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

Beta Sheets with a Twist: The Conformation of Helical Polyisocyanopeptides Determined by Using Vibrational Circular Dichroism

Detailed information on the architecture of polyisocyanopeptides based on vibrational circular dichroism (VCD) spectroscopy in combination with DFT calculations is presented. It is demonstrated that the screw sense of the helical polyisocyanides can be determined directly from the C?N‐stretch vibrational region of the VCD spectrum. Analysis of the VCD signals associated with the amide I and amide II modes provides detailed information on the peptide side‐chain arrangement in the polymer and indicates the presence of a helical β‐sheet architecture, in which the dihedral angles are slightly different to those of natural β‐sheet helices.     

Matrix Isolation‐Vibrational Circular Dichroism Spectroscopy of 3‐Butyn‐2‐ol and its Binary Aggregates

Vibrational circular dichroism (VCD) spectroscopy has a unique specificity to chirality and is highly sensitive to the conformational equilibria of chiral molecules. On the other hand, the matrix‐isolation (MI) technique allows substantial control over sample compositions, such as the sample(s)/matrix ratio and the ratio among different samples, and yields spectra with very narrow bandwidths. We combined VCD spectroscopy with the MI technique to record MI‐VCD and MI‐vibrational absorption spectra of 3‐butyn‐2‐ol at different MI temperatures, which allowed us to investigate the conformational distributions of its monomeric and binary species. Good mirror‐imaged MI‐VCD spectra of opposite enantiomers were achieved. The related conformational searches were performed for the monomer and the binary aggregate and their vibrational absorption and VCD spectra were simulated. The well‐resolved experimental MI‐VCD bands provide the essential mean to assign the associated vibrational absorption spectral features correctly to a particular conformation in case of closely spaced bands. By varying the matrix temperature, we show that one can follow the self‐aggregation process of 3‐butyn‐2‐ol and confidently correlate the MI‐VCD spectral features with those obtained for a 0.1 M CCl₄ solution and as a neat liquid at room temperature. Comparison of the aforementioned experimental VCD spectra shows conclusively that there is a substantial contribution from the 3‐butyn‐2‐ol aggregate even at 0.1 M concentration. This spectroscopic combination will be powerful for studying self‐aggregation of chiral molecules, and chirality transfer from a chiral molecule to an interacting achiral molecule and in electron donor–acceptor chiral complexes.     

Conformations of Serine in Aqueous Solutions as Revealed by Vibrational Circular Dichroism

Vibrational circular dichroism (VCD) spectroscopy is utilized to reveal the detailed conformational distributions of the dominant serine species in aqueous solutions under three representative pH conditions of 1.0, 5.7, and 13.0, together with vibrational absorption (VA) spectroscopy, density functional theory (DFT), and molecular dynamics simulation. The experimental VA and VCD spectra of serine in H₂O and D₂O in the fingerprint region under three pH values are obtained. DFT calculations at the B3LYP/6‐311++G(d,p) level are carried out for the protonated, zwitterionic, and deprotonated serine species. The lowest‐energy conformers of all three species are identified and their corresponding VA and VCD spectra simulated. A comparison between the gas‐phase simulations and the experimental VA and VCD spectra suggests that one or two of the most stable conformers of each species contribute predominantly to the observed data, although some discrepancies are noted. To account for the solvent effects, both the polarizable continuum model and the explicit solvation model are considered. Hydrogen‐bonded protonated, zwitterionic, and deprotonated serine–(water)₆ clusters are constructed based on radial distribution function analyses and molecular dynamics snapshots. Geometry optimization and VA and VCD simulations are performed for these clusters at the B3LYP/6‐311++G(d,p) level. Inclusion of the explicit water molecules is found to improve the agreement between theory and experiment noticeably in all three cases, thus enabling conclusive conformational distribution analyses of serine in aqueous solutions directly.     

