DECARBOXYLATION

OF -KETOACIDS

HYDROLYSIS OF A -KETOESTER GIVES A -KETOACID

Claisen
Condensation
O
CH3CH2CH2

-Ketoester
O

NaOCH3

C OMe
CH3OH

CH3CH2CH2

CH3CH2CH2

C CH

CH2CH3

Ketone

- CO2

C CH C OMe
CH2CH3

H3O+

hydrolysis

O
CH3CH2CH2

then, the -ketoacid

decarboxylates in acid

C CH C OH
CH2CH3

-Ketoacid

Decarboxylation of a -Ketoacid
6-ring

concerted step
O
C

heat + acid

C O
C

O
C

H
C

O
C O

enol
tautomerization
Carbon dioxide is easily lost
since a nice 6-membered
ring transition state can be
formed for a concerted
process.

O
C

CH

O C O

ketone

SYNTHESIS OF KETONES
FROM -KETOESTERS
ALKYLATION / DECARBOXYLATION OF

-KETOESTERS

STEP ONE - MAKING THE -KETOESTER

.. discussed earlier
O

a-ketoester

CH3 C O CH2 CH3

O

NaOCH2CH3

CH3 C O CH2 CH3

CH3 C CH2 C O CH2 CH3

+ CH3 CH2 O H

Claisen
condensation

a different R group
could be used here

STEP TWO - ALKYLATE THE -KETOESTER

CH3 C CH2 C O CH2 CH3

NaOCH2CH3
CH3I
O

CH3 C C C O CH2 CH3

H3C CH3

a primary halide
is best

STEP THREE - HYDROYSIS AND DECARBOXYLATION

O

CH3 C C C O CH2 CH3

H3C CH3
-ketoester
H3O

this
part will be
the ketone

-ketoacid

CH3 C C C O H
H3C CH3
heat

easily when heated in acid

(see next slide)

- CO2

CH3
CH3 C CH
CH3

-ketoacids decarboxylate

ketone

ALKYLATION CAN BE SKIPPED

O
CH3CH2CH2

NaOCH3

C OMe
CH3OH

CH3CH2CH2

C CH C OMe
CH2CH3

H3O+

O
CH3CH2CH2

C CH2CH2CH3

an unbranched ketone

DITHIANE ANIONS

Conversion of Aldehydes to Ketones

Dithiane Anions
a 1,3-dithiane

O
R C H

HSCH2CH2SH

H2SO4

aldehyde

-H2O

various
methods

R'

R C R' H2/Ni
R
or
ketone
Hg(OAC)2
H2SO4

acidic H

butyllithium
(strong base)

R'

- ..

.. -

R'
SN 2

C S
anion is stabilized
by empty 3d
orbitals on sulfur

PATTERNS

PATTERNS
HO
R CH2 C

(H)

-hydroxy to C=O

O
CH C R
R

Type of
Condensation
Reaction

(H)

3-hydroxyaldehyde or

ALDOL

3-hydroxyketone

-H2O

O
R CH2 C

O
R CH2 C

C R

O
CH C OR
R

, -unsaturated C=O
2-propen-1-al or
2-propen-1-one

-keto ester

ALDOL
(with loss of H2O)

CLAISEN

PATTERNS
O

R CH2 C

-keto acid

CH C OH
R

heat

CONTINUED

H3O+

O
R CH2 C
ketone

H3O+

DECARBOXYLATION
R-X (alkylation)
O

CH2 + CO2
R

R CH2 C

O
CH C OR
H

from Claisen

SOME OTHER APPLICATIONS

ACYLOIN CONDENSATIONS

Acyloin Condensation
Na
O
2

R C OR'

Na
xylene

H2O
mechanism
not required

Na

O O
R C C R

OH O
R CH C R

an acyloin

This is a good way to make large rings.High dilution.

A Cyclic Acyloin Condensation

O
C OC2H5
(C32H64)

O
Na
xylene

(C32H64)

C
C OH
H

C OC2H5
O

Zn(Hg)
Conc HCl

(C32H64)

CH2
CH2

cyclotetratriacontane
A VERY BIG RING !

PATTERN

HO

R CH C R

-hydroxyketone
an acyloin

ACYLOIN

CATENANES

Catenanes
O

(C34H68)

(C32H64)

C
OC2H5
OC2H5
C
O

Na

Interlocked
rings.

xylene
cyclo-C34

C
(C34H68)

(C32H64)
CH

a Catenane
(1 - 2% yield)

OH

HELL-VOLHARD-ZELINSKY
-BROMOACIDS AND -BROMOESTERS

Hell-Volhard-Zelinsky Reaction
O
R CH C OH
H

1) P, Br2
2) H O+
3

O
R CH C OH
Br

-bromoacid

PBr3
O
R CH C Br

H3O+
(workup step)

..

:O H
R CH C Br
Br

Br

Acid halides have

a larger enol content
than ketones.

O
R CH C Br
Br

Double bonds react Resonance increases the electron

with bromine!
density in the double bond. Enols
are more reactive than alkenes.

Synthesis of Aminoacids and a-Hydroxyacids

neutralization step not shown

O
CH C OH + NH3

CH C OH

Br

NH2

phenylalanine

O
CH3 CH C OH
Br

NaOH

O
CH3 CH C OH
OH

lactic acid

REFORMATSKY REACTION
A COUSIN TO THE GRIGNARD REACTION

Reformatsky Reaction
O

O
R CH C OH
Fischer
Esterification
or via the
acid chloride

Br

R CH C O CH2CH3
Br

-bromoester
Zn, ether

O
R CH C O CH2CH3

H3C C OH
H

R CH C O CH2CH3
1)

O
H3C C H

2)

H 3O +

ZnBr

Reformatsky
reagent
Reacts like a
Grignard reagent!