Practical and efficient recyclable oxidative system for the preparation of symmetrical disulfides under aerobic conditions

Article abstract of DOI:10.1080/17415993.2020.1856849

An efficient and practical oxidative coupling of thiols to symmetrical disulfides is developed at room temperature under aerobic conditions. The commercially available sodium methoxide solution 30 wt. % in methanol together with the air was used as a retrievable promoter system and green oxidant, respectively, for the preparation of symmetrical disulfides. The desired products were obtained in good to high yields by an economical procedure. No overoxidation of the symmetrical disulfides was observed, and various functional groups were well tolerated in the current protocol. Moreover, the new reagent reduces the generation of hazardous waste due to its high reusability. The reaction proceeded in the absence of light, and it was not inhibited by TEMPO. Also, the low yield of TEMPO-benzyl thiol adduct was detected under these conditions. Based on our experiments, a possible mechanism was proposed in the absence and presence of TEMPO.

Full text of DOI:10.1080/17415993.2020.1856849

Journal of Sulfur Chemistry
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/gsrp20
Practical and efficient recyclable oxidative system
for the preparation of symmetrical disulfides
under aerobic conditions
Ong Chiu Ling , Thorsten Heidelberg , Juan Joon Ching & Nader Ghaffari
Khaligh
To cite this article: Ong Chiu Ling , Thorsten Heidelberg , Juan Joon Ching & Nader
Ghaffari Khaligh (2020): Practical and efficient recyclable oxidative system for the preparation
of symmetrical disulfides under aerobic conditions, Journal of Sulfur Chemistry, DOI:
10.1080/17415993.2020.1856849
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JOURNAL OF SULFUR CHEMISTRY
https://doi.org/10.1080/17415993.2020.1856849
Practical and efficient recyclable oxidative system for the
preparation of symmetrical disulfides under aerobic
conditions
Ong Chiu Linga, Thorsten Heidelbergb, Juan Joon Ching a and Nader Ghaffari
a
Khaligh
aNanotechnology and Catalysis Research Center, Institute for Advanced Studies, University of Malaya, Kuala
Lumpur, Malaysia; bDepartment of Chemistry, Faculty of Science, University of Malaya, Kuala Lumpur,
Malaysia
ABSTRACT
ARTICLE HISTORY
Received 24 July 2020
Accepted 19 November 2020
An efficient and practical oxidative coupling of thiols to symmet-
rical disulfides is developed at room temperature under aerobic
conditions. The commercially available sodium methoxide solu-
tion 30 wt. % in methanol together with the air was used as a
retrievable promoter system and green oxidant, respectively, for the
preparation of symmetrical disulfides. The desired products were
obtained in good to high yields by an economical procedure. No
overoxidation of the symmetrical disulfides was observed, and var-
ious functional groups were well tolerated in the current proto-
col. Moreover, the new reagent reduces the generation of haz-
ardous waste due to its high reusability. The reaction proceeded
in the absence of light, and it was not inhibited by TEMPO. Also,
the low yield of TEMPO-benzyl thiol adduct was detected under
these conditions. Based on our experiments, a possible mech-
anism was proposed in the absence and presence of TEMPO.
KEYWORDS
Thiol; oxidative coupling;
symmetric disulfide; reaction
mechanisms; sustainable
chemistry
CONTACT Nader Ghaffari Khaligh
ngkhaligh@gmail.com, ngkhaligh@um.edu.my; Juan Joon Ching
jcjuan@um.edu.my Nanotechnology and Catalysis Research Center, Institute for Advanced Studies, University of
Malaya, Kuala Lumpur 50603, Malaysia
Supplemental data for this article can be accessed here. https://doi.org/10.1080/17415993.2020.1856849
© 2020 Informa UK Limited, trading as Taylor & Francis Group

