Espacio deFormaciónMultimodal

Klein, D. (2012). Ethers and Epoxides; Thiols and Sulfides. En Organic Chemistry(pp. 630-634). USA: Wiley.

Ethers and Epoxides; Thiols and Sulfides

630 CHAPTER 14 Ethers and Epoxides; Thiols and Sulfides

MEDICALLYSPEAKING Polyether Antibiotics

O

Me

O

Me

O

Me

O

Me

H

HMe

H

H

MeH

H MeH

H

Me

OO

O

O

O O

O

O

Nonactin

O

HO HO Me

HH

MeMe

HMe

H

Et

OO O

O

OHMe

HMe

MeO

Me

OHO

Monensin

ionophores

lipophilic

14.5 Preparation of Ethers

Industrial Preparation of Diethyl EtherDiethyl ether is prepared industrially via the acid-catalyzed dehydration of ethanol. The mecha-nism of this process is believed to involve an SN2 process.

OH

Proton transfer SN2 attack Proton transfer

Ethanol Diethyl ether

O

S O

O

O

HH O

H

O+H

H

O+

HO HO

A molecule of ethanol is protonated and then attacked by another molecule of ethanol in an SN2 process. As a final step, deprotonation generates the product. Notice that a proton is used

klein_c14_622-670hr.indd 630 11/8/10 6:06 PM

630 CHAPTER 14 Ethers and Epoxides; Thiols and Sulfides

MEDICALLYSPEAKING Polyether Antibiotics

O

Me

O

Me

O

Me

O

Me

H

HMe

H

H

MeH

H MeH

H

Me

OO

O

O

O O

O

O

Nonactin

O

HO HO Me

HH

MeMe

HMe

H

Et

OO O

O

OHMe

HMe

MeO

Me

OHO

Monensin

ionophores

lipophilic

14.5 Preparation of Ethers

Industrial Preparation of Diethyl EtherDiethyl ether is prepared industrially via the acid-catalyzed dehydration of ethanol. The mecha-nism of this process is believed to involve an SN2 process.

OH

Proton transfer SN2 attack Proton transfer

Ethanol Diethyl ether

O

S O

O

O

HH O

H

O+H

H

O+

HO HO

A molecule of ethanol is protonated and then attacked by another molecule of ethanol in an SN2 process. As a final step, deprotonation generates the product. Notice that a proton is used

klein_c14_622-670hr.indd 630 11/8/10 6:06 PM

14.5 Preparation of Ethers 631

MECHANISM 14.1 THE WILLIAMSON ETHER SYNTHESIS

NaXR HO R CH3ONa+

R O–

±The resulting alkoxide ion

then functions as a nucleophileand attacks the alkyl halide

in an SN2 process

C X

H

H

HIn the first step,

a hydride ion functions as a baseand deprotonates the alcohol

Na±

H–

Proton transfer Nucleophilic attack

This process is named after Alexander Williamson, a British scientist who first demonstrated this method in 1850 as a way of preparing diethyl ether. Since the second step is an SN2 process, steric effects must be considered. Specifically, the process works best when methyl or primary alkyl halides are used. Secondary alkyl halides are less efficient because elimination is favored over substitution and tertiary alkyl halides cannot be used. This limitation must be taken into account when choos-ing which C O bond to form. For example, consider the structure of tert-butyl methyl ether. MTBE was used heavily as a gasoline additive until concerns emerged that it might contribute to groundwater contamination. As a result, its use has declined in recent years. There are two possible routes to consider in the preparation of MTBE, but only one is efficient.

OH

CH3OH

O

MTBE

1) NaH2) CH3I

1) NaH

I2)

The first route is efficient because it employs a methyl halide, which is a suitable substrate for an SN2 process. The second route does not work because it employs a tertiary alkyl halide, which will undergo elimination rather than substitution.

BY THE WAYtert

tert

O

tert-Butyl methyl ether(MTBE)

in the first step of the mechanism, and then another proton is liberated in the last step of the mechanism. The acid is therefore a catalyst (not consumed by the reaction) that enables the SN2 process to proceed.

This process has many limitations. For example, it only works well for primary alcohols (since it proceeds via an SN2 pathway), and it produces symmetrical ethers. As a result, this pro-cess for preparing ethers is too limited to be of any practical value for organic synthesis.

