REACTIONS OF REACTIONS OF αα--HYDROGENS :HYDROGENS :ALKYLATION AND HALOGENATIONALKYLATION AND HALOGENATION

REACTIONSREACTIONS

C CH

O..

:

Until now we have looked at reactionsof the C=O group - nucleophilic additions and substitutions

Now we will look at reactions thatresult from the acidity of the alphahydrogen

Good nucleophilesreact at C=O

Strong basesremove theα-hydrogens

REACTIONS OF CARBONYL CONTAINING COMPOUNDSREACTIONS OF CARBONYL CONTAINING COMPOUNDS

Chaps 16, 17, 18, 19

Chap 21

ACIDITY OF ACIDITY OF αα--HYDROGENSHYDROGENS

ENOLATE IONS

C CH

OC C

O

C CO

..

..

..

..:

:

::

-

-

α-hydrogen

base“enolateion”

:B

However, theion is morenucleophilicat carbon.

acidic : pKa ~ 25

αα--HydrogensHydrogens andand EnolateEnolate IonsIons

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

density-HOMO

HOMO

CH3 CO

CH2CH3

CO

CH2

:::.. ..

..-

-

Charge is on oxygenbut carbon isnucleophilic

REACTIVESITE

NEGATIVECHARGE

..

The nucleophilic electron pair is in the HOMO

note thebonding

major

C CO

C CO

..

..

..:

::

-

-

I CH3

I CH3

Mechanisms are often drawnfrom the enolate resonance form like this:

Rather than from theketolate form like this:

EnolateEnolate Ions asIons as NucleophilesNucleophilesMORE NUCLEOPHILIC AT CARBON, BUT BEST REPRESENTED AS THE ENOLATE

enolate

ketolate

It just keepson going andgoing …..

ALKYLATION OF KETONESALKYLATION OF KETONES

CATALYTIC BASES = NaOH, KOH, NaOR

NON-CATALYTIC BASES = NaH, LDA REACT ONCE

REACT REPEATEDLY

one shot.

OC CH3 THF

OC CH2

.. _

OC CH2 CH3

NaH

AlkylationAlkylation of aof a KetoneKetone

α-hydrogensCH3-I

one mole one mole

+ H2

one mole

NON-CATALYTIC BASES REACT ONCE

monoalkylation

CH3-IOC CH2

.. _

LDATHF

NCHCHCH3

CH3

CH3 CH3

: :_

Li+

“LDA”Lithium Diisopropyl Amide

a strong base

one shot.

Sodium HydrideNaH

ALKYLATION OF CYCLOHEXANONEALKYLATION OF CYCLOHEXANONE

O O

O

CH3CH2 I OCH2CH3

:

::

:..

..

-

-

:..

NaOH

enolateion

OCH2CH3

CH2CH3

CH3CH2CH3CH2

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

CATALYTIC BASES REACT REPEATEDLY

It just keepson going andgoing …..

OCH3

OCH3

CH3

OCH3

CH3

CH3

OCH3

CH3

CH3

CH3

Alkylation follows the sequenceshown below.

Sequence of Alkylation Sequence of Alkylation -- Cyclohexanone and BaseCyclohexanone and Base

OCH3

OCH3

- -

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

ALKYLATION OF KETONESALKYLATION OF KETONES

NON-CATALYTIC BASES = NaH, LDA

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

one shot.

NCHCHCH3

CH3

CH3 CH3

: :_

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)

one shot.

ALKYLATION OF KETONESALKYLATION OF KETONES

ENAMINES

ALKYLATION OF CYCLOHEXANONEALKYLATION OF CYCLOHEXANONEENAMINES ALSO GIVE MONOALKYLATION

O N CH3CH2 I

OCH2CH3

NCH2CH2

Alkylates onceand stops !

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

+ I -..

one shot.

NCH3

NCH3

Sequence of Alkylation: Enamine Sequence of Alkylation: Enamine

Steric hindrance

yellow areais planar

O OCH3

OCH3CH3

OCH3

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 enamineis not favored.This enamine

is favored.

