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5368 Chem. Commun., 2011, 47, 5368–5375 This journal is c The Royal Society of Chemistry 2011
Cite this: Chem. Commun., 2011, 47, 5368–5375
Recent advances in hydrogen-bondedhexameric encapsulation complexesLiat Avram,a Yoram Cohen*a and Julius Rebek Jr.*b
DOI: 10.1039/c1cc10150a
Basic research in the chemistry of hexameric resorcin[4]arenes and pyrogallol[4]arenesduring the last decade is reviewed. Applications of NMR methods to determine solutionstructures, host guest properties and exchange dynamics are discussed. The scientificissue is the behavior of molecules in small spaces; the challenge is to translate thisinformation to practical applications in, say, catalysis or transport.
In response to the invitation to write
a short review on calixarene capsules
in the new millennium, we have limited
the topic to resorcinarenes and closely
related structures. There are extensive
reviews1 that cover the subject up to
1996, just before an epiphany occurred
that changed the way resorcin[4]arenes
and pyrogallol[4]arenes have since been
viewed in the community. The eye-opener
was due to Atwood and MacGillivray2
who published the X-ray structure of 1a
(Fig. 1). Crystals of this compound
obtained from hot nitrobenzene revealed
a huge hexameric assembly, essentially
an inflated cube, with resorcinarenes
as the sides and water molecules at the
corners.2 The space inside was nearly
1400 A3, occupied by an unknown
number of disordered solvent molecules
(we show 8 benzenes modeled inside).
There was vapor pressure osmometry
evidence that the assembly persisted in
solution as well. Resorcinarenes as
modules offering curvature for larger
structures – carcerands and cavitands –
had already, in the decades since the large-
scale synthesis developed by Hogberg,3
made a gigantic impact on supramolecular
chemistry.4 But it was the self-assembly
a School of Chemistry, The Sackler Faculty ofExact Sciences, Tel Aviv University,Ramat Aviv 69978, Tel Aviv, Israel.E-mail: [email protected]
b The Skaggs Institute for Chemical Biologyand Department of Chemistry,The Scripps Research Institute,10550 North Torrey Pines Road,La Jolla, California 92037, U.S.A.E-mail: [email protected]
Liat Avram
Liat Avram was born inTel-Aviv, Israel, in 1977 andreceived her B.Sc. (1999),M.Sc. (2001) and Ph.D.(2006), from the School ofChemistry at Tel-Aviv Univer-sity. Since then she has been aresearch associate in the groupof Prof. Yoram Cohen. Herresearch interests includediffusion NMR and MRI inchemical and biological systems.
Yoram Cohen
Yoram Cohen, was born inIsrael in 1956, and receivedhis B.Sc. (1981) and Ph.D.(1987) from the HebrewUniversity of Jerusalem. Hewas a Fulbright post docfellow at UCSF (1987–1990).He joined the School ofChemistry of Tel-Aviv Univer-sity in 1992 and was appointedProfessor in 2004. From2004–2008 he headed theDepartment of OrganicChemistry of Tel-Aviv Univer-sity and the Strauss Centerfor Computational Neuro-
Imaging (2005–2008) and since 2008 he is the Head of theSchool of Chemistry of Tel-Aviv University. His researchactivites span from supramolecular chemistry in solution andmolecular nano-capsules to the applications of advanced MRItechniques for studying the structure and functions of the centralnervous system (CNS) with special emphasis on diffusion NMRand MRI.
