Triple helicate constructed by covalent bondings: Crystal structure and effective synthesis based on propeller-like substructures

Article abstract of DOI:10.1021/ol051477o

(Chemical Equation Presented) A triple helicate, having a macrocyclic aromatic amide structure, was synthesized in high yield because of a preorganized component of the tertiary benzenetrianilide moieties in a propeller-like syn conformation at both ends. The helicity was derived from tilted T-shaped aromatic-aromatic (CH-π) interactions between each of the N-phenyl rings.

Full text of DOI:10.1021/ol051477o

ORGANIC
LETTERS
2005
Vol. 7, No. 17
3785-3787
Triple Helicate Constructed by Covalent
Bondings: Crystal Structure and
Effective Synthesis Based on
Propeller-like Substructures
Masahide Tominaga, Hyuma Masu, Kosuke Katagiri, Takako Kato, and
Isao Azumaya*
Faculty of Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri UniVersity,
1314-1 Shido, Sanuki, Kagawa 769-2193, Japan
azumayai@kph.bunri-u.ac.jp
Received June 23, 2005
ABSTRACT
A triple helicate, having a macrocyclic aromatic amide structure, was synthesized in high yield because of a preorganized component of the
tertiary benzenetrianilide moieties in a propeller-like syn conformation at both ends. The helicity was derived from tilted T-shaped aromatic
−
aromatic (CH−π) interactions between each of the N-phenyl rings.
The helical structure is a common, attractive topological
feature that is widely observed in synthetic or biological
molecules.1 Helical structures have been constructed by
various methodologies; for example, metal coordination in
self-assembled nanomolecules,2 hydrogen bonding in helices
of â-peptides,3 hydrogen bonding associated with parallel
aromatic-aromatic interaction in some discoidal compounds4
or in DNA, solvent effect or guest inclusion in phenylene
ethynylene foldamers,5 or weak internal CH-π interactions
in tertiary aromatic polyamides.6 In this context, there are
(3) (a) Appella, D. H.; Christianson, L. A.; Karle, I. L.; Powell, D. R.;
Gellman, S. H. J. Am. Chem. Soc. 1996, 118, 13071-13072. (b) Seebach,
D.; Matthews, J. L. Chem. Commun. 1997, 2015-2022. (c) Gellman, S. H.
Acc. Chem. Res. 1998, 31, 173-180. (d) Cheng, R. P.; Gellman, S. H.;
DeGrado, W. F. Chem. ReV. 2001, 101, 3219-3232.
(4) (a) Lightfoot, M. P.; Mair, F. S.; Pritchard, R. G.; Warren, J. E. Chem.
Commun. 1999, 1945-1946. (b) Azumaya, I.; Uchida, D.; Kato, T.;
Yokoyama, A.; Tanatani, A.; Takayanagi, H.; Yokozawa, T. Angew. Chem.,
Int. Ed. 2004, 43, 1360-1363.
(5) (a) Nelson, J. C.; Saven, J. G.; Moore, J. S.; Wolynes, P. G. Science
1997, 277, 1793-1796. (b) Oh, K.; Jeong, K.-S.; Moore, J. S. Nature 2001,
414, 889-893.
(6) 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.
(1) (a) Rowan, A. E.; Nolte, R. J. M. Angew. Chem., Int. Ed. 1998, 37,
63-68. (b) Albrecht, M. Chem. ReV. 2001, 101, 3457-3497. (c) Hill, D.
J.; Mio, M. J.; Prince, R. B.; Hughes, T. S.; Moore, J. S. Chem. ReV. 2001,
101, 3893-4011. (d) Nakano, T.; Okamoto, Y. Chem. ReV. 2001, 101,
4013-4038. (e) Schmuck, C. Angew. Chem., Int. Ed. 2003, 42, 2448-
2452.
(2) (a) Lehn, J.-M.; Rigault, A.; Siegel, J.; Harrowfield, J.; Chevrier,
B.; Moras, D. Proc. Natl. Acad. Sci. U.S.A. 1987, 84, 2565-2569. (b)
Constable, E. C.; Ward, M. D.; Tocher, D. A. J. Am. Chem. Soc. 1990,
112, 1256-1258. (c) Potts, K. T.; Keshavarz-K, M.; Tham, F. S.; Abrun˜a,
H. D.; Arana, C. R. Inorg. Chem. 1993, 32, 4422-4435. (d) Kersting, B.;
Meyer, M.; Powers, R. E.; Raymond, K. N. J. Am. Chem. Soc. 1996, 118,
7221-7222. (e) McMorran, D. A.; Steel, P. J. Angew. Chem., Int. Ed. 1998,
37, 3295-3297.
10.1021/ol051477o CCC: $30.25
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Published on Web 07/28/2005

