A calixarene is a macrocycle or cyclic oligomer based on a hydroxyalkylation product of a phenol and an aldehyde.[1][2] 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.
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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.[3] Calixarenes as parent compounds are sparingly soluble and are high melting crystalline solids.[4]
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] Calixarenes are structurally related to the pillararenes.
| Calix[4]arene with para-tert-butyl substituents | 3D representation of a cone conformation |
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). 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. In 1894 the Lederer-Manasse hydroxyalkylation was invented as a synthetic tool for the preparation of hydroxylmethyl phenols, bringing calixarenes one step closer. 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. 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. 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. In these days structure elucidation was limited to determination of molar mass by freezing-point depression and functional group analysis.
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 used in the oil industry.
The word calixarene was coined by C. David Gutschein 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.
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. Calix[5]arene and the C70 fullerene in p-xylene form a ball-and-socket supramolecular complex.[5] Calixarenes also form exo-calix ammonium salts with aliphatic amines such as piperidine.[6]
Molecular self-assembly of resorcinarenes and pyrogallolarenes lead 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). (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.[7]
Calixarenes are applied in enzyme mimetics, ion sensitive electrodes or sensors, selective membranes, non-linear optics[8] and in HPLC stationary phases. In addition, in nanotechnology calixarenes are used as negative resist for high-resolution electron beam lithography [2].
A tetrathia[4]arene is found to mimic aquaporin proteins.[9] 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 resorcin[4]arene cavitand is found to accelerate the reaction rate of a Menshutkin reaction between quinuclidine and butylbromide by a factor of 1600.[10]
In heterocalixarenes the phenolic units are replaced by heterocycles,[11] 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.
Calix[4]arene 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.[12][13]
Calix[4]arenes 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.