Oxidative Detoxification of Sulfur-Containing Chemical Warfare Agents by Electrophilic Iodine

Article abstract of DOI:10.1021/acs.joc.8b02306

Mild oxidation of sulfur-containing chemical warfare agents was performed in organic medium by electrophilic iodine reagents. Kinetic experiments on sulfur mustard (HD) showed rapid (t_1/2 < 3 min) and selective oxidation to the nonvesicant sulfoxide product (HD-SO) in acetonitrile or propylene carbonate solutions (9% water added) containing excess N-iodosuccinimide (NIS). Molecular iodine solutions in these solvents led to similar results as with NIS but at much slower rates (t_1/2 ～ 90 min). Higher donor number solvents, such as THF, DMF, or DMSO, showed slower rates with both iodine and NIS. The oxidation of the nerve agent O-ethyl-S-2-(N,N-diisopropylaminoethyl)methylphosphonothioate (VX) selectively to the nontoxic ethyl methylphosphonic acid product exhibited fast rates (t_1/2 = 6 min) using NIS in DMSO solution. In all other solvents tested with VX, rates were slower (t_1/2 ～ 30-70 min). Oxidation experiments under the same conditions with chloroethyl ethyl sulfide (HD simulant) and O,S-diethyl methylphosphonothioate (VX simulant) led to much faster reaction rates. These transformations are believed to proceed through electrophilic iodine attack on the sulfur moiety and display solvent dependency based on the agents' structural and chemical properties.

Full text of DOI:10.1021/acs.joc.8b02306

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Article
Oxidative Detoxification of Sulfur-Containing
Chemical Warfare Agents by Electrophilic Iodine
Boris Smolkin, Noam Levi, Naama Karton-Lifshin, Lea Yehezkel, Yossi Zafrani, and Ishay Columbus
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02306 • Publication Date (Web): 17 Oct 2018
Downloaded from http://pubs.acs.org on October 20, 2018
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Oxidative Detoxification of Sulfur-Containing Chemical Warfare Agents by
Electrophilic Iodine
Boris Smolkin*, Noam Levi, Naama Karton-Lifshin, Lea Yehezkel, Yossi Zafrani and
Ishay Columbus*
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Department of Organic Chemistry, Israel Institute for Biological Research, P.O. Box 19, Ness
Ziona 74100, Israel
O
S
EtO
P
S
Cl
Cl
N(iPr)2
Toxic CWAs
Me
VX
HD
Selective
Oxidation
"
"
I
Solvent/
H2O
O
O
EtO P OH
Me
S
Non-Toxic
Products
Cl
Cl
EMPA
HD-SO
Abstract
Mild oxidation of sulfur-containing chemical warfare agents (CWAs) was performed in
organic medium by electrophilic iodine reagents. Kinetic experiments on sulfur mustard
(
HD, 1) showed rapid (t <3 min) and selective oxidation to the non-vesicant sulfoxide
1/2
product (HD-SO, 5) in acetonitrile or propylene carbonate solutions (9% water added)
containing excess of NIS (N-iodosuccinimide). Molecular iodine solutions in these
solvents led to similar results as with NIS, however at much slower rates (t ~90 min).
1
/2
Higher donor number (DN) solvents, such as THF, DMF or DMSO, showed slower rates
with both iodine and NIS. The oxidation of the nerve agent VX (O-ethyl-S-2-(N,N-
diisopropylaminoethyl)methylphosphonothioate, 2) selectively to the non-toxic EMPA
(
ethyl methylphosphonic acid, 7) product exhibited fast rates (t =6 min) using NIS in
1/2
DMSO solution. In all other solvents tested with 2, rates were slower (t ~30-70 min).
1
/2
Oxidation experiments under the same conditions with chloroethyl-ethylsulfide (CEES,
HD simulant, 3) and O,S-diethyl methylphosphonothioate (DEMPT, VX simulant, 4) led
to much faster reaction rates. These transformations are believed to proceed through
electrophilic iodine attack on the sulfur moiety, and display solvent dependency based on
the agents' structural and chemical properties.
