A safe and compact flow platform for the neutralization of a mustard gas simulant with air and light

Article abstract of DOI:10.1039/d0gc01142h

A low footprint, mobile, robust and frugal chemical neutralization technology is reported for the oxidative neutralization of a mustard gas simulant. It relies on the inherent properties of a highly engineered continuous flow setup and carefully optimized and simple, yet robust, experimental conditions. The neutralization protocol uses only non-toxic, widely available and cheap chemicals. The continuous flow setup integrates a singlet oxygen generator and exploits its oxidative power to neutralize 2-chloroethyl ethyl sulfide (CEES), the most common thioether mustard gas simulant. The flow reactor can be connected to either pressurized oxygen or air and handles CEES as a 1 M solution in EtOH containing a trace amount (0.06 molpercent) of a non-toxic and widely available photosensitizer (Methylene Blue). Upon irradiation with visible light (orange or white light), total and highly selective neutralization towards the corresponding non-toxic sulfoxide (1-chloro-2-(ethylsulfinyl)ethane, CEESO) is obtained with reactor effluents containing less than 1percent of the corresponding potentially toxic sulfone (1-chloro-2-(ethylsulfonyl)ethane, CEESO2). With a low footprint (L × W × H 94 × 42 × 40 cm), this neutralization technology can be equipped on a vehicle for on-site interventions, localized at a neutralization facility or both. This experimental work is also supported with the computational rationalization of the reactivity of CEES towards singlet oxygen.

Full text of DOI:10.1039/d0gc01142h

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Green Chemistry
COMMUNICATION
A safe and compact flow platform for the neutralization of a
mustard gas simulant with air and light
<Received 00th January 20xx,
Accepted 00th January 20xx
Noémie Emmanuel,a, ¶ Pauline Bianchi,a, ¶ Julien Legrosb and Jean-Christophe M. Monbaliua,*
DOI: 10.1039/x0xx00000x
A low footprint, mobile, robust and frugal chemical neutralization technology is reported for the oxidative neutralization of
a mustard gas simulant. It relies on the inherent properties of a highly engineered continuous flow setup and carefully
optimized and simple, yet robust, experimental conditions. The neutralization protocol uses only non-toxic, widely
available and cheap chemicals. The continuous flow setup integrates a singlet oxygen generator and exploits its oxidative
power to neutralize 2-chloroethyl ethyl sulfide (CEES), the most common thioether mustard gas simulant. The flow reactor
can be connected to either pressurized oxygen or air and handles CEES as a 1 M solution in EtOH containing a trace
amount (0.06 mol%) of a non-toxic and widely available photosensitizer (Methylene Blue). Upon irradiation with visible
light (orange or white light), total and highly selective neutralization towards the corresponding non-toxic sulfoxide (1-
chloro-2-(ethylsulfinyl)ethane, CEESO) is obtained with reactor effluents containing less than 1% of the corresponding
potentially toxic sulfone (1-chloro-2-(ethylsulfonyl)ethane, CEESO2). With a low footprint (L x W x H 94 x 42 x 40 cm), this
neutralization technology can be embarked on a vehicle for on-site interventions, localized at a neutralization facility or
both. The experimental work is also supported with a computational rationalization of the reactivity of CEES towards
singlet oxygen.
www.rsc.org/
consequences of
destruction of stockpiles, related equipment and
infrastructure.2,4
a CWA attack and to supervise the
Introduction
Chemical warfare agents (CWAs, Figure 1) were conceived in
the darkest converging alleys of Science and Industry to
optimize debilitating, incapacitant or lethal activity for
maintaining military superiority.1 World War II stressed the
emergence of much more redoubtable nuclear warfare, even
though large stockpiles of CWAs were maintained worldwide
and new chemical agents were developed. Since WWII, CWAs
were sporadically used for armed conflicts with the last reports
dating back to 2017-2018 in the Middle East. The tragedy with
CWAs remains that it also affects civilians who lack protection
gears and antidotes.2
Fig. 1. Representative examples of Schedule I CWAs.
The Chemical Weapons Convention (CWC) entered in force
in 1997 with the ambition to prohibit the possession,
manufacture and use of CWAs and was ratified by 193
countries.3 Besides prohibition, it also aims at developing
resources, procedures and capacities to treat the
There are still large inventories of CWAs reminiscent of
previous conflicts, either as a latent, still usable threat or as
spoiled ammunitions. Besides, the availability of various
chemicals on small to medium scale as well as emerging
process technologies with a very low footprint have also raised
significant concerns with the potential local production of
CWAs for chemical terrorism.5 Following the inception of the
CWC, a total of 8 countries declared CWAs, 7 of which have
now completed the destruction of 97% of the declared
inventories worldwide. The USA has announced the
destruction of 90% of its total inventory and aims at a
complete destruction by 2023.6,7
a. Center for Integrated Technology and Organic Synthesis, MolSys Research Unit,
University of Liège, B-4000 Liège (Sart Tilman), Belgium
jc.monbaliu@uliege.be www.citos.uliege.be
b. Normandie Université, INSA Rouen, UNIROUEN, CNRS COBRA laboratory (UMR
6014 & FR3038) 76000 Rouen (France)
¶
Equal contributions.
