Chem34 L16 Carbonyl Condensation Reactions

Chem 34
Carbonyl Condensation Reactions

•  Reaction with other carbonyl compounds
–  The presence or absence of a leaving group on the

electrophilic carbonyl carbon determines the structure
of the product.
•  Four Types of Reactions:
–  Aldol reaction
–  Claisen reaction
–  Michael reaction
–  Robinson annulation
•  Every reaction (here) forms a new carbon-carbon bond at

the α carbon to a carbonyl group.
•  The Aldol Reaction
–  General Features:
•  Two molecules of an aldehyde or ketone react with each other in the
presence of a base to form a β-hydroxy carbonyl compound.
–  E.g.
–  Mechanism:
–  A reversible equilibrium.
–  The position of the equilibrium depends on the base and the
carbonyl compound.
•  -OH is the base
•  Aldol reactions can be carried out with either aldehydes or ketones
–  Aldehydes: equilibrium favors product
–  Ketones: equlibrium favors starting materials
–  An aldol reaction is a nucleophilic addition in which an
enolate is the nucleophile.
–  General Feature:
•  The α carbon of one carbonyl component becomes bonded to the
carbonyl carbon of the other component
–  Dehydration of the Aldol Product
•  Loses water from the α and β carbons to form an α,β-unsaturated
carbonyl compound.
–  Dehydration of the Aldol Product
•  Mechanism: Elimination, unimolecular, conjugate base (E1cB)
•  Two steps: deprotonation followed by loss of -OH
–  Retrosynthetic Analysis
•  E.g. What starting material is needed to prepare the following
compound by an aldol reaction?
•  Step 1: Locate the α and β carbons of the carbonyl group

–  When a carbonyl group has 2 different α carbons, choose the side that contains the
OH group (in a β-hydroxy carbonyl compound) or is a part of the C=C (in an α,β-
unsaturated carbonyl compound)
•  Step 2: Break the molecule into two components between the α and β
carbons.
–  The α carbon and all remaining atoms bonded to it belong to one carbonyl
component. The β carbon and all remaining atoms bonded to it belong to the other
carbonyl component. Both components are identical.
•  Crossed Aldol Reactions
–  An aldol reaction between two different carbonyl compounds is
called crossed aldol or mixed aldol reaction
–  When two different aldehydes both having α H atoms are

combined in an aldol reaction, four different β-hydroxy compounds
are formed - not synthetically useful.
•  Crossed Aldol reactions
–  Synthetically useful reactions:
•  A crossed aldol when only one carbonyl component has α H atoms.
•  E.g. Benzaldehyde (C6H5CHO; electrophile)acetaldehyde (CH3CHO) or

acetone ((CH3)2C=O) in the presence of base forms a single α,β–unsaturated
carbonyl compound after dehydration.
–  Synthetically useful reactions:
•  A crossed aldol when one carbonyl component has especially acidic α H

atoms.
•  The β-dicarbonyl compound always becomes the enolate component of the

aldol reaction.
–  Synthetically useful reactions: diethyl malonate and benzaldehyde
•  β-dicarbonyl compounds: active methylene compounds:

–  β-dicarbonyl compound
–  1,3-dinitriles
–  α-cyano carbonyl compounds
–  Useful Transformations of Aldol Products:
•  Directed Aldol reactions
–  Clearly defines which carbonyl compound becomes the

nucleophilic enolate and which reacts at the electrophilic carbonyl
carbon.
–  Strategy:
•  Prepare the enolate of one carbonyl component with LDA
•  Add the second carbonyl compound (the electrophile) to this enolate
•  Directed Aldol reactions
–  E.g.
•  Draw the product of the following directed aldol reaction:
•  2-methylcyclohexanone forms an enolate on the less substituted carbon, which

then reacts with the electrophile, CH3CHO
•  Intramolecular Aldol reactions
–  Aldol reactions with dicarbonyl compounds can be used to make
five- and six-membered rings.
–  Mechanism
•  Intramolecular Aldol reactions
–  Equilibrium favors formation of the more stable five-membered ring
over much less stable three-membered ring.
•  The Claisen Reaction
–  Two molecules of an ester react with each other in the presence of

an alkoxide base to form a β-keto ester.
–  A Claisen reaction is a nucleophilic substitution in which an enolate

is the nucleophile.
–  An example of nucleophilic substitution:
–  Mechanism:
•  The Crossed Claisen and Related Reactions
–  A Claisen reaction between two different carbonyl compounds is
called a crossed Claisen reaction.
–  (Synthetically) Useful Crossed Claisen Reactions

•  Between two different esters when only one has α hydrogens.
–  (Synthetically) Useful Crossed Claisen Reactions

