Vibrational Circular Dichroism Spectroscopy with a Classical Polarizable Force Field: Alanine in the Gas and Condensed Phases.

Polarizable force fields are an essential component for the chemically accurate modeling of complex molecular systems with a significant degree of fluxionality, beyond harmonic or perturbative approximations. In this contribution we examine the performance of such an approach for the vibrational spectroscopy of the alanine amino acid, in the gas and condensed phases, from the Fourier transform of appropriate time correlation functions generated along molecular dynamics (MD) trajectories. While the infrared (IR) spectrum only requires the electric dipole moment, the vibrational circular dichroism (VCD) spectrum further requires knowledge of the magnetic dipole moment, for which we provide relevant expressions to be used with polarizable force fields. The AMOEBA force field was employed here to model alanine in the neutral and zwitterionic isolated forms, solvated by water or nitrogen, and as a crystal. Within this framework, comparison of the electric and magnetic dipole moments to those obtained with nuclear velocity perturbation theory based on density-functional theory for the same MD trajectories are found to agree well with one another. The statistical convergence of the IR and VCD spectra is examined and found to be more demanding in the latter case. Comparisons with experimental frequencies are also provided for the condensed phases.

Mid-IR and CH stretching vibrational circular dichroism spectroscopy to distinguish various sources of chirality: The case of quinophaneoxazoline based ruthenium(II) complexes.

Five diastereomers of ruthenium(II) complexes based on quinolinophaneoxazoline ligands were investigated by vibrational circular dichroism (VCD) in the mid-IR and CH stretching regions. Diastereomers differ in three sources of chirality: the planar chirality of the quinolinophane moiety, the central chirality of an asymmetric carbon atom of the oxazoline ring, and the chirality of the ruthenium atom. VCD, allied to DFT calculations, has been found to be effective in disentangling the various forms of chirality. In particular, a VCD band is identified in the CH stretching region directly connected to the chirality of the metal. The analysis of the calculated VCD spectra is carried out by partitioning the complexes into fragments. The anharmonic analysis is also performed with a recently proposed reduced-dimensionality approach: such treatment is particularly important when examining spectroscopic regions highly perturbed by resonances, like the CH stretching region.

Multidimensional vibrational circular dichroism for insect wings: Comparison of species.

This study reports the microscopic measurements of vibrational circular dichroism (VCD) on four different insect wings using a quantum cascade laser VCD system equipped with microscopic scanning capabilities (named multi-dimensional VCD [MultiD-VCD]). Wing samples, including (i) beetle, Anomala albopilosa (female), (ii) European hornet, Verspa crabro flavofasciata Cameron, 1903 (female), (iii) tiny dragonfly, Nannophya pygmae Rambur, 1842 (male), and (iv) dragonfly, Symetrum gracile Oguma, 1915 (male), were used in this study. Two-dimensional patterns of VCD signals (~10 mm × 10 mm) were obtained at a spatial resolution of 100 µm. Measurements covered the absorption peaks assigned to amides I and II in the range of 1500-1740 cm-1 . The measurements were based on the enhancement of VCD signals for the stereoregular linkage of peptide groups. The patterns were remarkably dependent on the species. In samples (i) and (ii), the wings comprised segregated domains of protein aggregates of different secondary structures. The size of each microdomain was approximately 100 µm. In contrast, no clear VCD spectra were detected in samples (iii) and (iv). One possible reason was that the chain of stereoregular polypeptides was too short to achieve VCD enhancement in samples (iii) and (iv). Notably, the unique features were only observed in the VCD spectra because the IR spectra were nearly the same among the species. The VCD results hinted at the connection of protein microscopic structures with the wing flapping mechanisms of each species.

Control of Dynamic Chirality in Donor-Acceptor Fluorophores.

Very recently, the control of dynamic chirality has emerged as a powerful strategy to design chiral functional materials. In this context, we describe herein a molecular design in which a tethered configurationally stable binaphthyl chiral unit efficiently controls the dynamic chirality of donor-acceptor fluorophores, involving diverse indolocarbazoles as electron donors and terephthalonitrile as an electron acceptor. The high conformational discrimination in such a molecular system suggested by density functional theory calculations is experimentally probed using electronic and vibrational circular dichroism and confirmed by the crystallization of these chiral molecules in gel and their single crystal X-ray diffraction analysis. In addition to extending the scope of dynamic chirality control to donor-acceptor fluorophores, this work also highlights the positive effect of the configurationally stable chiral inductor on the magnitude of the dissymmetry factors of the active dynamically chiral fluorophores, both in ground and excited states, through chiral perturbation.

