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16. Chemistry of Benzene: Electrophilic Aromatic Substitution.

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Presentation on theme: "16. Chemistry of Benzene: Electrophilic Aromatic Substitution."— Presentation transcript:

1 16. Chemistry of Benzene: Electrophilic Aromatic Substitution

2 2 Substitution Reactions of Benzene and Its Derivatives Benzene is aromatic: a cyclic conjugated compound with 6  electrons Reactions of benzene lead to the retention of the aromatic core

3 3 Why this Chapter? Continuation of coverage of aromatic compounds in preceding chapter…focus shift to understanding reactions Examine relationship between aromatic structure and reactivity Relationship critical to understanding of how biological molecules/pharmaceutical agents are synthesized

4 Electrophilic Aromatic Substitution Reactions (EAS): Reactions typical of addition to alkenes do not work on aromatic double bonds. Need more electrophilic (more positive) halogen in order to break an aromatic double bond.

5 5 EAS: Bromination FeBr 3 acts as a catalyst to polarize the bromine reagent and so make it more positive (more electrophilic) The  electrons of the aromatic ring act as a nucleophile toward the now more electrophilic Br 2 (in the FeBr 3 complex) The cationic addition intermediate is called a sigma complex EAS occurs in two steps: Addition followed by Elimination Addition

6 6 Elimination EAS: Bromination The cationic addition intermediate (sigma complex) transfers a proton to FeBr 4 - (from Br - and FeBr 3 ) Aromaticity is restored (in contrast with addition in alkenes which is not followed by elimination) EAS occurs in two steps: Addition followed by Elimination

7 7 EAS: Bromination The cationic addition intermediate (sigma complex) transfers a proton to FeBr 4 - (from Br - and FeBr 3 ) Aromaticity is restored (in contrast with addition in alkenes which is not followed by elimination) EAS occurs in two steps: Addition followed by Elimination Elimination is driven by the stability of becoming aromatic

8 Other Aromatic Substitutions Chlorine and iodine (but not fluorine, which is too reactive) can produce aromatic substitution products Chlorination requires FeCl 3 Iodine must be oxidized (with Cu + or peroxide) to form a more powerful I + species

9 Example: 9 A common Amino Acid

10 10 Aromatic Nitration The combination of nitric acid and sulfuric acid produces NO 2 + (nitronium ion) The reaction with benzene produces nitrobenzene

11 Reduction of Nitration Product: 11 To put an amino (NH 2 ) group on an aromatic ring  first Nitrate  then reduce

12 12 Aromatic Sulfonation Substitution of H by SO 3 (sulfonation) with a mixture of sulfuric acid and SO 3 Reactive species is sulfur trioxide or its conjugate acid Reaction is Reversible: Can remove sulfonyl group with H +,H 2 O, heat

13 Aromatic Hydroxylation 13 Hard to directly add –OH to an aromatic ring in lab. Formation of Electrophile

14 14 Biological systems use Enzymes to hydroxylate aromatics Aromatic Hydroxylation

15 Alkylation of Aromatic Rings: The Friedel–Crafts Reaction Alkylation (substitution of Carbon compounds) among most useful electrophilic aromatic subsitution reactions Aromatic substitution of R + for H + Aluminum chloride promotes the formation of the carbocation Addition Elimination Electrophilic C + forms

16 16 Friedel-Crafts Alkylation: Limitations Only alkyl halides can be used (F, Cl, I, Br) Will not work with rings containing an amino group substituent or a strongly electron-withdrawing group Aryl halides (Ar-X) and vinylic halides (CH 2 =CH-X) do not react (their carbocations are too hard to form)

17 17 Friedel-Crafts Alkylation: Control Problems Multiple alkylations can occur because the first alkylation is activating (makes aromatic ring more nucleophilic so more likely to add again)

18 18 Similar to those that occur during electrophilic additions to alkenes Can involve H or alkyl shifts Friedel-Crafts Alkylation: Control Problems Carbocation Rearrangements

19 Example: 19

20 20 Friedel-Crafts Acylation Reaction of an acid chloride (RCOCl) and an aromatic ring in the presence of AlCl 3 introduces acyl group,  COR Benzene with acetyl chloride yields acetophenone

