Functional-Group Interconversions, Heterocycle Syntheses & Multicomponent Reactions
The final part gathers the reactions that swap one functional group for another, that build rings containing nitrogen, oxygen and sulfur, and that assemble a complex product from three or four simple pieces in one pot. Three families in one file. Functional-group interconversions: make ethers (Williamson), primary amines cleanly (Gabriel, Delépine), alkenes by anti elimination (Hofmann, with the Hofmann-vs-Zaitsev orientation rule), interconvert halides (Finkelstein, Appel), remove a carbon as CO₂ (Hunsdiecker), invert an alcohol while substituting it (Mitsunobu), turn a nitrile + carbocation into an amide (Ritter), N-methylate or reductively aminate (Eschweiler–Clarke, Leuckart), make esters at equilibrium (Fischer), and build α-amino acids (Strecker). Heterocycle syntheses: indoles (Fischer), furans/pyrroles/thiophenes (Paal–Knorr), pyrroles (Knorr), dihydropyridines/pyridines (Hantzsch), quinolines (Skraup, Doebner–Miller), iso- and tetrahydroisoquinolines (Bischler–Napieralski, Pictet–Spengler), and dihydropyrimidinones (Biginelli). Multicomponent: the Ugi (4-component) and Passerini (3-component) isocyanide reactions. Two layers on every reaction: a hand-held beginner path (plain “what it does”, RDKit scheme, arrow-by-arrow mechanism, graded worked examples, trap boxes) and a research-grade advanced/reference path (mechanism & stereoelectronics, regio- and chemoselectivity, scope & FG-tolerance tables, variants, selectivity comparisons, research-level problems). The file closes with a Book master index of all nine parts.
The 22 sections in Part 9
- 1The Williamson ether synthesis Free below
- 2The Gabriel synthesis (& the Delépine variant)
- 3The Hofmann elimination (& Hofmann vs Zaitsev)
- 4The Finkelstein reaction (halide exchange)
- 5The Appel reaction (alcohol → halide)
- 6The Hunsdiecker reaction (RCOOAg → R–Br)
- 7The Mitsunobu reaction (alcohol + acidic Nu, inversion)
- 8The Ritter reaction (nitrile + carbocation → amide)
- 9Reductive amination: Eschweiler–Clarke & Leuckart–Wallach
- 10The Fischer esterification (acid + alcohol ⇌ ester)
- 11The Strecker amino-acid synthesis
- 12The Fischer indole synthesis
- 13The Paal–Knorr synthesis (furan / pyrrole / thiophene)
- 14The Knorr pyrrole synthesis
- 15The Hantzsch dihydropyridine / pyridine synthesis
- 16The Skraup & Doebner–Miller quinoline syntheses
- 17Bischler–Napieralski & Pictet–Spengler (isoquinolines)
- 18The Biginelli dihydropyrimidinone synthesis
- 19The Passerini reaction (3-component)
- 20The Ugi reaction (4-component)
- 21The nine parts at a glance
- 22What Part 9 (this file) contains
The Williamson ether synthesis
Free extractSection AA.1 of Part 9, reproduced in full from the book — figures and all. No sign-in, no paywall on this section.
An alkoxide (or phenoxide) attacks a primary alkyl halide from the back, kicks out the halide, and the two oxygens-and-carbons become an ether. The single most general way to make an ether with a chosen pair of groups.
In one line: deprotonate an alcohol to its alkoxide (R–O⁻), then let it do an SN2 on a primary alkyl halide (or tosylate) R′–X to give the ether R–O–R′. Because it is SN2, the halide-bearing carbon must be unhindered (methyl or primary).
The alcohol is first converted to its conjugate base with NaH, Na metal, or K₂CO₃ (for phenols); the alkoxide is the real nucleophile.
Mechanism — Williamson (SN2 at the halide carbon)
- Deprotonation: R–OH + NaH → R–O⁻ Na⁺ + H₂ (alkoxide formed).
- Backside attack: the alkoxide oxygen attacks the primary carbon of R′–X from the side opposite X; a pentacoordinate SN2 transition state forms.
