Chapter 16 Ethers, Epoxides, and Sulfides Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. 2

16.1 Nomenclature of Ethers, Epoxides, and Sulfides 2

Substitutive IUPAC Names of Ethers Name as alkoxy derivatives of alkanes. CH3OCH2 CH3 CH3CH2OCH2CH2CH2Cl methoxyethane 1-chloro-3-ethoxypropane CH3CH2OCH2 CH3 ethoxyethane 3

Functional Class IUPAC Names of Ethers Name as "ethers" , listing the groups attached to oxygen as substituents, in alphabetical order. CH3OCH2 CH3 CH3CH2OCH2CH2CH2Cl ethyl methyl ether 3-chloropropyl ethyl ether CH3CH2OCH2 CH3 diethyl ether 3

Substitutive IUPAC Names of Sulfides Name as alkylthio derivatives of alkanes. CH3SCH2CH3 SCH3 methylthioethane (methylthio)cyclopentane CH3CH2SCH2CH3 ethylthioethane 3

Functional Class IUPAC Names of Sulfides Name as "sulfides" in a manner analogous to that when using "ether" as the parent. CH3SCH2CH3 SCH3 ethyl methyl sulfide cyclopentyl methyl sulfide CH3CH2SCH2CH3 diethyl sulfide 3

Oxirane (Ethylene oxide) Oxetane Oxolane (tetrahydrofuran) Names of Cyclic Ethers O O O Oxirane (Ethylene oxide) Oxetane Oxolane (tetrahydrofuran) Oxane (tetrahydropyran) 1,4-Dioxane O O O 3

Names of Cyclic Sulfides Thiirane Thietane S S Thiolane Thiane 3

16.2 Structure and Bonding in Ethers and Epoxides Bent geometry at oxygen analogous to water and alcohols 8

Bond angles at oxygen are sensitive to steric effects H H CH3 H 112° 105° 108.5° 132° O (CH3)3C O C(CH3)3 CH3 CH3 9

An oxygen atom affects geometry in much the same way as a CH2 group Most stable conformation of diethyl ether resembles that of pentane. 10

An oxygen atom affects geometry in much the same way as a CH2 group Most stable conformation of tetrahydropyran resembles that of cyclohexane. 10

16.3 Physical Properties of Ethers 11

solubility in water (g/100 mL) Table 16.1 Ethers resemble alcohols more than alkanes with respect to solubility in water solubility in water (g/100 mL) very small 7.5 Hydrogen bonding to water possible for ethers and alcohols; not possible for alkanes. O 9 OH 12

Table 16.1 Ethers resemble alkanes more than alcohols with respect to boiling point Intermolecular hydrogen bonding possible in alcohols; not possible in alkanes or ethers. 36°C 35°C O 117°C OH 12

16.4 Crown Ethers 11

Properties: They form stable complexes with metal ions. Crown Ethers Structure: These are cyclic polyethers derived from repeating —OCH2CH2— units. Properties: They form stable complexes with metal ions. Applications: They participate in synthetic reactions involving anions. 14

= the number of atoms in the ring. 6 = the number of oxygens. 18-Crown-6 = the number of atoms in the ring. 6 = the number of oxygens. O A region of negative charge is concentrated in the cavity inside the molecule. 15

18-Crown-6 O K+ This negative region forms a stable Lewis acid/Lewis base complex with K+. 15

Ion-Complexing and Solubility K+F– alone is not soluble in benzene. But when 18-crown-6 is added: O O F– K+ benzene The 18-crown-6 complex of K+ dissolves in benzene. 16

Ion-Complexing and Solubility K+ benzene + F– F– is carried into benzene to preserve electroneutrality. 16

Application to organic synthesis Complexation of K+ by 18-crown-6 solubilizes potassium salts in benzene. The anion of the salt is in a relatively unsolvated state in benzene (sometimes referred to as a "naked anion"). The unsolvated anion is very reactive. Only catalytic quantities of 18-crown-6 are needed. 20

Example KF CH3(CH2)6CH2Br CH3(CH2)6CH2F 18-crown-6 benzene (92%) 20

16.5 Preparation of Ethers 1. Acid catalyzed condensation of alcohols. 2. Williamson ether synthesis. 11

Acid-Catalyzed Condensation of Alcohols* 2 CH3CH2CH2CH2OH H2SO4, 130°C CH3CH2CH2CH2OCH2CH2CH2CH3 (60%) *Best for symmetrical ethers, discussed earlier in Section 15.7. 10

