Preparation and unique circular dichroism phenomena of urea-functionalized self-folding resorcinarenes bearing chiral termini through asymmetric hydrogen-bonding belts

Article abstract of DOI:10.1039/b418880b

Chiral macrocycles with eight (R)- and (S)-methylbenzylurea residues on the resorcinarene skeleton linked through a hexyl or dodecyl spacer having amide linkages have been prepared by the reactions of the corresponding octaamine derivative with (R)- and (

Full text of DOI:10.1039/b418880b

View Article Online / Journal Homepage / Table of Contents for this issue
A R T I C L E
Preparation and unique circular dichroism phenomena of
urea-functionalized self-folding resorcinarenes bearing chiral termini
through asymmetric hydrogen-bonding belts†
Osamu Hayashida,*a,c Jun-ichi Ito,b Shinji Matsumotob and Itaru Hamachia,c
a Institute for Materials Chemistry and Engineering, Graduate School of Engineering,
Kyushu University, Hakozaki, Higashi-ku, Fukuoka, 812-8581, Japan
b Department of Chemistry and Biochemistry, Graduate School of Engineering,
Kyushu University, Hakozaki, Higashi-ku, Fukuoka, 812-8581, Japan
c PRESTO, JST, 4-1-8 Honcho Kawaguchi, Saitama, 332-0012, Japan.
E-mail: ohaya@ms.ifoc.kyushu-u.ac.jp
Received 17th December 2004, Accepted 4th January 2005
First published as an Advance Article on the web 21st January 2005
Chiral macrocycles with eight (R)- and (S)-methylbenzylurea residues on the resorcinarene skeleton linked through a
hexyl or dodecyl spacer having amide linkages have been prepared by the reactions of the corresponding octaamine
derivative with (R)- and (S)-a-methylbenzylisocyanate, respectively. In chloroform, the urea-functionalized
resorcinarenes with hexyl spacers form intramolecular hydrogen bonds by bundling the urea and amide residues in a
cyclic fashion to give a self-folding cavitand. The urea and amide residues are cooperatively oriented in the same
direction to result in asymmetric hydrogen-bonding belts. Unique circular dichroism (CD) bands are induced in the
absorption wavelength ranges of the macrocyclic skeleton, caused by a chirality transmission from their chiral urea
termini through hexyl spacers in the self-folded conformation. On the other hand, urea-functionalized resorcinarenes
with a longer dodecyl spacer do not show such unique CD bands on the macrocycle, because of their weaker
propensity for hydrogen bond formation. The characteristic CD bands of the urea-functionalized self-folding
macrocycles disappeared upon complexation with anions such as chloride and bromide, reflecting breaking of the
intramolecular hydrogen-bonding belts.
Introduction
Self-folding cavitands1 are synthetic hosts in which intramolec-
ular hydrogen bonding and solvophobic effects play important
roles in maintaining their unique conformation. Rebek and
co-workers reported that resorcinarene2-based (2) cavitands
bearing four aromatic walls, each having two amide groups,
fold into a deep open-ended cavity by means of intramolecular
3
=
(C O · · · HN) hydrogen bonds in non-polar solvents (Fig. 1).
These molecules provide an internal cavity suitable for encap-
sulating small, complementary organic molecules and ions as
a guest. The eight amide groups provide a head-to-tail belt
of hydrogen bonds along the wide rim of the resorcinarene.3
The belt of the hydrogen-bonded amide groups makes possible
two cycloenantiomers, with clockwise and counterclockwise
orientations of the amide bonds (Fig. 1). In solutions at
ambient temperature, the interconversion between these two
conformational enantiomers occurs through the reorientation
of the hydrogen-bonding arrays. A possible strategy for the
development of chiral self-folding cavitands4 is control of the
formation of either of the two cycloenantiomers at the dynamic
level.
Fig. 1 Head-to-tail hydrogen-bonded belt formed cooperatively by
eight amide groups of Rebek’s self-folding cavitand. Interconversion
of two cycloenantiomers, with clockwise and counterclockwise orien-
tation of the amide bonds, is shown. The large circles represent the
resorcinarene skeleton; R is an alkyl group.
capable of providing an asymmetric internal cavity, on the basis
of a molecular design that allows the introduction of an optically
active urea moiety onto each of the eight OH groups of the
resorcinarene skeleton (2) through an alkyl spacer having an
amide linkage.7 Urea-functionalized resorcinarenes are expected
to form similar intramolecular hydrogen bonds in a non-polar
solvent, with the direction of the hydrogen-bonded arrays being
controlled to some extent by steric hindrance of the neighboring
chiral moieties, as schematically shown in Fig. 2.
In this context, we report preparation of the urea-
functionalized self-folding resorcinarene derivatives as well as
their unique circular dichroism (CD) spectroscopic features
in chloroform. We have discovered that, in chloroform, CD
bands were induced in the absorption wavelength range of
the macrocyclic skeleton, which were transmitted from the
remote chiral urea termini in the asymmetrically self-folded
conformation.
On the other hand, urea moieties5 also act as strong hydrogen-
bond donors and acceptors. These have been frequently used
as functional groups for the formation of supramolecular
architectures.6 For example, modifications at the wide rim of
calix[4]arene with bulky urea residues resulted in supramolecular
dimeric capsules, in which cationic guests such as tetraethylam-
monium cations were encapsulated.6 On these grounds, we were
interested in the development of chiral self-folding cavitands4
† Electronic supplementary information (ESI) available: NMR and CD
spectra of 1, CD spectrum of 10-S, and FAB MS spectra of 1 : 1
adducts of 1 with chloride ion and bromide ion. See http://www.rsc.org/
suppdata/ob/b4/b418880b/
6 5 4
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 6 5 4 – 6 6 0
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
©

View Article Online
Fig. 2 Schematic representations for the self-folding of 1. In chloro-
form, the urea moieties (black ovals) of 1 form intramolecular hydrogen
bonds clockwise or counterclockwise in a cyclic fashion, the direction
of which is controlled by the neighboring chiral termini. A chirality
transmission from the chiral urea termini to the macrocycles through
hexyl spacers results in CD bands at 280 nm, in the absorption
wavelength range of the macrocyclic skeleton (A). Intermolecular
hydrogen bonds with an encapsulated anion (Cl−), resulting in the
decrease and disappearance of the CD bands at 280 nm (B). Each asterisk
(ꢀ) represents a chiral center.
