The central focus of the Singleton research group is the study of organic, organometallic, and bioorganic reaction mechanisms, and the key tool that we use in these studies is the determination o kinetic isotope effects (KIEs). In the mid-1990's, we developed a method for the high precision combinatorial determination of small KIEs at natural abundance by NMR. Its direct applicability to complex unlabeled reactants makes this methodology 1-2 orders of magnitude faster than studies requiring labeling. At the same time, it is much more versatile - our technique can look at a great number of reactions that would have been impractical or impossible to study by labeling or mass spectral methods, and the choice of reactants can be readily changed in response to each new experimental result. The simultaneous determination of a complete set of 13C, 2H, and 17O isotope effects possible with our methodology provides a much greater level of information than available from conventional methods. In addition, substantial evidence has accumulated supporting the reliable accuracy of our results.
A related advance has been theoretical - the discovery that excellent predictions of KIEs are possible, provided that the calculated transition structure accurately reflects the mechanism. This has allowed us to use KIEs to provide an experimental basis for transition state geometry. The combination of our experimental methodology and theory has repeatedly been successfully applied to resolve controversies, to experimentally establish critical details of important reaction mechanisms, and to find new mechanisms for basic reactions.
The cutting edge in our group is the study of dynamic effects in ordinary reactions in solution. As we have studied reaction mechanisms, we have found that the conventional framework for understanding reactions using transition state theory is often not adequate, and we have found that dynamic effects? play a role in organic reactions much more often than currently thought. In studying such reactions, our goal is to revise the fundamental understanding of reactivity and selectivity in organic chemistry.
"Newtonian Kinetic Isotope Effects. Observation, Prediction, and Origin of Heavy-Atom Dynamic Isotope Effects" K. K. Kelly, J. S. Hirschi, and D. A. Singleton, J. Am. Chem. Soc. 2009, 131, 8382-8383.
"Dynamics and the Failure of Transition State Theory in Alkene Hydroboration" Y. Oyola and D. A. Singleton, J. Am. Chem. Soc. 2009, 131, 3130-3131.
"Transition State Geometry Measurements from 13C Isotope Effects. The Experimental Transition State for the Epoxidation of Alkenes with Oxaziridines" J. S. Hirschi, T. Takeya, C. Hang, and D. A. Singleton, J. Am. Chem. Soc. 2009, 131, 2397-2403.
"Control Elements in Dynamically-Determined Selectivity on a Bifurcating Surface," J. B. Thomas, J. R. Waas, M. Harmata, and D. A. Singleton, J. Am. Chem. Soc. 2008, 130, 14544-14555.
"Phenomenon of Optical Self-Purification of Chiral Non-Racemic Compounds," V. A. Soloshonok, H. Ueki, M. Yasumoto, S. Mekala, J. S. Hirschi, and D. A. Singleton, J. Am. Chem. Soc. 2007, 129, 12112-12114.
"Dynamic Effects on the Periselectivity, Rate, Isotope Effects, and Mechanism of Cycloadditions of Ketenes with Cyclopentadiene," B. R. Ussing, C. Hang, and D. A. Singleton, J. Am. Chem. Soc. 2006, 128, 7594-7607.
"'Concerted' Transition State, Stepwise Mechanism. Dynamics Effects in C2-C6 Enyne Allene Cyclizations," T. Bekele, M. A. Lipton, D. A. Singleton and C. F. Christian, J. Am. Chem. Soc. 2005, 127, 9216-9223.
"Mechanism and Origin of Enantioselectivity in the Rh2(OAc)(DPTI)3-Catalyzed Cyclopropenation of Alkynes," D. T. Nowlan III and D. A. Singleton, J. Am. Chem. Soc. 2005, 127, 6190-6191.
"Isotope Effects and the Nature of Enantioselectivity in the Shi Epoxidation. The Importance of Asynchronicity," D. A. Singleton and Z. Wang, J. Am. Chem. Soc. 2005, 127, 6679-6685.
"The Normal Range for Secondary Swain-Schaad Exponents Without Tunneling or Kinetic Complexity," J. Hirschi and D. A. Singleton, J. Am. Chem. Soc. 2005, 127, 3294-3295.
"Isotope Effects, Dynamics, and the Mechanism of Solvolysis of Aryldiazonium Cations in Water," B. R. Ussing and D. A. Singleton, J. Am. Chem. Soc. 2005, 127, 2888-2899.