The development of an environmentally benign sulfide oxidation procedure and its assessment by green chemistry metrics

Article abstract of DOI:10.1039/b815986f

Different Iron (III) species were used as catalysts in sulfoxidation reactions giving excellent yields and high chemoselectivity. Among the iron (III) species, the best one was a solid β-cyclodextrin-FeBr₃ complex. Sulfoxidation takes place wit

Full text of DOI:10.1039/b815986f

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PAPER
www.rsc.org/greenchem | Green Chemistry
The development of an environmentally benign sulfide oxidation procedure
and its assessment by green chemistry metrics
Claudio Omar Kinen, Laura Isabel Rossi* and Rita Hoyos de Rossi*
Received 12th September 2008, Accepted 24th October 2008
First published as an Advance Article on the web 21st November 2008
DOI: 10.1039/b815986f
Different Iron (III) species were used as catalysts in sulfoxidation reactions giving excellent yields
and high chemoselectivity. Among the iron (III) species, the best one was a solid
b-cyclodextrin-FeBr complex. Sulfoxidation takes place with high chemoselectivity in the
3
presence of other groups such as isothiocyanate. Good results were obtained when these reactions
were analyzed using green chemistry metrics.
Introduction
Sulfoxides and other organosulfur compounds are important
1
synthetic intermediates in organic chemistry and are valu-
able in the preparation of biologically and pharmaceutically
2
relevant materials. One of the oxidation reactions found in
pharmaceutical research and production is that of a sulfide to a
3
sulfoxide, which is achieved with a very wide variety of reagents.
When there are several different functional groups present in
4
a molecule as in esomeprazole, a sulfoxide-containing drug,
chemoselective transformations are of great significance. This
has often been difficult in sulfoxidation chemistry because oxida-
5
tions of other functional groups can take place simultaneously.
Furthermore, sulfoxides can undergo overoxidation to sulfones
and therefore it is important that the catalyst has a low reactivity
Scheme 1 Redox mediators in catalytic and selective oxidation of
sulfide.
6
towards the sulfoxides.
reactions and it was shown that several sulfides give sulfoxides
with excellent yields in the presence of a catalytic amount
In view of the general and continuous interest in the oxidation
7
of sulfides and particularly in the development of synthetic
of [Fe(NO
3
)
3
·9H
2
O] as oxidant. Furthermore, these complexes
8
methods for the selective conversion of sulfides into sulfoxides,
can be re-used several times. These reactions were performed
by recycling the solid CD-Fe complexes while the substrate,
iron(III) nitrate and the organic solvent were renewed.
Based on previous studies using catalysts containing FeBr
we are currently involved in the study of reaction methodologies
9
to achieve chemoselective sulfoxidation reactions.
12b
From a study of different combinations of metallic bromides
and/or metallic nitrates it was concluded that combinations of
iron salts formed an excellent catalytic system for the oxidation
3
stabilized by complexation with DMSO or with different
cyclodextrins we considered it of interest to explore the scope
of their use in the chemoselective synthesis of sulfoxides.
Complexes with cyclodextrins are of particular interest because
of the possibility of inducing enantiomeric excess.
10
of sulfides to sulfoxides (Scheme 1). Electrochemical studies
in the presence of iron salts lead one to propose that the
reaction occurs within the coordination sphere of the metal
where the substrate is activated to be oxidized by the bromine
We report here that substrates such as 4-(methylthio)-
phenylisothiocyanate 1; 4-(methylthio)benzoic acid 2; 4-
III
generated from the Fe bromide and the nitric acid. The water
molecules and/or the oxygen present in the system subsequently
oxygenated the substrate. Selectivity fails whenever this metal
(
(
methylthio)acetophenone, 3; 2-(methylthio)benzoic acid 5; 2-
methylthio)bromo benzene 6 and 2-(methylthio) benzaldehyde
11
was absent.
7
are oxidized with very high chemoselectivity and in excellent
12
In a previous paper, we have reported on the synthesis,
characterization and catalytic activity of several cyclodextrins-
yields (Scheme 2). It should be noted that highly oxidizable
functions such as isothiocyanate or aldehyde remain unchanged
under the reaction conditions used.
