CHEMICAL REACTIVITY , DIPOLE MOMENT AND FIRST HYPERPOLARIZABILITY OF ARISTOLOCHIC ACID I

Aristolochic acids (AAs) have been used in the treatment of oedema in Chinese herb medicine since long ago. In this paper, molecular electrostatic potential, chemical reactivity and non linear optical properties of aristolochic acid I (AA I) have been analyzed using density functional theory employing 6-311++G(d,p) basis set. The chemical reactivity of the molecule has been explained with the help of chemical reactivity descriptors, molar refractivity and the molecular electrostatic potential surface (ESP). The calculated dipole moment and first order hyperpolarizability show that the molecule possesses non-linear optical property.


INTRODUCTION
Plant based natural products cover a major sector of the medicinal field.As such, focus on plant research has increased all over the world.Herbs containing aristolochic acids (AAs), a family of nitrophenanthrene carboxylic acids (Aristolochiaceae), have an increasing global medical attention (Cronin et al. 2002).Mixture of aristolochic acid I (AA I) and aristolochic acid II (AA II) is a principal chemical constituent of Aristolochia species (Pailer et al. 1995).Herbal drugs derived from Aristolochia spp.have been known before middle age in the treatment of snake bites (Rosenmund & Reichstein 1943).Their roots have different biological functions such as; treatment of stomach-ache, hypertension relief, leukocyte enhancement, rheumatism relief, edema therapy, toothache, gout, eczema etc (Kupchan & Doscoth 1962;Mizuno et al. 1991;Tang and Eisenbrand 1992;Bensky et al. 1993).Thirugnanasampandan et al. 2008 reported the antioxidant properties of different Aristolochia spp.However, AAs are found to have nephrotoxic and carcinogenic properties, and may cause renal failure in human (Zheng et al. 2000;Li et al. 2001;Balachandran et al. 2005;Cosyns 2003;Attaluri et al. 2010;Das 2016).
Alkaloids have very complex structure and occupy unique place in the field of natural products.Their structural elucidation, synthesis and the determination of constituents is a big challenging problem.Vibrational spectroscopy is a valuable method for studying electronic structures and dynamical behavior of the alkaloids (Mishra et al. 2014).Raman and IR spectroscopic methods are the traditional methods of vibrational analysis, and particularly useful for non-destructive characterization of substances (Chamers 2002).In the recent years, there has been increasing interest in the application of ab initio calculations to alkaloids as the calculations provide additional interpretation of the vibrational spectroscopic data as demonstrated in our earlier studies (Joshi et al. 2014;Mishra et al. 2014).In this communication, the chemical reactivity and non linear optical properties have been calculated as an aid to our previous publication (Joshi et al. 2013).The calculations have been made by the density functional theory (DFT) (Hohenberg & Kohn 1964) using Gaussian 09 program (Frisch et al. 2009) employing 6-311++G (d,p) basis set.The chemical structure of AA I is shown in the Fig. 1.

Computational method
Using the standard parameters, geometry optimization has been made as the first task by DFT (Hohenberg & Kohn 1964) method, without any constraints of molecular symmetry.The optimized parameters have been used for all the other calculations.The calculations were carried in the personal system using Gaussian 09 program (Frisch et al. 2009) in the frame work of closed-shell Becke's three parameters (Lee-Yang-Parr hybrid exchange correlation) functional (B3LYP) (Becke 1993, Lee et al. 1988, Perdew & Wang 1992) employing 6-311++G(d,p) basis set.The optimized ground state structure was confirmed to be a minimum energy and shown in the Fig. 2. The chemical reactivity descriptors, which are helpful to explain the stability and reactivity of the molecule has been calculated on the basis of Koopmans's theorem (Parr & Yang 1998) using B3LYP/6-311++G(d,p).Visualization and confirmation of the calculated data were done by using the program CHEMCRAFT (Zhurko & Zhurko 2005).

Chemical reactivity
The chemical reactivity of a molecule can be explained in three ways: (i) by MEP (molecular electrostatic potential surface) mapping (ii) global and local reactivity descriptors, and (iii) the molar refractivity (MR).

Molecular electrostatic potential surface (MEP):
The MEP is a visualization method to understand the relative polarity, reactivity, size and the structureactivity of a molecule including biomolecules and drugs (Chidangil et al. 1998).In such surfaces, the negative electrostatic potential corresponds to attraction of the protons by the concentrated electron density in the molecule (from lone pair, pi-bonds etc.).Similarly, positive electrostatic potential corresponds to the repulsion of the proton by the atomic nuclei in the region where low electron density exists and the nuclear charge is incompletely shielded.The MEP mapping together with electron density (ED) and electrostatic potential surface (ESP) of AA I were given in our previous publication (Joshi et al. 2013).
In a surface, the potential increases in the color order red < orange < yellow < green < blue.Fig. 3 shows the distribution of Mulliken charges and natural charges in the molecule whereas a comparison of Mulliken charges and natural charges obtained by different basis sets is listed in the Table 1. ).The chemical potential, measure of the tendency of electron donation from the equilibrium position is given by:

Fig. 3. Plot of Mulliken charges and Natural charges obtained by B3LYP/6-311++G(d,p).
( The global hardness ( ), that indicates the resistance to transfer the charge and the softness ( ), that measures the charge transfer properties are defined by: (2) (3) E HOMO and E HOMO in equations ( 1) and ( 2) are the energies of frontier molecular orbitals; the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO), respectively.
Similarly, the electrophilicity index (ω) which represents the property of molecule to accept the electron from the surroundings can be calculated as: Further, a new reactivity index ( ), which indicates the stabilization in energy when the system acquires additional charge from the environment up to the saturation, was calculated as: (5) The calculated values of these indices are listed in the Table 2.The calculated high value of electrophilicity index (ω) shows that the molecule behaves as a strong electrophile.) and local electrophilicity indices (ω ω ω ) have been calculated using the equations (6 -10) and listed in the Table 3. = q k (N+1) -q k (N) for nucleophilic attack.
= S , = S and = S (9) ω = ω , ω = ω and ω = ω (10) From the Table, the oxygen atoms O2 (at five member ring), O4 (at carboxyl group) and the carbon atoms C17, C21, C22 (in rings) and C25 (at methoxy group) have suitable high potential for nucleophilic attack and where and ω values are maximum.Similarly, oxygen atoms O6 and O7 of nitro group and, carbon atom C17 in the ring are prone to the electrophilic attack where and ω values are maximum.Therefore, it can be noticed that the nitro groups are more reactive in comparison to the methoxy and carboxyl group.

Molar refractivity:
MR is important property used in quantitative structure property relationship.It reflects arrangements of the electron shells of ions in molecules and yields information about their electronic polarization.It relates the refractive index, molecular weight and the density, and is accomplished by a change in properties of ions under the influence of electric fields of the neighbouring ions.The molar refractivity (R; cm 3 mol -1 ) is given by Lorentz-Lorentz (Padrόn et al. 2002, Verma et al. 2005) where n is refractive index, M is the molar mass, is the density, electronic polarizability and the Avogadro's constant.
Thus the molar refractivity measures the polarizability of the ions i.e., the displacement of the electronic shell/s with respect to its nucleus.The above equation holds for both the liquid and solid state of the system.The value of R depends upon the wavelength of the light used to measure the refractive index.For radiation of infinite wavelength it represents the real volume of the molecular system.The molar refractivity, which is responsible for the binding property of the title molecule with different amino acids, was calculated to be 49.8163units.

NON LINEAR OPTICAL (NLO) PROPERTIES
NLO deals with the interaction of materials in the presence of applied electromagnetic field, which changes the wave number, phase and the other physical properties (Shen 1984).In presence of an applied electric field, the energy of a system is a function of the field.In recent years, the NLO phenomena have attracted much attention because of their potential applications in optical communication, optical sensing, data storage, computing etc (Zhang et al. 2002;Zhang et al. 2007;Kolev et al. 2008).The first hyperpolarizability ( of the molecular system, and the related properties polarizability ( and anisotropy of polarizability ( have been calculated using 6-311++G(d,p) basis set.First order hyperpolarizability is a third rank tensor that can be described by 3x3x3 matrix.The 27 components of 3d-matrix can be reduced to 10 components by Kleinman symmetry (Kleinman 1962).The hyperpolarizability can be defined as the coefficients of Taylor series expansion of the energy expansion in the external electric field.As x, y, z components of and obtained from Gaussian 09 output are in atomic unit (a.u.), the values were converted into electrostatic units (e.s.u.) using conversion factors (for : 1 a.u.= 0.1482 x10 -24 esu; for : 1 a.u.= 0.0086393 x10 -30 e.s.u.) and listed in the Table 4. Urea is one of the molecules which have the good non linear optical property and it is used as a critical parameter for comparative studies ( = 1.3732Debye and = 3.7289x10 -31 cm 5 /e.s.u.).For the title compound the first order hyperpolarizability by B3LYP/6-31++G(d,p) method is 10.7805 x10 -31 cm 5 /e.s.u. which is about three times more than that of urea, while by HF/6-31++G(d,p) the first order hyperpolarizability is 8.6044x10 -31 cm 5 /e.s.u., which is about two times more than that of urea.
Hence, the compound under study has a good non linear property.

CONCLUSION
The chemical reactivity, molecular electrostatic potential surface (MEP) and the non linear optical properties of molecule AA I have been calculated using DFT employing 6-311++G(d,p) basis set.The calculated local electrophilicity indices show that the oxygen atoms O2, O4 and the carbon atoms C21, C22 and C25 are prone to the nucleophilic attack.But the oxygen atoms O6 and O7 at the nitro group and the carbon atom C17 suitable for the electrophilic attack.The carboxyl group is more reactive than the methoxy group and less reactive than the nitro group.The value of dipole moment is 7.5888 D and the first order hyperbolarizability obtained by DFT/HF about 3/2 times higher than of urea show the strong non linear optical property of the molecule.