Organic Chemistry, 7 L. G. Wade, Jr. Chapter , Prentice Hall

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1 Organic Chemistry, 7 th Edition L. G. Wade, Jr. Chapter 17 Reactions of Aromatic Compounds 2010, Prentice Hall

2 Electrophilic Aromatic Substitution Although h benzene s pi electrons are in a stable aromatic system, they are available to attack a strong electrophile to give a carbocation. This resonance-stabilized carbocation is called a sigma complex because the electrophile is joined to the benzene ring by a new sigma bond. Aromaticity is regained by loss of a proton. Chapter 17 2

3 Mechanism of Electrophilic Aromatic Substitution Chapter 17 3

4 Bromination of Benzene Chapter 17 4

5 Mechanism for the Bromination of Benzene: Step Br Br FeBr 3 Br Br FeBr 3 (stronger electrophile than Br 2 ) Before the electrophilic aromatic substitution can take place, the electrophile must be activated. A strong Lewis acid catalyst, such as FeBr 3, should be used. Chapter 17 5

6 Mechanism for the Bromination of Benzene: Steps 2 and 3 Step 2: Electrophilic attack and formation of the sigma complex. H H H H H Br Br FeBr 3 H H H H Br H + FeBr 4 - H H Step 3: Loss of a proton to give the products. H H H H Br H FeBr 4 - H H H Br H + FeBr 3 + HBr H H Chapter 17 6

7 Energy Diagram for Bromination Chapter 17 7

8 Chlorination and Iodination Chlorination is similar to bromination. AlCl 3 is most often used as catalyst, but FeCl 3 will also work. Iodination requires an acidic oxidizing agent, like nitric acid, to produce iodide cation. H + + HNO 3 + ½ I 2 I + + NO 2 + H 2 O Chapter 17 8

9 Solved Problem 1 Predict the major product(s) of bromination of p-chloroacetanilide. Solution The amide group ( NHCOCH 3 ) is a strong activating and directing group because the nitrogen atom with its nonbonding pair of electrons is bonded to the aromatic ring. The amide group is a stronger director than the chlorine atom, and substitution occurs mostly at the positions ortho to the amide. Like an alkoxyl group, the amide is a particularly strong activating group, and the reaction gives some of the dibrominated product. Chapter 17 9

10 Nitration ti of Benzene HNO 3 H 2 SO 4 NO 2 + H 2 O Sulfuric acid acts as a catalyst, allowing the reaction to be faster and at lower temperatures. HNO 3 and H 2 SO 4 react together to form the electrophile of the reaction: nitronium ion (NO + 2 ). Chapter 17 10

11 Mechanism for the Nitration of Benzene Chapter 17 11

12 Reduction of the Nitro Group NO 2 Zn, Sn, or Fe aq. HCl NH 2 Treatment t with zinc, tin, or iron in dilute acid will reduce the nitro to an amino group. This is the best method for adding an amino group to the ring. Chapter 17 12

13 Sulfonation of Benzene H + SO 2 SO 4 3 SO 3 H Sulfur trioxide (SO 3 ) is the electrophile in the reaction. A7%mixtureofSO 3 and H 2 SO 4 is commonly referred to as fuming sulfuric acid. The SO 3 H groups is called a sulfonic acid. Chapter 17 13

14 Mechanism of Sulfonation Benzene attacks sulfur trioxide, forming a sigma complex. Loss of a proton on the tetrahedral carbon and reprotonation of oxygen gives benzenesulfonic acid. Chapter 17 14

15 Desulfonation Reaction SO 3 H + H 2 O H +, heat H + H 2 SO 4 Sulfonation is reversible. The sulfonic acid group may be removed from an aromatic ring by heating in dilute sulfuric acid. Chapter 17 15

16 Mechanism of Desulfonation In the desulfonation reaction, a proton adds to the ring (the electrophile) and loss of sulfur trioxide gives back benzene. Chapter 17 16

17 Nitration ti of Toluene Toluene reacts 25 times faster than benzene. The methyl group is an activator. The product mix contains mostly ortho and para substituted molecules. Chapter 17 17

18 Oth Ortho and dpara Substitution Ortho and para attacks are preferred because their resonance structures include one tertiary carbocation. Chapter 17 18

