Mass spectrometric study of heterogeneous catalytic monooxidation of the S-position of thiophenes with hydrogen peroxide

Article abstract of DOI:10.1134/S0036024409130330

A biomimetic catalytic reaction system is developed experimentally for heteromonooxidation of heteroaromatic compounds. The system consists of two interacting simultaneous reactions, decomposition of H₂O₂ and oxidation of the substra

Full text of DOI:10.1134/S0036024409130330

ISSN 0036ꢀ0244, Russian Journal of Physical Chemistry A, 2009, Vol. 83, No. 13, pp. 2371–2375. © Pleiades Publishing, Ltd., 2009.
BIOPHYSICAL
CHEMISTRY
Mass Spectrometric Study
of Heterogeneous Catalytic Monooxidation of the SꢀPosition
of Thiophenes with Hydrogen Peroxide
I. T. Nagieva
Baku State University, Baku, Azerbaijan
eꢀmail: inara@yahoo.com
Received January 14, 2009
Abstract—A biomimetic catalytic reaction system is developed experimentally for heteromonooxidation of
heteroaromatic compounds. The system consists of two interacting simultaneous reactions, decomposition
of H2O2 and oxidation of the substrate. This leads to the synthesis, isolation, and identification of the Sꢀmonꢀ
oxide of thiophenes.
DOI: 10.1134/S0036024409130330
INTRODUCTION
are still open questions, while thiopheneꢀ1ꢀdioxide
and its derivatives were studied in detail [1]. Synthesis
of 1ꢀmonoxide can be developed as a nontraditional
method of oxidation, namely, coupled oxidation of
substrates with hydrogen peroxide in the presence of
catalytic bioimitators.
The development of theoretical and experimental
methods for monooxidation of heteroatomic comꢀ
pounds with hydrogen peroxide is of considerable
interest because these reactions give valuable intermeꢀ
Heterocyclic compounds containing N, O, and S
atoms in the ring play an important role in living
nature; they form natural compounds such as alkaꢀ
loids, antibiotics, natural pigments, vitamins, nucleic
acids, and proteins. Of particular importance are fiveꢀ
and sixꢀmembered heteroaromatic compounds,
which are generally subdivided into
(fiveꢀmembered, with one heteroatom) and
cient (sixꢀmembered). Thiophene and its derivatives
are ꢀredundant heterocycles with pronounced aroꢀ
π
ꢀredundant
π
ꢀdefiꢀ
diates with S
O functional groups.
π
maticity; thiophene is active in electrophilic substituꢀ
tion reactions.
Our goal was to develop a reaction system for hetꢀ
ero monooxidation of heteroaromatic compounds
with a
π
ꢀexcess (fiveꢀmembered 3,4ꢀdibromoꢀ2,5ꢀ
Thiophene and its substituted compounds are relaꢀ
tively stable to oxidants. However, in reactions with
H2O2 in acid or peracid media, they are oxidized to
sulfoxides (not isolated in a free state). Both comꢀ
pounds are typical diene systems capable of diene synꢀ
thesis.
Among acyclic sulfoxides, of greatest importance
are 2,5ꢀdimethylsulfoxide and acyclic sulfoxides from
oil, obtained by oxidation of the sulfurꢀcontaining
components of oil. Among heterocyclic thiophene
oxides (tetrahydrothiopheneꢀ1,1ꢀdioxide), sulfolane
and sulfolenes (dihydrothiopheneꢀ1,1ꢀdioxide) are
widely known. Sulfolane is not very toxic, and its
alkylꢀsubstituted derivatives are reagents for extracting
aromatic compounds (benzene, toluene, and cumene)
from oil.
dimethylthiophene) consisting of two interrelated
simultaneous reactions: decomposition of H2O2 and
oxidation of the substrate.
Many thiophenes, in particular, Sꢀdisulfides, are
pharmaceuticals. Therefore, prospects for the prepaꢀ
ration of a new oxidized form of thiophene in the form
of Sꢀmonoxide are promising for the synthesis of a new
class of drugs.
EXPERIMENTAL
Synthesis and identification of thiopheneꢀ1ꢀmonꢀ
oxide and its derivatives are still open questions in the
chemistry of thiophene, a ꢀredundant aromatic comꢀ
π
pound. However, thiopheneꢀ1ꢀdioxide and its derivaꢀ
tives, which are more readily available oxides, were
studied in detail. The difficulty lies in the methods
developed for the synthesis of thiopheneꢀ1ꢀmonoxide.
