CARBONYL CONDENSATION REACTIONS
CARBONYL CONDENSATION REACTIONS
Aldol Reaction Dehydration of Aldol Products Intramolecular Aldol Reaction Claisen Condensation Reaction Intramolecular Claisen Condensation • Michael Reaction • Stork Enamine Reaction • Robinson Annulation Reaction • • • • •
General Mechanism of Carbonyl Condensation
O C R C
One carbonyl partner with an alpha hydrogen atom is converted by base into its enolate ion.
H OH
OH2 R
This enolate ion acts as a nucleophilic donor and adds to the electrophilic carbonyl group of the acceptor partner
O C C:
N u c le o p h ilic Donor
: O: C
E le c tro p h ilic A c c e p to r
O C R C C
..
O
..
:
O H2
O C R C C OH
N e w C -C B o n d
+
-OH
Protonation of the tetrahedral alkoxide ion intermediate gives the neutral condensation product.
ALDOL REACTION
• occurs between two aldehyde or ketone molecules with a catalytic base • reaction can occur between two components that have alpha hydrogens • reversible condensation reaction • two highlights: enolate formation and nucleophilic attack at a carbonyl carbon • Aldol products are: alpha-ß-unsaturated aldehydes/ketones and ß-hydroxy aldehydes/ketones
Mechanism of the Aldol Reaction
H O:
B a s e re m o ve s a n a c id ic a lp ha hyd ro g e n fro m o ne a ld e hyd e m o le c ule , yie ld ing a re s o na nc e s ta b ilize d e no la te io n.
O H C H H C H
O
: O: C C H3
.. :O:CH3 H C
H
.. C
+ H2 O
C
H
H
H
The enolate ion attacks a second aldehyde molecule in a nucleophilic addition reaction to give a tetrahedral alkoxide ion intermediate.
O C C H H
HH
H2 O
:OH C C H3 H H C H
O C H + - OH
Protonation of the alkoxide ion intermediate yields neutral aldol product and regenerates the base catalyst.
Dehydration of Aldol Products: Synthesis of Enones
• ß-hydroxy aldehydes and ß-hydroxy ketones formed in aldol reactions can be easily dehydrated to yield conjugated enones • Dehydration is catalyzed by both acid and base • Reaction conditions for dehydration are only slightly more severe than for condensation • Conjugated enones are more stable than nonconjugated enones
Dehydration of Aldol Products
B a s e -c a ta lyz e d
.. :O:
OH
-
O C C
OH C H
OH C C
C
E n o la te io n
O C C C
+
O H-
A cid -ca ta lyze d
H O
+
O C C
OH C H
O C C C
H
OH +
2
C C
Enol
C
+
H3 O
+
Mixed Aldol Reaction
• If two similar aldehydes/ketones react under aldol conditions, 4 products may be formed • A single product can be formed from two different components :
If one carbonyl component has no alphahydrogens or if one carbonyl compound is much more acidic than the other.
Intramolecular Aldol Reaction:
• Treatment of certain dicarbonyl compounds with base can lead to cyclic products • A mixture of cyclic products may result , but the more strain-free ring is usually formed
Intramolecular Aldol Reaction of 2, 5hexanedione yields 3-methyl-2cyclopentenone
O C C H3 H a b C CH3 H C C H H O
2,5- H exanedione
Path A
-O H
O H H
H
O H H
H
C C C
H C- H C H CH3 O
C C C
H C H C H CH3 OH
N aO H , H 2O
.. :OH.. O H C C H H C C C C H3 H H OH H
O
+ H2 O
CH 3
3 -M e th yl-2 -cyclo p e n te n o n e
P a th b
N aO H , H 2O
O H H H C C C H
-OH
C H3 C CH3 O
..
..
O H H
O H C C
H H C H
H H
H
O C C
H H C H C CH3 O
- C CH3 C H H O
C
OH H3 C
.. :OH..
H 3C
O
O
H C H3
+
H3 C H
2
O
(2-Methylcyclopropenyl)ethanone (NOT formed)
Claisen Condensation Reaction
• Carbonyl condesation that occurs between two ester components and gives a ß-keto ester product • Reaction is reversible and has a mechanism similar to aldol reaction • Major difference from aldol condensation is the expulsion of an alkoxide ion from the tetrahedral intermediate of the initial Claisen adduct • 1 equivalent of base is needed to drive the reaction to completion because the product is often acidic
Mechanism of Claisen Condensation:
• involves nucleophilic acyl substitution of an ester enolate ion on the carbonyl group of a second ester molecule • tetrahedral intermediate expels an alkoxide leaving group to yield an acyl substitution product
Mechanism of the Claisen Condensation Reaction
O
Ethoxide base abstracts an acidic alpha hydrogen atom from an ester molecule, yielding an ester enolate ion
C H3C O Et
- O Et
O :C H 2 C O E t
N u cle o p h ilic d o n o r
+
EtO H
In a n u c le o p h ilic a d d itio n , th is io n a d d s to a s e c o n d e s te r m o le c u le , g iv in g a te tra h e d ra l in te rm e d ia te .
:O: C H 3 C O Et
E le ctro p h ilic a cce p to r
.. :O: C H3C O Et
O C H2C O Et
T h e te tra h e d ra l in te rm e d ia te is n o t sta b le . It e xp e ls e th o xid e io n to yie ld th e n e w ca rb o n yl co m p o u n d , e th yl a ce to a ce ta te .
B u t e th o x id e io n is b a s ic e n o u g h to c o n v e r t th e b e ta - k e to e s te r p r o d u c t in to its e n o la te , th u s s h if itn g th e e q u ilib r iu m a n d d r iv in g th e r e a c tio n to c o m p le tio n .
