1. Created by Professor William Tam & Dr. Phillis Chang Ch. 20 - 1 Chapter 20 Amines

2. Ch. 20 - 2 About The Authors These PowerPoint Lecture Slides were created and prepared by Professor William Tam and his wife, Dr. Phillis Chang. Professor William Tam received his B.Sc. at the University of Hong Kong in 1990 and his Ph.D. at the University of Toronto (Canada) in 1995. He was an NSERC postdoctoral fellow at the Imperial College (UK) and at Harvard University (USA). He joined the Department of Chemistry at the University of Guelph (Ontario, Canada) in 1998 and is currently a Full Professor and Associate Chair in the department. Professor Tam has received several awards in research and teaching, and according to Essential Science Indicators, he is currently ranked as the Top 1% most cited Chemists worldwide. He has published four books and over 80 scientific papers in top international journals such as J. Am. Chem. Soc., Angew. Chem., Org. Lett., and J. Org. Chem. Dr. Phillis Chang received her B.Sc. at New York University (USA) in 1994, her M.Sc. and Ph.D. in 1997 and 2001 at the University of Guelph (Canada). She lives in Guelph with her husband, William, and their son, Matthew.

3. Ch. 20 - 3 1.Nomenclature  1 o Amines  2 o Amines

4. Ch. 20 - 4  3 o Amines

5. Ch. 20 - 5 1A.Arylamines

6. Ch. 20 - 6 1B.Heterocyclic Amines

7. Ch. 20 - 7 2.Physical Properties and Structure of Amines 2A.Physical Properties

8. Ch. 20 - 8 2B.Structure of Amines  N: sp 3 hybridized  Trigonal pyramidal  Bond angles close to 109.5 o

9. Ch. 20 - 9  3 o Amines with three different groups ●The two enantiomeric forms interconvert rapidly  Impossible to resolve enantiomers ●Pyramidal or nitrogen inversion  Barrier ~ 25 kJ/mol  Enough to occur rapidly at room temperature

10. Ch. 20 - 10  Ammonium salts with four different groups enantiomers can be resolved

11. Ch. 20 - 11 3.Basicity of Amines: Amine Salts

12. Ch. 20 - 12  The aminium ion of a more basic amine will have a larger pK a than the aminium ion of a less basic amine

13. Ch. 20 - 13 >> By releasing electrons, R— stabilizes the alkylaminium ion through dispersal of charge >

14. Ch. 20 - 14

15. Ch. 20 - 15 3A.Basicity of Arylamines

16. Ch. 20 - 16 ●Five resonance structures

17. Ch. 20 - 17 ●Only two resonance structures

18. Ch. 20 - 18

19. Ch. 20 - 19 3B.Basicity of Heterocyclic Amines

20. Ch. 20 - 20

21. Ch. 20 - 21 3C.Amines versus Amides  Amides are far less basic than amines (even less basic than arylamines). The pK a of the conjugate acid of a typical amide is about zero Larger resonance stabilization Smaller resonance stabilization

22. Ch. 20 - 22 < >

23. Ch. 20 - 23 3D.Aminium Salts and Quaternary Ammonium Salts However, R 4 N ⊕ ⊖ OH are strong bases (as strong as NaOH) Cannot act as bases

24. Ch. 20 - 24 3E.Solubility of Amines in Aqueous Acids

25. Ch. 20 - 25 3F.Amines as Resolving Agents  Enantiomerically pure amines are often used to resolve racemic forms of acidic compounds by the formation of diastereomeric salts

26. Ch. 20 - 26

27. Ch. 20 - 27 4.Preparation of Amines 4A.Through Nucleophilic Substitution Reactions  Alkylation of ammonia

28. Ch. 20 - 28

29. Ch. 20 - 29  Alkylation of azide ion and reduction

30. Ch. 20 - 30  The Gabriel synthesis

31. Ch. 20 - 31  Alkylation of 3 o amines

32. Ch. 20 - 32 4B.Preparation of Aromatic Amines through Reduction of Nitro Compounds

33. Ch. 20 - 33 4C.Preparation of Primary, Secondary, and Tertiary Amines through Reductive Amination

34. Ch. 20 - 34  Mechanism

35. Ch. 20 - 35  Examples

36. Ch. 20 - 36 4D. Preparation of Primary, Secondary, or Tertiary Amines through Reduction of Nitriles, Oximes, and Amides

37. Ch. 20 - 37  Examples

38. Ch. 20 - 38  Examples

39. Ch. 20 - 39 4D.Preparation of Primary Amines through the Hofmann and Curtius Rearrangements  Hofmann rearrangement

40. Ch. 20 - 40  Examples

41. Ch. 20 - 41  Mechanism

42. Ch. 20 - 42  Curtius rearrangement

43. Ch. 20 - 43 5.Reactions of Amines  Acid-base reactions  Alkylation

44. Ch. 20 - 44  Acylation

45. Ch. 20 - 45  Electrophilic aromatic substitution NH 2 :powerful activating group, ortho-para director

46. Ch. 20 - 46 5A.Oxidation of Amines

47. Ch. 20 - 47 6.Reactions of Amines with Nitrous Acid  Nitrous acid (HONO) is a weak, unstable acid

48. Ch. 20 - 48 6A.Reactions of Primary Aliphatic Amines with Nitrous Acid 1 o aliphatic amine (aliphatic diazonium salt) (highly unstable)

