Chapter 16 Ethers, Epoxides, and Sulfides Dr. Wolf's CHM 201 & 202 16-1 2

Nomenclature of Ethers, Epoxides, and Sulfides Dr. Wolf's CHM 201 & 202 16-2 2

Substitutive IUPAC Names of Ethers name as alkoxy derivatives of alkanes CH3OCH2 CH3 methoxyethane CH3CH2OCH2CH2CH2Cl 1-chloro-3-ethoxypropane CH3CH2OCH2 CH3 ethoxyethane Dr. Wolf's CHM 201 & 202 16-3 3

Functional Class IUPAC Names of Ethers name the groups attached to oxygen in alphabetical order as separate words; "ether" is last word CH3OCH2 CH3 ethyl methyl ether CH3CH2OCH2CH2CH2Cl 3-chloropropyl ethyl ether CH3CH2OCH2 CH3 diethyl ether Dr. Wolf's CHM 201 & 202 16-4 3

Substitutive IUPAC Names of Sulfides name as alkylthio derivatives of alkanes CH3SCH2 CH3 methylthioethane SCH3 (methylthio)cyclopentane CH3CH2SCH2 CH3 ethylthioethane Dr. Wolf's CHM 201 & 202 16-5 3

Functional Class IUPAC Names of Sulfides analogous to ethers, but replace “ether” as last word in the name by “sulfide.” CH3SCH2 CH3 ethyl methyl sulfide SCH3 cyclopentyl methyl sulfide CH3CH2SCH2 CH3 diethyl sulfide Dr. Wolf's CHM 201 & 202 16-6 3

Oxirane (Ethylene oxide) Oxetane Oxolane (tetrahydrofuran) Names of Cyclic Ethers O O O Oxirane (Ethylene oxide) Oxetane Oxolane (tetrahydrofuran) O O O Oxane (tetrahydropyran) 1,4-Dioxane Dr. Wolf's CHM 201 & 202 16-7 3

Names of Cyclic Sulfides Thiirane Thietane Thiolane S Thiane Dr. Wolf's CHM 201 & 202 16-8 3

Structure and Bonding in Ethers and Epoxides bent geometry at oxygen analogous to water and alcohols, i.e. sp3 hybidization Dr. Wolf's CHM 201 & 202 16-9 8

Bond angles at oxygen are sensitive to steric effects H H CH3 H 105° 108.5° O (CH3)3C O C(CH3)3 CH3 CH3 112° 132° Dr. Wolf's CHM 201 & 202 16-10 9

An oxygen atom affects geometry in much the same way as a CH2 group most stable conformation of diethyl ether resembles pentane Dr. Wolf's CHM 201 & 202 16-11 10

An oxygen atom affects geometry in much the same way as a CH2 group most stable conformation of tetrahydropyran resembles cyclohexane Dr. Wolf's CHM 201 & 202 16-12 10

Physical Properties of Ethers Dr. Wolf's CHM 201 & 202 16-13 11

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 Dr. Wolf's CHM 201 & 202 16-14 12

solubility in water (g/100 mL) 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 Dr. Wolf's CHM 201 & 202 16-15 12

Crown Ethers Dr. Wolf's CHM 201 & 202 16-16 13

structure cyclic polyethers derived from repeating —OCH2CH2— units Crown Ethers structure cyclic polyethers derived from repeating —OCH2CH2— units properties form stable complexes with metal ions applications synthetic reactions involving anions Dr. Wolf's CHM 201 & 202 16-17 14

negative charge concentrated in cavity inside the molecule 18-Crown-6 O negative charge concentrated in cavity inside the molecule Dr. Wolf's CHM 201 & 202 16-18 15

negative charge concentrated in cavity inside the molecule 18-Crown-6 O negative charge concentrated in cavity inside the molecule Dr. Wolf's CHM 201 & 202 16-19 15

forms stable Lewis acid/Lewis base complex with K+ 18-Crown-6 O K+ forms stable Lewis acid/Lewis base complex with K+ Dr. Wolf's CHM 201 & 202 16-20 15

forms stable Lewis acid/Lewis base complex with K+ 18-Crown-6 O K+ forms stable Lewis acid/Lewis base complex with K+ Dr. Wolf's CHM 201 & 202 16-21 15

Ion-Complexing and Solubility K+F– not soluble in benzene Dr. Wolf's CHM 201 & 202 16-22 16

Ion-Complexing and Solubility K+F– benzene add 18-crown-6 Dr. Wolf's CHM 201 & 202 16-23 16

