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ChemieInternational Edition: DOI: 10.1002/anie.201702744
German Edition:
DOI: 10.1002/ange.201702744

Reaction Monitoring

Oxidative Neutralization of Mustard-Gas Simulants in an On-Board
Flow Device with In-Line NMR Monitoring
Baptiste Picard, Boris Gouilleux, Thomas Lebleu, Jacques Maddaluno, Isabelle Chataigner,
Ma]l Penhoat, FranÅois-Xavier Felpin,* Patrick Giraudeau,* and Julien Legros*
Abstract: The fast and effective neutralization of the mustardgas simulant 2-chloroethyl ethyl sulfide (CEES) using a simple
and portable continuous flow device is reported. Neutralization takes place through a fully selective sulfoxidation bya stable source of hydrogen peroxide (alcoholic solution of
urea–H2O2 adduct/MeSO3H freshly prepared). The reaction
progress can be monitored with an in-line benchtop NMR
spectrometer, allowing a real-time adjustment of reaction
conditions. Inherent features of millireactors, that is, perfectcontrol of mixing, heat and reaction time, allowed theneutralization of 25 g of pure CEES within 46 minutes ina 21.5 mL millireactor (tR = 3.9 minutes). This device, which
relies on affordable and nontoxic reagents, fits into a suitcase,and can be deployed by police/military forces directly on theattack site.

The use of chemical weapons by terrorist groups has becomea plausible threat since several chemical warfare agents(CWA) are currently available to perpetrators, including
mustard compounds with the simplest bis(2-chloroethyl)
sulfide as prominent member.[1, 2] This blister agent is wellknown under common names such as mustard agent, yperiteor HD; this viscous liquid is used as a weapon throughdispersion by spraying or explosion, hence the denomination“mustard gas”. The extreme toxicity of HD is due to theequilibrium with the strongly electrophilic episulfonium form,
which also makes it carcinogenic (Scheme 1). Conventional
processes for the destruction of large quantities of mustard[*] B. Picard, Dr. T. Lebleu, Dr. J. Maddaluno, Prof. I. Chataigner,
Dr. J. Legros
Normandie Universit8, INSA Rouen, UNIROUEN, CNRSCOBRA laboratory (UMR 6014 & FR3038)
76000 Rouen (France)
E-mail: julien.legros@univ-rouen.fr
B. Gouilleux, Prof. F.-X. Felpin, Dr. P. Giraudeau
CEISAM CNRS, UMR6230, Universit8 de Nantes, BP 92208
2 rue de la HoussiniHre, 44322 Nantes (France)
E-mail: fx.felpin@univ-nantes.fr
patrick.giraudeau@univ-nantes.fr
Prof. F.-X. Felpin, Dr. P. Giraudeau
Institut Universitaire de France
1 rue Descartes, 75005 Paris (France)
Dr. M. Penhoat
Universit8 de Lille, CNRS, USR 3290, MSAP
Miniaturisation pour la SynthHse l’Analyse et la Prot8omique
59000 Lille (France)
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.201702744.

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Scheme 1. Oxidation of mustard gas yperite (HD) into the corresponding sulfoxide (HDO) and sulfone (HDO2).

agents (e.g. shells from World War I, Syrian stockpiles)
require highly secure sites, specifically dedicated for thispurpose. The neutralization/destruction of chemical warfare
agents is generally conducted under harsh conditions, that is,direct pyrolysis, hydrolysis in strongly basic solutions ortransformations with aggressive oxidants.[3–6] The limited
solubility of HD in water explains the poor efficiency of thehydrolysis path. In contrast, oxidation has to be regarded as
the method of choice to neutralize this CWA, at least if theprocess retained is very selective toward the sulfoxide, since
overoxidation affords a highly toxic sulfone (Scheme 1).
In recent years, the academic community has madeprogresses towards the implementation of highly selective
sulfoxidation of HD simulants with peroxides, singlet oxygen,hypochlorite, for instance, in the presence of metal promoters(including polyoxometallates and metal–organic frameworks)
or in microemulsion media.[7–17] However, most of these
protocols are unsuited for large scales or use in real situation.
Considering that the terrorist threat would most likely
embody the form of a small and concealable chemical bomb
introduced into a densely populated area, the possibility ofintervening directly on site represents a decisive advantage.
Therefore, the deployment of robust and transportableequipment allowing a rapid and selective oxidation ofmustard gas is of utmost importance. Continuous flow devices
fulfil all these requirements: they are compact systems whichallow high control on reaction time as well as on heat andmass transfer, and the process can be easily up-scaled without
optimization of new conditions.[18, 19] Moreover, hazardous
chemicals such as oxidants are easily handled in a flow
system,[20–24] and it offers the possibility of automation and inline analysis.[25–27] Herein we show that the fast neutralizationof sulfur mustard simulants can be achieved by fully selective
oxidation in a flow apparatus monitored by an in-line
1
H NMR low-field instrument (Scheme 2).
The toolbox of organic chemists overflows with oxidants,
among which hydrogen peroxide is certainly one of the mostconvenient to use, especially under its UHP form (urea-H2O2

