1. Chapter 21 Phenols 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
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 Diels-Alder reaction is another example of a pericyclic reaction
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 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
Chapter 21