Aromatic Hydroxylation by Cytochrome P450:  Model Calculations of Mechanism and Substituent Effects

Christine M. Bathelt, Lars Ridder,† Adrian J. Mulholland, and Jeremy N. Harvey*
School of Chemistry, University of Bristol, Cantock's Close, Bristol BS8 1TS, UK
J. Am. Chem. Soc., 2003, 125 (49), pp 15004–15005
DOI: 10.1021/ja035590q
Publication Date (Web): November 15, 2003
Copyright © 2003 American Chemical Society
†

 Current address:  Molecular Design & Informatics, N.V. Organon, P.O. Box 20, 5430 Oss, The Netherlands.

,
*

In papers with more than one author, the asterisk indicates the name of the author to whom inquiries about the paper should be addressed.

, jeremy.harvey@bris.ac.uk

Abstract

Abstract Image

The mechanism and selectivity of aromatic hydroxylation by cytochrome P450 enzymes is explored using new B3LYP density functional theory computations. The calculations, using a realistic porphyrin model system, show that rate-determining addition of compound I to an aromatic carbon atom proceeds via a transition state with partial radical and cationic character. Reactivity is shown to depend strongly on ring substituents, with both electron-withdrawing and -donating groups strongly decreasing the addition barrier in the para position, and it is shown that the calculated barrier heights can be reproduced by a new dual-parameter equation based on radical and cationic Hammett σ parameters.

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History

  • Published In Issue December 10, 2003
  • Received April 11, 2003

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