Theoretical insight into the effect of fluorine substituents on the rearrangement step in Fischer indolisations

Abstract

Houk and co-workers clarified several aspects of the mechanism of the Fischer indole synthesis, showing that the SCS-MP2/6-31G(d)//MP2/6-31G(d) method is suitable for studying the mechanism in water. Fluorine substitution can affect the kinetic and thermodynamic parameters of a reaction, hence the work reported here considers the impact of fluorine substituents located on the ketone component of the starting phenylhydrazone in a Fischer indole synthesis. When one of the nitrogens is protonated, the presence of one fluorine decreases the activation energy of the key [3,3]-sigmatropic rearrangement and increases the thermodynamic stability of the resulting non-aromatic imine; the presence of two fluorines also reduces the activation energy versus the unsubstituted situation, but by a smaller amount. For a non-protonated sequence, although the presence of one fluorine again decreases the activation energy of the key [3,3]-sigmatropic rearrangement, inclusion of two fluorines actually increases the activation energy slightly.