Decontamination and remediation of the sulfur mustard simulant CEES with “off-the-shelf” reagents in solution and gel states: A proof-of-concept study

Article abstract of DOI:10.1002/open.201700063

The decontamination and remediation of sulfur mustard chemical warfare agents remains an ongoing challenge. Herein, we report the use of “off-the-shelf” metal salts alongside commercially available peroxides to catalyze the degradation of the simulant 2-chloroethyl ethyl sulfide (CEES) in solution and encapsulated within a supramolecular gel.

Full text of DOI:10.1002/open.201700063

DOI: 10.1002/open.201700063
Decontamination and Remediation of the Sulfur Mustard
Simulant CEES with “Off-the-Shelf” Reagents in Solution
and Gel States: A Proof-of-Concept Study
[
a]
Jennifer R. Hiscock,* Gianluca P. Bustone, and Ewan R. Clark*
[
13]
The decontamination and remediation of sulfur mustard chem-
ical warfare agents remains an ongoing challenge. Herein, we
report the use of “off-the-shelf” metal salts alongside commer-
cially available peroxides to catalyze the degradation of the
simulant 2-chloroethyl ethyl sulfide (CEES) in solution and en-
capsulated within a supramolecular gel.
conditions, such as those recently reported by Jong et al. Ef-
forts in this area are underrepresented for this class of CWA in
comparison to others, as illustrated by Churchill and co-work-
ers in an extensive Review of CWA destruction and detection
[14]
methods.
The catalytic detoxification of HD, as overviewed by Smith,
is achieved through three main reactive processes: oxidation,
[15]
dehydrohalogenation, and hydrolysis. Here, in this proof-of-
concept study, we report the use of readily obtainable, cheap
materials for the remediation of the HD simulant 2-chloroethyl
ethyl sulfide (CEES) through catalytic oxidation of the central
sulfur functionality, which prevents the formation of the reac-
tive cyclic cationic intermediate. Over oxidation to produce the
sulfone is not desirable, as this compound is also known to act
as a vesicant. Metal-catalyzed formation of chiral sulfoxides is
well studied, but achiral catalytic oxidation has largely been ig-
nored—in the laboratory, racemic oxidation is easily accessed
Sulfur mustards, particularly bis(2-chloroethyl)sulfide (HD), are
[1]
a well-documented class of chemical warfare agent (CWA).
They act as vesicants, reacting through the cyclic intermediate
[
2]
shown in Scheme 1 with biological macromolecules such as
[
3–6]
DNA.
Furthermore, there are currently no medical counter-
measures available to treat the basic cause of a mustard agent
[
7]
injury.
[16]
at elevated temperatures with simple peroxides. Oxidative
remediation of HD “in the field”, in contrast, requires minimal
solvent use, ambient reaction conditions, and reasonable reac-
tion rates to be useful, but not chiral control.
Metal acetylacetonates have frequently been employed as
soluble metal sources for the in situ formation of chiral sulfur
[17,18]
oxidation catalysts,
and it has been observed that pre-
Scheme 1. The detoxification of HD through primary oxidation to the sulfox-
ide followed by secondary oxidation to the sulfone.
formed catalysts give better ee values, which can be attributed
[19]
to catalytic oxidation owing to remaining M(acac)2. In light
of this, and the known utility of metal acetylacetonates as oxi-
[
20]
Despite control of these substances through the Geneva
dation catalysts in other systems, we screened a range of
first row transition metal acetylacetonate complexes as “off-
the-shelf” catalysts for the oxidation of HD-simulant CEES.
Initial studies were conducted in a two-phase system of
CDCl /aqueous H O (30 wt%) solution, with the reactions
[
8]
[9]
Protocol (1925) and Chemical Weapons Convention (1993),
[
6,10–12]
HD use continues.
