For each molecule in the homodesmotic reaction, Auto3D 24 is used to identify the lowenergy conformer and compute the energies. Auto3D locates the low-energy conformers by enumerating conformer candidates, optimizing the ensemble and selecting those with the lowest energies. In the Auto3D configuration, the isomer engine is RDKit 31 and the optimization engine is AIMNet2 . The processes for obtaining low-energy conformer and thermodynamical properties using Auto3D are detailed in the original paper . Electronic energy, enthalpy and Gibbs free energy are the primary metrics for characterizing RSE. The workflow obtains RSE in these three different metrics simultaneously. Unless otherwise noted, the RSE in this work is reported in terms of enthalpy to be consistent with the historical experimental methods that determine RSE via heat of formation .