Organocatalysts Fold To Generate an Active Site Pocket for the Mannich Reaction

Abstract

Catalysts containing urea, thiourea, and tertiary amine groups fold into a three-dimensional organized structure in solution both in the absence as well as in the presence of substrates or substrate analogues, as indicated by solution NMR and computational studies. These foldamer catalysts promote Mannich reactions with both aliphatic and aromatic imines and malonate esters. Hammett plot and secondary kinetic isotope effects provide evidence for the C–C bond forming event as the turnover-limiting step of the Mannich reaction. Computational studies suggest two viable pathways for the C–C bond formation step, differing in the activation modes of the malonate and imine substrates. The results show that the foldamer catalysts may promote C–C bond formation with an aliphatic substrate bearing a cyclohexyl group by enhanced binding of the substrates by dispersion interactions, but these interactions are largely absent with a simpler catalyst. Additional control experiments demonstrate the ability of simple thio...