Addition of Alcohols to Alkenes (CH3)2C=CH2 + CH3OH (CH3)3COCH3 tert-Butyl methyl ether This is a commercial method of preparation. tert-Butyl methyl ether (MTBE) was produced on a scale exceeding 15 billion pounds per year in the U.S. during the 1990s. It is an effective octane booster in gasoline, but contaminates ground water if allowed to leak from storage tanks. Further use of MTBE is unlikely. 23

16.6 The Williamson Ether Synthesis Think SN2! primary alkyl halide + alkoxide nucleophile 11

Good for preparing unsymmetrical ethers. Example CH3CH2CH2CH2ONa + CH3CH2I Alkyl halide (1o or Me), SN2 substrate Alkoxide, Nucleophile CH3CH2CH2CH2OCH2CH3 + NaI (71%) Good for preparing unsymmetrical ethers. 25

Another Example + CH3CHCH3 ONa CH2Cl (84%) CH2OCHCH3 CH3 Alkyl halide must be primary or methyl Alkoxide ion can be derived from a methyl, primary, secondary, or tertiary alcohol. + CH3CHCH3 ONa CH2Cl (84%) CH2OCHCH3 CH3 26

Origin of Reactants CH3CHCH3 OH Nao CH2OH SOCl2 CH2OCHCH3 CH3 CH2Cl + ONa (84%) 26

What happens if the alkyl halide is not primary ? CH2ONa + CH3CHCH3 Br CH2OH + H2C CHCH3 Elimination by the E2 mechanism becomes the major reaction pathway. 27

16.7 Reactions of Ethers: A Review and a Preview 11

Summary of reactions of ethers No reactions of ethers except epoxides have been encountered to this point. Most ethers are relatively unreactive. Their low level of reactivity is one reason why ethers are often used as solvents in chemical reactions. Ethers oxidize in air to form explosive hydroperoxides and peroxides. 27

16.8 Acid Catalyzed Cleavage of Ethers 11

Cleavage of ethers works well with HBr or HI. Initial cleavage is at the least hindered carbon, see mechanism. Example Forms CH3Br first. CH3CHCH2CH3 HBr CH3CHCH2CH3 + CH3Br heat OCH3 Br (81%) 31

Mechanism CH3 CH3CHCH2CH3 O CH3CHCH2CH3 Br CH3 CH3CHCH2CH3 O H + H Br • • •• CH3CHCH2CH3 Br CH3 CH3CHCH2CH3 O H + •• •• H Br • • HBr (repeat) •• • • CH3 Br CH3CHCH2CH3 O H •• Br – • • 31

Cleavage of Cyclic Ethers HI ICH2CH2CH2CH2I •• 150°C •• HI H O •• + • • I – HI (repeat) Mechanism H O •• • • I 32

16.9 Preparation of Epoxides: A Review and a Preview 11

Preparation of Epoxides Epoxides are prepared by two major methods. Both begin with alkenes. 1. Reaction of alkenes with peroxy acids like m-chloroperoxybenzoic acid, (Section 6.19). 2. Conversion of alkenes to vicinal halohydrins, followed by treatment with base, (Section 16.10). 30

16.10 Conversion of Vicinal Halohyhdrins to Epoxides 11

Example H H OH NaOH O H2O Br H A bromohydrin (81%) – O via: H Br • • •• – via: 5

Epoxidation via Vicinal Halohydrins Br Br2 NaOH O H2O OH anti addition inversion Corresponds to overall syn addition of oxygen to the double bond. 3

Epoxidation via Vicinal Halohydrins Br H3C Br2 H H3C CH3 H NaOH H H3C CH3 H2O H O CH3 OH anti addition inversion Corresponds to overall syn addition of oxygen to the double bond. 3

16.11 Reactions of Epoxides: A Review and a Preview

In General... Reactions of epoxides involve attack by a nucleophile and proceed with ring-opening. For ethylene oxide: H2C CH2 O Nu—H + Nu—CH2CH2O—H 10

In General... For epoxides where the two carbons of the ring are differently substituted: Nucleophiles attack here when the reaction is catalyzed by acids. Anionic nucleophiles attack here (least substituted position). CH2 O C R H 10

Reactions of Epoxides All reactions involve nucleophilic attack at carbon and lead to opening of the ring. An example is the reaction of ethylene oxide with a Grignard or organolithium reagent (discussed in Section 15.4 as a method for the synthesis of alcohols). 7

