Carboxylic acid and derivatives (Part III)

Carboxylic acid and derivatives (Part III)

Part 1. Substitution 1. Enol ann enolate 2. Reactivity of Enols 3. Alpha Halogenation of Aldehydes and Ketones 4. Alpha Bromination of Carboxylic Acids 5. Acidity of Alpha Hydrogen Atoms 6. Reactivity of Enolate Ions 7. Halogenation of Enolate Ions 8. Alkylation of Enolate Ions 9. The Malonic Ester Synthesis 10. The Acetoacetic Ester Synthesis

Part 2. Condensation 1. Condensation Reactions 2. Condensations of Aldehydes and Ketones 3. Carbonyl Condensation Reactions versus Alpha-Substitution Reactions 4. Dehydration of Aldol Products: Synthesis of Enones 5. Using Aldol Reactions in Synthesis 6. Mixed Aldol Reactions 7. Intramolecular Aldol Reactions 8. The Claisen Condensation Reaction 9. Mixed Claisen Condensations 10. Intramolecular Claisen Condensations: The Dieckmann Cyclization 11. The Michael Reaction 12. The Stork Enamine Reaction 13. The Robinson Annulation Reaction

1. Enol and enolate The Position The carbon next to the carbonyl group is designated as being in the position Electrophilic substitution occurs at this position through either an enol or enolate ion

1. Enol and enolate Tautomers Are Not Resonance Forms Tautomers are structural isomers Resonance forms are representations of contributors to a single structure Tautomers interconvert rapidly while ordinary isomers do not

1. Enol and enolate Enols The enol tautomer is usually present to a very small extent and cannot be isolated However, since it is formed rapidly, it can serve as a reaction intermediate

1. Enol and enolate Acid Catalysis of Enolization Brønsted acids catalyze keto-enol tautomerization by protonating the carbonyl and activating the protons

1. Enol and enolate Base Catalysis of Enolization Brønsted bases catalyze keto-enol tautomerization The hydrogens on the carbon are weakly acidic and transfer to water is slow In the reverse direction there is also a barrier to the addition of the proton from water to enolate carbon

2. Reactivity of Enols The Mechanism of Alpha-Substitution Reactions Enols behave as nucleophiles and react with electrophiles because the double bonds are electron-rich compared to alkenes

2. Reactivity of Enols General Mechanism of Addition to Enols When an enol reacts with an electrophile the intermediate cation immediately loses the OH proton to give a substituted carbonyl compound

3. Alpha Halogenation of Aldehydes and Ketones Aldehydes and ketones can be halogenated at their positions by reaction with Cl 2, Br 2, or I 2 in acidic solution

Evidence for the Rate-Limiting Enol Formation The rate of halogenation is independent of the halogen's identity and concentration In D 3 O + the H s are replaced by D s at the same rate as halogenation This because the barrier to formation of the enol goes through the highest energy transiton state in the mechanism

Elimination Reactions of -Bromoketones -Bromo ketones can be dehydrobrominated by base treatment to yield,b-unsaturated ketones

4. Alpha Bromination of Carboxylic Acids The Hell Volhard Zelinskii Reaction Carboxylic acids do not react with Br 2 (Unlike aldehydes and ketones) They are brominated by a mixture of Br 2 and PBr 3 (Hell Volhard Zelinskii reaction)

Mechanism of Bromination PBr 3 converts -COOH to COBr, which can enolize and add Br 2

5. Acidity of Alpha Hydrogen Atoms Enolate Ion Formation Carbonyl compounds can act as weak acids (pk a of acetone = 19.3; pk a of ethane = 60) The conjugate base of a ketone or aldehyde is an enolate ion - the negative charge is delocalized onto oxygen

Reagents for Enolate Formation Ketones are weaker acids than the OH of alcohols so a a more powerful base than an alkoxide is needed to form the enolate Sodium hydride (NaH) or lithium diisopropylamide [LiN(i-C 3 H 7 ) 2 ] (LDA) are strong enough to form the enolate LDA: Not nucleophilic

-Dicarbonyls Are More Acidic When a hydrogen atom is flanked by two carbonyl groups, its acidity is enhanced Negative charge of enolate delocalizes over both carbonyl groups

Acidities of Organic Compounds

6. Reactivity of Enolate Ions The carbon atom of an enolate ion is electron-rich and highly reactive toward electrophiles (enols are not as reactive)

