Aldehydes and Ketones - Wiley

Aldehydes and Ketones

20 20.1 Introduction to Aldehydes and Ketones

DID YOU EVER WONDER . . .

20.2 Nomenclature

why beta-carotene, which makes carrots orange, is reportedly good for your eyes?

20.3 Preparing Aldehydes and Ketones: A Review

T

his chapter will explore the reactivity of aldehydes and ketones. Specifically, we will see that a wide variety of nucleophiles will react with aldehydes and ketones. Many of these reactions are common in biological pathways, including the role that beta-carotene plays in promoting healthy vision. As we will see several times in this chapter, the reactions of aldehydes and ketones are also cleverly exploited in the design of drugs. The reactions and principles outlined in this chapter are central to the study of organic chemistry and will be used as guiding principles throughout the remaining chapters of this textbook.

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20.4 Introduction to Nucleophilic Addition Reactions 20.5 Oxygen Nucleophiles 20.6 Nitrogen Nucleophiles 20.7 Mechanism Strategies 20.8 Sulfur Nucleophiles 20.9 Hydrogen Nucleophiles 20.10 Carbon Nucleophiles 20.11 Baeyer-Villiger Oxidation of Aldehydes and Ketones 20.12 Synthesis Strategies 20.13 Spectroscopic Analysis of Aldehydes and Ketones

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2

CHAPTER 20


DO YOU REMEMBER? Before you go on, be sure you understand the following topics. If necessary, review the suggested sections to prepare for this chapter: UÊ À}>À`ÊÀi>}iÌÃÊ-iVÌÊ£Î°È®ÊÊ

UÊ ,iÌÀÃÞÌiÌVÊ>>ÞÃÃÊ-iVÌÊ£Ó°Î®

UÊ "Ý`>ÌÊvÊ>VÃÊ-iVÌÊ£Î°£ä® 6ÃÌÊÜÜÜ°ÜiÞ«ÕÃ°VÊÌÊViVÊÞÕÀÊÕìÀÃÌ>`}Ê>`ÊvÀÊÛ>Õ>LiÊ«À>VÌVi°

20.1 Introduction to Aldehydes and Ketones Aldehydes (RCHO) and ketones (R2CO) are similar in structure in that both classes of compounds possess a C5O bond, called a carbonyl group: Carbonyl Group

O R

O H

R

An aldehyde

R

A ketone

The carbonyl group of an aldehyde is flanked by one carbon atom and one hydrogen atom, while the carbonyl group of a ketone is flanked by two carbon atoms. Aldehydes and ketones are responsible for many flavors and odors that you will readily recognize: O

H3CO

O

O

O H

HO

H

H Vanillin (Vanilla flavor)

Cinnamaldehyde (Cinnamon flavor)

(R )-Carvone (Spearmint flavor)

Benzaldehyde (Almond flavor)

Many important biological compounds also exhibit the carbonyl moiety, including progesterone and testosterone, the female and male sex hormones. O

OH H

H H

H

H

O

H

O Progesterone

Testosterone

Simple aldehydes and ketones are industrially important; for example: O H

O H

Formaldehyde

H3C

CH3

Acetone

Acetone is used as a solvent and is commonly found in nail polish remover, while formaldehyde is used as a preservative in some vaccine formulations. Aldehydes and ketones are also used as building blocks in the syntheses of commercially important compounds, including pharmaceuticals and polymers. Compounds containing a carbonyl group react with a large variety of nucleophiles, affording a wide range of possible products. Due to the versatile reactivity of the carbonyl group, aldehydes and ketones occupy a central role in organic chemistry.

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20.2

3

Nomenclature

20.2 Nomenclature Nomenclature of Aldehydes Recall that four discrete steps are required to name most classes of organic compounds (as we saw with alkanes, alkenes, alkynes, and alcohols): 1. 2. 3. 4.

Identify and name the parent. Identify and name the substituents. Assign a locant to each substituent. Assemble the substituents alphabetically.

Aldehydes are also named using the same four-step procedure. When applying this procedure for naming aldehydes, the following guidelines should be followed: When naming the parent, the suffix “-al” indicates the presence of an aldehyde group: O H Butane

Butanal

When choosing the parent of an aldehyde, identify the longest chain that includes the carbon atom of the aldehydic group: The parent must include this carbon atom

Parent=Octane

H

O

Parent=Hexanal

When numbering the parent chain of an aldehyde, the aldehydic carbon is assigned number 1, despite the presence of alkyl substituents, U bonds, or hydroxyl groups: Correct

H

1

O

2

3

4

Incorrect 5

6

H

7

OH

7

O

6

5

4

3

2

1

OH

It is not necessary to include the locant in the name, because it is understood that the aldehydic carbon is the number 1 position. As with all compounds, when a chirality center is present, the configuration is indicated at the beginning of the name; for example: O H Cl (R)-2-chloro-3-phenylpropanal

A cyclic compound containing an aldehyde group immediately adjacent to the ring is named as a carbaldehyde: O H

Cyclohexanecarbaldehyde

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4

CHAPTER 20


The International Union of Pure and Applied Chemistry (IUPAC) nomenclature also recognizes the common names of many simple aldehydes, including the three examples shown below: O H

O

O H

H3C

Formaldehyde

H

H

Acetaldehyde

Benzaldehyde

Nomenclature of Ketones Ketones, like aldehydes, are named using the same four-step procedure. When naming the parent, the suffix “-one” indicates the presence of a ketone group: O

Butane

Butanone

The position of the ketone group is indicated using a locant. The IUPAC rules published in 1979 dictate that this locant be placed immediately before the parent, while the IUPAC recommendations released in 1993 and 2004 allow for the locant to be placed immediately before the suffix “-one”: O 1

2

3

4

5

6

7

3-heptanone or heptan-3-one

Both names above are acceptable IUPAC names. IUPAC nomenclature recognizes the common names of many simple ketones, including the three examples shown below: O O H3C

O CH3

CH3

Acetone

Acetophenone

Benzophenone

Although rarely used, IUPAC rules also allow simple ketones to be named as alkyl alkyl ketones. For example, 3-hexanone can also be called ethyl propyl ketone: O C Ethyl propyl ketone

SKILLBUILDER 20.1 NAMING ALDEHYDES AND KETONES LEARN the skill

*ÀÛìÊ>ÊÃÞÃÌi>ÌVÊ1* ®Ê>iÊvÀÊÌiÊvÜ}ÊV«Õ`\

O

SOLUTION STEP 1 ìÌvÞÊ>`Ê>iÊÌiÊ «>ÀiÌ°

/iÊwÀÃÌÊÃÌi«ÊÃÊÌÊìÌvÞÊ>`Ê>iÊÌiÊ«>ÀiÌ°Ê ÃiÊÌiÊ}iÃÌÊV>ÊÌ>ÌÊVÕìÃÊÌiÊV>ÀLÞÊ}ÀÕ«]Ê>`ÊÌiÊÕLiÀÊÌiÊ V>ÊÌÊ}ÛiÊÌiÊV>ÀLÞÊ}ÀÕ«ÊÌiÊÜiÃÌÊÕLiÀÊ«ÃÃLi\

8 7 2

4

1 3

9 6

5

O 3-nonanone

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20.2

5

Nomenclature

iÝÌ]ÊìÌvÞÊÌiÊÃÕLÃÌÌÕiÌÃÊ>`Ê>ÃÃ}ÊV>ÌÃ\ STEP 2 ìÌvÞÊ>`Ê>iÊÌiÊ ÃÕLÃÌÌÕiÌÃ° STEP 3 ÃÃ}Ê>ÊV>ÌÊÌÊi>VÊ ÃÕLÃÌÌÕiÌ°

STEP 4 ÃÃiLiÊÌiÊ ÃÕLÃÌÌÕiÌÃÊ >«>LiÌV>Þ° STEP 5 ÃÃ}ÊÌiÊVw}ÕÀ>ÌÊ vÊ>ÞÊVÀ>ÌÞÊViÌiÀÃ°

4,4-dimethyl

8

7 2

4

1 3

9 6

5

6-ethyl

O

>Þ]Ê>ÃÃiLiÊÌiÊÃÕLÃÌÌÕiÌÃÊ>«>LiÌV>Þ\ÊÈiÌÞ{]{ìÌÞÎ>i°Ê ivÀiÊ VVÕ`}]ÊÜiÊÕÃÌÊ>Ü>ÞÃÊViVÊÌÊÃiiÊvÊÌiÀiÊ>ÀiÊ>ÞÊVÀ>ÌÞÊViÌiÀÃ°Ê/ÃÊV«Õ`Ê ìÃÊ iÝLÌÊ iÊ VÀ>ÌÞÊ ViÌiÀ°Ê 1Ã}Ê ÌiÊ ÃÃÊ vÀÊ -iVÌÊ x°Î]Ê ÌiÊ RÊ Vw}ÕÀ>ÌÊ ÃÊ >ÃÃ}i`ÊÌÊÌÃÊVÀ>ÌÞÊViÌiÀ\

R O

/iÀivÀi]ÊÌiÊV«iÌiÊ>iÊÃÊ(R)-6-ethyl-4,4-dimethyl-3-nonanone.

PRACTICE the skill 20.1 ÃÃ}Ê>ÊÃÞÃÌi>ÌVÊ1* ®Ê>iÊÌÊi>VÊvÊÌiÊvÜ}ÊV«Õ`Ã\ O

O H

(a)

Br Br

O

(b)

(c) O

O

H H

(d)

APPLY the skill

20.2

(e) À>ÜÊÌiÊÃÌÀÕVÌÕÀiÊvÊi>VÊvÊÌiÊvÜ}ÊV«Õ`Ã\

>® S®Î]Î`LÀ{iÌÞVÞViÝ>iÊ Ê L®Ê Ó]{ìÌÞÎ«iÌ>i V® R®ÎLÀLÕÌ>> 20.3 *ÀÛìÊ>ÊÃÞÃÌi>ÌVÊ1* ®Ê>iÊvÀÊÌiÊV«Õ`ÊLiÜ°Ê iÊV>ÀivÕ\Ê/ÃÊV«Õ`Ê>ÃÊÌÜÊVÀ>ÌÞÊViÌiÀÃÊV>ÊÞÕÊw`ÊÌi¶®° O

20.4

«Õ`ÃÊÜÌÊÌÜÊV>ÀLÞÊiÌiÃÊ>ÀiÊ>i`Ê>ÃÊ>>iÊìÃÆÊvÀÊiÝ>«i\ O

O

2,3-butanedione

/iÊV«Õ`Ê>LÛiÊÃÊ>Ê>ÀÌwV>Êy>ÛÀÊ>`ì`ÊÌÊVÀÜ>ÛiÊ««VÀÊ>`ÊÛiÊ Ìi>ÌiÀÊ««VÀÊÌÊÃÕ>ÌiÊÌiÊLÕÌÌiÀÊy>ÛÀ°ÊÌiÀiÃÌ}Þ]ÊÌÃÊÛiÀÞÊÃ>iÊV«Õ`ÊÃÊ >ÃÊÜÊÌÊVÌÀLÕÌiÊÌÊL`ÞÊ`À°Ê >iÊÌiÊvÜ}ÊV«Õ`Ã\ O

(a)

O

O

O

(b)

O

(c)

O

O

need more PRACTICE? Try Problems 20.44–20.49

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6

CHAPTER 20


20.3 Preparing Aldehydes and Ketones: A Review In previous chapters, we have studied a variety of methods for preparing aldehydes and ketones, which are summarized in Tables 20.1 and 20.2, respectively. TABLE 20.1 A SUMMARY OF ALDEHYDE PREPARATION METHODS COVERED IN PREVIOUS CHAPTERS

TABLE 20.2 A SUMMARY OF KETONE PREPARATION METHODS COVERED IN PREVIOUS CHAPTERS

REACTION

REACTION

SECTION

"Ý`>ÌÊvÊ*À>ÀÞÊVÃÊ £Î°£äÊ Ê OH O Ê PCC Ê CH2Cl2 R H ÊR 7iÊÌÀi>Ìi`ÊÜÌÊ>ÊÃÌÀ}ÊÝ`â}Ê>}iÌ]Ê«À>ÀÞÊ>VÃÊ >ÀiÊÝ`âi`ÊÌÊV>ÀLÝÞVÊ>V`Ã°ÊÀ>ÌÊvÊ>Ê>ìÞìÊ ÀiµÕÀiÃÊ>ÊÝ`â}Ê>}iÌ]ÊÃÕVÊ>ÃÊ*

]ÊÌ>ÌÊÜÊÌÊvÕÀÌiÀÊ Ý`âiÊÌiÊÀiÃÕÌ}Ê>ìÞì°

SECTION

"Ý`>ÌÊvÊ-iV`>ÀÞÊVÃÊ £Î°£äÊ Ê OH O Ê Na2Cr2O7 Ê H2SO4, H2O R R R R Ê ÊÊÛ>ÀiÌÞÊvÊÃÌÀ}ÊÀÊ`ÊÝ`â}Ê>}iÌÃÊV>ÊLiÊÕÃi`ÊÌÊ Ý`âiÊÃiV`>ÀÞÊ>VÃ°Ê/iÊÀiÃÕÌ}ÊiÌiÊìÃÊÌÊ ÕìÀ}ÊvÕÀÌiÀÊÝ`>Ì° "âÞÃÃÊvÊiiÃÊ °£Ê ÊR R R R 1) O3 Ê O O Ê 2) DMS R R R R Ê Ê/iÌÀ>ÃÕLÃÌÌÕÌi`Ê>iiÃÊ>ÀiÊVi>Ûi`ÊÌÊvÀÊiÌiÃ°

"âÞÃÃÊvÊiiÃÊ °£Ê Ê H H H ÊH 1) O3 Ê O O 2) DMS ÊR R R R Ê Ê"âÞÃÃÊÜÊVi>ÛiÊ>Ê 5 Ê`ÕLiÊL`°ÊvÊiÌiÀÊV>ÀLÊ >ÌÊLi>ÀÃÊ>ÊÞ`À}iÊ>Ì]Ê>Ê>ìÞìÊÜÊLiÊvÀi`°

V` >Ì>Þâi`ÊÞ`À>ÌÊvÊ/iÀ>ÊÞiÃÊ £ä°nÊ Ê O Ê H2SO4, H2O Ê HgSO4 CH3 R R Ê Ê/ÃÊ«ÀVi`ÕÀiÊÀiÃÕÌÃÊÊ>Ê>ÀÛÛÊ>``ÌÊvÊÜ>ÌiÀÊ >VÀÃÃÊÌiÊUÊL`]ÊvÜi`ÊLÞÊÌ>ÕÌiÀâ>ÌÊÌÊvÀÊ>Ê iÌÞÊiÌi°

Þ`ÀLÀ>Ì"Ý`>ÌÊvÊ/iÀ>ÊÞiÃÊ £ä°nÊ Ê H 1) R2B H Ê R 2) H2O2, NaOH ÊR O Ê ÊÞ`ÀLÀ>ÌÝ`>ÌÊÀiÃÕÌÃÊÊ>Ê>Ì>ÀÛÛÊ>``ÌÊvÊÜ>ÌiÀÊ>VÀÃÃÊ>ÊUÊL`]ÊvÜi`ÊLÞÊÌ>ÕÌiÀâ>ÌÊvÊ ÌiÊÀiÃÕÌ}ÊiÊÌÊvÀÊ>Ê>ìÞì°Ê

Àiì À>vÌÃÊVÞ>ÌÊ £°ÈÊ Ê O O Ê Ê R Cl R Ê AlCl Ê 3 Ê À>ÌVÊÀ}ÃÊÌ>ÌÊ>ÀiÊÌÊÌÊÃÌÀ}ÞÊì>VÌÛ>Ìi`ÊÜÊÀi>VÌÊ ÜÌÊ>Ê>V`Ê>ìÊÊÌiÊ«ÀiÃiViÊvÊ>ÊiÜÃÊ>V`ÊÌÊ«À`ÕViÊ >Ê>ÀÞÊiÌi°

CONCEPTUAL CHECKPOINT 20.5 ìÌvÞÊÌiÊÀi>}iÌÃÊiViÃÃ>ÀÞÊÌÊ>ViÛiÊi>VÊvÊÌiÊvÜ}ÊÌÀ>ÃvÀ>ÌÃ\

OH

O

O

OH O

H

(a)

(b) H

O

O

(d)

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(c)

O

O H

(e)

(f)

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20.4

Introduction to Nucleophilic Addition Reactions

7

20.4 Introduction to Nucleophilic Addition Reactions The electrophilicity of a carbonyl group derives from resonance effects as well as inductive effects: Resonance

Induction -

O

d-

O

O

+

d±

One of the resonance structures exhibits a positive charge on the carbon atom, indicating that the carbon atom is deficient in electron density (I+). Inductive effects also render the carbon atom deficient in electron density. As a result, this carbon atom is particularly electrophilic and is susceptible to attack by a nucleophile. Molecular orbital calculations suggest that nucleophilic attack occurs at an angle of approximately 107° to the plane of the carbonyl group, and in the process, the hybridization state of the carbon atom changes (Figure 20.1). 107° angle –

Nuc

Nuc

R

¡

O

FIGURE 20.1 7iÊ>ÊV>ÀLÞÊ}ÀÕ«ÊÃÊ >ÌÌ>Vi`ÊLÞÊ>ÊÕVi«i]Ê ÌiÊV>ÀLÊ>ÌÊÕìÀ}iÃÊ >ÊV>}iÊÊÞLÀ`â>ÌÊ>`Ê }iiÌÀÞ°

– O

R

R

R

sp 2 (Trigonal planar)

sp 3 (Tetrahedral )

The carbon atom is originally sp2 hybridized with a trigonal planar geometry. After the attack, the carbon atom is sp3 hybridized with a tetrahedral geometry. In recognition of this geometric change, the resulting alkoxide ion is often called a tetrahedral intermediate. This term appears many times throughout the remainder of this chapter. In general, aldehydes are more reactive than ketones toward nucleophilic attack. This observation can be explained in terms of both steric and electronic effects: 1.

Steric effects. A ketone has two alkyl groups (one on either side of the carbonyl) that contribute to steric hindrance in the transition state of a nucleophilic attack. In contrast, an aldehyde has only one alkyl group, so the transition state is less crowded and lower in energy.

2.

Electronic effects. Recall that alkyl groups are electron donating. A ketone has two electrondonating alkyl groups that can stabilize the I+ on the carbon atom of the carbonyl group. In contrast, aldehydes have only one electron-donating group: O

O

R d± R

R d± H

A ketone has two electron-donating alkyl groups that stabilize the partial positive charge

An aldehyde has only one electron-donating alkyl group that stabilizes the partial positive charge

The I+ charge of an aldehyde is less stabilized than a ketone. As a result, aldehydes are more electrophilic than ketones and therefore more reactive. Aldehydes and ketones react with a wide variety of nucleophiles. As we will see in the coming sections of this chapter, some nucleophiles require basic conditions, while others require acidic conditions. For example, recall from Chapter 13 that Grignard reagents are very strong nucleophiles that will attack aldehydes and ketones to produce alcohols: OH

O 1) MeMgBr

R

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R

2) H2O

R

R

Me

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CHAPTER 20


The Grignard reagent itself provides for strongly basic conditions, because Grignard reagents are both strong nucleophiles and strong bases. This reaction cannot be achieved under acidic conditions, because, as explained in Section 13.6, Grignard reagents are destroyed in the presence of an acid. The Grignard reaction above follows a general mechanism for the reaction between a nucleophile and a carbonyl group under basic conditions (Mechanism 20.1). This general mechanism has two steps: (1) nucleophilic attack followed by (2) proton transfer.

MECHANISM 20.1 NUCLEOPHILIC ADDITION UNDER BASIC CONDITIONS Nucleophilic attack O

Proton transfer -

O

O

-

Nuc

H

OH

H

Nuc The carbonyl group is attacked by a nucleophile, forming a tetrahedral intermediate

Nuc

The tetrahedral intermediate is protonated upon treatment with a mild proton source

Aldehydes and ketones also react with a wide variety of other nucleophiles under acidic conditions. In acidic conditions, the same two mechanistic steps are observed, but in reverse order—that is, the carbonyl group is first protonated and then undergoes a nucleophilic attack (Mechanism 20.2).

MECHANISM 20.2 NUCLEOPHILIC ADDITION UNDER ACIDIC CONDITIONS Proton transfer O

Nucleophilic attack +

H

-

O

H A

OH

Nuc

Nuc The carbonyl group is first protonated, rendering it even more electrophilic

The protonated carbonyl group is then attacked by a nucleophile

In acidic conditions, the first step plays an important role. Specifically, protonating the carbonyl group generates a very powerful electrophile: +

O

H

H O

O

H¬A

·

+

Very powerful electrophile

It is true that the carbonyl group is already a fairly strong electrophile; however, a protonated carbonyl group bears a full positive charge, rendering the carbon atom even more electrophilic. This is especially important when weak nucleophiles, such as H2O or ROH, are employed, as we will see in the upcoming sections. When a nucleophile attacks a carbonyl group under either acidic or basic conditions, the position of equilibrium is highly dependent on the ability of the nucleophile to function as a leaving group. A Grignard reagent is a very strong nucleophile, but it does not function as a leaving group (a carbanion is too unstable to leave). As a result, the equilibrium so greatly favors products that the reaction effectively occurs in only one direction. With a sufficient amount of nucleophile present, the ketone is not observed in the product mixture. In contrast, halides are

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20.5

9

Oxygen Nucleophiles

good nucleophiles, but they are also good leaving groups. Therefore, when a halide functions as the nucleophile, the equilibrium actually favors the starting ketone: O

HO Cl

R

R

+ HCl

R

R

Once equilibrium has been achieved, the mixture consists primarily of the ketone, and only small quantities of the addition product. In this chapter, we will explore a wide variety of nucleophiles, which will be classified according to the nature of the attacking atom. Specifically, we will see nucleophiles based on oxygen, sulfur, nitrogen, hydrogen, and carbon (Figure 20.2). Oxygen Nucleophiles

Sulfur Nucleophiles

O

S

H

H

H

Nitrogen Nucleophiles

Hydrogen Nucleophiles

Carbon Nucleophiles

H

H

RMgBr

-

H Al

N

H R

H

H -

H

C

N

O R FIGURE 20.2 6>ÀÕÃÊÕVi«iÃÊÌ>ÌÊV>Ê >ÌÌ>VÊ>ÊV>ÀLÞÊ}ÀÕ«°

H

H

S

S

H

H

H

N H O

O

R

H

H R

Ph + H Ph P C Ph H

-

B H H

The remainder of the chapter will be a methodical survey of the reactions that occur between the reagents in Figure 20.2 and ketones and aldehydes. We will begin our survey with oxygen nucleophiles.

CONCEPTUAL CHECKPOINT O

20.6 À>ÜÊ>ÊiV>ÃÊvÀÊi>VÊvÊÌiÊ Ài>VÌÃÊLiÜ\

HO

O

HO Cl

1) EtMgBr

+ HCl

2) H2O

(a)

(b)

20.5 Oxygen Nucleophiles Hydrate Formation When an aldehyde or ketone is treated with water, the carbonyl group can be converted into a hydrate: O

HO OH

+

H2O Hydrate

The position of equilibrium generally favors the carbonyl group rather than the hydrate, except in the case of very simple aldehydes, such as formaldehyde: O H3C

HO OH CH3

+

H2O

+

H2O

H3C

CH3

99.9%

O H

HO OH H

H

H

> 99.9%

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10

CHAPTER 20


The rate of reaction is relatively slow under neutral conditions but is readily enhanced in the presence of either acid or base. That is, the reaction can be either acid catalyzed or base catalyzed, allowing the equilibrium to be achieved much more rapidly. Consider the base-catalyzed hydration of formaldehyde (Mechanism 20.3).

MECHANISM 20.3 BASE-CATALYZED HYDRATION Nucleophilic attack -

-

O H

Proton transfer O

O

OH

H

H

H

H

OH

H

OH

The carbonyl group is attacked by hydroxide, forming a tetrahedral intermediate

H

H

OH

The tetrahedral intermediate is protonated by water to form the hydrate

In the first step, a hydroxide ion (rather than water) functions as a nucleophile. Then, in the second step, the tetrahedral intermediate is protonated with water, regenerating a hydroxide ion. In this way, hydroxide serves as a catalyst for the addition of water across the carbonyl group. Now consider the acid-catalyzed hydration of formaldehyde (Mechanism 20.4).

