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.     

Electronic Structure and Circular Dichroism of Natural Alboatisins Isolated from Aerial Parts of Isodon Albopilosus: DFT and TDDFT Study

The stable conformations of a series of bioactive molecules, (?)-alboatisins A?C, are identified via Monte Carlo searching with the MMFF94 molecular mechanics force field. Then, the optical rotation (OR) values, vibrational circular dichroism (VCD), and electronic circular dichroism (ECD) spectra were calculated using the gradient-corrected density functional theory method. The vibrational and transition modes of molecular chirality were explored in terms of their microscopic origin. The calculated specific rotations are in agreement with the experimental values. From the OR analysis, it was concluded that optical rotation values areregulated by hydroxyl substitution. Vibrations occurring on the chiral skeleton may cause strong absorption in VCD spectra; VCD spectra are thus the spectral response to deformation vibrations on the chiral carbon skeleton. The lowest-energy negative Cotton effect is caused by σ→π^* transition. Frontier molecular orbital analysis showed that strong ECD absorptions are produced when the dominant transition on the chiral skeleton is asymmetric; ECD spectra show the result of transitions lacking asymmetry on the chiral skeleton.     

Combined use of three forms of chiroptical spectroscopies in the study of the absolute configuration and conformational properties of 3-phenylcyclopentanone, 3-phenylcyclohexanone,and 3-phenylcycloheptanone

Three forms of chiroptical spectroscopies, electronic circular dichroism (ECD), vibrational circular dichroism (VCD), and optical rotatory dispersion (ORD) have been employed to study the configuration and conformational properties of the three molecules: (S)-3-phenylcyclopentanone, (S)-3-phenylcyclohexanone, and (S)-3-phenylcycloheptanone (including (S)-3-phenylcyclopentanone-2,2,5,5-d₄ and (S)-3-phenylcyclohexanone-2,2,6,6-d₄). ECD and VCD spectra in the mid-IR for the three molecular systems are marginally dependent on fine conformational details, as interpreted in terms of standard DFT computational methods, with common spectroscopic features to the three systems clearly identified. Accounting for vibronic coupling mechanisms reproduces the structuring of ECD n→π^∗ band. The ORD curves are quite similar for the three types of molecules, but their interpretation highlights a crucial role played by conformations of the cycloalkanone ring in the case of (S)-3-phenylcycloheptanone. The same conclusions are reached by considering the VCD spectra in the CH-stretching region.     

Induced Chiroptical Changes of a Water‐Soluble Cryptophane by Encapsulation of Guest Molecules and Counterion Effects

We report the synthesis of the water‐soluble cryptophanol derivative 1 and the study of the chiroptical properties of its two enantiomers (>99 % ee) by polarimetry, electronic circular dichroism (ECD), and vibrational circular dichroism (VCD). We show that cryptophanol 1 exhibits unusual chiroptical properties in water under basic conditions (pH>12). For instance, the shapes of the ECD and VCD spectra of 1 in water were strongly dependent on the nature of the alkali metal ions (Li⁺, Na⁺, K⁺, Cs⁺) surrounding the cryptophane and whether or not a guest molecule is present inside the cavity of the host. To the best of our knowledge, this is the first example in which the nature of these counterions governs the chiroptical properties of a host molecule. Moreover, specific ECD spectra were obtained depending on the size of the guest molecules. This makes 1 a good sensor for small neutral molecules in aqueous solvent. Finally, VCD experiments associated with DFT calculations show that the chiroptical changes can be directly correlated to the presence of charges close to the aromatic rings and with a conformational change of the alkyl chains upon encapsulation.     

Determination of the Absolute Configuration of (−)‐Mirtazapine by Vibrational Circular Dichroism

The absolute configuration of the (−)‐enantiomer of mirtazapine was determined by means of vibrational circular dichroism (VCD). The observed VCD of (−)‐mirtazapine showed excellent correlation with the calculated VCD of the (R)‐enantiomer. This is in agreement with the absolute configuration as determined by independent synthesis starting from (R)‐phenylglycine.     

Aromatic Cluster Sensor of Protein Folding: Near‐UV Electronic Circular Dichroism Bands Assigned to Fold Compactness

Both far‐ and near‐UV electronic circular dichroism (ECD) spectra have bands sensitive to thermal unfolding of Trp and Tyr residues containing proteins. Beside spectral changes at 222 nm reporting secondary structural variations (far‐UV range), L_b bands (near‐UV range) are applicable as 3D‐fold sensors of protein's core structure. In this study we show that both L_b(Tyr) and L_b(Trp) ECD bands could be used as sensors of fold compactness. ECD is a relative method and thus requires NMR referencing and cross‐validation, also provided here. The ensemble of 204 ECD spectra of Trp‐cage miniproteins is analysed as a training set for “calibrating” Trp?Tyr folded systems of known NMR structure. While in the far‐UV ECD spectra changes are linear as a function of the temperature, near‐UV ECD data indicate a non‐linear and thus, cooperative unfolding mechanism of these proteins. Ensemble of ECD spectra deconvoluted gives both conformational weights and insight to a protein folding?unfolding mechanism. We found that the L_b²⁹³ band is reporting on the 3D‐structure compactness. In addition, the pure near‐UV ECD spectrum of the unfolded state is described here for the first time. Thus, ECD folding information now validated can be applied with confidence in a large thermal window (5≤T≤85 °C) compared to NMR for studying the unfolding of Trp?Tyr residue pairs. In conclusion, folding propensities of important proteins (RNA polymerase II, ubiquitin protein ligase, tryptase‐inhibitor etc.) can now be analysed with higher confidence.     

