Tetrahedron Letters
Synthesis of azobenzenes with high reactivity towards reductive
cleavage: Enhancing the repertoire of hypersensitive azobenzenes
and examining their dissociation behavior
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Taejun Eom, Anzar Khan
Department of Chemical and Biological Engineering, Korea University, 02841 Seoul, South Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Trifluoromethyl (CF3), cyano (CN), and nitro (NO2) groups were demonstrated to be effective acceptors in
the molecular design of triple-donor/acceptor-based hypersensitive azobenzenes. The synthesis of these
reactive scaffolds requires only two steps with overall yields ranging from 70 to 73%. UV–Vis absorption
spectroscopy indicated that in all cases, a few seconds of exposure to mild reducing conditions is suffi-
cient for complete cleavage of the azo bond. Liquid chromatography coupled with mass spectrometry
(LC-MS) established the formation of two aniline fragments in the case of the CF3 and CN-substituted
azobenzenes. In the case of the NO2-substituted compound, however, partial reduction of the nitro group
results in the formation of three different anilines.
Received 26 March 2020
Revised 30 April 2020
Accepted 6 May 2020
Available online 11 May 2020
Keywords:
Azobenzene reduction
Azo scission
Ó 2020 Elsevier Ltd. All rights reserved.
Redox active
Reductive cleavage
Introduction
Result and discussion
The reductive cleavage of the azo (N@N) bond serves as a basis
for various release/activation mechanisms in chemical biology and
materials science applications (Fig. 1) [1–7]. In most of these appli-
cations, a rapid dissociation of the azo bond is required. For exam-
ple, drug delivery to the colon relies on fast rupture of a cross-
linked azobenzene coat to release active therapeutics [3]. In sens-
ing, bioimaging, and theranostics applications, cleavage of the azo
linkage under mild hypoxic conditions translates to reliability of
detection [4]. Thus, an easily obtained azobenzene scaffold with
enhanced activity is an important research goal. In this context,
we have recently shown that an increase in the number of donor
substituents in a donor/acceptor system enhances the azo scission
reaction to very high levels [8]. The most active system contained
three donors and one acceptor and complete azo cleavage could be
achieved with a 0.5 mM aqueous sodium dithionite solution in
<10 s. A previous state-of-the-art system required 12-times higher
concentration of the reductant to achieve a similar response [9]. In
our previous study, only one molecule, with methyl benzoate ester
as the acceptor, was identified as the true hyperactive scaffold. This
prompted us to investigate the synthesis and cleavage properties
of new triple-donor/acceptor systems to check the versatility of
the concept.
The synthesis begins with copper-catalyzed amination of
dimethoxyiodobenzene with ethylethanolamine to afford the tri-
ple-donor fragment (1) in 78% yield (Scheme 1). In the second step,
1 was combined with electron deficient anilines possessing triflu-
oromethyl (CF3), cyano (CN), or nitro (NO2) groups through a dia-
zotization reaction [10]. The isolated yields for this step range
from 90 to 95%. In this way, azobenzenes 2–4 can be prepared in
two synthetic steps (Figs. S1–S6). The hydroxyl group in azoben-
zenes 2–4 can potentially be functionalized based upon a desired
application [8]. For instance, in sensing applications, a dye can be
attached through an esterification reaction.
In the 1H NMR spectra, the aromatic resonances indicate that
the CF3 group is nearly as electron-withdrawing as the azo bond
and the two sets of protons located on the aromatic ring containing
the acceptor unit (Fig. S1) resonate very close to each other. In the
case of the CN group, the protons on the adjacent carbons to the
acceptor move downfield indicating that it is a stronger electron-
withdrawing group than CF3 (Fig. S3). In the case of the NO2 group,
this signal moves further downfield and indicates that it is the
strongest acceptor in the present set of compounds (Fig. S5). The
Hammett substituent constants for the three groups (CF3 = +0.54,
CN = +0.66, NO2 = +0.77) support this hypothesis. In the UV–Vis
spectra, the three compounds exhibit strong absorption bands in
the range of 350–600 nm belonging to the
transition (Fig. 2 and Figs. S7–S9). The absorption maxima for
p-p* electronic
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Corresponding author.
0040-4039/Ó 2020 Elsevier Ltd. All rights reserved.
Eom, Taejun