19 Energy Diagram Chapter 17 19

20 Meta Substitution When substitution occurs at the meta position, the positive charge is not delocalized onto the tertiary carbon, and the methyl groups has a smaller effect on the stability of the sigma complex. Chapter 17 20

21 Alkyl l Group Stabilization ti CH 2 CH 3 Br 2 FeBr 3 CH 2 CH 3 o-bromo (38%) Br CH 2 CH 3 CH 2 CH Br m-bromo (< 1%) Br p-bromo (62%) Alkyl groups are activating substituents and ortho, para-directors. This effect is called the inductive effect because alkyl groups can donate electron density to the ring through the sigma bond, making them more active. Chapter 17 21

22 Substituents with Nonbonding Electrons Resonance stabilization is provided by a pi bond between the OCH 3 substituent btit tand dthe ring. Chapter 17 22

23 Meta Attack on Anisole Resonance forms show that the methoxy group cannot stabilize the sigma complex in the meta substitution. Chapter 17 23

24 Bromination of Anisole A methoxy group is so strongly activating that anisole is quickly tribrominated without a catalyst. Chapter 17 24

25 The Amino Group Aniline reacts with bromine water (without a catalyst) to yield the tribromoaniline. Sodium bicarbonate is added to neutralize the HBr that is also formed. Chapter 17 25

26 Summary of Activators t Chapter 17 26

27 Activators t and Deactivators t If the substituent on the ring is electron donating, the ortho and para positions will be activated. If the group is electron withdrawing, the ortho and para positions will be deactivated. Chapter 17 27

28 Nitration ti of Nitrobenzene Electrophilic substitution reactions for nitrobenzene are 100,000 times slower than for benzene. The product mix contains mostly the meta isomer, only small amounts of the ortho and para isomers. Chapter 17 28

29 Ortho Substitution on Nitrobenzene The nitro group is a strongly deactivating group when considering its resonance forms. The nitrogen always has a formal positive charge. Ortho or para addition will create an especially unstable intermediate. Chapter 17 29

30 Meta Substitution on Nitrobenzene Meta substitution will not put the positive charge on the same carbon that bears the nitro group. Chapter 17 30

31 Energy Diagram Chapter 17 31

32 Deactivators and Meta- Directors Most electron withdrawing groups are deactivators and meta-directors. The atom attached to the aromatic ring has a positive or partial positive charge. Electron density is withdrawn inductively along the sigma bond, so the ring has less electron density than benzene and thus, it will be slower to react. Chapter 17 32

33 Oth Ortho Attack of facetophenone In ortho and para substitution of acetophenone, one of the carbon atoms bearing the positive charge is the carbon attached to the partial positive carbonyl carbon. Since like charges repel, this close proximity of the two positive charges is especially unstable. Chapter 17 33

34 Meta Attack on Acetophenone The meta attack on acetophenone avoids bearing the positive charge on the carbon attached to the partial positive carbonyl. Chapter 17 34

35 Other Deactivators Chapter 17 35

36 Nitration ti of Chlorobenzene When chlorobenzene is nitrated t the main substitution products are ortho and para. The meta substitution product is only obtained in 1% yield. Chapter 17 36

37 Halogens Are Deactivators t X Inductive Effect: Halogens are deactivating because they are electronegative and can withdraw electron density from the ring along the sigma bond. Chapter 17 37

38 Halogens Are Ortho, Para- Directors Resonance Effect: The lone pairs on the halogen can be used to stabilize the sigma complex by resonance. Chapter 17 38

39 Energy Diagram Chapter 17 39

40 Summary of Directing Effects Chapter 17 40

41 Effect of Multiple l Substituents t The directing effect of the two (or more) groups may reinforce each other. Chapter 17 41

42 Effect of Multiple Substituents (Continued) The position in between two groups in Positions 1 and 3 is hindered for substitution, and it is less reactive. Chapter 17 42

43 Effect of Multiple Substituents (Continued) OCH 3 OCH 3 Br OCH 3 O 2 N Br 2 FeBr 3 O 2 N Br O 2 N Br major products obtained If directing effects oppose each other, the most powerful activating group has the dominant influence. Chapter 17 43

