Phenol-derived calixarenes

The facile condensation reaction between formaldehyde and phenols or their derivatives provides a major route into rigid macrocycles used in supramolecular chemistry. Calixarenes, the best-known class of phenol-derived macrocycles, are prepared this way, as are spherands and their relatives. Cyclotriveratrylene, however, is an excellent exemplar of the molecular basket type of ligand and has been known for the best part of a century. The basic cyclotriveratrylene synthesis is shown in Figure 3.1. The original procedure by Mrs. Gertrude Maud Robinson [1] has since been refined by others and many variations are known [2,3]. 

Calix[n]arenes are cyclic condensation products of para-substituted phenol derivatives and formaldehyde [29], They are highly interesting for the development of sensitive coatings due to their conformational flexibility and the ease by which they may be modified chemically. Chemical modification can be done either in the meta position, or by reactions at the hydroxy group. In this way, bulky substituents [30], chelating substituents [31], aromatic residues [32], crown ethers [33,34], peptides [35,36], etc. can be introduced. A first approach to combinatorial synthesis of calix[4]arene receptors has been published by Reinhoudt and co-workers [37,38], who prepared calixarenes with different substituents. In solution, these calixarenes lead to formation of hetero-oligomers with barbiturates, and these hetero-oligomers were detected by MALDI-TOF mass spectrometry and H-NMR spectroscopy. 

Figure 1.2 Phenol-derived and resorcinol-derived calixarenes...

Calixarenes are [1 Jmetacyclophanes (1) that acquired their name because of the resemblance of the shape of one of the conformers of the smallest member of their family to a type of Greek vase called a calix crater (Figure 1.1). The name was initially chosen to apply specifically to the phenol-derived cyclic oligomers, but it has subsequently taken on a more generic aspect and is now applied to a wide variety of structurally related types of compounds. The calixarenes were first discussed in comprehensive fashion in 1989 in the first volume of Monographs in Supramolecular Chemistry, where the literature on the subject that had been published up to that time was covered in reasonably complete detail in 222 pages. Since 1989, however, there has been such a rapid expansion of the field that a somewhat less comprehensive coverage of topics is now necessary if this... 

The calixarene family can be subdivided into two major branches, the phenol-derived cyclooligomers (2) and the resorcinol-derived cyclooligomers (3), as shown in Figure 1.2. Both are discussed in the previous volume. The present monograph, however, will deal almost exclusively with the phenol-derived compounds, the resorcinol-derived compounds having been the subject of a 1994 publication in Monographs in Supramolecular Chemistry and a long review article. ... 

Calix[n]arenes, which are phenolic macrocycles (Figure 1.5), were popularized by Gutsche in 1978, although calixarenes date back to Baeyer s work on phenol-formaldehyde chemistry in the ISTOs. " Calix[n]arenes are composed of phenolic units. The phenolic units are linked by methylene bridges at their 2- and 6-positions [meta positions). Gutsche et al. discovered that even-numbered calix[n]arenes ( = 4, 6, 8) were selectively obtained by tuning the reaction conditions for the phenolic derivatives and formaldehyde. 

The corresponding X-ray crystal structures of these triptycene-derived calixarenes and analogues were also obtained. As shown in Fig. 18.2a, b, macrocycle la adopted a typical cone conformation with a highly symmetric structure, while trans-isomer 2a adopted a chair conformation with two opposite phenol rings in the same plane [11a, b]. Similar stmctural features were also found in the crystals of their derivatives 5 and 6 [11c]. In the case of 7a, b and e [1 Id, e] (Fig. 18.2c) and 8a [12] (Fig. 18.2d), the crystal structures showed that they adopted cone conformations with fixed cavities while 7g [lie] was in a 1,2-altemate conformation. 

Calixarenes (from the Latin ca/ x) may be understood as artificial receptor analogues of the natural cyclodextrins (96,97). In its prototypical form they feature a macrocycHc metacyclophane framework bearing protonizable hydroxy groups made from condensation of -substituted phenols with formaldehyde (Fig. 15b). Dependent on the ring size, benzene derivatives are the substrates most commonly included into the calix cavity (98), but other interesting substrates such as C q have also been accommodated (Fig. 8c) (45). 

