3,6-Di(pyridin-2-yl)-1,2,4,5-tetrazine (pytz) mediated metal-free mild oxidation of thiols to disulfides in aqueous medium

Article abstract of DOI:10.1039/c6ra01509c

Thiols are efficiently oxidized to disulfides (RSSR) in the presence of 3,6-di(pyridin-2-yl)-1,2,4,5-tetrazine (pytz) in aqueous medium, as well as in the absence of a solvent under mild and metal-free conditions. A broad range of alkyl, aryl and heterocyclic symmetrical disulfides can be easily obtained in almost quantitative yields. The X-ray single crystal structure of 2-aminocyclopent-1-ene-1-carbothioic dithioperoxyanhydride (disulfide obtained from 2-aminocyclopentene-1-dithiocarboxylic acid, ACDA) is reported. The reaction mechanism has been studied thoroughly. It is shown that the reaction proceeds through the formation of an organosulphur radical. Pytz interacts with thiol to accept one electron and produces an organosulphur radical. Pytz ultimately accepts two electrons to form H₂pytz and is capable of oxidizing 2 equivalents of thiols.

Full text of DOI:10.1039/c6ra01509c

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PAPER
3
,6-Di(pyridin-2-yl)-1,2,4,5-tetrazine (pytz)
mediated metal-free mild oxidation of thiols to
Cite this: RSC Adv., 2016, 6, 39356
disulfides in aqueous medium†
Suvendu Samanta, Shounak Ray, Abhisek Brata Ghosh and Papu Biswas*
Thiols are efficiently oxidized to disulfides (RSSR) in the presence of 3,6-di(pyridin-2-yl)-1,2,4,5-tetrazine
(pytz) in aqueous medium, as well as in the absence of a solvent under mild and metal-free conditions. A
broad range of alkyl, aryl and heterocyclic symmetrical disulfides can be easily obtained in almost
quantitative yields. The X-ray single crystal structure of 2-aminocyclopent-1-ene-1-carbothioic
dithioperoxyanhydride (disulfide obtained from 2-aminocyclopentene-1-dithiocarboxylic acid, ACDA) is
reported. The reaction mechanism has been studied thoroughly. It is shown that the reaction proceeds
through the formation of an organosulphur radical. Pytz interacts with thiol to accept one electron and
Received 18th January 2016
Accepted 13th April 2016
DOI: 10.1039/c6ra01509c
produces an organosulphur radical. Pytz ultimately accepts two electrons to form H
of oxidizing 2 equivalents of thiols.
2
pytz and is capable
www.rsc.org/advances
6p–r
telluride. However, most of these reagents are toxic, hazardous
and generate harmful wastes. Numerous homogenous as well as
1
. Introduction
Oxidative coupling of thiols to disuldes is one of the most heterogeneous catalysts have also been reported using molecular
important chemical processes in both chemistry and biology. In oxygen as the primary oxidant which include Fe(BTC) MOF (BTC:
7a
nature, the formation of disulde bonds is essential for stabili- 1,3,5-benzenetricarboxylate), gold nanoparticles deposited on
7
b
7c
zation of biologically active folded conformations of peptides and CeO
, diaryl tellurides under photosensitized conditions, Ag O
2
2
1
7d
proteins. Furthermore, control of several metabolic pathways as nanoparticle incorporated mesoporous silica, Eosin Y under
well as gene expression are related to the enzymatic reduction of visible light irradiation, cobalt(II) phthalocyanines in ionic liq-
disulde bonds. The formation of the disulde bonds is not only uid, selenium ionic liquid, basic and neutral alumina, iron
important for living cells, but it also has applications in the and cobalt complexes, intercalated [Mo O
chemical industry in anti-oxidants, pharmaceuticals, pesticides a Zn(II)–Al(III) layered double hydroxide host and Ni-nano-
and as vulcanization agents. Disuldes are also crucial inter- particles. The oxidative dimerization of thiols in presence of
oxygen was also reported using laccases as catalyst, with Et
and organic compounds such as sulfonyl, sulfenyl. Moreover, DMF under sonication. Catalyst and additive free synthesis of
7e
2
7f
7g
7h–j
7k
7l,m
VI
2
(O
2
n
CC(S)Ph
2
)
]
2 2
in
7
3
7o
4
8a
mediates in the synthesis of sulphur containing heterocycles
N in
3
5
8b
8c
due to relative high stability of the disulde bonds toward disuldes from thiols in bio-based green solvent ethyl lactate
organic reactions, such as oxidation, alkylation and acylation, and in ethanol have also been reported very recently.
