Lecture 2 - Reactions of Aromatic Compounds
Lecture 2 - Reactions of Aromatic Compounds
Lecture 2 - Reactions of Aromatic Compounds
Department of Pharmacy
Reactions of
Aromatic Compounds
Lecture 2
Prepared by
Dr. Kutaiba Ibrahim Alzand
1. Electrophilic Aromatic
Substitution Reactions
Overall reaction
Some of the most important reactions of aromatic
compounds are those in which an electrophile replaces
one of the hydrogen atoms of the ring.
H E
E+
+ H+
Figure 15.1 Electrophilic aromatic substitution reactions.
SO3H X
SO3 X2
H2SO4
FeX3
O
O R Cl HNO3
AlCl3 H2SO4 NO2
R
RCl
AlCl3
R
2. A General Mechanism for Electrophilic
Aromatic Substitutions
C Br C
+ Br2
C C Br
+ Br2 No Reaction
Benzene does not undergo electrophilic
addition, but it undergoes electrophilic
aromatic substitution
H E
E A
+H A
(H substituted by E)
Mechanism
● Step 1
+ E E
E
slow
r.d.s.
E
B E
H
+ H B
fast
Br
Br2
+ HBr
FeCl3
heat
(75%)
(weak
electrophile)
Br + FeBr4
(very reactive
electrophile)
Mechanism (Cont’d)
Step 2
The benzene ring donates
an electron pair to the
terminal bromine, forming
the arenium ion and
neutralizing the formal
positive charge on the
Br
other bromine.
slow r.d.s.
Br Br Br
Mechanism (Cont’d)
Step 3
Br
Br FeBr3 Br
H + H Br
+ FeBr3
A proton is removed from the
(catalyst
arenium ion to form bromobenzene
regenerated)
and regenerate the catalyst.
F2: too reactive, gives a mixture of mono-,
di- and polysubstituted products
F2 F F F
Lewis F
acid
+ +
F + others
I2: very unreactive even in the presence of
Lewis acids; usually need to add an
2+
oxidizing agent (e.g. HNO3, Cu , H2O2)
e.g.
I
I2
(86%)
HNO3
I
I2
(65%)
CuCl2
4. Nitration of Benzene
Benzene undergoes nitration on reaction with a mixture of
concentrated nitric acid and concentrated sulfuric acid.
Concentrated sulfuric acid increases the rate of the reaction
by increasing the concentration of the electrophile, the
nitronium ion (NO2+), as shown in the first two steps of the
following mechanism.
NO2
conc. HNO3
+ H3O+
conc. H2SO4
50-55oC + HSO4
(85%)
Electrophile in this case is NO2 (nitronium ion)
Mechanism
In this step nitric
acid accepts a proton
O O from the stronger
HO S O H + HO N acid, sulfuric acid.
O O
NO2
H2O NO2
H + H3O+
Answer
The rate is dependent on the concentration of NO2+ ion formed
from protonated nitric acid.
Because H2SO4 (HOSO3H) is a stronger acid, a mixture of it and
HNO3 will contain a higher concentration of protonated nitric acid
than will nitric acid alone. That is, the reaction,
SO3 is protonated to O
form SO3H+ O S O H
O
● Step 2
H
O
S O O H
O O
S other
O + resonance
slow H structures
O O H
S O
fast
O S O H
H HSO4
O + H2SO4
25oC - 80oC
SO3H
dil. H2SO4
H2O, 100oC
6. Friedel–Crafts Alkylation
The following is a general equation for a Friedel–
Crafts alkylation reaction:
Electrophile in this case is R
● R = 2o or 3o
o
● or R ClAlCl3 (R = 1 )
Mechanism
Step 1
This mechanism is illustrated below using 2-chloropropane
and benzene.
The complex dissociates to
form a carbocation and AlCl4-.
Cl AlCl3 Cl AlCl3
+ AlCl4
Mechanism (Cont’d)
Step 2
Cl AlCl3
H
via
H+
OH
BF3
+
60oC
via H
O BF3
PRACTICE Problem 2.3
Outline all steps in a reasonable mechanism for the formation of
isopropylbenzene from propene and benzene in liquid HF. Your mechanism
must account for the product being isopropylbenzene, not propylbenzene.
