A very simple method for the preparation of symmetrical disulfides

Article abstract of DOI:10.1016/j.tetlet.2004.09.100

Addition of sulfuryl chloride to an alkyl- or arylthiol in a 1:2 ratio under solvent free conditions or in CH₂Cl₂ solution produces the corresponding disulfides in nearly quantitative yields. A serendipitiously discovered, extremely simple, fast and previously unreported method for the preparation of symmetrical aliphatic, aromatic and heteroaromatic disulfides is reported. Addition of sulfuryl chloride to an alkyl- or arylthiol in a 1:2 ratio under solvent free conditions or in dichloromethane solution produces the corresponding disulfides in nearly quantitative yields with the concomitant elimination of gaseous SO₂ and 2 equiv of HCl. Thus, optimally the reaction needs no work-up at all leaving the disulfide as the sole product in excellent yield. In dichloromethane solution, the reaction is conveniently carried out in a rotary evaporator by mixing the solvent, thiol and SO₂Cl₂ in a round-bottomed flask followed by evaporation of the volatiles.

Full text of DOI:10.1016/j.tetlet.2004.09.100

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 8489–8491
A very simple method for the preparation of symmetrical disulfides
Reko Leino* and Jan-Erik Lonnqvist
¨
ꢀ
ꢀ
Department of Organic Chemistry, Abo Akademi University, FIN-20500 Abo, Finland
Received 9 August 2004; revised 8 September 2004; accepted 13 September 2004
Available online 30 September 2004
Abstract—A serendipitiously discovered, extremely simple, fast and previously unreported method for the preparation of symmet-
rical aliphatic, aromatic and heteroaromatic disulfides is reported. Addition of sulfuryl chloride to an alkyl- or arylthiol in a 1:2 ratio
under solvent free conditions or in dichloromethane solution produces the corresponding disulfides in nearly quantitative yields with
the concomitant elimination of gaseous SO2 and 2equiv of HCl. Thus, optimally the reaction needs no work-up at all leaving the
disulfide as the sole product in excellent yield. In dichloromethane solution, the reaction is conveniently carried out in a rotary evap-
orator by mixing the solvent, thiol and SO2Cl2 in a round-bottomed flask followed by evaporation of the volatiles.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
CH2Cl2
or neat
2 R-SH + SO2Cl2
R-S-S-R + SO2 (g) + 2 HCl (g)
Disulfides play significant roles in biological and chemi-
cal processes and serve as versatile reagents in organic
synthesis.1 Being readily available from commercial
suppliers and easily synthesized, thiols serve as the
most frequently employed precursors to disulfides.
Consequently, the most exploited and well documented
methods for disulfide preparation involve the controlled
oxidation of thiols under a range of experimental condi-
tions using a broad range of reagents and oxidants.2–25
Nevertheless, most if not all of the previously reported
methods produce the desired disulfide with concomitant
formation of solid waste by-products requiring time and
solvent consuming purification procedures prior to iso-
lation of the pure product. Additional disadvantages in-
clude the use of often expensive, rare or toxic reagents
and metal oxidants, low yields, long reaction times
and high reaction temperatures, or the risk of overoxi-
dation of the product disulfides to sulfoxides. Thus,
there still exists a need for simple, clean and efficient oxi-
dative methods that would produce the target disulfides
in high yields without complicated work-up steps. Here
we report a facile, cheap and extremely simple high
yielding procedure for the preparation of some symmet-
rical disulfides based on the addition of sulfuryl chloride
to the corresponding thiol in dichloromethane or, in the
case of volatile thiols, under solvent free conditions
ice-bath
R = alkyl, aryl, hetaryl
Scheme 1. Synthesis of symmetrical disulfides.
(Scheme 1). The only by-products produced in this reac-
tion are gaseous SO2 and HCl, which are both spontane-
ously eliminated from the reaction mixture leaving the
disulfide as the sole product, in most cases in nearly
quantitative yield. To our knowledge, this method has
not been described previously in the literature and
provides a high yield access to a range of symmetrical
aliphatic, aromatic and heteroaromatic disulfides
(Table 1).
