A New Model of Atomic Nucleophilicity Index and Its Application in the Field of QSAR

A New Model of Atomic Nucleophilicity Index and Its Application in the Field of QSAR

Hiteshi Tandon (Manipal University Jaipur, Jaipur, India), Tanmoy Chakraborty (Department of Chemistry, Manipal University Jaipur, Jaipur, India) and Vandana Suhag (Manipal University Jaipur, Jaipur, India)
DOI: 10.4018/IJQSPR.2019070104
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A new ansatz is suggested for computing the atomic nucleophilicity index (N) for atoms of 103 elements of the periodic table resting upon the mutual action of two periodic properties, atomic polarizability (α) and effective nuclear charge (Zeff). The effectiveness of the model is illustrated by the explicit periodic behaviour. In addition, molecular nucleophilicity (NAM) is being proposed as an arithmetic mean of the atomic nucleophilicities of the constituent atoms of the given molecule. Due to the nonexistence of a benchmark for atomic nucleophilicity, molecular nucleophilicity index is evaluated and a comparative analysis is made with the existing data as a validity test. Furthermore, computed density functional theory (DFT) based reactivity descriptor, viz. atomic nucleophilicity index, have been employed to construct a quantitative structure–activity relationship (QSAR) model, using regression analysis, to study the biological activities of testosterone derivatives.
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The emergence of varied concepts, which explicate the physicochemical properties of atoms, molecules as well as ions, has led to an increased interest in the construction of empirical scales (Swain & Scott, 1953; Ritchie, 1986; Legon & Millen, 1987; Mayr & Patz, 1994; Pérez, Toro-Labbé, Aizman, & Contreras, 2002; Jaramillo, Domingo, & Pérez, 2006). Nucleophilicity and electrophilicity are two such concepts, which aid in the explanation of various reactivity patterns and related phenomenon. Nucleophilicity is a term used for defining an electron rich species, i.e., a nucleophile, while electrophilicity describes an electron deficient species, i.e. an electrophile. The rationalization of chemical reactivity concerning reaction pathways, substituent effects, selectivity, solvent interactions and so on has been possible due to the accessibility of empirical scales of nucleophilicity and electrophilicity (Mayr & Patz, 1994). Both the parameters nucleophilicity as well as electrophilicity have been described in a kinetic concept (Mayr & Patz, 1994; Mayr, Kempf, & Ofial, 2003; Mayr et al., 2001). The energy stabilization of an electron deficient species on gaining an extra electronic charge from the surroundings was theoretically defined as electrophilicity (Parr, Szentpàly, & Liu, 1999). However, the quantitative definitions of nucleophilicity have been confined to a great extent, and the formulated scales and their practical utilization have been limited. So far it has been impossible to construct a nucleophilicity scale, which is universal. It is thus crucial to ascertain whether the concept of nucleophilicity can be described excluding the effect of electrophile, reaction pathway, solvent, leaving group, reaction conditions and its own intrinsic properties or not (Edwards, 1954). Defining nucleophilicity in the theoretical context is even more complex process. When an electronic charge is lost by a nucleophile there is an increment in its total energy as a result of which the plot between total energy and electron numbers is a curvature with an opposite sign. Thus, Parr et al. variational model, which described electrophilicity, is not applicable (Parr et al., 1999).

Based on the electronic nature of bond breaking and making in a chemical reaction, reactions have been divided into polar and non-polar reactions. Polar reactions occur through zwitter ion species whereas non-polar reactions occur through those species, which contain radical character. Polar reactivity is shown by those organic molecules which bear polarized functional groups, and it is characterized by nucleophilic/electrophilic interactions. It is thus valuable to have models of reactivity indices, which are facile and capable of predicting the nucleophilic and electrophilic behaviour of organic molecules.

It is well-known that testosterone is a significant sex hormone, which performs important functions in the body. It is found to be associated with regulation of sex drive, fat distribution, bone mass, muscle mass, muscle strength and production of sperm and red blood cells (RBCs) as well. Therefore, a study relating to the activity of testosterone and its derivatives seems to be important in understanding its effects in the body. In addition, these studies may assist in elucidating the alteration in the functions of testosterone due to changes in its levels because of different factors such as aging and stress.

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