Stereospecific change in conformation upon complexation of an exoditopic tetraamide host with a bis(ammonium) guest: Chiral recognition and strong CD signaling

Article abstract of DOI:10.1039/b510134d

Upon complexation of a rectangular-shaped achiral macrocyclic host with chiral guests, twisting deformation occurs to induce exciton-type bisignated CD, whereas a chiral rectangular host undergoes a similar structural change only with the matching enantio

Full text of DOI:10.1039/b510134d

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Stereospecific change in conformation upon complexation of an
exoditopic tetraamide host with a bis(ammonium) guest: chiral
recognition and strong CD signaling{
Ryo Katoono, Hidetoshi Kawai, Kenshu Fujiwara and Takanori Suzuki*
Received (in Cambridge, UK) 20th July 2005, Accepted 31st August 2005
First published as an Advance Article on the web 13th September 2005
DOI: 10.1039/b510134d
chromophores (lmax 320 nm).8 We report here the chiral-sensing
Upon complexation of a rectangular-shaped achiral macro-
properties of newly designed macrocycles 1 based on their
cyclic host with chiral guests, twisting deformation occurs to
induce exciton-type bisignated CD, whereas a chiral rectangular
host undergoes a similar structural change only with the
matching enantiomer of a chiral guest.
complexation-induced changes in conformation.
Molecular recognition is one of the main topics in host–guest
chemistry.1 Chiral recognition is especially important in relation to
biological systems where many neurotransmitters and hormones
contain asymmetric centers. Inspired by the dynamic recognition
systems in nature,2 we recently developed a terephthalamide-type
exotopic host molecule.3 Upon complexation with catecholamine-
type biogenic compounds, such as adrenaline,3b the host undergoes
a drastic change in geometry with the formation of a supra-
molecular cyclophane structure by hydrogen bonding at amide
carbonyl groups. For a terephthalamide unit incorporated into a
cyclic structure in another host,4 the two carbonyl groups are
preorganized in a syn arrangement, which is suitable for guest
binding. We envisaged that a host with a larger-sized ring can
adopt both rectangular and skewed shapes5 and may undergo
dynamic molecular recognition thanks to interconversion between
them upon complexation. Exoditopic hosts such as 1 are more
promising in terms of homotropic allosteric effects, as shown in
Scheme 1. When the direction of twisting is controlled6 by the
asymmetric centers of the bidentate guest, such as (S,S)-2, a strong
bisignated CD signal is generated upon complexation due to
the exciton coupling7 of 1,4-bis(phenylethynyl)benzene (BPEB)
Exoditopic host 1a was prepared by the repeated Sonogashira
coupling of N,N9-bis(4-iodophenyl)terephthalamide 4a (Scheme 2),
which was obtained from terephthaloyl chloride and N-butyl-4-
iodoaniline.9 Reaction of 4a with TMS-acetylene followed by
deprotection gave bis(acetylene) 5a, which was then reacted with
Scheme 1
Division of Chemistry, Graduate School of Science, Hokkaido
University, Sapporo 060-0810, Japan. E-mail: tak@sci.hokudai.ac.jp;
Fax: +81 11 706-2714; Tel: +81 11 706-2714
{ Electronic supplementary information (ESI) available: spectral data and
synthetic procedures for the new compounds [1a, 1b, (S,S,S,S)/(R,R,R,R)-
1c, (R,R)-1d, (S,S)-2, (S)-3, 4a, (S,S)/(R,R)-4c, 5a, (S,S)/(R,R)-5c, 6a, 6b
and (S,S)/(R,R)-6c]. See http://dx.doi.org/10.1039/b510134d
Scheme 2
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1,4-diiodobenzene to give the bis(iodobenzene) derivative 6a.
Pseudo high-dilution coupling between 5a and 6a gave the
macrocyclic tetraamide 1a,{ which was isolated as stable colorless
crystals. When 2,5-diiodo-p-xylene was used in place of diiodo-
benzene, the host 1b{ with four additional methyl groups could be
prepared in a similar manner. The NMR spectrum of 1b exhibits a
sharp singlet for these methyl groups, suggesting free rotation of
the xylene moiety in 1b.
which are far from the binding sites for (S,S)-2. Small but
significant downfield shifts of 0.02 ppm for the methyl protons in
the middle of BPEB chromophores clearly show that complexation
with (S,S)-2 induces a change in geometry of the macrocycle 1b, by
which these methyl groups are deshielded by another BPEB unit.