few examples in which a pre-organized helical moiety is
utilized to construct the entire helical structure in covalently
bonded macrocycles. In the course of our investigation of
the stereochemistry of an aromatic tertiary amide,7 we found
that N,N′,N′′-trimethyl-N,N′,N′′-triphenyl-1,3,5- benzenetri-
carboxyamide (1) exists in a propeller-like chiral conforma-
tion due to intramolecular tilted T-shaped aromatic-aromatic
(CH-π) interactions (Figure 1).8 We have applied this
N-ethylated by a usual method, followed by deacetylation
by 4 M HCl at reflux to give 4-bromo-N-ethylaniline (3).
The coupling reaction of 3 and 1,4-benzenediboronic acid
using PdCl2(PPh3)2 with K3PO4 in DMF-H2O at 100 °C for
2 days gave 4 in 71% yield. The mixture of 4 and 1,3,5-
benzenetricarboxylic acid (3:2 in molar ratio) was treated
with 2.4 equiv of Ph3PCl2 in 1,1,2,2-tetracholoroethane (50
mM for 4) at 120 °C for 8 h. The crude product was purified
by gel permeation chromatography (GPC) to give the
macrocyclic aromatic amide 2 in 50% yield.
The yield in the macrocyclic reaction was much higher
than that of the other multicomponent amide condensation
reaction from acid chlorides and amines.10 This is because
the trianilide moieties at both ends of the macromolecule
tend to exist in a syn conformation as shown in trianilide 1;
that is, the fragments would work as a preorganized structure
during the macrocylic amide formation.
Prismatic single crystals of compound 2 were obtained
from a chloroform solution by slow evaporation of the
solvent. X-ray crystallographic analysis showed that the
crystal belonged to the space group Pca21, which contains
two sets of enantiomeric helical conformers per unit cell
(Figure 2).11 Both enantiomers of helicate 2 alternate along
the c-axis, and the racemic row of the helicates piles up with
chloroform molecules along the b-axis. Therefore, the crystal
is achiral, as opposed to the other 1,3,5-benzenetricarboxylic
acid derivatives with no fixed chiral element that frequently
show spontaneous resolution.4,12 The unit cell contains 16
molecules of chloroform to fill the space among the
macrocyclic amide molecules.
Figure 1. Structural formula and stereoview of the crystal structure8
in a space-filling model of 1.
Figure 3a shows a stereoview of the sole molecule in the
unit cell. The molecule is 18 Å in length and ca. 10 Å in
diameter. The tricarbonyl trianilide moieties exist in similar
conformations as observed in the triamide 1 reported
previously,8 except that each has slightly larger torsion angles
where the torsion angle of the six amide bonds (CPh-C-
N-CPh) are 18.3°, 15.6°, 27.4°, 23.5°, 21.1°, and 20.0°, those
moiety as a helically preorganized structural fragment to
construct helicate 2. In this paper, we report the crystal
structure of this helicate and its synthesis.
Helicate 2 is synthesized by a direct condensation reaction
of aromatic diamine 4 with 1,3,5-benzenetricarboxylic acid
using dichlorotriphenylphosphorane as a condensation re-
agent (Scheme 1), a very effective method for macrocyclic
aromatic amide construction.9 The synthesis of diamine 4
was based on the Miyaura-Suzuki coupling to extend the
phenylene chain. First, 4-bromoaniline was acetylated and
(7) (a) Itai, A.; Toriumi, Y.; Tomioka, N.; Kagechika, H.; Azumaya, I.;
Shudo, K. Tetrahedron Lett. 1989, 30, 6177-6180. (b) Azumaya, I.;
Yamaguchi, K.; Okamoto, I.; Kagechika, H.; Shudo, K. J. Am. Chem. Soc.
1995, 117, 9083-9084.
(8) (a) Yamaguchi, K.; Matsumura, G.; Kagechika, H.; Azumaya, I.; Ito,
Y.; Itai, A.; Shudo, K. J. Am. Chem. Soc. 1991, 113, 5474-5475. (b)
Azumaya, I.; Kagechika, H.; Yamaguchi, K.; Shudo, K. Tetrahedron 1995,
51, 5277-5290.
Scheme 1
(9) (a) Azumaya, I.; Okamoto, T.; Imabeppu, F.; Takayanagi, H.
Tetrahedron 2003, 59, 2325-2331. (b) Azumaya, I.; Okamoto, T.;
Imabeppu, F.; Takayanagi, H. Heterocycles 2003, 60, 1419-1424.
(10) (a) Kiggen, W.; Vo¨gtle, F. Angew. Chem., Int. Ed. 1984, 23, 714-
715. (b) Grammenudi, S.; Vo¨gtle, F. Angew. Chem., Int. Ed. 1986, 25,
1122-1125.
(11) X-ray data were collected on a Bruker Smart1000 CCD detector.
The crystal structure was solved by direct methods SHELXS-97 (Sheldrick,
1997) and refined by full-matrix least-squares SHELXL-97 (Sheldrick,
1997). All non-hydrogen atoms were refined anisotropically. All hydrogen
atoms were included as their calculated positions. Crystal data for 2:
C84H72N6O6‚4CHCl3; M ) 1738.95 g mol-1, orthorhombic, Pca21, colorless
prism measuring 0.30 × 0.25 × 0.25 mm, T ) 150 K, a ) 33.749(12) Å,
b ) 12.982(5) Å, c ) 19.167(7) Å, R ) â ) γ ) 90°, V ) 8398(5) Å3, Z
) 4, Dcalcd ) 1.375 Mg m-3, µ ) 0.453 mm-1, Tmax ) 0.8952, Tmin
)
0.8761, GOF on F2 ) 0.950, R1 ) 0.0892, wR2 ) 0.2229 ([I > 2σ(I)], R1
) 0.1618, and wR2 ) 0.2679 (all data). CCDC-275835.
(12) (a) Hanabusa, K.; Koto, C.; Kimura, M.; Shirai, H.; Kakehi, A.
Chem. Lett. 1997, 429-430. (b) Dale, S. H.; Elsegood, M. R. J. Acta
Crystallogr., Sect. E: Structure Reports Online 2003, E59, o836-o837.
3786
Org. Lett., Vol. 7, No. 17, 2005

