A. Hernández-Laguna

Density functional theory and Monte Carlo study of octahedral cation ordering of Al/Fe/Mg cations in dioctahedral 2:1 phyllosilicates

Abstract The ordering of octahedral Al3+, Fe3+, and Mg2+ cations in dioctahedral 2:1 phyllosilicates was studied theoretically. Quantum mechanical calculations based on density functional theory (DFT) were performed for optimizing different cation distributions along the octahedral sheet. Three systems of two species (Al3+/Mg2+, Al3+/Fe3+, and Fe3+/Mg2+) were studied to obtain the cation exchange potentials Jn as first, second, third, and fourth nearest neighbors. Monte Carlo (MC) simulations based on the previously calculated cation exchange potentials Jn of these binary systems showed ordering phase transition in the distribution of the octahedral cations, with different ordering patterns. Ordered phases are depending on composition and on third and fourth neighbor range interactions. The effect of hydrostatic pressure can affect the cation ordering of the octahedral sheet. The two-species model was extended to a three-species ordering MC simulation model. In our case, we do not find perfect long-range ordering in the three-species systems. Instead we find some domains with different ordering patterns.

High-pressure behavior of 2M1 muscovite

Abstract The crystal structure and pressure influence (between 0-6 GPa) on 2M1 muscovite have been calculated by quantum-mechanical methods based on density functional theory (DFT) with optimized numerical LCAO basis sets and norm-conserving pseudopotentials. Tensions between 0.8 and 0 GPa have been also studied. Volumes as a function of pressure, computed from the generalized gradient approximation, are closer to the experimental data than volumes calculated from the local density approximation. The crystal structure, bond distances, and main geometrical features agree with previous experimental values. A third-order Birch-Murnagham equation is fitted, giving a bulk modulus of 60.1 GPa, which reasonably agrees with the experimental data. Axis compressibilities are slightly smaller than those of the experimental data. The most compressible axis is the c axis. Bond strains, angles, the main geometrical features, and polyhedral strains are studied as a function of pressure, and these vary according to the experimental behavior. Tetrahedral and angles and corrugation show an oscillating behavior in the range of pressures used. The most important compressibilities are those related to the interlayer space, as it corresponds to the weakest bonding in the structure. The highest compressibility in the T-O-T layer along the [001] direction is determined by the octahedral sheet thickness. The compressibilities along the a and b axes are determined by the tetrahedra, as the most compressible polyhedra, and the α angle. Therefore, with our results the utility of periodic DFT methods for studying crystal structure and the effect of hydrostatic pressure on 2M1 muscovite are once again validated, and they are suitable to describe the compression of the crystal structure in detail.

Reaction mechanism of the acyl-enzyme formation in β-lactam hydrolysis by means of quantum chemical modeling

Abstract The acylation step of the β-lactam hydrolysis by a class A β-lactamase has been modeled by means of the quantum chemical PM3 method. A model of the catalytic site of the protein has been built using two segments of three and four amino acids, respectively, which include four of the most important residues of the enzyme. The mechanism is based on that proposed by Strynadka et al. in 1992 (Strynadka et al., Nature 359 (1992) 700–705). The results confirm that Lys-73 is expected to be unprotonated in the wild-type enzyme, and therefore acts as a general base in the acylation step of the reaction. Previous contradictory results are discussed, and a new proton transfer pathway from Lys-73 to β-lactam nitrogen is proposed.

Comparative structural study of histamine and its 4-substituted derivatives

Abstract The geometries of histamine and a homologous series of 4-substituted agonists of H 2 -receptors of histamine, in both the N3-H and N1-H tautomeric forms in their open trans-trans conformation, were fully optimized in the RHF STO-4G approximation. With this “optimal” geometry, the conformational-energy maps corresponding to the rotation about the C-C bonds in the ethyl-ammonium side chain were determined. The geometries and the conformation of the side chain are compared. It is seen that geometry does not depend on substitution. It was also found that the substitution does not affect significantly the conformational properties. The trans-trans conformation is verified to be a transition state in all the series considered. It is concluded that neither the geometry, nor the conformation, seems to be a determinant of the H 2 -activity.