FeBr (CD-Fe) complexes. We found that cyclodextrin com-
3
plexes have a very good catalytic activity in sulfoxidation
Green chemistry was introduced with the aim to overcome
health and environmental problems at the source by developing
cleaner chemical processes for the chemical industry through
the design of innovative and environmentally benign chem-
Instituto de Investigaciones en Fisicoqu ´ı mica de C o´ rdoba (INFIQC),
Facultad de Ciencias Qu ´ı micas, Departamento de Qu ´ı mica Org a´ nica,
Universidad Nacional de C o´ rdoba, Ciudad Universitaria, 5000, C o´ rdoba,
Argentina. E-mail: lauraros@fcq.unc.edu.ar, ritah@fcq.unc.edu.ar
13–15
ical reactions.
We have analyzed the results in terms of
reported green metric parameters and we demonstrate that the
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because complete elimination of the catalyst from the product
could not be achieved without significant loss of the product
of interest. Entries 2 and 4 in Table 1 show that without the
catalyst the yield is very low or there is no reaction. Decreasing
the amount of the nitrate (compare entries 1 and 3 in Table 1)
did not result in a significant change in the yield of 1a. When
HNO was used the product of interest was obtained with very
3
good yield, Table 1 entry 7. It is remarkable that functions such
as the isothiocyanate group, that can react with nucleophiles
16
and with electrophiles or can isomerize to thiocyanate, survive
under the reaction conditions and remain unchanged. This is
very important because isothiocyanates are useful intermediates
Scheme 2
17
in organic synthesis, and they are also interesting for their
18
methodology proposed for the oxidation of sulfides fulfill several
of the green chemistry principles since the oxidant is oxygen from
the air, the reactions are highly selective producing a minimum
amount of waste and the catalyst is a non-contaminating metal.
biological activities.
The sulfoxidation reaction was also very efficient in the
presence of ortho and para carboxylic acid groups since 4-
(methylthio)benzoic acid 2 and 2-(methylthio)benzoic acid 5
gave the expected products. The results are summarized in
Table 2.
Excellent yield of 4-(methylsulfinyl)benzoic acid 2a was
obtained in most of the used conditions, Table 2 entries 1, 3
and 5. Nevertheless, in the absence of a catalyst, Table 2 entries
2 and 4, the sulfoxidation did not take place. The ortho derivative
is significantly more reactive than the para derivative under all
conditions and it is even reactive in the absence of the catalyst
(compare runs 2 with 7 and 4 with 9 in Table 2).
Results and discussion
Compound 1, 4-(methylthio)phenylisothiocyanate, was oxidized
with high yield and chemoselectivity using FeBr free or in
the form of complexes. As can be observed in Table 1, we
have obtained 4-(methylsulfinyl) phenylisothiocyanate 1a with
3
excellent yields using FeBr , the b-CD complex or the DMSO
3
complex. Although all the reactions gave almost quantitative
yield, the amount of isolated product is not the same because
the work-up is in some cases more complicated than in others.
No efforts were done to optimize the isolation procedures.
The best reaction conditions are those involving the b-CD
Under the same reaction conditions used for 1 and 2, 4-
(methylthio)acetophenone 3 was oxidized on the sulfur almost
quantitatively, although somewhat more slowly, compare for
instance run 1 in Table 3 with run 1 in Table 2.
complex as catalyst and Fe(NO
oxidation promoter, Table 1 entry 3, because the catalyst is easily
eliminated from the system by filtration and can be reused.
3
)
3
in catalytic amount as
In order to determine the importance of the group position,
we carried out the reaction with 2-(methylthio)phenyl isothio-
cyanate 4 (Table 1, entries 9–13), with 2-(methylthio) benzoic
acid 5 (Table 2, entries 7–10), with 2-(methylthio) bromobenzene
6 (Table 4, entries 1–3) and with 2-(methylthio)benzaldehyde 7
(Table 4, entries 4–6).
