Ethylenebis(N-methylimidazolium) chlorochromate (EBMICC): An efficient and selective reagent for the oxidation of thiols to disulfides

Article abstract of DOI:10.1007/s00706-007-0685-3

Ethylenebis(N-methylimidazolium) chlorochromate was prepared by addition of N-methylimidazole to 1,2-dibromoethane to form the corresponding dibromide salt and subsequent treatment of this salt with CrO₃ in 6N HCl solution. It is a stable yellow-orange solid, which oxidized thiols to the corresponding disulfides at room temperature. Selective oxidation of thiols in the presence of sulfides and hydroxyl groups was also achieved with this reagent.

Full text of DOI:10.1007/s00706-007-0685-3

Monatshefte fu¨r Chemie 138, 871–873 (2007)
DOI 10.1007/s00706-007-0685-3
Printed in The Netherlands
Ethylenebis(N-methylimidazolium) Chlorochromate (EBMICC): An Efficient
and Selective Reagent for the Oxidation of Thiols to Disulfides
ꢀ
Rahman Hosseinzadeh , Mahmood Tajbakhsh, Hamid Khaledi, and Keivan Ghodrati
Department of Chemistry, Mazandaran University, Babolsar, Iran
Received March 19, 2007; accepted (revised) March 30, 2007; published online June 22, 2007
# Springer-Verlag 2007
Summary. Ethylenebis(N-methylimidazolium) chlorochro-
mate was prepared by addition of N-methylimidazole to 1,2-
dibromoethane to form the corresponding dibromide salt and
ucts efficiently, many of them have certain lim-
subsequent treatment of this salt with CrO3 in 6 N HCl solu-
fluoride – Celite – O2 system [3s]. However, while
all these methods can generate the desired prod-
itations, such as instability, the need of an excess
tion. It is a stable yellow-orange solid, which oxidized thiols
amount of the reagent, and poor selectivity to sub-
strate. Therefore the introduction of a clean, mild,
and efficient method to synthesize disulfides is still
needed.
to the corresponding disulfides at room temperature. Selective
oxidation of thiols in the presence of sulfides and hydroxyl
groups was also achieved with this reagent.
Keywords. Ethylenebis(N-methylimidazolium)chlorochro-
mate; Oxidation; Thiols; Sulfides.
Results and Discussion
Introduction
As part of our continuous effort to develop new
efficient oxidizing agents [4], we synthesized eth-
Most methods to prepare disulfides involve oxidation
of thiols. Oxidation of thiols to disulfides without
over-oxidation is an important process in organic
chemistry and biochemistry, which has been exten-
sively investigated over the years. Disulfide bond
formation is important in peptides [1] and bioactive
molecules [2]. This conversion has been accom-
plished using reagents, such as molecular oxygen
[3a], metal ions [3b], Bu3SnOMe=FeCl3 [3c], nitric
oxide [3d], halogens [3e–h], sodium perborate [3i],
the borohydride exchange resin (BER)-transition
metal salt system [3j], a morpholine iodine com-
plex [3k], PCC [3l], 2,6-dicarboxylic pyridinium
chlorochromate [3m], ammonium persulfate [3n],
KMnO4=CuSO4 [3o], H2O2 [3p], solvent free per-
manganate [3q], PVP-N2O4 [3r], and the cesium
ylenebis(N-methylimidazolium)
(EBMICC) and studied its oxidizing properties for
thiols.
chlorochromate
EBMICC is easily and cheaply prepared from
N-methylimidazole and 1,2-dibromoethane followed
by treatment with CrO3 in the presence of HCl in high
yield. It is soluble in DMF, acetone, and acetonitrile,
and insoluble in methylenechloride, n-hexane, and
diethyl ether. It shows a pH value of 2.6 (0.01 N
aqueous solution) that attest to its less acidic character
ꢀ
Corresponding author. E-mail: r.hosseinzadeh@umz.ac.ir

