Synthesis and Hierarchical Self-Assembly of Cavity-Containing Facial Amphiphiles

Article abstract of DOI:10.1021/jo035130f

The synthesis and aggregation behavior of cavity-containing facial amphiphiles is described. The molecules consist of a glycoluril-based rigid cavity functionalized with two water-soluble benzoate groups. By specific molecular recognition processes in water, the amphiphilic hosts self-assemble in a hierarchical process to form arrays of molecules. Depending on the counterions, these arrays can be assembled into well-defined aggregates of mesoscopic size. The size and shape of the aggregates can be tuned by variations in the size and substitution pattern of the cavities of the host molecules.

Full text of DOI:10.1021/jo035130f

Syn th esis a n d Hier a r ch ica l Self-Assem bly of Ca vity-Con ta in in g
F a cia l Am p h ip h iles
J ohannes A. A. W. Elemans,* Ralf R. J . Slangen, Alan E. Rowan, and Roeland J . M. Nolte
Department of Organic Chemistry, NSRIM institute, University of Nijmegen, Toernooiveld,
6525 ED Nijmegen, The Netherlands
jelemans@sci.kun.nl
Received J uly 31, 2003
The synthesis and aggregation behavior of cavity-containing facial amphiphiles is described. The
molecules consist of a glycoluril-based rigid cavity functionalized with two water-soluble benzoate
groups. By specific molecular recognition processes in water, the amphiphilic hosts self-assemble
in a hierarchical process to form arrays of molecules. Depending on the counterions, these arrays
can be assembled into well-defined aggregates of mesoscopic size. The size and shape of the
aggregates can be tuned by variations in the size and substitution pattern of the cavities of the
host molecules.
In tr od u ction
known that exhibit this facial amphiphilicity. They bind
to membrane interfaces in order to target peptide se-
quences to membrane-bound receptors.5 These am-
phiphiles can also cause membrane fusion6 and make
membranes permeable.7 In particular Gellman and co-
workers have carried out considerable work on determin-
ing the factors that govern the self-association of these
types of molecules in water8 and on the ability of the
aggregates to include hydrophobic fluorescent probes.
However, no aggregate morphology studies of facial
amphiphiles have been reported so far. It is, therefore,
of general interest to investigate whether these molecules
are able to form mesoscopic architectures and, in par-
ticular, if their unusual topology can be expressed in a
unique morphology of their aggregates.
Recent work in our group has revealed that host
molecules based on glycoluril with water-soluble pyri-
dinium groups at their convex side can self-assemble to
form well-defined “razorblade-like” aggregates in water.9
Related hosts with ruthenium-bipyridine groups were
found to form rectangular aggregates, which, in a second
level of organization self-assembled into “cigar-like”
structures.10 A major driving force for the self-assembly
of these types of molecules into nanosized structures is
the formation of dimers, in which one cavity side-wall of
a host is buried in the cavity of its dimeric partner and
vice versa. As an extension of this work we describe in
Amphiphilic molecules are essential in the mainte-
nance and function of biological systems, and most of the
synthetic amphiphiles that have been studied to mimic
these natural systems have the same type of topology: a
compact, polar headgroup, to which one or more long
hydrophobic hydrocarbon chains are attached.1 As a
result of this topology, amphiphiles readily aggregate in
aqueous solutions, in which they expose their headgroups
to the water and dehydrate their tails by clustering them
together into a hydrophobic environment. Depending on
the nature of the headgroup and the number and length
of the hydrocarbon tails, the morphology of the supramo-
lecular aggregate that is formed can be in many cases
rationally correlated to the topology of the amphiphile.2
Although these amphiphiles of the “classical type” have
received much attention over the past few decades, there
recently appears to be increasing interest in the develop-
ment of amphiphiles with a strongly deviating topology.3
Kahne et al. were the first to introduce the term “facial
amphiphilic” molecules, which are defined as molecules
with rigid structures containing separated hydrophilic
and hydrophobic “faces”.4 In Nature, helical peptides are
(1) Fendler, J . H. Membrane Mimetic Chemistry; J ohn Wiley &
Sons: New York, 1982.
(2) Israelachvili, J . N.; Marcelja, S.; Horn, R. G. Q. Rev. Biophys.
1980, 13, 121.
(3) (a) Nakashima, N.; Asakuma, S.; Kunitake, T. J . Am. Chem. Soc.
1985, 107, 509. (b) Nusselder, J .-J . H.; Engberts, J . B. F. N. J . Am.
Chem. Soc. 1989, 111, 5000. (c) Mun˜oz, S.; Gokel, G. W. J . Am. Chem.
Soc. 1993, 115, 4899. (d) Menger, F. M.; Littau, C. A. J . Am. Chem.
Soc. 1993, 115, 10083. (e) Venkatesan, P.; Cheng, Y.; Kahne, D. J .
Am. Chem. Soc. 1994, 116, 6955. (f) J anout, V.; Lanier, M.; Regen, S.
L. J . Am. Chem. Soc. 1997, 119, 640. (g) Broderick, S.; Davis, A. P.;
Williams, R. P. Tetrahedron Lett. 1998, 39, 6083. (h) Nguyen, J . Q.;
Iverson, B. L. J . Am. Chem. Soc. 1999, 121, 2639. (i) Shawaphun, S.;
J anout, V.; Regen, S. L. J . Am. Chem. Soc. 1999, 121, 5860. (j)
Vandenburg, Y. R.; Smith, B. D.; Pe´rez-Paya´n, M. N.; Davis, A. P. J .
Am. Chem. Soc. 2000, 122, 3252. (k) J anout, V.; J ing, B. W.; Staina, I.
V.; Regen, S. L. J . Am. Chem. Soc. 2003, 125, 4436.
(5) Kaiser, E. T.; Kezdy, F. J . Science 1984, 223, 249.
(6) Takahashi, S. Biochemistry 1990, 29, 6257.
(7) Lear, J . D.; Wasserman, Z. R.; DeGrado, W. F. Science 1988,
240, 1177.
(8) (a) Stein, T. M.; Gellman, S. H. J . Am. Chem. Soc. 1992, 114,
3943. (b) McQuade, D. T.; Barrett, D. G.; Desper, J . M.; Hayashi, R.
K.; Gellman, S. H. J . Am. Chem. Soc. 1995, 117, 4862. (c) McQuade,
D. T.; Quinn, M. A.; Yu, S. M.; Polans, A. S.; Krebs, M. P.; Gellman, S.
H. Angew. Chem., Int. Ed. 2000, 39, 758.
(9) Reek, J . N. H.; Kros, A.; Nolte, R. J . M. Chem. Commun. 1996,
245.
(10) (a) Elemans, J . A. A. W.; de Gelder, R.; Rowan, A. E.; Nolte R.
J . M. Chem. Commun. 1998, 1553. (b) Elemans, J . A. A. W.; Rowan,
A. E.; Nolte, R. J . M. J . Am. Chem. Soc. 2002, 124, 1532.
(4) Cheng, Y.; Ho, D. M.; Gottlieb, C. R.; Kahne, D.; Bruck, M. A.;
J . Am. Chem. Soc. 1992, 114, 7319.
10.1021/jo035130f CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/23/2003
9040
J . Org. Chem. 2003, 68, 9040-9049

Cavity-Containing Facial Amphiphiles
CHART 1
CHART 2
this paper the synthesis and self-assembling properties
of benzoic acid-functionalized host molecules 1-4 (Chart
1), which vary in cavity size and substitution pattern. It
will be shown that, upon deprotonation of the benzoic acid
groups, these variations in size and substitution pattern,
together with the choice of the counterions, can have a
strong influence on the self-assembling behavior of the
molecules in water.11
Resu lts a n d Discu ssion
Syn th esis. As starting material for the synthesis of
the benzoic acid-functionalized host molecules, cyclic
ether 5 was used, which was synthesized by a reaction
of ditoluylglycoluril12 with paraformaldehyde (Chart 2).
Its aromatic methyl groups were oxidized with KMnO4
in water to give the dibenzoic acid compound 6 in a yield
of 96%. Ureidoalkylation of 6 with p-dimethoxybenzene
in a mixture of acetic anhydride and trifluoracetic acid
afforded the dibenzoic acid-functionalized host 3 in 81%
yield. This reaction was only completed after 3 days,
which is surprising since the analogous reaction to
synthesize a similar host that has phenyl instead of
benzoic acid groups just took 1 h.13 The low reactivity of
6 is attributed to the relatively slow formation of the
reactive intermediate, which is believed to be a car-
bonium-imonium ion.14 The electron-withdrawing benzoic
acid substituents of 6 apparently disfavor the formation
of this intermediate.