( pyrrolidine + CH( pyrrolidine + CH33I )I )

αα--BROMINATIONBROMINATIONOF KETONESOF KETONES

BrominationBromination

O

OBr

OBrBr

OBrBr

BrO

BrBr

BrBr

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 + yellowprecipitate

R CCH2

O..

I I

R CCH2

O

I

NaOH

I2

2x more R CC

O

I

I

I

H O:..-..

R COH

OC I

I

I

:

goodleavinggroup

-

H2ONaOH

It just keepson going andgoing …..

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 HO

R CH2 C HO

R CH2 COH

HCH C H

O

R

+

R CH2 CH C C HO

R

TheThe AldolAldol CondensationCondensation

base

an aldol(β-hydroxyaldehyde)

ald+ol

H3O+ - H2O

α,β-unsaturated aldehyde

aldols easily losewater to form adouble bond

CH3 C HO: :

+ O H:.._

..

: : : :.._

.. _

CH3 C HO: :

CH2 C HO: :

.._

:..

:

: :

: :..

: :

+ H2O

:..

: :

CH3 C

O

H

H

+ :OH....

_

CH2 C HO

CH2 C HO

CH2 C HO

CH2 C HO

_

_

CH3 CO

H

CH2 C H

OCH3 C

O

H

AldolAldol Condensation Condensation ---- MechanismMechanism

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

KetonesKetones Also GiveAlso Give AldolAldol CondensationsCondensations

CO

CH3COH

CH3

CH2

C OCH2

C O

.. NaOH

C CH3

CHC O

“aldol”

-H2O-

“CROSSED” ALDOL“CROSSED” ALDOLCONDENSATIONSCONDENSATIONS

CrossedCrossed AldolAldol CondensationsCondensationsKETONE + ALDEHYDE

CO

H COH

HCH2

C OCH2

C O

CH CH CO

..

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

OCR H

OCR R

δ+

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.OCC H

R

ROCC R

R

R

- -:: ::.. ..

Moresubstituentson the double bond

more stable

Which enolate willform fastest?

..

..

..: :

..: :

..:

..:

-

-

-

-CH3CH2 CO

CH3

CH3CH2 CO

CH2 CH3CH2 CO

CH2

CH3CH CO

CH3 CO

CH3CHCH3

disubstituted

monosubstituted

2.

aldehyde enolate ketone enolate

In “mixed” reactions the ketone enolateusually 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 CO

CH2 CO

CH3CH3CH2+

x2 x2

8 POSSIBLE PRODUCTS !

two different self dimers two different self dimers

four mixed products

A Ba 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 CO

CH2CH2CH2 CO

CH3

NaOH

:-

α1 α2

Why don’t α2 hydrogens react ?

CH2PhC CH2

O

Ph

O O

PhPh

O

PhPh

Ph Ph

KOHEtOH

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

OR CH3

CH2 C O CH2

OR CH3

CH2 CO

R CH CR

OO CH2 CH3

+ NaOCH2CH3

+

CH3 CH2 O H

TheThe ClaisenClaisen Ester CondensationEster Condensation

a β-ketoesterCH3CH2OH

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

OCH3 C OC2H5

O

CH2 C OC2H5

OCH2 C

OOC2H5

ClaisenClaisen Ester Condensation MechanismEster Condensation Mechanism

3): :

.. _

CH3 C

O

CH2 C OC2H5

O

: :

+ O C2H5:....

_

CH2 C OC2H5

OCH3 C OC2H5

O

Dieckmann CondensationDieckmann Condensation

C

CH

O

O

CH3

C OO

CH3

O

CO

O CH3

CH2CH2CH2CH2 COOMeMeOOC

..

