Molecular chirality and chiral capsule-type dimer formation of cyclic triamides via hydrogen-bonding interactions

Article abstract of DOI:10.1039/c2cc18177k

Chiral properties of bowl-shaped cyclic triamides bearing functional groups with hydrogen-bonding ability were examined. Chiral induction of cyclic triamide 3a was observed by addition of chiral amine in solution, and chiral separation was achieved by sim

Full text of DOI:10.1039/c2cc18177k

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Chemical Communications
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Volume 48 | Number 40 | 18 May 2012 | Pages 4781–4912
ISSN 1359-7345
COMMUNICATION
I. Azumaya, A. Tanatani et al.
Molecular chirality and chiral capsule-type dimer formation of cyclic
triamides via hydrogen-bonding interactions
1359-7345(2012)48:40;1-8

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COMMUNICATION
Molecular chirality and chiral capsule-type dimer formation of cyclic
triamides via hydrogen-bonding interactionswz
Noriko Fujimoto,a Mio Matsumura,a Isao Azumaya,*b Shizuka Nishiyama,a Hyuma Masu,c
Hiroyuki Kagechikad and Aya Tanatani*a
Received 31st December 2011, Accepted 21st February 2012
DOI: 10.1039/c2cc18177k
Chiral properties of bowl-shaped cyclic triamides bearing
functional groups with hydrogen-bonding ability were examined.
Chiral induction of cyclic triamide 3a was observed by addition
of chiral amine in solution, and chiral separation was achieved
by simple crystallization to afford chiral capsule-type dimer
structure of 4a.
Molecular tectonics using weak intermolecular interactions,1
such as hydrogen bonding,2 has attracted much attention for
the development of functional organic materials with well-
ordered three-dimensional structures.3 For example, bowl-shaped
macrocyclic molecules, such as calixarenes,4 with multiple
Fig. 1 Structure and conformations of cyclic triamide 1.
hydrogen bonds are useful templates for construction of
resides in the cavity of the other molecule.10 Further, syn-1 has
conformational chirality based on the direction of the amide
bond. At present, the enantiomers of syn-1 have not been
separated, and only racemic crystals have been obtained by
crystallization of 1 and its derivatives. In this study, we
examined the chiral properties in solution and the formation
of the capsule-type dimer in the crystal state for cyclic triamides
bearing functional groups at the 5-positions. Chiral separation
of one derivative was achieved by simple crystallization.
In the bowl-shaped syn structure, functional groups with
hydrogen-bonding ability at the 5-positions would lie in the
same direction, and might interact with other molecules via a
unique hydrogen-bond network structure. Such functionalization
might also affect the chiral properties of cyclic triamides. There-
fore, we designed cyclic triamides 2–5, bearing 5-carboxyl groups
or derivatives (ester or amide). The substituents on the amide
nitrogen atoms were chosen to be n-propyl or n-pentyl, on the
basis of solubility considerations (Scheme 1). The cyclic triamides
2 with 5-ester groups were prepared by the condensation of
monomethyl 5-(n-alkylamino)isophthalate in the presence
of dichlorotriphenylphosphorane.9 Hydrolysis or amidation of
2 afforded the acid (3) or amide (4 and 5) derivatives,
respectively.
various functional molecules, including specific receptors5
and capsule-type supramolecules.6,7 We have synthesized cyclic
tris(N-methyl-m-benzamide) 18 by condensation reaction of
m-methylaminobenzoic acid and examined its conformational
properties.9 Cyclic triamide 1 has a bowl-shaped syn crystal
structure, in which the three phenyl groups are directed to the
same side. In solution, it exists in rapid equilibrium between
the syn conformer (major) and the anti conformer, in which
one phenyl group is flipped in the opposite direction to the
other two (Fig. 1). Although the size of the cavity in syn-1 is
rather small, it plays a significant role in dimer formation of
the cyclic triamide bearing substituents at the 5-positions in
the crystalline state, because the substituent of one molecule
a Department of Chemistry, Faculty of Science, Ochanomizu
University, 2-1-1 Otsuka, Bunkyo-ku, Tokyo 112-8610, Japan.
E-mail: tanatani.aya@ocha.ac.jp; Fax: +81-3-5978-2716;
Tel: +81-3-5978-2716
b Faculty of Pharmaceutical Sciences at Kagawa Campus, Tokushima
Bunri University, 1314-1 Shido, Sanuki, Kagawa 769-2193, Japan.
E-mail: i-az@kph.bunri-u.ac.jp; Fax: +81-87-894-0181;
Tel: +81-87-894-5111 ext 6308
c Chemical Analysis Center, Chiba University, 1-33 Yayoi-cho,
Inage-ku, Chiba 263-8522, Japan. E-mail: masu@faculty.chiba-u.jp
d Graduate School of Biomedical Science, Institute of Biomaterials and
Bioengineering, Tokyo Medical and Dental University,
2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan.
E-mail: kage.omc@tmd.ac.jp
The conformations of the cyclic triamides were determined
by temperature-dependent 1H NMR spectroscopy. Cyclic
triamide 1 showed a broad spectrum at room temperature,
and two sets of signals corresponding to the syn and anti
conformers were observed at lower temperature.8–10 The
conformers could be assigned based on the observation of
H2 protons of the anti conformer at higher field (6.35 ppm for 1).
w This article is part of the ChemComm ‘Chirality’ web themed issue.
z Electronic supplementary information (ESI) available: Experimental
procedures, valuable temperature 1H NMR, and X-ray crystallo-
graphic analysis. CCDC [CCDC NUMBER(S)]. For ESI and crystallo-
graphic data in CIF or other electronic format see DOI: 10.1039/
c2cc18177k
c
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Chem. Commun., 2012, 48, 4809–4811 4809

