## 2 The History of Crown Ethers  
Macrocyclic polyethers are crown ethers; they possess various ethylene oxide units covalently linked in a macrocyclic ring either substituted or unsubstituted and form the simplest form of cyclic oligomers of dioxane [36]. In 1967, [PERSON] prepared a crown ether to synthesize a complexing agent that could bind-divalent cations [37]. Two catecholate groups were linked through one hydroxyl. It reveals that the polydentate ligand partially envelopes the cation through phenolic hydroxyls ionization and neutralizes the bound dictation. [PERSON] found that this isolated by-product forms a potent complex with K\({}^{+}\) ions. The cyclic polyethers are complexing agents with a unique tendency to bind alkali metal cations [38,39]. [PERSON] got fame through his dibenzo crown ethers work. Crown ether strong footed the areas of phase transfer catalysts, organic synthesis, and other disciplines [40]. In 1987, [PERSON], [PERSON], and [PERSON] were awarded the Nobel Prize for chemistry because of their research on crown ethers and cryptands. Their work led to developing a new area of chemistry, such as supramolecular chemistry or macrocyclic [37]. Macrocyclic chemistry deals with macrocycle interactions with various metal ions. After [PERSON]'s crown ethers discovery, numerous macrocycles were synthesized, and their ability to form complexes was investigated [10]. Over the past years, great efforts have been made to synthesize crown ethers because of their application, especially regarding the drug delivery process [41]. The central feature of these compounds is the ability to form selective and stable complexes with various organic and inorganic cations. Before [PERSON]'s synthesis, a few examples of macrocycles were known [42]. He used nucleophiles such as resorcinol (1,3-dihydroxybenzene) and reacted with various substituted diol derivatives, resulting in the formation of various macrocyclic polyethers in the presence of [PERSON]'s acid catalyst. The condensation of acetone and furan led to the formation of furan-acetone tetramer as shown in Scheme 2. Initially, these compounds were named anhydrous tetramers because of the loss of four water molecules in the reaction [43]. In 1957, [PERSON], [PERSON], and [PERSON] treated an oxirane with alkyl aluminum, magnesium, and zinc to produce dioxane and various cyclic compounds; cyclic tetramer of ethylene oxide was one of them as shown in Figure 1[44]. In the year 1959, [PERSON] et al., synthesized a cyclic tetramer using propylene oxide. At that time potential of the cyclic compounds was not appreciated [45]. 2,2\({}^{\prime}\)-Dichlorodiethyl ether reaction with mono-protected catechol using sodium hydroxide in \(n\)-butanol and after deprotection results in the phenolic derivative. Catechol that was unprotected in the initial mixture gave rise to the crown ether. [PERSON] found that in the presence of sodium hydroxide, the solubility of dibenzo-18-crown-6 as shown in Figure 2. increased in methanol. It was due to the complexation between the crown ether and the sodium ion. [PERSON] also showed that oxygen could be replaced by nitrogen and sulfur; likewise, other species can coordinate to the electron-rich compounds. [PERSON] et al. introduced host-guest complexation, which describes the nitration between the host (crown ether) and the guest (metal ion) [10]. Compounds like crown ethers now became a central structure in supramolecular (host/guest) chemistry [46]. Since dibenzo-18-crown-6 synthesis, various macrocycles are prepared, and their effect on host-guest interactions and separation science is widely studied. It helped to understand their properties as well as ionophores and crown ethers, which are biologically significant. Nonactin, a macrotetrolide antibiotic, is a naturally present ionophore whose principles of binding and transport cation abilities are now better understood through crown ether [47]. In addition to nonactin, there is another important biologically active compound, Valinomycin.