11-1 Organic Chemistry William H. Brown Christopher S. Foote Brent L. Iverson William H. Brown Christopher S. Foote Brent L. Iverson

11-11-11

Organic Organic ChemistryChemistry

William H. BrownWilliam H. Brown

Christopher S. FooteChristopher S. Foote

Brent L. IversonBrent L. Iverson

William H. BrownWilliam H. Brown

Christopher S. FooteChristopher S. Foote

Brent L. IversonBrent L. Iverson

11-11-22

Ethers & Ethers & EpoxidesEpoxides

Chapter 11Chapter 11

11-11-33

StructureStructure

The functional group of an ether is an oxygen atom bonded to two carbon atoms• in dialkyl ethers, oxygen is sp3 hybridized with bond

angles of approximately 109.5°. • in dimethyl ether, the C-O-C bond angle is 110.3°

H

H O

H

C H

H

H

C••

••

11-11-44

StructureStructure

• in other ethers, the ether oxygen is bonded to an sp2 hybridized carbon

• in ethyl vinyl ether, for example, the ether oxygen is bonded to one sp3 hybridized carbon and one sp2 hybridized carbon

CH3CH2-O-CH=CH2Ethoxyethene

(Ethyl vinyl ether)

11-11-55

Nomenclature: ethersNomenclature: ethers

IUPAC: the longest carbon chain is the parent • name the OR group as an alkoxy substituent

Common names: name the groups bonded to oxygen in alphabetical order followed by the word etherether

2-Methoxy-2-methylpropane

(tert-Butyl methyl ether)

Ethoxyethane(Diethyl ether)

CH3

CH3

CH3CH2OCH2CH3CH3OCCH3

trans-2-Ethoxy-cyclohexanol

OCH2CH3

OH

11-11-66

Nomenclature: ethersNomenclature: ethers

Although cyclic ethers have IUPAC names, their common names are more widely used• IUPAC: prefix ox-ox- shows oxygen in the ring• the suffixes -iraneirane, -etaneetane, -olaneolane, and -aneane show three,

four, five, and six atoms in a saturated ring

Oxirane(Ethylene oxide)

Oxolane(Tetrahydrofuran)

Oxane(Tetrahydropyran)

1,4-Dioxane

OO1

2 3

O

O

OO

Oxetane

11-11-77

Physical PropertiesPhysical Properties

Although ethers are polar compounds, only weak dipole-dipole attractive forces exist between their molecules in the pure liquid state

11-11-88

Physical PropertiesPhysical Properties

Boiling points of ethers are • lower than alcohols of comparable MW• close to those of hydrocarbons of comparable MW

Ethers are hydrogen bond acceptors• they are more soluble in H2O than are hydrocarbons

11-11-99

Preparation of EthersPreparation of Ethers

Williamson ether synthesis:Williamson ether synthesis: SN2 displacement of halide, tosylate, or mesylate by alkoxide ion

2-Methoxypropane(Isopropyl methyl ether)

Iodomethane(Methyl iodide)

Sodiumisopropoxide

++CH3 CH3

CH3ICH3CHO-Na

+ CH3CHOCH3 Na+I-SN2

11-11-1010


• yields are highest with methyl and 1° halides, • lower with 2° halides (competing -elimination)• reaction fails with 3° halides (-elimination only)

CH3

CH3

CH3CO- K+ CH3BrSN2

CH3

CH3

CH3COCH3 K+Br-++

Potassiumtert-butoxide

Bromomethane(Methyl bromide)

2-Methoxy-2-methylpropane(tert-Butyl methyl ether)

CH3

CH3

CH3CBr CH3O-Na

+ E2CH3

CH3C=CH2 CH3OH Na+Br

-+++

2-Bromo-2-methylpropane

Sodiummethoxide

2-Methylpropene

11-11-1111


Acid-catalyzed dehydration of alcohols• diethyl ether and several other ethers are made on an

industrial scale this way

• a specific example of an SN2 reaction in which a poor leaving group (OH-) is converted to a better one (H2O)

2CH3CH2OHH2SO4140°C CH3CH2OCH2CH3 H2O+

Ethanol Diethyl ether

11-11-1212


• Step 1: proton transfer gives an oxonium ion

• Step 2: nucleophilic displacement of H2O by the OH group of the alcohol gives a new oxonium ion

