Oxidation of organic sulfides by N-halamine compounds

Article abstract of DOI:10.1080/10426500701247102

N-halamine chemistry has been an important research topic in these laboratories for over two decades, offering many exciting opportunities both from practical and pedagogical points of view. One of these opportunities is in the use of polymer- and silica gel-bound N-halamines as selective oxidizing agents for organosulfur compounds. In this study, they have been employed to selectively oxidize organic sulfides including dimethyl sulfide and chloroethyl ethyl sulfide, the chemical mustard stimulant. The latter oxidation produced the less toxic sulfoxide derivative with about 70% conversion, with no sulfone produced, and only about 30% accompanying conversion to sulfoxide hydrolysis products. In this article, we report a combination of experimental and computational results. Copyright Taylor and Francis Group, LLC.

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Oxidation of Organic Sulfides
by N-Halamine Compounds
Akin Akdag a , Jie Liang a & S. D. Worley a
a Auburn University, Department of Chemistry and
Biochemistry , Auburn, Alabama, USA
Published online: 07 Jun 2007.
To cite this article: Akin Akdag , Jie Liang & S. D. Worley (2007) Oxidation of Organic
Sulfides by N-Halamine Compounds, Phosphorus, Sulfur, and Silicon and the Related
Elements, 182:7, 1525-1533, DOI: 10.1080/10426500701247102
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Phosphorus, Sulfur, and Silicon, 182:1525–1533, 2007
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500701247102
Oxidation of Organic Sulfides by N-Halamine Compounds
Akin Akdag
Jie Liang
S. D. Worley
Auburn University, Department of Chemistry and Biochemistry,
Auburn, Alabama, USA
N-halamine chemistry has been an important research topic in these laboratories
for over two decades, offering many exciting opportunities both from practical and
pedagogical points of view. One of these opportunities is in the use of polymer- and
silica gel-bound N-halamines as selective oxidizing agents for organosulfur com-
pounds. In this study, they have been employed to selectively oxidize organic sulfides
including dimethyl sulfide and chloroethyl ethyl sulfide, the chemical mustard stim-
ulant. The latter oxidation produced the less toxic sulfoxide derivative with about
70% conversion, with no sulfone produced, and only about 30% accompanying con-
version to sulfoxide hydrolysis products. In this article, we report a combination of
experimental and computational results.
Keywords N-halamines; organic sulfides; oxidation; polymer bound reagents
INTRODUCTION
Oxidation of sulfide compounds has been explored extensively.1 Rea-
sons for these studies relate to possible biological, chemical, and envi-
ronmental implications.2 Although these compounds are used as medic-
inal agents, they can be toxic and used as chemical warfare agents.3 As
warfare agents, probably the most infamous organosulfur compound is
sulfur mustard which is bis(2-chloroethyl)sulfide (Figure 1).4 The mus-
tard agent is an extremely dangerous material that induces blisters on
the skin and in lungs and has caused numerous deaths and disfigure-
ments under battlefield conditions.
Received October 17, 2006; accepted December 11, 2006.
This work has been supported by The US Air Force through Contract F08637-02-C-
7020 and the HaloSource Company. The authors thank Drs. J. F. Williams and M. L.
Mckee for helpful discussions during the course of this work. The computer time was
provided by the Alabama Supercomputer facility.
Address correspondence to S. Worley, Auburn University, Department of Chemistry
and Biochemistry, Auburn, AL 36849, USA. E-mail: worlesd@auburn.edu
1525