The FeBr and its DMSO complex are completely soluble in
3
the reaction system and difficult to separate from the reaction
products without an important loss of the product of interest
and consequently a decrease in the isolated product. For this
For substituents –COOH, Br and –COH the reactivity of the
o-substituted compounds is significantly higher than that of the
reason, although FeBr
3
appears as a more efficient catalyst
12b,19
since less reaction time is required, its use is not recommended
p-substituted derivatives.
Contrasting with that, in the case
a
Table 1 Oxidation reactions of x-(methylthio)phenylisothiocyanate to x-(methylsulfinyl)phenylisothiocyanate
b
c
d
e
Entry
x-
Oxidant (%)
Catalyst
Time
% Substrate
% Yield
1
2
3
4
5
6
7
8
9
0
1
2
3
4-
4-
4-
4-
4-
4-
4-
4-
2-
2-
2-
2-
2-
Fe(NO
Fe(NO
Fe(NO
Fe(NO
Fe(NO
Fe(NO
3
3
3
3
3
3
)
)
)
)
)
)
3
3
3
3
3
3
(10)
(10)
(5)
(5)
(10)
(10)
b-CD-Fe
—
b-CD-Fe
—
3.0
3.6
6.0
6.0
2.5
5.5
2.5
5.5
20.0
20.0
20.0
8.5
0
75
0
87
0
0
0
93f
25
f
96f
f
13
FeBr
DMSO-Fe
3
90
95
HNO
HNO
3
(13)
(13)
)
)
(13)
(13)
)
FeBr
—
3
100f
f
3
50
50
38
g
Fe(NO
Fe(NO
3
3
(10)
(10)
b-CD-Fe
—
62
100
100
100
70
h
1
1
1
1
3
3
N.R.
HNO
HNO
3
FeBr
—
3
N.R.
N.R.
3
g
Fe(NO
3
3
(10)
DMSO-Fe
20.0
30
a
Solvent acetonitrile, oxidant Fe(NO
3
)
3
·9H
2
O or nitric acid, ratio substrate : catalyst 1.00 : 0.05 mol, at room temperature with stirring, under air
c d
b
but in a closed system. Catalysts: b-CD-Fe = complex (b-cyclodextrin)FeBr
3
; DMSO-Fe = (FeBr
3 2 3
) (DMSO) . Reaction time in hours. Percent
e
f
substrate recovered. Percent yield of oxidation products after isolation and purification. Percent yield of product and/or substrate determined by
1
g
h
H NMR analysis of the raw reaction products. Unidentified products, percent conversion of substrate. N.R. = no reaction.
2
24 | Green Chem., 2009, 11, 223–228
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a
Table 2 Oxidation reaction of x-(methylthio)benzoic acid to x-(methylsulfinyl)benzoic acid
b
c
d
e
Entry
x-
Oxidant (%)
Catalyst
Time
% Substrate
% Yield
1
2
3
4
5
6
7
8
9
4-
4-
4-
4-
4-
2-
2-
2-
2-
2-
Fe(NO
Fe(NO
3
3
)
)
3
3
(10)
(10)
b-CD-Fe
4.0
19.0
2.5
22.0
2.0
2.0
20.0
1.0
0
100
0
100
0
0
30
0
100 f
N.R.
100
N.R.
95
100
70
—
HNO
HNO
3
(13)
(13)
)
)
)
(13)
(13)
)
FeBr
—
3
3
Fe(NO
Fe(NO
Fe(NO
3
3
3
3
3
3
(10)
(10)
(10)
DMSO-Fe
b-CD-Fe
–
HNO
HNO
3
FeBr
—
3
100g
3
20.0
1.5
66
0
44
1
0
Fe(NO
3
3
(10)
DMSO-Fe
93
a
Solvent acetonitrile, oxidant Fe(NO
3
)
3
·9H
2
O, ratio substrate : catalyst 1.00 : 0.05 mol, at room temperature with stirring, under air but in a
c d
b
closed system. Catalysts: b-CD-Fe = complex (b-cyclodextrin)FeBr
3
; DMSO-Fe = (FeBr
3 2 3
) (DMSO) . g Reaction time in hours. Percent substrate
e
f
recovered. Percent yield of oxidation products after isolation and purification. N.R. = no reaction. Percent yield of product and/or substrate
1
determined by H NMR analysis of the raw reaction products.
