Determination of the absolute configuration of chiral alpha-aryloxypropanoic acids using vibrational circular dichroism studies: 2-(2-chlorophenoxy) propanoic acid and 2-(3-chlorophenoxy) propanoic acid

The enantiomers of 2-(2-chlorophenoxy) propanoic acid and 2-(3-chlorophenoxy) propanoic acid were resolved on a chiral HPLC column and investigated using mid-infrared vibrational circular dichroism (VCD). Experimental infrared vibrational absorption and VCD spectra were measured in CDCl3 solution in the 2000-900 cm-1 region and compared with the ab initio predictions of absorption and VCD spectra. The predicted spectra were obtained with density functional theory using B3LYP/6-31G* basis set for the stable and dominant conformers. But the predicted spectra did not provide unambiguous structural information due to intermolecular hydrogen bonding in solution. To eliminate the hydrogen bonding effects, the acids were converted to the corresponding methyl esters and the experimental absorbance and VCD spectra of methyl esters were measured. B3LYP predicted spectra were also obtained for the stable and dominant conformers of the esters. From a comparison of the experimental VCD spectra of methyl esters with corresponding ab initio predictions, the absolute configurations of esters, and therefore of their parent acids, are unambiguously determined to be (+)-(R).     

Absolute configurations, predominant conformations and tautomeric structures of enantiomeric tert-butylphenylphosphine oxides

Enantiomeric tert-butylphenylphosphine oxides have been isolated via resolution of the racemate with mandelic acid and investigated by using vibrational circular dichroism (VCD). Vibrational absorption and circular dichroism spectra of dextrorotatory, levorotatory, and racemic mixture of tert-butylphenylphosphine oxide have been measured in CDCl(3) and CHCl(3) solutions in the 2000-900 cm(-)(1) region. Experimental spectra are compared with the ab initio predictions of absorption and VCD spectra obtained with density functional theory using B3LYP/6-31G basis set for different tautomeric structures and conformers of (S)-tert-butylphenylphosphine oxide. This comparison indicates that (-)-tert-butylphenylphosphine oxide is of the (S)-configuration and indicates only one tautomeric structure and one conformation predominant for tert-butylphenylphosphine oxide in CDCl(3) and CHCl(3) solutions.     

Absolute configuration and conformation analysis of 1-phenylethanol by matrix-isolation infrared and vibrational circular dichroism spectroscopy combined with density functional theory calculation

The absolute configuration and conformation of 1-phenylethanol (1-PhEtOH) have been determined by matrix-isolation infrared (IR) and vibrational circular dichroism (VCD) spectroscopy combined with quantum chemical calculations. Quantum chemical calculations have identified that there are three conformers, namely, I, II, and III, in which characteristic intramolecular interactions are found. The IR spectrum-conformation correlation for 1-PhEtOH has been developed by the Ar matrix-isolation IR measurement and used for the assignments of the observed IR bands. In a dilute CCl(4) solution, 1-PhEtOH exists predominantly as conformer I along with a trace amount of conformer II. By considering conformations and intermolecular hydrogen-bonding in the spectral simulation for (S)-1-PhEtOH, we have successfully reproduced the VCD spectrum of (-)-1-PhEtOH observed in a dilute CS(2) solution. Thus, (-)-1-PhEtOH is of S-configuration and conformer I in the dilute solution. The same method has been applied to analyze the VCD spectra measured in the liquid state of (-)-1-PhEtOH. The absolute configuration of 1-PhEtOH in the condensed phase is enabled by identifying VCD bands that are insensitive to conformational changes and intermolecular interactions. The present work provides a combinatorial procedure for determination of both the absolute configuration and the conformation of chiral molecules in a dilute solution and condensed phase.     

Vibrational circular dichroism and absolute configuration of chiral sulfoxides: tert-butyl methyl sulfoxide

Mid-infrared vibrational unpolarised absorption and vibrational circular dichroism (VCD) spectra of CCl4 solutions of tert-butyl methyl sulfoxide (1) are reported. The spectra are compared to ab initio density functional theory (DFT) calculations carried out using two functionals, B3PW91 and B3LYP, and two basis sets, 6-31G* and TZ2P. The VCD spectra are calculated using Gauge-invariant atomic orbitals (GIAOs). The analysis of the VCD spectrum confirms the R(-)/S(+) absolute configuration of 1. The advantages and disadvantages of VCD spectroscopy in determining the absolute configurations of chiral sulfoxides are discussed.     

