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Chapter 22

Carbonyl Alpha - Substitution Reactions - Lecture and Textbook Notes Chapter 22

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Cecilia Kutas

CHM247H1 Jasmyn Lee Chapter 22: Carbonyl Alpha Substitution Reactions 22.1 Keto-Enol Tautomerism  The position next to a point of reference is the alpha (α) position +  An electrophile (E ) can be substituted for an α H  Tautomers – the spontaneous interconversion between two isomers; usually with the change in position of a hydrogen o Keto and enol isomers are tautomers  Tautomers vs. Isomers o Tautomers – constitutional isomers; different compounds with different structures  Have atoms arranged differently o Resonance Forms – different representations of a single compound  Differ only in position of π and non-bonding electrons  The reaction proceeds by way of o Electron rich intermediates form new C-C bond with E o Enol is more electron rich than alkene, because OH has a powerful electron donating resonance effect  Keto and enol forms are tautomers of the carbonyl group in equilibrium with each other tautomers differ in the position of “=” and H atom o Enol form is difficult to isolate – must be stabilized by conjugation or by intermolecular hydrogen bonding o Enol formation is catalyzed by acid and base  In β-dicarbonyl compounds the enol form predominates o The enol form is stabilized by conjugation and intermolecular Hydrogen bonding, especially as a 6- membered ring  Acid Catalyzed Enol Formation 1. Protonation occurs first – forms a resonance stabilized carbocation 2. The proton is them removed – forms the enol 1 CHM247H1 Jasmyn Lee  Base Catalyzed Enol Formation 1. α proton is removed first – forms a resonance stabilized enolate 2. Enolate picks up a proton from water – forms the enol 22.2 Reactivity of Enols: The Mechanism of Alpha-Substitution Reactions  Like alkenes, enols react with electrophiles  Electron donation from HO makes them more reactive than alkenes Examples of enol reactivity 22.3 Alpha Halogenation of Aldehydes and Ketones  α – halogenation of aldehydes and ketones – acid catalyzed  Also works well with 2l and2I  Mechanism of Acid Catalyzed α Substitution o Slow, rate determining formation of enol o Then fast nucleophilic attack on halogen and deprotonation  Rate = k [ketone] [H+] (no halogen term) o i.e. enol formation is rate determining o α – bromination, α – chlorination, α – iodination; all proceed at the same rate  To substitute deuterium, use3D O 22.4 α-Bromination of Carboxylic Acids  α-bromination of carbonyl compounds by Br2in acetic acid is limited to aldehydes and ketones o α-bromination goes by an enolate mechanism but carboxylic acid, esters and amides don’t form enolate  Carboxylic acids can be α brominated by a mixture of 3Br and2Br (Hell-Volhard-Zelinkski)  The Hell-Volhard-Zelinski Reaction 2 CHM247H1 Jasmyn Lee o First step: Formation of Acid Halide 22.5 Acidity of Alpha Hydrogen Atoms: Enolate Ion Formation Comparing Acidity of Different Kinds of Protons  A hydrogen on the α position of a carbonyl compound is weakly acidic and can be removed by a strong base to yield an enolate ion  Compares pKa values  Acidity of a proton is increased by 1. Resonance stabilization 2. Negative charge on O in the conjugate base  Enolate can be formed from esters, 3° amides (less acidic) and nitriles  Protons α to two carbonyl groups are especially acidic o Three resonance contributors o Resonance delocalizes the negative charge on two different oxygen atoms 3 CHM247H1 Jasmyn Lee Common bases used to form enolate  Stronger base drives equilibrium to enolate side because enolate formation is an acid-base equilibrium  To form an enolate in essentially 100% yield  need a strong non-nucleophilic base to deprotonate carbonyl compound o Lithium diisopropyl amide o A strong, bulky base, not nucleophilic o Wont add to carbonyl  All three alkylation’s subject toNusual S 2 restrictions 4 CHM247H1 Jasmyn Lee 22.6 Reactivity of Enolate Ions  Enolate ions are more useful than enols 1. Enolate ions can be prepared and isolated; enols are only short-lived intermediates 2. Enolates are more reactive than enols and undergo many reactions that enols do not o Enols – neutral o Enolate – negative charge  Enolate ions are looked at either as vinylic alkoxide or as α-keto carbanions  As nucleophiles, enolates react with many electrophiles  Resonance stabilized enolate has two potential reaction – oxygen or carbon  Usually reacts at Carbon end; this site is more nucleophilic (used to be under 22.4) Base Promoted α-halogenation  Aldehydes and ketones undergo base-promoted α-halogenation
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