9。零 CHAPTER 16 ETHERS EPOXIDES, AND SULFIDES n contrast to alcohols with their rich chemical reactivity, ethers(compounds contain- ng a C-o-C unit)undergo relatively few chemical reactions. As you saw when we discussed Grignard reagents in Chapter 14 and lithium aluminum hydride reduc- tions in Chapter 15, this lack of reactivity of ethers makes them valuable as solvents in a number of synthetically important transformations. In the present chapter you will learn of the conditions in which an ether linkage acts as a functional group, as well as the methods by which ethers are prepared Unlike most ethers, epoxides(compounds in which the C-O-C unit forms a three-membered ring) are very reactive substances. The principles of nucleophilic substi- tution are important in understanding the preparation and properties of epoxides Sulfides(rsr)are the sulfur analogs of ethers. Just as in the preceding chapter where we saw that the properties of thiols(RSH)are different from those of alcohols, we will explore differences between sulfides and ethers in this chapter. 16.1 NOMENCLATURE OF ETHERS, EPOXIDES, AND SULFIDES Ethers are named, in substitutive IUPAC nomenclature as alkoxy derivatives of alkanes Functional class IUPAC names of ethers are derived by listing the two alkyl groups in the general structure ROR'in alphabetical order as separate words, and then adding the word"ether"at the end. When both alkyl groups are the same, the prefix di- precedes the name of the alkyl group CH3CH,OCH,CH: CH3 CH,OCH3 CH3CH,OCH, CH, CH,CI Substitutive IuPac name: Ethoxyethane I-Chloro-3-ethoxypropane Functional class IUPAC name Diethyl ether 3-Chloropropyl ethyl ether 619 Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
619 CHAPTER 16 ETHERS, EPOXIDES, AND SULFIDES I n contrast to alcohols with their rich chemical reactivity, ethers (compounds containing a C±O±C unit) undergo relatively few chemical reactions. As you saw when we discussed Grignard reagents in Chapter 14 and lithium aluminum hydride reductions in Chapter 15, this lack of reactivity of ethers makes them valuable as solvents in a number of synthetically important transformations. In the present chapter you will learn of the conditions in which an ether linkage acts as a functional group, as well as the methods by which ethers are prepared. Unlike most ethers, epoxides (compounds in which the C±O±C unit forms a three-membered ring) are very reactive substances. The principles of nucleophilic substitution are important in understanding the preparation and properties of epoxides. Sulfides (RSR) are the sulfur analogs of ethers. Just as in the preceding chapter, where we saw that the properties of thiols (RSH) are different from those of alcohols, we will explore differences between sulfides and ethers in this chapter. 16.1 NOMENCLATURE OF ETHERS, EPOXIDES, AND SULFIDES Ethers are named, in substitutive IUPAC nomenclature, as alkoxy derivatives of alkanes. Functional class IUPAC names of ethers are derived by listing the two alkyl groups in the general structure ROR in alphabetical order as separate words, and then adding the word “ether” at the end. When both alkyl groups are the same, the prefix di- precedes the name of the alkyl group. CH3CH2OCH2CH3 Ethoxyethane Diethyl ether Substitutive IUPAC name: Functional class IUPAC name: CH3CH2OCH3 Methoxyethane Ethyl methyl ether CH3CH2OCH2CH2CH2Cl 1-Chloro-3-ethoxypropane 3-Chloropropyl ethyl ether Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
CHAPTER SIXTEEN Ethers, Epoxides, and Sulfides Ethers are described as symmetrical or unsymmetrical depending on whether the two groups bonded to oxygen are the same or different Unsymmetrical ethers are also called mixed ethers. Diethyl ether is a symmetrical ether; ethyl methyl ether is an unsymmet rical ether Cyclic ethers have their oxygen as part of a ring-they are heterocyclic compounds (Section 3. 