Role of hydrogen bonding in the selectivity of aromatic Mannich reaction of tyramines: Macrocyclization vs. linear condensation

Tyramines (beta-(4-hydroxyphenyl)ethylamines) present intermolecular associations via O-H center dot center dot center dot N hydrogen bonds, leading to the formation of "macrocyclization templates" in solution, which account for the obtained macrocyclic products in the aromatic Mannich reaction of these compounds with formaldehyde. However, the intermolecular association of tyramine is strongly affected by the presence of 2-naphthol, and its reaction with formaldehyde produces Mannich bases with linear tricomponents instead of macrocyclic products. The preference of tyramines to associate with 2-naphthol rather than with themselves is explained with the aid of semi-empirical and ab initio chemical calculations for the proposed hydrogen-bond based complexes, from energetic and molecular orbitals approaches. (C) 2019 Elsevier B.V. All rights reserved.