有机化学（英文原版）：Chapt16

619 CHAPTER 16 ETHERS, EPOXIDES, AND SULFIDES I n contrast to alcohols with their rich chemical reactivity, ethers (compounds contain- ing 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 (RSRH11032) 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 RORH11032 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. CH 3 CH 2 OCH 2 CH 3 Ethoxyethane Diethyl ether Substitutive IUPAC name: Functional class IUPAC name: CH 3 CH 2 OCH 3 Methoxyethane Ethyl methyl ether CH 3 CH 2 OCH 2 CH 2 CH 2 Cl 1-Chloro-3-ethoxypropane 3-Chloropropyl ethyl ether Back Forward Main Menu TOC Study Guide TOC Student OLC 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 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. 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 tetrahy- dropyran are acceptable synonyms for oxolane and oxane, respectively. 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 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 (ClCH 2 ±) and a methyl group (CH 3 ±) attached to oxygen. Its structure is ClCH 2 OCH 3 . 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 heterocy- cles 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. CH 3 CH 2 SCH 2 CH 3 Ethylthioethane Diethyl sulfide SCH 3 (Methylthio)cyclopentane Cyclopentyl methyl sulfide S Thiirane CH 3 OCH 2 CH 2 OCH 3 1,2-Dimethoxyethane OO 1,4-Dioxane CH 3 OCH 2 CH 2 OCH 2 CH 2 OCH 3 Diethylene glycol dimethyl ether (diglyme) O 1 23 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 nomen- clature. Sulfides are sometimes in- formally 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 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. Typical carbon–oxygen bond distances in ethers are similar to those of alcohols (H11015142 pm) and are shorter than carbon–carbon bond distances in alkanes (H11015153 pm). An ether oxygen affects the conformation of a molecule in much the same way that a CH 2 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 exam- ple, 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 tetrahy- drofuran have dipole moments in the 1.7- to 1.8-D range—about the same as that of water. H 2 C O CH 2 147 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 108.5°HCH 3 O Methanol 112°CH 3 CH 3 O Dimethyl ether 132° O C(CH 3 ) 3 (CH 3 ) 3 C 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 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 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 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. H11001R 2 O Ether (Lewis base) M H11001 Metal ion (Lewis acid) R 2 O M H11001 Ether–metal ion complex CH 3 CH 2 OCH 2 CH 3 Diethyl ether 35°C 7.5 g/100 mL Boiling point: Solubility in water: CH 3 CH 2 CH 2 CH 2 CH 3 Pentane 36°C Insoluble CH 3 CH 2 CH 2 CH 2 OH 1-Butanol 117°C 9 g/100 mL 622 CHAPTER SIXTEEN Ethers, Epoxides, and Sulfides H9254 H11001 H9254 H11002 FIGURE 16.1 Hydro- gen bonding between di- ethyl ether and water. The dashed line represents the attractive force between the negatively polarized oxygen of diethyl ether and one of the positively polarized hy- drogens of water. The elec- trostatic potential surfaces illustrate the complementary interaction between the electron-rich (red) region of diethyl ether and the elec- tron-poor (blue) region of water. Back Forward Main Menu TOC Study Guide TOC Student OLC 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 contain- 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 atoms. 12-Crown-4 and 18-crown-6 are a cyclic tetramer and hexamer, respectively, of repeat- ing ±OCH 2 CH 2 ± units; they are polyethers based on ethylene glycol (HOCH 2 CH 2 OH) as the parent alcohol. PROBLEM 16.4 What organic compound mentioned earlier in this chapter is a cyclic dimer of ±OCH 2 CH 2 ± 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- like exterior associated with the CH 2 groups. When KF is added to a solution of 18- crown-6 in benzene, potassium ion (K H11001 ) 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 non- polar (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 H11001 ). K H11001 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 624 CHAPTER SIXTEEN Ethers, Epoxides, and Sulfides POLYETHER ANTIBIOTICS O ne way in which pharmaceutical companies search for new drugs is by growing colonies of microorganisms in nutrient broths and assay- ing the substances produced for their biological ac- tivity. This method has yielded thousands of antibi- otic substances, of which hundreds have been developed into effective drugs. Antibiotics are, by definition, toxic (anti H11005 “against”; bios H11005 “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 technol- ogy. They are characterized by the presence of sev- eral 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 mem- brane. 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. Com- pounds such as monensin and the crown ethers that affect metal ion transport are referred to as ionophores (“ion carriers”). C H O CH 3 CH 3 HOCH 2 HOH H O CH 3 H O H CH 3 O CH 2 CH 3 H O O CO 2 H CH 3 OCH 3 CH 3 CH 3 CH 3 CH 3 O OH O H O H O Na H11001 H CH 3 H O CH 3 CH 2 H H 3 C O O HO CH 3 CH 3 O OCH 3 Br H11002 CH 3 (a) (b) 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 Menu TOC Study Guide TOC Student OLC MHHE Website this complex (Figure 16.2b), K H11001 , with an ionic radius of 266 pm, fits comfortably within the 260–320 pm internal cavity of 18-crown-6. Nonpolar CH 2 groups dominate the outer surface of the complex, mask its polar interior, and permit the complex to dissolve in nonpolar solvents. Every K H11001 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 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. 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 knowl- edge of biological processes in which metal ions, including Na H11001 and K H11001 , 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 (CH 3 ) 2 CHOCH(CH 3 ) 2 by this method on an industrial scale. 