Calix arenes selective functionalization

In contrast to the parent calix[4]arenes, selective functionalization of the resorcinol-based calix[4]arenes [ 18] has hardly been studied. Partly functionalized cavi-tands have only been isolated as side products in the synthesis of tetrafunctionalized cavitands [19, 20]. Although such dissymmetric cavitands have been used in the synthesis of chiral cavitands [21] and hemicarcerands [20] with promising applications [22], their synthesis was never studied in detail. While our work was in progress [23], Sorrell and Richards showed that cavitands can be selectively functionalized at the upper rim by means of a Claisen rearrangement [24]. In this paper we describe the synthesis of partly bridged octols [25] together with a novel route to functionalize these cavitands selectively in a proximal way. 

Arduini, A., Fabbi, M., Mantovani, M., etal., Calix[4]arenes blocked in a rigid cone conformation by selective functionalization at the lower rim. J. Org. Chem. 1995, 60, 1454-1457. 

The partial and selective functionalization allows the design and synthesis of a large variety of receptors for ions and neutral molecules bearing mixed functionalities. Especially in calix[4]arenes, the significant differences in the pK.d values of the phenolic OH groups allow their stepwise deprotonation and hence their selective functionalization. 

Calix[4]arenes can be functionalized both at the phenolic OH groups (lower rim) and at the para positions of the phenol rings (upper rim).21 A special class of selectively functionalized calix[4]arenes comprises bridged calix[4]arenes in which two phenol rings are connected by a cap.22 An important subgroup of this class are the calixspherands in which a calix[4]arene is diametrically bridged with a rigid terphenyl moiety. 

Only one calix[4]arene derivative is known which selectively complexes ions [133], CHEMFETs based on a calix[4]arene 34 functionalized with four thiocarbamoyl moieties, respond selectively to Cu " " ions in the presence of Ca ", Cd and Pb ". The selectivities ranged from logATcu = -1.6 to -2.0. Extraction experiments with calix[4]arene 34 also showed affinity for other soft metal ions like Hg + and Ag+ [138]. 

Four examples are known of calix[6]arene derivatives which have been used as receptor molecules in potentiometric measuring devices. Calix[6]arene 36 functionalized with six ethylester moieties showed a moderate selectivity for hexylammo-nium ions in the presence of smaller primary alkylammonium ions (logA = —1.0 to — 1.4) in ion-selective electrodes [140]. The same derivative 36 also proved to be sensitive towards Cs ions [141]. CHEMFETs with calix[6]arenes, functionalized with three diethylamido moieties (37) or with three phosphate moieties (38), are selective for guanidinium ions [142]. The fourth example is calix[6]arene 39 functionalized with two thiophosphoryl groups which is selective for Pb " ions... 

In contrast to the example just presented, most routes for selective functionalization on the upper rim take advantage of the relative ease with which selective functionalization on the lower rim can be effected. Procedures have been described in Section 5.1 for preparing mono-, di-, tri-, and tetraethers and -esters of calix[4]arenes. Comparably selective procedures are less available at the present... 

In a conceptually similar approach, sulfonated phosphacalix[4]arenes (Scheme 17) were used in combination with [Rh(acac)(CO)2l to catalyze hy-droformylation of 1-octene and 1-decene (158). The hydrophobic cavity of the calix[4]arene moiety was suitable to incorporate the olefinic substrate, and therefore these rhodium-phosphacalix[4]arene complexes functioned as reverse phase transfer catalysts, as well. As a consequence, the activity of these catalysts was 2-4 times higher than that of a [Rh(acac)(CO)2] -I- TPPTS -t- DMCD combination under otherwise identical conditions. Linear to branched selectivities were comparable (n/iso ratio 1.7-3.0), and the catalysts could be reused in the aqueous phase several times with no loss of activity and selectivity. 

Calix[4]arenes (1) represent a class of synthetic molecules that has been a subject of research in our group for the past decade. Several methods have been developed for the selective functionalization of calix[4]arenes both at the lower and the upper rim most of them have been summarized in a review article [9]. In this section only a recent example will be described. 

For the design of new receptor molecules with unique complexation properties calix[4]arenes have been combined with several other building blocks making use of the methods for their selective functionalization that were developed. In this paragraph the combination of calix[4]arenes with glycol chains (8), a terphenyl (9), and a uranyl containing salophen moiety (10) will be discussed. 

Selective Functionalization The possibility to selectively append substituents at the endo rim is of prime interest for the synthesis of new hosts based on large calixarenes. In the selective modification of large calixarenes, the number of the possible partially substituted derivatives (16,28, and 46 for calix[7]-, -[8]-, and -[9] arenes, respectively) increases exponentially by increasing the number of phenol rings. Notwithstanding this inherent difficulty, the regioselective functionalizatiOTi at the endo rim of p-tert-butylcalix[7]arene C[7] has been obtained [21] through a... 

Some years ago, a simple and convenient route to selectively functionalize the calix[8]arene exo rim was introduced [34]. The easily accessible 1,5-xylylene-bridged derivatives 26a-b, can be easily deprotected by hydrogenolysis to give 27a-b which can be selectively functionalized at the free phenolic rings because of their higher reactivity with respect to the (9-alkylated ones. In this way, the first examples of caUx[8]arenes partially substituted with p-nitro,p-amino, quinone, and hydroquinone functionalities have been obtained (Scheme 7.2) [34, 64]. 

