Mechanism of the oxidation of aromatic sulfides catalysed by a water soluble iron porphyrin

Article abstract of DOI:10.1039/b209004j

The oxygen atom transfer-electron transfer (ET) mechanistic dichotomy has been investigated in the oxidation of a number of aryl sulfides by H₂O₂ in acidic (pH 3) aqueous medium catalysed by the water soluble iron(III) porphyrin 5,10,15,20-tetraphenyl-21H,23H-porphine-p,p′,p″,p?-tetrasulfo nic acid iron(III) chloride (FeTPPSCl). Under these reaction conditions, the iron-oxo complex porphyrin radical cation, P⁺ Fe(IV)=O, should be the active oxidant. When the oxidation of a series of para-X substituted phenyl alkyl sulfides (X = OCH₃, CH₃, H, Br, CN) was studied the corresponding sulfoxides were the only observed product and the reaction yields as well as the reactivity were little influenced by the nature of X as well as by the bulkiness of the alkyl group. Labelling experiments using H₂ ¹⁸O or H₂¹⁸O₂ clearly indicated that the oxygen atom in the sulfoxides comes exclusively from the oxidant. Moreover, no fragmentation products were observed in the oxidation of a benzyl phenyl sulfide whose radical cation is expected to undergo cleavage of the β C-H and C-S bonds. These results would seem to suggest a direct oxygen atom transfer from the iron-oxo complex to the sulfide. However, competitive experiments between thioanisole (E° = 1.49 V vs. NHE in H₂O) and N,N-dimethylaniline (E° = 0.97 V vs. NHE in H₂O) resulted in exclusive N-demethylation, whereas the oxidation of N-methylphenothiazine (10, E° = 0.95 V vs. NHE in CH₃CN) and N,N-dimethyl-4-methylthioaniline (11, E° = 0.65 V vs. NHE in H₂O) produced the corresponding sulfoxide with complete oxygen incorporation from the oxidant. Since an ET mechanism must certainly hold in the reactions of 10 and 11, the oxygen incorporation experiments indicate that the intermediate radical cation, once formed, has to react with PFe(IV)=O (the reduced form of the iron-oxo complex which is formed by the ET step) in a fast oxygen rebound. Thus, an ET step followed by a fast oxygen rebound is also suggested for the other sulfides investigated in this work.

Full text of DOI:10.1039/b209004j

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Mechanism of the oxidation of aromatic sulfides catalysed by a
water soluble iron porphyrin
Enrico Baciocchi,* Maria Francesca Gerini, Osvaldo Lanzalunga, Andrea Lapi and
Maria Grazia Lo Piparo
Dipartimento di Chimica, Università “La Sapienza”, P. le A. Moro 5, 00185, Rome, Italy.
E-mail: enrico.baciocchi@uniroma1.it
Received 16th September 2002, Accepted 2nd December 2002
First published as an Advance Article on the web 16th December 2002
The oxygen atom transfer–electron transfer (ET) mechanistic dichotomy has been investigated in the oxidation of a
number of aryl sulfides by H2O2 in acidic (pH 3) aqueous medium catalysed by the water soluble iron() porphyrin
5,10,15,20-tetraphenyl-21H,23H-porphine-p,pЈ,pЉ,pٞ-tetrasulfonic acid iron() chloride (FeTPPSCl). Under these
reaction conditions, the iron–oxo complex porphyrin radical cation, Pϩ Fe()᎐O, should be the active oxidant.
ؒ
᎐
When the oxidation of a series of para-X substituted phenyl alkyl sulfides (X = OCH3, CH3, H, Br, CN) was studied
the corresponding sulfoxides were the only observed product and the reaction yields as well as the reactivity were
little influenced by the nature of X as well as by the bulkiness of the alkyl group. Labelling experiments using H218O
or H218O2 clearly indicated that the oxygen atom in the sulfoxides comes exclusively from the oxidant. Moreover, no
fragmentation products were observed in the oxidation of a benzyl phenyl sulfide whose radical cation is expected to
undergo cleavage of the β C–H and C–S bonds. These results would seem to suggest a direct oxygen atom transfer
from the iron–oxo complex to the sulfide. However, competitive experiments between thioanisole (EЊ = 1.49 V vs.
