1. Reactions of Aromatic Compounds
Organic Chemistry, 8th Edition L. G. Wade, Jr.
Chapter 17 Lecture
Reactions of Aromatic Compounds

2. Friedel–Crafts Alkylation
Synthesis of alkyl benzenes from alkyl halides and a Lewis acid, usually AlCl3.
Reactions of alkyl halide with Lewis acid produces a carbocation, which is the electrophile.

3. Mechanism of the Friedel–Crafts Reaction
Step 1
Step 2
Step 3

4. Protonation of Alkenes
An alkene can be protonated by HF.
This weak acid is preferred because the fluoride ion is a weak nucleophile and will not attack the carbocation.

5. Alcohols and Lewis Acids
Alcohols can be treated with BF3 to form the carbocation.

6. Limitations of Friedel–Crafts
Reaction fails if benzene has a substituent that is more deactivating than halogens.
Rearrangements are possible.
The alkylbenzene product is more reactive than benzene, so polyalkylation occurs.

7. Rearrangements

8. Solved Problem 2 Solution
Devise a synthesis of p-nitro-t-butylbenzene from benzene.
Solution
To make p-nitro-t-butylbenzene, we would first use a Friedel–Crafts reaction to make t-butylbenzene. Nitration gives the correct product. If we were to make nitrobenzene first, the Friedel–Crafts reaction to add the t-butyl group would fail.
Copyright © 2006 Pearson Prentice Hall, Inc.

9. Friedel–Crafts Acylation
Acyl chloride is used in place of alkyl chloride.
The product is a phenyl ketone that is less reactive than benzene.

10. Mechanism of Acylation
Step 1: Formation of the acylium ion.
Step 2: Electrophilic attack to form the sigma complex.

11. Mechanism of Acylation (Continued)
Step 3: Loss of a proton to form the product.

12. Hint
Friedel–Crafts acylations are generally free from rearrangements and multiple substitution. They do not go on strongly deactivated rings, however.

13. Clemmensen Reduction
The Clemmensen reduction is a way to convert acylbenzenes to alkylbenzenes by treatment with aqueous HCl and amalgamated zinc.

14. Nucleophilic Aromatic Substitution
A nucleophile replaces a leaving group on the aromatic ring.
This is an addition–elimination reaction.
Electron-withdrawing substituents activate the ring for nucleophilic substitution.

15. Mechanism of Nucleophilic Aromatic Substitution
Step 1: Attack by hydroxide gives a resonance-stabilized complex.
Step 2: Loss of chloride gives the product.
Step 3: Excess base deprotonates the product.

16. Activated Positions
Nitro groups ortho and para to the halogen stabilize the intermediate (and the transition state leading to it).
Electron-withdrawing groups are essential for the reaction to occur.

17. Benzyne Reaction: Elimination–Addition
Reactant is halobenzene with no electron- withdrawing groups on the ring.
Use a very strong base like NaNH2.

18. Benzyne Mechanism Sodium amide abstracts a proton.
The benzyne intermediate forms when the bromide is expelled and the electrons on the sp2 orbital adjacent to it overlap with the empty sp2 orbital of the carbon that lost the bromide.
Benzynes are very reactive species due to the high strain of the triple bond.

19. Nucleophilic Substitution on the Benzyne Intermediate

20. With strong electron-withdrawing
Hint
With strong electron-withdrawing
groups ortho or para, the addition–elimination mechanism is more likely. Without these activating groups, stronger conditions are required, and the benzyne mechanism is likely.

21. Aromatic Substitutions Using Organometallic Reagents
Friedel–Craft reactions have limitations.
Rearrangements.
Multiple alkylations.
Cannot occur on deactivated rings.
Need strong electrophiles.
Organometallic reagents can add alkyl groups to the benzene without these limitations.

22. Organocuprate Reagents
R—X Li R—Li LiX
2 R—Li CuX R2CuX LiX
Lithium dialkylcuprate reagents (Gilman reagents) can be prepared by reaction of two equivalents of an organolithium reagent with cuprous iodide.

23. Coupling Using Organocuprate Reagents
Mechanisms vary depending on the alkyl halide and organocuprate used.
Cannot be SN2 because vinyl and aryl halides work well in this reaction.

24. The Heck Reaction
Palladium-catalyzed coupling of an aryl or vinyl halide with an alkene.
Produces C–C bond at the less substituted end of the alkene.
Triethylamine or sodium acetate is added to neutralize the HX produced.

25. Examples of the Heck Reaction

26. The Suzuki Reaction Also called the Suzuki coupling.
Palladium-catalyzed substitution that couples an aryl or vinyl halide with an alkyl, alkenyl, or aryl boronic acid or boronate ester.

27. Synthesis of Boronate Esters
The boronate esters can be synthesized from alkyl-, vinyl-, and arylboronic acids.
Can also be made by the hydroboration of double and triple bonds.

28. Examples of the Suzuki Reaction

29. Chlorination of Benzene
Addition to the benzene ring may occur with excess of chlorine under heat and pressure.
The first Cl2 addition is difficult, but the next two moles add rapidly.

30. Catalytic Hydrogenation
Elevated heat and pressure are required.
Possible catalysts: Pt, Pd, Ni, Ru, Rh.
Reduction cannot be stopped at an intermediate stage.

31. Birch Reduction
This reaction reduces the aromatic ring to a nonconjugated 1,4-cyclohexadiene.
The reducing agent is sodium or lithium in a mixture of liquid ammonia and alcohol.

32. Mechanism of the Birch Reduction

33. Limitations of the Birch Reduction

34. Side-Chain Oxidation
Alkylbenzenes are oxidized to benzoic acid by heating in basic KMnO4 or heating in Na2Cr2O7/H2SO4.
The benzylic carbon will be oxidized to the carboxylic acid.

35. Side-Chain Halogenation
The benzylic position is the most reactive.
Br2 reacts only at the benzylic position.
Cl2 is not as selective as bromination, so results in mixtures.

36. Mechanism of Side-Chain Halogenation

37. Hint
In predicting reactions on side chains of aromatic rings, consider resonance forms that delocalize a charge or a radical electron onto the ring.

38. SN1 Reactions
Benzylic carbocations are resonance- stabilized, easily formed.
Benzyl halides undergo SN1 reactions.

39. SN2 Reactions
Benzylic halides are 100 times more reactive than primary halides via SN2.
The transition state is stabilized by a ring.

40. Examples of SN2 Reactions of Benzyl Halides

41. Oxidation of Phenols to Quinones
Phenol will react with oxidizing agents to produce quinones.
Quinones are conjugated 1,4-diketones.
This can also happen (slowly) in the presence of air.

42. Electrophilic Aromatic Substitution of Phenols
Phenols are highly reactive because the hydroxyl group stabilizes the sigma complex formed.
Usually alkylated or acylated using relatively weak Friedel– Crafts catalysts (such as HF) to avoid overalkylation or overacylation.