TOPIC 6: ALDOL REACTIONS AND THE SYNTHESIS AND REACTIONS OF b-DICARBONYL COMPOUNDS (Chapters 17 and 19)

OBJECTIVES Provide a rationale for the acidity of a-hydrogens Illustrate the behavior of enols and enolates as nucleophiles in reactions with a variety of electrophiles Develop stategies for the formation of complex molecules form simple starting materials by making carbon-carbon bonds Describe the reactions of ester enolates (nucleophiles) with esters (electrophiles) to give b-keto esters via Claisen and crossed Claisen condensatiions. Describe the synthesis of ketones using the above products. Describe the reactions of other active methyene compounds and the synthesis of acid derivatives. Describe the preparation and alkylation of enamines. Use this knowledge to predict the products of reactions of this type and to be able to synthesize compounds using these procedures.

INTRODUCTION: REVIEW OF THE ELECTROPHILICITY OF CARBONYLS Addition Addition-Elimination

THE ACIDITY OF THE a-HYDROGENS OF CARBONYL COMPOUNDS: ENOLATE ANIONS S:17.1 Prob: 17.34 Protons a- to Carbonyl Groups are More Acidic Than Other Protons on Carbon Note: Protons attached to the carbonyl carbon of aldehydes are not particularly acidic, the conjugate base is not resonance stabilized. pKa 19.2 9.0 pKa 50 44 25

The negative charge of the conjugate base is . through .

KETO AND ENOL TAUTOMERS Base Catalyzed Tautomerization Keto and enol forms are in equilibrium.

Acid Catalyzed Tautomerization Keto and enol forms are in equilibrium. The keto form is normally more stable

REACTIONS VIA ENOLS AND ENOLATE ANIONS S:17.3 Prob:17.37,39 Preview: Enols and enolates are nucleophilic

Racemization of Aldehydes and Ketones Experimental Observation: Compounds with a stereogenic center bearing a hydrogen atom adjacent to a carbonyl group undergo rapid racemization in mildly acidic or basic conditions.

Mechanistic Rationale:                                                                                                  Ibuprofen Ibuprofen marketed as racemate Only the S isomer is active Body converts R to S by inversion of stereogenic center adjacent to carbonyl

a-Halogenation of Aldehydes and Ketones Acidic conditions: Enolizable protons are subject to substitution with bromine upon treatment with Br2. Mechanistic Rationale: The nucleophilic enol undergoes reaction with bromine

Basic conditions: All of the enolizable protons are substituted with bromine and the resulting trihalomethyl group itself is cleaved. Mechanistic Rationale: The nucleophilic enolate undergoes reaction with bromine

? Problems 17.37,39 ?

-HALO ACIDS Formation of -halo acids: The Hell-Volhard-Zelinski reaction Reactions of -halo acids: Nucleophilic substitution of bromide http://cc.oulu.fi/~genetwww/ http://www.lef.org/prod_desc/item00128.html

Diethylpropion is a stimulant, is marketed as Tenuate™ for appetite suppression. Propose a synthesis of diethylpropion from benzene and any other starting materials. ?

THE ALDOL REACTION: ADDITION OF ENOLATES TO ALDEHYDES & KETONES S:17.4,5 Prob:17.31, 33,35 The aldol reaction: The reaction of an aldehyde with an aldehyde enolate

Heating causes dehydration to form a,b-unsaturated aldehyde Mechanism:

Recognizing products and starting materials of aldol reactions Aldol condensations give a,b-unsaturated carbonyl compounds

Crossed-aldol reactions Problem: Propose starting materials to prepare 2-methyl-2-pentenal by an aldol reaction

Mixed aldols between two aldehydes with enolizable protons can give four different products

Crossed aldol condensations are only useful when one of the components is non-enolizable and a good electrophile (e.g., an aldehyde) e.g.,

Aldol condensations of ketones Crossed-aldol condensations of ketone enolates and non-enolizable aldehydes (Claissen-Schmidt reaction) Aldol condensations of ketones Remember: Avoid proposing crossed-aldol reactions if both components are enolizable

Aldol reactions are also catalyzed by acid…. Problem: Write the mechanistic steps of the following reaction (show curved arrows and intermediates)

The reversibility of the aldol reaction The aldol reaction is reversible. The reverse reaction proceeds through exactly the same intermediates as the forward reaction. Problem: Write the mechanistic steps of the following acid-catalyzed reverse aldol reaction (show curved arrows and intermediates). Problem: Show the mechansim for the reverse base-catalyzed aldol reaction.

