22.

3 a-HALOGENATION OF CARBONYL COMPOUNDS 1057

enol introduces hydrogen from solvent at the a-carbon; this fact accounts for the observed
isotope exchange. This carbon of an enol, like that of an enolate ion, is not asymmetric. The
absence of chirality in the enol accounts for the racemization observed in acid.

PROBLEM
22.11 Give a curved-arrow mechanism for (a) the racemization shown in Eq. 22.19; (b) the deu-
terium exchange shown in Eq. 22.18.

22.3 a-HALOGENATION OF CARBONYL COMPOUNDS

A. Acid-Catalyzed a-Halogenation
This section begins a survey of reactions that involve enols and enolate ions as reactive
intermediates. Halogenation of an aldehyde or ketone in acidic solution usually results in the
replacement of one a-hydrogen by halogen.
O O

Br2 + Br L L C L CH3 Br L L C L CH2 L Br + HBr

S 25 °C
S
HOAc (22.20)

p-bromoacetophenone 1-(4-bromophenyl)-2-bromoethanone
(69–72% yield)

)
Cl

H3O|
A O + Cl2 AO + HCl (22.21)

cyclohexanone 2-chlorocyclohexanone
(61–66% yield)

Enols are reactive intermediates in these reactions.

S " $ $
O HO
H3O|
L C L CH
" ) )
CAC (22.22a)

aldehyde or enol
ketone

Like other “alkenes,” enols react with halogens; but unlike ordinary alkenes, enols add only one
halogen atom. After addition of the first halogen to the double bond, the resulting carbocation
intermediate loses a proton instead of adding the second halogen. (Addition of the second halo-
gen would form a tetrahedral addition intermediate which, in this case, is relatively unstable.)

3 OH 3O L H |O L H O3
1 1 1 1
" $ " " " S "
LCAC L C LL C L 1 3_
L C LL C L 3 Br 1 3
L C L C L + HBr
S 1 1
) |
" " "
1 3
3 Br 1 3
3 Br 1 3
3 Br
1 L Br
3 Br 1 3
1 1
(22.22b)
1058 CHAPTER 22 • THE CHEMISTRY OF ENOLATE IONS, ENOLS, AND a,b-UNSATURATED CARBONYL COMPOUNDS

Acid-catalyzed halogenation provides a particularly instructive case study that shows the
importance of the rate law in determining the mechanism of a reaction. Under the usual reac-
tion conditions, the rate law for acid-catalyzed halogenation is
rate = k[ketone][H3O|] (22.23)

This rate law implies that, even though the reaction is a halogenation, the rate is independent of
the halogen concentration. Thus, halogens cannot be involved in the transition state for the
rate-limiting step of the reaction (Sec. 9.3B). From this observation and others, it was deduced
that enol formation (Eq. 22.22a) is the rate-limiting process in the acid-catalyzed halogenation
of aldehydes and ketones. Because the halogen is not involved in enol formation, it does not ap-
pear in the rate law at the concentrations of halogen ordinarily used.

S " " $ S "

O OH O
O|
L C L CH L CAC L C L C L Br + HBr
H3

)
Br2
" "
(fast)
(22.24)

rate-limiting
process

Enol formation is described in this equation as the rate-limiting process. This process consists of two
elementary steps, as shown in Eq. 22.17b. The rate-limiting step of acid-catalyzed enolization is the
second step, removal of the a-proton. The same step, therefore, is also the rate-limiting step of a-
halogenation.

Because only one halogen is introduced at a given a-carbon in acidic solution, it follows
that introduction of a second halogen is much slower than introduction of the first. The slower
halogenation is probably a consequence of the stability of the carbocation intermediate that is
formed by reaction of the halogen with the halogenated enol. This carbocation is destabilized
by the electron-attracting polar effect of two halogens:

1 L Br
3 Br 1 3
1 1
3 Br 3
1
$ $ $| "
HO HO
1 3_
C L C L Br 3 Br
1
) ) ) "
CAC (22.25)

Br
carbocation intermediate
halogenated enol is destabilized by the polar effect
of two bromines

If the rate-limiting transition state resembles this carbocation, then the transition state should
have very high energy and the rate should be small.

