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Calixarenes Macrocycles with (Almost) Unlimited Possibilities.

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Calixarenes, Macrocycles with (Almost) Unlimited Possibilities
Volker Bohmer
The condensation reaction between p ferf-butylphenol and formaldehyde leads
in a single step to good yields of cyclic
oligomers in which, depending on the reaction conditions, either four, six, or
eight phenol units are joined by methylene bridges. The beakerlike shape of
the most stable conformation of the tetramer has led to their being given the
name “calixarenes” (calix = chalice).
Resorcinol can undergo condensation in
a similar manner with a variety of aldehydes to afford cyclic tetramers with the
same basic structure (the resorcarenes).
In both cases the reaction does not require the use of dilution techniques, so
that large quantities of product can be
readily obtained. In addition, the parent
compounds can be modified in various
ways, in particular at the phenolic hydroxy groups or the phenyl residues;
these approaches can be used separately
or in combination. Calixarenes are thus
ideal starting materials for the synthesis
of various types of host molecules and
can also act as building blocks for the
construction of larger molecular systems
with defined structures and functions.
1. Introduction
The name calixarenes was introduced by Gutsche“] for the
cyclic oligomers which are obtained from the condensation of
formaldehyde with p-alkylphenols under alkaline conditions.”. 21
The use of this word (“calix” means “beaker” in Latin and Greek)
was suggested in particular by the shape of the tetramer, which
can (and generally does) adopt a bowl- or beakerlike conformation which indicates the possibility of the inclusion of “guest”
Cyclic tetramers of this type had been described (or postulatedI3“1)before and in some cases synthesized by defined reaction
Most of these attempts were made with the goal of
understanding the formation and properties of phenol-formaldehyde condensates on the basis of defined oligomeric model compounds. However. it required a point of view different from that
of the polymer chemist to put this class of substances into the
perspective of their present importance. Pedersen’s discovery of
the crown ethers stimulated the development of those areas of
research known today as host-guest chemistry, inclusion compounds, or even supramolecular chemistry; the importance of
the “cyclic oligonuclear phenolic compounds” was thus seen in
a completely different light.
[*] Dr. V. Biihmer
lnstitut fCir Organische Chemie der Universitiit
Abteilung Lehraint Chemie
J.-J.-Becher-Wzg 34, SB1. D-55099 Mainz (FRG)
Telefax: Int. code (6131)39-5419
Their potential applications range from
use as highly specific ligands for analytical chemistry, sensor techniques and
medical diagnostics to their use in the
decontamination of waste water and the
construction of artificial enzymes and
the synthesis of new materials for nonlinear optics or for ultrathin layers and
sieve membranes with molecular pores.
Keywords: calixarenes . host-guest compounds . metacyclophanes . resorcarenes
. supramolecular chemistry
The condensation of resorcinol with aldehydes (but not with
formaldehyde) under acidic conditions also leads to cyclic tetramers, and here again the initial structural postulates date
back to the 1940s.[’]It is thus only logical to denote these compounds, which are also [l. 1.1.I]metacyclophanes, as calixarenes, since nomenclature is normally based on the basic skeleton
of a class of substances.
In what follows the name calix[n]arenes will generally be used
for 1.-metacyclophanes (general formula I), regardless of
whether the phenolic hydroxy groups are intraannular ( m d o ) or
extraannular (exo) or whether individual units bear any phenolic OH groups at all. Although this review will deal primarily
with calixarenes derived from phenol (calixarenes of type IT),
important results concerning calix[4Jarenes derived from resorcinol (calixarenes of type Ill) will also be discussed. The term
“resorcarenes” will be used to distinguish calixarenes of type I11
Scheme 1. I: Calix[n]arenes or 1,-metacyclophanes, 11: Calix[n]arenes of phenol (or
calixarenes in the narrow sense). The hydroxy groups are in the endo position. 111:
Calix[4]arenes derived from resorcinol o r resorc[4]arenes. The hydroxy groups are
in the P X O position.
V. Bohmer
from those of type 11. Compounds will also be referred to in
which the niethylene bridges or the phenol units are replaced by
other related structural elements. However, orthocyclophanes
such as the cyclotriveratrylenes or c r y p t o p h a n e ~ [ and
~ ] other
macrocycles containing phenol building blocks will not be dealt
with here.
2. Syntheses
2.1. One-Pot Procedures
The interest which calixarenes have aroused in the last ten
years[51is due in the main to their ready availability. Multigram
amounts can be obtained on a laboratory scale in a relatively
simple manner starting from cheap starting materials; in this
calixarenes differ from many other synthetic macrocycles.
It is mainly thanks to the work of Gutsche that today the
reaction conditions for the direct "one-pot synthesis" of calixarenes 1 with four, six, o r eight tert-butylphenol units are known
very exactly.[', Condensation of tert-butylphenol with formaldehyde under alkaline conditions (NaOH, KOH) leads in one
step to the tetra-,[6a1hexa-,[6b1 or octamer[6c1in yields (after
recrystallization) of about SO, 85, and 63 %, respectively.
(n = 4-8)
The reaction conditions determine which. calixarene is
formed.['] The optimum amount of base for the formation of the
tetramer and octamer appears to lie at about 0.03 mole NaOH
per mole tert-butylphenol, the tetramer requiring higher temperatures (diphenyl ether, reflux) than the octamer (xylene, reflux). Considerably larger amounts of base (0.4 mole K O H per
mole tert-butylphenol) favor the formation of the hexamer.
This ready availability of the calixarenes is quite amazing,
since during this reaction either 8, 12, or 16 covalent bonds are
newly formed in a defined manner. N o other example is known
in polymer chemistry in which four, six, o r eight molecules of
two different bifunctional starting materials form almost solely
one cyclic tetra-, hexa-, and octamer, respectively. These cyclic
compounds are in fact much more readily available than the
corresponding linear oligomers.
Even though (at least in the case of tevt-butylphenol) the synthetic conditions are known relatively exactly, many questions
still remain with regard to the reaction mechanism. While various steps in the reaction between phenols and formaldehyde are
well understood[','] (and such steps must occur several times
during the formation of the calixarenes), the reasons for the
formation of particular calixarenes are virtually unknown. It is
remarkable that macrocycles with an even number of phenol
units are formed preferably['] (cf. Table 1 ) . There is a considerable amount of evidence that the calix[4]arene is the thermodynamically most stable product (it can for example be obtained
from calix[6]- or calix[8]arene under basic conditions), while
calix[8]arene is formed under kinetic control. In contrast, a template effect has been suggested as an explanation for the formation of ~alix[6]arene.[~"]
Gutsche proposed an intramolecular
reaction for the conversion of calix[8]arene into calix[4]arene."]
However, experiments with a mixture of labeled and unlabeled
calix[8]arene as the starting material show a rapid statistical
distribution of the label in the tetramer.rgblThe conversion of
calix[6]arene into calix[4]arene also argues against an intramolecular "constriction process".
More concisely, the ready availability of the calixarenes applies
only when p-tert-butylphenol is used as the starting material.
While the results for p-tert-pentylphenol are similar['01 (although
the yields are somewhat lower), the formation of the hexamer
starting from p-tert-octylphenol [p-(1,1,3,3-tetramethylbutyl)phenol] has been mentioned,"] but not yet described in detail.
p-Adamantylphenol apparently yields only the octamer (71 Y O ) .
Calixarenes with an odd number of building blocks (S,['] 7,[l2]
and even 9[11 and greater[9b1)have also been obtained from
p-tert-butylphenol by direct condensation, but the yields are
considerably lower. However, the formation of a tetramer has
not yet been described starting from either p-phenylphenol o r
from p-n-alkylphenols (including p-cresol) . Calix[7]arenes can
Volker Bohmer was born in I941 in Rauscha near Gorlitz and studied chemistry at the Universitat Mainz. He received his doctorate in I969 under the supervision of Prof. H. Kanimerer,for
work on phenolic multinuclear compounds as supportsfor synthetic matrix reactions. With the
e-xception of a stay as a guest lecturer at the university in Le Mans (1976177) he has remained
loyal to the Uniwrsitat Mainz. He has played a major role in the development of the Department ,for Teacher Trainees in Chemistry, where he is now Acudemic Director. His research
interests are defined oligomers and particularly calixarenes. He is the author of approximatel},
130 publications, of which more than 50 have been concerned with calixarenes.
Angen. Chrm. I n f . Ed. Engl. 1995, 34, 713-745
be obtained, however, from p-cresol and p-ethylphenol.[' 31 One
reason for these confusing results certainly lies in the different
solubilities of the various compounds which partly precipitate
during the synthesis. Table 1 contains a survey of the "one-pot''
syntheses presently known.
one of the possible products of the one-pot
reaction.['] Macrocycles with several CH,0 - C H , bridges can however be more readily prepared by the elimination of water
from doubly hydroxymethylated phenols
or from ~ l i g o m e r s . ~ ' ~
Macrobi~ - ~ ~ and
-tricyclic compounds with CH,-0-CH,
Table 1. Yield ["h]ofcalix[n]arenes in one-pot syntheses starting fromp-substituted
(R) phenols. Values in parentheses refer to chromatographically isolated products.
References are given in square brackets.
bridges have been obtained from the corresponding functionalized phenol ether derivatives by Williamson
22 1131
24 [13]
(10) [I41
49 [6a]
6 - 7 [lo]
31 [lS]
I-pentyl [a]
r-octyl [b]
26 [14]
30 [lo]
2.2. Stepwise Syntheses
'! [14]
37-41 [lo]
30 1161
71 [ l l ]
10 (171
33 [18]
16 [18]
(10) [19]
(41) [20]
[a] r-Pentyl = 1.1-dimethylpropyl (-C(CH,),-CH,-CH,).
tramethylbutyl (-C(CH,),-CH,-C(CH,),).
[b] r-Octyl
12 [I71
12 [18]
7-14 [I91
= 1.1.3,3-te-
Results obtained in recent years suggest that the one-pot conditions (condensation with formaldehyde in the presence of alkali metal hydroxides in nonpolar solvents) are also applicable
when diphenols are used as starting materials; this could open
the way to a variety of interesting macrocycles. Thus, for example 1.3-bis(2-hydroxy-5-tert-butylphenyl)propane can undergo reaction with formaldehyde in the presence of NaOH to
give the cyclic dimer 2 in 90 YOyield.["] In contrast, the reactions
of 2,2'-dihydroxy-5,5'-di-tert-butylbiphenyllead to either the
cyclic trimer (3a) or the tetramer (3b) in about 50% yield,
The calixarenes obtained from a one-pot synthesis necessarily
have the same substituent in all thep-positions. Calixarenes with
different substituents can be obtained by the stepwise synthesis
described by Hayes and Hunter[z5Jand further optimized by
Klmmerer, Happel et a1.[261This stepwise synthesis starts from
an o-bromo-p-alkylphenol and uses a series of alternating hydroxymethylation and condensation steps to build up a linear
oligomer with a hydroxymethyl group at one end; this can then
be cyclized under dilution conditions after the other o-position
has been freed by dehalogenation (Scheme 2).
Sa n = 3
Sb n = 4
Scheme 2. Stepwise synthesis of calix[n]arenes (I = 2 to
depending on the size of the alkali metal cation present,["] while
the relatively rigid macrocyclic diphenol 4 can be converted to
the cyclic dimer 5.[231
Condensation with formaldehyde under alkaline conditions
can also lead to products with dimethylene ether bridges. The
"dihomooxacalix[4]arene" 6 was identified at an early stage as
Angrii . C%cni. I n / . Ed. Engf. 1995, 34. 713 -745
The yields obtained in the cyclization step are generally very
good, but because of the large number of steps the synthesis is
complicated and the overall yield low. In addition the number of
possible substituents in the p-position compatible with the synthetic steps involved is limited.
In special cases a shorter approach to linear, monohydroxymethylated tetramers has been described;[271however, the stepwise synthesis["] appears at present to be generally of only
historical interest (see Section 2.6). But, even today it would
probably be the primary choice for the synthesis of calixarenes
which are built up from different alkylphenol units, and the
calix[5]arenes prepared by this strategy are still the only known
examples of this type.[26h,f1
71 5
V. Bohmer
2.3. Fragment Condensation
While the last step in the stepwise synthesis involves the cyclization of one linear starting molecule in one intramolecular
reaction step, it is also possible to prepare (in particular) calix[4]arenes from two (or more) fragments, that is the cyclization
step is preceded by (at least) one intermolecular condensation
step. Condensations using the “3 +
and “2 + 2”[301principles have been used for the synthesis of a range of calix[4]arenes 7; substituents such as COOR, NO,, N=N-Ph, and
halogen can be present in the p - p o ~ i t i o n . ~ ~ ~ ‘ .
It also appears feasible to prepare calix[5]- and calix[6]arenes
in this manner (i.e.. according to the “3 + 2” or “3 + 3” principle); however. only one example of the synthesis of a calix[6]arene has so far been described.[29’, 331 Apparently the conditions for the synthesis (TiCl,/dioxane) lead to the cleavage of
Ar-CH,-Ar bonds, since “ 3 + 3” experiments led among other
products to calix[4]arenes, while a calix[5]arene was obtained as
a by-product in the preparation of 8.[33bl
The tendency for the formation of calix[4]arenes observed in
the presence of TiCI, can be applied in the “2 x 1 + 2 x I ” synthesis, which was used to obtain calix[4]arenes 9 with two alternating building units (including 4-chloro-3.5-dimethylphenol)
in about 10% yield.r35]
Compounds with substituted bridges (Ar-CHR-Ar; Ar denotes aryl throughout the
and those with rn-substituted
phenol units have also been prepared in this way.[321The best
yields (up to 35 O/O) have so far been obtained in dioxane in the
presence of TiCI,; however, the optimum conditions for the
reaction and the workup differ in each case. For example, the
trihydroxycalixarene 8 was obtained in dioxane by using sulfuric acid as the catalyst.133a1
11 can be treated
with paraformaldehyde in xylene to
give calix[4]arenes
12 with four exohydroxy groups[371
in yields upto 35%
The possibility of forming a
new intramolecular
hydrogen bond benu
groups appears to
play an important role in the formation of the product, since 12
is for example not formed from the o-bridged dimer isomeric to
11, in which such hydrogen bonds are already present.[381In
addition, the yield
decreases to 5 %
in the case of
12b.[38b1The step+ 2 CHaO
wise synthesis can
also be used to pre- 2 H20
pare calix[4]arenes
of type 12 which
contain different
a R = C(CHs),
substituents in the
The calix[4]arene 10 with extraannular hydroxy groups was
formed in considerably better yield (60 YO)from the condensation of mesitol with chloromethylated mesitol in nitromethane
using SnCI, as the catalyst.1361Complications, which again appear to be due to the cleavage of Ar-CH,-Ar bonds, are observed when other
chlorometh ylated
are used.
