Chapter 22: Enolate Anions:
Acyl Addition and Acyl
Substitution
• There are other carbon acids, specifically involving the proton
on an α-carbon in aldehydes, ketones or esters.
• With a suitable base, these carbonyl compounds generate a
new type of carbon nucleophile called an enolate anion.
1
To begin, you should know:
2
• Nomenclature for aldehydes, ketones and acid derivatives. (chapter 5, section 5.9 and
chapter 16, sections 16.2, 16.4)
• The acid-base reaction, and factors that contribute to the position of the acid-base
equilibrium. (chapter 6, sections 6.1, 6.3)
• What contributes to acid strength. (chapter 6, section 6.3)
• What contributes to base strength. (chapter 6, section 6.4)
• The fundamentals of kinetic and thermodynamic controlled reactions. (chapter 7, sections
7.6, 7.7, 7.10)
• The fundamentals of equilibrium reactions and factors that influence the position of the
equilibrium. chapter 7, section 7.10
• The concept of resonance and resonance stability. (chapter 5, section 5.9.C)
• Be able to draw resonance contributors and understand their significance. (chapter 5,
section 5.9.C and chapter 21, section 21.3)
• Rate of reaction. (chapter 7, section 7.11)
• Rotamers and conformations. (chapter 8, sections 8.1, 8.4)
• Know the reactions that generate ketones and aldehydes. (chapter 17, section 17.2 and
chapter 21, section 21.3.C)
• Keto-enol tautomerism. (chapter 10, sections 10.6.C, 10.6.D and chapter 18, section 18.5)
• The E2 reaction. (chapter 12, sections 12.1, 12.2)
• The SN2 reaction with alkyl halides. (chapter 11, sections 11.1, 11.2, 11.3)
• Understand differences in nucleophilic strength. (chapter 11, section 11.3)
• Formation of Grignard reagents and organolithium reagents. (chapter 15, section 15.1,
15.5)
• Grignard reagents and organolithium reagents are strong bases. (chapter 15, sections 15.3,
15.5.B)
To begin, you should know:
3
• Amines react as acids in the presence of a strong base. (chapter 15, section 15.5.B and
chapter 6, section 6.4.A)
• Acyl addition reactions of nucleophiles. (chapter 16, section 16.3 and chapter 18, section
18.1)
• Acyl addition of organometallic reagents to aldehydes and ketones. (chapter 18, section
18.4)
• The reaction of alcohols and amines with aldehydes and ketones. (chapter 18, sections
18.6, 18.7)
• Know the reactions that generate carboxylic acids. (chapter 17, section 17.4 and chapter
20, section 20.2)
• Know the reactions that generate acid derivatives. (chapter 20, sections 20.3-20.6)
• Acyl substitution reactions. (chapter 16, section 16.8 and chapter 20, section 20.1)
• Recognize electron releasing and withdrawing substituents. (chapter 3, section 3.7 and
chapter 21, section 21.3)
• How to identify a good leaving group. (chapter 11, section 11.2)
• Know how to convert alkoxide anions to the corresponding alcohol via an acid-base
workup. (chapter 5, section 5.7 and chapter 6, section 6.2 and chapter 18, section 18.1)
• E- and Z nomenclature. (chapter 9, section 9.4)
• Absolute configuration and stereogenic centers. (chapter 9, sections 9.1, 9.3)
• Diastereomers. (chapter 9, section 9.5)
• Decarboxylation. (chapter 12, section 12.6)
When completed, you should know:
4
• The α-proton of a ketone or aldehyde is a weak acid, and can be removed by a strong
base to give a resonance stabilized enolate anion. Deprotonation may occur via the enol
tautomer. The α-proton of an aldehyde is slightly more acidic than that of a ketone.
• The α-proton of an aldehyde or ketone is less acidic as more carbon substituents are
added. As more electron withdrawing groups are added, the α-proton becomes more
acidic, so a 1,3-diketone is more acidic than a ketone. The more acidic proton of an
unsymmetrical ketone is the one attached to the less substituted carbon atom.
l•c
• Enolate anions react as nucleophiles. They give nucleophilic acyl addition reactions with
aldehydes and ketones. The condensation reaction of an aldehyde or ketone enolate with
another aldehyde or ketone is called an aldol condensation. Self-condensation of
symmetrical aldehydes or ketones leads to a single product under thermodynamic
conditions. Condensation between two different carbonyl compounds gives a mixture of
products under thermodynamic conditions, but can give a single product under kinetic
control conditions.
