Di- and Polysubstitution
 Orientation
on nitration of monosubstituted
benzenes.
S u b s ti tu e n t
o rth o
m e ta
-
p ara
o rth o +
p ara
m e ta
55
99
trac e
38
96
4
30
100
O CH 3
44
CH 3
58
Cl
70
Br
37
1
62
99
1
CO O H
18
80
2
20
80
CN
19
80
1
20
80
NO 2
6.4
9 3.2
0.3
6.7
93.2
4
-
trac e
22-1
Directivity of substituents
22-2
Directivity of substituents
22-3
Di- and Polysubstitution
 Two
characteristics of a substituent
• Orientation:
• Certain substituents direct preferentially to ortho & para
positions; others to meta positions.
• Substituents are classified as either ortho-para directing or
meta directing toward further substitution.
• Rate
• Certain substituents cause the rate of a second substitution to
be greater than that for benzene itself; others cause the rate to
be lower.
• Substituents are classified as activating or deactivating toward
further substitution.
22-4
Di- and Polysubstitution
• -OCH3 is ortho-para directing.
O CH 3
O CH 3
O CH 3
NO 2
+ HN O3
+
CH 3 CO O H
+ H2 O
NO 2
A n iso le
o -N i tro an i s ol e
(4 4% )
p -N i tro a n i s ol e
(55% )
• -COOH is meta directing.
COO H
+ HN O 3
B e n z oi c
aci d
H 2 SO 4
CO O H
N O2
CO O H
+
100°C
CO O H
+
N O2
NO 2
o- N i trob e n z oi c
aci d
(18%)
m - N i trob e n z oi c
aci d
(80%)
p- N i trobenzo ic
aci d
(2%) 22-5
:
O
O
O
O
OCAr
:
Recall the polysubstitution in
FC alkylation.
R
:
I:
:
Br :
:
Cl :
:
:
F:
:
OCR
O
O
O
O
CH
CR
COH
COR
O
CNH 2
Strongly
deactivating
:
N HCAr
:
:
N HCR
:
M e ta Direc ting
:
OR
:
:
OH
:
Moderately
deactivating
N R2
:
Weakly
deactivating
N HR
:
Weakly
activating
N H2
:
Moderately
activating
:
Strongly
activating
:
O rth o -p a ra Dir ectin g
Di- and Polysubstitution
N O2
SO 3 H
N H3
+
C
C F3
N
C C l3
22-6
Di- and Polysubstitution
 Generalizations:
• Directivity: Alkyl, phenyl, and all substituents in which
the atom bonded to the ring has an unshared pair of
electrons are ortho-para directing. All other
substituents are meta directing.
• Activation: All ortho-para directing groups except the
halogens are activating toward further substitution.
The halogens are weakly deactivating.
22-7
Di- and Polysubstitution. Example
• The order of steps is important.
CH 3
o,p
HN O 3
K 2 Cr 2 O 7
H 2 SO 4
H 2SO4
CH 3
N O2
m
CO O H
o,p
N O2
p -N i tro b e n z oi c
ac i d
m
CO O H
K 2 Cr 2 O 7
H NO 3
H 2 SO 4
H2 S O 4
CO OH
NO 2
m -N i tro b e n z oi c
ac i d
Note the key point: transformation of o,p director into m director.
22-8
Theory of Directing Effects
 The
rate of EAS is limited by the slowest step in
the reaction.
 For almost every EAS, the rate-determining step
is attack of E+ on the aromatic ring to give a
resonance-stabilized cation intermediate.
 The more stable this cation intermediate, the
faster the rate-determining step and the faster
the overall reaction.
22-9
Theory of Directing Effects
 The
orientation of the subsitution is controlled by
the stability of the carbocation being formed by
attack of the electrophile. Different carbocations
formed depending on position of substitution.
 Products
are formed under kinetic control. In
some cases, equilibrium can be established
leading to different products. (FC alkylation)
22-10
Theory of Directing Effects
• -OCH3 is directing: assume ortho-para attack. Here
only para attack is shown.
OCH3
OCH3
slow
+ N O2 +
:O C H 3
OCH3
:
3
:
:O C H
:
:
+
:O CH3
fast
+
-H
+
N O2
H
(d)
N O2
+
+
H
N O2
(e)
N O2
H
(f)
N O2
H
(g)
Very stable resonance structure. Why?
22-11
Theory of Directing Effects
• -OCH3 is directing; assume meta attack.
OCH3
+
N O2
+
OCH3
+
slow
OCH3
+
H
N O2
(b)
OCH3
fas t
H - H+
H
N O2
(a)
OCH3
+ NO
2
N O2
(c)
No corresponding very stable resonance structure. o, p
preferred!
22-12
Theory of Directing Effects
• -CO2H is directing; assume meta attack.
CO O H
+ NO 2
+
slo w
CO O H
(a)
CO O H
H
H
H
N O2
N O2
N O2
(b )
CO O H
CO O H
f as t
+
-H
N O2
(c)
22-13
Theory of Directing Effects
• -CO2H is directing: assume ortho-para attack.
