Thermodynamic and Kinetic Control Determine the Sesquiterpene Reaction Pathways Inside Nanocapsules

Terpene and terpenoid syntheses are challenging tasks because of the required multiple synthetic steps, exact functionalization, and difficult purification that reduce the yields. One of the propitious methods to tackle this problem is the synthesis of terpenes inside nanocapsules. Nanocapsules based on resorcinarene moieties have recently been employed experimentally to generate sesquiterpenes, but the improvement of product distribution control in such nanoreactors is currently challenging due to a lack of specificity. In the current work, we study the in-capsule reactions employing multiscale modeling techniques along with a high-temperature Langevin molecular dynamics simulation protocol as well as the potential of mean force using the umbrella sampling technique. Additionally, we generate a sesquiterpene database with information derived from quantum chemical calculations. Using these methods, we shed light on thermodynamics, kinetics, product selectivity, and the chemical mechanism of sesquiterpene formation inside the resorcinarene-based nanocapsule. We find that, although the capsule produces many of the most stable known sesquiterpenes, several very stable sesquiterpenes are not formed. We ascribe this to reaction mechanisms involving intrinsically high energy secondary cations, which are avoided, even in the capsule. The current reaction modeling approach is expected to aid in the design of synthetic strategies for in-capsule sesquiterpene production.