**1. Introduction**

Facilitated transmembrane transport by molecular carriers that selectively recognize and transport ionic species is an important and complex physiological process [1]. Nature has evolved millions of years to generate highly selective cation carriers, for which the transport mechanisms are controlled via a membrane potential (i.e., electrogenic valinomycin) or pH gradient (i.e., neutral monensin) [2]. Most of the previously reported artificial systems cannot achieve this type of stable potential, due to their poor selectivity. Macrocyclic crown-ethers have already proven to be e fficient cation channels [2,3]. Whether these macrocycles are covalently connected [3–7] or self-assembled via H-bonding [8–19], they form ion-channels, performing e ffective transport of ions across lipid bilayers. The structural variation between closely related synthetic carriers or channels could lead to a huge di fference in activities [8–14].

Artificial ion-channels presenting high K+/Na<sup>+</sup> selectivity are rare. We unexpectedly discovered that benzo-15-crown-5-ethers are showing far superior selectivity for K<sup>+</sup> cation when compared with benzo-18-crown-6 congeners [15–19]. So far, research e fforts have mainly focused on the electrogenic polarization across the membrane, related to a net transfer of charge via neutral alkyl-benzoureido-15-crown-5-ether channels [15]. Moreover, we also demonstrated that cholesteric or squalene moieties appended to cation binding benzo-15-crown-5-ether show the most efficient transport among similar structures to a certain extent [16]. Under the same conditions, squalene-benzoamido-15-crown-5-ether has the highest selectivity for K<sup>+</sup> over Na<sup>+</sup>, SK+/Na+ = 58.3, [17] while hexylbenzo-ureido-15-crown-5-ether has lower SK+/Na+ = 17 [15].

We know from previous studies [20–24] that the transport activity has an optimal relationship with lipophilicity of carriers, while the disposition of the alkyl groups on the carrier backbone proved to be important too. The self-assembly behaviors of the functional transporting system are directly determining the structural dynamics that control the self-organized superstructures along cation recognition and transport pathways. The transport mechanism is determined by the optimal coordination rather than classical dimensional compatibility between crown-ether and cation, and systematic changes of the structure lead to adaptive selection in cation-transport activity [25].

As far as we know the alkyl skeleton isomerism was rarely considered to be a determinant factor to influence the transport activity. The structural variability of the alkyl tails of the macrocyclic superstructures at the interface within the membrane have been not specifically studied in our previous work. Herein, we continue our exploration and we serendipitously found that simple small variations on the structure of the linear or branched octyl tails in octyl-benzoureido-15-crown-5-ethers **1**, **r2**, **s2**, and racemic **3** (Figure 1, Scheme S1) are strongly influencing the transport activities of monovalent cations. Together with this result, we confirmed another unexpected phenomenon; the carrier-induced electrogenic influx of K<sup>+</sup> cations is considerably boosted when coupled with proton transporter like carbonyl cyanide-4-(trifluoromethoxy) phenylhydrazone (FCCP) [25].

**Figure 1.** Crown-ether compounds **1**, **r2**, **s2**, **3** and the H<sup>+</sup> transporter carbonyl cyanide-4- (trifluoromethoxy)phenylhydrazone (FCCP) reported in this article.

Simultaneous addition of **1**, **r2**, **s2**, **3** and FCCP leads to the induction of K+/H<sup>+</sup> antiport via the formation of an electrical potentials across the membrane. This coupling of K<sup>+</sup> and H<sup>+</sup> fluxes can proceed without a potential via non-electrogenic K+/H<sup>+</sup> exchanges across the membrane. We observe an unprecedented increase in the selectivity [15,16] from SK+/Na+ = 3.6 to 48.8 in the best case.
