Chapter 23 Carbonyl Condensation Reactions

Condensation Is a Chemical reaction in which two molecules or (functional groups) combine to form one single molecule, together with the loss of a small molecule. Usually water molecule.

Most common condensation reaction occurs between Carbonyl group and amino group such as condensation between two amino acids to form peptide.

Condensation between hydrazine hydrate or phenyl hydrazine with aldehydes and ketones to form characteristic hydrazones and with di carbonyl compound to form heterocyclic ring.

Also reaction of alcohols and acids which known as esterification is considered a condensation process because it involves a production of water molecule

Alpha Substitution Rxns (Ch. 22)

Carbonyl Condensation Rxns Treatment of acetaldehydes with strong base leads to formation of aldol

Deuterium Exchange in Carbonyl compounds

The Aldol Condensation

The Mixed Aldol Condensation

b) Aldol condensation Under the influence of or , two molecules of an aldehyde or a ketone, which , may combine to form a β-Hydroxy aldehyde or β-Hydroxy ketone. This reaction is called the . dilute base dilute acid contained α-hydrogen Aldol condensation

Mechanism:

If aldehyde or ketone does not contain an α-hydrogen, a simple Aldol condensation cannot take place. For example:

Outline Aldol Carbonyl Condensation Micheal Reaction Claisen

1. Carbonyl Condensation Carbonyl compounds are both the electrophile and nucleophile in carbonyl condensation reactions

Aldol Condensation Acetaldehyde reacts in basic solution (NaOEt, NaOH) with another molecule of acetaldehyde The b-hydroxy aldehyde product is aldol (aldehyde + alcohol) This is a general reaction of aldehydes and ketones

General Condensations

Mechanism of Aldol Reactions Aldol reactions, like all carbonyl condensations, occur by nucleophilic addition of the enolate ion of the donor molecule to the carbonyl group of the acceptor molecule The addition intermediate is protonated to give an alcohol product

Predicting Aldol Products The product will have an alcohol and a carbonyl in a 1,3 relationship (a beta-hydroxy carbonyl)

1. Claisen Condensation Condensation of Two Ester Molecules. The product of a Claisen condensation is a β-keto ester. In a Claisen condensation, one molecule of carbonyl compound is the nucleophile and second molecule is electrophile. The new C-C bond connect the α-carbon of one molecule and the carbon that was formerly the carbonyl carbon of the other molecule

Mechanism of the Claisen Condensation Similar to aldol condensation: nucleophilic acyl substitution of an ester enolate ion on the carbonyl group of a second ester molecule If the starting ester has more than one acidic a hydrogen, the product -keto ester has a doubly activated proton that can be abstracted by base Requires a full equivalent of base rather than a catalytic amount The deprotonation drives the reaction to the product

Learning Check: Predict the product of Claisen condensation of ethyl propanoate

Solution: Predict the product of Claisen condensation of ethyl propanoate

Mixed Claisen Condensations Successful when one of the two esters acts as the electrophilic acceptor in reactions with other ester anions to give mixed -keto esters

2.Conjugate Carbonyl Additions: The Michael Reaction Enolates can add as nucleophiles to ,-unsaturated aldehydes and ketones to give the conjugate addition product

Mechanism of the Michael Nucleophilic addition of a enolate ion donor to the  carbon of an ,-unsaturated carbonyl acceptor

Learning Check: Make the following using a Michael Reaction:

Solution: Make the following using a Michael Reaction:

Learning Check: Which of the following statements explains why the following aldehyde will not undergo an aldol reaction with itself? The benzene ring makes the carbonyl group unreactive towards aldol reactions. A carbonyl group must be connected to two alkyl groups in order to undergo an aldol reaction. The molecule does not possess any hydrogens α to the carbonyl group. Electrophilic aromatic substitution competes favorably with the aldol reaction. Nucleophilic acyl substitution competes favorably with the aldol reaction.

Solution: Which of the following statements explains why the following aldehyde will not undergo an aldol reaction with itself? The benzene ring makes the carbonyl group unreactive towards aldol reactions. A carbonyl group must be connected to two alkyl groups in order to undergo an aldol reaction. The molecule does not possess any hydrogens α to the carbonyl group. Electrophilic aromatic substitution competes favorably with the aldol reaction. Nucleophilic acyl substitution competes favorably with the aldol reaction.

