12. Alcohols, Ethers, Epoxides and Thiols

(••) Identify the two possible combinations of haloalkane and alkoxide that can be used to make the following ether.

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(•••) The reaction of alkoxides with haloalkanes is not a viable way to form ethers. (a) Why? (b) Why can thioethers be formed by an analogous reaction?

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How could the reaction in Figure 13.67(b) be modified to produce the following ether?

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Fluoxetine hydrochloride (Prozac®) is a widely used antidepressant. How might you stereoselectively install the indicated ether functional group (ROR) in (R)-fluoxetine?

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Predict the product when the dihydroxybenzene shown is treated with a single equivalent of both base and haloalkane.

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What is the product of the following reaction?

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Predict the product of the following substitution/addition reactions involving phenoxides. [Because this problem represents a review of current and previous material, section numbers have been provided for your reference.]

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Predict the product of the following reactions. [Two of them are Williamson ether syntheses. Why isn't the other?].

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Identify the alkene and alcohol partners that could be used to make the following ethers.

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Predict the product of the following reactions. [Two of them are Williamson ether syntheses. Why isn't the other?].

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Suggest a phenoxide and an alkyl halide to make the following aryl alkyl ethers.

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Two different Williamson ether syntheses can be used to make the compound in (a). Show them. The compound in (b), however, can only be made one way. Show it and explain why a second Williamson ether synthesis is not possible.

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(••) In contrast to Assessment 13.102, only one combination of haloalkane and alkoxide can be used in the Williamson ether synthesis to make the ether shown. Identify the combination and explain why it is the only combination that works.

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Predict the product of the following reactions. [Two of them are Williamson ether syntheses. Why isn't the other?].

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(••••) LOOKING BACK In Chapter 12, we learned that crown ethers were used to increase the rate of S_N2 reactions (Assessment 12.80). Suggest a synthesis of 15-crown-5 using the reactions learned here in Chapter 13.

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Suggest a phenoxide and an alkyl halide to make the following aryl alkyl ethers.

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(••••) Provide the reagents necessary to carry out the following synthesis. What is the purpose of steps (a) and (e)?

(a) _____

(b) _____

(c) _____

(d) _____

(e) _____

(f) _____

How could you synthesize isopropyl propyl ether, using isopropyl alcohol as the only carbon-containing reagent?

a. Draw the product of each of the following reactions:

2. CH3CH2CH2OH→2. CH3Br1. NaH

What is the best way to prepare the following ethers using an alkyl halide and an alkoxide ion?

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A chemist wanted to synthesize the anesthetic 2-ethoxy-2-methylpropane. He used ethoxide ion and 2-chloro-2-methylpropane for his synthesis and ended up with no ether. What was the product of his synthesis? What reagents should he have used?

Design a synthesis for each of the following, using an intramolecular reaction:

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The compound shown below has three different types of OH groups, all with different acidities. Show the structure produced after this compound is treated with different amounts of NaH followed by a methylating reagent. Add a brief explanation.

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(a) 1 equivalent of NaH, followed by 1 equivalent of CH3I and heat

(b) 2 equivalents of NaH, followed by 2 equivalents of CH3I and heat

(c) 3 equivalents of NaH, followed by 3 equivalents of CH3I and heat

Show how you would use the Williamson ether synthesis to prepare the following ethers. You may use any alcohols or phenols as your organic starting materials.

(d) ethyl n-propyl ether (two ways)

(e) benzyl tert-butyl ether (benzyl = Ph-CH2- )

Show how you would accomplish the following transformations. Some of these examples require more than one step.

(d) 5-chloropent-1-ene → 2-methyltetrahydrofuran 

Show how you would accomplish the following transformations. 

Some of these examples require more than one step.

(e) 2-chlorohexan-1-ol → 1,2-epoxyhexane

A student wanted to use the Williamson ether synthesis to make (R)-2-ethoxybutane. He remembered that the Williamson synthesis involves an SN2 displacement, which takes place with inversion of configuration. He ordered a bottle of (S)-butan-2-ol for his chiral starting material. He also remembered that the SN2 goes best on primary halides and tosylates, so he made ethyl tosylate and sodium (S)-but-2-oxide. After warming these reagents together, he obtained an excellent yield of 2-ethoxybutane.

(a) What enantiomer of 2-ethoxybutane did he obtain? Explain how this enantiomer results from the SN2 reaction of ethyl tosylate with sodium (S)-but-2-oxide.

(b) What would have been the best synthesis of (R)-2-ethoxybutane?

(c) How can this student convert the rest of his bottle of (S)-butan-2-ol to (R)-2-ethoxybutane?

The Williamson ether synthesis involves the displacement of an alkyl halide or tosylate by an alkoxide ion. Would the synthesis shown be possible by making a tosylate and displacing it? If so, show the sequence of reactions. If not, explain why not and show an alternative synthesis that would be more likely to work.

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Both LiAlH4 and Grignard reagents react with carbonyl compounds to give alkoxide ion intermediates (that become protonated in an aqueous workup). Those alkoxides can react with 1° or methyl alkyl halides or tosylates to give ethers. Show how the following ethers can be formed in this two-step process. As starting materials you may use any reactants containing 7 carbons or fewer.

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Show how you would synthesize the following ethers in good yield from the indicated starting materials and any additional reagents needed.

(a) cyclopentyl n-propyl ether from cyclopentanol and propan-1-ol

Show how the following ethers might be synthesized using

(1) alkoxymercuration– demercuration and

(2) the Williamson synthesis.

(When one of these methods cannot be used for the given ether, point out why it will not work.)

(d) 1-methoxy-1-methylcyclopentane

Show how the following ethers might be synthesized using

(1) alkoxymercuration– demercuration and

(2) the Williamson synthesis.

(When one of these methods cannot be used for

the given ether, point out why it will not work.)

(e) 1-isopropoxy-1-methylcyclopentane

Show how the following ethers might be synthesized using

(1) alkoxymercuration– demercuration and

(2) the Williamson synthesis.

(When one of these methods cannot be used for

the given ether, point out why it will not work.)

(e) 1-isopropoxy-1-methylcyclopentane

Show how you would synthesize the following ethers in good yield from the indicated starting materials and any additional reagents needed.

(b) n-butyl phenyl ether from phenol and butan-1-ol

Both LiAlH4 and Grignard reagents react with carbonyl compounds to give alkoxide ion intermediates (that become protonated in an aqueous workup). Those alkoxides can react with 1° or methyl alkyl halides or tosylates to give ethers. Show how the following ethers can be formed in this two-step process. As starting materials you may use any reactants containing 7 carbons or fewer.

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Both LiAlH4 and Grignard reagents react with carbonyl compounds to give alkoxide ion intermediates (that become protonated in an aqueous workup). Those alkoxides can react with 1° or methyl alkyl halides or tosylates to give ethers. Show how the following ethers can be formed in this two-step process. As starting materials you may use any reactants containing 7 carbons or fewer.

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In Chapter 14, we saw that Agent Orange contains (2,4,5-trichlorophenoxy) acetic acid, called 2,4,5-T. This compound is synthesized by the partial reaction of 1,2,4,5-tetrachlorobenzene with sodium hydroxide, followed by reaction with sodium chloroacetate, ClCH₂CO₂Na.

(a) Draw the structures of these compounds, and write equations for these reactions.

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