Organic Chemistry

1. Chapter 23: Ester EnolatesChapter 23: Ester Enolates
and theand the
Claisen CondensationClaisen CondensationRecall theRecall the
aldolaldol
addition:addition:
Can we doCan we do
this withthis with
esterester
enolates?enolates?

2. The Claisen CondensationThe Claisen Condensation
 Driven byDriven by deprotonationdeprotonation of 3-oxoalkanoate (“of 3-oxoalkanoate (“ββ–ketoester”).–ketoester”).
Step 1:Step 1: Ester Enolate FormationEster Enolate Formation
Endothermic as writtenEndothermic as written
Mechanism: Addition-EliminationMechanism: Addition-Elimination
Has to be the same or transesterification will occur
AcidicAcidic

3. Step 2:Step 2: Nucleophilic AdditionNucleophilic Addition
Step 3:Step 3: EliminationElimination

4. Step 4:Step 4: Deprotonation of 3-OxoesterDeprotonation of 3-Oxoester
Step 5:Step 5: Protonation on Aqueous Work-upProtonation on Aqueous Work-up
ClaisenClaisen
This step drives the reaction to the product as the anion.This step drives the reaction to the product as the anion.

5. Products of Claisen condensation areProducts of Claisen condensation are alkyl 3-alkyl 3-
oxoalkanoatesoxoalkanoates (IUPAC), common name(IUPAC), common name ββ-keto--keto-
esters and, generally,esters and, generally, ββ-dicarbonyl-dicarbonyl compoundscompounds
The hydrogens between the two carbonyls areThe hydrogens between the two carbonyls are
unusuallyunusually acidicacidic: Due to inductive effect of: Due to inductive effect of
two carbonyls and resonance in the anion.two carbonyls and resonance in the anion.

6. Low pLow pKKaas mean that alkoxide or hydroxide can make the enolatess mean that alkoxide or hydroxide can make the enolates stoichiometricallystoichiometrically!!

7. 1,3-Dicarbonyl Compounds Form1,3-Dicarbonyl Compounds Form
EnolsEnols ReadilyReadily
O O
H
O O
H
65%35%
100°C
H Bonding in enol is symmetrical:H Bonding in enol is symmetrical:
oror ??
J. Am. Chem. Soc.
2006, 128, 854.

8. Acidity of Claisen product is essential to driveAcidity of Claisen product is essential to drive
the reaction. Without the acidic H, reactionthe reaction. Without the acidic H, reaction
goes in the reverse!goes in the reverse!
No goNo go, starting on the left., starting on the left. Goes from right to leftGoes from right to left, when starting with the, when starting with the
product (made by a different route, as will be seen later).product (made by a different route, as will be seen later).
MechanismMechanism of reverse Claisen condensation:of reverse Claisen condensation:

9. But:But: If one partner hasIf one partner has nono αα--hydrogenshydrogens (not(not
enolizable):enolizable):
Crossed Claisen CondensationCrossed Claisen Condensation
GivesGives mixturesmixtures of products (as in the caseof products (as in the case
of the crossed aldol addition).of the crossed aldol addition).
H O O
O O
+
1. Na+ -OCH2CH3,
CH3CH2OH
2. H+, H2O
H O
O O
80%
Ethyl 3-oxopropanoate

10. Mixed Ketone Claisen CondensationMixed Ketone Claisen Condensation
KetonesKetones areare more acidicmore acidic than esters, functionthan esters, function
asas enolateenolate partners. Their competitive aldolpartners. Their competitive aldol
additions are reversible, but Claisen is not.additions are reversible, but Claisen is not.
pKa = 19pKa = 25
This is general forThis is general for
R
O O

11. Intramolecular Claisen CondensationIntramolecular Claisen Condensation
((Dieckmann CondensationDieckmann Condensation))
Ethyl 2-oxocyclohexanecarboxylate
Mixed Claisen-Dieckmann CondensationMixed Claisen-Dieckmann Condensation
O
O
80%
O
O
O O
O O
1. Na+ -OCH2CH3,
CH3CH2OH
2. H+, H2O
O O
OO
O O

12. Use ofUse of ββ--Dicarbonyl CompoundsDicarbonyl Compounds
O O
acidicacidic
Derived enolates are relatively non-basic,Derived enolates are relatively non-basic,
but good nucleophiles:but good nucleophiles:
O O O O
1. Base
2. RX
RH
Particularly useful forParticularly useful for oxoestersoxoesters derived fromderived from
Claisen condensations, because hydrolysis leadsClaisen condensations, because hydrolysis leads
toto oxoacidsoxoacids whichwhich decarboxylatedecarboxylate..

