2. © 2011 Pearson Education, Inc. 1 Organic Chemistry 6 th Edition Paula Yurkanis Bruice Chapter 16 Reactions of Substituted Benzenes Dr. Halligan CHM 236 Spring 2012

3. © 2011 Pearson Education, Inc. Ch. 16 Overview Reactions of alkyl side chains on benzene Electron-donating and withdrawing effects of substituents for EAS reactions Designing syntheses of di- and tri-substituted benzenes Arenediazonium Salt Reactions Nitrous Acid Mechanism Nucleophilic Aromatic Substitution: Addition- Elimination and Benzyne Mechanisms 2

4. © 2011 Pearson Education, Inc. 3 Examples of Substituted Benzenes

5. © 2011 Pearson Education, Inc. 4 In disubstituted benzenes, the relative positions of the two substituents are indicated by numbers or by prefixes: Nomenclature of Substituted Benzenes

6. © 2011 Pearson Education, Inc. 5 The two substituents are listed in alphabetical order:

7. © 2011 Pearson Education, Inc. 6 Common names are preferred in naming certain substituted benzenes, e.g., toluene, aniline, phenol. Do not deconstruct the common name; e.g., do not change “toluene” to “methylbenzene.” The substituent that is part of the common name is position 1, but do not label as such in the chemical name.

8. © 2011 Pearson Education, Inc. 7 Some disubstituted benzenes have common names that incorporate both substituents:

9. © 2011 Pearson Education, Inc. 8 Naming Polysubstituted Benzenes The substituents are numbered in the direction that results in the lowest possible number:

10. © 2011 Pearson Education, Inc. 9 The substituent incorporated into the common name is the 1-position: Always give substituents the lowest possible numbers!

11. © 2011 Pearson Education, Inc. 10 Substituted benzenes undergo the five electrophilic aromatic substitution reactions discussed in Chapter 15:

12. © 2011 Pearson Education, Inc. 11 The slow step of an electrophilic aromatic substitution reaction is the formation of the carbocation intermediate: Electron-donating substituents increase the rate of substitution reactions by stabilizing the carbocation intermediate. Electron-withdrawing substituents decrease the rate of substitution reactions by destabilizing the carbocation intermediate.

13. © 2011 Pearson Education, Inc. 12 Inductive Electron Withdrawal Electron Donation by Hyperconjugation

14. © 2011 Pearson Education, Inc. 13 Resonance Electron Donation and Withdrawal Substituents such as NH 2, OH, OR, and Cl donate electrons by resonance, but they also withdraw electrons inductively:

15. © 2011 Pearson Education, Inc. 14 Substituents such as C=O, CΞN, SO 3 H, and NO 2 withdraw electrons by resonance:

16. © 2011 Pearson Education, Inc. 15 Electron-donating substituents increase the reactivity of the benzene ring toward electrophilic aromatic substitution Electron-withdrawing substituents decrease the reactivity of the benzene ring toward electrophilic aromatic substitution

17. © 2011 Pearson Education, Inc. 16 Electron donation into the benzene ring by resonance is more significant than inductive electron withdrawal from the ring: Electron-Donating Substituents

18. © 2011 Pearson Education, Inc. 17 Resonance donation into the benzene ring competes with resonance donation into the carbonyl Overall, these substituents weakly release electrons Inductive withdrawal into the benzene ring also occurs

19. © 2011 Pearson Education, Inc. 18 These substituents are less effective in donating electrons into the ring because…

20. © 2011 Pearson Education, Inc. 19 Alkyl, aryl, and CH=CHR groups are weakly activating substituents because they are slightly more electron donating than they are electron withdrawing:

21. © 2011 Pearson Education, Inc. 20 These substituents donate into the ring by resonance and withdraw electrons from the ring inductively: They withdraw electrons inductively more strongly than they donate electrons by resonance

