Fourier Transform Infrared Spectroscopy and Vibrational Circular Dichroism Assisted Elucidation of the Solution-State Supramolecular Speciation in Racemic and Enantiopure Ketoprofen.

The molecular structure and solution-state molecular interactions in the popular non-steroidal anti-inflammatory drug, ketoprofen, are extensively studied with the aim of gaining a better understanding of the chemical behavior of its solution state and its connection to its nucleation pathway and crystallization outcome. Using as reference solid-state X-ray structures of enantiomeric and racemic forms of ketoprofen, a set of self-assembly models underpinned by density functional theory calculations has been considered for the analysis of spectroscopic data, infrared (IR) and vibrational circular dichroism (VCD), obtained for solutions of the samples as a function of composition and solvent. From our results it can be concluded that, contrary to the general belief for generic carboxylic acids, there are no cyclic dimeric structures of ketoprofen present in solution, but rather linear arrays made up of two (in high polar or diluted media) or more units (in low polar or low dilution media). This observation is in line with the idea that the weak contacts (other than H-bonding) would hold the key to molecular self-assembly, in agreement with recent studies on other aromatic carboxylic acids.

The synergy of different solid-state techniques to elucidate the supramolecular assembly of two 1H-benzotriazole polymorphs.

1H-Benzotriazole crystallizes as two different polymorphs, namely 4aα and 4aß. One polymorph is chiral and it resolves spontaneously as conglomerates. The other polymorph crystallizes in a centrosymmetric space group and it is therefore achiral. In both polymorphs supramolecular structures are formed starting from achiral monomers. An analysis of these two polymorphs of 1H-benzotriazole has been carried out by a complete strategy involving different solid-state experimental techniques and quantum chemical calculations (DFT, Density Functional Theory). In particular, X-ray crystallography, NMR spectroscopy and vibrational spectroscopy techniques (FarIR, IR and Raman) that are not sensitive to chirality have been used to characterize the two polymorphs structurally. Vibrational spectroscopy (VCD, Vibrational Circular Dichroism) that is sensitive to chirality was employed to determine the absolute configuration (M or P helices) of the chiral supramolecular structure of 4aα.

Conformational aspects of polymorphs and phases of 2-propyl-1H-benzimidazole.

This paper reports on the polymorphism of 2-propyl-1H-benzimidazole (2PrBzIm) induced by temperature change. Upon heating, an irreversible reconstructive-type phase transition at T = 384 K from the ordered form I (P212121) to a new polymorph, form II HT (Pcam), was observed. The structural transformation between forms I and II involves significant changes in the crystal packing, as well as a key conformational variation around the propyl chain of the molecule. After the first irreversible phase transition, the II HT form undergoes two further (reversible) phase transitions upon cooling at 361 K (II RT) and 181 K (II LT). All three phases (forms II HT, II RT and II LT) have almost identical crystal packing and, given the reversibility of the conversions as a function of temperature, they are referred to as form II temperature phases. They differ, however, with respect to conformational variations around the propyl chain of 2PrBzIm. Energy calculations of the gas-phase conformational energy landscape of this compound about its flexible bonds allowed us to classify the observed conformational variations of all forms into changes and adjustments of conformers. This reveals that forms I and II are related by conformational change, and that two of the form II phases (HT and RT) are related by conformational adjustment, whilst the other two (RT and LT) are related by conformational change. We introduce the term 'conformational phases' for different crystal phases with almost identical packing but showing changes in conformation.

A vibrational circular dichroism (VCD) methodology for the measurement of enantiomeric excess in chiral compounds in the solid phase and for the complementary use of NMR and VCD techniques in solution: the camphor case.