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of resorcin[4]arenes per se2 that inspired
most of the work of the last decade. The
demonstration, by Mattay’s group,5a that
pyrogallol[4]arenes (2) also form gigantic
hexameric capsules in the solid state
further increased the interest in these
systems.5
In 1998, Atwood published the struc-
ture of a crystalline dimeric resorcinarene
3 (Fig. 2) held together by isopropyl
alcohols that encloses some 230 A3 of
space. This was co-crystallized with the
parent fullerene C60 and no guest
could be identified inside.6 At nearly
the same time, Aoki crystallized a
dimeric structure 4 with a Et4N+ ion
inside.7 Here the seam of hydrogen
bonds holding the capsule together
included 8 water molecules. Whether
either of these capsules persisted in
solution could not be established, but
two years later Shivanyuk, Rissanen
and Kolehmainen8a crystallized a dimeric
capsule 5 bridged by water molecules
with Et3NH+ inside (Fig. 3). Its existence
in solution depended on the solvent:
competitive solvents such as methanol
or DMSO disrupted the capsule, but
NMR using wet chloroform showed the
dimeric encapsulation complex. The
guest signals featured sizeable upfield
shifts and slow exchange with the free
species (on the NMR timescale) and
integration indicated a dimeric capsule.8a
However, it was not totally clear if the
two to one ratio found for this system
implies that a dimer is the major species
in solution. When the self-assembly of 1c
in the presence of tetraethylammonium
salts was studied, hexamers encapsulating
two guests were found.8b Even earlier,
Aoyama’s research group had found that
the b-anomer of methyl D-glucopyranoside
was selectively extracted into a CCl4solution of 1c to give a host–guest
complex with a 2 : 1 stoichiometric ratio.9a
Accordingly, a dimeric capsule complex 6
was proposed and seemed a reasonable
fit, given the volume of the guest (136 A3),
a proposition that later was found to be
erroneous (vide infra).9b
One of the new structural developments
in the last decade was the introduction
of pyridine-derived resorcinarenes 7
(Fig. 4) by Mattay and coworkers.10a
They showed that dimeric capsule 72
exists in solution and in the solid state,
as well as in the gas phase.10b In the
chloroform solution of 7, two species
were observed and were assigned to the
monomer and dimer of the pyridine-
derived resorcin[4]arene. However, a
few years later it was shown, with the
aid of diffusion NMR,11 that in chloro-
form solution the dimeric and hexameric
capsules prevail (Fig. 4c).10c Another
innovation involved the use of fluorous
‘‘feet’’,12a halogenated lower rims12b and
side chain trapped solvent.12c
Fig. 1 Chemical structures of resorcin[4]arenes 1 and pyrogallol[4]arenes 2. A modeled
hexameric form of 1 incorporates 8 water molecules to complete the seam of hydrogen bonds
and is shown with 8 molecules of encapsulated benzene. Overall, the structure is an inflated cube
with resorcin[4]arenes as each side and water at each corner.
Fig. 2 The solid state structure of a dimeric resorcin[4]arene 3. The seam of hydrogen bonds
includes 8 isopropyl alcohols. Another dimeric structure 4 with a Et4N+ ion inside has a seam of
hydrogen bonds that comprises 8 water molecules.
Julius Rebek Jr.
Julius Rebek, Jr. is the Director of The Skaggs Insti-tute for Chemical Biology at The Scripps ResearchInstitute. He was born in Hungary and educated at theUniversity of Kansas and the Massachusetts Instituteof Technology. He held professorships at UCLA, theUniversity of Pittsburgh and MIT before moving toLa Jolla in 1996. His research interests includesynthetic, self-replicating molecules, self-assemblingsystems, recognition phenomena and molecular behaviorin small spaces.
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These observations all caution that the
most abundant structure in solution is
not necessarily the one found in the solid
state, and that extrapolation from solid
state to solution in these systems is risky.
The direct observation of guests
inside the hexameric host capsule in
solution had to await the new millen-
nium. Like many others, the La Jolla
group had already adopted and adapted
the resorcinarene platform for use in
molecular recognition as capsules13 and
deep cavitands.14 They found that in
wet chloroform, which was the widely
used standard solvent for these studies,
the resorcinarene actually dissolved
(a good sign, since in scrupulously dried
solvents the resorcinarenes have low
solubilty and give broad, uninterpretable
NMR spectra). Addition of Hex4N+Br�
to the solution resulted in separate sets
of signals for the bound and free
ammonium salt, with the bound material
exhibiting large upfield shifts in the
NMR spectrum.15 The separated signals
indicate that large energetic barriers
separate the inside and outside of the
capsule, since many hydrogen bonds
must be broken to allow the exchange
of molecules between the two environ-
ments (about which, more later).
Integration of the spectra clearly showed
the 6 : 1 ratio of resorcinarene to
ammonium salt. The use of quaternary
ammonium salts was inspired by the
nature of the inner surface of the capsule.