compared to the corresponding free thiols, the protection of thiol
Most of these catalytic procedures listed above suffer from
8d
groups can conveniently be achieved as disulde. Consequently, one or more of the following disadvantages, long reaction times,
several effective reagents and methods have been developed for difficult work-up procedure, require higher or lower tempera-
the oxidative coupling of thiols, including stoichiometric ture to obtain satisfactory results, strong basic or acidic media
6
a
6b
6c
oxidizing agents such as KMnO
4
,
MnO
2
,
anhydrous K
3 4
PO ,
and require metal based catalyst, sometime relatively expensive
6d
6e
6f
2
dichromates, VO(acac) ,
copper salt, rhenium–sulfoxide metal. Additionally, a large variety of oxidation products can
complex, rhodium(I) complex, pyridinium chlorochromate,
possibly be formed during thiol oxidation, such as sulfones,
pyridinium uorochromate, N-phenyltriazolinedione, molec- sulfoxides and sulfonic acids along with disulde. It is then of
ular bromine supported on silica gel, trichloroisocyanuric interest to develop a mild, efficient, metal free selective process
acid, 1,3-dibromo-5,5-dimethylhydantoin, and diaryl organo for the transformation of thiols into disuldes avoiding over
oxidation to oxygenated sulfur products.
6g
6h
6i
6j
6k
6
l
6m
6n
s-Tetrazine derivatives are highly electroactive heterocycles
Department of Chemistry, Indian Institute of Engineering Science and Technology,
as they have very high electron affinity which makes them easily
Shibpur, Howrah, 711 103, India. E-mail: papubiswas_besus@yahoo.com
9
reducible and the electron poorest C–N heterocycles. s-Tetra-
1
13
†
Electronic supplementary information (ESI) available: Table S1, H and
C
zine molecules can reversibly be reduced in organic solvents.
Almost all tetrazine molecules accept one electron to form
NMR spectra, CIFs. CCDC 1437412 and 1437413. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c6ra01509c
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Fig. 1 3,6-Di(pyridin-2-yl)-1,2,4,5-tetrazine (pytz).
this method. The reaction time was reduced considerably when
the reaction temperature was slightly increased from room
ꢀ
temperature to 40 C (Table 1, entry 9). However, no improve-
Scheme 1 Reduction of s-tetrazine (Tz) to dihydrotetrazine (H
2
Tz) (a)
ment appeared by further increasing the temperature and lower
reaction temperature than room temperature had a negative
effect on the reaction yield. Notably, decreasing the amount of
pytz to 0.5 equiv. gave the identical result to those of 1.0 equiv.
pytz (Table 1, entry 10). The reaction was also carried out in 9 : 1
via anion radical in organic solvent (b) in water.
a stable anion radical. Tetrazine derivatives can also accept
a second electron though addition of second electron is not
electrochemically reversible in standard conditions. The corre-
sponding dianion radical formed probably highly basic in
character and easily be protonated to produce 1,4-dihydrote-
(v/v) water : ethanol mixture anticipating relatively poor solu-
bility of few aromatic thiols in water to get almost quantitative
yield (Table 1, entry 11). However, no expected oxidation of
thiols occurred without pytz as the oxidant (Table 1, entry 12). In
order to exclude the possibility of air being involved in the
reaction, a control reaction under an inert atmosphere was
performed and no inuence on the yield was observed. So, the
optimum conditions are reported in entries 10 and 11, whereby
water or water : ethanol (9 : 1) solution of the thiophenol (1
9,10
trazine
as shown in Scheme 1a. Furthermore, in aqueous
medium, s-tetrazines accepts two electrons and two protons to
9b
produce 1,4-dihydrotetrazines (Scheme 1b).
Interaction of tetrazine molecules with proton donors such
11a
11b
as dialkyl thiourea
demonstrated previously. Reduction of 3,6-diphenyl-s-tetrazine
PhTz) by 10-methyl-9,10-dihydroacridine (AcrH ) in presence of
and phenol derivative
has been
ꢀ
equiv.) and pytz (0.5 equiv.) was stirred at 40 C. The progress of
(
2
the reaction was monitored by TLC and gas chromatography
and complete conversion was achieved in 12 min. Chromato-
graphic purication of the reaction mixture gave diphenyl
disulde in >98% yield.
scandium ion as promoter has also been reported by Fukuzumi
et al. In presence of Sc , hydride transfer from AcrH to PhTz
2
12
3+
occurs easily at ambient temperature to give 10-methyl-
+
acridinium ion (AcrH ). So, due to this highly electron decient
nature of s-tetrazines, they can be utilized as two electron oxi-
dising agent under suitable conditions. Recently, we have re- 2.2. Scope of the reaction
ported the synthesis of 2-substituted benzimidazoles and
benzothiazoles from different aldehydes and oxidation of
alcohols to carbonyls using 3,6-di(pyridin-2-yl)-1,2,4,5-tetrazine
With the results of our initial feasibility and optimization study
in hand, we turned our attention toward exploring the substrate
(
pytz) molecule as catalyst under visible light irradiation at
a
Table 1 Screening of the optimal reaction conditions
13
ambient temperature. In our continuous effort to expand the
synthetic utility of pytz molecule (Fig. 1), herein we report the
pytz mediated metal-free efficient oxidative coupling of thiols to
disuldes under mild conditions in aqueous medium.
