Molecular recognition of chiral diporphyrin receptor with a macrocyclic cavity for intercalation of aromatic compounds

Article abstract of DOI:10.1246/bcsj.20110230

Chiral diporphyrin receptor 1, which has a macrocyclic cavity for the intercalation of aromatic guest molecules, was designed and synthesized from pyrrole in five steps. The binding constants (Ka) revealed the greater affinity of 1 for more electron-deficient aromatic guests. The complexation between 1 and 1,3,5-trinitrobenzene (G8) (Ka = 1850M^-1) was much stronger than that between porphyrin monomer 3 and G8 (Ka = 50M^-1). This result strongly suggests that G8 was intercalated into the cavity of 1 via cooperative double π-π stacking. Interestingly, 1 enabled the naked-eye detection of an aromatic explosive G8; a dark-red solution of 1 in CHCl3 turned into a colloidal suspension upon addition of G8, and the light was scattered. Fluorescence spectroscopy was also useful for the selective detection of G8; fluorescence of 1 was quenched by complexation with G8, which was visible with the naked eye. Despite modest binding constants for dinitrobenzene derivatives, 1 showed a good ability to discriminate the enantiomers of twelve chiral compounds bearing a dinitrophenyl group by NMR spectroscopy. The MM calculations with the MM3 force field reproduced inclusion complexes between 1 and nitroaromatic compounds. The mechanism of chiral discrimination is proposed.

Full text of DOI:10.1246/bcsj.20110230

© 2012 The Chemical Society of Japan
Bull. Chem. Soc. Jpn. Vol. 85, No. 1, 101-109 (2012)
101
Molecular Recognition of Chiral Diporphyrin Receptor with a
Macrocyclic Cavity for Intercalation of Aromatic Compounds#
Tadashi Ema,* Norichika Ura, Katsuya Eguchi, and Takashi Sakai*
Division of Chemistry and Biochemistry, Graduate School of Natural Science and Technology, Okayama University,
Tsushima, Okayama 700-8530
Received August 2, 2011; E-mail: ema@cc.okayama-u.ac.jp
Chiral diporphyrin receptor 1, which has a macrocyclic cavity for the intercalation of aromatic guest molecules, was
designed and synthesized from pyrrole in five steps. The binding constants (Ka) revealed the greater affinity of 1 for more
electron-deficient aromatic guests. The complexation between 1 and 1,3,5-trinitrobenzene (G8) (Ka = 1850 M¹1) was
much stronger than that between porphyrin monomer 3 and G8 (Ka = 50 M¹1). This result strongly suggests that G8 was
intercalated into the cavity of 1 via cooperative double ³-³ stacking. Interestingly, 1 enabled the naked-eye detection of
an aromatic explosive G8; a dark-red solution of 1 in CHCl3 turned into a colloidal suspension upon addition of G8, and
the light was scattered. Fluorescence spectroscopy was also useful for the selective detection of G8; fluorescence of 1 was
quenched by complexation with G8, which was visible with the naked eye. Despite modest binding constants for
dinitrobenzene derivatives, 1 showed a good ability to discriminate the enantiomers of twelve chiral compounds bearing a
dinitrophenyl group by NMR spectroscopy. The MM calculations with the MM3 force field reproduced inclusion
complexes between 1 and nitroaromatic compounds. The mechanism of chiral discrimination is proposed.
Chirality is significant because chiral biomolecules such as
proteins, nucleic acids, and carbohydrates play a central role
in life. Chiral recognition is also important, and it has been
extensively studied.1 One application of chiral recognition/
discrimination is to determine the enantiomeric purity of chiral
compounds. NMR chiral shift reagents and chiral solvating
agents have been developed for this purpose,2-4 and we have
reported chiral macrocyclic hosts, which use hydrogen bonding
as the driving force of complexation.4 These hosts making use
of hydrogen bonds, however, cannot exert chiral discrimination
toward guests bearing no hydrogen-bonding sites.
(a)
(b)
The ³-³ stacking interaction plays an important role in
biomolecules, organic materials, and host-guest complexes.5-7
The ³-³ stacking is so weak that other interactions, such as
hydrogen bonds, need to be used to increase the host-guest
binding affinity.8 Recently, the ³-³ stacking interaction has
been successfully used in the chiral recognition of fullerenes
and carbon nanotubes.9,10 Because there are few examples that
employ ³-³ stacking as a sole driving force of enantioselective
complexation, it is challenging to develop a chiral receptor
capable of showing excellent chiral recognition/discrimination
based on the ³-³ stacking interaction.
