16-1 Aldehydes & Ketones Chapter 16. 16-2 The Carbonyl Group In this and several following...

16-16-11

Aldehydes Aldehydes & &

KetonesKetones

Chapter 16

Chapter 16Chapter 16

16-16-22

The Carbonyl GroupThe Carbonyl Group

In this and several following chapters, we study the physical and chemical properties of classes of compounds containing the carbonyl group, C=O.• aldehydes and ketones (Chapter 16)

• carboxylic acids (Chapter 17)

• acid halides, acid anhydrides, esters, amides (Chapter 18)

• enolate anions (Chapter 19)

16-16-33

16.1 16.1 The Carbonyl GroupThe Carbonyl Group

• the carbonyl group consists of one sigma bond formed by the overlap of sp2 hybrid orbitals and one pi bond formed by the overlap of parallel 2p orbitals.

• pi bonding and pi antibonding MOs for formaldehyde.

16-16-44

StructureStructure

• the functional group of an aldehyde is a carbonyl group bonded to a H atom and a carbon atom.

• the functional group of a ketone is a carbonyl group bonded to two carbon atoms.

Propanone(Acetone)

Ethanal(Acetaldehyde)

Methanal(Formaldehyde)

O O O

CH3CHHCH CH3CCH3

16-16-55

16.2 16.2 A.A. NomenclatureNomenclature

IUPAC names:• the parent chain is the longest chain that contains

the functional group.

• for an aldehyde, change the suffix from -e-e to –al.–al.

• for an unsaturated aldehyde, change the infix from -an--an- to -en--en-; the location of the suffix determines the numbering pattern.

• for a cyclic molecule in which -CHO is bonded to the ring, add the suffix –carbaldehyde.carbaldehyde.

16-16-66

B.B. Nomenclature: Aldehydes Nomenclature: Aldehydes

the IUPAC retains the common names benzaldehyde and cinnamaldehyde, as well formaldehyde and acetaldehyde.

H

O

3-Methylbutanal 2-Propenal(Acrolein)

(2E)-3,7-Dimethyl-2,6-octadienal(Geranial)

1

2

3

4

5

6

7

8H

O

H

O

CHO HO CHO

Cyclopentane-carbaldehyde

trans-4-Hydroxycyclo-hexanecarbaldehyde

14

CHOC6H5

CHO

trans-3-Phenyl-2-propenal(Cinnamaldehyde)

Benzaldehyde

16-16-77

Nomenclature: KetonesNomenclature: Ketones

IUPAC names • the parent alkane is the longest chain that

contains the carbonyl group.

• indicate the ketone by changing the suffix -e-e to -one.-one.

• number the chain to give C=O the smaller number.

• the IUPAC retains the common names acetone, acetophenone, and benzophenone.

Propanone(Acetone)

Benzophenone 1-Phenyl-1-pentanoneAcetophenone

O O OO

16-16-88

Order of Precedence, Table 16.1Order of Precedence, Table 16.1

For compounds that contain more than one functional group indicated by a suffix.

16-16-99

C.C. Common Names Common Names

• for an aldehyde, the common name is derived from the common name of the corresponding carboxylic acid.

• for a ketone, name the two alkyl or aryl groups bonded to the carbonyl carbon and add the word ketone.

HCH

O

HCOH

O

CH3CH

O

CH3COH

O

Formaldehyde Formic acid Acetaldehyde Acetic acid

Ethyl isopropyl ketone Diethyl ketone Dicyclohexyl ketone

O OO

16-16-1010

16.3 16.3 Physical PropertiesPhysical Properties

Oxygen is more electronegative than carbon (3.5 vs 2.5) and, therefore, a C=O group is polar.

• aldehydes and ketones are polar compounds and interact in the pure state by dipole-dipole interaction.

• they have higher boiling points and are more soluble in water than nonpolar compounds of comparable molecular weight.

16-16-1111

Preparation of aldehydes and ketonesPreparation of aldehydes and ketones

Review of methods previously seen in 3010.

• Oxidation of alkenes with conc. KMnO4

• Oxidation of alkenes with O3

• Oxidation of 1o alcohols with PCC

• Oxidation of 2o alcohols with Na2Cr2O4 + H2SO4

• Oxidation of glycols with HIO4

• Hydroysis of alkynes

• Hydroboration/oxidation of alkynes

16-16-1212

16.4 16.4 Reaction Themes , Nu attack at CReaction Themes , Nu attack at C

One of the most common reaction themes of a carbonyl group is addition of a nucleophile to form a tetrahedral carbonyl addition compound.

