Post on 19-May-2018
Chapter 19
Condensation and Conjugate Addition Reactions of Carbonyl
CompoundsMore Chemistry of Enolates
Ch. 19 - 1
Ch. 19 - 2
1. Introduction Carbonyl condensation reactions
● Claisen condensationO
ORR'
O
ORR'
H
O
OR
O
R'
R'ROH +
+1. NaOR
2. H3O+
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Ch. 19 - 3
O
HR'
O
HR'
H
OH
H R'
O
HR'
R'
R'
O
H
+Base
(addition)
"condensation"
+OH H
● Aldol addition and condensation
Ch. 19 - 4
O
R
O
R
H
Nu
1. Nu
2. H3O+
Conjugate addition reactions● e.g.
Ch. 19 - 5
2. The Claisen Condensation: A Synthesis of β-Keto Esters
O
R'OR
O
R'
H HOR
O
OR
O
H R'
R'
+
+ROH
1. NaOR
2. H3O+
Ch. 19 - 6
Mechanism● Step 1
O
R'OR
H H
OR+ ROH+
O
ORR'
H
O
ORR'
H
Ch. 19 - 7
O
ORR'
O
OR
R'H
+
Mechanism● Step 2
O
OR
O
H R'
R'
RO
O
OR
O
H R'
R'RO +
Ch. 19 - 8
O
OR
O
H R'
R'
OR(pKa ~ 9)
Mechanism● Step 3
O
OR
O
R'
R'+
ROH
(pKa ~ 16)
Ch. 19 - 9
O
OR
O
R'
R'
O
OR
O
R'
R'
O
OR
O
R'
R'
Ch. 19 - 10
Mechanism● Step 4
O
OR
O
R'
R'
H O
H
H
+
(rapid)
O
OR
O
R'
R'H
(keto form)
OH
OR
O
R'
R'(enol form)
Ch. 19 - 11
Claisen condensation
● An Acyl Substitution(nucleophilic addition-elimination reaction)
● Useful for the synthesis of β-keto esters
Ch. 19 - 12
Claisen condensation● Esters that have only one α hydrogen
do not undergo the usual Claisen condensation
e.g. O
OMe
H The α carbon has onlyone α hydrogen
⇒ does not undergo Claisen condensation
⇒This is because an ester with only one hydrogen will not have an acidic hydrogen when step 3 is reached, and step 3 promotes the favorable equilibrium that ensures the forward reaction
Ch. 19 - 13
Examples of Claisen condensation
O
OMe(1) 2
NaOMeO
OMe
O
+ MeOH
H3O+O
OMe
O
H
Ch. 19 - 14
Examples of Claisen condensation
O
OEt(2) 2
NaOEtO
OEt
O
+ EtOH
O
OEt
O
H
H3O+
Ch. 19 - 15
2A. Intramolecular Claisen Condensations:The Diekmann Condensation
Intramolecular Claisen condensation● Diekmann condensation● Useful for the synthesis of five- and
six-membered ringsMeO
O O
OMe
O
OMe
O
1. NaOMe
2. H3O+
12
3
4
5
67
12
3
4
5
6 7
Ch. 19 - 16
O
OMe
O
MechanismOMeMeO
O O
OMe123
4
5
67
H OMe
O
12
34
5
6
7
OMe
OO
OMe
O
OMe2
3
4
5
6 7 1
O
OMe
OH
OMe
O
OMe
O
O HH
H(This favorableequilibrium drives the reaction)
Ch. 19 - 17
Other examples
EtO
O
OEt123456
O
1. NaOEt
2. H3O+ OEt
OO
(1)
12
34
56
Ch. 19 - 18
Other examples
(2)MeO
O
OMe
O Me
1. NaOMe
2. H3O+
OMe
OO
MeOMe
OO
Me
not
Why?
Ch. 19 - 19
2B. Crossed Claisen Condensations Crossed Claisen condensations are
possible when one ester component has no α hydrogensand, therefore, is unable to form an enolate ion and undergo self-condensation
O
OMe
O
OMe
O
OMe
O1. NaOMe
2. H3O++
(no α-hydrogen)
Ch. 19 - 20
Mechanism
O
OMe
H
OMe+
O
OMe+ MeOH
O
OMe
O
OMe
O
OMe
O
OMe
O
H
Ch. 19 - 21
Mechanism
O
OMe
O
H
(This favorable equilibriumdrives the reaction)
OMe
O
OMe
O
H O H
H
O
OMe
O
Ch. 19 - 22
Other examples
O
OEtO
OEt
O
OEt
O
1. NaOEt
2. H3O+
+
(1)
(no α hydrogen)
(2) O
MeO OMe
O
OMe+
1. NaOMe
2. H3O+
O
MeO OMe
O
(no α carbon)
Ch. 19 - 23
Recall: esters that have only one αhydrogen cannot undergo Claisen Condensation by using sodium alkoxide
However, they can be converted to the β-keto esters by reactions that use very strong bases such as lithium diisopropyamide (LDA)
Ch. 19 - 24
O
OMe
O
OMe
O
OMe
Cl
O
LDA
THF
O
Ch. 19 - 25
3. β-Dicarbonyl Compounds by Acylation of Ketone Enolates
O
HH
O O
OO
NaNH2
Et2OO
Ph OMe
(kineticenolate)
slightly more acidic
Ch. 19 - 26
Intramolecular example
Ha
O
Hb O
OMe
Hc
12345671. NaOMe
2. H3O+
O O
12
3 4
56
7
● The product was formed by deprotonation of Hb, the enolate formed at C5 and then adding to C1
Ch. 19 - 27
● Questionsi. Give the structure of the
product by deprotonation of Ha, and adding the resulting enolate (at C7) to C1. Explain why this product is not formed.
