STEREOCHEMISTRY OF CALIXARENES.
J. Klimentová and P. Vojtíšek
Department of Inorganic Chemistry, Faculty of Science, Charles University, Prague, Czech Republic
Calixarenes are a fascinating class of macrocyclic compounds, which has recently attracted a lot of attention because of their potential wide use in many areas of research and industry. Having started in the 19th century by reactions of phenol and aldehydes performed by Adolph von Baeyer; and continued by a considerable effort of David C. Gutsche in the 1970s, the chemistry of calixarenes has developed into a wide and well-explored area . Calixarenes have been used principally as spacers bearing functional groups in a well-defined arrangement, allowing their desired cooperation .
The utilization of calixarenes as molecular platforms possesses a few advantages. First, the synthesis of these macrocycles can be easily accomplished by a well-known procedure in good yields. The size of the macrocycle can be successfully controlled by the reaction conditions . The starting materials (p-tert.butylphenol and formaldehyde) are inexpensive and common. Calixarenes can be easily modified both on their upper and lower rim , which allows to change their chemical and physical properties as required. Finally, the four possible conformations of the calixarene macrocycle, easily immobilized by lower-rim substitution , are the main reason for the advantage of using calixarenes as molecular platforms.
Recently, heterocalixarene macrocycles have been synthesized. These compounds contain a heteroatom (S, N, Si) or a functional group based on heteroatom (SO, SO2) instead of the methylene bridge, which is responsible for their greater conformational flexibility .
The conformation and symmetry of the calixarene molecule is important for its function as a spacer bearing substituents in a defined arrangement, which allows their interaction, interaction with cations, anions or neutral molecules, cooperation in ion pair binding etc. [2, 5]. Another important factor is the rigidity or flexibility of the substituents and of the calixarene skeleton. The rigidity of the latter can be achieved by bridging the upper or lower rim of the calixarene molecule, effectively locking its movements . Furthermore, the conformation of the calixarene platform can be influenced by the interactions of its hydrophobic cavity or aromatic rings with cations or neutral molecules by the means of cation-p interactions, p-p interactions or van der Waals interactions. The substituents on the upper or lower rim may also participate in shaping of the calixarene molecule. The possible interactions (beside the above mentioned ones) may involve inter- or intramolecular hydrogen bonding, electrostatic interactions, donor-acceptor interactions (cation complexes or Lewis acid-base pairing) and sterical hindrance. In conclusion, the final shape of the calixarene platform results from the combination of all these effects.
To elucidate the influence of the substitution on the upper and lower rim of the calixarene and inter- or intramolecular interactions on the conformation of the calixarene molecule, we decided for the Cambridge Structural Database  as the largest source of information (about 1,500 calixarene structures). The conformation of the calixarene molecules and inter- or intramolecular interactions of these compounds can be easily determined from the crystal structure data. Nevertheless, this information might not fully correspond to the conformational behavior of the calixarene molecules in solution.
To describe the conformation of the calixarene skeleton, a variety of geometrical parameters can be calculated (e.g. the distances between the oxygen or carbon atoms on the lower or upper rim, the angles of the planes of the phenyl rings etc.). We have decided to describe the calixarene conformation by the defining of a reference plane to which the angles of the four phenyl rings are related. The most convenient reference plane appears to be the plane of the four methylene bridging groups (for the vast majority of structures, the deviation of the methylene carbon atoms from this plane is below 0.01 nm). The angles of the phenyl rings (ai, i = 1-4) are calculated in the scale 0-360º (see Fig. I).
Fig. I : The definition of the phenyl ring angles ai.
Next step in the description of the calixarene conformations is the definition of geometrical parameters a, b, d according to (1).
a = 0.25*(a1 + a2 + a3 + a4)
b = | a1 + a3 | - | a2 + a4 | (1)
d = | a1 - a3 | + | a2 - a4 |
The parameter a is the average value of the phenyl ring angles a1 - a4 (numbering reflects the order of the phenyl rings in the calixarene molecule, e.g. a1, a2 corresponds to adjacent rings, a1, a3 to opposite rings etc.). The parameter b reflects the distortion of the calixarene molecule towards C2v symmetry (for calixarenes in the cone conformation). Finally, d reflects the distortion towards Cs symmetry (again, for calixarenes in the cone conformation). Further examples of the dependence of the parameters a, b, d on the calixarene conformation are depicted in Fig. II (the schemes show slices through the calixarene opposite rings and usual angles).
Fig. II : Parameters a, b, d in dependence on the calixarene conformation and symmetry.
The parameters a, b, d reflect the conformation of the calixarene molecules (see Fig. II). For example, all calixarenes in the cone conformation have a < 90º and the values of b, d reflect their distortion towards C2v, Cs or C1 symmetry (the latter for both b, d significantly different from zero). The dependence of the b, d values is shown on the group of heterocalixarenes in Fig. III.
The dependence of the parameters b, d on the symmetry of the calixarene is shown on the example of non-complexed calixarenes in the cone conformation symmetrically tetrasubstituted on the upper and lower rim (Fig. IV).
The deformation of the symmetrically tetrasubstituted cone-calixarene molecules towards C2v, Cs or C1 symmetry is caused by the above-mentioned types of interactions, principally cation complexation, p-p stacking, hydrogen bonding and sterical hindrance. Some examples are given on Fig. V.
The dependence of the calixarene symmetry on changing the substitution pattern of the upper or lower rim can be also considered. Nevertheless, the dependence is complex and results from the combination of sterical and electronic effects. Our further attempts on this field are in progress.
Due to the large amount of CSD data and limited space in this abstract, only a few examples of the influence of the interactions on the shape of the calixarene molecule are presented.
 C.D. Gutsche, Calixarenes, Monographs in Supramolecular Chemistry, The Royal Society of Chemistry, J.F. Stoddart , Cambridge 1989
 S. Shinkai, A. Ikeda, Chem. Rev., 97 (1997), 1713-1734
 Macrocycle Synthesis, editor D. Parker, Oxford University Press, New York 1996
 P. Lhoták, Eur. J. Org. Chem., (2004), 1675-1692
 P.D. Beer, P. Gale, Angew. Chem. Int. Ed., 40 (2001), 486-516
 CSD, Cambridge Crystallographic Data Centre (CCDC)