Jones M., Fleming S.A. Organic Chemistry

19.2 Many Carbonyl Compounds Are Weak Brønsted Acids 939

C

H

O

..

CH

2

D

C

H

O

..

CD

3

C

H

O

CH

2

D

+

OD

2

..

D

2

O

..

D

3

O

..

deprotonate (D

+

)

on oxygen

protonate (D

+

)

on carbon

repeat

exchange

two times

Once-exchanged

acetaldehyde

Resonance-stabilized

intermediate

C

H

O

CH

2

D

..

+

C

H

O

CH

2

D

..

D

+

D

Tautomers

FIGURE 19.15 Reaction of the enol

with D

3

O



will generate deuterated

acetaldehyde.

WORKED PROBLEM 19.5 Write a mechanism for the equilibration of acetaldehyde

and its enol form in acid. This problem may seem mindless, and it certainly has

little intellectual content at this point, but it is an important drill problem. Doing

this problem is part of “reading organic chemistry with a pencil.”

ANSWER This process must become part of your chemical vocabulary from now

on. First the carbonyl oxygen is protonated and then the resulting cation is depro-

tonated at carbon to give the enol. This process is a keto–enol tautomerization

even though we are dealing with the aldehyde in this particular case.

+

H

3

O

H

3

C

H

..

O

..

H

2

C

H

..

O

H

+

..

H

2

O

H

2

C

H

..

O

H

..

+

OH

2

H

Notice that the steps in the enol acetaldehyde reaction are simply the reverse

of the acetaldehyde enol reaction (Fig. 19.15). Note also that in acid, as in base,

aldehydes and ketones that have α hydrogens are in equilibrium with their enol forms.

We will soon see that although enols are in equilibrium with the related keto forms,

it is usually the keto forms that are favored.This equilibrium is called the keto–enol

tautomerization.The carbonyl compound and its associated enol are called tautomers.

U

Recently, it has become possible to generate the simplest enol, vinyl alcohol

(hydroxyethene),in such a fashion that the acid or base catalysts of the previous reac-

tions are absent (Fig. 19.16). As long as it is protected from acids or bases, the enol

very low

pressure

Vinyl alcohol

(the simplest enol)

800–900 ⬚C

CH

2

CH

2

CH

2

H

OH

H

OH

H

2

C

H

2

C C

CH

2

+

C

WEB 3D

FIGURE 19.16 The parent of all

enols, vinyl alcohol, is stable as long

as it is protected from acid or base

catalysts.

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

CC

H

122.3⬚

119.1⬚

126.2⬚

109.7⬚

O

CC

H

1.08

1.34

1.08

0.96

O

121.8⬚

A

⬚

A

⬚

A

⬚

A

⬚

1.38

A

⬚

FIGURE 19.17 The structure of

vinyl alcohol.

C

R

O

..

CH

2

R

C

CHR

?

OH

..

FIGURE 19.18 Where does the

equilibrium between carbonyl

compound and enol lie? Which

tautomer is more stable?

C

HH

K ~ 6 x 10

–7

Acetaldehyde

O

..

CH

3

C

CH

2

OH

..

C

K ~ 5 x 10

–9

Acetone

O

..

CH

3

H

3

CH

3

C

CH

2

OH

..

FIGURE 19.19 For simple aldehydes

and ketones, it is the carbonyl form

that is favored at equilibrium.

PROBLEM 19.6 It is impossible to protect vinyl alcohol from all acidic and basic

materials, and so it eventually reverts to the carbonyl form, acetaldehyde. Explain

what the unavoidable acid and base catalysts are.

So far we have seen that α hydrogens can be removed from carbonyl compounds,

and that carbonyl compounds are often in equilibrium with their enol forms. The

next question to address is the position of the equilibrium between a carbonyl com-

pound and its tautomeric form, the enol. Where does the equilibrium lie, and how

does it depend on structure (Fig.19.18)? Simple aldehydes and ketones are predom-

is stable and can be isolated and studied. The detailed structure of vinyl alcohol

provides no surprises. Bond lengths and angles are not unusual (Fig. 19.17).

inantly in their carbonyl forms.Figure 19.19 shows the equilibrium constants,K,for

acetone and acetaldehyde.These numbers are typical for other simple aldehydes and

ketones. Neither simple ketones nor simple aldehydes are very highly enolized,

although aldehydes generally exist somewhat more in their enol forms than ketones.