Ion-Complexing and Solubility F– K+ benzene 18-crown-6 complex of K+ dissolves in benzene Dr. Wolf's CHM 201 & 202 16-24 16

Ion-Complexing and Solubility K+ benzene F– carried into benzene to preserve electroneutrality + F– Dr. Wolf's CHM 201 & 202 16-25 16

Application to organic synthesis Complexaton of K+ by 18-crown-6 "solubilizes" salt in benzene Anion of salt is in a relatively unsolvated state in benzene (sometimes referred to as a "naked anion") Unsolvated anion is very reactive Only catalytic quantities of 18-crown-6 are needed Dr. Wolf's CHM 201 & 202 16-26 20

Example KF CH3(CH2)6CH2Br CH3(CH2)6CH2F 18-crown-6 benzene (92%) 16-27 Dr. Wolf's CHM 201 & 202 16-27 20

Preparation of Ethers Dr. Wolf's CHM 201 & 202 16-28 21

Acid-Catalyzed Condensation of Alcohols* 2CH3CH2CH2CH2OH H2SO4, 130°C CH3CH2CH2CH2OCH2CH2CH2CH3 (60%) *Discussed earlier in Section 15.7 Dr. Wolf's CHM 201 & 202 16-29 10

Addition of Alcohols to Alkenes (CH3)2C=CH2 + CH3OH (CH3)3COCH3 tert-Butyl methyl ether Dr. Wolf's CHM 201 & 202 16-30 23

The Williamson Ether Synthesis Think SN2! primary alkyl halide + alkoxide nucleophile Dr. Wolf's CHM 201 & 202 16-31 24

Example CH3CH2CH2CH2ONa + CH3CH2I CH3CH2CH2CH2OCH2CH3 + NaI (71%) Dr. Wolf's CHM 201 & 202 16-32 25

Another Example CH2Cl + CH3CHCH3 ONa CH2OCHCH3 CH3 (84%) 16-33 26 Dr. Wolf's CHM 201 & 202 16-33 26

Alkyl halide must be primary Another Example Alkoxide ion can be derived from primary, secondary, or tertiary alcohol Alkyl halide must be primary CH2Cl + CH3CHCH3 ONa CH2OCHCH3 CH3 (84%) Dr. Wolf's CHM 201 & 202 16-34 26

Origin of Reactants CH3CHCH3 CH2OH OH HCl Na CH2Cl + CH3CHCH3 ONa CH2OCHCH3 (84%) CH3 Dr. Wolf's CHM 201 & 202 16-35 26

What happens if the alkyl halide is not primary? CH2ONa + CH3CHCH3 Br Dr. Wolf's CHM 201 & 202 16-36 27

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. Dr. Wolf's CHM 201 & 202 16-37 27

Reactions of Ethers: A Review and a Preview Dr. Wolf's CHM 201 & 202 16-38 28

Summary of reactions of ethers No reactions of ethers encountered to this point. 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. Dr. Wolf's CHM 201 & 202 16-39 27

Acid-Catalyzed Cleavage of Ethers Dr. Wolf's CHM 201 & 202 16-40 29

Example CH3CHCH2CH3 HBr CH3CHCH2CH3 + CH3Br heat OCH3 Br (81%) 16-41 Dr. Wolf's CHM 201 & 202 16-41 31

Mechanism CH3CHCH2CH3 O CH3 H Br CH3CHCH2CH3 O CH3 H + • • •• •• • • Dr. Wolf's CHM 201 & 202 16-42 31

Mechanism CH3CHCH2CH3 O CH3 H Br CH3CHCH2CH3 O H CH3CHCH2CH3 O CH3 H + • • •• CH3 H Br • • •• CH3CHCH2CH3 O H • • •• CH3CHCH2CH3 O CH3 H + •• Br – •• • • • • •• CH3 Br •• Dr. Wolf's CHM 201 & 202 16-43 31

Mechanism CH3CHCH2CH3 O CH3CHCH2CH3 Br CH3 H Br HBr CH3CHCH2CH3 O H • • •• CH3CHCH2CH3 Br CH3 H Br • • •• HBr CH3CHCH2CH3 O H • • •• CH3CHCH2CH3 O CH3 H + •• Br – •• • • • • •• CH3 Br •• Dr. Wolf's CHM 201 & 202 16-44 31

Cleavage of Cyclic Ethers HI ICH2CH2CH2CH2I 150°C (65%) Dr. Wolf's CHM 201 & 202 16-45 32

