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Simultaneous Encapsulation Molecules Held at Close Range.

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Reviews
J. Rebek, Jr.
Host—Guest Chemistry
Simultaneous Encapsulation: Molecules Held at Close
Range
Julius Rebek, Jr.*
Keywords:
molecular capsules · molecular
recognition · self-assembly ·
stereoisomerism ·
tautomerism
Angewandte
Chemie
2068
2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/anie.200462839
Angew. Chem. Int. Ed. 2005, 44, 2068 – 2078
Angewandte
Molecular Capsules
Chemie
Reversible encapsulation creates spaces where molecules are temporarily isolated from others in solution. Molecules are held within the
space of the capsule for lifetimes ranging from milliseconds to hours,
and conventional NMR spectroscopy can be used to report on the
chemical and magnetic environment as well as the arrangement of the
molecules in the encapsulation complex. The complexes self-assemble
when, and only when, the spaces inside the capsules are appropriately
filled. The weak intermolecular forces that hold these self-assemblies
together allow equilibration of the encapsulation complexes at ambient
temperatures and pressures in the liquid phase. When two or more
molecules are simultaneously encapsulated, intermolecular
phenomena are revealed in solution that cannot be observed by other
methods. We describe here the unique behavior that emerges from
molecules that are simultaneously encapsulated and includes new
forms of stereochemistry, isomerism, and asymmetry inside capsules.
1. Introduction
During the past two decades, molecular recognition—the
science of how molecules fit together—has progressed far
beyond the sequestration of ions by macrocyclic polyethers.[1]
Synthetic receptors with a variety of shapes have been
fashioned for binding their charged or neutral targets. These
systems all share one feature: the receptors offer concave
surfaces that complement their convex targets. The next
generation of receptors were fashioned to cover more of their
targets surfaces, and they became more selective. It therefore
appeared to us that an ultimate, if different, form of molecular
recognition could involve a receptor that completely surrounded the target, namely, encapsulated it. Covalent bonds
had already been used to make permanent arrangements of
molecules-within-molecules,[2, 3] but we pursued and achieved
reversible encapsulation by using the weak intermolecular
forces of recognition and the principles of self-assembly.
Multiple copies of small modules that fit together through
self-recognition were used to create a capsule—the superstructure that surrounds the target molecule. The alternative
to self-assembly is the synthesis of a single (and necessarily
very large) covalent structure.[4] The walls of the capsules
provide mechanical barriers that temporarily isolate molecules from the outside medium. The dynamic nature of the
system is simultaneously an advantage and a disadvantage.
The formation and dissociation of the capsules is reversible
since only weak intermolecular interactions such as hydrogen
bonds are involved. The systems reach thermodynamic
equilibrium rapidly under mild conditions in solution, but
they require analytical methods that operate on the same
timescale (such as NMR spectroscopy and electrospray mass
spectrometry). The inclusion complexes do not survive
purification by chromatography and only a few of our
encapsulation complexes have been characterized by X-ray
crystallography. Associated questions are: “What is it like
inside the capsule? Are there rules that govern the filling of
the space? What rules are valid for liquids? Which for gases?
Angew. Chem. Int. Ed. 2005, 44, 2068 – 2078
From the Contents
1. Introduction
2069
2. Identification of Guest
Molecules inside the Capsules
2069
3. Forces within Capsules
2072
4. Arrangements in the
Encapsulation Space
2073
5. Chiral Spaces
2075
6. Reactivity
2076
7. Conclusion
2077
Is there a best fit? Can the capsule be empty? Can two or
more molecules be inside? Can the space be made chiral?
Can reactions occur inside?” Relatively stable (that is, longerlived but still reversibly formed) encapsulation complexes can
be accessed by using the stronger forces of metal–ligand
interactions. Many examples now exist that utilize these
forces; they are described elsewhere.[5–10] They provide
parallel applications of the same principles of self-assembly
and encapsulation that characterize the hydrogen-bonded
capsules described here.
2. Identification of Guest Molecules inside the
Capsules
Our initial capsule, an assembly that grew out of a
collaborative effort with de Mendoza and co-workers in
Madrid, was a semispherical, dimeric structure held together
by a seam of eight hydrogen bonds.[11] The cavity size could
accommodate only one small molecule (see Figure 1 for the
structure of the capsule and its encapsulation of ethane). The
assembly was characterized in solution by NMR spectroscopy.
