Aldol and Claisen Condensations

7/28/2019 Aldol and Claisen Condensations

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REACTIONS OFa-HYDROGENS :ALDOL AND CLAISEN

CONDENSATION REACTIONS


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C CH

O

H

C CH

OH

H

C CH

O

NuNu:

:B

nucleophilic

addition

..-

removal

ofa-H

TYPES OF REACTIVITY FOR

ALDEHYDES AND KETONES

Good nucleophiles add. Strong bases removea-hydrogens.

Often, both processes compete.


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ALDOL CONDENSATION


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R CH2

C H

O

R CH2

C H

O

R CH2

C

OH

H

CH C H

O

R

+

R CH2

CH C C H

O

R

The Aldol Condensation

base

an aldol

(b-hydroxyaldehyde)

ald

+ol

H3O+ - H2O

a,b-unsaturated aldehyde

aldols easily lose

water to form a

double bond


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CH3C H

O: :

+ O H:.._

..

: : : :..

_.. _

CH3

C H

O: :

CH2

C H

O: :..

_

:

..

:

: :

: :..

: :

+ H2O

:..

: :

CH3

C

O

H

H

+ :OH..

..

_

CH2

C H

O

CH2

C H

O

CH2

C H

O

CH2

C H

O

_

_

CH3

CO

H

CH2

C H

O

CH3

C

O

H

Aldol Condensation -- Mechanism

fast

fast

slow

enolate ion

forms new

C-C bond


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+ _

CH3

C

H

O_

CH3

C

H

O

CH2

C

H

O

.. _

CH2

C

H

O

The Bond Forming Step

nucleophile

(donor)

carbonyl(acceptor)

enolate


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Ketones Also Give Aldol Condensations

C

O

CH3

C

OH

CH3

CH2

C OCH2

C O

..NaOH

C CH3

CH

C O

aldol

-H2O-


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CROSSED ALDOLCONDENSATIONS


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Crossed Aldol CondensationsKETONE + ALDEHYDE

C

O

H C

OH

H

CH2

C OCH2

C O

CH CH C

O

..

a chalcone

- H2O

NaOH

Works best to if an aldehyde isthe acceptor, since they are

more reactive; and works really

well if the aldehyde has no a-H.The ketone should have the a-H.

aldehyde

ketone

-


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IMPORTANT GUIDELINES

Aldehyde carbonyl groups are more reactive towardnucleophilic addition than ketone carbonyl groups.

OCR H

OCR R

d+d-

d+d-

+I +I

+I

Nu:

MORE

REACTIVE

Alkyl groupsdeactivate the

carbonyl ( +I )

to addition.

1.


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H-C-H CH3-C-H CH3-C-CH3

O O O

RELATIVE REACTIVITY OF C=O GROUPS

Density - LUMO plots ( color scale 0.000 to 0.030 )

MORE

REACTIVE

LESS

REACTIVE

THE EFFECT OF ALKYL SUBSTITUTION


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Ketones form enolate ions more easily than aldehydes.

O

CC

HR

R

O

CC

R

R

R

- -:: ::.. ..

More

substituents

on thedouble bond

more stable

Which enolate will

form fastest?

..

..

..: :

..: :

..:

..:

-

-

-

-CH3CH2 C

O

CH3

CH3CH

2C

O

CH2

CH3CH

2C

O

CH2

CH3CH C

O

CH3

C

O

CH3

CHCH3

disubstituted

monosubstituted

2.

aldehyde enolate ketone enolate


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In mixed reactions the ketone enolate

usually adds to the aldehyde.

ALDEHYDE + KETONE ?

The ketone forms the lower energy enolate (forms faster)

and it adds to the aldehyde (more reactive C=O).


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WHAT ABOUTTWO DIFFERENT KETONES ?


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HOW MANY PRODUCTS WITH THIS ONE ?

CH3

CO

CH2

CO

CH3

CH3CH

2+

x2 x2

8 POSSIBLE PRODUCTS !

two different self dimers two different self dimers

four mixed products

A B

a b c d

aB, bB, cA, dA

aA, bA cB, dB

.. which enolate do you think will form preferentially?