2
O. C. LING ET AL.
1. Introduction
Organosulfur compounds have been attracted much attention in different fields, such as
biology, chemical protection, sulfenylation of enolates, and the preparation of bioactive
organosulfur compounds [1–4]. The S–S bond formation is an essential step in the vulcan-
ization, peptide stabilization, and DNA-cleavage [5]. The ‘Merox process’ is employed in
the petroleum refinery industry for the thiol removal through the oxidative coupling of thi-
ols to disulfides using NaOH or ammonia [6]. Organic disulfides or disulfanes (R–S–S–R)
conventionally prepared by oxidative coupling of thiols or sulfur-containing compounds
[5,7], which occasionally leads to the formation of side products such as trimers and
polymers [8]. The thiosulfinates, thiosulfonates, and sulfonic acids often may be formed
during the oxidation of thiols due to the over-oxidization of products [9]. Thus, the oxida-
tive homocoupling of thiols to disulfides under mild and eco-friendly conditions without
over-oxidation is a significant process in organic chemistry and biochemistry [5,10].
A variety of synthetic methods have been reported for the synthesis of symmetrical
disulfides from the thiols, including enzymatic and electrochemical methods [10–12]. The
oxidative formation of S–S bond was reported by using a variety of catalysts, such as sul-
fonyl chloride/NaHCO3 [13], nanocatalysts [14], phase transfer catalysts [15], nitric oxide
[16], haloacid/dimethyl sulfoxide [17], hydrogen peroxide in fluoro alcohols [18], and
manganese (III) Schiff-base complex [19]. Also, the oxidation of the thiols to the symmet-
rical disulfides was carried out using base catalysts such as anhydrous potassium phosphate
[20] and trimethylamine under ultrasonic irradiation [21].
Unfortunately, some of these protocols typically have drawbacks; for example, (a) fab-
rication of the scarce and transition metal-containing catalysts through the multi-step
processes at high temperatures within long times along with separation and purification in

JOURNAL OF SULFUR CHEMISTRY
3
each step, (b) generation of hazardous wastes, (c) high reaction temperature for long reac-
tion times, (d) tedious workup procedure, (e) limited substrate-scope and low selectivity,
and (f) overoxidation of the products to the sulfoxide and sulfone, or oxidation of other
functional groups within the molecule or formation of the inactive metal-thiolate com-
plex [22]. Although hydrogen peroxide was considered to be a green oxidant, its industrial
synthesis via the so-called anthraquinone auto-oxidation process is not sustainable [23].
Furthermore, the overoxidation of products into sulfonic acids was reported for the base-
catalyzed oxidation of thiols in various heterogeneous catalyst systems [24]. Therefore, as
a sustainable alternative for the hazardous and toxic oxidants, it is preferred to carry out
the oxidative coupling thiols by molecular oxygen or air as green and cheap oxidants.
Herein, the commercially available sodium methoxide solution 30 wt. % in methanol
was used as a recyclable promoter system to conduct the aerobic oxidative coupling of
thiols into the symmetrical disulfides. Our experimental results demonstrated that the
simultaneous presence of molecular oxygen and thiolate in methanol, but neither reagent
individually, promotes the oxidation of thiols to the symmetrical disulfides.
2. Experimental
2.1. General
Unless specified, all chemicals were analytical grade and purchased from Merck, Sigma
Aldrich, and Fluka Chemical Companies and used without further purification. Products
were characterized by their physical constant and FT-IR, NMR, and Mass spectral analysis.
The purity determination of the substrates and reaction monitoring was accompanied by
TLC using silica gel SIL G/UV 254 plates. The purity determination and MS (EI) data of
the products was accomplished by GC-MS on an Agilent 6890N GC system with a 5973N
mass selective detector under 70 eV conditions. The FT-IR spectra were recorded on a
1
Perkin Elmer 781 Spectrophotometer used in the range of 4000–400 cm−1. H and 13C
NMR spectra were recorded with Bruker Avance III 600 and 400 MHz instruments. All
chemical shifts are quoted in parts per million (ppm) relative to TMS using a deuterated
solvent.
2.2. A typical procedure for the preparation of symmetrical disulfides
A variety of thiols (10 mmol) were added into sodium methoxide 30 wt. % in methanol
(1.85 mL, 10 mmol) (NaOMe/MeOH-30), and the solution was stirred at room temper-
ature under air atmosphere. After completion of the reaction, the desired products were
extracted with ethyl acetate or n-hexane (3 × 2 mL). The collected extracts were dried
over Na2SO4 and concentrated under reduced pressure. The pure symmetrical disulfides
were obtained as liquids or solids. The known and new products were characterized and
identified by melting point, FT-IR, 1H NMR and 13C NMR, and mass analysis.
2.3. The synthesis of 4,4ꢀ-dithiobisbenzoic acid
4-Mercaptobenzoic acid (1.54 g, 10.0 mmol) was added into sodium methoxide 30 wt. % in
methanol (3.7 mL, 20 mmol), and the mixture was stirred at room temperature under air

