1. Chapter 21 Amines Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.

2. 21.1 Amine Nomenclature Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.

3. Alkylamine: N attached to alkyl group. Arylamine: N attached to aryl group. Primary, secondary, or tertiary: is determined by number of carbon atoms directly attached to nitrogen. Classification of Amines

4. Two IUPAC styles: 1) Analogous to alcohols: replace -e ending with –amine. E.g. pentanamine 2) Name alkyl group and attach -amine as a suffix. E.g. isopropylamine Nomenclature of Primary Alkylamines (RNH 2 )

5. Examples: Some Primary Alkylamines CH 3 CHCH 2 CH 2 CH 3 NH 2 (RNH 2 : one carbon directly attached to N) CH 3 CH 2 NH 2 NH 2 ethylamine or ethanamine cyclohexylamine or cyclohexanamine 1-methylbutylamine or 2-pentanamine or pentan-2-amine

6. Name as derivatives of aniline. Nomenclature of Primary Arylamines (ArNH 2 ) p-fluoroaniline or 4-fluoroaniline 5-bromo-2-ethylaniline NH 2 F BrCH 2 CH 3

7. Amino Groups as Substituents p-aminobenzaldehyde Amino groups rank below OH groups and higher oxidation states of carbon. In such cases name the amino group as a substituent. See list of functional group priorities, Ch 17. NH 2 HC O HOCH 2 CH 2 NH 2 2-aminoethanol

8. Name as N-substituted derivatives of the parent primary amine. (N is a locant and is not alphabetized. It is treated the same way as a numerical locant). The parent amine is one with longest carbon chain. Secondary and Tertiary Amines

9. Examples CH 3 NHCH 2 CH 3 N-methylethylamine NHCH 2 CH 3 NO 2 Cl 4-chloro-N-ethyl-3-nitroaniline CH 3 N N,N-dimethylcycloheptylamine

10. From a primary From a tertiaryamine. Ammonium Salts CH 3 NH 3 + Cl – methylammonium chloride + N CH 3 H CH 2 CH 3 CF 3 CO 2 – N-ethyl-N-methylcyclopentylammonium trifluoroacetate

11. When all four atoms attached to N are carbon, the ion is called a quaternary ammonium ion and salts that contain it are called quaternary ammonium salts. + CH 2 N CH 3 I – benzyltrimethylammonium iodide Ammonium Salts

12. 21.2 Structure and Bonding Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.

13. 147 pm 106° 112° Alkylamines The most prominent feature is high electrostatic potential at nitrogen. Reactivity of nitrogen lone pair dominates properties of amines.

14. Compare geometry at N of: aniline (next slide), methylamine and formamide. sp 3 sp 2 Geometry at N Pyramidal geometry at sp 3 -hybridized N in methylamine. Planar geometry at sp 2 -hybridized N in formamide. C O NH 2 H C H H H

15. Angle that the C—N bond makes with bisector of H—N—H angle is a measure of geometry at N. sp 3 sp 2 Geometry at N ~125° 180° 142.5° Note: This angle is not the same as the H—N—H bond angle. aniline

16. Geometry at N 142.5° Geometry at N in aniline is pyramidal; closer to methylamine than to formamide. Hybridization of N in aniline lies between sp 3 and sp 2. Lone pair of N can be delocalized into ring best if N is sp 2 and lone pair is in a p orbital. Lone pair bound most strongly by N if pair is in an sp 3 orbital of N, rather than p. Actual hybridization is a compromise that maximizes binding of lone pair.

17. Electrostatic Potential Maps of Aniline Nonplanar geometry at N. Region of highest negative potential is at N. Planar geometry at N. High negative potential shared by N and ring. Figure 21.2 (page 934)

18. 21.3 Physical Properties Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.

19. Amines are more polar and have higher boiling points than alkanes; but are less polar and have lower boiling points than alcohols. Physical Properties CH 3 CH 2 CH 3 CH 3 CH 2 NH 2 CH 3 CH 2 OH dipole moment (  ): boiling point: 0 D1.2 D1.7 D -42°C17°C78°C

20. Boiling points of isomeric amines decrease in going from primary to secondary to tertiary amines. Primary amines have two hydrogens on N capable of being involved in intermolecular hydrogen bonding. Secondary amines have one. Tertiary amines cannot be involved in intermolecular hydrogen bonds. Physical Properties CH 3 CH 2 NHCH 3 CH 3 CH 2 CH 2 NH 2 (CH 3 ) 3 N b.p. less H-bonding and more branching 50°C34°C3°C

21. 21.4 Basicity of Amines Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.

