Dynamic molecular propeller: Supramolecular chirality sensing by enhanced chiroptical response through the transmission of point chirality to mobile helicity

Article abstract of DOI:10.1021/ja906810b

The secondary terephthalamide host 1a-H attached to four aryl blades was prepared from tetrabromide 2a by Suzuki-Miyaura coupling and undergoes a conformational change from a nonpropeller anti-form to a propeller-shaped syn-form upon complexation with dit

Full text of DOI:10.1021/ja906810b

Published on Web 10/29/2009
Dynamic Molecular Propeller: Supramolecular Chirality
Sensing by Enhanced Chiroptical Response through the
Transmission of Point Chirality to Mobile Helicity
Ryo Katoono,†,‡ Hidetoshi Kawai,†,§ Kenshu Fujiwara,† and Takanori Suzuki*,†
Department of Chemistry, Faculty of Science, Hokkaido UniVersity, Sapporo 060-0810 Japan,
School of Materials Science, Japan AdVanced Institute of Science and Technology (JAIST),
Nomi, Ishikawa, 923-1292, Japan, and PRESTO, Japan Science and Technology Agency (JST),
4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan
Received August 11, 2009; E-mail: tak@sci.hokudai.ac.jp
Abstract: The secondary terephthalamide host 1a-H attached to four aryl blades was prepared from
tetrabromide 2a by Suzuki-Miyaura coupling and undergoes a conformational change from a nonpropeller
anti-form to a propeller-shaped syn-form upon complexation with ditopic guests such as p-xylylenediam-
monium derivatives (R,R)/(S,S)-3 (chirality generation). Through transmission of the point chiralities attached
on the nitrogens in the chiral guests to the mobile helicity in 1a-H, the propeller-shaped host in the complex
is biased to prefer a particular handedness (chirality biasing). While chiral guests with simple point chiralities
such as (R,R)/(S,S)-3 exhibit only very weak CD activity, complexation with the dynamic propeller host
1a-H results in much stronger chiroptical signals (chiroptical enhancement). The chirality generation-chirality
biasing protocol was successfully applied to a neurotransmitter, (-)-phenylephrine 4, acting as a chiral
ditopic guest. When the chiral auxiliaries are attached to the host as in (R,R)-1b-H, complexation with
(S,S)-3 causes CD enhancement but not with (R,R)-3, due to chiral recognition.
Introduction
the side groups. In more dynamic systems, the substance exists
as a random coil before the addition of chiral guests, and the
Supramolecular Chirality Transfer Based on Dynamic Helic-
ity. Supramolecular chirality emerges as a result of intermo-
lecular chirality transfer,1 which is an important area of
fundamental chemistry that has been shown to have several
applications based on molecular recognition in terms of asym-
metric catalysts,2 memory materials,3 polymer science,4 and so
on. When intermolecular chirality transfer is studied in a
supramolecular assembly such as host-guest complexes,5
detailed mechanistic approaches become available through a
variety of spectroscopic measures such as NMR, UV-vis, or
circular dichroism (CD). Helical molecules have often been used
as an excellent motif for intermolecular chirality transfer, where
the helical sense is successfully controlled by external asym-
metric information, such as chiral guest molecules.6 Thus, in
some linear oligomeric/polymeric long-chained hosts that adopts
a folded helical geometry, the population of (P)/(M)-helices is
biased to prefer a particular handedness upon complexation with
chiral guests through encapsulation at the cavity or binding at
helical structure is formed only upon the admixture of a chiral
additive through unidirectional folding (Scheme 1a).7 These rare
examples have successfully demonstrated chirality generations
chirality biasing protocol, which is more advanced response by
inducing all-or-nothing-type chiroptical outputs.
In addition to helices of long-chained molecules, propeller-
shaped compounds8 are also attractive since they possess a
similar dynamic helicity. Hexaphenylbenzene adopts a propeller-
shaped geometry in a crystal phase9 with all of the phenyl groups
tilted in a conrotatory manner. Thus, persubstituted benzenes
can be considered to be another class of attractive motif for
studying supramolecular chirality transfer to dynamic helicity
(Scheme 1b). Since the molecules can adopt a variety of
conformations other than a propeller, control of the geometry
to enforce the propeller structure (chirality generation) is an
important concern in addition to control of the helical sense
(chirality biasing). In this context, our approach using the
† Department of Chemistry, Faculty of Science, Hokkaido University.
‡ School of Materials Science, Japan Advanced Institute of Science and
Technology (JAIST).
(7) (a) Ishikawa, M.; Maeda, K.; Yashima, E. J. Am. Chem. Soc. 2002,
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Soc. 2004, 126, 2022–2027. (c) Naidu, V. R.; Kim, M. C.; Suk, J.-
m.; Kim, H.-J.; Lee, M.; Sim, E.; Jeong, K.-S. Org. Lett. 2008, 10,
5373–5376. (d) In Dynamic Stereochemistry of Chiral Compounds:
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Angew. Chem., Int. Ed. 2003, 42, 5182–5185. (b) Rappoport, Z.; Biali,
S. E. Acc. Chem. Res. 1997, 30, 307–314. (c) Ito, S.; Fujita, M.; Morita,
N.; Asao, T. Bull. Chem. Soc. Jpn. 1995, 68, 3611–3620.
