A Predictive Model Towards Site‐Selective Metalations of Functionalized Heterocycles, Arenes, Olefins, and Alkanes using TMPZnCl⋅LiCl

Abstract

The development of a predictive model towards site‐selective deprotometalation reactions using TMPZnCl⋅LiCl is reported (TMP=2,2,6,6‐tetramethylpiperidinyl). The pKa 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.

Zinc-Mediated C–H Metalations in Modern Organic Synthesis

“…Moreover, the group has developed a computational model to predict site-selective deprotonation reactions using 3 . 16 The model was based on the assumption that for the neutral base, thermodynamic effects outweigh the kinetic effects, therefore the metalation will happen at the most acidic site and not at the site that would result from coordination of the base counterion to a Lewis basic direct metalation group in order to form an adduct. Calculations of p K a values of various functionalised aromatic and aliphatic compounds were carried out and, as predicted, in over 80% cases, the experimental data matched the model.…”