The signal for the encapsulated ethane molecule appears far
upfield (d = 1 ppm), shifted there as a result of the
anisotropy of the aromatic subunits of the capsule that
sandwich the ethane molecule.[12] The separate signals for free
and bound ethane allowed integration and the direct determination of equilibrium constants. This slow exchange
(typical lifetimes are ca. 1 s) in and out of the capsules and
[*] Prof. J. Rebek, Jr.
The Skaggs Institute for Chemical Biology and
Department of Chemistry
The Scripps Research Institute
10550 North Torrey Pines Road
La Jolla, California 92037 (USA)
Fax: (+ 1) 858-784-2876
E-mail: jrebek@scripps.edu
DOI: 10.1002/anie.200462839
2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2069
Reviews
J. Rebek, Jr.
Figure 1. Left: the structure of a self-complementary module capable
of forming a dimeric capsule through hydrogen bonding. Right: a view
of its solvent-accessible surfaces showing the space remaining in the
capsule (visualized with AVN software). The encapsulated molecule is
ethane.
the large upfield shifts of the protons of molecules inside are
characteristic of these assemblies and are common to all the
capsules we describe here. The NMR spectrum indicates the
magnetic environment experienced by encapsulated molecules, and integration of the spectra reveals the stoichiometry
of the entire assembly.
We used a similar array of hydrogen-bond donors and
acceptors to synthesize the larger semispherical structure
shown in Figure 2.[13] The capsule assembled in either
deuterated benzene or deuterated monofluorobenzene, but
the NMR spectra gave no hint of how many solvent molecules
were detained inside, or the number of subunits that formed
the capsule. A third capsule species appeared in the NMR
spectrum recorded in a mixture of the two solvents; accordingly, the new capsule must contain both solvents (but only
one molecule of each).[14] This indirect method was the first
indication of simultaneous encapsulation. This result—
namely the inclusion of different solvent molecules inside
the capsule—is general for large capsules and leads to the
unusual thermodynamic behavior of capsules constructed
from large molecules: several solvents are displaced into the
bulk solution and encapsulation is entropy driven. In contrast,
conventional recognition is enthalpy driven and complexes
tend to dissociate at higher temperatures.
It was not until we had a nonspherical (or more
specifically, a cylindrical) capsule in hand that we were able
Julius Rebek, Jr. was born in Hungary in
1944. In 1970 he obtained his PhD from
the Massachusetts Institute of Technology
(MIT) for studies on peptide chemistry with
Prof. D. S. Kemp. In the same year he
became Assistant Professor at the University
of California at Los Angeles and then Professor at the University of Pittsburgh (1976). In
1989 he returned to MIT as the Camille
Dreyfus Professor of Chemistry. In July 1996
he moved his research group to The Scripps
Research Institute to become the Director of
The Skaggs Institute for Chemical Biology.
His research focuses on molecular recognition and self-assembling systems.
2070
2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Figure 2. Top: the structure of a module for a large (400 3) capsule.
The molecule assembles as a spherical dimer in benzene and
encapsulates two solvent molecules.
to elucidate the additional rules governing the simultaneous
encapsulation of molecules. We will use this capsule to
explore most of the interactions of molecules at close range.
The synthesis and various calculations of the structure of this
capsule is shown in Scheme 1. Our initial experiments in
filling its space showed the preferential encapsulation of two
different molecules.[15] Benzene, toluene, and p-xylene were
all encapsulated under certain conditions, but when all three
of these solvents were present, one molecule of benzene and
one of p-xylene were preferentially encapsulated. Deuterated
mesitylene is the solvent of choice for driving molecules into
this capsule, as its dimensions exceed those of the cavity. Even
so, a capsule forms in the unpurified, commercial solvent and
it contains one molecule of deuterated benzene and one
molecule of deuterated p-xylene, both of which are impurities
in the solvent. (Note that impurities of even 0.1 % in the pure
solvent represent concentrations in the millimolar range,
which is the typical concentrations of the capsule used in
typical NMR experiments, and demonstrates the remarkable
ability of these capsules to sequester trace impurities.)
The largest of the reversibly formed capsules held
together by hydrogen bonds results from the self-assembly
of resorcinarenes and the closely related pyrogallolarenes
(Scheme 2). They show similar tendencies to assemble, the
difference being that the resorcinarenes require water for
assembly and the pyrogallols do not. The resorcinarenes hold
a special place in the history of encapsulation: they are the
most complicated capsules and, ironically, they are the easiest
to come by. Their simple synthesis—developed by Hg-
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Angew. Chem. Int. Ed. 2005, 44, 2068 – 2078
Angewandte
Molecular Capsules
Chemie
Scheme 1. Left: synthesis and structure of a cylindrical capsule. The peripheral alkyl groups that impart solubility in organic solvents are not
shown. Middle: a belt of eight bifurcated hydrogen bonds holds the capsule together and generates a tapered cavity of 420 3. Right: a schematic
abbreviation of the capsule, which is used elsewhere in this Review.
