[Show abstract][Hide abstract] ABSTRACT: Time-averaged conformations of (+/-)-1-[3,4-(methylenedioxy)phenyl]-2-methylaminopropane hydrochloride (MDMA, "ecstasy") in D(2)O, and of its free base and trifluoroacetate in CDCl(3), were deduced from their (1)H NMR spectra and used to calculate their conformer distribution. Their rotational potential energy surface (PES) was calculated at the RHF/6-31G(d,p), B3LYP/6-31G(d,p), B3LYP/cc-pVDZ and AM1 levels. Solvent effects were evaluated using the polarizable continuum model. The NMR and theoretical studies showed that, in the free base, the N-methyl group and the ring are preferentially trans. This preference is stronger in the salts and corresponds to the X-ray structure of the hydrochloride. However, the energy barriers separating these forms are very low. The X-ray diffraction crystal structures of the anhydrous salt and its monohydrate differed mainly in the trans or cis relationship of the N-methyl group to the alpha-methyl, although these two forms interconvert freely in solution.
Full-text · Article · Jul 2008 · Journal of Molecular Graphics and Modelling
[Show abstract][Hide abstract] ABSTRACT: Reactivity, selectivity and site activation are classical concepts in chemistry which are amenable to quantitative representation, in terms of static global, local and non local density response functions. The use of these electronic indexes describing chemical interconversion is developed in this work along the perspective of the pioneering work conducted in Chile by the late Professor Fernando Zuloaga, to whom this article is dedicated in memoriam. While global responses, represented as derivatives of the electronic energy with respect to the total number of electrons quantitatively describe the propensity of a system to interconvert into another chemical species (chemical reactivity), the local counterparts assesses well those regions in the molecule where the reactivity pattern dictated by the global quantities is developed (selectivity). Site activation/deactivation may in turn be described by the variations in the local or regional patterns of reactivity, that may be induced by solvent effects or chemical substitution. These concepts are illustrated for a series of chemical reactions in Organic Chemistry, including electrocyclic processes, cycloadditions and electrophilic addition reactions. Some relationships between quantitative scales of reactivity and reaction mechanisms are discussed.
No preview · Article · Mar 2004 · Journal of the Chilean Chemical Society
[Show abstract][Hide abstract] ABSTRACT: This paper presents SCF AM1 and CNDO/2 RF calculations of the potential energy surface of histamine monocation (HA) and the agonists 2-(4-thiazolyl)ethylamine (TIA) and 2-(4-oxazolyl)ethylamine (OXA). The similarity of the conformational and electronic structures between HA, TIA and OXA, suggests that both HA analogues should have agonist character, according to the intramolecular proton transfer model that we have proposed in order to explain the activation of the histamine H2 receptor. In this model both the intramolecular proton transfer and the basicity of the nitrogen atoms in the hydrogen bridge are assumed to trigger the activity of the receptor. In this context, the activity of the species analyzed here should decrease in the order HA, TIA, and OXA.
No preview · Article · Mar 1999 · Boletin de la Sociedad Chilena de Quimica
[Show abstract][Hide abstract] ABSTRACT: The effect of the basicity of methyl-amines on hydrogen bonding (HB) with HCOOH is examined in both gas and solution phases. In the gas phase, the strength of HE may be related to the proton affinity (PA) difference between the carboxylate anion and the methyl-amine, Delta PA = PA(HCOO-) - PA(NR3). The changes in the driving potential Delta PA are explained on the basis of electronic substituent effects. The electronic substituent effects are rationalized in terms of local reactivity indices such as the Fukui function and the local hardness and softness at the basic center. A simple model is then proposed to explain the enhancement I-IB in the solution phase. The HE pattern in the solution phase is changed by electrostatic and nonelectrostatic solvation of the zwitterionic and neutral species in equilibrium. (C) 1999 John Wiley & Sons, Inc.
[Show abstract][Hide abstract] ABSTRACT: The conformational properties of ten ring-methylated N-methyl- and N,N-dimethylanilines have been studied using 13C-NMR chemical shifts and spin-lattice relaxation times in CDCl3, and semi-empirical (AM1) quantum-chemical calculations. The experimental results indicate that, like aryl methyl ethers, N-methylanilines prefer conformations in which the N-methyl carbon lies near the ring plane. Ortho-substitution in these compounds, while forcing the N-methyl group to adopt an anti orientation with regard to the ortho substituent, does not induce any important changes from the vantage point of the electron donor ability of the amine function and therefore does not affect the N-methyl 13C chemical shifts or spin-lattice relaxation times to any appreciable extent. The preferred conformations of ortho-unsubstituted N,N-dimethylanilines leave the N-methyl carbon atoms oscillating on either side of the ring plane, but the conformational space of these compounds is strongly limited by ortho-methylation, so that in these cases one of the N-methyl carbon nuclei is forced to remain close to the aromatic ring plane, resulting in much shortened relaxation times and deshielding of that nucleus. The quantum mechanical calculations reproduce these results, allowing the relative stability of the methylated aniline conformers to be discussed in terms of competition between the nuclear repulsion energy and electron delocalization. Ortho-methylation of N,N-dimethylanilines leads to an increase of electron density around the nitrogen atom and a change from almost sp2 to almost sp3 nitrogen hybridization, in agreement with the experimental results, including the increased basicity of these compounds.
