**1. Introduction**

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The macrocycles known as calix[*n*]arenes, where *n* represents the number of phenolic units bridged by methylene groups, represent ideal building blocks in supramolecular chemistry for the development of scaffolds with a preorganized structure, a well-defined cavity size, and modifiable positions for the introduction of a variety of functional groups, as shown in Fig. 1 (Böhmer, 1995; Asfari et al., 2001). The development of novel calixarene derivatives with the capability to act as receptors, sensors, catalysts, or ion transporters designed for specific purposes has been exploited to a great extent with the smaller member of the family calix[4]arene, and to a lesser degree with calix[6]arene. In the particular case of calix[4]arenes, the ease of modification by introduction of several types of functional groups at the phenolic rim has led to the development of numerous examples of versatile compounds (Baklouti et al., 2006; Baldini et al., 2007). The variety of derivatives reported to date is related to the well established synthetic protocols, which allow the preparation of calix[4]arenes with regio- and atropisomeric control by deprotonation of the phenolic OH groups with specific alkali-metal bases. These synthetic methods have been extended to the more recently developed thiacalix[4]arenes, which feature sulfur atoms as bridging groups between the phenolic components.

The development of systems based on the larger members of the calixarene and thiacalixarene families, namely calix[8]arene and thiacalix[8]arene (from now on referred to indiscriminately as calix[8]arenes), has been slow relative to its smaller analogues. This is likely due to the number of phenolic OH and aromatic positions available for functionalization, for which the regioselective introduction of substituents remains a challenging synthetic task. As a consequence, reports on crystallographically characterized calix[8]arene derivatives are relatively sparse. While the solution structures can be determined by a variety of methods, notably NMR spectroscopy, crystallographic characterization still represents the most reliable proof of the spatial arrangement of the macrocycles, particularly when the mobility of the large calix[8]arene is concerned. The limited availability of structural data is likely related to the large number of degrees of freedom present in the larger macrocycles, which does not allow the long-range ordering required for single-crystal formation. A search of the Cambridge Structural Database affords 89 structures of methylene-bridged calix[8]arenes, compared to the numbers of the four- and six-member macrocycles (Table 1).

Calix[8]arenes Solid-State Structures: Derivatization and Crystallization Strategies 47

of receptors, as well as for the binding of non-oxophilic metals within the calixarene cavity. These include our recently reported 1,5-disubstituted *p-tert*-butylcalix[8]arene by introduction of a 2,6-dimethylpyridyl group (Hernández & Castillo, 2009). A general overview on the crystallization techniques for each type of calix[8]arenes derivative

Original reports on the synthesis of the parent *p-tert*-butylcalix[8]arene date back to 1955 (Cornforth et al., 1955), where it was described as a high-melting solid with a proposed octameric structure, based on osmometry and mass spectrometry (Gutsche & Muthukrishnan, 1978; Muthukrishnan & Gutsche, 1979). Unambiguous structural assignment as an octaphenol-containing macrocycle by X-ray crystallography was initially precluded by solvent loss from the plates obtained by recrystallization from chloroform. It therefore seemed necessary to obtain calix[8]arene derivatives that did not lose solvent readily under ambient conditions, in order to afford single crystals amenable for structural

One property of calix[8]arene that was inferred from the structure of its smaller congener calix[4]arene is its large macrocyclic cavity, although crystallographic characterization was needed in order to corroborate it. Confirmation of its large cavity size in the solid state made it an attractive alternative to crown ethers for the potential binding of large cationic species. Among other possibilities, this property placed it as an ideal candidate for the selective binding of oxophilic heavy metals, including alkali, alkaline earth, lanthanide and actinide metals through the phenolic oxygen atoms. It is therefore natural that some of the first crystallographically characterized calix[8]arene derivatives consisted of metal complexes where the usually flexible structure of the macrocycle becomes relatively rigid due to the presence of multiple oxygen-metal ion-oxygen bridges. These types of derivatives were extended to *p*-block elements, including metals and non-metals such as phosphorus,

Although chronologically the parent *p-tert*-butylcalix[8]arene was not the first calix[8]arene to be structurally characterized due to loss of solvent molecules when crystallized from chloroform, it was obtained shortly after the first report of a calix[8]arene derivative; crystals stable enough towards solvent loss were successfully obtained from the high-boiling (115 °C) solvent pyridine (Gutsche et al., 1985). Subsequent reports include the chloroform and acetonitrile clathrates (Schatz et al., 2001; Dale et al., 2003), as well as a new determination of the pyridine-derived crystals (Huang et al., 2001); the structure of calix[8]arene with H atoms in the *para* positions also includes a molecule of the solvent pyridine (Zhang & Coppens, 2001). The aforementioned cases are described as clathrates despite the pleated loop conformation adopted by the macrocycle (Fig. 2), which is favored by the maximization of intramolecular hydrogen bonding. This configuration lacks a well-defined, deep cavity for inclusion to take place, although the incipient guest molecules may interact via hydrogen

accompanies the discussion.

**2. Discussion** 

characterization.

germanium and bismuth.

**2.1 Description of solid-state structures 2.1.1 Unfunctionalized calix[8]arenes** 

bonds, particularly in the case of pyridine.

Fig. 1. Schematic representation of calix[*n*]arenes

The current chapter covers the synthetic strategies that have proven successful for the preparation of calix[8]arene derivatives amenable for structural characterization. One of them involves the formation of anionic derivatives, which are obtained by deprotonation of the phenolic OH groups, and render the calix[8]arenes as ligands towards main group and transition metals. Formally anionic phenolate derivatives have also been obtained by elimination of HCl from the reaction of calix[8]arenes with oxophilic transition-metal chlorides. These strategies have resulted in the prevalence of structural information on the 8-member macrocycles in which the calix[8]arene framework becomes rigid due to the formation of multiple oxygen-metal-oxygen bridges (Redshaw, 2003).


Table 1. Crystallographic structures reported in the CSD.

The other general strategy described in this chapter is the one involving the introduction of intramolecular covalent bridges to limit the conformational flexibility of calix[8]arenes (Geraci et al., 1995). In this respect, the use of cesium salts has allowed the regioselective introduction of covalent bridges to the 1 and 5 phenolic positions of *p*-*tert*-butylcalix[8]arene (Cunsolo et al., 1994). The importance of 1,5-substitution (or 1,5-3,7 substitution) resides in the high symmetry of such derivatives, relative to 1,2- or 1,4- derivatives, which appears to result in better packing interactions. In this context, we will discuss the introduction of nitrogen-containing spanning elements, which could lead to the development of new types

of receptors, as well as for the binding of non-oxophilic metals within the calixarene cavity. These include our recently reported 1,5-disubstituted *p-tert*-butylcalix[8]arene by introduction of a 2,6-dimethylpyridyl group (Hernández & Castillo, 2009). A general overview on the crystallization techniques for each type of calix[8]arenes derivative accompanies the discussion.