Angeu. Chem. Int. Ed. Ennl. 199534. 713-745
2.4. Bridged, Double, and Annelated Calixarenes
2.5. Resorcl4Jarenes
When the phenol used in the "2 x Z + 2 x I " synthesis of 9 is
replaced by a p-linked diphenol 13 (r,w-bis(4-hydroxyphenyl)alkane), it is possible to prepare calix[4]arenes such as 14 in
which two opposite p-positions are bridged by an aliphatic
Because of its greater reactivity resorcinol affords no defined
condensation products with formaldehyde. Cyclic tetramers can
however be obtained by acid-catalyzed condensation with other
less reactive aldehydes.['] Larger cyclic oligomers have so far not
been observed. The situation is complicated by the fact that for 18
because of the different relative configurations at the bridges
(-CHR-) four diastereomers are possible which may be classified
as rccc, rcct, rctt, and r t ~ t . [ ~ ~ l
The synthesis ofcompounds 14, with yields up to 34%,[401has
so far been realized for chain lengths rz = 5-16 and the substituents R = Me, tBu, alkyl, or cycloalkyl, phenyl, and chlorine. The byH
products can include double ca0 ; 00'
lix[4]arenes such as 15 in which two
calix[4]arene units are linked by two
aliphatic bridges.[411
When a dimer is replaced in the
"2 + 2" synthesis by a calix[4]-
arene of type 12 with two or four free
o-positions, it is possible to obtain compounds in which either two (16) or
P ? 00,
three (17) calix[4]arene units are linked
in a similar manner to the benzene rings
in naphthalene or anthrdcene ("annelated calixarenes") .[37h1 A further extension of these annelated structures appears possible.
OH 0
In 1980, Hogberg[431isolated the two isomers with the rccc
and rctt configurations from the condensation between resorcinol and acetaldehyde o r benzaldehyde; these are also formed
with other aldehydes.L441
The rcct compound was later isolated
in a few cases.[45]The fourth possible isomer ( r t c f )apparently
occurs in very small amounts and has only been isolated by
c h r ~ m a t o g r a p h y . [dl~ ~ ' ~
Conditions have however been found under which the all-cis
isomer (rccc)can be obtained in good to excellent yields from a
variety of
such as acetaldehyde.[43"]h e ~ t a n a l , ' ~ ~ " ]
d ~ d e c a n a l , [ ~d~~"d]e c e n a l , [3-oxopropanesulfonic
acid (in the
form of its cyclic a ~ e t a l ) , ~b~e' n] ~ a l d e h y d e [ ~(and
~ " ] substituted
benzaldehydes including 4-forrnylbenz0[15]crown-5~~~]),
thio~ h e n e - , [ and
~ ~ ~ferrocene~arboxaldehyde.'~~~
The rctt isomer is
often formed under kinetic control[43b1and is converted after
longer reaction times into the thermodynamically more stable
rccc isomer. The formation of Ar-CHR-Ar bonds must therefore be at least partially reversible. This isomerization, which is
useful for preparative purposes, cannot always be realized, and
the formation of the rcct and rctt isomers from pure rccc has
also been observed.[45b1
It appears certain that the intramolecular hydrogen bonds
between the OH groups of neighboring resorcinol units is the
main cause of the preferred formation of the cyclic tetramer and,
in combination with the preferred axial arrangement of the
groups R (cf. Section 3.2.3). also for the preferred formation of
the rccc isomer. Neither resorcinol monomethyl ether[45b1nor
resorcinols which bear substituents such as NO, or COOH in
2-position afford the cyclic tetramer,[44a1since these (also generally deactivating) substituents are in competition with the OH
OH hydrogen bonds. On the other hand, compounds 19 were
19a x
19b X
= OH
= Alkyl
R = H.
X = Alkyl
0 HO
V. Bohmer
WR :&”
obtained with p y r ~ g a l l o l [ ’ and
~ ~ with 2-alkyIresor~inols.[~~”~ In the case of calix[4]arenes, the relative
Since 2-alkylresorcinols have only two reactive ortho- or paraorientations of the phenol
positions (with respect to the hydroxy groups) they can also
react with formaldehyde to give calix[4]arenes 20 with
units shown in Scheme3
methylene bridges.15’]
can in principle be ascone
partial cone
sumed. Gutsche has introIt should be mentioned that cyclic tetramers have also been
duced the terms “cone”,
obtained (as their octamethyl ethers) from esters of 2,4“partial cone”, “1,2-alterdimethoxycinnamic acid by treatment with BF, ,I5’] a method
nate”, and “1,3-alternate“,
which opens up a new and interesting route to resorcarenes.
which are generally acceptR
ed today, to these basis
2.6. Other Related Macrocycles
conformations.[61a’ They
Scheme 3. The four basic conformations
of a calix[4]arene; compare also Figs. 1
differ with respect to the
and 3.
The descriptive quality of the name calixarene has been reposition of the phenolic
sponsible for its recent use for other similar macrocycles. Some
O H groups (and the p-poexamples follow.
sitions) with respect to the molecular plane (here easily defined by
The closest relatives of the calixarenes derived from phenol
the C atoms of the methylene bridges). A reference plane of this
are cyclic tetramers in which up to four methylene bridges are
type is also clearly defined in the case of the calix[5]arenes, but
replaced by sulfur bridges.[”] With the exception of the tenot for larger oligomers: the conformations of the latter have
trathio compound they were all obtained by stepwise syntheses
been described in the literature in a correspondingly bewildering
from linear 0Iigomers.1~’~~
Macrocycles with -CH,-NR-CH,- bridge(s) have been referred
to as azacalixarenes (e.g. hexahomotriazacalix[3]arene)in analogy
to the “dihomooxacalixarene” 6 and similar compounds.1241 3.1. Structures in the Crystal
“All-homocalixarenes”, that is macrocycles in which all the
3.1.1. Calixarenes of Type II
methylene bridges are replaced by ethylene bridges,[’ ’1 have been
obtained by Vogtle et al. from bisbromomethylated anisoles by
All crystal structures of calix[4]arenes with free O H groups so
b1 while Tashiro et al. have
Miiller-Roscheisen cy~lization,~~’”.
far reported,r621including those of compounds containing difsynthesized similar compounds via the corresponding CH,-Sferent phenolic ~nits,’~’]
have shown that the calixarene adopts
CH,-bridged macrocycles by using “traditional” procedures
the cone conformation, since the latter is stabilized by inknown from cyclophane ~hemistry.1~
61 []Metacyclophanes
tramolecular hydrogen bonds between the hydroxy groups.[64’
with anisole building blocks were prepared in a similar manThe arrangement of the molecules in the crystal lattice and the
possible inclusion of guest molecules are not particularly imporThe phenol building blocks have also been exchanged for
tant in this context (Fig. 1). This is the case even when a consid”I Recent examples include calixarenes
erable deformation of the cone conformation is caused by the
derived from f u r a n ~ . [ ’ ~ ”~.a~l]i x [ 3 ] i n d o l e s , and
~ ~ ~calix[4]naph”~
presence of
o r two[66]rn-methyl groups per phenol unit
It is a moot point as to whether the names used
and the resulting steric constraints.
are suitable in all cases, but further developments of this kind can
However, while in the p-tert-butylcalix[4]arene 1a (the toluene
be expected. Thus, for example, cyclic tetramers with Pt-bridged
complex of which exhibits C,, symmetryr6’]) the four phenol
uracil units also show structural analogies to caIi[4]arene~.[~~’ units are twisted by an angle of 123” with respect to the reference
plane, compounds
21 and 22 contain
two phenol units
3. The Conformations of the Parent Compounds
which are nearly
orthogonal to the
One of the most fascinating aspects of calixarenes lies in thereference
variety of conformations which they can assume; these result
while the two othfrom the (more or less) free rotation about the 5 bonds of the
ers are twisted out21
Ar-CH,-Ar groups.
Fig. 1. Calix[4]arenes in the cone
conformation (according to X-ray
structure analyses). Oxygen and nltrogen atoms are black, hydrogen
atoms in general not shown. Left:
wrr-butylcalix[4]arene 1a with included toluene [67];middle:p-sulfonic acid derivative with OH-vbonded
water as guest [68]; right: cesium salt
of 1a with the Cs’ ion in the molecular cavity [69].
Angew. Chem. In(. Ed. Engl. 1995. 34, 713-145
Fig. 2. Two typical conformations of calin[h]arenes in the crystal. seen
from two different perspectives (oxygen atoms
atoms not shown). Left:
172 b]; right: calix[h]arenep-sullonic acid (sodium
salt) 172~1.
wards. In other words, two opposite phenol units are almost
parallel. while the other two are almost orthogonal to one another. A similar deformation of the cone conformation in the
bridged calix[4]arenes 14 is caused by the aliphatic chain linking
the opposite p-positions; this deformation increases with decreasing chain
All the known crystal structures of cali~[5]arenes[’~’
also show
a conc-like molecular conformation, which is in turn determined
by intramolecular hydrogen bonds between the phenolic OH
groups. The distances between neighboring 0 atoms are however
on average somewhat larger than in the calix[4]arenes.
In ~alix[6]arenes”~~
two completely different conformations
have so far been observed in the crystalline state: a) all the OH
groups are on one side of the molecule, the methylene bridges
being arranged in a boat-shaped manner; b) groups of three
neighboring OH functionalities are present on the opposing sides
of the molecule (see Fig. 2). These two arrangements, each of
which then contains the maximum number of intramolecular hydrogen bonds, can be visualized by joining together two threequarter fragments of a calix[4]arene either in the same or in the
opposite sense.
A simple visualization of this type is no longer possible for the
or ~alix[8]arenes.[~~]
An unequivocal description of
their conformations makes use of the two torsional angles about
the Ar -CH2 bonds, which should always be
3.1.2. Other Aspects
The importance of the intramolecular hydrogen bonds for the
Conformation of calix[4]arenes with endo-OH groups becomes
clear when 22 is compared with 10, which exists in the 1,3-ulternote conformation[36](neighboring dipoles are arranged in an
opposing manner). An additional methyl group in the p-position of each phenolic unit would certainly not play a decisive
role in determining the conformation of 22 but would make the
two compounds regioisomers which can formally be interconverted by the exchange of these p-methyl groups for the OH
groups. In contrast, a cone conformation was found for 12a
with two intramolecular hydrogen bonds between the exo-OH
groups, a stabilization, which would also be possible in the
I ,2-alternate conformation.[38a’
The influence of the hydrogen bonds also becomes clear when
the structures of calix[4]arenes with less than four endo-OH
groups are considered. While the aminodiphenol 23 h[76c1still
exists in the cone conformation, the diphenol 23 b and the OH-
~ R { : R + &
free compound 23e take up the 1,3-alternate t ~ n f o r m a t i o n . [ ~ ~ ]
Removal of the tert-butyl groups from 23e leads to the parent
compound, which exists in the crystalline state in a “chair” form
in which opposing benzene rings are
The tetrathiocalix[4]arene 24,[781
analogous to l a , exists in the 1,3-a/ternate conformation,
tetraquinone 25a takes up
a partial cone confor24
3.1.3. Resorcarenes
The few known crystal structures of the parent compounds
with free OH groups are those of all-cis isomers,[801the configuration of which is thus confirmed.[44a1The molecules always
exist i n the cone Conformation in which the groups at the
bridging C atoms are arranged in an axial manner. Intramolecular hydrogen bonds between the OH groups of neighboring resorcinol units also provide a stabilizing factor, although
not all the intramolecular hydrogen bonds possible are formed.
for example when hydrogen bonds to included solvent molecules
In the known examples the macrocycle does not
have an exact fourfold symmetry, even in the recently described
tetraanions of some ammonium
however, C, symmetry has been found for a tetra(di-n-propylaminomethyl)
3.2. The Structure in Solution
3.2.1. Calix/4/arenes of Type II
Calix[4]arenes always exist in the cone conformation also in
solution.[" This is clear from the 'H N M R spectrum, which for
example in the case of the tc,rt-butylcalix[4]arene 1 a shows singlets for the hydroxy, the aromatic. and the terr-butyl protons.
The four methylene groups are also equivalent, but the two protons of each CH, group are nonequivalent in the cone conformation. Thus, at low temperatures a pair of doublets is observed with
a coupling constant of 12-14 Hz typical of geminal protons.
These signals become broader when the temperature is increased and eventually collapse to form a sharp singlet at higher
temperatures. This can best be explained in terms of a rapid
exchange between the two opposed (but identical) cone conformations, in which the OH groups pass through the interior of
the macrocycle, the originally equatorial proton becoming axial
and vice versa. Thus the N M R spectrum shows only an "averaged" signal.
Scheme 4. Ring inversion of />-substituted calix[4]arenes.
V. Bohmer
Table 2. Activation parameters for the ring inversion of calixarenes obtained from
simulation of the 'H NMR spectra as a function of temperature (lineshape analysis
of the Ar-CH2-Ar signals).
n / R (Cmpd.)
4 rBu (1 a)
8 rBu ( l e )
23 g
23 b
23 d
20 ( X = C,H,,) CDCI,
AS '
[calmol-' K-'1
- 5.0
- 6.0
- 1.4
- 13.9
Table 3. Energy barriers for the ring inversion ofcalixarenes obtained from the rate
constant for the spin exchange of the methylene protons at the coalescence temperature T, [a]. Comparison of ring size (n) and p-substituent (R) in two different
solvents [b].
t7;R (Cmpd.)
AC* [kcalmol-'1
4 rBu (1 a)
4 r-octyl
5,tBu (1 b)
6irBu ( I c )
7trBu ( I d )
8rlBu ( l e )
8 r-Octyl
9:lBu (1 f )
288 [cl
290 [Cl
AC' [kcalmol-'1 7 , [K]
1 9
< 183
[a] k = rr(Av2;2 3 J')1'2.[b] Values for 100 MHz spectra. taken from ref. [I]: [c]
300 MHz spectra.
Table4. Energy barriers for the ring inversion of calixarenes (analogous to
Table 3). Comparison of particular calixarenes.
or (n/R)
AC *
4:Me [a]
23 a
23 b
10.6 [cl
224 [b]
[76a, c]
[76a. c]
~ 3 1
23 f
23 h
5:Me [a]
The energy barrier for the ring inversion can be derived from
the temperature-dependence of the ' H NMR
Typical values are collected in Tables 2-4; they show that the
substituent in p-position has almost no influence on the energy
barrier. The latter, however, decreases when a nonpolar aprotic
solvent such as CDCI, or benzene is replaced by a polar solvent
such as pyridine. This is not surprising, since the inversion requires that the hydroxy groups pass through the ring, so that the
cyclic arrangement of the hydrogen bonds is temporarily interrupted or at least loosened. Solvents which can break hydrogen
bonds will thus lead to a decrease in the energy barrier.
Little is known about the mechanism of this cone-to-cone
rearrangement. Two limiting cases appear possible:['] a) a step-
Solvent AG' (25 -C) A H *
[kcalmol-'1 [kcalmol-'1
[a] Calix[4]- or calix[S]arene derived from p-cresol. [b] Determined from the signal
of the methylene protons. [c] Average value from three signals.
wise conversion through the sequence cone * partial-cone +
+ partial-cone + cone; b) a concerted conversion involving only one single transition state. Computer simulations (molecular dynamics) suggest the parrial cone
and alternate conformations as possible intermediates.[s41
While the 'H N M R spectrum of 21 provides no evidence for
deviation from fourfold symmetry (C,J even down to the lowest
temperatures studied ( - 130 "C) .[851 22 (which has eight methyl
groups in m-positions) exhibits two signals at - 80 "C for both the
Chen?. Int. Ed Engl. 1995, 34, 713-745
Cal ixa rene\
3.2.3. Other Calixlllarenes
Scheme 5. Possibilities for conformational interconversion in the case of octamethylcalix[rl&rene 22. a) ring inversion, b) pseudorotation.
aromatic protons and the methyl groups.[661Thus, as in the
crystal. the conformation with the lowest energy has C,, symmetry.