For the first time, the success of a methodology for the determination of enantiomeric excess (% ee) in chiral solid samples by vibrational circular dichroism (VCD) spectroscopy is reported. We have used camphor to determine the % ee in a blind sample constituted by a mixture of its two enantiomers as a test for the validity of our approach. IR and VCD spectra of different enantiomeric mixtures of R/S-camphor in Nujol mulls were recorded and linear regressions of VCD intensities (ΔAbs.) vs. % ee for selected bands were found. Finally, the VCD intensities of a blind sample were interpolated in these linear regressions, obtaining its % ee with a rms of 2.4. These results in the solid phase were complemented with the determination of % ee in the liquid phase by VCD and NMR techniques, which are proved to be complementary techniques to carry out this kind of analysis. In the same way as in the VCD solid phase, linear regressions of ΔAbs. vs. % ee for selected bands were established, obtaining a rms of 1.1 in the % ee determination of a blind sample. 1H NMR experiments at 600 MHz using the chiral solvating agent, (S,S)-ABTE, allow the determination of the proportions of enantiomers in CD2Cl2 solution with great accuracy. 13C CPMAS NMR spectra prove that this technique cannot be used for conglomerates and/or solid solutions.

Structure Determination, Conformational Flexibility, Internal Dynamics, and Chiral Analysis of Pulegone and Its Complex with Water.

In the current work we present a detailed analysis of the chiral molecule pulegone, which is a constituent of essential oils, using broadband rotational spectroscopy. Two conformers are observed under the cold conditions of a molecular jet. We report an accurate experimentally determined structure for the lowest energy conformer. For both conformers, a characteristic splitting pattern is observed in the spectrum, resulting from the internal rotation of the two non-equivalent methyl groups situated in the isopropylidene side chain. The determined energy barriers are 1.961911(46) kJ mol-1 and 6.3617(12) kJ mol-1 for one conformer, and 1.96094(74) kJ mol-1 and 6.705(44) kJ mol-1 for the other one. Moreover, a cluster of the lowest energy conformer with one water molecule is reported. The water molecule locks one of the methyl groups by means of a hydrogen bond and some secondary interactions, so that we only observe internal rotation splittings from the other methyl group with an internal rotation barrier of 2.01013(38) kJ mol-1 . Additionally, the chirality-sensitive microwave three-wave mixing technique is applied for the differentiation between the enantiomers, which can become of further use for the analysis of essential oils.

The Curious Case of 2-Propyl-1H-benzimidazole in the Solid State: An Experimental and Theoretical Study.

2-Propyl-1H-benzimidazole (2PrBzIm) is a small molecule, commercially available, which displays a curious behavior in the solid state. 2PrBzIm, although devoid of chirality by fast rotation about a single bond of the propyl group in solution, crystallizes as a conglomerate showing chiroptical properties. An exhaustive analysis of its crystal structure and a wide range of experiments monitored by vibrational circular dichroism spectroscopy eliminated all possibilities of an artifact. What remains is a new example of the unexplained phenomenon of persistent supramolecular chirality.

Conformational Flexibility of Limonene Oxide Studied By Microwave Spectroscopy.

Monoterpenoids are biogenic volatile organic compounds that play a major role in atmospheric chemistry by participating in the formation of aerosols. In this work, the monoterpenoid (R)-(+)-limonene oxide (C10 H16 O) was characterized in the gas phase by Fourier-transform microwave spectroscopy in a supersonic jet. Five conformers of limonene oxide, four equatorial and one axial considering the configuration of the isopropenyl group, were unambiguously identified from analysis of the rotational spectrum. The observed conformers include cis and trans forms, which are stabilized by a subtle balance of hydrogen bonds, dispersive interactions, and steric effects. Estimated conformational relative abundances surprisingly reveal that the abundance of the axial conformer is similar to that of some of the equatorial conformers. In addition, the potential energy surface was extensively explored by using density functional theory and ab initio methods.

Supramolecular organization of perfluorinated 1H-indazoles in the solid state using X-ray crystallography, SSNMR and sensitive (VCD) and non sensitive (MIR, FIR and Raman) to chirality vibrational spectroscopies.