NHE in H2O) and N,N-dimethylaniline (EЊ = 0.97 V vs. NHE in H2O) resulted in exclusive N-demethylation, whereas
the oxidation of N-methylphenothiazine (10, EЊ = 0.95 V vs. NHE in CH3CN) and N,N-dimethyl-4-methylthioaniline
(11, EЊ = 0.65 V vs. NHE in H2O) produced the corresponding sulfoxide with complete oxygen incorporation from
the oxidant. Since an ET mechanism must certainly hold in the reactions of 10 and 11, the oxygen incorporation
experiments indicate that the intermediate radical cation, once formed, has to react with PFe()᎐O (the reduced form
᎐
of the iron–oxo complex which is formed by the ET step) in a fast oxygen rebound. Thus, an ET step followed by a
fast oxygen rebound is also suggested for the other sulfides investigated in this work.
In the oxygen atom transfer mechanism the sulfoxide is
Introduction
formed by direct oxygen transfer from the iron()-oxo porphy-
The enzymatic oxidation of sulfides to sulfoxides by heme per-
rin radical cation to the sulfide, a process also called “oxene
oxidases [such as horseradish peroxidase (HRP), chloroperoxi-
transfer” (Scheme 1, path b). In the ET mechanism, the transfer
dase (CPO), lactoperoxidase (LPO) and lignin peroxidase
(LiP)] is an important process from both the synthetic and
mechanistic point of view.1 In particular, a number of studies
have been mainly directed to get information about the enzyme
active site structure and to distinguish between the two possible
reaction mechanisms, direct oxygen atom transfer (“oxene
process”) or electron transfer (ET).2
of one electron first occurs from the sulfide to Pϩ Fe()᎐O
ؒ
᎐
(path c) to form a sulfide radical cation and P–Fe()᎐O (com-
᎐
pound II). The sulfoxide is then formed either by transfer of the
oxygen atom from PFe()᎐O to the radical cation, the so called
᎐
“oxygen rebound” step (path d) or by reaction with the medium
(path e). The available evidence quite clearly indicates that the
sulfoxidations catalysed by peroxidases occur by an ET mech-
anism (paths c and d ϩ e).2a,2b,2f,3 An exception seems to be
represented by CPO where an oxygen atom transfer mechanism
has also been suggested.2d However, this enzyme differs from
the other peroxidases for the fifth iron ligand, which is a
cysteine thiolate instead of a histidine residue.
Such a mechanistic dichotomy is illustrated in Scheme 1
The studies on the enzymatic oxidation of sulfides have been
complemented by several investigations carried out using
synthetic peroxidase models, mainly iron tetraaryl por-
phyrins.2c,2e,2f,4 These compounds represent good models for
peroxidases since the active species, formed by reaction with a
suitable oxygen donor, can again be described as an iron()-
oxo porphyrin radical cation and therefore closely resemble the
enzyme active species compound I (Scheme 1, path a, where P is
now a synthetic porphyrin).5 Thus, also in the metalloporphyrin
promoted sulfoxidations the attention has been focused on the
mechanistic dichotomy described in Scheme 1.
In pioneering work Oae and coworkers suggested an ET
mechanism (Scheme 1, path c) for the sulfoxidation of a series
of aromatic sulfides promoted by an iron() porphyrin.4a How-
ever, Baciocchi and associates later presented results favouring
a direct oxygen atom transfer mechanism2c,2e (Scheme 1,
path b), a conclusion recently confirmed by Watanabe and co-
workers on the basis of a correlation between the oxidation rate
Scheme 1 Oxygen atom transfer mechanism vs. ET-oxygen rebound.
where Pϩ Fe()᎐O is the iron()-oxo porphyrin radical cation
ؒ
᎐
(also called compound I) which is the active species involved in
these reactions and is formed by reaction of the native enzyme
P–Fe() (P is a protoporphyrin IX) with hydrogen peroxide
(Scheme 1, path a).1
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 2 2 – 4 2 6
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 3
422

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constants and the sulfide oxidation potentials.2f Only when a
sulfide with a very low oxidation potential (0.96 V vs. NHE in
CH3CN) was used was the sulfoxidation suggested to proceed
via an ET process. Thus, it would seem that, in contrast to
peroxidases, the chemical models generally prefer to react by
the oxygen atom transfer mechanism.
Table 1 FeTPPSCl catalysed oxidation of aryl sulfides 1–8 (4-XC6-
H4SR), 9,10 and 11 by H2O2 in the presence of imidazole.
18O-incorporation
Sulfoxide
yield (%)a
Substrate
H218O
H218O2
0%b
0%
0%
0%
0%
n.d.
n.d.
0%
n.d.
0%
0%
98%
97%
n.d.
n.d.
