Structure and Dynamics in a Tetrameric Capsule
J. Am. Chem. Soc., Vol. 122, No. 44, 2000 10995
Encapsulation Studies. 1H NMR (600 MHz) experiments were
carried out on a Bru¨ker DRX-600 spectrometer. Deuterated solvents
were used as purchased from Cambridge Isotope Labs. Guest molecules
were used as purchased from Aldrich, except 1,3,5,7-tetramethyl-
adamantane (12), which was synthesized as previously reported.16 1D
encapsulation experiments were carried out with a monomer concentra-
tion of 2 mM and guest concentrations as noted. The binding constant
(Kapp) of 12 was determined by direct integration of free and bound
guest signals for a sample containing 1 equiv of 12 with respect to the
tetrameric capsule. All other binding constants were determined by
competition experiment.7 2D correlation experiments and 1D exchange
experiments were carried out on samples with a monomer concentration
of 10 mM and guest concentrations of 37.5 mM (15 equiv with respect
to tetramer). Kinetics of proton exchange were determined by monitor-
ing spin polarization transfer using a 180° pulse-delay-observe se-
quence,11 varying the mixing time from 5 µs to 500 ms.
Along with the difference in solvent polarity (and its effect on
hydrogen bond strength), the nature of the solvent-filled capsule
has been shown to play an important role in guest-exchange
processes.13
These results show that guest exchange occurs without
complete dissociation of the assembly, or even exchange of the
“in” and “out” methoxyl substituents. Two mechanisms for guest
exchange are consistent with this result. In the first, either a
single or two adjacent monomers swing open without dissociat-
ing to create a door in the assembly. When these doors close,
the methoxyls must return to their initial positions to fit into
the alternating folded pattern maintained by the monomers that
remain intact. This mechanism is reminiscent of guest exchange
in the softball family of dimeric capsules.13 A second pathway
involves dissociation of the tetramer into two identical dimers.
Here, the hydrogen-bound edge of the dimer locks the bridging
methoxyl groups in place. The symmetry considerations of the
process are subtle; unlike the tetramer, the dimers are chiral,
and dissociation yields either of a pair of two identical
enantiomers.
The specific mechanism is less important than its conse-
quences and more difficult to determine. The tetramer 14
possesses conformational stability that persists for multiple guest
exchanges. We have recently reported an encapsulation complex
in which hydrogen bonds maintain the imprint of a long-departed
chiral guest template.14 Tetrameric assemblies are capable of
generating great diversity,2b and the possible extension of
molecular imprinting to these systems holds much promise.
Synthesis. Cyclic Sulfinate (4). To a mixture of the dibromide 3
(235 mg, 0.380 mmol) and tetra-n-butylammonium bromide (24 mg,
0.076 mmol) in anhydrous DMF (7 mL) cooled to 0 °C was added
Rongalite (132 mg, 0.855 mmol, Acros Organics) as a solid. Stirring
was continued for 7 h at 0 °C, and the reaction was allowed to warm
to room temperature and stirred overnight. The reaction was poured
into water (25 mL) and extracted gently with Et2O (6 × 15 mL). The
combined organic extracts were dried over Na2SO4 and concentrated
to give the product (195 mg, 98%) as a white solid which was used
1
without further purification. H NMR (CDCl3) δ 1.61 (s, 18H), 3.56
(d, 1H, J ) 7.0 Hz), 3.75 (s, 3H), 3.78 (s, 3H), 4.41 (d, 1H, J ) 7.0
Hz), 5.17 (AB qr, 2H, J ) 18.9, 14.3 Hz). 13C NMR (CDCl3) δ 27.92,
50.62, 57.85, 60.99, 61.15, 87.29, 119.68, 119.93, 120.27, 126.91,
142.66, 144.56, 146.42, 146.46. IR (CHCl3 cast) cm-1 2984.9, 2938.5,
1766.0, 1480.7, 1448.9, 1396.4, 1372.0, 1293.8, 1245.4, 1141.6, 1074.0,
840.7, 757.6. MS (ESMS; MNa+) calcd for C20H28N2O10S2Na 543,
found 543.
Conclusions
Naphthalene Diester (6). Sulfinate 4 (195 mg, 0.375 mmol),
dimethylacetylenedicarboxylate (160 mg, 1.125 mmol), and benzene
(6 mL) were combined and heated at reflux for 2 h. DDQ (213 mg,
0.938 mmol) was added and reflux continued for 2 h. The reaction
was concentrated to dryness, and the residue was chromatographed over
silica gel (CH2Cl2) and triturated with MeOH to give the product as a
white solid (153 mg, 69%). 1H NMR (CDCl3) δ 1.63 (s, 18H), 3.91 (s,
6H), 3.96 (s, 6H), 8.56 (s, 2H). 13C NMR (CDCl3) δ 27.89, 53.04,
61.25, 87.22, 118.63, 124.85, 127.71, 129.32, 141.14, 145.76, 168.02.
