Relative Stability and Basicity of Enamines from Aminocatalysts

Abstract The relative thermodynamic stability of two series of enamines has been examined using DFT (mainly M06‐2X), MP2, and CCSD(T) calculations, supplemented by 1 H NMR spectroscopy in some cases. The basicity of enamines derived from pyrrolidine and various carbonyl compounds has been computationally compared in the gas phase and in water; the results indicate which enamines or iminium ions may predominate in nonpolar and polar acidic media when pyrrolidine and two or more carbonyl groups or carbonyl compounds are present in the reaction flask. The relative basicity of a second series of enamines, from propanal and chiral pyrrolidines or imidazolidin‐4‐ones, has also been investigated; this sheds light on the main intermediates that should be expected when two or more secondary amines are present in acid‐catalyzed aldehyde reactions. Non‐covalent interactions explain the stability of folded side‐chain conformers of O‐ silylated prolinol enamines, according to the predictions of M06–2X, ωB97X−D, and B3LYP−D3 (but not B3LYP). The significant stability of iminium ions containing appropriate electron‐donating atoms or groups accounts for the basicity of the corresponding enamines. These findings pave the way for the future development of dual aminocatalytic processes.