2
. Results and discussion
ꢀ
b
Entry
Solvent
Temp ( C)
Time (min)
Yield
2.1. Optimization of the reaction conditions
c
1
2
3
4
5
6
7
8
H
2
O
RT
20
20
20
20
20
20
20
20
12
12
12
20
>98%
91
Our initial efforts focused on identifying the optimal reaction
conditions for our proposed oxidation and are shown in Table 1.
In order to carry out this synthetic protocol, a model reaction of
thiophenol (1a) in presence of 1 equivalent 3,6-di(pyridin-2-yl)-
CHCl
CH Cl
EtOH
3
RT
RT
RT
RT
RT
RT
RT
40
2
2
94
97
96
89
MeOH
THF
1,2,4,5-tetrazine (pytz) in water at room temperature was per-
CH
3
CN
96
formed and thiophenol (1a) was smoothly and rapidly converted
into diphenyl disulde (2a) in almost quantitative yield within
a very short reaction time (Table 1, entry 1). Besides water,
a relatively lower yield was obtained when the reaction was 11
carried out in other organic solvents such as chloroform, 12
None
>98%
>98%
>98%
>98%
Trace
9
H
H
2
2
O
O
d
10
40
40
40
d
e
H O : EtOH
2
H
2
O
dichloromethane, ethanol, methanol, tetrahydrofuran and
acetonitrile (Table 1, entries 2–7). Interestingly, desired product solvent (10 mL solvents used for all cases), pytz (1 equiv., 2 mmol).
a
Reaction condition (until otherwise specied): 2 mmol thiophenol,
b
c
Isolated ydield aer chromatographic purication.
Room
was also achieved in quantitative yield when reaction was con-
ducted in absence of any solvent (Table 1, entry 8). The
temperature was considered as another possible variable for
temperature. Reaction carried out in presence of 0.5 equiv. (1 mmol)
pytz. Reaction done in absence of pytz.
e
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scope of our oxidation protocol. As shown in Scheme 2, the (Scheme 2, 2g–2k). Benzothioic S-acid (1l) and phenyl-
present protocol was found to be advantageous for the oxidation methanethiol (1m) were smoothly oxidized to give the disuldes
of various aromatic and aliphatic thiols to the corresponding in quantitative yields (Scheme 2, 2l and 2m).
ꢀ
disuldes. All reactions were carried out at 40 C as well as room
The scope of this oxidation methodology was further
temperature. The oxidation of thiophenol and its substituted expanded using aliphatic thiols (Scheme 2, 2n–2q). Our
derivatives to the corresponding disuldes were obtained in protocol demonstrated selective oxidation of the thiol in the
almost quantitative yields (Scheme 2, 2a–2f) with no apparent presence of hydroxy functional group (Scheme 2, 2q). Ethane-
substituent effects. Even, sterically hindered thiophenols thioic S-acid (1r) was also effectively oxidized to the corre-
bearing ortho carboxylic or amido substituents could efficiently sponding disulde (Scheme 2, 2r).
be converted to the corresponding disuldes (Scheme 2, 2e and
Conversion of the biologically important cysteine into the
2f). Heterocyclic thiols, such as 2-mercapto quinoline (1g), 2- cystine was also investigated. Clean and quantitative formation
mercaptopyridine (1h), 2-mercapto pyrimidine (1i), 2-mercap- of cystine in water was observed within a very short reaction
tobenzimidazole (1j) and 2-mercaptobenzothiazole (1k), can time (Scheme 2, 2s). In our study, the reaction time required for
also be oxidized conveniently to the corresponding disuldes above conversion is lower than that of previously reported
protocols (which are typically varies from one to few hours for
7b,c,e
other recently published protocols).
Encouraged by these results, we turned our attention to the
synthesis of tetraalkylthiuram disuldes. Tetraalkylthiuram
disuldes are known for their extensively used in the rubber
7
e
industry as an essential vulcanization reagent. Accordingly, 2-
aminocyclopentene-1-dithiocarboxylic acid (ACDA) was
oxidized to corresponding disulde (Scheme 2, 2t). Oxidation of
diethylcarbamodithioic acid to disulram (Scheme 2, 2u) has
also been carried out successfully. Disulram, which is
commonly sold under the trade name Antabuse, displays bio-
logical properties and known drug for treatment of chronic
7e,14
alcoholism.
In order to test the synthetic utility of this method, 2s was
prepared on a gram scale using water as solvent. The oxidation
of 1s (10 mmol, 1.21 g) with pytz (5 mmol, 1.18 g) under the
optimal reaction conditions afforded 2s in 96% yield (1.15 g).
As was previously observed that the transformation of
compound 1a into disulde 2a also takes place rapidly and
efficiently when carried out in absence of solvent (entry 8, Table
1
). Therefore, various liquid aryl and alkyl thiols were reacted
ꢀ
with 0.5 equivalent pytz at 40 C as well as ambient temperature
in absence of any solvent. Under these reaction conditions, both
aromatic and aliphatic liquid thiols were selectively oxidized to
their corresponding disuldes in near quantitative yields
(Scheme 3).
