CNGNGE JOHN MCMURRY CHAPTER 17 Carbonyl Alpha- Substitution and Condensation Reactions THIRD EDITION Organic Chemistry with Biological Applications
CHAPTER 17 Carbonyl AlphaSubstitution and Condensation Reactions
a-Substitution and Carbonyl Condensation Reactions Alpha-substitution reactions occur at the carbon next to the carbonyl carbon-the a position Involve substitution of a-hydrogen :9: An enolate ion by electrophile Proceed through enol or enolate ion intermediate A carbonyl An alpha-substituted compound carbonyl compound Carbonyl condensation reactions occur between two carbonyl An enol partners Combination of a-substitution and nucleophilic addition steps i- New C-C bond Gives B-hydroxy carbonyl compound A carbonyl An enolate A B-hydroxy compound ion carbonyl compound
Alpha-substitution reactions occur at the carbon next to the carbonyl carbon – the a position ▪ Involve substitution of a-hydrogen by electrophile ▪ Proceed through enol or enolate ion intermediate Carbonyl condensation reactions occur between two carbonyl partners ▪ Combination of a-substitution and nucleophilic addition steps ▪ Gives b-hydroxy carbonyl compound α-Substitution and Carbonyl Condensation Reactions
17-1 Keto-Enol Tautomerism Carbonyl compounds with a-hydrogens rapidly equilibrate with corresponding enol(ene alcohol) Interconversion known as keto-eno/tautomerism :Greek tauto,meaning"the same,”and meros,meaning“part” Individual isomers called tautomers Keto tautomer Enol tautomer
Carbonyl compounds with a-hydrogens rapidly equilibrate with corresponding enol (ene + alcohol) ▪ Interconversion known as keto-enol tautomerism ▪ Greek tauto, meaning “the same,” and meros, meaning “part” ▪ Individual isomers called tautomers 17-1 Keto-Enol Tautomerism
Keto-Enol Tautomerism Tautomers are constitutional isomers Isomers are different compounds with different structures Atoms arranged differently Different from resonance structures that differ only in the position of their electrons Most carbonyl compounds exist almost exclusively in the keto form at equilibrium 0 ← H3C CH3 H3C 99.9999% 0.0001% 99.9999999% 0.0000001% Cyclohexanone Acetone
Tautomers are constitutional isomers ▪ Isomers are different compounds with different structures ▪ Atoms arranged differently ▪ Different from resonance structures that differ only in the position of their electrons ▪ Most carbonyl compounds exist almost exclusively in the keto form at equilibrium Keto-Enol Tautomerism
Keto-Enol Tautomerism Tautomers are constitutional isomers The enol tautomer sometimes predominates when it can be stabilized by conjugation or by intramolecular hydrogen bond formation Nonacidic 0: H H:0: Base H HH H H H H Acidic Enolate ion
Tautomers are constitutional isomers ▪ The enol tautomer sometimes predominates when it can be stabilized by conjugation or by intramolecular hydrogen bond formation Keto-Enol Tautomerism
Keto-Enol Tautomerism Only a-hydrogens are acidic a-Hydrogens are acidic because the enolate ion that results from deprotonation is resonance stabilized with the electronegative oxygen of the carbonyl B-,/Hydrogens (and so on)are not acidic because the ion that results from deprotonation is not resonance stabilized Nonacidic H HH HH H :0: Base y C H HH H H H H Acidic Enolate ion
Only a-hydrogens are acidic ▪ a-Hydrogens are acidic because the enolate ion that results from deprotonation is resonance stabilized with the electronegative oxygen of the carbonyl ▪ b-, g-, d-Hydrogens (and so on) are not acidic because the ion that results from deprotonation is not resonance stabilized Keto-Enol Tautomerism
Keto-Enol Tautomerism Mechanism of acid-catalyzed (a)Acidic conditions enol formation -Protonated intermediate Keto tautomer can lose H+,either from the 1The carbonyl oxygen is protonated by an acid H-A, oxygen atom to regenerate giving a cation with two the keto tautomer or from resonance structures. the a carbon atom to yield an enol tautomer ②Loss of H+from the a position by reaction with A日 a base A gives the enol tautomer and regenerates HA catalyst. HA Enol tautomer
Mechanism of acid-catalyzed enol formation ▪ Protonated intermediate can lose H+ , either from the oxygen atom to regenerate the keto tautomer or from the a carbon atom to yield an enol tautomer Keto-Enol Tautomerism
Keto-Enol Tautomerism Mechanism of base- (b)Basic conditions 0 catalyzed enol formation Base removes the Keto tautomer The intermediate enolate acidic a hydrogen, ion,a resonance hybrid yielding an enolate ion with two resonance of two forms,can be structures. protonated either on carbon to generate the starting keto tautomer ②Protonation of the Enolate ion or on oxygen to give an enolate ion on oxygen gives the enol and 2 enol tautomer regenerates base catalyst. HO Enol tautomer
Mechanism of basecatalyzed enol formation ▪ The intermediate enolate ion, a resonance hybrid of two forms, can be protonated either on carbon to generate the starting keto tautomer or on oxygen to give an enol tautomer Keto-Enol Tautomerism
17-2 Reactivity of Enols:a-Substitution Reactions Enols are nucleophiles that react with electrophiles -There is a substantial build-up of electron density on the a carbon of the enol Electron-rich Enol tautomer Cngg Loaring All Pights Reserved
Enols are nucleophiles that react with electrophiles ▪ There is a substantial build-up of electron density on the a carbon of the enol 17-2 Reactivity of Enols: α-Substitution Reactions
Reactivity of Enols:a-Substitution Reactions General mechanism of carbonyl a-substitution reaction 。 Enol is formed with acid catalysis Electron pair from C=C Acid-catalyzed enol formation occurs Acid catalyst bond of enol attacks an by the usual mechanism. electrophile(E),forming new C-E bond and a An electron pair from the enol oxygen resonance stabilized attacks an electrophile(E),forming a new bond and leaving a cation intermediate intermediate that is stabilized by resonance between two forms. ·Loss of H+from oxygen yields the neutral alpha- Loss of a proton from oxygen yields substitution product and the neutral alpha-substitution product as a new C-O bond is formed. restores the C=O bond
General mechanism of carbonyl a-substitution reaction • Enol is formed with acid catalysis • Electron pair from C=C bond of enol attacks an electrophile (E+ ), forming new C-E bond and a resonance stabilized intermediate • Loss of H+ from oxygen yields the neutral alphasubstitution product and restores the C=O bond Reactivity of Enols: α-Substitution Reactions