CHM'224'•'Organic'Chemistry'IISpring'2013,'Des'Plaines'•'Prof.'Chad'Landrie
•Enolates*and*Carbonyl*Condensa0ons*(23.1)•Aldol*Condensa0on*(23.2823.6)•Claisen*Condensa0on*(23.7823.9)
Lecture'12:'February'28,'2013
Lichens: fungus + photosynthetic partner
S
OCoA
O
OO
17
35
2 Aldol S
OCoA
OO
17
35
2 OH
O
OHHO
17
35
2
orsellinic acid
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 12: February 28
Enol%and%Enolate
2
CCO
HC
CO
H
CCO
CCO
tautomerization
resonance
dissociationdissociation
H+ H++ +
• enlolate is the conjugate base of an enol• electron lone-pair is delocalized on C and O atoms
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 12: February 28
Subs.tu.on%Reac.ons%at%the%α3Carbon
3
Ch. 22: Enols and enolates are nucleophilic at the alpha carbon and undergo substitution with electrophiles.
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 12: February 28
Acidic%a3Hydrogens
4
αβ
ɣC H
OC
H3CH H
HH
C H
OC
H3C
HH
HC H
OC
H3C
HH
H
Main Points:1.acidic hydrogen is attached to the α-carbon2.simple aldehydes and ketones have pKa = 16-20; similar acidity to
OH group of water or most alcohols3.An α-hydrogen of an ester is less acidic than ketone or aldehyde4.A hydrogen that is α to two carbonyls is more acidic
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 12: February 28
Acidic%a3Hydrogens
5
Main Points:1.acidic hydrogen is attached to the α-carbon2.simple aldehydes and ketones have pKa = 16-20; similar acidity to
OH group of water or most alcohols3.An α-hydrogen of an ester is less acidic than ketone or aldehyde4.A hydrogen that is α to two carbonyls is more acidic
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 12: February 28
Factors%Effec.ng%Acidity
6
Inductive Effect• carbonyl group is electron
withdrawing• increases partial positive
charge on H atom• more acidic
Resonance• conjugate base stabilized by
resonance• charge delocalized over two
atoms, one of which is O• ↑ stable CB = more acidic
C
O
Hδ+
C H
O
C H
O
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 12: February 28
pKa%Values%of%Aldehydes,%Ketones%and%Esters
7
• α-hydrogens are much less acidic than carboxylic acids
• acids delocalization over two oxygens
• perspective: still a fairly weak acid
CO
OH
H CO
OH
CO
OH
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 12: February 28
pKa%Values%of%Aldehydes,%Ketones%and%Esters
8
• α-hydrogens are in the same acidity range as alcohols and water
• hydroxide (pKa H2O = 15.7) and alkoxides can deprotonate many α-Hs compounds
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 12: February 28
Aqueous%Equilibria%of%Ketones%and%Aldehydes
9
CO
H
H3CH3C
HH O + C
O
HH O+
H
H3C
H3C
hydroxide 2-methylpropanalpKa = 15.5
enolate waterpKa = 15.7
• α-hydrogens are in the same acidity range as alcohols and water
• hydroxide (pKa H2O = 15.7) and alkoxides can deprotonate many α-Hs compounds
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 12: February 28
Aqueous%Equilibria%of%Ketones%and%Aldehydes
10
• α-hydrogens are in the same acidity range as alcohols and water
• hydroxide (pKa H2O = 15.7) and alkoxides can deprotonate many α-Hs compounds
CO
H
H3CH3C
HH3C O + C
O
HH3C O+
H
H3C
H3C
methoxide 2-methylpropanalpKa = 15.5
enolate methanolpKa = 16.0
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 12: February 28
pKa%Values%of%Aldehydes,%Ketones%and%Esters
11
• esters are less acidic than ketones or aldehydes
• more competing resonance with ester O-atom = less delocalization of lone-pair on C-atom