22. AmineConj. AcidpK a NH 3 NH 4 + 9.3 CH 3 CH 2 NH 2 CH 3 CH 2 NH 3 + 10.8 Table 21.1 Basicity of Amines in Aqueous Solution CH 3 CH 2 NH 3 + is a weaker acid than NH 4 + ; therefore, CH 3 CH 2 NH 2 is a stronger base than NH 3. 1. Alkylamines are slightly stronger bases than ammonia (alkyl is weakly e-donating).

23. AmineConj. AcidpK a NH 3 NH 4 + 9.3 CH 3 CH 2 NH 2 CH 3 CH 2 NH 3 + 10.8 (CH 3 CH 2 ) 2 NH(CH 3 CH 2 ) 2 NH 2 + 11.1 (CH 3 CH 2 ) 3 N(CH 3 CH 2 ) 3 NH + 10.8 Notice that the difference separating a primary, secondary, and tertiary amine is only 0.3 pK units. Table 21.1 Basicity of Amines in Aqueous Solution 2. Alkylamines differ very little in basicity.

24. AmineConj. AcidpK a NH 3 NH 4 + 9.3 CH 3 CH 2 NH 2 CH 3 CH 2 NH 3 + 10.8 (CH 3 CH 2 ) 2 NH(CH 3 CH 2 ) 2 NH 2 + 11.1 (CH 3 CH 2 ) 3 N(CH 3 CH 2 ) 3 NH + 10.8 C 6 H 5 NH 2 C 6 H 5 NH 3 + 4.6 3. Arylamines are much weaker bases than ammonia or alkyl amines. (Aryl is an EWG.) Table 21.1 Basicity of Amines in Aqueous Solution

25. Summary: Effects of Structure on Basicity 1. Alkylamines are slightly stronger bases than ammonia. 2. Alkylamines differ very little in basicity. 3. Arylamines are much weaker bases than ammonia.

26. H2NH2N Decreased Basicity of Arylamines + + HN H H NH 2 + + H3NH3N pK a = 4.6 pK a =10.6 Stronger acid Weaker acid Stronger base Weaker base K = 10 6 Comparison of aryl and alkyl amine basicity. aniline cyclohexylamine

27. + H2NH2N + H HN H NH 2 + + H3NH3N Stronger acid Weaker acid When anilinium ion loses a proton, the resulting lone pair is delocalized into the ring through resonance. Thus, aniline is a weaker base since the electrons are less available. Decreased Basicity of Arylamines Weaker base Stronger base

28. C 6 H 5 NH 2 (C 6 H 5 ) 2 NH(C 6 H 5 ) 3 N pK a of conj. acid: 4.60.8~-5 Increasing delocalization (more possible resonance structures) makes diphenylamine a weaker base than aniline, and triphenylamine a weaker base than diphenylamine. Decreased Basicity of Arylamines

29. Effect of Substituents on Basicity of Arylamines 1. Alkyl groups (EDG) on the ring increase basicity, but only slightly (less than 1 pK unit). XNH 2 XpK a of conjugate acid H4.6 CH 3 5.3

30. Effect of Substituents on Basicity of Arylamines 2. Electron withdrawing groups (EWG), especially ortho and/or para to amine group, decrease basicity and can have a large effect. XNH 2 XpK a of conjugate acid H4.6 CF 3 3.5 NO 2 1.0

31. p-Nitroaniline NH 2 O N O – + N O O – – NH 2 + + The lone pair on -NH 2 is conjugated with the p- nitro group (more delocalization than in aniline). This delocalization is lost on protonation of -NH 2. Aniline is 3800 times more basic than p-nitroaniline. Aniline is ~1,000,000,000 times more basic than 2,4-dinitroaniline.