MECHANISM 20.4 ACID-CATALYZED HYDRATION Proton transfer

Nucleophilic attack

H H

O

+

O+

H

O

H

H

O

O

OH

H

H

H

OH

H

H

H

H

Proton transfer

H

H

H O+

H

H

OH

H The carbonyl group is protonated, rendering it more electrophilic

The protonated carbonyl group is attacked by water, forming a tetrahedral intermediate

The tetrahedral intermediate is deprotonated by water to form the hydrate

Under acid-catalyzed conditions, the carbonyl group is first protonated, generating a positively charged intermediate that is extremely electrophilic (it bears a full positive charge). This intermediate is then attacked by water to form a tetrahedral intermediate, which is deprotonated to give the product.

CONCEPTUAL CHECKPOINT 20.7 ÀÊÃÌÊiÌiÃ]ÊÞ`À>ÌiÊvÀ>ÌÊÃÊÕv>ÛÀ>Li]ÊLiV>ÕÃiÊ ÌiÊiµÕLÀÕÊv>ÛÀÃÊÌiÊiÌiÊÀ>ÌiÀÊÌ>ÊÌiÊÞ`À>Ìi°ÊÜiÛiÀ]Ê ÌiÊiµÕLÀÕÊvÀÊÞ`À>ÌÊvÊiÝ>yÕÀ>ViÌiÊv>ÛÀÃÊvÀ>ÌÊ vÊÌiÊÞ`À>Ìi\Ê*ÀÛìÊ>Ê«>ÕÃLiÊiÝ«>>ÌÊvÀÊÌÃÊLÃiÀÛ>Ì°

klein_c20_001-056v1.4.indd 10

O F3C

HO OH CF3

+

H2O F3 C

CF3

> 99.99%

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20.5

11

Oxygen Nucleophiles

Acetal Formation The previous section discussed a reaction that can occur when water attacks an aldehyde or ketone. This section will explore a similar reaction, in which an alcohol attacks an aldehyde or ketone: O

+

[H+]

2 ROH

BY THE WAY

RO OR

+

H2O

Acetal

7iÊÌiÊÃÌ>ÀÌ}ÊV«Õ`Ê ÃÊ>ÊiÌi]ÊÌiÊ«À`ÕVÌÊV>Ê >ÃÊLiÊV>i`Ê>ÊºiÌ>°»Ê AcetalÊÃÊ>ÊÀiÊ}iiÀ>Ê ÌiÀ]Ê>`ÊÌÊÜÊLiÊÕÃi`Ê iÝVÕÃÛiÞÊvÀÊÌiÊÀi>ìÀÊ vÊÌÃÊ`ÃVÕÃÃ°

In acidic conditions, an aldehyde or ketone will react with two molecules of alcohol to form an acetal. The brackets surrounding the H+ indicate that the acid is a catalyst. Common acids used for this purpose include para-toluenesulfonic acid (TsOH) and sulfuric acid (H2SO4): O S

O OH

HO

S

O

OH

O

p-toluenesulfonic acid (TsOH)

Sulfuric acid

As mentioned earlier, the acid catalyst serves an important role in this reaction. Specifically, in the presence of an acid, the carbonyl group is protonated, rendering the carbon atom even more electrophilic. This is necessary because the nucleophile (an alcohol) is weak; it reacts with the carbonyl group more rapidly if the carbonyl group is first protonated. A mechanism for acetal formation is shown in Mechanism 20.5. This mechanism has many steps, and it is best to divide it conceptually into two parts: (1) The first three steps produce an intermediate called a hemiacetal and (2) the last four steps convert the hemiacetal into an acetal:

MECHANISM 20.5 ACETAL FORMATION Proton transfer

O

+

Nucleophilic attack

H

+

O

H A

Proton transfer

H O

OH

A

R

OH

H O+ The carbonyl group is protonated, rendering it more electrophilic

The alcohol attacks the protonated carbonyl to generate a tetrahedral intermediate

R

OR

The tetrahedral intermediate is deprotonated to form a hemiacetal

Hemiacetal +

H A

H + H O

Proton transfer The OH group is protonated, thereby converting it into an excellent leaving group

OR Loss of a leaving group Proton transfer

OR

A

Nucleophilic attack

H + R O

OR Acetal

klein_c20_001-056v1.4.indd 11

H

O R

–H2O

+

R

Water leaves to regenerate the C“ O double bond

O

OR The intermediate is deprotonated, generating an acetal

The second molecule of the alcohol attacks the C“ O double bond to generate another tetrahedral intermediate

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12

CHAPTER 20


Let’s begin our analysis of this mechanism by focusing on the first part: formation of the hemiacetal, which involves the three steps in Figure 20.3. FIGURE 20.3 /iÊÃiµÕiViÊvÊÃÌi«ÃÊÛÛi`Ê ÊvÀ>ÌÊvÊ>Êi>ViÌ>°

Proton transfer

Nucleophilic attack

Proton transfer

Notice that the sequence of steps begins and ends with a proton transfer. This will be a recurring pattern in this chapter. Let’s focus on the details of these three steps: 1.

The carbonyl is protonated in the presence of an acid. The identity of the acid, HA+, is most likely a protonated alcohol, which received its extra proton from the acid catalyst:

H

+

A

H

H O+ R

2.

The protonated carbonyl is a very powerful electrophile and is attacked by a molecule of alcohol (ROH) to form a tetrahedral intermediate that bears a positive charge.

3.

The tetrahedral intermediate is deprotonated by a weak base (A), which is likely to be a molecule of alcohol present in solution.

Notice that the acid is not consumed in this process. A proton is used in step 1 and then returned in step 3, confirming the catalytic nature of the proton in the reaction. It is important to remember the specific order of these three steps, as we will soon encounter many other reactions that begin with the same three steps. These three steps are typical of reactions involving acid-catalyzed nucleophilic attack. Now let’s focus on the second part of the mechanism, conversion of the hemiacetal into an acetal, which is accomplished with the four steps in Figure 20.4. FIGURE 20.4 /iÊÃiµÕiViÊvÊÃÌi«ÃÊÌ>ÌÊ VÛiÀÌÊ>Êi>ViÌ>ÊÌÊ>Ê >ViÌ>°

Proton transfer

Loss of a leaving group

Nucleophilic attack

Proton transfer

Notice, once again, that the sequence of steps begins and ends with a proton transfer. A proton is used in the first step and then returned in the last step, but this time there are two middle steps rather than just one. When drawing the mechanism of acetal formation, make sure to draw these two steps separately. Combining these two steps is incorrect and represents one of the most common student errors when drawing this mechanism: Loss of a leaving group

+

OH2 OR

+ ROH

An SN 2 process cannot occur at this substrate

¡

Nucleophilic attack

These two steps cannot occur simultaneously, because that would represent an SN2 process occurring at a sterically hindered substrate. Such a process is disfavored and does not occur at an appreciable rate. Instead, the leaving group leaves first to form a resonance-stabilized intermediate, which is then attacked by the nucleophile in a separate step. The equilibrium arrows in the full mechanism of acetal formation indicate that the process is governed by an equilibrium. For many simple aldehydes, the equilibrium favors formation of the acetal, so aldehydes are readily converted into acetals by treatment with two equivalents of alcohol in acidic conditions: O H

H

+ 2 EtOH

[H+]

EtO

OEt

H

H

+ H2O

Products are favored at equilibrium

klein_c20_001-056v1.4.indd 12

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20.5

13

Oxygen Nucleophiles

However, for most ketones, the equilibrium favors reactants rather than products:

BY THE WAY /ÃÊÌiVµÕiÊiÝ«ÌÃÊiÊ

@ÌiiÀ½ÃÊ«ÀV«i]ÊÜVÊ Ü>ÃÊVÛiÀi`ÊÊÞÕÀÊ}iiÀ>Ê ViÃÌÀÞÊVÕÀÃi°ÊVVÀ`}Ê ÌÊiÊ @ÌiiÀ½ÃÊ«ÀV«i]Ê vÊ>ÊÃÞÃÌiÊ>ÌÊiµÕLÀÕÊÃÊ Õ«ÃiÌÊLÞÊÃiÊ`ÃÌÕÀL>Vi]Ê ÌiÊÃÞÃÌiÊÜÊV>}iÊÊ>Ê Ü>ÞÊÌ>ÌÊÀiÃÌÀiÃÊiµÕLÀÕ°

O H 3C

EtO

+

[H ]

+ 2 EtOH

CH3

OEt

H 3C

CH3

+ H2O

Reactants are favored at equilibrium

In such cases, formation of the acetal can be accomplished by removing one of the products (water) via a special distillation technique. By removing water as it is formed, the reaction can be forced to completion. Notice that acetal formation requires two equivalents of the alcohol. That is, two molecules of ROH are required for every molecule of ketone. Alternatively, a compound containing two OH groups can be used, forming a cyclic acetal. This reaction proceeds via the regular seven-step mechanism for acetal formation: three steps for formation of the hemiacetal followed by four steps for formation of the cyclic acetal: OH OH

OH

O

O

3 steps

OH

O

4 steps

Hemiacetal

O

+

H2O

Cyclic acetal

The seven-step mechanism for acetal formation is very similar to other mechanisms that we will explore. It is therefore critical to master these seven steps. To help you draw the mechanism properly, remember to divide the entire mechanism into two parts, where each part begins and ends with proton transfers. Let’s get some practice.

SKILLBUILDER 20.2

DRAWING THE MECHANISM OF ACETAL FORMATION O

LEARN the skill

EtO

À>ÜÊ >Ê «>ÕÃLiÊ iV>ÃÊ vÀÊ ÌiÊ vÜ}Ê ÌÀ>ÃvÀ>Ì\

OEt

[H2SO4] excess EtOH –H2O

SOLUTION

STEP 1 À>ÜÊÌiÊÌÀiiÊÃÌi«ÃÊ iViÃÃ>ÀÞÊvÀÊi>ViÌ>Ê vÀ>Ì°

/iÊ Ài>VÌÊ >LÛiÊ ÃÊ >Ê iÝ>«iÊ vÊ >V`V>Ì>Þâi`Ê >ViÌ>Ê vÀ>Ì]Ê Ê ÜVÊ ÌiÊ «À`ÕVÌÊ ÃÊ v>ÛÀi`Ê LÞÊ ÌiÊ ÀiÛ>Ê vÊ Ü>ÌiÀ°Ê /iÊ iV>ÃÊ V>Ê LiÊ `Ûì`Ê ÌÊ ÌÜÊ «>ÀÌÃ\ÊÊ £®ÊvÀ>ÌÊvÊÌiÊi>ViÌ>Ê>`ÊÓ®ÊvÀ>ÌÊvÊÌiÊ>ViÌ>°ÊÀ>ÌÊvÊÌiÊi>ViÌ>Ê ÛÛiÃÊÌÀiiÊiV>ÃÌVÊÃÌi«Ã\ Proton transfer

Nucleophilic attack

Proton transfer

7iÊ`À>Ü}ÊÌiÃiÊÌÀiiÊÃÌi«Ã]Ê>iÊÃÕÀiÊÌÊvVÕÃÊÊ«À«iÀÊ>ÀÀÜÊ«>ViiÌÊ>ÃÊìÃVÀLi`Ê Ê >«ÌiÀÊÈ®]Ê>`Ê>iÊÃÕÀiÊÌÊ«>ViÊ>Ê«ÃÌÛiÊV>À}iÃÊÊÌiÀÊ>««À«À>ÌiÊV>ÌÃ°Ê ÌViÊ Ì>ÌÊiÛiÀÞÊÃÌi«ÊÀiµÕÀiÃÊÌÜÊVÕÀÛi`Ê>ÀÀÜÃ° The tail of this arrow should be placed on a lone pair

Don’t forget the positive charges +

O

H H O

+

O

Et

Et

Don’t forget the second curved arrow that shows release of the proton

klein_c20_001-056v1.4.indd 13

H

H O

H

HO

+

O

Et

O

H

HO

OEt

Et

Hemiacetal

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14

CHAPTER 20


ÜÊiÌ½ÃÊvVÕÃÊÊÌiÊ>ÃÌÊvÕÀÊÃÌi«ÃÊvÊÌiÊiV>Ã]ÊÊÜVÊÌiÊi>ViÌ>ÊÃÊVÛiÀÌi`ÊÌÊ>Ê>ViÌ>\

STEP 2 À>ÜÊÌiÊvÕÀÊÃÌi«ÃÊ iViÃÃ>ÀÞÊÌÊVÛiÀÌÊ ÌiÊi>ViÌ>ÊÌÊ>Ê >ViÌ>°

Proton transfer


Proton transfer

Nucleophilic attack

"ViÊ>}>]ÊÌÃÊÃiµÕiViÊvÊÃÌi«ÃÊLi}ÃÊÜÌÊ>Ê«ÀÌÊÌÀ>ÃviÀÊ>`Êi`ÃÊÜÌÊ>Ê«ÀÌÊ ÌÀ>ÃviÀ°Ê7iÊ`À>Ü}ÊÌiÃiÊvÕÀÊÃÌi«Ã]Ê>iÊÃÕÀiÊÌÊ`À>ÜÊÌiÊ`ìÊÌÜÊÃÌi«ÃÊÃi«>À>ÌiÞ]Ê >ÃÊ`ÃVÕÃÃi`Êi>ÀiÀ°ÊÊ>``Ì]Ê>iÊÃÕÀiÊÌÊvVÕÃÊÊ«À«iÀÊ>ÀÀÜÊ«>ViiÌ]Ê>`Ê>iÊ ÃÕÀiÊÌÊ«>ViÊ>Ê«ÃÌÛiÊV>À}iÃÊÊÌiÀÊ>««À«À>ÌiÊV>ÌÃ\ The tail of this arrow should be placed on a lone pair

H

+

HO

OEt

H H O+ Et


OEt

H O

H

Et O O

–H2O

H

EtO

+

O

Et

Et

O

EtO

H

OEt

Et

Acetal


PRACTICE the skill 20.8 À>ÜÊ>Ê«>ÕÃLiÊiV>ÃÊvÀÊi>VÊvÊÌiÊvÜ}ÊÌÀ>ÃvÀ>ÌÃ\ O

MeO

OMe

O

[H2SO4] excess MeOH

OEt [TsOH] excess EtOH

–H2O

(b)

(a) EtO

O

O

OEt

MeO

OMe

[TsOH] excess MeOH

[H2SO4] excess EtOH

–H2O

–H2O

(c)

APPLY the skill

OEt

–H2O

(d)

20.9

À>ÜÊ>Ê«>ÕÃLiÊiV>ÃÊvÀÊi>VÊvÊÌiÊvÜ}ÊÀi>VÌÃ\

HO

OH

O

[H2SO4]

O O

–H2O

(a)

O

HO OH [H2SO4]

–H2O

O

O

(b) 20.10

*Ài`VÌÊÌiÊ«À`ÕVÌÊvÊi>VÊvÊÌiÊvÜ}ÊÀi>VÌÃ\ O

O [H2SO4] excess MeOH –H2O

?

(a)

HO

OH

[H2SO4] –H2O

?

(b)

need more PRACTICE? Try Problems 20.57, 20.62, 20.67

klein_c20_001-056v1.4.indd 14

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20.5

Acetals as Protecting Groups

HO

Acetal formation is a reversible process that can be controlled by carefully choosing reagents and conditions:

15

Oxygen Nucleophiles

O

OH +

[H ] –H2O

O

O

As mentioned in the previous section, acetal forH2O mation is favored by removal of water. To con+ [H ] vert an acetal back into the corresponding aldehyde or ketone, it is simply treated with water in the presence of an acid catalyst. In this way, acetals can be used to protect ketones or aldehydes. For example, consider how the following transformation might be accomplished: O

O

O OR

OH

?

This transformation involves reduction of an ester to form an alcohol. Recall that lithium aluminum hydride (LAH) can be used to accomplish this type of reaction. However, under these conditions, the ketone moiety will also be reduced. The problem above requires reduction of the ester moiety without also reducing the ketone moiety. To accomplish this, a protecting group can be used. The first step is to convert the ketone into an acetal: O

O

O OR

HO

O

O OR

OH [H+] –H2O

Notice that the ketone moiety is converted into an acetal, but the ester moiety is not. The resulting acetal group is stable under strongly basic conditions and will not react with LAH. This makes it possible to reduce only the ester, after which the acetal can be removed to regenerate the ketone: The three steps are summarized below: O

O

O OR

1) [H+], HO

OH

OH , –H2O

2) LAH 3) H3O+

CONCEPTUAL CHECKPOINT 20.11 *À«ÃiÊ>ÊivwViÌÊÃÞÌiÃÃÊvÀÊi>VÊvÊÌiÊvÜ}ÊÌÀ>ÃvÀ>ÌÃ\ O

20.12

O

*Ài`VÌÊÌiÊ«À`ÕVÌÃ®ÊvÀÊi>VÊÀi>VÌÊLiÜ\

O

O H3O+

(a) (a) O

O

O

?

OMe OMe

H3O+

?

H3O+

?

(b)

OH O

(c)

Ph Ph

O O

(b)

klein_c20_001-056v1.4.indd 15

O

O O

O

(c)

OH

O

H3O+

?

O

(d)

H H

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16

CHAPTER 20


MEDICALLYSPEAKING Acetals as Prodrugs Ê >«ÌiÀÊ£ÊÜiÊiÝ«Ài`ÊÌiÊVVi«ÌÊ vÊ «À`ÀÕ}Ãp«>À>V}V>ÞÊ >VÌÛiÊ V«Õ`ÃÊ Ì>ÌÊ >ÀiÊ VÛiÀÌi`Ê LÞÊ ÌiÊ L`ÞÊ ÌÊ >VÌÛiÊ V«Õ`Ã°Ê >ÞÊ ÃÌÀ>Ìi}iÃÊ >ÀiÊ ÕÃi`Ê Ê ÌiÊ ìÃ}Ê vÊ «À`ÀÕ}Ã°Ê "iÊ ÃÕVÊ ÃÌÀ>Ìi}ÞÊ ÛÛiÃÊ >Ê>ViÌ>ÊiÌÞ° ÃÊ >Ê iÝ>«i]Ê yÕVìÊ ÃÊ >Ê «À`ÀÕ}Ê Ì>ÌÊ VÌ>ÃÊ >Ê >ViÌ>Ê iÌÞ]Ê >`Ê ÃÊ Ã`ÊÊ>ÊVÀi>ÊÕÃi`ÊvÀÊÌiÊÌ«V>ÊÌÀi>ÌiÌÊ vÊiVâi>Ê>`ÊÌiÀÊÃÊV`ÌÃ°Ê

-Ê >ÃÊ ÃiÛiÀ>Ê «ÀÌ>ÌÊ vÕVÌÃ]Ê VÕ`}Ê «ÀiÛiÌ}Ê ÌiÊ>LÃÀ«ÌÊvÊvÀi}ÊÃÕLÃÌ>ViÃÊÌÊÌiÊ}iiÀ>ÊVÀVÕ>Ì°Ê /ÃÊvi>ÌÕÀiÊ«ÀÌiVÌÊÕÃÊvÀÊ>ÀvÕÊÃÕLÃÌ>ViÃ]ÊLÕÌÊÌÊ>ÃÊ«ÀiÛiÌÃÊLiiwV>Ê`ÀÕ}ÃÊvÀÊ«iiÌÀ>Ì}Êìi«ÊÌÊÌiÊÃ°Ê/ÃÊ ivviVÌÊÃÊÃÌÊ«ÀÕVi`ÊvÀÊ`ÀÕ}ÃÊVÌ>}Ê"Ê}ÀÕ«ÃÊÌ>ÌÊ V>ÊÌiÀ>VÌÊÜÌÊL`}ÊÃÌiÃÊÊÌiÊÃ½ÃÊÃÕÀv>Vi°Ê/ÊVÀVÕÛiÌÊ ÌÃÊ«ÀLi]ÊÌÜÊ"Ê}ÀÕ«ÃÊV>ÊLiÊÌi«À>ÀÞÊVÛiÀÌi`ÊÌÊ >Ê>ViÌ>°Ê/iÊ>ViÌ>Ê«À`ÀÕ}ÊÃÊV>«>LiÊvÊ«iiÌÀ>Ì}ÊÌiÊÃÊ ÀiÊ ìi«Þ]Ê LiV>ÕÃiÊ ÌÊ >VÃÊ ÌiÊ "Ê }ÀÕ«ÃÊ Ì>ÌÊ L`Ê ÌÊ ÌiÊ Ã°Ê "ViÊ ÌiÊ «À`ÀÕ}Ê Ài>ViÃÊ ÌÃÊ Ì>À}iÌ]Ê ÌiÊ >ViÌ>Ê iÌÞÊ ÃÊ ÃÜÞÊÞ`ÀÞâi`]ÊÌiÀiLÞÊÀii>Ã}ÊÌiÊ>VÌÛiÊ`ÀÕ}\

O

O O O

O HO

O

H F

Acetal moiety is removed

O

HO OH

H

H Fluocinonide

F

O

+

O OH

O

H Active drug

O F

F /Ài>ÌiÌÊ ÜÌÊ yÕVìÊ ÃÊ Ã}wV>ÌÞÊ ÀiÊ ivviVÌÛiÊ Ì>Ê `ÀiVÌÊÌÀi>ÌiÌÊÜÌÊÌiÊ>VÌÛiÊ`ÀÕ}]ÊLiV>ÕÃiÊÌiÊ>ÌÌiÀÊV>ÌÊ Ài>VÊ>ÊvÊÌiÊ>vviVÌi`Ê>Ài>Ã°Ê

Stable Hemiacetals In the previous section, we saw how to convert an aldehyde or ketone into an acetal. In most cases, it is very difficult to isolate the intermediate hemiacetal: O

RO + 2 ROH

Favored by the equilibrium

OH

∆

RO + ROH

OR

∆

+ H2O

Hemiacetal

Acetal

Difficult to isolate

Favored when water is removed

For ketones we saw that the equilibrium generally favors the reactants unless water is removed, which enables formation of the acetal. The hemiacetal is not favored under either set of conditions (with or without removal of water). However, when a compound contains both a carbonyl group and a hydroxyl group, the resulting cyclic hemiacetal can often be isolated; for example:

klein_c20_001-056v1.4.indd 16

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20.6

O

17


OH

O

[H+]

HO Cyclic hemiacetal

This will be important when we learn about carbohydrate chemistry in Chapter 24. Glucose, the major source of energy for the body, exists primarily as a cyclic hemiacetal: OH

OH

HO

O

∆

HO H

O

HO HO OH OH

OH

OH

Glucose (Open-chain)

Glucose (Cyclic hemiacetal)

CONCEPTUAL CHECKPOINT O

HO

20.13 À>ÜÊ>Ê«>ÕÃLiÊiV>ÃÊvÀÊÌiÊvÜ}ÊÌÀ>ÃvÀ>Ì\

[H2SO4]

OH

20.14 «Õ`Ê Ê >ÃÊ iVÕ>ÀÊ vÀÕ>Ê nH£{"Ó°Ê 1«Ê ÌÀi>ÌiÌÊÜÌÊV>Ì>ÞÌVÊ>V`]ÊV«Õ`ÊÊÃÊVÛiÀÌi`ÊÌÊÌiÊ VÞVVÊi>ViÌ>°ÊìÌvÞÊÌiÊÃÌÀÕVÌÕÀiÊvÊV«Õ`Ê°

HO

O

O

[H+]

Compound A

20.6 Nitrogen Nucleophiles Primary Amines In mildly acidic conditions, an aldehyde or ketone will react with a primary amine to form an imine: O

N H

[H+]

CH3

H

CH3NH2

Imines are compounds that possess a C5N double bond and are common in biological pathways. Imines are also called Schiff bases, named after Hugo Schiff, a German chemist who first described their formation. A six-step mechanism for imine formation is shown in Mechanism 20.6. It is best to divide the mechanism conceptually into two parts (just as we did to conceptualize the mechanism of acetal formation): (1) The first three steps produce an intermediate called a carbinolamine and (2) the last three steps convert the carbinolamine into an imine:

klein_c20_001-056v1.4.indd 17

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18

CHAPTER 20


MECHANISM 20.6 IMINE FORMATION Nucleophilic attack

Proton transfer

O

+

O

+

H A

H

H

Proton transfer

H N

OH

R

OH

A

H

H

N

N

+H

The amine attacks the protonated carbonyl to generate a tetrahedral intermediate

The carbonyl group is protonated, rendering it more electrophilic

R

The tetrahedral intermediate is deprotonated to form a carbinolamine

R Carbinolamine

Proton transfer +

H A


Proton transfer H + R N

R N

A

–H2O

The OH group is protonated, thereby converting it into an excellent leaving group

H + H O H N

Imine

The intermediate is deprotonated, to generate an imine

Note: There is experimental evidence that the first two steps of this mechanism (protonation and nucleophilic attack) more likely occur either simultaneously or in the reverse order of what is shown above. Most nitrogen nucleophiles are sufficiently nucleophilic to attack a carbonyl group directly, before protonation occurs. Nevertheless, the first two steps of the mechanism above have been drawn in the order shown (which

FIGURE 20.5 /iÊÃiµÕiViÊvÊÃÌi«ÃÊÛÛi`Ê ÊvÀ>ÌÊvÊ>ÊV>ÀL>i°

R

Water leaves, forming a C“N double bond

only rarely occurs), because this sequence enables a more effective comparison of all acid-catalyzed mechanisms in this chapter and also unifies the rationale behind proton transfers, as we will discuss in Sections 20.6 and 20.7. Interested students can learn more from the following literature references: 1. J. Am. Chem. Soc., 1974, 96(26), 7998–09 2. J. Org. Chem., 2007, 72(22), 8202–8215

Nucleophilic attack

Proton transfer

Proton transfer

Let’s begin our analysis of this mechanism by focusing on the first part: formation of the carbinolamine, which involves the three steps in Figure 20.5. Notice that these three steps are identical to the first three steps of acetal formation. Specifically, this sequence of steps involves a nucleophilic attack that is sandwiched between proton transfer steps. The identity of the acid, HA+, is most likely a protonated amine, which received its extra proton from the acid source: N H

+

A

H

+

N

H

R

Once the carbinolamine has been formed, formation of the imine is accomplished with three steps (Figure 20.6). Notice again that this reaction sequence begins and ends with proton transfers. FIGURE 20.6 /iÊÃiµÕiViÊvÊÃÌi«ÃÊÌ>ÌÊ VÛiÀÌÊ>ÊV>ÀL>iÊÌÊ>Ê i°

klein_c20_001-056v1.4.indd 18

Proton transfer


Proton transfer

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20.6

19


Rate

The pH of the solution is an important consideration during imine formation, with the rate of reaction being greatest when the pH is around 4.5 (Figure 20.7). If the pH is too high (i.e., if no acid catalyst is used), the carbonyl group is not protonated (step 1 of the mechanism) and the carbinolamine is also not protonated (step 4 of the mechanism); so the reaction occurs more slowly. If the pH is too low (too much acid is used), most of the amine molecules will be protonated: H

0

1

2

3

4

5

6

7

H

H

pH

H

H

N

R

FIGURE 20.7 /iÊÀ>ÌiÊvÊiÊvÀ>ÌÊ>ÃÊ>Ê vÕVÌÊvÊ«°

O+

+

N

R

H

H

H NOT a nucleophile

A nucleophile

Under these conditions, step 2 of the mechanism occurs too slowly. As a result, care must be taken to ensure optimal pH of the solution during imine formation.