Electronic Supplementary Information (ESI) available: fluidic components,
experimental procedures, details of the fluidic setup and procedures,
computational details, details for the off-line analyses (GC, HPLC) and structural
assignments (NMR). See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
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Among CWAs, 1-chloro-2-[(2-chloroethyl)sulfanyl]ethane the validation of a neutralization method. The lipophilic nature
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DOI: 10.1039/D0GC01142H
(CAS 505-60-2) commonly referred to as mustard gas or HD is of HD/CEES typically renders aqueous oxidation protocols
a Schedule I CWA with cytotoxic and vesicant properties.8 HD inefficient, hence often imposing surfactants14 or organic
is considered as the parent molecule of sulfur mustards. The solvents as carriers.15 Primary oxidizers typically include
unique reactivity and toxicity profile of sulfur mustards arise hydrogen peroxide,14,16–22 peracids15 or oxygen22–25 in the
from the combination of donor lone pairs nS on the sulfur presence of homogeneous26 or heterogeneous catalysts.16–
18,27–31
atom in the vicinity of two σ*C-Cl acceptors, hence potentially
Other oxidizers were also reported such as N-
forming strongly alkylating and toxic episulfonium species epi- iodosuccinimide/water (Table 1).32
HD (Figure 2a).9 The most common method of destruction of
The oxidative neutralization methods relying on reactive
HD relies on incineration,10,11 although such a method raises oxygen species are very attractive, especially when molecular
significant safety concerns not only for the emission of toxic oxygen is the primary oxidant source (Table 1). Zeolites2 and
gaseous or liquid emissions upon thermal treatment but also MOF-based heterogeneous materials and fibers were also
for the transportation risk.12 Chemical neutralization reported and successfully tested for the UV photooxidation of
methods10,11 (methods 1-3, Figure 2b) for sulfur mustards such CEES and actual samples of HD.23,28,33–36 These photooxidations
as HD or its most common simulant CEES (2-chloroethyl ethyl typically proceed with complete conversion and high to
sulfide) typically target either one of the lone pairs nS on sulfur complete selectivity towards the sulfoxide HDO with a catalytic
through selective oxidation towards a sulfoxide (method 1) or amount (typ. 1-2 mol%).23,28 The heterogeneous MOF
the σ*C-Cl acceptors through hydrolysis or displacement with a photocatalyst can be easily recovered after neutralization and
strong nucleophile (method 2).13 A third alternative method of is potentially reusable.35 Photoactive ferrocene-conjugated
chemical neutralization relies on dehydrohalogenation microporous polymers were also reported.24,25 Despite
protocols (method 3).
excellent results, these methods have only been reported on
the milligram scale and would face additional challenges for
reaching larger scales.
Organic homogeneous photosensitizers were also
considered under aerobic conditions such as Riboflavin
tetraacetate (RFTA) or riboflavin (vitamin B2).37,38 Under
irradiation with blue LEDs (450 nm) with 2 mol% RFTA at room
temperature, CEES was quantitatively and selectively
converted into CEESO in 10 min of irradiation. Boron-
dipyrromethene (BODIPY) PSs were assessed for the
photooxidation of CEES and actual samples of HD under blue
light irradiation in solution or impregnated on PVDF films and
textiles, providing CEES half-life down to 0.8 min.39
Other critical parameters are the compactness, robustness
and inherent safety related to the neutralization method.
Indeed, the neutralization setup must be transportable and
compact for rapid deployment on site. It must also provide
consistent neutralization with high selectivity yet relying on
simple, non-toxic, cheap and widely available chemicals. While
most of the oxidative procedures rely on batch setups, several
authors have considered continuous flow conditions and flow
reactors as process technologies endowed with unique
inherent features that could be exploited for the efficient
oxidation of CEES specifically for the use of oxygen and related
reactive species.40–45 In particular, photocatalysis in flow has
attracted significant attention both for the preparation of
advanced chemical structures and for the chemical destruction
(neutralization) of pollutants.46 Flow protocols relying on
either homogeneous or heterogeneous photocatalysts47–52
benefit from the synergistic combination of flow and
photochemistry: uniform irradiation with accurately controlled
irradiations times, hence leading to intensified reactions with
shorter and more selective reaction pathways.46,53–55 Flow
conditions are also typically considered as scale-independent
and easier to scale-up than conventional batch setups.46,53–56
Fig. 2. a. Reactivity and toxicity of HD; b. General chemical neutralization
methods for mustard gas (HD) and its most common simulant (CEES).
Method 1. Oxidation; Method 2. Hydrolysis; Method 3.
Dehydrohalogenation. Compounds with the light gray background are
considered low-toxicity neutralized species.
Although these oxidative neutralization methods seem
straightforward, the complex reaction profile of HD/CEES
makes them very cumbersome. For instance, the
overoxidation of HD/CEES leads to the formation of a strong
Michael acceptor sulfone CEVSO2/EVSO2,14–16 the toxicity of
which is comparable to the parent mustard. In all instances, its
formation must thus be limited to trace amounts. The
selectivity of the oxidation is therefore a critical parameter for
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Table 1. Selection of procedures for the neutralization of mustard gas HD and its simulant CEES
Entry
Author
Scale
Type
Catalyst
Oxidant
Solvent
Conditions
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Jackowski57
Landry29
Wynne30
Cibulka38
Farha28
5 mM
5.4 mg
0.85 mg
25 mg
25 mg
~780 g day-1
25 mg
28.7 mg
10 mg
172 mM
2.8 mg (HD)
25 mg
Batch a
Batch b
Batch b
Batch a
Batch b
Flow a
Batch b
Batch b
Batch a
Batch a
Batch b
Batch b
Batch b
Batch b
Batch b
Flow a
Rhodococcus R. IGTS8
V-mesoporous SiO2, 10%
ZnOPPc
N.A.
t-BuOOH
Air
H2O
CH2Cl2
Neat
MeCN/H2O
MeOH
MeOH
MeOH
CDCl3
[BMIm]HCO3
d4-MeOH
Neat
MeOH
MeOH
H2O
MeOH/H2O
EtOH
30 °C, 14 d, quant. c
r.t., 1 h, 97% d
λ, 32-34 °C, 24 h, quant. e
450 nm, r.t. 10 min; quant.
