Optimization of the synthesis of symmetric aromatic tri- and tetrasulfides

Article abstract of DOI:10.1021/jo0265481

The reaction of aromatic thiols with sulfur dichloride and sulfur monochloride to form the corresponding aromatic trisulfides, 2a-d, and tetrasulfides, 3a-d, has been optimized with respect to yield and purity. The use of pyridine as an amine base and the

Full text of DOI:10.1021/jo0265481

SCHEME 1
Op tim iza tion of th e Syn th esis of
Sym m etr ic Ar om a tic Tr i- a n d Tetr a su lfid es
Eli Zysman-Colman and David N. Harpp*
Deparment of Chemistry, McGill University, Montreal,
Quebec, Canada H3A 2K6
david.harpp@mcgill.ca
Received October 10, 2002
methods require the presynthesis of appropriate precur-
sors, which complicates the procedure.
The synthesis of unsymmetric trisulfides is more
difficult. Among the known procedures are the coupling
of chlorodisulfides with thiols17,18 or similarly with N-
arylamidthiosulfites.19 Other methods require the use of
unwieldly and often unstable hydrodisulfides (RSSH)20
or the desulfurization of highly functionalized dialkane-
sulfonic thioanhydrides (RSO2SSO2R′).9 Stable alkyl or
aryl phthalimido disulfides as sulfur transfer reagents,
developed in our lab,21 have been used as a key step in
the preparation of calicheamicin γ1I.22 Another procedure
involves the sequential coupling of two thiols using sulfur
dichloride.23 To our knowledge, no high-yield, general
method exists for the formation of unsymmetric tetra-
sulfides, although two such tetrasulfides were formed23
using sulfur monochloride as the coupling reagent.
As part of another research effort dedicated to the rapid
sulfurizing of oligonucleotides with these substrates, we
required pure samples of a variety of symmetric polysul-
fides.
Abstr a ct: The reaction of aromatic thiols with sulfur
dichloride and sulfur monochloride to form the corresponding
aromatic trisulfides, 2a -d , and tetrasulfides, 3a -d , has
been optimized with respect to yield and purity. The use of
pyridine as an amine base and the use of freshly distilled
sulfur monochloride (S2Cl2) serve as important alterations
to the synthetic method. Their physical properties have been
characterized, revealing some discrepancies with the litera-
ture.
The preparation of symmetric, acyclic trisulfides is
well-documented.1 The methods include the use of sulfur
dichloride2,3 with thiols in the absence of base, the
coupling of alkyl halides with sodium trisulfide,4 mixtures
of thiols5,6 or disulfides with sulfur,7 the reaction of a
metal sulfide with alkanesulfenyl chlorides,8 the reduc-
tion of thiosulfonates and disulfonyl sulfides with phos-
phines,9 and sulfur insertion reactions into thiosulfinates,
thiosulfonates,10 sulfides, and disulfides.11,12
We report a modification of two literature proce-
dures2,23 (Scheme 1) to form aromatic trisulfides 2a -d ,
wherein yields and purity are significantly improved. We
also report for the first time the synthesis of a corre-
sponding set of aromatic tetrasulfides 3a -d . All com-
Preparation of the analogous tetrasulfides is not as well
researched. To our knowledge, there exists no compre-
hensive study of the formation of this class. Oxidation of
hydrodisulfides in the presence of iodine,13 coupling of
thiols with dialkoxy disulfides (ROSSOR),14,15 sulfur
insertion reactions,12 and electrophilic aromatic substitu-
tion with sulfur monochloride16 have all been reported
as preparative methods.
1
pounds were characterized by H NMR, 13C NMR, MS,
and HRMS or elemental analysis; crystal structures of
2b and 3b were also obtained.
To a solution of easily accessible aromatic thiols 1a -d
and equimolar pyridine in anhydrous diethyl ether was
added a freshly distilled solution of sulfur dichloride for
2a -d or sulfur monochloride for 3a -d at -78 °C, Scheme
1. After workup, the sample was usually analytically pure
but could be recrystallized in the freezer with n-pentane.
The procedure was readily scaled up to 10 g.
The use of freshly distilled sulfur monochloride, ether
as the solvent, with pyridine as a hydrochloride sink and
possible activator were all necessary components of the
reaction to ensure the purity of the product and its high
These methods suffer from either low yields or the
formation of undesirable polysulfide byproducts. Some
(1) Steudel, R.; Kustos, M. In Encyclopedia of Inorganic Chemistry;
King, R. B., Ed.; J ohn Wiley & Sons: Athens, GA, 1994; Vol. 7, pp
4009-4038.
(2) Schoberl, A.; Wagner, A. Methoden der Organishen Chemie, 4th
ed.; Houben-Weyl: Stuttgart, 1955; Vol. 9.
