ALDEHYDES AND KETONES

Aldehyde

Ketone

O

CR H

R = H, alkyl, aryl

O

CR R'

R and R' = alkyl or arylR and R' cannot be hydrogen!

STRUCTURE

NOMENCLATURENOMENCLATURE

• Choose the longest continuous carbon chain that contains the carbonyl carbon

• Number from the end of the chain closest to the carbonyl carbon

• Ketone ending is -one

IUPAC Nomenclature of KetonesIUPAC Nomenclature of Ketones

Do the ketones section of Organic Nomenclature program!

CH3

CCH2

CH2CH3

O

2-Pentanone

EXAMPLES

O

CCH2 CH

CH3 CH2

CH2

CH3

CH3

4-Ethyl-3-hexanone

O

CH

CH3

CH3

3-Isopropylcyclopentanone

or 3-(1-Methylethyl)cyclopentanone

Common, or Trivial, Common, or Trivial, NamesNames

• Name each group attached to the carbonyl group as an alkyl group

• Combine into a name, according to the pattern:

alkyl alkyl’ ketone

NOTE: This is not all one word!

KETONESKETONES

CH3

CCH2

CH2CH3

O

Methyl propyl ketone

Example of Common NamesExample of Common Names

O

CCH2 CH2

CH3 CH3

Diethyl ketone

O

CCH3 CH3

acetone

dimethyl ketone

A common laboratorysolvent and cleaningagent

SPECIAL CASESSPECIAL CASES

C

O

benzophenone

diphenyl ketone

C

O

CH3

acetophenone

methyl phenyl ketoneKNOWTHESE

• Choose the longest continuous carbon chain that contains the carbonyl carbon

• Number from the end of the chain closest to the carbonyl carbon (carbon #1!)

• Aldehyde ending is -al

IUPAC Nomenclature of AldehydesIUPAC Nomenclature of Aldehydes

Do the aldehydes section of Organic Nomenclatureprogram.

EXAMPLES

CH3

CH2CH2

CH2C

O

Hpentanal

CH3CH

CHC

O

HCH3

Cl

2-chloro-3-methylbutanal

12

34

always carbon 1aldehyde group is

O

CH H

O

CCH3 H

O

CCH2 HCH3

O

CC HCH2CH3

O

CC HCH2CH2CH3

O

CCH2 HCH2CH2CH2CH3

Formaldehyde Acetaldehyde Propionaldehyde

Butyraldehyde Valeraldehyde

Caproaldehyde

1 2 3

4 5

6

Common Names of the AldehydesCommon Names of the Aldehydes

RECOGNIZE THESE

O

CH H

O

CH CH3

C

O

H

SPECIAL CASESSPECIAL CASES

formaldehyde

acetaldehyde

benzaldehyde

KNOWTHESE

C

C C C C C C H

O

Forming Common Names of AldehydesForming Common Names of Aldehydes

CHO

Cl

-chlorocaproaldehyde

( -chlorohexanal )

CHO

Cl

-chlorocaproaldehyde

( -chlorohexanal )

USE OF GREEK LETTERS

…….

is always the end of the chain, no matter how long

REACTIVITY OF THE C=O GROUPREACTIVITY OF THE C=O GROUP

NUCLEOPHILIC ADDITION

O

C

..:+

- O

C

..::-

+

THE CARBONYL GROUPTHE CARBONYL GROUP

electrophilic at carbon

nucleophilicat oxygen

Nu:

nucleophiles attack here

H+ or E+electrophiles add here

GENERALIZED CHEMISTRY

STEREOCHEMISTRYSTEREOCHEMISTRY

C O..

..

. .

THE CARBONYL GROUP IS PLANAR THE CARBONYL GROUP IS PLANAR (SP(SP22 HYBRIDIZED) HYBRIDIZED)

nucleophiles can attack from either top or bottom

Nu:

Nu:

LUMO OF FORMALDEHYDELUMO OF FORMALDEHYDE

Nu:

*

CO

CH

CO

CH

(LUMO)

C O

H

H

:..

nO

nucleophiles addto the larger lobe(on carbon)

H H

– Relative Reactivity: Aldehydes versus Ketones• Aldehydes are generally more reactive than ketones

– The tetrahedral carbon resulting from addition to an aldehyde is less sterically hindered than the tetrahedral carbon resulting from addition to a ketone

– Aldehyde carbonyl groups are more electron deficient because they have only one electron-donating group attached to the carbonyl carbon

NUCLEOPHILIC ADDITION TO C=ONUCLEOPHILIC ADDITION TO C=O

MECHANISMS

IN ACID AND IN BASE

+ :Nuslow

::..

