Vis/NIR light driven mild and clean synthesis of disulfides in the presence of Cu2(OH)PO4 under aerobic conditions

Article abstract of DOI:10.1039/c5ra05138j

A highly efficient one-pot strategy has been developed for the synthesis of disulfide in the presence of air under the irradiation of Vis/NIR light. Copper hydroxyphosphate (CHP) Cu₂(OH)PO₄, has been used as a Vis/NIR active photocatalyst. Disulfide forms on the surface of the catalyst by a radical mechanism. The protocol is useful for solvent free disulfide synthesis from a variety of thiols. This journal is

Full text of DOI:10.1039/c5ra05138j

View Article Online
View Journal
RSC Advances
This article can be cited before page numbers have been issued, to do this please use: P. N.D. Singh, Sk.
S. Shah and K. S, RSC Adv., 2015, DOI: 10.1039/C5RA05138J.
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. This Accepted Manuscript will be replaced by the edited,
formatted and paginated article as soon as this is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the Ethical guidelines still
apply. In no event shall the Royal Society of Chemistry be held
responsible for any errors or omissions in this Accepted Manuscript
or any consequences arising from the use of any information it
contains.
www.rsc.org/advances

Page 1 of 4
RSC Advances
View Article Online
DOI: 10.1039/C5RA05138J
Journal Name
RSCPublishing
COMMUNICATION
Vis/NIR Light Driven Mild and Clean Synthesis of
Disulfides in the presence of Cu2(OH)PO4 under
Aerobic Condition
Cite this: DOI: 10.1039/x0xx00000x
Received 00th January 2012,
Accepted 00th January 2012
Sk. Sheriff Shah,a S. Karthik,a and N. D. Pradeep Singh*a
DOI: 10.1039/x0xx00000x
www.rsc.org/
lungs.14 Disulfide bonds are also useful in drug delivery
A highly efficient one-pot strategy has been developed for the
synthesis of disulfide in the presence of air under the
irradiation of Vis/NIR light. Copper hydroxyphosphate
(CHP) Cu2(OH)PO4, has been used as a Vis/NIR active
photocatalyst. Disulfide forms on the surface of the catalyst
by a radical mechanism. The protocol is useful for solvent
free disulfide synthesis from variety of thiols.
systems and organic synthesis.15ꢀ17
In general peroxides, molecular oxygen, metal complexes,
halogens, and organic oxidants are used to synthesize disulfides
from their corresponding thiols.18ꢀ23 Dhakshinamoorthy et al.
used Fe(BTC) to perform aerobic oxidation of thiols to
disulfides.24 Copper salts can be used as a catalyst for oxidative
coupling of thiols to disulfides.25,26 However, most of the
procedures require, oxidants, heat, base, solvent or very
expensive reagents. Among the photocatalytic methods, Oba et
al. used diaryltellurides under photosensitized condition to
make disulfides.27 Recently, Li and coꢀworkers applied CdSe
QDs in the photocatalytic oxidation of thiols to disulfides.28
These methods uses UV light or very toxic materials.
Organic molecules hardly interact with the visible light, which
is strongly emitted by the sun. Recently, researchers have used
a variety of visible lightꢀabsorbing transition metal complexes
to catalyze a broad range of reactions,1 amongst them
ruthenium bipyridyl complexes are well explored in visible
light activated reactions. MacMillan’s group has carried out
trifluoromethylation, CꢀH functionalization, coupling of αꢀ
carboxyl sp3 carbons with aryl halides and several other
reactions using Ru(bpy)3 complexes as photocatalyst.2ꢀ5 [2+2]
2+
photocycloadditions has been carried out by Yoon’s group
using visible light photocatalyst.6 Stephenson has shown
photoredox catalysis in flow reactors under the irradiation of
visible light.7
Considering above mentioned points; here we report a copper
based photocatalyst that is used for the coupling of thiols to
their corresponding disulfides. Disulfide bonds play a major
role in determining the structure and stability of protein.8
Interstrand disulfide bond between Cys residues can stabilize
the parallel βꢀsheet secondary structure.9 Cyclic disulfideꢀrich
peptides have exceptional stability and are promising
frameworks for drug design.10 Wang et al. showed hydrophobic
drugs can selfꢀassemble into nanomedicines by inserting
disulfide bond.11 Disulfide bonds are useful to introduce a selfꢀ
Figure 1. Conventional and Cu2(OH)PO4 photocatalyzed
approaches for disulfide synthesis.