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Introduction
Development of new, mild and universal decontamination/detoxification solutions against
chemical warfare agents (CWAs) is a continuous effort, especially under the circumstances
of using these malicious means in recent years.1,2 Among all known CWAs, the vesicant
sulfur mustard (bis-(2-chloroethyl)sulfide, HD, 1) and the toxic nerve agent VX (O-ethyl-
S-2-(N,N-diisopropylaminoethyl)methylphosphonothioate, 2) are considered as the most
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persistent (Figure 1). Due to their high stability and low volatility, 1 and 2 can persist for
months, posing physiological and ecological threat.4-7 In an attempt to deal with these
hazardous CWAs, numerous detoxification approaches have been examined over the last
decades, including simple reactions such as hydrolysis, elimination, substitution and
oxidation.8,9 It is worth mentioning that a considerable part of these studies have been
conducted on CWAs simulants, such as CEES (chloroethyl-ethylsulfide, 3) and DEMPT
(
O,S-diethyl methylphosphonothioate, 4) (simulants of 1 and 2, respectively).8
O
S
P
N
Cl
Cl
O
S
1
2
O
S
P
Cl
O
S
3
4
Figure 1. Sulfur containing CWAs and their simulants.
Usual CWAs degradation procedures require harsh reagents (such as strong
8
bases/acids/oxidants) in order to reach full degradation, however, with high ecological and
environmental cost. In order to avoid these conditions, development of benign procedures
is preferred. However, under mild conditions, toxic byproducts could also be formed. For
example, in the over oxidation of 1, the formation of the vesicant HD-SO (bis-(2-
2
chloroethyl)sulfone, 6) could be observed in addition to the non-vesicant HD-SO ((bis-(2-
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chloroethyl)sulfoxide, 5). As well, in the hydrolysis of 2, the toxic desethyl-VX (S-2-(N,N-
diisopropylaminoethyl)methylphosphonothioic acid, 8) could be formed in addition to the
non-toxic EMPA (ethyl methylphosphonic acid, 7) (Scheme 1).10 Therefore, the
development of a selective and mild method for the degradation of 1 and 2 to their
corresponding non-vesicant and non-toxic products still remains a challenge.
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Scheme 1. Non-Selective degradation of 1 and 2 to their products.
O
[
O]
O
S
[O]
S
S
(1)
Cl
Cl
Cl
Cl
Cl
Cl
O
1
5
6
non-vesicant
vesicant
OH-
O
P
O
P
O
+
N
(2)
N
P
O
S
HO
S
O
OH
2
7
8
non-toxic
toxic
8
Oxidation is one of the important approaches for CWAs detoxification, of which
hypochlorite derivatives and peroxide solutions are the most popular. Examples of such
9
9
formulas are bleach (sodium hypochlorite), STB (calcium hypochlorite), Fichlor (sodium
9
11
12
N,N-dichloroisocyanurate), L-Gel and Decon Green (based on peroxides). However,
these oxidants are characterized by several drawbacks. In addition to their non-selective
mode of action and tendency to over-oxidize, they are usually used as high polarity water-
base solutions, which restrict their interaction with hydrophobic agents such as 1 and 2,
especially in large quantities. Moreover, in some cases, the slow rates of oxidation
reactions require the use of special conditions such as high pH and elevated temperatures.
Recently, in addition to the aforementioned, inorganic macromolecules as some modified
MOFs (metal organic frameworks)13 and POMs (polyoxometalates)14 have been
introduced to the field of CWAs oxidation. To the best of our knowledge there is only one
example in which actual CWA has been proven to react through an oxidation mechanism
with MOFs.13b With regard to POMs, all the oxidation processes were reported solely on
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simulants of 1. Most recently, an efficient photocatalytic oxidation of 1 by an organic
photosensitizer incorporated in polymer coating and fabrics was reported.15
Following our ongoing studies to find benign and universal formulations for CWAs
decontamination,16-19 we examined the possibility of using electrophilic iodine reagents as
mild oxidants for sulfur containing CWAs. In the arsenal of CWAs degradation formulas
only few examples of iodine-containing reagents can be found. IBX (O-iodoxy benzoic
acid) and its derivatives are the most known, but they exert their reactivity by acting as α-
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nucleophiles. Moreover, there are several reports using povidon-iodine and solution of
iodine/tetraglycol/ethanol as topical ointments against skin lesions induced by 1.21-23 The
effect of these formulations was limited and their mode of action is not clear.