~400 nm, r.t., 15 min, quant. c
r.t., 3.9 min, quant. c
400 nm, 14 min, quant. c
r.t., 27 h, 50% c
Riboflavin tetraacetate, 2 mol%
NU-1000, 1 mol%
Methanesulfonic acid urea-H2O2 (UHP) adduct
NU-1000-PCBA, 0.7 mol%
Cu(hfac)2.H2O, 4 mol%
/
O2
O2
Legros20
Farha34
O2
t-BuOOH
H2O2
O2
Air
O2
O2
N.A.
H2O2
O2 or air
Clarck26
Zhao22
r.t., 30 min, quant. f
Karwacki39
Karwacki39
Farha33
BODIPYs
3-30 min, quant. g
BODIPY-I in fabric, 0.1 mol%
PCN-222, UMCM-313, 1 mol%
[Y(H9TPPA)(H2O)x]Cl2·yH2O
Me-DABCOF, 6-20 wt%
MIP/porphyrin, 0.25 mol%
Methylene Blue, 0.06 mol%
r.t. 30 min, quant. g
395-420 nm 12-18 min, quant.
400-500 nm, 28 min, quant. c
36 min-24 h, quant. c
r.t., 2 h, 99.3% c
Farha35
25 mg
50 mg
116.5 mg
~180 g day-1
Zafrani13
Estour21
This work
610 nm, 4 min, >99% h
a Homogeneous conditions; b heterogeneous conditions; c no sulfone detected; d CEESO/CEESO2 ratio of 3.1; e trace amounts for long reaction time; f 6% of CEESO2; g trace
amounts; h <1% of CEESO2
Seeberger was actually one of first to report the catalytic amounts (0.06 mol%) of a non-toxic, cheap and widely
photooxidation of thiodiglycol TDG (0.25 M) under continuous available organic photosensitizer (Methylene Blue); (c) only
flow conditions.58 The authors used tetraphenylporphyrin environmental and user-friendly reagents are involved,
(TPP, 2 mM) in chloroform as a photosensitizer. The reactor including the solvent (EtOH); (d) the reactor setup is mobile
was operated at room temperature under 6.9 bar of and can be embarked on a vehicle for on-site neutralization
counterpressure and under UV irradiation (450 W medium with minimal resources and it can be integrated with in-line
pressure mercury lamp). Analog TDG was oxidized with 95%, analysis for process monitoring and increased safety; (e)
yielding to a 3:1 mixture of the corresponding sulfoxide and quantitative conversion of simulant CEES is obtained with high
sulfone. Legros reported a compact flow process with an selectivity within 4 min of irradiation time under mild process
integrated in-line low field NMR20. The oxidation was carried conditions (20 °C, 9 bar) with unprecedented concentrations (1
out with the hydrogen peroxide/urea complex (UHP) in M in ethanol); (f) the process is virtually scaled-independent
methanol with methanesulfonic acid as promotor. The authors since it relies on intensified flow conditions that can be
reported complete and selective oxidation mustard gas transposed to much larger scales with larger commercial
simulant CEES within 3.9 min of residence time, and fluidic reactors. It provides the most cost effective, operator-
overoxidation to the sulfone was avoided by collecting the friendly and low footprint process with high atom economy
reaction effluents in
a quenching solution. Despite its reported so far for the oxidative neutralization of mustard gas
effectiveness, their procedure imposes the availability and simulant CEES.
transportation of explosive and corrosive reagents along with
the reactor setup. Moreover, the use of UHP releases
Experimental section
General information
stoichiometric amounts of urea in the effluents to be further
disposed.
Based upon our expertise in the design of flow processes
and in particular for the generation and handling of reactive
oxygen species5,59–61, a compact flow system (L x W x H 94 x 42
x 40 cm) was devised for enabling rapid deployment on site
and effective oxidative neutralization with frugal and benign
resources. We report herein an advanced continuous flow
setup for the selective oxidation of simulant CEES and further
document the reactivity of such thioethers through MP2 and
Natural Bond Order (NBO) computations. The combination of
both experimental and theoretical approaches led to a more
refined understanding of the unique features of the
photooxidation of thioethers. This process is unique compared
to the prior Art (Table 1, entry 16) since (a) it relies on the
unique features of a highly engineered continuous flow setup
using intensified and user-friendly conditions; (b) it uses the
powerful combination of oxygen (or air), visible light and trace
Conversion, selectivity and yield were determined by Gas
Chromatography coupled to Flame Ionization Detection (GC-
FID) or Mass Spectrometry (GC-MS) or by High Performance
Liquid Chromatography coupled to Diode-Array Detection
(HPLC-DAD). GC and HPLC conversions and yields were
determined using external calibration curves established with
commercial standards (2-chloroethylethyl sulfide, 2-
chloroethylethyl sulfone, ethyl vinyl sulfide, ethyl vinyl sulfone,
methyl vinyl sulfone, methyl phenyl sulfide, methyl phenyl
sulfoxide, methyl phenyl sulfone, dipropyl sulfide, dipropyl
sulfone, thiodipropionic acid, dibenzyl sulfide, dibenzyl
sulfoxide, dibenzyl sulfone, diphenyl sulfide, diphenyl
sulfoxide, diphenyl sulfone, tetrahydrothiophene sulfide,
tetrahydrothiophene sulfoxide, tetrahydrothiophene sulfone,
benzyl phenyl sulfide, diethyl sulfide, benzyl methyl sulfide,
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benzyl methyl sulfone, dibenzothiophene, dibenzothiophene Typical run
sulfone) or with synthesized reference samples following
reported procedures (see Supporting Information Section 2.2.4
View Article Online
DOI: 10.10o39f/DC0EGECS011w4i2tHh
Continuous flow photochemical neutralization
oxygen. The pump used to deliver the solution of 2-chloroethyl
ethyl sulfide (CEES, 1 M) and Methylene Blue (560 µM) in EtOH
was set to 1 mL min-1. The mass flow controller used to deliver
oxygen was set to 20 mLN min-1, and both streams were
conveyed through PFA tubing to the first glass fluidic module
of the Corning® Advanced-Flow™ LF/G1 skid Photo Reactor
upon irradiation at 610 nm (full intensity, 300 LEDs) at 20° C (9
bar of counterpressure) (Figure 6). The reactor effluent was
collected at steady state, diluted with EtOH and analyzed by
GC/FID (99% conversion, 99% selectivity, see Table 1).
