Synthesis and Chiroptical Properties of a Chiral Isotopologue of syn-Cryptophane-B.

We report the synthesis and absolute configuration (AC) of a chiral isotopologue of syn-cryptophane-B. Low chiral signatures were measured by polarimetry and electronic circular dichroism, whereas most significant chiroptical effects were observed by vibrational circular dichroism (VCD) and Raman optical activity (ROA). The comparison of experimental VCD and ROA spectra with those predicted by DFT calculations allows the determination of the AC of the two enantiomers as (-)589-MP-syn-2 and (+)589-PM-syn-2.

Conformational analysis of amphetamine and methamphetamine: a comprehensive approach by vibrational and chiroptical spectroscopy.

After cannabis, the most commonly used illicit substance worldwide is amphetamine and its derivatives, such as methamphetamine, with an ever-increasing number of synthetic modifications. Thus, fast and reliable methods are needed to identify them according to their spectral patterns and structures. Here, we have investigated the use of molecular spectroscopy methods to describe the 3D structures of these substances in a solution that models the physiological environment. The substances were analyzed by Raman and infrared (IR) absorption spectroscopy and by chiroptical methods, vibrational circular dichroism (VCD) and Raman optical activity (ROA). The obtained experimental data were supported by three different computational approaches based on density functional theory (DFT) and molecular dynamics (MD). Successful interpretation relies on good agreement between experimental and predicted spectra. The determination of the conformer populations of the studied molecules was based on maximizing the similarity overlap of weighted conformer spectra by a global minimization algorithm. Very good agreement was obtained between the experimental spectra and optimized-population weighted spectra from MD, providing a detailed insight into the structure of the molecules and their interaction with the solvent. The relative population of three amphetamine and six methamphetamine conformers was determined and is consistent with a previous NMR study. However, this work shows that only a few isolated conformers are not sufficient for the successful interpretation of the spectra, but the entire conformational space needs to be sampled appropriately and explicit interaction with the solvent needs to be included.

Molecular dynamics and Raman optical activity spectra reveal nucleotide conformation ratios in solution.

Nucleotide conformational flexibility affects their biological functions. Although the spectroscopy of Raman optical activity (ROA) is well suited to structural analyses in aqueous solutions, the link between the spectral shape and the nucleotide geometry is not fully understood. We recorded the Raman and ROA spectra of model nucleotides (rAMP, rGMP, rCMP, and dTMP) and interpreted them on the basis of molecular dynamics (MD) combined with density functional theory (DFT). The relation between the sugar puckering, base conformation and spectral intensities is discussed. Hydrogen bonds between the sugar's C3' hydroxyl and the phosphate groups were found to be important for the sugar puckering. The simulated spectra correlated well with the experimental data and provided an understanding of the dependence of the spectral shapes on conformational dynamics. Most of the strongest spectral bands could be assigned to vibrational molecular motions. Decomposition of the experimental spectra into calculated subspectra based on arbitrary maps of free energies provided experimental conformer populations, which could be used to verify and improve the MD predictions. The analyses indicate some flaws of common MD force fields, such as being unable to describe the fine conformer distribution. Also the accuracy of conformer populations obtained from the spectroscopic data depends on the simulations, improvement of which is desirable for gaining a more detailed insight in the future. Improvement of the spectroscopic and computational methodology for nucleotides also provides opportunities for its application to larger nucleic acids.

Combination of Resonance and Non-Resonance Chiral Raman Scattering in a Cobalt(III) Complex.

Resonance Raman optical activity (RROA) spectra with high sensitivity reveal details on molecular structure, chirality, and excited electronic properties. Despite the difficulty of the measurements, the recorded data for the Co(III) complex with S,S-N,N-ethylenediaminedisuccinic acid are of exceptional quality and, coupled with the theory, spectacularly document the molecular behavior in resonance. This includes a huge enhancement of the chiral scattering, contribution of the antisymmetric polarizabilities to the signal, and the Herzberg-Teller effect significantly shaping the spectra. The chiral component is by about one order of magnitude bigger than for an analogous aluminum complex. The band assignment and intensity profile were confirmed by simulations based on density functional and vibronic theories. The resonance was attributed to the S0 →S3 transition, with the strongest signal enhancement of Raman and ROA spectral bands below about 800 cm-1 . For higher wavenumbers, other excited electronic states contribute to the scattering in a less resonant way. RROA spectroscopy thus appears as a unique tool to study the structure and electronic states of absorbing molecules in analytical chemistry, biology, and material science.

