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
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