Chapter 16 Ethers, Epoxides, and Sulfides

16.5 Preparation of Ethers

Acid-Catalyzed Condensation of Alcohols 2CH 3 CH 2 CH 2 CH 2 OH H 2 SO 4, 130°C CH 3 CH 2 CH 2 CH 2 OCH 2 CH 2 CH 2 CH 3 (60%)

H+H+H+H+ (CH 3 ) 2 C=CH 2 + CH 3 OH (CH 3 ) 3 COCH 3 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 rating booster in gasoline, but contaminates ground water if allowed to leak from storage tanks. Further use of MTBE is unlikely. Addition of Alcohols to Alkenes

Think S N 2! Primary alkyl halide + alkoxide nucleophile The Williamson Ether Synthesis

(71%) CH 3 CH 2 CH 2 CH 2 ONa + CH 3 CH 2 I CH 3 CH 2 CH 2 CH 2 OCH 2 CH 3 + NaI Example

Williamson Ether Synthesis Has Limitations 1) Alkyl halide must be primary (RCH 2 X). 2) Alkoxides can be derived from primary, secondary or tertiary alcohols.

+ CH 3 CHCH 3 ONa CH 2 Cl (84%) CH 2 OCHCH 3 CH 3 Williamson Ether Synthesis Has Limitations 1) Alkyl halide must be primary (RCH 2 X). 2) Alkoxides can be derived from primary, secondary or tertiary alcohols. The reaction works particularly well with benzyl and allyl halides, which are excellent alkylating agents.

CH 3 CHCH 3 OHOHOHOH Na CH 2 OH HCl CH 2 OCHCH 3 CH 3 CH 2 Cl + CH 3 CHCH 3 ONa (84%) Origin of Reactants

What Happens if the Alkyl Halide Is Not Primary? CH 2 ONa + CH 3 CHCH 3 Br CH 2 OH + H2CH2CH2CH2C CHCH 3 Elimination by the E2 mechanism becomes the major reaction pathway.

16.7 Reactions of Ethers: A Review and a Preview

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. Summary of Reactions of Ethers

16.8 Acid-Catalyzed Cleavage of Ethers

CH 3 CHCH 2 CH 3 OCH 3 CH 3 Br HBr + (81%) CH 3 CHCH 2 CH 3 Br heat Example

CH 3 CH 3 CHCH 2 CH 3 O H Br CH 3 CHCH 2 CH 3 O CH 3 H + Br – Mechanism CH 3 CHCH 2 CH 3 Br HBr CH 3 Br CH 3 CHCH 2 CH 3 O H

HIHIHIHI 150°C ICH 2 CH 2 CH 2 CH 2 I (65%) O Cleavage of Cyclic Ethers

O HIHIHIHI H O + I – ICH 2 CH 2 CH 2 CH 2 I HIHIHIHI H O I Mechanism

16.9 Preparation of Epoxides: A Review and a Preview

Epoxides are prepared by two major methods. Both begin with alkenes. Reaction of alkenes with peroxy acids (6.19). Conversion of alkenes to vicinal halohydrins (6.18), followed by treatment with base (16.10). Preparation of Epoxides

16.10 Conversion of Vicinal Halohydrins to Epoxides

H OHOHOHOH Br H NaOH H2OH2OH2OH2O (81%) H H O Example O Br H H – via:

Epoxidation via Vicinal Halohydrins Br 2 H2OH2OH2OH2O OHOHOHOH NaOH O H H H3CH3CH3CH3C CH 3 H H H3CH3CH3CH3C Br H H3CH3CH3CH3C H Anti addition Inversion Corresponds to overall syn addition of oxygen to the double bond.

16.11 Reactions of Epoxides: A Review and a Preview

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 15.4 as a method for the synthesis of alcohols). Reactions of Epoxides

Reaction of Grignard Reagents with Epoxides H2CH2CH2CH2C CH 2 O R MgX CH 2 OMgX R H3O+H3O+H3O+H3O+ RCH 2 CH 2 OH

H2CH2CH2CH2C CH 2 O + 1. diethyl ether 2. H 3 O + (71%) Example CH 2 MgCl CH 2 CH 2 CH 2 OH

Reactions of epoxides involve attack by a nucleophile and proceed with ring-opening. For ethylene oxide: Nu—H + Nu—CH 2 CH 2 O—H H2CH2CH2CH2C CH 2 O In General...

For epoxides where the two carbons of the ring are differently substituted: In General... CH 2 O CRH Nucleophiles attack here when the reaction is catalyzed by acids. Anionic and other good nucleophiles in non- acidic conditions attack here.

16.12 Nucleophilic Ring-Opening Reactions of Epoxides

NaOCH 2 CH 3 CH 3 CH 2 OH (50%) Example O H2CH2CH2CH2C CH 2 CH 3 CH 2 O CH 2 CH 2 OH

O H2CH2CH2CH2C CH 2 CH 3 CH 2 O – CH 3 CH 2 O CH 2 CH 2 O H O CH 2 CH 3 – Mechanism – CH 3 CH 2 O CH 2 CH 2 O O CH 2 CH 3 H

Example O H2CH2CH2CH2C CH 2 KSCH 2 CH 2 CH 2 CH 3 ethanol-water, 0°C (99%) CH 2 CH 2 OH CH 3 CH 2 CH 2 CH 2 S

Stereochemistry Inversion of configuration at carbon being attacked by nucleophile. Suggests S N 2-like transition state. NaOCH 2 CH 3 CH 3 CH 2 OH O HHH OHOHOHOH H OCH 2 CH 3 (67%)

NH 3 H2OH2OH2OH2O (70%) R S R R Stereochemistry H3CH3CH3CH3C CH 3 H3CH3CH3CH3C O H H H H OHOHOHOH H2NH2NH2NH2N Inversion of configuration at carbon being attacked by nucleophile. Suggests S N 2-like transition state.

