A reversible reaction inside a self-assembled capsule

Article abstract of DOI:10.1021/ja062768a

Reversible encapsulation allows the direct observation of the isolated molecules under ambient conditions, at equilibrium and in the liquid phase. Here we show that capsules can amplify and stabilize molecules that are present in only trace concentrations

Full text of DOI:10.1021/ja062768a

Published on Web 06/30/2006
A Reversible Reaction Inside a Self-Assembled Capsule
Tetsuo Iwasawa, Enrique Mann, and Julius Rebek, Jr.*
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 April 20, 2006; E-mail: jrebek@scripps.edu
Substrates at enzyme active sites are temporarily isolated from
others in the bulk water solvent. The structured environments at
these sites are complementary to reactive intermediates and the high-
energy transition states that lead to them, and they have maximum
binding to the transition state. This is regarded as the quintessential
feature of enzyme catalysis. Synthetic structures can also stabilize
reactive species by isolating them. The unstable species may be
short-lived intermediates in chemical reactions or high-energy
conformations of otherwise stable molecules. The earliest example
was the stabilization of cyclobutadiene1 in a cage molecule
Figure 1. Two cavitands self-assemble through hydrogen bonding into a
permanently held together through covalent bonds. Reversibly
formed capsules, self-assembled through metal/ligand interactions,
can also isolate and temporarily stabilize reactive species; they allow
the direct observation of the stabilized molecules under ambient
conditions, at equilibrium and in the liquid phase. Species, such as
siloxanes,2 phosphine carbonyl adducts,3 and organometallics have
been stabilized.4 Hydrogen bonded capsules, such as 1 (Figure 1),
stabilize peroxides5 and high-energy helical conformations of
normal alkanes.6 We have now observed amplification and stabi-
lization of otherwise unfavored forms in ring/chain isomerization
reactions. These indicate that reversible reactions can take place
within encapsulation complexes.
cylindrical capsule 1‚1. Two representations of the capsule are shown. In
the center is the energy-minimized (MacroModel 5.5, Amber* force field)
structure 1‚1; the long alkyl chains and CH hydrogen atoms are omitted
for viewing clarity. Right: the cartoon representation.
The amplification within 1‚1 can be directly observed by NMR
spectroscopy through its effect on the ring/chain isomerizations
shown in Figures 2 and 3. The Schiff’s base 2 is the major form in
mesitylene-d12 solution, but the oxazine 3 is by far the dominant
form within the capsule. Likewise, the dimethylamino variant 5,
the major isomer in equilibrium with 4 in solution, becomes the
exclusive guest of the capsule.
The in-out exchange of encapsulated and free molecules of this
size takes hours at these conditions.7 A number of p-substituted
aldehydes were converted to their tautomeric Schiff’s bases
according to literature procedures. They all showed nearly exclusive
encapsulation of their corresponding ring forms.
Figure 2. Encapsulation experiments of 2/3 and 4/5 isomerization. The
encapsulations were carried out with the guest (2.70 × 10-3 mmol) and 1
(10 mg, 5.94 × 10-3 mmol) in mesitylene-d12 (1.5 mL). The ratios were
1
determined by H NMR (600 MHz, 300 K).
protons of the capsule, we examined the rate of the ring/chain
tautomerism with a commercially available imide,9 but no catalysis
was seen.
Does the isomerization reaction take place within the capsule,
outside in solution, or both? The interconversion of 2 and 3 takes
place relatively slowly under these conditions. For example, 2 can
be prepared in crystalline form,8 and a freshly prepared solution in
mesitylene-d12 shows less than 10% 3 present within 5 min.
Equilibrium is reached after 2 h. Yet, the encapsulation of 2 and 3
takes place rapidly under these conditions. Both freshly prepared
and equilibrated solutions of 2 gave the same results on addition
of the capsule: in the few minutes needed to acquire an NMR
spectrum, the capsule was more than 90% occupied by the
heterocycle 3. It is likely that 2 and 3 interconvert within the
capsule, but EXSY experiments with mixing times from 0.1 to 1 s
did not show cross-peaks for encapsulated 2 and 3. Accordingly,
the time scale for interconversion is >1 s. To check on the
possibility of acid catalysis of the interconversion by the imide
An additional series of Schiff’s bases 6a-e (Figure 4) were
prepared from the corresponding salicyl aldehydes and anilines.
None of these showed the presence of their heterocyclic tautomers
7a-e in mesitylene-d12 solution within the limits of NMR detection,
in accord with literature precedent for the unsubstituted case, 6a.10
Addition of the capsule showed only the encapsulated Schiff’s
bases for 6b and 6c. However, 6d showed a minor encapsulated
species, identified as the corresponding heterocycle 7d (Figure 5),
as it showed the characteristic NMR signatures of the cyclized
product. Specifically, geminal couplings of the hydrogens indicated
were 14.4 Hz as is known for other molecules of this sort. A similar
result occurred with the methoxy-substituted derivative 6e, the
cyclized molecule was present inside the capsule but not outside
in bulk solution. This suggests that the open chain molecule is
encapsulated, and it cyclizes inside the capsule; that is, the reversible
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C O M M U N I C A T I O N S
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Figure 5. Portions of H NMR spectrum of encapsulated 6d (600 MHz,
300 K, mesitylene-d12): (a) in upfield portion, two encapsulated CH3 groups
are situated at δ -2.35 and -2.59; (b) in mid-field portion, the AB-shaped
peaks of 7d@1‚1, Ha and Hb, are situated at δ 4.31 and 4.07, pointed with
arrows. The peaks labeled x are CH methines in 1‚1.
Figure 3. Portions of 1H NMR spectra of encapsulated 2/3 and 4/5
isomerization (600 MHz, 300 K, mesitylene-d12): (a) the peaks of 3@1‚1
and 2@1‚1 are labeled with letters and asterisks, respectively; (b) a
detectable amount of 4@1‚1 was not formed, and all protons of 5@1‚1
(except Hi which overlapped with peaks of solvent or 1‚1) are assigned.
The peaks labeled x are CH methines in 1‚1. (The AB-shaped peaks He
and Hf identify the heterocyclic guests, pointed with arrows; the complete
assignments of NMR spectra and ∆δ between free and encapsulated species
are available in the Supporting Information.)
environments, from which bulk solvents are largely excluded. The
similarities to enzyme active sites may be stronger than first
believed.
Acknowledgment. We are grateful to the Skaggs Institute and
the National Institutes of Health (GM 50174) for support. T.I. is a
Skaggs Postdoctoral Fellow. E.M. is a Spanish Ministerio de
Educacion y Ciencia (Secretaria de Estado de Universidades e
Investigacion) Postdoctoral Fellow.
Supporting Information Available: Temperature dependence of
the encapsulated equilibrium, chemical shifts and ∆δ of 3@1‚1 and
5@1‚1, and corroborative data of encapsulation experiments. This
material is available free of charge via the Internet at http://pubs.acs.org.
Figure 4. Schiff’s bases 6a-e. In mesitylene-d12 at 300 K, 6a-e show no
sign of cyclization to corresponding isomers 7a-e.
chemical reaction takes place within the capsule. Perhaps the
conformational restrictions within the capsule drive this equilibrium
to detectable amounts of cyclized form. The ortho hydroxyl function
may also facilitate the interconversion through intramolecular acid/
base catalysis. In any case, the heterocycle form is amplified and
stabilized within the structured solvent sphere that is the wall of
the capsule.
References
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The temperature dependence of the encapsulated equilibrium of
Figure 5 showed that the equilibrium constant remained unchanged
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It should be possible to amplify intermediates in bimolecular
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