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Topic 10

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Amines & Carbonyl Derivatives

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Amines & Carbonyl Derivatives — Key Facts for Makerere University (Uganda) Core concept: Amines are organic bases derived from ammonia (NH₃) by replacing H atoms with alkyl/aryl groups. Carbonyl derivatives include acid chlorides, anhydrides, esters, and amides — all derived from carboxylic acids High-yield points: Classification of amines (1°, 2°, 3°); basicity; preparation of amines; nucleophilic acyl substitution reactions; acetyl chloride and acetic anhydride reactions ⚡ Exam tip: Remember that basicity of amines decreases as: 3° > 2° > 1° in the gas phase, but 1° > 2° > 3° in aqueous solution (due to solvation effects)

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Amines & Carbonyl Derivatives — Makerere University (Uganda) Study Guide

1. Amines — Structure and Classification

Definition

Amines are organic compounds containing nitrogen with a lone pair of electrons. They are derived from ammonia (NH₃) where one or more hydrogen atoms are replaced by alkyl or aryl groups.

Classification

TypeStructureExample
Primary (1°) amineR–NH₂CH₃NH₂ (methylamine)
Secondary (2°) amineR₂NH(CH₃)₂NH (dimethylamine)
Tertiary (3°) amineR₃N(CH₃)₃N (trimethylamine)
Quaternary (4°) ammonium saltR₄N⁺X⁻(CH₃)₄N⁺Cl⁻ (tetramethylammonium chloride)

⚠️ Important note: In amine nomenclature:

  • 1° amine: The N is attached to ONE carbon group (and 2 H atoms)
  • 2° amine: The N is attached to TWO carbon groups (and 1 H atom)
  • 3° amine: The N is attached to THREE carbon groups (and no H atoms)

Nomenclature

  • Primary amines: Alkane + -amine

    • CH₃NH₂: Methanamine (methylamine)
    • C₂H₅NH₂: Ethanamine (ethylamine)
    • CH₃CH₂CH₂NH₂: Propan-1-amine
    • CH₃CH(NH₂)CH₃: Propan-2-amine

  • Secondary and tertiary amines (substituted on N):

    • CH₃–NH–CH₂CH₃: N-methylethanamine
    • (CH₃)₂N–CH₂CH₃: N,N-dimethylethanamine
    • The prefix “N-” indicates substituents on the nitrogen atom

Physical Properties

  • Lower MW amines are gases or liquids with strong ammonia-like or fishy odors
  • Higher MW amines are solids
  • 1° and 2° amines can H-bond (with themselves and water) → higher boiling points than 3° amines of similar MW
  • 3° amines cannot H-bond to themselves (no N–H bond) → lower boiling points than isomeric 1° or 2° amines
  • All amines with ≤6 carbons are water-soluble to some extent

2. Basicity of Amines

Why Are Amines Basic?

The nitrogen lone pair can accept a proton (H⁺) to form an ammonium ion: R–NH₂ + H₂O ⇌ R–NH₃⁺ + OH⁻ (Kb is the base dissociation constant) R–NH₂ + HCl → R–NH₃⁺Cl⁻ (amine salt)

Measuring Basicity

  • pKa of conjugate acid (R–NH₃⁺): Higher pKa = stronger base
  • pKb: Lower pKb = stronger base

Factors Affecting Basicity

1. Inductive Effect: Electron-donating groups (alkyl) increase basicity by pushing electron density toward N.

  • Basicity INCREASES: NH₃ < 1° amine < 2° amine < 3° amine (gas phase, inductive)
  • BUT in aqueous solution: 1° > 2° > 3° due to solvation effects

Solvation effect: Smaller conjugate acid (more concentrated positive charge) is better solvated by water.

  • 1° R–NH₃⁺ is smallest → most solvated → most stable → most basic in water
  • 3° R₃NH⁺ is bulkiest → least solvation → less stable → less basic in water

2. Resonance Effects: Aromatic amines (anilines) are much weaker bases than aliphatic amines because the lone pair on N is delocalized into the benzene ring.

CompoundpKa of conjugate acidReason
NH₃9.25Reference
CH₃NH₂10.64+I effect of CH₃
(CH₃)₂NH10.73Stronger +I (2 alkyl groups)
(CH₃)₃N9.80Solvation effect dominates
C₆H₅NH₂ (aniline)4.60Lone pair delocalized into benzene
NH₂CH₂CH₂NH₂ (ethylenediamine)9.98, 7.07Both nitrogens basic

3. Steric Hindering: Bulky groups near the N atom hinder solvation of the conjugate acid → decreases basicity in water.

3. Preparation of Amines

3.1 From Alkyl Halides (Ammonolysis)

R–X + 2NH₃ → R–NH₂ + NH₄X Problem: Produces a mixture of 1°, 2°, and 3° amines and quaternary salts. Better: Use excess ammonia to favor primary amine.

