Jones M., Fleming S.A. Organic Chemistry

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18.16 Additional Problems 929

)

COOH

COOCH

NaN

base

THF

)

1. toluene

benzene, 25 ⬚C

2. (CH

)

COH

1. NaOH/H

55 ⬚C

2. H

O/H

)

HCl/H

55 ⬚C

EtN(i-Pr)

acetone

OEt

–

PROBLEM 18.56 Treatment of phthalimide (1) with bromine

in aqueous sodium hydroxide, followed by acidification with

acetic acid, affords compound 2. A summary of spectral data for

2 follows. Deduce the structure of 2, and then propose a mech-

anism for its formation.

1. Br

/NaOH/H

⌬

2. HOAc

Compound 2

Mass spectrum: m/z  137 (M, 59%), 119 (100%), 93 (79%),

92 (59%)

IR (KBr): 3490 (m), 3380 (m), 3300–2400 (br), 1665 (s),

1245 (s), and 765 (m) cm

1

H NMR (DMSO-d

δ 6.52 (t, J = 8 Hz, 1H)

6.77 (d, J  8 Hz, 1H)

7.23 (t, J  8 Hz, 1H)

7.72 (d, J  8 Hz, 1H)

8.60 (br s, 3H, vanishes with D

C NMR (DMSO-d

): δ 109.5 (s), 114.5 (d), 116.2 (d), 131.1 (d),

133.6 (d), 151.4 (s), 169.5 (s)

⌬

(CH

)

–

PROBLEM 18.57 Sketch the transition state for the Cope

elimination (p. 914) shown below.

(72%)

PROBLEM 18.59 Write a mechanism for the Schmidt reaction

shown below. Hint: The first step is probably the formation of

an acylium ion, . Note also that the reagent is HN

not NH

Note that J

meta

and J

para

were not observed under these conditions.

PROBLEM 18.58

Design an experiment to test the stereo-

chemistry of the Cope elimination. How would one determine

that it is a cis hydrogen that is lost? Assume you can make any

labeled compounds you need.

carboxylic acid (G), propose structures for intermediates A–F.

Mechanisms are not necessary, but may be helpful in

some cases.

930 CHAPTER 18 Derivatives of Carboxylic Acids: Acyl Compounds

PROBLEM 18.61 Reaction of 1,3-diphenylisobenzofuran (1)

and vinylene carbonate (2) gives compound 3. Acid hydrolysis

of 3 affords 4. Propose a structure for 3 and write a mechanism

for its formation and hydrolysis to 4.

xylene

acetic acid

HCl/H

)

2. KCN/H

–

1. Ph

Use Organic Reaction Animations (ORA) to answer the

following questions:

PROBLEM 18.63 Select the reaction “Ester hydrolysis” and

click on the play button. Note the products of the reaction. Is

this reaction catalyzed by base, or does this reaction require a

stoichiometric amount of base?

PROBLEM 18.64 Observe the LUMO animation of the “Ester

hydrolysis.” Describe the LUMO of the starting ester (methyl

methanoate). On what atom is the LUMO density concentrat-

ed? Where else is there LUMO density? Why?

PROBLEM 18.65 Select the reaction “Nitrile hydrolysis” and

watch the LUMO animation. Stop the animation at the first

intermediate. Notice that the first molecular orbital animated is

along the axis. Then the animation shifts to a molecular

orbital that is perpendicular to the axis. These orbitals

are very close in energy. Why does the animation shift to the

second LUMO? Does this mean that a nucleophile (a water

molecule in this case) has more than one option for reaction

with the first intermediate?

PROBLEM 18.62 Write an arrow formalism mechanism for the

following reaction:

PROBLEM 18.60 Provide structures for compounds A–E.

Mechanisms are not necessary.