97%
n.d.
n.d.
n.d.
n.d.
97%
>99%
It should, however, be considered that the data with chemical
models obtained so far refer to organic solvents and therefore
do not allow a good comparison with peroxidase induced reac-
tions which are run in water. Indeed, it is known that on passing
from organic solvents to a much more polar aqueous medium
the substrate oxidation potentials significantly decrease (by 0.2–
0.4 V).6 Thus, an ET mechanism might be more favoured in
H2O than in an organic solvent and this might be the origin
of the different behaviours of the enzymatic and biomimetic
systems.
With this possibility in mind, we have thus studied the oxid-
ation of a number of aromatic sulfides by H2O2 in aqueous
acidic medium (pH 3) catalysed by the water soluble iron()
porphyrin 5,10,15,20-tetraphenyl-21H,23H-porphine-p,pЈ,pЉ,
pٞ-tetrasulfonic acid iron() chloride (FeTPPSCl) in the pres-
ence of imidazole. The low pH as well as the presence of imid-
azole should favour the heterolytic cleavage of the O–O bond in
H2O2 and thus the formation of the iron()-oxo porphyrin rad-
ical cation as it occurs in the peroxidase catalysed reactions
(Scheme 1).7 In particular, we have investigated the oxidation of
the alkyl aryl sulfides 1–8, benzyl aryl sulfide 9, N-methyl-
phenothiazine 10 and N,N-dimethyl-4-methylthioaniline 11
(Chart 1). These substrates span a significant range of oxid-
1 X = CH3O, R = CH3
2 X = CH3, R = CH3
3 X = H, R = CH3
4 X = Br, R = CH3
5 X = CN, R = CH3
6 X = CH3O, R = Et
7 X = CH3O, R = iPr
8 X = CH3O, R = tBu
9
79
72
57
31
32
90
78
31
83
60
28c
10
11
a Yields refer to the starting material, equimolar to H2O2. Average of at
least two determinations, the error is in all cases < 1%. b The same
area ratios for the (mϩ2)/z and m/z ions ( 0.5%) were measured in the
oxidations carried out under the same experimental conditions in
H216O. c Sulfoxidation was accompanied by the formation of a coupling
product suggested as being derived from reaction of the N-demethyl-
ated product with 11 (for details, see Experimental).
imidazole ratio used in these experiments was 1 / 0.03 / 3. In all
cases, sulfoxides were the exclusive oxidation products. The
only exception was 11 which also underwent N-demethylation
(see Experimental). It was verified that either in the absence of
FeTPPSCl or in the absence of H2O2 no products were formed.
The sulfoxide yields [referring to the same time of reaction (1 h)
and not optimised] are reported in Table 1. This table also
shows the percent of 18O incorporation in the sulfoxide when
the oxidation of the sulfides was carried out in 50 mM sodium
tartrate buffered aqueous solutions, pH 3, containing 10%
H218O or when H218O2 was used as the oxidant.
Examination of the data for the oxidation of sulfides 1–8
indicates that substantial sulfoxidation occurs in all cases. The
more reactive compound was 4-methoxythioanisole (79% yield)
whereas 32% of sulfoxide was observed with 4-cyanothio-
anisole. Sulfoxide yields are not significantly influenced by the
bulkiness of the R group. Considering the R groups, the sulf-
oxide yields were very high (80–90%) for R = Me, Et, i-Pr. A
lower yield (31%) was found when R = t-Bu.
Several competitive experiments have clearly shown that the
rate of sulfoxidation decreases by decreasing the substituent’s
electron donating power. Thus, 4-methoxythioanisole was 6.4
times more reactive than thioanisole whereas 4-cyanothio-
anisole appears to be 0.22 times less reactive than thioanisole.
The reaction selectivity is however not very large as also
observed by Watanabe and associates, albeit obtained in
organic solvents.2f
When the oxidations were carried out in labelled water, no
18O incorporation was observed in the product sulfoxides,
which indicates that the oxygen in the product does not derive
from the solvent but exclusively from the iron-oxo complex.
This result was fully confirmed by using 18O labelled H2O2: a
complete incorporation of 18O in the sulfoxide was always
observed. Interestingly, complete 18O incorporation from
H218O2 was also found with 10 and 11. Thus, in this respect,
substrates with an oxidation potential as low as 0.65 V vs. NHE
in H2O11 behave as thioanisole and the other less easily oxidis-
able sulfides.