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ChemieScheme 2. An integrated flow system with in-line NMR monitoring forthe sulfoxidation of mustard simulants chloroethyl phenyl sulfide(CEPS) and chloroethyl ethyl sulfide (CEES).

adduct; m.p. 90 8C), a very stable solid, hence transportable,
source of anhydrous hydrogen peroxide. Whereas H2O2
generally requires the assistance of a promoter for efficient
oxygen transfer, it has been shown that the simple use ofhexafluoroisopropanol (HFIP) as solvent was able to efficiently activate the oxidant;[28–31] this activation is mostly due
to an increase of the electrophilicity of peroxide oxygen
through strong H-bonding with the solvent.[31, 32] Notably,
B8gu8 and co-workers reported that complete oxidation ofvarious sulfides into sulfoxides was attained within only
5 minutes reaction time.[28] Hence, a preliminary experiment
involving mustard gas simulants (CEPS and CEES) anda solution of UHP (2 equiv) in HFIP was run in a classicalbatch setup (Scheme 3).

Scheme 3. Oxidation of half-mustards CEPS and CEES with UHP in
HFIP.

Full conversion of both substrates rapidly occurred and
CEPS underwent fully selective sulfoxidation (CEPSO).
However CEES, the closest analogue of the real warfare
agent HD,[33] was converted into sulfoxide CEESO (80 %),along with 20 % of a dimeric sulfonium salt (bisCEES), whose
formation has already been described, among several products, during hydrolysis.[34] A blank NMR experiment was thenperformed by diluting CEES in pure HFIP and after only
5 minutes, the dimeric sulfonium salt (bisCEES), was formed
selectively. The possible reversible dimerization of thebisCEES in the presence of UHP was evaluated on a benchmark test, but unfortunately, after 15 days of stirring thedimeric sulfonium salts remained very stable. Thus, to avoid
this competitive and irreversible dimerization affording
a compound of unknown toxicity, we switched to the lesspolar solvent methanol,[35, 36] in the presence of methanesulfonic acid as proton donor to dissociate/activate UHP.
Actually, CEES proved to remain stable in a MSA/methanol
mixture for hours in the absence of oxidant. These newconditions (methanol/MSA/UHP) were implemented ina two-stream flow reactor shown on Figure 1. Neat CEES
Angew. Chem. Int. Ed. 2017, 56, 7568 –7572

Figure 1. Continuous flow set-up for the oxidation of half-mustards
CEPS and CEES with UHP/MSA in methanol. See the Supporting
Information for details.

(23.36 mL, 0.2 mol), was pumped at a flow rate of
0.5 mL min@1 and met in a T-shaped mixer a solution of
UHP (1.3 equiv), MSA (2.6 equiv) in MeOH (30 equiv)
pumped at a flow rate of 5 mL min@1. The resulting stream
entered in a PFA tubing reactor (ID = 1.6 mm, L = 10.7 m,
V = 21.5 mL) with a residence time of tR = 3.9 minutes. The
reactor outlet was then collected into a bottle containing
40 mL of 10 % (w/w) aqueous NaHSO3. Therefore, a simple
extraction afforded the corresponding sulfoxide CEESO in> 99 % yield. Similar results (conditions and yield) wereobtained with CEPS.[37, 38]
These developments can be supported by the implementation of in-line analytical methods capable of monitoring thereaction on the fly. This enables the real-time characterizationof reaction products, kinetic studies and the optimization of
the reaction conditions. Obviously, high-field NMR spectrometers are not portable, but recent years have witnessed
the use of compact NMR spectrometers for these purposes,
either under a by-pass configuration[39–42] or within a flow
chemistry platform.[43] We incorporated such a low-field NMR
system within our continuous flow system in order to evaluate
the residence time tR at which the maximal conversion of
CEES into the sulfoxyde CEESO is achieved (Figure 2).
However, performing the reaction with short tR (less than
1 minute) in our setup involved high flow-rates, whichsignificantly impact the sensitivity and the resolution of the
NMR experiments. A first feature—commonly called “inflow
effect”—is the continuous replenishment of the excited spinsby unexcited ones. The latter must spend a sufficient timewithin the pre-polarization volume to reach their full thermal
polarization. When the flow rate is too high, the saturated
spins are refreshed by non-polarized ones leading to a loss of
sensitivity.[44–46] Another feature involved by flow NMR—
known as “outflow effect”—makes the use of high-flow
regimes even more problematic. When the receiver is open
during the detection of a flowing sample, some polarized andexcited spins leave out the sensitive volume before the end of