Scheme 2. Hexameric assemblies resembling cubes with one subunit at each face. Left: the pyrogallolarenes self-assemble in dry organic solvents
and can encapsulate four octane molecules. Right: the resorcinarenes require eight water molecules, one at each corner of the cube. The encapsulation of eight benzene molecules is shown.
berg[16]—accounts for their active pursuit in laboratories
worldwide.[17–26]
Chemical modifications of the resorcinarenes provided
the first cavitands[27] and carcerands,[28] and there is now a
growing body of evidence that the hexameric assemblies were
present some years before, but were not recognized as
hydrogen-bonded capsules. These form in wet organic solvents and contain a huge cavity (1375 3) that permits
encapsulation of more and ever larger guests, for example,
eight benzene molecules, three biphenyl molecules, and even
bulky tetraalkylammonium salts. The simultaneous encapsulation of tetrabutylammonium iodide and p-phenyltoluene is
shown in Figure 3. Neutral molecules such as covalent
antimony(v) bromides are encapsulated together with sizable
smaller molecules such as naphthalene, biphenyl, anthracene,
and azulene,[29] but slightly longer molecules, such as nheptylbenzene, trans-stilbene, azobenzene, p-terphenyl, are
not simulataneously encapsulated. The size, shape, polarity,
and polarizability of the aromatic effect influences the
simultaneous encapsulation, at least with nBu4SbBr.
Angew. Chem. Int. Ed. 2005, 44, 2068 – 2078
Figure 3. Encapsulation of an ion pair of tetrabutyl ammonium iodide
with p-phenyltoluene in the hexameric resorcinarene. The hydrogenbond network is shown as dashed lines.
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2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2071
Reviews
J. Rebek, Jr.
3. Forces within Capsules
The cylindrical capsule shown in Scheme 1 offers a
gradient of polarity and shape along its length: the four
aromatic units at the tapered ends offer a shallow, apolar (but
polarizable) surface that is rigidly fixed; the four pyrazine
units nearer the center are more polar but less polarizable and
capable of slight breathing motions; the seam of imide groups
around the center of the cavity is rich in hydrogen-bonding
donors and acceptors and is the most mobile section. The
entry and exit of the guests occurs through movement here,
and this region attracts polar groups of encapsulated molecules.[30, 31]
A molecule appears frozen in time and in space while
inside a capsule, typically for one to two seconds. Its
interactions with other encapsulated molecules are extended
and, compared to the random and rapid collisions and
exchange of partners that occur in bulk solution, are
intensified or amplified in the capsule. It is possible to align
the two molecules inside the cylindrical capsule so that only
certain areas of their surfaces come into contact. To our
knowledge this cannot be achieved by other methods and it
provides a means by which subtle, intermolecular forces can
be evaluated pairwise, and at the molecular level.
The ideal situation for a planned simultaneous encapsulation of two different molecules is one in which two
molecules of the same species do not fill the appropriate
amount of space but the combination of the two different
molecules do. Fujita and co-workers have referred to this
situation as an “and/or gate” and have encountered many
such phenomena in metal–ligand capsules.[32] We were able to
transfer this principle to the encapsulation of gases. Small
molecules such as cyclopropane, methane, or ethane do find
their way into the cylindrical capsule alone, nor does
naphthalene, anthracene, or azulene. However, when both
methane and anthracene are present, the NMR spectra are
very sharp and illustrate that one molecule of each species is
inside (Figure 4).[33] This occurrence allowed us to look at
molecules that we had not been able to encapsulate under
normal conditions. These studies also led to the (not surprising) conclusion that gases need more space: filling about 55 %
of the space or a packing coefficient of 55 % is optimal for
Figure 4. Anthracene and methane are encapsulated together, but
neither component alone assembles an encapsulation complex.
2072
2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
typical liquids,[34] but gases having packing coefficients as low
as 30 % have been encountered. A good question to ask is:
what does a single molecule experience as a phase inside these
capsules? Its collisions with the walls are hardly inelastic,
particularly as attractive forces exist between the p lining of
the capsule and the C H bonds of small hydrocarbon gases.[35]
These molecules are not billiard balls knocking around in a
three-dimensional table. The notion of pressure is, accordingly, hard to define under these conditions.
