1 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 pKa 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 – 19.802 Class Note 19.1 Acidity of α-hydrogens A. pKa of α-hydrogen of carbonyl derivatives HNHROHOROHROHHOR'R' R'R'α HOROR'OHROR'OHHOR'O B. Resonance effect3 19.2 Keto-Enol Tautomerism HROR'ROHR' A. Mechanism in acidic condition B. Mechanism in basic condition4 19.3 How Enols and Enolate Ions React A. Analysis of enols and enolates5 19.4 Halogenation of the α-Carbon of Aldehydes and Ketones A. Acid-catalyzed halogenation CH3OX2 (Cl2, Br2, I2)H3O+CH2OX6 B. Base-promoted halogenation CH2OX2 (Cl2, Br2, I2)(excess)HO-RCX2OR C. Haloform reaction CH3OX2 (Cl2, Br2, I2)(excess)HO-OOCHX3+7 19.5 Halogenation of the α-Carbon of Carboxylic Acids: The Hell-Volhard-Zelinski (HVZ) Reaction OHOR1) PBr3, Br22) H2OOHORBr8 19.6 α-Halogenated Carbonyl Compounds in Synthesis A. Analysis of α-halogenated carbonyl Compounds B. Examples9 19.7 Using LDA to form an Enolate Nlithium diisopropylamide (LDA) 19.8 Alkylation of the α-Carbon of Carbonyl Compounds A. Analysis of the reaction10 B. Examples (i) OOCH31) LDA, THF2) CH3I (ii) CN1) LDA, THF2) CH3CH2I11 C. Potential problem in alkylation of the α-carbon of carbonyl compounds OCH31) LDA, THF2) CH3I12 19.9 Alkylation and Acylation of the α-Carbon via an Enamine Intermediate ONHpyrrolidine+Nenamine+H2Ocatalytic H+ A. Examples O2) CH3Br3) H2O, H+1) catalytic H+NH13 19.10 Alkylation of the β-Carbon: the Michael Reaction A. Michael reaction CH3OCH3OH3CO+CH3O-14 B. Examples (i) OOCH3OH3COO+base (?) (ii) OCH2CH3O+CNH3CObase (?)15 C. Stork enamine reaction NCH3O+HClH2O16 19.11 The Aldol Reaction HORbaseHOROHR A. Mechanism17 19.12 Dehydration of Aldol Addition Products: Formation of α,β-Unsaturated Aldehydes and Ketones A. Aldol condensation B. Examples (i) HOHO+MeO-MeOH (ii) OEtO-EtOHNa+18 19.13 The Mixed Aldol Reaction A. Potential problem in aldol reaction (i) OEtO-EtOHNa+ (ii) HO+OMeO-MeOHNa+19 B. Solution (i) HOHO+MeO-MeOHNa+20 19.14 The Claisen Condensation and 19.15 The Mixed Claisen Condensation OR'ORbaseOR'OROR+HOR' A. Mechanism21 B. Examples (i) OCH2CH3Obase (?) (ii) OCH3OOCH2CH3O+base (?)22 19.16 Intramolecular Condensation and Addition Reactions A. Intramolecular Claisen reaction (Dieckmann condensation) (i) H3CO OCH3OOMeO-MeOHNa+ (ii) H3CH2COOCH2CH3OOEtO-EtOHNa+23 B. Intramolecular aldol reaction (i) H3C CH3OOMeO-MeOHNa+ (ii) H3CCH3OOEtO-EtOHNa+24 (iii) H3CHOOEtO-EtOHNa+ (iv) Robinson annulation CH3O+ObaseH+, heatO+H2O25 19.17 Decarboxylation of 3-Oxocarboxylic Acids A. Easier in acidic condition: mechanism R OHOOR OOO B. Examples of compounds containing 3-oxocarboxylic acid HO OHOOROHOOR26 19.18 The Malonic Ester Synthesis: Synthesis of Carboxylic Acids and 19.19 The Acetoacetic Ester Synthesis: Synthesis of Methyl Ketones H3CH2CO OCH2CH3OO?ROHO27 A. Examples: OHOOHOOHO28 19.20 Designing a Synthesis VI: Making New Carbon-Carbon Bonds H3CO OCH3OOsynthesis