Amide conformational switching induced by protonation of aromatic substituent

Article abstract of DOI:10.1021/ol034344g

(Matrix presented) Introduction of an electron-withdrawing group on the aromatic ring of N-methylacetanilide decreased the ratio of the cis conformer, and the ratio correlates well with the Hammett σ values of the substituents. These steric properties can be applied to achieve amide conformational swiching by protonation at the aromatic substituent of 4-[bis(dimethylamino)]-N-methylacetanilide or N-[p-(dimethylamino)phenyl]-N-phenylacetamide.

Full text of DOI:10.1021/ol034344g

ORGANIC
LETTERS
2003
Vol. 5, No. 8
1265-1267
Amide Conformational Switching
Induced by Protonation of Aromatic
Substituent
Ryu Yamasaki,† Aya Tanatani,† Isao Azumaya,†,‡ Shoichi Saito,†
,†
Kentaro Yamaguchi,§ and Hiroyuki Kagechika*
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo, 7-3-1 Hongo,
Bunkyo-ku, Tokyo 113-0033, Japan, and Chemical Analysis Center, Chiba UniVersity,
1-33 Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
kage@mol.f.u-tokyo.ac.jp
Received February 27, 2003
ABSTRACT
Introduction of an electron-withdrawing group on the aromatic ring of N-methylacetanilide decreased the ratio of the cis conformer, and the
ratio correlates well with the Hammett σ values of the substituents. These steric properties can be applied to achieve amide conformational
swiching by protonation at the aromatic substituent of 4-[bis(dimethylamino)]-N-methylacetanilide or N-[p-(dimethylamino)phenyl]-N-
phenylacetamide.
The amide bond structure of amide derivatives often plays
a key role in functions such as molecular recognition events
or biological activities.1 In contrast to the extended trans
structures of most secondary amides, such as acetanilide (1a)
and benzanilide (2a),2,3 the corresponding N-methylated
compounds, 3a and 4a, respectively, exist in cis form in the
crystals and predominantly in cis form in various solvents
(Figure 1).4 The cis conformational preference is useful as a
building block to construct aromatic molecules with unique
† The University of Tokyo.
‡ Present address: School of Pharmaceutical Sciences, Kitasato Univer-
sity.
§ Chiba University.
(1) (a) Greenberg, A., Breneman, C. M., Liebman, J. F., Eds. The amide
linkage: Structural significance in chemistry, biochemistry, and materials
science; John Wiley & Sons: New York, 1999. (b) Rebek, J., Jr. Acc. Chem.
Res. 1999, 32, 278-286. (c) Cheng, R. P.; Gellman, S. H.; DeGrado, W.
F. Chem. ReV. 2001, 101, 3219-3232. (d) Hill, D. J.; Mio, M. J.; Prince,
R. B.; Hughes, T. S.; Moore, J. S. Chem. ReV. 2001, 101, 3893-4011.
(2) In this paper, cis and trans are defined as shown in Figure 1 in order
to describe the molecular conformations consistently, since E and Z can be
interconverted simply by a change of the substituents.
(3) (a) Stewart, W. E.; Sidwell, T. H., III. Chem. ReV. 1970, 70, 517-
551. (b) Kashino, S.; Ito, K.; Haisa, M. Bull. Chem. Soc. Jpn. 1979, 52,
365-369.
Figure 1. Cis-conformational preference of N-methylated anilides.
crystal or solution structures.5 In the present study, we
demonstrate that the conformational properties of 3a can be
applied to achieve amide conformational switching by
protonation at a remote substituent.6
10.1021/ol034344g CCC: $25.00 © 2003 American Chemical Society
Published on Web 03/27/2003

