SUBSTITUENTS EFFECTS AND LINEAR
FREE-ENERGY RELATIONSHIPS
It is known that different substuents exert a different effect on e.g. the
acid strength of acetic acids. In particular the presence of groups more
electronegative than hydrogen increases the strength of the acid with
respect to acetic acid.
Many detailed relationships between substituent groups and chemical
properties have been identified, which, in many cases, can be expressed
quantitatively and are useful for both interpreting reaction mechanisms and
for predicting reaction rates and equilibria.
substituent groups
chemical properties
The most widely applied of these relationships is the Hammett equation,
which relates rates and equilibria of many reactions of compounds
containing substituted phenyl groups.
It was noted in the 1930s that there is a relationship between the
acid
strengths of substituted benzoic acids and the rates of many other
chemical reactions, for instance the rates of hydrolysis of substituted ethyl
benzoates.
The correlation is illustrated in this graph, where log k/k0 is plotted against log K/K0.
log k/k0
k and k
are the rate constants of the
hydrolysis of substituted or simple ethyl
-2.0
p-NO2
m-NO2
benzoate:
PhCOOEt + OH PhCOOH + EtOH
-
p-Cl
8.0
p-Me
-0.4
p-OMe
m-NH2
and K0 are the acid dissociation
constants of the corresponding benzoic
acids:
-1.2
PhCOOH PhCOO- + H+
p-NH2
log K/K0
-2.0
-0.8
-0.4
0.4
0.8
1.2
Neither
the principles of thermodynamics nor theories of reaction rates
require that there have to be such linear relationships. There are, in fact,
numerous reaction series that fail to show such correlations.
The
origin of these correlations can be explained considering the
relationships between the equation of correlation and the free energy
changes involved in the two processes.
The line depicted in the graph has this equation:
m log
that is
k
K
= log k
K0
0
in which m is the slope of the line
m (log K log K0) = (log k log k0)
Let us try to substitute the equilibrium constants K and the rate constants k
with the corresponding free energies:
The linear correlation therefore indicates that the change in free energy of
activation on the introduction of a series of substituent groups is directly
proportional to the change in the free energy of ionization that is caused by
the same series of substituents on benzoic acid.
The various correlations arising from such directly proportional changes in
free energies are called linear free energy relationships.
Since G and G are combinations of enthalpy and entropy terms, a linear
free-energy relationship between two reaction series can result from one of
three circumstances:
H is constant and the S terms are proportional for the two series
H is proportional for the two series and S is constant
H and S are linearly related
The Hammett correlation of free energy can also be expressed in this way:
for equilibrium constants
for rate constants
The
substituent constant
reaction constant
numerical values of terms and are defined by specifying the
ionization of benzoic acids as the standard reaction to which the reaction
constant = 1 is assigned.
The substituent constant can be determined for a series of substituent
groups by measurements of the acid dissociation constant of the substituted
benzoic acids.
The values so defined are used in the correlation of other reaction series,
and the values of the reactions are thus determined.
The relationship between the two equations
1
m log
K
k
= log
K0
k0
and
is evident when the Hammett equation is expressed in terms of free energy.
G0
-G
+
= =
2.3 RT
2.3 RT
For standard reaction, in which =1 :
Thus, substituting into equation 1:
-G
2.3 RT
log k - log k0
log
m=
k
k0
G0
2.3 RT
The value of reflects the effects that the substituent group has on the
free energy of ionization of substituted benzoic acids. The effect of the
substituent results from a combination of factors.
A group
can cause the polarization of electron density around the ring
through the system in both the reactant and the product. This affects the
position of the equilibrium.
In the case of a reaction rate the relative effect on the reactant and on the
transition state will determine the effect on the energy of activation.
The effect of substituent results from a combination of factors.
A substituent can exert three different effects:
1) Resonance effect
it is an effect of polarization and redistribution of the charge through the
system of the molecule:
F
N
C
N
C
OMe
OMe
2) Field effect
It is an effect caused by the dipoles of the bonds between groups with
different electronegativity and results from the through-space electrostatic
interaction.
Substituents more electronegative than aromatic carbon atom generate a
positive charge on the substituted carbon atom, while substituents less
electronegative than the aromatic carbon atom will have the opposite effect.
The resulting dipoles can perturb the electronic situation in two ways. The
presence of the charge separation will influence the energy associated with
development of charge elsewhere in the molecule:
+
Y
+
Y
unfavorable
favorable
favorable
unfavorable
3) Inductive effect
The presence of the charge separation will influence the energy associated
with development of charge elsewhere in the molecule.
This is transmission of bond dipoles through the intervening bonds by
successive polarizations of each bond:
Y
+
Y
-
favorable
+
Y
-
X
unfavorable
+
+
+
+
X
unfavorable
+
+
+
+
X
favorable
The Hammett equation does not take in exam steric effects, because it is
applied only to meta and para substituents, that do not interact sterically with
the reaction centre.
In addition to m and p, other values of are reported in the tables, in
particular + an - that reflect a recognition that the extent of resonance can
vary for different reactions.
