Ch.16 Chemistry of Benzene: Electrophilic Aromatic Substitution
Electrophilic aromatic substitution:
E
H
H
H
E+
H
H
+ H+
H
H
H
H
H
H
Some electrophilic aromatic substitution:
X
Halogenation
NO2
Nitration
SO3H
Sulfonation
R
Alkylation
O
C
R
Acylation
16.1 Bromination of Aromatic Rings
Bromination:
Br
Br 2
+ HBr
FeBr 3
electrophilic addition mechanism:
H
Cl
H
H
Cl-
Cl
- similar first electrophilic addition mechanism
but aromatic rings are less reactive (more stable) than alkenes
- need catalyst for aromatic electrophilic substitution
FeBr 3
+
Br
Br
δBr3Fe
Br
δ+
Br
or
+
FeBr 4- + Br
a strong electrophile
Br +
Br
Br
allylic carbocation
three resonance forms : stable
but, much less reactive than the aromatic
reactant → endothermic, high Ea, slow reaction
Br
- electrophilic aromatic substitution need higher
activation energy than alkene does
E
Energy
E a, alkene
H
alkene + E
+
E a, benzene
benzene + E +
Reaction progress
E
overall substitution: addition + rearomatization
Br+
slow
Br
H
FeBr 4-
nonaromatic
intermediate
Br
+ HBr + FeBr3
fast
aromatic
product
X
Br
Br
H
addition
nonaromatic
product
electrophilic bromination
Energy
H
E
Ea
Br
Br
H
benzene + Br2
Br
+ HBr
Reaction progress
16.2 Other Aromatic Substitutions
Chlorination
H3C
N
Cl
O
Cl 2
+ HCl
cat FeCl 3
Cl
N
86%
Diazepam
(tranquilizer)
Iodination
2 I+ + 2 Cu+
l2 + 2 Cu 2+
I
l2
cat CuCl 2
65%
Nitration : HNO3 + H2SO4 (cat)
O
H+
H
O
NO 2+
N O
N O
O
H
O
H
+ H 2O
CH3
NO2
O2N
NO2
HNO3
NO2
cat H2SO4
85%
Trinitrotoluene (TNT)
reduction of nitro to aniline
NO2
NH2
1. SnCl2, H3O+
2. OH-
Sulfonation : fuming sulfuric acid, SO3 + H2SO4 (cat)
H+
O
O
H
S O
S O
O
O
NH2
SO3H
SO3
cat H2SO4
SO2NH2
95%
sulfanilimide
(a sulfa drug)
alkali fusion reaction
SO3H
OH
1. NaOH, 300oC
2. H3O
CH3
p-Cresol (72%)
+
CH3
16.3 Alkylation of Aromatic Rings: The Friedel-Craft Reactions
Friedel-Craft Alkylation
Cl
AlCl 3
+ H 3C
CH 3
H 3C
CH 3
+
AlCl 4-
Cl
AlCl 3
+ H 3C
CH 3
+ HCl
Cumene (85%)
Limitation:
- only useful for RCl not for ArCl or vinyl chloride
- aromatic rings with electron-withdrawing groups are unreactive
- aromatic rings with amino group are unreactive: amines under go
acid-base reaction with AlCl3
Y
+
AlCl 3
R X
NO reaction
Y = NR3+, NO2, CN, SO3H, CHO, COR, COOH, COOR
= NH 2, NHR, NR 2
polyalkylation problem
C(CH 3)3
+ (CH 3)3CCl
AlCl 3
C(CH 3)3
+
C(CH 3)3
minor
- use excess of benzene for mono alkylation
major
skeleton rearrangement: carbocation
+
AlCl 3
+
Cl
65%
35%
carbocations: skeleton rearrangement to a more stable cation
CH 2
H
Hydride shift
H
H 3C
CH 2
H 3C
CH 3
+
Alkyl shift
H 3C
CH 3
CH 3
Cl
AlCl 3
16.4 Acylation of Aromatic Rings
Friedel-Craft Acylation
CH 3
O
O
AlCl 3
+
Cl
CH 3
+ HCl
80oC
Acetophenone (95%)
O
AlCl 3
+
Cl
R
O
C
+
R
O C R
- no polyacylation: less reactive acyl product
AlCl 4-
16.5 Substituent Effects in Substituted Aromatic Rings
1. Reactivity
NO 2
relative rate
of nitration
6 x 10-8
Cl
0.033
H
1
OH
1000
2. Orientation
OH
OH
OH
OH
NO 2
HNO 3
+
+
H2SO4, 25oC
NO 2
o-Nitrophenol
50%
CN
CN
m-
NO 2
p-
0%
50%
CN
CN
NO 2
HNO 3
+
+
H2SO4, 25oC
NO 2
o-Nitrobenzonitrile
17%
m-
NO 2
p-
81%
2%
Substituent Effects in Electrophilic Aromatic Substitution
electron-poor
-SO3H
-NO2
-NR3+
-CN
-COOH
electron-rich
-CHO
-COCH3 -COOCH3
meta-directing
deactivators
-I
-Ph
-F
-Br
-Cl
ortho- and paradirecting
deactivators
no meta-directing activators
-H
-OMe -OH
-CH3 -NHCOCH3
alkyl
ortho- and paradirecting
activators
-NH2