32. Heterocyclic Amines N H N is more basic than piperidinepyridine pK a of conjugate acid: 11.2 pK a of conjugate acid: 5.2 (an alkylamine) (resembles an arylamine in basicity)

33. Heterocyclic Amines N is more basic than imidazolepyridine pK a of conjugate acid: 7.0 pK a of conjugate acid: 5.2 N H N

34. Imidazole N H N Which nitrogen is protonated in imidazole ? H+H+ H+H+ N H N H + + N H N H loss of aromaticity

35. Imidazole N H N Protonation in the direction shown gives a resonance stabilized cation. H+H+ N H N H + N H N H + resonance stabilized cation

36. 21.5 Tetraalkylammonium Salts as Phase-Transfer Catalysts

37. Phase-Transfer Catalysis Phase-transfer agents promote the solubility of ionic substances in nonpolar solvents. They are able to transfer the ionic substance from an aqueous phase to a non-aqueous one. Phase-transfer agents increase the rates of reactions involving anions. The anion when in nonpolar media is relatively unsolvated and very reactive compared to media like water or alcohols.

38. + Phase-Transfer Catalysis Quaternary ammonium salts are phase-transfer catalysts. They are soluble in nonpolar solvents. N H3CH3C CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 Cl – Methyltrioctylammonium chloride

39. Phase-Transfer Catalysis The substituents on N are nonpolar thus enhance the solubility of the ion in nonpolar solvents. Benzyltriethylammonium chloride Cl – + N CH 2 CH 3 CH 2

40. Example The S N 2 reaction of sodium cyanide with butyl bromide occurs much faster when benzyl- triethylammonium chloride is present than when it is not. CH 3 CH 2 CH 2 CH 2 Br + NaCN CH 3 CH 2 CH 2 CH 2 CN + NaBr benzyltriethylammonium chloride

41. Cl – (aqueous) CN – + Cl – + CN – (aqueous) Anion exchange in the aqueous phase + N CH 2 CH 3 CH 2 + N CH 2 CH 3 CH 2 Mechanism

42. CN – (aqueous solvent) (butyl bromide used as solvent) CN – Mechanism Transfer to the organic phase + N CH 2 CH 3 CH 2 + N CH 2 CH 3 CH 2

43. CN – CH 3 CH 2 CH 2 CH 2 Br+ Br – CH 3 CH 2 CH 2 CH 2 CN+ Mechanism SN2 reaction in the organic phase + N CH 2 CH 3 CH 2 + N CH 2 CH 3 CH 2 (butyl bromide solvent)

44. 21.6 Reactions That Lead to Amines: A Review and a Preview

45. Preparation of Amines Two questions to answer: 1) How is the C—N bond to be formed ? 2) How do we obtain the correct oxidation state of nitrogen (and carbon) ?

46. Methods for C—N Bond Formation 1. Nucleophilic substitution by azide ion (N 3 – ) (Section 8.1, 8.11) 2. Nitration of arenes (Section 12.3) 3. Nucleophilic ring opening of epoxides by ammonia or amines (Section 16.12) 4. Nucleophilic addition of amines to aldehydes and ketones (Sections 17.10, 17.11) 5. Nucleophilic substitution by ammonia on  -halo acids (Section 20.15) 6. Nucleophilic acyl substitution (Sections 19.4, 19.5, and 19.11)

47. 21.7 Preparation of Amines by Alkylation of Ammonia

48. Alkylation of Ammonia Desired reaction is: 2 NH 3 +R—XR—NH 2 + NH 4 X via: H3NH3N R X H3NH3N R + X – + + then: H3NH3N + + H N H H R H3NH3N H + + N H H R

49. Alkylation of Ammonia The method doesn't work well in practice because it usually gives mixtures of primary, secondary, and tertiary amines, plus the quaternary salt due to multiple alkylation. NH3NH3 RX RNH2RNH2 R2NHR2NH R3NR3N R4NR4N + X – (mixtures)

50. Example CH 3 (CH 2 ) 6 CH 2 Br NH 3 CH 3 (CH 2 ) 6 CH 2 NH 2 (45%) + CH 3 (CH 2 ) 6 CH 2 NHCH 2 (CH 2 ) 6 CH 3 (43%) As octylamine is formed, it competes with ammonia for the remaining 1-bromooctane. Reaction of octylamine with 1-bromooctane gives N,N-dioctylamine.

51. 21.8 The Gabriel Synthesis of Primary Alkyl Amines

52. This method yields primary amines without formation of secondary or other amines as byproducts. It uses an S N 2 reaction on an alkyl halide to form the C—N bond. The nitrogen-containing nucleophile is N-potassiophthalimide. Gabriel Synthesis O O N K + –

53. The pKa of phthalimide is 8.3. N-potassiophthalimide is easily prepared by the reaction of phthalimide with KOH. O O N – K + O O NHNH KOH N-Potassiophthalimide

54. – N-Potassiophthalimide as a Nucleophile O O N R X + O O N R + X – SN2SN2 The N of phthaIimide becomes the N in the primary amine.