21 21 Friedel-Crafts Acylation: Mechanism Similar to alkylation Reactive electrophile: resonance-stabilized acyl cation An acyl cation does not rearrange = Acylium ion AdditionElimination Electrophilic C + forms

22 EAS: Summary 22

23 Substituent Effects Substituents that donate electrons make ring more nucleophilic Electron donating groups (edg) activate the ring toward EAS Substitutients that withdraw electrons make less nucleophilic Electron withdrawing groups (ewg) deactivate the ring toward EAS NucleophileElectrophile

24 24 Substituent Effects Substituents influence by induction edg activate the ring toward EASewg deactivate the ring toward EAS Halogens, C=O, CN, and NO 2 withdraw electrons through  bond connected to ring Alkyl groups donate electrons

25 25 Substituent Effects Substituents influence by resonance edg activate the ring toward EAS Halogen, OH, alkoxyl (OR), and amino substituents donate electrons

26 26 Substituent Effects Substituents influence by resonance ewg deactivate the ring toward EAS C=O, CN, NO 2 substituents withdraw electrons from the aromatic ring by resonance

27 27 Substituent Effects Substituents influence by resonance edgs put negative character at o- and p- positions (make o- and p- positions more nucleophilic) Direct incoming electrophile into o- or p- spots ewgs put positive character at o- and p- positions (make o- and p- positions less nucleophilic) Direct incoming electrophile into m- spots

28 28

29 29 Explanation of Substituent Effects Activating groups donate electrons to the ring, stabilizing the Wheland intermediate (carbocation) Deactivating groups withdraw electrons from the ring, destabilizing the Wheland intermediate

30 Ortho- & Para-Directing Activators: Alkyl Groups Alkyl groups activate: direct further substitution to positions ortho and para to themselves Alkyl group is most effective in the ortho and para positions

31 31 Ortho- and Para-Directing Activators: OH and NH 2 Alkoxyl, and amino groups have a strong, electron-donating resonance effect Most pronounced at the ortho and para positions

32 32 Ortho- & Para-Directing Deactivators: Halogens Electron-withdrawing inductive effect outweighs weaker electron- donating resonance effect Resonance effect is only at the ortho and para positions, stabilizing carbocation intermediate

33 33 Meta-Directing Deactivators Inductive and resonance effects reinforce each other Ortho and para intermediates destabilized by deactivation of carbocation intermediate Resonance cannot produce stabilization

34 34 Summary:

35 35 Another Summary:

36 Trisubstituted Benzenes: Additivity of Effects If the directing effects of the two groups are the same, the result is additive

37 Learning Check: 37 Br 2, FeBr 3 ?

38 Solution: 38 Br 2, FeBr 3 ?

39 39

40 40 Substituents with Opposite Effects If the directing effects of two groups oppose each other, the more powerful activating group decides the principal outcome Usually gives mixtures of products

41 41 Meta-Disubstituted Compounds The reaction site is too hindered To make aromatic rings with three adjacent substituents, it is best to start with an ortho-disubstituted compound

42 Nucleophilic Aromatic Substitution Aryl halides with ewg’s o- and p- react with nucleophiles Sanger’s reagent: For labeling proteins in biochemistry

43 Nucleophilic Aromatic Substitution 43

44 Nucleophilic Aromatic Substitution 44

45 45 Nucleophilic Aromatic Substitution ewg’s o- and p- stabilize the intermediate Intermediate Meisenheimer complex is stabilized by electron- withdrawal Halide ion is lost to give aromatic ring

46 Benzyne Phenol is prepared on an industrial scale by treatment of chlorobenzene with dilute aqueous NaOH at 340°C under high pressure Elimination reaction gives a triple bond intermediate called benzyne

47 47 Evidence for Benzyne Bromobenzene with 14 C* only at C1 gives substitution product with label scrambled between C1 and C2 Reaction proceeds through a symmetrical intermediate in which C1 & C2 are equivalent— must be benzyne

48 48 Structure of Benzyne Benzyne is a highly distorted alkyne The triple bond uses sp 2 -hybridized carbons, not the usual sp The triple bond has one  bond formed by p–p overlap and another by weak sp 2 –sp 2 overlap

