Amines. Amines are bases usually the base involved in biochemical acid-base reactions.

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1 Amines

2 Amines Amines are derivatives of ammonia. Amines are bases usually the base involved in biochemical acid-base reactions. Vitamins comes from the term vital amines - not all vitamins are amines.

3 21.1 Amine Nomenclature

4 Amine Nomenclature Amines are classified by the degree of substitution at N. Primary amine Secondary amine Tertiary amine Amines are named as alkylamines or as alkanamines. Ethylamine or ethanamine Cyclohexylamine or cyclohexanamine 1-Methylbutylamine or 2-pentanamine

5 Amine Nomenclature Aniline is the parent name for amino derivatives of benzene. p-fluoroaniline or 4-Fluoroaniline 5-Bromo-2-ethylaniline Compounds with two amines are named as diamines. 1,2-Propanediamine or Propane-1,2-diamine 1,6-Hexanediamine or hexane-1,6-diamine 1,4-Benzenediamine or benzene-1,4-diamine

6 Amine Nomenclature Amines as substituents are called an amino substituent. 2-Aminoethanol p-aminobenzaldehyde Substuents on the amine have N as locant. 4-Chloro-N-ethyl-3-nitroaniline N,N-Dimethylcycloheptylamine

7 Amine Nomenclature Quaternary amines are named as ammonium ions. Methylammonium chloride N-Ethyl-N-methylcyclopentylammonium trifluoroacetate Benzyltrimethylammonium iodide

8 21.2 Structure and Bonding

9 Structure and Bonding In alkylamines nitrogen and carbon are both sp 3 hybridized with a concentration of electron density on the nitrogen.

10 Structure and Bonding In arylamines like aniline the pyramidal nitrogen is flattened suggesting hybridization in between sp 3 and sp 2. Methylamine Aniline Formamide Electrostatic potential map should be a compromise between the maps with sp 3 than sp 2 N shown.

11 Structure and Bonding In arylamines resonance structures show the delocalization of the N lone pair of electrons. Most stable Lewis structure for aniline

12 21.3 Physical Properties

13 Physical Properties Amines are more polar than alkanes and less polar than alcohols and the dipole moment and boiling points reflect this. CH 3 CH 2 CH 3 m = 0 D bp -42 C CH 3 CH 2 NH 2 m = 1.2 D bp 17 C CH 3 CH 2 OH m = 1.7 D bp 78 C

14 Physical Properties Primary amines are more polar than secondary amines which are more polar than tertiary amines and the boiling points reflect this. CH 3 CH 2 CH 3 NH 2 bp 50 C CH 3 CH 2 NHCH 3 bp 34 C (CH 3 ) 3 N bp 3 C

15 21.4 Basicity of Amines

16 Basicity of Amines When considering the basicity of amines, bear in mind that: The more basic the amine, the weaker its conjugate acid. The more basic the amine, the larger the pk a of its conjugate acid. In acid amines are protonated: pk a 4.7 pk a 10.7 In base ammonium salts are deprotonated: pk a 10.7 pk a 15.7

17 Relative Basicity of Amines The most important relationships are: 1. Alkylamines are slightly stronger bases than ammonia. 2. Alkylamines differ very little among themselves in basicity. 3. Arylamines are about 1 million times (6 pk units) weaker bases than ammonia and alkylamines. pk a 4.6 pk a 10.6

18 Relative Basicity of Amines

19 Relative Basicity of Amines Conjugation of a second aryl group further decreases the basicity of an arylamine. Amine C 6 H 5 NH 2 (C 6 H 5 ) 2 NH (C 6 H 5 ) 3 N pk a of conjugate acid:

20 Relative Basicity of Amines Effect of aryl substitution on the basicity of an arylamine. Resonance delocalization of the unshared electron pair of the amine group onto the nitro substituent.

21 Relative Basicity of Amines Nonaromatic heterocyclic compounds, piperidine, for example, are similar in basicity to alkylamines. Piperidine pk a of conjugate acid 11.2 Pyridine pk a of conjugate acid 5.2 When nitrogen is part of an aromatic ring its basicity decreases markedly. Pyridine resembles an arylamine.

22 Relative Basicity of Amines Imidazole is 100 times more basic than pyridine. The ion is stabilized by the electron delocalization shown in the resonance structures. Electrostatic potential map shows this.