3.2 Gabriel Synthesis

Phthalimide + KOH → potassium phthalimide → R–X → N-alkyl phthalimide → H₂N–R (primary amine) Advantage: Clean method for primary amines; avoids over-alkylation.

3.3 From Carboxylic Acids

Hofmann Rearrangement (of amides): R–CONH₂ + Br₂ + 4NaOH → R–NH₂ + Na₂CO₃ + 2NaBr + H₂O Product: One carbon shorter than the starting amide!

3.4 Reductive Amination

Carbonyl compound + amine + reducing agent → amine: R–CHO + R’NH₂ + NaBH₃CN → R–CH₂–NHR’ (secondary amine) R–CO–R’ + R”NH₂ + NaBH₃CN → R–C(R’)–NHR” (tertiary amine)

3.5 Reduction of Nitro Compounds

R–NO₂ + 3H₂ → R–NH₂ + 2H₂O (catalytic hydrogenation or Sn/HCl)

4. Reactions of Amines

4.1 As Bases

  • R–NH₂ + HCl → R–NH₃⁺Cl⁻ (white crystalline salts — water soluble)
  • These salts are soluble in water but insoluble in organic solvents
  • Amine salts are converted back to amines by addition of strong base: R–NH₃⁺Cl⁻ + NaOH → R–NH₂ + NaCl + H₂O

4.2 Acylation (Formation of Amides)

1° and 2° amines react with acid chlorides, acid anhydrides, and esters to form amides:

With acetyl chloride: R–NH₂ + CH₃COCl → R–NHCOCH₃ + HCl CH₃CH₂NH₂ + (CH₃CO)₂O → CH₃CH₂NHCOCH₃ + CH₃COOH (N-ethylacetamide)

Note: 3° amines cannot be acylated (no N–H bond to replace).

4.3 Reaction with Nitrous Acid (HNO₂)

Primary amines + HNO₂: R–NH₂ + HNO₂ → R–OH + N₂ + H₂O

  • Violent reaction with aliphatic 1° amines (nitrogen gas evolution)
  • Used to detect and estimate 1° amines quantitatively

Secondary amines + HNO₂: R₂NH + HNO₂ → R₂N–NO (N-nitrosoamine) — yellow oily liquid

Tertiary amines + HNO₂: No reaction (used to distinguish 3° amines from 1° and 2°).

Aromatic amines (aniline) + HNO₂: Forms benzenediazonium salt (C₆H₅–N₂⁺Cl⁻) — important intermediate for synthesis.

4.4 Carbylamine Reaction (Isocyanide Test)

1° amines + CHCl₃ + KOH (alc.) → R–NC (isocyanide/foul-smelling compound) Test for 1° amines: Foul odor indicates a primary amine. 2° and 3° amines: No reaction.

5. Carbonyl Derivatives — Overview

The carboxylic acid derivatives all contain the acyl group (R–C=O):

DerivativeStructureReactivityExample
Acid chlorideR–COClHIGHESTAcetyl chloride (CH₃COCl)
Acid anhydrideR–CO–O–CO–RHighAcetic anhydride ((CH₃CO)₂O)
EsterR–COOR’MediumEthyl acetate (CH₃COOC₂H₅)
AmideR–CONH₂LowAcetamide (CH₃CONH₂)
CarboxylateR–COO⁻LOWESTSodium acetate (CH₃COONa)

Reactivity order (most → least electrophilic): Acid chloride > Acid anhydride > Ester > Amide > Carboxylate anion

6. Acid Chlorides (R–COCl)

Preparation

R–COOH + SOCl₂ → R–COCl + SO₂ + HCl R–COOH + PCl₅ → R–COCl + POCl₃ + HCl

Properties

  • Colorless liquids or low-melting solids
  • Pungent, irritating odor
  • React violently with water (hydrolysis): R–COCl + H₂O → R–COOH + HCl
  • Solvolysis in alcohols: R–COCl + R’OH → R–COOR’ + HCl

Reactions

  1. With alcohols: R–COCl + R’OH → R–COOR’ + HCl (ester)
  2. With amines: R–COCl + R’₂NH → R–CONR’₂ + HCl (amide)
  3. With water: R–COCl + H₂O → R–COOH + HCl
  4. Friedel-Crafts acylation: R–COCl + AlCl₃ → R–CO–Ar (aryl ketone)

7. Acid Anhydrides (R–CO–O–CO–R)

Preparation

  1. From acid chloride + carboxylate salt: R–COCl + R’COONa → R–CO–O–CO–R’ + NaCl
  2. Dehydration of carboxylic acids (P₂O₅): 2R–COOH → (R–CO)₂O + H₂O (requires high temperature)