Theoretical proton affinities of histamine, amthamine and some substituted derivatives

Abstract We have characterized tautomers and conformers (T/Cs) of 4-methyl, 4-chloro, 4-nitro, N α methyl histamines (4(5)-2′-aminoethylimidazole), amthamine (2-amino-5-(2′-aminoethyl)-4-methylthiazol) and amthamine derivatives (2-amino-5-(2′-aminoethyl)-thiazole, and 4-methyl-5-(2′-aminoethyl)-thiazole) neutral and as monocations by means of the RHF wavefunctions at the 6-31G ** //6-31G ** level, using analytical gradients. All these compounds are agonists of the H 2 receptors of histamine. Most stable T/Cs of histamine derivatives are gauche with an internal hydrogen bond (HyB). These HyBs have been characterized with the help of the topological analysis of the charge density. Monocations are also gauche with stronger HyBs, in both N (1,3) –H and N (3) –H tautomers. Amthamine and amthamine derivatives show trans conformations as the most stable structures. N (3) –H gauche monocations are the most stable structures. gauche conformers present electrostatic internal interactions characterized by means of topological analysis of the charge density, giving bond critical points. We have calculated proton affinity (PA) differences relative to ammonia with the help of isodesmic reactions. All histamine derivatives are strong bases in the gas phase, especially methyl derivatives. Amthamine yields a conformer structure and PA very close to that of the histamine. Two other amthamine derivatives yield lower PAs than that of amthamine. Reactivity of histamine as well as substituent effects are discussed. Possible interactions with the H 2 receptors of histamine are also discussed.

MOLECULAR STRUCTURE AND CONFORMATIONAL ANALYSIS OF CHIRAL ALCOHOLS. APPLICATION TO THE ENANTIOSELECTIVITY STUDY OF LIPASES

Abstract The molecular structures of the chiral compounds 1-phenylethanol, 2-hexanol and 1-phenylethanol acetate have been studied theoretically by ab initio methods. Conformational analysis and electronic structure studies have been carried out with these molecules at STO-3G ∗ and 6-31G ∗ basis sets. For the study of the interaction of lipases with substrates, a simplified model of the tetrahedral intermediate has been calculated at the 6-31G ∗ //4-31G ∗ level. Molecular mechanics simulations of the interaction of these compounds with the lipases of Candida rugosa, Pseudomonas cepacia and Rhizomucor miehei have been used to study the enantioselectivity of these lipases in the transesterification reaction of the chiral alcohols. The theoretical results have been compared with experimental data and good agreement was observed. It can be concluded that the enantioselectivity of these lipases is controlled by the formation of a tetrahedral intermediate, whereas Michaelis complex formation has a much lower significance.

Electronic structure and conformational properties of (carboxy-alkenyl)-phosphonic acids

Abstract The general conformational properties and electronic structure of (carboxy-alkenyl)-phosphonic derivatives were determined at RHF/STO-3G∗ level. In all the series, low rotation barriers were found for the two C C P O conformers. In the compounds in which the interactions between the carboxylic and phosphonic moieties are smaller, the most stable conformers are the C C P O s- cis ones. In most of the conformers, the C C C O system presents the disposition s-cis. The Z-(2-carboxy-vinyl) and Z-(2-carboxy-propenyl) phosphonic acids present intramolecular hydrogen bonds, existing in at least four conformer with internal hydrogen bonds. These last compounds were more rigorously studied at RHF/3-21G∗ and RHF/6-31G∗∗ levels. The most stable conformer shows a trans structure for the C C P O angle, with an intramolecular hydrogen bond located between the hydroxylic hydrogen of phosphonic group and the carbonyl oxygen of carboxylic moiety. A secondary conformer is found with a double intramolecular hydrogen bond between two hydroxylic hydrogens of the phosphonic moiety and the oxygen of carboxylic bond. Another secondary conformer appears with an intramolecular hydrogen bond between the oxygen of the phosphoryl bond and the hydroxylic hydrogen of the carboxylic group. A study of the topology of charge densities is carried out. This analysis reveals bonds with an ionic participation. A very weak π conjugation, variable with the conformers, is found in the C C P O system, as well as a strongly polarized PO partial triple bond. The intramolecular hydrogen bonds give rise to cyclic structures.

