Chapter 22: Carbonyl Alpha-Substitution Reactions Why this Chapter? Many schemes make use of carbonyl a-substitution reactions. These reaction are one the few general methods for making C-C bonds.

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

22.1 Keto–Enol Tautomerism A carbonyl compound with a hydrogen atom on its alpha carbon rapidly equilibrates with its corresponding enol Compounds that differ only by the position of a moveable proton are called tautomers Tautomers are structural isomers: They are not resonance forms! (Resonance forms are representations of contributors to a single structure) Tautomers interconvert rapidly while ordinary isomers do not

Enols The enol tautomer is usually present to a very small extent and cannot be isolated Since the enol is formed rapidly, it can serve as a reaction intermediate

Acid Catalysis of Enolization Brønsted acids catalyze keto- enol tautomerization by protonating the carbonyl and activating the  protons

Base Catalysis of Enolization The hydrogens on the  carbon are weakly acidic and transfer to water is slow Transfer of the a hydrogen to a base though is rapid

Base Catalysis of Enolization Brønsted bases catalyze keto-enol tautomerization

Learning Check: Name the following and draw structures for their enol tautomers : A. B. C. D. E.

Solution: Name the following and draw structures for their enol tautomers : A. Cyclopentanone Ethyl acetate B. C. Methyl thioacetate Acetic Acid D. Phenylacetone E.

Learning Check: Which of the following explains why protons α to a carbonyl group show enhanced acidity? An inductive effect from the adjacent carbonyl weakens the C-H bond. The conjugate base is stabilized by resonance. The charge that results after deprotonation is delocalized. An inductive effect from the adjacent carbonyl weakens the C-H bond; and the conjugate base is stabilized by resonance. all of these

Solution: Which of the following explains why protons α to a carbonyl group show enhanced acidity? An inductive effect from the adjacent carbonyl weakens the C-H bond. The conjugate base is stabilized by resonance. The charge that results after deprotonation is delocalized. An inductive effect from the adjacent carbonyl weakens the C-H bond; and the conjugate base is stabilized by resonance. all of these

22.2 Reactivity of Enols: The Mechanism of Alpha-Substitution Reactions Enols behave as nucleophiles and react with electrophiles because the enol double bonds are electron-rich

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

22.3 Alpha Halogenation of Aldehydes and Ketones Aldehydes and ketones can be halogenated at their  positions by reaction with Cl2, Br2, or I2 in acidic solution

Mechanism of Acid-Catalyzed Bromination The enol tautomer reacts with an electrophile The keto tautomer loses a proton

Evidence for Rate-Limiting Enol Formation The rate of halogenation is independent of the halogen's identity and concentration In D3O+ the  H’s are replaced by D’s at the same rate as halogenation (if addition of D were involved in the rate determining step then the rate would have slowed with D20) This because the barrier to formation of the enol goes through the highest energy transition state in the mechanism (Formation of the enol is the rate determining step)

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

Learning Check: Know how to…. Write the complete mechanism of the deuteration of acetone on treatment with D3O+

Learning Check: Show how you might prepare 1-penten-3-one from 3-pentanone.

Solution: Show how you might prepare 1-penten-3-one from 3-pentanone.

22.4 Alpha Bromination of Carboxylic Acids: The Hell–Volhard–Zelinskii Reaction Carboxylic acids do not react with Br2 (unlike aldehydes and ketones) So Carboxylic acids must be converted to acid halides first and then the acid halide hydrolyzed back to the acid. Bromination of carboxyilic acids by a mixture of Br2 and PBr3 is the Hell–Volhard–Zelinskii reaction

Mechanism of Bromination by Hell–Volhard–Zelinskii PBr3 converts -COOH to –COBr, which can enolize and add Br2

Learning Check: Know how to…. If methanol rather than water is added at the end of a Hell- Volhard-Zelinskii reaction a methyl ester is produced. Show the reagents needed and propose a mechanism for each step.

22.5 Acidity of Alpha Hydrogen Atoms: Enolate Ion Formation Carbonyl compounds can act as weak acids 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 more powerful base than an alkoxide is needed to form the enolate Sodium hydride (NaH) or Lithium diisopropylamide [LiN(i-C3H7)2] are strong enough to form the enolate

Lithium Diisopropylamide (LDA) LDA is from butyllithium (BuLi) & diisopropylamine (pKa  40) Soluble in organic solvents and effective at low temperature with many compounds 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

Learning Check: Identify the most acidic hydrogens in each of the following: Rank in order of decreasing acidity.

Solution: Identify the most acidic hydrogens in each of the following: Rank in order of decreasing acidity. (#1 most acidic) 3 2 1

22.6 Reactivity of Enolate Ions The carbon atom of an enolate ion is electron- rich and highly reactive toward electrophiles (enols are not as reactive) Reaction on oxygen yields an enol derivative (less common) Reaction on carbon yields an a-substituted carbonyl compound (more common) More common

Base promoted a-halogenation Iodoform Reaction: Test for a methyl ketone Iodoform = CHI3 = yellow solid

22.7 Alkylation of Enolate Ions Base-promoted reaction occurs through an enolate ion intermediate SN2 reaction:,the leaving group X can be -Cl, -Br, -I, or tosylate R should be 1o or methyl and preferably should be allylic (CH=CH-CH2-X ) or benzylic (Ph-CH2-X ) 2o halides react poorly, and 3o halides don't react at all because of competing elimination

