CHEM 4113 ORGANIC CHEMISTRY II LECTURE NOTES 1

CHAPTER 16
1. Aromatic Electrophilic Substitution

Aromatic compounds are electron rich species ( 6 -electrons in the aromatic ring).
Nonetheless, they do not undergo standard electrophilic addition similar to alkenes because to do so
would permanently disrupt the aromaticity of the ring. However, aromatic compounds do undergo
reaction with certain potent electrophiles, but by an Aromatic Electrophilic Substitution mechanism.

E
The resonance stabilized cation produced when an
electrophile adds to benzene is much more stable than
E one produced by electrophilic addition to an alkene.
N H E However, it is much less stable than benzene itself.
E Thus, electrophilic attack on a benzene has a high
R activation energy, and is therefore rather slow.
G The benzene reaction is slower because the starting
Y material is so much more stable.

Why benzene is much less reactive than alkenes

All Aromatic Electrophilic Substitution reactions have the same basic three steps:
1. Generation of the electrophilic species. A catalyst (usually a powerful Lewis Acid
such as AlCl3 ) is required to generate the electrophilic reacting species.
2. Attack of the -electrons of the aryl ring on the electrophile, with formation of a
resonance stabilized cation. This step is reminiscent of electrophilic addition to an
alkene. The carbocation intermediate is greatly stabilized by resonance delocalization.
Nonetheless, this is a high energy step because of the disruption of the aromaticity of
the ring.
3. Loss of a proton from the cation intermediate at the site of substitution to regenerate an
aromatic ring.
 2
H H E H E H
C E+ C C C E
HC CH HC H HC H HC H
HC CH HC CH HC CH HC CH
C C C C
H H H H
E+ is an electron- RESONANCE STABILIZED CATION
defficient species

H
C E
HC C Loss of H+ E
HC CH from tetrahedral
C
H H
carbon regenerates
Substitution
Product Aromaticity orbitals of delocalized
intermediate

General Mechanism of Electrophilic Aromatic Substitution

H H H +H
E E E E
+ +

Resonance Hybrid
Contributing Resonance Structures

Resonance stabilized arenonium ion.

a. Specific Examples of Aromatic Electrophilic Substitution

Many different substituents can be introduced onto the ring by this process. Halogenation,
nitration, sulfonation, acylation and alkylation can be carried out with the proper choice of reagents
and conditions.

1. Halogenation. Br 2 , Cl 2 and I2 are all, by themselves, unreactive toward aromatic rings,

and a promoter or catalyst are required to obtain a suitable reaction. In all three cases, a Lewis
Acid such as FeBr3 , AlCl3 or CuCl2 will promote electrophilic addition to the ring. The
complexed halogen molecule is then attacked by nucleophilic aromatic ring in a slow, rated
determining step.
 3
Generation of halogen electrophile

Br Br + FeBr3 Br Br FeBr3
Lewis Actual reagent - Weakened
Acid bond between two bromines.
Catalyst Potent electrophile.

H Br
C
HC C H
Br Br FeBr3 + FeBr4-
HC CH
C
H

Br
FeBr3 + HBr +
Catalyst
regenerated

Electrophilic Halogenation

2. Nitration and Sulfonylation. Benzene reacts with concentrated nitric acid (HNO3 ) in the
presence of sulfuric acid (H2 SO4 ) catalyst. The electrophile in this reaction is the nitronium
ion (NO2 +), which is generated by protonation of HNO3 (sulfuric acid is about 103 stronger
acid) and subsequent loss of water. The nitronium ion adds to the benzene ring to form a
carbocation intermediate, which then loses a proton to regenerate the aromatic ring.

Another electrophilic substitution reaction of benzene is conversion to a sulfonic acid by a

solution of sulfur trioxide (SO3 ) and sulfuric acid (called fuming sulfuric acid). The central
sulfur atom of sulfur trioxide is extremely electron defficient and is thus a very potent
electrophile.

O O
H2SO4
H O N H O N O N O + H2O
Catalyst
O H O
Nitronium ion
Potent electrophile
O
H NO2
C Additional
N HC C H Resonance
O HC CH Forms
C
H
NO2
+ H20 + H+

Electrophilic Nitration
 4
O H O other
S H2SO4 S O resonance
O O structures
O
O
S OH
O Benzene sulfonic acid

Aromatic Sulfonation

3. Friedel-Crafts Acylation. When benzene reacts with an acid chloride in the presence of a
Lewis Acid catalyst, such as AlCl3 , a ketone is formed. In this reaction, an acyl group,
-C(=O)R, is introduced onto an aromatic ring, hence the term acylation. The electrophile is a
carbocation called an acylium ion (or acyl cation), which is formed when the acid chloride
reacts with the Lewis Acid.