Properties

  • Less reactive than acid chlorides
  • No fire and fumes (unlike acid chlorides)
  • Hydrolyze slowly with water: (R–CO)₂O + H₂O → 2R–COOH
  • React with alcohols: (R–CO)₂O + R’OH → R–COOR’ + R–COOH (ester + acid)

Important Anhydrides

  • Acetic anhydride ((CH₃CO)₂O): Most important; used as acetylating agent
  • Phthalic anhydride: Used in dye and plastic synthesis
  • Succinic anhydride: Five-membered cyclic anhydride

8. Esters (R–COOR’)

Nomenclature

R–COOR’ naming: Alkyl alkanoate

  • CH₃COOCH₃: Methyl ethanoate (methyl acetate)
  • CH₃COOC₂H₅: Ethyl ethanoate (ethyl acetate)
  • HCOOC₂H₅: Ethyl methanoate (ethyl formate)
  • C₆H₅COOCH₃: Methyl benzoate

Physical Properties

  • Pleasant, fruity odors (many are found in essential oils and fruits)
  • Lower boiling points than acids of similar MW (no H-bonding between ester molecules)
  • Slightly soluble in water; miscible in common organic solvents
  • Good solvents for lacquers, paints, and varnishes

Reactions of Esters

  1. Hydrolysis:

    • Acid-catalyzed: R–COOR’ + H₂O ⇌ R–COOH + R’OH
    • Base-catalyzed (saponification): R–COOR’ + NaOH → R–COONa + R’OH (irreversible)

  2. Ammonolysis: R–COOR’ + NH₃ → R–CONH₂ + R’OH (forms amide)

  3. Reduction:

    • LiAlH₄: R–COOR’ → R–CH₂OH + R’OH (two alcohols)
    • NaBH₄ does NOT reduce esters

  4. Reaction with amines: R–COOR’ + R”NH₂ → R–CONHR” + R’OH (transesterification type)

9. Amides (R–CONH₂)

Nomenclature

  • R–CONH₂: Alkanamide (e.g., CH₃CONH₂ = acetamide)
  • R–CONHR’: N-alkylalkanamide (e.g., CH₃CONHCH₃ = N-methylacetamide)
  • R–CONR’₂: N,N-dialkylalkanamide (e.g., CH₃CON(CH₃)₂ = N,N-dimethylacetamide)

Physical Properties

  • Highest boiling points of all carboxylic acid derivatives (strong H-bonding)
  • 1° and 2° amides H-bond strongly → often solids or high-boiling liquids
  • N,N-dimethylacetamide (DMF) is a widely used polar aprotic solvent

Reactions

  1. Hydrolysis:

    • Acid: R–CONH₂ + H₂O/H⁺ → R–COOH + NH₄⁺
    • Base: R–CONH₂ + NaOH → R–COONa + NH₃

  2. Dehydration (P₂O₅): R–CONH₂ → R–CN (nitrile) + H₂O

  3. Hofmann Rearrangement (degradation to amine with one less carbon): R–CONH₂ + Br₂ + 4NaOH → R–NH₂ + Na₂CO₃ + 2NaBr + H₂O

10. Nitriles (R–CN)

Properties

  • Cyanide group (–C≡N) is linear (sp hybridization)
  • Polar molecules with moderate boiling points
  • Water-soluble for lower MW (acetonitrile is miscible)

Preparation

  1. From alkyl halides + NaCN: R–X + NaCN → R–CN + NaX
  2. From amides + P₂O₅: R–CONH₂ → R–CN + H₂O
  3. From aldehydes + KCN/HCl: R–CHO + KCN → R–CH(OH)CN → (dehydration) → R–CN

Reactions

  1. Hydrolysis: R–CN + 2H₂O/H⁺ → R–COOH + NH₄⁺ (carboxylic acid) R–CN + OH⁻/H₂O → R–COO⁻ + NH₃ (carboxylate)

  2. Reduction: R–CN + 2H₂ → R–CH₂NH₂ (primary amine) LiAlH₄ or H₂/Ni

  3. Grignard + R–CN: R–CN + R’MgX → (after hydrolysis) R–C(=O)–R’ (ketone) Note: Grignard adds to C≡N → imine → hydrolyzes to ketone

11. Mechanism: Nucleophilic Acyl Substitution

All reactions of acid derivatives follow the same pattern:

Step 1: Nucleophile attacks carbonyl carbon
Step 2: Tetrahedral intermediate forms (Nuc–C–O⁻)
Step 3: Elimination of leaving group (X⁻ or OR' or NH₂ etc.)
Step 4: Restoration of C=O double bond

Why does reactivity vary?

