The investigation of fluorine substitution in difluoroanilines with focus on 2,6-difluoroaniline by spectroscopic methods, density functional theory approach, and molecular docking

Abstract

In this study, the spectroscopic features and reactive nature of difluoroanilines, with special attention on 2,6-difluoroaniline (2,6-DFA), are explored thoroughly to gain insight into the effect of fluorine substitution in aniline derivatives. The quantum chemically obtained spectral properties including Fourier transform infrared, Raman, ultraviolet, and 1H and 13C nuclear magnetic resonance spectra were obtained by using Density Functional Theory (DFT) calculations at B3LYP/6-311++G(d,p) level of theory, and given along with the ones measured experimentally. The reactivity characteristics such as Fukui descriptor, electrostatic potential, and electronegativity were defined based on electron density generated theoretically. The position of fluorine substitution does not significantly alter the amide group reactivity making all difluoroanilines compatible to each other in terms of the reactivity. The time-dependent DFT was used to calculate the electronic properties such as excitation energies, maximum wavelengths, oscillator strengths, and molecular orbitals energies, and given along with the density of state diagrams. The intramolecular interactions were mapped by reduced density gradient method to reveal possible fluorine influence on the amide group and its reactivity, and the strongest van der Waals interactions in 2,6-DFA were observed. Besides, the thermodynamic and nonlinear optical properties of the title molecule were also investigated. The 2,6-DFA molecule seems to be appealing for multidisciplinary studies about the relevant nonlinear optical properties. To explore the binding capability of 2,6-DFA and see the influence of fluorine substitution in difluoroanilines, molecular docking was performed on a model enzyme structure of T4 lysozyme. Ligand-enzyme binding energies of 2,6-DFA is nearly the same with that of 2,5 DFA and 3,5 DFA at the same binding site which differs from the remaining derivatives.