7. Friedel–Crafts Acylation
O
The R C group is called an acyl group, and a reaction
whereby an acyl group is introduced into a compound is
called an acylation reaction.
Two common acyl groups are the acetyl group and the
benzoyl group. (The benzoyl group should not be
confused with the benzyl group, -CH2C6H5).
The Friedel–Crafts acylation reaction is often carried out by
treating the aromatic compound with an acyl halide (often an
acyl chloride). Unless the aromatic compound is one that is
highly reactive, the reaction requires the addition of at least one
equivalent of a Lewis acid (such as AlCl3) as well. The product
of the reaction is an aryl ketone:
Acyl chlorides, also called acid chlorides, are easily
prepared by treating carboxylic acids with thionyl chloride
(SOCl2) or phosphorus pentachloride (PCl5):
Friedel–Crafts acylations can also be carried out using
carboxylic acid anhydrides. For example,
O AlCl3 R
+
R Cl 80oC
Electrophile in this case is R–C≡O (acylium ion)
Mechanism
In most Friedel–Crafts acylations the electrophile appears to be an
acylium ion formed from an acyl halide in the following way:
O O
+ AlCl3 R C Cl AlCl3
R Cl
AlCl4 + R C O R C O
Mechanism (Cont’d)
R C O
O O O
R R R
Mechanism (Cont’d)
O O
R
Cl AlCl3 R
H
● Can be prepared by
SOCl2
O O
C or C
R OH R Cl
PCl5
Solved Problem 2.1
Show how an acylium ion could be formed from acetic anhydride
in the presence of AlCl3.
AlCl3
(How is this
formed?)
Reason 1o cation (not stable)
H
Cl + AlCl + AlCl4
3
1,2-hydride
shift
H 3o cation
(more
stable)
When benzene is alkylated with butyl bromide, for example, some of
the developing butyl cations rearrange by a hydride shift. Some of the
developing 1o carbocations (see following reactions) become more
stable 2o carbocations. Then benzene reacts with both kinds of
carbocations to form both butylbenzene and secbutylbenzene:
Friedel–Crafts reactions usually give poor yields
when powerful electron-withdrawing groups are
present on the aromatic ring or when the ring
bears an –NH2, –NHR, or –NR2 group. This applies
to both alkylations and acylations.
O OH O R
NO2 N(CH3)3 CF3 SO3H NH2
>
>
>
>
>
>
These usually give poor yields
in Friedel-Crafts reactions
The amino groups, –NH2, –NHR, and –NR2, are
changed into powerful electron-withdrawing
groups by the Lewis acids used to catalyze Friedel-
Crafts reactions
H
H H
N H N AlCl3
>
+ AlCl3
Cl , AlCl 3 No Friedel-Crafts
reaction
Polyalkylations often occur
OH BF3
+ +
60oC
(24%) (14%)
Solved Problem 2.2
When benzene reacts with 1-chloro-2,2-dimethylpropane (neopentyl chloride) in
the presence of aluminum chloride, the major product is 2-methyl-2-
phenylbutane, not 2,2-dimethyl-1-phenylpropane (neopentylbenzene). Explain
this result.
Answer
9. Synthetic Applications of Friedel-Crafts
Acylations: The Clemmensen Reduction
& Wolff–Kishner Reductions
R [H] R
9A. The Clemmensen Reduction
One general method for reducing a ketone to a methylene
group—called the Clemmensen reduction—consists of
refluxing the ketone with hydrochloric acid containing
amalgamated zinc.
O
R Zn/Hg R
HCl
reflux
Clemmensen reduction of ketones
● A very useful reaction for making
alkyl benzenes that cannot be made
via Friedel-Crafts alkylations
e.g.
?
