Chiral spherical molecule constructed from aromatic amides: Facile synthesis and highly ordered network structure in the crystal

Article abstract of DOI:10.1021/jo800585h

(Chemical Equation Presented) A novel chiral spherical molecule composed of aromatic amide was synthesized in short steps. The molecule is constructed from four benzene rings connected by six amide bonds and has multiple functionalizable points and an asymmetric structure. The racemic spherical molecule constructed channel network structures in the crystalline state.

Full text of DOI:10.1021/jo800585h

molecules,5 and it is important to find new types of spherical
molecules with pseudopolyhedral structure that can be synthe-
sized and modified more easily than typical polyhedral.
Chiral Spherical Molecule Constructed from
Aromatic Amides: Facile Synthesis and Highly
Ordered Network Structure in the Crystal
For this purpose, we designed a new type of spherical
molecule and developed an effective synthesis. The aromatic
amide 1 is a simple spherical molecule constructed from four
benzene rings connected by six amide bonds. It has pseudo-C3
symmetry and is a chiral structure, as a result of the direction
of its amide bonds,6 with multiple functionalizable nitrogen
atoms. Here, we report an effective construction and structural
analysis of the novel chiral spherical molecule 1. X-ray
crystallographic analyses reveal attractive 3-D network structures
of the racemic or enantiopure spherical molecules.
Hyuma Masu,† Kosuke Katagiri,† Takako Kato,†
Hiroyuki Kagechika,‡ Masahide Tominaga,† and
Isao Azumaya*,†
Faculty of Pharmaceutical Sciences at Kagawa Campus,
Tokushima Bunri UniVersity, 1314-1 Shido, Sanuki,
Kagawa 769-2193, Japan, and School of Biomedical
Science, Tokyo Medical and Dental UniVersity,
Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan
In the synthesis of the spherical molecule, preorganization
of the small partial structures was used effectively.7 Previously,
we have succeeded in the synthesis of a cyclic aromatic amide
trimer in high yield, by utilizing the stereochemistry of tertiary
aromatic amide in the presence of dichlorotriphenylphosphorane
as condensation reagent.8 The cyclic amide trimer 3 was
obtained in this manner.9 Subsequently, direct conversion from
nitro groups of 3 to ethylamino groups was successful by
catalytic hydrogenation in the presence of acetonitrile (Scheme
1).10 Direct condensation of alkylated triamine 4 with trimesic
acid provided the spherical amide 1. An overall yield of 1 from
commercially available 3-amino-5-nitrobenzoic acid is 18% in
only four steps.
azumayai@kph.bunri-u.ac.jp
ReceiVed March 14, 2008
Cyclic amide trimer 3 and 4 have two enantiomeric bowl-
shaped conformations based on the direction of the amide bond.9
These atropisomers are not separable because they are easily
converted to each other by flipping of benzene rings in a solution
at ambient temperature.9 The addition of a trimesic acid as a
capping group covalently captures this conformation and
generates a fixed chiral structure. Therefore, 1 is obtained as a
racemic mixture of both enantiomers. Chiral separation of
racemic 1 was carried out by chiral HPLC. The enantiopure
A novel chiral spherical molecule composed of aromatic
amide was synthesized in short steps. The molecule is
constructed from four benzene rings connected by six amide
bonds and has multiple functionalizable points and an
asymmetric structure. The racemic spherical molecule con-
structed channel network structures in the crystalline state.
Spherical molecules are of interest because of their high
symmetry and associated customizable functionality.1 For
example, they are expected to be valuable scaffolds for
stereoselective organic reactions2 or dendrimer cores,3 because
they have mechanical rigidity and well-defined conformation.
Moreover, bulky spherical molecules can generate interesting
3-D architecture in the crystalline state.4 Consequently, extensive
efforts have been devoted to obtaining functional spherical
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† Tokushima Bunri University.
‡ Tokyo Medical and Dental University.
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Fujiwara, Y.; Itoh, M.; Yamaguchi, K.; Shudo, K. J. Am. Chem. Soc. 1991,
113, 2833–2838. (c) Itai, A.; Toriumi, Y.; Saito, S.; Kagechika, H.; Shudo, K.
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10.1021/jo800585h CCC: $40.75
Published on Web 06/10/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 5143–5146 5143

