17.4 The Aldol Reaction: The Addition of Enolate Anions to...
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ORGANIC CHEMISTRY Department of Chemistry, Xiamen University Chapter 17 17.4 The Aldol Reaction: The Addition of Enolate Anions to Aldehydes and Ketones
Transcript of 17.4 The Aldol Reaction: The Addition of Enolate Anions to...
ORGANIC CHEMISTRY
Department of Chemistry, Xiamen University
Chapter 17
17.4 The Aldol Reaction: The Addition of Enolate Anions to Aldehydes and
Ketones
ORGANIC CHEMISTRY
Department of Chemistry, Xiamen University
Chapter 17
Aldol addition (aldol reaction)
2 CH3CHO CH3CHCH2CHOOH10% NaOH, H2O
5°C 3-Hydroxybutanal(50%)
β−hydroxyaldehyde("aldol")
2 PhCH2CHO PhCH2CHOH
CHCHOPh 90%EtOH
NaOH
ORGANIC CHEMISTRY
Department of Chemistry, Xiamen University
Chapter 17
Mechanism Mechanism
OHCH2 C H
O
HCH2 C H
OCH2 C H
O+
CH2 C HO
CH3 C HO
+
CH3 CHO
CH2 C HO
CH2 C HO
H OHCH3 CH
OHCH2 C H
OOH+
H OH
ORGANIC CHEMISTRY
Department of Chemistry, Xiamen University
Chapter 17
17.4A Dehydration of the Aldol Addition Product
The aldols formed in aldol additions can be easily dehydrated to yield conjugated enals (enones).
COH
CCO
H
CC
CO
H+ or OH∆
+ H2O
An aldol A conjugated enal (enone)
Aldol condensation — A condensation reaction is one in which molecules are joined through the intermolecular elimination of a small molecule such as water or an alcohol.
ORGANIC CHEMISTRY
Department of Chemistry, Xiamen University
Chapter 17
Mechanism Mechanism
CH3 CHOH
CH C HO
HOHCH3 CH CH C H
O
+ H OH + OH
The conditions needed for aldol dehydration are often only a bit more vigorous (slightly higher temperature, for example) than the conditions needed for the aldol dimerization itself.As a result, conjugated enals (enones) are often obtained directly from aldol reactions, and the intermediate β-hydroxy carbonyl compounds aren’t usually isolated.
ORGANIC CHEMISTRY
Department of Chemistry, Xiamen University
Chapter 17
17.4B Synthetic Applications
2 RCH2CHO OHH2O
RCH2CH CHCHOR
OHNaBH4 RCH2CH CHCH2OH
R
OH
An aldol A 1,3-diolAldehyde HAH2O
RCH2CH CCHOR
LiAlH4
RCH2CH CCH2OHR
H2/Nihigh
pressure
RCH2CH2 CHCH2OHR
H2/Pd-C
RCH2CH2 CHCHOR
A saturated alcohol
An α,β-unsaturated aldehyde
An allylic alcoholAn aldehyde
ORGANIC CHEMISTRY
Department of Chemistry, Xiamen University
Chapter 17
17.4C The Reversibility of Aldol Additions
The aldol addition is reversible — retro-aldol reaction.
CH3 COH
CH2 C CH3
O OH
+
CH3
CH3 CO
CH2 C CH3
O
CH3H2O
CH3 CO
CH3
CH3 C CH3
OCH2 C CH3
O
OH
H2O
(5%)
2(95%)
ORGANIC CHEMISTRY
Department of Chemistry, Xiamen University
Chapter 17
17.4D Acid-Catalyzed Aldol Condensations
CH3 C CH3
OCH3 C CH3
OHCH3 C CH3
OH
CH3 C CH2
OH CH3 C CH3
OH
CH3 C CH3
OH
CH3 C CH2
OH
CH3 C CH2
OHCO
CH3
CH3
H+
H+
H+
ORGANIC CHEMISTRY
Department of Chemistry, Xiamen University
Chapter 17
17.5 Crossed Aldol Reactions
ORGANIC CHEMISTRY
Department of Chemistry, Xiamen University
Chapter 17
CH3CHO + CH3CH2CHO
CH3CH CH2CHOOH
CH3CH CHCHOOH
CH3
CH3CH2CH CHCHOOH
CH3
CH3CH2CH CH2CHOOH
OH
H2O
+
++
ORGANIC CHEMISTRY
Department of Chemistry, Xiamen University
Chapter 17
17.5A Practical Crossed Aldol ReactionsCH3CH2CHOC6H5CHO +
10°COH
C6H5CH CCHOCH3
C6H5CH2CHOC6H5CHO + 20°COH
C6H5CH CCHOC6H5
HCHO CH3CHO+OH
HOCH2 CH2CHO
Benzaldehyde Propanal 2-Methhyl-3-phenyl-2-propenalAn α,β-unsaturated aldehyde
Benzaldehyde Phenylacetaldehyde 2,3-Diphenyl-2-propenal
Formaldehyde Acetaldehyde 3-Hydroxypropanal
OH
2 HCHO(HOCH2)3CCHO
ORGANIC CHEMISTRY
Department of Chemistry, Xiamen University
Chapter 17
17.5B Claisen-Schmidt ReactionWhen ketones are used as one component, the crossed aldol reactions are called Claisen-Schmidt reactions.
PhCHO CH3 CO
C(CH3)3+
C CH
H
C C(CH3)3
O
88~93%
Ph
PhCHO CH3 CO
CH3+ PhCH CH CO
CH3
NaOH-H2OEtOH
OH
100°C
ORGANIC CHEMISTRY
Department of Chemistry, Xiamen University
Chapter 17
17.5C Condensations with NitroalkanesThe α hydrogens of nitroalkanes are appreciably acidic (pKa =10), much more acidic than those of aldehydes and ketones.
R CH2 NO
O
BR CH N
O
OR CH N
O
O+ HB
C6H5CHO CH3NO2+OH
C6H5CH CHNO2H2, Ni
C6H5CH2CH2NH2
ORGANIC CHEMISTRY
Department of Chemistry, Xiamen University
Chapter 17
17.5D Condensations with NitrilesThe α hydrogens of nitriles are also appreciably acidic (CH3CN pKa =25), but less so than those of aldehydes and ketones.
C6H5CHO C6H5CH2CN+EtO
C6H5CH CEtOH
C6H5
CN
ORGANIC CHEMISTRY
Department of Chemistry, Xiamen University
Chapter 17
17.6 Cyclizations via Aldol Condensations
ORGANIC CHEMISTRY
Department of Chemistry, Xiamen University
Chapter 17
The aldol condensation also offers a convenient way to synthesize molecules with five and six-membered rings ( and sometimes even larger rings).
CH3C(CH2)3CH2CCH3
O O CH3
C CH3O
85%
KOH, H2O
CH3C(CH2)3CH2CCH3
O OCH3C(CH2)3CHCCH3
O OOH
CH3
C CH3O
OH2O
CH3
C CH3O
OH
HHOH
CH3
C CH3O
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