The conformational conversion from C,, to C,, occurs by ring
inversion (route a ) and not by pseudorotation (route b); this
follows from the equal values of the energy barriers for the coalescence of the signals for CH, and ArH on the one side and the CH,
groups on the other.[661This energy barrier is however nearly
5 kcalmol-' lower than that for example for l a . If the
same energy level is assumed in all cases for the (energetically
highest) transition state, this indicates a higher energy level (because of the "loosened" hydrogen bonds) for the C,, conformation. which may generally be involved in the conformational
in terconversion.
3.2.2. Larger Calixarenes of' Type I1
As in the case of calix[4]arenes, the ' H N M R spectra of all
other calixarenes exhibit a singlet for the methylene protons in
solution when the temperature is sufficiently high (e.g. 50 "C).
At lower temperatures (e.g. -40 "C) this singlet splits into one
pair of doublets for calix[S]arenes, while in the case of calix[6]and calix[7]arenes three and seven pairs are observed, respectively.["' Remarkably, calix[8]arenes also give rise to only one pair
of doublets at low temperatures.[871Apparently the intramolecular hydrogen bonds stabilize a highly symmetrical conformation with a regular "up and down" arrangement of the phenol
units in which all the methylene bridges are equivalent, while the
environment of the protons is similar to that in calix[4]arenes.
The higher cyclic oligomers again adopt very unsymmetrical
conformations.'" 1'
The number of signals indicates that the calix[6]arenes have a
conformation with a plane of symmetry, a center of symmetry,
or a twofold axis. In the case of a calix[6]arene with two different
phenol building blocks in an alternating arrangement, which
from its molecular structure contains a threefold axis, the result
is that at low temperatures a completely unsymmetrical conformation is observed.[8s1
The lower barrier to the ring inversion for the calix[5]-, calix[6]-,
and calix[7]arenes (see Table 3), as determined from dynamic
NMR spectra, corresponds to the greater flexibility to be expected for the larger rings. Surprisingly the temperature dependence of the signals for the methylene protons of the calix[8]arenes in CDCI, corresponds very closely to that found for
the ~alix[4]arenes.'~~",
"I The greater flexibility of the "eightmembered" ring is only noticeable in a solvent such as pyridine
which breaks down the hydrogen bonds; here only a singlet is
observed for the methylene protons at the lowest temperatures
studied ( - 90 C).
C'iic,rii. l i i i .
Ed Eiig/. 1995. 34. 713-745
The calix[4]arenes 10 and 24 exhibit only a singlet for the
methylene protons across a large temperature range. It is thus
logical to assume a fixed I ,3-alternate conformation for these
molecules, as is found in the crystalline state,[36.78a1 although
this result could also be explained on the basis of a completely
flexible molecule. In contrast, 1,-metacyclophanes such as 23e
which bear no O H groups['.771 and calix[4]arenes of type 12
with exo-hydroxy groups are indeed flexible. Energy barriers for
calix[4]arenes with only two or three endo-OH groups and for
calix[4]arenes which contain NH, groups rather than OH
groups can be found in Table 4.
There have been few studies on the conformations of resorcarenes in solution.[891Because of their lower solubility their
octaesters have normally been
however, these ester
groups introduce additional steric effects.[901The rccc isomer
shows only one set of signals for all the protons of the resorcinol
unit.["] It apparently adopts a cone conformation with effective
C,, symmetry and an axial arrangement of the substituents R,
which is in turn stabilized by intramolecular hydrogen bonds.
There are no indications of the presence of a cone conformation
with an equatorial arrangement of the groups R on the bridges,
and even at lower temperatures no evidence for the formation of
a conformation with C,, symmetry (in which the octaesters occurL9"])as found for example for 22. In the case of the rcct and
rctt isomers there is an equilibrium between the "diamond" or
"chair" conformation found for the octaesters and the cone
conformation[891in which one or two groups on the bridges are
The resorcarene 20 with methylene bridges, derived from 2hexylresorcinol, has a C,, cone conformation at low temperature and undergoes a cone + cone inversion with AC' =
12.0kcalmol-', a value which is clearly lower than that observed for calix[4]arenes with endo-OH groups.["] Although
intraannular groups such as the O H groups can slow the ring
inversion for steric reasons, the difference appears to be caused
primarily by the weaker hydrogen bonds of the extraannular
hydroxy groups (see also the spectroscopic data in Table 5 ) .
4. Some Properties
Calixarenes generally have very high melting points (often
above 300 "C, in some cases even above 400 "C) and a low solubility in all standard solvents.". 2. 921 (Their ready preparation
by one-pot syntheses may be due in part to the fact that insoluble products precipitate out under the reaction conditions). The
melting points can however be modified[931and the solubility in
organic solvents improved[92".b1 by the use of suitable derivdtives [see Section 5 ) . It is even possible to achieve solubility in
water (up to 0.3 mol L- I ) .[92c1
The physical behavior of calixarenes is mainly determined by
the intramolecular hydrogen bonds between the phenolic OH
groups. The strength of the latter can be established from IR
and ' H N M R spectra (Table 5). In general all calixarenes with
endo-OH groups exhibit a considerable shift of the OH frequency
to lower wavenumbers compared to the free phenols; this shift is
much lower for compounds with exo-OH groups such as 12.
Here, as in the resorcarenes (18,20) only pairs of hydrogen-bond
72 1
V. Bohmer
Table 5. Spectroscopic characterization of the intramolecular hydrogen bonds in
selected calixarenes; values taken from refs. [I ,2.39c,51 a. Solvent
for IR and ' H N M R spectroscopy CHCI, or CDCI,.
6 values
14 ( n = 5 )
14 ( n =7)
14 ( n = 9)
14 ( n = 16)
3230 [d]
3290 [a]
3150 [d]
3250 [d]
6.9316.87 [b]
8.65K3.47 [h]
8.50 [c]
9.6019.28 [b]
12 (R = H)
18 (R = C,,H,d
20 (X = C,H,,)
[a] KBr pellet. [b] Two different OH groups. [c] [DJAcetone.
ed OH groups are possible[9'] but not a completely closed ring.
In the 'H N M R spectra there is a corresponding shift of the OH
signals to lower field. Both effects are in general parallel (see
Table 5 ) . in particular for compounds with endo-hydroxy groups.
When the cone conformation of bridged calixarenes of type 14
is deformed by shorter chains (this deformation has been characterized quantitatively by a series of X-ray crystal struct u r e ~ ["1) ~ ~there
~ ~ is a continuous weakening of the intramolecular hydrogen bonds.L7u1
This has also been confirmed
by photo-CIDNP (CIDNP = chemically induced dynamic nuclear polarization) studies.[941
The acidity of the phenolic O H groups, which is for example
important for all selective substitution reactions, is also determined by the system of intramolecular hydrogen bonds. The
pK,, of calix[4]arenes is considerably reduced in comparison
with the pK, values of corresponding phenols, as semiempirical
calculations suggest.f841However, the pKa2 value lies considerably higher.f971
An example is provided by the values for the dissociation of
the first two phenolic OH groups in calix[4]arenetetrasulfonate,
which have recently been determined by two groups to be 3.34
and 11.S[981and 3.26 and 11.8.[991The reduction in pK,, is lower
for corresponding calix[6]- and cali~[8]arenes["~~
and is comparable with that of the pK,, value for linear oligomers.[lu'lThe
dependence reported earlier of the pK,, value of calix[4]arenes
containing a p-nitrophenol unit on the p-substituent of the opposing phenol unit['021was not confirmed in later studies.
Very little is known about the acidity of r e s ~ r c a r e n e s . [ " ~
the case of the rccc isomer the first four protons can be readily
removed to give a symmetrical tetraanion (which is stabilized by
four intramolecular 0 - . . . HO bridges),["31 while even methoxide in methanol cannot remove any further protons. However,
the different conformation of the rcft isomer permits the formation of the corresponding octaanion.
5. Fundamental Reactions of Calixarenes
Chemical modification of calixarenes does not only permit
the synthesis of new host molecules by the introduction of additional functional groups, it also allows control of the conforma122
tion of calixarenes and hindrance of conformational inversion.
In addition, larger molecules based on calixarene units are becoming increasingly available (see Section 6). In this respect
calixarenes are greatly superior to other macrocyclic molecules
such as crown ethers or c y c l ~ d e x t r i n s . [ ~ ~ ]
5.1. Calixarenes of Type I1
Calixarenes derived from phenol can undergo modification in
two main ways: I ) by the introduction of residues (functional
groups) at the phenolic hydroxy groups; 2) by (electrophilic)
substitution in the p-position with respect to the phenolic hydroxy group (subsequent to elimination of the tot-butyl group
originally present).
5.1.1. Complete 0-Alkylation and 0-Acylation
The reaction of all the OH groups with monofunctional
reagents to give ether or ester derivatives can generally be carried out without any problems.i1. In the case of calix[4]arenes
this has an additional interesting aspect: since larger substituents (acetyl, propyl, or
cannot pass through the
macrocycle, it is possible to fix all the conformations discussed
above and to isolate them as stable conformers. In the meantime, not only have a large number of 0-alkyl and 0-acyl
derivatives been obtained in defined conformations, but in some
cases all four conformers have been obtained in a pure
As Table 6 demonstrates for one example, these conformations can be readily distinguished from their 'H N M R spectra
Table 6. Number and type of signals in the 'H NMR spectra of tetraethers of
1er~-butyIcalix[4]arene26 (n = 4. Y = CH,-R and 0-CH,-R, R = C(CH,),).
purfrul c o w
2s (2 x 2H)
2d ( 2 x 4 H )
4d (4x2 H)
3 s (1 :2: 1 )
2 s (2 x 2H)
2d ( 2 x 4 H )
1 s (4H)
2d ( 2 x 2 H )
(and also determined in mixtures) .[1u61 Furthermore, the conformations of such derivatives have often been confirmed by
X-ray structural analysis. Figure 3 shows some examples.
It has often been possible to obtain tetraalkylated derivatives
solely in the cone conformation. Apart from simple ethers with
ethyleneglycol (26a)r'081or pyridylmethyl groups (26b),[1091the
following are worthy of mention because of their importance as
ionophores (see Section 8): ester (27a),i"01 amide (27b),["'] and
ketone derivatives (27~)!"'~,
The latter can be readily obtained by reactions with reagents such as Br-CH,-CO-OR, CICH,-CO-NR, , and C1-CH,-CO-R, respectively. Sterically more
demanding residues can also be introduced with retention of the
cone conformation, as is shown by the synthesis of the phosphinate esters 26c" 1 3 ] and in particular the dendrimers 26e.[1141
The formation of the cone conformation often appears to be
favored by a template effect of the metal ions present (such as
Na ') (cf. the selectivity of ligands of this type). Thus the reacA n g e u . Chem. In[. Ed. Engl. 1995,34. 713-745
tion of ethyl bromoacetate with 1 a in acetone in the presence of
Na,CO, affords 100% of the cone isomer, while in the presence
of Cs,CO, thepartial cone isomer is formed quantitatively. This
effect is not so apparent in the case of the calix[4]arene which is
unsubstituted in p-position. The same is true for 1 a when acetone is replaced by dimethylformamide ( D M F ) as solvent; alternate conformations have not been observed in this
contrast, ethers of type 26a were obtained by alkylation with
Fig. 3. Derivatives of calix[4]arenes
with fixed conformations (oxygen
atoms are black, hydrogen atoms not
shown). Left: tetraacetate in the purriul
cone conformation [107a]; middle: tetraethyl ether in the 1,2-nlternule conformation [I07 b]; right: tetraethoxyethyl ether in the 1.3-ullernaleconformation [107c].
However, defined derivatives of calix[5]arene have so far only
been obtained in the cone conformation. For larger macrocycles
(calix[6]arene and above) the complete fixation of a certain conformation by means of large substituents on the phenolic oxygen
atoms appears less probable, since there will be an increasing
tendency for thep-substituents to swing through the ring.", 1211
Substituents at the oxygen atoms can in turn be modified by
further reactions. As examples we can mention hydrolylZ2] transesterification,[122blaminolysis,['231and reducsis,"
t i ~ n [ ' of
~ ~esters
] of type 27a. Many such esters['231and amides
27b['"'] have been obtained in this manner from the acid 27d
and the acid chloride 27e, and also the alcohol 26d has served
as a precursor for further derivatives.['24a]Homologous alcohols with 3-hydroxypropoxy groups were obtained recently by
hydroboration of ally1 ethers.['24b1
d Y = CH,CH,OH
- A
"C H
X =
X = N-(Alkyl),
X = Alkyl
X = O H
X - C I
the corresponding tosylates in D M F with Cs,CO, as the base in
the 1,3-alternate conformation (selectivity up to 100 %, isolated
yield up to 75%0),['~~']
while in the presence of N a H the cone
conformation was f ~ r r n e d . [ " ~Studies
on the formation of the
p-substituted tetrabenzoates 26f showed a clear dependence of
the resulting conformation on both the p-substituent in the benzoyl group to be introduced and thep-substituent present in the
calixarene." ' 61 Even these few examples show that a general
concept for the synthesis of a particular 0-acyl or 0-alkyl
derivative in a certain conformation is not in sight at present
because of the many factors involved and may perhaps never be
The complete reaction of all hydroxy groups to give derivatives
of types 26 and 27 has also been described for calix[S]-,[' ' 71 caIix[6]-,[l. lO8.~10b.l18.1191an~ca~~x[~jarenes,~l.ll.ll0b.ll9b.l20al
Different conformations should be obtainable, at least in the case
of the calix[5]arenes, since it is probable that 0-alkyl groups larger
than the propyl group cannot pass through the macrocycle.[' 17b1
A n x r w . C'lirun. 1n1. Ed. Engl. 1995, 34, 113-745
5.1.2. Selective Reactions at the Hydroxy Groups
The regloselective reaction of single hydroxy groups in calixarenes is important for many purposes, in particular for the
construction of larger molecules starting from several calixarene
building units (see Section 6) .I' 251 The possible regioisomers have
been denoted in the case of calix[4]arenes by expressions such as
distal or proximal; however, the numbering of the phenol units
as used below (in analogy to the alternate conformations) is
more readily applicable to higher oligomers.['261
One of the first examples of selective functionalization to be
described was that of the tribenzoate of the unsubstituted cali~[4]arene.['~
triesters were later obtained in acetonitrile by using 1-methylimidazole as the base['281). The remaining O H group can undergo etherification; thus, monoethers are
accessible after hydrolysis of the ester groups.['",
Direct monoalkylation has been carried out using an excess of
the alkylating agent and K,CO, (0.6 equiv in CH,CN) or CsF
(1.2 equiv in D M F ) as a very weak base,['301 but also with NaH
The conin toluene['05a31 3 1 1 or with Ba(OH), in DMF,['05d1
trolled cleavage of 1,3-diethers[' or tetraethers with either one
or three equivalents of trimethylsilyl iodide offers another possible alternative." 321 Monoesters were also obtained in a similar
manner from 1,3-diesters by reaction with imidazole.[1281The
direct formation of triethers (in the syn,syn arrangment, see
Section 5.1.3) was achieved by using BaO/Ba(OH), in
117a. 1331
By far the best results in the selective 0-alkylation (as in
1341) of calix[4]arenes were obtained by reaction
of two equivalents of a relatively weak base (e.g. 1 mole K,CO,
per mole of calix[4]arene).[' A variety of 1,3-diethers (includ723
V. Bohmer
ing the 2-pyridylmethyl
see below) were thus obtained
in yields (of the pure compound) which were often higher than
those of the corresponding tetraethers. These results can also be
readily understood on a theoretical basis,['251 since the most
stable anion (stabilized by two intramolecular hydrogen bonds)
of the monoether formed in the first step is obtained by deprotonation of the opposing hydroxy group (Scheme 6).
as exemplified by the 1,3,5,7-tetrabenzyl ether of calix[8]arene
1 e described recently.['441
It is of course possible to obtain in a sequence of synthetic
steps derivatives containing different 0-acyl or 0-alkyl
residues;["s". 135a9 1 3 6 h 142b, '451 in the case of calix[4]arenes[105a.