1H-Indazole derivatives exhibit a remarkable property since some of them form chiral supramolecular structures starting from achiral monomers. The present work deals with the study of three perfluorinated 1H-indazoles that resolve spontaneously as conglomerates. These conglomerates can contain either a pure enantiomer (one helix) or a mixture of both enantiomers (both helices) with an enantiomeric excess (e.e.) of one of them. The difficulty of the structural analysis of these types of compounds is thus clear. We outline a complete strategy to determine the structures and configurations (M or P helices) of the enantiomers (helices) forming the conglomerates of these perfluorinated 1H-indazoles based on X-ray crystallography, solid state NMR spectroscopy and different solid state vibrational spectroscopies that are either sensitive (VCD) or not (FarIR, IR and Raman) to chirality, together with quantum chemical calculations (DFT).

Solvent Effects on the Monomer/Hydrogen-Bonded Dimer Equilibrium in Carboxylic Acids: (+)-(S)-Ketopinic Acid as a Case Study.

The hydrogen-bond-assisted self-association process of a chiral semirigid carboxylic acid, namely, (+)-(S)-ketopinic acid, has been studied. The multiconformational monomer/dimer equilibrium has been evaluated by means of a concentration-dependent FTIR study that enabled the experimental equilibrium constants of the dimer formation reaction (Kdim ) to be determined in two solvents of different polarity. In CDCl3 , dimeric forms predominate, even in diluted solutions (KdimCF =5.074), whereas in CD3 CN the self-association process is hindered and monomers are always the main species, irrespective of solute concentration (KdimAN =0.194). The reliability of the dimerization constants and the derived mono- and dimeric experimental fractions have been proven by means of accurate matching between the experimental vibrational circular dichroism spectra of the species and the theoretical spectra generated by considering the simultaneous weighted contributions of the concomitant monomers and dimers.

Hyperconjugative and Electrostatic Interactions as Anomeric Triggers in Archetypical 1,4-Dioxane Derivatives.

The anomeric effect accounts for the greater thermodynamic stability of axially arranged six-membered heterocycles holding an electronegative substituent at the C1 position. Within a frame of no general consensus, two different theories are typically claimed to justify this effect mostly based on either hyperconjugative or electrostatic factors. Here we report a theoretical-experimental study of the role of both as anomeric triggers in two archetypical 1,4-dioxane derivatives, using a suitable combination of spectroscopic (IR and vibrational circular dichroism) and computational techniques for the analysis of the solvation environment effect in their anomeric choices. VCD and IR spectroscopies are used as conformer-discriminating tools: a detailed analysis of the evolution of the spectral profiles allows assessing the theoretically predicted changes in the experimental α/ß ratios when changing the polar solvent, which are fully explained on the basis of an extensive NBO energy partition scheme that provides a detailed view of the role of hyperconjugative and electrostatic interactions as anomeric regulators. Our results suggest that the anomeric equilibrium cannot be described by a single stereoelectronic effect but by the combined contribution of hyperconjugation and electrostatic repulsions, so that the ß-anomeric choice in polar solvents is markedly driven by the strong attenuation of electrostatic repulsive interactions that occurs in solution.

DFT study of the hydrolysis reaction in atranes and ocanes: the influence of transannular bonding.

