An anodic aromatic C,C cross-coupling reaction using parallel laminar flow mode in a flow microreactor

Article abstract of DOI:10.1039/c5cc01253h

We have successfully demonstrated an efficient anodic aromatic C,C cross-coupling reaction using parallel laminar flow mode in a two-inlet flow microreactor. The model reaction proceeded effectively even in single flow-through operations and the desired c

Full text of DOI:10.1039/c5cc01253h

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An anodic aromatic C,C cross-coupling reaction
using parallel laminar flow mode in a flow
microreactor†
Cite this: Chem. Commun., 2015,
51, 4891
Received 10th February 2015,
Accepted 12th February 2015
Toshihiro Arai, Hiroyuki Tateno, Koji Nakabayashi, Tsuneo Kashiwagi and
Mahito Atobe*
DOI: 10.1039/c5cc01253h
www.rsc.org/chemcomm
We have successfully demonstrated an efficient anodic aromatic the overoxidation of the cross-coupling products is usually
C,C cross-coupling reaction using parallel laminar flow mode in a unavoidable during the reaction because the oxidation potentials
two-inlet flow microreactor. The model reaction proceeded effectively of the cross-coupling products such as biaryl compounds are
even in single flow-through operations and the desired cross-coupling generally lower than those of the corresponding substrates. To
product was obtained in much higher current yields compared to the solve these problems, several approaches have recently been
reaction in a conventional batch type cell.
demonstrated. Waldvogel et al. reported the electrochemical
cross-coupling between phenols and arenes using boron-doped
The aromatic C,C cross-coupling reactions are the central methods diamond (BDD) anodes in fluorinated media. In this demonstration,
for syntheses of ligands, polymers, and natural products containing employing water or methanol as a mediator represents the key
non-symmetric biaryl structures.1 Although a number of synthetic improvement for achieving nonsymmetrical biaryls with superb
approaches for aromatic C,C cross-coupling have been developed selectivity and synthetic attractive yields.13 On the other hand,
so far, transition metal-catalyzed reaction has emerged as one of Yoshida and co-workers reported the efficient aromatic C,C
the most powerful methods in the past decades.2–4 In this kind cross-coupling reaction by the use of the radical-cation pool
of reaction, installation of leaving groups on aromatic rings is method, which involves generation and accumulation of an unstable
necessary, and hence it takes additional steps and the presence radical cation of an aromatic compound by low-temperature
of a leaving group leads to additional waste production. On the electrochemical oxidation and a subsequent reaction with
other hand, transition metal catalyzed C–H bond activation for another aromatic compound.14 Thus, development of an efficient
C,C cross-coupling reactions has been of great interest in recent anodic C,C cross-coupling reaction of aromatic compounds has
years because no prefunctionalized starting aromatic compounds been receiving significant research interest and a further investi-
are needed.5,6 However, these reactions still require complex, gation is still a challenging target.
toxic, and expensive transition metal catalysts. Therefore, a reaction
that does not require transition metal catalyst is an attractive have been developed in recent years.15 A flow microreactor has
alternative from both academic and practical points of view.7,8
several features such as large surface-to-volume rate, short
Meanwhile, electrosynthetic processes using a flow microreactor
Electrochemical oxidation which enables a straightforward molecular diffusion distance, and short residence time in the
activation of C–H bonds is economically and environmentally reactor, and therefore it provides ideal reaction circumstances
attractive since only electrons serve as reagents and the reaction compared to a classical batch type reactor.16 Especially, the use
proceeds under mild conditions.9–11 Actually, the anodic of parallel laminar flow mode in a two-inlet flow microreactor
oxidation in the mixture of two aromatic compounds can provide allows effectively chemoselective electrochemical reaction.17
the cross-coupling products but their selectivities are usually The channel of the flow microreactor is small enough to ensure
low.12 In these cases, the homo-coupling reactions also occur by that the flow is stable and laminar. When two solutions are
the non-selective oxidation of the starting materials. In addition, introduced through the two inlets (called inlets 1 and 2 in Fig. 1),
a stable liquid–liquid interface could be formed and mass transfer
between input streams occurred only via diffusion. Actually, in
our previous work, the formation of liquid–liquid parallel laminar
Department of Environment and System Sciences, Yokohama National University,
79-7 Tokiwadai, Hodogaya-ku, Yokohama, Kanagawa 240-8501, Japan.