Iodine and iodination reagents are known for their high solubility in organic solvents and
their ability to oxidize sulfides. Nonetheless, there are only few literature examples where
molecular iodine is used for sulfide oxidation, all of which are catalyzed by certain
nucleophiles.24,25 As reported, such reactions include sulfide nucleophilic attack on iodine
to form a postulated iodosulfonium cation, which subsequently reacts to yield a sulfoxide.26
Another well-known iodination/oxidation reagent is NIS (N-iodosuccinimide), which is
widely used for the activation of thioglycosides in carbohydrate chemistry.27
Inspired by this chemistry, we sought to use iodonium ion generated either by molecular
iodine or NIS, as a mild oxidant for the decontamination of divalent sulfur containing
CWAs, i.e. 1 and 2. Herein, we disclose our results on the selective and efficient
degradation of these agents by iodonium species relative to their common simulants (3 and
4
).
Results and Discussion
Screening of iodine-containing oxidants. Several iodine-based oxidants were initially
screened for potential degradation of sulfur containing CWAs. This screening for the
oxidation of 3 included KIO , KIO , KI and I in organic solutions (such as acetonitrile
4
3
3
2
(
ACN) and propylene carbonate (PC)) containing water as a reagent (10:1 v/v
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respectively). In a typical experiment, 3 was reacted with excess of oxidant (5-11 equiv.)
at room temperature and monitored by 13C{ H} NMR. From all the aforementioned
1
oxidants, only I exhibited reactivity towards the oxidation of 3, and therefore was selected
2
for further investigation.
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Reactions of 1 and 3 with Iodine (I ). Decontamination methodologies usually require
2
excess of decontaminant for an efficient process. First attempts have shown maximum
solubility of 11 equivalents of iodine under the experimental conditions in most tested
organic solvents (2 L of 3 in 1 mL solvent at room temperature). Aprotic organic solvents
containing water (10:1 v/v, respectively) were screened for optimal reaction rates. The
results are summarized in Table 1. Sulfide 3 was oxidized by I in a selective and fast
2
manner to the corresponding sulfoxide 9 (Scheme 2) in ACN, PC and acetone (AC)
solutions (entries 1-3). No further oxidation to sulfone was observed even after 18 hours
from reaction completion (Figure S1 in the supporting Information). DMF showed fast
reaction, however, with lower selectivity forming different by-products. Oxidation in THF
or DMSO was selective, but with longer reaction times (entries 4, 6). The high selectivity
of this reaction (in spite of the high excess of oxidant used) coupled with the fast reaction
rates, encouraged us to further investigate this transformation.
Table 1. Kinetic rates for the oxidation of 1 and 3 by molecular iodine in different solvents
t1/2 of 3
oxidation (min)
<3
t1/2c of 1
oxidation (min)
92
Entry
Solventa
ACN
PC
1
2
3
4
5
6
<3
<3
88
NAd
AC
THF
7
1080
NAd
960b
DMF
DMSO
NAb
30
a
b
c
Solvent/water 10:1 (v/v). Mixture of products. Due to iodine decomposition during the reaction
d
course and deviation from first order kinetics, an average half-life times were calculated. Reaction
stopped at 40% conversion after 400 min.
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Scheme 2. Oxidative detoxification of 1 and 3 by iodine and water.
O
O
S
S
I , H O
S
2
2
H O
2
Cl
R
Cl
R
HO
R
1: R = Cl
3: R = H
Solvent
5
9
: R = Cl
: R = H
10: R = OH
11: R = H
S
Cl
Cl
Cl
Cl
O
S
O
S
HO
OH
1
3
1
2
Figure 2. C{ H} NMR spectra showing the oxidation of 1 by iodine in ACN/H O (10:1) to the sulfoxide
products (5 and 10) at: (A) 27 min; (B) 93 min; (C) 188 min; (D) 448 min; (E) 1048 min.
In a similar manner, 1 was treated with molecular iodine under the same conditions as 3 to
form sulfoxide 5. Oxidation rates were much slower, presumably due to the additional
28
electron withdrawing chlorine atom. In ACN and PC the average half-life times were ~90
minutes (Table 1, entries 1-2 and Figures S2-S4 in the Supporting Information). During
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the reaction, 5 further reacts with water to afford the hydrolyzed sulfoxide 10 (Scheme 2
and Figure 2). In other solvents, the reaction rates were much slower (entries 3-6), and in
some cases the reaction stopped without reaching full conversion (entries 3, 5). Moreover,
a deviation from first order reaction kinetics was observed, seemingly due to the decrease
in iodine concentration, which is consumed by competitive reactions. It is known from
previous reports, iodine decays slowly in organic solvents to the non-active triiodide anion
1
1
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and other species, and water accelerates this decay. Indeed, iodine solutions that were
prepared 24 hours prior to reaction were not reactive. Therefore, in order to improve the
rates and the efficiency of the reaction, the more stable iodonium source NIS was used.
