Amines

Amines are organic compounds derived from ammonia (NH₃) by replacement of one, two, or three hydrogen atoms with alkyl or aryl groups. They are classified into:

• Primary amines (1°): R—NH₂ (e.g., methylamine CH₃NH₂)
• Secondary amines (2°): R₂NH (e.g., dimethylamine (CH₃)₂NH)
• Tertiary amines (3°): R₃N (e.g., trimethylamine (CH₃)₃N)
• Quaternary ammonium salts: R₄N⁺ X⁻ (e.g., tetramethylammonium chloride)

Structure: the nitrogen atom in amines has sp³ hybridization, with a lone pair in a hybrid orbital. The geometry is trigonal pyramidal (angles ≈ 107°, as in ammonia). At room temperature, tertiary amines with three different substituents undergo rapid nitrogen inversion (passing through a planar sp² transition state), preventing isolation of enantiomers.

Aromatic amines: the main example is aniline (C₆H₅NH₂). In aniline, the nitrogen lone pair is partially conjugated with the benzene ring (resonance), making it less basic and less nucleophilic than aliphatic amines.

Real-world applications: amines are present in many drugs (antidepressants, antihistamines, local anesthetics), dyes (azo dyes), and are the building blocks of amino acids and proteins. Trimethylamine is responsible for the smell of decomposing fish.

Amines are Brønsted bases: the nitrogen lone pair accepts a proton to form a quaternary ammonium ion. $$\mathrm{RNH_2 + H_2O \rightleftharpoons RNH_3^+ + OH^-}$$ The pKₐ of the conjugate base (RNH₃⁺) measures basicity: the higher the pKₐ, the stronger the base.

Basicity order in water (aliphatic amines): $$\mathrm{(CH_3)_2NH > CH_3NH_2 > (CH_3)_3N > NH_3}$$ (2° > 1° > 3° > NH₃)

The order may be surprising one would expect 3° > 2° > 1° from the +I inductive effect of alkyl groups. In water, basicity is determined by two factors:

• Inductive effect (+I): alkyl groups donate electrons to nitrogen, increasing electron density on the lone pair and therefore basicity. Expected order: 3° > 2° > 1°.
• Solvation: the ammonium ion RNH₃⁺ is stabilized by hydrogen bonding with water. The more H atoms bonded to N⁺, the greater the solvation. 1° (3 H) is better solvated than 2° (2 H) and 3° (1 H).
• Steric effect: bulky groups hinder solvent approach to the ammonium ion, reducing solvation.

The net result in water: 2° ≈ 1° > 3°. In the gas phase (no solvent), the order is 3° > 2° > 1°.

Aniline and aromatic amines: they are much less basic than aliphatic amines (pKₐ of aniline = 4.6, pKₐ of CH₃NH₂ = 10.6). The nitrogen lone pair is delocalized by resonance into the aromatic ring, reducing availability for protonation.

Real-world applications: the different basicities are exploited in separating amine mixtures (acid-base extraction) and in drug design: many drugs act as weak bases that are protonated in the acidic stomach and absorbed in the intestine.

The main synthetic methods for amines are:

1. Reduction of aromatic nitro compounds: $$\mathrm{Ar-NO_2 \xrightarrow{Sn/HCl} Ar-NH_2}$$ Aromatic nitro compounds (obtained by SEAr nitration) are reduced to anilines with Sn/HCl, Fe/HCl, or H₂/Pd-C. This is the most common method for preparing aromatic amines.

2. Alkylation of ammonia (Hofmann reaction): $$\mathrm{NH_3 + R-X \to R-NH_3^+ X^- \xrightarrow{base} R-NH_2}$$ SN2 reaction: ammonia (nucleophile) attacks the alkyl halide. Problem: the primary amine produced is more nucleophilic than ammonia and reacts further, giving mixtures of 1°, 2°, 3° amines and quaternary salts. To limit polyalkylation, a large excess of NH₃ is used.