(3) Clayton, J . O.; Etzler, D. H. J . Chem. Soc. 1974, 69, 974.
(4) Reid, E. E. Organic Chemistry of Bivalent Sulfur; Chemical
Publishing Company: New York, 1960; Vol. 3.
(5) Vineyard, B. D. J . Org. Chem. 1966, 31, 601.
(6) Otten, S.; Frohlich, R.; Haufe, G. Heterocycles 1999, 51, 505-
512.
(7) Westlake J r., H. E.; Laquer, H. L.; Smyth, C. P. J . Am. Chem.
Soc. 1949, 72, 436-438.
(8) Buckman, J . D.; Field, L. J . Org. Chem. 1967, 32, 2.
(9) Hayashi, S.; Furukawa, M.; Yamamoto, J .; Hamamura, K. Chem.
Pharm. Bull. 1967, 15, 1310-1314.
(17) Bo¨hme, H.; Van Ham, G. J ustus Liebigs Ann. Chem. 1958, 617,
62.
(18) Von Szczepanaski, C.; Heindl, J .; Schroeder, E.; Kessler, H. J .;
Redmann, U. German Patent, 1972.
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Menichetti, S. Tetrahedron Lett. 1989, 30, 2991-2994.
(11) Harpp, D. N.; Hou, Y.; Abu-Yousef, I. A. Tetrahedron Lett. 2000,
41, 7809.
(19) Nakabayashi, T.; Tsurugi, J . J . Org. Chem. 1961, 26, 2482.
(20) Kresze, G.; Patzscheke, J . Chem. Ber. 1960, 93, 380.
(21) Harpp, D. N.; Ash, D. K. Int. J . Sulfur Chem. A 1971, 1, 211-
214.
(22) Nicolaou, K. C.; Hummel, C. W.; Nakada, M.; Shibayama, K.;
Pitsinos, E. N.; Saimoto, H.; Mizuno, Y.; Baldenius, K.-U.; Smith, A.
L. J . Am. Chem. Soc. 1993, 115, 7625.
(23) Harpp, D. N.; Derbesy, G. Tetrahedron Lett. 1994, 35, 5381-
5384. The method in this article can be used to prepare the aliphatic
analogues; however, the yields are not generally as high as in this
modification.
(12) Harpp, D. N.; Rys, A. Z. Tetrahedron Lett. 2000, 41, 7169-7172.
(13) Kawamura, S.; Nakabayashi, T.; Horii, T.; Hamada, M. Ann.
Rep. Radiat. Cent. Osaka Prefect. 1977, 18, 81-82.
(14) Steudel, R.; Schmidt, H. Chem. Ber. 1994, 127, 1219-1221.
(15) Steudel, R.; Kruger, P.; Florian, I.; Kustos, M. Z. Anorg. Allg.
Chem. 1995, 621, 1021-1024.
(16) Ricci, J . S.; Bernal, I. J . Chem. Soc. B 1979, 1928-1932.
10.1021/jo0265481 CCC: $25.00 © 2003 American Chemical Society
Published on Web 02/14/2003
J . Org. Chem. 2003, 68, 2487-2489
2487

TABLE 1. Da ta for Tr i- a n d Tetr a su lfid es
The nitro analogues 2d and 3d also precipitated from
solution. In all cases, no higher order polysulfides were
observed upon completion of the reaction. This proved
to be important and beneficial, as separation of polysul-
fides by chromatography is often problematic as a result
of their very similar properties.
Compound 2a had previously been reported to be an
oil;10,25,32 however, after being placed in the freezer in
n-pentane for 24 h, pure crystals were determined.
Crystal structures of 2b and 3b were determined. The
geometry of these aromatic polysulfides is unexcep-
tional15,33,34 compared to that previously reported for
others of this class, with an average S-S bond length of
2.045 Å.
yieldb
entry thiol SnCl2 product (%)
mp
(°C)
lit. mp
(°C)
a
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1
2
1
2
1
2
1
2
2a
3a
2b
3b
2c
3c
2d
3d
61
71
97
99
97
97
51-52
30-31
78-79
62-64
61-64
53-57
ca. 526
34-3527
82-8424
oil28,d, 71-7229
68-7125, 70-7130
90 131-136c 114-11630
99 154-158
a
n ) 1 for sulfur dichloride, n ) 2 for sulfur monochloride.
Yields reported after one recrystallization. c Sample turned dark
yellow at 122-124 °C. The combustion analysis in the reference
is not accurate and the claim of synthesis should be questioned.
b
d
All compounds in Table 1 were bench-stable for months;
however, on exposure to light they would decompose in
a matter of hours, forming different-order polysulfides
of n ) 2-6. No special precautions need be made with
respect to air exposure if the compounds are weighed and
used directly. Thermally, tetrasulfides were less stable
than their trisulfide counterparts. The nitro group sig-
nificantly increased the thermal stability of the com-
pounds.
