Carbonyl Alpha Chem Libretexts

22: CARBONYL ALPHA-
SUBSTITUTION
REACTIONS
22.0: CHAPTER OBJECTIVES AND INTRODUCTION TO CARBONYL ALPHA-
SUBSTITUTION REACTIONS
 OBJECTIVES
After completing this section, you should be able to write a general mechanism for an alpha‑substitution reaction of a carbonyl
compound.
 KEY TERMS
Make certain that you can define, and use in context, the key terms below.
alpha (α) position
alpha‑substitution reaction
 STUDY NOTES
An “alpha‑substitution reaction” of a carbonyl compound is a reaction in which one of the hydrogen atoms on the carbon adjacent to
the carbonyl group is substituted by some other atom or group. Attack by the electrophile (E+) can occur on the enol or enolate
intermediate.
There are four common types of reactions involving compounds containing a carbonyl bond. The first two, nucleophilic addition and
nucleophilic acyl substitution, have been discussed in previous chapters.
Nucleophilic addition occurs due to the electrophilic nature of the carbonyl carbon. After addition of a nucleophile, the carbonyl becomes a
tetrahedral alkoxide intermediate which is usually protonated to become an -OH group.
H
O 1) Nu:- O
2) H3O+
Nu
Nucleophilic Addition to a Carbonyl
Nucleophilic acyl substitution is similar in that a tetrahedral alkoxide intermediate is formed after nucleophilic addition to the carbonyl.
However, subsequent removal of the leaving group allows for the C=O (carbonyl) bond to reform. Overall, there is a substitution of the
leaving group with the incoming nucleophile.
O O
+ Nu + L
R L R Nu
L = Leaving Group
Nucleophilic Acyl Substitution Involving a Carbonyl
22.0.1 https://chem.libretexts.org/@go/page/36420
REACTIONS AT THE ALPHA CARBON
The remaining common carbonyl reaction types are α-substitutions and carbonyl condensations. Both utilize the special properties of
carbons directly adjacent to carbonyls which are called α-carbons. These reactions, which can be regarded as the backbone of much
synthetic organic chemistry, usually result in the replacement of a hydrogen attached to an α-carbon with some type of electrophile. These
reactions involve two new nucleophilic species called the enol and the enolate.
This chapter will focus on α-substitutions reactions. Although there are many carbonyl containing functional groups, the initial investigation
in this chapter will focus on α-substitutions reactions using aldehydes and ketones. Important examples considered in this chapter include α-
halogenation and α-alkylation.
a -Substitution Reactions
O
X
ion
genat
alo
O a -H
H
a -A
lky
lati
on
Aldehyde / Ketone O
R
22.0: Chapter Objectives and Introduction to Carbonyl Alpha-Substitution Reactions is shared under a CC BY-SA 4.0 license and was authored, remixed,
and/or curated by Steven Farmer & Dietmar Kennepohl.
22.1: KETO-ENOL TAUTOMERISM
 OBJECTIVES
After completing this section, you should be able to
1. write an equation to illustrate keto‑enol tautomerism.
2. write a detailed mechanism for acid‑catalyzed keto‑enol tautomerism.
3. write a detailed mechanism for base‑catalyzed keto‑enol tautomerism.
4. draw the structure of the enol form of a given carbonyl compound.
 KEY TERMS
enol
keto
tautomerism
tautomers
enolate ion
 STUDY NOTES
Keto‑enol tautomerism was first introduced in Section 9.4, in the discussion of the hydration of alkynes. The subject was raised again in
the chapter entitled A Preview of Carbonyl Compounds, during the brief overview of the alpha‑substitution reactions of carbonyl
compounds. You may wish to review these sections before proceeding.
Often, the position of a carbon atom near a carbonyl group is designated using Greek letters. The atom adjacent to the carbonyl is alpha, the
next removed is beta and so on. The carbon in the carbonyl group is used as reference point and is not assigned a Greek letter. Likewise,
hydrogens bare the same Greek letter as the carbon atoms to which they are attached. α-Hydrogens are bonded to α-carbons and β-
hydrogens are bonded to β-carbons etc.
d b
O
g a
The presence of α-hydrogens in a molecule provides the possibility of certain chemical reactions, which will be discussed in this chapter
and in Chapter 23. Because of this, the ability to identify α-hydrogens is an important skill. As shown below, pentanal has two α-
hydrogens. Note that aldehyde hydrogens are not given a Greek letter, they are simply referred to as an aldehyde hydrogen.
Not an
a -Hydrogen
O
H2
H3C C C
C C H
H2 H2
a -Hydrogens
α-hydrogens, which are attached to a carbon directly adjacent to a carbonyl group, display unusual acidity. This is almost exclusively due to
the resonance stabilization of the carbanion conjugate base, called an enolate, as illustrated in the diagram below. The effect of the the
stabilizing C=O is seen when comparing the pKa for the α-hydrogens of aldehydes (~16-18), ketones (~19-21), and esters (~23-25) to that
of a typical alkyl C-H bond (~40-50).
O O O
H Base
C C C
C C C
Enolate Ion
 EXAMPLE 22.1.1
Indicate any α-hydrogens contained in the following molecules:

O O
O
O
Solution
O O
H H
H H
H
No a -Hydrogens
O O
H
H H H
H H H
H H H
KETO-ENOL TAUTOMERIZATION
Because of the acidity of α-hydrogens, many carbonyl containing compounds undergo a proton-transfer equilibrium called tautomerism.
Tautomers are readily interconverted constitutional isomers, usually distinguished by a different location for an atom or a group. Because
tautomers involve the rearrangement of atoms, they are distinctly different than resonance forms, which only differ in the position of bonds
and lone pair electrons. This discussion focuses on carbonyl groups with α-hydrogens, which undergo keto-enol tautomerism. Keto implies
that the tautomer contains a carbonyl bond while enol implies the presence of a double bond and a hydroxyl group.
The keto-enol tautomerization equilibrium is dependent on stabilization factors of both the keto tautomer and the enol tautomer. For simple
carbonyl compounds under normal conditions, the equilibrium usually strongly favors the keto tautomer (acetone, for example, is >99.999%
keto tautomer). The keto tautomer is preferred because it is usually more stable than the enol tautomer by about 45–60 kJ/mol, which is
mainly due to the C=O double bond (-749 kJ/mol) being stronger than the C=C double bond (-611 kJ/mol). Because ketones have two alky
groups donating electron density into the carbonyl carbon, they tend to be more stable and therefore less apt to form the enol tautomer than
aldehydes. For example, propanal is 1000 times more likely to be in its enol tautomer than acetone. With carboxylic acid derivatives, the
leaving group tends to stabilize the carbonyl through electron donation which makes the formation of the enol tautomer much less likely. In
general, ketones are over 100,000,000 times more likely to be in an enol tautomer form than esters.
O H
H O
C H C H
H 3C C H 3C C
H H
Acetone Propen-2-ol
Keto Tautomer Enol Tautomer
(>99.999%) (~1.7 x 10-7%)
H
O O
H3C C H3C C
C H C H
H H
H
Propanal Propen-1-ol
(~1 x 10-4%)
H
O O
H C CH3 H C CH3
C O C O
H H
H
Ethyl Ethanoate 1-Methoxyethen-1-ol
(<1 x 10-15%)
Aldehydes and symmetrical ketones typically only have one possible enol tautomer while asymmetrical ketones can have two or more. The
preferred enol tautomer formed can be often be predicted by considering effects which can stabilize alkenes, such as conjugation and alkyl
group substitution. The asymmetrical ketone, 2-methylcyclohexanone has two possible enol tautomers. Of the two tautomers, 2-methyl-1-
cyclohexen-1-ol, is the more stable and therefore preferred due to the presence of an additional alkyl substituent. Likewise, 1-phenyl-1-
propen-2-ol is the more stable enol tautomer of 1-phenyl-2-propanone due to conjugation with the phenyl ring.
OH O OH
Double Bond has 2-Methylcyclohexanone Double Bond has

more alkyl substituents fewer alkyl substituents
(More Stable Enol Tautomer)
OH O OH
Double Bond is conjugated 1-Phenyl-2-propanone Double Bond is not

with the phenyl ring conjugated with the
(More Stable Enol Tautomer) phenyl ring
1,3-DICARBONYLS
In certain cases additional stabilizing effects allow the enol tautomer to be preferred in the tautomerization equilibrium. In particular, the 1,3
arrangement of two carbonyl groups can work synergistically to stabilize the enol tautomer, increasing the amount present at equilibrium.
The diketone, 2,4-pentanedione, is in its enol form 85% of the time under normal conditions. The positioning of the carbonyl groups allows
for the formation of a stabilizing intramolecular hydrogen bond between the hydroxyl group of the enol and the carbonyl oxygen. The
alkene group of the enol tautomer is also conjugated with the carbonyl double bond which provides additional stabilization. Both of these
stabilizing effects are not possible in the keto tautomer.
Hydrogen
Bonding
H
O O O O
C C C C
H3 C C CH3 H3 C C CH3
H2
H
2,4-Pentanedione 4-Hydroxy-3-
(15%) penten-2-one (85%)
H H
O O O O
C C C C
H 3C C CH3 H 3C C CH3
H H
Conjugated
Double Bond
Another effect which can stabile an enol tautomer is aromaticity. When considering the molecule 2,4-cyclohexadienone, the enol tautomer is
the aromatic molecule phenol. The stabilization gained by forming an aromatic ring is sufficient to make phenol the exclusive tautomer
present in the equilibrium.
O OH
H
H H
2,4-Cyclohexandienone Phenol
(Keto form, Non-aromatic) (Enol form,aromatic)
 EXAMPLE 22.1.1
Please all of the possible enol tautomers for the following compounds. If more than one is possible then indicate which is the most
stable and why.
a)
b)
c)
Solution
a)
b)
H H H
O O O O O O
O O O
This enol tautomer is the most stable due

to hydrogen bonding, conjugation, and the
ketone being in the enol form rather than
the ester.
c)
MECHANISM FOR CATALYZED KETO-ENOL TAUTOMERIZATION