A CYCLIC CLAISEN CONDENSATION

NaOMeMeOH

PATTERNSPATTERNS

R CH2 COH

RCH C R

O

R

R CH2 C C C RO

RR

3-hydroxyaldehyde or3-hydroxyketone(H)

(H)

β-hydroxy to C=O

α,β-unsaturated C=O

2-propen-1-al or2-propen-1-one

ALDOL

ALDOL

CLAISENR CH2 CO

CH C ORO

R

β-keto ester

Type of CondensationReaction

-H2O

(with loss of H2O)

SYNTHESISSYNTHESIS

CCH3

OCH2

CH2

CCH2

O

CH2 CH CH CH2 CH3

CCH3

CH2

CH2C

CH

O

CH2 CH CH CH2 CH3

OHKOH

O

CH3

CH2

C CCH2 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

H2Ni

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

CONJUGATE ADDITIONCONJUGATE ADDITION

MICHAEL ADDITION

C CCO

C CCO

C CCO

Addition ofAddition of NucleophilesNucleophiles toto EnonesEnonesConjugate Addition or Michael Addition

++

- -.. .. ..: : : : :

:Nu :Nu

C CCOH

C CCO

H

Nu

Nuconjugateaddition

1,2-addition 1,4-addition

C CCO

CH3

H

H

HC C

CO

CH3

H

HCH

:N

C CCO

CH3

H

HH

C

H

:N

:N C H-OH

In conjugate addition the nucleophile addsand then picks up ahydrogen from thesolvent medium.

::

:

:.. ..

..-

-

CONJUGATE ADDITIONCONJUGATE ADDITION

C CCO

H

H

H

R

weaknucleophiles/bases

strongbases

CONJUGATE ADDITIONCONJUGATE ADDITIONGENERALIZATION

direct to C=O1,2-addition

conjugate addition1,4-addition

stereochemistryalso mattersconjugated ketone

αβ

• Strong bases give direct addition to C=O (1,2-addition) unlessthe C=O group is sterically hindered by large groups

Organolithium compounds RLi

Grignard reagents RMgX

Lithium Aluminum Hydride LiAlH4

Strong Bases : 1,2Strong Bases : 1,2--AdditionAddition

• Good nucleophiles and weak bases give conjugate addition (1,4-addition), also known as Michael Addition, especially if the C=O group is hindered.

Amines R-NH2

Alcohols R-O-H Water H-O-H

Enolates

Organocopper and cadmium compounds( RMgX + CuCl or CdCl2 )

Lithium dialkylcuprates( RLi + CuCl )

Cyanide ion :C N:

Weak Bases : 1,4Weak Bases : 1,4--AdditionAddition

..

..

......

OH CH3O O

CH3

O O_

+:CH3

_:CH3

_

CH3Li (CH3)2CuLi

CH3MgI

CuCl

ADDITION TO CARBONYLADDITION TO CARBONYL

orCH3MgI

C-Li and C-Mg bonds are more ionic (stronger bases)

weaker bases addby 1,4 addition

strong bases addby 1,2 addition

R-Cu and R-Cd bonds are more covalent (weaker bases)

(CH3)2Cdor

STEREOCHEMISTRY ALSO MATTERSSTEREOCHEMISTRY ALSO MATTERS

C CCO

CHH

H

HCH3

CH3

C CCOH

CHH

HCH3

H CH3

CH3

C CCOH

H

H

HCH3H

C CCO

H

H

H

H

CH3MgBr

CH3MgBr

major product

major product

large groups herepromote 1,4 addition

LARGE GROUPS ON EITHER SIDE OF THE CARBONYL FAVOR CONJUGATE ADDITION

large groups here canalso promote 1,4 addition

large groups herepromote 1,2 addition

small groups heremake 1,2 additionmore probable

STERIC HINDRANCE

FRONTIER MO THEORYFRONTIER MO THEORY

CONJUGATED KETONES

FRONTIER MO THEORYFRONTIER MO THEORY

HOMO

LUMO

ELECTROPHILEELECTROPHILE

NUCLEOPHILENUCLEOPHILE

HOMO

E+ :Nu-

FILLED MOs

FILLED MOs

LUMO MAPPED ONTO ELECTRON LUMO MAPPED ONTO ELECTRON DENSITYDENSITY

A

A

B

B

BLUE REPRESENTS MAXIMUM DENSITY OF LUMO

ROBINSON ANNELATIONROBINSON ANNELATION

FORMING RINGS BY COMBININGCONJUGATE ADDITION WITH AN ALDOL CONDENSATION

METHYL VINYL KETONE (MVK)

OCO

CH3

HH

HO

CCO

CH3

HH

H

O

CH2 CH2

CO

CH3

O

.. ..

