Chapter 21

Phenols and Aryl Halides: Nucleophilic

Aromatic Substitution

Chapter 21 2

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 3

Nomenclature of Phenols

Phenol is the parent name for the family of hydroxybenzenes Methylphenols are called cresols

Chapter 21 4

Synthesis of Phenols

Laboratory Synthesis

Phenols can be made by hydrolysis of arenediazonium salts

Chapter 21 5

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 6

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 7

The second reaction is a radical chain reaction with a 3o benzylic

radical as the chain carrier

Chapter 21 8

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 9

Reactions of Phenols as Acids

Strength of Phenols as Acids

Phenols are much stronger acids than alcohols

Chapter 21 10

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 11

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 12

Other Reactions of the O-H Group of Phenols Phenols can be acylated with acid chlorides and anhydrides

Chapter 21 13

Phenols in the Williamson Ether Synthesis

Phenoxides (phenol anions) react with primary alkyl halides to

form ethers by an SN2 mechanism

Chapter 21 14

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 15

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 16

Sulfonation

Sulfonation gives mainly the the ortho (kinetic) product at low

temperature and the para (thermodynamic) product at high

temperature

Chapter 21 17

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 18

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 19

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 20

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 21

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 22

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 23

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 24

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 25

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 26

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 27

The reaction proceeds by an elimination-addition mechanism

through the intermediacy of a benzyne (benzene containing a

triple bond)

Chapter 21 28

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 29

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 30

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 7-

9 region

13C NMR

The carbon atoms of phenols and aryl halides appear in the region

d 135-170