In this research, we have developed a clean method for
disulfide synthesis by using copper hydroxyphosphate (CHP)
Cu2(OH)PO4 photocatalyst as shown in figureꢀ1. This protocol
does not require any sacrificial agents or oxidants.
healing ability in
a covalently crossꢀlinked rubber and
Recently, hydroxyphosphate (CHP) has gained much attention
polymeric materials.12,13 6,6´ꢀdithiodinicotinic acid reacts with
cell –SH groups to form mixed disulfide bonds that help to
reduce the dissemination of the tumour from the brain to the
29
mainly because of its magnetic, and catalytic properties.30,31
Xiao et al. used Cu2(OH)PO4 as a catalyst for hydroxylation of
This journal is © The Royal Society of Chemistry 2012
J. Name., 2012, 00, 1-3 | 1

RSC Advances
Page 2 of 4
View Article Online
COMMUNICATION
Journal Name
DOI: 10.1039/C5RA05138J
phenol, benzene and naphthol in presence of H2O2.32 Recently,
Wang et al. showed Cu2(OH)PO4, as a NIR active photocatalyst
for decomposition of 2,4ꢀdichlorophenol.33 Two Cu atom in
CHP has a two different environments, the axially elongated
CuO4(OH)2 octahedra share their corners with axially
6
7
Isopropanol/H2O
no catalyst
3
48
2
83
32
0
0
8
THF/H2O
92, 90
35,[d] 34[e]
compressed
CuO4(OH)
trigonal
bipyramids.
The
[a] Methyl thioglycolate (1.6 mmol) and the catalyst (0.042mmol) were
added in 10 ml of THF/H2O mixture irradiated by a 125 W medium pressure
mercury lamp with wavelength λ >400 nm in presence of air. [b] Based on
the isolated pure product. [c] TON: mmol of substrate converted/ mmol of
catalyst. [d] First reuse. [e] Second reuse.
photogenerated electron–hole pairs at the CuO4(OH) trigonal
bipyramids are separated by transferring the electrons to the
neighboring CuO4(OH)2 octahedra.34 Thus, the well separated
electron–hole pairs are capable of doing the photochemical
reactions. Most of the photocatalysts are active in UVꢀVisible
region and they are quite inactive in NIR region, which
constitutes about 43% of sunlight, so we looked for a
photocatalyst that is active both in visible as well as NIR region
of the solar spectrum and able to work under aerobic condition.
Thus, Cu2(OH)PO4 meets our both the criteria which are useful
to convert thiols to their corresponding disulfide under aerobic
condition in the presence of light without addition of any
oxidants.
The synthesized catalyst was characterized by scanning
electron microscopy (SEM), UV/Vis/NIR absorption and XRD.
The SEM image of Cu2(OH)PO4 shows wellꢀshaped crystals,
which are 5ꢀ6 µm in length and 2ꢀ2.5 µm in width, with a deep
valley on the surface. The UV/Vis/NIR absorption spectrum of
the Cu2(OH)PO4 sample obtained from its diffuse reflectance
spectrum shows a high absorption in the NIR region. All the
diffraction peaks can be indexed to the orthorhombic phase of
Cu2(OH)PO4 (JCPDS No. 720592) with the lattice constants
a=8.08Å , b=8.430Å , and c=5.90Å (Fig. S1, ESI†).
