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.

肼取代均三嗪（hydrazine-substituted s-triazine）与醛（aldehyde）或酮（ketone）发生缩合反应，可得到与广泛应用的酸不稳定酰腙（acid-labile acyl hydrazone）等效的产物。以甲醛捕获剂为助剂对该类腙进行水解实验，并通过高效液相色谱（High Performance Liquid Chromatography, HPLC）监测反应进程，结果显示：在pH＞5的条件下，三嗪取代腙的水解稳定性弱于乙酰腙。其反应活性变化趋势与对应乙酰腙一致，水解速率遵循如下序列：芳香醛衍生腙＜芳香酮衍生腙＜脂肪族酮衍生腙。计算化学与实验研究表明，在均三嗪的酸解离常数（pKa）附近（pH约为5），水解稳定性出现反转。相较于乙酰腙类似物，三嗪环的质子化会延缓三嗪基腙的酸催化水解过程。该实验现象支持相关机理解释，即腙分子N1位点的抗质子化能力是影响反应速率的关键因素。