19,30,35,39
for experimental procedures).
Structural identity was
confirmed by H and 13C NMR spectroscopy (400 MHz Bruker
Avance spectrometer) in CDCl3 (Supporting Information
Sections 2.4 and 2.5). Ethanol, acetonitrile, water, Rose Bengal,
Methylene Blue, 9,10-dicyanoanthracene, oxygen and air were
obtained from commercial sources, and used without
1
additional
purification.
CAUTION:
1-chloro-2-
(ethylsulfinyl)ethane (CEES) is a highly toxic and severe
vesicant. It must be handled with great care under a fume
hood. The access to 1-chloro-2-[(2-chloroethyl)sulfanyl]ethane
(mustard gas or HD) is subjected to military clearance under
very strict conditions.
Results and Discussion
Computations
The photooxidation of thioethers has been widely discussed in
the literature through mechanistic and computational studies,
and various mechanisms were postulated and assessed.63–77
Depending on the photosensitization, the oxidation can
proceed either through the addition of the thioether substrate
onto singlet oxygen or through electron transfer (ET) involving
the superoxide anion.66,78 The photooxidation of thioethers
with singlet oxygen is consensually recognized as a complex
reaction sequence leading to various oxidations products,
among which the corresponding sulfoxides are typically the
major product, along with variable amounts of sulfones and
oxidative fragmentation products.65,69,74,76 The process goes
through the formation of several key intermediates (Figure 3),
the first of which being a weakly bound peroxysulfoxide
Computations were performed at the MP2/6-31+G** or
B3LYP/6-31+G** level of theory with the Gaussian 09 package
of programs (Revision D.01) with implicit solvent (PCM, ε =
24.852, ethanol). Stationary points were optimized with
gradient techniques (tight optimization convergence).
Transition states were localized using the Newton-Raphson
algorithm, and the nature of the stationary points was
determined by analysis of the Hessian matrix. Intrinsic reaction
coordinate (IRC) calculations were performed on
representative transition states. NBO calculations and
population analysis were performed at the B3LYP/6-
31+G**level on the optimized structures (MP2/6-31+G**).
Graphical representations of the HOMO of thioethers were
obtained through the FormChk utility in Gaussian 0962.
intermediate
A that forms upon the addition of the
nucleophilic thioether substrate onto electrophilic singlet
oxygen. Intermediate A was actually never isolated. The fate of
the later determines the output of the photochemical process.
Intermediate A typically undergoes physical quenching in
apolar aprotic solvents, while it is stabilized in protic solvents,
hence drastically improving the efficiency of the
photooxidation.73,79 The exact nature of the second
intermediate B has fed intense debate in the literature;
advanced mechanistic and computations studies pointed
towards hydroperoxysulfonium ylide B2 rather than
thiadioxirane B1.63–77 The reaction of each molecule of singlet
oxygen can potentially result in 2 equiv. of sulfoxide.64,73
Experimental setup
Mesofluidic setup. Mesofluidic experiments were carried with
a Corning® Advanced-Flow™ Lab Photo Reactor (1 fluidic
module, 2.6 mL internal volume) and in a Corning® Advanced-
Flow™ LF/G1 skid Photo Reactor (5 fluidic modules integrated
with static mixers and connected in series, 13 mL total internal
volume). Feed and collection lines consisted of PFA tubing
(1/8” o.d. or 1/4” o.d.) equipped with PFA or SS Swagelok
connectors and ferrules. The liquid feed was handled with
ThalesNano MicroHPLC pumps, and the gas feed (oxygen or
air) was handled with a Bronkhorst EL FLOW Prestige mass
flow controller. The reactor was maintained at reaction
temperature with a LAUDA Integral XT 280 thermostat. The
LED panels were maintained at 10 °C with a LAUDA RP845.
Downstream pressure was regulated with a back pressure
regulator from Zaiput Flow Technologies (BPR-10 or BPR-100).
Optionally, an in-line IR (FlowIRTM from Mettler-Toledo
equipped with a DTGS detector using HappGenzel apodization,
a Silicon probe connected via a FlowIRTM sensor and a high
pressure heated 10 µL cell) or NMR (43 MHz Spinsolve™
carbon NMR spectrometer from Magritek®) was inserted
downstream (Supporting Information Section 2.3).
