rxn is approximated as the difference in electronic energy (∆E rxn ) computed using GFN2-xTB while ∆G •, ‡ is approximated as the difference in heat of formation (∆∆H ‡ f ) computed using PM3 (collectively referred to as "SQM"). GFN2-xTB is chosen due to its computational efficiency, while PM3 is chosen because it is available in both ORCA 4.0 and Gaussian09 (see below). For each DHA structure the VHF structure is automatically generated using RDKit. 5 + 5n rot random conformations (where n rot is the number of rotateable bonds in the molecule) are generated using RD-Kit and optimized using GFN2-xTB. Optimizations that result in discrepancies between the input and output connectivity are discarded. The lowest energy conformers of DHA and VHF are used to compute ∆E rxn . In some cases the conformational search is done systematically (see next subsection) at the SQM as described below.