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 colours of Rome in the walls of Cástulo (Linares, Spain).

Wall paintings have become one of the most relevant, complex and challenging research subjects in Archaeometry. Minimally- or non-invasive, accurate and multidisciplinary methods are needed to successfully address the problems posed by their physical and chemical properties and by their analysis techniques. Specifically, the analytical method implemented for the study of this type of samples must enable a precise separation of the chemical information from backgrounds and scenes, allowing the identification of pigment's components in overlapping layers, the detection of minority components and the elucidation of pigment mixtures. Thus, this paper puts forward a multidisciplinary approach towards these goals by means of the combined use of micro Energy Dispersive X-ray Fluorescence (µEDXRF) surface mapping and single-spot micro-Raman spectroscopy and µEDXRF analysis. The samples under research come from the site of Cástulo (Linares, Spain), one of the most important Roman cities in the Iberian Peninsula. It must be emphasized the uniqueness of the walls of Cástulo, their optimal conservation state and the richness and variety of the colour's palette used in their decoration, which make them an excellent and representative example of Roman wall paintings.

A Mechanism-Based Sphingosine-1-phosphate Lyase Inhibitor.

The synthesis of a series of vinylated analogues of sphingosine-1-phosphate together with their unambiguous configurational assignment by VCD methods is reported. Among them, compound RBM10-8 can irreversibly inhibit human sphingosine-1-phosphate lyase (hS1PL) while behaving also as an enzyme substrate. These findings, together with the postulated mechanism for S1PL activity, reinforce the role of RBM10-8 as a new mechanism-based hS1PL inhibitor.

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.

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-Aided Vibrational Circular Dichroism Spectroscopy Study of (-)-S-cotinine.

The implementation of a strategy comprising the use of vibrational circular dichroism spectroscopy and DFT calculations allows determination of the solution-state conformational distribution in (-)-S-cotinine, giving further proof of the extra conformer-discriminating potential of this experimental technique, which may offer unique molecular fingerprints of subtly dissimilar molecular conformers of chiral samples. Natural bond orbital electronic structure calculations of the rotational barrier height between the two main conformers of the species indicate that hyperconjugative effects are the key force governing the conformational equilibrium. The negligible effect of the solvent's polarity over both structure and conformational energy profile supports this result.

Vibrational circular dichroism and theoretical study of the conformational equilibrium in (-)-S-nicotine.

We report an extensive study of the molecular and electronic structure of (-)-S-nicotine, to deduce the phenomenon that controls its conformational equilibrium and to solve its solution-state conformer population. Density functional theory, ab initio, and molecular mechanics calculations were used together with vibrational circular dichroism (VCD) and Fourier transform infrared spectroscopies. Calculations and experiments in solution show that the structure and the conformational energy profile of (-)-S-nicotine are not strongly dependent on the medium, thus suggesting that the conformational equilibrium is dominated by hyperconjugative interactions rather than repulsive electronic effects. The analysis of the first recorded VCD spectra of (-)-S-nicotine confirmed the presence of two main conformers at room temperature. Our results provide further evidence of the hypersensitivity of vibrational optical activity spectroscopies to the three-dimensional structure of chiral samples and prove their suitability for the elucidation of solution-state conformer distribution.

Study of the chelating properties of Ge(OH)2 functionality as metal binding group for Zn2+ cation in simplified protease-like environments: a DFT analysis.