The high selectivity of disulfides was formed in the presence of
water. In case of insolubility in water, THF/water mixture is the
suitable solvent (Table 1, entry 1). Organic solvents provide the
moderate yield of disulfide when compared to water (Table 1, entry
4, 5). Then we extended our studies towards reusability of
Cu2(OH)PO4 for this disulfide formation. It was reused for two
consecutive runs without much loss in its activity (Table 1, entry 8).
The XRD pattern of the fresh and two times used Cu2(OH)PO4
shows clearly that the crystalline nature is preserved during the
photocatalysis (Fig. S2, ESI†).With the optimized conditions at
hand, we explored the disulfide formation by using different thiols.
The yields as well as TON of different thiols presented in table 2
were based on isolated products of disulfides.
Table 2. Substrate scope for the conversion of thiols to corresponding
disulfides.[a]
Cu2(OH)PO4, air
R-S-S-R
R-SH
Water/THF, RT,
λ > 400 nm
Yield [%][b]
TON[c]
36
The proposed disulfide formation was first evaluated and optimized
with methyl thioglycolate (model compound). Typically, the copper
catalyst was dispersed in THF/water and to it methyl thioglycolate
was added. The reaction mixture was allowed to stir for an hour in
the dark and then irradiated (λ > 400 nm or λ = 828 nm) for a
specified time period in the presence of air at room temperature
(Table 1). Only the desired disulfide was detected. In the absence of
light and copper catalyst (table 1, entry 2, 7), the reaction fails to
produce disulfide.
Entry
Substrate
1
2
3
4
5
6
7
8
9
HOCH2CH2SH
CH3OCOCH2SH
HOOCCH2CH2SH
HSCH2CH2CH2SH
C6H5SH
95
98
98
56
92
93
85
90
76
37
37
21
35
Table 1. Various reaction conditions for the coupling of methyl thioglycolate
to form methyl glycolate disulfide [a]
.
4ꢀMeOC6H4SH
4ꢀMeC6H4SH
35
O
O
Cu2(OH)PO4, air
32
SH
S
O
Water/THF, RT,
λ > 400 nm
O
O
S
4ꢀ ClC6H4SH
34
O
Entry conditions
time[h]
yield [%][b]
[TON][c]
4ꢀ F3CC6H4SH
29
[a] Conditions : thiols (1.6mmol) and catalyst (0.042mmol) in 10 ml of water
{in case of insolubility in water, THF/H2O mixture was used (entry 2, 4, 5ꢀ9
)}, exposed to light for 2 hours (λ > 400 nm). [b] Based on isolated pure
product. [c] TON calculated from isolated product.
1
2
3
4
5
THF/H2O
dark
2
28
2
93
0
35
0
Water
92
70
78
35
27
30
Aliphatic thiols were converted in excellent yields (table 2, entry 1ꢀ
4) and the catalyst was quite tolerant to various functional groups
(table 2, entry 6ꢀ9). Thiophenol and its substituted derivatives are
quite tolerant to the photocatalyst as well as they were coupled
DCM
3
Isopropanol
3
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 2012

Page 3 of 4
Journal Name
RSC Advances
View Article Online
COMMUNICATION
DOI: 10.1039/C5RA05138J
oxidatively to their corresponding disulfides in good to excellent
yield (table 2, entry 5ꢀ9). Encouraged by these results, we extended
our investigations towards the NIR photocatalysis. Recently,
upconversion nanoparticles are quite useful for working in NIR
region.35 But upconversion nanoparticles are quite expensive and
required toxic metals. On the other hand, our photocatalyst
Cu2(OH)PO4 exhibited wide absorbance from 650 nm to 1600 nm
and easy to synthesize. Hence we thought to explore the coupling
reactions of thiols to disulfides using NIR light in the presence of
photocatalyst, Cu2(OH)PO4. The coupling reaction of different thiols
under the irradiation of NIR light in the presence of Cu2(OH)PO4 is
shown in tableꢀ3. In presence of NIR light, disulfides were formed
smoothly. Aliphatic as well as aromatic thiols were converted to
their corresponding disulfides in good yields.
