Chapter 22.

Carbonyl Alpha-
Substitution Reactions
羰基 - 取代反應

Based on McMurry’s Organic Chemistry, 9th edition

 Reaction
There are three regions of reactivity in
aldehydes and ketones (2) attack by electrophile
(H+)
O

α C
C
H
R (1) attack by nucleotrophile
(NaBH4, RMgX) (CH 19)
(3) α-carbon with acidic H
, enolate (CH 22,23)

醛、酮的三大類主要化學反應 :
α － H 的反應、親核加成反應、 氧化還原反應
2
 The  Position
 The carbon next to the carbonyl group is designated
as being in the  position
 Electrophilic substitution occurs at this position through
either an nucleophile enol 烯醇 or enolate ion 烯醇陰離子

nucleophile

base

acid

3
 Why this Chapter?

 Many schemes make use of carbonyl 

-substitution reactions.
 These reaction are one the few general
methods for making C-C bonds.

4
22.1 Keto–Enol Tautomerism 酮和烯醇互變異構性

(CH 9.4)
 A carbonyl compound with a hydrogen atom on its  carbon
rapidly equilibrates with its corresponding enol isomer
 Tautomers 互變異構物 : Isomers that interconvert
spontaneously, usually with the change in position of a
hydrogen

5
 Tautomers Are Not Resonance Forms
 Tautomers are constitutional isomers (different compound)
 Have their atoms arranged differently
 Resonance forms are different representations of a single compound
 Differ in the position of the  and nonbonding electrons
 Tautomers interconvert rapidly while ordinary isomers do not
 Most monocarbonyl compounds exist in their keto form at equilibrium

6
 Enols 烯醇
 The enol tautomer is usually present to a very small extent and cannot be
isolated
 However, Enols can serve as a reaction intermediate (active intemediate),

responsible for much of the chemistry of carbonyl compounds, α－ H 的反
應與烯醇有關

keto enol

• Keto-enol tautomerism of carbonyl compounds is

catalyzed by both acids and bases 7
 Acid Catalysis of Enolization

 Acid catalysis
occurs due to
protonation of
carbonyl oxygen
atom
 Base Catalysis of Enolization

 Carbonyl compound
can act as an acid
and donate one of
its a hydrogens to a
sufficiently strong
base, yielding an
enolate ion
 -Hydrogen Are Acidic

•Only the hydrogen on the  position of carbonyl group

are acidic
• , -Hydrogen are not acidic

烯醇陰離子

10
22.2 Reactivity of Enols:  -Substitution Reactions
 Enols behave as nucleophiles and react with
electrophiles
 The double bonds of enols are more electron-rich
and correspondingly more reactive than alkenes

nucleophile
electron-rich

11
 General Mechanism of Addition to Enols

 When an enol reacts

with an electrophile the
intermediate cation
immediately loses the
OH proton to give -
substituted carbonyl
compound

12
 22.3 Alpha Halogenation of Aldehydes and Ketones
 Aldehydes and ketones can be halogenated at their 
positions by reaction with Cl2, Br2, or I2 in acidic solution

•
Ketone halogenation also occurs in biological systems

13
Mechanism of Acid- Rate-Limiting step

Catalyzed Bromination

 -substitution reaction is
proceeded by acid-
catalyzed formation of an
enol intermediate

14
 Evidence for the Rate-Limiting Enol Formation
The rate of halogenation depends only on concentration of ketone and acid and is
independent of the halogen's concentration
If an aldehyde or ketone is treated with D 3O+, the  hydrogens are replaced by deuterium
at the same rate as halogenation

Common intermediate , formation of the enol , is involved in both processes

Reaction rate = k [ketone] [H+]

15
 Elimination Reactions of -Bromoketones

 -Bromo ketones can be dehydrobrominated by

base treatment to yield ,-unsaturated ketones

16
22.4 Alpha Bromination of Carboxylic Acids:
The Hell–Volhard–Zelinskii (HVE) Reaction
 Acids, esters, and amides s do not react with Br2 (unlike aldehydes and
ketones).
 Don’t enolize to a sufficient extent.
 Carboxylic acids are brominated by a mixture of Br2 and PBr3 (Hell–Volhard–
Zelinskii reaction)