SCHEME 1. Synthesis of Spherical Molecules
FIGURE 2. Structure of 1 in the crystal. Ball-and-stick model (left)
and space-filling model (right). The ethyl groups are faded to make
clear the shape of the spherical core.
compounds ((+)-1 and (-)-1) showed clear mirror-imaged CD
spectra in acetonitrile (Figure 1).
X-ray crystallographic analysis was performed on a single
crystal of racemic compound 1 that was obtained from a
chloroform/methanol solution by slow evaporation of the
solvent. Figure 2 shows that compound 1 has an expected
spherical structure. The diameter of the circumscribed sphere
of the four benzene rings is ∼9.5 Å and the longest diameter
of a space-filling model (between the carbonyl carbon atoms
facing each other) is ∼12 Å.
In the racemic crystal of 1, the enantiomers are arranged
alternately in a doughnut shape toward the a and b axes of the
unit cell (Figures 3a and 3c). Furthermore, this network layer
is laminated along the c axis, forming a channel network
structure (Figure 3b). This circular shaped channel, which has
a diameter of ∼4.0 Å (based on van der Waals radius) contains
water molecules. It is known that bulky spherical molecule can
FIGURE 3. Packing structure in a racemic crystal of 1. Ball-and-stick
model (a), space-filling model (b), and channel network structure (c).
Magenta- and cyan-colored molecules are enantiomers of each other.
Water molecules are omitted for clarity.
construct a highly ordered aggregation in crystalline state.11 In
this case, the construction of highly ordered network structure
is associated by weak intermolecular interactions (CH/O and
CH/π interactions;12 see Supporting Information).
In contrast, chiral separated enantiopure (+)-1 did not form
a channel-shaped network structure in the crystalline state
(Figure 4). The chiral molecules built up as a 1-D columnar
structure. This means that the difference of types of the weak
(11) (a) Yaghi, O. M.; Sun, Z.; Richardson, D. A.; Groy, T. L. J. Am. Chem.
Soc. 1994, 116, 807–808. (b) Chen, B.; Eddaoudi, M.; Reineke, T. M.; Kampf,
J. W.; O’Keeffe, M.; Yaghi, O. M. J. Am. Chem. Soc. 2000, 122, 11559–11560.
(c) Hoffart, D. J.; Coˆte´, A. P.; Shimizu, G. K. H. Inorg. Chem. 2003, 42, 8603–
8605. (d) Dalgarno, S. J.; Cave, G. W. V.; Atwood, J. L. Angew. Chem., Int.
Ed. 2006, 45, 570–574.
FIGURE 1. CD spectra of enantiopure (+)-1 and (-)-1 in acetoni-
trile.
5144 J. Org. Chem. Vol. 73, No. 13, 2008