For reaction of 6 with other aromatic molecules, e.g.,
benzene, p-xylene, and 1,4-dimethoxynaphthalene, it was
necessary to replace the relatively stable cyclic ether
groups of 6 by better leaving groups. First, the carboxylic
acid functions of 6 were protected by esterification in
methanol to give dimethyl ester 7 (Chart 2). Apart from
the desired compound, considerable amounts of side-
products were formed in which one or both of the cyclic
ether functions had opened to give compounds with
methyl ether groups. Compound 7, however, could be
easily isolated from this mixture by column chromatog-
raphy (yield 56%). It was also possible to use the crude
product mixture in the following step, which is the acid-
catalyzed acylation with acetic anhydride to give the
tetraacetoxy derivative 8, which was obtained as a single
product (70% yield). This reaction was only completed
after 40 h, which is also a much longer time than was
needed for the analogous reaction in the case of the
diphenylglycoluril-derived compound (3 h). Compound 8
was subsequently treated with thionyl chloride to give
the tetrachloride 9 in 84% yield. This activated compound
was then used in Lewis acid-catalyzed Friedel-Crafts
alkylation reactions with benzene, p-xylene, and 1,4-
dimethoxynaphthalene as substrates to give host mol-
ecules 10, 11, and 13 in yields of 36, 34, and 71%,
respectively, after purification by column chromatogra-
phy. The yields of 10 and 11 are relatively low because
considerable amounts of single-walled host compounds
were present in the reaction mixtures. Prolonged reaction
times and variation of the Lewis acid did not improve
the yields. Host 12 was synthesized directly from cyclic
ether 7 and p-dimethoxybenzene in a similar way as
described for 3.
(11) Part of this work has appeared as a short communication:
Elemans, J . A. A. W.; Slangen, R. R. J .; Rowan, A. E.; Nolte, R. J . M.
J . Incl. Phenom. Macrocycl. Chem. 2001, 41, 65.
(12) Butler, A. R.; Leitch, E. J . Chem. Soc., Perkin Trans. 2 1980,
103.
(13) Sijbesma, R. P.; Nolte, R. J . M. Recl. Trav. Chim. Pays-Bas
1993, 112, 643.
(14) (a) Hellman, H. Angew. Chem. 1957, 69, 463. (b) Zaugg, H. E.
Synthesis 1970, 2, 49. (c) Zaugg, H. E. Synthesis 1984, 16, 85.
Saponification of the methyl ester-protected hosts 10-
13 proceeded smoothly in a mixture of dioxane, methanol,
and aqueous 4 N NaOH (15:4:1, v/v/v),15 affording the
J . Org. Chem, Vol. 68, No. 23, 2003 9041

Elemans et al.
TABLE 1. Dim er iza tion Con sta n ts a n d CIS Va lu es of
Com p ou n d s Na 1-4 in D2O a t 298 K
compound
Kdimer (M-1
)
∆G (kJ /mol)
CIS (ppm)a
Na 1
Na 2
Na 3
Na 4
<5b
b
b
145c
630c
-12.3
-16.0
-23.7
-1.38
-1.29
-1.60
1.45 × 104 d
a
Value calculated for the side-wall protons Ha (see Chart 1).
b
Dimerization was too weak to determine
a reliable value.
c Estimated error ) 10%. Estimated error ) 20%.
d
indicating their fast exchange on the NMR time scale.
Only in the case of Na 4 were the shifting resonances
somewhat broadened at concentrations above 5 mM. The
signals of the side-wall protons Ha (see Chart 1) were
monitored versus the concentration, and the titration
curves thus obtained were fitted to an equation governing
the self-association of two molecules. The calculated
dimerization constants (Kdimer) and the complexation-
induced shift (CIS) values of the shifting proton signals
are summarized in Table 1.
F IGURE 1. X-ray crystal structure of 12 (four molecules, with
four CH2Cl2 solvent molecules included), showing the arrange-
ment of the host molecules in dimers, in which the cavity of
one host is filled by a side-wall of its neighbor and vice versa.
The results show that the dimerization becomes stron-
ger when substituents are introduced at the cavity side-
walls, i.e. when the hydrophobic surface of the cavity
becomes larger.17 Without any substituents, dimerization
is negligible (cf. the Kdimer of Na 1). The extremely strong
dimerization of Na 4 is attributed to the presence of a
large hydrophobic cleft formed by the naphthalene side-
walls. For hosts Na 1-3, the observed trend in dimer-
ization strength is similar to that of related substituted
hosts in chloroform.18 In water, however, the intermo-
lecular interactions are generally much stronger due to
the hydrophobic effect.19 This is further reflected in the
large CIS values of the Ha-protons, which indicate that
the side-walls of the molecules are inserted more deeply
within the cavity of their dimeric partner than in the case
of their chloroform-soluble analogues.18
Although the strength of dimerization of the am-
monium salts NH41-4 could not be determined by
dilution titrations, 1H NMR spectra of low-concentration
solutions of these compounds (<0.2 mM) in water showed
shifts of the cavity side-wall proton signals that were
comparable to those of their sodium salt analogues. This
indicates that in the case of both salts, self-assembly of
the cavities of the molecules occurs.
crude carboxylate disodium salts as precipitates. These
could be dissolved in water, whereupon protonation with
aqueous 37% HCl gave the benzoic acid-functionalized
hosts 1-4 as precipitates in nearly quantitative yields.
The sodium salts of compounds 1-4, Na 1-4, were
prepared by suspension of the former compounds in
demineralized water, to which 2 equiv of sodium hydrox-
ide were added. Upon stirring, the compounds completely
dissolved, whereafter they were lyophilized. The am-
monium salts of 1-4, NH41-4, were prepared by sus-
pension of the former compounds in aqueous ammonia
(30%). Again, the compounds dissolved upon stirring,
whereupon the excess ammonia was evaporated and the
products were lyophilized. The sodium and ammonium
salts turned out to be very hygroscopic and were therefore
stored under nitrogen at -18 °C.
NMR Dilu tion Exp er im en ts. The self-association
properties of the benzoate-functionalized hosts in water
were investigated by 1H NMR dilution studies. There
appeared to be large solubility differences between the
sodium and the ammonium salts of the molecules, i.e.,
the sodium salts were soluble in water up to relatively
high concentrations (>30 mM), whereas the ammonium
salts hardly dissolved at all. For this reason, reliable
NMR dilution titrations could only be carried out on the
F lu or escen ce Dilu tion Exp er im en ts. Due to the
very low solubility of the ammonium salts NH41-4 in
water, their self-association behavior could not be inves-
tigated by NMR techniques, and instead fluorescence
spectroscopy was used. The fluorescence dependence of
NH41 on the concentration of this compound in water is
shown in Figure 2. Upon excitation of the π f π*
transition band of the aromatic rings in the molecule (at
290 nm in the UV-vis spectrum), a broad emission
1
sodium salts. For compounds Na 1-4, H NMR spectra
were recorded of samples of at least 10 different concen-
trations varying between 0.2 and 10 mM. In this con-
centration range, for all compounds, only the signals of
the protons of the cavity side-walls and of their 1,4-
attached substituents displayed significant upfield shifts
(>0.05 ppm). Increasing the temperature or the addition
of acetone caused a decrease in these shifts. The concen-
tration-dependent changes in the NMR spectra are in line
with the formation of dimeric structures. An example of
such a dimeric arrangement is depicted in Figure 1,
which shows the crystal structure16 of host 12.
(16) (a) Holder, S. J .; Elemans, J . A. A. W.; Barbera´, J .; Rowan, A.
E.; Nolte, R. J . M. Chem. Commun. 2000, 355. (b) Holder, S. J .;
Elemans, J . A. A. W.; Donners, J . J . J . M.; Boerakker, M. J .; de Gelder,
R.; Barbera´, J .; Rowan, A. E.; Nolte, R. J . M. J . Org. Chem. 2001, 66,
391.
(17) Similar results have been obtained for dimerization of related
facial amphiphiles in buffered aqueous solution; see: Isaacs, L.; Witt,
D.; Fettinger, J . C. Chem. Commun. 1999, 2549.
In water, for hosts Na 1-4, average signals were
observed for protons in the monomer and the dimer,
(18) Reek, J . N. H.; Elemans, J . A. A. W.; de Gelder, R.; Rowan, A.
E.; Nolte, R. J . M. Tetrahedron 2003, 59, 175.
(15) Tesser, G. I.; Bolvert-Geerts, I. C. Int. J . Pept. Protein Res. 1975,
7, 295.
(19) Tanford, C. In The Hydrophobic Effect, 2nd ed.; Wiley: New
York, 1980.