C O
OH
H H
C O
OH
H C O
O
C O
OH
H
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 12: February 28
Aqueous%Equilibria%of%Ketones%and%Aldehydes
12
• significant percent of ester exists in equilibria with alkoxides or hydroxides
• this is a key requirement for the Aldol condensation we’ll talk about shortly
CO
OEt
HH
HH3CH2C O + C
O
OEtH3CH2C O+
H
H3C
H3C
ethoxide ethy acetatepKa = 25.6
enolate ethanolpKa = 16.0
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 12: February 28
pKa%Values%of%Dicarbonyls
13
• Dicarbonyl compounds are significantly more acidic
• additional carbonyl = more resonance = more stable CB = more acidic acid
C
O
CH3H H
O
H3C
C
O
CH3H
O
H3CC
O
CH3
O
H3C C
O
CH3
O
H3CHH
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 12: February 28
Aqueous%Equilibria%of%Dicarbonyls
14
• 1,3-dicarbonyls completely deprotonated by hydroxide and alkoxides
• even diesters are completely deprotonated
H3CH2C O + H3CH2C O+H
ethoxide diethyl malonatepKa = 13.0
enolate ethanolpKa = 16.0
OEtEtO
O O
H HOEtEtO
O O
H
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 12: February 28
Complete%Deprotona.on%by%Strong%Bases
15
• LDA is a strong bases capable of completely deprotonating carbonyls
• LDA is made by adding butyl lithium to diisopropyl amine
N
H
NLi+
CH2Li+
+ +
n-butyl lithium(n-BuLi)
diisopropyl amine lithium diisopropyl amide(LDA)
butane
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 12: February 28
Complete%Deprotona.on%by%Strong%Bases
16
• amides (CBs of amines) fully deprotonate even esters
• this is a key requirement when you want to avoid having any of the reactant carbonyl in solution
CO
OEt
HH
HN + C
O
OEtN+
H
H3C
H3C
LDA ethy acetatepKa = 25.6
enolate diisopropyl aminepKa = 36.0
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 12: February 28
Enolate%Regiochemistry
18
Kinetic Control• strong base (irreversible
deprotonation)• large base (increase sterics);
usually LDA• aprotic solvent (e.g., THF) to
prevent reprotonation• low temperature (ensure
lower energy TS path followed)
Thermodynamic Control• base whose pKa is close to
carbonyl (reversible)• protic solvent (e.g., EtOH) to
promote reprotonation• room temp or higher
(promote reversibility)• most stable product (more
substituted alkene) is obtained
OHH
CH3H
basesolvent,
temp.
OHH
CH3base
solvent,
temp.
OCH3H
H
kinetic enolate(least substituted)
thermodynamic enolate(most substituted)
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 12: February 28
Thermodynamic%Enolate
19
OHH
CH3H
CH3O
OHH
CH3thermodynamic enolate(most substituted)
OCH3H
Hkinetic enolate(least substituted)
Thermodynamic Control• base whose pKa is close to carbonyl (Keq~1; reversible)• protic solvent (e.g., EtOH) to promote reprotonation• room temp or higher (promote reversibility)• most stable product (more substituted alkene) is obtained
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 12: February 28
Kine.c%Enolate
20
OHH
HCH3
N
OHH
CH3thermodynamic enolate(most substituted)
OCH3H
Hkinetic enolate(least substituted)
OH
HCH3H
N
OHH
H
CH3
N
Kinetic Control
• strong base (irreversible deprotonation)
• large base (increase sterics); lower energy TS is the one with least sterics
• aprotic solvent (e.g., THF) to prevent reprotonation
• low temperature (ensure lower energy TS path followed)
δ–δ–
δ–δ–
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 12: February 28
Chapter%Summary
22
CH
OE Y+
CH
O
E
Enolates are nucleophiles!
