Amines and Nitrogen Compounds

Amines are organic derivatives of ammonia (NH₃) in which one or more hydrogen atoms are replaced by alkyl or aryl groups. They are among the most important functional groups in pharmaceutical chemistry — approximately 40% of all modern drugs contain an amine functional group. Examples include adrenaline (a neurotransmitter and drug), morphine (an analgesic), chloramphenicol (an antibiotic), procaine (a local anesthetic), diphenhydramine (an antihistamine), amitriptyline (an antidepressant), and sildenafil (Viagra) (a vasodilator). For HAAD candidates, understanding amine chemistry is therefore not optional — it is essential for drug recognition, drug metabolism, acid-base chemistry in the body, and the interpretation of pharmacological interactions. This chapter covers the structure, classification, nomenclature, properties, and reactions of amines.

Classification of Amines

Amines are classified based on the number of hydrogen atoms replaced in NH₃:

Primary (1°) amines: One alkyl/aryl group attached to nitrogen (R–NH₂) Secondary (2°) amines: Two alkyl/aryl groups attached to nitrogen (R₂NH) Tertiary (3°) amines: Three alkyl/aryl groups attached to nitrogen (R₃N)

Additionally:

• Quaternary (4°) ammonium salts: R₄N⁺ — nitrogen with four substituents and a positive charge (e.g., choline, tetraalkylammonium salts)
• Diamines: Amines with two –NH₂ groups (e.g., ethylenediamine, putrescine, cadaverine)

Example of classification:

• CH₃–NH₂ = Methylamine (1°)
• CH₃–NH–C₂H₅ = Ethylmethylamine (2°)
• (CH₃)₃N = Trimethylamine (3°)
• (CH₃)₄N⁺Cl⁻ = Tetramethylammonium chloride (quaternary)

Nomenclature of Amines

Common Names

List the alkyl groups attached to nitrogen in alphabetical order, followed by “amine”:

• CH₃–NH₂ = Methylamine
• C₂H₅–NH₂ = Ethylamine
• CH₃–NH–C₂H₅ = Ethylmethylamine
• (C₂H₅)₂NH = Diethylamine

IUPAC Names

For primary amines, find the longest carbon chain containing the –NH₂ group and use the suffix -amine:

• CH₃–CH₂–NH₂ = Ethanamine (not ethylamine)
• CH₃–CH₂–CH₂–NH₂ = Propan-1-amine
• CH₃–CH(NH₂)–CH₃ = Propan-2-amine

For secondary and tertiary amines:

• Use the prefix N- to indicate substituents attached to nitrogen
• Name the amine as a primary amine and prefix the other substituents with N-
• Example: CH₃–NH–C₂H₅ = N-methylethanamine

Aromatic Amines

• Aniline = C₆H₅–NH₂ (benzenamine)
• N-methylaniline = C₆H₅–NH–CH₃ (N-methylbenzenamine)
• Diphenylamine = (C₆H₅)₂NH

Physical Properties of Amines

Boiling point: Amines with similar molecular weights have lower boiling points than alcohols because nitrogen is less electronegative than oxygen, making the N–H bond less polar than the O–H bond and therefore forming weaker hydrogen bonds:

• Ethanol (MW = 46): BP = 78°C
• Dimethylamine (MW = 45): BP = 7°C
• Ethylamine (MW = 45): BP = 17°C

Solubility in water: Amines with up to about 6 carbons are soluble in water (the N atom can accept hydrogen bonds from water). Solubility decreases with increasing carbon chain length.

Odor: Lower aliphatic amines have a distinctive fishy odor — trimethylamine is responsible for the smell of decaying fish. Higher amines have progressively less odor. Putrescine (butane-1,4-diamine) and cadaverine (pentane-1,5-diamine) are polyamines with foul odors and are produced during protein decomposition.

Basicity: The most important chemical property of amines is their basicity. Amines are weak bases that can be protonated by acids to form ammonium salts: R–NH₂ + HCl → R–NH₃⁺Cl⁻ (amine salt)

The basicity of amines is measured by the pKb value (lower pKb = stronger base):

• Primary aliphatic amines: pKb ≈ 3–5 (relatively strong bases)
• Secondary aliphatic amines: slightly more basic than primary
• Tertiary aliphatic amines: slightly more basic than secondary
• Aromatic amines (aniline): pKb ≈ 9.4 (much weaker base — aromatic ring withdraws electrons by resonance)
• Amides: pKb ≈ 15 (very weak bases — the nitrogen’s lone pair is delocalized into the carbonyl)

Why are aliphatic amines more basic than aromatic amines? In aniline, the nitrogen’s lone pair is partially delocalized into the aromatic ring (by resonance), making it less available for protonation. In aliphatic amines, the alkyl groups are electron-donating by induction (+I effect), pushing electron density toward nitrogen and making it more nucleophilic and basic.