:_

O

CC

O

Nu

:..

:

C

O

Nu

+ H2O

:..

C

O

Nu

Hfast

_

..

Nucleophilic Addition to CarbonylNucleophilic Addition to CarbonylBasic or Neutral SolutionBasic or Neutral Solution

analkoxideion

BASIC SOLUTIONGood nucleophilesand strong bases(usually charged)

-

or on adding acid

+:Nu

slow:

..

O

C

H

C

O

Nu

H+

O

C

H:O

C+ H

+fast

+:..

..

Nucleophilic Addition to Carbonyl Nucleophilic Addition to Carbonyl Acid CatalyzedAcid Catalyzed

Acid catalysis speeds the rate of addition of weak nucleophiles and weak bases (usually uncharged).

more reactive toaddition than the un-protonated precursor

ACIDIC SOLUTION

(+)

pH 5-6stronger acidprotonates thenucleophile

CYANOHYDRINSCYANOHYDRINS

+ CN_

R C R

O

R C R

O

CN

R C R

O

CN

+ R C R

O

CN

H

: : : :

: : :

..

..

_

_..

OH2

A cyanohydrin

Addition of CyanideAddition of CyanideBuffered to pH 6-8

In acid solution there would be little CN-, and HCN (g) would be a problem (poison).

a cyanohydrin

:C N:

N

N

N

N

CH3

CH3

CH2CH2COOHCH2CH2COOH

CH3

CH3

Fe

C

N..

CYANIDE ION BONDS TO HEMOGLOBINCYANIDE ION BONDS TO HEMOGLOBIN

Cyanide bonds (irreversibly) to thesite (Fe II) whereoxygen usually bonds.

CYANIDE ISIS A POISON

You die ofsuffocation -lack of oxygen.

HCN is a gas that you can easily breathe into your lungs.

..

SYNTHESIS OF SYNTHESIS OF -HYDROXYACIDS-HYDROXYACIDS

CH3

OC

OH

C

CH3

N

C

OH

C

CH3

OOH

SYNTHESIS OF AN SYNTHESIS OF AN -HYDROXYACID-HYDROXYACID

1) NaOH/H2O/2) H3O+

NaCN

pH 8

acetophenone

a cyanohydrin

Aldehydes also work unless they are benzaldehydes,which give a different reaction (benzoin condensation).

HYDROLYSIS OF THE HYDROLYSIS OF THE NITRILE GROUPNITRILE GROUP

C=O + NaCN C-OH

R-X + NaCN R-CN + NaXacetone

SN2

CN

SYNTHESIS OF NITRILES (AND CYANOHYDRINS)SYNTHESIS OF NITRILES (AND CYANOHYDRINS)

REVIEWREVIEW

….. both can be hydrolyzed

cyanohydrin

nitrile

+NaOH

H2O/C N R R C

O

O Na:NH3..

..

..:

: +-

HYDROLYSIS OF THE CYANO GROUP (NITRILES)HYDROLYSIS OF THE CYANO GROUP (NITRILES)

METHOD ONE : strong base + H2O + heat

gas

H3O+

R CO

O H....

..: R-CN

R-COOH

synthesis ofcarboxylic acids

OVER ALL

Nitriles are hydrolyzed to carboxylic acids.

neutralize

METHOD TWO : strong acid + H2O + heat

C N R R CO

O H(NH4)2

SO4+....