Calix[n]arenes (n=4,6,8) are cyclic condensation products of ap-substituted phenol and formaldehyde [58]. Gutsche and co-workers [59,60] have developed procedures for the synthesis of calixarenes and caHxarene derivatives. 

As hosts for cations, the phenolic oxygen atoms at the calixarene lower rim (Figure 3.81) have the potential to act in a similar way to the anisole residues of the spherands, either in the original hydroxyl form or as alkyl ether derivatives. This kind of behaviour has been observed for the methyl ether of the parent /j-f-butylcalix[4] arene (compound 3.121) upon reaction with a mixture of sodium benzoate, one... 

While the selective interactions of functionalised calixarenes with cations have been studied broadly for almost three decades, the application of cal-ixarene-based receptors for anion recognition is a relatively new research topic [2]. This review is focused on recent developments in the design and synthesis of calixarene-based anion receptors. Although the name calixarene was originally designated only for phenol-formaldehyde derivatives 1, recently many structural variations and mutations have been formed. Some of them, such as calixpyrroles [3], are widely used for anion recognition nevertheless, this review is restricted only to classical calixarenes 1 and newly discovered thiacalix-arenes 2 [4]. 

Well-examined complexes include derivatives of macrocyclic polyphenols known as calixarenes [147] (Fig. 29, Table 13). Lanthanide complexes containing up to eight phenolic units (calix[8]arene) were reported. 

Although promiscuous in their choice of guest-compounds, the only well-defined catalytic system based upon the calixarenes, which has been documented, is the one described by Shinkai [61]. He has studied the acid-catalyzed addition of water (Scheme 6) to lV-benzyl-l,4-dihydronicotinamide in the presence of a para-sulfonatocalix[6]arene and its methoxycarbonyl derivative. The polyanionic nature of the upper rim, containing the sulfonate groups, provides a site for the stabilization of the cationic intermediate. The lower rim, which carries the phenolic... 

The term calix[n]arenes indicates a class of phenolic metacyclophanes derived from the condensation of phenols and aldehydes. The name was coined by Gutsche and derives from the Latin calix because of the vase-like structure that these macrocycles assume when all the aromatic rings are oriented in the same direction.1 The bracketed number indicates the number of aromatic rings and hence defines the size of the macrocycle. To identify the phenol from which the calixarene is derived, the para substituent is designated by name. Thus the cyclic tetramer derived from p-f-butylphenol and formaldehyde is named p-f-butylcalix[4]arene, or with a more systematic but still simplified nomenclature proposed by Gutsche and used in this chapter 5,11,17,23-Te trakis( 1,1 -dimethylethyl)-25,26,27,28-tetrahydroxy calix [4] arene, 1 (Scheme 7.1). The systematic name reported by Chemical Abstracts is pentacyclo[19.3.1.13,7.19 13.115 19]octacosa-l (25),3,5,7(28),9,11,13(27),15,17, 19(26), 21,23-dodecaene-25,26,27,28-tetrol-5,l l,17,23-tetrakis(l, 1 -dimethylethyl). 

The most readily available calixarenes are compounds derived from p-t-butylphenol, 1-3. In order to introduce functional groups at the upper rim of the calix, the f-butyl group has to be removed, and this can be performed in 70-90% yield by reacting the p-f-butylcalixarenes with an excess of anhydrous aluminium trichloride in toluene in the presence of phenol at room temperature (Scheme 7.10). The unsubstituted p-//calixarenes thus obtained are versatile intermediates which give access to hosts having a large variety of properties. 

Again at the beginning of the 1970 s, other classes of synthetic macrocycles were being investigated, not necessarily in connection with biological problems. For instance, the rich chemistry of Schiff base derivatives (Fig. 4.8) was being developed and yielded the first macrocyclic complexes in 1979 (Fig. 4.9). Another type of interesting macrocyclic molecules are the calixarenes (Fig. 4.8) the history of which can be traced back to the first experiments, in Berlin in 1872, of Adolf von Baeyer (Nobel prize in chemistry in 1905) who treated p-substituted phenols with formaldehyde in the presence of acid or base. 

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