Self-folding cavitands of nanoscale dimensions

Article abstract of DOI:10.1021/ja001562l

New types of resorcinarene-based nanoscale container molecules 2 and 3 are described. They feature reversibly folding unimolecular cavities of nanoscale dimensions and ~800 A³ internal volume; they are among the largest synthetic unimolecular hosts prepared to date. Two seams of intramolecular hydrogen bonds, provided by 12 secondary amides, control the guest uptake and release. The hydrogen bonds resist the unfolding of the host and increase the energetic barrier to guest exchange. Exchange is slow on the NMR time scale (room temperature), and kinetically stable complexes result. The direct observation of bound species and the stoichiometry of the complexes are reported. A series of adamantyl and cyclohexyl guests 11-19 of various shapes and lengths were prepared and used to estimate the hosts' capacities. Compound 2 exists in an S-shaped conformation and its two cavities act independently; each half of host 2 formed kinetically stable complexes with either two identical or different guest molecules. The C-shaped host 3 accommodates rigid and long guests with association constants (K(a)) between 500 ± 50 M^-1 (-ΔG²⁹⁵ = 3.6 ± 0.1 kcal mol^-1) and 270 ± 100 M^-1 (-ΔG²⁹⁵ = 3.2 ± 0.2 kcal mol^-1) for adamantyl derivatives. With the more flexible and/or shorter guests, fast exchange between the free and complexed guest species was observed at room and higher temperatures (in toluene-d₈). Guest exchange rates of the new hosts are considerably faster than rates seen with typical hemicarceplexes but slower than those of other open-ended cavitands.

Full text of DOI:10.1021/ja001562l

8880
J. Am. Chem. Soc. 2000, 122, 8880-8889
Self-Folding Cavitands of Nanoscale Dimensions
Ulrich Lu1cking, Fabio C. Tucci, Dmitry M. Rudkevich,* and Julius Rebek, Jr.*
Contribution from The Skaggs Institute for Chemical Biology and The Department of Chemistry,
The Scripps Research Institute, MB-26, 10550 North Torrey Pines Road, La Jolla, California 92037
ReceiVed May 5, 2000
Abstract: New types of resorcinarene-based nanoscale container molecules 2 and 3 are described. They feature
reversibly folding unimolecular cavities of nanoscale dimensions and ∼800 Å3 internal volume; they are among
the largest synthetic unimolecular hosts prepared to date. Two seams of intramolecular hydrogen bonds, provided
by 12 secondary amides, control the guest uptake and release. The hydrogen bonds resist the unfolding of the
host and increase the energetic barrier to guest exchange. Exchange is slow on the NMR time scale (room
temperature), and kinetically stable complexes result. The direct observation of bound species and the
stoichiometry of the complexes are reported. A series of adamantyl and cyclohexyl guests 11-19 of various
shapes and lengths were prepared and used to estimate the hosts’ capacities. Compound 2 exists in an S-shaped
conformation and its two cavities act independently; each half of host 2 formed kinetically stable complexes
with either two identical or different guest molecules. The C-shaped host 3 accommodates rigid and long
guests with association constants (Ka) between 500 ( 50 M-1 (-∆G295 ) 3.6 ( 0.1 kcal mol-1) and 270 (
100 M-1 (-∆G295 ) 3.2 ( 0.2 kcal mol-1) for adamantyl derivatives. With the more flexible and/or shorter
guests, fast exchange between the free and complexed guest species was observed at room and higher
temperatures (in toluene-d8). Guest exchange rates of the new hosts are considerably faster than rates seen
with typical hemicarceplexes but slower than those of other open-ended cavitands.
Introduction
Molecular recognition in chemistry generally involves the
matching of concave shapes and surfaces of synthetic receptors
to the convex shapes and surfaces of their smaller targets. The
manifest destiny of this enterprise is inevitablesmolecular hosts
that completely surround their guests.1 The earliest expressions
were the “molecule-within-molecule” complexes of Cram and
Collet, carcerands and cryptophanes. In these, covalent bonds
define the host molecules2 and trap guest molecules more or
less irreversibly.3 In hemicarcerandssmolecules with larger
portalssguests move in and out more freely, but only slowly.4
The high kinetic stability of these systems allows the direct
observation of reactive intermediates and the detection of new
types of stereoisomerism that arise from restricted motions of
molecules within the cramped quarters.5 The molecular recogni-
tion involved in the covalent systems is not conducive to
equilibrium measurements and the thermodynamic parameters
that can be obtained from them; rather, the recognition is kinetic.
Reversibly formed capsules, held together by intermolecular
Figure 1. Cartoon representations of self-folding cavitands (top) and
self-folding nanoscale containers (bottom), i.e., unimolecular capsules.
(1) (a) Cram, D. J.; Cram, J. M. Container Molecules and their Guests;
Royal Society of Chemistry: Cambridge, 1994. (b) Conn, M. M.; Rebek,
J., Jr. Chem. ReV. 1997, 97, 1647-1668. (c) Rudkevich, D. M.; Rebek, J.,
Jr. Eur. J. Org. Chem. 1999, 1991-2005.
forces, provide one means of accomplishing recognition under
equilibrium conditions and are the current vehicles, that is to
say, self-assembly is the technique of choice during the past
decade.6 This approach gives rise to larger molecular containers
that can encapsulate increasingly larger guests and incorporate
the properties required for, say, catalysis. Unexpectedly, we
found that even open-ended hosts, the self-folding cavitands
1,7 share some of these properties, and here we relate our latest
experiences with these systems.
(2) Higler, I.; Timmerman, P.; Verboom, W.; Reinhoudt, D. N. Eur. J.
Org. Chem. 1998, 2689, 9-2702.
(3) (a) Jasat, A.; Sherman, J. C. Chem. ReV. 1999, 99, 931-967. (b)
Collet, A.; Dutasta, J.-P.; Lozach, B.; Canceill, J. Top. Curr. Chem. 1993,
165, 103-129.
(4) (a) Cram, D. J.; Tanner, M. E.; Knobler, C. B. J. Am. Chem. Soc.
1991, 113, 7717-7727. (b) Cram, D. J.; Blanda, M. T.; Paek, K.; Knobler,
C. B. J. Am. Chem. Soc. 1992, 114, 7765-7773. (c) Robbins, T. A.; Knobler,
C. B.; Bellew, D. R.; Cram, D. J. J. Am. Chem. Soc. 1994, 116, 111-122.
(d) Slow decomplexation at 295 K: Cram, D. J.; Jaeger, R.; Deshayes, K.
J. Am. Chem. Soc. 1993, 115, 10111-10116.
(5) (a) Cram, D. J.; Tanner, M. E.; Thomas, R. Angew. Chem., Int. Ed.
Engl. 1991, 30, 1024-1027. (b) Warmuth, R. Angew. Chem., Int. Ed. Engl.
1997, 36, 1347-1350. (c) Warmuth, R.; Marvel, M. A. Angew. Chem.,
Int. Ed. Engl. 2000, 39, 1117-1119. (d) Timmerman, P.; Verboom, W.;
van Veggel, F. C. J. M.; van Duynhoven, J. P. M.; Reinhoudt, D. N. Angew.
Chem., Int. Ed. Engl. 1994, 33, 2345-2348.
The key feature of these containers (Figures 1 and 2) is the
conformational stability provided by their intramolecular hy-
drogen bonds. These bonds maintain the shape of the structure;
(6) (a) Rebek, J., Jr. Acc. Chem. Res. 1999, 32, 278-286. (b) de
Mendoza, J. Chem. Eur. J. 1998, 4, 1373-1377. (c) Rebek, J., Jr. Chem.
Commun. 2000, 637-643. See also ref 1b,c.
