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11

11 The of , , Glycols, and Sulfides

The chemistry of ethers is closely intertwined with the chemistry of halides, , and . Ethers, however, are considerably less reactive than these other types of com- pounds. This chapter covers the synthesis of ethers and shows why the linkage is rela- tively unreactive. Epoxides are heterocyclic compounds in which the ether linkage is part of a three- membered ring. Unlike ordinary ethers, epoxides are very reactive. This chapter also presents the synthesis and reactions of epoxides. Because glycols are , it might seem more appropriate to consider them along with alco- hols. Although glycols do undergo some reactions of alcohols, they have unique chemistry that is related to that of epoxides. For example, we’ll see that epoxides are easily converted into gly- cols; and both epoxides and glycols can be easily prepared by the oxidation of alkenes. Sulfides (thioethers), analogs of ethers, are also discussed briefly in this chapter. Al- though sulfides share some chemistry with their ether counterparts, they differ from ethers in the way they react in oxidation reactions, just as differ from alcohols. In this chapter we’ll also learn the principles governing intramolecular reactions: reactions that take place between groups in the same molecule. Finally, the strategy of organic synthe- sis will be revisited with a classification of reactions according to the way they are used in syn- thesis, and a further discussion of how to plan multistep syntheses.

11.1 SYNTHESIS OF ETHERS AND SULFIDES

A. Williamson Ether Synthesis Some ethers can be prepared from alcohols and alkyl halides. First, the is converted into an (Sec. 8.6A):

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11.1 SYNTHESIS OF ETHERS AND SULFIDES 483

OH O Na

Ph CH CH ++Na H Ph CH CH H (11.1a) 3 THF 3 2 an alkoxide (conjugate of the alcohol) Then, the alkoxide is allowed to react as a with a methyl halide, primary alkyl halide, or the corresponding sulfonate to give an ether.

O_ Na| O CH3 L CH Ph" CH CH3 I 3 Ph" CH CH3 Na| I_ LLan alkoxide + L LLan ether + (11.1b) (90% yield) Some sulfides can be prepared in a similar manner from thiolates, the conjugate bases of thiols.

OH CH3CH2 OTs CH (CH ) SH _ CH (CH ) S CH (CH ) S CH CH OTs 3 2 3 CH OH 3 2 3 _ L 3 2 3 2 3 _ L 3 L LL + 1-butanethiol 1-butanethiolate butyl ethyl , or (1-ethylthio) (78% yield) (11.2) Both of these reactions are examples of the Williamson ether synthesis, which is the prepa- ration of an ether by the of an alkoxide (and, by extension, a sulfide by the alkylation of a thiolate). This synthesis is named for Alexander William Williamson (1824–1904), who was professor of chemistry at the University of London.

The Williamson ether synthesis is an important practical example of the SN2 reaction (Table 9.1, p. 379). In this reaction the conjugate base of an alcohol or acts as a nucle- ophile; an ether is formed by the displacement of a halide or other .

1 1 2 1 1 1 2 1 (11.3) R O _ R I R O R I _ L 1 3 + L 1 3 LL1 + 1 33 Tertiary and many secondary alkyl halides cannot be used in this reaction. (Why?) In principle, two different Williamson syntheses are possible for any ether with two differ- ent alkyl groups.

R1 O1 R2 X _ 1 1 2 (11.4) L 1 3 + L R O R X_ 2 1 1 LL1 R O _ R X + L 1 3 + L

The preferred synthesis is usually the one that involves the alkyl halide with the greater SN2 reactivity. This point is illustrated by Study Problem 11.1.

Study Problem 11.1 Outline a Williamson ether synthesis for tert-butyl methyl ether.

CH3

H3CC" O CH3 LLL "CH3 tert-butyl methyl ether 11_BRCLoudon_pgs4-4.qxd 11/26/08 8:56 AM Page 484

484 CHAPTER 11 • THE CHEMISTRY OF ETHERS, EPOXIDES, GLYCOLS, AND SULFIDES

Solution From Eq. 11.4, two possibilities for preparing this compound are the reaction of methyl with potassium tert-butoxide and the reaction of tert-butyl bromide with . Only the former combination will work.

(CH ) C O K H C Br CH O (CH ) C Br (11.5) 3 3 _ | 3 3 _ Na| 3 3 L ++L L satisfactory does not reaction occur; why? (CH3)3C O CH3 LL Do you know why and tert-butyl bromide would not work? (See Sec. 9.5G.)

