Solvent-dependent conformational switching of the aromatic N-methyl amides depending upon the acceptor properties of solvents

Article abstract of DOI:10.1016/j.tetlet.2006.08.012

An aromatic N-methyl amide containing N-(2-pyridyl) and 2,6-pyridinedicarboxamide moieties switches its conformation from cis to trans depending upon the acceptor number of solvents.

Full text of DOI:10.1016/j.tetlet.2006.08.012

Tetrahedron Letters 47 (2006) 7143–7146
Solvent-dependent conformational switching of the aromatic
N-methyl amides depending upon the acceptor
properties of solvents
Iwao Okamoto,* Mayumi Nabeta, Misaki Yamamoto, Maiko Mikami,
Tetsuya Takeya and Osamu Tamura
Showa Pharmaceutical University, 3-3165 Higashi-Tamagawagakuen, Machida, Tokyo 194-8543, Japan
Received 20 July 2006; revised 1 August 2006; accepted 4 August 2006
Available online 22 August 2006
Abstract—An aromatic N-methyl amide containing N-(2-pyridyl) and 2,6-pyridinedicarboxamide moieties switches its conformation
from cis to trans depending upon the acceptor number of solvents.
Ó 2006 Elsevier Ltd. All rights reserved.
O
O
CH3
N
The conformation of a molecule or supramolecule can
greatly influence function,1 and the amide bond is a very
attractive structural unit which can form two conforma-
tions, cis and trans.2 Although most secondary aromatic
amides, such as benzanilide or acetanilide, favor trans
conformation, N-methyl derivatives such as 1 favor cis
conformation (Scheme 1).3 This characteristic building
block can construct several unique compounds,4 and
the switching of amide conformation can lead to
significant changes in the structure and function of large
molecules.5,6 If the conformational switching of these
structural units can be controlled with the outer
conditions, the molecules can work as external stimuli
responsive molecular devices.
N
CH3
cis-1
trans-1
Scheme 1. The conformational preference of N-methylbenzanilide.
N-methyl amides such as 1. While the spectrum of 2 at
room temperature shows a single set of signals, lowering
of the temperature resulted in peak broadening, leading
to the appearance of two sets of signals, due to the cis
and trans conformers. The aromatic proton signals of
the cis conformer were shifted upfield from those of
the trans conformer. The integration values at 183 K
indicated a 95:5 ratio of cis and trans conformers (Table
1, entry 1).
The pyridine ring serves as a ligand for metals or a
hydrogen bond acceptor.7 Therefore, we designed the
pyridine-containing N-methyl aromatic amides 2–8 as
congeners of N-methyl benzanilide that might be readily
conformationally switchable. Here we report that the
conformational preference is influenced by intramolecu-
lar dipole interaction, and we also describe the solvent-
dependent conformational switching of 8.
Next we synthesized amides 3–8 and investigated their
conformational ratios. 1H NMR measurements were
carried out in CD2Cl2 at 183 K, and the conformer
ratios are summarized in Table 1. The ratios of cis and
trans conformers for 3–6 were similar to that of 2 (en-
tries 2–5). Table 1 also shows the data for amides 7
and 8, which contain three pyridine rings and two amide
bonds. The spectra of these amides at 183 K indicate
that cis–cis is the major conformer and cis–trans is a
minor conformer, while the trans–trans conformer was
not detected. The ratio of cis-7 and trans-7, representing
cis–cis and cis–trans, respectively, was 88:12 (entry 6),
which can be regarded as ratio similar to those of 2–6
We first synthesized N-methyl-N-(2-pyridyl)-2-pyridine-
carboxamide (2). 1H NMR spectroscopy of 2 in CD2Cl2
showed the characteristic structural features of aromatic
*
Corresponding author. Tel./fax: +81 42 721 1579; e-mail:
iokamoto@ac.shoyaku.ac.jp
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.08.012

7144
I. Okamoto et al. / Tetrahedron Letters 47 (2006) 7143–7146
Table 1. The conformational ratio of amides 2–8 in CD2Cl2
O
O
CH3
R1
N
N
N
R3
R1
N
N
N
R3
CH3
R2
R2
cis
trans
Entry
Amide
R1
R2
R3
Cis:transa
1
2
3
4
5
6
7
2
H
H
H
NO2
H
H
H
H
H
H
H
Br
95:5
98:2
96:4
96:4
3
4
Br
CO2Me
H
H
5
6
94:6
7c
8c
H
H
cis-NMeCO-2-Py
H
88:12b
61:39b
cis-CONMe-2-Py
a The ratios were calculated from integration values of 1H NMR signals at 183 K.