872
R. Hosseinzadeh et al.
in comparison to PCC and N-methylpiperidinium
chlorochromate (the pH of 0.01 N solutions of PCC
and N-methylpiperidinium chlorochromate were
found to be 1.75 and 1.85 [5]). One more advantage
of EBMICC is that it is much less hygroscopic and
can be used after one year of its preparation without
any decomposition, which is not the case with PCC
and similar Cr(VI) reagents. Thiols can be oxidized
to the corresponding disulfides with EBMICC in ace-
tonitrile at room temperature (Scheme 1).
The results presented in the Table 1 indicate that
aromatic and aliphatic thiols were oxidatively cou-
pled very fast in excellent yields. Heteroaromatic
thiols, such as 2-mercaptobenzothiazole and 2-mer-
captobenzimidazole were converted to the corre-
sponding disulfide partially (Table 1, entries 13 and
14), and after longer reaction time with a higher
molar ratio of reagent no more coupling was ob-
served. Interestingly, 2-hydroxyethylthiol gave only
bis(2-hydroxyethyl) disulfide (Table 1, entry 12).
This shows that the reagent selectively oxidizes
the mercapto group in the presence of a hydroxyl
group under the present reaction conditions. More-
over, as shown in Table 1, although EBMICC oxi-
dizes thiols very fast it is inert toward sulfides even
in refluxing acetonitrile (Table 1, entries 15–18).
These results attest to the very high selectivity of
this reagent in the oxidation of thiols in the pres-
ence of sulfides.
In order to show the advantages and drawbacks of
this reagent over some other oxidants we have com-
pared some of our results with those reported in
literature in Table 2. Thus EBMICC oxidizes thio-
phenol very fast at room temperature in excellent
yield while other similar reagents take rather long
reaction times to dimerize thiophenol.
In conclusion, we showed that EBMICC is an effi-
cient, rapid, mild, and inexpensive reagent for the
oxidation of thiols to the corresponding disulfides.
This reagent oxidizes thiols quntitatively in the pres-
ence of sulfides or hydroxyl groups. We consider
that our procedure represents a useful addition to
the array of procedures for the oxidation of thiols.
Scheme 1
Table 1. Coupling of thiols using EBMICC in CH3CN
Entry
Substrate
Product
Yield=%a,b
Ref.c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
Ph-SH
4-Me-Ph-SH
4-Cl-Ph-SH
(Ph-S-)2
(4-Me-Ph-S-)2
(4-Cl-Ph-S-)2
(4-Br-Ph-S-)2
(2-Naphtyl-S-)2
(2-HOOC-Ph-S-)2
(PhCH2-S-)2
(HOOCCH2-S-)2
(1-Pentyl-S-)2
(1-Octyl-S-)2
(Cyclohexyl-S-)2
(HOCH2CH2-S-)2
(2-1,3-Benzodiazole-S-)2
(2-1,3-Benzothiazole-S-)2
–
94
95
92
92
91
91
92
93
90
90
92
91
27
30
[6a]
[6b]
[6c]
[6d]
[6d]
[6e]
[6d]
[6f]
[3o]
[6g]
[6d]
[6h]
[6i]
[6j]
–
4-Br-Ph-SH
2-Naphthyl-SH
2-HOOC-Ph-SH
PhCH2-SH
HOOCCH2-SH
1-Pentyl-SH
1-Octyl-SH
Cyclohexyl-SH
HOCH2CH2-SH
2-1,3-Benzodiazole-SH
2-1,3-Benzothiazole-SH
Ph-S-Me
nBu-S-nBu
PhCH2-S-CH2Ph
CH2CHCH2-S-CH2CHCH2
N.R.d
N.R.d
N.R.d
N.R.d
–
–
–
–
–
–
a
All the reactions for thiols were completed in less than 5 min
Yields refer to isolated products
All products were identified by comparing melting point, IR, and NMR with those of authentic samples reported in literature
Reactions are carried out in refluxing acetonitrile for 2 h
b
c
d

