Beautiful Concepts of Organic Chemistry Slayed by Ugly Experiments
Department Chemie der Ludwig-Maximilians-Universität München
Butenandtstr. 5-13, 81377 München, Germany, Herbert.Mayr@cup.uni-muenchen.de
In 1870, the great British biologist Thomas Henry Huxley described the “great tragedy of science” as the slaying of a beautiful hypothesis by an ugly experiment.1 During our work on quantifying polar organic reactivity we encountered inconsistencies with established concepts of organic chemistry. Tracing the origins of these discrepancies revealed that these principles
should never have been formulated as general rules. Three examples will be discussed
1) Reactivity selectivity principle:2 Though the failure of the principle that an increase of reactivity is generally associated with a decrease in selectivity has been demonstrated to be obsolete by several authors in the 1970s, it is still considered as a general rule with some exceptions. It will be discussed, why this principle cannot hold generally. Its application is only justified, when reactions close to the diffusion limit are considered. In activation-controlled reactions, selectivity may decrease, increase, or remain constant as reactivity
increases.
2) Leffler-Hammond’s α = δΔG≠/δΔG0 as a measure for the position of the transition state.3,4 Leffler’s suggestion that α values close to 1 correspond to late transition states, while α values close to 0 correspond to early transition states, is based on the assumption 0 < α < 1. Bordwell’s discovery of the nitroalkane anomaly, where α adopts values outside the expected range, was the first example demonstrating the limitations of Leffler’s concept. It will be
demonstrated that α is not generally suitable for determining the position of transition states.
3) Kornblum’s rule and Salem-Klopman concept of charge and orbital controlled reactions:5 The ambident reactivities of the prototype nucleophiles, thiocyanate, cyanide, nitrite, cyanate, nitronate, and phenolate anions, do not follow these rules or the related Principle of hard and soft acids and bases. Changes from kinetic to thermodynamic control, and from activation- to diffusion-limited reactivity have to be considered when interpreting ambident reactivities. Marcus theory provides a suitable approach to ambident reactivity.
Recent examples support this analysis.6
(1) T. S. Huxley, Nature 1870, 400-406.
(2) H. Mayr, A. R. Ofial, Angew. Chem. Int. Ed. Engl. 2006, 45, 1844-1854.
(3) H. Mayr, A. R. Ofial, Isr. J. Chem. 2023, 63, e202300054.
(4) H. Mayr, A. R. Ofial, Acc. Chem. Res. 2016, 49, 952-965.
(5) H. Mayr, M. Breugst, A. R. Ofial, Angew. Chem. Int. Ed. 2011, 50, 6470-6505.
(6) R. J. Mayer, M. Breugst, N. Hampel, A. R. Ofial, H. Mayr, J. Org. Chem. 2019, 84, 8837-8858