17
 Alpha Bromination of Carboxylic Acids
 PBr3 converts –COOH to –COBr which enolizes more
easily than does the acid
 The enol form of the acid bromide reacts with Br2 to
give -bromo acid bromide
 Water is used to hydrolyze the -bromo acid bromide to
yield -bromo acid product
 22.5 Acidity of Alpha Hydrogen Atoms:
Enolate Ion Formation

Carbonyl compounds can act as weak acids (pKa of acetone = 19.3; pKa of ethane = 60)
 Much more acidic than alkane. Less acidic than water (pKa = 15.7) or alcohol (pKa = 16-19). 醛酮－ H 的酸性比烷
强，但比醇、水弱
 The conjugate base of a ketone or aldehyde is an enolate ion - the negative charge is delocalized onto
oxygen
 Strong base is needed for enolate ion formation

Sodium hydride (NaH) or lithium diisopropylamide [LiN(i-C3H7)2] (LDA) 二異丙胺鋰

CH3CH2OH

Ethanol
pKa= 16
19
 Acidity of -Hydrogens
-Hydrogens are more acidic because the enolate
anion is stabilized by
1. delocalization of its negative charge
2. the electron-withdrawing inductive effect of the
adjacent electronegative oxygen
O
CH3 - C-CH2 -H + :A-

:
O O-
:
CH3 - C CH2 CH3 - C= CH2 + H- A
Enolate anion
醛和酮 -H 的酸性可從誘導效應和共振效應兩方面來解釋。
• 從誘導效應看，羰基是一個較強的吸電子基團，使得 -C 上負電荷穩定
，增加了－ C － H 酸性。
• 從共振效應看， -C 上負電荷與羰基的鍵共振，共軛的結構使 -C 上
負 20
電荷的電子向羰基流動，結果使負電荷的電子雲密度減少而穩定。
12

21
 Reagents for Enolate Formation
 Ketones are weaker acids than the OH of alcohols so a a
more powerful base than an alkoxide is needed to form the
enolate
 In the presence of hydroxide or alkoxide ions, only a small
amount of enolate ion is present at equilibrium.
 Sodium hydride (NaH) or lithium diisopropylamide [LiN(i-
C3H7)2] (LDA) 二異丙胺鋰 are strong enough to form the
enolate

O -
O O
H

H + -OCH2CH3 _ + HOCH2CH3
H H

pKa = 19 equilibrium lies

pKa = 16
to the left enolate ion
K< 1
22
 Lithium Diisopropylamide (LDA)

LDA is from butyllithium (BuLi) and diisopropylamine (pKa  36)
 Soluble in organic solvents and effective at low temperature with
many compounds
 Not nucleophilic (steric hindrance base)
 LDA can convert a carbonyl compound completely to its enolate

LDA is a strong base,

but not a strong
nucleophile
立體阻礙性大的強鹼 ，
不能作為親核試劑

K>> 1
100%

pKa = 19
pKa = 36
23
 -Dicarbonyls Are More Acidic
 When a hydrogen atom is flanked by two carbonyl
groups, its acidity is enhanced
 Negative charge of enolate delocalizes over both
carbonyl groups

 - 二羰基化合物由於－ H 的酸性强。在鹼的作用下，容易形成烯醇負離子
，作為親核試劑。 24
Table 22.1: Acidities of Organic Compounds

25
26
 22.6 Reactivity of Enolate Ions
 The carbon atom of an enolate ion is electron-rich and highly reactive toward electrophiles (enols are not as
reactive)
 Enolate ions can be looked at either as vinylic alkoxides (C=C–O-) or as α-keto carbanions (-C–C=O)
 Enolate ions can react with electrophiles

