This proposal is directed towards the elucidation of chemical mechanisms of NADPH/02-supported cytochrome P-450-catalyzed oxidations. The key feature of the approach is that the oxygenation of a small number of carefully chosen mo compounds will be subjected to thorough scrutiny by means of combinations of physical organic probes of reaction mechanism. Reactions to be studied include benzylic hydroxylation of toluenes and ethylbenzenes, O-dealkylation of p-Nitrophenetole, and epoxidation of styrenes, 1, 7-octadiene, and related acetylenes. The probes to be utilized include kinetic deuterium isotope effects, substituent effects, stereospecificity, stereoselectivity, and deuterium shifts; they will be employed in both inter - and intramolecular experimental designs to probe both the product-forming step as well as its relationship to overall turnover. Through the unique approach of simultaneous use of combinations of these probes we will attain much greater definition than heretofore possible of changes in bonding, geometry, hybridization, and electrol distribution experienced by this sustrate as it undergoes oxygenation. In several instances these criteria will also be used to compare P-450-catalyzed oxygenations supported by aryl-iodoso compounds to these supported by NADPH/02. The information learned in this study will greatly improve our understanding of the mechanisms of substrate oxygenation, of the nature of the enzymic oxidant itself, and by inference the mechanism of the oxygen activation process.
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