9042 J . Org. Chem., Vol. 68, No. 23, 2003

Cavity-Containing Facial Amphiphiles
TABLE 2. P r op er ties of th e Aggr ega tes F or m ed by
Am m on iu m Ca r boxyla te Hosts in Wa ter
average
length
(nm)b
average
width
CAC
(M)a
aspect ratio
compound
(nm)b
(length/width)b
NH41
NH42
NH43
NH44
2 × 10-5 200-250
60-80
3.5 ( 1
9 ( 3
25 ( 5
c
5 × 10-7 1500-2500 200-400
3 × 10-7 1500-2500 70-100
2 × 10-8
c
c
a
Critical aggregation constant as determined from the fluores-
b
cence titrations. Determined from the dimensions of 200-300
unique aggregates obtained from various samples. c No well-
defined aggregates were observed.
emission intensity of the maximum increased. The ob-
served concentration and temperature effects on the
fluorescence spectra of NH41 point to the formation of
assemblies, which have their aromatic rings in close
proximity, resulting in their mutual quenching. At
concentrations higher than 5 × 10-4 M-1, scattering
occurs due to the formation of larger aggregates. A
similar fluorescence behavior has been reported for the
self-assembly of bis(phenylglycine) oxalyl amides in
water.21
F IGURE 2. Selected fluorescence emission spectra (λex ) 290
nm) of NH41 in water at concentrations of (a) 10-8, (b) 10-6
(c) 5 × 10-6, (d) 2 × 10-5, and (e) 10-4 M.
,
Concentration-dependent fluorescence studies were
also carried out with compounds NH42-4. In all cases,
the same types of plots of concentration versus fluores-
cence emission were obtained (Figure 3). When the
concentration of the amphiphile was increased, a maxi-
mum and a subsequent minimum in emission were
observed. These maxima and minima shifted to higher
concentration values in the order NH44 < NH43 ) NH42
< NH41, whereas the degree of quenching decreased in
the same order. In addition, the concentration at which
scattering occurred increased. The fluorescence titration
curves thus give a good indication of the self-association
and further aggregation behavior of the ammonium salts
of 1-4. A common approach to determine the critical
aggregation constant (CAC) of a surfactant is the ap-
plication of the “pseudo-phase-separation model”, which
treats the aggregate as a separate phase that is formed
in the solution containing the amphiphile.22 In the case
of the ammonium salts NH41-4, this occurrence of phase
separation coincides with the concentration in the titra-
tion curves where the emission reaches a minimum
(Figure 3). Hence, these values were taken as the CAC
values of the compounds (see Table 2).
Electr on Micr oscop y Stu d ies. To investigate if the
self-association of the benzoate facial amphiphiles would
result in the formation of assemblies on a mesoscopic
scale, solutions and dispersions of the compounds in
water were investigated with the help of transmission
electron microscopy (TEM). None of the sodium salts
were found to form large aggregates, as was already
expected from the samples used for the NMR dilution
studies, which remained clear up to relatively high
concentrations. Even when relatively concentrated samples
(30 mM) of Na 4 (the molecule that dimerized most
strongly) were studied, no nanosized structures were
observed. In contrast to this, the turbid dispersions of
all the ammonium salts in water (0.1% w/v) indicated
F IGURE 3. Fluorescence dilution curves (λem ) 345 nm) of
compounds NH41 (b, solid line), NH42 (O, dashed line), NH43
(9, solid line), and NH44 (+, dashed line) in water at 298 K.
between 300 and 400 nm was observed, the intensity of
which increased until the concentration was raised to
10-6 M-1. A clear drop in intensity was then observed
until a minimum was reached at a concentration of
approximately 2 × 10-5 M-1, whereupon the emission
started to quickly increase again. This increase coincided
with the evolvement of turbidity in the solution. At the
same time, in addition to the emission at ∼345 nm, a
new, longer-wavelength emission in the fluorescence
spectrum became evident. The evolvement of this broad
emission between 400 and 450 nm is attributed to the
formation of excimers. A similar formation of excimers,
although from a different compound, viz., poly-(S)-ty-
rosine, with λem ) 420 nm has been reported in the
literature and has been taken as evidence for the stacking
of p-hydroxyphenyl rings.20 The dilution titration curve
of NH41 (λem ) 345 nm), which is composed from the data
presented in Figure 2, is shown in Figure 3. The
maximum and minimum emission are clearly visible at
concentrations of 10-6 (I ) 300 au) and 2 × 10-5 M (I )
95 au) of NH41, respectively. When the temperature was
increased, this maximum and minimum were found to
shift to higher concentrations, and simultaneously the
(21) J okic´, M.; Makarevic´, J .; Zˇinic´, M. J . Chem. Soc., Chem.
Commun. 1995, 1723.
(20) Lehrer, S. S.; Fasman, G. D. Biopolymers 1964, 2, 199.
(22) Shinoda, K.; Hutchinson, E. J . Phys. Chem. 1962, 66, 577.
J . Org. Chem, Vol. 68, No. 23, 2003 9043

Elemans et al.
Compound NH44 did not form well-defined structures but
rather undefined lumps of material. Electron diffraction
experiments indicated that none of the structures were
crystalline. The typical geometrical features of the ob-
served structures are summarized in Table 2. As can be
seen the length/width aspect ratio increases going from
NH41 to NH42 to NH43. These increases are correlated
to the increase in self-association strength observed from
the fluorescence measurements. The shapes or dimen-
sions of the aggregates were not influenced by changes
in concentration of the amphiphile used.
In fr a r ed Mea su r em en ts. The fact that the am-
monium salts form nanosized aggregates and the sodium
salts do not implies that the ammonium ions in the
former salts play an important role in the self-assembly
process. It is well-known that these ions can form very
strong hydrogen bonds with carboxylate anions.24 They
serve as quadruple hydrogen bond donors, whereas each
of the carboxylate groups in principle can act as multiple
hydrogen bond acceptors due to the presence of five lone
pairs of electrons.25 To investigate the role of this
hydrogen bonding in the self-assembly of the am-
phiphiles, cast films of aqueous dispersions of both the
sodium and ammonium salts were studied by reflectance
infrared spectroscopy. Because of charge delocalization,
carboxylate anions characteristically exhibit a vibration
due to the asymmetrical O-C-O stretching motion
between 1600 and 1550 cm-1 26
Indeed, a vibration at
.
approximately 1605 cm-1 was present in the spectra of
KBr samples of all the sodium salts. In the spectra of
the KBr samples of the ammonium salts, however, this
asymmetrical O-C-O stretching vibration was absent.
Instead, for these compounds a set of superimposed
carbonyl vibrations was present between 1740 and 1660
cm-1. This is an indication that the carboxylate groups
are involved in hydrogen bonding interactions. The N-H
stretching vibrations of the ammonium ions were visible
as a broad, poorly defined, and intense absorption
between 3700 and 2700 cm-1. In the cast films of aqueous
dispersions (0.5%, w/v) of the sodium salts, no significant
shifts in the O-C-O stretching vibrations were observed
when compared to the spectra of these compounds in
KBr. In cast films of aqueous dispersions (0.5%, w/v) of
the ammonium salts, however, the set of superimposed
carbonyl vibrations observed in the KBr samples had
sharpened and split into two distinct vibrations at
approximately 1715 and 1680 cm-1, corresponding to the
urea carbonyl and carboxylate functions, respectively. In
addition, the N-H stretching vibration of the ammonium
ions had narrowed considerably to a stretching vibration
of relatively low intensity at 3160 cm-1. These changes
in the infrared spectrum are an indication that in the
cast films of aqueous dispersions of the ammonium salts,
the hydrogen bonding interactions that are present
between the ammonium ions and the carboxylate groups
F IGURE 4. TEM images of aggregates formed in water by
(a) NH41, (b) NH42, and (c) NH43. All samples are platinum
shadowed.
the presence of large aggregates. The addition of acetone
to these samples led to the formation of clear solutions,
apparently as a result of the dissociation of the as-
semblies.23 TEM studies revealed that compounds NH41-3
indeed formed well-defined aggregates with a uniform,
quasirectangular shape and rounded corners (Figure 4).
(24) (a) Kinbara, K.; Kai, A.; Maekawa, Y.; Hashimoto, Y.; Naruse,
S.; Hasegawa, M.; Saigo, K. J . Chem. Soc., Perkin Trans. 2 1996, 247.
(b) Kinbara, K.; Hashimoto, Y.; Sukegawa, M.; Nohira, H.; Saigo, K.
J . Am. Chem. Soc. 1996, 118, 3441. (c) Kinbara, K.; Kobayashi, Y.;
Saigo, K. J . Chem. Soc., Perkin Trans. 2 2000, 111. (d) Lee, S. B.; Hong,
J .-I. Tetrahedron Lett. 1996, 37, 8501.
(25) Matsumoto, A.; Odani, T.; Chikada, M.; Sada, K.; Miyata, M.
J . Am. Chem. Soc. 1999, 121, 11122.
(23) It is well-known that the addition of acetone or methanol
strongly reduces hydrophobic interactions.
(26) Rao, C. N. R. In Chemical Applications of Infrared Spectroscopy;
Academic Press: New York, 1963.
