Difficulty: Advanced | Prerequisites: NAS, carbonyl additions, alpha functionalization.
Amines are nitrogen-containing organic compounds that show up everywhere in biology and pharmaceuticals. Understanding their basicity, synthesis, and reactions ties together much of what you have learned about nucleophiles, leaving groups, and carbonyl chemistry. This section also covers amino acids (the building blocks of proteins), peptide bond formation, and an introduction to carbohydrate chemistry (sugars). These are the topics where organic chemistry starts to feel like biochemistry. You should already be comfortable with SN2 reactions, reductions with LAH and NaBH₄, and imine/enamine formation.
Amines are basic nitrogen compounds classified as 1°, 2°, or 3°. They can be made by SN2 with ammonia (often over-alkylated), Gabriel synthesis (clean 1° amines), azide displacement + reduction, or reductive amination (the most versatile method). Amino acids are alpha-amino carboxylic acids made by Gabriel, malonic ester, or Strecker synthesis. Peptide bonds are formed with protecting groups (BOC) and coupling agents (DCC). Carbohydrates are polyhydroxy aldehydes or ketones that cyclise to form hemiacetals.
Primary amine (1°): R-NH₂. One alkyl group on nitrogen.
Secondary amine (2°): R₂NH. Two alkyl groups on nitrogen.
Tertiary amine (3°): R₃N. Three alkyl groups on nitrogen.
Umbrella flip (nitrogen inversion): Amines undergo rapid inversion (about 6 kcal/mol barrier), interconverting enantiomers. This means most amines cannot be resolved into stable chiral forms. Exception: quaternary ammonium salts and some rigid ring systems.
Gabriel amine synthesis: Phthalimide + base → nucleophilic nitrogen → SN2 with alkyl halide → hydrolysis or hydrazinolysis gives a clean primary amine without over-alkylation.
Reductive amination: Carbonyl + amine + NaBH₄ at pH 4.5 → amine. The most versatile method for making 1°, 2°, or 3° amines. Forms an imine or iminium ion in situ, then reduces it.
Curtius rearrangement: Acyl azide + heat → isocyanate (+ N₂). The isocyanate is then hydrolysed to give an amine (+ CO₂). Produces an amine with one fewer carbon than the starting acid. With an alcohol present, gives a carbamate instead.
Hofmann rearrangement: Primary amide + NaOH/Br₂ → amine + CO₂. Same net result as Curtius (loss of one carbon), but starts from the amide.
BOC (tert-butoxycarbonyl): A protecting group for the amine end of an amino acid during peptide synthesis. Removed with trifluoroacetic acid (CF₃COOH, pKa ~ 0).
Zwitterion: The form of an amino acid at physiological pH, where the amine is protonated (NH₃⁺) and the carboxylate is deprotonated (COO⁻).
Strecker synthesis: Aldehyde + NH₃ + HCN → aminonitrile → hydrolysis → amino acid. Forms both the amino and carboxylic acid groups in one sequence.
Anomeric carbon: The carbon in a sugar that was the carbonyl carbon in the open-chain form. It becomes a new stereocentre when the sugar cyclises.
Reducing sugar: A sugar that can be oxidised (usually because it has a free or accessible aldehyde group). Aldoses are reducing sugars.
Kiliani-Fischer homologation: Adds one carbon to an aldose sugar using HCN, then H₂/Ni, then H₃O⁺.
Simple amines: name the alkyl groups attached to nitrogen. Isopropylamine, diisopropylamine, N-methyl ethylamine, N-ethyl-N-methyl propylamine.
Cyclic amines: aziridine (3-ring), azetidine (4-ring), pyrrolidine (5-ring), piperidine (6-ring).
Amino acids use both common names and systematic names (e.g. 2-aminoacetic acid = glycine).
All amines have sp³ nitrogen with a lone pair, except aniline, where the lone pair is conjugated with the aromatic pi system (sp² nitrogen).
NH₃ → NH₄⁺: pKa 9.26.
Methylamine → methylammonium: pKa 10.6.
Diethylamine → diethylammonium: pKa 10.7.
Triethylamine → triethylammonium: pKa 9.81 (slightly lower because R groups make protonation sterically harder, and the protonated form is less stabilised by solvation).
Aniline: pKa 4.63 (much weaker base, lone pair delocalised into the ring).
Pyrrole: pKa -3.8 (the lone pair is part of the aromatic sextet, not available for protonation).
Pyridine: pKa 5.25 (the lone pair is in the plane of the ring, not part of the aromatic system, so it is available).
Electron-withdrawing groups on the carbon next to NH₂ destabilise the protonated form (put δ⁺ near NH₃⁺), lowering basicity. Electron-donating groups stabilise the protonated form, increasing basicity.
SN2 with NH₃: alkyl halide + excess NH₃ → primary amine. Problem: the product is also a nucleophile and reacts further, giving mixtures of 1°, 2°, 3° amines and quaternary salts. Use a large excess of NH₃ to limit over-alkylation.
