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).     

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.     

Lactic acid in solution: investigations of lactic acid self-aggregation and hydrogen bonding interactions with water and methanol using vibrational absorption and vibrational circular dichroism spectroscopies

The infrared vibrational absorption (VA) and vibrational circular dichroism (VCD) spectral features of L-(+)-lactic acid (LA) in CDCl3 solution are concentration dependent, showing evidence of oligomerization with increasing concentrations. To understand the observed spectra, geometry optimizations, vibrational frequencies, and VA and VCD intensities were evaluated for (LA)n with n=1-4 using density functional theory calculations at the B3LYP6-311++G(d,p), B3LYP/cc-pVTZ, and in some cases, B3LYP/aug-cc-pVTZ levels of theory. Comparisons with the experimental spectra indicate that the lowest energy LA dimer (AA), formed by two C Double Bond O...HO hydrogen bonds, is one of the dominating species in solution at room temperature. Possible contributions from the LA trimer and tetramer are also discussed. To model the VA and VCD spectra of LA in water and in methanol, both implicit polarizable continuum model and explicit hydrogen bonding considerations were used. For explicit hydrogen bonding, geometry optimizations of the AA-(water)n and AA-(methanol)n complexes, with n=2,4,6, were performed, and the corresponding VA and VCD spectra were simulated. Comparisons of the calculated and experimental VA and VCD spectra in the range of 1000-1800 cm(-1) show that AA-(water)n with n=6 best reproduces the experimental spectra in water. On the other hand, AA-(methanol)n with n=2 reproduces well the experimental results taken in methanol solution. In addition, we found evidence of chirality transfer, i.e., some vibrational bands of the achiral water subunits gain VCD strength upon complexation with the chiral LA solute. The study is the first to use VCD spectroscopy to probe the structures of LA aggregates and hydrogen bonding solvation clusters in the solution phase.     

Direct determination of absolute configuration of methyl-substituted phenyloxiranes: combined experimental and theoretical approach

Three possible methyl-substituted phenyloxiranes have been synthesized in enantioenriched form (89-99% enantiomeric excess (ee)), and their vibrational absorption (VA) and vibrational circular dichroism (VCD) spectra have been recorded. The experimental spectra are compared to theoretical spectra obtained from quantum mechanical calculations (density functional theory with the B3LYP hybrid exchange correlation functional with 6-31++G*, aug-cc-pVDZ, or aug-cc-pVTZ basis set) and related to the physical structure of the compounds. The absolute configuration could be established directly in each case by comparing experimental and theoretical spectra. In addition, we have been able to document the changes that occur both in structures and in the VA and VCD spectra due to substituent effects on the oxirane ring.     

Determination of molecular stereochemistry using vibrational circular dichroism spectroscopy: absolute configuration and solution conformation of 5-formyl-cis,cis-1,3,5-trimethyl-3-hydroxymethylcyclohexane-1-carboxylic acid lactone

The determination of the absolute configuration of chiral molecules is an important aspect of molecular stereochemistry. Vibrational circular dichroism (VCD) is the extension of electronic CD into the infrared region where fundamental vibrational transitions occur. VCD has a number of advantages over all previous methods of absolute configuration assignment. The absolute configuration and predominant solution-state conformation in CDCl(3) of the chiral lactone, 5-formyl-cis,cis-1,3,5-trimethyl-3-hydroxymethylcyclohexane-1-carboxylic acid lactone, 1, obtained by the comparison of measured and calculated VCD spectra, are reported. It is found that (-)-1 corresponds to the absolute configuration (1S,3S,5R)-1.     

