Espacio deFormaciónMultimodal

Klein, D. (2012). Ethers and Epoxides; Thiols and Sulfides. En Organic Chemistry(pp. 643-650). USA: Wiley.

Ethers and Epoxides; Thiols and Sulfides

14.10 Ring-Opening Reactions of Epoxides 643

14.10 Ring-Opening Reactions of Epoxides

Epoxides have significant ring strain, and as a result, they exhibit unique reactivity. Specifically, epoxides undergo reactions in which the ring is opened, which alleviates the strain. In this sec-tion, we will see that epoxides can be opened under conditions involving a strong nucleophile or under acid-catalyzed conditions.

Reactions of Epoxides with Strong NucleophilesWhen an epoxide is subjected to attack by a strong nucleophile, a ring-opening reaction occurs. For example, consider the opening of ethylene oxide by a hydroxide ion.

O HO

OH

NaOHH2O

The transformation involves two mechanistic steps (Mechanism 14.5).

CONCEPTUAL CHECKPOINT

14.16

OHO O H

Ti[OCH(CH3)2]4(±)-DET

?(a) (b) OH ?O O H

Ti[OCH(CH3)2]4(–)-DET

(c) OH?O O H

Ti[OCH(CH3)2]4(±)-DET (d) OH

?O O H

Ti[OCH(CH3)2]4(–)-DET

MECHANISM 14.5 EPOXIDE RING OPENING WITH A STRONG NUCLEOPHILE

OH

HO

O

In the first step, hydroxide

functions as a nucleophile and

opens the ring in an SN2 process

HO

O–

–OH

The resulting alkoxide ion is

then protonated by water

HO

H

Proton transferNucleophilic attack

The first step of the mechanism is an SN2 process, involving an alkoxide ion functioning as a leaving group. Although we learned in Chapter 7 that alkoxide ions do not function as leaving groups in SN2 reactions, the exception here can be explained by focusing on the

klein_c14_622-670hr.indd 643 11/8/10 6:07 PM

648 CHAPTER 14 Ethers and Epoxides; Thiols and Sulfides

When the starting epoxide is unsymmetrical, the regiochemical outcome depends on the nature of the epoxide. If one side is primary and the other side is secondary, then attack takes place at the less hindered primary position, just as we would expect for an SN2 process.

OH

X1˚Nucleophileattacks here

(less hindered)

HXO

2˚

However, when one side of the epoxide is a tertiary position, the reaction is observed to occur at the more substituted, tertiary site.

HO

X

HX

Nucleophile attacks here,even though it is more hindered

O

3˚

1˚

Why should this be the case? It is true that the primary site is less hindered, but there is a factor that is even more dominant than steric hindrance. That factor is an electronic effect. A proton-ated epoxide is positively charged, and the positively charged oxygen atom withdraws electron density from the two carbon atoms of the epoxide.

OH±

d± d±

Each of the carbon atoms bears a partial positive charge ( +). That is, they both have partial carboca-tionic character. Nevertheless, these two carbon atoms are not equivalent in their ability to support a partial positive charge. The tertiary position is significantly better at supporting a partial positive charge, so the tertiary position has significantly more partial carbocationic character than the primary position. The protonated epoxide is therefore more accurately drawn in the following way.

OH±

d±d±

There are two important consequences of this analysis: (1) the more substituted carbon is a stron-ger electrophile and is therefore more susceptible to nucleophilic attack and (2) the more substi-tuted carbon has significant carbocationic character, which means that its geometry is described as somewhere between tetrahedral and trigonal planar, allowing nucleophilic attack to occur at that position even though it is tertiary.

To summarize, the regiochemical outcome of acid-catalyzed ring opening depends on the nature of the epoxide.

Primary vs. tertiary

Dominant factor=electronic effect

O

3˚

1˚

Attackshere

H+

Primary vs. secondary

Dominant factor=steric effect

O

2˚

1˚

Attackshere

H+

klein_c14_622-670hr1.indd 648 11/15/10 1:24 PM

14.10 Ring-Opening Reactions of Epoxides 649

There are two factors competing to control the regiochemistry: electronic effects vs. steric effects. The former favors attack at the more substituted position, while the latter favors attack at the less substituted position. To determine which factor is dominant, we must analyze the epoxide. When the epoxide possesses a tertiary position, the electronic effect will be dominant. When the epoxide possesses only primary and secondary positions, the steric effect will be dominant. The regiochemistry of acid-catalyzed ring opening is just one example where steric effects and electronic effects compete. As we progress through the course, we will see other examples of electronic vs. steric effects.

In the previous section (ring opening with strong nucleophiles), the regiochemistry was more straightforward, because electronics was not a factor at all. The epoxide was attacked by a nucleophile before being protonated, so the epoxide did not bear a positive charge when it was attacked. In such a case, steric hindrance was the only consideration.

Now let’s turn our attention to the stereochemistry of ring-opening reactions under acid-catalyzed conditions. When the attack takes place at a chirality center, inversion of configuration is observed. This result is consistent with an SN2-like process involving back-side attack of the nucleophile.

O

Me

Attack takes placeat a chirality center

The configurationhas been inverted

OH

ORMe

[H±]ROH

LEARN the skill

O

HMeEt Et EtOH

[H2SO4] ?SOLUTION

1.

O

HMeEt Et

2˚3˚

SKILLBUILDER 14.5 DRAWING THE MECHANISM AND PREDICTING THE PRODUCT OF ACID-CATALYZED RING OPENING

STEP 1

klein_c14_622-670hr.indd 649 11/8/10 6:07 PM

14.10 Ring-Opening Reactions of Epoxides 643

14.10 Ring-Opening Reactions of Epoxides

Epoxides have significant ring strain, and as a result, they exhibit unique reactivity. Specifically, epoxides undergo reactions in which the ring is opened, which alleviates the strain. In this sec-tion, we will see that epoxides can be opened under conditions involving a strong nucleophile or under acid-catalyzed conditions.

Reactions of Epoxides with Strong NucleophilesWhen an epoxide is subjected to attack by a strong nucleophile, a ring-opening reaction occurs. For example, consider the opening of ethylene oxide by a hydroxide ion.

O HO

OH

NaOHH2O

The transformation involves two mechanistic steps (Mechanism 14.5).

