Aldol and claisen

ACIDITY OF ACIDITY OF αα-HYDROGENS-HYDROGENS

ENOLS and ENOLATE IONS

C C

H

O

C C

O

C C

O

..

..

..

..:

:

::

-

-

α-hydrogen

base“enolate ion”

:B

However, theion is morenucleophilicat carbon.

acidic : pKa ~ 25

αα - - Hydrogens and Enolate IonsHydrogens and Enolate Ions

Strong bases will remove a hydrogen on the carbon next to acarbonyl group (α -hydrogen) to make a resonance stabilizedconjugate base.

NaOH, KOH, NaOR, NaH, LDA, etc.

Major resonancecontributor:charge is beston oxygen =

ACETONE ENOLATE IONACETONE ENOLATE ION

density-electrostatic potential

HOMO

..

The nucleophilic electron pair is in the HOMO

major

C C

O

C C

O

..

..

..:

::

-

-

I CH3

I CH3

Mechanisms are often drawnfrom the enolate resonance form like this:

Rather than from theketolate form like this:

Enolate Ions as NucleophilesEnolate Ions as NucleophilesMORE NUCLEOPHILIC AT CARBON, BUT BEST REPRESENTED AS THE ENOLATE

enolate

ketolate

αα -BROMINATION-BROMINATIONOF KETONESOF KETONES

BrominationBromination

O

O

Br

O

Br

Br

O

Br

Br

Br

O

Br

Br

Br

Br

KOH

Br2

O OBr Br

:

: : :::

.... ..

.. ..

..

Difficult to stop at monobromination

-

-

It just keepson going andgoing …..

IODOFORM REACTIONIODOFORM REACTION

Iodoform ReactionIodoform Reaction

R CCH3

O

R CO

O

NaCHI3

NaOH

I2+ yellow

precipitate

R CCH2

O

..

I I

R CCH2

O

I

NaOH

I2

2x more R CC

O

I

I

I

H O:..-..

R COH

O

C I

I

I

:

goodleavinggroup

-

H2ONaOH


ALKYLATION OF KETONESALKYLATION OF KETONES

CATALYTIC BASES = NaOH, KOH, NaOR

NON-CATALYTIC BASES = NaH, LDA REACT ONCE

REACT REPEATEDLY

O

C CH3THF

O

C CH2.. _

O

C CH2 CH3

NaH

Alkylation of a KetoneAlkylation of a Ketone

α -hydrogensCH3-I

one mole one mole

+ H2

one mole

NON-CATALYTIC BASES REACT ONCE

monoalkylation

CH3-IO

C CH2.. _

LDATHF

NCHCHCH3 CH3

CH3 CH3

: :

_Li+

“LDA”Lithium Diisopropyl Amide

a strong base

Sodium Hydride

NaH

ALKYLATION OF CYCLOHEXANONEALKYLATION OF CYCLOHEXANONE

O O

O

CH3CH2 I O

CH2CH3:

::

:..

..

-

-

:..

NaOH

enolateion

O

CH2CH3CH2CH3

CH3CH2CH3CH2

difficult to stopat monoalkylationwith NaOH or KOH(catalyst, not used up)

CATALYTIC BASES REACT REPEATEDLY


O

CH3

O

CH3CH3

O

CH3CH3

CH3

O

CH3CH3

CH3CH3

Alkylation follows the sequenceshown below.

Sequence of Alkylation - Cyclohexanone and BaseSequence of Alkylation - Cyclohexanone and Base

O

CH3

O

CH3

- -

It is difficult to stop at monoalkylationeven if one mole of CH3I is used.

This enolate haslower energy - the double bond ismore substituted.Steric hindrance is not a problem.

CH3-I This enolate hashigher energy.

O

KOH

CH3I Large or bulky groups may follow adifferent sequence than this one.

SAMESIDEFIRST


NON-CATALYTIC BASES = NaH, LDA

Monoalkylation is Obtained by UsingMonoalkylation is Obtained by Using “ “Non-Catalytic Bases”Non-Catalytic Bases”

A “non-catalytic base” is used up, and not regenerated.

OH

HNaH

:H O

H

O

H

OCH3

H

CH3I

+ H2

Na+

:

: : :

+ NaI

.. ..

-

-:

..

:..

-

onemole

gone

stoichiometric base

NCHCHCH3

CH3

CH3CH3

: :

_Li

+

“LDA”Lithium Diisopropyl Amide

a strong base

LDA is also a non-catalytic base. It is too strong a base to be regenerated after it is used to remove a proton from an aldehyde or ketone.