Synthesis and chiroptical properties of cryptophanes having C1-symmetry

New enantiopure cryptophanes 3-7 having C(1)-symmetry have been synthesized. Electronic circular dichroism (ECD) and vibrational circular dichroism (VCD) have been used to investigate their chiroptical properties, and the results are compared to those obtained for cryptophane-A (1) having D(3)-symmetry. The ECD spectra of compounds 3-7 show Cotton effects that differ from those of cryptophane-A. However, our results suggest that a confident determination of the absolute configuration of the monofunctionalized cryptophanes can be made using ECD spectroscopy. Interestingly, we have found that the ECD spectra of cryptophanes, especially the (1)L(b) transition, are very sensitive to the nature of the solvent. These spectral modifications are essentially due to bulk solvent properties rather than the ability of a particular solvent to insert into the cavity of cryptophanes. On the other hand, VCD spectra of the monofunctionalized cryptophanes have not revealed significant spectral modifications with respect to the VCD spectrum of the CHCl(3) at cryptophane-A complex, except for CHCl(3) at 7 and to a smaller extent for CHCl(3) at 6. These spectral modifications, which essentially consist in lower intensities of VCD bands associated with the cryptophane backbone, were perfectly reproduced by ab initio calculations performed at DFT (B3PW91/6-31G*) level. These results clearly demonstrate that VCD measurements associated with DFT calculations allow an easy determination of the absolute configuration of cryptophane-A derivatives.     

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.     

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 absorption and circular dichroism studies of (-)-camphanic acid

Vibrational absorption and circular dichroism (VCD) spectra of (-)-(1S,3R)-camphanic acid have been measured in deuterated chloroform solutions at different concentrations (0.005, 0.045, and 0.200 M) in the mid-infrared spectral range. Experimental spectra have been compared with the density functional theory (DFT) absorption and VCD spectra, calculated using the B3PW91 functional and cc-pVTZ basis set for three conformers of both the monomer and the dimer forms of (-)-(1S,3R)-camphanic acid. These calculations indicate that, in the dilute solution, the conformer with intramolecular hydrogen-bonding between the hydroxyl and lactone groups is of lowest energy and represents 70% of the different monomer conformers at room temperature, whereas, in concentrated solution, the dimer formed by intermolecular hydrogen-bonding of carboxyl groups of the two distinct monomer conformations is stabilized. The vibrational absorption and circular dichroism spectra calculated from the Boltzmann population of the individual monomer and dimer conformers are in very good overall agreement with the corresponding experimental spectra, allowing the absolute conformation and configuration of (-)-(1S,3R)-camphanic acid in dilute and concentrated solution, respectively. Experiments were also performed on (-)-(1S,3R)-camphanic chloride for which the populations predicted by DFT calculations are found to be in disagreement with those deduced from experimental spectra.     

Absolute configuration of C2-symmetric spiroselenurane: 3,3,3',3'-tetramethyl-1,1'-spirobi[3 H,2,1]benzoxaselenole

The enantiomers of 3,3,3',3'-tetramethyl-1,1'-spirobi[3 H,2,1]benzoxaselenole have been separated on a chiral preparative chromatographic column. The experimental vibrational circular dichroism (VCD) spectra have been obtained for both enantiomers in CH(2)Cl(2). The theoretical VCD spectra have been obtained by means of density functional theoretical calculations with the B3 LYP density functional. From a comparison of experimental and theoretical VCD spectra, the absolute configuration of an enantiomer with positive specific rotation in CH(2)Cl(2) at 589 nm is determined to be R. This conclusion has been verified by comparing results of experimental optical rotatory dispersion (ORD) and electronic circular dichroism (ECD) to predictions of the same properties using the B3 LYP functional for the title compound.     

Determination of molecular structure in solution using vibrational circular dichroism spectroscopy: the supramolecular tetramer of S-2,2'-dimethyl-biphenyl-6,6'-dicarboxylic acid