b The ratios of cis–cis and cis–trans conformers are presented. Trans-trans conformer was not detected.
c The structures of 7 and 8 are as follows:
O
CH3
O
CH3
O
H3C
H3C
O
N
N
N
N
N
N
N
N
N
N
7
8
by considering symmetrical structure of 7 with two
amide bonds. However, the ratio of 8 was clearly differ-
ent from those of the other amides, that is, the ratio of
the trans isomer was increased to 61:39 (entry 7).
and toluene and THF resulted in trans preference (en-
tries 5 and 6). The results of entries 2, 3, and 5 demon-
strate that the conformational switching between cis and
trans conformers can be induced in dichloromethane/
toluene by changing the solvent ratio.
This characteristic feature can be interpreted in terms of
the dipole effect around the central pyridine ring and
carbonyl groups (Scheme 2),8 because the dipole interac-
tion makes the two carbonyl groups of the amides lie in
the anti direction (from A to B), and consequently the
terminal pyridine rings exhibit steric repulsion. This ste-
ric repulsion in B can be released by conformational
change to the cis–trans conformer (C), so that the pop-
ulation of trans conformer of 8 becomes larger than
those of 2–7.
Karelson and co-workers reported a correlation between
the cis–trans preference and the dielectric constant of the
solvent for some formamide derivatives.2b However in
our case, it does not appear that the results can be inter-
preted in terms of dielectric constant or dipole moment
of the solvent. On the other hand, acceptor number
(AN), as proposed by Gutmann,9 appeared to be a good
predictor of cis-preference. Thus, amide 8 exhibited a
higher cis-ratio in a solvent with higher AN, and
trans-preference in a solvent with low AN. To our
knowledge, this is the first example of the conforma-
tional switching of amides in accordance with the accep-
tor number of solvents.
In order to investigate the characteristics of 8 in more
detail, several other solvents were used for NMR mea-
surements; the results and physical properties of the sol-
vents are summarized in Table 2. The cis conformer was
preferred to the trans isomer both in methanol (entry 1)
and in dichloromethane (entry 2), whereas acetone
reduced the preference for the cis conformer (entry 4),
A solvent with higher AN can better coordinate or sol-
vate to the amide carbonyl group, and hence reduce the
dipole interaction with the central pyridine ring. This
O
O
N
N
N
O
N
N
H3C
O
H3C
H3C
CH3
H3C
O
CH3
O
N
N
N
N
N
N
N
N
N
N
B
A
C
( syn-cis-cis )
( anti-cis-cis )
( cis-trans )
Scheme 2. The conformational equilibrium of 8.

I. Okamoto et al. / Tetrahedron Letters 47 (2006) 7143–7146
Table 2. The conformational ratio of amide 8 in various solvents at 183 K
7145
N
N
H3C
O
O
CH3
H3C
O
H3C
N
N
N
N
N
N
N
N
O
trans
cis
Entry
Solvent
ANa
DNa
ea
la
Cis:transb
1
2
3
4
5
6
Methanol
Dichloromethane
(Dichloromethane + toluene)c
Acetone
Toluene
THF
41.3
20.4
—
12.5
7.9d
8.0
19
—
—
17.0
0.1
20.2
32.6
9.0
—
20.7
2.3
7.4
1.7
1.6
—
2.9
0.3
1.7
88:12
61:39
54:46
52:48
25:75
19:81
a AN: acceptor number, DN: donor number,9 e: relative dielectric constant, l: dipole moment [D].10
b The ratios were calculated from integration values of 1H NMR signals at 183 K. The ratios of cis–cis conformer and cis–trans conformer are
presented. Trans-trans conformer was not detected.
c A mixture of dichloromethane and toluene (50:50) was used as a solvent.
d Calculated from AN of benzene according to the reported method.11
O
H3C
O
O
CH3
H3C
O
N
N
N
N
N
N
N
N
CH3
N
N
cis
trans
9
91 : 9 in CD2Cl2 (183 K)
80 : 20 in C6D5CD3 (183 K)
Scheme 3. The solvent dependency of the conformational preference of 9.
coordination makes the carbonyl group syn to pyridine
nitrogen, and hence favors cis-conformation. Such a sol-
vent with high AN can also coordinate to the nitrogen
atom of terminal pyridine ring. Because ortho substitu-
tion of N-aryl group increases the ratio of trans con-
former in some N-methyl amides,12,3b similar effect can
be expected for amide 8, resulting from coordination
to terminal pyridine ring. However, considering the fact
that the cis–trans conformational switching is the char-
acteristic of amide 8,13 interaction around the central
pyridine ring is also essential.
