Reaction of bis(2-chloroethyl) sulfide with N,N′-dichlorobis(2,4,6-trichlorophenyl)urea

Full text of DOI:10.1021/jo990783a

J . Org. Chem. 1999, 64, 8031-8033
8031
viable synthetic procedure for N,N′-dichlorobis(2,4,6-
trichlorophenyl)urea is also reported.
Rea ction of Bis(2-ch lor oeth yl) Su lfid e w ith
N,N′-Dich lor obis(2,4,6-tr ich lor op h en yl)u r ea
Resu lts a n d Discu ssion
D. K. Dubey,* R. C. Malhotra,
R. Vaidyanathaswamy, and R. Vijayaraghavan
HD was reacted with CC-2 in both hydrophobic and
hydrophilic environments, as the formulations made and
screened6 were also of varying polarity. Two reactants
were also treated in different mole ratios, since in a given
decontamination scenario they are likely to react in
arbitrary proportions. Results show that the nature of
the products formed in these reactions depended on the
reaction medium and the mole ratios of the reactants.
In protic medium (CH3CN:H2O, 50:50), the product
profile of bis(2-chloroethyl) sulfide and N,N′-dichloro-
bis(2,4,6-trichlorophenyl)urea depended on their respec-
tive mole ratios (Scheme 1). When the HD:CC-2 ratio was
1:0.5, the major degraded product was bis(2-chloroethyl)
sulfoxide (3) (Scheme 1a). At equimolar concentration
(Scheme 1b), instead of the expected bis(2-chloroethyl)
sulfone, the main product obtained was 2-chloroethyl 1,2-
dichloroethyl sulfoxide (5) with a small quantity of 3. At
a 1:1.5 mole ratio of HD:CC-2 (Scheme 1c), bis(1,2-
dichloroethyl) sulfoxide (6) was the major degraded
product rather than bis(2-chloroethyl) sulfone (7). In all
the reactions CC-2 was quantitatively converted into bis-
(2,4,6-trichlorophenyl)urea (4). The remaining about 10-
20% products were higher chlorinated sulfoxides and
sulfones (based on GC-MS data) which could not be
characterized as they formed an intractable mixture.
Separate reactions of bis(2-chloroethyl) sulfoxide with
CC-2 also yielded the same compounds, i.e., 5-7, similar
to Scheme 1b,c. All of these products are nontoxic
compared to the bis(2-chloroethyl) sulfide, as is evident
from our earlier reported animal experiments,6 where no
mortality and vesication were observed in mice even after
applying 6LD50 of HD topically and decontaminating it
with CC-2 based formulations. Moreover, in the majority
of recommended decontamination reactions of HD the
compounds 3 and 7 are the main products.4 The ad-
ditional compounds formed in this reaction are R-chlo-
rinated sulfoxides (in protic medium), and sulfide (in
aprotic medium); and reduction in the toxicity and
vesication action of HD on introduction of chlorine at the
R-position is well-documented.7
Defence R. & D. Establishment, J hansi Road,
Gwalior 474002 M.P., India
Received May 12, 1999
In tr od u ction
Bis(2-chloroethyl) sulfide (HD) is a potent chemical
warfare agent with serious toxic effects.1 There is no
specific antidote available against HD, and antidotes that
were screened in laboratory animals gave only limited
protection against its systemic toxicity.2,3 The chemical
decontamination of HD immediately after contact is still
the best method of protection. The prerequisite for such
a decontaminating chemical is that it must instantly
convert HD into nontoxic products. In comparison to
hydrolysis and other oxidation reactions,4 the reaction
of HD with an organic chloramine such as dichloramine-T
is rapid enough to decontaminate it instantly, even at
subzero temperatures.5 On the basis of these results,
decontamination formulations containing dichloramine-T
and another chloramine, N,N′-dichlorobis(2,4,6-trichlo-
rophenyl)urea (CC-2), were prepared with different ma-
trixes, such as petroleum jelly, fuller’s earth, and gum
acacia, which varied in their polarity and protic environ-
ment. Experiments have shown that while dichlor-
amine-T based formulations were found to be unstable
and the available chlorine decreased with time, CC-2-
based formulations exhibited higher stability. These were
therefore evaluated for their decontamination efficiency
against dermally applied HD in mice. It is interesting to
note that formulations exhibited excellent protection and
the results of these animal experiments are reported
elsewhere.6
With regard to the chemical decontamination of a
potent toxic compound like HD, it is necessary to know
the nature of the products arising from such decontami-
nation reaction for obvious reasons. We report here the
complete reaction profile of HD with CC-2 in varying
proportions and in medium of different polarity. Keeping
in view the requirement for large quantities of CC-2 for
decontamination formulations, an improved commercially
P r op osed Mech a n ism
Mechanistically it is established that in aqueous
medium the first step in chlorination of sulfides is
electrophilic attack of chlorine on sulfur, generating
sulfonium cation8 (C) (Scheme 2). Subsequently nucleo-
philic displacement of chlorine by water with elimination
of HCl produces sulfoxide (E). The nitranium ion (D)
formed on CC-2 molecule after expelling positive chlorine
most likely picks up the proton either from the aqueous
environment or from liberated HCl. If the concentration
of CC-2 is half than that of HD, the reaction stops here
only. This means that almost all the sulfide gets con-
(1) (a) Papirmeister, B.; Feister, A. J .; Robinson, S. I.; Ford, R. D.
