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

H OH

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.

ALDOL REACTION ‡ occurs between two aldehyde or ketone molecules with a catalytic base ‡ reaction can occur between two components that have alpha hydrogens ‡ reversible condensation reaction ‡ two highlights: enolate formation and nucleophilic attack at a carbonyl carbon ‡ Aldol products are: alpha-ß-unsaturated aldehydes/ketones and ß-hydroxy aldehydes/ketones .

O H C H H C H .Mechanism of the Aldol Reaction HO: Base removes an acidic alpha hydrogen from one aldehyde molecule. yielding a resonancestabilized enolate ion.

.O : O: C CH3 H . :O : - .. 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 .

.OH C C H3 HH H H Protonation of the alkoxide ion intermediate yields neutral aldol product and regenerates the base catalyst.H 2O :OH C O C + .

Dehydration of Aldol Products: Synthesis of Enones ‡ ß-hydroxy aldehydes and ß-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 .

: O: OH C C C Enolate ion O C C C + OH- .Dehydration of Aldol Products Base-catalyzed O C C OH C H OH ..

Acid-catalyzed O C C OH C H O C C H + H O C C Enol OH2+ C C + H3 O + .

Mixed Aldol Reaction ‡ If two similar aldehydes/ketones react under aldol conditions. . 4 products may be formed ‡ A single product can be formed from two different components : If one carbonyl component has no alphahydrogens or if one carbonyl compound is much more acidic than the other.

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 .

Hexanedione .5. 5hexanedione yields 3-methyl-2cyclopentenone O C CH3 H b a C CH 3 H C C H H O 2.Intramolecular Aldol Reaction of 2.

Path A -OH O H -H C C H C CH3 C C H H H O H C C H H C CH3 C C H H H OH O .

O H H C C H H C C CH3 H C H OH O H O + 2 CH 3 3-Methyl-2-cyclopentenone .. :OH .NaOH. H2O ..

OH . H2O O C CH3 H C CH3 C C H H H O .Path b NaOH.

C H C H O O H H C C H H C CH3 H C C H O . H O H H C C H H C CH3 .. H O ...

OH H 3C .. :OH . H CH3 H3C O O H3 C + H2 O (2-Methylcyclopropenyl)ethanone (NOT formed) ..

Claisen Condensation Reaction ‡ Carbonyl condesation that occurs between two ester components and gives a ß-keto ester product ‡ Reaction is reversible and has a mechanism similar to aldol reaction ‡ Major difference from aldol condensation is the expulsion of an alkoxide ion from the tetrahedral intermediate of the initial Claisen adduct ‡ 1 equivalent of base is needed to drive the reaction to completion because the product is often acidic .

Mechanism of Claisen Condensation: ‡ involves nucleophilic acyl substitution of an ester enolate ion on the carbonyl group of a second ester molecule ‡ tetrahedral intermediate expels an alkoxide leaving group to yield an acyl substitution product .

OEt .Mechanism of the Claisen Condensation Reaction O Ethoxide base abstracts an acidic alpha hydrogen atom from an ester molecule. yielding an ester enolate ion CH3COEt .

this ion adds to a second ester molecule. giving a tetrahedral intermediate. It expels ethoxide ion to yield the new carbonyl compound.O :CH2COEt Nucleophilic donor + EtOH In a nucleophilic addition.. ethyl acetoacetate. . :O: CH3C OEt Electrophilic acceptor . :O: OEt O CH3C CH2COEt The tetrahedral intermediate is not stable.

. O O CH3 CCH2 COEt + Et O- O_ O CH3 CCHCOEt + EtOH . thus shifitng the equilibrium and driving the reaction to completion..But ethoxide ion is basic enough to convert the beta-keto ester product into its enolate.

O O CH3CCH2COEt + OH2 .H3O+ Protonation by addition of acid in a separate step yields the final product.

Mixed Claisen Condesation ‡occurs only when one of the two ester components has no alpha-hydrogens. and thus can¶t form enolate ion ‡can also be carried out between esters and ketones resulting a synthesis of ß-diketones .

