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.

Transfer and Amplification of Chirality Within the "Ring of Fire" Observed in Resonance Raman Optical Activity Experiments.

We report extremely strong chirality transfer from a chiral nickel complex to solvent molecules detected as Raman optical activity (ROA). Electronic energies of the complex were in resonance with the excitation-laser light. The phenomenon was observed for a wide range of achiral and chiral solvents. For chiral 2-butanol, the induced ROA was even stronger than the natural one. The observations were related to so-called quantum (molecular) plasmons that enable a strong chiral Rayleigh scattering of the resonating complex. According to a model presented here, the maximal induced ROA intensity occurs at a certain distance from the solute, in a three-dimensional "ring of fire", even after rotational averaging. Most experimental ROA signs and relative intensities could be reproduced. The effect might significantly increase the potential of ROA spectroscopy in bioimaging and sensitive detection of chiral molecules.

Aggregation of lactic acid in cold rare-gas matrices and the link to solution: a matrix isolation-vibrational circular dichroism study.

The matrix isolation (MI) technique has been utilized with vibrational circular dichroism (VCD) spectroscopy to obtain MI-VCD spectra of lactic acid (LA) in cold argon matrices, in addition to their MI-IR spectra. The experiments have been done at three different deposition temperatures (10 K, 16 K and 24 K) under different Ar flow rates so that different degrees of LA self-aggregation occur. The structural and spectral investigations of the LA monomer and the larger (LA)2,3,4 aggregates have been undertaken at three levels of theory (B3LYP/6-311++G(2d,p), B3LYP-D3BJ/6-311++G(2d,p) and B3LYP-D3BJ/def2-TZVPD) to evaluate the effects of dispersion correction and basis sets on optimized structures, relative conformer energies, and IR/VCD spectral features. Interestingly, the relative conformer energies vary considerably with and without dispersion correction, especially when the molecule gets larger and when it is placed in solution. Such uncertainties in the relative energies and in the vibrational band positions and IR/VCD intensities highlight the challenges in interpreting experimental spectroscopic data, especially those obtained in solution. With the narrow MI-IR band width and highly characteristic MI-VCD spectral features and the trend observed at three temperatures, we have been able to correlate the spectral features confidently to those of the LA monomer and the larger (LA)2,3,4 aggregates, with the aid of theoretical modeling. Finally, by noting the similarity of MI-IR and especially MI-VCD features obtained at 24 K with those of the 0.2 M solution, and with the aid of spectral simulation at the B3LYP-D3BJ/def2-TZVPD level, a composition of LA aggregates dominated by the LA tetramer and trimer has been identified. This conclusion differs from the previous reports where the LA dimer was identified as the main species at even higher concentration in CDCl3. The present work showcases the power of MI-VCD spectroscopy in aiding solution spectral assignment and in providing insight into the complex self-aggregation behavior of LA in solution.

Reduction of Water/Oil Interfacial Tension by Model Asphaltenes: The Governing Role of Surface Concentration.

In this work, pendant drop techniques and molecular dynamics (MD) simulations were employed to investigate the effect of asphaltene concentrations on the interfacial tension (IFT) of the oil/water interface. Here, oil and asphaltene were represented by, respectively, common organic solvents and Violanthrone-79, and two types of concentration, i.e., bulk concentration and surface concentration, were examined. Correlations between the IFTs from experiments and MD simulations revealed that surface concentration, rather than the commonly used bulk concentration, determines the reduction of oil/water IFTs. Through analyzing the hydrogen bonding, the underlying mechanism for the IFT reduction was proposed. Our discussions here not only enable the direct comparison between experiments and MD simulations on the IFTs but also help with future interfacial studies using combined experimental and simulation approaches. The methodologies used in this work can be extended to many other oil/water interfaces in the presence of interfacially active compounds.

Stereochemical Properties of Multidentate Nitrogen Donor Ligands and Their Copper Complexes by Electronic CD and DFT.

