Chapter 16 Ethers, Epoxides, and Sulfides. 16.5 Preparation of Ethers

Chapter 16Chapter 16Ethers, Epoxides, and SulfidesEthers, Epoxides, and Sulfides

16.516.5

Preparation of EthersPreparation of Ethers

Acid-Catalyzed Condensation of AlcoholsAcid-Catalyzed Condensation of Alcohols

2CH2CH33CHCH22CHCH22CHCH22OHOH

HH22SOSO44, 130°C, 130°C

CHCH33CHCH22CHCH22CHCH22OOCHCH22CHCH22CHCH22CHCH33

(60%)(60%)

HH++

(CH(CH33))22C=CHC=CH22 + CH + CH33OHOH (CH(CH33))33COCHCOCH33

terttert-Butyl methyl ether-Butyl methyl ether

terttert-Butyl methyl ether (MTBE) was produced on a-Butyl methyl ether (MTBE) was produced on a

scale exceeding 15 billion pounds per year in the U.S.scale exceeding 15 billion pounds per year in the U.S.

during the 1990s. It is an effective octane rating booster induring the 1990s. It is an effective octane rating booster in

gasoline, but contaminates ground water if allowed togasoline, but contaminates ground water if allowed to

leak from storage tanks. Further use of MTBE is unlikely.leak from storage tanks. Further use of MTBE is unlikely.

Addition of Alcohols to AlkenesAddition of Alcohols to Alkenes

Think SThink SNN2!2!

PrimaryPrimary alkyl halide + alkoxide nucleophile. alkyl halide + alkoxide nucleophile.

16.616.6

The Williamson Ether SynthesisThe Williamson Ether Synthesis

(71%)(71%)

CHCH33CHCH22CHCH22CHCH22OONa +Na + CHCH33CHCH22II

CHCH33CHCH22CHCH22CHCH22OOCHCH22CHCH33 ++ NaI NaI

ExampleExample

Williamson Ether Synthesis Has LimitationsWilliamson Ether Synthesis Has Limitations

1) Alkyl halide must be primary (RCH1) Alkyl halide must be primary (RCH22X).X).2) Alkoxides can be derived from primary, secondary or 2) Alkoxides can be derived from primary, secondary or tertiary alcohols.tertiary alcohols.

OH

O

O Na

BrSN2

SecondaryAlkoxide

PrimaryAlkyl halide

OH

O

O Na

BrSN2

SecondaryAlkoxide

PrimaryAlkyl halide

++ CHCH33CHCHCHCH33

OONaNa

CHCH22ClCl

(84%)(84%)CHCH22OOCHCHCHCH33

CHCH33

Williamson Ether Synthesis Has LimitationsWilliamson Ether Synthesis Has Limitations

1) Alkyl halide must be primary (RCH1) Alkyl halide must be primary (RCH22X).X).2) Alkoxides can be derived from primary, secondary or 2) Alkoxides can be derived from primary, secondary or tertiary alcohols.tertiary alcohols.

The reaction The reaction works particularly works particularly well with benzyl well with benzyl and allyl halides, and allyl halides, which are which are excellent excellent alkylating agents.alkylating agents.

CHCH33CHCHCHCH33

OOHH

NaNa

CHCH22OHOH

HClHCl

CHCH22OOCHCHCHCH33

CHCH33

CHCH22ClCl ++ CHCH33CHCHCHCH33

OONaNa

(84%)(84%)

Origin of ReactantsOrigin of Reactants

What Happens if the Alkyl Halide Is Not Primary?What Happens if the Alkyl Halide Is Not Primary?

CHCH22OONaNa ++ CHCH33CHCHCHCH33

BrBr

CHCH22OOHH ++ HH22CC CHCHCHCH33

Elimination by the E2 mechanism becomesElimination by the E2 mechanism becomes

the major reaction pathway.the major reaction pathway.

16.716.7

Reactions of Ethers:Reactions of Ethers:

A Review and a PreviewA Review and a Preview

No reactions of ethers encountered to this No reactions of ethers encountered to this point.point.

Ethers are relatively unreactive.Ethers are relatively unreactive.

Their low level of reactivity is one reason why Their low level of reactivity is one reason why ethers are often used as solvents in chemical ethers are often used as solvents in chemical reactions.reactions.

Ethers oxidize in air to form explosive Ethers oxidize in air to form explosive hydroperoxides and peroxides.hydroperoxides and peroxides.

