Nik Nur Shamiha Nik Dzulkefli

Pharmaceutical Chemistry Unit

SPH

Why this chapter?

Aldehydes and ketones are

intermediates in the synthesis of many

pharmaceutical agents, in almost all

biological pathways, and in numerous

industrial processes.

So, an understanding of their properties

and reactions is essential!

Chapter Outline Carbonyl Compound

Aldehyde & Ketone in Daily Life

Aldehyde and ketones are responsible for many flavors and

odors that you will readily recognize :

INTRODUCTION

Aldehyde contain the carbonyl group a group in

which a carbon atom has a double bond to oxygen :

Carbonyl group

Oxygen Carbonyl

Carbon Carbonyl

The carbonyl group in aldehyde is bonded to at

least one hydrogen atom.

Using R, we can designate the general formula as:

C

O

R Hor RCHO ( R = alkyl or aryl or H)

C

O

R H

INTRODUCTION

Ketone: the carbon atom in the carbonyl group is

bonded to two hydrocarbon groups :

C

O

R'R

R, R' = substituents

= alkyl or aryl

NOMENCLATURE

o IUPAC

o Common name

IUPAC Names of Aldehydes

Common Names of Aldehydes

In the common system, aldehydes are named with ending aldehyde

C

O

HH C

O

HCH3C

O

H

Formaldehyde Acetaldehyde Benzaldehyde

a. IUPAC Names of Ketones

b. Common Names of Ketones

PHYSICAL PROPERTIES

a. Boiling Point

b. Solubility

Physical Properties PROPERTY OBSERVATION

Boiling Point

Solubility

RCHO having 5 Cs are H2O soluble because they can form hydrogen bond with H2O.

RCHO having > 5 Cs are slightly soluble in H2O.

+

-

H O

H + Hydrogen bond with water.

Physical Properties

Bp, Mp & Solubility of Aldehydes :

Physical Properties

Bp, Mp & Solubility of Ketones :

Physical Properties

Boiling Points and Solubility of Aldehydes and Ketones

The carbonyl group is strongly polar but does not produce hydrogen bonding (It has no polar hydrogens). As a result, due to the dipole-dipole interaction, the boiling points of aldehydes and ketones are higher than the nonpolar hydrocarbons and the alkyl halides but lower than those of alcohols.

Formaldehyde is gas at room temperature (b.p. = -21 C) but heavier aldehydes are liquids. Acetone, the simplest ketone, is liquid at room temperature (b.p. = 56 C).

Lower molecular weight aldehydes and ketones are water soluble. Acetone, formaldehyde and acetaldehyde are miscible in water.

Physical Properties

Hydrogen bonding typically occurs when a hydrogen atom bonded to O, N, or F, is

electrostatically attracted to a lone pair of

electrons on an O, N, or F atom in another

molecule.

Polar hydrogens

Preparation

Preparation of Aldehydes: 1. Oxidation of 1 alcohol 2. Reduction of Acyl Chlorides 3. Partial reduction of Ester

Preparation of Ketones: 1. Oxidation of 2 Alcohol 2. Friedel Crafts Acylation

Preparation of Aldehydes: 1. Oxidation of 1 alcohol 2. Reduction of Acyl Chlorides 3. Partial reduction of Ester

Preparation

A) Oxidation of 1o Alcohols

General formula:

Using PCC as oxidizing agent :

PCC: Pyridinium chlorochromate

A) Oxidation of 1o Alcohols

Using strong oxidizing agent:

CH3CH2OH CH3 C OH

O

Ethanol Ethanoic Acid

H2CrO

4

acetone35oC

CH3CH2OH CH3 C OH

O

Ethanol Ethanoic Acid

KMnO4/ H+

B) Reduction of Acyl Chlorides

R C

O

Cl

acid chloride lithium aluminium tri(t-butoxy)hydride

Li+ -

AlH(O-t-Bu)3R C

O

H

aldehyde

CH3CHCH2C

CH3 O

Cllithium aluminium tri(t-butoxy)hydride

Li+ -

AlH(O-t-Bu)3CH3CHCH2C

CH3 O

H

Example:

* Lithium aluminium tri(t-butoxy)hydride is a milder reducing agent that reacts faster with acid chlorides than with aldehydes.

