A library of the enol and enolate mediated carbonyl compound reactions: Intermolecular a-alkylation and acetoacetic and malonic ester synthesis via enolate anions Chapters 22 and 23 Intramolecular a-alkylation Favorskii rearrangement via enolate anions extra Intermolecular a-halogenation and haloform reaction via enols and enolate anions Chapters 22

A library of the enol and enolate mediated carbonyl compound reactions: Self-condensation Self and mixed Aldol and Claisen via enols and enolate anions Chapter 23

Intramolecular condensation A library of the enol and enolate mediated carbonyl compound reactions: Intramolecular condensation Dieckmann via enolate anions Chapter 23

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

Enols and enolate anions behave as nucleophiles and react with electrophiles because the double bonds are electron-rich compared to alkenes

Part A: Keto–Enol Tautomerism A carbonyl compound with a hydrogen atom on its a carbon rapidly equilibrates with its corresponding enol Compounds that differ only by the position of a moveable proton are called tautomers The enol tautomer is usually present to a very small extent and cannot be isolated, but is formed rapidly, and serves as a reaction intermediate

1H-NMR spectrum of neat 2,4-pentanedione

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

Base Catalysis of Enolization Brønsted bases catalyze keto-enol tautomerization The hydrogens on the α 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

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

a-Halogenation of Aldehydes and Ketones Aldehydes and ketones can be halogenated at their α positions by reaction with Cl2, Br2, or I2 in either the acidic or basic solutions.

Mechanism of Acid-Catalyzed Electrophilic Substitution

Mechanism of Acid-Catalyzed Electrophilic Substitution

α-Bromoketones Undergo Facile Elimination Reaction to Yield α,b-unsaturated Carbonyl Compounds for 1,4-addition Reactions.

a-Bromination of Carboxylic Acids: The Hell–Volhard–Zelinskii Reaction Carboxylic acids do not react with Br2. Unlike aldehydes and ketones, they are brominated by a mixture of Br2 and PBr3

Mechanism of the Hell–Volhard–Zelinskii Reaction PBr3 converts -CO2H to –COBr, which can enolize and add Br2

Part B: Enolate Ion Formation Carbonyl compounds can act as weak acids (pKa of acetone = 19.3; pKa of ethane = 60) The conjugate base of a ketone or aldehyde is an enolate ion - the negative charge is delocalized onto oxygen

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

Reagents for Enolate Formation Ketones are weaker acids than the OH of alcohols but can be deprotonated to a small extent by an alkoxide anion (RO-) to form the enolate. This is sufficient in reactions with strong electrophiles such as Br2. Sodium hydride (NaH) or lithium diisopropylamide [LiN(i-C3H7)2] are strong enough to form large amounts of the enolates required for a-alkylation reactions. LDA is generated from butyllithium (BuLi) and diisopropylamine (pKa = 40) and is soluble in organic solvents.

Mechanism of Base-Promoted Electrophilic Halogenation 1. The base abstracts the a-H from the keto tautomer. 2. The resulting enolate anion reacts with an electrophile.

The Haloform Reaction Base-promoted reaction occurs through an enolate anion intermediate. Monohalogenated products are themselves rapidly turned into enolate anions and further halogenated until the trihalo compound is formed from a methyl ketone. The product is cleaved by hydroxide with -CX3 as a leaving group.

a-Alkylation of Enolate Ions via Lithium Enolate Salts Even unreactive ketones will be easily deprotonated with LDA to give stable, isolable lithium enolate salts.

a-Alkylation of Enolate Ions Alkylation occurs when the nucleophilic enolate ion reacts with the electrophilic alkyl halide or tosylate and displaces the leaving group SN2 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

Mechanism of Base-Promoted Electrophilic Alkylation

Intramolecular a-alkylation reaction: Favorskii rearrangement. Intramolecular a-alkylation in the Favorskii rearrangement proceeds via enolate anion generated within the molecule. The molecule must contain a leaving group, usually a halide. The purpose of the reaction is two fold: 1. Molecular rearrangements of ketones to carboxylic acids and 2. Ring contraction reaction to make high energy small size and/or fused rings.

Mechanism

Intramolecular a-alkylation reaction: Favorskii rearrangement resulting in ring contractions.

β-Dicarbonyls Are More Acidic When a hydrogen atom is flanked by two carbonyl groups, its acidity is enhanced (Table 22.1) Negative charge of enolate delocalizes over both carbonyl groups

Relative acidities are dictated by the substituents on the carbonyl group.

Ethyl Acetoacetate Ester Diethyl Malonate Ester Acetoacetic and malonic esters are easily converted into the corresponding enolate anions by reaction with sodium ethoxide in ethanol. The enolates are good nucleophiles that react rapidly with alkyl halides to give an a-substituted derivatives. The product has an acidic α-hydrogen, allowing the alkylation process to be repeated.

Formation of Enolate and Alkylation

Formation of Enolate and Alkylation

2. The Malonic Ester Synthesis For preparing a carboxylic acid from an alkyl halide while lengthening the carbon chain by two atoms 3. The Acetoacetic Ester Synthesis Overall: converts an alkyl halide into a methyl ketone

Synthesis of ketones using acetoacetic ester via the decarboxylation of acetoacetic acid b-Ketoacid from hydrolysis of ester undergoes decarboxylation to yield a ketone via the enol

Synthesis of carboxylic acids using malonic ester via the decarboxylation of malonic acid The malonic ester synthesis converts an alkyl halide into a carboxylic acid while lengthening the carbon chain by two atoms

Decarboxylation of b-Ketoacids Decarboxylation requires a carbonyl group two atoms away from the β CO2H The second carbonyl permit delocalization of the resulting enol The reaction can be rationalized by an internal acid-base reaction

Generalization: b-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

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