Theoretical model for an alternate mechanism for the cytochrome P-450 hydroxylation of quadricyclane

Abstract

During the past decade the mechanism of enzymatic hydroxylation of saturated hydrocarbons has come under increased scrutiny.’ The widely accepted mechanism for the catalytic cycle for cytochrome P-450 monooxygenase hydroxylation of alkanes is thought to involve the recombination of an iron-bound hydroxyl radical with a carbon-centered free radical in a process termed “oxygen rebound”.2 Another related area of chemistry that has developed simultaneously is the use of “radical clock’ substrates to estimate the magnitude of the rate constant for the oxygen rebound step ( k o ~ ) . If alkane hydroxylation is initiated by hydrogen abstraction, then the free-radical intermediate may be hydroxylated directly (&) or it may undergo rearrangement (k,) and subsequent recombination to afford a rearranged alcohol as exemplified for the P-450 hydroxylation of bicyclo[2.1 .O]pentane (Scheme 1). Ortiz de Montellano and reported a 7:l ratio of unrearranged (4) to rearranged (5) alcohols, implying that the oxygen rebound step is about seven times faster than the ring-opening of bicyclo[2.1 .O]pent2-yl radical (2) in Scheme 1. We predict a classical activation barrier for rearrangement of 2 to cyclopenten-4-yl radical 3 of 6.8 kcdmol (AG*298 = 6.23 kcaVmol) at the PMP4 level and a rate constant at 25 “C of k, = 1.7 x lo8 s ’ . ~ A recent estimate of the rate constant for radical recombination to form unrearranged alcohol 4 is OH = 2.2 x 1O’O During the past several years the kinetic scale for these very rapid radical reactions has approached the theoretical limit for the frequency factor kTlh = Measured unimolecular rate constants for rearrangement of aryl-substituted cyclopropylcarbinyl radical of 5 x 10’’ s-’ have been r e p ~ r t e d ~ ~ . ~ requiring an estimated rebound rate constant for enzymatic hydroxylation8 with methane monooxygenase of kOH > 1OI3 SKI.