(c)
Recently, we have reported the design and synthesis of chiral
diporphyrin receptor 1 (Figure 1).11 Because this is the first
example of positioning two porphyrins in a parallel but chiral
manner at a distance suitable for sandwiching aromatic
molecules, the function of 1 is worthy of investigation even
if a large number of porphyrin dimers have been reported for
various purposes.12 We found that 1, which has a macrocyclic
cavity to include aromatic guest molecules via cooperative
double ³-³ stacking interactions, enabled the naked-eye
detection of an aromatic explosive as well as chiral discrim-
Figure 1. (a) Chemical and (b), (c) optimized structures of
(R)-1. NMR complexation-induced shifts (¦¤) for the
Ha and Hb atoms are shown in Figure 3. The geometry was
optimized by MM3 calculations with CAChe WorkSystem
Pro ver. 5.02 (Fujitsu).
Published on the web December 30, 2011; doi:10.1246/bcsj.20110230

102
Bull. Chem. Soc. Jpn. Vol. 85, No. 1 (2012)
Molecular Recognition via ³-³ Stacking
MeO2C
(i) CF3CO2H, CH2Cl2
+
CHO
O
N
N
(ii) DDQ
H
H
67%
2
O
R
R
NH
N
N
HN
3: R = OMe
4: R = OH
KOH aq, THF
93%
(R)-BINOL
EDC, DMAP
CH2Cl2
61%
4
HO
O
(R)-5: R =
(R)-1
EDC, DMAP
CH2Cl2
28%
Scheme 1. Synthesis of chiral receptor (R)-1.
G2: R1 = R2 = H
ination by NMR spectroscopy. Here we report the binding and
chiral discriminating abilities of 1 in detail.
R1
G3: R1 = F, R2 = H
G4: R1 = Cl, R2 = H
G5: R1 = Br, R2 = H
G6: R1 = R2 = F
NO2
Results and Discussion
NO2
R2
We designed chiral receptor 1 based on the following
strategies. First, two porphyrins, which have rigidity, a large
³-surface, and a great ring-current effect, were disposed in
parallel at a distance of ca. 7 ¡ suitable for the inclusion of
aromatic guests. Second, chiral spacers were used to link the
two porphyrins, forming a chiral cavity. BINOL was considered
to be a good spacer because of moderate rigidity/flexibility and
the ring-current effect. Molecular mechanics (MM) calculations
indicated that the two porphyrins in 1 are arranged in an offset
face-to-face geometry with an interplanar distance of 5.8-7.2 ¡,
which is suitable for the intercalation of aromatic molecules
(Figure 1). We also expected that the macrocyclic framework
would be useful for the restriction of the orientation of the
bound guest, which would be favorable for chiral discrimina-
tion, and for the suppression of self-aggregation of the receptor.
The synthesis of 1 could be achieved easily in five steps from
pyrrole (Scheme 1).11 The stepwise macrocyclization with 4
and 5 to give 1 was found to be much more efficient than the
direct macrocyclization with 4 and BINOL to give 1. In the
synthesis of 5, we observed that the second esterification of the
two hydroxy groups in BINOL proceeded much more slowly
than the first esterification, which allowed us to obtain 5
selectively. It seemed that the use of the isolated intermediate
5 was important for the subsequent macrocyclization to occur
cleanly. It is interesting that such a sophisticated receptor
1 could be constructed easily by using the relatively simple
porphyrin 4 and the commercially available BINOL.
NO2
G1
F
F
R
NO2
N
N
F
F
F
F
O
NO2
NO2
F
G7: R = CO2Me
G8: R = NO2
G9
G10
Figure 2. Guest compounds.
1
CDCl3 was monitored at 25 °C by H NMR. Upon addition
of any guest, the Ha signal underwent an upfield shift, while
the Hb signal experienced a downfield shift, as represented
in Figures 3a and 3b (Ha and Hb atoms are designated in
Figure 1). The binding constants (Ka) were determined by
NMR titration; a nonlinear least-squares method was applied
to the Ha signal that was upfield shifted upon addition
of the guest (Figure 3b).13 As for G8, the Ka value was
determined by UV-vis titration (Figure 4); the absorbance
change at 505 nm was used for the curve fitting. The data are
listed in Table 1.
The Ka value increases in the following order: G1 < G2 <
G3 < G6 < G8. This trend indicates the greater affinity of
³-basic 1 for more electron-deficient, ³-acidic aromatic guests.
The complexation between 1 and G8 (Ka = 1850 M¹1) was
We investigated whether 1 could bind aromatics as expected.
