A versatile one-pot synthesis of dialkyl disulfides and sulfides

Article abstract of DOI:10.1081/SCC-200050331

Conversions of monofluoroalkyl and alkyl bromides to the corresponding dialkyl disulfides in a one-pot synthesis using thiourea followed by basic hydrogen peroxide are described. Modified methods afford access to unsymmetrical disulfides and sulfides.

Full text of DOI:10.1081/SCC-200050331

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A Versatile One‐Pot Synthesis of Dialkyl
Disulfides and Sulfides
David W. Emerson a , Byron L. Bennett a & Spencer M. Steinberg a
a Department of Chemistry , The University of Nevada , Las Vegas, NV, USA
Published online: 20 Aug 2006.
To cite this article: David W. Emerson , Byron L. Bennett & Spencer M. Steinberg (2005) A Versatile One‐Pot
Synthesis of Dialkyl Disulfides and Sulfides, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 35:5, 631-638, DOI: 10.1081/SCC-200050331
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Synthetic Communicationsw, 35: 631–638, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1081/SCC-200050331
A Versatile One-Pot Synthesis of Dialkyl
Disulfides and Sulfides
David W. Emerson, Byron L. Bennett, and Spencer M. Steinberg
Department of Chemistry, The University of Nevada,
Las Vegas, NV, USA
Abstract: Conversions of monofluoroalkyl and alkyl bromides to the corresponding
dialkyl disulfides in a one-pot synthesis using thiourea followed by basic hydrogen
peroxide are described. Modified methods afford access to unsymmetrical disulfides
and sulfides.
Keywords: Disulfides, fluorine and fluorine compounds, sulfides
INTRODUCTION
The study of self-assembled monolayers (SAMs) from organosulfur
compounds is currently an active area of research. Dialkyl disulfides can be
used to produce monomolecular layers on certain metal surfaces, e.g., Au
and Ag,[1–4] underscoring the importance of synthesizing disulfides useful
for forming SAMs. Interest continues in this field and extensive reviews
have appeared.[5,6] Insights have been gained about mechanisms by which
disulfides evolve into monomolecular layers on Au and/or Ag surfaces.[7–9]
Thiols, disulfides, and sulfides too are of interest.[10,11] This continuing
activity suggests that simple synthetic methods for making disulfides and
sulfides will be useful. Heretofore disulfides containing fluorine have incor-
porated perfluorinated sections of the carbon chain, but terminal monofluo-
rinated chain-ends may prove interesting.
Received in the USA 12 November 2004
Address correspondence to David W. Emerson, Department of Chemistry,
The University of Nevada, Box 454003, Las Vegas, NV 89154-4003, USA. E-mail:
emerson@unlv.nevada.edu

632
D. W. Emerson, B. L. Bennett, and S. M. Steinberg
Attempts to synthesize 4-fluoro-1-butanethiol, 1) from 1-bromo-4-fluoro-
butane, 2) by forming the intermediate isothiuronium salt (ITUS) followed by
an alkaline workup1,[12] resulted mainly in tetrahydrothiophene,[13] possibly
by an intramolecular displacement reaction despite fluoride being a poor
leaving group.
Work by others showed varying degrees of complexity in the reagents
employed and the steps needed to get the final product. Basic hydrogen
peroxide oxidized an arenethiol to disulfide, sulfinate, and sulfonate but the
disulfide was not the precursor of the other two products.[14] Fluorine-contain-
ing alkanethiols were produced by action of base on ITUs and were oxidized
by atmospheric oxygen.[15,16] Aqueous in situ-generated alkali metaldisulfides
and alkyl halides produced symmetrical disulfides.[17–19] Piperidinium tetra-
thiotungstate or tetrathiomolybdate[20] and benzyltriethylammonium tetraco-
sathioheptamolybdate[21] produce disulfides. An aralkanethiol of some
complexity made from an ITUS was oxidized to the disulfide by iodine.[4]
Conversion of alkyl thiocyanates to disulfides by aqueous ammonia was
reported.[22]
RESULTS AND DISCUSSION
Our strategy was to prepare the ITUSs from alkyl halides by inverse addition
of the soft, nonbasic nucleophile, thiourea. We added a mixture of sodium
hydroxide and hydrogen peroxide to the reaction mixture expecting that
the liberated thiol would be oxidized promptly to the disulfide[23] and that
fewer unwanted side reactions would result. Extraction and cleanup of
the product followed. Three methods are described in the Experi-
mental section. Starting with 4-fluoro-1-bromobutane (2) we synthesized
the hitherto unknown 4-fluoro-1-butyl disulfide (3) that is presumably a
more stable compound than the thiol (1). We also report synthesis of the
unknown 3-fluoro-1-propyl disulfide (5) from 1-bromo-3-fluoropropane (4).
We prepared solutions of the ITUSs from (2) and (4) by inverse addition of
thiourea followed by addition of sodium hydroxide and hydrogen peroxide
to liberate the thiols and oxidize them rapidly. Solvent extraction and evapor-
ation followed by distillation afforded the desired products in acceptable yield
and high purity. No effort was made to optimize yields. The identities of
(3) and (5) were confirmed by nuclear magnetic resonance (NMR), Fourier
transform infrared (FTIR), and mass[24] spectroscopy and elemental
analysis. We also made simple symmetrical and unsymmetrical dialkyl disul-
fides and a sulfide in acceptable yields, Table 1 & Scheme 1, and found that
1This paper was apparently not abstracted by Chemical Abstracts. It is a convin-
cingly documented example of the synthesis of a volatile alkanethiol via the ITUS
route.

