Melamine-(H2SO4)3/melamine-(HNO3)3 instead of H2SO4/HNO3: A safe system for the fast oxidation of thiols and sulfides under solvent-free conditions

Article abstract of DOI:10.1080/17415993.2015.1074688

Melamine reacted with neat sulfuric acid and fuming nitric acid readily to form two new organic solid acids, namely melamine-(H2SO4)3 and melamine-(HNO3)3. Mixture of them acts as a unique powerful system instead of a hazardous H2SO4/HNO3 system for the direct oxidation of thiols. Also, this system can oxidize the sulfides in the presence of a catalytic amount of KBr and few drops of water. This procedure offers advantages such as very low reaction time, simple work-up, excellent yield and matching with some green chemistry protocols.

Full text of DOI:10.1080/17415993.2015.1074688

Journal of Sulfur Chemistry
ISSN: 1741-5993 (Print) 1741-6000 (Online) Journal homepage: http://www.tandfonline.com/loi/gsrp20
Melamine-(H SO ) /melamine-(HNO ) instead of
2
4 3
3 3
H SO /HNO : a safe system for the fast oxidation
2
4
3
of thiols and sulfides under solvent-free conditions
Gholamabbas Chehardoli & Mohammad Ali Zolfigol
To cite this article: Gholamabbas Chehardoli & Mohammad Ali Zolfigol (2015): Melamine-
(
H SO ) /melamine-(HNO ) instead of H SO /HNO : a safe system for the fast oxidation
2 4 3 3 3 2 4 3
of thiols and sulfides under solvent-free conditions, Journal of Sulfur Chemistry, DOI:
0.1080/17415993.2015.1074688
1
To link to this article: http://dx.doi.org/10.1080/17415993.2015.1074688
Published online: 19 Aug 2015.
Submit your article to this journal
Article views: 6
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at
http://www.tandfonline.com/action/journalInformation?journalCode=gsrp20
Download by: [Universite Laval]
Date: 25 September 2015, At: 07:21

Journal of Sulfur Chemistry, 2015
http://dx.doi.org/10.1080/17415993.2015.1074688
Melamine-(H SO ) /melamine-(HNO ) instead of
2
4 3
3 3
H SO /HNO : a safe system for the fast oxidation of thiols and
2
4
3
sulfides under solvent-free conditions
Gholamabbas Chehardoli and Mohammad Ali Zolfigolb
a∗
a
Department of Medicinal Chemistry, School of Pharmacy, Hamadan University of Medical Sciences,
5178, Hamadan, Iran; Faculty of Chemistry, Bu-Ali Sina University, Hamedan, Iran
b
6
(
Received 28 May 2015; accepted 15 July 2015)
Melamine reacted with neat sulfuric acid and fuming nitric acid readily to form two new organic solid
acids, namely melamine-(H2SO4)3 and melamine-(HNO3)3. Mixture of them acts as a unique powerful
system instead of a hazardous H2SO4/HNO3 system for the direct oxidation of thiols. Also, this system
can oxidize the sulfides in the presence of a catalytic amount of KBr and few drops of water. This proce-
dure offers advantages such as very low reaction time, simple work-up, excellent yield and matching with
some green chemistry protocols.
Keywords: melamine-(H2SO4)3; melamine-(HNO3)3; oxidation; thiols; sulfides
1. Introduction
Solid acid reagents are unique acid catalysts/reagents that have become popular over the last
two decades. They have proved to be useful to chemists in the laboratory and industry due to
the good activation of adsorbed compounds, reaction rate enhancement, selectivity and easier
work-up.[1,2]
Oxidative coupling of thiols to disulfides is of practical importance in synthetic chemistry
and biochemistry. Disulfides have found industrial applications as vulcanizing agents and are
important synthetic intermediates with many applications in organic synthesis.[3] Disulfides are
also essential moieties of biologically active compounds for peptide and protein stabilization.[4]
*
Corresponding author. Email: cheh1002@gmail.com
2015 Taylor & Francis
©