2CH 3 CH 2 CH 2 CH 2 OH 1-Butanol H 2 SO 4 130°C CH 3 CH 2 CH 2 CH 2 OCH 2 CH 2 CH 2 CH 3 Dibutyl ether (60%) H 2 O Water H11001 CH 3 (CH 2 ) 6 CH 2 Br 1-Bromooctane KF, benzene, 90°C 18-crown-6 CH 3 (CH 2 ) 6 CH 2 F 1-Fluorooctane (92%) H11001 O O O O O O 18-Crown-6 benzene K H11001 F H11002 Potassium fluoride (solid) O O O O O O 18-Crown-6-potassium fluoride complex (in solution) F H11002 K H11001 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 Approximately 4 H11003 10 9 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 symmetri- cal 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 S N 2 substitution. Methyl halides and pri- mary 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 S N 2 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- propoxide: Sodium isopropoxide (CH 3 ) 2 CHONa CH 2 Cl Benzyl chloride (CH 3 ) 2 CHOCH 2 Benzyl isopropyl ether (84%) NaCl Sodium chloride H11001H11001 CH 3 CH 2 I Iodoethane CH 3 CH 2 CH 2 CH 2 ONa Sodium butoxide CH 3 CH 2 CH 2 CH 2 OCH 2 CH 3 Butyl ethyl ether (71%) NaI Sodium iodide H11001H11001 H11001RO H11002 Alkoxide ion RH11032 X Alkyl halide RORH11032 Ether X H11002 Halide ion CH 3 OH Methanol (CH 3 ) 3 COCH 3 tert-Butyl methyl ether H11001 H H11001 CH 2 (CH 3 ) 2 C 2-Methylpropene 626 CHAPTER SIXTEEN Ethers, Epoxides, and Sulfides tert-Butyl methyl ether is of- ten 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 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? (a) (c) (CH 3 ) 3 COCH 2 C 6 H 5 (b) CH 2 ?CHCH 2 OCH(CH 3 ) 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 alkox- ide 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 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 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 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. E2 CH 3 CH 2 ONa Sodium ethoxide H11001 Br Bromocyclopentane (major products) CH 3 CH 2 OH Ethanol H11001 Cyclopentene S N 2 ONa Sodium cyclopentanolate H11001 CH 3 CH 2 Br Ethyl bromide OCH 2 CH 3 Cyclopentyl ethyl ether CH 3 CH 2 O 16.7 Reactions of Ethers: A Review and a Preview 627 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website 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- ing 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 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 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 H11022 HBr H11022H11022 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. (c) A third ether gave one mole of 1,5-dibromopentane per mole of ether. RORH11032 Ether H11001 2HX Hydrogen halide H 2 O Water H11001 Two alkyl halides H11001RX RH11032X heat H11001 CH 3 Br Bromomethane OCH 3 CH 3 CHCH 2 CH 3 sec-Butyl methyl ether Br CH 3 CHCH 2 CH 3 2-Bromobutane (81%) HBr heat H11001ROH Alcohol HX Hydrogen halide H11001 H 2 O Water RX Alkyl halide RORH11032 Ether H11001 HX Hydrogen halide H11001 RH11032OH Alcohol RX Alkyl halide H11001CH 3 CH 2 OCH 2 CH 3 Diethyl ether O 2 Oxygen HOO CH 3 CHOCH 2 CH 3 1-Ethoxyethyl hydroperoxide 628 CHAPTER SIXTEEN Ethers, Epoxides, and Sulfides Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website SAMPLE SOLUTION (a) In the reaction of dialkyl ethers with excess hydrogen bromide, each alkyl group of the ether function is cleaved and forms an alkyl bro- mide. Since bromocyclopentane and 1-bromobutane are the products, the start- ing ether must be butyl cyclopentyl ether. A mechanism for the cleavage of diethyl ether by hydrogen bromide is outlined in Figure 16.4. The key step is an S N 2-like attack on a dialkyloxonium ion by bromide (step 2). HBr heat OCH 2 CH 2 CH 2 CH 3 Butyl cyclopentyl ether H11001 CH 3 CH 2 CH 2 CH 2 Br 1-Bromobutane Br Bromocyclopentane 16.8 Acid-Catalyzed Cleavage of Ethers 629 Overall Reaction: CH 3 CH 2 OCH 2 CH 3 H11001 HBr ±￡ 2CH 3 CH 2 Br H11001 H 2 O heat Water Step 1: Proton transfer to the oxygen of the ether to give a dialkyloxonium ion. O H11001 H Br Diethyloxonium ion Bromide ion Step 2: Nucleophilic attack of the halide anion on carbon of the dialkyloxonium ion. This step gives one molecule of an alkyl halide and one molecule of an alcohol. Step 3 and Step 4: These two steps do not involve an ether at all. They correspond to those in which an alcohol is converted to an alkyl halide (Sections 4.8–4.13). Mechanism: CH 3 CH 2 CH 3 CH 2 CH 3 CH 2 CH 3 CH 2 CH 3 CH 2 CH 3 CH 2 CH 3 CH 2 Hydrogen bromide Hydrogen bromide Hydrogen bromide Diethyl ether Diethyl ether H11001 O H H11001 Br H11002 H11001 Diethyloxonium ion Bromide ion slow Ethyl bromide Ethyl bromide Ethanol Ethanol slow Ethyl bromide Water fast Br O±H ±￡ CH 3 CH 2 Br H11001 CH 3 CH 2 OH H11001 fast Br H11002 ±￡ CH 3 CH 2 Br H11001 H 2 OCH 3 CH 2 OH H11001 H Br –O H H ± ± H11002 FIGURE 16.4 The mechanism for the cleavage of ethers by hydrogen halides, using the reaction of diethyl ether with hydro- gen bromide as an example. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website PROBLEM 16.10 Adapt the mechanism shown in Figure 16.4 to the reaction: With mixed ethers of the type RORH11032, the question of which carbon–oxygen bond is broken first arises. Although some studies have been carried out on this point of mech- anistic detail, it is not one that we need examine at our level of study. 16.9 PREPARATION OF EPOXIDES: A REVIEW AND A PREVIEW There are two main laboratory methods for the preparation of epoxides: 1. Epoxidation of alkenes by reaction with peroxy acids 2. Base-promoted ring closure of vicinal halohydrins Epoxidation of alkenes was discussed in Section 6.18 and is represented by the general equation The reaction is easy to carry out, and yields are usually high. Epoxidation is a stereo- specific syn addition. The following section describes the preparation of epoxides by the base-promoted ring closure of vicinal halohydrins. Since vicinal halohydrins are customarily prepared from alkenes (Section 6.17), both methods—epoxidation using peroxy acids and ring closure of halohydrins—are based on alkenes as the starting materials for preparing epoxides. 16.10 CONVERSION OF VICINAL HALOHYDRINS TO EPOXIDES The formation of vicinal halohydrins from alkenes was described in Section 6.17. Halo- hydrins are readily converted to epoxides on treatment with base: R 2 C CR 2 Alkene X 2 H 2 O HO H11002 HO X R 2 C CR 2 Vicinal halohydrin R 2 C O CR 2 Epoxide H11001 H C 6 H 5 C 6 H 5 H CC (E)-1,2-Diphenylethene H11001 CH 3 COOH O Peroxyacetic acid HOC 6 H 5 HC 6 H 5 trans-2,3-Diphenyloxirane (78–83%) CH 3 COH O Acetic acid R 2 C CR 2 Alkene H11001 RH11032COOH O Peroxy acid R 2 C O CR 2 Epoxide H11001 RH11032COH O Carboxylic acid Tetrahydrofuran O ICH 2 CH 2 CH 2 CH 2 I 1,4-Diiodobutane (65%) HI 150°C 630 CHAPTER SIXTEEN Ethers, Epoxides, and Sulfides Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website Reaction with base brings the alcohol function of the halohydrin into equilibrium with its corresponding alkoxide: Next, in what amounts to an intramolecular Williamson ether synthesis, the alkoxide oxygen attacks the carbon that bears the halide leaving group, giving an epoxide. As in other nucleophilic substitutions, the nucleophile approaches carbon from the side oppo- site the bond to the leaving group: Overall, the stereospecificity of this method is the same as that observed in per- oxy acid oxidation of alkenes. Substituents that are cis to each other in the alkene remain cis in the epoxide. This is because formation of the bromohydrin involves anti addition, and the ensuing