Tetrahedral carbonyl addition compound

+ CR

R

O CNu

O -

RR

Nu -

16-16-1313

Reaction Themes , O attack at HReaction Themes , O attack at H

A second common theme is reaction with a proton or other Lewis acid to form a resonance-stabilized cation.• protonation increases the electron deficiency of

the carbonyl carbon and makes it more reactive toward nucleophiles.

B -

C OR

R

H-Nu

H-B

C OR

RH

B -

C OR

RH

CNu

O-H

RR

C OR

RH

H-B

+fast +

++

+slow

Tetrahedral carbonyl addition compound

++ +

16-16-1414

Reaction Themes, stereochemistryReaction Themes, stereochemistry

• often the tetrahedral product of addition to a carbonyl is a new chiral center.

• if none of the starting materials is chiral and the reaction takes place in an achiral environment, then enantiomers will be formed as a racemic mixture.

Nu-

C OR

R'

NuO

R'R

NuO

RR'

+H3O+

NuOH

RR'

NuOH

R'R

+

A racemic mixtureA new chiralcenter is created

Approach fromthe bottom face

Approach fromthe top face

16-16-1515

16.5 16.5 Addition of C NucleophilesAddition of C Nucleophiles

Addition of carbon nucleophiles is one of the most important types of nucleophilic additions to a C=O group.• a new carbon-carbon bond is formed in the

process.

• we study addition of these carbon nucleophiles.

RMgX RLi - C RC C - NA Grignard

reagentAn organolithium

reagentAn alkyne

anionCyanide ion

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A.A. Grignard Reagents Grignard Reagents

Given the difference in electronegativity between carbon and magnesium (2.5 - 1.3), the C-Mg bond is polar covalent, with C- and Mg+.• in its reactions, a Grignard reagent behaves as a

carbanion. Carbanion:Carbanion: an anion in which carbon has an

unshared pair of electrons and bears a negative charge.• a carbanion is a good nucleophile and adds to the

carbonyl group of aldehydes and ketones.

16-16-1717

Grignard Reagents, 1Grignard Reagents, 1oo alcohols alcohols

• addition of a Grignard reagent to formaldehyde followed by H3O+ gives a 1° alcohol.

• Note that these reactions require two steps.

CH3CH2-MgBr

O

H-C-H

O -[MgBr]+

CH3CH2-CH2 HClH2O

OH

CH3CH2-CH2 Mg2+

ether

1-Propanol(a 1° alcohol)

Formaldehyde

+

+

A magnesiumalkoxide

16-16-1818


• addition to any other aldehyde, RCHO, gives a 2° alcohol (two steps).

MgBr

H

O

O -[MgBr]

+

HClH2O

OH

Mg2+

+ether

Acetaldehyde(an aldehyde)

+

A magnesiumalkoxide

1-Cyclohexylethanol(a 2° alcohol;

(racemic)

16-16-1919


• addition to a ketone gives a 3° alcohol (two steps).

Ph-MgBrO

Ph

O -[MgBr]

+HClH2O Ph

OHMg2+

+

Acetone(a ketone)

ether

+

A magnesiumalkoxide

2-Phenyl-2-propanol(a 3° alcohol)

Phenyl-magnesium bromide

16-16-2020

Grignard ReagentsGrignard Reagents

Problem:Problem: 2-phenyl-2-butanol can be synthesized by three different combinations of a Grignard reagent and a ketone. Show each combination.

Work backwards to get starting materials.

C-CH2CH3

CH3

OH

16-16-2121

Grignard ReagentsGrignard Reagents

Problem:Problem: 2-phenyl-2-butanol can be synthesized by three different combinations of a Grignard reagent and a ketone. Show each combination.

Look at:

Acetophenone Propiophenone 2-butanone

+ EtMgBr + MeMgBr + PhMgBr

C-CH2CH3

CH3

OH

16-16-2222

B.B. Organolithium Compounds Organolithium Compounds

Organolithium compounds, RLi, give the same C=O addition reactions as RMgX but generally are more reactive and usually give higher yields.

Lithium is monovalent and does not insert between C and X like Mg.

Like the Grignard this requires two steps.

LiO

O- Li+

HClH2O

OH

3,3-Dimethyl-2- butanone

3,3-Dimethyl-2-phenyl-2-butanol(racemic)

+

Phenyl-lithium

A lithium alkoxide(racemic)

16-16-2323

C.C. Salts of Terminal Alkynes Salts of Terminal Alkynes

Addition of an alkyne anion followed by H3O+ gives an -acetylenic alcohol.

