dithioalkanediol was
dissolved in a small amount of CH2Cl2 (3–4 mL). An excess of thionyl
chloride (>6 equivalents) was dissolved in CH2Cl2 such that the com-
bined volume was 10 mL, was added dropwise with stirring to the
dithioalkanediol. The mixture was refluxed for 4 h. After cooling, the
mixture was washed with three 15 mL portions of water, followed by
three 10 mL portions of water and three 10 mL portions of 5% NaHCO3
and then once with 15 mL of water. The CH2Cl2 layer was dried over
anhydrous Na2SO4 overnight, then filtered through glass wool. The
CH2Cl2 was then removed by evaporation under a stream of nitrogen,
and then purified by bulb-to-bulb distillation under reduced pressure.
Yields: QN2 68%; QN3 70%. The products were characterized by
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1
H NMR spectroscopy and the purity of each sesquimustard was deter-
mined to be >99% by GCMS. δH (CDCl3) QN2: 3.66 (t, J 7.7), 2.89