Synthesis of Dialkyl Disulfides and Sulfides
633
Scheme 1.
components of the extract of a reaction mixture containing dialkyl disulfides,
separated on a thin layer chromatography (TLC) plate, can be identified by
flash heating gas chromatography-mass spectrometry (GC-MS) of coating
scraped from the plate and heated by a Pt filament pyrolyzer. Compound 3
in addition to the parent compound, produced tetrahydrothiophene as the
major conmponent and 5 yielded mostly the parent compound and small
amounts of diallyldisulfide and 1,2-dithiolane.
A mixture of unsymmetrical disulfides can be made by making different
ITUSs in the same vessel, followed by oxidation with basic hydrogen
peroxide. With equimolar amounts of two different ITUSs there is approxi-
mately twice as much unsymmetrical disulfide compared to the two sym-
metrical products. Symmetrical sulfides may be prepared by adding the
same alkyl halide to the solution in which the ITUS was prepared, and then
adding base without an oxidant. An unsymmetrical sulfide was made by
adding an alkyl halide different from the one used to make the ITUS and
then adding base.
Table 1. Isolated yields and parent ions[24]
Compound, No.
Method
Yielda %
Notes, Refs.
M/z ¼ 214
[F-(CH2)4-S]2, 3
A
C
A
B
B
B
B
B
40
52b
58
[F-(CH2)3-S]2 5
[H-(CH2)4-S]2 6
[H-(CH2)5-S]2 7
M/z ¼ 186
69.9
69
M/z ¼ 178
M/z ¼ 206
[H-(CH2)5-S-S-(CH2)4-H] 8
6, 7, 8
[H-(CH2)5-S-(CH2)4-H] 9
M/z ¼ 192[24,28]
M/z ¼ 178, 192, 206
m/z ¼ 160[28]
50
59
aIsolated yield based on alkyl halide.
bYield on basis of the ITUS was 63%.

634
D. W. Emerson, B. L. Bennett, and S. M. Steinberg
EXPERIMENTAL
Bromofluoroalkanes were obtained from Aldrich Chemical Co. and were used
without further purification. The tetrahydrofuran (THF), ethyl ether, mixed
hexanes, and pentane used evaporated without leaving a residue. Hydrogen
peroxide was supplied by VWR. The TLC plates, 5 ꢀ 20cm, 250 m silica gel
GF coated were supplied by Analtech. Useful directions for syntheses of
ITUSs exist.[25] Temperatures are uncorrected and reported distillation tempera-
tures are the oven temperatures of the Kugelrohr apparatus. Distillation
pressures were measured with a simple mercury manometer. House vacuum
varied between 380 and 200 torr. The GC-MS analyses were performed on a
Varian 3400 GC/Saturn 3 system equipped with a J & W Scientific DB-5-
MS column (30m ꢀ 0.25mm, 0.25m film). The samples were injected in
dichloromethane. The temperature of the GC oven was held for 6 min at
408C and then ramped to 2808C at 128C/min. Flash heating GC/MS
employed a CDS pyroprobe 2000 connected to a Varian Model 3400 GC and
a Varian Saturn 3 mass spectrometer. Samples were heated at 300–5008C for
20sec. Volatilized products were separated on a Supelco EC-5 capillary
column (30 m ꢀ 0.25mm, 0.25m film) and analyzed by electron impact mass
spectrometry. The GC oven was programmed as shown previously.
The FTIR spectra of neat samples between NaCl disks were obtained on
a Nicollet 200 instrument. The high-field NMR spectra were obtained on
1
a Bruker AMX400 spectrometer in 5 mm sample tubes (Wilmad). H and
13C chemical shifts are quoted relative to solvent resonance(s) as internal
standard. 19F chemical shifts are externally referenced to CFCl3 (convention:
upfield shifts are negative). H-H COSY spectra were acquired to confirm
1
signal assignments for the H spectra of 3 and 5.
Compounds and CAS Registry numbers are: thiourea [62-56-6], 1-bromo-
4-fluorobutane, 2, [462-72-6], 1-bromo-3-fluoropropane, 4 [352-91-0], n-butyl
disulfide, 6 [629-45-8], n-pentyl disulfide, 7, [112-51-6], n-butyl n-pentyl
disulfide, 8 [72437-52-6], and n-butyl n-pentyl sulfide, 9 [24768-42-1].[29]
Method A
Preparation of 4-fluoro-1-butyl Disulfide, 3
A solution of 0.380 g, 5 mmol, of thiourea in 2 mL of THF and 1 mL of water
was added with vigorous stirring to 0.775 g, (4.9 mmol) of 2, in 2 mL of THF
in a round-bottomed flask. Thiourea was added in eight portions, five minutes
apart with heating. The heat was then turned off and the mixture was stirred
overnight. The reaction mixture was transferred to a 25 mL Erlenmeyer
flask; 5 mL of ethyl ether and 2 mL of hexanes were added. Three mL of
2 N sodium hydroxide, (6 mmol), and 0.306 mL of 25% hydrogen peroxide,