2.3. Crystal structure
In general, the formation of disulde (S–S) bond from the
oxidation of thiol bond (S–H) could be conrmed from the FT-
IR spectrum. To prove formation of disulde bond unambigu-
ously, single crystal X-ray structure of compound 2t (Scheme 2)
has been determined. Crystallographic data and selected details
of structure determinations are given in Table S1 (ESI†) and
Fig. 2 shows the ORTEP representation of compound 2t. The
thioperoxyanhydride group exhibits an open book structure.
˚
The S–S bond distance is found to be 2.0112(7) A and the
dihedral angle between two S–S–C planes (S2–S3–C7 and S3–S2–
Scheme 2 Oxidation of thiols to disulfides in aqueous medium.
ꢀ
˚
C6) is 87.99 . The two C–S bond distances [1.8069(19) A for S2–
Reaction conditions (until otherwise specified): thiols (2 mmol), pytz (1
˚
ꢀ
C6 and 1.793(2) A for S3–C7] are almost identical, as are the two
mmol), 9 : 1H
2
O/EtOH (10 mL), 40 C or room temperature. Isolated
˚
˚
C]S bond distances [1.671(2) A for S1–C6 and 1.669(2) A for S4–
C7]. Two S–S–C bond angles, S3–S2–C6 and S2–S3–C7, are
yields are shown. Time required for room temperature reaction is
a
shown in parenthesis. Reaction carried out in water only.
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Fig. 3 Cyclic voltammogram (CV) of 3,6-di(pyridin-2-yl)-1,2,4,5-tet-
razine (pytz) in water. Scan rate for cyclic voltammetric measurements
ꢁ
1
were 50 mV s
.
Scheme 3 Oxidation of liquid thiols to disulfides in absence of solvent.
Reaction conditions (until otherwise specified): thiols (2 mmol), pytz (1
ꢀ
mmol), 40 C or room temperature. Isolated yields are shown. Time
required for room temperature reaction is shown in parenthesis.
Scheme 4 Proposed mechanism for 3,6-di(pyridin-2-yl)-1,2,4,5-tet-
razine (pytz) mediated oxidation of thiols to disulfides.
Fig. 2 ORTEP representation of the compound 2t showing 50%
probability displacement ellipsoids. Hydrogen atoms are omitted for
clarity.
monitored by absorption spectroscopy. Pytz molecule exhibits
an absorption maximum at 534 nm in water, whereas H pytz
2
shows an ill-dened shoulder at about 405 nm in visible region.
Accordingly, a water–ethanol (9 : 1 v/v) solution of pytz (1 mmol)
was reacted with thiophenol (2 mmol) and the progress of the
reaction was monitored spectrophotometrically. Fig. 4 shows
that while the absorption curves pass through the isosbestic
points at 473 and 595 nm, the more intense peak at 534 nm
gradually disappears at the expense of evolution of a less
1
07.28(7) and 106.41(7), respectively. Both the double bonded
sulphur atoms (S1 and S4) form strong intramolecular hydrogen
bond with N–H hydrogens. The pertinent bond distances and
angles are shown in Table S2 (ESI†).
2.4. Reaction mechanism
In order to elucidate the mechanism of the pytz mediated
oxidation of the thiols to corresponding disuldes, the elec-
trochemical behaviour of the pytz molecule was studied by
cyclic voltammetry in water. Pytz shows one quasi-reversible
reduction peak at +0.045 V (DEp ¼ 0.12 V) in water (Fig. 3).
Pytz molecule accepts two electrons and two protons in water to
9
d
2
produce H pytz as demonstrated by Cosnier et al. recently. The
result is consistent with the fact that tetrazines are chemically
reduced by a two-protons, two-electrons process into 1,4-dihy-
drotetrazines. Based upon these results, a plausible catalytic
pathway is proposed in Scheme 4. In presence of two equivalent
of thiols, pytz is transformed in to H pytz by accepting two
2
electrons and two proton from two thiol molecules. On the
other hand, thiol (RSH) forms RSc radical. Coupling of two RSc
Fig. 4 Spectral changes of 3,6-di(pyridin-2-yl)-1,2,4,5-tetrazine (pytz,
1
mmol) in presence of thiophenol (2 mmol) in water–ethanol (9 : 1, v/
radical produce RSSR. The formation of H
2
pytz can be v) solution.