9044 J . Org. Chem., Vol. 68, No. 23, 2003

Cavity-Containing Facial Amphiphiles
F IGURE 5. Schematic representation of the proposed hierarchical self-assembly of facial amhiphiles NH41-4. (a) Formation of
a dimer. (b) Assembly of dimers in a one-dimensional array. (c) Stitching of bilayers by the NH4+ ions resulting in the formation
of 2D sheets (top view). (d) Stacking of the 2D sheets on top of each other (side-view).
are much better defined than those in the KBr samples
of the freshly prepared compound.
solutes is highly unfavorable unless a cooperative self-
assembly process between molecular in sufficiently large
aggregates occurs. Considering the various possible
interactions, a hierarchical self-assembly27 model for
compounds NH41-4, which accounts for such a coopera-
tive process, is proposed (Figure 5). On the basis of the
1H NMR data, an essential intermolecular interaction is
the “face-to-face” dimerization, in which two receptor
cavities are mutually filled (Figure 5a). In a subsequent
P ow d er Diffr a ction Exp er im en ts. To get more
information about the precise ordering of compounds
NH41-4 in their aggregates, dried samples of dispersions
(0.1%, w/v) of the ammonium carboxylate receptors were
investigated by X-ray powder diffraction. For all the
compounds, a strong reflection, which can be attributed
to a repeating distance of 9.5-9.8 Å, was observed. In
addition to this strong reflection, a series of reflections
of much lower intensity were observed, which makes the
overall interpretation very difficult. It was, however,
evident that the diffractogram of each amphiphile dis-
played reflections at similar 2φ values, which strongly
indicates that the aggregates formed by the ammonium
salts are all isomorphic.
(27) For some recent examples of supramolecular architectures that
are formed by hierarchical self-assembly, see: (a) Wong, G. C. L.; Tang,
J . X.; Lin, A.; Li, Y.; J anmey, P. A.; Safinya, C. R. Science 2000, 288,
2035. (b) Brunsveld, L.; Vekemans, J . A. J . M.; Hirschberg, J . H. K.
K.; Sijbesma, R. P.; Meijer, E. W. Proc. Natl. Acad. Sci. U.S.A. 2002,
99, 4977. (c) Fenniri H.; Deng, B. L.; Ribbe, A. E. J . Am. Chem. Soc.
2002, 124, 11064. (d) Petitjean, A.; Cuccia, L. A.; Lehn, J .-M.;
Nierengarten, H.; Schmutz, M. Angew. Chem., Int. Ed. 2002, 7, 1195.
(e) Elemans, J . A. A. W.; Rowan, A. E.; Nolte, R. J . M. J . Mater. Chem.
2003, in press.
Hier a r ch ica l Self-Assem bly of th e Am p h ip h iles.
In water, the formation of hydrogen bonds between
J . Org. Chem, Vol. 68, No. 23, 2003 9045

Elemans et al.
process, these dimeric units can form long, one-dimen-
sional arrays, in which the hydrophobic aromatic surfaces
of the molecules are minimally exposed to the aqueous
phase and all the hydrophilic carboxylate groups are
directed to the outside. Hence, a bilayer of facial am-
phiphiles results (Figure 5b). Similar bilayer formation
has been observed in the solid state in the case of related
receptors functionalized with long aliphatic tails.16 In a
third process, which in principle can occur simulta-
neously with the growth of the dimeric array, the
ammonium cations can act as a “glue” and stitch the
bilayers together by the formation of hydrogen bonds to
form a 2-dimensional (2D) sheet (Figure 5c). In the case
of Na 1-4, this stitching cannot occur, and hence the self-
assembly process of these molecules stops at the stage
of the dimer or the dimeric array and no aggregates on
a mesoscopic scale are formed. Finally, it is proposed that
the 2D sheets of the ammonium amphiphiles stack on
top of each other to give the aggregates their final
3-dimensional shape.28 Molecular modeling showed that
the thickness of one 2D sheet amounts to approximately
9.2-9.5 Å, a value that corresponds reasonably well with
the strong reflection observed in the powder diffracto-
gram of the ammonium benzoate hosts (d ) 9.5-9.8 Å).
A similar stacking of 2D sheets has been observed before
for other related glycoluril-based hosts.9,16 It is not
unlikely that also the 2D sheets of amphiphiles are
stitched together by the ammonium ions, which can form,
apart from hydrogen bonds between the bilayer arrays,
additional hydrogen bonds between the carboxylate func-
tions in different sheets (Figure 5d).
What is unique about the aggregates formed by NH41-4
is that their growth stops after a certain point, i.e., no
infinite assemblies are formed. This effect has been
observed before for other aggregates of glycoluril-based
receptors in water9,10 and is believed to be governed by a
subtle balance between the enthalpy, i.e., the interaction
strength between the molecules that constitute the
aggregate, and the entropy of the self-assembly process.
After the aggregates have grown to a certain size, the
attachment of new monomers to their water-soluble
exterior will be energetically no longer favorable. Ad-
ditional experiments were carried out with dispersions
of NH41 in water in which the concentrations of the
amphiphile were 0.05% and 0.5% w/v, respectively. In
both cases, TEM studies showed that the formed ag-
gregates had similar sizes as those formed from the 0.1%
w/v dispersions, which strongly suggests that their final
structure is controlled by the thermodynamic equilibri-
um. Another interesting aspect of the aggregates is that
their final shape appears to be dependent on the substi-
tution pattern of the cavity side-walls of the amphiphiles.
This control over shape and size of self-assembled
structures is one of the great challenges of today’s
supramolecular chemistry.29 Calculations have shown
that the substitution pattern of the receptor cavity has
an influence not only on the strength of dimerization but
also on the strength of the π-π interactions between the
external faces of thedimers.18 1,4-Dimethoxy-substituted
side-walled molecules display stronger intermolecular
interactions than 1,4-dimethyl-substituted ones, which
in turn interact more strongly than unsubstituted ben-
zene side-walls. For the ammonium salts NH41-4, these
differences in interaction strength are reflected in the
fluorescence spectra of the compounds, in which the
degree of quenching increases going from NH41 to NH42
and then to NH43. In line with the differences in
interaction strength between the external faces of the
dimers, the dimeric array of molecules of NH43 in water
possibly grows longer than the dimeric array of molecules
of NH42, which in turn grows longer than the array
formed by NH41. If the growth of the dimeric array occurs
in the direction of the long sides of the aggregates (the
x-direction in Figure 5c), this assumption perfectly
explains the differences observed in the lengths of the
aggregates formed by the ammonium compounds. The
other growth processes, i.e., the stitching of the bilayers
in the direction of the short sides of the aggregates (the
y-direction in Figure 5c), and the stacking of the 2D
sheets (the z-direction in Figure 5d), are in competition
with the growth of the dimeric array. In summary, it is
proposed that when the dimerization and subsequent
bilayerlike assembly of the hydrophobic faces of the
molecules become more favorable, the other growth
processes are relatively disfavored, resulting in an in-
crease of the length/width aspect ratio.
Con clu sion
It has been demonstrated that a new series of facial
amphiphiles, i.e., rigid receptor cavities functionalized
with benzoate groups on their convex sides, can form
discrete superstructures on a mesoscopic scale. In water,
the hydrophobic cavities of the molecules form dimeric
structures, which in a subsequent process are proposed
to arrange themselves into bilayerlike arrays in which
the hydrophobic parts of the molecules are maximally
shielded form the aqueous environment. Further growth
of these bilayers into nanosized aggregates appears to
be strongly dependent on the countercations of the
amphiphiles. When these are sodium ions, no superstruc-
tures are formed because the self-assembly stops at the
stage of the array of dimers. However, when ammonium
ions are used, these form strong hydrogen bonds with
the carboxylate anions, and as a result, the bilayers are
stitched together to form large architectures. The shape
and dimensions of these architectures appear to be
directly related to the strength of dimerization of the
amphiphiles, which is in turn dependent on the substitu-
tion pattern of the cavity side-walls of these compounds.
Thus, by introducing small changes in the hydrophobic
part of these facial amphiphiles, the size and shape of
their final superstructures can be controlled in a fashion
similar to crystal engineering.30
(29) (a) Ghadiri, M. R.; Granja, J . R.; Milligan, R. A.; McRee, D. E.;
Khazanovich, N. Nature 1993, 366, 324. (b) Lbotak, P.; Shinkai, S.
Tetrahedron Lett. 1995, 36, 4829. (c) Philp, D.; Stoddart, J . F. Angew.
Chem., Int. Ed. Engl. 1996, 35, 1155. (d) Vreekamp, R. H.; van
Duynhoven, J . P. M.; Hubert, M.; Verboom, W.; Reinhoudt, D. N.
Angew. Chem., Int. Ed. Engl. 1996, 35, 1215. (e) Gillard, R. E.; Raymo,
F. M.; Stoddart, J . F. Chem. Eur. J . 1997, 3, 1933. (f) Balagurusamy,
V. S. K.; Ungar, G.; Percec, V.; J ohansson, G. J . Am. Chem. Soc. 1997,
119, 1539. (g) Chemseddine, A.; Moritz, T. Eur. J . Inorg. Chem. 1999,
235. (h) Rebek, J ., J r. Acc. Chem. Res. 1999, 32, 278. (i) Aizenberg, J .;
Black, A. J .; Whitesides, G. M. Nature 1999, 398, 495. (j) Ozin, G. A.