Chart 1
ation potential values (from 0.88 V vs. NHE in CH3CN for 118
to 1.85 V vs. NHE in CH3CN for 52f). Moreover it is known
that in addition to producing sulfoxide, the radical cation of 9
also undergoes β C–H and C–S bond cleavage leading to
benzylic derivatives (vide infra).2d Thus 9 may represent a mech-
anistic probe to detect the occurrence of an ET mechanism.
Another important observation was that the oxidation of 9
by FeTPPSCl led exclusively to the formation of the corre-
sponding sulfoxide without the formation of fragmentation
products, disulfide, benzyl alcohol and benzaldehyde, that are
Results and discussion
The sulfides were reacted for 1 h with an equimolar concen-
tration of hydrogen peroxide in the presence of FeTPPSCl and
imidazole9 in 50 mM sodium tartrate buffered aqueous solu-
tion (pH 3) containing 5% acetonitrile as cosolvent, at 25 ЊC
and under an argon atmosphere. The sulfide / FeTPPSCl /
instead expected when 9؉ is a reaction intermediate, as shown
ؒ
in Scheme 2 and as it was actually found in the oxidations
catalysed by HRP2d and LiP12 which indeed occur by an ET
mechanism.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 2 2 – 4 2 6
423

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Scheme 2 Fragmentation pathways for 9؉
.
ؒ
Scheme 3
There is no doubt that the lack of fragmentation products in
the oxidation of 9 coupled with the complete incorporation
of 18O from H218O2 in the sulfoxide (or the absence of 18O
incorporation in the reaction carried out in H218O) appear fully
consistent with the previous hypotheses suggesting that sulf-
oxidation catalysed by synthetic iron porphyrins generally takes
place by an oxygen atom transfer mechanism. In addition, our
data would seem to indicate that such a mechanism should
also hold with substrates of very low oxidation potential like
10 and 11.
In spite of the reasonableness of the above conclusion, it
must, however, be recognised that the data at hand might be
consistent as well with an ET mechanism where the oxygen
rebound step of the radical cation is so fast as to completely
overcome the other possible reactions of this species, i.e. frag-
mentation and/or reaction with the medium. In this respect, it
has also to be noted that an ET mechanism should be still more
likely with iron porphyrins than with peroxidases given the
much higher oxidising power of the iron-oxo complex formed
in the former case with respect to that of the active oxidant
formed by peroxidases.13 Therefore, we deemed it worthwhile to
investigate further this possibility and to this purpose some
competitive experiments were carried out where a sulfide was
made to react with H2O2/FeTPPSCl in the presence of a com-
pound of lower oxidation potential which was expected to react
with FeTPPSCl under the same oxidising conditions by an ET
mechanism. We felt that in case a preferential oxidation of the
sulfide were observed, this would have been a quite decisive
result in favour of a sulfoxidation occurring by the oxygen atom
transfer mechanism.
exclusive N-demethylation was also observed in the oxidation
of 12, where the arylsulfide and N-methylaniline moieties are in
the same molecule, but isolated from one another (Scheme 3,
reaction b).
These results clearly indicate that either N,N-dimethylaniline
and thioanisole both react by the ET mechanism or that the ET
reaction of N,N-dimethylaniline is much faster than the oxygen
atom transfer reaction of thioanisole. A clearcut distinction
between these two possibilities is certainly difficult, however, we
feel that a quite reasonable choice in favour of the former pos-
sibility may be made on the basis of the results obtained in the
oxidation of sulfides 10 and 11which have both the N-methyl-
amino and sulfur moieties directly bonded to the aromatic ring
(Table 1).
Both 10 and 11 are aromatic N-methylamines with an oxid-
ation potential lower than that of N,N-dimethylaniline. It is
therefore very likely that, as observed with N,N-dimethyl-
anilines,14 and also in the light of the competitive experiment,
they undergo an ET process when reacted with FeTPPSCl/
H2O2. However, in this case, owing to the presence of the ring
bonded sulfur functionality, the oxidation of these compounds
led to sulfoxides, which clearly shows that the radical cation is
an intermediate en route to the sulfoxide formation.17 Still more
important is that complete18O incorporation was observed in
the sulfoxide formed from 10 and 11. Hence, not only a radical
cation is formed in these reactions, but this species must form
the sulfoxide in an oxygen rebound step (Scheme 1, path d),
which has to be a very fast process in order to overcome the
؉
tendency of the very stable 10؉ and 11 to diffuse in and to
ؒ
ؒ
react with the medium.