CONCEPTUAL CHECKPOINT

14.16

OHO O H

Ti[OCH(CH3)2]4(±)-DET

?(a) (b) OH ?O O H

Ti[OCH(CH3)2]4(–)-DET

(c) OH?O O H

Ti[OCH(CH3)2]4(±)-DET (d) OH

?O O H

Ti[OCH(CH3)2]4(–)-DET

MECHANISM 14.5 EPOXIDE RING OPENING WITH A STRONG NUCLEOPHILE

OH

HO

O

In the first step, hydroxide

functions as a nucleophile and

opens the ring in an SN2 process

HO

O–

–OH

The resulting alkoxide ion is

then protonated by water

HO

H

Proton transferNucleophilic attack

The first step of the mechanism is an SN2 process, involving an alkoxide ion functioning as a leaving group. Although we learned in Chapter 7 that alkoxide ions do not function as leaving groups in SN2 reactions, the exception here can be explained by focusing on the

klein_c14_622-670hr.indd 643 11/8/10 6:07 PM

644 CHAPTER 14 Ethers and Epoxides; Thiols and Sulfides

FIGURE 14.4

N

Reaction coordinate

Freeenergy

(G)

Alkoxide

Ether+NaOH

O

+NaOH

substrate. In this case, the substrate is an epoxide that exhibits significant ring strain and is therefore higher in energy than the substrates we encountered when we first learned about SN2 reactions. The effects of a high-energy substrate are illustrated in the energy diagram in Figure 14.4. The blue curve represents a hypothetical SN2 process in which the substrate is an ether and the leaving group is an alkoxide ion. The energy of activation for such a process is quite large, and more importantly, the products are higher in energy than the starting materials, so the equilibrium does not favor products. In contrast, when the starting substrate is an epoxide (red curve), the increased energy of the substrate has two pronounced effects: (1) the energy of activation is reduced, allowing the reaction to occur more rapidly, and (2) the products are now lower in energy than the starting materials, so the reaction is thermodynamically favorable. That is, the equilibrium will favor products over starting materials. For these reasons, an alkoxide ion can function as a leaving group in the ring-opening reactions of epoxides.

Many strong nucleophiles can be used to open an epoxide.

1) RONa2) H2O

O

1) NaCN2) H2O

1) NaSH2) H2O

1) RMgBr2) H2O

1) LAH2) H2O

OH

NC

OH

RO

OH

HS

OH

R

OH

H

All of these nucleophiles are reagents that we have previously encountered, and they can all open epoxides. These reactions exhibit two important features that must be considered, regiochemis-try and stereochemistry.

1. Regiochemistry. When the starting epoxide is unsymmetrical, the nucleophile attacks at the less substituted (less hindered) position.

HO

Nuc

This position is less hindered,so the nucleophile attacks here

O

2) H2O1) Nuc–

This steric effect is what we would expect from an SN2 process.

2. Stereochemistry. When the attack takes place at a chirality center, inversion of configuration is observed.

The configurationhas been inverted

OH

Nuc

Attack takes placeat a chirality center

O 2) H2O1) Nuc –

This result is also expected for an SN2 process as a consequence of the requirement for back-side attack of the nucleophile. Notice that the configuration of the other chirality center is not affected by the process. Only the center being attacked undergoes an inversion of configuration.

klein_c14_622-670hr.indd 644 11/8/10 6:07 PM

648 CHAPTER 14 Ethers and Epoxides; Thiols and Sulfides

When the starting epoxide is unsymmetrical, the regiochemical outcome depends on the nature of the epoxide. If one side is primary and the other side is secondary, then attack takes place at the less hindered primary position, just as we would expect for an SN2 process.

OH

X1˚Nucleophileattacks here

(less hindered)

HXO

2˚

However, when one side of the epoxide is a tertiary position, the reaction is observed to occur at the more substituted, tertiary site.

HO

X

HX

Nucleophile attacks here,even though it is more hindered

O

3˚

1˚

Why should this be the case? It is true that the primary site is less hindered, but there is a factor that is even more dominant than steric hindrance. That factor is an electronic effect. A proton-ated epoxide is positively charged, and the positively charged oxygen atom withdraws electron density from the two carbon atoms of the epoxide.

OH±

d± d±

Each of the carbon atoms bears a partial positive charge ( +). That is, they both have partial carboca-tionic character. Nevertheless, these two carbon atoms are not equivalent in their ability to support a partial positive charge. The tertiary position is significantly better at supporting a partial positive charge, so the tertiary position has significantly more partial carbocationic character than the primary position. The protonated epoxide is therefore more accurately drawn in the following way.

OH±

d±d±

There are two important consequences of this analysis: (1) the more substituted carbon is a stron-ger electrophile and is therefore more susceptible to nucleophilic attack and (2) the more substi-tuted carbon has significant carbocationic character, which means that its geometry is described as somewhere between tetrahedral and trigonal planar, allowing nucleophilic attack to occur at that position even though it is tertiary.

To summarize, the regiochemical outcome of acid-catalyzed ring opening depends on the nature of the epoxide.

Primary vs. tertiary

Dominant factor=electronic effect

O

3˚

1˚

Attackshere

H+

Primary vs. secondary

Dominant factor=steric effect

O

2˚

1˚

Attackshere

H+

klein_c14_622-670hr1.indd 648 11/15/10 1:24 PM

14.10 Ring-Opening Reactions of Epoxides 649

There are two factors competing to control the regiochemistry: electronic effects vs. steric effects. The former favors attack at the more substituted position, while the latter favors attack at the less substituted position. To determine which factor is dominant, we must analyze the epoxide. When the epoxide possesses a tertiary position, the electronic effect will be dominant. When the epoxide possesses only primary and secondary positions, the steric effect will be dominant. The regiochemistry of acid-catalyzed ring opening is just one example where steric effects and electronic effects compete. As we progress through the course, we will see other examples of electronic vs. steric effects.

In the previous section (ring opening with strong nucleophiles), the regiochemistry was more straightforward, because electronics was not a factor at all. The epoxide was attacked by a nucleophile before being protonated, so the epoxide did not bear a positive charge when it was attacked. In such a case, steric hindrance was the only consideration.

Now let’s turn our attention to the stereochemistry of ring-opening reactions under acid-catalyzed conditions. When the attack takes place at a chirality center, inversion of configuration is observed. This result is consistent with an SN2-like process involving back-side attack of the nucleophile.

O

Me

Attack takes placeat a chirality center

The configurationhas been inverted

OH

ORMe

[H±]ROH

LEARN the skill

O

HMeEt Et EtOH

[H2SO4] ?SOLUTION

1.

O

HMeEt Et

2˚3˚

SKILLBUILDER 14.5 DRAWING THE MECHANISM AND PREDICTING THE PRODUCT OF ACID-CATALYZED RING OPENING

STEP 1

klein_c14_622-670hr.indd 649 11/8/10 6:07 PM

650 CHAPTER 14 Ethers and Epoxides; Thiols and Sulfides

PRACTICE the skill

2.

O

HMeEt Et

This chirality center will be invertedas a result of back-side attack

SN2Proton transfer

HMeEt Et

OH OSO3H

HMeEt Et

H

O+

O

OH

H

MeEt

Et

HEt +

EtO

H

Proton transfer

EtO

OH

H

MeEt

EtEt H

O

O H

MeEt

Et

HEt +

OH

14.20

O ?(a)HCl

O

Me?

(b)

HBr

O

MeEt

EtOH[H2SO4] ?

