Expanded calix[4]arene tetraurea capsules [17]

Full text of DOI:10.1021/ja002345n

9868
J. Am. Chem. Soc. 2000, 122, 9868-9869
Expanded Calix[4]arene Tetraurea Capsules
Young Lag Cho, Dmitry M. Rudkevich,* and
Julius Rebek, Jr.*
The Skaggs Institute for Chemical Biology and
the Department of Chemistry
The Scripps Research Institute, La Jolla, California 92037
ReceiVed June 29, 2000
Since their invention 5 years ago, calix[4]arene tetraureas 1‚1
have become the most extensively studied molecular capsules.1
Their architecture comprises the bowl-shaped curvature of the
calixarene 1 in the cone conformation (Figure 1) and the four
self-complementary ureas on the upper rim. Their hydrogen bond
donors and acceptors allow a dimeric assembly to form, in the
manner of two hemispheres, giving a capsule 1‚1 held together
by a seam of 16, intermolecular CdO‚‚‚H-N hydrogen bonds
around the equator. The capsule features a well-defined, roughly
spherical cavity of ∼7 Å diameter, with an internal volume of
∼200 Å3, and accommodates benzene- or chloroform-sized
molecules and even some terpenes such as camphor. The exchange
rate of guests is slow on the NMR time scale (at ambient
temperatures), and separate, sharp signals are seen in the NMR
spectra for free and encapsulated guest.2 More recently, examples
of heirarchical assembly,3 polymerization,4 and chiral recognition5
were all revealed through reversible self-assembly of 1‚1. Here
we relate our initial experiences with a second generation of these
calixarene tetraureas, those intended to offer expanded cavities
for guest encapsulation.
Figure 1. Calix[4]arene based capsules 1‚1 and 2‚2 assembled through
hydrogen bonding. Top left: Schematic representation of hydrogen
bonding in dimer 1‚1.
The synthesis of the new structures began with the tetrabromo
tetrabenzyloxy calix[4]arene 3 prepared earlier by Gutsche.6 The
depth of the cavity was increased by Suzuki reaction with
p-nitrophenyl boronic acid, Pd(PPh3)4, and Na2CO3 in a mixture
of toluene and water (Scheme 1). The benzylic protection was
then removed with AlCl3 to afford tetranitrocalixarene 4 in 61%
overall yield (Scheme 1). The phenols of 4 were alkylated with
ClCH2C(O)NEt2 (Na2CO3, MeCN, 83%), and the nitro groups
were reduced (H2, Raney/Ni, 58%). Finally, acylation of the
resulting amino groups with the appropriate isocyanates gave the
ureas 2a,b in 60-83% yields. These are tan-colored solids;
tetraurea 2b is soluble in most chlorinated solvents but the
solubility of tetraurea 2a was disappointingly limited.
Figure 2. 1H NMR spectra in CD2Cl2 (600 MHz, 295 K) of (a) capsule
2b‚2b, (b) guest 10, (c) 10 + 2b, 1:0.5, and (d) 10 + 2b, 1:1. Further
addition (>2 equiv) of 2b does not change the spectrum. The guest i-Pr
group is indicated by an arrow.
Solutions of 2b in apolar solvents (CDCl3, CD2Cl2) show well-
resolved 1H NMR spectra, featuring two unusually downfield urea
C(O)-NH singlets of equal intensity between 9 and 8.5 ppm
(Figure 2a and Supporting Information). These resonances are
concentration (0.1-20 mM) and temperature (250-310 K)
independent. These downfield signals are characteristic of capsule
formation and this was confirmed through heterodimerization
experiments: the downfield shifts of the urea NH for 2a and 2b
are different, but mixing their solutions in a 1:1 ratio in CD2Cl2
Scheme 1
(1) (a) Shimizu, K. D.; Rebek, J., Jr. Proc. Natl. Acad. Sci. U.S.A. 1995,
92, 12403-12407. (b) Hamann, B. C.; Shimizu, K. D.; Rebek, J., Jr. Angew.
Chem., Int. Ed. Engl. 1996, 35, 1326-1329. (c) Mogck, O.; Bo¨hmer, V.; Vogt,
W. Tetrahedron 1996, 52, 8489-8496. X-ray structure: Mogck, O.; Paulus,
E. F.; Bo¨hmer, V.; Thondorf, I.; Vogt, W. Chem. Commun. 1996, 2533-
2534.
gave rise to yet another set of NH resonances. These reflect the
slow (on the NMR time scale) formation of a mixed dimer.
