CARBONYL CONDENSATION REACTIONS

CARBONYL CONDENSATION REACTIONS

Aldol Reaction Dehydration of Aldol Products Intramolecular Aldol Reaction Claisen Condensation Reaction Intramolecular Claisen Condensation Michael Reaction Stork Enamine Reaction Robinson Annulation Reaction

General Mechanism of Carbonyl Condensation

O C R C

H OH
One carbonyl partner with an alpha hydrogen atom is converted by base into its enolate ion.

OH2 R
This enolate ion acts as a nucleophilic donor and adds to the electrophilic carbonyl group of the acceptor partner

O C C:

Nucleophilic Donor

:O: C
Electrophilic Acceptor

O C R C C

..

O
..

OH2

O C R

C C OH
New C-C Bond

-OH

Protonation of the tetrahedral alkoxide ion intermediate gives the neutral condensation product.

Mechanism of the Aldol Reaction

HO:
Base removes an acidic alpha hydrogen from one aldehyde molecule, yielding a resonancestabilized enolate ion.

O H C H H C H

: O: C CH3

.. C

+ H2O

C
H H

H
The enolate ion attacks a second aldehyde molecule in a nucleophilic addition reaction to give a tetrahedral alkoxide ion intermediate.

O CH3 C C C H HH H H

.. :O : -

H2O

: OH C

C + OH C C H3 HH H H
Protonation of the alkoxide ion intermediate yields neutral aldol product and regenerates the base catalyst.

Dehydration of Aldol Products: Synthesis of Enones

-hydroxy aldehydes and -hydroxy ketones formed in aldol reactions can be easily dehydrated to yield conjugated enones Dehydration is catalyzed by both acid and base Reaction conditions for dehydration are only slightly more severe than for condensation Conjugated enones are more stable than nonconjugated enones

Dehydration of Aldol Products

Base-catalyzed

O C C

OH
OH

.. :O :

OH C C

C H

Enolate ion

O C C C
+

OH-

Acid-catalyzed

O C C

OH C H
O C C
H
+

O C C
Enol

OH2+ C

H3O

Intramolecular Aldol Reaction:

Treatment of certain dicarbonyl compounds with base can lead to cyclic products A mixture of cyclic products may result , but the more strain-free ring is usually formed

Intramolecular Aldol Reactions

Intramolecular aldol reactions are most successful for formation of five- and six-membered rings. Consider 2,7-octadione, which has two a-carbons.
a O a O KOH HO O a O KOH OH (n ot formed) -H2 O -H2 O (formed) O O

O 2,7-Octanedione O a

Intramolecular Aldol Reaction of 2, 5hexanedione yields 3-methyl-2-cyclopentenone

O C CH3 H b a C CH3 H C C H H O

2,5- Hexanedione

Path A

-OH

H C C- H H C CH3 C C H H H O
H C C H H C CH3 C C H H H OH O

NaOH, H2O

.. :O H .. O H H C C H HC CH3 C C H H OH

O H O + 2

CH 3 3-Methyl-2-cyclopentenone

Claisen Condensation, Ester Substitution

Esters also form enolate anions which participate in nucleophilic acyl substitution.
O 2 CH3 COEt Ethyl ethan oate (Ethyl acetate) 1 . EtO Na
+

+ EtOH CH3 CCH2 COEt 2 . H2 O, HCl Eth yl 3-oxobutanoate Ethanol (Ethyl acetoacetate)

The product of a Claisen condensation is a -ketoester.

O O a C C C
A -ketoest er

Recognition Element

OR

Claisen Condensation
Claisen condensation of ethyl propanoate
O OEt Ethyl propan oate
+

O OEt Ethyl propan oate

1 . Et O Na

O OEt + EtOH

2 . H2 O, HCl

Eth yl 2-methyl-3oxopen tan oate (racemic)

Here the enolate part of one ester molecule has replaced the alkoxy group of the other ester molecule.

Mechanism: Claisen Condensation

Step 1: Formation of an enolate anion.
Et O O + H CH -COEt 2 pK a = 22 (w eaker acid) OO EtOH + CH2 -COEt CH2 =COEt pK a 15.9 Res on ance-s tab ilized enolate anion (stronger acid )

Step 2: Attack of the enolate anion on a carbonyl carbon gives a TCAI.