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 CO2 (“decarboxylation”) to yield a substituted monoacid

Decarboxylation of -Ketoacids Decarboxylation requires a carbonyl group two atoms away from the CO2H

Overall Conversion The malonic ester synthesis converts an alkyl halide  carboxylic acid while lengthening the carbon chain by 2 atoms

Preparing Cycloalkane Carboxylic Acids 1,4-dibromobutane reacts twice, giving a cyclic product 3-, 4-, 5-, and 6-membered rings can be prepared in this way

Learning Check: Use a malonic ester synthesis to prepare the following:

Solution: Use a malonic ester synthesis to prepare the following:

Learning Check: Use a malonic ester synthesis to prepare the following:

Solution: Use a malonic ester synthesis to prepare the following:

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

Acetoacetic Ester (Ethyl Acetoacetate)  carbon flanked by two carbonyl groups readily becomes an enolate ion that can be alkylated by an alkyl halide Process can be repeated to add a second alkyl halide

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

Learning Check: Prepare 2-pentanone using an acetoacetic ester synthesis: Hint:

Solution: Prepare 2-pentanone using an acetoacetic ester synthesis: Hint:

Biological Alkylations

What is the predominant enol form of the following molecule? Learning Check: What is the predominant enol form of the following molecule? 2. 1. 3. none of these is favored over the others 5. 4. 1 2 3 4 5

What is the predominant enol form of the following molecule? Solution: What is the predominant enol form of the following molecule? 2. 1. 3. none of these is favored over the others 5. 4. 1 2 3 4 5

Learning Check: It will form an acetal. It will form a diol. Which of the following will occur when the following optically active compound is placed in dilute acid? It will form an acetal. It will form a diol. It will become an alcohol. It will lose its optical activity. none of these

Solution: It will form an acetal. It will form a diol. Which of the following will occur when the following optically active compound is placed in dilute acid? It will form an acetal. It will form a diol. It will become an alcohol. It will lose its optical activity. none of these

Identify the expected major product of the following reaction. Learning Check: Identify the expected major product of the following reaction. 3. 1. 2. 5. 4. 1 2 3 4 5

Identify the expected major product of the following reaction. Solution: Identify the expected major product of the following reaction. 3. 1. 2. 5. 4. 1 2 3 4 5

Learning Check: enolate carboxylate acid bromide enol α-bromoketone Which of the following intermediates is encountered in the Hell-Volhard-Zelinskii reaction? enolate carboxylate acid bromide enol α-bromoketone acid bromide enolate

Solution: enolate carboxylate acid bromide enol α-bromoketone Which of the following intermediates is encountered in the Hell-Volhard-Zelinskii reaction? enolate carboxylate acid bromide enol α-bromoketone acid bromide enolate

How many protons with a pKa < 22 exist in the following molecule? Learning Check: How many protons with a pKa < 22 exist in the following molecule? 1 2 3 4

How many protons with a pKa < 22 exist in the following molecule? Solution: How many protons with a pKa < 22 exist in the following molecule? 1 2 3 4

Learning Check: Which of the following reagents will not form an enolate upon reaction with a ketone? 1. 2. 3. 5. 4. Choice One Choice Two Choice Three Choice Four Choice Five

Solution: Which of the following reagents will not form an enolate upon reaction with a ketone? 1. 2. 3. 5. 4. Choice One Choice Two Choice Three Choice Four Choice Five

Which of these carbonyl compounds is most acidic? Learning Check: Which of these carbonyl compounds is most acidic?

Which of these carbonyl compounds is most acidic? Solution: Which of these carbonyl compounds is most acidic?

Rank from least to most acidic. Learning Check: Rank from least to most acidic. A < B < C < D D < B < A < C D < A < C < B D < A < B < C C < B < A < D

Rank from least to most acidic. Solution: Rank from least to most acidic. A < B < C < D D < B < A < C D < A < C < B D < A < B < C C < B < A < D

The equilibrium will favor the products in the following reaction. Learning Check: The equilibrium will favor the products in the following reaction. True False

The equilibrium will favor the products in the following reaction. Solution: The equilibrium will favor the products in the following reaction. True False

Predict the major product(s) of the following reaction. Learning Check: Predict the major product(s) of the following reaction. 2. 1. 3. 5. 4. 1 2 3 4 5

Predict the major product(s) of the following reaction. Solution: Predict the major product(s) of the following reaction. 2. 1. 3. 5. 4. 1 2 3 4 5

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

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

Predict the product of the following sequence of reactions. Learning Check: Predict the product of the following sequence of reactions. 2. 3. 1. 4. None of these 5. 1 2 3 4 5

Predict the product of the following sequence of reactions. Solution: Predict the product of the following sequence of reactions. 2. 3. 1. 4. None of these 5. 1 2 3 4 5

Learning Check: True False An acetoacetic ester synthesis can be used to make the following compound. True False

Solution: An acetoacetic ester synthesis can be used to make the following compound. True False

Learning Check: Which of the following cannot be prepared by the acetoacetic ester synthesis sequence? 1. 2. 3. 5. 4. 1 2 3 4 5

Solution: Which of the following cannot be prepared by the acetoacetic ester synthesis sequence? 1. 2. 3. 5. 4. 1 2 3 4 5