Fig. 3. Commonly accepted intermediates and mechanism for the reaction
of thioethers with singlet oxygen under photosensitized conditions. Singlet
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oxygen is typically generated from ground state molecular oxygen upon
irradiation in the presence of a photosensitizer (PS). A common organic PS is
Methylene Blue.
stereoelectronic or delocalization effects, yet a more precise
scale was required.
View Article Online
DOI: 10.1039/D0GC01142H
The structures of HD, CEES and 1a-f were optimized at the
MP2/6-31+G** level of theory in ethanol. In order to have
more precise information on the availability of the non-
bonding nS orbitals on the sulfur atom of each of these
thioethers, NBO and electronic population analyses were
carried out at the B3LYP/6-31+G** level of theory on the
The access to HD is subjected to military clearance under
very strict conditions, while small inventories of its most
widely accepted simulant (CEES) can be purchased. CEES is
however still a very toxic and severe vesicant that must be
handled with great care, hence precluding its direct use for
large-scale optimization. Decision was made to undertake a
preliminary computational study on the reactivity of HD and
CEES towards singlet oxygen for comparison with other widely
available non-toxic thioethers, the handling of which for
preliminary experiments with singlet oxygen would not raise a
significant safety hazard. Obviously, the model thioethers must
echo the peculiar inherent reactivity of HD/CEES for enabling
fast transposition with minimal readjustment to CEES. The
rationale behind such an approach was to limit the exposure
to extremely toxic chemicals upon the optimization of the
process conditions. In silico modeling enables to compute
quantitative or semi-quantitative models and data, which are
particularly relevant when high toxicity chemicals are at
stakes.
optimized structures (MP2/6-31+G**).
A second order
perturbation theory analysis of the Fock matrix in the NBO
basis provided a convenient metric (Figure 4) to sense
stereoelectronic features that are responsible for a decreased
availability of the non-bonding nS orbitals on the sulfur atom,
thus indicating a lower efficiency for the reaction with singlet
oxygen. Only the potential donor/acceptor interactions (Eint)
involving the non-bonding nS and acceptors such as σ*C-X (X =
C, Cl) or *C=C were looked at on the most stable conformers of
CEES, HD and 1a-f.
From the NBO and population analyses (Figure 4), it can be
seen that dialkyl sulfides such as CEES, HD and 1a have well-
localized HOMO centered on the sulfur atom and are
characterized by low to negligible donor/acceptor interactions
(Figure 4).
The efficiency of singlet oxygen oxidation of thioethers is
not only very sensitive to reaction conditions, but it also
critically depends on the inherent structural and
stereoelectronic features of the thioether substrate. The
availability of the non-bonding nS orbitals on the sulfur atom,
which correlates to its intrinsic nucleophilicity, is thus
paramount to ensure quick and efficient scavenging of singlet
oxygen to form peroxysulfoxide intermediate A. Any factor
that potentially decreases the availability of the non-bonding
nS orbitals on the sulfur atom will therefore potentially reduce
the efficiency of the reaction with singlet oxygen. As discussed
in the Introduction (Figure 2a), the reactivity and toxicity
profiles of sulfur mustards HD and CEES arise from the
combination of a donor lone pair nS on the sulfur atom in the
vicinity of two σ*C-Cl acceptors; such stereoelectronic feature
might thus impact the oxidative neutralization process. It is
therefore critical to have access to a metric for assessing the
extent of such stereoelectronic feature for supporting the
rational selection of an appropriate non-toxic model thioether.
In order to quantify the availability of the non-bonding nS
orbitals and thus to provide insights on the potential for
reaction with singlet oxygen, a preliminary computational
study was undertaken on a series of model thioethers with
defined structural and stereoelectronic features (Figure 4). The
selected model thioethers included CEES and HD, as well as
other alkyl, aryl and benzyl thioethers (1a-f), more specifically,
dipropyl sulfide (1a), (chloromethyl)(ethyl)sulfide (1b), benzyl
methyl sulfide (1c) methyl phenyl sulfide (1d), diphenyl sulfide
(1e) and dibenzothiophene (1f). Thus the selection of
thioethers 1a-f included thioethers with qualitatively expected
high (1a), intermediate (1c, 1d) and low (1b, 1e, 1f) availability
of non-bonding nS orbitals, thus mirroring a potentially
decreasing reactivity towards electrophilic singlet oxygen. This
qualitative scale relies on the structural analysis of the
compounds 1a-f and the identification of any potential strong
Fig. 4. Selection of model thioethers 1a-f for the computational study. The
stereoelectronic interaction between a donor non-bonding nS and a vicinal
acceptor (σ*C-X (X = C, Cl) or *C=C were looked at on the most stable
conformers of CEES, HD and 1a-f) is expressed in kcal mol-1. HOMO (isovalue
0.02) are represented for thioethers CEES, HD and 1a-f.
By contrast, chloromethyl ethyl sulfide (1b) features a
strongly interacting non-bonding nS in the direct vicinity of a
σ*C-Cl acceptor and a less localized HOMO. Benzyl methyl sulfide
(1c) features a medium stereoelectronic effect (Eint = 4.0 kcal mol-1)
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involving a neighboring σ*C-C orbital. Major differences appear for photooxidation of both 1a and CEES are expVeiecwteAdrticlteoOnlbinee
DOI: 10.1039/D0GC01142H
1d and to a larger extent to 1e,f, where the delocalization of the transposable on HD.
non-bonding nS orbitals to the aromatic ring drastically affects
Based on the computational results, preliminary trials were
their availability. Dibenzothiophene 1f comes with a very carried out under photosensitized conditions to calibrate the
strong stereoelectronic interaction (Eint = 18.7 kcal mol-1 for each singlet oxygen oxidation process. The flow setup is described
nS orbital). The results from the NBO and population analyses in Figure 6. It consisted of 5 specialty glass fluidic modules
are in agreement with the data from the literature, which (FMs) of 2.6 mL each connected in series for a total of 13 mL.
