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