Chemistry Reference
In-Depth Information
In the aniline and phenol equilibria, the dissociating hydrogen ion is one atom away from the phenyl ring, whereas
in the benzoic acid equilibrium it is two atoms. Thus, substituents are able to exert a greater effect on the
dissociation in aniline and phenol than in benzoic acid and the value is > 1. In phenylacetic and phenyopropionic
acids, the hydrogen ion that dissociates is three and four atoms away, respectively, from the phenyl ring.
Substituents are able to exert a lesser effect on the equilibrium than on the benzoic acid equilibrium and < 1.
Some illustrative values of for substituents in the
meta
and
para
positions are given in Table
1
.
Table 1:
values for some groups.
Substituent
m
p
-H
0.0
0.0
-NO
2
0.71
0.78
-Cl
0.37
0.23
-OMe
0.12
-0.27
By definition, for hydrogen is 0. The positive values of for the nitro goup indicates that it is electron-withdrawing.
In order to understand the magnitudes of the values for the nitro group in
meta
versus
para
positions, the
mechanisms of electron withdrawal or donation have to be considered. For a nitro group in the
meta
position,
electron-withdrawal is due to an inductive effect produced by the electronegativity of the constituent atoms.
If only induction were operative, one would expect the electron-withdrawing effect of a nitro group in the
para
position to be less than in the
meta
position. The larger value for a
para
-substituted nitro group results from the
combination of both inductive and resonance effects. For chlorine, the electronegativity of the atom produces an
inductive electron-withdrawing effect, with the magnitude of the effect in the
para
position being less than in the
meta
position. For chlorine, only the inductive effect is possible.
The methoxy group can be electron-donating or -withdrawing, depending on the position of substitution. In the
meta
position, the electronegativity of the oxygen atom produces an inductive electron-withdrawing effect. In the
para
position, only a small inductive effect would be expected. Moreover, an electron-donating resonance effect occurs
for the methoxy group in the
para
position, giving an overall electron-donating effect.
There are some limitations to these electronic parameters. For example, Hammet substituent constants cannot be
measured for the
ortho
position since the substituents in this position have an important steric, as well as electronic,
effect.
HYDROPHOBICITY
The formulation of the Hansch model was a real breakthrough in QSARs. First, Hansch recognized that
n
-
octanol/water partition coefficients are, like some other molecular properties, an additive constitutive molecular
property,
i.e.
they can be estimated from additive increments. The choice of
n
-octanol as reference solvent is
justified by several reasons.
n
-Octanol is comparable to a biological membrane.
It is overall lipophilic, but its hydroxyl group can act as a hydrogen donor as well as a hydrogen acceptor. Thus, it
may be considered to be “lipophilic but not hydrophobic”, as biological membranes are. Lipophilicity is considered
to be the ratio between the solubility of a substance in
n
-octanol and its solubility in water. It is usually expressed as
the logarithm of the partition coefficient
P
, where
P
is equal to the ratio: drug in the
n
-octanol phase/drug in the
aqueous phase. The determination of the partition coefficient
P
by the “shake flask” method with presaturated
solvents is generally used, and extensive experimental details for this method have been published [5].
log
P
= log ([drug]
org
/[drug]
aq
)
(4)
