To compute the energy barrier an adiabatic scan is performed (using ORCA) for the breaking CC bond, which is constrained to 12 values out to 3.5 Å starting from the DHA structure with the lowest energy. When screening all 230 billion molecules the highest energy structure and energy is used as an estimate for the transition state. However, for the single and double substituted case the highest energy structure is used as starting point for a transition state (TS) search using PM3 in Gaussian09 while computing the Hessian in each step. For the molecules where the TS search converged it is verified that the normal mode associated with the imaginary frequency lies along the reacting CC-bond. The low energy VHF GFN2-xTB conformer is reoptimized using PM3, and the PM3 barrier is computed. This TS connects DHA with with s-cis-VHF while the lowest energy VHF conformer is usually s-trans-VHF, so the implicit assumption is that s-cis-VHF and s-trans-VHF are in thermal equilibrium, i.e. that the barrier between the two VHF conformations is lower than the barrier between s-cis-VHF and DHA (Figure ).