Remote-controlled nucleophilicity III: A valuable model to explain and predict the observed regioselectivity of the electrophilic attack on substituted 4-methylpyridine anions

Abstract

In a comparative study, the stability of lithiated methylpyridine and the reactivity of side chain functionalized 4-methylypridines were investigated. In contrast to gas phase calculations, the observed N-coordination of the lithium to 4-methylpyridine anions is shown to be a solvent effect. Furthermore, lithiated methylpyridines are predicted to be dimeric in THF.The regioselectivity of the picoline anion alkylation was subject to an in-depth study. The activation barriers for the methylation of methylpyridine in Cα, C(3), and N position were determined and compared with partial NPA charges in an attempt to explain the observed selectivity. While there is no correlation of the charges with the selectivity, the calculated activation energies not only fit well with experimental conditions but also parallel the predominantly observed regioselectivity of alkylation at the exocyclic carbon atom. In agreement with the experiment no attack at the C(3) is observed. In case of a Cα and N methylation mixture (for the 4-(phenyl(tosyl)methylpyridine), the activation barrier difference between the two pathways diminishes to almost 0 kcal/mol.