Dual Activation Modes Enable Bifunctional Catalysis of Aldol Reactions by Flexible Dihydrazides

Hydrazides are known to catalyze reactions of α,β-unsaturated aldehydes via transient iminium formation. The iminium intermediate displays enhanced electrophilicity, which facilitates conjugate additions and cycloadditions. We observed that a hydrazide embedded in a seven-membered ring catalyzes homoaldol condensation of a simple aldehyde in a process that displays an approximate second-order dependence on the hydrazide. This finding suggests a dual activation mechanism involving both iminium and enamine intermediates. The unexpected nucleophilic activation mode led us to examine a series of simple dihydrazides for bifunctional catalysis of the aldol condensation. The two cyclic hydrazide units were connected via linear polymethylene linkers, which are inherently flexible. Substantial increases in initial reaction rate, relative to a monohydrazide, were observed for polymethylene linkers of sufficient length, with a maximum at 10 methylenes. Reactions promoted by this dihydrazide displayed an approximate first-order dependence on catalyst concentration, which suggested a bifunctional catalytic mechanism. Even for a dihydrazide with an 18-methylene linker, a substantial increase in relative initial rate was observed. These observations show that significant coordination can be achieved between two catalytically active moieties even when these moieties are connected via many flexible bonds.