Deprotonation in anodic methoxylation of fluoroethyl phenyl sulfides using site-isolated heterogeneous bases

Article abstract of DOI:10.1039/b809998g

On the basis of the concept of site isolation in electrochemical reactions, we have successfully demonstrated acceleration of the deprotonation step in anodic methoxylation of fluoroethyl phenyl sulfides using silica gel supported bases. The Royal Society

Full text of DOI:10.1039/b809998g

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Deprotonation in anodic methoxylation of fluoroethyl phenyl sulfides
using site-isolated heterogeneous basesw
Toshiki Tajima*a and Hitoshi Kuriharab
Received (in Cambridge, UK) 12th June 2008, Accepted 11th July 2008
First published as an Advance Article on the web 10th September 2008
DOI: 10.1039/b809998g
On the basis of the concept of site isolation in electrochemical
reactions, we have successfully demonstrated acceleration of the
deprotonation step in anodic methoxylation of fluoroethyl phenyl
sulfides using silica gel supported bases.
In principle, opposing reagents (e.g. acid/base and oxidizing/
reducing reagents) cannot be put in a single reactor owing to
their mutual destruction. About 30 years ago, Cohen et al.
demonstrated one-pot multistep reactions with the concept of
site isolation, which was defined as that the attachment of
opposing reagents to the respective insoluble polymers suppresses
their mutual destruction.1 Since the pioneering work of Cohen
et al., sol–gel materials,2 layered clays,3 star polymers,4 magnetic
particles,5 and microcapsules6 have been applied to site-isolated
catalysts toward one-pot multistep reactions.7
Fig. 1 Cyclic voltammograms of (a) MTBD (0.01 M) and (b) Si-TBD
(0.01 M) in 0.1 M NaClO4–MeCN, recorded at a Pt disk electrode
Electrodes in electrochemical reactions are inherently site-
(f = 0.8 mm). The scan rate was 100 mV sꢀ1
.
isolated heterogeneous redox reagents. Therefore, an anode
and a cathode, which are respectively equivalent to oxidizing
and reducing reagents, can be put in a single reactor. On the
other hand, site isolation between electrodes and solid-supported
reagents would also be achieved. Namely, solid-supported
reagents should act as site-isolated heterogeneous reagents in
electrochemical reactions without the oxidative and reductive
destruction at electrodes. We have recently developed novel
electrolytic systems for organic electrosynthesis using solid-
supported acids8 and bases.9 In a series of studies, it was found
that solid-supported acids and bases are electrochemically stable
and thus reusable for many times. Breinbauer and Nad also
reported that direct electrochemical oxidation of polymer-
immobilized furans is difficult because of steric reasons.10 We
can regard their electrochemical stability and reactivity as site
isolation in electrochemical reactions.
problem. Thus, we herein demonstrate acceleration of the
deprotonation step in anodic methoxylation of fluoroethyl phenyl
sulfides using site-isolated heterogeneous bases.
First of all, in order to demonstrate the site isolation between
the anode and solid-supported bases, we measured the cyclic
voltammograms of 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene
(MTBD), which is a strong base, and silica gel supported
1,5,7-triazabicyclo[4.4.0]dec-5-ene (Si-TBD) in MeCN. As
shown in Fig. 1, MTBD was easily oxidized at ca. 1.0 V vs.
SCE, while Si-TBD was not oxidized at all in the same potential
range. These results support the concept of site isolation in
electrochemical reactions.