ii. Give the structure of the product by deprotonation of Hc, and adding the resulting enolate (at C2) to C6. Explain why this product is not formed.
Ch. 19 - 28
4. Aldol Reactions: Addition of Enolates and Enols to Aldehydes and Ketones
O
H
OH
H
O10% NaOH
H2O, 5 oC2
⇒ contains both an aldehyde and an alcohol functional group
⇒ aldol addition
Ch. 19 - 29
4A. Aldol Addition Reactions Mechanism of the aldol addition
O
H
O
HH
HO
O
H
O
H+ H2O
O
H
OHO H
O
H
OH
+ HO
Ch. 19 - 30
4B. The Retro-Aldol Reaction
Mechanism
OOH OHO
H2O2
OO
HO
HOO O
O
+
HO HO+HO
Ch. 19 - 31
4C. Aldol Condensation Reactions: Dehydration of the Aldol Addition Product
Dehydration of the aldol addition product● Aldol condensation
O
H
OH
HOH
O
H+ H2O + OH
Ch. 19 - 32
4C. Acid-Catalyzed AldolCondensations
O
2H3O
+ O+ H2O
Ch. 19 - 33
MechanismO
H O H
H
+O
H
H
OH2 OH
OH
OH
OHO OH2
HH2O:
O
+ H2O
+ H3O+
Ch. 19 - 34
4E. Synthetic Applications of AldolReactions
Aldol additions and aldol condensations● Important methods for carbon-
carbon bond formation● Useful synthesis for
β-hydroxyl carbonyl compounds α,β-unsaturated carbon
compounds
Ch. 19 - 35
RH
OAldehyde
OH O
HR
base
Aldol
R
RH
OHOHNaBH4
1,3-diol
R
O
HR
α,β-unsaturatedaldehyde
HA, -H2O
R
OH
R
R
Allylicalcohol
LiAlH4
OH
R
R
Saturatedalcohol
H2/Nihigh
pressure
O
HR
Aldehyde
H2, Pd-C
R
Ch. 19 - 36
5. Crossed Aldol Condensations
O
H H
O
H H
O OH
OH
H
O
OH OOOH
+ HOH2O
+
+ +
Ch. 19 - 37
5A. Crossed Aldol Condensations Using Weak Bases
O
H
O
+
O
HO
OOH
H
aldoladdition
dehydration
Ch. 19 - 38
O
H H
O
H
O
HH
OH
H
Na2CO3 (aq)+
Ch. 19 - 39
O O Li
5B. Crossed Aldol Condensations UsingStrong Bases: Lithium Enolates and Directed Aldol Reactions
Directed Aldol Synthesis using a strong base, iPr2NLi (LDA)
O
H
OLDA, THF
-78 oC
O
H
O OHH2O
Ch. 19 - 40
The use of a weaker base under protic conditions● Formation of both kinetic and
thermodynamic enolates● Results in mixture of crossed aldol
products
Ch. 19 - 41
O O O
O
HO OH O
OH
1.2. H2O
(Thermodynamicenolate)
(Kineticenolate)
HO
proticsolvent
+
Ch. 19 - 42
Suggest a synthesis of the following compound using a directed aldol synthesis O OH
O OH
● Retrosynthetic analysis
disconnection
OO
+
Ch. 19 - 43
Synthesis
O O
LDA
O Li
O
H1.