COOH

ClO)

NO)

)

SOCl

150 ⬚C

1. LiAlH

ether, 35 ⬚C

2. H

(CH

)

benzene 25 ⬚C

30% H

2 h

100 ⬚C

Carbonyl Chemistry 2:

Reactions at the α Position

931

19.1 Preview

19.2 Many Carbonyl Compounds Are

Weak Brønsted Acids

19.3 Racemization of Enols and

Enolates

19.4 Halogenation in the α Position

19.5 Alkylation in the α Position

19.6 Addition of Carbonyl

Compounds to the α Position:

The Aldol Condensation

19.7 Reactions Related to the Aldol

Condensation

19.8 Addition of Acid Derivatives to

the α Position: The Claisen

Condensation

19.9 Variations on the Claisen

Condensation

19.10 Special Topic: Forward and

Reverse Claisen Condensations

in Biology

19.11 Condensation Reactions in

Combination

19.12 Special Topic: Alkylation of

Dithianes

19.13 Special Topic: Amines in

Condensation Reactions, the

Mannich Reaction

19.14 Special Topic: Carbonyl

Compounds without

α Hydrogens

19.15 Special Topic: The Aldol

Condensation in the Real

World, an Introduction to

Modern Synthesis

19.16 Summary

19.17 Additional Problems

MAKING CARBON–CARBON BONDS All plants and animals such as these fish, the

coral, and the diver use enol chemistry in the citric acid cycle as a way to make

carbon–carbon bonds.

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

I want to beg you, as much as I can, dear sir, to be patient towards all that

is unsolved in your heart and try to love the

questions themselves

—RAINER MARIA RILKE,

LETTERS TO A YOUNG POET

19.1 Preview

In this chapter, we explore the chemistry of the α position in the carbonyl com-

pounds we met in Chapters 16–18. Our ability to understand complex reactions

and to construct complicated molecules will greatly increase. There really is lit-

tle fundamentally new chemistry—much of what we find from now on will be

applications of reactions we already know, placed in more complicated settings.

For example, in Chapter 16 we saw a vast array of additions of nucleophiles to

carbon–oxygen double bonds.Here that same reaction appears,when a new nucleo-

phile, an enolate, adds to carbonyl groups to yield products of increased com-

plexity. The reaction is the same old addition, but the context makes it look

complicated (Fig. 19.1).

Rilke (1875–1926) was a German lyric poet much influenced by the French sculptor, Rodin. The italics are

Rilke’s.

A nucleophile

NuNu

–

An enolate

(a new nucleophile)

FIGURE 19.1 Additions of

nucleophiles to carbonyl compounds.

ESSENTIAL SKILLS AND DETAILS

1. Two reactions critical to understanding the material in this chapter are enol formation

in acid and enolate formation in base. Be sure you understand these two basic reactions

completely.

2. The central reactions of this chapter are the aldol and Claisen condensations. Both

acid- and base-catalyzed aldol reactions exist.The Claisen condensation only succeeds

under basic conditions.

3. Although both the acid- and base-catalyzed aldol condensations lead to the same

initial product, a β-hydroxy carbonyl compound, the reaction usually goes further

in acid (sometimes in base) to give an α,β-unsaturated carbonyl compound. All

β-hydroxy carbonyl compounds and all α,β-unsaturated carbonyl compounds can,

in principle, be made through aldol or closely related condensations.This observation

is an important problem-solving tool. Always look for the α,β-unsaturated carbonyl

compound.

19.2 Many Carbonyl Compounds Are Weak Brønsted Acids 933

Watch out for the addition of nucleophiles to α,β-unsaturated carbonyl compounds to

give enolates.This process, called the Michael reaction, is very common in Nature, in

organic synthesis, and in organic chemistry problems.

5. The synthetic procedures known as the acetoacetate synthesis and the malonic ester

synthesis are very useful. Acetoacetate can be used to make ketones and malonic esters

can be used to make carboxylic acids.

6. Alkylation of enolates provides an excellent route for making carbon–carbon bonds.

TABLE 19.1 Some pK

Values

for Simple Ketones and

Aldehydes

Compound

COCH

19.9

COCH

19.3

PhCOCH

18.3

PhCH

COCH

18.3

PhCH

COCH

15.9

Cyclohexanone

(α hydrogen) 18.1

CHO 16.7

(CH

)

CHCHO 15.5

The proton to be lost is underlined when

there is a choice.

–

= 15–20

–

FIGURE 19.2 Carbonyl compounds

bearing hydrogen at the α position

are weak acids, with pK

values in

the high teens.

–

Lose

–

γ Carbon

β Carbon

Butanal

α Carbon

FIGURE 19.3 There are three possible anions that can be formed from butanal by breaking an sp

/1s

carbon–hydrogen bond.

