Towards an Observation of Active Conformations in Asymmetric Catalysis: Interaction‐Induced Conformational Preferences of a Chiral Thiourea Model Compound

Abstract

The observation of the active species is the goal of most spectroscopic investigations on enantioselective organocatalysts in solution. Although NMR spectroscopy is widely applied, it has low sensitivity for conformational changes or the chiral nature of the interactions. In the present work, we exemplify the use of vibrational circular dichroism (VCD) spectroscopy for the characterization of a chiral thiourea model compound in nonpolar and polar solvents, as well as for a detailed analysis of its interaction with a model reactant. We discuss solvent-induced conformational changes of the thiourea, and provide evidence for an unexpected binding topology between the thiourea and an acetate anion. The results clearly showcase the possibilities offered by using VCD spectroscopy in the characterization of chiral organocatalysts.

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

“…[11] Subsequently,astudy on ac hiral thiourea model compound revealed the advantages of VCD spectroscopyf or studies on intermoleculari nteractions by showing that it can providei nteresting structural insights into the acetate-binding of thioureas. [12] Due to the importance of bifunctional catalysts, we herein investigate reactant binding to TUC by means of VCD spectroscopy.T he actual active conformation in the presence of both reactants, as it is shown in Scheme 1, is difficult to study though, as the simultaneous binding of the reactants will lead to an immediate and fast reaction and thus ag enerally low concentration of the active complex. Therefore, we focus on carboxylic acids as model substrates, which presumably interact simultaneously with both binding sites of TUC without initiating ar eaction.…”

Bifurcatriol, a New Antiprotozoal Acyclic Diterpene from the Brown Alga Bifurcaria bifurcata

“…In particular, the combination of stereochemical sensitivity with the rich structural content of vibrational spectra by VCD and Raman Optical Activity (ROA) has brought forward very reliable approaches for the AC determination of natural products [ 16 , 17 ]. In addition, the conformational sensitivity of vibrational spectroscopy allowed some insights into very interesting conformational variations in natural products [ 18 ] as well as peptides and other chiral molecules [ 19 , 20 , 21 ].…”

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

“…Reproduced from ref. [31] In Figure 3b, we show a comparison of the experimental IR and VCD spectra of pure 12 and those computed at B3LYP/6-311+G(2d,p)/IEFPCM(CHCl 3 ) level of DFT. The basis for the spectra predictions was a comprehensive conformational analysis that pointed to a trans-conformation of the thiourea moiety as energetically most favorable structure (cf.…”

“…Reproduced from ref. [31] plex structure shown in Scheme 3, with bifurcated hydrogen bonding pattern between thiourea and acetate and an additional hydrogen bond between acetate and solvent. We showed that this bifurcated structure must significantly contribute to the conformational equilibrium.…”

“…In the latter studies, binding constants are regularly determined in order to quantify the discriminating power of the thiourea selector. For our first study on thiourea‐reactant complex formation, we selected the structurally very simple N,N'‐bis(α‐phenyl ethyl)thiourea 12 (Scheme ), which strongly binds acetate and chiral carboxylates . As it forms a 1:1 complex with acetate in non‐polar solvents, an equimolar mixture of 12 and tetrabutylammonium acetate (TBAA) served as our first model system for which we recorded the IR and VCD spectra in CDCl 3 solution.…”