a
Table 3 Oxidation reaction of 4-(methylthio)acetophenone to 4-(methylsulfinyl)acetophenone
b
c
d
e
Entry
Oxidant (%)
Catalyst
Time
% Substrate
% Yield
1
2
3
4
5
Fe(NO
Fe(NO
3
3
)
)
3
3
(10)
(10)
b-CD-Fe
6.0
22.5
2.5
22.5
3.0
0
92
0
78
100f
8
f
—
HNO
HNO
3
(13)
(13)
)
FeBr
—
3
100f
f
3
22
Fe(NO
3
3
(10)
DMSO-Fe
0
95
a
Solvent acetonitrile, oxidant Fe(NO
3
)
3
·9H
2
O, ratio substrate : catalyst 1.00 : 0.05 mol, at room temperature with stirring, under air but in a
b
c
d
closed system. Catalysts: b-CD-Fe = complex (b-cyclodextrin)FeBr
3
; DMSO-Fe = (FeBr
3
)
2
(DMSO)
3
.
Reaction time in hours. Percent substrate
e
f
1
recovered. Percent yield of oxidation products after isolation and purification. Percent yield of product and/or substrate determined by H NMR
analysis of the raw reaction products.
a
Table 4 Oxidation reaction of 2-(methylthio)bromobenzene 6 and 2-(methylthio)benzaldehyde 7
b
c
d
e
Entry
Substrate
Oxidant (%)
Catalyst
Time
% Substrate
% Yield
1
2
3
4
5
6
6
6
6
7
7
7
Fe(NO
Fe(NO
3
3
)
)
3
3
(10)
(10)
b-CD-Fe
3.0
3.0
2.8
3.0
3.0
6.7
0
100
0
0
95
92 g
f
—
N.R.
h
HNO
3
(13)
)
)
FeBr
3
100
Fe(NO
Fe(NO
3
3
(10)
(10)
b-CD-Fe
—
100f
f
3
3
5
100
h
HNO
3
(13)
FeBr
3
0
a
Solvent acetonitrile, oxidant Fe(NO
3
)
3
·9H
2
O, ratio substrate : catalyst 1.00 : 0.05 mol, at room temperature with stirring, under air but in a closed
b
c
d
e
system. Catalysts: b-CD-Fe = complex (b-cyclodextrin)FeBr
3
. Reaction time in hours. Percent substrate recovered. Percent yield of oxidation
f
1
products after isolation and purification. Percent yield of product and/or substrate determined by H NMR analysis of the raw reaction products.
g
h
N.R. = no reaction. Without purification.
of the isothiocyanate derivatives the p-substituted compound
reacts very well but the o-substituted derivatives do not react at
all or give other products (see Table 1, runs 9–13). Mechanistic
studies are currently being done in our laboratory in order to
understand the substituent effect.
was obtained. We think that the reason for this is that the amino
group reacts faster than the sulfur group with nitrogen oxides
formed in the reaction medium and consumes irreversibly those
species which are needed to initiate the oxidation process. These
reactions are currently under investigation in our laboratory and
will be a matter for future publications.
In previous work, we reported that substrates such as
4
(
-(methylthio) benzaldehyde; 4-(methylthio)benzylalcohol; 2-
methylthio)benzothiazole; 2-(benzylthio)benzothiazole were
oxidized with very high chemoselectivity and in excellent
The reaction conditions used in the present work meets several
green chemistry principles since a catalytic amount of oxidant
20
is used, in fact the real oxidant is oxygen, the catalyst is a non-
contaminating metal and the reactions are carried out at room
temperature under normal pressure.
19
yields. It should be noted that highly oxidizable functions
such as benzaldehyde, benzylic alcohol, benzylic methylene and
heterocyclic sulfur or nitrogen atoms remained unchanged under
the reaction conditions.