Reactions of 1 and 3 with NIS. The reagent NIS turned out to be highly efficient. Under
the same reaction conditions described above for iodine, 3 was oxidized selectively to the
corresponding sulfoxide 9 in all solvents tested in less than 15 minutes (t < 3 min).
1
/2
Furthermore, the oxidation of 1 by NIS to the non-vesicant sulfoxide 5 was significantly
faster in comparison to iodine. Reactions in ACN, PC and AC reached full conversion
within 10-15 min (t1/2 < 3 min). Reactions in THF, DMF and DMSO also reached full
conversion in shorter half-life times relatively to the slow rates and partial conversions with
iodine (Table 2 and Figure S5 in the Supporting Information). It is worth mentioning that
in contrast to iodine solutions, NIS solutions were found to be stable for prolonged periods
of time (over a month) without significant decomposition.
The results with NIS showed a clear dependence between the solvent and the reaction rate.
While there was no obvious indication for correlation with solvent polarity, a correlation
was observed between the reaction rates and the solvent basicity (donor number, DN).
Namely, the lower the solvent’s DN, the higher the kinetic rate constant of the oxidation
reaction. For example, while the reaction was very fast in ACN (DN=14.1, entry 1), it was
relatively slow in DMSO (DN=29.8, entry 6).
The reactivity of NIS towards 1 was compared to its common bromine derivative NBS (N-
bromosuccinimide). The same trend as with NIS was observed in the reaction of 1 with
NBS in ACN vs. DMSO. In ACN the reaction was fast (entry 8) yet not selective, affording
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a mixture of sulfoxide 5 and the bromination product 12 (Figure 3). In DMSO the
conversion was much slower (entry 9), but selective in respect to the sulfoxide product.
0
1
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Table 2: Kinetic rates for the oxidation of 1 and 3 by NIS or NBS in different solvents.
t1/2 of 3
oxidation
(min)
t1/2 of 1
oxidation
(min)
Donor
Entry Solventa Oxidant number
1
2
3
4
5
6
7
8
9
ACN
PC
NIS
NIS
NIS
NIS
NIS
NIS
NIS
NBS
NBS
14.1
15.1
17.0
20.0
26.6
29.8
<3
<3
<3
<3
<3
<3
-
<3
<3
<3
4
AC
THF
DMF
DMSO
DMSOb
ACN
53
62
148
<3c
35
14.1
29.8
-
DMSO
-
a
b
c
Solvent/H O 10:1. Solvent/D O 10:1. Mixture of 5 and 12 was obtained.
2
2
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(A)
(B)
(C)
a (1)
Cl
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a
S
Cl
Cl
b
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9
0
1
2
3
4
5
6
7
8
9
0
(
5)
O
S
c
d
d
c
c
Cl
d
NHS+NIS
NHS+NBS
O
(12)
h
e
g
S
Cl
Cl
f
f
Br
h
g
e
Figure 3. 13C{ H} NMR spectra presenting the oxidation reaction of 1. (A) starting material (1); (B)
oxidation by NIS in ACN/H O (10:1) to the sulfoxide product (5); (C) oxidation by NBS in ACN/H
10:1) to a mixture of 5 and 12.
1
2
2
O
(
Mechanism of HD (1) oxidation: solvent role. In order to understand the mechanism of
the oxidation of sulfides with NIS and the role of the solvent, we looked for a sulfide that
undergo rather slow oxidation process. Ethylphenylsulfide 13 undergoes slow enough
1
3
oxidation in PC to enable reaction monitoring on C NMR timescale. In less than two
minutes after reacting 13 with 4 equivalents of NIS in PC (no water added), changes in the
1
3
1
C{ H} NMR chemical shifts spectrum were observed, especially for the carbons adjacent
to the sulfur atom (Figures S6-S7 in the Supporting Information). These changes are
attributed to the formation of an intermediate believed to be a sulfonium complex. Next,
water was added to complete the reaction. At this point, formation of the sulfoxide 14 via
substitution of the iodide by water was observed. The latter transformation was
significantly slower than the first step, taking 12 min to complete after the addition of water
(
Figure S6C-E in the Supporting Information). This difference implies that the second step,
substitution by water, is the slower step. Additional support was obtained from kinetic
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
isotope effect (KIE) experiments. 1 was reacted with NIS in DMSO/D O in comparison to
2
DMSO/H O under the same conditions above. A slowdown in the reaction rate was
2
observed with k /k = 2.4 (Table 2, entries 6-7) in accordance with reported hydrolysis
H
D
values of secondary solvent isotope effect.30 Based on these results, we propose a
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
mechanism for the oxidation of 1 by NIS/H O, which explains the kinetic rate dependence
2
on solvent (scheme 3).