(c)

O

MeEt

Me H2O[H2SO4] ?

(d)

O

Me MeOH[H2SO4] ?

(e)

O

MeEt

?(f)

HBr

14.21

O

MeEt H

OHO

OH

MeEt

[H2SO4]

Try Problems 14.43d, 14.49, 14.50

STEP 2

need more PRACTICE?

APPLY the skill

STEP 3

klein_c14_622-670hr.indd 650 11/8/10 6:07 PM

14.10 Ring-Opening Reactions of Epoxides 643

14.10 Ring-Opening Reactions of Epoxides

Epoxides have significant ring strain, and as a result, they exhibit unique reactivity. Specifically, epoxides undergo reactions in which the ring is opened, which alleviates the strain. In this sec-tion, we will see that epoxides can be opened under conditions involving a strong nucleophile or under acid-catalyzed conditions.

Reactions of Epoxides with Strong NucleophilesWhen an epoxide is subjected to attack by a strong nucleophile, a ring-opening reaction occurs. For example, consider the opening of ethylene oxide by a hydroxide ion.

O HO

OH

NaOHH2O

The transformation involves two mechanistic steps (Mechanism 14.5).

CONCEPTUAL CHECKPOINT

14.16

OHO O H

Ti[OCH(CH3)2]4(±)-DET

?(a) (b) OH ?O O H

Ti[OCH(CH3)2]4(–)-DET

(c) OH?O O H

Ti[OCH(CH3)2]4(±)-DET (d) OH

?O O H

Ti[OCH(CH3)2]4(–)-DET

MECHANISM 14.5 EPOXIDE RING OPENING WITH A STRONG NUCLEOPHILE

OH

HO

O

In the first step, hydroxide

functions as a nucleophile and

opens the ring in an SN2 process

HO

O–

–OH

The resulting alkoxide ion is

then protonated by water

HO

H

Proton transferNucleophilic attack

The first step of the mechanism is an SN2 process, involving an alkoxide ion functioning as a leaving group. Although we learned in Chapter 7 that alkoxide ions do not function as leaving groups in SN2 reactions, the exception here can be explained by focusing on the

klein_c14_622-670hr.indd 643 11/8/10 6:07 PM

644 CHAPTER 14 Ethers and Epoxides; Thiols and Sulfides

FIGURE 14.4

N

Reaction coordinate

Freeenergy

(G)

Alkoxide

Ether+NaOH

O

+NaOH

substrate. In this case, the substrate is an epoxide that exhibits significant ring strain and is therefore higher in energy than the substrates we encountered when we first learned about SN2 reactions. The effects of a high-energy substrate are illustrated in the energy diagram in Figure 14.4. The blue curve represents a hypothetical SN2 process in which the substrate is an ether and the leaving group is an alkoxide ion. The energy of activation for such a process is quite large, and more importantly, the products are higher in energy than the starting materials, so the equilibrium does not favor products. In contrast, when the starting substrate is an epoxide (red curve), the increased energy of the substrate has two pronounced effects: (1) the energy of activation is reduced, allowing the reaction to occur more rapidly, and (2) the products are now lower in energy than the starting materials, so the reaction is thermodynamically favorable. That is, the equilibrium will favor products over starting materials. For these reasons, an alkoxide ion can function as a leaving group in the ring-opening reactions of epoxides.

Many strong nucleophiles can be used to open an epoxide.

1) RONa2) H2O

O

1) NaCN2) H2O

1) NaSH2) H2O

1) RMgBr2) H2O

1) LAH2) H2O

OH

NC

OH

RO

OH

HS

OH

R

OH

H

All of these nucleophiles are reagents that we have previously encountered, and they can all open epoxides. These reactions exhibit two important features that must be considered, regiochemis-try and stereochemistry.

1. Regiochemistry. When the starting epoxide is unsymmetrical, the nucleophile attacks at the less substituted (less hindered) position.

HO

Nuc

This position is less hindered,so the nucleophile attacks here

O

2) H2O1) Nuc–

This steric effect is what we would expect from an SN2 process.

2. Stereochemistry. When the attack takes place at a chirality center, inversion of configuration is observed.

The configurationhas been inverted

OH

Nuc

Attack takes placeat a chirality center

O 2) H2O1) Nuc –

This result is also expected for an SN2 process as a consequence of the requirement for back-side attack of the nucleophile. Notice that the configuration of the other chirality center is not affected by the process. Only the center being attacked undergoes an inversion of configuration.

klein_c14_622-670hr.indd 644 11/8/10 6:07 PM

14.10 Ring-Opening Reactions of Epoxides 645

PRACTICE the skill

SOLUTION

1.

O

H2˚

3˚ (Less hindered)

N

2.

N

O

H This chirality centerwill be inverted

Nucleophilic Attack Proton Transfer

C

HO H

N

C N–

H

O H

C

N

–O

H HO

14.17

O

Me 2) H2O1) PhMgBr ?(a) (b)

O

Me ?1) NaCN2) H2O

STEP 1

STEP 2

STEP 3

LEARN the skillO

H

1) NaCN2) H2O ?

SKILLBUILDER 14.4 DRAWING THE MECHANISM AND PREDICTING THE PRODUCT OF THE REACTION BETWEEN A STRONG NUCLEOPHILE AND AN EPOXIDE

klein_c14_622-670hr.indd 645 11/8/10 6:07 PM

14.10 Ring-Opening Reactions of Epoxides 649

There are two factors competing to control the regiochemistry: electronic effects vs. steric effects. The former favors attack at the more substituted position, while the latter favors attack at the less substituted position. To determine which factor is dominant, we must analyze the epoxide. When the epoxide possesses a tertiary position, the electronic effect will be dominant. When the epoxide possesses only primary and secondary positions, the steric effect will be dominant. The regiochemistry of acid-catalyzed ring opening is just one example where steric effects and electronic effects compete. As we progress through the course, we will see other examples of electronic vs. steric effects.

In the previous section (ring opening with strong nucleophiles), the regiochemistry was more straightforward, because electronics was not a factor at all. The epoxide was attacked by a nucleophile before being protonated, so the epoxide did not bear a positive charge when it was attacked. In such a case, steric hindrance was the only consideration.

Now let’s turn our attention to the stereochemistry of ring-opening reactions under acid-catalyzed conditions. When the attack takes place at a chirality center, inversion of configuration is observed. This result is consistent with an SN2-like process involving back-side attack of the nucleophile.

O

Me

Attack takes placeat a chirality center

The configurationhas been inverted

OH

ORMe

[H±]ROH

LEARN the skill

O

HMeEt Et EtOH

[H2SO4] ?SOLUTION

1.

O

HMeEt Et

2˚3˚

SKILLBUILDER 14.5 DRAWING THE MECHANISM AND PREDICTING THE PRODUCT OF ACID-CATALYZED RING OPENING

STEP 1

klein_c14_622-670hr.indd 649 11/8/10 6:07 PM

650 CHAPTER 14 Ethers and Epoxides; Thiols and Sulfides

PRACTICE the skill

2.