15). Several have specific IUPAC names. Oxirane Oxolane Oxane (Ethylene oxide) (Tetrahydrofuran) (Tetrahydropyran) Recall from Section 6.18 that In each case the ring is numbered starting at the oxygen. The IUPAC rules also permit epoxides oxirane(without substituents)to be called ethylene oxide. Tetrahydrofuran and tetrahy -epoxy derivatives of alkanes dropyran are acceptable synonyms for oxolane and oxane, respectivel n substitutive IUPAC nomen. clature PROBLEM 16.1 Each of the following ethers has been shown to be or is sus- pected to be a mutagen, which means it can induce mutations in test cells. Write he structure of each of these ethers (a) Chloromethyl methyl ether (b)2-(Chloromethyl)oxirane(also known as epichlorohydrin) SAMPLE SOLUTION (a)Chloromethyl methyl ether has a chloromethyl group (CICH2-)and a methyl group (CH3)attached to oxygen. Its structure is Many substances have more than one ether linkage. Two such compounds, often used as solvents, are the diethers 1, 2-dimethoxyethane and 1, 4-dioxane. Diglyme, also CH3OCH2CH2OCH3 CH3OCH2CH2OCH2CH2OCH3 Molecules that contain several ether functions are referred to as polyethers. Polyethers have received much recent attention, and some examples of them will appear in Section 16.4 Sulfides are so The sulfur analogs(rs-)of alkoxy groups are called alkylthio groups. The first two of the following examples illustrate the use of alkylthio prefixes in substitutive thioethers, but this term is nomenclature of sulfides. functional class iupac names of sulfides are derived not part ot systematic iUPAc exactly the same way as those of ethers but end in the word"sulfide. Sulfur heterocy les have names analogous to their oxygen relatives, except that ox-is replaced by thi. Thus the sulfur heterocycles containing three-, four-, five, and six-membered rings are named thiirane, thietane, thiolane, and thane, respectively CH3CH2SCH, CH3 Ethylthioethane (Methylthio Thiirane Diethyl sulfide Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
Ethers are described as symmetrical or unsymmetrical depending on whether the two groups bonded to oxygen are the same or different. Unsymmetrical ethers are also called mixed ethers. Diethyl ether is a symmetrical ether; ethyl methyl ether is an unsymmetrical ether. Cyclic ethers have their oxygen as part of a ring—they are heterocyclic compounds (Section 3.15). Several have specific IUPAC names. In each case the ring is numbered starting at the oxygen. The IUPAC rules also permit oxirane (without substituents) to be called ethylene oxide. Tetrahydrofuran and tetrahydropyran are acceptable synonyms for oxolane and oxane, respectively. PROBLEM 16.1 Each of the following ethers has been shown to be or is suspected to be a mutagen, which means it can induce mutations in test cells. Write the structure of each of these ethers. (a) Chloromethyl methyl ether (b) 2-(Chloromethyl)oxirane (also known as epichlorohydrin) (c) 3,4-Epoxy-1-butene (2-vinyloxirane) SAMPLE SOLUTION (a) Chloromethyl methyl ether has a chloromethyl group (ClCH2±) and a methyl group (CH3±) attached to oxygen. Its structure is ClCH2OCH3. Many substances have more than one ether linkage. Two such compounds, often used as solvents, are the diethers 1,2-dimethoxyethane and 1,4-dioxane. Diglyme, also a commonly used solvent, is a triether. Molecules that contain several ether functions are referred to as polyethers. Polyethers have received much recent attention, and some examples of them will appear in Section 16.4. The sulfur analogs (RS±) of alkoxy groups are called alkylthio groups. The first two of the following examples illustrate the use of alkylthio prefixes in substitutive nomenclature of sulfides. Functional class IUPAC names of sulfides are derived in exactly the same way as those of ethers but end in the word “sulfide.” Sulfur heterocycles have names analogous to their oxygen relatives, except that ox- is replaced by thi-. Thus the sulfur heterocycles containing three-, four-, five-, and six-membered rings are named thiirane, thietane, thiolane, and thiane, respectively. CH3CH2SCH2CH3 Ethylthioethane Diethyl sulfide SCH3 (Methylthio)cyclopentane Cyclopentyl methyl sulfide S Thiirane CH3OCH2CH2OCH3 1,2-Dimethoxyethane O O 1,4-Dioxane CH3OCH2CH2OCH2CH2OCH3 Diethylene glycol dimethyl ether (diglyme) 1 O 2 3 Oxirane (Ethylene oxide) O Oxetane O Oxolane (Tetrahydrofuran) O Oxane (Tetrahydropyran) 620 CHAPTER SIXTEEN Ethers, Epoxides, and Sulfides Recall from Section 6.18 that epoxides may be named as -epoxy derivatives of alkanes in substitutive IUPAC nomenclature. Sulfides are sometimes informally referred to as thioethers, but this term is not part of systematic IUPAC nomenclature. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
