Matrix effects in MI-VCD spectra of two chiral oxiranes and their potential microscopic origin.

Combining vibrational circular dichroism (VCD) spectroscopy with the matrix isolation (MI) technique opens up interesting possibilities to study chiral molecules. MI involves the isolation of guest species in inert solid matrices at cryogenic temperatures. Hence, MI-VCD measures are solid-state VCD measurements, and as such, can suffer from mostly birefringance-related artefacts in the same way as common solid-state VCD measurements. In this contribution, we demonstrate that the sample preparation condition have tremendous impact on the quality and reliability of the recorded MI-VCD spectra. While MI-IR spectra are basically blind to these artefacts, the variation of deposition temperatures and host flow rates seem to control whether high quality MI-VCD spectra are obtained or if depolarization effects lead to completely obscured spectra. For two selected examples, styrene oxide (SO) and 1-phenyl propylene oxide (PPO), we discuss how the various experimental conditions may lead to the aforementioned effects and give a microscopic description of their origin.

Gauging the Strength of the Molecular Halogen Bond via Experimental Electron Density and Spectroscopy.

Strong and weak halogen bonds (XBs) in discrete aggregates involving the same acceptor are addressed by experiments in solution and in the solid state. Unsubstituted and perfluorinated iodobenzenes act as halogen donors of tunable strength; in all cases, quinuclidine represents the acceptor. NMR titrations reliably identify the strong intermolecular interactions in solution, with experimental binding energies of approx. 7 kJ/mol. Interaction of the σ hole at the halogen donor iodine leads to a redshift in the symmetric C-I stretching vibration; this shift reflects the interaction energy in the halogen-bonded adducts and may be assessed by Raman spectroscopy in condensed phase even for weak XBs. An experimental picture of the electronic density for the XBs is achieved by high-resolution X-ray diffraction on suitable crystals. Quantum theory of atoms in molecules (QTAIM) analysis affords the electron densities and energy densities in the bond critical points of the halogen bonds and confirms stronger interaction for the shorter contacts. For the first time, the experimental electron density shows a significant effect on the atomic volumes and Bader charges of the quinuclidine N atoms, the halogen-bond acceptor: strong and weak XBs are reflected in the nature of their acceptor atom. Our experimental findings at the acceptor atom match the discussed effects of halogen bonding and thus the proposed concepts in XB activated organocatalysis.

Simultaneous observation of halogen-lone pair and halogen-π interactions of ferrocene derivatives under cryogenic conditions.

Contrasting cryosolutions and matrix isolation infrared spectroscopy, we investigate weak intermolecular interactions in complexes of iodo trifluoroethene (C2F3I) and N,N-dimethyl ferrocenyl amine as well as the parent ferrocene. In liquid xenon, solely the C-I⋯N halogen bond can be observed, while the confined environment in solid argon allows for the characterization of C-I⋯π and π⋯π bonded complexes.

Matrix-isolation and cryosolution-VCD spectra of α-pinene as benchmark for anharmonic vibrational spectra calculations.

The inclusion of anharmonicity in vibrational spectral analyis remains associated to small molecular systems with up to a dozen of atoms, with half a dozen of non-hydrogen atoms, typically thesize of propylene oxide. One may see two reasons for this: first of all, larger systems are often thought to be computationally too demanding (high computational costs) for a full anharmonic vibrational analysis. Second, the identification of resonances and their correction is often considered something only expert theoreticians could address because of the lack of unequivocal criteria. In this contribution, we illustrate that resonances can indeed become a complex problem, which can be handled almost transparently thanks to recent advances in vibrational perturbation theory (VPT2). The study also emphasizes the importance and the central role played by experiment in benchmarking novel theoretical approaches. In fact, we herein provide the currently highest resolution VCD spectra available for α- and ß-pinene obtained under matrix-isolation conditions and in liquid Xenon as solvent. They are interpreted by VPT2 with novel tests for the identification of resonances. Hence, the study demonstrates the mutual stimulation of advances in both experimental techniques and computational models.