The second alkyl group in a ketone, which is a methyl group in the case of acetone,

19.2 Many Carbonyl Compounds Are Weak Brønsted Acids 941

stabilizes the carbon–oxygen double bond more than it does a carbon–carbon double

bond (Fig. 19.20).

Energy

Enol form

Keto form

Aldehyde

form

C

ΔG' > ΔG

H

OH

CH

2

C

H

O

CH

3

C

H

3

C

O

CH

3

C

H

3

C

OH

CH

2

Stabilization of

C

O by CH

3

Stabilization of

C

C by CH

3

ΔG

ΔG'

FIGURE 19.20 Acetone is less

enolized than acetaldehyde because

of the greater stabilization provided

to the keto form by the second

methyl group.

PROBLEM 19.7 From a bond strength analysis (ΔH),decide whether the keto or enol

form of acetone is more stable. Use the data from Table 8.2 (p. 337).These mol-

ecules both contain sp

2

/sp

3

carbon–carbon bonds. Use a value of 101.4 kcal/mol

for these bonds.

More complex carbonyl compounds can be much more strongly enolized.

β-Dicarbonyl compounds (1,3-dicarbonyl compounds) exist largely in their enol

forms, for example (Fig. 19.21). In the enol forms of these compounds, it is possi-

ble to form an intramolecular hydrogen bond, thus forcing the equilibrium position

away from the diketo forms. There is also conjugation between the carbon–carbon

..

C

K = 3.2

O

..

CH

3

C

O

..

C

HH

H

3

C

O

..

CH

3

C

O

..

C

H

3

C

..

C

K = 0.1

O

..

CH

3

C

O

..

CH

3

OCH

3

O

C

O

..

CH

3

C

O

..

C

H

C

HH

..

WEB 3D

FIGURE 19.21 β-Dicarbonyl

compounds are more enolized than

are monoketones.

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

double bond and the remaining carbonyl group in these enols (Fig. 19.22). We will

revisit the β-dicarbonyl compounds in Section 19.5c.

..

C

O

..

CH

3

C

O

..

H

3

C

O

..

CH

3

C

O

..

C

H

3

C

Hydrogen bond

Conjugated

double bond

Conjugated

double bond

C

HH

FIGURE 19.22 The formation of an

intramolecular hydrogen bond, as

well as conjugation between the

carbon–carbon double bond and the

carbonyl group, contributes to the

increased stability of enols in

β-dicarbonyl compounds.

K > 10

13

2,4-Cyclohexadienone Phenol

O

..

H

OH

..

FIGURE 19.23 The equilibrium

constant for enolization of

cyclohexadienone is estimated

to be greater than 10

13

.

The ultimate stabilized enol is phenol. It is estimated that the equilibrium con-

stant for formation of the aromatic enol form from the nonaromatic ketone is greater

than 10

13

(Fig. 19.23).

19.2b Enolates of Acid Derivatives Hydrogens in the α position of acid

derivatives are acidic for the same reasons that α hydrogens are acidic in aldehydes

and ketones. The conjugate bases are resonance stabilized by the adjacent carbonyl

or nitrile group (Fig. 19.24). The ease of deprotonation at the α position varies,

..

–

B

..

–

B

H

O

..

C

Aldehyde

Enolate

H

2

C

H

O

..

C

H

2

C

H

O

..

C + BH

H

2

C

α

..

–

B

OR

O

..

C

Ester

Enolate

O

..

OR

..

OR

..

C

H

2

C

O

..

C + BH

H

2

C

..

–

B

Nitrile

..

H

2

C

–

..

+ BH

..

CN

..

CN

H

2

CCN

..

–

B

H

2

C

α

..

–

B

H

2

C

α

FIGURE 19.24 A hydrogen at the α

position of an acyl compound or

nitrile is acidic and can be removed

by base to give an enolate, or, in the

case of nitriles, a resonance-stabilized

species much like an enolate.

19.2 Many Carbonyl Compounds Are Weak Brønsted Acids 943

however, depending on the ability of the adjacent carbonyl group to provide stabi-

lization (Table 19.2).

Esters and amides are more stabilized by resonance than are aldehydes and

ketones.Therefore their carbonyl groups have less double-bond character, and they

are weaker acids at the α position. Notice the connection between resonance stabi-

lization and acidity. The more resonance stabilized the starting material, the more

difficult it is to remove a proton from it.

