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: ycohen@post.tau.ac.il

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: jrebek@scripps.edu

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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This journal is c The Royal Society of Chemistry 2011 Chem. Commun., 2011, 47, 5368–5375 5369

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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5370 Chem. Commun., 2011, 47, 5368–5375 This journal is c The Royal Society of Chemistry 2011

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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5374 Chem. Commun., 2011, 47, 5368–5375 This journal is c The Royal Society of Chemistry 2011

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.

Notes and references

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4 D. J. Cram and J. M. Cram, ContainerMolecules and Their Guests, Royal Soc. ofChemistry, Cambridge, 1994.

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7 K. Murayama and K. Aoki, Chem.Commun., 1998, 607–608.

8 (a) A. Shivanyuk, K. Rissanen andE. Kolehmainen, Chem. Commun., 2000,1107–1108; (b) L. Avram and Y. Cohen,Org. Lett., 2008, 10, 1505–1508.

9 (a) Y. Kikuchi, Y. Tanaka, S. Sutarto,K. Kobayashi, H. Toi and Y. Aoyama,J. Am. Chem. Soc., 1992, 114,10302–10306; (b) T. Evan-Salem,I. Baruch, L. Avram, Y. Cohen, L. C.Palmer and J. Rebek, Jr., Proc. Natl. Acad.Sci. U. S. A., 2006, 103, 12296–12300.

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12 (a) S. Shimizu, T. Kiuchi and N. Pan,Angew.Chem., Int. Ed., 2007, 46, 6442–6445;(b) S. J. Dalgarno, N. P. Power,J. Antesberger, R. M. McKinlay andJ. L. Atwood, Chem. Commun., 2006,3803–3805; (c) O. V. Kulikov, N. P. Rath,D. Zhou, I. A. Carasel and G. W. Gokel,New J. Chem., 2009, 33, 1563–1569.

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Fig. 14 Application of FRET in capsule assembly.33 (Left) Energy transfer occurs whenever at

least one donor (green, pyrene) and acceptor (red, perylene) labels appear on the same capsule.

(Right) Resorcin[4]arenes (green) and pyrogallol[4]arenes (orange) strictly self-sort during

assembly and do not exchange panels between their respective hexamers in solution. Image

reproduced with permission from Ref. 33.

Fig. 15 Promiscuity among other capsules. The tetra-imide cylindrical capsule (left) and the

hexameric resorcin[4]arene (center) form a heterodimeric species (right). All three capsules

coexist in CHCl3. Image reproduced with permission from Ref. 35.

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41 Y. Cohen, T. Evan-Salem and L. Avram,Supramol. Chem., 2008, 20, 71–79.

42 (a) A. Baeyer, Ber. Dtsch. Chem. Ges.,1872, 5, 25–26; (b) C. Liebermann andS. Lindenbaum, Ber. Dtsch. Chem. Ges.,1904, 37, 1171–1180.

43 J. Antesberger, G. W. V. Cave, M. C.Ferralelli, M. W. Heaven, C. L. Rastonand J. L. Atwood, Chem. Commun., 2005,892–894.

44 A. Scarso, personal communication.45 (a) S. J. Dalgarno, N. P. Power and

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