Since previous studies had clearly demonstrated that the
N-demethylation of N,N-dimethylanilines induced by FeTPP-
SCl is an ET reaction,14 thioanisole (EЊ = 1.49 V vs. NHE in
H2O)15 was reacted with H2O2/FeTPPSCl in the presence of
N,N-dimethylaniline (EЊ = 0.97 V vs. NHE in H2O).16 The result
was that only the N-demethylation product was formed
(Scheme 3, reaction a), thus indicating that only the compound
with the lower oxidation potential was oxidised. Interestingly,
The above results are very important as they indicate that
complete 18O incorporation from H2O2 can actually be consist-
ent with an ET mechanism and that the occurrence of a fast
oxygen rebound step is a very plausible hypothesis. Thus, in
view of the higher oxidation power of the active oxidant of the
iron porphyrins compared to that of peroxidases, there is no
reason not to think that the ET mechanism is also valid with the
other sulfides examined in this work, the absence of fragmen-
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 2 2 – 4 2 6
424

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tation products found with 9 being probably ascribable too
to an oxygen rebound step faster than fragmentation of the
radical cation, a relatively slow reaction.20 In fact, the oxygen
N-methyl-N-(2-phenylthioethyl)aniline(12) was synthesised
by adding, over a period of 10 min, a solution of N-methyl-
aniline (1.4 g, 13 mmol) in 5 mL of toluene to a stirred solution
of (2-chloroethyl) phenyl sulfide29 (0.92 g, 5.3 mmol) in 5 mL of
toluene in a two-neck round bottom flask. The mixture was
stirred under reflux for four days, it was then cooled to room
temperature and 6 mL of 0.1 M NaOH were added in order to
dissolve the hydrochloride. The mixture was extracted with
ethyl acetate and the organic fractions were collected, dried over
anhydrous Na2SO4 and evaporated under reduced pressure.
Chromatography on silica gel using hexane/ethyl acetate (50:1)
rebound step for sulfides 1–8 is expected to be much faster than
؉
with 10 and 11, given the much lower stability of 1؉ –8 with
ؒ
ؒ
؉
respect to 10؉ and 11
.
ؒ
ؒ
Conclusion
In conclusion, the data presented here make it possible to
suggest that in water the sulfoxidation of aromatic sulfides
catalysed by HRP and LiP as well as by biomimetic systems
probably occurs by the same ET mechanism. The different
behaviours of the two systems may simply be due to differences
in the efficiency of the oxygen rebound step which appears to be
much higher in the biomimetic than in the enzymatic reaction.
Thus, in the former case it is much more difficult to get evidence
for the presence of a radical cation intermediate by looking at
the formation of fragmentation products or via 18O incorpor-
ation studies. Such a difference in the oxygen rebound efficiency
is probably due to the fact that in the enzymatic systems (com-
pared to the biomimetic ones) it may be much more difficult
for the radical cation, once formed, to approach the oxygen of
1
as an eluant gave 1.0 g of a white solid (75% yield). H-NMR
(CDCl3), δ: 2.92 (s, 3H), δ: 3.05 (t, 2H), δ: 3.53 (t, 2H), δ: 6.59–
6.73 (m, 4H), δ: 7.15–7.39 (m, 6H). EI-MS: m/e = 120 (100%),
77 (15%), 104 (8%), 243 (Mϩ, 7%), 51 (6%), 91 (4%).
Reaction products
The sulfoxides of all substrates were prepared by reaction of the
corresponding sulfides with sodium metaperiodate in aqueous
ethanol solution.30
N-(2-phenylthioethyl)-aniline was prepared by reacting anil-
ine and (2-chloroethyl)-phenyl sulfide29 using the procedure
reported for 12. Yield: 85%. 1H-NMR (CDCl3), δ: 1.6 (broad s,
1H), δ: 3.15 (t, 2H), δ: 3.36 (t, 2H), δ: 6.57–6.75 (m, 3H), δ: 7.14–
7.32 (m, 5H), δ: 7.37–7.41 (m, 2H). EI-MS: m/e = 106 (100%),
124 (23%), 77 (21%), 229 (Mϩ, 14%), 65 (10%), 51 (9%).
The purity of all the synthesised compounds (> 99%) was
checked by GC, GC-MS and 1H-NMR.
PFe()᎐O, due to the steric requirements of the enzyme active
᎐
site, which are particularly stringent with HRP and LiP.21 Such
significant steric requirements should be absent in synthetic
iron porphyrins.
