Modeling Nazarov cyclization inside a [Si4L6]8− nanocage: effects of charge and size

• Nazarov cyclization studied in [Si 4 L 6 ] 8- nanocage using combined DFT and MD. • Protonation step is the key contributor to rate acceleration upon encapsulation. • [Si 4 L 6 ] 8- cage stabilizes carbocation intermediates more than the [Ga 4 L 6 ] 12- cage. • [Si 4 L 6 ] 8- cage encapsulate less solvent molècules than [Ga 4 L 6 ] 12- cage. The Nazarov cyclization in a [Si 4 L 6 ] 8- tetrahedral nanocage is investigated by means of a combination of density functional theory (DFT) calculations and molecular dynamics (MD) simulations. Experimentally, the reaction is accelerated within the Si-cage relative to that in solution but slightly less accelerated compared to the [Ga 4 L 6 ] 12- analogue. In this work the following questions are addressed: how does [Si 4 L 6 ] 8- affect key steps of the reaction? What are the origins of the rate acceleration in the [Si 4 L 6 ] 8- ? Where does the difference in rate acceleration between these two cages stem from? To determine the relative stability of the protonated substrate within the cage compared to that in solution, the main step in the process, we establish a computational scheme involving the calculation of Gibbs binding energies of neutral and protonated species by means of MD simulations, along with computation of Gibbs energy of protonation at DFT level. The results are compared to that in solvent and within that of [Ga 4 L 6 ] 12- nanocage, revealing the influence of encapsulated solvent. Overall, the results are in good agreement with experiments, both in solution and for the two metallocages, thereby providing deeper understanding of the effects of charge and size in the supramolecular cage-catalyzed Nazarov cyclization.