Generation of acyl cation electrophile

O O O
AlCl3 AlCl4-
C C C
R Cl R R
Acyl Cation
O O
O H
C C C
C HC C H R -H+ R
R
HC CH
C
H
Intramolecular Acylation
A very useful variation of this reaction involves the intramolecular addition of acid
chlorides to benzene rings that a connected to the chain that bears the acid chloride.
AlCl3
C
Cl O C
O
Friedel-Crafts Acylation

4. Friedel-Crafts Alkylation. The reaction of an alkyl halide with benzene in the presence of
a Lewis Acid catalyst gives an alkylbenzene. The electrophile in a Friedel-Crafts alkylation is
formed by the complexation of the Lewis Acid (usually AlCl3) with the halogen of the alkyl
halide in much the same way that the electrophile in the halogenation of benzeneis formed.
Either the alkyl halide-Lewis Acid complex or the carbocation derived from it can serve as the
electrophile.
 5
Generation of carbonium ion electrophile

Cl NOTE: In some cases

AlCl3 rearrangements of the
R C R R C R AlCl4- initially formed carbonium
R R ion my occur to give isomeric
R = Alkyl or H carbonium alkylation products
promary, secondary ion
or tertiary
H
C CR3 CR3
HC C H -H+
R C R
HC CH
R C
H Alkyl group makes this product
morereactive than benzene
NOTE: In order to minimize the formation of poly-alkylated products this reaction
is usually run using a large excess of benzene, such that the electrophile is more likely
to encounter the benzene rather than the initially formed product.

Friedel-Crafts Alkylation

1. Polysubstitution- The product from alkylation is more reactive than the reactant
CH2CH3
CH3CH2Br
AlCl3 / 0˚C
less more
reactive reactive
2. Rearrangement- The initial carbocation electrophile will rearrange, if possible,
and the rearranged carbocation will lead to the major product.
CH CH CH
2 2 3 CH(CH3)3
CH3CH2CH2Br
+
AlCl3 / 0˚C
expected product rearranged product
30% 70%
3. Reactivity- The ring must be as reactive as a halobenzene.
NO2

CH3CH2Br
NO REACTION
AlCl3 / 0˚C
4. Amines- The ring must not contain an amine which will react with the catalyst to
form a stable salt which is unreactive.
NH2 Cl3Al NH2
AlCl3

Limitations of the F-C Alkylation Reaction

b. Regiochemistry of Electrophilic Aromatic Substitution on Substituted Benzenes.

The 5 ring positions of monosubstituted benzenes are not equally reactive. The ring
substituent determines (a) the orientation of the second substituent (either ortho, meta or para) and (b)
the reactivity of the ring towards substitution ( and hence the rate of reaction).
 6
Substituent Name Directing Activating (A)
Group of Group Effect Deactivating (D)

NH2 NR2 amino ortho, para A

D A
E C
OH hydroxy ortho, para A C T
R I
E V
OR alkoxy ortho, para A A A
S T
O I I
NH C acylamino ortho, para A
N O
R G N
R alkyl ortho, para A

X (X = F,Cl,Br,I) halogens ortho, para D

D
O D E
C acyl meta D E A
R C C
O O R T
C C carboxy, carboxamido meta D E I
OH NH2 A V
O S
C carboalkoxy meta D A
I T
OR N I
SO3H sulfonic acid meta D G O
N
CN cyano meta D

NO2 nitro meta D

Directing and Activating Groups in Electrophilic Substitution

A substituent exerts a directing effect because of kinetic control of the reaction. The
intermediate with the lowest energy transition state is formed in the greatest amount (the Hammond
Postlulate tells us that the TS resembles the intermediate). Thus we can evaluate the relative energies
of the various intermediates (i.e. o,p vs m) and predict that the ones with the lowest energy will be
formed in the greatest yields.