Selective Chirality Transfer to the Bis(trifluoromethylsulfonyl)imide Anion of an Ionic Liquid.

Chirality transfer from the chiral molecule (R)-1,2-propylene oxide to the achiral anion of the 1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide ionic liquid is observed. The chiral probe selectively affects one part of the binary ionic liquid, i. e., it has previously been shown experimentally and theoretically that this particular imidazolium cation can be affected by chirality transfer, but in the present system chirality is almost exclusively transferred to the anion and not to both parts of the solvent (anion and cation). This observation is of high relevance because of its selectivity and because anion effects are usually much more important in ionic liquid research than cation effects. From ab initio molecular dynamics simulations, a conformational analysis and dissected vibrational circular dichroism spectra are obtained to study the chirality transfer. While in the neat ionic liquid two mirror imaged trans conformers of the anion occur almost equally, we observe an excess of one of these conformers in the presence of the chiral solute, causing optical activity of the anion. Although the cis conformers are not tremendously affected by the chirality transfer, they gain in total population when (R)-1,2-propylene oxide is dissolved in the ionic liquid.

Chiral and Structural Polymorphism of Fibril Architectures of Homologous Lysozymes.

Amyloid fibrils are fascinating and complex structures with the multilayered chiral organization. Using the multimodal methodology, including VCD, ECD, cryo-EM, and TEM, we characterized in detail different levels of organization (secondary structure/protofilament/mesoscopic structure) of amyloid fibrils prepared from proteins highly homologous in the structure (hen egg white and human lysozymes). Our results demonstrate that small changes in the native protein structure or preparation conditions translate into significant differences in the handedness and architecture of the formed fibrils at various levels of their complexity. In particular, fibrils of hen egg white and human lysozymes obtained in vitro at the same preparation conditions, possess different secondary structure, protofilament twist and ultrastructure. Yet, formed fibrils adopted a relatively similar mesoscopic structure, as observed in high-resolution 3D cryo-EM, scarcely used up to now for fibrils obtained in vitro in denaturing condition. Our results add to other puzzling experiments implicating the indeterministic nature of fibril formation.

Synthesis, characterization and absolute configurations of methyl ladderanoates.

Methyl esters of [5]-ladderanoic acid and [3]-ladderanoic acid were prepared by esterification of the acids isolated from biomass at a wastewater treatment plant. Optical rotations at six different wavelengths (633, 589, 546, 436, 405 and 365 nm) and vibrational circular dichroism (VCD) spectra in the 1800-900 cm-1 region were measured in CDCl3 solvent and compared with quantum chemical (QC) predictions using B3LYP functional and 6-311++G(2d,2p) basis set with polarizing continuum model representing the solvent. QC predictions gave negative optical rotations at all six wavelengths for (R)-methyl [5]-ladderanoate and positive optical rotations for (R)-methyl [3]-ladderanoate, the same signs as previously reported for the corresponding acids. The crystal structure of (-)-methyl [5]-ladderanoate independently confirmed (R) configuration. The QC-predicted VCD spectra using Boltzmann population weighted spectra of individual conformers did not provide satisfactory quantitative agreement with the experimental VCD spectra. An improved quantitative agreement for VCD spectra could be obtained when conformer populations were optimized to maximize the similarity between experimental and predicted VCD spectra, but more improvements in VCD predictions are needed.

Chiral explosives: A theoretical investigation of structure and chiroptical properties of triacetone triperoxide and hexamethylene triperoxide diamine.