O

HMeEt Et

This chirality center will be invertedas a result of back-side attack

SN2Proton transfer

HMeEt Et

OH OSO3H

HMeEt Et

H

O+

O

OH

H

MeEt

Et

HEt +

EtO

H

Proton transfer

EtO

OH

H

MeEt

EtEt H

O

O H

MeEt

Et

HEt +

OH

14.20

O ?(a)HCl

O

Me?

(b)

HBr

O

MeEt

EtOH[H2SO4] ?

(c)

O

MeEt

Me H2O[H2SO4] ?

(d)

O

Me MeOH[H2SO4] ?

(e)

O

MeEt

?(f)

HBr

14.21

O

MeEt H

OHO

OH

MeEt

[H2SO4]

Try Problems 14.43d, 14.49, 14.50

STEP 2

need more PRACTICE?

APPLY the skill

STEP 3

klein_c14_622-670hr.indd 650 11/8/10 6:07 PM

644 CHAPTER 14 Ethers and Epoxides; Thiols and Sulfides

FIGURE 14.4

N

Reaction coordinate

Freeenergy

(G)

Alkoxide

Ether+NaOH

O

+NaOH

substrate. In this case, the substrate is an epoxide that exhibits significant ring strain and is therefore higher in energy than the substrates we encountered when we first learned about SN2 reactions. The effects of a high-energy substrate are illustrated in the energy diagram in Figure 14.4. The blue curve represents a hypothetical SN2 process in which the substrate is an ether and the leaving group is an alkoxide ion. The energy of activation for such a process is quite large, and more importantly, the products are higher in energy than the starting materials, so the equilibrium does not favor products. In contrast, when the starting substrate is an epoxide (red curve), the increased energy of the substrate has two pronounced effects: (1) the energy of activation is reduced, allowing the reaction to occur more rapidly, and (2) the products are now lower in energy than the starting materials, so the reaction is thermodynamically favorable. That is, the equilibrium will favor products over starting materials. For these reasons, an alkoxide ion can function as a leaving group in the ring-opening reactions of epoxides.

Many strong nucleophiles can be used to open an epoxide.

1) RONa2) H2O

O

1) NaCN2) H2O

1) NaSH2) H2O

1) RMgBr2) H2O

1) LAH2) H2O

OH

NC

OH

RO

OH

HS

OH

R

OH

H

All of these nucleophiles are reagents that we have previously encountered, and they can all open epoxides. These reactions exhibit two important features that must be considered, regiochemis-try and stereochemistry.

1. Regiochemistry. When the starting epoxide is unsymmetrical, the nucleophile attacks at the less substituted (less hindered) position.

HO

Nuc

This position is less hindered,so the nucleophile attacks here

O

2) H2O1) Nuc–

This steric effect is what we would expect from an SN2 process.

2. Stereochemistry. When the attack takes place at a chirality center, inversion of configuration is observed.

The configurationhas been inverted

OH

Nuc

Attack takes placeat a chirality center

O 2) H2O1) Nuc –

This result is also expected for an SN2 process as a consequence of the requirement for back-side attack of the nucleophile. Notice that the configuration of the other chirality center is not affected by the process. Only the center being attacked undergoes an inversion of configuration.

klein_c14_622-670hr.indd 644 11/8/10 6:07 PM

14.10 Ring-Opening Reactions of Epoxides 645

PRACTICE the skill

SOLUTION

1.

O

H2˚

3˚ (Less hindered)

N

2.

N

O

H This chirality centerwill be inverted

Nucleophilic Attack Proton Transfer

C

HO H

N

C N–

H

O H

C

N

–O

H HO

14.17

O

Me 2) H2O1) PhMgBr ?(a) (b)

O

Me ?1) NaCN2) H2O

STEP 1

STEP 2

STEP 3

LEARN the skillO

H

1) NaCN2) H2O ?

SKILLBUILDER 14.4 DRAWING THE MECHANISM AND PREDICTING THE PRODUCT OF THE REACTION BETWEEN A STRONG NUCLEOPHILE AND AN EPOXIDE

klein_c14_622-670hr.indd 645 11/8/10 6:07 PM

646 CHAPTER 14 Ethers and Epoxides; Thiols and Sulfides

O

Me ?(c)1) NaSH2) H2O (d)

O

Me ?1) LAH2) H2O

(e)

O

MeEt

?1) NaSH2) H2O

(f)

O

MeEt

?1) LAH2) H2O

14.18

O

MeMe ?NaOHH2O

14.19 meso

Try Problems 14.42a, 14.42c, 14.42e–h, 14.43a, c

PRACTICALLYSPEAKING Ethylene Oxide as a Sterilizing Agent for Sensitive Medical Equipment

DNA

NH2

DNA

HN

OH

O

2

Acid-Catalyzed Ring OpeningIn the previous section, we saw the reactions of epoxides with strong nucleophiles. The driving force for such reactions was the removal of ring strain associated with the three-membered ring of an epoxide. Ring-opening reactions can also occur under acidic conditions. As an example, consider the reaction between ethylene oxide and HX.

OOH

X

HX

need more PRACTICE?

APPLY the skill

klein_c14_622-670hr.indd 646 11/8/10 6:07 PM

650 CHAPTER 14 Ethers and Epoxides; Thiols and Sulfides

PRACTICE the skill

2.

O

HMeEt Et

This chirality center will be invertedas a result of back-side attack

SN2Proton transfer

HMeEt Et

OH OSO3H

HMeEt Et

H

O+

O

OH

H

MeEt

Et

HEt +

EtO

H

Proton transfer

EtO

OH

H

MeEt

EtEt H

O

O H

MeEt

Et

HEt +

OH

14.20

O ?(a)HCl

O

Me?

(b)

HBr

O

MeEt

EtOH[H2SO4] ?

(c)

O

MeEt

Me H2O[H2SO4] ?

(d)

O

Me MeOH[H2SO4] ?

(e)

O

MeEt

?(f)

HBr

14.21

O

MeEt H

OHO

OH

MeEt

[H2SO4]

Try Problems 14.43d, 14.49, 14.50

STEP 2

need more PRACTICE?

APPLY the skill

STEP 3

klein_c14_622-670hr.indd 650 11/8/10 6:07 PM

14.10 Ring-Opening Reactions of Epoxides 645

PRACTICE the skill

SOLUTION

1.

O

H2˚

3˚ (Less hindered)

N

2.

N

O

H This chirality centerwill be inverted

Nucleophilic Attack Proton Transfer

C

HO H

N

C N–

H

O H

C

N

–O

H HO

14.17

O

Me 2) H2O1) PhMgBr ?(a) (b)

O

Me ?1) NaCN2) H2O

STEP 1

STEP 2

STEP 3

LEARN the skillO

H

1) NaCN2) H2O ?