• Dialkyl amides are formed by the reaction of an amine with an organolithium reagent, and
they are considered to be non-nucleophilic bases.
• Kinetic control is favored by a strong base that generates a conjugate acid weaker than
the carbonyl compound, a polar aprotic solvent, short reaction times and low
temperatures. Thermodynamic control is favored by a strong base that generates a
conjugate acid stronger than the carbonyl compound, a polar protic solvent, long reaction
times, and high temperatures.
• Dehydration of enolate condensation products leads to a conjugated carbonyl
compound.
• The intramolecular condensation of an α,ω-dialdehyde or diketone leads to a cyclic
compound.
When completed, you should know:
5
• An ester enolate is formed by reaction with a strong base, and the resulting enolate anion
can condense with an aldehyde, a ketone, or another ester. Ester enolates react with
aldehydes or ketones to form β-hydroxy esters. aldehyde or ketone enolate anions react
with esters to form β-hydroxy esters, 1,3-diketones or β-keto aldehydes.
• Enolate anions react as nucleophiles. They give nucleophilic acyl substitution reactions
with acid derivatives. The condensation reaction of one ester with another is called a
Claisen condensation and it generates a β-keto ester. A mixed Claisen condensation
under thermodynamic conditions leads to a mixture of products, but kinetic control
conditions can give a single product.
• The intramolecular Claisen condensation is called a Dieckmann condensation, and it
generates a cyclic compound.
• Malonic esters can be converted to the enolate anion and condensed with aldehydes,
ketones, or acid derivatives. The reaction of malonic acid with an aldehyde using pyridine
as a base is called the Knoevenagel condensation.
• A β-keto ester can be hydrolyzed to a β-keto acid, and heating leads to decarboxylation.
Malonic acid derivatives, as well as β-ketone acids decarboxylate upon heating.
• Enolate anions react with alkyl halides by a SN2 reaction to give alkylated carbonyl
compounds.
• Triphenylphosphine reacts with alkyl halides to form phosphonium salts. Organolithium
bases react with alkyltriphenylphosphonium salts to give phosphorus ylids are formed,
which react with aldehydes and ketones to give alkenes in what is known as the Wittig
reaction.
6
Aldehydes and Ketones are Weak Acids
• The carbonyl group is electron withdrawing with respect to the attached carbon atoms
in an aldehyde or ketone.
• The carbonyl group will induce a dipole in the adjacent carbon (the α-carbon is δ–),
which in turn leads to a dipole between that carbon and its attached hydrogen (the αproton), as shown in 1.
• This so-called α-hydrogen or α-proton is δ+.
• The presence of a carbonyl group in an aldehyde or a ketone makes the α-proton
slightly acidic.
• The α-proton in an aldehyde has an experimentally measured pKa of about 15-16
(about the same as the OH unit in methanol or ethanol), and the pKa of the α-proton of a
ketone is about 19-21.
• Aldehydes are slightly stronger acids than ketones.
!"
H or R
1
O
O
!"
!+
C
R2
H
R1
!+
#-proton
#-carbon
+H
H or R
R2
R1
inductive effects
7
Keto-Eol Tautomerism
• Keto-Enol tautomerism occurs with ketones and aldehydes, and the
carbonyl form is more stable.
• For most aldehydes and ketones only a tiny amount of enol is present.
• Acetone (2), for example exists primarily as the ketone, and experiments show
only 1.5 x 10-4 % enol.
• The reaction of diatomic bromine and acetone converted 2 to 1-bromo-2-propanone
(α-bromoacetone, 4). The second product in this reaction is HBr.
• By this experiment, the enol content of acetone, and presumably of other simple
ketones, is remarkably small. This experiment shows that 4 is generated from 2.
O
OH
2
3
O
Br2
O
Br
2
4
+
HBr
8
Reaction with Diatomic Bromine
• The acid catalyzed reaction begins with the acid-base reaction of acetone to give
oxocarbenium ion 5, but the presence of an acid catalyst also increases the percentage of enol
3.
• Enol 3 reacts with diatomic bromine as a nucleophile to give 6, which loses a proton to give
4.
• It is reasonable to assume that the reaction of 2 and bromine to give 4, without the acid
catalyst, also proceeds by the enol.
• Once the enol reacts the will acetone tautomerize to give more 3, which reacts with bromine.
