The Chemistry of Ethers, Epoxides, Glycols, and Sulfides

The Chemistry of Ethers, Epoxides, Glycols, and Sulfides The chemistry of ethers is closely intertwined with the chemistry of alkyl halides, alcohols, and alkenes. Ethers, however, are considerably less reactive than these other types of compounds. This chapter covers the synthesis of ethers and shows why the ether linkage is relatively unreactive. Epoxides are heterocyclic compounds in which the ether linkage is part of a threemembered ring. Unlike ordinary ethers, epoxides are very reactive. This chapter also presents the synthesis and reactions of epoxides. Because glycols are diols, it might seem more appropriate to consider them along with alcohols. 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 glycols; and both epoxides and glycols can be easily prepared by the oxidation of alkenes. Sulfides (thioethers), sulfur analogs of ethers, are also discussed briefly in this chapter. Although sulfides share some chemistry with their ether counterparts, they differ from ethers in the way they react in oxidation reactions, just as thiols 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 synthesis will be revisited with a classification of reactions according to the way they are used in synthesis, and a further discussion of how to plan multistep syntheses.. SYNTESIS OF ETERS AND SUFIDES A. Williamson Ether Synthesis Some ethers can be prepared from alcohols and alkyl halides. First, the alcohol is converted into an alkoxide (Sec. 8.6A): 482

I. SYNTESIS OF ETERS AND SUFIDES 48 O Ph C Na Ph C TF an alkoxide (conjugate base of the alcohol) Then, the alkoxide is allowed to react as a nucleophile with a methyl halide, primary alkyl halide, or the corresponding sulfonate ester to give an ether. O Na 2 (.a) O _ Na Ph C I an alkoxide O Ph C C Na I _ an ether (90% yield) (.b) Some sulfides can be prepared in a similar manner from thiolates, the conjugate bases of thiols. (C 2 ) S -butanethiol _ O O (C 2 ) S _ -butanethiolate C 2 OTs C S _ (C 2 ) C 2 OTs butyl ethyl sulfide, or (-ethylthio)butane (78% yield) (.2) Both of these reactions are examples of the Williamson ether synthesis, which is the preparation of an ether by the alkylation of an alkoxide (and, by extension, a sulfide by the alkylation of a thiolate). This synthesis is named for Alexander William Williamson (824 904), who was professor of chemistry at the University of ondon. The Williamson ether synthesis is an important practical example of the S N 2 reaction (Table 9., p. 79). In this reaction the conjugate base of an alcohol or thiol acts as a nucleophile; an ether is formed by the displacement of a halide or other leaving group. R (.) 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 different alkyl groups. R O _ O _ O _ R I X X (.4) The preferred synthesis is usually the one that involves the alkyl halide with the greater S N 2 reactivity. This point is illustrated by Study Problem.. R O R O _ X _ Study Problem. Outline a Williamson ether synthesis for tert-butyl methyl ether. CCO tert-butyl methyl ether

484 CAPTER TE CEMISTRY OF ETERS, EPOXIDES, GYCOS, AND SUFIDES Solution From Eq..4, two possibilities for preparing this compound are the reaction of methyl bromide with potassium tert-butoxide and the reaction of tert-butyl bromide with sodium methoxide. Only the former combination will work. ( ) C O _ K C Br O _ Na ( ) C Br (.5) satisfactory reaction ( ) C O does not occur; why? Do you know why sodium methoxide and tert-butyl bromide would not work? (See Sec. 9.5G.) PROBEMS. Complete the following reactions. If no reaction is likely, explain why. C (a) Na I ( ) 2 CO (b) S (c) C Na O _ ( ) C Br (d) C 2 5 O _ NaO ( equiv.) K ( ) CC 2 OTs 2 C A C C 2 Cl O 25 C C 2 5 O.2 Suggest a Williamson ether synthesis, if one is possible, for each of the following compounds. If no Williamson ether synthesis is possible, explain why. (a) 0C 2 C 2 O C 2 (b) ( ) 2 CS (c) ( ) COC( ) B. Alkoxymercuration Reduction of Alkenes 2 C A CC 2 C 2 C 2 g(oac) 2 -hexene 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: ( ) 2 CO AcOg C 2 C C 2 C 2 C 2 OAc OC( ) 2 -acetoxymercuri-2-isopropoxyhexane AcOg C 2 C C 2 C 2 C 2 NaB 4 C C 2 C 2 C 2 g borates OC( ) 2 OC( ) 2 2-isopropoxyhexane (9% yield) (.6a) (.6b)