Table 4. Substrate scope for the solventꢀfree conversion of thiols to their
corresponding disulfides in the presence of visible light.[a]
Entry
Substrate
Yield[b]
TON[c]
1
2
3
4
5
6
HOCH2CH2SH
CH3OCOCH2SH
4ꢀ ClC6H4SH
53
56
52
53
45
51
20
21
20
20
17
19
4ꢀMeOC6H4SH
SHCH2CH2CH2SH
4ꢀMeC6H4SH
Table 3. Substrate scope for the conversion of thiols to their corresponding
[a] Conditions : thiols (1.6 mmol) and catalyst (0.042mmol) are mixed
properly and exposed to light for 4 hours (λ > 400 nm). [b] Based on isolated
pure product. [c] TON calculated from isolated product.
disulfides in the presence of NIR light.[a]
Entry
Substrate
Yield[%][b]
TON[c]
30
The interaction between the catalyst and the thiols were studied
to understand the reaction mechanism. Cu2(OH)PO4 catalyst
solution was stirred for half an hour in the dark in two different
vials. In one vial we added methyl thioglycolate and another we
added 2ꢀmercaptoethanol, the reaction mixtures were stirred for
another half an hour in the dark to allow maximal complexation
between the catalyst and the thiol, then we added both the
reaction mixtures to a single vial and irradiated with visible
light in the presence of air for about 2 hours, methyl glycolate
disulfide and bis(2ꢀhydroxyethyl) disulfide were formed
exclusively. We have not observed any heterocoupling during
the course of the reactions (Fig. S3, ESI†). Above experiments
indicates that, the disulfides have been formed on the surface of
the catalyst before diffuse to the solution.
1
2
3
4
5
6
HOCH2CH2SH
CH3OCOCH2SH
HOOCCH2CH2SH
4ꢀ ClC6H4SH
80
83
92
70
80
65
32
35
27
4ꢀMeOC6H4SH
4ꢀMeC6H4SH
30
25
[a] Conditions: thiols (1.6 mmol) and catalyst (0.042mmol) in 10 ml of water
{in case of insolubility in water, THF/H2O mixture was used ( entry 2, 4ꢀ6)
}, exposed to NIR light for 12 hours (λ = 828 nm) [for NIR light source we
used an 828 nm diode laser]. [b] Based on isolated pure product. [c]TON
calculated from isolated product.
The involvement of oxygen suggests that free radical species
take part in the reaction. To confirm the presence of radicals in
the
catalysis,
we
have
used
TEMPO,
(2,2,6,6
One of the most famous ancient philosophers in Greece,
Aristotle, said “No Coopora nisi Fluida”, which means “No
reaction occurs in the absence of solvent.”36 During the course
of our investigations, we were interested in solventꢀfree
formation of disulfide, as solventꢀfree system has many
advantages: reduced pollution, low costs, and simplicity in
process and handling. The oxidative coupling of thiols were
carried out by mixing properly the desired thiols with the
catalyst in a vial and exposed to visible light under constant
tetramethylpiperidinꢀ1ꢀyl)oxyl, to establish the presence of Sꢀ
centered radicals.37 In our experiments we have not detected the
reactions between TEMPO with the thiol, the addition of
TEMPO to the catalytic mixture decrease the disulfide yields.
On the basis of our experiments with the radical scavengers, we
conclude that free radicals play an important role in the
catalytic process. By looking into literature29 as well as our
reaction conditions we proposed the mechanism for disulfide
formation, which is shown in schemeꢀ1.
stirring (λ > 400 nm). The results are presented in table 4.