In calix[4]arenes, when the substituent at the lower rim is larger than ethyl, the conformational interconversion among these structures does not occur and it is possible to isolate the four stereoisomers/ Synthetic protocols for the selective functionalization of the OH groups of calix[4]arenes (regioselective alkylation) and for the selective synthesis of certain stereoisomers of tetraalkoxy calix[4]arenes stereoselective alkylation) have been developed." ... 

Fully 0-alkylated calix[6]arenes, either lipophilic or water soluble, have been previously synthesized and studied for the complexation of ions and neutral molecules [28]. However, very little work has been done on the selective functionalization of calix[6]arenes both at the upper and the lower rim, to create new structures useful for Molecular Recognition. By treating p-tert-butylcalix[6]arene 2 with CH3I in acetone, in the presence of K2CO3, the symmetrical 1,3,5-trimethyl derivative 18 was prepared in 27% yield [29,30]. This compound shows a very simple pattern in the and NMR... 

In order to obtain more information about the factors that influence the ratios of the conformations and the interconversion process we investigated the properties of partially fixed calix[4]arenes. Using different methods for selective functionalization, we synthesized a series of mixed diethyldimethyl ethers (17), that are partially rigidified because of the presence of the ethoxy groups [16]. The partial fixation precludes one or two of the conformations and in this way also certain pathways for interconversion are excluded. Table 1 shows the ratios of conformations of the four... 

Another way of rigidifying the tetramethyl ether is by bridging the upper rim of the calix[4]arene. We prepared compounds 19 from the selectively functionalized... 

Except for two examples of mono-p-allylcalix[4]arenes [21] functionalization of the upper rim of calix[4]arenes has only been performed at all four para-positions simultaneously. We realized that the selectively lower nm-functionalized calix[4]arenes can be useful starting materials for the selective introduction of functional groups at the upper rim, and we have developed several strategies to prove this. 

Direct Substitution. A second method for the selective functionalization of the upper rim takes advantage of the fact that electrophilic aromatic substitutions are faster on phenols than on alkylated phenols. Starting with dialkylated calix[4]arenes a wide variety of electrophiles (Br, NO2, CH2=0, HgOTFA) can be introduced selectively on the para-positions of the phenol rings in yields > 80% (compounds 20b) [10]. 

Although the chemistry of calix[4]arenes is very interesting and (selectively) functionalized calix[4]arenes can have very useful properties, as was demonstrated above, the full potential of calix[4]arenes becomes apparent in their combinations with other building blocks. We will discuss a number of very successful compounds that are being used for different applications. 

In a study of alternative ways for the selective functionalization of the lower lim, by letting the unsubstituted calix[4]arene react with electrophiles with two reactive groups, we obtained not only the desired 1,2- and 1,3-bridged calix[4]arenes but in some cases... 

The number of possible O-alkylation products of calix[5]arenes is greater than those of calix[4]arenes and consequently there are also more possibilities for constructing asymmetrical substituted derivatives by O-alkylation. In general, selective functionalization of calix[5]arenes is not yet very advanced. The crown ether derivatives which we recently obtained are the first examples of selective O-alkylation [21a]. Such a 1,3-crown ether (which has Cs symmetry as indicated) can be made asymmetric by further monoalkylation or monoacylation at one of the remaining proximal OH groups [21b]. 

The recent rapid development of selectively functionalized calix[6]arenes also has a large, yet unexplored potential for obtaining inherently chiral derivatives. Two different diastereomeric 1,2-dibenzylethers of t-butylcalix[6]arene (syn and anti) have been obtained, for instance, from which the anti isomer (17) is chiral (C2 symmetry) [22]. The free energy barrier for their mutual interconversion (about 27 kcal mol ) should also be sufficient to isolate the enantiomers of 17. 1,2,4-Tri-O-alkyl or -acylderivatives [23] should be separable into the enantiomers as long as neither the O-acyl nor the p-substituent can penetrate the annulus. The macrobicyclic 2,5-esters 18 obtained from 1,4-di-p-methylbenzylethers are also chiral, having Ca-symmetry in the all-syn isomer [24]. 

After calixarenes were rediscovered and their structures were elucidated by Gutsche [1,2], the molecules have been studied in great detail thanks to their vase-like shape and their ability to complex guest molecules. At first, most efforts dealt with the synthesis of tetrafunctionalized calix[4]arenes [3-7], but more recently attention has increasingly been focused on the introduction of functional groups at specific positions in the molecule. This has resulted in a number of convenient syntheses for selectively functionalized calix[4]arenes [8], viz. mono- [9, 10], 1,2-di- [10-12], 1,3-di [13-15] and trifunctionalized [10,16,17] calix[4]arenes, making these molecules valuable building blocks in supramolecular chemistry. 

Kimura and coworkers [17], Diamond [18], and Damien et al. [19] have described that the polymeric calix-[4]arenes have been used as ionophores in ion selective electrodes for Na (based on calixarene esters and amides) and for Na and Cs (based on p-alkylcalixarene acetates). The electrodes are stated to function as poten-tiometric sensors as well, having good selectivity for primary ion, virtually no response to divalent cations, and being stable over a wide pH range. 

Schazmann B, Alhashimy N, Diamond D (2006) Chloride selective calix[4]arene optical sensor combining urea functionality with pyrene excimer transduction. J Am Chem Soc 128 8607-8614... 

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