Enamine/Dienamine and Brønsted Acid Catalysis: Elusive Intermediates, Reaction Mechanisms, and Stereoinduction Modes Based on in Situ NMR Spectroscopy and Computational Studies

[Image: see text] Over the years, the field of enantioselective organocatalysis has seen unparalleled growth in the development of novel synthetic applications with respect to mechanistic investigations. Reaction optimization appeared to be rather empirical than rational. This offset between synthetic development and mechanistic understanding was and is generally due to the difficulties in detecting reactive intermediates and the inability to experimentally evaluate transition states. Thus, the first key point for mechanistic studies is detecting elusive intermediates and characterizing them in terms of their structure, stability, formation pathways, and kinetic properties. The second key point is evaluating the importance of these intermediates and their properties in the transition state. In the past 7 years, our group has addressed the problems with detecting elusive intermediates in organocatalysis by means of NMR spectroscopy and eventually theoretical calculations. Two main activation modes were extensively investigated: secondary amine catalysis and, very recently, Brønsted acid catalysis. Using these examples, we discuss potential methods to stabilize intermediates via intermolecular interactions; to elucidate their structures, formation pathways and kinetics; to change the kinetics of the reactions; and to address their relevance in transition states. The elusive enamine in proline-catalyzed aldol reactions is used as an example of the stabilization of intermediates via inter- and intramolecular interactions; the determination of kinetics on its formation pathway is discussed. Classical structural characterization of intermediates is described using prolinol and prolinol ether enamines and dienamines. The Z/E dilemma for the second double bond of the dienamines shows how the kinetics of a reaction can be changed to allow for the detection of reaction intermediates. We recently started to investigate substrate–catalyst complexes in the field of Brønsted acid catalysis. These studies on imine/chiral phosphoric acid complexes show that an appropriate combination of highly developed NMR and theoretical methods can provide detailed insights into the complicated structures, exchange kinetics, and H-bonding properties of chiral ion pairs. Furthermore, the merging of these structural investigations and photoisomerization even allowed the active transition state combinations to be determined for the first time on the basis of experimental data only, which is the gold standard in mechanistic investigations and was previously thought to be exclusively the domain of theoretical calculations. Thus, this Account summarizes our recent mechanistic work in the field of organocatalysis and explains the potential methods for addressing the central questions in mechanistic studies: stabilization of intermediates, elucidation of structures and formation pathways, and addressing transition state combinations experimentally.