Can. J . Chem. 1999, 77, 2001. (k) Li, M.; Schnablegger, H.; Mann, S.
Nature 1999, 402, 393. (l) Orr, G. W.; Barbour, L. J .; Atwood, J . L.
Science 1999, 285, 1049.
(28) Heights of the aggregates were estimated to be between 50 and
100 nm from the platinum shadow in the TEM pictures.
9046 J . Org. Chem., Vol. 68, No. 23, 2003

Cavity-Containing Facial Amphiphiles
was dissolved in CH2Cl2 (200 mL), and the organic layer was
washed with a saturated aqueous NaHCO3 solution (200 mL)
and with water (200 mL), dried (MgSO4), filtered, and evapo-
rated to dryness. Purification by column chromatography
(silica, eluent 1% MeOH in CHCl3, Rf ) 0.16) afforded 3.2 g
(56%) of 7 as a white solid: mp 221 °C; IR (KBr pellet) ν 3048,
2960, 2927, 2854, 1748, 1736, 1714, 1475, 1451, 1389, 1212,
Exp er im en ta l Section
Syn th eses: 8b,8c-Di(4-m eth ylp h en yl)p er h yd r o-2,6-d i-
oxa -3a ,4a ,7a ,8a -tetr a a za cyclop en ta [d ef]flu or en e-4,8-d i-
on e (5). Ditoluylglycoluril (7.3 g, 23 mmol) and paraformal-
dehyde (3.4 g, 113 mmol) were suspended in DMSO (50 mL).
Aqueous 1 N NaOH was added dropwise until a pale yellow
solution was obtained, and the mixture was stirred for 16 h.
The solution was acidified to pH 1 with aqueous 37% HCl and
refluxed for 2 h. After the mixture was cooled, water (10 mL)
was slowly added while stirring vigorously and the resulting
precipitate was filtered and washed with water (20 mL) and
cold ethanol (50 mL). The product was dried under vacuum to
give 8.45 g (92%) of 5 as a white powder: 1H NMR (CDCl3,
1
1290, 1254, 1178, 1110, 1020 cm-1; H NMR (CDCl3, 300.13
MHz) δ 7.82 (d, 4H, 3J ) 8.0 Hz), 7.28 (d, 4H, 3J ) 8.0 Hz),
2
2
5.68 (d, 4H, J ) 10.7 Hz), 4.52 (d, 4H, J ) 10.7 Hz), 3.87 (s,
6H) ppm; 13C{1H} NMR (CDCl3, 75.47 MHz) δ 165.9, 158.1,
137.5, 131.4, 130.0, 127.9, 79.1, 72.1, 52.3; EI-MS m/z 494 (M)+.
Anal. Calcd for C24H22N4O8: C, 58.30; H, 4.48; N, 11.33.
Found: C, 58.86; H, 4.03; N, 11.22.
3
3
300.13 MHz) δ 7.04 (d, 4H, J ) 6.5 Hz), 6.96 (d, 4H, J ) 6.5
Hz), 5.63 (d, 4H, 2J ) 10.6 Hz), 4.54 (d, 4H, 2J ) 10.6 Hz),
2.21 (s, 6H) ppm; 13C{1H} NMR (CDCl3, 75.47 MHz) δ 159.1,
139.8, 130.2, 129.9, 128.4, 80.1, 72.5, 21.6 ppm.
Meth yl 4-1,3,4,6-Tetr a [(a cetyloxy)m eth yl]-6a -[4-(m eth -
oxyca r bon yl)p h en yl]-2,5-d ioxop er h yd r oim id a zo[4,5-d ]-
im id a zol-3-ylben zoa te (8). Compound 7 (3.9 g, 7.9 mmol)
and p-toluenesulfonic acid monohydrate (0.40 g, 2.1 mmol)
were suspended in acetic anhydride (15 mL), and the mixture
was stirred at 110 °C for 40 h. After cooling, the dark solution
was poured into aqueous 1 N NaOH (300 mL) and the product
was extracted with CH2Cl2 (100 mL). The organic layer was
washed with a saturated aqueous NaCl solution (200 mL) and
with water (200 mL), dried (MgSO4), and evaporated to
dryness. The residue was dissolved in a minimal amount of
CHCl3, and this solution was added dropwise to stirred diethyl
ether. After filtration, 3.9 g (70%) of 8 was obtained as an off-
white powder: mp 269 °C; IR (KBr pellet) ν 3050, 2925, 2854,
4-[8b-(4-Ca r boxyp h en yl)-4,8-d ioxop er h yd r o-2,6-d ioxa -
3a ,4a ,7a ,8a -tetr a a za cyclop en ta [d ef]flu or en -8-yl]-ben zo-
ic Acid (6). A suspension of 5 (5.0 g, 12.3 mmol) and KMnO4
(10 g, 63 mmol) in water (125 mL) was refluxed for 16 h. After
cooling, the brown suspension was filtered over infusorial
earth. The residue was washed with aqueous 1 N NaOH (100
mL), and the pale yellow filtrate was acidified to pH 1 with
aqueous 37% HCl while stirring vigorously. The precipitate
was filtered off, washed with water (200 mL), and dried under
vacuum over P2O5 to give 5.5 g (96%) of 6 as a white powder.
A sample was recrystallized from acetic acid for analysis: mp
302 °C (dec); IR (KBr pellet) ν 3500-3000, 3069, 2938, 1754,
1744, 1616, 1437, 1410, 1367, 1285, 1220, 1114, 1019 cm-1
1H NMR (CDCl3, 300.13 MHz) δ 7.75 (d, 4H, 3J ) 8.5 Hz),
;
1736, 1702, 1467, 1409, 1385, 1309, 1293, 1252, 1028 cm-1
;
3
2
6.97 (d, 4H, J ) 8.5 Hz), 5.68 (d, 4H, J ) 11.6 Hz), 5.28 (d,
4H, 2J ) 11.6 Hz), 3.89 (s, 6H), 2.03 (s, 12H) ppm; 13C{1H}
NMR (CDCl3, 75.47 MHz) δ 169.7, 165.5, 156.1, 135.7, 131.7,
129.6, 128.3, 86.6, 66.7, 52.4, 20.7 ppm; FAB-MS m/z 721
(M + Na)+. Anal. Calcd for C32H34N4O14: C, 55.01; H, 4.91; N,
8.02. Found: C, 54.91; H, 4.79; N, 8.12.
1H NMR (CDCl3/CD3OD 9:1 (v/v), 300.13 MHz) δ 7.85 (d, 4H,
3
2
3J ) 8.2 Hz), 7.30 (d, 4H, J ) 8.2 Hz), 5.66 (d, J ) 11.1 Hz),
2
4.57 (d, 4H, J ) 11.1 Hz) ppm; 13C{1H} NMR (CDCl3/CD3OD
9:1 (v/v), 75.47 MHz) δ 166.4, 157.3, 136.2, 131.5, 129.3, 127.1,
78.5, 71.3 ppm; FAB-MS m/z 467 (M + H)+. Anal. Calcd for
C
22H18N4O8(CH3COOH): C, 54.76; H, 4.21; N, 10.64. Found:
Meth yl 4-1,3,4,6-Tetr a (ch lor om eth yl)-6a -[4-(m eth oxy-
ca r bon yl)p h en yl]-2,5-d ioxop er h yd r oim id a zo[4,5-d ]im id -
a zol-3-ylben zoa te (9). Compound 8 (400 mg, 0.66 mmol) was
suspended in thionyl chloride (2 mL). One drop of water was
added, and the mixture was stirred under argon for 20 h.
Diethyl ether (10 mL) was added, and the white suspension
was stored at 4 °C for 2 h. The precipitate was filtered off and
dried under vacuum to give 290 mg (84%) of 9 as a white, very
hygroscopic powder: mp 258 °C (dec); IR (KBr pellet) ν 3052
(ArH), 2955, 1749, 1729, 1451, 1438, 1410, 1317, 1282, 1115
C, 54.76; H, 4.50; N, 10.35.