C:- Na+HC

OC O -Na+HC

HClH2O

C OHHC

1-Ethynyl-cyclohexanol

A sodiumalkoxide

+

CyclohexanoneSodiumacetylide

16-16-2424

Salts of Terminal AlkynesSalts of Terminal Alkynes

H2O

HO C CHH2SO4, HgSO4

1. (sia)2BH

2. H2O2, NaOH

O

HO CCH3

HO CH2CH

O

An -hydroxyketone

A -hydroxyaldehyde

Addition of water or hydroboration/oxidation

of the product gives an enol which rearranges.

16-16-2525

D.D. Addition of HCN Addition of HCN

HCN adds to the C=O group of an aldehyde or ketone to give a cyanohydrin.

Cyanohydrin:Cyanohydrin: a molecule containing an -OH group and a -CN group bonded to the same carbon.

2-Hydroxypropanenitrile(Acetaldehyde cyanohydrin)

+ HC N CH3C-C NCH3CH

OH

H

O

16-16-2626

Addition of HCNAddition of HCN

Mechanism of cyanohydrin formation:• Step 1: nucleophilic addition of cyanide to the

carbonyl carbon.

• Step 2: proton transfer from HCN gives the cyanohydrin and regenerates cyanide ion.

-• •

+H3C

CH3C

O CO -

H3C

H3C

CN

NC

CO -

H3C

H3C

C NNH C C

C

H3C

H3C

O-H

NC N++

-• •

16-16-2727

CyanohydrinsCyanohydrins

The value of cyanohydrins:• 1. acid-catalyzed dehydration of the alcohol gives

an alkene.

• 2. catalytic reduction of the cyano group gives a 1° amine.

Propenenitrile(Acrylonitrile)

+

acidcatalyst


CH3CHC N NCH2=CHC H2 O

OH

CHC

OH

N 2H2Ni

OH

CHCH2NH2

2-Amino-1-phenylethanol(racemic)

+

Benzaldehydecyanohydrin

(racemic)

16-16-2828

CyanohydrinsCyanohydrins The value of cyanohydrins:

• 3. acid-catalyzed hydrolysis of the nitrile gives a carboxylic acid.

2-Hydroxypropanoic acid

acidcatalyst


CH3CHC N CH3- CHCOOH H 2O

OHOH

16-16-2929

16.6 16.6 Wittig ReactionWittig Reaction

The Wittig reaction is a very versatile synthetic method for the synthesis of alkenes from aldehydes and ketones.

Triphenyl-phosphine oxide

Methylene-cyclohexane

A phosphoniumylide

++-+

CH2 Ph3P=OPh3P-CH2

Cyclohexanone

O

16-16-3030

Phosphonium Ylides (Wittig reagent)Phosphonium Ylides (Wittig reagent)

Phosphonium ylides are formed in two steps:• Step 1: nucleophilic displacement of iodine by

triphenylphosphine.

• Step 2: treatment of the phosphonium salt with a very strong base, most commonly BuLi, NaH, or NaNH2.

Ph3P CH3-I Ph3P-CH3 I

Triphenylphosphine

++

SN2

Methyltriphenylphosphonium iodide(an alkyltriphenylphosphine salt)

CH3CH2CH2CH2 - Li + H-CH2-PPh3 I-

- CH2-PPh3CH3CH2CH2CH3 LiI

A phosphoniumylide

Butane

Butyllithium++

+

++

16-16-3131

Wittig ReactionWittig Reaction

Phosphonium ylides react with the C=O group of an aldehyde or ketone to give an alkene.• Step 1: nucleophilic addition of the ylide to the

electrophilic carbonyl carbon.

• Step 2: decomposition of the oxaphosphatane.

CR2O

CH2Ph3P CH2

-:O CR2

Ph3P

O CR2

Ph3P CH2-+

An oxaphosphetane

+

A betaine

CH2

O CR2

Ph3PPh3P=O R2C=CH2

An alkene

+

Triphenylphosphineoxide

16-16-3232


• Examples:Examples:

O Ph3P + Ph3P=O

2-Methyl-2-heptene

+

Acetone

PhO

HPh3P Ph Ph Ph3P=O

Phenyl-acetaldehyde

+ ++

(Z)-1-Phenyl-2-butene(87%)

(E)-1-Phenyl-2-butene(13%)

PhO

H

OEtPh3P

OPh

OEt

O

Ph3P=O

Ethyl (E)-4-phenyl-2-butenoate(only the E isomer is formed)

++

Phenyl-acetaldehyde

16-16-3333


• some Wittig reactions are Z selective, others are E selective.