- Leaving-group loss & inversion: X⁻ departs, the new C–O bond forms, and configuration at that carbon inverts (if it was a stereocentre) → ether R–O–R′.
How would you make tert-butyl methyl ether (MTBE) by Williamson? Which pairing works? Medium
Predict the product of treating a 1,2-halohydrin (2-chloroethanol, deprotonated) with base. Easy
⚠ Common mistakes & exam traps
- Use a primary (or methyl) halide. Secondary is sluggish; tertiary halides eliminate (E2) with the basic alkoxide instead of substituting.
- Symmetry trap. For an unsymmetrical ether there are two disconnections — always choose the one that puts X on the unhindered carbon.
- Phenyl ethers: aryl halides do not do SN2; make aryl alkyl ethers by alkylating a phenoxide (ArO⁻ + R–X), not by using Ar–X.
- Elimination side-reaction. Hindered alkoxides (KOtBu) are strong bases — keep the electrophile primary to avoid E2.
SN2 stereoelectronics and the epoxide (intramolecular) case, alternatives for aryl and hindered ethers (Ullmann, Cu, Ag₂O, Mitsunobu), and use in protecting-group chemistry.
Stereoelectronics and the intramolecular (epoxide) variant
Williamson is a textbook SN2: rate = k[RO⁻][R′X], backside attack, inversion at the electrophilic carbon, and a reactivity order CH₃ > 1° > 2° >> 3° (3° does not react by SN2). Intramolecular versions are governed by Baldwin's rules: 3-exo-tet (halohydrin → epoxide) and 5-exo-tet ring closures are fast and favoured; 4-exo and 6-endo are slower. The epoxide route is stereospecific — an anti-halohydrin gives a defined epoxide diastereomer.
| Electrophile | Williamson outcome | Reason / fix |
|---|---|---|
| CH₃X, 1° R–X | clean ether | ideal SN2 |
| 2° R–X | moderate yield, some alkene | slower SN2; competing E2 |
| 3° R–X | mostly alkene (E2) | put LG on the other partner |
| Ar–X | no reaction (SN2) | use ArO⁻ + R–X, or Cu/Ullmann, or SNAr |
| halohydrin (intramol.) | epoxide (3-exo-tet) | stereospecific; needs anti geometry |
Alternatives for the cases Williamson cannot do
For diaryl ethers and hindered aryl alkyl ethers, use Ullmann-type copper catalysis or modern Cu/Pd C–O couplings (see Part 8). Silver(I) oxide promotes selective O-alkylation (useful in carbohydrate chemistry, where it favours mono-etherification of a chosen –OH). The Mitsunobu reaction (this Part, AA.5) couples an alcohol directly with an acidic pronucleophile (including phenols) with inversion — effectively a Williamson that uses R–OH instead of R–X and avoids strong base.
Show solution
Show solution
Show solution
Then the closure. Deprotonate the –OH; the alkoxide performs an intramolecular 3-exo-tet SN2 on the adjacent C–Br, with inversion at C3 (the carbon that loses bromide) and retention at C2 (its bonds are never broken). Only the conformer with O and Br anti-periplanar can close, so the halohydrin's relative configuration fixes cis vs trans.
Answer: start from the (2R,3S) (or its enantiomer (2S,3R)) diastereomer. C2 stays R and C3 inverts S → R, giving (2R,3R)-2,3-epoxybutane — the chiral trans-epoxide. The other diastereomer, (2R,3R) (or (2S,3S)), closes to the (2R,3S) = meso = cis-epoxide.
Further reading.
- Named for Alexander William Williamson, who reported the alkoxide + alkyl halide ether synthesis in the mid-19th century (c. 1850).
- Baldwin, J. E. ‘Rules for Ring Closure’, J. Chem. Soc., Chem. Commun. 1976, 734–736.
Read the rest of Part 9
The remaining 21 sections of this part — The Gabriel synthesis (& the Delépine variant), The Hofmann elimination (& Hofmann vs Zaitsev), The Finkelstein reaction (halide exchange), The Appel reaction (alcohol → halide) — and all nine parts of Named Reactions are part of ChemVidya Full Access, along with the other books, 55 Study Notes and 6,000+ practice questions.
See plans Read it in the app