Dr. Wolf's CHM 201 & Conversion of Vicinal Halohydrins to Epoxides

Dr. Wolf's CHM 201 & H OHOHOHOH Br H NaOH H2OH2OH2OH2O (81%) H H O ExampleExample

Dr. Wolf's CHM 201 & O Br H H –H OHOHOHOH Br H NaOH H2OH2OH2OH2O (81%) H H O ExampleExample via:

Dr. Wolf's CHM 201 & anti addition Epoxidation via Vicinal Halohydrins Br 2 H2OH2OH2OH2O OHOHOHOH Br

Dr. Wolf's CHM 201 & 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

Dr. Wolf's CHM 201 & 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

Dr. Wolf's CHM 201 & 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

Dr. Wolf's CHM 201 & Reactions of Epoxides: A Review and a Preview

Dr. Wolf's CHM 201 & 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

Dr. Wolf's CHM 201 & Reaction of Grignard Reagents with Epoxides CH 2 OMgX H3O+H3O+H3O+H3O+ H2CH2CH2CH2C O RMgXR RCH 2 CH 2 OH

Dr. Wolf's CHM 201 & H2CH2CH2CH2C CH 2 O + 1. diethyl ether 2. H 3 O + (71%) ExampleExample CH 2 MgCl CH 2 CH 2 CH 2 OH

Dr. Wolf's CHM 201 & 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...

Dr. Wolf's CHM 201 & 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:

Dr. Wolf's CHM 201 & Nucleophilic Ring-Opening Reactions of Epoxides

Dr. Wolf's CHM 201 & NaOCH 2 CH 3 CH 3 CH 2 OH (50%) ExampleExample O H2CH2CH2CH2C CH 2 CH 3 CH 2 O CH 2 CH 2 OH

Dr. Wolf's CHM 201 & O H2CH2CH2CH2C CH 2 CH 3 CH 2 O –Mechanism

Dr. Wolf's CHM 201 & O H2CH2CH2CH2C CH 2 CH 3 CH 2 O –– CH 3 CH 2 O CH 2 CH 2 O Mechanism

Dr. Wolf's CHM 201 & 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

Dr. Wolf's CHM 201 & 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

Dr. Wolf's CHM 201 & (99%) ExampleExample 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

Dr. Wolf's CHM 201 & StereochemistryStereochemistry 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%)

Dr. Wolf's CHM 201 & NH 3 H2OH2OH2OH2O (70%) R S R R StereochemistryStereochemistry 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

Dr. Wolf's CHM 201 & NH 3 H2OH2OH2OH2O (70%) ++++ ---- R S R R StereochemistryStereochemistry H3CH3CH3CH3C CH 3 H3CH3CH3CH3C O H H H H OH H2NH2NH2NH2N H3NH3NH3NH3N O H3CH3CH3CH3C H H3CH3CH3CH3C H

Dr. Wolf's CHM 201 & 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

Dr. Wolf's CHM 201 & Anionic nucleophile attacks less-crowded carbon 1. diethyl ether 2. H 3 O + MgBr + O H2CH2CH2CH2C CHCH 3 CH 2 CHCH 3 OHOHOHOH (60%)

Dr. Wolf's CHM 201 & (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

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

Dr. Wolf's CHM 201 & ExampleExample 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

Dr. Wolf's CHM 201 & ExampleExample 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

Dr. Wolf's CHM 201 & Mechanism O H2CH2CH2CH2C CH 2 + H Br – O H2CH2CH2CH2C CH 2 H Br

Dr. Wolf's CHM 201 & Mechanism O H2CH2CH2CH2C CH 2 + H O Br CH 2 CH 2 H Br – O H2CH2CH2CH2C CH 2 H Br

Dr. Wolf's CHM 201 & 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

Dr. Wolf's CHM 201 & 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

Dr. Wolf's CHM 201 & 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

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

Dr. Wolf's CHM 201 & 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

Dr. Wolf's CHM 201 & b CH 3 OH CH 3 CH CCH 3 CH 3 OHOHOHOH OCH 3 (76%) C H H3CH3CH3CH3C CH 3 OHOHOHOH consistent with carbocation character at transition state Nucleophile attacks more-substituted carbon H 2 SO 4 C ++ ++ ++

Dr. Wolf's CHM 201 & StereochemistryStereochemistry Inversion of configuration at carbon being attacked by nucleophile (73%) HHO HBr H OHOHOHOH Br H

Dr. Wolf's CHM 201 & (57%) R S R R StereochemistryStereochemistry 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

Dr. Wolf's CHM 201 & R S R R StereochemistryStereochemistry 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

Dr. Wolf's CHM 201 & H2OH2OH2OH2O HClO 4 (80%) anti-Hydroxylation of Alkenes HH CH 3 COOH O HHO H OHOHOHOH OH H

Dr. Wolf's CHM 201 & Epoxides in Biological Processes

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

Dr. Wolf's CHM 201 & enzyme-catalyzed oxygen transfer from O 2 to alkene enzymes are referred to as monooxygenases Biosynthesis of Epoxides + + C C ++ O2O2O2O2 H+H+H+H+ C C O NADH H2OH2OH2OH2O + NAD + enzyme

Dr. Wolf's CHM 201 & this reaction is an important step in the biosynthesis of cholesterol Example: biological epoxidation of squalene O 2, NADH monoxygenase O

Dr. Wolf's CHM 201 & Preparation of Sulfides

Dr. Wolf's CHM 201 & 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

Dr. Wolf's CHM 201 & Oxidation of Sulfides: Sulfoxides and Sulfones

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

Dr. Wolf's CHM 201 & ExampleExample SCH 3 NaIO 4 SCH 3 O –+ Sodium metaperiodate oxidizes sulfides to sulfoxides and no further. (91%) water

Dr. Wolf's CHM 201 & ExampleExample H2O2H2O2H2O2H2O2 1 equiv of H 2 O 2 or a peroxy acid gives a sulfoxide, 2 equiv give a sulfone (74-78%) (2 equiv) SCH CH 2 SCH O –++ CH 2 O –

Dr. Wolf's CHM 201 & Alkylation of Sulfides: Sulfonium Salts

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

Dr. Wolf's CHM 201 & ExampleExample CH 3 (CH 2 ) 10 CH 2 SCH 3 CH 3 I CH 3 (CH 2 ) 10 CH 2 SCH 3 CH 3 + I–I–I–I–

Dr. Wolf's CHM 201 & Section Spectroscopic Analysis of Ethers

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

Dr. Wolf's CHM 201 & Wave number, cm -1 Figure 16.8 Infrared Spectrum of Dipropyl Ether C—O—C CH 3 CH 2 CH 2 OCH 2 CH 2 CH 3

Dr. Wolf's CHM 201 & H—C—O proton is deshielded by O; range is ca.  ppm. 1 H NMR CH 3 CH 2 CH 2 OCH 2 CH 2 CH 3  0.8 ppm  1.4 ppm  3.2 ppm

Dr. Wolf's CHM 201 & Chemical shift ( , ppm) CH 3 CH 2 CH 2 OCH 2 CH 2 CH 3

Dr. Wolf's CHM 201 & ppm Carbons of C—O—C appear in the range  ppm ppm 13 C NMR O

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

Dr. Wolf's CHM 201 & Molecular ion fragments to give oxygen-stabilized carbocation. m/z 102 CH 3 CH 2 O CHCH 2 CH 3 CH 3 CH 3 CH 2 O + CH CH 3 CH 3 CH 2 O + CHCH 2 CH 3 m/z 87 m/z 73 Mass Spectrometry +

End of Chapter 16