Ground state reactant and transition state geometries for dimethyl malonate Michael addition reactions were built using Schrödinger’s R-Group Enumeration. R-groups were placed on various different positions of the Michael acceptor. Once generated, structures were conformationally searched using Schrödinger’s MacroModel (version 12.7) with OPLS3e. The lowest energy conformation for every structure was subsequently optimised using Gaussian16 (Revisions A.03 and C.01) using AM1 (IEFPCM=Water)//AM1 and wB97X-D/def2-TZVP (IEFPCM=Water)//wB97X-D/def2-TZVP.
For distortion/interaction-activation strain calculations, python code (available on the associated GitHub page: https://github.com/the-grayson-group/distortion-interaction_ML) was used to separate the distorted reactant structures before single point energies were calculated using Gaussian16 (Revision C.01) using AM1 and the DFT level of theory used in the original transition structure calculation and in solvent.