107'. 1 4 5 ~ (and
recently calix[6]arenes[' 38c1)different
conformational isomers have also been described. The use of
protecting groups for the preparation of particular conformers is
demonstrated by the two examples[10sa.
shown in Scheme 7.
+OH ,j
Scheme 6. Anions of a calix[4]arene monoether.
The formation of two isomeric (syn,anti) 1,3-dibenzoates.
both in good yields, in the acylation with excess benzoyl chloride
and NaH under very similar reaction conditions (THF, 0°C.
and toluene, reflux, respectively) is remarkable.
Dialkylation with a stoichiometric amount (in practice often
2.2 equivalents) of the alkylating agent in the presence of an
excess of a strong base (e.g. NaH in D M F / T H F ) would on the
other hand have to occur via the 2,4-dianion or via the trianion,
from which the formation of the 1,2-diether should also be
favored for statistical reasons. This has indeed been shown in a
number of cases,[1361although the yields of 1,2-diethers (which
are also sterically less favored than the 1,3-diethers) are in
general Iower.[136cl
An alternative route to 1,2-diethers is the selective cleavage of
neighboring ether groups by TiBr,, as shown for example in the
case of the tetramethyl ether of
The synthesis of the
1,2-bis(3,5-dinitrobenzoate)of tert-butylcalix[4]arene has been
carried out starting from the corresponding 1,3-diester in the
presence of imidazole.['281
While the regioselective derivatization of calix[5]arenes by
0-alkylation or 0-acylation with monofunctional reagents has
not yet been described, an increasing number of partial esters o r
ethers of (mostly tert-butyl-substituted) calix[6]arenes has
been obtained recently. Some preparatively useful examples include 1,4-diethers[' 38a, '] as well as 1,2,4,5-tetraether~['~~".
and 1,2-diether~['~~"I
as well as
1,2-di- and pentaesters" 391 have also been prepared. It has recently been possible to obtain all the methyl ethers of tert-butylcalix[6]arene 1 c (in some cases in very good yields)[1401as well as ten
of the twelve possible pyridylmethyl ethers.['38h1
It is difficult (or at present not possible) to provide a rational
explanation for the regioselective formation of certain 0-alkyl
or 0-acyl products. Thus, for example the (unsubstituted) calix[6]arene affords the 1,2,3-trimethyl ether[141]under conditions which when applied to the tert-butylcalix[6]arene 1 c lead
to the 1,3,5-trimethyl
One of the products isolated
from the phosphorylation of l c with POCI(OEt), and
PSCl(OEt), was a 1,2,4-trie~ter.['~~]
Other more sophisticated selective functionalizations of the
phenolic OH groups can however be expected in the near future,
Scheme 7. Specific synthesis of calix[4]arene derivatives in a certain conformation
using benzyl residues as protecting groups.
Subsequent reactions at the 0-alkyl groups can also occur in
a selective manner, as shown by the monohydrolysis of tetraethyl esters of type 27 a in nonpolar s ~ l v e n t s . ~Using
' ~ ~ ] the
more reactive tetra-tert-butyl ester two opposing ester groups
can be hydrolzed.[122'1
5.1.3. Conformations of 0-Alkyl Derivatives
The residues present in partially 0-alkylated (or 0-acylated)
products can also lie either on the same side (syn) or on opposite
sides (anti) of the molecule. In contrast to the situation of the
conformationally completely fixed tetra derivatives, it is not
appropriate to use the terms cone, partial cone, etc. to describe
such diastereomers (conformers) derived from calix[4]arenes,
since free OH groups can still pass through the macrocycle, as
is shown unequivocally by subsequent reactions in which derivatives with d ~ e r e n conformations
are obtained.['33c*14'] Thus,
for example, a 1,3-diether in the syn-configuration can (at least in
principle) assume a cone, partial cone, or 1,3-alternate conformation. Thus these terms should be used in such cases only for the
characterization of conformations, while the relative orientation
of the residues is described well by the terms s-yn and anti.[621
In practice syn-l,3-diethers exist in the cone conformation,
which is characterised by the presence of one pair of doublets (AX
system) for the methylene protons (A6 = 0.5-0.6). Anti-1.3-diethers, also show only one pair of doublets (AB system) for the
methylene protons ; however, the difference in the chemical shift
is smaller (Ah sz 0.2). To explain this, a conformation has been
proposed in which the opposite phenol units are coplanar; [ 1 0 7 b , 1 3 1hl this may, however, be equivalent to a rapid interconversion of the two equivalent 1,2-alternate conformat i o n ~ . [ ' In
~ ~the
] case of l ,2-diethers the syn isomers adopt the
cone and the anti isomers the partial cone conformation, respecAngiw. Chcm. Int. Ed. EngI. 1995, 34, 713-745
tively. This can readily be explained by the formation of a maximum number of OH-OH hydrogen bonds.['491
Interesting. and in the main still unsolved, questions are posed
by the methyl ethers of calix[4]arenes. The tetramethyl ethers are
surprisingly nearly as flexible as compounds with four free OH
groups. However. a mixture of several conformations generally
exists in solution because
of the lack of intramoleccone
ular hydrogen bonds
(Scheme 8);(107b.l S 0 l the
composition of such a
partial cone
mixture is determined
among other Factors by
the s ~ l v e n tand
~ ' by
~ ~the
substituents in the p-posiScheme X. Conformational interconvertions." ''1
Temperaturesion for ietramethyl ethers of cahx[4]dependent
d o not only provide the
energy differences between the various conformations;[' ''] two-dimensional exhange N M R spectroscopy can be used in special cases to determine the rate constants for their interconversion.[' '21
Although in the case of calix[4]arenes methoxy groups can
also pass through the ring, mono- and dimethyl ethers are fixed
in the cone conformation (with respect to the NMR timescale) up
to high temperatures ( 1 25 OC).['sO1No information is yet available on the energy barrier for the cone + cone interconversion,
although it is apparent that this stabilization is caused by a combination of steric effects and intramolecular hydrogen bonds.
ination of trimethylamine and addition of a nucleophile to the
intermediately formed quinonemethide allows the introduction
of very different residues.['"]
The number of possible derivatives can be imagined when one
considers the combination of these reactions with suitable
derivatizations at the phenolic OH groups (see Scheme 9).
5.1.4. Substitution in p-Position
It is fortuitous that the calixarenes derived from tevt-butylpheno1 are obtained particularly readily, since the tert-butyl group
can easily be removed by AICl,-catalyzed transalkylation in the
presence of a suitable acceptor such as toluene or
plays a key role in calixarene chemistry, since a
large variety of calixarenes with different substituents in the p-positions can be obtained by subsequent electrophilic substitution.
Virtually all the common substitutions which are possible for
phenols (or phenol ethers) have been carried out on calixarenes or
their alkyl ether derivatives: h a l ~ g e n a t i o n , [I's~5~,
nitration," 'I sulfonation,'' 581 sulfochlorination,[' '91 chloromethylation.llh'] aminomethylation,['611acylation,['621 and coupling
with diazonium
S ~ l f o n a t i o n [ 'and
products have also been obtained directly by @so-substitution
of the rerr-butyl groups, and nitro compounds in addition via
the sulfonic acids" 58a1 or the nitroso compounds.[' 5 7 1 Claisen
rearrangements of allyl ethers['*', ' 531 and Fries rearrangementsI'661 have also been carried out.
The substituents thus introduced can undergo further reactions.". 861 lsomerization and/or ozonolysis of ally1 groups,[' 5 3 1
haloform reactions of acetyl groups,"
aryl -aryl coupling by
the Suzuki
reduction of nitro-," 1 5 , l6*1 a20-,"~] or
acyl groups."
o r further substitution at chlorosulfone'' 5 9 1 and
chloromethyl g r ~ u p s [ ' ~160,
' ' ~ 1691 are just some important examples, in a by no means complete list, in which the "quinonemethide route" deserves special mention: aminomethylation with
dimethylamine, quaternization ("complete methylation"), elim-
Scheme 9. Summary of important chemical modifications which have been realized
for calix[n]arenes of Type 11: a, h, i, n : Formation of various ethers or esters. b:
Transbutylation; c: Oxidation to quinones; d : Hydrolysis of ester groups, reduction
of ester, amide, o r nitrile groups; e: @so-Nitration; f: Sulfonation; g: Electrophilic
substitutions (halogenation. sulfonation, sulfochlorination, formylation, acylation,
coupling with didzonium salts, chloromethylation, aminomethylation); k: Claisen
rearrangement. Fries rearrangement; I: Reduction of nitro groups, aryl-aryl coupling, haloform oxidation, transformation of allyl groups; m: Nucleophilic substitution of quaternary ammonium groups.
Again it is very desirable not to substitute all thep-positions but
only certain positions, if possible selectively." "I Although partial
substitutions such as nitration,"
165a1 formylation," ''I
iodination,r156c1aminomethylation[1701of calix[4]arenes (or their
tetraethers) have been described, each carefully directed selective functionalization begins with the OH groups. The selectivity
that can be achieved here can then be transferred to the p-positions, since (as a rule) phenol units are more reactive than phenol ether o r ester units.
The most important strategies described are the following,
which can be combined to effect the synthesis of "more ambitious" structures:
- the selective de- or better transbutylation of partially O-alkylated or 0-acylated calixarenes under carefully controlled
reaction conditions, which has been successful in the case
of calix[4]-[' 13'c1 and calix[6]arene
- the selective substitution of partially 0-alkylated or O-acylated calixarenes. In the case of the calix[4]arenes examples
of b r ~ m i n a t i o n , [ ' ~ ~formylation,['
35c1 acylation,['721 nitration['35c. 1681 and aminomethylation['35'1 are known;
- the selective Claisen rearrangement, which has been described for m o n ~ - and
[ ~ 1,3-diallyl
~ ~ ~
of calix[4]arenes.
It can easily be predicted that these strategies will find further
application in the future.
V. Bohmer
5.1.5. Further Reactions
An important modification of the calixarene skeleton is the
oxidation of phenol units to p-quinones. The first examples of
calixquinones were obtained from multistep syntheses ;(791 however, the direct oxidation of phenol units or even of tertbutylphenol units is also possible, T1(00CCF3), being the most
important reagent for this purpose.['731 It is also possible to
oxidize phenol units in the presence of phenol ether" 741 or phenol ester units." 7 3 1 Mono-, di-, and triquinone derivatives of
calix[4]arene and diquinones of ~ a l i x [ 6 ] a r e n e [have
' ~ ~ ~been prepared in this manner and in some cases characterized by X-ray
crystal structure
Apart from reduction to give hydroquinone units," 7 3 1 various addition reactions to the quinone system have been described;" 7s1these can in principle be used for the introduction
of substituents at the m-position with respect to the endo-hydroxy
The complete oxidation of the methylene bridges to carboxyl
groups and their subsequent reduction to hydroxy groups has
also been reported;['761the stereochemistry of the latter step is
Many studies have dealt with the elimination of the phenolic
OH groups[76* 1771 (with the goal of carrying out further substitution reactions at the free endo positions) or their exchange
for NHZ[1781
or SH groupsf78.1 7 7 a 1 . While the complete reductive cleavage of all the phosphate groups using potassium in
liquid ammonia was carried out successfully for calix[4]-, calix[6]-, and c a l i ~ [ 8 ] a r e n e s , the
~ ' ~reaction
with liquid ammonia
led to the introduction of only two amino
in the case of the tert-butylcalix[4]arene 1 a the complete "replacement" of all OH groups by SH was p~ssible.['~"~
The decisive step in the synthesis of 24 was the Newman-Kwart rearrangement of the thiocarbamates.
Biali et al. have introduced an interesting strategy for the
modification of the calixarene skeleton. Mild oxidation of 1 a
with phenyltrimethylammonium tribromide leads to spirodienones such as 28 or 29;" 79a, b1 t r i s p i r o d i e n ~ n e s ~ 'are
formed from 1 c. Starting from 28 it was possible to phosphorylate and subsequently eliminate the two (neighboring) OH
groups['8o]as well as to introduce one endo-amino group.['8']
markable examples are provided by the introduction of eight
ferrocene residues[48b1and the selective reaction of only one
hydroxy group per resorcinol unit[1821(see Section 7.3).
Electrophilic substitutions in the 2-position of the resorcinol
units are also possible. These include b r ~ m i n a t i o n , [ 'coupling
with diazonium salts,['841and aminomethylation.[slb,l S 5 l HOWever, the most "spectacular" compounds, which were prepared
from the cyclic tetramer of resorcinol, will be described in the
next section.
6. Macrobicyclic and Multimacrocyclic Compounds
The reactions between calixarenes and bifunctional reagents
can lead, through bridging, to macrobicyclic molecules. In addition, more complex ("multimacrocyclic") structures such as
double or triple calixarenes, cavitands, carcerands etc. have
been prepared from calixarenes or resorcarenes.
6.1. Derivatives of Calixarenes of Type I1
The first crown ethers 30 derived from tert-butylcalix[4]arene
were prepared as early as 19831'861and at the same time they
provided the first examples of selective alkylation in the 1,3-p0sition. While these crown ethers assume a cone conformati or^,^'*^] the subsequent alkylation of the remaining OH groups
leads to derivatives which can be fixed in the cone, partial cone,
or 1,3-aZternate conformation.1188a1Di-0-alkylation in the 1,3position with a monofunctional reagent, followed by cyclization
with the corresponding ditosylate (Cs,C03/CH3CN) is an alternative route, which, because of the template effect of the Cs+
ions, leads to compounds in the 1,3-alternate conformat i ~ n . ~Analogous
' ~ ~ ~ ] reactions were used to prepare bis-crown
ether derivatives in the 1,3-alternate conformation['sa1as well as
larger molecules consisting of two calix[4]arene units linked by
The accessibility of 1,2-dimethyl ethers also made possible
the synthesis of mono- and bis-crown ethers of calix[4]arenes
in which two neighboring phenol units are bridged.['371
While we were recently able to obtain 1,3-crown ethers in good
5.2. Resorcarenes
Exhaustive 0-acylation and 0-alkylation with
monofunctional reagents is also no problem here.