49 Benzylic Oxidation Alkyl side chains with a C-H next to the ring can be oxidized to  CO 2 H by strong reagents such as KMnO 4 and Na 2 Cr 2 O 7 O 2, Co(III) Converts an alkylbenzene into a benzoic acid, Ar  R  Ar  CO 2 H

50 Examples: 50

51 51 Benzylic Bromination Reaction of an alkylbenzene with N-bromo-succinimide (NBS) and benzoyl peroxide (radical initiator) introduces Br into the side chain

52 52 Mechanism of NBS (Radical) Reaction Abstraction of a benzylic hydrogen atom by a bromine radical generates an intermediate benzylic radical which reacts with Br 2 to yield product Br· radical cycles back into reaction to carry chain

53 Benzylic radical is stabilized by resonance 53 Mechanism of NBS (Radical) Reaction

54 Aromatic Reductions Aromatic rings are inert to catalytic hydrogenation under conditions that reduce alkene double bonds Can selectively reduce an alkene double bond in the presence of an aromatic ring

55 Aromatic Reductions Reduction of aromatic ring requires more powerful reducing conditions 55 high pressure rhodium catalysts

56 56 Reduction of Aryl Alkyl Ketones Aromatic ring activates neighboring carbonyl group toward reduction Ketone is converted into an alkylbenzene by cat H 2 /Pd

57 Examples: 57

58 Learning Check: 58 Synthesize para-chlorobenzoic acid from benzene. Synthesize meta-chlorobenzoic acid from benzene.

59 Solution: 59 Synthesize para-chlorobenzoic acid from benzene. Synthesize meta-chlorobenzoic acid from benzene.

60 Synthesis of Trisubstituted Benzenes plan a sequence of reactions in right order is valuable to synthesis of substituted aromatic rings

61 Synthesis of Trisubstituted Benzenes 61 Work Backwards

62 Synthesis of Trisubstituted Benzenes 62 Work Backwards

63 Synthesis of Trisubstituted Benzenes 63

64 Learning Check: 64 Synthesize 4-chloro-2-propylbenzenesulfonic acid from benzene.

65 Solution: 65 Synthesize 4-chloro-2-propylbenzenesulfonic acid from benzene.

66 Learning Check: Which of the following groups is an activator?

67 Solution: Which of the following groups is an activator? Generally and except for the halogens, groups with lone pairs of electrons adjacent to the ring are activators.

68 A.-Cl B.-CHO C.-CN D.-NO 2 E.None of the above Which of the following groups is an ortho- para- director? Learning Check:

69 A.-Cl B.-CHO C.-CN D.-NO 2 E.None of the above Which of the following groups is an ortho- para- director? Solution: Although –Cl is a deactivator, it’s lone pairs of electrons stabilize electrophilic aromatic substitution reactions and it is an o- p- director.

70 Which of the following groups most strongly activates an aromatic ring toward Friedel-Crafts acylation? A.-NH 2 B.-OCH 3 C.-O-C(=O)CH 3 D.NO 2 E.H Learning Check:

71 Which of the following groups most strongly activates an aromatic ring toward Friedel-Crafts acylation? A.-NH 2 B.-OCH 3 C.-O-C(=O)CH 3 D.NO 2 E.H Solution: Although the –NH 2 group is a stronger activator it complexes with AlCl 3 to form a strongly deactivating ammonium group. Consequently, the methoxy is a better activator.

72 Which compound is the major product of the chlorination shown below? Learning Check:

73 Which compound is the major product of the chlorination shown below? Solution: The nitrogen is an activator and o- p- director. The C=O is a deactivator.

74 Which step in the following reaction will cause the proposed synthesis to fail? Learning Check:

75 Which step in the following reaction will cause the proposed synthesis to fail? Solution: Addition of water in step “D” occurs with Markovnikov selectivity.