The 24 aromatic rings provide p bonds
that may be regarded as a thin coating
of negative charge on the concave inside
surface of the capsule. The partial
positive charges of the hydrogens on
the convex outer surfaces of the ammonium
guests are ideal complements for the
capsules. Smaller salts also made capsular
assemblies, a hint that other occupants
were also inside. Typically, capsules have
slightly more than half the interior space
filled by guests;16 in these cases, the
counterions and some solvent chloro-
form molecules were coencapsulated to
reach this level of occupancy. In 2001 the
La Jolla group showed that even neutral
molecules would go inside, provided that
they filled the space properly.17
The clear evidence that the resting
state of resorcin[4]arenes (and even
pyrogallol[4]arenes) in conventional wet
organic solvents is that of hexameric
capsules was provided by the Tel Aviv
group.18 Using diffusion NMR11 they
showed that the ammonium guests or
other neutral guests are not needed for the
capsules to assemble in solution; solvents
such as chloroform and benzene alone
could be the occupants.18 Indeed, using
diffusion coefficients, which is a means for
obtaining the effective size of the molecular
species under investigation and hence its
weight, it was shown that lipophilic
resorcin[4]arenes and pyrogallol[4]arenes
self-assemble spontaneously18,19 into hexa-
meric capsules in non-polar organic
solvents. It was also shown that the
Fig. 3 A third dimeric capsule 5 also uses water molecules to encapsulate Et3NH+ in the solid
state. It persists in wet CHCl3 solution as shown by NMR. A cartoon of the dimeric structure
proposed for the encapsulated b-anomer of methyl-D-glucopyranoside is shown as 6.
Fig. 4 (a) The structure of 7, (b) The X-ray structure of 7 showing a dimeric capsule10b (c) The
DOSY of a 20 mM CDCl3 solution of 1c and 7 showing that 7 forms both hexameric (just as 1c)
and dimeric capsules in solution. Image reproduced with permission from Ref. 10c
Fig. 5 The 1H NMR signal for benzene alone in 1c (a); 8 benzenes are inside. When a small
amount of CHCl3 is added new capsule species appear (b). When benzene and CHCl3 are
cosolvents, a distribution of capsules are present (c) The signals of encapsulated chloroform
(d) and dichloromethane (e) molecules (400 MHz, 298 K) in a 20 mMCHCl3 or CH2Cl2 solution
of 2b, respectively.
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encapsulated solvent molecules exhibit
upfield shifted resonances in their NMR
spectra, separated from those of the
solvents in bulk solution.18–20
In wet, non-deuterated solvents 1c
encapsulates six and eight molecules of
chloroform and benzene, respectively.21a
Figs 5a–c show the NMR trace of
encapsulated benzene alone, and after
the addition of different amounts of
chloroform. The broadened single peak
in Fig. 5a indicates some (slow) exchange
of benzene in and out of the capsule;
the spectrum in Fig. 5b shows that
several capsules coexist – the original
with 8 benzene guests, another with
7 benzenes and 1 chloroform and so
on – while Fig. 5c shows the whole
distribution of species that are present.21b
In pyrogallol[4]arenes21c very peculiar
NMR signals were observed for the
encapsulated chloroform and methylene
chloride molecules as shown in Figs 5d
and e, respectively.
Using diffusion NMR, the Tel Aviv
group demonstrated that 8 water
molecules are needed to form the hexa-
meric capsules of resorcin[4]arene in
solution,22 as shown in Fig. 6. In the
wet chloroform solution of 1c, for
example, only one peak of water was
observed implying that the diffusion
coefficient of that peak should be a
weighted average of water in the different
pools. It was found that only when the
1c : H2O ratio was smaller than 6 : 8 was
the diffusion coefficient of water exactly
that of the hexameric capsules, implying
that in solution a [(1c)6(H2O)8] capsule
prevails.22 Water is not the only comple-
ment to 1 that leads to hexameric
capsules; a recent publication shows that
alcohols can also complete the seam of
hydrogen bonds in the solid state23 and
in solution (vide infra).24
The closely related pyrogallol[4]-
arenes, which were shown to form hexa-
meric structures in the solid state5,25 were
also probed by diffusion NMR.19,20
Here, diffusion NMR provided the
proof that in the case of the hexameric
pyrogallol[4]arene capsules, watermolecules
are not part of the supramolecular struc-
ture in solution.19,20 Based on this obser-
vation, the La Jolla group speculated
that such pyrogallol[4]arene hexamers
should prevail in solution in extremely
non-polar organic systems, which cannot
accommodate water molecules.26 Indeed,
they found that the hexameric capsule of
pyrogallol[4]arene can spontaneously
self-assemble when a suitable hydro-
carbon is present, and the guest will
even contort itself to fill the space. For
example, they found that six molecules of
octane are encapsulated as modeled
in Fig. 7.26
In the hexameric capsule of pyrogallol[4]-
arenes the 1H NMR signals of the
encapsulated hydrocarbon solvent
molecules showed a peculiar pattern, as
shown in Fig. 8. The NMR spectra
and assignments for encapsulated octane
(a) and heptadecane (b) are shown in
Fig. 8. The gradual downfield shifts for
the signals of octane from the methyl
groups (C1/C8) to C4 reflect their average
distances from the pyrogallolarene
centers. When a long chain hydro-
carbon such as C17 is taken up inside
the same capsule, it appears to be neatly
folded. This folding follows from the
NMR spectra of the encapsulated hydro-
carbon C17 where the largest upfield
shifts occurred in the central methylene
(C9) of the hydrocarbon and at its ends.