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Chemiedetected and monitored through the flow reaction. The
experiments were carried out at decreasing flow rates, that is,
at increasing residence times. The overlapping triplets at
1.25 ppm—arising from the overlaps between the methylgroups of CEES and CEESO—progressively turned intoa simple triplet matching with the disappearance of CEES
(Figure 3). The conversion rate as a function of tR wasmonitored by computing the ratio between the peak area ofthe signals at 3.8 and 1.25 ppm for each kinetic point. Figure 3
displays the percentage of sulfoxide computed for six different residence times: full conversion is reached within 67 s,
stressing the efficiency of the neutralization method.
In conclusion, we have implemented a simple and mobile
device allowing fast neutralization of mustard gas simulants.
The neutralization occurs through complete and fully selec-

Figure 2. Continuous flow system including a benchtop NMR spectrometer directly connected to the outlet of the reactor.

the acquisition.[44, 46] This phenomenon leads to a reduction of
the effective transverse relaxation time and involves a significant line-broadening. Here, these limitations were circumvented by finely tuning the flow system, consisting in reducing
the reactor volume and previously dissolving the neat CEES
in methanol (further details are available in the Supporting
Information). Thanks to this optimization, it was possible toassess the conversion rate on a range of tR from 16.2 to 100.8 s
without exceeding a flow-rate of 3 mL min@1, which is anacceptable flow regime in our NMR flow system regarding
the aforementioned limitations. The benchtop NMR spectrometer employed in this study (Spinsolve from Magritek)
works at 43.62 MHz, relies on a permanent magnet and works
without deuterated solvents.[47] This reduces the cost of themonitoring and avoids undesired isotopic effects. The downside of using non-deuterated methanol is the overlap between
the huge solvent signal and the resonances of interest. Thisdrawback became even more critical at high flow-rates (e.g.
3 mL min@1) due to the inherent line broadening occurringwith flowing samples.[44, 45] To outmatch this limitation, we
implemented a tailored NMR pulse sequence capable of
suppressing multiple solvent resonances at low magnetic fieldunder flow conditions. The experiment combined a continuouspresaturation with a WET-180-NOESY Scheme that werecently described (see the Supporting Information forpulse sequence and parameters).[46] The WET-180 block,[48]added during the preparation step, combines a train of
selective shaped pulses applied together with gradient spoilers to selectively disperse the longitudinal component of thesolvent magnetization. The Scheme includes a hard 18088 pulse
directly after the last selective pulse with a modification of theflip angle providing a narrower residual solvent signal witha cleaner phase. This block was followed by a NOESY
excitation with a two-step phase cycling leading to a reductionof the faraway solvent effect and a flatter baseline close to theresidual solvent signal.[49] As a result of the efficient solvent
signal suppression, the CEESO peak at 3.8 ppm could be7570

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Figure 3. Neutralization of CEES monitored by an in-line NMR system.
Top and middle: Two NMR spectra recorded at different tR. Note thatthe peak with a * corresponds to a 13C satellite line from the residual
solvent signal at 3.3 ppm. Bottom: Percentage of CEESO as a functionof the residence time.

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Communications
tive sulfoxidation (> 99 %) in a millitube reactor usinga handy oxidizing system (an alcoholic mixture of highly
stable urea-H2O2 adduct and methane sulfonic acid) that canbe readily prepared on demand for on site operation.
Intensification at multi-gram scale has been performed andshowed full reproducibility: 25 g of neat half-mustard CEES
have been neutralized within 46 minutes, and kilogram scale
could be reached by using adequate pumps without any
further changes. When optimized, an in-line real-time monitoring of the reaction efficiency is possible thanks to tailoredspectroscopic methods on a benchtop NMR spectrometer. In
practice, our mobile device could be embarked in a vehicle forfield intervention: the toxic agent would be directly pumped
from the suspicious gear into the millireactor and neutralizedon site.[50]Acknowledgements
The authors gratefully acknowledge support from the CNRS
« Attentats Recherche » program. J.L. is grateful to Dr M. De
Paolis and Dr I. Decostaire for fruitful discussions. The
authors from Normandie Universit8 also thank the LabexSYNORG (ANR-11-LABX-0029), the R8gion Normandie(MicroChim Project and CRUNCh network) and the European France (Manche)-England cross-border cooperation
program INTERREG IV A “AI-CHEM CHANNEL” cofinanced by ERDF for support. The authors from the
University of Nantes acknowledge the R8gion Pays de la
Loire (grant R8soNantes) for financial support. FXF and PG
are members of the Institut Universtaire de France (IUF).

Conflict of interest
The authors declare no conflict of interest.
Keywords: chemical warfare agents · continuous flow ·hydrogen peroxide · NMR spectroscopy · oxidation
How to cite: Angew. Chem. Int. Ed. 2017, 56, 7568 – 7572
Angew. Chem. 2017, 129, 7676 – 7680

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introduced inside the gear by an additional pump/tubing tosolubilise the CWA.

Manuscript received: March 16, 2017
Revised manuscript received: April 25, 2017
Version of record online: May 22, 2017

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