..

..

..

..: : : :: -

:-

NaOCH3CH3OH

H-OCH3

..O-CH3: ..

-

O-CH3: ..- ..

+

Conjugate Addition ofConjugate Addition of CyclopentanoneCyclopentanone to MVKto MVK

: :

can continue

methyl vinyl ketoneMVK

enolateweak base

ROBINSON ANNELATIONROBINSON ANNELATION

OCO

CH3

HH

HO

CH2 CH2

CO

CH3

O

CH2 CH2

CCH2

OO

OO

:-

H3O+

(workup)

Michaeladdition

Annelation(ring formation)

NaOCH3

CH3OH

-

FROM PREVIOUS SLIDE

USES MVK TO BUILD A RING

internal aldol condensation

O

O CH2

CHC O

CH3

O

ONaOEt

EtOH

MICHAEL ADDITION + ALDOL CONDENSATIONMICHAEL ADDITION + ALDOL CONDENSATION

ANOTHER EXAMPLE

Most acidic setof hydrogensreacts first.

1

2

MICHAEL

ALDOL

DECARBOXYLATIONOF β-KETOACIDS

ClaisenCondensation

β-Ketoester

β-Ketoacid

hydrolysis

HYDROLYSIS OF A β-KETOESTER GIVES A β-KETOACID

… then, the β-ketoaciddecarboxylates in acid

CH3CH2CH2 CO

CHCH2CH3

H- CO2

Ketone

CH3CH2CH2 CO

OMe CH3CH2CH2 CO

CHCH2CH3

CO

OMeNaOCH3

CH3OH

H3O+

CH3CH2CH2 CO

CHCH2CH3

CO

OH

OC

CCO

H

O

OC

C

H

CO

O

CO

CH C OO

DecarboxylationDecarboxylation of a of a ββ--KetoacidKetoacid

enol

ketone

Carbon dioxide is easily lostsince a nice 6-memberedring transition state can be formed for a concertedprocess.

concerted step

heat + acid

6-ring

tautomerization

SYNTHESIS OF KETONESSYNTHESIS OF KETONESFROM FROM ββ--KETOESTERSKETOESTERS

ALKYLATION / DECARBOXYLATION OF β-KETOESTERS

CH3 C O CH2

OCH3

CH3 C O CH2

OCH3

CH3 CO

CH2 CO

O CH2 CH3

+ NaOCH2CH3

+ CH3 CH2 O H

a β-ketoester

Claisencondensation

a different R groupcould be used here

STEP ONE STEP ONE -- MAKING THE MAKING THE ββ--KETOESTERKETOESTER….. discussed earlier

STEP TWO STEP TWO -- ALKYLATE THE ALKYLATE THE ββ--KETOESTERKETOESTER

CH3 CO

CH2 CO

O CH2 CH3

CH3 CO

C CO

O CH2 CH3CH3 CH3

NaOCH2CH3CH3I

a primary halideis best

STEP THREE STEP THREE -- HYDROYSIS AND DECARBOXYLATIONHYDROYSIS AND DECARBOXYLATION

β-ketoacids decarboxylateeasily when heated in acid

(see next slide)