intramolecular nucleophilic substitution reaction takes place with inver- sion of configuration at the carbon that bears the halide leaving group. anti addition inversion of configuration H Br H 3 C OH HH 3 C H H 3 C O H H 3 C cis-2,3-Epoxybutane HC H 3 C H 3 CC H (Z)-2-Butene (cis-2-butene) anti addition inversion of configuration CH 3 Br H OH HH 3 C CH 3 H O H H 3 C trans-2,3-Epoxybutane CH 3 C H H 3 CC H (E)-2-Butene (trans-2-butene) H11001 H11002 C R R O C X R R X H11002 O C R C RR R Epoxide NaOH H 2 O H OH Br H trans-2-Bromocyclohexanol H O H 1,2-Epoxycyclohexane (81%) C R R O C H H11002 HO X R R Vicinal halohydrin OH H H11001 H11002 C R R O C X R R 16.10 Conversion of Vicinal Halohydrins to Epoxides 631 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website PROBLEM 16.11 Is either of the epoxides formed in the preceding reactions chi- ral? Is either epoxide optically active when prepared from the alkene by this method? About 2 H11003 10 9 lb/year of 1,2-epoxypropane is produced in the United States as an intermediate in the preparation of various polymeric materials, including polyurethane plastics and foams and polyester resins. A large fraction of the 1,2-epoxypropane is made from propene by way of its chlorohydrin. 16.11 REACTIONS OF EPOXIDES: A REVIEW AND A PREVIEW The most striking chemical property of epoxides is their far greater reactivity toward nucle- ophilic reagents compared with that of simple ethers. Epoxides react rapidly with nucle- ophiles under conditions in which other ethers are inert. This enhanced reactivity results from the ring strain of epoxides. Reactions that lead to ring opening relieve this strain. We saw an example of nucleophilic ring opening of epoxides in Section 15.4, where the reaction of Grignard reagents with ethylene oxide was described as a synthetic route to primary alcohols: Nucleophiles other than Grignard reagents also open epoxide rings. There are two fundamental ways in which these reactions are carried out. The first (Section 16.12) involves anionic nucleophiles in neutral or basic solution. These reactions are usually performed in water or alcohols as solvents, and the alkox- ide ion intermediate is rapidly transformed to an alcohol by proton transfer. Nucleophilic ring-opening reactions of epoxides may also occur under conditions of acid catalysis. Here the nucleophile is not an anion but rather a solvent molecule. Acid-catalyzed ring opening of epoxides is discussed in Section 16.13. HY H11001 R 2 C O CR 2 Epoxide Alcohol H H11001 R 2 C Y CR 2 OH Y H11002 Nucleophile H11001 R 2 C O CR 2 Epoxide R 2 C Y CR 2 O H11002 Alkoxide ion R 2 C Y CR 2 OH Alcohol H 2 O Grignard reagent RMgX H11001 H 2 C O CH 2 Ethylene oxide 1. diethyl ether 2. H 3 O H11001 RCH 2 CH 2 OH Primary alcohol H 2 C O CH 2 Ethylene oxide CH 2 MgCl Benzylmagnesium chloride H11001 1. diethyl ether 2. H 3 O H11001 CH 2 CH 2 CH 2 OH 3-Phenyl-1-propanol (71%) 632 CHAPTER SIXTEEN Ethers, Epoxides, and Sulfides Angle strain is the main source of strain in epoxides, but torsional strain that re- sults from the eclipsing of bonds on adjacent carbons is also present. Both kinds of strain are relieved when a ring-opening reaction occurs. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website There is an important difference in the regiochemistry of ring-opening reactions of epoxides depending on the reaction conditions. Unsymmetrically substituted epoxides tend to react with anionic nucleophiles at the less hindered carbon of the ring. Under conditions of acid catalysis, however, the more highly substituted carbon is attacked. The underlying reasons for this difference in regioselectivity will be explained in Sec- tion 16.13. 16.12 NUCLEOPHILIC RING-OPENING REACTIONS OF EPOXIDES Ethylene oxide is a very reactive substance. It reacts rapidly and exothermically with anionic nucleophiles to yield 2-substituted derivatives of ethanol by cleaving the car- bon–oxygen bond of the ring: PROBLEM 16.12 What is the principal organic product formed in the reaction of ethylene oxide with each of the following? (a) Sodium cyanide (NaCN) in aqueous ethanol (b) Sodium azide (NaN 3 ) in aqueous ethanol (c) Sodium hydroxide (NaOH) in water (d) Phenyllithium (C 6 H 5 Li) in ether, followed by addition of dilute sulfuric acid (e) 1-Butynylsodium (CH 3 CH 2 CPCNa) in liquid ammonia SAMPLE SOLUTION (a) Sodium cyanide is a source of the nucleophilic cyanide anion. Cyanide ion attacks ethylene oxide, opening the ring and forming 2-cyanoethanol: Nucleophilic ring opening of epoxides has many of the features of an S N 2 reac- tion. Inversion of configuration is observed at the carbon at which substitution occurs. H H O 1,2-Epoxycyclopentane NaOCH 2 CH 3 CH 3 CH 2 OH OCH 2 CH 3 H OH H trans-2-Ethoxycyclopentanol (67%) H 2 C CH 2 O Ethylene oxide NaCN ethanol–water 2-Cyanoethanol NCCH 2 CH 2 OH H 2 C O CH 2 Ethylene oxide (oxirane) KSCH 2 CH 2 CH 2 CH 3 ethanol–water, 0°C CH 3 CH 2 CH 2 CH 2 SCH 2 CH 2 OH 2-(Butylthio)ethanol (99%) RCH O CH 2 Anionic nucleophiles attack here. Nucleophiles attack here when reaction is catalyzed by acids. 16.12 Nucleophilic Ring-Opening Reactions of Epoxides 633 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website Unsymmetrical epoxides are attacked at the less substituted, less sterically hindered carbon of the ring: PROBLEM 16.13 Given the starting material 1-methyl-1,2-epoxycyclopentane, of absolute configuration as shown, decide which one of the compounds A through C correctly represents the product of its reaction with sodium methoxide in methanol. The experimental observations combine with the principles of nucleophilic substi- tution to give the picture of epoxide ring opening shown in Figure 16.5. The nucleophile attacks the less crowded carbon from the side opposite the carbon–oxygen bond. Bond formation with the nucleophile accompanies carbon–oxygen bond breaking, and a sub- stantial portion of the strain in the three-membered ring is relieved as it begins to open in the transition state. The initial product of nucleophilic substitution is an alkoxide anion, which rapidly abstracts a proton from the solvent to give a H9252-substituted alcohol as the isolated product. The reaction of Grignard reagents with epoxides is regioselective in the same sense. Attack occurs at the less substituted carbon of the ring. C C O H 3 C CH 3 HCH 3 2,2,3-Trimethyloxirane NaOCH 3 CH 3 OH CH 3 CHCCH 3 CH 3 O CH 3 OH 3-Methoxy-2-methyl-2-butanol (53%) H 3 C H H 3 C R R H O (2R,3R)-2,3-Epoxybutane NH 3 , H 2 O CH 3 CH 3 OHH HH 2 N R S (2R,3S)-3-Amino-2-butanol (70%) 634 CHAPTER SIXTEEN Ethers, Epoxides, and Sulfides Manipulating models of these compounds can make it easier to follow the stereo- chemistry. R Y O H11002 R OH H9252-Substituted alcohol R O H9254H11002 Y H9254H11002H11002 Y Epoxide R Nucleophile Y O Alkoxide ionTransition state FIGURE 16.5 Nucleophilic ring opening of an epoxide. CH 3 O 12 35 4 1-Methyl-1,2- epoxycyclopentane OCH 3 HO CH 3 Compound A CH 3 OH CH 3 O Compound B CH 3 CH 3 O OH Compound C Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website Epoxides are reduced to alcohols on treatment with lithium aluminum hydride. Hydride is transferred to the less crowded carbon. Epoxidation of an alkene, followed by lithium aluminum hydride reduction of the result- ing epoxide, gives the same alcohol that would be obtained by acid-catalyzed hydration (Section 6.10) of the alkene. 