Chapter 21
Phenols and Aryl Halides: Nucleophilic
Aromatic Substitution
 Structure and Nomenclature of Phenols
Phenols have hydroxyl groups bonded directly to a benzene ring

Naphthols and phenanthrols have a hydroxyl group bonded to a polycyclic
benzenoid ring
Chapter 21
2
 Nomenclature of Phenols
Phenol is the parent name for the family of hydroxybenzenes

Methylphenols are called cresols
Chapter 21
3
 Synthesis of Phenols
 Laboratory Synthesis
Phenols can be made by hydrolysis of arenediazonium salts
Chapter 21
4
 Industrial Syntheses
1. Hydrolysis of Chlorobenzene (Dow Process)


Chlorobenzene is heated with sodium hydroxide under high pressure
The reaction probably proceeds through a benzyne intermediate (Section 21.11B)
2. Alkali Fusion of Sodium Benzenesulfonate

Sodium benzenesulfonate is melted with sodium hydroxide
Chapter 21
5
3. From Cumene Hydroperoxide


Benzene and propene are the starting materials for a three-step sequence that
produces phenol and acetone
Most industrially synthesized phenol is made by this method
The first reaction is a Friedel-Crafts alkylation
Chapter 21
6
The second reaction is a radical chain reaction with a 3o benzylic
radical as the chain carrier
Chapter 21
7
The third reaction is a hydrolytic rearrangement (similar to a
carbocation rearrangement) that produces acetone and phenol

A phenyl group migrates to a cationic oxygen group
Chapter 21
8
 Reactions of Phenols as Acids
 Strength of Phenols as Acids
Phenols are much stronger acids than alcohols
Chapter 21
9
Phenol is much more acidic than cyclohexanol
Experimental results show that the oxygen of a phenol is more
positive and this makes the attached hydrogen more acidic


The oxygen of phenol is more positive because it is attached to an electronegative
sp2 carbon of the benzene ring
Resonance contributors to the phenol molecule also make the oxygen more
positive
Chapter 21
10
 Distinguishing and Separating Phenols from Alcohols
and Carboxylic Acids
Phenols are soluble in aqueous sodium hydroxide because of
their relatively high acidity


Most alcohols are not soluble in aqueous sodium hydroxide
A water-insoluble alcohol can be separated from a phenol by extracting the
phenol into aqueous sodium hydroxide
Phenols are not acidic enough to be soluble in aqueous sodium
bicarbonate (NaHCO3)


Carboxylic acids are soluble in aqueous sodium bicarbonate
Carboxylic acids can be separated from phenols by extracting the carboxylic acid
into aqueous sodium bicarbonate
Chapter 21
11
 Other Reactions of the O-H Group of Phenols
Phenols can be acylated with acid chlorides and anhydrides
Chapter 21
12
 Phenols in the Williamson Ether Synthesis
Phenoxides (phenol anions) react with primary alkyl halides to
form ethers by an SN2 mechanism
Chapter 21
13
 Cleavage of Alkyl Aryl Ethers
Reaction of alkyl aryl ethers with HI or HBr leads to an alkyl halide
and a phenol

Recall that when a dialkyl ether is reacted, two alkyl halides are produced
Chapter 21
14
 Reaction of the Benzene Ring of Phenols
 Bromination
The hydroxyl group is a powerful ortho, meta director and usually
the tribromide is obtained

Monobromination can be achieved in the presence of carbon disulfide at low
temperature
 Nitration
Nitration produces o- and p-nitrophenol

Low yields occur because of competing oxidation of the ring
Chapter 21
15
 Sulfonation
Sulfonation gives mainly the the ortho (kinetic) product at low
temperature and the para (thermodynamic) product at high
temperature
Chapter 21
16
 The Kolbe Reaction
 Carbon dioxide is the electrophile for an electrophilic aromatic
substitution with phenoxide anion



The phenoxide anion reacts as an enolate
The initial keto intermediate undergoes tautomerization to the phenol product
Kolbe reaction of sodium phenoxide results in salicyclic acid, a synthetic
precursor to acetylsalicylic acid (aspirin)
Chapter 21
17
 The Claisen Rearrangement
Allyl phenyl ethers undergo a rearrangement upon heating that
yields an allyl phenol
The process is intramolecular; the allyl group migrates to the
aromatic ring as the ether functional group becomes a ketone