The development of protease's inhibitors is an active field of research in the pharmaceutical industry. As concerns the design of new inhibitors, the theoretical study of the binding patterns and energies of known metal binding groups (MBGs) toward Zn(2+) using quantum-chemical calculations may offer a better understanding of their interaction models and may be useful for the improvement and design of novel ZBGs. Here the properties of gem-Ge(OH)(2)-based compounds as ZBG were assessed theoretically using DFT calculations. [Zn(Imdz)(2) R - OH(2)](2+) complexes (Imdz =imidazole rings; R = imidazole ring, acetic acid molecule or acetate anion) were used to partially reproduce the coordination sphere in metalloproteases (ACE, amgiotensin converting enzyme, and TLN, thermolysine) being inhibited by related compounds (i.e., silanediols). The MBG- Zn(2+) interaction was analyzed through the energy of the reaction: [Zn(Imdz)(2) R - OH(2)](2+) + L → [Zn(Imdz)(2) R - L](2+) + H(2)O using DFT (M06L/cc-pVDZ) in gas-phase and in solution (IEF-PCM). Although the functional used (M06L) has proven its efficiency to study systems containing transition metal governed by non-covalent interactions, dispersion effects were implemented by the correction of the computed energies using the DFT-D3 program. Accounting for dispersion effects produced a systematic increase of c.a. 13 kJ mol(-1) on the energies, whereas the effect of solvent goes in the opposite direction (i.e., BE under the IEF-PCM model are on average 125 kJ mol(-1) lower). The Ge(OH)(2) - Zn(2+) interaction seems to be similar (or even stronger) than the Si(OH)(2) -Zn(2+). Their better performance as ZBG is explained by the combined NBO-AIM analysis. The results of this work may encourage the preparation, isolation, and experimental assay of the chelating properties of these compounds, which may propose a new family of protease's inhibitors.

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.

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).

Quantum chemical study of silanediols as metal binding groups for metalloprotease inhibitors.

DFT (B3LYP and M06L) as well as ab initio (MP2) methods with Dunning cc-pVnZ (n=2,3) basis sets are employed for the study of the binding ability of the new class of protease inhibitors, i.e., silanediols, in comparison to the well-known and well-studied class of inhibitors with hydroxamic functionality (HAM). Active sites of metalloproteases are modeled by [R3M-OH2]²âº complexes, where R stands for ammonia or imidazole molecules and M is a divalent cation, namely zinc, iron or nickel (in their different spin states). The inhibiting activity is estimated by calculating Gibbs free energies of the water displacement by metal binding groups (MBGs) according to: [R3M-OH2]²âº + MBG → [R3M-MBG]²âº + H2O. The binding energy of silanediol is only a few kcal mol(-1) inferior to that of HAM for zinc and iron complexes and is even slightly higher for the triplet state of the (NH3)3Ni²âº complex. For both MBGs studied in the ammonia model the binding ability is nearly the same, i.e., Fe²âº(t) > Ni²âº(t) > Fe²âº(q) > Ni²âº(s) > Zn²âº. However, for the imidazole model the order is slightly different, i.e., Ni²âº(t) > Fe²âº(t) > Fe²âº(q) > Ni²âº(s) ≥ Zn²âº. Equilibrium structures of the R3Zn ²âº complexes with both HAM and silanediol are characterized by the monodentate binding, but the bidentate character of binding increases on going to iron and nickel complexes. Two types of intermediates of the water displacement reactions for [(NH3)3M-OH2]²âº complexes were found which differ by the direction of the attack of the MBG. Hexacoordinated complexes exhibit bidentate bonding of MBGs and are lower in energy for M=Ni and Fe. For Zn penta- and hexacoordinated complexes have nearly the same energy. Intermediate complexes with imidazole ligands have only octahedral structures with bidentate bonding of both HAM and dimethylsilanediol molecules.

Effect of substituents and hydrogen bonding on barrier heights in dehydration reactions of carbon and silicon geminal diols.

Activation barrier heights for the dehydration reaction of geminal carbinols and silanediols R'R″X(OH)(2) (X = C, Si) were estimated at the B3LYP and MP2 levels of theory employing Dunning's correlation-consistent triple-zeta basis sets. It was shown that the barrier height for carbon derivatives steadily decreases upon substitution by R groups, usually termed as electron-donating, such as alkyl and amino groups. Substitution by electron-withdrawing groups leads, however, only to small changes in barrier heights compared to that of methanediol. A similar tendency was also found for silicon derivatives, but high activation barriers of this reaction remain even for amino group substituted silanediols. Introduction of additional water molecules into the reactive space of carbinol dehydration drastically reduces barrier heights and brings the transition state energy for methanediol close to the experimental value. The difference between dehydration barrier heights for both methanediol and carbinols with electron-rich substituents becomes well-defined for dimeric species. The higher acidity of the hydroxyl group protons in molecules containing halogens and C==O groups brings about a noticeable growth in the dehydration barrier heights of these compounds. This difference in barrier heights for oligomeric species may be the reason for the stability of carbinols with electron-rich substituents.