In this mechanism the postulated sulfonium cation is stabilized by the solvent. The higher
the solvent’s Lewis basicity (higher DN) the stronger the interactions with the sulfonium
cation intermediate, thus reducing the reaction rate. DMSO (with the highest DN of all the
tested solvents) displays the lowest rate of sulfide to sulfoxides transformation with both
NIS and NBS (Scheme 3 and Table 2, entries 6 and 9).
2
Scheme 3. Proposed mechanism of the oxidation of 1 by NIS in solvent/H O.
O
I
I
N
O
H O
O
S
S
O
S
2
+
I2
+
HN
Cl
Cl
Cl
Cl
sol.
fast
slow
Cl
Cl
O
sol.
Mechanism of HD (1) oxidation: oxidant role (NIS vs. NBS). We have noticed that
immediately after addition of NIS, the color of the reaction solution turns brown. This may
imply on the formation of molecular iodine during the reaction. The same visual result was
obtained when KI was added to NIS solution. In addition, in reactions conducted with
different ratios of NIS to sulfide, at least two equivalents were found to be the minimum
needed to reach full conversion to sulfoxide. On the other hand, reaction with NBS was
colorless, and one equivalent was needed to reach a full conversion. When more than one
equivalent was used, the reaction did not yield the sulfoxide selectively. Based on these
observations, we propose that the reaction with NIS forms HI, which immediately reacts
with another equivalent of NIS to produce iodine (Scheme 3). Hence, the reaction solution
stays close to neutral (pH ~ 6). In contrast, the reaction with NBS produces HBr, which
lowers the pH of the solution (pH ~ 1) without consuming NBS (Figure S8 in the
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Supporting Information). The low pH accelerates the release of bromonium cation, hence,
increasing the reaction rate of sulfide oxidation. When an excess of NBS is used, the
released bromide anion continues to react with the sulfonium cation to produce a
bromination by-product presumably via Pummerer type reaction in addition to the
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
sulfoxide product.31,32
Reactions of 2 and 4 with Iodine (I ) and NIS. In light of the oxidation results with 1, we
2
were intrigued to examine whether electrophilic iodine will be efficient oxidant for the
degradation of the thiophosphonates 2 and 4 in organic solutions. The reaction of 4 with I2
3
1
(
11 equivalents, solvent/water 10:1) monitored by P NMR showed selectivity towards P-
S bond cleavage, yielding only the hydrolysis product 7. The reaction rates were relatively
fast (half-life times of minutes), however, in some solvents the reactions did not proceed
to completion, probably due to the decomposition of iodine (Table 3, entries 3-6).
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9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Table 3. Kinetic rates for the oxidation of 2 and 4 by I
2
or NIS in different solvents.
t1/2 of 4
t of 2
1/2
t of 2
0.9
Solventa
Entry
Oxidant
oxidation (min) oxidation (min) oxidation (min)
3980f
280f
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
ACN
PC
I2
I2
<3
<3
93
27
3
AC
I2
<6b
320d
4
5
6
THF
DMF
I2
I2
I2
<4c
<10c
<3c
43
NR
16c
2920f
DMSO
7
8
9
ACN
PC
NIS
NIS
NIS
NIS
NIS
NIS
<3
<3
<3
<3
<3
69
30e
44
60
45d
6
AC
1
0
THF
DMF
11
1
2
DMSO
<3
c
a
b
d
Solvent/H O 10:1. Stopped at 80% conversion. Stopped at 95-97% conversion. Stopped at
2
e
f
~50% conversion. Averaged result (deviation from first order reaction kinetic). Stopped at ~90%
Conversion.