Therefore, the development of cheap
and accessible decontamination and remediation technologies
is of great importance, with design informed through funda-
mental studies, which explore the evaporation, degradation,
and vapor emission properties of HD under environmental
3
2
2
1
monitored by using H NMR spectrocopy; the results are
shown in Figure 1 and Table 1. Mustard agents and their relat-
ed simulants are highly soluble in organic solvents and the bi-
phasic conditions confine the CWA simulant to an organic
phase, sealing it beneath the aqueous hydrogen peroxide solu-
tion. This limits CEES transfer through both physical contact
and evaporation, with the added benefit that aqueous byprod-
ucts or starting materials are easily separated from the organic
phase after the neutralization process ends.
[
a] Dr. J. R. Hiscock, G. P. Bustone, Dr. E. R. Clark
School of Physical Sciences
University of Kent
Park Wood Road, Canterbury
Kent, CT2 7NH (UK)
E-mail: j.r.hiscock@kent.ac.uk
e.r.clark@kent.ac.uk
Supporting Information and the ORCID identification number(s) for the
author(s) of this article can be found under https://doi.org/10.1002/
open.201700063.
The metal complexes were found to increase the rate of
CEES oxidation in the order of VO(acac)2 > Co(acac)3
Zn(acac)2 > Cr(acac)3 > Fe(acac)3 > Cu(acac)2 Ni(acac)2
>
>
ꢀ
2017 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.
Mn(acac) . Although VO(acac) is inarguably the most efficient
3
2
This is an open access article under the terms of the Creative Commons
Attribution License, which permits use, distribution and reproduction in
any medium, provided the original work is properly cited.
oxidation catalyst, it leads to significant overoxidation. In light
of the toxicity, cost, low activity, and increased cost of the of
ChemistryOpen 2017, 00, 0 – 0
1
ꢀ 2017 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
These are not the final page numbers! ÞÞ

1
Figure 2. H NMR spectra of a) CEES (0.20 mm), b) Cu(hfac)
2 2
·H O (0.01 mm),
c) Cu(hfac) ·H O (0.01 mm) and CEES (0.20 mm) in CDCl (1 mL).
2
2
3
Figure 1. Percentage of CEES consumed under the following conditions:
CEES (0.20 mm), catalyst (0.01 mm), CDCl (1.00 mL), and 30% hydrogen per-
oxide in water (0.10 mL) without shaking: ꢀ VO(acac) ; ꢀ Mn(acac) ; ꢀ
Co(acac) ; ꢀ Ni(acac) ; ꢀ Zn(acac) ; ꢀ Cr(acac) ; ꢀ Cu(acac) ; ꢀ Fe(acac)
3
2
3
3
2
2
3
2
3
.
Table 1. Percentage of CEES oxidized after 165 h under the following
conditions: CEES (0.20 mm), catalyst (0.01 mm), CDCl (1.00 mL), and 30%
3
hydrogen peroxide in water (0.10 mL) without shaking. Figures given to
the nearest whole number.
[
a]
Catalyst
Total oxidation Primary oxidation Secondary oxidation
[
%]
[%]
[%]
VO(acac)
2
74
3
49
3
46
9
30
26
10
13
24
0
4
1
1
1
1
2
[
a]
Mn(acac)
Co(acac)
Ni(acac)
Zn(acac)
3
3
51
10
32
27
11
15
2
2
Cr(acac)
Cu(acac)
3
Figure 3. Percentage of CEES oxidized under the following conditions: CEES
0.20 mm), catalyst (0.01 mm), CDCl (1.00 mL) and 30% hydrogen peroxide
in water (0.10 mL) with shaking: ꢁ Cu(hfac) ·H O; ꢁ Cu(acac) ; ꢁ no catalyst.
2
(
3
Fe(acac)
3
2
2
2
[a] No data available at 165 h; data obtained after 147 h.
was oxidized without catalyst, with Cu(acac) , and with
2
manganese, cobalt, nickel, and chromium complexes, as well
as the extreme difficulty in monitoring the iron-containing re-
action with NMR, we chose to focus our efforts on the copper-
and zinc-based systems; although work is ongoing exploring
other systems.
