A quantitative approach to polar organic reactivity

^$Presented at the 8^th International Symposium on Computational Methods in Toxicology and Pharmacology Integrating Internet Resources, CMTPI-2015, June 21–25, 2015, Chios, Greece.

Abstract

A method is presented which allows one to predict toxic effects which are triggered by the formation of covalent bonds between electron-deficient (electrophilic) compounds and biological electron-rich (nucleophilic) targets, as proteins or nucleic acids. It is based on our comprehensive nucleophilicity and electrophilicity scales, which we constructed as an aid for the planning of organic syntheses. For the construction of these scales, rate constants for the reactions of benzhydrylium ions (aryl₂CH⁺) and structurally related quinone methides with nucleophiles have been measured and correlated by the equation lg k(20 °C) = s_N(E + N), which yields absolute rate constants k (L mol^–1 s^–1) from one parameter for electrophiles (the electrophilicity E) and two for nucleophiles (the nucleophilicity parameter N and the susceptibility s_N). A freely accessible database (http://www.cup.uni-muenchen.de/oc/mayr/DBintro.html) is described, which presently comprises data for 1000 nucleophiles and 260 electrophiles and provides links to the original literature reports. The kinetic scales are complemented by a thermodynamic counterpart, which enables one to calculate association constants K (L mol^–1) of electrophiles with nucleophiles from the empirical Lewis acidity parameters LA and Lewis basicity parameters LB by the equation lg K (20°C) = LA + LB.

Keywords:

• electrophilicity
• kinetics
• Lewis acidity
• Lewis basicity
• linear free energy relationships
• thermodynamics

Acknowledgements

This work was supported by the Deutsche Forschungsgemeinschaft (SFB 749, project B1).

Disclosure statement

No potential conflict of interest was reported by the authors.

Notes

^$ Presented at the 8^th International Symposium on Computational Methods in Toxicology and Pharmacology Integrating Internet Resources, CMTPI-2015, June 21–25, 2015, Chios, Greece.

1. In an updated correlation [65], this value was changed to s_N = 1.06.

2. Actually, the full correlation was only carried out for the benzhydrylium ions [35], and the quinone methides were integrated later [36].

3. Classification of the electrophiles and nucleophiles: 5 stars (reference electrophile/nucleophile); 4 stars (quasi-reference electrophile/nucleophile); 3 stars (three or more reference electrophiles/nucleophiles have been used for the determination of the reactivity parameters); 2 stars (only two reference electrophiles/nucleophiles have been used for the determination of the reactivity parameter E or N and reasonable s_N); 1 star (only one reference electrophile/nucleophile has been used for the determination of the reactivity parameter E or N, s_N was estimated); if a blue star is displayed, please see the ‘comments’ entries.