4
O. C. LING ET AL.
atmosphere for eight hours. The solution was concentrated by rotary evaporator under vac-
uum and adjusted to pH = 2 by adding hydrochloric acid (0.02 M). The white precipitate
was collected and dried under reduced pressure.
3. Results and discussion
3.1. Aerobic oxidation of various thiols promoted by using sodium methoxide
solution 30 wt. % in methanol
The benzyl mercaptan was selected as a model substrate, and initial experiments were con-
ducted to find the optimal conditions. Different mole ratios of the model substrate and
NaOMe/MeOH-30% were stirred at room temperature under air atmosphere for one hour.
The GC-MS showed a 100% conversion when one equivalent of NaOMe/MeOH-30% was
employed, and the corresponding disulfide was isolated in 97% yield by a simple extrac-
tion workup. Although a significant drop in the yield (58%) was observed by reducing
the amount of NaOMe/MeOH∼30% (0.5 equiv.) during one hour, the reaction showed
a 100% conversion, and the desired disulfide was obtained in 93% isolated yield after
12 hours.
Two blank experiments, one in methanol and the other in ethanol, were carried out at
room temperature under air atmosphere. In contrast to a previous report [25], the corre-
sponding disulfide was not detected even after 24 hours (monitored by TLC and GC-MS),
and benzyl mercaptan was recovered. Also, the stirring of benzyl mercaptan into a solu-
tion of triethylamine (1.0 equiv.) in methanol at room temperature under air atmosphere
gave no disulfide after one hour (monitored by TLC and GC-MS). A low yield of diben-
zyl disulfide (12%) was detected after one hour when the model reactant was added into
one equivalent of NaOH in methanol at room temperature under air atmosphere. This low
yield was probably due to the limited solubility of NaOH in methanol, as switching to a
mixture of methanol/water solvent (80/20 v/v%) partially improved the yield (42%).
The sodium benzyl thiolate (BnS−Na+) was obtained in 97% yield as a white solid after
evaporation of methanol when the model reaction was carried out at room temperature
under N2 atmosphere (See Supplementary Information, Figure S1). Dibenzyl disulfide was
detected, the presence of one multiplet at 7.30–7.22 ppm and one singlet at 3.59 ppm, in
∼3% yield by 1H NMR analysis.
The model reaction was completed within 20 min when pure oxygen at 0.3 MPa pres-
sure was injected in the reaction vessel at room temperature. The air was chosen instead
of pure oxygen as an oxidant due to the cost-efficiency of the strategy, including the cost
of purchase, logistics supply, maintenance, storage, etc. Therefore, the treatment of various
thiols with one equivalent of NaOMe/MeOH-30% at room temperature under air atmo-
sphere was chosen as the optimized conditions for the aerobic oxidative coupling of thiols
into symmetrical disulfides.
As one can see in Table 1, a broad scope of thiols including primary, secondary, ter-
tiary, aromatic, and heteroaromatic thiols were smoothly transformed to the corresponding
disulfides within 32 min to 10 h stirring at room temperature under air atmosphere. The
substituents such as methoxy, amine, and carboxylic acid were well tolerated (Table 1,
entries 3–5). The short, medium, and long-chain linear aliphatic symmetrical disulfides
were also obtained in 95–97% yields (Table 1, entries 7–9). It is worth mentioning that the