H30 + Ethyl benzoylacetate O O C CH2 COEt EtO H . NaH/THF 2.Example of Mixed Claisen Condensation O C OEt Ethyl Benzoate (Acceptor) O + C H3 COEt Ethyl Acetate (Donor) 1.

Intramolecular Claisen Condensation: Dieckmann Cyclization ‡ can be carried out with diesters ‡ works best on 1. 6-diesters and 1.6-diesters ‡ 6-membered cyclic ß-keto esters result from cyclization of 1.7-diesters .7-diesters ‡ 5-membered cyclic ß-ketoesters result from Dieckmann cyclization of 1.

ethanol 2. Na+ -OEt.7. Na+ -OEt. H3O+ O O C OEt EtOH OEt Ethyl 2-oxocyclopentanecarboxylate (82%) O OEt O OEt Diethyl heptanediote (a 1. ethanol 2.Examples of Intramolecular Claisen Condensation O OEt O Diethyl hexanedioate (a 1. H3O+ O O C + OEt Ethyl-2-oxocyclohexane carboxylate .Diester) 1.6 -Diester) 1.

yielding an enolote ion. H H COOEt Na + .OEt .Intramolecular Claisen Condensation Mechanism O OEt Base abstracts an acidic alpha-proton from the carbon atom next to one of the ester groups.

.. : O H - + EtOH tEO COOEt Intramolecular nucleophilic addition of the ester enolate ion to the carbonyl group of the second ester group at the other end of the chain then gives a cyclic tetrahedral intermediate..

.tEO : O: . - H COOEt Loss of alkoxide ion from the tetrahedral intermediate forms a cyclic beta-keto ester. .

.. - COOEt O + EtO H . : . . + Deprotonation of the acidic beta-keto ester gives an enolate ion« O H COOEt tEO .

H 3O + «which is protonated by addition of aqueous acid at the endoth the reaction to generate the neutral beta-keto ester product. +H O 2 H COOEt O .

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

The Michael Reaction O C The base catalyst removes an acidic alpha proton from the starting beta-keto ester to generate a stabilized enolate ion nucleophile. O C C CH3 H Na .OEt + EtO H .

. O + EtOH C .C The nucleophile adds to the alpha..O O C . C CH3 unsaturated ketone O H H electrophile in a Michael reaction to C C generate a new enolate H3C C H as product. H3C C H H HO C C C CH3 H CO2Et .beta-keto EtO .

EtOH O H H O C C C H3C C C CH3 + EtOH H H CO2Et . either from solvent or from starting keto ester. to yield the final addition product.The enolate product abstracts an acidic proton.

Some Michael Acceptors and Michael Donors Michael Acceptors H2C CHCHO Propenol H2C CHCO2Et Ethyl Propanoate H2C CHC N Propenenitrile H2C CHCOCH3 3-Buten-2-one H2C CHNO2 Nitroethylene H2C CHCONH2 Propenamide Michael Donors Beta-Diketone RCOCH2COR' RCOCH2CO2Et Beta-Keto Ester EtO2 CCH2 CO2Et Malonic Ester RCOCH2C N Beta-Keto nitrile RCH2NO2 Nitro compound .

ß-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.ßunsaturated carbonyl compound . ßunsaturated 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.Stork Enamine Reaction ‡ enamine adds to an alpha.

Example of Stork Enamine Reaction O N H N . H 2C O CHCCH 3 -H 2O Cyclohexanone ..O N+ .5-diketone . CH 2CHCCH 3 An enamine N O CH 2CH 2CCH 3 OH2 O O CH2CH2CCH3 + N H A 1..

Robinson Annulation Reaction: Carbonyl Condensation Reaction in Synthesis ‡ leads to the formation of substituted cyclohexenones ‡ 2 step process: Michael reaction Intramolecular Aldol reaction ‡ Treatment of a ß-diketone or ß-keto ester with an alpha. which is followed by intramolecular aldol cyclization . ßunsaturated ketone leads first to a Michael addition.

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