In situ electrogeneration of o-benzoquinone and high yield reaction with benzenethiols in a microflow system

Article abstract of DOI:10.1039/c2cc17979b

We have successfully demonstrated that a microflow reactor is extremely useful in controlling reactions involving an unstable o-benzoquinone. The key features of the method are an effective o-benzoquinone generation and its rapid use for the following rea

Full text of DOI:10.1039/c2cc17979b

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COMMUNICATION
In situ electrogeneration of o-benzoquinone and high yield reaction with
benzenethiols in a microflow systemw
Tsuneo Kashiwagi,a Fumihiro Amemiya,a Toshio Fuchigamia and Mahito Atobe*ab
Received 21st December 2011, Accepted 20th January 2012
DOI: 10.1039/c2cc17979b
We have successfully demonstrated that a microflow reactor is
extremely useful in controlling reactions involving an unstable
o-benzoquinone. The key features of the method are an effective
o-benzoquinone generation and its rapid use for the following
reaction without decomposition in a microflow system.
o-Quinones are useful and important synthetic building blocks
in organic and medicinal chemistry.1–15 However, o-quinones are
too reactive and unstable to store and not easy to handle because
of their lability; that is, decomposition, isomerization, or poly-
merization often occur during storage. Therefore, these
o-quinones are usually prepared by the in situ oxidation of
the corresponding catechols in the presence of a reaction
partner.14,15 However, the oxidation potentials of the reaction
Fig. 1 Schematic representation of the electrogeneration of o-benzoqui-
partners, especially nucleophiles, are often the same or lower
none and the following reaction with a benzenethiol in the microflow
than those of the corresponding catechols, and therefore the
presence of the partners would prevent the desired oxidation
of the catechols.14 To avoid the decomposition of o-quinones
and competing oxidation, catechols must be oxidized in the
absence of organic substrate and then used immediately for the
following reaction.
reactor.
oxidation of catechol and benzenethiols as a model reaction
(Fig. 1). The reaction products are diphenyl sulfide derivatives,
which are valuable synthetic intermediates frequently found in
bioactive compounds and polymeric materials.18
The microflow reactor fabricated for the model reaction
consists of two parts, an electrolysis part for the generation of
o-benzoquinone and a chemical reaction part for its rapid use
for Michael addition reaction. The electrochemical generation
of o-benzoquinone capitalized on the oxidation of catechol.15
This method enables rapid generation of o-benzoquinone and does
not require the use of a chemical oxidant that can complicate
downstream processes. In order to obtain a sufficient bulk
conversion, we chose a graphite plate as an anode material for
the microreactor because of its large superficial area in a
specific size. On the other hand, a Pt plate was employed as
a cathode material since a cathodic process in the electro-
synthesis is hydrogen evolution.
Microflow reactors are ideal for conducting such transfor-
mations because they enable the precise control of short-lived
species. In doing so, they facilitate highly selective reactions that
are difficult to achieve in a conventional reactor. In addition,
microflow reactors offer advantages such as large specific inter-
facial area, short molecular diffusion distance, and short residence
time in the reactors.16 Yoshida et al. have successfully demon-
strated that the short-lived species such as o-bromophenyllithium
can be generated in a microflow system and then immediately
transferred to a vessel in which a following electrophilic reaction
takes place to give final products in high yields.17
In this communication, we wish to demonstrate that a
microflow reactor is extremely useful in controlling reactions
involving an unstable o-quinone. We chose a Michael addition
reaction between o-benzoquinone generated from electrochemical
Prior to using the microflow reactor, the model reaction was
examined in a conventional batch type cell using 4-isopropyl-
benzenethiol as a nucleophile (Table 1, entry 1). At first, when
catechol and 4-isopropylbenzenethiol were mixed in the same
electrolytic cell (in-cell method), the desired product was
obtained in 13% yield. According to I–E curves of catechol
and 4-isopropylbenzenethiol, oxidation potentials of both
catechol and 4-isopropylbenzenethiol were relatively close to
each other (Fig. 2). Hence, the competing oxidation that most
likely occurred is an issue for this reaction.
a Department of Electronic Chemistry, Tokyo Institute of Technology,
4259 Nagatsuta-cho, Midori-ku, Yokohama, 226-8502, Japan
b Department of Environment and System Sciences, Yokohama
National University, 79-7 Tokiwadai, Hodogaya-ku, Yokohama,
240-8501, Japan. E-mail: atobe@ynu.ac.jp; Fax: +81-45-339-4214;
Tel: +81-45-339-4214
w Electronic supplementary information (ESI) available: Chemicals
and experimental details. See DOI: 10.1039/c2cc17979b
c
2806 Chem. Commun., 2012, 48, 2806–2808
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Table 1 Chemical yields of 3 in the sequential reaction using a batch
type cell and microreactora
Table 2 Effect of the flow rate and current density on yield of 3a
Entry Flow rate/mL minÀ1 Current density/mA cmÀ2 Yieldb (%)
1
2
3
4
5
6
7
0.01
0.05