23 Amines as Natural Products An imidazole ring is a structural unit in two biologically important compounds, histidine and histamine. Histidine Other well-known amines. Histamine Nicotine Cocaine

24 Amines as Natural Products Neurotransmitters: Epinephrine Serotonin Polyamines that exist as polycations in the blood stream: Spermidine Spermine

25 21.5 Tetraalkylammonium Salts as Phase-Transfer Catalysts

26 Tetraalkylammonium Salts as Phase-Transfer Catalysts Many quaternary ammonium salts are soluble in solvents of low polarity such as benzene, decane, and halogenated hydrocarbons. Methyltrioctylammonium chloride Benzyltriethylammonium chloride

27 Phase-Transfer Catalysis These quaternary ammonium salts catalyze reactions carried out with two phases: aqueous and an immiscible organic phase. aqueous organic

28 21.6 Reactions That Lead to Amines: A Review and a Preview

31 21.7 Preparation of Amines by Alkylation of Ammonia

32 Preparation of Amines by Alkylation of Ammonia Reaction equation: Limitation is polyalkylation: Octylamine (45%) N,N-Dioctylamine (43%)

33 21.8 The Gabriel Synthesis of Primary Alkylamines

34 A three step process. The Gabriel Synthesis Step 1. Formation of N-Potassiophthalimide. pk a 8.3 pk a 15.7 Step 2. Alkylation of N-Potassiophthalimide.

35 The Gabriel Synthesis Step 3. Release of the primary amine. Aqueous acid or base can also be used.

36 21.9 Preparation of Amines by Reduction

37 Reduction of Azides Reduction of azides with lithium aluminum hydride. Reaction equation. Examples.

38 Reduction of Nitriles Reduction of nitriles with lithium aluminum hydride or hydrogen and catalyst yields a primary amine. Reaction equation. Examples.

39 Reduction of the Nitro Group Reduction of nitro groups with hydrogen and catalyst or a metal and acid is a good route to aryl amines. Examples.

40 Reduction of Amides Reduction of amides with lithium aluminum hydride yields primary, secondary or tertiary amines. Reaction equation. Example forming a primary amine.

41 Reduction of Amides Formation of secondary or tertiary amines. Examples.

42 Mechanism of Reduction of Amides Reaction equation. Mechanism. Step 1. Hydride attack.

43 Mechanism of Reduction of Amides Step 2. Elimination. Step 3. Hydride attack.

44 21.10 Reductive Amination

45 Reductive Amination Single reaction combining the formation of imines from ketones with reduction of the imine to an amine. Reaction equation. Example with ammonia. Intermediate.

46 Reductive Amination Example with a primary amine. Intermediate. N-substituted imines are known as Schiff s base.

47 Reductive Amination Example with a secondary amine. The species reduced may be the hemiaminal, iminium ion or the enamine. Hemiaminal Iminium ion

48 Reductive Amination Variation using sodium cyanoborohydride.

49 21.11 Reactions of Amines: A Review and a Preview

51 21.12 Reaction of Amines with Alkyl Halides

52 Reaction of Amines with Alkyl Halides N-Benzylaniline (85 87%) Polyalkylation ultimately yields quaternary ammonium salts. Methyl iodide has high reactivity and is often used.

53 21.13 The Hofmann Elimination

54 The Hofmann Elimination Elimination reaction with an ammonium cation as the leaving group. Reaction Equation. Formation of the base. Elimination step.

55 The Hofmann Elimination The elimination gives the least substituted alkene. Example. 1-Butene (95%) trans-2-butene & cis-2-butene (5% combined)

56 The Hofmann Elimination Steric effects control the elimination step.

57 21.14 Electrophilic Aromatic Substitution in Arylamines

58 Nitration of Aniline Direct nitration yields tars so the amine is first protected as an amide that is later hydrolyzed. N-Acetylarylamine Reaction sequence.

59 Hydrolysis. Nitration of Aniline

60 Halogenation of Aniline Aniline is so activated that polyhalogenation occurs without catalyst. Example.

61 Halogenation of Aniline Acylation reduces the reactivity and monohalogenation is possible. Example.

62 Friedel-Crafts Reactions of Aniline Direct reaction of aniline is usually not successful but reaction with the protected amine is possible. Example.

63 21.15 Nitrosation of Alkylamines

64 Nitrosation of Alkylamines Acidified solutions of sodium nitrite yield nitrosyl cation. Nitrous acid Nitrosyl cation Reaction of nitrosyl cation with secondary amines.