SKILLBUILDER 14.4 DRAWING THE MECHANISM AND PREDICTING THE PRODUCT OF THE REACTION BETWEEN A STRONG NUCLEOPHILE AND AN EPOXIDE

klein_c14_622-670hr.indd 645 11/8/10 6:07 PM

646 CHAPTER 14 Ethers and Epoxides; Thiols and Sulfides

O

Me ?(c)1) NaSH2) H2O (d)

O

Me ?1) LAH2) H2O

(e)

O

MeEt

?1) NaSH2) H2O

(f)

O

MeEt

?1) LAH2) H2O

14.18

O

MeMe ?NaOHH2O

14.19 meso

Try Problems 14.42a, 14.42c, 14.42e–h, 14.43a, c

PRACTICALLYSPEAKING Ethylene Oxide as a Sterilizing Agent for Sensitive Medical Equipment

DNA

NH2

DNA

HN

OH

O

2

Acid-Catalyzed Ring OpeningIn the previous section, we saw the reactions of epoxides with strong nucleophiles. The driving force for such reactions was the removal of ring strain associated with the three-membered ring of an epoxide. Ring-opening reactions can also occur under acidic conditions. As an example, consider the reaction between ethylene oxide and HX.

OOH

X

HX

need more PRACTICE?

APPLY the skill

klein_c14_622-670hr.indd 646 11/8/10 6:07 PM

14.10 Ring-Opening Reactions of Epoxides 647

This transformation involves two mechanistic steps (Mechanism 14.6).

MECHANISM 14.6 ACID-CATALYZED RING OPENING OF AN EPOXIDE

OOH

X

O

H+

X–

±In the first step,the epoxide is

protonated

The protonated epoxide is then attacked by a

nucleophile in an SN2 process

H X

Proton transfer SN2

The first step is a proton transfer, and the second step is nucleophilic attack (SN2) by a halide ion. This reaction can be accomplished with HCl, HBr, or HI. Other nucleophiles such as water or an alcohol can also open an epoxide ring under acidic conditions. A small amount of acid (often sulfuric acid) is used to catalyze the reaction.

O

OH

HO

OH

RO

H2O

ROH[H±]

[H±]

The brackets around the H indicate that the acid functions as a catalyst. In each of the reac-tions above, the mechanism involves a proton transfer as the final step of the mechanism.

OH

HO

O H OSO3H H HO

H HOO

H+ OH

OHH

+

Proton transfer Proton transferSN2

The first two steps are analogous to the two steps in Mechanism 14.6. The additional proton transfer step at the end of the mechanism is required to remove the charge formed after the attack of a neutral nucleophile. The process above is used for the mass production of ethylene glycol.

O

Ethylene oxide

OHHOEthylene glycol

[H2SO4]H2O

Each year, over three million tons of ethylene glycol are produced in the United States via the acid-catalyzed ring opening of ethylene oxide. Most of the ethylene glycol is used as antifreeze.

As we saw in the previous section, there are two important features of ring-opening reactions: the regiochemical outcome and the stereochemical outcome. We’ll begin with regiochemistry.

klein_c14_622-670hr.indd 647 11/8/10 6:07 PM

646 CHAPTER 14 Ethers and Epoxides; Thiols and Sulfides

O

Me ?(c)1) NaSH2) H2O (d)

O

Me ?1) LAH2) H2O

(e)

O

MeEt

?1) NaSH2) H2O

(f)

O

MeEt

?1) LAH2) H2O

14.18

O

MeMe ?NaOHH2O

14.19 meso

Try Problems 14.42a, 14.42c, 14.42e–h, 14.43a, c

PRACTICALLYSPEAKING Ethylene Oxide as a Sterilizing Agent for Sensitive Medical Equipment

DNA

NH2

DNA

HN

OH

O

2

Acid-Catalyzed Ring OpeningIn the previous section, we saw the reactions of epoxides with strong nucleophiles. The driving force for such reactions was the removal of ring strain associated with the three-membered ring of an epoxide. Ring-opening reactions can also occur under acidic conditions. As an example, consider the reaction between ethylene oxide and HX.

OOH

X

HX

need more PRACTICE?

APPLY the skill

klein_c14_622-670hr.indd 646 11/8/10 6:07 PM

14.10 Ring-Opening Reactions of Epoxides 647

This transformation involves two mechanistic steps (Mechanism 14.6).

MECHANISM 14.6 ACID-CATALYZED RING OPENING OF AN EPOXIDE

OOH

X

O

H+

X–

±In the first step,the epoxide is

protonated

The protonated epoxide is then attacked by a

nucleophile in an SN2 process

H X

Proton transfer SN2

The first step is a proton transfer, and the second step is nucleophilic attack (SN2) by a halide ion. This reaction can be accomplished with HCl, HBr, or HI. Other nucleophiles such as water or an alcohol can also open an epoxide ring under acidic conditions. A small amount of acid (often sulfuric acid) is used to catalyze the reaction.

O

OH

HO

OH

RO

H2O

ROH[H±]

[H±]

The brackets around the H indicate that the acid functions as a catalyst. In each of the reac-tions above, the mechanism involves a proton transfer as the final step of the mechanism.

OH

HO

O H OSO3H H HO

H HOO

H+ OH

OHH

+

Proton transfer Proton transferSN2

The first two steps are analogous to the two steps in Mechanism 14.6. The additional proton transfer step at the end of the mechanism is required to remove the charge formed after the attack of a neutral nucleophile. The process above is used for the mass production of ethylene glycol.

O

Ethylene oxide

OHHOEthylene glycol

[H2SO4]H2O

Each year, over three million tons of ethylene glycol are produced in the United States via the acid-catalyzed ring opening of ethylene oxide. Most of the ethylene glycol is used as antifreeze.

As we saw in the previous section, there are two important features of ring-opening reactions: the regiochemical outcome and the stereochemical outcome. We’ll begin with regiochemistry.

klein_c14_622-670hr.indd 647 11/8/10 6:07 PM

14.10 Ring-Opening Reactions of Epoxides 643

14.10 Ring-Opening Reactions of Epoxides

Epoxides have significant ring strain, and as a result, they exhibit unique reactivity. Specifically, epoxides undergo reactions in which the ring is opened, which alleviates the strain. In this sec-tion, we will see that epoxides can be opened under conditions involving a strong nucleophile or under acid-catalyzed conditions.

Reactions of Epoxides with Strong NucleophilesWhen an epoxide is subjected to attack by a strong nucleophile, a ring-opening reaction occurs. For example, consider the opening of ethylene oxide by a hydroxide ion.

O HO

OH

NaOHH2O

The transformation involves two mechanistic steps (Mechanism 14.5).