Mechanism ICH2CH2CH2CH2I O HI + O H •• •• •• 16-46 32 Dr. Wolf's CHM 201 & 202 16-46 32

Mechanism ICH2CH2CH2CH2I O HI – I I + O O H H •• •• •• •• • • •• •• Dr. Wolf's CHM 201 & 202 16-47 32

Mechanism O ICH2CH2CH2CH2I HI HI I – H O + I O H •• •• •• •• • • •• •• Dr. Wolf's CHM 201 & 202 16-48 32

Preparation of Epoxides: A Review and a Preview Dr. Wolf's CHM 201 & 202 16-49 1

Preparation of Epoxides Epoxides are prepared by two major methods. Both begin with alkenes. reaction of alkenes with peroxy acids (Section 6.19) conversion of alkenes to vicinal halohydrins, followed by treatment with base (Section 16.10) Dr. Wolf's CHM 201 & 202 16-50 30

Conversion of Vicinal Halohydrins to Epoxides Dr. Wolf's CHM 201 & 202 16-51 2

Example H OH Br H NaOH O H2O H (81%) Dr. Wolf's CHM 201 & 202 16-52 5

Example H H OH NaOH O H2O Br H (81%) – O via: H H Br •• • • • • • • Dr. Wolf's CHM 201 & 202 16-53 5

Epoxidation via Vicinal Halohydrins Br Br2 H2O OH anti addition Dr. Wolf's CHM 201 & 202 16-54 3

Epoxidation via Vicinal Halohydrins Br Br2 NaOH H2O O OH anti addition inversion corresponds to overall syn addition of oxygen to the double bond Dr. Wolf's CHM 201 & 202 16-55 3

Epoxidation via Vicinal Halohydrins Br H3C Br2 H NaOH H3C H CH3 H H2O H O CH3 OH anti addition inversion corresponds to overall syn addition of oxygen to the double bond Dr. Wolf's CHM 201 & 202 16-56 3

Epoxidation via Vicinal Halohydrins Br H3C Br2 H3C H H NaOH H3C H H CH3 CH3 H H2O H O CH3 OH anti addition inversion corresponds to overall syn addition of oxygen to the double bond Dr. Wolf's CHM 201 & 202 16-57 3

Reactions of Epoxides: A Review and a Preview Dr. Wolf's CHM 201 & 202 16-58 6

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 reagent (discussed in Section 15.4 as a method for the synthesis of alcohols). Dr. Wolf's CHM 201 & 202 16-59 7

Reaction of Grignard Reagents with Epoxides MgX R H2C CH2 O CH2 CH2 OMgX H3O+ RCH2CH2OH Dr. Wolf's CHM 201 & 202 16-60 9

Example CH2 CH2MgCl H2C + O 1. diethyl ether 2. H3O+ CH2CH2CH2OH (71%) Dr. Wolf's CHM 201 & 202 16-61 29

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 Dr. Wolf's CHM 201 & 202 16-62 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: CH2 O C R H Dr. Wolf's CHM 201 & 202 16-63 10

Nucleophilic Ring-Opening Reactions of Epoxides Dr. Wolf's CHM 201 & 202 16-64 9

Example O H2C CH2 NaOCH2CH3 CH3CH2OH CH3CH2O CH2CH2OH (50%) 16-65 11 Dr. Wolf's CHM 201 & 202 16-65 11

Mechanism CH3CH2 O – O H2C CH2 • • •• • • •• 16-66 12 Dr. Wolf's CHM 201 & 202 16-66 12

Mechanism CH3CH2 O – O H2C CH2 – CH3CH2 O CH2CH2 • • •• • • •• •• • • Dr. Wolf's CHM 201 & 202 16-67 12

Mechanism CH3CH2 O – O H2C CH2 O CH2CH3 H – CH3CH2 O CH2CH2 • • •• • • Dr. Wolf's CHM 201 & 202 16-68 12

Mechanism CH3CH2 O – O H2C CH2 O CH2CH3 H – CH3CH2 O CH2CH2 O CH2CH3 – •• • • – O H2C CH2 • • •• O CH2CH3 • • H •• – CH3CH2 O •• CH2CH2 •• •• •• •• O CH2CH3 • • – •• •• CH3CH2 O CH2CH2 O H •• •• •• Dr. Wolf's CHM 201 & 202 16-69 12

Example O H2C CH2 KSCH2CH2CH2CH3 ethanol-water, 0°C CH2CH2OH CH3CH2CH2CH2S (99%) Dr. Wolf's CHM 201 & 202 16-70 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 Dr. Wolf's CHM 201 & 202 16-71 11