55. Cleavage of Alkylated Phthalimide O O N R + H2OH2O H2NH2N R + CO 2 H acid or base Imide hydrolysis is nucleophilic acyl substitution. primary amine

56. Cleavage of Alkylated Phthalimide Hydrazinolysis is an alternative method of releasing the amine from its phthalimide derivative. O O N R H2NH2N R + O O NH H 2 NNH 2

57. – O O K + N + C 6 H 5 CH 2 Cl DMF O O N CH 2 C 6 H 5 (74%) Example

58. + C 6 H 5 CH 2 NH 2 O O N CH 2 C 6 H 5 H 2 NNH 2 (97%) O O NH

59. 21.9 Preparation of Amines by Reduction

60. Almost any nitrogen-containing compound can be reduced to an amine, including: azides, nitriles, nitro-substituted benzene derivatives, and amides. Preparation of Amines by Reduction

61. S N 2 reaction, followed by reduction, gives a primary alkylamine. Synthesis of Amines via Azides CH 2 CH 2 BrCH 2 CH 2 N 3 NaN 3 (74%) CH 2 CH 2 NH 2 (89%) 1. LiAlH 4 2. H 2 O Azides may also be reduced by catalytic hydrogenation.

62. Synthesis of Amines via Nitriles CH 3 CH 2 CH 2 CH 2 Br NaCN (69%) CH 3 CH 2 CH 2 CH 2 CN CH 3 CH 2 CH 2 CH 2 CH 2 NH 2 (56%) H 2 (100 atm), Ni Nitriles may also be reduced by lithium aluminum hydride. S N 2 reaction, followed by reduction, gives a primary alkylamine. The reduction also works with cyanohydrins.

63. Synthesis of Amines via Nitroarenes HNO 3 (88-95%) Cl NO 2 H 2 SO 4 (95%) 1. Fe, HCl 2. NaOH Cl NH 2 Aryl nitro groups may be reduced with Sn or Fe + HCl or by catalytic hydrogenation.

64. Synthesis of Amines via Amides (86-89%) COH O 1. SOCl 2 2. (CH 3 ) 2 NH CN(CH 3 ) 2 O (88%) 1. LiAlH 4 2. H 2 O CH 2 N(CH 3 ) 2 Only LiAlH 4 is an appropriate reducing agent for this reaction.

65. 21.10 Reductive Amination

66. The aldehyde or ketone equilibrates with the imine faster than hydrogenation of C=O occurs. Synthesis of Amines via Reductive Amination + NH 3 fast + H2OH2O In reductive amination, an aldehyde or ketone is subjected to catalytic hydrogenation in the presence of ammonia or an amine. O C R R' NH C R R'

67. Synthesis of Amines via Reductive Amination O C R R' + NH 3 fast NH C R R' + H2OH2O H 2, Ni NH 2 R R' C H And the imine undergoes hydrogenation faster than the aldehyde or ketone, so an amine is the product.

68. Example: Ammonia Gives a Primary Amine O +NH 3 H NH 2 H 2, Ni ethanol (80%) via: NH Sodium triacetoxyborohyride, Na(CH 3 CO 2 ) 3 BH, is a useful chemical reagent for this reduction. It is readily available and non-toxic. Catalytic reduction is shown below.

69. Example: Primary Amines Give Secondary Amines H 2, Niethanol (65%) CH 3 (CH 2 ) 5 CH 2 NH + H2NH2N CH 3 (CH 2 ) 5 CH O via: NCH 3 (CH 2 ) 5 CH

70. Example: Secondary Amines Give Tertiary Amines H 2, Ni, ethanol (93%) + CH 3 CH 2 CH 2 CH O N H N CH 2 CH 2 CH 2 CH 3

71. CHCH 2 CH 2 CH 3 N + Possible intermediates for the prevoius reaction include: N CH CHCH 2 CH 3 CHCH 2 CH 2 CH 3 N HO Example: Secondary Amines Give Tertiary Amines

72. 21.11 Reactions of Amines: A Review and a Preview

73. Reactions of Amines Reactions of amines almost always involve the nitrogen lone pair, either: N H X as a base: N C O as a nucleophile: or Attacks H Attacks C