That is, both ends and the middle are
near the shallow bowls of the pyrogallol-
arene subunits.26
The folding of alkyl groups is a general
feature of encapsulation in these systems
and was studied with a series of alkyl
ammonium salts with resorcin[4]arene
1c.27 As shown in the spectra of Fig. 9,
the methyl group of the tetrahexyl
salt enjoys the furthest upfield shift, and
presumably, can penetrate the cavity
of a resorcinarene panel. What folding
there is – and the diastereotopic signals
of C2 are consistent with this behavior –
must take place near the N atom. The
longer heptyl and octyl groups ‘‘buckle’’
and C4 is nearest the cavitand.
A peculiar observation is that despite
the ability of the resorcin[4]arenes
capsules to accommodate tertiary amines
and tetraalkyl ammonium salts, the corres-
ponding hexameric capsules of pyrogallo-
[4]arene were found to encapsulate only
tertiary amines in chloroform solution.20
Moreover, it was found that protonation
of encapsulated tertiary amines results in
the ejection of the ammonium salts
formed.28 Clearly, this is not a steric
effect, as diffusion NMR showed that
the protonated amine was ejected from
the capsule cavity while the hexameric
capsule was still intact.28 The power of
diffusion NMR in characterizing such
capsular host–guest systems was demon-
strated again when the complexation ofFig. 6 Diffusion coefficients of 1c (K) and water ( ) as a function of the 1c/H2O ratio in
chloroform.22
Fig. 7 A hexameric capsule of pyrogallol[4]arene self-assembles in suitable hydrocarbons
without the need for water. Six molecules of octane are shown in the modeled capsule.
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the lipophilic resorcin[4]arene 1c with
glutaric acid and the b-anomer of
methyl-D-glucopyranoside (see 6) was
revisited.9b There we could show that
the 1 : 1 and 2 : 1 ratio between 1c and
glutaric acid or glucoside, respectively,
represent hexamers of 1c encapsulating
six or three molecules of the guests,
respectively.9b Fig. 10 shows the signal
decay as a function of the gradient
strength of a representative peak of 1c,
encapsulated glucoside and biscalix[5]-
arene (11). The molecular weight of 11
is 2398 g mol�1, which is slightly higher
than that of the dimer of 1c. This figure
also shows a graphical presentation of the
normalized signal decay of 1c, encapsulated
glucoside, and 11, as compared with
that of the encapsulated tetrahexyl salt.
According to Fig. 10, the same signal
decays are obtained for the encapsulated
glucoside, encapsulated tetrahexyl salt
and 1c, which are all significantly smaller
than the signal decay of the biscalix[5]-
arene (11).
How things get in and out of these
hexamers is puzzling and we have made
some attempts to answer this in the case
of large tetralkylammonium guests.27
There is a size dependence of the exchange
(exit) rate, with the larger guests leaving
more slowly. For R4N+ the activation
free energies for exit as a function of
R are: R = C3 13.1; C4 = 14.8;
C5 = 16.7 and C7 = 17.1 kcal M�1. At
first glance, this could merely reflect
tighter binding of the larger guests, but
equilibrium studies and competition
experiments show the opposite trend.