Clemmensen reduction of ketones
● Cannot use Friedel-Crafts alkylation
Cl
gives
AlCl3
but
NOT
Rearrangements of carbon chains do
not occur in Friedel-Crafts acylations
O
O AlCl3 R
+
R Cl 80oC
(no rearrangement
of the R group)
O
O Zn/Hg
conc. HCl
Cl
reflux
AlCl3
9B. The Wolff–Kishner Reduction
Another method for reducing a ketone to a methylene group is
the Wolff–Kishner reduction, which involves heating the ketone
with hydrazine and base.
The Wolff–Kishner reduction complements the Clemmensen
reduction in that it is conducted under basic conditions, whereas
the Clemmensen reduction involves acidic conditions.
The Wolff–Kishner reduction proceeds via a hydrazone
intermediate that is not isolated during the reaction.
Ethyl phenyl ketone can be reduced to propylbenzene by the
Wolff–Kishner reduction as follows, for example.
9B. The Wolff–Kishner Reduction
NH2
O N
NH2NH2, KOH
heat
Hydrazone intermediate
H2O + N2 +
(82%)
Practice Problem 2.5
Starting with benzene and the appropriate acyl chloride or
acid anhydride, outline a synthesis of each of the following:
Answer:
10. Substituents Can Affect Both the
Reactivity of the Ring and the
Orientation of the Incoming Group
E
faster or slower than
E
E
E
E
(ortho) (meta) (para)
(o) (m) ( p)
Electrophilic
reagent Arenium
A substituted ion
benzene
Z donates Y withdraws
electrons electrons
Z Y
>
>
The ring is more The ring is electron
electron rich and poor and reacts
reacts faster with more slowly with
an electrophile an electrophile
● Reactivity
Since electrophilic aromatic substitution is
electrophilic in nature, and the rate
determining step (r.d.s.) is the attack of an
electrophile (E ) with the benzene -electrons,
an increase in e⊖ density in the benzene ring
will increase the reactivity of the aromatic ring
towards attack of an electrophile, and result in
a faster reaction.
● Reactivity
⊖
On the other hand, a decrease in e
density in the benzene ring will decrease
the reactivity of the aromatic ring towards
the attack of an electrophile, and result in
a slower reaction.
● Reactivity
Substituent
–EDG
Increasing activity
–H
–EWG
● Reactivity
EDG (electron-donating group) on
benzene ring
Increases electron density in the benzene ring
More reactive towards electrophilic aromatic
substitution
● Reactivity
EWG (electron-withdrawing group) on
benzene ring
Decreases electron density in the
benzene ring
Less reactive towards electrophilic
aromatic substitution
● Reactivity towards electrophilic
aromatic substitution
EDG EWG
> >
Regiochemistry: directing effect
● General aspects
Either o-, p- directing or m-
directing
Rate-determining step is -
electrons on the benzene ring
attacking an electrophile (E )
Y
o r t ho
attack
Y Y Y
E E E
o -I o -II o -III
Y
met a
attack
Y Y Y
E E E
m -I m -II m -III
Y
p ar a
attack
Y Y Y
p -I p -II p -III
E E E
If you look at these Y
resonance structures
E
closely, you will notice that
for ortho- or para- o-I
substitution, each has one
resonance form with the
positive charge attached to Y
the carbon that directly
attached to the substituent
Y (o-I and p-II)
p-II
E
When Y = EWG, these resonance
forms (o-I and p-II) are highly unstable