16.2 Structure and Bonding in Ethers and Epoxide 16.2 STRUCTURE AND BONDING IN ETHERS AND EPOXIDES Bonding in ethers is readily understood by comparing ethers with water and alcohols Van der Waals strain involving alkyl groups causes the bond angle at oxygen to be larger in ethers than alcohols, and larger in alcohols than in water. An extreme example is di tert-butyl ether, where steric hindrance between the tert-butyl groups is responsible for a dramatic increase in the C-o-c bond angle cH是cH,c1c是cc参a models of water ater Methanol Dimethyl ether Di-ferl-butyl ether ol, dimethyl ether, and (e typical carbon-oxygen bond distances in ethers are similar to those of alcohols their geometries, and examine pm)and are shorter than carbon-carbon bond distances in alkanes(153 pm). bond angle. Compare the C-o An ether oxygen affects the conformation of a molecule in much the same way bond distances in dimethyl ether that a CH2 unit does. The most stable conformation of diethyl ether is the all-staggered and di-tert-butyl ether. anti conformation. Tetrahydropyran is most stable in the chair conformation-a fact that has an important bearing on the structures of many carbohydrates Chair conformation of tetrahydropyraN Incorporating an oxygen atom into a three-membered ring requires its bond angle to be seriously distorted from the normal tetrahedral value In ethylene oxide, for exam- ple, the bond angle at oxygen is 61.5 H2C、CH2C-0- C angle615° C-C-O angle 59.20 Thus epoxides, like cyclopropanes, are strained. They tend to undergo reactions that open the three-membered ring by cleaving one of the carbon-oxygen bond PROBLEM 16.2 The heats of combustion of 1, 2-epoxybutane (2-ethyloxirane) and tetrahydrofuran have been measured: one is 2499 kJ/mol(597. 8 kcal/mol); the other is 2546 kJ/mol(609 1 kcal/mol). Match the heats of combustion with the respective compounds Ethers, like water and alcohols, are polar. Diethyl ether, for example, has a dipe moment of 1. 2 D Cyclic ethers have larger dipole moments; ethylene oxide and tetra drofuran have dipole moments in the 1.7-to 1. 8-D range--about the same as that of Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
16.2 STRUCTURE AND BONDING IN ETHERS AND EPOXIDES Bonding in ethers is readily understood by comparing ethers with water and alcohols. Van der Waals strain involving alkyl groups causes the bond angle at oxygen to be larger in ethers than alcohols, and larger in alcohols than in water. An extreme example is ditert-butyl ether, where steric hindrance between the tert-butyl groups is responsible for a dramatic increase in the C±O±C bond angle. Typical carbon–oxygen bond distances in ethers are similar to those of alcohols (142 pm) and are shorter than carbon–carbon bond distances in alkanes (153 pm). An ether oxygen affects the conformation of a molecule in much the same way that a CH2 unit does. The most stable conformation of diethyl ether is the all-staggered anti conformation. Tetrahydropyran is most stable in the chair conformation—a fact that has an important bearing on the structures of many carbohydrates. Incorporating an oxygen atom into a three-membered ring requires its bond angle to be seriously distorted from the normal tetrahedral value. In ethylene oxide, for example, the bond angle at oxygen is 61.5°. Thus epoxides, like cyclopropanes, are strained. They tend to undergo reactions that open the three-membered ring by cleaving one of the carbon–oxygen bonds. PROBLEM 16.2 The heats of combustion of 1,2-epoxybutane (2-ethyloxirane) and tetrahydrofuran have been measured: one is 2499 kJ/mol (597.8 kcal/mol); the other is 2546 kJ/mol (609.1 kcal/mol). Match the heats of combustion with the respective compounds. Ethers, like water and alcohols, are polar. Diethyl ether, for example, has a dipole moment of 1.2 D. Cyclic ethers have larger dipole moments; ethylene oxide and tetrahydrofuran have dipole moments in the 1.7- to 1.8-D range—about the same as that of water. H2C O CH2 147 pm 144 pm C O C C C O angle 61.5° angle 59.2° Anti conformation of diethyl ether Chair conformation of tetrahydropyran H H O 105° Water H CH 108.5° 3 O Methanol CH3 112° CH3 O Dimethyl ether 132° O C(CH3)3 (CH3)3C Di-tert-butyl ether 16.2 Structure and Bonding in Ethers and Epoxides 621 Use Learning By Modeling to make models of water, methanol, dimethyl ether, and di-tert-butyl ether. Minimize their geometries, and examine what happens to the C±O±C bond angle. Compare the C±O bond distances in dimethyl ether and di-tert-butyl ether. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
