Jones M., Fleming S.A. Organic Chemistry

19.6 Addition of Carbonyl Compounds to the Position: The Aldol Condensation 979

␣

advantage of Michael addition should ultimately win out.This notion suggests that

strong nucleophiles such as hydride (H



) and alkyllithium compounds, which surely

add irreversibly to carbonyls, might be found to give the products of attack at the

carbonyl group, and such is the case (Fig. 19.85).

+

1. LiAlH

4

ether

2. H

2

O

1. CH

3

Li

2. H

2

O

H

O

H

(94%)

(81%)

No addition to

the alkene portion

(2%)

HO

H

CH

3

H

3

C

O

CH

3

H

3

C

OH

CH

3

FIGURE 19.85 Two irreversible addition reactions to the carbonyl group of an

α,β-unsaturated carbonyl compound.

1. ether

–70 ⬚C

2. H

2

O

1. catalytic

CuI, ether

2. H

2

O

(Bu)

2

CuLi+

CH

3

MgBr++

O

CH

3

H

3

C

H

3

C

O

HO

(53%)

CH

3

CH

3

H

3

C

Bu

O

(87%) (4%)

Cuprate additions

FIGURE 19.86 Cuprates and copper-catalyzed Grignard reagents add in Michael

fashion to α,β-unsaturated carbonyl compounds.

A very common reaction in organic synthesis is the addition of a cuprate (p. 798)

to an enone. Although the organometallic cuprate is a strong base and there-

fore might be expected to add to the carbonyl carbon, this reagent is found to

give Michael addition products (Fig. 19.86). Grignard reagents usually give 1,2-

addition with α,β-unsaturated aldehydes, but the outcome of Grignard addition

to α,β-unsaturated ketones is difficult to predict. Steric factors are thought to con-

trol the selectivity of such Grignard additions. However, Grignard reactions that

are copper catalyzed dependably undergo Michael addition to α,β-unsaturated

compounds.

Summary

In this section, we have seen two variations on the aldol theme, the Knoevenagel

condensation and the Michael reaction. In all of these reactions, a single nucleo-

phile adds to a single electrophile. The reactions are fundamentally the same as

the aldol condensation; the variations arise from the structural differences of the

nucleophiles.

19.7 Reactions Related to the Aldol Condensation

In the next few pages, we will use what we know of the simple aldol condensation

to understand some related reactions. We will start with reactions that are very sim-

ilar to simple aldol reactions,and slowly increase the complexity.The connection to the

simple,prototypal acid- and base-catalyzed aldol reactions will always be maintained.

19.7a Intramolecular Aldol Condensations Like most intermolecular reac-

tions, the aldol reaction has an intramolecular version.If a molecule contains both an

enolizable hydrogen and a receptor carbonyl group, an intramolecular addition will

be theoretically possible. Particularly favorable are intramolecular cyclizations that

980 CHAPTER 19 Carbonyl Chemistry 2: Reactions at the Position␣

NHCOOCH

3

O

OR

HO

R = complex series of sugar molecules

A B

C

SSSCH

3

NHCOOCH

3

O

OR

Michael

reaction

DNA in

cancer

cells

HO

S

NHCOOCH

3

O

OR

HO

S

NHCOOCH

3

–

O

OR

..

HOHO

S

NHCOOCH

3

–

O

OR

+

Dead

cancer

cell

S

HH

–

FIGURE 19.87 The operation of the antitumor agent calicheamicin.

The Michael reaction is critical to the operation of the anticancer drug

calicheamicin (Fig. 19.87). In the first step of its operation, the trisulfide bond in

A is broken.The nucleophilic sulfide then adds in Michael fashion to give the eno-

late (B). This addition changes the shape of the molecule, bringing the ends of the

two acetylenes closer together. A cyclization occurs to give a diradical (C), and this

diradical abstracts hydrogen from the cancer cell’s DNA, which ultimately kills the

cell.Calicheamicin depends for its action on the change of shape.Before the Michael

reaction, the ends of the two acetylenes are too far apart to cyclize. They are freed

to do so only when the sulfur adds to the α,β-unsaturated carbonyl.