13. Examples:Examples:
Note: Rsec!

14. Same TS as the McLafferty rearrangementSame TS as the McLafferty rearrangement
Enol Keto

15. Examples:Examples:

16. Alkylation of ethyl 3-oxobutanoate (ethyl
acetoacetate), followed by ester
hydrolysis, and finally decarboxylation
gives 3-substituted or 3,3-disubstituted
methyl ketones. This is called the
acetoacetic ester synthesis.
Advantage over direct ketone enolate alkylation:Advantage over direct ketone enolate alkylation:
MuchMuch less basic enolateless basic enolate; obviates E2 for R; obviates E2 for Rsecsec..

17. Examples:Examples:

18. Starting from diethyl propanedioate (malonic
ester) the same sequence (alkylation,
hydrolysis, decarboxylation) gives 2-alkylated
and 2,2-dialkylated acetic acids, a method
called the malonic ester synthesis.

19. Michael AdditionMichael Addition
Reaction of 3-oxo ester enolates withReaction of 3-oxo ester enolates with αα,,ββ––
unsaturated carbonyls (1,4-addition)unsaturated carbonyls (1,4-addition)
1,4-Addition is the thermodynamic process,1,4-Addition is the thermodynamic process,
1,2-addition does occur, but is reversible.1,2-addition does occur, but is reversible.

20. Robinson AnnulationRobinson Annulation
70%70%
Recall:Recall: Robinson annulationRobinson annulation is a sequence ofis a sequence of MichaelMichael
additionaddition, followed by, followed by intramolecular aldol condensationintramolecular aldol condensation
Goes via:Goes via:
Michael adductMichael adduct

21. αα-Hydroxycarbonyls-Hydroxycarbonyls
Important function in nature and in drugs. HowImportant function in nature and in drugs. How
do we make it? Ideal retrosynthesis is:do we make it? Ideal retrosynthesis is:
Alkanoyl anionAlkanoyl anion
Problem: We cannot make alkanoyl anions from aldehydes,Problem: We cannot make alkanoyl anions from aldehydes,
because bases will either deprotonate alpha to makebecause bases will either deprotonate alpha to make
enolate or add to carbonyl function as nucleophiles.enolate or add to carbonyl function as nucleophiles.
Therefore, we need to useTherefore, we need to use masked alkanoyl anions.masked alkanoyl anions.
R
OHO
R
O O
:

22. 1.1. StoichiometricStoichiometric reagents:reagents: 1,3-Dithia-1,3-Dithia-
cyclohexanecyclohexane (1,3-dithiane) anions(1,3-dithiane) anions
Dithiane is acidic because of theDithiane is acidic because of the polarizabilitypolarizability
of sulfur, stabilizes adjacent charge.of sulfur, stabilizes adjacent charge.

23. • Synthetic ApplicationsSynthetic Applications
Reverse polarizationReverse polarization Deprotection
1,2-Addition

24. Other alkylating agents: AnotherOther alkylating agents: Another
aldehyde/ketone synthesisaldehyde/ketone synthesis
HR
O HS SH, ZnCl2
S S
R
1.
2.
Li
1. R'X
2. HgCl2
R'R
O
1.
2. HgCl2
O
R
O
OH
:

25. 2.2. CatalyticCatalytic version: Alkanal couplingversion: Alkanal coupling
usingusing thiazolium ion catalystthiazolium ion catalyst
Crucial for catalysis is:Crucial for catalysis is:
Six electrons:
Carbene

26. MechanismMechanism of aldehyde coupling:of aldehyde coupling:

27. Drawback of the catalytic version: OnlyDrawback of the catalytic version: Only symmetricalsymmetrical coupling.coupling.
In nature: Thiamine (vitamin B1)In nature: Thiamine (vitamin B1)
A = H, ThiamineA = H, Thiamine
A = , thiamine pyrophosphateA = , thiamine pyrophosphate