Triacetone triperoxide (TATP) and hexamethylene triperoxide diamine (HMTD) are cyclic peroxides that exhibit atropisomerism resulting from restricted rotation around three peroxide bonds. As a result, one pair of enantiomers with D3 symmetry and another pair of enantiomers with C2 symmetry can be identified. Previous studies, based on mass spectrometry data and computational results, have shown that conformations of TATP with D3 and C2 symmetry can be isolated. Assuming that enantiomer samples of TATP and HMTD can be obtained with sufficient enantiopurity, we investigated their chiroptical properties, namely, optical rotatory dispersion (ORD), vibrational circular dichroism (VCD), and Raman optical activity (VROA). ORD curves and VCD spectra are seen to be very similar for D3 - and C2 -symmetric atropisomers with the same overall helicity. Predicted VROA results, however, show significant differences between D3 - and C2 -symmetric atropisomers with the same overall helicity. The D3 -symmetric atropisomer is predicted to exhibit considerably larger magnitude vibrational optical activity signals than the C2 -symmetric atropisomer.

Infrared and vibrational circular dichroism spectra of methyl ß-D-glucopyranose in water: The application of the quantum cluster growth and clusters-in-a-liquid solvation models.

The infrared (IR) and vibrational circular dichroism (VCD) spectra of methyl ß-D-glucopyranose in water were measured. Both implicit and explicit solvation models were utilized to explain the observed spectra. The vast body of existing experimental and theoretical data suggested that about eight explicit water molecules are needed to account for the solvent effects, supported by the current Quantum Cluster Growth (QCG) analysis. Extensive manual and systematic conformational searches of the molecular target and its water clusters were carried out by using a recently developed conformational searching tool, conformer-rotamer ensemble sampling tool (CREST), and the microsolvation model in the associated QCG code. The Boltzmann averaged IR and VCD spectra of the methyl ß-D-glucopyranose-(water)n (n = 8) conformers in the PCM of water provide better agreement with the experimental ones than those with n = 0, 1, and 2. The explicit solvation with eight water molecules was shown to greatly modify the conformational preference of methyl ß-D-glucopyranose from its monomeric form. Further analyses show that the result is consistent with the existence of long-lived methyl ß-D-glucopyranose monohydrates with the additional explicit water effects being accounted for with the quantum mechanical treatment of the other seven close-by water molecules in the PCM of water.

Conformations of Steroid Hormones: Infrared and Vibrational Circular Dichroism Spectroscopy.

Steroid hormone molecules may exhibit very different functionalities based on the associated functional groups and their 3D arrangements in space, i.e., absolute configurations and conformations. Infrared (IR) and vibrational circular dichroism (VCD) spectra of four different steroid hormones, namely dehydroepiandrosterone (DHEA), 17α-methyltestosterone (MTTT), (16α,17)-epoxyprogesterone (Epoxy-P4), and dehydroepiandrosterone acetate (AcO-DHEA), were measured in deuterated dimethyl sulfoxide and some also in carbon tetrachloride. Extensive conformational searches were carried out using the recent developed conformer-rotamer ensemble sampling tool (CREST) which also accounts for solvent effects using an implicit solvation model. All the CREST conformational candidates were then reoptimized at the B3LYP-D3BJ/def2-TZVPD with the PCM of solvent. The good agreements between the experimental IR and VCD spectra and the theoretical simulations provide a conclusive information about their conformational distribution and absolute configurations. The experimental and theoretical IR and VCD spectra of AcO-DHEA in the carbonyl and alkene stretching region showed some discrepancies, and the possible causes related to solvent effects, large amplitude motions and levels of theory used in the modelling were explored in detail. As part of the investigation, additional calculations at the B3LYP-D3BJ/6-31++G (2d,p) and B3LYP-D3BJ/cc-pVTZ levels, as well as some 'mixed' calculations with the double-hybrid functional B2PLYP-D3 were also carried out. The results indicate that the double-hybrid functional is important for predicting the correct IR band pattern in the carbonyl and alkene stretching region.

Conformational Distributions of Phenyl ß-D-Glucopyranoside and Gastrodin in Solution by Vibrational Optical Activity and Theoretical Calculations.