SKILLBUILDER 20.3 DRAWING THE MECHANISM OF IMINE FORMATION LEARN the skill

À>ÜÊ>Ê«>ÕÃLiÊiV>ÃÊvÀÊÌiÊvÜ}ÊÌÀ>ÃvÀ>Ì\ Et N

O [H2SO4] EtNH2 –H2O

SOLUTION /iÊÀi>VÌÊ>LÛiÊÃÊ>ÊiÝ>«iÊvÊiÊvÀ>Ì°Ê/iÊiV>ÃÊV>ÊLiÊ`Ûì`ÊÌÊ ÌÜÊ«>ÀÌÃ\Ê£®ÊvÀ>ÌÊvÊÌiÊV>ÀL>iÊ>`ÊÓ®ÊvÀ>ÌÊvÊÌiÊi° À>ÌÊvÊÌiÊV>ÀL>iÊÛÛiÃÊÌÀiiÊiV>ÃÌVÊÃÌi«Ã\ Proton transfer

Nucleophilic attack

Proton transfer

7iÊ `À>Ü}Ê ÌiÃiÊ ÌÀiiÊ ÃÌi«Ã]Ê >iÊ ÃÕÀiÊ ÌÊ «>ViÊ ÌiÊ i>`Ê >`Ê Ì>Ê vÊ iÛiÀÞÊ VÕÀÛi`Ê >ÀÀÜÊÊÌÃÊ«ÀiVÃiÊV>Ì]Ê>`Ê>iÊÃÕÀiÊÌÊ«>ViÊ>Ê«ÃÌÛiÊV>À}iÃÊÊÌiÀÊ>««À«À>ÌiÊÊ V>ÌÃ°Ê ÌViÊÌ>ÌÊiÛiÀÞÊÃÌi«ÊÀiµÕÀiÃÊÌÜÊVÕÀÛi`Ê>ÀÀÜÃ° The tail of this arrow should be placed on a lone pair STEP 1 À>ÜÊÌiÊÌÀiiÊÃÌi«ÃÊ iViÃÃ>ÀÞÊÌÊvÀÊ>Ê V>ÀL>i°

O

H

+


O

H N H Et


klein_c20_001-056v1.4.indd 19

H

H H

H H

N Et

H

HO

+

N

Et

H

N

H

HO

N

Et

Et

Carbinolamine

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20

CHAPTER 20


ÜÊ iÌ½ÃÊ vVÕÃÊ Ê ÌiÊ ÃiV`Ê «>ÀÌÊ vÊ ÌiÊ iV>Ã]Ê Ê ÜVÊ ÌiÊ V>ÀL>iÊ ÃÊ VÛiÀÌi`ÊÌÊ>Êi°Ê/ÃÊÀiµÕÀiÃÊÌÀiiÊÃÌi«Ã\ Proton transfer


Proton transfer

"ViÊ>}>]ÊÌÃÊÃiµÕiViÊvÊÃÌi«ÃÊLi}ÃÊÜÌÊ>Ê«ÀÌÊÌÀ>ÃviÀÊ>`Êi`ÃÊÜÌÊ>Ê«ÀÌÊ ÌÀ>ÃviÀ°Ê>iÊÃÕÀiÊÌÊ«>ViÊÌiÊi>`Ê>`ÊÌ>ÊvÊiÛiÀÞÊVÕÀÛi`Ê>ÀÀÜÊÊÌÃÊ«ÀiVÃiÊV>Ì]Ê >`Ê>iÊÃÕÀiÊÌÊ«>ViÊ>Ê«ÃÌÛiÊV>À}iÃÊÊÌiÀÊ>««À«À>ÌiÊV>ÌÃ\ The tail of this arrow should be placed on a lone pair STEP 2 À>ÜÊÌiÊÌÀiiÊÃÌi«ÃÊ iViÃÃ>ÀÞÊÌÊVÛiÀÌÊÌiÊ V>ÀL>iÊÌÊ>Ê i°

Don’t forget the positive charges

H N

HO

H H

Et

+

+

H

H N H

O

H N

H + Et N Et

Et H

–H2O

Et

N

N

H

Et

Imine


PRACTICE the skill 20.15 À>ÜÊ>Ê«>ÕÃLiÊiV>ÃÊvÀÊi>VÊvÊÌiÊvÜ}ÊÌÀ>ÃvÀ>ÌÃ\ O

Et

N

O

N

[ TsOH] MeNH2

[ TsOH] EtNH2

–H2O

–H2O

(a)

APPLY the skill

(b)

20.16

*Ài`VÌÊÌiÊ>ÀÊ«À`ÕVÌÊvÀÊi>VÊvÊÌiÊvÜ}ÊÀi>VÌÃ\ O [H+] NH3

–H2O

(a) 20.17

? [H+]

NH2

H

20.18

O

[H+] –H2O

(b)

?

*Ài`VÌÊÌiÊ>ÀÊ«À`ÕVÌÊvÀÊi>VÊvÊÌiÊvÜ}ÊÌÀ>iVÕ>ÀÊÀi>VÌÃ\ O

(a)

NH2

–H2O

O

?

[H+]

NH2

(b)

–H2O

?

ìÌvÞÊÌiÊÀi>VÌ>ÌÃÊÌ>ÌÊÞÕÊÜÕ`ÊÕÃiÊÌÊ>iÊi>VÊvÊÌiÊvÜ}ÊiÃ\ N

N

(a)

N

(b)

(c)

need more PRACTICE? Try Problems 20.72, 20.86

Many different compounds of the form RNH2 will react with aldehydes and ketones, including compounds in which R is not an alkyl group. In the following examples, the R group of the amine has been replaced with a group that has been highlighted in red:

R

OH

[H+] HO–NH2

O R

–H2O

R

R

An oxime

klein_c20_001-056v1.4.indd 20

[H+] H2N–NH2

O

N R

R

–H2O

N R

NH2

R

A hydrazone

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20.6

LOOKING AHEAD

21


When hydroxylamine (NH2OH) is used as a nucleophile, an oxime is formed. When hydrazine (NH2NH2) is used as a nucleophile, a hydrazone is formed. The mechanism for each of these reactions is directly analogous to the mechanism of imine formation.

Þ`À>âiÃÊ>ÀiÊÃÞÌiÌV>ÞÊ ÕÃivÕ]Ê>ÃÊÜiÊÜÊÃiiÊ ÊÌiÊ`ÃVÕÃÃÊvÊÌiÊ 7vvÃiÀÊÀi`ÕVÌÊ >ÌiÀÊÊÌÃÊV>«ÌiÀ°

PRACTICALLYSPEAKING Beta-Carotene and Vision iÌ>V>ÀÌiiÊ ÃÊ >Ê >ÌÕÀ>ÞÊ VVÕÀÀ}Ê V«Õ`Ê vÕ`Ê Ê >ÞÊ À>}iVÀi`Ê vÀÕÌÃÊ >`Ê Ûi}iÌ>LiÃ]Ê VÕ`}Ê V>ÀÀÌÃ]Ê ÃÜiiÌÊ «Ì>ÌiÃ]Ê «Õ«Ã]Ê >}iÃ]Ê V>Ì>Õ«iÃ]Ê >`Ê >«ÀVÌÃ°Ê ÃÊ iÌi`ÊÊÌiÊV>«ÌiÀÊ«iiÀ]ÊLiÌ>V>ÀÌiiÊÃÊÜÊÌÊLiÊ }`Ê vÀÊ ÞÕÀÊ iÞiÃ°Ê /Ê ÕìÀÃÌ>`Ê ÜÞ]Ê ÜiÊ ÕÃÌÊ iÝ«ÀiÊ Ü>ÌÊ >««iÃÊÌÊLiÌ>V>ÀÌiiÊÊÞÕÀÊL`Þ°ÊiÊvÀ>ÌÊ«>ÞÃÊ>Ê «ÀÌ>ÌÊÀiÊÊÌiÊ«ÀViÃÃ°

ı-carotene

iÌ>V>ÀÌiiÊ ÃÊ iÌ>Lâi`Ê Ê ÌiÊ ÛiÀÊ ÌÊ «À`ÕViÊ ÛÌ>ÊÊ>ÃÊV>i`ÊÀiÌ®\

OH Vitamin A (Retinol)

6Ì>Ê Ê ÃÊ ÌiÊ Ý`âi`]Ê >`ÊiÊvÊÌiÊ`ÕLiÊL`ÃÊ ÕìÀ}iÃÊ ÃiÀâ>ÌÊ ÌÊ «À`ÕViÊ££cisÀiÌ>\

OH This bond undergoes isomerization

This group is oxidized 11-cis-retinal

/iÊÀiÃÕÌ}Ê>ìÞìÊÌiÊ Ài>VÌÃÊ ÜÌÊ >Ê >Ê }ÀÕ«Ê vÊ>Ê«ÀÌiÊV>i`Ê«Ã®ÊÌÊ «À`ÕViÊ À`«Ã]Ê ÜVÊ «ÃÃiÃÃiÃÊ>ÊiÊiÌÞ\

H

O

H2N–Protein

11-cis-retinal

H

O

H

N

Protein

Rhodopsin

ÃÊìÃVÀLi`ÊÊ-iVÌÊ£Ç°£Î]ÊÀ`«ÃÊV>Ê>LÃÀLÊ>Ê«ÌÊvÊ}Ì]ÊÌ>Ì}Ê>Ê«ÌÃiÀâ>ÌÊvÊÌiÊcisÊ`ÕLiÊL`Ê ÌÊ vÀÊ >Ê transÊ `ÕLiÊ L`°Ê /iÊ ÀiÃÕÌ}Ê V>}iÊ Ê }iiÌÀÞÊ ÌÀ}}iÀÃÊ>ÊÃ}>ÊÌ>ÌÊÃÊÕÌ>ÌiÞÊìÌiVÌi`ÊLÞÊÌiÊLÀ>Ê>`ÊÌiÀ«ÀiÌi`Ê>ÃÊÛÃ°

klein_c20_001-056v1.4.indd 21

Ê ìwViVÞÊ vÊ ÛÌ>Ê Ê V>Ê i>`Ê ÌÊ º}ÌÊ LìÃÃ]»Ê >Ê V`ÌÊ Ì>ÌÊ «ÀiÛiÌÃÊ ÌiÊ iÞiÃÊ vÀÊ >`ÕÃÌ}Ê ÌÊ `ÞÊ ÌÊÊ iÛÀiÌÃ°

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22

CHAPTER 20


CONCEPTUAL CHECKPOINT 20.19 *Ài`VÌÊÌiÊ«À`ÕVÌÊvÊi>VÊvÊÌiÊvÜ}ÊÀi>VÌÃ\

20.20 ìÌvÞÊÌiÊÀi>VÌ>ÌÃÊÌ>ÌÊÞÕÊÜÕ`ÊÕÃiÊÌÊ>iÊi>VÊvÊ ÌiÊvÜ}ÊV«Õ`Ã\

[H+]

O

HO–NH2 –H2O

(a)

?

N

OH

N

(a) O

NH2

(b)

[H+]

?

H2N–NH2 –H2O

(b)

Secondary Amines

R

R N

O

In acidic conditions, an aldehyde or ketone will react with a secondary amine to form an enamine:

[H+]

Enamines are compounds in which the nitrogen lone pair is delocalized by the presence of an adjacent C5C double bond. A mechanism for enamine formation is shown in Mechanism 20.7

R N

H

R

An enamine

MECHANISM 20.7 ENAMINE FORMATION Proton transfer

Nucleophilic attack +

O

H

O

+

R

H N

OH

R

H¬A

Proton transfer

OH

A

H N

N

R The carbonyl group is protonated, rendering it more electrophilic

The amine attacks the protonated carbonyl to generate a tetrahedral intermediate

+

R

R

R

The tetrahedral intermediate is deprotonated to form a carbinolamine

Carbinolamine

Proton transfer

H¬A


Proton transfer R

R N

A

Enamine

The intermediate is deprotonated to generate an imine

R + R N

–H2O

Note: There is experimental evidence that the first two steps of this mechanism (protonation and nucleophilic attack) more likely occur either simultaneously or in the reverse order of what is shown above. Most nitrogen nucleophiles are sufficiently nucleophilic to attack a carbonyl group directly, before protonation occurs. Nevertheless, the first two steps of the mechanism above have been drawn in the order shown (which

Water leaves and a C“N double bond forms

The OH group is protonated thereby converting it into an excellent leaving group

H + H O

H

klein_c20_001-056v1.4.indd 22

+

N

R

R

only rarely occurs), because this sequence enables a more effective comparison of all acid-catalyzed mechanisms in this chapter and also unifies the rationale behind proton transfers, as we will discuss in Sections 20.6 and 20.7. Interested students can learn more from the following literature references: 1. J. Am. Chem. Soc., 1974, 96(26), 7998–09 2. J. Org. Chem., 2007, 72(22), 8202–8215

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20.6

23


This mechanism of enamine formation is identical to the mechanism of imine formation except for the last step: R + H N

R N

[H+]

RNH2

RNH2

O

An imine

R

R + R N

R N

H

[H+]

R2NH

R2NH

An enamine

The difference in the iminium ions explains the different outcomes for the two reactions. During imine formation, the nitrogen atom of the iminium ion possesses a proton that can be removed as the final step of the mechanism. In contrast, during enamine formation, the nitrogen atom of the iminium ion does not possess a proton. As a result, elimination from the adjacent carbon is necessary in order to yield a neutral species.

SKILLBUILDER 20.4

DRAWING THE MECHANISM OF ENAMINE FORMATION Et

LEARN the skill

O

À>ÜÊ>Ê«>ÕÃLiÊiV>ÃÊvÀÊÌiÊvÜ}ÊÀi>VÌ\

Et N

[H2SO4] Et2NH –H2O

SOLUTION /iÊÀi>VÌÊ>LÛiÊÃÊ>ÊiÝ>«iÊvÊi>iÊvÀ>Ì°Ê/iÊiV>ÃÊV>ÊLiÊ`Ûì`ÊÌÊ ÌÜÊ«>ÀÌÃ\Ê£®ÊvÀ>ÌÊvÊÌiÊV>ÀL>iÊ>`ÊÓ®ÊvÀ>ÌÊvÊÌiÊi>i° À>ÌÊvÊÌiÊV>ÀL>iÊÛÛiÃÊÌÀiiÊiV>ÃÌVÊÃÌi«Ã\ Proton transfer

Nucleophilic attack

Proton transfer

7iÊ `À>Ü}Ê ÌiÃiÊ ÌÀiiÊ ÃÌi«Ã]Ê >iÊ ÃÕÀiÊ ÌÊ «>ViÊ ÌiÊ i>`Ê >`Ê Ì>Ê vÊ iÛiÀÞÊ VÕÀÛi`Ê >ÀÀÜÊÊÌÃÊ«ÀiVÃiÊV>Ì]Ê>`Ê>iÊÃÕÀiÊÌÊ«>ViÊ>Ê«ÃÌÛiÊV>À}iÃÊÊÌiÀÊ>««À«À>ÌiÊÊ V>ÌÃ°Ê ÌViÊÌ>ÌÊiÛiÀÞÊÃÌi«ÊÀiµÕÀiÃÊÌÜÊVÕÀÛi`Ê>ÀÀÜÃ° Don’t forget the positive charges

The tail of this arrow should be placed on a lone pair STEP 1 À>ÜÊÌiÊÌÀiiÊÃÌi«ÃÊ iViÃÃ>ÀÞÊÌÊvÀÊ>Ê V>ÀL>i°

O

N

+

+

H

O

H N Et Et


klein_c20_001-056v1.4.indd 23

H H

N Et

Et

HO

Et

Et N+ Et

H

N

Et

HO

N Et

Et

Carbinolamine

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24

CHAPTER 20


ÊÌiÊÃiV`Ê«>ÀÌÊvÊÌiÊiV>Ã]ÊÌiÊV>ÀL>iÊÃÊVÛiÀÌi`ÊÌÊ>Êi>iÊ Û>Ê>ÊÌÀiiÃÌi«Ê«ÀViÃÃ°Ê"ViÊ>}>]ÊÌÃÊÃiµÕiViÊLi}ÃÊ>`Êi`ÃÊÜÌÊ«ÀÌÊÌÀ>ÃviÀÃ\ Proton transfer


The tail of this arrow should be placed on a lone pair

Don’t forget the positive charges

H

Et STEP 2 À>ÜÊÌiÊÌÀiiÊÃÌi«ÃÊ iViÃÃ>ÀÞÊÌÊVÛiÀÌÊÌiÊ V>ÀL>iÊÌÊ>Ê i>i°

HO

N Et

Et

+

H H N Et

Et + N

N Et

H O

+

Proton transfer

Et H

H

–H2O

Et

Et N

Et N

Et

Et

Enamine


PRACTICE the skill 20.21 À>ÜÊ>Ê«>ÕÃLiÊiV>ÃÊvÀÊi>VÊvÊÌiÊvÜ}ÊÀi>VÌÃ\ Et

Et N

O [TsOH]

–H2O

(a)

[H2SO4]

O

Et2NH

N

Et2NH –H2O

(b) N

O [H2SO4]

Me2NH –H2O

(c)

APPLY the skill

20.22

*Ài`VÌÊÌiÊ>ÀÊ«À`ÕVÌÊvÀÊi>VÊvÊÌiÊvÜ}ÊÀi>VÌÃ\ O

[H+] N –H2O

(a)

20.23

H

H N

?

O [H+] –H2O

(b)

*Ài`VÌÊÌiÊ>ÀÊ«À`ÕVÌÊvÀÊi>VÊvÊÌiÊvÜ}ÊÌÀ>iVÕ>ÀÊÀi>VÌÃ\ NH O

[H+] –H2O

H

O

?

(a) 20.24

? [H+]

N

–H2O

?

(b) ìÌvÞÊÌiÊÀi>VÌ>ÌÃÊÌ>ÌÊÞÕÊÜÕ`ÊÕÃiÊÌÊ>iÊi>VÊvÊÌiÊvÜ}Êi>iÃ\ N N

(a)

N

(b)

(c)

need more PRACTICE? Try Problem 20.72

klein_c20_001-056v1.4.indd 24

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20.6

25


Wolff-Kishner Reduction At the end of the previous section, we noted that ketones can be converted into hydrazones. This transformation has practical utility, because hydrazones are readily reduced under strongly basic conditions: NNH2

H H KOH/H2O heat

A hydrazone

(82%)

This transformation is called the Wolff-Kishner reduction, named after the German chemist Ludwig Wolff (University of Jena) and the Russian chemist N. M. Kishner (University of Moscow). This provides a two-step procedure for reducing a ketone to an alkane: N

O

NH2 H H

[H+] H2N¬NH2

KOH / H2 O

–H2O

heat

+ N2 (80%)

The second part of the Wolff-Kishner reduction is believed to proceed via Mechanism 20.8.

MECHANISM 20.8 THE WOLFF-KISHNER REDUCTION Proton transfer

H

Proton transfer H

N N

H

H

N-

-

OH

N

N H

N

H

H N

N

Proton transfer

-

OH

Proton transfer H H

O

The intermediate is protonated

-

One of the protons is removed, forming a resonance-stabilized intermediate

H

H

O

H

The carbanion is protonated, generating the product

H -


Another proton is removed

H N

-

N

Nitrogen gas is expelled, generating a carbanion

Notice that four of the five steps in the mechanism are proton transfers, the exception being the loss of N2 gas to generate a carbanion. This step warrants special attention, because formation of a carbanion in a solution of aqueous hydroxide is thermodynamically unfavorable (significantly uphill in energy). Why, then, does this step occur? It is true that the equilibrium for this step greatly disfavors formation of the carbanion, and therefore, only a very small number of molecules will initially lose N2 to form the carbanion. However, the resulting N2 gas then

klein_c20_001-056v1.4.indd 25

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26

CHAPTER 20


bubbles out of the reaction mixture, and the equilibrium is adjusted to form more nitrogen gas, which again leaves the reaction mixture. The evolution of nitrogen gas ultimately renders this step irreversible and forces the reaction to completion. As a result, the yields for this process are generally very good.

CONCEPTUAL CHECKPOINT 20.25 *Ài`VÌÊÌiÊ«À`ÕVÌÊvÊÌiÊÌÜÃÌi«Ê«ÀVi`ÕÀiÊLiÜ]Ê>`Ê`À>ÜÊ>Ê iV>ÃÊvÀÊÌÃÊvÀ>Ì\

O 1) [H+], H2N–NH2, –H2O 2) KOH / H2O, heat

?

