Chapter 24: Amines and Heterocycles
Primary, secondary, tertiary: count the carbons on nitrogen
Amines put a nitrogen atom into an alkane framework, and nearly everything in this chapter follows from the two features that nitrogen brings: a lone pair of electrons and a modest electronegativity. Before any of that chemistry, though, comes bookkeeping, and the bookkeeping convention is worth stating carefully because it differs from the one used for alcohols and halides. An amine is classified by the number of carbon substituents bonded directly to nitrogen. Methylamine, CH₃NH₂, has one and is primary. Dimethylamine, (CH₃)₂NH, has two and is secondary. Trimethylamine, (CH₃)₃N, has three…
Reading base strength from the pKaH ladder
Every comparison of amine basicity in this chapter — and every buffering, salt-forming, and drug-formulation argument built on it — runs through one convention, so it is worth nailing down. Basicity is measured by how the conjugate acid behaves: take the base, protonate it, and ask how acidic the resulting ammonium ion is. That number is the pKa of the conjugate acid, abbreviated pKaH. A strong base gives a conjugate acid that clings to its proton, meaning a weak acid, meaning a high pKa. So the ladder reads in one direction: the higher the pKaH, the stronger the base. Students who memorize…
Aniline's discount: a lone pair on loan to the ring
The comparison that anchors this section is worth setting up honestly, because the two molecules differ by exactly one feature. Cyclohexylamine is an NH₂ group on a saturated six-membered ring; aniline is an NH₂ group on a benzene ring; their conjugate acids have pKa values of 10.7 and 4.6. Six log units is a factor of about 10⁶, and no inductive argument gets close to explaining it — an sp2 carbon is somewhat more electron-withdrawing than an sp3 carbon, but that effect is worth one or two pKa units, not six. The dominant effect is resonance. Aniline's nitrogen, though pyramidal in…
Alkylation routes: why one equivalent of ammonia is never enough
Treat the failure first, because understanding it motivates everything that follows. Mix bromoethane with one equivalent of ammonia and the first SN2 event gives ethylammonium bromide, which equilibrates with free ethylamine in the basic mixture. Now two nucleophiles compete for every remaining molecule of bromoethane: ammonia, and ethylamine. The ethyl group donates electron density toward nitrogen, so ethylamine is the stronger nucleophile — the very effect that makes alkylamines stronger bases than ammonia makes them faster alkylators. Each substitution therefore breeds a better…
Reductions that end in amines — and the carbon-count bookkeeping
The reduction chemistry of this section is best organized around a single question: how many carbons does the product amine have, relative to what you started with? Every route answers differently, and exam problems turn on the difference. The nitrile route adds one. Cyanide ion is a fine SN2 nucleophile, so bromoethane gives propanenitrile — three carbons now, because the nitrile carbon counts. LiAlH₄ delivers two hydride equivalents to the C≡N triple bond, and aqueous workup liberates propan-1-amine, CH₃CH₂CH₂NH₂. Read as a two-step sequence from the halide, the transformation is RBr to…
Reductive amination: carbonyl in, amine out
Every other amine synthesis in this chapter installs nitrogen onto a pre-formed skeleton; reductive amination assembles the skeleton and the nitrogen in one operation, which is why it is the single most used amine synthesis in pharmaceutical chemistry. The mechanism is carbonyl chemistry from earlier chapters, redirected. The amine nitrogen attacks the electrophilic carbonyl carbon of a ketone or aldehyde, giving after proton shuffling a carbinolamine — a tetrahedral carbon bearing both OH and NR2. Under the mildly acidic conditions of the reaction (the optimal pH is around 4-5), the hydroxyl…
Hofmann elimination: making nitrogen leave, and paying for it in regiochemistry
Do not confuse this reaction with the Hofmann rearrangement of the synthesis section: that one shortens an amide to an amine with Br₂/NaOH, while this one builds an alkene from a quaternary ammonium salt. Only the name is shared. The Hofmann elimination is the chapter's best example of chemists engineering a reaction rather than finding one. The obstacle is thermodynamic and structural at once: for E2 to occur, the carbon-nitrogen bond must break heterolytically, and an amide ion (H₂N⁻) is far too high in energy to leave. The fix is to make the nitrogen leave as a neutral, stable molecule…
Arenediazonium salts: swap nitrogen for almost anything
The reaction that opens this chemistry is diazotization. Sodium nitrite in cold aqueous HCl generates nitrous acid, which is protonated and dehydrated to the nitrosonium ion, NO+. Aniline's nitrogen — still nucleophilic, however weak a base the resonance discount has made it — attacks NO+ to give an N-nitrosamine, which tautomerizes and dehydrates under the acidic conditions to the arenediazonium ion, Ar–N≡N⁺. The temperature specification of 0-5 degrees Celsius is not fussiness: arenediazonium salts decompose to phenols in warm water, so they are made cold and used promptly, almost always in…
Pyrrole and imidazole: aromatic rings that spend the lone pair
Five-membered aromatic heterocycles solve an arithmetic problem: a five-atom ring has only two ring double bonds, four pi electrons, two short of a sextet. The heteroatom makes up the difference by donating a lone pair into the ring. In pyrrole, the nitrogen sits sp2-hybridized with its lone pair in the perpendicular p orbital, conjugated with the two C=C units — six electrons, cyclic, planar, continuous overlap: aromatic by every Hückel criterion. The measurable consequences are large: pyrrole's resonance energy is on the order of two-thirds of benzene's, its ring protons resonate in the…
Pyridine: aromatic, basic, and stingy toward electrophiles
Set pyrrole and pyridine side by side and the pair becomes a single lesson about where a lone pair lives. Pyrrole's nitrogen donates its lone pair into the ring to complete the sextet: aromatic, electron-rich, non-basic. Pyridine's nitrogen does not need to donate a pair — the six ring atoms each supply one p electron, exactly as in benzene — so its lone pair stays home, in an sp2 hybrid lying in the ring plane, geometrically orthogonal to the pi system. Protonation therefore costs pyridine nothing aromatic: pyridinium is just as aromatic as pyridine. That is why pyridine is a real base, pKaH…
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