Amides are the most resonance stabilized of acyl compounds and therefore the

weakest acids. In an amide’s polar resonance form it is the relatively electropositive

nitrogen atom that bears the positive charge (Table 19.2; Fig. 19.25).Thus the polar

form is relatively stable. There is no substantial chemistry of amide enolates.

H



C

O

HH

3

C

H



C

O

CH

3

H

3

C

H



C

O

OCH

2

CH

3

H

3

C

H



C

O

NH

2

H

3

C

H



CNH

3

C

TABLE 19.2 e Acidity of Some

Acyl Compounds

a

Compound pK

a

16.7

19.3

24

25

24

Acetone

Ethyl acetate

Acetamide

Acetonitrile

Acetaldehyde

a

e arrow shows the proton lost.

C

O

R

C

O

–

+

R

C

O

OR

R

C

O

–

+

OR

R

C

O

N

R

C

O

–

+

N

R

C

O

–

+

OR

R

C

O

–

+

N

R

Aldehyde/

ketone

Strongest

acid

Weakest

acid

Ester

Amide

FIGURE 19.25 Esters and amides are more stabilized by resonance than aldehydes and

ketones. It is harder to remove an α hydrogen from the R group of these more stable

species.They are weaker acids as shown by their higher pK

a

values.

α C

H

pK

a

~

25

α N

H

pK

a

~ 18

–

(–)

..

H

2

CNH

(harder)

base

(easier)

base

HH

O

..

C

..

H

2

CNH

2

O

..

C

Enolate

Amidate

..

H

3

CNH

O

..

C

FIGURE 19.26 There are two kinds

of α hydrogen in most amides. It is

much easier to remove the proton

attached to nitrogen than the

proton attached to carbon.

PROBLEM 19.8 Explain why α hydrogens on the nitrogen of amides are more

acidic than α hydrogens on carbon (Fig. 19.26).

The problem is that the α hydrogens on the amide nitrogen are more acidic than

the α hydrogens on carbon, and therefore are more easily removed by base to give

anions (Fig. 19.26).

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

PROBLEM SOLVING

In many problems there are clues in the very question itself! Here’s one:

Whenever you see LDA on a problem—every time—think “deprotonation.”

LDA, a strong, very hindered base, is going to remove the most sterically

available hydrogen to give an anion. That anion must be stabilized by resonance,

however.

–

(–)

..

H

3

CN

No

α hydrogens

on nitrogen

CH

3

CH

3

O

..

C

..

H

2

CN

Enolate anion

CH

3

CH

3

O

..

C

LDA = Lithium Diisopropyl Amide

–

..

Li

+

N

FIGURE 19.27 Amides in which there

are no hydrogens attached to

nitrogen can form enolates.

Summary

Ketones and aldehydes bearing α hydrogens are in equilibrium with their enol

forms, although for simple ketones and aldehydes the carbonyl forms are great-

ly favored.This equilibrium is the keto–enol tautomerization.Equilibration with

the enol form can be either acid- or base-catalyzed.The enol form can be favored

in special cases. Esters and other acid derivatives also have acidic α hydrogens.

LDA is a strong base that can be used to drive ketones, aldehydes, or esters com-

pletely to their corresponding enolates.

19.3 Racemization of Enols and Enolates

Now that we know something of the origins of enols and enolates, and we have seen

that enols are in equilibrium with carbonyl compounds, it is time to move on to a

look at reactions of these species.

We saw in the previous sections that as long as an enol or enolate can be formed,

hydrogens in the α position can be exchanged for deuterium through treatment with

deuterated acid or base (Fig. 19.28).Treatment of a simple optically active aldehyde

or ketone with acid or base results in loss of optical activity, racemization, as long as

C

RR

O

CD

2

D

2

O

C

RR

O

CH

2

C

RR

O

CD

2

DO

–

D

2

O

D

3

O

+

FIGURE 19.28 Exchange reactions

of carbonyl compounds bearing α

hydrogens can be either acid or base

catalyzed.

If there are no hydrogens on the nitrogen, it becomes possible to form enolates.

Strong,hindered bases such as lithium diisopropylamide (LDA, Fig. 19.27) are gen-

erally used because they are sufficiently basic and nonnucleophilic.

19.3 Racemization of Enols and Enolates 945

(S)

O

..

CH

3

CH

2

CH

3

HNO

3

37 ⬚C

CH

3

COOH

C

H

(S)

O

..