Full-text · Article · Mar 1998 · Boletin de la Sociedad Chilena de Quimica
[Show abstract][Hide abstract] ABSTRACT: Conformational analysis of famotidine (FAMO) and some analogues have been performed using AM1 calculations. In addition, Conformational analysis were done on the 2-guanidinylthiazole moiety in order to see the effect of the N-sulfamoyl fragment and the methylthioethyl chain of FAMO on the thiazole ring. The results revealed that the N6H form (the guanidinium cation) was the most stable and might therefore be the best candidate for interacting with the histamine H2-receptor. The calculations for the N6H forms of FAMO and analogues showed a strong hydrogen bond anchoring the guanidine chain in the same plane as the thiazole ring, in agreement with X-ray diffraction and 1H NMR studies.
No preview · Article · Feb 1997 · Journal of Molecular Structure THEOCHEM
[Show abstract][Hide abstract] ABSTRACT: The interactions between the H2 antagonists cimetidine, ranitidine and famotidine with a basic molecular model for the histamine H2 receptor have been analyzed. The calculated potential energies of the antagonist-H2 receptor complexes follow an order consistent with the published binding data, indicating that famotidine is the best H2 receptor ligand. Comparison with the interactions found for histamine and this H2 receptor model suggests that the protonated imiddazole moiety of cimetidine, the dimethylammonio moiety of protonated ranitidine and the protonated guanidinyl moiety of famotidine are bioisosteric with the protonated aliphatic amine group of histamine. Asp 98 in helix 3 appears to be the main residue for antagonist recognition, but some residues in helix 5 may be involved, apparently by serving to guide the antagonist into the binding pocket.
No preview · Article · Aug 1996 · Molecular Engineering
[Show abstract][Hide abstract] ABSTRACT: A 3D model of the canine H2 receptor was built and analysed. This model was constructed using primary sequence comparisons and three-dimensional homology building with bacteriorhodopsin serving as a template. The energy analysis of the interaction between the N3H+ form and the N1H+ form of histamine with the receptor shows that both have the same binding affinity for the H2 receptor, but only the N3H+ form provokes structural changes. The calculated potential energies are consistent with the published binding data and suggest that Asp 98 is the principal residue for ligand recognition. On the basis of sequence alignment studies we postulate that Glu 270 in helix 7 may be important for activation of the H2 receptor. Docking studies of the N3H+ folded conformation in our model show that an intramolecular hydrogen bond between N3 and the amino group of the histamine molecule is broken, and the histamine then adopts a conformation similar to the N3H+ extended form to interact optimally with the H2 receptor. Mutations were made in the H2 receptor model to mimic published experimental point mutations. The interactions of the mutated receptor models with histamine are consistent with the experimental data.
No preview · Article · Jan 1996 · Molecular Engineering
[Show abstract][Hide abstract] ABSTRACT: A model for catecholamine storage in vesicles is analyzed wilhin the SCRF-CNDO/2 approach in-luding conlinuum solvenl effects. The model considers lhe approach of cationic norepinephrine (NE) 10 a positively charged guanidinium moieyy. lon-pair formalion is found for ¡he whole range of dielectric eonslants. Even though slablc slales of II-bonded parlnns are found for large dielectric constants, this proecss is ruled out to occur bccause it involvcs 100 high cnergies. 11 appears that the medium's polarily is determinant in lowering the energy barrier between the ion-pair complex and the separatcd parlners. Thus, as the mediul11 dielectric constanl increases. ¡he equi-librium between the two statcs is enhanced.
Full-text · Article · Sep 1991 · International Journal of Quantum Chemistry
[Show abstract][Hide abstract] ABSTRACT: The reaction field (RF) model of solvent effects, implemented within the SCF-CNDO/2 scheme of calculation, has been applied to analyze the proton transfer in the NH3…HCOOH system in the presence of several polarizable media. The aim of such a study was to characterize the tatutomeric equilibrium between the neutral and zwiterionic forms of H-bonded amino acids in aprotic solvents. Qualitative results concerning the energetics of this equilbrium show the stabilization of two different H-bonded complexes, corresponding to two separate minima in the free energy surface. These well known double minima potentials are found to be dependent on both the intermolecular NO distance and the strength of the reaction field. The behavior of this model is qualitatively consistent with experimental observations of nitrogen-substituted amino acids in solution: both show, for low values of the dielectric constant, tautomeric equilibria where the H-bonded complexes appear to be more stable than the corresponding monomeric forms. The charge transfer process associated with the proton migration along the H-bond is also discussed. It is found that the amount of charge transferred increases with the NO distance and with the RF strength, In order to test the general approach and compare it with previous work, calculations on the real monomeric systems glycine, β-alanine, and γ-amino butyric acid was also performed.
No preview · Article · Jan 1988 · International Journal of Quantum Chemistry
[Show abstract][Hide abstract] ABSTRACT: Ab initio STO-3G and 4-31G calculations for a linearly hydrogen-bonded complex between formic acid and ammonia are reported. Nuclear geometry relaxation along the hydrogen-bonding potential was permitted in all calculations. In most of the calculations an external field simulating the presence of the internal field in N,N-dialkyl amino acid crystals was imposed in an approximately self-consistent manner. Such a field with the proper strength is found to induce a zwitterionic stable, double-minimum, hydrogen-bonding potential function. The response of the hydrogen-bonding potential to field orientation, strength, and asymmetry has been investigated. The calculations provide a semiquantitative explanation for the temperature-dependent infrared spectra observed for several of these crystalline compounds.
No preview · Article · Jan 1985 · The Journal of Physical Chemistry