trianilide, with the same chirality in the propeller-like
conformation in one macromolecule, were joined through
three phenylene groups at their para positions without any
large conformational change, which holds the macrocyclic
amide in a helicate. The angle of the twist between two
benzenetricarbonyl moieties at both ends of the molecule is
101°. The observed intermolecular tilted T-shaped aromatic-
aromatic (CH-π) interaction between the two phenylene
groups of both trianilide moieties is shown in Figrue 3b;
this is the driving force to form the helical structure for the
macrocyclic amide.
1H NMR measurements of 2 at ambient temperature
showed that the equilibrium between the two enantiomeric
helical conformers is fast because the two ortho protons on
the N side of each phenylene ring or two prochiral methylene
protons of the N-ethyl group are not distinguished (see the
Supporting Information). Preliminary DNMR measurements
in dichloromethane-d2 revealed that an equilibrium between
the two enantiomeric helical conformers was definitely
slower at low temperatures because the signals became
broader as the temperature was lowered, but did not split
into two sets of peaks at 178 K (data not shown). Therefore,
even at low temperatures, the lifetime of enantiomeric helical
conformers is too short on an NMR time scale. These
dynamic behaviors of helicate 2 are caused by the inherently
weak nature of the aromatic-aromatic interaction, and so
the structure in a helicate with one chirality is not tightly
fixed.
Figure 2. Projection on the ac plane of the unit cell of 2.
of Ar-CO are 58.1°, 57.9°, 50.9°, 52.5°, 51.0°, and 54.0°,
and those of Ar-NCEt are 72.6°, 68.5°, 85.4°, 81.1°, 77.3°,
and 61.2° (averaged torsion angles in 1 are 3°, 52°, and 63°,
respectively). These means that two sets of tricarbonyl
In conclusion, we have designed and synthesized a triple
helicate, a macrocyclic aromatic amide with a helical
structure. The yield in the macrocyclization reaction is very
high due to the preorganized propeller-like structure of
tertiary trianilide moieties. It is notable that the helicity of
the helicate was induced by intramolecular tilted T-shaped
aromatic-aromatic (CH-π) interactions, which were ob-
served in the crystal structure. Because the interaction was
sufficiently weak, the helicate came to have dynamic features,
such as the helical structures being able to interconvert to
each other at an ambient temperature. We could create a
“softly constrained” helical structure using a tilted T-shaped
aromatic-aromatic (CH-π) interaction. We are now ap-
plying this concept to construct a chiral architecture with
dynamic behavior.
Figure 3. (a) Stereoview of molecule 2 in a space-filling model
(hydrogens were omitted for simplicity). (b) Relative positions of
each of the three phenylene groups in the upper, middle, and bottom
part of molecule 2. The ring center-ring center distances of each
two phenylene groups from the left in a clockwise direction are
5.40, 5.14, 5.17 Å (upper), 5.31, 4.71, 4.71 Å (middle), and 5.05,
5.45, 5.08 Å (bottom).
Supporting Information Available: Synthetic proce-
dures, NMR spectra, and mass spectrum of 2. This material
is available free of charge via the Internet at http://pubs.acs.org.
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