The infrared (IR) and vibrational circular dichroism (VCD) spectra of S-2,2'-dimethyl-biphenyl-6,6'-dicarboxylic acid, S-1, in CDCl(3) solution are concentration-dependent, showing that oligomerization occurs with increasing concentration. DFT calculations support the conclusion that the oligomer formed is the cyclic tetramer (S-1)(4), in which S-1 monomers are linked by hydrogen(H)-bonded (COOH)(2) moieties. Due to the existence of two inequivalent tautomeric conformations of each (COOH)(2) moiety, six inequivalent conformations of (S-1)(4) are possible. B3LYP/6-31G* DFT calculations predict that the conformation "aaab", possessing three equivalent (COOH)(2) conformations, a, and one tautomeric conformation, b, has the lowest free energy. B3LYP/6-31G* IR and VCD spectra vary substantially with conformation. The B3LYP/6-31G* IR and VCD spectra of the C=O stretch modes of "aaab" are in excellent agreement with the experimental spectra, while those of all other conformations exhibit poor agreement, confirming the prediction that the "aaab" conformation is the predominant conformation. Comparison of the calculated IR and VCD spectra of the six conformations to the experimental spectra in the range 1100-1600 cm(-1) further supports this conclusion. The study is the first to use VCD spectroscopy to determine the structure of a supramolecular species.     

Absolute configuration of diterpenoids from Jatropha dioica by vibrational circular dichroism

The absolute configuration of jatropholone A 1 and B 2, including the possibility to observe the vibrational circular dichroism (VCD) capacity to differentiate between two epimeric compounds in the presence of an inherently dissymmetric chromophore, which normally dominates VCD and electronic circular dichroism (ECD) spectra, followed after comparison of their experimental and DFT calculated VCD spectra, allowed us to conclude that although non-local (M/P) chirality generated by atropisomerism dominates over local chirality generated by an (R/S) change, the stereogenic center can confidently be assigned by VCD after DFT calculations. In addition, the absolute configurations of jatrophatrione 3 and citlalitrione 4, a compound proposed as a taxonomic marker for the genus Jatropha, were assigned by contrasting their respective calculated and experimental IR and VCD spectra. The evaluation of Flack and Hooft parameters obtained from the single-crystal X-ray diffraction data of jatropholone B acetate 6, and of 4 independently confirmed the absolute configurations of these molecules.     

Correlation of structure and vibrational spectra of the zwitterion L-alanine in the presence of water: an experimental and density functional analysis

Infrared vibrational spectra were collected along with the vibrational circular dichroism (VCD) spectra for the zwitterions alpha-D-alanine, alpha-L-alanine, alpha-D-mannose and alpha-L-mannose as potassium bromide (KBr) pressed samples. VCD for D- and L-alanine dissolved in water was also measured and compared against the spectra resulting from KBr pressed samples. The experimental data were compared against the ab initio B3LYP/6-31G* optimized geometry. The zwitterion structure of alpha-L-alanine was stabilized by the addition of water molecules. Computationally, beta-L-mannose was studied and resulting expected VCD bands assigned. We present the molecular structures resulting VCD spectra and infrared vibrational spectra from experimentation as compared with the computed results.     

Vibrational circular dichroism DFT study on bicyclo[3.3.0]octane derivatives

The absolute configurations of four bicylco[3.3.0]octane derivatives: endo-bicyclo[3.3.0]octane-2,6-diol, endo-2,6-diacetoxybicyclo[3.3.0]octane, endo-bicyclo[3.3.0]octane-2,6-dione and bicyclo[3.3.0]octa-2,6-dien-2,6-bistriflate were studied by vibrational circular dichroism (VCD). These chiral derivates are of interest as intermediates in the asymmetric synthesis of enantiomerically pure natural products and chiral ligands for asymmetric catalysis. VCD has been used to determine the absolute configuration of each compound, proving the capability of VCD for molecules with several stereogenic centres. IR and VCD spectra have been simulated at the B3LYP/6-31G¹ level for all possible diastereomers. Based on the agreement between the experimental and the calculated spectrum, the stereochemistry of each compound could be assigned. The predicted absolute configurations are found to agree with literature data.     

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.     

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.     