The unstable keto intermediate undergoes keto-enol tautomerization to give the
phenol group
The reaction is concerted, i.e., bond making and bonding breaking
occur at the same time
Chapter 21
18
Allyl vinyl ethers also undergo Claisen rearrangement when
heated

The product is a g-unsaturated carbonyl compound
The Cope rearrangement is a similar reaction
Both the Claisen and Cope rearrangements involve reactants that
have two double bonds separated by three single bonds
Chapter 21
19
The transition state for the Claisen and Cope rearrangements
involves a cycle of six orbitals and six electrons, suggesting
aromatic character

This type of reaction is called pericyclic
The Diels-Alder reaction is another example of a pericyclic
reaction
Chapter 21
20
 Quinones
Hydroquinone is oxidized to p-benzoquinone by mild oxidizing
agents


Formally this results in removal of a pair of electrons and two protons from
hydroquinone
This reaction is reversible
Every living cell has ubiquinones (Coenzymes Q) in the inner
mitochondrial membrane

These compounds serve to transport electrons between substrates in enzymecatalyzed oxidation-reduction reactions
Chapter 21
21
 Aryl Halides and Nucleophilic Aromatic
Substitution
Simple aryl and vinyl halides do not undergo nucleophilic
substitution
Back-side attack required for SN2 reaction is blocked in aryl
halides
Chapter 21
22
SN2 reaction also doesn’t occur in aryl (and vinyl halides) because
the carbon-halide bond is shorter and stronger than in alkyl
halides


Bonds to sp2-hybridized carbons are shorter, and therefore stronger, than to
sp3-hybridized carbons
Resonance gives the carbon-halogen bond some double bond character
Chapter 21
23
 Nucleophilic Aromatic Substitution by Addition-
Elimination: The SNAr Mechanism
Nucleophilic substitution can occur on benzene rings when strong
electron-withdrawing groups are ortho or para to the halogen
atom

The more electron-withdrawing groups on the ring, the lower the temperature
required for the reaction to proceed
Chapter 21
24
The reaction occurs through an addition-elimination mechanism


A Meisenheimer complex, which is a delocalized carbanion, is an intermediate
The mechanism is called nucleophilic aromatic substitution (SNAr)
The carbanion is stabilized by electron-withdrawing groups in the
ortho and para positions
Chapter 21
25
 Nucleophilic Aromatic Substitution through an
Elimination-Addition Mechanism: Benzyne
Under forcing conditions, chlorobenzene can undergo an apparent
nucleophilic substitution with hydroxide

Bromobenzene can react with the powerful base amide
Chapter 21
26
The reaction proceeds by an elimination-addition mechanism
through the intermediacy of a benzyne (benzene containing a
triple bond)
Chapter 21
27
A calculated electrostatic potential map of benzyne shows added
electron density at the site of the benzyne p bond

The additional p bond of benzyne is in the same plane as the ring
When chlorobenzene labeled at the carbon bearing chlorine reacts
with potassium amide, the label is divided equally between the C-1
and C-2 positions of the product

This is strong evidence for an elimination-addition mechanism and against a
straightforward SN2 mechanism
Chapter 21
28
Benzyne can be generated from anthranilic acid by diazotization


The resulting compound spontaneously loses CO2 and N2 to yield benzyne
The benzyne can then be trapped in situ using a Diels-Alder reaction
 Phenylation
Acetoacetic esters and malonic esters can be phenylated by
benzyne generated in situ from bromobenzene
Chapter 21
29
 Spectroscopic Analysis of Phenols and Aryl
Halides
 Infrared Spectra
Phenols show O-H stretching in the 3400-3600 cm-1 region
 1H NMR
The position of the hydroxyl proton of phenols depends on
concentration


In phenol itself the O-H proton is at d 2.55 for pure phenol and at d 5.63 for a 1%
solution
Phenol protons disappear from the spectrum when D2O is added
The aromatic protons of phenols and aryl halides occur in the d 79 region

13C
NMR
The carbon atoms of phenols and aryl halides appear in the region
d 135-170
Chapter 21
30