Experimental Section
1
General. For H and 13C NMR, chemical shifts are reported in
ppm on the δ scale relative to TMS or residual solvent. Coupling
constants J are in hertz. Unless otherwise noted, NMR spectra were
measured at room temperature. Reactions were carried out in dry
solvents, unless otherwise mentioned.
Synthesis of 3-(Ethylamino)-5-nitrobenzoic Acid 2. Ethyl
iodide (0.250 mL, 3.10 mmol) was added to 3-amino-5-nitrobenzoic
acid (1.00 g, 5.49 mmol) in hexamethylphosphoric triamide (55
mL) under argon. After the solution was heated at 80 °C with
stirring for 16 h, 100 mL of AcOEt was added. The mixture was
washed with distilled water and brine. The organic layer was dried
over Na2SO4, filtered, and evaporated. The residues were purified
by column chromatography with chloroform/methanol. 3-Amino-
5-nitrobenzoic acid (0.317 g, 1.74 mmol) was recovered, and
product 2 (0.525 g, 67%) was obtained as a yellow powder.
Sufficient compound was obtained by repeat of similar method;
1
mp 186-187 °C; H NMR (400 MHz, CDCl3) δ 8.06 (1H, t, J )
1.4), 7.49-7.46 (2H, m), 4.39 (2H, q, J ) 7.1), 3.25 (2H, q, J )
7.2), 1.41 (3H, t, J ) 7.2), 1.30 (3H, t, J ) 7.2); MS(FAB) m/z
210 (M+). Anal. Calcd for C9H10N2O4: C, 51.43; H, 4.80; N, 13.33.
Found: C, 51.49; H, 4.60; N, 13.36. Other spectral data is described
in ref 9b.
Synthesis of Cyclic Trimer 3. Dichlorotriphenylphosphorane
(6.02 g, 18.1 mmol) was added to 2 (1.96 g, 9.32 mmol) in 1,1,2,2-
tetrachloroethane (22 mL) under argon. After heating at 140 °C
with stirring for 7 h, the solution was evaporated. The residue was
purified by column chromatography with chloroform/methanol.
Preparative GPC with chloroform gave product 3 (1.38 g, 77%) as
a white powder; mp 222-225 °C; 1H NMR (400 MHz, DMSO) δ
8.26 (s, 3H), 8.19 (S, 3H), 7.67 (S, 3H), 3.77 (6H, m), 1.09 (t, J )
7.0, 9H); 13C NMR (100 MHz, DMSO) δ 167.0, 148.4, 143.0,
140.1, 134.0, 125.6, 122.0, 44.3, 12.8; MS(FAB) m/z 577 (MH+).
Anal. Calcd for C27H24N3O6: C, 56.25; H, 4.20. Found: C, 56.09;
H, 3.78. Other spectral data is described in ref 9b.
FIGURE 4. Packing structure in a chiral crystal of enantiopure (+)-1.
Top view (a) and side view (b). The molecules except in the center
column are colored in cyan, and water molecules are omitted to make
the arrangement clear.
Synthesis of Cyclic Trimer 4. After five vacuum/H2 cycles to
remove air from the reaction tube, the stirred mixture of the cyclic
trimer 3 (0.865 g, 1.50 mmol), 10% Pd/C (0.260 g, 30 wt % of the
substrate), acetonitrile (1.18 mL, 22.5 mmol), and acetic acid (0.520
mL, 9.08 mmol) in methanol (20 mL) and activated molecular
sieves 3Å (5 g) was hydrogenated at ordinary pressure (balloon) at
room temperature. After 5.5 days, acetic acid (0.520 mL, 9.08
mmol) and acetonitrile (0.590 mL, 11.3 mmol) were added. Then,
the reaction mixture was stirred at room temperature for 3 days,
filtered, and evaporated. The residue was purified by column
chromatography with chloroform/methanol. And then, preparative
GPC with chloroform gave product 4 (0.532 g, 62%) as a white
powder; mp g 300 °C; IR (KBr) 3352, 2970, 2932, 1637, 1588
intermolecular interactions due to asymmetry of the spherical
molecule brings about a change of the shape of network structure
in the crystal (Figures S4 and S5 in Supporting Information).
In conclusion, we have designed a novel chiral spherical
molecule and synthesized it in short steps by means of
stereochemistry of the aromatic amide. It suggests that the
preorganized aromatic amide component is useful for construc-
tion of various 3-D macromolecules.13 In addition, the spherical
molecule constructed a channel-shaped network by the multiple
weak intermolecular interactions in the crystalline state. These
features may be useful for the construction of functional
molecular 3-D networks, such as molecular channels for
clathration. Three stereoisomers of 1 (each consisting of two
enantiomers) based on the directions of the amide bonds are
also expected to exist. Differences in the direction of the
functional groups in these spherical structures may result in
unique organizational features, and we are currently attempting
to synthesize the other isomers.
1
cm-1; H NMR (400 MHz, DMSO, 393K) δ 6.34 (3H, s), 6.26
(3H, s), 6.01 (3H, m), 5.02 (3H, s), 3.66 (6H, q, J ) 7.2), 2.96
(6H, m), 1.10 (9H, t, J ) 6.8), 1.07 (9H, t, J ) 7.2); 13C NMR
(100 MHz, DMSO, 393K) δ 149.1, 142.7, 139.0, 115.2, 112.7,
110.5, 43.8, 37.5, 14.1, 12.6; MS(FAB) m/z 571 (MH+). Anal. Calcd
for C33H42N6O3 ·1/3(CHCl3): C, 65.73; H, 7.05; N, 13.66. Found:
C, 65.60; H, 7.04; N, 13.62. 1H and 13C NMR spectra for 4 indicate
many broad peaks at room temperature.9b VT-NMR spectra for 4
are shown in Supporting Information.
Synthesis of Spherical Molecule 1. Dichlorotriphenylphospho-
rane (0.666 g, 2.00 mmol) was added to mixture of 4 (0.114 g,
0.200 mmol) and 1,3,5-benzenetricarboxylic acid (0.0462 g, 0.220
mmol) in 1,1,2,2-tetrachloroethane (10 mL) under argon. After
heating at 120 °C with stirring for 5 h, the solution was evaporated.
The residue was purified by column chromatography with chloroform/
methanol. Preparative GPC with chloroform gave product 1 (0.809
g, 56%) as a white powder; mp g 300 °C; IR (KBr) 3445, 3074,
2967, 2933, 1654, 1590 cm-1; 1H NMR (400 MHz, CDCl3) δ 6.98
(3H, s), 6.81 (3H, t, J ) 1.6), 6.79 (3H, t, J ) 1.6), 6.67 (3H, t, J
) 1.8), 3.89-3.78 (6H, m), 3.75-3.64 (6H, m), 1.17 (9H, t, J )
(12) (a) Desvergne, J.-P.; Bitit, N.; Castellan, A.; Bouas-Laurent, H. J. Chem.
Soc. Perkin Trans. 2 1983, 109–114. (b) Desiraju, G. R. Acc. Chem. Res. 1991,
24, 290–296. (c) Nishio, M.; Umezawa, Y.; Hirota, M.; Takeuchi, Y. Tetrahedron
1995, 51, 8665–8701. (d) Nishio, M.; Hirota, M.; Umezawa, Y. The CH/
πInteraction, EVidence Nature, and Consequences, Wiley-VCH, New York, 1998.
(e) Xie, Z.; Liu, L.; Yang, B.; Yang, G.; Ye, L.; Li, M.; Ma, Y. Cryst. Growth
Des. 2005, 5, 1959–1964.
(13) (a) Azumaya, I.; Okamoto, T.; Imabeppu, F.; Takayanagi, H. Tetrahedron
2003, 59, 2325–2331. (b) Tominaga, M.; Masu, H.; Katagiri, K.; Kato, T.;
Azumaya, I. Org. Lett. 2005, 7, 3785–3787. (c) Masu, H.; Okamoto, T.; Kato,
T.; Katagiri, K.; Tominaga, M.; Goda, H.; Takayanagi, H.; Azumaya, I.
Tetrahedron Lett. 2006, 47, 803–807. (d) Tominaga, M.; Hatano, T.; Uchiyama,
M.; Masu, H.; Kagechika, H.; Azumaya, I. Tetrahedron Lett. 2006, 47, 9369–
9371. (e) Tominaga, M.; Masu, H.; Katagiri, K.; Azumaya, I. Tetrahedron Lett.
2007, 48, 4369–4372.
J. Org. Chem. Vol. 73, No. 13, 2008 5145