Structure of Zinc and Nickel Histidine Complexes in Solution Revealed by Molecular Dynamics and Raman Optical Activity.

The histidine residue has an exceptional affinity for metals, but solution structure of its complexes are difficult to study. For zinc and nickel complexes, Raman and Raman optical activity (ROA) spectroscopy methods to investigate the link between spectral shapes and the geometry were used. The spectra were recorded and interpreted on the basis of ionic equilibria, molecular dynamics, ab initio molecular dynamics, and density functional theory. For zwitterionic histidine the dominant tautomer was determined by the decomposition of experimental spectra into calculated subspectra. An octahedral structure was found to prevail for the ZnHis2 complex in solution, in contrast to a tetrahedral arrangement in the crystal phase. The solution geometry of NiHis2 is more similar to the octahedral structure found by X-ray. The Raman and ROA structural determinations of metal complexes are dependent on extensive computations, but reveal unique information about the studied systems.

Electronic Circular Dichroism-Circularly Polarized Raman (eCP-Raman): A New Form of Chiral Raman Spectroscopy.

This Concept article summarizes recent work on the development of a new form of chiral Raman spectroscopy, eCP-Raman, which combines two spectroscopies: electronic circular dichroism (ECD) and circularly polarized Raman (CP-Raman). First, some puzzling observations while carrying out Raman optical activity (ROA) measurements of several transition metal complexes under resonance are described, as well as the search for the mechanisms responsible. Then an equation for quantifying the eCP-Raman contribution is presented, followed by several examples of how eCP-Raman influences the IR -IL spectra of achiral and chiral solvent molecules and of a number of chiral solutes under resonance. The conditions to extract resonance ROA, when the eCP-Raman contribution is minimized, are also discussed. Finally, we comment on the potential applications of eCP-Raman.

Low-frequency Raman optical activity provides insight into the structure of chiral liquids.

Vibrational frequencies of modes involving intermolecular motions in liquids are relatively small, in the Raman scattering close to the excitation frequency, and the bands may merge into a diverging uninterpretable signal. Raman optical activity (ROA) spectral shapes in this region, however, are structured more and may better reflect the nature of the studied systems. To understand the origin of the signal and its relation to the molecules, ROA spectra of six chiral neat liquids are recorded and analyzed on the basis of molecular dynamics and density functional theory computations. The theory of Raman scattering of liquids is discussed and adapted for modeling based on clusters and periodic boundary conditions. A plain cluster approach is compared to a crystal-like model. The results show that the low-frequency optical activity can be reliably modeled and related to the structure. However, momentary arrangement of molecules leads to large variations of optical activity, and a relatively large number of geometries need to be averaged for accurate simulations. The intermolecular modes are intertwined with intramolecular ones and start to dominate as the frequency goes down. The low-frequency ROA signal thus reflects the chemical composition and coupled with the modeling it provides a welcome means to study the structure and interactions of chiral liquids.

α-Synuclein conformations followed by vibrational optical activity. Simulation and understanding of the spectra.

α-Synuclein is a neuronal protein which adopts multiple conformations. These can be conveniently studied by the spectroscopy of vibrational optical activity (VOA). However, the interpretation of VOA spectra based on quantum-chemical simulations is difficult. To overcome the hampering of the computations by the protein size, we used the Cartesian tensor transfer technique to investigate links between the spectral shapes and protein structure. Vibrational circular dichroism (VCD) and Raman optical activity (ROA) spectra of α-synuclein in disordered, α-helical and ß-sheet (fibril) forms were measured and analyzed on the basis of molecular dynamics and density functional theory computations. For the disordered and α-helical conformers, a high fidelity of the simulated spectra with a reasonable computational cost was achieved. Most experimental spectral features could be assigned to the structure. So far unreported ROA marker bands of the secondary structure were found for the lower-frequency and CH stretching vibrations. Fibril VCD spectra were simulated with a rigid periodic model of the geometry and the results are consistent with previous studies based on cryogenic electron microscopy. The fibrils also give a specific ROA signal, but unlike VCD it is currently not fully explicable by the simulations. In connection with the computational modeling the VOA spectroscopy thus appears as an extremely useful tool for monitoring α-synuclein and other proteins in solutions.