Williamson Ether SynthesisEthers can be readily prepared via a two-step process called a Williamson ether synthesis.

R OH R O R1) NaH2) RX

We learned both of these steps in the previous chapter. In the first step, the alcohol is deproton-ated to form an alkoxide ion. In the second step, the alkoxide ion functions as a nucleophile in an SN2 reaction (Mechanism 14.1).

klein_c14_622-670hr.indd 631 11/8/10 6:06 PM

630 CHAPTER 14 Ethers and Epoxides; Thiols and Sulfides

MEDICALLYSPEAKING Polyether Antibiotics

O

Me

O

Me

O

Me

O

Me

H

HMe

H

H

MeH

H MeH

H

Me

OO

O

O

O O

O

O

Nonactin

O

HO HO Me

HH

MeMe

HMe

H

Et

OO O

O

OHMe

HMe

MeO

Me

OHO

Monensin

ionophores

lipophilic

14.5 Preparation of Ethers

Industrial Preparation of Diethyl EtherDiethyl ether is prepared industrially via the acid-catalyzed dehydration of ethanol. The mecha-nism of this process is believed to involve an SN2 process.

OH

Proton transfer SN2 attack Proton transfer

Ethanol Diethyl ether

O

S O

O

O

HH O

H

O+H

H

O+

HO HO

A molecule of ethanol is protonated and then attacked by another molecule of ethanol in an SN2 process. As a final step, deprotonation generates the product. Notice that a proton is used

klein_c14_622-670hr.indd 630 11/8/10 6:06 PM

14.5 Preparation of Ethers 631

MECHANISM 14.1 THE WILLIAMSON ETHER SYNTHESIS

NaXR HO R CH3ONa+

R O–

±The resulting alkoxide ion

then functions as a nucleophileand attacks the alkyl halide

in an SN2 process

C X

H

H

HIn the first step,

a hydride ion functions as a baseand deprotonates the alcohol

Na±

H–

Proton transfer Nucleophilic attack

This process is named after Alexander Williamson, a British scientist who first demonstrated this method in 1850 as a way of preparing diethyl ether. Since the second step is an SN2 process, steric effects must be considered. Specifically, the process works best when methyl or primary alkyl halides are used. Secondary alkyl halides are less efficient because elimination is favored over substitution and tertiary alkyl halides cannot be used. This limitation must be taken into account when choos-ing which C O bond to form. For example, consider the structure of tert-butyl methyl ether. MTBE was used heavily as a gasoline additive until concerns emerged that it might contribute to groundwater contamination. As a result, its use has declined in recent years. There are two possible routes to consider in the preparation of MTBE, but only one is efficient.

OH

CH3OH

O

MTBE

1) NaH2) CH3I

1) NaH

I2)

The first route is efficient because it employs a methyl halide, which is a suitable substrate for an SN2 process. The second route does not work because it employs a tertiary alkyl halide, which will undergo elimination rather than substitution.

BY THE WAYtert

tert

O

tert-Butyl methyl ether(MTBE)

in the first step of the mechanism, and then another proton is liberated in the last step of the mechanism. The acid is therefore a catalyst (not consumed by the reaction) that enables the SN2 process to proceed.

This process has many limitations. For example, it only works well for primary alcohols (since it proceeds via an SN2 pathway), and it produces symmetrical ethers. As a result, this pro-cess for preparing ethers is too limited to be of any practical value for organic synthesis.

Williamson Ether SynthesisEthers can be readily prepared via a two-step process called a Williamson ether synthesis.

R OH R O R1) NaH2) RX

We learned both of these steps in the previous chapter. In the first step, the alcohol is deproton-ated to form an alkoxide ion. In the second step, the alkoxide ion functions as a nucleophile in an SN2 reaction (Mechanism 14.1).

klein_c14_622-670hr.indd 631 11/8/10 6:06 PM

632 CHAPTER 14 Ethers and Epoxides; Thiols and Sulfides

LEARN the skill

O

SOLUTION

O

Phenyl Primary

sp2N sp2

N

OHX±

OOH1) NaOH2) CH3CH2I

14.5

O

(a)

O

(b)

OMe

(c)

14.6

SKILLBUILDER 14.2 PREPARING AN ETHER VIA A WILLIAMSON ETHER SYNTHESIS

STEP 1

O

14.7

O

Try Problems 14.33a,c, 14.37, 14.40, 14.42d, 14.43bneed more PRACTICE?