For R4N+ the apparent association
constants for encapsulation as a function
of R are: R = C3–5 4 104; C6 = 1200;
C7= 450 and C8= 150M�1. Accordingly,
it is necessary to propose an opening of
limited size!27
A mechanism is shown in cartoon
form (Fig. 11) where the guest exits from
a capsule through an opening created by
removal of one resorcinarene panel.
Alcohols can, in principle, replace
the water molecules in the structure of
the hexameric capsules but can also be
encapsulated like other guests.23,24 The
different sites that alcohols can occupy in
such systems are shown in Fig. 12.
Using diffusion NMR it was possible
to show that some alcohols are only
encapsulated, while others are part of
the hexameric capsules (just like water
molecules) and other alcohols occupy
both sites.24 Interestingly, this conclu-
sion was reached by monitoring the effect
of exchange on the diffusion measure-
ments performed using the longitudinal
eddy current (LED) diffusion NMR
sequence.29 This sequence is generally
used in diffusion ordered spectroscopy
(DOSY),30 and is more sensitive to the
effects of exchange.31 It was also demon-
strated with the aid of diffusion that
tertiary alkylamines and quaternary
alkylammonium interact with the hexa-
meric capsules both from the inside and
the outside.32
Self-sorting has become one of
the earmarks of self-assembling systems
because the corrections that occur during
the assembly process involve con-
stant distinctions between ‘‘self’’ and
‘‘non-self’’. Resorcinarenes and pyrogallol-
arenes share so much in terms of size,
shape and chemical surfaces that deter-
mine their recognition properties. But do
they self-sort? The Tel Aviv group20 first
approached this problem using diffusion
NMR techniques and showed that no
evidence of scrambling of the components
of the two respective hexameric capsules
occurs, while scrambling does occur when
two resorcin[4]arenes or two pyrogallol[4]-
arenes are used. When 1b and 2b were
mixed no change in the starting diffusion
coefficient was observed, as shown in
Fig. 13a. However, when 1b and 1c
were mixed, equilibration in the starting
diffusion coefficients was observed with
time, as shown in Fig. 13b.
The La Jolla group studied the problem
using Foerster resonance energy transfer
(FRET) techniques.33 The hexamers
of resorcinarenes bearing either perylene
or pyrene readily exchanged their sub-
units when mixed (Fig. 14),33a as did
hexamers of pyrogallolarenes32b bearing
either perylene or pyrene, but no evidence
of exchange of the modules from a
resorcinarene hexamer to a pyrogallo-
larene hexamer was found. Moreover,
even the assembly process was strictly
self-sorting.33c
The gas phase would have things
differently.34 Schalley and coworkers
showed that in the mass spectrometer
Fig. 8 The NMR spectra and assignments for encapsulated octane (a) and heptadecane (b) are
shown. The furthest upfield signals are from hydrogens closest to the pyrogallol[4]arene centers.
For C17 the methylenes (C9 and C8) show the largest upfield shifts so the hydrocarbon must
be folded.
Fig. 9 The NMR spectra and assignments for ammonium salts encapsulated in the hexameric
resorcin[4]arene. The longer chains ‘‘buckle’’ to place C4 closest to the cavitand (curved line).
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not only hetero-hexamers, but all manner
of mixed oligomers could be observed and
characterized.34a How does this happen?
It may be that in the near vacuum the
loss of water molecules is compensated
by the additional hydrogen bonding
components of the pyrogallol and hetero-
oligomerization occurs. Even simpler,
there may just be differences of behavior
in the two different phases of solution
and gas.
It is possible to hybridize in a different
sense. Specifically, a cylindrical capsule
(Fig. 15) and the hexameric resorcinarene
form a heterodimeric species, in the
presence of a guest such as chloroform.35
It was possible to monitor the hybridiza-
tion in real time using FRET techniques.
Self-sorting does not occur in this specific
system, but the system can be reset to the
starting state (the self-sorted state) by
offering a good guest for the cylindrical
capsule such as benzanilide.
These results emphasize that the issue
of self-sorting in the self-assembly of
even the simplest hexameric capsules of
resorcin[4]arenes (1) and pyrogallol[4]-
arenes (2) in the different phases is difficult
to reconcile and explain.