Ch. 22: Alpha Substitutions of Carbonyl Compounds
CH
OE Y
CH
O
EYH
Ch. 23: Condensation Reactions of Carbonyls
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 12: February 28
Chapter%Summary
23
+CH
O
H CH3
O Aldol CondensationCH
O OH
HCH3
+CH
O
H3C OCH3
O Claisen CondensationCH
O O
CH3
+CH
O
H3C Cl
O AcylationCH
O O
CH3
+CH
O
H3CCl
AlkylationCH
OCH3
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 12: February 28
Aldol%Condensa.on
24
O
H2 KOH, H2O HO H
H
Oheat
elimination H
O
aldehyde β-hydroxyaldehyde α,β-unsaturated aldehyde
• condensation of two aldehyde molecules under alkaline conditions
• usually cannot isolate β-hydroxyaldehyde; it quickly undergoes elimination to the alkene
• alkene is more stable since it is conjugated with the carbonyl
aldol = aldehyde & alcohol
Requirements:
•aldehyde: Keq > 1; much slower for ketones (Keq << 1)
•α-carbon must be 1º or 2º (have two Hs)
•alkaline conditions (hydroxide)
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 12: February 28
“Aldol”%Condensa.on%for%Ketones
25
•the equilibrium for acyclic ketones lies far to the left
•ketones are more stable and less electrophilic
O
CH32
HO H
CH3
O
ketone β-hydroxyaldehyde
98%
2%
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 12: February 28
Intramolecular%“Aldol”%of%Diketones%Possible
26
O
OH
O
O
Na2CO3, H2O
heat
OH H H
97%
• Intramolecular aldols (even for diketones) particularly favorable when five- or six-membered rings are formed.
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 12: February 28
Intramolecular%“Aldol”%of%Diketones%Possible
27
• Intramolecular aldols (even for diketones) particularly favorable when five- or six-membered rings are formed.
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 12: February 28
Intramolecular%“Aldol”%of%Diketones%Possible
28
• Many natural products are synthesized through biosynthetic intramolecular aldol condensation of polyketides
• Polyketide = compound with alternating ketone and methylene (CH2) groups
Lichens: fungus + photosynthetic partner O O O
S
OCoA12345678 S
OCoA
O
OO
17
35
2
S
OCoA
OO
17
35
2OH
O
OHHO
17
35
2tautomerization
& hydrolysis
Aldol
orsellinic acid
•orsellinic acid isolated from lichens•shown to block neuronal apoptosis•radical scavenging ability
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 12: February 28
Aldol%Mechansim
29
Board Work:1. Enolate formation.2. Nucleophilic Addition.3. Elimination of hydroxide (really?)
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 12: February 28
Mixed%Aldols
31
Problem:Four possible products are
possible with two enolizable aldehydes
Solution1. Only one reactant can form an enolate, or2. One reactant is more reactive toward
addition than the other3. Use LDA to completely deprotonate one
component (preventing self-condensation), then add the second.
H
O
H
O+
H
O
HO
H
O
HOH
OOH
H
OOH
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 12: February 28
Mixed%Aldols
32
• formaldehyde cannot form an enolate• formaldehyde is highly reactive; reacts faster with enolate than the enolate reacts with another aldehyde (self-condensation)
H H
O
H
O+
K2CO3
H2O, Et2O H
O
OHformaldehyde 3-methylbutanal 2-hydroxymethyl-3-
methylbutanal
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 12: February 28
Mixed%Aldols
33
• aromatic aldehydes cannot form enolates (no α-hydrogens)• enolate of acetone reacts much faster with aldehyde than with another ketone
• ketones are less electrophilic and more sterically hindered
H3CO
H
O
H3C CH3
O+
NaOH, H2O
30 ºCH3CO
CH3
O
p-methoxybenzaldehyde acetone 4-p-methoxyphenyl-3-buten-2-one
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 12: February 28
Mixed%Aldols
34
• using a strong bases, such as LDA, will completely deprotonate first component and prevent self-condensation
• enolate will react rapidly with second component (aldehyde)
CH3
O
(H3C)3CH H
LDA, THF
-78 ºCCH3
O
(H3C)3CH
H
O
1.
