Preparation of molecular cage by coordination of m-Calix[3]amide bearing pyridine with palladium complex

Article abstract of DOI:10.1246/cl.2012.249

m-Calix[3]amide having pyridine on the benzene ring (PyC3A) was synthesized by the cyclization of methyl 3-nonylamino-5-(pyridin-4-yl)benzoate using lithium 1,1,1,3,3,3-hexamethyldisilazide (LiHMDS). The molecular cage 3Pd· 2PyC3A was prepared from a 2:3 mixture of PyC3A and [Pd(dppp)(OTf)₂] in CDCl₃/CD₃OD (5/1 in volume). On the other hand, in CDCl₃, the formation of a polymeric mixture was confirmed.

Full text of DOI:10.1246/cl.2012.249

doi:10.1246/cl.2012.249
Published on the web February 25, 2012
249
Preparation of Molecular Cage by Coordination of m-Calix[3]amide Bearing Pyridine
with Palladium Complex
Ryohei Yamakado,1 Shinri Sugimoto,1 Shin-ichi Matsuoka,1 Masato Suzuki,1
Yasuhiro Funahashi,2 and Koji Takagi*1
1Department of Materials Science and Engineering, Nagoya Institute of Technology,
Gokiso, Showa-ku, Nagoya, Aichi 466-8555
2Department of Frontier Materials, Nagoya Institute of Technology,
Gokiso, Showa-ku, Nagoya, Aichi 466-8555
(Received November 23, 2011; CL-111127; E-mail: takagi.koji@nitech.ac.jp)
m-Calix[3]amide having pyridine on the benzene ring
(PyC3A) was synthesized by the cyclization of methyl 3-
nonylamino-5-(pyridin-4-yl)benzoate using lithium 1,1,1,3,3,3-
hexamethyldisilazide (LiHMDS). The molecular cage 3Pd¢
2PyC3A was prepared from a 2:3 mixture of PyC3A and
[Pd(dppp)(OTf)2] in CDCl3/CD3OD (5/1 in volume). On the
other hand, in CDCl3, the formation of a polymeric mixture was
confirmed.
rings in the same orientation relative to the amide bond, and the
anti-conformer has one benzene ring turning in the other
direction. It is found that the preferable conformation depends
on the solvent character ([syn]/[anti] = 74/26 in CDCl3 and
96/4 in CD3OD).9
In our previous work, m-calix[3]amide derivatives carrying
oligothiophene chromophore on the benzene ring were synthe-
sized and the self-assembly of a ³-conjugated system influenced
by the solvent character was reported.14 Despite extensive
research8-11 on the conformation of calix[3]amides in crystal
and solution states, only a minimal effort15 has been devoted for
the application as functional molecules. As mentioned above, the
shape of the building block is of importance to obtain self-
assembled molecular capsules. With the fact that m-calix[3]-
amide prefers the syn-conformer in CH3OH in mind, we
investigated the construction of m-calix[3]amide-based molecular
cage not by covalently fixing the conformation but by tuning the
conformation with the solvent character. In this article, we will
describe the synthesis and conformation analysis of a new m-
calix[3]amide having pyridine on the benzene ring by using
variable temperature (VT)-NMR, and the formation of molecular
cage with palladium complexes.
3-Nonylaminobenzoic acid and its methyl ester bearing
pyridine at the 5-position were prepared as monomers. Following
our previous report,14 methyl 3-bromo-5-nonylaminobenzoate
was synthesized in three steps starting from 3-bromo-5-nitro-
benzoic acid. The subsequent Suzuki coupling reaction with 4-
pyridineboronic acid in the presence of tetrakis(triphenylphos-
phine)palladium(0) afforded methyl 3-nonylamino-5-(pyridin-4-
yl)benzoate (1) in 58% yield. The hydrolysis of methyl ester 1
under the acidic condition gave 3-nonylamino-5-(pyridin-4-
yl)benzoic acid (2) in 68% yield.