DFT‐Aided Vibrational Circular Dichroism Spectroscopy Study of (−)‐S‐cotinine

The implementation of a strategy comprising the use of vibrational circular dichroism spectroscopy and DFT calculations allows determination of the solution‐state conformational distribution in (?)‐S‐cotinine, giving further proof of the extra conformer‐discriminating potential of this experimental technique, which may offer unique molecular fingerprints of subtly dissimilar molecular conformers of chiral samples. Natural bond orbital electronic structure calculations of the rotational barrier height between the two main conformers of the species indicate that hyperconjugative effects are the key force governing the conformational equilibrium. The negligible effect of the solvent’s polarity over both structure and conformational energy profile supports this result.     

Interplay of Exciton Coupling and Large‐Amplitude Motions in the Vibrational Circular Dichroism Spectrum of Dehydroquinidine

A detailed analysis of the computed structure, energies, vibrational absorption (VA) and circular dichroism (VCD) spectra of 30 low‐energy conformers of dehydroquinidine reveals the existence of families of pseudo‐conformers, the structures of which differ mostly in the orientation of a single O?H bond. The pseudo‐conformers in a family are separated by very small energy barriers (i.e., 1.0 kcal mol^?1 or smaller) and have very different VCD spectra. First, we demonstrate the unreliable character of the Boltzmann factors predicted with DFT. Then, we show that the large differences observed between the VCD spectra of the pseudo‐conformers in a family are caused by large‐amplitude motions involving the O?H bond, which trigger the appearance/disappearance of strong VCD exciton‐coupling bands in the fingerprint region. This interplay between exciton coupling and large‐amplitude‐motion phenomena demonstrates that when dealing with flexible molecules with polar bonds, vibrational averaging of VCD spectra should not be neglected. In this regard, the dehydroquinidine molecule considered here is expected to be a typical example and not the exception to the rule.     

Conformational Sensitivity in Photoelectron Circular Dichroism of 3‐Methylcyclopentanone

A study of (R)‐3‐methylcyclopentanone [(R)‐3‐MCP] by photoelectron spectroscopy and photoelectron circular dichroism (PECD) is presented. The synchrotron radiation gas‐phase photoelectron spectra of (R)‐3‐MCP were measured and are discussed on the basis of different theoretical methodologies. The experimental dichroism of (R)‐3‐MCP for selected deconvoluted valence states and for the carbonyl carbon 1s core state are reported and reproduced well by calculated dispersions generated by considering the contributions of two different conformers. The theoretical dichroic parameters are calculated by employing a multicentre basis set of B‐spline functions and a Kohn–Sham Hamiltonian. Temperature‐dependent PECD studies of the HOMO state and the carbonyl carbon 1s core level allowed the separation of the contributions of each conformer by photoelectron dichroism. This new approach clearly shows how the PECD methodology is sensitive to conformational and structural changes of unoriented (R)‐3‐MCP in the gas phase, opening up new perspectives in the characterisation of chiral molecular systems.     

Vibrational circular dichroism of polypeptides and proteins

Vibrational circular dichroism spectra of poly-L-tyrosine, poly-L-phenylalanine, myoglobin and-lactoglobulin were measured in solution for the amide I region. These measurements are shown to be consistent with previous determinations of the secondary structures of these species.     

Vibrational Circular Dichroism and Theoretical Study of the Conformational Equilibrium in (−)‐S‐Nicotine

We report an extensive study of the molecular and electronic structure of (?)‐S‐nicotine, to deduce the phenomenon that controls its conformational equilibrium and to solve its solution‐state conformer population. Density functional theory, ab initio, and molecular mechanics calculations were used together with vibrational circular dichroism (VCD) and Fourier transform infrared spectroscopies. Calculations and experiments in solution show that the structure and the conformational energy profile of (?)‐S‐nicotine are not strongly dependent on the medium, thus suggesting that the conformational equilibrium is dominated by hyperconjugative interactions rather than repulsive electronic effects. The analysis of the first recorded VCD spectra of (?)‐S‐nicotine confirmed the presence of two main conformers at room temperature. Our results provide further evidence of the hypersensitivity of vibrational optical activity spectroscopies to the three‐dimensional structure of chiral samples and prove their suitability for the elucidation of solution‐state conformer distribution.     

