1. Chapter 16 Chemistry of Benzene: Electrophilic Aromatic Substitution

2. Introduction • Electrophilic aromatic substitution is the most common reaction of aromatic compounds • It replaces a proton (H+) on an aromatic ring with another electrophile (E+) • It leads to the retention of the aromatic core

3. Some electrophilic aromatic substitution reactions

4. 1.Bromination of Aromatic Rings • Benzene is a site of electron density • Its 6  electrons are in a cyclic conjugated system • Its 6  electrons are sterically accessible to other reactants because they are located above or below the plane

5. Benzene acts as an electron donor (a Lewis base or nucleophile) • It reacts with electron acceptors (Lewis acids or electrophiles) • Benzene’s  electrons participate as a Lewis base in reactions with Lewis acids

6. Bromination of benzene occurs in two steps: • Step 1: The  electrons act as a nucleophile toward Br2 (in a complex with FeBr3) to form a nonaromatic carbocation intermediate • Step 2: The resonance-stabilized carbocation intermediate loses H+ to regenerate the aromatic ring

7. Electrophilic Alkene Addition

8. Electrophilic Aromatic Bromination • Aromatic rings are less reactive toward electrophiles than alkenes • Unlike alkenes, benzene does not react rapidly with Br2 in CH2Cl2 • For bromination, benzene requires FeBr3 as a catalyst to polarize the bromine reagent and make it more electrophilic

9. Step 1: The  electrons act as a nucleophile and attack the polarized Br2 (in a complex with FeBr3) to form a nonaromatic carbocation intermediate • It is a slow, rate-limiting step (high DG‡) • The carbocation is doubly allylic (nonaromatic) and has three resonance forms

10. The carbocation intermediate is not aromatic and is high in energy (less stablethan benzene)

11. Step 1 is endergonic, has a high DG‡ and is a slow reaction

12. Step 2: The resonance-stabilized carbocation intermediate loses H+ to regenerate the aromatic ring and yield a substitution product in which H+ is replaced by Br+ • It is similar to the 2nd step of an E1 reaction • The carbocation intermediate transfers a H+ to FeBr4- (from Br- and FeBr3) • This restores aromaticity (in contrast with addition in alkenes)

13. Step 2 is exergonic, has a low DG‡ and is a fast reaction

14. Electrophilic Aromatic Bromination: Mechanism

15. Why is there electrophilic aromatic substitution rather than addition? • Substitution reaction retains the stability of the aromatic ring and is exergonic Addition Loss of aromaticity Endergonic Substitution Retention of aromaticity Exergonic

16. Practice Problem: Monobromination of toluene gives a mixture of three bromotoluene products. Draw and name them.

17. 2.Other Aromatic Substitutions • The reaction with bromine involves a mechanism that is similar to many other reactions of benzene with electrophiles • The cationic intermediate was first proposed by G. W. Wheland and is often called the Wheland intermediate

18. Electrophilic Aromatic Substitution • An electrophilic aromatic substitution reaction involves two steps: • reaction of an electrophile E+ with an aromatic ring • loss of H+ from the resonance-stabilized carbocation intermediate to regenerate the aromatic ring

19. The same general mechanism is used by other aromatic substitutions including: • Chlorination • Iodination • Nitration • Sulfonation F is too reactive for monofluorination

20. Aromatic Chlorination • Benzene ring reacts with Cl2 in the presence of FeCl3catalyst to yield chlorobenzene • It requires FeCl3 to polarize Cl2 (make it more electrophilic)

21. Aromatic Iodination • Benzene ring reacts with I2 in the presence of anoxidizing agent (H2O2or CuCl2) to yield iodobenzene • Iodine must be oxidized to form a more powerful electrophilic I+ species (with Cu2+ or peroxide)

22. Aromatic Nitration • Benzene ring reacts with a mixture of concentrated nitric and sulfuric acids (HNO3 and H2SO4) to yield nitrobenzene • The combination of nitric acid and sulfuric acid produces NO2+ (nitronium ion), an electrophile

23. The electrophileNO2+ is produced when HNO3 is protonated by H2SO4 and loses H2O

24. NO2+ reactswith benzene to give a carbocation intermediate which loses H+ to yield nitrobenzene

25. Aromatic nitration is useful in the pharmaceutical industry because the nitro-substituted product can be reduced by Fe or SnCl2 to yield arylamine

26. Aromatic Sulfonation • Benzene ring reacts with fuming sulfuric acid (a mixture of H2SO4and SO3) to yield benzenesulfonic acid • The reactive electrophile is either HSO3+ or neutral SO3depending on reaction conditions

