CHAPTER SIXTEEN Ethers, Epoxides, and Sulfides POLYETHER ANTIBIOTICS ne way in which pharmaceutical companies with metal ions the structure of the monensin- search for new drugs is by growing colonies of sodium bromide complex is depicted in Figure 16.3b microorganisms in nutrient broths and assay. where it can be seen that four ether oxygens and ing the substances produced for their biological ac- two hydroxyl groups surround a sodium ion. The tivity. This method has yielded thousands of antib- alkyl groups are oriented toward the outside of the otic substances, of which hundreds have been complex, and the polar oxygens and the metal ion developed into effective drugs. Antibiotics are, by are on the inside The hydrocarbon like surface of definition, toxic(anti="against" bios="life"), and the complex permits it to carry its sodium ion the goal is to find substances that are more toxic to through the hydrocarbon-like interior of a cell mem- infectious organisms than to their human hosts. brane. This disrupts the normal balance of sodium Since 1950, a number of polyether antibiotics ions within the cell and interferes with important have been discov ered using fermentation technol- processes of cellular respiration. Small amounts of ogy. They are characterized by the presence of sev- monensin are added to poultry feed in order to kill eral cyclic ether structural units, as illustrated for the parasites that live in the intestines of chickens. Com- case of monensin in Figure 16.3a. Monensin and pounds such as monensin and the crown ethers that other naturally occurring polyethers are similar to affect metal ion transport are referred to as crown ethers in their ability to form stable complexes ionophores ("ion carriers") H CH CH3 OH HOCH,IO OCH OH HHH CH2 H CH CH COH (a) CH, CH H H H3 CH CH FIGURE 16.3(a)The structure of monensin; (b) the structure of the monensin-sodium bromide complex showing coor dination of sodium ion by oxygen atoms of monensin. Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
624 CHAPTER SIXTEEN Ethers, Epoxides, and Sulfides POLYETHER ANTIBIOTICS One way in which pharmaceutical companies search for new drugs is by growing colonies of microorganisms in nutrient broths and assaying the substances produced for their biological activity. This method has yielded thousands of antibiotic substances, of which hundreds have been developed into effective drugs. Antibiotics are, by definition, toxic (anti “against”; bios “life”), and the goal is to find substances that are more toxic to infectious organisms than to their human hosts. Since 1950, a number of polyether antibiotics have been discovered using fermentation technology. They are characterized by the presence of several cyclic ether structural units, as illustrated for the case of monensin in Figure 16.3a. Monensin and other naturally occurring polyethers are similar to crown ethers in their ability to form stable complexes with metal ions. The structure of the monensin– sodium bromide complex is depicted in Figure 16.3b, where it can be seen that four ether oxygens and two hydroxyl groups surround a sodium ion. The alkyl groups are oriented toward the outside of the complex, and the polar oxygens and the metal ion are on the inside. The hydrocarbon-like surface of the complex permits it to carry its sodium ion through the hydrocarbon-like interior of a cell membrane. This disrupts the normal balance of sodium ions within the cell and interferes with important processes of cellular respiration. Small amounts of monensin are added to poultry feed in order to kill parasites that live in the intestines of chickens. Compounds such as monensin and the crown ethers that affect metal ion transport are referred to as ionophores (“ion carriers”). C H O CH3 CH3 HOCH2 OH H H O CH3 H O H CH3 O CH2 CH3 H O O CO2H CH3 OCH3 CH3 CH3 CH3 CH3 O OH O H O H O Na H CH3 H O CH3CH2 H H3C O O HO CH3 CH3 O OCH3 Br CH3 (a) (b) FIGURE 16.3 (a) The structure of monensin; (b) the structure of the monensin–sodium bromide complex showing coordination of sodium ion by oxygen atoms of monensin. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
