Inter- and Intramolecular Cooperativity Effects in Alkanolamine-Based Acid–Base Heterogeneous Organocatalysts

[Image: see text] Intramolecular cooperativity in heterogeneous organocatalysts is investigated using alkanolamine-functionalized silica acid–base catalysts for the aldol condensation reaction of 4-nitrobenzaldehyde and acetone. Two series of catalysts, one with and one without silanol-capping, are synthesized with varied alkyl linker lengths (two to five) connecting secondary amine and terminal hydroxyl functionalities. The reactivity of these catalysts is assessed to determine the relative potential for intermolecular (silane amine–surface silanol) vs intramolecular (amine–hydroxyl within a single silane) cooperativity, the impact of inhibitory surface–silane interactions, and the role of alkyl linker length and flexibility. For the array of catalysts tested, those with longer linker lengths generally give increased catalytic activity, although the turnover frequency trends differ between catalysts with and without surface silanol capping. Catalysts with alkyl-substituted amines lacking a terminal hydroxyl demonstrate an adverse effect of chain length, where the larger alkyl substituent on the amine provides steric hindrance depressing catalytic activity, while giving additional evidence for improved rates afforded by intramolecular cooperativity in the alkanolamine materials. The silanol-capped alkanolamine catalyst with the longest alkyl linker is found to be the most active alkanolamine catalyst due to its hydrophobized surface, which removes hypothesized silanol–alkanolamine inhibitory interactions, with the sufficient length and flexibility of its amine–hydroxyl linker allowing for favorable conformations for cooperativity. This study demonstrates the feasibility of and important factors affecting intramolecular cooperative activity in acid–base heterogeneous organocatalysis.