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intense ill-dened shoulder at 405 nm. Furthermore, H
2
pytz voltammetric (CV) measurements were carried out with a three-
molecule could easily be recovered from the reaction mixture by electrode assembly comprising glassy carbon working elec-
column chromatography. Recovery of H pytz was further trode, a platinum auxiliary electrode, and an aqueous Ag/AgCl
2
conrmed by its proton NMR and single crystal X-ray structure reference electrode. The concentration of the supporting elec-
(
Fig. S1, ESI†). Another interesting aspect of this reaction is that trolyte potassium chloride (KCl) was 0.1 M, while that of the pytz
recovered H pytz could easily be oxidized to pytz with NaNO was 1 mM. GC analyses were performed on an Agilent Tech-
HCl mixture to reuse as recoverable reagent for oxidation of nologies 6890 N network GC system with an FID detector using
thiols to disuldes. a J & W HP-5 column (30 m, 0.32 mm internal diameter) and n-
2
2
/
To prove that the reaction follows a radical pathway, reaction decane as the internal standard. Thin layer chromatography
was carried out in the presence of a radical scavenger, TEMPO (TLC) was performed on EMD pre-coated plates (silica gel 60
(
2,2,6,6-tetramethylpiperidinoxyl). Addition of TEMPO in a 1 : 1 F254, Art 5715) and visualized by uorescence quenching under
molar proportion (with respect to pytz) to the reaction mixture, UV light. Column chromatography was performed on Silica Gel
only trace yield can be identied by GC. (60–120 Mesh).
4
.3. General experimental procedure for the synthesis of
3. Conclusions
disulde in water ethanol (9 : 1, v/v)
In summary, we have developed a highly efficient metal free
oxidation of thiols to disuldes using 3,6-di(pyridin-2-yl)-
To a solution of thiol (2 mmol) in 10 mL water–ethanol (9 : 1)
was added pytz (1 mmol) and the mixture was stirred at 40 C or
ꢀ
1,2,4,5-tetrazine (pytz) as oxidant. A wide variety of aromatic,
room temperature. The progress of the reaction was monitored
by TLC and gas chromatography. Aer completion of the reac-
tion, solvent was evaporated at reduced pressure and the
product was dissolved in minimum volume of ethyl acetate. The
solvent was concentrated in vacuo, and puried by column
chromatography using silica gel (hexane/ethyl acetate) to get
desired product.
aliphatic and heterocyclic thiophenols could be converted in
excellent yields under mild conditions to the corresponding
disuldes. The present procedure shows the following favour-
able features: (1) the reaction does not require any metal based
oxidant; (2) the reaction proceeds under neutral and mild
conditions (neither acid nor base required) and thus making it
suitable with acid- or base sensitive substrates; (3) the reaction
can be carried out in aqueous medium as well as in the absence
of solvents at room temperature; (4) the present method is
effective for a wide range of substrates bearing various func-
tional groups; (5) our developed protocol should be suitable for
large-scale synthesis of disuldes from thiols. Furthermore,
4.4. General experimental procedure for the synthesis of
disulde in water
To a solution of thiol (2 mmol) in water (10 mL) was added pytz
ꢀ
(
1 mmol) and the mixture was stirred at 40 C or room
temperature. A white precipitation appeared while stirring. The
product was ltered, washed thoroughly with water and dried
overnight.
2
H pytz could be recovered from the reaction mixture, which can
be re-oxidized by known oxidation procedures to pytz for re-
used.
7a
1,2-Diphenyldisulfane (Scheme 2, entry 2a ). Reaction was
done in water–ethanol (9 : 1) following the general method and
the product was puried by column chromatography. White
4
. Experimental
ꢀ
1
4.1. Materials
solid, yield: 0.21 g, 98%. Mp: 60 C. H NMR (400 MHz, CDCl
,
3
d ppm): 7.504 (d, 4H, J ¼ 7.6), 7.306 (t, 3H, J ¼ 7.6, 8.0), 7.243 (t,
H
Solvents were puried according to standard methods prior to
use, while all other substances and reagents used, were
commercially available and used as received. The synthesis of
3H, J ¼ 7.2, 7.6).
7
a
1
,2-Bis(4-methoxyphenyl)disulfane (Scheme 2, entry 2b ).
Reaction was done in water–ethanol (9 : 1) following the general
method and the product was puried by column chromatog-
3
,6-di(pyridin-2-yl)-1,2,4,5-s-tetrazine (pytz) was carried out
9,15
following the method reported earlier.
1
raphy. Off yellow liquid, yield: 0.27 g, 98%. H NMR (400 MHz,
CDCl
3
0
, d
H
ppm): 7.388 (m, 4H), 6.819 (m, 4H), 3.794 (s, 6H).
4
.2. Physical measurements
0
1,1 -(4,4 -Disulfanediylbis(4,1-phenylene))diethanone (Scheme
16
The electronic absorption spectra were measured at room 2, entry 2c ). Reaction was done in water–ethanol (9 : 1)
temperature on an Agilent 8453 diode array spectrophotometer. following the general method and the product was puried by
H NMR spectra were recorded on a Bruker Avance DPX 300, 400 column chromatography. Yellow solid, yield: 0.29 g, 98%. H
1
1
1
3
and 500 MHz NMR spectrometer and C NMR spectra were NMR (400 MHz, CDCl
3
, d
H
ppm): 7.891 (d, 4H, J ¼ 8.0), 7.541 (d,
1
measured using 125 MHz spectrometer. All H data were re- 4H, J ¼ 8.0), 2.544 (s, 6H).