10.1021/ja001562l CCC: $19.00 © 2000 American Chemical Society
Published on Web 08/30/2000

Self-Folding CaVitands of Nanoscale Dimensions
J. Am. Chem. Soc., Vol. 122, No. 37, 2000 8881
Scheme 1a
(a) 1,2-Difluoro-4,5-dinitrobenzene (3 equiv), Et3N (16 equiv), DMF,
70 °C, 16 h, 57%. (b) Ra/Ni, H2, toluene/MeOH, 3:1, 40 °C, 12 h,
>90%. (c) C2H5C(O)Cl (∼10 equiv), Py (18 equiv), CH2Cl2, -78 °C,
1 h. Then NH2NH2/H2O (10 equiv), toluene-EtOH, 1:1, 85 °C, 4.5 h,
13%, or C2H5C(O)Cl (∼10 equiv), K2CO3 (20 equiv), EtOAc/H2O, then
NH2NH2/H2O (10 equiv), toluene/EtOH, 1:1, 85 °C, 4.5 h, 66%. (d)
1,2-Difluoro-4,5-dinitrobenzene (2 equiv), Et3N (10 equiv), DMF, 70
°C, 15 h, 65%. (e) Ra/Ni, H2, toluene, 40 °C, 3 h, 65%. (f)
1,4-Diformylbenzene (0.5 equiv), nitrobenzene, 140 °C, 24-36 h, 52%.
(g) 1,2,5,6-Tetraketopyracene 8 (0.5 equiv), AcOHGlac/THF, 1:100,
reflux, 15 h, 55% C- + S-isomers (∼1:1 ratio). (h) 1,2-Acenaphthene-
quinone, AcOHGlac/THF, 1:100, reflux, 3 h, 78%.
Figure 2. Self-folding cavitand 17 (side and top views, only one
cycloenantiomer is depicted) and self-folding containers 2 and 3.
the deep cavities for guest inclusion result. The uptake and
release of guests involves folding and unfolding of the host,
achieved by varying either solvent polarity and/or temperature.
The hydrogen bonds at the upper rim resist the unfolding of
the vaselike structure and increase the energetic barrier to guest
exchange. Accordingly, exchange is slow on the NMR time
scale (ambient temperatures and 600 MHz), and kinetically
stable complexes result. While the stability criterion is relative,
the slow exchange permits direct observation of included
species, their orientation in the cavity, and determination of the
stoichiometry of the complexes.7,8 The hosts have been further
elaborated to self-complementary systems.9,10
The synthesis and characterization of nanoscale cavitands is
the present subject and the specific structures are 2 and 3 (Figure
2). They consist of two deepened, self-folding cavitands
covalently connected through an extended aromatic spacer.
These are among the largest of synthetic unimolecular hosts,11
featuring cavity dimensions of g20 × 10 Å and an internal
volume of ∼800 Å3. At first glance, the molecules resemble
hemicarcerands, but the dynamic qualities mentioned above offer
facile access to the cavity under ambient conditions; they also
accommodate guests of nanoscale dimensions and, as we shall
see, more than one guest at a time.12
Results and Discussion
Synthesis (Scheme 1). The synthesis of unimolecular con-
tainers 2 and 3 is based on the regioselective functionalization
of resorcinarenes9,12 and the modular deepening of cavitands.13
Partial bridging of the hydroxyls in resorcinarene 4 with 1,2-
difluoro-4,5-dinitrobenzene led to hexanitro derivative 5. The
NO2 groups were reduced (H2, Ra/Ni, toluene) and then acylated
with propanoyl chloride (Py, CH2Cl2, -78 °C, or K2CO3,
EtOAc/H2O, rt).14 The remaining two resorcinol hydroxyls were
(11) For other approaches toward nanosize host molecules, see: (a)
Timmerman, P.; Nierop, K. G. A.; Brinks, E. A.; Verboom, W.; van Veggel,
F. C. J. M.; van Hoorn, W.-P.; Reinhoudt, D. N. Chem. Eur. J. 1995, 1,
132-143. (b) Higler, I.; Timmerman, P.; Verboom, W.; Reinhoudt, D. N.
J. Org. Chem. 1996, 61, 5920-5931. (c) Higler, I.; Verboom, W.; van
Veggel, F. C. J. M.; de Jong, F.; Reinhoudt, D. N. Liebigs Ann./Recueil
1997, 1577-1586. (d) Chopra, N.; Sherman, J. C. Angew. Chem., Int. Ed.
Engl. 1999, 38, 1955-1957. (e) Chopra, N.; Naumann, C.; Sherman, J. C.
Angew. Chem., Int. Ed. Engl. 2000, 39, 194-196. (f) Lu¨tzen, A.; Renslo,
A. R.; Schalley, C. A.; O’Leary, B. M.; Rebek, J., Jr. J. Am. Chem. Soc.
1999, 121, 7455-7456. Earlier examples of unimolecular capsules: (g)
Chapman, R. G.; Sherman, J. C. J. Am. Chem. Soc. 1998, 120, 9818-
9826. (h) Brody, M. S.; Schalley, C. A.; Rudkevich, D. M.; Rebek, J., Jr.
Angew. Chem., Int. Ed. Engl. 1999, 38, 1640-1644.
(7) (a) Rudkevich, D. M.; Hilmersson, G.; Rebek, J., Jr. J. Am. Chem.
Soc. 1998, 120, 12216-12225. (b) Rudkevich, D. M.; Hilmersson, G.;
Rebek, J., Jr. J. Am. Chem. Soc. 1997, 119, 9911-9912.
(8) Ma, S.; Rudkevich, D. M.; Rebek, J., Jr., Angew. Chem., Int. Ed.
Engl. 1999, 38, 2600-2602.
(9) (a) Renslo, A. R.; Rudkevich, D. M.; Rebek, J., Jr. J. Am. Chem.
Soc. 1999, 121, 7459-7460. (b) Renslo, A. R.; Tucci, F. C.; Rudkevich,
D. M.; Rebek, J., Jr. J. Am. Chem. Soc. 2000, 122, 4573-4582.
(10) Saito, S.; Rudkevich, D. M.; Rebek, J., Jr. Org. Lett. 1999, 1, 1241-
1244.
(12) Portion of this work has been published as a preliminary com-
munication: Tucci, F. C.; Renslo, A. R.; Rudkevich, D. M.; Rebek, J., Jr.
Angew. Chem., Int. Ed. Engl. 2000, 39, 1076-1079.
(13) Tucci, F. C.; Rudkevich, D. M.; Rebek, J., Jr. J. Org. Chem. 1999,
64, 4555-4559.

8882 J. Am. Chem. Soc., Vol. 122, No. 37, 2000
Lu¨cking et al.
Figure 3. Model self-folding cavitands 9 and 10.
also acylated under these conditions, but they were deprotected
with NH2NH2 in toluene/EtOH to give hexaamide diol 6. Reac-
tion of 6 with another equivalent of 1,2-difluoro-4,5-dinitroben-
zene produced dinitro derivative 7a, which was readily reduced
with Ra/Ni to give diamine 7b. Heterocyclization and simul-
taneous oxidation15 of 7b with terephthaldicarboxaldehyde in
hot nitrobenzene as solvent and oxidant resulted in host 2 in
52% yield.
Condensation of 7b with 1,2,5,6-tetraketopyracene 8 (AcO-
Hglac/THF, 1:100, reflux) gave 55% of the C-shaped container
3 together with its S-shaped isomer (not shown). They were
separated by chromatography. The assignment of the C- (3) and
S-shaped diastereomers was performed through 1H NMR
spectroscopy and ROESY experiments with their host-guest
complexes and will be described below. Self-folding cavitands
9 and 10, which adequately represent the structural “halves” of
the hosts 2 and 3, respectively, were also prepared and used
for the model studies (Figure 3). Thus, cavitand 9 was first
isolated as a byproduct in the reaction between 7b and
terephthaldicarboxaldehyde; its synthesis was further optimized
by using a larger excess of the dialdehyde. Reflux of diamine
7b with 1,2-acenaphtenequinone (AcOHglac/THF, 3 h) resulted
in cavitand 10 in 78% yield. Guest molecules 11, 12, and 15-
19 were synthesized by acylation of 1-adamantanamine and
cyclohexylamine with the corresponding acid chlorides.
Spectroscopic Properties and Conformational Analysis.
Self-folding cavitands 1 possess a vase-shaped C4 symmetrical
structure of 8 × 10 Å dimensions.7 As follows from the
extensive IR and 1H and 13C NMR spectroscopic studies,
molecular modeling, and X-ray analysis,7,8,16 the upper rim of
1 features a seam of intramolecular hydrogen bonds formed by
the eight secondary amide groups. Four longer intramolecular
but interannular CdO‚‚‚HN hydrogen bonds bridge the neigh-
boring aromatic walls; four shorter, intraannular hydrogen bonds
fix the orientations of the two amides on a given o-phenylene-
1
Figure 4. Portions of the H NMR spectra (600 MHz, 295 K) of (a)
9 in CD2Cl2, (b) 9 in toluene-d8, (c) 2 in CD2Cl2, and (d) 2 in toluene-
d8. In the downfield region, the NH singlets are seen at 8-12 ppm.
