Aggregation Dynamics Of Lithium Diisopropylamide And Their Mechanistic Influence On Reactivity

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Lithium diisopropylamide (LDA) is the premier base in organic chemistry ever since its development in 1950 by Hammel and Levine. In a comprehensive survey of reagents in approximately 500 natural product syntheses, LDA emerged at the top attesting to its wide range of synthetic applications and efficacy. Significant efforts to the understanding of its complex coordination chemistry and affiliated mode of reactivity has led to a review by Collum that painted a seemingly coherent and general picture of LDA-mediated reactions. This mechanistic view, however, was gleaned under conditions in which LDA aggregate equilibria proceeded very quickly compared to the rate of the reaction. The kinetics of LDA aggregation, therefore, were inconsequential and hidden to the investigator. While shifting the focus to more reactive substrates that required a reduction in temperature to -78 °C to maintain convenient time scales for monitoring reaction rates, something odd happened. Instead of conventional first-order substrate decays that had been observed for almost twenty years, we began to observe nonstandard curvatures with evidence of substrate-independent rates, autocatalysis and lithium salt catalysis. The mechanistic intricacy was eventually traced to one common culprit: the rate of LDA aggregation at -78 °C in tetrahydrofuran (THF) had become rate-limiting with the rate of substrate reaction now being post-rate-limiting. The work described herein presents three experimental accounts that peer into the mechanism of three LDA-aggregation limited reactions: LDA-mediated ortholithiations of fluoroand trifluoromethyl arenes and the 1,4-addition to unsaturated esters. Although the studies are internally consistent, a chaotic mechanistic picture emerged that appeared to lack coherency. A theoretical treatise of LDA aggregation concludes this work in an attempt to comprehend the source of this complexity and garner a more general understanding. Dozens of reactive forms of LDA emerged as part of a potential energy surface that began to explain our experimental findings. Despite significant advances, we have only scratched the surface of the mechanistic diversity of LDA aggregation. The kinetic tools and knowledge, however, are now in place to peer ever deeper into this mechanistic extravaganza.

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lda; Aggregation; Kinetics


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Union Local


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Collum, David B

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Chen, Peng
Coates, Geoffrey

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Chemistry and Chemical Biology

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Ph. D., Chemistry and Chemical Biology

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Doctor of Philosophy

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dissertation or thesis

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