16.5 Preparation of Ethers omplex(Figure 16.2b), K, with an ionic radius of 266 pm, fits comfortably within 260-320 pm internal cavity of 18-crown-6. Nonpolar CH2 groups dominate the outer surface of the complex, mask its polar interior, and permit the complex to dissolve in nonpolar solvents. Every K that is carried into benzene brings a fluoride ion with it, resulting in a solution containing strongly complexed potassium ions and relatively unsolvated fluoride ions 18-Crown-6 18-Crown-6-potassium fluoride fluoride complex (in solution) In media such as water and alcohols, fluoride ion is strongly solvated by hydro- gen bonding and is neither very basic nor very nucleophilic. On the other hand, the poorly solvated, or"naked, " fluoride ions that are present when potassium fluoride dis solves in benzene in the presence of a crown ether are better able to express their anionic reactivity. Thus, alkyl halides react with potassium fluoride in benzene containing 18 crown-6, thereby providing a method for the preparation of otherwise difficultly acces sible alkyl fluorides CH3(CH2)CH,Br CH3(CH2)6CH,F The reaction proceeds in the -Bromooctane I-Fluorooctane(92%) direction indicated because a C-F bond is much stronger No reaction is observed when the process is carried out under comparable conditions but than a C-Br bond with the crown ether omitted Catalysis by crown ethers has been used to advantage to increase the rate of many organic reactions that involve anions as reactants. Just as important, though, is the increased understanding that studies of crown ether catalysis have broug our knowl- edge of biological processes in which metal ions, including Na and K, are transported through the nonpolar interiors of cell membranes. 16.5 PREPARATION OF ETHERS Because they are widely used as solvents, many simple dialkyl ethers are commercially available. Diethyl ether and dibutyl ether, for example, are prepared by acid-catalyzed condensation of the corresponding alcohols, as described earlier in Section 15.7 CHa,O 0H 00>CH; CH,CH,CH,OCH, CH,CH, CH3+H,O 1-Butanol Dibutyl ether(60%o) In general, this method is limited to the preparation of symmetrical ethers in which both alkyl groups are primary Isopropyl alcohol, however, is readily available at low cost and gives high enough yields of disopropyl ether to justify making( CH3)2CHOCH(CH3)2 by this method on an industrial scale Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
this complex (Figure 16.2b), K, with an ionic radius of 266 pm, fits comfortably within the 260–320 pm internal cavity of 18-crown-6. Nonpolar CH2 groups dominate the outer surface of the complex, mask its polar interior, and permit the complex to dissolve in nonpolar solvents. Every K that is carried into benzene brings a fluoride ion with it, resulting in a solution containing strongly complexed potassium ions and relatively unsolvated fluoride ions. In media such as water and alcohols, fluoride ion is strongly solvated by hydrogen bonding and is neither very basic nor very nucleophilic. On the other hand, the poorly solvated, or “naked,” fluoride ions that are present when potassium fluoride dissolves in benzene in the presence of a crown ether are better able to express their anionic reactivity. Thus, alkyl halides react with potassium fluoride in benzene containing 18- crown-6, thereby providing a method for the preparation of otherwise difficultly accessible alkyl fluorides. No reaction is observed when the process is carried out under comparable conditions but with the crown ether omitted. Catalysis by crown ethers has been used to advantage to increase the rate of many organic reactions that involve anions as reactants. Just as important, though, is the increased understanding that studies of crown ether catalysis have brought to our knowledge of biological processes in which metal ions, including Na and K, are transported through the nonpolar interiors of cell membranes. 16.5 PREPARATION OF ETHERS Because they are widely used as solvents, many simple dialkyl ethers are commercially available. Diethyl ether and dibutyl ether, for example, are prepared by acid-catalyzed condensation of the corresponding alcohols, as described earlier in Section 15.7. In general, this method is limited to the preparation of symmetrical ethers in which both alkyl groups are primary. Isopropyl alcohol, however, is readily available at low cost and gives high enough yields of diisopropyl ether to justify making (CH3)2CHOCH(CH3)2 by this method on an industrial scale. 2CH3CH2CH2CH2OH 1-Butanol H2SO4 130°C CH3CH2CH2CH2OCH2CH2CH2CH3 Dibutyl ether (60%) H2O Water CH3(CH2)6CH2Br 1-Bromooctane KF, benzene, 90°C 18-crown-6 CH3(CH2)6CH2F 1-Fluorooctane (92%) O O O O O O 18-Crown-6 benzene KF Potassium fluoride (solid) O O O O O O 18-Crown-6-potassium fluoride complex (in solution) F K 16.5 Preparation of Ethers 625 The reaction proceeds in the direction indicated because a C±F bond is much stronger than a C±Br bond. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
