Origin of catalysis by [Ga4L6]12- metallocage on the Prins reaction

The Prins cyclization of citronellal is a significant reaction for synthesizing new carbon–carbon bonds, typically catalyzed by acidic conditions, serving as a crucial industrial intermediate for menthol production. The present work aims to investigate, by means of computational methods, the host-guest catalytic mechanism within the [Ga4L6]12- metallocage, which promotes the formation of minor alkene products, emulating the selectivity observed in biological terpene synthases. A combination of molecular dynamics simulations, DFT, and QM/MM calculations were employed to explore the reaction profiles, revealing the dynamics of encapsulation and the role of protonation and cyclization steps. Our study confirms that the metallocage does not directly modify the reaction, but rather provides a unique microenvironment within its cavity that facilitates acid-catalyzed reactions under basic or neutral conditions in solution. Indeed, modification of basicity of the citronellal reactant once encapsulated turns out to be critical for the process. Moreover, conversely to what is expected, the metallocage does not promote a conformational preorganization of the guest to a more compact conformation prone to undertake the cyclization. Identifying these factors offers a detailed understanding of rate enhancement by metallocages that can be of general applicability.