Hypersensitive Inhibition of Organocatalysts by Halide Salts: Are Two Catalysts Involved in the Mannich Reaction?

Conformationally flexible tertiary amine – thiourea−urea catalysts 1 and 2 for the Mannich reaction between imines and malonate esters are efficiently inhibited by quaternary ammonium halides. NMR titrations, isothermal titration calorimetry (ITC) and NOE experiments showed that the catalysts bind chloride and bromide ions with relatively high affinities (K=103–105 M−1 in acetonitrile). The halide ions not only block the active site of the catalysts, but they also induce refolding into catalytically inactive conformations upon complexation in an allosteric‐like event. At substoichiometric inhibitor:catalyst ratios, the catalysts 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. To rationalize the observed hypersensitivity, different kinetic scenarios were examined. For catalyst 2 and the Takemoto catalyst (6), the data is consistent with 2nd order dependency on catalyst concentration, suggesting that a mechanism involving only a single catalyst in the catalytic cycle is not operative. For catalyst 1, an alternative scenario involving 1st order in catalyst and catalyst poisoning at low concentrations of 1 could also rationalize the hypersensitivity. Interestingly, inhibition of catalysts 1 and 2 by halide salts led to significant loss of enantioselectivity, in contrast to the Takemoto catalyst 6 which was inhibited but with essentially no change in enantioselectivity.