APPLY the skill

PRACTICE the skill

LOOKING BACK

STEP 3

STEP 2

N

klein_c14_622-670hr.indd 632 11/8/10 6:06 PM

14.5 Preparation of Ethers 631

MECHANISM 14.1 THE WILLIAMSON ETHER SYNTHESIS

NaXR HO R CH3ONa+

R O–

±The resulting alkoxide ion

then functions as a nucleophileand attacks the alkyl halide

in an SN2 process

C X

H

H

HIn the first step,

a hydride ion functions as a baseand deprotonates the alcohol

Na±

H–

Proton transfer Nucleophilic attack

This process is named after Alexander Williamson, a British scientist who first demonstrated this method in 1850 as a way of preparing diethyl ether. Since the second step is an SN2 process, steric effects must be considered. Specifically, the process works best when methyl or primary alkyl halides are used. Secondary alkyl halides are less efficient because elimination is favored over substitution and tertiary alkyl halides cannot be used. This limitation must be taken into account when choos-ing which C O bond to form. For example, consider the structure of tert-butyl methyl ether. MTBE was used heavily as a gasoline additive until concerns emerged that it might contribute to groundwater contamination. As a result, its use has declined in recent years. There are two possible routes to consider in the preparation of MTBE, but only one is efficient.

OH

CH3OH

O

MTBE

1) NaH2) CH3I

1) NaH

I2)

The first route is efficient because it employs a methyl halide, which is a suitable substrate for an SN2 process. The second route does not work because it employs a tertiary alkyl halide, which will undergo elimination rather than substitution.

BY THE WAYtert

tert

O

tert-Butyl methyl ether(MTBE)

in the first step of the mechanism, and then another proton is liberated in the last step of the mechanism. The acid is therefore a catalyst (not consumed by the reaction) that enables the SN2 process to proceed.

This process has many limitations. For example, it only works well for primary alcohols (since it proceeds via an SN2 pathway), and it produces symmetrical ethers. As a result, this pro-cess for preparing ethers is too limited to be of any practical value for organic synthesis.

Williamson Ether SynthesisEthers can be readily prepared via a two-step process called a Williamson ether synthesis.

R OH R O R1) NaH2) RX

We learned both of these steps in the previous chapter. In the first step, the alcohol is deproton-ated to form an alkoxide ion. In the second step, the alkoxide ion functions as a nucleophile in an SN2 reaction (Mechanism 14.1).

klein_c14_622-670hr.indd 631 11/8/10 6:06 PM

632 CHAPTER 14 Ethers and Epoxides; Thiols and Sulfides

LEARN the skill

O

SOLUTION

O

Phenyl Primary

sp2N sp2

N

OHX±

OOH1) NaOH2) CH3CH2I

14.5

O

(a)

O

(b)

OMe

(c)

14.6

SKILLBUILDER 14.2 PREPARING AN ETHER VIA A WILLIAMSON ETHER SYNTHESIS

STEP 1

O

14.7

O

Try Problems 14.33a,c, 14.37, 14.40, 14.42d, 14.43bneed more PRACTICE?

APPLY the skill

PRACTICE the skill

LOOKING BACK

STEP 3

STEP 2

N

klein_c14_622-670hr.indd 632 11/8/10 6:06 PM

14.6 Reactions of Ethers 633

Alkoxymercuration-DemercurationRecall from Section 9.5 that alcohols can be prepared from alkenes via a process called oxymercuration-demercuration.

R

R

R

H

RR

H

R

HO

H2) NaBH4

1) Hg(OAc)2 , H2O

The net result is a Markovnikov addition of water (H and OH) across an alkene. That is, the hydroxyl group is ultimately placed at the more substituted position. The mechanism for this process was discussed in Section 9.3.

If an alcohol (ROH) is used in place of water, then the result is a Markovnikov addition of the alcohol (RO and H) across the alkene. This process is called alkoxymercuration-demercuration, and it can be used as another way of preparing ethers.

R

R

R

H RO

RR

H

RH2) NaBH4

1) Hg(OAc)2, ROH

CONCEPTUAL CHECKPOINT

14.6 Reactions of Ethers

Ethers are generally unreactive under basic or mildly acidic conditions. As a result, they are an ideal choice as solvents for many reactions. Nevertheless, ethers are not completely unreactive, and two reactions of ethers will be explored in this section.

