Graphite oxide: A selective and highly efficient oxidant of thiols and sulfides

Article abstract of DOI:10.1039/c1ob06102j

The selective oxidation of thiols to disulfides and sulfides to sulfoxides using graphite oxide (GO), a heterogeneous carbocatalyst obtained from low cost, commercial starting materials is described. The aforementioned oxidation reactions were found to proceed rapidly (as short as 10 min in some cases) and in good yield (51-100%) (19 examples). No over-oxidation of the substrates was observed, and GO's heterogeneous nature facilitated isolation and purification of the target products.

Full text of DOI:10.1039/c1ob06102j

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Graphite oxide: a selective and highly efficient oxidant of thiols and sulfides†
Daniel R. Dreyer,‡ Hong-Peng Jia,‡ Alexander D. Todd, Jianxin Geng and Christopher W. Bielawski*
Received 6th July 2011, Accepted 19th August 2011
DOI: 10.1039/c1ob06102j
The selective oxidation of thiols to disulfides and sulfides
to sulfoxides using graphite oxide (GO), a heterogeneous
carbocatalyst obtained from low cost, commercial starting
materials is described. The aforementioned oxidation reac-
tions were found to proceed rapidly (as short as 10 min
in some cases) and in good yield (51–100%) (19 examples).
No over-oxidation of the substrates was observed, and GO’s
heterogeneous nature facilitated isolation and purification of
the target products.
As a result of these strongly oxidizing conditions, a wide range of
oxygen-containing functional groups is introduced to graphite’s
surface (Fig. 1).10 Accordingly, GO is both highly acidic and a
strong oxidizer,10 and exhibits a propensity to undergo reduction
when exposed to various chemical reagents.10
The oxidation of organosulfur compounds (e.g., thiols and sul-
fides) is of great importance in synthesis, drug metabolism and the
preparation of bioconjugates.1,2 While a large number of methods
have been developed for such purposes, a persistent challenge is
over-oxidation. For example, disulfides, which may be obtained
through the dimerization of thiols, can undergo further oxidation
to their corresponding thiosulfinates, disulfoxides, sulfinyl sulfones
or disulfones. Likewise, the oxidation of sulfides often leads
to not only sulfoxides but also sulfones or sulfonic acids. To
address these important issues, a wide range of sophisticated
catalysts (frequently containing transition metals as the active
species) has been developed.2 Indeed, catalysts based on iron,3,4
palladium,5 and molybdenum,6,7 among other metals, have led
to reduced reaction times and improved selectivity for the target
products. However, despite these advances, many metal-containing
catalysts are inapplicable in pharmaceutical or biotechnological
applications due to toxicity concerns and separation challenges.
Thus, the development of highly active but metal-free oxidants
for organosulfur compounds is of high value. Moreover, the use
of heterogeneous catalysts enables the rapid and straightforward
isolation of the target compounds, usually via filtration or
distillation, as well as the recovery and reuse of the catalyst
itself.8,9
Fig. 1 Proposed structure of graphite oxide (GO) based on the Lerf–
Klinowski model.10,11
Recently we reported that GO10 is capable of heterogeneously
facilitating a broad range of synthetic transformations including
alcohol,15,16 olefin,15,17 and C–H oxidations,17 alkyne hydrations,15
and combinations thereof.18 Though typically more challenging
to prepare than GO, other acidic and oxidizing carbon materials
(e.g., graphite intercalation compounds (GICs) incorporating
strong acids and oxidized carbon nanotubes) have also been
used to facilitate chemical reactions, including carbonylations,19
decarboxylation,20 and dehydrogenations.21 The use of metal-
free carbons such as GO in synthesis takes advantage of
their unique characteristics, including their biocompatibility,22,23
heterogeneity, high surface area, and rich surface chemistry,
as well as their low cost and ease of preparation.24 As a
result, GO and other “carbocatalysts”25 may be distinguished
from metallo- or organocatalysts used for similar purposes.
Building upon GO’s demonstrated oxidative properties,15 we
envisioned utilizing this material for the facile and selective
preparation of disulfides and sulfoxides from thiols and sulfides,
respectively.
In a preliminary experiment, thiophenol (25 mg) was treated
with GO (75 mg) at 100 ◦C in CHCl3 (0.3 mL) for 10 min
in a sealed vessel. After workup by dissolution of the crude
reaction mixture in CHCl3 (50 mL) followed by filtration of the
heterogeneous carbon and removal of the volatile solvent, the thiol
was determined by 1H NMR spectroscopy (CDCl3) to have been
quantitatively converted to diphenyldisulfide.26 Compared to pre-
viously reported oxidative couplings of thiols using metal catalysts
(e.g., high surface area iron metal–organic frameworks; MOFs),4
appreciably less time was required (10 min versus several hours) to
We envisioned that many of the aforementioned challenges
for accessing practical organosulfur oxidants may be addressed
through the use of graphite oxide (GO). Often employed as a
precursor to graphene-like materials,12,13 GO may be synthesized
by treating graphite with K2S2O8 and P2O5, followed by KMnO4
in concentrated H2SO4, and finally worked up in aqueous H2O2.14
Department of Chemistry and Biochemistry, The University of Texas at
Austin, 1 University Station, A1590, Austin, TX, USA. E-mail: bielawski@
cm.utexas.edu
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c1ob06102j
‡ D. R. Dreyer and H.-P. Jia contributed equally to this work.