16.13 ACID-CATALYZED RING-OPENING REACTIONS OF EPOXIDES As we’ve just seen, nucleophilic ring opening of ethylene oxide yields 2-substituted derivatives of ethanol. Those reactions involved nucleophilic attack on the carbon of the ring under neutral or basic conditions. Other nucleophilic ring-openings of epoxides like- wise give 2-substituted derivatives of ethanol but either involve an acid as a reactant or occur under conditions of acid catalysis: A third example is the industrial preparation of ethylene glycol (HOCH 2 CH 2 OH) by hydrolysis of ethylene oxide in dilute sulfuric acid. This reaction and its mechanism (Figure 16.6) illustrate the difference between the ring openings of epoxides discussed in the preceding section and the acid-catalyzed ones described here. Under conditions of acid catalysis, the species that is attacked by the nucleophile is not the epoxide itself, but rather its conjugate acid. The transition state for ring opening has a fair measure of carbocation character. Breaking of the ring carbon–oxygen bond is more advanced than formation of the bond to the nucleophile. Transition state for attack by water on conjugate acid of ethylene oxide H 2 C CH 2 O O H9254H11001 H9254H11001 H9254H11001 H H H H 2 C O CH 2 Ethylene oxide HBr 10°C 2-Bromoethanol (87–92%) BrCH 2 CH 2 OH H 2 C O CH 2 Ethylene oxide CH 3 CH 2 OH H 2 SO 4 , 25°C 2-Ethoxyethanol (85%) CH 3 CH 2 OCH 2 CH 2 OH H 2 C O CH(CH 2 ) 7 CH 3 1,2-Epoxydecane 1. LiAlH 4 2. H 2 O 2-Decanol (90%) CH 3 CH(CH 2 ) 7 CH 3 OH H 2 C O CHCH 3 1,2-Epoxypropane C 6 H 5 MgBr Phenylmagnesium bromide H11001 1. diethyl ether 2. H 3 O H11001 1-Phenyl-2-propanol (60%) C 6 H 5 CH 2 CHCH 3 OH 16.13 Acid-Catalyzed Ring-Opening Reactions of Epoxides 635 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website Because carbocation character develops at the transition state, substitution is favored at the carbon that can better support a developing positive charge. Thus, in con- trast to the reaction of epoxides with relatively basic nucleophiles, in which S N 2-like attack is faster at the less crowded carbon of the three-membered ring, acid catalysis promotes substitution at the position that bears the greater number of alkyl groups: C C O H 3 C CH 3 HCH 3 2,2,3-Trimethyloxirane CH 3 OH H 2 SO 4 CH 3 CHCCH 3 OCH 3 CH 3 HO 3-Methoxy-3-methyl-2-butanol (76%) 636 CHAPTER SIXTEEN Ethers, Epoxides, and Sulfides Overall Reaction: H 2 C ± CH 2 H11001 H 2 O Ethylene oxide 1,2-Ethanediol (ethylene glycol) 1,2-Ethanediol Water H 3 O H11001 Step 1: Proton transfer to the oxygen of the epoxide to give an oxonium ion. Step 2: Nucleophilic attack by water on carbon of the oxonium ion. The carbon– oxygen bond of the ring is broken in this step and the ring opens. Step 3: Proton transfer to water completes the reaction and regenerates the acid catalyst. Mechanism: fast CH 2 ± CH 2 slow TS O HOCH 2 CH 2 OH H 2 C ± CH 2 H11001 H ± O Ethylene oxide TS O H H H11001 Hydronium ion Hydronium ion H 2 C ± CH 2 H11001 H 2 O Ethyleneoxonium ion Water Ethyleneoxonium ion H11001 Water H ± O O ± H 2-Hydroxyethyloxonium ion 2-Hydroxyethyloxonium ion CH 2 ± CH 2 H ± O Water T S ±￡ ±￡ fast TS O + W H H 2 C ± CH 2 TS O + W H O H H T S O H H T S O ± H H11001 HOCH 2 CH 2 OH H H T S H11001 H T S S H11001 H11001 H T S O ± H S BA BA FIGURE 16.6 The mecha- nism for the acid-catalyzed nucleophilic ring opening of ethylene oxide by water. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website Although nucleophilic participation at the transition state is slight, it is enough to ensure that substitution proceeds with inversion of configuration. PROBLEM 16.14 Which product, compound A, B, or C, would you expect to be formed when 1-methyl-1,2-epoxycyclopentane of the absolute configuration shown is allowed to stand in methanol containing a few drops of sulfuric acid? Compare your answer with that given for Problem 16.13. A method for achieving net anti hydroxylation of alkenes combines two stereo- specific processes: epoxidation of the double bond and hydrolysis of the derived epoxide. PROBLEM 16.15 Which alkene, cis-2-butene or trans-2-butene, would you choose in order to prepare meso-2,3-butanediol by epoxidation followed by acid- catalyzed hydrolysis? Which alkene would yield meso-2,3,-butanediol by osmium tetraoxide hydroxylation? 16.14 EPOXIDES IN BIOLOGICAL PROCESSES Many naturally occurring substances are epoxides. You have seen two examples of such compounds already in disparlure, the sex attractant of the gypsy moth (Section 6.18), and in the carcinogenic epoxydiol formed from benzo[a]pyrene (Section 11.8). In most cases, epoxides are biosynthesized by the enzyme-catalyzed transfer of one of the oxygen atoms of an O 2 molecule to an alkene. Since only one of the atoms of O 2 is H 2 O HClO 4 C 6 H 5 COOH O X H OH OH H trans-1,2-Cyclohexanediol (80%) H O H 1,2-EpoxycyclohexaneCyclohexene HBr H OH Br H trans-2-Bromocyclohexanol (73%) H O H 1,2-Epoxycyclohexane (2R,3R)-2,3-Epoxybutane CH 3 OH H 2 SO 4 CH 3 CH 3 OHH HCH 3 O R S (2R,3S)-3-Methoxy-2-butanol (57%) H 3 C H H 3 C R R H O 16.14 Epoxides In Biological Processes 637 CH 3 O 12 35 4 1-Methyl-1,2- epoxycyclopentane OCH 3 HO CH 3 Compound A CH 3 OH CH 3 O Compound B CH 3 CH 3 O OH Compound C Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website transferred to the substrate, the enzymes that catalyze such transfers are classified as monooxygenases. A biological reducing agent, usually the coenzyme NADH (Section 15.11), is required as well. A prominent example of such a reaction is the biological epoxidation of the poly- ene squalene. The reactivity of epoxides toward nucleophilic ring opening is responsible for one of the biological roles they play. Squalene 2,3-epoxide, for example, is the biological precursor to cholesterol and the steroid hormones, including testosterone, progesterone, estrone, and cortisone. The pathway from squalene 2,3-epoxide to these compounds is triggered by epoxide ring opening and will be described in Chapter 26. 