27. The reactive electrophile is either sulfur trioxide SO3 or its conjugate acid HSO3+

28. The reaction occurs via the Wheland intermediate (carbocation)

29. The reaction is reversible (Sulfonation is favored in strong acid; desulfonation, in hot, dilute aqueous acid)

30. Aromatic sulfonic acids are useful as intermediates in the synthesis of dyes and pharmaceuticals. • Example: Sulfadrugs A sulfadrug

31. Aromatic sulfonic acids undergo alkali fusion reaction • Heating with NaOH at 300 ºC followed by neutralization with acid replaces the SO3H group with an OH • Example: Synthesis of p-cresol

32. Practice Problem: How many products might be formed on chlorination of o-xylene (o-dimethylbenzene), m-xylene, and p-xylene?

33. Practice Problem: When benzene reacts with D2SO4, deuterium slowly replaces all six hydrogens in the aromatic ring. Explain.

34. 3.Alkylation of Aromatic Rings: The Friedel-Crafts Reaction • Benzene ring reacts with an alkyl chloride in the presence of AlCl3 catalyst to yield an arene • Alkylation was first reported by Charles Friedel and James Crafts in 1877

35. Friedel-Crafts alkylation – is an electrophilic aromatic substitution in which the electrophile is a carbocation, R+. • AlCl3catalyst promotes the formation of the alkyl carbocation, R+, from the alkyl halide, RX • The Wheland (carbocation) intermediate forms • Alkylation is the attachment of an alkyl group to benzene; R+ substitutes for H+

36. Friedel-Crafts Alkylation Reaction: Mechanism

37. Limitations of the Friedel-Crafts Alkylation • Only alkyl halides can be used (F, Cl, Br, I) • Aryl halides and vinylic halides do not react (their carbocations are too high in energy to form)

38. No reaction occurs if the aromatic ring has an amino group or a strongly electron-withdrawing group substituent • Amino groups react with AlCl3 catalyst in an acid-base reaction

39. It is difficult to control the reaction. Multiple alkylations can occur because the first alkylation is activating • Polyalkylation is often observed

40. Carbocation rearrangements occur during alkylation, particularly when a 1o alkyl halide is used • Catalyst, temperature and solvent affect the amount of rearrangement Rearranged Unrearranged

41. Carbocation rearrangements of Friedel-Crafts alkylation • are similar to those that occur during electrophilic additions to alkenes • can involve hydride (H:-) or alkyl shifts More Stable

43. Limitations of the Friedel-Crafts Alkylation • Only alkyl halides can be used (F, Cl, Br, I) • No reaction occurs if the aromatic ring has an amino group or a strongly electron-withdrawing group substituent • It is difficult to control the reaction. Multiple alkylations can occur because the first alkylation is activating • Carbocation rearrangements occur during alkylation, particularly when a 1o alkyl halide is used

44. Practice Problem: The Friedel-Crafts reaction of benzene with 2- chloro-3-methylbutane in the presence of AlCl3 occurs with carbocation rearrangement. What is the structure of the product?

45. Practice Problem: Which of the following alkyl halides undergo Friedel-Crafts reaction without rearrangement? Explain. • CH3CH2Cl • CH3CH2CH(Cl)CH3 • CH3CH2CH2Cl • (CH3)3CCH2Cl • Chlorocyclohexane

46. Practice Problem: What is the major monosubstitution product from Friedel-Crafts reaction of benzene with 1- chloro-2-methylpropane in the presence of AlCl3?

47. 4.Acylation of Aromatic Rings: The Friedel-Crafts Reaction • Benzene ring reacts with a carboxylic acid chloride, RCOCl, in the presence of AlCl3 catalyst to yield an acylbenzene • Acylation is the attachment of an acyl group,-COR, to benzene; RCO+ substitutes for H+

48. Friedel-Crafts acylation – is an electrophilic aromatic substitution in which the reactive electrophile is a resonance-stabilized acyl cation, RCO+. • AlCl3catalyst promotes the formation of the acyl cation, RCO+, from the acyl chloride, RCOCl • The acyl cation, RCO+, does not rearrange; it is resonance-stabilized • The Wheland (carbocation) intermediate forms

49. Friedel-Crafts Acylation Reaction: Mechanism • The mechanism of Friedel-Crafts acylation is similar to Friedel-Crafts alkylation

50. In Friedel-Crafts acylation, there is no carbocation rearrangement nor multiple substitution • No carbocation rearrangement: The acyl cation, RCO+, does not rearrange because it is resonance-stabilized by interaction of the vacant orbital on C with lone pair of electrons on O • No multiple substitution: Acylated benzene is less reactive than nonacylated benzene