Compounds 4-(methylthio)aniline 8, 2-(methylthio)aniline 9
and 4-(methylthio)phenylisocyanate 10 were not completely
consumed after 50 hours, and a complex mixture of products
21
The definitions of green chemistry related terms, as well as
22
the green metrics are frequently revised in modern literature. It
is generally agreed that metrics must be clearly defined, simple,
measurable and objective rather than subjective. Some of the
most commonly used metric are the environmental factor based
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on molecular weight (Emw), atom economy (AE), mass intensity
temperature, the reaction was also done without any solvent
and the yield obtained was excellent. The MI value was 1.2 in
this case, thus very close to the ideal value. The reason why
we used more solvent in all the other reactions is because that
was needed to take samples and determine the time needed for
completion.
(
MI), reaction mass efficiency (RME), the environmental impact
23
factor based on mass (E ) and the carbon efficiency (CE).
m
The reactions reported here meet several of the green chemistry
principles with very satisfactory green metrics.
Atom economy (AE), mass intensity (MI), reaction mass
efficiency (RME) and the carbon efficiency (CE) have been
proposed in the last decade as a measure of environmental sus-
22b
Experimental
tainability in terms of minimisation theoretical waste amount.
24
AE was introduced by Trost and is a theoretical measure of the
chemical and environmental efficiency of a chemical reaction
based on stoichiometric equation; it does not consider solvents,
possible excess of reagents, formation of unwanted products, etc.
MI takes into account the yield, stoichiometry, the solvent and
the reactant used in the reaction. RME is a more sophisticated
measure of greenness which allows for the effect of yield and
the excess or catalytic amount of reactants used, but it does not
account for solvent use. Finally, CE is the percentage of carbon
in the reactants that remain in the final product, this parameter is
not very important here because the oxidation does not involve
carbon, it mainly reflects the yield of the reactions. In an ideal
situation % AE ª 100, MI ª 1, % RME ª 100, % CE ª 100.
In Table 5 the green metrics calculated for our reaction mix-
tures are summarized. The results show that our reactions have
an excellent CE; which in this case is equal to the yield because
all carbon atoms of the reactant are present in the product.
In the same direction, the high yields, the catalytic amounts
of oxidant and the use of catalyst produce very good values of
RME. On the other hand, the MI values obtained are acceptable
since not much solvent is used. It is important to remark that
this reaction can be carried out with much less solvent than the
amount used which results in a significant improvement of the
MI parameter. In fact, we carry out one reaction using substrate
1
The H NMR spectra were carried out in a 400 MHz Bruker
Avance II spectrometer. The chromatograms were carried out in
a GC-14B Shimadzu chromatograph and mass spectra in MS-
GC CQ5050 Shimadzu GC-Mass Spectrometer.
The solvents used, Fe(NO
alytical grade commercially available samples and used as
received. Cyclodextrin-FeBr and DMSO-FeBr complexes were
prepared as described in previous papers.
methylthio)phenylisothiocyanate 1; 4-(methylthio)benzoic acid
; 4-(methylthio)acetophenone, 3; 2-(methylthio)phenyl isothio-
3
)
3
·9H
2
O and FeBr , were an-
3
3
3
12a,25
Substrates 4-
(
2
cyanate 4; 2-(methylthio)benzoic acid 5; 2-(methylthio) bro-
mobenzene 6; 2-(methylthio)benzaldehyde 7; 4-(methylthio)-
aniline 8, 2-(methylthio)aniline 9 and 4-(methylthio)phe-
nylisocyanate 10 were obtained from commercial suppliers. The
1
products were characterized by the H NMR spectra and/or by
MS-GC.
General procedure
All reactions were carried out in a closed reaction tube, 165 mL,
with magnetic stirring at room temperature. The volume of
the reaction vessel is important because it must have enough
oxygen for the oxidation reaction. The molar ratios substrate :
catalyst : nitrate were 1.00 : 0.05 : 0.10 or 0.13. In a typical
procedure, the substrate (1 mmol) was dissolved in acetonitrile
(2.6 mL) and the iron complex (0.05 mmol) and the iron (III)
nitrate (0.10 mmol) or nitric acid (0.13 mmol) were added.
