Identifying reactive normal modes and their effect on regioselectivity in Myers–Saito and Schmittel cyclization of enyne–allenes: a combined perspective between the reaction force constant and statistical tools

Abstract

This paper presents a theoretical study on the distinguishable regiodivergent C₂–C₇ Myers–Saito and C₂–C₆ Schmittel routes of benzannelated enyne–allene cycloaromatizations, in which substitutions on the terminal alkyne by alkyl (–CH₃, –CH₂CH₃, –CH(CH₃)₂ and –C(CH₃)₃) and aryl (–C₆H₅ and –C₆H₂(CH₃)₃) groups were included. Mechanistic differences were found between substituents attached to alkynes with and without α-H, whereas in the former the Schmittel cyclization proceeds together with 1,8-H migration, in the latter it does so as the sole primitive event. It was also observed that bulky substituents preferentially favor the C₂–C₆ Schmittel route, and the statistical prediction of regioselectivity is greatly affected when the ratio of accessible vibrational microstates of the transition states is included, especially in highly competing routes, i.e., ΔΔG^‡ → 0. Aiming to gain a deeper understanding, an analysis based on reaction force F(ξ) and reaction force constant κ(ξ) was performed to gain insights into the competing routes. The reactive normal modes were unveiled by means of the correlation between κ(ξ) and the force constant of reaction modes κ_i(ξ), given by a statistical protocol based on the partial least square with vector importance in projection (PLS-VIP) method. These findings suggest how the vibrational energy can be reorganized in competing paths from a static approach.