Triazine-Substituted and Acyl Hydrazones: Experiment and Computation Reveal a Stability Inversion at Low pH.

Condensation of a hydrazine-substituted s-triazine with an aldehyde or ketone yields an equivalent to the widely used, acid-labile acyl hydrazone. Hydrolysis of these hydrazones using a formaldehyde trap as monitored using HPLC reveals that triazine-substituted hydrazones are more labile than acetyl hydrazones at pH>5. The reactivity trends mirror that of the corresponding acetyl hydrazones, with hydrolysis rates increasing along the series (aromatic aldehyde<aromatic ketone<aliphatic ketone). Computational and experimental studies indicate a reversal in stability around the triazine pKa (pH∼5). Protonation of the triazine moiety retards acid-catalyzed hydrolysis of triazinyl hydrazones in comparison to acetyl hydrazone analogues. This behavior supports mechanistic interpretations suggesting that resistance to protonation of the hydrazone N1 is the critical factor in affecting the reaction rate.