The problem could be solved by using nontraditional
oxidation procedures.
Using inorganic bioimitators [1] for monooxidaꢀ
tion of heteroatomic substances at hetero positions
opens up new opportunities in fine organic synthesis
because S
O monoxides can be obtained by chemꢀ
ical conjugation without resorting to complex techꢀ
nologies. In thiophene chemistry, synthesis and idenꢀ
As is known, one of the methods for the synthesis of
tification of thiopheneꢀ1ꢀmonoxide and its derivatives thiophenes is coherent synchronization of substrate
2371

2372
NAGIEVA
oxidation and H2O2 decomposition. The gasꢀphase ligand is much more stable to the destructive action of
region of freeꢀradical chain oxidation with hydrogen the oxidant than porphyrins. Therefore, oxidation
peroxide was successfully used for the synthesis of can be conducted in a static system for a prolonged
4ꢀvinylpyridine (VP) Nꢀmonoxide of a ꢀdeficient time. Two types of bioimitator were synthesized,
π
heteroaromatic compound [2]. However, all attempts which differed only in the valence state of the iron
to use this variant of simultaneous oxidation with ion. They were tested in simultaneous oxidation of
hydrogen peroxide to obtain thiophene Sꢀmonoxides as simple thiophenes in order to obtain a derivative of
π
ꢀredundant heteroaromatic compounds failed. Under thiopheneꢀ1ꢀmonoxide.
conditions similar to those for gasꢀphase Nꢀoxidation
with hydrogen 4ꢀVPꢀperoxide, Sꢀoxidation was not
observed; when taken in small amounts, 3,4ꢀdimethylꢀ
2,5ꢀdibromothiophene underwent oxidative destrucꢀ
tion (~4%), and the major reaction was decomposition
of H2O2.
The catalytic bioimitators were synthesized by the
Udenfried procedure [5], in which 1.75 M NH4OH
was added to an aqueous solution of 0.25 M Fe2(SO4)3
(Sigma Aldrich Chemical) (when the Fe3+ ion was
required at the active center of the catalyst) until
Fe(OH)3 completely precipitated. The solution was
filtered off and washed with hot water. The precipitate
was soluble in aqueous EDTA (Sigma Aldrich Chemꢀ
ical). The resulting sample was adsorbed by depositing
it on alumina.
To prepare a catalyst with Fe2+ at the active center,
aqueous EDTA was added to aqueous FeSO4, and the
resulting complex was deposited on Al2O3. Alumina
was used in neutral or basic form.
π
ꢀDeficient heteroaromatic compounds (such as
pyridine) easily undergo various freeꢀradical reacꢀ
tions, while ꢀredundant thiophenes are stable to freeꢀ
π
radical attack. In view of this property of thiophene,
freeꢀradical simultaneous oxidation with hydrogen
peroxide was replaced by a biomimetic catalytic proꢀ
cedure. It was necessary to synthesize a biomimetic
catalyst on which the catalytic decomposition of H2O2
could lead to an oxidative catalytic intermediate and
“active oxygen” would be an electrophile because
thiophenes readily undergo electrophilic reactions.
The apparatus was a threeꢀneck flask equipped
with a reflux condenser, a thermometer, a liquid samꢀ
pling tube, a stirrer, and a furnace for heating the reacꢀ
tor. The reflux condenser had an outlet (for gaseous
products) connected via a rubber hose to a gasometer.
Recently, a new field of catalysis has been develꢀ
oped to create catalysts of a new generation, namely,
soꢀcalled bioimitators that model the individual funcꢀ
tions of enzymes in conventional chemical systems.
They differ in the method for the synthesis of imitators
themselves and their functions, as well as the types of
biochemical oxidation reactions being modeled. One
of the successful models of oxidation (catalase, peroxꢀ
ide, and monoxygenase reactions) is PPFe3+OH (iron
protoporphin) deposited on alumina [3].
The products were identified and quantitatively
characterized by gas liquid and liquid chromatograꢀ
1
phy, chromatography–mass spectrometry, and H
NMR spectroscopy.
The following thiophenes served as substrates:
3,4ꢀdibromothiophene, 2,5ꢀdimethylthiophene, and
3,4ꢀdibromoꢀ2,5ꢀdimethylthiophene. The solvents
were acetone, methanol, and dichloromethane. The
oxidant was perhydrol of reagent grade.