The aromatic compounds G1-G10 were selected as guests
(Figure 2). Complexation of 1 with G1-G7 and G9-G10 in
¹1
stronger by ¹2.2 kcal mol
than that between porphyrin

T. Ema et al.
(a)
Bull. Chem. Soc. Jpn. Vol. 85, No. 1 (2012)
103
[G6]
(b)
(c)
[G6]/mM
Figure 3. (a) Complexation-induced shifts (¦¤) for all the aromatic protons of (R)-1 (10 mM) as a function of [G6] in CDCl3 at
25 °C. The Ha and Hb atoms are designated in Figure 1. The signals for the meso-phenyl groups, the pyrrolic ¢ protons, and the
binaphthyl groups are shown in red, green, and black, respectively. (b) Plots of the ¦¤ values for the aromatic protons of (R)-1 as a
function of [G6]. (c) Plausible conformational change of 1 deduced by the NMR titration. The porphyrin rings and the chiral
spacers are represented by the gray and black bars, respectively, while the aromatic guest is represented by the green bar.
monomer 3 and G8 (Ka = 50 M¹1), and the former (¦H° =
As we have reported previously,11 the Hb signal for 1
(8.83 ppm) appeared at a higher magnetic field than expected,
which becomes clear by comparison with the corresponding
signal for 5 (10.32 ppm). This suggests that 1 takes a
conformation where the edge of one porphyrin ring is close
to the other one as shown in Figure 3c. Because a single Hb
signal was observed (Figure 3a), 1 experienced a fast con-
formational change (Figure 3c). On the other hand, the Ha
signal appeared at a much lower magnetic field than expected,
which may be due to a specific conformation of the adjacent
C=O group. Upon inclusion of a guest molecule, the two
porphyrin rings become parallel, which makes the chemical
shifts of the Ha and Hb atoms in 1 come closer to those of the
corresponding atoms in 5. Although the ring-current effect of
the included aromatic guest molecule may also affect the
chemical shifts of the Ha and Hb atoms in 1, the effect of the
conformational change of 1 seems to be predominant. Such a
¹1
¹8.4 kcal mol¹1, T¦S° = ¹4.0 kcal mol at 25 °C) was more
¹1
enthalpy-driven than the latter (¦H° = ¹5.7 kcal mol
T¦S° = ¹3.4 kcal mol
,
¹1
at 25 °C). These results strongly
suggest that G8 was intercalated into the cavity of 1 via the
cooperative double ³-³ stacking. The Ka values of 1 for the
electron-deficient guests G7 and G9 were reasonably high,
whereas that for G10, which is electron-deficient enough, was
much lower than expected. The latter result may be due to the
steric hindrance caused by the limited size of the cavity in 1.
Table 1 also indicates that the Ka value decreases in the
following order: G2 > G4 > G5. This is also due to the steric
hindrance of the halogen atom (H < Cl < Br). Although we
expected the CH/³ interactions for cyclohexane, the Ka value
was too small to determine, which suggests that 1 has a specific
cavity where only aromatic molecules bearing the nitro groups
can be nicely included.

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Bull. Chem. Soc. Jpn. Vol. 85, No. 1 (2012)
Molecular Recognition via ³-³ Stacking
Figure 5. The naked-eye detection of explosive G8.
(a) A solution of (R)-1 (10 mM) in CHCl3. (b) After
addition of G7 as a control (1 equiv). (c) After addition of
G8 (1 equiv).
of 1 in CHCl3 turned into a suspension upon addition of G8
(10 mM, 1 equiv), and the light illuminated from the front side
was scattered (Figure 5c). This phenomenon was observed
only for G8; for example, no visual change occurred when G7
was added to a solution of 1 in CHCl3 (Figure 5b). Thus,
1 acted as a unique naked-eye explosive sensor. We were
intrigued with the driving force of the formation of the
suspension (Figure 5c). It is unlikely that G8 included in the
cavity of 1 contributed directly to the insolubility of the whole
complex. We speculate that the formation of the tight inclusion
complex suppressed the flexibility and/or mobility of the
porphyrin rings, which triggered a linear intercomplex (supra-
molecular aggregate) formation that was dependent on the
concentration, although the detailed structure of the supra-
molecular aggregate remains to be investigated. On the other
hand, fluorescence spectroscopy was also useful for the
selective detection of G8 (Figure 6). When G8 was added to
a dilute solution of 1 (50 ¯M), no precipitates appeared, and
fluorescence quenching of 1 was observed with excitation at
537 nm, which is an isosbestic point observed in the UV-vis
titration. The fluorescence intensity at 635 nm decreased by
37% and 91% in the presence of 0.4 and 5.3 mM of G8,
respectively (Figure 6b). In contrast, the decrease in fluores-
cence intensity was only 6% in the presence of 5.3 mM of G2
(not shown). Figure 6c clearly demonstrates that 1 is a good
naked-eye sensor for G8.