The four walls of the capsule are at right angles and the
cross-section generates a square array of aromatic pyrazine
surfaces. How are encapsulated aromatic compounds positioned in this cavity? A diagonal arrangement offers the most
space and is expected to minimize contacts that lead to steric
effects (electron–electron repulsions), but what if the contacts
are weakly attractive as in CH–p interactions? Many
attempts to find aromatic molecules that would wedge into
the corners failed to show the expected loss of symmetry in
their NMR spectra, thus indicating that spinning of the
encapsulated molecules remained fast—at least on the NMR
timescale. We therefore created a situation in which even the
spinning of a molecule would be affected by simultaneous
encapsulation, with the size of one guest limiting the rotational motions of another.[36] This situation reflects the
constant tradeoffs between freedom of movement and the
very attractions between molecules that define the liquid
state. The cubelike 2,2-paracyclophane fits snugly into one
end of the cylindrical capsule, as shown in Figure 5. Any
Figure 5. Simultaneously encapsulated molecules affect the spinning
of paracyclophane, and is size-dependent. Left: the complex formed
between carbon tetrachloride and paracyclophane (middle). Right: the
paracyclophane enjoys a snug fit at one end of the capsule.
spinning motion of the cyclophane must result in a breathing
motion of the capsule walls, and it is the only case we have
encountered in which spinning was slow on the NMR
timescale. The dimensions of the guest are such that it is too
long to tumble while it is within the capsule and is too bulky to
move past a simultaneously encapsulated molecule. The
flexibility is likely to be greater near the more pliable
hydrogen bonds at the center of the capsule than at the
covalent bonds at the ends. One end of the cyclophane is
forced into the tapered ends of the cavity and we believe that
the contact with this narrowing space hinders the rotation of
the molecule. Accordingly, simultaneously encapsulated large
molecules force the paracyclophane deeper into the tapered
ends and slow its rotation further. The largest simultaneously
encapsulated guest, cyclohexane, slows the spinning rate the
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Angew. Chem. Int. Ed. 2005, 44, 2068 – 2078
Angewandte
Molecular Capsules
Chemie
most—with a barrier of about 16 kcal mol 1—while the
smallest, ethane, shows a barrier for the spinning of a little
less than 15 kcal mol 1. This fine-tuning is a subtle and
unexpected effect, but it is confirmed by the change in
chemical shifts: the furthest upfield cyclophane signal appears
in the presence of the largest simultaneously encapsulated
molecule.
One question remains, to what extent do the encapsulated
molecules respond to events outside the capsule? Since these
systems are at equilibrium with the outside their very
existence represents a response to the situation in the bulk
solution. There is evidence, however, that more subtle
influences also exist. Specifically a chiral environment outside
an achiral capsule can affect the spectrum of a molecule
inside. We investigated the effect of chiral solvents and
additives such as lanthanide shift reagents, but found no
measurable effects, but when asymmetric centers were
covalently attached to the capsule we were able to resolve
diastereotopic hydrogen atoms of an encapsulated molecule
in the NMR spectra. Thus, the steric effects and magnetic
effects can be separated by encapsulation. It appears that the
former cannot penetrate the walls of the capsule but the latter
can.[37]
4. Arrangements in the Encapsulation Space
4.1. “Social Isomers”
The restrictions on the translational motions of molecules
inside capsules can be easily appreciated since the structure of
the capsule itself provides mechanical boundaries. However,
there are also restrictions on the tumbling and, as we
encountered above, spinning motions. Earlier, Reinhoudt
and co-workers defined a new form of isomerism—carceroisomerism—which arose as a result of restricted tumbling of a
single molecule in an unsymmetrical capsule.[38] This
restricted tumbling is also a necessary, but not sufficient,
requirement for the “social isomerism” we encountered.[39]
Two different arrangements—social isomers—are
observed by NMR spectroscopy (Figure 6) when one mole-
Figure 6. Interactions between single molecules of solvents and
solutes. Left: the simultaneous encapsulation of chloroform and Nmethyl-p-toluidine generates two “social isomers”, in which the interaction of the chloroform with the N-methyl group is favored. Right:
simultaneously encapsulated benzene with N-methyl-p-toluidine; the
interaction of benzene with the C-methyl group is slightly favored.