..:H2SO4

H2O/

no mechanismat this time

HYDROLYSIS OF THE CYANO GROUP (NITRILES)HYDROLYSIS OF THE CYANO GROUP (NITRILES)

R-CN

R-COOH

OVER ALL

Nitriles are hydrolyzed to carboxylic acids.

synthesis ofcarboxylic acids

HYDRATESHYDRATES

+ H2O

O

CR R'

R C R'

O

O

H

H

a hydrate

H+

hydrates are unstableand cannot be isolatedin most cases

Addition of WaterAddition of Water

most hydrates revert to an aldehyde or ketone as soon as they form

aldehyde or ketonefavored

+ H2O

O

CR R'

R C R'

O

O

H

H

• Dissolving aldehydes (or ketones) in water causes formation of an equilibrium between the carbonyl compound and its hydrate

– The hydrate is also called a gem-diol (gem i.e. geminal, indicates the presence of two identical substituents on the same carbon)

– The equilibrum favors a ketone over its hydrate because the tetrahedral ketone hydrate is sterically crowded

O H

O HH

C

O

OHH

HO

C

O

OH

H

OH

H

H

O HH O

HH

H

.. ..

....

.. ..

..

....

..

: : : :

:

+

+

+ a hydrate

WATER ADDS TO THE CARBONYL GROUP OF WATER ADDS TO THE CARBONYL GROUP OF ALDEHYDES AND KETONES TO FORM HYDRATESALDEHYDES AND KETONES TO FORM HYDRATES

for most compounds the equilibrium favors the starting materials and you cannot isolate the hydrate

catalyzed by atrace of acid

In a reaction where all steps arereversible, the steps in the reversereaction are the same as those inthe forward reaction, reversed!

MICROREVERSIBILITY:

..+

O HO

OH

H

H

..: :

+

+

..

ACID CATALYSISACID CATALYSIS

O H

+

..:

:NuAcid catalysis enhances the reactivityof the carbonyl group - nucleophilicaddition proceeds more easily.

weak nucleophilescan react

RECALL

an excess of H2O18

shifts the equilibriumto the right

R C

O

R

OH

H

O

R ROH2

O

R R

ISOTOPE EXCHANGE REVEALS THE PRESENCE ISOTOPE EXCHANGE REVEALS THE PRESENCE OF THE HYDRATEOF THE HYDRATE

18

18

18

+ H+

exchange shows the presence of a symmetricintermediate

+H2O18 -H2O

OH

OHO

CCl

Cl

Cl HOH

OHC

O

HCl

Cl

Cl

SOME STABLE HYDRATESSOME STABLE HYDRATES

chloral chloral hydrate

cyclopropanone cyclopropanone hydrate

120o expected60o required

109o expected60o required

sp2 sp3

+

these also indicate that hydrates are possible

SOME ADDITIONAL STABLE HYDRATESSOME ADDITIONAL STABLE HYDRATES

C CH

O

HOH

OHC C

O

HH

O

C C

O

HPh

O

C CPh

O

HOH

OH

glyoxal

phenylglyoxal

ACETALS ANDACETALS ANDHEMIACETALSHEMIACETALS

R C R'

O

ROH R C

O

R'

O

H

R

R C

O

R'

O

H

R

ROH R C

O

R'

O

R

R

+

+ H O

H

+

Addition of AlcoholsAddition of Alcohols

addition of one mole

addition of second mole

hemiacetal

an acetal

H+

H+

TWO MOLES OF ALCOHOL WILL ADD

C O

R

H

C

R

H

OH

ORC

R

H

OR

OR

C

R

R

OR

ORC

R

R

OH

ORC O

R

R

ROH

ROH

ROH

ROH

aldehyde

ketone

hemiacetal acetal

(ketal)*(hemiketal)*

ACETALS AND HEMIACETALSACETALS AND HEMIACETALS

*older term *older term

hemiacetal

C

O

R R

H O

R

H

C

O

R R

H

OH R

C

O

R R

H

RHO

C

O

R R

H

RO

ORH

.. ..

..

..

..

..

..

..

..

: : :

:

:

:

++

+

..R O

H

H+

ACID CATALYZEDACID CATALYZEDFORMATION OF AFORMATION OF AHEMIACETALHEMIACETAL

ROH H2SO4 R O H

H

+ +

..

+

Normally the startingmaterial is favored -but a second moleculeof alcohol can reactif in excess (next slide)

Like a hydroniumion

firstaddition

acetal

H O

R

H

OR

H

C

O

R R

H

RO

ORH

C

O

R R

H

RO

H

CR R

RO

C

O

R R

R

RO

H

C

O

R R

R

RO

O HH

ORH

H

:....