0.10
0.14
0.10
0.10
0.10
1.5
1.5
1.5
1.5
1.1
3.0
6.0
8
48
88
66
48
48
32
Entry
Reactor type
Yieldc (%)
a
Experimental conditions: anode, graphite plate; cathode, Pt plate;
electrode distance, 80 mm; solvent, AcCN; substrate, 10 mM catechol;
supporting electrolyte, 100 mM NaClO4; nucleophile, 10 mM
1
2
3
Batch type cell (in-cell)
Batch type cell (ex-cell)
Microflow reactorb
13
32
88
b
4-isopropylbenzenethiol; base, 10 mM 2,6-lutidine. Determined by
HPLC.
a
Experimental conditions: anode, graphite plate; cathode, Pt plate;
current density, 1.5 mA cmÀ2; solvent, AcCN; substrate, 10 mM
catechol; supporting electrolyte, 100 mM NaClO4; nucleophile, 10 mM
could be observed in these cases. On the other hand, at
0.14 mL minÀ1 of the flow rate (Table 2, entry 4), the yield
decreased again. This can be explained by an insufficient bulk
conversion due to a higher flow rate. Actually, ca. 30% of the
starting material was recovered in this case. At 1.1 mA cmÀ2
of the current density (Table 2, entry 5), the yield was less than
50% due to an insufficient bulk conversion. On the other
hand, at higher current densities (Table 2, entries 6 and 7), the
yield was 50% or worse since overoxidation took place.
Actually, black precipitates were confirmed in these cases.
Finally, to demonstrate the generality of this methodology,
we also investigated Michael addition reactions between o-benzo-
quinone generated from electrochemical oxidation of catechol
and other benzenethiols using the microflow reactor, and
compared with those using the batch type electrolytic cell
(in-cell method).
b
4-isopropylbenzenethiol; base, 10 mM 2,6-lutidine. Electrode distance,
80 mm; flow rate, 0.1 mL minÀ1
c
.
Determined by HPLC.
As shown in Table 3, the yields in all cases were higher for
reactions run with the microflow reactor. The generation
amount of o-benzoquinone in the first electrochemical oxida-
tion step of the microreactor process should be the same for all
the reactions since the electrolysis part of the reactor is the
same. Therefore, overall yields for the two-step sequence are
reflection of the Michael addition. Since the nucleophilicity of
Fig. 2 I–E curves of (A) 10 mM catechol and (B) 10 mM 4-isopro-
pylbenzenethiol at a graphite disk anode (4 mm +) in 100 mM
NaClO4 + 10 mM 2,6-lutidine acetonitrile solution.
Subsequently, 4-isopropylbenzenethiol was added to the
batch type electrolytic cell after the catechol electrochemical
oxidation (ex-cell method) in order to prevent the competing
oxidation (Table 1, entry 2). In this case, the product yield
improved to 32%. However, black precipitates were confirmed
before addition of 4-isopropylbenzenethiol. The formation of the
precipitate indicated decomposition of the o-benzoquinone19
during the extended electrolysis time needed to accumulate
sufficient quantities of the intermediate. On the other hand, by
using the microflow reactor, the desired product yield was
significantly improved to 88% (the productivity was 13.8 mg hÀ1).
This result apparently suggests that o-benzoquinone could be
generated effectively without interference of the thiol oxidation,
and in addition the generated o-benzoquinone could be used
rapidly for the reaction with 4-isopropylbenzenethiol without
decomposition (Table 1, entry 3).
Table 3 Michael addition reactions between o-benzoquinone generated
from electrooxidation of catechol and benzenethiolsa
Nucleophile
Product
Reactor type
Microflow reactorb 88
Yieldb (%)
Batch type cell
13
Microflow reactorb 79
Batch type cell
n.d.
Microflow reactorb 81
Batch type cell
7
Then the influence of the flow rate and current density on
the model sequential reaction using the microflow reactor was
examined (Table 2). The yield of 3 increased with an increase in the
flow rate, and the highest value was obtained at 0.1 mL minÀ1
(Table 2, entries 1, 2, and 3). At lower flow rates, the decomposi-
tion and overoxidation of o-benzoquinone occurred due to a
longer residence time in the reactor. In fact, black precipitates
a
Experimental conditions: anode, graphite plate; cathode, Pt plate;
electrode distance, 80 mm; current density, 1.5 mA cmÀ2; flow rate,
0.1 mL minÀ1; solvent, AcCN; substrate, 10 mM catechol; supporting
electrolyte, 100 mM NaClO4; nucleophile, 10 mM 4-isopropylbenze-
b
nethiol; base, 10 mM 2,6-lutidine. Determined by HPLC.
c
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all three thiols studied is roughly equivalent, the three reactions
led to similar yields. On the other hand, in batch processes
(in-cell method), product yields would be dependent on the
oxidation potential of benzenethiols used because catechol and
benzenethiols are mixed in the same electrolytic cell in these
cases. Hence, the yields for batch processes are all low because
of competitive oxidation of the thiol nucleophile.
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In summary, we have developed an effective method for the
generation and reaction of o-benzoquinone using a microflow
system. The key features of the method are an effective
o-benzoquinone generation and its rapid use for the following
reaction in the microflow system. It is hoped that this facile and
novel reaction system will highlight the utility of flow reactors
for optimizing reactions involving sensitive intermediates.
¨
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2808 Chem. Commun., 2012, 48, 2806–2808
This journal is The Royal Society of Chemistry 2012