Theoretical Determination of Nuclear Probability Density Distributions. Two-Rotor Molecules

In the present work, we attempt to give a mathematical description for the non-rigidity of some deformable molecules, as a function of temperature. For this purpose, we propose the calculation of probability density maps of finding a two-rotor molecule in a given conformation and at a given temperature, as a function of the rotation angles. The theory is limited to relatively light rotors so that the calculation must be performed into the quantum mechanics framework. From the probability density maps, we consider the calculation of some observable parameters. The theory is applied to the double internal rotation in the series of the standard and deutered xylene molecules. Nuclear probability density maps are given for various temperatures. The main conclusion is that the deuteration does not affect, as least in a large extent, the conformation distributions.

Conformational polymorphic changes in the crystal structure of the chiral antiparasitic drug praziquantel and interactions with calcium carbonate

Graphical abstract Figure. No Caption available. Abstract Praziquantel is an antiparasitic drug used for decades. Currently, the praziquantel commercial preparation is a racemic mixture, in which only the levo‐enantiomer possesses anthelmintic activity. The knowledge of its properties in the solid state and other chemical‐physical properties is necessary for improving its efficacy and applications. Drug solid dispersions were prepared with calcium carbonate at 1:5 drug to excipient weight ratio by solvent evaporation method. Then, the modification of the crystal structure of the racemic polymorph of praziquantel in presence of calcium carbonate has been studied by means of several analytical techniques (DSC, TGA, XRD, SEM, FTIR, Raman spectroscopy and chiral liquid chromatography). This study has been completed with atomistic calculations based on empirical interatomic force fields and quantum mechanics methods applied to the crystal structure of praziquantel and of intermolecular interactions. The results evidenced that calcium carbonate provoked a conformational change in the praziquantel molecule yielding the formation of different polymorphs of praziquantel crystal. These alterations were not observed replacing calcium carbonate with colloidal silica as excipient in the solid dispersion.

Theoretical Study of the Proton Affinities of Some Substituted Derivatives of Histamine and Homologous Compounds. Structure-Activity Relationships

The molecular and electronic structure of 2-methyl, 2-amino-histamine derivatives, and 5-(2′-aminoethyl)-2,4-dimethylthiazole heve been studied by means of ab initio quantum mechanical calculations at 6-31G**//6-31G** and MP2/6-31G**//6-31G** levels. Tautomers and conformers (T/C) of these derivatives were characterized as neutral and monocation forms. Most stable T/C’s of these compounds have the alkyl chain oriented towards the heterocyclic ring in a gauche disposition with an electrostatic internal interaction. Topology of the electronic charge density has been performed in the main structures in order to characterize internal hydrogen bonds and interactions. Proton affinity (PA) differences relative to ammonia of these compounds have been calculated by using direct and isodesmic reactions. This study of PA has been extended at the MP2/6-31G**//6-31G** level for histamine (4(5)-2′-aminoethylimidazole), 4-methyl, 4-chloro, 4-nitro, Nα-methyl, and Nα,Nα-dimethyl-histamine derivatives, amthamine (2-amino-5-(2′-aminoethyl)-4-methylthiazol) and amthamine derivatives (2-amino-5-(2′-aminoethyl)-thiazole, and 4-methyl-5-(2′-aminoethyl)-thiazole). All histamine derivatives are strong bases in the gas phase, especially the Nα,Nα-dimethyl) derivative. Amthamine yields conformers and PA very close to that of the histamine. The calculated PA values at the three levels (MP2/6-31G**//6-31G**, 6-31G**//6-31G** and MP2/6-31G**//MP2/6-31G** (only for the leader compounds)) show similar values.