These social isomers do not interconvert within the capsule because
the molecules cannot squeeze past one another and the p-substituted
aromatic is too long to tumble freely within the capsule.
Angew. Chem. Int. Ed. 2005, 44, 2068 – 2078
cule of chloroform and one molecule of N-methyl-p-toluidine
are simultaneously encapsulated within the cylinder. The
isomers could, in principle, interconvert through the tumbling
of the aromatic molecule. This process is quite slow on the
NMR timescale at ambient temperature, although on heating,
shorter molecules such as p-xylene begin to tumble while still
inside the cylindrical capsule. The other means by which the
two isomers could interconvert requires that one molecule
slides past the other within the capsule. We have evidence of
this only for narrow molecules such as short, normal alkanes.
These thin, flexible molecules can slither past others of a
similar kind inside, but any branching increases the steric
barriers to the process.
4.2. Solvation of a Single Molecule
Social isomerism is a consequence of the dimensions of
the cylindrical capsule and those of the molecules inside. We
have used social isomerism to assess interactions between
specific functional groups of the simultaneously encapsulated
molecules. The limitations on motion constrain intermolecular contact between the guests to two areas. Again, the
concentrations are amplified—the volume of the capsule
(ca. 4 10 25 L) translates into molar concentrations of each
encapsulated molecule. From another viewpoint, we can
observe the interaction of a solute with a single molecule of
solvent in equilibrium at ambient temperatures. We tested 3
toluene derivatives (p-ethyl-, p-N-methyl-, and p-O-methyl)
in combination with 12 simultaneously encapsulated solvents.[40] NMR spectroscopic analysis allowed the direct
determination as to whether the solvent molecules had a
preference for one end of the toluene derivatives or the other.
The NMR spectra offer snapshots of short-lived relationships
between molecules isolated from the bulk solution. We know
of no other method that is capable of this determination in
solution, but related studies are available in supersonic jets in
the gas phase or through matrix isolation in frozen argon.[41]
4.3. Tautomeric Equilibria
We used the cylindrical capsule as a controlled nanoscale
environment to influence the keto–enol equilibria. The
equilibrium constants for encapsulated b-ketoesters show
values that differ, both larger and smaller, by an order of
magnitude from those of the free tautomers in solution. For
complexes with a single, large encapsulated guest, the inner
surfaces of the capsule and the seam of hydrogen bonds
influence the equilibrium between the encapsulated keto and
enol forms. For complexes of smaller b-ketoesters, solvents
can be simultaneously encapsulated, and the solvent influences the equilibria: the solvent reduces the space available and
affects the positioning of the ester in the capsule.[42] Events are
no longer stochastic in the capsule and solution-phase
descriptions may not be adequate to capture the nature of
the events inside.
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2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2073
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J. Rebek, Jr.
4.4. Isotope Effects
One of the most subtle cases of social isomerism was
encountered with the isotopic substitution of one of the ends
of an encapsulated molecule. Equilibrium isotope effects are
somewhat of a rarity in molecular recognition, but are not
insignificant.[43, 44] Deuterium substitution of C H bonds tends
to make the molecules slightly more polar. Perdeuterated pxylene was found to be preferentially encapsulated with CCl4
than was undeuterated p-xylene. The isotope effect in the
competition experiments was about 1.3 in favor of the
deuterated material.[45] We were then able to locate the
regions of the structure that were susceptible to these subtle
changes. Most of the isotope effect was located at the methyl
groups of the p-xylene molecule; isotope substitutions on the
aromatic ring had marginal effects. We next prepared a
sample in which one methyl group was deuterated and one
was not. This study showed the preferential binding of the
deuterated methyl group to the tapered end of the cavity,
away from the simultaneously encapsulated CCl4 molecule
(Figure 7). The experimental results were also reproduced by
high-level computational analyses.[46]
4.5. Constellation Isomers
solution. The relative stability of the constellational isomers
depends on the polarity of the guest molecule and their ability
to interact with the capsule. All combinations of the two
guests appears to be energetically acceptable and fit well into
the capsule. The different arrangements represent different
information, and lead to the possibility of their use in data
storage.
Two isomeric constellations correspond to a binary
system, and the symmetry of the capsule limits the number
of states to six.[48] Three different guests offer 18 possibile
states, including a constellational triplet with one of each
guest inside. It is unlikely that NMR spectoscopy will be able
to resolve all 18 combinations of these solvents inside, and
alternative spectroscopic techniques must be found. One such
assembly exists, but involves the encapsulation of anions and
neutral molecules (Figure 9).[49] Unexpectedly, a number of
anions are driven into the capsule when dissolved in CHCl3 as
The cylindrical capsule can contain three molecules each
of CHCl3, 1,2-dichloroethane, or isopropyl chloride. The
NMR spectrum shows two signals in a 2:1 ratio in each case.