Results and discussion
Molecular design and preparation
Resorcinarene (2) is a bowl-shaped cyclic resorcinol tetramer
with four alkyl tails (R = undecyl in the present case), which are
known to be oriented in the same direction.2 We have designed
self-folding macrocycles7 bearing chiral termini by introducing
(R)- and (S)-methylbenzylurea residues, respectively, onto each
OH group of resorcinarene through a hexyl spacer, 1-R and
1-S (n = 6), respectively. In Fig. 3 are shown the space-filling
CPK models8 (top and side views) with estimated molecular
dimensions for 1-R in the case of a folded conformation.
The bowl-shaped resorcinarene platform with four undecyl
chains sustains a folded conformation in which eight branches
having chiral urea termini can be spontaneously packed through
intramolecular hydrogen-bonding interactions in an appropriate
solvent system. Other urea-functionalized resorcinarenes having
a longer (dodecyl) spacer were also designed in order to
investigate the chain-length dependency of the hydrogen bond
formation (9-R and 9-S (n = 12)). The distance between the
chiral urea termini and the macrocycle skeleton of 9 is about
twice as long as that in 1.
Fig. 3 A space-filling representation of 1-R. Top view (A) and side view
(B). The undecyl groups are replaced by methyl groups for clarity.
tion sequence given in Scheme 1. An octaacid derivative of
resorcinarene 4 was prepared by reaction of 2 with tert-butyl
bromoacetate, followed by treatment with TFA. A precursor of
1, the octaamine derivative of resorcinarene 7, was prepared by
condensation of the corresponding carboxylic acid derivative
4 with (6-aminohexyl)carbamic acid tert-butyl ester in the
presence of the BOP reagent, followed by removal of the
protecting groups. Reactions of octaamine 7 with (R)- and
(S)-a-methylbenzyl isocyanate proceeded to give urea-linked
resorcinarene derivatives 1-R and 1-S, respectively (yields 46–
56%). The use of the (12-aminododecyl)carbamic acid tert-butyl
ester in place of (6-aminohexyl)carbamic acid tert-butyl ester
afforded the corresponding resorcinarenes bearing eight (R)-
and (S)-methylbenzylurea residues with a dodecyl spacer, 9-R
and 9-S, respectively. We also prepared the mono-urea derivative
10-S having an S-configuration by using 4-hexylphenol in place
of 2, in a manner similar to that applied in the synthesis of 1-S.
Cyclic hydrogen-bonding belts
In view of investigations of the CPK molecular models of 1-R
(Fig. 3), all branches with urea moieties are oriented in the same
direction, as mentioned above. The urea moieties linked to the
chiral centers of 1-R approach close to each other and are twisted
in the same direction in a location suitable for intramolecular
hydrogen bonding with its neighbors. The formation of such
a hydrogen-bond network by bundling the urea and amide
residues in a cyclic fashion gives a self-folding cavitand, as
schematically shown in Fig. 2. When all of the urea or amide
residues are oriented in the same direction, the cyclic hydrogen-
bonding belts are formed cooperatively.
In general, small urea molecules at higher concentrations tend
to self-assemble by hydrogen-bonding interactions in non-polar
organic solvents.9 First, the hydrogen-bonding properties of
Resorcinarenes bearing eight (R)- and (S)-methylbenzylurea
residues, 1-R and 1-S, were prepared by following the reac-
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 6 5 4 – 6 6 0
6 5 5

View Article Online
methods.11 A urea-functionalized resorcinarene with a longer
dodecyl spacer, 9-S, however, gave values of 1561 and 1667 cm−1
=
for the N–H deformation band and C O stretching vibrations,
respectively, indicating its weaker propensity for urea hydrogen-
bonding belt formation. In the case of 9-S, the conformational
flexibility originating from the dodecyl spacer seems to be
preventing the urea residues from forming strong intramolecular
hydrogen bonds.
Circular dichroism phenomena induced by the self-folding
conformation
Resorcinarenes and their derivatives show a characteristic
absorption band at around 280 nm which is attributed to an
electric transition moment of the resorcinol ring; the electronic
absorption spectrum of 1-S is shown in Fig. 5, as a typical ex-
ample. At least in the concentration range of UV measurements,
1-S exists in a monomeric state, as confirmed by a Beer’s plot.
Achiral resorcinarene derivatives such as 5 did not show any
detectable CD bands in the absorption wavelength ranges of the
macrocyclic skeleton. Weak absorption bands of 1-undecyl-3-(1-
phenylethyl)urea 11-S (a terminal methylbenzylurea analogue of
1-S) on the other hand, have shorter wavelengths – 254, 260, and
267 nm in chloroform (Fig. 5).
Scheme 1 Preparation of urea-functionalized resorcinarenes (R =
(CH2)10CH3).
1-S in chloroform solution (1.3 mM) were evaluated by FT-
IR measurements, and compared with those for the mono-
urea derivative 10-S (10 mM) in a monomeric state,10 as a
component analogue of 1-S. The absorption frequency of the
N–H deformation band of 1-S (dN = 1565 cm−1) is higher
–
H
−1
=
than for 10-S (dN = 1554 cm ), whereas the C O stretching
–
H
frequency of 1-S (m
= 1658 cm−1) is lower than for 10-S
=
Fig. 5 UV spectra of 1-S (A) and 11-S (B) in chloroform.
C
O
(m
= 1668 cm−1) (Fig. 4), indicating the formation of in-
=
C
O
tramolecular hydrogen bonds for most urea and amide residues
of 1-S. A monomeric dispersion of 1-S was also suggested
by NMR spectroscopy, without any detectable concentration
dependence on the chemical shifts of urea protons of 1, within
the concentration range 0.1–2.4 mM (see ESI†). A similar
property in the hydrogen-bonding properties of macrocyclic urea
1-R was also confirmed by identical methods (dN = 1565 and
The asymmetric characters of the octa-ureas 1-R and 1-S
were examined by CD spectroscopy, especially in the wavelength
ranges of the terminal urea residues (254, 260, and 267 nm)
and the macrocyclic skeleton (280 nm). A chloroform solution
of compound 1-S showed positive CD bands at 254, 261, and
267 nm as well as a negative band at 280 nm, as shown in Fig. 6.