Acidic CleavageWhen heated with a concentrated solution of a strong acid, an ether will undergo acidic cleav-age, in which the ether is converted into two alkyl halides.

H2OR O R R X R XHexcess

heatX

± ±

This process involves two substitution reactions (Mechanism 14.2).

14.8

OEt

(a)

O

(b)

OMe(c)

O

(d)

14.9

14.10

klein_c14_622-670hr.indd 633 11/8/10 6:06 PM

632 CHAPTER 14 Ethers and Epoxides; Thiols and Sulfides

LEARN the skill

O

SOLUTION

O

Phenyl Primary

sp2N sp2

N

OHX±

OOH1) NaOH2) CH3CH2I

14.5

O

(a)

O

(b)

OMe

(c)

14.6

SKILLBUILDER 14.2 PREPARING AN ETHER VIA A WILLIAMSON ETHER SYNTHESIS

STEP 1

O

14.7

O

Try Problems 14.33a,c, 14.37, 14.40, 14.42d, 14.43bneed more PRACTICE?

APPLY the skill

PRACTICE the skill

LOOKING BACK

STEP 3

STEP 2

N

klein_c14_622-670hr.indd 632 11/8/10 6:06 PM

14.6 Reactions of Ethers 633

Alkoxymercuration-DemercurationRecall from Section 9.5 that alcohols can be prepared from alkenes via a process called oxymercuration-demercuration.

R

R

R

H

RR

H

R

HO

H2) NaBH4

1) Hg(OAc)2 , H2O

The net result is a Markovnikov addition of water (H and OH) across an alkene. That is, the hydroxyl group is ultimately placed at the more substituted position. The mechanism for this process was discussed in Section 9.3.

If an alcohol (ROH) is used in place of water, then the result is a Markovnikov addition of the alcohol (RO and H) across the alkene. This process is called alkoxymercuration-demercuration, and it can be used as another way of preparing ethers.

R

R

R

H RO

RR

H

RH2) NaBH4

1) Hg(OAc)2, ROH

CONCEPTUAL CHECKPOINT

14.6 Reactions of Ethers

Ethers are generally unreactive under basic or mildly acidic conditions. As a result, they are an ideal choice as solvents for many reactions. Nevertheless, ethers are not completely unreactive, and two reactions of ethers will be explored in this section.

Acidic CleavageWhen heated with a concentrated solution of a strong acid, an ether will undergo acidic cleav-age, in which the ether is converted into two alkyl halides.

H2OR O R R X R XHexcess

heatX

± ±

This process involves two substitution reactions (Mechanism 14.2).

14.8

OEt

(a)

O

(b)

OMe(c)

O

(d)

14.9

14.10

klein_c14_622-670hr.indd 633 11/8/10 6:06 PM

634 CHAPTER 14 Ethers and Epoxides; Thiols and Sulfides

MECHANISM 14.2 ACIDIC CLEAVAGE OF AN ETHER

FORMATION OF FIRST ALKYL HALIDE

A halide ion functions as a

nucleophile and attacksthe oxonium ion, ejecting

an alcohol as a leaving group

The ether is protonated,

generating anoxonium ion

H XH3C CH3O HH3C O XH3CO CH3

HH3C

+X–

± ±

SN2Proton transfer

H2O

FORMATION OF SECOND ALKYL HALIDE

The alcohol isprotonated,

generating an oxonium ion

H XHH3C O H3C XO HH

H3C + X–

± ±

SN2Proton transfer

A halide ion functions as a nucleophile and attacks the oxonium ion, ejecting water as

a leaving group

The formation of the first alkyl halide begins with protonation of the ether to form a good leaving group, followed by an SN2 process in which a halide ion functions as a nucleophile and attacks the protonated ether. The second alkyl halide is then formed with the same two steps—protonation followed by an SN2 attack. If either R group is tertiary, then substitution is more likely to proceed via an SN1 process rather than SN2.

When a phenyl ether is cleaved under acidic conditions, the products are phenol and an alkyl halide.

RX H2O

OR

OH

Phenol

excessHX

heat ± ±

The phenol is not further converted into a halide, because neither SN2 nor SN1 processes are efficient at sp2-hybridized centers.