1526
A. Akdag et al.
FIGURE 1 Structure of mustard and CEES.
Even though sulfides can be easily oxidized by a variety of oxidizing
agents,5 most of the oxidizing agents are inefficient for the mustard
analogue in terms of terminating the reaction at the sulfoxide stage;
there is usually further oxidation on to sulfones or fragmented prod-
ucts, which are known to be more toxic than the sulfoxide.6 Therefore,
there is a need for an efficient and selective oxidizing agent for chemical
mustard, and in general, an oxidizing agent that is specific for convert-
ing sulfides into sulfoxides, rather than to the more highly oxidized
sulfones.
We have previously demonstrated that thiols can be oxidized se-
lectively to disulfides with use of monochloro poly(styrenehydantoin)
beads.7 Many other reports had appeared in the literature regard-
ing oxidizing organosulfur compounds with N-halamines, such as
N-chlorosuccinimide and N-bromosuccinimide;8 however, use of the
polymer-bound N-halamines for the purposes mentioned above was
unique.
Surface bound N-halamine chemistry has been developed in these
laboratories since the late 1980s (see Figure 2 for some examples).9
The main purpose of these compounds has been for microbiological in-
activation, and in this regard, they have been subjected to numerous
biocidal studies. They have been shown to be excellent biocides and
proposed to be antibiological warfare agents (for biocidal activities, see
Ref. 9 and for the activity of chlorine grafted medical textiles against
anthrax see Ref. 10). However, these compounds have not been tested
as anti chemical warfare agents, e.g. for the sulfur mustard agent.
In this article, our aim was to examine the oxidation of thioethers
by use of monomer and polymer-bound N-halamine-containing com-
pounds. The mechanism of the oxidation reaction for dimethyl sul-
fide was investigated with ab initio DFT calculations at the B3LYP/6-
311+G(2d,p) level. This computational method was chosen because
it has been demonstrated to give excellent mechanistic predictions
for other reactions involving N-halamines.11 Experimentally, dimethyl
sulfide and a mustard derivative, chloroethyl ethyl sulfide (CEES),
were also subjected to oxidation with several N-halamine containing

Oxidation of Organic Sulfides
1527
FIGURE 2 Examples of the N-halamine-based materials.
materials. Characterization of the products was accomplished by anal-
yses of their 13C-NMR spectra, which were also calculated using the
GIAO method.
RESULTS AND DISCUSSION
In initial studies, dimethyl sulfide (DMS) was used as a model com-
pound. It was reacted with 1-chloro-5,5-dimethylhydantoin (mcH) in
water to yield a single sulfur-containing product, dimethylsulfoxide
(DMSO), along with 5,5-dimethylhydantoin (H). The reaction was mon-
itored by observance of the disappearance of the white solid mcH, which
was water insoluble; whereas H is water soluble. Encouraged by this
result, we then reacted DMS with 1,3-dichloro-5,5-dimethylhydantoin
(dcH) in water. The 13C-NMR spectrum showed that the sulfoxide was
produced along with the sulfone. This result was due to the fact that
the imide N-halamine function (on the dcH), which is less stable than
the amide N-halamine function in water toward hydrolysis, was readily
dissociated into hypochlorous acid.11 The HOCl was more reactive and
less selective than was the mcH. After these reactions were completed,
the solutions were acidic.

1528
A. Akdag et al.
FIGURE 3 Proposed mechanism of oxidation of DMS to DMSO.
Based upon the previous observation, we have proposed a reaction
mechanism (Figure 3) in which the first step involves the lone pairs
on the sulfur abstracting the oxidative chlorine from mcH, which then
abstracts a proton from water to form hydroxide and H. The resulting
sulfenyl chloride then is attacked by hydroxide to form sulfenyl hy-
droxide, and then the chloride abstracts the proton to yield hydrogen
chloride and dimethyl sulfoxide (DMSO). This reaction mechanism was
supported by ab initio calculations at the level of B3LYP/6-311+G(2d,p).
These calculations are summarized in Figure 3 and Table I. The inter-
mediate WI was proposed in the literature for oxidation of aromatic
sulfides with N-chlorosuccinimide.12 Although we have not employed
any acid to initiate the reaction, such an intermediate is not likely due
to the electronic nature of the nitrogen in structures WI and WII. More-
over, calculations at the level of B3LYP/6-311+G(2d,p) level of theory
showed that WII undergoes bond breakage between the nitrogen and
the neighboring carbons. The computations for mcH reacting with DMS
to form H and DMSO predict that the overall reaction is exothermic
and spontaneous (Table I). When solvation effects were included in the
calculations, all steps in the proposed mechanism became reasonable
energetically.
With these results in hand, we employed dichloro (polystyrenehydan-
toin) beads to oxidize DMS in water. Although we had observed that we