We evaluated the chiral discrimination ability of 1. Because
1 showed moderate affinity for dinitrobenzene derivatives
(Table 1), we converted alcohols, an amine, and ketones into
3,5-dinitrobenzoyl esters, a 3,5-dinitrobenzoyl amide, and 2,4-
dinitrophenylhydrazones, respectively. NMR spectra for the
1:1 mixtures of (R)-1 and G11-G22 (10 mM) were measured
in CDCl3. The results are summarized in Table 2. In all cases,
host-guest complexation is a fast-exchange equilibrium, where
the observed signal is the weighted average of the chemical
shift values for unbound and bound enantiomers. As shown in
Table 2, chiral discrimination of G11-G22 was successfully
achieved by 1. Host 1, having no aliphatic hydrocarbon groups
that may interfere with the NMR signals for the guests, has a
wide detection window (ca. 0-7 ppm), which is advantageous
Figure 4. UV-vis spectral change of (R)-1 (50 ¯M) upon
addition of G8 (0-0.8 mM) in CHCl3. The inset shows the
absorbance change at 505 nm with a curve fitting.
Table 1. Binding Constants of (R)-1 for Aromatic Guests
¹1 a)
¹1 b)
Guest
Ka/M
0.1
¦G°/kcal mol
G1
G2
G3
G4
G5
G6
G7
G8
+1.4
¹1.2
¹1.6
¹1.0
¹0.8
¹2.1
¹2.2
¹4.5
¹2.0
+0.3
¹0.8
¹0.1
7.7
15.2
5.8
3.6
35.8
42.9
1850c)
28.5
0.6
G9
G10
(R)-G11
(S)-G11
4.2
1.2
a) In chloroform at 25 °C. Determined by NMR titration except
for G8 (UV-vis titration). b) Calculated from ¦G° =
¹RT ln Ka. c) The Ka value determined by the NMR titration
at a dilute concentration of (R)-1 (50 ¯M) was 1610.
conformational change can also explain the relatively small
binding constants of 1 for the aromatic compounds (Table 1).
Most signals for the meso-phenyl group exhibited relatively
large complexation-induced shifts, whereas the signals for
the binaphthyl group showed little or no changes (Figures 3a
and 3b). These behaviors suggest that the conformational
change of 1 is caused by the tilting movement around (i) the
C-C bonds at the meso-positions and (ii) the ester bonds.
Unexpectedly, we noticed the formation of precipitates only
when G8, which is an explosive that is more powerful than
2,4,6-trinitrotoluene (TNT), was added to a solution of 1 in
CDCl3 during the NMR titration experiment. Because the
development of chemosensors for aromatic explosives has been
a challenging subject,14,15 we investigated the utility of 1 as a
chemosensor for G8. As shown in Figure 5, a dark-red solution

T. Ema et al.
Bull. Chem. Soc. Jpn. Vol. 85, No. 1 (2012)
105
(a)
After we had obtained the results in Table 2, we determined
the Ka values of (R)-1 for (R)-G11 and (S)-G11 to investigate
the mechanism of chiral discrimination by NMR spectroscopy.
As shown in Table 1, the Ka values were very small (Ka =
¹1
¹1
4.2 M for (R)-G11 and Ka = 1.2 M for (S)-G11), which
suggests that G11 is sterically more hindered than the
corresponding methyl ester G7. The percentages of the host-
guest complex ([complex]/[1]0) at 10 mM can be calculated
to be 3.8% and 1.1% for (R)-G11 and (S)-G11, respectively.
We were therefore surprised to see that chiral discrimination
(Table 2 and Figure 8) was possible, based on such weak
binding, even if the degree of enantioselectivity was moderate
(Ka(R)/Ka(S) = 3.5). Upon complexation with (R)-1, the signal
for (R)-G11 shifted to a higher magnetic field than that for
(S)-G11 (Table 2 and Figure 8). We suppose that this chiral
discrimination by NMR spectroscopy was achieved by the
enantioselective binding although the difference in geometry
might also be important as described below.