flow in the microreactor was confirmed by electrochemical
E-mail: atobe@ynu.jp; Fax: +81-45-339-4214; Tel: +81-45-339-4214
measurements and computational fluid dynamics simulations.17c
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c5cc01253h
Therefore, when substrates and nucleophile solutions were
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Table 1 Anodic C,C cross-coupling reaction between 1 and 2 using a
batch type cell and flow microreactorsa
Fig. 1 Schematic representation of liquid–liquid parallel laminar flow in
the two-inlet electrochemical flow microreactor.
introduced through inlets 1 and 2, respectively, substrates
could be oxidized dominantly to generate unstable intermediates
such as radical cations and cations while the oxidation of
nucleophiles was avoided. Consequently the intermediates
generated at the anode surface could rapidly diffuse to the bulk
electrolytic solution and react with nucleophiles to afford desired
coupling products. Thus, this system can enable chemoselective
anodic oxidation under mild conditions.
Herein, we wish to report that the use of parallel laminar
flow mode in a two-inlet flow microreactor is extremely useful
for the selective anodic oxidation of an aromatic substrate
and the subsequent C,C cross-coupling reaction with another
aromatic nucleophile. In this demonstration, we chose an anodic
cross-coupling reaction between naphthalene 1 and pentamethyl-
benzene 2 as a model reaction (Table 1).12 In this model reaction,
the desired cross-coupling product 3 can be obtained via the
reaction between the electrogenerated radical cations of 1 and 2 as
a coupling partner. Hence, the selective oxidation of 1 is necessary
for achievement of the cross-coupling.
First of all, oxidation potentials of substrate 1, nucleophile 2,
and the desired product 3 were measured in a conventional
undivided electrochemical cell by linear sweep voltammetry. As
shown in Fig. 2, the oxidation potentials of 2 and 3 were lower
than that of 1. Also the oxidation potentials of 2 and 3 were close
to each other. These results indicate that undesired anodic
oxidation of nucleophile 2 and in addition overoxidation of 3
would be unavoidable in the conventional batch type reactor.
Subsequently we measured linear sweep voltammograms for
the oxidation of 2 in the practical flow microreactor. When an
electrolytic solution with 2 was introduced through only inlet 1 of
Fig. 1, the higher oxidation current of 2 could be observed at the
1.5 V vs. Ag wire as shown in Fig. 3(b). In contrast, the oxidation
current of 2 clearly decreased when an electrolytic solution with 2
was introduced through inlet 2 while an electrolytic solution
without 2 was introduced through inlet 1 (Fig. 3(c)). These results
suggest that the parallel laminar flow was formed in the reactor
and the use of parallel laminar flow mode enabled preventing 2
from reaching the anode and being oxidized.
Entry Reactor type
Flow rate (mL minÀ1
)
Current yieldd (%)
1
2
3
4
5
Batch type cell
Flow mode (a)b
Flow mode (b)b
Flow mode (c)b
Flow mode (c)b
—
49
66
85
n.d.
n.d.
0.47
0.47c
0.47
0.93
a
Experimental conditions: anode, Pt plate; cathode, Pt plate; current
density, 25 mA cmÀ2; charge passed, 0.2 F molÀ1; solvent, CH3CN/
CH3COOH (volume ratio = 9 : 1); substrate, 500 mM of 1; nucleophile,
b
500 mM of 2; supporting electrolyte, 100 mM of Bu4NBF4. Electrode
c
d
distance, 20 mm. Total flow rate. Determined by HPLC. The current
yield is the theoretical amount of electricity divided by the amount
actually employed for the generation of the desired product.
Fig. 2 Linear sweep voltammograms of (a) naphthalene 1, (b) penta-
methylbenzene 2, and (c) cross-coupling product 3. Conditions: substrate
conc., 10 mM; supporting electrolyte, 100 mM Bu4NBF4; solvent, CH3CN/
CH3COOH (volume ratio = 9 : 1); working electrode, Pt disc (j = 3 mm);
counter electrode, Pt plate (2 Â 2 cm2); scan rate, 10 mV sÀ1
.