CHAPTER SIXTEEN Ethers, Epoxides, and Sulfides State ppb xem bew he xc d cata oe ded ition om met ethe is prepared (CH3)C=CH2+ CH3OH (CH3)3 COCH3 tert-Butyl methyl ether is of. Small amounts of tert-butyl methyl ether are added to gasoline as an octane booster. The ten referred to as MTBe daily consumption of gasoline is so high that the demand for tert-butyl methyl ether exceeds our present capacity to produce it. ether. "Remember. italicized PROBLEM 16.5 Outline a reasonable mechanism for the formation of tert-butyl phabetizing, and tert-butyl methyl ether according to the preceding equation The following section describes a versatile method for preparing either symmetri cal or unsymmetrical ethers that is based on the principles of bimolecular nucleophilic 16.6 THE WILLIAMSON ETHER SYNTHESIS is named for A long-standing method for the preparation of ethers is the williamson ether synthesis. Nucleophilic substitution of an alkyl halide by an alkoxide gives the carbon-oxygen bond ritish chemist who used it of an ether: to prepare diethyl ether in R-X ROR+: X Alkoxide Alkyl Ether Halide ion halide Preparation of ethers by the williamson ether synthesis is most successful when the alkyl halide is one that is reactive toward SN2 substitution. Methyl halides and CH3,,CH,ONa CH3 CH, -,, CH,OCH CH3+ Nal Sodium butoxide iodoethane Butyl ethyl ether(71%0) Sodium ethyl ether could be prepared by a williamson ether synthesis n PROBLEM 16.6 Write equations describing two different ways in which benzyl econdary and alkyl halides are not suitable, because they tend to react with alkoxide bases elimination rather than by SN2 substitution. Whether the alkoxide base is primary, secondary, or tertiary is much less important than the nature of the alkyl halide. Thus benzyl isopropyl ether is prepared in high yield from benzyl chloride, a primary chloride that is incapable of undergoing elimination, and sodium iso- CH3)2CHONa CH2Cl—>(CH3)2 CHOCH2 Nacl Sodium Benzyl chloride Benzyl isopropyl ether So chloride Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
Approximately 4 109 lb of tert-butyl methyl ether is prepared in the United States each year by the acid-catalyzed addition of methanol to 2-methylpropene: Small amounts of tert-butyl methyl ether are added to gasoline as an octane booster. The daily consumption of gasoline is so high that the demand for tert-butyl methyl ether exceeds our present capacity to produce it. PROBLEM 16.5 Outline a reasonable mechanism for the formation of tert-butyl methyl ether according to the preceding equation. The following section describes a versatile method for preparing either symmetrical or unsymmetrical ethers that is based on the principles of bimolecular nucleophilic substitution. 16.6 THE WILLIAMSON ETHER SYNTHESIS A long-standing method for the preparation of ethers is the Williamson ether synthesis. Nucleophilic substitution of an alkyl halide by an alkoxide gives the carbon–oxygen bond of an ether: Preparation of ethers by the Williamson ether synthesis is most successful when the alkyl halide is one that is reactive toward SN2 substitution. Methyl halides and primary alkyl halides are the best substrates. PROBLEM 16.6 Write equations describing two different ways in which benzyl ethyl ether could be prepared by a Williamson ether synthesis. Secondary and tertiary alkyl halides are not suitable, because they tend to react with alkoxide bases by E2 elimination rather than by SN2 substitution. Whether the alkoxide base is primary, secondary, or tertiary is much less important than the nature of the alkyl halide. Thus benzyl isopropyl ether is prepared in high yield from benzyl chloride, a primary chloride that is incapable of undergoing elimination, and sodium isopropoxide: Sodium isopropoxide (CH3)2CHONa CH2Cl Benzyl chloride (CH3)2CHOCH2 Benzyl isopropyl ether (84%) NaCl Sodium chloride CH3CH2I Iodoethane CH3CH2CH2CH2ONa Sodium butoxide CH3CH2CH2CH2OCH2CH3 Butyl ethyl ether (71%) NaI Sodium iodide RO Alkoxide ion R X Alkyl halide ROR Ether X Halide ion CH3OH Methanol (CH3)3COCH3 tert-Butyl methyl ether H CH2 (CH3)2C 2-Methylpropene 626 CHAPTER SIXTEEN Ethers, Epoxides, and Sulfides tert-Butyl methyl ether is often referred to as MTBE, standing for the incorrect name “methyl tert-butyl ether.” Remember, italicized prefixes are ignored when alphabetizing, and tert-butyl precedes methyl. The reaction is named for Alexander Williamson, a British chemist who used it to prepare diethyl ether in 1850. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