Wavelength/nm
(c)
(b)
We performed computational calculations to study the
inclusion behavior in more detail. Because the ³-³ stacking
interaction involves London dispersion force, it is ideal to
perform the ab initio calculations at the highest level. However,
because rigorous calculations for such a large molecule are not
realistic, we searched for an alternative method using G7 as a
guest. When the semiempirical MO calculations such as the
PM3 and PM5 methods were performed, initial complexes
converged into unbound structures with the guest molecule
evicted. On the other hand, the MM calculations with the MM3
force field turned out to give a stable inclusion complex. An
optimized structure is shown in Figures 9a and 9b. The
aromatic guest molecule G7 is closely sandwiched by the
two porphyrins, whose interplanar distance is 6.4-7.2 ¡. The
conformation of 1 is slightly altered upon complexation
presumably due to an induced-fit. As shown in Figure 1, the
two Ha atoms in 1 are directed inside to create a relatively small
cavity. As a result, (i) the nitro group most deeply inserted
acts as an anchor, restricting the orientation of G7 (Figure 9b),
and (ii) the alkoxy group in G7 is located in proximity to the
binaphthyl moiety (Figure 9a). These two factors must be
important for chiral discrimination (Table 2). To investigate the
mechanism of chiral discrimination, we performed the calcu-
lations on the complexes between 1 and G11. The optimized
structures are shown in Figures 9c and 9d. The 3,5-dinitro-
benzoyl group in G11 is intercalated less deeply and more
tilted than that in G7, which is due to the bulkiness of G11,
although the interplanar distances in the (R)-1-(R)-G11 com-
plex (6.5-7.5 ¡) and the (R)-1-(S)-G11 complex (6.3-7.5 ¡)
are only slightly longer than that in the 1-G7 complex (6.4-
7.2 ¡). Nevertheless, the 3,5-dinitrobenzoyl group in G11 is
fixed in the same direction as that in G7. As a result, the
stereocenter of G11 is close to the binaphthyl moiety in 1.
The methyl group in (R)-G11 points straight to the benzoate
moiety at the meso-position of 1 (Figure 9c), whereas that in
(S)-G11 is located on the periphery of the porphyrin ring
(Figure 9d). The former is apparently located in a shielding
region. Therefore, these geometries are in agreement with the
NMR spectrum that the methyl signal of (R)-G11 appeared at a
higher magnetic field than that of (S)-G11 upon complexation
with (R)-1.
[G8]/mM
Figure 6. (a) Fluorescence quenching of (R)-1 (50 ¯M) in
CHCl3 upon addition of G8 (0-5.3 mM). -ex = 537 nm.
(b) Fluorescence change at 635 nm. (c) Fluorescence before
and after addition of G8 (5.3 mM). -ex = 365 nm.
to the analysis of a broad range of chiral compounds. In
addition to esters G11-G14 with the methyl group at the
stereocenter, esters G15-G19 with two aryl groups at the
stereocenter could also be analyzed well, among which G18
and G19 were differentiated by 19F NMR. The signal for amide
G20 was also resolved completely. The signals for the methyl
group of the R enantiomers of G11-G13 and G20 appeared at
a higher magnetic field. The signals for the two methyl groups
of G21 and for the olefinic proton of G22 were split. Thus,
excellent chiral discrimination has been achieved despite the
use of only ³-³ stacking as a driving force of complexation.
We confirmed that a linear correlation exists between the
theoretical and observed % ee values (Figure 7). When the
effect of the amount of 1 on the signal separation was
examined, increasing the amount of 1 increased the degree of
the signal separation (Figure 8). These results indicate that
1 can be used as a reagent for the determination of the
enantiomeric purity. The following control experiments were
also done: when 1-phenylethanol and the corresponding
benzoate ester were used as guests instead of G11, the signals
were not split by 1 at all, probably because of very low affinity.
When 5 was used as a chiral host for G11, no chiral
discrimination was attained, which indicates that the specific
cavity in 1 is essential for binding and chiral discrimination of
the guest.

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Bull. Chem. Soc. Jpn. Vol. 85, No. 1 (2012)
Molecular Recognition via ³-³ Stacking
Table 2. Selected Regions of NMR Spectra of Racemic Guests G11-G22 in the Presence of (R)-1a)
Guest
Spectrum
Guest
Spectrum
G11
G17
G12
G18
G13
G14
G15
G16
G19
G20
G21
G22
1
a) 600 MHz H NMR of G11-G17 and G20-G22 and 565 MHz 19F NMR of G18-G19 in the presence of (R)-1 (10 mM, 1 equiv) in
CDCl3 at 22 °C. The resonances for the protons or fluorines indicated by the arrows are shown in the right column. In the case where
the signals for the enantiomers were assigned by adding some amount of one enantiomer to the above solution, (R)- and (S)-
enantiomers are represented by filled and open circles, respectively.
Conclusion
We searched for a chiral receptor exerting an excellent chiral
(a)
(b)
recognition/discrimination power by using the ³-³ stacking as
the driving force of complexation. Such a chiral receptor will
widen the scope of application in the field of chiral analysis.