We’ll start with butanal (pK

 16.7) and look at the three possible anions we

might form from it by breaking an sp

/1s carbon–hydrogen bond (Fig. 19.3). First

of all, the dipole in the carbon–oxygen bond will stabilize an adjacent anion more

than a more remote anion. Loss of the α hydrogen will lead to a more stable anion

19.2 Many Carbonyl Compounds Are

Weak Brønsted Acids

One of the remarkable things about carbonyl compounds is that they are not only

electrophiles (see the addition reactions throughout Chapters 16–18 and Fig. 19.1),

but are proton donors as well.

19.2a Enolates of Ketones and Aldehydes The pK

values of typical alde-

hydes and ketones are generally in the high teens (Table 19.1). It is the hydrogen at

the ␣ position, the position adjacent to the carbon–oxygen double bond,that is lost

to a base as a proton (Fig. 19.2). Our first task is to see why these compounds are

weak acids at their α positions, and then to see what new chemistry results from

this acidity.

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

–

This α anion is most

stabilized by the

O dipole

–

FIGURE 19.4 The dipole in the

carbon–oxygen bond will stabilize an

adjacent anion more than a more

distant anion.

sharing the negative charge (Fig. 19.5). It is this stabilization that makes the α posi-

tion, but only the α position, a proton source. The intermediate is called an enolate

anion,because it is part alkene (ene),part alcohol (ol ), and an anion (ate). Please note

again that the enolate anion is not “part of the time an alkoxide” and “part of the

time a carbanion,” but all of the time a single species, the resonance-stabilized enolate.

–

Resonance-stabilized enolate

–

α Carbon

FIGURE 19.5 Loss of the α hydrogen

leads to a resonance-stabilized

enolate anion.

–

protonation

at carbon

(a)

Carbonyl compound

Enol

–

protonation

at oxygen

(b)

O/HO

FIGURE 19.6 Reprotonation of the

enolate can lead either to (a) the

original carbonyl compound or to

(b) the related enol.

than loss of either the β or γ hydrogen (Fig. 19.4). Moreover, one of these anions,

but only one of them, is stabilized by the resonance resulting from the oxygen atom

The enolate anion can reprotonate in two ways. If it reacts with a proton source at

carbon, the original carbonyl compound is regenerated (Fig. 19.6a). If it protonates at

19.2 Many Carbonyl Compounds Are Weak Brønsted Acids 935

oxygen, the neutral enol (p. 448) is formed (Fig. 19.6b). In aqueous base, carbonyl

compounds are in equilibrium with their enol forms.

Watch out! Arrows can emanate from either one of a pair of resonance forms.

One can always write an acceptable arrow formalism from any legitimate resonance

form. You should be able to write an arrow formalism using either resonance form.

WORKED PROBLEM 19.1 Write a mechanism for the base-catalyzed equilibration

of the carbonyl and enol forms of acetone.

ANSWER This problem is not hard, but it needs to be done right now. To be able

to do the more complicated material that will appear later, these simple intercon-

versions must become second nature to you. This problem is drill, but it is never-

theless very important.

Loss of either the α hydrogen from acetone or the hydroxyl hydrogen of the

enol form of acetone leads to the same enolate. Protonation at carbon gives the

ketone; protonation at oxygen gives the enol. It is formation of the enolate that

allows the equilibration to take place.

–

deprotonation

protonation

–

WEB 3D

The orbital picture of Figure 19.7 clearly shows the source of the stabilization

of the enolate. The three 2p orbitals overlap to form an allyl-like system (p. 373).

–

Allyl

–

Enolate

FIGURE 19.7 A comparison of the

enolate and allyl anions.

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

Two of the four π electrons are accommodated in the lowest bonding molecular

orbital, Φ

, and two in the nonbonding orbital, Φ

. The presence of the oxygen

atom makes the enolate less symmetrical than an allyl system formed from three

carbon 2p orbitals. The bonding orbital (Φ

) of the enolate has its highest

electron density on the oxygen atom. The electron density resides mostly on

the carbon of the enolate in the Φ

orbital, the HOMO. The carbon atom is

the usual nucleophilic site because it is the electrons in Φ

that react with an

electrophile.

How important is the electronegative oxygen atom to the stabilization of the eno-

late? The pK

of propene is 43 and that of acetaldehyde is 16.7. There is a 10

dif-

ference in acidity in the two molecules, which can be attributed to the influence of

the oxygen (Fig. 19.8).