Ethylenebis(N-methylimidazolium) Chlorochromate
873
Table 2. Comparison of EBMICC with some of the other
reagents for the oxidation of thiophenol
References
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Reagent
Conditions
Time=min
(Yield=%)
Ref.
EBMICC
Bu3SnOMe=FeCl3
PCC
(NH4)2S2O8
Caro’s acid=SiO2
Piperazinium
dichromate
CH3CN=rt
CH3CN=rt
CH2Cl2=rt
Solid state
CH3CN=20ꢁC
CHCl3=rt
5 (94)
120 (99)
114 (97)
10 (79)
270 (93)
210 (92)
–
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[3c]
[3l]
[3n]
[7]
[8]
Experimental
Preparation of Ethylenebis(N-methylimidazolium)
Chlorochromate (EBMICC)
A mixture of 4.0 g N-methylimidazole (48.7 mmol) and 1.9cm3
1,2-dibromoethane (22 mmol) was stirred in 40 cm3DMF
at 120ꢁC for 2 h. After cooling the mixture the white solid
formed was filtered off, washed with diethyl ether, and dried
under vacuum. Then it was dissolved in 40 cm3 6 N HCl and
was slowly added to a stirred solution of 4.4 g CrO3 (44 mmol)
in 40cm3 6 N HCl. The reaction mixture was cooled to 0ꢁC
and the yellow-orange solid formed was collected by filtration,
washed with cold H2O, and dried under vacuum to give 7 g
EBMICC (69%). Mp: 99–101ꢁC; 1H NMR (300.13 MHz,
DMSO-d6): ꢀ ¼ 3.75 (s, 2CH3), 4.60 (s, 2CH2), 7.43 (s, 2H-
imi), 7.49 (s, 2H-imi), 8.78 (s, 2H, NCHN) ppm; 13C NMR
(75.48 MHz, DMSO-d6): ꢀ ¼ 36.4 (CH3), 48.9 (CH2), 122.8
(imi-C), 124.4 (imi-C), 137.6 (NCHN) ppm; IR (KBr): 945,
897, 740 cmꢂ1; Anal. calcd for C10H16Cl2Cr2N4O6: C 25.93,
H 3.48, Cr 22.45, found: C 25.97, H 3.54, Cr 22.12.
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c) Hosseinzadeh R, Tajbakhsh M, Vahedi H (2005)
Synlett 2769
[5] Tajbakhsh M, Ghaemi M, Sarabi S, Ghasemzadeh M,
Heravi MM (2000) Monatsh Chem 131: 1213
General Procedure for the Oxidation of Thiols with
EBMICC
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Raghavan S, Rajender A, Joseph SC, Rasheed MA
(2001) Synth Commun 31: 1477; e) Champman H
(1982) Dictionary of Organic Compounds, 5th edn, Vol.
II. New York, p 2376; f) Harrison, DC (1927) Biochem J
21: 1404; g) Sanz R, Aguado R, Pedrosa MR, Arnaiz FJ
(2002) Synthesis 856; h) Meshram HM, Bandyopdhyay
A, Reddy GS, Yadav JS (2000) Synth Commun 30: 701;
i) Khazaei A, Zolfigol MA, Rostami A (2004) Synthesis
2959; j) Firouzabadi H, Mohadjer D, Entezari-Moghadam
M (1988) Bull Chem Soc Jpn 31: 1217
In a round-bottomed flask a solution of 5 mmol thiol in 50cm3
MeCN was treated with 5 mmol EBMICC and the mixture
stirred at room temperature. The progress of the reaction
was monitored by GC or TLC. The solvent was evaporated
in vacuum and 100 cm3 diethyl ether were added to the resi-
due. The supernatant was decanted and the insoluble residue
was washed with diethyl ether (3ꢃ25cm3). The ether extracts
were concentrated under reduced pressure and the crude prod-
uct was purified by distillation or by passing through a short
column of silica gel.
[7] Movassagh B, Lakouraj MM, Ghodrati K (1999) Synth
Commun 29: 3597
Acknowledgements
[8] Movassagh B, Lakouraj MM, Ghodrati K (2002) Indian
J Chem 41B: 1293
We are thankful to the Mazandaran University Research
Council for the partial support of this work.