JOURNAL OF SULFUR CHEMISTRY
5
Table 1. Aerobic oxidative coupling of various thiols in the presence of NaOMe/MeOH ∼ 30% (1.0
equiv.) at room temperature under air atmosphere.
Melting point/°C
Isolated
Entry
Substrate 1
Product 2
Time/h
yield/%
Found
Reported
1
55 min
97
Oil
58–59 [26]
2
3
4.2
1.8
94
95
60–61
77–79
57 [27]
75–77 [28]
4
5
6
8
7
8
85
96
97
319–321
33–34
> 300 [28]
33–34 [29]
176–177
181–183 [29]
7
8
35 min
9
97
95
Oil
Oil
Oil [30]
20–31 [26]
62.8 [31]
9
9
95
95
63–64
Oil
10
32 min
Oil [26]
(continued).

6
O. C. LING ET AL.
Table 1. Continued.
11
10
90
89–90
–
linear aliphatic thiols having longer hydrocarbon chain required a longer reaction time in
comparison with octane thiol (Table 1, entries 8 and 9 vs. 7). The sterically hindered thi-
ols such as cyclohexane thiol and 1-adamantane thiol gave the corresponding disulfides in
95% and 90% yields, respectively (Table 1, entries 10 and 11).
Our results showed that the reaction time was influenced by the nature of the sub-
stituents on the aromatic ring, for example, the aerobic oxidative homocoupling of 4-
amino thiophenol is more favorable than 4-mercaptobenzoic acid (Table 1, entry 3 and
4). The shorter reaction time in the oxidative coupling of 4-amino thiophenol and 4-
methoxythiophenol could be attributed to the effect of amine and methoxy groups (Table1,
entries 3 and 5).
The corresponding symmetrical disulfides were obtained in good to high yields without
trimer or polymer by-products, over oxidation into sulfones, or β-H abstraction from the
disulfide to produce olefin and RSS− or RS−, which indicates a clean transformation. The
selectivity of the current oxidative system was demonstrated when substrate such as 4-
mercaptobenzoic acid was treated under optimal conditions, which afforded the respective
product in 85% yield (Table 1, entry 4). Many reported methods in the literature failed to
oxidize the tertiary thiol, possibly due to steric hindrance, whereas 1-adamantanethiol gave
the desired product in 90% yield at room temperature after 10 hours (Table 1, entry 11).
4-Nitrothiophenol was not oxidized even after 12 h, probably due to the most stable of the
4-nitrothiophenolate anion.
3.2. Study of the reaction mechanism
Many studies have been reported on the mechanism of oxidative coupling of thiols [10,11].
It was indicated that only the anionic thiolates could be oxidized into symmetrical disul-
fides [32]. Also, the redox potential of the thiol-disulfide system is usually pH-dependent,
and the oxidation of thiolate can be modulated by the inductive effect of substituents next
to sulfur atom [33].
Several experiments were performed to gain insight into the oxidative coupling mech-
anism in the presence of NaOMe/MeOH-30%.
3.3. Influence of water and methanol
It was found that a small amount of water (0.2 mL per 2.0 mmol benzyl thiol) had no
notable effect on the yield and the reaction time of the model reaction (see Supplemen-
tary Information, Figure S2). However, the benzyl thiol (BnSH) remains unchanged when
an aqueous solution of sodium benzyl thiolate was left for 12 hours without stirring at
room temperature under the air atmosphere, and the dibenzyl disulfide was not detected