0
7a
ported in parts per million (ppm) relative to tetramethylsilane
2,2 -Disulfanediyldianiline (Scheme 2, entry 2d ). Reaction
(
d
H
¼ 0) in the deuterated solvents. The electrospray ionization was done in water–ethanol (9 : 1) following the general method
mass spectra (ESI-MS) were measured on a Micromass Qtof YA and the product was puried by column chromatography.
2
carried out in water at 25 C under a nitrogen atmosphere CDCl
using mAUTOLABIII/FRA2 electrochemical analyzer. Cyclic 7.152 (dd, 4H, J ¼ 2, 2.4, 3.2), 4.340 (br, 4H).
ꢀ
1
63 mass spectrometer. Electrochemical measurements were Yellow solid, yield: 0.24 g, 98%. Mp: 93 C. H NMR (400 MHz,
ꢀ
3
, d
H
ppm): 6.582 (t, 2H, J ¼ 7.6), 6.706 (d, 2H, J ¼ 8.4),
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0
16
ꢀ
1
2
,2 -Disulfanediyldibenzoic acid (Scheme 2, entry 2e ). solid, yield: 0.24 g, 98%. Mp: 108–110 C. H NMR (400 MHz
Reaction was done in water–ethanol (9 : 1) following the general CDCl
, d
ppm): 7.349–7.240 (m, 10H), 3.612 (s, 4H).
H
3
18
method. White solid precipitated, ltered, washed with water
1,2-Diundecyldisulfane (Scheme 2, entry 2n ). Reaction was
ꢀ
1
and dried. White solid, yield: 0.30 g, 98%. Mp: 289 C. H NMR done in water–ethanol (9 : 1) following the general method and
(
1
400 MHz, DMSO-d
6
, d
H
ppm): 13.538 (s, 2H), 8.030 (dd, 2H, J ¼ the product was puried by column chromatography. Colorless
1
.2, 0.8), 7.618–7.527 (m, 4H), 7.347–7.307 (m, 2H).
oil, yield: 0.09 g, 98%. H NMR (400 MHz, CDCl
3
, d
H
ppm): 2.672
0
0
N,N -(2,2 -Disulfanediylbis(2,1-phenylene))dibenzamide (t, 4H, J ¼ 7.6, 7.2), 1.701–1.583 (m, 8H), 1.390–1.296 (m, 28H),
(
Scheme 2, entry 2f). Reaction was done in water–ethanol (9 : 1) 0.876 (t, 6H, J ¼ 6.8).
0
16
following the general method and the product was puried by
2,2 -Disulfanediyldiacetic acid (Scheme 2, entry 2o ). Reac-
1
column chromatography. Off white solid, yield: 0.45 g, 98%. H tion was done in water following the general method and the
NMR (300 MHz, CDCl , d
ppm): 8.865 (s, 2H), 8.427 (d, 2H, J ¼ product was puried by column chromatography. White solid,
3
H
ꢀ
1
8
(
.4), 7.616 (t, 4H, J ¼ 6.9, 1.5), 7.513–7.344 (m, 2H), 7.431–7.166 yield: 0.17 g, 99%. Mp: 107 C. H NMR (400 MHz, CDCl
, d
3 H
1
3
m, 6H), 7.261–7.189 (m, 2H), 6.872 (dd, 2H, J ¼ 0.9, 6.6, 7.5).
C
ppm): 2.48 (s, 6H).
0
NMR (125 MHz, DMSO-d ) d 167.3, 132.7, 130.7, 129.2, 129.9,
28.5. HRMS (ESI ): m/z ¼ 457.1423, [100%, MH ]; calcd. for Reaction was done in water–ethanol (9 : 1) following the general
2,2 -Disulfanediyldisuccinic acid (Scheme 2, entry 2p).
6
C
+
+
1
C H N O S : 457.1044.
method and yellow solid is precipitated, ltered, washed with
2
6
21 2 2 2
17
1
1
,2-Di(quinolin-2-yl)disulfane (Scheme 2, entry 2g ). Reac- water and dried. Off white solid yield: 0.29 g, 99%. H NMR (400
tion was done in water–ethanol (9 : 1) following the general MHz, CDCl , d ppm): 3.890–3.720 (m, 2H), 2.907–2.777 (m,
method and the product was puried by column chromatog- 2H), 2.695 (dd, 2H, J ¼ 4.4, 16). C NMR (125 MHz, CDCl
3
H
1
3
) d
C
3
1
+
raphy. Yellow solid, yield: 0.31 g, 98%. H NMR (400 MHz, 179.9, 179.2, 53.1, 40.8. HRMS (ESI ): m/z ¼ 299.1034, [100%,
+
CDCl
4
3
, d
H
ppm): 7.930 (m, 4H), 7.750 (d, 2H, J ¼ 8), 7.630 (m, MH ]; calcd for C
8 11 8 2
H O S : 298.9895.
0
18
H), 7.430 (t, 2H, J ¼ 8).
