Quantum-Chemical Elucidation of the Mechanism of the NIH-Shift during Aryl Hydroxylation Catalyzed by Cytochrome P-450

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The ring substituent dependence in the NIH-shift (the migration of a hydrogen atom during aryl hydroxylation catalyzed by cytochrome P-450) was investigated by semi-empirical molecular orbital calculations. The lowest energy path, the intrinsic reaction coordinate, was found on the 3N-6 dimensional potential energy hypersurface of the protonated arene oxide ring opening (aniline and acetanilide were selected as substrates of class I, and benzene and anisole as substrates of class II). The conclusions are as follows : a) The NIH-shift occurs by a simple and common mechanism regardless of class I or class II categorization; i.e., the Meisenheimer-type intermediate having a para-quinoid structure spontaneously produced from the protonated arene oxide passes over the saddle point of hydrogen migration to an adjacent position of the aromatic ring. b) The theoretically obtained reaction rate constants reproduce quantitatively the experimental data on the retention of deuterium, on the assumption that the deuterium retention is determined by the rate constant reflecting the potential energy barrier height from the Meisenheimer-type tetrahedral intermediate to the final product. This result may suggest that the P-450-catalyzed 4-hydroxylation of aromatics involves a tetrahedral intermediate as the first product with the absence of epoxide formation.
公益社団法人日本薬学会の論文
1986-11-25