and unfavorable, thus not favoring the
formation of o- and p- regioisomers,
and m- product will form preferentially
On the other hand, if Y = EDG, these
resonance forms (o-I and p-II) are
extra-stable (due to resonance effect
or positive inductive effect of Y), thus
favoring the formation of o- and p-
regioisomers
Classification of different substituents
Y
Y (EDG)
–NH2, –NR2 Strongly o-, p-
–OH, –O
activating directing
–NHCOR Moderately o-, p-
–OR activating directing
–R (alkyl) Weakly o-, p-
–Ph activating directing
–H NA NA
Classification of different substituents
Y
Y (EWG)
G G G
>
>
>
+ E
H E H E
O
C Deactivate the ring by the
CH3
e.g. resonance effect
F
>
E
(EWG ≠ halogen)
E
(major)
NO2
(ortho)
CF3
-H
(highly unstable due to
NO2 the negative inductive
(ortho)
(not favorable)
effect of –CF3)
CF3 (highly unstable due to negative
inductive effect of –CF3)
NO2 -H
(para)
(para)
(not favorable) NO2
CF3
(positive charge never
attaches to the carbon
NO2 directly attached to the
(meta) EWG: –CF3) relatively
more favorable
CF3 CF3 CF3
-H
(relatively more (meta)
favorable than o-, p- products) NO2
11D. Ortho/Para-Directing Groups
EDG EDG EDG
E
E
+
E
ortho para
(major)
NO2
(ortho)
OCH3
NO2 (extra resonance
-H
structure due to
(ortho)
(favorable)
positive mesomeric
effect of –OCH3)
OCH3 OCH3 OCH3
(para)
NO2 - H+
OCH3
NO2
(para)
NO2 (favorable)
NO2
For halogens, two opposing effects
Cl Cl
>
NO2
(ortho)
Cl Cl Cl Cl
NO2 NO2 NO2 NO2
Cl
NO2 (extra resonance
-H
structure due to
(ortho) resonance effect of
(favorable)
–Cl)
Cl Cl Cl
(para)
NO2 -H
NO2 NO2 NO2
Cl Cl
Cl
NO2
(para)
NO2 (favorable)
NO2
11E. Ortho/Para Direction and
Reactivity of Alkylbenzenes
R R R
>
>
>
+ E
H E H E
Relatively
E
stable
contributor
CH3 CH3 CH3
>
E E E
Meta attack CH3
E E E
CH3
Para attack
Relatively
stable
E
contributor
CH3 CH3 CH3
>
E E E
11F. Summary of Substituent Effects
on Orientation and Reactivity
Y Y (EDG)
–NH2, –NR2 Strongly o-, p-
–OH, –O
activating directing
–COOR, –COR,
Moderately m-
–CHO, –COOH,
deactivating directing
–SO3H, –CN
CH3
- RH
C C C C
- LG
A benzyl
cation
C C C C
CCl3 CHCl2
Cl2
heat or
light
Mechanism
● Chain initiation
peroxides
X X 2X
heat or
light
● Chain propagation
H H
C6H5 C H + X C6H5 C + H X
H H
● Chain propagation
H H
C6H5 C + X X C6H5 C X +X
H H
● Chain termination
H H
C6H5 C + X C6H5 C X
H H
e.g.
CH3 NBS, ROOR or light
Br
O
Benzyl bromide
(–bromotoluene)
NBS is N Br (64%)
Br NaOEt OEt
EtOH
(not observed)
- Ha
Ha Hb
- Hb
13B. Additions to the Double Bond of
Alkenylbenzenes
HBr
RO OR Br
heat
Br
HBr
(no
peroxides)
Mechanism (top reaction)
RO OR 2 RO
RO + H Br Br + RO H
Br
Br
+ Br
(more stable (less stable)
benzylic radical)
+ H Br
Br Br
Mechanism (bottom reaction)
H
Br
Br
13C. Oxidation of the Side Chain
O
CH3
1. KMnO4, HO-, OH
2. H3O+
(100%)
O
1. KMnO4, HO-, OH
2. H3O+
O
1. KMnO4, HO-, OH
2. H3O+
O
1. KMnO4, HO-, OH
2. H3O+
O O
1. KMnO4, HO-, OH
2. H3O+
Using hot alkaline KMnO4, alkyl,
alkenyl, alkynyl and acyl groups all
oxidized to –COOH group
For alkyl benzene, 3o alkyl groups resist
oxidation
1. KMnO4, HO-,
No Reaction
2. H3O+
1. O3, CH3CO2H O
R R
2. H2O2 OH
14. Synthetic Applications
CH3
How?