The methine CH triplets are situated at 6-6.5 ppm.
diamine unit. The head-to-tail seam results in two cycloenan-
tiomers,17 with clockwise and counterclockwise orientation of
the HN-CO bonds. The interconversion between two enanti-
omers is slow on the NMR time scale in CDCl3 and aromatic
solvents and fast in more polar acetone-d6.
The CH triplet of the methine bridge in 1 is situated downfield
of 5.5 ppm at room temperature (in CDCl3 and aromatic
solvents). This chemical shift is usually used to estimate the
degree of the cavitand’s conformational mobility; the methine
shifts downfield of 5.5 ppm indicate a stable vase conformation,
while shifts upfield of 4 ppm are characteristic of the C2V
symmetrical kite conformation.18,13 The 1H NMR spectra of self-
folding cavitands 9 and 10 and containers 2 and 3 also showed
the spectroscopic earmarks of the vase conformation of their
cavities at room temperature (in deuterated chlorinated solvents
and aromatic solvents), with the characteristic methine CH
signals at ∼6 ppm. Moreover, the amide NH singlets are situated
downfield of 8 ppm, indicating their involvement in strong
hydrogen bonding (Figures 4-6).
(14) When n-octanoyl chloride was used as an acylating agent, the cor-
responding hosts, homologous to 2 and 3 (octyl-2 and octyl-3), were also
isolated and characterized. However, molecular modeling and also prelimi-
nary 1H NMR experiments showed that the long octyl chains result in sig-
nificant steric hindrances and prevent the encapsulation processes. Moreover,
in the case of the octyl-2 compound, the alkyl chains were seen self-
encapsulated within the internal cavity (1H NMR, benzene-d6 or toluene-
d8, 295 K). Selected data for Octyl-2: Yield 41%; MALDI-MS m/z 4653
avg. ([M + H]+, calcd for C296H422N16O28H 4653). Selected data for octyl-
3: Yield 39% (C + S isomers); mp > 250 °C; MALDI-MS m/z less polar
band 4717, polar band 4725 avg. ([M + H]+, calcd for C302H420N16O28H
4723.8).
Additional features arise from the nonsymmetrical wall
arrangements of 2 and 3. Specifically, the H NMR spectra of
model cavitand 9 showed that the molecule has no mirror plane
(CD2Cl2, toluene-d8) and possesses seven different downfield
1
(17) Cycloenantiomerism: (a) Prelog, V.; Gerlach, H. HelV. Chim. Acta
1964, 47, 2288-2294. (b) Goodman, M.; Chorev, M. Acct. Chem. Res.
1979, 12, 1-7. (c) Yamamoto, C.; Okamoto, Y.; Schmidt, T.; Ja¨ger, R.;
Vo¨gtle, V. J. Am. Chem. Soc. 1997, 119, 10547-10548. In agreement with
the Prelog’s terminology, enantiomers 1 possess the clock- and counter-
clockwise “directionality” of the eight secondary amide “building blocks”
in an otherwise identical “distribution pattern”, or the sequence or
connectivity.
(15) For the typical procedure, see: Yadagiri, B.; Lown, J. W. Synth.
Commun. 1990, 20, 955-963.
(16) For further structural details (X-ray and 1H and 13C NMR) of self-
folding cavitands 1, including the enantiomerically pure compounds, see:
Shivanyuk, A.; Rissanen, K.; Ko¨rner, S. K.; Rudkevich, D. M.; Rebek, J.,
Jr. HelV. Chim. Acta 2000, 83, 1778-1790.
(18) (a) Moran, J. R.; Ericson, J. L.; Dalcanale, E.; Bryant, J. A.; Knobler,
C. B.; Cram, D. J. J. Am. Chem. Soc. 1991, 113, 5707-5714. (b) Tucci, F.
C.; Rudkevich, D. M.; Rebek, J., Jr. Chem. Eur. J. 2000, 6, 1007-1016.

Self-Folding CaVitands of Nanoscale Dimensions
J. Am. Chem. Soc., Vol. 122, No. 37, 2000 8883
1
Figure 5. (Top) schematic representation of cycloenantiomerism and tautomerism in cavities 2 and 9. (Bottom) portions of the H NMR spectra
(600 MHz, 295 K) of (a) 9 in toluene-d8 with 2% (vol) TFA, (b) 2 in toluene-d8 with 2% (vol) DMF-d7, and (c) same as part b after addition of
2% (vol) TFA.
Since the benzimidazole NH proton is also involved, such
racemization would require the tautomerization of this hetero-
cycle. Addition of TFA (∼2-3% vol) catalyzes the cyclorace-
mization: only three amide singlets are observed (a time-aver-
aged plane of symmetry in 9 develops and the (protonated) benz-
imidazole NH signals shift downfield to ∼14 ppm (Figure 5a).
1
The H NMR spectra of compound 2 are sharp in benzene-
d6, toluene-d8, CD2Cl2, and CDCl3 at room temperature (Figure
4c,d). From molecular modeling and also by analogy with
cavitand 9 (Figure 7), the C(O)-NH amides of each cavitand
form a seam of five intramolecular hydrogen bonds within a
vaselike structure, and the additional hydrogen bond is formed
between the benzimidazole NH and its neighboring CdO
oxygen. Each cycloenantiomeric cavitand in 2 possesses either
clockwise or counterclockwise arrangements of the head-to-
tail amides. Indeed, two cyclodiastereomers of 2 are now clearly
observed in ∼1:2 ratio; multiple NH and aromatic CH reso-
1
nances are seen as two nonequal sets in the H NMR spectra
(Figure 4c,d). The origin of this diastereoselection is presently
unknown. Addition of competitive DMF-d7 (∼2-3% vol) did
not accelerate the interconversion between the diastereomers
of 2 (Figure 5b). The reason for this is that the -NH- T dN-
tautomerism of the benzimidazole wall is still slow in the
absence of a proton source. Addition of TFA (∼2-3% vol)
does accelerate this process: the mirror plane, running the long
axis of structure 2, is now established on the NMR time scale;
only three amide and nine aromatic CH singlets are observed.
The imidazole NH singlet is shifted toward ∼14 ppm but is
Figure 6. (Top) schematic representation of cycloenantiomerism in
now obscured by the TFA signal (Figure 5c).
cavities 3 and 10. (Bottom) downfield portions of the 1H NMR spectra
1
The H NMR spectrum of cavitand 10 exhibits an average
C2V symmetry, as only three (broad) NH singlets and three
triplets for the methine CH fragments in a 2:1:1 ratio are
observed (Figure 6a). In contrast to cavitand 9, this speaks for
the fast interconversion between the two cycloenantiomeric
(600 MHz, 295 K) of (a) 10 in toluene-d8, (b) 3 in toluene-d8, (c) 3 in
benzene-d6, and (d) 3 in p-xylene-d10.
NH singlets (Figure 4a,b). Obviously, cycloracemization of the
CdO‚‚‚H-N seam takes place slowly, if it takes place at all.

8884 J. Am. Chem. Soc., Vol. 122, No. 37, 2000
Lu¨cking et al.
Figure 7. Energy-minimized structures (Amber* force field, MacroModel 6.5 program) of self-folding cavities in (a) cavitand 1, (b) hosts 2 and
9 (The imidazole N-H‚‚‚OdC-NH hydrogen bond is indicated by an arrow.), and (c) hosts 3 and 10. The extended polycyclic wall is not involved
in hydrogen bonding. Long alkyl chains and CH bonds have been omitted for viewing clarity. For all cases, only one cycloenantiomer is depicted.
forms of the amides; the extended aromatic wall in 10 is not
involved in the seam of hydrogen bonds.
1
The H NMR spectra of compound 3 are relatively sharp in
benzene-d6 and toluene-d8 but broad in p-xylene-d10 at room
temperature (Figure 6b-d), suggesting that the inner cavity
conformation is sensitive to solvation. The NH resonances are
observed dowfield of 8 ppm, and the corresponding IR spectra
show hydrogen-bonded NH stretching absorptions at 3244 cm-1
(in toluene-d8). From molecular modeling and also by analogy
with cavitands 1 and 10 (Figure 7), the secondary amides of
each cavitand form a seam of five intramolecular hydrogen
bonds within a vaselike structure. Multiple amide NH resonances
in the 1H NMR spectra of 3 indicate that two cyclodiastereomers
are also formed; no diastereoselectivity is observed in this case.
