CATALYTIC REACTIONS INVOLVING AZOMETHINES .11. KINETICS OF CONDENSATION OF HISTAMINE WITH 3-HYDROXYPYRIDINE-4-ALDEHYDE . AN INTRAMOLECULAR MANNICH REACTION

The kinetics of the condensation of the pyridoxal analog 3-hydroxypyridine-4-aldehyde with histamine to yield VII have been investigated. It has been established that the reaction proceeds via rapid imine formation followed by a much slower ring-closure step. Under the conditions in which total histamine concentration far exceeds that of aldehyde, the rate-limiting step of imine formation changes from carbinolamine formation to carbinolamine dehydration. From the pH dependence of the observed first-order rate constants for conversion of imine species to final product, values of rate constants for ring closure of each imine species have been determined. Two favored mechanisms of product formation are provided. These are, nucleophilic attack of the 5 position of the neutral imidazolyl group on the unprotonated imine linkage and a like attack of the anionic imidazolyl group; both paths being assisted by proton donation from the phenolic hydroxyl group. © 1969, American Chemical Society. All rights reserved.