Acid-catalyzed dehydration of small 1º-alcohols constitutes a specialized industrial method of preparing symmetrical ethers. This reaction cannot be employed to prepare unsymmetrical ethers because a mixture of products is likely to be obtained. Also, 2o and 3o alcohols cannot be used for this reaction because they dehydrate to form alkenes by an E1 mechanism (Section 17-6).
\[\ce{2 CH_3CH_2-OH + H_2SO_4 ->[130\;^oC] CH_3CH_2\bond{-}O\bond{-}CH_2CH_3 + H_2O} \tag{18.2.1} \]
Mechanism
In the first step of the reaction mechanism, one alcohol is protonated to become a good leaving group. In the second step, a second alcohol displaces water from the protonated alcohol during an SN2 reaction yielding a protonated ether. In the final step, this intermediate is deprotonated to yield the symmetrical ether.
Williamson Ether Synthesis
One important procedure, known as the Williamson Ether Synthesis, proceeds by an SN2 reaction of an alkoxide nucleophile with a primary alkyl halide or tosylate. As previously discussed in Section 17-2, alkoxides are commonly created by deprotonating an alcohol with a strong base, such as sodium hydride (NaH). Simple alcohols can be used a solvent during a Williamson ether synthesis and with their alkoxide created through the addition of sodium metal (Na(s)).
Planning a Williamson Ether Synthesis
The Williamson ether synthesis has the same limitations as other SN2 reactions, as discussed in Section 11-3. Since alkoxide anions are strong bases, utilizing 2o or 3o halogen leaving groups could possibly produce an E2 elimination product. When considering the synthesis of an unsymmetrical ether, there are two different combinations of reactants possible and each should be carefully considered. In general, the pathway which utilizes the least sterically hindered halogen will be preferred.
The key bond cleavage in the target molecule involves a C-O bond. Because unsymmetrical ethers have two unique C-O bonds, each can be broken to provide a unique set of reactants. After cleavage, the fragment with the oxygen will become an alkoxide. The other fragment will become a halogen or tosylate.
Worked Example \(\PageIndex{1}\)
How would you prepare the following molecule using a Williamson Ether Synthesis?
- Answer
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Analysis: The ether is asymmetrical so each of the C-O bonds can be broken to create a different set of possible reactants. After cleavage of the C-O bond, pathway 1 shows a 3o halogen as the starting material. This reaction will most likely not be effective due to alkoxides reacting with 3o halogens to preferable form an alkenes by E2 elimination. Pathway 2 shows a 1o halogen as a starting material which is favorable for SN2 reactions.
Pathway 1
Solution 1
Pathway 2
Solution 2
Ether Synthesis Using Silver Oxide
A variation of the Williamson ether synthesis uses silver oxide (Ag2O) in the place of the strong base. The conditions of this variation are milder than the typical Willamson synthesis because a strong base and the formation of an alkoxide intermediate are not necessary. This reaction is particually useful when converting the -OH groups on a sugar into ethers.
Mechanism
During this reaction a partial positively charged silver in Ag2O gives draws electron density from the iodine in CH3I. This correspondingly removes electron density from the adjacent carbon increasing its partial positive charge which increases its electrophlicity. This allows the alcohol to act as a nucleophile in the subsequent SN2 reaction.
Ether Synthesis Using Alkoxymercuration
Alkoxymercuration, is patterned after the oxymercuration reaction discussed in Section 8-4. Reaction of an alkene with an alcohol in the presence of a trifluoroacetate mercury (II) salt [(CF3CO2)2Hg] prodcues an alkoxymercuration product. Demercuration using sodium borohydride (NaBH4) yields an ether product. Overall, this reaction allows for the Markovnikov addition of an alcohol to an alkene to create an ether. Note that the alcohol reactant is used as the solvent, and a trifluoroacetate mercury (II) salt is used in preference to the mercuric acetate (trifluoroacetate anion is a poorer nucleophile than acetate). Most 1o, 2o, 3o alcohols can be successfully used for this reaction.
Mechanism
The mechanism of alkoxymercuration is similar to that of oxymercuration, with electrophillic addition of the mercuric species to the alkene. The alcohol nucleophile attacks the more substituted carbon of the three-membered ring via a SN2 reaction. Finally, sodium borohydride (NaBH4) provides a reductive demercuration to form the ether product.
Planning the Synthesis of an Ether using Alkoxymercuration
The key bond cleavage in the target molecule involves a C-O bond. Because unsymmetrical ethers have two unique C-O bonds, each can be broken to provide a unique set of reactants. After cleavage, the fragment with the oxygen will become an alcohol. The alkyl fragment will lose a hydrogen from a adjacent carbon to form an alkene. The main point to consider when choosing a possible synthesis pathways is the ability of the alkyl fragment to form an alkene.
Worked Example \(\PageIndex{2}\)
How would you prepare the following molecule using a alkoxymercuration?
- Answer
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Analysis: The ether is symmetrical so each C-O bond of the ether can be cleaved to produce a set of starting materials for consideration. Pathway one shows a set of starting material which should work well for this reaction. The alcohol, methanol, can easily be used as a solvent. Although the alkene does not have a defined more and less substituted side, its symmetry will prevent a mixture of product from forming. The fragmentation for pathway 2 shows starting material which are not viable for this reaction. The alkyl fragment only has one carbon which cannot be used to form an alkene starting material. This means pathway 2 is not a viable method for the synthesis of the target molecule.
Pathway 1
Solution 1
Pathway 2