Recognition of the True and False Resonance Raman Optical Activity.

Resonance Raman optical activity (RROA) possesses all aspects of a sensitive tool for molecular detection, but its measurement remains challenging. We demonstrate that reliable recording of RROA of chiral colorful compounds is possible, but only after considering the effect of the electronic circular dichroism (ECD) on the ROA spectra induced by the dissolved chiral compound. We show RROA for a number of model vitamin B12 derivatives that are chemically similar but exhibit distinctively different spectroscopic behavior. The ECD/ROA effect is proportional to the concentration and dependent on the optical pathlength of the light propagating through the sample. It can severely alter relative band intensities and signs in the natural RROA spectra. The spectra analyses are supported by computational modeling based on density functional theory. Neglecting the ECD effect during ROA measurement can lead to misinterpretation of the recorded spectra and erroneous conclusions about the molecular structure.

Raman Optical Activity of Glucose and Sorbose in Extended Wavenumber Range.

Raman optical activity (ROA) is pursued as a promising method for structural analyses of sugars in aqueous solutions. In the present study, experimental Raman and ROA spectra of glucose and sorbose obtained in an extended range (50-4000 cm-1 ) are interpreted using molecular dynamics and density functional theory, with the emphasis on CH stretching modes. A reasonable theoretical basis for spectral interpretation was obtained already at the harmonic level. Anharmonic corrections led to minor shifts of band positions (up to 25 cm-1 ) below 2000 cm-1 , while the CH stretching bands shifted more, by ∼180 cm-1 , and better reproduced the experiment. However, the anharmonicities could be included on a relatively low approximation level only, and they did not always improve the harmonic band shapes. The dependence on the structure and conformation shows that the CH stretching ROA spectral pattern is a sensitive marker useful in saccharide structure studies.

Understanding CH-Stretching Raman Optical Activity in Ala-Ala Dipeptides.

Raman optical activity (ROA) becomes a standard method to monitor peptide conformation. However, the signal in the CH-stretching region is particularly difficult to measure and interpret. In order to understand the structural information contained in this part of the spectrum, data obtained on a custom-made ROA spectrometer have been analyzed for the model Ala-Ala molecule, with the help of molecular dynamics (MD) and density functional theory computations. The Ala-Ala enantiomers provided the "mirror image" spectra, which proves that the signal can be reliably measured, in spite of a rather low ROA/Raman intensity ratio (∼2 × 10-5). The theoretical modeling indicated that the most intense ROA bands can be attributed to locally asymmetric CH3 and αCH vibrations, whereas symmetric methyl CH-stretching modes contribute less. A simplified model made it possible to estimate the contribution of local chirality of the two alanine residues to the resultant ROA pattern. In spite of a significant frequency shift (over 100 cm-1) because of the anharmonic corrections, the harmonic level was able to explain the main spectral features. The anharmonic corrections were treated by second-order perturbation and limited vibrational configuration interaction procedures. This allowed for assignment of some weaker spectral features because of the combination and overtone vibrations. The results show that the peptide CH-stretching ROA signal contains rich structural information, reflecting also the peptide environment. The experimental data, however, need to be deciphered by relatively complex and time-consuming spectral simulations.

Two Spectroscopies in One: Interference of Circular Dichroism and Raman Optical Activity.

Previously, we and other laboratories have reported an unusual and strong Raman optical activity (ROA) induced in solvents by chiral dyes. Various theories of the phenomenon appeared, but they were not capable of explaining fully the observed ROA band signs and intensities. In this work, an analysis based both on the light scattering theory and dedicated experiments provides a more complete understanding. For example, double-cell magnetic circular dichroism and magnetic ROA experiments with copper-porphyrin complex show that the induced chirality is observed without any contact of the solvents with the complex. The results thus indicate that a combination of electronic circular dichroism (ECD) with the polarized Raman scattering is responsible for the effect. The degree of circularity of solvent vibrational bands is a principal molecular property participating in the event. The insight and the possibility to predict the chirality transfer promise future applications in spectroscopy, chemical analysis and polarized imaging.

Insight into vibrational circular dichroism of proteins by density functional modeling.