CH

3

CH

2

CH

3

C

H

(R )

O

..

CH

3

CH

2

CH

3

C

+

H

FIGURE 19.29 Optically active carbonyl compounds are racemized in acid or base, as long as an α hydrogen

is present on the stereogenic carbon.

the stereogenic carbon is in the position α to the carbon–oxygen double bond, and as long

as there is an α hydrogen (Fig. 19.29).

(S)

(R)

O

..

CH

3

CH

2

CH

3

CH

2

CH

3

CH

2

CH

3

C

Ph

C

H

..

H

2

O

Planar, achiral

enol

protonation

..

HO

H

3

O

..

+

H

3

O

..

+

CC CC=

Ph

H

CH

3

CH

2

CH

3

..

HO

C

Ph

CH

3

CH

3

H

OH

2

..

OH

2

..

H

2

O

deprotonation

H

C

+

CH

2

CH

3

..

HO

C

Ph

CH

3

H

2

O

deprotonation

H

C

CH

2

CH

3

C

Ph

CH

3

H

C

CH

2

CH

3

C

Ph

CH

3

H

C

+

O

..

H

3

O

..

+

O

..

+

FIGURE 19.30 Protonation of the planar enol must

result in formation of equal amounts of two

enantiomers. An optically active carbonyl compound is

racemized on enol formation.

(S)

O

..

O

..

CH

3

CH

2

CH

3

CH

2

CH

3

CH

3

C

*

Ph

C

H

2

O / OH

The planar, achiral enolate

..

–

C

O

C

The chiral (S) carbonyl

compound

C

Ph

O

..

CH

2

CH

3

CH

3

C

=

Ph

CH

2

CH

3

CH

3

..

Ph

FIGURE 19.31 Resonance stabilization of the enolate depends on overlap of the 2p orbitals on carbon and oxygen. Maximum

overlap requires planarity, and the planar enolate is necessarily achiral. Racemization has been accomplished at the enolate stage.

Remember that the asterisk tells you that the structure is a single enantiomer.

Once again the mechanism depends on enol formation in acid, or enolate for-

mation in base. In acid, an achiral, planar enol is formed (Fig. 19.30). Re-formation of

the keto form occurs by equal protonation from either side of the enol.In base,removal

of the α hydrogen generates a planar enolate anion that is also achiral (Fig. 19.31).

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

For overlap between the 2p orbitals on carbon and oxygen to be maximized, the eno-

late must be planar, and the planar structure has a nonstereogenic carbon at the α

position. A racemic mixture is formed when the enolate reprotonates (Fig. 19.32).

Addition of a proton must take place with equal probability at the two equivalent

faces (“top” green; “bottom” red) of the planar molecule. Racemization will also

occur with esters and other acid derivatives that have a hydrogen on a stereogenic

α carbon.

(S)

(R)

O

..

C

Ph

C

O

..

C

Ph

C

CH

2

CH

3

O

CC

Ph

H

CH

3

OH

..

H

OH

–

..

protonation

OH

..

+

OH

..

+

Enantiomers!

H

CH

3

CH

2

CH

3

CH

3

CH

2

CH

3

H

FIGURE 19.32 Reprotonation of the

enolate from the two equivalent faces

must give a pair of enantiomers.

19.4 Halogenation in the ␣ Position

We have already learned that halogens (X

2

) are able to react with alkenes, alkynes,

and (with a little help) aromatic rings. Halogenation is also a useful tool for adding

functionality to ketones, aldehydes, carboxylic acids, and esters.

19.4a Halogenation of Ketones and Aldehydes Halogenation at the α

position of ketones and aldehydes is one of the relatively rare examples of a reaction

that takes a different course in its acid- and base-catalyzed versions. As you will see,

though, the two reactions are closely related.

Treatment of a ketone or an aldehyde containing an α hydrogen with halogen

(X

2

,X  I, Cl, or Br) in acid results in the replacement of an α hydrogen with a

halogen atom (Fig. 19.33). For the specific example shown in Figure 19.33, the

C

R

O

..

O

..

CH

3

CH

2

CH

3

CH

3

CH

2

CH

3

acid

X

2

C

RX

CH

2

C

Ph

O

..

O

..

CH

HNO

3

/CH

3

COOH

I

2

C

Ph

C

37 ⬚C

X = I, Br, or Cl

CH

3

I

..

