Ch.23 Carbonyl Condensation Reactions Carbonyl reactions O O- + C C E C Nu- Carbonyl-Carbonyl Condensation O O O HO C H + C H C C H C C C C α α α 23.1 Mechanism of Carbonyl Condensation Reactions ; enolate + carbonyl compounds O C O O OO - C H OH C C C C C C α H2O OOH C C C 23.2 Condensation of Aldehydes and Ketones: The Aldol reaction Aldol: aldehyde + alcohol O NaOEt OOH 2 HCH HCHβ 3 3 EtOH α Aldol (a β-hydroxy aldehyde) reversible reaction: the position of equilibrium depends on the reaction conditions and substrate structures RCH2CHO: condensation product is favored R2CHCHO: starting aldehyde is favored CHO NaOH 2 CHO EtOH OH 90% O O OH NaOH 2 H H EtOH low yield Ketones: starting is favored O O NaOH 2 EtOH OH 5% O O NaOH 2 OH EtOH 22% Mechanism of aldol reaction O C H CH O O 3 O O - H C H OH C C C H C H C H H C CH H α H 3 H H H H2O O OH H C C H C CH3 H H 23.3 Condensation versus α-Substitution - enolates formed in the α-alkylation reaction can be self-condensed For α-substitution reaction: kinetic irreversible deprotonation - complete generation of enolate prior to self-condensation is required ; use full equivalent of strong base at low temperature - electrophile is then added after complete generation of enolates O + O Li O R-X 1 eq. LDA R THF, -78oC For carbonyl condensation reaction: - use catalytic amount of weaker base - small amount of enolates generated self-condense with other carbonyl compounds O 0.05 eq. O O O O NaOCH3 H CH3 H CH H CH3 H CH2 3 CH3OH CH3OH O OH NaOCH3 + H CH3 23.4 Dehydration of Aldol Products: Synthesis of Enones Enone: dehydration, β-leaving groups are labile O OH O H+ β + H2O or OH- H enone Base-catalyzed O OH - O OH O OH + HO- β β H Acid-catalyzed H O OH O H+ O OH2 β + H O+ β 3 H - dehydration conditions are often more vigorous (high temp) than the Aldol condensation - conjugated enones are often obtained directly from the Aldol reaction conditions without isolation of the intermediate β- hydroxy carbonyl compounds Direct dehydration can drive the unfavorable aldol reaction to completion O O O NaOH OH EtOH 92% 23.5 Using Aldol Reactions in Synthesis synthesis of 1,3-diol from aldol adduct O OH O - KOH [H ] H H EtOH HO HO 1,3-diol α,β-unsaturated carbonyls could be further manipulated O O O KOH H2 H H H EtOH Pt-C [H-] (industrially, H 2/Pt) OH 23.6 Mixed Aldol Reactions mixed-Aldol reaction: condense different carbonyl compounds ; synthetically useful O O H H + HO HO O O KOH Symmetrical products + H H EtOH O O H H + HO HO Mixed products For clean mixed aldol reaction: ; need selective formation of one type of enolate ; add the second carbonyl compound after complete enolate formation 1. use one carbonyl with no α-hydrogens O O CHO NaOEt + EtOH 2. use one doubly activated carbonyls EtO2CCO2Et EtO2CCO2Et NaOEt EtO2CCO2Et + R R CHO Na+ 3. use two step sequence: typical enolate formation + addition of 2nd carbonyl O + + O OH O Li O O Li 1 eq. LDA RCHO H2O R R THF, -78oC 23.7 Intramolecular Aldol Reactions Aldol cyclization: symmetric 1,4- and 1,5-dicaybonyls produce cyclopentenone and cyclohexenone O O NaOH O EtOH O O NaOH EtOH O Reversible aldol reaction: produce the more stable product ; less strained 5 and 6-membered rings are formed predominantly over 3- or 4-membered rings O O path a - O a NaOH H OH EtOH CH3 HO CH3 CH3 O b path a HO CH3 CH3 - NaOH CH3 OH EtOH H CH3 CH3 O O NOT formed 23.8 Condensation of Esters: The Claisen Condensation Reaction Claisen condensation; O 1. NaOEt OO 2 EtOH H3COEt EtOβ CH3 + α 2. H3O β-keto ester - for esters with more than one α-protons: irreversible reaction and need full equivalent of base mechanism: O C O O EtO CH3 O O - OEt C H OEt C C C EtO C EtO C H EtO C CH HHα 3 H HH O O O O EtOH + C C -OEt + C C EtO C CH3 EtO C CH3 H irreversible HH stable enolate + H3O O O - for esters with more than one α-protons: irreversible reaction, C C EtO C CH3 and need full equivalent of base HH 23.9 Mixed Claisen Condensations ester + ester O O O O 1. NaH OEt + OEt H3COEt THF + 2. H3O ketone + ester (no α-hydrogens, ethyl formate) O O OO 1. NaOEt + HOEt H + 2. H3O 23.10 Intramolecular Claisen Condensations; The Dieckmann Cyclization intramolecular condensation O 1. NaOEt CO2Et EtO2C + CO2Et 2. H3O O O O O OEt 1. NaOEt OEt OEt + 2. H3O use of β-keto ester: alkylation + decarboxylation sequence O O O O 1. NaOEt OEt OEt 2. Br + H3O heat O 23.11 The Michael Reaction Michael reaction: conjugate addition (1,4-addition) of enolate into α,β-unsaturated carbonyl compound O Nu O Nu-H O Nu H - stable enolates add to an unhindered α,β-unsaturated carbonyl compound in 1,4-fashion: 1,3-dicarbonyl enolates O O OO O 1. NaOEt OEt + OEt + 2. H3O O Michael donors OO OO OO RR'ROEtEtO OEt O CN R RNO2 Michael acceptors O O O H EtO O NC O2N H2N 23.12 The Stork Enamine Reaction Enamine: prefer conjugate addition into α,β-unsaturated carbonyl compound O HNR2 NR2 O N N H 87% Enamine: O O necleophilic α-carbon NR2 NR2 Stork enamine reaction: Michael-type addition O N N O N H O O O N O H2O + N H - enamine: readily hydrolyzed by water - 1,5-diketone synthesis 23.13 The Robinson Annulation Reaction Robinson annulation: Michael + intramolecular Aldol reaction CO Et CO Et 2 NaOEt 2 + O O Michael O O reaction Aldol NaOEt reaction CO2Et O Synthesis of steroid by Robinson annulation: H3C O O O base H C + 3 O O O base CH O 3 H3C O O HO Estrone 23.14 Biological Carbonyl Condensation Reactions mixed Aldol reaction: acetyl-CoA O O H C SCoA H3C SCoA 2 mixed-Aldol CO2H OH Acetyl CoA CO H O HO C 2 (a thioester) 2 CO2H HO2C Citric acid O O O O OO H3C SCoA H2C SCoA H3C C SCoA SCoA CoAS H2 Acetoacetyl CoA Chemistry @ Work A Prologue to Metabolism - almost all metabolic processes used by living organisms involve one or more of the four carbonyl reactions HOH O H O Glycolysis - HO O HO OH 2 H3C H OH H H O D-Glucose Pyruvate CHO HOC H H2C OH H2C OH H OH OH O OH HO H HO H HO H HO H H OH H OH H O H H O H OH H OH H OH H OH CH OH 2 CH2OH CH2OH CH2OH retro-Aldol Problem Sets Chapter 23 28, 42, 43, 45, 46, 56.