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

Abstract: 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 trans-I and trans-II CuIII cyclam whereas trans-III is the only non-substituted trans CuII cyclam stereoisomer found outside of the host molecule experimentally. Quantum chemical calculations can provide valuable insight into the intermolecular interactions involved in these inclusion complexes. All five possible trans stereoisomers of CuII cyclam were studied within the host to compute the interaction energy and free energy of association for each complex. The relative free energies of the five free cyclams confirm that trans-I and trans-II are the most energetically accessible stereoisomers from the initial trans-III starting point. Energy decomposition analysis was used to identify the attractive and repulsive interactions between cyclam and cucurbit[8]uril and showed that trans-II encounters repulsive forces almost three times greater than trans-I, which may explain the 7:3 ratio of trans-I to trans-II that occurs experimentally. Optimized complex geometries with trans-III, IV, and V show that the cyclams protrude out of cucurbit[8]uril, whereas trans-I and trans-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 stereoisomer, trans-III, does not form a complex.