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Table 1 Optimization of the GO-catalyzed oxidation of thiophenola
Entry
Carbon (loading)
Reaction temperature (◦C)
Reaction time
Conversionb (%)
1
2
3
4
5
6
7
8
—
100
100
100
100
100
100
100
40
60
80
100
100
100
10 min
10 min
20 min
30 min
60 min
10 min
10 min
10 min
10 min
10 min
10 min
10 min
10 min
3.5
100
98
94
96
81
100
5
22
86
7
10
23
GO (300 wt%)
GO (300 wt%)
GO (300 wt%)
GO (300 wt%)
GO (20 wt%)
GO (60 wt%)
GO (60 wt%)
GO (60 wt%)
9
10
11
12
13
GO (60 wt%)
Graphite (60 wt%)
Activated carbon (60 wt%)
Hydrazine-reduced graphene oxidec (60 wt%)
a Reaction conditions: thiophenol (25 mg), carbon (type and amount indicated), and CDCl3 (0.3 mL) were combined in sealed 7.5 mL vial for the time
and temperature indicated. b Conversion of thiophenol to diphenyldisulfide was monitored by 1H NMR spectroscopy (CDCl3) using 1,4-dinitrobenzene
as an internal standard. c Prepared according to previously reported methods (see ESI†).
achieve quantitative reaction using GO under similar temperatures
and catalyst loadings. After observing quantitative conversion
in only a few minutes, subsequent efforts were directed toward
optimizing the reaction times, GO loadings, and reaction tem-
peratures employed. Minimal changes in the conversion were
observed upon increasing the reaction time (Table 1, entries
2–5). While 20 wt% GO afforded 81% of the target product
(entry 6), increasing the loading to 60 wt% GO was found to be
sufficient to drive the oxidation reaction to quantitative conversion
(entry 7).27 We also found that variations in the reaction tem-
perature (ranging from 40–100 ◦C) had a significant effect on
the isolated yield of the disulfide product (entries 7–10). At low
temperatures, minimal yield of product was obtained; however,
a quantitative conversion was generally observed at reaction
temperatures at or above 100 ◦C. Indicating that the observed
reactivity was due to GO’s unique chemical properties, only
minimal yields of the disulfide product were obtained when natural
flake graphite, activated carbon, or hydrazine-reduced graphene
oxide28 were substituted for GO (entries 11–13). Likewise, only a
low yield of diphenyldisulfide (3.5%; entry 1) was obtained in the
absence of a carbon promoter under otherwise identical conditions
(100 ◦C, 10 min).
Using the optimized experimental conditions described above
(25 mg thiol, 15 mg GO, 0.3 mL CHCl3, 100 ◦C, 10 min), we
next explored the substrate scope of this method. As shown
in Table 2, a wide range of thiols showed excellent conversion
to their respective disulfides when treated with GO, and pure
products were obtained after short reaction times by dissolution
of the crude reaction mixtures in CHCl3 (50 mL), filtration of the
residual carbon, removal of the volatile solvent under vacuum,
and purification via column chromatography in some cases. The
reactivity of alkyl thiols (entries 2–3, 10) appeared slightly lower
than that of aryl thiols (entries 1, 4–9), despite slightly longer
reaction times (30 min versus 10 min), consistent with our previous
observation that GO often exhibits higher activity toward arene-
functionalized substrates.15,17,18 As a further indicator of the
preferential reactivity of aryl thiols over alkyl thiols, a 1 : 1 molar
mixture of thiophenol and 1-butanethiol (total mass: 25 mg) was
treated with GO (60 wt%) under optimized conditions (100 ◦C,
10 min). Using 1H NMR spectroscopy, the crude product mixture
(63% conversion) was found to contain a 1.0 : 5.0 : 2.9 molar
ratio of dibutyldisulfide : butylphenyldisulfide : diphenyldisulfide,
as well as unreacted 1-butylsulfide (34%) and a small amount of
unreacted thiophenol (<5%).
Perturbation of the electronic properties of aromatic thiols
through the incorporation of electron-donating or -withdrawing
substituents did not significantly affect the isolated yield of the
desired product. For example, both electron rich (entries 4–7)
and electron deficient thiols (entries 8–9) gave excellent isolated
yields of the respective disulfides (94–99%). No over-oxidation
(including N-oxidation, in the case of 2-aminothiophenol) was
observed in any of the reactions performed, as has been ob-
served with chromic potassium sulfate (CrK(SO4)2·12 H2O) and
other transition metal-based oxidation catalysts.29 While this
challenge has been addressed using more sophisticated metal
species (e.g., MOFs,4 cobalt imidazoles or cobalt porphyrins,30
and various bismuth species31) such catalysts often do not appear
to show the breadth of reactivity that has been demonstrated
with GO.