The conformational landscapes of two highly flexible monosaccharide derivatives, namely phenyl ß-D-glucopyranoside (ph-ß-glu) and 4-(hydroxymethyl)phenyl ß-D-glucopyranoside, also commonly known as gastrodin, were explored using a combined experimental and theoretical approach. For the infrared, Raman, and the associated vibrational optical activity (VOA), i.e., vibrational circular dichroism and Raman optical activity, experiments of these two compounds in DMSO and in water were carried out. Extensive and systematic conformational searches were performed using a recently developed conformational searching tool called CREST (conformer-rotamer ensemble sampling tool) in the two solvents. Fourteen and twenty-four low-energy conformers were identified at the DFT level for ph-ß-glu and gastrodin, respectively. The spectral simulations of individual conformers were done at the B3LYP-D3BJ/def2-TZVPD level with the polarizable continuum model of the solvents. The VOA spectral features exhibit much higher specificity to conformational differences than their parent infrared and Raman. The excellent agreements achieved between the experimental and simulated VOA spectra allow for the extraction of experimental conformational distributions of these two carbohydrates in solution directly. The experimental percentage abundances based on the hydroxymethyl (at the pyranose ring) conformations G+, G-, and T for ph-ß-glu were obtained to be 15%, 75%, and 10% in DMSO and 53%, 40%, and 7% in water, respectively, in comparison to the previously reported gas phase values of 68%, 25%, and 7%, highlighting the important role of solvents in conformational preferences. The corresponding experimental distributions for gastrodin are 56%, 22%, and 22% in DMSO and 70%, 21%, and 9% in water.

How Crystal Symmetry Dictates Non-Local Vibrational Circular Dichroism in the Solid State.

Solid-State Vibrational Circular Dichroism (VCD) can be used to determine the absolute structure of chiral crystals, but its interpretation remains a challenge in modern spectroscopy. In this work, we investigate the effect of a twofold screw axis on the solid-state VCD spectrum in a combined experimental and theoretical analysis of P21 crystals of (S)-(+)-1-indanol. Even though the space group is achiral, a single proper symmetry operation has an important impact on the VCD spectrum, which reflects the supramolecular chirality of the crystal. Distinguishing between contributions originating from molecular chirality and from chiral crystal packing, we find that while IR absorption hardly depends on the symmetry of the space group, the situation is different for VCD, where completely new non-local patterns emerge. Understanding the two underlying mechanisms, namely gauge transport and direct coupling, will help to use VCD to distinguish polymorphic forms.

Vibrational Circular Dichroism Spectroscopy of Chiral Molecular Crystals: Insights from Theory.

Chirality is a curious phenomenon that appears in various forms. While the concept of molecular (RS-)chirality is ubiquitous in chemistry, there are also more intricate forms of structural chirality. One of them is the enantiomorphism of crystals, especially molecular crystals, that describes the lack of mirror symmetry in the unit cell. Its relation to molecular chirality is not obvious, but still an open question, which can be addressed with chiroptical tools. Vibrational circular dichroism (VCD) denotes chiral infrared (IR) spectroscopy that is susceptible to both, the molecular as well as the intermolecular space by means of vibrational transitions. When carried out in the solid state, VCD delivers a very rich set of non-local contributions that are determined by crystal packing and collective motion. Since its discovery in the 1970s, VCD has become the method of choice for the determination of absolute configurations, but its applicability reaches beyond towards the study of different crystal forms and polymorphism. This brief review summarises the theoretical concepts of crystal chirality and how computations of solid-state VCD can shed light into the intimate connection of chiral structure and vibrational optical activity.

Vibrational circular dichroism enantiomeric similarity index improvement for absolute configuration discrimination using individual infrared scaling factors.

The use of IR individual scaling factors (ISF) for the correction of DFT-calculated frequencies, and its effect on IR and VCD similarity functions, has been evaluated using (+)-(R)-3-methylcyclopentanone as a probe molecule. Contrary to using a single scaling factor to improve spectra matching, this approach sequentially searches for the optimal scaling factor for each calculated transition using a computational search algorithm to maximize the overlap of the calculated and observed IR spectra expressed as the IR similarity (SIR ) function. The obtained ISFs are then applied to the calculated frequencies, which are used to produce a scaled VCD spectrum for comparison with the observed trace, thereby yielding enantiomeric similarity index (ESI) values as a similarity measure. This procedure provides a significant improvement of the SIR and ESI values when compared with the use of a single scale factor, showing 15.1% and 34.1% in average increments, respectively, and values as high as 0.98 and 0.94, respectively. When a set of manually found ISFs is used, most differences in SIR and ESI performance disappear, and nearly perfect spectra matches are found throughout the levels of theory tested. This suggests that the observed differences in computed IR/VCD spectra with commonly used levels of theory are related to differences in frequency rather than to intensity accuracy. Finally, the use of ISFs is expected to enhance the ability to aide stereochemical assignments, particularly in cases where sufficiently accurate frequencies are difficult to obtain due to the system size or complexity.