Enantioselective Synthesis of Diaryl Sulfoxides Enabled by Molecular Recognition.

The enantioselective sulfoxidation of diaryl-type sulfides was accomplished using a chiral manganese porphyrin complex equipped with a remote molecular recognition site. Despite the marginal size difference between the two substituents at the prostereogenic sulfur center, hydrogen bonding enabled the formation of chiral sulfoxides with exquisite enantioselectivities (16 examples, up to 99% ee). Aside from the precise orientation of a distinct substrate, the quinolone lactam offers an excellent entry point for further derivatization.

Dynamic chiral self-recognition in aromatic dimers of styrene oxide revealed by rotational spectroscopy.

Chiral molecular recognition is a pivotal phenomenon in biomolecular science, governed by subtle balances of intermolecular forces that are difficult to quantify. Non-covalent interactions involving aromatic moieties are particularly important in this realm, as recurring motifs in biomolecular aggregation. In this work, we use high-resolution broadband rotational spectroscopy to probe the dynamic conformational landscape enclosing the self-pairing topologies of styrene oxide, a chiral aromatic system. We reach a definite assignment of four homochiral and two heterochiral dimers using auxiliary quantum chemistry calculations as well as structure-solving methods based on experimental isotopic information. A complete picture of the dimer conformational space is obtained, and plausible routes for conformational relaxation are derived. Molecular structures are discussed in terms of conformational flexibility, the concerted effort of weak intermolecular interactions, and their role in the expression of the molecular fit.

Absolute Configurations of Synthetic Molecular Scaffolds from Vibrational CD Spectroscopy.

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 chromophores, no chemical derivatization, and no growth of suitable crystals. In the past decade, it has become increasingly recognized by chemists from various fields of synthetic chemistry such as total synthesis and drug discovery as well as from developers of asymmetric catalysts. This perspective article gives an overview about the most important experimental aspects of a VCD-based AC determination and explains the theoretical analysis. The comparison of experimental and computational spectra that leads to the final conclusion about the AC of the target molecules is described. In addition, the review summarizes unique VCD studies carried out in the period 2008-2018 that focus on the determination of unknown ACs of new compounds, which were obtained in its enantiopure form either through direct asymmetric synthesis or chiral chromatography.

The vibrational CD spectra of propylene oxide in liquid xenon: a proof-of-principle CryoVCD study that challenges theory.

Propylene oxide (PO) is one of the smallest chiral molecules and thus the ideal candidate to benchmark both new experimental and theoretical approaches. Previous studies on the fingerprint region of the IR and VCD spectra of PO under matrix-isolation conditions revealed a good performance of theoretical approaches to reproduce anharmonic frequencies and intensities. For certain bands which were found to be involved in Fermi resonances, theory did not agree with the experimental observations. Herein we present the IR and VCD spectra of PO recorded in liquefied xenon, an experimental environment which combines the advantages of solution phase and matrix environment. This unique environment allows us to record well-resolved VCD signatures of many combination modes. We show that the VCD signatures of the Fermi resonant modes previously reported for MI-VCD conditions are likely to arise due to matrix effects. Therefore, we compare the experimental results obtained in liquid xenon with state-of-the-art anharmonic spectra calculations in order to shed more light on the assignments of the IR and VCD spectral signatures of PO.

How to treat C-F stretching vibrations? A vibrational CD study on chiral fluorinated molecules.

The analysis of vibrational circular dichroism and infrared spectra typically requires the prediction of spectra on the density functional theory level. In particular for absolute configuration determinations, for which the comparison between experiment and theory is often supported by similarity analysis algorithms, it is important that frequencies, relative band intensities and VCD signs are predicted correctly. Due to the poor prediction of harmonic frequencies, carbon-fluorine stretching vibrations are often strongly misplaced by common hybrid functionals such as B3LYP. Herein we show that the M06-2X functional provides harmonic C-F stretching frequencies with an accuracy sufficient for a reliable spectra analysis. We briefly discuss the origin of this exceptional performance and show that it is likely to be related to a cancellation of errors.

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

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.

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

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.