TABLE 2. Tem p er a tu r e Stu d y of Th iol Cou p lin g w ith
Su lfu r Mon och lor id e
entry
product
temp (°C)
yieldb (%)
mp (°C)
1
2
3
3b
3b
3b
-78
0
99
91
86
62-64
60-61
63-64
rta
a
b
rt ) 25 ( 1 °C. Yields reported after one recrystallization.
This optimized method provides a convenient prepara-
tion of acyclic aromatic tri- and tetrasulfides in high yield
and purity from readily accessible materials under very
mild conditions.
SCHEME 2
Exp er im en ta l Section
Gen er a l Exp er im en ta l. All reagents were commercially
available and were used without further purification save for
the following exceptions. Methylene chloride was distilled over
calcium hydride. Diethyl ether was dried over molecular sieves.
Sulfur monochloride, S2Cl2 (135-137 °C), was distilled according
to procedures adapted from Fieser and Fieser (100:4:1 S2Cl2/
sulfur/charcoal).35 Sulfur dichloride, SCl2 (59-60 °C), was
fractionally distilled over 0.1% phosphorus pentachloride, PCl5.
Both S2Cl2 and SCl2 were used immediately after distillation.
All glassware was oven-dried. All melting points are uncorrected.
NMR spectra were recorded in CDCl3 at 300, 400, or 500 MHz
for 1H and 75, 101, or 125 MHz for 13C.
Syn th esis of p-Ar yl Tr isu lfid es. An example of the syn-
thetic procedure is as follows. A solution of thiol (20 mmol, 1
equiv) and pyridine (20 mmol, 1 equiv) in 50 mL of diethyl ether
was allowed to stir under nitrogen at -78 °C. A solution of sulfur
dichloride (10.0 mmol, 0.5 equiv) in 50 mL of ether was added
dropwise over 0.5 h. The reaction mixture was allowed to stir
for a further 1.5 h. The reaction mixture was quenched with 25
mL of H2O. The organic phase was washed 3 × 25 mL of H2O or
until the aqueous phase became clear. The organic phase was
dried over MgSO4. This mixture was vacuum filtered, and the
solvent was removed first under reduced pressure and then in
vacuo.
yield (Table 1). Maintaining the temperature at -78 °C
may also serve to increase purity as compared with
previous syntheses.24,25 We investigated this criterion by
repeating the reaction for the production of 3b at 0 °C
and at room temperature, Table 2. The yields remained
high but decreased with increasing temperature, as did
the purity of the sample. It therefore seems that the
coupling rate of the second equivalent of thiol to the
intermediate (Scheme 2) is faster than its decomposition.
The addition of pyridine as the amine base distin-
guishes this method from previous uses of sulfur dichlo-
ride or sulfur monochloride as coupling agents. While this
is a simple alteration in the normal procedure, the greatly
enhanced yields and purity clearly show the advantage.
It is likely that the increased yield and higher purity is
because the pyridinium salt is insoluble in the ether
solvent. Upon addition of the yellow chlorosulfane to the
thiol/pyridine solution, an immediate conversion to a
white precipitate was observed. The precipitation of this
pyridinium salt byproduct apparently drives the reaction
to completion. It may also be that the activated inter-
mediate is that of a sulfenyl pyridinium complex or a
thiosulfenyl pyridinium complex (Scheme 2). Activated
complexes of sulfur monochloride are not without prece-
dent.31
(27) Lechler, H.; Holzschneider, F. Chem. Ber. 1925, 58, 417.
(28) Saville, R. W. J . Chem. Soc. 1958, 2880-2888.
(29) Kawamura, S.; Horii, T.; Tsurugi, J . J . Org. Chem. 1971, 36,
3677-3680.
(30) Feher, F.; Kurz, D. Z. Naturforsch., B: Chem. Sci. 1968, 23,
1030-1033.
(31) Rees, C. W.; Rakitin, O. A.; Marcos, C. F.; Torroba, T. J . Org.
Chem. 1999, 64, 4376-4380.
(32) Harpp, D. N.; Granata, A. Tetrahedron Lett. 1976, 35, 3001.
(33) Cox, P. J .; Wardell, J . L. Acta Crystallogr. 1997, C53, 122-
124.
(24) Harpp, D. N.; Smith, R. A. J . Org. Chem. 1979, 44, 4140-4144.
(25) Harpp, D. N.; Ash, D. K.; Smith, R. A. J . Org. Chem. 1980, 45,
(34) Howie, R. A.; Wardell, J . L. Acta Crystallogr. 1996, C52, 1533-
1534.