Pulegone, which has a pleasant peppermint-camphor smell, is isolated from the oil of pennyroyal (pennyroyal tea is commonly used as an herbal remedy; pulegone is extremely toxic). Treatment of pulegone with steam yields 3-methylcyclohexanone. Propose a pathway for this reaction. What is the byproduct of this reaction. http://wicca.com/celtic/herbal/images/pennyroyal.gif

Cyclizations via aldol condensations

Problem [Solomons 17.31b] - How would you achieve the following transformation?

? Problem [Solomons 17.33] – Identify the structures of compounds A-C.

? Problems 17.31,33,35 ?

LITHIUM ENOLATES S:17.7 Prob:17.34 Enolates are generated in equilibrium with OH-. They are not isolated, but used in situ. Use of a stronger base (e.g., lithium diisopropylamide, LDA) allows for generation of the lithium enolate, and then, in a separate step, the addition of an electrophile.

Lithium enolates in directed crossed-aldol reactions Lithium anions in alkylation reactions

Kinetic versus Thermodynamic Lithium Enolates The regiochemistry of lithiation is controlled by temperature

a,b-UNSATURATED CARBONYL COMPOUNDS S17.8,9 Prob:17.32 Synthesis of a,b-unsaturated carbonyl compounds Aldol reactions (see above) a-Selenation

Electron Distribution in a,b-unsaturated ketones

Selective Reduction of ,-Unsaturated Carbonyl Compounds

Additions to a,b-unsaturated ketones

Enolate + a,b-unsaturated ketone (Michael addition) Michael addition and subsequent aldol cyclization (Robinson annulation)

Comparing Nucleophilicity of Enolates and Electrophilicity of Enones

b-DICARBONYL COMPOUNDS: INTRODUCTION Question: Why is the b-dicarbonyl system more acidic than an alcohol (pKa~18)?

Answer: The anion is stabilized by resonance Consequently, there is a lot of enol in equilibrium

THE CLAISEN CONDENSATION: THE SYNTHESIS OF b-KETO ESTERS S:19.2 Prob:19.25,41 Overall reaction

Examples

Mechanism First step – formation of enolate Question: How much enolate forms? What are the pKa values?

Second step - attack of enolate (nucleophile) on the carbonyl carbon (electrophile) of another molecule of ester Question: Is this reaction favorable?

Third step - deprotonation of b-dicarbonyl compound (product) to form enolate Question: Is this reaction favorable? What are the pKa values?

Fourth step - protonation of enolate to form the b-dicarbonyl product by addition of acid Question: It this reaction favorable? What are the pKa values?

Another question: Why does the reaction fail when the ester has two substituents on the a carbon?

Example Two esters in same molecule

Crossed Claisen and other Condensations Remember the rule for crossed aldol condensation reactions (i.e., one component cannot form an enolate) ethyl oxalate

Problem – How would you achieve the following transformations?

? Problems 19.25,41 ?

THE ACETOACETIC ESTER SYNTHESIS: SYNTHESIS OF METHYL KETONES S:19.3 Prob: 19.26 Overall reaction

Mechanism Deprotonation: Enolate formation Alkylation Ester hydrolysis (see 18.7B) and decarboxylation (see 18.11)

Examples

Synthetic Design

THE MALONIC ESTER SYNTHESIS: SYNTHESIS OF SUBSTITUTED ACETIC ACIDS S:19.4 Prob: 19.27 Overall reaction

Mechanism Deprotonation: Enolate formation Alkylation Ester hydrolysis (see 18.7B) and decarboxylation (see 18.10)

Examples

Synthetic Design

Examples Barbituates (Solomons 19.12)

Problem [Solomons 19.26e,27] - How would you achieve the following transformations?

? Problems 19.36 ?