19.7 Reactions Related to the Aldol Condensation 981

THE GENERAL

BASE-CATALYZED CASE

SPECIFIC BASE- AND

ACID-CATALYZED EXAMPLES

B

BH

+

BH ++

–

CO

R

CCH

3

O

..

O

CCH

2

O

..

O

..

H

2

O

KOH

H

2

O

H

2

SO

4

C

R

C

O

C

CH

2

..

....

..

–

HO

..

....

..

C

OH

R

C

CH

2

..

O

..

C

OH

R

C

CH

R

..

O

..

C

R

C

CH

O

..

O

..

O

..

O

..

O

(83%)

(96%)

..

O

..

CH

3

CH

3

CH

3

H

3

C

–

B

..

–

(–)

–

O

..

WEB 3D

FIGURE 19.88 The mechanism for

intramolecular aldol reactions.

form the relatively strain-free five- and six-membered rings. The products are still

β-hydroxy ketones (or the dehydration products, α,β-unsaturated ketones), and the

mechanism of the reaction remains the same (Fig. 19.88).

PROBLEM 19.28 Write the mechanisms for the acid- and base-catalyzed aldol

condensations of the molecule at the bottom of Figure 19.88.

PROBLEM 19.29 Write the mechanisms for the acid- and base-catalyzed reverse

aldol reaction for 3-hydroxy-3-methylcycloheptanone. Hint: See Problem Solving,

p. 968.

O

H

3

C

OH

3-Hydroxy-3-methylcycloheptanone

982 CHAPTER 19 Carbonyl Chemistry 2: Reactions at the Position␣

FIGURE 19.89 A retrosynthetic

analysis suggests that a crossed aldol

reaction between diethyl ketone and

acetone should give 5-hydroxy-4,5-

dimethyl-3-hexanone.

One possible dehydration:

H

3

C

base

O

CH

3

CH

3

C

OH

D

CH

2

H

3

C

O

CH

3

H

C

CH

3

C

CH

2

CH

3

CH

2

CH

3

–

H

3

C CH

3

C

base

O

H

3

C CH

2

C

O

H

3

C CH

2

C

CH

3

CH

3

O

OH

O

H

3

C

O

..

CH

2

C

D

H

3

C

CH

3

C

CH

3

CH

2

CH

2

CH

3

C

O

–

CH

3

CH

2

CH

2

CH

3

C

base

O

CH

3

CH

2

C

O

CH

3

CH

2

C

A

B

C

CH

3

CH

3

CH

3

CH

2

CH

3

CH

3

CH

2

CH

3

O

OH

H

3

C

CH

3

C

O

CH

3

CH

2

CH

3

CH

O

..

C

CH

3

CH

2

CH

2

CH

3

C

O

CH

FIGURE 19.90 When this synthetic

route is attempted, four β-hydroxy

ketones, A, B, C, and D, are likely

to be produced.

19.7b Crossed Aldol Condensations In practice, not all β-hydroxy ketones

can be formed efficiently by aldol reactions. Suppose we were set the task of syn-

thesizing 5-hydroxy-4,5-dimethyl-3-hexanone (Fig. 19.89). We recognize it as a

potential aldol product through the dissection shown in the figure, which suggests

that an aldol condensation of diethyl ketone and acetone should be a good route to

the molecule. An aldol condensation between two different carbonyl compounds is

called a crossed (or mixed) aldol condensation.

+

..

CH

C C

OOH

CH

3

CH

2

..

C

O

CH

3

CH

2

CH

2

CH

3

..

C

O

H

3

CCH

3

CH

3

5-Hydroxy-4,5-dimethyl-3-hexanone

CH

3

CH

3

However, a little thought about the mechanism reveals potential problems.Two

enolates can be formed and each enolate has two carbonyl groups to attack

(Fig. 19.90). Thus, four products, A, B, C, and D, are possible (more if any of the

β-hydroxy ketones are dehydrated to α,β-unsaturated ketones), and all are likely to

be formed in comparable yield. The enolate of diethyl ketone can add to the car-

bonyl of acetone or diethyl ketone to give A and B. Similarly, the enolate of acetone

gives C and D by reaction with the two carbonyl compounds.

