TlPF6 (1.5 equivalents) was pre-dissolved in CD3OD, added to the solution of 5 and a second proton spectrum was recorded immediately after (Figure ). A clear change in the chemical shifts pertaining to the alkyl-protons of the K222 scaffold can be observed in the 1 H NMR spectra. On the other hand, the three aromatic protons show little to no change. These experimental findings were supplemented with density functional theory (DFT) calculations performed on both the Tl(I) as well as the K(I) complexes with ligand 5. For reference, DFT calculations were also performed for the already reported complex of K222 with potassium (Supporting Information). Comparison of the oxygen-and nitrogen-metal bonds showed good agreement between the calculated and experimentally determined structures. The structures for Tl(5) + (Figure ) and K(5) + are similar, with all 6 oxygens and 2 nitrogen atoms of the macrocycle involved in interactions with the metal centre (Supporting Information Figure ). Slightly longer distances between putative coordinating atoms and metal centre were detected for the calculated Tl(I) complex structure compared to the K(I) analogue (Supporting Information Table ). Comparison of the Tl(I) with the K(I) coordination environments revealed that the K(I) ion sits more centrally in the cryptand scaffold whereas in the case of Tl(I), the ion is located near the plane formed by the four non-aromatic oxygen and nitrogen atoms. These calculations suggest that the binding mode of K(I) and Tl(I) are similar with regards to 5 but that in the case of Tl(I), the metal ion is less encapsulated by the cryptand which could indicate lower stability. Altogether, these experimental and computational studies strongly suggest that an interaction between the chelator and Tl(I) is occurring and that it is, as expected, between the oxygen and nitrogen atoms of the K222 cryptand and the thallium cation. As additional confirmation, the NMR solution was analysed by ESI-MS and the mass peak for a thallium ion bound by 5 was detected (Supplementary Information Figure ).