Two factors in activating/deactivating effect:
inductive effect: electronegativity differences
resonance effect: lone pair electrons, double bond
Inductively withdrawing groups
- positive charges at the neighboring atom
inductively withdrawing
−
δ
+
δ
X
δ−O
C
δ+ R
δ−O
C
δ+ OR
C
δ+
X= F, Cl, Br, I
inductively donating
R
δ−
N
O
N
−
δ+ O δ
Resonance effect: withdraw or donate electrons through a π-bond
- the effect is greatest at the ortho and para positions
electron withdrawing resonance effect
O
C
O
C
R
δ−
Z
Y+
δ
O
C
R
δ−O
C
δ+ R
C
δ+
δ−
N
O
C
R
O
N
−
δ+ O δ
R
Electron donating resonance effect
- the effect is greatest at the ortho and para positions
OH
Y
O
O
H
NH 2
OH
O
H
OR
H
X
X= halogen
- inductive effect and resonance effect don't necessary act in the
same direction
; -X, -O, -N atoms are inductively withdrawing groups but electrondonating resonance effect
16.6 An Explanation of Substituent Effects
Activating/deactivating effect
Activating groups: donate electrons to the ring
- stabilize carbocation intermediate
- lower the activation energy for carbocation formation
Deactivating groups: withdraw electrons from the ring
- destabilize carbocation intermediate
- raise the activation energy for carbocation formation
Y
>
E+
Y
H
>
E+
E+
Y
H
Y
E
stabilized
carbocation
E
E
destabilized
carbocation
Orientating Effect
ortho, para directors:
- lone pair electrons
- stabilize carbocation intermediate by resonance
NH 2
OH
R
halogens:
- inductively deactivating
- but ortho, para directing by resonance stabilization
Br
alkyl group: ortho, para activator
CH 3
NO 2
NO 2+
ortho
63%
CH 3
NO 2
NO 2
Most stable
CH 3
CH 3
CH 3
meta
3%
CH 3
NO 2
CH 3
NO 2
NO 2
CH 3
CH 3
CH 3
NO 2
NO 2
NO 2
para
34%
Most stable
OH, NH2 group: ortho, para activator
OH
OH
NO 2
NO 2+
ortho
50%
NO 2
OH
NO 2
NO 2
Most stable
OH
OH
OH
meta
0%
OH
NO 2
OH
NO 2
NO 2
OH
OH
OH
OH
NO 2
NO 2
NO 2
NO 2
para
50%
Most stable
- stabilizing resonance interactions for ortho and para additions
halogen group: ortho, para adectivator
Cl
Cl
NO 2
NO 2+
ortho
35%
NO 2
Cl
NO 2
NO 2
Most stable
Cl
Cl
Cl
meta
1%
Cl
NO 2
Cl
NO 2
NO 2
Cl
Cl
Cl
Cl
NO 2
NO 2
NO 2
NO 2
para
64%
Most stable
- inductively deactivating
- stabilizing resonance interactions for ortho and para additions
EWG group: meta deactivator
δ+CHO
Cl +
CHO
Cl
CHO
Cl
Cl
ortho
δ−
O
19%
H
C δ+
Least stable
CHO
meta
CHO
Cl
72%
CHO
Cl
Cl
CHO
CHO
CHO
Cl
Cl
Cl
para
9%
Least stable
destabilizing inductive interactions for ortho and para additions
A Summary of Substituent Effects in Aromatic Substitution
Substituents
Reactivity
Orientation Inductive Effect Resonance Effect
-CH3
activating
ortho
para
weak; electrondonating
none
-OH, -NH2
activating
ortho
para
weak; electronwithdrawing
strong; electrondonating
-F, Cl, Br, I
deactivating
ortho
para
strong; electronwithdrawing
weak; electrondonating
-N+(CH3)3
deactivating
meta
strong; electronwithdrawing
none
-NO2, -CN, CHO, -CO2Me, - deactivating
COCH3, -COOH
meta
strong; electronwithdrawing
strong; electronwithdrawing
16.7 Trisubstituted Benzenes: Additivity of Effects
1. two groups reinforce each other:
CH 3
CH 3
NO 2
HNO 3
H2SO 4
NO 2
NO 2
2. two groups oppose each other: more powerful directing group
wins, but mixture of products often result
CH 3
CH 3
Br 2
Br
OH
OH
3. sterically hindered site: further substitution rarely occurs between
the two groups in a metadisubstituted compound
too hindered
CH 3
Cl 2
Cl
CH 3
CH 3