2,2 -Disulfanediyldiethanol (Scheme 2, entry 2q ). Reaction
7
a
1
,2-Di(pyridin-2-yl)disulfane (Scheme 2, entry 2h ). Reaction was done in water–ethanol (9 : 1) following the general method
was done in water–ethanol (9 : 1) following the general method and the product was puried by column chromatography.
1
and the product was puried by column chromatography. Yellow oil. Yield: 0.15 g, 98%. H NMR (300 MHz, CDCl
3
, d
Yellow solid, yield: 0.21 g, 98%. Mp: 57 C. H NMR (300 MHz, ppm): 3.827 (dd, 4H, J ¼ 5.6, 5.4, 6.6), 2.882–2.796 (m, 4H), 1.993
CDCl , d
ppm): 8.401 (d, 2H, J ¼ 3.9), 7.565 (d, 4H, J ¼ 3.6), (t, 2H, J ¼ 7.8, 6.6).
.071 (t, 2H, J ¼ 3.9, 4.2).
Acetic dithioperoxyanhydride (Scheme 2, entry 2r ). Reac-
,2-Di(pyrimidin-2-yl)disulfane (Scheme 2, entry 2i ). Reac- tion was done in water following the general method and the
tion was done in water–ethanol (9 : 1) following the general product was puried by column chromatography. Off white
H
ꢀ
1
3
H
7
a
7
7
a
1
1
3 H
method and the product was puried by column chromatog- solid, yield: 0.14 g, 98%. H NMR (400 MHz, CDCl , d ppm):
ꢀ
1
raphy. Yellow solid. yield: 0.22 g, 98%. Mp: 58 C. H NMR (300 2.480 (s, 6H).
7g
MHz CDCl
(
3
, d
H
ppm): 8.572 (dd, 4H, J ¼ 1.2, 3.3), 7.374–7.324
Cystine (Scheme 2, entry 2s ). Reaction was done in water
following the general method and white solid is precipitated,
m, 2H).
1
,2-Di(1H-benzo[d]imidazol-2-yl)disulfane (Scheme 2, entry ltered, washed with water and dried. White solid, yield: 0.23 g,
18
ꢀ
1
2
j ). Reaction was done in water–ethanol (9 : 1) following the 99% mp: 262 C. H NMR (300 MHz, D O + NaOH, d ppm):
2 H
general method and white solid is precipitated, ltered, washed 3.340 (t, 2H, J ¼ 5.4), 2.873 (dd, 2H, J ¼ 5.1, 14.1), 2.665 (dd, 2H, J
1
with water and dried. White solid, yield: 0.29 g, 98%. H NMR ¼ 7.5, 13.8).
(
(
400 MHz DMSO-d , d ppm): 7.719 (dd, 4H, J ¼ 3.2, 2.8), 7.374
2-Aminocyclopent-1-enecarbothioic dithioperoxyanhydride
(Scheme 2, entry 2t). Reaction was done in water following the
6
H
dd, 4H, J ¼ 3.2, 2.8), 6.637 (br, 2H).
18
1
,2-Di(benzo[d]thiazol-2-yl)disulfane (Scheme 2, entry 2k ). general method and yellow solid is precipitated, ltered,
1
Reaction was done in water–ethanol (9 : 1) following the general washed with water and dried. Yellow solid, yield: 0.31 g, 98%. H
method and yellow solid is precipitated, ltered, washed with NMR (500 MHz, DMSO-d , d ppm): 10.997 (s, 2H), 9.273 (s, 2H),
water and dried. Yellow solid, yield: 0.32 g, 98%. Mp: 186 C. H 2.912 (t, 4H, J ¼ 7.0), 2.680 (t, 4H, J ¼ 7.5), 1.855 (t, 4H, J ¼ 7.5).
6
H
ꢀ
1
1
3
NMR (400 MHz CDCl
H, J ¼ 15.6), 7.510–7.314 (m, 4H).
Benzoic dithioperoxyanhydride (Scheme 2, entry 2l ).
Reaction was done in water–ethanol (9 : 1) following the general
method and the product was puried by column chromatog- water–ethanol (9 : 1) following the general method and the
3
, d
H
ppm): 7.940 (d, 2H, J ¼ 16.0), 7.777 (d,
C NMR (125 MHz, DMSO-d
6
) d
20.6. HRMS (ESI ): m/z ¼ 317.1357, [100%, MH ]; calcd for
: 317.0275.
Antabuse (Scheme 2, entry 2u ). Reaction was done in
C
201.5, 148.2, 117.1, 35.3, 32.3,
+
+
2
7
a
12 17 2 4
C H N S
7e
ꢀ
1
raphy. White solid, yield: 0.26 g, 98%. Mp: 233 C. H NMR (400 product was puried by column chromatography. Off white
ꢀ
1
MHz CDCl
3
, d
H
ppm): 8.123–8.075 (m, 2H), 7.949–7.925 (m, 1H), solid, yield: 0.29 g, 98% mp: 71 C. H NMR (300 MHz, CDCl
, d
3 H
7
.683–7.286 (m, 7H).
ppm): 3.951 (t, 8H, J ¼ 6.0), 1.325 (t, 6H, J ¼ 1.0), 1.235 (d, 6H, J
7a
+
+
1
,2-Dibenzyldisulfane (Scheme 2, entry 2m ). Reaction was ¼ 5.4). HRMS (ESI ): m/z ¼ 297.0983, [100%, MH ]; calcd for
done in water–ethanol (9 : 1) following the general method and
the product was puried by column chromatography. White
10 21 2 4
C H N S : 297.0588.