2. H2OCH3
O
(H3C)3C
HO
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 12: February 28
Claisen%Condensa.on
36
Aldol: Addition of Enolate to Aldehyde
Claisen: Addition of Enolate to an Ester
aldehydeenolate
β-hydroxycarbonyl
CH
OCO
CH
O
COH
H
CRO
OCO
CRO
O
CO
OR
+
+
enolate ester
β-ketoester
α
β
α
β
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 12: February 28
Claisen%Condensa.on
37
H3C O
O
CH3+
H3C O
O
CH3 O
O
CH3H3C
O
+ HO CH3
1. NaOCH2CH3
2. H3O+
ethyl acetate ethyl 3-oxobutanoate
ethanol
ethyl acetate
• self-condensation between two molecules of ester• typically use alkoxide base identical to alkyl group on ester to prevent transesterification
• overall: an acylation at the α-carbon
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 12: February 28
X
Claisen%Condensa.on
38
H3C O
O
CH3 O
O
CH3H3C
O1. NaOCH2CH3
2. H3O+
O
O
CH3 O
O
CH3
O1. NaOCH2CH3
2. H3O+H3C H3C
H3C HH H
O
O
CH3 O
O
CH3
O1. NaOCH2CH3
2. H3O+H3C H3C
H3C CH3H3C H
1º
2º
3º
• the α-carbon must be primary or secondary for Claisen• little to no product formed when α-carbon is tertiary• final product is deprotonated as it is formed
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 12: February 28
Claisen%Mechanism
39
Board Work:1. Enolate formation by alkoxide.2. Tetrahedral intermediate.3. Addition-Elimination gives β-ketoester4. Final product is deprotonated.
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 12: February 28
Intramolecular%Claisen:%Dieckmann%Cycliza.on
40
• esters of dicarboxylic acids undergo intramolecular Claisen (aka Dieckmann)
• Used mainly to form 5- and 6-membered rings
OCO
C O
O
H H
CCOO O
OHH
NaOCH2CH3
CCOO O
OHC
C O O
OH
O
CC O
OH
O
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 12: February 28
Intramolecular%Claisen:%Dieckmann%Cycliza.on
41
• esters of dicarboxylic acids undergo intramolecular Claisen (aka Dieckmann)
• Used mainly to form 5- and 6-membered rings
O
O
O O
O
O
Oα
βα
β
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 12: February 28
Mixed%Claisen
42
• mixed Claisen analogous to mixed aldol• best results obtained when one ester incapable of forming an enolate
O
OCH3
O
OCH3+
1. NaOCH3
2. H2O/H3O+
O
OCH3
O
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 12: February 28
Mixed%Claisen
43
• mixed Claisen analogous to mixed aldol• best results obtained when one ester incapable of forming an enolate
H O
O
O O
O
O
O
ethyl formate diethyl carbonate ethyl benzoate
Non-enolizable Esters
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 12: February 28
Biological%“Claisen”
44
acetoacetyl CoA
cholesterol
• thioesters are common intermediates in biological systems
• condensation of two acetyl-CoAs is a “Claisen-like” reaction
• leaving group is a thiolate instead of alkoxide
• acetoacetyl CoA is an intermediate in mevalonate pathway to cholesterol
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 12: February 28
Biological%“Claisen”
FaRy3Acid%Bioynthesis
45
reduction
stearic acid
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 12: February 28
Claisen3Like:%Acyla.on%of%Ketones%with%Esters
46
O
O O
O1. NaH
2. H3O++
O
O
O
O
O O
+1. NaOCH2CH3
2. H3O+
OO
cycloheptanone diethyl carbonate ethyl (2-oxocycloheptane)-carboxylate(a β-ketoester)
ethyl benzoate benzephenone 1,3-diphenyl-1,3-propandione(a 1,3-diketone)
• ketones can be acylated with esters and carbonates• similar to Claisen condensation• works best when ester is non-enolizable
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 12: February 28
Claisen3Like:%Acyla.on%of%Ketones%with%Esters
47
• ketones can be acylated with esters and carbonates• similar to Claisen condensation• works best when ester is non-enolizable
C C
OH3C
H H O
O CH31. NaOCH2CH3
2. H3O+ CC
OH
H3C
O
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 12: February 28
Synthesis
48
O
OCH3
O
O
+
H
O
OH
O
O
O
O
+OH
O
Amita & Aaron
Shiloh & Ho Miae & AJ
Andrew & Min
Albert & Chirag