This ratio corresponds to molecules at the ends of the capsule
and those near its center, respectively. Again, the simultaneously encapsulated molecules do not exchange positions
while inside. Any three molecules (73–75 3 each) optimally
fill the capsule as they occupy about 52–54 % of the space
(420 3). When two different guests are encapsulated, the
spectra show up to four additional species which correspond
to two sets of constellational isomers (Figure 8). The isomers
represent molecules held in different arrangements in the
space of the capsule, that is, in different constellations.[47] All
the isomers could be identified in every pairwise combination
of the solvents, with the equilibrium distributions of isomers
depending on the concentrations of the solvents in the bulk
Figure 9. Encapsulation of three molecules. Left: anions are encapsulated simultaneously with chloroform solvent. The anions occupy the
center of the capsule and interact with its belt of hydrogen bonds.
Right: when both chloroform and isopropyl chloride are present a
capsule with three different species is observed.
Figure 7. Equilibrium isotope effects through simultaneous encapsulation. Left: the deuterated xylene is preferentially encapsulated over the
nondeuterated isotope. Right: the deuterated methyl group is more
attracted to the resorcinarene that defines the end of the capsule.
2074
Figure 8. Isomeric constellations. Left: the capsule accommodates
three molecules of chloroform (top) or three molecules of isopropyl
chloride (bottom). Right: new isomeric arrangements in space can be
observed for the capsules having two molecules of one solvent and
one of the other when both solvents are present.
2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Angewandte
Molecular Capsules
Chemie
their tetrabutylammonium salts. A cavitand of readily accessible size can completely surround an ion pair,[50] but we chose
large cations to avoid this. The driving force is believed to be
the ability of the ion to interact with the polar groups at the
center of the capsule and the relatively weak interactions of
the ions with solvent. We found that a PF6 ion could be
sandwiched between simultaneously encapsulated chloroform and isopropyl chloride molecules, and were able to show
the formation of other combinations of three different
molecules inside.[51]
methods. The longer lifetimes and limited inner space of
capsules are likely to amplify stereochemical recognition over
that in the bulk solution. Every encounter of a molecule with,
for example, mandelic acid in bulk solution, involves asymmetry, but contacts are made at random and many of these
place the asymmetric centers far apart. Only the average
distance is experienced and recorded. Inside the capsule the
asymmetric carbon atom of mandelic acid and its its partner
molecule point toward the remaining space in the cavity
4.6. Diastereomers
We have also observed that three small chiral molecules,
such as propylene sulfides, can be accommodated inside the
cylindrical capsule. The odd number of molecules inside has
the inevitable consequence that each capsule is chiral, and the
constellational isomerism shown here involves diastereomers
(Figure 10).[52] The assignments could be made using an
Figure 11. A chiral molecule in an achiral capsule creates a chiral space
around it. Left: chiral styrene oxide is encapsulated with isopropyl chloride. The two methyl groups of the latter show different signals in the
NMR spectrum. Middle: simultaneous encapsulation of styrene oxide
and 2-chlorobutane leads to two diastereomers being observed in the
NMR spectrum. Right: mandelic acid is encapsulated with 2-butanol
and the two asymmetric centers encounter each other in the center of
the capsule. A 65 % diastereoselectivity results.
Figure 10. Diastereomeric constellations. Six possible arrangements
are possible for the small chiral molecule propylene sulfide in the cylindrical capsule. The four assemblies shown each contain both enantiomers and were identified by NMR spectroscopy. All assemblies are
chiral since an odd number of molecules are in each capsule.
optically pure propylene sulfide and the gradual addition of
racemic material. Each isomer could be assigned at 60 % ee.
Accordingly, it is possible to use encapsulation to determine
enantiomeric excesses of small molecules inside, but there are
many other ways to do this.