Ab initio calculations for 1a and 3a showed that the
phenomenon can be understood in terms of destabilized trans
structure of 3a with a large torsion angle of the Ph-N bond,
due to the steric hindrance between the two methyl groups
and to electronic repulsion between the carbonyl and the
phenyl groups.7 From this result, it seems reasonable that
the electronic properties of the N-aromatic ring would affect
the stability difference between cis and trans conformers.
Substituent effects on amide rotational barriers have been
well studied by using dynamic NMR techniques,8,9 while no
significant dependency of cis/trans equilibrium on the
aromatic substituents was found.10 Our ab initio calculations
with the HF/6-31G* basis set showed that the relative
stability of the cis conformer of 3a was decreased by
introduction of a p-nitro group (data not shown). This result
led us to investigate the cis/trans energy differences (∆G°,
[∆G°cis - ∆G°trans]) of various N-methylacetanilides. All
monosubstituted N-methylacetanilides (3b-o) exist in two
conformers at low temperature.11 In each case, the major
conformer was assigned as cis (∆G° < 0), based on the
chemical shifts, and the ratio of the cis conformer decreases
as the group on the aromatic ring of 3 becomes more
electron-withdrawing. Significantly, the change of ∆G°
shows a good correlation (R ) 0.978) with the Hammett’s
σ values,12 with a slope of 1.01 (Figure 2). Considering this
σ ) 0.71 for one m-nitro group) exists in trans form as the
major conformer (∆G° ) 0.28 kcal/mol).
In contrast to the above results, the introduction of
substituents on the N-phenyl ring of benzanilides (4) only
slightly affects the cis conformational preference. The ∆G°
value for 4a or 4b with a p-methoxy group is -1.55.
1
Compound 4c with a p-nitro group showed an H NMR
spectrum at 193 K corresponding to a single conformer,
assigned as the cis form.2
The substituent effects on the confomation of N-methyl-
acetanilides (3) indicate that the electronic character of the
N-phenyl group contributes at least partially to cis confor-
mational preference. This means that the more electron-
deficient aromatic ring would prefer the cis relationship to
the carbonyl oxygen when the amide bears two different
N-aromatics. In fact, such conformations (named conformer
A, Figure 3) are observed in the crystals and in the
Figure 3. Solution equilibrium of N,N-diarylamides 5-7 in CD2-
Cl2.
predominant solution structures of N,N-diarylacetamides 5
and 6.13 The free energy difference between the two
conformers A and B of 5 (∆G° ) 1.13 kcal/mol) is larger
than that of 6 (∆G° ) 0.56 kcal/mol), as would be expected
Figure 2. Plot of ∆G° vs Hammett’s substituent constant (σ). The
substituent (X) is H (3a), p-N(CH3)2 (3b), p-OCH3 (3c), p-CH3
(3d), p-Br (3e), p-CF3 (3f), p-CN (3g), p-NO2 (3h), m-N(CH3)2
(3i), m-NH2 (3j), m-OCH3 (3k), m-Cl (3l), m-CF3 (3m), m-CN (3n),
and m-NO2 (3o). In the calculation of the fitting line (∆G° ) -1.40
+ 1.01 σ, R ) 0.978), the data of 3b, 3c, and 3i, having less than
2% of the minor conformer, were excluded.
(6) (a) Irie, M., Ed. Chem. ReV. 2000, 100, 1683-1890. (b) Pease, A.
R.; Jeppesen, J. O.; Stoddart, J. F.; Luo, Y.; Collier, C. P.; Heath, J. R.
Acc. Chem. Res. 2001, 34, 433-444. (c) Feringa, B. L. Acc. Chem. Res.
2001, 34, 504-513.
(7) Saito, S.; Toriumi, Y.; Tomioka, N.; Itai, A. J. Org. Chem. 1995,
60, 4715-4720.
(8) Oki, M. Applications of Dynamic NMR Spectroscopy to Organic
Chemistry; VCH Publishers: New York, 1985.
(9) Rao, K. G.; Rao, C. N. R. J. Mol. Struct. 1973, 15, 303-306.
(10) Waisser, K.; Palat, K., Jr.; Exner, O. Collect. Czech. Chem. Commun.
1999, 64, 1295-1306.
linearity, N-methylacetanilide bearing an electron-withdraw-
ing group (σ > 1.39) was expected to prefer the trans
conformation. Indeed, N-methyl-m,m-dinitroacetanilide (3p,
(11) The structures 3 and the rotational barrier (∆Gq) are shown in the
Supporting Information. The ∆Gq value of the para-substituted compounds
correlates well with the Hammett σ value, while the meta substitution affects
less on the ∆Gq value.
(4) (a) Pederson, B. F.; Pederson, B. Tetrahedron Lett. 1965, 2995-
3001. (b) Nanjan, M. J.; Kannappan, V.; Ganesan, R. Indian J. Chem. 1979,
18B, 461-463. (c) Itai, A.; Toriumi, Y.; Tomioka, N.; Kagechika, H.;
Azumaya, I.; Shudo, K. Tetrahedron Lett. 1989, 30, 6177-6180.
(5) Tanatani, A.; Yamaguchi, K.; Azumaya, I.; Fukutomi, R.; Shudo,
K.; Kagechika, H. J. Am. Chem. Soc. 1998, 120, 6433-6442 and references
cited therein.
(12) Smith, M. B.; March, J. March’s AdVanced Organic Chemistry:
Reactions, Mechanisms, and Structures, 5th ed.; John Wiley & Sons: New
York, 1999; p 370.
(13) The ratio of the conformers of 6 was determined by using 6-d5 in
which all hydrogen atoms on the unsubstituted phenyl group were replaced
by deuterium atoms, since the methyl group signals did not show complete
separation.
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Org. Lett., Vol. 5, No. 8, 2003