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§ PRESTO, Japan Science and Technology Agency (JST).
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16896 J. AM. CHEM. SOC. 2009, 131, 16896–16904
10.1021/ja906810b CCC: $40.75  2009 American Chemical Society

Dynamic Molecular Propeller
A R T I C L E S
Scheme 1
helicity. When chiral auxiliaries are attached to the tertiary amide
nitrogens as in syn-(R,R)-1b-Me [N-R1 ) (R)-N-C*HMe(c-Hex);
R2 ) Me], the point chiralities would be intramolecularly
transmitted to the mobile helicity10 of the propeller structure to
prefer a particular handedness. This is indeed the case, and the
chiroptical properties ascribed to the propeller geometry for syn-
(R,R)-1b-Me (CD: ∆ε ) -7.7 at 291 nm) were more than 10-
fold greater than those for the quasi-centrosymmetric anti-(R,R)-
1b-Me with a nonpropeller structure (∆ε ) -0.61 at 291 nm),
despite the fact that they have identical chiral auxiliaries.11
These characteristics give us the opportunity to construct a
supramolecular chiral sensing system with enhanced chiroptical
output based on our dynamic molecular propeller, which was
designed as described below. Both the syn- and anti-forms of
tetraarylterephthalamides 1a/b-H can act as host molecules at
the amide carbonyls for hydrogen-bond-donating guests with
ammonium and/or phenol moieties.12,13d,14 In contrast to the
tertiary amides 1a/b-Me, the syn- and anti-forms of secondary
amides 1a/b-H [R1 ) CH2(c-Hex)/C*HMe(c-Hex); R2 ) H]
would easily interconvert in solution. In the absence of any guest
molecules, the anti-form of 1a/b-H should be predominant in
the equilibrated mixture due to the complete cancellation of
amide-dipole repulsion. Alternatively, the syn-form of 1a/b-H
would be far more suitable for capturing a ditopic guest by
forming supramolecular complexes with a hover-overed cyclo-
phane-structure (Scheme 3).
Scheme 2
Thus, the achiral secondary amide host 1a-H would exist as
the anti-form with an achiral nonpropeller geometry in guest-
free conditions, and might be converted to the propeller-shaped
chiral syn-form upon complexation with a ditopic guest such
as p-xylylenediammonium derivatives 3 (chirality generation).
This system can be considered to be a new example of dynamic
molecular recognition,7,13,14 where the host structure is drasti-
cally changed upon complexation. When the point chiralities
attached to the ditopic guest as in (R,R)/(S,S)-3 are successfully
transmitted intermolecularly to the host, the helicity of the syn-
1a-H unit in the supramolecular complexes should be biased
to favor a particular handedness (chirality biasing). Although
simple point chiralities on the guest generally produce only
minor CD activity, successful transmission to the helical
(10) (a) Jiang, X.; Lim, Y.-K.; Zhang, B. J.; Opsitnick, E. A.; Baik, M.-
H.; Lee, D. J. Am. Chem. Soc. 2008, 130, 16812–16822. (b) Suzuki,
T.; Tanaka, S.; Kawai, H.; Fujiwara, K. Chem. Asian J. 2007, 2, 171–
177. (c) Mazaleyrat, J.-P.; Wright, K.; Gaucher, A.; Toulemonde, N.;
Dutot, L.; Wakselman, M.; Broxterman, Q. B.; Kaptein, B.; Oancea,
S.; Peggion, C.; Crisma, M.; Formaggio, F.; Toniolo, C. Chem.sEur.
J. 2005, 11, 6921–6929. (d) Kwit, M.; Rychlewska, U.; Gawron´ski,
J. New J. Chem. 2002, 26, 1714–1717. (e) Superchi, S.; Casarini, D.;
Laurita, A.; Bavoso, A.; Rosini, C. Angew. Chem., Int. Ed. 2001, 40,
451–454. (f) Clayden, J.; Lund, A.; Vallverdu´, L.; Halliwell, M. Naure
2004, 431, 966–971.
directing effect of amide dipoles is interesting, and induces the
conrotatory tilting of substituents in syn-2,3,5,6-tetraaryltereph-
thalamides, as shown below.