The enol tautomer has valuable nucleophilic characteristics. In neutral media, tautomerization is slow but it can be speed up by catalysis
with acids or bases. Both pathways involve two separate proton transfer steps. Because enols are a key reactive intermediate, these
mechanistic steps will be used repeatedly in later reactions. The following mechanistic steps represent the continuous interconversion
between the keto and enol tautomers.
Overall Process
H
O
O
C H
C C
C
ACIDIC CONDITIONS
Keto Tautomer → Enol Tautomer
In the first step, the carbonyl oxygen is protonated by an acid to form an intermediate oxonium ion. A base removes an α-hydrogen during
the second step forming a double bond by an E2 type reaction. This causes the pi electrons of the protonated carbonyl to move to the oxygen
to form the hydroxyl group of the enol product and regenerating the acid catalyst.
1) Protonation of the carbonyl to form an oxonium ion
H
O H B O
+ B
C H C H
C C
Keto Tautomer Oxonium Ion

2) Deprotonation of an α-hydrogen to form an enol
H
H
O O
B + H B
C H C
C C
Enol Tautomer
Enol Tautomer → Keto Tautomer

First, one of the lone pairs of electrons on the enol oxygen moves to form a pi bond with the adjacent carbon to create a oxonium ion. This
also causes the pi bond electrons from the enol double bond to attack the electrophilic H+ provided by acid catalyst forming a C-H bond in
the α-position. This produced oxonium ion intermediate is subsequently deprotonated to form the neutral ketone and regenerate the acid
catalyst.
1) Protonation at the α-carbon
H
H
O H B O
+ B
C C H
C C
Enol Tautomer Oxonium Ion

2) Deprotonation
H B O
O
C H + H B
C H C
C
Keto Tautomer
UNDER BASIC CONDITIONS

Keto Tautomer → Enol Tautomer
In the first step, a base removes an α-hydrogen from a carbonyl containing compound to form an alkene by an E2 like process. The causes
the pi electrons of the carbonyl bond to move onto the carbonyl oxygen to form an enolate anion. The oxygen of the enolate anion is
protonated in the second step to create a neutral enol and regenerate the base catalyst.
1) Deprotonation of a α-hydrogen to form an enolate ion
O O
B + H B
C H C
C C
Keto Tautomer Enolate
2) Protonation the enolate ion to form an enol
H
O H B O
C + B
C C
C
Enol Tautomer
l
Enol Tautomer → Keto Tautomer
The mechanistic return to the keto tautomer begins with deprotonation of the hydroxyl hydrogen to produce an enolate ion. Then lone pair
electrons from the enolate anion attack an electrophilic H+ through conjugation with the double bond. This simultaneously forms the
carbonyl double bond, adds an alpha hydrogen, and regenerates the base catalyst.
1) Deprotonation of the enol hydrogen
H B
O O
+ H B
C C
C C
Enolate
2) Protonation of the α-carbon
O H B O
C C H + B
C C
Keto Tautomer
BIOLOGICAL ENOL FORMING REACTIONS

One very important family of isomerase enzymes catalyzes the shifting of a carbonyl group in sugar molecules using a process called an
carbonyl isomerization. Carbonyl isomerization often involves converting between a ketose and an aldose. (recall that the terms ketose and
aldose refer to sugar molecules containing ketone and aldehyde groups, respectively).
O H H O H
C O
C O R C
R C
H H H
Ketose Aldose
Carbonyl Isomerization
Mechanism
Carbonyl isomerization can only occur if there is an OH group adjacent to the carbonyl. Isomerization forms an ene-diol intermediate which
has both OH hydrogens available to be removed to form a carbonyl. If the hydrogen from the original OH group is removed a new carbonyl
bond is formed.
B H B
H
O H O H H O H
C O C O
C O R C
R C R C
H H H
B B H H
Ketose Ene-diol Aldose
Carbonyl isomerization is involved in the metabolism of carbohydrates (starches and sugars) to their eventual conversion to CO2 and H2O.
First, starches are broken down into glucose in the digestive tract. In the cells, the first step of the glycolysis pathway involves an enzyme
converting glucose to glucose-6-phosphate. This is followed by the enzyme-catalyzed tautomerization of glucose-6-phosphate (an aldose) to
fructose-6-phosphate (a ketose) through an enediol intermediate. Notice how the carbonyl has moved from the 1-carbon (terminal) to the 2-
carbon.
OH OH O OH OH OH
OP OH OH OP OH O
Glucose-6-phosphate Fructose-6-phosphate
EXERCISES
1) Draw the enol forms of the following molecules
a. 4-methylcyclohexanone
b. Ethyl thioactetate
c. Methyl acetate
d. Butanal
e. 1-phenyl-2-butanone
2) How many α-hydrogens do each of the molecules from the previous question have? Label them.
3) Draw all of the mono-enol forms for the following molecule. Which ones are most stable? Why?
O
O
4) Under normal conditions cyclohexanone exists in the enol tautomer in a much higher percentage than acetone. Explain.
5) The 1,3-dicarbonyl shown below is only as acidic as acetone and does not form a detectable amount of the enol tautomer. Please explain.
6) For the following compound please identify the most acidic hydrogen atom. Remember that for an enolate conjugate base to be stabilized
through conjugation, the lone pair electrons need to be contained in a p orbital which is parallel to the p orbitals which form the C=O pi
bond.
7) Nonconjugated ß, gamma-unsaturated ketones, such as 2-hexen-4-one, can be converted to their α, ß-unsaturated isomers by treatment
with an acid catalyst. Please propose a mechanism for this isomerization.
O O
b H 3O + b
a g a g
SOLUTIONS
1)
(a)
(b)
(c)
(d)
(e)
2)
(a)
(b)
(c)
(d)
(e)
3)
Additional resonance forms stabilizes this enol.
This enol has fewer resonance forms and is therefore less stable.
4) The enol tautomer of cyclohexanone has more alky substituents than the enol tautomer of acetone. This makes the double bond of the
enol double bond of cyclohexanone more stable and easier to form.
OH
OH
Enol of Cyclohexane Enol of Acetone

5) In many situations, the enol tautomer fo the a 1,3-dicarbonyl is preferred in the tautomerization equilibrium due to stabilizing effects
created by the second carbonyl. However, in this case the alpha hydrogen used to create the enol tautomer is attached to a brigehead carbon
of a bicyclic ring system. The positioning of the enol and the carbonyl prevents the formation of a stabilizing intramolecular hydrogen bond
between the hydroxyl group of the enol and the carbonyl oxygen. Also, the inherent steric restrictions of a bicyclic ring system prevents the
formation of a double bond using a bridgehead carbon. Instead, an enol tautomer of the molecule would be expected to form outside the 1,3-
dicarbonyl. This enol lacks the stabilizing effects typical of a 1,3-dicarbonyl, so it is not preferred in the tautomerization equilibrium.
H H
´
O OH
HO O O O
Not Formed
6) The presence of two methyl groups on one of the α-carbons of the carbonyl means that the two hydrogens on the other α-carbon may be
deprotonated to form an enolate. When the indicated axial hydrogen is deprotonated the p-orbital formed is parallel with the carbonyl p-
orbitals and can participate in overlap. If the equatorial hydrogen were to be deprotonated, the p-orbital formed would be perpendicular with
the carbonyl p-orbitals and prevented from participating in overlap.
Most Acidic Hydrogen
CH3 CH3
H CH3 CH3
-H
O H O
H
p-orbital overlap
CH3 CH3
H CH3 H CH3
-H
O O
H
No p-orbital overlap
7)
H
H OH2 O
O OH
+ H OH2
H Enol
OH2
H OH2 O
H OH2 O
OH
+ H OH2
H H
22.1: Keto-Enol Tautomerism is shared under a CC BY-SA 4.0 license and was authored, remixed, and/or curated by Steven Farmer, Dietmar Kennepohl,
Layne Morsch, & Layne Morsch.
22.2: REACTIVITY OF ENOLS- THE MECHANISM OF ALPHA-SUBSTITUTION
REACTIONS
 OBJECTIVES
After completing this section, you should be able to write a detailed mechanism for an acid‑catalyzed, alpha‑substitution reaction of a
carbonyl compound.
HOW ENOLS REACT

The oxygen of an enol can donate electron density into its double bond making it electron-rich and more reactive than typical alkenes.
H
H
O O
C C
C C
Enol Tautomer
Nucleophilic
Carbanion
As seen in the electrostatic potential map for propen-2-ol (CH3COH=CH2), the enol tautomer of acetone, shows an increased electron
density on the α-carbon (yellow) especially when compared to the -CH3 carbon (blue/green). One of the resonance forms of an enol places a
lone pair of electrons and a negative charge on the α-carbon forming a carbanion nucleophile. Enols react with electrophiles in a similar
fashion as other carbanion nucleophiles, such as Grignard reagents.
H
O
H
H C H
C C
H H
Electron Rich
Carbon
MECHANISM OF ALPHA SUBSTITUTION REACTIONS USING AN ENOL

The mechanism begins with the acid-catalyzed tautomerization to form an enol via the mechanism discussed in Section 22.1. Lone pair
electrons on the enol oxygen move to become a C=O pi bond thus creating a positively charged oxonium ion. This also causes electrons
from the C=C enol pi bond to attack an electrophile forming a C-E sigma bond. These two electron movements in concert represent the enol
acting as a nucleophile. In the last step, an H+ is removed from the carbonyl oxygen, regenerating the acid catalyst, and forming an α-
substituted carbonyl .
1) Acid catalyzed tautomerization to form an enol
H
O
H3O+ O
C H
C C
Slow C
2) The nucleophilic enol attacks the electrophile
H H
O E O
C E
C C
C
Oxonium
Ion
3) Deprotonation of the carbonyl to produce an α-substituted product
B
H O
O E +
C H B
C E C
C
a -Substitution
STEREOCHEMICAL IMPLICATION OF ENOL FORMATION