20.7 Mechanism Strategies Compare the mechanistic steps for the formation of acetals, imines, and enamines (Figure 20.8). Each of the mechanisms has been divided into two parts, and in all cases, the first part consists of the same three steps. In addition, even the second part of each mechanism begins with the same first two steps (proton transfer followed by loss of a leaving group). In other words, these three mechanisms are identical until the fifth step, in which water is lost (loss of a leaving group), shown in red in Figure 20.8. Rather than viewing these reactions as three separate, unrelated reactions, it is best to view them as nearly identical with different endings. Acetal formation has one additional nucleophile attack, giving a total of seven steps. In contrast, imine formation and enamine formation do not exhibit a nucleophilic attack during the second part of the mechanism, giving a total of only six steps. FORMATION OF HEMIACETAL Proton transfer

Nucleophilic attack

Proton transfer

FORMATION OF ACETAL

FORMATION OF CARBINOLAMINE Proton transfer

Nucleophilic attack

Proton transfer

Nucleophilic attack

Proton transfer

Nucleophilic attack

Proton transfer

FORMATION OF IMINE Loss of a leaving group

Proton transfer

FORMATION OF CARBINOLAMINE Proton transfer


Proton transfer

Proton transfer

FORMATION OF ENAMINE Proton transfer


Proton transfer

FIGURE 20.8 ÊV«>ÀÃÊvÊÌiÊÃiµÕiViÊvÊÃÌi«ÃÊvÀÊ>ViÌ>]Êi]Ê>`Êi>iÊvÀ>Ì°

In each of these mechanisms, there are four proton transfer steps. In order to draw the mechanism correctly, it is critical to draw these proton transfers properly. To do so, it will be helpful to remember the following rules that dictate when and why proton transfers occur in acid-catalyzed conditions: s 4HECARBONYLGROUPSHOULDBEPROTONATEDBEFOREITISATTACKED4HISGENERATESAMORE powerful electrophile, and it avoids formation of a negative charge that would occur if the nucleophile attacked the carbonyl directly.

klein_c20_001-056v1.4.indd 26

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20.7

Mechanism Strategies

27

s !VOIDFORMATIONOFTWOPOSITIVECHARGESONASINGLEINTERMEDIATE4HISTYPEOFINTERMEDIate will generally be too high in energy to form. s 4HELEAVINGGROUPSHOULDBECOMENEUTRALWHENITLEAVES$ONOTEXPELHYDROXIDEASA leaving group; rather, it should first be protonated so that it can leave as water. s !TTHEENDOFTHEMECHANISM APROTONTRANSFERISUSEDTOFORMANEUTRALPRODUCT The four rules above correspond with each of the four proton transfers, respectively. These four rules can be consolidated into one master rule that defines when and why proton transfer steps are utilized: In acidic conditions, all reagents, intermediates, and leaving groups should either be neutral (no charge) or bear one positive charge. All of the proton transfers in the mechanism occur in order to fulfill this requirement. Acetals, imines, and enamines can be converted back into ketones by treatment with excess water under acid-catalyzed conditions: RO

OR

H3O+

R N

R

O

H3O+

R N H3O+

Each of the reactions above is called a hydrolysis reaction, because in each case bonds are cleaved by treatment with water. These three reactions are essentially the reverse of the reactions we have seen. The following procedure should be used in drawing the mechanisms for the above hydrolysis reactions: 1.

Begin by drawing all of the intermediates without any curved arrows. For example, suppose that we want to draw the mechanism for hydrolysis of an acetal to form a ketone: RO

OR

H3O+

O

We did not learn the mechanism for this reaction; however, we did learn the mechanism for acetal formation. Think about the first intermediate in acetal formation (a protonated carbonyl), and then draw that intermediate as the last intermediate of the hydrolysis reaction: OR

+

H

O

O

OR The last intermediate should be a protonated carbonyl

Continue working backward until you have drawn all of the intermediates. 2.

Then, working forward, draw the curved arrows that are necessary to transform each intermediate into the next intermediate. At each stage, make sure you are following the master rule for proton transfers in acid-catalyzed conditions.

The skill of being able to draw the reverse of a known mechanism is incredibly important and will be used again for other reactions in the remaining chapters of this book. The following example illustrates this procedure.

klein_c20_001-056v1.4.indd 27

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28

CHAPTER 20


SKILLBUILDER 20.5

DRAWING THE MECHANISM OF A HYDROLYSIS REACTION

LEARN the skill

*À«ÃiÊ>ÊiV>ÃÊvÀÊÌiÊvÜ}ÊÌÀ>ÃvÀ>Ì\

O

O

O H3O+

+ HO

OH

SOLUTION /ÃÊÃÊ>ÊÞ`ÀÞÃÃÊÀi>VÌÊÊÜVÊ>ÊVÞVVÊ>ViÌ>ÊÃÊ«ii`ÊÌÊvÀÊ>ÊiÌi°Ê7iÊÌiÀivÀiÊ iÝ«iVÌÊÌiÊiV>ÃÊÌÊLiÊÌiÊÀiÛiÀÃiÊvÊ>ViÌ>ÊvÀ>Ì°Ê i}ÊLÞÊVÃìÀ}Ê>ÊvÊÌiÊ ÌiÀi`>ÌiÃÊÛÛi`ÊÊ>ViÌ>ÊvÀ>Ì\

OH +

H +

HO

O

HO

H

First intermediate

Ketone

O

Acetal

LOOKING BACK vÊÞÕÊii`ÊÌÊ «ÃÊÞÕÀÊ>ÀÀÜ «ÕÃ}ÊÃÃ]Ê}Ê ÌÊ-iVÌÊÈ°n°

klein_c20_001-056v1.4.indd 28

O

O

+

O

O

H

O

O

Acetal

7iÊ Ã«ÞÊ `À>ÜÊ >Ê vÊ ÌiÃiÊ ÌiÀi`>ÌiÃÊ Ê ÀiÛiÀÃiÊ ÀìÀÊ ÃÊ Ì>ÌÊ ÌiÊ wÀÃÌÊ ÌiÀi`>ÌiÊ >LÛiÊ}}Ìi`®ÊLiViÃÊÌiÊ>ÃÌÊÌiÀi`>ÌiÊvÊÌiÊÞ`ÀÞÃÃÊiV>Ã\

OH

O

+

O

+

H

OH

OH

OH

H

+

O

H

O

Hemiacetal

STEP 1 À>ÜÊ>ÊÌiÀi`>ÌiÃÊ vÀÊ>ViÌ>ÊvÀ>ÌÊÊ ÀiÛiÀÃiÊÀìÀ°

O

+

+

O

OH

OH

H

O

O

OH

H

O

+

O

HO

O

Hemiacetal

HO

+

O

H

O

O

Last intermediate

Ketone

H

Þ`ÀÞÃÃÊvÊÌiÊ>ViÌ>ÊÕÃÌÊÛÛiÊÌiÃiÊÌiÀi`>ÌiÃ]ÊÊÌiÊÀìÀÊÃÜÊ>LÛi°ÊvÊ>ÞÊ vÊÌiÊÌiÀi`>ÌiÃÊ>ÃÊ>Êi}>ÌÛiÊV>À}i]ÊÌiÊÞÕÊ>ÛiÊ>ìÊ>ÊÃÌ>i° 7ÌÊÌiÊÌiÀi`>ÌiÃÊ«>Vi`ÊÊÌiÊVÀÀiVÌÊÀìÀ]ÊÌiÊw>ÊÃÌi«ÊÃÊÌÊ`À>ÜÊÌiÊÀi>}iÌÃÊ >`ÊVÕÀÛi`Ê>ÀÀÜÃÊÌ>ÌÊÃÜÊÜÊi>VÊÌiÀi`>ÌiÊÃÊÌÀ>ÃvÀi`ÊÌÊÌiÊiÝÌÊÌiÀi`>Ìi°Ê i}ÊÜÌÊÌiÊ>ViÌ>]Ê>`ÊÜÀÊvÀÜ>À`ÊÕÌÊÀi>V}ÊÌiÊiÌi°Ê/ÃÊÀiµÕÀiÃÊÌ>ÌÊ ÞÕÀÊ>ÀÀÜ«ÕÃ}ÊÃÃÊ>ÀiÊÊ}`ÊÃ>«i° >iÊ ÃÕÀiÊ ÌÊ ÕÃiÊ ÞÊ ÌiÊ Ài>}iÌÃÊ Ì>ÌÊ >ÀiÊ «ÀÛì`]Ê >`Ê LiÞÊ ÌiÊ >ÃÌiÀÊ ÀÕiÊ vÀÊ «ÀÌÊÌÀ>ÃviÀÃ°ÊÀÊiÝ>«i]ÊÌÃÊ«ÀLiÊ`V>ÌiÃÊÌ>ÌÊÎ"+ÊÃÊ>Û>>Li°Ê/ÃÊi>ÃÊÌ>ÌÊ HÎ"+ÊÃÕ`ÊLiÊÕÃi`ÊvÀÊ«ÀÌ>Ì}]Ê>`ÊÓ"ÊÃÕ`ÊLiÊÕÃi`ÊvÀÊì«ÀÌ>Ì}°Ê ÊÌÊ ÕÃiÊÞ`ÀÝìÊÃ]Ê>ÃÊÌiÞÊ>ÀiÊÌÊ«ÀiÃiÌÊÊÃÕvwViÌÊµÕ>ÌÌÞÊÕìÀÊ>V`V>Ì>Þâi`ÊV`ÌÃ°Ê««V>ÌÊvÊÌiÃiÊÀÕiÃÊ}ÛiÃÊÌiÊvÜ}Ê>ÃÜiÀ\

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20.7

OH

OH

O

O

O

O

+

O H

+

O

+

OH

H

+

H

29

Mechanism Strategies

H H

H

O

H

O

HO

O

O

O

H

H

H

Acetal

Hemiacetal

H

STEP 2 À>ÜÊÌiÊVÕÀÛi`Ê>ÀÀÜÃÊ >`ÊiViÃÃ>ÀÞÊÀi>}iÌÃÊ vÀÊi>VÊÃÌi«ÊvÊÌiÊ iV>Ã°

+

O H

H

OH H O

+

O

HO

+

O

O

HO

H

+

OH

H

H

Ketone

ÌViÊÌiÊÕÃiÊvÊiµÕLÀÕÊ>ÀÀÜÃ]ÊLiV>ÕÃiÊÌiÊ«ÀViÃÃÊÃÊ}ÛiÀi`ÊLÞÊ>ÊiµÕLÀÕ]Ê>ÃÊ Ìi`ÊÊ«ÀiÛÕÃÊÃiVÌÃ°

PRACTICE the skill 20.26 *À«ÃiÊ>Ê«>ÕÃLiÊiV>ÃÊvÀÊi>VÊvÊÌiÊvÜ}ÊÞ`ÀÞÃÃÊÀi>VÌÃ\ EtO

O

OEt H3

O+

O

H3O+

20.27

+

N

+ MeNH2 O

O

(d)

APPLY the skill

(b)

H

O

H3O+

(c)

O H3O+

+ 2 EtOH

(a)

N

N

H

HO

OH

*À«ÃiÊ>Ê«>ÕÃLiÊiV>ÃÊvÀÊÌiÊÀi>VÌÊLiÜ\ O

O

N

[H2SO4]

OH H2N

HO

Hint: ÌÊÃÊÌÊiViÃÃ>ÀÞÊÌÊ«iÊÌiÊ>ViÌ>ÊÌÊ>ÊiÌiÊÇÊÃÌi«Ã®ÊvÜi`ÊLÞÊVÃ}ÊÌiÊ iÊÈÊÃÌi«Ã®°ÊÊ«>ÕÃLiÊiV>ÃÊV>ÊLiÊ`À>ÜÊÜÌÊviÜiÀÊÌ>Ê£ÎÊÃÌi«Ã°Ê-Ì>ÀÌÊÜÀ}ÊÜÌÊÌiÊ>ViÌ>ÊÕÃ}ÊÌiÊÃÌi«ÃÊiViÃÃ>ÀÞÊÌÊ«iÊ>Ê>ViÌ>®]Ê>`ÊÊvÀÊ>ÊÌiÀi`>ÌiÊÌ>ÌÊV>ÊLiÊ>ÌÌ>Vi`ÊLÞÊÌiÊ>Ê}ÀÕ«°Ê>iÊÃÕÀiÊÌÊ>Û`Ê`À>Ü}Ê>Ê-NÓÊ«ÀViÃÃÊ >ÌÊ>ÊÃÌiÀV>ÞÊìÀi`ÊÃÕLÃÌÀ>Ìit need more PRACTICE?

klein_c20_001-056v1.4.indd 29

Try Problem 20.65

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30

CHAPTER 20


The Medically Speaking box below provides two examples of hydrolysis reactions that are exploited in drug design.

MEDICALLYSPEAKING Prodrugs Methenamine as a Prodrug of Formaldehyde À>ìÞìÊ>ÃÊ>ÌÃi«ÌVÊ«À«iÀÌiÃÊ>`ÊV>ÊLiÊi«Þi`ÊÊ ÌiÊÌÀi>ÌiÌÊvÊÕÀ>ÀÞÊÌÀ>VÌÊviVÌÃÊ`ÕiÊÌÊÌÃÊ>LÌÞÊÌÊÀi>VÌÊ ÜÌÊ ÕVi«iÃÊ «ÀiÃiÌÊ Ê ÕÀi°Ê ÜiÛiÀ]Ê vÀ>ìÞìÊ V>Ê LiÊÌÝVÊÜiÊiÝ«Ãi`ÊÌÊÌiÀÊÀi}ÃÊvÊÌiÊL`Þ°Ê/iÀivÀi]Ê ÌiÊÕÃiÊvÊvÀ>ìÞìÊ>ÃÊ>Ê>ÌÃi«ÌVÊ>}iÌÊÀiµÕÀiÃÊ>ÊiÌ`Ê vÀÊ ÃiiVÌÛiÊ ìÛiÀÞÊ ÌÊ ÌiÊ ÕÀ>ÀÞÊ ÌÀ>VÌ°Ê /ÃÊ V>Ê LiÊ >VV«Ãi`ÊLÞÊÕÃ}Ê>Ê«À`ÀÕ}ÊV>i`ÊiÌi>i\ N N

N

iÌi>iÊÃÊ«>Vi`ÊÊÃ«iV>ÊÌ>LiÌÃÊÌ>ÌÊ`ÊÌÊ`ÃÃÛiÊ >ÃÊÌiÞÊÌÀ>ÛiÊÌÀÕ}ÊÌiÊ>V`VÊiÛÀiÌÊvÊÌiÊÃÌ>VÊLÕÌÊ `Ê`ÃÃÛiÊViÊÌiÞÊÀi>VÊÌiÊL>ÃVÊiÛÀiÌÊvÊÌiÊÌiÃÌ>ÊÌÀ>VÌ°ÊiÌi>iÊÃÊÌiÀiLÞÊÀii>Ãi`ÊÊÌiÊÌiÃÌ>ÊÌÀ>VÌ]Ê ÜiÀiÊ ÌÊ ÃÊ ÃÌ>LiÊ ÕìÀÊ L>ÃVÊ V`ÌÃ°Ê "ViÊ ÌÊ Ài>ViÃÊ ÌiÊ >V`VÊ iÛÀiÌÊ vÊ ÌiÊ ÕÀ>ÀÞÊ ÌÀ>VÌ]Ê iÌi>iÊ ÃÊ Þ`ÀÞâi`]Ê Àii>Ã}Ê vÀ>ìÞì]Ê >ÃÊ ÃÜÊ >LÛi°Ê Ê ÌÃÊ Ü>Þ]Ê iÌi>iÊÃÊÕÃi`Ê>ÃÊ>Ê«À`ÀÕ}ÊÌ>ÌÊi>LiÃÊìÛiÀÞÊvÊvÀ>ìÞìÊ Ã«iVwV>ÞÊ ÌÊ ÌiÊ ÕÀ>ÀÞÊ ÌÀ>VÌ°Ê /ÃÊ iÌ`Ê «ÀiÛiÌÃÊ ÌiÊÃÞÃÌiVÊÀii>ÃiÊvÊvÀ>ìÞìÊÊÌiÀÊÀ}>ÃÊvÊÌiÊL`ÞÊ ÜiÀiÊÌÊÜÕ`ÊLiÊÌÝV°

N Methenamine

CONCEPTUAL CHECKPOINT

/ÃÊV«Õ`ÊÃÊ>ÊÌÀ}iÊ>>}ÕiÊvÊ>Ê>ViÌ>°Ê/>ÌÊÃ]Êi>VÊ V>ÀLÊ>ÌÊÃÊViVÌi`ÊÌÊÌÜÊÌÀ}iÊ>ÌÃ]ÊÛiÀÞÊÕVÊiÊ >Ê >ViÌ>Ê Ê ÜVÊ >Ê V>ÀLÊ >ÌÊ ÃÊ ViVÌi`Ê ÌÊ ÌÜÊ ÝÞ}iÊ >ÌÃ°ÊÊV>ÀLÊ>ÌÊÌ>ÌÊÃÊViVÌi`ÊÌÊÌÜÊiÌiÀ>ÌÃÊ"Ê ÀÊ ®ÊV>ÊÕìÀ}Ê>V`V>Ì>Þâi`ÊÞ`ÀÞÃÃ\ Z

O

Z H3O+

R

R

R

20.28 ÃÊÃÜÊ>LÛi]ÊiÌi>iÊÃÊÞ`ÀÞâi`ÊÊ>µÕiÕÃÊ >V`ÊÌÊ«À`ÕViÊvÀ>ìÞìÊ>`Ê>>°Ê À>ÜÊ>ÊiV>ÃÊ ÃÜ}ÊvÀ>ÌÊvÊiÊiVÕiÊvÊvÀ>ìÞìÊÌiÊÀi>}ÊwÛiÊiVÕiÃÊvÊvÀ>ìÞìÊ>ÀiÊi>VÊÀii>Ãi`ÊÛ>Ê>ÊÃ>ÀÊ ÃiµÕiViÊ vÊ ÃÌi«Ã®°Ê /iÊ Àii>ÃiÊ vÊ i>VÊ iVÕiÊ vÊ vÀ>ìÞìÊÃÊ`ÀiVÌÞÊ>>}ÕÃÊÌÊÌiÊÞ`ÀÞÃÃÊvÊ>Ê>ViÌ>°Ê/Ê}iÌÊ ÞÕÊÃÌ>ÀÌi`]ÊÌiÊwÀÃÌÊÌÜÊÃÌi«ÃÊ>ÀiÊ«ÀÛì`ÊLiÜ\

R

H

N

Z“ O or N

>VÊ vÊ ÌiÊ V>ÀLÊ >ÌÃÊ Ê iÌi>iÊ V>Ê LiÊ Þ`ÀÞâi`]Ê Àii>Ã}ÊvÀ>ìÞì\ N H3O+

N

N

O

+

H

N

N N

N

H

N

/iÊiÊiÌÞÊÃÊÕÃi`ÊÊÌiÊìÛi«iÌÊvÊ>ÞÊ«À`ÀÕ}Ã°Ê iÀiÊÜiÊÜÊiÝ«ÀiÊiÊÃÕVÊiÝ>«i° /iÊV«Õ`ÊLiÜ]ÊL>LÕÌÞÀVÊ>V`]ÊÃÊ>Ê«ÀÌ>ÌÊ iÕÀÌÀ>ÃÌÌiÀ\ O

OH

H

O N

OH

a

H2O

/iÊ V«Õ`Ê iÝÃÌÃÊ «À>ÀÞÊ Ê ÌÃÊ VÊ vÀ]Ê ÜVÊ V>ÌÊ VÀÃÃÊ ÌiÊ «>ÀÊ iÛÀiÌÊ vÊ ÌiÊ L`LÀ>Ê L>ÀÀiÀ°Ê *À}>LìÊ ÃÊ >Ê «À`ÀÕ}Ê ìÀÛ>ÌÛiÊ ÕÃi`Ê ÌÊ ÌÀi>ÌÊ «>ÌiÌÃÊ ÜÊ iÝLÌÊÌiÊÃÞ«ÌÃÊvÊ>ÊìwViVÞÊvÊL>LÕÌÞÀVÊ>V`\

b g

N N

Formaldehyde

Imines as Prodrugs

H

+

+ 4 NH4 H

H2N

N

+

N

+

6

N

H

N

N

O

NH2

F

g-aminobutyric acid

Ê ìwViVÞÊ vÊ ÌÃÊ V«Õ`Ê V>Ê V>ÕÃiÊ VÛÕÃÃ°Ê `ÃÌ iÀ}Ê L>LÕÌÞÀVÊ >V`Ê `ÀiVÌÞÊ ÌÊ >Ê «>ÌiÌÊ ÃÊ ÌÊ >Ê ivviVÌÛiÊ ÌÀi>ÌiÌ]Ê LiV>ÕÃiÊ ÌiÊ V«Õ`Ê ìÃÊ ÌÊ Ài>`ÞÊ VÀÃÃÊ ÌiÊ L`LÀ>ÊL>ÀÀiÀ°Ê7ÞÊÌ¶ÊÌÊ«ÞÃ}V>Ê«]ÊÌiÊ>Ê}ÀÕ«Ê ÃÊ«ÀÌ>Ìi`Ê>`ÊÌiÊV>ÀLÝÞVÊ>V`ÊiÌÞÊÃÊì«ÀÌ>Ìi`\ H N+

H H

klein_c20_001-056v1.4.indd 30

O -

O

Progabide

Cl /iÊ V>ÀLÝÞVÊ >V`Ê >ÃÊ LiiÊ VÛiÀÌi`Ê ÌÊ >Ê >ì]Ê >`Ê ÌiÊ >Ê}ÀÕ«Ê>ÃÊLiiÊVÛiÀÌi`ÊÌÊ>ÊiÊ}}Ìi`®°ÊÌÊ «ÞÃ}V>Ê«]ÊÌÃÊV«Õ`ÊiÝÃÌÃÊ«À>ÀÞÊ>ÃÊ>ÊiÕÌÀ>ÊV«Õ`ÊÕV>À}i`®]Ê>`ÊÌÊV>ÊÌiÀivÀiÊVÀÃÃÊÌiÊL`LÀ>ÊL>À-

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20.8

ÀiÀ°Ê"ViÊÊÌiÊLÀ>]ÊÌÊÃÊVÛiÀÌi`ÊÌÊL>LÕÌÞÀVÊ>V`ÊÛ>Ê Þ`ÀÞÃÃÊvÊÌiÊiÊ>`Ê>ìÊiÌiÃ\ OH

31

*À}>LìÊÃÊÕÃÌÊiÊiÝ>«iÊÊÜVÊÌiÊiÊiÌÞÊ>ÃÊLiiÊ ÕÃi`ÊÊÌiÊìÛi«iÌÊvÊ>Ê«À`ÀÕ}°

O N

F

Sulfur Nucleophiles

NH2

hydrolysis

O H2N

OH

Cl

20.8 Sulfur Nucleophiles In acidic conditions, an aldehyde or ketone will react with two equivalents of a thiol to form a thioacetal: O

[H+]

+ 2 RSH

RS

SR + H2O

Thioacetal

The mechanism of this transformation is directly analogous to acetal formation, with sulfur atoms taking the place of oxygen atoms. If a compound with two SH groups is used, a cyclic thioacetal is formed: O +

S

[H+]

HS

S

SH

+ H2O

Cyclic thioacetal

When treated with Raney nickel, thioacetals undergo desulfurization, yielding an alkane:

S

S

R

R

H

Raney Ni

H

R

R

Raney Ni is a spongy form of nickel that has adsorbed hydrogen atoms. It is these hydrogen atoms that ultimately replace the sulfur atoms, although a discussion of the mechanism for desulfurization is beyond the scope of this text. The reactions above provide us with another two-step method for the reduction of a ketone: O

H 1) [H+],HS

H

SH

2) Raney Ni

This method involves formation of the thioacetal followed by desulfurization with Raney nickel. It is the third method we have encountered for achieving this type of transformation. The other two methods are the Clemmensen reduction (Section 19.6) and the Wolff-Kishner reduction (Section 20.6).

klein_c20_001-056v1.4.indd 31

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32

CHAPTER 20


CONCEPTUAL CHECKPOINT 20.29 *Ài`VÌÊÌiÊ>ÀÊ«À`ÕVÌÊvÀÊi>VÊÀi>VÌÊLiÜ\

20.30 À>ÜÊÌiÊÃÌÀÕVÌÕÀiÊvÊÌiÊVÞVVÊV«Õ`ÊÌ>ÌÊÃÊ«À`ÕVi`ÊÜiÊ>ViÌiÊÃÊÌÀi>Ìi`ÊÜÌÊ£]Î«À«>i`ÌÊÊÌiÊ «ÀiÃiViÊvÊ>Ê>V`ÊV>Ì>ÞÃÌ°

O 1) [H+], HS

SH

2) Raney Ni

(a)

?

O HS Acetone

O 1) [H+], HS

H

2) Raney Ni

(b)

SH

SH

1,3-propanedithiol

?

20.9 Hydrogen Nucleophiles When treated with a hydride reducing agent, such as LAH or sodium borohydride (NaBH4), aldehydes and ketones are reduced to alcohols: 1) LAH 2) H2O

O R

OH

R

R

R

NaBH4, MeOH

These reactions were discussed in Section 13.4, and we saw that LAH and NaBH4 both function as delivery agents of hydride (H−). The precise mechanism of action for these reagents has been heavily investigated and is somewhat complex. Nevertheless, the simplified version shown in Mechanism 20.9 will be sufficient for our purposes.