Summary of Reactions of EthersSummary of Reactions of Ethers

16.816.8Acid-Catalyzed Cleavage of EthersAcid-Catalyzed Cleavage of Ethers

CHCH33CHCHCHCH22CHCH33

OOCHCH33

CHCH33BrBrHHBrBr

++

(81%)(81%)


BrBrheatheat

ExampleExample

CHCH33


OO ••••••••

HH BrBr ••••••••

••••


OOCHCH33 HH++

••••

BrBr––

•••••••• ••••

••••

MechanismMechanism


BrBr

HHBrBr

••••

••••••••

CHCH33BrBr


OOHH

••••••••

HHII

150°C150°CIICHCH22CHCH22CHCH22CHCH22II

(65%)(65%)

OO

Cleavage of Cyclic EthersCleavage of Cyclic Ethers

OO••••

••••

HHII

HH

OO••••

++

•••• II ••••••••

••••

––

IICHCH22CHCH22CHCH22CHCH22II

HHII

HH

OO•••• II••••

••••••••

••••

MechanismMechanism

16.916.9

Preparation of Epoxides:Preparation of Epoxides:

A Review and a PreviewA Review and a Preview

Epoxides are prepared by two major methods.Epoxides are prepared by two major methods.Both begin with alkenes.Both begin with alkenes.

Reaction of alkenes with peroxy acidsReaction of alkenes with peroxy acids(6.19).(6.19).

Conversion of alkenes to vicinalConversion of alkenes to vicinalhalohydrins (6.18), followed by treatmenthalohydrins (6.18), followed by treatmentwith base (16.10).with base (16.10).

Preparation of EpoxidesPreparation of Epoxides

16.1016.10

Conversion of Vicinal HalohydrinsConversion of Vicinal Halohydrins

to Epoxidesto Epoxides

HHOOHH

BrBrHH

NaOHNaOH

HH22OO

(81%)(81%)

HH

HH

OO

ExampleExample

OO

BrBr

HHHH

••••••••

••••

•••• ••••••••––

via:via:

Epoxidation via Vicinal HalohydrinsEpoxidation via Vicinal Halohydrins

BrBr22

HH22OO

OOHH

NaOHNaOH

OO

HHHHHH33CC

CHCH33

HH

HH

CHCH33

HH33CC

BrBr

HHHH33CCCHCH33HH

AntiAnti

additionadditionInversionInversion

Corresponds to overall syn addition ofCorresponds to overall syn addition ofoxygen to the double bond.oxygen to the double bond.

16.1116.11Reactions of Epoxides:Reactions of Epoxides:A Review and a PreviewA Review and a Preview

All reactions involve nucleophilic attack All reactions involve nucleophilic attack at carbon and lead to opening of the ring.at carbon and lead to opening of the ring.

An example is the reaction of ethylene oxide An example is the reaction of ethylene oxide with a Grignard reagent (discussed in 15.4 with a Grignard reagent (discussed in 15.4 as a method for the synthesis of alcohols).as a method for the synthesis of alcohols).

Reactions of EpoxidesReactions of Epoxides

Reaction of Grignard ReagentsReaction of Grignard Reagentswith Epoxideswith Epoxides

HH22CC CHCH22

OO

RR MgMgXX

CHCH22 CHCH22 OOMgMgXX

RR

HH33OO++

RRCHCH22CHCH22OOHH

HH22CC CHCH22

OO

++

1. diethyl ether1. diethyl ether2. H2. H33OO++

(71%)(71%)

Example Example

CHCH22MgMgClCl

CHCH22CHCH22CHCH22OOHH

Reactions of epoxides involve attack by aReactions of epoxides involve attack by anucleophile and proceed with ring-opening.nucleophile and proceed with ring-opening.For ethylene oxide:For ethylene oxide:

Nu—H Nu—H ++

Nu—Nu—CHCH22CHCH22O—O—HH

HH22CC CHCH22

OO

In General...In General...

For epoxides where the two carbons of theFor epoxides where the two carbons of thering are differently substituted:ring are differently substituted:

In General...In General...

CHCH22

OO

CC

RR

HH

Nucleophiles attack hereNucleophiles attack herewhen the reaction iswhen the reaction iscatalyzed by acids.catalyzed by acids.

Anionic and other good Anionic and other good nucleophiles in non-nucleophiles in non-acidic conditions attack acidic conditions attack here.here.