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RSC Advances
.5. General experimental procedure for the synthesis of
Paper
4
3 (a) R. J. Cremlyn, An Introduction to Organosulfur Chemistry,
Wiley-VCH, New York, 1996; (b) H.-W. Engels, in Ullmann's
Encyclopedia of Industrial Chemistry, ed. B. Elvers, S.
Hawkins, W. Russey and G. Schulz, Cambridge, New York,
disulde without solvent
Pytz (1 mmol) was added to the liquid thiol (2 mmol) and the
ꢀ
mixture was stirred at 40 C or room temperature. The progress
5
th edn, 1993, vol. 23, p. 365; (c) Organic Sulfur Chemistry:
of the reaction was monitored by TLC and gas chromatography.
Aer completion of the reaction, the mixture was dissolved in
minimum volume of ethyl acetate. The solvent was concen-
trated in vacuo, and puried by column chromatography using
silica gel (hexane/ethyl acetate) to get desired product.
Structure and Mechanism, ed. S. Oae, CRS Press, Boca Raton
FL, USA, 1991; (d) G. H. Whitham, Organosulfur chemistry,
Oxford University Press, New York, 1995; (e)
D. L. Holbrook, Handbook of Petroleum Rening Processes,
ed. R. A. Meyers, McGraw-Hill, New York, 1996, ch. 11.3; (f)
E. Kuhle and E. Klauke, Angew. Chem., Int. Ed. Engl., 1977,
6, 735.
J. Srogl, J. Hyvl, A. Reveszb and D. Schroder, Chem. Commun.,
009, 3463.
(a) A. L. Schwan and R. R. Strickler, Org. Prep. Proced. Int.,
4.6. X-ray crystallography
1
Crystals suitable for structure determinations were obtained by
slow evaporation of their dichloromethane–acetonitrile solu-
tions. Single crystals were mounted on glass bers and coated
with peruoropolyether oil. Intensity data were collected at
´
´
´ ´
¨
4
5
2
1
2
999, 31, 579; (b) W. Ge and Y. Wei, Green Chem., 2012, 14,
066; (c) Y. Liu, H. Wang, J. Zhang, J.-P. Wan and C. Wen,
150(2) K on a Bruker-AXS SMART APEX II diffractometer
equipped with a CCD detector using graphite-monochromated
RSC Adv., 2014, 4, 19472.
˚
Mo Ka radiation (l ¼ 0.71073 A). The data were processed
6
(a) A. Shaabani, F. Tavasoli-Rad and D. G. Lee, Synth.
Commun., 2005, 35, 571; (b) E. P. Papadopoulos, A. Jarrar
and C. H. Issidoides, J. Org. Chem., 1966, 31, 615; (c)
A. V. Joshi, S. Bhusare, M. Baidossi, N. Qasheh and
Y. Sasson, Tetrahedron Lett., 2005, 46, 3583; (d) C. Lopez,
A. Conzales Cossio and C. Palomo, Synth. Commun., 1985,
19
with SAINT, and absorption corrections were made with
19
SADABS. The structures were solved by direct and Fourier
2
methods and rened by full-matrix least-squares based on F
20
21
using SHELXTL and SHELX-97 soware packages. The non-
hydrogen atoms were rened anisotropically, while the
hydrogen atoms were placed at geometrically calculated posi-
tions with xed isotropic thermal parameters. Crystallographic
data and selected details of structure determinations are given
in Table 1.
15, 1197; (e) S. Raghavan, A. Rajender, S. C. Joseph and
M. A. Rasheed, Synth. Commun., 2001, 31, 1477; (f) J. Choi
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J. B. Arterburm, M. C. Perry, S. L. Nelson, B. R. Dible and
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2461; (j) M. N. Bhattacharjee, M. K. Chauduri and
H. S. Dasgupta, Synthesis, 1982, 588; (k) A. Christoforou,
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Commun., 2001, 31, 1825; (n) A. Alam, Y. Takaguchi and
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Acknowledgements
S. S. is indebted to CSIR, India for his Senior Research Fellow-
ship [08/003(0083)/2011-EMR-1]. P. B. acknowledges CSIR-India
for the Project (Sanction letter no. 01(2459)/11/EMR-II dated 16/
05/2011). Authors are thankful to Prof. Bibhutosh Adhikary,
Department of Chemistry, IIEST, Shibpur for his helpful
suggestion during preparation of single crystals and determi-
nation of structures. The authors also acknowledge the
Sophisticated Analytical Instruments Facility at North Eastern
1
Hill University (SAIF-NEHU) for H NMR analysis.
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