We present evidence that the privileged use of the 3,5‐bis(trifluoromethyl)phenyl group in thiourea organocatalysis is due to the involvement of the ortho‐CH bond in the binding event with Lewis‐basic sites. We utilized a combination of low‐temperature IR spectroscopy, 2D NMR spectroscopy, nano‐MS (ESI) investigations, as well as density functional theory computations [M06/6‐31+G(d,p), including solvent corrections as well as natural bond orbital and atoms‐in‐molecules analyses] to support our conclusions that bear implications for catalyst design.

Bordwell's method of overlapping indicators was used to determine the pK(a) values of some of the most popular (thio)urea organocatalysts via UV spectrophotometric titrations. The incremental effect of CF(3) groups on acidic strength was also investigated. The pK(a)'s are in the range of 8.5-19.6. The results may lead to a better understanding of noncovalent organocatalysis and may aid in future catalyst development.

We report a new thiourea-Brønsted acid cooperative catalytic system for the enantioselective cyanosilylation of aldehydes with yields up to 90% and enantioselectivities up to 88%. The addition of an achiral acid was found to be crucial for high asymmetric induction. Mechanistic investigations using a combination of NMR, ESI-MS, and density functional theory computations (including solvent corrections) at the M06/6-31G(d,p) level of theory suggest that the key catalytic species results from the cooperative interaction of bifunctional thioureas and an achiral acid that form well-defined chiral hydrogen-bonding environments.

Racemic benzylic amines undergo kinetic resolution via benzoylation with benzoic anhydride in the presence of a dual catalyst system consisting of a readily available amide-thiourea catalyst and 4-dimethylaminopyridine (DMAP). An evaluation of various experimental parameters was performed in order to derive a more detailed understanding of what renders this process selective. The catalyst's aggregation behavior and anion-binding ability were evaluated in regard to their relevance for the catalytic process. Alternate scenarios, such as catalyst deprotonation or the in situ formation of a neutral chiral acylating reagent were ruled out. Detailed computational studies at the M06/6-31G(d,p) level of theory including solvent modeling utilizing a polarized continuum model provide additional insights into the nature of the ion pair and reveal a range of important secondary interactions that are responsible for efficient enantiodiscrimination.

Determining the structure of reactive intermediates is the key to understanding reaction mechanisms. To access these structures, a method combining structural sensitivity and high time resolution is required. Here ultrafast polarization-dependent two-dimensional infrared (P2D-IR) spectroscopy is shown to be an excellent complement to commonly used methods such as one-dimensional IR and multidimensional NMR spectroscopy for investigating intermediates. P2D-IR spectroscopy allows structure determination by measuring the angles between vibrational transition dipole moments. The high time resolution makes P2D-IR spectroscopy an attractive method for structure determination in the presence of fast exchange and for short-lived intermediates. The ubiquity of vibrations in molecules ensures broad applicability of the method, particularly in cases in which NMR spectroscopy is challenging due to a low density of active nuclei. Here we illustrate the strengths of P2D-IR by determining the conformation of a Diels-Alder dienophile that carries the Evans auxiliary and its conformational change induced by the complexation with the Lewis acid SnCl(4), which is a catalyst for stereoselective Diels-Alder reactions. We show that P2D-IR in combination with DFT computations can discriminate between the various conformers of the free dienophile N-crotonyloxazolidinone that have been debated before, proving antiperiplanar orientation of the carbonyl groups and s-cis conformation of the crotonyl moiety. P2D-IR unequivocally identifies the coordination and conformation in the catalyst-substrate complex with SnCl(4), even in the presence of exchange that is fast on the NMR time scale. It resolves a chelate with the carbonyl orientation flipped to synperiplanar and s-cis crotonyl configuration as the main species. This work sets the stage for future studies of other catalyst-substrate complexes and intermediates using a combination of P2D-IR spectroscopy and DFT computations.