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FORMATION OF RINGS


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Formation of Rings

O

CH3

O

CH2

CH3

O

OH

O

CH3

CH3

C

O

CH2CH

2CH

2C

O

CH3

NaOH

:-

a1 a2

Why donta2 hydrogens react ?


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CH2

PhC

CH2

O

Ph

O O

PhPh

O

PhPh

Ph Ph

KOH

EtOH

TETRAPHENYLCYCLOPENTADIENONE


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O

O H H

OH

OO

1) O3

2) H3O+

KOH

Aldol

H2SO4

- H2O

OH-

An Interesting Sequence


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CLAISEN CONDENSATIONS


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CH2 C O CH2

O

R CH3

CH2C O CH

2

O

R CH3

CH2

C

O

R CH C

R

O

O CH2CH

3

+ NaOCH2CH3

+

CH3

CH2

O H

The Claisen Ester Condensation

a b-ketoesterCH3CH2OH

Notice that

the base, the solvent and the leaving group

CH3CH2O-Na+, CH3CH2OH, CH3CH2O

-

all match (this is required in most cases).


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1)

2)

+

:..

..

CH3C OC

2H

5

O

O C2H

5

_ :

_ : :.. _

CH3

C OC2H

5

O

:

_

CH2

C OC2H

5

O

: :

.. _

CH2C OC

2H

5

O

CH3

C OC2H

5

O

CH2

C OC2H

5

O

CH2

C

O

OC2H

5

Claisen Ester Condensation Mechanism

3)

: :.. _

CH3

C

O

CH2

C OC2H

5

O

: :

+ O C2H5:..

..

_

CH2

C OC2H

5

O

CH3

C OC2H

5

O


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Dieckmann Condensation

C

CH

O

O

CH3

C O

O

CH3

O

C

O

O CH3

CH2CH

2CH

2CH

2COOMeMeOOC

..

A CYCLIC CLAISEN CONDENSATION

NaOMe

MeOH


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PATTERNS

R CH2

COH

R

CH C RO

R

R CH2

C C C R

O

RR

3-hydroxyaldehyde or

3-hydroxyketone(H)

(H)

b-hydroxy to C=O

a,b-unsaturated C=O2-propen-1-al or

2-propen-1-one

ALDOL

ALDOL

CLAISENR CH2

C

O

CH C OR

O

R

b-keto ester

Type of

Condensation

Reaction

-H2O

(with loss of H2O)


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SYNTHESIS


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C

CH3

OCH2

CH2

CCH

2

O

CH2CH CH CH

2CH

3

C

CH3

CH2

CH2

CCH

O

CH2CH CH CH

2CH

3

OHKOH

O

CH3

CH2

C CCH2 CH3

H H

- H2O

Synthesis of a Perfumery Compound

Why dont the

other sets ofa-Hreact?

cis-Jasmone

Scent of Jasmine in perfumes.

Aldol Condensation

Dehydration

cis cis12

a3a4


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+CH2

CH C H

O

OHO

P

OH

OO

CH2

C CH2

O P OH

OH

O O

O

Glyceraldehyde-3-phosphate

CH2

CH C CH C CH2

O P OH

O

O

O

OH

OH

HOHO

P

OH

O O

Dihydroxyacetone phosphate

Fructose-1,6-diphosphate

a

ALDOLCONDENSATION

enzyme

Biological Synthesis of Fructose


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CH3

CH2

CH2

C H

O

CH3

CH2

CH2

C H

O

a

NaOH CH3 CH2 CH2 C

OH

CHCH2

CH3

C H

H

O

CH3

CH2

CH2

C

OH

CHCH2

CH3

C H

H

O

H2

Ni

CH3

CH2

CH2

C

OH

CHCH2

CH3

C H

O

HH

H

ALDOL

CONDENSATION

HYDROGENATION

2-Ethyl-3-hydroxyhexanal

2-Ethyl-1,3-hexanediol

--used in "6-12" insect repellent

Synthesis of an Insect Repellent

Aldol and Claisen Condensations

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