Chapter 22

Reaction of Benzene and its Derivatives

22-1

Reactions of Benzene
Substitution
Halogenation: H + Cl 2 Fe Cl 3 Cl + HCl Chlorobe nzene Nitration: H + HN O 3 H2 SO 4 N O2 + H2 O Nitrobenzen e

at a ring carbon.
Contrast to radical mechanism for benzylic hyrdogens

22-2

Reactions of Benzene
Sulfonation: H + SO 3 H 2 SO 4 SO 3 H

Benzenesulfonic acid Alk ylation : Friedel Crafts H + RX A lX3 R + HX An alk ylbenzene Acylation: Friedel Crafts O A lX3 H + RCX O CR + HX An acylbenze ne
22-3

Electrophilic Aromatic Substitution

Electrophilic

aromatic substitution:
E

+ E

+ H

We

study several common electrophiles

how each is generated. the mechanism by which each replaces hydrogen.

22-4

EAS: General Mechanism

A

general mechanism
Step 1: H + E
+

s low , rate determin ing

Electrophile + Step 2: H E
fast

E Res on ance-s tabilized cation intermed iate

+ E + H

General

question: What are the electrophiles and how are they generated? Look at particular reactions.
22-5

Chlorination
Step 1: Generation of the electrophile: a chloronium ion.
Cl Cl
+

Cl Fe Cl Cl

Cl

Cl

Cl Fe Cl

Cl Fe Cl 4 An ion pair containing a chloronium ion

Chlorine Ferric chloride (a Lewis (a Lewis bas e) acid)

Cl A molecular complex with a positive charge on chlorine

Step 2: Attack of the chloronium ion on the ring.

+ Cl slow , rate determining + H + Cl + Resonan ce-stab ilized cation in termediate; th e positive charge is delocalized onto three atoms of the ring22-6 Cl Cl H H

Chlorination
Step 3: Proton ejection regenerates the aromatic character of the ring.
+

H Cl

Cl-FeCl3

fast

Cl + HCl + FeCl3 Chlorob enzene

Cation intermediate

22-7

Addition vs Substitution
Energy

diagram for the bromination of benzene.

22-8

Nitration (Nitric and Sulfuric Acids)

Generation

of the nitronium ion, NO2+

O HSO4 + H O O N H O Conjugate acid of nitric acid

Step 1: Proton transfer to nitric acid.

HSO3 O H + H O N O Sulfuric acid Nitric acid

Step 2: Loss of H2O gives the nitronium ion, a very strong electrophile. Dehydrated nitric acid.
H H O O N O H H O + O N O The nitronium ion

22-9

Nitration,
Attack of electrophile as before..
Step 1: Attack of the nitronium ion) on the aromatic ring.
H + + O N O N O2 + H N O2

H +

N O2

+ Resonance-stabilized cation interme diate

Step 2: Proton transfer regenerates the aromatic ring.

H O H + NO2 + NO2 +

H O H H

22-10

Synthesis, Nitro Amines

The

nitro group can be reduced to a 1 amino group.

COOH + 3 H2 NO2 4-N itroben zoic acid Ni (3 atm) COOH + 2 H2 O

NH2 4-Aminoben zoic acid

Notice the carboxylic was untouched.

22-11

Sulfonation
Carried

out using concentrated sulfuric acid containing dissolved sulfur trioxide.

+ SO3 Benzene H2 SO4 SO3 H Benzenesulfonic acid

22-12

Friedel-Crafts Alkylation
Friedel-Crafts

alkylation forms a new C-C bond between an aromatic ring and an alkyl group.
+ Benzene Cl AlCl3 + HCl

2-Chloropropane Cumene (Isoprop yl chlorid e) (Isopropylbenzen e)

22-13

Friedel-Crafts Alkylation
Step 1: Formation of an alkyl cation as an ion pair.
R Cl
+

Cl Al Cl Cl

Cl R Cl Al Cl
+

R+ AlCl4 An ion pair containing a carbocation

Cl A molecular complex
+

Step 2: Attack of the alkyl cation.

+ R+ H R + H R + H R

A resonance-stabilized cation

Step 3: Proton transfer regenerates the aromatic ring.