In this way, acetone is converted to 4, but it is a slow process. The acid catalyst accelerates the
reaction.
O
H
O
H
H+
H+
O
H
Br–Br
2
5
H
Br–
+
3
O
O
Br
Br
6
O
4
9
Higher Enol Content
• The presence of heteroatoms at the α-carbon should stabilize the enol
form, and this is generally correct.
• Titration of 2,4-pentanedione (7; known as acetylacetone) with
bromine, as with the reaction of 2, gives 3-bromo-2,4-pentnaedione.
• There is 79.7% of the enol, 8, consistent with the concept of enol
stabilization by an adjacent heteroatom substituent.
O
O
7
H
O
O
8
Enolate Anions
10
• A carbonyl group is electron withdrawing, and there is a
"through-bond" inductive effect in 1.
• There is also a "through-space" inductive effect where the
negatively polarized carbonyl oxygen is attracted to the positively
polarized α-hydrogen.
• The inductive effects in the ketone or aldehydes are one
contributing factor to the acidity.
• Another major contributing factor is the charge delocalization
(resonance) of the conjugate base. A more stable conjugate base
shifts the equilibrium of the acid-base reaction to the right (more
product) leading to a large Ka (smaller pKa), which is equated with
greater acid strength.
11
Enolate Anions
• The conjugate base of the acid base reaction with 1 is 9, an enolate anion. Enolate anion 9 is
resonance stabilized and there are two resonance contributors.
• The negative charge is delocalized on oxygen in resonance contributor 9A and on carbon in
resonance contributor 9B.
• The electron potential map 9C shows the charge distribution, and more red (higher electron
density) is concentrated on the carbon than on the oxygen, although this depends on the
counterion.
• This resonance delocalization makes the conjugate base 9 more stable, which shifts the acidbase equilibrium to the right.
• The α−proton in 2 is easier to remove (i.e., that hydrogen atom is more acidic).
H:Base
(acid)
(base)
(conjugate base)
(conjugate acid)
O
O
H
O
:Base
CH2
2
CH2
9A
O
!–
9C
:Base
3
!+
!–
O
O
H
9B
CH2
CH2
9B
9A
12
Enolate Anions
• The acid-base reaction of 2 clearly shows that the δ+ polarized proton on the α-carbon of acetone
is the acid, and reaction with an undefined base gives a conjugate base (9) and a conjugate acid
(H-Base, as yet undefined).
• Deprotonation of carbon in 2 gives 9A, and the resonance contributor is 9B.
• Without addition of any base, a small amount of enol 3 is present along with 2 due to
tautomerization (see above).
• Once added, the base may react with the acidic proton of the enol rather than with the α-proton to
give 9B, which is a resonance contributor with 9A.
• Since the keto form (2) is the dominant species, deprotonation of 2 to give 9 is commonly used to
describe this reaction, but deprotonation via the enol is a viable mechanistic pathway.
H:Base
(acid)
(base)
(conjugate base)
(conjugate acid)
O
O
H
O
:Base
CH2
2
CH2
9A
O
:Base
3
O
O
H
9B
CH2
CH2
9B
9A
13
Enolate Anions
• When compared to carboxylic acids with a pKa of 1-5, ketones and aldehydes (pKa of about 1521) are weak acids. Acetone (2) has a pKa for the α-hydrogen of about 20.
• A very strong base is required to remove the proton (in red) from the α-carbon.
• The term strong base means that the conjugate acid generated from the base must be a
much weaker acid than acetone, so the pKa of that conjugate acid must be >22 on average.
• The pKa of the α-proton in acetone (2) is about 20.
• With a focus on the proton marked in red, 3,3-dimethyl-2-butanone (10), has a pKa of about 20.8.
• 11 has a pKa of about 21.3.
• An alkyl group such as methyl is electron releasing relative to the carbonyl group, and the
presence of one methyl group on the α-carbon in 11 makes the α-proton less acidic by about 0.5
pKa unit when compared with 10.
• If a phenyl group is attached to the α-carbon, as in 1-phenyl-1-ethanone (12; acetophenone), the
α-proton more polarized and more acidic. The pKa of the proton in 12 is about 16.5.
• The α-proton of an aldehyde is generally more acidic than that of a ketone, as noted above.
• The measured pKa of the proton in acetone (2, a ketone) is 20, and that of ethanal (acetaldehyde,
13) is 16.5.