....

.. :::

:..

..

..

..

..

....

..

:

::

:

:

CR R

RO: :+

+

+

+ +

+

FORMATION OF THE ACETAL ( FORMATION OF THE ACETAL ( from the hemiacetal ) )

Resonancestabilizedcarbocation

SN1

second addition

hemiacetal

remove

WATER SEPARATORWATER SEPARATOR

AZEOTROPE

Two miscible liquids that distillas a single substance with aboiling point that is lower thaneither of the original liquids.

benzene 80o Cwater 100o Cbenzene-water azeotrope

69.4o C

when cooled, the azeotrope separates

benzene and water do not mix,but in the azeotrope the vapors(gases) mix and distill together

benzene

water

benzene+ water

Az

C

O

R R

H

RO

ORH

C

O

R R

R

RO

O HHC

O

R R+

2

+

Removal of watershifts equilibrium

REMOVAL OF WATER SHIFTS THE EQUILIBRIUMREMOVAL OF WATER SHIFTS THE EQUILIBRIUM( Le Chatelier Principle )

starting materialsare favored

STABILITY OF ACETALS AND HEMIACETALSSTABILITY OF ACETALS AND HEMIACETALS

Most hemiacetals are not stable, except for those of sugars(see later).

Acetals are not stable in aqueous acid, but they are stable to aqueous base.

COR

ORC O

ROH

ROH

COR

OR

AQUEOUSACID

AQUEOUSBASE no reaction

H2SO4

H2O

H2O

NaOH

+

CYCLIC ACETALSCYCLIC ACETALS

+

2 CH3OH

dry acidCH3 C CH3

O

CH3 C CH3

O

O

CH3

CH3

Dry acid = HCl gas HCl in methanol HOTs

Formation of 2,2-DimethoxypropaneFormation of 2,2-Dimethoxypropane

dry acid = HCl gas or p-toluenesulfonic acid

CH3 S OH

O

O

HCl (g)

remove H2O

THIS IS A NON-CYCLIC ACETAL

(TsOH)

mp 106oC

CYCLIC ACETALSCYCLIC ACETALSCyclic acetals can be formed if a bifunctional alcohol is used.

C

O

CH3

CH2 CH2

OH OH CH2 CH2

O O

CCH3

1,2-ethanediol

acetophenoneH2O

H+/ benzene

OSHSH SS

H2O

H+/ benzene

1,3-propanedithiol

PROTECTING GROUP STRATEGYPROTECTING GROUP STRATEGY

TARGET NON-TARGET

TARGET NON-TARGET

NON-TARGET NEWGROUP

NON-TARGET NEWGROUP

Add Protecting Group

React UnprotectedGroup

RemoveProtectingGroup

Functional Group 1 Functional Group 2

UnchangedChanged

O

Br Br

OO

MgBr

OO

COOMgBr

OOO

COOH

USE OF A CYCLIC ACETAL AS A PROTECTING GROUPUSE OF A CYCLIC ACETAL AS A PROTECTING GROUP

The GrignardReaction TakesPlace in BasicSolution - TheAcetal is Stable

H3O+

Acetals Hydrolyzein Acidic Solution

SUMMARYSUMMARY

H2O

hydrate

hemiacetal acetal

R-O-H

H2O

R-O-H

ADDITION OF WATER AND ALCOHOLSADDITION OF WATER AND ALCOHOLS

WATER

ALCOHOLS

C

OOH OR RO OR

C

OOH OH

RO OR OROH+2

no reactionNaOHH2O

H2OH+ acetals are

stable to basebut not toaqueous acid

cyclic hemiacetal

R-O-H

H2O

cyclic acetal

C

OO O

CH2 CH2

OH OH cyclicacetal

H2O

C

O

OHO

OH

O

OR

OFTEN USEDAS A PROTECTIVEGROUP

STABLE IF FORMED FROM ACARBOHYDRATE

A STARCH OR“POLYSACCHARIDE”IF FORMED FROMCARBOHYDRATES

CYCLIZATIONSCYCLIZATIONS

Tuliskan mekanisme dan produk dari reaksi berikut:

H

O

HO1.H+

2.H+

O

HOCH2CH2OH

ADDITIONS OF AMINES ADDITIONS OF AMINES TO CARBONYL GROUPSTO CARBONYL GROUPS

Aldehydes and Ketones

MANTRAMANTRA

Reactions with C=O :

Primary amines yield imines

Secondary amines yield enamines

Tertiary amines do not react

we will come back to this again and again

N HR

H

N HR

R

N RR

R

primary secondary tertiary

.. .. ..