  • Better leaving groups (weaker bases) = faster reactions
  • Acid chloride: Cl⁻ is excellent leaving group
  • Amide: NH₂⁻ is a terrible leaving group (very strong base) → amides are least reactive

12. Exam-Style Questions & Tips

Common exam question patterns at Makerere:

  1. “Name the following amines and state whether they are 1°, 2°, or 3°”
  2. “Arrange the following amines in order of basicity and explain your answer”
  3. “Write equations for the preparation of amines by [method]”
  4. “Predict the products of [derivative] + [reagent]”
  5. “Explain why amides are less reactive than acid chlorides”
  6. “Describe how you would distinguish between 1°, 2°, and 3° amines”

⚡ Exam tips:

  • Basicity of amines in aqueous solution: aliphatic > NH₃ > aromatic (aniline is much weaker)
  • 3° amines have no N–H bond → cannot be acylated or form nitrosoamines
  • Ester + base → carboxylate (soap = saponification); Ester + acid → no change in oxidation state
  • Amides can be dehydrated to nitriles (P₂O₅) and hydrolyzed to acids

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13. Hofmann Elimination

When 4° ammonium salts are heated with Ag₂O or OH⁻, they undergo elimination to give alkenes:

(CH₃)₃N⁺–CH₂–CH₂–CH₃ + OH⁻ → (CH₃)₃N + CH₂=CH–CH₃ + H₂O

Mechanism: E2 elimination of the 4° ammonium cation. Use: Structure determination — which β-hydrogen is eliminated indicates the structure of the original amine.

14. Azo Coupling

Aromatic diazonium salts couple with activated aromatic rings (phenols, anilines) to form azo compounds:

C₆H₅–N₂⁺Cl⁻ + C₆H₅OH → C₆H₅–N=N–C₆H₄–OH + HCl Conditions: Weakly acidic or weakly basic medium; cold temperature (0–5°C)

Uses: Synthesis of azo dyes (vivid colors); structure determination of aromatic amines.

15. Important Synthetic Routes

From Acid to Amine (Hofmann Rearrangement)

CH₃CONH₂ → (Br₂/NaOH) → CH₃NH₂ (methylamine)

From Nitrile to Amine

CH₃CN → (LiAlH₄) → CH₃CH₂NH₂ (ethylamine)

From Acid Chloride to Amide

CH₃COCl + 2NH₃ → CH₃CONH₂ + NH₄Cl

From Ester to Primary Alcohol

CH₃COOEt → (LiAlH₄) → CH₃CH₂OH + EtOH

16. Biological Amines

Biogenic Amines

  • Histamine: Vasodilator, released in allergic reactions
  • Serotonin: Neurotransmitter
  • Dopamine: Neurotransmitter
  • Adrenaline (epinephrine): Fight-or-flight hormone

Alkaloids

Nitrogen-containing natural products from plants, often with strong biological activity:

  • Morphine: Analgesic (painkiller)
  • Quinine: Antimalarial (from cinchona bark)
  • Caffeine: Stimulant (from coffee, tea)
  • Nicotine: Stimulant (from tobacco)
  • Cocaine: Anesthetic and stimulant

Practice Problems

Q1: Arrange in order of increasing basicity: (a) NH₃, CH₃NH₂, (CH₃)₂NH, C₆H₅NH₂ (b) CH₃NH₂, ClCH₂NH₂, CH₃OCH₂NH₂

Q2: Write equations for: (a) Ethanamine + acetyl chloride (b) Propan-1-amine + nitrous acid (c) Methylamine + CO₂ (under pressure) (d) Acetyl chloride + excess NH₃

Q3: Describe the mechanism of hydrolysis of an ester in acidic conditions.

Q4: How would you distinguish between: (a) Primary and tertiary amines (b) Ester and carboxylic acid (c) Acetamide and ethyl acetate

Q5: An amine with molecular formula C₃H₉N reacts with nitrous acid to give nitrogen gas. What is the structure of the amine? If it gave an oily N-nitroso compound, what would the structure be?

Q6: Write the structures of the products of: (a) Propanoic anhydride + methanol (b) Acetyl chloride + aniline (c) Ethyl acetate + aqueous NaOH (heat)

Common Mistakes to Avoid

  1. Confusing basicity order in water vs gas phase: In water: 1° > 2° > 3°; In gas phase: 3° > 2° > 1°
  2. Forgetting that 3° amines cannot be acylated: They have no N–H bond to substitute.
  3. Confusing amides and amines: Amides contain C=O attached to N; amines contain only N (no C=O).
  4. Thinking NaBH₄ reduces esters: It doesn’t — use LiAlH₄ for ester reduction.
  5. Confusing the nitrile (–CN) with the cyanide ion (CN⁻) in mechanisms: In nitriles, C is electrophilic; the lone pair is on N.

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