OTHER COMPOUNDS WITH ACIDIC HYDROGEN ATOMS ON CARBON Active hydrogen (methylene) compounds have two electron withdrawing groups attached to the same carbon. The most common type (except for two carbonyls) are cyano and carbonyl, but several others are possible. The -CH2- group is very acidic and reacts like ethyl acetoacetate and diethyl malonate.

Examples

DIRECT ALKYLATION OF ESTERS AND NITRILES Recall the direct alkylation of ketones using LDA (Solomons 17.7C) Esters can be alkylated in an analogous manner

THE KNOEVENAGEL CONDENSATION S:19.8 Prob:19.31 Aldol condensation of a stabilized enolate Example

MICHAEL ADDITIONS Examples S:19.9 Prob:19.30 Conjugate addition reaction of a stabilized enolate to an enone (i.e., 1,4-addition). Examples

SYNTHESIS OF ENAMINES: STORK ENAMINE REACTIONS S.19.11 Prob.19.50 Recall that aldehydes and ketones react with primary amines to form imines. Analogous reactions with secondary amines form enamines.

Mechanistic rationale for the formation of enamines

Enamines have high electron density at nitrogen and carbon They are most nucleophilic at carbon The initial product can be hydrolyzed to a ketone

Mechanistic rationale for the hydrolysis reaction

Examples of Enamines Reacting as Nucleophiles

TOPIC 5 REVIEW Enolate Anions Protons a- to carbonyl groups are more acidic than other protons on carbon

The aldol reaction: The reaction of an aldehyde with an aldehyde enolate

Problem [Solomons 19.39] - How could you prepare Darvon, a powerful analgesic, from ethyl phenyl ketone?

Crossed aldol condensations are only useful when one of the components is non-enolizable and a good electrophile (e.g., an aldehyde) e.g.,

Lithium enolates are useful in directed crossed-aldol reactions and in alkylation reactions Additions to a,b-unsaturated ketones

Enolate + a,b-unsaturated ketone (Michael addition) Michael addition and subsequent aldol cyclization (Robinson annulation)

The ß-dicarbonyl system more acidic than an alcohol (pKa~18), why? The anion is stabilized by resonance The Claisen condensation: the synthesis of ß-keto esters

? Problem [Solomons 19.38] - Fenchone is a terpenoid isolated from fennel oil. Provide the structure of intermediates and reagents (a)-(n) in the following scheme (cont. next slide).

? Problems 19.30,31,50 ?

Crossed Claisen and other Condensations Remember the rule for crossed aldol condensation reactions (i.e., one component cannot form an enolate)

The Acetoacetic Ester Synthesis: Synthesis Of Methyl Ketones

The Malonic Ester Synthesis: Synthesis Of Substituted Acetic Acids

Direct Alkylation Of Esters And Nitriles The Knoevenagel Condensation Aldol condensation of a stabilized enolate

Synthesis Of Enamines Stork Enamine Reactions Reaction of ketones and aldehydes with secondary amines form enamines

PROBLEM SOLVING AND SYNTHETIC STATEGIES ? Problem - Propose a synthetic pathway to achieve the following transformation.                

Problem [Solomons 17.43] - Multistriatin, a elm bark beetle pheromone is a bicyclic acetal. Draw the diol-ketone from which multistriatin is derived. Propose a synthesis of multistriatin from 3-pentanone and 2-methyl-3-butenoic acid ? http://www.tarahill.com/treelore/trees.html http://www.ag.ohio-state.edu/~ohioline/hyg-fact/2000/2065.html

Problem [Solomons 17.32] – Describe the key mechanistic steps in the following reaction (i.e., write a mechanism). ?

TOPIC 6 (CHAPTER 17,19) ON EXAM 5 Types of Questions Predict the products obtained from given starting materials Rationalize the outcome of a reaction (i.e., propose a mechanism, draw key intermediates) Develop multistep synthetic strategies. Do the problems in the book; they are great examples of the types of problems on the exam! Preparing for Exam 5 - Get up-to-date NOW! - Work as many problems as possible. Do the problems first, then consult the solutions manual. - Work in groups, discuss chemistry, teach and test each other. - Do the “Learning Group Problem” at the end of the chapter.