2
G. Chehardoli and M.A. Zolfigol
Scheme 1. Preparation of melamine-(H2SO4)3 (I) and melamine-(HNO3)3 (II).
The most important protocol for the preparation of disulfides is the oxidative coupling of thiols
and varieties of reagents have been reported for this purpose.[5]
Organic sulfoxides are useful synthetic intermediates for the construction of various chem-
ically and biologically active molecules. They often play an important role as therapeutic
agents such as anti-ulcer (proton pump inhibitor), antibacterial, antifungal, anti-atherosclerotic,
anthelmintic, antihypertensive and cardiotonic agents, as well as psychotonics and vasodilators.
The oxidation of sulfides is the most straightforward method for the synthesis of sulfoxides.
There are a lot of reagents available for the oxidation of sulfides, but many of them cause over-
oxidation to sulfones. Therefore, the conditions of the reaction, that is, time, temperature and
the relative amount of oxidants, have to be controlled to avoid forming side products of the
oxidation.[6–8]
In 2010, we used melamine hydrogen peroxide as an efficient reagent for the chemo and
homoselective oxidation of thiols and sulfides.[9]
In continuation of our studies on the application of solid acids,[10,11] we found that melamine
readily reacts with concentrated sulfuric acid and fuming nitric acid to give melamine-(H2SO4)3
(I) and melamine-(HNO3)3 (II). It is interesting to note that these exothermic reactions are fast,
easy and clean not requiring any work-up (Scheme 1).
Herein, we wish to report that the mixture of these solid acids can be used as an oxidation
system for the oxidation of thiol and sulfide derivatives under solvent-free conditions.
2. Results and discussions
A wide range of thiols were subjected to oxidation in the presence of melamine-
H2SO4)3/melamine-(HNO3)3 at room temperature under mild, heterogeneous and solvent-free
(
conditions. All products were obtained with good to excellent yields.
Since the melamine-(H2SO4)3/melamine-(HNO3)3 system could not oxidize the sulfides alone
(
Table 1, Entry 12), we decided to use KBr as the catalyst for the oxidation of various sulfides in
the presence of few drops of water (Scheme 2 and Table 1).
Scheme 2. Fast oxidation of thiols and sulfides under solvent-free condition.

Journal of Sulfur Chemistry
3
Scheme 3. Homoselective monosulfoxidation of thianthrene.
Scheme 4. Proposed mechanism for the oxidation of thiols and sulfides using melamine-(H2SO4)3/melamine-(HNO3)3
system.
An excellent homoselectivity (5) was observed in the oxidation of thianthrene. When thi-
anthrene was subjected to oxidation (Table 1, Entry 16), conversion to mono-sulfoxide was
observed and surprisingly further oxidation to disulfoxidation or monosulfonation did not occur
(Scheme 3).
A plausible mechanism for the oxidation of thiols and sulfides using melamine-(H2SO4)3
/melamine-(HNO3)3 is shown in Scheme 4 based on literature [11–13] and our observations

4
G. Chehardoli and M.A. Zolfigol
Table 1. Fast oxidative coupling of thiols and sulfides using melamine-(H2SO4)3/melamine-(HNO3)3 system under
solvent-free conditions.
Entry
Substratea,b (1 mmol)
Product
Isolated yield (%)
1
2
3
4
5
4-Br-Ph-SH
4-Cl-Ph-SH
4-CH3-Ph-SH
4-Br-Ph-SH
Ph-SH
4-Br-Ph-S)2
4-Cl-Ph-S)2
4-CH3-Ph-S)2
4-Br-Ph-S)2
Ph-S)2
87
85
81
90
92
6
7
77
87
80
8
9
4-OCH3-Ph-SH
PH-CH2-SH
4-OCH3-Ph-S)2
PH-CH2-S)2
71
89
1
0
11
78
1
1
2
3
–c
77
1
1
4
5
89
79
1
6
93
1
1
7
8
78
84
(
Continued).