76 What is the major product of the reaction of nitrobenzene with Br 2 /FeBr 3 ?

77 Which of the following compounds would react fastest with HNO 3 /H 2 SO 4 ? 1. nitrobenzene (PhNO 2 ) 2. toluene (PhCH 3 ) 3. bromobenzene (PhBr) 4. anisole (PhOCH 3 ) 5. benzoic acid (PhCOOH)

78 Which structure is a major intermediate formed in the electrophilic nitration of chlorobenzene?

79 Which series of reactions will convert benzene into p- nitrobenzoic acid? 1. CH 3 Br/AlBr 3 followed by HNO 3 /H 2 SO 4 followed by KMnO 4 /H 2 O 2. HNO 3 /H 2 SO 4 followed by KMnO 4 /H 2 O followed by CH 3 Br/AlBr 3 3. KMnO 4 /H 2 O followed by CH 3 Br/FeBr 3 followed by HNO 3 /H 2 SO 4 4. CH 3 Br/AlBr 3 followed by KMnO 4 /H 2 O followed by HNO 3 /H 2 SO 4 5. HNO 3 /H 2 SO 4 followed by CH 3 Br/AlBr 3 followed by KMnO 4 /H 2 O

80 Select the major product of the following reaction

81 What is the electrophile in the following aromatic substitution?

82 1. X 2. X 3. X 4. X 5. X What is the best sequence of reactions to synthesize the desired product (Pr = propyl)? Step 1Step 2Step 3 1 HNO 3 /H 2 SO 4 PrMgBr/H 3 O + H 2 /Pd 2 HNO 3 /H 2 SO 4 AlCl 3 /PrBrH 2 /Pd 3 AlCl 3 /PrClHNO 3 /H 2 SO 4 H 2 /Pd 4 HNO 3 /H 2 SO 4 H 2 /PdPrMgBr/H 3 O + 5 AlCl 3 /CH 3 CH 2 COClHNO 3 /H 2 SO 4 H 2 /Pd

83 What are the reagents necessary for step 3 in the following transformation? 1. CH 3 COCl/AlCl 3 2. CH 3 CH 2 Br/AlBr 3 3. SO 3 /H 2 SO 4 4. H 2 /Pd 5. SOCl 2 /AlCl 3

84 Which of the following carbons of the benzyl radical has the smallest unpaired electron density?

85 What would be the main product of nitration of benzenesulfonic acid? 1. o-nitrobenzenesulfonic acid 2. p-nitrobenzenesulfonic acid 3. 2-nitrobenzoic acid 4. m-nitrobenzenesulfonic acid 5. m-nitrobenzoic acid

86 Fluorine is less deactivating than chlorine in the aromatic electrophilic substitution reactions. What is the main reason for this reactivity trend? 1. Fluorine forms stronger π bonds than chlorine, providing more resonance stabilization. 2. Chlorine is more electronegative than fluorine. 3. Because of it size chlorine has stronger inductive influence than fluorine. 4. Fluorine is smaller, making the entry of electrophiles easier. 5. Chlorine forms complexes with electrophiles, diminishing their reactivity.

87 Which of the following represent the intermediate formed in the reaction between p-chloronitrobenzene and hydroxide ion?

88 Based on the electronic structure, what kind of substituent effect would you expect from the nitroso group? 1. o,p-directing, deactivating 2. o,p-directing activating 3. m-directing, activating 4. m-directing, deactivating

89 Which one is not a limitation of Friedel-Crafts alkylations? 1. carbocation rearrangements may occur 2. polyalkylation products are possible 3. only substrates with selected activating groups can be used 4. vinyl halides cannot be used to generate electrophiles 5. the halogen in the aluminum halide must match one in the alkyl halide

90 What is the major product of the following reaction?

91 What is the result of the reaction between m- bromotoluene and sodium amide? 1. 2-aminotoluene 2. 3-aminotoluene 3. 4-aminotoluene 4. all of these 5. none of these

92 Aromatic compounds can be oxidized to their radical cations by removal of just one electron. Which of the following will be the easiest to oxidize to a radical cation?

93 Which of the following is not a practical method to generate an electrophile for aromatic substitution reaction? 1. HNO 3 /H 2 SO 4 2. Cl 2 /FeBr 3 3. I 2 /CuCl 2 4. SO 3 /H 2 SO 4 5. CH 3 COCl/AlBr 3


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