During an acid-catalyzed enol formation, an α-hydrogen is removed to form a sp2-hybridized, trigonal planar C=C bond which removes any
chiral information from the original alpha carbon. Because the enol alkene is planar the incoming electrophile can attack from either the top
or the bottom of the molecule. If the α-carbon of the starting material has a defined stereochemistry or if a new stereocenter if formed during
the reaction, the product will typically be a racemic mixture of enantiomers at the site of substitution.
One of the easiest ways of displaying this process is through acid-catalyzed racemization. If a carbonyl compound has an α-carbon with a
defined stereochemisty and an α-hydrogen, a racemic mixture can be formed simply through tautomerization. The addition of acid promotes
the formation of the enol tautomer which removes the chiral information of the α-carbon. The enol then attacks an H+ electrophile to reform
the keto tautomer which then contains a racemic mixture of enantiomers.
O
C * H
CH3 C
Stereocenter is R Ph CH3
H Stereocenter is R
O +
H3 O + O H
C * H +
CH3 C C CH3
CH3 C
Ph CH3
Ph O
Starting Material Chiral Information C * CH3
CH3 C
is Lost
Ph H
Stereocenter is S
Example of Acid-Catalyzed Racemization
EXERCISES
1) Which of the following optically active ketones would undergo acid-catalyzed racemization? Explain.
O O O
H2 H2 H2
CH3 C C CH3 C C CH3 C C
C C C C C C
H2 H2 H2 H2
H CH3 CH3H2C CH3
A B C
2) When cis-Decalone is treated with an acid it becomes trans-Decalone almost exclusively becomes trans-Decalone. Explain.
O O
H H
H 3O +
H H
Cis-Decalone Trans-Decalone
SOLUTIONS
1) Molecule A would not because the alpha carbon is not a stereocenter. Molecule B would because the alpha carbon is a stereocenter and
contains a hydrogen. Molecule C would not because it does not contain an alpha hydrogen.
2) This change involves a process call epimerization. Epimers as diastereomers which differ at only one chiral carbon. Epimerization is a
process where only one of multiple chiral carbons is changed. In this example, the stereocenter in questions is a chiral carbon. The addition
of an acid promotes this carbon becoming part of an enol thereby losing its chiral information. When the enol tautomer converts back the
ketone tautomer the a mixture of both cis and trans epimers should form. However, as discussed in a previous section, we know that the
trans isomer of the decalin ring system is more stable than the cis. Because there is a defined difference in stability, the trans isomer of
decalone is preferred.
22.2: Reactivity of Enols- The Mechanism of Alpha-Substitution Reactions is shared under a CC BY-SA 4.0 license and was authored, remixed, and/or
curated by Steven Farmer, Dietmar Kennepohl, Layne Morsch, & Layne Morsch.
22.3: ALPHA HALOGENATION OF ALDEHYDES AND KETONES
 OBJECTIVES
1. write an equation to illustrate the alpha halogenation of aldehydes and ketones.
2. identify the product formed from the alpha halogenation of a given aldehyde or ketone.
3. identify the carbonyl compound, the reagents, or both, needed to prepare a given α‑halogenated aldehyde or ketone.
4. illustrate the importance of the alpha halogenation of carbonyl compounds as an intermediate step in the synthesis of
α,β‑unsaturated aldehydes and ketones.
5. write a detailed mechanism for the acid‑catalyzed halogenation of a ketone.
6. describe the evidence provided by kinetic experiments supporting the suggestion that the acid‑catalyzed, alpha halogenation of
ketones proceeds via the rate‑determining formation of an enol.
 STUDY NOTES
Note: α‑bromo ketones are a good starting material to generate α,β‑unsaturated ketones by dehydrobromination.
Aldehydes and ketones can substitute an α-hydrogen for a halogen atom in the presence of an acid. This reaction takes place using acid
catalyzed tautomerization to form a nucleophilic enol, which then reacts with an electrophilic halogen (Cl2, Br2 or I2). Because an enol
intermediate is used, a racemic mixture of products can be produced. A particularly useful variation of this reaction uses bromine in an
acetic acid solvent. The α-bromo substituted product can then be readily transformed into an α, β‑unsaturated carbonyl through reaction
with pyridine and heat.
GENERAL REACTION (Α SUBSTITUTION)

O O
X2
C H C X + HX
C Acetic Acid C
X = Br, Cl, I
Aldehyde a -Halogen
or
Ketone
 EXAMPLE 22.3.1
ACID CATALYZED MECHANISM

The mechanism begins with protonation of the carbonyl oxygen followed by removal of an α-hydrogen to form the enol. Lone pair electrons
from the enol oxygen move to form a carbonyl while the pi electrons from the double bond attack the halogen forming an oxonium ion
intermediate with a C-X sigma bond in the α-position. Deprotonation of the oxonium ion intermediate provides the α-halogen substituted
product and regenerates the acid catalyst.
1) Protonation by the acid catalyst
H Base H
O
O
C H + Base
C H
C
C
Aldehyde or Ketone Oxonium
2) Removal of an α-hydrogen to form the enol. This step is slow and represent the rate determine step.
H
H
O Base Slow O
H + H Base
C C
C C
Enol
3) Nucleophilic attack on the halogen

H
X X H
O O
X + X
C C
C C
4) Deprotonation
X H O
O
C X + HX
C X C
C
a -Halo Product
EXPERIMENTAL EVIDENCE OF THE ENOL INTERMEDIATE
This reaction was the focus of one of the first mechanistic investigations in organic chemistry. In the early 1900's chemist Arthur Lapworth
showed that the rates of chlorination, bromination, and iodination of acetone were all the same. Also, it was shown that the rates for all three
halogenation reactions were first-order with respect to acetone and the acid catalyst but independent of the halogen concentration (overall
second-order for the mechanism). The rate law expression for the α-halogenation of a ketone can be given by:
rate = k [ketone] [H+]
This implies that the halogen participates in the mechanism through a fast step which occurs after the rate-determining step. These
observations led Lapworth to theorize that the rate-determining step of the mechanism involves converting acetone to a more reactive form.
The fact that the substitution occurs on the α-carbon led Lapworth to propose that the more reactive form was an enol tautomer of acetone.
Synthetic Uses for α-Halogenated Carbonyls
The product of an α-bromination can be converted to an α, β‑unsaturated carbonyl by reaction with pyridine and heat which causes the
elimination of H and Br. This reaction takes place by an E2 elimination mechanism and creates a C=C double bond which is conjugated
with the carbonyl. In order to promote an E2 reaction, a sterically hindered base, pyridine, is often used.
An example of this reaction involves the α-bromination of 2-methylcyclopentanone to form 2-bromo-2-methylcyclopentanone. Because
enol tautomers prefer to form on the more substituted α-carbon, α-bromination also occurs on the more substituted α-carbon. Although the
enol intermediate causes a racemic mixture of the α-brominated compound to form, it is irrelevant because the chiral carbon is subsequently
converted to an achiral alkene. Subsequent reaction with pyridine and heat forms the α,β‑unsaturated ketone, 2-methyl-2-cyclopentenone.
DEUTERIUM EXCHANGE
More evidence for the formation of an enol intermediate was provided using a reaction called deuterium exchange. Deuterium is an isotope
of hydrogen which contains one proton and one neutron. Due to the acidic nature of α-hydrogens, they can be exchanged with deuterium by
reaction with the isotopic form of water, D2O (deuterium oxide-heavy water). The process is accelerated by addition of the deuterium
equivalent of a strong acid, such as deuterium chloride (DCl), which quickly reacts with D2O to form D3O+, the deuterium equivalent of
hydronium (H3O+). If an excess of D2O is used, the exchange process continues to the end result of all α-hydrogens present in a given
compound being replaced with deuterium. Deuterium exchange is an effective method for introducing an isotopic label into a molecule.
Also, deuterium does not appear in 1H NMR, so deuterium exchange can help determine peak assignments.
GENERAL REACTION (DEUTERIUM EXCHANGE)
O O
H D 3O + D
C C
C C
 EXAMPLE 22.3.2
O D 3O + O
H 3C CH3 D 3C CD3
Acetone Hexadeuteroacetone
Acetone-d6
Deuterated Acetone
MECHANISM IN ACIDIC CONDITIONS

The mechanism for deuterium exchange is virtually the same as keto-enol tautomerism under acidic conditions, as shown in Section 22.2.
The only difference is that when the keto tautomer is reformed a deuterium is placed in the α-position.
1) Formation of an enol
D
O +
D 3O O
C H
C Slow C
C
Aldehyde Enol
or
Ketone
2) α-Deuteration
D
D O
D D D
O Fast O
C C D + D2 O
C C
3) De-deuteration to form the keto tautomer
O D O
D D O Fast
D C D + D 3O +
C C
C
 EXAMPLE 22.3.1
A simple method for determining the number of α-hydrogen in a compound is through reaction of D3O+. The reaction product is then
isolated and its molecular weight is determined by mass spectrometry. For example, if cyclopentanone is reacted with D3O+, the
isolated product has a molecular weight of 88 g/mol. Please explain how this method works and how many α-hydrogens
cyclopentanone is predicted to have.
Solution
During acid catalyzed deuterium exchange each α-hydrogen in the compound is replaced with a deuterium. For each proton (AW = 1)
replaced with a deuterium (AW = 2) the molecular weight of the compound is increased by one. Since cyclopentanone has a molecular
weight of 84 g/mol and the isolated product has a molecular weight of 88 g/mol it can be predicted that cyclopentanone has four α-
hydrogens.
Kinetic investigations into the mechanism of this reaction provided further evidence for the formation of a reactive enol intermediate. It was
shown that the rate of deuterium exchange was the same as the rate of halogenation for ketones. This implies that both reactions have a
common intermediate involved in the rate determining step of their mechanism, an enol.
O
C Br
C
+
Br
O OH
H3O+ or D3O+
C H C Fast
C C
Slow
Enol D+ O
C D
C
EXERCISES
1) Please draw the products of the following reactions
O
I2
A
H3O +
2)Draw out the mechanism for the following reaction.

O O
H D3O+ H
H D
3) How might you form 2-hepten-4-one from 4-heptanone?