Two Reactions Sites on Enolates Reaction on oxygen yields an enol derivative Reaction on carbon yields an a-substituted carbonyl compound

7. Halogenation of Enolate Ions The Haloform Reaction Base-promoted reaction occurs through an enolate ion intermediate

Further Reaction: Cleavage Monohalogenated products are themselves rapidly turned into enolate ions and further halogenated until the trihalo compound is formed from a methyl ketone The product is cleaved by hydroxide with CX 3 as a leaving group

8. Alkylation of Enolate Ions Alkylation occurs when the nucleophilic enolate ion reacts with the electrophilic alkyl halide or tosylate and displaces the leaving group

Constraints on Enolate Alkylation S N 2 reaction:, the leaving group X can be chloride, bromide, iodide, or tosylate R should be primary or methyl and preferably should be allylic or benzylic Secondary halides react poorly, and tertiary halides don't react at all because of competing elimination

9. The Malonic Ester Synthesis For preparing a carboxylic acid from an alkyl halide while lengthening the carbon chain by two atoms

Formation of Enolate and Alkylation Malonic ester (diethyl propanedioate) is easily converted into its enolate ion by reaction with sodium ethoxide in ethanol The enolate is a good nucleophile that reacts rapidly with an alkyl halide to give an a-substituted malonic ester

Dialkylation The product has an acidic -hydrogen, allowing the alkylation process to be repeated

Hydrolysis and Decarboxylation The malonic ester derivative hydrolyzes in acid and loses CO 2 ( decarboxylation ) to yield a substituted monoacid

Decarboxylation of b-ketoacids Decarboxylation requires a carbonyl group two atoms away from the CO 2 H The second carbonyl permit delocalization of the resulting enol The reaction can be rationalized by an internal acid-base reaction

Reminder of Overall Conversion The malonic ester synthesis converts an alkyl halide into a carboxylic acid while lengthening the carbon chain by two atoms

Preparation Cycloalkane Carboxylic Acids 1,4-dibromobutane reacts twice, giving a cyclic product Three-, four-, five-, and six-membered rings can be prepared in this way

10. The Acetoacetic Ester Synthesis Overall: converts an alkyl halide into a methyl ketone

Acetoacetic Ester (Ethyl Acetoacetate) carbon is flanked by two carbonyl groups, so it readily becomes an enolate ion This which can be alkylated by an alkyl halide and also can react with a second alkyl halide

Decarboxylation of Acetoacetic Acid -Ketoacid from hydrolysis of ester undergoes decarboxylation to yield a ketone via the enol

Generalization: -Keto Esters The sequence: enolate ion formation, alkylation, hydrolysis/decarboxylation is applicable to -keto esters in general Cyclic b-keto esters give 2-substituted cyclohexanones

Part 1. Substitution 1. Enol ann enolate 2. Reactivity of Enols 3. Alpha Halogenation of Aldehydes and Ketones 4. Alpha Bromination of Carboxylic Acids 5. Acidity of Alpha Hydrogen Atoms 6. Reactivity of Enolate Ions 7. Halogenation of Enolate Ions 8. Alkylation of Enolate Ions 9. The Malonic Ester Synthesis 10. The Acetoacetic Ester Synthesis

Part 2. Condensation 1. Condensation Reactions 2. Condensations of Aldehydes and Ketones 3. Carbonyl Condensation Reactions versus Alpha-Substitution Reactions 4. Dehydration of Aldol Products: Synthesis of Enones 5. Using Aldol Reactions in Synthesis 6. Mixed Aldol Reactions 7. Intramolecular Aldol Reactions 8. The Claisen Condensation Reaction 9. Mixed Claisen Condensations 10. Intramolecular Claisen Condensations: The Dieckmann Cyclization 11. The Michael Reaction 12. The Stork Enamine Reaction 13. The Robinson Annulation Reaction

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

1. Condensation Reactions Mechanism Carbonyl condensation reactions utilize -substitution steps An enolate ion adds as a nucleophile to the electrophilic acceptor

2. Condensations of Aldehydes and Ketones: The Aldol Reaction Acetaldehyde reacts in basic solution (NaOEt, NaOH) with another molecule of acetaldhyde The b-hydroxy aldehyde product is aldol (aldehyde + alcohol) This is a general reaction of aldehydes and ketones

