Effect of aromatic-aromatic interactions on the conformational stabilities of macrocycle and preorganized structure during macrocyclization

Article abstract of DOI:10.1021/jo802801n

The crystal structures and dynamic behavior in solution of aromatic amides containing terphenyl groups were revealed by X-ray crystallographic analysis and VT-NMR measurements. Controlling the synthetic yield and molecular shape of the macrocycles with in

Full text of DOI:10.1021/jo802801n

Effect of Aromatic-Aromatic Interactions on the Conformational
Stabilities of Macrocycle and Preorganized Structure during
Macrocyclization
Kosuke Katagiri, Taichi Tohaya, Hyuma Masu, Masahide Tominaga, 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 January 6, 2009
The crystal structures and dynamic behavior in solution of aromatic amides containing terphenyl groups
were revealed by X-ray crystallographic analysis and VT-NMR measurements. Controlling the synthetic
yield and molecular shape of the macrocycles with intramolecular aromatic-aromatic interactions was
successfully achieved. N,N′-Diethyl-N,N′-diterphenyl-1,3-benzenedicarboxamide (2) exists in the syn
conformation and two terphenyl groups are on the same side of the plane of the central benzene ring due
to attractive aromatic-aromatic interactions between the two terphenyl moieties. The yield of the
macrocyclization reaction of 1,3-benzenedicarboxylic acid with bis(ethylamino)terphenyl (4) was relatively
high (55% yield) because an intermediate in the macrocyclization reaction was preorganized in the syn
conformation, which is similar to the diamide 2. On the other hand, N,N′-diethyl-N,N′-diterphenyl-1,4-
benzenedicarboxamide (3) exists in the anti conformation and two terphenyl groups are positioned on
opposite sides of the plane of the central benzene ring. In contrast to the 1,3-derivative, the yield of the
macrocyclization reaction of the 1,4-benzenedicarboxylic acid with the diamine 4 was low (19% yield).
Although macrocycle 5 exists in a planar conformation in the crystal and in solution, macrocycle 6 exists
in a twisted conformation. A deformation of the twist was induced by a tilted T-shaped aromatic-aromatic
interaction between the central phenylene rings of the macrocycle.
Introduction
of programmed assemblies help to fix the bonding direction and
are driven by relatively weak noncovalent interactions such as
hydrogen bonding, CH-π interactions, and aromatic-aromatic
interactions.6 As we reported previously, we found that the cis
preference of tertiary aromatic amide could be used for effective
amidomacrocyclization, that is N-alkylaminobenzoic acids was
coupled with themselves by a one-step reaction with tetrachlo-
rosilane or dichlorotriphenylphosphorane to give amide mac-
rocycles.7 In a large macrocyclic compound synthesis, the rather
weak aromatic-aromatic interactions also contribute to a stable
intermediate conformation, i.e., induce a preorganized structure.
Recently, Fallis’s group and Marsella’s group reported the
correspondence of intramolecular aromatic-aromatic interac-
Macrocyclic amide compounds have attracted significant
attention because of their unique properties, shapes, and
applications.1 The synthetic strategies for preparation of mac-
rocyclic compounds2 is based on template synthesis,3metal-
supported self-assembly of small molecules,4 and cyclization
reactions of preorganized small partial molecules.5 These types
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2804 J. Org. Chem. 2009, 74, 2804–2810
10.1021/jo802801n CCC: $40.75 2009 American Chemical Society
Published on Web 03/06/2009

Crystal Structures of Aromatic Amides
SCHEME 1. The Synthesis of Aromatic Diamides 2 and 3
tions to the synthetic yield for macrocyclization and the stability
of twisted conformation.6e,f During our investigations into the
effective synthesis of amide macrocycles, we found that a simple
partial structure preorganized by aromatic-aromatic interactions,
preferably containing a syn conformation of aromatic tertiary
diamides, was extremely effective for constructing covalently
bonded macrocyclic compounds.8 In this paper, we report on
the crystal structure and dynamic behavior in solution of
aromatic amides with a p-terphenyl backbone containing 1,3-
benzenedicarboxamide and 1,4-benzenedicarboxamide moieties.
The effect of aromatic-aromatic interactions on the synthetic
yield and stable conformation are discussed.
Results and Discussion
Diamides 2 and 3 were synthesized by the reaction of 1,3-
benzenedicarbonyl chloride or 1,4-benzenedicarbonyl chloride
with N-ethylaminoterphenyl 1 (Scheme 1).
X-Ray crystallographic analysis was performed on a single
crystal of 2 that was obtained by slow evaporation of a
chloroform solution.9 The crystal belongs to the space group
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Imabeppu, F.; Katagiri, K.; Masu, H.; Kato, T.; Tominaga, M.; Therrien, B.;
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j
P1 (Figure 1), and the unit cell contains four molecules of 2.
Two amide moieties exist in a syn conformation, which places
the terphenyl groups in the same direction. In this crystal, the
intramolecular tilted T-shaped aromatic-aromatic (CH-π)
interaction between the two central phenylene rings of both
terphenyl groups was observed (Figure 1c).
The single crystals of 3 were also obtained by slow evapora-
tion of a chloroform solution.10 The crystal belongs to the space
group C2/c (Figure 2), and the unit cell contains four molecules
of 3. Two amide moieties exist in an anti conformation, which
places the terphenyl groups in opposite directions.
To evaluate the dynamic behavior of 2 and 3 in solution, the
VT-NMR measurements in dichloromethane-d2 were performed.
The different conformers of the diamides (2, 3) would arise from
the conformation of the amide groups (E or Z). Additionally,
the torsion angles of the carbonyl planes with the central benzene
ring (syn or anti) and the N-terphenyl bond with the amide plane
will be different. In these compounds, the N-terphenyl rotation
can generally be neglected because the rotation of the N-
terphenyl bonds is fast on the 1H NMR time scale such that the
ortho protons on the N-terphenyl group (H2b and H3b in Figure
j
(9) Crystal data of 2: C48H40N2O2; M ) 676.82, triclinic, space group P1, a
) 10.391(2) Å, b ) 19.155(4) Å, c ) 19.178(4) Å, R ) 107.102(2) deg, ꢀ )
93.505(3)°, γ ) 91.272(2)°, V ) 3638.3(12) Å3, Z ) 4, Dcalcd ) 1.236 Mg m-3
,
T ) 120 K, µ(MoKR) ) 0.075 mm-1, GOF on F2 ) 0.807, 17831 reflections
measured, 13718 unique (Rint ) 0.0236) which were used in all calculations.
The final R1 and wR2 (F2) were 0.0529 and 0.1302 [I > 2σ(I)]. Additional material
comprising full details of the X-ray data collection and final refinement parameters
including anisotropic thermal parameters and a full list of the bond lengths and
angles have been deposited with the Cambridge Crystallographic Data Center
in CIF format as supplementary Publication No. CCDC-712723. Copies of the
data can be obtained free of charge on application to CCDC, 12 Union Road,
Cambridge, CB21EZ, UK, (fax +44 1223 336 033; e-mail deposit@
ccdc.cam.ac.uk).
(10) Crystal data of 3: C48H40N2O2 ·2CHCl3; M ) 915.56, monoclinic, space
group C2/c, a ) 30.709(5) Å, b ) 8.472(1) Å, c ) 18.198(3) Å, ꢀ ) 111.575(2)°,
V ) 4402(1) Å3, Z ) 4, Dcalcd ) 1.381 Mg m-3, T ) 150 K, µ(MoKR) ) 0.434
mm-1, GOF on F2 ) 1.129, 10371 reflections measured, 4405 unique (Rint
)
(8) (a) Tominaga, M.; Masu, H.; Katagiri, K.; Azumaya, I. Tetrahedron Lett.
2007, 48, 4369–4372. (b) Tominaga, M.; Masu, H.; Katagiri, K.; Kato, T.;
Azumaya, I. Org. Lett. 2005, 7, 3785–3787.
0.0319) which were used in all calculations. The final R1 and wR2 (F2) were
0.0638 and 0.1687 [I > 2σ(I)]. Cambridge Crystallographic Data Center
Publication No. CCDC-712724.
J. Org. Chem. Vol. 74, No. 7, 2009 2805

Katagiri et al.
FIGURE 1. The crystal structure of 1,3-diamide terphenyl benzene 2
in the thermal ellipsoids model: (a) front view and (b) top view. (c)
Stick model of 2; the parts of the phenylene units in the middle of the
terphenyl group are drawn as a space-filling model. The ring center-ring
center distance of the two phenylene groups is 5.244 Å, and the angle
between the two phenylene groups is 83.37°.
FIGURE 2. The crystal structure of 1,4-diamide terphenyl benzene 3
in the thermal ellipsoids model.
3) are magnetically equivalent. The difference in the chemical
shifts between the signals at high and low temperatures indicates
that the compositions of different conformational structures (E/Z
or syn/anti, or both) are in fast equilibrium and this equilibrium
is temperature dependent. Figure 3 shows the temperature
1
dependence of the H NMR spectra in the aromatic region of
diamides 2 and 3, which are very similar to that of N,N′-
dimethyl-N,N′-diphenyl-1,3- and -1,4-benzenedicarboxamide.11
The chemical shifts of the terphenyl protons (ortho to the amide
bond: H2b in Figure 3a) of diamide 2 moved upfield (from 6.97
at 293 K to 6.81 ppm at 173 K) because the ratio of the syn
conformation that has a higher chemical shift value increased
as the temperature was lowered. Furthermore, peak broadening
at 253-273 K suggests that there is an equilibrium of a species
with a Z isomer that exists as a small amount, and the
coalescence point of the H2b peaks at 243-253 K is due to the
E/Z conversion (Figure 3a, ∆Gq ) 13.1 ( 0.3 kcal mol-1). On
the other hand, the chemical shifts of the terphenyl protons
(ortho to the amide bond: H3b in Figure 3b) of diamide 3 were
lower than those of 2 and were temperature independent. This
FIGURE 3. (a) The temperature dependence of 1H NMR signals of 2
1
in the aromatic region. (b) The temperature dependence of H NMR
signals of 3 in the aromatic region.
showed that aromatic-aromatic interactions were faint and this
is due to the larger distance between the terphenyl groups.
Next, macrocyclic tetraamide 5 was synthesized by the direct
amide coupling of 1,3-benzenedicarboxylic acid with 1,4-bis(4-
N-ethylaminophenyl)benzene 48b by using dichlorotriphenylphos-
phorane, which has been previously reported to be an effective
coupling reagent to construct macrocyclic aromatic amides.12
A
mixture of 1,3-benzenedicarboxylic acid and the diamine 4 (1:1
(12) (a) Itai, A.; Toriumi, Y.; Saito, S.; Kagechika, H.; Shudo, K. J. Am.
Chem. Soc. 1992, 114, 10649–10650. (b) Azumaya, I.; Kagechika, H.; Fujiwara,
Y.; Itoh, M.; Yamaguchi, K.; Shudo, K. J. Am. Chem. Soc. 1991, 113, 2833–
2838.
(11) Azumaya, I.; Kagechika, H.; Yamaguchi, K.; Shudo, K. Tetrahedron
1995, 51, 5277–5290.
2806 J. Org. Chem. Vol. 74, No. 7, 2009

Crystal Structures of Aromatic Amides
SCHEME 2. The Synthesis of a Macrocyclic Compound 5 and a Twisted Molecule 6
SCHEME 3. Preorganized Structure during the Formation
of the Macrocyclic Compounds: (a) the Intermediate of a
Condensation of 1,3-Benzenedicarboxylic Acid with 4 Exists
in the syn Conformation and (b) the Intermediate of a
Condensation of 1,4-Benzenedicarboxylic Acid with 4 Exists
in the anti Conformation
X-Ray crystallographic analysis was performed on a single
crystal of 5, which was obtained from a mixture of chloroform,
ethyl acetate, and methanol by slow evaporation of the solvent.14
The crystal belongs to the space group P21/n (Figure 4), and
the unit cell contains two molecules of the macrocycle 5.
In the crystal structure of 5, weak intermolecular interactions
between adjacent molecules were observed and the arrangement
of the molecules leads to the formation of a network structure
(Figure 5a). The two sets of macrocyclic compound 5 per unit
cell alternate along the b and c axes with C-H· · ·O interactions
(Figure 5b). Furthermore, the macrocycles 5 form columnar
stacking along the a axis with C-H · · · O interactions
(C6-H6· · ·O1: 2.442 Å) and CH-π interactions (C3-H3· · ·C13:
2.896 Å) (Figure 5c).
Next, a single crystal of 6 was obtained from a mixture of
chloroform, ethyl acetate, and ethanol by slow evaporation of the
solvent.15 The crystal structure of 6 is shown in Figure 6. The
intramolecular tilted T-shaped aromatic-aromatic interaction be-
tween central phenylene groups of the terphenyl moieties was
observed and forces the molecule to form a twisted conformation
(Figure 6c). The crystal belonged to the space group P21/c, which
contains two sets of enantiomeric twisted conformers per unit cell.
This resulted in the crystal having no optical activity. The unit cell
contains 8 molecules of ethanol and 12 molecules of water to fill
the space among the macrocycles. The aggregate of a single
enantiomer of 6 aligns along the c axis, with the enantiomeric rows
alternating along both the a and b axes (Figure 7a), and the racemic
rows on the bc plane of the macrocycle aligning along the a axis
(Figure 7b).
in molar ratio) was treated with 2.4 equiv of Ph3PCl2 in 1,1,2,2-
tetrachloroethane (50 mM of the amine) at 120 °C for 8 h. The
crude product was purified by silica gel column chromatography
(eluent: CHCl3:MeOH ) 10:1) and gel permeation chromatography
to give the macrocyclic aromatic amide 5 with a 55% yield. In
contrast to the high yield in the synthesis of 2, a condensation of
1,4-benzenedicarboxylic acid and the diamine 4 under the same
conditions gave macrocyclic tetramide 6 with only a 19% yield
(Scheme 2). Furthermore, a reaction of 1,2-benzenedicarboxylic
acid and 4 gave a product with the same mass number in only
trace amounts, which could not be fully characterized. The
difference of the yield of the macrocycles is thought to arise from
the major conformation of an intermediate during the reaction. That
is, these macrocyclizations would proceed under kinetic control.13
In the reaction yielding 5, the final amide coupling of the
intermediate right before the cyclization would proceed easily as
the intermediate exists primarily in the syn conformation. In
contrast, in the reaction yielding 6, the final amide coupling of the
intermediate would not proceed easily because the ratio of the anti
conformation of the intermediate is higher than that of 5 (Scheme
3). As such, the synthetic yield depended on the preorganized
structure of the intermediate, which is induced by intramolecular
aromatic-aromatic interactions.
To evaluate the dynamic behavior of the macrocyclic aromatic
amides 5 and 6 in solution, VT-NMR measurements in di-
FIGURE 4. The crystal structure of 5 in the thermal ellipsoids model:
(a) front view and (b) side view.
(13) Rowan, S. J.; Cantrill, S. J.; Cousins, G. R. L.; Sanders, J. K. M.;
Stoddart, J. F. Angew. Chem., Int. Ed. 2002, 41, 898–952.
J. Org. Chem. Vol. 74, No. 7, 2009 2807

Katagiri et al.
FIGURE 5. (a) Weak interactions (light blue line) with adjacent
molecules in the bc plane. (b) Weak interactions (light blue line) with
adjacent molecules along the a axis. (c) Packing diagram of 5 in the
stick model, which is viewed along the a axis.
FIGURE 6. The crystal structure of 6 in the thermal ellipsoids model:
(a) front view and (b) top view. (c) Stick model of 6; the parts of the
phenylene units in the middle of the terphenyl group are drawn as space-
filling models. The hydrogen atom-the ring center distance of the two
phenylene groups is 3.153 Å.
chloromethane-d2 were performed (Figure 8). The phenylene
protons ortho to the carbonyl groups of 5 are observed as singlets
at room temperature (H5a in Figure 8), but the signals broadened
and split at 243 K. This observation indicated that the inversion
of the phenylene groups at the head parts of the macrocyclic
compound 5 (Scheme 4) slowed as the temperature was lowered.
Furthermore, the peak broadening of 5 in the aromatic region
was observed and suggests that the rotation of the N-terphenyl
bonds is slower than that of diamide 2. On the other hand, a
single set of signals was observed for macrocycle 6 at both room
and low temperatures (see the Supporting Information). This
suggested that the tilted T-shaped aromatic-aromatic interac-
tions, which exist between the two central phenylene rings of
terphenyl groups, were too weak to keep the twisted conforma-
tion of the macrocycle. As such, the equilibrium between the
two enantiomeric conformers 6 is fast. Although the prochiral
proton signals did not split into two sets of peaks at 183 K, the
racemization was definitely slower at low temperatures because
the signals broadened as the temperature was lowered.
Conclusions
In conclusion, the yield of the macrocyclization reaction
of 1,3-benzenedicarboxylic acid with bis(ethylamino)terphen-
yl(4)producedahighyieldbecauseN,N′-diethyl-N,N′diterphenyl-
1,3-benzenedicaboxamide 2, which corresponded to an inter-
mediate on the macrocyclization, existed in the syn confor-
mation due to attractive aromatic-aromatic interactions
between the two closely positioned terphenyl groups. Con-
versely, the yield of the macrocyclization reaction of 1,4-
benzenedicarboxylic acid with bis(ethylamino)terphenyl (4)
was relatively low because N,N′-diethyl-N,N′-diterphenyl-
1,4-benzenedicaboxamide (3) existed in the anti conformation
and the two terphenyl groups were located on opposite sides.
The meta-macrocycle 5 existed in a planar conformation and
the para-macrocycle 6 existed in a twisted conformation. A
deformation of the twist in 6 was induced by a tilted T-shaped
aromatic-aromatic interaction between the central phenylene
rings of the macrocycle. That is, the aromatic-aromatic
interaction works effectively on the intermediate of the
macrocyclization in the meta-macrocycle synthesis and on
the ground state conformation for the para-macrocycle 6. We
are now exploring various macrocycles with interesting
topological properties. Here, the effects of intramolecular
aromatic-aromatic interactions on both the synthetic yield
and the stability of the conformations are being examined.
(14) Crystal data of 5: C60H52N4O4; M ) 893.06, monoclinic, space group
P21/n, a ) 7.765(2) Å, b ) 24.472(7) Å, c ) 13.084(4) Å, ꢀ ) 101.834(5)°, V
) 2433.5(12) Å3, Z ) 2, Dcalcd ) 1.219 Mg m-3, T ) 150 K, µ(MoKR) ) 0.077
mm-1, GOF on F2 ) 0.946, 14448 reflections measured, 5493 unique (Rint
)
0.0980) which were used in all calculations. The final R1 and wR2 (F2) were
0.0874 and 0.2175 [I > 2σ(I)]. Cambridge Crystallographic Data Center
Publication No. CCDC-688290.
(15) Crystal data of 6: C64H64N4O9; M ) 1033.19, monoclinic, space group
P21/c, a ) 16.925(3) Å, b ) 15.637(3) Å, c ) 22.381(4) Å, ꢀ ) 103.617(4)°,
V ) 5756.8(19) Å3, Z ) 4, Dcalcd ) 1.192 Mg m-3, T ) 150 K, µ(MoKR) )
0.080 mm-1, GOF on F2 ) 0.986, 17239 reflections measured, 5188 unique
(Rint ) 0.1071) which were used in all calculations. The final R1 and wR2 (F2)
were 0.0797 and 0.2193 [I > 2σ(I)]. Cambridge Crystallographic Data Center
Publication No. CCDC-688291.
2808 J. Org. Chem. Vol. 74, No. 7, 2009

Crystal Structures of Aromatic Amides
1
FIGURE 8. The temperature dependence of H NMR signals of 5 in
the aromatic region.
SCHEME 4. The Inversion of the m-Phenylene Groups of
Macrocycle 5
FIGURE 7. Packing diagram of 6 in a stick model presentation. The
solvent molecules and hydrogen atoms are omitted for clarity, and the
enantiomeric conformations are shown in red and blue, respectively.
(a) View along the c axis. (b) Projection on the ac plane of the unit
cell of 6.
mixture, and then the solution was heated at 100 °C for 8 h. The
mixture was poured into water and extracted with chloroform. The
organic layer was dried (Na2SO4) and evaporated to give a crude
product, which was purified by silica gel column chromatography
(eluent: chloroform) to give 2 in 84% yield as a white powder: mp
Experimental Section
4′-N-Ethylaminophenyl-4-phenylbenzene (1). Pd/C (10%) was
slowly added to a solution of 4-nitro-p-terphenyl (1.09 mmol) in
dry ethanol (100 mL) with stirring for 4 h under H2. Acetonitrile
(285 µL) and molecular sieves, which were activated, were added
with stirring for 20 h. The Pd/C was filtered and the solvent was
removed under reduced pressure. The crude products were purified
by silica gel column chromatography (eluent: chloroform) to give
1 in 21% yield as white powder: mp 213 °C; 1H NMR (400 MHz,
CDCl3) δ 7.64-7.59 (m, 6H), 7.52-7.50 (m, 2H), 7.46-7.42 (m,
2H), 7.36-7.31 (m, 1H), 6.82 (d, J ) 8.8 Hz, 2H), 3.24 (q, J )
7.2 Hz, 2H), 1.31 ppm (t, J ) 7.2 Hz, 3H); 13C NMR (400 MHz,
CDCl3) δ 140.92, 140.17, 138.87, 128.76, 127.86, 127.39, 127.09,
126.95, 126.57, 113.50, 38.92, 14.74 ppm; FAB-MS m/z 273.15.
Anal. Calcd for C20H19N·1/6H2O: C, 86.92; H, 7.05; N, 5.07. Found:
C, 86.90; H, 7.09; N, 5.08.
1
273-274 °C; H NMR (400 MHz, CDCl3) δ 7.61-7.49 (m, 6H),
7.37-7.32 (m, 5H), 7.14-7.11 (m, 1H), 6.93 (d, J ) 8.4 Hz, 3H),
3.95 (q, J ) 7.2 Hz, 2H), 1.22 ppm (t, J ) 7.2 Hz, 3H); 13C NMR
(400 MHz, CDCl3) δ 169.53 (C ) O), 142.30, 140.42, 140.36,
138.74, 138.55, 136.40, 129.40, 129.29, 128.86, 128.20, 127.58,
127.44, 127.17, 126.96, 45.34, 13.02 ppm; FAB-MS m/z 676.31.
Anal. Calcd for C48H40N2O2 ·1/14CHCl3: C, 84.24; H, 5.89; N, 4.09.
Found: C, 84.33; H, 5.84; N, 4.11.
Bis-1,4-(N-ethyl-N-terphenylamino)carboxybenzene (3). 1,3-
Benzenedicarbonylchloride (0.183 mmol) was slowly added to a
solution of 4-N-ethylamino-p-terphenyl (1) (0.366 mmol) in pyridine
(3.6 mL) with stirring for 2 h at 100 °C. After 2 h, 1,3-
benzenedicarbonyl chloride (0.029 mmol) was added to the reaction
mixture, and then it was heated at 100 °C for 8 h. The mixture was
poured into water and extracted with chloroform. The organic layer
was dried (Na2SO4) and evaporated to give a crude product, which
was purified by silica gel column chromatography (eluent: chlo-
roform) to give 3 in 81% yield as white powder: mp 229-231 °C;
Bis-1,3-(N-ethyl-N-terphenylamino)carboxybenzene (2). 1,3-
Benzenedicarbonyl chloride (0.283 mmol) was slowly added to a
solution of 4-N-ethylamino-p-terphenyl (1) (0.566 mmol) in pyridine
(5.6 mL) with stirring for 2 h at 100 °C. After 2 h, 1,3-
benzenedicarbonyl chloride (0.029 mmol) was added to the reaction
J. Org. Chem. Vol. 74, No. 7, 2009 2809

Katagiri et al.
1H NMR (400 MHz, CDCl3) δ 7.56-7.54 (m, 6H), 7.46-7.33 (m,
5H), 7.17 (s, 1H), 7.00 (d, J ) 8.4 Hz, 3H), 3.94 (q, J ) 7.2 Hz,
2H), 1.21 ppm (t, J ) 7.2 Hz, 3H); 13C NMR (400 MHz, CDCl3)
δ 169.36 (CdO), 140.48, 140.40, 139.04, 138.62, 137.26, 128.85,
128.24, 128.07, 127.59, 127.53, 127.46, 127.29, 127.01, 45.49,
12.95 ppm; FAB-MS m/z 676.31. Anal. Calcd for C48H40N2O2 ·1/
11CHCl3: C, 83.99; H, 5.88; N, 4.07. Found: C, 83.93; H, 5.95; N,
4.05.
Twisted Macrocyclic Aromatic Amide 6. To a solution of 1,4-
bis(4-N-ethylaminophenyl)benzene (4) (120 mg, 0.38 mmol) and
a 1,4-dicarboxylic acid (63.1 mg, 0.38 mmol) in 1,1,2,2-tetrachlo-
roethane (7.6 mL) under argon was added dichlorotriphenylphos-
phorane (608 mg, 1.82 mmol) with stirring. The mixture was heated
at reflux for 8 h, then the reaction mixture was poured into ice and
extracted with ethyl acetate. The organic layer was washed with 4
M HCl, saturated aqueous NaHCO3, and brine, dried (Na2SO4),
and evaporated to give a crude product, which was purified by silica
gel column chromatography (eluent: CHCl3:MeOH ) 10:1) and
preparative gel permeation chromatography using JAIGEL-2H and
JAIGEL-2.5H column with chloroform as the mobile phase to give
the macrocycle 6 in 19% yield as a white powder: mp >300 °C
Macrocyclic Aromatic Amide 5. To a solution of 1,4-bis(4-N-
ethylaminophenyl)benzene (4) (120 mg, 0.38 mmol) and a 1,3-
dicarboxylic acid (63.1 mg, 0.38 mmol) in 1,1,2,2-tetrachloroethane
(7.6 mL) under argon was added dichlorotriphenylphosphorane (608
mg, 1.82 mmol) with stirring. The mixture was heated at reflux for
8 h, then the reaction mixture was poured into ice and extracted
with ethyl acetate. The organic layer was washed with 4 M HCl,
saturated aqueous NaHCO3, and brine, dried (Na2SO4), and
evaporated to give a crude product, which was purified by silica
gel column chromatography (eluent: CHCl3:MeOH ) 10:1) and
preparative gel permeation chromatography using JAIGEL-2H and
JAIGEL-2.5H column with chloroform as the mobile phase to give
the macrocycle 5 in 55% yield as a white powder: mp >300 °C
1
dec; H NMR (400 MHz, CDCl3, 27 °C) δ 7.32 (s, 8H), 7.28 (d,
J ) 8.6 Hz, 8H), 7.19 (s, 8H), 6.96 (d, J ) 8.4 Hz, 8H), 3.97 (q,
J ) 7.0 Hz, 8H), 1.21 ppm (t, J ) 7.0 Hz, 12H); 13C NMR (400
MHz, CDCl3) δ 162.29, 142.23, 139.05, 138.74, 137.38, 128.10,
128.08, 127.37, 127.30, 45.37, 12.87 ppm.; FAB-MS m/z 893.4;
ESI-HRMS m/z found 892.3991, calcd for C60H52N4O4 m/z 892.3989.
Anal. Calcd for C60H32N4O4 ·8H2O: C, 77.86; H, 6.06; N, 6.05.
Found: C, 77.60; H, 5.69; N, 6.06.
1
dec; H NMR (400 MHz, CDCl3, 27 °C) δ 7.58 (s, 2H), 7.44 (s,
Acknowledgment. K.K. is grateful for a Grant-in-Aid for
8H), 7.28 (d, J ) 8.4 Hz, 8H), 7.04 (d, J ) 7.2 Hz, 4H), 6.91 (d,
J ) 8.0 Hz, 2H), 6.86 (d, J ) 8.4 Hz, 8H), 3.98 (br s, 8H), 1.24
ppm (t, J ) 7.2 Hz, 12H); 13C NMR (400 MHz, CDCl3) δ 170.07,
142.41, 138.60, 137.90, 137.24, 128.68, 128.46, 128.06, 127.19,
127.12, 45.02, 12.95 ppm; FAB-MS m/z 893.4; ESI-HRMS m/z
found 892.4011, calcd for C60H52N4O4 m/z 892.3989. Anal. Calcd
for C60H32N4O4 ·3H2O: C, 78.63; H, 6.00; N, 6.11. Found: C, 78.55;
H, 5.89; N, 6.04.
Young Scientists (Start-up), Japan (No. 18890226).
1
Supporting Information Available: Copies of H and 13C
NMR spectroscopic data (PDF) and crystallographic analysis
data. This material is available free of charge via the Internet
at http://pubs.acs.org.
JO802801N
2810 J. Org. Chem. Vol. 74, No. 7, 2009