Vibrational Excitons in CH-Stretching Fundamental and Overtone Vibrational Circular Dichroism Spectra

Summary. A set of vibrational circular dichroism (VCD) spectra in the CH-stretching fundamental region for about twenty compounds belonging to the class of essential oils was empirically analyzed by the use of a sort of vibrational exciton mechanism, involving three centers. Through a general formula applicable to many coupled dipole oscillators, the rotational strengths of the previously identified vibrational excitons are evaluated. The results are then critically reviewed by the use of recent ab initio methodology, as applied to selected molecules of the original set. Further insight is gained by model calculations adding up the contribution of the coupling between electric dipole moments associated with normal mode behavior and that of the polarizability from polarizable groups. The former part is responsible for the excitonic behavior of the VCD spectra. For the same selected molecules we have also investigated whether some excitonic behavior is taking place in the second overtone region, and have concluded that this is not the case.     

Spectrum–Structure Relationship in Carbohydrate Vibrational Circular Dichroism and Its Application to Glycoconjugates

Preliminary reports of the nature of the vibrational circular dichroism (VCD) peak at around 1145 cm^?1, which is characteristic of axial glycosidic sugars and is called the glycoside band (J. Am. Chem. Soc. 2004 , 126, 9496), have been throughly examined. Through systematic carbohydrate measurements, it was found that the sign of the glycoside band reflects not only the anomeric configuration but also the pyranose conformation. Isotope and theoretical studies characterized its vibrational mode as C1–H1 deformation coupled with C1–O1 stretching, which indicates its applicability to more‐complicated glycoconjugates. In this study, for the first time, carbohydrate VCD spectra were reliably predicted by means of density functional theory (DFT) calculations. The VCD technique was applied to glycopeptides, and simultaneous analysis of both the carbohydrate and aglycan parts was carried out.     

振动圆二色谱在轴手性β-双咔啉N—O衍生物立体化学研究中的应用

采用振动圆二色谱(VCD)方法研究了一个具有高度催化活性的轴手性结构的双咔啉N—O化合物的立体化学结构. 在B3LYP/6-311+G(d)水平上得到的计算结果表明, 对于具有负旋光值的双咔啉N—O化合物化合物, 其绝对构型是aS. 同时, 分别计算了双咔啉N—O化合物的电子圆二色谱(ECD)和旋光值, 并与实验结果进行了比较. 在化合物结构完全正确条件下, VCD, ECD和旋光数据均表明, 具有负旋光值的该化合物的绝对构型是aS.     

Vibrational Circular Dichroism Spectroscopy of Three Multidentate Nitrogen Donor Ligands: Conformational Flexibility and Solvent Effects

A series of multidentate nitrogen donor ligands have been synthesized and characterized and their conformational distributions in solution have been investigated. Vibrational absorption (VA) and vibrational circular dichroism (VCD) spectroscopy, complemented with DFT calculations, have been used to probe the conformations of these important ligands in solution directly. These three ligands demonstrate very different conformational flexibility; the pyridine subunits and amine groups may adopt a number of different conformations. Experimental VA and VCD data measured in CDCl₃ have been compared to the theoretical spectra of all possible most stable conformers. Solvent effects have been taken into account by using the implicit polarizable continuum model and explicit solvation model. The explicit hydrogen‐bonding solvation model is important for explaining the VCD sign‐reverse phenomenon in the amide I region. Good agreement has been achieved between experimental and predicted spectra for all three ligands; thus allowing detailed examination of the related conformational structures and distributions in solution.     

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.     

Trans-methyl-azido-bis(triisopropylphosphin)platin(II), [PtN3(CH3)(PiPr3)2]

Trans-methyl-azido-bis(triisopropylphosphine)platinum(II), [PtN₃(CH₃)(PⁱPr₃)₂] [PtN₃(CH₃)(PⁱPr₃)₂] has been prepared by reductive elimination of ethane from [Pt(CH₃)₃N₃]₄ in the presence of triisopropylphosphine at 80 °C. The complex is characterized by IR and NMR spectroscopy and by crystal structure determination, as well as by ab initio calculations. [PtN₃(CH₃)(PⁱPr₃)₂], which is in trans-configuration here, crystallizes in the monoclinic space group P2₁, Z = 2, and with the lattice dimensions a = 806.9(1), b = 1384.3(1), c = 1093.8(1) pm, β = 94.107(10)°.     

