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Aldehydes & Ketones. Chapter 16. Chapter 16. The 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)

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Aldehydes ketones
Aldehydes & Ketones

Chapter 16

Chapter 16


The carbonyl group
The 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 1 the carbonyl group
16.1 The 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.


Structure

H

C

H

C

H

C

H

C

H

C

C

H

3

3

3

Methanal

Ethanal

Propanone

(Formaldehyde)

(Acetaldehyde)

(Acetone)

Structure

  • 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.

O

O

O


16 2 a nomenclature
16.2 A.Nomenclature

  • IUPAC names:

    • the parent chain is the longest chain that contains the functional group.

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

    • for an unsaturated aldehyde, change the infix from -an- to -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.


B nomenclature aldehydes
B. Nomenclature: Aldehydes

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


Nomenclature ketones
Nomenclature: Ketones

  • IUPAC names

    • the parent alkane is the longest chain that contains the carbonyl group.

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

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

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


Order of precedence table 16 1
Order of Precedence, Table 16.1

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


C common names
C. 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.


16 3 physical properties
16.3 Physical 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.


Preparation of aldehydes and ketones
Preparation 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 4 reaction themes nu attack at c
16.4 Reaction 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.


Reaction themes o attack at h
Reaction 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.


Reaction themes stereochemistry
Reaction 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.


16 5 addition of c nucleophiles
16.5 Addition 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.


A grignard reagents
A. 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: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.


Grignard reagents 1 o alcohols
Grignard Reagents, 1o alcohols

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

  • Note that these reactions require two steps.


Grignard reagents 2 o alcohols
Grignard Reagents, 2o alcohols

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


Grignard reagents 3 o alcohols
Grignard Reagents, 3o alcohols

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


Grignard reagents
Grignard Reagents

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.


Grignard reagents1
Grignard Reagents

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


B organolithium compounds
B. 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.


C salts of terminal alkynes
C. Salts of Terminal Alkynes

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


Salts of terminal alkynes
Salts of Terminal Alkynes

  • Addition of water or hydroboration/oxidation

    of the product gives an enol which rearranges.


D addition of hcn

O

H

C

H

C

H

H

C

C

H

C

-

C

3

3

2-Hydroxypropanenitrile

(Acetaldehyde cyanohydrin)

D. Addition of HCN

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

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

O

+

N

N

H


Addition of hcn
Addition 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.


Cyanohydrins
Cyanohydrins

  • 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.


Cyanohydrins1

acid

O

O

H

H

catalyst

C

H

C

H

C

C

H

-

C

H

COOH

H

O

3

3

2

2-Hydroxypropanenitrile

2-Hydroxypropanoic acid

(Acetaldehyde cyanohydrin)

Cyanohydrins

  • The value of cyanohydrins:

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

N


16 6 wittig reaction
16.6 Wittig Reaction

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


Phosphonium ylides wittig reagent
Phosphonium Ylides (Wittig reagent)

  • Phosphonium ylidesare 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.


Wittig reaction
Wittig 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.


Wittig reaction1
Wittig Reaction

  • Examples:


Wittig reaction2
Wittig Reaction

  • 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.


Wittig reaction modification omit
Wittig Reaction Modification - Omit

  • Horner-Emmons-Wadsworth modification:

    • uses a phosphonoester.

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


Wittig reaction modification omit1
Wittig Reaction Modification - Omit

  • phosphonoesters are prepared by successive SN2 reactions:

    attack by the phosphite, then

    attack by Br-


Wittig reaction modification omit2
Wittig Reaction Modification - Omit

  • 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.


16 7 a addition of h 2 o hydrates
16.7 A.Addition of H2O, 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.


Addition of h 2 o hydrates
Addition of H2O, 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.


B addition of alcohol hemiacetals
B. Addition of Alcohol, hemiacetals

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

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


Addition of alcohols in base
Addition 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.


Addition of alcohols in acid
Addition 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.


Addition of alcohol cyclic hemiacetals
Addition of Alcohol, cyclic hemiacetals

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


Addition of alcohol cyclic hemiacetals1
Addition of Alcohol, cyclic hemiacetals

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


Addition of alcohols acetals
Addition of Alcohols, acetals

  • Hemiacetals can react with alcohols to form acetals.