CONCEPTUAL CHECKPOINT

14.16

OHO O H

Ti[OCH(CH3)2]4(±)-DET

?(a) (b) OH ?O O H

Ti[OCH(CH3)2]4(–)-DET

(c) OH?O O H

Ti[OCH(CH3)2]4(±)-DET (d) OH

?O O H

Ti[OCH(CH3)2]4(–)-DET

MECHANISM 14.5 EPOXIDE RING OPENING WITH A STRONG NUCLEOPHILE

OH

HO

O

In the first step, hydroxide

functions as a nucleophile and

opens the ring in an SN2 process

HO

O–

–OH

The resulting alkoxide ion is

then protonated by water

HO

H

Proton transferNucleophilic attack

The first step of the mechanism is an SN2 process, involving an alkoxide ion functioning as a leaving group. Although we learned in Chapter 7 that alkoxide ions do not function as leaving groups in SN2 reactions, the exception here can be explained by focusing on the

klein_c14_622-670hr.indd 643 11/8/10 6:07 PM

648 CHAPTER 14 Ethers and Epoxides; Thiols and Sulfides

When the starting epoxide is unsymmetrical, the regiochemical outcome depends on the nature of the epoxide. If one side is primary and the other side is secondary, then attack takes place at the less hindered primary position, just as we would expect for an SN2 process.

OH

X1˚Nucleophileattacks here

(less hindered)

HXO

2˚

However, when one side of the epoxide is a tertiary position, the reaction is observed to occur at the more substituted, tertiary site.

HO

X

HX

Nucleophile attacks here,even though it is more hindered

O

3˚

1˚

Why should this be the case? It is true that the primary site is less hindered, but there is a factor that is even more dominant than steric hindrance. That factor is an electronic effect. A proton-ated epoxide is positively charged, and the positively charged oxygen atom withdraws electron density from the two carbon atoms of the epoxide.

OH±

d± d±

Each of the carbon atoms bears a partial positive charge ( +). That is, they both have partial carboca-tionic character. Nevertheless, these two carbon atoms are not equivalent in their ability to support a partial positive charge. The tertiary position is significantly better at supporting a partial positive charge, so the tertiary position has significantly more partial carbocationic character than the primary position. The protonated epoxide is therefore more accurately drawn in the following way.

OH±

d±d±

There are two important consequences of this analysis: (1) the more substituted carbon is a stron-ger electrophile and is therefore more susceptible to nucleophilic attack and (2) the more substi-tuted carbon has significant carbocationic character, which means that its geometry is described as somewhere between tetrahedral and trigonal planar, allowing nucleophilic attack to occur at that position even though it is tertiary.

To summarize, the regiochemical outcome of acid-catalyzed ring opening depends on the nature of the epoxide.

Primary vs. tertiary

Dominant factor=electronic effect

O

3˚

1˚

Attackshere

H+

Primary vs. secondary

Dominant factor=steric effect

O

2˚

1˚

Attackshere

H+

klein_c14_622-670hr1.indd 648 11/15/10 1:24 PM

14.10 Ring-Opening Reactions of Epoxides 649

There are two factors competing to control the regiochemistry: electronic effects vs. steric effects. The former favors attack at the more substituted position, while the latter favors attack at the less substituted position. To determine which factor is dominant, we must analyze the epoxide. When the epoxide possesses a tertiary position, the electronic effect will be dominant. When the epoxide possesses only primary and secondary positions, the steric effect will be dominant. The regiochemistry of acid-catalyzed ring opening is just one example where steric effects and electronic effects compete. As we progress through the course, we will see other examples of electronic vs. steric effects.

In the previous section (ring opening with strong nucleophiles), the regiochemistry was more straightforward, because electronics was not a factor at all. The epoxide was attacked by a nucleophile before being protonated, so the epoxide did not bear a positive charge when it was attacked. In such a case, steric hindrance was the only consideration.

Now let’s turn our attention to the stereochemistry of ring-opening reactions under acid-catalyzed conditions. When the attack takes place at a chirality center, inversion of configuration is observed. This result is consistent with an SN2-like process involving back-side attack of the nucleophile.

O

Me

Attack takes placeat a chirality center

The configurationhas been inverted

OH

ORMe

[H±]ROH

LEARN the skill

O

HMeEt Et EtOH

[H2SO4] ?SOLUTION

1.

O

HMeEt Et

2˚3˚

SKILLBUILDER 14.5 DRAWING THE MECHANISM AND PREDICTING THE PRODUCT OF ACID-CATALYZED RING OPENING

STEP 1

klein_c14_622-670hr.indd 649 11/8/10 6:07 PM

14.10 Ring-Opening Reactions of Epoxides 643

14.10 Ring-Opening Reactions of Epoxides

Epoxides have significant ring strain, and as a result, they exhibit unique reactivity. Specifically, epoxides undergo reactions in which the ring is opened, which alleviates the strain. In this sec-tion, we will see that epoxides can be opened under conditions involving a strong nucleophile or under acid-catalyzed conditions.

Reactions of Epoxides with Strong NucleophilesWhen an epoxide is subjected to attack by a strong nucleophile, a ring-opening reaction occurs. For example, consider the opening of ethylene oxide by a hydroxide ion.

O HO

OH

NaOHH2O

The transformation involves two mechanistic steps (Mechanism 14.5).

CONCEPTUAL CHECKPOINT

14.16

OHO O H

Ti[OCH(CH3)2]4(±)-DET

?(a) (b) OH ?O O H

Ti[OCH(CH3)2]4(–)-DET

(c) OH?O O H

Ti[OCH(CH3)2]4(±)-DET (d) OH

?O O H

Ti[OCH(CH3)2]4(–)-DET

MECHANISM 14.5 EPOXIDE RING OPENING WITH A STRONG NUCLEOPHILE

OH

HO

O

In the first step, hydroxide

functions as a nucleophile and

opens the ring in an SN2 process

HO

O–

–OH

The resulting alkoxide ion is

then protonated by water

HO

H

Proton transferNucleophilic attack

The first step of the mechanism is an SN2 process, involving an alkoxide ion functioning as a leaving group. Although we learned in Chapter 7 that alkoxide ions do not function as leaving groups in SN2 reactions, the exception here can be explained by focusing on the

klein_c14_622-670hr.indd 643 11/8/10 6:07 PM

644 CHAPTER 14 Ethers and Epoxides; Thiols and Sulfides

FIGURE 14.4

N

Reaction coordinate

Freeenergy

(G)

Alkoxide

Ether+NaOH

O

+NaOH

substrate. In this case, the substrate is an epoxide that exhibits significant ring strain and is therefore higher in energy than the substrates we encountered when we first learned about SN2 reactions. The effects of a high-energy substrate are illustrated in the energy diagram in Figure 14.4. The blue curve represents a hypothetical SN2 process in which the substrate is an ether and the leaving group is an alkoxide ion. The energy of activation for such a process is quite large, and more importantly, the products are higher in energy than the starting materials, so the equilibrium does not favor products. In contrast, when the starting substrate is an epoxide (red curve), the increased energy of the substrate has two pronounced effects: (1) the energy of activation is reduced, allowing the reaction to occur more rapidly, and (2) the products are now lower in energy than the starting materials, so the reaction is thermodynamically favorable. That is, the equilibrium will favor products over starting materials. For these reasons, an alkoxide ion can function as a leaving group in the ring-opening reactions of epoxides.

