Bifunctional Catalysis of a Crossed Aldol Condensation by Diamines: Impact of Tether Composition and Length

The crossed aldol condensation between hydrocinnamaldehyde and 2,6-dimethoxybenzaldehyde was used to explore bifunctional catalysis by a set of diamines. The catalytic mechanism appears to involve nucleophilic activation of hydrocinnamaldehyde, as the enamine, and electrophilic activation of 2,6-dimethoxybenzaldehyde, as the iminium. Our goal was to learn how catalytic efficacy is influenced by variations in the molecular scaffold that displays the two primary amine groups. One set of diamines contained oligomethylene linkers of 4 to 16 carbons, and another set contained oligoether linkers (-O-CH₂-CH₂- repeat unit) of 5 to 20 atoms. These flexible diamines were compared with a previously described peptide-based catalyst in which a helical conformation induces spatial proximity of the two amine groups. The most effective catalysis among the oligomethylene-linked diamines was observed for tethers of 12 to 16 carbon atoms. Among the oligoether-linked diamines, the most effective catalysis was observed for tethers of 8 to 14 atoms. The helix-forming α/β-peptide, with 15 atoms between the two amine groups, was superior to oligomethylene-linked diamines with tethers of comparable lengths, but the α/β-peptide diamine was matched in catalytic prowess by oligoether diamines. The superiority of oligoether tethers relative to oligomethylene tethers is attributed to conformational differences between the tethers. Collectively, the data support the conclusion that relatively long, flexible tethers can enable a pair of reactive groups to function cooperatively, at least when each reactive group forms a covalent intermediate.