74. Reactions of Amines 1. Basicity (Section 21.4). 2. Reaction with aldehydes and ketones (Sections 17.10, 17.11). 3. Reaction with acyl chlorides (Section 19.4), anhydrides (Section 19.5), and esters (Section 19.11). Reactions already discussed

75. 21.12 Reaction of Amines with Alkyl Halides

76. Amines act as nucleophiles toward alkyl halides. X + N R H + X N R H + – + N R H + Reaction with Alkyl Halides

77. NH 2 + ClCH 2 NHCH 2 (85-87%) NaHCO 3 90°C (4 mol)(1 mol) Example: Excess amine

78. + CH 3 I (99%) methanolheat CH 2 N(CH 3 ) 3 CH 2 NH 2 + I – Example: Excess alkyl halide (3 mol)(1 mol) This is referred to as exhaustive methylation.

79. 21.14 Electrophilic Aromatic Substitution in Aryl Amines

80. Nitration of Aniline NH 2 is a very strongly activating group. NH 2 not only activates the ring toward electrophilic aromatic substitution, it also makes it more easily oxidized. Attempted nitration of aniline fails because nitric acid oxidizes aniline to a black tar.

81. Strategy for Nitration of Aniline Step 1: Decrease the reactivity of aniline by converting the NH 2 group to an amide. CH(CH 3 ) 2 NH 2 CH(CH 3 ) 2 NHCCH 3 O O CH 3 COCCH 3 O (98%) (acetyl chloride may be used instead of acetic anhydride)

82. Step 2: Nitrate the amide formed in the first step. CH(CH 3 ) 2 NHCCH 3 O HNO 3 CH(CH 3 ) 2 NHCCH 3 O NO 2 (94%) Strategy for Nitration of Aniline

83. Step 3: Remove the acyl group from the amide by hydrolysis. CH(CH 3 ) 2 NHCCH 3 O NO 2 KOH ethanol, heat CH(CH 3 ) 2 NH 2 NO 2 (100%) Strategy for Nitration of Aniline

84. This occurs readily without necessity of protecting amino group, but difficult to limit it to monohalogenation. Halogenation of Arylamines CO 2 H NH 2 Br 2 acetic acid (82%) CO 2 H NH 2 Br

85. Monohalogenation of Arylamines Cl NHCCH 3 O CH 3 (74%) Cl 2 acetic acid NHCCH 3 O CH 3 Decreasing the reactivity of the arylamine by converting the NH 2 group to an amide allows halogenation to be limited to monosubstitution.

86. Friedel-Crafts Reactions The amino group of an arylamine must be protected as an amide when carrying out a Friedel-Crafts reaction3 NHCCH 3 O CH 2 CH 3 CH 3 CCl O AlCl 3 (57%) NHCCH 3 O CH 2 CH 3 CCH 3 O Otherwise –NH 2 will complex with the AlCl 3.

87. 21.15 Nitrosation of Alkylamines

88. Nitrite Ion, Nitrous Acid, and Nitrosyl Cation H + – O NO O NO H H + O NO H H + + NO + O H H nitrite ion nitrous acid nitrosyl cation

89. Nitrosyl Cation and Nitrosation + NO + NN NO + The nitrosation reaction.

90. Nitrosation of Secondary Alkylamines + NO + H + N NO N NO + H Nitrosation of secondary amines gives an N-nitroso amine. N H R R R R R R

91. Example (CH 3 ) 2 NH NaNO 2, HCl H2OH2O (88-90%) (CH 3 ) 2 N NO N-nitrosodimethylamine (leather tanning)

92. Some N-Nitroso Amines N-nitrosopyrrolidine (nitrite-cured bacon) N N O N-nitrosonornicotine (tobacco smoke) N N O N

93. Nitrosation of Primary Alkylamines + Analogous to nitrosation of secondary amines to this point. + NO N H H R N NO + H H R + H + N NO R H

94. Nitrosation of Primary Alkylamines H + N NO R H H + This species reacts further. N NO R H H + H + + H N NO R H + N NO R H

95. Nitrosation of Primary Alkylamines H O H + Nitrosation of a primary alkylamine gives an alkyl diazonium ion. Process is called diazotization. + H N NO R H + N N R

96. Primary Alkyl Diazonium Ions + N N R Primary alkyl diazonium ions are unstable and readily lose N 2 to give carbocations. R + + N N