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Fig. 2 CD spectra of 3a (5.2 ꢁ 10ꢀ4 M) in the presence of various
concentrations of (R)-(+)-bornylamine in acetonitrile (20 1C).
D[y] represents the difference from the corresponding value of the
amine only. Inset: plot of ꢀD[y] values at 212 nm vs. equivalents of
amine with respect to 3a.
equivalents of bornylamine, and further additions decreased
the intensity. Thus, although the nature of the interaction
between 3a and bornylamine and the structure of the complex
were not established, chiral induction of syn-3a bearing
carboxyl groups occurred in the presence of chiral amine.
X-Ray crystallographic analysis indicated that the crystal of
3b recrystallized from acetonitrile corresponded to a head-to-
head dimer of syn-3b, in which the three carboxyl groups in
one molecule form double hydrogen bonds with those in the
other molecule (Fig. 3a and b). The two molecules of syn-3b in
the dimer are enantiomeric, and the crystal is racemic (space
group: P63/m). The dimer contains a capsule-like inner space
surrounded by six phenyl rings. The longest diameter of
the inner space based on the van der Waals radius is ca. 3.2 A.
The hydrogen-bonded dimers are laminated along the c axis of the
unit cell to form a columnar packing structure (Fig. 3c and d). The
columns are ordered along the ab plane of the unit cell.
Scheme 1 Structures and synthetic schemes of cyclic triamides 2–5.
(a) Ph3PCl2, (CHCl2)2, 120 1C; (b) 2 M NaOH, EtOH, rt; (c) 7 M NH3,
MeOH, rt; (d) 40% CH3NH2, CH3OH, rt.
In all compounds examined, the syn conformer is the major
species (DG0 o 0). In the case of 1, the ratio of the syn
conformer was increased in more polar solvents, being 85%
and 97% in CD2Cl2 and CD3OD, respectively. A similar
tendency was observed for compounds 2 with 5-ester groups,
as well as in other cyclic triamides bearing alkyl, phenyl,
bromo, or amino groups at the 5-positions.10 Interestingly,
the cyclic triamides bearing 5-carboxyl (3) or 5-carboxamide
groups (5) did not show this tendency. The ratio of the syn
conformer was 94% for 5a and 95% for 5b in CD2Cl2, while it
was 97% for both in CD3OD. Further, among the cyclic
triamides 3 bearing 5-carboxyl groups, only the syn conformer
was observed in CD2Cl2, while the ratio of the syn conformer
in CD3OD was similar to those of other cyclic trimers. This
result suggests that hydrogen-bonding networks stabilize the
syn conformers of cyclic triamides 3 and 5 (Table 1).
In the crystal of 4b obtained from methanolic solution, the
enantiomeric pair of syn-4b formed a similar capsule-type
dimer structure (space group: P21/c) (Fig. 4). In this case,
