Aniline Pka

PREDICTION OF IONIZATION CONSTANT (pKa) OF SUBSTITUTED ANILINE BY SEMI- EMPIRICAL CALCULATION. R.Margabandu, K.Subramani*. Department of Chemistry, Islamiah College, Vaniyambadi, PIN- 635751, Tamil Nadu. India. Email: [email protected]

Abstract In this work we studied the relationship between mullikan and ZDO electron population on nitrogen atom of subsituted anilines with its dissociation constant. Mullikan electron population were calculated in semi- empirical (PM3) method. Semi-empirical methods are faster than abi nitio and DFT method. Key Words : pKa, PM3, Mullikan electron population INTRODUCTION Ionization constant of acids and bases (pKa) are very important [3] property. These constants have profound effect on the physiochemical [6] properties of a compound. In rational drug discovery pKa value are essential for optimization of ADME characteristics since compounds in their unionized form tend to be less soluble but can more easily penetrate lipophilic barrier existing between them. Furthermore, Ionization constant have the effect on rate[8] of reaction and reactivity of order of acids and bases towards specific reagent(based on HSAB principal)[7] since strength of the acid or bases depends on its pKa value. RESULT AND DISCUSSION In quantum mechanical calculation we can generate the following information pertaining the molecule, energy , dipole moment, electron population on individual atoms, energy of all molecular orbital and bond order between the atom. From the knowledge of above value we can generate so many descriptors like hardness, softness, electrophilicity index, fuki function, local softness and group electrophilicity and so on. The descriptor is selected based on property of molecule to be correlated. Here mullikan and ZDO (Zero differential overlap) electron population on base nitrogen atom is related with its ionization constant(pKa).The table 1[15] shows the pKa value of different subsitituted aniline.

Table 1

S.No 1 2 3 4 5 6 7 8 9 10 11 12 13

Compound name 3-fluro aniline 3- chloroaniline 4- chloro aniline 2- Bromo aniline 3- Bromo aniline 4- Bromo aniline 3,5 Dibromo aniline 3-Ethoxy aniline 2-Iodo aniline 2-methyl aniline 3-methyl aniline 3- nitro aniline 4-Nitro aniline

Exp,.pKa Value 3.5 3.46 4.15 2.53 3.58 3.86 2.34 4.18 2.6 4.44 4.73 2.46 1

The table 2 shows the mullikan and ZDO electron population on base nitrogen atom of aniline. Table 2

S.No 1 2 3 4 5 6 7 8 9 10 11 12 13

Mullikan charge on base nitrogen -0.0043 -0.0038 -0.0043 0.0036 -0.0031 -0.0096 0.0024 -0.009 0.002 -0.0102 -0.0097 0.0023 0.0117

ZDO Charge on base nitrogen 0.074 0.0744 0.0731 0.0818 0.0749 0.0732 0.0812 0.0687 0.08 0.0658 0.0674 0.0803 0.0942

The table 3 shows the experimental pKa and pKa calculated by ZDO electron population.Equation 1 is generated[9] and used to calculate the pKa value from ZDO charge density. Graph 1 shows the comparison of experimental pKa and pKa calculated using ZDO population. pKa = -156.94 x ZDO population + 2.89 ―1 ( Correlation coefficient(r) = 0.93, Standard Deviation = 0.27 ) Table 3

S.No 1 2 3 4 5 6 7 8 9 10 11 12 13

ZDO Charge 0.074 0.0744 0.0731 0.0818 0.0749 0.0732 0.0812 0.0687 0.08 0.0658 0.0674 0.0803 0.0942

Exp,. pKa 3.5 3.46 4.15 2.53 3.58 3.86 2.34 4.18 2.6 4.44 4.73 2.46 1

Calc,.pKa 3.57 3.52 3.69 3.51 3.43 3.68 2.59 4.29 2.7 4.69 4.47 2.71 0.81

Residual -0.07 -0.06 0.46 -0.98 0.15 0.18 -0.25 -0.11 -0.1 -0.25 0.26 -0.25 0.19

Graph 1 ZDO Calc, pka Vs Exp, pka 5

pka

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The table 4 shows the experimental pKa and pKa calculated by mullikan electron population.Equation 2 is generated and used to calculate the pKa value from mullikan charge density. Graph 2 shows the comparison of experimental pKa and pKa calculated using mullikan population. pKa = -136.54 x Mullikan population + 13.68 ―2 (Correlation coefficient(r) = 0.95, Standard Deviation = 0.23)

Table 4 S.No 1 2 3 4 5 6 7 8 9 10 11 12 13

Mullikan -0.0043 -0.0038 -0.0043 0.0036 -0.0031 -0.0096 0.0024 -0.009 0.002 -0.0102 -0.0097 0.0023 0.0117

Exp,. pKa 3.5 3.46 4.15 2.53 3.58 3.86 2.34 4.18 2.6 4.44 4.73 2.46 1

Calc,.pKa 3.56 3.48 3.56 2.32 3.37 4.39 2.51 4.3 2.57 4.49 4.41 2.52 1.02

Residual 0.06 0.02 -0.59 -0.21 -0.21 0.53 0.17 0.12 -0.03 0.05 -0.32 0.06 0.02

Graph 2

pka

Mulliken Calc pka, Vs Exp,. pka 5 4.5 4 3.5 3 2.5 2 1.5 1 0.5 0

Exp,. Calc,.

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EXPERIMENTAL SECTION All the Molecules are geometry optimized at PM3(semi-empirical)[5] level of theory in RHF method with convergence limit of 10 x 10 –10 kcal/ mol. The value of atomic charge density ,mullikan and ZDO, of nitrogen is taken for linear fit in labfit software. Geometry optimization was done by in argus lab[10 -13]. The geometry optimized molecules are shown below.

CONCLUTIONS Ionization constant (pKa) for base can be calculated from the ZDO and Mullikan charge density value of base nitrogen atom of anilines (base compound). REFFERENCES 1. Donard dwyer, BMC chemical biology,2005,5.2. 2. Gergely volgyi, Ph.D dissertation, semmel weis University, department of pharmaceutical chemistry, Budpest, 2007. 3. Xing Yuan, Guang-Hua Lu, Li-Minsu. Biomedical and environmental sciences,18,281285,2005. 4. Macros C.Rezende. Journal of the Brazilian chemical society , Vol.12,No:1, 73-80, 2001. 5. Lemi Trker, Turk J.Biol.,204.2000,291-298. 6. Stephen jelfs, peter ertl, paul selzer. Novartis institute of biomedical research , Basel, Switzerland. 7. Asit K. Chandra, Minh Tho nguyen. Int.J.Mol.Sci.,2002,3,310-323. 8. Peter james smish, Lorraine marion noble, 56th Canadian chemical conference of the chemical insituteof Canada, june 1973. 9. Ammar.A Ibrahim Eid and A.Abdalrazaq. American journal of applied sciences 6(7) 1385-1389,2009 10. www.planaria-software.com 11. Shalini Mehta, Yogeeswari perumal, Sri ram Dharmarj, Induja sridharan, Journal of zheijang Uvivversity Science B-2007 8 (1),45-55. 12. Erick L.Bastos, Wilhelm J.bader, ARKIVOC 2007 (xiii) 257-272 13, Farhan Ahmed Pasha, Hemant kumar srivastana , yakoobbeg and pashupati Prasad sigh. Ammerican journal of immunology 2(1);23 – 28,2006 14. www.chem.wise..edu/areas/reich/pKatable/kaimine.gif