Cu(hfac) ·H O, respectively. It is tentatively proposed that the
2
2
enhanced Lewis acidity of Cu(hfac) ·H O, owing to the elec-
2
2
tron-withdrawing CF groups of the hfac ligand, strengthens
3
substrate binding and subsequent activation. The slight agita-
tion at the beginning of the experimental protocol and hfac in-
[
21,22]
II
Copper sulfoxidation catalysis is well known,
though
corporation gives rates for this Cu compound competitive
general mechanisms are not established. Direct combination of
Cu(acac) and CEES in CDCl leads to paramagnetic broadening
with those shown in Figure 1.
There are many instances where the neutralization of mus-
tard agents in the solution state is undesirable. Liquids may
flow, adhere to surfaces, and be easily vaporized. Any neutrali-
zation process that occurs unconfined still represents a relative-
ly high contamination hazard. However, these associated risks
can be minimized by confining the solution-state neutraliza-
tion processes within a solid. The body of work produced by
Gale and co-workers has explored the use of supramolecular
gels as decontamination and remediation materials for organo-
2
3
of the protons of the S-adjacent methylene groups, indicating
interaction of the sulfur with the copper center. Hypothesizing
that this complexation may play a role in the overall oxidation
process, we synthesized the more Lewis acidic Cu(hfac) ·H O,
2
2
which showed analogous binding behavior with CEES
(
(
Figure 2), also observed by electron paramagnetic resonance
see the Supporting Information).
Comparative studies of Cu(acac)2 and Cu(hfac) ·H O were
2
2
[23–27]
conducted in similar manner to before, but, mindful that diffu-
sion from the aqueous layer might limit oxidation rates, the
mixtures were agitated for 2 s after addition.
phosphorus (OP) CWAs.
These materials were found to un-
dergo physical-state transitions in the presence of the OP CWA
soman or simulants, showing potential use as OP CWA sensors.
They were also shown to absorb OP CWA simulants, destroying
them in situ, and prompting interest in their use as possible
decontamination materials. Here, we present a complimentary
II
As shown in Figure 3, both Cu complexes at 5 mol% with
respect to CEES result in the increased oxidation rate of this
simulant. Over a 125 h period, 28, 43, and 66% of the CEES
&
ChemistryOpen 2017, 00, 0 – 0
www.chemistryopen.org
2
ꢀ 2017 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

system, presenting supramolecular gels as remediation and de-
contamination materials for HD, in combination with peroxides
and metallocatalysts.
1
Figure 5. H NMR spectra after 27 h of a) 1 (40 mg), simulant (0.25 mm),
tBuOOH (0.25–0.30 mm) in CDCl (0.92 mL); b) 1 (40 mg), simulant
(0.25 mm), Cu(hfac) ·H O (0.01 mm), tBuOOH (0.25–0.30 mm) in CDCl
3
Supramolecular gelators self-associate through the forma-
tion of intermolecular hydrogen bonds, resulting in the crea-
tion of a fibrous network (Figure 4) trapping the remaining sol
to produce a gel. These gels are sensitive to external stimuli,
2
2
3
(
0.92 mL). Black: resonance belonging to CEES; blue: resonance belonging
to the corresponding oxidized products.
spect to CEES, was found to increase the percentage of oxida-
tion product from 13 to 50% over 27 h, as compared to
a sample without catalyst. Further gel/sol studies conducted
with varying concentrations of gelator, peroxide, and catalyst
(
see the Supporting Information) exhibit minimal peak broad-
ening and suggest only the presence of primary oxidative pro-
cesses, meaning the presence of the undesired sulfone is not
observed under these conditions.
In summary, this proof-of-concept study has shown that the
cheap, commercially available transition-metal complexes are
able to act as catalysts for the oxidation of the sulfur mustard
simulant CEES in a two-phase solution with hydrogen perox-
ide. We have shown that limited agitation and substitution of
Figure 4. TEM images of a xerogel obtained from 1 (35 mg) and a saturated
solution of Cu(hfac)
formation.