(Memorization Jingle)

AMINES:

PRIMARY AMINESPRIMARY AMINES

IMINESIMINES

C

R

R

N G

O H

H

+.. HA

+ H2OC O

R

R

C

R

R

N GG NH2

an imine

Addition-Elimination:Addition-Elimination:The Formation of IminesThe Formation of Imines

Addition of the amineis followed by a lossof water (elimination).

primaryamine

Imines are compoundswith a C=N bond

G is a primaryalkyl group

.. a “carbinolamine”intermediate

C

OH

N

H

..+

ketone oraldehyde

+slow

G NH2C O

R

R

G N

H

H

C

R

R

O H G N

H

C OH

R

R

.. ..

..+ .. ..

..

.. fast +C

R

R

G N

H

O H

H

C

R

R

NG

H

Mechanism of Imine FormationMechanism of Imine FormationH-O

H

H-O-HH

+ H-O-HH

+proton exchangesacid-catalyzed

addition

loss of water (elimination)

..

+

H-O

H

NG C

R

R..

deprotonationH-O-H

H

+

an imine

+

weak base addition - acid catalyzed

1

2

+ + H2OC O

R

R

NH2 R C N

R

R

R..

an imine

Formation of Simple IminesFormation of Simple Imines

These reactions do not favor the formation of the imine unless:

- the product is insoluble (crystallizes or precipitates) or

- water is removed to drive the equilibrium

removeoverall result

Reactions occur fastest at pH 4-5 Mild acid facilitates departure of the hydroxyl group from the aminoalcohol intermediate without also protonating the nitrogen of the amine starting compound

Hydrolysis of Simple IminesHydrolysis of Simple Imines

++ H2O C O

R

R

NH2 RC N

R

R

R..

an imine

H3O+

In an excess of aqueous acid, simple imines hydrolyzeback to the aldehyde or ketone and the amine from which they were orginally formed …..

Imines that are not soluble, however, are difficult tohydrolyze.

REVERSAL

CRYSTALLINE IMINESCRYSTALLINE IMINES

HYDRAZONE AND OXIME DERIVATIVES

There are some special amines thatyield insoluble products (imines) that are easy to crystallize …..

CRYSTALLINE IMINESCRYSTALLINE IMINES

:NH2OH

R-NH-NH2

hydroxylamine

varioushydrazinecompounds

NHNH2

NO2

O2N2,4-dinitrophenyl- hydrazine

C NHNH2

O

NH2 semicarbazine..

....

shownbelow

+ + H2OC O

R

R

NH2 OH C

R

R

N OH..

an oximehydroxylamine

Formation of OximesFormation of Oximes

aldehydeor ketone

(usually crystallizes)

Formation of HydrazonesFormation of Hydrazones

+ + H2OC O

R

R

NH2 NH R C

R

R

N NH R..

a hydrazonea hydrazine

aldehydeor ketone

+

+ H2O

C O

R

R

NH2 NH NO2

NO2

C

R

R

N NH

NO2

NO2

..

2,4-dinitrophenylhydrazine

2,4-2,4-DinitrophenylhydrazonesDinitrophenylhydrazones2,4-dinitrophenylhydrazine

insolubleredred, orangeorange or yellowyellow precipitate forms a 2,4-DNP

2,4-dinitrophenylhydrazone

aldehydeor ketone

(precipitates)

+

+ H2O

C O

R

R

NH2 NH C NH2

O

C

R

R

N NH C NH2

O

..

semicarbazide

Formation of SemicarbazonesFormation of Semicarbazones

a semicarbazone

semicarbazine

aldehydeor ketone

(usually crystallizes)

DERIVATIVESDERIVATIVES

A derivative is a solid compound (formed from theoriginal compound) whose melting point can helpto identify the original compound.

