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MCAT Organic Chemistry Review

The document describes various carbonyl condensation reactions including aldol reactions, Claisen condensations, and Michael additions. It provides mechanisms for key reactions like the aldol reaction and Claisen condensation. It also discusses intramolecular variants of these reactions that can generate cyclic products. Specific examples illustrated include the Dieckmann cyclization and Robinson annulation reaction.

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Vetina Lirio
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582 views

MCAT Organic Chemistry Review

The document describes various carbonyl condensation reactions including aldol reactions, Claisen condensations, and Michael additions. It provides mechanisms for key reactions like the aldol reaction and Claisen condensation. It also discusses intramolecular variants of these reactions that can generate cyclic products. Specific examples illustrated include the Dieckmann cyclization and Robinson annulation reaction.

Uploaded by

Vetina Lirio
Copyright
© Attribution Non-Commercial (BY-NC)
We take content rights seriously. If you suspect this is your content, claim it here.
Available Formats
Download as PPT, PDF, TXT or read online on Scribd
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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--unsaturated aldehydes/ketones and -hydroxy aldehydes/ketones

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 : -

H 2O

: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 C H
OH

.. : O:

OH C C

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

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

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

O C CH3 H b a C CH 3 H C C H H O

2,5- Hexanedione

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

NaOH, H2O

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

O H O + 2

CH 3 3-Methyl-2-cyclopentenone

Path b
NaOH, H2O

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

..

..

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

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

OH H 3C

.. :OH .. H CH3

H3C

H3 C + H2 O

(2-Methylcyclopropenyl)ethanone (NOT formed)

Claisen Condensation Reaction


Carbonyl condesation that occurs between two ester components and gives a -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

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
- OEt

O :CH2COEt
Nucleophilic donor

EtOH
In a nucleophilic addition, this ion adds to a second ester molecule, giving a tetrahedral intermediate.

:O: CH3C OEt

Electrophilic acceptor

.. :O: OEt

CH3C CH2COEt
The tetrahedral intermediate is not stable. It expels ethoxide ion to yield the new carbonyl compound, ethyl acetoacetate.

But ethoxide ion is basic enough to convert the beta-keto ester product into its enolate, thus shifitng the equilibrium and driving the reaction to completion.

O O CH3 CCH2 COEt + Et O-

O_ O CH3 CCHCOEt + EtOH ..

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

CH3CCH2COEt + OH2

Mixed Claisen Condesation


occurs only when one of the two ester components has no alpha-hydrogens, and thus cant form enolate ion can also be carried out between esters and ketones resulting a synthesis of -diketones

Example of Mixed Claisen Condensation


O C OEt
Ethyl Benzoate
(Acceptor)

O
+

C H3 COEt
Ethyl Acetate
(Donor)

1. NaH/THF 2. H30 +

Ethyl benzoylacetate

C CH2 COEt
EtO H

Intramolecular Claisen Condensation: Dieckmann Cyclization


can be carried out with diesters works best on 1, 6-diesters and 1,7-diesters 5-membered cyclic -ketoesters result from Dieckmann cyclization of 1,6-diesters 6-membered cyclic -keto esters result from cyclization of 1,7-diesters

Examples of Intramolecular Claisen Condensation


O OEt O
Diethyl hexanedioate (a 1,6 -Diester) 1. Na+ -OEt, ethanol 2. H3O+

O C OEt EtOH

OEt

Ethyl 2-oxocyclopentanecarboxylate (82%)

O OEt O OEt
Diethyl heptanediote (a 1,7- Diester) 1. Na+ -OEt, ethanol 2. H3O+

O C + OEt

Ethyl-2-oxocyclohexane carboxylate

Intramolecular Claisen Condensation Mechanism


O OEt
Base abstracts an acidic alpha-proton from the carbon atom next to one of the ester groups, yielding an enolote ion.

H H

COOEt

Na + - OEt

.. :

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.

. .

+
Deprotonation of the acidic beta-keto ester gives an enolate ion

H COOEt

tEO .
.

COOEt O
+

EtO H

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, -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


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 O C - C The nucleophile adds to the alpha,beta-keto EtO .. C CH3 unsaturated ketone O H H electrophile in a Michael reaction to C C generate a new enolate H3C C H 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 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

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 .. H 2C

O CHCCH 3

-H 2O Cyclohexanone
- O N+ .. CH 2CHCCH 3
An enamine

O CH 2CH 2CCH 3

OH2

O CH2CH2CCH3 + N H

A 1,5-diketone

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 -diketone or -keto ester with an alpha, unsaturated ketone leads first to a Michael addition, which is followed by intramolecular aldol cyclization

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