PROBLEMS
22.12 (a) Sketch a reaction-free energy diagram for acid-catalyzed enol formation using the mech-
anism in Eq. 22.17b as your guide. Assume that the second step, proton removal from the
a-carbon, is rate-limiting.
(b) Incorporating the results of part (a), sketch a reaction-free energy diagram for the acid-
catalyzed halogenation of an aldehyde or ketone.
22.13 Explain why:
(a) the rate of iodination of optically active 1-phenyl-2-methyl-1-butanone in acetic
acid/HNO3 is identical to its rate of racemization under the same conditions.
(b) the rates of bromination and iodination of acetophenone are identical at a given acid con-
centration.
 22.3 a-HALOGENATION OF CARBONYL COMPOUNDS 1059

B. Halogenation of Aldehydes and Ketones in Base:

The Haloform Reaction
Halogenation of aldehydes and ketones with a-hydrogens also occurs in base. In this reaction,
all a-hydrogens are substituted by halogen.
a-hydrogens
O O

3NaOH + (CH3)3C L C L CH3 + 3Br2 (CH3)3C L C L CBr3 + 3Na|Br_ + 3H2O

S NaOH, 0 °C
S
(22.26a)
H2O/dioxane

no a-hydrogens

When the aldehyde or ketone starting material is either acetaldehyde or a methyl ketone (as in
Eq. 22.26a), the product of halogenation is a trihalo carbonyl compound, which is not stable
under the reaction conditions. This compound reacts further to give, after acidification of the re-

trihalomethane—that is, a compound of the form HCX3, where X = halogen.)

action mixture, a carboxylic acid and a haloform. (Recall from Sec. 8.1A that a haloform is a

O O
_OH O|
(CH3)3C L C L CBr3 (CH3)3C L C L OH + HCBr3
S H3
S
(22.26b)
(71–74% yield)
bromoform

The conversion of acetaldehyde or a methyl ketone into a carboxylic acid and a haloform by
halogen in base, followed by acidification, as exemplified by Eq. 22.26a–b, is called the halo-
form reaction. Notice that, in a haloform reaction, a carbon–carbon bond is broken.
The mechanism of the haloform reaction involves the formation of an enolate ion as a re-
active intermediate.
O O
S _
R L C L CH3 + OH_ R L C L CH
2 2 + H2O
S
(22.27a)
enolate ion

The enolate ion reacts as a nucleophile with halogen to give an a-halo carbonyl compound.
O O
S _
R L C L CH 1 L Br
2 2 + 3 Br 1 3 1 3 + 3 Br
R L C L CH2Br 1 3_
1 1 S 1 1
(22.27b)

However, halogenation does not stop here, because the enolate ion of the a-halo ketone is
formed even more rapidly than the enolate ion of the starting ketone. The reason is that the
polar effect of the halogen stabilizes the enolate ion and, by Hammond’s postulate, the transi-
tion state for enolate-ion formation. Consequently, a second bromination occurs.

S " S "
O H O H O
Br L Br
R L C L C L Br R L C L C L Br R L C L CHBr2 + Br_
S

" 2
_
(22.27c)

+ H2O 3
1
1H
_3 O
H
1

The dihalo carbonyl compound brominates again even more rapidly. (Why?)
O O

R L C L CHBr2 R L C L CBr3 + Br_ + H2O

S Br2
S
OH_ (22.27d)
1060 CHAPTER 22 • THE CHEMISTRY OF ENOLATE IONS, ENOLS, AND a,b-UNSATURATED CARBONYL COMPOUNDS

A carbon–carbon bond is broken when the trihalo carbonyl compound undergoes a nucle-
ophilic acyl substitution reaction.

3O3 3O2 3_ 3O 3 3O 3
"
R L C L CBr3 R L C L CBr3 R LCLO 2 L H + _3 CBr3 R LCLO 2 3_ + H L CBr3
S S S

" 2 2
_3 OH
2 3 OH
a trihalomethyl

2 2
anion (22.27e)