16.1216.12

Nucleophilic Ring-OpeningNucleophilic Ring-Opening


NaOCHNaOCH22CHCH33

CHCH33CHCH22OHOH

(50%)(50%)

ExampleExample

OO

HH22CC CHCH22

CHCH33CHCH22OO CHCH22CHCH22OOHH

••••••••OO

HH22CC CHCH22

CHCH33CHCH22 OO••••

•••• ••••––

••

••CHCH33CHCH22 OO

••••

••••CHCH22CHCH22 OO

••••HH OO CHCH22CHCH33

••••••

••••

••

––

MechanismMechanism

––••

••CHCH33CHCH22 OO

••••

•••• ••••CHCH22CHCH22 OO••••

OO CHCH22CHCH33••••

••

••

HH

ExampleExample

OO

HH22CC CHCH22

KSCHKSCH22CHCH22CHCH22CHCH33

ethanol-water, 0°Cethanol-water, 0°C

(99%)(99%)

CHCH22CHCH22OOHHCHCH33CHCH22CHCH22CHCH22SS

StereochemistryStereochemistry

Inversion of configuration at carbon being Inversion of configuration at carbon being attacked by nucleophile.attacked by nucleophile.

Suggests SSuggests SNN2-like transition state.2-like transition state.

NaOCHNaOCH22CHCH33

CHCH33CHCH22OHOHOO

HHHH

HHOOHH

HH

OCHOCH22CHCH33

(67%)(67%)

NHNH33

HH22OO

(70%)(70%)

RR

SS

RR

RR


HH33CC CHCH33

HH33CC CHCH33

OOHH

HHHH

HH OOHHHH22NN


Suggests SSuggests SNN2-like transition state.2-like transition state.

NHNH33

HH22OO

(70%)(70%)

--

RR

SS

RR

RR


HH33CC CHCH33

HH33CC CHCH33

OOHH

HHHH

HH OOHHHH22NN

HH33NN OO

HH33CCHH

HH33CCHH

NaNaOCHOCH33

CHCH33OHOHCHCH33CCHH CCHCCH33

CHCH33

OOHH

CHCH33OO

(53%)(53%)

CCCC

HH

HH33CC CHCH33

CHCH33OO

Consistent with SConsistent with SNN2-like transition state.2-like transition state.

Good Nucleophiles Attack Less-Crowded CarbonGood Nucleophiles Attack Less-Crowded Carbon

Good Nucleophiles Attack Less-Crowded CarbonGood Nucleophiles Attack Less-Crowded Carbon

1. diethyl ether1. diethyl ether2. H2. H33OO++

MgMgBrBr

++

OO

HH22CC CHCHCHCH33

CHCH22CHCHCHCH33

OOHH

(60%)(60%)

Hydride anion attacksHydride anion attacksless-crowdedless-crowded

carbon.carbon.

Lithium Aluminum Hydride Reduces EpoxidesLithium Aluminum Hydride Reduces Epoxides

OO

HH22CC CH(CHCH(CH22))77CHCH33

1. LiAlH1. LiAlH44, diethyl ether, diethyl ether

2. H2. H22OO

(90%)(90%)OOHH

HH33CC CH(CHCH(CH22))77CHCH33

16.1316.13Acid-Catalyzed Ring-OpeningAcid-Catalyzed Ring-Opening


ExampleExample

OO

HH22CC CHCH22CHCH33CHCH22OOCHCH22CHCH22OOHH

(87-92%)(87-92%)

CHCH33CHCH22OCHOCH22CHCH22OCHOCH22CHCH33 formed only on formed only on

heating and/or longer reaction times.heating and/or longer reaction times.

CHCH33CHCH22OHOH

HH22SOSO44, 25°C, 25°C

ExampleExample

OO

HH22CC CHCH22 HHBrBr

10°C10°CBrBrCHCH22CHCH22OOHH

(87-92%)(87-92%)

BrCHBrCH22CHCH22Br formed only on heating and/or Br formed only on heating and/or

longer reaction times with excess HBr.longer reaction times with excess HBr.

MechanismMechanism

BrBr••••

••••••••

––••••

••••

••

••OO••••

BrBr

CHCH22CHCH22 HH

••••••••

••••OO

HH22CC CHCH22

••••HHBrBr

••••••••

••••

••••OO

HH22CC CHCH22++

HH

Acid-Catalyzed Hydrolysis of Ethylene OxideAcid-Catalyzed Hydrolysis of Ethylene Oxide

••••OO

HH22CC CHCH22

••••

OO••••

HH

HH

HH++

••••OO

HH22CC CHCH22++

HHOO••••

HH

HH

••••

Step 1Step 1Step 1Step 1

••••OO

HH22CC CHCH22++

HH

OO

••••••••

HH

HH


••••++

••

••OO

OO

CHCH22CHCH22

HH

HH

HH

••

••



••••++

••

••OO

OO

CHCH22CHCH22

HH

HH

HH

OO••••

••••

HH

HH

••

••

OO ••••

HH

HH++

HH

••••

••

••OO

OO

CHCH22CHCH22

HH

HH

••••

••

••


Acid-Catalyzed Ring Opening of EpoxidesAcid-Catalyzed Ring Opening of Epoxides

Nucleophile attacks more substituted carbon Nucleophile attacks more substituted carbon of protonated epoxide.of protonated epoxide.