Supplementary data
1H NMR spectra of amides 2–9 in CD2Cl2, and 8 in
various solvents are available. Supplementary data
associated with this article can be found, in the online
version, at doi:10.1016/j.tetlet.2006.08.012.
References and notes
1. (a) Lehn, J.-M. Supramolecular Chemistry; VCH: Wein-
heim, 1995; (b) Balzani, V.; Credi, A.; Venturi, M.
Molecular Devices and Machines; Wiley-VCH: Weinheim,
2004.
2. (a) Yamasaki, R.; Tanatani, A.; Azumaya, I.; Saito, S.;
Yamaguchi, K.; Kagechika, H. Org. Lett. 2003, 5, 1265–
1267; (b) Leis, J.; Klika, K. D.; Karelson, M. Tetrahedron
1998, 54, 7497–7504; (c) Troganis, A. N.; Sicilia, E.;
Barbarossou, K.; Gerothanassis, I. P.; Russo, N. J. Phys.
Chem. A 2005, 109, 11878–11884; (d) Plass, M.; Griehl, C.;
Kolbe, A. J. Mol. Struct. 2001, 570, 203–214.
3. (a) Itai, A.; Toriumi, Y.; Tomioka, N.; Kagechika, H.;
Azumaya, I.; Shudo, K. Tetrahedron Lett. 1989, 30, 6177–
6180; (b) Azumaya, I.; Kagechika, H.; Fujiwara, Y.; Itoh,
M.; Yamaguchi, K.; Shudo, K. J. Am. Chem. Soc. 1991,
113, 2833–2838.
4. (a) Azumaya, I.; Yamaguchi, K.; Okamoto, I.; Kagechika,
H.; Shudo, K. J. Am. Chem. Soc. 1995, 117, 9083–9084;
(b) Azumaya, I.; Kagechika, H.; Yamaguchi, K.; Shudo,
The importance of dipole interaction between the cen-
tral pyridine ring and the carbonyl group was confirmed
by examining amide 9, having a positionally changed
1
central pyridine ring. H NMR of 9 revealed that cis
conformation was preferred both in dichloromethane
(AN: 20.4) and in toluene (AN: 7.9), as shown in
Scheme 3, in contrast to entries 2 and 5 in Table 2.
In conclusion, we investigated the conformational pref-
erence of aromatic amides containing 2- and 2,6-substi-
tuted pyridine rings.14 Among them, amide 8 showed a
unique switching of the cis–trans conformation accord-
ing to the solvent acceptor ability. This N-methyl pyr-
idyl amide structure is very useful as a structural unit,
because the conformational structure in a solvent can
be predicted by considering its acceptor number.

7146
I. Okamoto et al. / Tetrahedron Letters 47 (2006) 7143–7146
K. Tetrahedron Lett. 1996, 37, 5003–5006; (c) Azumaya, I.;
at 0 °C, and ethyl chloroformate (5.00 mmol) was added,
followed by stirring for 1 h. To this mixture, 2-(methyl-
amino)pyridine (5.00 mmol) was added, and the resulting
mixture was stirred at ambient temperature for 3 h, then
filtrated. The solvent was removed by evaporation, and
the resulting mixture was flash-chromatographed to afford
the desired amide. Compound 2: Mp 77.5 °C; 1H NMR
(300 MHz, CDCl3) d 8.30 (m, 2H), 7.71 (m, 2H), 7.54 (dt,
J = 1.9, 7.8 Hz, 1H), 7.20 (m, 1H), 7.03 (m, 2H), 3.61 (s,
3H). Anal. Calcd for C12H11N3O: C, 67.59; H, 5.20; N,
19.71. Found: C, 67.51; H, 5.22; N, 19.52. Compound 3:
Okamoto, I.; Nakayama, S.; Tanatani, A.; Yamaguchi,
K.; Shudo, K.; Kagechika, H. Tetrahedron 1999, 55,
11237–11246; (d) Tanatani, A.; Yokoyama, A.; Azumaya,
I.; Takakura, Y.; Mitsui, C.; Shiro, M.; Uchiyama, M.;
Muranaka, A.; Kobayashi, N.; Yokozawa, T. J. Am.
