Presentation on theme: "Intermolecular a-alkylation and acetoacetic and malonic ester"— Presentation transcript:
1 A library of the enol and enolate mediated carbonyl compound reactions: Intermolecular a-alkylationand acetoacetic and malonic estersynthesisvia enolate anionsChapters 22 and 23Intramolecular a-alkylationFavorskii rearrangementvia enolate anionsextraIntermolecular a-halogenationand haloform reactionvia enols and enolate anionsChapters 22
2 A library of the enol and enolate mediated carbonyl compound reactions: Self-condensationSelf and mixed Aldol and Claisenvia enols and enolate anionsChapter 23
3 Intramolecular condensation A library of the enol and enolate mediated carbonyl compound reactions:Intramolecular condensationDieckmannvia enolate anionsChapter 23
4 The α PositionThe carbon next to the carbonyl group is designated as being in the α positionElectrophilic substitution occurs at this position through either an enol or enolate ion
5 Enols and enolate anions behave as nucleophiles and react with electrophiles because the double bonds are electron-rich compared to alkenes
6 Part A: Keto–Enol Tautomerism A carbonyl compound with a hydrogen atom on its a carbon rapidly equilibrates with its corresponding enolCompounds that differ only by the position of a moveable proton are called tautomersThe enol tautomer is usually present to a very small extent and cannot be isolated, but is formed rapidly, and serves as a reaction intermediate
8 Acid Catalysis of Enolization Brønsted acids catalyze keto-enol tautomerization by protonating the carbonyl and activating the α protons
9 Base Catalysis of Enolization Brønsted bases catalyze keto-enol tautomerizationThe hydrogens on the α carbon are weakly acidic and transfer to water is slowIn the reverse direction there is also a barrier to the addition of the proton from water to enolate carbon
10 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.
11 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.
12 Mechanism of Acid-Catalyzed Electrophilic Substitution
13 Mechanism of Acid-Catalyzed Electrophilic Substitution
15 α-Bromoketones Undergo Facile Elimination Reaction to Yield α,b-unsaturated Carbonyl Compounds for 1,4-addition Reactions.
16 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
17 Mechanism of the Hell–Volhard–Zelinskii Reaction PBr3 converts -CO2H to –COBr, which can enolize and add Br2
18 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
22 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.
23 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.
24 The Haloform ReactionBase-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.
25 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.
26 a-Alkylation of Enolate Ions Alkylation occurs when the nucleophilic enolate ion reacts with the electrophilic alkyl halide or tosylate and displaces the leaving groupSN2 reaction:, the leaving group X can be chloride, bromide, iodide, or tosylateR should be primary or methyl and preferably should be allylic or benzylicSecondary halides react poorly, and tertiary halides don't react at all because of competing elimination
27 Mechanism of Base-Promoted Electrophilic Alkylation
29 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.
34 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
35 Relative acidities are dictated by the substituents on the carbonyl group.
36 Ethyl Acetoacetate Ester Diethyl Malonate EsterAcetoacetic 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.
39 2. The Malonic Ester Synthesis For preparing a carboxylic acid from an alkyl halide while lengthening the carbon chain by two atoms3. The Acetoacetic Ester SynthesisOverall: converts an alkyl halide into a methyl ketone
40 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
41 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
42 Decarboxylation of b-Ketoacids Decarboxylation requires a carbonyl group two atoms away from the β CO2HThe second carbonyl permit delocalization of the resulting enolThe reaction can be rationalized by an internal acid-base reaction
43 Generalization: b-Keto Esters The sequence: enolate ion formation, alkylation, hydrolysis/decarboxylation is applicable to b-keto esters in generalCyclic b-keto esters give 2-substituted cyclohexanones
44 Preparation Cycloalkane Carboxylic Acids 1,4-dibromobutane reacts twice, giving a cyclic productThree-, four-, five-, and six-membered rings can be prepared in this way