Blackmond, Donna - The Scripps Research Institute

研究领域

Kinetic Methodology. Blackmond has pioneered the development of Reaction Progress Kinetic Analysis (RPKA), a methodology combining highly accurate in-situ data collection with a rigorous mathematical analysis that permits rapid determination of concentration dependences of reactants. In contrast to the classical role of kinetics, in which measurements of concentration dependences most often are asked simply to corroborate a previously proposed mechanism, the Blackmond group’s approach is to employ kinetic studies at the outset of an investigation of ill-defined reaction network to suggest reaction mechanisms. This “kinetic-assisted mechanistic analysis” aids in the design of further supporting experiments including conventional mechanistic tools such as studies of isotope effects and spectroscopic studies for structural and compositional information. One of the most powerful aspects of the methodology is its ability to deconvolute rate processes occurring on the catalytic cycle from those occurring off the cycle. Prominent examples of the application of this methodology to quantitative understanding of complex organic reactions and reaction networks include asymmetric hydrogenation, asymmetric organocatalytic reactions, Pd-catalyzed C-C and C-N bond forming reactions, and transition-metal catalyzed competitive reactions including kinetic resolutions. Reaction Progress Kinetic Analysis finds important application in the pharmaceutical industry, where streamlining process R&D based on Blackmond’s kinetic analysis is becoming an industry-wide standard. Nonlinear effects of catalyst enantiopurity. Experimental and theoretical studies in the Blackmond group have derived relationships between catalyst ee and reaction rate that complement the standard tool of studying product ee as a function of catalyst ee. Prof. Blackmond’s work provides a means of testing proposed models for nonlinear effects and expands the power of studies of nonlinear effects to serve as a meaningful mechanistic probe. The concepts developed in this work led Prof. Blackmond to consideration of what has been termed the “ultimate nonlinear effect”, that of the origin of biological homochirality. She carried out the first kinetic studies and developed the first kinetic model exploring the mechanism of asymmetric amplification in the Soai autocatalytic reaction. She continues investigations of this reaction, with current projects focusing on determining the nature of the transition state species in this reaction as well as probing spatiotemporal aspects of absolute asymmetric synthesis by carrying out autocatalysis in well-defined microfluidic reactor networks. Biological homochirality and amino acid phase behavior. More recently Prof. Blackmond has expanded the range of models to rationalize the origin of biological homochirality from proposals based purely on chemical reactions to those based on physical phase behavior of chiral molecules as well as a combination of chemical and physical processes. She has demonstrated that highly enantioenriched solutions of amino acids can be produced from nearly racemic mixtures via solution-solid partitioning of the enantiomers. Reactions catalyzed by amino acids that are carried out in such systems show nonlinear product ee consistent with this highly enantioenriched solution composition. This concept was then greatly expanded in scope with the discovery that eutetic compositions could be “tuned” by judicious choice of additives that alter crystal structure and solubility. In sharp contrast to autocatalytic reaction models, which invoke “far-from-equilibrium” behavior, this eutectic model is a pure equilibrium treatment. This distinction has important implications for scenarios concerning the time course over which the evolution of homochirality may have developed. Probing the phase behavior of amino acids in conjunction with solution racemization led to separate work showing how one hand of a chiral solid could be transformed completely into its enantiomorph from a nearly racemic mixture of the two. Because interconversion in solution allows an enantiomer that had been part of an L crystal to become part of a D crystal, this has been dubbed the “chiral amnesia” process.

