Chapter 19: Carbonyl Compounds III Learning Objectives: 1. Write the mechanism for keto-enol tautomerization and explain the consequence of such tautomerizarion in the optical chiral of compound. 2. Remember the approximate p Ka value for the α-hydrogen of a carbonyl group. 3. Provide appropriate bases for the formation of enolate and use such enolate for halogenation and alkylation. 4. Be able to write the general electron-pushing (arrow-pushing) mechanisms of Aldol reaction, Michael reaction, Claisen condensation, and Dieckmann condensation. 5. Be able to write the general electron-pushing (arrow-pushing) mechanisms for decarboxylation of 3-oxocarboxylic acids 6. Be able to employ the above-mentioned reaction for the formation of new carbon-carbon bond Sections: 19.1 Acidity of α-hydrogens* 19.2 Keto-Enol Tautomerism* 19.3 How Enols and Enolate Ions React* 19.4 Halogenation of the α-Carbon of Aldehydes and Ketones* 19.5 Halogenation of the α-Carbon of Carboxylic Acids: The Hell-Volhard-Zelinski (HVZ) Reaction 19.6 α-Halogenated Carbonyl Compounds in Synthesis* 19.7 Using LDA to form an Enolate* 19.8 Alkylation of the α-Carbon of Carbonyl Compounds* 19.9 Alkylation and Acylation of the α-Carbon via an Enamine Intermediate 19.10 Alkylation of the β-Carbon: the Michael Reaction* 19.11 The Aldol Reaction* 19.12 Dehydration of Aldol Addition Products: Formation of α,β -Unsaturated Aldehydes and Ketones* 19.13 The Mixed Aldol Reaction 19.14 The Claisen Condensation* 19.15 The Mixed Claisen Condensation 19.16 Intramolecular Condensation and Addition Reactions* 19.17 Decarboxylation of 3-Oxocarboxylic Acids* 19.18 The Malonic Ester Synthesis: Synthesis of Carboxylic Acids 19.19 The Acetoacetic Ester Synthesis: Synthesis of Methyl Ketones 19.20 Designing a Synthesis VI: Making New Carbon-Carbon Bonds 19.21 Reactions at the α-carbon in Biological Systems # * Sections that will be focused # Sections that will be skipped Recommended additional problems 19.44 – 19.52, 19.54 – 19.64, 19.66 – 19.80 1 Class Note 19.1 Acidity of α-hydrogens A. pKa of α-hydrogen of carbonyl derivatives O O O O R' α R' R' R' NHR OR R H H H H H O O O O O O R' OR R' R R' H H H H B. Resonance effect 2 19.2 Keto-Enol Tautomerism O OH R' R R' R H A. Mechanism in acidic condition B. Mechanism in basic condition 3 19.3 How Enols and Enolate Ions React A. Analysis of enols and enolates 4 19.4 Halogenation of the α-Carbon of Aldehydes and Ketones A. Acid-catalyzed halogenation O O X2 (Cl2, Br2, I2) + H3O CH3 CH2 X 5 B. Base-promoted halogenation O X2 (Cl2, Br2, I2) O (excess) R HO- R CH2 CX2 C. Haloform reaction O X2 (Cl2, Br2, I2) O (excess) HO- CH O 3 + CHX3 6 19.5 Halogenation of the α-Carbon of Carboxylic Acids: The Hell-Volhard-Zelinski (HVZ) Reaction 1) PBr , Br O 3 2 O 2) H2O R R OH OH Br 7 19.6 α-Halogenated Carbonyl Compounds in Synthesis A. Analysis of α-halogenated carbonyl Compounds B. Examples 8 19.7 Using LDA to form an Enolate N lithium diisopropylamide (LDA) 19.8 Alkylation of the α-Carbon of Carbonyl Compounds A. Analysis of the reaction 9 B. Examples (i) 1) LDA, THF OCH3 2) CH3I O (ii) 1) LDA, THF 2) CH3CH2I CN 10 C. Potential problem in alkylation of the α-carbon of carbonyl compounds O 1) LDA, THF CH3 2) CH3I 11 19.9 Alkylation and Acylation of the α-Carbon via an Enamine Intermediate O N catalytic H+ + N H2O H + pyrrolidine enamine A. Examples 1) catalytic H+ O N H 2) CH3Br + 3) H2O, H 12 19.10 Alkylation of the β-Carbon: the Michael Reaction A. Michael reaction O O O - CH3O + CH CH 3 H3C 3 13 B. Examples (i) O O O base (?) + H3CO OCH3 (ii) O O base (?) CN OCH CH + 2 3 H3C 14 C. Stork enamine reaction O N HCl H2O + CH3 15 19.11 The Aldol Reaction OH O O base R R H H R A. Mechanism 16 19.12 Dehydration of Aldol Addition Products: Formation of α,β -Unsaturated Aldehydes and Ketones A. Aldol condensation B. Examples (i) O O - H MeO + H MeOH (ii) O EtO- Na+ EtOH 17 19.13 The Mixed Aldol Reaction A. Potential problem in aldol reaction (i) O EtO- Na+ EtOH (ii) O O MeO- Na+ + MeOH H 18 B. Solution (i) O O - + H MeO Na + H MeOH 19 19.14 The Claisen Condensation and 19.15 The Mixed Claisen Condensation O O O base R R OR' + HOR' OR' R A. Mechanism 20 B. Examples (i) O base (?) OCH2CH3 (ii) O O base (?) OCH3 + OCH2CH3 21 19.16 Intramolecular Condensation and Addition Reactions A. Intramolecular Claisen reaction (Dieckmann condensation) (i) H3CO OCH3 MeO- Na+ MeOH O O (ii) O EtO- Na+ H3CH2CO OCH2CH3 EtOH O 22 B. Intramolecular aldol reaction (i) H3C CH3 MeO- Na+ MeOH O O (ii) O EtO- Na+ H3C CH3 EtOH O 23 (iii) O EtO- Na+ H3C H EtOH O (iv) Robinson annulation O O + base H , heat + + H2O CH3 O 24 19.17 Decarboxylation of 3-Oxocarboxylic Acids A. Easier in acidic condition: mechanism O O O O R OH R O B. Examples of compounds containing 3-oxocarboxylic acid O O O O HO OH OH R R 25 19.18 The Malonic Ester Synthesis: Synthesis of Carboxylic Acids and 19.19 The Acetoacetic Ester Synthesis: Synthesis of Methyl Ketones O O O ? R H3CH2CO OCH2CH3 OH 26 A. Examples: O O O OH OH OH 27 19.20 Designing a Synthesis VI: Making New Carbon-Carbon Bonds O O CO2H synthesis of from H3CO OCH3 28 .