Amines & Amides
🟢 Lite — Quick Review (1h–1d)
Rapid summary for last-minute revision before your exam.
Amines & Amides — Key Facts for SLMC Medical (Sri Lanka)
- Amines are organic derivatives of ammonia (NH₃) where one or more H atoms are replaced by alkyl/aralkyl groups
- Classification: 1° amine (R–NH₂), 2° amine (R₂NH), 3° amine (R₃N); quaternary ammonium (R₄N⁺)
- Amides are R–CO–NH₂ (primary amide), R–CO–NHR (N-substituted amide), or R–CO–NR₂ (tertiary amide)
- Basicity order: Aliphatic amine > Ammonia > Aromatic amine (aniline is the weakest base)
- ⚡ Exam tip: Gabriel synthesis, Hofmann rearrangement, and amide bond hydrolysis are high-yield for SLMC
🟡 Standard — Regular Study (2d–2mo)
Standard content for students with a few days to months.
Amines & Amides — SLMC Medical (Sri Lanka) Study Guide
Amines — Structure and Classification
Amines are classified by the number of alkyl groups attached to nitrogen:
| Type | Formula | Example | pKb (basicity) |
|---|---|---|---|
| Primary (1°) | R–NH₂ | Methylamine CH₃NH₂ | ~3.4 |
| Secondary (2°) | R₂NH | Dimethylamine (CH₃)₂NH | ~3.3 |
| Tertiary (3°) | R₃N | Trimethylamine (CH₃)₃N | ~4.2 |
| Quaternary ammonium | R₄N⁺X⁻ | Tetramethylammonium chloride | N/A (no basic lone pair) |
Aniline (C₆H₅NH₂) is a primary aromatic amine — the nitrogen lone pair is delocalized into the benzene ring, making it much less basic than aliphatic amines.
Physical Properties of Amines
| Property | Observation |
|---|---|
| Boiling point | 1° and 2° amines: hydrogen bonding → higher BP than 3° amines of same MW |
| 3° amines | No H on N → no hydrogen bonding → lower BP |
| Solubility | Lower MW amines (C₁–C₃) soluble in water due to H-bonding with H₂O |
| Odor | Many amines have fishy odor (trimethylamine); putrescine and cadaverine (polyamines) have foul smell |
Chemical Properties of Amines
1. Basicity
Amines act as weak bases due to the lone pair on nitrogen:
- R–NH₂ + H₂O ⇌ R–NH₃⁺ + OH⁻
- Kb values: aliphatic amines ~10⁻³ to 10⁻⁴; aniline Kb ~10⁻⁹
Basicity order (strongest to weakest base): Aliphatic 1° > Aliphatic 2° > Aliphatic 3° > Ammonia > Aniline > Heterocyclic aromatic amines
Why? Steric hindrance (3° has 3 bulky R groups blocking the lone pair) + solvation effects + resonance stabilization of conjugate acid.
2. Salt Formation (Reaction with Acids)
R–NH₂ + HCl → R–NH₃⁺Cl⁻ (amine salt)
- Amine salts are typically water-soluble
- Used to make water-soluble drug formulations from insoluble amine drugs (e.g., amino acid synthesis)
- Addition of base regenerates the free amine
3. Reaction with Acid Chlorides and Anhydrides (Acylation)
R–NH₂ + (R’CO)₂O → R–NHCO–R’ + R’–COOH
- Primary amine → N-substituted amide (secondary amide)
- Secondary amine → N,N-disubstituted amide (tertiary amide)
- Used to “protect” amine groups in organic synthesis
4. Carbylamine Reaction (Test for Primary Amines)
R–NH₂ + CHCl₃ + KOH → R–NC (isocyanide) + 3KCl + 3H₂O
- Produces a foul, pungent odor (isocyanides have extremely bad smell)
- This is a specific test for primary amines — secondary and tertiary amines do NOT give this reaction
5. Reaction with Nitrous Acid (HNO₂)
- 1° aliphatic amine + HNO₂ → R–OH + N₂↑ (diazonium salt decomposes; nitrogen gas evolution — diagnostic!)