Synthesis of Dialkyl Disulfides and Sulfides
635
(2.3 mmol), were mixed and added dropwise with vigorous stirring over a 20-
minute period. The mixture was stirred for 1 h and allowed to stand for one
day. The mixture was separated and the top layer was extracted with
saturated brine. The bottom layer was extracted with 5 mL of ethyl ether.
The combined organic layer was dried over anhydrous sodium sulfate. A
small portion of this solution was spotted across a TLC plate, developed
with dichloromethane; Rf ¼ 0.70. This band was scraped off, eluted with
dichloromethane and the eluate was analyzed by GC-MS. The parent ion
and base peak was at m/z 214 with fragments of intensities ꢁ8% at 140,
120, 87, and 55. The product layer was rotary evaporated at house vacuum.
The cloudy residue was filtered through cotton in a Pasteur pipette and
chased with 0.5 mL of ethyl ether. The clear solution was again rotary evapo-
rated and a drop of the residue was applied to a TLC plate and developed.
Some of the coating was analyzed by flash heating GC-MS giving the same
result as before. A Kugelrohr distillation yielded a first fraction at 25–
1008C at ,2 torr that was discarded. A second fraction boiling at 107–
1098C at ,1 torr was collected; 0.209 g.; 39.9%. The liquid tended to bead
up in the receiver suggesting a high surface tension. The viscous residue
weighed 0.008 g and was not further investigated. Calculated for
C8H16F2S2: C 44.83% H 7.52%; Found C 45.16 % H 7.32%. EI MS (70 eV)
1
m/z Mþ Calculated: 214.066, observed 214. H NMR (400.1 MHz, CDCl3,
2
3
295 K) d 4.43 (d,t, JFH ¼ 47 Hz, JHH ¼ 7 Hz, 4H, FCH2CH2CH2CH2S)
3
2.72 (t, JHH ¼ 7 Hz, 4H, FCH2CH2CH2CH2S) 1.83 (br, 4H, FCH2CH2CH2-
1
CH2S) 1.78 (m, 4H, FCH2CH2CH2CH2S). 13Cf Hg NMR (100.6 MHz,
1
CDCl3, 295 K) d 83.67 (d, JFC ¼ 165 Hz, 2C, FCH2CH2 CH2CH2S), 38.5
3
(s, 2C, FCH2CH2CH2CH2S), 29.3 (d, JFC ¼ 20Hz, 2C, FCH2CH2CH2CH2S)
25.1 (d, 3JFC ¼ 4 Hz, 2C, FCH2CH2CH2CH2S). 19F NMR (376.5MHz, CDCl3,
2
3
295K) d 2223.6 (t,t, JHF ¼ 47 Hz, JHF ¼ 26 Hz, 2F, FCH2) FTIR (neat,
NaCl disks, cm21 n 2961, 2906, 2866, 1475, 1449, 1416, 1390, 1298, 1267,
1248, 1209, 1158, 1064, 1037, 982, 947, 924, 893, 799.
Preparation of 3-fluoro-1-propyl Disulfide, 5
The preparation was performed essentially the same way as the preparation of
3. Thiourea, 0.83 g, (11 mmol), and 1.38 g, (9.6 mmol), 4, in 2:1 THF/water
reacted overnight. A 5 : 2 ether/hexanes mixture and a solution of 7.5 mL,
20 mmol, of 2 N sodium hydroxide and 1.02 mL of 25% hydrogen peroxide,
7.5 mmol, were added. After separation and solvent evaporation a Kugerohr
distillation at ,1 torr yielded two fractions ,938C and 93–978C that
proved to be identical by proton NMR. Elemental analysis, calculated for
C6H12F2S2: C 38.69%, H 6.49%; Found C 38.58% H 6.29%. EI MS (70 eV)
1
m/z Mþ Calculated: 186.034 observed 186. H NMR (400.1 MHz, CDCl3,
2
3
295 K) d 4.53 (d,t, JFH ¼ 47 Hz, JHH ¼ 6 Hz, 4H, FCH2CH2CH2S–) 2.78
3
(t, JHH ¼ 7 Hz, 4H, FCH2CH2CH2S–) 2.08 (d -t,t (overlapping),