These systems can be improved by modifying the
organic ligand of the redox center or replacing it with
simpler and more readily accessible organic ligands
with a similar action. This was implemented on a
PPFe3+OH/Al2O3 bioimitator, in which ethylenediꢀ
aminetetraacetic acid (EDTA) was used instead of
protoporphin for coordinating the Fe3+ ion [4]. The
choice of EDTA as an organic ligand was not accidenꢀ
tal. Thus, the wellꢀknown oxidative systems of Hamilꢀ
ton and Udenfried contain triꢀ and bivalent iron
bonded to EDTA. An analysis of the mechanism of
enzymatic processes involving hydrogen peroxide
(catalase and peroxidases) excluded reactions that
proceeded by the radicalꢀchain mechanism, which
had nothing in common with enzymatic oxidation. In
enzymatic catalysis, the catalytic redox centers are
involved in selective oxidation in a concerted way
together with acid–base centers. The new bioimitator
(catalyst) should possess acid–base and redox cataꢀ
lytic centers, on the one hand, and be capable of oxiꢀ
dation by the mechanism of coherent simultaneous
reactions, on the other hand. Moreover, in liquidꢀ
In all runs, the substrate (0.1 g) was dissolved in one
of the above solvents. Then perhydrol was added to the
solution of the substrate (S) in an amount correspondꢀ
ing to the molar ratio S : H2O2 = 1 : 1.5 or 2.0. The
mixture was loaded into a static reactor and heated to
50–55°C. A catalyst (0.1–0.150 g) was added to the
reactor, and a magnetic stirrer was switched on. At the
first stage, the reaction proceeded for ~5 h, whereupon
a sample was collected for analysis. The rate of oxygen
release was traced by the gasometer and decreased
drastically within ~5 h, which pointed to a low conꢀ
centration of H2O2. After that time, the catalyst had
the highest activity. The product yields were insignifiꢀ
cant, but clearly traced on mass spectra. Then the perꢀ
hydrol charge was increased tenfold to provide the
most favorable conditions for coupled oxidation. The
reaction was conducted for 1 day and more. Samples
were intermittently collected for analysis, which
showed that H2O2 was present and allowed us to judge
the activity of the bioimitator.
After two separations on a liquid chromatograph,
phase oxidation with hydrogen peroxide, the EDTA we isolated the probable basic product 3,4ꢀdibromoꢀ
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MASS SPECTROMETRIC STUDY OF HETEROGENEOUS CATALYTIC MONOOXIDATION
2373
2,5ꢀdimetylthiopheneꢀ1ꢀmonoxide (I
). The 1H NMR ing the oxidation toward the formation of 1ꢀmonoxꢀ
spectrum of dimethylthiopheneꢀ1ꢀmonoxide was ide. As shown below, both factors considerably affect
recorded for the first time. In the mass spectra of the the formation of 1ꢀmonoxide and the reaction rate.
product, the most intense signal was that of an ion with The oxidation was conducted under the aboveꢀ
a mass of 44 (C–S fragment), which could serve as a described conditions. Three different solvents were
characteristic mass for identification of thiopheneꢀ1ꢀ used, and qualitatively different data were obtained.
monoxide and its derivatives. Note that, for thiophene The use of CH2Cl2 did not lead to pronounced converꢀ
and its derivatives, the ion with a mass of 44 had no sion of the substrate because water (an aqueous soluꢀ
characteristic intensity of a monoxide. The reaction tion of hydrogen peroxide) promoted delamination of
was considered finished when molecular oxygen the reaction mixture into three immiscible phases, two
ceased to evolve. The heterogeneous catalyst was easꢀ of which were liquids, and the third was the catalytic
ily separated from the liquid part of the reaction mixꢀ solid. This system can hardly be efficient. As solvents,
ture (which is obviously its advantage) and tested for we used acetone and methanol, which formed a
activity in the decomposition of H2O2. It showed high homogeneous mixture with the substrate and water.
activity every time and could be reused in substrate
When acetone was used as a solvent, the substrate
oxidation. Control runs with pure solvents were perꢀ
was selectively oxidized with hydrogen peroxide. The
formed to check their stability to oxidation with
yield of the product with mass number 283 was ~25 wt %.
hydrogen peroxide under catalytic conditions.