The corresponding octaesters have often been used
for structural determinations or for isomer separa891 Retion because of their better
Angew. Chem. Int. Ed. Engl. 1995, 34, 713-145
yield starting from tert-butylcalix[5]arene (including an example
of a 1.2-crown),'1y11crown ethers derived from larger calixarenes have not so far been described, although the first examples
of 1,3- and 1.4-crowns of calix[6]arenes are known.f'89b,cl
However, macrobicyclic derivatives of calix[6]arenes have
been reported. The reactions of dicarboxylic acid dichlorides with
1,4-diethers of l c led to 2,5-bisIactone~.~'~"~
l g Z 1The bridging of
opposite phenol units by reaction of 1c with bishalomethylated
arenes took place in the presence of KOSiMe, as the base. Exhaustive methylation of the remaining OH groups led to tetramethyl ethers which interestingly adopt different conformat i o n ~ . [ While
' ~ ~ ~ 31 a with its voluminous anthracene bridge
apparently retains its conformation, the phenyl-bridged compound 31 b assumes a conformation in which this bridge is
threaded through the macroring, thus motivating the authors to
speak of a "self-anchored rotaxane".['y21
because the tetralactam ring is collapsed and the host molecule is
thus unable to take up a guest. The double calix[4]arenes 38
have been prepared starting from 1a, the last step occurring in
analogy to the synthesis of 14. In contrast to 15 and 33, the two
calix[4]arene units (which exist in the cone conformation) in 38
are bridged in a head-to-tail manner.f2001
X =#
x =+
A structure which can be modified in a variety of ways and
which has unique complex-forming properties (see Section 8.3.1)
is generated by combining the rigid rn-terphenyl skeleton with
which can be obcalix[4]arenes. In these calixspherands 32,[lg3J
tained from the free ~ a l i x [ 4 ] a r e n e s ~or
' ~ from
~ ' ~ their 1,3-dimethyl
e t h e r ~ [ ' ~ ~ by
" . ~reaction
with bisbromomethylated m-terphenyls, the bridge again connects two opposite phenol units. In
contrast, the intramolecular bridging reaction with phthalic acid
dichloride involves neighboring phenol ~ n i t s , l " ~ so
] that the
phthaloyl residue can in principle be used as a protecting group
Other bifunctional reagents, in
for neighboring OH groups.f1951
particular those which d o not tend to 1,3bridging for steric reasons, have been
used successfully for the synthesis of
double (33) o r even triple calixarer~es.['~~]
Starting from the readily available 1,3X
diacid 27d (in the form of its dichloride
\ H
p j
or dimethyl ester) and diamines or azacrowns, it was possible to obtain azacalix
crown ethers 34[12371971or calixcryptands 35 a.['"] The calixcryptand
35 b was prepared in an analogous man33
ner starting from the corresponding 1,3diether."98"1 The Schiff bases 36['991and
the ferrocene carbonamides 37['98b1are also worthy of mention.
1,3-Diesters of 3,5-dinitrobenzoic acid lead after reduction of
the nitro groups and subsequent double intramolecular bridging
by amide bonds to "double-cavity calixarenes".f'341 However, in
this case the name promises more than the molecules in fact offer,
Angiw. Clziw l n l .
td. Enxl. 1995. 34, 713-145
Derivatives in which the oxygen atoms of three neighboring
phenol units are linked covalently by a single atom have also been
prepared. The corresponding "multicyclic" phosphates can be
obtained by heating "open-chain'' diethyl phosphates with elimination of
ethanol[2011or directly by reactions with
phosphorus pentachloride.[2021 Treat1.
ment of 1 a with silicon tetrachloride
leads to the double calix[4]arene 39
bridged by two silicon atoms; in 39 the
two cavities are oriented in opposite dir e c t i o n ~ . fSimilar
~ ~ ~ ] structures containing a I u r n i n ~ m [ ' ~or~ ~t i' t a n i ~ m [ ' ~are
also known, and even the bridging of all
four oxygen atoms of 1a by a single atom
(P, Mo, W)[z051has been described (see
Section 9.2).
Starting from calix[4]arenes functionalized at opposing p-positions (at the "upper rim"), bridged calixarenes (40)" '71, '061
and double calixarenes (41)['56b* ' 0 7 ] have been obtained in
which the two cavities are oriented in opposing directions. Attempts to demethylate these "upper rim" calix crown ethers" ']
(40, X = CH,-(0-CH,-CH,),-0-CH,,
Y = CH,), which resemble the bridged calix[4]arenes 14, were not successful. However, the potential for the synthesis of molecules of the general
type 40 and 41 is by no means exhausted.
/pepR Rf$!jq
Y , Y :
0 ; 00'
Y, Y
06 00
V. Bohmer
For example, one interesting aspect is bridging by the structural element CH,-CH,-CO-CH,-CH,, which can be converted
by reaction with nitromalonaldehyde into a methylene-bridged
p-nitrophenol unit, so that (formally) two new calix[4]arene systems are formed. Compounds of type 42 can thus be described
as ‘’ bicyclocalix[4]arenes”.[2081
6.2. Derivatives of Resorcarenes
By far the most ambitious three-dimensional structures have
been prepared starting from calixarenes based on resorcinol, in
particular by Cram et al. Although these compounds will not be
discussed in detail here, the general principles are presented.
Intramolecular linkage of the oxygen functions of neighboring
resorcinol units in the all-cis isomer leads to the (more or less)
rigid structures 43 with a permanent cavity (“enforced cavity”);
these have been given the general name cavitands by Cram.12091
A great variety of examples with X = CH,, (CH,), , and (CH,),
have been synthesized from reactions of resorcarenes with
BrCH,CI or the corresponding ditosylates and in many cases
these have been characterized by X-ray structural analysis.“ 831
Cyclization has also been achieved by using Si(Bu), ,[’Io1
or P(0)OR.[Z”clMolecules with deeper cavities
are obtained if larger units are used for intramolecular bridging,
for example, by reaction with ferrocene dicarboxylic acid di~ h l o r i d e ~ ~or~ ’dichloroquinoxaline.~z1.2]
forms.[213a]The differing reactivity of the
units with free hydroxy groups can also
be used for further
(Claisen rearrangement,r213b1 dehalogenation[213cJ).
Cavitands of the
type 43 can be functionalized in various ways in the 2-position of resorcinol, starting for example from 2-bromoresorcinol units, which can be
obtained by bromination of the original calixarene prior to its
conversion to the c a ~ i t a n d . [ ’ ~In~ this
connection we should
mention the remarkable quadruple sidechain bromination of
cavitands of 2-methylre~orcinol,[~‘~~
which proceeds in very
good yields without any attack on the Ar-CHR-Ar structures.
This is explained by the fact that the ring structure does not
allow the formation of a planar benzyl radical.
Two of these functionalized cavitands 43a, b can be connected through four bridges at the 2-positions in different ways.[”’l
as exemplified in Scheme 10.
Scheme 10. Synthesis of carcerands or hemicarcerands with the inclusion o f a guest
(prisoner) of suitable size (symbolized by the ellipse).
B = 0-X-0
Apart from the completely bridged compounds, (nonspecific)
incomplete reactions also afford singly, doubly, and triply bridged
c a v i t a n d ~ . [ ~The
l ~ ~remaining
six, four, or two hydroxy groups
can then be used for further reactions, for example to introduce
a different type of bridge (see Section 7.2). Two isomeric dimers
44a, b (“ditopic cavitands”) can be isolated if this additional
bridging is carried out by using the tetrafunctional fluoranil;
X-ray structural analysis has shown these to have the C and Z
During this linkage reaction one (or even two) smaller molecules can be included in the new, completely closed cavity. Although these molecules are not held by covalent bonds, they can
no longer escape from the cavity, since the openings available
are too small. Cram has thus introduced the quite logical name
“carcerand” for compounds of type 45 and “carceplex” for their
inclusion complexes.
Several carcerands of this type (45a, b) have been described.
They differ in the resorcarene 18 from which they are derived,
and in particular in the structural elements which link two cavitands to form a carcerand. The presence of a molecule suitable
for inclusion is necessary for the successful formation of a
carcerand.”’ sd,
The linkage of two cavitands (43c, d) by only three bridges can
also occur,12161and this makes similar inclusions possible
(Scheme 10). In compounds 46 one of the “doors” is large enough
to permit the “imprisoned” molecule to “escape” under drastic
conditions (heating for a longer period under high vacuum or in
Angew. Chem. I n [ . Ed. Engi. 1995. 34, 713-745
suitable solvents). Compound 46 has thus been given the name
Hemicarcerands have a stable cavity which cannot collapse,
even when it is empty. Their openings are however large enough
(at least in principle) to permit smaller molecules to pass through
them. This goal can also be achieved when two cavitands are
linked by four bridges when, as in the examples 45c-h, these
bridges are large
The chirality of compounds 47 and 48 is due solely to the
chirality of the single units. However, calixarenes offer an additional possibility for the preparation of chiral host molecules
because of their nonplanar molecular structure. Such inherently
chiral calixarenes[2’81have so far mainly been members of the
calix[4]arene family.
7.2. Asymmetric Calixarenes
X =
x@2 owo
X =
X =
X =
451 x
450 x
Such an “empty” hemicarcerand is now prepared to take up
any suitable molecule or atom which is offered. Thus hemicarceplexes with a large variety of included molecules which d o not
need to be present during the synthesis are available (see Section
9.6). Remarkable “prisoners” include noble gases, but also larger
molecules such as cyclophanes have undergone inclusion.[2‘’I
7. Chiral Calixarenes
The first attempts involved the synthesis of calix[4]arenes with
three (in the sequence AABC)[30a1or
different p-substituted phenol units (7) or the introduction of a single m-substituted phenol unit.[32a.L 7 5 1
In order to obtain stable enantiomers the ring inversion, which
in this case is equivalent to racemization, must be prevented, for
example by the introduction of sufficiently large groups at the
phenol oxygen atoms. Because of the asymmetry of such calixarenes it is necessary to achieve complete conversion of all the
O H groups to a derivative in the cone
this can cause problems. which are probably also due to the
However, the tetrapropyl ether of a calix[4]arene
containing one 3-methyl-4-isopropylphenol unit has been prepared in the cone conformation and separated into its enantiomers by chromatography using chiral stationary
The same asymmetric pattern can in principle be achieved by
0-alkylation (or 0-acylation) when different residues are bonded
to the phenol oxygen atoms,[’0g.l 3 I a 1 thus at the same time fixing
the conformation. For this, at least two different groups are
required for an all-syn arrangement of the 0-alkyl groups. Additional possibilities arise when the 0-alkyl groups are in an untiarrangement; thus, for example, compounds of the
type 49 or 50 are chiral. Such
compounds[2231have been
described mainly by Shinkai
y\ O&H
7.1. Derivatives with Chiral Substituents
Just like any other molecules calixarenes can be converted
into chiral derivatives by the introduction of chiral substituents.
In the case of calixarenes derived from phenols this can be done
either at the phenolic OH groups or at thep-positions. Examples
for this have been described mainly by Shinkai et al.“ 19]
The use of enantiomerically pure reagents leads directly to
pure enantiomeric products (e.g. 47, a),
providing that the
derivatization occurs without racemization. Thus, it is possible
to obtain larger amounts of products, which is not yet the case
in the examples to be discussed in Sections 7.2 and 7.3 below.
et a1,1131%2211 and Pappa49
lardo et al. . [ 1 0 9 . 2 2 2 1
Chiral cavitands 51 have been obtained from resorcarenes
using a similar principle by introducing two different bridges (A,
B) . I 2 13al
The 1,3-derivatives 52 of calix[4]arenes of the type AABB are
readily prepared compounds with inherent chirality and are as
usual obtained in very good
Here the asymmetry is due to the fact that
y\ o
Angru. Chwn. Inr Ed. Engl. 1995. 34,
the plane of symmetry of the
calixarene moiety differs
from that of the oxygen substituent
V. Bohmer
analogy, for example, to the atropisomers of biphenyls. Examples of 1,2-diether derivatives 53 of calix[4]arenes of the type
ABAB can also be prepared;[2261this is however more difficult
since 1,2-di-O-alkylation typically occurs less selectively than
Finally in this section we should mention the spirodienones
28, which can be obtained from calix[4]arenes (and probably
also from higher oligomers) .[1791 Cr(CO), complexes of tetraethers of calix[4]arenes can also be asymmetrical.[2271
7.3. Dissymmetric Calixarenes
Dissymmetric calixarenes with an n-fold axis of symmetry are
particularly attractive, not only from the aesthetic point of view.
Calix[4]arenes 54 with C, symmetry have been obtained with
yields in the cyclization step of up to 30%.[6532281
Because of the equivalence of their phenol units all the 0alkylation products (from mono- to tetraethers) are available in
a defined manner. 1,3-Diether derivatives in particular (which
have C, symmetry) have been prepared in good yields and separated into their e n a n t i o m e r ~ . [ ~ ~ ~ ~
The cyclocondensation of 2,4-dihydroxy-3-hydroxymethyl
benzophenone leads surprisingly to the calix[5]arene 55 with C ,
symmetry, as has been shown unequivocally by NMR spectroscopy and mass spectrometry as well as by X-ray structural
analysis.i831This is not only an unusual example of a molecule
with inherent C , symmetry but also the first calix[5]arene
derived from resorcinol in which in contrast to the resorcarenes all the resorcinol units are connected in the 2,6-posi-
C,-symmetrical derivatives of the resorcarenes have recently been obtained
by controlled esterification of only one
OH group per resorcinol
Compounds such as 56 could provide the
starting point for many new attractive host molecules. The formation of the oxazine rings in the condensation of resorcarene
with primary amines and formaldehyde occurs also regioselect i ~ e l y . [ ' In
~ ~this
~ ~case
~ l the C, symmetry was confirmed by an
X-ray structural analysis.[' s5cl
While the calixarene-like macrocycles 3 with biphenyl
are flexible (and thus achiral), their biphenyl units can be fixed
in a particular conformation by etherification; this leads to chiral derivatives with atropisomeric units. Derivatives with overall
C, symmetry have been obtained in excellent yields from the
cyclic trimer 3a,[2311
while the isomer with D, symmetry is apparently less readily available.
8. Calixarenes as Host Molecules
One of the most important properties of calixarenes is without doubt their ability to include smaller molecules and ions
reversibly. Although the parent compounds form inclusion
compounds in the solid state with such different guests as arenes
(benzene, anisole, pyridine, tetralin), acetone, chloroform, acetonitrile, methanol, and water[1~2.621
(see also Fig. l), in solution their derivatives have become important as host molecules
or ligands.