UV-Vis and electronic circular dichroism (ECD) spectroscopy, complemented with Density Functional Theory (DFT) calculations, were used to elucidate the structural diversities of three multidentate nitrogen donor ligands and two associated copper complexes in solution directly. The three chiral salen ligands all consist of trans-cyclohexane-1,2-diamine as a chiral scaffold and also of pyridine rings as chromophores, differing only in the linking groups between the two functional groups mentioned above. Very different ECD intensities and somewhat different ECD patterns were observed for these ligands and satisfactorily interpreted theoretically. For the geometry optimization and spectral simulation of the open-shell metal complexes, the LANL2DZ basis set with effective core potential for the Cu and Cl atoms and pure cc-pVTZ for the rest of the atoms was utilized. The performance of the same calculations with the polarization functions (f,g) from the cc-pVTZ basis added to the LANL2DZ basis was compared. While the three ligands exhibit different conformational flexibility, the associated copper complexes show great rigidity imposed by the metal-ligand coordination, taking on a single structure in each case. In addition, dispersion interactions were shown to change the conformational stability ordering of the ligands noticeably and to exert considerable influence on the simulated UV-Vis and ECD spectra. Chirality 28:545-555, 2016. © 2016 Wiley Periodicals, Inc.

Rotational spectroscopy of methyl benzoylformate and methyl mandelate: structure and internal dynamics of a model reactant and product of enantioselective reduction.

Pure rotational spectra of a prototypical prochiral ester, methyl benzoylformate (MBF), and the product of its enantioselective reduction, (R)-(-)-methyl mandelate (MM), were measured in the range of 5-16 GHz, using a cavity-based molecular beam Fourier-transform microwave spectrometer. Potential conformers were located using density functional theory calculations, and one conformer of each species was identified experimentally. The minimum energy conformer of MBF, in which the ester group is in a Z orientation, was observed for the first time. Based on an atoms-in-molecules analysis, MBF contains a weak CH···O=C hydrogen bond between the carbonyl oxygen atom of the ester group and the nearest hydrogen atom of the aromatic ring. In the minimum energy conformer of MM, the ester group is oriented to accommodate a hydrogen bond between the hydrogen atom of the hydroxyl group and the carbonyl oxygen atom (OH···O=C), rather than the sp(3) oxygen atom (OH···O-C). For both species, splittings of the rotational transitions were observed, which are attributed to methyl internal rotation, and the orientations and barrier heights of the methyl tops were determined precisely. The barrier heights for MBF and MM are 4.60(2) and 4.54(3) kJ mol(-1), respectively, which are consistent with values predicted by high-level wavefunction-based calculations. On the basis of an atoms-in-molecules analysis, we propose that destabilization of the sp(3) oxygen atom of the ester group most directly dictates the barrier height.

Conservation of Helicity in a Chiral Pyrrol-2-yl Schiff-Base Ligand and Its Transition Metal Complexes.

Tetradentate enantiopure Schiff-base ligand (R,R) and (S,S)-bis(pyrrol-2-ylmethyleneamine)-cyclohexane (H2L) and its five transition metal complexes with Ni(II), Cu(II), Zn(II), Pd(II), and Pt(II) were synthesized. Their structural properties, in particular, the ligand chirality, coordination topology, and the resulting helicity in solution, were investigated by using IR, vibrational circular dichroism (VCD), UV-vis, and electronic circular dichroism (ECD) spectroscopies, complemented with density functional theory calculations. Conformational searches and the associated spectral simulations for the ligands and the complexes were performed at the B3LYP/Gen level. Comparison of the experimental and theoretical IR and VCD spectral signatures of these complexes reveal that the Zn complex takes on a dinuclear, distorted tetrahedral coordination topology around the metal centers, whereas the other four metal complexes adopt the mononuclear, distorted square-planar coordination arrangement in solution. The helicity of all systems studied was identified to be M with the (R,R) ligand and P with the (S,S) ligand, dictated by the ligand chirality and the strong preference for the chair configuration by the cyclohexane moiety. Furthermore, the resulting helicity was found to dominate the ECD spectral features, even though the helicity-determining angles are close to zero for the nearly square-planar metal complexes. The related VCD spectral features are sensitive to both helicity of the complex and the chirality of the ligands, as well as the coordination topology. The simulated ECD spectra for the P and M helicity of the [Zn-(R,R)-L]2 complex shows almost mirror-imaged ECD spectral features, whereas very similar ECD spectra were recently reported for the P- and M-dinuclear Mn complexes with a di-µ-oxo dimetal core as a linker. We highlight the advantages of utilizing multiple chiroptical techniques and theoretical spectral simulations to correlate chiroptical spectral features with multiple chirality and helicity elements in the systems.

Absolute Configuration and Conformation of Two Fráter-Seebach Alkylation Reaction Products by Film VCD and ECD Spectroscopic Analyses.

Two chiroptical spectroscopic techniques, namely, electronic and vibrational circular dichroism (ECD and VCD), as well as NMR spectroscopy have been utilized to determine the absolute configurations and geometries of two Fráter-Seebach alkylation reaction products with long hydrocarbon chains. The experimental studies have been complemented with density functional theory calculations. Strong characteristic bisignate VCD signatures in the carbonyl stretching region have been observed for both compounds in film state. Truncated models, i.e., without the long CH2 chains, have been utilized to examine different hydrogen-bonding topologies between two monomeric moieties and to simulate the corresponding IR and VCD spectra of the dimers. In addition, the exciton coupling model has also been applied to the -C═O groups of the two monomeric moieties, which can be coupled through intermolecular hydrogen-bonding. On the basis of these simplified approaches, the absolute configurations of the compounds have been unambiguously assigned using VCD and ECD spectroscopy. Spectral simulations in the IR and UV-vis regions have also been carried out with the full dimers to validate the fitness of the truncated model. The study shows that the combination of the film VCD and ECD techniques is a relatively straightforward method to determine the absolution configurations of such synthetic compounds.

Identifying dominant conformations of N-acetyl-L-cysteine methyl ester and N-acetyl-L-cysteine in water: VCD signatures of the amide I and the C=O stretching bands.

Infrared (IR) and vibrational circular dichroism (VCD) spectra of N-Acetyl-L-Cysteine Methyl Ester (NALCME) and N-Acetyl-L-Cysteine (NALC) in D2O under different pHs were measured. We focus on the VCD signatures of the amide I and the C=O stretching spectral signatures of the neutral NALCME and NALC species and the related ones of the deprotonated NALC species in the region of 1800-1500 cm(-1). A sign inversion is observed for the amide I VCD band going from the neutral NALCME and NALC to the deprotonated NALC species. Density functional theory (DFT) calculations were carried out to search for the possible conformations of these three species and to simulate their IR and VCD spectra at the B3LYP/aug-cc-pVTZ level in the gas phase and with the polarization continuum model of water solvent. The most stable conformations found for neutral NALCME and NALC exhibit drastically difference VCD patterns, whereas those of deprotonated NALC show similar patterns. We establish an empirical structural-spectral relationship where the aforementioned VCD signatures can be used as spectral markers to identify dominant conformations of these two amino acid derivatives under different pHs. It is recognized that the dominant conformers identified using the VCD spectral markers differ from those based on the relative DFT energies for neutral NALCME and NALC. The influence of solvent on both the conformational geometries and their relative stabilities is discussed. The aforementioned discrepancy can be attributed to the explicit solute-solvent hydrogen-bonding interactions which are not accounted for in the calculations. The empirical structural-spectral relationship identified can potentially be applied to large, related amino acids and polypeptides in water.

Diastereomeric preference of a triply axial chiral binaphthyl based molecule: a concentration dependent study by chiroptical spectroscopies.