Transfer of Supramolecular Chirality Based on Terephthala-
mide-Based Molecular Propellers. We recently found that tereph-
thalamide derivatives 1 with four aryl blades are sterically
hindered molecules in which all six substituents are largely
twisted toward the central benzene core. Consequently, there
are two rotational isomers (syn and anti) in terms of the direction
of the two amide groups at the 1,4-positions (Scheme 2), which
can be isolated as noninterconvertible atropisomers in the case
of tertiary amides 1a/b-Me [R1 ) CH2(c-Hex)/C*HMe(c-Hex);
R2 ) Me]. The substituents are skewed toward either direction
to give numerous conformations. Due to the directing effects
of the amide dipoles to reduce electrostatic repulsion, the anti-
isomer adopts a (pseudo)centrosymmetric structure, whereas the
syn-isomer preferably exists as a chiral propeller for which the
helicity interconverts very rapidly (mobile helicity). Two
enantiomeric propellers with (P) and (M)-helicity are present
in equal amounts for syn-1a-Me [R1 ) CH2(c-Hex); R2 ) Me],
which has no asymmetric elements other than the mobile
(11) Katoono, R.; Kawai, H.; Fujiwara, K.; Suzuki, T. Chem. Commun.
2008, 4906–4908.
(12) (a) Kawai, H.; Katoono, R.; Nishimura, K.; Matsuda, S.; Fujiwara,
K.; Tsuji, T.; Suzuki, T. J. Am. Chem. Soc. 2004, 126, 5034–5035.
(b) Katoono, R.; Kawai, H.; Fujiwara, K.; Suzuki, T. Tetrahedron
Lett. 2004, 45, 8455–8459.
(13) (a) Hayashi, T.; Asai, T.; Hokazono, H.; Ogoshi, H. J. Am. Chem.
Soc. 1993, 115, 12210–12211. (b) Fujita, N.; Biradha, K.; Fujita, M.;
Sakamoto, S.; Yamaguchi, K. Angew. Chem., Int. Ed. 2001, 40, 1718–
1721. (c) Petitjean, A.; Khoury, R. G.; Kyritsakas, N.; Lehn, J.-M.
J. Am. Chem. Soc. 2004, 126, 6637–6647. (d) Kawai, H.; Katoono,
R.; Fujiwara, K.; Tsuji, T.; Suzuki, T. Chem.sEur. J. 2005, 11, 815–
824. (e) Haino, T.; Fukunaga, C.; Fukazawa, Y. Org. Lett. 2006, 8,
3545–3548. (f) Degenhardt, C. F.; Lavin, J. M.; Smith, M. D.; Shimizu,
K. D. Org. Lett. 2005, 7, 4079–4081.
(14) Katoono, R.; Kawai, H.; Fujiwara, K.; Suzuki, T. Chem. Commun.
2005, 5154–5156.
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A R T I C L E S
Katoono et al.
Scheme 3
Scheme 4. Reagents (a) 4-MeO-C6H4-B(OH)2, Pd(PPh3)4, Na2CO3
aq., DME, Toluene (y. 89% for a and 91% for b); (b) NaH, MeI,
THF (y. 26% for syn-a, 52% for anti-a and 42% for syn-b, 12% for
anti-b)
each of the amide nitrogens in the 2,3,5,6-tetrakis(p-methoxy-
phenyl)terephthalamide hosts 1 (Scheme 2). The latter acts as
a chiral handle to bias the direction of skewing of the amide
groups in a propeller-shaped syn-conformation. The lack of
strong absorption of the chiral auxiliary in the UV region is
favorable for studying the chiroptical properties of the hosts 1
in the presence/absence of guest molecules by CD spectroscopy.
The secondary terephthalamide hosts 1a/b-H were prepared
by Suzuki-Miyaura coupling16 of 2,3,5,6-tetrabromotereph-
thalamide derivatives 2a/b11 and 4-methoxyphenylboronic acid
(Scheme 4), which were obtained as mixtures of easily inter-
convertible syn- and anti-forms (vide infra). A methoxy group
1
attached to the aryl blades can simplify the aryl region of H
NMR spectra to facilitate the analysis of complexation. The
tertiary terephthalamides 1a/b-Me were prepared by N-methy-
lation of the corresponding secondary amides 1a/b-H, and
obtained as a mixture of two atropisomers in terms of the relative
direction of the amide groups. Due to the high rotational barrier
about the Ccentral-Camide bonds, the syn- and anti-isomers of 1a/
b-Me were easily separated by column chromatography. These
atropisomers are not interconvertible at all even at an elevated
temperature, and thus we can use syn- and anti-1a/b-Me
separately for control experiments.11
As ditopic guest molecules (Scheme 3), p-xylylenediammo-
nium derivatives 3 and (-)-phenylephrine salt 4·H+ were
selected, and these are expected to form hover-overed complexes
through binding at the two carbonyl groups of the hosts 1. The
(R)/(S)-1-cyclohexylethyl group is again used as a chiral
auxiliary in the guests (R,R)/(S,S)-3 to study the chiral recogni-
tion properties upon the formation of 1a/b-H·(R,R)/(S,S)-3
complexes. The chiral ditopic guests (R,R)/(S,S)-3 were prepared
from terephthalaldehyde and (R)/(S)-1-cyclohexylethylamine.
The chiral monotopic guest (R)-BnN+H2C*HMe(c-Hex) [(R)-
5] was also prepared as a reference in a similar manner from
benzaldehyde and obtained as a tetrafluoroborate salt.