Next, we evaluated the reactivity of 2 with iodine. In the same manner, 2 was reacted with
iodine to give solely the product 7, without forming the toxic product 8 (cleavage of P-O
bond). In comparison to 4, the rates were slower (time scale of hours) with the exception
of DMSO, which was considerably faster (entry 6). In neither cases full conversion was
obtained (entries 1-6), and in some solvents deviation from first order reaction kinetics was
observed (in these cases t1/2 and t were measured, entries 1,2,4).
0.9
As with sulfides, NIS showed better performance than iodine towards the degradation of
the thiophosphonates (entries 7-12). 4 underwent very fast decomposition (t < 3 min) in
1
/2
all tested solvents giving selectively product 7. The t reaction of 2 with NIS in ACN, PC,
1
/2
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AC and THF ranged between 30-70 minutes (Figure S9 in the Supporting Information).
Contrary to iodine, the reactions with NIS reached full conversion (except in DMF).
Moreover, in some solvents, acceleration during the reactions course was observed,
probably due to the decrease in pH induced by the formation of 7 (Figure S10 in the
Supporting Information). In contrast to the sulfide trend, no correlation between solvents’
DN and the kinetic rates was observed. However, as with iodine, the reaction with NIS in
DMSO was exceptionally faster under the same conditions (t1/2 = 6 min, entry 12, Figure
S11 in the Supporting Information). For comparison reasons, NBS was reacted with 2
under the same conditions as with NIS. The reaction was selective as well and afforded
only product 7. NBS shows faster reaction rates in all solvents tested (t1/2 < 5 min). This
can be explained by the low pH induced by HBr liberation in the oxidation process as
previously described.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Insights into the oxidation mechanism of thiophosphonates 2 and 4. Two important
observations resulted from the above-mentioned experiments: (1) The oxidative
degradation rate of 4 was much faster than that of 2 (Table 3, entries 7-12). (2) The
oxidative degradation rate of 2 itself was faster in DMSO relatively to the other solvents
(note that the oxidation of sulfide 1 in DMSO was the slowest).
Regarding the first point, previous studies have established that thiophosphonates (such as
4, the ‘head’ part of 2) undergo oxidation to the corresponding sulfonium ion intermediate,
which in turn serves as a good leaving group for a sequential fast hydrolysis reaction
(
Scheme 4, reaction A).33,34 Yang et al. have shown that in the presence of an amine group,
such as in the case of 2, the amine is the first to be oxidized under neutral and basic
conditions. When an excess of oxidant was used, it was suggested that the N-oxide
3
4
intermediate can be further oxidized on the sulfur moiety at a slower rate. Moreover, tests
we have conducted separately on diisopropylethylamine 15 (the amine ‘tail’ of 2) under
the same conditions (NIS, ACN/H O) showed a very fast decomposition to acetaldehyde
2
and diisopropylamine (Scheme 4, reaction B). A similar reaction was previously described
3
5
for tertiary amines and NBS. Since reactions (A) and (B) are both faster than reaction (C)
Scheme 4), we can assume that the formation of electron deficient species from 2, such as
(
N-iodoammonium, N-oxide or aldehyde, will reduce the reactivity of the sulfur moiety
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8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
towards oxidation. This may explain the relatively slow rate of the decomposition of 2 by
I2 or NIS in comparison to 4.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 4. Proposed mechanism for the degradation of 4, 15 and 2 by electrophilic iodine species.
O
O
P
O
P
(A)
I2 or NIS
P
EtO
S
I
EtO
S
EtO
OH
H O
2
4
(VX 'head')
7
(B)
NIS
O
N
N
N
H
+
I
H O
2
H
15 (VX 'tail')
(C)
O
O
P
O
P
I2 or NIS
P
N
N
I
EtO
S
EtO
S
EtO
OH
H O
2
2
(VX)
Comperative Reaction Rates: (A) > (C), (B) > (C)
7
Regarding the second point, it was shown that the oxidation step in oxidative degradation
3
6
of thiophosphonates is the rate-limiting step. Consequently, the hydrolysis step is the fast
step. The rate increase observed with I and NIS when DMSO is used can be rationalized
2
by DMSO ability to stabilize the charged transition-state of this rate-limiting step. On the
other hand, in the case of sulfide 1 oxidation, the rate-limiting step is the hydrolysis. Thus,
stabilization of the positively charged sulfonium intermediate by DMSO (high DN) will
slow the reaction rate. The different stages DMSO is involved in the oxidation reaction of
both sulfides and thiophosphonates, explains the opposite trend observed in reactions
kinetics. Namely, when DMSO is used as solvent, sulfide degradation is slower while
thiophosphonate degradation is faster.