5. Chiral Spaces
Asymmetric capsules can be synthesized from assemblies
held together with covalent bonds,[53] or, through the principles of self-assembly, with hydrogen bonds[54] and metal–
ligand interactions.[55, 56] Enantioselection within these systems has, with very few exceptions,[52b] been disappointing,
and the syntheses are lengthy and problematic. An alternative
method involves the placement of a chiral molecule in an
achiral capsule, because the remaining space is also chiral! But
can that space distinguish between enantiomers of the second
molecule? Complexes with simultaneously encapsulated
chiral molecules in an achiral cavity is ideally, perhaps
uniquely, suited to this situation. Diastereomeric complexes
can be formed in a process similar to classical resolution
Angew. Chem. Int. Ed. 2005, 44, 2068 – 2078
(Figure 11). This effect of a single enantiomer influences the
simultaneously encapsulated molecule for a lifetime on the
order of one second. The frenzied exchange of partners that
occurs in the bulk solution contrasts with the strict pairing and
the fixed orientations of the two encapsulated molecules. The
effects of the asymmetric environment on molecules such as
isopropyl chloride showed that the two methyl groups become
diastereotopic. This result means that they experience the
steric asymmetry presented by the three different groups of
the nearby mandelic acid—hydrogen, hydroxy, and carboxyl.
The chiral molecule imparts a magnetic asymmetry as well,
which affects the remaining space.[57] The phenyl group is at
the end of the capsule, “behind” the asymmetric center and
acts as an excellent anchor. The positioning is optimal but we
can hardly claim that we can control the process. Rather, each
system has its characteristics and things can be made to
happen within those constraints by manipulating the sizes,
shapes, and functional groups. Molecules such as racemic 2butanol, which can interact well with mandelic acid, generate
some diastereoselectivity. Although the levels of diastereoselectivity are, at best, 60–70 % and are low by the standards of
modern catalytic asymmetric synthesis, they are quite high for
systems held together by only hydrogen bonding.[58]
Unexpected results can emerge even when two related
molecules are simultaneously encapsulated. We encountered
these initially as “complexes within complexes”, as shown in
Figure 12. The benzoic acid and pyridone dimers are isolated
in the capsule and protected from exchange of partners from
the bulk solution. The compounds are held in contact within
the capsule by hydrogen bonding. The complexes of trans-
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2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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J. Rebek, Jr.
Figure 12. “Complexes inside complexes.” Top: Two molecules of benzoic acid or a pyridone are encapsulated as their hydrogen-bonded
dimers. Bottom: trans-cyclohexane diol is encapsulated as a pair of
enantiomers, while 2-bromo-3-methylbutyric acid forms a complex in
which two identical molecules are encapsulated.
cyclohexane diols are more stable when two enantiomers
occupy the capsule, rather than two identical molecules. This
would come as no surprise to crystallographers, as centrosymmetric arrangements tend to be preferred in the solid
state for packing reasons. The bromoacids shown in Figure 12,
however, show the opposite preference: the capsule with two
identical molecules is favored. The reason for this result is
hard to specify, but it is not likely to be the steric effects of the
asymmetric centers, as these are more than 6 apart and are
shielded by the intervening carboxy groups. There appears to
be little difference in the packing of the bromoacid diastereomers in the capsule. We suggest that, in addition to the wellappreciated steric effects, electronic effects may play a role in
chiral recognition.
6. Reactivity
Simultaneous encapsulation creates an environment in
which two molecules might be induced to react, or, if their
arrangement is wrong, be prevented from reacting. We
investigated a bimolecular Diels–Alder reaction of encapsulated p-benzoquinone and cyclohexadiene (Figure 13). The
reaction in bulk solution has a half-life of more than one year
at millimolar concentrations in deuterated p-xylene solution.
However, after addition of the capsule to the reactants at
these concentrations, the product could be seen inside the
capsule by NMR spectroscopy after only one day.[59] Initially,
the capsule contains two molecules of the quinone, but
gradually fills with the product, which must arise from the
encapsulation of a low concentration of the cyclohexadiene.
The Diels–Alder adduct is the best guest available to the
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2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Figure 13. Encapsulated cycloaddition reactions. Top: phenylazide and
phenylacetylene are preferentially encapsulated together and are positioned with their functional groups near one another at the center of
the capsule. The cycloaddition gives exclusively the encapsulated
regioisomer shown. Bottom: simultaneous encapsulation of p-benzoquinone and cyclohexadiene, both at a concentration of about 4 m in
the semispherical capsule. The complex was calculated with AVN software and illustrates the reagents poised for an encapsulated Diels–
Alder reaction. The acceleration in reaction rate is nearly 200-fold in
the capsule, but product inhibition prevents catalytic turnover.
capsule, and the generation of a catalytic cycle is prevented by
product inhibition. Nonetheless an acceleration of about 200fold results. A truly catalytic system was found when
thiophene dioxide was used as the diene: the Diels–Alder
adduct with quinone is displaced by further reactant quinone
and a catalytic cycle develops.