In an effort to expand GO’s reactivity within the family
of organosulfur species, we turned next toward exploring the
oxidation of sulfides to their respective sulfoxides. In a preliminary
experiment, diphenylsulfide was oxidized to diphenylsulfoxide in
86% isolated yield after 24 h at 100 ◦C (300 wt% GO) (Scheme 1);
no other oxidation products were observed in the crude reaction
mixture. In a similar manner to that described above, the reaction
was optimized with respect to GO loading, reaction temperature,
and reaction time (see ESI†). We found that GO loadings below
300 wt% were less effective in affording the desired products;
however, no improvement in isolated yield was observed at higher
loadings. Though the loadings used herein were higher than
those typically used with metal catalysts,1,29 GO’s low cost and
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Table 2 Oxidation of various thiols using GOa
Entry
1
Starting material
Product
Reaction time
10 min
Yieldb (%)
100
2
3
30 minc
30 minc
77
90
4
5
10 min
10 min
95
96
6
10 min
10 min
10 min
10 min
30 minc
97
97
99
94
75
7
8
9
10
a All reactions were performed at 100 ◦C in sealed 7.5 mL vials using 25 mg thiol, 15 mg GO (60 wt%) and 0.3 mL CHCl3 for the indicated reaction time.
b Isolated yield after purification by column chromatography. c Relatively low yields (40–65%) were observed after 10 min; higher yields were obtained
after 30 min.
column chromatography, including those that featured S-alkyl
substituents. Variations in the electronic structure of the arene-
substituted sulfides were found to have only a slight influence on
the yield of the sulfoxide product. For example, an electron rich
sulfide (p-methoxythianisole, entry 8) was oxidized in 96% isolated
Scheme 1 Oxidation of diphenyl sulfide using GO.
yield, whereas an electron deficient analogue (p-chlorothianisole,
entry 9) was obtained in 81% yield under otherwise identi-
heterogeneity make it a practical choice.15 In addition to providing
an economical, facile route to the target products, it was found that
the spent catalyst, which had undergone partial deoxygenation
(see below), was able to be reoxidized to GO using the same
oxidation methods used with the graphite starting material. As
observed in the aforementioned thiol coupling reactions, minimal
reactivity was observed when carbons other than GO were used
(i.e., graphite, activated carbon, or hydrazine-reduced graphene
oxide).
As summarized in Table 3, a broad range of sulfides was
successfully converted to their corresponding sulfoxides using GO
under optimized conditions (25 mg sulfide, 75 mg GO, 0.3 mL
CHCl3, 100 ◦C, 24 h). Excellent yields of the corresponding
products were obtained in most cases after purification by
cal conditions. Compared to previously reported Ru and Fe
catalysts (utilizing O2 or H2O2 as the oxidant), GO provides
increased yield and increased selectivity for the sulfoxide over the
sulfone.32,33
To ascertain the fate of the GO used in the aforementioned
oxidation reactions, the residual carbon was separated from
a reaction mixture containing 25 mg thiophenol, 15 mg GO,
0.3 mL CDCl3 after 10 min at 100 ◦C by filtration and the
resulting material was characterized. Compared to the GO starting
material, the FT-IR spectrum (KBr) of the recovered carbon
exhibited attenuated stretching frequencies ascribed to the C–OH,
C
O, and C–O moieties (see Fig. S3, ESI†). The FT-IR spectrum
also revealed new signals that were attributed to the presence
of aromatic and olefinic species. The deoxygenation of GO was
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Table 3 Oxidation of various sulfides by using GOa
Acknowledgements
Entry Starting material
1
Product
Yieldb
89%
This work was generously supported by the National Science
Foundation (grant No. DMR-0907324) and the Robert A. Welch
Foundation (grant No. F-1621).
2
3
4
92%
90%
51%
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later confirmed via X-ray photoelectron spectroscopy (XPS) and
elemental combustion analysis (see Fig. S1–S2, Table S5, ESI†).
For example, while the as-prepared GO exhibited a C : O ratio
of 2.6 : 1 by XPS, the material recovered after reacting GO with
thiophenol showed a C : O ratio of 9.2: 1.
In summary, GO was discovered to effectively facilitate the
oxidation of thiols and sulfides to their corresponding disulfides
and sulfoxides, respectively, and with good selectivity. In all cases
studied herein, the necessary reaction times required were found
to be relatively short (as brief as 10 min), the recovered yields
were high, and purification of the product was facilitated by GO’s
heterogeneous nature. As such, the methods described provide a
practical approach to the oxidation of sulfur compounds; one that
does not lead to the over-oxidation often seen with metal catalysts
used for similar purposes.29,32,33
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The Royal Society of Chemistry 2011
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