Primary amine: one R group on N (RNH2). Secondary: two R groups (R2NH). Tertiary: three R groups (R3N). Quaternary ammonium: four R groups on N+ (R4N+) — positively charged, not a base.
⚗️ Amines
Basicity: alkyl amines > NH3 > aryl amines
Amine Basicity Order
Alkyl amines are stronger bases than ammonia (alkyl groups donate electrons). Aryl amines (aniline) are much weaker bases — lone pair delocalized into ring. EWG on ring further decrease basicity.
⚗️ Amines
Amines are nucleophiles — react with acid chlorides, esters, alkyl halides
Amine as Nucleophile
The nitrogen lone pair makes amines good nucleophiles. React with: acid chlorides → amides (fast). Esters → amides (slower). Alkyl halides → alkylation (gives higher substituted amine).
⚗️ Amines
Gabriel synthesis: phthalimide → primary amine only
Gabriel Synthesis
Only reliable way to make pure primary amines without over-alkylation. Phthalimide (N-H, pKa ~9) + base → anion → alkylate → hydrazine hydrolysis → primary amine + phthalhydrazide.
⚗️ Amines
Hofmann elimination: quaternary ammonium + heat → least substituted alkene
Hofmann Elimination
Opposite of Zaitsev — gives least substituted alkene (anti-Zaitsev). Bulky base attacks least hindered beta-H. Used to determine amine structure by identifying the alkene product.
The most practical way to make amines: aldehyde or ketone + primary or secondary amine → imine or iminium ion → reduced with NaBH₃CN (sodium cyanoborohydride, mild enough to not reduce starting carbonyl) → amine product. One-pot reaction. Starting materials: RCHO + R'NH₂ → RCH₂NHR' after reduction. Works for primary, secondary, and tertiary amine targets. NaBH₃CN preferred over NaBH₄ (too reactive).
Step 1
Carbonyl + amine → imine/iminium (acid cat.)
Step 2
NaBH₃CN reduces imine → amine
Why NaBH₃CN
Selective — reduces C=N but not C=O at pH ~7
Product
Amine with new C-N bond
⚗️ Amines
Diazotization: primary aryl amine + NaNO₂/HCl → diazonium salt (ArN₂⁺)
Diazonium Salts
Primary aromatic amines react with NaNO₂ + HCl at 0–5°C → diazonium salt (ArN₂⁺Cl⁻). Diazonium salts are highly reactive and versatile synthetic intermediates. Reactions: replace N₂ with: OH (water → phenol), CN (CuCN → aryl nitrile), Cl/Br (CuCl/CuBr — Sandmeyer reaction), F (BF₄⁻ → Balz-Schiemann), I (KI → aryl iodide), H (H₃PO₂ → deamination). Coupling with activated arenes → azo dyes.
Amides form when amines react with activated carboxylic acid derivatives. Reactivity order: acid chloride (fastest) > anhydride > ester > amide. Acid chlorides give amides in excellent yield with simple mixing. Direct reaction of carboxylic acid + amine requires heat and a coupling agent (DCC) or activation. Amides are the most stable carboxylic acid derivative — the nitrogen lone pair donates into C=O, reducing electrophilicity.
⚗️ Amines
Hofmann rearrangement: primary amide + Br₂/NaOH → primary amine (loses one C)
Hofmann Rearrangement
Different from Hofmann elimination! Hofmann rearrangement: RCONH₂ + Br₂ + NaOH → RNH₂ (primary amine) + CO₂. The carbon chain LOSES one carbon (RCONH₂ → RNH₂, not RCNH₂). Mechanism: N-bromination → loss of Br⁻ → nitrene intermediate → rearrangement → isocyanate → hydrolysis → amine. Useful to make primary amines that are one carbon shorter than the starting amide.