Medical Defence Against Mustard Gas; CRC Press Inc.: Boca Raton,
FL, 1991. (b) Dacre, J . C.; Goldman, M. Pharmacol Rev. 1996, 48, 290.
(2) (a) Callaway, S.; Pearce, K. A. Br. J . Pharmacol. 1958, 13, 395.
(b) Vojvodic, V.; Milosavljevic, B; Bojanic, N. Fundam. Appl. Toxicol.
1985, 5, 160. (c) Vijayaraghavan, R.; Sugendran, K.; Pant, S. C.;
Husain, K.; Malhotra, R. C. Toxicology 1991, 69, 35.
(3) Somani, S. M.; Babu, S. R. Int. J . Clin. Pharmacol. Ther. Toxicol.
1989, 27, 419.
(4) (a) Yang, Y. C.; Baker, J . A.; Ward, J . R. Chem. Rev. 1992, 92,
1729. (b) Yang, Y. C. Chem. Ind. 1995, 1 May, 334.
(5) Dubey, D. K.; Nath, R.; Malhotra, R. C.; Tripathi, D. N.
Tetrahedron Lett. 1993, 34, 7645.
(6) (a) Vijayaraghavan, R.; Reddy, P. M. K.; Dubey, D. K.; Kumar,
P.; Singh, R. Second C. B. Medical Treatment Symposium, 7-12 J uly,
1996, NC laboratory Speiz, Switzerland. (b) Reddy, P. M. K.; Dubey,
D. K.; Kumar, P.; Vijayaraghavan, R. Ind. J . Pharmacol. 1996, 28,
227.
(7) Sartori, M. F. The War Gases; Van Nostrand: New York, 1939;
Part 1, pp 228-232.
(8) Senning, A. Sulfur in Organic and Inorganic Chemistry; Marcel
Dekker: New York, 1982; Vol. 4, pp 201-218.
10.1021/jo990783a CCC: $18.00 © 1999 American Chemical Society
Published on Web 09/30/1999

8032 J . Org. Chem., Vol. 64, No. 21, 1999
Notes
Sch em e 1
Sch em e 2
At still higher concentrations of CC-2, the repetition
of this sequence with H leads to R,R′-dichloro sulfoxide.
The remaining small quantity of nonchlorinated sulfoxide
3 (Scheme 1b) further oxidizes to the corresponding
sulfone. It is interesting that gem-dichlorination does not
occur from H inspite of the fact that the CHCl proton of
the 2-chloroethyl 1,2-dichloroethyl sulfoxide is certainly
more acidic than those on the other R-carbon. The exact
reason for this is not known, but it can probably be
attributed to the fact that sulfoxides have strong confor-
mational preferences,9 and it is possible to selectively
remove one of the diastereotopic protons from conforma-
tionally biased oxochlorosulfoxonium ion similar to the
R,R′-dichlorination of sulfoxides observed by Klein.9b
In aprotic medium and at equimolar concentration, the
reaction of HD and CC-2 yields 2-chloroethyl 1,2-dichlo-
rivinyl sulfide along with complete conversion of CC-2
to bis(2,4,6-trichlorophenyl)urea (Scheme 1d). The reac-
tion is assumed to proceed in similar fashion as that of
HD and dichloramine-T.5 If the mole ratio of HD:CC-2 is
1:0.5, some amount of HD remains unreacted. This
indicates that for complete decontamination of HD in
aprotic environment at least an equimolar amount of
CC-2 is necessary, while in aqueous medium even 0.5 mol
of CC-2 is sufficient for complete conversion of sulfur-
mustard to its sulfoxide.