In addition, mono-urea derivatives such as 10-S and 11-S show
–H
1
m
C
O = 1658 cm−1). Kobayashi and Seki reported similar results
similar CD bands at 255, 261, and 268 nm with ca. of the
=
intensity of 1-S (see ESI for 10-S†). These results suggest8that the
CD bands at shorter wavelengths are originally attributable to
the optically active urea residues. On the other hand, the negative
CD band at 280 nm indicates a remote chirality transmission
from the chiral urea termini to the macrocycles through hexyl
spacers; i.e., the originally achiral macrocyclic skeleton of 1-S
gains induced chirality through the asymmetric cyclic hydrogen-
bonding belts around the urea terminus in chloroform, as
shown schematically in Fig. 2. A similar character was observed
for 1-R, which had an inverted CD spectrum (Fig. 6). No
concentration dependency in the CD spectra of 1 was observed,
at least within the concentration range 15–760 lM (see ESI†),
indicating that 1 exists in a monomeric state. The formation of
intramolecular hydrogen bonds of 1 is responsible for the unique
CD phenomena, which was evidenced by the following results.
for hydrogen bond formation in urea derivatives by identical
Fig. 4 FT-IR spectra of 1-S (solid line) and 10-S (dotted line) in
chloroform at 298 K.
6 5 6
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 6 5 4 – 6 6 0

View Article Online
Fig. 6 CD spectra of 1-S and 1-R in chloroform (A) or in chloro-
form–methanol (3 : 97 v/v) (B). CD spectra of 9-S and 9-R in chloroform
(C).
Fig. 7 Partial 1H NMR spectra of 1-S at 298 K in the presence of Cl−
(as a tetrabutylammonium salt): 0, 1, 5, 10, 20, 30, and 40 equiv. (from
bottom to top) (A). The corresponding NMR titration curves for Cl−
(᭹) and Br− (᭺) (B).
(i) The CD band of 1-S at 280 nm weakened to ca. 42% of
its original intensity in chloroform–methanol (92 : 8 v/v) and
completely disappeared in chloroform–methanol (3 : 97 v/v)
(Fig. 6). Methanol breaks intramolecular hydrogen bonds. (ii)
Resorcinarenes having a dodecyl spacer, 9-S and 9-R, which
were lacking effective intramolecular hydrogen-bonding belts,
as mentioned above, did not show meaningful CD bands at
longer wavelengths of around 280 nm (Fig. 6). The CD signal
of 1 at 280 nm, which is the effect of the individual chiral
urea termini on the macrocycle skeleton, arose owing to the
formation of asymmetric hydrogen-bonded arrays to give a self-
folded conformation.12
be evaluated due to its weak binding affinity. Most interestingly,
the CD bands of 1-S at 280 nm were weakened upon addition of
chloride (Fig. 8) and bromide. The extent of change in CD bands
upon complexation with guests follows the sequence: Cl− > Br−
ꢀ ClO4−, reflecting the guest-binding affinities of 1-S. These
results suggested that the encapsulated guest anions disrupted
the formation of intramolecular hydrogen bonds of 1-S, as
schematically shown in Fig. 2, so that the resulting complexes
did not show any CD phenomena at 280 nm. Such conformation
changes around the urea residues of 1 upon complexation with
anions were monitored by circular dichroism measurements. A
similar complexation behavior for 1-R with these anions was
also confirmed by identical methods.
Conformational changes upon guest binding
An interesting potential use of the self-folding cavitand is as
a host13 for inclusion of guest anions. First, the guest-binding
behavior of 1-S was observed by FAB spectrometry. MS peaks
for 1 : 1 adducts with Cl− and Br− were directly detected; m/z
3 568 [M + Cl]− and 3 613 [M + Br]− (see ESI†). Second, the
guest-binding behavior of 1-S for anions has been investigated
by 1H NMR spectroscopy. Upon addition of chloride (as a
tetrabutylammonium salt) to a CDCl3 solution containing 1-
1
S, the H NMR signals due to the urea protons of 1-S were
sharpened with concomitant downfield shifts, showing a simple
saturation behavior for the complexation, as shown in Fig. 7.
These results indicate again that 1 has a self-folding cavity
suitable for binding an anion, as schematically shown in Fig. 2.
A similar complexation behavior for 1-S was also confirmed
with bromide. The binding constants (K) for 1 : 1 host–guest
complexes were evaluated on the basis of computer-aided least-
squares curve fitting methods applied to the NMR data (K =
1000 and 600 M−1 for chloride and bromide, respectively). On
Fig. 8 CD spectra of 1-S in chloroform in the presence of Cl− (as a
tetrabutylammonium salt): 0, 2, 7, 12, 22, 31, and 36 equiv. (from A to
G).
−
the other hand, the K value of 1-S for the ClO4 ion could not
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 6 5 4 – 6 6 0
6 5 7

View Article Online
[72H, m, CH2(CH2)9CH3], 1.74 [8H, m, 4H, CH2(CH2)9CH3],
4.21 [8H, d, J = 16.4, OCH2CO (non-equivalent)], 4.46 [8H,
d, J = 16.4, OCH2CO (non-equivalent)], 4.48 (4H, t, J = 7.2,
CH-Ar), 6.35 (4H, s, Ar–H2), 6.49 (4H, s, Ar–H5), 12.7 (8H,
br s, COOH); dC (125 MHz, CD3OD, Me4Si) 15.0 ((CH2)10CH3),
24.2 ((CH2)10CH2CH3), 29.6 (CH), 31.4 ((CH2)6CH2CH3)), 33.6
(CHCH2CH2CH2), 36.1 (CHCH2CH2), 37.2 (CHCH2), 68.2
(OCH2), 102.3 (Ar–C2), 127.9, 129.8 (Ar–C4,5,6), 156.21 (Ar–
C1,3), 173.34 (CO). m/z calcd. for C88H127O24Na: 1568.9. Found:
1568.0 [M − H]−.