Elimination = alkene from quaternary ammonium; Rearrangement = amine from amide
⚗️ Amines
Amine nucleophilicity order in SN2: 3° < 2° < 1° < NH₃ (steric control)
Amine Nucleophilicity vs Basicity
Nucleophilicity of amines in SN2 reactions is controlled by STERIC effects: primary amines are better nucleophiles than tertiary (less hindered). Basicity order (gas phase): 3° > 2° > 1° > NH₃ (more alkyl groups donate electrons). In aqueous solution basicity order is complicated by solvation. Key distinction: nucleophilicity = kinetics (how fast it reacts). Basicity = thermodynamics (equilibrium). They are not always the same.
⚗️ Amines
Curtius rearrangement: acyl azide → isocyanate → amine (loses C as CO₂)
Curtius Rearrangement
Similar to Hofmann — also makes primary amines one carbon shorter. Acyl azide (RCON₃) → heat → isocyanate (R-N=C=O) + N₂. Isocyanate + H₂O → carbamic acid → amine + CO₂. Or trap isocyanate with alcohol → urethane. Acyl azides made from acyl chlorides + NaN₃. Useful when Hofmann conditions (Br₂/NaOH) might damage sensitive groups. Pyrolysis conditions (no base needed).
In multi-step synthesis, amines must be protected to prevent unwanted reactions. Boc (tert-butoxycarbonyl): added with Boc₂O, removed with TFA or HCl in dioxane (acid labile). Cbz (benzyloxycarbonyl): added with CbzCl, removed by hydrogenolysis (H₂/Pd-C). Fmoc: removed by base (piperidine) — used in solid-phase peptide synthesis. Choose protection based on other functional groups and deprotection conditions needed.
Many neurotransmitters and drugs are amines. Dopamine (catecholamine): reward, movement — depleted in Parkinson's. Serotonin (indolamine): mood, sleep — SSRIs block reuptake. Histamine (imidazole amine): immune response, allergy — antihistamines block H₁ receptors. Acetylcholine (quaternary ammonium ester): nerve-muscle junction. Epinephrine/norepinephrine: fight-or-flight. All pH-dependent — protonated at physiological pH (positively charged, water soluble).
🎓 Common Exam Questions
Q: How are primary, secondary, and tertiary amines classified?
A: Classification is based on the number of carbon-containing groups (R groups) attached to nitrogen. Primary (1°): one R group (RNH₂). Secondary (2°): two R groups (R₂NH). Tertiary (3°): three R groups (R₃N). Quaternary ammonium (R₄N⁺): four R groups, positively charged — not a base.
Q: Why are alkyl amines stronger bases than aniline (aryl amine)?
A: Alkyl groups donate electrons to nitrogen, increasing electron density and basicity. Aryl amines (aniline) are weaker bases because the nitrogen lone pair is delocalized into the benzene ring via resonance — less available to accept a proton. Electron-withdrawing groups on the ring further decrease basicity; electron-donating groups increase it.
Q: What is Gabriel synthesis and why is it used to make primary amines?
A: Gabriel synthesis uses phthalimide (N-H compound, pKa ~9) as a nitrogen source. Base converts it to the phthalimide anion, which alkylates via SN2. Hydrazine hydrolysis cleaves the product to give a pure primary amine + phthalhydrazide. It avoids over-alkylation (common problem when amines react with alkyl halides directly) and guarantees a primary amine product.
Q: What is Hofmann elimination and how does it differ from Zaitsev's rule?
A: Hofmann elimination occurs when a quaternary ammonium salt is heated with base — it gives the least substituted alkene (anti-Zaitsev). The bulky trimethylamine leaving group and bulky base favor attack on the least hindered beta-hydrogen. Zaitsev's rule predicts the most substituted alkene; Hofmann gives the opposite. Used to determine amine structure.
Q: How do amines act as nucleophiles in reactions with acid chlorides and alkyl halides?
A: The nitrogen lone pair attacks electrophiles. With acid chlorides: amine → amide (fast, goes to completion). With esters: slower amide formation. With alkyl halides: SN2 alkylation → higher-substituted amine + HX byproduct. Over-alkylation is a problem — you may get a mixture of 1°, 2°, 3° amines and quaternary salt. Gabriel synthesis avoids this.
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