In deuterated aromatic solvents (e.g. benzene and toluene) at
least 10 equal NH singlets are seen downfield of 8 ppm, while
12 are expected for two diastereomers undergoing slow ex-
change. Since one amide NH in each of the cavitand subunits
does not participate in the cyclic arrays, these signals appear
upfield, in the aromatic region of the spectrum.
Host-Guest Properties. Large, nanoscale host molecules
rarely show kinetically stable complexes.11a-d,f This is because
large holes in their structures permit fast entry and exit of
solvents and most guests to occur. The corresponding NMR
chemical shift changes describe an average of the guest’s many
environments. For 2 and 3 kinetically stabile complexes did
form, even though the seam of hydrogen bonds around the rim
of the structures was incomplete.
The internal diameter of unimolecular cavities 2 and 3 was
reasonably estimated by comparison with self-folding cavitand
17,16 and is ∼9-10 Å. The internal length of ∼18-20 Å was
estimated from molecular modeling (Figure 8) and also experi-
mentally, using a series of molecular rulers19 (11-19), i.e., guest
molecules of well-defined length and shape. Their dimensions
are shown in Figure 9. In molecule 2 two cavities can freely
rotate with respect to each other, but host 3 is rigid. By analogy
with self-folding cavitands 1,7 it was anticipated that adamantyl-
and cyclohexyl-containing molecules 11-19 would be the
Figure 8. Energy-minimized structures (Amber* force field, Macro-
Model 6.5 program) of self-folding nanoscale hosts 2 (top, C- and
S-shaped structures) and 3 (bottom). Long alkyl chains and CH bonds
have been omitted for viewing clarity.
appropriate guest species for the inner space in cavitands 9,
10, 2, and 3.
Upon complexation with 11-19 the 1H NMR spectra of hosts
2, 3, 9, and 10 do undergo the expected changes (Figure 10).
Integration clearly indicates the 1:1 stoichiometry for the
complexes of model cavitand 9 with guest molecules 11, 12,
14, 16-18; the NMR signals of the accommodated inside guests
(19) Concept of molecular rulers: Ko¨rner, S. K.; Tucci, F. C.; Rudkevich,
D. M.; Heinz, T.; Rebek, J., Jr. Chem. Eur. J. 2000, 6, 187-195.

Self-Folding CaVitands of Nanoscale Dimensions
J. Am. Chem. Soc., Vol. 122, No. 37, 2000 8885
Figure 9. Guests 11-19 and their calculated dimensions.
Figure 11. Fragments of the ROESY spectra (toluene-d8, 295 K) of
(a) 12‚2‚12 [Selected exchangeable cyclohexyl CH resonances of free
and encapsulated species 12 are indicated. The exchange cross-peaks
for the CH3-aryl signal (at ∼2.2 ppm) and for the aromatic portion of
guest 12 are absent. Two diastereomeric complexes 12‚2‚12 are seen.]
and (b) 3‚17. [The exchange cross-peaks for the CH3-aryl signal (at
∼2.2 ppm, indicated by an arrow), aromatic portion, and adamantyl
resonances of free and encapsulated guest 17 are present. The internal
standard singlet is marked as before.]
1-position is generally not shifted upfield in the NMR spectra:
only the cyclohexane and the adamantane skeleton is oriented
toward the bottom of the cavity 9 and the functional group
toward the top. The upper limit of the association constant values
Kass of ∼80 M-1 (-∆G0 ∼ 2.5 kcal mol-1) was estimated for
guests 11, 12, 14, 16-18 directly from the integration of the
1
corresponding H NMR spectra at 295 K in toluene-d8.
As was the case with 9, host 2 gave upfield 1H NMR signals
between 0 and -3 ppm on complexation with adamantane and
cyclohexane guests (for example, Figure 10g). However, in host
2, two guest molecules 11, 12, 14, 16-18 were detected by
integration inside the host’s inner space, a stoichiometry not
anticipated for such long guests by molecular modeling. The
ROESY spectrum (Figure 11a) of the 12‚2‚12 complex showed
the exchange cross-peaks only between the signals of the
complexed cyclohexyl moiety of 12 with the signals for free
12 but not for the aromatic portion of the guest. This implies
that the molecule 2 does not wrap around both ends of the guest
in a C-shaped structure but rather possesses an S-shape with
two cavities acting independently (Figure 12).
Figure 10. Encapsulation of adamantanes and cyclohexanes. Upfield
portions of the 1H NMR spectra of the complexes (600 MHz, toluene-
d8) (a) 15‚10 at 295 K, (b) 15‚10 at 220 K (In the downfield region, all
six NH singlets of cavitand 10 are clearly seen now at 8.5-11 ppm, as
expected for the cyclic arrangement of the hydrogen bonds.), (c) 3‚17
at 295 K, (d) S-3‚17 at 280 K (No upfield signals were observed at
295 K.), e) 3‚18 at 295 K, (f) 9‚12 at 295 K, and (g) 12‚2‚12 at 295 K.
(The internal standard singlet is marked as “o”.)
For the complexed cyclohexanes 11 and 12, doubled multiple
sets, for each CH proton of the cyclohexyl fragment, were
detected between 0 and -3 ppm (Figure 10g). Now in addition
to the chiral environment, two diastereomeric complexes are
formed. This was further confirmed by the ROESY spectrum
of 12‚2‚12 where two sets of the encapsulated cyclohexyl
fragments were clearly seen (Figure 11a).
were seen upfield 0 ppm at room temperatures. For the
complexed 1-substituted adamantanes 14, 16-18, all four
signals of the skeleton protons can be clearly seen inside host
9 between 0 and -2 ppm. For the complexed cyclohexanes 11
and 12, at least 10 multiple signalssfor each CH proton of the
cyclohexyl fragmentsare seen inside between 0 and -3 ppm
(Figure 10f). This, once again, is because the inner environment
of the cavity is chiral when cycloracemization of the amides is
slow. The functional group at the cyclohexane or adamantane
In a competition 1H NMR experiment between the bis-
adamantane complex 16‚2‚16 and cyclohexane guest 12 in

8886 J. Am. Chem. Soc., Vol. 122, No. 37, 2000
Lu¨cking et al.
0.1 kcal mol-1) and 270 ( 100 M-1 (-∆G295 ) 3.2 ( 0.2 kcal
mol-1) were calculated for the 1:1 complexes 3‚17 and 3‚18,
respectively. These are an order of magnitude higher than seen
for the complexes of 1 with related adamantanes.7
With the more flexible guest 16 and/or shorter (<14 Å)
adamantanes 13-15 (Figure 9), slow exchange between the free
and complexed guest species was observed only at temperatures
<280 K (toluene-d8). For the complex 3‚19, but not for S-3‚
19, the encapsulated n-(CH2)6CH3 signals of 19 were detected
at temperatures e240 K in toluene-d8. In short, from the NMR
measurements with molecular rulers 17-19 and by comparison
with the dimensions of self-folding cavitand 1,7,16 the inner-
space dimensions of host 3 of ∼9 × 18 Å were reasonably
estimated.
The ROESY spectrum of complex 3‚17 gave an estimate for
the guest exchange rate constant of k ∼ 0.5 ( 0.3 s-1 at 295
K.22 This rate is considerably faster than exchange in Cram’s
hemicarceplexes with sizable guests at higher temperatures (k
e 1 × 10-2 s-1, g373 K)3,4 but slower than that of the open-
ended cavitand 1 (k ∼ 2 ( 1 s-1 at 295 K).7,23
Mechanistic Considerations. The guest exchange rate is
governed by the intramolecular hydrogen bonds at the rim of
structures of 2 and 3. When these are disrupted, as on addition
of DMF-d7 to toluene-d8 solutions of the complexes with 2 and
3, the upfield guest signals disappear. It is unlikely that TFA is
a better guest than, say, adamantanes, but DMF is expected to
compete well for the cavity. Both of these solvents also compete
for the hydrogen bonds. Likewise, at temperatures g320 K,
exchange rates with 3 become fast on the NMR time scale for
all guests tested. Model cavitand 10 does not form kinetically
stable complexes with adamantanes 13-19, even at room
temperature (see also Figure 10a,b).
