title: Aromatic hydroxylation by cytochrome P450: model calculations of mechanism and substituent effects.
abstract: 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 sigma parameters.
authors.affiliation: School of Chemistry, University of Bristol, Cantock's Close, Bristol BS8 1TS, UK.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Bathelt
authors.forename: Lars
authors.initials: L
authors.lastname: Ridder
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Mulholland
authors.forename: Jeremy N
authors.initials: JN
authors.lastname: Harvey
mesh_terms: D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry* / Q000378:metabolism*; D006841:Hydrocarbons, Aromatic / Q000737:chemistry* / Q000378:metabolism*; D006900:Hydroxylation; D008958:Models, Molecular; D013816:Thermodynamics
chemical_list: D006841:Hydrocarbons, Aromatic; D003577:Cytochrome P-450 Enzyme System