16.7 Reactions of ethers a review and a preview The alternative synthetic route using the sodium salt of benzyl alcohol and an isopropyl halide would be much less effective, because of increased competition from elimination as the alkyl halide becomes more sterically hindered. PROBLEM 16.7 Only one combination of alkyl halide and alkoxide is appropri ate for the preparation of each of the following ethers by the Williamson ether synthesis. What is the correct combination in each case? (c)(CH3)3COCH2 C6H5 CHCH.O (b)CH2=CHCH2 OCH(CH3)2 SAMPLE SOLUTION (a) The ether linkage of cyclopentyl ethyl ether involves a rimary carbon and a secondary one. Choose the alkyl halide corresponding to he primary alkyl group, leaving the secondary alkyl group to arise from the alkox ide nucleophile ONa CHa CH, Br Sodium cyclopentanolate Ethyl bromide Cyclopentyl ethyl ether The alternative combination, cyclopentyl bromide and sodium ethoxide is not ppropriate, since elimination will be the major reaction CHach2oNa+ CH3CH2OH+ Bromocyclopentane Ethanol Cyclopentene (major products) Both reactants in the Williamson ether synthesis usually originate in alcohol pre- cursors. Sodium and potassium alkoxides are prepared by reaction of an alcohol with the appropriate metal, and alkyl halides are most commonly made from alcohols by reaction with a hydrogen halide(Section 4.8), thionyl chloride(Section 4. 14), or phosphorus tri- bromide(Section 4. 14). Alternatively, alkyl p-toluenesulfonates may be used in place of alkyl halides; alkyl p-toluenesulfonates are also prepared from alcohols as their imme- diate precursors(Section 8. 14) 16.7 REACTIONS OF ETHERS: A REVIEW AND A PREVIEW Up to this point, we havent seen any reactions of dialkyl ethers. Indeed, ethers are one of the least reactive of the functional groups we shall study. It is this low level of reac- tivity, along with an ability to dissolve nonpolar substances, that makes ethers so often used as solvents when carrying out organic reactions. Nevertheless, most ethers are haz ardous materials, and precautions must be taken when using them. Diethyl ether is extremely flammable and because of its high volatility can form explosive mixtures in air relatively quickly. Open flames must never be present in laboratories where diethyl ether is being used. Other low-molecular-weight ethers must also be treated as fire hazards PROBLEM 16.8 Combustion in air is, of course, a chemical property of ethers that is shared by many other organic compounds. Write a balanced chemical equa tion for the complete combustion(in air) of diethyl ether Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
The alternative synthetic route using the sodium salt of benzyl alcohol and an isopropyl halide would be much less effective, because of increased competition from elimination as the alkyl halide becomes more sterically hindered. PROBLEM 16.7 Only one combination of alkyl halide and alkoxide is appropriate for the preparation of each of the following ethers by the Williamson ether synthesis. What is the correct combination in each case? (a) (c) (CH3)3COCH2C6H5 (b) CH2œCHCH2OCH(CH3)2 SAMPLE SOLUTION (a) The ether linkage of cyclopentyl ethyl ether involves a primary carbon and a secondary one. Choose the alkyl halide corresponding to the primary alkyl group, leaving the secondary alkyl group to arise from the alkoxide nucleophile. The alternative combination, cyclopentyl bromide and sodium ethoxide, is not appropriate, since elimination will be the major reaction: Both reactants in the Williamson ether synthesis usually originate in alcohol precursors. Sodium and potassium alkoxides are prepared by reaction of an alcohol with the appropriate metal, and alkyl halides are most commonly made from alcohols by reaction with a hydrogen halide (Section 4.8), thionyl chloride (Section 4.14), or phosphorus tribromide (Section 4.14). Alternatively, alkyl p-toluenesulfonates may be used in place of alkyl halides; alkyl p-toluenesulfonates are also prepared from alcohols as their immediate precursors (Section 8.14). 16.7 REACTIONS OF ETHERS: A REVIEW AND A PREVIEW Up to this point, we haven’t seen any reactions of dialkyl ethers. Indeed, ethers are one of the least reactive of the functional groups we shall study. It is this low level of reactivity, along with an ability to dissolve nonpolar substances, that makes ethers so often used as solvents when carrying out organic reactions. Nevertheless, most ethers are hazardous materials, and precautions must be taken when using them. Diethyl ether is extremely flammable and because of its high volatility can form explosive mixtures in air relatively quickly. Open flames must never be present in laboratories where diethyl ether is being used. Other low-molecular-weight ethers must also be treated as fire hazards. PROBLEM 16.8 Combustion in air is, of course, a chemical property of ethers that is shared by many other organic compounds. Write a balanced chemical equation for the complete combustion (in air) of diethyl ether. E2 CH3CH2ONa Sodium ethoxide Br Bromocyclopentane (major products) CH3CH2OH Ethanol Cyclopentene SN2 ONa Sodium cyclopentanolate CH3CH2Br Ethyl bromide OCH2CH3 Cyclopentyl ethyl ether CH3CH2O 16.7 Reactions of Ethers: A Review and a Preview 627 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