22. © 2011 Pearson Education, Inc. 21 These substituents withdraw electrons both inductively and by resonance:

23. © 2011 Pearson Education, Inc. 22 These substituents are powerful electron-withdrawing groups: Except for the ammonium ions, these substituents withdraw electrons both inductively and by resonance

24. © 2011 Pearson Education, Inc. 23 The substituent already attached to the benzene ring determines the location of the new substituent:

25. © 2011 Pearson Education, Inc. 24 All activating substituents are ortho–para directors:

26. © 2011 Pearson Education, Inc. 25 The weakly deactivating halogens are ortho–para directors:

27. © 2011 Pearson Education, Inc. 26 All substituents that are more deactivating than halogens are meta directors:

28. © 2011 Pearson Education, Inc. 27 An ortho,para-directing substituent:

29. © 2011 Pearson Education, Inc. 28 An ortho,para-directing substituent:

30. © 2011 Pearson Education, Inc. 29 An meta-directing substituent:

31. © 2011 Pearson Education, Inc. 30 Electron-withdrawing groups stabilize a base and therefore increase the strength of its conjugate acid Electron-donating groups destabilize a base and thus decrease the strength of its conjugate acid The Effect of Substituents on pK a

32. © 2011 Pearson Education, Inc. 31 The more electronic deficient a substituent on phenol, the stronger the acid: To understand the relative pK a values, consider the delocalization of the phenolate anion (stars show anion distribution): Unstable Stable: “through resonance” of anion into nitro More stable anion = lower pK a

33. © 2011 Pearson Education, Inc. 32 The more electronic deficient a substituent on benzoic acid, the stronger the acid: Substituent effect on pK a is minimal in benzoic acids because only inductive electronic effects are present: Why? Because the benzene ring is cross conjugated with the carboxylate anion

34. © 2011 Pearson Education, Inc. 33 The more electronic deficient a substituent on a protonated aniline, the stronger the acid: To understand the relative pK a values, consider the delocalization of the aniline lone pair of the conjugate base (stars show anion distribution): Unstable Stable: “through resonance” of lone pair into nitro More stable lone pair = lower pK a

35. © 2011 Pearson Education, Inc. 34 The ortho–para product ratio decreases with an increase in the size of the substituents:

36. © 2011 Pearson Education, Inc. 35

37. © 2011 Pearson Education, Inc. 36 Methoxy and hydroxy substituents are so strongly activating that halogenation is carried out without a Lewis acid: The presence of Lewis acid and excess bromine generates the tribromo derivative:

38. © 2011 Pearson Education, Inc. 37 A benzene ring with a meta director cannot undergo a Friedel–Crafts reaction:

39. © 2011 Pearson Education, Inc. 38 Aniline and N-substituted anilines do not undergo Friedel–Crafts reaction: Phenol and anisole undergo Friedel–Crafts reactions at the ortho and para positions Aniline cannot be nitrated, because it is oxidized by nitric acid

40. © 2011 Pearson Education, Inc. 39 In designing a disubstituted benzene, consider the order of substitution:

41. © 2011 Pearson Education, Inc. 40 The Friedel–Crafts acylation must be carried out first, because the nitro group is strongly deactivating:

42. © 2011 Pearson Education, Inc. 41 In the synthesis of para-chlorobenzoic acid from toluene, the methyl group is oxidized after chlorination: In the synthesis of meta-chlorobenzoic acid, the methyl group is oxidized before chlorination:

43. © 2011 Pearson Education, Inc. 42 To synthesize p-propylbenzenesulfonic acid: Introduce the propyl group by Friedel–Crafts acylation followed by reduction. Sulfonation of the propylbenzene product affords the para derivative. How is the meta derivative prepared? Friedel–Crafts acylation Sulfonation Carbonyl reduction

44. © 2011 Pearson Education, Inc. 43 Synthesis of Trisubstituted Benzenes

45. © 2011 Pearson Education, Inc. 44 Steric hindrance makes the position between the substituents less accessible

