This chapter outlines the basic principles of the density functional theory (DFT). The introduction of electron density to develop the Kohn-Sham approach has been systematically presented. The various approximations such as LDA, GGA, and hybrid functional for the exchange-correlation energy have been discussed. A separate discussion on the basis sets has also been included. The advantages and shortcomings of DFT based techniques are also revealed. The formulation of time-dependent DFT has been presented in a concise manner. This chapter is intended to provide an overview of the theoretical background of the methods adopted in the succeeding chapters.

This chapter focuses on the practical application of DFT in molecular systems. We discuss the process of “geometry optimization” and the idea behind it, which is the very first step of every DFT calculation. We introduce the Gaussian, a popular software program to perform such calculations. We continue to discuss the capability of this program with a brief theoretical background, wherever needed. We talk about several kinds of calculations to be performed by the Gaussian such as thermodynamics, population analysis, NMR, NLO, NBO, TDDFT calculations to name a few. More importantly, we discuss how to perform these calculations, extract, and interpret the results. Ideally, this chapter provides all the ingredients needed to grasp the results discussed in the forthcoming chapters.

In this chapter, we present and discuss DFT study on three dichloro substituted (1, 3-thiazol-2-yl) acetamides; 26DTA, 24DTA and 34DTA using the B3LYP/6-31+G(d,p) method. We focus on the need of scaling the normal modes of vibrations and test two scaling schemes on 26DTA. We analyze their performance by comparing the scaled values against FTIR data. Subsequently, a detailed comparative study on the spectroscopic properties of 24DTA and 34DTA has been performed using a better scaling scheme. In addition, the NBO analysis is employed to explain the coordination ability of molecules and several electronic parameters are obtained to describe their chemical reactivity. This chapter is expected to provide the first flavor of the real application of DFT on biologically active molecules.

4-hydroxy-l-proline is formed by hydroxylation of proline, an amino acid found in protein, whose inhibition results in hair problems in humans, causing scurvy disease. In this chapter, we discuss the DFT study on cis and trans conformers of 4- hydroxy-l-proline, i.e., CHLP and THLP using the B3LYP/6-31+G(d,p)level. The equilibrium structures of both conformers are obtained to analyze their vibrational properties. We have also discussed the results of an in-depth study on cis-4-hydroxy-d-proline (CHDP). The scan of potential energy surface provides the global minimum structure of CHDP along with its possible conformers. HOMO, LUMO, and MESP surfaces as well as charge distribution, are used to explain the chemical reactivity. The equilibrium geometry of CHDP dimer has been obtained and intermolecular interactions are explored by the NBO analyses. Vibrational analysis has been carried out on CHLP, THLP, and CHDP (monomer and dimer). A complete assignment to vibrational modes has been presented based on their potential energy distribution. The calculated frequencies, after proper scaling, are compared with experimental FT-IR frequencies recorded by KBr disc and Nujol mull techniques. Several electronic as well as thermodynamic parameters have also been reported.

This chapter deals with three biologically active natural products, triclisine, rufescine, and imerubrine. The B3PW91/6-311+G(d,p) level of DFT is used to obtain the optimized structures of molecules under study. We carried out vibrational analyses of triclisine and rufescine at their optimized structures and provided detailed assignments of the prominent vibrational modes. The computed infrared frequencies are found to be in good agreement with the experimentally determined FT-IR spectra of both molecules. Similarly, their properties are also studied with the help of HOMO, LUMO, MESP surfaces, and several electronic as well as thermodynamic parameters. The vibrational spectrum of imerubrine is analyzed and the normal modes are accurately assigned based on the potential energy distribution. The nuclear magnetic resonance shifts of imerubrine are also obtained, analyzed, and compared with the corresponding experimental values. The chemical reactivity of imerubrine is also explained using HOMO, LUMO, and MESP surfaces as well as a number of reactivity descriptors.

In this chapter, we present an exhaustive study on a synthetic compound, 4- Amino-3-(4-hydroxybenzyl)-1H-1,2,4-triazole-5(4H)-thione (4AHT) and its tautomer employing both experimental and theoretical methods. 4AHT was synthesized by the reaction of 4-hydroxyphenylacetic acid and thiocarbohydrazide. The derivatives of 1,2,4-triazole are known to display antiviral, antidepressant, antimicrobial and antiinflammatory activities. A DFT study on thione and thiol tautomers of 4AHT has been performed using the B3LYP/6-31+G(d,p) level. The calculated geometrical parameters are obtained to be in compliance with corresponding crystallographic values. The FTIR spectrum of 4AHT obtained by the KBr disc technique has been explained by assigning the normal modes based on their potential energy distributions. The UVvisible spectrum of the title compound has been discussed by calculating the electronic transitions in several excited states using the TD-DFT method. The 1H-NMR spectrum has also been studied by the GIAO method, which provides a good linear correlation between calculated and experimental chemical shifts. These spectroscopic results propose the dominance of the thione form of 4AHT in the solid-state and NH-SH tautomerism in the liquid form. This chapter is designed to provide a complete picture of the DFT based studies on molecular systems.

In this exclusive chapter, we present a brief overview of the quantum theory of atoms in molecule (QTAIM) proposed by R. F. W. Bader. This theory is based on the topological analysis of the electron density and related parameters. One of the strengths of this theory is the accurate prediction, characterization, and quantification of various interactions, including H-bond and van der Waals interactions. Herein, we discuss the important aspects of QTAIM regarding the intra- and intermolecular interactions in biologically active molecules discussed in the preceding chapters. Within the framework of the QTAIM, I mention the criteria of H-bonds and characterize the various H-bonds on the basis of topological parameters, and continue to quantify the strength of the H-bond. I will also describe a very user-friendly software AIMAll to perform the QTAIM analysis and explain the obtained results. In order to provide the contents digestive, I will include examples of molecules from Chapters 3, 4, and 5. I believe that this chapter will guide the readers interested in various kinds of interactions in biologically active molecules.