 Reaction on oxygen yields an enol derivative

 Reaction on carbon yields an -substituted carbonyl compound

27
Reactivity of Enolate Ions

electron rich

(H+) (X2, RX)

(Hard and soft acid

and base, HSAB)

28
Base-promoted Halogenation of Ketone and Aldehyde

 Aldehydes and ketones undergo base-promoted

α halogenation
 Weaker bases (NaOH) are effective for
halogenation because it is not necessary to
convert the ketone completely into its enolate ion
 Base-promoted Halogenation of Ketone and Aldehyde
 Multiple Halogenations products
 Difficult to stop at monosubstitution
 The -halo ketone produced is more reactive than ketone.
 Enolate ion stabilized by e--withdrawing halogen.

enolate -bromo ketone

O O O O
Cl Cl Cl Cl Cl Cl
C l2
H Cl Cl Cl Cl
_
OH , H2 O

•
鹼催化鹵化反應，反應一般難以停留在單取代上，而得到多鹵素取 代反應産物。
• 酸催化鹵化反應，控制適當的條件，可以得到單鹵素取代反應産物。

30
 Haloform Reaction 鹵仿反應
 Base-promoted halogenation of aldehydes and
ketones is seldom used
 If excess base and halogen are used, a methyl
ketone 甲基酮 is triply halogenated and then
cleaved by base in the haloform reaction
 A halogen-stabilized carbanion acts as a leaving
group

solid
 Haloform Reaction 鹵仿反應
• Methyl ketones replace all three H’s with halogen.
Trihalomethyl is good leaving group.
• The trihalo ketone then reacts with hydroxide ion to
give carboxylic acid and haloform.

addition elimination

Nucleophilic acyl substitution Substitution

product
trihalomethyl ketone

haloform
solid
32
Haloform Reaction

33
 Iodoform Test 碘仿試驗
•
When the halogen is iodine, the haloform
product (HCI3,iodoform) is a solid that
separates out as a yellow precipitate.
• Iodoform test identify a methyl ketone 甲基酮
• 用 I2 ＋ NaOH （或 NaOI ）作試劑，則得到碘仿的黃色晶體沉
澱，用來鑑別甲羰基結構的醛酮 (-CO-CH3) 。
• 鹵仿反應的另一個應用就是縮短碳鏈，製備少一個碳的羧酸

O O O
-
excess I2 C CI3 OH C OH
C CH3
-
OH
-
CI3
acetophenone O
-
C O HCI3 
苯乙酮

Iodoform,
yellow ppt. 34
 Acid Catalyzed Halogenation of Ketones 補充

 Acid catalyzed halogenation can selectively halogenate only

one or two -H’s depending on how much halogen is used.
 Use acetic acid as solvent and catalyst.

•
鹼催化反應，反應一般難以停留在單取代上，而得到多鹵素取
代反應産物。 35
•
酸催化反應，控制適當的條件，可以得到單鹵素取代反應産物。
* Acid Catalyzed Halogenation of Ketones 補充

• Acid-catalyzed -halogenation

Step 1: acid-catalyzed enolization

OH slow H-O R
R' -C- C-R C C rate-limiting step
R R' R
enol

Step 2: nucleophilic attack of the enol on halogen

36
 22.7 Alkylation of Enolate Ions
 The most important reaction of enolate ions is alkylation 烷基化
 Base-promoted reaction occurs through an enolate ion intermediate
 The reaction usually takes place primarily at the a carbon, forming a new C-C bond.
烯醇陰離子通常發生 C-alkylation, 產生一新 C-C鍵,增長碳鏈

α
α

37
Constraints on Enolate Alkylation

SN2 reaction- the leaving group X can be chloride,
bromide, iodide, or tosylate
 R should be primary or methyl and preferably should
be allylic or benzylic
 Secondary halides react poorly, and tertiary halides
don't react at all because of competing elimination

Leaving group

38
Syntheses Using -Dicarbonyl Compounds
 More acidic than alcohols.
 Easily deprotonated by alkoxide ions and
alkylated or acylated.
 At the end of the synthesis, hydrolysis
removes one of the carboxyl groups.
O O O O
 