Conformational Analysis of Secondary Terephthalamides
1a/b-H. In contrast to tertiary amides 1a/b-Me, the achiral
secondary host 1a-H was obtained as a mixture of syn- and
anti-forms, which rapidly interconvert due to the very low
rotational barrier about Ccentral-Camide bonds. As expected, only
two sets of resonances were observed for anisyl protons in the
aromatic region in the 1H NMR spectrum of 1a-H in CDCl3 at
room temperature (Figure S1a of the Supporting Information).
Conformational searches with MacroModel software17 indicated
that both the syn- and anti-forms have energy-minimized
preference of the host induces CD enhancement at the longer-
wavelength region of the propeller-shaped host molecules, which
makes it easier to detect the guest. These are the central points
of our design concept for supramolecular chirality sensing with
chiroptical enhancement through the transmission of point
chirality to mobile helicity. The successful supramolecular
detection of a neurotransmitter, (-)-phenylephrine 4, by the host
1a-H is also demonstrated.
Cooperative binding at the two carbonyl groups of the
terephthalamide host also enables us to distinguish the targeted
ditopic guests from the corresponding monotopic guests because
the latter cannot induce CD enhancement due to the lack of a
change in the structure of the host from the anti- to syn-form
upon complexation. Thus, even when they have the same point
chirality, monotopic and ditopic guests can be distinguished by
their CD spectra. When 1b-H with chiral auxiliaries is used as
a host, combination with a chiral guest would form diastereo-
meric complexes in which chiral auxiliaries on the host and
the guest work cooperatively (matched)/uncooperatively (mis-
matched) to control the helical sense. Thus, these diastereomeric
complexes would adopt different structures from each other,
and the chiral sense of the enantiomeric guests could be easily
distinguished by CD spectroscopy.14,15 This is the case for the
combination of (R,R)-1b-H with (S,S)/(R,R)-3. We describe here
the full details of these supramolecular chirality-transfer events
by using dynamic hosts 1a/b-H with a propeller-shaped mobile
helicity.
Results and Discussion
Molecular Design and Preparation. The achiral cyclohexyl-
methyl (a) or chiral 1-cyclohexylethyl (b) group is attached to
(16) (a) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457–2483. (b)
Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed.
2005, 44, 4442–4489.
(15) (a) Ikeda, T.; Hirata, O.; Takeuchi, M.; Shinkai, S. J. Am. Chem. Soc.
2006, 128, 16008–16009. (b) Borovkov, V. V.; Inoue, Y. Org. Lett.
2006, 8, 2337–2340.
(17) MacroModel v6.5, Schro¨dinger Inc., 1998, and the GB/SA solvation
model for chloroform through 5000-step Monte Carlo simulations
using the Amber* force field, and the PRCG minimization algorithm.
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A R T I C L E S
Figure 2. (a) UV and (b) CD spectra of (R,R)-1b-H (bold line), anti-
(R,R)-1b-Me (thin line), and syn-(R,R)-1b-Me (dashed line) measured in
CH2Cl2 at room temperature.
Figure 1. Energy-minimized structures of 1a-H adopting (a) anti-form
(achiral nonpropeller geometry) and (b) syn-form (chiral propeller geometry)
according to Monte Carlo simulations in CHCl3. The anti-form preference
over syn-forms is also the case for the N,N′-dimethyl derivative (anti: -108.0
kJ mol-1; syn: -104.9 kJ mol-1) where the methyl groups are replaced for
the cyclohexylmethyl groups, thus the bulkiness of cyclohexyl group does
nothing to do with the anti-preference in 1a-H.
Scheme 5
structures, with the latter more stable than the former by 7.7 kJ
mol-1, as is commonly observed with 1,4-arylenedicarboxamide
derivatives.18 Preference for the anti-form of 1a-H can be
explained based on electrostatic interaction, and the energy-
minimized geometry for the anti-form is a nonpropeller geom-
etry, in which the amide dipole interactions are completely
canceled (Figure 1a).
However, the syn-form was predicted to adopt a propeller-
shaped conformation, in which the two amide groups are skewed
in a conrotatory manner to reduce the repulsion of dipoles to
some extent (Figure 1b). These considerations are consistent
with the results in our preliminary communication11 for the
preferred geometries of tertiary amides syn-1a/b-Me (propeller-
shaped) and anti-1a/b-Me (nonpropeller-shaped), which were
isolated from each other and then analyzed crystallographically.