4-[13b-(4-Ca r boxyp h en yl)-1,4,8,11-tetr a m eth oxy-6,13-
d ioxo-5,7,12,13b ,13c,14-h exa h yd r o-5a ,6a ,12a ,13a -t et r a -
a za ben zo[5,6]a zu len o[2,1,8-ija ]ben zo[f]a zu len -13-yl]ben -
zoic Acid (3): Meth od A. Compound 6 (650 mg, 1.39 mmol)
and p-dimethoxybenzene (580 mg, 4.18 mmol) were dissolved
in a mixture of acetic anhydride (1.5 mL) and trifluoroacetic
acid (1.5 mL). The mixture was heated at 100 °C for 64 h. After
the mixture was cooled, methanol (6 mL) was added dropwise
and the precipitate was filtered off and washed with methanol
(50 mL) and diethyl ether (50 mL) to yield 800 mg (81%) of 3
as a white solid. Meth od B. Starting from 12 (120 mg, 0.16
mmol), this compound was synthesized as described for 1:
yield, 112 mg (97%) of 3 as a white solid; mp 309 °C (dec); IR
(KBr pellet) ν 3500-3300, 3046, 2937, 2915, 2837, 1727, 1702,
1678, 1484, 1467, 1427, 1413, 1360, 1305, 1261, 1225, 1080
1
cm-1; H NMR (CDCl3, 300.13 MHz) δ 7.85 (d, 4H, 3J ) 8.6
2
Hz), 7.07 (d, 4H, 3J ) 8.6 Hz), 5.35 (d, 4H, J ) 11.4 Hz), 5.27
(d, 4H, 2J ) 11.4 Hz), 3.90 (s, 6H) ppm; 13C{1H} NMR (CDCl3,
75.47 MHz) δ 165.5, 153.9, 133.7, 132.5, 130.1, 128.7, 86.8,
66.7, 52.5 ppm; FAB-MS m/z 642 (M + H)+. Anal. Calcd for
C
24H22N4O6Cl4: C, 47.70; H, 3.67; N, 9.27. Found: C, 47.91;
cm-1 1H NMR (DMSO-d6, 300.14 MHz) δ 7.74 (d, 4H, 3J )
;
H, 3.58; N, 9.15.
8.4 Hz), 7.20 (d, 4H, 3J ) 8.4 Hz), 6.86 (s, 4H), 5.43 (d, 4H,
Meth yl 4-13b-[4-(Meth oxyca r bon yl)p h en yl]-6,13-d ioxo-
5,7,12,13b,13c,14-h exah ydr o-5a,6a,12a,13a-tetr aazaben zo-
[5,6]a zu len o[2,1,8-ija ]ben zo[f]a zu len -13-ylben zoa te (10).
A mixture of 9 (1.50 g, 2.48 mmol) and AlCl3 (2.31 g, 17.3
mmol) in benzene (20 mL) was refluxed under nitrogen for 120
h. After the mixture was cooled, aqueous 6 N HCl (20 mL)
was added and the mixture was refluxed for 1 h. To the dark
yellow solution was added CH2Cl2 (100 mL), and the organic
layer was washed with water (2 × 200 mL) and evaporated to
dryness. The product was purified by column chromatography
(silica, CH2Cl2/MeOH 197:3, v/v, Rf ) 0.30) to yield 650 mg
(36%) of 10 as a white powder: mp 315 °C (dec); IR (KBr pellet)
2J ) 16.0 Hz), 3.75 (s, 12H), 3.72 (d, 4H, J ) 16.0 Hz) ppm;
2
13C{1H} NMR (DMSO-d6, 75.47 MHz) δ 170.6, 160.5, 154.6,
142.1, 134.8, 133.5, 132.3, 131.3, 116.1, 88.2, 60.6, 40.3 ppm;
FAB-MS m/z 707 (M + H)+. Anal. Calcd for C38H34N4O10: C,
64.58; H, 4.85; N, 7.93. Found: C, 64.64; H, 4.80; N, 7.82.
Meth yl 4-8b-[4-(Meth oxyca r bon yl)p h en yl]-4,8-d ioxo-
p er h yd r o-2,6-d ioxa -3a ,4a ,7a ,8a -tetr a a za cyclop en ta -[d ef]-
flu or en -8-ylben zoa te (7). Compound 6 (5.4 g, 11.6 mmol) was
suspended in methanol (300 mL); 98% H2SO4 (0.25 mL) was
added, and the mixture was refluxed for 16 h. After the
mixture was cooled, the solvent was evaporated. The residue
ν 3050, 2956, 2921, 1722, 1454, 1422, 1283, 1115 cm-1
;
1H
3
(30) (a) Desiraju, G. R. Crystal Engineering: The Design of Organic
Solids; Elsevier: Amsterdam, 1989. (b) Russell, V. A.; Ward, M. D.
Chem. Mater. 1996, 8, 1654. (c) Desiraju, G. R. Chem. Commun. 1997,
1475. (d) Ashton, P. R.; Fyfe, M. C. T.; Hickingbottom, S. K.; Menzer,
S.; Stoddart, J . F.; White, A. J . P.; Williams, D. J . Chem. Eur. J . 1998,
4, 577. (e) Desiraju, G. R. Acc. Chem. Res. 2002, 35, 565.
NMR (CDCl3, 300.13 MHz) δ 7.83 (d, 4H, J ) 8.6 Hz), 7.24
3
(d, 4H, J ) 8.6 Hz), 7.29-7.23 (m, 4H), 7.16-7.09 (m, 4H,),
2
2
4.81 (d, 4H, J ) 15.8 Hz), 4.11 (d, 4H, J ) 15.8 Hz), 3.87 (s,
6H) ppm; 13C{1H) NMR (75.47 MHz, CDCl3) δ 166.8, 157.5,
138.7, 136.3, 130.8, 130.1, 129.5, 128.2, 128.0, 84.9, 52.1, 45.3
J . Org. Chem, Vol. 68, No. 23, 2003 9047

Elemans et al.
ppm; FAB-MS m/z 615 (M + H)+. Anal. Calcd for C36H30N4O6:
water (2 mL). Aqueous 1 N HCl was slowly added until pH )
1 while stirring the mixture vigorously. The formed precipitate
was filtered off (small G3 filter, without the application of
vacuum), washed with water (1 mL), and dried under vacuum
over P2O5 to yield 75 mg (95%) of 1 as a white solid: mp 380
°C (dec); 1H NMR (DMSO-d6, 300.13 MHz) δ 7.83 (d, 4H, 3J )
C, 70.35; H, 4.92; N, 9.12. Found: C, 70.73; H, 4.89; N, 8.77.
Met h yl 4-13b -[4-(Met h oxyca r b on yl)p h en yl]-1,4,8,11-
tetr a m eth yl-6,13-d ioxo-5,7,12,13b,13c,14-h exa h yd r o-5a ,-
6a ,12a ,13a -tetr a a za ben zo[5,6]a zu len o[2,1,8-ija ]ben zo[f]-
a zu len -13-ylben zoa te (11). Compound 9 (240 mg, 0.40 mmol)
was suspended in 1,2-dichloroethane (10 mL). p-Xylene (2.5
mL) and SnCl4 (0.5 mL, 4 mmol) were added, and the mixture
was refluxed under nitrogen for 64 h. After the mixture was
cooled, aqueous 6 N HCl (15 mL) was added and the mixture
was refluxed for 1 h. After the mixture was cooled, CH2Cl2
(100 mL) was added, and the organic layer was washed with
water (2 × 100 mL) and evaporated to dryness. After purifica-
tion by column chromatography (silica, CH2Cl2/MeOH 397:3,
v/v, Rf ) 0.21), 60 mg (23%) of 11 was obtained as a white
powder: mp 354 °C (dec); IR (KBr pellet) ν 3054, 2952, 2930,
3
8.6 Hz), 7.24 (d, 4H, J ) 8.6 Hz), 7.29-7.23 (m, 4H), 7.16-
7.09 (m, 4H), 4.81 (d, 4H, 2J ) 15.8 Hz), 4.11 (d, 4H, 2J ) 15.8
Hz) ppm; 13C{1H) NMR (75.47 MHz, CDCl3) δ 166.8, 157.5,
138.7, 136.3, 130.8, 130.1, 129.5, 128.2, 128.0, 84.9 (NC(Ar)N),
52.1 (C(O)OCH3), 45.3 ppm; FAB-MS m/z 587 (M + H)+. Anal.
Calcd for C34H26N4O6: C, 69.62; H, 4.46; N, 9.55. Found: C,
69.87; H, 4.76; N, 9.37.
4-[13b-(4-Ca r boxyp h en yl)-1,4,8,11-tetr a m eth yl-6,13-d i-
oxo-5,7,12,13b,13c,14-h exa h yd r o-5a ,6a ,12a ,13a -tetr a a za -
ben zo[5,6]a zu len o[2,1,8-ija ]ben zo[f]a zu len -13-yl]ben zo-
ic Acid (2). Starting from 11 (80 mg, 0.12 mmol), this
compound was synthesized as described for 1: yield, 74 mg
(96%) of 2 as a white solid; mp > 400 °C (dec); IR (KBr pellet)
ν 3182, 2048, 2959, 2924, 1727, 1694, 1674, 1475, 1449, 1413,
1308, 1266, 1221, 1141 cm-1; 1H NMR (DMSO-d6, 300.13 MHz)
1726, 1713, 1458, 1422, 1408, 1288, 1117 cm-1
;
1H NMR
3
(CDCl3, 400.13 MHz) δ 7.78 (d, 4H, J ) 8.6 Hz), 7.23 (d, 4H,
2
3J ) 8.6 Hz), 6.85 (s, 4H), 5.06 (d, 4H, J ) 15.7 Hz), 3.86 (s,
6H), 3.85 (d, 4H, 2J ) 15.7 Hz), 2.46 (s, 12H) ppm; 13C{1H}
NMR (CDCl3, 100.61 MHz) δ 166.2, 157.7, 139.9, 135.4, 134.6,
130.5, 129.9, 128.2, 84.6, 52.2, 40.6, 20.2 ppm; FAB-MS m/z
671 (M + H)+. Anal. Calcd for C40H38N4O6: C, 71.63; H, 5.71;
N, 8.35. Found: C, 71.51; H, 5.62; N, 8.18.
