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.

中文翻译：

---

烯胺/二胺和布朗斯台德酸催化：基于原位NMR光谱和计算研究的难以捉摸的中间体，反应机理和立体诱导模式。

多年来，关于机理研究，对映选择性有机催化领域在新型合成应用的开发中无与伦比地增长。反应优化似乎是凭经验而不是理性的。合成发展和机理理解之间的这种抵销过去是并且通常是由于检测反应性中间体的困难以及无法通过实验评估过渡态而造成的。因此，机理研究的第一个关键点是检测难以捉摸的中间体，并根据其结构，稳定性，形成途径和动力学特性对其进行表征。第二个关键点是评估这些中间体及其在过渡态下的性质的重要性。在过去的7年中，我们的小组已经解决了通过NMR光谱法以及最终的理论计算来检测有机催化中难以捉摸的中间体的问题。广泛研究了两种主要的活化方式：仲胺催化和最近的布朗斯台德酸催化。使用这些例子，我们讨论了通过分子间相互作用来稳定中间体的潜在方法。阐明其结构，形成途径和动力学；改变反应动力学；并解决它们在过渡状态中的相关性。脯氨酸催化的醛醇缩合反应中难以捉摸的烯胺被用作通过分子间和分子内相互作用稳定中间体的一个例子。讨论了其形成途径动力学的确定。使用脯氨醇和脯氨醇醚烯胺和二烯胺描述了中间体的经典结构表征。二烯胺第二个双键的Z / E困境显示了如何改变反应动力学以检测反应中间体。我们最近开始研究布朗斯台德酸催化领域的底物-催化剂配合物。这些对亚胺/手性磷酸络合物的研究表明，高度发达的NMR和理论方法的适当结合可以为手性离子对的复杂结构，交换动力学和H键性质提供详细的见解。此外，这些结构研究和光异构化的结合甚至仅允许仅根据实验数据首次确定活性过渡态组合，这是机械研究中的金标准，以前被认为仅是理论计算的领域。因此，本报告总结了我们在有机催化领域的最新机理研究，并解释了解决机理研究中的核心问题的潜在方法：中间体的稳定化，结构和形成途径的阐明以及实验性地研究过渡态的组合。