Absolute configuration and conformational stability of (+)-2,5-dimethylthiolane and (-)-2,5-dimethylsulfolane

Enantiopure (+)-2,5-dimethylthiolane and (-)-2,5-dimethylsulfolane were prepared using literature procedures and investigated using vibrational circular dichroism (VCD). Experimental absorption and VCD spectra of (+)-2,5-dimethylthiolane and (-)-2,5-dimethylsulfolane in CCl(4) solution in the 2000-900 cm(-)(1) region were compared with the ab initio predictions of absorption and VCD spectra obtained with density functional theory using the B3LYP/6-311G(2d, 2p) basis set for different conformers of (2R,5R)-2,5-dimethylthiolane and (2R,5R)-2,5-dimethylsulfolane. This comparison indicates that (+)-2,5-dimethylthiolane is of the (2R,5R)-configuration and has two predominant conformations in CCl(4) solution. In addition, (-)-2,5-dimethylsulfolane is of (2R,5R)-configuration and has only one predominant conformation. The stereochemical assignment is in agreement with literature.     

Chromatographic resolution, solution and crystal phase conformations, and absolute configuration of tert-butyl(dimethylamino)phenylphosphine-borane complex

The enantiomers of tert-butyl(dimethylamino)phenylphosphine-borane complex 2 have been separated by HPLC using cellulose tris-p-methylbenzoate as chiral stationary phase. The borane protection could be removed without racemization and the P-configuration of the free aminophosphine 1 has shown to be stable in solution. Infrared (IR) and vibrational circular dichroism (VCD) spectra have been measured in CD2Cl2 solution for both enantiomers. B3LYP/6-31+G(d) DFT calculations allowed a prediction that complex (S)-2 exists as three conformers in equilibrium and computed population-weighted IR and VCD spectra. Predicted and experimental IR and VCD spectra compared very well and indicate that enantiomer (+)-2 has the S absolute configuration. This assignment has been confirmed by an X-ray diffraction study on a single crystal of (+)-2. The crystal structure of enantiomerically pure 2 appears to be very close to the most stable computed conformer which proved to be predominant in solution.     

Configurational and conformational analysis of chiral molecules using IR and VCD spectroscopies: spiropentylcarboxylic acid methyl ester and spiropentyl acetate

The chiral monosubstituted derivatives of spiropentane, spiropentylcarboxylic acid methyl ester, 1, and spiropentyl acetate, 2, have been synthesized in optically active form. Configurational and conformational analysis of 1 and 2 has been carried out using infrared (IR) and vibrational circular dichroism (VCD) spectroscopies. Analysis of the experimental IR and VCD spectra has been carried out using ab initio density functional theory (DFT). For both 1 and 2, DFT predicts two populated conformations. Comparison to experiment of the conformationally averaged IR and VCD spectra of 1 and 2, predicted using DFT, provides unequivocal evidence of the predicted conformations and yields the absolute configurations R(-)/S(+) for 1 and R(+)/S(-) for 2. These absolute configurations are consistent with the R(-)/S(+) absolute configuration of spiropentylcarboxylic acid, assigned previously via X-ray crystallography of its alpha-phenylethylammonium salt.     

Structural transitions in polyribocytidylic acid induced by changes in pH and temperature: vibrational circular dichroism study in solution and film states

Changes in vibrational absorption and vibrational circular dichroism (VCD) spectra of polyribocytidylic acid (polyC) in buffered D(2)O solution as a function of pH and temperature are reported. Analysis of these spectral data led us to establish the absorption band at approximately 1693 cm(-1) and associated negative VCD couplet as diagnostic markers of the double-helical form of polyC. An alternate interpretation suggesting quadruplex formation for polyC is also discussed. In addition to the solution state spectral data, pH-dependent absorption and VCD spectra for polyC films derived from dilute H(2)O solutions are also presented. The pH-dependent changes in the absorption and VCD spectra of polyC films are found to be similar to those observed for polyC in solution.     

DFT study of vibrational circular dichroism spectra of D-lactic acid-water complexes

This paper presents a discussion of the interaction energies, conformations, vibrational absorption (VA, harmonic and anharmonic) and vibrational circular dichroism (VCD) spectra for conformers of monomeric chiral d(-)-lactic acid and their complexes with water at the DFT(B3LYP)/aug-cc-pVDZ and DFT(B3LYP)/aug-cc-pVTZ levels. A detailed analysis has been performed principally for the two most stable complexes with water, differing by lactic acid conformation. The VCD spectra were found to be sensitive to conformational changes of both free and complexed molecules, and to be especially useful for discriminating between different chiral forms of intermolecular hydrogen bonding complexes. In particular, we show that the VCD modes of an achiral water molecule after complex formation acquire significant rotational strengths whose signs change in line with the geometry of the complex. Using the theoretical prediction, we demonstrate that the VCD technique can be used as a powerful tool for structural investigation of intermolecular interactions of chiral molecules and can yield information complementary to data obtained through other molecular spectroscopy methods.     

