Self-folding cavitands

Article abstract of DOI:10.1021/ja982970g

A novel class of resorcinarene-based cavitands 2a-e that fold into a deep (8 x 10 ? dimensions) open-ended cavity by means of intramolecular hydrogen bonds has been synthesized. As follows from the FTIR and ¹H NMR spectral data in apolar solvent, a seam of eight intramolecular hydrogen bonds is stitched along the upper rim of the structure 2a-e; the amide C=O···H-N interactions bridge adjacent rings-interannular binding-and are held in place by the seven-membered intraannular hydrogen bonds. The self- folding in 2a-e is reversibly controlled by solvent and temperature. Complexation of self-folding cavitands 2a-e with organic molecules such as (1-substituted) adamantanes, lactams, and cyclohexane derivatives was demonstrated by ¹H NMR spectroscopy in CDCl₃, benzene-d₆ and p-xylene- d₁₀; the binding energy -ΔG°values of 2-4 kcal mol^-1 in p-xylene- d₁₀ at 295 K were calculated. The exchange between complexed and free guest species is slow on the NMR time-scale, and it is proposed that hydrogen bonds are responsible for these unique features. Employing the pronounced upfield ¹H NMR shifts of the complexed guest molecules, attempts were made to study the structure of the caviplexes 'from inside', and the orientation of the encapsulated adamantanes 12, 13, as well as noncovalent interactions of complexed ε-caprolactam 9b with the host walls were deduced. Even though the guest-exchange process in 2a-e is slow on the NMR time scale (k = 2 ± 1 s^{- 1}), it is still faster than that observed for the completely closed hydrogen-bonded calixarene-based capsules or for covalently sealed hemicarceplexes. This places them in an unusual position in the scale of cavity-containing receptors and opens new perspectives to use 2a-e in catalysis and as ¹H NMR supramolecular shift reagents.

Full text of DOI:10.1021/ja982970g

12216
J. Am. Chem. Soc. 1998, 120, 12216-12225
Self-Folding Cavitands
Dmitry M. Rudkevich, Go1ran Hilmersson, and Julius Rebek, Jr.*
Contribution from The Skaggs Institute for Chemical Biology and The Department of Chemistry,
The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037
ReceiVed August 18, 1998
Abstract: A novel class of resorcinarene-based cavitands 2a-e that fold into a deep (8 × 10 Å dimensions)
open-ended cavity by means of intramolecular hydrogen bonds has been synthesized. As follows from the
FTIR and 1H NMR spectral data in apolar solvent, a seam of eight intramolecular hydrogen bonds is stitched
along the upper rim of the structure 2a-e; the amide CdO...H-N interactions bridge adjacent ringssinterannular
bindingsand are held in place by the seven-membered intraannular hydrogen bonds. The self-folding in 2a-e
is reversibly controlled by solvent and temperature. Complexation of self-folding cavitands 2a-e with organic
molecules such as (1-substituted) adamantanes, lactams, and cyclohexane derivatives was demonstrated by 1H
NMR spectroscopy in CDCl3, benzene-d6 and p-xylene-d10; the binding energy -∆G° values of 2-4 kcal
mol-1 in p-xylene-d10 at 295 K were calculated. The exchange between complexed and free guest species is
slow on the NMR time-scale, and it is proposed that hydrogen bonds are responsible for these unique features.
Employing the pronounced upfield 1H NMR shifts of the complexed guest molecules, attempts were made to
study the structure of the caviplexes “from inside”, and the orientation of the encapsulated adamantanes 12,-
13, as well as noncovalent interactions of complexed ꢀ-caprolactam 9b with the host walls were deduced.
Even though the guest-exchange process in 2a-e is slow on the NMR time scale (k ) 2 ( 1 s-1), it is still
faster than that observed for the completely closed hydrogen-bonded calixarene-based capsules or for covalently
sealed hemicarceplexes. This places them in an unusual position in the scale of cavity-containing receptors
1
and opens new perspectives to use 2a-e in catalysis and as H NMR supramolecular shift reagents.
Introduction
monolayers have been presented on a gold surface.9 We have
been using cavitands to study encapsulation phenomena, the
behavior of molecules temporarily isolated from bulk solution.
These capsules involve reversibly formed calix[4]arene dimers10
and the larger, deeper cylinders based on the resorcinarene
cavitands.11 The capsules are held together by a seam of
intermolecular hydrogen bonds. These weak forces permit the
assemblies to form and dissipate over a range of time scales
and to encapsulate guests reversibly. Some phenomena that have
emerged from the study of these systems are self-inclusion,
pairwise selection of guest molecules,11 and even chemical
catalysis. In the present work, we explore the use of intramo-
lecular hydrogen bonding and solvent effects to control the size
Cavitands are synthetic structures with enforced cavities,
molecular vessels capable of binding complementary organic
compounds and ions.1 They were first prepared by Cram from
Ho¨gberg’s resorcinarenes 1,2 and eventually were used in the
syntheses of carcerands,3 the closed-surface container molecules,
velcrands, the dimeric structures with large solvophobic sur-
faces,4 and other molecular cavities.5 The binding properties of
cavitands have been examined in the solid state, the gas phase,
in solution,1,6-8 and even at an interface, self-assembled
(1) (a) Moran, J. R.; Karbach, S.; Cram, D. J. J. Am. Chem. Soc. 1982,
104, 5826-5828. (b) Cram, D. J.; Karbach, S.; Kim, H.-E.; Knobler, C.
B.; Maverick, E. F.; Ericson, J. L.; Helgeson, R. C. J. Am. Chem. Soc.
1988, 110, 2229-2237. (c) Tunstad, L. M.; Tucker, J. A.; Dalcanale, E.;
Weiser, J.; Bryant, J. A.; Sherman, J. C.; Helgeson, R. C.; Knobler, C. B.;
Cram, D. J. J. Org. Chem. 1989, 54, 1305-1312. (d) Cram, D. J. Science
1983, 219, 1177-1183. (e) Cram, D. J.; Cram, J. M. Container Molecules
and their Guests; Royal Society of Chemistry: Cambridge, 1994, pp 85-
130.
(2) (a) Ho¨gberg, A. G. S. J. Am. Chem. Soc. 1980, 102, 6046-6050. (b)
Ho¨gberg, A. G. S. J. Org. Chem. 1980, 45, 4498-4500. For a timely review
see: Timmerman, P.; Verboom, W.; Reinhoudt, D. N. Tetrahedron 1996,
52, 2663-2704.
(7) (a) Dalcanale, E.; Soncini, P.; Bacchilega, G.; Ugozzoli, F. J. Chem.
Soc., Chem. Commun. 1989, 500-502. (b) Soncini, P.; Bonsignore, S.;
Dalcanale, E.; Ugozzoli, F. J. Org. Chem. 1992, 57, 4608-4612. (c)
Dalcanale, E.; Costantini, G.; Soncini, P. J. Inclusion Phenom. Mol.
Recognit. Chem. 1992, 13, 87-92.
(8) Gas-phase complexation studies: (a) Vincenti, M.; Dalcanale, E.;
Soncini, P.; Guglielmetti, G. J. Am. Chem. Soc. 1990, 112, 445-447. (b)
Vincenti, M.; Minero, C.; Pelizzetti, E.; Secchi, A.; Dalcanale, E. Pure Appl.
Chem. 1995, 67, 1075-1084. (b) Dickert, F. L.; Baumler, U. P. A.;
Stathopulos, H. Anal. Chem. 1997, 69, 1000-1005.
(9) (a) Schierbaum, K. D.; Weiss, T.; Thoden van Velzen, E. U.;
Engbersen, J. F. J.; Reinhoudt, D. N.; Gopel, W. Science 1994, 265, 1413.
(b) Huisman, B.-H.; Rudkevich, D. M.; van Veggel, F. C. J. M.; Reinhoudt,
D. N. J. Am. Chem. Soc. 1996, 118, 3523-3524.
(3) For a review, see: Sherman, J. C. Tetrahedron 1995, 51, 3395-
3422. See also ref 1e, pp 131-216.
(4) Cram, D. J.; Choi, H.-J.; Bryant, J. A.; Knobler, C. B. J. Am. Chem.
Soc. 1992, 114, 7748-7765.
(5) (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.
(6) (a) Cram, D. J.; Stewart, K. D.; Goldberg, I.; Trueblood, K. N. J.
Am. Chem. Soc. 1985, 107, 2574-2575. (b) Tucker, J. A.; Knobler, C. B.;
Trueblood, K. N.; Cram, D. J. J. Am. Chem. Soc. 1989, 111, 3688-3699.