Chemical Reactions of Amines

As Bases: Salt Formation

Amines react with acids to form salts — this is clinically important because amine drugs (which are often basic) are administered as salts to improve solubility and stability:

• Amphetamine sulfate (drug for ADHD)
• Ephedrine hydrochloride (decongestant)
• Procaine hydrochloride (local anesthetic)
• Diphenhydramine hydrochloride (Benadryl)

The salt form is typically water-soluble and can be administered orally, intravenously, or intramuscularly.

As Nucleophiles: Acylation

Amines (particularly primary and secondary) react with acid chlorides, acid anhydrides, and other acylating agents to form amides: R–NH₂ + (CH₃CO)₂O → CH₃–CONHR + CH₃COOH

Acylation of aniline: Aniline reacts with acetic anhydride to form acetanilide (N-phenylacetamide). This is important because acetanilide was the precursor to paracetamol (acetaminophen) — the acetylation reduces the susceptibility of aniline to oxidation and modulates the pharmacological activity.

Primary amines give secondary amides (one N-H replaced by the acyl group); secondary amines give tertiary amides (no N-H remaining).

Reaction with Nitrous Acid (HNO₂)

This is one of the most characteristic reactions of amines and is used to distinguish between primary, secondary, and tertiary amines:

Primary aliphatic amines + HNO₂: Produce alcohols with evolution of N₂ gas: R–NH₂ + HNO₂ → R–OH + N₂↑ + H₂O

The evolution of nitrogen gas is the basis of a qualitative test for primary amines. This reaction is also important biologically — nitric oxide (NO), a signaling molecule in the cardiovascular system, is produced from arginine via a similar enzymatic reaction.

Primary aromatic amines + HNO₂: At 0–5°C, they form diazonium salts (which are stable at low temperatures): C₆H₅–NH₂ + NaNO₂ + 2HCl →(0–5°C) C₆H₅–N₂⁺Cl⁻ + 2H₂O

Secondary amines + HNO₂: Form N-nitrosoamines (N-nitroso compounds — some of which are carcinogenic): R₂NH + HNO₂ → R₂N–N=O + H₂O

Tertiary amines + HNO₂: Form nitroamines or are merely protonated (no characteristic reaction).

Carbylamine Reaction (Isocyanide Test)

Primary amines (both aliphatic and aromatic) react with chloroform (or dichloroethylene) and alcoholic KOH to produce carbylamines (isocyanides) — compounds with an extremely foul, nauseating odor: R–NH₂ + CHCl₃ + 4KOH → R–NC + 3KCl + 3H₂O

Secondary and tertiary amines do not give this reaction. The carbylamine test is therefore used to distinguish primary amines from secondary and tertiary amines.

Heterocyclic Amines

Many pharmacologically important compounds contain nitrogen atoms within a ring system (heterocyclic compounds). Key examples include:

Pyridine (C₅H₅N): A six-membered aromatic heterocycle with one nitrogen. It is a basic heterocycle (pKb ≈ 8.8). Pyridine is used as a solvent and as a precursor to many herbicides and pharmaceuticals. Nicotine (the addictive compound in tobacco) contains a pyridine ring fused to a pyrrolidine ring.

Pyrrole (C₄H₅N): A five-membered aromatic heterocycle with one nitrogen. Pyrrole is not basic (its nitrogen’s lone pair is part of the aromatic sextet). The porphyrin ring system (which forms the core of hemoglobin, myoglobin, and chlorophyll) contains four pyrrole units.

Pyrimidine (C₄H₄N₂): A six-membered aromatic heterocycle with two nitrogen atoms. The pyrimidine bases — cytosine, thymine, and uracil — are components of DNA and RNA.

Purine (C₅H₄N₄): A fused five- and six-membered heterocycle with four nitrogen atoms. The purine bases — adenine and guanine — are the other two bases in DNA and RNA. Caffeine (in coffee and tea) and theobromine (in chocolate) are methylxanthines derived from purine.

Histamine: A heterocyclic amine derived from histidine (an amino acid). Histamine is released during allergic reactions and is responsible for itching, sneezing, and vasodilation. Antihistamine drugs (like diphenhydramine) are histamine H1 receptor antagonists.

Serotonin (5-hydroxytryptamine, 5-HT): A neurotransmitter derived from tryptophan. Dysregulation of serotonin is linked to depression and anxiety. SSRIs (Selective Serotonin Reuptake Inhibitors) like fluoxetine (Prozac) are antidepressants that increase serotonin levels in the synaptic cleft.

⚡ Exam tip: Primary aliphatic amines give N₂ gas with nitrous acid (HNO₂) — this distinguishes them from secondary and tertiary amines. Aromatic amines (aniline) form diazonium salts with HNO₂ at 0–5°C. Amides are much less basic than amines (pKb of amide ~15 vs. pKb of aliphatic amine ~3-5). Remember the order of basicity: aliphatic amines > aromatic amines (aniline) > amides.

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