Lithium Diisopropyl AmideLithium Diisopropyl Amide

(iPr)2N (iPr)2NH..

:..- (iPr)2N

..:-

+ α -H Xdifficult

(need to add Lio)


ENAMINES

ALKYLATION OF CYCLOHEXANONEALKYLATION OF CYCLOHEXANONEENAMINES ALSO GIVE MONOALKYLATION

O N CH3CH2 I

O

CH2CH3

N

CH2CH2

Alkylates onceand stops !

To perform a second alkylationyou must make the enamine allover again!

+ I-

..

N

CH3

N

CH3

Sequence of Alkylation: Enamine Sequence of Alkylation: Enamine

Steric hindrance

yellow areais planar

O O

CH3

O

CH3CH3

O

CH3

Difficult to go beyond dialkylationbecause of steric hindrance.

Alkylations go one-at-a-time.You must make a new enamineeach time.

firsttime

secondtime

Notice the different order ofmethylation from that with base.

This enamine is not favored.This enamine

is favored.

( pyrrolidine + CH( pyrrolidine + CH33I )I )

REACTIONS OF REACTIONS OF αα -HYDROGENS :-HYDROGENS : ALDOL AND CLAISENALDOL AND CLAISEN CONDENSATION REACTIONSCONDENSATION REACTIONS

C CH

O

H

C CH

OH

H

C CH

O

NuNu::B

nucleophilicaddition

.. -

removalof α-H

TYPES OF REACTIVITY FOR TYPES OF REACTIVITY FOR ALDEHYDES AND KETONESALDEHYDES AND KETONES

• Good nucleophiles add.• Strong bases remove α -hydrogens.

Often, both processes compete.

ALDOL CONDENSATIONALDOL CONDENSATION

R CH2 C H

O

R CH2 C H

OR CH2 C

OH

H

CH C H

O

R

+

R CH2 CH C C H

O

R

The Aldol CondensationThe Aldol Condensation

base

an aldol(β -hydroxyaldehyde)

ald+ol

H3O+ - H2O

α ,β -unsaturated aldehyde

aldols easily losewater to form adouble bond

CH3 C 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 C

O

H

CH2 C H

O

CH3 C

O

H

Aldol Condensation -- MechanismAldol Condensation -- Mechanism

fast

fast

slow

enolate ion

forms new C-C bond

+ _CH3 C

H

O_

CH3 C

H

O

CH2

C

H

O

.._

CH2

C

H

O

The Bond Forming StepThe Bond Forming Step

nucleophile(donor)

carbonyl(acceptor)

enolate

Ketones Also Give Aldol CondensationsKetones Also Give Aldol Condensations

C

O

CH3C

OH

CH3CH2C OCH2

C O

..NaOH

C CH3CH

C O

“aldol”

-H2O

-

““CROSSED” ALDOLCROSSED” ALDOL CONDENSATIONSCONDENSATIONS

Crossed Aldol CondensationsCrossed Aldol CondensationsKETONE + ALDEHYDE

C

O

H C

OH

H

CH2C OCH2

C O

CH CH C

O

..

a “chalcone”

- H2O

NaOH

Works best to if an aldehyde isthe “acceptor”, since they aremore reactive; and works reallywell if the aldehyde has no α-H.

The ketone should have the α-H.

aldehyde

ketone

-

IMPORTANT GUIDELINESIMPORTANT GUIDELINES

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

O

CR H

O

CR Rδ+

δ-δ+

δ-+I +I

+I

Nu:

MOREREACTIVE

Alkyl groupsdeactivate thecarbonyl ( +I )to addition.

1.

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

O O O

RELATIVE REACTIVITY OF C=O GROUPSRELATIVE REACTIVITY OF C=O GROUPS

Density - LUMO plots ( color scale 0.000 to 0.030 )

MOREREACTIVE

LESSREACTIVE

THE EFFECT OF ALKYL SUBSTITUTION

Ketones form enolate ions more easily than aldehydes.

O

CC HR

RO

CC RR

R

- -:: ::.. ..

More substituentson the double bond

more stable

Which enolate willform fastest?

..

..

..: :

..: :

..:

..:

-

-

-

-CH3CH2 C

O

CH3

CH3CH2 C

O

CH2 CH3CH2 C

O

CH2

CH3CH C

O

CH3 C

O

CH3CHCH3

disubstituted

monosubstituted

2.

aldehyde enolate ketone enolate

In “mixed” reactions the ketone enolate usually adds to the aldehyde.

