John E. McMurry www.cengage.com/chemistry/mcmurry Chapter 22 Carbonyl Alpha-Substitution Reactions Paul D. Adams University of Arkansas 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 enolate or enol ion Why this Chapter?
Many schemes make use of carbonyl substitution reactions. These reaction are one the few general methods for making C-C bonds. 22.1 KetoEnol 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 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 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 Acid Catalysis of Enolization Brnsted acids catalyze keto-enol tautomerization by protonating the carbonyl and
activating the protons Base Catalysis of Enolization
Brnsted 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
22.2 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 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 Hs are replaced by Ds at the same rate as halogenation
This is because the barrier to formation of the enol goes through the highest energy transition state in the mechanism Elimination Reactions of -Bromoketones -Bromo ketones can be dehydrobrominated by base treatment to yield ,-unsaturated ketones
22.4 Alpha Bromination of Carboxylic Acids Carboxylic acids do not react with Br2 (unlike aldehydes and ketones) They are brominated by a mixture of Br2 and PBr3 (Hell VolhardZelinskii reaction)
Mechanism of Bromination PBr3 converts COOH to COBr, which can enolize and add Br2 22.5 Acidity of Alpha Hydrogen Atoms: 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 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(iC3H7)2] are strong enough to form the enolate Lithium Diisopropylamide (LDA)
LDA is from butyllithium (BuLi) and 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 (Table 22.1) Negative charge of enolate delocalizes over both carbonyl groups
Table 22.1: Acidities of Organic Compounds 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 Reaction on carbon yields an -substituted carbonyl compound 22.7 Alkylation of Enolate Ions
Base-promoted reaction occurs through an enolate ion intermediate Constraints on Enolate Alkylation 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 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 -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 into a carboxylic acid while lengthening the carbon chain by two atoms
Preparation of 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 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 can be alkylated by an alkyl halide and also can react with a second alkyl halide Generalization: -Keto Esters
The sequence: enolate ion formation, alkylation, hydrolysis/decarboxylation is applicable to -keto esters in general Cyclic -keto esters give 2-substituted cyclohexanones Biological Alkylations Lets Work a Problem Which of the following substances would undergo
the haloform reaction? a) CH3COCH3 b) c) Acetophenone CH3CH2CHO
d) CH3CO2H e) CH3C N Answer
In the haloform reaction, there is an -substitution whereby the methyl ketone is trihalogenated at the position. The trihalomethyl group is displaced by OH. This reaction is used as a test for methyl ketones. + reactions would come from reactions a, and b; while reactions would come from c, d, and e.
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