CH3CH2-O-HO

OH-O-S-O-H CH3CH2-O-H

H O

O- O-S-O-H

++

An oxonium ion

+

fast andreversible

CH3CH2-O-H CH3CH2-O-H

H

SN2

H

CH3CH2-O-CH2CH3

H

O-H

A new oxonium ion

++

++

11-11-1313


Step 3: proton transfer to solvent completes the reaction

CH3CH2-O-CH2CH3

H H

O-H CH3CH2-O-CH2CH3 H O-H

H

++

proton transfer

++

11-11-1414


Acid-catalyzed addition of alcohols to alkenes• yields are highest using an alkene that can form a

stable carbocation• and using methanol or a 1° alcohol that is not prone to

undergo acid-catalyzed dehydration

+

acidcatalyst

2-Methoxy-2-methylpropane

CH3 CH3

CH3

CH3C=CH2 CH3OH CH3COCH3

11-11-1515


• Step 1: protonation of the alkene gives a carbocation

• Step 2: reaction of the carbocation (an electrophile) with the alcohol (a nucleophile) gives an oxonium ion

CH3

CH3C=CH2 H O

H

CH3

CH3

CH3CCH3 O

H

CH3++

++

CH3CCH3

CH3

HOCH3

OCH3CCH3

H

CH3

CH3

++

+

11-11-1616


Step 3: proton transfer to solvent completes the reaction

CH3 O H

O

CH3

CH3CCH3

H CH3

CH3 O

H

H

O

CH3CCH3

CH3

CH3

++

++

11-11-1717

Cleavage of EthersCleavage of Ethers

Ethers are cleaved by HX to an alcohol and a haloalkane

• cleavage requires both a strong acid and a good nucleophile; therefore, the use of concentrated HI (57%) and HBr (48%)

• cleavage by concentrated HCl (38%) is less effective, primarily because Cl- is a weaker nucleophile in water than either I- or Br-

R-O-R + H-X R-O-H + R-X

11-11-1818


A dialkyl ether is cleaved to two moles of haloalkane

O 2HBr Br H2Oheat+ +2

Dibutyl ether 1-Bromobutane

11-11-1919


• Step 1: proton transfer to the oxygen atom of the ether gives an oxonium ion

• Step 2: nucleophilic displacement on the 1° carbon gives a haloalkane and an alcohol

• the alcohol is then converted to an haloalkane by another SN2 reaction

CH3CH2-O-CH2CH3 H O H

H

CH3CH2-O-CH2CH3

H H

O H+

++

+

An oxonium ion

fast andreversible

Br:- CH3CH2-O-CH2CH3

H

SN2CH3CH2-Br

H

O-CH2CH3

++ +

11-11-2020


3°, allylic, and benzylic ethers are particularly sensitive to cleavage by HX• tert-butyl ethers are cleaved by HCl at room temp• in this case, protonation of the ether oxygen is

followed by C-O cleavage to give the tert-butyl cation

OHCl+

OH+

SN1

+ Cl-

Cl

A 3° carbocationintermediate

A tert-butylether

11-11-2121

Oxidation of EthersOxidation of Ethers

Ethers react with O2 at a C-H bond adjacent to the ether oxygen to give hydroperoxides• reaction occurs by a radical chain mechanism

Hydroperoxide:Hydroperoxide: a compound containing the OOH group

O O2 O

O-O-H

A hydroperoxideDiethyl ether+

OO2

OO-O-H

Diisopropyl ether

+

A hydroperoxide

11-11-2222

Silyl Ethers as Protecting GroupsSilyl Ethers as Protecting Groups

When dealing with compounds containing two or more functional groups, it is often necessary to protect one of them (to prevent its reaction) while reacting at the other• suppose you wish to carry out this transformation

4-Pentyn-1-ol 4-Heptyn-1-ol

OH

H

OH?

11-11-2323


• the new C-C bond can be formed by alkylation of an alkyne anion

• the OH group, however, is more acidic (pKa 16-18) than the terminal alkyne (pKa 25)

• treating the compound with one mole of NaNH2 will give the alkoxide anion rather than the alkyne anion

OH

H Na+NH2-

O-Na+

H NH3

pKa 25pKa 16-18

++

11-11-2424


A protecting group must• add easily to the sensitive group• be resistant to the reagents used to transform the

unprotected functional group(s)• be removed easily to regenerate the original functional

group

In this chapter, we discuss trimethylsilyl (TMS) and other trialkylsilyl ethers as OH protecting groups

11-11-2525


Silicon is in Group 4A of the Periodic Table, immediately below carbon• like carbon, it also forms tetravalent compounds such

as the following

O=Si=O CH3-Si-CH3

CH3

CH3

CH3-Si-Cl

CH3

CH3

H-Si-HH

H

Silicon dioxide Tetramethylsilane ChlorotrimethylsilaneSilane

11-11-2626


An -OH group can be converted to a silyl ether by treating it with a trialkylsilyl chloride in the presence of a 3° amine