CH3 C CH2 C OCH2CH3 CH3CH2O C CH2 C OCH2CH3

acetoacetic ester, pKa =11 malonic ester, pKa = 13

乙醯乙酸乙酯 丙二酸酯
O  O
 
CH3 C CH3 CH3 C OCH2CH3 CH3CH2OH
ethyl acetate ethanol
acetone pKa= 15.9
pKa= 19-20 pKa= 23-24
 - 二羰基化合物由於－ H 的酸性强。在鹼的作用下，容易形成烯醇負離子
，作為親核試劑，在合成上是重要的增長碳鏈的試劑 39
Acidity of -Dicarbonyl Compounds
Malonic Ester Synthesis 丙二酸酯合成法

 For preparing a carboxylic acid from an alkyl

halide while lengthening the carbon chain by
two atoms
丙二酸酯合成法製備乙酸衍生物

Temporary
ester group O O
activate 
－H CH 3 CH 2 O C CH 2 C OCH 2 CH 3

41
 Formation of Enolate and Alkylation
 Malonic ester (diethyl propanedioate) is easily converted
into its enolate ion by reaction with sodium ethoxide
(pKa= 16 ) in ethanol
 The enolate is a good nucleophile that reacts rapidly with
an alkyl halide to give an -substituted malonic ester

丙二酸酯合成法製備乙酸衍生物
Three step in synthesis: (1), (2), (3) step

(1) (2)

S N2

pKa= 13
 Dialkylation

 The product has an acidic -hydrogen, allowing the

alkylation process to be repeated

43
 Hydrolysis and Decarboxylation
 The malonic ester derivative hydrolyzes in acid and loses CO2
(“decarboxylation” 脫羧反應 ) to yield a substituted monoacid

(3)

44
 Decarboxylation of -Ketoacids
 Decarboxylation requires a carbonyl group two atoms
away from the CO2H
 Decarboxylation 脫羧反應 takes place through a cyclic
transition state, initially giving an enol form that
quickly tautomerizes to the product.
tautomerism

 
- diacid heat

-Ketoacids
  heat

45
 Overall Conversion
 The malonic ester synthesis converts an alkyl
halide into a carboxylic acid while lengthening
the carbon chain by two atoms
 A malonic ester synthesis goes through
alkylation of the enolate, hydrolysis, and
decarboxylation. To design a synthesis,
look at the product and see what groups
are added to acetic acid. Use those
groups to alkylate malonic ester, then
hydrolyze and decarboxylate.
 The Malonic Ester Synthesis
 The malonic ester synthesis is useful for the
preparation of mono- and disubstituted acetic acid of
the following types

丙二酸酯合成法製備乙酸衍生物

O
RCH2 COH A monosubstituted
O O acetic acid
EtOCCH2 COEt
Diethyl malonate R O
(Malonic ester) RCHCOH A disubstituted
acetic acid
O
(~ CH3 COH )

48
 Preparation Cycloalkane Carboxylic Acids
 1,4-dibromobutane reacts twice, giving a cyclic product
 Three-, four-, five-, and six-membered rings can be
prepared in this way

49
 Malonic Ester Synthesis
 Consider the synthesis of this target molecule

These two carbons, acetic acid

O
are from malonic ester
CH3 O OH
5-Methoxypentanoic acid
•Synthesis of this target molecule:
Step 1: malonic ester is first converted to its enolate
anion by an alkali metal alkoxide
N a+
COOEt COOEt
+ - + +
Et O N a Et OH
COOEt COOEt
Diethyl malonate Sodium Sodium salt of Ethanol
pK a 13.3 ethoxide diethyl malonate pK a 15.9
(stronger acid) (stronger base) (weaker base) (weaker acid) 50
Step 2: alkylation with alkyl halide
N a+
COOEt S N2
CH3 O Br +
COOEt
COOEt
CH3 O + N a + Br-
COOEt
Step 3: acidification and thermal decarboxylation
of the diester gives the target molecule
COOEt H+,heat, H2O
CH3 O
COOEt