O
O
C H3CC H2C O Et + EtO-
O_
O + EtO H
C H3CC H C O Et ..
H3O+
P rotonation by addition of acid in a separate step yields the final product.
O
O
C H 3 C C H 2 C O Et + O H 2
Mixed Claisen Condesation
•occurs only when one of the two ester components has no alpha-hydrogens, and thus can’t form enolate ion •can also be carried out between esters and ketones resulting a synthesis of ß-diketones
Example of Mixed Claisen Condensation
O C OEt
+
O
1 . N a H /T H F
C H 3 CO E t
E th yl B e n zo a te
(A c c e p to r)
2. H30
+
E th yl A ce ta te
(D o n o r)
E th yl b e n zo yla ce ta te
O
O
C C H CO E t 2
E tO H
Intramolecular Claisen Condensation: Dieckmann Cyclization
• can be carried out with diesters • works best on 1, 6-diesters and 1,7-diesters • 5-membered cyclic ß-ketoesters result from Dieckmann cyclization of 1,6-diesters • 6-membered cyclic ß-keto esters result from cyclization of 1,7-diesters
Examples of Intramolecular Claisen Condensation
O OEt O
D iethyl hexanedioate (a 1,6 -D iester) 1. N a+ -O E t, ethanol 2. H 3O +
O
O C OEt E tO H
OEt
E thyl 2-oxocyclopentanecarboxylate (82% )
O OEt O OEt
D ie th yl h e p ta n e d io te (a 1 ,7 - D ie s te r) 1 . N a + -O E t, e th a n o l 2. H 3O +
O
O C + OEt
E th yl-2 -o xo c yc lo h e xa n e c a rb o xyla te
Intramolecular Claisen Condensation Mechanism
O OEt
Base abstracts an acidic alpha-proton from the carbon atom next to one of the ester groups, yielding an enolote ion.
H H COOEt
Na+
- OEt
. . :
O H
-
+
E tO H
tE O
COOEt
Intramolecular nucleophilic addition of the ester enolate ion to the carbonyl group of the second ester group at the other end of the chain then gives a cyclic tetrahedral intermediate.
tE O
:
H COOEt
O:
..
Loss of alkoxide ion from the tetrahedral intermediate forms a cyclic beta-keto ester.
. .
+
tE O
. .
:
-
Deprotonation of the acidic beta-keto ester gives an enolate ion…
O
H COOEt
.
-
COOEt O
+
E tO H
H 3O +
…which is protonated by addition of aqueous acid at the endoth the reaction to generate the neutral beta-keto ester product.
+
H O 2
H COOEt O
Michael Reaction
• Conjugate addition of a carbon nucleophile to an
alpha, ß-unsaturated acceptor Best Michael Reactions:
• Between unusually acidic donors (ß-ketoesters or ßdiketones) • Unhindered alpha,ß-unsaturated acceptors
• Stable enolates are Michael donors, and alpha,ßunsaturated compounds are Michael acceptors
The Michael Reaction
O C
The base catalyst removes an acidic alpha proton from the starting beta-keto ester to generate a stabilized enolate ion nucleophile.
O C C CH3 H
+
EtO H
Na
- O Et
O
O
+
C C The nucleophile adds to the alpha,beta-keto Et O .. C C H 3 unsaturated ketone H O H electrophile in a Michael reaction to C C generate a new enolate H H3C C as product. H HO O
Et O H
C H3C
..
C C
C CH3 H C O 2Et
C H
The enolate product abstracts an acidic proton, either from solvent or from starting keto ester, to yield the final addition product.
EtO H
O C
H H O C C C H C C H 3 + EtO-
H3C H
H C O2Et
Some Michael Acceptors and Michael Donors
Michael Acceptors
H2C H2C H2C H2C C H C H O P ro p e n o l C HC O 2 Et E th yl P ro p a n o a te C HC N P ro p e n e n itrile C HC O C H 3 3 -B u te n -2 -o n e N itro e th yle n e
Michael Donors
B e ta -D ik e to n e R C O CH 2 C O R' R C O CH 2 C O 2 Et B e ta -K e to E s te r Et O 2 C CH 2 C O 2 Et M a lo n ic E s te r R C O CH 2 C N R CH 2 N O 2 B e ta -K e to n itrile N itro c o m p o u n d
H 2 C C HN O 2
H 2 C C H C O N H 2 P ro p e n a m id e
Stork Enamine Reaction
• enamine adds to an alpha,ß-unsaturated carbonyl
acceptor in a Michael- type process • Overall reaction is a three-step sequence: Step 1: Enamine formation from a ketone Step 2: Michael-type addition to an alpha, ßunsaturated carbonyl compound Step 3: Enamine Hydrolysis back to ketone • net effect of Stork Enamine reaction sequence is the Michael addition of a ketone to an alpha,ßunsaturated carbonyl compound
Example of Stork Enamine Reaction
O
N
O N .. H2C C H C C H3
H
-H 2 O C yclohexanone
A n enam ine
O
- O N+ .. C H2C H C C H3
O N C H2C H2C C H3
O H2
O C H2C H2C C H3 + N H A 1,5-diketone
Robinson Annulation Reaction: Carbonyl Condensation Reaction in Synthesis • leads to the formation of substituted cyclohexenones
• 2 step process: Michael reaction Intramolecular Aldol reaction • Treatment of a ß-diketone or ß-keto ester with an alpha, ßunsaturated ketone leads first to a Michael addition, which is followed by intramolecular aldol cyclization