Here we have designed and synthesized chiral porphyrin dimer
1 with a macrocyclic cavity suitable for the intercalation of
aromatics. It should be noted that 1 has no aliphatic hydro-
carbon groups and that such a specific structure could be
constructed in only five steps from pyrrole. The binding
constants determined indicated that 1 had greater affinity for
more electron-deficient aromatic guests. In fact, 1 showed a
good ability to discriminate the enantiomers of chiral com-
pounds bearing a dinitrophenyl group by NMR spectroscopy.
Unexpectedly, 1 also functioned as a naked-eye sensor for
explosive, 1,3,5-trinitrobenzene (G8). Therefore, we also
expect various applications of 1.
Figure 7. (a) A selected region of 600 MHz 1H NMR of
(S)-G11 (1.9 mg, 10 mM) with various enantiomeric
purities in the presence of (R)-1 (9.6 mg, 10 mM) in
CDCl3 (0.6 mL) at 22 °C. Observed % ee values calculated
from the integrals are indicated in the parentheses.
(b) Correlation between the theoretical and observed %
ee values.
Experimental
Materials. The receptor 1 and guests G11, G12, G20, and
G21 were prepared as reported previously.11 The aromatic
compounds G1-G10 and all the synthetic reagents and solvents
were purchased.

T. Ema et al.
Bull. Chem. Soc. Jpn. Vol. 85, No. 1 (2012)
107
(a)
(e)
(d)
(c)
(b)
(a)
(b)
(c)
1
Figure 8. 600 MHz H NMR of rac-G11 (1.9 mg, 10 mM)
in the presence of (R)-1 (0-15 mM) in CDCl3 (0.6 mL) at
22 °C. (R)-1: (a) no addition; (b) 0.75 equiv; (c) 1.0 equiv
(9.6 mg); (d) 1.25 equiv; (e) 1.5 equiv. Filled and open
circles represent (R)- and (S)-enantiomers, respectively.
(d)
Typical Procedure for the Preparation of G13-G19. To
a solution of 3,5-dinitrobenzoyl chloride (553 mg, 2.40 mmol)
in pyridine (1.6 mL) under N2 in an ice bath was added the
corresponding alcohol (2.10 mmol). The mixture was stirred at
room temperature overnight. The reaction was quenched with
water, and the product was extracted with EtOAc. The organic
layer was dried over MgSO4, and concentrated.
1-(4-Fluorophenyl)ethyl 3,5-Dinitrobenzoate (G13):
Purification by silica gel column chromatography (hexane/
EtOAc (6:1)) afforded G13 as colorless crystals (63%): mp
117-119 °C; 1H NMR (CDCl3, 400 MHz): ¤ 1.75 (d, J =
6.4 Hz, 3H), 6.20 (q, J = 6.4 Hz, 1H), 7.07-7.11 (m, 2H), 7.44-
7.48 (m, 2H), 9.15 (d, J = 2.2 Hz, 2H), 9.22 (t, J = 2.2 Hz,
1H); 13C NMR (CDCl3, 100 MHz): ¤ 21.9, 74.8, 115.7 (d, J =
21.5 Hz), 122.4, 128.3 (d, J = 8.2 Hz), 129.4, 134.0, 135.9 (d,
J = 3.0 Hz), 148.6, 161.7, 162.7 (d, J = 246.9 Hz); IR (KBr):
3098, 3051, 2986, 2878, 1732, 1628, 1605, 1543, 1512, 1454,
1346, 1277, 1227, 1165, 1061, 1003, 922, 841, 721 cm¹1; Anal.
Calcd for C15H11FN2O6: C, 53.90; H, 3.32; N, 8.38%. Found:
C, 53.62; H, 3.35; N, 8.23%; HRMS (EI): calcd for
C15H11FN2O6 334.0601, found 334.0620 (M+).
1-(4-Methoxyphenyl)ethyl 3,5-Dinitrobenzoate (G14):
Purification by silica gel column chromatography (hexane/
EtOAc (3:1)) afforded G14 as a yellow oil (65%):16 1H NMR
(CDCl3, 400 MHz): ¤ 1.75 (d, J = 6.6 Hz, 3H), 3.82 (s, 3H),
6.19 (q, J = 6.6 Hz, 1H), 6.91-6.94 (m, 2H), 7.40-7.43 (m,
2H), 9.14 (d, J = 2.2 Hz, 2H), 9.21 (t, J = 2.2 Hz, 1H);
13C NMR (CDCl3, 100 MHz): ¤ 21.6, 55.3, 75.3, 114.0,
122.2, 127.9, 129.4, 132.1, 134.3, 148.5, 159.8, 161.8; IR
(KBr): 3101, 2970, 2937, 2839, 1728, 1628, 1612, 1549, 1516,
1460, 1344, 1248, 1169, 1057, 1032, 997, 922, 833, 773,
721 cm¹1; HRMS (EI): calcd for C16H14N2O7 346.0801, found
346.0784 (M+).