(10) (a) Shimizu, K. D.; Rebek, J., Jr. Proc. Natl Acad. of Sci. USA 1995,
92, 12403-12407. (b) Hamman, B. C.; Shimizu, K. D.; Rebek, J., Jr. Angew.
Chem., Int. Ed. Engl. 1996, 35, 1326-1330. (c) Castellano, R. K.;
Rudkevich, D. M.; Rebek, J., Jr. J. Am. Chem. Soc. 1996, 118, 10002-
10003. (d) Castellano, R. K.; Rudkevich, D. M.; Rebek, J., Jr. Proc. Natl.
Acad. Sci. U.S.A. 1997, 94, 7132-7137.
(11) (a) Heinz, T.; Rudkevich, D. M.; Rebek, J., Jr. Nature 1998, 394,
764-766. (b) Ma, S.; Rudkevich, D. M.; Rebek, J., Jr. J. Am. Chem. Soc.
1998, 120, 4977-4981.
10.1021/ja982970g CCC: $15.00 © 1998 American Chemical Society
Published on Web 11/12/1998

Self-Folding CaVitands
J. Am. Chem. Soc., Vol. 120, No. 47, 1998 12217
Synthesis. Resorcinarenes 1a,c, and their 2′-methyl derivative
1b were coupled with 1,2-difluoro-4,5-dinitrobenzene17 in DMA
in the presence of Et3N with the formation of bright yellow
octanitro compounds 4a,b, and c in 25-40% yields (Scheme
1). Reduction of the octanitro derivatives with SnCl2‚2H2O in
boiling EtOH and concentrated HCl afforded the relatively
unstable and oxygen-sensitive octaamines. Subsequent acylation
with appropriate acyl chlorides under Schotten-Baumann
conditions in EtOAc-H2O in the presence of K2CO3 gave
octaamides 2a-e and 5 as colorless solids (Scheme 1).18 From
this reaction the incompletely acylated products, heptaamides
6a,b, were also isolated and characterized. Model compounds
7a,b for spectroscopic comparisons were prepared by acylation
of 1,2-diamino-4,5-dimethoxybenzene19 with octanoyl and chlo-
roacetyl chloride, respectively. Cavitand 3 (R ) (CH2)10CH3)
was synthesized for comparison purposes from resorcinarene
1a and 2,3-dichloroquinoxaline following the published proce-
dure.7
Figure 1. Schematic representation of the concept of reversibly self-
folding cavitands. Dashed lines indicate sites of intramolecular hydrogen
bonds.
and shape of cavitands, their folding and unfolding behavior,
and their binding of complementary guests (Figure 1). The
complexes of such self-folding cavitands, the caviplexes, feature
unusually high kinetic stability in solution, and we interpret their
behavior through the effects of hydrogen bonding on the host’s
conformational dynamics.12,13
Spectroscopic Properties and Conformational Behavior.
All three octanitro compounds 4a-c are clearly C2V conformers
Results and Discussion
In Ho¨gberg’s resorcinarenes 1 (Figure 2), the eight hydroxy
groups form intramolecular hydrogen bonds, and these interac-
tions rigidify the structure by stabilizing the C4V cone conforma-
tion.14 When the OH hydrogens are substituted, the flexibility
of the resorcinarene skeleton increases, and conformations with
other symmetries become preferred.2 Condensation with (het-
ero)aryl halides builds up the walls on the rim of the macrocyclic
structure and creates the cavitands and velcrands. The confor-
mational dynamics of these molecules have been thoroughly
described by Cram.4,15 The molecule flutters between C4V and
C2V symmetries. The former is preferred at higher temperatures
and has all four walls up; it features a well-defined, vase-like
shape. The latter has these walls flipped outward in a kite-like
shape and is the dominant conformation below room temper-
ature. The barrier to interconversion is typically 10-12 kcal/
mol for cavitands with unsubstituted resorcinols and 17-19 kcal/
mol with 2′-alkylated ones.4,15
We prepared new variants, cavitands 2a-e, functionalized
with eight secondary amides at the upper rim of the molecule
(Figure 2). Molecular modeling16 indicated that the vicinal
secondary amides could form intramolecular hydrogen bonds
through a seven-membered ring (Figure 3). In octaamides 2a-e
hydrogen bonds can also bridge adjacent rings. The result is a
deepened vase, and the walls form a stall and forestall the
1
at room temperature, and their H NMR spectra possess, in
particular, two sets of aromatic resonances (see Experimental
Section). At >330 K, however, 4a and c undergo transformation
1
to the C4V conformer (in CDCl3). In contrast, the H NMR
spectra of octaamides 2a-e in various nonpolar solvents showed
the spectroscopic earmarks of the C4V conformation15 at room
temperature, including the characteristic methine CH triplet at
ca. 6 ppm (Figure 4). The N-H resonances for 2a-e are far
downfield, and the FTIR spectroscopic data also suggest strong
hydrogen bonding (Table 1). Of particular interest are the two
amide NH singlets found in the 1H NMR spectra of 2a,b,d,e in
apolar solvents (Table 1).20,21 The two amides present hydrogen
bonds that can bridge adjacent ringssinterannular bindings
and are held in place by the seven-membered intraannular
hydrogen bonds (Figure 5). One of the hydrogen bonds is less
sensitive to temperature and is shielded from external solvent,
whereas the other is somewhat more exposed to the solvent.
The two N-H signals coalescence at higher temperatures. The
amides provide a head-to-tail seam of intramolecular hydrogen
bonds along the upper rim of the structure 2a-e. These
hydrogen bonds are coherent and may offer each other the added
benefits of cooperativity.22,13
In media more competitive for hydrogen bonds (DMSO-d6-
CDCl3 or DMSO-d6-p-xylene-d10 mixtures) the signals for the
1
conformational change to the kite. Both H NMR and FTIR
(17) Kazimierczuk, Z.; Dudycz, L.; Stolarski, R.; Shugar, D. Nucleosides
Nucleotides 1981, 8, 101-117.
spectroscopy, described below, support the role of these
intramolecular hydrogen bonds in these self-folding cavitands
2a-e and determine the unusual complexation properties of
these molecules.
(18) We also prepared and characterized (1H NMR, HRMS-FAB) the
corresponding octakis(tolylsulfonylamides) by reduction of 4a,b and
subsequent acylation with TsCl in dry pyridine, evaporation, and precipita-
tion with cold MeOH. Their 1H NMR spectra in CDCl3 and benzene-d6
showed similar behavior as for 2a-e and 5, respectively. However, no
complexation with lactams and monosubstituted adamantanes was detected
(12) Preliminary publication: Rudkevich, D. M.; Hilmersson, G.; Rebek,
J., Jr. J. Am. Chem. Soc. 1997, 119, 9911-9912. Mass spectrometric
characterization of the ion-labeled complexes will be published elsewhere.
(13) A cyclic array of cooperative intramolecular hydrogen bonds is
somewhat responsible for the structure of valinomycin, a natural ionophore,
and its complexes with cations, see: Dobler, M. In ComprehensiVe
Supramolecular Chemistry; Gokel, G. W., Ed.; Pergamon: Elmsford, NY,
1996; p 267-313.
(14) (a) Abis, L.; Dalcanale, E.; Du vosel, A.; Spera, S. J. Org. Chem.
1988, 53, 5475-5479. (b) Aoyama, Y.; Tanaka, Y.; Sugahara, S. J. Am.
Chem. Soc. 1989, 111, 5397-5404. (c) Abis, l.; Dalcanale, E.; Du vosel,
A.; Spera, S. J. Chem. Soc., Perkin Trans. 2 1990, 2075-2080. For X-ray
studies, see also ref 1c and Hibbs, D. E.; Hursthouse, M. B.; Malik, K. M.
A.; Adams, H.; Stirling, C. J. M.; Davis, F. Acta Crystallogr. 1998, C54,
987-992.
1
by H NMR spectroscopy.
(19) Zhou, Z.-L.; Weber, E.; Keana, J. F. W. Tetrahedron Lett. 1995,
36, 7583-7586 and references therein.
(20) Cavitand 2c, functionalized with eight chloroacetylamido groups,
exhibits only one amide NH singlet at 295 K in CDCl3 and benzene-d6. At
low temperatures in CDCl3, the N-H singlet broadened then separated (Tc
≈ 235 K), and at temperatures lower 230 K two N-H signals were clearly
observed. No coalescence was observed for model, nonmacrocyclic
compound 7b up to 215 K in CDCl3. Such a spectroscopic behavior of 2c
implies the fast interconversion between the amide sites on the NMR time
scale at room temperature.