We have examined the effects of environmental perturbations, specifically solvents and concentrations, on axial chirality of a recently synthesized axially chiral binaphthyl fluorene based salen ligand, named AFX-155, {[2,2'-(1E,1'E)-(R)-1,1'-binaphthyl-2,2'-diylbis(azan-1-yl-1-ylidene)bis(methan-1-yl-1-ylidene)bis(4-((7-(diphenylamino)-9,9-dihexyl-9H-fluoren-2-l)ethynyl)-phenol)]}. Chirality and dominant conformations of AFX-155 in CDCl3 solvent have been characterized using vibrational absorption (VA) and vibrational circular dichroism (VCD) spectroscopy in combination with DFT calculations. AFX-155 exhibits triple axial chirality: one is at the binaphthyl ring and the other two are related to the axes of chirality along the -C-N bonds where Cs are part of the binaphthyl group. To evaluate solvent and concentration dependence, complementary VA and VCD experiments in both THF-d8 and CDCl3 have been performed, as well as the optical rotatory dispersion (ORD) and electronic CD (ECD) measurements in CDCl3 under much diluted conditions. While the binaphthyl chirality is determined by the synthetic route, the results show that the latter two axial chirality labels of the dominant diastereomers are concentration dependent. Under much diluted conditions, R-binaphthyl, R_intra_HB//R_extra_HB (R-RR) is favoured, whereas R-binaphthyl, S_intra_HB//S_extra_HB (R-SS) is the dominant species in a concentrated solution. This diastereomeric interconversion is found to be independent of the two solvents used. To provide insights into this interesting finding, conformational searches and the related spectral simulations have been carried out at the DFT/B3LYP/6-31G(d) level.

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.

A comparative VCD study of methyl mandelate in methanol, dimethyl sulfoxide, and chloroform: explicit and implicit solvation models.

Vibrational absorption (VA) and vibrational circular dichroism (VCD) spectra of methyl mandelate, a prototype chiral molecule, in a series of organic solvents, namely methanol (MeOH-d(4)), dimethyl sulfoxide (DMSO-d(6)), and chloroform (CDCl(3)), have been measured in the finger print region from 1800 to 1150 cm(-1). Implicit solvation models in the form of polarizable continuum model and explicit solvation models have been employed independently and simultaneously. The goal is to evaluate their efficiencies in dealing with solvent effects in each solution and to establish a general strategy to adequately account for effects of solvents. Molecular dynamics (MD) simulation and radial distribution function analysis have been performed to aid the construction of the explicit solvation models. Initial geometry searches have been carried out at the B3LYP/6-31G(d) level for the methyl mandelate monomer and its explicit 1 : 1 and 1 : 2 solute-solvent hydrogen-bonded complexes. B3LYP/cc-pVTZ has been used for all the final geometry optimizations, the vibrational frequency, VA and VCD intensity, and optical rotation dispersion (ORD) calculations. The results show that inclusion of solvent explicitly and implicitly at the same time has significant impacts on the appearance of the VA and VCD spectra, and is crucial for reliable spectral assignments when solvents are capable of hydrogen-bonding interactions with solutes. When no strong solvent-solute hydrogen-bonding interactions in the case of chloroform are expected, the gas phase monomer model is adequate for spectral interpretation, while inclusion of implicit solvation improves the frequency agreement with experiment. ORD spectra of methyl mandelate in the aforementioned solvents at different concentrations under 5 excitation wavelengths have also been measured. The comparison between the calculated and the experimental ORD spectra supports the conclusions drawn from the VA and VCD investigations.

Vibrational absorption and vibrational circular dichroism spectra of leucine in water under different pH conditions: hydrogen-bonding interactions with water.

