A Predictive Model Towards Site‐Selective Metalations of Functionalized Heterocycles, Arenes, Olefins, and Alkanes using TMPZnCl⋅LiCl
Moritz Balkenhohl, Harish Jangra, Ilya S. Makarov, Shumei Yang, Hendrik Zipse, Paul Knochel
Abstract
Abstract The development of a predictive model towards site‐selective deprotometalation reactions using TMPZnCl⋅LiCl is reported (TMP=2,2,6,6‐tetramethylpiperidinyl). The p K a values of functionalized N ‐, S ‐, and O ‐heterocycles, arenes, alkenes, or alkanes were calculated and compared to the experimental deprotonation sites. Large overlap (>80 %) between the calculated and empirical deprotonation sites was observed, showing that thermodynamic factors strongly govern the metalation regioselectivity. In the case of olefins, calculated frozen state energies of the deprotonated substrates allowed a more accurate prediction. Additionally, various new N ‐heterocycles were analyzed and the metalation regioselectivities rationalized using the predictive model.