O
O
O
O
O
H
H3C
C
2
H
H
H
H
10
H
11
12
H
13 H
14
Electron Withdrawing Groups
• If an α-carbon has more than one electron withdrawing group, the α-proton becomes increasingly
acidic as the number of groups attached to the carbonyl increases.
• The pKa of 2 is 20 whereas the pKa of 14 is 16.5, and that of 15 is 15.
• The electronegativity of the chlorine atom makes it electron withdrawing, so the α-proton in 14 is
expected to be more polarized and more acidic relative to the α-proton in 2, leading to an increase
in acidity of about 4.5 pKa units.
• The second electron withdrawing chlorine atom in 15 makes the α-proton even more acidic, but
the effect on pKa is not as large. I
• In general, the more powerful the electron withdrawing properties of a substituent at the αcarbon, the more acidic the α-proton, and the more powerful the electron releasing
properties of the substituents, the weaker the acidity of the α-proton.
• The enol content of chlorinated ketones 14 and 15 should be much higher.
O
O
O
H
H3C
C
2
H
Cl
H
H3C
C
14
H
H
Cl
H3C
C
15
H
Cl
15
Electron Withdrawing Groups
• If the pKa of methane is 58.
• cyanomethane (16; acetonitrile) has a pKa of 24.
• dicyanomethane (17) has a pKa of 11.2.
• tricyanomethane (18) has a pKa of –5.
• The presence of a cyano group leads to greater acidity, and the more
cyano groups that are present, the greater the electron withdrawing
effect, and the greater the acidity (lower pKa).
H
H
C!N
H
H
methane
H
H
H
16
C!N
H
C!N
H
17
C!N
C!N
C!N
H
18
16
Acyl Addition. The aldol condensation
• When an aldehyde was treated with an alkoxide base in an alcohol solvent heated to
reflux (heated at the boiling point of the alcohol). When the initial product was treated
with dilute aqueous acid at low temperatures, a β-hydroxy aldehyde (known
generically as an aldol) was isolated.
• This reaction has come to be called the aldol condensation.
• A typical example treats butanal (21) with NaOEt in refluxing ethanol, and an
aqueous acid second step (known as a reaction workup) gives 22 in 75% yield.
• When the reaction is repeated, but treated in the second step with hot and
concentrated acid, a conjugated aldehyde product (23) is formed in over 90% yield,
and it also contains 8 carbons.
• If 22, is isolated and purified, and then heated with aqueous acid, 23 is the product.
CHO
NaOEt
EtOH
reflux
21
CHO
CHO
H3O+
H3O+
dilute , 25°C
HO
heat
22
H3O+ , hot, concentrated
23
17
Aldol. Self-Condensation
• Formation of 23 is an acid-base reaction, and therefore an equilibrium
reaction.
• This means that 23 (the conjugate base) is in equilibrium with 21 (the acid).
• Under these conditions there is a small amount of 23 and a large amount of
21 at equilibrium.
• As 23 reacts with 21 the equilibrium is reestablished and, eventually, all of
21 reacts to give 24.
• A new carbon-carbon bond is formed in the product 24 (heavy bond marked
in blue), analogous to acyl addition of carbon nucleophile.
4
4
1
3
CHO
2
21
3
NaOMe
MeOH
O
2
4
reflux
1
H
2
O
6
7
H 21
O
8
6
24
8
H3O+
7
5
CHO
2
4
CHO
8
5
2
23B
3
1
3
1
17A H
O
4
3
1
5
HO
7
6
22
18
Mixed aldol reactions
• If acetone (2) is treated with aqueous NaOH in the presence of another carbonyl molecule such
as benzaldehyde (25), enolate (26) is formed in situ.
• This enolate anion may react with itself (with another molecule of 2 in a self-condensation
reaction), but it may also react with aldehyde 25 via acyl addition to give alkoxide 28.
• Mild hydrolysis gives the mixed aldol product, 26.
• There is a competition for the reaction of 27 with either 2 or 25 so at least two products are
possible in the reaction, 28 and the self-condensation product.
• In this reaction the second carbonyl derivative (25 in this case) does not have acidic an
hydrogen atom, so 27 is the only possible enolate anion.
• Under these conditions, enolate 27 is formed and if an excess of 25 is added, the major product
will 28 and then 26 after the aqueous acid workup.
