Reaction of Ethers with Strong Acid

Summary Nucleophilic substitution and 3 elimination reactions of alcohols 

Problem 9.32 Draw the product formed when (CH3)2CHOH is treated with each reagent. 

Because ethers are so unreactive, diethyl ether and tetrahydrofuran (fHF) are often used as solvents for organic reactions. 

HBr or HI serves as a strong acid that both protonates the O atom of the ether and is the source of a good nucleophile (Br or I ). Because both C-O bonds in the ether are broken, two successive nucleophilic substitution reactions occur. 

Mechanism 9.9 Mechanism of Ether Cleavage in Strong Acid— (CH3)3C0CH3 + hi (CH3)3CI + CH3I + H2O 

For example, cleavage of (CH3)3COCH3 with HI occurs at two bonds, as shown in Mechanism 9.9. The 3° alkyl group undergoes nucleophilic substitution by an SnI mechanism, resulting in 

---

In general, ethers are unreactive to most chemical reagents. An exception is the reaction of ethers with strong mineral acids such as HI or HBr. The three-membered ring ethers (epoxides or oxiranes), however, are notable... 

Oppenauer oxidation of the enol ether (34) affords the corresponding 17 ketone (37) (the enol ether is stable to the basic oxidation conditions). This ketone affords the corresponding 17a-ethynyl compound on reaction with metal acetylides. Hydrolysis of the enol ether under mild conditions leads directly to ethynodrel (39), an orally active progestin. This is the progestational component of the first oral contraceptive to be offered for sale. Treatment of the ethynyl enol ether with strong acid leads to yet another oral progestin employed as a contraceptive, norethindrone (40). ° In practice these and all other so-called combination contraceptives are mixtures of 1-2% mestranol... 

Ethers are prepared by either the Williamson ether synthesis or by reaction of alcohols with strong nonnucleophilic acids. The first method is best when Sn2 reactivity is high. In the latter case, elimination (dehydration) is a competing process at higher temperatures. 

Alcohols can be dehydrated with strong acid catalysts and high reaction temperatures to produce ethers. This method is particularly useful for the preparation of symmetrical lower alkyl ethers, such as ethyl ether. 

Strategies for preparing mixed, acyclic acetals on insoluble supports include the oxidative haloalkoxylation of support-bound enol ethers (Entry 6, Table 6.1) and the acid-catalyzed reaction of alcohols with resin-bound enol ethers [627]. Alternatively, resin-bound a-chloro ethers can be converted to mixed acetals by reaction with alcohols or phenols in the presence of strong bases (KO/Bu, HOfBu, DMF, 5 h) [550,628]. Polystyrene-bound a-(phenylseleno)ethers react with aliphatic alcohols under slightly acidic conditions (NIS, TfOH, DCM/dioxane (1 1), 0°C to 20 °C, 1 h) to yield mixed, acyclic acetals [628],... 

---