•  Between a ketone and an ester.
–  Variations of the Crossed Claisen Reactions

•  Reaction of an enolate with ethyl chloroformate and diethyl
carbonate.
•  Dieckmann Reaction
–  Intramolecular Claisen reaction of diesters form five- and six-
membered rings
•  Enolate of one ester is the nucleophile
•  Carbonyl carbon of the other is the electrophile
•  Dieckmann Reaction
–  Mechanism
•  The Michael Reaction
–  Involves two carbonyl components – the enolate of one carbonyl
compound and an α,β-unsaturated carbonyl compound
–  Involves the conjugate addition (1,4-addition) of a resonance-

stabilized enolate to the β carbon of an α,β-unsaturated carbonyl
system.
–  The Michael reaction always forms a new carbon-carbon bond on

the β carbon of the Michael acceptor.
–  Mechanism:
•  The Robinson Annulation
–  A ring-forming reaction that combines a Michael reaction with an
intromolecular aldol reaction
–  Starting materials:
•  α,β-unsaturated carbonyl compound
•  Enolate
–  Forms a six-membered ring and three new carbon-carbon bonds

– two σ bonds and one π.
–  Mechanism: Part [1] Michael Addition to form a 1,5-dicarbonyl
compound
–  Mechanism: Part [2] Intramolecular Aldol Reaction to form a 2-
cyclohexenone.
–  A ring-forming reaction that combines a Michael reaction with an
intramolecular aldol reaction
•  The Four Major Carbonyl Condensation Reactions:
•  Useful Variations:
•  Useful Variations:

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Chem 34

Carbonyl Condensation Reactions

•  Reaction with other carbonyl compounds

–  The presence or absence of a leaving group on the

•  Every reaction (here) forms a new carbon-carbon bond at

•  Step 1: Locate the α and β carbons of the carbonyl group

–  When two different aldehydes both having α H atoms are

•  A crossed aldol when only one carbonyl component has α H atoms.

•  E.g. Benzaldehyde (C6H5CHO; electrophile)acetaldehyde (CH3CHO) or

•  A crossed aldol when one carbonyl component has especially acidic α H

•  The β-dicarbonyl compound always becomes the enolate component of the

•  β-dicarbonyl compounds: active methylene compounds:

–  Clearly defines which carbonyl compound becomes the

•  2-methylcyclohexanone forms an enolate on the less substituted carbon, which

–  Two molecules of an ester react with each other in the presence of

–  A Claisen reaction is a nucleophilic substitution in which an enolate

–  (Synthetically) Useful Crossed Claisen Reactions

–  (Synthetically) Useful Crossed Claisen Reactions

–  Variations of the Crossed Claisen Reactions

–  Involves the conjugate addition (1,4-addition) of a resonance-

–  The Michael reaction always forms a new carbon-carbon bond on

–  Forms a six-membered ring and three new carbon-carbon bonds

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Chem34 L16 Carbonyl Condensation Reactions

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Chem 34

Carbonyl Condensation Reactions

• Reaction with other carbonyl compounds

– The presence or absence of a leaving group on the

• Every reaction (here) forms a new carbon-carbon bond at

• Step 1: Locate the α and β carbons of the carbonyl group

– When two different aldehydes both having α H atoms are

• A crossed aldol when only one carbonyl component has α H atoms.

• E.g. Benzaldehyde (C6H5CHO; electrophile)acetaldehyde (CH3CHO) or

• A crossed aldol when one carbonyl component has especially acidic α H

• The β-dicarbonyl compound always becomes the enolate component of the

• β-dicarbonyl compounds: active methylene compounds:

– Clearly defines which carbonyl compound becomes the

• 2-methylcyclohexanone forms an enolate on the less substituted carbon, which

– Two molecules of an ester react with each other in the presence of

– A Claisen reaction is a nucleophilic substitution in which an enolate

– (Synthetically) Useful Crossed Claisen Reactions

– (Synthetically) Useful Crossed Claisen Reactions

– Variations of the Crossed Claisen Reactions

– Involves the conjugate addition (1,4-addition) of a resonance-

– The Michael reaction always forms a new carbon-carbon bond on

– Forms a six-membered ring and three new carbon-carbon bonds

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•  Reaction with other carbonyl compounds

–  The presence or absence of a leaving group on the

•  Every reaction (here) forms a new carbon-carbon bond at

•  Step 1: Locate the α and β carbons of the carbonyl group

–  When two different aldehydes both having α H atoms are

•  A crossed aldol when only one carbonyl component has α H atoms.

•  E.g. Benzaldehyde (C6H5CHO; electrophile)acetaldehyde (CH3CHO) or

•  A crossed aldol when one carbonyl component has especially acidic α H

•  The β-dicarbonyl compound always becomes the enolate component of the

•  β-dicarbonyl compounds: active methylene compounds:

–  Clearly defines which carbonyl compound becomes the

•  2-methylcyclohexanone forms an enolate on the less substituted carbon, which

–  Two molecules of an ester react with each other in the presence of

–  A Claisen reaction is a nucleophilic substitution in which an enolate

–  (Synthetically) Useful Crossed Claisen Reactions

–  (Synthetically) Useful Crossed Claisen Reactions

–  Variations of the Crossed Claisen Reactions

–  Involves the conjugate addition (1,4-addition) of a resonance-

–  The Michael reaction always forms a new carbon-carbon bond on

–  Forms a six-membered ring and three new carbon-carbon bonds