2 2 3 ,
·H O in CHCl (1 mL) illustrating supramolecular fiber
II
acac ligand for hfac enhances the activity of the Cu -based cat-
alysts. These studies are the first example of the use of
undergoing gel–sol or sol–gel transitions as desired. We ex-
Cu(acac) derivatives as sulfoxidation catalysts rather than pre-
2
[
28]
plored a proof-of-principle system using gelator 1 in combi-
catalysts. Finally, Cu(hfac) ·H O can be incorporated into
2
2
nation with Cu(hfac) for the in situ remediation of CEES within
a supramolecular gel to enable the catalysis of CEES oxidation
within the solid state in the presence of the organic oxidant
tBuOOH. Work is ongoing to fully understand this catalytic pro-
cess under a variety of environmental conditions, determine ef-
fective CWA remediation times, and investigate further combi-
nations of catalyst, solvent, and peroxide. Next-generation sys-
tems are also under investigation to limit the oxidation process
to the sulfoxide only, preventing further production of
vesicants.
2
a gel. Attempts to incorporate Zn(acac) into a gel were pre-
2
vented by poor solubility under gelating conditions. Com-
pound 2 was used to test the reactivity of the urea functionali-
ty of 1 towards the other components of the remediatory gel
system in solution. The minimum concentration of 1 needed
to gelate a chloroform solution saturated with Cu(hfac) ·H O
2
2
À1
was identified as 25 mgmL through a series of inversion
tests.
We were unable to use aqueous H O for these gel studies,
2
2
as mass transport between the gel and aqueous phase is in-
credibly slow. Instead, we incorporated a 5–6m solution of tert-
butyl peroxide (tBuOOH) in decane into our gel systems to aid
the oxidation process. This peroxide is commercially available
on a bulk scale at a reasonable cost.
Acknowledgements
The authors would like to thank the University of Kent for the
Caldin Fellowship (J.R.H.), Ian Brown for his assistance with TEM
studies, and the University of Kent for funding and provision of
EPR resources.
These proof-of-concept gel studies were monitored by using
1
H NMR spectroscopy, with the conversion calculated through
comparative integration of these spectra over time, as shown
Figure 5. Owing to peak broadening effects, we were unable
to differentiate between primary and secondary CEES oxida- Conflict of Interest
tion, although evidence from these spectra suggests that both
of these oxidative processes are occurring within these sam-
The authors declare no conflict of interest.
ples. The encapsulation of CEES (0.25 mm) and tBuOOH (0.25–
0
.30 mm) in the presence of 4 mol% Cu(hfac) ·H O, with re-
2 2
ChemistryOpen 2017, 00, 0 – 0
www.chemistryopen.org
3
ꢀ 2017 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
These are not the final page numbers! ÞÞ

[
17] G. E. O’Mahony, P. Kelly, S. E. Lawrence, A. R. Maguire, ARKIVOC 2011, 1–
10.
[18] H. Srour, P. Le Maux, S. Chevance, G. Simonneaux, Coord. Chem. Rev.
013, 257, 3030–3050.
Keywords: catalysis · chemical warfare agents · hydrogen
bonding · mustard agents · supramolecular gels
1
2
[
[
[
[
[
[
[
19] A. Barbarini, R. Maggi, M. Muratori, G. Sartori, R. Sartorio, Tetrahedron:
Asymmetry 2004, 15, 2467–2473.
20] P. Plitt, H. Pritzkow, T. Oeser, R. Kraemer, J. Inorg. Biochem. 2005, 99,
[
[
1] A. W. Khan, S. Kotta, S. H. Ansari, J. Ali, R. K. Sharma, Def. Sci. J. 2013, 63,
87–496.
2] Q. Q. Wang, R. A. Begum, V. W. Day, K. Bowman-James, Org. Biomol.
Chem. 2012, 10, 8786–8793.
4
1230–1237.
21] E. R. Clark, J. J. Hayward, B. J. Leontowicz, M. U. Anwar, M. Pilkington,
J. M. Rawson, Dalton Trans. 2015, 44, 2071–2074.
22] S. E. Allen, R. R. Walvoord, R. Padilla-Salinas, M. C. Kozlowski, Chem. Rev.
[
[
3] K. Kehe, L. Szinicz, Toxicology 2005, 214, 198–209.
4] H. Thiermann, F. Worek, K. Kehe, Chem.-Biol. Interact. 2013, 206, 435–
443.
2
013, 113, 6234–6458.
[
[
5] K. G. Davis, G. Aspera, Ann. Emerg. Med. 2001, 37, 653–656.
