Organic chemistry tricks that make amines stick

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.

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.

The nitrogen lone pair makes amines good nucleophiles. React with: acid chlorides → amides (fast). Esters → amides (slower). Alkyl halides → alkylation (gives higher substituted amine).

Only reliable way to make pure primary amines without over-alkylation. Phthalimide (N-H, pKa ~9) + base → anion → alkylate → hydrazine hydrolysis → primary amine + phthalhydrazide.

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).

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.

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.

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.

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).