Both HI and HBr can be used to cleave ethers. HCl is less efficient, and HF does not cause acidic cleavage of ethers. This reactivity is a result of the relative nucleophilicity of the halide ions.

LOOKING BACKFor a review of the relative nucleophilicity of the halide ions, see Section 7.8.

CONCEPTUAL CHECKPOINT

14.11 Predict the products for each of the following reactions:

O ?(a)

excessHBrheat

O

?(b)

excessHI

heat

O

?(c)

excessHBrheat

O ?(d)

excessHI

heat

O

?(e)

excessHI

heat

O

?(f)

excessHBrheat

klein_c14_622-670hr1.indd 634 11/15/10 1:24 PM

14.6 Reactions of Ethers 633

Alkoxymercuration-DemercurationRecall from Section 9.5 that alcohols can be prepared from alkenes via a process called oxymercuration-demercuration.

R

R

R

H

RR

H

R

HO

H2) NaBH4

1) Hg(OAc)2 , H2O

The net result is a Markovnikov addition of water (H and OH) across an alkene. That is, the hydroxyl group is ultimately placed at the more substituted position. The mechanism for this process was discussed in Section 9.3.

If an alcohol (ROH) is used in place of water, then the result is a Markovnikov addition of the alcohol (RO and H) across the alkene. This process is called alkoxymercuration-demercuration, and it can be used as another way of preparing ethers.

R

R

R

H RO

RR

H

RH2) NaBH4

1) Hg(OAc)2, ROH

CONCEPTUAL CHECKPOINT

14.6 Reactions of Ethers

Ethers are generally unreactive under basic or mildly acidic conditions. As a result, they are an ideal choice as solvents for many reactions. Nevertheless, ethers are not completely unreactive, and two reactions of ethers will be explored in this section.

Acidic CleavageWhen heated with a concentrated solution of a strong acid, an ether will undergo acidic cleav-age, in which the ether is converted into two alkyl halides.

H2OR O R R X R XHexcess

heatX

± ±

This process involves two substitution reactions (Mechanism 14.2).

14.8

OEt

(a)

O

(b)

OMe(c)

O

(d)

14.9

14.10

klein_c14_622-670hr.indd 633 11/8/10 6:06 PM

634 CHAPTER 14 Ethers and Epoxides; Thiols and Sulfides

MECHANISM 14.2 ACIDIC CLEAVAGE OF AN ETHER

FORMATION OF FIRST ALKYL HALIDE

A halide ion functions as a

nucleophile and attacksthe oxonium ion, ejecting

an alcohol as a leaving group

The ether is protonated,

generating anoxonium ion

H XH3C CH3O HH3C O XH3CO CH3

HH3C

+X–

± ±

SN2Proton transfer

H2O

FORMATION OF SECOND ALKYL HALIDE

The alcohol isprotonated,

generating an oxonium ion

H XHH3C O H3C XO HH

H3C + X–

± ±

SN2Proton transfer

A halide ion functions as a nucleophile and attacks the oxonium ion, ejecting water as

a leaving group

The formation of the first alkyl halide begins with protonation of the ether to form a good leaving group, followed by an SN2 process in which a halide ion functions as a nucleophile and attacks the protonated ether. The second alkyl halide is then formed with the same two steps—protonation followed by an SN2 attack. If either R group is tertiary, then substitution is more likely to proceed via an SN1 process rather than SN2.

When a phenyl ether is cleaved under acidic conditions, the products are phenol and an alkyl halide.

RX H2O

OR

OH

Phenol

excessHX

heat ± ±

The phenol is not further converted into a halide, because neither SN2 nor SN1 processes are efficient at sp2-hybridized centers.

Both HI and HBr can be used to cleave ethers. HCl is less efficient, and HF does not cause acidic cleavage of ethers. This reactivity is a result of the relative nucleophilicity of the halide ions.

LOOKING BACKFor a review of the relative nucleophilicity of the halide ions, see Section 7.8.

CONCEPTUAL CHECKPOINT

14.11 Predict the products for each of the following reactions:

O ?(a)

excessHBrheat

O

?(b)

excessHI

heat

O

?(c)

excessHBrheat

O ?(d)

excessHI

heat

O

?(e)

excessHI

heat

O

?(f)

excessHBrheat

klein_c14_622-670hr1.indd 634 11/15/10 1:24 PM