6] K. Ghabili, P. S. Agutter, M. Ghanei, K. Ansarin, Y. Panahi, M. M. Shoja,
Crit. Rev. in Toxicol. 2011, 41, 384–403.
23] J. R. Hiscock, N. J. Wells, J. A. Ede, P. A. Gale, M. R. Sambrook, Org.
Biomol. Chem. 2016, 14, 9560–9567.
24] J. R. Hiscock, M. R. Sambrook, N. J. Wells, P. A. Gale, Chem. Sci. 2015, 6,
[
[
7] V. Kumar, E. V. Anslyn, J. Am. Chem. Soc. 2013, 135, 6338–6344.
8] 1925 Geneva Protocol http://static.un.org/disarmament/WMD/Bio/
5680–5684.
25] J. R. Hiscock, M. R. Sambrook, P. B. Cranwell, P. Watts, J. C. Vincent, D. J.
1
925GenevaProtocol.shtml, (accessed 11/10, 2016).
9] 1993 Chemical Weapons Convention, https://www.icrc.org/en/down-
load/file/1027/1993-chemical-weapons-icrc-eng.pdf, (accessed
1.10.2016).
Xuereb, N. J. Wells, R. Raja, P. A. Gale, Chem. Commun. 2014, 50, 6217–
[
6220.
[
26] J. R. Hiscock, F. Piana, M. R. Sambrook, N. J. Wells, A. J. Clark, J. C. Vin-
1
cent, N. Busschaert, R. C. D. Brown, P. A. Gale, Chem. Commun. 2013, 49,
[
10] H. P. Benschop, G. P. van der Schans, D. Noort, A. Fidder, R. H. Mars Groe-
9119–9121.
nendijk, L. P. A. de Jong, J. Anal. Toxicol. 1997, 21, 249–251.
[
[
27] M. R. Sambrook, J. R. Hiscock, A. Cook, A. C. Green, I. Holden, J. C. Vin-
cent, P. A. Gale, Chem. Commun. 2012, 48, 5605–5607.
28] J. van Esch, F. Schoonbeek, M. de Loos, H. Kooijman, A. L. Spek, R. M.
Kellogg, B. L. Feringa, Chem. Eur. J. 1999, 5, 937–950.
[
[
11] R. N. Saladi, E. Smith, A. N. Persaud, Clin. Exp. Dermatol. 2006, 31, 1–5.
12] M. Shohrati, M. Davoudi, M. Ghanei, M. Peyman, A. Peyman, Cutaneous
Ocul. Toxicol. 2007, 26, 73–81.
[13] H. Jung, D. Kah, K. C. Lim, J. Y. Lee, Environ. Pollut. 2017, 220, 478–486.
14] Y. J. Jang, K. Kim, O. G. Tsay, D. A. Atwood, D. G. Churchill, Chem. Rev.
[
2015, 115, PR1–PR76.
[15] B. M. Smith, Chem. Soc. Rev. 2008, 37, 470.
[16] K. Sato, M. Hyodo, M. Aoki, X. Q. Zheng, R. Noyori, Tetrahedron 2001,
Received: March 27, 2017
57, 2469–2476.
Version of record online && &&, 2017
&
ChemistryOpen 2017, 00, 0 – 0
www.chemistryopen.org
4
ꢀ 2017 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

COMMUNICATIONS
Two for the price of one: Innovative
countermeasures are needed to combat
the ongoing threat of chemical warfare
agents. This work showcases a step-
change in the development of novel
mustard agent (HD) remediation materi-
als by combining supramolecular gels
and transition-metal catalysts to provide
HD-simulant (CEES) sequestration and
remediation in a single system.
J. R. Hiscock,* G. P. Bustone, E. R. Clark*
& – &&
&
Decontamination and Remediation of
the Sulfur Mustard Simulant CEES
with “Off-the-Shelf” Reagents in
Solution and Gel States: A Proof-of-
Concept Study
ChemistryOpen 2017, 00, 0 – 0
www.chemistryopen.org
5
ꢀ 2017 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
These are not the final page numbers! ÞÞ