I n this chapter, we continue the chemistry of carbonyl compounds. In Chapters16 through 18, we concentrated on the carbonyl group itself and on nucleo-philic additions to the carbonyl carbon to form tetrahedral carbonyl additionintermediates and on products derived from collapse of these intermediates. Inthis chapter, we expand on the chemistry of carbonyl-eontaining compounds andconsider the consequences of the acidity of a-hydrogens and the formation of eno-late anions.

19.1 Formation and Reactions of EnolateAnions: An Overview

On the next page is the resonance-stabilized enolate anion (Section 16.9A)formed by treating acetaldehyde with base. This anion is best represented as ahybrid of two contributing structures. Of these, the structure with the negativecharge on the more electronegative oxygen atom makes the greater contribu-tion to the hybrid. Note that although the majority of the negative charge is onthe carbonyl oxygen, there is still a significant partial negative charge on thealpha carbon.

Crystals of tamoxifen(Problems 19.42, 21.61, and21.62) viewed under polar-izing light. Inset: a modelof tamoxifen.

OUTLINE19.1 Formation and

Reactions of EnolateAnions: An Overview

19.2 Aldol Reaction19.3 Claisen and Dieckmann

Condensations19.4 Claisen and Aldol

Condensations in theBiological World

19.5 Enamines19.6 Acetoacetic Ester

Synthesis19.7 Malonic Ester Synthesis19.8 Conjugate Addition to

a,,B-Unsaturated CarbonylCompounds

19.9 Crossed EnolateReactions Using LDA

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705

An enolate anion

:0II

CH3-C-H + NaOH

:0):?\ IIH - C - C- H ....0I(f------;.~I

H

:0:I

H-C=C-HI

H

The majority of the negativecharge in the hybrid is on oxygen

Enolate anions are important synthetic reagents because they react at carbon tocreate new carbon-carbon bonds in two types of reactions. First, they can functionas nudeophiles in SN2 reactions as shown in this general reaction.

o~ nucleophilic 0

Af ~.. substitution y .. -- R + R' Br: ) + :Br:R" SN2 R R'"R R RAn enolate A 10 haloalkane

anion or sulfonate

Second, they function as nudeophiles in carbonyl addition reactions. Here, weshow nudeophilic addition of an enolate anion to the carbonyl carbon of a ketone.

o :0)Jl~VK T R'/"R'

R

An enolate anion A ketone

nucleophilicaddition

o :0: R'R~'R R

A tetrahedral carbonyladdition intermediate

Enolate anions also add in this manner to the carbonyl groups of aldehydes andesters.

As shown by the charge distribution on the electrostatic potential map, the ma-jority of negative charge of an enolate anion is on the carbonyl oxygen. If reactionwere to occur at the carbonyl oxygen, the product would be a vinyl ether, whereasreaction at the a-carbon leads to alkylation.

An enolate anion

./"'-.... product has aR' 0 / C=C 1TbondsoR~R it is less stable

RA vinyl ether

product has a0 C=O 1Tbondsor /\. it is more stable

R' X "R'R R

Despite this charge distribution, enolate anions react primarily at carbon for tworeasons. First, there is always a counterion such as the Li+ or Na+ ion associatedwith the enolate anion. These counterions are more tightly associated with theoxygen atom than the alpha carbon. As a result, the counterion to some degreeblocks the approaching electrophile, thus reducing the likelihood of a productivecollision with the oxygen. In fact, enolates are thought to exist in solution as largeraggregates containing several counterions associated with several enolate oxygenatoms, and the solvent, effectively amplifying this effect.

706 Chapter 19 Enolate Anions and Enamines

the a,{3-unsaturated carbonyl compounds puts positive charge at the end (in thiscase, the (3-carbon) of the double bond, making it resemble a carbonyl group inits reactivity. Thus nudeophiles can add to this type of double bond, which we call"activated" for this reason.

:0: :0:

_f3~_f3~a a

Although the m.yor fraction of the partial positive charge (blue) ofan a,,B-unsaturatedaldehyde or ketone is on the carbonyl carbon, there is nevertheless a significant partialpositive charge on the beta carbon.

Note that aldol, Claisen, and Dieckmann condensations all give primaryproducts with oxygens in a 1,3 relationship. The Michael reaction with enolateanions gives products with oxygens in a 1,5 relationship. These relationshipsare a consequence of the polarization of the reagents. In aldol, Claisen, andDieckmann condensations, the carbonyl carbon is positive, and the a-position isnegative.

Elpot oja,f3-unsaturated carbonyl.

oAldol reaction A

Donor/a-carbon

New bond0- ~ \\P-+-~

Acceptorcarbonyl carbon

In a Michael reaction, the positive polarization of the carbonyl carbon is transmit-ted two carbons farther by the double bond.

oMichael reaction A

/Donora-carbon

New bond0- 0 \ 0-r-~

Acceptorf3-carbon

The Michael reaction takes place with a wide variety of a, {3-unsaturatedcarbonyl compounds as well as with a, {3-unsaturated nitriles and nitro com-pounds. The most commonly used types of nudeophiles in Michael reactionsare summarized in Table 19.1. The bases most commonly used to generatethe nudeophile are metal alkoxides, pyridine, and piperidine. It is importantto realize that other nudeophiles can undergo similar additions to the betacarbon of unsaturated carbonyl compounds, for example, amines, alcohols,and water.

We can write the following general mechanism for a Michael reaction. Notethat in Step 3 the base, B-, is regenerated, in accord with the experimental obser-vation that a Michael reaction requires only a catalytic amount of base rather thana molar equivalent.

19.8 Conjugate Addition to a.I3-Unsaturated Carbonyl Compounds 735

Q-CHObase~

o

(c)~o

o 0

0-11 0-11(b) ~ j) CCH3 + ~ j) CH(d) PhCHO +~CHO

~CHO(b) ~

(b)~

(b)

o

(a)Ph~

60 0II(c) + HCH

o

(a)~H

V~CHO(a) I~

l-Cyclopentenecarbaldehyde

~Ho

Propose a structural formula for each intermediate compound.

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PROBLEMS

19.23 When treated with base, the following compound undergoes an intramolecular aldolreaction to give a product containing a ring (yield 78%).

Propose a structural formula for this product.

19.24 Cydohexene can be converted to l-cydopentenecarbaldehyde by the following seriesof reactions.

The Aldol Reaction19.18 Draw a structural formula for the product of the aldol reaction of each compound

and for the a,j3-unsaturated aldehyde or ketone formed from dehydration of eachaldol product.

19.22 Show how to prepare each a,j3-unsaturated aldehyde by an aldol reaction followedby dehydration of the aldol product.

19.19 Draw a structural formula for the product of each crossed aldol reaction and forthe compound formed by dehydration of each aldol product.

19.20 When a 1:1 mixture of acetone and 2-butanone is treated with base, six aldol prod-ucts are possible. Draw a structural formula for each product.

19.21 Show how to prepare each a,j3-unsaturated ketone by an aldol reaction followed bydehydration of the aldol product.

Assignable in OWL Problems 753