Vibrational circular dichroism (VCD) spectroscopy is an excellent method to determine the secondary structure of proteins in solution. Comparison of experimental spectra with quantum-chemical simulations represents a convenient and objective way to extract information on the structure. This has been difficult for such large molecules where approximate theoretical models have to be used. In the present study we applied the Cartesian-coordinate based tensor transfer (CCT) making it possible to extend the density functional theory (DFT) and model spectral intensities of large globular proteins nearly at quantum-chemical precision. Indeed, comparison with experiment provided a better understanding of the dependence of VCD spectral shapes on the geometry, their sensitivity to fine structural details and interactions with the environment. On a model set of globular proteins the simulated spectra correlated well with experimental data and revealed which structural information can (and cannot) be obtained from this kind of spectroscopy. Although the VCD technique has been regarded as being rather insensitive to side-chain variations, we found that the spectra of human and hen lysozyme differing by a few amino acids only are quite distinct. This has been explained by long-distance coupling of the amide vibrations. Likewise, the modeling reproduced some spectral changes caused by protein deuteration even when the protein structure was conserved.

Identification of Lanthanide(III) Luminophores in Magnetic Circularly Polarized Luminescence Using Raman Optical Activity Instrumentation.

Luminescence of lanthanide(III) ions sensitively reflects atomic environment. However, the signal may be weak and covered by Raman scattering. In the present study magnetic circularly polarized luminescence (MCPL) is explored as a more sensitive tool to recognize the lanthanide signal and assign underlying electronic transitions. MCPL spectra of the Na3[Ln(DPA)3] (Ln = Ce, Pr, Nd, Sm, Eu, Tb, Dy, Ho, and Er) complexes were recorded on a Raman optical activity (ROA) instrument. The ROA spectrometer equipped with the 532 nm laser excitation sensitively detects differences in scattering of left- and right-circularly polarized light caused by the magnetic field. Weak bands sometimes invisible in unpolarized measurement could be detected as MCPL. Observed transitions were assigned with the aid of the ligand-field theory. MCPL also reflects the environment: chloride and nitrate salts (LnCl3 and Ln(NO3)3) provide a different signal than the complex; for NdIII the signal responds to distribution of chloride and nitrate ions around the metal. The MCPL technique thus appears useful for identification and assignment of lanthanide transitions and increases the potential of fluorescent probes for applications in analytical chemistry and imaging.

Diamagnetic Raman Optical Activity of Chlorine, Bromine, and Iodine Gases.

Magnetic Raman optical activity of gases provides unique information about their electric and magnetic properties. Magnetic Raman optical activity has recently been observed in a paramagnetic gas (Angew. Chem. Int. Ed. 2012, 51, 11058; Angew. Chem. 2012, 124, 11220). In diamagnetic molecules, it has been considered too weak to be measurable. However, in chlorine, bromine and iodine vapors, we could detect a significant signal as well. Zeeman splitting of electronic ground-state energy levels cannot rationalize the observed circular intensity difference (CID) values of about 10(-4). These are explicable by participation of paramagnetic excited electronic states. Then a simple model including one electronic excited state provides reasonable spectral intensities. The results suggest that this kind of scattering by diamagnetic molecules is a general event observable under resonance conditions. The phenomenon sheds new light on the role of excited states in the Raman scattering, and may be used to probe molecular geometry and electronic structure.

Detection of Circularly Polarized Luminescence of a Cs-Eu(III) Complex in Raman Optical Activity Experiments.

Circularly polarized luminescence (CPL) spectra are extremely sensitive to molecular structure. However, conventional CPL measurements are difficult and require expensive instrumentation. As an alternative, we explore CPL using Raman scattering and Raman optical activity (ROA) spectroscopy. The cesium tetrakis(3-heptafluoro-butylryl-(+)-camphorato) europium(III) complex was chosen as a model as it is known to exhibit very large CPL dissymmetry ratio. The fluorescent bands could be discriminated from true Raman signals by comparison of spectra acquired with different laser excitation wavelengths. Furthermore, the ROA technique enables fluorescence identification by measuring the degree of circularity. The CPL dissymmetry ratio was measured as the ROA circular intensity difference of 0.71, the largest one ever reported. The alternative CPL measurement enhances applications of lanthanides in analytical chemistry and chemical imaging of biological objects.