CO O H
+
+ NO 2
slo w
CO O H
CO O H
CO O H
CO O H
f as t
+
-H
H
N O2
(d )
H
N O2
(e )
H
N O2
NO 2
(f )
T h e m o s t d i s f av ore d
co n tri b u ti n g s tru ctu re
22-14
Activating-Deactivating (Resonance)
 Any
resonance effect, such as that of -NH2, -OH,
and -OR, that delocalizes the positive charge on
the cation has an activating effect toward further
EAS.
 Any
resonance effect, such as that of -NO2, -CN, C=O, and -SO3H, that decreases electron density
on the ring deactivates the ring toward further
EAS.
Next inductive
22-15
Activating-Deactivating (Inductive Effects)
 Any
inductive effect, such as that of -CH3 or
other alkyl group, that releases electron density
toward the ring activates the ring toward further
EAS.
 Any
inductive effect, such as that of halogen,
-NR3+, -CCl3, or -CF3, that decreases electron
density on the ring deactivates the ring toward
further EAS.
22-16
Activating-Deactivating (halogens)
• For the halogens, the inductive and resonance effects
run counter to each other, but the former is somewhat
stronger.
• The net effect is that halogens are deactivating but
ortho-para directing.
:C l
+
E
+
:C l
:
:
:
+ E
H
:
:
:C l
+
H
E
22-17
Nucleophilic Aromatic Substitution
 Aryl
halides do not undergo nucleophilic
substitution by either SN1 or SN2 pathways.
 They do undergo nucleophilic substitutions, but
by two mechanisms quite different from those
of nucleophilic aliphatic substitution.
• Nucleophilic aromatic substitutions are far less
common than electrophilic aromatic substitutions.
22-18
Benzyne Intermediates (strong base)
 When
heated under pressure with aqueous
NaOH, chlorobenzene is converted to sodium
phenoxide.
• Neutralization with HCl gives phenol.
-
Cl
O Na
+
2 N aO H
H2 O
p re s s u re , 3 00 o C
Ch l o ro benzen e
+
+ Na Cl + H O
2
So dium
p h e n o xi d e
Halogen reactivity: I > Br > Cl > F
22-19
Benzyne Intermediates (strong base)
• The same reaction with 2-chlorotoluene gives orthoand meta-cresol.
CH 3
CH 3
Cl
CH 3
OH
1 . Na O H, h e a t, p re s s u re
+
2 . HCl, H 2 O
2-M e th y l p h e n o l
(o - Cre s o l )
OH
3 -M e th y l p h e n o l
(m - Cre s o l )
• The same type of reaction can be brought about using
sodium amide in liquid ammonia. mixture (!)
CH 3
CH 3
+ N a NH 2
Cl
NH 3 ( l)
CH 3
+ N a Cl
+
o
(-33 C)
N H2
4-M e th y l an i l i n e
(p-T o l u i d i n e )
NH 2
3-M e th y l an i l i n e
(m -T o l u i d i n e )
22-20
Benzyne Intermediates
• -elimination of HX gives a benzyne intermediate, that
then adds the nucleophile to give products.
22-21
Benzyne Intermediates
• -elimination of HX gives a benzyne intermediate, that
then adds the nucleophile to give products.
CH 3
CH 3
Na NH 2
H
Cl
 -e l i m i n a ti o n
A b enzy ne
i n te rm e d i ate
22-22
Benzyne Intermediates
But wait, do we believe this crazy idea? We need some evidence….
A
B
22-23
Benzyne Intermediates
The deuterated fluoride below exchanges the D with
solvent ammonia although the deuterated bromide does
not. This indicates a relatively rapid exchange process for
the fluoro compound.
C
next
22-24
Benzyne Intermediates
explanation
22-25
Benzyne Intermediates
D
Get
same
product
Explation
next
22-26
Benzyne Intermediates
explanation
22-27
Addition-Elimination (nitro groups)
• When an aryl halide contains electron-withdrawing
NO2 groups ortho and/or para to X, nucleophilic
aromatic substitution takes place readily.
-
Cl
N O2
N a 2 CO 3 , H 2 O
+
O Na
N O2
o
100 C
NO 2
1-Ch l oro -2,4d i n i tro b e n z e n e
NO 2
S o d i u m 2,4-d i n i tro p h e n o xi d e
• Neutralization with HCl gives the phenol.
22-28
Meisenheimer Complex
• Reaction involves formation of reactive intermediate
called a Meisenheimer complex.
O
+N
O
Cl +
Nu
s l o w , rate
d e te rm i n i n g
(1 )
N O2
O
f a st
+N
O
O
Cl
Nu
N O2
(2 )
+N
O
Nu + :Cl
N O2
A M e i s e n h e i m e r co m p l e x
Similar to nucleophilic subsititution on carboxylic acid derivatives.
22-29