Amine Reactions
Amines are good nucleophiles (electron-rich nitrogen with available lone pair) and can attack alkyl halides (SN2 alkylation) or carbonyl derivatives (acylation to form amides). Both reactions are covered by mechanisms you learned in previous chapters.
Amine + Alkyl Halide = Alkylation
Primary amine attacks a primary or methyl alkyl halide in SN2:
R-NH₂ + R’-X → R-NH-R’ + HX (typically with a base to absorb HCl)
Problem: the secondary amine product is MORE nucleophilic than the starting primary amine (one alkyl donor → slightly more nucleophilic than two H). So after the first alkylation, the secondary amine attacks another alkyl halide → tertiary amine. Then tertiary attacks again → quaternary ammonium.
This “over-alkylation” is hard to control. Practical solutions:
- Use large excess of ammonia (tenfold or more). Statistically favors primary amine product.
- Use the Gabriel synthesis (see Section 10.5) to get a clean primary amine.
- Use reductive amination (Section 6.8) instead of direct alkylation.
Amine + Acid Chloride / Anhydride = Amide (Acylation)
R-NH₂ + R’-COCl + pyridine → R-NH-CO-R’ + pyridine-HCl.
Acylation is cleaner than alkylation because the product (amide) is NOT nucleophilic (amide nitrogen lone pair is delocalized into the carbonyl). So there is no over-acylation. One equivalent of acid chloride gives one equivalent of amide.
Anhydrides work similarly but half the anhydride is wasted as the free carboxylic acid byproduct. Esters + amine → amide is slower but possible.
Hofmann Elimination
Exhaustive methylation converts an amine to a quaternary ammonium by treating with excess methyl iodide. The resulting R-N⁺(CH₃)₃ is a good leaving group. When heated with hydroxide, the quaternary ammonium undergoes E2 elimination:
R-CH(CH₂R’)-N⁺(CH₃)₃ OH⁻ → alkene + N(CH₃)₃ + H₂O.
Unusually, Hofmann elimination gives the Hofmann product (less substituted alkene) as the major product, NOT Zaitsev. The reason: the bulky quaternary ammonium LG forces the hydroxide to abstract the less hindered beta-H (on the less substituted carbon), giving the less substituted alkene.
Diazonium Salt Chemistry (Brief)
Primary aryl amines (anilines) react with HNO₂ (from NaNO₂ + HCl) at 0-5°C to form diazonium salts: Ar-N₂⁺. These are versatile intermediates:
- Diazonium + H₂O → phenol.
- Diazonium + CuCl → aryl chloride.
- Diazonium + CuCN → aryl nitrile.
- Diazonium + coupling partner → azo dye (the basis of synthetic textile dyes).
This is specialized chemistry; MCAT rarely tests it in depth.
Biological Acylation
Biology uses acylation constantly:
- Acetylation of amines by acetyl-CoA: neurotransmitter synthesis (acetylcholine from choline + acetyl-CoA).
- Peptide bond formation: activated amino acids (aminoacyl-tRNA) acylate the next amino acid’s alpha-amine.
- Histone acetylation: lysine side-chain amines get acetylated by histone acetyltransferases (HATs), regulating chromatin structure.
Each of these is the biological version of the organic amine + activated acyl → amide reaction.