The leaving group in this reaction is a trihalomethyl anion. Usually, carbanions are too basic
to serve as leaving groups; but trihalomethyl anions are much less basic than ordinary carban-
ions. (Why?) However, the basicity of trihalomethyl anions, although low enough for them to
act as leaving groups, is high enough for them to react irreversibly with the carboxylic acid by-
product, as shown in the last part of Eq. 22.27e. This acid–base reaction drives the overall
haloform reaction to completion. (This situation is analogous to saponification, which is also
driven to completion by ionization of the carboxylic acid product; Sec. 21.7A.) The carboxylic
acid itself can be isolated by acidifying the reaction mixture, as shown in Eq. 22.26b.
Occasionally, the haloform reaction can be used to prepare carboxylic acids from readily
available methyl ketones. This reaction can also be used as a qualitative test for methyl
ketones, called the iodoform test. In the iodoform test, a compound of unknown structure is
mixed with alkaline I2. A yellow precipitate of iodoform (HCI3) is taken as evidence for a
methyl ketone (or acetaldehyde, the “methyl aldehyde”). The iodoform test is specific for
methyl ketones because only by replacement of three hydrogens with halogen does the carbon
become a good enough leaving group for the nucleophilic acyl substitution reaction shown in
Eq. 22.27e to occur.
Alcohols of the form shown in Eq. 22.28 also give a positive iodoform test because they are
oxidized to methyl ketones (or to acetaldehyde, in the case of ethanol) by the basic iodine so-
lution.

"
OH O

R L CH L CH3 R L C L CH3
I2, base
S
(22.28)
undergoes the
iodoform reaction

PROBLEMS
22.14 Give the products expected (if any) when each of the following compounds reacts with Br2
in NaOH.
# %CH3
"
(a) O (b) O (c) OH
" Ph L CH L CH3
C S
%C %

22.15 Give the structure of a compound C6H10O2 that gives succinic acid and iodoform on treat-
ment with a solution of I2 in aqueous NaOH, followed by acidification.

C. a-Bromination of Carboxylic Acids

Carboxylic acids can be brominated at their a-carbons. A bromine is substituted for an a-
hydrogen when a carboxylic acid is treated with Br2 and a catalytic amount of red phosphorus
 22.3 a-HALOGENATION OF CARBONYL COMPOUNDS 1061

or PBr3. (The actual catalyst is PBr3; phosphorus can be used because it reacts with Br2 to give
PBr3.)

CH3CH2CH2CH2CH2CO2H + Br2 CH3CH2CH2CH2CHCO2H + HBr

P or PBr3
"
(22.29)
hexanoic acid Br
2-bromohexanoic acid
(83–89% yield)

This reaction, called the Hell–Volhard–Zelinsky reaction after its discoverers, is sometimes
nicknamed the HVZ reaction.
The first stage in the mechanism of the HVZ reaction is the conversion of a small amount
of the carboxylic acid into the acid bromide by the catalyst PBr3 (Sec. 20.9A).

" "
O O

3 L CH L C L OH + PBr3 3 L CH L C L Br + P(OH)3
S S
(22.30a)
carboxylic acid an acid
with a-hydrogens bromide

From this point, the mechanism closely resembles that for the acid-catalyzed bromination of
ketones (Eqs. 22.22a and 22.22b). The enol of the acid bromide is the species that actually
brominates.

" " " " S

O OH O
L CH L C L Br L C A C L Br L C L C L Br + HBr
S Br2
"
(22.30b)
acid bromide enol form
Br
a-bromo acid
bromide

When a small amount of PBr3 catalyst is used, the a-bromo acid bromide reacts with the car-
boxylic acid to form more acid bromide, which is then brominated as shown in Eq. 22.30b.

" " S " " S

O O O O
L CH L C L OH + L C L C L Br L CH L C L Br + L C L C L OH
S S

" "
(22.31)
enters the bromination
Br sequence at Eq. 22.30b Br
a-bromo acid

Thus, when a catalytic amount of PBr3 is used, the reaction product is the a-bromo acid.
If one full equivalent of PBr3 is used, the a-bromo acid bromide is the reaction product; this
can be used in many of the reactions of acid halides discussed in Sec. 21.8A. For example, the
reaction mixture can be treated with an alcohol to give an a-bromo ester:

2 L Ph
(CH3)3COH
O Br2
O O

CH3CH2 C L OH CH3 CH C L Br CH3 CHC L OC(CH3)3 + (CH3)2NH Br

(CH3)2N
S P (1 equiv.)` S (a base)
S

" "
propanoic acid Br Br Ph
tert-butyl 2-bromopropanoate
(22.32)
1062 CHAPTER 22 • THE CHEMISTRY OF ENOLATE IONS, ENOLS, AND a,b-UNSATURATED CARBONYL COMPOUNDS

D. Reactions of a-Halo Carbonyl Compounds

Most a-halo carbonyl compounds are very reactive in SN2 reactions and can be used to pre-
pare other a-substituted carbonyl compounds.