Even when we attach the chiral auxiliary to the nitrogens,
the chiral secondary amide host (R,R)-1b-H seems to prefer a
quasi-centrosymmetric anti-form, which is shown by the fact
that the CD spectrum of (R,R)-1b-H is similar to that of
noninterconvertible atropisomeric tertiary amide anti-(R,R)-1b-
Me but not to that of syn-(R,R)-1b-Me in CH2Cl2 at room
temperature (Figure 2). Thus, the Cotton effect of (R,R)-1b-H
is rather weak due to the nonpropeller geometry in the guest-
free state since the strong Cotton effect around 290 nm in syn-
(R,R)-1b-Me is due to its propeller-shaped geometry where the
helicity is biased due to the intramolecular transmission of point
chirality (R-configuration) on each amide nitrogen to the mobile
helicity (preferred M-configuration).19
Complexation of Achiral Dynamic Host 1a-H with Chiral
Ditopic Guests (R,R)/(S,S)-3. The complexation of 1a-H with
(R,R)/(S,S)-3 would induce a dynamic change in the structure
of the host from the anti- to syn-form, and stronger chiroptical
signals might be produced when the helical sense of the
propeller-shaped host is biased by intermolecular transmission
of the point chiralities on the guests (R,R)/(S,S)-3, which will
be demonstrated as follows.
The complexation behavior of 1a-H with (R,R)-3 was first
investigated by 1H NMR spectroscopy in CDCl3 at room
temperature (Figure 3). Upon the gradual addition of (R,R)-3
to the solution of 1a-H (∼10 mM), a significant downfield shift
from δ 5.09 (0 equiv.) to 5.70 (1.5 equiv.) ppm was induced
for the NHC proton of the host. The C2h symmetric methylene
proton (HE) of the achiral host, as seen in the spectrum (a),
changed to a complicated pattern of C2 symmetry due to the
lack of a mirror plane in the complex 1a-H·(R,R)-3. Also, the
remarkable upfield shift was observed for the anisyl protons
(HA).20 These results can be accounted for by a change in the
conformation of the host from the anti- to syn-form through
complexation with two carbonyl groups. When the monotopic
guest (R)-5 was added, no change in chemical shifts was induced
other than a downfield shift for NHC, which indicated the
formation of hydrogen bonds at carbonyl groups but was not
In this way, the secondary amide hosts 1a/b-H were shown
to prefer the anti-form (Scheme 5). However, only the syn-
form can bind with a ditopic guest molecule at the two carbonyl
groups to form 1:1 complexes with a hover-overed supramo-
lecular cyclophane geometry.
(18) (a) Betson, M. S.; Clayden, J.; Lam, H. K.; Helliwell, M. Angew.
Chem., Int. Ed. 2005, 44, 1241–1244. (b) Clayden, J.; Vallverdu´, L.;
Clayton, J.; Helliwell, M. Chem. Commun. 2008, 561–563. (c)
Coluccini, C.; Grilli, S.; Lunazzi, L.; Mazzanti, A. J. Org. Chem. 2003,
68, 7266–7273. (d) Casarini, D.; Lunazzi, L. J. Org. Chem. 1996, 61,
6240–6243.
(19) The weaker Cotton effect around 255 nm commonly observed for
(R,R)-1b-H and both atropisomers of (R,R)-1b-Me is also present in
the tetrabromide precursor (R,R)-2b or syn/anti-(R,R)-N,N′-bis(1-
cyclohexylethyl)-N,N′-dimethyl-2,3,5,6-tetrabromoterephthalamides de-
rived by the N-methylation of (R,R)-2b (∆ε ) -2 to -4). Thus, the
shorter-wavelength region is not associated with the propeller/non-
propeller conformation.
(20) The corresponding protons (Ha and Hb) in the atropisomers anti-1a-
Me and syn-1a-Me are centered at 7.10 and 6.98 ppm (Figure S1,
parts c and e of the Supporting Information), respectively.
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A R T I C L E S
Katoono et al.
1
Figure 3. Spectral change in H NMR (300 MHz) upon complexation of 1a-H with (R,R)-3; (a) 0 equiv. (1a-H only), (b) 0.41 equiv., (c) 0.82 equiv., (d)
1
1.16 equiv., (e) 1.50 equiv., and (f) H NMR spectrum of (R,R)-3, measured in CDCl3 at room temperature.
accompanied by a change in geometry from anti to syn (Figure
S2A of the Supporting Information).
helical sense of the propeller conformation in complex 1a-
H·(S,S)-3 was biased to (M)-helicity (negative Cotton effect
around 300 nm) whereas that in 1a-H·(R,R)-3 was biased to
(P)-helicity (positive Cotton effect around 300 nm) through the
transfer of supramolecular chirality from the chiral auxiliaries
of the ditopic guest to the mobile helicity of the host.
A change in the conformation of the host 1a-H from the anti-
to syn-form upon complexation must be the key to realizing a
transfer of supramolecular chirality, since no Cotton effect was
induced around the absorption region of noninterconvertible
atropisomer anti-1a-Me upon the addition of chiral guest (R,R)-3
under similar conditions (Figure S3D of the Supporting Infor-
mation). This idea is further supported by the strong CD signal
induced upon the complexation of syn-1a-Me with chiral guest
(R,R)-3 (Figure S3A of the Supporting Information). Although
noninterconvertible atropisomer achiral syn-1a-Me adopts a
chiral propeller-shaped geometry and exists as a 1:1 mixture of
(P)- and (M)-helicity in the guest-free state, complexation with
Continuous changes in the CD spectrum were observed upon
complexation of the achiral dynamic secondary host with the
chiral ditopic guest in CH2Cl2 at room temperature (Figure 4A).