Conformational changes in the hosts are unavoidable during
the process of guest exchange, as openings must be created that
allow for guest substitution. For self-folding cavitands 1, it was
proposed that exchange of guests takes place through an
unfolding of the cavity. The seam of hydrogen bonds must be
(at least partly) disrupted during this process (Figure 1).7 The
exchange between the free and complexed adamantane guest
is ∼17 kcal mol-1 at 295 K, which is almost the same as the
interconversion barrier between the two amide signals.7 We
believe the same mechanism holds for hosts 2 and 3 (Figure
1).
Cram described two stable conformations for general cavitand
structures, the vase and kite.18 In the latter, the four walls are
flipped outward and the cavity disappears. Instead, the extended
aromatic surfaces have a strong tendency toward dimerization,
a process driven by solvophobic forces. These gave rise to the
velcraplex stuctures.13,18 To date, no intermediates in the vase
to kite change have been detected, but they may exist: structures
with one, two, or three walls flipped outward. The faster
exchange of smaller guests from 3 (and 10) hints at this
possibility. Their large walls are not held in place by hydrogen
bonds. These can flip open and expose the encapsulated guest
Figure 12. Rotational features in host 2.
toluene-d8, three different complexes were observed in a roughly
statistical ratio. Since the chemical shifts for the homomeric
complexes 16‚2‚16 and 12‚2‚12 were known (Figure 13a,b),
the signals for the heteromeric complex 12‚2‚16 can be assigned
(Figure 13c). Specifically, two sets of the encapsulated ada-
mantane signals were detected at ca. -1 ppm (Figure 13c), one
of each belongs to the 16‚2‚16 species. Further, the ROESY
spectrum (Figure 13d) of the 12‚2‚16 complex showed the
exchange cross-peaks between both sets of 1H NMR signals of
the complexed adamantyl moiety of 16 with the signals for free
16. In short, the cooperative binding of the two cavities in host
2 has yet to be realized. On the other hand, this bis-cavitand,
each half of which forms kinetically stable complexes with two
different guests,20 shows promise as a vehicle for accelerating
bimolecular reactions.
In contrast to 2, host 3 features cavities that are preorganized
for cooperative binding,21 and long (∼17-18 Å) rigid guests
17 and 18 readily form kinetically stable 1:1 complexes, 3‚17
and 3‚18. The four adamantyl signals and the CH3 or C2H5
groups of complexed 17 and 18 were observed upfield of 0
ppm (Figure 10c-e) and assigned by ROESY experiments
(Figure 11b).
These observations lay at the heart of the assignment of
C-shaped 3 and distinguished it from its S-shaped (S-3)
diastereomer. Only the adamantyl signals were seen for the
complex S-3‚17 and also for the model complex 10‚17.
Association constants (Ka) of 500 ( 50 M-1 (-∆G295 ) 3.6 (
(22) The rate constant k was calculated from the measurements of the
cross-peak to diagonal peak intensities and the molar fractions of the guest
compound 17 undergoing exchange. See for the detailed description: (a)
Perrin, C. L.; Dwyer, T. J. Chem. ReV. 1990, 90, 935-967. (b) Arvidsson,
P. I.; Ahlberg, P.; Hilmersson, G. Chem. Eur. J. 1999, 5, 1348-1354.
(23) Generally, much faster (k . 2 s-1) guest exchange processes take
place for open-ended cavities and the corresponding complexes are not
kinetically stable. The self-assembled dimeric capsules of calix[4]arene with
benzene guest show k ∼ 0.47 s-1 (298 K) (Mogck, O.; Pons, M.; Bo¨hmer,
V.; Vogt, W. J. Am. Chem. Soc. 1997, 119, 5706-5712), and the “tennis
ball” with ethane and methane shows k ∼ 0.5-1.1 s-1 (295 K) (Szabo, T.;
Hilmersson, G.; Rebek, J., Jr. J. Am. Chem. Soc. 1998, 120, 6193-6194).
(20) Pairwise selection of two different guests by a self-assembled
cylindrical capsule: (a) Heinz, T.; Rudkevich, D. M.; Rebek, J., Jr. Nature
1998, 394, 764-766. (b) Heinz, T.; Rudkevich, D. M.; Rebek, J., Jr. Angew.
Chem., Int. Ed. Engl. 1999, 38, 1136-1139. (c) Tucci, F. C.; Rudkevich,
D. M.; Rebek, J., Jr. J. Am. Chem. Soc. 1999, 121, 4928-4929. For the
very recent example from the carcerand chemistry, see ref 11e.
(21) Topologically similar bis-cavitands were reported by Cram: Cram,
D. J.; Tunstad, L. M.; Knobler, C. B. J. Org. Chem. 1992, 57, 528-535.
No kinetically stable complexes were detected for these hosts.

Self-Folding CaVitands of Nanoscale Dimensions
J. Am. Chem. Soc., Vol. 122, No. 37, 2000 8887
Figure 13. Homo-bis-caviplexes 12‚2‚12 and 16‚2‚16, and hetero-bis-caviplex 12‚2‚16. Upfield portions of the 1H NMR spectra of the complexes
(600 MHz, 295 K, toluene-d8) (a) 12‚2‚12, (b) 16‚2‚16, (c) 16‚2‚16 after addition of ∼0.1 equiv of 12 (Complex 12‚2‚16 emerged. Two encapsulated
adamantanes are indicated by arrows.), and (d) fragment of the ROESY spectrum (toluene-d8, 295 K) of the NMR experiment c. (Two encapsulated
adamantyl moieties of 16 are clearly seen in exchange with free 16.)
bonded capsules. They are unimolecular, of nanoscale dimen-
sions, and guest inclusion is still slow on the NMR time scale.
The most immediate applications of these hosts that come to
mind are as sensors for chemical analysis. A second use as
reaction chambers is also intriguing: the internal space is
nanoscale and the constant flow of substrates into and products
out of the cavity can be imagined in the future. In the meantime,
recent, concrete developments include the introduction of
additional binding24 and catalytically active25 sites on the
periphery of these structures. The synthesis of water-soluble
versions for molecular recognition in aqueous solution is also
underway.26
Experimental Section
General. Melting points were determined on a Thomas-Hoover
1
capillary melting point apparatus and are uncorrected. H NMR and
13C NMR spectra were recorded on Bruker AM-300 and Bruker DRX-
600 spectrometers. The chemical shifts were measured relative to
residual nondeuterated solvent resonances. FTIR spectra were recorded
on a Perkin-Elmer Paragon 1000 PC FT-IR spectrometer. Fast Atom
Bombardment (FAB) mass spectra were obtained with a VG ZAB-
VSE double focusing high-resolution mass spectrometer equipped with
a cesium ion gun; m-nitrobenzyl alcohol (NBA) was used as a matrix.
High-resolution matrix-assisted laser desorption/ionization (HR MALDI
FTMS) mass spectrometry experiments were performed on an IonSpec
HiResMALDI Fourier transform mass spectrometer; DHB was used
as a matrix. For high-resolution mass spectral data, for compounds with
molecular weight of g2000, lower than 10 ppm resolution was
guests in host 3.
Figure 14. Conformational features in unimolecular capsule 3.
(Bottom) proposed mechanisms for the exchange of small and large
(24) Renslo, A. R.; Rebek, J., Jr. Angew. Chem., Int. Ed. Engl. 2000, in
to displacement (Figure 14). For exchange of the longer, more
press.
rigid guests, one opening may not be enough: a second wall
may have to flip out to permit substitution.
(25) Starnes, S. D.; Rudkevich, D. M.; Rebek, J., Jr. Org. Lett. 2000, 2,
1995-1998.
(26) For the recent synthesis of water-soluble self-folding cavitands,
see: (a) Haino, T.; Rudkevich, D. M.; Rebek, J., Jr. J. Am. Chem. Soc.
1999, 121, 11253-11254. (b) Haino, T.; Rudkevich, D. M.; Shivanyuk,
A.; Rissanen, K.; Rebek, J., Jr. Chem. Eur. J. 2000, in press.
In conclusion, the self-folding containers reported here
represent a new species of molecular hosts, distinct from the
covalently sealed carcerands and the reversibly formed hydrogen-

8888 J. Am. Chem. Soc., Vol. 122, No. 37, 2000
Lu¨cking et al.
achieved.27 Electrospray ionization (ESI) mass spectra were recorded
on an API III Perkin-Elmer SCIEX triple quadrupole mass spectrometer.
