b-Dicarbonyl compounds Compounds having two carbonyl groups separated by an intervening carbon atom are called b-dicarbonyl compounds, and these compounds are highly versatile reagents for organic synthesis. O O O O C C C  R C C C OR' b b b-Dicarbonyl system b-Keto ester ** The pKa for such a proton is in the range 9-11, acidic enough to be removed easily by an alkoxide base to form an enolate. O O O H O OR C C C C C.. C + HOR H enolate anion pKa = 9-11 ......

. . .

. . . . .

. . . . O . O . . O O . O O C C C .. C C C R C OR' R C OR' R C OR' H H H Resonance structure of the anion of a b-keto ester Synthesis of b-keto ester (Claisen condensation)

O O O NaOC H 2 2 5 CH3COC2H5 CH3CC..HCOC2H5 + C2H5OH + Na (removed by distillation) Sodiumacetoacetic ester

HCl

O O

CH3CCH2COC2H5 Ethyl acetoacetate (acetoacetic ester) (76%) O O O O (1) NaOC2H5 R CH C + H CHC R CH2C CHCOC H + C H OH 2 OC2H5 OC2H5 + 2 5 2 5 (2) H3O R R (R may also be H) b-Keto ester Mechanism

Step1 ..

. O O .  ..

. + . OHC H + C H OH R CHC OC2H5 .. 2 5 RC.. H C OC2H5 2 5 H

..

. . . O .

RCH C OC2H5 Step 2

......

......

O . . . . O O

O . .

RCH2C + . RCH2C CH C OC2H5 HC C OC2H5

. C H O . OC2H5 R 2 5 .. R

..

. . . . . O . O ..

. + . OC2H5 RCH2C CH C OC2H5 .. R

Step 3

.. ..

.

. . O . O H O O .. .. . + . OC H + C H OH .. 2 5 RCH2C C C OC2H5 2 5 RCH2C C C OC2H5 R R Ethanol b-Keto ester Ethoxide ion b-Keto ester anion (weaker acid) (strong acid) (stronger base) (weaker base)

.. ..

. .. ..

. . .

......

. .

.

. .

. .

. . O O O O O O . .. RCH C C COC H 2 2 5 RCH2 C C COC2H5 RCH2 C C COC2H5 R R R

  O O  RCH2 C C CHOC2H5 H R Step 4 Resonance hybrid

  O O O O + H  H3O RCH2 C C COC2H5 RCH2 C C COC2H5 H (rapid) R R Keto form

OH O

RCH2 C C COC2H5 R Enol form O Only one  hydrogen CH3CHCOCH2CH3

CH3 Ethyl-2-methylpropanoate Crossed Claisen condensations

O O O O  (1) NaOC H COC2H5 + CH COC H 2 5 CCH2COC2H5 3 2 5 + (2) H3O Ethyl benzoate Ethyl benzoylacetate (60%) (no hydrogen) O O C OC H O 2 5 (1) NaOC2H5 CH2COC2H5 + CH C2H5OCOC2H5 + (2) H3O C OC2H5 Ethyl phenylacetate Diethyl carbonate O (no  carbon) Diethyl phenylmalonate (65%) Dieckmann condensation It is an intramolecular Claisen condensation. Thecarbon atom and the ester group for the condensation come from the same molecule. ** In general, Dieckmann condensation is useful only for the preparation of five- and six-membered rings. O O O O (1) NaOC2H5 OC2H5 C2H5OC(CH2)4COC2H5 + (2) H3O Diethyl hexanedioate Ethyl 2-oxocyclopentanecarboxylate (74-81%) (diethyl adipate) Mechanism OEt OEt O H O O O CH + .. OEt C OEt H OEt

Ethoxide anion removes The enolate anion attacks the carbonyl an hydrogen group at the other end of the chain O O EtO O H O H + OEt

OEt OEt

An ethoxide anion is expelled The ethoxide anion removes the acidic hydrogen located between two carbonyl groups. This favorable equilibrium drives the reaction. O O O O .. + HOEt H Cl OEt OEt

Addition of HCl rapidly protonates the anion, giving the final product. Acetoacetic ester synthesis utility 1- Preparation.. of mono and dialkylacetoacetic.. ester ...... O O . O Na+ . O .. CH3C CH2 COC2H5 + C2H5ONa CH3C CH COC2H5 + C2H5OH Acetoacetic ester Sodioacetoacetic ester R X ......

