Aldehydes and Aldehydes and Ketones II Aldol Ketones II Aldol

ReactionsReactions

Chapter 17Chapter 17

The Acidity of the The Acidity of the -Hydrogens-Hydrogens of of Carbonyl Compounds: Carbonyl Compounds: Enolate Enolate

AnionsAnions

One important characteristic of aldehydes and ketones is their ability to undergo nucleophilic addition at their carbonyl groups

A second important characteristic of carbonyl A second important characteristic of carbonyl compounds is the unusual acidity of hydrogen compounds is the unusual acidity of hydrogen atoms on carbon atoms adjacent to the carbonyl atoms on carbon atoms adjacent to the carbonyl group. (These hydrogen atoms are usually called group. (These hydrogen atoms are usually called the the hydrogens hydrogens, and the carbon to which they , and the carbon to which they are attached is called the are attached is called the carboncarbon))

The carbonyl group is strongly electron withdrawing The carbonyl group is strongly electron withdrawing and when a carbonyl compound loses an a proton, and when a carbonyl compound loses an a proton, the anion that is produced is the anion that is produced is stabilized by stabilized by resonanceresonance. .

The negative charge of the anion is delocalizedThe negative charge of the anion is delocalized

When this resonance-stabilized anion accepts a proton, it can do so in either of two ways:

The resonance-stabilized anion is called an The resonance-stabilized anion is called an enolate anionenolate anion

Keto-Enol TautomersKeto-Enol Tautomers• The keto and enol forms of carbonyl compounds are constitutional The keto and enol forms of carbonyl compounds are constitutional

isomers.isomers.

• They can easily interconvert in the presence of traces of an acid and base.They can easily interconvert in the presence of traces of an acid and base.

• Interconverted keto and enol forms are said to be Interconverted keto and enol forms are said to be tautomerstautomers and and interconversion is called interconversion is called tatumerizationtatumerization

In compounds whose molecules have two carbonyl groups In compounds whose molecules have two carbonyl groups separated by one separated by one -CH-CH22- - group (group (called called -dicarbonyl compounds-dicarbonyl compounds), ),

the amount of enol present at equilibrium is far higherthe amount of enol present at equilibrium is far higher

This can be attributed to stability gained through resonance This can be attributed to stability gained through resonance stabilization in a cyclic form, through hydrogen bondingstabilization in a cyclic form, through hydrogen bonding

REACTIONS VIA ENOLS REACTIONS VIA ENOLS AND ENOLATE ANIONSAND ENOLATE ANIONS

RacemizationRacemization

When a solution of (+)-sec-butyl phenyl ketone in aqueous ethanol is treated with either acids or bases, the solution gradually loses its optical activity. After a time, isolation of the ketone shows that it has been racemized

Racemization takes place in the presence of acids Racemization takes place in the presence of acids or bases because the ketone slowly but reversibly or bases because the ketone slowly but reversibly changes to its enol and changes to its enol and the enol is achiralthe enol is achiral. When . When the enol reverts to the keto form, it produces equal the enol reverts to the keto form, it produces equal amounts of the two enantiomers.amounts of the two enantiomers.

A Mechanism for the A Mechanism for the ReactionReaction

Base Catalyzed Reaction

Acid Catalyzed Reaction

ProblemProblem

Would you expect optically active ketones Would you expect optically active ketones such as the following to undergo acid- or such as the following to undergo acid- or base-catalyzed acemization? Explain your base-catalyzed acemization? Explain your answeranswer

• Ketones that have an Ketones that have an hydrogen react hydrogen react readily with halogens by substitution. readily with halogens by substitution.