CO

Cl

LiAlH(O-t-Bu)3

CO

H

LiAlH(O-t-Bu)3

benzoyl chloride benzaldehyde

CH3CHCH2C

O

Cl

CH3

CH3CHCH2C

O

H

CH3

isovaleryl chloride isovaleraldehyde

B) Reduction of Acyl Chlorides

C) Partial reduction of Ester

Certain carboxylic acid derivatives can be partially

reduced to yield aldehydes

Partial reduction of an ester by diisobutylaluminium

hydride (DIBAH) is an important lab-scale method of

aldehyde synthesis, and mechanistically related

processes also occur in biological pathways

1. DIBAH, toluene, -78C

2. H3O+ H

Methyl dodecanoate Dodecanal

Preparation

Preparation of Ketones: 1. Oxidation of 2 Alcohol 2. Friedel Crafts Acylation

A) Oxidation of 2 Alcohol

Examples

Ketones can be made from 2o alcohols by oxidation

* [O] =

B) Friedel Crafts Acylation

Aromatic ketones can be made by Friedel-Crafts Acylation

Examples

Reaction of Aldehydes: 1. Oxidation 2. Reduction 3. Nucleophilic Addition 4. Reaction with Grignard reagent

Reaction of Ketones: 1. Reduction 2. Nucleophilic Addition 3. Reaction with Grignard reagent

Reaction

Reaction of Aldehydes: 1. Oxidation 2. Reduction 3. Nucleophilic Addition

Reaction

1) Oxidation of Aldehydes

Aldehydes are easily oxidized to carboxylic acid by: strong oxidizing agent such as potassium permanganate,KMnO4 mild oxidizing agent such as silver oxide, Ag2O in aqueous ammonia (Tollens Test : differentiate between aldehyde & ketone)

General Reaction

R

C

H

O

[o]

R OH

O

Aldehyde Carboxylic Acid

CH3CH2CH2CH2COH

[O] :

KMnO4, OH-

K2Cr2O7/H2SO4 Ag(NH3)2

+OH- (Tollens reagent)

K2Cr2O7

H2SO4

=

O

CH3CH2CH2CH2CH

=

O

Pentanal Pentanoic acid

Examples

1) Oxidation of Aldehydes

In the laboratory, Tollens test may be used to distinguish between an aldehyde and ketone. Tollens reagent, a solution of Ag+ (AgNO3) and ammonia, oxidizes aldehyde, but not ketones. The silver ions is reduced

to metallic silver, which forms a layer called a silver mirror on the inside of the container

* Tollens test is used to distinguish aldehydes from ketones. Ketones DO NOT react with Tollenss reagent.

Tollens Test (Silver Mirror Test)

2) Reduction of Aldehydes

Hydride ionLithium aluminum

hydride (LAH)

Sodium

borohydride

H

H H

H

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

H:

Reduction of an aldehyde gives a

primary alcohol .

Aldehydes can be reduced to alcohol

by

H2/Ni or H2/Pd

LiAlH4 NaBH4

(most often used)

2) Reduction of Aldehydes

Examples:

CH3 C H

O

CH3 C H

O-

H

CH3 C H

OH

H

H+

ethanal

ethanol

LiAlH4

3) Nucleophilic Addition

Nucleophilic addition an addition reaction initiated by attack by an electron-rich reagent (a nucleophile) on a

carbonyl compound or derivative

The carbonyl groups in aldehydes and ketones are polarised because of the difference in the electronegativity of carbon and

oxygen.

The carbon atom carries a partial positive charge while oxygen atom carries a partial negative charge.

Aldehydes and ketones are susceptible to attack both by nucleophiles at the carbonyl carbon atom and by electrophiles

at the oxygen atom.

C O

electrophilic attack nucleophilic attack

- +

3) Nucleophilic Addition

Nucleophilic Addition Reaction Of

a. HCN: Cyanohydrin Formation

b. Grignard Reagent : Formation of Alcohol

3(a) Nucleophilic addition of hydrogen cyanide

C

O

R H HCN CR R'

OH

CNaldehyde

cyanohydrin

example

C

O

CH3 H HCN CCH3 H

OH

CNethanal

1-hydroxy-1-methylpropanenitrile

* Cyanohydrin may be formed using liquid HCN with a catalytic

amount of sodium cyanide or potassium cyanide.

3(b) Reaction With Grignard Reagent

A Grignard reagent (a strong nucleophile resembling a carbanion, R:- attacks the electrophilic carbonyl carbon atom to give an alkoxide intermediate.

Subsequent protonation gives an alcohol.