β-ketoester

β-ketoacid

ketone

CH3 CO

C CO

O CH2 CH3CH3 CH3

CH3 CO

C CO

O HCH3 CH3

CH3 CO

CHCH3

CH3

H3O

- CO2heat

thispart will bethe ketone

ALKYLATION CAN BE SKIPPEDALKYLATION CAN BE SKIPPED

CH3CH2CH2 CO

OMe CH3CH2CH2 CO

CHCH2CH3

CO

OMe

CH3CH2CH2 CO

CH2CH2CH3

NaOCH3

CH3OH

H3O+

an unbranched ketone

DITHIANE ANIONSDITHIANE ANIONS

Conversion ofConversion of AldehydesAldehydes toto Ketones Ketones DithianeDithiane AnionsAnions

SS

R HCR H

O HSCH2CH2SHa 1,3-dithiane

acidic H

SS

RSS

R R'

R' X

CR R'

O

R' X

..-

variousmethods

H2/Nior

Hg(OAC)2H2SO4

aldehyde

ketone

H2SO4

-H2O butyllithium(strong base)

SN2

C S..-

anion is stabilized by empty 3dorbitals on sulfur

PATTERNSPATTERNS

PATTERNSPATTERNS

R CH2 COH

RCH C R

O

R

R CH2 C C C RO

RR

3-hydroxyaldehyde or3-hydroxyketone(H)

(H)

β-hydroxy to C=O

α,β-unsaturated C=O

2-propen-1-al or2-propen-1-one

ALDOL

ALDOL

CLAISENR CH2 CO

CH C ORO

R

β-keto ester

Type of CondensationReaction

-H2O

(with loss of H2O)

DECARBOXYLATIONR CH2 C

OCH C OH

O

R

β-keto acid

H3O+heat

R CH2 CO

CH2

R+ CO2

PATTERNSPATTERNS CONTINUED

R CH2 CO

CH C ORO

H from Claisen

R-X (alkylation)

H3O+

ketone

SOME OTHER APPLICATIONS

ACYLOIN CONDENSATIONSACYLOIN CONDENSATIONS

2 R C OR'O

C CR RO O

Na+

Na+

R CHOH

C RO

AcyloinAcyloin CondensationCondensation

an acyloin

xyleneNa

H2O

mechanismnot required

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

C OC2H5

O

C OC2H5

O

(C32H64)C

C(C32H64)

O

OHH

CH2

CH2

(C32H64)

A CyclicA Cyclic AcyloinAcyloin CondensationCondensation

cyclotetratriacontane

Zn(Hg)Conc HCl

Na

xylene

A VERY BIG RING !

ACYLOINR CHOH

C RO α-hydroxyketone

an acyloin

PATTERNPATTERN

CATENANESCATENANES

(C34H68)(C32H64)

CO

OC2H5

C O

OC2H5

(C34H68)(C32H64)

CO

CH OH

Naxylene

cyclo-C34

a Catenane

(1 - 2% yield)

CatenanesCatenanesInterlockedrings.

HELL-VOLHARD-ZELINSKY

α-BROMOACIDS AND α-BROMOESTERS

HellHell--VolhardVolhard--ZelinskyZelinsky ReactionReaction

CH CO

OHRH

CH CO

OHRBr α-bromoacid

CH CO

BrRH

CH CO

BrRH

CH CO

BrRBrBr Br

H3O+

(workup step)

PBr3

P, Br21)

2) H3O+

:.. Acid halides have

a larger enol contentthan ketones.

Double bonds reactwith bromine!

Resonance increases the electrondensity in the double bond. Enolsare more reactive than alkenes.

Synthesis ofSynthesis of AminoacidsAminoacids and aand a--HydroxyacidsHydroxyacids

CH CO

OHBr

NH3 CH CO

OHNH2

+

phenylalanine

CH CO

OHCH3

BrCH C

OOHCH3

OH

NaOH

lactic acid

neutralization step not shown

REFORMATSKY REACTIONREFORMATSKY REACTION

A COUSIN TO THE GRIGNARD REACTION

Reformatsky ReactionReformatsky Reaction

CH CO

OHRBr

CH CO

ORBr

CH2CH3

α-bromoester

Zn, ether

CH CO

ORZnBr

CH2CH3

Reformatskyreagent

Reacts like a Grignard reagent!

