Lecture Notes in Chem.
2232
(Organic Chemistry II)
Dr. Joel R. Salazar
Chapter 5
Aldehydes and Ketones
II. Aldol Reactions
The Acidity of the a Hydrogens of Carbonyl
Compounds: Enolate Anions
Hydrogens on carbons a to carbonyls are unusually
acidic
◼ The resulting anion is stabilized by resonance to the carbonyl
◼ The enolate anion can be protonated at the carbon
or the oxygen
The resultant enol and keto forms of the carbonyl are
formed reversibly and are interconvertible
Keto and Enol Tautomers
Enol-keto tautomers are constitutional isomers that are
easily interconverted by a trace of acid or base
◼ Most aldehydes and ketones exist primarily in the keto
form because of the greater strength of the carbon-oxygen
double bond relative to the carbon-carbon double bond
b-Dicarbonyl compounds exist primarily in the enol
form
◼ The enol is more stable because it has a conjugated p
system and because of stabilization of the enol through
hydrogen bonding (more acidic pka =9 )
Reactions via Enols and Enolate Anions
◼ Reactions proceed via acid and base catalysts
◼ The intermediate enol or enolate has no stereocenter at the a
position
The mechanisms of base and acid catalysed
racemization are shown below
◼ Halogenation of Ketones
Ketones can be halogenated at the a position in the
presence of acid or base and X2
◼ Base-promoted halogenation occurs via an enolate
◼ Acid-catalyzed halogenation proceeds via the enol
◼ Haloform Reaction (test for methyl ketones)
Reaction of methyl ketones with X2 in the presence
of base results in multiple halogenation at the methyl
carbon
When methyl ketones react with X2 in aqueous hydroxide the
reaction gives a carboxylate anion and a haloform (CX3H)
◼ The trihalomethyl anion is a relatively good leaving group because
the negative charge is stabilized by the three halogen atoms
The Aldol Reaction: The Addition of
Enolate Anions to Aldehydes and Ketones
Acetaldehyde dimerizes in the presence of dilute
sodium hydroxide at room temperature
◼ The product is called an aldol because it is both an
aldehyde and an alcohol
The mechanism proceeds through the enolate anion
◼ Dehydration of the Aldol Product
If the aldol reaction mixture is heated, dehydration to
an a,b-unsaturated carbonyl compound takes place
◼ Dehydration is favorable because the product is stabilized by
conjugation of the alkene with the carbonyl group
In some aldol reactions, the aldol product cannot be isolated
because it is rapidly dehydrated to the a,b-unsaturated
compound
◼ Synthetic Applications
The aldol reaction links two smaller molecules and
creates a new carbon-carbon bond
Aldol reactions with ketones are generally
unfavorable because the equilibrium favors the
starting ketone
◼ The use of a special apparatus which removes product from
the reaction mixture allows isolation of a good yield of the
aldol product of acetone
◼ The Reversibility of Aldol Additions
Aldol addition products undergo retro-aldol reactions
in the presence of strong base
◼ Acid-Catalyzed Aldol Condensation
This reaction generally leads directly to the
dehydration product
Crossed Aldol Reactions
Crossed aldol reactions (aldol reactions involving two
different aldehydes) are of little use when they lead to
a mixture of products
◼ Practical Crossed Aldol Reactions
Crossed aldol reactions give one predictable product
when one of the reaction partners has no a hydrogens
◼ The carbonyl compound without any a hydrogens is put in
basic solution, and the carbonyl with one or two a
hydrogens is added slowly
◼ Dehydration usually occurs immediately, especially if an
extended conjugated system results
◼ Claisen-Schmidt Reactions
Crossed-aldol reactions in which one partner is a
ketone are called Claisen-Schmidt reactions
◼ The product of ketone self-condensation is not obtained
because the equilibrium is not favorable
◼ Condensation with Nitroalkanes
The a hydrogens of nitroalkanes are weakly acidic
(pKa = 10) because the resulting anion is resonance
stabilized
Nitroalkane anions can undergo aldol-like
condensation with aldehydes and ketones
◼ The nitro group can be easily reduced to an amine
Cyclization via Aldol Condensations
Intramolecular reaction of dicarbonyl compounds proceeds to form five-
and six-membered rings preferentially
◼ In the following reaction the aldehyde carbonyl carbon is attacked
preferentially because an aldehyde is less sterically hindered and
more electrophilic than a ketone
Lithium Enolates
In the presence of a very strong base such as lithium
diisopropyl amide (LDA), enolate formation is greatly
favored
◼ Weak bases such as sodium hydroxide produce only a small
amount of the enolate
◼ Regioselective Formation of Enolate Anions
Unsymmetrical ketones can form two different
enolates
The thermodynamic enolate is the most stable enolate
i.e. the one with the more highly substituted double
bond
◼ A weak base favors the thermodynamic enolate because an
equilibrium between the enolates is estabilished
The kinetic enolate is the enolate formed fastest and it
usually is the enolate with the least substituted double
bond
◼ A strong, sterically hindered base such as lithium
diisopropyl amide favors formation of the kinetic enolate
◼ Lithium Enolates in Directed Aldol Reactions
Crossed aldol reactions proceed effectively when a
ketone is first deprotonated with a strong base such as
LDA and the aldehyde is added slowly to the enolate
An unsymmetrical ketone can be selectively
deprotonated with LDA to form the kinetic enolate
and this will react with an aldehyde to give primarily
one product
◼ Direct Alkylation of Ketones via Lithium
Enolates
Enolates can also be alkylated with primary alkyl
halides via an SN2 reaction
◼ Unsymmetrical ketones can be alkylated at the least
substituted position if LDA is used to form the kinetic
enolate
Constraints on Enolate Alkylation
SN2 reaction:, the leaving group X can be chloride,
bromide, iodide, or tosylate
R should be primary or methyl and preferably should
be allylic or benzylic
Secondary halides react poorly, and tertiary halides
don't react at all because of competing elimination
a-Selenation: A Synthesis of a,b-
Unsaturated Carbonyl Compounds
A lithium enolate can be selenated with
benzeneselenyl bromide
The a-selenyl ketone is converted to the a,b-
unsaturated carbonyl compound by reaction with
hydrogen peroxide
◼ Elimination of the selenoxide produces the unsaturated
carbonyl
Additions to a,b-Unsaturated Aldehydes and
Ketones
a,b-Unsaturated aldehydes and ketones can react by
simple (1,2) or conjugate (1,4) addition
◼ Both the carbonyl carbon and the b carbon are electrophilic
and can react with nucleophiles
Stronger nucleophiles such as Grignard reagents
favor 1,2 addition whereas weaker nucleophiles such
as cyanide or amines favor 1,4 addition
◼ Conjugate Addition of Organocopper Reagents
Organocopper reagents add almost exclusively in a
conjugate manner to a,b-unsaturated aldehydes and
ketones
◼ Michael Additions
Addition of an enolate to an a,b-unsaturated carbonyl
compound usually occurs by conjugate addition
This reaction is called a Michael addition
A Robinson annulation can be used to build a new six-
membered ring on an existing ring
◼ Robinson annulation involves a Michael addition followed
by an aldol condensation to close the ring
Robinson Annulation
A Michael reaction to form a δ-diketone
followed by an intramolecular aldol
condensation to form a cyclohexenone.
H
C CH3
CH3 _
H C H OH
H
+
C
O H3C O O
=>
Mechanism for
Robinson Annulation (1)
=>
Mechanism for
Robinson Annulation (2)
=>