"
O CH3 O

2 L CH2 L C L Ph
(CH3)2S2 3 3 Br H3C L S L CH2 L C L Ph 3 Br
2 3_
S 25 °C, 30 min
S

2 2 2
(22.33)
|
acetone/H2O

(85% yield)

In the case of a-halo ketones, nucleophiles used in these reactions must not be too basic. For
example, dimethyl sulfide, used in Eq. 22.33, is a very weak base but a fairly good
nucleophile. (Stronger bases promote enolate-ion formation; and the enolate ions of a-halo
ketones undergo other reactions.) More basic nucleophiles can be used with a-halo acids be-
cause, under basic conditions, a-halo acids are ionized to form their carboxylate conjugate-
base anions; a second ionization to give an enolate ion, which would introduce a second neg-
ative charge into the molecule, does not occur.

) )
Cl 1) NaOH Cl
(2 equiv.)
2) H3O|
Cl L L OH + Cl L CH2 L CO2H Cl L L O L CH2 L CO2H + Cl_ (22.34)
chloroacetic acid
2,4-dichlorophenol 2,4-dichlorophenoxyacetic acid
(ionized by NaOH) (2,4-D, a selective herbicide;
87% yield)

H3O|
3 N ' C3 _ + Cl L CH2 L CO_
2 3 N ' C L CH2 L CO2H + Cl _ (22.35)
chloroacetate cyanoacetic acid
anion (77–80% yield)

The following comparison gives a quantitative measure of the SN2 reactivity of a-halo car-
bonyl compounds:
O O

Cl L CH2 L C L CH3 + KI I L CH2 L C L CH3 + KCl

S S relative rate:
acetone 35,000 (22.36a)

Cl L CH2CH2CH3 + KI acetone I L CH2CH2CH3 + KCl 1 (22.36b)

The explanation for the enhanced reactivity is probably similar to that for the increased reac-
tivity of allylic alkyl halides in SN2 displacements (Fig. 17.2, p. 803).
In contrast, a-halo carbonyl compounds react so slowly by the SN1 mechanism that this re-
action is not useful.

" $| S 1
CH3 O H3C O

H3C L C LL C L CH3 C L C L CH3 + 3 Cl1 3_

S
)
very slow
"
(22.37)

3 Cl1 3 H3C

In fact, reactions that require the formation of carbocations alpha to carbonyl groups gener-
ally do not occur. Although it might seem that an a-carbonyl carbocation should be reso-
nance-stabilized, its resonance structure is not important. (Why?)
 22.4 ALDOL ADDITION AND ALDOL CONDENSATION 1063

3O3 3 O 3|
$| S $ "
H3C H3C
C L C L CH3 C A C L CH3
) )
(22.38)
H3C H3C
not an important structure

In addition, the carbocation is destabilized by its unfavorable electrostatic interaction with the
bond dipole of the carbonyl group—that is, with the partial positive charge on the carbonyl
carbon atom.

3O3
d–

S
C
|
d+
(CH3)2C CH3

destabilizing
electrostatic interaction

PROBLEMS
22.16 What product is formed when
(a) phenylacetic acid is treated first with Br2 and one equivalent of PBr3, then with a large
excess of ethanol?
(b) propionic acid is treated first with Br2 and one equivalent of PBr3, then with a large ex-
cess of ammonia?
22.17 Give the structure of the product expected in each of the following reactions.
(a) O

CH3CH2CCH2Br +
S

2
1-bromo-2-butanone N
pyridine

(b) O O

BrCH2C L Ph + CH3C L O_ Na|

S S

a-bromoacetophenone sodium acetate

22.18 Give a curved-arrow mechanism for the reaction in Eq. 22.34. Your mechanism should show
why two equivalents of NaOH must be used.

22.4 ALDOL ADDITION AND ALDOL CONDENSATION

A. Base-Catalyzed Aldol Reactions

In aqueous base, acetaldehyde undergoes a reaction called the aldol addition.

"
O OH O

2 H3C L CH H3C L CH L CH2 L CH

S NaOH
S
H2O (22.39)
acetaldehyde 3-hydroxybutanal
(aldol)
(50% yield)