Reaction of Grignard Reagents with Epoxides MgX CH2 OMgX R H2C CH2 O H3O+ RCH2CH2OH 9

Example CH2 CH2MgCl H2C + O 1. diethyl ether 2. H3O+ CH2CH2CH2OH (71%) 29

16.12 Nucleophilic Ring-Opening Reactions of Epoxides 11

Epoxide Ring Opening O H2C CH2 Example NaOCH2CH3 CH3CH2OH CH3CH2O (50%) 11

Mechanism CH3CH2 O – – CH3CH2 O CH2CH2 O H2C CH2 O CH2CH3 H CH3CH2 O •• • • – – •• CH3CH2 O • • CH2CH2 O H2C CH2 •• O CH2CH3 • • •• H •• CH3CH2 O CH2CH2 H • • CH2CH3 – 12

Example O H2C CH2 KSCH2CH2CH2CH3 ethanol-water, 0°C (99%) CH2CH2OH CH3CH2CH2CH2S 11

Inversion of configuration at carbon being attacked by nucleophile. Stereochemistry OCH2CH3 O H NaOCH2CH3 CH3CH2OH H H OH (67%) Inversion of configuration at carbon being attacked by nucleophile. Suggests SN2-like transition state. 11

Inversion of configuration at carbon being attacked by nucleophile. Stereochemistry CH3 H3C R R H NH3 H OH H2N H O H2O R S H H3C CH3 (70%) Inversion of configuration at carbon being attacked by nucleophile. Suggests SN2-like transition state. 18

An SN2-like transition state. Stereochemistry An SN2-like transition state. H3C CH3 R H R NH3 H2O H OH O H2N H R S H H3C CH3 (70%) H3C H via: - + H H2N O H H3C 18

Anionic Nucleophile Attacks Less-crowded Carbon CH3CH CCH3 CH3 OH CH3O C H H3C CH3 O NaOCH3 CH3OH (53%) An unsymmetrical epoxide. 19

Anionic Nucleophile Attacks Less-crowded Carbon MgBr + O H2C CHCH3 1. diethyl ether 2. H3O+ CH2CHCH3 OH (60%) 15

Lithium Aluminum Hydride Reduces Epoxides H2C CH(CH2)7CH3 Hydride attacks less-crowded carbon. 1. LiAlH4, diethyl ether 2. H2O (90%) OH H3C CH(CH2)7CH3 16

16.13 Acid Catalyzed Ring-Opening Reactions of Epoxides 11

Example O H2C CH2 CH3CH2OH CH3CH2OCH2CH2OH H2SO4, 25°C (87-92%) CH3CH2OCH2CH2OCH2CH3 formed only on heating and/or longer reaction times. The first step is easy due to the strained three membered ring. 11

BrCH2CH2Br formed only on heating and/or longer reaction times. Example O H2C CH2 HBr BrCH2CH2OH 10°C (87-92%) BrCH2CH2Br formed only on heating and/or longer reaction times. 11

Mechanism Br – H2C CH2 O H2C CH2 + • • O H Br H O Br CH2CH2 H O H2C •• • • – H2C CH2 O H2C CH2 + • • O •• • • H Br •• • • H • • •• O Br CH2CH2 H O H2C CH2 •• 12

Acid-Catalyzed Hydrolysis of Ethylene Oxide Step 1 H2C CH2 • • O H2C CH2 + H Protonateoxygen O O • • H + • • •• •• • • H Step 2 + • • •• O CH2CH2 H Nucleophileattacks ring O • • O H2C CH2 + H 12

Acid-Catalyzed Hydrolysis of Ethylene Oxide •• O • • H + CH2CH2 Step 3 Deprotonate O •• • • H + • • •• O CH2CH2 H •• 12

Acid-Catalyzed Ring Opening of Epoxides Characteristics: Nucleophile attacks more substituted carbon of protonated epoxide. The more substituted carbon of the epoxide ring tolerates positive charge better. Inversion of configuration at site of nucleophilic attack. 30

Inversion of configuration at carbon being attacked by nucleophile. Stereochemistry Inversion of configuration at carbon being attacked by nucleophile. H3C CH3 R H R CH3OH H2SO4 H OH O CH3O H R S H H3C CH3 (57%) H3C H via: + + + O H CH3O H H H3C 18

Nucleophile Attacks More-substituted Carbon CH3CH CCH3 CH3 OH OCH3 (76%) C H H3C CH3 O CH3OH H2SO4 Consistent with carbocation character at transition state. 19