• Substitution takes place almost exclusively at Substitution takes place almost exclusively at the the carbon: carbon:

Halogenation of KetonesHalogenation of Ketones

Base-Promoted Base-Promoted HalogenationsHalogenations

A mechanism of the reaction:A mechanism of the reaction:

Acid-Catalyzed Acid-Catalyzed HalogenationsHalogenations

A mechanism of the reaction:A mechanism of the reaction:

When methyl ketones react with halogens in the When methyl ketones react with halogens in the presence of base, multiple halogenations always occur presence of base, multiple halogenations always occur

at the carbon of the methyl group. Multiple at the carbon of the methyl group. Multiple halogenations occur because introduction of the first halogenations occur because introduction of the first

halogen (owing to its electronegativity) makes the halogen (owing to its electronegativity) makes the remaining remaining hydrogens on the methyl carbon more hydrogens on the methyl carbon more

acidic acidic

The Haloform ReactionThe Haloform Reaction

Halogenation Step of the Haloform ReactionHalogenation Step of the Haloform Reaction

Cleavage Step of the Haloform Cleavage Step of the Haloform ReactionReaction

The haloform reaction is of synthetic utility as a means The haloform reaction is of synthetic utility as a means of converting methyl ketones to carboxylic acids. of converting methyl ketones to carboxylic acids.

THE ALDOL REACTION: THE ALDOL REACTION: THE ADDITION OF ENOLATE ANIONS TO THE ADDITION OF ENOLATE ANIONS TO

ALDEHYDES AND KETONESALDEHYDES AND KETONES

When acetaldehyde reacts with dilute sodium When acetaldehyde reacts with dilute sodium hydroxide at room temperature (or below), a hydroxide at room temperature (or below), a

dimerization takes place producing 3-hydroxybutanal. dimerization takes place producing 3-hydroxybutanal. Since 3-hydroxybutanal is both an aldehyde and an Since 3-hydroxybutanal is both an aldehyde and an

alcohol, it has been given the common name “aldol,” alcohol, it has been given the common name “aldol,” and reactions of this general type have come to be and reactions of this general type have come to be

known as known as aldol reactionsaldol reactions..

Mechanism for the Mechanism for the ReactionReaction

• If the basic mixture containing the aldol is heated, If the basic mixture containing the aldol is heated, dehydration takes place and 2-butenal dehydration takes place and 2-butenal

(crotonaldehyde) is formed. (crotonaldehyde) is formed. • Dehydration occurs readily because of the acidity Dehydration occurs readily because of the acidity

of the remaining of the remaining hydrogens and because the hydrogens and because the product is stabilized by having conjugated double product is stabilized by having conjugated double

bonds.bonds.

Dehydration of the Aldol Addition ProductDehydration of the Aldol Addition Product

The The aldol reactionaldol reaction is a general reaction of aldehydes is a general reaction of aldehydes that posses an that posses an hydrogen. hydrogen.

Synthetic ApplicationsSynthetic Applications

Problem Problem

The aldol reaction is important in organic The aldol reaction is important in organic synthesis because it gives us a method synthesis because it gives us a method for linking two smaller molecules by for linking two smaller molecules by introducing a carbon-carbon bond introducing a carbon-carbon bond between them. Because aldol products between them. Because aldol products contain two functional groups, contain two functional groups, -OH-OH and and --CHOCHO, we can use them to carry out a , we can use them to carry out a number of subsequent reactions. number of subsequent reactions.

One industrial process for the synthesis of One industrial process for the synthesis of 1-butanol begins with acetaldehyde. Show 1-butanol begins with acetaldehyde. Show how this synthesis might be carried out.how this synthesis might be carried out.