Chiroptical spectroscopic studies for the absolute configuration determination of hexahydrocurcumin and octahydrocurcumin.

Hexahydrocurcumin (HHC) and octahydrocurcumin (OHC) were synthesized, and their enantiomers were separated using supercritical fluid chromatography. The absolute configurations (ACs) of HHC and OHC were independently determined using experimental measurements and quantum theoretical predictions of vibrational circular dichroism, electronic circular dichroism, and optical rotatory dispersion. These studies lead to AC assignments of (-)-(R)-HHC and (+)-(R,R)-OHC. The AC of OHC is further confirmed by its structure determined from single crystal x-ray diffraction.

Absolute configuration assignment of stigmasterol oxiranes.

Diastereoisomeric stigmasterol oxiranes 4, 5, 8, and 9 are known phytosterol oxidation products (POPs) that have been evaluated for their cytotoxicity, although the results are of limited significance since, in most cases, they were evaluated as mixtures. Consequently, to establish biological activity hierarchy of these oxides, it is critical to evaluate individual pure POPs. Therefore, we now describe the obtention of individual molecules and their absolute configuration (AC) determination. The two acetylated C-5-C-6 oxiranes 6 and 7; the two acetylated C-22-C-23 oxides 10 and 11, obtained by means of Δ5 double bond protection-deprotection; and the four C-5-C-6, C-22-C-23 diepoxystigmasteryl acetates 19-22 were now individually gained and their AC determined by vibrational circular dichroism. Vibrational modes associated with the C-5-C-6 and the C-22-C-23 bonds were identified in dioxiranes 19-22 and used to assign the AC of monoepoxides 6, 7, 10, and 11. The AC of biological active non-acetylated molecules follows immediately. Due to the scarce spectroscopic information available for these POPs, the 1 H and 13 C NMR chemical shifts of 3-22 were assigned using 1D- and 2D-NMR experiments.

Synthesis and Stereochemical Characterization of a Novel Chiral α-Tetrazole Binaphthylazepine Organocatalyst.

A novel α-tetrazole-substituted 1,1'-binaphthylazepine chiral catalyst has been synthesized and its absolute configuration has been determined by DFT computational analysis of the vibrational circular dichroism (VCD) spectrum of its precursor. The VCD analysis, carried out through the model averaging method, allowed to assign the absolute configuration of a benzylic stereocenter in the presence of a chiral binaphthyl moiety. The 1,1'-binaphthylazepine tetrazole and the nitrile its immediate synthetic precursor, have been preliminarily tested as chiral organocatalysts in the asymmetric intramolecular oxa-Michael cyclization of 2-hydroxy chalcones for the synthesis of chiral flavanones obtaining low enantioselectivity.

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.

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.

Monitoring peptide tyrosine nitration by spectroscopic methods.

Oxidative stress can lead to various derivatives of the tyrosine residue in peptides and proteins. A typical product is 3-nitro-L-tyrosine residue (Nit), which can affect protein behavior during neurodegenerative processes, such as those associated with Alzheimer's and Parkinson's diseases. Surface enhanced Raman spectroscopy (SERS) is a technique with potential for detecting peptides and their metabolic products at very low concentrations. To explore the applicability to Nit, we use SERS to monitor tyrosine nitration in Met-Enkephalin, rev-Prion protein, and α-synuclein models. Useful nitration indicators were the intensity ratio of two tyrosine marker bands at 825 and 870 cm-1 and a bending vibration of the nitro group. During the SERS measurement, a conversion of nitrotyrosine to azobenzene containing peptides was observed. The interpretation of the spectra has been based on density functional theory (DFT) simulations. The CAM-B3LYP and ωB97XD functionals were found to be most suitable for modeling the measured data. The secondary structure of the α-synuclein models was monitored by electronic and vibrational circular dichroism (ECD and VCD) spectroscopies and modeled by molecular dynamics (MD) simulations. The results suggest that the nitration in these peptides has a limited effect on the secondary structure, but may trigger their aggregation.