Polymorphism of Amyloid Fibrils Induced by Catalytic Seeding: A Vibrational Circular Dichroism Study

Amyloidal protein fibrils occur in many biological events, but their formation and structural variability are understood rather poorly. We systematically explore fibril polymorphism for polyglutamic acid (PGA), insulin and hen egg white lysozyme. The fibrils were grown in the presence of “seeds”, that is fibrils of the same or different protein. The seeds in concentrations higher than about 5 % of the total protein amount fully determined the structure of the final fibrils. Fibril structure was monitored by vibrational circular dichroism (VCD) spectroscopy and other techniques. The VCD shapes significantly differ for different fibril samples. Infrared (IR) and VCD spectra of PGA were also simulated using density functional theory (DFT) and a periodic model. The simulation provides excellent basis for data interpretation and reveals that the spectral shapes and signs depend both on fibril length and twist. The understanding of fibril formation and interactions may facilitate medical treatment of protein misfolding diseases in the future.     

振动圆二色谱: 一种确定手性分子绝对构型的新方法

手性分子绝对构型的确定是一个极其重要且长期存在的问题. 振动圆二色谱是在红外波长区域测定分子圆二色性的一种新方法, 极大地扩展了圆二色谱的应用范围. 振动圆二色谱法通过构象搜索、量子化学计算等手段准确预测手性分子的振动圆二色谱图, 进而与实测谱图进行比较确定其绝对构型. 该方法已经得到了越来越广泛的应用, 必将成为一种有效测定手性分子绝对构型的常规方法.     

Matrix Isolation-Vibrational Circular Dichroism Spectroscopic Study of Conformations and Non-Covalent Interactions of Tetrahydro-2-Furoic Acid

The conformational landscape and aggregation behaviour of tetrahydro-2-furoic acid (THFA) were investigated by using matrix isolation-vibrational circular dichroism (MI-VCD). The well-resolved experimental MI-IR and MI-VCD features in an argon matrix at 10 K allow one to identify two dominant monomeric conformations as trans-THFA where the hydroxyl and carbonyl groups of COOH are at opposite sides, as well as one cis-conformer. At 24 K and 30 K deposition temperatures, the experimental IR and VCD spectral features reveal further growth of the binary THFA aggregates. Systematic conformational searches identified three vastly different binary binding topologies, resulting in a few hundred stable (THFA)₂ conformers. Interestingly, the main binary structures observed correspond to an unusual type of structure which is made of two trans-THFA subunits, in contrast to the usual double H-bonded ring binary structures, identified in a previous solution study. The present work showcases the power of MI-VCD spectroscopy in revealing unusual structures formed in a cold rare gas matrix.     

Determination of the Absolute Configuration of Pentacoordinate Chiral Phosphorus Compounds in Solution by Using Vibrational Circular Dichroism Spectroscopy and Density Functional Theory

Vibrational circular dichroism (VCD) spectroscopic measurements and density functional theory (DFT) calculations have been used to obtain the absolute structural information about four sets of diastereomers of pentacoordinate spirophosphoranes derived separately from l‐ (or d‐ ) valine and l‐ (or d‐ ) leucine for the first time. Each compound contains three stereogenic centers: one at the phosphorus center and two at the amino acid ligands. Extensive conformational searches for the compounds have been carried out and their vibrational absorption (VA) and VCD spectra have been simulated at the B3LYP/6‐311++G** level. Although both VA and VCD spectra are highly sensitive to the structural variation of the apical axis, that is, the O? P? O or N? P? O arrangement, the rotamers generated by the aliphatic amino side chains show little effect on both. The dominant experimental VCD features in the 1100–1500 cm^?1 region were found to be controlled by the chirality at the phosphorus center, whereas those at the C?O stretching region are determined by the chirality of the amino acid ligands. The good agreement between the experimental VA and VCD spectra in CDCl₃ solution and the simulated ones allows us to assign the absolute configurations of these pentacoordinate phosphorus compounds with high confidence. This study shows that the VCD spectroscopy complemented with DFT calculations is a powerful and reliable method for determining the absolute configurations and dominating conformers of synthetic phosphorus coordination complexes in solution.