MECHANISM 20.9 THE REDUCTION OF KETONES OR ALDEHYDES WITH HYDRIDE AGENTS Nucleophilic attack

Proton transfer -

O

O

H

R

R H

H

-

Al

H

R Lithium aluminium hydride (LAH ) functions as a delivery agent of hydride ions (H –)

H

O

O

H

H

R

R The resulting tetrahedral intermediate is protonated to form an alcohol

H

R

H

In the first step of the mechanism, the reducing agent delivers a hydride ion, which attacks the carbonyl group, producing a tetrahedral intermediate. This intermediate is then treated with a proton source to yield the product. This simplified mechanism does not take into account many important observations, such as the role of the lithium cation (Li+). For example, when

klein_c20_001-056v1.4.indd 32

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20.10

LOOKING BACK

33

Carbon Nucleophiles

12-crown-4 is added to the reaction mixture, the lithium ions are solvated (as described in Section 14.4), and reduction does not occur. Clearly, the lithium cation plays a pivotal role in the mechanism. However, a full treatment of the mechanism of hydride reducing agents is beyond the scope of this text, and the simplified version above will suffice. The reduction of a carbonyl group with LAH or NaBH4 is not a reversible process, because hydride does not function as a leaving group. Notice that the mechanism above employs oneway arrows (rather than equilibrium arrows) to signify that the reverse process is insignificant.

Þ`ÀìÊV>ÌÊvÕVÌÊ>ÃÊ >Êi>Û}Ê}ÀÕ«ÊLiV>ÕÃiÊ ÌÊÃÊÌÊÃÌÀ}ÞÊL>ÃV°Ê -iiÊ-iVÌÊÇ°n°®

CONCEPTUAL CHECKPOINT 20.31 *Ài`VÌÊ ÌiÊ >ÀÊ «À`ÕVÌÊ vÀÊ i>VÊ vÊ ÌiÊ vÜ}Ê Ài>VÌÃ\ O

1) LAH

2) H2O

(a)

?

20.32 7iÊ ÓÊ iÃÊ vÊ Liâ>ìÞìÊ >ÀiÊ ÌÀi>Ìi`Ê ÜÌÊ Ã`ÕÊÞ`ÀÝì]Ê>ÊÀi>VÌÊVVÕÀÃÊÊÜVÊ£ÊiÊvÊLiâ>ìÞìÊÃÊÝ`âi`Ê}Û}ÊLiâVÊ>V`®ÊÜiÊÌiÊÌiÀÊiÊvÊ Liâ>ìÞìÊÃÊÀi`ÕVi`Ê}Û}ÊLiâÞÊ>V®\ O

O H

O

OH H

OH

1) NaOH

H

2) H3O+

H

NaBH4,

MeOH

(b)

?

/ÃÊÀi>VÌ]ÊV>i`ÊÌiÊ >ââ>ÀÊÀi>VÌ]ÊÃÊLiiÛi`ÊÌÊ VVÕÀÊÛ>ÊÌiÊvÜ}ÊiV>Ã\ÊÊÞ`ÀÝìÊÊÃiÀÛiÃÊ>ÃÊ >ÊÕVi«iÊÌÊ>ÌÌ>VÊÌiÊV>ÀLÞÊ}ÀÕ«ÊvÊLiâ>ìÞì]Ê }iiÀ>Ì}Ê>ÊÌiÌÀ>i`À>ÊÌiÀi`>Ìi°Ê/ÃÊÌiÌÀ>i`À>ÊÌiÀi`>ÌiÊÌiÊvÕVÌÃÊ>ÃÊ>ÊÞ`ÀìÊÀi`ÕV}Ê>}iÌÊLÞÊìÛiÀ}Ê>ÊÞ`ÀìÊÊÌÊ>ÌiÀÊiVÕiÊvÊLiâ>ìÞì°ÊÊÌÃÊ Ü>Þ]ÊiÊiVÕiÊÃÊÀi`ÕVi`ÊÜiÊÌiÊÌiÀÊÃÊÝ`âi`°

O 1) LAH

2) H2O

(c)

?

>® 1Ã}ÊÌiÊiÝ«>>ÌÊ>LÛi]Ê`À>ÜÊÌiÊiV>ÃÊvÊÌiÊ

>ââ>ÀÊÀi>VÌ°

O 1) NaBH4

2) MeOH

(d)

L® 7>ÌÊÃÊÌiÊvÕVÌÊvÊÎ"+ÊÊÌiÊÃiV`ÊÃÌi«¶

?

V® 7>ÌiÀÊ>iÊÃÊÌÊÃÕvwViÌÊÌÊ>VV«ÃÊÌiÊvÕVÌÊvÊ ÌiÊÃiV`ÊÃÌi«°Ê Ý«>°

20.10 Carbon Nucleophiles Grignard Reagents When treated with a Grignard reagent, aldehydes and ketones are converted into alcohols, accompanied by the formation of a new C–C bond: O

H3C

OH O

OH 1) CH3MgBr

1) CH3MgBr 2) H2O

H

2) H2O

H

CH3

Grignard reactions were discussed in more detail in Section 13.6. The precise mechanism of action for these reagents has been heavily investigated and is fairly complex. The simplified version shown in Mechanism 20.10 will be sufficient for our purposes.

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CHAPTER 20


MECHANISM 20.10 THE REACTION BETWEEN A GRIGNARD REAGENT AND A KETONE OR ALDEHYDE Nucleophilic attack

Proton transfer -

O

O

H

R

R

R -

R

R

O

H

H

R

R

The Grignard reagent functions as a nucleophile and attacks the carbonyl group

LOOKING BACK

O

R

R

The resulting tetrahedral intermediate is protonated to form an alcohol

Grignard reactions are not reversible because carbanions generally do not function as leaving groups. Notice that the mechanism above employs one-way arrows (rather than equilibrium arrows) to signify that the reverse process is insignificant.

>ÀL>ÃÊÀ>ÀiÞÊvÕVÌÊ >ÃÊi>Û}Ê}ÀÕ«ÃÊLiV>ÕÃiÊ ÌiÞÊ>ÀiÊ}iiÀ>ÞÊÃÌÀ}ÞÊ L>ÃV°Ê-iiÊ-iVÌÊÇ°n°®

CONCEPTUAL CHECKPOINT 20.33 *Ài`VÌÊÌiÊ>ÀÊ«À`ÕVÌÊvÊi>VÊÀi>VÌÊLiÜ\ O

20.34 ìÌvÞÊÌiÊÀi>}iÌÃÊiViÃÃ>ÀÞÊÌÊ>VV«ÃÊi>VÊvÊ ÌiÊÌÀ>ÃvÀ>ÌÃÊLiÜ\ OH

2) H2O

(a)

Me

?

1) EtMgBr

OH

(a) O H

1) PhMgBr 2) H2O

(b)

OH

?

OH

(b)

O

O

O

(c)

1) PhMgBr 2) H3O+

? Cyannohydrin Formation When treated with hydrogen cyanide (HCN), aldehydes and ketones are converted into cyanohydrins, which are characterized by the presence of a cyano group and a hydroxyl group connected to the same carbon atom: O

HCN

HO CN

A cyanohydrin

This reaction was studied extensively by Arthur Lapworth (University of Manchester) and was found to occur more rapidly in mildly basic conditions. In the presence of a catalytic amount of base, a small amount of hydrogen cyanide is deprotonated to give cyanide ions, which catalyze the reaction (Mechanism 20.11).

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Carbon Nucleophiles

35

MECHANISM 20.11 CYANOHYDRIN FORMATION Nucleophilic attack

Proton transfer -

O

C

O

OH

N

H C

N

CN The cyanide ion functions as a nucleophile and attacks the carbonyl group, forming a tetrahedral intermediate

CN

The tetrahedral intermediate is protonated, generating a cyanohydrin

In the first step, a cyanide ion attacks the carbonyl to produce a tetrahedral intermediate. This intermediate then abstracts a proton from HCN, regenerating a cyanide ion. In this way, cyanide functions as a catalyst for the addition of HCN to the carbonyl group. Rather than using a catalytic amount of base to form cyanide ions, the reaction can simply be performed in a mixture of HCN and cyanide ions (from KCN). The process is reversible, and the yield of products is therefore determined by equilibrium concentrations. For most aldehydes and unhindered ketones, the equilibrium favors formation of the cyanohydrin: O

HO CN

KCN, HCN

H3C

CH3

R

R 78%

O

HO CN H

H

KCN, HCN

88%

HCN is a liquid at room temperature and is extremely hazardous to handle because it is highly toxic and volatile (b.p. = 26°C). To avoid the dangers associated with handling HCN, cyanohydrins can also be prepared by treating a ketone or aldehyde with potassium cyanide and an alternate source of protons, such as HCl: O

KCN, HCl

HO CN

Cyanohydrins are useful in syntheses, because the cyano group can be further treated to yield a range of products. Two examples are shown below: N HO

1) LAH

C

2) H2O

R

H

HO R

NH2 H O

H3O

+

HO

C OH

heat

R

H

In the first example, the cyano group is reduced to an amino group. In the second example, the cyano group is hydrolyzed to give a carboxylic acid. Both of these reactions and their mechanisms will be explored in more detail in the next chapter.

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CHAPTER 20


CONCEPTUAL CHECKPOINT 20.35 *Ài`VÌÊÌiÊ>ÀÊ«À`ÕVÌÊvÀÊi>VÊÀi>VÌÊLiÜ\ O

1) KCN, HCN 2) LAH

3) H2O

(a)

20.36 ìÌvÞÊÌiÊÀi>}iÌÃÊiViÃÃ>ÀÞÊÌÊ>VV«ÃÊi>VÊvÊ ÌiÊÌÀ>ÃvÀ>ÌÃÊLiÜ\ OH

?

OH

O OH

(a) O

OH H

1) KCN, HCl

2) H3O+, heat

OH

?

NH2

(b)

(b)

PRACTICALLYSPEAKING Cyanohydrin Derivatives in Nature Þ}`>ÊÃÊ>Ê>ÌÕÀ>ÞÊVVÕÀÀ}ÊV«Õ`ÊvÕ`ÊÊÌiÊ«ÌÃÊvÊ >«ÀVÌÃ]ÊÜ`ÊViÀÀiÃ]Ê>`Ê«i>ViÃ° vÊ}iÃÌi`]ÊÌÃÊV«Õ`ÊÃÊiÌ>Lâi`ÊÌÊ«À`ÕViÊ>ìÌÀi]Ê >Ê VÞ>Þ`À]Ê ÜVÊ ÃÊ VÛiÀÌi`Ê LÞÊ iâÞiÃÊ ÌÊ Liâ>ìÞìÊ>`Ê Ê}>Ã]Ê>ÊÌÝVÊV«Õ`\ OH HO OH

O

HO

O

HO OH

/ÃÊ>ÃÌÊÃÌi«Ê}iiÀ>ÌÊvÊ Ê}>Ã®ÊÃÊÕÃi`Ê>ÃÊ>ÊìviÃiÊiV>ÃÊLÞÊ>ÞÊÃ«iViÃÊvÊ«iìÃ°Ê/iÊ«iìÃÊ>Õv>VÌÕÀiÊ >`Ê ÃÌÀiÊ >ìÌÀi]Ê >`Ê Ê >Ê Ãi«>À>ÌiÊ V«>ÀÌiÌ]Ê ÌiÞÊ ÃÌÀiÊ iâÞiÃÊ Ì>ÌÊ >ÀiÊ V>«>LiÊ vÊ V>Ì>Þâ}Ê ÌiÊ VÛiÀÃÊ vÊ >ìÌÀiÊÌÊLiâ>ìÞìÊ>`Ê °Ê/ÊÜ>À`ÊvvÊ«Ài`>ÌÀÃ]Ê>Ê«iìÊÜÊÝÊÌiÊVÌiÌÃÊvÊÌiÊÌÜÊV«>ÀÌiÌÃÊ >`ÊÃiVÀiÌiÊ Ê}>Ã°

OH

O O

OH C

O C

H

N

N

+

HCN Toxic

Amygdalin

Mandelonitrile

Benzaldehyde

Wittig Reaction Georg Wittig, a German chemist, was awarded the 1979 Nobel Prize in Chemistry for his work with phosphorous compounds and his discovery of a reaction with enormous synthetic utility. Below is an example of this reaction, called the Wittig reaction (pronounced Vittig): O

H Ph -+ C P Ph H Ph H

C

H

This reaction can be used to convert a ketone into an alkene by forming a new C–C bond at the location of the carbonyl moiety. The phosphorus-containing reagent that accomplishes this transformation is called a phosphorane, and it belongs to a larger class of compounds called ylides. An ylide is a compound with two oppositely charged atoms adjacent to each

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20.10

37

Carbon Nucleophiles

other. The phosphorane above exhibits a negative charge on the carbon atom and a positive charge on the phosphorous atom. This ylide does, in fact, have a resonance structure that is free of any charges: H -C

+

P

H

Ph

H

Ph Ph

H

Ph C

P

Ph Ph

However, this resonance structure (with a C5P double bond) does not contribute much character to the overall resonance hybrid, because the p orbitals on C and P are vastly different in size and do not effectively overlap. A similar argument was used in describing S5O bonds in the previous chapter (Section 19.3). Despite this fact, the phosphorus ylide above, also called a Wittig reagent, is often drawn using either of the resonance structures shown above. A mechanism for the Wittig reaction is shown in Mechanism 20.12.

MECHANISM 20.12 THE WITTIG REACTION Nucleophilic attack H

O

-+

Ph

C P Ph H Ph

Nucleophilic attack

-

Rearrangement

Ph

O

Ph C + Ph P

BY THE WAY

Ý«iÀiÌ>ÊiÛìViÊ ÃÕ}}iÃÌÃÊÌ>ÌÊÌiÊ ÌiÀi`>ÌiÊLiÌ>iÊÃÊÞÊ vÀi`ÊÊÌi`ÊV>ÃiÃ°ÊÊ ÌiÀÊV>ÃiÃ]ÊÌÊ>««i>ÀÃÊÌ>ÌÊ ÌiÊ7ÌÌ}ÊÀi>}iÌÊ>ÞÊÀi>VÌÊ ÜÌÊÌiÊV>ÀLÞÊV«Õ`Ê Ê>ÊQÓ³ÓRÊVÞV>``ÌÊ «ÀViÃÃ]Ê`ÀiVÌÞÊ}iiÀ>Ì}Ê ÌiÊÝ>«Ã«iÌ>i°Ê/iÊ iV>ÃÊvÀÊÌÃÊÀi>VÌÊ ÃÊÃÌÊÕìÀÊÛiÃÌ}>Ì°

P

Ph Ph

C

H

O

+ Ph

P

–

+

Ph

Ph

H H An Oxaphosphetane

A lone pair on the oxygen atom functions as a nucleophile and attacks the phosphorus atom in an intramolecular attack

The oxaphosphetane decomposes to produce an alkene and triphenylphosphine oxide

The Wittig reagent is a carbanion and can attack the carbonyl group in the first step of the mechanism, generating an intermediate called a betaine (pronounced “bay-tuh-een”). A betaine is a neutral compound with two oppositely charged atoms that are not adjacent to each other. The negatively charged oxygen atom then attacks the positively charged phosphorous atom in an intramolecular nucleophilic attack, generating an oxaphosphetane. This compound then rearranges to give the alkene product. Wittig reagents are easily prepared by treating triphenylphosphine with an alkyl halide followed by a strong base: Ph Ph

P Ph

Triphenylphosphine

klein_c20_001-056v1.4.indd 37

H

C

H H A Betaine The Wittig reagent functions as a nucleophile and attacks the carbonyl group, forming a tetrahedral intermediate

Ph

O

1) CH3I 2) BuLi

Ph Ph Ph

+-

P

H

C

H

Wittig reagent

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CHAPTER 20


The mechanism of formation for Wittig reagents involves an SN2 reaction followed by deprotonation: Ph Ph

Ph

H3C I

P

Ph

+

P

Ph

Ph

H C

-

H

+

Ph

CH3CH2CH2CH2 Li

Ph

+-

P

C

Ph

H

H H

Triphenylphosphine

Since the first step is an SN2 process, the regular restrictions of SN2 processes apply. Specifically, primary alkyl halides will react more readily than secondary alkyl halides, and tertiary alkyl halides cannot be used. The Wittig reaction is useful for preparing mono-, di-, or trisubstituted alkenes. Tetrasubstituted alkenes are more difficult to prepare due to steric hindrance in the transition states. The following exercise illustrates how to choose the reagents for a Wittig reaction.

SKILLBUILDER 20.6

PLANNING AN ALKENE SYNTHESIS WITH A WITTIG REACTION

LEARN the skill

ìÌvÞÊÌiÊÀi>}iÌÃÊiViÃÃ>ÀÞÊÌÊ«Ài«>ÀiÊÌiÊV«Õ`ÊLiÜÊÕÃ}Ê>Ê7ÌÌ}ÊÀi>VÌ\

SOLUTION i}ÊLÞÊvVÕÃ}ÊÊÌiÊÌÜÊV>ÀLÊ>ÌÃÊvÊÌiÊ`ÕLiÊL`°Ê"iÊV>ÀLÊ>ÌÊÕÃÌÊ >ÛiÊLiiÊ>ÊV>ÀLÞÊ}ÀÕ«]ÊÜiÊÌiÊÌiÀÊÕÃÌÊ>ÛiÊLiiÊ>Ê7ÌÌ}ÊÀi>}iÌ°Ê/ÃÊ}ÛiÃÊ ÌÜÊ«ÌiÌ>ÊÀÕÌiÃÊÌÊiÝ«Ài\ STEP 1 1Ã}Ê>ÊÀiÌÀÃÞÌiÌVÊ >>ÞÃÃ]ÊìÌiÀiÊÌiÊ ÌÜÊ«ÃÃLiÊÃiÌÃÊvÊ Ài>VÌ>ÌÃÊÌ>ÌÊVÕ`ÊLiÊ ÕÃi`ÊÌÊvÀÊÌiÊ 5 Ê L`°

H

H O

O

Ph3P

PPh3

+

Method 1

+

Method 2

iÌ½ÃÊV«>ÀiÊÌiÃiÊÌÜÊiÌ`ÃÊLÞÊvVÕÃ}ÊÊÌiÊ7ÌÌ}ÊÀi>}iÌÊÊi>VÊV>Ãi°Ê,iV>ÊÌ>ÌÊ ÌiÊ7ÌÌ}ÊÀi>}iÌÊÃÊ«Ài«>Ài`ÊLÞÊ>Ê-NÓÊ«ÀViÃÃ]Ê>`ÊÜiÊÌiÀivÀiÊÕÃÌÊVÃìÀÊÃÌiÀVÊv>VÌÀÃÊ`ÕÀ}ÊÌÃÊ«Ài«>À>Ì°ÊiÌ`Ê£ÊÀiµÕÀiÃÊÌiÊÕÃiÊvÊ>ÊÃiV`>ÀÞÊ>ÞÊ>ì\ X 1) PPh3

Ph3P

2) BuLi

2° Alkyl halide

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Carbon Nucleophiles

39

LÕÌÊiÌ`ÊÓÊÀiµÕÀiÃÊÌiÊÕÃiÊvÊ>Ê«À>ÀÞÊ>ÞÊ>ì\ H

STEP 2

ÃìÀÊÜÊÞÕÊ ÜÕ`Ê>iÊi>VÊ «ÃÃLiÊ7ÌÌ}ÊÀi>}iÌ]Ê >`ÊìÌiÀiÊÜVÊ iÌ`ÊÛÛiÃÊÌiÊiÃÃÊ ÃÕLÃÌÌÕÌi`Ê>ÞÊ>ì°

PPh3

1) PPh3

X

2) BuLi

1° Alkyl halide

iÌ`Ê ÓÊ ÃÊ iÞÊ ÌÊ LiÊ ÀiÊ ivwViÌ]Ê LiV>ÕÃiÊ >Ê «À>ÀÞÊ >ÞÊ >ìÊ ÜÊ ÕìÀ}Ê -NÓÊ ÀiÊÀ>«`ÞÊÌ>Ê>ÊÃiV`>ÀÞÊ>ÞÊ>ì°Ê/iÀivÀi]ÊÌiÊvÜ}ÊÜÕ`ÊLiÊÌiÊ«ÀiviÀÀi`Ê ÃÞÌiÃÃ\ O

-

+

P Ph Ph Ph

PRACTICE the skill 20.37 ìÌvÞÊÌiÊÀi>}iÌÃÊiViÃÃ>ÀÞÊÌÊ«Ài«>ÀiÊi>VÊvÊÌiÊvÜ}ÊV«Õ`ÃÊÕÃ}Ê >Ê7ÌÌ}ÊÀi>VÌ\

APPLY the skill

(a)

(b)

(d)

(e)

20.38

(c)

ÃìÀÊÌiÊÃÌÀÕVÌÕÀiÊvÊLiÌ>V>ÀÌii]ÊiÌi`Êi>ÀiÀÊÊÌÃÊV>«ÌiÀ\

b-carotene

iÃ}Ê>ÊÃÞÌiÃÃÊvÊLiÌ>ÊV>ÀÌiiÊÕÃ}ÊÌiÊV«Õ`ÊLiÜÊ>ÃÊÞÕÀÊÞÊÃÕÀViÊvÊV>ÀLÊ>ÌÃ\

Br

20.39

ìÌvÞÊÌiÊÀi>}iÌÃÊiViÃÃ>ÀÞÊÌÊ>VV«ÃÊi>VÊvÊÌiÊÌÀ>ÃvÀ>ÌÃÊLiÜ\ OH

(a)

(b)

need more PRACTICE? Try Problems 20.51–20.53

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CHAPTER 20


20.11 Baeyer-Villiger Oxidation of Aldehydes and Ketones O

When treated with a peroxy acid, ketones can be converted into esters via the insertion of an oxygen atom:

O RCO3H

R

R

R

O

R

This reaction, discovered by Adolf von Baeyer and Victor Villiger in 1899, is called the BaeyerVilliger oxidation. This process is believed to proceed via Mechanism 20.13.

MECHANISM 20.13 THE BAEYER-VILLIGER OXIDATION Nucleophilic attack H

O

O R

-

O O

R

-

O R R

The peroxyacid functions as a nucleophile and attacks the carbonyl group, forming a tetrahedral intermediate

O

Proton transfer +

O H

Rearrangement

R

O

O

R

O

A proton is transferred from one location to another. This step can occur intramolecularly, because it would involve a five-membered transition state

O

O

O O

+

H

The carbonyl group is reformed, with simultaneous migration of an alkyl group

R

O

+ OH

R

The peroxy acid attacks the carbonyl group of the ketone, giving a tetrahedral intermediate that then undergoes an intramolecular proton transfer (or two successive intermolecular proton transfers). Finally, the C5O double bond is re-formed by migration of an R group. This rearrangement produces the ester. In much the same way, treatment of a cyclic ketone with a peroxy acid yields a cyclic ester, or lactone. O

O RCO3H

O

A lactone

When an unsymmetrical ketone is treated with a peroxy acid, formation of the ester is regioselective; for example: O O RCO3H

O

In this case, the oxygen atom is inserted on the left side of the carbonyl group, rather than the right side. This occurs because the isopropyl group migrates more rapidly than the methyl group during the rearrangement step of the mechanism. The migration rates of different groups, or migratory aptitude, can be summarized as follows: H > 3° > 2°, Ph > 1° > methyl

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20.12

Synthesis Strategies

41

A hydrogen atom will migrate more rapidly than a tertiary alkyl group, which will migrate more rapidly than a secondary alkyl group or phenyl group. Below is one more example that illustrates this concept: O

O H

O

RCO3H

H

In this example, the oxygen atom is inserted on the right side of the carbonyl, because the hydrogen atom exhibits a greater migratory aptitude than the phenyl group.

CONCEPTUAL CHECKPOINT 20.40 *Ài`VÌÊÌiÊ>ÀÊ«À`ÕVÌÊvÊi>VÊÀi>VÌÊLiÜ\ O

O RCO3H

?

(a)

O H

(b)

RCO3H

?

RCO3H

?

(c)

20.12 Synthesis Strategies Recall from Chapter 12 that there are two main questions to ask when approaching a synthesis problem: 1. 2.