RCH2OH Cl-Si-CH3

CH3

CH3

Et3N RCH2O-Si-CH3

CH3

CH3

Et3NH+Cl-+

Chlorotri-methylsilane

A trimethylsilylether

+ +

Triethyl-amine

Triethyl-ammonium

chloride

11-11-2727


• replacement of one of the methyl groups of the TMS group by tert-butyl gives a tert-butyldimethylsilyl (TBDMS) group, which is considerably more stable than the TMS group

• other common silyl protecting groups include the TES and TIPS groups

Si ClMe

MeMe

Si ClMe

MeSi ClSi Cl

EtEt

Et

Trimethylsilylchloride(TMSCl)

t-Butyldimethylsilylchloride

(TBDMSCl)

Triisopropylsilylchloride(TIPSCl)

Triethylsilylchloride(TESCl)

11-11-2828


• silyl ethers are unaffected by most oxidizing and reducing agents, and are stable to most nonaqueous acids and bases

• the TBDMS group is stable in aqueous solution within the pH range 2 to 12, which makes it one of the most widely used -OH protecting groups

• silyl blocking groups are most commonly removed by treatment with fluoride ion, generally in the form of tetrabutylammonium fluoride

RCH2O Si F- Bu4N+F-

THFRCH2OH SiF

A TBDMS-protectedalcohol

+ +

11-11-2929


• we can use the TMS group as a protecting group in the conversion of 4-pentyn-1-ol to 4-heptyn-1-ol

OH

H

O

H2. Na+NH2

-

3. Br

4-Heptyn-1-ol

4-Pentyn-1-ol

Si

O Si CH3

OH+

1. (CH3)3SiCl

CH3

CH3

CH3

CH3

CH34. Bu4N+F-

F Si CH3

CH3

CH3

11-11-3030

EpoxidesEpoxides

Epoxide:Epoxide: a cyclic ether in which oxygen is one atom of a three-membered ring• simple epoxides are named as derivatives of oxirane• where the epoxide is part of another ring system, it is

shown by the prefix epoxy-epoxy-• common names are derived from the name of the

alkene from which the epoxide is formally derived


CH2H2C

O1

2 3

cis-2,3-Dimethyloxirane(cis-2-Butene oxide)

1,2-Epoxycyclohexane(Cyclohexene oxide)

CO

C

HCH3HH3C

H

H

O1

2

11-11-3131

Synthesis of EpoxidesSynthesis of Epoxides

Ethylene oxide, one of the few epoxides manufactured on an industrial scale, is prepared by air oxidation of ethylene


CH2H2C

O

2CH2=CH2Ag

2+ O2

11-11-3232


The most common laboratory method is oxidation of an alkene using a peroxycarboxylic acid (a peracid)

CO-

COOH

Mg2+ CH3COOH

COOH

Cl

Magnesium monoperoxyphthalate

(MMPP)

2

Peroxyacetic acid (Peracetic acid)

meta-chloroperoxy-benzoic acid

(MCPBA)

O O

O

O

11-11-3333


Epoxidation of cyclohexene

RCOOHO

CH2Cl2O

H

H

RCOHO

A carboxylic acid

1,2-Epoxycyclohexane (Cyclohexene oxide)

A peroxy-carboxylic acid

Cyclohexene

++ RCOOHO

CH2Cl2O

H

H

RCOHO

A carboxylic acid

1,2-Epoxycyclohexane (Cyclohexene oxide)

A peroxy-carboxylic acid

Cyclohexene

++

11-11-3434


Epoxidation is stereospecific: • epoxidation of cis-2-butene gives only cis-2,3-

dimethyloxirane• epoxidation of trans-2-butene gives only trans-2,3-

dimethyloxirane

C CH3C

H CH3

H

RCO3HH3C H

H CH3

C C

Otrans-2-Butene trans-2,3-Dimethyloxirane

(a racemic mixture)

H CH3H3C H

C C

O

+

11-11-3535


A mechanism for alkene epoxidation must take into account that the reaction• takes place in nonpolar solvents, which means that no

ions are involved• is stereospecific with retention of the alkene

configuration, which means that even though the pi bond is broken, at no time is there free rotation about the remaining sigma bond

11-11-3636

Synthesis of Epoxides Synthesis of Epoxides

A mechanism for alkene epoxidation

1

23

4

C C

OH

OO C

R

O

C C

O

C

R

O

H

11-11-3737


Epoxides are can also be synthesized via halohydrins

• the second step is an internal SN2 reaction

CH3CH=CH2Cl2, H2O

CH3CH-CH2

OH

Cl

NaOH, H2OO

CH3CH CH2

A chlorohydrin(racemic)

