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18.2 Synthesis of Ethers

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    90953
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    Objectives

    After completing this section, you should be able to:

    1. write an equation to illustrate the industrial preparation of simple symmetrical ethers.
    2. write an equation to illustrate the Williamson synthesis of ethers.
      1. identify the ether obtained from the reaction of a given alkyl halide with a given alkoxide ion.
      2. identify the reagents needed to prepare a given ether through a Williamson synthesis.
      3. identify the limitations of the Williamson synthesis, and make the appropriate choices when deciding how best to synthesize a given ether.
      4. write an equation to describe the formation of an alkoxide from an alcohol.
      5. identify silver(I) oxide as a reagent which can be used in a Williamson synthesis.
    3. write an equation to show how an ether can be prepared by the alkoxymercuration‑demercuration of an alkene. 
      1. identify the product formed from the alkoxymercuration‑demercuration of a given alkene.
      2. identify the alkene, the reagents, or both, needed to prepare a given ether by the alkoxymercuration‑demercuration process.
      3. write the detailed mechanism of the reaction between an alkene, an alcohol and mercury(II) trifluoroacetate.
    Key Terms

    Make certain that you can define, and use in context, the key terms below. 

    • alkoxymercuration
    • oxymercuration
    • Williamson ether synthesis
    Study Notes

    We studied oxymercuration as a method of converting an alkene to an alcohol in Section 8.4. “Alkoxymercuration” is a very similar process, except that we are now converting an alkene into an ether. The two processes are compared below.

    In oxymercuration alkoxymercuration
    we react an alkene alkene
    with water an alcohol
    in the presence of Hg(O2CCH3)2 Hg(O2CCF3)2
    followed by treatment with NaBH4 NaBH4
    to produce an alcohol ether

    Review the mechanism of the oxymercuration reaction in Section 8.4, paying particular attention to the regiochemistry and the stereochemistry of the reaction. The mechanism is identical to alkoxymercuration.

    Ethers are usually prepared from alcohols or their conjugate bases. One important procedure, known as the Williamson Ether Synthesis, proceeds by an SN2 reaction of an alkoxide nucleophile with an alkyl halide. Reactions #1 and #2 below are two examples of this procedure. When applied to an unsymmetrical ether, as in this case, there are two different combinations of reactants are possible. Of these one is usually better than the other. Since alkoxide anions are strong bases, the possibility of a competing E2 elimination must always be considered. Bearing in mind the factors that favor substitution over elimination, a 1º-alkyl halide should be selected as a preferred reactant whenever possible. Thus, reaction #1 gives a better and cleaner yield of benzyl isopropyl ether than does reaction #2, which generates considerable elimination product.

     

     

    Worked Example 18.2.1

    How would you prepare the following molecule using a Williamson Ether Synthesis?

    Worked Example 1.png

    Answer

    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

    Pathway 1.png

    Solution 1

    Solution 1.png

    Pathway 2

    Pathway 2.png

    Solution 2

    Solution 2 .png

    A second general ether synthesis, alkoxymercuration, is patterned after the oxymercuration reaction. Reactions #3 and #4 are examples of this two-step procedure. Note that the alcohol reactant is used as the solvent, and a trifluoroacetate mercury (II) salt is used in preference to the acetate (trifluoroacetate anion is a poorer nucleophile than acetate). The mechanism of alkoxymercuration is similar to that of oxymercuration, with an initial anti-addition of the mercuric species and alcohol being followed by reductive demercuration.

    Acid-catalyzed dehydration of small 1º-alcohols constitutes a specialized industrial method of preparing symmetrical ethers. As shown in the following two equations, the success of this procedure depends on the temperature. At 110º to 130 ºC an SN2 reaction of the alcohol conjugate acid leads to an ether product.

    \[\ce{2 CH_3CH_2-OH + H_2SO_4 ->[130\;^oC] CH_3CH_2\bond{-}O\bond{-}CH_2CH_3 + H_2O} \tag{18.2.1}\]

    At higher temperatures (over 150 ºC) an E2 elimination takes place.

    \[\ce{CH3CH_2-OH + H_2SO_4 ->[150\;^oC] CH_2\bond{=}CH_2 + H_2O} \tag{18.2.2}\]

    This reaction cannot be employed to prepare unsymmetrical ethers. It is because a mixture of products is likely to be obtained. 

     

    Worked Example 18.2.2

    How would you prepare the following molecule using a alkoxymercuration?

    Worked Example 2.png

    Answer

    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

    2 Pathway 1 .png

    Solution 1

    2 Solution 1.png

    Pathway 2

    2 Pathway 2 .png

    Exercises

    Exercise 18.2.1

    When preparing ethers using the Williamson ether synthesis, what factors are important when considering the nucleophile and the electrophile?

    Answer

    The nucleophile ideally should be very basic, yet not sterically hindered. This will minimize any elimination reactions from occurring. The electrophile should have the characteristics of a good SN2 electrophile, preferably primary to minimize any elimination reactions from occurring.

    Exercise 18.2.2

    How would you synthesize the following ethers? Keep in mind there are multiple ways. The Williamson ether synthesis, alkoxymercuration of alkenes, and also the acid catalyzed substitution.

    18-3-Qu2.png

    Answer

    The Williamson ether syntheses require added catalytic base. Also, most of the halides can be interchanged, say for example for a -Br or a -Cl. Although, typically -I is the best leaving group.

    18-3-Sol2a.png

    18-3-Sol2b-d.png

    Note, there is only one ether (also called a silyl ether, and often used as an alcohol protecting group.) The other group is an ester.

    18-3-Sol2e.png

    Exercise 18.2.3

    Draw the electron arrow pushing mechanism for the formation of diethyl ether in the previous problem.

    Answer

    18-3-Sol3.png

    Exercise 18.2.4

    t-Butoxycyclohexane can be prepared two different ways from an alkene and an alcohol, draw both possible reactions.

    Answer

    18-3-Sol4.png

    While both are possible, the top route is likely easier because both starting materials are a liquid.

    Contributors and Attributions


    18.2 Synthesis of Ethers is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by LibreTexts.

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