(21) The barrier to interconversion (∆Gq) of the two types of N-H
signals is 17.4 ( 0.5 kcal mol-1 (Tc ≈ 87 °C) in toluene-d8 and p-xylene-
d10, see ref 12.
(22) For a detailed discussion of cooperative interactions involving
amides, see: (a) Guo, H.; Karplus, M. J. Phys. Chem. 1994, 98, 7104-
7105. (b) Bisson, A. P.; Hunter, C. A.; Morales, J. C.; Young, K. Chem.
Eur. J. 1998, 4, 845-851.
(15) 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.
(16) 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.

12218 J. Am. Chem. Soc., Vol. 120, No. 47, 1998
RudkeVich et al.
Figure 2. Ho¨gberg’s resorcinarenes 1 and derived cavitands 2 and 3.
Figure 3. Intramolecular hydrogen bonding in vicinal diamides, used for the synthesis of self-folding cavitands 2a-e. The self-complementary
donor and acceptor sites are indicated.
Scheme 1
“upper” end of the molecule, for example, the NH singlets and
the diamido aromatics, are broad, indicating a dynamic process,
which is probably the C4V to C2V interconversion.
a C2V conformer at room temperature and exibits two sets of
aromatic and 2′-Me protons in the 1H NMR spectra in different
solvents. The amide sites are remote from each other and there
is no hydrogen bonding between adjacent aromatic rings.
Accordingly, octaamide 5 has spectroscopic characteristics that
are very similar to those of the model 7a (Table 1).
Additional evidence of the cyclic array of hydrogen bonds
in 2a-e comes from symmetry considerations. Due to the head-
to-tail nature (either clockwise or counterclockwise) of the
hydrogen-bonding pattern in apolar solvents, the C(O)CH2
protons in 2a-e, but not in 7a,b, become diastereotopic (Figure
6A). In the case of octakis(chloroacetamido) cavitand 2c, this
For the model compounds 7a,b (Scheme 1, Table 1), a single
N-H resonance upfield 8.7 ppm was observed in nonpolar
solvents at room temperature. The N-H signal is much more
sensitive to temperature, and it is more concentration dependent
(1H NMR, FTIR).12 Obviously, the model 7a,b undergo fast
exchange between two intramolecular hydrogen-bonded struc-
tures, and at increased concentrations, intermolecular aggregates
can be formed (see also Figure 3).
Compound 5 that is based on 2′-methylresorcinarene 1b, is

Self-Folding CaVitands
J. Am. Chem. Soc., Vol. 120, No. 47, 1998 12219
Figure 5. Two views of the energy-minimized16 structure of cavitand
2; the long alkyl chains and CH hydrogens are omitted for viewing
clarity.
d6 show, in particular, seven distinct downfield amide NH
resonances within 10-8 ppm region and four CH methine
triplets at ca. 6 ppm. Obviously, a seam of cooperative hydrogen
bonds still exists, although the cycle is broken. The lone amino
group can act as a donor to the nearby carbonyls but not as an
acceptor to the nearby N-H bonds.
Complexation. Complexation properties of previously known
cavitands (alkylenedioxy-bridged, dialkylsilicon-bridged and
heterophenylene-bridged) have been studied in great detail by
Cram and Dalcanale.6-8 In solution, the affinity toward small
organic molecules was detected, but the complexation processes
are fast on the NMR time scale, and only time-averaged signals
can be seen when binding occurs. In the case of alkylenedioxy-
bridged cavitands, chemical shift changes of up to 0.28 ppm
were detected in CCl4 upon addition of (5% vol) CD2Cl2, CD3-
CN, CS2, CD3NO2, and C6D5CD3. The association constant
(Kass) of e100 M-1 was calculated for CD3CN at 300 K.6
Heterophenylene-bridged cavitands (for example, 3) showed
affinity toward aromatic molecules; Kass of up to 200 M-1 were
found in acetone-d6.7 We found that self-folding in cavitands
2a-e results in a number of novel features. First, the amide
groups deepen the cavity to dimensions of ca. 8 × 10 Å (Figure
5). Second, the size and shape of the deep cavity very much
resembles those of known7,15 cavitand 3. However, in contrast
to 3, the cavities in 2a-e are formed under thermodynamic
control. Third, exchange between complexed and free guest
species was slow on the NMR time-scale. We propose that the
circle of hydrogen bonds is responsible for these features.
Initially, we tested the behavior of 2a-e in aromatic solvents.
Undoubtedly, the deep but open-ended cavity is solvated, and
molecular modeling16 accommodates one molecule of p-xylene
or mesitylene and, at best, two molecules of benzene or CHCl3
inside. The solvent mixtures benzene-d6-CDCl3, benzene-d6-
p-xylene-d10, or benzene-d6-toluene-d8 give only one set of 1H
NMR signals at 25 °C.
1
Figure 4. Downfield region of the H NMR spectra (600 MHz, 295
K) of cavitand 2d (0.5 mM) in different solvents. The solvent signals
with corresponding satellites are marked.
Table 1. Spectroscopic Data for the Amide NH Signals in
Cavitands 2c,d,e and 5, and Model Compounds 7a,b in Various
Solventsa,b
solvent
δ, ppm
9.5
ν, cm-1
3253
2cc
CDCl3
benzene-d6
p-xylene-d10
9.6
9.4
benzene-d6-DMSO-d6, 10:1 9.7
2dc CDCl3
benzene-d6
9.9, 9.1
10.1, 9.9
10.2, 10.0
10.0, 9.8
9.8, 9.3
9.1
3240
3233
toluene-d8
p-xylene-d10
mesitylene-d12
CDCl3-DMSO-d6, 10:1
CDCl3
benzene-d6
p-xylene-d10
CDCl3
2ec
5
9.7, 8.8
9.8, 9.4
9.6, 9.5
7.9, 7.8
9.0 br, 8.3 br
9.2, 9.1
8.7d
3246
3419, 3255
benzene-d6
CDCl3-DMSO-d6, 1:10
CDCl3
benzene-d6
DMSO-d6
7a
7b
3421, 3309 w
3389, 3254 w
8.5d
9.2
CDCl3
8.5d
a At 0.5 mM, 295 ( 1 K. b Spectra of cavitands 2a and b are similar
to those of 2d and e, respectively. c The spectra are essentially
concentration independent (20-0.05 mM); error (0.1 ppm. d At 20
mM. The IR absorption ratios change in the expected concentration-
dependent manner toward the monomer upon dilution from 20 to 0.05
mM. br - broad signal, w - weak absorption.
Intuitively, it seemed that polycyclic alkanes, such as ada-
mantanes, and structures with hydrogen-bonding capabilities,
such as lactams, would have the right size and shape to fill the
cavity in 2a-e, and indeed, such complexes were detected.
Specifically, addition of excess N-cyclohexyluracyl 8, several
cyclic lactams (9a-c, 10, 11, and 14), or adamantane and its
amino and carboxy derivatives (12 and 13, Figure 7) to a
solution of 2 in benzene-d6 and p-xylene-d10 gave two sets of
results in a the large geminal coupling constant of 13.7 Hz in
CDCl3 and benzene-d6 (Figure 6B). As expected, addition of
5-10% (vol) of highly competitive DMSO-d6 breaks this circle
of hydrogen bonds, and the C(O)CH2Cl AB-system collapses
into a singlet (Figure 6B). In the same way, the two hydrogen-
bonded amide NH singlets in 2a,b,d, and e become one singlet
upon DMSO-d6 addition. Similar behavior was detected in some
calixarene-based capsules which feature head-to-tail cyclic
patterns of urea groups.10
1
signals in the H NMR spectra, both for the cavitands and the
corresponding caviplexes (Figures 8-10). The signals for the
guest species were clearly observed upfield of 0 ppm, a feature
characteristic of inclusion in a shielded environment and similar
to the shifts observed in covalently bound carceplexes.3
However, ferrocene, (1R)-(-)-camphorquinone, some Kemp’s
Even the heptaamides 6a,b exist in a vase conformation at
g295 K. The 1H NMR spectra of 6a,b in CDCl3 and benzene-

12220 J. Am. Chem. Soc., Vol. 120, No. 47, 1998
RudkeVich et al.
Figure 6. (A) Schematic depiction of the enantiomers caused by the head-to-tail cyclic array of hydrogen-bonded amides in compounds 2a-e. (B)
1
Region of the H NMR spectra (600 MHz, 295 K) of compound 2c in benzene-d6 (ca 0.5 mM) and in benzene-d6-DMSO-d6 mixtures.