Silica gel chromatography was performed with silica gel 60 (EM
Science or Bodman, 230-400 mesh). All experiments with moisture-
or air-sensitive compounds were performed in anhydrous solvents under
a nitrogen atmosphere.
154.66, 154.1, 149.8, 149.6, 149.4, 138.6, 137.8, 136.5, 135.6, 135.4,
134.9, 128.1, 124.3, 123.7, 121.6, 121.2, 120.4, 120.3, 116.4, 115.9,
33.4, 33.3, 33.0, 32.4, 32.1, 31.9, 30.8, 30.2, 29.8, 29.7, 29.6, 29.4,
28.0, 27.9, 22.7, 14.1, 10.4, 9.8; FTIR (CH2
Cl , cm-1) ν 3409, 3249,
2
2927, 2854, 1666, 1599, 1540, 1514, 1483, 1070, 898, 733, 710; ESI-
MS m/z 1919 ([M + H]+, calcd for C114H148N8O18H 1918).
Diamino Hexaamide Cavitand (7b). Dinitro cavitand 7a (57 mg,
29.8 µmol) was dissolved in a mixture of toluene (15 mL) and EtOH
(2 mL). A catalytic amount of commercial Raney nickel that had been
previously washed with EtOH (3 × 10 mL) was added. The resulting
suspension was evacuated and the reaction flask was filled with H2.
This operation was repeated five times and the mixture was stirred at
40 °C under a H2 atmosphere for 20 h. After cooling, the Raney nickel
was filtered off in a vacuum through a pad of Celite, followed by rinsing
with toluene and EtOH. The filtrates were combined and evaporated
under reduced pressure to give diamine 7b as a yellowish solid (52
mg, 28.1 µmol, 94%) which was taken to the next step without further
purification.
Molecular modeling was performed using the Amber* force field
in the MacroModel 5.5 and 6.5 program.28 Molecular volumes were
calculated with the GRASP program.29
Hexaamide Cavitand (6). Hexanitro cavitand 59 (400 mg, 0.25
mmol) was dissolved in a mixture of toluene (60 mL) and MeOH (20
mL). To this solution was added a catalytic amount of commercial
Raney nickel that had been previously washed with MeOH (2 × 5
mL). The resulting suspension was evacuated and the reaction flask
was filled with H2. This operation was repeated three times and the
mixture was stirred for 12 h at 40 °C under a H2 atmosphere. After
cooling, the Raney nickel was filtered off in a vacuum through a pad
of Celite and rinsed with toluene (50 mL) and MeOH (2 × 50 mL).
The filtrates were combined and evaporated under vacuum to give the
hexaamino cavitand as a brown solid (355 mg, 0.25 mmol, 100%) that
was taken to the next step without further purification. The hexaamino
cavitand (355 mg, 0.25 mmol) was dissolved in degassed CH2Cl2 (20
mL) and kept under N2. Pyridine (380 µL, 4.7 mmol) was added and
the mixture was cooled to -78 °C. Propionyl chloride (204 µL, 2.4
mmol) was added slowly and the resulting solution was kept at -78
°C for 1 h. The reaction was then allowed to slowly warm to room
temperature. After 14 h, the reaction mixture was diluted with CH2Cl2
(30 mL) and washed with 1 N HCl (50 mL) and brine (50 mL). After
drying, the organic layer was concentrated to give a residue (417 mg)
that consisted of a mixture of acylated products. This residue was then
was dissolved in a 1:1 v/v toluene/EtOH mixture (20 mL) and to that
was added NH2NH2-H2O (120 µL, 2.5 mmol). The mixture was stirred
at 85 °C for 4.5 h, after which it was concentrated in a vacuum and
chromatographed in silica gel, eluting with a 98:2 v/v CH2Cl2/MeOH
mixture. The product 6 was obtained as a yellow solid after trituration
with MeOH (55 mg, 31.0 µmol, 13%). Alternatively, hexaamide 6 was
prepared in 66% yield by acylation of the corresponding hexaamino
cavitand with propionyl chloride and K2CO3 in EtOAc/water, 1:1, and
Molecular Container (2). To a solution of 7b from the previous
experiment, was added terephthaldicarboxaldehyde (3.7 mg, 27.6 µmol)
in nitrobenzene (1 mL), the resulting solution was evacuated, and the
reaction flask was filled with N2. The reaction mixture was stirred at
140 °C for 30 h. The solvent was removed under reduced pressure and
the residue was purified by column chromatography (hexane/EtOAc,
4:1-2:1-1:1) to afford product 2 as a white solid (28 mg, 7.4 µmol,
1
52%). H NMR (toluene-d8/2% DMF-d7/2% TFA, 295 K) δ 10.07 (s,
4 H), 9.87 (s, 4 H), 9.43 (s, 4 H), 8.09 (s, 4 H), 7.87 (s, 4 H), 7.82 (s,
4 H), 7.73 (s, 4 H), 7.63 (s, 4 H), 7.52-7.44 (m, 6 H), 7.37 (s, 4 H),
7.22 (s, 4 H), 6.29 (t, J ) 7.8 Hz, 4 H), 6.13-6.05 (m, 4 H), 2.80-
2.00 (m, 40 H), 1.70-1.20 (m, 144 H), 1.1-0.75 (m, 60 H); FTIR
(toluene-d8, cm-1) ν 3617, 3244, 3186, 1660, 1608, 1508, 1479, 1402,
1269, 1221, 1154, 891; MALDI-MS m/z 3812 avg. ([M + H]+, calcd
for C236H302N16O28H 3812).
Molecular Container (3). The crude diamine 7b (17 mg, 9.2 µmol)
was dissolved in THF (2 mL) under a N2 atmosphere. 1,2,5,6-
Tetraketopyracene 830 (1.1 mg, 4.6 µmol) and glacial HOAc (20 µL)
were sequentially added, and the mixture was stirred under reflux for
12 h. After cooling, the solvent was evaporated and the residue was
chromatographed on a preparative thin-layer chromatography plate
(silica gel, 0.5 mm) eluting with a 98:2 v/v mixture of CH2Cl2/MeOH.
Two bands that correspond to the C and the S isomers were isolated
(less polar band ) 5.6 mg, more polar band ) 4.3 mg; combined yield
9.9 mg, 2.55 µmol, 55%). Compound 3 (C-isomer): mp > 250 °C; 1H
NMR (toluene-d8, 295 K) δ 11.08 (s, 1 H, NH), 10.21 (s, 1 H, NH),
10.14 (s, 1 H, NH), 9.91 (s, 1 H, NH), 9.76 (s, 1 H, NH), 9.09 (s, 1 H,
NH), 8.81 (s, 1 H, NH), 8.66 (s, 1 H, NH), 8.25 (s, 1 H, NH), 8.00 (s,
1 H, NH), 7.96-7.57 (m, 14 H), 7.33-6.79 (m, 24 H), 6.49 (m, 2 H,
CH), 6.33 (m, 2 H, CH), 6.19 (m, 2 H, CH), 6.11 (m, 2 H, CH), 2.75-
2.35 (m, 24 H), 2.29-1.88 (m, 16 H), 1.79-1.21 (m, 144 H), 1.06-
0.91 (m, 60 H); FTIR (0.5 mM in toluene-d8, cm-1) ν 3244, 3180,
2926, 2854, 1664, 1512, 1483, 1330, 1275, 1229, 1183, 936, 717;
MALDI-MS m/z 3882 avg. ([M + H]+, calcd for C242H300N16O28H
3882.2).
1
then O-deacylated. Mp > 250 °C; H NMR (benzene-d6, 330 K) δ
9.90 (br, 4 H), 7.68 (s, 2 H), 7.60 (s, 3 H), 7.46 (br, 1 H), 7.35 (s, 2
H), 6.98 (br, 2 H), 6.26 (t, J ) 8 Hz, 3 H), 4.57 (br, 1 H), 2.46-2.36
(m, 20 H), 1.57-1.24 (m, 90 H), 0.97-0.93 (m, 12 H); FTIR (benzene-
d6, cm-1) ν 3246, 2926, 2854, 1665, 1601, 1514, 1485, 1402, 1277,
1224, 937, 896; HRMS-MALDI-FTMS m/z 1776.1020 ([M + Na]+,
calcd for C108H148N6O14Na 1776.0951).
