Vibrational optical activity: From discovery and development to future challenges.

Chiroptical properties and spectroscopies are valuable tools to study chiral molecules and assign absolute configurations. The spectra that result from chiroptical measurements may be very rich and complex, and hide much of their information content. For this reason, the interplay between experiments and calculations is especially useful, provided that all relevant physico-chemical interactions that are present in the experimental sample are accurately modelled. The inherent difficulty associated to the calculation of chiral signals of systems in aqueous solutions requires the development of specific tools, able to account for the peculiarities of water-solute interactions, and especially its ability to form hydrogen bonds. In this perspective we discuss a multiscale approach, which we have developed and challenged to model the most used chiroptical techniques.

Theory and algorithms for chiroptical properties and spectroscopies of aqueous systems

https://chemistry-europe.onlinelibrary.wiley.com/doi/pdf/10.1002/ejoc.202000876

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

The oxadi-π-methane rearrangement of 2,4-cyclohexadienones to bicyclic ketones was found to proceed with high enantioselectivity (92-97% ee) in the presence of catalytic amounts of a chiral Lewis acid (15 examples, 52-80% yield). A notable feature of the transformation is the fact that it proceeds on the singlet hypersurface and that no triplet intermediates are involved. Rapid racemic background reactions were therefore avoided, and the catalyst loading could be kept low (10 mol %). Computational studies suggest that the enantioselectivity is determined within a Lewis acid bound singlet intermediate via a conical intersection. The utility of the method was demonstrated by a concise synthesis of the natural product trans-chrysanthemic acid.

Lewis Acid Catalyzed Enantioselective Photochemical Rearrangements on the Singlet Potential Energy Surface.

Solvation effects are essential for defining the shape of vibrational circular dichroism (VCD) spectra. Several approaches have been proposed to include them into computational models for calculating VCD signals, in particular those resting on the “cluster-in-a-liquid” model. Here we examine the capabilities of this ansatz on the example of flexible (1S,2S)-trans-1-amino-2-indanol solvated in dimethyl sulfoxide (DMSO). We compare cluster sets obtained from static calculations with results from explicit molecular dynamics (MD) trajectories based on either force field (FF) or first-principles (FP) methods. While the FFMD approach provides a broader sampling of configurational space, FPMD and time-correlation functions of dipole moments account for anharmonicity and entropy effects in the VCD calculation. They provide a means to evaluate the immediate effect of the solvent on the spectrum. This survey singles out several challenges associated with the use of clusters to describe solvation effects in systems showing shallow potential energy surfaces and non-covalent interactions. Static structures of clusters involving a limited number of solvent molecules satisfactorily capture the main effects of solvation in the bulk limit on the VCD spectra, if these structures are correctly weighted. The importance of taking into consideration their fluxionality, i.e. different solvent conformations sharing a same hydrogen bond pattern, and the limitations of small clusters for describing the solvent dynamics are discussed.

/pdf/assessing-cluster-models-of-solvation-for-the-description-of-h20aw1r2po.pdf

Assessing cluster models of solvation for the description of vibrational circular dichroism spectra: synergy between static and dynamic approaches

Vibrational circular dichroism (VCD) spectroscopy is one of the most powerful techniques for the determination of absolute configurations (AC), as it does not require any specific UV/vis chromophor...

Absolute Configurations of Synthetic Molecular Scaffolds from Vibrational CD Spectroscopy

Spectroscopic characterizations of key reaction intermediates are often considered the final confirmation of a reaction mechanism. This proof-of-principle study showcases the application of vibrational circular dichroism (VCD) spectroscopy for the characterization of in situ generated reaction intermediates using the key intermediates of enamine catalysis of Jorgensen-Hayashi-type prolinol ether catalysts as model system. By comparison of experimental and computed spectra, the enamines are shown to preferentially adopt an anti-conformation with E-configured C=C bond. For the parent prolinol catalyst, the structure and stereochemistry of the oxazolidine side product is determined as well. This study thus demonstrates that VCD spectra can provide insights into structural preferences of organocatalysts that utilize a covalent activation mechanism. Thereby it outlines new fields of applications for VCD spectroscopy and finally adds the technique to the toolbox of physical organic chemistry for in-depth mechanistic studies.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/chem.201905614

Stereochemistry of the Reaction Intermediates of Prolinol Ether Catalyzed Reactions Characterized by Vibrational Circular Dichroism Spectroscopy.