Table 1. Synthesis of symmetrical disulfides
Substrate
Methoda Product
Yield
(%)
n-C7H15SH
n-C12H25SH
2
2
2
2
2
2
3
1
1
C7H15SSC7H15
C12H25SSC12H25
96
98
95
98
98
98
99
96
Cyclohexylthiol
Benzylthiol
Dicyclohexyl disulfide
Dibenzyl disulfide
Fluorene-9-thiol
Benzenethiol
Benzenethiol
2-Pyridinethiol
2-Pyrimidinethiol
Difluoren-9-yl disulfide
Diphenyl disulfide
Diphenyl disulfide
2,20-Dipyridyl disulfide
2,20-Dipyrimidyl disulfide 69
Keywords: Thiols; Disulfides; Oxidation.
*
Corresponding author. Tel.: +358 2 2154132; fax: +358 2 2154866;
e-mail: reko.leino@abo.fi
a Method 1: CH2Cl2 solution. Method 2: Neat. Method 3: Reaction in
CH2Cl2 solution on a rotary evaporator.
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.09.100

8490
R. Leino, J.-E. Lo¨nnqvist / Tetrahedron Letters 45 (2004) 8489–8491
Thus, in summary, we have developed a new useful, effi-
cient and economically attractive method providing sim-
ple access to several useful symmetrical disulfides in
excellent yields. Unless otherwise specified, all solvents
and reagents were purchased from commercial suppliers
and used without further purification. Fluorene-9-thiol
was prepared from 9-bromofluorene according to a liter-
ature procedure.26
2852, 1447, 1260, 996cmꢁ1 1H NMR (400MHz,
.
CDCl3): d 1.14–1.34 (m, 10H), 1.55–1.63 (m, 2H),
1.72–1.80 (m, 4H), 1.97–2.03 (m, 4H), 2.61–2.69 (m,
2H). 13C NMR (400MHz, CDCl3): d 25.66, 26.05,
32.81, 49.91. EIMS m/z (RA): 230 (M+, 15), 148 (38),
84 (8), 83 (100), 82 (4), 81 (6), 55 (56), 53 (4). HRMS
calcd 230.1163 for C12H22S2. Found 230.1165.
2.4. Synthesis of dibenzyl disulfide
2. General procedures for the preparation
of symmetrical disulfides
From benzylthiol (1.24g, 10mmol) using method 2,
dibenzyl disulfide (1.20g, 98%) was obtained as white
crystals. IR (KBr disk): 3053, 3031, 1494, 1453, 758,
1
Method 1: To a solution of the thiol (2equiv) in 20mL
of CH2Cl2 was added dropwise a solution of SO2Cl2
(1.1equiv) in 20–30mL of CH2Cl2. The reaction mixture
was stirred for 30min and evaporated to dryness to
leave the desired disulfide.
696cmꢁ1. H NMR (400MHz, DMSO-d6): d 3.72 (s,
4H), 7.25–7.29 (m, 4H), 7.31–7.37 (m, 6H). 13C NMR
(400MHz, DMSO-d6): d 41.60, 127.28, 128.37, 129.35,
137.28. EIMS m/z (RA): 246 (M+, 44), 182 (4), 181
(24), 153 (2), 123 (7), 121 (8), 92 (43), 91 (100). HRMS
calcd 246.0537 for C14H14S2. Found 246.0535. Mp 66–
68°C.
Method 2: To the thiol (2equiv) was added SO2Cl2
(1.1equiv) during a period of 5–10min. The reaction
mixture was stirred for 30min and the excess reagents
evaporated using a rotary evaporator to leave the
desired disulfide.
2.5. Synthesis of difluoren-9-yl disulfide
From fluorene-9-thiol (1.98g, 10mmol) using method 2
in an ice bath, difluoren-9-yl disulfide (1.94g, 98%) was
obtained as white crystals. IR (KBr disk): 3037, 1443,
Method 3: A solution of the thiol (2equiv) dissolved in
20–30mL of CH2Cl2 was combined with a solution of
SO2Cl2 in 20mL of CH2Cl2 in a round-bottomed flask.
The flask was placed on a rotary evaporator and con-
centrated to dryness to leave the desired disulfide.
735, 426cmꢁ1 1H NMR (400MHz,): d 4.68 (s, 2H),
.