46. © 2011 Pearson Education, Inc. 45 A strongly activating substituent will win out over a weakly activating substituent or a deactivating substituent

47. © 2011 Pearson Education, Inc. 46 If the two substituents have similar activating properties, neither will dominate:

48. © 2011 Pearson Education, Inc. 47 Synthesis of Substituted Benzenes Using Arenediazonium Salts

49. © 2011 Pearson Education, Inc. 48 Preparation of the Diazonium Salt Mechanism: Nitrosonium ion formation

50. © 2011 Pearson Education, Inc. 49 Diazonium ion formation: Caution: Diazonium salts are explosive!

51. © 2011 Pearson Education, Inc. 50 The reaction stops because a secondary amine lacks a second proton:

52. © 2011 Pearson Education, Inc. 51 The bulky dialkyl amino group blocks the approach of the nitrosonium ion to the ortho position: [unnumbered fig, pg 690]

53. © 2011 Pearson Education, Inc. 52

54. © 2011 Pearson Education, Inc. 53 Consider the synthesis of para-chloroethylbenzene:

55. © 2011 Pearson Education, Inc. 54 Fluorination and Iodination of Benzene

56. © 2011 Pearson Education, Inc. 55 Hydroxylation of Benzene

57. © 2011 Pearson Education, Inc. 56 Summary of Diazonium Reactions

58. © 2011 Pearson Education, Inc. 57 Synthesis Example Synthetic target: Propose a synthesis from a monosubstituted benzene Answer:

59. © 2011 Pearson Education, Inc. 58 The Arenediazonium Ion as an Electrophile Only highly activated benzene rings can undergo this reaction Substitution takes place preferentially at the para position

60. © 2011 Pearson Education, Inc. 59 However, if the para position is blocked …

61. © 2011 Pearson Education, Inc. 60 Mechanism:

62. © 2011 Pearson Education, Inc. 61 Diazo Dyes Diazonium coupling affords synthetic dyes: Large dipole results in deep color (high extinction coefficient): Electronic “push-pull” produces a dipole

63. © 2011 Pearson Education, Inc. 62 Diazo Dyes and Sulfa Drugs Gerhard Domagk studied the antibiotic properties of diazo dyes. He was awarded the Nobel Prize for medicine in 1939 for his work. Domagk cured his daughter of strep with sulfanilamide Sulfanilamide looks like PABA, a bacterial nutrient: The dye prontosil is reduced to the sulfa drug sulfanilamide

64. © 2011 Pearson Education, Inc. 63 Nucleophilic Aromatic Substitution Reactions Nucleophilic aromatic substitution reactions require at least one strongly electron-withdrawing substituent to occur:

65. © 2011 Pearson Education, Inc. 64 Electron-withdrawing substituents increase the reactivity of the benzene ring toward nucleophilic substitution and decrease the reactivity of the benzene ring toward electrophilic substitution

66. © 2011 Pearson Education, Inc. 65

67. © 2011 Pearson Education, Inc. 66 The electron-withdrawing substituents must be ortho or para to the site of nucleophile attack, so that electrons of the attacking nucleophile can be delocalized into these substituents

68. © 2011 Pearson Education, Inc. 67 The incoming group has to be a stronger base than the group that is being replaced:

69. © 2011 Pearson Education, Inc. 68 Agent Orange and Nucleophilic Aromatic Substitution Synthesis of Agent Orange: Side reaction: Dioxin is carcinogenic and causes birth defects

70. © 2011 Pearson Education, Inc. 69 Formation of Benzyne

71. © 2011 Pearson Education, Inc. 70

72. © 2011 Pearson Education, Inc. 71

73. © 2011 Pearson Education, Inc. 72 Benzyne Is an Extremely Reactive Species

74. © 2011 Pearson Education, Inc. 73 Polycyclic Benzoid Hydrocarbons