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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