Dinitro Hexaamide Cavitand (7a). A solution of hexaamide 6 (53
mg, 30.3 µmol), 1,2-difluorodinitrobenzene (12 mg, 58.8 µmol), and
Et3N (42 µL, 0.30 mmol) in anhydrous DMF (10 mL) was stirred under
N2 for 15 h at 70 °C. The reaction mixture was cooled, and the volatiles
were removed under vacuum. The residue was chromatographed on
silica gel eluting with a 99:1 v/v mixture of CH2Cl2/MeOH. The dinitro
product was obtained as a yellow solid after trituration with MeOH
1
(38 mg, 19.8 µmol, 65%). Mp > 250 °C; H NMR (benzene-d6, 295
Cavitand (9). A solution of diamine 7b (34 mg, 18.4 µmol) and
terephthaldicarboxaldehyde (2.6 mg, 19.3 µmol) in nitrobenzene (1 mL)
was evacuated and the reaction flask was filled with N2. The reaction
mixture was stirred at 140 °C for 24 h. The solvent was removed under
vacuum and the residue was purified by column chromatography
(hexane/EtOAc, 4:1-2:1-1:1) to afford the product as a white solid
(24 mg, 12.2 µmol, 66%). 1H NMR (CDCl3, 295 K) δ 12.04 (s, 1 H),
10.06 (s, 1 H), 10.03 (s, 1 H), 9.74 (s, 1 H), 9.30 (s, 1 H), 9.14 (s, 1
H), 8.86 (s, 1 H), 8.23 (s, 1 H), 7.95-7.84 (m, 5 H), 7.75 (s, 1 H),
7.70 (s, 1 H), 7.63 (s, 1 H), 7.58 (s, 1 H), 7.45 (s, 1 H), 7.44 (s, 1 H),
7.35 (s, 1 H), 7.34 (s, 1 H), 7.31-7.24 (m, 3 H), 7.22 (s, 1 H), 7.21-
7.15 (m, 3 H), 5.76 (t, J ) 8.2 Hz, 1 H), 5.73-5.61 (m, 3 H), 2.75-
1.75 (m, 20 H), 1.50-1.10 (m, 90 H), 0.98-0.85 (m, 12 H); FTIR
(toluene-d8, cm-1) ν 3234, 3186, 2928, 2851, 1703, 1665, 1608, 1512,
1484, 1407, 1269, 891; ESI-MS m/z 1972 ([M + H]+, calcd for
K) δ 9.74 (s, 2 H), 9.70 (s, 1 H), 8.79 (s, 2 H), 7.93 (s, 2 H), 7.89 (s,
2 H), 7.86 (s, 2 H), 7.77 (s, 2 H), 7.53 (s, 2 H), 7.40 (s, 2 H), 7.31 (s,
2 H), 6.42 (t, J ) 8 Hz, 2 H), 6.17 (t, J ) 8 Hz, 1 H), 5.94 (t, J ) 8
Hz, 1 H), 2.49-2.05 (m, 20 H), 1.47-1.33 (m, 72 H), 1.22-0.93 (m,
30 H); 1H NMR (CDCl3, 295 K) δ 9.46 (s, 2 H), 9.32 (s, 2 H), 8.16 (s,
4 H), 7.69 (s, 2 H), 7.55 (s, 4 H), 7.36 (s, 2 H), 7.30 (s, 4 H), 7.27 (s,
2 H), 5.83-5.78 (m, 3 H), 5.60 (t, J ) 8 Hz, 1 H), 2.57-2.40 (m, 12
H), 2.30-2.21 (m, 8 H), 1.49-1.17 (m, 90 H), 0.92 (t, J ) 7 Hz, 12
H); 13C NMR (CDCl3, 295 K) δ 173.57, 173.56, 173.55, 155.5, 154.70,
(27) For details on high-resolution mass spectrometry, see: (a) Rose,
M. E.; Johnstone, R. A. W. Mass Spectrometry for Chemists and
Biochemists; Cambridge University Press: Cambridge, 1982. (b) Jennings,
K. R.; Dolnikowsi, G. G. Methods in Enzymology; McCloskey, J. A., Ed.;
Academic Press: New York, 1990; p 37 and references therein.
(28) Mohamadi, F.; Richards, N. G.; Guida, W. C.; Liskamp, R.; Lipton,
M.; Caufield, C.; Chang, G.; Hendrickson, T.; Still, W. C. J. Comput. Chem.
1990, 11, 440-467.
C122H154N8O15H 1972).
(29) (a) Nicholls, A.; Sharp, K. A.; Honig, B. Proteins 1991, 11, 281-
296. (b) Mecozzi, S.; Rebek, J., Jr. Chem. Eur. J. 1998, 4, 1016-1022.
(30) Clayton, M. D.; Marcinow, Z.; Rabideau, P. W. Tetrahedron Lett.
1998, 39, 9127-9130.

Self-Folding CaVitands of Nanoscale Dimensions
J. Am. Chem. Soc., Vol. 122, No. 37, 2000 8889
Cavitand (10). To a stirred solution of diamine 7b (90 mg, 39.5
µmol) and 1,2-acenaphthenequinone (21 mg, 118.5 µmol) in THF (20
mL) was added glacial HOAc (150 µL), and the resulting mixture was
refluxed for 3 h. After cooling, the volatiles were removed under
vacuum and the residue was purified by column chromatography eluting
initially with CH2Cl2 and then with a 99:1 v/v CH2Cl2/MeOH mixture.
The product was obtained as a yellow solid (75 mg, 31.0 µmol, 78%)
after trituration with MeOH. Mp > 250 °C; 1H NMR (benzene-d6, 295
K) δ 10.00 (br, 2 H), 9.90 (s, 2 H), 9.62 (s, 2 H), 8.29 (s, 2 H), 7.78
(s, 2 H), 7.71 (s, 2 H), 7.68 (d, J ) 8 Hz, 2 H), 7.54 (t, J ) 8 Hz, 2
H), 7.41 (s, 2 H), 7.29 (d, J ) 8 Hz, 2 H), 6.87 (s, 2 H), 6.40 (t, J )
8 Hz, 2 H), 6.17 (t, J ) 8 Hz, 1 H), 5.94 (br, 1 H), 2.64-1.25 (m, 152
H), 0.99-0.88 (m, 30 H); FTIR (CH2Cl2, cm-1) ν 3242, 2957, 2928,
2855, 1659, 1602, 1510, 1482, 1422, 1403, 1193, 1125, 1099, 895,
N-(1-Adamantyl)-4-(4-methylphenyl)benzamide (17). Mp 167-
169 °C (cyclohexane); 1H NMR (CDCl3, 295 K) δ 7.79 (d, J ) 8 Hz,
2 H), 7.63 (d, J ) 8 Hz, 2 H), 7.52 (d, J ) 8 Hz, 2 H), 7.28 (d, J )
8 Hz, 2 H), 5.88 (s, 1 H), 2.42 (s, 3 H), 2.16 (s, 9 H), 1.75 (dd, J ) 13
Hz, ∆ν ) 20 Hz, 6 H); 13C NMR (CDCl3, 295 K) δ 166.33, 143.71,
137.76, 137.16, 134.33, 129.75, 127.16, 126.96, 126.83, 52.26, 41.72,
36.34, 29.50, 21.10; FTIR (CDCl3, cm-1) ν 3434, 3029, 2911, 2852,
1906, 1659, 1610, 1530, 1512, 1489, 1301, 1248, 1088, 859, 817;
HRMS-MALDI-FTMS m/z 346.2149 ([M + H]+, calcd for C24H27-
NOH 346.2165).