CHAPTER SIXTEEN Ethers, Epoxides, and Sulfides 16.3 PHYSICAL PROPERTIES OF ETHERS It is instructive to compare the physical properties of ethers with alkanes and With respect to boiling point, ethers resemble alkanes more than alcohols. With to solubility in water the reverse is true: ethers resemble alcohols more than CH3, CH3 CH3 CH, CH,CH2 CH3 CH3 CH,CH2CH,OH g point: 117°C ability in water: 7.5 g/100 mL Insoluble 9g/100mL In general, the boiling points of alcohols are unusually high because of hydrogen bonding(Section 4.5). Attractive forces in the liquid phases of ethers and alkanes, which ack -OH groups and cannot form intermolecular hydrogen bonds, are much weaker, and their boiling points lower. As shown in Figure 16.1, however, the presence of an oxygen atom permits ethers to participate in hydrogen bonds to water molecules. These attractive forces cause ethers to dissolve in water to approximately the same extent as comparably constituted alco- hols. Alkanes cannot engage in hydrogen bonding to water. PROBLEM 16. 3 Ethers tend to dissolve in alcohols and vice versa. Represent the hydrogen-bonding interaction between an alcohol molecule and an ether molecule 16. 4 CROWN ETHERS Ro:+M- R,O-M Ether Metal Ether-metal ion FIGURE 16.1 Hydro- gen bonding between di- and water. th attractive force betw een the neaa ed of diethyl ether and one of drogens of water. The ele trostatic potential surfaces illustrate the complementary interaction between the electron-rich (red) region o diethyl ether and the elec tron-poor (blue) region of Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
16.3 PHYSICAL PROPERTIES OF ETHERS It is instructive to compare the physical properties of ethers with alkanes and alcohols. With respect to boiling point, ethers resemble alkanes more than alcohols. With respect to solubility in water the reverse is true; ethers resemble alcohols more than alkanes. Why? In general, the boiling points of alcohols are unusually high because of hydrogen bonding (Section 4.5). Attractive forces in the liquid phases of ethers and alkanes, which lack ±OH groups and cannot form intermolecular hydrogen bonds, are much weaker, and their boiling points lower. As shown in Figure 16.1, however, the presence of an oxygen atom permits ethers to participate in hydrogen bonds to water molecules. These attractive forces cause ethers to dissolve in water to approximately the same extent as comparably constituted alcohols. Alkanes cannot engage in hydrogen bonding to water. PROBLEM 16.3 Ethers tend to dissolve in alcohols and vice versa. Represent the hydrogen-bonding interaction between an alcohol molecule and an ether molecule. 16.4 CROWN ETHERS Their polar carbon–oxygen bonds and the presence of unshared electron pairs at oxygen contribute to the ability of ethers to form Lewis acid-Lewis base complexes with metal ions. R2O Ether (Lewis base) M Metal ion (Lewis acid) R2O M Ether–metal ion complex CH3CH2OCH2CH3 Diethyl ether 35°C 7.5 g/100 mL Boiling point: Solubility in water: CH3CH2CH2CH2CH3 Pentane 36°C Insoluble CH3CH2CH2CH2OH 1-Butanol 117°C 9 g/100 mL 622 CHAPTER SIXTEEN Ethers, Epoxides, and Sulfides FIGURE 16.1 Hydrogen bonding between diethyl ether and water. The dashed line represents the attractive force between the negatively polarized oxygen of diethyl ether and one of the positively polarized hydrogens of water. The electrostatic potential surfaces illustrate the complementary interaction between the electron-rich (red) region of diethyl ether and the electron-poor (blue) region of water. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