It has been reported that anodic oxidation of alkyl phenyl
sulfides in anhydrous organic solvents generally gives sulfonium
ions to form sulfonium salts with anions derived from supporting
electrolytes (Scheme 1, path A),11 while anodic substitution
reactions are favored in the presence of bases or nucleophiles,
and by the presence of electron-withdrawing groups at the
a-position of the sulfur atom (Scheme 1, path B).12,13 With these
facts in mind, we next measured the cyclic voltammograms of
2,2-difluoroethyl phenyl sulfide (1) in the absence and presence of
Si-TBD in MeCN. As shown in Fig. 2(a), two oxidation waves
were observed in the absence of Si-TBD. These waves correspond
to the oxidation of 1 and the resulting sulfonium salt, respectively
(Scheme 1, path A).11b In the presence of Si-TBD, the first
oxidation wave was shifted in the negative direction and became
larger as shown in Fig. 2(b). These results suggest that
Si-TBD accelerates the deprotonation of the radical cation
intermediate, which is followed by a rapid loss of the second
The concept of site isolation in electrochemical reactions may
also be applied to the use of solid-supported reagents in organic
electrosynthesis for accelerating the subsequent chemical reactions
that typically follow electron transfer at electrodes. For instance, it
is generally difficult to accelerate the deprotonation step in anodic
oxidation of organic compounds using homogeneous bases owing
to the oxidative destruction at the anode. The concept of site
isolation in electrochemical reactions would potentially solve the
a Global Edge Institute, Tokyo Institute of Technology, Yokohama
226-8502, Japan. E-mail: tajima.t.ac@m.titech.ac.jp;
Fax: +81-45-924-5169; Tel: +81-45-924-5169
b Department of Electronic Chemistry, Tokyo Institute of Technology,
Yokohama, 226-8502, Japan
w Electronic supplementary information (ESI) available: Chemicals
and experimental details. See DOI: 10.1039/b809998g
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product 2 was formed in low yield (Entry 1). In contrast,
the yield of 2 increased with increasing amount of Si-TBD
(Entries 2–4). These findings indicate that anodic methoxyla-
tion of 1 is promoted by Si-TBD, thereby suggesting that the
deprotonation of the radical cation intermediate is accelerated
by Si-TBD. However, the lifetime of the radical cation inter-
mediate generated at the anode surface seems to be too short
for it to be affected directly by the site-isolated Si-TBD. In the
presence of Si-TBD, the acid–base reaction between MeOH as
a solvent and Si-TBD should occur to generate methoxide ion
[eqn (1)]. The methoxide ion might act as a base in the
neighborhood of the anode surface to accelerate the deproto-
nation of the radical cation intermediate. When Si-TBD was
used (Entries 3 and 4), a larger amount of electricity was
required compared to that in the absence of Si-TBD
(Entry 1). This seems to be due to the oxidation of the
methoxide ion at the anode. Therefore, these results suggest
that the methoxide ion derived from eqn (1) acts as a base in
the neighborhood of the anode surface and hence it is oxidized
at the anode. On the other hand, the yield of 2 was correlated
with the basicity of silica gel supported bases (Entries 4–6).
These results indicate that Si-TBD is the most suitable for
accelerating the deprotonation step in anodic methoxylation of
1. The use of Si-TBD as not only a base but also a supporting
electrolyte9a increased the yield of 2 to 86% (Entry 7). In this
case, the methoxide ion derived from eqn (1) must form an
electrical double layer at the anode surface, because the
electrolysis was carried out in the absence of NaClO4 as a
supporting electrolyte. Therefore, the methoxide ion can attack
the radical cation intermediate generated at the anode surface
to accelerate its deprotonation more effectively. In sharp
contrast, when MTBD was used instead of Si-TBD, 1 was
completely recovered (Entry 8). In this case, the acid–base
reaction between MeOH and MTBD should take place to
generate methoxide ion homogeneously in the electrolytic
solution. Therefore, the methoxide ion seems to be mainly
oxidized at the anode. From the comparison of Entries 7 and 8,
it is clear that Si-TBD acts as a site-isolated heterogeneous base
in anodic methoxylation of 1. Furthermore, the methoxide ion
derived from eqn (1) seems to be mostly localized on the porous
silica gel surface because of the formation of the conjugate
acid–base pair. In other words, a methoxide ion concentration
gradient seems to form in the presence of Si-TBD (Entry 7).
Thus, it is suggested that the methoxide ion as well as the site-
isolated Si-TBD is protected within the porous silica gel matrix.
Scheme 1 Anodic oxidation of alkyl phenyl sulfides in anhydrous
organic solvents.
Fig. 2 Cyclic voltammograms of (a) 1 (0.01 M) and (b) 1 (0.01 M) in
the presence of 0.2 M Si-TBD in 0.1 M NaClO4–MeCN, recorded at a
Pt disk electrode (f = 0.8 mm). The scan rate was 100 mV sꢀ1
.
electron (Scheme 1, path B). The second oxidation wave for the
sulfonium salt disappeared, which also supports our suggestion.
