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

Ethers Formula is R—O—R¢where R and R¢ are alkyl or aryl. Symmetrical or unsymmetrical

Nomenclature of Ethers, Epoxides, and Sulfides 2

Substitutive IUPAC Names of Ethers name as alkoxy derivatives of alkanes CH3OCH2 CH3 CH3CH2OCH2CH2CH2Cl methoxyethane 3-chloro-1-ethoxypropane CH3CH2OCH2 CH3 ethoxyethane 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 CH3CH2OCH2CH2CH2Cl ethyl methyl ether 3-chloropropyl ethyl ether CH3CH2OCH2 CH3 diethyl ether 3

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

Structure and Polarity Oxygen is sp3 hybridized. Bent molecular geometry. Tetrahedral C—O—C angle is 110°. Polar C—O bonds.

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

Physical Properties of Ethers 11

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

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

Hydrogen Bond Acceptor Ethers cannot hydrogen bond with other ether molecules, so they have a lower boiling point than alcohols. Ether molecules can hydrogen bond with water and alcohol molecules. They are hydrogen bond acceptors.

Ethers as Solvents Ethers are widely used as solvents because they can dissolve nonpolar and polar substances. they are unreactive toward strong bases. Ethers are relatively unreactive. Their low level of reactivity is one reason why ethers are often used as solvents in chemical reactions.

Ether Complexes Grignard reagents: Complexation of an ether with a Grignard reagent stabilizes the reagent and helps keep it in solution. Electrophiles: The ether’s nonbonding electrons stabilize the borane (BH3).

Crown Ethers Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. 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 14

Crown Ether Complexes Crown ethers can complex metal cations in the center of the ring. The size of the ether ring will determine which cation it can solvate better. Complexation by crown ethers often allows polar inorganic salts to dissolve in nonpolar organic solvents.

forms stable Lewis acid/Lewis base complex with K+ 18-Crown-6 O K+ forms stable Lewis acid/Lewis base complex with K+ 15

Ion-Complexing and Solubility K+F– not soluble in benzene 16

Ion-Complexing and Solubility K+F– benzene add 18-crown-6 16

Ion-Complexing and Solubility F– K+ benzene 18-crown-6 complex of K+ dissolves in benzene 16

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

Application to organic synthesis Complexation of K+ by 18-crown-6 solubilizes potassium salts 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. 20

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

Preparation of Ethers 21

Acid-Catalyzed Condensation of Alcohols* 2 CH3CH2CH2CH2OH H2SO4, 130°C CH3CH2CH2CH2OCH2CH2CH2CH3 (60%) Method is good for primary alcohols. Diethyl ether is made on industrial scale using this method. Ethylene will form at higher temperatures. Secondary and tertiary alcohols give alkenes as main product. 10

Addition of Alcohols to Alkenes (CH3)2C=CH2 + CH3OH (CH3)3COCH3 tert-Butyl methyl ether 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

The Williamson Ether Synthesis 24

Williamson Ether Synthesis This method involves an SN2 attack of the alkoxide on an unhindered primary halide or tosylate. The alkoxide is commonly made by adding Na, K, or NaH to the alcohol

Example CH3CH2CH2CH2ONa + CH3CH2I CH3CH2CH2CH2OCH2CH3 + NaI (71%) 25

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

Origin of Reactants CH2OH HCl CH3CHCH3 OH Na 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

Reactions of Ethers: 28

Acid-Catalyzed Cleavage of Ethers Ethers can be cleaved by heating with concentrated HBr and HI. Reactivity: HI > HBr 29

Example CH3CHCH2CH3 HBr CH3CHCH2CH3 + CH3Br heat OCH3 Br (81%) 31

Mechanism of Ether Cleavage Step 1: Protonation of the oxygen. Step 2: The halide will attack the carbon and displace the alcohol (SN2).

Mechanism of Ether Cleavage Step 3: The alcohol reacts further with the acid to produce another mole of alkyl halide. This does not occur with aromatic alcohols (phenols).

Cleavage of Cyclic Ethers HI ICH2CH2CH2CH2I 150°C (65%) 32

Mechanism O ICH2CH2CH2CH2I HI HI H O + I – H O I •• •• •• • • •• • • 32

Autoxidation of Ethers In the presence of atmospheric oxygen, ethers slowly oxidize to hydroperoxides and dialkyl peroxides. Both are highly explosive. Precautions: Do not distill to dryness. Store in full bottles with tight caps.

Autoxidation of Ethers

Preparation of Epoxides: A Review and a Preview Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. 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, this chapter) 30

Synthesis of Epoxides Peroxyacids are used to convert alkenes to epoxides. Most commonly used peroxyacid is meta-chloroperoxybenzoic acid (MCPBA). The reaction is carried out in an aprotic acid to prevent the opening of the epoxide.

Halohydrin Cyclization If an alkoxide and a halogen are located in the same molecule, the alkoxide may displace a halide ion and form a ring. Treatment of a halohydrin with a base leads to an epoxide through this internal SN2 attack.

Another look H OH Br H NaOH O H2O H (81%) O Br H • • •• – 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

Reactions of Epoxides: A Review and a Preview 6

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

Example H2C O CH2 NaOCH2CH3 CH3CH2OH CH3CH2O CH2CH2OH (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

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 10

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

Acid-Catalyzed Ring-Opening Reactions of Epoxides 22

Example O H2C CH2 CH3CH2OH CH3CH2OCH2CH2OH H2SO4, 25°C (87-92%) CH3CH2OCH2CH2OCH2CH3 formed only on heating and/or longer reaction times. 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 – O H2C CH2 + H O H2C CH2 H Br O Br CH2CH2 H • • •• • • 12

Acid-Catalyzed Hydrolysis of Ethylene Oxide Step 1 H2C CH2 • • O H2C CH2 + H O O • • H + • • •• 12

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

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

Acid-Catalyzed Ring Opening of Epoxides Characteristics: Nucleophile attacks more substituted carbon of protonated epoxide. Inversion of configuration at site of nucleophilic attack. 30

Nucleophile Attacks More-substituted Carbon CH3CH CCH3 CH3 OH OCH3 (76%) C H H3C CH3 O CH3OH H2SO4 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

(57%) Stereochemistry H3C CH3 H CH3OH H OH O CH3O H H2SO4 H H3C CH3 Inversion of configuration at carbon being attacked by nucleophile 18

Stereochemistry H3C CH3 H CH3OH H OH O CH3O H H2SO4 H H3C CH3 H3C H + 18

anti-Hydroxylation of Alkenes CH3COOH O H H2O HClO4 (80%) H OH + enantiomer 35