Is there any change in the carbon skeleton? Is there any change in the functional group?

Let’s focus on these issues separately, beginning with functional groups.

Functional Group Interconversion In previous chapters, we learned how to interconvert many different functional groups (Figure 20.9). The reactions in this chapter expand the playing field by opening up the frontier of aldehydes and ketones. You should be able to fill in the reagents for each transformation in Figure 20.9. If you are having trouble, refer to Figure 13.13 for help. Then, you should be able to make a list of the various products than can be made from aldehydes and ketones and identify the required reagents in each case.

Reactions covered in this chapter

O

OH

X

FIGURE 20.9 ÕVÌ>Ê}ÀÕ«ÃÊÌ>ÌÊV>ÊLiÊ ÌiÀVÛiÀÌi`ÊÕÃ}ÊÀi>VÌÃÊ Ì>ÌÊÜiÊ>ÛiÊi>Ài`ÊÌÕÃÊv>À°

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CHAPTER 20


Reactions Involving a Change in Carbon Skeleton In this chapter, we have seen three C–C bond-forming reactions: (1) a Grignard reaction, (2) cyanohydrin formation, and (3) a Wittig reaction: O C

H

1) CH3MgBr 2) H2O

+

N

H C

C

Ph

Ph

H

OH

H3C

–

C P Ph

KCN, HCN

H C

OH C

C

We have only seen one C–C bond-breaking reaction: the Baeyer-Villiger oxidation: O C

O RCO3H

C

C

C O

These four reactions should be added to your list of reactions that can change a carbon skeleton. Let’s get some practice using these reactions.

SKILLBUILDER 20.7

PROPOSING A SYNTHESIS

LEARN the skill

*À«ÃiÊ>ÊivwViÌÊÃÞÌiÃÃÊvÀÊÌiÊvÜ}ÊÊ ÌÀ>ÃvÀ>Ì\

SOLUTION STEP 1 Ã«iVÌÊÜiÌiÀÊÌiÀiÊ ÃÊ>ÊV>}iÊÊÌiÊ V>ÀLÊÃiiÌÊ>`ÉÀÊ >ÊV>}iÊÊÌiÊìÌÌÞÊ ÀÊV>ÌÊvÊÌiÊ vÕVÌ>Ê}ÀÕ«Ã°

Ü>ÞÃÊLi}Ê>ÊÃÞÌiÃÃÊ«ÀLiÊLÞÊ>Ã}ÊÌiÊvÜ}ÊÌÜÊµÕiÃÌÃ\ 1. Is there any change in the carbon skeleton?Ê9iÃ°Ê/iÊ«À`ÕVÌÊ>ÃÊÌÜÊ>``Ì>ÊV>ÀLÊ >ÌÃ° 2. Is there any change in the functional groups?Ê °Ê ÌÊÌiÊÃÌ>ÀÌ}Ê>ÌiÀ>Ê>`ÊÌiÊ «À`ÕVÌÊ>ÛiÊ>Ê`ÕLiÊL`ÊÊÌiÊiÝ>VÌÊÃ>iÊV>Ì°ÊvÊÜiÊìÃÌÀÞÊÌiÊ`ÕLiÊL`ÊÊ ÌiÊ«ÀViÃÃÊvÊ>``}ÊÌiÊÌÜÊV>ÀLÊ>ÌÃ]ÊÜiÊÜÊii`ÊÌÊ>iÊÃÕÀiÊÌ>ÌÊÜiÊ`ÊÃÊÊ ÃÕVÊ>ÊÜ>ÞÊÌ>ÌÊÜiÊV>ÊÀiÃÌÀiÊÌiÊ`ÕLiÊL`° ÜÊiÌ½ÃÊVÃìÀÊÜÊÜiÊ}ÌÊÃÌ>ÊÌiÊ>``Ì>ÊÌÜV>ÀLÊ>ÌÃ°Ê /iÊvÜ}Ê q ÊL`ÊÃÊÌiÊiÊÌ>ÌÊii`ÃÊÌÊLiÊ>ì\ ÊÌÃÊV>«ÌiÀ]ÊÜiÊ>ÛiÊÃiiÊÌÀiiÊ q ÊL`vÀ}ÊÀi>VÌÃ°ÊiÌ½ÃÊVÃìÀÊi>VÊiÊ>ÃÊ>Ê«ÃÃLÌÞ°

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20.12

STEP 2 7iÊÌiÀiÊÃÊ>ÊV>}iÊ ÊÌiÊV>ÀLÊÃiiÌ]Ê VÃìÀÊ>ÊvÊÌiÊ q Ê L`vÀ}ÊÀi>VÌÃÊ >`Ê>ÊvÊÌiÊ q ÊL` LÀi>}ÊÀi>VÌÃÊÌ>ÌÊ ÞÕÊ>ÛiÊi>Ài`ÊÃÊv>À°

Synthesis Strategies

43

7iÊV>Êi`>ÌiÞÊÀÕiÊÕÌÊVÞ>Þ`ÀÊvÀ>Ì]Ê>ÃÊÌ>ÌÊ«ÀViÃÃÊÃÌ>ÃÊÞÊiÊ V>ÀLÊ>Ì]ÊÌÊÌÜ°Ê-ÊiÌ½ÃÊVÃìÀÊvÀ}ÊÌiÊ q ÊL`ÊÜÌÊiÌiÀÊ>ÊÀ}>À`ÊÀi>VÌÊÀÊ>Ê7ÌÌ}ÊÀi>VÌ° Ê À}>À`Ê Ài>}iÌÊ Ü½ÌÊ >ÌÌ>VÊ >Ê 5 Ê `ÕLiÊ L`]Ê ÃÊ ÕÃ}Ê >Ê À}>À`Ê Ài>VÌÊ ÜÕ`ÊÀiµÕÀiÊwÀÃÌÊVÛiÀÌ}ÊÌiÊ 5 Ê`ÕLiÊL`ÊÌÊ>ÊvÕVÌ>Ê}ÀÕ«ÊÌ>ÌÊV>ÊLiÊ >ÌÌ>Vi`ÊLÞÊ>ÊÀ}>À`ÊÀi>}iÌ]ÊÃÕVÊ>ÃÊ>ÊV>ÀLÞÊ}ÀÕ«\ HO H

O H 1) EtMgBr 2) H2O

/ÃÊ Ài>VÌÊ V>Ê ìi`Ê LiÊ ÕÃi`Ê ÌÊ vÀÊ ÌiÊ VÀÕV>Ê q Ê L`°Ê /Ê ÕÃiÊ ÌÃÊ iÌ`Ê vÊ

q ÊL`ÊvÀ>Ì]ÊÜiÊÕÃÌÊwÀÃÌÊvÀÊÌiÊiViÃÃ>ÀÞÊ>ìÞì]ÊÌiÊ«iÀvÀÊÌiÊÀ}>À`Ê Ài>VÌ]Ê>`ÊÌiÊw>ÞÊÀiÃÌÀiÊÌiÊ`ÕLiÊL`ÊÊÌÃÊ«À«iÀÊV>Ì°Ê/ÃÊV>ÊLiÊ>VV«Ãi`ÊÜÌÊÌiÊvÜ}ÊÀi>}iÌÃ\

1) BH3 # THF 2) H2O2 , NaOH

HO

OH

H

O H

PCC

1) EtMgBr

1) TsCl, py

2) H2O

2) NaOEt, heat

C¬C bond-forming reaction

/ÃÊ«ÀÛìÃÊÕÃÊÜÌÊ>ÊvÕÀÃÌi«Ê«ÀVi`ÕÀi]Ê>`ÊÌÃÊ>ÃÜiÀÊÃÊViÀÌ>ÞÊÀi>Ã>Li° iÌ½ÃÊÜÊiÝ«ÀiÊÌiÊ«ÃÃLÌÞÊvÊ«À«Ã}Ê>ÊÃÞÌiÃÃÊÜÌÊ>Ê7ÌÌ}Ê Ài>VÌ°Ê,iV>ÊÌ>ÌÊ>Ê7ÌÌ}ÊÀi>VÌÊV>ÊLiÊÕÃi`ÊÌÊvÀÊ>Ê 5 ÊL`]ÊÃÊ ÜiÊvVÕÃÊÊvÀ>ÌÊvÊÌÃÊL`\ /ÃÊL`ÊV>ÊLiÊvÀi`ÊvÊÜiÊÃÌ>ÀÌÊÜÌÊ>ÊiÌiÊ>`ÊÕÃiÊÌiÊvÜ}Ê7ÌÌ}Ê Ài>}iÌ\ O PPh3

/ÊÕÃiÊÌÃÊÀi>VÌ]ÊÜiÊÕÃÌÊwÀÃÌÊvÀÊÌiÊiViÃÃ>ÀÞÊiÌiÊvÀÊÌiÊÃÌ>ÀÌ}Ê>ii\ O

/ÃÊV>ÊLiÊ>VV«Ãi`ÊÜÌÊâÞÃÃ°Ê/ÃÊ}ÛiÃÊ>ÊÌÜÃÌi«Ê«ÀVi`ÕÀiÊvÀÊ>VV«Ã}ÊÌiÊìÃÀi`ÊÌÀ>ÃvÀ>Ì\ÊâÞÃÃÊvÜi`ÊLÞÊ>Ê7ÌÌ}ÊÀi>VÌ°Ê/ÃÊ>««À>VÊÃÊ `vviÀiÌÊÌ>ÊÕÀÊwÀÃÌÊ>ÃÜiÀ°ÊÊÌÃÊ>««À>V]ÊÜiÊ>ÀiÊÌÊ>ÌÌ>V}Ê>ÊÌÜV>ÀLÊV>]ÊLÕÌÊ À>ÌiÀ]ÊÜiÊ>ÀiÊwÀÃÌÊiÝ«i}Ê>ÊV>ÀLÊ>ÌÊ>`ÊÌiÊ>ÌÌ>V}Ê>ÊÌÀiiV>ÀLÊV>°

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44

CHAPTER 20


Ê ÃÕ>ÀÞ]Ê ÜiÊ >ÛiÊ `ÃVÛiÀi`Ê ÌÜÊ «>ÕÃLiÊ iÌ`Ã°Ê ÌÊ iÌ`ÃÊ >ÀiÊ VÀÀiVÌÊ >ÃÜiÀÃÊÌÊÌÃÊ«ÀLi]ÊLÕÌÊÌiÊiÌ`Êi«Þ}ÊÌiÊ7ÌÌ}ÊÀi>VÌÊÃÊiÞÊÌÊLiÊÀiÊ ivwViÌ]ÊLiV>ÕÃiÊÌÊÀiµÕÀiÃÊviÜiÀÊÃÌi«Ã° 1) BH3 # THF 2) H2O2 , NaOH 3) PCC 4) EtMgBr 5) H2O 6) TsCl, py 7) NaOEt, heat

1) O3 2) DMS 3) Ph3P

PRACTICE the skill 20.41 *À«ÃiÊ>ÊivwViÌÊÃÞÌiÃÃÊvÀÊi>VÊvÊÌiÊvÜ}ÊÌÀ>ÃvÀ>ÌÃ\ OH

(a)

(b) OH OH

(c)

(d)

O

Br

N

(e)

(f) O O

O EtO

OEt

(g) O

O

APPLY the skill

20.42 1Ã}Ê>ÞÊV«Õ`ÃÊvÊÞÕÀÊVÃ}]ÊìÌvÞÊ>ÊiÌ`ÊvÀÊ«Ài«>À}Êi>VÊvÊ ÌiÊvÜ}ÊV«Õ`Ã°ÊYour only limitation is that the compounds you use can have no more than two carbon atoms°ÊÀÊ«ÕÀ«ÃiÃÊvÊVÕÌ}ÊV>ÀLÊ>ÌÃ]ÊÞÕÊ>ÞÊ}ÀiÊÌiÊ «iÞÊ}ÀÕ«ÃÊvÊ>Ê7ÌÌ}ÊÀi>}iÌ°Ê/>ÌÊÃ]ÊÞÕÊ>ÀiÊ«iÀÌÌi`ÊÌÊÕÃiÊ7ÌÌ}ÊÀi>}iÌÃ° N

NH

(a)

(b)

O

O

O

(c)

O

(d)

HO N

OH

OH H2 N

HO

(e)

(f)

(g)

O

(h)

need more PRACTICE? Try Problems 20.55, 20.58, 20.67–20.69, 20.71, 20.75

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20.13

45

Spectroscopic Analysis of Aldehydes and Ketones

20.13 Spectroscopic Analysis of Aldehydes and Ketones Aldehydes and ketones exhibit several characteristic signals in their infrared (IR) and nuclear magnetic resonance (NMR) spectra. We will now summarize these characteristic signals.

IR Signals The carbonyl group produces a strong signal in an IR spectrum, generally around 1715 or 1720 cm−1. However, a conjugated carbonyl will produce a signal at a lower wavenumber as a result of electron delocalization via resonance effects: O

O

LOOKING BACK ÀÊ>ÊiÝ«>>ÌÊvÊÌÃÊ ivviVÌ]ÊÃiiÊ-iVÌÊ£x°Î°

1715 cm –1

1680 cm –1

Ring strain has the opposite effect on a carbonyl group. That is, increasing ring strain tends to increase the wavenumber of absorption: O

1715 cm –1

O

O

1745 cm –1

1780 cm –1

Aldehydes generally exhibit one or two signals (C–H stretching) between 2700 and 2850 cm−1 (Figure 20.10).

100

% Transmittance

80

2719 O

60 H 40

1726

20

FIGURE 20.10 Ê,ÊÃ«iVÌÀÕÊvÊ>Ê>ìÞì°

klein_c20_001-056v1.4.indd 45

0 4000

3500

3000

2500

2000

1500

1000

Wavenumber (cm⫺1)

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CHAPTER 20

Aldehydes and Ketones 1

H NMR Signals

In a 1H NMR spectrum, the carbonyl group itself does not produce a signal. However, it has a pronounced effect on the chemical shift of neighboring protons. We saw in Section 16.5 that a carbonyl group adds +1 ppm to the chemical shift of its neighbors: O R

R

R

R H

H

H

~1.2 ppm

H

~2.2 ppm

Aldehydic protons generally produce signals around 10 ppm. These signals can usually be identified with relative ease, because very few signals appear that far downfield in a 1H NMR spectrum (Figure 20.11).

O H

5

1

FIGURE 20.11 Ê£Ê ,ÊÃ«iVÌÀÕÊvÊ>Ê >ìÞì°

2 2

10

9

8

7

6

5

4

3

2

Chemical Shift (ppm)

13

C NMR Signals

In a 13C NMR spectrum, the carbon atom of a carbonyl group will generally produce a weak signal near 200 ppm. This signal can often be identified with relative ease, because very few signals appear that far downfield in a 13C NMR spectrum (Figure 20.12).

O 209.1 FIGURE 20.12 Ê£Î Ê ,ÊÃ«iVÌÀÕÊvÊ>ÊiÌi°

220

200

180

160

140

120

100

80

60

40

20

0


CONCEPTUAL CHECKPOINT 20.43 «Õ`Ê Ê >ÃÊ iVÕ>ÀÊ vÀÕ>Ê £äH£ä"Ê >`Ê iÝLÌÃÊ >Ê ÃÌÀ}ÊÃ}>Ê>ÌÊ£ÇÓäÊV£ÊÊÌÃÊ,ÊÃ«iVÌÀÕ°Ê/Ài>ÌiÌÊÜÌÊ£]ÓiÌ>i`ÌÊvÜi`ÊLÞÊ,>iÞÊViÊ>vvÀ`ÃÊÌiÊ«À`ÕVÌÊÃÜÊLiÜ°Ê ìÌvÞÊÌiÊÃÌÀÕVÌÕÀiÊvÊV«Õ`Ê°

klein_c20_001-056v1.4.indd 46

Compound A

1) [H+], HS

SH

2) Raney Ni

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47

Review of Concepts and Vocabulary

REVIEW OF REACTIONS

SYNTHETICALLY USEFUL REACTIONS

1. Þ`À>ÌiÊÀ>Ì 2. ViÌ>ÊÀ>Ì 3. ÞVVÊViÌ>Ê À>Ì

HO

O

[H+], H2O

OH

RCO3H

O

15

1

4. ÞVVÊ/>ViÌÊ À>Ì

H2C

ROH, –H2O

RO

OR

OH

HO

2

O

–H2O

3 [H+] RNH2 –H2O

8. "ÝiÊÀ>Ì S

9. Þ`À>âiÊÀ>Ì 10. 7vvÃiÀÊ,i`ÕVÌ

S

4 N

11. ,i`ÕVÌÊvÊ>ÊiÌi 12. À}>À`Ê,i>VÌ 14. 7ÌÌ}Ê,i>VÌ 15. >iÞiÀ6}iÀÊ"Ý`>Ì

[H+] R2NH –H2O

[H+] NH2OH –H2O

[H+] NH2NH2 –H2O

R

N

R N

OH

7

5

OH R

N

NH2

9 8

H

13

12

OH

6

H

CN

1) LAH 2) H2O

R

Raney Ni

13. Þ>Þ`ÀÊÀ>Ì

OH

1) RMgBr 2) H2O

SH

HS

O

14

HCN, KCN [H+]

–H2O

6. iÊÀ>Ì

PPh3

[H+]

5. iÃÕvÕÀâ>Ì 7. >iÊÀ>Ì

O

[H+]

11

85%

NaOH, H2O, heat

10

REVIEW OF CONCEPTS AND VOCABULARY SECTION 20.1 UÊ ÌÊ>ìÞìÃÊ>`ÊiÌiÃÊVÌ>Ê>Êcarbonyl group]Ê>`Ê LÌÊ>ÀiÊVÊÊ>ÌÕÀiÊ>`Ê`ÕÃÌÀÞÊ>`ÊVVÕ«ÞÊ>ÊViÌÀ>Ê ÀiÊÊÀ}>VÊViÃÌÀÞ°

SECTION 20.2 UÊ /iÊÃÕvwÝÊº>»Ê`V>ÌiÃÊ>Ê>ìÞ`VÊ}ÀÕ«]Ê>`ÊÌiÊÃÕvwÝÊ ºi»ÊÃÊÕÃi`ÊvÀÊiÌiÃ° UÊ Ê>}Ê>ìÞìÃÊ>`ÊiÌiÃ]ÊV>ÌÃÊÃÕ`ÊLiÊ>ÃÃ}i`Ê ÃÊ>ÃÊÌÊ}ÛiÊÌiÊV>ÀLÞÊ}ÀÕ«ÊÌiÊÜiÃÌÊÕLiÀÊ«ÃÃLi°

SECTION 20.3 UÊ ìÞìÃÊV>ÊLiÊ«Ài«>Ài`ÊÛ>ÊÝ`>ÌÊvÊ«À>ÀÞÊ>VÃ]Ê âÞÃÃÊvÊ>iiÃ]ÊÀÊÞ`ÀLÀ>ÌÝ`>ÌÊvÊÌiÀ>Ê >ÞiÃ° UÊ iÌiÃÊ V>Ê LiÊ «Ài«>Ài`Ê Û>Ê Ý`>ÌÊ vÊ ÃiV`>ÀÞÊ >VÃ]ÊâÞÃÃÊvÊ>iiÃ]Ê>V`V>Ì>Þâi`ÊÞ`À>ÌÊvÊÌiÀ>Ê>ÞiÃ]ÊÀÊÀiì À>vÌÃÊ>VÞ>Ì°

SECTION 20.4 UÊ /iÊ iiVÌÀ«VÌÞÊ vÊ >Ê V>ÀLÞÊ }ÀÕ«Ê ìÀÛiÃÊ vÀÊ ÀiÃ>ViÊivviVÌÃÊ>ÃÊÜiÊ>ÃÊ`ÕVÌÛiÊivviVÌÃ° UÊ ìÞìÃÊ>ÀiÊÀiÊÀi>VÌÛiÊÌ>ÊiÌiÃÊ>ÃÊ>ÊÀiÃÕÌÊvÊÃÌiÀVÊ ivviVÌÃÊ>`ÊiiVÌÀVÊivviVÌÃ° UÊ Ê }iiÀ>Ê iV>ÃÊ vÀÊ ÕVi«VÊ >``ÌÊ ÕìÀÊ L>ÃVÊ V`ÌÃÊÛÛiÃÊÌÜÊÃÌi«Ã\ 1.Ê ÕVi«VÊ>ÌÌ>VÊÌÊ}iiÀ>ÌiÊ>Êtetrahedral intermediate° 2.Ê *ÀÌÊÌÀ>ÃviÀ

klein_c20_001-056v1.4.indd 47

UÊ /iÊ«ÃÌÊvÊiµÕLÀÕÊÃÊì«iìÌÊÊÌiÊ>LÌÞÊvÊÌiÊ ÕVi«iÊÌÊvÕVÌÊ>ÃÊ>Êi>Û}Ê}ÀÕ«°

SECTION 20.5 UÊ 7iÊ>Ê>ìÞìÊÀÊiÌiÊÃÊÌÀi>Ìi`ÊÜÌÊÜ>ÌiÀ]ÊÌiÊV>ÀLÞÊ}ÀÕ«ÊV>ÊLiÊVÛiÀÌi`ÊÌÊ>Êhydrate°Ê/iÊiµÕLÀÕÊ}iiÀ>ÞÊv>ÛÀÃÊÌiÊV>ÀLÞÊ}ÀÕ«]ÊiÝVi«ÌÊÊÌiÊV>ÃiÊ vÊ ÛiÀÞÊ Ã«iÊ >ìÞìÃ]Ê ÀÊ iÌiÃÊ ÜÌÊ ÃÌÀ}Ê iiVÌÀ ÜÌ`À>Ü}ÊÃÕLÃÌÌÕiÌÃ° UÊ Ê>V`VÊV`ÌÃ]Ê>Ê>ìÞìÊÀÊiÌiÊÜÊÀi>VÌÊÜÌÊÌÜÊ iVÕiÃÊvÊ>VÊÌÊvÀÊ>Êacetal° UÊ ÊÌiÊ«ÀiÃiViÊvÊ>Ê>V`]ÊÌiÊV>ÀLÞÊ}ÀÕ«ÊÃÊ«ÀÌ>Ìi`Ê ÌÊvÀÊ>ÊÛiÀÞÊ«ÜiÀvÕÊiiVÌÀ«i° UÊ /iÊiV>ÃÊvÀÊ>ViÌ>ÊvÀ>ÌÊV>ÊLiÊ`Ûì`ÊÌÊÌÜÊ «>ÀÌÃ\ 1.Ê /iÊwÀÃÌÊÌÀiiÊÃÌi«ÃÊ«À`ÕViÊ>Êhemiacetal° 2.Ê /iÊ>ÃÌÊvÕÀÊÃÌi«ÃÊVÛiÀÌÊÌiÊi>ViÌ>ÊÌÊ>Ê>ViÌ>° UÊ ÀÊ >ÞÊ Ã«iÊ >ìÞìÃ]Ê ÌiÊ iµÕLÀÕÊ v>ÛÀÃÊ vÀ>ÌÊvÊÌiÊ>ViÌ>ÆÊÜiÛiÀ]ÊvÀÊÃÌÊiÌiÃ]ÊÌiÊiµÕLÀÕÊ v>ÛÀÃÊÀi>VÌ>ÌÃÊÀ>ÌiÀÊÌ>Ê«À`ÕVÌÃ° UÊ Ê>ìÞìÊÀÊiÌiÊÜÊÀi>VÌÊÜÌÊiÊiVÕiÊvÊ>Ê`Ê ÌÊvÀÊ>ÊVÞVVÊ>ViÌ>° UÊ /iÊÀiÛiÀÃLÌÞÊvÊ>ViÌ>ÊvÀ>ÌÊi>LiÃÊ>ViÌ>ÃÊÌÊvÕVÌÊ>ÃÊ«ÀÌiVÌ}Ê}ÀÕ«ÃÊvÀÊiÌiÃÊÀÊ>ìÞìÃ°ÊViÌ>ÃÊ >ÀiÊÃÌ>LiÊÕìÀÊÃÌÀ}ÞÊL>ÃVÊV`ÌÃ° UÊ i>ViÌ>ÃÊ>ÀiÊ}iiÀ>ÞÊ`vwVÕÌÊÌÊÃ>ÌiÊÕiÃÃÊÌiÞÊ>ÀiÊ VÞVV°