7.2), 1.16 (9H, t, J ) 7.2); 13C NMR (100 MHz, CDCl3) δ 169.0,
168.5, 144.2, 143.2, 140.6, 137.8, 131.0, 127.5, 126.9, 126.2, 45.2,
45.0, 12.9, 12.7; MS(FAB) m/z 727 (MH+). Anal. Calcd for
C42H42N6O6 ·1/2(H2O): C, 68.56; H, 5.89; N, 11.42. Found: C,
68.67; H, 5.67; N, 11.53.
X-ray Crystallographic Data for Racemic 1. C42H42N6O6,
1.5(H2O), Mr ) 753.84 g mol-1, monoclinic, Cc, a ) 15.580(2), b
) 27.514(3), c ) 9.2074(9) Å, ꢀ ) 92.224(2)°, V ) 3943.9(7) Å3,
Z ) 4, Dcalcd ) 1.270 Mg m-3, µ ) 0.088 mm-1, T ) 150 K,
2θmax ) 56.50°, 11003 reflections, 4466 unique (Rint ) 0.0460),
R1 ) 0.0604, wR2 ) 0.1464 (I > 2σ(I)), CCDC-650286. Other
details are described in Supporting Information, including a CIF
file.
) 120 K, 2θmax ) 54.20° 19063 reflections, 8129 unique (Rint )
0.0376), R1 ) 0.0501, wR2 ) 0.1151 (I > 2σ(I)), CCDC-680551.
Absolute structure of (+)-1 is not clarified. Other details are
described in Supporting Information, including a CIF file.
Acknowledgment. H.M. acknowledges partial funding of this
work by Grant-in-Aid for Young Scientists (B) (No. 18790021)
from the Ministry of Education, Culture, Sports, Science and
Technology, Japan. I.A. acknowledges a Kitasato University
Research Grant for Young Researchers (2003-2004).
Supporting Information Available: Copies of spectra and
chromatograms, expanded structural data and crystallographic
information files in CIF format. This material is available free
of charge via the Internet at http://pubs.acs.org.
X-ray Crystallographic Data for Enantiopure (+)-1. C42H42-
N6O6, 1.5(H2O), Mr ) 753.84 g mol-1, monoclinic, P21, a )
14.597(1), b ) 17.366(2), c ) 15.335(1) Å, ꢀ ) 91.590(1)°, V )
3885.7(6) Å3, Z ) 4, Dcalcd ) 1.289 Mg m-3, µ ) 0.090 mm-1, T
JO800585H
5146 J. Org. Chem. Vol. 73, No. 13, 2008