4) Show the products of the following reactions:
O
H2 D 2O
C C A
H 3C C H -
OD
H2
O
H C H D 2O
H C C CH3 B
H 2C CH2 D 3O +
C
H2
5) The following compound was reacted with D3O+. The only signals that could be found in the 1H NMR spectrum of the product were at
3.9 ppm (3H) and 6.6-6.9 ppm (4H). Please explain the results of the NMR.
H H
H2 O
O C
H 3C CH3
H H
SOLUTIONS
1)
O
I
A
2)
D
D
O D D
D D D O
O O O O D D
D
H H H
H H
D
O O O
D D
D D
D3 O + + H H
3) [1) Br2, H3O+; 2) Pyridine, Heat]

4)
O
O D D
H2 C
C C D C C CH
3
H3 C C H H2 C CH2
D2 C
H2
A B
5) A deuterium exchange reaction occurred. All of the alpha-hydrogens in the molecule have been exchanged with deuterium. Because
detueriums do not appear in a typical 1H NMR, only the remaining hydrogens appear.
H H
D2 O
O C
H 3C CD3
H H
22.3: Alpha Halogenation of Aldehydes and Ketones is shared under a CC BY-SA 4.0 license and was authored, remixed, and/or curated by Steven Farmer,
Dietmar Kennepohl, Layne Morsch, & Layne Morsch.
22.4: ALPHA BROMINATION OF CARBOXYLIC ACIDS
 OBJECTIVES
1. write an equation to illustrate the Hell‑Volhard‑Zelinskii reaction.
2. identify the product formed from the reaction of a given carboxylic acid with bromine and phosphorus tribromide.
3. identify the carboxylic acid, the reagents, or both, needed to synthesize a given α‑bromo carboxylic acid.
4. outline the stereochemical implications of the fact that the Hell‑Volhard‑Zelinskii reaction proceeds through the formation of an
acid bromide enol.
 KEY TERMS
Make certain that you can define, and use in context, the key term below.
Hell‑Volhard‑Zelinskii reaction
 STUDY NOTES
The reagents for the Hell‑Volhard‑Zelinskii reaction are given as bromine and phosphorus tribromide. In some questions, you may
observe that only bromine and phosphorus are listed as reagents. Really there is no difference, as phosphorus tribromide would be
formed in situ by the combination of bromine and red phosphorus:
3 BR + 2 P → 2 PBr
2 3
Excess bromine is required to ensure that enough reagent is available for the reaction with the enol.
HELL-VOLHARD-ZELINSKII REACTION
Although the α-bromination of some carbonyl compounds, such as aldehydes and ketones, can be accomplished with Br2 under acidic
conditions, the reaction will generally not occur with carboxylic acids, esters, and amides. Carboxylic acids do not enolize to a sufficient
extent since the carboxylic acid proton is preferably removed before an α-hydrogen. However, carboxylic acids, can be brominated in the α-
position with a mixture of Br2 and phosphorus tribromide (PBr3) in what is called the Hell-Volhard-Zelinskii reaction.
MECHANISM
This reaction is the combination of three separate reaction mechanisms all of which have been previously discussed. The mechanism starts
with the reaction of the carboxylic acid with PBr3 to form an acid bromide and HBr. Formation of an acid bromide is vital to this reaction
because they lack the acidic carboxylic acid proton and can enolize much more readily making α-bromination possible. Next, HBr catalyzes
the tautomerization of the acid bromide into its enol tautomer, acid bromide enol, which subsequently reacts with Br2 to give α-bromination.
Lastly, the product undergoes nucleophilic acyl substitution which cause the hydrolysis of the acid bromide to reform the carboxylic acid
and the HBr catalyst. Because an enol intermediate is formed, this reaction will form a racemic mixture at the α-carbon.
EXAMPLES
FURTHER REACTIONS OF Α-BROMO CARBOXYLIC ACIDS
α-Bromo carboxylic acids are extremely useful synthetic intermediates because the halogen is highly reactive towards SN2 reactions.
Having the electrophilic carbon of the carbonyl adjacent to the electrophilic α-carbon attached to the bromine allows an incoming
nucleophile to share its charge between the two. This stabilizes the transition state of the SN2 reaction, lowering the energy of activation,
and increasing reaction rates. Primary α-Halogenated carbonyls have SN2 reaction rates which are much greater than the corresponding
primary aliphatic halogens.
d+ d-
C O d- C O C O
Nuc Nuc + Br
C Br C Br Nuc C
d+ d-
Because bromides are capable of reacting with a wide variety of nucleophiles, α-bromo carboxylic acids serve as important intermediates.
Reaction of α-bromo carboxylic acids with an aqueous basic solution followed by an acidic work-up produces α-hydroxy carboxylic acids.
Reaction of α-bromo carboxylic acids with an excess of ammonia provides α-amination, which provides a possible route to amino acids.
EXAMPLE
EXERCISES
1) Explain why the following reaction occurs.
2) Draw the products of the following reactions:
a)
b)
SOLUTIONS
1) The first step represents the beginning of the Hell-Volhard-Zelinskii reaction which provides a-bromination and creates and acid bromide
intermediate. The second step adds methanol which reacts with the acid bromide to produce an ester.
2)
a)
b)
22.4: Alpha Bromination of Carboxylic Acids is shared under a CC BY-SA 4.0 license and was authored, remixed, and/or curated by Steven Farmer,
Dietmar Kennepohl, Layne Morsch, & Layne Morsch.
22.5: ACIDITY OF ALPHA HYDROGEN ATOMS- ENOLATE ION FORMATION
 OBJECTIVES
1. explain why the alpha hydrogens of carbonyl compounds are more acidic than the hydrogens in a typical hydrocarbon.
2. list the properties that make lithium diisopropylamide a suitable reagent for converting a wide range of carbonyl compounds into
their enolate anions.
3. arrange a given list of carbonyl compounds in order of increasing or decreasing acidity.
4. determine whether a given carbonyl‑containing compound is more or less acidic than selected other compounds, such as water,
ammonia, alcohols, alkanes, alkenes, alkynes and amines.
5. explain why dicarbonyl compounds, such as β‑diketones, are more acidic than compounds that contain only a single carbonyl group.
 KEY TERMS
β‑diketone
β‑keto ester
α-hydrogens are weakly acidic because their conjugate base, called an enolate, is stabilized though conjugation with the π orbitals of the
adjacent carbonyl. Removal of an α-hydrogen creates an sp2 hybridized carbon anion. The negative charge and lone pair electrons of the
carbon anion are contained in an unhybridized p orbital. Orbital overlap with p orbitals from the adjacent carbonyl pi bond allows for the
lone pair electrons and negative charge to be shared with the electronegative Carbonyl oxygen, stabilizing the negative charge of the enolate
ion.
Enolate conjugation can be represent by two major resonance forms represented by structures A and B which share the negative charge
(Shown Below). In resonance form A, the negative charge is on a carbon while in resonance form B the negative change is on an oxygen.
O O O
Base
C H C C
C C C
A B
Enolate Ion
Resonance form B is preferred because oxygen is highly electronegative and better able to stabilize the negative charge. Both resonance
form contribute to an overall resonance hybrid but not equally. Due to its stability, resonance form A makes a greater contribution to the
resonance hybrid structure. Form A’s increased contribution to the hybrid is seen when considering the electrostatic potential map of an
acetone enolate. The red/yellow color shows there is a high electron density around the oxygen. The yellow/green color around the enolate
carbon shows that there is a lower but still significant electron density present. Notice that the electron density on the enolate carbon is
much larger than the non-enolate carbon (blue color).
The effect of an adjacent carbonyl on the acidity of α-hydrogens is seen when comparing the pKa of aldehydes (~16-18) and ketones (~19-
21) to the pKa of an alkane (~50). The ability of the electronegative oxygen to stabilize a negative charge can be seen by considering the
pKa of an allyl C-H bond (~42). Having a C-H bond adjacent to a C=C double bond allows the conjugate base created by deprotonating an
allyl C-H bond to be stabilized by conjugation. However, the stability gained only provides a 108 increase in acidity when compared to an
alkane. In comparison, the presence of an electronegative oxygen allows the acidity of an α-hydrogen to be 1020 times greater than that of
an alkane.
O
R H
C H C
C
Aldehydes and Ketones Alkanes

(pKa ~ 20) (pKa ~ 50)
C C H Base C C C C
C C C
Adjacent Double Bond

(pKa ~ 42)
Although α-hydrogens are weakly acidic, typical strong bases such as a hydroxide or alkoxides are only capable of forming the enolate ion
in very low concentrations. This can leave a significant concentration of the electrophilic carbonyl carbon remaining, which can react with
the bases or the enolate. To achieve the complete deprotonation of aldehyde or ketone reactants to their enolate conjugate bases, a very
strong base such as LDA (lithium diisopropylamide) must be used. Complete deprotonation removes the carbonyl groups of the starting
material from the reaction mixture and prevents their ability to form unwanted products. Also, the large alkyl substituents sterically hinder
the ability of LDA and its corresponding amine (diisopropyl amine) to undergo nucleophilic addition to the carbonyl. In addition to
aldehydes and ketones, LDA readily deprotonates a wide variety of carbonyl containing functional groups including esters, amides and
nitriles. Ether solvents like tetrahydrofuran (THF) are commonly used for enolate formation reactions using LDA. Certain other strong
bases, such as alkyl lithium and Grignard reagents, cannot be used to make enolate anions because they rapidly and irreversibly add to the
carbonyl groups. Nevertheless, these very strong bases are useful in the preparation of LDA. By reacting n-butyllithium with
diisopropylamine (pKa 36), LDA can be easily formed.
EXAMPLE
Hydrogen atoms with two or more adjacent carbonyl groups are more acidic than typical α-hydrogens.
The enolate ions of compound such as β-diketones, β-keto-esters, and β-diesters are stabilized through additional resonance forms which
share the negative charge with multiple carbonyl oxygens. The acidity of these compounds is increased to the point where weaker bases,
such as sodium ethoxide (NaOCH2CH3) can be used to form the enolate.
The pKa and acidic hydrogens of multiple functional groups are shown in the table below.
* = a functional group with two ketones.
Functional Group Structure pKa

carboxylic acid HO–(C=O)R 5
nitro RCH2–NO2 9
β-diketone * R(O=C)–CH2–(C=O)R 9
β-ketoester * R(O=C)–CH2–(C=O)OR 11
β-diester * RO(O=C)–CH2–(C=O)OR 13
amide RNH–(C=O)R 15
alcohol RCH2–OH 16
aldehyde RCH2–(C=O)H 17
ketone RCH2–(C=O)R 20
thioester RCH2–(C=O)SR 21
ester RCH2–(C=O)OR 25
nitrile RCH2–C≡N 25
sulfone RCH2–SO2R 25
amide RCH2–(C=O)N(CH3)2 30
alkane CH3–R 50
22.5: Acidity of Alpha Hydrogen Atoms- Enolate Ion Formation is shared under a CC BY-SA 4.0 license and was authored, remixed, and/or curated by
Steven Farmer, Dietmar Kennepohl, Layne Morsch, William Reusch, & William Reusch.
22.6: REACTIVITY OF ENOLATE IONS
 OBJECTIVES
1. identify the two possible ways in which a given enolate anion could conceivably react with an electrophile.
2. write an equation to illustrate the haloform reaction.
3. identify the products formed from the reaction of a given methyl ketone with a halogen and excess base.
4. identify the methyl ketone, the reagents, or both, needed to obtain a specified carboxylic acid through a haloform reaction.
 KEY TERMS
haloform
haloform reaction
 STUDY NOTES
Because the negative charge on an enolate ion is delocalized, there are two reactive sites and therefore two potential products. The
α‑substituted product is much more common.
A “haloform” is any compound of the type CHX3, where X = Cl, Br or I. Of these three compounds, chloroform is the most common.
The haloform reaction describedin the reading is usually carried out with iodine. This reaction is called the “iodoform test,” and is one
of the reactions carried out in the laboratory as a simple qualitative test for methyl ketones.
HOW ENOLATES REACT

