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Chemistry 213 Clark College

Reactions at the α–Carbon

By exploiting the acidity of hydrogens attached to the carbon directly adjacent to a carbonyl (the α–
carbon), a new carbon nucleophile can be created, which is referred to as the enolate ion. This
nucleophile can behave similarly to other nucleophiles, by attacking halogens like alkenes, by
displacing 1° halides in SN2 reactions, and attacking electrophilic carbonyl carbons. We will focus on
the latter and investigate this category of condensation reactions.
Forming the Enolate Ion
Let’s consider the α–proton of propanal:

O O O
! The Enolate Ion!
H H H
H B
When the α–proton is removed by a base, the formed anion (conjugate base) is resonance-stabilized
through the carbonyl. This resonance structure, along with the inductive proximity of the carbonyl
group increase the acidity of this position, thus the pKa of a typical α–proton is 18-20. With this pKa, α–
protons are completely deprotonated with strong bases such as LDA, and are partially deprotonated
with common bases such as hydroxides or alkoxides. Each base will have its own utility based on
reactivity. To view this, we shall first investigate aldol reactions.
The Aldol Reaction
O O O OH O H
B B
H H H H
H

Aldol Product Dehydration Product


The aldol reaction brings together two aldehydes or ketones, with one acting as the enolate nucleophile
and the other as the carbonyl electrophile. Depending on the base used to deprotonate the α–carbon,
the reaction can either stop at the aldol product or proceed to the dehydration product, which is an
α,β-unsaturated carbonyl compound. We will first look at the mechanism using NaOH as the base; as
we do, observe the catalytic nature of the hydroxide base.
Aldol Product
H OH
O O O O O O OH

H H H H H
H
H HO
OH E2

O
Dehydration Product
(mix of E and Z isomers) H

The hydroxide begins by deprotonating the α–carbon, which then attacks the carbonyl carbon of
another aldehyde, opening up the carbonyl π bond. Protonating the carbonyl oxygen regenerates the
base and forms the aldol product. This hydroxide ion can then cause an E2 elimination with the second
α–proton to form the dehydration product.

Enolate/Aldol Notes Spring 2008 Page 1 of 7


Chemistry 213 Clark College
Controlling the Aldol Reaction
By using hydroxide as the base, only a small fraction of the parent aldehyde is deprotonated, which
sets up a self-condensation reaction with a second molecule of the parent aldehyde, What if the
desired reaction involves two different aldehydes, or a ketone with two different α–protons? What if we
want the aldol product? We will investigate methods to control the aldol reaction using base selection
and reaction stoichiometry.
Crossed Aldol Reactions
A crossed aldol reaction occurs between two different aldehydes. This reaction can be done cleanly in
NaOH when one of the aldehydes has no α–protons and is present in a large excess:
O

H O H
H (xs)
H
O NaOH

With such stringent requirements, this method of control has limited utility. If we look to the mechanism
for clues to controlling reaction, the problem lays with the sodium hydroxide. Since sodium hydroxide is
not a strong enough base to fully deprotonate the α–carbon, it can be difficult to introduce a second
carbonyl compound. Additionally, since NaOH is catalytic, the dehydration product forms readily. To
solve this problem, a stronger base is required: LDA. By using LDA, the original aldehyde can be
completely deprotonated, so it is solely the nucleophile. Also, without a catalytic base, the reaction can
be stopped at the aldol product. If the dehydration product is desired, a second elimination reaction
can be performed.
O 1) LDA O OH
An acidic work-up is required
2) O to protonate to alcohol.
H H
H

3) H3O+
Aldol Reactions with Ketones
Using LDA stoichiometrically can also control ketone reactions. To illustrate this example, we will use
2-methylpent-3-ene. Two different enolates can form, a more-substituted enolate at the #2 carbon and
a less-substituted enolate at the #4 carbon. The more-substituted enolate ion forms a more-substituted
alkene, which makes it slightly more stable, and is therefore the thermodynamic product. However,
steric hinderance favors deprotonation of the more accessible side, yielding the kinetic product. These
can be selected for by specific stoichiometry. Since the kinetic product is formed first, using a slight
excess of LDA (1.01 equiv) forms only the less-substituted enolate. Once an enolate forms, can
actually deprotonate other carbonyl compounds to form other enolates, and over time, the more-
substituted (thermodynamic) enolate. To form the thermodynamic product, a slight deficit of LDA is
used (0.99 equiv), which allows the kinetic product to form, and then slowly is converted to the
thermodynamic product.
OH O O O OH
1) 0.99 equiv LDA 1) 1.01 equiv LDA
Ph Ph
2) O 2) O
Ph Ph
H H
3) H3O+ 3) H3O+

Enolate/Aldol Notes Spring 2008 Page 2 of 7


Chemistry 213 Clark College
Claisen Reactions
Aldol-type reactions can also occur with esters. The reactions proceed similarly, however the presence
of a leaving group on the electrophilic carbonyl carbon creates a β–ketoester product. Crossed Claisen
reactions can be controlled with LDA similarly as well.
The Mechanism
O O O O O O O

EtO EtO EtO EtO EtO


EtO
H H
OEt OEt
The proton between two carbonyls is very acidic (pKa = 11-13)!
The ethoxide will readily deprotonate this position. An acidic
work-up is necessary to full protonate all positions.

O O H3O+ O O

EtO EtO
Examples:
O O O
1) MeOH A !-ketoester
OMe 2) H3O+ MeO

O 1) LDA O O
2) O
EtO EtO
EtO

3) H3O+
Claisen and Aldol reactions can also be intramolecular reactions with dicarbonyl compounds (the
intramolecular Claisen is referred to as the Dieckmann reaction). Depending on the nature of the
compound and the number of α–protons, multiple products can form.
Examples:
O
O O
1) NaOEt 2
1 2 3 1
5
4 6 OEt 2) H3O+ 4
5
6
3
O
The only enolate that will
form a stable ring size

b
O O b: only 1 !-
NaOH
H proton, no
H H O dehydration
a HO
O a product can form!
H
This reaction can be controlled by judicious use of LDA!