Further, from a NOESY experiment with tetraurea 2b (CD2Cl2),
NOE contacts were detected that are possible only in a dimer
rather than in a monomer (see Supporting Information).
When a CH2Cl2 solution of 2a with 2b was analyzed by
electrospray mass spectrometry (ESI-MS), three dimeric species
2a‚2a‚2Na+, 2b‚2b‚2Na+, and 2a‚2b‚2Na+ were clearly observed
at 1797, 2077, and 1937 daltons, respectively. These results show
that extended calix[4]arene tetraureas 2a,b self-assemble into
(2) Reviews: (a) Rebek, J., Jr. Chem. Commun. 2000, 637-643. (b)
Bo¨hmer, V.; Mogck, O.; Pons, M.; Paulus, E. F. In NMR in Supramolecular
Chemistry; Kluwer Academic Publishers: New York, 1999; pp 45-60.
(3) Castellano, R. K.; Nuckolls, C.; Eichhorn, S. H.; Wood, M. R.; Lovinger,
A. J.; Rebek, J., Jr. Angew. Chem., Int. Ed. Engl. 1999, 38, 2603-2606.
(4) Castellano, R. K.; Rudkevich, D. M.; Rebek, J., Jr. Proc. Natl. Acad.
Sci. U.S.A. 1997, 94, 7132-7137.
(5) (a) Castellano, R. K.; Kim, B. H.; Rebek, J., Jr. J. Am. Chem. Soc.
1997, 119, 12671-12672. (b) Castellano, R. K.; Nuckolls, C.; Rebek, J., Jr.
J. Am. Chem. Soc. 1999, 121, 11156-11163.
(6) Gutsche, C. D.; Pagoria, P. F. J. Org. Chem. 1985, 50, 5795-5802.
10.1021/ja002345n CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/21/2000

Communications to the Editor
J. Am. Chem. Soc., Vol. 122, No. 40, 2000 9869
time scale.9 Accordingly, only complexation induced shifts (CIS)
1
of the guest’s H NMR signals (rather than separate signals for
free and bound species) were detected in CD2Cl2 solution upon
dilution of the guest with increasing amounts of 2b‚2b (Figure
2b-d). In particular, o- and m-pyridinium CH protons shift ∼1-2
ppm and N-CH3 protons shift ∼1.5 ppm upfield (see Supporting
Information). This indicates their location inside the shielded
environment of 2b‚2b. The CIS data fit nicely into a complexation
model with one guest in the capsule, and for complex [2b‚2b‚9]
this stoichiometry was confirmed by a Job plot. From the 1H NMR
titrations in CD2Cl2, high association constant (Kass) values in a
range of 5.6 × 103 to 1.9 × 105 M-1 (-∆G295 ) 5.0-7.1 kcal/
mol) were obtained.
4. A solvent molecule may be present with the guest inside
the capsule. Upon encapsulation of guests 8-12, between 34 and
59% of the inner cavity 2‚2 is filled (Table 1 in Supporting
Information). A recent compilation of occupancy factors, or
packing coefficients (PC) of molecule-within-molecule complexes
in solution, indicates that an optimal PC value is ∼55%
occupancy.10 For 4-isopropyl-N-methyl pyridinium and N-methyl
quinuclidinium complexes [2b‚2b‚10] and [2b‚2b‚11], the PC’s
are only 37 and 34%, respectively, but an additional solvent
molecule would raise the figure to near optimal.
5. Complexation could additionally be followed by UV/vis
spectroscopy. Titration of the deep-red dye trans-4-[4-(dimethyl-
amino)styryl]-1-methyl-pyridinium iodide 11 resulted in a hyp-
sochromic shift of the λmax band from 518 to 497 nm (Figure
3b).11
Figure 3. (a) Guests 5-12. (b) Portion of the UV/vis titration with dye
11 in CH2Cl2 (295 K). The band at λmax ) 518 nm for free 11 shifts
toward λmax ) 497 nm upon addition of capsule 2b‚2b. [11] ) 25 µM;
[2b] up to 0.5 mM.
dimers in apolar solution. As with capsule 1‚1, a seam of 16 Cd
O‚‚‚H-N intermolecular hydrogen bonds at the upper rim is
formed; the dimerization constant value is apparently beyond the
NMR limits (>105 M-1). The egg-shaped cavity that results has
a volume estimated at ∼400 Å3, the largest volume for a calix-
[4]arene based capsule synthesized to date.7 According to
molecular modeling, the interiors can accommodate at least two
benzene- or chloroform-sized guest molecules.