1. O, P DIRECTORS. An electron donating group (DG) will stabilize the intermediate which
gives a + charge directly at the ring carbon to which the DG group is attached. Thus electron
donors are o,p directors because substitution at the ortho or para position will lead to an
intermediate with a + charge at the DG position. Electron donating groups are (a) those with
an unshared pair of electrons on the atom bonded to the ring, which can be delocalized into the
ring; or, (b) those without an unshared pair which are electron donating by induction or
hyperconjugation. Because o,p directors help to stabilize the + charge formed by electrophilic
addition, they are activating, that is they will react faster than benzene. The one exception is
seen with the halogens, which are o,p-directors but deactivating.

2. META DIRECTORS. An electron withdrawing group (WG) will destabilize the

intermediate which gives a + charge directly at the ring carbon to which the WG is attached.
 This will result in meta substitution, since the intermediate for meta substitution will not have a 7
+ charge at the ring carbon bearing the WG. Because all meta directors destabilize the +
charge of the intermediate, they are without exception deactivating, that is they all react more
slowly than benzene
DG (Donor Group) is a group that can stabilize a positive charge. This includes atoms that
can supply electrons via resonance (oxygen, nitrogen, sulfur). It also includes alkyl and aryl
groups that are inductively electron-releasing.
ORTHO SUBSTITUTION

DG DG DG DG DG
E C E C E C E
HC
C
CH E+ HC C C HC C H HC C H HC C H
H
HC CH HC CH HC CH HC CH HC CH
C C C C C
H H H H H
R-1 R-2 R-3 R-4
Ortho Substitution allows the Donor Group (DG) to provide an additional
measure of stability via the resonance structure R-4.
PARA SUBSTITUTION

H H H H H
C E E C E C E
C +
E C HC C H
HC CH HC C H HC C H HC C H
C CH C CH C CH C CH C CH
DG C DG C DG C DG C DG C
H H H H H
R-5 R-6 R-7 R-8
Substitution para to thedonor group also gives four important resonance
forms. (Form R-8 being the form that takes advantage of the lone-pair
electrons or the donor group.)
META SUBSTITUTION
H H H H
+ DG C E DG C E DG C E
DG C E C C H C C H
C CH C C H
C CH HC CH HC CH HC CH
C C C C
H H H H
R-9 R-10 R-11
Substitution meta to the donor group gives three of the standard
resonance forms, but in no case can the lone-pair of the donor
group be involved in any form of stabilization.

Electrophilic Aromatic Substitution of Donor Substituted Arenes

 DG DG DG DG
8
E
E+
H + E +
H
H E
Addition of an electrophile to a Donor substituted benzene can lead to three different
products: ortho, meta and para. Substitution ortho or para to the Donor group result
in intermediates with additional resonance stabilization that substitution at the meta
position does not have. As a result, the ortho and para substitution products are formed
at a faster rate than meta and they predominate in the product mixture. However, any
Donor Substituted arene will react faster than benzene; even at the meta position.

E
N Meta substitution has a higher energy
E intermediate due to less resonance stabilization
R
G Ortho, Para substitution leads to a more
Y stable, lower energy intermediate

reaction coordinate

Directing Effects of Donor Substituents on Electrophilic Substitution

c. Electrophilic Aromatic Substitution on Disubstituted Benzenes.

Further electrophilic substitution of a disubstituted benzene is governed by the same resonance

and inductive effects discussed for monosubstitution. However, it is now necessary to consider the
additive effects of the two different substituents present. The following are rules for predicting the
orientation of incomming groups in disubstituted benzenes.

1. If the groups reinforce one another, the orientation can be predicted by either group.

2. If an o,p-director and m-director are not reinforcing, the o,p-director controls the
orientation. The incomming group goes mainly ortho to the m-director

3. A strongly activating group competing with a weakly activating group controls the
orientation.

4. When two weakly activating or deactivating groups, or two strongly activating or

deactivating groups compete, substantial amounts of both isomers are obtained; there
is little preference.

5. Very little substitution occurs in the sterically hindered position between meta
substituents.

6. Very little substitution occursin the sterically hindered position ortho to a bulky o,p-
director such as a t-butyl group.
 9
CH3 CH3 CH3
Br2
+
FeBr3
CH3 CH3 CH3
major product minor product (very little)
rule 1 rule 5
CH3 CH3
Br2
FeBr3

OCH3 NO2
only product
rule 1
Cl Cl Cl
Br2
FeBr3
NO2 NO2 NO2
major product
rule 2

CH3 CH3 weak

Br2 rule 3
FeBr3

OCH3 OCH3 strong

Orientation Effects in Disubstituted Benzenes

d. Organic Synthesis Using Electrophilic Aromatic Substitution.

