Calixarene
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A calixarene is a macrocycle or cyclic oligomer based on a hydroxyalkylation product of a phenol and an
aldehyde [1]. The word calixarene is derived from calix or chalice because this type of molecule resembles a
vase and from the word arene that refers to the aromatic building block. Calixarenes have hydrophobic
cavities that can hold smaller molecules or ions and belong to the class of cavitands known in Host-guest
chemistry. Calixarene nomenclature is straightforward and involves counting the number of repeating units in
the ring and include it in the name. A calix[4]arene has 4 units in the ring and a calix[6]arene has 6. A
substituent in the meso position Rb is added to the name with a prefix C- as in C-methylcalix[6]arene.
Synthesis
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The aromatic components are derived from phenol, resorcinol or pyrogallol, For phenol, the aldehyde most
often used is simply formaldehyde, while larger aldehydes (acetaldehyde, or larger) are generally required in
condensation reactions with resorcinol and pyrogallol. The chemical reaction ranks under electrophilic
aromatic substitutions followed by an elimination of water and then a second aromatic substitution. The
reaction is acid catalysed or base catalysed. Calixarenes are difficult to produce because it is all too easy to
end up with complex mixtures of linear and cyclic oligomers with different numbers of repeating units. With
finely tuned starting materials and reaction conditions synthesis can also be surprisingly easy. In 2005,
research produced a pyrogallol[4]arene by simply mixing a solvent-free dispersion of isovaleraldehyde with
pyrogallol and a catalytic amount of p-toluenesulfonic acid in a mortar and pestle [2]. Calixarenes as parent
compounds are sparingly soluble and are high melting crystalline solids [3].
Structure
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Calixarenes are characterised by a three-dimensional basket, cup or bucket shape. In calix[4]arenes the
internal volume is around 10 cubic nanometers. Calixarenes are characterised by a wide upper rim and a
narrow lower rim and a central annulus. With phenol as a starting material the 4 hydroxyl groups are
intrannular on the lower rim. In a resorcin[4]arene 8 hydroxyl groups are placed extraannular on the upper
ring. Calixarenes exist in different chemical conformations because rotation around the methylene bridge is
not difficult. In calix[4]arene 4 up-down conformations exist: cone ( point group C2v,C4v), partial cone Cs, 1,2
alternate C2h and 1,3 alternate D2d. The 4 hydroxyl groups interact by hydrogen bonding and stabilize the
cone conformation. This conformation is in dymamic equilibrium with the other conformations. Conformations
can be locked in place with proper substituents replacing the hydroxyl groups which increase the rotational
barrier. Alternatively placing a bulky substituent on the upper rim also locks a conformation. The calixarene
based on p-tert-butyl phenol is also a cone [1].
History
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Adolf von Baeyer pioneered the chemistry of calixarenes although he was unable to determine its structure
and did not realise its potential (he was pursuing dyes).
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In 1872 he mixed benzaldehyde with pyrogallol and a strong acid and noted a red-brown resin with a marked
viscosity increase. He also used resorcinol and formaldehyde which he had to prepare from iodoform himself
because a commercial grade of formaldehyde at that time had not been realised yet.
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In 1894 the Lederer-Manasse hydroxyalkylation was invented as a synthetic tool for the preparation of
hydroxylmethyl phenols, bringing calixarenes one step closer.
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In 1902 Leo Baekeland made phenol formaldehyde resins a commercial success under the trade name
Bakelite. In these resins phenol and formaldehyde are exhaustively condensed with each other to form heavily
cross-linked polymers.
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The first attempt to control the reaction was made by Alois Zinke and Erich Ziegler in 1942. They employed
para substituted phenols which inhibits crosslinking and should result in a linear polymer with formaldehyde.
So in 1944 p-tert-butyl phenol with formaldehyde and sodium hydroxide in linseed oil as a solvent produced
for the first time a crystalline solid with a high melting point rather than a resin.
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In the same year another duo by the names of Niederl and Vogel did something similar with a para substituted
resorcinol and they were the first to postulate a cyclic tetramer.
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In these days structure elucidation was limited to determination of molar mass by freezing-point depression
and functional group analysis.
History
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John Cornforth was in 1955 the first to realize the potential of calixarenes as a basket analogue to enzymes
and repeated the work done by Zinke. he obtained a mixture of products and elicited the services of Dorothy
Crowfoot Hodgkin for structure elucidation by X-ray crystallography but with limited success. First commercial
success came to calixarenes in the nineteen fifties when the company Petrolite started a range of calixarene
products as demulsifiers user in the oil industry.
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The word calixarene was coined by David Gutsche [2] in 1975 who was also interested in this type of
compound as biomimetic, since the molecule resembled the calyx krater vases of ancient Greece. It was by
then established that unmodified calixarenes exhibit extensive conformational mobility so that the basket was
not much of a basket after all. Donald J. Cram fixed this shortcoming by inventing a way of immobilizing
calixarenes. He was able to freeze in a conformation by so called lower rim functionalization, replacing the
hydroxyl groups by larger substituents. The acetate calixarene fixates the molecule as a partial cone, whereas
the carbonate ester yields the full cone.
Host guest interactions
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Calixarenes are efficient sodium ionophores and are applied as such in chemical sensors. With the right
chemistry these molecules exhibit great selectivity towards other cations.
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Calixarenes are used in commercial applications as sodium selective electrodes for the measurement of
sodium levels in blood.