Journal of Sulfur Chemistry
5
Table 1. Continued
1
9
75
2
0
86
–
2
1
a
Melamine-(H2SO4)3 /melamine-(HNO3)3/Substrate: (0.5:0.5:1 mmol)
For the oxidation of sulfides, a catalytic amount of KBr and few drops of water is needed.
In the absence of KBr.
b
c
in the course of the reaction. We proposed that the reaction mechanism proceeds via in situ gen-
+
+
eration of NO . NO directly can oxidize the thiols, but for the oxidation of sulfides it needs a
+
–
+
catalytic amount of KBr and few drops of water. In the presence of NO , Br becomes Br and
then oxidizes the sulfides to sulfoxide in the presence of water (Scheme 4).
The above-mentioned oxidation reactions using melamine-(H2SO4)3/melamine-(HNO3)3
offer the following advantages: (a) in comparison with concentrated sulfuric acid and fuming
nitric acid, melamine-(H2SO4)3 and melamine-(HNO3)3 are very safe and easy to handle, (b)
production of these solid acids is very easy, (c) the procedure is highly efficient, (d) the yields of
products are high, and (e) work-up of the products is very simple, because these solid acids are
insoluble in organic solvents.
3. Conclusions
In conclusion, melamine-(H2SO4)3 and melamine-(HNO3)3 are two new safe and easy to handle
organic solid acid which are prepared easily. Mixture of them acts as a unique powerful system
for the fast oxidation of thiols and sulfides under mild and heterogeneous conditions. Melamine-
(
HNO3)3 acts as an oxidizing agent and melamine-(H2SO4)3 is a good organic proton source.
+
+
Oxidation reaction proceeded via in situ generation of NO . NO directly can oxidize the thiols
but for the oxidation of sulfides it needs a catalytic amount of KBr and few drops of water. These
procedures offer advantages such as simple work-up, good to excellent yields and matching with
some green chemistry protocols. As shown in the Table 1, Entry 21; this system may react with
some sensitive functional groups (such as amine group) and accomplish the undesired reaction.
4. Experimental
General: Chemicals were purchased from Fluka, Merck and Aldrich chemical companies. The
1
oxidation products were characterized by comparison with their spectral (IR, H-NMR, and
13
C-NMR) and physical data were compared with the authentic samples.

