The effect of alkylation, protonation, and hydroxyl group substitution on reversible alcohol and water addition to 2- and 4-formyl pyridine derivatives

Abstract

The formation of acetals and hemiacetals from carbonyl species and alcohols is a well-studied reaction. For purposes of reversible covalent bonding, a thermodynamically favored reaction that is also kinetically fast is desirable. Toward this goal, the regiochemical influence of hydroxyl or methoxy substitution on 2- and 4-formyl pyridine derivatives on alcohol and water addition was studied. The goal was to investigate carbonyl activation via the electron deficient pyridine ring and the roles of intramolecular general acid catalysis/hydrogen bonding catalysis from an adjacent hydroxyl and of resonance donation from an adjacent hydroxyl or methoxy group in these addition reactions. A qualitative screen of formyl pyridine derivatives at room temperature in neutral and acidic conditions for the formation of addition products was undertaken. In subsequent studies, N-alkylated formyl pyridine derivatives were used in order to take advantage of the activation of the carbonyl provided by the positively charged pyridine ring under neutral conditions. The presence of a hydroxyl group adjacent to the aldehyde generally deactivates it to alcohol or water addition, particularly under neutral conditions when the hydroxyl group is deprotonated. Based on our findings, resonance donation rather than intramolecular general acid catalysis/hydrogen bonding catalysis appears to be the dominant effect behind this deactivation for the pyridinium derivatives. However, the presence of a hydroxyl or methoxy group stabilizes the oxocarbenium ion intermediate that results in acetal formation and thus is essential for forming acetal under neutral conditions.