Allyl anion

–

= 43

Enolate

–

HC HC

–

= 16.7

FIGURE 19.8 The oxygen atom of

the enolate plays a crucial role in

promoting the acidity at the α

position. Acetaldehyde is much

more acidic than propene.

WORKED PROBLEM 19.2 Propanal can form two enols. What are they?

ANSWER There are stereochemical differences between the two enols. Like any

other unsymmetrical alkene, this enol can exist in Z or E forms.

–

(Z )-Enol (E )-Enol

Enolate formation reveals itself most commonly through the exchange

of α hydrogens in deuterated base. For example, treatment of acetaldehyde

with D

O/DO



results in exchange of all three α hydrogens for deuterium

19.2 Many Carbonyl Compounds Are Weak Brønsted Acids 937

hyde is 16.7 and that of water is 15.7. So, hydroxide is a weaker base than the

enolate anion and at equilibrium only a small amount of the enolate anion will

be present. Enolate formation is endothermic in this case (Fig. 19.10).

–

α Carbon α Carbon

FIGURE 19.9 In D

O/DO



, the three

α hydrogens of acetaldehyde are

exchanged for deuterium.

(Fig. 19.9). In order to understand this exchange process we need to consider the

reversibility of the deprotonation reaction. In hydroxide (here deuteroxide), not

all of the acetaldehyde will be transformed into the enolate.The pK

of acetalde-

Weaker

base

= 16.7

Weaker

acid

Enolate is stronger base

~ 15.7

Stronger

acid

–

HOD

FIGURE 19.10 Enolate formation

is an equilibrium reaction and is

endothermic in the case of

acetaldehyde.

Catalyst regenerated

Enolate

–

repeat two times

Fully exchanged

acetaldehyde

–

O/ O

FIGURE 19.11 The exchange

reaction is a catalytic process, with

deuteroxide ion (



OD) acting as

the catalyst.

These exchange reactions are typically run using catalytic amounts of base, DO



in a large excess of D

O. Under such conditions only a small amount of enolate can

be formed. However, any enolate present will react with the available water, in this

case D

O, to remove a deuteron and produce a molecule of exchanged acetaldehyde

(Fig. 19.11). A new molecule of DO



that can carry the reaction further is also

formed. Eventually all the available α hydrogens will be exchanged for deuterons.

PROBLEM 19.3 Explain why the aldehydic hydrogen in acetaldehyde (the one

bonded to the carbonyl carbon) does not exchange in D

O/DO



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

PROBLEM 19.4 Explain why the bicyclic ketone in the following reaction exchanges

only the two α hydrogens shown (H

) and not the bridgehead hydrogen, which is

also “α.” Hint: Use models and examine the relationship between the bridgehead

carbon–hydrogen bond and the π orbitals of the carbonyl group.

The α hydrogens of acetaldehyde can also be exchanged under acidic conditions

(Fig. 19.12). This result illustrates a general principle: In carbonyl chemistry, there will

usually (not quite always) be an acid-catalyzed version for every base-catalyzed reaction.

–

Bridgehead

hydrogen

WEB 3D

–

FIGURE 19.12 Exchange of the α

hydrogens of acetaldehyde can also

be carried out in deuterated acid,



Resonance-stabilized intermediate

FIGURE 19.13 The first step in the

acid-catalyzed exchange is addition

of a deuteron to the carbonyl oxygen.

A resonance-stabilized cation results.

Acetaldehyde

Enol

Product from

removal of H

from carbon

Protonated (D

)

acetaldehyde

Product from

removal of D

from oxygen

FIGURE 19.14 Removal of a proton

from carbon (green) generates the

neutral enol form. Removal of a

deuteron from oxygen (red)

regenerates starting material.

Now we have created a powerfully acidic species,the protonated carbonyl compound.

Removal of a deuteron from the oxygen simply reverses the reaction to regenerate

acetaldehyde and D



, but deprotonation at the α carbon generates the enol

(Fig. 19.14). Note that the product is not an anionic enolate, but the neutral enol. If this

enol regenerates the carbonyl compound in D



, exchanged acetaldehyde will result.

The mechanisms of the two reactions will be different, however, even though the

end results are similar or even identical.For example, in this acid-catalyzed exchange

reaction there is no base strong enough to remove an α hydrogen from the starting

acetaldehyde. The only reasonable reaction is protonation of the Brønsted basic

oxygen by D



to give a resonance-stabilized cation (Fig. 19.13).