19.7 Reactions Related to the Aldol Condensation 983

There are some simple ways to limit the possibilities in a crossed aldol reaction.

If one partner has no α hydrogens, it can function only as an acceptor, and not as the

nucleophilic enolate partner in the reaction (Fig. 19.91). For example, we might hope

..

H

2

O

..

H

2

O

–

CH

3

C

NaOH

H

2

O

..

H

3

C

C(CH

3

)

3

C(CH

3

)

3

C(CH

3

)

3

C

O

..

H

C

no

α hydrogens

O

..

CH

2

C

..

(CH

3

)

3

C(CH

3

)

3

C

(CH

3

)

3

C

O

–

..

O

–

..

O

CH

2

C

Only enolate possible

C

CH

O

C

O

..

O

..

O

..

HO

..

–

..

OH

H

C

CH

O

C

O

CH

3

CH

3

CH

2

CH

2

CH

2

CH

2

(CH

3

)

3

C

(CH

3

)

3

C

(CH

3

)

3

C

(CH

3

)

3

C

++

FIGURE 19.91 The crossed aldol

reaction of tert-butyl methyl

ketone and benzaldehyde can give

only two products. Benzaldehyde

has no α hydrogens and cannot

form an enolate.

(CH

3

)

3

C CH

3

C +

O

(CH

3

)

3

C CH

(90%)

CH

C

O

H

C

NaOH

CH

3

CH

2

OH

H

2

O

room temperature

32 h

O

FIGURE 19.92 In fact, there is only one major product in the aldol condensation of tert-butyl methyl ketone

and benzaldehyde.

for better luck in a reaction pairing tert-butyl methyl ketone and benzaldehyde. In

principle,however,there are still two possibilities,because the enolate can add to either

the ketone or the aldehyde to generate two different β-hydroxy ketones. When this

reaction is run, however, only one product is formed in substantial yield (Fig. 19.92).

PROBLEM 19.30 There is a reaction between benzaldehyde and hydroxide ion.

What is it, and why does it not interfere with the aldol condensation?

There are several reasons that this crossed aldol is successful. First, the rate of

addition of the enolate to the carbonyl group of benzaldehyde is much greater than

that of addition to tert-butyl methyl ketone because the carbonyl groups of alde-

hydes are more reactive than those of ketones. Second, the equilibrium constant for

the addition to an aldehyde carbonyl is more favorable than that for addition to a

Mixed aldol condensation

ketone carbonyl (Fig. 19.93).Third, because the addition and dehydration steps are

reversible,if elimination occurs, thermodynamics will favor the most stable product,

which in this case is the phenyl-substituted enone.

984 CHAPTER 19 Carbonyl Chemistry 2: Reactions at the Position␣

–

(–)

(CH

3

)

3

C CH

2

C

O

..

(CH

3

)

3

C CH

3

C

O

..

Less reactive

K

more

favorable

H

2

O

H

C

More reactive

O

..

–

..

O

–

..

H

2

O

..

O

(CH

3

)

3

C

CC

O

(CH

3

)

3

C

CC

C(CH

3

)

3

CH

3

O

..

OH

..

OH

H

(CH

3

)

3

C

O

(CH

3

)

3

C

CC

C(CH

3

)

3

CH

3

O

CH

2

H

CH

2

CH

2

CH

2

K

less

favorable

FIGURE 19.93 The carbonyl group of

benzaldehyde is more reactive than

that of tert-butyl methyl ketone, and

equilibrium favors the product for the

reaction with benzaldehyde but not

for the reaction with tert-butyl

methyl ketone.

The crossed aldol reaction is important enough to have been given its own name,

the Claisen–Schmidt condensation (Ludwig Claisen, 1851–1930).

Earlier in this chapter we saw LDA, a base that is effective in producing enolates

without the complications of addition to the carbonyl group. Because LDA is such a

strong base, all the initial carbonyl compound is driven to its enolate (Fig. 19.94).

(–)

–

..

H

2

O

N

–78 ⬚C

Li

+

O

CH

3

..

H

O

..