O
1
3
H3C
2
CH3
3
NaOMe, MeOH, reflux
Ph
O
2
25
4
1
2
H3C
OH
H
4
Ph
26
O
O
H
H3O+
3
H3C
2
CH2
1
Ph
4
O
3
2
H3C
1
O
4
O
27
28
Ph
H
H
19
Non-Nucleophilic Bases
• When acetone reacts with NaOEt in ethanol to form enolate anion 27, it is a
reversible acid-base reaction.
• Unreacted ketone or aldehyde always remains in the reaction, and this fact allows
self-condensation to occur.
• Amide bases (R2N:–), derived from secondary amines (R2NH), will generate the
enolate anion, but the equilibrium is pushed far to the right (towards the enolate anion
product).
• A typical and highly useful amide base is lithium diisopropylamide (30; commonly
abbreviated as LDA), formed by the acid-base reaction of a powerful base such as
butyllithium and the hydrogen atom attached to nitrogen in the parent amine,
diisopropylamine (29).
• Diisopropylamine is an acid in this reaction and diisopropylamide is its conjugate
base, with a pKa of about 25.
N
29
H
n-BuLi
THF , -78°C
N:
30
Li
+ n-Bu–H
20
Non-Nucleophilic Bases
• If lithium diisopropylamide (30) reacts with the carbonyl carbon of acetone (2), the acyl
addition product via path a would be 31.
• The carbon groups around nitrogen (the basic atom) provide quite a bit of steric
hindrance, which makes it difficult for the nitrogen to approach the sp2 hybridized carbon
atom via path a.
• Acyl addition to give 31 is very slow to the point of not being competitive with an acidbase reaction.
• This poor reactivity of the amide base in acyl addition is expressed by saying that
nitrogen is a poor nucleophile in this reaction.
• The acid-base reaction of 30 and 2 (path b) proceeds smoothly to give enolate anion
27 (the conjugate base) and diisopropylamine (the conjugate acid).
• The acid-base reaction of 30 and 2 proceeds readily to form the enolate anion, but acyl
addition to form 31 is so slow that virtually no 31 is formed.
• Since lithium diisopropylamide is a good base but a poor nucleophile, it is
termed a non-nucleophilic base.
a
Me
:CH2
i-Pr2N–H
b
Li
N:
O
27
+
b
30
Me
H–CH2
a
N
O
2
Me
Li
Me
31
O
21
Non-Nucleophilic Bases
• 2-Pentanone (32) reacts first with LDA to form the enolate anion
(not shown) and then with benzaldehyde (25) to form the aldol
alkoxide product.
• Subsequent mild acid hydrolysis gives 33 in 80% yield.
• Virtually no self condensation of 32 is observed in this
experiment, which suggests that the reaction is largely
irreversible.
1. LDA , THF , -78°C
O
2.
H
Ph
3. H3O+
32
O
C
O 25
C3H7
C3H7
CH2
H
Ph
33 OH
22
Non-Nucleophilic Bases
• Assume that 2-pentanone reacts with LDA to give enolate anion 34 (the two
resonance forms are 34A and 34B).
• To account for the observed lack of self-condensation, the equilibrium for this
acid-base reaction must be pushed towards 34.
• It means that 32 has been converted almost entirely to 34 so there is little or
no 43 available to react.
• A different carbonyl compound may be added in a second chemical step to
give 35.
• This is an over-statement of the facts, but it is useful assumption that explains
the results. Note that benzaldehyde is used, which has no α-protons and
cannot form an enolate anion.
O
O
LDA
C3H7
C3H7
32
C3H7
34A
O
34A
C3H7
CH2
H3O+
C
H
CH2
C3H7
O
Ph
O
25
CH2
H
Ph
35 O
Li
O
C
CH2
H
Ph
33
OH
Unsymmetrical Ketones
23
• There are two acidic hydrogen atoms in 2-pentanone: the pKa of Ha is about
20 and that of Hb is about 21.
• The α-carbon that bears Ha (in red) has only hydrogen atoms attached to it.
As noted earlier, an alkyl group is electron releasing relative to the α-carbon of
a ketone or aldehyde, so Hb is less polarized than Ha (it has a smaller δ+).
• This observation is consistent with the observation that Hb is less acidic.
• 2-Pentanone (32) is called an unsymmetrical ketone since two different
groups are attached to the carbonyl (the common name of 32 is ethyl methyl
ketone, which reflects the fact that it is unsymmetrical).
• In an unsymmetrical ketone with different substituents on the different αcarbons, it is possible that those two α- protons will have different pKa values
and one may be more acidic than the other.
O
LDA
Hb
Ha
32