Vibrational absorption and circular dichroism studies of trans-(3S,4S)-d6-cyclopentene in the gas phase

Vibrational absorption (IR) and circular dichroism (VCD) measurements of trans-(3S,4S)-d6-cyclopentene in the gas phase were performed in the C-H, C-D, and mid-infrared regions. In this study, we report the first VCD spectra recorded at high spectral resolution (up to 0.5 cm(-1)) with a very good signal-to-noise ratio (differential absorbance lower than 5 x 10(-6)). The quality of the experimental spectra allows us the observation of the vibration-rotation structure of the bands in both absorption and VCD spectra. Experimental spectra have been compared with the density functional theory (DFT) absorption and VCD spectra, calculated using B3LYP functional and cc-pVTZ basis set for the axial, equatorial, and planar conformers. Lorentzian and PQR band profiles have been used to convert the calculated dipolar and rotational strengths. In the mid-infrared (<2000 cm(-1)) region, predicted (population-weighted) spectra were in excellent agreement with experiment, allowing the determination of the absolute configuration of this molecule. Above 2000 cm(-1), a reasonable agreement was obtained even if anharmonicity was not considered and if Fermi resonance occurs in the C-D stretching region. Finally, a more precise analysis of the absorption spectrum has been achieved by taking into account anharmonicity of the C-H stretching and its coupling with the ring-puckering motion.     

Absolute configuration, predominant conformations, and vibrational circular dichroism spectra of enantiomers of n-butyl tert-butyl sulfoxide

Alkylation of the alpha-carbanion of (R)-(-)-tert-butyl methyl sulfoxide (4) with n-propyl bromide afforded (+)-n-butyl tert-butyl sulfoxide (1) to which the absolute configuration (R) was ascribed. This assignment was confirmed by X-ray analysis of the complex 6 obtained from the enantiomerically pure sulfoxide (-)-1 and mercury chloride. Vibrational absorption and circular dichroism spectra of (+)-1 were measured in CDCl3 solution in the 2000-900 cm(-1) region and compared with the ab initio predictions of absorption and VCD spectra obtained with density functional theory using the B3LYP/6-31G basis set for different conformers of (R)-1. This comparison indicated also that (+)-1 is of the (R)-configuration.     

Chirality transfer through hydrogen-bonding: experimental and ab initio analyses of vibrational circular dichroism spectra of methyl lactate in water

The infrared vibrational absorption (VA) and vibrational circular dichroism (VCD) spectra of methyl lactate were measured in the 1000-1800 cm(-1) region in the CCl(4) and H(2)O solvents, respectively. In particular, the chirality transfer effect, i.e. the H-O-H bending bands of the achiral water subunits that are hydrogen-bonded to the methyl lactate molecule exhibit substantial VCD strength, was detected experimentally. A series of density functional theory calculations using B3PW91 and B3LYP functionals with 6-311++G(d,p) and aug-cc-pVTZ basis sets were carried out to simulate the VA and VCD spectra of the methyl lactate monomer and the methyl lactate-(H(2)O)(n) complexes with n = 1, 2, 3. The population weighted VA and VCD spectra of the methyl lactate monomer are in good agreement with the experimental spectra in CCl(4). Implicit polarizable continuum model was found to be inadequate to account for the hydrogen-bonding effect in the observed VA and VCD spectra in H(2)O. The methyl lactate-(H(2)O)(n) complexes with n = 1, 2, 3 were used to model the explicit hydrogen-bonding. The population weighted VA and VCD spectra of the methyl lactate-H(2)O binary complex are shown to capture the main spectral features in the observed spectra in aqueous solution. The theoretical modeling shows that the extent of chirality transfer depends sensitively on the specific binding sites taken by the achiral water molecules. The observation of chirality transfer effect opens a new spectral window to detect and to model the hydrogen-bonding solvent effect on VCD spectra of chiral molecules.     

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.     

Structural transitions in polyriboadenylic acid induced by the changes in pH and temperature: vibrational circular dichroism study in solution and film states

A correlation of the changes in vibrational absorption and vibrational circular dichroism (VCD) spectral features with the structural changes of polyriboadenylic acid (polyA) as a function of pH is reported. Analysis of the solution spectral data as a function of pH led us to establishing the importance of a previously unrecognized absorption band at approximately 1665 cm(-1). The present studies indicate that this absorption band and associated VCD originate from the double-helical structure of polyA. The observed changes in solution-state VCD features are indicative of the pH-dependent transitions among the three acidic forms of polyA (A, B, and "frozen" form). In addition to the solution-state spectral data, pH-dependent absorption and VCD spectra for films of polyA, derived from dilute H2O solutions, are also presented. The pH-dependent changes in the absorption and VCD spectra of films are also correlated to the polyA structural changes.     

