A series of 12 synthetic ionophores containing an amide subtituent connected via a methylene bridge to an aza-crown ring were evaluated for their ability to transport Na+ across large unilamellar vesicles (LUVs) using dynamic Na-23 NMR spectroscopy. The structures contain lipophilic groups connected to the amide nitrogen, ranging in size from C5H11 to C18H37, and are either tertiary or secondary amides. The crown ether ring size was also varied from 12-C-4 to 15-C-5 to 18-C-6. Surprisingly, the Na+ transport efficiencies were very high, with one synthetic system exhibiting an overall transport rate constant similar to that for a naturally-occurring ionophore, monensin. The value of k2 was 2.1 X 10(4) s-1 for (18N)CH2CON(C10H21)2-Na+, which compares with 2.0 x 10(4) s-1 for monensin-Na+. The overall transport rate efficiency followed the same trend as that of the binding abilities of the ligands. In every case, the 18-C-6 derivatives were more effective transporters than their 15-C-5 analogues, which in turn were better than the 12-C-4’s. Ligands containing a secondary instead of a tertiary amide substituent were always poorer transporters. Homonuclear H-1 NOESY conclusively showed that this is due to the formation of an intramolecular H-bond between the amidic proton and the polyether ring. The Na+ transport mechanism, determined here for the first time for a synthetic ionophore in a bilayer environment, was shown to be controlled by diffusion of the complex across the bilayer. The value of k(diff) determined for [15N]CH2CON(C10H21)2-Na+ was 3.2 X 10(3) M s-1.