7.19 (t, 4H, J = 7.5Hz), 7.29 (t, 4H, J = 7.5Hz), 7.55
(d, 4H, J = 7.5Hz), 7.64 (d, 4H, J = 7.5Hz). 13C NMR
(400MHz, CDCl3): d 53.54, 119.85, 125.38, 127.47,
128.41, 140.89, 144.06. EIMS m/z (RA): 394 (M+, 2),
198 (6), 197 (10), 196 (30), 166 (20), 165 (100), 164 (9),
152 (10). HRMS calcd 394.0850 for C26H18S2. Found
394.0853. Mp 156–158°C.
2.1. Synthesis of diheptyl disulfide
From n-heptanethiol (6.60g, 50mmol) using method 2
in an ice bath, diheptyl disulfide (6.32g, 96%) was
obtained as a pale yellow liquid. IR (KBr disk): 2956,
2.6. Synthesis of diphenyl disulfide
1
2855, 1465, 723cmꢁ1. H NMR (400MHz, CDCl3): d
0.86 (t, J = 7.1Hz, 6H), 1.20–1.39 (m, 16H), 1.65 (quin,
4H, J = 7.4Hz), 2.65 (t, 4H, J = 7.4Hz). 13C NMR
(400MHz, CDCl3): d 14.04, 22.58, 28.47, 28.88, 29.21,
31.70, 39.18. EIMS m/z (RA): 262 (M+, 14), 164 (14),
131 (12), 101 (3), 87 (5), 58 (5), 57 (100), 55 (23). HRMS
calcd 262.1789 for C14H30S2. Found 262.1785.
From benzenethiol (11g, 100mmol) using method 2,
diphenyl disulfide (10.70g, 98%) was obtained as white
crystals. Alternatively, on 10mmol scale using method
3, diphenyl disulfide (1.08g, 99%) was likewise obtained
as white crystals. IR (KBr disk): 3069, 1578, 1474, 740,
1
686cmꢁ1. H NMR (400MHz, DMSO-d6): d 7.26–7.30
(m, 2H), 7.35–7.40 (m, 4H), 7.50–7.53 (m, 4H). 13C
NMR (400MHz, DMSO-d6): d 127.17, 127.57, 129.46,
135.75. EIMS m/z (RA): 218 (M+, 96), 185 (18), 154
(24), 109 (100), 77 (11), 69 (14), 65 (40), 51 (12). HRMS
calcd 218.0224 for C12H10S2. Found 218.0225. Mp 59–
61°C.
2.2. Synthesis of didodecyl disulfide
From n-dodecanethiol (10.10g, 50mmol) using method
2 in an ice bath, didodecyl disulfide (9.89g, 98%) was
obtained as white crystals. IR (KBr disk): 2923, 2851,
1470, 718cmꢁ1 1H NMR (400MHz, CDCl3): d 0.86
.
(t, J = 7.0Hz, 6H), 1.24–1.37 (m, 36H), 1.65 (quin,
J = 7.3Hz, 4H), 2.66 (t, J = 7.3Hz, 4H). 13C NMR
(400MHz, CDCl3): d 14.11, 22.67, 28.53, 29.22, 29.23,
29.34, 29.51, 29.59, 29.63, 29.64, 31.90, 39.21. EIMS
m/z (RA): 402 (M+, 58), 201 (21), 87 (22), 85 (31), 71
(55), 69 (29), 57 (100), 55 (48). HRMS calcd 402.3354
for C24H50S2. Found 402.3355. Mp 29–31°C.