NO2
CH3 group: ortho-, para-directing
NO2 group: meta-directing
CH3 CH3
CH3
NO2
+
If the order is reversed the wrong
regioisomer is produced
CH3
conc. HNO3 CH3Cl
conc. H2SO4 AlCl3
heat
NO2 NO2
CH3
NOT
NO2
COOH
NO2
We do not know how to substitute a
hydrogen on a benzene ring with a
–COOH group. However, side chain
oxidation of alkylbenzene could provide
the –COOH group
Both the –COOH group and the NO2
group are meta-directing
Route 1
CH3
COOH
1. KMnO4, HO-,
2. H3O+
NO2
Route 2
CH3 COO
H
CH3Cl 1. KMnO4, HO-,
AlCl3 2. H3O+
COOH
conc. HNO3
conc. H2SO4
NO2 heat
Which synthetic route is better?
● Recall “Limitations of Friedel-Crafts
Reactions, Section 15.8”
Friedel–Crafts reactions usually give
poor yields when powerful electron-
withdrawing groups are present on
the aromatic ring or when the ring
bears an –NH2, –NHR, or –NR2
group. This applies to both
alkylations and acylations
Route 2 is a better route
Br
Cl
AlCl3 Br2
FeBr3
O
Br Br
Zn/Hg
HCl, heat
O
14A. Use of Protecting and Blocking
Groups
Protected amino groups
● Example
NH2 NH2
?
Br
Problem
Not a selective synthesis, o- and p-
products + dibrominated and
tribrominated products will form
NH2 NH2 NH2
Br2
+
Br Br
Br
NH2
+ + others
Br Br
Solution
Introduce a deactivating group on
–NH2
O H
NH2 N O
CH3 Cl
pyridine CH3
(an amide)
The amide group is less activating than
–NH2 group
● No problem for over bromination
Br
O
1. H2SO4,
(hydrolysis
Cl H2O,
of amide)
pyridine 2. HO-
NHCOCH3 NHCOCH3
Br2, FeBr3
Br
NH2 NH2
Br
Problem
Difficult to get o-product without
getting p-product
Over nitration
Solution
Use of a –SO3H blocking group at the
p-position which can be removed later
NH2 NH2
NO2
O
1. dil. H2SO4
Cl 100oC
pyridine 2. HO-
SO3 HNO3
conc. H2SO4 SO3H H2SO4 SO3H NO2
60oC
14B. Orientation in Disubstituted
Benzenes
Directing effect of EDG usually
outweighs that of EWG
CF3 CF3
Br
Substitution does not occur to an
appreciable extent between meta-
substituents if another position is open
Cl Cl Cl Cl
X O2N NO2
HNO3
+ +
H2SO4
Br Br Br Br
NO2
62% 37% 1%
NHCOCH3 NHCOCH3
NO2
(iii)
COOMe COOMe
NO2
NHCOCH3
O 2N
COOMe
OCH3
CH3
Cl
(iv)
OCH3 OCH3
CH3 Cl CH3
+
Cl
Cl
Br
(v)
NO2
Cl Cl
Br
+
NO2 NO2
Br
15. Allylic and Benzylic Halides in
Nucleophilic Substitution
Reactions
R R'
H R
CH2X C C
X X
C C C C C C
H H R
Ar C X Ar C X Ar C X
H R R'
1o Benzylic 2o Benzylic 3o Benzylic
A Summary of Alkyl, Allylic, & Benzylic
Halides in SN Reactions
● These halides give mainly SN2
reactions:
H3C X R CH2 X R CH X
R'
H2/Ni H2/Ni
+
slow fast
benzene cyclohexadienes cyclohexene
H2/Ni
fast
cyclohexane
16A. The Birch Reduction
Na
NH3, EtOH
benzene 1,4-cyclohexadiene
Mechanism
Na
etc.
benzene benzene radical anion
EtOH
Na
H H etc.
H H
cyclohexadienyl radical
H
EtOH
H H etc. H H
H H H
cyclohexadienyl anion 1,4-cyclohexadiene
Synthesis of 2-cyclohexenones
OCH3 OCH3
Li
liq. NH3
EtOH (84%)
H3O+
H2O
O
2-cyclohexenone