CRYSTALLINE IMINES CAN BE USED AS DERIVATIVES

2-undecanone 231 12 122 634-chloroacetophenone 232 12 204 2364-phenyl-2-butanone 235 - 142 127

bp mpketones

semicarbazone2,4-dinitrophenyl- hydrazone

What you will see in the tables of unknowns:

BIOLOGICAL REACTIONSBIOLOGICAL REACTIONS

Pyridoxyl-5’-phosphate (P-5’-P)Pyridoxyl-5’-phosphate (P-5’-P)

N

H

OH

CH3

C HO

CH2OP

O

O

OH

Converts amino acids to -ketoacids, and vice versa.Biologically important in transamination reactions.

NH2 C

H

R

O

OH

..

N C

H

R

O

OH

N

H

OH

CH3

CH

R

- H2O

first imine

pyridoxyl-5’-phosphate

an amino acid

+

+

( P-5’-P )

formation ofthe imine

continued

N C

H

R

O

OH

N

H

OH

CH3

CH

R

N C

R

O

OH

N

H

OH

CH3

C

R

H

H

NH2

N

H

OH

CH3

CH2

R

C COH

R

O O

tautomerism

-ketoacid

pyridoxamine

H2O

:EnzEnz-H

H-Enz

Enz:

C COH

R

O O

CH COH

R

O

NH2

+

+

+

converts

hydrolysis ofthe new imine

first imine

new imine

Removing theamino group

NH2

N

H

OH

CH3

CH2

R

C COH

R

O Oa different-ketoacid

pyridoxamine

N C

R

O

OH

N

H

OH

CH3

C

R

H

H

tautomerism

hydrolysis of the imine

NH2 C

H

R

O

OH

TRANSFERRING THE AMINO GROUPTRANSFERRING THE AMINO GROUP

a differentamino acid

These steps are thereverse of those onthe previous slides.

SUMMARYSUMMARY

Amino Acid-1 + pyridoxyl-5’-phosphate -Ketoacid-1 +

pyridoxamine

-Ketoacid-2 + pyridoxamine Amino Acid-2 +

pyridoxyl- 5’-phosphate

( takes NH2 group )

( gives NH2 back )

( has NH2 )

a different one reactshere

SECONDARY AMINESSECONDARY AMINES

ENAMINESENAMINES

R C C R

H

R

O

R C C R

H

R

OH

NR2

C C

R

R R

NR2

+ R2NHH

+

H+

+ H2O

Formation of EnaminesFormation of Enamines

an enamine

..

generally removedby azeotropicdistillation

secondaryamine

-hydrogenis required

benzene

“carbinolamine”

C

R

R

N G

O H

H

..R C C R

H

R

OH

NR2

imine enamine

..

PRIMARY AMINESPRIMARY AMINES SECONDARY AMINESSECONDARY AMINES

-H2O -H2O no hydrogenon nitrogen

hydrogenon thenitrogen

COMPARISONCOMPARISON

hydrogen on theadjacent carbon

When there is no hydrogen onnitrogen, one is lost from carbon.

carbinolamine intermediates

SOME SECONDARY SOME SECONDARY AMINES FREQUENTLY AMINES FREQUENTLY USED TO FORMUSED TO FORMENAMINESENAMINES

N

H

N

H

N

O

H

piperidine

pyrrolidine

morpholineWater must be removed

1)

R C C R

H

R

O

R C C R

H

R

O H

R C C R

H

R

O H

: :

+ H+

+.. ..

:

+

2)

R C C R

H

R

O H+..

..

slow

N H

R R

+

:..

:

+..

R C C R

H

R N

R R

H

O H

R C C R

H

R

OH2

N

R R

Enamine FormationEnamine Formation

H-O-HH

+

H-O-HH

+

H

O-H

continued ….

MECHANISM

3)

:

+..

:

+

+

+

4)

: :

+ H+

R C C R

H

R

OH2

N

R R

R C C R

H

R N

R R

+ H2O

N

R R

R C C R

R

R C C R

H

R N

R R

R C C R

H

R N

R R

Enamine Formation (cont)Enamine Formation (cont)

enamine

O-HH

H3O+

H2O

+

water mustbe removedto force theequilibrium

MECHANISM

+

2)

C C

R

R R

N

R

R

C C

R

R R

N

R

R: +..