Probing solution conformations of l-DOPA: Integration of experiment and simulation via vibrational optical activity.

l-DOPA plays a critical role as a precursor to dopamine and is a standard treatment for Parkinson's disease. Recent research has highlighted the potential therapeutic advantages of deuterated l-DOPA analogs having a longer biological half-life. For their spectroscopic characterization, the in-detail characterization of l-DOPA itself is necessary. This article presents a thorough examination of the vibrational spectra of l-DOPA, with a particular emphasis on chirally sensitive VOA techniques. We successfully obtained high-quality Raman and ROA spectra of l-DOPA in its cationic form, under low pH conditions, and at a high concentration of 100 mg/ml. These spectra cover a broad spectral range, allowing for precise comparisons with theoretical simulations. We also obtained IR and VCD spectra, but they faced limitations due to the narrow accessible spectral region. Exploration of l-DOPA's conformational landscape revealed its intrinsic flexibility, with multiple coexisting conformations. To characterize these conformations, we employed two methods: one involved potential energy surface scans with implicit solvation, and the other utilized molecular dynamics simulations with explicit solvation. Comparing ROA spectra from different conformer groups and applying spectral decomposition proved crucial in determining the correct conformer ratios. The use of explicit solvation significantly improved the quality of the final simulated spectral profiles. The accurate determination of conformer ratios, rather than solely relying on the number of averaged spectra, played a crucial role in simulation accuracy. In conclusion, our study offers valuable insights into the structure and conformational behavior of l-DOPA and represents a valuable resource for subsequent spectroscopic studies of its deuterated analogs.

Monitoring Conformation and Protonation States of Glutathione by Raman Optical Activity and Molecular Dynamics.

Glutathione (GSH) is a common antioxidant and its biological activity depends on the conformation and protonation state. We used molecular dynamics, Raman and Raman optical activity (ROA) spectroscopies to investigate GSH structural changes in a broad pH range. Factor analysis of the spectra provided protonation constants (2.05, 3.45, 8.62, 9.41) in good agreement with previously published values. Following the analysis, spectra of differently protonated forms were obtained by extrapolation. The complete deprotonation of the thiol group above pH 11 was clearly visible in the spectra; however, many spectral features did not change much with pH. Experimental spectra at various pH values were decomposed into the simulated ones, which allowed us to study the conformer populations and quality of molecular dynamics (MD). According to this combined ROA/MD analysis conformation of the GSH backbone is affected by the pH changes only in a limited way. The combination of ROA with the computations thus has the potential to improve the MD force field and obtain more accurate populations of the conformer species. The methodology can be used for any molecule, but for a more detailed insight better computational techniques are needed in the future.

Application of inelastic neutron scattering to studies of CO2 reforming of methane over alumina-supported nickel and gold-doped nickel catalysts.

The methane reforming reaction with carbon dioxide as the oxidant over alumina-supported nickel and gold-doped nickel catalysts is studied using a variety of techniques such as reaction testing, vibrational spectroscopy (inelastic neutron scattering (INS), Raman scattering and infrared absorption), temperature-programmed oxidation (TPO), transmission electron microscopy and X-ray powder diffraction. The quantities of retained carbon and hydrogen are determined by TPO and INS, respectively. Minimal hydrogen retention indicates these catalysts to be very efficient at cycling hydrogen. The relative partitioning of hydrogen within the reaction media is used to formulate a qualitative description of the reaction kinetics. The presence of the gold modifier does not appear to provide any improvement in catalyst performance under the specified reaction conditions.

Characterization of C5 hydrocarbons relevant to catalysis.

A recent in situ infrared study on the selective hydrogenation of C5 dienes and monoenes over a Pd/Al(2)O(3) catalyst only reported incomplete vibrational assignments for some of the reagents, intermediates, and products encountered in that study. This work uses a combination of infrared absorption spectroscopy, Raman, and inelastic neutron scattering to characterize the vibrational spectra of pentane, 1-pentene, cis- and trans-2-pentene, cis- and trans-1,3-pentadiene, 1,4-pentadiene, cyclopentane, and cyclopentene. Ab initio calculations of the potential energy surface, geometry, and vibrational transition energies were performed and simulations of the vibrational spectra compared to the experimental data. Complete vibrational assignments for the majority of the molecules are presented. The potential for using gas-phase infrared measurements for studying heterogeneously catalyzed gas-phase reactions is also briefly considered.