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Created byProfessor William Tam & Dr. Phillis
Chang Ch. 19 - 1
Chapter 19Chapter 19
Condensation and Condensation and Conjugate Addition Conjugate Addition
Reactions of Carbonyl Reactions of Carbonyl CompoundsCompounds
More Chemistry of EnolatesMore Chemistry of Enolates
Ch. 19 - 2
1. Introduction Carbonyl condensation reactions.
● Claisen condensation:O
ORR'
O
ORR'
H
O
OR
O
R'
R'ROH +
+1. NaOR
2. H3O+
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An carbon anion(enolate) from oneester attacks the carbonyl of the other.
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:
An carbon anion(enolate) from oneattacks the carbonylof the other followedby dehydration.
Ch. 19 - 4
O
R
O
R
H
Nu
1. Nu
2. H3O+
Conjugate addition reaction: e.g. to an alkene conjugated to a carbonyl.
A nucleophile (could be an enolate) attacksthe carbon of the unsaturated carbonyl.Where Nu: is an enolate it is called a Michael addition.
Ch. 19 - 5
2. The Claisen Condensation: A Synthesis of -Keto Esters
O
R'OR
O
R'
H HOR
O
OR
O
H R'
R'
+
+ROH
1. NaOR
2. H3O+
An carbon anion(enolate) from oneester attacks the carbonyl of the other.
Ch. 19 - 6
Mechanism:●Step 1
O
R'OR
H H
OR+ ROH+
O
ORR'
H
O
ORR'
H
Base removes an hydrogenforming an enolate from oneester.
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 +
The enolate attacks the carbonyl of another esterwith loss of -OR.
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 -keto esters.
Ch. 19 - 12
Claisen condensation:● Esters that have only one
hydrogen do not undergo the usual Claisen condensation.
O
OMe
HThe carbon has only one hydrogen does not undergo the Claisen condensation using RO- (alkoxide). Use LDA, a stronger base, see slide 23. 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.
e.g.
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.2A. Intramolecular Claisen Condensations:Intramolecular Claisen Condensations:The Dieckmann CondensationThe Dieckmann Condensation
Intramolecular (cyclic) Claisen condensation:● Dieckmann condensation.● Useful for the synthesis of five-
and six-membered rings.MeO
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
Mechanism:
OMeMeO
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.2B. Crossed Claisen CondensationsCrossed Claisen Condensations Crossed Claisen condensations are
possible when one ester component has no hydrogens and, therefore, is unable to form an enolate ion and undergo self-condensation.
O
OMe
O
OMe
O
OMe
O1. NaOMe
2. H3O++
(no -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 hydrogen)
(2) O
MeO OMe
O
OMe+
1. NaOMe
2. H3O+
O
MeO OMe
O
(no carbon)
Ch. 19 - 23
Recall: esters that have only one hydrogen cannot undergo
Claisen Condensation by using sodium alkoxide.
However, they can be converted to the -keto esters by reactions that use very strong bases such as lithium diisopropyamide (LDA). LDA is strong enough to retain the anion.
Ch. 19 - 24
O
OMe
O
OMe
O
OMe
Cl
O
LDA
THF
O
Ch. 19 - 25
3. -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
1234567
1. 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. A five membered ring is more stable than a seven membered ring.
Ch. 19 - 27
● Questions:i. 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
The product contains both an aldehyde and an alcohol functional group.
Therefore: aldol addition
Ch. 19 - 29
4A.4A. Aldol Addition ReactionsAldol 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
Shown on slide 3.
Ch. 19 - 30
4B.4B. The Retro-Aldol ReactionThe Retro-Aldol Reaction
Mechanism for reverse aldol:
OOH OHO
H2O2
OO
HO
HOO O
O
+
HO HO
+HO
Ch. 19 - 31
4C.4C. Aldol Condensation Reactions: Aldol Condensation Reactions: Dehydration of the Aldol Addition Dehydration of the Aldol Addition ProductProduct
Dehydration of the aldol product.●Base catalyzed aldol
condensation:O
H
OH
HOH
O
H+ H2O + OH
Aldol product.
This dehydration is easier than normal because the double bond is conjugated with the carbonyl.
Ch. 19 - 32
4C.4C. Acid-Catalyzed AldolAcid-Catalyzed AldolCondensationsCondensations
O
2H3O
+ O
+ H2O
Ch. 19 - 33
Mechanism:
O
H O H
H
+O
H
H
OH2 OH
OH
OH
OHO OH2
HH2O:
O
+ H2O
+ H3O+
Followed by dehydration of the aldol product.
Ch. 19 - 34
4E.4E. Synthetic Applications of AldolSynthetic Applications of AldolReactionsReactions
Aldol additions and aldol condensations:● Important methods for carbon-
carbon bond formation.● Useful synthesis for:
-hydroxyl carbonyl compounds
-unsaturated carbon compounds
Ch. 19 - 35
RH
OAldehyde
OH O
HR
base
Aldol
R
RH
OHOHNaBH4
1,3-diol
R
O
HR
-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
+
+ +
Works best when onereactant does not havean hydrogen.
Ch. 19 - 37
5A.5A. Crossed Aldol Condensations Crossed Aldol Condensations Using Weak BasesUsing Weak Bases
O
H
O
+
O
HO
OOH
H
aldoladdition
dehydration
No hydrogen
Ch. 19 - 38
O
H H
O
H
O
HH
OH
H
Na2CO3 (aq)+
No hydrogen
Ch. 19 - 39
O O Li
5B.5B. Crossed Aldol Condensations UsingCrossed Aldol Condensations UsingStrong Bases: Lithium Enolates and Strong Bases: Lithium Enolates and Directed Aldol ReactionsDirected 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:
● Results in formation of both kinetic and thermodynamic enolates,
● Therefore, a 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
O
O
+
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 1
2
3
45
6
78
H2O
(-H2O)O
(not formed)
Ch. 19 - 46
O
H
O
HcHbHa
12345678
O
H
O
(Hb)
(path b)
12345
678
H2O
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 H
<
(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 -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.Stronger Nu: attacks the C=O.
Ch. 19 - 52
O
nucleophiles attack the carbonyl carbon or the carbon
O
O
Ch. 19 - 53
Conjugate addition of HCN:
O O
H
CNCN
EtOH, AcOH
NCOCN
H+
Weaker Nu: attacks to the C=O.
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
(Michael Addition Mechanism)
7A.7A. Conjugate Additions of Enolates: Conjugate Additions of Enolates: Michael AdditionsMichael Additions
O
H
O O
O
NaOMe (cat.)MeOH
2.
1.
MeO
O
O
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.7B. The Robinson AnnulationThe Robinson Annulation
O
O
O
OO
NaOH, MeOHO
O
O
(Michaelconjugateaddition)
(Aldol condensation)
Base(-H2O)
Ch. 19 - 58
Mechanism of the Robinson Annulation:O
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
+A 1o or 2o amine reacts with formaldehyde to form an imine (schiff base). The enol then reacts with the imine.
Mannich base
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:
The imine reacts with an enol producing a Mannich base.
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 reaction:O
R
O
H HNH
R''
R'
+ +
H+
O
R NR'
R''
H H
Ch. 19 - 67
END OF CHAPTER 19
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