Gabriel amine synthesis: phthalimide (deprotonated with base) does SN2 on an alkyl halide → N-alkyl phthalimide → hydrolysis (OH⁻, heat, H₂O) or hydrazinolysis (NH₂NH₂) → clean primary amine. Avoids over-alkylation entirely.
Azide method: alkyl halide + NaN₃ (SN2 in DMF) → alkyl azide → LAH reduction → primary amine. Also avoids over-alkylation.
2° Amine synthesis: use an amide nitrogen as the nucleophile. Amide + NaOMe/HoMe + benzyl halide → N-alkylated amide → hydrolysis → secondary amine. Or: trifluoroacetamide route.
3° Amine via SN2: secondary amine + alkyl halide + K₂CO₃ (in CH₃CN) → tertiary amine.
Reductive amination (the most versatile method):
Carbonyl + NH₃ + NaBH₄ at pH 4.5, in MeOH → primary amine.
Carbonyl + primary amine + NaBH₄ at pH 4.5 → secondary amine.
Carbonyl + secondary amine + NaBH₄ at pH 4.5 → tertiary amine.
Mechanism: the amine attacks the carbonyl → imine (or iminium ion) → NaBH₄ reduces the C=N to C-N.
Can also be used for intramolecular ring formation.
Acyl azide (made from acid chloride + NaN₃) + heat → isocyanate + N₂.
Isocyanate + H₂O → amine + CO₂.
Isocyanate + alcohol → carbamate (urethane).
Isocyanate + amine → urea.
Net result: the carboxylic acid loses one carbon and becomes an amine.
Primary amide + NaOH + Br₂ + H₂O → amine + CO₂.
Same net result as Curtius (one carbon lost). Mechanism involves N-bromination, base-induced rearrangement to an isocyanate, then hydrolysis.
Amine + excess CH₃I + K₂CO₃ → quaternary ammonium salt.
Quaternary ammonium salt + Ag₂O + heat → alkene (Hofmann elimination). Used historically to determine amine structure.
Made by nitration of the aromatic ring (H₂SO₄/HNO₃ → ArNO₂), then reduction (H₂/Pd or LAH/H₂O → ArNH₂).
Diazonium chemistry (Sandmeyer reaction): ArNH₂ + HONO/HCl → ArN₂⁺ (diazonium salt). The diazonium salt can be replaced by: NaI → ArI, CuBr → ArBr, CuCl → ArCl, CuCN → ArCN, H₃PO₂ → ArH, H₂O → ArOH.
Peptides: fewer than 50 amino acids. Proteins: 50 or more.
Amino acids exist as zwitterions at physiological pH: NH₃⁺ on one end, COO⁻ on the other.
The 5 amino acids to know well from the lecture: glycine (not chiral), alanine, valine, leucine, phenylalanine, serine, cysteine, asparagine, aspartic acid (pKa 3.7), glutamic acid (pKa 4.25), lysine, arginine, histidine, proline (secondary amine).
Gabriel synthesis (N-bond): alpha-bromo acid (from HVZ) + phthalimide → hydrolysis → amino acid.
Malonic ester route (R-bond): diethyl malonate or acetylamidomalonate + NaOMe/HoMe + alkyl halide → hydrolysis/decarboxylation → amino acid.
Strecker synthesis (carboxylic acid bond): aldehyde + NH₃ + HCN → aminonitrile → H₃O⁺/H₂O hydrolysis → amino acid.
H-bond method: ozonolysis of a suitable alkene → aldehyde → reductive amination (NH₃, pH 4.5, NaBH₄) → amino acid.
Read from N-terminus to C-terminus. The first amino acid gets its full name modified to end in "-yl", the last keeps its full name. Example: glycylalanine = Gly-Ala.
Direct coupling of amino acid chloride + amino acid gives a mixture of products (poor selectivity).
Solution: protecting groups.
Protect the amine of the first amino acid with BOC (tert-butoxycarbonyl).
Activate the carboxylate with DCC.
Couple with the second amino acid.
Remove BOC with CF₃COOH (trifluoroacetic acid).
Repeat for each additional amino acid.
Solid-phase peptide synthesis (Merrifield) follows the same logic but anchors the growing chain to a resin.
Sequencing technique: phenylisothiocyanate (PhNCS) reacts with the N-terminal amino acid → cyclisation → cleavage releases the first amino acid as a thiazolinone, leaving the rest of the peptide intact. Repeat to read the sequence one residue at a time.
Hofmann elimination: quaternary ammonium salt + Ag₂O + heat → alkene. Gives the less substituted (Hofmann) product.
Hofmann degradation: repeated Hofmann elimination used to break down cyclic amines and determine ring size.
Pyridine: six-membered ring, one nitrogen. Lone pair in the plane (sp², available for protonation). pKa 5.25.
Pyrimidine: six-membered ring, two nitrogens.
Pyrrole: five-membered ring, one nitrogen. Lone pair is part of the aromatic 6-electron system. pKa -3.8 (very weak base).
Bromination of pyrrole: at C-2 and C-5 (electron-rich positions). At 300°C with Br₂, multiple products form.