Theoretical study of the mechanisms of the hydrolysis and condensation reactions of silicon and titanium alkoxides: similarities and differences.

Stationary states for hydrolysis reactions in M(OCH(3))(4) + nH(2)O (M = Si, Ti; n = 1-3) systems are optimized at the B3LYP and MP2 levels with the Wachters basis set for titanium and the cc-pVDZ set for other atoms. Geometries of these states for M = Ti are characterized by trigonal bipyramidal (water molecules in front-side position) and octahedral coordination (for back-side position). Barrier heights for hydrolysis and condensation are substantially lower than those for silicon in keeping with experimental results. The lowering of the barrier heights on the addition of water molecules in the front-side position (reduction of hydrogen bond strain) exceeds that of the back-side addition (catalytic effect) for both M = Si and Ti, but the difference diminishes with n. The influence of oligomerization of titanium alkoxides on the rate of hydrolysis is studied on the model of the interaction of a Ti(2)(OCH(3))(8) dimer with one and two water molecules. It was shown that only terminal methoxy groups are exposed to hydrolysis and therefore the dimeric structure is retained in the process of the substitution of terminal methoxy groups. Barrier heights for terminal hydrolysis do not differ significantly from those of monomers. Barrier heights for condensation reactions obtained for the 2M(OMe)(n)(OH)(4-n) + H(2)O model system, are substantially (by ca. 10 kcal mol(-1)) lower for M = Ti and in both silicon and titanium species demonstrate a steady growth with n.

Mechanism of the catalytic activity of nucleophiles in the stepwise hydrolysis and condensation reactions of tetramethoxysilane.

Active ingredients: A model for the simplest hydrolysis reaction is applied to all stages of stepwise hydrolysis and condensation taking place during a sol-gel process. The picture shows the molecular structures of the transition states of the ammonia- (left) and OH(-)-promoted (right) condensation reactions of two Si(OH)(4) molecules, including an additional water molecule.The previously proposed model of the catalytic activity of nucleophiles in the hydrolysis reaction of tetramethoxysilane is expanded to the subsequent stages of hydrolysis, that is, the stepwise hydrolysis of (MeO)(4-x)(OH)(x)Si (x=1-3) molecules, and to the condensation reaction of completely hydrolysed species. The estimate of the reaction barrier heights by using the B3LYP and MP2 methods with correlation-consistent double-zeta basis sets allows us to predict the catalytic activity of bases for the different steps of hydrolysis and for condensation reactions. In general, the catalytic activity of bases decreases with the number of hydrolysed groups, vanishing in the case of ammonia at x=2 and remaining in the case of the hydroxyl anion up to x=3. In addition, the value of the catalytic activity of NH(3) and OH(-) is of the same order of magnitude for hydrolysis reactions, while the effect of the OH(-) anion substantially exceeds that of NH(3) for condensation reactions.

Role of structures with penta- and hexacoordinate silicon in the nucleophile-catalyzed hydrolysis of tetramethoxysilane.

The mechanism of the base catalyzed hydrolysis of tetramethoxysilane (TMOS), proposed earlier on the basis of experimental data, is assessed by theoretical methods, i.e. MP2 and B3LYP with 6-31G(d) and Dunning correlation-consistent basis sets. Models considered involve one and two hydrolyzing water molecules attacking (MeO)(4)Si in the frontside position with a nucleophile (NH(3) and OH(-)) in the backside position. This approach allowed us to simulate uniformly the catalytic action of weak and strong bases. It was shown that the presence of a base in the backside position considerably lowers the activation barrier for hydrolysis. The inclusion of the additional water molecule which results in a substantial lowering of the barrier for uncatalyzed hydrolysis does not change noticeably the catalytic effect. In both one- and two-water molecules models the structure of the transition state in the presence of a nucleophile becomes nearly octahedral in which hexacoordinate silicon and four oxygens of the TMOS moiety have a planar arrangement.