The main features of the newly prepared capsules are the
following.
6. Hybridization takes place between the original capsule and
the newer, deeper version. When tetraureas 1 (R ) CH2C(O)-
OEt) and 2b were mixed, a unique, nonsymmetrical capsule 1‚
2b was formed (1H NMR data in Supporting Information). It is
present, along with the corresponding homodimers, in roughly
statistical amounts and guarantees that the spacer of 2b did not
affect the energetics of the assembly into capsules. It may be
possible to drive the equilibria to the hybrid with appropriate
guests as has been shown with other capsules.5a
1. Sodium complexes of 2a and 2b were readily prepared by
solid-liquid extraction of sodium perchlorates and picrates into
their CH2Cl2 solutions. In these, the sodium cation is tightly
coordinated at the lower rim by the four carbonyl and four
phenolic ether oxygens.8 Solutions of these in apolar solvents
(CDCl3, CD2Cl2, etc.) also show self-assembly (1H NMR, ESI
MS). When Na+-complexes of 2a and 2b are mixed in CD2Cl2,
heterodimers are also formed (well-resolved NMR, ESI MS in
Supporting Information).
The features of capsules 2‚2 (size, exchange rate, and hybrid-
ization) place it in a special category among nanoscale self-
assembled cavities. They suggest uses as selective reaction
chambers for chemical catalysis, and we are working toward this
goal.
2. The solvent exchange in and out of the cavities is fast,
although dissociation of 2‚2 is slow on the NMR time scale. For
example, when 2‚2 is placed in mixtures of two suitable deuterated
solvents only a single species is observed. This contrasts with
the behavior of capsule 1‚1, which shows the presence of two
distinct species.1,2 Apparently, the large holes in the skeleton of
2‚2 permit the solvent molecules to pass rapidly in and out of
the dimer. This has consequences for the guest encapsulation,
since entropic gains of the solvent release are not favorable for
2‚2. Indeed, all attempts to encapsulate neutral guests of ap-
propriate size and shape inside the capsule failed. Neither the
flat and long 4,4′-dimethylbiphenyl 5 nor N-(p-tolyl)benzamide
6 nor even the bulkier adamantyl derivative 7 showed any
spectroscopic signs of encapsulation.
Acknowledgment. We are grateful to the National Institutes of Health
and The Skaggs Research Foundation for support of this work. We thank
Prof. B. D. Smith for providing the experimental protocol for the
preparation of p-nitrophenyl boronic acid. We also thank Prof. K.-S. Jeong
for the curve-fitting programs.
Supporting Information Available: Experimental protocols for the
synthesis of 2a,b and 4; molecular modeling; selected 1H NMR, NOESY,
and ESI-MS characterization data for assemblies 2‚2, their sodium
complexes and heterodimers; and 1H NMR titration data (PDF). This
material is available free of charge via the Internet at http://pubs.acs.org.
3. The positively charged N-alkyl pyridinium derivatives 8-11
and N-methylquinuclidinium 12 are strongly complexed inside
capsule 2b‚2b (Figure 3a), most probably due to the strong ion-
dipole interactions. The guest exchange rate is fast on the NMR
JA002345N
(9) For the complexation of alkylpyridinium cations with calixarenes, see:
Lothak, P.; Shinkai, S. J. Phys. Org. Chem. 1997, 10, 273-285 and literature
cited therein.
(10) Mecozzi, S.; Rebek, J., Jr. Chem. Eur. J. 1998, 4, 1016-1022.
(11) For the complexation of stilbene dyes with water-soluble calixarenes
in a 1:1 ratio, see: Nishida, M.; Ishii, D.; Yoshida, I.; Shinkai, S. Bull. Chem.
Soc. Jpn. 1997, 70, 2131-2140.
(7) Review on deeper cavities: Rudkevich, D. M.; Rebek, J., Jr. Eur. J.
Org. Chem. 1999, 1991-2005.
(8) (a) Scheerder, J.; van Duynhoven, J. P. M.; Engbersen, J. F. J.;
Reinhoudt, D. N. Angew. Chem., Int. Ed. Engl. 1996, 35, 1090-1093. (b)
Cho, Y. L.; Rudkevich, D. M.; Shivanyuk, A.; Rissanen, K.; Rebek, J., Jr.
Chem. Eur. J. 2000, in press.