Cyclic oligomerization was initially carried out using acid 2
based on the procedure reported by Azumaya et al. using SiCl4 as
the condensation reagent (Scheme 1, Path A).9,10 The preparative
GPC profile of crude products gave a multimodal curve ranging
from the oligomeric region to the high-molecular-weight region
(Figure S1,18 left). The MALDI-TOF-MS also indicated the
formation of macrocyclic oligomers in addition to the target
cyclic trimer (Figure S2, left). In the cyclic oligomerization of
3-nonylamino-5-phenylbenzoic acid, however, the cyclic trimer
could be selectively formed (not shown here). Thus the
introduction of the pyridine group in the monomer structure
might interrupt the effective cyclic trimerization. The cyclic
oligomerization of methyl ester 1 was then performed using
LiHMDS following to the method developed by Yokozawa et al.
(Scheme 1, Path B).12 In contrast to the result through Path A,
the preparative GPC profile showed a good peak separation of the
The noncovalent bond self-assembly of chemically-designed
components proceeds under thermodynamic equilibrium and thus
permits the generation of supramolecular cages or capsules
more easily than with covalent bond approaches. The size and
dimension control of supramolecular objects depends on the
shape of the building blocks. Stang1 and Fujita2 hitherto reported
many fantastic examples of self-assembled supramolecular
objects using the coordination of the pyridine nitrogen to
palladium complexes. They synthesized two- or three-dimen-
sional supramolecular objects with modified building blocks. For
example, ditopic building blocks with a predetermined angle
gave cyclic molecules, and the combination of ditopic and
tritopic building blocks afforded three-dimensional supramole-
cular cages. On the other hand, Shinkai and co-workers prepared
molecular capsules using bowl-shaped calix[n]arenes as the
building block through similar pyridine coordination to palla-
dium complexes.3-7 Molecular capsules constructed from two
bowl-shaped calix[n]arenes provided the large cavity, which
could be utilized as the host of fullerene encapsulation. In this
methodology, however, the immobilization of the cone con-
formation by the chemical bonding was necessary for building
the molecular capsules and the 1,3-alternate conformation gave
uncharacterizable oligomers.
Calix[3]amide classified by Azumaya8 is a cyclic trimer
having N-alkylbenzanilide skeletons. In particular, calix[3]amide
linked at the meta-position (m-calix[3]amide) likely adopts a
bowl-shaped structure (vide infra). A m-calix[3]amide was first
synthesized by Azumaya in one step using 3-alkylaminobenzoic
acid as a substrate and tetrachlorosilane9,10 or dichlorotriphenyl-
phosphorane8,11 as condensation reagents. On the other hand,
Yokozawa investigated the cyclic trimerization of a diphenyl-
acetylene monomer bearing 4-propylamino and 4¤-methoxycar-
bonyl groups using lithium 1,1,1,3,3,3-hexamethyldisilazide
(LiHMDS) as the base.12 In both methods, the cyclization
proceeded efficiently and cyclic trimers were obtained as the
main product, owing to the cis preference around the amide bond
of N-alkylbenzanilide units.13 m-Calix[3]amide is known to have
two conformers in solution. The syn-conformer has three benzene
Chem. Lett. 2012, 41, 249-251
© 2012 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

250
C9H19
HN
O
OH
Path A
SiCl4
2M aqHCl
Pyridine, reflux
N
reflux
2
C9H19
N
O
C9H19
HN
O
3
OCH3
Path B
LiHMDS
THF, 0oC
Figure 2. VT-NMR spectra of PyC3A in CDCl3 (From top to bottom:
323-233 K with interval of 10 K).
N
N
PyC3A
1
equilibrium at above 318 « 5 K because a pyridyl ¡-proton
signal of the syn-conformer (8.46 ppm) was coalesced with that
of the anti-conformer (8.66 ppm) (Figure 2). On the other hand,
these signals were separated at below 318 K. Following the report
by Azumaya et al.,9 an observed minor signal can be assigned to
a proton of the anti-conformer. The [syn]/[anti] ratio at 293 K
was calculated from the integral ratio of these pyridyl ¡-proton
signals to be [syn]/[anti] = 69/31 (Figure S318). The [syn]/[anti]
ratio was dependent on the temperature in which the syn-
population increased with the rise of temperature ([syn]/[anti] =
70/30 at 313 K and 66/34 at 233 K). The conformation was also
influenced by the solvent character. PyC3A existed as largely the
syn-conformer in pure CD3OD and the anti-population increased
with decreasing the percentage of CD3OD in CDCl3/CD3OD
mixed solvents (Figure S418).