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


Addition of alcohols acetals1
Addition of Alcohols, acetals

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

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


Addition of alcohols acetals2
Addition of Alcohols, acetals

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.


Addition of alcohols cyclic acetals
Addition 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.



C acetals as protecting grps
C. 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)


Acetals as protecting groups
Acetals 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.


D acetals as protecting groups

+

H

R

C

H

O

H

2

R

C

H

O

2

A tetrahydropyranyl

acetal

D. 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.

THP group

+

O

O

Dihydropyran


16 8 a addition of nitrogen nucleophiles
16.8 A.Addition 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.


Addition of nitrogen nucleophiles
Addition 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.


Addition of nitrogen nucleophiles1

+

H

H

N

2

-

H

O

2

C

yclohexylamine

H

/

N

i

2

Addition of Nitrogen Nucleophiles

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

  • imine formation:

  • reduction:

N

O

+

(An imine)

Cyclohexanone

H

N

N

(An imine)

Dicyclohexylamine


Addition of nitrogen nucleophiles2
Addition of Nitrogen Nucleophiles

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


Addition of nitrogen nucleophiles3
Addition of Nitrogen Nucleophiles

  • 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.


B addition of nitrogen nucleophiles
B. 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.

Table 16.4


16 9 a acidity of hydrogens
16.9 A.Acidity of -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.


Acidity of hydrogens
Acidity of -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.


Keto enol tautomerism
Keto-Enol Tautomerism

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


Keto enol tautomerism1
Keto-Enol Tautomerism

  • 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-.


B keto enol tautomerism table 16 5
B. Keto-Enol Tautomerism, Table 16.5

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


Keto enol tautomerism2
Keto-Enol Tautomerism

  • 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 10 a oxidation of aldehydes
16.10 A.Oxidation 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.


Oxidation of aldehydes

O

2

Oxidation 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.

O

O

2

CH

+

2

COH

Benzaldehyde

Benzoic acid


B oxidation of ketones

O

H

H

N

O

H

O

3

O

H

Cyclohexanone

Cyclohexanone

H

exanedioic acid

(keto form)

(enol form)

(Adipic acid)

B. 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.

O

O

O


16 11 reduction

Can Be

Can Be

Reduced to

Reduced to

O

H

R

C

H

O

H

R

C

H

R

'

2

R

C

H

R

C

R

'

R

C

H

R

C

H

R

'

3

2

16.11 Reduction

  • 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.

Aldehydes

Ketones

O

O


A metal hydride reduction

+

N

a

H

-

B

-

H

+

H

:

L

i

H

-

A

l

-

H

Sodium

L

ithium aluminum

H

ydride ion

borohydride

hydride (LAH)

A. 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.

H

H

H

H


Nabh 4 reduction
NaBH4 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.


Nabh 4 reduction1
NaBH4 Reduction

  • 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.


Lialh 4 reduction
LiAlH4 Reduction

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

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


B catalytic reduction

O

H

H

2

o

25

C, 2 atm

C

yclohexanone

C

yclohexanol

2

H

2

O

H

N

i

trans-

2-Butenal

(Crotonaldehyde)

B. Catalytic Reduction

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

O

Pt

+

O

H

1-Butanol


Catalytic reduction

2

H

2

O

H

N

i

trans-

2-Butenal

(Crotonaldehyde)

Catalytic 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.

O

H

1-Butanol


C clemmensen reduction in acid
C. Clemmensen Reduction, in acid

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


Wolff kishner reduction in base
Wolff-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.


16 12 a racemization
16.12 A.Racemization

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


B deuterium exchange
B. Deuterium Exchange

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


C halogenation
C. -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.


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.


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.


Halogenation in acid1
-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.


Halogenation in base1
-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.


Review of spectroscopy
Review 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.


H 1 nmr of butanal
H1 NMR of butanal


C 13 nmr of 2 heptanone
C13 NMR of 2-heptanone



Mclafferty rearrangement of butanal
McLafferty Rearrangement of butanal

  • Loss of alkene (even mass number)

  • Must have -hydrogen


Aldehydes ketones1
Aldehydes & Ketones

End Chapter 16


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