Ethers, Sulfides, Epoxides, and Sulfur Functional Groups

Dehydration, Williamson Synthesis, and Alkoxymercuration-Demercuration

Ethers are prepared industrially via dehydration of an alcohol. In the laboratory, the Williamson synthesis and alkoxymercuration-demercuration are the main methods of preparing ethers.

The main method to make ethers is via the Williamson synthesis of ethers from alcohols by addition of sodium hydride (NaH) followed by an alkyl halide (RX). Ethers can also be prepared from alkenes via alkoxymercuration-demercuration.

Dehydration of alcohols under acidic conditions will yield an ether. Dehydration is the removal of water from a compound. This dehydration method is limited to industrial production of small symmetrical ethers, such as dipropyl ether and dibutyl ether. Symmetrical ethers are ethers that have the same alkyl group on either side of the oxygen atom. The method requires the temperature to be between 110° and 130° Celsius. Temperatures greater than 130° Celsius form an alkene via E2 elimination rather than an ether via substitution. The narrow temperature range of 110° to 130° Celsius with primary alcohols favors the SN2 nucleophilic substitution reaction to occur. Acid protonates one alcohol, and then a second alcohol displaces that protonated hydroxyl group of the first alcohol, creating the ether. The alcohol must be used in excess for this reaction to proceed. The protonated alcohol is the substrate, and the second molecule of alcohol acts as a nucleophile. Secondary and tertiary alcohols follow an SN1 pathway in forming ethers.
CH3CH2OH+HOCH2CH3H2SO4CH3CH2OCH2CH3+H2O{\rm {CH_3CH_2{-}OH+HO{-}CH_2CH_3}}\xrightarrow{\rm {H_2SO_4}}{\rm {CH_3CH_2{-}O{-}CH_2CH_3+H_2O}}
In 1850 Scottish organic chemist Alexander William Williamson first described a synthetic method to form ethers that became known as the Williamson synthesis. The Williamson synthesis is an organic reaction used to convert an alcohol and an alkyl halide to an ether using a base, such as sodium hydroxide (NaOH). This reaction converts an alcohol and an alkyl halide into an ether. The base removes the proton from the alcohol, forming an alkoxide intermediate. In an SN2 reaction, the alkoxide intermediate then attacks the alkyl halide, producing the ether. The deprotonation of the alcohol forms an alkoxide, which is a very strong nucleophile. A nucleophile is a molecule or ion rich in electrons that donates a pair of electrons to form a covalent bond. The term is Greek for "nucleus loving." Since alkoxides are both strong bases and strong nucleophiles, an elimination reaction may compete with the ether-forming reaction. In the competing elimination reaction, the alkoxide intermediate can react with the alkyl halide to form an alkene, especially if the alkyl halide is secondary or tertiary. The Williamson synthesis works best when the alkyl halide is a methyl halide or primary halide.

Williamson Synthesis

The Williamson synthesis converts an alcohol into an ether. The first step of the mechanism is to remove a hydrogen from the alcohol to form an alkoxide. The alkoxide then attacks an alkyl halide to form the ether.
Ethers can also be prepared from alkenes via alkoxymercuration-demercuration in an electrophilic addition reaction. Alkoxymercuration-demercuration is using mercury acetate to form ethers (alkoxy groups). Alkoxymercuration involves the electrophilic addition of mercury acetate and an alkoxy group to an alkene. Demercuration is when a hydrogen replaces the acetoxymercury group. The reagents commonly used in this synthesis are mercury acetate (Hg(OAc)2) dissolved in alcohol or tetrahydrofuran (THF). Mercury is toxic and requires additional safety precautions. This reaction follows Markovnikov's rule and predicts the regioselectivity of the reaction, but the reaction is not stereoselective. Markovnikov's rule states that in an addition of an asymmetric reagent to an alkene, the more-electronegative atom of the reagent will bond to the more-substituted carbon of the alkene. There is a cyclic formation of the mercurinium ion, which is then opened by the attack of the alcohol on the most-substituted carbon to complete the alkoxymercuration. Sodium borohydride, NaBH4, completes the demercuration through reduction.

Alkoxymercuration-Demercuration of 1-hexene

Alkoxymercuration-demercuration of hexene uses mercury acetate dissolved in ethanol followed by reduction with sodium borohydride to produce 2-ethoxyhexane via a Markovnikov addition.