97. Example: Nitrosation of 1,1-Dimethylpropylamine NH 2 N N + HONO H2OH2O OH (80%) + (2%)(3%) + – N 2 Mechanism 21.2

98. There is no useful chemistry associated with the nitrosation of tertiary alkylamines. Nitrosation of Tertiary Alkylamines N R R R N NO + R R R

99. 21.16 Nitrosation of Arylamines

100. Reaction that occurs is electrophilic aromatic substitution. Nitrosation of Tertiary Arylamines N(CH 2 CH 3 ) 2 (95%) 1. NaNO 2, HCl, H 2 O, 8°C 2. HO – N(CH 2 CH 3 ) 2 N O

101. Similar to secondary alkylamines; Gives N-nitroso amines Nitrosation of N-Alkylarylamines NaNO 2, HCl, H 2 O, 10°C NHCH 3 (87-93%) NCH 3 NO

102. Nitrosation of Primary Arylamines Gives aryl diazonium ions. Aryl diazonium ions are much more stable than alkyl diazonium ions. Most aryl diazonium ions are stable under the conditions of their formation (0-10°C). ArN N + RNN + fast slow R + + N2N2 Ar + + N2N2 Alkyl: Aryl:

103. Example: (CH 3 ) 2 CH NH 2 NaNO 2, H 2 SO 4 H 2 O, 0-5°C (CH 3 ) 2 CH N N + HSO 4 –

104. Synthetic Origin of Aryl Diazonium Salts Ar H NO 2 Ar NH 2 Ar N N +

105. 21.17 Synthetic Transformations of Aryl Diazonium Salts

106. Transformations of Aryl Diazonium Salts Ar N N + H OHOH I F Br Ar Cl Ar CN

107. Preparation of Phenols Ar OH H 2 O, heat Ar N N +

108. Example 2. H 2 O, heat (CH 3 ) 2 CH NH 2 1. NaNO 2, H 2 SO 4 H 2 O, 0-5°C (CH 3 ) 2 CH OH (73%)

109. Preparation of Aryl Iodides Ar I Reaction of an aryl diazonium salt with potassium iodide: KI Ar N N +

110. Example 2. KI, room temp. 1. NaNO 2, HCl H 2 O, 0-5°C (72-83%) NH 2 Br I

111. Preparation of Aryl Fluorides Ar F Heat the tetrafluoroborate salt of a diazonium ion; process is called the Schiemann reaction. Ar N N +

112. Example (68%) NH 2 CCH 2 CH 3 O 2. HBF 4 1. NaNO 2, HCl, H 2 O, 0-5°C 3. heat F CCH 2 CH 3 O

113. Preparation of Aryl Chlorides and Bromides Ar Br Ar Cl Aryl chlorides and aryl bromides are prepared by heating a diazonium salt with copper(I) chloride or bromide. Substitutions of diazonium salts that use copper(I) halides are called Sandmeyer reactions. Ar N N +

114. Example (68-71%) NH 2 NO 2 2. CuCl, heat 1. NaNO 2, HCl, H 2 O, 0-5°C Cl NO 2

115. Example (89-95%) 2. CuBr, heat 1. NaNO 2, HBr, H 2 O, 0-10°C NH 2 Cl Br Cl

116. Preparation of Aryl Nitriles Ar CN Aryl nitriles are prepared by heating a diazonium salt with copper(I) cyanide. This is another type of Sandmeyer reaction. Ar N N +

117. Example (64-70%) 2. CuCN, heat 1. NaNO 2, HCl, H 2 O, 0°C NH 2 CH 3 CN CH 3

118. Transformations of Aryl Diazonium Salts Ar N N + H Hypophosphorous acid (H 3 PO 2 ) reduces diazonium salts; ethanol does the same thing. This is called reductive deamination.

119. Example (70-75%) NaNO 2, H 2 SO 4, H 3 PO 2 NH 2 CH 3 or NaNO 2, HCl, CH 3 CH 2 OH

120. Value of Diazonium Salts 1. Allows introduction of substituents such as OH, F, I, and CN on the ring. 2. Allows preparation of otherwise difficultly accessible substitution patterns.

121. Example Br NH 2 Br (74-77%) NaNO 2, H 2 SO 4, H 2 O, CH 3 CH 2 OH NH 2 Br 2 H2OH2O (100%)

122. 21.18 Azo Coupling

123. Azo Coupling Diazonium salts are weak electrophiles. React with strongly activated aromatic compounds by electrophilic aromatic substitution. Ar N N + Ar' H + Ar N N Ar' an azo compound Ar' must bear a strongly electron-releasing group such as OH, OR, or NR 2.

