Chapter 18: Ethers and Epoxides; Thiols and Sulfides
Ethers: an oxygen between two carbons
An ether contains an oxygen atom bonded to two carbon groups, written R–O–R′. When the two groups are identical the ether is symmetrical, as in diethyl ether; when they differ it is unsymmetrical, as in tert-butyl methyl ether. The oxygen is approximately sp³-hybridized and carries two lone pairs, giving a bent geometry with a C–O–C angle near 112° in dimethyl ether. Cyclic ethers place the oxygen in a ring: tetrahydrofuran (THF, a five-membered ring) and 1,4-dioxane (a six-membered ring with two oxygens) are the most common examples, and the three-membered cyclic ethers — epoxides — are…
The Williamson ether synthesis
The Williamson ether synthesis, in use since 1850, remains the most reliable general route to ethers. It consists of a single SN2 step: an alkoxide ion attacks an alkyl halide, displacing halide and forming the new C–O bond, RO⁻ + R′–X → R–O–R′ + X⁻. The alkoxide is generated first by deprotonating the alcohol with sodium hydride or sodium metal, or, for the more acidic phenols, with hydroxide. Everything that governs SN2 reactions governs this step. Backside attack requires an unhindered electrophilic carbon, so the halide component must be methyl or primary. With secondary halides the…
Acidic cleavage of ethers with HI and HBr
The inertness that makes ethers good solvents has one significant exception: hot, concentrated HI or HBr cleaves an ether into an alkyl halide and an alcohol (which excess acid may convert onward to a second alkyl halide). Two features of these acids are essential and explain why HCl is sluggish and why acids with non-nucleophilic counterions do nothing. First, the acid must be strong enough to protonate the weakly basic ether oxygen; protonation is what converts a hopeless alkoxide leaving group into a neutral alcohol. Second, the conjugate base — iodide or bromide — must be nucleophilic…
Crown ethers: cyclic polyethers that bind cations
Crown ethers, discovered by Charles Pedersen at DuPont in the 1960s, are cyclic polyethers built from repeating –OCH₂CH₂– units. Their names take the form m-crown-n, where m is the total number of atoms in the ring and n is the number of oxygens: 18-crown-6 is an eighteen-membered ring with six evenly spaced oxygens, 15-crown-5 has fifteen ring atoms and five oxygens, and 12-crown-4 has twelve and four. The defining property of a crown ether is cation binding. The ring folds so that the oxygen lone pairs converge on the central cavity, and a metal cation whose ionic radius matches the cavity…
Epoxides: strained rings and how to make them
An epoxide — systematically an oxirane — is a cyclic ether whose ring contains only three atoms. The internal angles of a three-membered ring are near 60°, far below the 109.5° that sp³ centers prefer, and the resulting angle and torsional strain amount to roughly 105 kJ/mol, comparable to cyclopropane. This strain energy is the organizing fact of epoxide chemistry. Opening the ring releases it, so the ring-opening transition state is reached easily, and epoxides react with nucleophiles under conditions where THF, dioxane, and open-chain ethers show no reaction at all. The simplest member,…
Acid-catalyzed ring opening: attack at the more substituted carbon
Epoxides open under acidic conditions that leave all other ethers untouched. Protonation of the ring oxygen converts it into a far better leaving group and drains electron density from both ring carbons; the strained ring then needs only a weak nucleophile — water, an alcohol, or a halide ion from HX — to open it. Aqueous acid converts an epoxide to a 1,2-diol (the industrial hydration of ethylene oxide to ethylene glycol), methanol with an acid catalyst gives a 2-methoxy alcohol, and anhydrous HBr gives a 2-bromo alcohol. When the two ring carbons are differently substituted, the…
Base-promoted ring opening: a conventional SN2 at the less hindered carbon
Epoxides are the only ethers that react with strong nucleophiles, and they do so without protonation or catalysis. The thermodynamic driving force is the release of ring strain: opening the three-membered ring liberates roughly 105 kJ/mol, enough to make an alkoxide — normally among the worst of leaving groups — depart as part of the ring-opening step. Hydroxide, alkoxides, thiolates, ammonia and amines, azide, acetylide anions, and Grignard reagents all open epoxides cleanly. The contrast with ordinary ethers is absolute: diethyl ether and THF are the solvents in which Grignard reagents are…
Thiols: sulfur analogs of alcohols
Thiols, R–SH, are the sulfur analogs of alcohols. Substitutive names add the suffix -thiol to the parent alkane name, keeping the parent's final -e (ethanethiol, 2-butanethiol), and the SH group is called mercapto (or sulfanyl) when cited as a substituent. The functional group's most notorious property is odor: 3-methyl-1-butanethiol is a component of skunk spray, and tert-butyl mercaptan is added in traces to odorless natural gas so that leaks announce themselves. Thiols are prepared from alkyl halides by SN2 displacement with hydrosulfide ion, HS⁻ (as NaSH). A large excess of hydrosulfide…
Sulfides, sulfonium salts, and the sulfur oxidation ladder
Sulfides — thioethers, R–S–R′ — are the sulfur analogs of ethers and are named the same way, with sulfide in place of ether: dimethyl sulfide, ethyl methyl sulfide. They are prepared by the direct sulfur analog of the Williamson synthesis: a thiolate ion, generated by deprotonating a thiol with hydroxide or an alkoxide, displaces halide from a methyl or primary alkyl halide in an SN2 step. Because thiolates are exceptional nucleophiles, these alkylations are fast and clean. The resemblance to ethers ends at the product. An ether oxygen, its lone pairs held close by the compact oxygen atom, is…
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