O CH 3 -C-OEt + O CH2 -COEt O
-

CH3 -C-CH2 -C-OEt OEt A tetrahedral carbonyl add ition in termediate

Mechanism: Claisen Condensation

Step 3: Collapse of the TCAI gives a -ketoester and an alkoxide ion.
O O CH3 -C-CH2 -C-OEt OEt O O CH3 -C-CH2 -C-OEt + Et O

Step 4: An acid-base reaction drives the reaction to completion. This consumption of base must be anticipated.
O O Et O + CH3 -C-CH-C-OEt H pK a 10.7 (stron ger acid) O O CH3 -C-CH-C-OEt + Et OH p Ka 15.9 (w eaker acid)

Intramolecular Claisen condensation: Dieckman Condensation

O Et O OEt O Die thyl h exanedioate (Dieth yl adipate)
+

1 . Et O Na

2 . H2 O, HCl O O OEt Ethyl 2-oxocyclopentanecarboxylate

+

Et OH

Acidic

Crossed Claisen Condsns

Crossed Claisen condensations between two different esters, each with a-hydrogens, give mixtures of products and are usually not useful. But if one ester has no a-hydrogens crossed Claisen is useful.
O HCOEt Eth yl formate O EtOCOEt Dieth yl carbonate OO EtOC-COEt Diethyl ethanedioate (Diethyl oxalate) O COEt Ethyl ben zoate

No a-hydrogens

Crossed Claisen Condsns

The ester with no a-hydrogens is generally used in excess.
O Ph OCH3 + O 1 . CH3 O Na OCH3 2 . H2 O, HCl
+

O Ph

O OCH3

Meth yl benzoate
Used in excess

Meth yl p ropan oate

Methyl 2-meth yl-3-oxo3-ph enylprop anoate (racemic)

Michael Reaction
Conjugate addition of a carbon nucleophile to an alpha, -unsaturated acceptor Best Michael Reactions: Between unusually acidic donors (-ketoesters or -diketones) Unhindered alpha,-unsaturated acceptors Stable enolates are Michael donors, and alpha,unsaturated compounds are Michael acceptors

The Michael Reaction

The base catalyst removes an acidic alpha proton from the starting beta-keto ester to generate a stabilized enolate ion nucleophile.

O C EtO H C

O C CH3 H
Na - OEt
+

O O C - C The nucleophile adds to the alpha,beta-keto EtO ..C CH3 unsaturated ketone H O H electrophile in a Michael reaction to C C generate a new enolate H H C C 3 as product.
O

EtOH

C .. H3C C H

H HO C C C CH3 H CO2Et

The enolate product abstracts an acidic proton, either from solvent or from starting keto ester, to yield the final addition product.

EtOH

O H H O C C C H3C C C CH3 + EtOH H H CO2Et

Some Michael Acceptors and Michael Donors

Michael Acceptors
H2C CHCHO Propenol H2C

Michael Donors

H2C H2C H2C H2C CHCONH2 Propenamide

Beta-Diketone RCOCH2COR' CHCO2Et Ethyl Propanoate RCOCH2CO2Et Beta-Keto Ester EtO2CCH2 CO2Et Malonic Ester CHC N Propenenitrile CHCOCH3 3-Buten-2-one RCOCH2C N Beta-Keto nitrile CHNO2 Nitroethylene RCH2NO2 Nitro compound

Stork Enamine Reaction

enamine adds to an alpha,-unsaturated carbonyl acceptor in a Michael- type process Overall reaction is a three-step sequence: Step 1: Enamine formation from a ketone Step 2: Michael-type addition to an alpha, unsaturated carbonyl compound Step 3: Enamine Hydrolysis back to ketone net effect of Stork Enamine reaction sequence is the Michael addition of a ketone to an alpha,unsaturated carbonyl compound

Example of Stork Enamine Reaction

O
N

N .. H2C

O CHCCH3

-H2O Cyclohexanone
O N+ .. CH2CHCCH3
An enamine

O CH2CH2CCH3

OH2

O CH2CH2CCH3 + N H

A 1,5-diketone

Enamines (and imines, Schiff bases)

Recall primary amines react with carbonyl compounds to give Schiff bases (imines), RN=CR2. Primary amine

But secondary amines react to give enamines Secondary Amine

Formation of Enamines
Examples:
O + N H O O + N H O H
+ + +

OH

H -H2 O

N An enamine O

OH

H -H2 O

An en amin e

Compare mechanisms of acid catalyzed aldol and enamine

O O CH3 -C-H + CH2 =C-H + :A-

O CH3 -CH-CH2 -C-H + H-A (racemic)

O SN2 N Br

OH

N
+

Br

The morph olin e en amin e of cyclohexan on e

3-Bromopropene (Allyl bromide)

An iminiu m bromid e (racemic)

Enamines - Alkylation
Hydrolysis of the iminium halide gives an alkylated aldehyde or ketone.
O N Br+

O HCl/ H 2 O 2-Allylcyclohexanone
+

O N ClH H Morpholinium chloride

+

Overall process is to render the alpha carbonss of ketone nucleophilic enough so that substitution reactions can occur.