1
Figure 8. Typical H NMR spectra (p-xylene-d10, 600 MHz, 295 K)
of the complexes of cavitand 2d (0.5 mM solution) with different guests.
(A) With ꢀ-caprolactam 9b (ca 20 equiv). (B) With N-cyclohexyluracyl
8 (8 equiv); guest-free cavitand 2d is also present due to low solubility
of the guest. (C) With C70 (3 equiv); guest-free cavitand 2d is also
present due to low solubility of the guest. The solvent signals with
Figure 7. (A) Guest molecules 8-14 used for complexation with
cavitands 2a-e. (B) Energy-minimized16 complex of 2 with adaman-
tane. Long alkyl chains, CH hydrogens and the rear of the structure
have been deleted for clarity.
corresponding satellites and the internal standard singlet are marked
“O” and “b”, respectively.
indicates that the cavity in 2 is unable to accommodate such a
sizable molecule, addition of up to 3 equiv of C70 to a solution
of 2d (0.5-0.8 mM concentration) gave two sets of signals in
triacid derivatives, 2(1H)-pyridone, 2-pyrrolidinone, and vale-
rolactam showed no kinetically stable complexes with 2 in the
1H NMR spectra in either benzene-d6 or p-xylene-d10.
The NMR signals of the cavitand skeleton, especially the
aromatics and the amide NH groups, also undergo significant
changes upon complexation (Figures 8-10). In contrast, cav-
itand 3 (R ) (CH2)10CH3) does not show such a behavior; only
slight changes in the chemical shifts of the host aromatics were
observed, and no encapsulated guest species were detected in
different titration experiments with ꢀ-caprolactam and adaman-
tanes.
1
the H NMR spectra (Figure 8C). From the integration, the
association constant Kass value of 400 ( 100 M-1 was estimated,
assuming 1:1 complexation at 295 K. However, the correspond-
ing Job plots also indicate the presence of the 2:1 2d‚C70
complex. Due to the low solubility of C70 in xylene, the
equilibria cannot be completely driven to the complex formation.
Even so, this appears to be a rare example of a kinetically stable
complex between C70 and synthetic receptor in an organic
solvent.23,24
Of particular interest is the formation of a complex between
70 and 2 in p-xylene-d10 solution. Although molecular modeling
The sharp and widely separated signals for free and bound
guest species indicate substantial energetic barriers for guest
C

Self-Folding CaVitands
J. Am. Chem. Soc., Vol. 120, No. 47, 1998 12221
1
Figure 9. Downfield and upfield regions of the H NMR spectra (p-xylene-d10, 600 MHz, 295 K) of cavitand 2d during complexation with
1-substituted adamantanes. (A) With 1-adamantanecarbonyl chloride. (B) With N-(1-adamantyl)acetamide; residual signals of guest-free cavitand
2d are also present due to weak complexation. (C) With 1-adamantanamine. The furthest upfield signal (ca. -2 ppm) is due to the NH2 resonance;
guest-free cavitand 2d is also present due to weak complexation. (D) With 1-[N-(1-adamantyl)]adamantanecarboxamide; two different complexes
are present. The solvent signals with corresponding satellites and the internal standard singlet are marked as before. The host and guest concentrations
are 0.5 and g25 mM, respectively.
exchange in and out of the vases 2a-e. The process is slow on
the NMR time scale at room temperature, a behavior for open-
cavity receptors that is unprecedented.25 In the preliminary
publication of these observations, it was proposed that the
solvent replacement by the guest takes place through an
unfolding of the cavity, for example the seam of hydrogen bonds
must be (partly) broken to release the solvent.12 To support this
mechanism, an EXSY experiment on the adamantane complex
with 2d in p-xylene-d10 was performed (see Experimental
Section). The activation barrier (∆Gq) for the exchange between
the free and complexed guest of 16.9 ( 0.4 kcal mol-1 at 295
K was found; the exchange rate constant k ) 2 ( 1 s-1was
calculated. This barrier is almost the same as the interconversion
barrier between the two amide signals,21 and we still interpret
this as no coincidence. Rather, the processes, unfolding and
guest exchange, are inextricably connected.
It was unexpected to find that an open-ended vessel could
so effectively desolvate and shield guest species from the
1
environment of the bulk solution. The significant upfield H
(23) The UV-vis spectra in p-xylene at 295 K showed the broad
absorbance increase at 400-600 nm upon titrating the C70 solution (10-5
-
(25) The only known example in resorcinarene host-guest chemistry
was reported by Aoyama et al.: (a) Kikuchi, Y.; Kato, Y.; Tanaka, Y.;
Toi, H.; Aoyama, Y. J. Am. Chem. Soc. 1991, 113, 1349-1354. (b)
Kobayashi, K.; Asakawa, Y.; Kikuchi, Y.; Toi, H.; Aoyama, Y. J. Am.
Chem. Soc. 1993, 115, 2648-2654. Slow exchange (on the NMR time scale)
between complexed and free guest and significant complexation-induced
upfield shifts of the 1H NMR signals for bound guest due to the ring-current
effects of the host aromatics were found even upon very weak complexation
(Kass e 10 M-1). The resorcinarene OH groups as well as CH-π interaction
were responsible for the complexation. For the review, see: Aoyama, Y.
In ComprehensiVe Supramolecular Chemistry, Vo¨gtle, F., Ed.; Pergamon:
Elmsford, NY, 1996; Vol. 2, p 279-307.
10-4 M constant concentration) with cavitands 2d and 2e (10-4_5 × 10-3
M concentration). This is in agreement with the previous complexation
studies between fullerenes and calixarenes, see ref 24.
(24) For extensive studies on complexation of C60 and larger fullerenes
by calixarenes in organic solvents, see: (a) Araki, K.; Akao, K.; Ikeda, A.;
Suzuki, T.; Shinkai, S. Tetrahedron Lett. 1996, 37, 73-76. (b) Ikeda, A.;
Yoshimura, M.; Shinkai, S. Tetrahedron Lett. 1997, 38, 2107-2110. (c)
Haino, T.; Yanase, M.; Fukazawa, Y. Angew. Chem., Int. Ed. Engl. 1997,
36, 259-260. (d) Haino, T.; Yanase, M.; Fukazawa, Y. Angew. Chem.,
Int. Ed. Engl. 1998, 37, 997-998. (e) Ikeda, A.; Suzuki, Y.; Yoshimura,
M.; Shinkai, S. Tetrahedron 1998, 54, 2497-2508.

12222 J. Am. Chem. Soc., Vol. 120, No. 47, 1998
RudkeVich et al.
1
Figure 10. Upfield and downfield regions of H NMR spectra (p-xylene-d10, 600 MHz, 295 K) of: (A) Cavitand 2e. (B) The complex with
N-(1-adamantyl)-cyclohehanecarboxamide. (C) The mixture of two different complexes, with N-(1-adamantyl)cyclohexanecarboxamide and N-(1-
adamantyl)-p-toluoylamide. The 2e concentration was 0.5 mM, and the guest concentration is ca. 50 mM. Residual signals of guest-free cavitand
2e are also present due to weak complexation. The solvent signals with corresponding satellites and the internal standard singlet are marked as
before.
NMR shifts of the complexed molecules offered the possibility
to examine the structural details of the complexes “from inside”,
that is, to determine the orientation of the guest and its
interaction with the receptor walls inside the cavity. In addition,
it was possible to determine how the macroscopic environment
(e.g., bulk solution, concentration or temperature changes, etc.)
influence the shielded complexed species. The self-folding
cavitands are in an unusual position in the scale of cavity-
containing receptors. Even though the guest exchange process
is slow on the NMR time scale (k ) 2 ( 1 s-1), it is still faster
than that observed for the completely closed hydrogen-bonded
Integration clearly indicates that only one guest molecule is
accommodated inside the deep cavity, a stoichiometry antici-
pated by molecular modeling.16 The association constant values
Kass of 400 ( 100 M-1 (-∆G° ) 3.5 ( 0.2 kcal mol-1) for
N-cyclohexyluracyl 8, 850 ( 25 M-1 (-∆G° ) 3.9 kcal mol-1
)
for ꢀ-caprolactam 9b, and 40 ( 10 M-1 (-∆G° ) 2.0 ( 0.3
kcal mol-1 12
)
for adamantanes 12,13 were obtained directly from
the integration of the NMR spectra at 295 K in p-xylene-d10.
However, in benzene-d6 and CDCl3 the binding affinities were
an order of magnitude lower, and -∆G° values of 0.5 ( 0.1
kcal mol-1 at 295 K were found for adamantanes 12,13; no
kinetically stable complex with 8 was detected in CDCl3.