The Equilibrium of the Aldol The aldol reaction is reversible, favoring the condensation product only for aldehydes with no substituent Steric factors are increased in the aldol product

Aldehydes and the Aldol Equilibrium

Ketones and the Aldol Equilibrium

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

3. Carbonyl Condensation Reactions versus Alpha-Substitution Reactions Carbonyl condensations and substitutions both involve formation of enolate ion intermediates Immediate addition of an alkyl halide to completes the alkylation reaction

Conditions for Condensations A small amount of base is used to generate a small amount of enolate in the presence of unreacted carbonyl compound After the condensation, the basic catalyst is regenerated

4. Dehydration of Aldol Products: Synthesis of Enones The -hydroxy carbonyl products dehydrate to yield conjugated enones The term condensation refers to the net loss of water and combination of 2 molecules

Dehydration of -Hydoxy Ketones and Aldehydes The hydrogen is removed by a base, yielding an enolate ion that expels the OH leaving group Under acidic conditions the OH group is protonated and water is expelled

Driving the Equilbrium Removal of water from the aldol reaction mixture can be used to drive the reaction toward products Even if the initial aldol favors reactants, the subsequent dehydration step pushes the reaction to completion

5. Using Aldol Reactions in Synthesis If a desired molecule contains either a -hydroxy carbonyl or a conjugated enone, it might come from an aldol reaction

Extending the Synthesis Subsequent transformations can be carried out on the aldol products A saturated ketone might be prepared by catalytic hydrogenation of the enone product

6. Mixed Aldol Reactions A mixed aldol reaction between two similar aldehyde or ketone partners leads to a mixture of four possible products This is not useful

Practical Mixed Aldols If one of the carbonyl partners contains no hydrogens and the carbonyl is unhindered (such as benzaldehyde and formaldehyde) it is a good electrophile and can react with enolates hen a mixed aldol reaction is likely to be successful 2-methylcyclohexanone gives the mixed aldol product on reaction with benzaldehyde

Mixed Aldols With Acidic Carbonyl Compounds Ethyl acetoacetate is completely converted into its enolate ion under less basic conditions than monocarbonyl partners Aldol condensations with ethyl acetoacetate occur preferentially to give the mixed product

7. Intramolecular Aldol Reactions Treatment of certain dicarbonyl compounds with base produces cyclic products by intramolecular reaction

Mechanism of Intramolecular Aldol Reactions Both the nucleophilic carbonyl anion donor and the electrophilic carbonyl acceptor are now in the same molecule. The least strained product is formed because the reaction is reversible

8. The Claisen Condensation Reaction Reaction of an ester having an hydrogen with 1 equivalent of a base to yield a -keto ester Features: If the starting ester has more than one acidic 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

9. Mixed Claisen Condensations Successful when one with -proton and the other wothout the proton

Esters and Ketones Reactions between esters and ketones, resulting in -diketones Best when the ester component has no hydrogens and can't act as the nucleophilic donor

10. Intramolecular Claisen Condensations: The Dieckmann Cyclization Intramolecular Claisen condensation Best with 1,6-diesters (product: 5-membered -ketoester) and 1,7-diesters (product: 6-membered -ketoester)

Alkylation of Dieckmann Product The cyclic -keto ester can be further alkylated and decarboxylated as in the acetoacetic ester synthesis

11. The Michael Reaction Enolates can add as nucleophiles to, -unsaturated aldehydes and ketones to give the conjugate addition product

Best Conditions for the Michael Reaction When a particularly stable enolate ion Example: Enolate from a -keto ester or other 1,3-dicarbonyl compound adding to an unhindered, -unsaturated ketone

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

12. The Stork Enamine Reaction Enamines are equivalent to enolates in their reactions and can be used to accomplish the transformations under milder conditions Enamines are prepared from a ketone and a secondary amine

Why Enamines Are Nucleophilic Overlap of the nitrogen lone-pair orbital with the double-bond π orbitals increases electron density on the carbon atom

Enamine Addition and Hydrolysis Enamine adds to an, -unsaturated carbonyl acceptor The product is hydrolyzed to a 1,5-dicarbonyl compound

13. The Robinson Annulation Reaction A two-step process: combines a Michael reaction with an intramolecular aldol reaction The product is a substituted 2-cyclohexenone

Analyze each problem carefully, and try to learn from it:

To devise a synthesis for a given target molecule: