4.

Structural Effects on Reactivity

4.1 Electronic Effects:
4.1.1 Inductive and field effects
4.1.2 Resonance effect
4.2 Steric Effects
4.2.1 Steric hindrance
4.2.2 Strain
4.2.3 Stereo electronic effect
4.3 Linear Free Energy Relationships
4.3.1 Hammett equation
4.3.2 Mechanistic implication of LFER
1
4.1 Electronic Effects
4.1.1 Inductive and field effect:
Inductive effect is a polarization through o-bond; drop off
rapidly with number of o-bonds.
Field effect is a polarization through space; drop off
rapidly with the distance.
In most cases, inductive and field effects operate together
and difficult to separate them. The following sytem is
designed to show only the field effects e.g.

2
H
H
Cl
Cl
COOH
Cl
Cl
H
H
COOH
pK
a
= 6.07 5.67
4.1.1 Inductive and field effects
(continued)
Electron donating group (+I): O
-
, COO
-
, CR
3
,
CHR
2
, CH
2
R, CH
3
, D
Electron withdrawing group (-I): NR
3
+
, SR
2
+
,
NH
3
+
, NO
2
, SO
2
R, CN, SO
2
Ar, CO
2
H, F, Cl,
Br, I, OAr, COOR, OR, COR, SH, SR, OH,
CCR, Ar, CH=CR
2

3
4.1 Electronic Effects
4.1.2 Resonance effect (mesomeric effect) is caused by
electron delocalization of t-bond; drop off gradually with
the number of t-bonds.
Electron donating group (+M): O
-
, S
-
, NR
2
, NHR, NH
2
,
NHCOR, OR, OH, OCOR, SR, SH, Br, I, Cl, F, (R), Ar
Electron withdrawing group (-M): NO
2
, CN, COOH, COOR,
CONH
2
, CONHR, CONR
2
, CHO, COR, SO
2
R, SO
2
OR,
NO, Ar
Electronic effect on reactivity can be considered by
comparison of the effects on transition state and reactants
e.g.

4
Ar C NH
2
+ OH
-
O
Ar C NH
2
O
OH
Ar C
OH
O
NH
2
Intermediate
Transition state
o

Electronic effect on reactivity

(continued)
Electron withdrawing groups (-I and M) or Ar will
lower the free energy of T.S. These groups have
much less effects on the free energy of reactants.
The free energy of activation is thus lowered with
the electron withdrawing groups.
5
Ar C NH
2
+ OH
-
O
Ar C NH
2
O
OH
Ar C
OH
O
NH
2
Intermediate
Transition state
o

4.2 Steric Effects

4.2.1 Steric hindrance (front strain, F-strain)
Relative rates of sovolysis of RBr with ethanol
R = CH
3
CH
3
CH
2
CH
3
CH
2
CH
2
(CH
3
)
2
CHCH
2
(CH
3
)
3
CCH
2

Relative Rate: 17.6 1 0.28 0.030 4.2 x 10
-6

4.2.2 Strain caused by steric repulsion
Relative rates of hydrolysis of RCl in 80% ethanol
R = Me
3
C Me
2
EtC MeEt
2
C Et
3
C Me
2
(i-Pr)C Me(i-Pr)
2
C
Relative Rate: 1 1.7 2.6 3.0 0.9 13.6
------Hyper conjugation-------------- B-strain
(back strain)

R =
Relative Rate: 43.7 0.35
I- strain
(internal strain)


6
Me
Me
4.2 Steric Effects
4.2.3 Stereo electronic effects
Conformational analysis

7
OH
Ph H
H
PhCONH CH
3
PhCOO
Ph H
H
NH
3
+
CH
3
HCl OH
Ph H
CH
3
PhCONH H
Cl
-
t-Bu
Cl
H
H
t-Bu
t-Bu
H
Cl
H
t-BuO
-
t-BuO
-
H
Cl
H
t-Bu
H
H
slow
4. 3 Linear free energy relationship
(LFER)
4.3.1 Hammett equation
For thermodynamic evaluation, log K/K
0
= o whereas o
is the substituent constant and is the reaction constant
Hammett arbitrarily assigned = 1 for the ionization of
substituted benzoic acids to determine o
p
and o
m
.

log K/K
0
= o
p



log K/K
0
= o
m


o = 0 for X = H

8
O
OH
X
O
O
-
X
+ H
+
+ H
+
O
O
-
X
O
OH
X
Hammett equation (continued)
When the resonance effect of an electron withdrawing
substituent can directly affect the reaction center the
substituent constants are correlated to o
-
better than o
p
.
o
-
is determined from the ionization of p-substituted
phenol.