MgBrCH3CH2C O

H3C

HC O- +MgBr

CH3

H

CH3CH2

C OH

CH3

H

CH3CH2

H3O+

2-butanol

alkoxideethanalethylmagnesium bromide

Grignard reagents react with aldehyde

to give secondary alcohol

Reaction of Ketones: 1. Reduction 2. Nucleophilic Addition 3. Reaction with Grignard reagent

Reaction

Ketones can be reduced to alcohols using:

a) lithium aluminium hydride (LiAlH4)

b) sodium borohydride (NaBH4)

c) catalytic hydrogenation

H+ = diluted acid such as H2SO4

R C R'

O-

H

R C R'

OH

H

H+

2o alcohol

R C R'

O

LiAlH4 or NaBH4 or H2, Niketone

CH3 C CH3

O-

H

H+

2-propanol

CH3 C CH3

O

H2/Ni

propanone

CH3 C CH3

OH

H

Example:

1. Reduction to Secondary Alcohols

CO

R R' HCN

C

O

CH3 CH3 HCN

CR R'

OH

CN

CCH3 CH3

OH

CN

ketone

cyanohydrin

example

propanone

2-hydroxy-2-methylpropanenitrile

* Cyanohydrin may be formed using liquid HCN with a

catalytic amount of sodium cyanide or potassium cyanide.

2. Nucleophilic addition of hydrogen cyanide

CO

R R' HCN

C

O

CH3 CH2CH3 HCN

CR CN

OH

R'

CCH3 CN

OH

CH2CH3

ketone

cyanohydrin

example

propan-2-one

H2O/H+

CR COOH

OH

R

a-hydroxyacid

NH4+

H2O/H+

CCH3 COOH

OH

CH2CH3

NH4+

'

Cyanohydrin can be hydrolysed to give -hydroxyacids.

The nitrile (-CN) group is converted to the COOH group by reflux the cyanohydrin with dilute sulphuric acid (H2O/H

+) or

concentrated HCl.

2 Nucleophilic addition of hydrogen cyanide

A Grignard reagent (a strong nucleophile resembling a

carbanion, R:- attacks the electrophilic carbonyl carbon atom to

give an alkoxide intermediate.

Subsequent protonation gives an alcohol.

MgBrCH3CH2C O

H3C

H3CC O- +MgBr

CH3

CH3

CH3CH2

C OH

CH3

CH3

CH3CH2

H3O+

2-methyl-2-butanol

alkoxideacetoneethylmagnesium bromide

3. Reaction with Grignard Reagent

Grignard reagents react with ketones

to give tertiary alcohol

Principles uses of Aldehyde & Ketone

Aldehydes and ketones are used as solvents, starting materials and reagents for the synthesis of other products.

Formaldehyde is well recognized as formalin solution used to defend biological specimens and to prepare, urea-formaldehyde glues and other polymeric products.

Aldehyde is used primarily as an initial material in the manufacture of acetic acid, ethyl acetic, vinyl acetate, polymers and drugs.

Benzaldehyde is used in perfumery with in dye industries. Acetone with ethyl methyl ketones are general industrial solvents.

Various aldehydes and ketones exemplar, butyraldehyde, vanillin, acetophenone, camphor, etc. are well recognized in support of their odours and flavours.

Principles uses of Aldehyde & Ketone

Aldehyde & Ketone in Daily Life

Aldehyde and ketones are responsible for many flavors and odors that you will readily recognize :

Tests to Distinguish Aldehydes and Ketones, and Aliphatic

Aldehydes and Aromatic Aldehydes

TESTS ALDEHYDES KETONES

Tollens Test / silver mirror test Reagent and condition:

- ammoniacal silver nitrate

solution ([Ag(NH3)2]+)

Observation:

Formation of silver mirror

Observation:

Silver mirror did not formed

* Ketones do not react with

Tollens reagent

Fehlings test / Benedicts test Reagent and condition:

-Solution of Cu2+ (aq) ions in an

alkaline solution of sodium

potassium tartate.

*Can be used to distinguish

between:

i) Aldehydes and ketones

ii) Aliphatic aldehydes and

benzaldehyde

Observation;

Blue colour of the Fehlings solution dissappears and

brick-red precipitate is

obtained

* Except benzaldehyde

Observation:

Blue colour remains.

* Ketones do not react with

Fehlings/Benedicts reagent

Schiffs test Reagent and condition:

- Schiffs reagent

Observation:

Formation of magenta-pink

colour (simple aldehydes)

* Except benzaldehyde and

a few aromatic aldehydes)

Observation:

Ketones (except propanone)

do not react with Schiffs reagent.

End of Chapter 8