Bromination of pyridine: requires harsh conditions because the ring is electron-poor (nitrogen withdraws electron density).
General formula: Cₙ(H₂O)ₙ. Polyhydroxy aldehydes (aldoses) or polyhydroxy ketones (ketoses).
Open-chain sugars cyclise to form hemiacetals (5-membered furanose or 6-membered pyranose rings).
The anomeric carbon is the one that was the carbonyl carbon. It becomes a new stereocentre upon cyclisation, giving alpha and beta anomers.
Ribose: a 5-carbon aldose (aldopentose). Forms a furanose ring. The sugar in RNA.
Glucose: a 6-carbon aldose (aldohexose). Forms a pyranose ring. The most important sugar in metabolism.
Sugar + CH₃OH + acid catalyst (HCl or cat CH₃OH₂⁺) → methyl glycoside + H₂O.
This is acetal formation at the anomeric carbon. Locks the ring form and prevents mutarotation.
An aldose is a reducing sugar: it can reduce Ag⁺ to Ag⁰ (Tollens' test / silver mirror test) because the open-chain aldehyde form is accessible in equilibrium.
The aldehyde is oxidised to a carboxylate (aldonic acid) in the process.
Adds one carbon to an aldose.
Steps: (1) HCN → cyanohydrin (gives two diastereomeric products at the new stereocentre). (2) H₂/Ni → reduces the nitrile to an aldehyde via an imine intermediate. (3) H₃O⁺ → hydrolyses to the new aldose.
Example: arabinose (5C) → glucose + mannose (both 6C, epimers at C-2).
Removes one carbon from an aldose.
Steps: (1) NH₂OH → oxime. (2) Tosyl chloride (TsCl) + NEt₃ → activated oxime. (3) NaOMe → eliminates to give the shorter aldose + HCN.
This is the reverse of Kiliani-Fischer.
The lecture notes show structures of sucrose (glucose + fructose), cellulose, and starch, all built from glycosidic bonds at the anomeric carbon.
Students often think more alkyl groups on nitrogen always increase basicity. While alkyl groups are electron-donating, steric effects and solvation also matter. Triethylamine is actually a weaker base than diethylamine in water.
The nitrogen lone pair in pyrrole is not available for protonation because it is part of the aromatic sextet. Students often confuse pyrrole (weak base) with pyridine (moderate base).
In reductive amination, students sometimes forget that pH 4.5 is critical. Too acidic protonates the amine. Too basic prevents water loss from the carbinolamine.
Gabriel synthesis only makes primary amines. Students sometimes try to use it for secondary or tertiary amine synthesis.
⚠️ Reductive amination is the most commonly tested amine synthesis. Be able to choose the correct carbonyl + amine combination for a target 1°, 2°, or 3° amine.
⚠️ Know the Curtius and Hofmann rearrangements: both lose one carbon and convert an acid (or amide) to an amine.
⚠️ Peptide synthesis with BOC/DCC: know the order of protection, coupling, and deprotection.
⚠️ Sandmeyer reactions: ArNH₂ → ArN₂⁺ → ArX. Know which copper salt (or reagent) gives which product.
⚠️ Kiliani-Fischer adds one carbon, dehomologation removes one carbon. Know the reagents for each.
⚠️ Amino acid synthesis: Gabriel, malonic ester, and Strecker. Each forms a different bond to the alpha carbon.
True or False: Pyrrole is a stronger base than pyridine.
False. Pyridine (pKa 5.25) is a much stronger base. Pyrrole's lone pair is tied up in the aromatic system.
Fill in the blank: Reductive amination uses ______ as the reducing agent.
NaBH₄.
True or False: The Curtius rearrangement produces an amine with the same number of carbons as the starting acid.
False. It loses one carbon (as CO₂).
Fill in the blank: The anomeric carbon in a sugar is the carbon that was the ______ in the open-chain form.
Carbonyl (aldehyde) carbon.
Q: Propose a synthesis of diethylamine from acetaldehyde.
A: Acetaldehyde + ethylamine + NaBH₄ at pH 4.5 in MeOH → diethylamine (reductive amination).
Q: What product forms when aniline is treated with HONO/HCl followed by CuCN?
A: Benzonitrile (ArCN). This is the Sandmeyer reaction: aniline → diazonium salt → replacement with CN via CuCN.
Q: Using the Kiliani-Fischer homologation, how many 6-carbon aldoses can you obtain from arabinose?
A: Two: glucose and mannose. They are C-2 epimers because the HCN addition creates a new stereocentre with two possible configurations.
Amine chemistry connects back to imine and enamine formation (from the carbonyl addition notes) and to amide chemistry (from the NAS notes). The Curtius and Hofmann rearrangements are conceptually similar to other 1,2-shifts you may encounter in rearrangement reactions. Amino acid and peptide chemistry leads into biochemistry. Carbohydrate chemistry (hemiacetals, acetals, anomeric carbon) is a direct application of the acetal chemistry from the carbonyl addition notes.
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