PROBLEMS 11.1 Complete the following reactions. If no reaction is likely, explain why. CH3I (a) (CH3)2CHOH Na + H2C A CH CH2 Cl (b) CH3SH NaOH L L +(1 equiv.) (c) CH3O_ Na| (CH3)3C Br + L CH3OH 25 °C (d) C H O K (CH ) CCH OTs 2 5 _ | 3 3 2 C H OH + L 2 5 11.2 Suggest a Williamson ether synthesis, if one is possible, for each of the following com- pounds. If no Williamson ether synthesis is possible, explain why. (a) CH2CH2 O CH2CH3 0LLL

(b) (CH3)2CH S CH3 L L (c) (CH3)3C O C(CH3)3 L L

B. Alkoxymercuration–Reduction of Alkenes Another method for the preparation of ethers is a variation of oxymercuration–reduction, which is used to prepare alcohols from alkenes (Sec. 5.4A). If the aqueous solvent used in the oxymercuration step is replaced by an alcohol solvent, an ether instead of an alcohol is formed after the reduction step. This process is called alkoxymercuration–reduction:

H2C A CHCH2CH2CH2CH3 Hg(OAc)2 (CH3)2CHOH ++(solvent) 1-

AcOHg CH2CH CH2CH2CH2CH3 H OAc (11.6a) L L + L "OCH(CH3)2 1-acetoxymercuri-2-isopropoxyhexane

AcOHg CH2CHCH2CH2CH2CH3 NaBH4 CH3CH CH2CH2CH2CH3 Hg borates L L + L ++ "OCH(CH3)2 "OCH(CH3)2 2-isopropoxyhexane (91% yield) (11.6b) 11_BRCLoudon_pgs4-4.qxd 11/26/08 8:56 AM Page 485

11.1 SYNTHESIS OF ETHERS AND SULFIDES 485

Contrast:

Hg(OAc) NaBH

H OH 2 4 H C CHR´ (oxymercuration–reduction)

R´ THF/HOH 3 $ + L L H2C A C $ "OH (11.7)

H Hg(OAc)2 NaBH4 H OR H C CHR´ (alkoxymercuration–reduction) HOR 3 + L L "OR

After reviewing the mechanism of oxymercuration in Eqs. 5.20a–d, pp. 187–188, you STUDY GUIDE LINK 11.1 should be able to write the mechanism of the reaction in Eq. 11.6a. The two mechanisms are Learning New Reactions from essentially identical, except that an alcohol instead of water is the nucleophile that reacts with Earlier Reactions the mercurinium ion intermediate.

PROBLEMS 11.3 (a) Give the mechanism of Eq. 11.6a and account for the regioselectivity of the reaction. (b) Explain what would happen in an attempt to synthesize the ether product of Eq. 11.6b by a Williamson ether synthesis. 11.4 Complete the following reaction: NaBH4 (CH3)2CH CH A CH2 C2H5OH Hg(OAc)2 L ++ 11.5 Explain why a mixture of two isomeric ethers is formed in the following reaction.

NaBH4 CH3CH2CHCHCH3 + CH3OH + Hg(OAc)2 11.6 Outline a synthesis of each of the following ethers using alkoxymercuration–reduction: (a) dicyclohexyl ether (b) tert-butyl isobutyl ether

C. Ethers from Alcohol Dehydration and Addition In some cases, two molecules of a can react with loss of one molecule of water to give an ether. This dehydration reaction requires relatively harsh conditions: strong and heat. H SO 2CH CH OH 2 4 CH CH O CH CH H O (11.8) 3 2 140 °C 3 2 2 3 2 L LL + This method is used industrially for the preparation of diethyl ether, and it can be used in the laboratory. However, it is generally restricted to the preparation of symmetrical ethers derived from primary alcohols. (A symmetrical ether is one in which both alkyl groups are the same.) Secondary and tertiary alcohols cannot be used because they undergo dehydration to alkenes (Sec. 10.1).

The formation of ethers from primary alcohols is an SN2 reaction in which one alcohol dis-

places water from another molecule of protonated alcohol (see Problem 10.60, p. 481). 1

| CH3CH2 OH HO CH2CH3 L 21 L "H H HOCH2CH3 (solvent)12 CH3CH2 "O| CH2CH3 H2O CH3CH2 O CH2CH3 H2OCH| 2CH3 (11.9) L 1 L + 12 LL12 + (protonated1 solvent molecule) 11_BRCLoudon_pgs4-4.qxd 11/26/08 8:56 AM Page 486

486 CHAPTER 11 • THE CHEMISTRY OF ETHERS, EPOXIDES, GLYCOLS, AND SULFIDES

High temperature is required because alcohols are relatively poor in the SN2 reaction. Tertiary alcohols can be converted into unsymmetrical ethers by treating them with dilute strong in an alcohol solvent. The conditions are much milder than those required for ether formation from primary alcohols. For example, ethyl tert-butyl ether can be prepared when tert-butyl alcohol is treated with ethanol (as the solvent) in the presence of an acid catalyst:

CH3 CH3

dilute H2SO4 H3CC" OH C2H5OH H3CC" OC2H5 H2O (11.10) LL + LL + "CH3 ethanol "CH3 (excess, solvent) tert-butyl alcohol ethyl tert-butyl ether (95% yield)

The key to using this type of reaction successfully is that only one of the alcohol starting ma- terials (in this case, tert-butyl alcohol) can readily lose water after protonation to form a rela- tively stable carbocation. The alcohol that is used in excess (in this case, ethanol) must be one that either cannot form a carbocation by loss of water or should form a carbocation much less readily.

H2SO4 H2SO4 (CH3)3C OH (CH3)3C OH CH3CH2 OH CH3CH2 OH L 1 L| 22 L| 2 L 2 1 "H "H

H O (CH ) C CH CH| H O (11.11) 2 3 3 | 3 2 2 2 1 + a tertiary a primary + 1 2 carbocation carbocation (does not form)

When the carbocation derived from the tertiary alcohol is formed, it reacts rapidly with ethanol, which is present in large excess because it is the solvent.

(CH3)3C| HO CH2CH3 (CH3)3CO| CH2CH3 (11.12) 2 L LL2 2 "H (loses a proton to solvent to give the product)

There is an important relationship between this reaction and alkene formation by alcohol dehydration. Alcohols, especially tertiary alcohols, undergo dehydration to alkenes in the presence of strong acids (Sec. 10.1). Ether formation from tertiary alcohols and the dehy- dration of tertiary alcohols are alternate branches of a common mechanism. Both ether for- mation and alkene formation involve carbocation intermediates; the conditions dictate which product is obtained. The dehydration of alcohols to alkenes involves relatively high temperatures and removal of the alkene and water products as they are formed. Ether for- mation from tertiary alcohols involves milder conditions under which alkenes are not re-

STUDY GUIDE LINK 11.2 moved from the reaction mixture. In addition, a large excess of the other alcohol (ethanol in Common Eq. 11.10) is used as the solvent, so that the major reaction of the carbocation intermediate Intermediates from Different Starting is with this alcohol. Any alkene that does form is not removed but is reprotonated to give Materials back the same carbocation, which eventually reacts with the alcohol solvent: 11_BRCLoudon_pgs4-4.qxd 11/26/08 8:56 AM Page 487

11.1 SYNTHESIS OF ETHERS AND SULFIDES 487

(CH3)3C OH L H2SO4, H2O -

H C H C CH3

3 3 CH3CH2OH $ $ H2SO4 (solvent) $C A CH2 $C CH3 H3CC" O CH2CH3 (11.13) HSO | _4 L LLL H3C H3C "CH3 carbocation intermediate This analysis suggests that the treatment of an alkene with a large excess of alcohol in the presence of an acid catalyst should also give an ether, provided that a relatively stable carbo- cation intermediate is involved. Indeed, such is the case; for example, the acid-catalyzed addi- tions of or ethanol to 2-methylpropene to give, respectively, methyl tert-butyl ether and ethyl tert-butyl ether are important industrial processes for the synthesis of these additives (Eq. 8.39, p. 370). CH

H3C 3 $ dilute H2SO4 $C A CH2 CH3OH H3CC" OCH3 (11.14) + LL H3C methanol "CH3 2-methylpropene methyl tert-butyl ether (MTBE)

Eqs. 11.10, 11.13, and 11.14 show that for the preparation of tertiary ethers, it makes no difference in principle whether the starting material from which the tertiary group is derived is an alkene or a tertiary alcohol.

PROBLEMS 11.7 Explain why the dehydration of primary alcohols can only be used for preparing symmetri- cal ethers. What would happen if a mixture of two different alcohols were used as the start- ing material in this reaction? 11.8 Complete the following reaction by giving the major organic product. (a) OH

dilute H2SO4 Ph" C CH3 CH3OH LL + (solvent) "CH3 (b) OH dilute H2SO4 CH3 + CH3CH2OH (solvent)

11.9 (a) Give the structure of an alkene that, when treated with dilute H2SO4 and methanol, will give the same ether product as the reaction in Problem 11.8a.

(b) Give the structure of two alkenes, either of which when treated with dilute H2SO4 and ethanol will give the same ether product as the reaction in Problem 11.8b. 11.10 Outline a synthesis of each ether using either alcohol dehydration or alkene addition, as ap- propriate.

(a) ClCH2CH2OCH2CH2Cl (b) 2-methoxy-2-methylbutane (c) tert-butyl isopropyl ether (d) dibutyl ether