124. Example OH + C6H5NC6H5N N + N NC 6 H 5 Cl –

125. 21.13 The Hofmann Elimination

126. The Hofmann Elimination This is an elimination reaction involving a quaternary ammonium hydroxide as the reactant and an alkene is the product. It is an anti elimination. The leaving group is a trialkylamine. The regioselectivity is opposite to the Zaitsev rule.

127. Ag 2 OH 2 O, CH 3 OH CH 2 N(CH 3 ) 3 + HO – These are prepared by treating quaternary ammmonium halides with moist silver oxide. HO replaces I and AgI precipitates. CH 2 N(CH 3 ) 3 I – + Quaternary Ammonium Hydroxides +AgI ↓ ––

128. 160°C CH 2 N(CH 3 ) 3 + HO – When heated, quaternary ammonium hydroxides undergo elimination. CH 2 (69%) + N(CH 3 ) 3 + H2OH2O The Hofmann Elimination

129. H CH 2 + N(CH 3 ) 3 – O H O H H N(CH 3 ) 3 CH 2 The Hofmann Elimination + +

130. heat Elimination occurs in the direction that gives the less-substituted double bond. This is called the Hofmann rule. N(CH 3 ) 3 + HO – CH 3 CHCH 2 CH 3 H2CH2CCHCH 2 CH 3 CH 3 CHCHCH 3 + (95%) (5%) Regioselectivity 1 2 3 4

131. Steric factors are important in the determining the regioselectivity of this elimination. The transition state that leads to 1-butene is less crowded than the one leading to cis or trans-2-butene. Regioselectivity

132. +N(CH 3 ) 3 H H H H CH 3 CH 2 largest group is between two H atoms. C H C H H CH 3 CH 2 major product Regioselectivity Looking down the 1-2 bond

133. +N(CH 3 ) 3 H H H CH 3 largest group is between an H atom and a methyl group. C H C CH 3 H minor product CH 3 Regioselectivity Looking down the 2-3 bond

134. 21.19 Spectroscopic Analysis of Amines

135. The N—H stretching band appears in the range 3000-3500 cm -1. Primary amines give two peaks in this region, one for a symmetrical stretching vibration, the other for an antisymmetrical stretch. Infrared Spectroscopy R N H H symmetric R N H H antisymmetric

136. Primary amines give two N—H stretching peaks, secondary amines give one (Figure 21.8). Infrared Spectroscopy

137. Compare chemical shifts in: 1 H NMR H3CH3C CH 2 NH 2 H3CH3C CH 2 OH N C H is more shielded than  3.9 ppm  4.7 ppm O C H

138. 13 C NMR Carbons bonded to N are more shielded than those bonded to O. CH 3 NH 2 CH 3 OH  26.9 ppm  48.0 ppm

139. max 204 nm 256 nm max 230 nm 280 nm max 203 nm 254 nm An amino group on a benzene ring shifts max to longer wavelength. Protonation of N causes UV spectrum to resemble that of benzene. UV-VIS NH 2 NH 3 +

140. Mass Spectrometry Compounds that contain only C, H, and O have even molecular weights. If an odd number of N atoms is present, the molecular weight is odd. A molecular-ion peak with an odd m/z value suggests that the sample being analyzed contains N. In fragmentation, a primary amine generates an M/Z of 30 and the (+) fragment is a monosubstituted N. (CH 2 NH 2 ) +

141. (CH 3 ) 2 NCH 2 CH 2 CH 2 CH 3 e–e– (CH 3 ) 2 NCH 2 CH 2 CH 2 CH 3 + CH 2 CH 2 CH 3 + (CH 3 ) 2 N CH 2 + Mass Spectrometry Nitrogen stabilizes carbocations, which drives the fragmentation pathways. With a 3 o amine, the (+) fragment is a trisubstituted N.

142. CH 3 NHCH 2 CH 2 CH(CH 3 ) 2 e–e– CH 3 NHCH 2 CH 2 CH(CH 3 ) 2 + CH 2 CH(CH 3 ) 2 + CH 3 NH CH 2 + Mass Spectrometry And with a 2 o amine, the (+) fragment is a disubstituted N.

143. End of Chapter 21 Amines