Transforming Predictions into Testable Hypotheses: The Case of Polar Organic Reactivity

Abstract

<p>Herbert Mayr’s research on reactivity scales tells a success story of how polar organic synthesis can be rationalized by a simple empirical relationship. In this work, we propose an extension to Mayr’s reactivity approach that is rooted in uncertainty quantification (UQ). It transforms the <i>unique</i> values of reactivity parameters (<i>s</i><sub>N</sub>, <i>N</i>, <i>E</i>) into value <i>distributions</i>. Through uncertainty propagation, these distributions can be exploited to quantify the uncertainty of bimolecular rate constants. Our UQ-based extension serves three purposes. First, predictions of polar organic reactivity can be transformed into testable hypotheses, which increases the overall reliability of the method and guides the exploration of new research directions. Second, it is also possible to quantify the discriminability of two competing reactions, which is particularly important if subtle reactivity differences matter. Third, since rate constant uncertainty can also be quantified for reactions that have yet to be observed, new opportunities arise for benchmarking computational chemistry methods (benchmarking <i>under uncertainty</i>). We demonstrate the functionality and performance of the UQ-extended reactivity approach at the example of the 2001/12 reference data set released by Mayr and co-workers [<i>J. Am. Chem. Soc.</i> <b>2001</b>, <i>123</i>, 9500; <i>J. Am. Chem. Soc.</i> <b>2012</b>, <i>134</i>, 13902]. As a by-product of the new approach, we obtain revised reactivity parameters for the electrophiles and the nucleophiles of the reference set.</p>