Apparently, some guests have difficulties competing with the
high concentrations of solvents for the interior of the cavity,
but even then the barriers to exchange remain high. At higher
temperatures (g60 °C), the signals for complexed and free
species become broad, and the guest signals eventually disappear
into the baseline.
calixarene-based capsule (k e 0.47 ( 0.1 s-1 26
) or for covalently
bound hemicarcerands (k ) 0.0093 s-1).27
Orientation inside the Cavity. Previously, the guest posi-
tioning inside cavitands was determined exclusively in the solid
state by X-ray crystallography.1,7,8 Due to the fast complex-
ation-decomplexation process on the NMR time scale, the
chemical shift changes report an average of many environments
and are not always easily interpreted. Soncini and Dalcanale
explained the upfield shift of NMe2 in the caviplex 3 (R )
(CH2)5CH3)‚p-nitro-N,N-dimethylaniline by an orientation, wherein
the NMe2 is deep inside the cavity, in acetone-d6 solution.7
Reinhoudt et al. deduced the structure of some steroid complexes
by systematic 1H NMR studies, employing various model host
and guest compounds.5 In contrast, for the complexes of self-
The NOESY spectrum of the 2d‚adamantane complex showed
NOE connectivities between the signals of the complexed
adamantane with the signals for the N-H and the catechol
aromatic protons. Accordingly, the guest molecule floats in the
cavity above the resorcinarene platform (Figure 7B), as antici-
pated by the solid-state structures of known caviplexes.7
For the complexed 1-substituted adamantanes, all three sets
of the skeleton protons can be clearly seen (Figures 9 and 10).
Due to the effects of the nearby aromatic ring-currents, the
chemical shifts of the guest signals are directly related to their
position inside the cavity. The functional group at the adaman-
tane 1-position is generally not shifted upfield in the NMR
1
folding cavitands 2a-e, the H NMR solution spectra speak
for themselves.
(26) Mogck, O.; Pons, M.; Bo¨hmer, V.; Vogt, W. J. Am. Chem. Soc.
1997, 119, 5706-5712.
(27) Cram, D. J.; Blanda, M. T.; Paek, K.; Knobler, C. B. J. Am. Chem.
Soc. 1992, 114, 7765-7773.

Self-Folding CaVitands
J. Am. Chem. Soc., Vol. 120, No. 47, 1998 12223
Figure 11. Dimerization of ꢀ-caprolactam in an apolar solvent and the energy-minimized16 structure of its complex with cavitand 2. Long alkyl
chains and CH hydrogens are omitted.
spectra, indicating that the adamantane skeleton is oriented
toward the bottom of the cavity and the functional group toward
the top. One exception was the case of 1-adamantanamine,
where the NH2-group is situated deeply inside the cavity and
the NH2 resonance is the signal most shielded and appears at
-2 ppm. The pattern of signals for the C-H resonances is also
reversed in this case (Figure 9C). Apparently, the interaction
of the weakly acidic NH2 hydrogens with the π-surface of the
resorcinarene is enough to favor this orientation over others
which offer only CH-π interactions.
1-[N-(1-Adamantyl)]adamantanecarboxamide, taken in ca. 50-
fold excess, gave two diastereomeric 1:1 complexes with 2d,e
in p-xylene-d10 solution (Figure 9D); two sets of characteristi-
cally upfield adamantane signals can be seen. Both adamantyl
ends have approximately the same affinity toward the receptor
cavity, as can be concluded from the integration. The adaman-
tane guest can spin about the long axis of the cavity but is too
large to tumble within it. The resulting diastereomerism has
precedent in carceplexes28 but was unknown in open-ended
cavities. In the cases of N-cyclohexyluracyl 8 and lactams 9b,c,
10, and 11, most of the cycloalkyl signals of the encapsulated
guest are broad at 295 K and situated between 0.5 and -3 ppm
(see also Figure 8A,B). The broadening may indicate the effects
of the reduced symmetry of the guests inside the circle of amides
and a reduced tumbling of these guests.
Hydrogen Bonding in a Shielded Environment. When
molecules possessing hydrogen bonding sites are placed inside
the cavity, they have the occasion to interact with each other
and/or with the walls, and these interactions can be strong or
weak.29 Lactams are known to dimerize in apolar solvents
through hydrogen bonding, and typical dimerization constant
values are usually 20-45 M-1 in benzene and 100-150 M-1
in CCl4.30 We showed that cavitands 2d,e encapsulate lactams,
namely ꢀ-caprolactam 9b, N-methylcaprolactam 10, 2-azacy-
lononanone 9c, 7-butyltetrahydro-2(3H)-azepinone 11, and
4-azatricyclo[4.3.1.13,8]undecan-5-one 13 (Figures 7 and 8B).
Smaller lactams, such 2-pyrrolidinone and valerolactam 9a, did
not show kinetically stable inclusion.
We then probed ꢀ-caprolactam 9b dimerization properties
within the complex of 2d,e.31 It was first determined that
ꢀ-caprolactam dimerizes in p-xylene-d10 with KD ) 50 ( 10
M-1 (-∆G° ) 2.3 kcal mol-1), a value in good agreement with
the previously published figures in similar solvents.30 All six
groups of protons changed their position upon dilution. Specif-
ically, changing the caprolactam concentration from ca. 95 mM
to 0.7 mM caused an upfield shift of the NH signal from 7.3 to
4.9 ppm; the CH2NH multiplet shifted from ca. 2.7 to 2.3 ppm
upfield. Upon addition of caprolactam to the p-xylene-d10
solution of cavitand 2d, both free and encapsulated species can
1
be clearly seen in the H NMR spectrum (Figure 8B), and the
association constant Ka of 850 ( 25 M-1 was calculated,
assuming a 1:1 complex. Surprisingly, no changes in chemical
shift for the encapsulated ꢀ-caprolactam molecules were detected
upon ca. 160-fold change of the total caprolactam concentration
(0.6-95 mM). This suggested that caprolactam does not form
dimers inside the cavity 2d; rather, the complexed ꢀ-caprolactam
molecule is shielded from those in bulk solution. The role of
the long chains on the amide functions have yet to be defined
in this context. In addition, hydrogen bonding is possible
between the ꢀ-caprolactam as a donor (or acceptor) and any of
the 2d (wall) amide groups (see Figure 11). This likely further
protects the lactam from the environment outside. Such hydro-
gen bonding was suggested by molecular modeling16 and by a
competition experiment. When a 1:1 mixture of caprolactam
9b and the acceptor but not donor, N-methylcaprolactam 10,
(ca. 40 mM each) was added to the 0.5 mM p-xylene-d10
solution of cavitand 2d, the 9b‚2d complex was observed
predominantly (>90%).
In conclusion, self-folding cavitands represent a new species
of molecular containers, distinct from the covalently sealed
carcerands and the reversibly formed hydrogen-bonded capsules.
The “self” refers to the effects of the hydrogen bonds on the
behavior of the molecules and is also the popular prefix for
molecular recognition phenomena of the decade: replication,
assembly, and organization. The deep cavities here are open,
but guest inclusion is slow on the NMR time scale. The uptake
and release of guests involves the folding and unfolding of the
host, achieved by either varying solvent polarity and/or tem-
perature. There is a possibility of using these containers as
(28) (a) 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. (b) Chapman, R. G.; Sherman, J. C. J. Am. Chem. Soc.
1995, 117, 9081-9082. For self-assembled capsules, see ref 11a.
(29) For earlier studies of hydrogen bonding inside synthetic (assembled)
niches, see: (a) Nowick, J. S.; Chen, J. S.; Noronha, G. J. Am. Chem. Soc.
1993, 115, 7636-7644. (b) Nowick, J. S.; Cao, T.; Noronha, G. J. Am.
Chem. Soc. 1994, 116, 3285-3289. (c) Ruf, M.; Weis, K.; Vahrenkamp,
H. Inorg. Chem. 1997, 36, 2130-2137. (d) Zimmerman, S. C.; Wang, Y.;
Bharathi, P.; Moore, J. S. J. Am. Chem. Soc. 1998, 120, 2172-2173.
(30) (a) Klemperer, W.; Cronyn, M. W.; Maki, A. H.; Pimentel, G. C.
J. Am. Chem. Soc. 1954, 76, 5846-5848. (b) Huisgen, R.; Walz, H. Chem.
Ber. 1956, 89, 2616-2629. (c) Hopmann, R. F. W. J. Phys. Chem. 1974,
78, 2341-2348. (d) Wagner, K.; Rudakoff, G.; Fro¨lich, P. Z. Chem. 1975,
15, 272-275. (e) Walmsley, J. A. J. Phys. Chem. 1978, 82, 2031-2035.