Chem. Soc. 2005, 127, 8553–8561.
5. Betson, M. S.; Clayden, J.; Lam, H. K.; Helliwell, M.
Angew. Chem., Int. Ed. 2005, 44, 1241–1244.
6. (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.
7. (a) Hofacker, A. L.; Parquette, J. R. Angew. Chem., Int.
Ed. 2005, 44, 1053–1057; (b) Yue, N. L. S.; Jennings, M.
C.; Puddephatt, R. J. Inorg. Chem. 2005, 44, 1125–1131;
(c) Heemstra, J. M.; Moore, J. S. Chem. Commun. 2004,
1480–1481; (d) Chatterjee, B.; Noveron, J. C.; Resendiz,
M. J. E.; Liu, J.; Yamamoto, T.; Parker, D.; Cinke, M.;
Nguyen, C. V.; Arif, A. M.; Stang, P. J. J. Am. Chem. Soc.
2004, 126, 10645–10656; (e) Crabtree, R. H.; Siegbahn, P.
E. M.; Eisenstein, O.; Rheingold, A. L.; Koetzle, T. F.
Acc. Chem. Res. 1996, 29, 348–354; (f) Fujita, M.; Oguro,
D.; Miyazawa, M.; Oka, H.; Yamaguchi, K.; Ogura, K.
Nature 1995, 378, 469–471.
8. (a) Perlepes, S. P.; Kabanos, T.; Hondrellis, V.; Tsangaris,
J. M. Inorg. Chim. Acta 1988, 150, 13–23; (b) Bould, J.;
Brisdon, B. J. Inorg. Chim. Acta 1976, 19, 159–163; (c)
Brown, R. F. C.; Radom, L.; Sternhell, S.; Rae, I. D. Can.
J. Chem. 1968, 46, 2577–2587.
9. Acceptor number and donor number are empirical
parameters describing electrophilic behavior and nucleo-
philic behavior of solvents, respectively: (a) Gutmann, V.
The Donor–Acceptor Approach to Molecular Interactions;
Plenum Press: New York, 1978; (b) Gutmann, V. Elec-
trochim. Acta 1976, 21, 661–670.
10. Chief CRC Handbook of Chemistry and Physics, 71st ed.;
Lide, D. R., Ed.; CRC Press: Boston, 1990; Vols. 1990–
1991.
11. (a) Linert, W.; Jameson, R. F. J. Chem. Soc., Perkin
Trans. 2 1993, 1415–1421; (b) Dimroth, K.; Reichardt, C.;
Siepmann, T.; Bohlmann, F. Liebigs Ann. Chem. 1963,
661, 1–37.
12. (a) Azumaya, I. Yakugaku Zasshi 2001, 121, 117–129; (b)
Azumaya, I.; Yamaguchi, K.; Kagechika, H.; Saito, S.;
Itai, A.; Shudo, K. Yakugaku Zasshi 1994, 114, 414–430.
13. Cis:trans conformational ratios of 2 at 183 K in CD2Cl2,
toluene-d8, and THF-d8 were 96:4, 91:9, and 93:7, respec-
tively. In the case of this simple amide 2, solvent-induced
conformational switching cannot be observed.
14. General procedure for the synthesis of amides is as follows:
A solution of pyridinecarboxylic acid (5.00 mmol) and
triethylamine (10.0 mmol) in tetrahydrofuran was stirred
1
Mp 141.0–142.5 °C; H NMR (300 MHz, CDCl3) d 8.49
(m, 2H), 8.17 (dd, J = 1.2, 4.9 Hz, 1H), 7.91 (dd, J = 2.2,
5.1 Hz, 1H), 7.64 (dt, J = 1.9, 7.8 Hz, 1H), 7.13 (d,
J = 8.1 Hz, 1H), 7.06 (ddd, J = 0.9, 4.9, 7.3 Hz, 1H),
3.63 (s, 3H). Anal. Calcd for C12H10N4O3: C, 55.81; H,
3.90; N, 21.70. Found: C, 55.69; H, 3.62; N, 21.91.