IR (CHCl3 cast) cm-1 2981.8, 2945.5, 1758.5, 1728.3, 1426.4, 1275.5,
1239.2, 1136.6, 1112.45. MS (ESMS; MNa+) calcd for C26H32N2O12-
SNa 619, found 619.
Naphthalene Diol (7). Naphthalene diester (6) (304 mg, 0.51 mmol)
was dissolved in CH2Cl2 and cooled to 0 °C. DIBAL (2.5 mL, 2.5
mmol) in toluene was added over 90 s, and the reaction was stirred at
0 °C for 2.5 min before adding EtOAc (5 mL) and water (5 mL) to
quench the reaction. Addition of THF (20 mL) and 1 N NaOH (10
mL) gave a separable mixture. The organic layer was washed with brine
(3 × 10 mL), and the organic extracts were dried over Na2SO4 and
concentrated to dryness. Chromatography over silica gel (3:7 hexanes:
EtOAc) yielded the product as a colorless oil (137 mg, 50%). 1H NMR
(CDCl3) δ 1.63 (s, 18H), 3.30 (s, 2H), 3.87 (s, 6H), 4.86 (s, 2H), 8.11
(s, 2H). 13C NMR (CDCl3) δ 27.93, 61.02, 64.59, 86.76, 116.83, 123.25,
127.26, 138.16, 140.89, 146.14. IR (CHCl3 cast) cm-1 3608-3140 (br),
2984.3, 2938.5, 1764.8, 1620.4, 1428.2, 1395.9, 1371.6, 1296.6, 1246.6,
1096.3, 755.7. MS (ESMS; MNa+) calcd for C24H32N2O10SNa 563,
found 563.
As with 2, the degrees of freedom available to 1 are few; the
main skeleton is largely rigid, and the hydrogen-bonding
preferences are well established. Despite this simplicity, from
the presence of two lowly methoxyl groups emerges self-
organization, encapsulation of guest molecules, unexpected
symmetry, and conformational memory. The “folding” of this
assembly and the dynamics of its substrate binding defy
prediction and reasonably reflect the state of the art in
supramolecular chemistry; yet the complexity of these processes
pales in comparison to the conformational changes and self-
organization performed by an enzyme while executing its
function.
Experimental Section
1
General. H NMR (600 MHz) and 13C NMR (151 MHz) spectra
were recorded on a Bru¨ker DRX-600 spectrometer. Infrared spectra
were recorded on a Perkin-Elmer Paragon FT-IR spectrometer. Matrix-
assisted laser desorption/ionization FTMS experiments were performed
on an IonSpec FTMS mass spectrometer. Electrospray MS experiments
were performed on a single-quadrupole Perkin-Elmer API-100 Sciex
mass spectrometer. Dichloromethane and THF were passed through
columns of activated aluminum oxide as described by Grubbs and co-
workers before use.15 Column chromatography was carried out using
silica gel 60 (35-75 µm) as purchased from EM Science. All reagents
and solvents were used as purchased from Aldrich Chemicals unless
otherwise indicated.
Naphthalene Dibromide (8). Naphthalene diol (7) (180 mg, 0.33
mmol) was dissolved in dry THF (5 mL), and carbon tetrabromide
(552 mg, 1.66 mmol) was added followed by triphenylphosphine (437
mg, 1.66 mmol). After stirring at room temperature for 18 h the reaction
was filtered through Celite and concentrated to dryness. Column
chromatography (1:1 hexanes:EtOAc) yielded the product as a colorless
Calculations. Molecular mechanics calculations were carried out
using the AMBER* force field as implemented by Macromodel version
6.5.5 Calculations at the semiempirical level were carried out using
Spartan.8 Cavity volumes were calculated using GRASP.5
(13) Santamaria, J.; Mart´ın, T.; Hilmersson, G.; Craig, S. L.; Rebek, J.,
Jr. Proc. Natl. Acad. Sci. U.S.A. 1999, 96, 8344-8347.
(14) Rivera, J. M.; Craig, S. L.; Mart´ın, T.; Rebek, J., Jr. Angew. Chem.,
Int. Ed. 2000, 39, 2130-2132.
(15) Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.;
Timmers, F. J. Organometallics 1996, 15, 1518-1520.
1
oil (167 mg, 75%). H NMR (CDCl3) δ 1.65 (s, 18H), 3.91 (s, 6H),
4.88 (s, 4H), 8.20 (s, 2H). 13C NMR (CDCl3) δ 27.95, 30.79, 61.08,
(16) Bolestova, G. I.; Parnes, Z. N.; Kursanov, D. N. Zh. Org. Khim.
1983, 19, 339-343.