Thermochemical kinetics of hydrolysis reactions of compounds with transannular intramolecular M…N bonds, i.e., atranes RM(OCH2CH2)3N and ocanes R2M(OCH2CH2)2NH (M = Si, Ge; R = F, Cl, Me), is studied at the B3LYP/aug-cc-pVDZ theoretical level. Several DFT methods are assessed for the reproduction of the experimental activation barrier for the Si-O bond cleavage of 1-methylsilatrane. Activation barriers for atranes and ocanes show the tendency for their growth with the decrease of the electronegativity of a substituent R on going from F to Me and their decrease from Si to Ge. Hydrolysis activation barriers of atranes and ocanes are compared with those of their acyclic analogs RM(OCH3)3 and R2M(OCH2)2NH in order to study the role of transannular M…N bonds in the stability of these molecules to hydrolysis. Substantially larger barriers for atranes support the opinion that stability of atranes may be explained by the formation of intramolecular bonds; however, the strengthening of transannular M…N bonds results in lower M-O cleavage barriers. It was proposed that the M-O cleavage barrier height is determined not by a weak M…N bonding itself, but rather by the contribution of a nitrogen lone pair to the antibonding orbitals of M-O bonds. The NBO analysis show that this interaction increases with the decrease of the electronegativity of a substituent R and decreases on going from atranes to ocanes. In ocanes, the presence of M…N bonds does not kinetically hinder the hydrolytic process; M-O cleavage activation barriers for acyclic analogs are higher. M-Hal cleavage barriers are substantially higher than those for M-O cleavage for R = F, but lower for R = Cl. Graphical Abstract The experimental barrier height of the Si-O bond cleavage in 1-methylsilatrane is well reproduced when three explicit water molecules are included in the B3LYP/aug-cc-pVDZ theoretical model.

Understanding the Aldo-Enediolate Tautomerism of Glycolaldehyde in Basic Aqueous Solutions.

The biochemically important interconversion process between aldoses and ketoses is assumed to take place via 1,2-enediol or 1,2-enediolate intermediates, but such intermediates have never been isolated. The current work was undertaken in an attempt to detect the presence of the 1,2-enediol structure of glycolaldehyde in alkaline medium, actually a 1,2-enediolate, and to try to clarify the scarce data existing about both the formation of deprotonated enediol and the aldo-enediolate equilibrium. The Raman spectra of neutral and basic solutions were recorded as a function of time for eleven days. Several bands associated with the presence of the enediolate were observed in alkaline medium. Glycolaldehyde exists as three different structures in aqueous solution at neutral pH, that is, hydrated aldehydes, aldehydes and dimers, with a respective ratio of approximately 4:0.25:1. Additionally, the formation of Z-enediolate forms takes place at basic pH, together with an increase in the concentration of aldehyde species, such as 2-oxoethan-1-olate, and a decrease in the concentrations of the hydrated aldehyde and dimeric forms. The theoretical ratio of ≈1.5:1 for aldehyde:Z-enediolate reproduces the experimental Raman spectrum in basic medium, with an additional contribution of the previously mentioned ratio between the hydrated aldehyde and dimeric forms. Finally, Raman spectroscopy allowed us to monitor the enolization of this carbohydrate model and conclude that aldo-enediol tautomerism-formally aldo-enediolate-happens when a suitable amount of basic species is added.

Deducing the molecular properties of zwitterionic, protonated, deprotonated, and double-deprotonated forms of L-cysteine from vibrational spectroscopy (IR, Raman, VCD) and quantum chemical calculations.

The behavior of L-cysteine (C3H7NO2S, (2R)-2-amino-3-sulfanylpropanoic acid) in water at different pH values was analyzed both experimentally and theoretically. The behavior was studied at pH values of 5.21 (at this pH, L-cysteine is a zwitterionic species), 1.00 (protonated species), 8.84 (monodeprotonated species), and 13.00 (dideprotonated species). We carried out a vibrational study using nonchiroptical (IR-Raman) and chiroptical (VCD) techniques complemented by quantum chemical calculations. We adopted a dual strategy, as follows. (i) The hybrid density functionals B3LYP and M062X and the ab initio MP2 method were employed, with the same 6-311++G (d,p) basis set, in order to characterize the relative energies and structures of an extensive set of conformers of L-cysteine. The presence of water was included by utilizing the IEF-PCM implicit solvation model. (ii) The vibrational analysis was made using a chirality-sensitive using a chirality-sensitive technique (VCD) and chirality-insensitive techniques (IR, including MIR and FIR, and Raman), especially in aqueous solution. The results obtained theoretically and experimentally were compared in order to deduce the most stable structures at each pH. Moreover, for the first time, the monodeprotonated anion of L-cysteine was detected in aqueous solution by means of IR, Raman and vibrational circular dichroism (VCD). Finally, analysis of the low-frequency region using the IR and Raman techniques was shown to be a very important way to understanding the conformational preference of the zwitterionic species.