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

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

Determination of the absolute configurations of natural products via density functional theory calculations of vibrational circular dichroism, electronic circular dichroism, and optical rotation: the iridoids plumericin and isoplumericin

The absolute configurations (ACs) of the iridoid natural products, plumericin (1) and isoplumericin (2), have been re-investigated using vibrational circular dichroism (VCD) spectroscopy, electronic circular dichroism (ECD) spectroscopy, and optical rotatory dispersion (ORD). Comparison of DFT calculations of the VCD spectra of 1 and 2 to the experimental VCD spectra of the natural products, (+)-1 and (+)-2, leads unambiguously to the AC (1R,5S,8S,9S,10S)-(+) for both 1 and 2. In contrast, comparison of time-dependent DFT (TDDFT) calculations of the ECD spectra of 1 and 2 to the experimental spectra of (+)-1 and (+)-2 does not permit definitive assignment of their ACs. On the other hand, TDDFT calculations of the ORD of (1R,5S,8S,9S,10S)-1 and -2 over the range of 365-589 nm are in excellent agreement with the experimental data of (+)-1 and (+)-2, confirming the ACs derived from the VCD spectra. Thus, the ACs initially proposed by Albers-Sch?nberg and Schmid are shown to be correct, and the opposite ACs recently derived from the ECD spectra of 1 and 2 by Els?sser et al. are shown to be incorrect. As a result, the ACs of other iridoid natural products obtained by chemical correlation with 1 and 2 are not in need of revision.     

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

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

Effects of strong and weak hydrogen bond formation on VCD spectra: a case study of 2-chloropropionic acid

The vibrational circular dichroism (VCD) spectrum of S-(-) and R-(+)-2-chloropropionic acid is thoroughly analyzed. Besides the VCD spectrum of the monomer, the dimers (stabilized by strong hydrogen bonds) and the 2-chloropropionic acid-CHCl(3) complexes (stabilized by a weak hydrogen bond) are studied both experimentally (in solution and in low-temperature Ar matrix) and by quantum chemical computations. It is shown that dimer formation drastically changes, and even weak complex formation can also substantially affect the overall shape of the VCD spectrum. The present and previous results can be generalized for the practice of absolute configuration determination of carboxylic acids by VCD spectroscopy. For these measurements, if bulky groups do not block dimer formation, comparison of the computed spectra of the dimers with the experimental spectra recorded in relatively concentrated (～0.1 mol dm(-3)) solutions is suggested. Our study also shows that due to the stabilization of monomers and/or the formation of weak complexes, the VCD spectrum recorded in CHCl(3) is more complex and, like in the present case, can have a lower intensity than that of the spectrum recorded in CCl(4). Therefore, if solubility allows, CCl(4) is a much preferred solvent over CHCl(3).     

Vibrational circular dichroism studies of molecular conformation and association of dipeptides

Vibrational circular dichroism (VCD) and infrared (IR) absorption spectra in the NH stretching region have been measured for the dipeptides, R′COAANHR′'(R′ = Me and tertBu; AA = Ala, Leu, Val and Phe; R′' = Me, isoBu and neoPe). Analyses of the VCD and absorption spectra indicated that the VCD bands for the NH stretching are quite sensitive to the state of hydrogen bonding as well as the local conformation of oligopeptides. VCD spectra exhibit a negative VCD band at 3420-3405 cm⁻¹ due to the C₅ conformer with an intramolecularly hydrogen-bonded five-membered ring. The intermolecularly hydrogen-bonded NH stretching vibration exhibits a characteristic negative—positive couplet from the high wavenumber side due to the antiparallel C₅C₅ dimer formation. Hydrogen-bonded oligomers beyond the dimer formed in highly concentrated solutions give rise to an additional negative VCD band on the lower wavenumber side of the hydrogen-bonded absorption band.     

Absolute configuration of tert-butyl-1-(2-methylnaphthyl)phosphine oxide

The enantiomers of tert-butyl-1-(2-methylnaphthyl)phosphine oxide 1 have been separated using a homemade HPLC column and an analytical gradient system. Vibrational absorption and circular dichroism spectra for both enantiomers have been measured in CD2Cl2 and CH2Cl2 solutions in the 2000-900 cm(-1) region. The fully relaxed potential energy surface of (S)-tert-butyl-1-(2-methylnaphthyl)phosphine oxide, obtained using the B3LYP functional with a 6-31G basis set, indicated two stable conformers with their populations in a approximately 2:1 ratio. The vibrational absorption and VCD spectra are predicted for these two conformers using the B3LYP functional with a 6-31G basis set. The comparison of predicted and experimental spectra indicated that (+)-tert-butyl-1-(2-methylnaphthyl)phosphine oxide is in the (S)-configuration. This assignment is supported by the ab initio prediction of positive optical rotation for the most stable conformer with an (S)-configuration and the nonequivalence sense of the tert-butyl group chemical shift observed in the 1H NMR spectrum of this enantiomer measured in the presence of (+)-(S)-mandelic acid as a chiral solvating agent.