4
-(methylthio)benzaldehyde and only 0.6 mL of solvent and the
product was obtained with excellent yield and the MI value
was 4.04. Since 4-(methylthio)benzaldehyde is liquid at room
a
Table 5 Green metrics calculated for the sulfoxidation reactions
b
Substrate
% Yield (Table;Entry)
MI
% RME
% CE
% AE
c
c
c
1
1
1
1
1
2
2
2
3
3
3
5
5
5
6
6
7
7
93 (1;1)
96 (1;3)
90 (1;5)
12.46
11.94
12.93
12.39
11.50
12.31
12.24
13.28
12.43
12.37
13.33
12.31
12.24
13.48
11.42
10.45
13.39
13.31
77.20
87.08
70.34
67.17
87.81
82.01
87.05
65.91
81.85
86.93
65.59
82.01
87.05
64.42
77.69
88.88
80.63
85.99
93
96
90
92.50
92.50
92.50
92.50
92.50
92.01
92.01
92.01
91.93
91.93
91.93
92.01
92.01
92.01
93.19
93.19
91.31
91.31
c
95 (1;6)
95
100 (1;7)
100 (2;1)
100 (2;3)
95 (2;5)
100 (3;1)
100 (3;3)
95 (3;5)
100 (2;6)
100 (2;8)
93 (2;10)
92 (4;1)
100 (4;3)
100 (4;4)
100 (4;6)
100
100
100
95
100
100
95
100
100
93
c
c
c
c
c
c
c
c
c
92
100
100
100
c
a
b
MI: mass intensity.% RME: percentage reaction mass efficiency. % CE: percentage carbon efficiency. % AE: percentage atom economy. The solvent
c
used in the purification step was not considered in the calculations. The amount of catalyst was not used in the calculations because it is recoverable
by filtration and it can be reused.
12b
2
26 | Green Chem., 2009, 11, 223–228
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The reactions were analyzed from time to time by thin layer
chromatography or by GC in order to determine the time of
the total consumption of the substrate. Under the same reaction
conditions, the total reaction time depended on the sulfide. The
reactions with cyclodextrin complexes are heterogeneous since
complexes are solid, not soluble in this system. Once the reaction
was over, diverse isolation and/or purification methods were
2-(Methylsulfinyl)bromobenzene 6a.
d
H
(400 MHz, CDCl ,
3
27
Me Si) 2.83 (3H, s, -CH ) and 7.37–7.98 (4H, m, ArH).
4
3
2
-(Methylthio)benzaldehyde 7. (400 MHz, CDCl
.45 (3H, s, -CH ), 7.25–7.77 (4H, m, ArH) and 10.91 (1H, s,
CHO).
2-(Methylsulfinyl)benzaldehyde 7a.
Me Si) 2.75 (3H, s, -CH ), 7.67–8.26 (4H, m, ArH) and 9.98
d
H
3
, Me Si)
4
2
3
d
H
(400 MHz, CDCl ,
3
used. In all cases 10 mL of CH
filtered and the solid washed several times with CH
organic layer was separated and washed with distilled water (3 ¥
0 mL) to remove any inorganic residue. Then, it was dried with
MgSO and the solvent was evaporated and recovered for further
2
Cl
2
were added, the solution was
4
3
+
2
Cl . The
(1H, s, CHO). m/z 168(M , 28%), 153(28), 152(100), 123(18),
2
109(10).
1
4
-(Methylthio)aniline 8.
d
H
(400 MHz, CDCl
3
, Me
4
Si) 2.43
Si) 2.39
4
(
(
3H, s, -CH ) and 6.63–7.21 (4H, m, ArH).
3
use. The residue was analysed by different chromatographic
and spectroscopic methods. In some cases after filtration, the
products were purified by column chromatography on silica
gel 60 (70–230 mesh ASTM). All reactions were conducted in
duplicate. In no case were sulfones detected.
2
-(Methylthio)aniline 9. (400 MHz, CDCl
3H, s, -CH ) and 6.74–7.45 (4H, m, ArH).
-(Methylthio)phenylisocyanate 10.