We then investigated anodic methoxylation of 112 as a model
reaction using silica gel supported bases as shown in Table 1.z
In the absence of bases, anodic methoxylation of 1 did not
proceed smoothly and the corresponding a-methoxylated
Table 1 Anodic methoxylation of 1 using silica gel supported bases
Electricity/
Faraday molꢀ1
Entry
Base
Yielda (%)
1
2
3
4
—
0.01 M Si-TBD (14.5)b
0.1 M Si-TBD
4
3
6
6
5
5
6
6
29
32
54
67
31
47
86
0 [98]f
0.2 M Si-TBD
ð1Þ
5
0.2 M Si-pyridinec (5.2)
0.2 M Si-pyperidined (11.2)
0.2 M Si-TBD
6
7e
8e
In order to demonstrate the scope and limitations, we next
investigated anodic methoxylation of fluoroethyl phenyl sulfides
3 and 5 in the absence and presence of Si-TBD as shown in
Table 2. Although 3 has a strongly electron-withdrawing CF3
group at the a-position of the sulfur atom, anodic methoxylation
0.2 M MTBD
a 19F NMR yield based on the CHF2 group using monofluorobenzene
b
as an internal standard. pKa value of the conjugate acid in parenth-
c
eses. Silica gel supported pyridine. Silica gel supported piperidine.
d
e
f
Electrolysis was carried out in the absence of NaClO4. Recovery of
of
3 did not proceed smoothly and the corresponding
1 in brackets.
a-methoxylated product 4 was formed in low yield in the
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Table 2 Anodic methoxylation of 3 and 5 in the absence and presence
of Si-TBD
Notes and references
z General procedure for anodic methoxylation of fluoroethyl phenyl
sulfides 1, 3, and 5: anodic methoxylation of a substrate (1 mmol) was
carried out with platinum plate electrodes (2 ꢂ 2 cm2) in 0.2 M Si-TBD
(particle size: 40–63 mm, loading: 0.91 mmol gꢀ1)/MeOH (based on the
concentration of TBD, 10 ml)) using an undivided cell. Constant
current electrolysis (5 mA cmꢀ2) was conducted with magnetic stirring
at room temperature. After the electrolysis, the yield of the product
was calculated by means of 19F NMR using a known amount of
monofluourobenzene (1 mmol) as an internal standard. The products
2,12b 4,12c and 613d were identified by comparison with the literature
Supporting
electrolyte
Electricity/
Entry
Rf
Faraday molꢀ1
Yielda (%)
1
values using H and 19F NMR and mass spectroscopy.
1
2
3
4
CF3
CF3
CH2F
CH2F
0.1 M NaClO4
0.2 M Si-TBD
0.1 M NaClO4
0.2 M Si-TBD
3
7
3
3
31
76
Trace
16
1 (a) B. J. Cohen, M. A. Kraus and A. Patchornik, J. Am. Chem.
Soc., 1977, 99, 4165–4167; (b) B. J. Cohen, M. A. Kraus and A.
Patchornik, J. Am. Chem. Soc., 1981, 103, 7620–7629.
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an internal standard.
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absence of Si-TBD (Entry 1). This result suggests that sponta-
neous deprotonation of the radical cation intermediate is not
favored in the absence of Si-TBD. In sharp contrast, 4 was
obtained in high yield in the presence of Si-TBD (Entry 2).
Anodic methoxylation of 5 did not proceed at all in the absence
of Si-TBD, because 5 has the low acidity of the a-proton of the
sulfur atom due to the weakly electron-withdrawing CH2F
group (Entry 3). On the other hand, the yield was low, but 6
was certainly formed in the presence of Si-TBD (Entry 4). These
findings indicate that the deprotonation step in anodic methox-
ylation of fluoroethyl phenyl sulfides is accelerated by Si-TBD.
In conclusion, we have successfully demonstrated accelera-
tion of the deprotonation step in anodic methoxylation of
fluoroethyl phenyl sulfides using site-isolated heterogeneous
bases. It is expected that solid-supported reagents will be
applied extensively in organic electrosynthesis to accelerate
the subsequent chemical reactions without the oxidative and
reductive destruction at electrodes. Furthermore, the concept
of site isolation in electrochemical reactions will enable us to
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This work was financially supported by a Grant-in-Aid for
Young Scientists (A) (No. 19685014) from The Ministry of
Education, Culture, Sports, Science and Technology, Japan.
Prof. A. K. Yudin and Prof. M. Atobe are acknowledged for
fruitful discussions.
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This journal is The Royal Society of Chemistry 2008
Chem. Commun., 2008, 5167–5169 | 5169