Oxidation of Organic Sulfides
1529
TABLE I The Energies, Enthalpies, and Gibbs Free Energies of the
Individual Steps in the Reaction Mechanism
ꢀE
ꢀH
ꢀG
ꢀG
Reaction
(kcal/mol) (kcal/mol) (kcal/mol)a (kcal/mol)b
mcH + DMS → Ha + DMSCl
Ha + H2O → H + OH−
123.75
42.12
−60.14
−117.12
−11.39
122.78
42.14
−58.01
−120.09
−13.17
123.06
43.87
−56.10
−121.99
−11.15
24.94
−8.01
DMSCl + OH → DMSOH + Cl−
DMSOH + Cl− → DMSO + HCl
Overall reaction
−28.07
−3.28
−14.41
aWithout solvation effects included; bWith solvation effects included (see text).
obtained the sulfoxide and the sulfone when dcH was employed, the
sole product was DMSO with the dichloro beads. This can be attributed
to steric hinderance for the polymer beads, which allowed little hydrol-
ysis of the imide N-Cl for the beads.
The experiments were then extended to inactivation of the mus-
tard stimulant. The chemical warfare agent bis(chloroethyl)sulfide is
extremely dangerous to handle; thus chloroethyl ethyl sulfide was em-
ployed in this work as the mustard derivative, as has been used in
previous studies.5,6 A similar procedure to that employed in the DMS
oxidation was applied to that of CEES. CEES was first reacted with
mcH to yield only the sulfoxide derivative in water. Despite the fact
that we obtained two products, sulfoxide and sulfone, for the oxidation
of DMS with dcH, the CEES reaction with dcH yielded only the sul-
foxide. From the analysis of the NMR spectra, it was also observed that
a small amount of elimination (ethyl vinyl sulfoxide) and substitution
(ethyl hydroxyethyl sulfoxide) products were obtained. The reactions
were complete within ca. 3 min.
The products were characterized with 13C-NMR; comparisons were
made with the literature13 and calculated data at the level of B3LYP/6-
311+g(2d,p) using the GIAO method.14 The structure was first opti-
mized at the same level; then single point calculations were performed
on the optimized structure to obtain isotropic shielding values, which
were subtracted from those for calculated tetramethylsilane to give
the calculated 13C-NMR spectrum. As seen in Table II, the calculated
and experimental data are in agreement qualitatively, but not quanti-
tatively. Because the calculations were performed for the compounds
in the gas phase, media effects and conformational averaging were
ignored.15
The N-halamine polymer-bound materials developed in these lab-
oratories, such as monochloro poly(styrenehydantoin) beads, the

1530
A. Akdag et al.
TABLE II Theoretical (Experimental)
13C-NMR valuesa
CEES
(ppm)
CEESO
(ppm)
Carbon #
C1
51.6
(43.6)
44.9
(33.0)
38.0
50.2
(37.4)
65.3
(53.0)
58.1
C2
C3
C4
(25.1)
14.1
(43.6)
9.6
(14.7)
(7.0)
aExperimental values were obtained for the
compounds dissolved in DMSO-d6.
monobromo- and dichloro-bead derivatives, and the halogenated
hydantoinylsiloxane-coated silica gel (monomer or polymer),16 which
have so far mainly been utilized for water disinfection and eliminat-
ing noxious odors from cutting oil fluids, should be useful in detoxify-
ing chemical agents. Unlike monochloro and dichloro hydantoin, these
polymeric materials are very stable to hydrolysis in water and selective
toward most chemical oxidation reactions.
In
a typical reaction with these polymeric materials, the
oxidizing agents (monochloro poly(styrenehydantoin) or dichloro
poly(styrenehydantoin) beads, or chlorinated hydantoinylsiloxane-
coated silica gel) were suspended in water, and then CEES was added
and allowed to react for 6 h (complete disappearance of the CEES was
observed after 2 h reaction time). Extended reaction times for 6 addi-
tional h were employed to ensure that the sulfoxide was not oxidized
further to the sulfone. In addition to the sulfoxide of CEES, we have
observed only small amounts (about 30 %) of hydroxyl and vinyl com-
pounds (See Figure 4) which can arise from direct hydrolyses of CEES.
No sulfone, a mustard derivative which is also toxic,17 was observed in
FIGURE 4 The products from oxidation of CEES with N-halamine-coated
materials.