H R + Cl AlCl3 R + AlCl3 + HCl
22-14

Friedel-Crafts Alkylation
There

are four major limitations on Friedel-Crafts alkylations:

1. Carbocation rearrangements are common
+

Cl Is obutyl chloride

AlCl 3 tert- Butylbe nzene

+ HCl

Benzene

CH3 CH3 CHCH2 -Cl

+ AlCl3

Isobutyl chloride

CH3 + CH3 C-CH2 -Cl-AlCl3 H a molecular complex

CH3 CH3 C+ AlCl4 CH3 an ion pair

22-15

Friedel-Crafts Alkylation
2. F-C alkylation fails on benzene rings bearing one or more of these strongly electron-withdrawing groups.
Y + RX AlCl3 N o reacti on

Wh en Y Equ als A n y of Th es e G rou p s, th e Ben ze n e Ri ng D oe s N o t U n d ergo Fri ed el -Crafts A lk ylation O CH SO3 H CF3 O CR C N CCl3
22-16

O COH NO2

O COR NR3
+

O CNH2

Friedel-Crafts Alkylation
3. F-C multiple alkylation can occur more rapidly than monoalkylation. The first alkyl group activates the ring to the second substitution.

4. The steps in the Friedel Crafts Alkylation are reversible and rearrangments may occur.

22-17

Friedel-Crafts Acylation
Friedel-Crafts

acylation forms a new C-C bond between a benzene ring and an acyl group.
O O + CH3 CCl Benzen e Acetyl ch loride Cl O AlCl3 4-Phenylbutan oyl chlorid e -Tetralon e AlCl3 Acetop henone + HCl

O + HCl

22-18

Friedel-Crafts Acylation
The

electrophile is an acylium ion.

O R-C Cl

An acyl chloride

Cl + Al-Cl Cl Aluminum chloride

(1)

O + Cl (2) R-C Cl Al Cl Cl A molecular complex with a positive charge charge on chlorine

O R-C+ AlCl4A n ion pair containing an acylium ion

22-19

Friedel-Crafts Acylation
An acylium ion is represented as a resonance hybrid of two major contributing structures.
complete valen ce she lls + R-C O: The more important contributing structure

+ R-C

O:

Friedel-Crafts

acylations are free of major limitation of Friedel-Crafts alkylations; acylium ions do not rearrange, do not polyacylate (why?), do not rearrange.
22-20

Synthesis, Friedel-Crafts Acylation

preparation

of unrearranged alkylbenzenes.
O A lCl 3

+ Cl

2-Methylpropanoyl chloride

O N 2 H 4 , KOH diethylene glycol

2-Methyl-1phen yl-1-propan one

Is obutylbe nzene

What else could be used here? 22-21

Other Aromatic Alkylations

Carbocations

are generated by

treatment of an alkene with a proton acid, most commonly H2SO4, H3PO4, or HF/BF3.
CH3 CH=CH2 Prop ene H3 PO4 Cumene

+
Benzen e
+ Benzene

treating an alkene with a Lewis acid.

AlCl 3 Phenylcyclohexane

Cyclohexene

22-22

Other Aromatic Alkylations

and by treating an alcohol with H2SO4 or H3PO4.
+ Benzene HO H3 PO 4 + H2 O

2-Methyl-2-propanol (tert- Butyl alcohol)

2-Methyl-2phe nylpropan e (tert- Butylbe nzene )

22-23

Di- and Polysubstitution

Orientation

on nitration of monosubstituted
ortho + p ara 99 96 100 99 20 20 6.7

benzenes.
Su bstitu ent ortho
Favor ortho/para substitution

OCH3 CH3 Cl Br COOH CN NO2

44 58 70 37 18 19 6.4

meta 4 1 80 80 93.2

para 55 38 30 62 2 1 0.3

meta trace 4 trace 1 80 80 93.2

22-24

Favor meta substitution

Directivity of substituents

22-25

Di- and Polysubstitution

Two

ways to characterize the substituent

Orientation: Some 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 Some 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.
22-26

Di- and Polysubstitution

-OCH3 is ortho-para directing.
OCH3 + HNO3 CH3 COOH o -N itroanis ole (44%) OCH3 NO2 + OCH3 + H2 O NO2 p -N itroanis ole (55%)

An isole

-COOH is meta directing.

COOH + HNO3 Ben zoic acid H2 SO4 100C o- N itroben zoic acid (18%) COOH NO2 + NO2 m- N itroben zoic acid (80%) NO2 p- N itrobenzoic acid (2%) 22-27 COOH + COOH

Di- and Polysubstitution

Orth o-para Directing

Strongly activating Moderately activating We ak ly activating We ak ly deactivating

O N HCR R
: :

N H2
:

N HR O N HCAr
:

N R2 O OCR
:

OH
: :

OR

O OCAr

Recall the polysubstitution in FC alkylation.

: :

F:
:

Cl :

Br :

I: O COR

Meta Directin g

Moderately deactivating Strongly deactivating

O O O CH CR COH O CNH 2 SO 3 H N O2 N H3
+

C N CF3 CCl3

22-28

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.