NH 3 H2OH2OH2OH2O (70%) ---- R S R R Stereochemistry H3CH3CH3CH3C CH 3 H3CH3CH3CH3C O H H H H OHOHOHOH H2NH2NH2NH2N H3NH3NH3NH3N O H3CH3CH3CH3C H H3CH3CH3CH3C H

NaOCH 3 CH 3 OH CH 3 CH CCH 3 CH 3 OHOHOHOH CH 3 O (53%) C C H H3CH3CH3CH3C CH 3 O Consistent with S N 2-like transition state. Good Nucleophiles Attack Less-Crowded Carbon

1. diethyl ether 2. H 3 O + MgBr + O H2CH2CH2CH2C CHCH 3 CH 2 CHCH 3 OHOHOHOH (60%)

Hydride anion attacks less-crowded carbon. Lithium Aluminum Hydride Reduces Epoxides O H2CH2CH2CH2C CH(CH 2 ) 7 CH 3 1. LiAlH 4, diethyl ether 2. H 2 O (90%) OHOHOHOH H3CH3CH3CH3C CH(CH 2 ) 7 CH 3

16.13 Acid-Catalyzed Ring-Opening Reactions of Epoxides

Example O H2CH2CH2CH2C CH 2 CH 3 CH 2 OCH 2 CH 2 OH (87-92%) CH 3 CH 2 OCH 2 CH 2 OCH 2 CH 3 formed only on heating and/or longer reaction times. CH 3 CH 2 OH H 2 SO 4, 25°C

Example O H2CH2CH2CH2C CH 2 HBr 10°C BrCH 2 CH 2 OH (87-92%) BrCH 2 CH 2 Br formed only on heating and/or longer reaction times with excess HBr.

Mechanism Br – O Br CH 2 CH 2 H O H2CH2CH2CH2C CH 2 H Br O H2CH2CH2CH2C CH 2 + H

Acid-Catalyzed Hydrolysis of Ethylene Oxide O H2CH2CH2CH2C CH 2 O HHH + O H2CH2CH2CH2C CH 2 + H O H H Step 1

O H2CH2CH2CH2C CH 2 + H O HH Step 2 + O O CH 2 CH 2 H H H Acid-Catalyzed Hydrolysis of Ethylene Oxide

Step 3 + O O CH 2 CH 2 HH H O HH O HH + H O O CH 2 CH 2 H H Acid-Catalyzed Hydrolysis of Ethylene Oxide

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

CH 3 OH C C H H3CH3CH3CH3C CH 3 O Consistent with carbocation character of transition state. Nucleophile Attacks More-Substituted Carbon H 2 SO 4 CH 3 CH CCH 3 CH 3 OHOHOHOH OCH 3 (76%)

Stereochemistry Inversion of configuration at carbon being attacked by nucleophile. (73%) HHO HBr H OHOHOHOH Br H

(57%) R S R R Stereochemistry H3CH3CH3CH3C CH 3 H3CH3CH3CH3C O H H H H OHOHOHOH CH 3 O CH 3 OH H 2 SO 4 Inversion of configuration at carbon being attacked by nucleophile.

R S R R Stereochemistry H3CH3CH3CH3C CH 3 H3CH3CH3CH3C O H H H H OH CH 3 O CH 3 OH H 2 SO 4 ++++ ++++ CH 3 O O H3CH3CH3CH3C H H3CH3CH3CH3C H H ++++ H

anti-Hydroxylation of Alkenes HH CH 3 COOH O HHO H 2 O, HClO 4 (80%) H OHOHOHOH OH H

16.15 Preparation of Sulfides

Prepared by nucleophilic substitution (S N 2). Preparation of RSR' +R'XS R – R S R' CH 3 CHCH CH 2 Cl NaSCH 3 methanol CH 3 CHCH CH 2 SCH 3

Section Spectroscopic Analysis of Ethers, Epoxides, and Sulfides

C—O stretching of ethers: between 1070 and 1150 cm -1 (strong) Infrared Spectroscopy

Infrared Spectrum of Dipropyl Ether

H—C—O proton is deshielded by O; range is  ppm. 1 H NMR of Ethers CH 3 CH 2 CH 2 OCH 2 CH 2 CH 3  0.8 ppm  1.4 ppm  3.2 ppm Epoxide ring protons slightly more shielded:  ~2.5 ppm.

Chemical shift ( , ppm) CH 3 CH 2 CH 2 OCH 2 CH 2 CH 3 Dipropyl Ether

H—C—S proton is less deshielded than H—C—O. 1 H NMR of Sulfides Oxidation of sulfides to sulfoxide deshields an adjacent C—H proton by ppm. An additional ppm downfield shift occurs on oxidation of the sulfoxide to the sulfone.  2.5 ppm CH 3 CH 2 CH 2 SCH 2 CH 2 CH 3

13 C NMR of Ethers and Epoxides Carbons of C—O—C appear in the range  ppm.  68  26 O But the ring carbons of epoxides are somewhat more shielded. C C O H HH CH 2 (CH 2 ) 2 CH 3  47  52