Conclusions
Chiral self-folding resorcinarene derivatives with eight (R)- and
(S)-methylbenzylurea residues linked through a hexyl spacer
having amide linkages, 1-R and 1-S, were designed and devel-
oped. In chloroform, these urea-functionalized resorcinarenes
formed intramolecular hydrogen bonds by bundling the urea
and amide residues in a cyclic fashion to give a self-folding
cavitand. The cooperatively oriented and hydrogen-bonded
urea residues gave unique CD phenomena in the absorption
wavelength ranges of the macrocyclic skeleton. In such a self-
folded conformation, the formation of an asymmetric cyclic
hydrogen-bonding belt is responsible for these unique CD bands,
in which the information on the chirality of the termini is trans-
ferred to the absorption wavelength of the macrocycle. These
characteristic CD bands for the urea-functionalized self-folding
macrocycles disappeared upon complexation with anions such
as chloride and bromide. Conformational changes of the urea-
functionalized resorcinarenes were successfully observed by CD
spectroscopy. We believe that our concept of the molecular
design of urea-functionalized self-folding resorcinarenes bearing
chiral termini provides a useful guidepost for developments of
smart molecules having sophisticated capabilities in areas such
as chiral recognition,14 molecular informatics,15 and catalytic
performance.16
Resorcinarene octaBoc-amine having a hexyl spacer (5)
A solution of N-1-tert-butoxycarbonyl-1,6-diaminohexane hy-
drochloride (1.0 g, 3.96 mmol) and triethylamine (0.56 ml,
3.96 mmol) in dry N,N-dimethylformamide (DMF, 5 ml) was
added dropwise to a solution of 4 (520 mg, 0.33 mmol),
benzotriazol-1-yloxytris(dimethylamino)phosphonium hexaflu-
orophosphate (BOP, 1.76 g, 3.96 mmol), and triethylamine
(0.37 ml, 2.64 mmol) in dry DMF (3 mL) under nitrogen at room
temperature. The resulting mixture was stirred for 12 h at room
temperature. EtOAc (100 ml) was added to the reaction mixture,
and the mixture was then washed with 10% aqueous citric acid
(25 ml), saturated aqueous sodium chloride (25 ml) and 5%
aqueous sodium hydrogen carbonate (25 ml), in that order. After
being dried (MgSO4), the solution was evaporated to dryness
under reduced pressure. The residue was chromatographed on
a column of silica gel (SiO2) with EtOAc–hexane (5 : 2 v/v) as
eluent. The product fraction was evaporated to dryness under
Experimental
General analyses and measurements
Elemental analyses were performed at the Microanalysis Center
of Kyushu University. IR spectra were recorded on a Perkin–
reduced pressure to give a white solid (0.4 g, 41%): mmax (film) 1681
−1
=
(amide C O) cm ; dH (400 MHz, CDCl3, Me4Si) 0.81 (12H, m,
1
Elmer Spectrum One spectrometer, H and 13C NMR spectra
CH2CH3), 1.2 [104H, m, CH2(CH2)9CH3, NHCH2CH2(CH2)2],
1.3–1.4 [72H, s C(CH3)3], 1.73 [8H, m, 4H, CH2(CH2)9CH3],
2.8–2.9 (16H, m, CH2CONHCH2CH2), 3.0 [16H, m,
CH2CONH(CH2)4CH2], 3.1 [32H, m, CH2CONH(CH2)5CH2,
CH2CONHCH2(CH2)6], 4.25 (16H, s, OCH2CO), 4.66 (4H,
m, CHAr), 6.37 (4H, s, Ar–H2), 6.56 (4H, s, Ar–H5),
6.7 and 7.5 (16H, m, NH); dC (125 MHz, CDCl3, Me4Si)
15.9 ((CH2)10CH3), 24.4 ((CH2)10CH2CH3), 28.4 (CH), 30.3
(C(CH3)3), 31.4, 31.6 ((CH2)6CH2CH3, OCONHCH2(CH2)4),
31.9 (CHCH2CH2CH2), 33.7 (CHCH2CH2), 37.5 (CHCH2),
40.9 (OCONHCH2), 42.2 (OCONH(CH2)5CH2), 71.0 (OCH2),
80.7 (C(CH3)3), 100 (Ar–C2), 128.3, 129.4 (Ar–C4,5,6),
156.0 (CO), 157.9 (Ar–C1,3), 169.6 (CO). Anal. Calcd. for
C176H304N16O32·H2O: C, 66.59; H, 9.72; N, 7.06. Found: C,
66.58; H, 9.63; N, 7.16. MALDI-TOF (positive mode, matrix:
dithranol): m/z calcd. for C170H304N16O32Na: 3179.4. Found:
3180.0 [M + Na]+. MS (FAB) m/z calcd. for C176H304N16O32Na:
3179.4. Found: 3178.6 [M + Na]+.
were taken on a Bruker DRX 600 spectrometer. Circular dichro-
ism spectra were run on a JASCO J-500C spectropolarimeter,
while a JEOL JMS-HX110A spectrometer and an Applied
Biosystems Voyager were used for FAB and MALDI-TOF mass
spectrometry, respectively.