3
3
δ 7.77 (d, 4H, J ) 8.3 Hz), 7.34 (d, 4H, J ) 8.3 Hz), 6.90 (s,
4H), 4.95 (d, 4H, 2J ) 16.0 Hz), 3.90 (d, 4H, 2J ) 16.0 Hz),
2.43 (s, 12H) ppm; 13C{1H} NMR (DMSO-d6, 75.47 MHz) δ
170.6, 160.9, 143.0, 140.4, 137.8, 135.0, 133.5, 132.5, 88.1, 42.2,
23.7 ppm; FAB-MS m/z 643 (M + H)+. Anal. Calcd for
Meth yl 4-1,4,8,11-Tetr a m eth oxy-13b-[4-(m eth oxyca r -
b on yl)p h en yl]-6,13-d ioxo-5,7,12,13b ,13c,14-h exa h yd r o-
5a ,6a ,12a ,13a -tetr a a za ben zo[5,6]a zu len o[2,1,8-ija ]ben zo-
[f]a zu len -13-ylben zoa te (12). Starting from 7 (310 mg, 0.63
mmol) and p-dimethoxybenzene (220 mg, 1.59 mmol) in a
mixture of acetic anhydride (1 mL) and trifluoroacetic acid (1
mL), this compound was synthesized as described for 6 to yield
375 mg (81%) of 12 as a white solid. Single crystals of 12 were
obtained by slow diffusion of diethyl ether in a solution of the
compound in dichloromethane: mp 336 °C (dec); IR (KBr
pellet) ν 3010, 2955, 2923, 2851, 1729, 1719, 1486, 1465, 1445,
C
38H34N4O6: C, 71.01; H, 5.33; N, 8.72. Found: C, 71.21; H,
5.55; N, 8.32.
4-[16b -(4-Ca r b oxyp h en yl)-5,9,14,18-t et r a m et h oxy-7,-
16-dioxo-6,8,15,16b,16c,17-h exa h yd r o-6a ,7a ,15a ,16a -tetr a -
a za n a p h t h o[2′,3′:5,6]a zu le n o[2,1,8-ija ]n a p h t h o[2,3-f]-
a zu len -16-yl]ben zoic Acid (4). Starting from 13 (65 mg,
0.078 mmol) this compound was synthesized as described for
1: yield, 60 mg (96%) of 4 as a white solid; mp 360 °C (dec);
1H NMR (DMSO-d6, 300.14 MHz) δ 7.98-7.92 (m, 4H), 7.82
3
3
1307, 1298, 1281, 1262, 1121, 1078 cm-1
;
1H NMR (CDCl3,
(d, 4H, J ) 8.4 Hz), 7.55-7.49 (m, 4H), 7.39 (d, 4H, J ) 8.4
Hz), 5.58 (d, 4H, 2J ) 16.0 Hz), 4.02 (d, 4H, 2J ) 16.0 Hz),
3.96 (s, 12H) ppm; 13C{1H} NMR (DMSO-d6, 50.32 MHz) δ
166.7, 156.6, 149.4, 138.2, 130.1, 129.7, 128.6, 127.5, 126.8,
122.7, 84.2, 62.5, 38.2 ppm; FAB-MS m/z 829 (M + Na)+. Anal.
Calcd for C46H38N4O10: C, 68.48; H, 4.75; N, 6.94. Found: C,
68.58; H, 4.79; N, 6.81.
3
3
300.13 MHz) δ 7.76 (d, 4H, J ) 8.5 Hz), 7.17 (d, 4H, J ) 8.5
2
Hz), 6.43 (s, 4H), 5.54 (d, 4H, J ) 15.9 Hz), 3.85 (s, 6H, 3.75
(s, 12H), 3.72 (d, 4H, 2J ) 15.9 Hz) ppm; 13C{1H} NMR (CDCl3,
75.47 MHz) δ 166.2, 157.6, 150.9, 139.3, 130.4, 129.8, 128.17,
126.8, 111.8, 84.9, 56.6, 52.2, 36.9 ppm; FAB-MS m/z 735
(M + H)+. Anal. Calcd for C40H38N4O10: C, 65.39; H, 5.21; N,
7.63. Found: C, 65.62; H, 5.12; N, 7.55.
Disodiu m -4-[13b-(4-car boxylatoph en yl)-6,13-dioxo-5,7,-
12,13b ,13c,14-h exa h yd r o-5a ,6a ,12a ,13a -t et r a a za b en zo-
[5,6]azu len o[2,1,8-ija ]ben zo[f]azu len -13-yl]ben zoate (Na1).
To a suspension of compound 1 (100 mg, 0.17 mmol) in water
(10 mL) was added an aqueous NaOH solution (5 mL contain-
ing 0.34 mmol of NaOH). The mixture was stirred overnight,
whereafter it was lyophilized to yield 108 mg (100%) of Na 1
as a very hygroscopic white foam, which was stored under
nitrogen at -18 °C: mp > 400 °C (dec); IR (KBr pellet) ν 3050,
2922, 1714, 1684, 1605, 1558, 1471, 1445, 1428, 1407, 1309,
Meth yl 4-5,9,14,18-Tetr a m eth oxy-16b-[4-(m eth oxyca r -
b on yl)p h en yl]-7,16-d ioxo-6,8,15,16b ,16c,17-h exa h yd r o-
6a,7a,15a,16a-tetr aazan aph th o[2′,3′:5,6]azu len o[2,1,8-ija ]-
n a p h th o[2,3-f]a zu len -16-ylben zoa te (13). Compound 9 (560
mg, 0.93 mmol) and 1,4-dimethoxynaphthalene (520 mg, 2.8
mmol) were dissolved in 1.2-dichloroethane (10 mL). SnCl4 (1.5
mL, 12 mmol) was added, and the mixture was refluxed under
nitrogen for 40 h. After the mixture was cooled, aqueous 6 N
HCl (10 mL) was added and the mixture was refluxed for 1 h.
After the mixture was cooled, CH2Cl2 (50 mL) was added and
the organic layer was washed with water (2 × 100 mL) and
evaporated to dryness. After purification by column chroma-
tography (silica, CH2Cl2/ MeOH 99:1, v/v, Rf ) 0.08), 550 mg
(71%) of 13 was obtained as an off-white solid: mp 337 °C (dec);
IR (KBr pellet) ν 3018, 2954, 2848, 1728, 1718, 1488, 1460,
1296, 1280, 1074 cm-1; 1H NMR (CDCl3, 300.13 MHz) δ 8.00-
7.94 (m, 4H), 7.86 (d, 4H, 3J ) 8.5 Hz), 7.45-7.39 (m, 4H),
1260 cm-1 1H NMR (D2O, 500.13 MHz, 6.0 mM) δ 7.56 (d,
;
4H, 3J ) 7.9 Hz), 7.20 (d, 4H, 3J ) 7.9 Hz), 7.18 (br s, 4H),
2
2
7.05 (br s, 4H), 4.58 (d, 4H, J ) 16.1 Hz), 4.20 (d, 4H, J )
16.1 Hz) ppm.
Disod iu m -4-[13b -(4-ca r b oxyla t op h en yl)-1,4,8,11-t et -
r a m eth yl-6,13-d ioxo-5,7,12,13b,13c,14-h exa h yd r o-5a ,6a ,-
12a ,13a -tetr a a za ben zo[5,6]a zu len o[2,1,8-ija ]ben zo[f]a zu -
len -13-yl]ben zoa te (Na 2). Starting from 2 (100 mg, 0.156
mmol), this compound was synthesized as described for Na 1:
yield, 107 mg (100%) of Na 2 as a very hygroscopic white foam;
mp 390 °C (dec); IR (KBr pellet) ν 3048, 2924, 1715, 1682, 1605,
1557, 1475, 1449, 1428, 1405, 1308, 1258 cm-1; 1H NMR (D2O,
3
2
7.31 (d, 4H, J ) 8.5 Hz), 5.76 (d, 4H, J ) 15.9 Hz), 4.03 (s,
12H), 3.89 (s, 6H), 3.86 (d, 4H, 2J ) 15.9 Hz) ppm; 13C{1H}
NMR (CDCl3, 75.47 MHz) δ 166.5, 156.2, 149.4, 138.0, 130.4,
129.6, 128.0, 127.3, 127.1, 122.3, 84.1, 62.6, 52.4, 38.9 ppm;
FAB-MS m/z 835 (M + H)+. Anal. Calcd for C48H42N4O10: C,
69.06; H, 5.07; N, 6.71. Found: C, 68.88; H, 5.05; N, 6.97.
