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Copper‐Mediated Selective Hydroxylation of a Non‐activated C−H Bond in Steroids: A DFT Study of Schönecker's Reaction
Author(s) -
Gupta Puneet,
Diefenbach Martin,
Holthausen Max C.,
Förster Moritz
Publication year - 2017
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201604829
Subject(s) - natural bond orbital , hydroxylation , chemistry , intramolecular force , density functional theory , ligand (biochemistry) , stereochemistry , selectivity , computational chemistry , organic chemistry , catalysis , receptor , biochemistry , enzyme
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.