emphasize that alkyl aryl and diaryl sulfides are considered as Each glass FM features a succession of high performance static
poor quenchers of singlet oxygen compared to dialkyl sulfides mixers to ensure high mass transfer efficiency between
due to their HOMO only partially localized on the sulfur gaseous and liquid effluents. Each FM is integrated with a
atom.67
double layer heat exchanger and is sandwiched between two
The transition state for the quenching of singlet oxygen by LED panels, each equipped with 30 high power LEDs of a
thioethers 1a, CEES and HD towards the corresponding defined wavelength (300 LEDs in total). The LED panels are
peroxysulfoxide intermediates A (1Aa, CEESOO and HDOO, integrated with a dedicated heat exchanger. The combination
respectively) were located at the MP2/6-31+G** level of of high-efficiency static mixers and high power LEDs makes this
theory in ethanol. The structure of the targeted sulfoxides (2a, reactor configuration particularly well suited for the
CEESO and HDO) are illustrated for the sake of comparison generation of singlet oxygen in the presence of organic
(Figure 5). These TSs display an orthogonal approach of singlet substrates.59 The reactor setup was kept under 9 bar of
oxygen relative to the thioether substrates and are structurally counterpressure with a dome-type backpressure regulator
related (Supporting Information Section 4).
(BPR). In-line low field NMR or IR spectrometers were
optionally inserted downstream for qualitative process
monitoring and samples were analyzed off-line either by GC or
HPLC (Supporting Information Section 2.2.1).
Solutions of representative commercial thioethers were
prepared in EtOH (1 M), unless solubility issues imposed a co-
solvent or a lower concentration (Supporting Information
Section 2.2.3), in the presence of an organic photosensitizer
(Figure 6 and Table 2). Methylene Blue (MB) was selected as
organic photosensitizer for the singlet oxygen reaction with
thioethers 1a-f rather than Rose Bengal for its improved
resistance to photobleaching and its overall better
performances as an organic photosensitizer (Supporting
Information Section 3.2.3). MB is a non-toxic, stable, widely
available and affordable organic photosensitizer. The liquid
feed solution was mixed with oxygen upon irradiation with the
Fig. 5. Structural features of the transition states for the reaction of
thioethers 1a, CEES, and HD with singlet oxygen, of the corresponding
peroxysulfoxide intermediates A and of the final sulfoxides. See Supporting
Information Section 4 for details. The corresponding S-O and O-O bond
lengths are listed here (values in Å): TS11a (S-O: 1.88, O-O: 1.36), TS1CEES (S-O:
appropriate wavelength at 25 °C under
9
bar of
counterpressure for a total estimated residence time of 10 min
(see Supporting Information Sections 2.2.3 and 3.1 for details).
1.87, O-O: 1.36), TS1 (S-O: 1.85, O-O: 1.36), 1Aa (S-O: 1.63, O-O: 1.46),
HD
CEESOO (S-O: 1.63, O-O: 1.46), HDOO (S-O: 1.63, O-O: 1.46), 2a (S-O: 1.54),
CEESO (S-O: 1.54), and HDO (S-O: 1.54).
Table 2. Calibration of the photooxidation process with singlet oxygen on model
thioethers (see also Figure 6 for the general setup)
Thioether
Solvent
(M)
Catalyst
(mol%)
Conv.
(%) c
>99 d
>99 e
>99 e
5 e
The structural and energetic features of these TSs are in
agreement with the work of Jensen and Clennan on other
dialkyl thioethers.63–65,68,70,75–77 The TSs connecting 1a, CEES
Entry
substrate
1
2
3
4
1a
1c
1d
1e
EtOH (1)
EtOH (1)
EtOH (1)
EtOH (1)
EtOH:2MeTHF
(0.1)
MB (0.06) a
MB (0.06) a
MB (0.06) a
MB (0.06) a
MB (0.06) a
and HD (TS1
,
1a
TS1
and TS1
, respectively) to the
CEES HD
corresponding peroxysulfoxide intermediates (1Aa, CEESOO
and HDOO) feature a rather long S-O bond (1.85-1.87 Å)
indicative of an early transition state and strong interactions
between the non-bonding nS orbitals and singlet oxygen.77 The
slightly shorter S-O bond length for TS1HD (1.85 Å) compared to
5
1f
0 e
CH3CN
DCA b
DCA b
6
7
1e
1f
47
49
TS11a, TS1
(1.87 Å) reflects the presence of two electrons
CH3CN
CEES
withdrawing Cl atoms. From the analysis of both NBO and TS
structures, it appeared that both 1a and CEES are potentially
good structural mimics of the parent HD for such
transformation, hence the results collected on the
a MB = Methylene Blue, Irradiation at 610 nm; b DCA = 9,10-dicyanoanthracene,
Irradiation at 395 nm; c Conditions (see Scheme 1): 25 °C, 10 min residence time,
9 bar; the selectivity towards the corresponding sulfoxides is given in the
Supporting Information (Table S3); Determined by GC-FID. Determined by
HPLC-DAD.