O

CH

2

..

–

..

O

..

O

..

(65%)

O

2-Hexanone

7-Hydroxy-5-decanone

Cyclohexyl ethyl ketone

Butanal

..

OH

1. LDA

THF

–78 ⬚C

2.

3. H

3

O

+

(79%)

OHO

O

OPh

O

H

OPh

FIGURE 19.94 A crossed

aldol reaction with LDA

as base. Because of its size,

LDA selectively

deprotonates the less

substituted side of the

initial ketone making the

kinetic enolate. Because of

its strength, LDA

completely deprotonates

the carbonyl compound. A

second carbonyl

compound can then be

added and undergo the

aldol reaction.The

alkoxide is protonated at

the end of the reaction

when water is added.

19.8 Addition of Acid Derivatives to the Position: The Claisen Condensation 985

␣

No aldol reaction is possible until the LDA is consumed and a second carbonyl compound

is added.This procedure is a convenient way to do crossed aldol reactions in a controlled

fashion. When there is a choice, LDA forms the more accessible, less substituted enolate.

Lithium diisopropylamide is a large,sterically encumbered base and removes a proton from

the sterically less hindered position to give what is called the kinetic enolate. Notice that

this reaction can be used to generate two new stereocenters adjacent to each other. This

procedure is very useful and has received considerable attention in the past 30 years.

19.8 Addition of Acid Derivatives to the ␣ Position:

The Claisen Condensation

The reaction between enolates and esters is an addition–elimination process in which

the enolate is the nucleophile that replaces the alkoxy group of the ester. This reac-

tion is similar to many you saw in Chapter 18.

19.8a Condensations of Ketone Enolates with Esters Many reactions can

occur between an ester and a ketone under basic conditions. It is unlikely that con-

densation of the ketone enolate with another molecule of ketone will be a problem,

because aldol reactions of ketones are reversible, and usually endothermic. So even

though the product of the aldol reaction will be formed, starting ketone will be

favored. If ketone is drained away through reaction with the ester, the reversibly

formed aldol product merely serves as a storage point for the ketone. The condensa-

tion of an ester enolate with an ester is usually not a problem because the ketone is a

much stronger acid (pK

a

19) than the ester (pK

a

24, see Table 19.2), and forma-

tion of the ketone enolate will be much preferred to formation of the ester enolate. In

the reaction between the ketone enolate and an ester, the enolate adds to the ester

carbonyl, alkoxide is lost, and a β-dicarbonyl compound is formed (Fig. 19.95). If a

''

C C

O

H

3

C

..

C

ether

1. Na

+

–

OEt

2. H

3

O

+

/H

2

O

CH

3

O

H

3

C

..

C

CH

2

..

O

H

3

C

..

C

OCH

2

CH

3

Overall reaction

Mechanism

..

OCH

2

CH

3

..

H

3

C

..

C

O

..

CH

3

CH

2

O

..

CH

3

CH

3

H

3

C

O

..

C C

O

..

CH

3

H

3

C

..

(43%)

+

..

–

(–) (–)

..

–

..

–

..

C

H HH H

C OEt

++H

2

O

..

OEtH

O

..

O

..

H

3

C

CH

3

C

H H

C

O

..

O

..

H

3

C

CH

3

C

H

C

O

..

O

..

H

3

C

1

2

3

4

5

Enolate formation

Addition

Elimination

Removal of

doubly  hydrogen

Acidification

C

H H

C

H

3

O

+

/H

2

O

FIGURE 19.95 The mechanism

of a crossed condensation reaction

between a ketone and an ester.

full equivalent of base is used, the doubly α hydrogen of the β-dicarbonyl compound

is removed to give a nicely resonance-stabilized anion.The reaction is completed by an

acidification step that regenerates the β-dicarbonyl compound in the absence of base.

PROBLEM 19.31 Why are esters less reactive in addition reactions than aldehydes

and ketones?

Frequently, the strong base sodamide (NaNH

2

) or LDA is used in condensing

esters with ketones.These conditions favor removal of the kinetically more accessi-

ble hydrogen when there is a choice of possible enolates (Fig. 19.96).