(f) Krikorian, S. E. J. Phys. Chem. 1982, 86, 1875-1881.
(31) Cram has described a carceplex with 2-pyrrolidinone and suggested
hydrogen bonding occurs between the guest NH and the inward-turned
unshared electron pairs of the host ArOCH2 walls. This orients the
2-pyrrolidinone cycle to the equatorial region of the carceplex cavity. See:
Robbins, T. A.; Knobler, C. B.; Bellew, D. R.; Cram, D. J. J. Am. Chem.
Soc. 1994, 116, 111-122.

12224 J. Am. Chem. Soc., Vol. 120, No. 47, 1998
RudkeVich et al.
27,37:28,36-Dimetheno-29H,31H,33H,35H-dibenzo[b,b′]bis[1,7]-
benzodioxonino[3,2-j:3′,2′-j′]benzo[1,2-e:5,4-e′]bis[1,3]-
benzodioxonin, 2,3,9,10,16,17,23,24-octakis(n-octanoylamido)29,-
reaction vessels for monosubstituted adamantane derivatives
since the corresponding acid chloride, amine, and isocyanate
are easily accommodated inside (Figure 7). As the constant flow
of the substrate into and the product out of the cavity can be
envisioned, turnover and true catalysis may be possible. The
introduction of additional (catalytically) useful sites on the upper
rim would also appear likely. The most immediate application
is in analysis. Cavitands 2 act as NMR shift reagents for number
of molecules, substituted adamantanes, lactams, and cyclohexane
1
31,33,35-tetranonyl- (2a): colorless foam; H NMR (benzene-d6) δ
10.02, 9.85 (2 × s, 8 H), 8.01, 7.78, 7.47, 7.31 (4 × s, 16 H), 6.36 (t,
J ) 8.2 Hz, 4 H), 2.6-2.1, 1.8-1.4, 1.3-1.1 (m, 160 H), 0.99 (t, J )
7.0 Hz, 12 H), 0.94 (t, J ) 7.0 Hz, 24 H); HRMS-FAB m/z 2550.6284
([M + Cs]+, calcd for C152H224N8O16Cs 2550.6015).
27,37:28,36-Dimetheno-29H,31H,33H,35H-dibenzo[b,b′]bis[1,7]-
benzodioxonino[3,2-j:3′,2′-j′]benzo[1,2-e:5,4-e′]bis[1,3]-
benzodioxonin, 2,3,9,10,16,17,23,24-octakis(cyclohexanoylamido)-
1
derivatives. Their H NMR spectra as mixtures can be easily
1
29,31,33,35-tetranonyl- (2b): mp >175 °C dec; H NMR (benzene-
analyzed in the upfield (negative ppm region) but not in their
usual regions because of overlapping resonances. For example,
Figure 10C shows how the distribution of two monosubstituted
adamantanes inside a cavity can be determined using only 1-2
mol % of 2e as a shift reagent. We are currently exploring these
applications and will report on them in due course.
d6) δ 9.85, 9.46 (2 × s, 8 H), 7.94, 7.73, 7.38, 7.35 (4 × s, 16 H), 6.30
(t, J ) 8.2 Hz, 4 H), 2.4-1.1 (m, 168 H), 0.93 (t, J ) 7.0 Hz, 12 H);
HRMS-FAB m/z 2422.3696 ([M + Cs]+, calcd for C144H192N8O16Cs
2422.3511).
27,37:28,36-Dimetheno-29H,31H,33H,35H-dibenzo[b,b′]bis[1,7]-
benzodioxonino[3,2-j:3′,2′-j′]benzo[1,2-e:5,4-e′]bis[1,3]-
benzodioxonin, 2,3,9,10,16,17,23,24-octakis(chloro-acetylamido)-
29,31,33,35-tetranonyl- (2c): mp >195 °C dec; 1H NMR (CDCl3) δ
9.54 (s, 8 H), 7.56 (s, 8 H), 7.30, 7.20 (2 × s, 8 H),5.77 (t, J ) 8.0 Hz,
4 H), 4.21, 4.10 (2 × d, J ) 13.6 Hz, 16 H), 2.25 (m, 8 H), 1.3 (m, 56
H), 0.91 (t, J ) 7.2 Hz, 12 H); 1H NMR (benzene-d6) δ 9.58 (s, 8 H),
7.75, 7.00 (2 × s, 8 H), 7.26 (s, 8 H), 6.28 (t, J ) 8.0 Hz, 4 H),), 3.58,
3.49 (2 × d, J ) 13.7 Hz, 16 H), 2.42 (m, 8 H), 1.5, 1.4, 1.3 (3 × m,
56 H), 0.93 (t, J ) 7.2 Hz, 12 H); HRMS-FAB m/z 2149.5553 ([M +
Cs]+, calcd for C104H120Cl8N8O16Cs 2149.5385).
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 a Bruker AM-300 and a Bruker
DRX-600 spectrometers. The chemical shifts were measured relative
to residual nondeuterated solvent resonances or TMS. 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.
For high-resolution mass spectral data (HRMS-FAB), for compounds
with molecular weight e500, the measured masses always agreed to
e5 ppm with the calculated values. For compounds with significantly
higher molecular weight (g2000), lower resolution was achieved.32 In
most of the cases, the FAB-MS measurements were taken in duplicate.
Matrix-assisted laser desorption/ionization (MALDI) mass spectrometry
experiments were performed on a PerSeptive Biosystems Voyager-Elite
mass spectrometer with delayed extraction, using 2,5-dihydroxybenzoic
acid (DHB) as a matrix. Electrospray ionization (ESI) mass spectra
were recorded on an API III Perkin-Elmer SCIEX triple quadrupole
mass spectrometer. FTIR spectra were recorded on a Perkin-Elmer
Paragon 1000 PC FT-IR 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. Com-
pounds 1a-c1b,1c and 3 (R ) (CH2)10CH3)7 were synthesized in
accordance with the literature protocols. Molecular modeling was
performed using the Amber* force field in the MacroModel 5.5
program.16
27,37:28,36-Dimetheno-29H,31H,33H,35H-dibenzo[b,b′]bis[1,7]-
benzodioxonino[3,2-j:3′,2′-j′]benzo[1,2-e:5,4-e′]bis[1,3]-
benzodioxonin, 2,3,9,10,16,17,23,24-octakis(n-octano-ylamido)29,-
1
31,33,35-tetraundecyl- (2d): mp 239-240 °C; H NMR (CDCl3) δ
9.90, 9.09 (2 × s, 8 H), 7.77, 7.20, 7.12, 7.09 (4 × s, 16 H), 5.79 (t,
1
J ) 8.1 Hz, 4 H), 2.6-1.2 (m, 168 H), 1.0-0.9 (m, 36 H); H NMR
(benzene-d6) δ 10.06, 9.86 (2 × s, 8 H), 8.00, 7.78, 7.47, 7.30 (4 × s,
16 H), 6.37 (t, J ) 8.2 Hz, 4 H), 2.58, 2.45, 2.42, 2.25, 2.11, 1.75,
1.65, 1.5, 1.4, 1.3-1.1 (12 × m, 176 H), 1.00 (t, J ) 7.0 Hz, 12 H),
0.96 (t, J ) 7.0 Hz, 24 H); 1H NMR (p-xylene-d10) δ 10.02, 9.82 (2 ×
s, 8 H), 8.00, 7.78, 7.47, 7.30 (4 × s, 16 H), 6.37 (t, J ) 8.2 Hz, 4 H),
2.58, 2.45, 2.42, 2.25, 2.11, 1.75, 1.65, 1.5, 1.4, 1.3-1.1 (12 × m, 176
1
H), 1.00 (t, J ) 7.0 Hz, 12 H), 0.96 (t, J ) 7.0 Hz, 24 H); H NMR
(mesitylene-d12) δ 9.79, 9.33 (2 × s, 8 H), 7.91, 7.63, 7.21, 7.13 (4 ×
s, 16 H), 6.16 (t, J ) 8.2 Hz, 4 H), 2.5-1.2 (mm, 176 H), 0.98 (t, J )
7.0 Hz, 12 H), 0.96 (t, J ) 7.0 Hz, 24 H); MALDI-MS m/z 2553 ([M
+ Na+], calcd 2553); HRMS-FAB m/z 2663.7505 ([M + Cs]+, calcd
for C160H240N8O16Cs 2662.7267).