d
e
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The first set of conditions involved MB (0.06 mol%) in the process conditions were further optimized. Given the
View Article Online
conjunction with oxygen and irradiation at 610 nm (orange complex reactivity profile of CEES, a vaDriOeIt:y10o.1f03s9id/De0GprCo0d11u4c2tHs
LEDs) for the generation of singlet oxygen (entries 1-5). are expected according to the data of the literature. Under the
Control experiments in the absence of light or in the absence experimental conditions of this report, 4 impurities were
of organic photosensitizer were carried out as well, and no detected (Scheme 1, Table 3), among which only CEESO2 (the
conversion was detected. Compound 1b was not tested since corresponding overoxidized sulfone) is considered as toxic
it reacted quickly with the solvent under these conditions.
since it potentially produces electrophilic ethyl vinyl sulfone
The experimental observations were analyzed in parallel EVS (Figure 2). Impurities I-1 and I-3 are formed through the
with the computation data (Table 2). It can be concluded that addition of EtOH on CEES and CEESO and can therefore be
thioethers 1a, 1c and 1d that are characterized by a low considered as neutralized species. Impurity I-2 is formed
stereoelectronic involvement of the non-bonding nS orbitals through the dechlorination of CEESO and is typically
(Eint  4.1 kcal mol-1) and a rather S-centered HOMO are considered as a non-toxic chemical. The identity of all
efficient quenchers of singlet oxygen under intensified flow impurities was confirmed by GC, GC-MS or NMR with
conditions, and are converted selectively and quantitatively to commercial or prepared samples.
the corresponding sulfoxides (Table 2, entries 1-3). No traces
The impact of various process parameters (irradiation time,
of sulfones or other oxidative fragmentation products were primary source of singlet oxygen, light intensity and nature) on
detected. By contrast, diaryl thioethers 1e,f were barely the efficiency and the selectivity of the photooxidation was
reactive towards singlet oxygen (entries 4,5). Changing the assessed (Table 3 and Supporting Information Section 3.2). In
photosensitizer to 9,10-dicyanoanthracene (0.06 mol%) in this process, the highest conversion of CEES must be reached
acetonitrile under irradiation at 395 nm (entries 6,7) led to 47 within a short residence time, and the oxidation must be
and 49% conversion for compounds 1e,f. Such conditions are selective enough to produce low amounts of CEESO2. The
typically associated with the generation of a superoxide and an emergence of other impurities such as I-1, I-2 and I-3 does not
electron transfer mechanism for the oxidation of thioethers impact negatively the process, since they are considered as
rather than
a
singlet oxygen oxidation,67,69,78 hence neutralized species as CEESO.
emphasizing the differences in terms of mechanism and its
implication for the oxidation of structurally diverse thioethers.
The choice of the involved mechanism depends not only on
the structural and stereoelectronic features of the thioether,
but also on the nature of the photosensitizer, which was not
evaluated with the computational approach, hence showing
the interests for combining computational with experimental
data.
Scheme 1. Oxidative neutralization of CEES under optimized continuous flow
conditions (see also Table 3).
The irradiation time can be reduced from 10 to 4 min upon
irradiation at 610 nm with full intensity in the presence of
oxygen while still reaching almost quantitative conversion of
CEES (entries 1 and 7, >99% and 92%, respectively) towards
mainly CEESO and other minor impurities (Scheme 1). A
further decrease to 2 min nevertheless left about 18% of
unreacted CEES in the reactor effluent (82% conversion). The
amount of CEESO2 increased with the conversion of CEES to
CEESO, yet it remained under 1%: 0.1% (2 min), 0.4% (4 min)
and 0.9% (10 min). Impurities I-1 (3%), I-2 (1%) and I-3 (3%)
were present in the reactor effluent from the experiment at 4
Fig. 6. a. Simplified flow chart for the photooxidation of thioethers including
CEES (BPR = back pressure regulator; MFC = mass flow controller; FM =
fluidic module; Feed A = substrate typically 1 M in EtOH with 0.06 mol% of
an organic photosensitizer; heat exchange on the reactive path and LED
panels are omitted for clarity). b. Photograph of the low footprint and
mobile chemical neutralization technology for the oxidative neutralization of
mustard gas simulant CEES upon irradiation at 610 nm (Corning® Advanced- min of irradiation time.
FlowTM G1/LF skid Photo Reactor; Courtesy of Corning®). The footprint of the
setup is L x W x H 94 x 42 x 40 cm. c. Details of a glass fluidic module with
the LED panels removed.
A stock solution of CEES (1 M) and MB (560 µM) was
prepared in EtOH (Supporting Information Section 2.2.3) and
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DOI: 10.1039/D0GC01142H
Table 3. Optimization of the oxidative neutralization of CEES under continuous flow conditions (see also Scheme 1).
Reactor effluent composition (%) d
Entry
Oxidant
RT
(min)
LEDs
(nm)
Conv. c
(%)
CEES
CEESO
CEESO2
I-1
I-2
I-3
1
2
O2
O2
O2
Air
Air
O2
Air
O2
Air
O2
10
10
10
10
10
4
610
white
white
610
>99 a
>99 a
>99 a
>99 a
>99 b
99 a
51 a
>99 a
68 a
0
0
95
96
95
84
85
92
14
98
55
68
1
1
1
1
0
0
0
1
0
0
0
0
0
0
0
3
4
0
3
2
1
2
1
1
1
1
0
2
1
1
3
1
3
0
3
4
0
15
14
3
5
610
0
6
610
1
7
4
610
81
0
0
8
4
white
white
610
0
9
4
41
28
0
10
2
82 a
0
a 1 M solution in EtOH with 0.06 mol% Methylene Blue (Rose Bengal for entry 3), processed at 20 °C under 9 bar of counterpressure; b 0.1 M solution in EtOH with 0.06 mol%
Methylene Blue, processed at 20 °C under 9 bar of counterpressure; c Determined by GC with an external calibration on commercial CEES; d Ratio of compounds determined by
GC. The references for compounds CEESO, CEESO2, I-1, I-2 and I-3 were either purchased from commercial sources or synthesized in the lab.