- 1° aromatic amine + HNO₂ → Benzenediazonium salt (at 0–5°C)
- 2° amine + HNO₂ → N-nitrosoamine (yellow oil)
- 3° amine + HNO₂ → no reaction (dissolves as nitrite salt)
6. Hofmann Elimination
Tertiary amine + alkyl halide → quaternary ammonium salt → heated with Ag₂O/KOH → elimination to alkene
- This is the Hofmann elimination — used to determine amine structure
- The least substituted alkene is formed preferentially (Hofmann product)
Amides — Structure and Properties
Amides have the formula R–CO–NR₂:
- Primary amide: R–CO–NH₂
- Secondary amide: R–CO–NHR
- Tertiary amide: R–CO–NR₂
Physical Properties
| Property | Observation |
|---|---|
| Boiling point | High for size due to hydrogen bonding; primary amide can H-bond with 2 donors + 2 acceptors |
| Solubility | Lower MW amides (formamide, acetamide) miscible with water |
| Density | Less than water |
Acetamide (CH₃CONH₂) is a solid at room temperature (BP 221°C) — much higher BP than expected for its MW due to extensive H-bonding.
Chemical Properties
1. Amphoterism
Amides are neutral — they do not act as acids or bases under normal conditions. The –NH₂ group of a primary amide is not acidic enough to react with bases, nor is the C=O basic enough to react with acids readily.
2. Hydrolysis
Acid-catalyzed: R–CONH₂ + H₂O/H⁺ → R–COOH + NH₃⁺ Base-catalyzed: R–CONH₂ + NaOH → R–COONa + NH₃↑
Amide bonds are very stable — hydrolysis requires strong acid or base and heat.
3. Hofmann Rearrangement
Primary amide + Br₂/NaOH → R–NH₂ (amine with one fewer carbon)
- This converts a primary amide to a primary amine with one less carbon atom
- Important in organic synthesis for making amines
- Example: Benzamide → Aniline
Peptide Bond (amide bond in biology)
The peptide bond connecting amino acids in proteins is a secondary amide (–CO–NH–):
- Planar and rigid due to resonance: the nitrogen lone pair donates into the C=O π-system
- Resonance stabilizes the peptide bond and restricts rotation
- Hydrolysis of peptide bonds requires proteolytic enzymes (pepsin, trypsin, chymotrypsin) or strong acid/base with heat
Important Biomedical Amines
- Histamine: vasodilator; causes allergic reactions, anaphylaxis; H₁-antihistamines block its effects
- Adrenaline (Epinephrine): catecholamine; acts on α and β adrenergic receptors
- Noradrenaline (Norepinephrine): vasoconstrictor; neurotransmitter
- Dopamine: neurotransmitter; precursor to adrenaline and noradrenaline
- Serotonin (5-HT): neurotransmitter; mood, appetite regulation
- GABA: inhibitory neurotransmitter; GABAergic drugs (benzodiazepines, barbiturates) enhance GABA effect
- Acetylcholine: neurotransmitter at neuromuscular junction; cholinergic drugs affect its action
Clinical and Medical Relevance
- Procaine, Lidocaine: amino ester/amide local anesthetics — procaine has –COO–CH₂–NEt₂ group; lidocaine has amide group
- Sulfonamides: sulfa drugs (antibacterials) — para-aminobenzenesulfonamide; competitive antagonist of PABA in bacterial folate synthesis
- PABA (para-aminobenzoic acid): used by bacteria to synthesize folic acid; sulfonamides are structural analogs that block this pathway
- Methylene blue: reduced form (leucomethylene blue) is used to treat methemoglobinemia; oxidized form used as a dye and antiseptic
- Benzocaine: topical anesthetic; amino ester-type local anesthetic
Common SLMC Exam Traps
- Aniline is a WEAK base — the lone pair is delocalized into the benzene ring. Students often think it’s a strong base.
- Amide hydrolysis under BASIC conditions produces an ammonia smell (NH₃) — this is a diagnostic feature
- Carbylamine reaction ONLY works for primary amines — a specific qualitative test
- Tertiary amines do NOT react with nitrous acid in the same way as 1° amines — they form nitrite salts instead of N-nitroso compounds
- The peptide bond is a secondary amide, not an imide — proteolytic enzymes (not regular acid/base) are needed to hydrolyze it
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