The photogenerated electronꢀhole pairs in Cu2(OH)PO4 are
separated by transferring electrons from CuO4(OH) trigonal
bipyramids (TBP) to the neighboring CuO4(OH)2 octahedra
(OCT), which creates CuIII sites at the CuO4(OH) trigonal
bipyramids (TBP) and CuI sites at the CuO4(OH)2
octahedra(OCT). The surface bound deprotonated thiols were
oxidized at TBP CuIII sites to generate sulfur centered radicals,
which coupled to form corresponding disulfide on the surface
of the catalyst before being diffuse to the solvent and
subsequently CuIII reduces to CuII. On the other hand CuI reacts
Solventꢀfree disulfide conversion gives a good yield of
disulfides, but the yields are less in comparison to solvent rich
systems, this may be due to the uneven exposure of light on the
catalyst. However, grinding of thiols with the catalyst does not
improve the yield. Initially, we thought that the solid thiols may
not react as effectively as their liquid partners in solventꢀfree
condition but the solid thiols were converted as well with a
good yield. Aliphatic and aromatic thiols were also converted to
their corresponding disulfides at a good yield.
This journal is © The Royal Society of Chemistry 2012
J. Name., 2012, 00, 1-3 | 3

RSC Advances
Page 4 of 4
View Article Online
COMMUNICATION
Journal Name
DOI: 10.1039/C5RA05138J
with H+ and O2 in the solution to generate CuII and completes
the full photocatalytic cycle.
10 C. K. Wang, G. J. King, S. E. Northfield, P. G. Ojeda, D. J. Craik,
Angew. Chem. Int. Ed., 2014, 53, 11236.
11 Y. Wang, D. Liu, Q. Zheng, Q. Zhao, H. Zhang, Y. Ma, J. K. Fallon,
Q. Fu, M. T. Haynes, G. Lin, R. Zhang, D. Wang, X. Yang, L. Zhao,
Z. He, F. Liu, Nano Lett., 2014, 14, 5577.
RS
TBP CuIII
OCT CuI
RS
12 J. Canadell, H. Goossens, B. Klumperman, Macromolecules, 2011,
44, 2536.
H
hν
13 J. A. Yoon, J. Kamada, K. Koynov, J. Mohin, R. Nicolay, Y. Zhang,
A. C. Balazs, T. Kowalewski, K. Matyjaszewski, Macromolecules,
2012, 45, 142.
eꢀ
O2
H2O
TBP CuII
RS
RS
TBP CuII
OCT CuI
OCT CuII
14 D. R. Grassetti, Nature, 1970, 228, 282.
RS
SR
15 J. H. Ryu, R. T. Chacko, S. Jiwpanich, S. Bickerton, R. P. Babu, S.
Thayumanavan, J. Am. Chem. Soc., 2010, 132, 17227.
16 N. Taniguchi, J. Org. Chem., 2007, 72, 1241.
17 S. Zhang, P. Qian, M. Zhang, M. Hu, J. Cheng, J. Org. Chem., 2010,
75, 6732.
Dimerization
H+ + OH-
H+ + RS-
RSH
TBP CuII
OCT CuII
RS-SR
H2O
18 J. L. G. Ruano, A. Parra, J. Alemán, Green Chem., 2008, 10, 706.
19 J. K. Vandavasi, W.P. Hub, C.Y. Chen, J. J. Wang, Tetrahedron,
2011, 67, 8895.
Scheme 1. Proposed mechanism for disulfide formation.
20 A. Corma, T. Rodenas, M, J. Sabater, Chem. Sci., 2012, 3, 398.
Conclusions
21 R. Priefer, Y. J. Lee, F. Barrios, J. H. Wosnick, A.M. Lebuis, P. G.
Farrell, D. N. Harpp, J. Am. Chem. Soc., 2002, 124, 5626.
22 J. B. Arterburn, M. C. Perry, S. L. Nelson, B. R. Dible, M. S.
In conclusion, we have developed an attractive and clean
catalytic procedure for the selective oxidative coupling of thiols
to their corresponding disulfides. This method does not require
any sacrificial agents, oxidants or solvent and, proceeds
efficiently under the irradiation of visible as well as NIR light
at room temperature. The disulfides have been formed on the
surface of the catalyst by coupling of thiyl radicals before being
diffuse to solvent. As this method has many advantages, so this
method can be an attractive alternative to existing procedures
for synthesizing disulfides from thiols.
Holguin, J. Am. Chem. Soc., 1997, 119, 9309.
