Hypersensitive Inhibition of Organocatalysts by Halide Salts

Conformationally flexible tertiary amine—thiourea-urea catalysts for the Mannich reaction between imines and malonate esters are efficiently inhibited by quaternary ammonium halides. NMR titrations, isothermal titration calorimetry and NOE experiments showed that the catalysts bind chloride and bromide ions with relatively high affinities (K = 103–105 M–1 in acetonitrile), and they refold into catalytically inactive conformations upon complexation. At substoichiometric inhibitor:catalyst ratios, the reactions displayed hypersensitivity to the inhibitors, with overall rates that were lower than those expected from simple 1st order kinetics and 1:1 inhibitor:catalyst stoichiometry. The Mannich reactions turned out to be 2nd order in catalyst, and this finding also readily explains the observed hypersensitivity.