2. H2O
O OH
Ch. 19 - 44
6. Cyclizations via AldolCondensations
Intramolecular Aldol condensation● Useful for the synthesis of five- and
six-membered rings● Using a dialdehyde, a keto
aldehyde, or a diketone e.g. O
H
OHO
O
Ch. 19 - 45
O
H
O
HcHbHa
12345678
O
H
O
(Ha)
(path a)
123456
78
OH
O 12
3
45
6
78
H2O
(-H2O) O
(not formed)
Ch. 19 - 46
O
H
O
HcHbHa
12345678
O
H
O
(Hb)
(path b)
123456
78H2O
1
2
34
5
6
78
O
OH
(-H2O)
O
Ch. 19 - 47
O
H
O
(Hc)
(path c)
12
34567
8
O
H
O
HcHbHa
12345678
H2O
12
34
5
67
8
H
OHO
(-H2O)
(not formed)
H
O
Ch. 19 - 48
● Although three different enolates are formed, cyclization usually occurs with an enolate of the ketone adding to the aldehyde
O
R R
O
R Hδ+δ+
δ−δ−
<
(Ketones are less reactive
toward nucleophiles)
(Aldehydes aremore reactive
toward nucleophiles)
⇒ Path c is least favorable
Ch. 19 - 49
● Path b is more favorable than path a because six-membered rings are thermodynamically more favorable to form than eight-membered rings
● Likewise, five-membered rings form far more readily than seven-membered rings
Ch. 19 - 50
7. Additions to α,β-Unsaturated Aldehydes and Ketones
O
+
Nu
O OHH2O
Nu
simple addition(1,2-addition)
Nu
OH2O
conjugate addition(1,4-addition)
O
HNu
Nu
Ch. 19 - 51
OH O
PhMgBrEt2O
2. H3O+
H
Ph
Ph+
(82%)(simple addition)
(18%)(conjugate addition)
O
1.
Ch. 19 - 52
O
α
β
nucleophiles attack the carbonyl carbon or the β carbon
Oβ
α
O
α
β
Ch. 19 - 53
Conjugate addition of HCN
O O
H
CNCN
EtOH, AcOH
NCOCN
H+
Ch. 19 - 54
O O
H
EtNHEtNH2
H2O(keto form)
Conjugate addition of an amine
EtNH2
ONEt H
H
OHEtNH(enol form)
Ch. 19 - 55
O O
(Micheal Addition)
7A. Conjugate Additions of Enolates: Michael Additions
O
H
O O
O
NaOMe (cat.)MeOH
2.
1.
MeO
OO
H OMe
Ch. 19 - 56
Other examples of Michael additions
MeOOC
MeOOC
OEt
O
O
OEtMeOOC
COOMe
1. NaOMe, MeOH
2.
(1)
(2)O
OMe COOMe
O
OMe
O
COOMe
O1. NaOMe, MeOH
2.
Ch. 19 - 57
7B. The Robinson Annulation
O
O
O
OO
NaOH, MeOHO
O
O
(Michaelconjugateaddition)
(Aldol condensation)
Base(-H2O)
Ch. 19 - 58
Mechanism of the Robinson AnnulationO
H
O
O
O
O
O
OOH
O
(Micheal addition)
MeO H
O
O
O
H
HO
O
O
O
Ch. 19 - 59
MeO H
O
O
O (intramolecularAldol
condensation)O
O
O
OHH
O
O
O
O
(dehydration)
HO
Mechanism of the Robinson Annulation
Ch. 19 - 60
8. The Mannich Reaction
O O
H H
O
NEt2
Et2NH
H2O
+ +
HCl
+
Ch. 19 - 61
O
H HEt2NH
OH
NH H
Et Et
OH
NH H
Et Et
HHCl
(-HOH)
NEt Et
H HO
NEt2
H HO OH
HCl
+
Mechanism of the Mannich Reaction
Ch. 19 - 62
Other examples of the Mannich Reaction
(1)
O O
NEt2
O
H HEt2NH
HCl+ +
(2)O O
H HNH
O
N+ +
HCl
Ch. 19 - 63
O
ROEt
R
O
O
OEtR
[*]O
OEtR
9. Summary of Important Reactions
1. NaOEt,
2. H3O+
[*] =
Claisen Condensations
O
Ph OEt
R
O
O
Ph OEt
[*]
ROEt
O
OEtO
O
EtO OEt[*]
ROEt
O
O H
O
H OEt
[*]
O
EtOOEt
O
ROEt
O
OO
OEt
[*]
Ch. 19 - 64
Aldol Condensations
O
HR
O
HR
NaOH, H2O
O
HR
OH
R
O
HR
R
(-H2O)
O
R' R'
1. LDA, THF, -78oC
2.
3. NH4Cl
O
HR
R' OHR'
Ch. 19 - 65
Simple & Conjugate (Michael) additions
O
R
OH
R'
1. R'MgBr, Et2O
2. H3O+
R(simple addition:major product)
NaCNEtOH, AcOH
O
R
CN
H
O
R
NH
H
R' R'NH2
O
R
MeOH, NaOMe
O
O
Ch. 19 - 66
Mannich reactionO
R
O
H HNH
R''
R'+ +
H+
O
R NR'
R''
H H
Ch. 19 - 67
END OF CHAPTER 19