COOH COOH
CH3 O CH3 O + CO 2
COOH 5-methoxypentanoic acid
51
Acetoacetic Ester Synthesis 乙醯乙酸乙酯合成法
 Overall: converts an alkyl halide into a methyl ketone having three more carbons

乙醯乙酸乙酯合成法製備丙酮衍生物

Temporary
ester group
activate
－H

O  O
CH3 C CH2 C OCH2CH3
 Acetoacetic Ester Synthesis

Product is mono- or di-substituted ketone.

乙醯乙酸乙酯合成法製備丙酮衍生物
O
CH3 CCH2 R A monosubstituted
O O acetone
CH3 CCH2 COEt
O
Ethyl acetoacetate
(Acetoacetic ester) CH3 CCHR A disubstituted
acetone
O R'
(~ CH3 CCH3 )

53
 Acetoacetic Ester (Ethyl Acetoacetate)
  carbon is flanked by two carbonyl groups, so it readily
becomes an enolate ion
 This can be alkylated by an alkyl halide and also can react
with a second alkyl halide
乙醯乙酸乙酯合成法製備丙酮衍生物
Three step in synthesis: (1), (2), (3) step
(1) (2)

SN2

pKa= 11

54
Decarboxylation of -Ketoesters

(3)
 Generalization: -Keto Esters
 The sequence of synthesis :
1. enolate ion formation,
2. alkylation,
3. hydrolysis/decarboxylation
is applicable to -keto esters in general
 Cyclic -keto esters give 2-substituted cyclohexanones

56
 An acetoacetic ester synthesis goes
through alkylation of the enolate,
hydrolysis, and decarboxylation. To
design a synthesis, look at the product
and see what groups are added to
acetone. Use those groups to alkylate
acetoacetic ester, then hydrolyze and
decarboxylate.
 Acetoacetic Ester Synthesis
 consider the AAE synthesis of this target molecule,
which is a monosubstituted acetone
these three carbons
are from ethyl the -R group of a
acetoacetate monosubstituted
acetone
O
CH 3 - C-CH 2 - CH 2 - CH=CH 2

5-Hexen-2-one
Step 1: formation of the enolate anion of AAE
O O
(1) N a+
+ Et O - N a+ - + Et O H
C O O Et C O O Et
Ethyl acetoacetate Sodium ethoxide Sodium salt of Ethanol
pK a 11 (stronger base) ethyl acetoacetate pK a 15.9
(stronger acid) (weaker base) (weaker acid) 58
 Step 2: alkylation with allyl bromide

O N a+ O
(2)
- + Br + N aBr
S N2
COOEt COOEt
3-Bromopropene
(Allyl bromide)

Step 3: acidification, and decarboxylation gives the target molecule

O
O H+,heat, H2O 

 COOH
COOEt

O
+ CO2
5-Hexen-2-one
(a monosubstituted acetone) 59
Direct alkylation of ketones, esters, nitriles
 Direcct alkylate at the  carbon of monocarbonyl
compounds, such as ketones, esters, nitriles
 Need a strong, hindered base, LDA (pKa~ 40)

pKa= 19

60
Direct alkylation of ketones, esters, nitriles

pKa= 25

pKa= 25
61
 Biological Alkylations
• Biosynthesis of Indolmycin from Indolylpyruvate

62
 Summary

 The α-substitution reaction of a carbonyl

compound through either an enol or enolate ion
intermediate is one of the four fundamental
reaction types in carbonyl-group chemistry
 Enol tautomers are normally present only to a
small extent at equilibrium and are difficult to
isolate
 React with electrophiles in an α-substitution reaction
 Malonic ester synthesis converts an alkyl halide
into a carboxylic acid
 Summary

 Acetoacetic ester synthesis converts an alkyl

halide into a methyl ketone