The triplet and open-shell singlet are essentially degenerate for the reaction 3a HIP --→ 4a: the open-shell singlet state is always lower in energy than the triplet in the QM/MM calculations, while the triplet is in most cases lower in the big-QM calculations. The spin density of the intermediates 3a HIP , 4a and 4b is highly delocalized over the QM region (see Table ). In contrast, the spin density of the corresponding reduced intermediates 3a red HIP , 4a red and 4f red (see Table ) is only localized on Cu (0.6), the Energies were calculated with B3LYP/def2-TZVPP and energies in italics were calculated with B3LYP/def2-SV(P) using the big-QM approach. All energies are reported in kJ/mol relative to 3a HIP in the open-shell singlet state for B3LYP/def2-TZVPP and the triplet state for the big-QM approach. Fig. Reaction 3 red HIP ---→ 4 red . Structures were optimized with TPSS/def2-SV(P). Distances are reported in Å and are omitted if they remain constant. Energies were calculated with B3LYP/def2-TZVPP and energies in italics were calculated with B3LYP/def2-SV(P) using the big-QM approach. All energies are reported in kJ/mol relative to 3 red HIP .