AsiaChem | Chemistry in Japan | December 2021 Volume 2 Issue 1

www.asiachem.news December 2021 | 75 Figure 4 (a) Electrostatic potential profile of permethylated pillar[5] arene. (b) Guest molecules for pillar[5–7]arenes. (c) Chemical structures of anionic pillar[5,6]arenes and guests, and summary of the association constants for each host–guest complex. Reproduced with permission from reference.27 Pillar[n]arenes capture electron acceptors that fit the pillar[n]arene cavity size. Pillar[n]arenes also form host–guest complexes with neutral guest molecules. Pillar[5]arenes can capture linear hydrocarbons such as n-hexane because of multiple efficient CH-π interactions between the C-H groups of hydrocarbons and electron-rich benzene groups in the 1,4-dialkoxybenzene units (Figure 4b).21 Linear molecules fit the pillar[5] arene cavity (ca. 4.7 Å). However, the host–guest interactions are less strong for n-alkanes (association constants: K = ca. 20–50 M-1). Linear alkanes with electron-withdrawing groups such as cyano, triazole, and halogens at both ends are better guest molecules than non-substituted linear alkanes. In particular, n-butylenes with these terminal substituents are good guest molecules (K > 103 M-1) because the pillar[5]arene height is suitable for the length of n-butylenes, and because of the high acidity of the C-H groups neighboring the electron-withdrawing groups. In pillar[6]arenes, the cavity size is ca. 6.7 Å, which is a suitable size for branched and cyclic compounds such as cyclohexane, ferrocenium and tropylium cations.22,23 An adamantane derivative is good guest molecules for pillar[7]arenes because the pillar[7]arene cavity size (ca. 8.7 Å) is suitable for the derivative.24 Substituents on the rims of pillar[n]arenes are important not only for enhancing the stability of the host–guest complex but also for changing the pillar[n]arene solubility. Normally, simple pillar[n]arenes with alkoxy groups are soluble in organic solvents such as halogenated and aromatic solvents. Host–guest complexation events are therefore mainly investigated in these organic solvents when simple pillar[n]arenes are used as the hosts. However, the solubilities of pillar[n]arenes depend on the types of the substituents. Cationic, anionic, and nonionic pillar[n]arenes are soluble in water, therefore water can be used as the host–guest complexation medium. In water, in addition to CH-π and charge-transfer interactions, hydrophobic–hydrophilic interactions stabilize host–guest complexes. In the case of cationic pillar[n]arenes, cationic–anionic interactions between the pillar[n]arenes and anionic guests also stabilize complexation.25 In the converse combination, anionic pillar[n]arenes can capture cationic guests by cationic–anionic interactions.26 Our group discovered that one application of the host–guest properties of pillar[n]arenes is the use of pillar[6]arene with carboxylic anions as a biosensor for the vitamin metabolite 1-methylnicotinamide (1-MNA, Figure 4c).27 1-MNA is produced from nicotinamide by the enzymatic reaction of cancer-associated nicotinamide N-methyltransferase (NNMT). In aggressive cancer cells, high levels of 1-MNA are observed because NNMT activity increases in cancer cells. In the detection of the cancer-related molecule, 1-MNA is therefore an important research target. 1-MNA is cationic and water-soluble, therefore we hypothesized that a pillar[n]arene with carboxylate anions could be used as a biosensor for 1-MNA in aqueous media. An anionic pillar[5]arene formed a 1:1 complex with 1-MNA in water. The association constant (K) of the host–guest complex was 1.14±0.13×103 M-1. The size of 1-MNA (ca. 0.58 nm × 0.68 nm) is larger than that of the pillar[5]arene cavity (ca. 0.47 nm), therefore the K value is not so high. Another weak point is that the anionic pillar[5]arene also formed relatively stable host–guest complex with nicotinamide (K = 1.28±0.19×102 M-1), which is metabolized to 1-MNA by NNMT and in present in normal cells. To overcome the problem, our next choice for increasing the association constant was use of an anionic pillar[6]arene. The association constant (K) of the pillar[6]arene–1-MNA complex is 8.05±0.96×103 M-1, which is eight times higher than that of the complex with pillar[5]arene. The cavity size of pillar[6]arene is ca. 0.67 nm, which should be suitable size for 1-MNA. Furthermore, the anionic pillar[6]arene hardly formed a host–guest complex with nicotinamide. The anionic pillar[6]arene therefore acted as a biosensor for 1-MNA. How can planar chiral pillar[n]arenes be separated? Simple pillar[n]arenes do not have stereogenic carbons, but show planar chirality because of the position of the alkoxy substituents (Figure 5a).28-31 Figure 5 (a) Planar chirality of pillar[5]arene. Separation of enantiomers by (b) introducing bulky substituents and (c) formation of [2]rotaxane. (d) A schematic representation of the planar chiral inversion triggered by achiral guest. Reproduced with permission from reference.31 In their single crystal structures, we found enantiomers in pS and pR forms in a 1:1 ratio. However, in most cases, we could not separate the enantiomers by chiral column chromatography because racemization occurred via rotation of the units. This means that separation of the enantiomers is possible if we can stop the unit rotation. One useful way to stop the unit rotation is introduction of bulky substituents on the rim because the steric hindrance inhibits the unit rotation (Figure 5b).29 When we installed cyclohexylmethyl groups on the rims, the unit rotation was inhibited, and the enantiomers were successfully separated by chiral column chromatography. This is the first example of the separation of pillar[n]arene enantiomers. Another method for enantiomer separation is formation of rotaxane structures in which a cyclic molecule is threaded onto an axle molecule and end-capped with bulky groups at the terminal of the axle molecule. Formation of a rotaxane structure also inhibits the unit rotation because of the presence of the axle in the cavity (Figure 5c).30

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