Inversion of configuration at site of nucleophilic Inversion of configuration at site of nucleophilic attack.attack.

Characteristics:Characteristics:

CHCH33OHOH

CCCC

HH

HH33CC CHCH33

CHCH33OO

Consistent with carbocation character of Consistent with carbocation character of transition state.transition state.

Nucleophile Attacks More-Substituted CarbonNucleophile Attacks More-Substituted Carbon

HH22SOSO44

CHCH33CHCH CCCHCH33

CHCH33OOHH

OCHOCH33

(76%)(76%)



(73%)(73%)

HH

HH

OO HHBrBr

HHOOHH

BrBrHH

(57%)(57%)

RR

SS

RR

RR


HH33CC CHCH33

HH33CC CHCH33

OOHH

HHHH

HH OOHHCHCH33OO

CHCH33OHOH

HH22SOSO44


RR

SS

RR

RR


HH33CC CHCH33

HH33CC CHCH33

OOHH

HHHH

HH OHOHCHCH33OOCHCH33OHOH

HH22SOSO44

++ ++CHCH33OO OO

HH33CCHH

HH33CCHH

HH++

HH

anti-Hydroxylation of Alkenesanti-Hydroxylation of Alkenes

HH

HH

CHCH33COCOOOHH

OO

HH

HH

OO

HH22O,O,

HClOHClO44

(80%)(80%)

HHOOHH

OHOHHH

16.1516.15

Preparation of SulfidesPreparation of Sulfides

Prepared by nucleophilic substitution (SPrepared by nucleophilic substitution (SNN2).2).

Preparation of RSR'Preparation of RSR'

++ R'R' XXSSRR––

••••••••

••••

••••RR SS R'R'

••••

CHCH33CHCHCHCH CHCH22

ClCl

NaSCHNaSCH33

methanolmethanolCHCH33CHCHCHCH CHCH22

SCHSCH33

Section 16.18Section 16.18

Spectroscopic AnalysisSpectroscopic Analysis

ofof

Ethers, Epoxides, and SulfidesEthers, Epoxides, and Sulfides

C—O stretching of ethers: between 1070 and C—O stretching of ethers: between 1070 and 1150 cm1150 cm-1-1 (strong) (strong)

Infrared SpectroscopyInfrared Spectroscopy

Infrared Spectrum of Dipropyl Ether Infrared Spectrum of Dipropyl Ether Infrared Spectrum of Dipropyl Ether Infrared Spectrum of Dipropyl Ether

H—C—H—C—OO proton is deshielded by proton is deshielded by OO; range is; range is 3.2-4.0 ppm. 3.2-4.0 ppm.

11H NMR of EthersH NMR of Ethers

CHCH33CCHH22CCHH22OOCCHH22CCHH22CHCH33

0.8 ppm0.8 ppm 0.8 ppm0.8 ppm 1.4 ppm1.4 ppm

3.2 ppm3.2 ppm

Epoxide ring Epoxide ring protons slightly more shielded: protons slightly more shielded: ~2.5 ppm. ~2.5 ppm.

01.02.03.04.05.06.07.08.09.010.0

Chemical shift (Chemical shift (, ppm), ppm)

CHCH33CCHH22CCHH22OCOCHH22CCHH22CHCH33

Dipropyl EtherDipropyl Ether

H—C—H—C—SS proton is less deshielded than H—C— proton is less deshielded than H—C—OO..

11H NMR of SulfidesH NMR of Sulfides

Oxidation of sulfides to sulfoxide deshields anOxidation of sulfides to sulfoxide deshields anadjacent C—H proton by 0.3-0.5 ppm. Anadjacent C—H proton by 0.3-0.5 ppm. Anadditional 0.3-0.5 ppm downfield shift occursadditional 0.3-0.5 ppm downfield shift occurson oxidation of the sulfoxide to the sulfone. on oxidation of the sulfoxide to the sulfone.

2.5 ppm2.5 ppm

CHCH3 3 CCHH22 CHCH2 2 SSCHCH2 2 CCHH22 CHCH33

1313C NMR of Ethers and EpoxidesC NMR of Ethers and Epoxides

Carbons of C—O—C Carbons of C—O—C appear in the rangeappear in the range 57-87 ppm. 57-87 ppm.

6868

2626

OO

But the ring carbonsBut the ring carbonsof epoxides areof epoxides aresomewhat moresomewhat moreshielded.shielded.

CC CC

OO

HH

HH HH

CHCH22(CH(CH22))22CHCH33

4747 5252

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Chapter 16 Ethers, Epoxides, and Sulfides. 16.5 Preparation of Ethers