6
G. Chehardoli and M.A. Zolfigol
Preparation of Melamine-(H2SO4)3and Melamine-(HNO3)3
In a 50 mL beaker, 6 g of H2SO4 (98%) or 7.09 g of HNO3 (65%) and 2.52 g of melamine were
stirred for 10 min and a white solid [melamine-(H2SO4)3] or melamine-(HNO3)3 was obtained.
4.1. General procedure for the solvent-free oxidation of thiols
Melamine-(H2SO4)3 [(0.21 g, 0.5 mmol)] and melamine-(HNO3)3 [(0.16 g, 0.5 mmol)] were
mixed with substrate [Table 1, Entries 1–11 (1 mmol)] and ground in a mortar and pestle for
5
min. The mixture was changed to a black paste. The completion of the reaction was monitored
by TLC. Then the product was extracted with CH2Cl2 (2 × 10 mL). Evaporation of the solvent
gave the pure products.
4.2. General procedure for the solvent-free oxidation of sulfides
Melamine-(H2SO4)3 [(0.21 g, 0.5 mmol)] and melamine-(HNO3)3 [(0.16 g, 0.5 mmol)], KBr
[(0.0095 g, 0.1 mmol)] and few drops of water were mixed with the substrate [Table 1, Entries
12–21, (1 mmol)] and ground in a mortar and pestle for 5 min. The mixture was changed to
a black paste. The completion of the reaction was monitored by TLC. Then the product was
extracted with boiling chloroform (2 × 10 mL) and dried with 5 g Na2SO4 and filtered off.
CHCl3 was removed by simple distillation and crude products were obtained with high purity.
Disclosure statement
No potential conflict of interest was reported by the authors.
Funding
The authors gratefully acknowledge partial support for this work by deputy of research, Hamadan University of Medical
Sciences [grant number 940208495], Hamadan, I.R. IRAN.
References
[
[
[
[
[
1] Sheldon RA, Van Bekkum H. Fine chemicals through heterogeneous catalysis. 1st ed. Weinheim: Wiley-VCH;
2
001.
2] Salehi P, Zolfigol MA, Shirini F, Baghbanzadeh M. Silica sulfuric acid and silica chloride as efficient reagents for
organic reactions. Curr Org Chem. 2006;10:2171–2189.
3] Christoforou A, Nicolaou G, Elemes Y. N-Phenyltriazolinedione as an efficient, selective, and reusable reagent for
the oxidation of thiols to disulfides. Tetrahedron Lett. 2006;47:9211–9213.
4] Shah STA, Khan KM, Fecker M, Voelter W. A novel method for the syntheses of symmetrical disulfides using
CsF-Celite as a solid base. Tetrahedron Lett. 2003;44:6789–6791.
5] Ghorbani-Vaghei R, Zolfigol MA, Moshfeghifar N, Koukabi N, Chehardoli, G. Poly(N-bromobenzene-1,3-
ꢀ
ꢀ
disulfonylamide), N,N,N ,N - tetrabromobenzene-1,3-disulfonylamide and DABCO-bromine complex: as novel
reagents for the oxidative coupling of thiols to disulfides. J Chin Chem Soc. 2007;54:791–794.
6] Kaczorowska K, Kolarska Z, Mitka K, Kowalski P. Oxidation of sulfides to sulfoxides. Part 2: oxidation by
hydrogen peroxide. Tetrahedron. 2005;61:8315–8327.
[
[
7] Hasaninejad A, Zolfigol MA, Chehardoli G, Mokhlesi M. Molybdatophosphoric acid as an efficient catalyst for the
catalytic and chemoselective oxidation of sulfides to sulfoxides using urea hydrogen peroxide as a commercially
available oxidant. J Serb Chem Soc. 2010;75:307–316.
[
[
8] Hasaninejad A, Chehardoli G, Zolfigol MA, Abdoli A. Uronium hydrogen sulfate/urea-hydrogen peroxide as a
green and metal-free catalytic system for the efficient, chemo- and homoselective oxidation of sulfides to sulfoxides.
Phosphorus, Sulfur. 2011;186:271–280.
9] Chehardoli G, Zolfigol MA. Melamine hydrogen peroxide (MHP): novel and efficient reagent for the chemo- and
homoselective and transition metal-free oxidation of thiols and sulfides. Phosphorus Sulfur. 2010;185:193–203.

Journal of Sulfur Chemistry
7
[
10] Chehardoli G, Zolfigol MA, Faal-rastegar T, Mallakpour S, Ghorbani-choghamarani A. 1,3,5-Triazine-2,4,6-
triyltrisulfamic acid (TTSA): a new organic solid acid for the nitrosation of secondary amines and oxidation of
urazoles in the presence of NaNO2 under mild and heterogeneous conditions. J Chem Sci. 2009;121:441–447.
[
11] Chehardoli G, Zolfigol MA, Azimi SB, Alizadeh E. Melamine-(H2SO4)3 and PVP-(H2SO4)n as solid acids: syn-
thesis and application in the first mono- and di-nitration of bisphenol A and other phenols. Chin Chem Lett.
2
011;22:827–830.
[12] Zolfigol MA. Silica sulfuric acid/NaNO2 as a novel heterogeneous system for production of thionitrites and
disulfides under mild conditions. Tetrahedron. 2001;57:9509–9511.
[
13] Ghorbani-Choghamarani A, Zolfigol MA, Ayazi-nasrabadi R. Metal-free catalytic oxidation of sulfides to sulfox-
ides with ammonium nitrate, ammonium hydrogen sulfate and ammonium bromide as catalyst. J Braz Chem Soc.
2
010;21:33–36.