Description:
<jats:title>Abstract</jats:title><jats:p>The regio‐ and stereoselective copper‐mediated hydroxylation of a non‐activated aliphatic C−H bond in steroids by dioxygen, initially reported by Schönecker et al. (<jats:italic>Angew. Chem. Int. Ed</jats:italic>. <jats:bold>2003</jats:bold>, <jats:italic>42</jats:italic>, 3240–3244), has recently evolved into a valuable synthetic tool. In the present work, a detailed mechanistic density functional theory (DFT) study addressing the origin of the remarkable selectivity of Schönecker's reaction is reported. The applied BLYP‐D3/def2‐TZVP(SDD) level of DFT is benchmarked against experimental and coupled‐cluster reference data. The resulting mechanistic scenario involves formation of a bis‐μ‐oxo dicopper complex as key intermediate. In this complex three C−H bonds of the pendant steroid ligand are predisposed towards intramolecular activation by the bis‐μ‐oxo dicopper core. The lowest activation barrier (12.0 kcal mol<jats:sup>−1</jats:sup>) is computed for β‐hydroxylation at the C12 position, in agreement with the experimental observations. Natural bond orbital (NBO) analysis reveals stabilizing orbital interactions that favor the β‐hydroxylation pathway over competing reaction channels.</jats:p>