27,37:28,36-Dimetheno-29H,31H,33H,35H-dibenzo[b,b′]bis[1,7]-
benzodioxonino[3,2-j:3′,2′-j′]benzo[1,2-e:5,4-e′]bis[1,3]-
benzodioxonin, 2,3,9,10,16,17,23,24-octakis(cyclohexa-noylamido)-
General Procedure for the Preparation of Octaamides 2a-e and
5, and Heptaamides 6. A mixture of octanitro compound 4a-c (0.12
mmol) and SnCl2‚2H2O (1 g, 4.4 mmol) was boiled in 20 mL of EtOH
and concentrated HCl (3-5 mL) for 5 h, cooled, and then poured onto
ice. The pH was adjusted to 10 with 2 M aqueous NaOH, and the
released octaamine was extracted with CH2Cl2 (2 × 50 mL). The
organic layer was washed with water (2 × 100 mL), dried over Na2-
SO4, and then evaporated to give the octaamines as greenish solids.
These were used immediately for the next step. The yields were 60-
65%, and the crude octaamines gave satisfactory mass-spectral data.
To a vigorously stirred mixture of the appropriate octaamine (0.08
mmol) and K2CO3 (0.1 g, 0.65 mmol) in EtOAc-H2O, 1:1 (20 mL)
was added the specified acid chloride (0.65 mmol) by syringe. The
reaction mixture was stirred for 2 h, the organic layer was separated,
and the aqueous layer was extracted with CH2Cl2 (2 × 25 mL). The
combined organic layers were washed with water (2 × 100 mL), dried
over MgSO4, and then evaporated. Pure amides 2a-e and 5 were
obtained as colorless solids in 50-55% yields by preparative TLC
(silica gel) using EtOAc-hexanes mixtures. Heptaamides 6a,b were
isolated as byproducts in ca. 10% yield through preparative TLC.
1
29,31,33,35-tetraundecyl- (2e): mp 108 °C dec; H NMR (benzene-
d6) δ 9.84, 9.37 (2 × s, 8 H), 7.93, 7.75, 7.41, 7.29 (4 × s, 16 H), 6.32
(t, J ) 8.1 Hz, 4 H), 2.4-1.1 (m, 168 H), 0.93 (t, J ) 7.0 Hz, 12 H);
1H NMR (p-xylene-d10) δ 9.55, 9.48 (2 × s, 8 H), 7.83, 7.66, 7.18,
7.03 (4 × s, 16 H), 6.21 (t, J ) 8.2 Hz, 4 H), 2.4-1.1 (m, 168 H),
0.97 (t, J ) 7.0 Hz, 12 H); MALDI-MS m/z 2425 ([M + Na+], calcd
2425); HRMS-FAB m/z 2535.4911 ([M + Cs]+, calcd for C152H208N8O16-
Cs 2534.4763).
27,37:28,36-Dimetheno-29H,31H,33H,35H-dibenzo[b,b′]bis[1,7]-
benzodioxonino[3,2-j:3′,2′-j′]benzo[1,2-e:5,4-e′]bis[1,3]-
benzodioxonin, 6,13,20,39-tetramethyl-2,3,9,10,16,17,23,24-octakis-
(n-octanoylamido)29,31,33,35-tetranonyl- (5): foam; 1H NMR
(DMSO-CDCl3, 10:1) δ 9.18, 9.11 (2 × s, 8 H), 7.46, 6.87 (2 × s, 8
H), 6.91, 6.03 (2 × s, 4 H), 3.93 (m, 4 H), 2.24, 2.04 (2 × s, 12 H),
2.5-2.3, 2.3-2.0, 1.9-1.7, 1.3-1.1 (m, 160 H), 0.90 (t, J ) 7.0 Hz,
12 H), 0.83 (t, J ) 7.0 Hz, 24 H); HRMS-FAB m/z 2606.6363 ([M +
Cs]+, calcd for C156H232N8O16Cs 2606.6641).
27,37:28,36-Dimetheno-29H,31H,33H,35H-dibenzo[b,b′]bis[1,7]-
benzodioxonino[3,2-j:3′,2′-j′]benzo[1,2-e:5,4-e′]bis[1,3]-
benzodioxonin, 2-amino-3,9,10,16,17,23,24-heptakis-(chloroacetyl-
amido)29,31,33,35-tetranonyl- (6a): mp 165 °C dec; 1H NMR
(benzene-d6) δ 9.98, 9.82, 9.59, 9.55, 9.51, 9.07, 8.34 (7 × s, 7 H),
7.8-7.4 (8 × s, 8 H), 7.2-7.0 (m, 8 H), 6.44, 6.39, 6.08, 6.03 (4 × t,
J ) 8.2 Hz, 4 H), 3.8-3.5 (m, 16 H), 2.4-2.2, 1.6-1.2, 1.0-0.9 (m,
(32) For technical 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.; Dolnikowski, G. G. In Methods in Enzymology; McCloskey, J. A.,
Ed.; Academic Press: New York, 1990; p 37 and references therein.

Self-Folding CaVitands
J. Am. Chem. Soc., Vol. 120, No. 47, 1998 12225
76 H); HRMS-FAB m/z 2073.5504 ([M + Cs]+, calcd for C102H119
Cl7N8O15Cs 2073.5669).
-
in a 1:1 molar ratio, under Schotten-Baumann conditions in EtOAc-
H2O in the presence of 2 equiv K2CO3.
27,37:28,36-Dimetheno-29H,31H,33H,35H-dibenzo[b,b′]bis[1,7]-
benzodioxonino[3,2-j:3′,2′-j′]benzo[1,2-e:5,4-e′]bis[1,3]-
benzodioxonin, 2-amino-3,9,10,16,17,23,24-heptakis-(n-octanoyl-
N-(1-Adamantyl)cyclohexanecarboxamide: mp 190-191 °C (cy-
clohexane); 1H NMR (p-xylene-d10) δ 4.54 (br s, 1 H), 2.0-1.5 (mm,
26 H); 13C NMR (CDCl3) δ 175.8, 51.8, 46.8, 42.1, 36.8, 30.2, 29.8,
26.2; HRMS-FAB m/z 262.2169 ([M + Na]+, calcd for C17H27NONa
262.2171).
1
amido)29,31,33,35-tetraundecyl- (6b): mp 200-205 °C; H NMR
(330 K, CDCl3) δ 9.49, 9.37, 9.22, 9.12 (4 × s, 4 H), 9.26, 8.49, 8.13
(3 × br s, 3 H), 7.73, 7.67 (2 × s, 2 H), 7.5-7.3 (m, 14 H), 5.82, 5.71
(4 × t, J ) 8.1 Hz, 4 H), 2.3-2.1, 1.8-1.7, 1.4-1.2, 1.0-0.9 (4 × m,
212 H); 1H NMR (330 K, benzene-d6) δ 9.80, 9.74, 9.66, 9.58, 9.50 (5
× s, 5 H), 9.22, 8.63 (2 × br s, 2 H), 8.0-7.9, 7.77, 7.73, 7.71, 7.69,
7.68, 7.41, 7.28, 7.27, 7.17 (m and 9 × s, 16 H), 6.39, 6.35, 6.14, 6.11
(4 × t, J ) 8.1 Hz, 4 H), 2.4-2.1, 2.0-1.7, 1.5-1.2, 1.0-0.9 (4 × m,
1
N-(1-Adamantyl)toluoylcarboxamide: mp 163 °C (toluene); H
NMR (p-xylene-d10) δ 7.60, 7.00 (2 × d, J ) 7.8 Hz, 4 H), 5.42 (br s,
1 H), 2.10 (s, 3H), 2.0-1.5 (3 × m, 15 H); 13C NMR (CDCl3) δ 167.0,
141.7, 133.5, 129.5, 127.2, 52.5, 42.1, 36.8, 29.9, 21.8; HRMS-FAB
m/z 270.1856 ([M + Na]+, calcd for C18H23NONa 270.1858).
1-[N-(1-Adamantyl)]adamantanecarboxamide: mp 315-316 °C
212 H); HRMS-FAB m/z 2536.6418 ([M + Cs]+, calcd for C152H226
N8O15Cs 2536.6222).
-
1
(EtOH); H NMR (p-xylene-d10) δ 4.86 (br s, 1 H), 2.1-1.5 (5 × m,
30 H); 13C NMR (CDCl3) δ 177.6, 51.6, 42.0, 41.2, 39.7, 36.8, 36.7,
29.7, 28.5; HRMS-FAB 314.2480 ([M + Na]+, calcd for C21H31NONa
314.2484).