Many strong nucleophiles can be used to open an epoxide.

1) RONa2) H2O

O

1) NaCN2) H2O

1) NaSH2) H2O

1) RMgBr2) H2O

1) LAH2) H2O

OH

NC

OH

RO

OH

HS

OH

R

OH

H

All of these nucleophiles are reagents that we have previously encountered, and they can all open epoxides. These reactions exhibit two important features that must be considered, regiochemis-try and stereochemistry.

1. Regiochemistry. When the starting epoxide is unsymmetrical, the nucleophile attacks at the less substituted (less hindered) position.

HO

Nuc

This position is less hindered,so the nucleophile attacks here

O

2) H2O1) Nuc–

This steric effect is what we would expect from an SN2 process.

2. Stereochemistry. When the attack takes place at a chirality center, inversion of configuration is observed.

The configurationhas been inverted

OH

Nuc

Attack takes placeat a chirality center

O 2) H2O1) Nuc –

This result is also expected for an SN2 process as a consequence of the requirement for back-side attack of the nucleophile. Notice that the configuration of the other chirality center is not affected by the process. Only the center being attacked undergoes an inversion of configuration.

klein_c14_622-670hr.indd 644 11/8/10 6:07 PM

648 CHAPTER 14 Ethers and Epoxides; Thiols and Sulfides

When the starting epoxide is unsymmetrical, the regiochemical outcome depends on the nature of the epoxide. If one side is primary and the other side is secondary, then attack takes place at the less hindered primary position, just as we would expect for an SN2 process.

OH

X1˚Nucleophileattacks here

(less hindered)

HXO

2˚

However, when one side of the epoxide is a tertiary position, the reaction is observed to occur at the more substituted, tertiary site.

HO

X

HX

Nucleophile attacks here,even though it is more hindered

O

3˚

1˚

Why should this be the case? It is true that the primary site is less hindered, but there is a factor that is even more dominant than steric hindrance. That factor is an electronic effect. A proton-ated epoxide is positively charged, and the positively charged oxygen atom withdraws electron density from the two carbon atoms of the epoxide.

OH±

d± d±

Each of the carbon atoms bears a partial positive charge ( +). That is, they both have partial carboca-tionic character. Nevertheless, these two carbon atoms are not equivalent in their ability to support a partial positive charge. The tertiary position is significantly better at supporting a partial positive charge, so the tertiary position has significantly more partial carbocationic character than the primary position. The protonated epoxide is therefore more accurately drawn in the following way.

OH±

d±d±

There are two important consequences of this analysis: (1) the more substituted carbon is a stron-ger electrophile and is therefore more susceptible to nucleophilic attack and (2) the more substi-tuted carbon has significant carbocationic character, which means that its geometry is described as somewhere between tetrahedral and trigonal planar, allowing nucleophilic attack to occur at that position even though it is tertiary.

To summarize, the regiochemical outcome of acid-catalyzed ring opening depends on the nature of the epoxide.

Primary vs. tertiary

Dominant factor=electronic effect

O

3˚

1˚

Attackshere

H+

Primary vs. secondary

Dominant factor=steric effect

O

2˚

1˚

Attackshere

H+

klein_c14_622-670hr1.indd 648 11/15/10 1:24 PM

14.10 Ring-Opening Reactions of Epoxides 649

There are two factors competing to control the regiochemistry: electronic effects vs. steric effects. The former favors attack at the more substituted position, while the latter favors attack at the less substituted position. To determine which factor is dominant, we must analyze the epoxide. When the epoxide possesses a tertiary position, the electronic effect will be dominant. When the epoxide possesses only primary and secondary positions, the steric effect will be dominant. The regiochemistry of acid-catalyzed ring opening is just one example where steric effects and electronic effects compete. As we progress through the course, we will see other examples of electronic vs. steric effects.

In the previous section (ring opening with strong nucleophiles), the regiochemistry was more straightforward, because electronics was not a factor at all. The epoxide was attacked by a nucleophile before being protonated, so the epoxide did not bear a positive charge when it was attacked. In such a case, steric hindrance was the only consideration.

Now let’s turn our attention to the stereochemistry of ring-opening reactions under acid-catalyzed conditions. When the attack takes place at a chirality center, inversion of configuration is observed. This result is consistent with an SN2-like process involving back-side attack of the nucleophile.

O

Me

Attack takes placeat a chirality center

The configurationhas been inverted

OH

ORMe

[H±]ROH

LEARN the skill

O

HMeEt Et EtOH

[H2SO4] ?SOLUTION

1.

O

HMeEt Et

2˚3˚

SKILLBUILDER 14.5 DRAWING THE MECHANISM AND PREDICTING THE PRODUCT OF ACID-CATALYZED RING OPENING

STEP 1

klein_c14_622-670hr.indd 649 11/8/10 6:07 PM

650 CHAPTER 14 Ethers and Epoxides; Thiols and Sulfides

PRACTICE the skill

2.

O

HMeEt Et

This chirality center will be invertedas a result of back-side attack

SN2Proton transfer

HMeEt Et

OH OSO3H

HMeEt Et

H

O+

O

OH

H

MeEt

Et

HEt +

EtO

H

Proton transfer

EtO

OH

H

MeEt

EtEt H

O

O H

MeEt

Et

HEt +

OH

14.20

O ?(a)HCl

O

Me?

(b)

HBr

O

MeEt

EtOH[H2SO4] ?

(c)

O

MeEt

Me H2O[H2SO4] ?

(d)

O

Me MeOH[H2SO4] ?

(e)

O

MeEt

?(f)

HBr

14.21

O

MeEt H

OHO

OH

MeEt

[H2SO4]

Try Problems 14.43d, 14.49, 14.50

STEP 2

need more PRACTICE?

APPLY the skill

STEP 3

klein_c14_622-670hr.indd 650 11/8/10 6:07 PM

14.10 Ring-Opening Reactions of Epoxides 643

14.10 Ring-Opening Reactions of Epoxides

Epoxides have significant ring strain, and as a result, they exhibit unique reactivity. Specifically, epoxides undergo reactions in which the ring is opened, which alleviates the strain. In this sec-tion, we will see that epoxides can be opened under conditions involving a strong nucleophile or under acid-catalyzed conditions.

Reactions of Epoxides with Strong NucleophilesWhen an epoxide is subjected to attack by a strong nucleophile, a ring-opening reaction occurs. For example, consider the opening of ethylene oxide by a hydroxide ion.