from the difference in the Hammett’s σ values of the two
substituents (R1 and R2). Interestingly, the benzamide 7 also
showed a crystal structure with the electron-poor nitrophenyl
group cis to the amide oxygen atom, like 5. The result that
the energy difference (∆G° ) 0.45 kcal/mol) is less than
half that of 5 is in accordance with the fact that the preferred
conformation of N-methylbenzanilide (4) was little affected
by the aromatic substituent.
The substituent effects observed in acetamides can be
applied to achieve amide conformational switching induced
by acid; that is, the conformation of acetamides having a
basic amino group on the aromatic ring is expected to be
altered by protonation on the amino group. In the case of
3b with a p-dimethylamino group, the addition of TFA-d
(excess over 3b) decreased the percentage of cis conformer
from 97.2% to 82.6% at 233 K. This small change is
+
reasonable, considering the σ value (0.60) of the NH3
group.12 In the case of 3q with two dimethylamino groups,
the major conformation (>99.9% cis in CD2Cl2) dramatically
changed to trans (76.1%) upon addition of TFA-d (Figure
4). The fact that the percentage of the cis conformer of 3a
(95.5% in CD2Cl2) was not affected (95.3%) by the addition
of TFA-d indicated that the amide conformational alteration
did indeed result from protonation on the dimethylamino
group. The percentage of cis conformer in CD3OD (>99.9%)
also decreased to 71.6% by the addition of DCl, but the
extent of the change was small. This indicates that the cis/
trans ratio of 3q depends significantly on the acidity of the
solvent. The estimated σ value of the m,m-bis(dimethyl-
amino) group using the correlation line shown in Figure 2
is 1.92 in CD2Cl2-TFA-d or 0.89 in CD3OD-DCl.
Similar amide conformational switching was observed in
the N,N-diarylacetamide 6. The amide 6 has a major
conformer A (76.9%) with the electron-rich p-dimethylami-
nophenyl group trans to the amide oxygen atom in CD2Cl2.
Upon addition of TFA-d, the conformer B-H+ became
predominant (84.7%). In the case of 6, conformational
switching from conformer A (72.6%) to B-H+ (83.5%) was
also observed in the experiment using CD3OD and DCl as
solvent and acid, respectively.
Figure 4. Amide conformational switching by acid. The amount
of acid is 3% w/w to solvent. Further addition of acid did not affect
the conformational ratio.
ular devices that undergo reversible conformational inter-
conversion between two or more stable states when exposed
to an external stimulus, such as light, electricity or a chemical
reaction, has received much attention.6 The molecular
conformational change of aromatic amides caused by remote
protonation may be applicable as a solvent acidity-dependent
molecular switch.14
Supporting Information Available: Experimental de-
1
tails, H NMR data, and crystal structures (5 and 6). This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL034344G
(14) (a) Matthews, O. A.; Raymo, F. M.; Stoddart, J. F.; White, A. J.;
Williams, D. J. New J. Chem. 1998, 1131-1134. (b) Roque, A.; Lodeiro,
C.; Pina, F.; Maestri, M.; Ballardini, R.; Balzani, V. Eur. J. Org. Chem.
2002, 2699-2709.
The results shown here are simple examples, but should
be applicable to the construction of pH-dependent aromatic
architecture. Recently the development of functional molec-
Org. Lett., Vol. 5, No. 8, 2003
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