Conclusions
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8
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According to the experimental results presented here, mild organic solutions (9% water
v/v) of NIS in ACN or PC were able to decontaminate 1 in a selective and very fast manner
to the non-vesicant sulfoxide 5. For the decontamination of 2, DMSO and PC solutions
showed the best results affording exclusively the non-toxic product 7. Although NBS
showed faster decontamination rates of 2, its non-selective mode of action toward 1
oxidation (when using excess of NBS) and the corrosivity of its solutions make it less
favorable than NIS as a universal decontamination agent. Hence, the use of NIS with the
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
7
green solvent PC makes it a powerful and attractive system for universal decontamination
process. In addition, our results showed that decomposition by oxidation of 3 (simulant of
1) and 4 (simulant of 2) were much faster relative to 1 and 2. These results should be taken
under consideration when establishing decontamination procedures only on simulants.
Experimental Section
Caution! These experiments should only be performed by trained personal using
applicable safety procedures.
1
3
Chemicals. VX (2), HD* ( C labeled of 1) and DEMPT (4) were obtained locally at IIBR
>99% purity). (2-chloroethyl)ethyl sulfide (CEES, 3), ethylphenylsulfide (13), N-
(
iodosuccinimide (NIS), N-bromosuccinimide (NBS) and all solvents (HPLC grade) were
purchased from commercial suppliers and used without further purification. Deionized
water was obtained from a laboratory water purification system.
13
1
31
1
NMR spectroscopy. C{ H} and P{ H} spectra were obtained at 125 and 202 MHz,
respectively, at room temperature on a 11.7 T (500 MHz) Bruker spectrometer (Avance III
1
3
31
HD). Chemical shifts were calibrated to TMS (for C) and Trimethylphosphate (for P)
as 0 ppm. The spectra were recorded using the standard parameters of the TopSpin NMR
software (version 3.5). Each data point was obtained from 32-64 scans, at a spectral width
of 200 ppm and 2s relaxation time. For comparison purposes, spectra of the kinetic
experiments were recorded under identical conditions. Integration was carried out
automatically using the Dynamic Center of Topspin software.
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1
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1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Degradation kinetics. Oxidant (Iodine, NIS or NBS, 11 equivalents, unless otherwise
mentioned) was added to a solution of solvent/water 10:1 v/v (1 mL) and stirred for two
minutes until all dissolved. The tested compound (CWA or simulant, 2µL, 1 equiv.) was
carefully added and the solution was transferred as is into a NMR tube for kinetic analysis.
Kinetic NMR acquisition sampling started as soon as possible (without lock or shimming)
until completion or no further change in reaction conversion was observed. Post-
acquisition analysis was performed by Dynamic Center software using build-in first order
fitting functions to determine half-life times.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Oxidation of Ethylphenelsulfide (13). Sulfide 13 (5 µL, 0.037 mmol) and NIS (33 mg, 4
equiv.) were added to 1 ml propylene carbonate (PC) (without added water) and the
1
3
reaction was monitored by C NMR. After identification of the sulfonium cation, 100 µL
of water were added and the reaction was furthered monitored by 13C NMR until full
conversion to the corresponding sulfoxide.
Author Information
Corresponding Authors
*
*
E-mail: ishayc@iibr.gov.il
Email: boriss@iibr.gov.il
Tel: 972-2-9381453; Fax: 972-8-9381548
ORCID
Ishay Columbus: 0000-0001-6620-6966
Boris Smolkin: 0000-0001-9383-8977
Notes
The authors declare no competing financial interest.
Acknowledgment
This work was internally funded by the Israeli Prime Minister’s office.
Associated Content
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Supporting Information
The Supporting Information is available free of charge on the ACS Publications website.
Oxidation kinetic profiles of HD (1) and VX (2); NMR spectra of oxidation reactions;
proposed mechanism for the oxidation of HD (1).
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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6
7
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9
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1
2
3
4
5
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7
8
9
0
References
1
2
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4
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0
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1
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3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
9
1
1
1
1
. Yang, Y.-C.; Baker, J. A.; Ward, J. R. Decontamination of Chemical Warfare
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