• Wittig reagents with an anion-stabilizing group, such as a carbonyl group, adjacent to the negative charge are generally E selective.

• Wittig reagents without an anion-stabilizing group are generally Z selective.

OEtPh3P

O

OEtPh3P

O

Resonance contributing structures for an ylide stabilized by an adjacent carbonyl group

16-16-3434

Wittig Reaction Modification - Wittig Reaction Modification - OmitOmit

Horner-Emmons-Wadsworth modification:• uses a phosphonoester.

• phosphonoester formation requires two steps (see next slide).

Br-CH2-C-OEtO

(MeO)3PBr-CH2-C-R

O

(MeO)2P-CH2-C-ROO

(MeO)2P-CH2-C-OEtOO

MeBr

MeBran -bromoester

an -bromoketone

+

+

An -phosphonoester

An -phosphonoketone

Trimethyl-phosphite

16-16-3535


• phosphonoesters are prepared by successive SN2 reactions:

attack by the phosphite, then

attack by Br-

(MeO)3P CH2-C-OEtO

Br

CH3-O-P-CH2-C-OEtO

OMe

OMe

Br

(MeO)2P-CH2-C-OEtOO

MeBr

+

+

SN2

SN2

An -phosphonoester

16-16-3636


• treatment of a phosphonoester with a strong base produces the modified Wittig reagent,

• an aldehyde or ketone is then added to give an alkene.

• a particular value of using a phosphonoester-stabilized anion is that they are almost exclusively E selective.

(MeO)2P-CH2-C-OEt

OO

O

H

OEt

O

MeO-P-O-O

OMe

1. strong base

2.Only the E isomer

is formed

+

Dimethylphosphateanion

16-16-3737

16.7 16.7 A.A. Addition of HAddition of H22O, hydratesO, hydrates

Addition of water (hydration) to the carbonyl group of an aldehyde or ketone gives a geminal diol, commonly referred to a gem-diol.

gem-diols are also referred to as hydrates.

C O + H2O COH

OHCarbonyl groupof an aldehyde

or ketone

A hydrate(a gem-diol)

acid or base

16-16-3838

Addition of HAddition of H22O, hydratesO, hydrates

• when formaldehyde is dissolved in water at 20°C, the carbonyl group is more than 99% hydrated.

• the equilibrium concentration of a hydrated ketone is considerably smaller.

H

HO H2O+

Formaldehyde

H

H OH

OH

Formaldehyde hydrate(>99%)

O H2O+

2,2-Propanediol(0.1%)

Acetone(99.9%)

OHOH

16-16-3939

B.B. Addition of Alcohol, hemiacetals Addition of Alcohol, hemiacetals

Addition of one molecule of alcohol to the C=O group of an aldehyde or ketone gives a hemiacetal.

Hemiacetal:Hemiacetal: a molecule containing an -OH and an -OR or -OAr bonded to the same carbon.

O H-OEtOH

OEt+

acid orbase

A hemiacetal

16-16-4040

Addition of Alcohols, in baseAddition of Alcohols, in base

Formation of a hemiacetal can be base catalyzed.• Step 1: proton transfer gives an alkoxide.

• Step 2: attack of RO- on the carbonyl carbon.

• Step 3: proton transfer from the alcohol to O- gives the hemiacetal and generates a new base catalyst.

B - H OR B H - OR+ +

fast andreversible

CH3-C-CH3

O–:O-R

O:–

CH3-C-CH3

OR

+

O:–

CH3-C-CH3

OR

H OROR

OH

CH3-C-CH3- OR++

16-16-4141

Addition of Alcohols, in acidAddition of Alcohols, in acid

Formation of a hemiacetal can be acid catalyzed.Step 1: proton transfer to the carbonyl oxygen.

Step 2: attack of ROH on the carbonyl carbon..

Step 3: proton transfer from the oxonium ion to A- gives the hemiacetal and generates a new acid catalyst.

O

CH3-C-CH3 H-A

O

CH3-C-CH3

H

A-

+

+ +

fast andreversible

O

CH3-C-CH3

H

H-O-R CH3-C-CH3

O-H

ORH

++

+

RH

CH3-C-CH3

O

OH

OR

OH

CH3-C-CH3 H-A

A -+

+

16-16-4242

Addition of Alcohol, cyclic hemiacetalsAddition of Alcohol, cyclic hemiacetals

• hemiacetals are only minor components of an equilibrium mixture, except where a five- or six-membered ring can form.