When the achiral host 1a-H (4.2 × 10-4 M) was mixed with
the chiral guest (R,R)-3 (0 to 4 equiv.), a positive Cotton effect
was induced in the absorption region of 1a-H (λext ≈ 300 nm).
The addition of enantiomeric guest (S,S)-3 (0 to 4 equiv.) to
1a-H induced a negative Cotton effect, as expected. The
observed ellipticity is different from that of chiral guests (R,R)/
(S,S)-3 themselves, and is shifted to a longer-wavelength region
with a much stronger intensity, thus demonstrating successful
chiroptical enhancement. The shape and sign of the induced
Cotton effect for the complex 1a-H·(S,S)-3 are similar to those
for uncomplexed tertiary amide syn-(R,R)-1b-Me (Figure 2b).
Since the negative Cotton effect of the latter was previously
shown to correspond to the (M)-helicity of the propeller,11 the
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A R T I C L E S
Figure 4. (A) Continuous changes in the CD spectrum upon complexation of achiral host 1a-H (4.2 × 10-4 M) with (R,R)/(S,S)-3; (a) 1 equiv. (4.2 × 10-4
M), (b) 2 equiv. (8.3 × 10-4 M), (c) 4 equiv. (1.7 × 10-3 M) of (R,R)-3 (blue line), (d) 1 equiv. (4.2 × 10-4 M), (e) 2 equiv. (8.3 × 10-4 M), (f) 4 equiv.
(1.7 × 10-3 M) of (S,S)-3 (red line), and CD spectra of (g) (R,R)-3 (black line; 2.7 × 10-4 M), and (h) (S,S)-3 (black line; 2.5 × 10-4 M): (B) Continuous
changes in the CD spectrum upon complexation of 1a-H (2.8 × 10-4 M) with (-)-phenylephrine 4·HBAr4; (a) 1 equiv. (2.8 × 10-4 M), (b) 2 equiv. (5.5
× 10-4 M), (c) 4 equiv. (1.1 × 10-3 M) (green line), and (d) CD spectrum of 4·HBAr4 (black line; 1.8 × 10-4 M). All spectra were measured in CH2Cl2
at room temperature.
(R,R)-3 biased the preferred sense of helicity to (P), as indicated
by the positive sign of the Cotton effect around 300 nm. The
hover-overed bridging geometry is necessary for the complex
to realize the supramolecular chirality transfer since the corre-
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Figure 5. Energy-minimized structures for the hover-overed complexes
of 1a′-H and (-)-norphenylephrine (4′)·H+ obtained by Monte Carlo
simulation: (left) (M)-helical propeller of 1a′-H and (right) (P)-helical
propeller of 1a′-H.
Figure 6. NMR titration curves for complexation of (R,R)-1b-H (2 mM)
with (a) (S,S)-3 (0-9 mM) (b amide proton NHC, ( methyl proton HF),
and (b) (R,R)-3 (0-10 mM) (O amide proton NHC, ] methyl proton HF),
measured in CDCl3 at 298 K.
Scheme 6
the case of 3 since the binding site is not adjacent to the
asymmetric center but is separated by another methylene unit
in 4.
First, complexation with achiral host 1a-H was studied by
NMR spectroscopy with the protonated form of 4 (4·H+)
(Figure S2B of the Supporting Information). Tetrakis[3,5-
bis(trifluoromethyl)phenyl]borate salt was used to attain high
solubility in CDCl3. Upon admixing, a significant downfield shift
(∆δ 3.3 ppm) for the phenolic OH proton as well as an upfield
shift for one of four aromatic protons in the guest 4·HBAr4
were observed, indicating the hover-overed complexation of
4·HBAr4 at the two carbonyl groups of 1a-H through hydrogen
bonds, which is accompanied by a change in the conformation
of the host from the anti- to syn-form, as in the case of 1a-
H·(R,R)/(S,S)-3 complexes.
In the CD spectra, a large positive Cotton effect was induced
when the dynamic host 1a-H was mixed with (-)-phenylephrine
salt 4·HBAr4 (λext ) 297 nm, ∆ε ) +8.8, 4 equiv.) (Figure
4B). If we consider that the noninterconvertible atropisomeric
tertiary amide syn-1a-Me caused a similar positive Cotton effect,
whereas anti-1a-Me failed to induce any CD signals upon
combination with 4·HBAr4 (Figures S3B and S3E of the
Supporting Information), the dynamic host 1a-H changed its
sponding monotopic guest (R)-5 cannot induce any CD signal
around 300 nm upon complexation with propeller-shaped syn-
1a-Me (Figure S3C of the Supporting Information).