Figure 9. (a) Side view and (b) top view of the (R)-1-G7
complex. Side views of (c) the (R)-1-(R)-G11 complex and
(d) the (R)-1-(S)-G11 complex, where the macrocyclic
moiety is shown in green, and (R)-G11 and (S)-G11 are
shown in red and magenta, respectively. The geometries
were optimized by MM3 calculations with CAChe Work-
System Pro ver. 5.02 (Fujitsu).
4-Methoxybenzhydryl 3,5-Dinitrobenzoate (G15): Puri-
fication by silica gel column chromatography (hexane/EtOAc
(7:1)) afforded G15 as a slightly yellow viscous oil (69%):17
1H NMR (CDCl3, 400 MHz): ¤ 3.81 (s, 3H), 6.90-6.94 (m, 2H),
7.18 (s, 1H), 7.28-7.44 (m, 7H), 9.21 (d, J = 2.4 Hz, 2H), 9.23
(t, J = 2.4 Hz, 1H); 13C NMR (CDCl3, 100 MHz): ¤ 55.3, 79.4,
114.1, 122.5, 126.9, 128.4, 128.7, 129.0, 129.5, 130.9, 134.0,
139.0, 148.6, 159.8, 161.7; IR (neat): 3099, 2955, 2854, 1732,
1628, 1611, 1545, 1514, 1460, 1346, 1271, 1250, 1163, 1076,
1032, 920, 829, 721, 700 cm¹1; HRMS (EI): calcd for
C21H16N2O7 408.0958, found 408.0977 (M+).
4-Methylbenzhydryl 3,5-Dinitrobenzoate (G16): Purifi-
cation by silica gel column chromatography (hexane/EtOAc
(7:1)) afforded G16 as a yellow foam (86%): 1H NMR (CDCl3,
400 MHz): ¤ 2.36 (s, 3H), 7.18 (s, 1H), 7.21 (d, J = 8.0 Hz,
2H), 7.33 (d, J = 8.0 Hz, 2H), 7.34-7.45 (m, 5H), 9.21 (d,
J = 2.0 Hz, 2H), 9.24 (t, J = 2.0 Hz, 1H); 13C NMR (CDCl3,

108
Bull. Chem. Soc. Jpn. Vol. 85, No. 1 (2012)
Molecular Recognition via ³-³ Stacking
22
1
100 MHz): ¤ 21.1, 79.6, 122.5, 127.1, 127.3, 128.4, 128.7,
129.46, 129.48, 133.9, 135.8, 138.5, 138.9, 148.6, 161.7; IR
(neat): 3099, 3032, 2916, 1732, 1630, 1545, 1514, 1458, 1346,
1267, 1163, 1076, 920, 821, 739, 721, 700 cm¹1; HRMS (EI):
calcd for C21H16N2O6 392.1008, found 392.1001 (M+).
2-Methylbenzhydryl 3,5-Dinitrobenzoate (G17): Purifi-
cation by silica gel column chromatography (hexane/EtOAc
(7:1)) afforded G17 as a slightly yellow viscous oil (27%):
1H NMR (CDCl3, 400 MHz): ¤ 2.38 (s, 3H), 7.21-7.30 (m, 4H),
7.33-7.38 (m, 5H), 7.39-7.51 (m, 1H), 9.21 (d, J = 2.2 Hz,
2H), 9.24 (t, J = 2.2 Hz, 1H); 13C NMR (CDCl3, 100 MHz):
¤ 19.5, 77.02, 122.5, 126.4, 126.7, 127.7, 128.5, 128.6, 128.8,
129.5, 130.9, 133.9, 135.8, 136.8, 138.0, 148.7, 161.7; IR
(neat): 3099, 3030, 2943, 2880, 1732, 1630, 1599, 1545, 1495,
1456, 1344, 1261, 1161, 1074, 1030, 920, 872, 847, 812, 791,
698 cm¹1; HRMS (EI): calcd for C21H16N2O6 392.1008, found
392.1003 (M+).
way: mp 174-176 °C; ½¡ꢀD ¹427 (c 0.50, CHCl3); H NMR
(CDCl3, 600 MHz): ¤ 1.17 (s, 3H), 1.29-1.40 (m, 2H), 1.64-
1.72 (m, 4H), 1.80-1.83 (m, 1H), 1.86-1.90 (m, 1H), 2.29-2.36
(m, 2H), 2.43-2.49 (m, 1H), 2.72-2.76 (m, 1H), 6.01 (s, 1H),
7.98 (d, J = 9.6 Hz, 1H), 8.29 (dd, J = 2.4, 9.6 Hz, 1H), 9.13
(d, J = 2.4 Hz, 1H), 11.25 (s, 1H); IR (KBr): 3312, 3117, 2924,
2853, 1622, 1591, 1506, 1418, 1337, 1306, 1254, 1221, 1126,
912, 831, 743 cm¹1; HRMS (EI): calcd for C17H20N4O4
344.1485, found 344.1487 (M+).