Predict the aldol reaction product of the following ketone. Learning Check: Predict the aldol reaction product of the following ketone. 1. 2. 3. 4. 5. 1 2 3 4 5

Predict the aldol reaction product of the following ketone. Solution: Predict the aldol reaction product of the following ketone. 1. 2. 3. 4. 5. 1 2 3 4 5

What type of reaction occurs in a Claisen condensation? Learning Check: What type of reaction occurs in a Claisen condensation? electrophilic aromatic substitution nucleophilic addition hydrolysis nucleophilic acyl substitution decarboxylation

What type of reaction occurs in a Claisen condensation? Solution: What type of reaction occurs in a Claisen condensation? electrophilic aromatic substitution nucleophilic addition hydrolysis nucleophilic acyl substitution decarboxylation

Learning Check: Select the correct Claisen condensation product for the following reaction. 1. 3. 2. 5. 4. 1 2 3 4 5

Predict the outcome of the following reaction. Solution: Predict the outcome of the following reaction. 1. 2. 3. 5. 4. 1 2 3 4 5

Alkylation of Aldehydes and Ketones 23-4 Alkylation of Aldehydes and Ketones Alkylation of enolates can be difficult to control. The alkylation of an aldehyde or ketone enolate is an example of a nucleophilic substitution reaction.

The alkylation of aldehydes and ketones is complicated by several unwanted side reactions. E2 elimination: Enolate ion is a fairly strong base. Alkylation is normally feasible using only halomethanes or primary haloalkanes. Condensation Reactions: Aldehyde alkylations usually fail because their enolate ions undergo a highly favorable condensation reaction. Multiple Alkylations: Even ketones may lose a second -hydrogen and become alkylated a second time. Regioisomeric Products: If the starting ketone is unsymmetrical, either -carbon may be alkylated.

An example of a successful alkylation of a ketone: The ketone possesses a single -hydrogen and the primary allylic halide is an excellent SN2 substrate.

Enamines afford an alternative route for the alkylation of aldehydes and ketones. Secondary amines react with aldehydes or ketones to produce enamines. The nitrogen substituent renders the enamine carbon-carbon double bond electron-rich. This electron density is concentrated at the -carbon, which makes it nucleophilic.

As a result of its nucleophilicity, electrophiles may attack the -carbon of the enamine. Enamines will react with haloalkanes resulting in alkylation at carbon to produce an iminium salt. The iminium salt is hydrolyzed during aqueous work-up, liberating the newly alkylated aldehyde or ketone and the original secondary amine.

Alkylation of an enimine is far superior to the alkylation of an enolate. Minimizes multiple alkylations: The iminium salt formed after the first alkylation is unable to react with additional haloalkane. It can be used to prepare alkylated aldehydes (aldehyde enolates undergo aldol condensation reactions).

Attack by Enolates on the Carbonyl Function: Aldol Condensation 23-5 Attack by Enolates on the Carbonyl Function: Aldol Condensation Aldehydes undergo base-catalyzed condensations. Treating an aldehyde at low temperature with a small amount NaOH results in the formation of dimer, which, when heated, is converted into an ,-unsaturated aldehyde. This reaction is known as an aldol condensation. It is general for aldehydes and sometimes succeeds with ketones.

The hydroxide ion serves as a catalyst for the reaction. The overall reaction is not very exothermic and yields are only 50-60%.

At elevated temperatures, the aldol is converted into its enolate ion, which loses hydroxide (normally a poor leaving group) to form the relatively stable final product.

The aldol condensation yields different products depending upon the reaction temperature. Low temperatures: a -hydroxycarbonyl compound Higher temperatures: an ,-unsaturated carbonyl compound

Ketones can undergo aldol condensation. The driving force of the aldol reaction of ketones is less than that of aldehydes because of the greater stability of ketones (about 3 kcal mol-1). The reaction is endothermic. The reaction can be driven towards completion by the continuous extraction of alcohol, or under more vigorous conditions, dehydration and the removal of water.

Crossed Aldol Condensation 23-6 Crossed Aldol Condensation An aldol condensation between the enolate of one aldehyde and the carbonyl of another results in a crossed aldol condensation. Enolates of both aldehydes will be present and may react with the carbonyl groups of either starting compound.

A single aldol product can be obtained from the reaction of two different aldehydes when one of them has no enolizable hydrogen atoms. The reaction is carried out by slowly adding the enolizable aldehyde to an excess of the nonenolizable reactant in the presence of a base.

Intramolecular Aldol Condensation 23-7 Intramolecular Aldol Condensation An intramolecular aldol condensation results from the reaction of an enolate ion and a carbonyl group within the same molecule. Reaction between different aldehyde molecules is minimized by running the reaction in a dilute solution. The kinetics of intramolecular 5-membered ring formation are also favorable.

Intramolecular ring closures of ketones are a ready source of cyclic and bicyclic ,-unsaturated ketones. Usually the least strained ring is formed (typically 5- or 6-membered). Intramolecular aldol condensations of ketones succeed while intermolecular condensations fail because of the more favorable entropy change for ring closure (1 molecule  1 molecule rather than 2 molecules  1 molecule).