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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Kurouchi, Hiroaki; Singleton, Daniel A (2018) Labelling and determination of the energy in reactive intermediates in solution enabled by energy-dependent reaction selectivity. Nat Chem 10:237-241
Bailey, Johnathan O; Singleton, Daniel A (2017) Failure and Redemption of Statistical and Nonstatistical Rate Theories in the Hydroboration of Alkenes. J Am Chem Soc 139:15710-15723
Issaian, Adena; Faizi, Darius J; Bailey, Johnathan O et al. (2017) Mechanistic Studies of Formal Thioboration Reactions of Alkynes. J Org Chem 82:8165-8178
Aziz, Hannah R; Singleton, Daniel A (2017) Concert along the Edge: Dynamics and the Nature of the Border between General and Specific Acid-Base Catalysis. J Am Chem Soc 139:5965-5972
Kurouchi, Hiroaki; Andujar-De Sanctis, Ivonne L; Singleton, Daniel A (2016) Controlling Selectivity by Controlling Energy Partitioning in a Thermal Reaction in Solution. J Am Chem Soc 138:14534-14537
Patel, Ashay; Chen, Zhuo; Yang, Zhongyue et al. (2016) Dynamically Complex [6+4] and [4+2] Cycloadditions in the Biosynthesis of Spinosyn A. J Am Chem Soc 138:3631-4
Nieves-Quinones, Yexenia; Singleton, Daniel A (2016) Dynamics and the Regiochemistry of Nitration of Toluene. J Am Chem Soc 138:15167-15176
Biswas, Bibaswan; Singleton, Daniel A (2015) Controlling Selectivity by Controlling the Path of Trajectories. J Am Chem Soc 137:14244-7
Plata, R Erik; Singleton, Daniel A (2015) A case study of the mechanism of alcohol-mediated Morita Baylis-Hillman reactions. The importance of experimental observations. J Am Chem Soc 137:3811-26
Andujar-De Sanctis, Ivonne L; Singleton, Daniel A (2012) Racing carbon atoms. Atomic motion reaction coordinates and structural effects on Newtonian kinetic isotope effects. Org Lett 14:5238-41

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