The cycloaddition of phenylacetylene and phenylazide is
also very slow at NMR spectroscopic concentrations and gives
roughly equal amounts of two regioisomeric triazoles. The
rate of reaction at ambient temperature and molar concentrations in mesitylene is also very slow. However, the
encapsulated product can be detected within three days at
millimolar concentrations in the presence of the cylindrical
capsule. Moreover, the selective formation of the encapsulated 1,4 isomer was observed.
The substrate shows size and shape selectivity, since
neither 1-naphthylazide nor 4-biphenylazide show rate accelerations in their cycloadditions with phenyl acetylene when in
the presence of the capsule. The naphthylazide is not
encapsulated while the biphenyl azide is quickly displaced
from the capsule by two phenylacetylene molecules.
The NMR spectra indicate that when both azide and
acetylene are present, the favored species is the capsule
containing one molecule of each reactant.[60] This result is a
consequence of the similarity of the two guests, and it allowed
the direct observation of the generated “Michaelis complex”
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Angew. Chem. Int. Ed. 2005, 44, 2068 – 2078
Angewandte
Molecular Capsules
Chemie
(Figure 13). The concentrations inside the capsule are about
4 m each—so viewed this way, there is no acceleration. The
capsule merely concentrates the reactants temporarily and
apparently in an orientation appropriate for reaction. This
arrangement of reactants is a characteristic feature of enzyme
catalysis. Compared with the reaction rate outside the capsule
(at 25 mm each reactant), the reaction within the capsule is
accelerated about 30 000-fold. Product inhibition normally
occurs in reactions where the products resemble transition
states, and this case was no exception. Maximum binding in
the transition state is the ideal situation; transition states are
moving targets and reactants and products are stationary and
more accessible. A recent example of an encapsulated
unimolecular rearrangement with catalytic turnover[61] promises additional applications, but overcoming the general
problem remains a challenge.
What is the source of the enhanced rate of reaction within
the capsule? The volume of the cylindrical capsule is about
400 3, and so each molecule in that space is at a concentration of about 4 m. We prefer to use these “real” concentrations, that is, molecules in a given volume, but this system
has also been calculated to exhibit one of the highest known
effective molarities.[62] Another approach concerns the time
factor: the encapsulated complex has a lifetime on the order
of one second, while in bulk solution a diffusion complex of
the two reactants lives less than a nanosecond. A third
consideration involves solvation: the walls of the capsule
correspond to the solvent molecules, and structural changes
undergone by the simultaneously encapsulated reactants—
from ground state to transition state and products—are not
mirrored by changes in solvation. No organization or
reorganization of the walls can take place; the arrangement
was determined by synthesis. We propose that the combination of well-defined volume, extended timing, and fixed
solvation of the encounter in a complex formed by simultaneously encapsulated species is different from earlier inclusion systems. Cyclodextrins, crown ethers, cyclophanes, and
conventional macrocyclic receptors have open-ended structures that are exposed to solvents and allow the guests to exit
rapidly. Whatever the source or sources of the effect, the
potential of complexes formed with simultaneously encapsulated guests to influence chemical reactivity was established
with these capsules and has been borne out with many other
encapsulation complexes.[63–65]
7. Conclusion
The present research on molecular capsules has its origins
in the discovery of cryptophanes by Collet et al.[66] and
carcerands by Cram et al.[67] None of the cryptophanes were
large enough to surround more than one molecule; typical
guests were small molecules, such as methane, or atoms, such
as xenon. The larger carcerands (in contrast to the capsules)
were sealed off and initially trapped any molecule that
happened to be inside at the time the final covalent bond was
formed. The encapsulation complexes are also descendants of
host–guest chemistry, a term that was introduced, as far as we
know, by Fieser and Fieser in their description of choleic acid
Angew. Chem. Int. Ed. 2005, 44, 2068 – 2078
complexes.[68] They are at the same time examples of
molecular self-assembly and the prefix “nano” could be
appropriately applied to them. We entered the study of
encapsulation phenomena through the side door of physical
organic chemistry; that door is still wide open.
I am grateful to the Skaggs Institute for Research and the
National Institutes of Health (GM 50174) for financial support
and to Professor T. Bartfai for advice. The many co-workers,
whose names appear in the reference section, have made this
research far more than work.
Received: December 6, 2004
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