Metadynamics with Discriminants: A Tool for Understanding Chemistry

We introduce an extension of a recently published method [Mendels et al. J. Phys. Chem. Lett. 2018, 9, 2776-2781] to obtain low dimensional collective variables for studying multiple states free energy processes in chemical reactions. The only information needed is a collection of simple statistics of the equilibrium properties of the reactants and product states. No information on the reaction mechanism has to be given. The method allows studying a large variety of chemical reactivity problems including multiple reaction pathways, isomerization, and stereo and regiospecificity. We applied the method to two fundamental organic chemical reactions. First we study the S(N)2 nucleophilic substitution reaction of a Cl in CH2Cl2 leading to an understanding of the kinetic origin of the chirality inversion in such processes. Subsequently, we tackle the problem of regioselectivity in the hydrobromination of propene revealing that the nature of empirical observations such as Markovnikov's rule lies in the chemical kinetics rather than the thermodynamic stability of the products.