. . O O

CH3C CH COC2H5 + NaX R Monoalkylacetoacetic ester + O O O K O .. CH C + 3 CH COC2H5 + (CH3)3CO K CH3C C COC2H5 + (CH3)3COH R R Monoalkylaceto- Potassium tert-butoxide R' X acetic ester O R' O

CH3C C COC2H5 + KX R Dialkylacetoacetic ester 2- Synthesis of monosubstituted methyl ketone (monosubstituted acetone) O O O O O O + dilute NaOH H3O CH3C CH COC2H5 CH3C CH CO Na CH3C CH COH heat R R R Monoalkylacetoacetic ester O Basic hydrolysis of the ester group Acidification heat CH3C CH2 + CO2 o 100 C R Decarboxylation of theb-Keto acid Specific examples Synthesis of 2-heptanone: O O O O (1) NaOC2H5/ C2H5OH (1) dilute NaOH CH C CH 3 2 COC2H5 CH3C CH COC2H5 + (2) CH3CH2CH2CH2Br (2) H3O Ethyl acetoacetate CH CH CH CH (acetoacetic ester) 2 2 2 3 Ethyl butylacetoacetate (69-72%)

O O O heat CH3C CH COH CH3C CH2 CO2

CH2CH2CH2CH3 CH2CH2CH2CH3 2-Heptanone (52-61% overall from ethyl acetoacetate) Utility of malonic ester synthesis (synthesis of substituted acetic acid) 1- Preparation of carboxylic acid (mono and dialkylacetic acid)

O O

C2H5O C CH2 C OC2H5

COOC2H5 COOC2H5 NaOC2H5 RX + CH COOC H RCHCOOC H 2 2 5 ethanol 2 5 Alkyl halide Diethyl malonate - Alkylated derivative (malonic ester) of diethylmalonate

(1) HO , H2O RCH COOH (2) H+ 2 (3) heat Carboxylic acid Mechanism Step 1 Diethyl malonate, the starting compound, forms a relatively stable enolate anion:

...... O O

C2H5O C CH C OC2H5 H OC2H5

..

.. .

. .

.

.

...... O O O O C2H5O C CH C OC2H5 C2H5O C C..H C OC2H5

+ HOC2H5

..

.. .

.

.

. . . O O

C2H5O C CH C OC2H5 Step2 This enolate anion can be alkylated in an SN2 reaction,

O O O O

C2H5O C C..H C OC2H5 C2H5O C CH C OC2H5 + X

R X R Enolate ion Monoalkylmalonic ester and the product can be alkylated again if our synthesis requires it:

O O O O (CH ) CO .. R' X C2H5O C CH C OC2H5 3 3 C2H5O C C C OC2H5 R R

O R' O

C2H5O C C C OC2H5 R Dialkylmalonic ester Step 3 The mono- or dialkylmalonic ester can then be hydrolyzed to a mono- or dialkylmalonic acid, and substituted malonic acids decarboxylate readily. Decarboxylation gives a mono- or disubstituted acetic acid.

O O O O (1) HO , H O heat C H O 2 2 5 C CH C OC2H5 + HO C CH C OH (2) H3O R R Monoalkylmalonic ester H O O O - CO C C 2 CH O 2 C OH HO C R R H Monoalkylacetic acid

O O R' O R' O (1) HO , H O heat C H O 2 2 5 C C C OC2H5 + HO C C C OH (2) H3O R R Dialkylmalonic ester H O O R' O - CO C C 2 O CH C OH HO C R R' R Dialkylacetic acid Specific examples of the malonic ester synthesis utility

1) A malonic ester utility in synthesis of hexanoic acid O O O O (1) NaOC2H5 C2H5O C CH C OC H 2 2 5 C2H5O C CH C OC2H5 (2) CH3CH2CH2CH2Br CH2CH2CH2CH3 Diethyl butylmalonate (80 - 90%) O (1) 50% KOH, reflux CH2 C OH (2) dilute H2SO4, reflux (- CO2) CH2CH2CH2CH3 Hexanoic acid (75%) 2) A malonic ester utility in synthesis of 2-ethylpentanoic acid

O O O O (1) NaOC2H5 C2H5O C CH2 C OC2H5 C2H5O C CH C OC2H5 (2) CH3CH2Br CH2CH3 Ethyldiethylethylmalonate (80 - 90%) O O O O (1) KOC(CH3)3 (1) HO , H2O C2H5O C C C OC2H5 HO C C C OH (2) CH CH CH I + 3 2 2 (2) H3O H3CH2CH2C CH2CH3 H3CH2CH2C CH2CH3 Diethyl ethylpropylmalonate Ethylpropylmalonic acid

H O O O 180oC CH3CH2CH2CH C OH - CO2 HO C C O CH2CH3 H CH CH C 3 2 2 CH2CH3 2-Ethylpentanoic acid 3) A malonic ester utility in synthesis of 2-methyldodecanoic acid

COOCH2CH3 COOCH2CH3 1) NaOCH2CH3, ethanol 1) NaOCH2CH3, ethanol CH2COOCH2CH3 CHCOOCH2CH3 2) CH Br 2) CH (CH ) CH Br Diethyl malonate 3 3 2 8 2 CH3

Diethyl -2-methyl-1,3-propanedioate (79-83%)

H C COOCH CH 3 2 3 1) KOH, ethanol-water H3C H C C 2) H+ H3C(CH2)8H2C COOCH CH H C(CH ) H C 2 3 3) heat 3 2 8 2 COOH Diethyl-2-decyl-2-methyl-1,3-propanedioate 2- Methyldodecanoic acid (61-74%)