Tandem Aldol Reaction from Acetal Mixtures by an Artificial Enzyme with Site-Isolated Acid and Base Functionalities

Site-isolation of catalysts can enable incompatible catalysts such as acid and base to be used in one pot for enhanced efficiency and other benefits. Although many synthetic platforms have been reported for this purpose, they generally do not possess the exquisite selectivity of site-isolated enzymes in nature. Here we report water-soluble protein-sized nanoparticles with site-isolated acids in the core and amines on the surface. The catalysts were made through molecular imprinting of cross-linked micelles, followed by facile one-step photoaffinity labeling of the imprinted binding site. With a tunable, substrate-specific active site, the bifunctional artificial enzyme catalyzed highly selective tandem cross aldol reaction between acetone and mixtures of isomeric aryl acetals. It could also transform a less reactive substrate over a more reactive one.