A large quantity of N,N′-dichlorobis(2,4,6-trichlorophen-
yl)urea is required for the preparation of decontamination
formulations, and early reported synthetic procedures
were inadequate to meet the requirement, as they were
either time-consuming, low yielding,10a or required
phosgene10b as one of the starting materials, which is
toxic to handle. A convenient, one-pot, high-yielding
commercially viable method was developed for the syn-
thesis of CC-2. This was done by chlorination of diphen-
ylurea in two steps; it was first chlorinated in acetic acid
and then in acetic acid + NaOH (pH 7.0) by passage of
chlorine gas. Successive aromatic and N-chlorination
verted into sulfoxide, as 1 mol of CC-2 contains two
positive chlorine. At higher concentrations of CC-2,
further R-chlorination of sulfoxide takes place; the prob-
able mechanism9 involves formation of chlorosulfoxonium
ion (F ) by electrophilic attack of chlorine from CC-2. A
subsequent elimination addition sequence of chlorine
from F and G respectively generates R-chlorinated sul-
foxide.
(10) (a) Chattaway, F. D.; Orton, K. J . P. Berichte 1901, 34, 1073.
(b) Pfansteil, R.; Pralatowski, F. M.; Scruton, H. A. US Patent
2,936,322, 1960.
(9) (a) Klein, J . Chem. Lett. 1979 4, 359. (b) Klein, J .; Stollar, H. J .
Am. Chem. Soc. 1973, 95, 7437.

Notes
J . Org. Chem., Vol. 64, No. 21, 1999 8033
Gen er a l Rea ction P r oced u r e of HD (1) a n d CC-2 (2). (i)
In Aqu eou s Med iu m . To a stirred and cooled (-10 °C) solution
of HD (0.06 mol) in CH3CN was added a suspension of CC-2
(0.03-0.095 mol in different reactions) in CH3CN:H2O (50:50).
The reaction was monitored by GC. Immediately after addition
of 2 an aliquot from the reaction mixture showed no HD. After
10-15 min the precipitate of 4 was filtered off and the solvent
was removed via rotary evaporation from the filtrate. The
remaining crude product was purified by column chromatogra-
phy over silica gel with benzene:acetone (95:5% v/v) as eluent.
Compounds 3, 5, and 6 could be well separated using the above
conditions.
Sch em e 3
2-Ch lor oeth yl 1,2-d ich lor oeth yl su lfoxid e (5): flakes from
n-hexane, mp 68 °C. 1H NMR (90 MHz) (CDCl3): δ 4.75 (dd 1H),
4.0 (m 4H), δ, 3.25 (m, 2H). IR (KBr): 2962, 1044, 704 cm-1. MS
(EI): m/z 209 (M + H)+, 211 (209 + 2)+, 213 (209 + 4)+, 192,
(209 - 17)+, 194 (192 + 2)+, 196 (192 + 4)+, 145 (209 - 64)+,
147 (145 + 2)+, 112 (209 - 97)+, 114 (112 + 2)+. Anal. Calcd for
C4H7OCl3S: C, 22.91; H, 3.34; Cl, 50.83; S, 15.27. Found: C,
22.61; H, 3.52; Cl, 50.51; S, 15.11.
yielded the desired product (Scheme 3). Use of Lewis acid
catalysts such as AlCl3 and BF3 offered no additional
advantage.
Con clu sion
This paper describes the reaction profile of bis(2-
chloroethyl) sulfide and N,N′-dichlorobis(2,4,6-trichlo-
rophenyl)urea, with the aim of using it as a potential
decontaminating agent. CC-2-based preparations can be
used as effective decontamination formulations against
HD, even at lower temperature, where other methods
become inoperable, as the reaction of CC-2 and HD is
instant at subzero temperature in both aprotic and protic
(aqueous) medium. Also, the convenient, one-pot, high-
yielding synthesis of CC-2 is reported, which can be
commercially exploited. Moreover, the synthetic utility
of CC-2 as a chlorinating agent parallel to N-chlorosuc-
cinimide can be further explored owing to its greater
stability and high positive chlorine content.