_

Nucleophilic Character of EnaminesNucleophilic Character of Enamines

nucleophilicat carbon

C

X

SN2

SN2

Reactions of Enamines as NucleophilesReactions of Enamines as Nucleophiles

an iminium salt

hydrolysis

R C C R

R

R

O

R C C R

R

H

O

C C

R

R R

N

R

R:

R X

R C C R

R

R

N

R R

R C C R

R

R

N

R R

+

+

:

+ X_

alkylation

O

NH

N N

CH3

OH2

CH3I

O

CH3

NH

..

..

+H+

+

H3O+

ALKYLATION OF A KETONEALKYLATION OF A KETONE

pyrrolidine

iminiumsalt

enamine

removewater

workup

Az

1)

R C C R

O

R

R

H H

N

R R

R C C R

O

R

R H

N

R R

H

R C C R

O

R

R H

..

..OH H

+

slow

:+

+

..:

+

..:

2)

N

R R

H+..

+..

R C C R

R

R

N

R R

:

N

R R

H

R C C R

O

R

R H

Hydrolysis of Iminium SaltsHydrolysis of Iminium Salts

continued ….

H-O-HH

+

H

O-H

MECHANISM

3)

R C C R

O

R

R H+..

R C C R

O

R

R

+

: :

H3O+

H

O-H

Hydrolysis of Iminium SaltsHydrolysis of Iminium SaltsMECHANISM

CC

R

RR

N

R

R

CC

R

RR

N

R

R

:

+..

_

R X

enamine

CH CH2CH2X

C CH3CH2X

O

C OCH2X

O

CH3

X CH2CH3

CCl CH3

O

CCl O

O

CH2CH3

SUBSTRATES FOR ENAMINE ALKYLATION SUBSTRATES FOR ENAMINE ALKYLATION (and acylation)

acylation

alkylation

primarysecondaryallylic

C ClR

O

C ClRO

Oacyl compoundsmay be used

X = Cl, Br, I

C ClR

O

C ClRO

O

many students assume that if acid chlorides are good the acid bromides and iodides must be better.

However …… acid bromides and iodides are difficult toprepare, and the iodides are quite unstable

….. you should use the chlorides.

In SN2 reactions you learned the rate sequence R-I > R-Br > R-Cland that iodides are better substrates than chlorides.

This is true.

Based on this knowledge …..

CHLORIDES, BROMIDES AND IODIDESCHLORIDES, BROMIDES AND IODIDES

They are easily prepared from the acid by: R-COOH + SOCl2

O

O

R

R2NH

H+

R X

H2O+H

+N

R R

N

R R

R

Enamine Reactions -- SummaryEnamine Reactions -- Summary

secondaryamine

alkyl oracylhalide

TERTIARY AMINESTERTIARY AMINES

DO NOT REACTDO NOT REACT

C

R

R

N R

O H

H

..

R C C R

H

R

OH

+

R C C R

H

R

OH

loses H from N

loses H from C

:..

unstablereverses

PRIMARY AMINE

SECONDARY AMINE

TERTIARY AMINE

N R

H

H

N-R

R

:

N-R

RR

N R

R

H

N R

R

R

COMPARISONCOMPARISON

H is lost to form intermediate

H is lost

no H to lose

You need to lose two H’s,one to form the intermediate,one to eliminate water.

The tertiary amine can’tform the carbinolamineintermediate becauseit lacks an H on N.

FORMING RINGSFORMING RINGS

SOME GUIDELINES

NH2

NH2

O CH

H+

N

N

CH2

CH2

NH

NHCH2

DILUTE SOLUTION AND EXACT STOICHIOMETRYDILUTE SOLUTION AND EXACT STOICHIOMETRYFAVOR RING FORMATIONFAVOR RING FORMATION

Excess formaldehyde (>2:1)and a more concentratedsolution favor the diimime.

1:1 molar ratio anddilute solution favorthe ring formation

In dilute solution the molecule is morelikely to react internally with itselfbecause encounters with other moleculeswill be less frequent.

Also rememberthat unstrained5- and 6-rings form easily,other sizes aredifficult.

pH = 5

HINT ON THE MECHANISM …..HINT ON THE MECHANISM …..

C=N can undergo additions just like C=O

N

NH2

CH2

H

..

+

forms ring

CRUCIALSTEP

Both are polar multiple bondsand both can undergo acid-catalyzed nucleophilic addition.

….. see if you can figure out the rest of the mechanism for Problem 16-18 on your own.

protonationfirst

pH 5

mildlyacidic

WITTIG REACTIONWITTIG REACTION

YlideYlideA compound or intermediate with both a positive and a negative charge on adjacent atoms.

X Y..- +

Betaine or ZwitterionBetaine or Zwitterion

A compound or intermediate with both a positive and a negative charge, not on adjacent atoms, but in differentparts of the molecule. X

-Y

+

:

BOND

MOLECULE

+ (C6H5)3P+

R1 C

R2

X

H

(C6H5)3P C R2

R1

H

X_

(C6H5)3P C

R2

R1

Preparation of a Phosphorous YlidePreparation of a Phosphorous Ylide

strong base

:

O-CH3

-

P Ph

Ph

Ph..

Triphenylphosphine( Ph = C6H5 )

:....

( WITTIG REAGENT )

+ ..-

an ylide

benzene

heat

precipitates

ether

C

(C6H5)3P C

R

R

(C6H5)3P C

R

R+

_ ..

Resonance in YlidesResonance in Ylides

..

3d 2p

d-p BACKBONDING

Remember that Phosphorousis a Period III element (d orbitals).

Backbonding to phosphorousreduces the formal chargesand stabilizes the negativecharge on carbon.

P

..

INSOLUBLE

very thermodynamicallystable molecule

ylide betaine

+ -

The Wittig ReactionThe Wittig ReactionMECHANISM

synthesis ofan alkene

+

:..

:_ +

C O

R1

R2

(C6H5)3P C

R4

R3

R2 C

R1

O

C R4

R3

P(C6H5)3

+C

R1

R2

C

R4

R3

O P(C6H5)3

:..

R2 C

R1

O

C R4

R3

P(C6H5)3

oxaphosphetane(UNSTABLE)

H

CH3

CH3

CH2CH3 CH3

CH3

O

H

CH2CH3Br

H

H

CH2CH3(C6H5)3P

H

:P(C6H5)3

+

H

CH2CH3(C6H5)3P

:

+

CH3ONa-ylide

CH3

CH3

O

SYNTHESIS OF AN ALKENE - WITTIG REACTIONSYNTHESIS OF AN ALKENE - WITTIG REACTION

ANOTHER WITTIG ALKENE SYNTHESISANOTHER WITTIG ALKENE SYNTHESIS

C

H

Br

HO

CH2Br

:P(C6H5)3

C P(C6H5)3

H

HBr-

+

PhLi

..C P(C6H5)3

H

- +

ylide

: ..

+

+-

triphenylphosphineoxide (insoluble)

P(C6H5)3O

O

..

C

H

MuscalureMuscalure

CH2(CH2)11CH3CH3(CH2)6CH2

HH

(Z)-9-tricosene

Sex pheromone of thecommon house fly.Musca Domestica

CH3(CH2)6 C

O

HCl CH2(CH2)12CH3

Wittig The reaction can be made to give the cis alkene (Z) by correct choice of solvent and temperature, or by theseparation of a mixture of cis and trans.

ORGANOMETALLICSORGANOMETALLICS

+

(R-MgBr)

M

_+

H2O

H +

R M

O

CR R

R C R

O

R

R C R

O

R

H

+ M (OH)x

: : : :

:

..

..

(R-Li)

Addition of Organometallic ReagentsAddition of Organometallic Reagents

ether

These reagents cannot exist in acid solution

workupstep

alcohol

:R -

Synthesis of Alcohols

Summary of Reactions of Summary of Reactions of Organometallics with Organometallics with Carbonyl CompoundsCarbonyl Compounds

• Organometallics with ketones yield tertiary alcohols• Organometallics with aldehydes yield secondary alcohols• Organometallics with formaldehyde yield primary alcohols.• Organometallics with carbon dioxide yield carboxylic acids.

etc.

All reviewto you