22-29

Di- and Polysubstitution

The order of steps is important.
CH3 HNO3 H2 SO4 CH3 NO2 K2 Cr2 O7 H2 SO4 NO2 p -N itroben zoic acid COOH HNO3 H2 SO4 NO2 m -N itroben zoic acid COOH

COOH K2 Cr2 O7 H2 SO4

22-30

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.

22-31

Theory of Directing Effects

The

orientation is controlled by the stability of the carbocation being formed by attack of the electrophile.

Products

are formed under kinetic control.

22-32

Theory of Directing Effects, ortho-para director.

-OCH3: assume ortho-para attack. Here only para attack is shown.
o,p director
OCH3 OCH3

+ N O2 +
:OCH3

slow +
N O2 - H+

:OCH3

OCH3

: OCH3

+ +
H (d) N O2 H N O2 (e ) H (f) N O2

fast

+
H N O2 (g)

Very stable resonance structure. Why? 22-33

Theory of Directing Effects , ortho-para director.

-OCH3; look at meta attack.
OCH3 + N O2 OCH3 + H N O2 (a) + H N O2 (b)
+

o,p director
slow

OCH3

OCH3 fast H - H+ + N O2 (c)

OCH3

N O2

No corresponding resonance structure putting positive charge on oxygen. 22-34

Theory of Directing Effects, meta director.

-CO2H : assume ortho-para attack.
COOH + NO2 + slow

Meta director

COOH

COOH

COOH fast -H+

COOH

H NO2 (d)

H NO2 H NO2 (e) (f) The mos t disfavored contribu ting structu re

NO2

Disfavored because CO2H is electron withdrawing 22-35

Theory of Directing Effects, meta director.

-CO2H; assume meta attack.
COOH + NO2
+

Meta director
slow COOH H NO2 (b) (c) COOH H NO2 fast + -H COOH

COOH H NO2 (a)

NO2

22-36

Activating-Deactivating Resonance Effects

Any

resonance effect, such as that of -NH2, -OH, and -OR, that delocalizes the positive charge on the cation by 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.
22-37

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.
22-38

Activating-Deactivating: Halogens
For the halogens, the inductive and resonance effects oppose each other. Inductive is somewhat stronger. Result: halogens are deactivating but ortho-para directing.
+

:Cl

+ E

:Cl

H E

+ :Cl

H E

: :

: :

22-39

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.
Benzyne using strong base. Addition/elimination typically with nitro activating groups.

22-40

Benzyne Intermediates
When

heated under pressure with aqueous NaOH, chlorobenzene is converted to sodium phenoxide.
Neutralization with HCl gives phenol.
Cl + 2 NaOH Ch lorobenzen e H2 O press ure, 300oC O Na
+

+ NaCl + H2 O Sodium ph enoxide

22-41

Benzyne Intermediates (strong base)

The same reaction with 2-chlorotoluene gives a mixture of ortho- and meta-cresol.
CH3 Cl 1 . NaOH, heat, p res sure 2 . HCl, H2 O CH3 OH + CH3

OH 2-Meth ylp henol 3-Methylphen ol (o- Cresol) (m- Cresol)

The same type of reaction can be brought about using sodium amide in liquid ammonia.
CH3 + NaNH2 Cl NH3 (l) (-33 C)
o

CH3 +

CH3 + NaCl NH 2

NH2 4-Methylaniline 3-Methylanilin e (p-Toluid ine) (m -Toluidin e)

22-42

Benzyne Intermediates
-elimination of HX gives a benzyne intermediate, that then adds the nucleophile to give products.
CH3 NaNH2 H Cl -elimin ation A b enzyne intermediate CH3

22-43

Benzyne Intermediates
But wait, do we believe this crazy idea? We need some evidence.

22-44

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.

next

22-45

Benzyne Intermediates
explanation

22-46

Orientation
The

methyl group is essentially just a marker to allow the observation of the mixture of products. Consider the methoxy group, -OCH3, stabilizing of positive charge via resonance but also inductively withdrawing. The methoxy group is not in resonance with the negative charge of the anion, Inductive Effect dominates. Next slide.

22-47

Benzyne Intermediates
D

Get same product

Explation next

22-48

Benzyne Intermediates
explanation

22-49

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 NO2 Na2 CO3 , H2 O 100 C NO2 1-Ch loro-2,4dinitrobenzen e NO2 Sodiu m 2,4-din itroph enoxide
o

O Na NO2

Neutralization with HCl gives the phenol.

22-50

Meisenheimer Complex
Reaction involves formation of reactive intermediate called a Meisenheimer complex.
O +N O Cl + NO2 O +N O Cl Nu NO2 O fast (2 ) +N O Nu + :Cl NO2 slow , rate d eterminin g Nu (1 )

A Meisenh eimer complex

Similar to nucleophilic subsititution on carboxylic acid derivatives. 22-51