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Chapter 20

Amines

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Nomenclature

1^o Amines

2^o Amines

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3^o Amines

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1A. Arylamines

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1B. Heterocyclic Amines

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Physical Properties and �Structure of Amines

2A. Physical Properties

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2B. Structure of Amines

N: sp³ hybridized

Trigonal pyramidal

Bond angles close to 109.5^o

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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

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Ammonium salts with four different groups

enantiomers

can be resolved

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Basicity of Amines:�Amine Salts

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The aminium ion of a more basic amine will have a larger pK_a than the aminium ion of a less basic amine

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By releasing electrons, R— stabilizes the alkylaminium ion through dispersal of charge

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3A. Basicity of Arylamines

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Five resonance structures

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Only two resonance structures

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3B. Basicity of Heterocyclic Amines

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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

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3D. Aminium Salts and Quaternary�Ammonium Salts

However, R₄N^⊕ ^⊖OH are strong bases (as strong as NaOH)

Cannot act

as bases

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3E. Solubility of Amines in Aqueous�Acids

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3F. Amines as Resolving Agents

Enantiomerically pure amines are often used to resolve racemic forms of acidic compounds by the formation of diastereomeric salts

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Preparation of Amines

4A. Through Nucleophilic Substitution �Reactions

Alkylation of ammonia

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Alkylation of azide ion and reduction

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The Gabriel synthesis

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Alkylation of 3^o amines

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4B. Preparation of Aromatic Amines �through Reduction of Nitro �Compounds

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4C. Preparation of Primary, Secondary,

and Tertiary Amines through Reductive

Amination

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Mechanism

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Examples

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4D. Preparation of Primary, Secondary,

or Tertiary Amines through

Reduction of Nitriles, Oximes,

and Amides

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Examples

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Examples

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4D. Preparation of Primary Amines

through the Hofmann and Curtius �Rearrangements

Hofmann rearrangement

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Examples

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Mechanism

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Curtius rearrangement

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Reactions of Amines

Acid-base reactions

Alkylation

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Acylation

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Electrophilic aromatic substitution

NH₂: powerful activating group, ortho-para director

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5A. Oxidation of Amines

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Reactions of Amines with�Nitrous Acid

Nitrous acid (HONO) is a weak, unstable acid

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6A. Reactions of Primary Aliphatic

Amines with Nitrous Acid

1^o aliphatic amine

(aliphatic diazonium salt)

(highly unstable)

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6B. Reactions of Primary Arylamines

with Nitrous Acid

(arenediazonium salt)

(stable at <5^oC)

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Mechanism

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Mechanism (Cont'd)

diazonium ion

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6C. Reactions of Secondary

Amines with Nitrous Acid

N-Nitroso-

amines

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6D. Reactions of Tertiary Amines with �Nitrous Acid

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Replacement Reactions of �Arenediazonium Salts

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7A. Syntheses Using Diazonium Salts

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

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7C. Replacement by —I

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7D. Replacement by —F

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7E. Replacement by —OH

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7F. Replacement by Hydrogen: �Deamination by Diazotization

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Coupling Reactions of �Arenediazonium Salts

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Examples

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Examples

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Examples

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Reactions of Amines with �Sulfonyl Chlorides

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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

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1^o Amine

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2^o Amine

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3^o Amine

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Synthesis of Sulfa Drugs

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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

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11B. Spectroscopic Analysis

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

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Aliphatic amines

1020 – 1220 cm^-1 (C–N)

Aromatic amines

1250 – 1360 cm^-1 (C–N)

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¹H NMR spectra

1^o and 2^o amines

N–H δ (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 α carbon of an aliphatic amine are deshielded by the electron-withdrawing effect of the nitrogen and absorb typically in the δ 2.2–2.9 region

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Protons on the β carbon are not deshielded as much and absorb in the range δ 1.0–1.7

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¹³C NMR spectra

23.0

34.0

14.3

29.7

42.5

¹³C NMR chemical shifts (δ)

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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 α and β carbons of aliphatic amines is a common mode of fragmentation

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Eliminations Involving �Ammonium Compounds

12A. The Hofmann Elimination

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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

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12B. The Cope Elimination

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Summary of Preparations and �Reactions of Amines

Preparation of amines

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Reactions of amines

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🕭 END OF CHAPTER 21 🕭