Complexation of Achiral Dynamic Host 1a-H with a
Neurotransmitter, (-)-Phenylephrine(4)·HBAr4. Similar to cat-
echolamine derivatives, (-)-phenylephrine (4) is an R1-adren-
ergic receptor agonist. Since this chiral neurotransmitter has two
hydrogen-bonding sites that are suitably separated to bind at
the carbonyl groups of terephthalamide-type host molecules,13d
its complexation with the present host molecules were also
examined. We were particularly interested if the point chirality
in 4 could be recognized by the host to enable its detection by
using CD spectra through supramolecular chirality transfer.
Chiral recognition for 4 should be more difficult than that in
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Dynamic Molecular Propeller
A R T I C L E S
Figure 7. (A) Continuous changes in the CD spectrum upon complexation of chiral host (R,R)-1b-H (3.0 × 10-4 M) with (S,S)-3; (a) 0 equiv. ((R,R)-1b-H
only (thin black line)), (b) 1 equiv. (3.0 × 10-4 M), (c) 2 equiv. (6.0 × 10-4 M), (d) 4 equiv. (1.2 × 10-3 M) (red line), and (e) CD spectrum of (S,S)-3 (bold
black line; 2.5 × 10-4 M): (B) Continuous changes in the CD spectrum upon complexation of (R,R)-1b-H (3.0 × 10-4 M) with (R,R)-3; (a) 0 equiv.
((R,R)-1b-H only (thin black line)), (b) 1 equiv. (3.0 × 10-4 M), (c) 2 equiv. (6.0 × 10-4 M), (d) 4 equiv. (1.2 × 10-3 M) (blue line), and (e) CD spectrum
of (R,R)-3 (bold black line; 2.7 × 10-4 M): (C) Continuous changes in the CD spectrum upon complexation of (R,R)-1b-H (3.2 × 10-4 M) with (R)-5; (a)
0 equiv. ((R,R)-1b-H only (thin black line)), (b) 1 equiv. (3.2 × 10-4 M), (c) 2 equiv. (6.5 × 10-4 M), (d) 4 equiv. (1.3 × 10-3 M) (sky blue line), and (e)
CD spectrum of (R)-5 (bold black line; 3.5 × 10-3 M). All spectra were measured in CH2Cl2 at room temperature.
conformation from anti to syn during complexation with biasing
of the propeller-geometry of 1a-H to (P)-helicity. On the basis
of a Monte Carlo simulation for the energy-minimized geo-
metry of modeled complex of host 1a′-H (R1 ) Me; R2 ) H)
with norphenylephrine 4′·H+, the hover-overed geometry with
a (P)-helical propeller structure (∆Hf ) -333.54 kcal mol-1
)
was more stable than that with (M)-helicity (-328.79 kcal
mol-1) (Figure 5). The predicted preference for the (P)-helicity
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is consistent with what was indicated by the positive sign of
experimental Cotton effect observed around 300 nm.
(R,R)-3 up to 4 equiv., marginal changes occurred to give a
positive Cotton effect, the sign of which is consistent with the
preference for (R,R)-3. Gradual changes of CD spectra with a
rise around 320 nm suggest the formation of complexes with
different shapes. The absence of CD spectral changes upon
complexation with the monotopic guest (R)-5 is also noteworthy.
The quite different behavior of (R,R)-1b-H toward (R,R)/(S,S)-3
and (R)-5 can be considered a new, rare example of stereospe-
cific chiroptical modulation.14,22
If we consider that the CD signal from (-)-phenyl-
ephrine(4)·HBAr4 itself is very small (∆ε < 0.2), then the
dynamic host enables chiroptical enhancement through the
transfer of supramolecular chirality from the point chirality in
the neurotransmitter to the mobile helicity of 1a-H. There are
two important points of this success: (1) the change in the
conformation of the host from the nonpropeller in anti-form to
propeller-shaped geometry in syn-form (chirality generation);
and (2) the helicity sense in favor of (P) by transmission of the
point chirality in the guest thanks to the hover-overed geometry
(chirality biasing).
Conclusions
One of the characteristic features of the secondary tereph-
thalamide hosts 1a/b-H is that the helical propeller structure is
attained only when they adopt a syn-conformation (chirality
generation), which is realized upon complexation with a suitable
ditopic guest (Scheme 1b). Although the resulting complexes
could not be isolated to conduct crystallographic study, the
spectroscopic analyses by NMR and CD provided compelling
evidence for the following characteristics of complexation. The
sense of the helicity for syn-1a-H is biased by the point
chiralities of (R,R)/(S,S)-3 or (-)-phenylephrine 4, which are
effectively transferred due to the hover-overed supramolecular-
cyclophane structure of the complexes (chirality biasing).
Alternatively, the dynamic host (R,R)-1b-H with asymmetric
centers on amide nitrogens has its own preferred helicity when
adopting the syn-form, and thus it exhibits chiral recognition
properties toward (R,R)/(S,S)-3.