ALDEHYDE + KETONE ?ALDEHYDE + KETONE ?

The ketone forms the lower energy enolate (forms faster)

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

WHAT ABOUTWHAT ABOUTTWO DIFFERENT KETONES ?TWO DIFFERENT KETONES ?

HOW MANY PRODUCTS WITH THIS ONE ?HOW MANY PRODUCTS WITH THIS ONE ?

CH3 C

O

CH2 C

O

CH3CH3CH2+

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?

FORMATION OF RINGSFORMATION OF RINGS

Formation of RingsFormation of Rings

O

CH3

O

CH2

CH3

O

OH

O

CH3

CH3 C

O

CH2CH2CH2 C

O

CH3

NaOH

:-

α1 α2

Why don’t α2 hydrogens react ?

CH2PhC

CH2

O

Ph

O O

PhPh

O

PhPh

Ph Ph

KOH

EtOH

TETRAPHENYLCYCLOPENTADIENONETETRAPHENYLCYCLOPENTADIENONE

O

OH

H

OH

OO

1) O3

2) H3O+

KOHAldol

H2SO4

- H2O

OH-

An Interesting SequenceAn Interesting Sequence

CLAISEN CONDENSATIONSCLAISEN CONDENSATIONS

CH2 C O CH2

O

R CH3

CH2 C O CH2

O

R CH3

CH2 C

O

R CH C

R

O

O CH2 CH3

+ NaOCH2CH3

+

CH3 CH2 O H

The Claisen Ester CondensationThe Claisen Ester Condensation

a β -ketoester

CH3CH2OH

Notice that the base, the solvent and the leaving group

CH3CH2O- Na+, CH3CH2OH, CH3CH2O

-

all match (this is required in most cases).

1)

2)

+

:..

..

CH3 C OC2H5

O

O C2H5

_ :_ : :

.. _

CH3 C OC2H5

O

:_

CH2 C OC2H5

O

: :.. _

CH2 C OC2H5

O

CH3 C OC2H5

O

CH2 C OC2H5

O

CH2 C

O

OC2H5

Claisen Ester Condensation MechanismClaisen Ester Condensation Mechanism

3)

: :.. _

CH3 C

O

CH2 C OC2H5

O

: :

+ O C2H5:

..

..

_

CH2 C OC2H5

O

CH3 C OC2H5

O

Dieckmann CondensationDieckmann Condensation

C

CH

O

O

CH3

C O

O

CH3

O

C

O

O CH3

CH2CH2CH2CH2 COOMeMeOOC

..

A CYCLIC CLAISEN CONDENSATION

NaOMe

MeOH

PATTERNSPATTERNS

R CH2 C

OH

R

CH C R

O

R

R CH2 C C C R

O

RR

3-hydroxyaldehyde or

3-hydroxyketone(H)

(H)

β-hydroxy to C=O

α ,β -unsaturated C=O

2-propen-1-al or

2-propen-1-one

ALDOL

ALDOL

CLAISENR CH2 C

O

CH C OR

O

R

β-keto ester

Type of CondensationReaction

-H2O

(with loss of H2O)

SYNTHESISSYNTHESIS

C

CH3

OCH2

CH2

CCH2

O

CH2 CH CH CH2 CH3

C

CH3

CH2

CH2

CCH

O

CH2 CH CH CH2CH3

OHKOH

O

CH3

CH2

C C

CH2 CH3

H H

- H2O

Synthesis of a Perfumery CompoundSynthesis of a Perfumery Compound

Why don’t theother sets of α-Hreact?

cis-JasmoneScent of Jasmine in perfumes.

Aldol Condensation

Dehydration

cis cisα1α2

α3

α4

+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

α

ALDOLCONDENSATION

enzyme

Biological Synthesis of FructoseBiological Synthesis of Fructose

CH3 CH2 CH2 C H

O

CH3 CH2 CH2 C H

O

α

NaOH CH3 CH2 CH2 C

OH

CHCH2CH3 C H

H

O

CH3 CH2 CH2 C

OH

CHCH2CH3 C H

H

O

H2

Ni

CH3 CH2 CH2 C

OH

CHCH2CH3 C H

O

H H

H

ALDOLCONDENSATION

HYDROGENATION

2-Ethyl-3-hydroxyhexanal

2-Ethyl-1,3-hexanediol

--used in "6-12" insect repellent

Synthesis of an Insect RepellentSynthesis of an Insect Repellent

Aldol and claisen

Education

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