the 5-carboxamide group of one molecule forms hydrogen
bonds with two adjacent carboxamide groups of the other
molecule.
Then, we examined the chiral properties of the cyclic
triamides in solution by examining the interaction with chiral
additives.11 Significant CD signals of 3a were induced in the
presence of (R)-(+)-bornylamine (Fig. 2). Interestingly, the
CD intensity was maximum in the presence of three
Interestingly, the cyclic triamide 4a formed chiral crystals
from acetonitrile (space group: P43212 or P41212), in which the
head-to-head capsule-type dimers consist of a single enantiomer of
syn-4a (Fig. 5). Two enantiomeric chiral crystals were obtained,
and could be distinguished by their CD spectra in KBr.
Table 1 Syn/anti equilibrium of cyclic triamides
In CD2Cl2
In CD3OD
Ratioa
(syn : anti)
DG0b/kcal
Ratioa
(syn : anti)
DG0b/kcal
molꢀ1
molꢀ1
Compound
1
77 : 23
79 : 21
79 : 21
499 : o1
499 : o1
Not soluble
Not soluble
94 : 6
ꢀ0.6
ꢀ0.7
97 : 3
95 : 5
94 : 6
93 : 7
91 : 9
96 : 4
94 : 6
97 : 3
97 : 3
ꢀ1.8
ꢀ1.5
ꢀ1.4
ꢀ1.3
ꢀ1.2
ꢀ1.6
ꢀ1.4
ꢀ1.8
ꢀ1.8
2a
2b
3a
3b
4a
4b
5a
5b
ꢀ0.7
oꢀ2.3
oꢀ2.4
ꢀ1.4
ꢀ1.5
Fig. 3 Crystal structure of 3b. (a) Side view and (b) top view of the
dimeric structure. (c) Packing structure and (d) space-filling model
along the c axis. Magenta- and cyan-colored molecules are enantio-
mers of each other. Hydrogen bonds are shown as black dotted lines.
Included solvent molecules are omitted for clarity.
95 : 5
a
Temperature is 263 K for N-methyl (1) and N-n-pentyl derivatives
b
(series b), or 253 K for N-n-propyl derivatives (series a). DG0
(kcal molꢀ1) = DG0 (syn) ꢀ DG0 (anti).
c
4810 Chem. Commun., 2012, 48, 4809–4811
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solution of 3–5, and the detailed analysis of the solution
structure is ongoing. These cyclic triamides have simple struc-
tures with chirality in the skeleton, exhibit unique dynamic
behaviors, and can be easily synthesized. The triamides bearing
hydrogen-bonding functional groups form interesting bowl-
shaped monomeric and capsule-type dimeric structures, which
may have application as molecular tectons, like other functional
macrocycles.
Notes and references
Fig. 4 Crystal structure of 4b. (a) Side view and (b) top view of the
dimeric structure. (c) Packing structure. Magenta- and cyan-colored
molecules are enantiomers of each other. Hydrogen bonds are shown
as black dotted lines. Included solvent molecules are omitted for
clarity.
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c
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Chem. Commun., 2012, 48, 4809–4811 4811