74 | December 2021 www.facs.website para-position). Because of the para-bridge linkage, the macrocycle had a highly symmetric pillar-shaped architecture, which was quite different from that of calix[n]arenes. Typical calix[n]arenes have vaseshaped structures because of the meta-bridge linkage (Figure 1b). We called this new type of macrocycle as pillar[5]arene because of its shape.10 What is the key to pillar[n]arene formation? The difficult part of macrocycle synthesis is formation of cyclic structures. The synthesis of macrocyclic structures requires connection of the ends of linear compounds. We obtained pillar[5]arene in high yield in one simple step under reaction conditions similar to those used for phenolic resin synthesis. The question is: why can we prepare pillar[5]arene in such a high yield? Generally, a template works well for macrocyclic compound synthesis in high yields. Macrocyclic compounds are formed by complexation with a template (guest). A single macrocyclic compound that reflects the template size can therefore be obtained in high yield in the presence of the template. In other words, the obtained macrocyclic compounds are thermodynamically stable products in the presence of the template. Without the template, a mixture of macrocyclic compounds with various cavity sizes is produced. The macrocyclic formation efficiency depends on the strain energies of the macrocyclic compounds. In the absence of a template, macrocyclic compounds formed in a kinetically controlled system. Careful tuning of the reaction temperature and time is therefore necessary to obtain macrocyclic compounds. In the synthesis of pillar[5]arene, we selectively obtained the product in high yield without careful reaction condition tuning, which indicates that some reagents work as a template for pillar[5]arene formation. We therefore investigated various reaction conditions to identify the template for selective production of pillar[5]arene. We realized that solvents for the cyclization acted as the templates for the selective formation of pillar[5]arene. When we used 1,2-dichloroethane, a cyclic pentamer, i.e., pillar[5]arene, was selectively obtained in high yield (>70%, Figure 2a).12 In contrast, with chloroform as the solvent, the obtained products were a mixture of linear oligomers and pillar[5–10]arenes (Figure 2b).13 These results are related to the host–guest properties of pillar[5] arenes. The cavity size of a pillar[5]arene is ca. 4.7 Å, which fits linear molecules. 1,2-Dichloroethane is a linear molecule, and therefore acts as a template for selective pillar[5]arene synthesis. In contrast, chloroform is a branched molecule, and therefore does not act as a template for a pillar[n]arene with a particular size. In chloroform, the reaction proceeds under kinetic control. Precise tuning of the reaction time therefore resulted in the synthesis of larger pillar[n]arene homologs (n= 6, 7, 8, 9 and 10), but their yields were low because of the kinetic control system.13 Based on these results, we tried to synthesize pillar[6] arene by using the template method. When we used chlorocyclohexane as a solvent, pillar[6]arene was obtained in 87% yield (Figure 2c). Chlorocyclohexane is a suitable size for the pillar[6]arene cavity, and therefore acts as a template for selective pillar[6]arene synthesis.14 How can pillar[n]arenes be functionalized? Simple pillar[n]arenes have alkoxy groups on both rims. The alkoxy groups can be converted to phenolic groups by deprotection. Pillar[n]arenes with phenolic groups are useful key compounds for producing functionalized pillar[n]arenes because phenolic groups show high functionality. The easiest way to functionalize pillar[n] arenes by using the reactivity of the phenolic groups is etherification between the phenolic groups and compounds with a halogen group.15-17 The introduction of triflate groups enables the use of cross-coupling reactions such as the Suzuki, Sonogashira coupling to directly connect aryl groups. Pillar[n]arenes with phenolic groups are therefore useful key compounds for preparing various functionalized pillar[n]arenes. Pillar[n]arenes with 2n phenolic groups can be produced by deprotection of alkoxy groups with BBr3 (Figure 3a). 10 Figure 3 Procedures for (a) per-, (b) mono-, and (c) di-functional pillar[5]arenes, and (d) rim-differentiated pillar[5]arenes. By tuning the deprotection conditions (Figure 3b), we prepared pillar[n]arenes with one phenolic group in moderate yields.15 In the case of pillar[n]arenes with two or more phenolic groups, a major problem is that these pillar[n]arenes have isomers. For example, difunctional ized pi l lar[5]arenes and pi l lar[6]arenes have f ive and seven possible isomers, respectively. These phenolic pillar[5,6]arenes cannot be obtained by direct deprotection of alkoxy groups because many constitutional isomers are generated by direct deprotection. We reported a new route for synthesizing pillar[5]arenes and pillar[6]arenes with two or more phenolic groups via oxidation–reduction of the pillar[n] arene units (Figure 3c). Pillar[5]arenes with one and two benzoquinone units, and pillar[6]arenes with one, two, three, and four benzoquinone units were obtained by direct oxidation of the units.16,17 Subsequent reduction of the benzoquinone units, gave pillar[5,6]arenes with phenolic groups at the same units. Rim-dif ferentiated pillar[5]arenes, which have the same f ive substituents on one rim, can be produced by a “pre-orientation” strategy, which was developed by Ma et al., and Zuilhof and Sue et al in 2018.18-20 In this strategy, hydroxymethyl groups were first installed into monomers (Figure 3d). The pre-orientation enabled successful synthesis of rim-differentiated pillar[5]arenes in moderate yields (ca. 15%–20%). A pillar[5]arene with five phenolic groups on one rim was obtained by using an oriented monomer with a benzyl group because deprotection of the benzyl group affords phenolic groups.20 What are good guests for pillar[n]arenes? Pillar[n]arenes are composed of electron-donating 1,4-dialkoxybezene units, therefore the interior cavity is an electron-rich space (Figure 4a).21-27
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