(S)-4-Hydroxypentanal Cyclic hemiacetals(major forms present at equilibrium)

OHH

O

O OH O OH+4

1 14 14

OH

OH

OH

HOH

OOHO

OHHO

HOCH2OH

OH

HOCH2OH

O

OHHO OH

12

36

6

12

anomericcarbon

Anomer of D-glucose cyclic hemiacetal(predominatesat equilibrium)

Anomer of D-glucose cyclic

hemiacetal

+4

5

D-Glucose(open chain form)

1234 5

34 5

6

16-16-4343

Addition of Alcohol, cyclic hemiacetalsAddition of Alcohol, cyclic hemiacetals

• at equilibrium, the anomer of glucose predominates because the -OH group on the anomeric carbon is equatorial.

O

OHHO

OH

HOO

OHOH

HO

HOCH2OH

OHO

HO

HO

OH

O

OHHO

HOCH2OH

OH

1234 5

6

anomericcarbon

Anomer

anomericcarbon

132

4 56

(equatorial)

1234 5

6

anomericcarbon

Anomer of

anomericcarbon

13

2

4 56

(axial)

redraw asa chair

conformation

redraw asa chair

conformation

OH

OH

16-16-4444

Addition of Alcohols, acetalsAddition of Alcohols, acetals

Hemiacetals can react with alcohols to form acetals.

Acetal:Acetal: a molecule containing two -OR or -OAr groups bonded to the same carbon.

OH

OEtH-OEt

H+ OEt

OEtH2O

A diethyl acetal

+

A hemiacetal

+

16-16-4545


Step 1: proton transfer from HA gives an oxonium ion.

Step 2: loss of water gives a resonance-stabilized cation.

HO

R-C-OCH3

H

H A

HHO

H

R-C-OCH3 A:-+

An oxonium ion

+

+

R-C OCH3

H

OHH

H

R-C OCH3 R-C

H

OCH3 H2O+

A resonance-stabilized cation

++

+

16-16-4646


Step 3: reaction of the cation (an electrophile) with methanol (a nucleophile) gives the conjugate acid of the acetal.

Step 4: proton transfer to A- gives the acetal and generates a new acid catalyst.

CH3-OH

H

R-C OCH3 R-C OCH3

H

OCH3H

A protonated acetal

++

+

A:- R-C OCH3

H

OCH3H OCH3

H

R-C-OCH3 H-A+(4)

An acetal

+

+

16-16-4747

Addition of Alcohols, cyclic acetalsAddition of Alcohols, cyclic acetals

• with ethylene glycol and other glycols, the product is a five-membered cyclic acetal.

• these are used as carbonyl protective groups.

+ H+

HOOHO

O

O

Cyclic acetal

+ H2O

16-16-4848

Dean-Stark Trap, Fig. 16.1Dean-Stark Trap, Fig. 16.1

16-16-4949

C.C. Acetals as Protecting Grps Acetals as Protecting Grps

Suppose you wish to bring about a Grignard reaction between these compounds.

But a Grignard reagent prepared from 4-bromobutanal will self-destruct! (react with C=O)

5-Hydroxy-5-phenylpentanal(racemic)

4-BromobutanalBenzaldehyde

??+

H

O

H

OH

OH O

Br

16-16-5050

Acetals as Protecting GroupsAcetals as Protecting Groups

• So, first protect the -CHO group as an acetal,

• then do the Grignard reaction.

• Hydrolysis in H+, HOH (not shown) removes the acetal to give the target molecule.

H

OBr

A cyclic acetal

+H+

H2OHO

OH+ Br O

O

BrO

O1. Mg, ether

2. C6H5CHO

O

OO-MgBr+

A chiral magnesium alkoxide(produced as a racemic mixture)

16-16-5151

D.D. Acetals as Protecting Groups Acetals as Protecting Groups

Tetrahydropyranyl (THP), as a protecting group for an alcohol.

• the THP group is an acetal and, therefore, stable to neutral and basic solutions, and to most oxidizing and reducting agents.

• it is removed by acid-catalyzed hydrolysis.

RCH2OH +OO RCH2O

Dihydropyran A tetrahydropyranylacetal

H+

THP group

16-16-5252

16.8 16.8 A.A. Addition of Nitrogen NucleophilesAddition of Nitrogen Nucleophiles

Ammonia, 1° aliphatic amines, and 1° aromatic amines react with the C=O group of aldehydes and ketones to give imines (Schiff bases). An imine has a CH=N bond.