Compound 4: Mp 104.0–105.5 °C; 1H NMR (300 MHz,
CDCl3) d 8.27 (d, J = 5.0 Hz, 1H), 7.73 (dd, J = 0.9,
7.7 Hz, 1H), 7.65 (dt, J = 1.9, 7.8 Hz, 1H), 7.57 (t,
J = 7.7 Hz, 1H), 7.37 (d, J = 7.9 Hz, 1H), 7.14 (br d,
J = 9.0 Hz, 1H), 7.11 (ddd, J = 0.9, 4.9, 7.4 Hz, 1H), 3.58
(s, 3H). Anal. Calcd for C12H10N3OBr: C, 49.34; H, 3.45;
N, 14.38. Found: C, 49.30; H, 3.43; N, 14.25. Compound
1
5: Mp 71.5–72.0 °C; H NMR (300 MHz, CDCl3) d 8.25
(dd, J = 1.3, 5.0 Hz, 1H), 8.02 (dd, J = 1.5, 7.6 Hz, 1H),
7.95 (dd, J = 1.4, 7.8 Hz, 1H), 7.87 (t, J = 7.7 Hz, 1H),
7.60 (dt, J = 1.7, 8.1 Hz, 1H), 7.16 (br d, J = 8.3 Hz, 1H),
7.05 (ddd, J = 0.9, 5.0, 7.5 Hz, 1H), 3.83 (s, 3H), 3.60 (s,
3H). Anal. Calcd for C14H13N3O3: C, 61.99; H, 4.83; N,
15.49. Found: C, 61.91; H, 4.92; N, 15.59. Compound 6:
1
Mp 145.0–146.0 °C; H NMR (300 MHz, CDCl3) d 8.92
(ddd, J = 0.9, 1.6, 4.7 Hz, 1H), 7.55 (dt, J = 1.7, 7.8 Hz,
1H), 7.36 (d, J = 6.8 Hz, 1H), 7.27 (t, J = 7.9 Hz, 1H),
7.02 (m, 2H), 6.85 (1H, J = 7.9 Hz,1H), 3.09 (s, 3H). Anal.
Calcd for C12H10N3OBr: C, 49.34; H, 3.45; N, 14.38.
Found: C, 49.30; H, 3.45; N, 14.43. Compound 7: Mp
1
140.0–140.5 °C; H NMR (300 MHz, CDCl3) d 8.31 (m,
2H), 7.73 (ddd, J = 0.4, 1.8, 7.6 Hz, 2H), 7.60 (m, 2H),
7.39 (t, J = 7.9 Hz, 1H), 7.24 (ddd, J = 1.3, 5.0, 7.7 Hz,
2H), 6.75 (d, J = 7.9 Hz, 2H), 3.23 (s, 6H). Anal. Calcd for
C19H17N5O2: C, 65.69; H, 4.93; N, 20.16. Found: C, 66.07;
H, 4.94; N, 20.19. Compound 8: Mp 113 °C; 1H NMR
(300 MHz, CDCl3) d 8.25 (ddd, J = 0.9, 2.0, 4.8 Hz, 2H),
7.75 (dd, J = 7.3, 8.2 Hz, 1H), 7.58 (m, 2H), 7.56 (m, 2H),
7.04 (ddd, J = 1.0, 4.9, 7.4 Hz, 2H), 7.00 (m, 2H), 3.33 (s,
6H). Anal. Calcd for C19H17N5O2: C, 65.69; H, 4.93; N,
20.16. Found: C, 65.83; H, 4.86; N, 20.23. Compound 9:
1
Mp 140.0–141.0 °C; H NMR (300 MHz, CDCl3) d 8.39
(ddd, J = 0.7, 2.0, 4.9 Hz, 2H), 8.35 (d, J = 2.2 Hz, 2H),
7.76 (t, J = 2.0 Hz, 1H), 7.56 (dt, J = 1.8, 7.7 Hz, 2H),
7.12 (ddd, J = 0.9, 4.9, 7.5 Hz, 2H), 6.85 (br d, J = 8.1 Hz,
2H), 3.54 (s, 6H). Anal. Calcd for C19H17N5O2: C, 65.69;
H, 4.93; N, 20.16. Found: C, 65.70; H, 4.74; N, 20.10.