Investigating the density functional theory of tautomeric equilibria of heteroaromatics - NBO study

Dissertation for Master's degree

M.Sc))

Inorganic Chemistry

Dissertation abstract:

Density Functional Theory (DFT) method at the DFT/6-31G level to investigate the structure We used geometry, relative energies and electronic properties of possible protropic tautomers in Nexium, Protonix and Lamivudine. The structure and relative energies of tautomers in different solvents have been predicted. The order of stability of these tautomers is: protonix < nexium < lamivudine, which were calculated by DFT method.

Hydration is another interesting topic discussed in this work, because the geometrical structure and stability of biological molecules are affected by the interaction with solvent molecules. The main goal of studying tautomerization is to evaluate proton transfer in drugs.

Probably one of the vital factors in determining the distribution of tautomers in biological materials is the environment. The energy parameters of the tautomeric forms in the aqueous phase (? = 78.5) and other solvents were obtained with the PCM model at the DFT/6-31G levels. Dipole moments were obtained for all drug tautomers in gas and aqueous phases. Usually, the dipole moment order is not the same as the energy order. However, the calculated dipole moment values ??are the highest in the aqueous phase, and it is observed that amine and ketone tautomers are more stable among all possible tautomeric forms. Our data show that the dipole moment in the aqueous phase is greater than in the gas phase, which indicates the sensitivity of tautomers to the polarizability of the solvent.

The effect of the solvent on the coverage of nitrogen and oxygen of the tautomers was investigated using the DFT method of the combination of PCM and GIAO models.

NBO analysis showed that the resonance of the lone pair of oxygen or nitrogen atom and NBO Lewisity (?* or ?*) increases with the increase of the P character of the lone pair of oxygen or nitrogen. We confirmed these results by natural molecular orbital analysis. For each NBO donor (i) and NBO acceptor (j), the stability energy (E2) is associated with i ? j destabilization.

The structural and vibrational properties of pharmaceutical tautomers were also studied. We also calculated the chemical shifts of anisotropy and ??.

1-1 Introduction

Tautomeric equilibria occur between two or more isomeric structures. Tautomerism is complex and depends on several phenomena: different types of migrating groups (electrophilic or nucleophilic), anionic and cationic properties, and tautomerism related to the migration of neutral groups. For example, the hydrogen atom in the organic bases of DNA can be moved to the nitrogen atoms or the oxygen of the ring, this change in the position of the hydrogen atom on the open organic ring is called tautomerization, as a result of which adenine and cytosine change to amino and imino forms, and guanine and thymine bases to keto and enol forms.

Also, many drugs and Or biologically active molecules can have two or more tautomeric structures in which proton migration occurs from one place to another place in the molecule. Adenine tautomers can be mentioned in the importance of prototherapy. Adenine is naturally paired with thymine, but the imino form of adenine is cytosine, in which case the code is read incorrectly and causes mutation. Therefore, the importance of understanding the potential of heteroaromatic systems for tautomerization and the role of tautomers in biological activity is clear. It affects Knowing the different tautomeric forms of drugs allows us to better interpret the mechanism of reactions under physiological conditions. Therefore, tautomerism plays an important role in the drug discovery process.

Tautomeric equilibrium is dependent on the dielectric constant of the solvent. Also, the balance depends on the intensity of the temperature.Because in biological systems we are dealing with aqueous medium (blood or plasma) or non-protic medium (cell membrane), therefore the polarity of the medium is important. Therefore, in our study, examining thermodynamic factors is also important. Also, for example, if it is placed below the biological pH (2.7), the molecule may exist in anionic form, and this issue causes problems with, for example, gastric drugs (Negsium and Protonix). In this case, the influence of side groups in the structure cannot be ignored. In this research, we intend to discuss the tautomeric balance of Negsium, Protonix, and Lamivudine drugs in different solvents.

These two drugs are proton pump inhibitor drugs whose main action is to reduce the long-term production of stomach acid. Of course, their function depends on the basicity of the pyridine ring, which controls the proton pump of the stomach and intestinal system. Because no serious research has been done on the prototherapy tautomerization of Nexium and Protonix drugs, in this research part of our study was done on them, and also studies were conducted on the drug lamivudine, which, like Nexium and Protonix, has sulfur in its structure. Different solvents were used. Also, the parameters of natural charge, valence electrons of brain electrons, total electron population, chemical shift, isotropic shell constant, energy gap, chemical potential, ?nmax, resonance energy, dipole moment and electrophilicity were investigated and the results were discussed and analyzed by comparing tables and graphs. rtl;">Abstract:

Density Functional Theory (DFT) method, at the DFT/6-31G level has been used to explore the geometries, relative energies, and electronic properties of all hypothetically possible prototropic tautomers of Nexium and Protonix and Lamivudine. The structure and relative energies of tautomers and in different are predicted. The order of stability for these tautomers is Protonix < Nexium < Lamivudine, calculated by DFT method.

Hydration is another interest of this work, as it has been well known that the structure, dynamics and stability of biological molecules are influenced by their interactions with hydration water. The main goal of the study of tautomerization is an evaluation of the water-assisted proton transfer in drugs.

Probably one of the most crucial factors determining the tautomer distribution in the biological material is the environment. The energetic parameters of the tautomeric forms in the aqueous phase (e = 78.5) and different solvent obtained with PCM continuum model of solvation at DFT/6-31G levels are obtained.

Polarity of compound may be described by its dipole moment. The calculated dipole moments obtained for all individual tautomers of drugs in both gas and aqueous phases are obtained. Generally, the polarities order is not comparable to the energetic stabilities order. However, calculated dipole moment values ??at both gas and aqueous phase indicate larger value for tautomers which might be an indication of stability of amine tautomer among all the possible tautomeric forms. Our data indicate further that the dipole moments change to higher values ??on going from gaseous state to the water phase, which is attributed to the sensitivity of the tautomers to the polarity of the solvent.

Solvent induced effect on nitrogen NMR shielding of tautomers is calculated using Density Runctional Theory combined with polarizable continuum model and using the continuous set gauge transformation.

The NBO analysis revealed that the resonance interaction between the lone pair of the oxygen or nitrogen atom and empty (?* or ?*) non-Lewis NBO increases with increasing the p character of the oxygen lone pair. We justify these results with natural bond orbital analysis.