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Calixarenes also form complexes with cadmium, lead, lanthanides and actinides. [3] Calix[5]arene and the C70
fullerene in p-xylene form a ball-and-socket supramolecular complex. [4] calixarenes also form exo-calix
ammonium salts with aliphatic amines such as piperidine. [4]
Self assembly
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Resorcinarenes and pyrogallolarenes self-assembly lead to larger supramolecular structures [5]. Both in the
crystalline state and in solution, they are known to form hexamers that are akin to certain Archimedean solids
with an internal volume of around one cubic nanometer (nanocapsules). (Isobutylpyrogallol[4]arene)6 is held
together by 48 intermolecular hydrogen bonds. The remaining 24 hydrogen bonds are intramolecular. The
cavity is filled by a number of solvent molecules. [5]
Platonic and Archimedean solids
Amphiphilic polydedron-shaped p-sulfonatocalix[4]arene building blocks, 3,
which have been previously shown to assemble into bilayers in an antiparallel
fashion, have been assembled in a parallel alignment into spherical, 4,
structures by the addition of pyridine N-oxide and lanthanide ions.
Crystallographic studies revealed the manner in which metal ion coordination
and substrate recognition direct the formation of these supramolecular
assemblies. The addition of greater amounts of pyridine N-oxide changed the
curvature of the the assembling surface and resulted in the formation of
extended tubules.
The amount of 'chemical space' enclosed by 4 is about 1,000 Å3. This space
houses 30 water molecules and two sodium ions. However, the van der Waals
volume
of
3
is
about
11,000
Å3.
4 is differentiated from 2 by several factors. First, the supramolecular forces
used to hold 2 together are hydrogen bonds, while a combination of van der
Waals forces, p-stacking forces, and metal ion coordinate covalent bonds is
employed for 4. Second, the surface which encloses the chemical space is
essentially one atom thick for 2, while it is the thickness of the psulfonatocalix[4]arene building block in 4 (hence, the 11,000 Å3 volume of the
assembly with only 1,000 Å3 of space within). Third, the contents of the capsule
are rather completely ordered for 4 (by the hydrogen bonds from the enclosed
water to the phenolic oxygen atom hydrogen bond acceptors at the base of the
p-sulfonatocalix[4]arene), but the contents are completely disordered for 2
(because of the lack of any directional bonding force connecting the skeleton of
the assembly to the contents therein).
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Calixarenes are applied in enzyme mimetics, ion sensitive electrodes or sensors, selective membrames, nonlinear optics [6]
http://www.rsc.org/publishing/journals/CC/article.asp?doi=b502045j
Applications
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and in HPLC stationary phase [7].
http://www.chromtech.net.au/grom-calixarene.cfm
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In addition, in nanotechnology calixarenes are used as negative resist for high-resolution electron beam
lithography [8].
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A tetrathia[4]arene is found to mimic aquaporin proteins [6]. This calixarene adopts a 1,3-alternate
conformation (methoxy groups populate the lower ring) and water is not contained in the basket but grabbed
by two opposing tert-butyl groups on the outer rim in a pincer. The nonporous and hydrophobic crystals are
soaked in water for 8 hours in which time the calixarene:water ratio nevertheless acquires the value of one.
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Calixarenes are able to accelerate reactions taking place inside the concavity by a combination of local
concentration effect and polar stabilization of the transition state. An extended resorcin[4]arene cavitand is
found to accelerate the reaction rate of a Menshutkin reaction between quinuclidine and butylbromide by a
factor of 1600 [7].
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In heterocalixarenes the phenolic units are replaced by heterocycles [8], for instance by furans in
calix[n]furanes and by pyridines in calix[n]pyridines. Calixarenes have been used as the macrocycle portion of
a rotaxane and two calixarene molecules covalently joined together by the lower rims form carcerands.
Esthetics
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Building esthetic molecules with calixarenes include thus far a molecular Football World Cup [9]
Fig. Shape relationship of the football world cup (left) with the fullerene-calix[4]arene conjugate 1 as a PM3-calculated
space-<ETH>lling model (middle) and a schematic VB structure representation (right).
References
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•
[1]
Gutsche, C. David (1989). Calixarenes. Cambridge: Royal Society of Chemistry. ISBN 0-85186-385-X.
[2]
Antesberger J, Cave GW, Ferrarelli MC, Heaven MW, Raston CL, Atwood JL (2005). "Solvent-free, direct
synthesis of supramolecular nano-capsules". Chemical communications (Cambridge, England) . (7): 892-4.
PMID 15700072.
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[3]
McMahon G, O’Malley S, Nolan K and Diamond D (2003). "Important Calixarene Derivatives – their
Synthesis and Applications". Arkivoc Part (vii). Article
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[4]
Nachtigall FF, Lazzarotto M and Braz FNJ (2002). "Interaction of Calix[4]arene and Aliphatic Amines: A
Combined NMR, Spectrophotometric and Conductimetric Investigation". Journal of the Brazilian Chemical
Society 13 (3). Article
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[5]
Atwood JL, Barbour LJ, Jerga A (2002). "Organization of the interior of molecular capsules by hydrogen
bonding". Proceedings of the National Academy of Sciences 99 (8): 4837-41. PMID 11943875.
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[6]
Thallapally PK, Lloyd GO, Atwood JL, Barbour LJ (2005). "Diffusion of water in a nonporous hydrophobic
crystal". Angewandte Chemie (International ed. in English) 44 (25): 3848-51. PMID 15892031.
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[7]
Purse BW, Gissot A, Rebek J Jr (2005). "A deep cavitand provides a structured environment for the
menschutkin reaction". Journal of the American Chemical Society 127 (32): 11222-3. PMID 16089433.
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•
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[8]
Subodh Kumar, Dharam Paul, Harjit Singh (2006). "Syntheses, structures and interactions
of heterocalixarenes". Arkivoc 05-1699LU: 17 - 25. PMID. Article
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