An assessment of DFT methods for predicting the thermochemistry of ion-molecule reactions of group 14 elements (Si, Ge, Sn).

Experimental mass-spectrometry data on thermochemistry of methide transfer reactions (CH3)3M(+) + M'(CH3)4 ↔ M(CH3)4 + (CH3)3M'(+) (M, M' = Si, Ge or Sn) and the formation energy of the [(CH3)3Si-CH3-Si(CH3)3](+) complex are used as benchmarks for DFT methods (B3LYP, BMK, M06L, and ωB97XD). G2 and G3 theory methods are also used for the prediction of thermochemical data. BMK, M06L, and ωB97XD methods give the best fit to experimental data (close to chemical accuracy) as well as to G2 and G3 results, while B3LYP demonstrates poor performance. From the first three methods M06L gives the best overall result. Structures and formation energies of intermediate "mixed" [(CH3)3M-CH3- M'(CH3)3] complexes not observed in experiment are predicted. Their structures, better described as M(CH3)4 [M'(CH3)3](+) complexes, explain their fast decompositions.

Conformational preference and chiroptical response of carbohydrates D-ribose and 2-deoxy-D-ribose in aqueous and solid phases.

This work targets the structural preferences of D-ribose and 2-deoxy-D-ribose in water solution and solid phase. A theoretical DFT (B3LYP and M06-2X) and MP2 study has been undertaken considering the five possible configurations (open-chain, α-furanose, ß-furanose, α-pyranose, and ß-pyranose) of these two carbohydrates with a comparison of the solvent treatment using only a continuum solvation model (PCM) and the PCM plus one explicit water molecule. In addition, experimental vibrational studies using both nonchiroptical (IR-Raman) and chiroptical (VCD) techniques have been carried out. The theoretical and experimental results show that α- and ß-pyranose forms are the dominant configurations for both compounds. Moreover, it has been found that 2-deoxy-D-ribose presents a non-negligible percentage of open-chain forms in aqueous solution, while in solid phase this configuration is absent.

Stabilizing factors of the molecular structure in silicon-based peptidomimetics in gas-phase and water solution. Assessment of the correlation between different descriptors of hydrogen bond strength.

The use of DFT (B3LYP and M06L) and ab initio (MP2) computational methods allowed us to perform a thorough conformational study of N-[dihydroxy (methyl)silyl]methylformamide (DHSF) and 3-[dihydroxy (methyl) silyl] propanamide (DHSP), that could be considered simplified models of the environment of the silanediol group in silicon gem-diols that have proven efficiency as protease inhibitors. We have found a total of 13 molecular conformations that represent minima in the potential energy surfaces of DHSF (six conformers) and DHSP (seven conformers). The key feature in their molecular structure is the occurrence of intramolecular hydrogen bonding between the hydroxyl and aminocarbonyl groups. We have estimated the strength of each individual hydrogen bond in the mentioned species using the descriptors proposed by three different methodologies, i.e., the quantum theory of atoms in molecules (QTAIM), the natural bond orbitals population analysis (NBO), and the so-called empirical Rozenberg's enthalpy-distance relationship. We have found a good correlation among the calculated values for the different descriptors within the whole set of conformers in the molecular systems in this study. We have also discussed the predicted order of stabilities of the different conformers of each species in terms of the so-called ring anomeric effect (RAE) and generalized anomeric effect (GAE). Finally, we also analyzed the discrepancies found in the order of stability when going from the isolated molecule approximation to water solution (PCM).

Chiral recognition of amino acid enantiomers by a crown ether: chiroptical IR-VCD response and computational study.