Resorcinarene octaester (3)
A mixture of potassium carbonate (3.1 g, 22 mmol), tert-butyl
bromoacetate (4.4 g, 22 mmol), resorcinarene2 (1.0 g, 0.9 mmol),
and dry acetone (100 ml) was refluxed for 16 h and cooled
to room temperature. An insoluble material was removed by
filtration, and the filtrate evaporated to dryness under reduced
pressure. The residue was chromatographed on a column of silica
gel (SiO2) with EtOAc–hexane (1 : 1 v/v) as eluent. The product
fraction was evaporated to dryness under reduced pressure to
give a pale yellow oil (1.8 g, 55%): dH (400 MHz, CDCl3, Me4Si)
0.85 (12H, m, CH2CH3), 1.2–1.3 [72H, m, CH2(CH2)9CH3],
1.4 [72H, s, C(CH3)3], 1.83 [8H, m, 4H, CH2(CH2)9CH3], 4.1
(16H, s, OCH2CO), 4.57 (4H, t, J = 7.2, CH-Ar), 6.19 (4H, s,
Ar–H2), 6.58 (4H, s, Ar–H5); dC (125 MHz, CDCl3, Me4Si) 14.50
((CH2)10CH3), 23.1 ((CH2)10CH2CH3), 28.4 (C(CH3)3, CH), 30.2
((CH2)6CH2CH3)), 32.3 (CHCH2CH2CH2), 34.9 (CHCH2CH2),
36.1 (CHCH2), 68.3 (C(CH3)3), 69.1 (OCH2), 100.2 (Ar–C2),
127.0 (Ar–C4,6), 128.5 (Ar–C5), 154.9 (Ar–C1,3), 168.9 (CO).
Anal. Calcd. for C120H192O24: C, 71.39; H, 9.56. Found: C, 71.35;
H, 9.56. MALDI-TOF (positive mode, matrix: dithranol): m/z
calcd. for C120H192O24Na: 2041.8. Found: 2040.7 [M + Na]+. MS
(FAB) m/z calcd. for C120H193O24: 2019.8. Found: 2018.3 [M +
H]+.
Resorcinarene octaamine having a hexyl spacer (7)
Trifluoroacetic acid (4 mL) was added to a solution of 5
(400 mg, 0.13 mmol) in dichloromethane (5 mL), and the
mixture stirred for 2 h at room temperature. After the sol-
vent was evaporated off under reduced pressure to give a
white solid (430 mg, quantitative): dH (400 MHz, CD3OD,
Me4Si) 0.8 (12H, m, CH2CH3), 1.2 [104H, m, CH2(CH2)9CH3,
NHCH2CH2(CH2)2], 1.4–1.5 (16H, m, CH2CONHCH2CH2),
1.5–1.6 [16H, m, CH2CONH(CH2)4CH2], 1.79 [8H, m, 4H,
CH2(CH2)9CH3], 2.8 (16H, m, CH2NH3), 3.1–3.3 (16H, m,
CH2CONHCH2), 4.2 (16H, s, OCH2CO), 4.66 (4H, t, J = 7.2,
CHAr), 6.42 (4H, s, Ar–H2), 6.70 (4H, s, Ar–H5); dC (125 MHz,
CD3OD, Me4Si) 13.5 ((CH2)10CH3), 22.8 ((CH2)10CH2CH3),
26.1 (CH), 29.9 ((CH2)6CH2CH3, OCONHCH2(CH2)4), 32.1
(CHCH2CH2CH2), 35.0 (CHCH2CH2), 36.1 (CHCH2), 39.1
(OCONHCH2), 39.6 (OCONH(CH2)5CH2), 68.9 (OCH2), 114
(Ar–C2), 116 (Ar–C5), 122 (Ar–C4,6), 154.6 (Ar–C1,3), 169.7
(CO). MALDI-TOF (positive mode, matrix: dithranol): m/z
calcd. for C136H24N16O16: 2356.5. Found: 2655.6 [M + H]+. MS
Resorcinarene octaacid (4)
Trifluoroacetic acid (5 mL) was added to a dichloromethane
(5 mL) solution of 3 (390 mg, 0.19 mmol), and the mixture
was stirred for 2 h at room temperature. The solvent was then
evaporated off under reduced pressure to give a white solid
−1
=
(290 mg, quantitative): mmax (film) 1717 (acid C O) cm ; dH
(400 MHz, CD3OD, Me4Si) 0.82 (12H, m, CH2CH3), 1.1–1.2
6 5 8
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 6 5 4 – 6 6 0

View Article Online
(FAB) m/z calcd. for C136H241N16O16: 2356.5. Found: 2355.6
[M + H]+.
CH2CH3), 1.2 [200H, m, CH2(CH2)9CH3, NHCH2CH2(CH2)8],
1.3–1.4 [72H, s, C(CH3)3], 1.73 [8H, m, 4H, CH2(CH2)9CH3],
2.8–2.9 (16H, m, CH2CONHCH2CH2), 3.0 [16H, m,
CH2CONH(CH2)8CH2], 3.1 [16H, m, CH2CONH(CH2)8CH2],
4.25 (16H, s, OCH2CO), 4.66 (4H, t, J = 6.8, CHAr), 6.37 (4H, s,
Ar–H2), 6.56 (4H, s, Ar–H5). Anal. Calcd. for C244H400N16O32:
C, 70.25; H, 10.53 N, 5.85. Found: C, 70.17; H, 10.28. N, 5.61.
MALDI-TOF (positive mode, matrix: dithranol): m/z calcd. for
C244H400N16O32K: 3868.8. Found: 3862.1 [M + K]+.
Resorcinarene bearing (R)-methylbenzylurea residues (1-R)
(R)-a-Methylbenzyl isocyanate (78 mg, 0.53 mmol) and tri-
ethylamine (0.10 ml, 0.7 mmol) were added to compound 6
(140 mg, 0.04 mmol) dissolved in dry dichloromethane (10 mL),
and the mixture was stirred for 12 h at room temperature.