23 A. R. Hajipour, S. E. Mallakpour, H. Adibi, J. Org. Chem., 2002, 67
,
8666.
24 A. Dhakshinamoorthy, M. Alvaro, H. Garcia, Chem. Commun., 2010,
46, 6476.
25 A. Dhakshinamoorthy, S. Navalon, D.Sempere, M. Alvaro, H. Garcia,
Chem. Cat. Chem., 2013, 5, 241.
26 M. S.Beigi, M. Hemmati, Appl. Organometal. Chem., 2013, 27, 734.
27 M. Oba, K. Tanaka, K. Nishiyama, W. Ando, J. Org. Chem., 2011,
76, 4173.
28 X. B. Li, Z.J. Li, Y.J. Gao, Q.Y. Meng, S. Yu, R. G. Weiss, C.H.
Tung, L.Z. Wu, Angew. Chem. Int. Ed., 2014, 53, 2085.
29 A. A. Belik, H.J. Koo, M.H. Whangbo, N. Tsujii,P. Naumov, E. T.
Muromachi, Inorganic Chemistry, 2007, 46, 8684.
Notes and references
a
Department of Chemistry, Indian Institute of Technology Kharagpur,
West Bengal, India, 71302.
30 X. Meng, K. Lin, J. Sun, M. Yang, D. Jiang, F.S. Xiao, Catalysis
Electronic Supplementary Information (ESI) available: [details of material,
Letters, 2001,71
, 3.
general procedure for disulfide synthesis and spectroscopic data.]. See
DOI: 10.1039/c000000x/
31 I. S. Cho, D. W. Kim, S. Lee, C. H. Kwak, S. T. Bae, J. H. Noh, S.
H. Yoon, H. S. Jung, D.W. Kim, K. S. Hong, Adv. Funct. Mater.
2008, 18, 2154.
,
1 D. M. Schultz, T.P. Yoon, Science, 2014, 343, 1239176.
32 F. S. Xiao, J. Sun, X. Meng, R. Yu, H. Yuan, D. Jiang, S. Qiu, R. Xu,
Applied Catalysis A: General, 2001, 207, 267.
2 J. Jin, D. W. C. MacMillan, Angew. Chem. Int. Ed., 2014, 53, 1.
3 Z. Zuo, D. T. Ahneman, L. Chu, J. A. Terrett, A. G. Doyle, D. W. C.
MacMillan, Science, 2014, 345, 437.
33 G. Wang, B. Huang, X. Ma, Z. Wang, X. Qin, X. Zhang, Y. Dai, M.
H. Whangbo, Angew. Chem. Int. Ed., 2013, 52, 4810.
34 Z.Li, Y.Dai, X.Ma, Y.Zhu, B.Huang, Phys. Chem. Chem. Phys.2014,
16, 3267.
4 P. V. Pham, D. A. Nagib, D. W. C. MacMillan, Angew. Chem. Int. Ed.,
2011, 50, 6119.
5 C. K. Prier, D. A. Rankic, D. W. C. MacMillan, Chem. Rev., 2013, 113
,
35 Y.Tang, W.Di, X.Zhai, R.Yang, W.Qin, ACS Catal. 2013,
36 K. Tanaka, F. Toda, Chem. Rev. 2000, 100, 1025.
3, 405.
5322.
6
T. P. Yoon, M. A. Ischay, J. Du, Nature Chem., 2010, 2, 527.
37 K. Y. D. Tan, G. F. Teng, W. Y. Fan, Organometallics, 2011, 30
,
7 J. W. Tucker, Y. Zhang, T. F. Jamison, C. R. J. Stephenson, Angew.
Chem. Int. Ed., 2012, 51, 4144.
4136.
8
9
H. J. Kim, J. H. Yoon, S. Yoon, J. Phys. Chem. A, 2010, 114, 12010.
A. M. Almeida, R. Li, S. H. Gellman, J. Am. Chem. Soc., 2012, 134
,
75.
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 2012