Due to their negative charges, enolates are better and more versatile nucleophiles than enols. The increased reactivity of enolates makes
them capable of a wider range of reactions than enols. Also, α-hydrogen containing compounds can be completely converted to an enolate
by reaction with a strong base. Whereas enols can only be created in small amounts through manipulating their equilibrium.
Since the negative charge of an enolate anion is delocalized between the α-carbon and an oxygen, electrophiles may bond to either atom.
Reactants having two or more reactive sites are called ambident, so this term applies to enolate anions. Either the C of the O reactive site in
an enolate may act as a nucleophile depending on the reaction conditions. Reactions with the oxygen would create a new O-E bond and
produce an enol derivative. Reactions with the α-carbon creates a new C-E bond and creates an α-substituted carbonyl compound. Although
reactions with the nucleophilic oxygen are possible, reactions involving the nucleophilic α-carbon are much more common, partially due to
the thermodynamic stability of the C=O bonds in the final products. Also, the enolate counter ion, such as Li+ or Na+, is more tightly
associated with the negatively charged enolate oxygen which can then block incoming electrophiles, reducing their chance of reaction at the
oxygen.
O Ambident
O
Enolate Ion
C C
C C
C-Addition E+ E+ O-Addition
More Stable
O Double Bond O E
C E C
C C
a -Substituted Carbonyl Enol Derivative
STEREOCHEMICAL IMPLICATION OF ENOLATE FORMATION
During enolate formation, an α-hydrogen is removed to form a sp2-hybridized, trigonal planar C=C bond which removes any chiral
information from the original α-carbon. Because the enol alkene is planar, the incoming electrophile can attack from either the top or the
bottom. If the α-carbon of the starting material has a defined stereochemistry or if a new stereocenter is formed during the reaction, the
product will be a racemic mixture of enantiomers.
O
E
R C*
R R'
O O Stereocenter is R
Base E+
H R' +
R C* R C
R R' R O
Stereocenter is R Chiral Information E
is Lost R C*
R' R
Stereocenter is S
BASE PROMOTED Α-HALOGENATION

An enolate reacts rapidly with a halogen to produce α-halogenated carbonyl products. This reaction has the tendency to overreact and create
polyhalogenated products. If a monohalogenated product is sought, the acid catalyzed halogenation reaction discussed in section 22.3 is
preferred. Because complete formation to the enolate is not necessary, weak bases, such as the hydroxide anion, are sufficient to produce
this reaction. Once a small amount of enolate is formed, it quickly reacts with the halogen. This removes the enolate and shifts the
equilibrium toward forming more enolate by Le Chatelier's principle.
O Na O O
NaOH, H2O X2
C H C C X + NaX
C Slow C Fast C
X = Cl, Br, I
Aldehyde or Enolate a -Halocarbonyl
Ketone
OVERREACTION DURING BASE PROMOTED Α-HALOGENATION

The α-hydrogens of halogenated carbonyl products are usually more acidic than the corresponding non-halogenated compounds. The
inductive electron withdrawing effect of the electronegative halogen stabilizes the negative charge of the enolate ion. This promotes further
enolate formation and also further halogenation of the α-carbon. Monohalogenated carbonyls form an enolate over 100 times faster than
their non-halogenated counterparts making multiple halogenations of the α-carbon frequent. This effect is exploited to cause the haloform
reaction.
O O O
H Base X2 X
C C C
C X C X C X
THE HALOFORM REACTION

Overall, the haloform reaction represents a method for the conversion of methyl ketones to carboxylic acids. Due to the increased reactivity
of α-halogenated products, methyl ketones typically undergo base promoted halogenation three times to give a trihalo-ketone. A halomethyl
ion leaving group is then substituted with a hydroxide ion during nucleophilic acyl substitution. The resulting carboxylate can then be
protonated to form a carboxylic acid.
O O
X2 O H3O + O
C H C X
C - C C C
OH O OH
H H X X
Methyl Ketone Trihalo Ketone Carboxylate Carboxylic Acid
+
HCX3
Haloform
EXAMPLE
O O
C 1) Br2, NaOH C
CH3 OH + CHBr3
2) H3O+
Acetophenone Benzoic Acid Bromoform
MECHANISM
Note! This reaction is considered to be base promoted and not base catalyzed because an entire equivalent of base is required for each α-
halogenation. Deprotonation of an α-hydrogen with hydroxide produces the nucleophilic enolate ion which subsequently reacts with the
halogen. The increasing acidity of α-halogenated ketone causes this reaction to occur two more times. Once formed, the -CX3 group
attached to the carbonyl can act as a leaving group. Nucleophilic acyl substitution with a hydroxide anion causes C-C bond cleavage and
eventually produces a haloform (CHCl3, CHBr3, CHI3) and a carboxylate anion. The carboxylate ion is easily protonated with acid to form
a carboxylic acid functional group. Often, this reaction is performed using iodine (I2) because the subsequent iodoform (CHI3) side-product
is a bright yellow solid which is easily filtered off.
This reaction represents one of the few examples of a carbanion leaving group. The trihalomethyl ion (-:CX3) is particularly stabilized due
to the inductive electron-withdrawing effects of the three halogens. The stability of the carbanion can be seen when considering the pKa
corresponding conjugate acid. In particular, bromoform (CHBr3) has a pKa of 13.7 which is more than 1020 times more acidic than a typical
alkane C-H bond.
1) Enolate formation
O O H OH
C H C + H2O
C C
H
H
Methyl Ketone Enolate
2) Nucleophilic attack on the halogen
3) Repeat the halogenation two more times

O O
X2
C X C X
C -
OH C
H H X X
Trihalo Ketone
4) Nucleophilic attack on the electrophilic carbonyl carbon
O
O
C X
C C X
C
X X HO
X X
OH
5) Nucleophilic acyl substitution
O O X
C X + C X
C C
HO OH X
X X
6) Deprotonation
O X O X
C H C X C + H C X
O X O X
Carboxylate Haloform
7) Protonation of the carboxylate
O O
H3 O +
C C H
O O
Carboxylic Acid
BIOLOGICAL HALOFORM REACTION