Scheme 1. Cyclic oligomerization of monomers 1 and 2.
Figure 1. ORTEP view of PyC3A¤ with thermal ellipsoids drawn at
50% probability. The hydrogen atoms are omitted for clarity.
oligomeric product from the high-molecular-weight product
(Figure S1,18 right). m-Calix[3]amide (PyC3A) was successfully
isolated by the preparative GPC in 16% yield. The MALDI-TOF-
MS showed a signal at m/z 967.6075 assignable to the proton
adduct of PyC3A.
For the preparation of the molecular cage (3Pd¢2PyC3A),
PyC3A and [Pd(dppp)Cl2] or [Pd(dppp)(OTf)2] was mixed with
the molar ratio of 2:3 in CDCl3/CD3OD (5/1 in volume,
19 mM). In the ESI-MS of the mixture using [Pd(dppp)Cl2] as the
palladium complex (Figure S518), no peak ascribed to the target
molecular cage was detected though incomplete coordinated
products were detected. Thus [Pd(dppp)Cl2] has a poor coordi-
nation ability with pyridine due to the lack of the cationic
character of palladium center. On the other hand, the ESI-MS of
the 2:3 mixture of PyC3A and [Pd(dppp)(OTf)2] showed strong
peaks at m/z 2043.6100 for [3Pd¢2PyC3A ¹ 2OTf]2+ and m/z
1312.4136 for [3Pd¢2PyC3A ¹ 3OTf]3+ (Figure 3) indicating
the formation of an ideal molecular cage (Scheme 2). In addition,
the 31P NMR and the diffusion-ordered NMR spectroscopy
(DOSY) were investigated to confirm the efficiency of capsule
formation. The phosphorous signal at 15.0 ppm for the original
[Pd(dppp)(OTf)2] completely disappeared and only one signal
was observed at 5.21 ppm by adding [Pd(dppp)(OTf)2] to
Figure 1 shows the single-crystal X-ray structure of N-
methyl analog of PyC3A, abbreviated hereafter as PyC3A¤. The
X-ray quality single crystals of PyC3A¤ were grown by slow
evaporation in mixed solvents containing chloroform and hexane.
The syn-conformer was observed similarly to m-calix[3]amide
having the benzene group.10 PyC3A¤ is obtained as a racemic
crystal, in which one enantiomer has a right-handed amide
skeleton and another has a left-handed amide skeleton. The X-ray
data indicated an almost planar structure around the amide bond
(an averaged dihedral angle Me-N-C-O was 2.3°) comparable to
that of m-calix[3]amide having the benzene group (1.5°).10 From
the IR spectroscopic study (carbonyl stretching vibration signal)
of PyC3A in the solid state, the dihedral angle around the amide
bond might not be affected by the electron density of the ³-
a CDCl3/CD3OD (5/1 in volume) solution of PyC3A
¹1
conjugated system (bithiophene; 1650 cm¹1, phenyl; 1650 cm
,
(Figure S618). The DOSY experiments for PyC3A and the 2:3
mixture of PyC3A and [Pd(dppp)(OTf)2] showed different
and pyridine; 1644 cm¹1).10,14 The bowl-shaped structure of
PyC3A¤ is suggested from the evidence of that the averaged
distance between C(2) carbon atoms (3.78 ¡) is shorter than that
between pyridine nitrogen atoms (5.02 ¡).
