How Do Substrates Bind to a Bifunctional Thiourea Catalyst? A Vibrational CD Study on Carboxylic Acid Binding

Abstract

Knowledge about the active conformation of an asymmetric catalyst is highly valuable in order to understand its stereoinductive power, but spectroscopic access to these structures is often limited. For the example of Takemoto's bifunctional thiourea, we demonstrate the capability of VCD spectroscopy to characterize the conformational preferences of the catalyst with and without having a reactant bound to it. In particular we show that the binding orientation of carboxylic acids can easily be derived from a computationally guided analysis of the spectra. Moreover, we identify characteristic marker bands, which are only visible in the VCD spectra of the catalyst/acid mixtures but not in the corresponding IR spectra. Lastly, we also discuss the problem that the popular DFT functional M06-2X, which we found to perform exceptionally well in the calculations of vibrational frequencies for fluorinated molecules, predicts incorrect structures of the molecular clusters. We relate this poor performance in predicting the structure of the binding topologies to an overestimation of dispersive CH-π and π-π interactions, which occur due to a neglect of the solvent molecules in the clusters. VCD spectroscopy is thus shown to be a powerful tool to identify and subsequently correct such mispredictions of solution-phase structures.

Transformation of Racemic Azlactones into Enantioenriched Dihydropyrroles and Lactones Enabled by Hydrogen‐Bond Organocatalysis

“…The hint at why the complex of chiral thiourea and the acid has much higher selectivity comes from the studies of Seidel and co‐workers on conjugate base‐stabilized carboxylic acids, exploiting the intramolecular activation of carboxylic acids by thiourea binding in asymmetric catalysis . Similarly, the binding of carboxylic acids to Takemoto's bifunctional thiourea and its impact on the catalyst conformation has been described using a combination of VCD and computational methods . In our case, intermolecular binding of the carboxylic acid to thiourea enhances the acidity of the carboxylic proton, which in turn activates the imine towards the addition of the nucleophile.…”

Recent Advances in the Application of Vibrational Circular Dichroism Spectroscopy for the Characterization of Asymmetric Catalysts

“…Particularly noteworthy in this respect is the strong VCD band at 1310 cm -1 (asterisked in Figure 4c), which was identified in a screening of different carboxylic acid substrates as a strong and characteristic marker band for the interaction of the Reproduced from ref. [37] associated conformational change of 13. It is independent of the added acid.…”

“…Takemoto's bifunctional thiourea 13 [36] and its interaction with a carboxylic acid that served as model system for reactant-catalyst binding studies. [37] For a VCD study on the substrate binding of 13, we had to focus on only one interacting molecule to prevent reactions to take place. [37] Therefore, we selected several carboxylic acids as model systems, which allowed both interaction with the Lewis basic site and protonation of the amine.…”

“…[37] For a VCD study on the substrate binding of 13, we had to focus on only one interacting molecule to prevent reactions to take place. [37] Therefore, we selected several carboxylic acids as model systems, which allowed both interaction with the Lewis basic site and protonation of the amine. As illustrated for octanoic acid (OA) as a substrate in Figure 4c, the IR spectral pattern is rather little affected by the addition of one equivalent of an aliphatic carboxylic acid.…”

“…While the thiourea binds a Lewis base and activates it for nucleophilic additions, the basic site activates the nucleophile, and Michael additions can be carried out with high yields and ee . Based on the good match between the experimental and computed IR and VCD of 13 , which are shown in Figure a, we could show that the catalyst itself adopts a trans‐conformation (Figure b, top), in which these two catalytic sites interact with each other.…”