Problem

Show how each of the following products could be Show how each of the following products could be synthesized from butanal:synthesized from butanal:

(a) 2-Ethyl-3-hydroxyhexanal(a) 2-Ethyl-3-hydroxyhexanal

(b) 2-Ethyl-2-hexen-1-ol(b) 2-Ethyl-2-hexen-1-ol

(e) 2-Ethyl-1-hexanol(e) 2-Ethyl-1-hexanol

(d) 2-Ethyl-1,3-hexanediol(d) 2-Ethyl-1,3-hexanediol

Problem

Ketones also undergo base-catalyzed aldol additionsKetones also undergo base-catalyzed aldol additions

CROSSED ALDOL REACTIONSCROSSED ALDOL REACTIONS

An aldol reaction that starts with two different An aldol reaction that starts with two different carbonyl compounds is called a carbonyl compounds is called a crossed aldol crossed aldol

reactionreaction. If both reactants have . If both reactants have -hydrogens, the -hydrogens, the reactions give a complex mixture of products. reactions give a complex mixture of products.

ProbleProblemm

Show how each of the four products just given is Show how each of the four products just given is formed in the crossed aldol addition between formed in the crossed aldol addition between acetaldehyde and propanal.acetaldehyde and propanal.

Crossed aldol reactions an practical, using bases such as NaOH, Crossed aldol reactions an practical, using bases such as NaOH, when one reactant does not have an a hydrogen and so cannot when one reactant does not have an a hydrogen and so cannot undergo self-condensation because it cannot form an enolate anion. undergo self-condensation because it cannot form an enolate anion.

Claisen-Schmidt Claisen-Schmidt ReactionsReactions

When ketones are used as one component, the crossed aldol When ketones are used as one component, the crossed aldol reactions are called reactions are called Claisen-Schmidt reactionsClaisen-Schmidt reactions. When sodium . When sodium hydroxide is used ketones do not self-condense appreciably (The hydroxide is used ketones do not self-condense appreciably (The equilibrium is unfavorable).equilibrium is unfavorable).

Mechanism for the Mechanism for the ReactionReaction

•In the In the Claisen-SchmidtClaisen-Schmidt reactions dehydration occurs readily reactions dehydration occurs readily because the double bond that forms is conjugated both with the because the double bond that forms is conjugated both with the carbonyl group and with the benzene ring. The conjugated carbonyl group and with the benzene ring. The conjugated system is thereby extended.system is thereby extended.

•An important step in a commercial synthesis of vitamin A makes An important step in a commercial synthesis of vitamin A makes use of a use of a C!aisen-SchmidtC!aisen-Schmidt reaction between geranial and acetone: reaction between geranial and acetone:

Cyclizations via Aldol Cyclizations via Aldol CondensationsCondensations

The aldol condensation also offers a convenient way The aldol condensation also offers a convenient way to synthesize molecules with five- and six-membered to synthesize molecules with five- and six-membered rings (and sometimes even larger rings). rings (and sometimes even larger rings).

This reaction almost certainly involves the formation of at least three different enolates.However, it is the enolate from the ketone side of the molecule that adds to the aldehyde group leading to the product.

The reason the aldehyde group undergoes addition preferentially The reason the aldehyde group undergoes addition preferentially may arise from the greater reactivity of aldehydes toward may arise from the greater reactivity of aldehydes toward nucleophilic addition generally. The carbonyl carbon atom of a nucleophilic addition generally. The carbonyl carbon atom of a ketone is less positive (and therefore less reactive toward a ketone is less positive (and therefore less reactive toward a nucleophile) because it bears two electron-releasing alkyl groups; nucleophile) because it bears two electron-releasing alkyl groups; it is also more sterically hindered.it is also more sterically hindered.

In reactions of this type, five-membered rings form far more In reactions of this type, five-membered rings form far more readily than seven membered rings.readily than seven membered rings.

ProblemProblem

What starting compound would you use in an aldol What starting compound would you use in an aldol cyclization to prepare each of the following?cyclization to prepare each of the following?

Directed Aldol Directed Aldol ReactionsReactions

If a very strong base is employed, the equilibrium lies far to If a very strong base is employed, the equilibrium lies far to the right. One very useful strong base for converting ketones the right. One very useful strong base for converting ketones to enolates is to enolates is lithium diisopropylamidelithium diisopropylamide, (, (ii-C-C33HH77))22NN--LiLi++ OR OR LDALDA

The enolate with the more highly substituted double bond is the thermodynamically more stable enolate. This enolate, called the thermodynamic enolate, is formed predominantly using a relatively weak base.