49. Ch. 20 - 49 6B.Reactions of Primary Arylamines with Nitrous Acid (arenediazonium salt) (stable at <5 o C)

50. Ch. 20 - 50  Mechanism

51. Ch. 20 - 51  Mechanism (Cont'd) diazonium ion

52. Ch. 20 - 52 6C.Reactions of Secondary Amines with Nitrous Acid N-Nitroso- amines

53. Ch. 20 - 53 6D.Reactions of Tertiary Amines with Nitrous Acid

54. Ch. 20 - 54 7.Replacement Reactions of Arenediazonium Salts

55. Ch. 20 - 55 7A.Syntheses Using Diazonium Salts

56. Ch. 20 - 56 7B.The Sandmeyer Reaction: Replacement of the Diazonium Group by -Cl, -Br, or -CN

57. Ch. 20 - 57

58. Ch. 20 - 58

59. Ch. 20 - 59 7C.Replacement by —I

60. Ch. 20 - 60 7D.Replacement by —F

61. Ch. 20 - 61 7E.Replacement by —OH

62. Ch. 20 - 62 7F.Replacement by Hydrogen: Deamination by Diazotization

63. Ch. 20 - 63 8.Coupling Reactions of Arenediazonium Salts

64. Ch. 20 - 64  Examples

65. Ch. 20 - 65  Examples

66. Ch. 20 - 66  Examples

67. Ch. 20 - 67 9.Reactions of Amines with Sulfonyl Chlorides

68. Ch. 20 - 68 9A.The Hinsberg Test  Sulfonamide formation is the basis for a chemical test, called the Hinsberg test, that can be used to demonstrate whether an amine is primary, secondary, or tertiary

69. Ch. 20 - 69  1 o Amine

70. Ch. 20 - 70  2 o Amine

71. Ch. 20 - 71  3 o Amine

72. Ch. 20 - 72 10.Synthesis of Sulfa Drugs

73. Ch. 20 - 73 11.Analysis of Amines 11A.Chemical Analysis  Dissolve in dilute aqueous acid  Moist pH paper  basic  Hinsberg test  1 o aromatic amines  azo dye formation with 2-naphthol

74. Ch. 20 - 74 11B.Spectroscopic Analysis  IR ●1 o amines  3300 – 3555 cm -1 (N–H)  two bands ●2 o amines  3300 – 3555 cm -1 (N–H)  one band only ●3 o amines  No bands at 3300 – 3555 cm -1 region

75. Ch. 20 - 75 ●Aliphatic amines  1020 – 1220 cm -1 (C–N) ●Aromatic amines  1250 – 1360 cm -1 (C–N)

76. Ch. 20 - 76  1 H NMR spectra ●1 o and 2 o amines  N–H  (0.5 – 5 ppm), usually broad, exact position depends on the solvent, concentration, purity and temperature ●N–H protons are not usually coupled to protons on adjacent carbons ●Protons on the  carbon of an aliphatic amine are deshielded by the electron- withdrawing effect of the nitrogen and absorb typically in the  2.2–2.9 region

77. Ch. 20 - 77 ●Protons on the  carbon are not deshielded as much and absorb in the range  1.0–1.7

78. Ch. 20 - 78  13 C NMR spectra 23.034.0 14.329.742.5 13 C NMR chemical shifts (  )

79. Ch. 20 - 79  Mass spectra ●The molecular ion in the mass spectrum of an amine has an odd number mass (unless there is an even number of nitrogen atoms in the molecule) ●The peak for the molecular ion is usually strong for aromatic and cyclic aliphatic amines but weak for acyclic aliphatic amines ●Cleavage between the  and  carbons of aliphatic amines is a common mode of fragmentation

80. Ch. 20 - 80 12.Eliminations Involving Ammonium Compounds 12A.The Hofmann Elimination

81. Ch. 20 - 81

82. Ch. 20 - 82  Although most eliminations involving neutral substrates tend to follow the Zaitsev rule, eliminations with charged substrates tend to follow what is called the Hofmann rule and yield mainly the least substituted alkene

83. Ch. 20 - 83

84. Ch. 20 - 84 12B.The Cope Elimination

85. Ch. 20 - 85 13.Summary of Preparations and Reactions of Amines  Preparation of amines

86. Ch. 20 - 86

87. Ch. 20 - 87  Reactions of amines

88. Ch. 20 - 88

89. Ch. 20 - 89

90. Ch. 20 - 90  END OF CHAPTER 21 