Propene Methyloxirane(racemic)

SN2

An epoxide

internal SN2+ ClC C

O

Cl

C CO

11-11-3838


• halohydrin formation is both regioselective and stereoselective; for alkenes that show cis,trans isomerism, it is also stereospecific (Section 6.3F)

• conversion of a halohydrin to an epoxide is stereoselective

Problem:Problem: account for the fact that conversion of cis-2-butene to an epoxide by the halohydrin method gives only cis-2,3-dimethyloxirane

cis-2,3-Dimethyloxiranecis-2-Butene

C CH

CH3

H

H3CC C

H3CH

O

CH3H

1. Cl2, H2O

2. NaOH, H2O

11-11-3939


Sharpless epoxidation• stereospecific and enantioselective

OH

R1R2

R3

Ti(O-iPr)4

Ti(O-iPr)4

OOH

R3

R2

OH

R1

O

R3

R2

OH

R1

O

A

B

OH

OH

(-)-Diethyl tartrate

+

(+)-Diethyltartrate

+

+An allylicalcohol

tert-Butylhydroperoxide

EtOOCCOOEt

OH

OHEtOOC

COOEtOH

OH(2S,3S)-(-)-Diethyl tartrate (2R,3R)-(+)-Diethyl tartrate

11-11-4040

Reactions of EpoxidesReactions of Epoxides

Ethers are not normally susceptible to attack by nucleophiles

Because of the strain associated with the three-membered ring, epoxides readily undergo a variety of ring-opening reactions

+ HNu C C

Nu

HO

C C

O

:

11-11-4141


Acid-catalyzed ring opening• in the presence of an acid catalyst, such as sulfuric

acid, epoxides are hydrolyzed to glycols

+


1,2-Ethanediol(Ethylene glycol)

H2O H+HO

OHO

11-11-4242


Step 1: proton transfer to oxygen gives a bridged oxonium ion intermediate

Step 2: backside attack by water (a nucleophile) on the oxonium ion (an electrophile) opens the ring

Step 3:proton transfer to solvent completes the reaction

O

OH H

H2C CH2

OH H

H

H2C CH2

O

H+

OH H

CH2 CH2

OH

+

OH H

+

+

1(1)

2

2

3

3

CH2 CH2

OH

OH

H3O+

11-11-4343


Attack of the nucleophile on the protonated epoxide shows anti stereoselectivity• hydrolysis of an epoxycycloalkane gives a trans-1,2-

diol

H2OH+

1,2-Epoxycyclopentane(Cyclopentene oxide)

(achiral)

trans-1,2-Cyclopentanediol(a racemic mixture)

O

OH

OH

OH

OH+ +

11-11-4444


Compare the stereochemistry of the glycols formed by these two methods

RCO3H

OsO4, t-BuOOH

H

H

O

OH

OH

H+

H2O

OH

OHtrans-1,2-Cyclopentanediol

(formed as a racemic mixture)

cis-1,2-Cyclopentanediol(achiral)

OH

OH

+

11-11-4545

EpoxidesEpoxides

• the value of epoxides is the variety of nucleophiles that will open the ring and the combinations of functional groups that can be prepared from them

HSCH2CHOH

CH3

H2O/H3O+

HOCH2CHOHCH3

CHH2C

O

CH3

H2NCH2CHOH

CH3

CCH2CHOHCH3

N

Na+SH-/ H2O

NH3Na+C N-/H2O

2. H2O1. HC C- Na+

HC CCH2CHOH

CH3

A -mercaptoalcohol

Methyloxirane

A -aminoalcoholA -hydroxynitrile

A -alkynylalcoholA glycol

11-11-4646


Treatment of an epoxide with lithium aluminum hydride, LiAlH4, reduces the epoxide to an alcohol• the nucleophile attacking the epoxide ring is hydride

ion, H:-

Phenyloxirane(Styrene oxide)

1-Phenylethanol

CH2

O

CH

OH

1. LiAlH4

2. H2OCH-CH3

11-11-4747

Ethylene Oxide Ethylene Oxide

• ethylene oxide is a valuable building block for organic synthesis because each of its carbons has a functional group

Na+CN-

CH3NH2

C C-Na+CH3

OH

O N

OH

CH3H

N COH

N OCH3

O

H2SO4

H2/M

N

OH

CH3

OH

N N-HCH3

OH

H2N

SOCl2

NH3

N

Cl

CH3

Cl

(1)(2)