We report on a combined experimental and computational study of the chiral recognition of the amino acid serine in protonated form (L/D-SerH(+)), by the crown ether (all-S)-(18-crown-6)-2,3,11,12-tetracarboxylic acid (S-18c6H4). Infrared and vibrational circular dichroism spectroscopies (IR-VCD) are employed to characterize the chiroptical response of the complexes formed by S-18c6H4 with the L-SerH(+) and D-SerH(+) enantiomers in dried thin films obtained from aqueous solutions. The study focuses on vibrational modes directly related to the intermolecular hydrogen bonds between the crown ether derivative and serine, responsible for crown-serine binding, namely, the C═O and C-O stretching modes, and on the C-O-H bending mode, which yield intense IR and VCD signals in the range of wavenumbers 900-2000 cm(-1). The experimental spectra are analyzed in combination with a computational structural survey and optimization at different levels of density functional theory. The conformational landscape of the complexes is found to be primarily governed by a bowl-like structure of the crown ether host and a tripodal coordination of the protonated R-NH3(+) group of serine with the oxygen atoms of the central ether ring. Additionally, one or two of the carboxylic side groups of the crown ether interact with the -COH and -COOH groups of serine. Chiral selectivity is probed by recording the IR and VCD spectra of dried thin films obtained from aqueous solutions with equimolar concentrations of the two serine enantiomers and the macrocycle. The results demonstrate a marked chiral recognition of L-SerH(+) relative to D-SerH(+) by the S-18c6H4 substrate, which arises from the favorable host-guest coordination through H-bonds at optimum distances and collinear orientations, also involving a limited distortion of the crown ether backbone.

Study of the photoinduced supramolecular chirality in columnar liquid crystals by infrared and VCD spectroscopies.

IR and VCD spectroscopies are employed to clarify the molecular origins of supramolecular chirality in azobenzene-containing columnar liquid crystals. The different columnar mesomorphic assemblies, Colr and Colh, of an achiral and a chiral propeller-like hydrogen-bonded complex, respectively, are used for this study. The mesomorphic behavior of the achiral complex is studied here for the first time, and the structural parameters of its Colr mesophase are determined by X-ray diffraction. Both complexes bear azobenzene units and this makes it possible to implement photoresponsive columnar architectures, the chirality of which can be induced and modulated by irradiation with 488 nm circularly polarized light (CPL). Thin films of the respective rectangular and hexagonal columnar phases of these complexes have been processed in order to study the IR absorption spectra and the vibrational circular dichroism responses upon irradiation with CPL. These studies allow confirming that the outer part of the columns, consisting on azobenzene groups, is mainly involved in the photoinduced supramolecular chirality, rather than the inner part of the columns where a melamine core is located. This supports a structural model based on the helical disposition of the azobenzene groups along the stacked propeller-like complexes.

IR-Raman-VCD study of R-(+)-pulegone: influence of the solvent.

R-(+)-Pulegone is a natural monoterpene obtained from the essential oils of a variety of plants. It is used in flavouring agents, perfumery and aromatherapy. In this work, a study of the molecular structure and the infrared and Raman spectra of this chemical is presented. Theoretical calculations reveal the existence of two conformers depending on the position of the methyl group (axial and equatorial), being the equatorial conformer the most stable. A complete and reliable assignment of the IR and Raman spectra of the title compound is made, and the results are used to carry out a detailed interpretation of the VCD spectrum of this compound in the 4000-900 cm(-1) region. Finally, the influence of the solvent in the VCD bands (intensity and sign) has been tested comparing the neat liquid spectrum with the VCD spectra recorded with four solvents.

Rotational strength sign and normal modes description: A theoretical and experimental comparative study in bicyclic terpenes.

A comparative study of the Vibrational circular dichroism (VCD) patterns in three bicyclic terpenes with related molecular structures, (+)-(R)-α-pinene, (-)-(S)-ß-pinene, and (-)-(S)-verbenone, is carried out. The study is done in the light of normal mode descriptions from a previous vibrational analysis. Although normal modes corresponding to identical molecular moieties shown the same description, rotational strength does not follow the Cahn-Ingold-Prelog descriptor-related sign in some cases, i.e., they do not present opposite signs depending on stereochemical description of the molecule.