Experimental section
General oxidation procedure
Methods
The sulfide (10 µmol), FeTPPSCl (0.3 µmol) and imidazole
(30 µmol) were magnetically stirred in 5 mL of 50 mM sodium
tartrate buffer solution, pH 3, containing 5% of acetonitrile as
cosolvent, at 25 ЊC, under an argon atmosphere. H2O2 or H218O2
(10 µmol) in 0.5 mL of buffer solution was gradually added
over 1 h using a syringe pump. After the addition of the internal
standard (4-methoxyacetophenone) the products of the reac-
tion were extracted with CH2Cl2 and dried over Na2SO4. The
same experimental conditions were used when the oxidations
were carried out in H218O.
1H-NMR spectra were recorded on a Bruker AC300P spectro-
meter in CDCl3. GC-MS analyses were performed on a HP5890
GC (OV1 capillary column, 12 m × 0.2 mm) coupled with a
HP5970 MSD. LC-MS analyses were performed on a Fisons
Instruments VG-Platform Benchtop LC-MS (positive ion
electrospray mass spectra, ESPϩ) spectrometer and GC analy-
ses on a Varian 3400 GC (OV1 capillary column, 25 m ×
0.2 mm). HPLC analyses were carried out on a Hewlett
Packard 1050 liquid chromatograph fitted with a UV–Vis
detector and a reversed phase (C18) column.
Product analysis
Materials
Reaction products were characterised by GC, GC-MS, HPLC
and 1H-NMR by comparison with authentic specimens. Yields
were determined by GC, H-NMR and HPLC and referred to
the starting material. A good recovery of materials (> 95%) was
observed in all the experiments.
High purity commercial samples of thioanisole (Fluka),
N-methylphenothiazine
1
(Aldrich),
N,N-dimethylaniline
(Aldrich), 4-methoxyacetophenone (Fluka), imidazole (Fluka)
and tartaric acid (Aldrich) were used as received. Tartrate
buffer solution was prepared using Milli Q grade water.
Acetonitrile (HPLC grade) was purchased from Carlo Erba.
H218O (10%) and H218O2 (2.3 M, 90% 18O) were purchased
from Isotec Inc. The 18O content of H218O2 was determined
according to the literature.22 5,10,15,20-tetraphenyl-21H,23H-
porphine-p,pЈ,pЉ,pٞ-tetrasulfonic acid tetrasodium salt dodeca-
hydrate (Aldrich) was metallated according to the literature
procedure.23
4-Substituted thioanisoles were prepared by reaction of the
corresponding thiophenols (Aldrich) with CH3I in basic
methanol solution.24 4-Methoxyphenyl ethyl sulfide (6) and
4-methoxyphenyl isopropyl sulfide (7) were prepared by treating
4-methoxythiophenol with respectively EtBr25 and iPrI26 in
EtOϪ/EtOH.
4-Methoxyphenyl tertbutyl sulfide (8) was prepared by acid
catalysed reaction of 4-methoxythiophenol with tBuOH.27
Potassium 4-(benzylthio)benzyl sulfonate (9) was synthesised
according to the literature procedure.2d
N,N-dimethyl-4-methylthioaniline (11) was prepared by react-
ing 4-methylthioaniline with CH3I following the literature
procedure.28
Oxidation of N,N-dimethyl-4-methylthioaniline (11)
The same experimental procedure described above was fol-
lowed. In addition to the corresponding sulfoxide a second
reaction product was observed (yield referred to the starting
substrate 12%), which showed the following properties:
1H-NMR (CDCl3) δ: 2.37 (s, 3H), δ: 2.39 (s, 3H), δ: 3.00 (s, 6H),
δ: 3.15 (s, 3H), δ: 6.47–6.54 (m, 2H), δ: 6.94–6.99 (m, 2H), δ:
7.17–7.25 (m, 3H) and GC-MS m/e = 318 (Mϩ, 100%), 303
(30%), 256 (11%), 224 (9%), 137 (9%). This product should
derive from the coupling between 11؉ and its N-demethylated
ؒ
product, N-methyl-4-methylthioaniline. To get a further sup-
port on the nature of this coupling product a mixture of 11 and
N-methyl-4-methylthioaniline was reacted with the genuine
one-electron oxidant potassium 12-tungstocobalt()ate31 and
the same kind of coupling product was observed.32
Competitive oxidation of thioanisole and N,N-dimethylaniline
An equimolar amount of thioanisole and N,N-dimethylaniline
(10 µmol each) were reacted with 0.6 µmol of FeTPPSCl and
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 2 2 – 4 2 6
425

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6 M. Jonsson, D. D. M. Wayner and J. Lusztyk, J. Phys. Chem., 1996,
100, 17539–17543.