Interest in the haloform reaction has increased since the discovery that certain plants and marine algae can biosynthize chloroform,
bromoform, and other small halocarbons through an analogous process. Previously it was assumed that these toxic compounds were present
in the environment as a man-made pollutants.
The likely starting material of the biosynthesis are biogenic methyl ketones, a halogen anion, and oxygen. The enzyme, chloroperoxidase,
catalyzes the polyhalogenation of the methyl groups. As in the haloform reaction, the final biosynthesis step involves a nucleophilic acyl
substitution with a hydroxide anion to create a haloform and a carboxylate anion.
O Chloroperoxidase O O
+ 3 Cl- + 3/2 O2 + 3 -OH + CHCl3
R CH3 R CCl3 R O
Methyl Ketone Trichloromethyl Carboxylate Chloroform
Ketone anion
EXERCISES
1) Please predict the expected products of the following reactions:
a)
b)
SOLUTIONS
a)
b)
22.6: Reactivity of Enolate Ions is shared under a CC BY-SA 4.0 license and was authored, remixed, and/or curated by Steven Farmer, Dietmar Kennepohl,
Layne Morsch, & Layne Morsch.
22.7: ALKYLATION OF ENOLATE IONS
 OBJECTIVES
1. write a general mechanism for the attack of an enolate anion on an alkyl halide.
2. write a reaction sequence to illustrate the preparation of carboxylic acids via the malonic ester synthesis.
3. identify the product formed, and all the intermediates, in a given malonic ester synthesis.
4. identify all of the compounds needed to prepare a given carboxylic acid by a malonic ester synthesis.
5. write a detailed mechanism for each of the steps involved in a malonic ester synthesis.
6. write a reaction sequence to illustrate the preparation of ketones through the acetoacetic ester synthesis.
7. identify the product formed, and all the intermediates, in a given acetoacetic ester synthesis.
8. identify all of the compounds needed to prepare a given ketone by an acetoacetic ester synthesis.
9. write a detailed mechanism for each of the steps involved in an acetoacetic ester synthesis.
10. identify the product or products formed when a given lactone, ester, nitrile or ketone is treated with lithium diisopropylamide
followed by an alkyl halide.
11. identify the compounds needed to prepare a given α‑substituted ketone, ester, lactone or nitrile by a method involving the alkylation
of an enolate anion.
 KEY TERMS
alkylation
malonic ester synthesis
 STUDY NOTES
The two syntheses discussed in this section provide routes to a wide variety of carboxylic acids and methyl ketones. You may wish to
review the factors influencing SN2 reactions (Section 11.3) in conjunction with this section.
You should try to memorize the structures of malonic ester and ethyl acetoacetate. The IUPAC names of these compounds are shown in
the table below.
Structure Common name IUPAC name
malonic acid propanedioic acid
malonic ester or
diethyl propanedioate
diethyl malonate
acetoacetic acid 3‑oxobutanoic acid
ethyl acetoacetate or
ethyl 3‑oxobutanoate
acetoacetic ester
ALKYLATION OF ENOLATES
Enolates can be alkylated in the alpha position through an SN2 reaction with alkyl halides. During this reaction an α-hydrogen is replaced
with an alkyl group and a new C-C bond is formed. The limitations of SN2 reactions still apply. This includes preferring a good primary or
secondary leaving group, X = chloride, bromide, iodide, tosylate. Tertiary leaving groups cannot be used in this reaction and typically give
undesired E2 elimination products. A very strong base, such as LDA, is often used because of its ability to form the enolate completely.
Removal of the carbonyl starting material from the reaction mixture makes it unavailable for nucleophilic addition by the enolate.
Aldehydes are usually not directly alkylated because their enolates prefer to undergo the carbonyl condensation reactions discussed later in
Section 23.1. In addition, the acidic hydrogen on carboxylic acids inhibits the formation of an enolate, and makes their direct alkylation
difficult. Esters, including lactones, and symmetrical ketones readily undergo direct alkylation. However, direct alkylations, like all enolate-
based reactions, can form a racemic mixture if the alkylated α-carbon produced is chiral.
GENERAL REACTION
O O
1) LDA
C H C R + H N[CH(CH3)2]2 + LiX
C 2) R X C
Ester or Ketone a -Alkylated Product Diisopropyl Amine Lithium Halide
X = Chloride, bromide,
iodide, tosylate
MECHANISM
1) Enolate formation
CH(CH3)2
Li N
O CH(CH3)2
Li O CH(CH3)2
C H LDA + H N
C
C C CH(CH3)2
Enolate Diisopropyl Amine
2) SN2 attack
H
Li O O H
H C X H
C C C + Li X
C R C R
a -Alkylated Product
EXAMPLES
O O
1) LDA
C H C CH3
H 3C C 2) CH3I H 3C C
H H H2
Acetone 2-Butanone
O O
H 1) LDA H 3C
O O
2) CH3I
O O
H 1) LDA CH3
O H O H
2) CH3I
Valerolactone 2-Methylvalerolactone
(Racemic)
When an unsymmetrical ketone with two sets of non-equivalent α-hydrogens is treated with a base, two possible enolates can form.
Regioselective enolate formation is possible under the proper conditions. The main determinant is whether the reaction is under kinetic
control (rate) or thermodynamic control (equilibrium). Although a predominant product can be produced, a mixture of products is usually
formed causing a reduction in product yield.
O
H
Removal of CH3
2o H
Kinetic Enolate
Less Substituted
2o H O 3o H
Forms Faster
Less Sterically H H More Sterically
Hindered H Hindered
CH3
Removal of O
3o H H
CH3
H
Thermodynamic Enolate
More Substituted
More Stable
THERMODYNAMIC ENOLATES
The thermodynamic enolate is formed when the more substituted α-hydrogen is removed. This leads to the more alkyl substituted, therefore
the more stable, enolate to be formed. The presence of additional alkyl groups causes the formation of the thermodynamic enolate to be
sterically hindered and kinetically slow, especially when a bulky base like LDA is used. Thermodynamic enolates are favored by conditions
which allow for equilibration between the possible enolates. When the ketone starting material is not completely deprotonated, equilibrium
between the possible enolates and the α-hydrogens of the ketone can occur. During equilibrium, interconversion between the enolates allows
the lower energy of the thermodynamic enolate to dominate. Other conditions can also promote the formation of the thermodynamic
enolate, such as higher reaction temperatures, or the use of a smaller less sterically hindered base such as sodium hydride (NaH). Weaker
bases, such as sodium ethoxide, do not completely deprotonate the ketone starting material which also allows for enolate equilibrium to
occur.
Example of enolate equilibration
O O O O
H H H
+ +
CH3 CH3 CH3
Less Stable More Stable

Enolate Anion Enolate Anion
O O O
H H 0.9 Eq LDA H CH3I
CH3 H CH3
25 oC
H CH3 H H CH3
Thermodynamic Enolate Thermodynamic Product

More Substituted
More Stable
KINETIC ENOLATES
Kinetic enolates are favored under conditions which do not allow for equilibration between the enolates, such as the use of a strong bulky
base, like LDA, in a molar equivalent to the ketone starting material. Kinetic enolates are formed when the less substituted α-hydrogen is
deprotonated. Being less sterically hindered allows this α-hydrogen to be deprotonated faster even though it forms a less thermodynamically
stable enolate. Using a molar equivalent of LDA completely converts the ketone starting material to an enolate, removing it from the
reaction mixture and preventing equilibration between the possible enolates. Low reaction temperatures (-78 oC) prevent enolate
equilibration and promote the formation of the kinetic enolate.
O O O
H H 0.9 Eq LDA CH3I H 3C
H H
25 oC
H CH3 CH3 H CH3
Kinetic Enolate Kinetic Product

Less Substituted (Racemic)
Forms Faster
When and enolate of an asymmetric ketone is stabilized through additional resonance forms there is no competition between possible
enolates despite kinetic or thermodynamics conditions. The resonance stabilized enolate will be preferentially alkylated to the point that
formation of the alkylated products of other possible enolates will be minimal.
EXAMPLE
More Acidic
a -Hydrogens
O O
1) LDA
C C
C CH3 2) CH3I C CH3
H2 H CH3
1-Phenyl-2-propanone 1-Methyl-1-phenyl-
2-propanone
(Racemic)
MALONIC ESTER SYNTHESIS

The malonic ester synthesis is a series of reactions which converts an alkyl halide to a carboxylic acid with two additional carbons. One
important use of this synthesis pathway is that it allows for the creation of α-alkylated carboxylic acids which cannot be created by direct
alkylation.
The starting material of this reaction is a malonic ester: a diester derivative of malonic acid. Diethyl propanedioate, also known as diethyl
malonate, is the malonic ester most commonly used in pathway. Since it is a 1,3-dicarbonyl compound, diethyl malonate has relatively
acidic α-hydrogens (pKa = 12.6) and can be transformed to its enolate using sodium ethoxide as a base. Other alkoxide bases are not
typically used given the possibility of a transesterification reaction.
Et = -CH2CH3
O O O O O O
C C C C C C
HO C OH RO C OR EtO C OEt
H2 H2 H2
Malonic Acid Malonic Ester Diethyl Malonate
GENERAL REACTION
OEt
O C O
1) NaOEt
CH2 + R X R C
2) NaOH C OH
O C H2
3) H3O+, Heat
OEt
Diethyl malonate Alkyl Halide a -Alkyl Carboxylic
Acid
PREDICTING THE PRODUCT OF A MALONIC ESTER SYNTHESIS

The product of a Malonic Ester Synthesis can be created by simply replacing the halogen on the alkyl halide with a -CH2CO2H group.
Malonic Ester
Synthesis H2 O
R X R C C
OH
MALONIC ESTER SYNTHESIS TAKES PLACE IN FOUR STEPS:

1) Enolate Formation
Reacting diethyl malonate with sodium ethoxide (NaOEt) forms a resonance-stabilized enolate.
2) Alkylation
The enolate is alkylated via an SN2 reaction to form an monoalkylmalonic ester.
O O O O
S N2
C C CC + X
EtO C OEt EtO C OEt
H H R
R X Monoalkylmalonic ester
3) Ester hydrolysis and protonation
After alkylation, the diester undergoes hydrolysis with sodium hydroxide to form a dicarboxylate. Subsequent protonation with acid forms a
monoalkyl malonic acid.
O O O O
1) NaOH
C C C C + HOEt
EtO C OEt HO C OH
2) H3O+
H R H R
Monoalkyl Malonic Acid
4) Decarboxylation & Tautomerization

Monoalkyl malonic acids decarboxylate when heated, forming an α-alkyl carboxylic acid and carbon dioxide (CO2). Decarboxylation can
only occur in compounds with a second carbonyl group two atoms away from carboxylic acid such as in malonic acids and β-keto acids.
The mechanism occurs via a concerted mechanism involving a proton transfer between the carboxyl acid hydrogen and the nearby carbonyl
group to form the enol of a carboxylic acid and CO2. The enol undergoes tautomerization to form the carboxylic acid.
H OH O
O O Heat Tautomerization
O C O + C R C R
C C HO C HO C
HO C O
H R H H H
Carbon Dioxide Carboxylic Acid Enol a -Alkylated
Carboxylic acid
EXAMPLE
OEt
O
O C 1) NaOEt
CH2 + CH3CH2CH2CH2 Br CH3CH2CH2CH2 CH2 C
O C 2) NaOH
3) H3O+, Heat OH
OEt
Diethyl malonate 1-Bromobutane Hexanoic Acid
DIALKYLATION
The presence of two α-hydrogens in malonic esters allows for a second alkylation to be performed prior to decarboxylation. This leads to
dialkylated carboxylic acids. Due to the lack of stereochemical control inherent in enolate based reactions, if the two added alkyl groups are
different, a racemic mixture of products will result.
EXAMPLES
OEt OEt OEt
O C O C O C O
1) NaOEt H 1) NaOEt (CH2)3CH3 1) NaOH
CH2 C C C (CH2)3CH3
2) CH3(CH2)3 Br (CH2)3CH3 2) CH3(CH2)3 Br (CH2)3CH3 2) H3O+, Heat HO C
O C O C O C H (CH2)3CH3
OEt OEt OEt
2-Butylhexanoic acid
In a variation of the dialkylation reaction - if one molar equivalent of malonic ester is reacted with one molar equivalent of a dihaloalkane
and two molar equivalents of sodium ethoxide, a cyclization reaction occurs. By changing the dihaloalkane, three, four, five, and six-
membered rings can be created.
OEt OEt O O
H2 H2
O C O C H EtO C C HO C C
1) NaOEt NaOEt CH2 1) NaOH CH2
CH2 C C C
2) BrCH2CH2CH2CH2Br CH2CH2CH2CH2 Br EtO C 2) H3O+, Heat
O C O C C CH2 H C CH2
H2 H2
OEt OEt O
Cyclopentanecarboxylic acid
THE ACETOACETIC ESTER SYNTHESIS

