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: rmargabandu@yahoomail.com

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
 Exp,.pKa
S.No Compound name Value
1 3-fluro aniline 3.5
2 3- chloroaniline 3.46
3 4- chloro aniline 4.15
4 2- Bromo aniline 2.53
5 3- Bromo aniline 3.58
6 4- Bromo aniline 3.86
7 3,5 Dibromo aniline 2.34
8 3-Ethoxy aniline 4.18
9 2-Iodo aniline 2.6
10 2-methyl aniline 4.44
11 3-methyl aniline 4.73
12 3- nitro aniline 2.46
13 4-Nitro aniline 1

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

Table 2

Mullikan ZDO Charge

charge on base on base
S.No nitrogen nitrogen
1 -0.0043 0.074
2 -0.0038 0.0744
3 -0.0043 0.0731
4 0.0036 0.0818
5 -0.0031 0.0749
6 -0.0096 0.0732
7 0.0024 0.0812
8 -0.009 0.0687
9 0.002 0.08
10 -0.0102 0.0658
11 -0.0097 0.0674
12 0.0023 0.0803
13 0.0117 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
 ZDO
S.No Charge Exp,. pKa Calc,.pKa Residual
1 0.074 3.5 3.57 -0.07
2 0.0744 3.46 3.52 -0.06
3 0.0731 4.15 3.69 0.46
4 0.0818 2.53 3.51 -0.98
5 0.0749 3.58 3.43 0.15
6 0.0732 3.86 3.68 0.18
7 0.0812 2.34 2.59 -0.25
8 0.0687 4.18 4.29 -0.11
9 0.08 2.6 2.7 -0.1
10 0.0658 4.44 4.69 -0.25
11 0.0674 4.73 4.47 0.26
12 0.0803 2.46 2.71 -0.25
13 0.0942 1 0.81 0.19

Graph 1

ZDO Calc, pka Vs Exp, pka

3 Series1
pka

2 Series2

0
1 2 3 4 5 6 7 8 9 10 11 12 13
Compoun No

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 Mullikan Exp,. pKa Calc,.pKa Residual

1 -0.0043 3.5 3.56 0.06
2 -0.0038 3.46 3.48 0.02
3 -0.0043 4.15 3.56 -0.59
4 0.0036 2.53 2.32 -0.21
5 -0.0031 3.58 3.37 -0.21
6 -0.0096 3.86 4.39 0.53
7 0.0024 2.34 2.51 0.17
8 -0.009 4.18 4.3 0.12
9 0.002 2.6 2.57 -0.03
10 -0.0102 4.44 4.49 0.05
11 -0.0097 4.73 4.41 -0.32
12 0.0023 2.46 2.52 0.06
13 0.0117 1 1.02 0.02

Graph 2
Mulliken Calc pka, Vs Exp,. pka

5
4.5
4
3.5
3 Exp,.
pka

2.5
2 Calc,.
1.5
1
0.5
0
1 2 3 4 5 6 7 8 9 10 11 12 13
Compound No

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).

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