A calixarene is a macrocycle or cyclic oligomer based on a hydroxyalkylation product of a phenol and an aldehyde. 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 calixarene has 4 units in the ring and a calixarene has 6. A substituent in the meso position Rb is added to the name with a prefix C- as in C-methylcalixarene.
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 pyrogallolarene by simply mixing a solvent-free dispersion of isovaleraldehyde with pyrogallol and a catalytic amount of p-toluenesulfonic acid in a mortar and pestle. Calixarenes as parent compounds are sparingly soluble and are high melting crystalline solids.
Calixarenes are characterised by a three-dimensional basket, cup or bucket shape. In calixarenes the internal volume is around 10 cubic angstroms. 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 resorcinarene 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 calixarene 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. Calixarenes are structurally related to the pillararenes.
|Calixarene with para-tert-butyl substituents||3D representation of a cone conformation|
In 1872 Adolf von Baeyer, a famous German chemist, mixed various aldehydes, including formaldehyde, with phenols in the presence of a strong acid. The resulting tars defied characterization but represented the opening chapter of what was to become the field of phenol/formaldehyde chemistry. Leo Baekland, Belgian by birth and a naturalized American citizen, discovered that these tars could be transformed to a hard, brittle substance which he marketed as “Bakelite”, the first commercial synthetic plastic. The success of Bakelite spurred serious investigations into the chemistry of the phenol/formaldehyde reaction, one result of which was the discovery in 1942 by the Austrian chemist Alois Zinke that p-alkyl phenols and formaldehyde in the presence of a strong base yield mixtures containing, inter alia, cyclic tetramers. Concomitantly, the American chemists Joseph Niederl and H. J. Vogel obtained similar cyclic tetramers from the acid-catalyzed reaction of resorcinol and aldehydes such as benzaldehyde. A number of years later the British chemist John Cornforth showed that the product from p-tert-butylphenol and formaldehyde is a mixture of the cyclic tetramer and another ill-defined cyclomer. His interest in these compounds was in the tuberculostatic properties of their oxyethylated derivatives. In the early 1970s the American chemist C. David Gutsche, recognizing the basket-like shape of the cyclic tetramer and the possibility that it might furnish the framework for building an enzyme mimic, initiated a study that extended for three decades. His attention to these compounds came from acquaintance with the Petrolite company’s commercial demulsifiers made by oxyethylation of the still ill-defined products from p-alkylphenols and formaldehyde. He introduced the name “calixarene” (“calix” the Greek name for a vase-like pottery; “arene” for the presence of aryl groups in the cyclic array) and established the structures for the cyclic tetramer, hexamer and octamer; worked out procedures for obtaining these materials in good to excellent yields; established procedures for attaching functional groups to both the upper and lower rims; and explored the conformational properties of these flexible molecules showing that the cyclic tetramer can be frozen into its basket shape (the “cone” conformation) by the introduction of sufficiently large substituents on the lower rim. Concomitant with Gutsche’s work was that of the German chemists Hermann Kämmerer and Voker Böhmer who developed methods for the stepwise synthesis of calixarenes and the Italian chemists Giovanni Andreetti, Rocco Ungaro and Andrea Pochini who were the first to obtain definitive x-ray crystallographic pictures of some of the calixarenes. In the mid 1980s other groups of investigators entered the field of calixarene chemistry which has become an important facet of supramolecular chemistry and which commands the attention of hundreds of scientists around the world. The Niederl cyclic tetramers from resorcinol and aldehydes were studied in detail by the American chemist Donald J. Cram who called the derived compounds “cavitands” and “carcerands”. An accurate and detailed history of the calixarenes along with extensive discussion of calixarene chemistry can be found in the 1989 publication (ref 1) as well as the second edition in 2008
Host guest interactions
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. Calixarenes are used in commercial applications as sodium selective electrodes for the measurement of sodium levels in blood. Calixarenes also form complexes with cadmium, lead, lanthanides and actinides. Calixarene and the C70 fullerene in p-xylene form a ball-and-socket supramolecular complex. Calixarenes also form exo-calix ammonium salts with aliphatic amines such as piperidine.
Molecular self-assembly of resorcinarenes and pyrogallolarenes led to larger supramolecular assemblies. 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). (Isobutylpyrogallolarene)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.
Calixarenes in general, and more specifically calixarenes have been extensively used as molecular platform to build up supramolecular catalysts. The design of this kind of catalysts consists in functionalizing the upper rim of the lower rim of calixarenes with ligands able to bind metal cations, notably Cu(II) or Zn(II), or other active functions. These compounds are active in the catalysis of hydrolytic reactions.
Calixarenes are applied in enzyme mimetics, ion sensitive electrodes or sensors, selective membranes, non-linear optics and in HPLC stationary phases. In addition, in nanotechnology calixarenes are used as negative resist for high-resolution electron beam lithography .
A tetrathiaarene is found to mimic aquaporin proteins. 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.
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 resorcinarene cavitand is found to accelerate the reaction rate of a Menshutkin reaction between quinuclidine and butylbromide by a factor of 1600.
In heterocalixarenes the phenolic units are replaced by heterocycles, 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.
Calixarene was used as scaffold to assemble a construct bearing four Tn-antigen unit, at upper rim, and the immunoadjuvant P3CS, at lower rim. The construct showed a cluster effect in the production of Tn specific IgG antibodies in mice when compared to an analogous monovalent construct. This reveals perspectives for potential applications in cancer immunotherapy.
Calixarenes with XXYZ or WXYZ substitution patterns at the upper rim are inherently chiral and their enantiomers can be resolved by chiral column chromatography. Recently, inherently chiral calixarenes have been synthesised in good yields by asymmetric ortholithiation using a chiral oxazoline directing group. This removes the need for resolution techniques.
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- IUPAC, Compendium of Chemical Terminology, 2nd ed. (the "Gold Book") (1997). Online corrected version: (1995) "Calixarenes".
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- Tatum, Prima R. (2009). The study of methods to synthesize silylated calixarenes in the 1,3-alternate conformation. ISBN 978-1-109-07989-0.