Tetrahedron Letters
Phase-transfer-mediated electrochemical reaction: anodic disulfide
bond formation under biphasic condition
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Masahito Takahashi, Yohei Okada, Yoshikazu Kitano, Kazuhiro Chiba
Department of Applied Biological Science, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo 183-8509, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The use of bromide ion as a redox mediator promotes electrochemical reactions in the non-conductive
cyclohexane phase. Anodically oxidized species of bromide ion in the conductive methanol phase can
Received 24 March 2014
Revised 23 April 2014
Accepted 30 April 2014
Available online xxxx
bring oxidizing power across phases to induce oxidative disulfide bond formation of
a
hydrophobically-tagged tripeptide, which is located predominantly in the cyclohexane phase. In addition
to commonly used tetraalkylammonium salts, inorganic sodium salt can also be effective alternatives for
the bromide source.
Keywords:
Ó 2014 Published by Elsevier Ltd.
Phase-transfer mediator
Anodic disulfide bond
Biphasic
Bromide ion
Introduction
significantly enhance the utility of this methodology, especially
for hydrophobic substrates that are not soluble in polar electrolyte
Chemical events between two substances located in different
phases of a heterogeneous mixture are often ineffective because
the accessibility of reagents is limited. A typical example is an
organic molecule and an inorganic salt in a biphasic solution of a
less-polar solvent and water in which the reaction is generally
slow or sometimes barely takes place. Phase-transfer catalysis,
which facilitates the migration of a reactant from one phase into
another phase, has been proposed to solve this problem.1 This early
finding has led to the development of chiral phase-transfer cata-
lysts that have been widely applied in academic research and
industrial production.2
solutions. Although various redox mediators have been developed
and have found creative applications in organic electrochemistry,4
the construction of mediators that function across phases in bipha-
sic conditions remains challenging.
We have been developing soluble tag-assisted chemistry, which
employs hydrophobic benzyl alcohols as supports for various
organic processes.5 The tagged substrates are soluble in less-polar
solvents to realize effective liquid phase reactions, also enabling
selective precipitation or extraction from polar solvents that can
facilitate their separation. Our ongoing challenge is to apply the
tagged substrates for electrochemical reactions, mainly focusing
on how to obtain homogeneous solutions suitable for both the
hydrophobic tag and ionic supporting electrolyte. We have demon-
strated two strategies so far, one uses a tetrahydrofuran/methanol
monophasic mixture6 and the other takes advantage of a ‘thermo-
morphic’ cyclohexane/methanol biphasic mixture,7 where the sys-
Organic electrochemistry has provided
a straightforward
method to trigger electron transfer events at the surface of elec-
trodes, including anodic oxidation and cathodic reduction, which
can generate reactive intermediates.3 The fundamental limitation
for this methodology is the requirement of conductivity, namely,
the solvent must be sufficiently polar to dissolve the ionic support-
ing electrolyte. This also means that substrates should be less
hydrophobic to maintain a homogeneous condition; otherwise they
are not able to access the surface of electrodes effectively, severely
inhibiting electron transfer events. In a similar fashion to a phase-
transfer catalyst, a ‘phase-transfer mediator’ that can bring anodic
oxidizing and/or cathodic reducing power across phases could
tem is heated to form
a monophasic, relatively ‘less-polar’
electrolyte solution. When oxidative disulfide bond formation
was used as a model for the former strategy, we found that both
direct anodic oxidation of the tagged substrate and an indirect med-
iated mechanism can occur. If the mediator can bring anodic oxidiz-
ing power across the phases, it might function even in a biphasic
mixture. Described herein is a ‘phase-transfer-mediated’ electro-
chemical reaction in which the desired anodic disulfide bond for-
mation can be induced in such a biphasic mixture where the
substrate cannot access the surface of the electrodes.
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Corresponding author. Tel./fax: +81 42 367 5667.
0040-4039/Ó 2014 Published by Elsevier Ltd.