Stable Conformers In Gas Phase Research Articles

An NMR-based approach for the design of crystallization processes for rigid molecules and effects of molecular rigidity and impurities on crystallization pathways

A methodology based on NMR analysis to enable development of crystallization procedures for relatively rigid molecules is presented. The number of relatively stable conformers in solution and their relative proportions are determined from peak splitting of equivalent protons and their relative areas as measured by NMR. Experimental data indicated that slow conformational interconversion was limiting crystallization at low temperatures. Variable temperature NMR analysis was utilized to determine rotamers’ peak coalescence and identify a suitable crystallization solvent. This NMR-based approach led to the development of a manufacturing crystallization recipe of a relatively rigid molecule that was impossible to crystallize via a scalable process. Furthermore, prediction of relatively stable conformer in gas phase, determined by Molecular Dynamics (MD) calculations were in acceptable agreement with data obtained from NMR analyses. Finally, the effects of molecular rigidity and impurities on crystallization and oiling-out pathways are described and an approach to avoid oiling-out is presented.

Conformational landscape and low lying excited states of imatinib.

The conformational changes of imatinib (IMT) are crucial for understanding the ligand-receptor interaction and its mechanism of action [Agofonov et al. (2014) Nature Struct Mol Biol 21:848-853]. Therefore, here we investigated the free energy conformational landscape of the free IMT base, aiming to describe the three-dimensional structures and energetic stability of its conformers. Forty-five unique conformers, within an energy window of 4.8kcalmol(-1) were identified by a conformational search in gas-phase, at the B3LYP/6-31G(d) theoretical level. Among these, the 20 most stable, as well as 4 conformers resulting from optimization of experimental structures found in the two known polymorphs of IMT and in the c-Abl complex were further refined using the 6-31+G(d,p) basis set and the polarizable continuum solvation model. The most stable conformers in gas-phase and water exhibit a V-shaped structure. The major difference between the most stable free conformers and the bioactive conformers consists in the relative orientation of the pyrimidine-pyridine groups responsible for hydrogen bonding interactions in the ATP-binding pocket. The ratio of mole fractions corresponding to the two known (α and β) polymorphic forms of IMT was estimated from the calculated thermochemical data, in quantitative agreement with the existing experimental data related to their solubility. The electronic absorption spectrum of this compound was investigated in water and explained based on the theoretical TD-DFT results, considering the Boltzmann population-averaged computed data at CAM-B3LYP/6-31+G(d,p) level of theory for the nine most stable conformers.

Interaction of alanine with small water clusters; Ala–(H 2O) n ( n = 1, 2 and 3): A density functional study

Density functional theory (DFT) calculations for the hydrogen bond interaction between alanine (Ala) and water clusters Ala–(H 2O) n ( n = 1, 2 and 3) have been carried at B3LYP/6-31G(d) level of theory. The optimized Ala–(H 2O) n complexes are solvated in aqueous medium using polarizable continuum model (PCM) to see the effect of bulk water interaction on Ala–(H 2O) n complexes. Structural parameters and stabilities of the Ala–(H 2O) n ( n = 1, 2 and 3) conformers have been discussed in terms of relative stable energies. The Ala–(H 2O) n complexes, A [Ala + (H 2O)], C [Ala + (H 2O) 2] and E [Ala + (H 2O) 3], where the water molecule is attached only with –COOH group of Ala molecule, are the most stable conformers in gas phase and aqueous medium for n = 1, 2 and 3 clusters. However, the Ala–(H 2O) n complexes, where water molecules are attached through both, –COOH and –NH 2 groups of Ala are less stable. Thus, the conformers, A, C and E are the most favorable conformers in gas phase and aqueous medium. The clusters with three water molecules are dominated by strong hydrogen bond interactions over one and two water molecules. The strength of hydrogen bond interaction in Ala–(H 2O) n complexes are increasing on going from gas phase to aqueous medium. All Ala–(H 2O) n complexes are shown thermodynamically stable with respect to separate monomers in gas phase and aqueous medium. Potential energy curves are drawn for the conformers, A, C and E and found that the depth of the potential well increases upon the addition of the water molecules in Ala–(H 2O) n complexes.

Tautomeric properties, conformations and structure of 2-hydroxyacetophenone methanesulfonylhydrazone

The compound, 2-hydroxyacetophenone methanesulfonylhydrazone (apmsh) has been synthesized and its crystal structure has been investigated by X-ray analysis. The compound crystallizes in the monoclinic space group P21/ c and the following unit cell parameters: a = 20.9496(15) Å, b = 4.9849(4) Å, c = 10.2300(8) Å; α = 90°, β = 98.2750(10)°, γ = 90°; V = 1057.21(14) Å 3 and Z = 1. The molecular geometry of the apmsh in the ground state has been calculated using the restricted Hartree–Fock with HF/6-31G** and density functional method with B3LYP/6-31G** basis set. The optimized bond lengths and bond angles obtained by using B3LYP/6-31G** are in better agreement with the experimental values than those by using RHF/6-31G**. The conformers located at minima by PM3 semi-empirical calculation were re-optimized by using B3LYP/6-31G** method. Quantum-chemical calculations indicate that enol-imine tautomeric form is favored and the most stable conformer in gas phase is approximately 6 kcal/mol stable than next conformer.

Ab initio Conformational Analysis of Glutamic Acid, Chemical Shift Anisotropy and Population Studies

We report on glutamic acid rotation and its stable conformer in gas phase. The calculations were performed by HF/6-31G* and B3lyp/6-31G* levels of theory. There is a pertubation in the population diagram of the C3 that shows nucleophilic or radical attack will probably occur at this site. This fact is confirmed by the charge distribution and CSA (chemical shift anisotropy) diagrams. The energies and the relative energies are given as a function of rotational angle. Also, low and high-energy barriers of N-H rotation computed at various level of theory have been obtained. Vibrational frequencies of the structure were done to verify the minima of the energy.

Rotational isomerism and solvent effect on infrared intensities of ν(CO) stretching band in methyl alkyl ketones

A solvent-sensitive rotational equilibrium has been observed in several methyl alkyl keyones. This equilibrium arises from the rotational of the R group around thr R-(CO) bond. The variation in relative intensity of the two bands observed in methyl isobutyl ketone has been measured. Frequency and intensity of each band and the total intensity have been ralated to the solvent properties using the G parameter as a measure solvent polarity. From these relationships the stable conformer in gas phase has been determined.