44 Fi Friedel Crafts Alkylation l Synthesis of alkyl benzenes from alkyl halides and a Lewis acid, usually AlCl 3. Reactions of alkyl halide with Lewis acid produces a carbocation, which is the electrophile. Chapter 17 44

45 Mechanism of the Friedel Crafts Reaction Step 1 Step 2 Step 3 Chapter 17 45

46 Protonation ti 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. Chapter 17 46

47 Alcohols l and Lewis Acids Alcohols can be treated with BF 3 to form the carbocation. Chapter 17 47

48 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. Chapter 17 48

49 Rearrangements Chapter 17 49

50 Solved Problem 2 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 ti gives the correct product. If we were to make nitrobenzene first, the Friedel Crafts reaction to add the t-butyl group would fail. Chapter 17 50

51 Fi Friedel Crafts Acylation Acyl chloride is used in place of alkyl chloride. The product is a phenyl ketone that is less reactive than benzene. Chapter 17 51

52 Mechanism of Acylation Step 1: Formation of the acylium ion. Step 2: Electrophilic attack to form the sigma complex. Chapter 17 52

53 Clemmensen Reduction The Clemmensen reduction is a way to convert acylbenzenes to alkylbenzenes by treatment t t with aqueous HCl and amalgamated zinc. Chapter 17 53

54 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. Chapter 17 54

55 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. Chapter 17 55

56 Activated t 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. Chapter 17 56

57 Benzyne Reaction: Elimination- Addition Reactant is halobenzene with no electron- withdrawing groups on the ring. Use a very strong base like NaNH 2. Chapter 17 57

58 Benzyne Mechanism Sodium amide abstract a proton. The benzyne intermediate forms when the bromide is expelled and the electrons on the sp 2 orbital adjacent to it overlap with the empty sp 2 orbital of the carbon that lost the bromide. Benzynes are very reactive species due to the high strain of the triple bond. Chapter 17 58

59 Nucleophilic Substitution on the Benzyne Intermediate Chapter 17 59

60 Chlorination of Benzene Addition to the benzene ring may occur with excess of chlorine under heat and pressure. The first Cl 2 addition is difficult, but the next two moles add rapidly. An insecticide Chapter 17 60

61 Catalytic ti Hydrogenation CH 3 CH 3 3 H 2, 1000 psi Ru, 100 C CH 3 CH 3 Elevated heat and pressure is required. Possible catalysts: Pt, Pd, Ni, Ru, Rh. Reduction cannot be stopped at an intermediate stage. Chapter 17 61

62 Birch Reduction H H H H H H Na or Li H NH 3 (l), ROH H H H H H H H 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. Chapter 17 62

63 Mechanism of the Birch Reduction Chapter 17 63

64 Limitations it ti of the Birch Reduction Chapter 17 64

65 Side-Chain i Oxidation CH 2 CH 3 KMnO 4, NaOH H 2 O, 100oC CO 2 H (or Na 2 Cr 2 O 7, H 2 SO 4, heat) Alkylbenzenes are oxidized to benzoic acid by heating in basic KMnO 4 or heating in Na 2 Cr 2 O 7 /H 2 SO 4. The benzylic carbon will be oxidized to the carboxylic acid. Chapter 17 65

66 Side-Chain i Halogenation Br CH 2 CH 3 Br 2 or NBS CHCH 3 hν The benzylic position is the most reactive. Br 2 reacts only at the benzylic position. Cl 2 is not as selective as bromination, so results in mixtures. Chapter 17 66

67 Mechanism of Side-Chain Halogenation Chapter 17 67

68 S N 1R Reactions Benzylic carbocations are resonancestabilized, easily formed. Benzyl halides undergo S N 1 reactions. CH 2 Br CH 3 CH 2 O H, heat CH 2 OCH 2 CH 3 Chapter 17 68

69 S N 2R Reactions Benzylic halides are 100 times more reactive than primary halides via S N 2. The transition state is stabilized by a ring. Chapter 17 69

70 Oxidation of Phenols OH Cl Na 2 Cr 2 O 7 H 2 SO 4 O Cl O 2-chloro-1,4-benzoquinone 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. Chapter 17 70