CH3CH H2N H+

CH3CH=N H2 O+ +

Acetaldehyde Aniline An imine(a Schiff base)

O

An imine(a Schiff base)

AmmoniaCyclohexanone

++ NH3 H2 OO NHH

+

16-16-5353

Addition of Nitrogen NucleophilesAddition of Nitrogen Nucleophiles

Formation of an imine occurs in two steps.Step 1: carbonyl addition followed by proton

transfer.

Step 2: loss of H2O and proton transfer to solvent.

C

O

H2N-R

H

H

C

O:-

N-RO

H

N-R

H

C++

O H

H

H HC

OH

N-R N-RH

C

OHH

OH

H

C N-R OH

H

H An imine

+

+

++

++H2O

16-16-5454


• a value of imines is that the carbon-nitrogen double bond can be reduced to a carbon-nitrogen single bond.

• imine formation:

• reduction:

+

Dicyclohexylamine

Cyclohexanone(An imine)

Cyclohexylamine

O N

N

H

-H2O

H2 / Ni

H+

H2N

(An imine)

N

16-16-5555


Rhodopsin (visual purple) is the imine formed between 11-cis-retinal (vitamin A aldehyde) and the protein opsin.

11

12

11-cis-Retinal Rhodopsin(Visual purple)

H2N-opsin

H N-opsinH O

+

16-16-5656


Secondary amines react with the C=O group of aldehydes and ketones to form enamines.

• the mechanism of enamine formation involves formation of a tetrahedral carbonyl addition compound followed by its acid-catalyzed dehydration.

• we discuss the chemistry of enamines in more detail in Chapter 19.

O H-NH

+

N H2 O

An enaminePiperidine(a secondary amine)

++

Cyclohexanone

16-16-5757

B.B. Addition of Nitrogen Nucleophiles Addition of Nitrogen Nucleophiles

• the carbonyl group of aldehydes and ketones reacts with hydrazine and its derivatives in a manner similar to its reactions with 1° amines.

O H2NNH2 NNH2 H2O+

Hydrazine

+

A hydrazone

H2N-NHCNH2

H2N-OH

H2N-NH

H2N-NH NO2

O2N

Reagent, H2N-R

Hydroxylamine Oxime

Phenylhydrazine

2,4-Dinitrophenyl-hydrazine

Semicarbazide

2,4-Dinitrophenylhydrazone

Semicarbazone

Name of Derivative FormedName of Reagent

Phenylhydrazone

O

Table 16.4

16-16-5858

16.9 16.9 A.A. Acidity of Acidity of -Hydrogens-Hydrogens

Hydrogens alpha to a carbonyl group are more acidic than hydrogens of alkanes, alkenes, and alkynes but less acidic than the hydroxyl hydrogen of alcohols.

CH3CH2O-HO

CH3CCH2-H

CH2=CH-HCH3CH2-H

CH3C C-H

Type of Bond pKa16

20

2544

51

16-16-5959

Acidity of Acidity of -Hydrogens-Hydrogens

-Hydrogens are more acidic because the enolate anion is stabilized by: 1. delocalization of its negative charge..

2. the electron-withdrawing inductive effect of the adjacent electronegative oxygen.

CH3-C-CH2-HO

:A-

O

CH3-C CH2

O -

CH3-C=CH2 H-A

Resonance-stabilized enolate anion

+ +

16-16-6060

Keto-Enol TautomerismKeto-Enol Tautomerism

• protonation of the enolate anion on oxygen gives the enol form; protonation on carbon gives the keto form.

Enolate anion

Enol formKeto form

-O

CH3-C-CH2 CH3-C=CH2

CH3-C=CH2

H-A

CH3-C-CH3 + A- A- +

H-AOH

O-

O

16-16-6161


• acid-catalyzed equilibration of keto and enol tautomers occurs in two steps.

Step 1: proton transfer to the carbonyl oxygen.

Step 2: proton transfer to the base A-.

O

CH3-C-CH3 H-A

O

CH3-C-CH3

H

A-+

+

+Keto form

• •

The conjugate acidof the ketone

fast andreversible

O

CH3-C-CH2-H

H

:A-

OH

CH3-C=CH2 H-A

Enol form

+

+

slow+

16-16-6262

B.B. Keto-Enol Tautomerism, Table 16.5 Keto-Enol Tautomerism, Table 16.5

Keto-enol equilibria for simple aldehydes and ketones lie far toward the keto form.