16.15 PREPARATION OF SULFIDES Sulfides, compounds of the type RSRH11032, are prepared by nucleophilic substitution reac- tions. Treatment of a primary or secondary alkyl halide with an alkanethiolate ion (RS – ) gives a sulfide: It is not necessary to prepare and isolate the sodium alkanethiolate in a separate operation. Because thiols are more acidic than water, they are quantitatively converted to their alka- nethiolate anions by sodium hydroxide. Thus, all that is normally done is to add a thiol to sodium hydroxide in a suitable solvent (water or an alcohol) followed by the alkyl halide. CH 3 CHCH Cl CH 2 3-Chloro-1-butene CH 3 CHCH SCH 3 CH 2 Methyl 1-methylallyl sulfide (62%) NaSCH 3 methanol RS H11002 Na H11001 Sodium alkanethiolate H11001 S N 2 XRH11032 Alkyl halide RSRH11032 Sulfide H11001 X H11002 Na H11001 Sodium halide O 2 , NADH, a monooxygenase H 3 C CH 3 CH 3 CH 3 CH 3 CH 3 CH 3 CH 3 Squalene H 3 C CH 3 CH 3 CH 3 CH 3 CH 3 CH 3 CH 3 O 1 2 3 Squalene 2,3-epoxide H11001H11001 R 2 C O CR 2 enzyme R 2 C CR 2 O 2 H 2 OH H11001 NAD H11001 H11001H11001H11001NADH 638 CHAPTER SIXTEEN Ethers, Epoxides, and Sulfides K a for CH 3 SH is 1.8 H11003 10 H1100211 (pK a H11005 10.7). Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website PROBLEM 16.16 The p-toluenesulfonate derived from (R)-2-octanol and p- toluenesulfonyl chloride was allowed to react with sodium benzenethiolate (C 6 H 5 SNa). Give the structure, including stereochemistry and the appropriate R or S descriptor, of the product. 16.16 OXIDATION OF SULFIDES: SULFOXIDES AND SULFONES We saw in Section 15.14 that thiols differ from alcohols in respect to their behavior toward oxidation. Similarly, sulfides differ from ethers in their behavior toward oxidiz- ing agents. Whereas ethers tend to undergo oxidation at carbon to give hydroperoxides (Section 16.7), sulfides are oxidized at sulfur to give sulfoxides. If the oxidizing agent is strong enough and present in excess, oxidation can proceed further to give sulfones. When the desired product is a sulfoxide, sodium metaperiodate (NaIO 4 ) is an ideal reagent. It oxidizes sulfides to sulfoxides in high yield but shows no tendency to oxidize sulfoxides to sulfones. Peroxy acids, usually in dichloromethane as the solvent, are also reliable reagents for converting sulfides to sulfoxides. One equivalent of a peroxy acid or of hydrogen peroxide converts sulfides to sul- foxides; two equivalents gives the corresponding sulfone. PROBLEM 16.17 Verify, by making molecular models, that the bonds to sulfur are arranged in a trigonal pyramidal geometry in sulfoxides and in a tetrahedral geom- etry in sulfones. Is phenyl vinyl sulfoxide chiral? What about phenyl vinyl sulfone? Oxidation of sulfides occurs in living systems as well. Among naturally occurring sulfoxides, one that has received recent attention is sulforaphane, which is present in broccoli and other vegetables. Sulforaphane holds promise as a potential anticancer agent because, unlike most anticancer drugs, which act by killing rapidly dividing tumor cells faster than they kill normal cells, sulforaphane is nontoxic and may simply inhibit the formation of tumors. CH 2 SCH Phenyl vinyl sulfide H11001 2H 2 O 2 Hydrogen peroxide acetic acid CH 2 O H11002 2H11001 SCH O H11002 Phenyl vinyl sulfone (74–78%) H11001 Water 2H 2 O H11001 water SCH 3 Methyl phenyl sulfide NaIO 4 Sodium metaperiodate H11001 SCH 3 O H11002 Methyl phenyl sulfoxide (91%) H11001 NaIO 3 Sodium iodate oxidize oxidize RRH11032S Sulfide RRH11032S O H11002 H11001 Sulfoxide RRH11032S O H11002 O 2H11001 H11002 Sulfone 16.16 Oxidation of Sulfides: Sulfoxides and Sulfones 639 Third-row elements such as sulfur can expand their va- lence shell beyond eight electrons, and so sulfur–oxy- gen bonds in sulfoxides and sulfones are sometimes rep- resented as double bonds. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website 16.17 ALKYLATION OF SULFIDES: SULFONIUM SALTS Sulfur is more nucleophilic than oxygen (Section 8.7), and sulfides react with alkyl halides much faster than do ethers. The products of these reactions, called sulfonium salts, are also more stable than the corresponding oxygen analogs. PROBLEM 16.18 What other combination of alkyl halide and sulfide will yield the same sulfonium salt shown in the preceding example? Predict which combi- nation will yield the sulfonium salt at the faster rate. A naturally occurring sulfonium salt, S-adenosylmethionine (SAM), is a key sub- stance in certain biological processes. It is formed by a nucleophilic substitution in which the sulfur atom of methionine attacks the primary carbon of adenosine triphosphate, dis- placing the triphosphate leaving group as shown in Figure 16.7. S-Adenosylmethionine acts as a biological methyl-transfer agent. Nucleophiles, par- ticularly nitrogen atoms of amines, attack the methyl carbon of SAM, breaking the car- bon–sulfur bond. The following equation represents the biological formation of epineph- rine by methylation of norepinephrine. Only the methyl group and the sulfur of SAM are shown explicitly in the equation in order to draw attention to the similarity of this reac- tion, which occurs in living systems, to the more familiar S N 2 reactions we have studied. CHCH 2 NHO HO OH H H Norepinephrine H11001 enzyme CH 3 S H11001 SAM H11001 CH 3 CHCH 2 NHO HO OH H H H11001 S H11002H H11001 CH 3 CHCH 2 NHO HO OH H Epinephrine Dodecyldimethylsulfonium iodide CH 3 (CH 2 ) 10 CH 2 SCH 3 I H11002 H11001 CH 3 CH 3 (CH 2 ) 10 CH 2 SCH 3 Dodecyl methyl sulfide CH 3 I Methyl iodide H11001 H11001 S N 2 XRH11033 Alkyl halideSulfide S RH11032 R Sulfonium salt X H11002 S RH11032 R RH11033 H11001 CCH 3 SCH 2 CH 2 CH 2 CH 2 N H11001 S O H11002 Sulforaphane 640 CHAPTER SIXTEEN Ethers, Epoxides, and Sulfides Use Learning By Model- ing to view the geometry of sul- fur in trimethylsulfonium ion. The S in S-adenosylmethio- nine indicates that the adenosyl group is bonded to sulfur. It does not stand for the Cahn–Ingold–Prelog stereochemical descriptor. Epinephrine is also known as adrenaline and is a hormone with profound physiological effects designed to prepare the body for “fight or flight.” Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website 16.18 SPECTROSCOPIC ANALYSIS OF ETHERS Infrared: The infrared spectra of ethers are characterized by a strong, rather broad band due to C±O±C stretching between 1070 and 1150 cm H110021 . Dialkyl ethers exhibit this band at near 1100 cm H110021 , as the infrared spectrum of dipropyl ether shows (Figure 16.8). 