+ values used for reactions in
which there is direct resonance
interaction between an electrondonor substituent and a cationic
reaction centre
O-
O-
-O
O-
OCH3
CH2
OCH3
- values used for reactions in
which there is direct resonance
interaction between the substituent
and an an electron-rich reaction site.
One approach is to correct for the added resonance interaction. This is done
in a modification of the Hammett equation known as the Yukawa-Tsuno
equation:
log
K
K0
= () + (r)(+--)
The additonal parameter r is adjusted from reaction to reaction: it reflects
the extent of the additional resonance component. A large r corresponds to
a reaction with a large resonance component, whereas when r goes to zero,
the equation is identical to the original Hammett equation.
large r
r goes to zero
reaction with a large resonance component
original Hammett equation
When there is direct conjugation with an electronic rich reaction center, an
equation analogous to the previous can be employed, using - instead of +.
Tables of values for many substituents have been collected; some values are given
in this table, but substituents constants are available for a much wider range of
substituents. The value for any substituent reflects the interactions of the
substituent with the reacting site by a combination of resonance and field
interactions.
This table shows a number of values. The value reflects the sensitivity of
the particular reaction to substituent effects
Let us now consider how linear free-energy relationships can provide insight into
reaction mechanism.
The
choice of benzoic acid ionization as the reference raction for the Hammett
reaction leads to > 0 for electron-withdrawing groups and < 0 for electronreleasing groups, since electron-withdrawing groups favour the ionization of the acid
and electron-releasing groups have the opposite effect.
electron-withdrawing
groups
>0
electron-releasing
groups
<0
From
a point of view: will be positive for all reactions favored by electron
releasing groups and negative for all reactions favored by electron releasing groups.
reactions favoured by
electron-withdrawing
groups
>0
reactions favoured
by electron-releasing
groups
<0
If the rates of a reaction serie show a satisfactory correlation, both the sign and
magnitude of provide information about the transition state for the reaction.
For example: the value for the saponification of substituted methyl benzoates is
+2.38. This indicated that electron-withdrawing groups facilitate the reaction and that
the reaction is somewhat more sensitive to substituent effects than the ionization of
benzoic acids.
O
R
OMe
OH
H2O
OH + MeOH
= +2.38
The observation that the reaction is favored by electron withdrawing substituents is
in agreement with the accerted mechanism for ester saponification: the tetrahedral
intermediate is negatively charged and its formation should therefore be favored by
electron-withdrawing substituents that can stabilize the developing charge.
There
is also a ground state effect working in the same direction: electronwithdrawing substituents will tendo to make the carbonyl group more electrophilic and
favor the addition of hydroxide ion.
The solvolysis of aryl methyl chlorides in ethanol shows a r value of -5.0, indicating
that electron-releasing groups greatly increase the reaction rate and supporting a
mechanism involving ionization as the rate-determining step. Electron-releasing
groups can facilitate the ionization by a stabilizing interaction with the electrondeficient carbocation that develops as ionization proceeds.
Ph
Ar
Cl
slow
Ph
Ar
+ Cl
EtOH
fast
Ph
Ar
OEt
+ HCl
= -5.0
The relatively large r shows that the reaction is very sensitive to substituents effects
and implies that there is a large redistribution of charge in the transition state.
Not all the reactions can be fitted by the Hammet equations or the multiparameter
variants. There can be several reasons for this. The most common is that the
mechanism of the reaction depends on the nature of the substituent.
In a multistep reaction, for example, one step may be rate-determining in the case of
electron-withdrawing substituents, but a different step may become rate-limiting when
the substituent is electron-releasing.
The rate of semicarbazone formation of benzaldehydes shows a nonlinear Hammet plot
with of about 3.5 for electron-withdrawing groups. The change in is believed to be the
result of a change in the rate-limiting step.
O
Ar
OH H
N
NH2
Ar
N
H
O
O
H2NHN
OH H
N
NH2
Ar
N
H
O
NH2
Ar
H
N
NH2
H2O
rate-limiting step for
electron-releasing groups
rate-limiting step for
electron-withdrawing groups
Any reaction which shows a major shift in transition-state structure over the substituent
series would be expected to give a nonlinear Hammet plot, since a variation in the extent
of resonance participation would then be expected.
By comparing +, - and sI, individual substituents can be separated into three groups.
Alkyl
groups are electron-releasing by
both resonance and polar effects.
Substituents
such as alkoxy, hydroxy and amino,
which can act as resonance donors, have negative
p and + values, but when polar effects are
dominant, these substituents acts as electron
attracting groups, as illustrated by the m and I
values.
third group of substituents are electronwithdrawing by both resonance and polar
interactions. These include carbonyl groups in
aldehydes, ketones, esters and amides, as well
as cyano, nitro and sulfonyl substituents.
-M
-I
-M
+I
+M
+I
Me, Et, But
-NH2, OH-Br, -Cl, -F
MeO-, EtOPh
-CF3
Me3N+
O
H3C
N
H
H 3C
O
N
O-
H3C
O-
C N