636
D. W. Emerson, B. L. Bennett, and S. M. Steinberg
3
1
3JFH ¼ 26 Hz, JHH ¼ 6.5 Hz (average), 4H, FCH2CH2CH2S–). 13Cf Hg
1
NMR (100.6 MHz, CDCl3, 295 K)
d
82.1 (d, JFC ¼ 165 Hz, 2C,
2
FCH2CH2CH2S), 34.1 (d, JFC ¼ 4 Hz, 2C, FCH2CH2CH2S), 30.0
(d, JFC ¼ 20 Hz, 2C, FCH2CH2CH2S). 19F NMR (376.5 MHz, CDCl3,
3
2
3
295K)d 2225.8 (t,t, JHF ¼ 47 Hz, JHF ¼ 26 Hz, 2F, FCH2). FTIR (neat,
NaCl disk, cm21, n 2966, 2904, 1472, 1434, 1388, 1347, 1286, 1261, 1211,
1168, 1076, 1057, 1016, 893.
Method B
Dimethyl sulfoxide (DMSO) was used as a solvent. The alkyl halide and
thiourea were added to a flask on a stirrer/hot plate without a reflux
condenser. After completion of the reaction, the solution of sodium
hydroxide and hydrogen peroxide2[26] was added gradually with stirring
followed by heating to 608C for 0.5 h or more. Water and pentane were
added to the cooled mixture with vigorous stirring and the workup was
completed in the usual manner. The hydrocarbon extraction solvent extracts
nonpolar components from a polar reaction mixture with vanishingly small
quantities of other components.[27] Mixtures of unsymmetrical and symmetri-
cal disulfides were made by using two different alkyl halides and proceeding
as one would in making a disulfide. About twice as much unsymmetrical
disulfide (statistical mixtures can also be made by photolyzing mixtures of
disulfides)[28] is made compared to the two symmetrical disulfides that also
result. To make an unsymmetrical sulfide, the ITUS of one halide was
prepared in DMSO, a different alkyl halide was then added followed by two
equivalents of base. The remainder of the procedure was the same.
Method C
The alkyl halide 2 (10.1 mmol) and acetonitrile were combined and
(12.9 mmol) of thiourea was added in seven portions. The mixture was
heated to 55–658C for 15 minutes. Pentane was added and the solid
was filtered off. The filtrate was evaporated via an air stream and the solid
was triturated with pentane to remove any unreacted 2. The solid ITUS
fractions were combined and dissolved in methanol. A mixture of 7 mL of
2 N sodium hydroxide and 0.7 mL (5.1 mmol) hydrogen peroxide was added
gradually with pentane, as the extraction solvent. Passing the dried extract
through 1.2 cm of alumina topped with 1 cm of activated carbon pellets in a
2Solvation of peroxyanions ROO2 inhibits reactions with sulfoxides. We found that
HOO2 evidently reacts with the thiolate ion in preference to DMSO.

Synthesis of Dialkyl Disulfides and Sulfides
637
Pasteur pipette and rotary evaporation led to 0.555 g of 3 in high purity
without distillation. Yield, 52% basis alkyl halide, 63% basis ITUS.
Supplementary Data
NMR, FTIR, and GC-MS spectra of 3 & 5 are available by request addressed
to any co-author.
ACKNOWLEDGMENTS
We thank Dr. Allen L. Johnson for helpful discussions, Mahin Behnia for
technical assistance and Milagro Navarro for some preparations and GC
analyses. The Nevada NSF EPSCoR Program provided for the purchase of
a 19F (5 mm) probe and material support.
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