16.4 Crown Ethers The strength of this bonding depends on the kind of ether. Simple ethers form relatively weak complexes with metal ions. A major advance in the area came in 1967 when Charles J. Pedersen of Du Pont described the preparation and properties of a class of Pedersen was a corecipient polyethers that form much more stable complexes with metal ions than do simple ethers. of the 1987 Nobel Prize in Pedersen prepared a series of macrocyclic polyethers, cyclic compounds contain- chemistry ing four or more oxygens in a ring of 12 or more atoms. He called these compounds crown ethers, because their molecular models resemble crowns. Systematic nomencla ture of crown ethers is somewhat cumbersome. and so pedersen devised a shorthand description whereby the word"crown"is preceded by the total number of atoms in the ring and is followed by the number of oxygen ator 12-Crown-4 18-Crown-6 he parent i 12-Crc and 18-crown-6 are a cyclic tetramer and hexamer, respectively, of repeat CH2- units; they are polyethers based on ethylene glycol(HOCH2CHrOH) Acohol PROBLEM 16.4 What organic compound mentioned earlier in this chapter is a yclic dimer of -OCH2CH2--units The metal-ion complexing properties of crown ethers are clearly evident in their effects on the solubility and reactivity of ionic compounds in nonpolar media. Potassium fluoride(Kf)is ionic and practically insoluble in benzene alone, but dissolves in it when 18-crown-6 is present. The reason for this has to do with the electron distribution of 18- crown-6 as shown in Figure 16.2a. The electrostatic potential surface consists of essen- tially two regions: an electron-rich interior associated with the oxygens and a hydrocarbon- FIGURE 16.2 like exterior associated with the CH2 groups. When KF is added to a solution of 18- electrostatic potential map crown-6 in benzene, potassium ion(K )interacts with the oxygens of the crown ether of 18-crown-6. The region of to form a Lewis acid-Lewis base complex. As can be seen in the space-filling model of highest electron density and their lone pairs. The outer periphery of the crown ether(blue)is relatively non polar(hydrocarbon-like)and soluble in nonpolar solvent fom o benzene.(b)Aspace crown ether where it is bound Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
The strength of this bonding depends on the kind of ether. Simple ethers form relatively weak complexes with metal ions. A major advance in the area came in 1967 when Charles J. Pedersen of Du Pont described the preparation and properties of a class of polyethers that form much more stable complexes with metal ions than do simple ethers. Pedersen prepared a series of macrocyclic polyethers, cyclic compounds containing four or more oxygens in a ring of 12 or more atoms. He called these compounds crown ethers, because their molecular models resemble crowns. Systematic nomenclature of crown ethers is somewhat cumbersome, and so Pedersen devised a shorthand description whereby the word “crown” is preceded by the total number of atoms in the ring and is followed by the number of oxygen atoms. 12-Crown-4 and 18-crown-6 are a cyclic tetramer and hexamer, respectively, of repeating ±OCH2CH2± units; they are polyethers based on ethylene glycol (HOCH2CH2OH) as the parent alcohol. PROBLEM 16.4 What organic compound mentioned earlier in this chapter is a cyclic dimer of ±OCH2CH2± units? The metal–ion complexing properties of crown ethers are clearly evident in their effects on the solubility and reactivity of ionic compounds in nonpolar media. Potassium fluoride (KF) is ionic and practically insoluble in benzene alone, but dissolves in it when 18-crown-6 is present. The reason for this has to do with the electron distribution of 18- crown-6 as shown in Figure 16.2a. The electrostatic potential surface consists of essentially two regions: an electron-rich interior associated with the oxygens and a hydrocarbonlike exterior associated with the CH2 groups. When KF is added to a solution of 18- crown-6 in benzene, potassium ion (K) interacts with the oxygens of the crown ether to form a Lewis acid-Lewis base complex. As can be seen in the space-filling model of O O O O 12-Crown-4 O O O O O O 18-Crown-6 16.4 Crown Ethers 623 Pedersen was a corecipient of the 1987 Nobel Prize in chemistry. (a) (b) FIGURE 16.2 (a) An electrostatic potential map of 18-crown-6. The region of highest electron density (red ) is associated with the negatively polarized oxygens and their lone pairs. The outer periphery of the crown ether (blue) is relatively nonpolar (hydrocarbon-like) and causes the molecule to be soluble in nonpolar solvents such as benzene. (b) A space- filling model of the complex formed between 18-crown-6 and potassium ion (K). K fits into the cavity of the crown ether where it is bound by Lewis acid-Lewis base interaction with the oxygens. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
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