Uncovering the mechanism of selective stabilization of high-energy diastereoisomers via inclusion.

Unlabelled: Supramolecular systems may be used to stabilize otherwise unstable isomers to find alternative synthetic pathways. It has been reported that cucurbit[8]uril can stabilize -I and -II Cu cyclam, whereas -III is the only non-substituted Cu cyclam diastereoisomer found outside of the host molecule experimentally. Quantum chemistry methods can provide valuable insight into the intermolecular interactions involved in these inclusion complexes. All five possible diastereoisomers of Cu cyclam were studied within the host molecule to calculate the interaction energy and free energy of association for each complex. The relative free energies of the five free cyclams confirm that -I and -II are the most energetically accessible diastereoisomers from the initial -III starting point. Energy decomposition analysis was used to identify the attractive and repulsive interactions between cyclam and cucurbit[8]uril and showed that -II encounters repulsive forces almost three times greater than -I, which may explain the 7:3 ratio of -I to -II within cucurbit[8]uril that occurs experimentally. Optimized complex geometries with -III, IV, and V show that the cyclams protrude out of cucurbit[8]uril, whereas -I and -II become more encapsulated and elongate the host, suggesting that the position of the cyclam is extremely important when forming non-covalent interactions. Our results agree with the experimental findings and provide greater insight into why the most stable isolated cyclam diastereoisomer, -III, does not form a complex.

Supplementary Information: The online version contains supplementary material available at 10.1007/s00214-023-03077-7.