Oxidation of Organic Sulfides
1531
any of the reactions of these polymer materials with extended amounts
of reaction time.
CONCLUSIONS
In this study we have concentrated on the oxidation of organic sulfides,
including the sulfur mustard simulant CEES with N-halamine mate-
rials. A reaction mechanism was proposed for the oxidation process
which was supported by DFT calculations. The product characteriza-
tion was accomplished by 13C-NMR, utilizing literature and calculated
values. The N-halamine-containing materials, i.e., N-halamine-bound
polystyrene and silica gel, can deactivate the sulfur mustard simulant
to its sulfoxide, which is less toxic. This work thus demonstrates the
utility of employing polymer-bound oxidizing agents to selectively per-
form an important detoxification reaction.
EXPERIMENTAL
General
The N-halamine-containing polystyrene beads were supplied by the
HaloSource Company (Seattle, WA), and N-halamine-coated silica gel
was prepared according to our published procedure.16 The calculations
were performed with Gaussian 03.18 Solvation effects were included
to the stationary geometries obtained at B3LYP/6-311+G(2d,p) level
with the conductor-like polarizable continuum(CPCM) using UAKS
cavities.19 A 1.9 kcal/mol correction factor was added to all solvation
free energies, and another 2.4 kcal/mol correction factor was added to
the water molecule.20 1H and 13C NMR spectra were recorded on ei-
ther a Bruker AC 250 spectrometer or a Bruker AV 400 spectrometer,
referenced to internal tetramethylsilane (TMS) at 0.0 ppm. Relative
1
product yields were determined by integration of the areas of the H
NMR signals for the products in the crude product mixtures.
1-Chloro-5,5-dimethylhydantoin
To a suspension of 1,3-dichloro-5,5-dimethylhydantoin (4.0 g, 0.020
mmol) in 100 ml of water was added 5,5-dimethylhydantoin (2.6 g,
0.020 mol). The mixture was stirred for 2 h at room temperature and
then filtered. The white solid was dried at ambient temperature. Spec-
1
tral data were: H-NMR (250 MHz, CDCl3): δ 1.5 (s, 6 H), 9.4(s, 1H);
13C-NMR(62.5 MHz, CDCl3) δ 174.9, 154.0, 67.3, 22.0.

1532
A. Akdag et al.
Reaction of Sulfides with 1-Chloro-5,5-dimethylhydantoin or
1,3-Dichloro-5,5-dimethyl Hydantoin
To a suspension of 1-chloro-5,5-dimethylhydantoin (1 mole equivalent)
in 100 ml of water was added dimethyl sulfide or chloroethyl ethyl sul-
fide (1 mole equivalent). The mixture was stirred until all white solid
disappeared. The reaction is complete within ca. 3 min. Then the sol-
vent was removed, and the products in DMSO-d6 were analyzed by
NMR (see text). The reaction with 1,3-dichloro-5,5-dimethylhydantoin
was repeated with 1:2 mole ratio of dcH and the sulfides.
Reaction of the Sulfides with the N-Halamine-containing
Bead Materials
To a suspension of the solid bead materials or N-halamine-coated silica
gel (3 g) in 50 ml of water was added the dimethyl sulfide or chloroethyl
ethyl sulfide (0.5 g), and the mixture was stirred for 12 h. The reaction
was complete within ca. 120 min. Then the mixture was filtered from the
beads or the silica gel, and excess solvent was removed by evaporation.
The residue in DMSO-d6 was analyzed by 13C-NMR (see text).
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