Aldehydes and Ketones II Aldol Reactions Chapter 17 Aldehydes and Ketones II Aldol Reactions

The Acidity of the -Hydrogens of Carbonyl Compounds: Enolate Anions One important characteristic of aldehydes and ketones is their ability to undergo nucleophilic addition at their carbonyl groups

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

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

Keto-Enol Tautomers The keto and enol forms of carbonyl compounds are constitutional isomers. They can easily interconvert in the presence of traces of an acid and base. Interconverted keto and enol forms are said to be tautomers and interconversion is called tatumerization

In compounds whose molecules have two carbonyl groups separated by one -CH2- group (called -dicarbonyl compounds), the amount of enol present at equilibrium is far higher This can be attributed to stability gained through resonance stabilization in a cyclic form, through hydrogen bonding

REACTIONS VIA ENOLS AND ENOLATE ANIONS Racemization 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 or bases because the ketone slowly but reversibly changes to its enol and the enol is achiral. When the enol reverts to the keto form, it produces equal amounts of the two enantiomers.

A Mechanism for the Reaction Base Catalyzed Reaction Acid Catalyzed Reaction

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

Substitution takes place almost exclusively at the  carbon: Halogenation of Ketones Ketones that have an  hydrogen react readily with halogens by substitution. Substitution takes place almost exclusively at the  carbon:

Base-Promoted Halogenations A mechanism of the reaction:

Acid-Catalyzed Halogenations A mechanism of the reaction:

The Haloform Reaction When methyl ketones react with halogens in the presence of base, multiple halogenations always occur at the carbon of the methyl group. Multiple halogenations occur because introduction of the first halogen (owing to its electronegativity) makes the remaining  hydrogens on the methyl carbon more acidic

Halogenation Step of the Haloform Reaction

Cleavage Step of the Haloform Reaction

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

THE ALDOL REACTION: THE ADDITION OF ENOLATE ANIONS TO ALDEHYDES AND KETONES When acetaldehyde reacts with dilute sodium hydroxide at room temperature (or below), a dimerization takes place producing 3-hydroxybutanal. Since 3-hydroxybutanal is both an aldehyde and an alcohol, it has been given the common name “aldol,” and reactions of this general type have come to be known as aldol reactions.

Mechanism for the Reaction

Dehydration of the Aldol Addition Product If the basic mixture containing the aldol is heated, dehydration takes place and 2-butenal (crotonaldehyde) is formed. Dehydration occurs readily because of the acidity of the remaining  hydrogens and because the product is stabilized by having conjugated double bonds.

Synthetic Applications The aldol reaction is a general reaction of aldehydes that posses an  hydrogen.

Problem

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

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

Problem Show how each of the following products could be synthesized from butanal: (a) 2-Ethyl-3-hydroxyhexanal (b) 2-Ethyl-2-hexen-1-ol (e) 2-Ethyl-1-hexanol (d) 2-Ethyl-1,3-hexanediol

Ketones also undergo base-catalyzed aldol additions

CROSSED ALDOL REACTIONS An aldol reaction that starts with two different carbonyl compounds is called a crossed aldol reaction. If both reactants have -hydrogens, the reactions give a complex mixture of products.

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

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

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

Mechanism for the Reaction

In the Claisen-Schmidt reactions dehydration occurs readily because the double bond that forms is conjugated both with the carbonyl group and with the benzene ring. The conjugated system is thereby extended. An important step in a commercial synthesis of vitamin A makes use of a C!aisen-Schmidt reaction between geranial and acetone:

Cyclizations via Aldol Condensations The aldol condensation also offers a convenient way to synthesize molecules with five- and six-membered 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 may arise from the greater reactivity of aldehydes toward nucleophilic addition generally. The carbonyl carbon atom of a ketone is less positive (and therefore less reactive toward a nucleophile) because it bears two electron-releasing alkyl groups; it is also more sterically hindered. In reactions of this type, five-membered rings form far more readily than seven membered rings.

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

Directed Aldol Reactions If a very strong base is employed, the equilibrium lies far to the right. One very useful strong base for converting ketones to enolates is lithium diisopropylamide, (i-C3H7)2N-Li+ OR LDA

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 LDA. This ensures production of the enolate in which the proton has been removed from the less substituted a carbon

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

Additions to ,-Unsaturated Aldehydes and Ketones Michael Additions When ,-unsaturated aldehydes and ketones react with nucleophilic reagents, they may do so in two ways. They may react by a simple addition, that is, one in which the nucleophile adds across the double bond of the carbonyl group; or they may react by a conjugate addition.

In many instances both modes of addition occur in the same mixture In many instances both modes of addition occur in the same mixture. Consider the Grignard reaction: The simple addition is favored, and this is generally the case with strong nucleophiles. Conjugate addition is favored when weaker nucleophiles are em ployed.

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

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

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

Problem Propose step-by-step mechanisms for both transformations of the Robinson annulation sequence just shown. Would you expect 2-methyl-l,3-cyclohexane-dione to be more or less acidic than cyclohexanone? Explain your answer.

Problem What product would you expect to obtain from the base-catalyzed Michael reaction of I ,3-diphenyl-2-propen-1-one and acetophenone? of 1,3- diphenyl-2-propen-l-one and cyclopentadiene? Show all steps in each mechanism.