(35) Fieser, L. F.; Fieser, M. Reagents for Organic Synthesis; J ohn
Wiley and Sons: New York, 1967; Vol. 1.
5155-5160.
(26) Beilsteins Handbuchen Der Organischen Chemie, 1965; Vol. 6,
E111.
2488 J . Org. Chem., Vol. 68, No. 6, 2003

Dip h en yl Tr isu lfid e (2a ). Yield 61%; recrystallization from
n-pentane at -15 °C afforded light white needles; mp 51-52 °C
Dip h en yl Tetr a su lfid e (3a ). Yield 71%; recrystallization
from n-pentane at -15 °C afforded light yellow needles; mp 30-
31 °C (lit. mp27 34-35 °C).
1
(lit. mp26 ∼5 °C); H NMR δ 7.14-7.34 (m, 6H), 7.47-7.59 (m,
4H); 13C NMR δ 127.14, 127.47, 129.05, 137.00; MS (EI) m/z (rel
intensity) 250 (4.3), 218 (100.0) -S, 185 (16.2) -S2, 154 (15.4),
141 (9.7) -SC6H5, 109 (76.5) -S2C6H5. HRMS for C12H10S3:
249.9945. Found: 249.993(6)
Bis(p-tolyl) Tetr a su lfid e (3b). Yellow powder. Yield 99%;
recrystallization from n-pentane at -15 °C afforded bright yellow
needles; mp 62-64 °C (lit. mp oil,28 71-72 °C29).
Bis(p-br om op h en yl) Tetr a su lfid e (3c). Light yellow, flaky
solid. Yield 97%; mp 53-57 °C; 1H NMR δ 7.38 (AB, 4H J )
8.40 Hz); 13C NMR δ 131.7, 132.3, 132.4, 132.4; MS (EI) m/z (rel
intensity) 440 (1.6), 408 (6.7) -S, 376 (100) -S2, 189 (74.5)
-S2C6H4Br, 108 (76.2) -S2C6H4Br. Anal. Calcd for C12H8S4Br2:
C, 32.74; H, 1.83. Found: C, 32.77; H, 1.43.
Bis(p-tolyl) Tr isu lfid e (2b). Yield 97%; recrystallization
from n-pentane at -15 °C afforded light yellow needles; mp 78-
79 °C (lit. mp24 82-84 °C).
Bis(p -b r om op h en yl) Tr isu lfid e (2c). The product was a
light, flaky solid. Yield 97%; mp 61-64 °C (lit. mp30 70-71 °C).
Bis(p-n itr op h en yl) Tr isu lfid e (2d ). The above procedure
was scaled up by a factor of 2. Upon quenching with 100 mL of
H2O, a grayish precipitate formed. This precipitate was vacuum
filtered and further washed with 2 × 100 mL of H2O. The filtrate
was further purified as above, and the solute was dried. The
products were combined to yield a tan-colored solid. Yield 90%;
mp 122-124 °C turning dark yellow then melting at 131-136
°C (lit. mp30 114-116 °C).
Syn th esis of p-Ar yl Tetr a su lfid es. The following is a
general example of the synthetic procedure. A solution of thiol
(40 mmol, 2 equiv) and pyridine (40 mmol, 2 equiv) in 100 mL
of diethyl ether was allowed to stir under nitrogen at -78 °C. A
solution of sulfur monochloride (20.0 mmol, 1 equiv) in 100 mL
of ether was added dropwise over 0.5 h. The reaction mixture
was allowed to stir for a further 1.5 h. The reaction mixture was
quenched with 100 mL of H2O. The organic phase was washed
3 × 50 mL of H2O or until the aqueous phase became clear; the
organic phase was dried over MgSO4. This mixture was vacuum
filtered, and the solvent was removed first under reduced
pressure and then in vacuo.
Bis(p-n itr op h en yl) Tetr a su lfid e (3d ). Upon quenching
with 100 mL of H2O, a grayish precipitate formed. This
precipitate was vacuum filtered and further washed with 2 ×
100 mL of H2O. The filtrate was further purified as above, and
the solute was dried. The products were combined to yield a
sandy colored solid. Yield 99%; mp 154-158 °C; 1H NMR δ 7.88
(AB, 4H J ) 9.20 Hz); 13C NMR δ 124.4, 126.3, 144.0, 146.9;
MS (CI) m/z (rel intensity) 308 (100) -S. Anal. Calcd for
C12H8N2O4S4 + NH4: 389.9711. Found: 389.971(6).
Ack n ow led gm en t. We thank the Natural Sciences
and Engineering Research Council (NSERC) for sup-
port. E.Z.-C. thanks FCAR for a personal scholarship.
We thank Dr. Anne-Marie Lebuis for resolving the
structures of 2b and 3b.
J O0265481
J . Org. Chem, Vol. 68, No. 6, 2003 2489