1 H NMR: The chemical shift of the proton in the H±C±O±C unit of an ether is very similar to that of the proton in the H±C±OH unit of an alcohol. A range H9254 3.3–4.0 ppm is typical. In the 1 H NMR spectrum of dipropyl ether, shown in Figure 16.9, the assignment of signals to the various protons in the molecule is CH 3 CH 2 CH 2 OCH 2 CH 2 CH 3 H9254 0.8 ppm H9254 0.8 ppm H9254 1.4 ppm H9254 3.2 ppm 16.18 Spectroscopic Analysis of Ethers 641 NH 2 NH 2 N N N N O H11002 O H11002 O H11002 O S H11001 NH 3 H11002 OCCHCH 2 CH 2 CH 3 H11001 P H11001 P H11001 PHO OH O OH O OH O CH 2 O OHHO OHHO H 2 O, enzyme N N N N CH 2 H11001 Methionine: ATP: SAM: O O S H11001 NH 3 H11002 OCCHCH 2 CH 2 CH 3 FIGURE 16.7 Nucleophilic substitution at the primary carbon of adenosine triphosphate (ATP) by the sulfur atom of methionine yields S-adenosylmethionine (SAM). The reaction is catalyzed by an enzyme. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website 642 CHAPTER SIXTEEN Ethers, Epoxides, and Sulfides Wave number, cm H110021 Transmittance (%) CH 3 CH 2 CH 2 OCH 2 CH 2 CH 3 C±O±C 0.01.02.03.04.0 Chemical shift (δ, ppm) 6.07.08.09.010.0 5.0 ( 3.13.23.3 0.7 0.60.80.9 1.4 FIGURE 16.8 The infrared spectrum of dipropyl ether (CH 3 CH 2 CH 2 OCH 2 CH 2 CH 3 ). The strong peak near 1100 cm H110021 is due to C±O±C stretching. FIGURE 16.9 The 200-MHz 1 H NMR spectrum of dipropyl ether (CH 3 CH 2 CH 2 OCH 2 CH 2 CH 3 ). Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website 13 C NMR: The carbons of an ether function (C±O±C) are about 10 ppm less shielded than those of an alcohol and appear in the range H9254 57–87 ppm. The chemical shifts in tetrahydrofuran offer a comparison of C±O±C and C±C±C units. UV-VIS: Simple ethers have their absorption maximum at about 185 nm and are trans- parent to ultraviolet radiation above about 220 nm. Mass Spectrometry: Ethers, like alcohols, lose an alkyl radical from their molecular ion to give an oxygen-stabilized cation. Thus, m/z 73 and m/z 87 are both more abun- dant than the molecular ion in the mass spectrum of sec-butyl ethyl ether. PROBLEM 16.19 There is another oxygen-stabilized cation of m/z 87 capable of being formed by fragmentation of the molecular ion in the mass spectrum of sec- butyl ethyl ether. Suggest a reasonable structure for this ion. 16.19 SUMMARY Section 16.1 Ethers are compounds that contain a C±O±C linkage. In substitutive IUPAC nomenclature, they are named as alkoxy derivatives of alkanes. In functional class IUPAC nomenclature, we name each alkyl group as a separate word (in alphabetical order) followed by the word “ether.” Epoxides are normally named as epoxy derivatives of alkanes or as sub- stituted oxiranes. Sulfides are sulfur analogs of ethers: they contain the C±S±C func- tional group. They are named as alkylthio derivatives of alkanes in sub- stitutive IUPAC nomenclature. The functional class IUPAC names of sul- fides are derived in the same manner as those of ethers, but the concluding word is “sulfide.” CH 3 SCH 2 CH 2 CH 2 CH 2 CH 2 CH 3 Substitutive IUPAC name: 1-(Methylthio)hexane Functional class name: Hexyl methyl sulfide OH 2-Methyl-2,3-epoxypentane 3-Ethyl-2,2-dimethyloxirane CH 3 OCH 2 CH 2 CH 2 CH 2 CH 2 CH 3 Substitutive IUPAC name: 1-Methoxyhexane Functional class name: Hexyl methyl ether CHCH 3 CH 3 CH 2 O H11001 m/z 73 H11001 CH 2 CH 3 CHCH 2 CH 3 CH 3 CH 2 O H11001 m/z 87 H11001 CH 3 CH 3 CH 2 O H11001 CHCH 2 CH 3 CH 3 m/z 102 O 26.0 ppm 68.0 ppm 16.19 Summary 643 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website Section 16.2 The oxygen atom in an ether or epoxide affects the shape of the mole- cule in much the same way as an sp 3 -hybridized carbon of an alkane or cycloalkane. Section 16.3 The carbon–oxygen bond of ethers is polar, and ethers can act as proton acceptors in hydrogen bonds with water and alcohols. But ethers lack OH groups and cannot act as proton donors in forming hydrogen bonds. Section 16.4 Ethers form Lewis acid-Lewis base complexes with metal ions. Certain cyclic polyethers, called crown ethers, are particularly effective in coor- dinating with Na H11001 and K H11001 , and salts of these cations can be dissolved in nonpolar solvents when crown ethers are present. Under these conditions the rates of many reactions that involve anions are accelerated. Sections 16.5 The two major methods for preparing ethers are summarized in Table and 16.6 16.1. CH 3 (CH 2 ) 4 CH 2 Br 1-Bromohexane KOCCH 3 , 18-crown-6 acetonitrile, heat O X CH 3 (CH 2 ) 4 CH 2 OCCH 3 O X Hexyl acetate (96%) ORH11032H H9254H11002 H9254H11001 O R R O Diethyl etherPentane 644 CHAPTER SIXTEEN Ethers, Epoxides, and Sulfides TABLE 16.1 Preparation of Ethers Reaction (section) and comments Acid-catalyzed condensation of alco- hols (Sections 15.7 and 16.5) Two molecules of an alcohol condense in the presence of an acid catalyst to yield a dialkyl ether and water. The reaction is limited to the synthesis of symmetrical ethers from primary alcohols. The Williamson ether synthesis (Sec- tion 16.6) An alkoxide ion displaces a halide or similar leaving group in an S N 2 reaction. The alkyl halide cannot be one that is prone to elimination, and so this reaction is limited to methyl and primary alkyl halides. There is no limitation on the alkoxide ion that can be used. General equation and specific example Alkoxide ion RO H11002 H11001H11001 Primary alkyl halide RH11032CH 2 X Ether ROCH 2 RH11032 Halide ion X H11002 Sodium isobutoxide (CH 3 ) 2 CHCH 2 ONa H11001H11001 Ethyl bromide CH 3 CH 2 Br Ethyl isobutyl ether (66%) (CH 3 ) 2 CHCH 2 OCH 2 CH 3 Sodium bromide NaBr Alcohol 2RCH 2 OH H11001 Ether RCH 2 OCH 2 R Water H 2 O H H11001 Propyl alcohol CH 3 CH 2 CH 2 OH Dipropyl ether CH 3 CH 2 CH 2 OCH 2 CH 2 CH 3 H 2 SO 4 heat Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website Section 16.7 Dialkyl ethers are useful solvents for organic reactions, but dangerous ones due to their tendency to form explosive hydroperoxides by air oxi- dation in opened bottles. Section 16.8 The only important reaction of ethers is their cleavage by hydrogen halides. The order of hydrogen halide reactivity is HI H11022 HBr H11022 HCl. Sections 16.9 Epoxides are prepared by the methods listed in Table 16.2. and 16.10 Section 16.11 Epoxides are much more reactive than ethers, especially in reactions that lead to cleavage of their three-membered ring. H11001 HBr heat CH 2 OCH 2 CH 3 Benzyl ethyl ether CH 2 Br Benzyl bromide CH 3 CH 2 Br Ethyl bromide RORH11032 Ether H11001 2HX Hydrogen halide H 2 O Water H11001H11001 Alkyl halide RX Alkyl halide RH11032X 16.19 Summary 645 TABLE 16.2 Preparation of Epoxides Reaction (section) and comments Peroxy acid oxidation of alkenes (Sections 6.18 and 16.9) Peroxy acids transfer oxygen to alkenes to yield epoxides. Stereospecific syn addition is observed. Base-promoted cyclization