Enhanced sampling reveals the main pathway of an organic cascade reaction

Chemical reactions are usually hard to be simulated using conventional molecular simulations since the transition state is di ffi cult to be captured. Therefore, enhanced sampling methods are implemented to accelerate the occurrence of chemical reactions. In this investigation, we present an application of metadynamics in simulating an organic multi-step cascade reaction. The analysis of the reaction trajectory reveals the barrier heights of both forward and reverse reactions. We also present a discussion of the advantages and disadvantages of generating the reactive pathway using enhanced sampling molecular simulations and the intrinsic reaction coordinate (IRC) algorithm.