An enantioselective sulfimidation of 3-thiosubstituted 2-quinolones and 2-pyridones was achieved with a stoichiometric nitrene source (PhI=NNs) and a silver-based catalyst system. Key to the success of the reaction is the use of a chiral phenanthroline ligand with a hydrogen bonding site. The enantioselectivity does not depend on the size of the two substituents at the sulfur atom but only on the binding properties of the heterocyclic lactams. A total of 21 chiral sulfimides were obtained in high yields (44-99 %) and with significant enantiomeric excess (70-99 % ee). The sulfimidation proceeds with high site-selectivity and can also be employed for the kinetic resolution of chiral sulfoxides. Mechanistic evidence suggests the intermediacy of a heteroleptic silver complex, in which the silver atom is bound to one molecule of the chiral ligand and one molecule of an achiral 1,10-phenanthroline. Support for the suggested reaction course was obtained by ESI mass spectrometry, DFT calculations, and a Hammett analysis.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/anie.202016561

Silver‐Catalyzed Enantioselective Sulfimidation Mediated by Hydrogen Bonding Interactions

We demonstrate that VCD spectroscopy can reveal insights into the conformational preferences of the iminium ion obtained from MacMillan's imidazolidinone catalyst. For both the isolated and in situ generated iminium ion, the comparison of experimental and computed VCD spectra directly confirms that conformer 2b ("Houk-conformer") is the dominant structure in solution. This conclusion is reached without any in-depth interpretation of the spectroscopic data, just by visual comparison of the spectral signatures. For the parent catalyst 1 and its salts 1·HCl and 1·HClO4, we report a comprehensive analysis of the conformational preferences in two solvents. VCD spectroscopy is subsequently shown to be able to reveal small conformational changes induced by solute-solvent and solute-anion interactions.

Vibrational CD study on the solution phase structures of the MacMillan catalyst and its corresponding iminium ion.

Abstract In this study, we characterize the dynamic stereochemistry of a biphenyl‐2,2’‐bis(proline amide) catalyst in chloroform and DMSO as representative weakly and strongly hydrogen bonding solvents. Using vibrational circular dichroism (VCD) spectroscopy and density functional theory (DFT) based spectra calculations, we show that the preferred axial stereochemistry of the catalyst is determined by solute‐solvent interactions. Explicitly considering solvation with DMSO molecules is found to be essential to correctly predict the conformational preferences of the catalyst. Furthermore, we investigate the stereochemistry of the corresponding enamines and imidazolidinones that are formed upon reaction with isovaleraldehyde. The enamines are found to rapidly convert to endo‐imidazolidinones and the thermodynamically favored exo‐imidazolidinones are formed only slowly. The present study demonstrates that the stereochemistry of these imidazolidinones can be deduced directly from the VCD spectra analysis without any further detailed analysis of NMR spectra. Hence, we herein exemplify the use of VCD spectroscopy for an in situ characterization of intermediates relevant in asymmetric catalysts.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/chem.202201317

Tino P. Golub

Papers

Absolute Configurations of Synthetic Molecular Scaffolds from Vibrational CD Spectroscopy

Stereochemistry of the Reaction Intermediates of Prolinol Ether Catalyzed Reactions Characterized by Vibrational Circular Dichroism Spectroscopy.

Silver‐Catalyzed Enantioselective Sulfimidation Mediated by Hydrogen Bonding Interactions

Vibrational CD study on the solution phase structures of the MacMillan catalyst and its corresponding iminium ion.

Dynamic Stereochemistry of a Biphenyl‐Bisprolineamide Model Catalyst and its Imidazolidinone Intermediates