Dataset Information

Mechanistic Analysis of Oxidative C-H Cleavages Using Inter- and Intramolecular Kinetic Isotope Effects.

ABSTRACT: A series of monodeuterated benzylic and allylic ethers were subjected to oxidative carbon-hydrogen bond cleavage to determine the impact of structural variation on intramolecular kinetic isotope effects in DDQ-mediated cyclization reactions. These values are compared to the corresponding intermolecular kinetic isotope effects that were accessed through subjecting mixtures of non-deuterated and dideuterated substrates to the reaction conditions. The results indicate that carbon-hydrogen bond cleavage is rate determining and that a radical cation is most likely a key intermediate in the reaction mechanism.

SUBMITTER: Jung HH

PROVIDER: S-EPMC2904620 | biostudies-literature | 2009 Dec

REPOSITORIES: biostudies-literature

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Mechanistic Analysis of Oxidative C-H Cleavages Using Inter- and Intramolecular Kinetic Isotope Effects.

Jung Hyung Hoon HH Floreancig Paul E PE

Tetrahedron 20091201 52

A series of monodeuterated benzylic and allylic ethers were subjected to oxidative carbon-hydrogen bond cleavage to determine the impact of structural variation on intramolecular kinetic isotope effects in DDQ-mediated cyclization reactions. These values are compared to the corresponding intermolecular kinetic isotope effects that were accessed through subjecting mixtures of non-deuterated and dideuterated substrates to the reaction conditions. The results indicate that carbon-hydrogen bond clea ...[more]

PMID: 20640173

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Project description:Phosphoryl transfer reactions are ubiquitous in biology and the understanding of the mechanisms whereby these reactions are catalyzed by protein and RNA enzymes is central to reveal design principles for new therapeutics. Two of the most powerful experimental probes of chemical mechanism involve the analysis of linear free energy relations (LFERs) and the measurement of kinetic isotope effects (KIEs). These experimental data report directly on differences in bonding between the ground state and the rate-controlling transition state, which is the most critical point along the reaction free energy pathway. However, interpretation of LFER and KIE data in terms of transition-state structure and bonding optimally requires the use of theoretical models. In this work, we apply density-functional calculations to determine KIEs for a series of phosphoryl transfer reactions of direct relevance to the 2'-O-transphosphorylation that leads to cleavage of the phosphodiester backbone of RNA. We first examine a well-studied series of phosphate and phosphorothioate mono-, di- and triesters that are useful as mechanistic probes and for which KIEs have been measured. Close agreement is demonstrated between the calculated and measured KIEs, establishing the reliability of our quantum model calculations. Next, we examine a series of RNA transesterification model reactions with a wide range of leaving groups in order to provide a direct connection between observed Brønsted coefficients and KIEs with the structure and bonding in the transition state. These relations can be used for prediction or to aid in the interpretation of experimental data for similar non-enzymatic and enzymatic reactions. Finally, we apply these relations to RNA phosphoryl transfer catalyzed by ribonuclease?A, and demonstrate the reaction coordinate-KIE correlation is reasonably preserved. A prediction of the secondary deuterium KIE in this reaction is also provided. These results demonstrate the utility of building up knowledge of mechanism through the systematic study of model systems to provide insight into more complex biological systems such as phosphoryl transfer enzymes and ribozymes.

Dataset Information

Mechanistic Analysis of Oxidative C-H Cleavages Using Inter- and Intramolecular Kinetic Isotope Effects.

Publications

Mechanistic Analysis of Oxidative C-H Cleavages Using Inter- and Intramolecular Kinetic Isotope Effects.

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