OH

O

O

CH3CH CH2=CH

CH3CCH3

Keto form Enol form% Enol atEquilibrium

6 x 10-5

OH

CH3C=CH2 6 x 10-7

O

O OH

OH

1 x 10-6

4 x 10-5

16-16-6363


For certain types of molecules, however, the enol is the major form present at equilibrium.• for -diketones, the enol is stabilized by

conjugation of the pi system of the carbon-carbon double bond and the carbonyl group.

• for acyclic -diketones, the enol is further stabilized by hydrogen bonding.

16-16-6464

16.10 16.10 A.A. Oxidation of AldehydesOxidation of Aldehydes

Aldehydes are oxidized to carboxylic acids by a variety of oxidizing agents, including H2CrO4.

They are also oxidized by Ag(I).• in one method, a solution of the aldehyde in

aqueous ethanol or THF is shaken with a slurry of silver oxide.

CHO H2CrO4 COOH

Hexanal Hexanoic acid

Vanillic acidVanillin

++CH

HO

CH3OO O

CH3O

HO

COH

Ag2OTHF, H2O

NaOHAgHCl

H2O

16-16-6565

Oxidation of AldehydesOxidation of Aldehydes

Aldehydes are oxidized by O2 in a radical chain reaction.• liquid aldehydes are so sensitive to air that they

must be stored under N2.

Benzoic acidBenzaldehyde

+CH

O O

COH2O22

16-16-6666

B.B. Oxidation of Ketones Oxidation of Ketones

• ketones are not normally oxidized by chromic acid

• they are oxidized by powerful oxidants at high temperature and high concentrations of acid or base.

Hexanedioic acid (Adipic acid)

Cyclohexanone(keto form)

Cyclohexanone(enol form)

HNO3

O

HOOH

OO OH

16-16-6767

16.11 16.11 ReductionReduction

• aldehydes can be reduced to 1° alcohols.

• ketones can be reduced to 2° alcohols.

• the C=O group of an aldehyde or ketone can also be reduced to a -CH2- group.

AldehydesCan Be

Reduced to KetonesCan Be

Reduced to

O OOH

RCHRCH2 OH

RCH3

RCR'RCHR'

RCH2 R'

16-16-6868

A.A. Metal Hydride Reduction Metal Hydride Reduction

The most common laboratory reagents for the reduction of aldehydes and ketones are NaBH4 and LiAlH4.

• both reagents are sources of hydride ion, H:-, a very powerful nucleophile.

Hydride ionLithium aluminum hydride (LAH)

Sodium borohydride

H

H H

H

H-B-H H-Al-HLi +Na+ H:

16-16-6969

NaBHNaBH44 Reduction Reduction

• reductions with NaBH4 are most commonly carried out in aqueous methanol, in pure methanol, or in ethanol.

• one mole of NaBH4 reduces four moles of aldehyde or ketone.

4RCHO

NaBH4

(RCH2O)4B- Na

+ H2O4RCH2OH

A tetraalkyl borateborate salts

+

+ methanol

16-16-7070

NaBHNaBH4 4 ReductionReduction

The key step in metal hydride reduction is transfer of a hydride ion to the C=O group to form a tetrahedral carbonyl addition compound.

Na+

H

H

H-B-H

O

R-C-R'

O BH3

H

R-C-R'

Na+

H2OO-H

H

R-C-R'

This H comes from waterduring hydrolysis

This H comes from thehydride reducing agent

+

16-16-7171

LiAlHLiAlH4 4 ReductionReduction

• unlike NaBH4, LiAlH4 reacts violently with water, methanol, and other protic solvents.

• reductions using it are carried out in diethyl ether or tetrahydrofuran (THF).

4RCR LiAlH4 (R2CHO)4Al- Li

+ H2O

H+ or OH-

OH

4RCHR+ +aluminum saltsA tetraalkyl

aluminate

etherO

16-16-7272

B.B. Catalytic Reduction Catalytic Reduction

Catalytic reductions are generally carried out at from 25° to 100°C and 1 to 5 atm H2.

+25 oC, 2 atm

Pt

Cyclohexanone Cyclohexanol

O OH

H2

1-Butanol trans-2-Butenal(Crotonaldehyde)

2H2

NiH

O

OH

16-16-7373

Catalytic ReductionCatalytic Reduction

A carbon-carbon double bond may also be reduced under these conditions.