Triethylsilanol: molecular conformations and role of the hydrogen-bonding oligomerization in its vibrational spectra.

We report a theoretical study of the molecular structure of the triethylsilanol molecule and a thorough conformational analysis of the species following the Boltzmann's distribution law. The vibrational spectra of the title molecule have been assigned by means of the combined use of experimental data obtained from IR and Raman spectra and theoretical DFT calculations with the subsequent implementation of the SQMFF methodology. The role of hydrogen bonding in the shifting of the vibrational bands of the silanol group in the spectra of the liquid phase is discussed using a model of triethylsilanol dimer.

Structure and vibrational spectra of Ti(IV) hydroxides and their clusters with expanded titanium coordination. DFT study.

Equilibrium structures of H(4-n)Ti(OH)n (n = 2-4) molecules and the Ti(OH)4 dimer and trimers were optimized at the B3LYP level of theory. Theoretical vibrational frequencies of TiO stretching modes obtained with several basis sets were compared with the existing experimental frequencies of these vibrations, and the 6-31+G(d) set was chosen for cluster calculations. Only one energy minimum was found for the [Ti(OH)4](2) dimer, but two isomers without symmetry elements stabilized by internal hydrogen bonds and two isomers, belonging to C(s) and C(i) point groups, with free OH groups were found as minima at the [Ti(OH)4](3) potential energy surface. The structure with the linear arrangement of hexacoordinated titanium atoms in the Ti3O12 skeleton may be proposed for trimeric species observed in liquid titanium alkoxides as the only structure satisfying experimental spectroscopic evidence about the presence of center of inversion in these species. Frequency changes of TiO4 modes which accompany the oligomer formation are predicted and discussed.

Validation of the existence of tetrameric species of potassium trimethylsilanolate in the gas phase with a theoretical cluster model: role of the counterion as charge localizer in the structure.

We have investigated, theoretically, the structural properties of potassium trimethylsilanolate in the gas phase at a B3LYP/6-31+G* level. For this purpose, a simplified ionic cluster model based on potassium trimethylsilanolate tetramers, proposed in the literature as the structural units of this compound in the solid state, was developed. Furthermore, we compared the validity of the model with two simpler ones: a monomer of potassium trimethylsilanolate and a trimethylsilanolate anion in the gas phase. The developed ionic cluster model was found to be best in reproducing the experimental structure of potassium trimethylsilanolate, supporting, at the same time, the existence of such tetrameric species (previously identified experimentally from mass spectrometry data by Weiss et al.) in the gas phase. Finally, NBO calculations highlighted the important role of the potassium counterion as a charge localizer in the structure of these chemical species.

Conformations, structures, and vibrational spectra of triethylchloro- and triethylbromosilane using theoretical methods, gas phase electron diffraction, and IR and Raman spectroscopy.

Conformational studies of triethylchlorosilane (TECS) and triethylbromosilane (TEBS) and the elucidation of their gas phase molecular structures have been accomplished by the combined use of theoretical (ab initio and density functional theory) calculations and experimental data from gas phase electron diffraction experiments. Additionally, analysis of the experimental features observed in the IR and Raman spectra recorded for both compounds has allowed us to propose a complete description of the vibrational spectra of both compounds, including an explanation of certain bands, which can only be correctly assigned when more than one conformer is considered to be present.

An experimental and theoretical study of the molecular structure and vibrational spectra of iodotrimethylsilane (SiIMe3).

The gas-phase molecular structure of iodotrimethylsilane (ITMS) has been determined from electron diffraction data. Infrared and Raman spectra have been completely assigned. The experimental work is supported by ab initio HF and MP2 calculations for the gas-phase structure determination and DFT(B3LYP) calculations, combined with Pulay's SQM method, for the vibrational spectra data.