Inversion of configuration at carbon being attacked by nucleophile. Stereochemistry H O H OH HBr H Br (73%) Inversion of configuration at carbon being attacked by nucleophile. 11

anti-Hydroxylation of Alkenes CH3COOH O H Goes through the epoxide. H2O HClO4 (80%) H OH Note: Dil. KMnO4 and OsO4 give syn diols. + enantiomer 35

16.15 Preparation of Sulfides 11

Prepared by nucleophilic substitution (SN2). Preparation of RSR' Prepared by nucleophilic substitution (SN2). – •• • • •• R S R' R S + R' X CH3CHCH CH2 Cl NaSCH3 methanol SCH3 allylic carbon

16.16 Oxidation of Sulfides: Sulfoxides and Sulfones 11

Oxidation of RSR' R S R' O – ++ sulfone + R S R' O – R S R' sulfide •• R S R' • • O – ++ sulfone + •• R S R' O • • – •• R S R' sulfide sulfoxide Either the sulfoxide or the sulfone can be isolated depending on the oxidizing agent and reaction conditions.

Example + SCH3 O – SCH3 NaIO4 water (91%) •• • • •• Sodium metaperiodate oxidizes sulfides to sulfoxides and no further.

Example SCH CH2 SCH O – ++ CH2 H2O2 (2 equiv) (74-78%) •• •• • • 1 equiv of H2O2 or a peroxy acid gives a sulfoxide, 2 equiv give a sulfone. •• SCH CH2 SCH O • • •• – ++ CH2 H2O2 (2 equiv) (74-78%)

16.17 Alkylation of Sulfides: Sulfonium Salts 11

Sulfides Can Act as Nucleophiles + •• •• R S + R" X R S R" X– • • R' R' Product is a sulfonium salt. Example CH3I + CH3(CH2)10CH2SCH3 CH3(CH2)10CH2SCH3 I– CH3

16.18 Spectroscsopic Analysis of Ethers, Epoxides and Sulfides 11

Figure 16.4 Infrared Spectrum of Dipropyl Ether C—O stretching of ethers: 1070 and 1150 cm-1 (strong) Francis A. Carey, Organic Chemistry, Fifth Edition. Copyright © 2003 The McGraw-Hill Companies, Inc. All rights reserved. 8

Infrared Spectroscopy Epoxides exhibit bands for C—O stretching at: 810-950 cm-1 (asymmetric stretch) and 1250 cm-1 (symmetric stretch). There is also a third band in the range 750-840 cm-1. C O H CH2(CH2)8CH3 n = 837, 917, and 1265 cm-1 6

Infrared Spectroscopy Sulfoxides exhibit strong S—O absorption in the range 1030-1070 cm-1. Sulfones have two S—O absorptions: 1120-1160 cm-1 (symmetric stretch) and 1290-1350 cm-1 (asymmetric stretch). ++ S O • • •• – H3C CH3 O •• + S • • – H3C CH3 n = 1050 cm-1 n = 1139 and 1298 cm-1 6

H—C—O proton is deshielded by O; range is ca.  3.3-4.0 ppm. 1H NMR H—C—O proton is deshielded by O; range is ca.  3.3-4.0 ppm. CH3 CH2 CH2 OCH2 CH2 CH3  0.8 ppm  1.4 ppm  3.2 ppm 6

Fig. 16.4 (b) 1H NMR 1

H—C—S proton is less deshielded than H—C—O. 1H NMR H—C—S proton is less deshielded than H—C—O. CH3 CH2 CH2 S CH2 CH2 CH3  2.5 ppm Oxidation of sulfides to sulfoxide deshields an adjacent C—H proton by 0.3-0.5 ppm. An additional 0.3-0.5 ppm downfield shift occurs on oxidation of the sulfoxide to the sulfone. 6

13C NMR Carbons of C—O—C appear in the range  57-87 ppm. But the ring carbons of epoxides are somewhat more shielded. C O H CH2(CH2)2CH3 d 47 d 52 d 68 d 26 O

Fig. 16.4 (c) 13C NMR

UV-VIS Simple ethers have their absorption maximum at about 185 nm and are transparent to ultraviolet radiation above about 220 nm.

Mass Spectrometry The molecular ion fragments to give an oxygen-stabilized carbocation. •+ CH3CH2O CHCH2CH3 m/z 102 •• CH3 CH3CH2O + CH CH3 CHCH2CH3 m/z 87 m/z 73 ••

End of Chapter 16 Ethers, Epoxides, and Sulfides 11