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48

CHAPTER 20


SECTION 20.6 UÊ Ê>V`VÊV`ÌÃ]Ê>Ê>ìÞìÊÀÊiÌiÊÜÊÀi>VÌÊÜÌÊ>Ê «À>ÀÞÊ>iÊÌÊvÀÊ>Êimine° UÊ /iÊwÀÃÌÊÌÀiiÊÃÌi«ÃÊÊiÊvÀ>ÌÊ«À`ÕViÊ>Êcarbinolamine]Ê >`Ê ÌiÊ >ÃÌÊ ÌÀiiÊ ÃÌi«ÃÊ VÛiÀÌÊ ÌiÊ V>ÀL>iÊ ÌÊ>Êi° UÊ >ÞÊ`vviÀiÌÊV«Õ`ÃÊvÊÌiÊvÀÊ, ÓÊÜÊÀi>VÌÊÜÌÊ >ìÞìÃÊ>`ÊiÌiÃÆÊvÀÊiÝ>«i\ 1.Ê 7iÊ Þ`À>âiÊ ÃÊ ÕÃi`Ê >ÃÊ >Ê ÕVi«iÊ ÓNHÓ®]Ê >Ê hydrazoneÊÃÊvÀi`° 2.Ê 7iÊ Þ`ÀÝÞ>iÊ ÃÊ ÕÃi`Ê >ÃÊ >Ê ÕVi«iÊ Ó"®]Ê >ÊoximeÊÃÊvÀi`° UÊ Ê >V`VÊ V`ÌÃ]Ê >Ê >ìÞìÊ ÀÊ iÌiÊ ÜÊ Ài>VÌÊ ÜÌÊ >ÊÃiV`>ÀÞÊ>iÊÌÊvÀÊ>Êenamine°Ê/iÊiV>ÃÊvÊ i>iÊvÀ>ÌÊÃÊìÌV>ÊÌÊÌiÊiV>ÃÊvÊiÊvÀ>ÌÊiÝVi«ÌÊvÀÊÌiÊ>ÃÌÊÃÌi«° UÊ ÊÌiÊWolff-Kishner reduction]Ê>ÊÞ`À>âiÊÃÊÀi`ÕVi`ÊÌÊ>Ê >>iÊÕìÀÊÃÌÀ}ÞÊL>ÃVÊV`ÌÃ°

SECTION 20.7 UÊ Ê>V`VÊV`ÌÃ]Ê>ÊÀi>}iÌÃ]ÊÌiÀi`>ÌiÃ]Ê>`Êi>Û}Ê }ÀÕ«ÃÊ iÌiÀÊ ÃÕ`Ê LiÊ iÕÌÀ>Ê Ê V>À}i®Ê ÀÊ ÃÕ`Ê Li>ÀÊ iÊ«ÃÌÛiÊV>À}i° UÊ HydrolysisÊ vÊ >ViÌ>Ã]Ê iÃ]Ê >`Ê i>iÃÊ ÕìÀÊ >V`VÊ V`ÌÃÊ«À`ÕViÃÊiÌiÃÊÀÊ>ìÞìÃ°

UÊ À}>À`ÊÀi>VÌÃÊ>ÀiÊÌÊÀiÛiÀÃLi]ÊLiV>ÕÃiÊV>ÀL>ÃÊ`Ê ÌÊvÕVÌÊ>ÃÊi>Û}Ê}ÀÕ«Ã° UÊ 7iÊÌÀi>Ìi`ÊÜÌÊÞ`À}iÊVÞ>ìÊ ®]Ê>ìÞìÃÊ>`Ê iÌiÃÊ >ÀiÊ VÛiÀÌi`Ê ÌÊ cyanohydrins°Ê ÀÊ ÃÌÊ >ìÞìÃÊ>`ÊÕìÀi`ÊiÌiÃ]ÊÌiÊiµÕLÀÕÊv>ÛÀÃÊvÀ>ÌÊvÊÌiÊVÞ>Þ`À° UÊ /iÊWittig reactionÊV>ÊLiÊÕÃi`ÊÌÊVÛiÀÌÊ>ÊiÌiÊÌÊ>Ê >ii°Ê/iÊWittig reagentÊÌ>ÌÊ>VV«ÃiÃÊÌÃÊÌÀ>ÃvÀ>ÌÊ ÃÊ V>i`Ê >Ê phosphorane]Ê ÜVÊ Li}ÃÊ ÌÊ >Ê >À}iÀÊ V>ÃÃÊvÊV«Õ`ÃÊV>i`Êylides° UÊ /iÊiV>ÃÊvÊ>Ê7ÌÌ}ÊÀi>VÌÊÛÛiÃÊÌ>ÊvÀ>ÌÊ vÊ>Êbetaine]ÊÜVÊÕìÀ}iÃÊ>ÊÌÀ>iVÕ>ÀÊÕVi«VÊ >ÌÌ>V]Ê }iiÀ>Ì}Ê >Ê oxaphosphetane°Ê ,i>ÀÀ>}iiÌÊ }ÛiÃÊÌiÊ«À`ÕVÌ° UÊ *Ài«>À>ÌÊvÊ7ÌÌ}ÊÀi>}iÌÃÊÛÛiÃÊ>Ê-NÓÊÀi>VÌ]Ê>`Ê ÌiÊÀi}Õ>ÀÊÀiÃÌÀVÌÃÊvÊ-NÓÊ«ÀViÃÃiÃÊ>««Þ°

SECTION 20.11 UÊ ÊBaeyer-Villiger oxidationÊVÛiÀÌÃÊ>ÊiÌiÊÌÊ>ÊiÃÌiÀÊLÞÊ ÃiÀÌ}Ê>ÊÝÞ}iÊ>ÌÊiÝÌÊÌÊÌiÊV>ÀLÞÊ}ÀÕ«°Ê ÞVVÊ iÌiÃÊ«À`ÕViÊVÞVVÊiÃÌiÀÃÊV>i`Êlactones° UÊ 7iÊ>ÊÕÃÞiÌÀV>ÊiÌiÊÃÊÌÀi>Ìi`ÊÜÌÊ>Ê«iÀÝÞÊ>V`]Ê vÀ>ÌÊ vÊ ÌiÊ iÃÌiÀÊ ÃÊ Ài}ÃiiVÌÛi]Ê >`Ê ÌiÊ «À`ÕVÌÊ ÃÊ ìÌiÀi`Ê LÞÊ ÌiÊ migratory aptitudeÊ vÊ i>VÊ }ÀÕ«Ê iÝÌÊ ÌÊÌiÊV>ÀLÞ°

SECTION 20.12

SECTION 20.8 UÊ Ê>V`VÊV`ÌÃ]Ê>Ê>ìÞìÊÀÊiÌiÊÜÊÀi>VÌÊÜÌÊÌÜÊ iµÕÛ>iÌÃÊ vÊ >Ê ÌÊ ÌÊ vÀÊ >Ê thioacetal°Ê vÊ >Ê V«Õ`Ê ÜÌÊÌÜÊ-Ê}ÀÕ«ÃÊÃÊÕÃi`]Ê>ÊVÞVVÊÌ>ViÌ>ÊÃÊvÀi`° UÊ 7iÊÌÀi>Ìi`ÊÜÌÊ,>iÞÊVi]ÊÌ>ViÌ>ÃÊÕìÀ}ÊdesulfurizationÊÌÊÞi`Ê>ÊiÌÞiiÊ}ÀÕ«°

UÊ /ÃÊ V>«ÌiÀÊ iÝ«Ài`Ê ÌÀiiÊ q Ê L`vÀ}Ê Ài>VÌÃ\Ê £®Ê>ÊÀ}>À`ÊÀi>VÌ]ÊÓ®ÊVÞ>Þ`ÀÊvÀ>Ì]Ê>`ÊÎ®Ê>Ê 7ÌÌ}ÊÀi>VÌ° UÊ /ÃÊV>«ÌiÀÊiÝ«Ài`ÊÞÊiÊ q ÊL`LÀi>}ÊÀi>VÌ\Ê ÌiÊ >iÞiÀ6}iÀÊÝ`>Ì°

SECTION 20.13

SECTION 20.9 UÊ 7iÊÌÀi>Ìi`ÊÜÌÊ>ÊÞ`ÀìÊÀi`ÕV}Ê>}iÌ]ÊÃÕVÊ>ÃÊÌÕÊ >ÕÕÊ Þ`ÀìÊ ®Ê ÀÊ Ã`ÕÊ LÀÞ`ÀìÊ > {®]Ê >ìÞìÃÊ>`ÊiÌiÃÊ>ÀiÊÀi`ÕVi`ÊÌÊ>VÃ° UÊ /iÊÀi`ÕVÌÊvÊ>ÊV>ÀLÞÊ}ÀÕ«ÊÜÌÊÊÀÊ > {ÊÃÊÌÊ >ÊÀiÛiÀÃLiÊ«ÀViÃÃ]ÊLiV>ÕÃiÊÞ`ÀìÊìÃÊÌÊvÕVÌÊ>ÃÊ>Ê i>Û}Ê}ÀÕ«°

SECTION 20.10 UÊ 7iÊÌÀi>Ìi`ÊÜÌÊ>ÊÀ}>À`Ê>}iÌ]Ê>ìÞìÃÊ>`ÊiÌiÃÊ >ÀiÊVÛiÀÌi`ÊÌÊ>VÃ]Ê>VV«>i`ÊLÞÊÌiÊvÀ>ÌÊ vÊ>ÊiÜÊ q ÊL`°

UÊ >ÀLÞÊ }ÀÕ«ÃÊ «À`ÕViÊ >Ê ÃÌÀ}Ê ,Ê Ã}>Ê >ÀÕ`Ê £Ç£xÊ V£°Ê Ê VÕ}>Ìi`Ê V>ÀLÞÊ «À`ÕViÃÊ >Ê Ã}>Ê >ÌÊ >Ê ÜiÀÊÜ>ÛiÕLiÀ]ÊÜiÊÀ}ÊÃÌÀ>ÊVÀi>ÃiÃÊÌiÊÜ>ÛiÕLiÀÊvÊ>LÃÀ«Ì° UÊ ìÞ`VÊ qÊ L`ÃÊ iÝLÌÊ iÊ ÀÊ ÌÜÊ Ã}>ÃÊ LiÌÜiiÊ ÓÇääÊ>`ÊÓnxäÊV£° £

UÊ Ê >Ê Ê ,Ê Ã«iVÌÀÕ]Ê >Ê V>ÀLÞÊ }ÀÕ«Ê >``ÃÊ ³£Ê ««Ê ÌÊ ÌiÊViV>ÊÃvÌÊvÊÌÃÊi}LÀÃ]Ê>`Ê>Ê>ìÞ`VÊ«ÀÌÊ «À`ÕViÃÊ>ÊÃ}>Ê>ÀÕ`Ê£äÊ««° £Î

UÊ Ê>Ê Ê ,ÊÃ«iVÌÀÕ]Ê>ÊV>ÀLÞÊ}ÀÕ«Ê«À`ÕViÃÊ>ÊÜi>Ê Ã}>Êi>ÀÊÓääÊ««°

KEY TERMINOLOGY acetalÊ UUU >iÞiÀ6}iÀÊÝ`>ÌÊ UUU LiÌ>iÊ UUU V>ÀL>iÊ UUU V>ÀLÞÊ}ÀÕ«Ê UUU VÞ>Þ`ÀÃÊ UUU

klein_c20_001-056v1.4.indd 48

ìÃÕvÕÀâ>ÌÊ UUU i>iÊ UUU i>ViÌ>Ê UUU Þ`À>ÌiÊ UUU Þ`À>âiÊ UUU Þ`ÀÞÃÃÊ UUU

iÊ UUU >VÌiÊ UUU }À>ÌÀÞÊ>«ÌÌÕìÊ UUU Ý>«Ã«iÌ>iÊ UUU ÝiÊ UUU «Ã«À>iÊ UUU

ÌiÌÀ>i`À>ÊÌiÀi`>ÌiÊ UUU Ì>ViÌ>Ê UUU 7ÌÌ}ÊÀi>VÌÊ UUU 7ÌÌ}ÊÀi>}iÌÊ UUU 7vvÃiÀÊÀi`ÕVÌÊ UUU ÞìÊ UUU

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Skillbuilder Review

SKILLBUILDER REVIEW 20.1 NAMING ALDEHYDES AND KETONES STEP 1 ÃiÊÌiÊ}iÃÌÊ V>ÊVÌ>}ÊÌiÊV>ÀLÞÊ }ÀÕ«]Ê>`ÊÕLiÀÊÌiÊV>Ê ÃÌ>ÀÌ}ÊvÀÊÌiÊi`ÊVÃiÃÌÊ ÌÊÌiÊV>ÀLÞÊ}ÀÕ«°

STEP 2 AND 3 ìÌvÞÊ ÌiÊÃÕLÃÌÌÕiÌÃ]Ê>`Ê>ÃÃ}Ê V>ÌÃ°

4,4-dimethyl

8 7 2

4

1 3

9 2

4

1 3

5

O

9

R

6 5

O

O

4,4-dimethyl-6-ethyl

6-ethyl

O

3-nonanone

STEP 5 ÃÃ}ÊÌiÊ Vw}ÕÀ>ÌÊvÊ>ÞÊVÀ>ÌÞÊ ViÌiÀ°

8

7

6

STEP 4 ÃÃiLiÊÌiÊ ÃÕLÃÌÌÕiÌÃÊ>«>LiÌV>Þ°

(R)-4,4-dimethyl-6-ethyl -3-nonanone

Try problems 20.1–20.4, 20.44–20.49

20.2 DRAWING THE MECHANISM OF ACETAL FORMATION STEP 1 À>ÜÊÌiÊÌÀiiÊÃÌi«ÃÊiViÃÃ>ÀÞÊvÀÊi>ViÌ>ÊvÀ>Ì° Proton transfer

Nucleophilic attack

H¬A

O

+

Proton transfer

H

+

O

COMMENTS UÊ ÛiÀÞÊÃÌi«Ê>ÃÊÌÜÊVÕÀÛi`Ê>ÀÀÜÃ°Ê À>ÜÊÌiÊ«ÀiVÃiÞ° UÊ ÊÌÊvÀ}iÌÊÌiÊV>À}iÃ° UÊ À>ÜÊi>VÊÃÌi«ÊÃi«>À>ÌiÞ°

OH

R¬O¬H

OH

A

H O+

OR

R

STEP 2 À>ÜÊÌiÊvÕÀÊÃÌi«ÃÊÌ>ÌÊVÛiÀÌÊÌiÊi>ViÌ>ÊÌÊ>Ê>ViÌ>° Proton transfer

OH

H¬A

H + H O

+

Nucleophilic attack


–H2O

+

R

R + H O

R¬ O ¬H

O

Proton transfer

OR

OR

A

OR

OR OR

Try Problems 20.8–20.10, 20.57, 20.62, 20.67

20.3 DRAWING THE MECHANISM OF IMINE FORMATION STEP 1 À>ÜÊÌiÊÌÀiiÊÃÌi«ÃÊiViÃÃ>ÀÞÊvÀÊV>ÀL>iÊvÀ>Ì° Nucleophilic attack

Proton transfer +

O H¬A

+

O

H R¬NH2

COMMENTS UÊ >VÊ«>ÀÌÊvÊÌiÊiV>ÃÊLi}ÃÊ ÜÌÊ>Ê«ÀÌÊÌÀ>ÃviÀÊ>`Êi`ÃÊ ÜÌÊ>Ê«ÀÌÊÌÀ>ÃviÀ° UÊ ÛiÀÞÊÃÌi«Ê>ÃÊÌÜÊVÕÀÛi`Ê>ÀÀÜÃ°Ê >iÊÃÕÀiÊÌÊ`À>ÜÊÌiÊ«ÀiVÃiÞ° UÊ ÊÌÊvÀ}iÌÊÌiÊ«ÃÌÛiÊV>À}iÃ°Ê /iÀiÊÃÕ`ÊLiÊÊi}>ÌÛiÊ V>À}iÃ° UÊ À>ÜÊi>VÊÃÌi«ÊÃi«>À>ÌiÞ]Ê vÜ}ÊÌiÊ«ÀiVÃiÊÀìÀÊvÊ ÃÌi«Ã°

Proton transfer

OH

OH A

H

N

N

R

+

H

H

R

STEP 2 À>ÜÊÌiÊÌÀiiÊÃÌi«ÃÊÌ>ÌÊVÛiÀÌÊÌiÊV>ÀL>iÊÌÊ>Êi° Loss of a leaving group

Proton transfer

OH

H¬A

N R

H

+

H + H O N

–H2O

R + H N

Proton transfer R R–NH2

N

H

R

Try Problems 20.15–20.18, 20.72, 20.86

klein_c20_001-056v1.4.indd 49

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CHAPTER 20


20.4 DRAWING THE MECHANISM OF ENAMINE FORMATION COMMENTS UÊ >VÊ«>ÀÌÊvÊÌiÊiV>ÃÊ Li}ÃÊÜÌÊ>Ê«ÀÌÊÌÀ>ÃviÀÊ >`Êi`ÃÊÜÌÊ>Ê«ÀÌÊ ÌÀ>ÃviÀ° UÊ ÛiÀÞÊÃÌi«Ê>ÃÊÌÜÊVÕÀÛi`Ê >ÀÀÜÃ°Ê>iÊÃÕÀiÊÌÊ`À>ÜÊ ÌiÊ«ÀiVÃiÞ° UÊ ÊÌÊvÀ}iÌÊÌiÊ«ÃÌÛiÊ V>À}iÃ°Ê/iÀiÊÃÕ`ÊLiÊÊ i}>ÌÛiÊV>À}iÃ° UÊ À>ÜÊi>VÊÃÌi«ÊÃi«>À>ÌiÞÊ vÜ}ÊÌiÊ«ÀiVÃiÊÀìÀÊvÊ ÃÌi«Ã°

STEP 1 À>ÜÊÌiÊÌÀiiÊÃÌi«ÃÊiViÃÃ>ÀÞÊvÀÊV>ÀL>iÊvÀ>Ì° Nucleophilic attack

Proton transfer H

+

O H¬A

O

+

Proton transfer OH

OH

R2NH

A

H

N

N

R +R

R

R

STEP 2 À>ÜÊÌiÊÌÀiiÊÃÌi«ÃÊÌ>ÌÊVÛiÀÌÊÌiÊV>ÀL>iÊÌÊ>Êi>i° Proton transfer

OH

H¬A

N

H + H O

+

Nucleophilic attack


R

N

R

–H2O

R + R N

R

R2NH

R

R N

H

R

Try Problems 20.21–20.24, 20.72

20.5 DRAWING THE MECHANISM OF A HYDROLYSIS REACTION STEP 1 7À}ÊL>VÜ>À`Ã]Ê`À>ÜÊ>ÊÌiÀi`>ÌiÃ°

STEP 2 UÊvÌiÀÊ`À>Ü}Ê>ÊÌiÀi`>ÌiÃ]ÊÌiÊ`À>ÜÊ>Ê Ài>}iÌÃÊ>`ÊVÕÀÛi`Ê>ÀÀÜÃÊÕÃ}ÊÌiÊvÜ}ÊÀÕiÃ\ UÊÊ>V`VÊV`ÌÃ]Ê>ÊÀi>}iÌÃ]ÊÌiÀi`>ÌiÃ]Ê>`Ê i>Û}Ê}ÀÕ«ÃÊiÌiÀÊÃÕ`ÊLiÊiÕÌÀ>ÊÀÊÃÕ`Ê Li>ÀÊiÊ«ÃÌÛiÊV>À}i° UÊ1ÃiÊÞÊÌÃiÊÀi>}iÌÃÊÌ>ÌÊ>ÀiÊ>Ài>`ÞÊ«ÀiÃiÌ°

first draw this intermediate +

H

O

O

then draw the other intermediates, working backward

Try Problems 20.26, 20.27, 20.65

20.6 PLANNING AN ALKENE SYNTHESIS WITH A WITTIG REACTION ÊEXAMPLE ìÌvÞÊ ÊÌiÊÀi>VÌ>ÌÃÊÞÕÊ ÊÜÕ`ÊÕÃiÊÌÊ«Ài«>ÀiÊ ÊÌÃÊV«Õ`ÊÛ>Ê>Ê 7ÌÌ}ÊÀi>VÌ°

STEP 1 1Ã}Ê>ÊÀiÌÀÃÞÌiÌVÊ>>ÞÃÃ]ÊìÌiÀiÊÌiÊÌÜÊ «ÃÃLiÊÃiÌÃÊvÊÀi>VÌ>ÌÃÊÌ>ÌÊVÕ`ÊLiÊÕÃi`ÊÌÊvÀÊÌiÊ

5 ÊL`°

H

O

H PPh3

PPh3

+

+

Method 1

Method 2

STEP 2 ÃìÀÊÜÊÞÕÊ ÜÕ`Ê>iÊi>VÊ«ÃÃLiÊ 7ÌÌ}ÊÀi>}iÌ]Ê>`ÊìÌiÀiÊ ÜVÊiÌ`ÊÛÛiÃÊÌiÊiÃÃÊ ÃÕLÃÌÌÕÌi`Ê>ÞÊ>ì° x

O

X

Will undergo SN2 more readily

2˚ Alkyl halide

1˚ Alkyl halide

Try Problems 20.37–20.39, 20.51–20.53

20.7 PROPOSING A SYNTHESIS STEP 1 i}ÊLÞÊ >Ã}ÊÌiÊvÜ}ÊÌÜÊ µÕiÃÌÃ\ £°ÊÃÊÌiÀiÊ>ÊV>}iÊÊÌiÊ V>ÀLÊÃiiÌ¶ Ó°ÊÃÊÌiÀiÊ>ÊV>}iÊÊÌiÊ vÕVÌ>Ê}ÀÕ«Ã¶

AU/ED: long page klein_c20_001-056v1.4.indd 50

STEP 2 vÊÌiÀiÊÃÊ>ÊV>}iÊÊÌiÊV>ÀLÊÃiiÌ]Ê VÃìÀÊ>ÊvÊÌiÊ q ÊL`vÀ}ÊÀi>VÌÃÊ>`Ê >ÊvÊÌiÊ q ÊL`LÀi>}ÊÀi>VÌÃÊÌ>ÌÊÞÕÊ>ÛiÊ i>Ài`ÊÃÊv>À

q ÊL`vÀ}ÊÀi>VÌÃÊÊÌÃÊV>«ÌiÀ UÊÀ}>À`ÊÀi>VÌ UÊ Þ>Þ`ÀÊvÀ>Ì UÊ7ÌÌ}ÊÀi>VÌ

q ÊL`LÀi>}ÊÀi>VÌÃÊÊÌÃÊV>«ÌiÀ UÊ >iÞiÀ6}iÀÊÝ`>Ì

CONSIDERATIONS ,iiLiÀÊÌ>ÌÊÌiÊìÃÀi`Ê«À`ÕVÌÊÃÕ`ÊLiÊÌiÊ >ÀÊ«À`ÕVÌÊvÊÞÕÀÊ«À«Ãi`ÊÃÞÌiÃÃ° >iÊÃÕÀiÊÌ>ÌÊÌiÊÀi}ViV>ÊÕÌViÊvÊi>VÊ ÃÌi«ÊÃÊVÀÀiVÌ° Ü>ÞÃÊÌÊL>VÜ>À`ÊÀiÌÀÃÞÌiÌVÊ>>ÞÃÃ®Ê>ÃÊÜiÊ >ÃÊvÀÜ>À`]Ê>`ÊÌiÊÌÀÞÊÌÊLÀ`}iÊÌiÊ}>«° ÃÌÊÃÞÌiÃÃÊ«ÀLiÃÊÜÊ>ÛiÊÕÌ«iÊVÀÀiVÌÊ >ÃÜiÀÃ°Ê ÊÌÊviiÊÌ>ÌÊÞÕÊ>ÛiÊÌÊw`ÊÌiÊºi»Ê VÀÀiVÌÊ>ÃÜiÀ°

Try Problems 20.41, 20.42, 20.55, 20.58, 20.67–20.69, 20.71, 20.75 30/04/10 16.47

51

Practice Problems

Note:ÊÃÌÊvÊÌiÊ*ÀLiÃÊ>ÀiÊ>Û>>LiÊÜÌ WileyPLUS]Ê>ÊiÊÌi>V}Ê>`Êi>À}ÊÃÕÌ°

PRACTICE PROBLEMS 20.44

*ÀÛìÊ>ÊÃÞÃÌi>ÌVÊ1* ®Ê>iÊvÀÊi>VÊvÊÌiÊvÜ}ÊV«Õ`Ã\

O

O H

O

O

(a)

H

O

O

(a)

(b)

O H

(c)

20.51

À>ÜÊ ÌiÊ «À`ÕVÌÃÊ vÊ i>VÊ 7ÌÌ}Ê Ài>VÌÊ LiÜ°Ê vÊ ÌÜÊÃÌiÀiÃiÀÃÊ>ÀiÊ«ÃÃLi]Ê`À>ÜÊLÌÊÃÌiÀiÃiÀÃ\Ê

(d) O H

HO

(e)

(f)

Br

?