3. Reduction of nitriles and amides:

• R—C≡N + LiAlH₄ (or H₂/Pd) → R—CH₂—NH₂ (primary amine, chain extension by 1 C)
• RCONH₂ + LiAlH₄ → R—CH₂—NH₂ (primary amine)
• RCONR'R'' + LiAlH₄ → R—CH₂—NR'R'' (2° or 3° amines)

4. Gabriel synthesis: The Gabriel synthesis uses the potassium salt of phthalimide to give pure primary amines without polyalkylation. Phthalimide is an acidic imide (pKₐ ≈ 8.3) deprotonated by KOH. The phthalimide anion (nucleophile) reacts with R—X via SN2. Hydrazine (NH₂NH₂) liberates the primary amine by acyl nucleophilic substitution.

Real-world applications: reduction of nitro compounds is the industrial method for producing aniline (over 4 million tonnes/year), an intermediate for dyes, polymers (polyurethanes), and drugs. The Gabriel synthesis is used to prepare amino acids in the laboratory.

Diazonium salts (Ar—N≡N⁺ X⁻) are extremely versatile aromatic compounds in organic synthesis. They are prepared by diazotization of primary aromatic amines: $$\mathrm{Ar-NH_2 + NaNO_2 + 2HCl \xrightarrow{0-5^\circ C} Ar-N\equiv N^+ Cl^- + NaCl + 2H_2O}$$ The reaction must be carried out at 0–5°C because diazonium salts are unstable at higher temperatures (they decompose releasing N₂). The mechanism involves formation of nitrous acid (HNO₂) from NaNO₂ + HCl, which nitrosates the amine.

Substitution reactions (with N₂ loss):

• Hydrolysis: ArN₂⁺ + H₂O (Δ) → Ar—OH + N₂ + H⁺ (phenols)
• Sandmeyer substitution with halogens: CuCl → ArCl, CuBr → ArBr, CuCN → ArCN (aromatic nitriles, then hydrolyzable to acids)
• Substitution with KI: ArN₂⁺ + I⁻ → Ar—I + N₂ (aromatic iodides, difficult to obtain otherwise)
• Schiemann substitution with HBF₄: ArN₂⁺ BF₄⁻ (Δ) → Ar—F + N₂ + BF₃ (aromatic fluorides)
• Reductive deamination with H₃PO₂: ArN₂⁺ + H₃PO₂ → Ar—H + N₂ + H₃PO₃

Coupling reactions (without N₂ loss): The diazonium salt acts as a weak electrophile and reacts with phenols (ArOH) or aromatic amines (ArNR₂) at the para position (or ortho if para is occupied), forming azo dyes: $$\mathrm{Ar-N\equiv N^+ + Ar'-H \to Ar-N=N-Ar' + H^+}$$ The product has the azo group (—N=N—) that conjugates the two aromatic rings, extending electron delocalization and absorbing visible light (hence the bright colors).

Real-world applications: azo dyes constitute over 60% of world dye production (methyl red, methyl orange, butter yellow). Methyl orange is also a pH indicator (transition at pH 3.1–4.4). The Sandmeyer reaction allows introduction of halogens at specific ring positions not accessible via direct SEAr.

Amines are key intermediates in many syntheses, thanks to their nucleophilicity, basicity and the ways they can be transformed.

Protecting amines:

• The —NH₂ group is very reactive (nucleophilic). To "protect" it while reacting on other groups, it is converted into an amide (acetylation: R—NHCOCH₃) or a carbamate (Boc₂O → R—NH—Boc).
• Deprotection is by acid hydrolysis (Boc → HCl/CH₂Cl₂; Fmoc → mild base).

Transformation into other groups:

• Primary amines → isocyanates (R—N=C=O) reacting with alcohols → urethanes (polyurethanes).
• Secondary amines → nitrosamines (R₂N—NO), carcinogenic compounds formed with nitrites.
• Hofmann rearrangement: an amide treated with Br₂/NaOH → primary amine with loss of CO₂.
• Hofmann elimination: R₄N⁺OH⁻ (Δ) → the least-substituted alkene (Hofmann rule, opposite to Zaitsev).

Amines in biology:

• Amino acids contain the —NH₂ (or NH₃⁺) group.
• The DNA nitrogenous bases (adenine, guanine, cytosine) are heterocyclic amines.
• Dopamine, serotonin, adrenaline are biogenic amines.
• Alkaloids (morphine, quinine, strychnine) contain amine nitrogens.

Real-world applications: polyurethanes are used in foams (mattresses, insulation), elastomers, coatings. Carbamates are pesticides (carbaryl). Nylon (a polyamide) is a condensation polymer of amines and acids.