of vicinal halohydrins (Section 16.10) This reaction is an intramolecular version of the Williamson ether synthesis. The alcohol function of a vicinal halohydrin is con- verted to its conjugate base, which then displa- ces halide from the adjacent carbon to give an epoxide. General equation and specific example Alkene R 2 C?CR 2 Peroxy acid RH11032COOH O X Carboxylic acid RH11032COH O X H11001H11001 Epoxide R 2 C±CR 2 O ± ± 2,3-Dimethyl-2-butene (CH 3 ) 2 C?C(CH 3 ) 2 CH 3 CO 2 OH 2,2,3,3-Tetramethyloxirane (70–80%) C±C ± ± ± ± O ± ± H 3 CCH 3 H 3 CCH 3 Vicinal halohydrin R 2 C±CR 2 HO X W W Epoxide R 2 C±CR 2 O ± ± R 2 C±CR 2 O X W W H11002 HO H11002 3-Bromo-2-methyl-2-butanol (CH 3 ) 2 C±CHCH 3 HO W Br W 2,2,3-Trimethyloxirane (78%) (CH 3 ) 2 C±CHCH 3 O ± ± NaOH H 2 O Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website Section 16.12 Anionic nucleophiles usually attack the less substituted carbon of the epoxide in an S N 2-like fashion. Section 16.13 Under conditions of acid catalysis, nucleophiles attack the carbon that can better support a positive charge. Carbocation character is developed in the transition state Inversion of configuration is observed at the carbon that is attacked by the nucleophile, irrespective of whether the reaction takes place in acidic or basic solution. Section 16.14 Epoxide functions are present in a great many natural products, and epox- ide ring opening is sometimes a key step in the biosynthesis of other sub- stances. Section 16.15 Sulfides are prepared by nucleophilic substitution (S N 2) in which an alkanethiolate ion attacks an alkyl halide. Section 16.16 Oxidation of sulfides yields sulfoxides, then sulfones. Sodium metaperio- date is specific for the oxidation of sulfides to sulfoxides, and no further. C 6 H 5 SH Benzenethiol C 6 H 5 SNa Sodium benzenethiolate C 6 H 5 SCH 2 C 6 H 5 Benzyl phenyl sulfide (60%) NaOCH 2 CH 3 C 6 H 5 CH 2 Cl RS H11002 Alkanethiolate H11001 H11001 X H11002 HalideAlkyl halide XR Sulfide RS RH11032 CH 3 OH H 2 SO 4 CH 3 CHCCH 3 OCH 3 CH 3 HO 3-Methoxy-3-methyl-2-butanol (76%) C C O H 3 C CH 3 HCH 3 2,2,3-Trimethyloxirane Nucleophile attacks this carbon. RCH O CR 2 Epoxide H11001 H H11001 CR 2 RCH OH YH H11001 H11002H H11001 H9252-substituted alcohol RCHCR 2 OH Y RCH O H11001 CR 2 H HY C C O H 3 C CH 3 HCH 3 2,2,3-Trimethyloxirane NaOCH 3 CH 3 OH CH 3 CHCCH 3 CH 3 O CH 3 OH 3-Methoxy-2-methyl-2-butanol (53%) Nucleophile attacks this carbon. RCH O CR 2 Epoxide H11001 Nucleophile Y H11002 CR 2 RCH O H11002 Y CR 2 RCH OH Y H9252-substituted alcohol 646 CHAPTER SIXTEEN Ethers, Epoxides, and Sulfides Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website Hydrogen peroxide or peroxy acids can yield sulfoxides (1 mol of oxidant per mole of sulfide) or sulfone (2 mol of oxidant) per mole of sulfide. Section 16.17 Sulfides react with alkyl halides to give sulfonium salts. Section 16.18 An H±C±O±C structural unit in an ether resembles an H±C±O±H unit of an alcohol with respect to the C±O stretching frequency in its infrared spectrum and the H±C chemical shift in its 1 H NMR spectrum. PROBLEMS 16.20 Write the structures of all the constitutionally isomeric ethers of molecular formula C 5 H 12 O, and give an acceptable name for each. 16.21 Many ethers, including diethyl ether, are effective as general anesthetics. Because simple ethers are quite flammable, their place in medical practice has been taken by highly halogenated nonflammable ethers. Two such general anesthetic agents are isoflurane and enflurane. These com- pounds are isomeric; isoflurane is 1-chloro-2,2,2-trifluoroethyl difluoromethyl ether; enflurane is 2-chloro-1,1,2-trifluoroethyl difluoromethyl ether. Write the structural formulas of isoflurane and enflurane. 16.22 Although epoxides are always considered to have their oxygen atom as part of a three- membered ring, the prefix epoxy in the IUPAC system of nomenclature can be used to denote a cyclic ether of various sizes. Thus H11001 XRH11033 Alkyl halideSulfide S RH11032 R Sulfonium salt X H11002 S RH11032 R RH11033 H11001 CH 3 I Methyl iodide H11001 Dimethyl sulfide CH 3 CH 3 S Trimethylsulfonium iodide (100%) CH 3 CH 3 I H11002 S CH 3 H11001 oxidize oxidize RRH11032S Sulfide RRH11032S O H11002 H11001 Sulfoxide RRH11032S O H11002 O 2H11001 H11002 Sulfone H 2 O 2 (1 mol) C 6 H 5 CH 2 SCH 3 Benzyl methyl sulfide Benzyl methyl sulfoxide (94%) C 6 H 5 CH 2 SCH 3 H11001 O H11002 Problems 647 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website may be named 2-methyl-1,3-epoxyhexane. Using the epoxy prefix in this way, name each of the following compounds: (a) (c) (b) (d) 16.23 The name of the parent six-membered sulfur-containing heterocycle is thiane. It is num- bered beginning at sulfur. Multiple incorporation of sulfur in the ring is indicated by the prefixes di-, tri-, and so on. (a) How many methyl-substituted thianes are there? Which ones are chiral? (b) Write structural formulas for 1,4-dithiane and 1,3,5-trithiane. (c) Which dithiane isomer is a disulfide? (d) Draw the two most stable conformations of the sulfoxide derived from thiane. 16.24 The most stable conformation of 1,3-dioxan-5-ol is the chair form that has its hydroxyl group in an axial orientation. Suggest a reasonable explanation for this fact. Building a molecular model is helpful. 16.25 Outline the steps in the preparation of each of the constitutionally isomeric ethers of molecular formula C 4 H 10 O, starting with the appropriate alcohols. Use the Williamson ether synthesis as your key reaction. 16.26 Predict the principal organic product of each of the following reactions. Specify stereo- chemistry where appropriate. (a) (b) (c) CH 3 CH 2 CHCH 2 Br OH NaOH CH 3 CH 2 I H11001 C ONa CH 3 CH 3 CH 2 H Br H11001 CH 3 CH 2 CHCH 3 ONa OH O O 1,3-Dioxan-5-ol O O H 3 C H 3 C CH 2 CH 2 CH 3 O O CHCH 2 CH 2 CH 3 O H 2 C 2 CH 3 CH 34 5 61 648 CHAPTER SIXTEEN Ethers, Epoxides, and Sulfides Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website (d) (e) (f) (g) (h) (i) (j) 16.27 Oxidation of 4-tert-butylthiane (see Problem 16.23 for the structure of thiane) with sodium metaperiodate gives a mixture of two compounds of molecular formula C 9 H 18 OS. Both products give the same sulfone on further oxidation with hydrogen peroxide. What is the relationship between the two compounds? 16.28 When (R)-(H11001)-2-phenyl-2-butanol is allowed to stand in methanol containing a few drops of sulfuric acid, racemic 2-methoxy-2-phenylbutane is formed. Suggest a reasonable mechanism for this reaction. 