Redox-induced conformational alteration of N,N-diarylamides

Article abstract of DOI:10.1021/ol702504x

We constructed a novel molecular conformational alteration system with an N-aryl-N-phenylacetamide structure, in which the N-aryl group consists of a hydroquinone-p-quinone system as a redox-dependent aromatic trigger. The amide conformation depended on t

Full text of DOI:10.1021/ol702504x

ORGANIC
LETTERS
2007
Vol. 9, No. 26
5545-5547
Redox-Induced Conformational
Alteration of N,N-Diarylamides
Iwao Okamoto,*,† Ryu Yamasaki,§ Mika Sawamura,† Takako Kato,¶
Naomi Nagayama,† Tetsuya Takeya,† Osamu Tamura,† Hyuma Masu,¶
Isao Azumaya,¶ Kentaro Yamaguchi,¶ Hiroyuki Kagechika,# and Aya Tanatani*,‡,
Showa Pharmaceutical UniVersity, 3-3165 Higashi-Tamagawagakuen, Machida, Tokyo
194-8543, Japan, Graduate School of Pharmaceutical Sciences, The UniVersity of
Tokyo, Tokyo, Japan, Faculty of Pharmaceutical Sciences at Kagawa Campus,
Tokushima Bunri UniVersity, Kagawa, Japan, School of Biomedical Science, Tokyo
Medical and Dental UniVersity, Tokyo, Japan, Department of Chemistry, Faculty of
Science, Ochanomizu UniVersity, 2-1-1 Otsuka, Bunkyo-ku, Tokyo 112-8610, Japan,
and PRESTO, Japan Science and Technology Agency (JST), Japan
iokamoto@ac.shoyaku.ac.jp; tanatani.aya@ocha.ac.jp
Received October 13, 2007
ABSTRACT
We constructed a novel molecular conformational alteration system with an N-aryl-N-phenylacetamide structure, in which the N-aryl group
consists of a hydroquinone p-quinone system as a redox-dependent aromatic trigger. The amide conformation depended on the oxidation
−
state of the aryl group, and the two states (compounds 2 and 3) were reversibly converted to each other by redox reactions. Such compounds
would be applied as useful structural units for external stimulus-responsive control on the shape and function of large molecules or
supramolecules.
The three-dimensional structural and the dynamic behavior
of a molecule is an important issue for regulating the
molecular function or biological activity.1 Although it is not
easy to control or predict the shape of a large molecule or
supramolecule, sometimes conformational change of a small
unit can work as a hinge or a trigger of a larger system
including functional synthetic polymers and proteins.2 In such
a case, small functionality bearing the conformational
alteration in response to external stimuli is of major interest.3
Thus, molecules that change conformation, depending on pH,
solvent, temperature, and so forth, have been developed. On
the other hand, redox reaction is very important because
many biochemical, electrochemical, and chemical reactions
involve redox processes. However, only a few compounds
exhibiting redox-induced conformational changes have been
reported.4
† Showa Pharmaceutical University.
§ The University of Tokyo.
¶ Tokushima Bunri University.
(2) (a) Clayden, J.; Lund, A.; Vallverdu´, L.; Helliwell, M. Nature 2004,
431, 966-971. (b) Kern, D.; Zuiderweg, E. R. P. Curr. Opin. Struct. Biol.
2003, 13, 748-757. (c) Seebach, D.; Schreiber, J. V.; Abele, S.; Daura,
X.; van Gunsteren, W. F. HelV. Chim. Acta 2000, 83, 34-57.
(3) (a) Feringa, B. L. Acc. Chem. Res. 2001, 34, 504-513. (b) Balzani,
V.; Credi, A.; Raymo, F. M.; Stoddart, J. F. Angew. Chem., Int. Ed. 2000,
39, 3348-3391. (c) Irie, M., Ed. Chem. ReV. 2000, 100, 1683-1890.
# Tokyo Medical and Dental University.
‡ Ochanomizu University.
JST.
(1) (a) Balzani, V.; Credi, A.; Venturi, M. Molecular DeVices and
Machines; Wiley-VCH: Weinheim, Germany, 2004. (b) Feringa, B. L.,
Ed. Molecular Switches; Wiley-VCH: Weinheim, Germany, 2001.
10.1021/ol702504x CCC: $37.00
© 2007 American Chemical Society
Published on Web 11/16/2007