1.0 µmol of H2O2 following the general procedure described
above. After the work up, the reaction mixture was analysed by
GC, GC-MS and H-NMR. The only product observed was
N-methylaniline (comparison with an authentic specimen), in
addition to the unreacted starting materials. There was no
evidence for the formation of methyl phenyl sulfoxide.
1
7 S. J. Yang and W. Nam, Inorg. Chem., 1998, 37, 606–607.
8 L. Engman, J. Persson, C. M. Andersson and M. Berglund, J. Chem.
Soc., Perkin Trans.2, 1992, 1309–1313.
9 The presence of imidazole should make negligible any 18O exchange
between the iron-oxo complex and H2O due to the so called
oxo–hydroxo tautomerism (ref. 10).
10 J. Bernadou and B. Meunier, Chem. Commun., 1998, 2167–2173 and
references therein.
11 M. Jonsson, J. Lind, G. Merényi and T. E. Eriksen, J. Chem. Soc.,
Perkin Trans. 2, 1995, 67–70.
12 E. Baciocchi, M. F. Gerini and O. Lanzalunga, unpublished results.
13 (a) J. T. Groves and J. A. Gilbert, Inorg. Chem., 1986, 25, 123–125;
(b) H. Sugimoto, H. C. Tung and D. T. Sawyer, J. Am. Chem. Soc.,
1988, 110, 2465–2470.
14 E. Baciocchi, M. F. Gerini, O. Lanzalunga, A. Lapi, M. G. Lo
Piparo and S. Mancinelli, Eur. J. Org. Chem., 2001, 2305–2310.
15 M. Bietti, E. Baciocchi and S. Steenken, J. Phys. Chem. A, 1998, 102,
7337–7342.
Competitive oxidation of thioanisole and 4-methoxythioanisole
or 4-cyanothioanisole
An equimolecular amount of thioanisole and 4-methoxythio-
anisole or 4-cyanothioanisole (10 µmol each) were reacted with
0.6 µmol of FeTPPSCl and 1.0 µmol of H2O2 following the
general procedure described above. After the work up, the
relative yields of the two sulfoxides were determined by GC and
1H-NMR.
18O incorporation experiments
16 I. Saito, T. Matsuura and K. Inoue, J. Am. Chem. Soc., 1983, 105,
3200–3206.
In the oxidations carried out using H218O as the solvent or
H218O2 as the oxidant, 18O incorporation in the formed sulf-
oxide was calculated from the areas of the molecular ion peaks of
4-X–C6H4–S(18O)–R (mϩ2)/z and 4-X–C6H4–S(16O)–R (m/z)
determined via LC-MS for 4-CH3O–C6H4–S(O)–CH(CH3)2 and
GC-MS for the other sulfoxides. A correction was made to take
into account the presence of 34S by subtracting its contribution
to the (mϩ2)/z ion of the sulfoxide produced.
17 The reaction of the radical cation with PFe()᎐O may, of course,
᎐
also lead to N-demethylated products in addition to sulfoxides. This
؉
actually occurs with 11؉ , whereas with 10 only sulfoxidation is
ؒ
ؒ
observed (ref. 18).
18 The competition between the two processes should depend on the
relative charge/spin densities on sulfur and nitrogen atoms of the
radical cation. Preliminary calculations carried out on 11؉ (with
ؒ
the GAUSSIAN 9819 package using a DFT approach at the B3LYP/
6-311g** level of theory) indicates that approximately the same spin
is localised on the SCH3 and N(CH3)2 groups, 0.29 and 0.33
respectively, while the charge density is 0.19 and 0.29, respectively.
19 M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria,
M. A. Robb, J. R. Cheeseman, V. G. Zakrzewski, J. A. Montgomery,
R. E. Stratmann, J. C. Burant, S. Dapprich, J. M. Millam,
A. D. Daniels, K. N. Kudin, M. C. Strain, O. Farkas, J. Tomasi,
V. Barone, M. Cossi, R. Cammi, B. Mennucci, C. Pomelli,
C. Adamo, S. Clifford, J. Ochterski, G. A. Petersson, P. Y. Ayala,
Q. Cui, K. Morokuma, D. K. Malick, A. D. Rabuck,
K. Raghavachari, J. B. Foresman, J. Cioslowski, J. V. Ortiz,
B. B. Stefanov, G. Liu, A. Liashenko, P. Piskorz, I. Komaromi,
R. Gomperts, R. L. Martin, D. J. Fox, T. Keith, M. A. Al-Laham,
C. Y. Peng, A. Nanayakkara, C. Gonzalez, M. Challacombe,
P. M. W. Gill, B. G. Johnson, W. Chen, M. W. Wong, J. L. Andres,
M. Head-Gordon, E. S. Replogle and J. A. Pople, Gaussian, Inc.,
Pittsburgh, PA, 1998.