After the solvent was evaporated to dryness under reduced
pressure, the residue was chromatographed on a column of
silica gel (SiO2) with chloroform–methanol (9 : 1 v/v) as
eluent. The product fraction was evaporated to dryness un-
Resorcinarene octaamine having an undecyl spacer (8)
This compound was prepared by reaction of 7 with tri-
fluoroacetic acid in a manner similar to that applied to
the synthesis of 6 to give a white solid (380 mg, quan-
titative): dH (400 MHz, CD3OD, Me4Si) 0.8 (12H, m,
CH2CH3), 1.2 [200H, m, CH2(CH2)9CH3, NHCH2CH2(CH2)8],
1.4–1.5 (16H, m, CH2CONHCH2CH2), 1.5–1.6 [16H, m,
CH2CONH(CH2)10CH2], 1.79 [8H, m, 4H, CH2(CH2)9CH3],
2.8 (16H, m, CH2NH3), 3.1–3.3 (16H, m, CH2CONHCH2), 4.2
(16H, s, OCH2CO), 4.66 (4H, t, J = 6.8, CHAr), 6.42 (4H, s,
Ar–H2), 6.70 (4H, s, Ar–H5).
der reduced pressure to give a white solid (83 mg, 56%):
−1
=
mmax (FT-IR) 1658 (C O), 1565 (NH) cm ; dH (600 MHz,
CDCl3, Me4Si) 0.86 (12H, m, CH2CH3), 1.23–1.28 [104H,
m, CH2(CH2)9CH3, NHCH2CH2(CH2)2], 1.3–1.4 [56H, m,
CH2CONHCH2CH2, CH2CONH(CH2)4CH2, CH3CH], 1.75
[8H, m, 4H, CH2(CH2)9CH3], 2.0 (8H, m, CH3CH), 3.0 (16H,
m, CH2CONHCH2), 3.2 (16H, m, CH2CONH(CH2)5CH2),
4.46, 4.81, 5.7–6.4 (36H, m, OCH2CO, CH-Ar, NHCONH),
7.15, 7.2 (48H, m, Ar–H); dC (125 MHz, CDCl3, Me4Si)
14.1 ((CH2)10CH3), 22.7 ((CH2)10CH2CH3), 23.4 (CHCH3), 26.5
(CH), 28.8–30.2 ((CH2)6CH2CH3), OCONHCH2(CH2)4), 31.9
(CHCH2CH2CH2), 34.4 (CHCH2CH2), 36.5 (CHCH2), 39.1
(OCONHCH2), 39.7 (OCONH(CH2)5CH2), 49.5 (CHCH3),
68.5 (OCH2), 125.8, 126.8, 128.4, 145.0 (Ph), 129.9 (Ar–
C2), 152.8 (Ar–C5), 155.1 (Ar–C1,3), 158.4, 168.0 (CO).
MALDI-TOF (positive mode, matrix: dithranol): m/z calcd. for
C208H312N24O24Na: 3555.8. Found: 3559.5 [M + Na]+. MS (FAB)
m/z calcd. for C208H313N24O24: 3533.9. Found: 3533.0 [M + H]+.
Anal. Calcd. for C208H312N24O24·3H2O: C, 69.55; H, 8.94; N,
9.37%. Found: C, 69.68; H, 8.86; N, 8.99%.
Resorcinarene bearing (R)-methylbenzylurea residues (9-R)
This compound was prepared by reaction of 8 with (R)-a-
methylbenzyl isocyanate in a manner similar to that applied
to the synthesis of 1-R. The crude product was purified by
silica gel chromatography with chloroform-methanol (9 : 1 v/v)
as eluent. The product fraction was evaporated to dryness
under reduced pressure to give a white solid (130 mg, 65%):
−1
=
mmax (FT-IR) 1667 (C O), 1561 (NH) cm ; dH (400 MHz,
CDCl3, Me4Si) 0.83 (12H, m, CH2CH3), 1.17–1.24 [200H,
m, CH2(CH2)9CH3, NHCH2CH2(CH2)8], 1.3–1.4 [56H, m,
CH2CONHCH2CH2, CH2CONH(CH2)10CH2, CH3CH], 1.91
[8H, m, 4H, CH2(CH2)9CH3], 2.0 (8H, m, CH3CH), 3.0 (16H,
m, CH2CONHCH2), 3.2 (16H, m, CH2CONH(CH2)11CH2),
4.42, 4.76, 6.8 (36H, m, OCH2CO, CHAr, NHCONH),
7.1–7.2 (48H, m, Ar–H); dC (125 MHz, CDCl3, Me4Si)
14.5 ((CH2)10CH3), 23.1 ((CH2)10CH2CH3), 23.8 (CHCH3),
27.4 (CH), 29.9 ((CH2)6CH2CH3), OCONHCH2(CH2)4), 32.3
(CHCH2CH2CH2), 35.0 (CHCH2CH2), 37.5 (CHCH2), 39.8
(OCONHCH2), 40.7 (OCONH(CH2)5CH2), 50.2 (CHCH3),
69.0 (OCH2), 126.3, 127.4, 128.9, 140 (Ph), 128 (Ar–C2), 151,
154 (Ar–C5), 154.2 (Ar–C1,3), 157.6, 167.2 (CO). MS (FAB)
m/z calcd. for C256H409N24O24: 4207.1. Found: 4205.9 [M + H]+.
Anal. Calcd. for C256H408N24O24 · H2O: C, 72.76; H, 9.75; N,
7.99%. Found: C, 72.70; H, 9.64; N, 7.75%.
Resorcinarene bearing (S)-methylbenzylurea residues (1-S)
This compound was prepared by reaction of 6 with (S)-a-
methylbenzyl isocyanate in a manner similar to that applied
to the synthesis of 1-R. The crude product was purified by
silica gel chromatography with chloroform–methanol (9 : 1 v/v)
as eluent. The product fraction was evaporated to dryness
under reduced pressure to give a white solid (69 mg, 46%):
mmax (FT-IR) 1658 (C(O), 1565 (NH) cm−1; dH (600 MHz,
CDCl3, Me4Si) 0.86 (12H, m, CH2CH3), 1.23–1.28 [104H,
m, CH2(CH2)9CH3, NHCH2CH2(CH2)2], 1.3–1.4 [56H, m,
CH2CONHCH2CH2, CH2CONH(CH2)4CH2, CH3CH], 1.75
[8H, m, 4H, CH2(CH2)9CH3], 2.0 (8H, m, CH3CH), 3.0 (16H,
m, CH2CONHCH2), 3.2 (16H, m, CH2CONH(CH2)5CH2),
4.46, 4.81, 5.7–6.4 (36H, m, OCH2CO, CHAr, NHCONH),
7.15, 7.2 (48H, m, Ar–H); dC (125 MHz, DMSO-d6, Me4Si)
13.2 ((CH2)10CH3), 21.8 ((CH2)10CH2CH3), 22.5 (CHCH3), 25.6
(CH), 28.5–29.9 ((CH2)6CH2CH3), OCONHCH2(CH2)4), 31.0
(CHCH2CH2CH2), 33.5 (CHCH2CH2), 35.6 (CHCH2), 38.2
(OCONHCH2), 38.9 (OCONH(CH2)5CH2), 48.6 (CHCH3),
67.8 (OCH2), 124.9, 125.9, 127.5, 144.2 (Ph), 129.0 (Ar–
C2), 151.9 (Ar–C5), 154.2 (Ar–C1,3), 157.6, 167.2 (CO).