CH CO

ORC

CH2CH3

CH3 OHH

CCH3 HO1)

2) H3O+

FischerEsterificationor via theacid chloride

ENOL CONTENTENOL CONTENT

C CH

OC C

OH

K

KetoKeto--Enol TautomerismEnol Tautomerism

keto enol

For most ketones, the keto formpredominates in the equilibrium

AS A GENERAL RULE: ENOLS ARE AS A GENERAL RULE: ENOLS ARE UNSTABLEUNSTABLE

C C

O Hol

ene

ENOLS :( have -OH attached to a double bond)Think of this combination as unstable.

OH

Phenols are not “enols” and they arevery stable (benzene resonance).

NOTE :

H3C C

O

CH2

H

C CH2H3C

O H

TAUTOMERISMTAUTOMERISMTAUTOMERS :

species inequilibriumthat differ inthe positionof a proton orother group.

enol

keto

ENERGY

Most enols are not favored,

unstable enol

To interconvert tautomers,a proton is transferred from oxygen to carbon.

ENOL KETO

they rapidly change to keto.

Mechanism, nextslide…..

TautomerismTautomerism is Catalyzed by Traces of is Catalyzed by Traces of Either Acid or BaseEither Acid or Base

C CH

O

C CO

H

C CO

C CO

H-O

H-OH

..

..: :

..:

..:

: :

keto

enol

BASECATALYSIS

-

-

enolateion

-:....

resonance structures

H-O -:.... +

..:

TautomerismTautomerism is Catalyzed by Traces of is Catalyzed by Traces of Either Acid or BaseEither Acid or Base

C CH

OC C

O

H

H

C CO

H

O-HH

:

....:

keto

enol

ACIDCATALYSIS

H-O-HH

..

..:

+

+

H-O-HH ++..

:

+OH H

H

C CH2H3C

OH

H3C C

O

CH2

HC CH2H3C

OH

H

O H

H

+C CH2H3C

OH

H

C CH2H3C

O H

H

+

+

OH H

H+

CONVERSION OF AN ENOL TO A KETONECONVERSION OF AN ENOL TO A KETONE

ENOL

KETONE

( catalyzed by small amounts of acid )

O OH

OCCH3 CH3 CH2 C CH3

OH

CH2 CH C CH3

OCH2 CH C CH2

OH

EnolEnol Percentages are LowPercentages are Lowin Most Ordinaryin Most Ordinary KetonesKetones

4.1 x 10-4 %

< 2 x 10-4 %

2.5 x 10-3 %

FACTORS THAT STABILIZE FACTORS THAT STABILIZE THE ENOL FORMTHE ENOL FORM

…… increasing the amount in the equilibrium

OH

O

RRH

OH

O

R RH

MOSTLY RESONANCEMOSTLY RESONANCE

Resonance helps stabilize the enol.

Phenyl substituents R also help to stabilize the enol by extending the resonance system.

Equivalent R groups results in symmetrywhich also stabilizes the enol.

(i.e., equivalent resonance contributors )

1.

2.

3.

CH3 C CH2 C HO O

CH3 C C C HOH O

CH3 C CH2 C CH3

O OCH3 C C C CH3

OH O

CH3 C CH2 C OC2H5

O OCH3 C C C OC2H5

OH O

EnolEnol Percentages in 1,3Percentages in 1,3--DiketonesDiketonesare Higherare Higher

98 %

80 %

8 %

ENOLS ARE MORE ACIDIC THAN THEIR KETO FORM

MAKE COMPLEXES WITH FeCl3 (like phenols)

ENOLS ARE NUCLEOPHILIC / REACT RAPIDLY WITH X2

ARE AN IMPORTANT INTERMEDIATE IN ACID-CALTALYZED ALDOL CONDENSATIONS

SOME ADDTIONAL PROPERTIES OF ENOLS

Discussed in class (if time).