In summary, the newly designed secondary amides 1a/b-H
can serve as a new class of dynamic hosts that induce strong
CD signaling upon complexation with chiral ditopic guests
which exhibit only weak chiroptical output before complexation
(chiroptical enhancement). Since only cooperative binding with
ditopic guests induces the change in the conformation of the
hosts from the anti- to syn-form accompanied by biasing of the
sense of helicity, the signaling hosts do not exhibit an enhance-
ment of the CD signal by a monotopic guest (R)-5, which
endows the present system with additional recognition proper-
ties. This work has demonstrated chirality generation-chirality
biasing protocol, for which only a few examples of long-chain
oligomer/polymer have been shown to achieve. Our well-
designed molecular propellers are another class of compounds
for further exploiting the field of less well-developed supramo-
lecular chirality.
Complexation of Chiral Dynamic Host 1b-H with Chiral
Ditopic Guests (R,R)/(S,S)-3. The chiral terephthalamide host
(R,R)-1b-H with a chiral auxiliary on each of the amide
nitrogens would exhibit a preference for the sense of dynamic
helicity7c,21 when it adopts the syn-form with a propeller
geometry. In fact, noninterconvertible atropisomer syn-(R,R)-
1b-Me exists predominantly as an (M)-propeller which shows
a negative Cotton effect around 290 nm.11 Alternatively, chiral
guests of (R,R)/(S,S)-3 have their own preference for the
propeller helicity of the host [(P) and (M), respectively] when
they form complexes with achiral host 1a-H/Me with a hover-
overed geometry. Thus, we can expect chiral-recognizing events
to occur upon the complexation of chiral dynamic host (R,R)-
1b-H with chiral ditopic guests (R,R)/(S,S)-3 (Scheme 6).
First, diastereomeric complexation of the chiral host (R,R)-
1
1b-H with chiral guests (R,R)/(S,S)-3 was investigated by H
NMR spectroscopy. When a solution of (S,S)-3 (∼10 mM) was
added to the host solution (2 mM) in CDCl3 at 298 K, the typical
upfield shift was induced again for the anisyl protons (HA),
which indicated a change in the conformation from the anti- to
syn-form upon complexation (matched pair; Figure S4A of the
Supporting Information). The titration curves using amide
protons and methyl protons on the stereogenic center are shown
in Figure 6. We assumed a 1:1 ratio for the (R,R)-1b-H·(S,S)-3
complex, and then curve-fitted the observed data to give a
binding constant Ka of 2 × 103 M-1 (Figure 6a). However, an
inflection point is present in the titration curves beyond the
addition of 1 equiv. of (R,R)-3 to the host (mismatched pair;
Figures 6b, S4B of the Supporting Information). This anomaly
suggests that several species are involved in the equilibrium
for the complexation of (R,R)-1b-H with (R,R)-3.
Complexation of the chiral dynamic host (R,R)-1b-H with
(R,R)/(S,S)-3 was further investigated by a CD spectral method
(Figure 7). Upon the addition of (S,S)-3 to the solution of (R,R)-
1b-H in CH2Cl2 at room temperature, a negative Cotton effect
at around 300 nm gradually increased, as in the case of 1a-
H·(S,S)-3 (Figure 4a), which indicates that the less CD active
anti-form of (R,R)-1b-H is transformed into the propeller-shaped
syn-form, and is biased toward the (M)-sense by the cooperative
influence of the internal and external auxiliaries on the helical
sense in the complex (matched pair). However, almost no change
was observed upon the addition of (R,R)-3 up to 1 equiv. Thus,
the mismatched pair does not induce CD modification, though
NMR titration suggests a similar binding constant (K ) ∼103
M-1) for (R,R)-1b-H·(R,R)-3. Upon the further addition of
Acknowledgment. The authors express their sincere gratitude
to Prof. Nobuhiko Yui (JAIST) for his continuing encouragement.
Supporting Information Available: Experimental details
(synthetic procedures and spectral data of new compounds), and
figures (Figures S1-S5). This material is available free of charge
via the Internet at http://pubs.acs.org.
JA906810B
(22) The sensing of chirality with configurationally-stable tertiary amide
syn-(R,R)-1b-Me was also examined (Figure S5 of the Supporting
Information),23 where the matched pair of syn-(R,R)-1b-Me and (S,S)-3
gave strong chiroptical output from the cooperative preference for (M)-
helicity, as expected. Mismatched enantiomeric guest (R,R)-3 had much
smaller effects on the CD spectrum. The monotopic guest (R)-5 failed
to modify the CD spectrum, as in the combination of syn-1a-Me and
(R)-5.
(23) As shown by the lack of induction of a Cotton effect upon the mixing
of conformationally stable anti-1a-Me and chiral guest (R,R)-3, the
chiral amide anti-1b-Me does not act as a host for the ditopic guests
(R,R)/(S,S)-3.
(21) (a) Montgomery, C. P.; New, E. J.; Parker, D.; Peacock, R. D. Chem.
Commun. 2008, 4261–4263. (b) Preston, A. J.; Gallucci, J. C.;
Parquette, J. R. Org. Lett. 2006, 8, 5259–5262. (c) Miyake, H.;
Sugimoto, H.; Tamiaki, H.; Tsukube, H. Chem. Commun. 2005, 4291–
4293.
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