Enolate/Aldol Notes Spring 2008 Page 3 of 7


Chemistry 213 Clark College

Reactions of β–Ketoesters
A unique feature of the β–ketoester products of claisen-type reactions is the ability readily
decarboxylate the ester group, providing a route for the synthesis of complex ketones. The
decarboxylation reaction proceeds via a 3-step process in which the ester is saponified to the
carboxylic acid, and then an intramolecular, concerted reaction occurs to form an enol and create
carbon dioxide. The enol readily tautomerizes to the ketone form of the molecule.
O O O
1) NaOH + CO2
EtO 2) H3O+
3) !
1+2

H
O O 3 O O OH

HO O

This process works only if the carbonyl is β to the ester group – this allows for the 6-membered ring
transition state. A few examples of this reaction are shown below.
O O O O
1) NaOEt 1) NaOH
+
Ph OEt 2) H3O+ Ph OEt 2) H3O Ph Ph
3) !
Ph A "traditional" Claisen reaction, followed by
decarboxylation, results in a symmetric ketone.
O O O O O
1) NaOEt 1) NaOH
EtO Ph 2) Br 2) H3O+ Ph
EtO Ph
3) !

This process is put to specific use in two industrial synthesis: the acetoacetic ester synthesis and the
malonic ester synthesis.
O O O O

OEt EtO OEt


Acetoacetic ester Malonic ester

Each compound is subjected to α–deprotonation and used as a nucleophile with a 1° alkyl halide in an
SN2-type subsitution. It is then followed by a decarboxylation, to yield a substituted acetone (from
acetoacetic ester) or a substituted acetic acid (from malonic ester).

Enolate/Aldol Notes Spring 2008 Page 4 of 7


Chemistry 213 Clark College
O O O O O O
1) NaOEt 1) NaOEt 1) NaOH
OEt 2) PhCH2I OEt 2) OEt 2) H3O+
Br Ph 3) !
Ph

Substituted
acetone
Ph

O O O O O
1) NaOEt 1) NaOH Substituted
EtO OEt 2) CH3CH2I EtO OEt 2) H3O+ acetic acid
HO
3) !

Reactions of α,β–Unsaturated Carbonyl Compounds


We have seen that the product of many aldol reactions is an α,β-unsaturated carbonyl compound. The
alkene bond is conjugated with the carbonyl group, which leads to additional resonance structures
when describing the electronic distribution within the molecule (and therefore the available sites of
nucleophilicity and electrophilicity).

O O O

H H H
All carbonyl compounds !,"-unsaturated compounds
have this resonance have an additional resonance
structure that describes structure which sets up an
the electrophilicity of the
additional electrophilic site on
carbonyl carbon.
the molecule!
Therefore, there are two reaction types to consider: the “traditional” reactions of carbonyl compounds
with a nucleophile, which is a 1,2-addition, and attack at the β–carbon, which is a 1,4-addition. The
route of attack depends on the type of nucleophile used – Grignard and organolithium reagents favor
attack at the carbonyl carbon, resulting in a 1,2-addition product, whereas Gilman reagents and enolate
ions favor attack at the β–carbon, resulting in a 1,4-addition product.
1,2-addition

O O OH
H+
Nuc
H H H
Nuc Nuc

1,4-addition

O O OH O
H+
Nuc
H H Nuc H Nuc H Nuc
Enol Keto

Enolate/Aldol Notes Spring 2008 Page 5 of 7


Chemistry 213 Clark College

Examples
O O OH
NaOH 1) tBuLi
H aldol H 2) H2O

1,2-addition with an alkyllithium reagent

Ph
O
1) (PhCH2)2CuLi
2) H2O
H

1,4-addition with a Gilman Reagent


Michael Additions
Michael additions are 1,4-addtion reactions using an enolate nucleophile to an α,β-unsaturated
carbonyl compound. The resulting product of these reactions is a 1,5-dicarbonyl compound.
O O O
1) LDA
EtO 1 2) O 2
2 4 3 EtO 1 3
4
5
5
3) H3O+

The mechanism for the reaction begins by forming an enolate ion, which then attacks the β position of
the unsaturated carbonyl compound, technically forming another enolate ion with the negative charge
on the oxygen. Acidic work-up forms the enol, which tautomerizes to the keto product.

H+
O O O O O

EtO EtO EtO


H N

O O O OH

A 1,5-dicarbonyl compound EtO EtO

Some Examples:
O O O
NaOEt
OEt O EtO H
xs
H

Enolate/Aldol Notes Spring 2008 Page 6 of 7


Chemistry 213 Clark College

O O O O O O
NaOEt 1) NaOH
EtO OEt O EtO OEt 2) H3O+ HO Ph
3) !
Ph
O
Ph
After some Michael additions, an α–proton outside of the two carbonyls can be deprotonated to form a
ring-closed aldol/dehydration product. The combined process is called a Robinson Annulation (or a
ring-forming reaction!).

O O
O O
1) 0.99 eq LDA NaOH
2) O H
H
3) H3O+
The process and mechanism is a Michael addition followed by an aldol reaction. This can be done
step-wise, as shown in the example above, but first using LDA to form the enolate for the Michael
addition, and then doing the aldol/dehydration in NaOH. The reaction can also be performed using a
catalytic base, such as NaOH or NaOR.

O
O Ph O
O
NaOEt
H
H O
Ph
Ph

Michael product Dehydration product

Enolate/Aldol Notes Spring 2008 Page 7 of 7