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“Radical-Based Regioselective C?H Functionalization of Electron-Deficient Heteroarenes: Scope, Tunability, and Predictability” J. Am. Chem. Soc., 2013, ASAP (with F. O’Hara and P.S. Baran). “The Interplay of Thermodynamics and Kinetics in Dictating Organocatalytic Reactivity and Selectivity” Pure and App. Chem., 2013, ASAP, http://dx.doi.org/10.1351/PAC-CON-13-01-14 (with J. Burès and A. Armstrong). “In-Situ Kinetic Studies of the Trifluoromethylation of Caffeine with Zn(SO2CF3)2” Tetrahedron, 2013, 69, 5604-5608 (with R.D. Baxter). Special issue honoring Melanie Sanford “Chemical and Physical Models for the Origin of Biological Homochirality” Top. Curr. Chem., 2013, 333, 83-108 (with J.E. Hein and D. Gherase). “Pasteur’s Tweezers Revisited: On the Mechanism of Attrition-Enhanced Deracemization and Resolution of Chiral Conglomerate Solids" J. Am. Chem. Soc., 2012, 134, 12629-12636 (with J.E. Hein, B.H. Cao, C. Viedma, and R.M. Kellogg). “Observation of a Transient Intermediate in Soai’s Asymmetric Autocatalysis: Insights from 1H NMR Turnover in Real Time” Angew. Chemie Int. Ed., 2012, 51, 9539-9542 (with T. Gehring, M. Quaranta, B. Odell, and J.M. Brown). “Curtin–Hammett Paradigm for Stereocontrol in Organocatalysis by Diarylprolinol Ether Catalysts” J. Am. Chem. Soc., 2012, 134, 6741-6750 (with J. Burès and A. Armstrong). “Mechanistic Rationalization of Unusual Kinetics in Pd-Catalyzed C–H Olefination” J. Am. Chem. Soc., 2012, 134, 4600-4606 (with R.D. Baxter, K. Engle, and J.-Q. Yu). “On the Origin of Single Chirality of Amino Acids and Sugars in Biogenesis” Acc. Chem. Res., 2012, 45, 2045-2054 (with J.E. Hein). Special issue on Origins of Chemical Evolution, invited review “A New Reagent for Direct Difluoromethylation" J. Am. Chem. Soc., 2012, 134, 1494-1497 (with Y. Fujiwara, J. Dixon, R. Rodriguez, R.D. Baxter, D. Dixon, M. Collins, and P.S. Baran). “Kinetic Correlation Between Aldehyde/Enamine Stereoisomers in Reactions Between Aldehydes With α-Stereocenters and Chiral Pyrrolidine-Based Catalysts” Chemical Sci., 2012, 3, 1273-1277 (with J. Burès and A. Armstrong). “Enamine Carboxylates as Stereodefining Intermediates in Prolinate Catalysis” Org. Lett., 2011, 13, 5644-5647 (with J.E. Hein, J. Burès, M. Hughes, Y.-H. Lam, K.N. Houk, and A. Armstrong). “A Route to Enantiopure RNA from Nearly Racemic Precursors” Nature Chemistry, 2011, 3, 704-706 (with J.E. Hein and E. Tse). “Kinetic Profiling of Prolinate-Catalyzed α-Amination of Aldehydes” Org. Lett., 2011, 13, 4300-4303 (with J.E. Hein and A. Armstrong). "Innate C-H Trifluoromethylation of Heterocycles" PNAS, 2011, 108, 14411-14415 (with Y.N. Chen, T. Bruekl, R.D. Baxter, Y. Fujiwara, I.B. Seiple, S. Su, and P.S. Baran). “Mechanistic Rationalization of Organocatalyzed Conjugate Addition of Linear Aldehydes to Nitro-Olefins” J. Am. Chem. Soc., 2011, 133, 8822-8825 (with J. Burès and A. Armstrong). “The Origin of Biological Homochirality” Royal Society Philosophical Trans. B, 2011, 366, 2878-2884 (sole author). Special issue from RS Symposium “The Chemical Origins of Life” “Reservoir Catalysis: Rationalization of Anomalous Reaction Orders in Pd-Catalyzed Amination of Aryl Halides” Inorganica Chim. Acta, 2011, 369, 292-295 (with A. Ferretti and C. Brennan). Invited special issue honoring Robert G. Bergman “Unusual Inverse Temperature Dependence on Reaction Rate in the Asymmetric Autocatalytic Alkylation of Pyrimidyl Aldehydes” J. Am. Chem. Soc., 2010, 132, 15104-15107 (with M. Quaranta, T. Gehring, B. Odell, and J.M. Brown) “Unusual Reversal of Enantioselectivity in the Proline-Mediated α-Amination of Aldehydes Induced by Tertiary Amine Additives” J. Am.Chem. Soc., 2010 132, 7598-7599 (with A. Moran, M. Hughes, and A. Armstrong).