3
500.13 MHz, 3.6 mM) δ 7.54 (d, 4H, J ) 8.3 Hz), 7.16 (d, 4H,
2
3J ) 8.3 Hz), 6.33 (s, 4H), 4.84 (d, 4H, J ) 16.2 Hz), 3.82 (d,
2
4H, J ) 16.2 Hz), 2.20 (s, 12H) ppm.
4-[13b-(4-Ca r boxyp h en yl)-6,13-d ioxo-5,7,12,13b,13c,14-
h exah ydr o-5a,6a,12a,13a-tetr aazaben zo[5,6]azu len o-[2,1,8-
ija ]ben zo[f]a zu len -13-yl]ben zoic Acid (1). Compound 10
(85 mg, 0.14 mmol) was stirred in a mixture of dioxane,
methanol, and aqueous 4 N NaOH (15:4:1, v/v/v, 8 mL) for 16
h. The precipitate was filtered off, dried, and redissolved in
Disod iu m -4-[13b -(4-ca r b oxyla t op h en yl)-1,4,8,11-t et -
r a m et h oxy-6,13-d ioxo-5,7,12,13b ,13c,14-h exa h yd r o-5a ,-
6a ,12a ,13a -tetr a a za ben zo[5,6]a zu len o[2,1,8-ija ]ben zo[f]-
a zu len -13-yl]ben zoa te (Na 3). Starting from 3 (100 mg, 0.142
mmol), this compound was synthesized as described for Na 1:
9048 J . Org. Chem., Vol. 68, No. 23, 2003

Cavity-Containing Facial Amphiphiles
yield, 106 mg (100%) of Na 3 as a very hygroscopic white foam,
which was stored under nitrogen at -18 °C; mp 321 °C (dec);
IR (KBr pellet) ν 3047, 2927, 2841, 1726, 1701, 1603, 1558,
1472, 1438, 1308, 1258, 1080 cm-1; 1H NMR (D2O, 500.13 MHz,
> 400 °C (dec); IR (KBr pellet) ν 3700-2700, 2947, 1730-1670,
1471, 1448, 1422, 1406, 1311, 1218 cm-1; 1H NMR (D2O, 400.13
3
3
MHz, 0.8 mM) δ 7.60 (d, 4H, J ) 8.0 Hz), 7.25 (d, 4H, J )
2
8.0 Hz), 6.63 (s, 4H), 4.95 (d, 4H, J ) 16.3 Hz), 3.91 (d, 4H,
3
3
5.2 mM) δ 7.53 (d, 4H, J ) 8.2 Hz), 7.13 (d, 4H, J ) 8.2 Hz),
2J ) 16.3 Hz), 2.32 (s, 12H) ppm.
2
2
5.94 (s, 4H), 5.24 (d, 4H, J ) 16.3 Hz), 3.69 (d, 4H, J ) 16.3
Hz), 3.45 (s, 12H) ppm.
Dia m m on iu m -4-[13b -(4-ca r b oxyla t op h en yl)-1,4,8,11-
t et r a m et h oxy-6,13-d ioxo-5,7,12,13b ,13c,14-h exa h yd r o-
5a ,6a ,12a ,13a -tetr a a za ben zo[5,6]a zu len o[2,1,8-ija ]ben zo-
[f]a zu len -13-yl]ben zoa te (NH43). Starting from 3 (100 mg,
0.142 mmol), this compound was synthesized as described for
NH41 to yield 105 mg (100%) of NH43 as a very hygroscopic
white foam, which was stored under nitrogen at -18 °C: mp
309 °C (dec); IR (KBr pellet) ν 3700-2700, 2933, 1730-1670,
1485, 1465, 1427, 1407, 1353, 1299, 1259, 1077 cm-1; 1H NMR
Disod iu m -4-[13b -(4-ca r b oxyla t op h en yl)-1,4,8,11-t et -
r a m et h oxy-6,13-d ioxo-5,7,12,13b ,13c,14-h exa h yd r o-5a ,-
6a ,12a ,13a -tetr a a za ben zo[5,6]a zu len o[2,1,8-ija ]ben zo[f]-
a zu len -13-yl]ben zoa te (Na 4). Starting from 4 (100 mg, 0.124
mmol), this compound was synthesized as described for Na 1:
yield, 105 mg (100%) of Na 4 as a very hygroscopi white foam,
which was stored under nitrogen at -18 °C; mp > 400 °C (dec);
IR (KBr pellet) ν 3053, 2927, 2839, 1729, 1707, 1603, 1559,
1467, 1439, 1392, 1306, 1258, 1077 cm-1; 1H NMR (D2O, 300.13
3
(D2O, 400.13 MHz, 0.7 mM) δ 7.58 (d, 4H, J ) 8.1 Hz), 7.18
3
2
(d, 4H, J ) 8.1 Hz), 6.14 (s, 4H), 5.29 (d, 4H, J ) 16.1 Hz),
3
3
2
MHz, 2.9 mM) δ 7.63 (d, 4H, J ) 7.2 Hz), 7.31 (d, 4H, J )
3.76 (d, 4H, J ) 16.1 Hz), 3.54 (s, 12H) ppm.
2
7.2 Hz), 6.98 (br s, 4H), 6.05 (br s, 4H), 5.40 (d, 4H, J ) 15.8
Hz), 4.03 (d, 4H, J ) 15.8 Hz), 3.65 (s, 12H) ppm.
Dia m m on iu m -4-[13b -(4-ca r b oxyla t op h en yl)-1,4,8,11-
t et r a m et h oxy-6,13-d ioxo-5,7,12,13b ,13c,14-h exa h yd r o-
5a ,6a ,12a ,13a -tetr a a za ben zo[5,6]a zu len o[2,1,8-ija ]ben zo-
[f]a zu len -13-yl]ben zoa te (NH44). Starting from 4 (100 mg,
0.124 mmol), this compound was synthesized as described for
NH41 to yield 104 mg (100%) of NH44 as a very hygroscopic
white foam, which was stored under nitrogen at -18 °C: mp
360 °C (dec); IR (KBr pellet) ν 3700-2700, 2931, 2852, 1730-
1670, 1460, 1427, 1409, 1356, 1306, 1047 cm-1; 1H NMR (D2O,
2
Diam m on iu m -4-[13b-(4-car boxylatoph en yl)-6,13-dioxo-
5,7,12,13b,13c,14-h exah ydr o-5a,6a,12a,13a-tetr aazaben zo-
[5,6]azu len o[2,1,8-ija ]ben zo[f]azu len -13-yl]ben zoate (NH4-
1). Compound 1 (100 mg, 0.17 mmol) was dissolved in aqueous
ammonia (5 mL, 30%). The mixture was stirred overnight; the
excess ammonia was evaporated, and the residue was lyoph-
ilized to yield 106 mg (100%) of NH41 as a very hygroscopic
white foam, which was stored under nitrogen at -18 °C: mp
380 °C (dec); IR (KBr pellet) ν 3700-2700, 2939, 1740-1675,
1468, 1426, 1312, 1280, 1220 cm-1; 1H NMR (D2O, 300.13 MHz,
3
300.13 MHz, 0.4 mM) δ 7.72 (d, 4H, J ) 7.8 Hz), 7.40 (d, 4H,
2
3J ) 7.8 Hz), 7.20 (br s, 4H), 6.35 (br s, 4H), 5.49 (d, 4H, J )
2
15.8 Hz), 4.16 (d, 4H, J ) 15.8 Hz), 3.75 (s, 12H) ppm.
3
3
0.8 mM) δ 7.58 (d, 4H, J ) 8.0 Hz), 7.19 (d, 4H, J ) 8.0 Hz),
7.18 (m, 4H), 7.03 (m, 4H), 4.57 (d, 4H, 2J ) 16.0 Hz), 4.14 (d,
4H, J ) 16.0 Hz) ppm.
Ack n ow led gm en t. The authors thank Dr. R. de
Gelder and Dr. M. C. Feiters for their help with the
powder diffraction experiments.
2
Dia m m on iu m -4-[13b -(4-ca r b oxyla t op h en yl)-1,4,8,11-
tetr a m eth yl-6,13-d ioxo-5,7,12,13b,13c,14-h exa h yd r o-5a ,-
6a ,12a ,13a -tetr a a za ben zo[5,6]a zu len o[2,1,8-ija ]ben zo[f]-
a zu len -13-yl]ben zoa te (NH42). Starting from 2 (100 mg,
0.156 mmol), this compound was synthesized as described for
NH41 to yield 105 mg (100%) of NH42 as a very hygroscopic
white foam, which was stored under nitrogen at -18 °C: mp
Su p p or tin g In for m a tion Ava ila ble: General experimen-
tal procedures. This material is available free of charge via
the Internet at http://pubs.acs.org.
J O035130F
J . Org. Chem, Vol. 68, No. 23, 2003 9049