2.7. Synthesis of 2,20-dipyridyl disulfide
From 2-pyridinethiol (0.56g, 5mmol) using method 1 in
an ice bath, 2,20-dipyridyl disulfide (0.53g, 96%) was
obtained as a yellow powder. IR (KBr disk): 3414,
1
3051, 3018, 2421, 1605, 1444, 770, 616cmꢁ1. H NMR
(400MHz, DMSO-d6):
d
7.35 (ddd, J = 7.5Hz,
J = 4.8Hz, J = 0.9Hz, 2H), 7.69 (dt, J = 8.1Hz,
J = 0.9Hz, 2H), 7.88 (ddd, J = 8.1Hz, J = 7.5Hz, J =
1.8Hz, 2H), 8.55 (ddd, J = 4.8Hz, J = 1.8Hz,
J = 0.9Hz, 2H). 13C NMR (400MHz, DMSO-d6): d
119.64, 121.87, 138.25, 149.67, 157.27. EIMS m/z
(RA): 220 (M+, 100), 187 (16), 156 (56), 155 (26), 129
2.3. Synthesis of dicyclohexyl disulfide
From cyclohexylthiol (5.80g, 50mmol) using method 2
in an ice bath, dicyclohexyl disulfide (5.46g, 95%) was
obtained as a transparent liquid. IR (KBr disk): 2928,

R. Leino, J.-E. Lo¨nnqvist / Tetrahedron Letters 45 (2004) 8489–8491
8491
7. DMSO with dichlorodioxomolybdenum: Sanz, R.;
(8), 83 (8), 78 (42), 51 (15). HRMS calcd 220.0129 for
C10H8N2S2. Found 220.0133. Mp 127–129°C.
´
Aguado, R.; Pedrosa, M. R.; Arnaiz, F. J. Synthesis
2002, 856–858.
8. DMSO with trimethylchlorosilane and cyanuric chloride:
Karimi, B.; Hazarkhani, H.; Zareyee, D. Synthesis 2002,
2513–2516.
2.8. Synthesis of 2,20-pyrimidyl disulfide
ˇ
9. Diazenecarboxamides: Kosmrlj, J.; Kocevar, M.; Polanc,
From 2-pyrimidinethiol (1.12g, 10mmol) using method
1 in an ice bath, di-2-pyrimidyl disulfide (0.77g, 69%
yield) was obtained as a yellow powder after filtration.
S. J. Chem. Soc., Perkin Trans. 1 1998, 3917–3919.
10. Permanganate on silica gel: Noureldin, N. A.; Caldwell,
M.; Hendry, J.; Lee, D. G. Synthesis 1998, 1587–1589.
11. Manganese dioxide: (a) Hirano, M.; Yakabe, S.; Chika-
mori, H.; Clark, J. H.; Morimoto, T. J. Chem. Res. (S)
1998, 310–311; (b) Firouzabadi, H.; Abbassi, M.; Karimi,
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12. Sodium iodate: Hirano, M.; Yakabe, S.; Ando, K.-i.;
Morimoto, T. J. Chem. Res. (S) 1998, 816–817.
13. Hydrotalcite: Hirano, M.; Monobe, H.; Yakabe, S.;
Morimoto, T. J. Chem. Res. (S) 1999, 374–375.
IR (KBr disk): 3071, 3035, 1597, 1432, 744, 627cmꢁ1
.
1H NMR (400MHz, DMSO-d6): d 7.35 (dt, J = 4.8Hz,
J = 0.5Hz, 2H), 8.69 (dd, J = 4.8Hz, J = 0.5Hz, 4H).
13C NMR (400MHz, DMSO-d6): d 119.16, 158.58,
167.84. EIMS m/z (RA): 222 (M+, 98), 158 (100), 112
(15), 80 (28), 79 (39), 57 (17), 53 (27), 52 (19). HRMS
calcd 222.0034 for C8H6N4S2. Found 222.0026. Mp
139–141°C.
14. Phase transfer catalysis: Abele, E.; Abele, R.; Lukevics, E.
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15. CaroÕs acid on silica gel: Movassagh, B.; Lakouraj, M. M.;
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16. Trichloronitromethane: Demir, A. S.; Igdir, A. C.; Maha-
sneh, A. S. Tetrahedron 1999, 55, 12399–12404.
Acknowledgements
The authors wish to thank Pa¨ivi Pennanen (NMR) and
Markku Reunanen (EIMS) for their assistance in char-
acterization of the products.
17. Hydrogen peroxide in hexafluoroisopropanol: Kesavan,
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V.; Bonnet-Delpon, D.; Begue, J.-P. Synthesis 2000, 223–
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18. Benzyltriphenylphosphonium peroxymonosulfate: Haji-
pour, A. R.; Mallakpour, S. E.; Adibi, H. J. Org. Chem.
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