JOURNAL OF SULFUR CHEMISTRY
7
(see Supplementary Information, Figure S3). Thus, it is indicated that the water can inhibit
the aerobic oxidation of the benzyl thiol and benzyl thiolate. A mixture of benzyl thiol and
dibenzyl disulfide was detected in a ratio of about 1:1 when methanol was added to sodium
benzyl thiolate under the above conditions, at room temperature under air atmosphere for
12 hours without stirring, in the absence of any reagents or other additives (see Supple-
mentary Information, Figure S4). This fact reveals that thiolate can be intermediate in the
current protocol.
3.4. Influence of air and light
As mentioned, the dibenzyl disulfide (Bn2S2) was detected only in <3% yield as well
as sodium benzyl thiolate (BnS−Na+) in 97% yield (see Supplementary Information,
Figure S1) when an equimolar mixture of benzyl thiol and NaOMe/MeOH-30% was stirred
at room temperature for one hour under N2 atmosphere. This experiment demonstrated
that the oxygen in the air plays a vital role as the oxidant.
To the investigation of the light effect, an equimolar mixture of MeONa/MeOH-30% and
benzyl thiol was stirred at room temperature in a round-bottom flask, which was covered
with aluminum foil. The result was almost the same as the reaction at ambient light; hence,
the current strategy is not light-induced.
3.5. Mechanism aerobic oxidative homocoupling of thiol in the basic medium
The possible mechanism for this oxidative coupling of thiols in NaOMe-MeOH-30%
(Conc. 6.27 mmol/mL) is proposed in Scheme 1. It is well-known that organic thiol (RSH)
transformed to its anion in the presence of a strong base [34].
The thiolate anion can react with oxygen in the air to generate a thiyl radical (RS•) and
superoxide ion (O2•−) through a reversible single electron transfer (SET) [35,36]. NaOMe-
MeOH-30% can also promote this molecular oxygen electro-reduction. Then, two thiyl
radicals dimerize to give the symmetrical disulfide. The peroxide anion can also oxidize
another molecule of thiol through a hydrogen atom transfer mechanism [37], which leads
to generating the thiyl radical and hydrogen peroxide anion (HO2−). Moreover, the reac-
tion between HO2− and benzyl mercaptan can give the benzylthiolate anion and hydrogen
peroxide, whereas H2O2 can generate molecular oxygen for beginning a new oxidative
chain reaction. This fact is in agreement with our experimental results.
In consideration of the mechanism of the aerobic oxidative coupling of thiols, NaOMe-
MeOH-30% system acts as a homogeneous recyclable promoter system that abstracts
hydrogen from thiol and also activates the molecular oxygen in the air to give the thiyl
radical.
As previously indicated, the thiophenolate anions can be stabilized through a res-
onance of the electron pair on the sulfur atom with the π system of the ben-
zene ring [38]. Therefore, based on the reactivity sequence of thiophenols viz. p-
aminothiophenole > thiophenol > 4-methoxythiophenol∼4-mercaptobenzoic
acid
> > p-nitrothiophenol (Table 1, entries 2–5), it was proposed that reaction of the anion
with oxygen is rate-limiting as Russell et al. reported a similar reactivity sequence for the
oxidation of carbanions [39]. If ionization of the thiol was rate-limiting, the reverse order
of reactivity was expected.

8
O. C. LING ET AL.
Scheme 1. A possible route of aerobic oxidative homocoupling of benzyl thiol using high recyclable
NaOMe/MeOH-30% at room temperature under the air atmosphere.
3.6. Influence of TEMPO
In continuation of the mechanism study, the model reaction was carried out in the presence
of 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) (5.0 mol %) as a thiyl radical (RS•) scav-
enger. In contrast to a previous report [40], two products viz. dibenzyl disulfide (Bn2S2)
and TEMPO-benzyl sulfide adduct (TEMPO-SBn) were detected by the GC-MS analysis in
a ratio of 93.5% and 6.5%, respectively (Table 2, entry 1) (see Supplementary Information,
Figure S5–S8). The ratio of TEMPO-SBn adduct to Bn2S2 remained practically unchanged
when the molar ratio of TEMPO/BnSH was raised to one or three equivalents (Table 2,
entries 2 and 3).
The Bn2S2 showed fragment ions at m/z 91, 181, 214, and 246 with a base peak m/z
91, which was characteristic of the fragment [C6H5CH2]+• (see Supplementary Informa-
tion, Figure S5). The symmetrical dibenzyl sulfide ion [C6H5–CH2–S–CH2–C6H5]+• was
characterized at m/z 214, which was formed through the loss of one sulfur atom from the
parent molecular ion of Bn2S2 [C6H5–CH2–S–S–CH2–C6H5]+• at m/z 246.