16.29 Select reaction conditions that would allow you to carry out each of the following stereo- specific transformations: (a) (b) 16.30 The last step in the synthesis of divinyl ether (used as an anesthetic under the name Vinethene) involves heating ClCH 2 CH 2 OCH 2 CH 2 Cl with potassium hydroxide. Show how you could prepare the necessary starting material ClCH 2 CH 2 OCH 2 CH 2 Cl from ethylene. O H CH 3 (S)-1,2-propanediol O H CH 3 (R)-1,2-propanediol C 6 H 5 SNa C 6 H 5 CH 3 H H C 6 H 5 Cl CH 3 (CH 2 ) 16 CH 2 OTs H11001 CH 3 CH 2 CH 2 CH 2 SNa HCl CHCl 3 CH O CH 2 CH 3 OH CH 2 C 6 H 5 O H11001 CH 3 ONa NH 3 methanol OH 3 C Br NaN 3 dioxane–water O HH CH 3 CC H11001 COOH O Problems 649 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website 16.31 Suggest short, efficient reaction sequences suitable for preparing each of the following com- pounds from the given starting materials and any necessary organic or inorganic reagents: (a) (b) from bromobenzene and cyclohexanol (c) from bromobenzene and isopropyl alcohol (d) C 6 H 5 CH 2 CH 2 CH 2 OCH 2 CH 3 from benzyl alcohol and ethanol (e) from 1,3-cyclohexadiene and ethanol (f) from styrene and ethanol 16.32 Among the ways in which 1,4-dioxane may be prepared are the methods expressed in the equations shown: (a) (b) Suggest reasonable mechanisms for each of these reactions. 16.33 Deduce the identity of the missing compounds in the following reaction sequences. Show stereochemistry in parts (b) through (d). (a) (b) Compound E (C 3 H 7 ClO) Compound F (C 3 H 6 O) 1. LiAlH 4 2. H 2 O KOH, H 2 O Cl H CH 3 CO 2 H CH 2 CHCH 2 Br 1. Mg 2. CH 2 ?O 3. H 3 O H11001 Compound A (C 4 H 8 O) Compound B (C 4 H 8 Br 2 O) Br 2 Compound C (C 4 H 7 BrO) KOH heat KOH, 25°C O Compound D ClCH 2 CH 2 OCH 2 CH 2 Cl Bis(2-chloroethyl) ether O O 1,4-Dioxane NaOH H110012HOCH 2 CH 2 OH Ethylene glycol 2H 2 O Water O O 1,4-Dioxane H 2 SO 4 heat C 6 H 5 CHCH 2 SCH 2 CH 3 OH O C 6 H 5 CH 2 CHCH 3 OH O C 6 H 5 CH 2 OCH 3 from O COCH 3 650 CHAPTER SIXTEEN Ethers, Epoxides, and Sulfides Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website (c) (d) 16.34 Cineole is the chief component of eucalyptus oil; it has the molecular formula C 10 H 18 O and contains no double or triple bonds. It reacts with hydrochloric acid to give the dichloride shown: Deduce the structure of cineole. 16.35 The p-toluenesulfonate shown undergoes an intramolecular Williamson reaction on treat- ment with base to give a spirocyclic ether. Demonstrate your understanding of the terminology used in the preceding sentence by writing the structure, including stereochemistry, of the product. 16.36 All the following questions pertain to 1 H NMR spectra of isomeric ethers having the molecular formula C 5 H 12 O. (a) Which one has only singlets in its 1 H NMR spectrum? (b) Along with other signals, this ether has a coupled doublet–septet pattern. None of the protons responsible for this pattern are coupled to protons anywhere else in the mole- cule. Identify this ether. (c) In addition to other signals in its 1 H NMR spectrum, this ether exhibits two signals at relatively low field. One is a singlet; the other is a doublet. What is the structure of this ether? (d) In addition to other signals in its 1 H NMR spectrum, this ether exhibits two signals at relatively low field. One is a triplet; the other is a quartet. Which ether is this? 16.37 The 1 H NMR spectrum of compound A (C 8 H 8 O) consists of two singlets of equal area at H9254 5.1 (sharp) and 7.2 ppm (broad). On treatment with excess hydrogen bromide, compound A is converted to a single dibromide (C 8 H 8 Br 2 ). The 1 H NMR spectrum of the dibromide is similar to that of A in that it exhibits two singlets of equal area at H9254 4.7 (sharp) and 7.3 ppm (broad). Sug- gest reasonable structures for compound A and the dibromide derived from it. base OH CH 2 CH 2 CH 2 OTs C 6 H 5 C 15 H 20 O Cineole HCl C Cl CH 3 CH 3 CH 3 Cl Compound I (C 7 H 12 ) OsO 4 , (CH 3 ) 3 COOH (CH 3 ) 3 COH, HO H11002 H 2 O H 2 SO 4 Compound J (C 7 H 14 O 2 ) (a liquid) Compound L (C 7 H 14 O 2 ) (mp 99.5–101°C) C 6 H 5 CO 2 OH Compound K CH 3 O CH 3 Compound G (C 4 H 8 O) Compound H (C 5 H 12 OS) NaOH NaSCH 3 H Cl CH 3 CH 3 OHH Problems 651 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website 652 CHAPTER SIXTEEN Ethers, Epoxides, and Sulfides 0.01.02.03.04.0 Chemical shift (δ, ppm) 6.07.08.09.010.0 5.0 3.6 3.53.73.8 2.22.4 5 2 22 2 110120130140150 Chemical shift (δ, ppm) 170180190200210 160 50607080 1020304090100 C 9 H 10 O C C CH CH 2 CH 2 CH 2 FIGURE 16.10 The 200-MHz 1 H NMR spectrum of a compound, C 10 H 13 BrO (Problem 16.38). The integral ratios of the signals reading from left to right (low to high field) are 5:2:2:2:2. The sig- nals centered at 3.6 and 3.7 ppm are two overlapping triplets. FIGURE 16.11 The 13 C NMR spectrum of a compound, C 9 H 10 O (Problem 16.39). Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website 16.38 The 1 H NMR spectrum of a compound (C 10 H 13 BrO) is shown in Figure 16.10. The com- pound gives benzyl bromide, along with a second compound C 3 H 6 Br 2 , when heated with HBr. What is the first compound? 16.39 A compound is a cyclic ether of molecular formula C 9 H 10 O. Its 13 C NMR spectrum is shown in Figure 16.11. Oxidation of the compound with sodium dichromate and sulfuric acid gave 1,2- benzenedicarboxylic acid. What is the compound? 16.40 Make a molecular model of dimethyl sulfide. How does its bond angle at sulfur compare with the C±O±C bond angle in dimethyl ether? 16.41 View molecular models of dimethyl ether and ethylene oxide on Learning By Modeling. Which one has the greater dipole moment? Do the calculated dipole moments bear any relation- ship to the observed boiling points (ethylene oxide: H1100110°C; dimethyl ether: H1100225°C)? 16.42 Find the molecular model of 18-crown-6 (Figure 16.2) on Learning By Modeling, and exam- ine its electrostatic potential surface. View the surface in various modes (dots, contours, and as a transparent surface). Does 18-crown-6 have a dipole moment? Are vicinal oxygens anti or gauche to one another? 16.43 Find the model of dimethyl sulfoxide [(CH 3 ) 2 S?O] on Learning By Modeling, and exam- ine its electrostatic potential surface. To which atom (S or O) would you expect a proton to bond? 16.44 Construct a molecular model of trans-2-bromocyclohexanol in its most stable conformation. This conformation is ill-suited to undergo epoxide formation on treatment with base. Why? What must happen in order to produce 1,2-epoxycyclohexane from trans-2-bromocyclohexanol? 16.45 Construct a molecular model of threo-3-bromo-2-butanol. What is the stereochemistry (cis or trans) of the 2,3-epoxybutane formed on treatment of threo-3-bromo-2-butanol with base? Repeat the exercise for erythro-3-bromo-2-butanol. Problems 653 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website