8.1. Complexation of Metal Ions: Calixarenes as Ionophores
8.1.1. Unmodified Calixarenes
Simple tert-butylcalixarenes are capable of (proton-coupled)
transport of alkali metal ions (especially Cs') through an organic membrane (CH,Cl,/CCl,); while the selectivity for Cs'
was found to be highest for 1a, the highest transport rate was
found for 1 e.[lolThe suggestion made by Izatt that Cs+ ions
could be complexed within the cavities of calixarene anions
provided the best explanation so far for the high transport
rate, which was observed under analogous conditions for the
bridged calixarenes 14 when n = 8.[391This is also supported by
the structure of the Cs' salt[691of 1 a (see Fig. 1 c) and by the
results of 131Cs NMR measurements on the Cs complexes of
Harrowfield et al. have described a number of other neutral
complexes of Ca2+,[2331lanthanoides (La, Eu, Pr, Tm,
~ ~ ) , [ 2 32 334 a, - d ] and actinoides(UOi+, Th'V);[2351apart from
l a , l c , and l e the bishomocalixarene 6 was also used as a
ligdnd.[234c1Bimetallic complexes with 1
b1 are of interest
because of their photophysical properties.[234d*
p-(Phenylazo)calixarenes bind silver and mercury ions selectively; this has been explained on the basis of metal ion induced
azo-hydrazone t a u t o m e r i ~ m . [The
~ ~ ~tetramercaptocalixarene
24 in the 1,3-alternate conformation forms 1 :2 complexes with
m e r c ~ r y . 1bl
8.1.2. Neutral Ligands of the Podand Type
Complexation of Alkali Metal and Alkaline Earth Metal Ions
Derivatives with the structures 27a-c have been studied in
detail (extraction studies, complex formation constants in hoA n g w . Chem. In[. Ed. Engl. 1995, 34, 713-745
mogeneous solution, ion transport through liquid memI l e , I 7d, 122al and several general rules can be forbranes) ,[I lob,
- Both esters and ketones prefer to complex alkali metal ions
rather than alkaline earth metal ions.
- The ion selectivity depends on the ring size and in the case of
calix[4]arenes also on the conformation.[’05b1
- Tetrdesters in the cone conformation are selective for Na’
(e.g. P(Na’)//J(K’) = 400 in methanol[’ lob]), while the other
conformations favor K+.[105b1
- Pentaesters (cone)complex the larger cations preferably without making any particular distinction between K + , Rb’, and
assumed on the basis of N M R measurements that all analogous
complexes have a similar type of structure in solution.
The fourfold symmetry, which follows from the spectrum of
the free ligand in solution, thus apparently represents the time
average of two (identical) conformations with twofold symmetry which are in equilibrium via a
fourfold transition state. The com‘yOrg5jyR‘
plexation of a cation (see
Scheme 11) causes the carbonyl
groups to twist inwards and
a “true”
the ligdnd
in the complex
try,[219b,240, 2411
Hexaesters prefer Cs’ (e.g. the hexaethyl ester of the calix[6]arene unsubstituted in the p-position shows a Cs+/Na’
selectivity of 230 in extraction experiments), while octaesters
no longer exhibit any complexing abilities of note.“
“Fine tuning” of the selectivities is possible by varying the
alkoxy groups.[135a1
Tertiary amides bind alkali metal ions considerably more
strongly than do the esters (Ig /j’ in MeOH is larger by almost
3), but at the cost of
In contrast to ester and ketone derivatives, amides are also
stronger complexing agents for alkaline earth metal ions (high
fl values for Ca”, Sr”, and Ba2+ with respect to that for
Mg2’ ; the C a 2 + / M g 2 +selectivity of 7.8 (lg fl in MeOH) is the
largest observed for neutral ligands).[1211
Derivatives with mixed functionalities[”ob’
36b, 2371 offer a further possibility for tailoring the complexing properties.
In the case of tetraester derivaScheme
N a + complex of
tives Of the CaliX[4]areneS 54, twothe tetraester derivative 27a.
fold symmetry is also observed in
solution at low temperatures and the complex is kinetically (and
probably thermodynamically) less stable.[65]This is in agreement with the considerable decrease in the complex formation
constants (by more than five orders of magnitude for Na’) for
the tetraester derivatives of bridged calix[4]arenes (14) when the
length of the bridge is reduced from eight to five carbon
atoms.[40’The deformation thus caused can no longer be accomodated in the complex.
Little is known about the structure (and in some cases even
about the composition) of corresponding derivatives of larger
calixarenes. The hexaamide 27 b (n = 6 ) apparently forms a 1 :2
complex with Na’ which probably exists in a cone-like conformation.“ lsal In contrast, guanidinium ions form 1 : 1 complexes,
the corresponding trimethoxytriamide being clearly more selective. Hexaester or hexaamide derivatives of this type generally
exist in solution as mixtures of conformers, while in the crystalline
state a I ,2,3-syn-4,5,6-anti-conformation
is often found.[2.62b1
’ ’
Structure of the Complexes
Complexes of 27a (n = 4) with N a f or Li+ in CDCI, are
kinetically stable on the N M R timescale.”
Their ‘H NMR
spectra are consistent with effective C, symmetry. This is also
the case for the free ligands (see Table 7), although relaxation
Table 7. Comparison of the ‘H NMR spectra of 27a and its kinetically stable Lit
and N a t complexes in CDCI, (6 values, in parentheses the change in 8).
27 a
7.04 (+0.29)
4.81 (+0.03)
4.61 ( - 0.22)
3.36 (+0.19)
4.44 (+0.25)
1.38 (+0.11)
1.12 (+0.07)
7.09 (+0.34)
4.45 ( - 0.33)
4.22 ( - 0.61)
3.37 (f0.20)
4.35 (+0.16)
1.39 (+0.12)
1.11 (+0.06)
Other Cations
Tetraamides such as 27b (n = 4) also form complexes with
lanthanide ions,[2421which in contrast to the free ligands are often
soluble in polar solvents (water,
The Tb”’ complex exhibits luminescence in aqueous solution with a high quantum yield and long lifetime.[2421The luminescence properties
can be further enhanced when one of the amide groups is
replaced by a “sensitizer” group (e.g. phenacyl, 4-phenylphenacyl)
Ester derivatives of type 27a ( n = 5 ) can also complex silver
The complexation of transition metals (heavy metals)
is certainly favored by the incorporation of “softer” donor
atoms such as nitrogen (as the amine)
2451 s u l f ~ r , [ ’2461
or phosphorus.12471Systematic, and in particular comparable,
studies on the complexation of metal ions are scarce, so that
general conclusions cannot yet be drawn. The examples in Table 8
indicate the possibilities available.[’ 241 Simple ethers of the
measurements show the latter to have a mobility greater than
that of the complexes.[2381All known ligands of the type 27a-c
(n = 4) adopt a deformed cone conformation in the crystalline
state in which two phenol units are almost parallel and the other
two are “bent outwards”.[2.62b1 The carbonyl oxygen atoms
also point outwards.
At present the only crystal structure known is that of the K +
complex of the tetraamide,“ I d ] which shows “ideal” C4,-symmetry.[2391The K + ion is embedded in a “sandwich-like’’ manner
between the planes of the phenol and carbonyl oxygen atoms,
which are slightly twisted about the common fourfold axis. It is
Angrw. Clrrin. lnt. Ed. Engl. 1995, 34, 713-145
Table 8. 0-Alkyl derivatives of /rr/-butyIcalix[4]arene in the cunr conformation as
an ionophore in CHEMFETs [124].
Detectable ion
0-Alkyl group
Y ’ = Y’ = OCH,CH,SCH,; Y2 = Y4 = OH
Y’ - Y4 = OCH,CH,SC(S)N(C,H,),
Y ’ - Y4 = OCH,CH,0CH,C(S)N(CH,)2
Y’ - Y4 = OCH,C(S)N(CH,),
V. Bohmer
calix[4]arene can also complex silver ions; however, the arenes
function as n-electron bases. N M R studies and X-ray crystal
structure analyses of ethers in the cone and partial cone conformation show that the Ag+ ion is bound in a sandwich-like
manner between two opposite phenyl units.[2481
8.1.3. C a l k Crowns, Caiix Cryptands
Among the alkali metal ions K + is complexed selectively by
crown ethers of the type 30 (n = 3), which can be used as carriers
in liquid membrane^.[^^^",^] It is interesting that the free
dimethyl ether apparently exists in the cone conformation, while
the K' complex adopts a (flattened) partial cone conformation.['93b1Derivatives in the cone, partial cone, and l ,3-alternate
conformations can be obtained when the methoxy groups are
replaced by ethoxy groups; these are sufficiently stable for the
Here, the partial cone conformation has
shown the highest K t / N a + selectivity ( 1 . 2 ~lo4) so far observed for a synthetic ionophore.['ssl
Cs+-selective ligands are obtained if the crown ether ring is
enlarged ( n = 4).[250"1The most active in this case are derivatives (Y = nPr. iPr, n-octyl) which are fixed in the 1,3-alterna~e
conformation.['89d1The Cs+/Na' selectivities of 3 x lo4 and
greater found for extraction (o-nitrophenyl hexyl ether) from
acid solutions (1 M HNO,) offer promising prospects for the enrichment of 137Csfrom radioactive waste. This high selectivity is
due to interactions between the "soft" Cs+ ion and the n elect r o n ~ , [ ~ ~which
* ~ ~ were
' ~ confirmed by the X-ray structure
analysis of a Cs+ picrate complex.['89a1 1,3-Crown ethers
derived from calix[5]arene also show Cs' selectivity,12511while
no particular complexing properties have been described for the
1,2-crowns based on calix[4]arene.
The calixspherands 32 form alkali metal ion complexes of
unusual kinetic stability.[' 9 3 *2521 The half-lives for the decomplexation of Na' and K f in CDCI, (saturated with D,O), are
3.7 and 2.2 years (!), respectively, when Y = Y' = Y 2 = CH,.
In the crystalline state and also in solution the free ligand is
present in the cone c o n f ~ r r n a t i o n [ '(an
~ ~ ~earlier
~ ~ ~ ~ re~~
port['93b1suggested otherwise), while in the complex it adopts
a flattened partial cone conformation. The complexed ion is thus
extremely effectively shielded against attack by (for example)
water molecules, so that its removal from the complex by stepwise solvation is hindered.
The substitution described above gives a half-life of only 2.8 h
for the particularly interesting R b + ion. The results of force field
calculations[253]indicate that the larger cation causes a more
pronounced bending of the m-terphenyl bridge and thus a decreased shielding. The increase in the kinetic stability with increasing size of the substituent Y2 on the central ring of the
m-terphenyl unit is in agreement with this explanation.['93c1The
half-life for decomplexation increases to 139 h when Yz = Et,
and to 180dayswhen Y2= iPr, while the thermodynamic stability of the complexes remains the same. The half-lives for the
exchange of Rb+ for N a + / K + in polar solvents such as acetone
or DMS01252b1
are sufficiently large to enable practical applications in the area of medical diagnostics (the Rb/Kr method).[254a1
Even for Ag' ions the kinetic stabilities achieved are considerable;[254b1these can certainly be increased by partial replacement of the donor oxygen atoms by sulfur.
8.1.4. Ligands with Additional Ionizable Croups
The introduction of additional ionizable groups makes it possible in principle to obtain neutral complexes with metal ions,
which should for example make the transport of cations through
liquid membranes independent of the anion. Under suitable
conditions calixarene carboxylic acids of the type 27d bind alkali
metal ions, and in particular alkaline earth metal ions, much
more strongly than do the corresponding esters, ketones, or
amides," 22c1 high Ca2 +/Mg2 selectivities again being observed. Like similar siderophores, derivatives with hydroxamic
acid residues show a great affinity for Fe3+
If the number of carboxy groups in compounds of type 27 are
matched with the charge of the cation, ligands are obtained
which form neutral complexes. Very recent examples include
Ca2+-selective l i g a n d ~ ' ~and
~ ~ receptors
for lanthanoides
(Eu3', Tb3+),[255c1
which in addition to amide functions contain two and three -OCH,COOH groups, respectively. The combination of such ionizable groups with, for example, the structure of the calix crowns should open up further possibilities.
In contrast to many (in practice competing) heavy metal ions
with an octahedral coordination sphere, uranyl ions (UO;')
prefer to form complexes with hexagonal (or pentagonal) planar
coordination; suitable derivatives of calix[6]arene (or calix[5]arene) readily make this possible. Shinkai et al. in particular
have studied calix[5]- and calix[6]arenes with s u l f ~ n a t e [ *or~ ~ ~ , ~ ~
phosphonate ~ I - o u P Sin~the
~ p-position
~ ~ ~ ] and/or 0-alkyl groups
such as -CH2COOH[256a,b,f1
or -CH,C(0)NHOH[256'1 as uranophiles in extraction and transport experiments.[256b1Under
suitable conditions complex formation constants of up to
K,,,,,, = 1018-10'9 (the values for the analogous calix[4]arenes
are 15-16 powers of ten lower) and selectivities of Kurany,/
KMe= 1012-1017 have been observed. The low rate of complexation and decomplexation, which is orders of magnitude lower
than for the corresponding linear oligomers, seems to be a problem.[256d]The presence of only three carboxyl groups with C ,
symmetry affords selectivity advantages with respect to hexacarboxylic acids (27d).[256f1 Molecular dynamics simulations on
the complexation of UO: by calix[6]arenes were described re~ e n t I y .' 1g ]~ ~
8.1.5. Chvomoionophores
For sensor applications the generation of an optical signal as
a direct result of the complexation of a metal ion is desirable. In
recent years a series of calix[4]arene derivatives has been synthesized which exhibit a change in their absorption (UVjVis) or
fluoresecence spectra in the presence of metal ions and which
thus have potential for applications in optical sensors.12571The
examples discussed below also show the wide range of possible
variations in the calixarene skeleton.
The triester 57 (Li+)[258a1,the tetraester 58 (Lit better than
and the crown ether 59 (K+)['291exhibit considerable changes (bathochromic shifts) in their absorption spectra
when the metal ions given in parentheses are added; these are
due to the dissociation of the azophenol o r nitrophenol units in
the metal complex. While in the case of 57 and 58 the phenolate
oxygen atom acts directly as a donor, the complexation of 58
probably occurs in the conventional manner (with phenol and
Angew. Chem. Inr. Ed. Ennl. 199534.713-745
Cal I xarcnes
R =
carbonyl oxygen atoms as the donors). The proximity of the
positive charge of the metal cation will however favor the deprotonation of the nitrophenol in the presence of a suitable amine.
Large bathochromic shifts in the longer wavelength range are
observed in the case of indophenol derivatives;[2591these result
from the interaction between the metal ion and the carbonyl
oxygen of the chromophoric system. Compound 60 shows NaCselectivity,['5y"J while a corresponding derivative with two opposing indophenol units is Ca2'-selective.[259h1The trimethyl
ether 61i2h0J
is constructed on the same principle used in 57: it
contains a benzothiazole-substituted phenol unit, the fluorescence spectrum of which shows Li +-selective changes.
