Can an Alcohol Act As an Acid/Base Catalyst in Water Solution? An Experimental and Theoretical Study of Imidazole Catalysis of the Aqueous Morita–Baylis–Hillman Reaction

The formation of carbon–carbon sigma bonds by the organocatalyzed Morita–Baylis–Hillman (MBH) reaction constitutes a convenient method for the synthesis of valuable, highly functionalized molecules. Its large-scale implementation is however hampered both by its poor performance with substrates such as α,β-unsaturated ketones and by the reduction of the nucleophilicity of the catalyst when using water as a solvent. Recent work from our laboratories has shown that a bicyclic imidazolyl alcohol (BIA) overcomes these limitations and is a much more efficient catalyst than imidazole for the aqueous MBH reactions of cyclic enones. The role of the hydroxyl group in the former catalyst is not easy to understand, however, since these reactions take place in water solution. We have studied the mechanism of the aqueous MBH reaction between 2-cyclohexenone and isatin, catalyzed either by imidazole or by the BIA catalyst, using a combined experimental and computational approach. The data allowed us to propose mechanist...