65 Nitrosation of Alkylamines Reaction of nitrosyl cation dimethylamine. N-Nitrosodimethylamine Common nitrosoamines that are all carcinogenic. Found in beer and herbicides In fried bacon that was cured with sodium nitrite In tobacco smoke

66 Nitrosation of Primary Alkylamines Nitrosoamines react further to form diazonium cations.

67 Nitrosation of Primary Alkylamines Secondary and tertiary diazonium cations decompose to a carbocation. Reaction equation. Reaction pathway. 2-Methyl-2-butanol (80%) Alkenes (5% total)

68 21.16 Nitrosation of Arylamines

69 Nitrosation of Arylamines Nitrosation of tertiary aryl amines is possible. Secondary aryl amines form a N-nitrosoamine.

70 Nitrosation of Primary Arylamines Primary arylamines yield a diazonium cation. Example.

71 Reactivity of Aryl Diazonium Cations

72 21.17 Synthetic Transformations of Aryl Diazonium Salts

73 Formation of Phenols Diazonium cations are hydrolyzed to phenols. Reaction equation. Example.

74 Formation of Aryl Iodides Diazonium cations react with potassium iodide to form aryl iodides. Reaction equation. Example.

75 Formation of Aryl Fluorides Diazonium cations formed with the tetrafluoroborate anion form aryl fluorides. The Schiemann reaction. Reaction equation. Example.

76 Formation of Aryl Chlorides and Bromides Diazonium cations react with copper(i) bromide and copper(i) chloride to form the corresponding aryl bromide or chloride. Reaction equation. Examples.

77 Formation of Aromatic Nitriles Diazonium cations react with copper(i) cyanide to form the aromatic nitrile. Reactions that use copper(i) salts to replace nitrogen in diazonium salts are called Sandmeyer reactions. Reaction equation. Example.

78 Reduction of Aryl Diazonium Cations Diazonium cations are reduced by with hypophosphorous acid (H 3 PO 2 ) or with ethanol. Reaction equation. Example.

79 Value of Aryl Diazonium Cations The value of aryl diazonium cations rests on: 1. The introduction of substituents that are otherwise difficult. These include fluoro, iodo, cyano, and hydroxy. 2. Preparation of compounds with substitution patterns that are otherwise inaccessible. Example.

80 21.18 Azo Coupling

81 Azo Coupling Aryl diazonium cations are weak electrophiles that attack activated aromatics. Example. Methyl red (62 66%)

82 Azo Coupling and Dyes Chrysoidine, an azo dye for silk, cotton, and wool, first came on the market in 1876 and remains in use today. Chrysoidine

83 Azo Coupling and Dyes Dyes approved by the FDA for use in food.

From Dyes to Drugs Antibacterial sulfa drugs burst on the scene in the 1930 s. An azo dye called Prontosil was inactive in vitro but active in vivo.

84 From Dyes to Drugs Antibacterial sulfa drugs burst on the scene in the 1930 s. An azo dye called Prontosil was inactive in vitro but active in vivo. Gerhard Domagk was awarded the 1939 Nobel Prize in Medicine or Physiology for his work with this drug. In the body, Prontosil undergoes a reductive cleavage of its azo linkage to form sulfanilamide, which is the substance actually responsible for the observed biological activity.

85 From Dyes to Drugs Two of the most widely used sulfur drugs. Sulfathiazole Sulfadiazine Many bacteria that were once susceptible to sulfa drugs have become resistant.

86 21.19 Spectroscopic Analysis of Amines

87 Infra Red Spectroscopy Primary alkyl- and arylamines exhibit two peaks in the range cm 1. Secondary amines have one peak here.

88 1 H NMR Spectroscopy Nitrogen is less electronegative than oxygen and so shields neighboring nuclei to a greater extent. The chemical shifts and splittings of amino group protons are variable and are sensitive to solvent, concentration, and temperature.

89 13 C NMR and UV vis Spectroscopy 13 C NMR. Carbons that are bonded to nitrogen are more shielded than those bonded to oxygen. UV-VIS. The longest wavelength absorption involves promoting one of the unshared electrons of nitrogen to an antibonding σ* orbital (n σ*) with l max near 200 nm. Protonation affects this.

90 Mass Spectrometry The molecular ion of compounds with an odd number of nitrogens is odd; an even number of nitrogens give an even molecular weight. Nitrogen is exceptionally good at stabilizing adjacent carbocation sites and the fragmentation patterns are dominated by cleavage of groups from the carbon atom attached to the nitrogen.

Chapter 22 Amines. Nomenclature Amines are classified according to the degree of substitution at nitrogen.

Chapter 22 Amines. Nomenclature Amines are classified according to the degree of substitution at nitrogen. CH. 22 Chapter 22 Amines Amines are very important in biological chemistry. Most of the bases in biological acid-base reactions are amines. They are also very important nucleophiles in biochemical reactions.