The anthryl group can also act as a fluorophore, and the
undergo changes in their fluorescence spectra
in the presence of Li', Na', and K' ions. The intramolecular
photodimerization of anthryl residues has been made use of in the
derivatives 65,r2641
the observed effects depending on the nature
of the binding to the calixarene. In the case of 65 a the photodimer
complexes Na' ions better than does the starting material,
and the thermal back reaction is slowed down considerably by
Na' ions; with 65b, however, the extractability of the Na' ions
is decreased considerably by the dimerization.[264h1
85a, X * CHzCHzO, Y = CH,CH,OCIH,
The tetraesters 62 and 63,[2611
in which two pyrene residues o r
a pyrene and a p-nitrobenzyl residue, respectively, are attached
to opposite phenol units, provide an impressive demonstration
of the conformational change discussed in Section 8.1.2 which
occurs on coinplexation of Na' ions in derivatives of type 27. In
the free hgdnds these two groups can come into contact, while
they are spatially separated in the Na' complex. Thus 62 shows
a strong (intramolecular) excimer emission for the pyrene
residues which is reduced by Na' ions in favor of the monomer
In 63, however, the fluorescence of the pyrene
residue is quenched by the nitrobenzyl group.r26'I The complexation of N d ions again separates the two groups'and thus
prevents the fluorescence quenching.[2621
65b. x = C n ~ C ( 0 ) o C n z C n z o .Y = Cn,cn,cH,
The following observation is also of interest in connection
with light-switchable molecular
Ditopic receptors
for metal ions are obtained when two molecules of type 27d are
joined by the ester residues.r2h51'H NMR studies show that a
metal ion can interchange in an intramolecular manner between
the two binding sites. Similar ditopic receptors can be obtained
when the linkage occurs by two bridges[z65c1and certainly can
also be equipped with chromophoric groups. An (intramolecular) exchange could then also be followed optically.
8.2. Complexation of Organic Cations
Water-soluble calixarene derivatives such as the p-sulfonic
acids complex ammonium ions;""] this is mainly due to the
electrostatic interaction with the calixarene anion.'" 71 Depending
on the pH value (and the variations in the charge distribution in
the host induced thereby) the inclusion can occur in different
The tetraanions of resorcarenes are also good
receptors for quaternary ammonium ions such as choline, association constants of up to lo5 Lmol-' being observed.['031Cor-
V. Bohmer
responding complexes have been detected in vacuum using a mass spectrometer.la11
Neutral ligands such as the alkyl
(26, Y = nPr) can function as
rc-bases and complex tetraalkylammonium ions in organic solY = Alkyl
The triester and triether
66 of the trioxacalix[3]arene in the
cone conformation exhibit high
affinity for ammonium ions in
extraction experiments because of their threefold symmetry,1268'. dl
8.3. Complexation of Anions
In comparison with the large variety of ligands which have
been described for metal cations the development of selective
host molecules for anions is still in its infancy. This is also true
for receptors based on calixarenes. Thus calix[4]arenes with two
opposite cobaltocene groups which in solution form 1 : 1 and 1 : 2
complexes unspecifically with mono- and dianions have only
recently been synthesized.[269a]Selectivity for H,PO, with respect to HSO, and CI- (electrochemical
detection by cyclovoltammetry in aceI
tone) has been reported for the ferrocenamide-bridged calix[4]arene 37 .[ b, 269b1
The sulfonamide 67 binds anions by hydrogen bonds; a remarkable selectivity
(10') was found in CDCI, for HSO; (with
an association constant of lo5 Lmol-')
with respect for example to CI- or
NO; .[I 59a1 Calix[4]arenes with urea
residues bound by spacers to the "lower
rim" bind halide ions (CI- > Br- > I - ,
K,,, up to 7 x lo3 Lmol-' in CDC1,).[2701
Consideration of the structures described
in Section 8.1 indicates that the development of receptors which
can bind cations and anions selectively at the same time can only
be a question of time. Such ligands would be of considerable
importance for transport across liquid membranes (see Addendum).
The selective inclusion of halide ions in the solid state by
metal complexes of phosphonites derived from resorcarenes is
mentioned for the sake of completeness.r21l b l
8.4. Complexation of Neutral Molecules
The development of host molecules for neutral guests, a possibility which was indicated by the first X-ray structural analyses
of calixarenes, is basically still in its infancy. Unspecific complexation of aromatic hydrocarbons (caused by hydrophobic
interactions) has for example been described for various watersoluble calixarenes; a certain selectivity is derived from the ring
size.['"] Measurements of association constants for a genuine
molecular inclusion are made difficult by the fact that it is necessary to work below the critical micelle concentration, and it is
in fact often the case that a suitable guest (e.g. a dye) is chosen
according to the host available.[2711
The inclusion of organic guest molecules has also been observed for cavitands derived from resorcarenes.[212b1These
compounds can in principle be used for the removal of organic
impurities from
Aoyama et al. have carried out detailed studies on the use of
resorcarenes 18 (in particular with R = C,,H,,) as host molecules. In nonpolar solvents such as chloroform they bind a large
number of guest molecules which contain hydroxy
The predominant interaction occurs through hydrogen bonds
(Scheme 12),[2741which involve two
neighboring OH groups of the host and
one OH group of the guest.
Guests such as d i o l ~ , [ ~ ~sug~".~]
',dl or dicarboxylic acids1273e1
are bound through (at least) two contacts of this type. In the case of simple
alcohols CH-rc interactions (which canScheme ,2. Inleracllon
with the hydroxy groups
not be excluded in other cases) are also
involved as a second
Cono f a guest G inresorcarenes.
siderable selectivities have been observed in spite of the relatively simple
structure of the host. Thus dicarboxylic acids can be differentiated according to their
and diols with respect to the
In constereochemical arrangement of the hydroxy
trast to glucose, fructose can be solubilized in CCI, by complexand the formation of glycosides from ribose occurs
with high stere~selectivity.['~~~~
In the formation of complexes
with glycosides there is an additional strong cooperative effect
due to hydrogen bonds between the associated guest mole~ u l e s . [ h1' ~Water-soluble
calixarenes (R = CH,CH,SO,H)
derived from resorcinol (18) ,[2751 from pyrogallol (19a),[276a1
and from 2-methylresorcinol (19 b)[276b1can bind molecules
such as hydrophobic sugars and n ~ c l e o s i d e s ~as' ~ well
~ ~ as
amino acids[276a]
in solution, the host functioning as a TC base.
A resorcarene derivative obtained by aminomethylation with
proline can serve as a chiral NMR shift reagent.[276c1
9. Supramolecular Structures
Self-assembly to give supramolecular structures : catch-phrases such as these (in some cases already overused) characterize
recent developments which go beyond the narrow area of hostguest chemistry. In what follows we shall discuss (without making any claim to completeness) various relevant results in the
calixarene area which reflect present trends and possible future
9.1. The Crystalline State
A variety of remarkable supramolecular arrangements have
been described for calixarenes in the crystalline state. These are
in some cases determined by weak forces,[2771interactions between methyl groups and rc systems often playing a decisive
role.['a71 As well as the inclusion of one guest molecule in a
single molecular
it is also possible for two molecules
of, for example, tevt-butylcalix[4]areneto encapsulate one single
Angew. Chem. I n f . Ed. Engl. 1995, 34,113-145
guest molecule ( a n i ~ o l e ) . [ The
~ ~ ~ double[278b1
or triple inclusion[234c1of guests has also been observed. Self-complexation
can lead to chainlike molecular arrangements.[71c,
In the
case of alkali metal salts of calix[4]arene sulfonates J. L. Atwood
et al. have described layer-type structures, which they describe
as “organic
In the case of transition metals “second
sphere” and with Eu3+ even “third sphere” coordination by
calixarenes has been
9.2. Liquid Crystalline Systems
The calix[n]arenes 68 (Y = CH,) can form liquid crystalline
phases as is typical for azomethines of this
mesophases are however obtained when Y = nPr and n = 4,
since the calixarene is now fixed in the cone conformation,[282b1
so that the molecules have a “rigid” bowl-shaped mesogeneous
center. Columnar mesophases are also observed for 69, the center here being even more rigid because of the quadruple binding
of a tungsten atom.[2831Similar examples (70) were described
earlier starting from all-cis r e s o r c a r e n e ~ , 2841
[ ~ ~ ~in which the
axial arrangement of the methyl groups at the bridges leads to
the conformational fixation of the center.
by cross-linking reactions.[286b1Mono- and multilayers have also
been transferred to suitable carriers using the Langmuir- Blodgett technique.[’65b*
2 8 6 c * d ] Thioether derivatives of cavitands
form monolayers spontaneously on gold surfaces.[288*
Such results may have considerable potential in sensor techniques or nonlinear optics. The affinity of various sugars for
monolayers of 18 (R = C , ,H2,) (and correspondingly modified
electrodes) has already been demon~trated.~~~~]
It is possible by transferring monolayers of the calix[6]arene 71 to polymeric carrier materials (poly[l-(trimethylsi1yl)-I-propyne]) to obtain membranes
whose permeability for gases can be regulated by their “molecular pore
S i Z e ~ ) , [ 2 8 6 c - e l The permeability for SF,
was already too small to be measured
after only two layers had been transferred, whereas smaller molecules like
nitrogen and helium still diffused through the membrane. The
“perm selectivity” P(He)/P(N,) was found to be 21 f 4 .
9.4. Aggregation in Solution
R = -C-CnH2.+,
Long-chain p-acylcalixarenes, for example, p-dodecanoylcalix[S]arenes, and their linear analogues, form stable gels in a
variety of organic solvents (including some alcohols) .[2y01 Comparisons with the corresponding methyl ethers and p-alkylcalixarenes show that a three-dimensional network is built up, probably through hydrogen bonds between the hydroxy and carbonyl
groups. Calix[4]arene ethers which
bear a self-complementary a-pyridone
residue at two opposite p-positions
prefer to form linear aggregates linked
by hydrogen bonds which can be “denatured” by urea
influence of the conformation is shown
CH3- N- CH3
by the aggregation of the (moderately)
CH3 c1water-soluble tetraammonium salt
72; while the isomer with the cone con72
formation forms micelles, that with
the 1,3-alternate conformation does
It should be mentioned in this connection that because of its
permanent dipole moment the cone tetrapropyl ether of tetranitrocalix[4]arene can undergo orientation in thin polymethylmethacrylate (PMMA) films when strong electrical fields are
applied :[28Sa] it was possible to increase the concentration of the
“NLO-phore” to 100 Y O ( !(NLO
= nonlinear optic) .[285b3
9.3. Mono- and Multilayers
Suitably substituted calixarenes can also be spread on
aqueous subphases; depending on the derivative, the hydrophilic end can lie on the “upper rim” or the “lower
rim”.[’o8a,1 6 5 h , 2 8 6 . 2 8 7 1 Monolayers of this type can be stabilized
Compounds such as 73 with “rectangular surfaces” (“velcrands”) form defined dimers (“velcraplexes”) in solution and
in the crystal by the “lock and key principle”.[293’ The 2-methyl
groups of two opposing resorcinol units (A, C) are oriented upwards, the other two
(B, D) outwards. The methyl
groups A and C then act
as “pegs” and fit into
the “holes” formed by B
and D. Both homo- and
heterodimers are found in
chloroform with association constants of up to
105 ~
~ ~ l - 1 , [ 2 9 3 ~ 1
V. Bohmer
9.5. Calixarenes as Transacylase Models
Calixarenes and calixarene derivatives can be used as catalysts, for example for solvolysis reactions,’294] or as phase transfer
catalysts.1’08b,1 1 8 b , 2 9 5 1 A particularly interesting system which
has been characterized in detail is the Ba2+ complex of the crown
ether 30 ( n = 3, R = ~ B u ) . [ ’ ~It~exhibits
typical features of an
enzyme catalysis, such as “burst kinetics” and steady state behavior for an intermediate product. Under certain conditions the
methanolysis of p-nitrophenyl acetate is accelerated by a factor
of 10; since this effect is not caused by either Ba2+ ions or the
crown ether when used separately it appears justified to speak of
a “supramolecular catalyst” (Scheme 13). The monoacetate of
30 was isolated and identified as an intermediate in the reaction;
its alkaline methanolysis is accelerated by a factor of more than
a million by Ba2+ and Sr2+ ions.[2971The catalytic cycle has a
turnover number of 5.5 x
min-’ (i.e. eight cycles per day);
while this is of course not comparable with those typical for
enzymes, the model system is unique in type.
Thus for example oxygen gives maleindialdehyde~2991
by a synthetic route which, while certainly not cheap, is definitely
unique. According to the authors the interior of carcerands or
hemicarcerands must be considered as a “new state of matter”.
9.7. Conclusions
The few examples discussed here demonstrate that the title
chosen for this report is certainly not an exaggeration. Many
research groups are striving to synthesize even larger molecular
systems with controlled functionalities. The calixarene structure, which behaves as a “molecular chameleon”13001can be
used in many ways as a building block. A final example which
helps to make this clear is the molecule with a permanent cavity
of about 1.5 to 2.0 nm in diameter[3011,consisting of two subunits of types I and 11, which are bridged by a total of eight
relatively rigid bridges.
10. Addendum[3021
From the multitude of new derivatives of calix[4]arenes products derived from p-~yanomethylcalix[4]areneshould be mentioned which can be converted in good yield to the dodecabenzyl
derivative (74 in the cone or 1,3-alternate conformation)[3031or
by an aldol condensation with benzaldehydes to 75. In these
cases the cyano functionalities are still available, so that comR
Scheme 13. The Ba” complex of calix[4J-crown-5 as a transacylase model
While similar catalytic effects can be observed for crown
ethers of tert-butylcalix[5]arene, crown ethers derived from
bridged calixarenes and from C,-calixarenes are inactive,[2981
probably because they exist in a more rigid conformation with
the hydroxy groups oriented inwards.
9.6. Reactions within the “Interior” of Molecules
Completely new perspectives have been opened up by the inclusion of smaller molecules in carcerands and hemicarcerands, a
process characterized by Cram as “constrictive bonding”. It was
possible using such a hemicarcerand as a “molecular reaction
vessel” to produce the highly reactive cyclobutadiene from a-pyrone as the “prisoner” (in this instance the word guest is not
really appropriate!). Cyclobutadiene normally reacts immediately, for example to yield cyclooctatetraene by dimerization.
However, the perfect isolation of each single molecule prevents
such intermolecular reactions : at normal temperatures cyclobutadiene is stable in the interior of the hemicarcerand. The controlled reaction with reactants which are small enough to pass
through the “gate” of the hemicarcerand is however possible.
pounds such as 74 could serve as starting materials for novel
dendrimers. The possibilities for incorporation of phosphorus
are also apparently unlimited;[3041 compounds containing
phosphorus with coordination numbers from 3 to 6 have been
described.[304a,bl Of particular interest are sandwich-like
organometallic compounds which are formed in good yields by
metalation of up to four of the “phenolic outer surfaces” by (for
example) cyclopentadienyl derivatives of rhodium or iridiThese compounds are stable, have been characterized
by X-ray crystallography, and because of the presence of “positive” phenol building blocks they are suited for the inclusion of
Further progress has been made in the selective derivatization
(0-alkylation and acylation) of c a l i ~ [ 6 ] a r e n e s . [The
~ ~ ~effects
the dominant factors, such as relative acidity of the O H groups,
conformation of the intermediates, size and reactivity of the
reagent, are apparently slowly becoming much clearer. As in the
case ofcalix[4]arenes the substitution pattern obtained can also
be transferred to the p-positions, for example by selective transAngew. Clirm. I n t . Ed. Engl. 1995, 34, 713-145
butylation (see below) or by i p s ~ - n i t r a t i o n . [ ~ ’In
~ ~addition
numerous ethers, the first examples of “double” calix[6]arenes
have also been obtained.[306c1 derviatives of calix[8]arenes have also
been obtained in yields of up to SO%.[307a1 These have been
converted by means of difunctional reagents to the first 1.5-0bridged calix[8]arenes 76.[307h1
The isolation of the 1,2,4-tri- and
1.2,3,4-tetramethyl ethers of t-butylcalix[8]arene 1e in yields of
68 and 71 YO.respectively, demonstrates that other substitution
patterns are also
The combination of calix[6]arenes with building blocks that
have threefold ~ y r n r n e t r y [ ~
’ ~ to
~ afford larger host molecules
such as 77 and 78 is remarkable: the coupling can take place
either at the “upper rim”[308a1or the “lower rim”.[308b,’09’ In
each case the starting material was the 1,3,S-trimethyl ether of
1 c. Initial derivatization of the hydroxyl groups or the p-positions was followed by reaction with trifunctional reagents[3081
or in the case of the inherently chiral C,-symmetrical cryptocalix[6]arenes 78 b[3091by the formation of the cyclotriveratrylene
system in analogy to ~ r y p t o p h a n e s . ~ ~ ’
x = (Cal)-O
which the porphyrin
system is linked to
(79)(3101 or
‘1 calix[4]arene
units to form larger
structures have also
been prepared for the
first time in preparatively satisfactory yields. In this case it is
possible to start from calix[4]arene derivatives with benzaldehyde
side arms (on the upper or lower rim) and to build up the
porphyrin system by condensation with p y r r ~ l e . [ ~ ~3’1 ”1 1.