To obtain more information on the complexation-induced
structural changes,10 the complexation of 1a and (S,S)-2 was
followed by an examination of the circular dichroism (CD)
spectrum. Upon the gradual addition of (S,S)-2 to a solution of 1a
(1.2 6 1024 M) in CH2Cl2, a pair of negative (lext 345 nm; De 212)
and positive (310, +10) Cotton effects were observed (Fig. 2).
Such a bisignated CD (A 5 222) is characteristic of the exciton
coupling7 of the chromophores. Since the longest-wavelength
absorption of 1a is assigned to that of the BPEB unit with a
transition moment along the long axis,8 the observed negative
couplet indicates twisting deformation of the macrocycle into a
skewed conformation with predominant M-helicity6a,7 (Scheme 1).
The sigmoidal curvature (Fig. 2, inset) for the relationship between
the guest/host ratio and De indicates that the present complexation
exhibits positive homotropic allosterism.11 In contrast, the
When we started with 4c derived from chiral N-(1-phenyl-
ethyl)-4-iodoaniline, (R,R)- and (S,S)-6c were obtained following
procedures similar to those for 6a. The double Sonogashira
coupling between (S,S)-6c and its precursor (S,S)-5c gave the
homochiral host (S,S,S,S)-1c.{ Its enantiomer, (R,R,R,R)-1c,{ was
obtained from (R,R)-5c and (R,R)-6c. Macrocyclization between
(R,R)-5c and achiral 6a gave (R,R)-1d,{ in which only one of the
two terephthalamide units possesses chiral auxiliaries. The optical
23
rotations ([a]D in CHCl3) for (S,S,S,S)-1c, (R,R,R,R)-1c and
(R,R)-1d are +1240, 21250 and 2602u, respectively.
The X-ray analysis§ of achiral host 1a shows that it adopts a
Ci-symmetric distorted rectangular form with approximate dimen-
sions of 7.4 6 19.2 s (separation between amide nitrogens)
(Fig. 1). In the terephthalamide moiety, two carbonyl groups are
arranged in the syn form (dihedral angle 1.0u) and the central
phenylene group is rotated about 40u with respect to the amide
units. The BPEB chromophores are arranged in parallel without
any close intramolecular contacts. Since tetramethylated macro-
cycle 1b§ with a different packing arrangement adopts a nearly
identical molecular shape, the observed rectangular form should
not result from the packing force in the crystal, but rather
must be the intrinsically favored geometry for the macrocycles
prepared here.
+
monodentate guest (S)-3 [Ph-CHMe-NH2 -CH2-Ph (50 equiv.)]
did not induce any couplet in the CD spectrum. The latter result
indicates that the twisting deformation is caused not by simple
binding with guests but by the formation of a supramolecular
paracyclophane structure with the proper bidentate guests. The
out-of-plane deviations of two carbonyl groups of 1a toward
different directions upon complexation with 2 are responsible for
twisting into the skewed conformation. These results show that
bis(ammonium)-type chiral guest (S,S)-2 binds at each of the two
terephthalamide moieties of macrocyclic host 1a to induce a
change in geometry to a chiral skewed conformation, and
(S)-phenylethyl auxiliaries on the guest bias the chiral sense of
twisting in favor of M-helicity. Since the CD signal of (S,S)-2 is
very weak (lext 261 nm; De +0.68), complexation with 1a results
in much easier detection of (S,S)-2 with light of longer wavelength
(‘‘chiroptical enhancement’’).
A complexation study was performed with the achiral hosts 1a,b
and the bidentate chiral guest (S,S)-2 containing two phenylethyl-
ammonium units. The p-xylene-a,a9-diyl unit in guest 2 is
expected to provide the ammonium units with a suitable
separation to bridge the terephthalamide moiety in 1. Upon
portionwise addition of (S,S)-2 to a solution of 1b in CDCl3
(1023 M), the terephthaloyl protons of the host exhibit a gradual
upfield shift from 7.15 (0 equiv.) to 7.09 (2.2 equiv.) ppm. On the
other hand, in the presence of 1.6 equiv. of 1b, the phenylene
protons of (S,S)-2 (7.17 ppm) show a significant upfield shift of
0.50 ppm. These complexation-induced shifts (CISs) indicate the
proximity of these aromatic units in the host–guest complex.