Si) 2.48 (3H, s, -CH ) and 7.02–7.22 (4H, m, ArH).
d
H
3
, Me
4
3
4
d
H
(400 MHz, CDCl ,
3
Me
4
3
Reactants and products characterization
Green metric calculations
4
-(Methylthio)phenylisothiocyanate 1.
d
H
(400 MHz, CDCl
3
,
The green metrics were calculated using the procedures reported
in the literature. They are defined as follows:
Me
4
Si) 2.48 (3H, s, -CH ) and 7.10–7.22 (4H, m, ArH). m/z
3
22b
+
1
5
81(M , 100%), 166(91), 135(12), 122(20), 108(35), 90(8), 69(8),
0(10).
Mass intensity (MI)
4
-(Methylsulfinyl)phenylisothiocyanate 1a.
CDCl , Me Si) 2.73 (3H, s, -CH ) and 7.35–7.67 (4H, m, ArH).
m/z 197(M , 23%), 182(100), 166(51), 150(22), 134(15), 108(21),
d
H
(400 MHz,
Total mass used in a process or process step (g)
=
3
4
+
3
Mass of product (g)
9
0(8), 69(6), 50(12).
-(Methylthio)benzoic acid 2.
.54 (3H, s, -CH ) and 7.31–7.94 (4H, m, ArH). m/z 168(M ,
00%), 151(43), 135(7), 123(12), 108(5), 105(5), 69(11), 45(20).
-(Methylsulfinyl)benzoic acid 2a. (400 MHz, CDCl
Si) 2.84 (3H, s, -CH ) and 7.76–8.20 (4H, m, Ar). m/z
mass of products
4
d
H
(400 MHz, CDCl
3
, Me
4
Si)
Â
+
Reaction mass efficiency (RME) =
¥100
2
1
3
mass of reactants
Â
4
d
H
3
,
Carbon efficiency (CE)
Me
4
3
+
o
o
1
1
84(M , 2%), 168(27), 153(21), 152(100), 151(82), 123(20),
08(11), 97(12), 77(19), 65(12), 45(28).
N of moles of product x N of carbons in product
=
¥100
o
o
(
N of moles of reactant x N of carbons in reactant)
Â
4-(Methylthio)acetophenone 3.
d
H
(400 MHz, CDCl
3
, Me Si)
4
2
.52 (3H, s, -CH ), 2.57 (3H, s, -CH
3
3
) and 7.25–7.88(4H; m;
+
ArH). m/z 166(M , 77%), 151(100), 123(31), 108(17), 79(21),
5(37).
molecular weight of product
Atom economy (AE) =
¥100
4
molecular weight of reactant
Â
4
-(Methylsulfinyl)acetophenone 3a.
d
H
(400 MHz, CDCl
3
,
Me
4
Si) 2.61 (3H, s, -CH ), 2.73 (3H, s, -CH
3
3
) and 7.48–
An example of a typical calculation follows
26
+
8
1
9
.06 (4H; m; ArH). m/z 182(M , 59%), 167(100), 162(42),
53(10), 152(81), 151(80), 139(20), 123(19), 121(15), 108(12),
1(7), 76(18), 63(13), 45(24), 43(31).
4-(Methylthio)phenylisothiocyanate (0.181 g, 1 mmol, FW
181.28) reacts with the iron (III) nitrate nonahydrate (0.040 g,
0.10 mmol, FW 404.00) and molecular oxygen (0.016 g,
0
0
4
.5 mmol, FW 32.0) in the presence of iron complex (0.068 g,
.05 mmol, FW 1369.17) in acetonitrile (2.6 mL, 2.044 g) to give
-(methylsulfinyl)phenylisothiocyanate (FW 197.28) isolated in
2
-(Methylthio)phenylisothiocyanate 4.
d
H
(400 MHz, CDCl ,
3
Me
4
Si) 2.51 (3H, s, -CH ) and 7.12–7.30 (4H, m, ArH).
3
2
-(Methylthio)benzoic acid 5. (400 MHz, CDCl , Me
d
H
3
4
Si)
93% yield (0.93 mmol, 0.183 g). The amount of catalyst was not
used in the calculations because it is recoverable by filtration
and it can be reused. For AE, reagents in catalytic quantities
and catalysts are not considered in the calculation.