A second issue concerns the nature
of resorcinarenes in dry solvents. What
happens when there are not enough
water molecules to complete the seam
of hydrogen bonds needed, say, for the
hexamer or possibly the dimer? This
was approached recently by Mattay and
coworkers,36 who used DOSY techniques
to detect a 1 : 1 complex of resorcinarene
with a 2,2,2-trifluoro-1-phenylethanol,
a 2 : 1 complex with 2-butanol and a
hexamer (rather than a dimeric capsule)
with 2-ethyl-octanol. No encapsulated
guests were apparent from the spectra,
so it was concluded that these systems
are under rapid in/out exchange. However,
these conditions are quite different from
Aoyama and coworkers’ conditions9a in
which two-phase extractions from water
gave the encapsulated species in slow
exchange.
A third mystery has to do with the
peculiar selectivity of the hexamers. Alkyl
ammonium salts are excellent guests for
the hexameric capsules of resorcinarenes
but not for the pyrogallolarenes.20,28
However, trialkylamines are excellent
guests for the latter. Cation/p inter-
actions would favor the opposite result,
so what causes this selectivity? This is
even more peculiar since Philip and
Kaifer were able to encapsulate the
charged cobaltocenium both in 1c and
2b.37 They were also able to encapsulate
a series of nitroxides in 1c.38 The Atwood
group was able to load several fluoro-
phores in pyrogallol[4]arenes and study
their spectroscopic characteristics but
Fig. 11 The exit of tetralkylammonium guests from the hexameric resorcin[4]arene. Larger
guests leave more slowly although they are bound more weakly than smaller guests. An opening
created by removing a resorcin[4]arene panel is proposed.
Fig. 12 Possible sites a–c occupied by alcohols in a solution of the hexameric capsule of 1c.
Image reproduced with permission from Ref. 24.
Fig. 10 The 1H NMR signal decay as a function of the gradient strength (G) (400 MHz, 298 K)
of one of the peaks of (a) the encapsulated b-anomer of methyl-D-glucopyranoside, (b) 1c and
(c) a biscalix[5]arene (11) with a molecular weight of 2398 g mol�1. (d) The natural log of the
normalized signal decay (ln (I/I0)) as a function of the b value of the representative peak of 1c
( ), the encapsulated b-anomer of methyl-D-glucopyranoside (’), the biscalix[5]arene ( ) and
of the encapsulated THABr ( ).
Fig. 13 Diffusion coefficients of the peaks of 1b ( ), 1c ( ), and 2b ( ) in a mixture of (a) 1b/2b
and (b) 1b/1c as a function of the time after preparation of the mixture, and after two and eight
hours of reflux. Image reproduced with permission from Ref. 20.
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there the loading was relatively low.39 So
currently there are more examples of
guest encapsulation in resorcin[4]arene
hexamers than in pyrogallol[4]arene
hexamers, but that could soon change.40
Even fewer guests have been found to
be encapsulated in the hexameric capsule
of calixpyridine[4]arene (7).10c,41 It should
be noted, however, that these observa-
tions are not only connected to the affinity
of the different guests towards the cavities
of 1 and 2 but also reflect the affinity
of the solvent used (generally CDCl3)
towards the cavity of the hexamers of 1
and 2.
Conclusions
It is probable that self-assembly of these
systems is more than a century old,42 as
any synthesis that produces 1 or 2 in the
presence of wet organic solvents can give
encapsulation complexes, but the capsule
can form even without solvents.43 The
self-assembly of up to 22 molecules
(at least in the case of resorcin[4]arenes
with benzene) bodes well for future investi-
gations of encapsulation phenomena. Since
some resorcinarenes are commercially
available or are easy to prepare, the
barrier to entry of experimental work in
this field is low. Already, the use of the
resorcin[4]arene capsule as a reaction
chamber44 indicates progress and further
applications can be expected. Another
avenue that should be further explored
is the metallo-supramolecular capsules,
which were omitted from this review
since the subject was thoroughly treated
elsewhere quite recently.45 The behavior
of molecules in small spaces is quite
different from that in dilute solutions.
These capsules offer an essentially hydro-
phobic environment, isolated from
solvent, where single molecule guests
enjoy high (B1 molar) concentrations.
Apart from their use in physical organic
chemistry, their resemblance to enzyme
active sites makes them appealing models
for some biological phenomena.
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