JOURNAL OF SULFUR CHEMISTRY
9
Table 2. Mechanistic studies on the model reaction
in the presence of TEMPOa.
The ratio of products/%b
The molar ratio of
Entry
Benzyl thiol to TEMPO
Bn2S2
TEMPO-SBn
1
2
3
1.0:0.05
1.0:1.0
1.0:3.0
93.5
89.8
89.3
6.5
10.2
10.8
aReaction conditions: benzyl thiol (1.0 mmol), solution of
NaOMe/MeOH ∼ 30%(1.0 mmol), airatmosphere, roomtem-
perature, reaction time (55 min).
bMonitored by GC-MS.
TEMPO-SBn fragment ions were observed at m/z 91, 160, 216, and 280 with a base peak
m/z 91 (see Supplementary Information, Figure S6). The peaks at m/z 280 and 188 were
assigned to the parent molecular ion of TEMPO-SBn ion and [TEMPO–S]+•, respectively.
The base peak at m/z 91 was also assigned to the fragment [C6H5CH2]+•, and the peak at
m/z 109 was probably due to a radical cation with a formula of [C7H11N]•+
.
These experiments demonstrated that the oxidation of thiols by NaOMe/MeOH-30% is
independent of TEMPO concentration.
Other control experiments were performed in the presence of TEMPO. Although the
reaction of TEMPO and benzyl thiol did not proceed under the nitrogen atmosphere, the
adduct TEMPO-SBn and Bn2S2 were detected in the presence of molecular oxygen (see
Supplementary Information, Figure S9–S13). This result suggests that the oxidation of
thiols by TEMPO is also molecular oxygen dependent. Therefore, it was concluded that
TEMPO promoted the oxidation of thiols by superoxide through either electron transfer
or covalent reaction.
These results encourage us to present an alternative reaction mechanism of aerobic
oxidative coupling of benzyl thiol in the presence of TEMPO under an air atmosphere
in a base medium (Scheme 2). Regarding the acidity of TEMPO (pKa(TEMPO) = 5.5), the
protonation of TEMPO is excluded in the current protocol. The reaction of TEMPO with
thiyl radicals of benzyl mercaptan gives TEMPO-SBn adduct.
3.7. Reusability of the current catalytic system for the aerobic oxidative coupling of
thiols
Finally, the reusability of NaOMe/MeOH-30% was monitored using sequential oxidation
of benzyl thiol under optimized reaction conditions. After completion reaction (monitored
by TLC), the product was extracted with n-hexane (4 × 5 mL). The solvent was evaporated
from the collected extractions by a rotary evaporator, which gave a pure desired prod-
uct. The fresh thiol was added to the residue NaOMe/MeOH-30%, and the reaction was
conducted for the next run. The pure 2a was obtained in 97–95% yields as well as 100% con-
version for ten subsequence runs. These results showed that the current oxidative system
is highly recyclable.
3.8. Investigation of a large scale application
2,2ꢀ-dithiobisbenzothiazole (MBTS) is a well-known accelerator in the rubber and
plastic industry. To illustrate the potential industrial application of the protocol, a

10
O. C. LING ET AL.
Scheme 2. Alternative reaction mechanism of aerobic oxidative coupling benzyl thiol in the presence
of MeONa/MeOH ∼ 30% and TEMPO under an air atmosphere at room temperature.
gram scale aerobic oxidative coupling of 2-mercaptobenzothiazole was performed. 2-
Mercaptobenzothiazole (16.7 g, 100 mmol) was stirred in NaOMe/MeOH-30% (18.5 mL,
100 mmol) at room temperature under air atmosphere overnight. The 2,2ꢀ-dithiobisbenzo-
thiazole was obtained in a high purity 92% isolated yield (30.6 g) by using a simple n-hexane
extraction without using a high-cost column chromatography technique.
3.9. Merits and superiority of the current aerobic oxidative coupling of thiols
Our oxidative coupling system was superior in comparison with the most reported method
and reagents in the literature, for example, Soleiman-Beigi and Arzehgar reported the syn-
thesis of diphenyl disulfide in 90% yield from thiophenol using 1.5 equivalents morpholin-
4-ium morpholine-4-carbo-dithioate and CuCl together with 18 equivalent KOH at 110°C
after 20 h [41]. Also, diphenyl disulfide was obtained in 72–94% yield using a solution of
dithioates of Meldrum’s acid, dimedone, or barbituric acid in DMF or DMSO as sulfur
transfer reagents in the presence of Cs2CO3 and Et3N at 60–100°C within four hours in