The kinetically favored enolate can be formed cleanly through the use of lithium diisopropylamide (LDA). This strong, sterically hindered base rapidly removes the proton from the less substituted a carbon of the ketone.

Regioselectivity can be achieved when unsymmetrical ketones are used in directed aldol reactions by generating the kinetic enolate using LDALDA. This ensures production of the enolate in which the proton has been removed from the less substituted a carbon

ProblemProblem

Starting with ketones and aldehydes of your choice, outline a directed aldol synthesis of each of the following using LDA.

Additions to Additions to ,,-Unsaturated -Unsaturated Aldehydes and KetonesAldehydes and Ketones

Michael AdditionsMichael AdditionsWhen When ,,-unsaturated aldehydes and ketones react with -unsaturated aldehydes and ketones react with nucleophilic reagents, they may do so in two ways. They may react nucleophilic reagents, they may do so in two ways. They may react by a by a simple additionsimple addition, that is, one in which the nucleophile adds , that is, one in which the nucleophile adds across the double bond of the carbonyl group; or they may react by across the double bond of the carbonyl group; or they may react by a a conjugate additionconjugate addition. .

In many instances both modes of addition occur in the same In many instances both modes of addition occur in the same mixture. Consider the Grignard reaction: mixture. Consider the Grignard reaction:

The simple addition is favored, and this is generally the case with The simple addition is favored, and this is generally the case with strong nucleophiles. Conjugate addition is favored when weaker strong nucleophiles. Conjugate addition is favored when weaker nucleophiles are em ployed.nucleophiles are em ployed.

Although structures Although structures BB and and CC involve separated charges, they involve separated charges, they make a significant contribution to the hybrid because, in each, the make a significant contribution to the hybrid because, in each, the negative charge is carried by electronegative oxygen. Structures negative charge is carried by electronegative oxygen. Structures BB and and CC also indicate that b also indicate that both the corbonyl carbon and the oth the corbonyl carbon and the carbon should bear a partial positive chargecarbon should bear a partial positive charge. They indicae that . They indicae that one shouId represent the hybrid in the following way:one shouId represent the hybrid in the following way:

Conjugate additions of enolate anions to Conjugate additions of enolate anions to ,,--unsaturated carbonyl compounds are known generally unsaturated carbonyl compounds are known generally as as Michael additionsMichael additions..

The following sequence illustrates how a conjugate The following sequence illustrates how a conjugate aldol addition (aldol addition (Michael additionMichael addition) followed by a simple ) followed by a simple aldol condensationaldol condensation may be used to build one ring onto may be used to build one ring onto another. This procedure is known as the another. This procedure is known as the Robinson Robinson annulationannulation (ring forming) reaction. (ring forming) reaction.

Problem Problem

(a)(a) Propose step-by-step mechanisms for both Propose step-by-step mechanisms for both transformations of the Robinson annulation sequence transformations of the Robinson annulation sequence just shown. just shown.

(b)(b) Would you expect 2-methyl-l,3-cyclohexane-dione Would you expect 2-methyl-l,3-cyclohexane-dione to be more or less acidic than cyclohexanone? to be more or less acidic than cyclohexanone? Explain your answer.Explain your answer.

ProblemProblemWhat product would you expect to obtain from the What product would you expect to obtain from the base-catalyzed Michael reaction base-catalyzed Michael reaction

(a)(a) of I ,3-diphenyl-2-propen-1-one and acetophenone? of I ,3-diphenyl-2-propen-1-one and acetophenone?

(b)(b) of 1,3- diphenyl-2-propen-l-one and of 1,3- diphenyl-2-propen-l-one and cyclopentadiene? Show all steps in each mechanism.cyclopentadiene? Show all steps in each mechanism.