It was identified as (mass number 284)
Br Br
H
RESULTS AND DISCUSSION
A series of experiments on the catalytic oxidation
of thiophenes to the corresponding 1ꢀmonoxides in
the presence of the EDTA Fe3+OH/Al2O3 catalyst
were started with 3,4ꢀdibromoꢀ2,5ꢀdimethylꢀ
thiophene. To solve the problem, it was necessary to
minimize the participation of unsaturated bonds in
S
O
The side process was oxidation of the solvent that
formed the products of hydrogenation and hydroxylaꢀ
tion, namely, glycols in large amounts.
The transformations in the system can be schematꢀ
oxidation and use the effects of substituents in directꢀ ically represented as
Br Br
H
Br Br
S
S
O
H O, acetone
2
+ H2O2
.
CH3CH(OH)–CH2OH + CH3–CCH3(OH)–CHOH–CH3
The formation of glycols from acetone in this reacꢀ oxidation with hydrogen peroxide for a long time.
tion can be of interest in itself. Acetone behaved like From this, we inferred that CH3OH had a minimal
an active component of the system and affected the effect on the chemical transformation. Moreover, the
formation of the oxidation product. Hence, it was necꢀ absence of oxidation products indicated that the
essary to get rid of these additional effects on the forꢀ decomposition of H2O2 on the imitator occurred as a
mation and expenditure of intermediates. If intermeꢀ heterogeneous catalytic reaction without release of
diates are formed only from hydrogen peroxide, we free radicals in solution. Otherwise, the free OH radiꢀ
can expect selective and predictable oxidation of the cals would have reacted with methanol because these
substrate. Of certain interest is the oxidation of aceꢀ are highly reactive species. Methanol was used as a solꢀ
tone itself in the absence of a substrate. It was estabꢀ vent even for the oxidation of 3,4ꢀdibromoꢀ2,5ꢀdimeꢀ
lished that, at the initial stages, the reaction formed thylthiophene with hydrogen peroxide. 1ꢀMonoxide
isopropanol and only small amounts of the products of was synthesized by a simple procedure according to
destructive oxidation acetaldehyde and acetic acid. the scheme (the yield in wt % is given in parentheses)
Therefore, we can suggest that the H2O2–H2O–
EDTA Fe3+OH/Al2O3–acetone reaction mixture has
Br Br
3+
EDTA Fe /Al O , MeOH
2
3
reducing properties owing to the combination of
hydrogen peroxide, acetone, and imitator.
+ H2O2
S
Before using methanol as a solvent in the oxidation
of 3,4ꢀdibromoꢀ2,5ꢀdimethylthiophene, we checked
its stability to oxidation in the absence of the substrate
under the conditions identical to those described
above. We found that it was completely inactive in the
Br Br
SO2
Br Br
Br Br
H
H
O
;
;
.
SO
S
O
I(30.0)
II(16.0)
III(10.0)
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2374
NAGIEVA
44
100.0
50.0
7348220.
51
131
39
161
205
59
255
271
67
147
119
105
82
213
93
184
243
173
286
199
73
227
m/z
Fig. 1. Mass spectrum of the purified reaction product 3,4ꢀdibromoꢀ2,5ꢀdimethylthiopheneꢀ1ꢀmonoxide; scan 487–509.
The products were characterized for the first
time by 1H NMR and mass spectrometry. One of the
products was ~8.0% 3,4ꢀdibromothiophene, which
was 36.0% of the unchanged raw material. Figure 1
H2O2
H2O
EDTA Fe3+OH/Al2O3
EDTA Fe3+OOH/Al2O3
presents the mass spectrum (
product in the scan range 487–509. The mass
) 286 relates to molecule , and the intense
m/z) of the purified
(1)
I
(
m
/
z
I
H2O2
H2O + O2
peak with a mass of 44 (which can be assigned to the
C–S fragment) can serve as a characteristic mass in
identifying thiopheneꢀ1ꢀmonoxide and its derivaꢀ
2H2O2 = 2H2O + O2
General reaction
tives. Figure 2 shows the 1H NMR spectrum of
I.
Secondary reaction
The chemical shift (Fig. 2, 1.7 ppm) of
I
is
smaller than the chemical shifts of 3,4ꢀdibromoꢀ
2,5ꢀdimethylthiophene (2.38 ppm) and 3,4ꢀdibromoꢀ
2,5ꢀdimethylthiopheneꢀ1ꢀdioxide (2.19 ppm). As
to compounds II and III, they were identified by
mass spectrometry and additionally by liquid chroꢀ
matography in the case of III. Determination of II
only by mass spectra without an analog can be a
source of error.
