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

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>i.e.</i>, ΔΔ<i>G</i>^‡ → 0. Aiming to gain a deeper understanding, an analysis based on reaction force <i>F</i>(<i>ξ</i>) and reaction force constant <i>κ</i>(<i>ξ</i>) was performed to gain insights into the competing routes. The reactive normal modes were unveiled by means of the correlation between <i>κ</i>(<i>ξ</i>) and the force constant of reaction modes <i>κ</i>_<i>i</i>(<i>ξ</i>), 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.