title: Copper-Mediated Selective Hydroxylation of a Non-activated C-H Bond in Steroids: A DFT Study of Schönecker's Reaction.
abstract: 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. (Angew. Chem. Int. Ed. 2003, 42, 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-1) 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.
authors.affiliation: Institut für Anorganische und Analytische Chemie, Johann Wolfgang Goethe-Universität Frankfurt, Max-von-Laue-Straße 7, 60438, Frankfurt am Main, Germany.|Present address: Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1, 45470, Mülheim an der Ruhr, Germany.
authors.forename: Puneet
authors.initials: P
authors.lastname: Gupta
authors.affiliation: Institut für Anorganische und Analytische Chemie, Johann Wolfgang Goethe-Universität Frankfurt, Max-von-Laue-Straße 7, 60438, Frankfurt am Main, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Diefenbach
authors.affiliation: Institut für Anorganische und Analytische Chemie, Johann Wolfgang Goethe-Universität Frankfurt, Max-von-Laue-Straße 7, 60438, Frankfurt am Main, Germany.
authors.forename: Max C
authors.identifier: http://orcid.org/0000-0001-7283-8329
authors.initials: MC
authors.lastname: Holthausen
authors.affiliation: Institut für Anorganische und Analytische Chemie, Johann Wolfgang Goethe-Universität Frankfurt, Max-von-Laue-Straße 7, 60438, Frankfurt am Main, Germany.
authors.forename: Moritz
authors.initials: M
authors.lastname: Förster
mesh_terms: D002244:Carbon / Q000737:chemistry; D002384:Catalysis; D056831:Coordination Complexes / Q000737:chemistry; D003300:Copper / Q000737:chemistry*; D006859:Hydrogen / Q000737:chemistry; D006900:Hydroxylation; D008968:Molecular Conformation; D010100:Oxygen / Q000737:chemistry; D013237:Stereoisomerism; D013256:Steroids / Q000737:chemistry*; D013816:Thermodynamics
chemical_list: D056831:Coordination Complexes; D013256:Steroids; D002244:Carbon; D003300:Copper; D006859:Hydrogen; D010100:Oxygen
keywords: copper; density functional calculations; hydroxylation; reaction mechanisms; steroids