986 CHAPTER 19 Carbonyl Chemistry 2: Reactions at the Position␣

–

..

H

3

O

1. NaNH

2

2.

3. H

3

O

+

/H

2

O

..

+

H

2

O

Na

+

–

NH

2

ether

addition

enolate

formation

removal of

doubly 

hydrogen

elimination

acidification

C

H

(CH

3

)

2

CHCH

2

(CH

3

)

2

CHCH

2

(CH

3

)

2

CHCH

2

O

..

C

CH

2

O

..

–

..

C

O

..

C

O

..

C

EtO

..

OEt

..

C

O

..

OEt

..

HOEt

..

–

O

..

O

..

O

..

O

..

O

(74%)

(51%)

O

..

O

(–) (–)

..

NH

2

H H

CH

2

CH(CH

3

)

2

CH

2

CH(CH

3

)

2

(CH

3

)

2

CHCH

2

CH

2

CH(CH

3

)

2

(CH

3

)

2

CHCH

2

CH

2

CH(CH

3

)

2

(CH

3

)

2

CHCH

2

CH

2

CH(CH

3

)

2

CH

2

THE GENERAL CASE

A SPECIFIC EXAMPLE

O

OEt

CH

2

C

CH

..

–

CH

2

FIGURE 19.96 Amide bases are often used in crossed aldol condensations of esters and ketones. They lead to formation of

the kinetic enolate through removal of the most accessible hydrogen.

19.8 Addition of Acid Derivatives to the Position: The Claisen Condensation 987

␣

19.8b Ester Enolates React with Esters Esters are approximately seven

pK

a

units less acidic than alcohols. Nevertheless, it is possible for some ester eno-

late to be formed in the presence of a base such as an alkoxide ion, even though the

reaction must be substantially endothermic (Fig. 19.97).

HO

pK

a

~ 17

Enolate

Ester

pK

a

~ 24

–

..

O

RO

..

RO RO

..

C +

CH

2

O

..

C

CH

2

O

..

C

CH

2

H

OC(CH

3

)

3

OC(CH

3

)

3

FIGURE 19.97 Formation of

an enolate anion from an

ester. Because tert-butyl

alcohol has a pK

a

of about 17,

and the ester a pK

a

of about

24, this reaction must be

highly endothermic.

Why doesn’t the alkoxide in Figure 19.97 add to the ester carbonyl group and start

a base-catalyzed transesterification reaction? It does! If one is not careful to use the

same OR group in the alkoxide and the ester, then mixtures of products are found

(Fig. 19.98). As long as the OR groups match, however, the base-catalyzed transes-

terification doesn’t change anything—the product is the same as the starting material.

..

OCH

3

..

OCH

2

CH

3

..

OCH

2

CH

3

–

C

..

H

3

CH

3

C

CH

2

CH

3

O

C

addition

elimination

O

..

OCH

3

–

..

H

3

C OCH

3

+ C

New ester

O

..

–

..

O

..

OCH

3

..

OCH

3

..

OCH

3

–

C

..

H

3

CH

3

C

CH

3

O

C

addition

elimination

of CH

3

O

..

–

..

OCH

3

–

..

H

3

C OCH

3

+ C

No net change!

O

..

–

..

O

..

FIGURE 19.98 A base-catalyzed transesterification reaction will generate a new ester unless

the OR group of the alkoxide is identical to the OR group of the ester.

What can the ester enolate do? It can react with the acidic alcohol to reproton-

ate,regenerating the starting ester.However, it can also react with any other electrophile

in the system. The carbonyl group of the ester is just such a species, and it can react

with the ester enolate in an addition reaction. Although the product is more com-

plex, the addition reaction is no different from any other addition of a nucleophile

to an ester carbonyl (Fig. 19.99).The second step of the reaction is also analogous to

previous reactions. The tetrahedral intermediate can expel the enolate in a simple

reverse of the original addition reaction, or it can lose alkoxide to give a molecule of

β-keto ester.This reaction is called the Claisen condensation after Ludwig Claisen,

Both nucleophiles add

to the Lewis acid—the

ester carbonyl

C

–

Nu

..