• by careful choice of experimental conditions, it is often possible to selectively reduce a carbon-carbon double in the presence of an aldehyde or ketone.

1-Butanol trans-2-Butenal(Crotonaldehyde)

2H2

NiH

O

OH

O OHRCH=CHCR' RCH=CHCHR'

1. NaBH4

2. H2O

O

RCH=CHCR' H2Rh RCH2CH2CR'

O

+

16-16-7474

C.C. Clemmensen Reduction, in acid Clemmensen Reduction, in acid

• refluxing an aldehyde or ketone with amalgamated zinc in concentrated HCl converts the carbonyl group to a methylene group.

Zn(Hg), HClOH O OH

16-16-7575

Wolff-Kishner Reduction, in baseWolff-Kishner Reduction, in base

• in the original procedure, the aldehyde or ketone and hydrazine are refluxed with KOH in a high-boiling solvent.

• the same reaction can be brought about using hydrazine and potassium tert-butoxide in DMSO.

+

diethylene glycol (reflux)

KOH

N2

Hydrazine

+ H2 NNH2

+ H2O

O

16-16-7676

16.12 16.12 A.A. RacemizationRacemization

Racemization at an -carbon may be catalyzed by either acid or base.

O

Ph

OH

Ph

O

PhAn achiral

enol(R)-3-Phenyl-2-

butanone(S)-3-Phenyl-2-

butanone

16-16-7777

B.B. Deuterium Exchange Deuterium Exchange

Deuterium exchange at an -carbon may be catalyzed by either acid or base.

+

Acetone-d6 Acetone+

O O

CH3CCH3 6D2O CD3CCD3 6HODD

+

or OD-

16-16-7878

C.C.-Halogenation-Halogenation

-Halogenation: aldehydes and ketones with at least one -hydrogen react at an -carbon with Br2 and Cl2.

• reaction is catalyzed by both acid and base.

O

Br2 CH3COOH

OBr

HBr

Acetophenone

++

-Bromo-acetophenone

16-16-7979

-Halogenation, in acid-Halogenation, in acid

Acid-catalyzed -halogenation.Step 1: acid-catalyzed enolization.

Step 2: nucleophilic attack of the enol on halogen.

Step 3: (not shown) proton transfer to solvent completes the reaction.

H

R

R'-C-C-R

O

R'

C C

H-O R

R

slow

C

R

RH-O

C

R'

Br BrR'

C C

O Br

R

R

H

Br:-+fast+

16-16-8080

-Halogenation, in base-Halogenation, in base

Base-promoted -halogenation.Step 1: formation of an enolate anion.

Step 2: nucleophilic attack of the enolate anion on halogen.

••+

--

Resonance-stabilized enolate anion

+slow

O H

R

O

C C

R'R'

C C

O:

R'-C-C-R -:OH H2OR

R

R

R

+fast

R'

C C

O Br

R

R BrBr Br +

-

R'

C C

O: R

R

16-16-8181

-Halogenation, in acid-Halogenation, in acid

Acid-catalyzed halogenation: • introduction of a second halogen is slower than

the first.

• introduction of the electronegative halogen on the -carbon decreases the basicity of the carbonyl oxygen toward protonation.

16-16-8282

-Halogenation, in base-Halogenation, in base

Base-promoted -halogenation:• each successive halogenation is more rapid than

the previous one.

• the introduction of the electronegative halogen on the -carbon increases the acidity of the remaining -hydrogens and, thus, each successive -hydrogen is removed more rapidly than the previous one.

16-16-8383

Review of SpectroscopyReview of Spectroscopy

IR Spectroscopy•Very strong C=O stretch around 1710 cm-1.

•Conjugation lowers frequency.

•Ring strain raises frequency.

•Additional C-H stretch for aldehyde: two absorptions ~ 2720 cm-1 and 2820 cm-1.

16-16-8484

HH11 NMR of butanal NMR of butanal

16-16-8585

CC1313 NMR of 2-heptanone NMR of 2-heptanone

16-16-8686

MS of butanalMS of butanal

16-16-8787

McLafferty Rearrangement of butanalMcLafferty Rearrangement of butanal

Loss of alkene (even mass number) Must have -hydrogen

16-16-8888

Aldehydes Aldehydes & &

KetonesKetones

End Chapter 16End Chapter 16

16-1 Aldehydes & Ketones Chapter 16. 16-2 The Carbonyl Group In this and several following...

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Transcript of 16-1 Aldehydes & Ketones Chapter 16. 16-2 The Carbonyl Group In this and several following...