The acetoacetic ester synthesis is a series of reactions which converts alkyl halides into a methyl ketone with three additional carbons. This
reaction creates an α-substituted methyl ketone without side-products. The starting reagent for this pathway is ethyl 3-oxobutanoate, also
called ethyl acetoacetate, or acetoacetic ester. Like other 1,3-dicarbonyl compounds, ethyl acetoacetate is more acidic than ordinary esters
being almost completely converted to an enolate by sodium ethoxide.
GENERAL REACTION
O O O
1) NaOEt
C C + R X C R
H3C C OEt 2) NaOH H 3C C
H2 3) H3O+, Heat H2
Acetoacetic ester Alkyl Halide a -Alkyl Methyl
Ketone
PREDICTING THE PRODUCT OF AN ACETOACETIC ESTER SYNTHESIS

The product of a acetoacetic ester synthesis can be created by replacing halogen on the alkyl halide with a -CH2COCH3 group.
Acetoacetic Ester
Synthesis H2 O
R X R C C
CH3
REACTION STEPS
1) Formation of the enolate
As previously described, the α-hydrogens of acetoacetic ester are rather acidic (pKa = 10.7) allowing the enolate to be easily formed when
sodium ethoxide is used as a base.
Na OEt
O Na O
H
C C H + HOEt
H3 C C H H3 C C
COOEt COOEt
Acetoacetic ester Sodioacetoacetic ester
2) Alkylation via an SN2 Reaction

Subsequent reaction with an alkyl halide produces a monoalkylacetoacetic ester.
Na O O
R X SN 2
C R
C H + NaX
H3 C C H3 C C H
COOEt COOEt
Monoalkylacetoacetic ester
3) Ester hydrolysis and decarboxylation

Hydrolysis with NaOH followed by protonation produces an alkylated beta-ketoacid. β-ketoacids are easily decoboxylated to form an α-
alkyl substituted methyl ketone and carbon dioxide (CO2) using a similar mechanism as the malonic ester synthesis.
O O O
R 1) NaOH R Heat
C C C R
H3 C C H 2) H3O+ H3 C C H -CO2 H3 C C
H2
COOEt COOH
Monoalkyl b-ketoacid Monoalkyl-
methyl ketone
EXAMPLES
O O 1) NaOEt O
+ Br
2) NaOH C
OEt
3) H3O+, Heat
Acetoacetic ester 1-Bromopropane 2-Hexanone
Much like the malonic ester synthesis, a second alkyl group can added before the decarboxylation step.
O First Alkylation O Second Alkylation O O
H 1) NaOEt R 1) NaOEt R 1) NaOH R
C C C C
H 3C C H H 3C C H 2) R'X H 3C C R' H 3C C R'
2) RX 2) H3O+, Heat
COOEt COOEt COOEt H
The reaction steps of the acetoacetic ester synthesis can also be applied to other β-keto esters with acidic α-hydrogens. Because the α-
hydrogens between the two carbonyls are the most acidic, they are preferentially deprotonated allowing for a single enolate to be formed.
Even cyclic beta-keto esters can be alkylated and subsequently decarboxylated to give an α-alkylated cyclic ketone.
EXAMPLES
O O O O O
H 1) NaOEt 1) NaOH
C C
OEt 2) CH3CH2Br OEt 2) H3O+, Heat
DIRECT ALKYLATION OF NITRILES
The presence of acidic α-hydrogens in nitriles gives them the ability to form an enolate equivalent which can be also be directly alkylated.
GENERAL REACTION
H H H R
1) LDA
N C C N C C
2) R X
R R
Nitrile a -Alkyl nitrile
MECHANISM
Base
R' X
H H R'
N C C N C C N C C H
H
R R R
Nitrile Enolate Analog a -Alkyl nitrile
EXAMPLE
PLANNING A SYNTHESIS USING ENOLATE ALKYLATIONS

When planning a synthesis that could involve enolates, the key is to recognize the functionality which can form an enolate. During
retrosynthetic analysis a C-C bond is broken between the α-carbon and the β-carbon away from this functionality. It is also important to be
able to identify specific groups of atoms which indicate if a malonic ester or an acetoacetic ester synthesis can be used. Having multiple C-C
bonds which can be broken allows for multiple synthetic pathways.
After retrosynthetically breaking the C-C bond, the fragment with the functionality will gain a hydrogen and the other fragment will gain a
halogen. Sometimes the fragment with the functionality will become diethyl malonate or acetoacetic ester.
O O
R C * R C H
O C O C
H2 H2
O
R C R'
O C
H2
* R' Br R'
Direct Alkylation of an Ester
H2 H2
N C C * N C C H
H2
N C C R
* R Br R
Direct Alkylation of a Nitrile
O O O
H C * Et C C Et
O C O C O
H2 H2
O Diethylmalonate
H C R
O C
H2
* R Br R
Malonic Ester Synthesis
O O O
C * C C Et
CH3 C CH3 C O
H2 H2
O Acetoacetic Ester
C R
CH3 C
H2
* R Br R
Acetoacetic Ester Synthesis
WORKED OUT EXAMPLE:

Plan a synthesis of the following molecule using an alkylation of an enolate. Consider multiple pathways and explain which is preferable.
O
The target molecule does not contain the appropriate fragments to utilize either the malonic ester or acetoacetic acid synthesis so direct
alkylation of a ketone will likely be used. When analyzing this molecule, there are three α-β C-C bonds which could be cleaved to create a
possible starting material. When looking at the possible starting materials, A and C are asymmetrical ketones and therefore can create
multiple products during alkylation. B is a symmetrical ketone and should be the most likely to create the target molecule in high yield.
O O
H
O O
H
B
O
O
H
Possible Synthesis
O
O LDA
+ Br
EXERCISES
QUESTIONS
1) Propose a synthesis for each of the following molecules from this malonic ester.
(a)
(b)
(c)
2) Why can't you prepare tri substituted acetic acids from a malonic ester?
3) Propose a synthesis for the following molecule via a malonic ester.
4) How might you prepare the following compounds from an alkylation reaction?
(a)
(b)
(c)
(d)
(e)
(f)
SOLUTIONS
1
(a) 1) Malonic Ester, NaOEt, 2) 4-Methylbenzyl Bromide, 3) Base, 4) Acid, Heat
(b) 1) Malonic Ester, NaOEt, 2) 3-bromohexane, 3) Base, 4) Acid, Eat
(c) 1) Malonic Ester, NaOEt, 2) 1-Bromo-2,3,3-trimethylbutane, 3) Base, 4) Acid, Heat
2
Malonic esters only contain two acid protons.
3
4
(a)
(b)
(c)
(d)
(e)
(f)
22.7: Alkylation of Enolate Ions is shared under a CC BY-SA 4.0 license and was authored, remixed, and/or curated by Steven Farmer, Dietmar Kennepohl,
Layne Morsch, William Reusch, & William Reusch.
22.S: CARBONYL ALPHA-SUBSTITUTION REACTIONS (SUMMARY)
CONCEPTS & VOCABULARY
Four common types of reactions involving carbonyl reactions: 1) nucleophilic addition; 2) nucleophilic acyl substitution; 3) alpha
substitution; 4) carbonyl condensations. The first two were previously discussed and the second two involve the properties of the carbon
directly adjacent to the carbonyls, α carbons.
Alpha-substitution reactions results in the replacement of an H attached to the alpha carbon with an electrophile.
The nucleophile in these reactions are new and called enols and enolates.
In this chapter, the focus is on α substitutions reactions with aldehydes and ketones.
22.1 Keto-Enol Tautomerization
Greek letters are used to denote the carbon atoms near carbonyls.
The carbon in the carbonyl is the reference point and the alpha carbon is adjacent to the carbonyl carbon.
Hydrogen atoms attached the these carbons denoted with Greek letters will have the same designation, so an alpha hydrogen is attached
to an alpha carbon.
Aldehyde hydrogens not given Greek leters.
α hydrogens display unusual acidity, due to the resonance stabilization of the carbanion conjugate base, called an enolate.
Tautomers are readily interconverted constitutional isomers, usually distinguished by a different location for an atom or a group, which
is different than resonance.
The tautomerization in this chapter focuses on the carbonyl group with alpha hydrogen, which undergo keto-enol tautomerism.
Keto refers to the tautomer containing the carbonyl while enol implies a double bond and a hydroxyl group present in the tautomer.
The keto-enol tautomerization equilibrium is dependent on stabilization factors of both the keto tautomer and the enol tautomer, though
the keto form is typically favored for simple carbonyl compounds.
The 1,3 arrangement of two carbonyl groups can work synergistically to stabilize the enol tautomer, increasing the amount present at
equilibrium.
The positioning of the carbonyl groups in the 1,3 arrangement allows for the formation of a stabilizing intramolecular hydrogen bond
between the hydroxyl group of the enol and the carbonyl oxygen as well as the alkene group of the enol tautomer is also conjugated with
the carbonyl double bond which provides additional stabilization.
Aromaticity can also stabilize the enol tautomer over the keto tautomer.
Under neutral conditions, the tautomerization is slow, but both acid and base catalysts can be utilized to speed the reaction up.
Biological enol forming reactions use isomerase enzymes to catalyze the shifting of a carbonyl group in sugar molecules, often
converting between a ketose and an aldose in a process called carbonyl isomerization.
22.2 Reactivity of Enols: The Mechanism of Alpha-Substitution Reactions
The oxygen of the enol donates electron density to the double bond making it more electron rich and thus more reactive than a typical
alkene.
The mechanism starts with an acid-catalyzed tautomerization to form an enol.
The double bond is then able to act as a nucleophile and attack an electrophile.
The final product is an alpha-substituted carbonyl after the deprotonation of the carbonyl to also regenerate the acid-catalyst.
The enol formed has planar geometry, which means the electrophile can attach on the top or bottom of the alpha-carbon.
A racemic mixture can result if a sterocenter is created at the site of substitution.
22.3 Alpha Halogenation of Aldehydes and Ketones
Aldehydes and ketons can undergo a substitution of an alpha hydrogen to a halogen.
An acid-catalyzed tautomerization starts the mechanism followed by the enol attacking molecular halogens.
The nucleophile in this reaction is the enol and the electrophile is the halogen.
Mechanistic studies showed that the reaction was a first-order in the ketone.
The halogen is part of a fast step after the rate-determing step.
The formation of an enol intermediate was provided using a reaction called deuterium exchange.
Due to the acidic nature of α hydrogens they can be exchanged with deuterium by reaction with the isotopic form of water, D2O.
The mechanism for deuterium exchange is virtually the same as that of keto-enol tautomerism under acidic conditions, the difference
being a deuterium is placed in the α-position.
Both alpha halogenation and deuterium exhange reactions were found to have a common intermediate involved in the rate determining
step of their mechanism, an enol.
22.4 Alpha Bromination of Carboxylic Acids
22.S.1 https://chem.libretexts.org/@go/page/207031
The α-bromination of some carbonyl compounds, such as aldehydes and ketones, can be accomplished with Br2 under acidic conditions,
but the reaction will generally not occur with more stable carboxylic acid derivatives.
Carboxylic acids do not enolize to a sufficient extent since the carboxylic acid proton is preferably removed before an α-hydrogen.
Carboxylic acids, can be brominated in the α position with a mixture of Br2 and phosphorus tribromide (PBr3) in what is called the Hell-
Volhard-Zelinskii reaction.
α-Bromo carboxylic acids are extremely useful synthetic intermediates because the halogen is highly reactive towards SN2 reaction.
Reaction of a α-bromo carboxylic acids with an excess of ammonia provides α-amination, which is a possible route to amino acids.
22.5 Acidity of Alpha Hydrogen Atoms: Enolate Ion Formation
α hydrogens are weakly acidic because the conjugate base, called an enolate, is stabilized though conjugation with the π orbitals of the
adjacent carbonyl.
The enolate has two resonance structures to contribute to the resonance hybrid.
While α-hydrogens are weakly acidic, typical strong bases such as hydroxide or alkoxide are only capable of forming the enolate ion in
very low concentrations.
To achieve complete deprotonation of aldehyde or ketone reactants to their enolate conjugate bases, a very strong base such as LDA
(lithium diisopropylamide) must be used.
Hydrogen atoms with two or more adjacent carbonyl groups are more acidic than typical α hydrogens, such as β-diketones, β-keto-
esters, and β-diesters, which create enolates that are stabilized through additional resonance forms which share the negative charge with
multiple carbonyl carbons.
The acidity of these compounds is increased to the point where typical strong bases such as hydroxide and alkoxide can be used to form
the enolate.
22.6 Reactivity of Enolate Ions
Enolates are better nucleophlies than enols.
α-hydrogen containing compounds can be completely converted to an enolate by reaction with a strong base whereas enols can only be
created in small amounts through manipulating their equilibrium.
Either the C of the O reactive site in an enolate may act as a nucleophile depending on the reaction conditions, but reactions involving
the nucleophilic α-carbon are more common, partially due to the thermodynamic stability of the C=O bonds in the final products.
An enolate reacts rapidly with a halogen to produce α-halogenated carbonyl products.
The α-hydrogens of halogenated carbonyl products are usually more acidic than the corresponding non-halogenated compounds, which
promotes polyhalogenated products.
The Haloform reaction represents a method for the conversion of methyl ketones to carboxylic acids.
This reaction is considered a base promoted and not base catalyzed because an entire equivalent of base is required for each α-
halogenation.
Deprotonation of an α-hydrogen with hydroxide produces the nucleophilic enolate ion which subsequently reacts with the halogen.
The increasing acidity of α-halogenated ketone causes this reaction to occur two more times.
Once formed, the CX3 group attached to the carbonyl can act as a leaving group, eventually produces a haloform (CHCl3, CHBr3, CHI3)
and a carboxylate anion.
22.7 Alkylation of Enolate Ions
Enolates can be alkylated in the alpha position through an SN2 reaction with alkyl halides.
An α hydrogen is replaced with an alkyl group and a new C-C bond is formed.
Very strong bases like LDA are often used to fully deprotonate the carbonyl and completely form the enolate.
Direct alkylations, like all enolate-based reactions, will form a racemic mixture if the alkylated alpha carbon is chiral.
When an unsymmetrical ketone with two sets of nonequivalent alpha hydrogens is treated with a base, two possible enolates can form.
The main determinant for which enolate is formed is whether the reaction is under kinetic control (rate) or thermodynamic (equilibrium)
control.
The thermodynamic enolate is formed when the more substituted alpha hydrogen is removed, yielding the more alkyl substituted,
therefore the most stable, enolate.
Formation of the thermodynamic enolate is sterically hindered and is kinetically slow, especially with a bulky base like LDA.
Kinetic enolates are formed when the less substituted alpha hydrogen is deprotonated, being less sterically hindered allows this alpha
hydrogen to be deprotonated faster even though it forms a less thermodynamically stable enolate.
The malonic ester synthesis is a series of reactions which converts an alkyl halide to a carboxylic acid with two additional carbons.
The importance of this synthesis pathways is that it allows for the creation of alpha alkylated carboxylic acids which cannot be created
by direct alkylation.
The acetoacetic ester synthesis is a series of reaction which converts alkyl halides into a methyl ketone with three additional carbons.
This reaction creates an alpha substituted methyl ketone without side-products.
In retrosynthetic analysis, a C-C bond is broken between the alpha carbon and the beta carbon away from this functionality.
SKILLS TO MASTER
Skill 22.1 Determine alpha carbons and alpha hydrogens.
Skill 22.2 Draw the enols formed from carbonyl derivatives.
Skill 22.3 Provide the mechanism for the keto-enol tautomerization under neutral, acidic and basic conditions.
Skill 22.4 Provide the mechanism for the enol-keto tautomerization under neutral, acidic and basic conditions.
Skill 22.5 Draw the products of halogenation reactions.
Skill 22.6 Provide the mechanism for halogenation reactions.
Skill 22.7 Write an equation to illustrate the Hell‑Volhard‑Zelinskii reaction.
Skill 22.8 Identify the product formed from the reaction of a given carboxylic acid with bromine and phosphorus tribromide.
Skill 22.9 Explain why the alpha hydrogen of carbonyl compounds are more acidic than a typical hydrogen.
Skill 22.10 Explain why dicarbonyl protons are more acidic than compounds that contain a single carbonyl.
Skill 22.11 Provide a mechanism for the haloform reaction.
Skill 22.12 Provide a mechanism for an alkylation reaction with an enolate.
Skill 22.13 Provide a mechanism for malonic ester synthesis.
Skill 22.14 Propose synthesis for alkylated carboxylic acids.
Skill 22.15 Provide a mechanism for acetoacetic acid synthesis.
Skill 22.16 Propose a synthesis for alkylated methyl ketones.
SUMMARY OF REACTIONS
Alkylation
22.S: Carbonyl Alpha-Substitution Reactions (Summary) is shared under a CC BY-SA 4.0 license and was authored, remixed, and/or curated by Steven
Farmer & Dietmar Kennepohl.

Carbonyl Alpha Chem Libretexts

Uploaded by

Copyright:

Available Formats

Carbonyl Alpha Chem Libretexts

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Carbonyl Alpha Chem Libretexts

Uploaded by

Copyright:

Available Formats

22: CARBONYL ALPHA-

Nucleophilic Acyl Substitution Involving a Carbonyl

Indicate any α-hydrogens contained in the following molecules:

Double Bond has 2-Methylcyclohexanone Double Bond has

Double Bond is conjugated 1-Phenyl-2-propanone Double Bond is not

This enol tautomer is the most stable due

MECHANISM FOR CATALYZED KETO-ENOL TAUTOMERIZATION

Keto Tautomer Enol Tautomer

Keto Tautomer Oxonium Ion

Enol Tautomer → Keto Tautomer

Enol Tautomer Oxonium Ion

UNDER BASIC CONDITIONS

Keto Tautomer Enolate

2) Protonation the enolate ion to form an enol

BIOLOGICAL ENOL FORMING REACTIONS

Ketose Ene-diol Aldose

Additional resonance forms stabilizes this enol.

Enol of Cyclohexane Enol of Acetone

HOW ENOLS REACT

MECHANISM OF ALPHA SUBSTITUTION REACTIONS USING AN ENOL

Keto Tautomer Enol Tautomer

STEREOCHEMICAL IMPLICATION OF ENOL FORMATION

Example of Acid-Catalyzed Racemization

GENERAL REACTION (Α SUBSTITUTION)

ACID CATALYZED MECHANISM

Aldehyde or Ketone Oxonium

3) Nucleophilic attack on the halogen

MECHANISM IN ACIDIC CONDITIONS

3) De-deuteration to form the keto tautomer

2)Draw out the mechanism for the following reaction.

3) How might you form 2-hepten-4-one from 4-heptanone?

3) [1) Br2, H3O+; 2) Pyridine, Heat]

Aldehydes and Ketones Alkanes

Adjacent Double Bond

Functional Group Structure pKa

HOW ENOLATES REACT

a -Substituted Carbonyl Enol Derivative

BASE PROMOTED Α-HALOGENATION

OVERREACTION DURING BASE PROMOTED Α-HALOGENATION

THE HALOFORM REACTION

Acetophenone Benzoic Acid Bromoform

2) Nucleophilic attack on the halogen

3) Repeat the halogenation two more times

4) Nucleophilic attack on the electrophilic carbonyl carbon

5) Nucleophilic acyl substitution

7) Protonation of the carboxylate

BIOLOGICAL HALOFORM REACTION

malonic acid propanedioic acid

acetoacetic acid 3‑oxobutanoic acid

Ester or Ketone a -Alkylated Product Diisopropyl Amine Lithium Halide

Enolate Diisopropyl Amine

Less Stable More Stable

Thermodynamic Enolate Thermodynamic Product

Kinetic Enolate Kinetic Product

MALONIC ESTER SYNTHESIS

PREDICTING THE PRODUCT OF A MALONIC ESTER SYNTHESIS

MALONIC ESTER SYNTHESIS TAKES PLACE IN FOUR STEPS:

3) Ester hydrolysis and protonation

Monoalkyl Malonic Acid