(70%) Stereochemistry H3C CH3 H NH3 H OH O H2N H H2O H H3C CH3 Inversion of configuration at carbon being attacked by nucleophile Suggests SN2-like transition state Dr. Wolf's CHM 201 & 202 16-72 18

(70%) d- Stereochemistry H3C CH3 H NH3 H OH O H2N H H2O H H3C CH3 H3C Dr. Wolf's CHM 201 & 202 16-73 18

Anionic nucleophile attacks less-crowded carbon CH3CH CCH3 CH3 OH CH3O C H H3C CH3 O NaOCH3 CH3OH (53%) consistent with SN2-like transition state Dr. Wolf's CHM 201 & 202 16-74 19

Anionic nucleophile attacks less-crowded carbon MgBr + O H2C CHCH3 1. diethyl ether 2. H3O+ CH2CHCH3 OH (60%) Dr. Wolf's CHM 201 & 202 16-75 15

Lithium aluminum hydride reduces epoxides H2C CH(CH2)7CH3 Hydride attacks less-crowded carbon 1. LiAlH4, diethyl ether 2. H2O OH H3C CH(CH2)7CH3 (90%) Dr. Wolf's CHM 201 & 202 16-76 16

Acid-Catalyzed Ring-Opening Reactions of Epoxides Dr. Wolf's CHM 201 & 202 16-77 22

Example O H2C CH2 CH3CH2OH CH3CH2OCH2CH2OH H2SO4, 25°C (87-92%) CH3CH2OCH2CH2OCH2CH3 formed only on heating and/or longer reaction times Dr. Wolf's CHM 201 & 202 16-78 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 Dr. Wolf's CHM 201 & 202 16-79 11

Mechanism O H2C CH2 O H2C CH2 + H Br – H Br • • • • •• • • • • •• •• Dr. Wolf's CHM 201 & 202 16-80 12

Mechanism Br – O H2C CH2 O H2C CH2 + H H Br O Br CH2CH2 H • • •• • • Dr. Wolf's CHM 201 & 202 16-81 12

Figure 16.6 Acid-Catalyzed Hydrolysis of Ethylene Oxide Step 1 H2C CH2 H2C CH2 + O O O • • H + • • H • • •• H O • • • • H Dr. Wolf's CHM 201 & 202 16-82 12

Figure 16.6 Acid-Catalyzed Hydrolysis of Ethylene Oxide Step 2 • • O H2C CH2 •• + H • • + O CH2CH2 H •• •• Dr. Wolf's CHM 201 & 202 16-83 12

Figure 16.6 Acid-Catalyzed Hydrolysis of Ethylene Oxide • • H + Step 3 • • O CH2CH2 H O •• • • H • • + O CH2CH2 H •• •• •• •• Dr. Wolf's CHM 201 & 202 16-84 12

Acid-Catalyzed Ring Opening of Epoxides Characteristics: nucleophile attacks more substituted carbon of protonated epoxide inversion of configuration at site of nucleophilic attack Dr. Wolf's CHM 201 & 202 16-85 30

Nucleophile attacks more-substituted carbon OCH3 C H H3C CH3 O CH3OH CH3CH CCH3 C H2SO4 OH CH3 (76%) consistent with carbocation character at transition state Dr. Wolf's CHM 201 & 202 16-86 19

Nucleophile attacks more-substituted carbon OCH3 C H H3C CH3 OH CH3OH d+ d+ CH3CH CCH3 C H2SO4 OH CH3 d+ (76%) consistent with carbocation character at transition state Dr. Wolf's CHM 201 & 202 16-86b 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 Dr. Wolf's CHM 201 & 202 16-87 11

(57%) Stereochemistry H3C CH3 H CH3OH H OH O CH3O H H2SO4 H H3C CH3 Inversion of configuration at carbon being attacked by nucleophile Dr. Wolf's CHM 201 & 202 16-88 18

Stereochemistry H3C CH3 H CH3OH H OH O CH3O H H2SO4 H H3C CH3 H3C H d+ Dr. Wolf's CHM 201 & 202 16-89 18

anti-Hydroxylation of Alkenes CH3COOH O H H2O HClO4 H OH H OH (80%) Dr. Wolf's CHM 201 & 202 16-90 35

Epoxides in Biological Processes Dr. Wolf's CHM 201 & 202 16-91 1

Naturally Occurring Epoxides are common are involved in numerous biological processes Dr. Wolf's CHM 201 & 202 16-92

