A radical clock investigation of microsomal cytochrome P-450 hydroxylation of hydrocarbons. Rate of oxygen rebound

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DOIResolve DOI: http://doi.org/10.1021/ja00015a025
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TypeArticle
Journal titleJournal of the American Chemical Society
ISSN0002-7863
Volume113
Issue15
Pages56995707; # of pages: 9
AbstractA number of alkyl-substituted cyclopropanes for which the rates of ring opening of the corresponding cyclopropylcarbinyl radicals have been determined (see preceding paper in this issue) have been used as substrates for hydroxylation by phenobarbital-induced, rat liver microsomal cytochrome P-450 at 37 °C. Three of these compounds gave both ring-closed and ring-opened alcohols, thus allowing the rate constant, kOH, for "oxygen rebound" onto the corresponding carbon-centered radicals to be determined. In particular, both trans- (1bH) and cis- (1cH) 1,2-dimethylcyclopropane gave 4-penten-2-ol (2bOH) and 2-methyl-3-buten-1-ol (3bOH) together with the corresponding trans- (1bOH) or cis- (1cOH) 2-methylcyclopropanemethanols. Of much greater importance, for both 1bH and 1cH the ratios of the yields of the secondary-to-primary ring-opened alcohols, i.e., [2bOH]/[3bOH], were the same, within experimental error as the ratio of the rates of ring opening of the corresponding trans- (1b•) and cis- (1c•) methylcyclopropylmethyl radicals in solution at 37 °C. This indicates that when 1b• and 1c• are formed from their parent hydrocarbons by H-atom abstraction in the hydrophobic pocket of cytochrome P-450 they are not detectably constrained in their subsequent reactions by their unusual environment. From the ratio of the yields of the unrearranged alcohol to each of the rearranged alcohols we calculate kOH values of 1.5 and 1.6 × 1010 s-1 for 1bH as substrate and values of 1.9 and 1.8 × 1010 s-1 for 1cH as substrate. Consistent with these values we have obtained kOH = 2.2 × 1010 s-1 for bicyclo[2.1.0]pentane as substrate. Substrates such as methylcyclopropane and 1,1-dimethylcyclopropane, for which the corresponding cyclopropylmethyl radicals undergo relatively slow ring opening, yielded only the ring-closed alcohols on oxidation with cytochrome P-450. 1,1,2,2-Tetramethylcyclopropane gave only a trace of a ring-opened alcohol, corresponding to kOH = 2.5 × 1011 s-1 for this substrate. Hexamethylcyclopropane gave no detectable ring-opened alcohol from which observation a limit for kOH > 5 × 1011 s-1 can be calculated. Possible explanations for the unexpected behavior of these last two, relatively bulky, substrates are discussed.
Publication date
LanguageEnglish
AffiliationNational Research Council Canada (NRC-CNRC)
Peer reviewedYes
NPARC number21276458
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Record identifier2cae26e8-4564-46ba-bf70-529a5b226fc0
Record created2015-10-13
Record modified2016-05-09
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