H

(a) O

À>ÜÊÌiÊÃÌÀÕVÌÕÀiÊvÀÊi>VÊV«Õ`ÊLiÜ\

Ph

>®Ê «À«>i`> L®Ê {«iÞLÕÌ>>

Ph

Ph Ph P Ph

O

O

20.45

CH3

H3C

CF3

F3C

(b) O

(b)

Ph Ph P Ph

H

?

Ph Ph P Ph

H

?

Ph

V®Ê (S)Î«iÞLÕÌ>> `®Ê Î]Î]x]xÌiÌÀ>iÌÞ{i«Ì>i O

i®Ê (R)ÎÞ`ÀÝÞ«iÌ>> v®Ê iÌ>Þ`ÀÝÞ>ViÌ«ii }®Ê Ó]{]ÈÌÀÌÀLiâ>ìÞì

H

(c)

®Ê ÌÀLÀ>ViÌ>ìÞì ®Ê (3R,4R)Î]{`Þ`ÀÝÞÓ«iÌ>i

Ph Ph P Ph

O

20.46

À>ÜÊ >Ê VÃÌÌÕÌ>ÞÊ ÃiÀVÊ >ìÞìÃÊ ÜÌÊ iVÕ>ÀÊ vÀÕ>Ê {Hn"]Ê >`Ê «ÀÛìÊ >Ê ÃÞÃÌi>ÌVÊ 1* ®Ê >iÊvÀÊi>VÊÃiÀ°

20.47

À>ÜÊ >Ê VÃÌÌÕÌ>ÞÊ ÃiÀVÊ >ìÞìÃÊ ÜÌÊ iVÕ>ÀÊ vÀÕ>Ê xH£ä"]Ê >`Ê «ÀÛìÊ >Ê ÃÞÃÌi>ÌVÊ 1* ®Ê >iÊvÀÊi>VÊÃiÀ°Ê7VÊvÊÌiÃiÊÃiÀÃÊ«ÃÃiÃÃiÃÊ>ÊVÀ>ÌÞÊViÌiÀ¶Ê

H

?

(d)

20.52 À>ÜÊÌiÊÃÌÀÕVÌÕÀiÊvÊÌiÊ>ÞÊ>ìÊiiì`ÊÌÊ«Ài«>ÀiÊ i>VÊ vÊ ÌiÊ vÜ}Ê 7ÌÌ}Ê Ài>}iÌÃ]Ê >`Ê ÌiÊ ìÌiÀiÊÜVÊ7ÌÌ}ÊÀi>}iÌÊÜÊLiÊÌiÊÃÌÊ`vwVÕÌÊÌÊ«Ài«>Ài°Ê

Ý«>ÊÞÕÀÊVVi\Ê

20.48

À>ÜÊ>ÊVÃÌÌÕÌ>ÞÊÃiÀVÊiÌiÃÊÜÌÊiVÕ>ÀÊ vÀÕ>Ê ÈH£Ó"]Ê >`Ê «ÀÛìÊ >Ê ÃÞÃÌi>ÌVÊ 1* ®Ê >iÊ vÀÊi>VÊÃiÀ°Ê

CH3

Ph

(a)

Ph P Ph

(c)

Ph Ph P Ph

Ph H

(b)

Ph Ph P Ph

H

20.49

Ý«>Ê ÜÞÊ ÌiÊ 1* Ê >iÊ vÊ >Ê V«Õ`Ê ÜÊ iÛiÀÊi`ÊÜÌÊÌiÊÃÕvwÝÊº£i°»Ê

20.50

ÀÊ i>VÊ «>ÀÊ vÊ ÌiÊ vÜ}Ê V«Õ`Ã]Ê ìÌvÞÊ ÜVÊV«Õ`ÊÜÕ`ÊLiÊiÝ«iVÌi`ÊÌÊÀi>VÌÊÀiÊÀ>«`ÞÊÜÌÊ >ÊÕVi«i\Ê

klein_c20_001-056v1.4.indd 51

30/04/10 16.47

52

CHAPTER 20


20.53

-ÜÊ ÜÊ >Ê 7ÌÌ}Ê Ài>VÌÊ V>Ê LiÊ ÕÃi`Ê ÌÊ «Ài«>ÀiÊ i>VÊvÊÌiÊvÜ}ÊV«Õ`Ã°ÊÊi>VÊV>Ãi]Ê>ÃÊÃÜÊÜÊ ÌiÊ7ÌÌ}ÊÀi>}iÌÊÜÕ`ÊLiÊ«Ài«>Ài`\Ê

20.60

*Ài`VÌÊÌiÊ>ÀÊ«À`ÕVÌÃ®ÊvÀÊi>VÊÀi>VÌÊLiÜ°Ê O 1) LAH 2) H2O

(a) (a)

O

(b)

1) PhMgBr 2) H2O

(b) O

(c)

(C6H5)3P=CH2

(c)

20.54

ÃiÊ>ÊÀ}>À`ÊÀi>}iÌÊ>`Ê>ÊiÌiÊÌ>ÌÊV>ÊLiÊ ÕÃi`ÊÌÊ«À`ÕViÊi>VÊvÊÌiÊvÜ}ÊV«Õ`Ã\Ê >®Ê ÎiÌÞÎ«iÌ>Ê L®Ê £iÌÞVÞViÝ> V®Ê ÌÀ«iÞiÌ>Ê `®Ê x«iÞx>

O HCN, KCN

(d)

20.55

9ÕÊ >ÀiÊ ÜÀ}Ê Ê >Ê >LÀ>ÌÀÞ]Ê >`Ê ÞÕÊ >ÀiÊ }ÛiÊ ÌiÊ Ì>ÃÊ vÊ VÛiÀÌ}Ê VÞV«iÌiiÊ ÌÊ £]x«iÌ>i`°Ê 9ÕÀÊ wÀÃÌÊ ÌÕ}ÌÊ ÃÊ Ã«ÞÊ ÌÊ «iÀvÀÊ >Ê âÞÃÃÊ vÜi`Ê LÞÊ Ài`ÕVÌÊ ÜÌÊ ]Ê LÕÌÊ ÞÕÀÊ >LÊ ÃÊ ÌÊ iµÕ««i`Ê vÀÊ >Ê âÞÃÃÊ Ài>VÌ°Ê -Õ}}iÃÌÊ >Ê >ÌiÀ>ÌÛiÊ iÌ`Ê vÀÊ VÛiÀÌ}Ê VÞV«iÌiiÊ ÌÊ £]x«iÌ>i`°ÊÊ ÀÊi«]ÊÃiiÊ-iVÌÊ£Î°{ÊÀi`ÕVÌÊvÊiÃÌiÀÃÊÌÊ}ÛiÊ>VÃ®°Ê

20.61

-Ì>ÀÌ}Ê ÜÌÊ VÞV«iÌ>iÊ >`Ê ÕÃ}Ê >ÞÊ ÌiÀÊ Ài>}iÌÃÊ vÊ ÞÕÀÊ VÃ}]Ê ìÌvÞÊ ÜÊ ÞÕÊ ÜÕ`Ê «Ài«>ÀiÊ i>VÊvÊÌiÊvÜ}ÊV«Õ`Ã\Ê HO COOH

(a)

20.56

(b)

(c)

*Ài`VÌÊ ÌiÊ >ÀÊ «À`ÕVÌÃ®Ê vÀÊ ÌiÊ ÌÀi>ÌiÌÊ vÊ >ViÌiÊÜÌÊÌiÊvÜ}ÊV«Õ`Ã\Ê >®Ê Q+RÊ]Ê ÎÊ]ÊÓ"®Ê

L®Ê Q+RÊ]Ê ÎNHÓÊ]ÊÓ"®

V®Ê Q+RÊ]ÊiÝViÃÃÊ Ì"]ÊÓ"®Ê

`®Ê Q+RÊ]Ê Î®Ó Ê]ÊÓ"®

+

O

+

i®Ê Q RÊ]Ê ÓNHÓÊ]ÊÓ"®Ê

v®Ê Q RÊ]Ê Ó"Ê]ÊÓ"®

}®Ê > {]Êi"Ê

®Ê *

®Ê ]Ê Ê

®Ê Ì} ÀÊvÜi`ÊLÞÊÓ"

®Ê ÈHx®ÎP5 Ó ÎÊ

®Ê ÊvÜi`ÊLÞÊÓ"

(d)

20.57 *À«ÃiÊ >Ê «>ÕÃLiÊ iV>ÃÊ vÀÊ ÌiÊ vÜ}Ê ÌÀ>ÃvÀ>Ì\Ê

(e)

20.62

ÕÌ>À>ìÞìÊ ÃÊ >Ê }iÀV`>Ê >}iÌÊ Ì>ÌÊ ÃÊ ÃiÌiÃÊÕÃi`ÊÌÊÃÌiÀâiÊi`V>ÊiµÕ«iÌÊÌÊÃiÃÌÛiÊÌÊLiÊ i>Ìi`Ê Ê >Ê >ÕÌV>Ûi°Ê Ê `ÞÊ >V`VÊ V`ÌÃ]Ê }ÕÌ>À>ìÞìÊ iÝÃÌÃÊ Ê >Ê VÞVVÊ vÀÊ LiÜÊ À}Ì®°Ê À>ÜÊ >Ê «>ÕÃLiÊ iV>ÃÊvÀÊÌÃÊÌÀ>ÃvÀ>Ì\Ê O

O

O HO

O NH2

HO

O

[H+]

H

O

HO

[H3O+]

H

OH

O

H

EtOH

Glutaraldehyde

20.58 iÛÃiÊ>ÊivwViÌÊÃÞÌiÃÃÊvÀÊÌiÊvÜ}ÊÌÀ>ÃvÀ>ÌÊÀiV>ÊÌ>ÌÊÊ>ìÞìÃÊ>ÀiÊÀiÊÀi>VÌÛiÊÌ>ÊiÌiÃ®\Ê O

O O

H

HO

20.63 *Ài`VÌÊ ÌiÊ >ÀÊ «À`ÕVÌÃ®Ê LÌ>i`Ê ÜiÊ i>VÊ vÊ ÌiÊvÜ}ÊV«Õ`ÃÊÕìÀ}iÃÊÞ`ÀÞÃÃÊÊÌiÊ«ÀiÃiViÊ vÊÎ"+\Ê N

H

N

(a)

20.59 /Ài>ÌiÌÊ vÊ V>ÌiVÊ ÜÌÊ vÀ>ì-

(b)

O

(c)

OH

ÞìÊÊÌiÊ«ÀiÃiViÊvÊ>Ê>V`ÊV>Ì>ÞÃÌÊ«À`ÕViÃÊ >Ê V«Õ`Ê ÜÌÊ iVÕ>ÀÊ vÀÕ>Ê ÇHÈ"Ó°Ê À>ÜÊÌiÊÃÌÀÕVÌÕÀiÊvÊÌÃÊ«À`ÕVÌ°

OCH3

O OH Catechol

klein_c20_001-056v1.4.indd 52

O

O

O

(d)

(e)

30/04/10 16.47

53

Practice Problems

20.64

ìÌvÞÊ >Ê vÊ ÌiÊ «À`ÕVÌÃÊ vÀi`Ê ÜiÊ ÌiÊ V«Õ`ÊLiÜÊÃÊÌÀi>Ìi`ÊÜÌÊ>µÕiÕÃÊ>V`\ O

O

(g)

N O

?

excess H3O+

O

O [H+]

(h)

ethylene glycol (1 equivalent)

H

20.65

À>ÜÊ>Ê«>ÕÃLiÊiV>ÃÊvÀÊi>VÊvÊÌiÊvÜ}Ê ÌÀ>ÃvÀ>ÌÃ\ H3O+

H

H

H2 N

[H+] OH

O

H3O+

N

?

HCN, KCN

(i) O

(b)

?

O

O

N

(a)

OH

(−H2O)

N

N

?

[H+] HS

?

(j) H

OH

(−H2O)

O

O [H+]

H2O

O

(c)

H

HO

20.67 ìÌvÞÊÌiÊÃÌ>ÀÌ}Ê>ÌiÀ>ÃÊiiì`ÊÌÊ>iÊi>VÊvÊ ÌiÊvÜ}Ê>ViÌ>Ã\

OH O

O

O

20.66

*Ài`VÌÊÌiÊ>ÀÊ«À`ÕVÌÃ®ÊvÀÊi>VÊvÊÌiÊvÜ}Ê Ài>VÌÃ\Ê

(a)

(b)

O

CH3 N

(a)

NH2

O

[H+] (−H2O)

?

(c)

OEt

O

O

(d)

O

O

20.68

1Ã}Ê iÌ>Ê >ÃÊ ÞÕÀÊ ÞÊ ÃÕÀViÊ vÊ V>ÀLÊ >ÌÃ]Ê ìÃ}Ê>ÊÃÞÌiÃÃÊvÀÊÌiÊvÜ}ÊV«Õ`\Ê

?

1) PhMgBr

(b)

2) H2O

O

O CH3CO3H

(c)

?

O

20.69

O

[H+]

(e)

*À«ÃiÊ>ÊivwViÌÊÃÞÌiÃÃÊvÀÊi>VÊvÊÌiÊvÜ}Ê ÌÀ>ÃvÀ>ÌÃ\

?

CH3CO3H

(d)

O

N H

O

?

O

(a) O

(−H2O)

O

[H+]

(f)

NH2 (−H2O)

klein_c20_001-056v1.4.indd 53

O

?

O

O

O

(b) O

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54

CHAPTER 20


20.70 /iÊV«Õ`ÊLiÜÊÃÊLiiÛi`ÊÌÊLiÊ>ÊÜ>Ã«Ê«iÀi°Ê À>ÜÊÌiÊ>ÀÊ«À`ÕVÌÊvÀi`ÊÜiÊÌÃÊV«Õ`ÊÃÊ Þ`ÀÞâi`ÊÊ>µÕiÕÃÊ>V`\Ê

20.75

*À«ÃiÊ>ÊivwViÌÊÃÞÌiÃÃÊvÀÊi>VÊvÊÌiÊvÜ}Ê ÌÀ>ÃvÀ>ÌÃ\ O

(a) O O O

Br

(b)

20.71

*À«ÃiÊ>ÊivwViÌÊÃÞÌiÃÃÊvÀÊi>VÊvÊÌiÊvÜ}Ê ÌÀ>ÃvÀ>ÌÃ\

O O

(c)

(a) MeO OMe

OH

Br

CN Br

(b)

(d) O NH

O

(c)

(e)

20.72

À>ÜÊ >Ê «>ÕÃLiÊ iV>ÃÊ vÀÊ ÌiÊ vÜ}Ê ÌÀ>ÃvÀ>Ì\

Br H

O

O

N

NH2 NH2

(f)

[H2SO4] [–H2O]

O

N

N

20.73 7iÊVÞViÝ>iÊÃÊÌÀi>Ìi`ÊÜÌÊÓ"]Ê>ÊiµÕLÀÕÊÃÊiÃÌ>LÃi`ÊLiÌÜiiÊVÞViÝ>iÊ>`ÊÌÃÊÞ`À>Ìi°Ê/ÃÊ iµÕLÀÕÊ}Ài>ÌÞÊv>ÛÀÃÊÌiÊiÌi]Ê>`ÊÞÊÌÀ>ViÊ>ÕÌÃÊ vÊÌiÊÞ`À>ÌiÊV>ÊLiÊìÌiVÌi`°ÊÊVÌÀ>ÃÌ]ÊÜiÊVÞV«À«>iÊÃÊÌÀi>Ìi`ÊÜÌÊÓ"]ÊÌiÊÀiÃÕÌ}ÊÞ`À>ÌiÊ«Ài`>ÌiÃÊ >ÌÊiµÕLÀÕ°Ê-Õ}}iÃÌÊ>ÊiÝ«>>ÌÊvÀÊÌÃÊVÕÀÕÃÊLÃiÀÛ>Ì°Ê

(g)

(h) O

O

20.74

ÃìÀÊ ÌiÊ ÌÀiiÊ VÃÌÌÕÌ>Ê ÃiÀÃÊvÊ`Ý>iÊ {Hn"Ó®\Ê O

O

O

O O O

1,2-dioxane

1,3-dioxane

1,4-dioxane

"iÊvÊÌiÃiÊVÃÌÌÕÌ>ÊÃiÀÃÊÃÊÃÌ>LiÊÕìÀÊL>ÃVÊV`ÌÃÊ>ÃÊÜiÊ>ÃÊ`ÞÊ>V`VÊV`ÌÃÊ>`ÊÃÊÌiÀivÀiÊÕÃi`Ê >ÃÊ>ÊVÊÃÛiÌ°ÊÌiÀÊÃiÀÊÃÊÞÊÃÌ>LiÊÕìÀÊ L>ÃVÊV`ÌÃÊLÕÌÊÕìÀ}iÃÊÞ`ÀÞÃÃÊÕìÀÊ`ÞÊ>V`VÊ V`ÌÃ°Ê/iÊÀi>}ÊÃiÀÊÃÊiÝÌÀiiÞÊÕÃÌ>LiÊ>`Ê «ÌiÌ>ÞÊiÝ«ÃÛi°ÊìÌvÞÊi>VÊÃiÀ]Ê>`ÊiÝ«>ÊÌiÊ «À«iÀÌiÃÊvÊi>VÊV«Õ`°

klein_c20_001-056v1.4.indd 54

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55

Integrated Problems

INTEGRATED PROBLEMS 20.76

«Õ`Ê Ê >ÃÊ iVÕ>ÀÊ vÀÕ>Ê ÇH£{"Ê >`Ê Ài>VÌÃÊÜÌÊÃ`ÕÊLÀÞ`ÀìÊÊiÌ>ÊÌÊvÀÊ>Ê>V°Ê /iÊ £Ê ,Ê Ã«iVÌÀÕÊ vÊ V«Õ`Ê Ê iÝLÌÃÊÞÊÌÜÊÃ}>Ã\Ê>Ê`ÕLiÌÊIÊrÊ£Ó®Ê>`Ê>ÊÃi«ÌiÌÊIÊrÊÓ®°Ê/Ài>Ì}ÊV«Õ`Ê Ê ÜÌÊ £]ÓiÌ>i`ÌÊ - Ó Ó-®Ê vÜi`Ê LÞÊ ,>iÞÊ ViÊ}ÛiÃÊV«Õ`Ê °Ê >®Ê ÜÊ>ÞÊÃ}>ÃÊÜÊ>««i>ÀÊÊÌiÊ£Ê ,ÊÃ«iVÌÀÕÊvÊ V«Õ`Ê ¶ L®Ê ÜÊ>ÞÊÃ}>ÃÊÜÊ>««i>ÀÊÊÌiÊ£Î Ê ,ÊÃ«iVÌÀÕÊvÊ V«Õ`Ê ¶ V®Ê iÃVÀLiÊÜÊÞÕÊVÕ`ÊÕÃiÊ,ÊÃ«iVÌÀÃV«ÞÊÌÊÛiÀvÞÊÌiÊ VÛiÀÃÊvÊV«Õ`ÊÊÌÊV«Õ`Ê °

20.78 ìÌvÞÊ ÌiÊ ÃÌÀÕVÌÕÀiÃÊ vÊ V«Õ`ÃÊ Ê ÌÊ Ê LiÜ]Ê >`Ê ÌiÊ ìÌvÞÊ ÌiÊ Ài>}iÌÃÊ Ì>ÌÊ V>Ê LiÊ ÕÃi`Ê ÌÊ VÛiÀÌÊ VÞViÝiiÊÌÊV«Õ`Ê ÊÊÕÃÌÊiÊÃÌi«° H3O+

H2CrO4

A

B +

[H ] NH2NH2 (–H2O)

D

20.79

KOH / H2O heat

C

ìÌvÞÊÌiÊÃÌÀÕVÌÕÀiÃÊvÊV«Õ`ÃÊÊÌÊ ÊLiÜ\ O

20.77

1)

1Ã}Ê ÌiÊ vÀ>ÌÊ «ÀÛì`Ê LiÜ]Ê ì`ÕViÊ ÌiÊ ÃÌÀÕVÌÕÀiÃÊvÊV«Õ`ÃÊ]Ê ]Ê ]Ê>`Ê \Ê A (C10H12)

Br2 FeBr3

Mg

A

B

H 2) H2O

H

PCC

D 1) EtMgBr

1) O3 2) DMS

(C11H16O)

2) H2O

E

C (C9H10O)

HO

OH

[H+], −H2O

D

20.80 Ê >ìÞìÊ ÜÌÊ iVÕ>ÀÊ vÀÕ>Ê {HÈ"Ê iÝLÌÃÊ >Ê,ÊÃ}>Ê>ÌÊ£Ç£xÊV£° >®Ê *À«ÃiÊÌÜÊ«ÃÃLiÊÃÌÀÕVÌÕÀiÃÊÌ>ÌÊ>ÀiÊVÃÃÌiÌÊÜÌÊ ÌÃÊvÀ>Ì° L®Ê iÃVÀLiÊÜÊÞÕÊVÕ`ÊÕÃiÊ£Î Ê ,ÊÃ«iVÌÀÃV«ÞÊÌÊ ìÌiÀiÊÜVÊvÊÌiÊÌÜÊ«ÃÃLiÊÃÌÀÕVÌÕÀiÃÊÃÊVÀÀiVÌ°Ê

N

B [H+], (CH3)2NH

AlCl3

C

(–H2O)

20.81

Ê V«Õ`Ê ÜÌÊ iVÕ>ÀÊ vÀÕ>Ê H£ä"Ê iÝLÌÃÊ >Ê ÃÌÀ}Ê Ã}>Ê >ÌÊ £ÈnÇÊV£ÊÊÌÃÊ,ÊÃ«iVÌÀÕ°Ê/iÊ £Ê>`Ê £Î Ê ,ÊÃ«iVÌÀ>ÊvÀÊÌÃÊV«Õ`Ê>ÀiÊÃÜÊ LiÜ°ÊìÌvÞÊÌiÊÃÌÀÕVÌÕÀiÊvÊÌÃÊV«Õ`°Ê 3

Proton NMR

2 2

9

8

3

7

6

5

4

3

2

1


Carbon 13 NMR 128.3 132.5 199.9 200

180

127.7

31.3

7.9

136.7 160

140

120

100

80

60

40

20

0


klein_c20_001-056v1.4.indd 55

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CHAPTER 20


20.82 Ê V«Õ`Ê ÜÌÊ iVÕ>ÀÊ vÀÕ>Ê £ÎH£ä"Ê «À`ÕViÃÊ >Ê ÃÌÀ}Ê Ã}>Ê >ÌÊ £ÈÈäÊV£ÊÊÌÃÊ,ÊÃ«iVÌÀÕ°Ê/iÊ £Î Ê ,ÊÃ«iVÌÀÕÊvÀÊÌÃÊV«Õ`ÊÃÊÃÜÊLiÜ°Ê ìÌvÞÊÌiÊÃÌÀÕVÌÕÀiÊvÊÌÃÊV«Õ`°Ê Carbon 13 NMR 130.0 128.3 132.4 137.5

196.7 200

190

180

170

160

150

140

130

120

110

100


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20.83

CHALLENGE PROBLEMS 20.84

À>ÜÊ>Ê«>ÕÃLiÊiV>ÃÊvÀÊi>VÊvÊÌiÊvÜ}ÊÌÀ>ÃvÀ>ÌÃ\ O

N

O

H3

H

H N

O+

H + H3C + CH3

HO

(a) O OCH3 O

(c)

H

H3O+

(b) O H

H

+

NH2NH2

[H2SO4]

O

H

O [H2SO4]

OH

(d)

N N

O

O

OCH3

OH

OCH3

O

O

[H2SO4]

(e) OH

OH

OCH3 [TsOH]

(f) HO

O

O

OH

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O

O [H3O+]

H

H

O

O

Paraformaldehyde

klein_c20_001-056v1.4.indd 56

30/04/10 16.47