Acknowledgements
This work was carried out with the financial support of the
Ministero dell’Istruzione, dell’Università
e della Ricerca
(MIUR).
References
1 H. B. Dunford, in Heme Peroxidase, John Wiley, New York, 1999.
2 (a) S. Kobayashi, M. Nakano, T. Kimura and A. P. Schaap,
Biochemistry, 1987, 26, 5019–5022; (b) D. R. Doerge, N. M. Cooray
and M. E. Brewster, Biochemistry, 1991, 30, 8960–8964; (c) E.
Baciocchi, O. Lanzalunga and F. Marconi, Tetrahedron Lett., 1994,
35, 9771–9774; (d ) E. Baciocchi, M. Ioele, O. Lanzalunga,
S. Malandrucco and S. Steenken, J. Am. Chem. Soc., 1996, 118,
8973–8974; (e) E. Baciocchi, O. Lanzalunga and B. Pirozzi,
Tetrahedron, 1997, 53, 12287–12298; ( f ) Y. Goto, T. Matsui,
S. Ozaki, Y. Watanabe and S. Fukuzumi, J. Am. Chem. Soc., 1999,
121, 9497–9502.
3 (a) D. R. Doerge, Arch. Biochem. Biophys., 1986, 244, 678–685;
(b) U. Perez and H. B. Dunford, Biochemistry, 1990, 29, 2757–2763;
(c) U. Perez and H. B. Dunford, Biochim. Biophys. Acta, 1990,
1038, 98–104; (d ) A. Tuyman, M. K. S. Vink, H. L. Dekker,
H. E. Shoemaker and R. Wever, Eur. J. Biochem., 1998, 258, 906–
913; (e) E. Baciocchi, M. F. Gerini, P. J. Harvey, O. Lanzalunga and
S. Mancinelli, Eur. J. Biochem., 2000, 267, 2705–2710.
3
Ϫ1 2d
20 The decay rate of 9؉ is 2.6 × 10 s
.
ؒ
21 A. M. English and G. Tsaprailis, Adv. Inorg. Chem.,, 1995, 43,
79–125.
22 L. Fieser and M. Fieser, in Reagents in Organic Chemistry,
John Wiley & Sons Inc., New York, 1967.
23 E. B. Fleisher, J. M. Palmer, T. S. Srivastava and A. Chatterjee,
J. Am. Chem. Soc., 1971, 93, 3162–3167.
24 R. B. Wargner and H. D. Zook, in Synthetic Organic Chemistry,
John Wiley, New York, 1965, p. 787–796.
25 C. M. Suter and H. L. Hansen, J. Am. Chem. Soc., 1932, 54, 4100–
4105.
26 A. I. Vogel, J. Chem. Soc., 1948, 1820–1833.
27 N. C. Cutress, T. B. Grindley, A. R. Katritzky and R. D. Topsom,
J. Chem. Soc., Perkin Trans. 2, 1974, 263–268.
28 J. P. Dinnocenzo, S. B. Karki and J. P. Jones, J. Am. Chem. Soc.,
1993, 115, 7111–7116.
29 W. R. Kirner and G. H. Richter, J. Am. Chem. Soc., 1929, 51, 3409–
3412.
4 (a) S. Oae, Y. Watanabe and K. Fujimori, Tetrahedron Lett., 1982,
23, 1189–1192; (b) W. Ando, R. Tajima and T. Takata, Tetrahedron
Lett., 1982, 23, 1685–1688; (c) T. Takata, R. Tajima and W. Ando,
Phosphorus Sulfur, 1983, 16, 67–78.
5 (a) B. Meunier, Chem Rev., 1992, 92, 1411–1456; (b) R. A. Sheldon,
in Metalloporphyrins in Catalytic Oxidations, M. Dekker Inc.,
New York, 1994.
30 C. R. Johnson and N. J. Leonard, J. Org. Chem., 1962, 27, 282–284.
31 L. Eberson, J. Am. Chem. Soc., 1983, 105, 3192–3199.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 2 2 – 4 2 6
426