(3) (4) (6)

(8)(5) (7)

11-11-4848

Ethylene OxideEthylene Oxide

• part of the local anesthetic procaine is derived from ethylene oxide

• the hydrochloride salt of procaine is marketed under the trade name Novocaine

O

O

H2N

N

Procaine

OH

O

H2N

HON+

NHO

+

Ethyleneoxide

Diethyl-amine

11-11-4949

EpichlorohydrinEpichlorohydrin

The epoxide epichlorohydrin is also a valuable building block because each of its three carbons contains a reactive functional group• epichlorohydrin is synthesized from propene

Cl2Cl HCl

3-Chloropropene(Allyl chloride)

Propene

+ 500°C +

Cl2/H2O ClOH

Cl HCl+ +Cl

OCl

OHCl Ca(OH)2 CaCl2

Epichlorohydrin(racemic)

+ +Cl

Step 1:

Step 2:

Step 3:

11-11-5050


• the characteristic structural feature of a product derived from epichlorohydrin is a three-carbon unit with -OH on the middle carbon, and a carbon, nitrogen, oxygen, or sulfur nucleophile on the two end carbons

Epichlorohydrin

OCl

ONu

OHNuNuNu Nu

11-11-5151


• an example of a compound containing the three-carbon skeleton of epichlorohydrin is nadolol, a -adrenergic blocker with vasodilating activity

HO

HO

OHO

HN

Nadolol(racemic)

HO

HO

O-

H2N

a nucleophile derivedby removal of the acidic H from an -OH group

the nitrogennucleophile of a 1° amine

OCl

11-11-5252

Crown EthersCrown Ethers

Crown ether:Crown ether: a cyclic polyethera cyclic polyether derived from ethylene glycol or a substituted ethylene glycol• the parent name is crown, preceded by

a number describing the size of the ring and followed by the number of oxygen atoms in the ring

O

OO

O

OO

18-Crown-6

11-11-5353

Crown EthersCrown Ethers

The diameter of the cavity created by the repeating oxygen atoms is comparable to the diameter of alkali metal cations• 18-crown-6 provides very

effective solvation for K+

11-11-5454

ThioethersThioethers

The sulfur analog of an ether• IUPAC name: select the longest carbon chain as the

parent and name the sulfur-containing substituent as an alkylsulfanyl group

• common name: list the groups bonded to sulfur followed by the word sulfidesulfide

Ethylsulfanylethane(Diethyl sulfide)

2-Ethylsulfanylpropane(Ethyl isopropyl sulfide)

S S

11-11-5555

NomenclatureNomenclature

Disulfide:Disulfide: contains an -S-S-S-S- group• IUPAC name: select the longest carbon chain as the

parent and name the disulfide-containing substituent as an alkyldisulfanyl group

• Common name: list the groups bonded to sulfur and add the word disulfidedisulfide

Ethyldisulfanylethane(Diethyl disulfide)

SS

11-11-5656

Preparation of SulfidesPreparation of Sulfides

Symmetrical sulfides: treat one mole of Na2S with two moles of a haloalkane

A sulfide++ Na2S2RX RSR 2NaX

ClClNa2S

S2Na

+Cl

-SN2

Thiolane(Tetrahydrothiophene)

1,4-Dichlorobutane

++

11-11-5757

Preparation of SulfidesPreparation of Sulfides

Unsymmetrical sulfides: convert a thiol to its sodium salt and then treat this salt with an alkyl halide (a variation on the Williamson ether synthesis)

SN2

Sodium 1-decanethiolate+

+

CH3(CH2)8CH2S- Na+ CH3I

CH3(CH2)8CH2SCH3 Na+ I-

1-Methylsulfanyldecane(Decyl methyl sulfide)

11-11-5858

Oxidation SulfidesOxidation Sulfides

Sulfides can be oxidized to sulfoxides and sulfones by the proper choice of experimental conditions

25oC 25oC

Methyl phenyl sulfide

Methyl phenyl sulfoxide

Methyl phenyl sulfone

S-CH3S-CH3H2 O2 NaIO4

OS-CH3

O

O

2CH3-S-CH3 O2 2CH3-S-CH3

Ooxides ofnitrogen

Dimethyl sulfide Dimethyl sulfoxide+

11-11-5959

Ethers Ethers

& &

EpoxidesEpoxidesEnd of Chapter 11End of Chapter 11

Documents

11-1 Organic Chemistry William H. Brown Christopher S. Foote Brent L. Iverson William H. Brown Christopher S. Foote Brent L. Iverson