The conventional framework for understanding reactivity and selectivity in organic reactions fails for reactions influenced by dynamic effects. It is proposed to investigate the role of dynamic effects in some of the most common and important reactions in chemistry. In hydroboration, initially published results have called into question all of the standard ideas used to explain selectivity in these reaction;the proposed studies would use isotope effects and selectivity studies to determine the breadth of importance of dynamic effects in these reactions, and would explore ways to improve selectivity based on the its understanding as a dynamic phenomenon. In [2,3]-sigmatropic rearrangements, initial results suggest that dynamics can provide a unified explanation for competing [2,3] and [1,2] rearrangements, and the proposed mechanistic studies would a broad reinterpretation of these reactions. In Diels-Alder reactions and the [2 + 2] cycloadditions of ketenes, recent studies have found that the Newtonian ideas of inertia and mass-dependent acceleration can be the real deciding factor in selectivity. The proposed studies would examine ways to recognize these effects and how broadly they affect reactions. In ozonolysis, initial results have found that the intermediate primary ozonide is unique "hot" in only part of the molecule, and the planned studies would examine how structural effects on energy motion through molecules affects product ratios. Finally, experimental results have implicated that a dynamic effect, previously considered only for triatomic reactions, broadly facilitates the general acid-base catalyzed reactions of organic and enzymatic chemistry. Experiments are proposed to define in particular examples the role of the effect in catalysis. The health-relatedness of this work derives from its impact on the understanding of reactions important in the synthesis of medicinally important substances and reactions important in biological pathways.

Public Health Relevance

The synthesis of pharmaceuticals and the manipulation of biological pathways depend on the rational design and control of chemical reactions, which in turn depend on the understanding of chemical reactions. Our research is providing fundamental news ways to understand reactions that should aid in their invention, development, and regulation.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Synthetic and Biological Chemistry A Study Section (SBCA)
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Lees, Robert G
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Texas A&M University
Schools of Arts and Sciences
College Station
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Bogle, Xavier S; Singleton, Daniel A (2012) Dynamic origin of the stereoselectivity of a nucleophilic substitution reaction. Org Lett 14:2528-31
Quijano, Larisa Mae M; Singleton, Daniel A (2011) Competition between reaction and intramolecular energy redistribution in solution: observation and nature of nonstatistical dynamics in the ozonolysis of vinyl ethers. J Am Chem Soc 133:13824-7
Hirschi, Jennifer S; Takeya, Tetsuya; Hang, Chao et al. (2009) Transition-state geometry measurements from (13)c isotope effects. The experimental transition state for the epoxidation of alkenes with oxaziridines. J Am Chem Soc 131:2397-403
Oyola, Yatsandra; Singleton, Daniel A (2009) Dynamics and the failure of transition state theory in alkene hydroboration. J Am Chem Soc 131:3130-1
Wang, Zhihong; Hirschi, Jennifer S; Singleton, Daniel A (2009) Recrossing and dynamic matching effects on selectivity in a Diels-Alder reaction. Angew Chem Int Ed Engl 48:9156-9
Kelly, Kelmara K; Hirschi, Jennifer S; Singleton, Daniel A (2009) Newtonian kinetic isotope effects. Observation, prediction, and origin of heavy-atom dynamic isotope effects. J Am Chem Soc 131:8382-3
Ralph, Erik C; Hirschi, Jennifer S; Anderson, Mark A et al. (2007) Insights into the mechanism of flavoprotein-catalyzed amine oxidation from nitrogen isotope effects on the reaction of N-methyltryptophan oxidase. Biochemistry 46:7655-64
Christian, Chad F; Takeya, Tetsuya; Szymanski, Michael J et al. (2007) Isotope effects and the mechanism of epoxidation of cyclohexenone with tert-butyl hydroperoxide. J Org Chem 72:6183-9
Soloshonok, Vadim A; Ueki, Hisanori; Yasumoto, Manabu et al. (2007) Phenomenon of optical self-purification of chiral non-racemic compounds. J Am Chem Soc 129:12112-3
Ussing, Bryson R; Hang, Chao; Singleton, Daniel A (2006) Dynamic effects on the periselectivity, rate, isotope effects, and mechanism of cycloadditions of ketenes with cyclopentadiene. J Am Chem Soc 128:7594-607

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