CHAPTER SIXTEEN Ethers, Epoxides, and Sulfides A second dangerous property of ethers is the ease with which they undergo oxi- dation in air to form explosive peroxides. Air oxidation of diethyl ether proceeds accord g to the equation CH3 CH,OCH,CH3+ O CH3 CHOCH-CH HOO Diethyl ether Oxygen 1-Ethoxyethyl hydroperoxide The reaction follows a free-radical mechanism and gives a hydroperoxide, a compound of the type ROOH. Hydroperoxides tend to be unstable and shock-sensitive On stand ing, they form related peroxidic derivatives, which are also prone to violent decomposi tion. Air oxidation leads to peroxides within a few days if ethers are even briefly exposed to atmospheric oxygen. For this reason, one should never use old bottles of dialkyl ethers, and extreme care must be exercised in their disposa 16.8 ACID-CATALYZED CLEAVAGE OF ETHERS Just as the carbon-oxygen bond of alcohols is cleaved on reaction with hydrogen halides (Section 4.8), so too is an ether linkage broken RX H Alcohol Hydrogen kyl Water alide ROR′+KXRX+R'OH Ether Hydroge Alcohol The cleavage of ethers is normally carried out under conditions(excess hydrogen halide, heat) that convert the alcohol formed as one of the original products to an alkyl halide. Thus, the reaction typically leads to two alkyl halide molecules ROR′+2HX RX +RX + HO Ether Hydrogen Two alkyl halid halide CH3CHCH, CH3 CH3 CHCH, CH3 CH3 Br sec-Butyl methyl ether 2-Bromobutane (81%) Bromomethane The order of hydrogen halide reactivity is HI> HBr >> HCl. Hydrogen fluoride is not effective PROBLEM 16.9 A series of dialkyl ethers was allowed to react with excess hydro- gen bromide, with the following results Identify the ether in each case (a)One ether gave a mixture of bromocyclopentane and 1-bromobutane (b)Another ether gave only benzyl bromide (ca third ether gave one mole of 1, 5-dibromopentane per mole of ether. Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
A second dangerous property of ethers is the ease with which they undergo oxidation in air to form explosive peroxides. Air oxidation of diethyl ether proceeds according to the equation The reaction follows a free-radical mechanism and gives a hydroperoxide, a compound of the type ROOH. Hydroperoxides tend to be unstable and shock-sensitive. On standing, they form related peroxidic derivatives, which are also prone to violent decomposition. Air oxidation leads to peroxides within a few days if ethers are even briefly exposed to atmospheric oxygen. For this reason, one should never use old bottles of dialkyl ethers, and extreme care must be exercised in their disposal. 16.8 ACID-CATALYZED CLEAVAGE OF ETHERS Just as the carbon–oxygen bond of alcohols is cleaved on reaction with hydrogen halides (Section 4.8), so too is an ether linkage broken: The cleavage of ethers is normally carried out under conditions (excess hydrogen halide, heat) that convert the alcohol formed as one of the original products to an alkyl halide. Thus, the reaction typically leads to two alkyl halide molecules: The order of hydrogen halide reactivity is HI HBr HCl. Hydrogen fluoride is not effective. PROBLEM 16.9 A series of dialkyl ethers was allowed to react with excess hydrogen bromide, with the following results. Identify the ether in each case. (a) One ether gave a mixture of bromocyclopentane and 1-bromobutane. (b) Another ether gave only benzyl bromide. (c) A third ether gave one mole of 1,5-dibromopentane per mole of ether. ROR Ether 2HX Hydrogen halide H2O Water Two alkyl halides RX R X heat CH3Br Bromomethane OCH3 CH3CHCH2CH3 sec-Butyl methyl ether Br CH3CHCH2CH3 2-Bromobutane (81%) HBr heat ROH Alcohol HX Hydrogen halide H2O Water RX Alkyl halide ROR Ether HX Hydrogen halide ROH Alcohol RX Alkyl halide CH3CH2OCH2CH3 Diethyl ether O2 Oxygen HOO CH3CHOCH2CH3 1-Ethoxyethyl hydroperoxide 628 CHAPTER SIXTEEN Ethers, Epoxides, and Sulfides Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website