Chapter 21 Phenols and Aryl Halides: Nucleophilic Aromatic Substitution

1
Chapter 21Phenols and Aryl Halides Nucleophilic
Aromatic Substitution
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

3

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

4

• Synthesis of Phenols
• Laboratory Synthesis
• Phenols can be made by hydrolysis of
  arenediazonium salts

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

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

7

• The second reaction is a radical chain reaction
  with a 3o benzylic radical as the chain carrier

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

9

• Reactions of Phenols as Acids
• Strength of Phenols as Acids
• Phenols are much stronger acids than alcohols

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

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

12

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

13

• Phenols in the Williamson Ether Synthesis
• Phenoxides (phenol anions) react with primary
  alkyl halides to form ethers by an SN2 mechanism

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

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

16

• Sulfonation
• Sulfonation gives mainly the the ortho (kinetic)
  product at low temperature and the para
  (thermodynamic) product at high temperature

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)

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

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

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

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

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

23

• SN2 reaction also doesnt 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

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

25

• The reaction occurs through an addition-eliminatio
  n 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-withdrawin
  g groups in the ortho and para positions

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

27

• The reaction proceeds by an elimination-addition
  mechanism through the intermediacy of a benzyne
  (benzene containing a triple bond)

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-additio
  n mechanism and against a straightforward SN2
  mechanism

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

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