At 10 min of irradiation time, only impurities I-2 (1%) and I- orange LEDs (610 nm) or white LEDs (4000K) provided >99.9%
3 (3%) were detected besides CEESO2. It is expected that the conversion of CEES. The reactor effluent from the experiment
longer irradiation time oxidized completely I-1 towards I-3. At with the 610 nm LEDs contained 95% of CEESO, and traces of
the shortest residence time (2 min), impurity I-3 was not CEESO2 (0.6%), I-1 (0.5%), I-2 (2%) and I-3 (1%). The reactor
detected while impurities I-1 and I-2 reached 2% and 1%, effluent from the experiment with white LEDs had a similar
respectively. These observations indicate a potential filiation composition with 96% of CEESO, and traces of CEESO2 (1%), I-2
between I-3 and I-1, as well as I-2 (EVSO) and CEESO, although (1%) and I-3 (3%). Decreasing the residence time to 4 min still
other reaction paths might be incriminated (See Supporting afforded quantitative conversion of CEES under white LEDs
Information Section 2.2.4). Impurity I-2 is also believed to arise irradiation. In the latter case, the crude reactor effluent
from the specific reactivity of the corresponding contained 98% of CEESO along with 0.5% of CEESO2 and less
hydroperoxysulfonium ylide B2 intermediate (Figure 3).80 than 2% of I-2. Pure oxygen could be replaced with air,
Impurity I-1 most likely arises from a slow reaction between although the concentration of the solution had to be
the substrate CEES and the solvent upon storage of the feed decreased 10-fold to maintain full conversion within 10 min of
solution. Such reaction was not significant upon standing in residence time. Within 4 min of irradiation in the presence of
the feed, and is likely to be accelerated in the flow reactor with air, white LEDs gave better photooxidation performances than
the local heat generated by the LEDs (Supporting Information the orange LEDs, affording 68% conversion in CEES (51% under
Section 2.2.4).
The efficiency of the photooxidation is typically greater
irradiation at 610 nm). Both samples were free of CEESO2.
To summarize the optimization of the chemical oxidative
with pure oxygen rather than air. This is logical and explainable neutralization of CEES, the best results involved process
as the proportion of oxygen is simply lower in air. Within 4 min conditions relying on oxygen under 4 min irradiation either at
of irradiation at 610 nm (full intensity), the conversion of CEES 610 nm or under white light at room temperature and 9 bar of
reached 99% with pure oxygen while it decreased to 51% with counterpressure. Under these conditions, only a trace amount
air under the same conditions. For the longest irradiation time of CEESO2 is formed. Air can also be utilized for the
(10 min), either oxygen or air gave a similar conversion (99%). neutralization of CEES, affording complete conversion of CEES
The reactor effluent from the experiment with air within 4 min yet with a longer irradiation time (10 min).
of irradiation was exempt from CEESO2, although this is most
likely related to the low conversion of CEES than to the nature
of the primary source of singlet oxygen. The amount of
Conclusion
impurity I-1, was slightly higher for the experiment with air
(4%) than for the experiment with oxygen (3%). Impurity I-3
was absent from the reaction with air, while 3% were formed
in the presence of oxygen.
This work illustrates the development of a low footprint,
mobile, robust and frugal chemical neutralization technology
for the oxidative neutralization of a mustard gas simulant. It
relies on the unique features of
a highly engineered
The intensity and the nature of the light source were also
looked at (Supporting Information Section 3.2.4). Decreasing
the LEDs intensity typically led to lower conversions, and the
maximum intensity was used for most of the trials. With
oxygen or air at the longest irradiation time (10 min), either
continuous flow setup and robust conditions using non-toxic
and widely available chemicals. The experimental work is also
supported with
a computational rationalization of the
reactivity of selected thioethers towards singlet oxygen. The
optimized conditions use concentrated solutions of CEES in
8 | J. Name., 2012, 00, 1-3
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ethanol with a trace amount of MB upon irradiation with 10
orange or white light. Quantitative conversion was obtained 11
within 4 min of irradiation time under mild process conditions
(20 °C, 9 bar). Oxygen or air can be utilized as primary oxidant, 12
although with air longer irradiation times or lower feed
concentrations are typically required. Under optimized 13
conditions, only trace amounts of toxic CEESO2 are detected in
the reactor effluent, hence providing an extremely cost
effective, operator-friendly and low footprint process for the 14
oxidative neutralization of CEES. The neutralization technology
can be embarked on a vehicle for on-site interventions, 15
localized at a neutralization facility or both. The ability to
transpose these optimized conditions to larger scales with 16
commercial Corning Advanced-Flow Reactors with minimal
reoptimization definitively opens up new perspectives for the 17
safe chemical neutralization of mustard gas with a minimal
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Conflicts of interest
There are no conflicts to declare.
21
22
23
24
Acknowledgments
This work was supported by the University of Liège (Welcome
Grant WG-13/03, JCMM) and by the French Community of
Belgium (Concerted Research Action ARC-icFlow, Integrated
Continuous Flow Photoreactors). Computational resources
have been provided by the “Consortium des Équipements de
Calcul Intensif” (CÉCI), funded by the “Fonds de la Recherche
Scientifique de Belgique” (F.R.S.-FNRS) under Grant No.
2.5020.11. Dr. Morgan Hans is acknowledged for carrying out
the GC/MS experiments.
25
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