MALDI-TOF (positive mode, matrix: dithranol): m/z calcd. for
C208H312N24O24Na: 3555.8. Found: 3563.9. [M + Na]+ MS (FAB)
m/z calcd. for C208H313N24O24: 3533.9. Found: 3532.8 [M + H]+.
Anal. Calcd. for C208H312N24O24·3H2O: C, 69.65; H, 8.94; N,
9.37%. Found: C, 69.81; H, 8.80; N, 9.12%.
Resorcinarene bearing (S)-methylbenzylurea residues (9-S)
This compound was prepared by reaction of 8 with (R)-a-
methylbenzyl isocyanate in a manner similar to that applied
to the synthesis of 1-S. The crude product was purified by
silica gel chromatography with chloroform–methanol (9 : 1 v/v)
as eluent. The product fraction was evaporated to dryness
under reduced pressure to give a white solid (200 mg, 98%):
−1
=
mmax (FT-IR) 1667 (C O), 1561 (NH) cm ; dH (400 MHz,
CDCl3, Me4Si) 0.83 (12H, m, CH2CH3), 1.17–1.24 [200H,
m, CH2(CH2)9CH3, NHCH2CH2(CH2)8], 1.3–1.4 [56H, m,
CH2CONHCH2CH2, CH2CONH(CH2)10CH2, CH3CH], 1.91
[8H, m, 4H, CH2(CH2)9CH3], 2.0 (8H, m, CH3CH), 3.0 (16H,
m, CH2CONHCH2), 3.2 (16H, m, CH2CONH(CH2)11CH2),
4.42, 4.76, 6.8 (36H, m, OCH2CO, CHAr, NHCONH),
7.1–7.2 (48H, m, Ar–H); dC (125 MHz, CDCl3, Me4Si)
14.5 ((CH2)10CH3), 23.1 ((CH2)10CH2CH3), 23.8 (CHCH3),
27.4 (CH), 29.9 ((CH2)6CH2CH3), OCONHCH2(CH2)4), 32.3
(CHCH2CH2CH2), 35.0 (CHCH2CH2), 37.5 (CHCH2), 39.8
(OCONHCH2), 40.6 (OCONH(CH2)5CH2), 51.0 (CHCH3),
66.1 (OCH2), 126.2, 127.3, 128.9, 145 (Ph), 128 (Ar–C2), 156,
154 (Ar–C5), 156.2 (Ar–C1,3), 158.7, 168.1 (CO). Anal. Calcd.
Resorcinarene octaBoc-amine having an undecyl spacer (6)
This compound was prepared by reaction of 4 with N-1-tert-
butoxycarbonyl-1,6-diaminododecane hydrochloride in a man-
ner similar to that applied to the synthesis of 5. The crude
product was purified by silica gel chromatography with EtOAc–
hexane (5 : 2 v/v) as eluent. The product fraction was evapo-
rated to dryness under reduced pressure to give a white solid
(840 mg, 78%): dH (400 MHz, CDCl3, Me4Si) 0.81 (12H, m,
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 6 5 4 – 6 6 0
6 5 9

View Article Online
for C256H408N24O24·2H2O: C, 72.45; H, 9.75; N, 7.95%. Found:
Int. Ed. Engl., 1995, 34, 713; (d) P. Timmerman, W. Verboom and
D. N. Reinhoudt, Tetrahedron, 1996, 52, 2663.
3 A. Shivanyuk, K. Rissanen, S. Ko¨rner, D. M. Rudkevich and J.
Rebek, Jr., Helv. Chim. Acta, 2000, 83, 1778.
C, 72.36; H, 9.64; N, 7.69%.
Mono-urea derivative bearing (S)-methylbenzylurea residues
(10-S)
4 (a) B. Botta, G. D. Monache, P. Salvatore, F. Gasparrini, C. Villani,
M. Botta, F. Corelli, A. Tafi, E. Gace-Baitz, A. Santini, C. F. Carvlho
and D. Misiti, J. Org. Chem., 1997, 62, 932; (b) P. T. Lewis, C. J. Davis,
M. C. Saraiva, W. D. Treleaven, T. D. McCarley and R. M. Strongin,
J. Org. Chem., 1997, 62, 6110; (c) P. C. B. Page, H. Heaney and E. P.
Sampler, J. Am. Chem. Soc., 1999, 121, 6751; (d) S. Saito, C. Nuckolls
and J. Rebek, Jr., J. Am. Chem. Soc., 2000, 122, 9628; (e) B. Botta,
M. Botta, A. Filippi, A. Tafi, G. D. Monache and M. Speranza,
J. Am. Chem. Soc., 2002, 124, 7658; (f) P. C. B. Page, H. Heaney,
M. J. McGrath, E. P. Sampler and R. F. Wilkins, Tetrahedron Lett.,
2003, 44, 2965; (g) J. Y. Boxhall, P. C. B. Page, M. R. J. Elsegood, Y.
Chan, H. Heaney, K. E. Holmes and M. J. McGrath, Synlett, 2003,
1002.
5 K. H. Choi and A. D. Hamilton, Coord. Chem. Rev., 2003, 240, 101.
6 (a) R. K. Castellano, C. Nuckolls and J. Rebek, Jr., J. Am. Chem. Soc.,
1999, 121, 11156; (b) Y. L. Cho, D. M. Rudkevich, A. Shivanyuk, K.
Rissanen and J. Rebek, Jr., Chem. Eur. J., 2000, 6, 3788.