Supramolecular paracyclophane formation through double hydro-
gen bonding at the shorter axes of 1 most likely accounts for this
observation. Notable CISs were also found in the BPEB units,
To construct a more advanced chiral sensing system based on
the complexation-induced change in geometry of the macrocyclic
host, complexation of the chiral host 1c with the chiral guest 2 was
examined to see if the asymmetric auxiliaries on the macrocycle
Fig. 2 Continuous changes in the CD spectrum upon complexation of
achiral 1a (1.2 6 1024 M) with (S,S)-2 in CH2Cl2: a) 0.5 equiv., b)
1.0 equiv., c) 1.5 equiv., d) 2.0 equiv., e) 4.0 equiv. and f) 6.0 equiv. [inset]
Sigmoidal relationship between De and the ratio of (S,S)-2/1a.
Fig. 1 X-ray structure of achiral host 1a measured at 2120 uC.
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other hand, similar complexation between (R,R,R,R)-1c and
(S,S)-2 did not induce any bisignated CD, suggesting that the
rectangular shape of the macrocycle is retained for the mismatched
pair. These results demonstrate the outstanding chiral recognition
properties of exoditopic host 1c, which exhibits a stereospecific
response with 2 by providing a strong bisignated CD signal
only with a matched chiral guest (‘‘stereospecific chiroptical
modulation’’).
Complexation studies of 1c with neurotransmitters containing
chiral benzylammonium units are now in progress to examine the
possible applicability of the present motif as novel sensory systems.
Scheme 3
Notes and references
{ Electronic and CD spectral data in CH2Cl2 are as follows. 1a: lmax/nm
317 (log e 4.99); 1b: lmax/nm 317 (log e 4.96); (R,R,R,R)-1c: lmax/nm 306
(log e 4.98), lext/nm 333 (De 268.1), 311 (248.8), 291 (270.4), 267 (26.9),
249 (267.4); (S,S,S,S)-1c lext/nm 333 (De +68.3), 313 (+49.0), 290 (+71.0),
267 (+8.0), 251 (+67.0); (R,R)-1d: lmax/nm 313 (log e 4.95), lext/nm 337
(De 230.1), 318 (216.1), 299 (228.9), 269 (+0.7), 250 (226.2); (S,S)-2
(BF42)(BAr42) [Ar 5 3,5-(CF3)2C6H3]: lmax/nm 274 (log e 3.59), 269
(3.70), 261 (3.65), lext/nm 268 (De +0.61), 261 (+0.68), 255 (+0.48); (S)-3
BF42: lmax/nm 268 (log e 2.49), 262 (2.69), 257 (2.68), lext/nm 268
(De +0.18), 261 (+0.21), 255 (+0.13).
§ Crystal data of 1a: MF C76H68N4O4, FW 1101.40, monoclinic P21/n,
a 5 18.788(4), b 5 8.976(2), c 5 18.881(4) s, b 5 90.193(6)u, V 5
3184.0(12) s3, r (Z 5 2) 5 1.149 g cm23, T 5 153 K, R 5 11.2%. Crystal
data of 1b?AcOEt solvate: MF C88H92N4O8, FW 1333.72, monoclinic
C2/c, a 5 33.738(7), b 5 8.957(2), c 5 27.599(6) s, b 5 111.546(3)u,
V 5 7758(3) s3, r (Z 5 4) 5 1.142 g cm23, T 5 153 K, R 5 8.3%. CCDC
279787–279788. See http://dx.doi.org/10.1039/b510134d for crystallographic
data in CIF or other electronic format.
Fig. 3 [upper] Continuous changes in the CD spectrum upon complexa-
tion of (S,S,S,S)-1c (1.4 6 1024 M) with (S,S)-2 in CH2Cl2: a) 0 equiv., b)
2 equiv. and c) 4 equiv. [lower] Continuous changes in the CD spectrum
upon complexation of (R,R,R,R)-1c (1.1 6 1024 M) with (S,S)-2 in
CH2Cl2: d) 0 equiv., e) 2 equiv. and f) 4 equiv.
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a
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couplet in the CD spectrum by exciton coupling. With the
mismatched enantiomer, twisting deformation would not occur
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This journal is ß The Royal Society of Chemistry 2005