Quantum chemical calculations (Ab Initio & DFT), hirshfeld surface analysis, crystal structure and molecular docking study of 2-chloro-4-(4-fluoro-phenyl)-6- isopropyl-pyrimidine-5-carboxylic acid methyl ester

Abstract

Pyrimidine derivatives are well-known nitrogen containing heterocyclic compound which play an important role in medicinal and pharmaceutical applications. The synthesized compound, 2-chloro-4-(4-fluoro-phenyl)-6-isopropyl-pyrimidine-5-carboxylic acid methyl ester has been confirmed by single crystal X-ray diffraction studies. Title compound crystallizes in monoclinic space group P21/c with a = 8.5272(11) Å, b = 17.774(2) Å, c = 10.2732(14) Å, β = 111.005(2)° and Z = 4. The number of weak but significant C–H···O, C–H···N, C–F···π and π–π interactions take part, in the stability of the crystal packing and also the quantitative contributions of these interactions towards the crystal packing are investigated by Hirshfeld surface analysis. A static disorders have been observed in isopropyl substituent group of atoms C20 and C21 due to anisotropic thermal motion. Ab-initio and Density Functional Theory (DFT) calculations have been carried out for the title molecule using RHF/6-311G and B3LYP/6-311G basis set respectively without polarization function, predicting the optimized geometry which can well reproduce structural parameters. Mullikan charge distributions conforms the role of specific atom especially the donor/acceptor groups in the intermolecular interactions. In the present study, the neutral chlorine Cl (Mullikan charge is 0.0038 and 0.0256 by RHF and B3LYP respectively) does not take part in intermolecular interaction, whereas fluorine F (Mullikan charge is −0.4358 and −0.3319 by RHF and B3LYP respectively) took active part in intermolecular interactions. The calculated HOMO and LUMO energies show that charge transfer occur in the molecule. To investigate the effect of different substituted groups on molecular conformation and hence on its pharmacology, the title compound redesigned with different halogens replacing fluorine of fluoro-phenyl ring and docked with human estrogen receptor (2IOK) and attempted to predict the best drug.