+
2
1
9
.50 (3H, s, -CH ) and 7.20–8.16 (4H, m, ArH). m/z 168(M ,
00%), 153(47), 135(20), 122(60), 121(53), 108(13), 105(23),
7(11), 69(18), 45(40).
3
Mass intensity = (0.181 + 0.040 + 2.044 + 0.016)/0.183 =
2
-(Methylsulfinyl)benzoic acid 5a.
Si) 2.90 (3H, s, -CH ) and 7.59–8.10 (4H, m, ArH). m/z
66(27%), 136(100), 121(1), 108(42), 92(3), 82(9), 69(15), 50(6).
d
H
(400 MHz, CDCl
3
,
1
2.46 g/g
Me
4
3
Reaction mass efficiency = [0.183/(0.181 + 0.040+ 0.016)] ¥
1
1
00 = 77.2%
2-(Methylthio)bromobenzene 6. (400 MHz, CDCl
d
H
3
,
Atom Economy = (197.28/181.28 + 32.00) ¥ 100 = 92.5%
Carbon efficiency = (0.93 ¥ 8)/(1 ¥ 8) = 93%
Me
4
Si) 2.43 (3H, s, -CH ) and 6.81–7.69 (4H; m; ArH).
3
This journal is © The Royal Society of Chemistry 2009
Green Chem., 2009, 11, 223–228 | 227

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Conclusions
Pandit, Ultrasonics Sonochem., 2007, 14, 135; (c) Y. Yuan and Y. Bian,
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It can be concluded that FeBr and its complexes with cy-
3
clodextrin or DMSO are excellent catalysts for chemoselective
sulfoxidation reactions. The cyclodextrin complex is the best
because it not only gave very good yields of products but it was
easily handled under normal laboratory conditions. It could be
easily isolated after the reaction and eventually re-used, this
4
9, 1441; (f) K. Matsumoto, T. Yamaguchi and T. Katsuki, Chem.
Commun., 2008, 1704.
9 A reviewer has pointed out that oxidation reactions account for
only 4% of the reactions carried out in the pharmaceutical industry
(
see J. S. Carey, D. Laffan, C. Thomson and M. T. Williams, Org.
Biomol. Chem., 2006, 4, 2337) however one of the reasons why
oxidation reactions are not more frequently used is due to the
fact that the procedures available are not clean or safe enough
cannot be made with FeBr or with its DMSO complex because
3
they are soluble in the reaction media. Besides, the isolation
of the reaction products was very simple when cyclodextrin
complexes were used as catalyst. All these reactions are achieved
in the presence of a catalytic amount of nitrate and the oxygen
from the air is the oxidant agent. From the green chemistry point
of view, the reactions reported here follow several of its principles
and they have very good green metrics. It is also important to
remark that the reactions take place a room temperature and
under normal pressure.
In summary, we report herein a green and efficient method
for the selective oxidation of sulfides to sulfoxides under very
mild heterogeneous conditions with high yields and excellent
chemoselectivity in the presence of other reactive groups such
as p-isothiocyanate, o- and p-carboxylic acid, p-acetyl, o-bromo
and o-aldehyde.
(
see ref 2c). In 2006, the ACS GCI pharmaceutical Roundtable
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5 P. Tundo and F. Aric o` , Chemistry Inter., 2007, 29, 4.
This research was supported in part by the Consejo Nacional
de Investigaciones Cient ´ı ficas y T e´ cnicas (CONICET), Agencia
Nacional de Promoci o´ n Cient ´ı fica y T e´ cnica (FONCYT),
the Secretar ´ı a de Ciencia y T e´ cnica (SECyT) of Universidad
Nacional de C o´ rdoba, Argentina. C.O.K. is a grateful recipient
of a fellowship from CONICET.
16 (a) C. Karunakaran, S. K. T. Sheerin and P. N. Palanisamy, J. Chem.
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20 We carried out experiments in closed systems of various volume and
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21 P. Glavic and R. Lukman, J. Cleaner Production, 2007, 15, 1875.
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28 | Green Chem., 2009, 11, 223–228
This journal is © The Royal Society of Chemistry 2009