= 1
When the resonance effect of an electron donating
substituent can directly affect the reaction center the
substituent constants are correlated to o
+
better than o
p
.
o
+
is determined from the rate constants (log k/k
0
= o)
of the following reaction in which is assigned as -1



X OH X O
-
+ H
+
X C
CH
3
CH
3
Cl
H
2
O 10%
acetone 90%
X C
CH
3
CH
3
+
X C
CH
3
CH
3
OH
The substituent constants (o)
Group o
p
o
m
o
p
+
o
m
+
o
p
-

O
-
-0.81 -0.47 -4.27 -1.15 -
NMe
2
-0.63 -0.10 -1.7 - -
NH
2
-0.57 -0.09 -1.3 -0.16
OH -0.38 0.13 -0.92 - -
OMe -0.28 0.10 -0.78 0.05 -
CMe
3
-0.15 -0.09 -0.26 -0.06 -
Me -0.14 -0.06 -0.31 -0.10 -
H 0 0 0 0 0
Ph 0.05 0.05 -0.18 0 -
COO
-
0.11 0.02 -0.41 -0.10 -
F 0.15 0.34 -0.07 0.35 -
Cl 0.24 0.37 0.11 0.40 -
Br 0.26 0.37 0.15 0.41 -
I 0.28 0.34 0.14 0.36 -
10
Group o
p
o
m
o
p
+
o
m
+
o
p
-

N=NPh 0.34 0.28 0.17 - -
COOH 0.44 0.35 0.42 0.32 0.73
COOR 0.44 0.35 0.48 0.37 0.68
COMe 0.47 0.36 - - 0.87
CF
3
0.53 0.46 - - 0.57
NH
3
+
0.60 0.86 - - -
CN 0.70 0.62 0.66 0.56 1.00
SO
2
Me 0.73 0.64 - - -
NO
2
0.81 0.71 0.79 0.73 1.27
NMe
3
+
0.82 0.88 0.41 0.36 -
N
2
+
1.93 1.65 1.88 - 3
Electron withdrawing groups
have positive o.
Electron donating groups
have negative o.
Hammett equation (continued)
o can be categorized into three groups using inductive (I)
and resonance (mesomeric, M) effects
(- I): Me, Et, Me
3
C
(+M,+I): Ac, CN, NO
2
, CF
3
, Me
3
N
+

(-M, +I): AcNH, AcO, NH
2
, Br, Cl, F, OH, MeO, EtO, Ph
Hammett Equation is an LFER
AG
0
= -RT ln K
0

AG
x
= -RT ln K
x


AG
0
- AG
x
= RT ln K
0
/K
x
= 2.3 RT o
AG
x
= AG
0
- 2.3 RT o
AG
0
and 2.3 RT are constant at a specific temperature. If
changing of the substituent on the substrate does not change
the reaction mechanism is also constant and AG
x
has linear
relationship with o.

11
4.4 Mechanistic implication of LFER
If a plot of log k/k
0
against an appropriate set of o give a
linear line, the LFER is valid and the slope of the plot is
(the reaction constant).
The linear line obtained from the plot indicates that the
reaction mechanism and the coordination of the transition
states do not change upon the variation of the substituent.
The values can be used to give information about the
structures of the transition states
A positive indicates that the reaction center in the
transition state becomes more negative comparing to the
starting material.
A negative indicates that the reaction center in the
transition state becomes more positive comparing to the
starting material.
12
4.4 Mechanistic implication of LFER
The size of ,, suggests how well the charge on the reaction
center in the transition state can be transferred to the
substituent.
Exercise: Propose a reasonable mechanism for saponification
of methylbenzoate ( = +2.38) and specify the rate determining
step of the reaction.
Exercise: Match the following values i.e. +2.45, +0.75, -2.39
and -7.29 to the following reactions.
(a) nitration of substituted benzene
(b) ionization of substituted benzenethiols
(c) ionization of substituted benzenephosphonic acids
(d) reaction of substituted N,N-dimethylanilines and methyl
iodide
Exercise: What is the isokinetic temperature?


13
4.4 Mechanistic implication of LFER
A plot of log k/k
0
against an appropriate set of o is sometime
not linear.
The curved line obtained from the plot indicates that the
coordination of the transition states are shifted upon the
variation of the substituent.
The reflected line obtained from the plot usually indicates that
change of the rate determining step upon the variation of the
substituent.
Exercise: Propose a reasonable mechanism for the following
reaction and specify the rate determining step that agrees with the
values

14
= 3.5 for electron donating groups
= -0.25 for electron withdrawing groups
ArCH NNHCNH
2
O
ArCH O + H
2
NNHCNH
2
O
Answer to the exercise
(a) Nitration of substituted benzene 7.29
(b) ionization of substituted benzenethiols +2.45
(c) ionization of substituted benzenephosphonic
acids +0.75
(d) reaction of substituted N,N-dimethylanilines
with methyl iodide 2.39

15
C
O
OCH
3
OH
-
rds.
C
O
-
OCH
3
OH
C
O
OH
-CH
3
O
-
CH
3
O
-
- CH
3
OH
C
O
O
-
Answer to the exercise
16
NNHCNH
2
ArC
O
H
ArCHNHNHCNH
2
O OH
ArCHNHNHCNH
2
O
O
-
ArCH O + H
2
NNHCNH
2
O
H
+
H
+
ArCHNHNHCNH
2
O
OH
2
+
-H
+
NNHCNH
2
ArC
O