¹1
diffusion coefficients (D = 5.89 « 0.3 © 10¹10 m2 s and D =
3.74 « 0.6 © 10¹10 m2 s¹1) (Figures S7, S8, and Table S1)18
indicating the quantitative capsule formation. From the results,
we estimated the hydrodynamic radii (RH) by the Einstein-Stokes
equation (RH = 0.60 nm for PyC3A and RH = 0.96 nm for
3Pd¢2PyC3A).16 The increase in RH indicated the change of
molecular shape. In contrast, 2:1 mixture showed a complicated
In a CDCl3 solution at 293 K, 1H NMR spectrum gave many
signals indicating the existence of syn- and anti-conformers. The
VT-NMR measurement was investigated to gain insight into the
equilibrium between two conformers. PyC3A existed in the rapid
Chem. Lett. 2012, 41, 249-251
© 2012 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

251
α-pyridyl H
PCH2CH2CH2P
PCH2CH2CH2P
NCH2C8H17
*
Figure 4. Expanded 1H NMR spectra of 3Pd¢2PyC3A in CDCl3/
CD3OD (5/1 in volume). Some aromatic proton signals marked with
asterisk were too overlapped to be assigned.
In conclusion, m-calix[3]amide having pyridine on the
benzene ring was synthesized to obtain a molecular cage by the
coordination to palladium complexes. The conformation study
was carried out using 1H NMR spectra to find out that m-
calix[3]amide bearing pyridine preferred the syn-conformer in
CD3OD. The 2:3 mixture of PyC3A and [Pd(dppp)(OTf)2] in
CDCl3/CD3OD = 5/1 (in volume) gave molecular cage (3Pd¢
Figure 3. ESI-MS of 2:3 mixture of PyC3A and [Pd(dppp)(OTf)2].
6+
1
2PyC3A), which was supported by ESI-MS, DOSY, H NMR,
R
N
O
O
R
O
R
N
and 31P NMR spectra. On the other hand, in CDCl3, the formation
of polymeric mixture was indicated. Accordingly, the conforma-
tion change of PyC3A triggered by solvent character has a large
impact on the formation of molecular cage.
N
R
N
O
R
O
N
O
R
N
Ph2
P
N
OTf
OTf
N
N
LPd
N
PdL
+
Pd
6TfO
LPd
References and Notes
P
Ph2
N
N
1
2
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N
N
N
PyC3A
3
4
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N
R
N
O
O
N
R
O
R
L = Ph2PCH2CH2CH2PPh2
3Pd 2PyC3A
5
6
Scheme 2. Preparation of 3Pd¢2PyC3A from PyC3A and
[Pd(dppp)(OTf)2].
7
8
1H- and 31P NMR spectrum, and DOSY experiments gave several
diffusion coefficients (Figures S6, S9, and S11C).18 The 1H NMR
spectrum of the 2:3 mixture in CDCl3/CD3OD (5/1 in volume)
showed a new set of signals (Figure 4 and S11D18). The pyridyl
¡-proton signals at 8.43 ppm for the syn-conformer and 8.61 ppm
for the anti-conformer observed in the original PyC3A vanished
and a new proton signal was detected only at 8.90 ppm.
Accordingly, m-calix[3]amide included in molecular cage
3Pd¢2PyC3A would be fixed as the syn-conformer. Finally, the
solvent dependency on the cage formation was investigated. The
2:3 mixture of PyC3A and [Pd(dppp)(OTf)2] in CDCl3 gave
a broad 1H NMR17 and DOSY spectra which indicated the
formation of polymeric mixture (Figures S10 and S11E18). Two
pyridyl ¡-proton signals (8.99 and 9.17 ppm) still remained
impling the existence of both the syn- and anti-conformers. The
presence of the anti-conformer in CDCl3 may be responsible for
the interruption of the effective cage formation. These findings
indicate that the conformation change of PyC3A induced by the
solvent character dramatically affects the formation of molecular
cage 3Pd¢2PyC3A.
9
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17 The pyridyl ¡-proton signals (8.46 ppm for syn and 8.66 ppm for
anti) disappeared owing to the coordination to palladium cation.
18 Supporting Information is available electronically on the CSJ-
Journal Web site, http://www.csj.jp/journals/chem-lett/index.html.
Chem. Lett. 2012, 41, 249-251
© 2012 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/