CH 3
Cl
Cl
+
FeCl 3
Cl
Cl
Cl
Cl
NOT formed
- alternative preparation 1,2,3-trisubstituted compound
CH 3
CH 3
NO 2
HNO 3
O 2N
CH 3
NO 2
NO 2
+
H2SO 4
NO 2
16.8 Nucleophilic Aromatic Substitution
nucleophilic aromatic substitution: no SN1, SN 2 mechanism
OH
Cl
O 2N
NO 2
1. NaOH
O 2N
NO 2
+ Cl-
2. H3O+
NO 2
NO 2
100%
sp2 orbital (unstable)
Cl
+ Cl-
X
no SN1 reaction
HO Cl
X
no SN2 reaction
addition/elimination mechanism
Cl
NO 2
-
OH
Cl
OH
OH
NO 2
+ Cl-
NO 2
Meisenheimer complex
- nucleophilic aromatic substitution occurs only if the aromatic
ring has electron withdrawing group(s) in ortho or para position
to the halogen
- meta substituent has no resonance stabilization
nucleophilic aromatic substitution: need ortho or para EWG
Cl
-
OH
NO 2
NO 2
-
para
Cl
OH
O 2N
OH
O 2N
Cl
meta
-
OH
OH
O
N
O
Cl
OH
X
NO 2
OH
O
N
O
Cl
OH
ortho
Cl
Cl
Cl
NO 2
no stabilization of charge
by nitro group
16.9 Benzyne
nucleophilic aromatic substitution of non-activated system
; need high temperature and high pressure
OH
Cl
1. NaOH, H 2O, 340 oC, 2500psi
+ NaCl
2. H3O+
benzyne intermediate; elimination/addition mechanism
OH
Cl
H
-
OH
H 2O
- HCl
elimination
addition
Benzyne
H
evidence for benzyne mechanism: 14C labeling at C1
Cl
*
H
KNH 2
NH 3
*
NH 3
*
NH 3
addition
Benzyne
symmetrical
50%
H
H
+
*
50%
NH 3
trapping benzyne intermediate
O
Br
H
KNH 2
O
NH 3
Diels-Alder adduct
Benzyne
dienophile
H
C
C
H C
H
C
H
C
C
16.10 Oxidation of Aromatic Compounds
Oxidation of Alkylbenzene Side Chains
aromatic rings; inert to KMnO4
benzylic CH2: oxidized to -COOH by KMnO4, Na2Cr2O7
KMnO 4
COOH
H 2O
industrial procedure
COOH
CH 3
O2
Co (III)
CH 3
COOH
CH 3
attack benzylic C-H bonds
CH 3
CH 3
H 3C
C
KMnO 4
H 2O
NO reaction
Bromination of Alkylbenzene Side Chains
Br
O
NBS
(PhCO 2)2
CCl 4
+
N H
O
radical mechanism
H
H
R
H
Br
H
R
Br 2
R +
HBr
O
HBr +
N Br
O
O
Br2 +
Br
N H
O
Br
resonance stabilized benzylic radical
H
H
H
H
H
H
H
H
16.11 Reduction of Aromatic Compounds
Catalytic Hydrogenation of Aromatic Rings
aromatic rings; inert to normal hydrogenation conditions
O
O
H2, Pd
EtOH
but, at high pressure of H2 and high temperature or use reactive
rhodium catalyst
; reduced to cycloalkanes
CH 3
CH 3
Pt
EtOH
o
25 C
HO
CH 3
H2 (2000 psi)
H2(1 atm)
Rh/C EtOH
25oC
100%
CH 3
HO
100%
Reduction of Aryl Alkyl Ketones
; neighboring carbonyl groups are reactive under reducing condition
O
O
H2, Pd
Cl
AlCl 3
EtOH
AlCl 3
+
Cl
nitro groups are reduced under the reaction conditions
O
O 2N
H2, Pd
EtOH
H 2N
synthesis of complex molecules starting from simple
precursors;
- pharmaceutical industry: new drugs
- chemical industry: economical routes to known
compounds
- academic: applications + pure challenges
planning synthesis needs
- knowledge about organic reactions
- practical ability: any problems
retrosynthetic analysis: design reaction schemes
backward in case complex molecules
16.12 Synthesis of Trisubstituted Benzenes
NO 2
?
.....
Cl
HNO 3
H2SO 4
NO 2
NO 2
Cl 2, FeCl 3
X
Cl
HNO 3
H2SO 4
Cl
Br
?
COOH
Br
Br
KMnO 4
COOH
Br
CH 3Cl
AlCl 3
Br2, FeBr 3
CH 3
Br 2, FeBr 3
Br 2, FeBr 3
CH 3Cl, AlCl 3
COOH
CH 3
O
O
Cl
H2, Pd/C
Cl
Cl
NO 2
deactivated ring
will not undergo
Friedel-Craft rxn
NO 2
HNO 3
H2SO 4
;Cl
NO 2
no correct isomer
Chemistry @ Work Combinatorial Chemistry
R4
O
N
R3
R1
N
R2
+
+
Benzodiazepine library
(R1-R4 are various substituents)
Chemistry @ Work
2,180,106 compounds
Problem Sets
Chapter 16
28, 33, 35, 40, 54, 64, 70