应用电子圆二色光谱方法确定手性金属配合物的绝对构型

与电子能级跃迁相关的电子圆二色(ECD)光谱因其研究对象宽泛,与涉及振动能级的振动圆二色(VCD)光谱互补,已成为应用于手性立体化学研究的集成手性光谱的主流表征手段。本文概述了确定手性金属配合物绝对构型的三种主要方法,详细介绍了ECD光谱法在确定手性金属配合物绝对构型中的应用,其中着重强调了激子手性方法,并对集成手性光谱学未来的发展趋势做出了展望。     

An Unexpected Atropisomerically Stable 1,1‐Biphenyl at Ambient Temperature in Solution,Elucidated by Vibrational Circular Dichroism (VCD)

Biphenyls with only two substituents at the ‘peri'‐position normally show rotation about their chiral axis at room temperature. Using vibrational circular dichroism (VCD), we found no evidence for rotation of (P)‐2′‐[(4S)‐4,5‐dihydro‐4‐(1‐methylethyl)oxazol‐2‐yl][1,1′‐biphenyl]‐2‐methanol ((P,S)‐ 1 ) in CDCl₃ about its chiral axis due to stabilization by intramolecular H‐bonding. All rotamers of 1 were calculated at the DFT level, and, from these optimized structures, the VCD spectra were calculated and compared to the measured VCD spectra. The best agreement between calculated and measured spectra is obtained when two rotamers are present in solution. These rotamers differ primarily in their intramolecular H‐bonding interactions, having either OH???N (the form present in the solid state) or OH???O H‐bonds, i.e., a rotation of the heterocycle in 1 takes place in solution.     

Electronic Circular Dichroism Imaging (ECDi) Casts a New Light on the Origin of Solid-State Chiroptical Properties

Solid-state ECD (ss-ECD) spectra of a model microcrystalline solid, finasteride, dispersed into a KCl pellet were recorded by using the synchrotron radiation source at the Diamond B23 beamline. Scanning a surface of 36 mm² with a step of 0.5 mm, we measured a set of ECD imaging (ECDi) spectra very different from each other and from the ss-ECD recorded with a bench-top instrument (1 cm² area). This is due to the anisotropic part of the ECD (ACD), which averages to zero in solution or on a large number of randomly oriented crystallites, but can otherwise be extremely large. Two-way singular value decomposition (SVD) analysis, through experimental and simulated TDDFT spectra, disclosed that the measured and theoretical principal components are in line with each other. This finding demonstrates that the observed isotropic ss-ECD spectrum is governed by the anisotropy of locally oriented crystals. It also introduces a new quality for ss-ECD measurements and opens a new future for probing and mapping chiral materials in the solid state such as active pharmaceutical ingredients (APIs).     

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.     

Simulation of Electronic Circular Dichroism of Nucleic Acids: From the Structure to the Spectrum

We present a quantum mechanical (QM) simulation of the electronic circular dichroism (ECD) of nucleic acids (NAs). The simulation combines classical molecular dynamics, to obtain the structure and its temperature‐dependent fluctuations, with a QM excitonic model to determine the ECD. The excitonic model takes into account environmental effects through a polarizable embedding and uses a refined approach to calculate the electronic couplings in terms of full transition densities. Three NAs with either similar conformations but different base sequences or similar base sequences but different conformations have been investigated and the results were compared with experimental observations; a good agreement was seen in all cases. A detailed analysis of the nature of the ECD bands in terms of their excitonic composition was also carried out. Finally, a comparison between the QM and the DeVoe models clearly revealed the importance of including fluctuations of the excitonic parameters and of accurately determining the electronic couplings. This study demonstrates the feasibility of the ab initio simulation of the ECD spectra of NAs, that is, without the need of experimental structural or electronic data.     

Vibrational circular dichroism and ab initio structure elucidation of an aromatic foldamer

Ab initio calculations together with vibrational circular dichroism (VCD) are validated as very accurate tools for studying conformations and estimating conformational energies and helical handedness preferences of an entire, large (112 atoms), abiotic foldamer.     

A Tunable,Fullerene-Based Molecular Amplifier for Vibrational Circular Dichroism

Vibrational circular dichroism (VCD) studies are reported on a chiral compound in which a fullerene C₆₀ moiety is used as an electron acceptor and local VCD amplifier for an alanine-based peptide chain. Four redox states are investigated in this study, of which three are reduced species that possess low-lying electronic states as confirmed by UV/Vis spectroelectrochemistry. VCD measurements in combination with (TD)DFT calculations are used to investigate (i) how the low-lying electronic states of the reduced species modulate the amplification of VCD signals, (ii) how this amplification depends on the distance between oscillator and amplifier, and (iii) how the spatial extent of the amplifier influences amplification. These results pave the way for further development of tailored molecular VCD amplifiers.