Determination of Binding Constants.
In the NMR
titration, to a solution of 1 (10 mM) in CDCl3 (0.6 mL) was
added a small amount of CDCl3 containing guest, and 1H NMR
spectra were then measured at 25 °C. The change in the
Ha signal of 1 was monitored at several different concentrations
of guest. On the other hand, in the NMR titration, to a solution
of 1 (50 ¯M) in CHCl3 (3.0 mL) was added a small amount of
CHCl3 containing G8, and UV-vis spectra were then measured
at a constant temperature. The absorbance change at 505 nm
was monitored at several different concentrations of G8.
Several isosbestic points were observed, indicating 1:1 com-
plexation. The binding constant was calculated by the nonlinear
least-squares curve-fitting method. The thermodynamic param-
eters were obtained from the van’t Hoff plots.
4-(Trifluoromethyl)benzhydryl
3,5-Dinitrobenzoate
(G18): Purification by silica gel column chromatography
(hexane/EtOAc (7:1)) afforded G18 as a slightly yellow
viscous oil (65%): 1H NMR (CDCl3, 400 MHz): ¤ 7.23 (s, 1H),
7.39-7.44 (m, 5H), 7.57 (d, J = 8.2 Hz, 2H), 7.67 (d, J =
8.2 Hz, 2H), 9.22 (d, J = 2.2 Hz, 2H), 9.26 (t, J = 2.2 Hz, 1H);
13C NMR (CDCl3, 100 MHz): ¤ 78.9, 122.7, 123.8 (q, J =
270.8 Hz), 125.8 (q, J = 3.7 Hz), 127.3, 127.4, 129.02, 129.04,
129.5, 130.7 (q, J = 32.0 Hz), 133.5, 137.9, 142.7, 148.7,
161.6; IR (KBr): 3101, 3036, 2943, 2882, 1740, 1628, 1543,
1497, 1458, 1420, 1342, 1327, 1273, 1165, 1126, 1069, 1018,
968, 918, 833, 806, 772, 721, 698 cm¹1; HRMS (EI): calcd for
C21H13F3N2O6 446.0726, found 446.0728 (M+).
2-Fluorobenzhydryl 3,5-Dinitrobenzoate (G19): Purifi-
cation by silica gel column chromatography (hexane/EtOAc
(7:1)) afforded G19 as colorless crystals (64%): mp 140-
141 °C; 1H NMR (CDCl3, 400 MHz): ¤ 7.09-7.14 (m, 1H),
7.18-7.22 (m, 1H), 7.33-7.48 (m, 8H), 9.21 (d, J = 2.2 Hz,
2H), 9.25 (t, J = 2.2 Hz, 1H); 13C NMR (CDCl3, 100 MHz):
¤ 74.0 (d, J = 2.9 Hz), 116.0 (d, J = 21.6 Hz), 122.6, 124.5
(d, J = 3.7 Hz), 126.2 (d, J = 12.7 Hz), 127.0, 128.2 (d, J =
3.0 Hz), 128.7, 128.8, 129.5, 130.4 (d, J = 8.9 Hz), 133.7,
137.6, 148.7, 160.1 (d, J = 247.6 Hz), 161.4; IR (KBr): 3105,
MM Calculations.
MM calculations on (R)-1, the
(R)-1-G7 complex, the (R)-1-(R)-G11 complex, and the
(R)-1-(S)-G11 complex were done with CAChe WorkSystem
Pro ver. 5.02 (Fujitsu), where the structures were optimized by
the MM3 method.
This work was supported by a Grant for Research for
Promoting Technological Seeds from Japan Science and
Technology Agency (JST) and by Okayama Foundation for
Science and Technology. We thank Takasago International
Corporation for providing us with (S)-1-(4-fluorophenyl)etha-
nol. We are grateful to the SC-NMR Laboratory of Okayama
University for the measurement of NMR spectra.
References
#
Dedicated to Emeritus Professor H. Ogoshi (Kyoto
University) on the occasion of his 77th birthday.
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¹1
1
1231, 1165, 1076, 1030, 972, 914, 814, 760, 721, 694 cm
;
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6-Methylbicyclo[4.4.0]dec-1-en-3-one 2,4-Dinitrophenyl-
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