Among many types of structural units, we have been
interested in amide structures, which play important roles
in both proteins and many bioactive molecules.5 We found
unique structural properties of aromatic amides, and some
of them exhibit external stimulus-responsive conformational
alteration.6-8 Here, we describe a novel molecular system
based on redox-responsive alteration of amide conformation.
The hydroquinone-p-quinone system was chosen as the
redox-dependent aromatic moiety, and was introduced on
the amide nitrogen atom of acetanilide. Thus N,N-diarylac-
etamides 1-3 were designed as redox-responsive molecules
(Figure 1).
dimethoxyl derivative 1, which lacks intermolecular hydrogen-
bonding ability, also exists in (E)-amide conformation, like
2. Each amide exhibits significant distortion of the amide-
N-aryl framework from planarity.9
The conformational preferences, due to electronic repulsion
between the carbonyl and the aryl groups, appear consistent
with the relative π-electron densities of the two N-aromatic
parts.10 Thus the more π-electron-rich N-aryl group located
trans to the amide oxygen atom (Figure 3). The tendency is
Figure 3. Conformational alteration caused by π-electron density.
Figure 1. Redox-responsive N,N-diarylacetamides.
also observed in the pH-dependent switching system of
acetanilides.6
To investigate the conformational preferences of these
amides in solution, 1H NMR measurements were performed
at various temperatures. Each amide afforded a spectrum with
one set of signals at 303 K, whereas the signals of two
conformers appeared at low temperature. The major con-
formers of 1 (73%) and 2 (77%) were assigned as (E)-amides
based on the chemical shifts and NOE data (Table 1). This
The amides 1-3 were synthesized from 2,5-dimethoxy-
N-phenylaniline by the usual method, and their crystal
structures were analyzed (Figure 2). The hydroquinone
1
Table 1. Conformational Analyses of Amides by H NMR
Measurement
major
major ratio temp
∆G° a
amide conformer
(%)
(K)
solvent (kJ/mol)
1
2
3
E
E
Z
73
77
95
213
253
178
CD2Cl2
CD3OD
CD2Cl2
-1.8
-2.5
+4.4
a ∆G° ) ∆G°(E) - ∆G°(Z)
Figure 2. Crystal structures of the amides 1-3.
was confirmed by time-course measurement after sample
preparation at low temperature (Supporting Information).
Thus, the crystal of 1 was mixed with frozen CD2Cl2 at 143
derivative 2 exists in (E)-amide conformation, while the
oxidized amide 3 exists in (Z)-amide conformation. The
1
K and the H NMR spectrum was measured when the
temperature reached 203 K. The major peak of the acetyl
group of compound 1 was predominant, but with the passage
(4) (a) Kanazawa, H.; Higuchi, M.; Yamamoto, K. J. Am. Chem. Soc.
2005, 127, 16404-16405. (b) Kim, H. G.; Lee, C.-W.; Yun, S.; Hong, B.
H.; Kim, Y.-O.; Kim, D.; Ihm, H.; Lee, J. W.; Lee, E. C.; Tarakeshwar, P.;
Park, S.-M.; Kim, K. S. Org. Lett. 2002, 4, 3971-3974. (c) Ballardini, R.;
Balzani, V.; Credi, A.; Gandolfi, M. T.; Venturi, M. Acc. Chem. Res. 2001,
34, 445-455. (d) Collin, J.-P.; Dietrich-Buchecker, C.; Gavin˜a, P.; Jimenez-
Molero, M. C.; Sauvage, J.-P. Acc. Chem. Res. 2001, 34, 477-487.
(5) The amide linkage: Structural significance in chemistry, biochemistry,
and materials science; Greenberg, A., Breneman, C. M., Liebman, J. F.,
Eds.; John Wiley & Sons: New York, 1999.
(6) Yamasaki, R.; Tanatani, A.; Azumaya, I.; Saito, S.; Yamaguchi, K.;
Kagechika, H. Org. Lett. 2003, 5, 1265-1267.
(7) Yamasaki, R.; Tanatani, A.; Azumaya, I.; Masu, H.; Yamaguchi, K.;
Kagechika, H. Cryst. Growth Des. 2006, 6, 2007-2010.
(8) (a) Okamoto, I.; Nabeta, M.; Hayakawa, Y.; Morita, N.; Takeya, T.;
Masu, H.; Azumaya, I.; Tamura, O. J. Am. Chem. Soc. 2007, 129, 1892-
1893. (b) Okamoto, I.; Nabeta, M.; Minami, T.; Nakashima, A.; Morita,
N.; Takeya, T.; Masu, H.; Azumaya, I.; Tamura, O. Tetrahedron Lett. 2007,
48, 573-577. (c) Okamoto, I.; Nabeta, M.; Yamamoto, M.; Mikami, M.;
Takeya, T.; Tamura, O. Tetrahedron Lett. 2006, 47, 7143-7146.
(9) The dihedral angles between the amide plane and the dioxyphenyl
and phenyl planes were 80.61° and 62.45° for 1, 88.72° and 80.09° for 2,
and 65.11° and 77.80° for 3, respectively.
(10) Saito, S.; Toriumi, Y.; Tomioka, N.; Itai, A. J. Org. Chem. 1995,
60, 4715-4720.
5546
Org. Lett., Vol. 9, No. 26, 2007