Taking into account these results, we conducted preparative
scale experiments of an anodic C,C cross-coupling reaction
using a batch type cell and flow microreactors. In the batch surface. On the other hand, the current yield of 3 was improved
type cell, the desired cross-coupling product 3 was obtained in to some extent by using flow mode (a) as this mode could avoid
an unsatisfactory current yield (Table 1, entry 1). In this case, as the overoxidation of 3 (Table 1, entry 2). In fact, no precipita-
we predicted, many polymeric precipitations attributed to tions were confirmed after the electrolysis in the electrolytic
unselective oxidation such as the overoxidation of coupling solution ejected from the reactor. Furthermore, the use of
products were observed at both the cell bottom and the anode parallel laminar flow mode in the two-inlet flow microreactor
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Table
2
Anodic C,C cross-coupling reactions between naphthalene
derivatives and alkylbenzenesa
Entry Substrate
Nucleophile Product
Current yieldb (%)
1
85c
2
3
33d
Fig. 3 Linear sweep voltammograms of 2 in 100 mM Bu4NBF4–CH3CN/
CH3COOH (volume ratio = 9 : 1) solution using the two-inlet flow micro-
reactor with the Pt anode. The Ag wire as a quasi-reference electrode was
placed externally, downstream near the outlet of the flow microreactor.
Scan rate was 100 mV sÀ1. (a) Electrolytic solution without 2 was introduced
through inlet 1 at a flow rate of 0.47 mL minÀ1. (b) Electrolytic solution with 2
5d
(500 mM) was introduced through inlet 1 at a flow rate of 0.47 mL minÀ1
.
(c) Electrolytic solution with 2 (1 M) was introduced through inlet 2 and
electrolytic solution without 2 was introduced through inlet 1, both at a flow
rate of 0.23 mL minÀ1
.
4
51d
a
enabled the current yield of 3 to increase up to 85% and the
homo-coupling product of 1 was hardly detected after the
electrolysis (Table 1, entry 3). This result suggests that 1 was
preferentially oxidized at the anode and the radical cation of 1
was efficiently generated to react with 2. Consequently, the
cross-coupling reaction proceeded in a good current yield. In
sharp contrast, when the electrolytic solution containing 2 was
introduced at the outlet of the flow microreactor, the desired
cross-coupling product 3 was not detected at all (Table 1, entry
4) even under a faster flow rate condition (Table 1, entry 5). This
is ascribed to the fact that the stability of the radical cation of 1
generated at the anode was insufficient to transfer it to the
outlet of the reactor without decomposition or side-reactions.
From these facts, it can be stated that the liquid–liquid parallel
laminar flow mode is essentially required for an efficient
anodic C,C cross-coupling reaction.
Experimental conditions: anode, Pt plate; cathode, Pt plate; current
density, 25 mA cmÀ2; charge passed, 0.2 F molÀ1 of substrate; solvent,
CH3CN/CH3COOH (volume ratio = 9 : 1); substrate conc., 500 mM;
nucleophilic conc., 500 mM; supporting electrolyte, 100 mM of
b
Bu4NBF4; total flow rate, 0.47 mL minÀ1
.
Current yield is the theoret-
ical amount of electricity divided by the amount actually employed for
the generation of the desired product. c Determined by HPLC. d Determined
by NMR.
Hence, the current yield of the desired cross-coupling product was
significantly improved compared to that in the conventional batch
type cell. It is also noted that the reaction was achieved in single
flow-through operations and under very mild conditions. We
hope that our results promote the research concerning an anodic
aromatic C,C cross-coupling reaction.
Notes and references
Finally, we also carried out anodic C,C cross-coupling reactions
between naphthalene derivatives and alkylbenzenes using the
liquid–liquid parallel laminar flow mode in the flow microreactor
(Table 2). The reaction of 1 with 4 gave the desired cross-coupling
product 5 in reasonable current yield (Table 2, entry 2). On the
other hand, when mesitylene 6 was used as a nucleophile, the
current yield of 7 decreased due to the low nucleophilicity of 6
(Table 2, entry 3). However, the electron-deficient naphthalene
such as 2-bromonaphthalene 8 reacted with 6 to give the
corresponding cross-coupling product 9 in a much higher
current yield (Table 2, entry 4). Thus, this system has potential
to be applied to syntheses of various biaryl compounds.
In conclusion, we have demonstrated the anodic aromatic
C,C cross-coupling reaction using parallel laminar flow mode
in the two-inlet flow microreactor. By using the parallel laminar
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