7 Preliminary communication: O. Hayashida, J. Ito, S. Matsumoto and
I. Hamachi, Chem. Lett., 2004, 33, 994.
This compound was prepared by using 4-hexylphenol in
place of 2 in a manner similar to that applied to the
synthesis of 1-S. The crude product was purified by silica
gel chromatography with chloroform–methanol (9 : 1 v/v)
as eluent. The product fraction was evaporated to dryness
under reduced pressure to give a white solid (12 mg, 7%):
−1
=
mmax (FT-IR) 1668 (C O), 1554 (NH) cm ; dH (400 MHz,
CDCl3, Me4Si) 0.84–0.87 (3H, t, J = 12, CH2CH3), 1.0–1.4
[10H, m, CH2(CH2)3CH3, NHCH2CH2(CH2)2, CH3CH], 1.4–
1.5 [47H, m, CH2CONHCH2CH2(CH2)2CH2], 1.5–1.6 (2H, m,
CH3(CH2)3CH2), 2.6 (2H, t, J = 16, CH3(CH2)4CH2), 3.0–3.2
(2H, m, CH2CONHCH2), 3.3 (2H, m, CH2CONH(CH2)5CH2),
4.4 (2H, s, OCH2CO), 4.7–4.8 (2H, m, urea NH), 6.6 (1H,
m, amide NH), 6.8–7.1 (4H, m, CH2ArO), 7.4 (5H, m,
ArCHCH3); dC (125 MHz, CDCl3, Me4Si) 14.5 ((CH2)5CH3),
23.6 ((CH2)4CH2CH3), 24.5 (CHCH3), 29.8 ((CH2)2CH2CH3),
OCONHCH2(CH2)4), 32.7 (ArCH2CH2), 36.1 (ArCH2), 39.5,
40.8 (OCONHCH2, OCONH(CH2)5CH2), 51.3 (CHCH3), 68.5
(OCH2), 115.5 (Ar–C2,6), 126.7, 128.3, 129.7, 130.6, 145.3 (Ph,
Ar–C3,5), 137.7 (Ar–C4), 156.2 (Ar–C1), 158.7, 169.5 (CO).
MS (HI) m/z calcd. for C29H44N3O3: 481.7. Found: 482.3 [M +
H]+. Anal. Calcd. for C29H44N3O3: C, 72.31; H, 9.00; N, 8.72%.
Found: C, 72.19; H, 8.87; N, 9.09%.
8 Optimized using MM2 force fields: P. Aped and N. L. Allinger, J. Am.
Chem. Soc., 1992, 114, 1.
9 (a) F. S. Schoonbeek, J. H. van Esch, R. Hulst, R. M. Kellogg and
B. L. Feringa, Chem. Eur. J., 2000, 6, 2633; (b) J. Brinksma, B. L.
Feringa, K. L. Kellogg, R. Vreeker and J. van Esch, Langmuir, 2000,
16, 9249; (c) M. de Loos, J. van Esch, R. M. Kellogg and B. L.
Feringa, Angew. Chem., Int. Ed., 2001, 40, 613; (d) B. Moulton and
M. J. Zaworotko, Chem. Rev., 2001, 101, 1629.
10 At a concentration of 10 mM, 10-S exists in a monomeric state as
confirmed by the Beer’s plot.
11 T. Kobayashi and T. Seki, Langmuir, 2003, 19, 9297.
12 The extent of conformational enantiomer excess was not obvious
because of the broadened NMR spectra of 1-R and 1-S due to rapid
interconversions on the NMR timescale.
13 (a) F. C. Tucci, D. M. Rudkevich and J. Rebek, Jr., Chem. Eur. J.,
2000, 6, 1007; (b) S. D. Starnes, D. M. Rudkevich and J. Rebek, Jr.,
J. Am. Chem. Soc., 2001, 123, 4659; (c) U. Lucking, J. Chen, D. M.
Rudkevich and J. Rebek, Jr., J. Am. Chem. Soc., 2001, 123, 9929;
(d) V. A. Azov, P. J. Skinner, Y. Yamakoshi, P. Seiler, V. Gramlich and
F. Diederich, Helv. Chim. Acta, 2003, 86, 3648.
Acknowledgements
This is partially supported by Tokuyama Science Foundation.
References
1 (a) D. M. Rudkevich, G. Hilmersson and J. Rebek, Jr., J. Am. Chem.
Soc., 1998, 120, 12216; (b) J. W. M. Nissink, H. Boerrigter, W.
Verboom, D. N. Reinhoudt and J. H. van der Maas, J. Chem. Soc.,
Perkin Trans. 2, 1998, 2541; (c) D. M. Rudkevich and J. Rebek, Jr.,
Eur. J. Org. Chem., 1999, 1991; (d) T. Haino, D. M. Rudkevich, A.
Shivanyuk, K. Rissanen and J. Rebek, Jr., Chem. Eur. J., 2000, 6,
3797; (e) U. Lu¨cking, F. C. Tucci, D. M. Rudkevich and J. Rebek, Jr.,
J. Am. Chem. Soc., 2000, 122, 8880.
14 (a) B. Hinzen, P. Seiler and F. Diederich, Helv. Chim. Acta, 1996,
79, 942; (b) J. L. Sessler and A. Andrievsky, Chem. Eur. J., 1998, 4,
159; (c) S. Allenmark, Chirality, 2003, 15, 409; (d) E. Engeldinger, D.
Armspach and D. Matt, Chem. Rev., 2003, 103, 4147.
15 R. Glen, Chem. Commun., 2002, 2745.
16 (a) T. H. Webb and C. S. Wilcox, Chem. Soc. Rev., 1993, 22, 383;
(b) M. C. Feiters, A. E. Rowan and R. J. M. Nolte, Chem. Soc. Rev.,
2000, 29, 375; (c) L. R. Nassimbeni, Acc. Chem. Res., 2003, 36, 631.
2 (a) A. G. S. Ho¨gberg, J. Am. Chem. Soc., 1980, 102, 6046; (b) A. G. S.
Ho¨gberg, J. Org. Chem., 1980, 45, 4498; (c) V. Bo¨hmer, Angew. Chem.,
6 6 0
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 6 5 4 – 6 6 0