of time at 203 K, a minor peak appeared, with a rate constant
of 4.2 × 10-5 s-1 (from E to Z isomer).
In summary, the aromatic amides 1 and 2 exist in (E)-
amide form, while 3 exists in (Z)-amide form, both in the
crystal and in solution. Redox reaction of the hydroquinone-
benzoquinone moiety on the acetamide skeleton could be
performed reversibly, and would be accompanied by amide
conformational alteration (Figure 5). This system provides
On the other hand, the quinone form 3 existed predomi-
nantly (95%) in (Z)-amide conformation, as assigned from
the chemical shifts and NOE data.11 The major conformers
of these amides 1-3 in solution are consistent with the
crystal structures, with the amide oxygen atom being located
trans to the more electron-rich N-substituents.
Redox properties of these amides were investigated by
cyclic voltammetry. Figure 4 shows the voltammograms of
Figure 4. Cyclic voltammograms of 2 (blue curve), 2 containing
200 equiv of acetic acid (green curve), 3 (red curve), and 3
containing 200 equiv of acetic acid (orange curve). Each sample
was measured in an acetonitrile solution (4.0 mM) containing 0.1
M tetra-n-butylammonium perchlorate at a platinum electrode.
Sweep rate: 100 mV/s.
Figure 5. Redox-dependent conformational alteration.
2 and 3 in the presence of excess acetic acid as a proton
source, and in its absence. An irreversible oxidation wave
was observed for 2 in the presence or absence of acetic acid,
resulting from oxidation of the hydroquinone moiety. In
contrast, 3 showed a reversible redox wave, which became
irreversible and shifted to the positive direction in the
presence of acetic acid, due to reduction of the quinone
moiety. These irreversible redox waves in the presence of
acid suggest that electrochemical conversion can occur.12
Based on these data, the electrochemical interconversion
was investigated.13 The amide 2 was oxidized in a constant
potential manner at +1.40 V (vs Ag/AgCl) to give 3 in 82%
yield, and 3 was reduced similarly at -0.15 V with acetic
acid as the proton source to give 2 in 92% yield. The
electrochemical redox reaction can be carried out reversibly,
and therefore amide conformational alteration under redox
control is suitable for providing direct output.
a simple example of conformational alteration, in which the
redox reaction controls the predominant amide conformation
in equilibrium. These results are also important in order to
understand the behavior of N-quinonyl-type bioactive com-
pounds in nature.14 At the same time, this redox-responsive
type of conformational control has wide potential for
controlling the shape and function of large molecules or
supramolecules.
Acknowledgment. We are grateful to Prof. Toshihiro
Kondo, Ochanomizu University, for helpful discussions. I.O.
acknowledges the support of the Takeda Science Foundation.
A.T. acknowledges the support of the Mitsubishi Chemical
Corporation Fund and the Asahi Glass Foundation.
Supporting Information Available: Experimental details
for synthesis and electrochemical reactions, 1H NMR spectra,
and X-ray crystallographic data for 1, 2, and 3. This material
is available free of charge via the Internet at http://pubs.acs.org.
(11) Similar preference was observed in THF-d8 at 168 K, thus 3 exists
in (Z)-amide form predominantly (96%).
(12) (a) Uno, B.; Okumura, N.; Goto, M.; Kano, K. J. Org. Chem. 2000,
65, 1448-1455. (b) Egeland, R. D.; Marken, F.; Southern, E. M. Anal.
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Chem. Commun. 1987, 1236-1238. (d) Kimura, M.; Kaneko, Y. J. Chem.
Soc., Dalton Trans. 1984, 3, 341-343.
OL702504X
(13) Electrochemical oxidation was performed in a solution of 0.1 M
tetra-n-butylammonium perchlorate in acetonitrile, using platinum mesh as
working and counter electrodes, and Ag/AgCl electrodes as the reference
for constant potential oxidation. Acetic acid (200 equiv) was added as a
proton source. Constant potential reduction was performed similarly.
(14) (a) Thepchatri, P.; Eliseo, T.; Cicero, D. O.; Myles, D.; Snyder, J.
P. J. Am. Chem. Soc. 2007, 129, 3127-3134. (b) Lee, Y.-S.; Marcu, M.
G.; Neckers, L. Chem. Biol. 2004, 11, 991-998. (c) Neckers, L.; Lee, Y.-
S. Nature 2003, 425, 357-359. (d) Stebbins, C. E.; Russo, A. A.; Schneider,
C.; Rosen, N.; Hartl, F. U.; Pavletich, N. P. Cell 1997, 89, 239-250.
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