Biosynthesis of Epoxides C + O2 H+ + NADH enzyme C C + H2O + NAD+ O enzyme-catalyzed oxygen transfer from O2 to alkene enzymes are referred to as monooxygenases Dr. Wolf's CHM 201 & 202 16-93

Example: biological epoxidation of squalene O2, NADH monoxygenase O this reaction is an important step in the biosynthesis of cholesterol Dr. Wolf's CHM 201 & 202 16-94

Preparation of Sulfides Dr. Wolf's CHM 201 & 202 16-95 1

– R S R' R S + R' X NaSCH3 CH3CHCH CH2 Cl CH3CHCH CH2 SCH3 methanol Preparation of RSR' prepared by nucleophilic substitution (SN2) – •• • • •• R S R' R S + R' X NaSCH3 CH3CHCH CH2 Cl CH3CHCH CH2 SCH3 methanol Dr. Wolf's CHM 201 & 202 16-96

Oxidation of Sulfides: Sulfoxides and Sulfones Dr. Wolf's CHM 201 & 202 16-97 1

R S R' O – + O – ++ R S R' R S R' O – sulfide sulfoxide sulfone Oxidation of RSR' •• R S R' O • • – + O • • •• – ++ •• R S R' R S R' O • • •• – sulfide sulfoxide sulfone either the sulfoxide or the sulfone can be isolated depending on the oxidizing agent and reaction conditions Dr. Wolf's CHM 201 & 202 16-98

SCH3 O – + SCH3 NaIO4 water (91%) Example •• • • •• Sodium metaperiodate oxidizes sulfides to sulfoxides and no further. Dr. Wolf's CHM 201 & 202 16-99

SCH CH2 SCH O – ++ CH2 H2O2 (2 equiv) (74-78%) Example •• •• • • 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%) Dr. Wolf's CHM 201 & 202 16-100

Alkylation of Sulfides: Sulfonium Salts Dr. Wolf's CHM 201 & 202 16-101 1

Sulfides can act as nucleophiles + •• •• R S + R" X R S R" X– • • R' R' product is a sulfonium salt Dr. Wolf's CHM 201 & 202 16-102

CH3I + CH3(CH2)10CH2SCH3 CH3(CH2)10CH2SCH3 I– CH3 Example 16-103 Dr. Wolf's CHM 201 & 202 16-103

Spectroscopic Analysis of Ethers Dr. Wolf's CHM 201 & 202 16-104 1

Infrared Spectroscopy C—O stretching: 1070 and 1150 cm-1 (strong) Dr. Wolf's CHM 201 & 202 16-105 6

Figure 16.8 Infrared Spectrum of Dipropyl Ether CH3CH2CH2OCH2CH2CH3 C—O—C 2000 3500 3000 2500 1000 1500 500 Wave number, cm-1 Dr. Wolf's CHM 201 & 202 16-106 8

d 1.4 ppm d 0.8 ppm d 0.8 ppm CH3 CH2 CH2 OCH2 CH2 CH3 d 3.2 ppm 1H NMR H—C—O proton is deshielded by O; range is ca. d 3.3-4.0 ppm. d 1.4 ppm d 0.8 ppm d 0.8 ppm CH3 CH2 CH2 OCH2 CH2 CH3 d 3.2 ppm Dr. Wolf's CHM 201 & 202 16-107 6

CH3 CH2 CH2 OCH2 CH2 CH3 1 Chemical shift (d, ppm) 16-108 1.0 2.0 3.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0 10.0 Chemical shift (d, ppm) Dr. Wolf's CHM 201 & 202 16-108 1

Carbons of C—O—C appear in the range d 57-87 ppm. 13C NMR Carbons of C—O—C appear in the range d 57-87 ppm. 26.0 ppm O 68.0 ppm Dr. Wolf's CHM 201 & 202 16-109

UV-VIS Simple ethers have their absorption maximum at about 185 nm and are transparent to ultraviolet radiation above about 220 nm. Dr. Wolf's CHM 201 & 202 16-110

+ + Molecular ion fragments to give oxygen-stabilized carbocation. Mass Spectrometry Molecular ion fragments to give oxygen-stabilized carbocation. •+ CH3CH2O CHCH2CH3 m/z 102 •• CH3 + + CH3CH2O CH CH3CH2O CHCH2CH3 •• •• m/z 73 CH3 m/z 87 Dr. Wolf's CHM 201 & 202 16-111

End of Chapter 16