–

..

O

RO

..

RO

..

ROH

..

C

CH

3

..

O

OR

..

OR

..

C

H

3

C

..

O

RO

..

C

CH

2

..

O

RO

..

O

..

C

CH

2

CH

3

C

..

O

OR

..

OR

..

O

..

C

H

3

C

O

..

CH

3

..

RO

C

CH

2

CH

3

C

+

–

OR

Acetoacetic ester

O

..

O

..

CH

3

+C

Nu

..

–

OR

..

FIGURE 19.99 In the first step of the reaction between an ester enolate and an ester, the nucleophilic ester enolate adds to the

electrophilic carbonyl carbon of the ester. In the second step the alkoxide ion is lost from the tetrahedral intermediate.

Claisen condensation

988 CHAPTER 19 Carbonyl Chemistry 2: Reactions at the Position␣

who has many reactions named for him. Recall the Claisen–Schmidt condensation,

for example (p. 984). There are more to come.

The Claisen condensation bears the same relationship to the aldol condensation as

the addition of a nucleophile to an ester bears to the addition of a nucleophile to an

aldehyde or ketone. Whereas the tetrahedral alkoxide formed in both aldehyde (or

ketone) reactions can only revert to starting material or protonate, both ester reactions

have the added option of losing the ester alkoxide. What is added in ester chemistry is

the possibility of the elimination phase of the addition–elimination process (Fig.19.100).

Nu

–

..

O

RO

..

RO

..

C

CH

3

O

Nu

..

C

CH

3

O

H

..

CCH

O

CH

3

CH

3

Nu

..

CH

OH

CH

3

Nu

–

..

C

O

CH

3

O

H

2

..

C

CH

3

–

..

O

H

..

C

CH

3

CH

2

CH

2

O

H

..

CH

3

C

..

O

HH

..

C

..

C

-Hydroxy aldehyde

–

..

RO

..

+

–

..

HO

..

+

–

..

HO

..

+

Nu

..

–

addition

Nu

..

–

addition

aldol

elimination

protonation

OH

..

H

2

O

..

H

2

O

..

O

RO

..

C

CH

3

2

–

CH

2

CH

2

–

..

O

RO

..

C

H

3

C

..

O

OR

..

C

..

O

RO

..

C

CH

3

O

..

C

-Keto ester

..

RO

..

+

Claisen elimination

FIGURE 19.100 The aldol condensation is just one example of the addition of a nucleophile to a carbonyl group

followed by protonation. The Claisen condensation is just one example of the addition–elimination sequence

available to esters.

FIGURE 19.101 Thermodynamics

favors the pair of esters (starting

material) in the Claisen condensation,

not the β-keto ester product.The

reaction to form the β-keto ester is

endothermic.

There is an easy way out of this thermodynamic bind, however. In the last step

of the Claisen condensation a molecule of alkoxide catalyst is regenerated.The cat-

alyst is regenerated in the aldol condensation as well, and in the aldol reaction the

catalyst goes on to form another enolate.In the Claisen condensation, however, there

is another, faster reaction possible. The β-keto ester product is by far the strongest

acid in the system as it contains hydrogens that are α to two carbonyl groups. The

anion formed by deprotonation of the β-keto ester is resonance stabilized by both

carbonyl groups (recall Problem 19.25). The pK

a

values of β-keto esters are about

11 (Table 19.3), and therefore these molecules are about 10

13

more acidic than the

starting esters! By far the best reaction for the alkoxide regenerated at the end of

..

O

RO

..

C

CH

3

..

O

RO

..

C

CH

3

–

..

O

RO

..

RO

..

C

CH

2

CH

3

O

..

C

Two esters stabilized

by ester resonance

Only one ester stabilized

by ester resonance

..

–

..

OR

..

HOR

++

As in aldol condensations of ketones, in the Claisen condensation it is the start-

ing materials that are favored thermodynamically (Fig. 19.101). Esters are stabilized

by resonance and there are two ester groups in the starting materials but only one

in the product.The result is a thermodynamic favoring of the two separated esters.

Jones M., Fleming S.A. Organic Chemistry

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