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.
O 2 H
O C R
Nc o h u le p ilic Dn r oo
This enolate ion acts as a nucleophilic donor and adds to the electrophilic carbonyl group of the acceptor partner
: : O : C C
E c p ilic le tro h Ac p r c e to
O C R C C
O C C C O + H H O R
Nw - B n e CC o d
Protonation of the tetrahedral alkoxide ion intermediate gives the neutral condensation product.
• 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
Base removes an acidic alpha hydrogen from one aldehyde molecule, yielding a resonancestabilized enolate ion.
O H C H H C H
: O: C CH 3
The enolate ion attacks a second aldehyde molecule in a nucleophilic addition reaction to give a tetrahedral alkoxide ion intermediate.
O C 3 C C C H H H H H H
.. : :O
:H O O CCC + H O H C3 H H HH
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
O C C
.. :O :
OH C C
O C C C
O C C
O C C
C C C
H + O 3
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 CC 3 H H b a C C3 H H CC HH O
2 -H aei n , e nd e 5 x o
H C C- H H C CH3 C C H H H O
O H C C H H C CH3 C C H H H OH
.. :OH.. O H H C H H C C
O HO + 2
C C C H3 H H OH
CH 3 3-Methyl-2-cyclopentenone
NaO H2O H,
O C CH3 H C CH3 H C C H H O
H H C CH H C - C CH3 H C H O
O H H C C H H C CH3 H C C H O
H O H3 C
.. :..HO H C 3 H
H3 C + H2 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
Ethoxide base abstracts an acidic alpha hydrogen atom from an ester molecule, yielding an ester enolate ion
CH 3 C O Et
- O Et
O : HC E C 2 O t
Nc o h d n r u le p ilic o o
EO t H
In a n c o h u le p ilic a d n d itio , th io a d to a s c n is n d s eo d e te m le u , g in a s r o c le iv g te h d l in rm d te tra e ra te e ia .
: : O C 3 O t HC E
E c p ilic le tro h ac p r c e to
.. :O: OEt
T ete a e r l in r e ia h tr h da temd te isn t s b . It e p lse o id o ta le x e th x e io toy ldth n w ab n l n ie e e cr oy c mo n , e y a e a e te o p u d th l c to c ta .
Bt e oi e o i b s e o g u t x h d i ns ai c nuh t c ne t e e - e et r o ov r h bt k t t a o s e p d c i t i s n l t ,t u r ut n t e o e h s o o a s i i n t e q i i ru a d rv g h t gh eu b m n d i f l i i n t e e c o t c m eo . h r at n o o p t n i l i
O O O C 3 C 2 O t +t H H C CE E
O O _ O t C CO + H H HE E C 3 .C t .
Poo aio b a d io o a id r t n t n y d it n f c inas p r t se y ld t ef a e aae t p ie s h in l po u t r d c.
OO C CO O H H E+2 C2 t H C 3
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 CO Et
C H3 COEt
2. H30 +
E y b n o la eae t l ezy ct t h
C 2 Ot C HC E
EH t O
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
. + te n N O ho , O E 1 a- E ta l t . O H O2 3+ D y en i a i t lha d t e h xe e o ( 1 - i sr a, Dt ) 6 e e
O O C O E t E t O H
O E t
E l2x yo nn aol t t y - ocp t e r x e h oc l ea cby a (2) 8 %
O O E t O
1 a- E t a l . + te n N O ho , 2 3+ . O H
O C O E t +
O E t
Dh h t n i t i t y ea d e e l p eo ( 1- i sr a, D t ) 7 ee E l2x yo x eao l t t y - o ch a c b y e h o c l e n r xa -
Intramolecular Claisen Condensation Mechanism
Base abstracts an acidic alpha-proton from the carbon atom next to one of the ester groups, yielding an enolote ion.
Na+ - OEt
C Ot OE
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.
t O E
: : O .
H C Ot OE
Loss of alkoxide ion from the tetrahedral intermediate forms a cyclic beta-keto ester.
Deprotonation of the acidic beta-keto ester gives an enolate ion…
tE O .
E tO H
…which is protonated by addition of aqueous acid at the endoth the reaction to generate the neutral beta-keto ester product.
H COOEt O
• 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
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
Na - OEt
The nucleophile adds to the alpha,beta-keto unsaturated ketone electrophile in a Michael reaction to generate a new enolate as product.
O C EtO O C H3C C
O C CH3
H C H
C .. H3C C H
H HO C C C CH3 H C O 2 Et
The enolate product abstracts an acidic proton, either from solvent or from starting keto ester, to yield the final addition product.
O H HO C C C H3C C C C 3 + EtOH H H H C 2Et O
Some Michael Acceptors and Michael Donors
H C C O Po e o C HH r pn l 2 E t y r p n ae H C C 2 t Eh l Po a o t C HO 2 H C C N Po e e i rl C H r p n nt i e 2 H C C C 3 3B t n2o e C H O H - ue - - n 2 H C N 2 N r eh l n C HO i o t ye e t 2 H C C N 2 Po e a i e C HO H r pnm d 2
e - kt e t D o R C 2 R Ba i e n C HO ' O C O R C 2 2 t Ba e Ee C H E O C e- t sr t Ko t E 2 C 2 2 t M n Ee O HO t C C E a i sr l c t o R C 2 N Ba e n ie C H O C e - t ir t Ko t l R HO C2 2 N N oo p n ir cm u t o d
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 C3 H CC C HH 2
H -O 2 C han An i e y ene n an c xo l o em
O N . + . CH 3 HC CH 2 C
N C HH H2 3 CC C 2
O C2H C3 + H 2 H CC N H
A, - i e n 1d t e 5 ko
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