In the case of 79a the calixarene even acts as a template.[3111
The linkage of a correspondingly functionalized porphyrin
with a calixarene derivative represents a second synthetic
79b is chiral because of the alanine residues present.
Further exciting developments in these directions can be expected.
Larger molecules with up to three calix[4]arene units have
also been constructed for the first time from derivatives which
Although the spacexist in the 1.3-ulternute
ers so far used in the linkages (bisphenol A) are still too long
(and thus too flexible) for the term “nanotubes” to be really
valid, this goal now appears attainable in the short term. It has
been shown for suitable derivatives in the 1,3-alternate conform a t i ~ n [ ~ that
~ * ~ Ag’
ions can probably be transported
through such “tubes”. Double calix[4]arenes in which two units
are linked by Cu” complexes[3131or hydrogen bonds[3141are
also of interest. It is remarkable that only the formation of
dimers, and not of larger associates, is reported.
Cram et al. have synthesized new hemicarcerands of type 45
which contain other bridges.[3151Using the corresponding carceplexes it is possible to carry out either reactions of the included
molecule (e.g. oxidation of divalent phenols to quinones without
the observation of side react i o n ~ [ ~ ’ ~or~ ’reactions
at the
bridges without loss of the included molecule.[3
reactions of included molecules
are also possible.[3161
The carcerands 80 prepared by
Reinhoudt et al. are particularly
remarkable; these consist of a
cavitand based on resorcarene
and a ~ a l i x a r e n e . [ ~ ’In
~ ”contrast
to compounds 45 they have no
plane of symmetry orthogonal to
the fourfold axis of the molecules
and thus have a permanent dipole moment in the direction of
this axis. Included molecules can thus take up two orientations,
as has been shown in the case of dimethylacetamide and Nmethylpyrrolidone. However, these rotate rapidly about the
molecular axis, so that the carceplex as such has effective C,
symmetry. The authors consider that they have discovered a
new type of stereoisomerism. which they refer to as carceroisomerism. Carceplexes of this type could conceivably be used for
information storage on a “molecular basis”. Since resorcarenes
containing long-chain thioether residues at the bridges can form
V. Bohmer
monolayers on gold surfaces,r2883
317b1 such systems are in principle thus “manageable”.
A large number of new ~ h r o m o - ~ ~and
’ * ]f l ~ o r o g e n i c [ca~~~]
lixarene derivatives has been prepared. Of particular interest
are: pyrene derivatives (cf. 62,63) of type 66[319”1
for ammonium ions, guanidinium-sensitive pyrene derivatives of 1c[319c1
and chromogenic calix[6]arenes containing an indoaniline unit
(cf. 60), which are sensitive to uranyl
The capabilities
of the basic calix[4]arene skeleton are particularly clear in the
case of the ditopic receptors 81 -83. Compound 81 combines
hard and soft donor groups on one side of the molecule,132o1
while 82 exhibits “cooperation” in the bonding of metal ions by
the ether amide ligand functions Y’ and Y2 on the both sides of
the m0lecule.1~~
‘1 The calix[4]arene-salen hybrid 83 is a bifunctional receptor for NaH,P0,.[322]
Y’ = Y 2 = CHZ-CO-N(Et)z
The multifarious possibilities available to calixarenes are
demonstrated further by the use of specifically modified derivatives as phase transfer catalysts,[3231as pseudo-stationary
phases in capillary electrophoresis13241and as host components
in sensorsr3251(e.g. for organic molecules), though space does not
permit a detailed discussion. Redox-active hosts such as calixarenes with p-quinone units may however provide new possibilitie~.‘~~~~
Special mention should be made of the separation and purification of C,, with the help of c a l i x a r e n e ~ . [ ~In~ ’contrast
C7,,, C,, forms a relatively insoluble 1 : 1 complex with tertbutylcalix[8]arene in toluene; this can be purified by recrystallization and split into its components with CHCI,, which can
then readily be separated. The denser C,, sinks to the bottom of
the vessel and can in this way be obtained in larger quantities
with a degree of purity >99.5%.[327”1Enrichment of C,, is
possible by complexation with tert-butylcalix[6]arene. Thus the
authors suggest that the readily available calixarenes afford an
inexpensive approach to the expensive fullerenes. The supramolecular interaction between fullerenes and calixarenes or
similar host
also appears to be of fundamental
Our own work in this area has been supported by the Deutsclze
ForschungsgemeinschaJt and the European Community, and we
thank both organizations for this support. I also wish to thank
those many colleagues who have helped in the preparation of this
manuscript both by critical discussion and constructive suggestions and by providing me with results, manuscripts, and figures.
M y thanks are due in particular to Dr. I. ThondorLfor the figures
based on X-ray structural analyses and to Dr. C. Griittner and
Dipl.-Cliem. 0. Mogck for their careful corrections.
Received: December 11. 1993
Addendum: November 29, 1994 [A431E]
German version: Angew. Chem. 1995, 107, 785
Translated by Dr. T. N. Mitchell, Dortmund ( F R G )
[l] C. D. Gutsche, Culixurenes, The Royal Society of Chemistry. Cambridge.
England. 1989.
[2] Calixurenes. A Versatile Class of’Macruc.yclic.Compounds, (Eds. : J. Vicens, V.
Bohmer), Kluwer, Dordrecht, 1991.
[3] a) An exact molecular weight determination was difficult and several “tetramers” were later shown to be octamers. b) An excellent description of the
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[5] a) See also the recent review of some aspects of the chemistry of calixarenes
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171 Although the pentamer i s obtained in considerably lower yield. it can be
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Stewart. C. D. Gutsche, Org. Prep. Proc. f n t . 1993, 25, 137-139. b) I n the
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1221 T. Yamato, K . Hasegawa, Y Saruwatari, L. K. Doamekpor, Chem. Brr. 1993,
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1311 a) ('. Griittner. V. Biihmer, W. Vogt. I. Thondorf, S. E. Biali. F. Grynszpan,
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1341 We recently obtained calix[6]arenes. including examples with O H groups in
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[75] Since the aromatic systems (including the atoms bonded to them) can be
considered to be planar even as a very good approximation, a calix[n]arene
can in principle be described by (n-1) pairs of such torsional angles. However, n pairs are given for the sake ofclarity. The cone conformation (and any
cone-like conformation) is characterized by a continual change of sign (+ - )
within these pairs. The other conformations of calix[4]arenes are described as
+ - ; 1.2-alrernute + ~, + +, - +. -,
follows: partial cone + -, +
and 1,3-alternute + + , -, + +, -. The conformations of calix[6]arenes
(Fig. 2) have torsional angles with the following sign sequences:
Compare: F. Ugozzoli, G. D. Andreetti, J. Incl. Phenom. Mol. Recogn. 1992.
13. 337-348.
1761 a ) F. Grynszpan. Z. Goren. S. E. Biali. J Org. Cheni. 1991, 56, 532536; b) F. GrynSzpdn, S. E. Biali. Tetruhedron Lert. 1991. 32. 51555158. c)The compound originally described in 23a turned out to be
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Delaigue, M. W Hosseini. Tetrahedron Lett. 1993. 34. 8111-8112.
1791 a)Y. Morita, T. Agawa, Y Kai, N. Kanehisa, N. Kasai, E. Nomura, H.
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[90] In these octaesters, which are derivatives of isomers with different configurations, the conformation with an axialarrangement ofthe groups at thecarbon
atoms of the bridges seems to be general (but see ref. [45c]). The rrcc isomer
has a flattened cone conformation with C, symmetry, often described as the
boat conformation. The interconversion C, -+ C, occurs via a transition
state with C,, symmetry. The rcct isomer has a chair conformation with C,,
symmetry, which can be the time average of twopartiul cone or two 1.2-alternore conformations. The rccf isomer lakes up a 1,2-uIrentute conformation
with C, symmetry. which has also been described as the diamond conformation (see ref. (45al).
-. +,
1911 The two signals, each for four OH protons, which are observed in CDCI, but
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[921 Solubilities in benzonitrile (and several other solvents) have recently been
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[931 Melting point differences of up to 180°C can be caused merely by different
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[loll V. Bohmer, E. Schade. C. Antes, J. Pachta, W. Vogt, H. Kimmerer, Makromol. Chem. 1983, 184, 2361 -2376.
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[lo31 See for example: H.-J. Schneider, D. Giittes. U. Schneider, J. Am. Chern. Soc.
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[lo61 Conclusions as to the conformation can also be reached on the basis of the
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[I201 a ) Z. Goren. S E. Biali. J. Chem. SOC.Perkin Trans. I 1990, 1484-1487; cf.
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[I211 a ) C. D. (iutsche. L. .I. Bauer. J. AJW.Chwn. Soc. 1985. 107. 6059-6063; b) H.
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[I221 a ) I<.
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[I231 R Ostaszc\vski. T. W. Stevens. W. Verboom, D. N. Reinhoudt. Red. Trail.
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[I251 J. D. v a n Loon. W. Verboom. D. N. Reinhoudt. Org. Prep. Prored. I n t . 1992.
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[ I X ] While i i numbering of all the C atoms based o n the IUPAC name i s also used.
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2S.27-dihydroxy-26.28-dimethoxycalix[4]arene(see ref. Ill). this inconsequence appears to cause no confusion in practice.
[I271 a ) C. D. (iutsche, L.-G. Lin. 7Wuhedron 1986. 42. 1633-1640; b) for a
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[I291 A M. King. C . P. Moore. K. R. A. Samankumara Sandanayake, 1.0.
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[I301 L. C. Groenen. B. H. M . Ruel, A. Casnati, W. Verboom, A. Pochini, R. Ungaro, D. N. Reinhoudt, Tdruhrdron 1991, 47, 8379-8384.
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[I351 a ) E. M. Collins. M. A. McKervey, S. J. Harris, J. Chem. Soc. Perkin Trans. I
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[1371 a ) A . Arduini. A. Casnati. L. Dodi. A. Pochini, R. Ungaro, J. Chem. Sor.
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(1381 a ) S Kanainathareddy, C . D. Gutsche. J. Org Chem. 1992. 57, 3160-3166;
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(1411 .i
K . Moran. D. M. Roundhill, Inorg. Chem. 1992, 31. 4213-4215.
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(1481 A structure, in which the opposing phenol units are really coplanar. would
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(1491 J. A. Kanters, A. Schouten, E. Steinwender, J. H . van der Mads, L. C. Groenen. D. N. Reinhoudt, J. Mu/. Struct. 1992. 269, 49-64.
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12181 Comprehensive review: V. Bohmer, D. Kraft, M. Tabatabai, J. inel. phenom.
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Angew. Chem. Int. Ed. Engl. 1995. 34, 713-745
[219] a ) Otherwise a complex mixture of isomeric or similar derivatives would he
formed. Thus for example four different mono- o r trialkyl derivatives (with a
. ~ i ' ru
i n n g e m e n t ) o r four different tetraalkyl derivatives in the coneconformalion arc possihle; h) L. Zetta, A. Wolff, W. Vogt, K.-L. Platt. V. Bohmer,
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(223) Unfortunately a recent systematic classification (cf. ref. [221]) of all possibilities contain5 some mistakes and inconsistencies. The number of different
0-alkylatioii products (in brackets the number of the chiral compounds) is as
follows: 34 (17) tetra-, 13 (9) tri-. 8 (3) dialkyl ethers. Compare: V. Bohmer.
D Kraft. W Vogt. Suprirmol. C h i . 1994, 3. 229-301.
"7241 V. UBhnier. A . Wolff. W. Vogt. J. Chmnm. Sot.. Chein. Coninmiin. 1990, 968-970.
12251 Mono- and tri-0-alkyl derivatives of calix[4]arenes of the type AABB have
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[226] F Marschollek. V. Bohmer. W. Vogt, unpublished results.
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[229] S T. Pickard. W. H. Pirkle. M T2ibatahai. W. Vogt, V. Biihmer. Chwirhn 1993.
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[230] This demonstrates best that the transitions between calixarenes in the narrow
scnse (Type 11) and the resorcarenes (Type 111) are gradual. For other calix[4]areiies uith resorcmol units, which are bonded through the Z.h-positions,
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(231j P O'Suilivan. V. Biihmer. W Vogt. E. F. Paulus, R. A . Jakohi, C / 7 1 ~Ber.
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[232] R . Assmith, V. Biihmer, J. M. Harrowfield. M. 1. Ogden, W. R. Richmond,
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[2351 a ) .I. M. Harrowfield. M. 1. Ogden, A. H. White. J. Clienr. Soc. Dolton ?'runs.
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[236] t. Noniuru. H Taniguchi. Y. Otsuji. Bull. Climi. Soc. Jpn. 1993.66. 3797~
[2371 K . Kimura, T. Matsuha. Y. Tsujimura. M. Yokoyama, A n d . Chem. 1992. 64.
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(2381 .A. Yamada. T. Murase. K . Kikukawa. T. Arimura. S. Shinkai. J. Chmn~.Soc.
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(2391 Sincc this highly aesthetic structure is one of the most often reproduced
represenlalions of' calixarenes we shall not include it here.
[240] The synergistic effect of acetonitrile on the complexation of alkali metal ions
ciiii illso be undcrstood on the basis that its inclusion in the hydrophobic
cn\'ity favors fourfold symmetry. a ) A. F. Danil de Namor. N. Apaza de
Sueroa. M A. McKervey. G . Barrett. F. Arnaud-Neu. M.-J. Schwing-Weill, J.
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M . C' C"tb;tleiro. B. M. Vuano. M. Salomon, 0. 1. Pieroni, D. A. P. Tanaka.
C. Y N2. M. A L. Tanco, N. M. Rodriguez. J. D. C. Garcia, A. R. Casal.
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[241] i t ) The cont'ormational change ofthe 0-alkyl groups can also be used in order
to align them for an interaction with a further guest: H . Murakami.
S Shinkai. J. Chcm. SO[..Clwm. Conmmun. 1993, 1533-1535; b) results of
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WipYf. .I Ain Ch~~rn.
Soc. 1993, 115. 8298-8312.
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unlimited, calixarenep, almost, macrocyclic, possibilities
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