O HO

OH

NaOHH2O

The transformation involves two mechanistic steps (Mechanism 14.5).

CONCEPTUAL CHECKPOINT

14.16

OHO O H

Ti[OCH(CH3)2]4(±)-DET

?(a) (b) OH ?O O H

Ti[OCH(CH3)2]4(–)-DET

(c) OH?O O H

Ti[OCH(CH3)2]4(±)-DET (d) OH

?O O H

Ti[OCH(CH3)2]4(–)-DET

MECHANISM 14.5 EPOXIDE RING OPENING WITH A STRONG NUCLEOPHILE

OH

HO

O

In the first step, hydroxide

functions as a nucleophile and

opens the ring in an SN2 process

HO

O–

–OH

The resulting alkoxide ion is

then protonated by water

HO

H

Proton transferNucleophilic attack

The first step of the mechanism is an SN2 process, involving an alkoxide ion functioning as a leaving group. Although we learned in Chapter 7 that alkoxide ions do not function as leaving groups in SN2 reactions, the exception here can be explained by focusing on the

klein_c14_622-670hr.indd 643 11/8/10 6:07 PM

644 CHAPTER 14 Ethers and Epoxides; Thiols and Sulfides

FIGURE 14.4

N

Reaction coordinate

Freeenergy

(G)

Alkoxide

Ether+NaOH

O

+NaOH

substrate. In this case, the substrate is an epoxide that exhibits significant ring strain and is therefore higher in energy than the substrates we encountered when we first learned about SN2 reactions. The effects of a high-energy substrate are illustrated in the energy diagram in Figure 14.4. The blue curve represents a hypothetical SN2 process in which the substrate is an ether and the leaving group is an alkoxide ion. The energy of activation for such a process is quite large, and more importantly, the products are higher in energy than the starting materials, so the equilibrium does not favor products. In contrast, when the starting substrate is an epoxide (red curve), the increased energy of the substrate has two pronounced effects: (1) the energy of activation is reduced, allowing the reaction to occur more rapidly, and (2) the products are now lower in energy than the starting materials, so the reaction is thermodynamically favorable. That is, the equilibrium will favor products over starting materials. For these reasons, an alkoxide ion can function as a leaving group in the ring-opening reactions of epoxides.

Many strong nucleophiles can be used to open an epoxide.

1) RONa2) H2O

O

1) NaCN2) H2O

1) NaSH2) H2O

1) RMgBr2) H2O

1) LAH2) H2O

OH

NC

OH

RO

OH

HS

OH

R

OH

H

All of these nucleophiles are reagents that we have previously encountered, and they can all open epoxides. These reactions exhibit two important features that must be considered, regiochemis-try and stereochemistry.

1. Regiochemistry. When the starting epoxide is unsymmetrical, the nucleophile attacks at the less substituted (less hindered) position.

HO

Nuc

This position is less hindered,so the nucleophile attacks here

O

2) H2O1) Nuc–

This steric effect is what we would expect from an SN2 process.

2. Stereochemistry. When the attack takes place at a chirality center, inversion of configuration is observed.

The configurationhas been inverted

OH

Nuc

Attack takes placeat a chirality center

O 2) H2O1) Nuc –

This result is also expected for an SN2 process as a consequence of the requirement for back-side attack of the nucleophile. Notice that the configuration of the other chirality center is not affected by the process. Only the center being attacked undergoes an inversion of configuration.

klein_c14_622-670hr.indd 644 11/8/10 6:07 PM

14.10 Ring-Opening Reactions of Epoxides 645

PRACTICE the skill

SOLUTION

1.

O

H2˚

3˚ (Less hindered)

N

2.

N

O

H This chirality centerwill be inverted

Nucleophilic Attack Proton Transfer

C

HO H

N

C N–

H

O H

C

N

–O

H HO

14.17

O

Me 2) H2O1) PhMgBr ?(a) (b)

O

Me ?1) NaCN2) H2O

STEP 1

STEP 2

STEP 3

LEARN the skillO

H

1) NaCN2) H2O ?

SKILLBUILDER 14.4 DRAWING THE MECHANISM AND PREDICTING THE PRODUCT OF THE REACTION BETWEEN A STRONG NUCLEOPHILE AND AN EPOXIDE

klein_c14_622-670hr.indd 645 11/8/10 6:07 PM

14.10 Ring-Opening Reactions of Epoxides 649

There are two factors competing to control the regiochemistry: electronic effects vs. steric effects. The former favors attack at the more substituted position, while the latter favors attack at the less substituted position. To determine which factor is dominant, we must analyze the epoxide. When the epoxide possesses a tertiary position, the electronic effect will be dominant. When the epoxide possesses only primary and secondary positions, the steric effect will be dominant. The regiochemistry of acid-catalyzed ring opening is just one example where steric effects and electronic effects compete. As we progress through the course, we will see other examples of electronic vs. steric effects.

In the previous section (ring opening with strong nucleophiles), the regiochemistry was more straightforward, because electronics was not a factor at all. The epoxide was attacked by a nucleophile before being protonated, so the epoxide did not bear a positive charge when it was attacked. In such a case, steric hindrance was the only consideration.

Now let’s turn our attention to the stereochemistry of ring-opening reactions under acid-catalyzed conditions. When the attack takes place at a chirality center, inversion of configuration is observed. This result is consistent with an SN2-like process involving back-side attack of the nucleophile.

O

Me

Attack takes placeat a chirality center

The configurationhas been inverted

OH

ORMe

[H±]ROH

LEARN the skill

O

HMeEt Et EtOH

[H2SO4] ?SOLUTION

1.

O

HMeEt Et

2˚3˚

SKILLBUILDER 14.5 DRAWING THE MECHANISM AND PREDICTING THE PRODUCT OF ACID-CATALYZED RING OPENING

STEP 1

klein_c14_622-670hr.indd 649 11/8/10 6:07 PM

650 CHAPTER 14 Ethers and Epoxides; Thiols and Sulfides

PRACTICE the skill

2.

O

HMeEt Et

This chirality center will be invertedas a result of back-side attack

SN2Proton transfer

HMeEt Et

OH OSO3H

HMeEt Et

H

O+

O

OH

H

MeEt

Et

HEt +

EtO

H

Proton transfer

EtO

OH

H

MeEt

EtEt H

O

O H

MeEt

Et

HEt +

OH

14.20

O ?(a)HCl

O

Me?

(b)

HBr

O

MeEt

EtOH[H2SO4] ?

(c)

O

MeEt

Me H2O[H2SO4] ?

(d)

O

Me MeOH[H2SO4] ?

(e)

O

MeEt

?(f)

HBr

14.21

O

MeEt H

OHO

OH

MeEt

[H2SO4]

Try Problems 14.43d, 14.49, 14.50

STEP 2

need more PRACTICE?

APPLY the skill

STEP 3

klein_c14_622-670hr.indd 650 11/8/10 6:07 PM