. SYNTESIS OF ETERS AND SUFIDES 485 Contrast: 2 C A C R O OR g(oac) 2 TF/O g(oac) 2 OR NaB 4 NaB 4 C CR O C CR (oxymercuration reduction) (alkoxymercuration reduction) (.7) OR STUDY GUIDE INK. earning New Reactions from Earlier Reactions After reviewing the mechanism of oxymercuration in Eqs. 5.20a d, pp. 87 88, you should be able to write the mechanism of the reaction in Eq..6a. The two mechanisms are essentially identical, except that an alcohol instead of water is the nucleophile that reacts with the mercurinium ion intermediate. PROBEMS. (a) Give the mechanism of Eq..6a and account for the regioselectivity of the reaction. (b) Explain what would happen in an attempt to synthesize the ether product of Eq..6b by a Williamson ether synthesis..4 Complete the following reaction: ( ) 2 C C A C 2 C 2 5 O g(oac) 2 NaB 4.5 Explain why a mixture of two isomeric ethers is formed in the following reaction. NaB 4 C 2 C CC O g(oac) 2.6 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 Alkene Addition In some cases, two molecules of a primary alcohol can react with loss of one molecule of water to give an ether. This dehydration reaction requires relatively harsh conditions: strong acid and heat. 2 C 2 O ethanol 2 SO 4 40 C C 2 O C 2 2 O diethyl ether (.8) This method is used industrially for the preparation of diethyl ether, and it can be used in the laboratory. owever, 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. 0.). The formation of ethers from primary alcohols is an S N 2 reaction in which one alcohol displaces water from another molecule of protonated alcohol (see Problem 0.60, p. 48). C 2 O 2 C 2 O C 2 2 O2 O C 2 OC 2 2 C 2 C 2 O2 2 OC 2 (protonated solvent molecule) (.9)

486 CAPTER TE CEMISTRY OF ETERS, EPOXIDES, GYCOS, AND SUFIDES igh temperature is required because alcohols are relatively poor nucleophiles in the S N 2 reaction. Tertiary alcohols can be converted into unsymmetrical ethers by treating them with dilute strong acids 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: CCO tert-butyl alcohol C 2 5 O ethanol (excess, solvent) dilute 2 SO 4 CCOC 2 5 2 O ethyl tert-butyl ether (95% yield) (.0) The key to using this type of reaction successfully is that only one of the alcohol starting materials (in this case, tert-butyl alcohol) can readily lose water after protonation to form a relatively 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. ( ) C O 2 SO 4 ( ) C O 2 2 C 2 O 2 SO 4 C 2 O 2 2 2 O 2 ( ) C a tertiary carbocation C 2 a primary carbocation (does not form) 2 O 2 (.) 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. ( ) C O2 C 2 ( ) C 2 C 2 2 (loses a proton to solvent to give the product) O (.2) STUDY GUIDE INK.2 Common Intermediates from Different Starting Materials 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. 0.). Ether formation from tertiary alcohols and the dehydration of tertiary alcohols are alternate branches of a common mechanism. Both ether formation 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 formation from tertiary alcohols involves milder conditions under which alkenes are not removed from the reaction mixture. In addition, a large excess of the other alcohol (ethanol in Eq..0) is used as the solvent, so that the major reaction of the carbocation intermediate is with this alcohol. Any alkene that does form is not removed but is reprotonated to give back the same carbocation, which eventually reacts with the alcohol solvent:

. SYNTESIS OF ETERS AND SUFIDES 487 ( ) C O 2 SO 4, - 2 O C C A C 2 C 2 SO 4 SO 4 _ C C C 2 O C CCO C 2 C 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 carbocation intermediate is involved. Indeed, such is the case; for example, the acid-catalyzed additions of methanol 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 gasoline additives (Eq. 8.9, p. 70). C C A C 2 C O methanol dilute 2 SO 4 CCO (.4) 2-methylpropene methyl tert-butyl ether (MTBE) Eqs..0,., and.4 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. PROBEMS.7 Explain why the dehydration of primary alcohols can only be used for preparing symmetrical ethers. What would happen if a mixture of two different alcohols were used as the starting material in this reaction?.8 Complete the following reaction by giving the major organic product. (a) O dilute Ph C O 2 SO 4 (b) O C 2 O dilute 2 SO 4.9 (a) Give the structure of an alkene that, when treated with dilute 2 SO 4 and methanol, will give the same ether product as the reaction in Problem.8a. (b) Give the structure of two alkenes, either of which when treated with dilute 2 SO 4 and ethanol will give the same ether product as the reaction in Problem.8b..0 Outline a synthesis of each ether using either alcohol dehydration or alkene addition, as appropriate. (a) ClC 2 C 2 OC 2 C 2 Cl (b) 2-methoxy-2-methylbutane (c) tert-butyl isopropyl ether (d) dibutyl ether