JOURNAL OF SULFUR CHEMISTRY
11
the N2 atmosphere [26]. The same product was afforded in 98% yield at room temperature
after 4.2 hours in the presence of NaOMe/MeOH-30%.
Only 39% and 44% yield of dihexyl disulfide and dicyclohexyl disulfide were obtained
using 15 mol% of MnCO3 and gallic acid in water at 80°C in pH = 9, adjusted by Na2CO3
solution, under 0.3 MPa pressure of molecular oxygen [42]. Furthermore, the reagents were
not recyclable, and the products were required to purify by the column chromatography.
The dioctyl disulfide and dicyclohexyl disulfide were isolated in 97% and 95% yield by a
simple separation process using one equivalent highly recyclable of NaOMe/MeOH-30%
system at room temperature under air atmosphere after 35 and 32 min, respectively.
Iodine together with a stoichiometric amount of DMSO was used for the preparation of
the symmetric disulfides in good to high yield under conventional and microwave heating
conditions; however, this method failed for aliphatic thiols [43].
Tert-butyl nitrite (TBN) with oxygen was also used to preparation of symmetrical disul-
fides [44]. The use of pure oxygen, generation of NOX as by-products, higher temperature,
and lower yields within longer reaction times are the disadvantages of this methodology in
comparison with the current protocol.
Although the oxidative coupling of 1-adamantane thiol to the corresponding disulfide
was reported using RhH(PPh3)4/1,4-bis(diphenylphosphino)butane (dppb) and pure oxy-
gen at 40 °C after two hours, this transition metal-containing catalyst is expensive, and it
can generate a metal waste through leaching [45]. Moreover, the RhH(PPh3)4/dppb was
not recovered or recycled. Bis-adamantyl disulfide was obtained in 95% yield and selec-
tivity 100% after ten hours in the air atmosphere at room temperature by our highly recy-
clable MeONa/MeOH-30% system. Bis-adamantyl disulfide was characterized by FTIR, 1H
NMR, 13C NMR, and mass spectra (see Supplementary Information, Figures S14–S16).
4. Conclusion
In conclusion, we have demonstrated efficient and simple oxidation of thiols to symmet-
rical disulfides in good to high yields and 100% conversions using sodium methoxide
solution 30 wt.% in methanol under ambient conditions. The current protocol is practi-
cal convenience and highly recyclable. This method can be highly attractive for industrial
applications owing to its merits, such as high to the excellent yield of desired products,
broad substrate scope, cost-effectiveness, and simple purification in the scale-up proce-
dures. Moreover, the current oxidative system could be sustainability recycled into the next
runs, and no by-products and over oxidation were observed. The reaction mechanism of
the oxidative coupling of thiols was investigated in the presence of NaOMe/MeOH∼30%
and TEMPO, and an intermediate adduct of TEMPO-benzyl sulfide was detected by GC-
MS. We are working to develop the continuous-flow procedure of this batch oxidative
coupling thiols to disulfides.
Acknowledgments
This work was supported by a Grant (RK005-2018) from the University of Malaya, Malaysia. The
authors are grateful to staff members in the Analytical and Testing Center of Nanotechnology &
Catalysis Research Center, the University of Malaya for partial support of this work.

12
O. C. LING ET AL.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Funding
This work was supported by a Grant (RK005-2018) from the University of Malaya, Malaysia.
ORCID
Juan Joon Ching http://orcid.org/0000-0002-8253-6049
Nader Ghaffari Khaligh http://orcid.org/0000-0001-9585-9253
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