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 -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 enzyme-
catalyzed 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  bond
 The additional  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  2.55 for pure phenol and at  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  7-

9 region

 13C
NMR
The carbon atoms of phenols and aryl halides appear in the region
 135-170

Chapter 21 30