4-(4-Ethylphenyl)benzoic Acid. A solution of 4-ethylphenylmag-
nesium bromide, prepared from bromo-4-ethylbenzene (1.38 mL, 10.0
mmol), magnesium turnings (267 mg, 11.0 matg), and anhydrous Et2O
(10 mL), was added dropwise to a rapidly stirring solution of trimethyl
borate (280 µL, 2.5 mmol) and anhydrous Et2O (3 mL) over a 45 min
period. The resulting white suspension refluxed for 30 min, and then
a mixture of sodium hydroxide (1.25 g, 31.3 mmol), 4-iodobenzoic
acid (1.55 g, 6.3 mmol), PdCl2 (11 mg, 62.5 µmol), and water (45
mL) was added slowly. The resulting mixture was refluxed for another
hour and then was extracted with Et2O (2 × 100 mL). The combined
organic extracts were washed with brine, dried over MgSO4, and
filtered. The solvent was removed in a vacuum and the resulting white
solid was purified by column chromatography, eluting with a 2:1 v/v
mixture of hexanes/EtOAc. The product was obtained as a white solid
after recrystallization from EtOH (423 mg, 1.87 mmol, 30%). 1H NMR
(acetone-d6, 295 K) δ 8.10 (d, J ) 8 Hz, 2 H), 7.77 (d, J ) 8 Hz, 2 H),
7.65 (d, J ) 8 Hz, 2 H), 7.34 (d, J ) 8 Hz, 2 H), 2.69 (q, J ) 7 Hz,
2 H), 1.26 (t, J ) 7 Hz, 3 H); 13C NMR (acetone-d6, 295 K) δ 167.6,
146.2, 145.4, 138.1, 131.1, 130.1, 129.5, 128.0, 127.6, 29.1, 16.1.
N-(1-Adamantyl)-4-(4-ethylphenyl)benzamide (18). Mp 198-200
°C (cyclohexane); 1H NMR (CDCl3, 295 K) δ 7.79 (d, J ) 8 Hz, 2 H),
7.63 (d, J ) 8 Hz, 2 H), 7.55 (d, J ) 8 Hz, 2 H), 7.31 (d, J ) 8 Hz,
2 H), 5.87 (s, 1 H), 2.72 (q, J ) 8 Hz, 2 H), 2.16 (s, 9 H), 1.75 (dd,
J ) 13 Hz, ∆ν ) 20 Hz, 6 H), 1.30 (t, J ) 8 Hz, 3 H); 13C NMR
(CDCl3, 295 K) δ 166.4, 144.1, 143.8, 137.4, 134.3, 128.4, 127.2, 127.1,
126.9, 52.3, 41.7, 36.4, 29.5, 28.5, 15.6; FTIR (CDCl3, cm-1) ν 3434,
3028, 2911, 2852, 1906, 1657, 1610, 1529, 1513, 1490, 1302, 1248,
1005, 829; HRMS-MALDI-FTMS m/z 360.2338 ([M + H]+, calcd
for C25H29NOH 360.2322).
780, 678; MALDI-FTMS m/z 2427 ([M + H]+, calcd for C156H214
-
N8O14H 2424.6).
General Procedure for the Preparation of Amide Guests (11,
12, 16-19). The acid chloride (1-2 equiv) was dissolved in EtOAc
(2-3 mL) and added to a rapidly stirred mixture of the amine (1 equiv)
and K2CO3 (2 equiv) in a 1:1 EtOAc/H2O mixture (50 mL). After 3 h,
the mixture was diluted with EtOAc (100 mL) and the organic layer
was separated, washed with brine, dried over MgSO4, and filtered. The
solvent was removed in a vacuum to give amides 11, 12, and 15-18
as white solids in 56-90% yields. 4-(4-Methylphenyl)benzoic acid was
prepared by the literature protocol31 and converted into the correspond-
ing acid chloride by refluxing in thionyl chloride for 3 h under N2.
N-(Cyclohexyl)-n-octanoylamide (11). Mp 74-75 °C; 1H NMR δ
5.37 (br s, 1H, NH), 3.77 (m, 1H, CH-cycl), 2.13 (t, J ) 7.6 Hz, 2H,
C(O)CH2), 1.91 (dd, J ) 12.3, 3.2 Hz, 2 H, CH2), 1.71-1.09 (m, 18
H, CH2), 0.88 (t, J ) 6.9 Hz, 3 H, CH3); 13C NMR δ 172.6, 48.4, 37.5,
33.7, 32.1, 29.6, 29.4, 26.3, 25.9, 25.3, 23.0, 14.5; IR ν 3292, 2919,
2852, 1633, 1548, 1471, 1443, 1248, 1210, 967, 890, 719, 610, 562;
HRMS-FAB m/z 226.2170 ([M + H]+, calcd for C14H28NO 226.2171).
N-(Cyclohexyl)-4-(4-methylphenyl)benzamide (12). Mp 223-224
1
°C; H NMR (300 MHz, CDCl3, 295 K) δ 7.82 (d, J ) 8.2 Hz, 2H),
7.63 (d, J ) 8.2 Hz, 2 H), 7.51 (d, J ) 8.2 Hz, 2 H), 7.28 (d, J ) 8.2
Hz, 2 H), 6.04 (d, J ) 7.6 Hz, 1 H), 4.06-3.96 (m, 1 H), 2.41 (s, 3 H),
2.08-2.04 (m, 2 H), 1.80-1.74 (m, 2 H), 1.70-1.65 (m, 2 H), 1.47-
1.40 (m, 2 H),1.30-1.20 (m, 2 H); 13C NMR (75 MHz, CDCl3, 295
K) δ 166.8, 144.4, 138.3, 137.6, 133.8, 130.0, 127.7, 127.3, 127.2,
49.0, 33.7, 26.0, 25.3, 21.5; HRMS-MALDI-FTMS m/z 294.1843 ([M
+ H]+, calcd for C20H23NOH 294.1852).
N-(1-Adamantyl)-p-(n-heptyl)benzamide (19). Mp 87-88 °C; 1H
NMR (600 MHz, CDCl3, 295 K) δ 7.64 (d, J ) 8 Hz, 2 H), 7.23 (d,
J ) 8 Hz, 2 H), 5.84 (br s, 1 H), 2.63 (2 × d, J ) 7.8 Hz, 2 H), 2.1,
1.75, 1.6, 1.35, 1.3 (5 × m, 25 H), 0.89 (t, J ) 7.5 Hz, 3 H); 13C NMR
(CDCl3, 295 K) δ 167.0, 146.7, 143.8, 133.8, 128.8, 127.1, 52.5, 42.1,
36.8, 36.2, 32.2, 31.7, 29.9, 29.55, 29.52, 23.0, 14.5; HRMS-MALDI-
FTMS m/z 354.2800 ([M + H]+, calcd for C24H35NOH 354.2791).
N-(1-Adamantyl)-p-methylcinnamamide (15). Mp 136-137 °C;
1H NMR (CDCl3, 295 K) δ 7.57 (d, J ) 16 Hz, 1 H), 7.36 (d, J ) 8
Hz, 2 H), 7.16 (d, J ) 8 Hz, 2 H), 6.36 (d, J ) 16 Hz, 1 H), 5.41 (br
s, 1 H), 2.36 (s, 3 H), 2.1, 1.7 (2 × m, 15 H); 13C NMR (CDCl3, 295
K) δ 165.5, 140.5, 140.0, 132.7, 129.9, 128.1, 121.5, 52.5, 42.1, 36.8,
29.8, 21.8; HRMS-MALDI-FTMS m/z 318.1820 ([M + Na]+, calcd
for C20H25NONa 318.1828).
N-(1-Adamantyl)-n-octanoylamide (16). Mp 68-69 °C (MeCN);
1H NMR (300 MHz, CD2Cl2, 295 K) δ 5.12 (s, 1 H), 2.07-2.00 (m,
4 H), 1.98-1.91 (m, 6 H), 1.70-1.62 (m, 6 H), 1.61-1.50 (m, 3 H),
1.34-1.21 (m, 8 H), 0.87 (t, 7.0 Hz, 3 H); 13C NMR (75 MHz, CD2-
Cl2, 295 K) δ 172.3, 51.8, 42.0, 38.1, 36.7, 32.1, 30.0, 29.5, 29.4, 23.0,
14.2; ESI-MS m/z 278 ([M + H]+, calcd for C18H31NOH 278).
Acknowledgment. We are grateful for financial support from
the Skaggs Research Foundation and the National Institutes of
Health. U.L. thanks Alexander von Humboldt Stiftung, Feodor-
Lynen programm for the scholarship. Drs. Laura Pasternack and
Dee-Hua Huang are sincerely acknowledged for their assistance
with the 2D NMR experiments. We also grateful to Prof. Go¨ran
Hilmersson of Go¨teborg University and to Drs. Adam R. Renslo
and Lubomir Sebo for experimental advice.
(31) Bumagin, N. A.; Bykov, V. V. Tetrahedron 1997, 53, 14437-14450.
JA001562L