Vibrational absorption (VA) and vibrational circular dichroism (VCD) spectroscopy have been used to study leucine, a flexible branched-chain amino acid, in aqueous solution. The VA spectra in the range of 1800-1250 cm(-1) of leucine in D(2)O under three representative pHs from strongly acidic (pH = 1), near neutral (pH = 6), to strongly basic (pH = 13), have been measured. The related VCD spectrum has been obtained under near neutral condition. Searches have been carried out to identify the most stable conformers of the Zwitterionic, protonated, and deprotonated forms of leucine in water. The geometry optimization, harmonic frequency calculations, and VA and VCD intensities have been computed at the B3LYP/6-311++G(d,p) level with the implicit polarizable continuum solvation model. While the observed VA spectra under three pHs can be well interpreted with the inclusion of the implicit solvation model, both implicit and explicit solvation models have been found to be crucial for the adequate interpretation of the complex VCD features observed. Molecular dynamics simulations and radial distribution functions have been used to aid the modeling of the leucine-(water)(N) clusters. It has been recognized that the insertion of a water molecule between the COO(-) and NH(3) (+) functional groups in the explicit solvated clusters is critical to reproduce the VCD signatures observed. Furthermore, the inclusion of the implicit bulk water environment has been found to be essential to lock water molecules, which are directly hydrogen bonded to leucine, into the positions expected in solution. The application of the explicit and implicit solvation models simultaneously allows new insights into the hydrogen bonding network surrounding leucine in aqueous solution and the role of the surrounding bulk water in stabilizing such hydrogen-bonding network.

Vibrational circular dichroism spectroscopy of two chiral binaphthyl diphosphine ligands and their palladium complexes in solution.

BINAP (2,2'-diphenylphosphino-1,1'-binaphthyl) is a unique binaphthyl diphosphine ligand with axial chirality. The palladium complexes of BINAP and of its derivative TOLBINAP have found extensive applications in the field of asymmetric syntheses. The conformational changes in the BINAP and TOLBINAP ligands before and after coordination with palladium have been investigated using density functional theory, vibrational absorbance (VA) and vibrational circular dichroism (VCD) spectroscopy. VA and VCD spectra of these two chiral ligands and their corresponding palladium complexes have been recorded in CDCl(3) solution. Extensive conformational searches have been carried out for both the ligands and the associated palladium complexes. Coordination with palladium has been found to introduce structural rigidity to the ligands. The calculated VA and VCD spectra of the ligands and complexes in the gas phase show substantial differences to the experimental data. Incorporation of the implicit polarisable continuum solvation model has provided much better agreement between theory and experiment, especially for the complexes, allowing clear identification of the species and conformations. This and the high specificity of VCD spectral signatures to chirality and to conformations suggest the potential applications of VCD spectroscopy for following these important catalytic species in solution reactions directly.

Conformational distributions of N-acetyl-L-cysteine in aqueous solutions: a combined implicit and explicit solvation treatment of VA and VCD spectra.

The conformational distributions of N-acetyl-L-cysteine (NALC) in aqueous solutions at several representative pH values are investigated using vibrational absorption (VA), UV/Vis, and vibrational circular dichroism (VCD) spectroscopy, together with DFT and molecular dynamics (MD) simulations. The experimental VA and UV/Vis spectra of NALC in water are obtained under strongly acid, neutral, and strongly basic conditions, as well as the VCD spectrum at pH 7 in D(2)O. Extensive searches are carried out to locate the most stable conformers of the protonated, neutral, deprotonated, and doubly deprotonated NALC species at the B3LYP/6-311++G(d,p) level. The inclusion of the polarizable continuum model (PCM) modifies the geometries and the relative stabilities of the conformers noticeably. The simulated PCM VA spectra show significantly better agreement with the experimental data than the gas-phase ones, thus allowing assignment of the conformational distributions and dominant species under each experimental condition. To further properly account for the discrepancies noted between the experimental and simulated VCD spectra, PCM and the explicit solvent model are utilized. MD simulations are used to aid the modelling of the NALC-(water)(N) clusters. The geometry optimization, harmonic frequency calculations, and VA and VCD intensities are computed for the NALC-(water)(3,4) clusters at the B3LYP/6-311++G(d,p) level without and with the PCM. The inclusion of both explicit and implicit solvation models at the same time provides a decisively better agreement between theory and experiment and therefore conclusive information about the conformational distributions of NALC in water and hydrogen-bonding interactions between NALC and water molecules.

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 H(2)O and D(2)O 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.