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 (Section 6.18) conversion of alkenes to vicinal halohydrins, followed by treatment with base (Section 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 –H OHOHOHOH Br H NaOH H2OH2OH2OH2O (81%) H H O Example via:

anti addition Epoxidation via Vicinal Halohydrins Br 2 H2OH2OH2OH2O OHOHOHOH Br

anti addition inversion Epoxidation via Vicinal Halohydrins Br 2 H2OH2OH2OH2O OHOHOHOH NaOH corresponds to overall syn addition of oxygen to the double bond Br O

anti addition inversion Epoxidation via Vicinal Halohydrins Br 2 H2OH2OH2OH2O OHOHOHOH NaOH corresponds to overall syn addition of oxygen to the double bond Br H H3CH3CH3CH3C CH 3 O H H H3CH3CH3CH3C H

anti addition inversion Epoxidation via Vicinal Halohydrins Br 2 H2OH2OH2OH2O OHOHOHOH NaOH corresponds to overall syn addition of oxygen to the double bond Br H H3CH3CH3CH3C CH 3 O H H H3CH3CH3CH3C H H H3CH3CH3CH3C H

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

Reaction of Grignard Reagents with Epoxides CH 2 OMgX H3O+H3O+H3O+H3O+ H2CH2CH2CH2C O RMgXR 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 nucleophiles 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 –Mechanism

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

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

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

(99%) Example O H2CH2CH2CH2C CH 2 KSCH 2 CH 2 CH 2 CH 3 ethanol-water, 0°C 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 OH 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 OH 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 Anionic nucleophile attacks less-crowded carbon

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

(90%) Hydride 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 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

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

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

Figure 16.6 Acid-Catalyzed Hydrolysis of Ethylene Oxide O H2CH2CH2CH2C CH 2 + H O H2CH2CH2CH2C CH 2 + O HHH + O H H Step 1

Figure 16.6 Acid-Catalyzed Hydrolysis of Ethylene Oxide O H2CH2CH2CH2C CH 2 O +HH H Step 2 + O O CH 2 CH 2 HH H

Figure 16.6 Acid-Catalyzed Hydrolysis of Ethylene Oxide O HH Step 3 + O O CH 2 CH 2 HH H O HH + H O O CH 2 CH 2 HH

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 CH 3 CH CCH 3 CH 3 OHOHOHOH OCH 3 (76%) C C H H3CH3CH3CH3C CH 3 O consistent with carbocation character at transition state Nucleophile attacks more-substituted carbon H 2 SO 4

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 OH CH 3 O Inversion of configuration at carbon being attacked by nucleophile CH 3 OH H 2 SO 4

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

H2OH2OH2OH2O HClO 4 (80%) anti-Hydroxylation of Alkenes HH CH 3 COOH O HHO H OHOHOHOH OH H