Chem 232 Summary of Alpha Substitutions page 1 Aldol Condensation- aldehyde (or ketone) enolate condenses with aldehyde (or ketone):

O CH O O H 3 H CH  3 CH3 C C C C CH C C CH2 CH2 H -H O H H O OH 2 H nucleophile electrophile -hydroxy aldehyde -unsaturated aldehyde The nucleophile can be a ketone enolate or aldehyde enolate and the electrophile (shaded) can be an aldehyde or ketone.

 Crossed Aldol- Condensation between two different carbonyls. The component without hydrogens is the electrophile:

O O O OH O  C CH C C CH CH3 C H CH -H2O CH 2 CH3 H 3 ketone enolate no -hydrogens -unsaturated ketone

 Aldol Cyclizations- A dicarbonyl produces an enolate and carbonyl in the same molecule: enolate from a O OH 1,5-diketone  CH OH 3 CH3 O O -H2O O CH2 CH3 CH3 CH2 O

Claisen Condensation- Similar to Aldol condensation except the nucleophile is an ester enolate; O O O O O O

+ EtO C CH C OEt EtO C CH2 C EtO C CH2 CH3 C OEt 2 ketoester CH3 CH3  Dieckmann Cyclization- Internal Claisen condensation similar to Aldol cyclization. A 1,6 diester gives a 5-membered ring and a 1,7 diester gives a 6-membered ring: O

OEt O OEt cyclic ketoester C C OEt O O  Crossed Claisen- Similar to crossed Aldol- Electrophile has nohydrogens: O O O O C C EtO EtO C CH2 EtO C CH2 ketoester

 Variations on Crossed Claisen- ketone enolate and ester condensation. Esters, carbonates, formates and oxalates are common electrophiles: O O O O O O O O

H C OEt H EtO C OEt OEt ethyl formate  -ketoaldehyde diethyl carbonate -ketoester O O O O O OEt diketoester EtO C C OEt O diethyl oxalate Chem 232 Summary of Alpha Substitutions page 2 -dicarbonyl enolates- Acetoacetic Ester Synthesis and Malonate Ester synthesis Acetoacetic Ester Synthesis- starting with -keto ester to make substituted acetone: O O O O O + 1) NaOEt H3O CH C CH2 substituted CH C CH C OR CH3 C CH C OR 3 3 2 heat acetone 2) CH -Br CH3 acetoacetic ester 3 CH3 -CO2 (-keto ester) Hydrolysis and decarboxylation steps: continued O O O O O H O+ heating 3 CH C CH CH C CH C OR CH C CH C OH 3 2 3 3 -CO heat 2 CH3 CH3 CH3 acidic hydrolysis of ester group Mechanism of decarboxylation:

H H O O O O O tautomerize CH3 C H CH C C CH3 C C 3 O O CH CH CH CH CH 3 CH3 3

Malonate Ester synthesis- alkylation of enolate followed by decarboxylation gives substituted acetic acids: O O O O H O+ O 1) NaOEt 3 substituted RO C CH C OR RO C CH C OR HO C CH2 acetic acid 2 2) CH -Br heat 3 CH malonic ester 3 -CO2 CH 3 Two successive alkylations:

CH3 O O O CH CH O O O CH O H O+ 2 3 1) NaOEt 1) NaOEt 2 3 HO C C H RO C CH2 C OR RO C CH C OR RO C C C OR 2) CH3-Br 2) CH3CH2Br heat CH CH CH3 malonic ester 3 3 -CO2 di-substituted acetic acid Useful for cycloalkane carboxylic acids: O O O O O + H 1) NaOEt H3O RO C C C OR RO C C RO C CH2 C OR heat 2) Br-CH2-CH2-CH2-Br malonic ester -CO 3) NaOEt 2

Michael Reaction- 1,4 addition across the double bond of -unsaturated carbonyl:

O OH Michael O acceptor CH2 CH C CH3 + CH H3O CH2 CH C 3 CH2 CH C CH3

CH3 C CH C OR CH3 C CH C OR CH C CH C OR tautomerizes 3 Michael O O O O to ketone O donor O