When proposing synthesis that are based upon electrophilic aromatic substitution, it is
important to introduce the target substituents in an order such that their activating/directing tendencies
are synergistic rather than opposed. In the synthesis of disubstituted benzenes, the first substituent
present determines the incoming second. The order of introducing substituents must be carefully
planned to yield the desired product

1. If two substituents are o,p-director and m-director and they have an ortho or para
orientation, it is necessary to introdue the o,p-director first.

2. If two substituents are o,p-director and m-director and they have and they have a meta
orientation, add the m-director first.

3. If the two substituents are meta directors and they have an ortho or para orientation,
one of the meta directors has been formed from an ortho, para directing substituent.

4. If the two substituents are o,p-directors and they have a meta orientation, one of the
substituents has been formed from a meta director.
 CH3 10

CH3Cl HNO3 CH3Cl HNO3

AlCl3 H2SO4 AlCl3 H2SO4

NO2
Incorrect Order- adding the NO2 group
first would result in meta orientation
Cl
Cl2 HNO3 Cl2 HNO3
AlCl3 H2SO4 AlCl3 H2SO4

NO2
Incorrect Order - adding the Cl group
first would result in o,p orientation

Electrophilic Aromatic Substitution in Synthesis

2. Nucleophilic Aromatic Substitution (Addition-Elimination).

Simple aryl halides do not undergo nucleophilic substitution by either SN1 or SN2 processes.
For S N1 to occur, ionization of the benzene-halogen bond would produce an unstable aryl
carbocation; where the empty sp2 orbital would be perpendicular to the orbitals of the benzene ring.
No overlap is possible in such a case, therefore no stabilization occurs. For SN2 to occur, backside
attack would require the nucleophile to attack from within the ring...this is impossible.

Ionization of C-X bond

SN1 leads to unstable cation
X Process unlikely.
ionization
of C-X bond

Nuc

Backside attack of
SN2 nucleophile is prevented
X Nuc by steric hindrance
"Backside"
attack Process impossible.

Simple Nucleophilic Substitution on Aryl Halides

While simple aryl halides are unreactive toward nucleophilic substitutionas described above,
certain aryl halides bearing electron-withdrawing groups which are ortho or para to the halide leaving
group undergo a special kind of substitution reaction. This reaction is called a nucleophilic aromatic
substitution and occurs via an addition-elimination mechanism.

Electron-withdrawing groups positioned at the ortho/para positions greatly stabilize the

negative charge of the anionic intermediate formed when the nucleophile adds to the -system of the
arene. Thus groups such as -NO2 and-CN, which are deactivators toward electrophilic attack,
encourage nucleophilic attack. Once the stabilized benzenanion has formed, the aromatic ring is
regenerated by loss of a leaving group. Halide anions are good leaving groups, although a hydride
can be displaced from a suitably substituted benzene. The greater the number of electron-withdrawing 11
groups ortho/para to the leaving group, the more rapid the reaction and less vigorous condition.

Cl

NaOCH3 NO REACTION
Rate = 0
Cl OCH3
In electrophilic aromatic substitution, the
NaOCH3 nitrogroup is the most powerful deactivator,
Rate = 1 but in nucleophilic aromatic substitution it is
the most powerful activating function
NO2 NO2
Cl OCH3
NO2 NO2
NaOCH3
Rate = 106
NO2 NO2
Nucleophilic Aromatic Substitution

OCH3 OCH3
-
O2N Cl + OCH3 O2N O2N
Cl Cl
Addition
NO2 NO2 NO2
other resonance structures delocalize
negative charge onto nitro groups

- Cl - Elimination
O2N OCH3

NO2

- OCH3
OCH3
O2N Cl O2N
Cl
NO2 NO2

Mechanism of Nucleophilic Aromatic Substitution

3. Substitution Involving Benzyne (Elimination-Addition).

A second special mechanism for synthesis of substituted benzene occurs in the presence of a
strong base. This reaction occurs via the intermediacy of a species which has the benzene ring intact
as well as having a "triple bond". It is called Benzyne and is so reactive that it is rapidly converted to
products at all temperatures above absolute sero. The mechanism of Benzyne formation is
conceptualy similar to alkene formation by E2 processes. With very strong bases,such as amide
NH 2 -, the proton ortho to a halide is abstracted by the base. The pair of electrons from the C-H bond
left behind then form a " -bond" causing the loss of a halide leaving group. The new Benzyne 12
appears to have a triple bond in the ring. The Benzyne can then undergo addition reactions.