THE GENERAL CASE

A SPECIFIC EXAMPLE

FIGURE 19.33 Treatment of a ketone containing an α hydrogen with iodine, bromine, or chlorine in acid leads to α

halogenation.

19.4 Halogenation in the Position 947

␣

enol is formed first and, like most alkenes, reacts with iodine to displace iodide

and form a resonance-stabilized cation (Fig. 19.34). The iodide ion deprotonates

the intermediate cation generating the α-iodo carbonyl compound, and ending

the reaction.

C

R

OH

..

CH

3

C

R

Enol formation

Iodination

..

CH

3

C

R

O

..

CH

3

C

R

O

..

CH

2

H

OH

2

+

..

OH

..

C

Enol

R

CH

2

C

R

O

H

O

..

H

CH

2

C

R

..

CH

2

+

..

I

..

I

..

I

..

I

..

I

..

I

..

I

..

–

Resonance-stabilized intermediates

WEB 3D

FIGURE 19.34 Under acidic conditions the enol is formed and then reacts with iodine to give the resonance-stabilized cation.

Deprotonation leads to the α-iodide.

Earlier, we saw how deuterium replaces all α hydrogens in acetaldehyde. Why

doesn’t the α-iodo compound react further to add more iodines? The way to answer

a question such as this one is to work through the mechanism of the hypotheti-

cal reaction and see if you can find a point at which it is disfavored. In this case,

that point appears right away. It is enol formation itself that is slowed by the intro-

duction of the first halogen. The introduced iodine inductively withdraws elec-

trons and disfavors the first step in enol formation, protonation of the carbonyl

group (Fig. 19.35).

C

R

H

CH

2

C

R

CH

2

C

R

O

..

O

..

CH

2

+

The dipole in the C

I bond destabilizes

the protonated carbonyl and makes it

difficult to form

O

..

δ

–

δ

+

δ

+

δ

+

H

OH

2

..

I

..

δ

–

I

..

δ

–

I

..

FIGURE 19.35 Protonation of the α-iodoketone is disfavored by the

electron-withdrawing character of the halogen.

Enol halogenation

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

It is not easy to predict the extent of this sequence of enol formations and

halogenations. It is not reasonable to expect you to anticipate that further enol

formation would be sufficiently slowed so as to make the monoiodo compound

the end product. On the other hand, it is not so difficult to understand this effect.

Rationalization of results is much easier than predicting new reactions (or in this

case, no reaction).

Under basic conditions matters are quite different. In fact, it is very difficult

to stop the reaction at the monoiodo stage. The general result is that all α hydro-

gens are replaced with halogen. Note that ketones might have α hydrogens on

either side of the carbonyl. For molecules with three α hydrogens on one side,

methyl ketones, the reaction goes even further in what is called the haloform

reaction. In base, it is not the enol that is formed, but the enolate (Fig. 19.36).

C

R

CH

2

C

R

CH

2

C

R

O

..

O

..

CH

3

base base

C

R

O

..

O

..

C

–

C

R

CH

2

I

..

I

..

I

..

C

The C

I dipole stabilizes

the iodonated enolate

R

C

H

I

..

I

..

O

..

δ

+

δ

–

O

..

FIGURE 19.36 The initially formed α-iodo carbonyl compound is a stronger acid than the carbonyl compound

itself.The introduced iodine makes enolate formation easier.

This anion reacts in S

N

2 fashion with iodine to generate the α-iodo carbonyl

compound. Now, however, the electron-withdrawing inductive effect of iodine

makes enolate formation easier, not harder, as for enols. The negative charge of

the enolate is stabilized by the electron-withdrawing effect. A second and third

displacement reaction on iodine generates the α,α,α-triiodo carbonyl compound

(Fig. 19.37). Similar reactions are known for bromine and chlorine.

I

..

I

..

I

..

C

R

CH

C

R

CH

C

R

O

..

O

..

CH

2

base

C

R

O

..

O

..

–

C

R

CI

2

CHI

2

CI

2

C

R

I

..

I

..

O

..

O

..

base

+

–

I

..

O

..

C

R

CI

3

+

–

I

..

A triiodo

ketone

Enolates

I

..

I

..

WEB 3D

FIGURE 19.37 Sequential enolate formations and iodinations lead to the α,α,α-triiodo carbonyl compound.

Jones M., Fleming S.A. Organic Chemistry

Подождите немного. Документ загружается.