Chirality and diastereoselection of Δ/Λ-configured tetrahedral zinc complexes through enantiopure Schiff base complexes: combined vibrational circular dichroism, density functional theory, 1H NMR, and X-ray structural studies

The metal-centered Δ/Λ-chirality of four-coordinated, nonplanar Zn(A(^)B)(2) complexes is correlated to the chirality of the bidentate enantiopure (R)-A(^)B or (S)-A(^)B Schiff base building blocks [A(^)B = (R)- or (S)-N-(1-(4-X-phenyl)ethyl)salicylaldiminato-κ(2)N,O with X = OCH(3), Cl, Br]. In the solid-state the (R) ligand chirality induces a Λ-M configuration and the (S) ligand chirality quantitatively gives the Δ-M configuration upon crystallization as deduced from X-ray single crystal studies. The diastereoselections of the pseudotetrahedral zinc-Schiff base complexes in CDCl(3) solution were investigated by (1)H NMR and by vibrational circular dichroism (VCD) spectroscopy. The appearance of two signals for the Schiff-base -CH═N- imine proton in (1)H NMR indicates an equilibrium of both Δ- and Λ-diastereomers with a diastereomeric ratio of roughly 20:80% for all three ligands. VCD proved to be very sensitive to the metal-centered Δ/Λ-chirality because of a characteristic band representing coupled vibrations of the two ligand's C═N stretch modes. The absolute configuration was assigned on the basis of agreement in sign with theoretical VCD spectra from Density Functional Theory calculations.     

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.     

Harmonic and anharmonic features of IR and NIR absorption and VCD spectra of chiral 4-X-[2.2]paracyclophanes

The vibrational absorption spectra and vibrational circular dichroism (VCD) spectra of both enantiomers of 4-X-[2.2]paracyclophanes (X = COOCD3, Cl, I) have been recorded for a few regions in the range of 900-12000 cm(-1). The analysis of the VCD spectra for the two IR regions, 900-1600 cm(-1) and 2800-3200 cm(-1), is conducted by comparing with DFT calculations of the corresponding spectra; the latter region reveals common motifs of vibrational modes for the three molecules for aliphatic CH stretching fundamentals, whereas in the mid-IR region, one is able to identify specific signatures arising from the substituent groups X. In the CH stretching region between 2900 and 2800 cm(-1), we identify and interpret a group of three IR VCD bands due to HCH bending overtone transitions in Fermi resonance with CH stretching fundamental transitions. The analysis of the NIR region between approximately 8000 and approximately 9000 cm(-1) for X = COOCD3 reveals important features of the aromatic CH stretching overtones that are of value since the aromatic CH stretching fundamentals are almost silent. The intensifying of such overtones is attributed to electrical anharmonicity terms, which are evaluated here by ab initio methods and compared with literature data.     

Effects of complex formation on vibrational circular dichroism spectra

The determination of absolute configurations of chiral compounds using VCD is performed by comparing measured vibrational circular dichroism (VCD) spectra with calculated spectra. The process is based on two facts: the two enantiomers have rotational strengths of opposite sign, and the absolute configuration of the molecule used in the calculation is known. However, calculations on isolated molecules very often predict VCD intensities of very different magnitude or even different signs compared to the spectra measured in solution. Therefore, we have carefully analyzed what type of changes are induced by complexation of a solvent molecule to a solute. In the theoretical example of benzoyl-benzoic acid (in a particular chiral conformation) hydrogen bonded to the achiral NH3, we distinguish six cases, ranging from no or very small changes in the rotational strengths of solute modes (case A) to changes of sign of rotational strengths (case B), changes in magnitude (case C), nonzero rotational strengths for modes of the achiral solvent ("transfer of chirality", case D), large frequency shifts accompanied by giant enhancements of the IR and VCD intensities of modes involved in hydrogen bonding (case E), and emergence of new peaks (case F). In this work, all of these situations will be discussed and their origin will be elucidated. On the basis of our analysis, we advocate that codes for VCD rotational strength calculation should output for each mode i the angle xi(i) between the electric and magnetic transition dipole moments because only "robust modes" with xi far from 90 degrees should be used for the determination of the absolute configuration.