C Cl NaOCH3 C H2O C OH C H
+
C THF C C C
H H OH
CH3 Elimination CH3 Addition CH3 CH3
Benzyne No specific regiochemistry
MECHANISM

1st Elimination step

C Cl -
C Cl -Cl- C
OCH3
C C C
H
CH3 CH3 CH3 H3C
nd
2 Addition step

C C OH2 C
OH2 C + C
C OH2
CH3 CH3 CH3

C OH C H
C C
H OH
CH3 CH3
Substitution via Benzyne Intermediate

4. Reduction of the Aromatic Ring.

Benzene and its derivatives are stabilized by resonance; benzene is very resistant to the
catalytic hydrogenation of its double bonds. High temperatures and pressures of H2 , and/or a highly
specific transition-metal catalyst are required. During this process the benzene ring is reduced
completely to a cyclohexane ring. It is impossible to stop the catalytic hydrogenation of benzene at the
diene or alkene stage.
 13
H2, Pt/C H2, Pt/C H2, Pt/C
high temp high temp high temp
high pressure high pressure high pressure
VERY FAST FASTEST
SLOW

A particularly useful alternative to Pt, Pd and Ni hydrogenation catalyst is Rhodium

metal deposited on a carbon surface. Rh/C. This allows hydrogenation at low
temperatures and one atmosphere pressure of H2.

CH3 Rh/C CH3

1 atm. H
CH3 25˚C 2 CH3
Catalytic Hydrogenation of Benzene

a. Dissolving-Metal Reduction of Aromatic Rings (Birch Reduction).

Aromatic rings are difficult to reduce by catalytic hydrogenation, however, they are easy to
reduce by a dissolving-metal reduction process (remember the dissolving-metal reducton of alkynes).
Treatment of aromatic compounds with either Li or Na in a mixed NH3 /ethanol solvent leads to the
formation of 1,4-cyclohexadiene rings. Thus process is known as the Birch Reduction.

When a monosubstituted benzene is subjected to Birch Reduction, the regiochemistry of the

1,4-diene is determined by the type of substituent present on the ring. Electron donating groups will
form 1-substituted-1,4-cyclohexadienes, whereas electron withdrawing groups wil give 3-substituted-
1,4-cyclohexadienes.

Electron Donating Substituents Electron Withdrawing Substituents

CH3 CH3 CN CN

OCH3 OCH3 NO2 NO2

Regiochemistry of Birch Reduction

5. Side Chain Oxidations.

The aromatic ring of benzene is very stable to oxidation except under very vigorous
conditions. In fact, when an alkyl benzene is oxidized, the alkyl group is oxidized to an acid group, -
COOH, while the ring is left intact. The length of the chain does not matter, all carbons except the
one directly attached to the ring (which becomes the C or -COOH) will be lost. For this reaction to 14
succeed, there must be at least one H atom on the C attached to the ring.

CH3
CH CH2CH3 COOH
KMnO4
H2O
100˚C, 24 h
CH3 COOH
CrO3, H2SO4
100˚, 48h

CH3 COOH

COOH
Mn or Cr
forcing
conditions COOH

C(CH3)3
Mn or Cr
forcing NO REACTION
No Hydrogen conditions

Side Chain Oxidation of Alkylbenzenes

6. Benzylic Brominations.

The considerable stability afforded to cations, anions or radicals situated on a carbon directly
attached to the ring ( i.e. the benzylic position) is a function of the ability of these benzylic
intermediates to delocalize charge into the benzene ring through resonance. Thus benzylic carbons are
similar to allylic carbons and can undergo similar reactions, in particular they can be selectively
brominated through the use of N-Bromosucinimide (NBS).

Benzyl cation,radical or anion (* denotes +, - or )

* CH2 CH2 CH2 CH2

* *

CH2 Planar array of -orbitals for

the delocalized intermediate

Resonance Structures of Benzyl Intermediates

 15
O heat, light O
and/or
H2C C peroxides H2C C
N Br N + Br
H2C C CCl4 H2C C
O O

H H
H C
C
H Br H + HBr

benzyl radical-resonance stabilized

O O
H2C C H2C C
N Br + HBr N H + Br2
H2C C H2C C
O O
H H Br
C C
+ Br2
H H + Br

Benzylic Bromination with NBS