General Procedure for the Preparation of Octanitro Compounds
4a-c. To a solution of resorcinarene 1a-c (1 mmol) and 1,2-difluoro-
4,5-dinitrobenzene17 (0.9 g, 4.4 mmol) in DMA (20 mL) was added
Et3N (1.3 mL). The solution was heated at 120 °C for 4-5 h, cooled,
and diluted with water (300-400 mL). The precipitate was filtered
off, washed with water (3 × 100 mL), and dried. The products were
purified by column chromatography with CH2Cl2 as an eluent and
precipitated with cold MeOH. The yellow solids were obtained in 25-
40% yields.
EXSY experiments. The EXSY spectra of complex 2d‚adamantane
were recorded at 295 K at 600 MHz with the phase sensitive NOESY
pulse sequence supplied with the Bruker software. TPPI was used to
obtain quadrature detection in F1. Each of the 480 F1 increments was
the accumulation of 16 scans. The relaxation delay was 2.4 s. The
mixing time was 500 ms. Before Fourier transformation, the FIDs were
multiplied by a π/2 shifted square sine bell function in both the F2 and
the F1 domain. The data file was zero-filled, resulting in a spectrum of
4K × 1K real data points, with a resolution of 1.75 Hz/point in F2 and
7.03 Hz/point in F1. The rate constants k were calculated from the
measurements of the cross-peak (IAB, IBA) to diagonal peak intensities
(IAA, IBB) and the molar fractions (XA, XB) of the different compounds
undergoing exchange.
27,37:28,36-Dimetheno-29H,31H,33H,35H-dibenzo[b,b′]bis[1,7]-
benzodioxonino[3,2-j:3′,2′-j′]benzo[1,2-e:5,4-e′]bis[1,3]-
benzodioxonin, 2,3,9,10,16,17,23,24-octanitro-29,31,33,35-tetra-
nonyl- (4a): mp >250 °C dec; 1H NMR (CDCl3, 295 K) δ 7.66, 7.61
(2 × s, 8 H), 7.25, 6.20 (2 × s, 4 H), 7.10, 7.08 (2 × s, 4 H), 3.90 (m,
4 H), 2.1, 2.0 (2 × m, 8 H), 1.4-1.2 (m, 56 H), 0.87 (t, J ) 7.2 Hz,
12 H); ESI-MS m/z 1648 ([M + H]+, calcd for C88H96N8O24 1649).
27,37:28,36-Dimetheno-29H,31H,33H,35H-dibenzo[b,b′]bis[1,7]-
benzodioxonino[3,2-j:3′,2′-j′]benzo[1,2-e:5,4-e′]bis[1,3]-
benzodioxonin, 6,13,20,39-tetramethyl-2,3,9,10,16,17,23,24-octanitro-
29,31,33,35-tetranonyl- (4b). The compound is structurally similar to
A yk1z B
k-1
k ) k1 + k-1
1
the previously prepared by Cram.4 Mp >350 °C; H NMR (CDCl3,
295 K) δ 7.78, 7.48 (2 × s, 8 H), 7.08, 5.97 (2 × s, 4 H), 3.87 (m, 4
H), 2.40, 2.21 (2 × s, 12 H), 2.2-2.0 (2 × m, 8 H), 1.5-1.2 (m, 56
H), 0.84 (t, J ) 7.0 Hz, 12 H); MS-FAB m/z 1838 ([M + Cs]+, calcd
for C92H104N8O24Cs 1838).
1
r + 1
k ) ln
τm r - 1
where r ) 4XAXB (IAA + IBB)/(IAB + IBA) - (XA - XB)2
27,37:28,36-Dimetheno-29H,31H,33H,35Hsdibenzo[b,b′]bis[1,7]-
benzodioxonino[3,2-j:3′,2′-j′]benzo[1,2-e:5,4-e′]bis[1,3]-
benzodioxonin, 2,3,9,10,16,17,23,24-octanitro-29,31,33,35-tetraun-
decyl- (4c): mp >350 °C; 1H NMR (CDCl3, 295 K) δ 7.66, 7.60 (2 ×
s, 8 H), 7.23, 6.22 (2 × s, 4 H), 7.10, 7.08 (2 × s, 4 H), 3.93 (m, 4 H),
2.1, 2.0 (2 × m, 8 H), 1.4-1.2 (m, 72 H), 0.89 (t, J ) 7.2 Hz, 12 H);
1H NMR (CDCl3, 330 K) δ 7.63 (s, 8 H), 7.21, 6.22 (2 × br s, 4 H),
7.04 (s, 4 H), 3.95 (t, J ) 7.6 Hz, 4 H), 2.1, 2.0 (2 × m, 8 H), 1.4-1.2
(m, 72 H), 0.89 (t, J ) 7.2 Hz, 12 H); HRMS-FAB m/z 1893.6656
([M + Cs]+, calcd for C96H112N8O24Cs 1893.6844).
See also ref 33.
1H NMR Binding Experiments. Binding studies were performed
at 295 ( 1 K. The stoichiometry of complexation and the association
constant Kass values were determined in CDCl3, benzene-d6, and
p-xylene-d10 at a constant (0.5-1.0 mM) concentration of host 2 and
variable concentrations (1-100 mM) of a guest 8-14 by integration
of the corresponding complex and free host signals. The concentration
of complex formed was determined directly by referring to the integrals
of the upfield shifted signals and the cavitand NH, aromatics, or methine
CH signals.
For ꢀ-caprolactam 9b, the dimerization constant KD value was
obtained in p-xylene-d10 by simultaneously monitoring the NH, CH2-
NHC(O), and CH2C(O)NH chemical shifts at a concentration of 0.7-
95 mM. The Horman-Dreux algorithm was employed in the calcula-
tions;34 the nonspecific oligomerization30 of ꢀ-caprolactam was neglected.
General Procedure for the Preparation of Bis-amides 7a,b. To a
vigorously stirred mixture of 1,2-diamino-4,5-dimethoxybenzene19 (0.34
g, 2 mmol) and K2CO3 (0.69 g, 5 mmol) in EtOAc-H2O, 1:1 (20 mL)
was added the appropriate acid chloride (5 mmol) by syringe. The
reaction mixture was stirred for 2 h, the organic layer was separated,
and the aqueous layer was extracted with CH2Cl2 (2 × 25 mL). The
combined organic layer was washed with water (2 × 100 mL), dried
over MgSO4, and evaporated. Pure amides 7a,b were obtained as tan
solids in 75-85% yields after recrystallization from toluene.
1,2-Dimethoxy-4,5-bis(n-octanoylamido)benzene (7a): mp 140-
Acknowledgment. We are grateful to the Skaggs Research
Foundation and the National Institutes of Health for support.
The Wallenberg Foundation provided fellowship support to G.H.
We also thank Dr. Emily Maverick of UCLA for advice and
Ing. Ben Lammerink of Twente University for experimental
assistance at the initial stage of this work.
1
141 °C; H NMR (CDCl3) δ 8.2 (s, 2 H), 6.85 (s, 2 H), 3.82 (s, 6 H),
2.31 (t, J ) 7.8 Hz, 4 H), 1.7, 1.4, 1.3 (3 × m, 20 H), 0.90 (t, J ) 7.1
Hz, 6 H); 13C NMR (CDCl3) δ 173.0, 147.4, 123.9, 105.0, 56.5, 37.5,
32.1, 29.7, 29.4, 26.2, 23.0, 14.5; HRMS-FAB m/z 443.2873 ([M +
Na]+, calcd for C24H40N8O4Na 443.2886).
Supporting Information Available: Representative 1H
NMR spectra (12 pages, print/PDF). See any current masthead
page for ordering information and Web access instructions.
1,2-Dimethoxy-4,5-bis(chloroacetylamido)benzene (7b): mp 185
°C; 1H NMR (CDCl3) δ 8.6 (s, 2 H), 7.03 (s, 2 H), 4.22 (s, 4 H), 3.90
(s, 6 H); 13C NMR (CDCl3) δ 165.6, 148.1, 122.8, 108.8, 56.6, 43.2;
HRMS-FAB m/z 321.0401 ([M + Na]+, calcd for C12H14Cl2N8O4Na
321.0409).
JA982970G
General Procedure for the Preparation of Adamantane Amides
(12,13). Amides 12, 13 were prepared analogously to 7a,b in 80-
90% yields from the corresponding amines and acid chlorides, mixed
(33) Perrin, C. L.; Dwyer, T. J. Chem. ReV. 1990, 90, 935-967.
(34) Horman, I.; Dreux, B. HelV. Chim. Acta 1984, 67, 754-764.