Bis(1,2-d ich lor oeth yl) su lfoxid e (6): needles from n-hex-
1
ane, mp 126 °C. H NMR (90 MHz) (CDCl3): δ 5.12 (t, 2H), 4.1
(m, 4H). IR (KBr) 2962, 1066, 735 cm-1. MS (EI): m/z 243 (M +
H)+, 245 (243 + 2)+, 247 (243 + 4)+, 249 (243 + 6)+, 252 (243 +
8)+, 146 (243 - 97)+, 148 (146 + 2)+, 150 (146 + 4)+, 111 (146 -
35)+, 113 (111 + 2)+, 97, 99 (97 + 2)+, 101 (97 + 4)+, 61 (97 -
35)+, 63 (61 + 2)+. Anal. Calcd for C4H6OCl4S: C, 19.67; H, 2.45;
Cl, 58.19; S, 13.11. Found: C, 19.89; H, 2.62; Cl, 58.28; S, 13.00.
Compounds 3 and 7 were also characterized from their
spectral data.12
(ii) In Ap r otic Med iu m . The reaction of 1 with 2 was instant
in apolar carbon tetrachloride medium also. The procedure is
similar to that already reported for HD and dichloramine-T.5
Analytical data for compound 8 were also reported earlier.5
Syn t h esis of N,N′-Dich lor ob is(2,4,6-t r ich lor op h en yl)-
u r ea (2). Bis(diphenyl)urea (∼25 g, 0.117 mol) was dissolved
in ∼200 mL of acetic acid at 70 °C by stirring. It was chlorinated
by passing chlorine for 4 h with stirring; absorption of chlorine
ceased with complete precipitation of bis(2,4,6-trichloropheny-
l)urea. This indicated the completion of aromatic chlorination.
The mixture was cooled to ∼10 °C in an ice bath, and sodium
hydroxide was added in portions to bring the pH of the mixture
to almost 7. Chlorine was further passed till all the organic
matter was redissolved. The mixture was poured into water to
precipitate CC-2, which was washed with water, filtered, and
recrystallized from toluene or hexane:dichloromethane. After
drying the yield was 51 g (88%) of prismatic crystals, mp 178-
180 °C. The positive chlorine content of 1 was checked by
standard iodometric titration.13 It was found to be 14.51%
(theoretical value 14.54%). 1H NMR (90 MHz) (CDCl3): δ 7.2
(s). IR (KBr): 3066, 1717, 1284, 822 cm-1. MS (EI): m/z 484 (M)+,
486 (M + 2)+, 488 (M + 4)+, 490 (M + 6)+, 492 (M + 8)+, 449 (M
- 35)+, 451 (449 + 2)+, 453 (449 + 4)+, 455 (449 + 6)+, 457 (449
+ 8)+, 414 (M - 70)+, 416 (414 + 2)+, 418 (414 + 4)+, 420 (414
+ 6)+.
Exp er im en ta l Section
The synthesis of bis (2-chloroethyl) sulfide has been described
previously.11 It was prepared inhouse and was greater than 98%
pure by NMR and GC analysis. CAUTION: HD is a ca r cin o-
gen , vesica n t, a n d cytotoxic a gen t. Th is com p ou n d sh ou ld
be h a n d led in a fu m e cu p boa r d by a n exp er in ced p er son ,
w ith p r op er p er son a l p r otective m ea su r es. Diphenyl urea
was obtained from Aldrich Chemical Co. and was used as such
without further purification. Chlorine gas was purified by
passing through a calcium chloride tower.
(11) Reid, E. E., ed. Chemistry of Bivalent Sulfur; Chemical Publish-
ing Co. New York, 1960, Chapter 5.
(12) (a) Hsu, F. L.; Szafraniec, L. L.; Beaudry, W. T.; Yang, Y. C. J .
Org. Chem. 1990, 55, 4153. (b) Yang, Y. C.; Szafraniec, L. L.; Beaudry,
W. T.; Davis, F. A. J . Org. Chem. 1990, 55, 3664.
(13) Kirk, R. E.; Othmer, D. F. Encyclopedia of Chemical Technology
4th ed.; J ohn Wiley & Sons: New York, 1992; Vol. 4, p 274.
J O990783A