H2O2
H2O
EDTA Fe3+OH/Al2O3
EDTA Fe3+OOH/Al2O3
(2)
Br Br
S
Br Br
SO
In the system under study, as well as similar oxiꢀ
dation systems, the substrate is oxidized by a simulꢀ
taneous mechanism. The reaction mechanism can
be represented by the following schemes including
the general transformations in the system,
Br Br
+ H2O2 =
S
Br Br
SO
+H2O General reaction
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MASS SPECTROMETRIC STUDY OF HETEROGENEOUS CATALYTIC MONOOXIDATION
2375
Schemes (1) and (2) show the simultaneous reacꢀ
tions of the coupled reaction. Scheme (1) shows the
formation of an intermediate of the two reactions, and
scheme (2) illustrates how the intermediate causes and
accelerates the secondary reaction (which is concurꢀ
rent with the first reaction).
To study the effect of the valence state of the iron
ion, we performed an experiment in which the cataꢀ
1.718
lyst differed from its precursor in the central ion
(which was Fe2+). 3,4ꢀDibromoꢀ2,5ꢀdimethylthꢀ
iophene was oxidized in the H2O2–H2O–CH3OH–
EDTA Fe2+OH/Al2O3 system under identical condiꢀ
tions. This system showed low activity in oxidation.
Thus, the total yield of the products with mass numꢀ
bers 299 and 301, which were assigned to the comꢀ
Br Br
H
pound
with a mass of 300 and a comꢀ
SO
O
pound with a mass of 302, was <1%. Consequently, the
valence state of the iron ion at the active site of the catꢀ
alyst predetermines the result of oxidation. It was also
important to study the effects of the character and
number of substituents in thiophene on the oxidation
of the latter. Under identical conditions in the H2O2–
H2O–CH3OH–EDTA Fe2+OH/Al2O3–3,4ꢀdibroꢀ
mothiophene system, only H2O2 underwent vigorꢀ
ous decomposition. However, the transformation of
2,5ꢀdimethylthiophene under the same conditions
gave products with masses of 154, 222, and 279, which
point to more profound oxidation of the substrate,
although conversion was above 90 wt %.
1.8
1.7
1.6
, ppm
δ
1
Fig. 2. H NMR spectrum of 3,4ꢀdibromoꢀ2,5ꢀdimethꢀ
ylthiopheneꢀ1ꢀmonoxide.
pounds in the presence of a heterogeneous biomimetic
catalyst (EDTA, Fe3+OH/Al2O3).
REFERENCES
Thus, the nature of substituents and their number
in thiophene substantially affected the qualitative and
quantitative characteristics of biomimetic oxidation
with hydrogen peroxide. Therefore, 3,4ꢀdibromoꢀ2,5ꢀ
dimethylthiophene was the correct choice of a subꢀ
strate.
1. T. M. Nagiev, Interaction of Sinchronous Reactions in
Chemistry and Biology (ELM, Bants, 2001), p. 404 [in
Russian].
2. A. M. Magerramov, I. T. Nagieva, and M. A. Allaꢀ
kherdiyev, in Proc. of the 2nd Eur. Catalysis Symp., Sept.
23–26, 2001, Pisa, Italy (2001) p. 41.
To summarize, the highly efficient reaction system
developed in this study allowed us to solve the problem
of synthesis, isolation, and identification of the derivꢀ
atives of thiophene Sꢀmonoxide. This reaction system,
consisting of two coherent simultaneous reactions—
decomposition of H2O2 and hetero monooxidation of
heteroaromatic compounds—led to highly efficient
liquidꢀphase Sꢀmonooxidation of thiophene and its
3. A. M. Magerramov and M. A. Allakherdiyev, in Proc. of
the 16th Intern. Congress of Chemical and Process Eng.,
Aug. 22–26, 2004, Prague, Czech Republic (2004),
p. 233.
4. A. M. Magerramov, I. T. Nagieva, and M. A. Allakhverꢀ
diev, in Proc. of the 19 Intern. Congress on Chemistry
(Kushadasy, Turkey, 2005), OGPꢀ103.
5. S. Udenfried, C. Clark, J. Axelrod, and B. Brodie,
derivatives as
π
ꢀredundant heteroaromatic comꢀ
J. Biol. Chem. 208, 731 (1954).
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