Diastereomer discrimination was observed in the formation of a metallomacrocycle from a racemic ligand based on Tröger's base. The metallomacrocycle exhibited a dramatic increase in fluorescence intensity compared to the ligand and its fluorescence was efficiently quenched by C(60).

A bis(18-crown-6) Tröger's base receptor and 4substituted hepta-1,7-diyl bisammonium salt ligands have been used as a model system to study the interactions between non-polar side chains of peptides and an aromatic cavity of a protein. NMR titrations and NOESY/ROESY NMR spectroscopy were used to analyze the discrimination of the ligands by the receptor based on the substituent of the ligand, both quantitatively (free binding energies) and qualitatively (conformations). The analysis showed that an allanti conformation of the heptane chain was preferred for most of the ligands, both free and when bound to the receptor, and that for all of the receptor-ligand complexes, the substituent was located inside or partly inside of the aromatic cavity of the receptor. We estimated the free binding energy of a methyl-and a phenyl group to an aromatic cavity, via CH-π, and combined aromatic CH-π and π-π interactions to be À 1.7 and À 3.3 kJ mol À 1 , respectively. The experimental results were used to assess the accuracy of different computational methods, including molecular mechanics (MM) and density functional theory (DFT) methods, showing that MM was superior. Results and Discussion Description of the model systemReceptor 1 consists of a Tröger's base motif with 18-crown-6 moieties fused to each end of the aromatic cavity, and is synthesized in one step by the condensation of commercially [a] A

2-Pyridone-fused 2,2'-bipyridine derivatives and were synthesised. X-Ray diffraction analysis of revealed a highly complex solid state structure with a disordered molecule imbedded in a channel structure formed by a centrosymmetric lattice of hexagonally packed, hydrogen bonded columns. The columns are assembled from three symmetry independent molecules. Dimerisation of the self-complementary cis-amide hydrogen bond motif is overridden by the fulfilment of the proton coordination ability of the phenanthroline nitrogens in accordance with Etter's rules of hydrogen bond priorities.

The consecutive binding of two potassium ions to a bis(18-crown-6) analogue of Tröger’s base (BCETB) in water was studied by isothermal titration calorimetry using four different salts, KCl, KI, KSCN, and K 2 SO 4 . A counterintuitive result was observed: the enthalpy change associated with the binding of the second ion is more negative than that of the first (Δ H bind,2 ° < Δ H bind,1 ° ). This remarkable finding is supported by continuum electrostatic theory as well as by atomic scale replica exchange molecular dynamics simulations, where the latter robustly reproduces experimental trends for all simulated salts, KCl, KI, and KSCN, using multiple force fields. While an enthalpic K + –K + attraction in water poses a small, but fundamentally important, contribution to the overall interaction, the probability of the collapsed conformation (COL) of BCETB, where both crown ether moieties (CEs) of BCETB are bent in toward the cavity, was found to increase successively upon binding of the first and second potassium ions. The promotion of the COL conformation reveals favorable intrinsic interactions between the potassium coordinated CEs, which further contribute to the observation that Δ H bind,2 ° < Δ H bind,1 ° . While the observed trend is independent of the counterion, the origin of the significantly larger magnitude of the difference Δ H bind,2 ° – Δ H bind,1 ° observed experimentally for KSCN was studied in light of the weaker hydration of the thiocyanate anion, resulting in an enrichment of thiocyanate ions close to BCETB compared to the other studied counterions.

A model system to study interactions between aromatic cavities and non‐polar side chains was developed and studied by different NMR methods, where a weak but evident side‐chain discrimination was observed. The experimental quantitative and qualitative data was used to evaluate different computational methods, with the conclusion that, for this system, molecular mechanics gave more accurate results than density functional theory calculations. More information can be found in the Full Paper by P.‐O. Norrby, K. Wärnmark, et al. (DOI: 10.1002/chem.202100890).