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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 H
or 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

Inthecommonsystem,aldehydesarenamedwith
endingaldehyde
C
O
H H
C
O
H CH
3
C
O
H
Formaldehyde Acetaldehyde Benzaldehyde
a.IUPACNamesofKetones

b.CommonNamesofKetones

PHYSICAL PROPERTIES
a. Boiling Point
b. Solubility

PhysicalProperties
PROPERTY OBSERVATION
Boiling
Point
Solubility
RCHO having 5 Cs are H
2
O soluble because they can form hydrogen bond with
H
2
O.
RCHO having > 5 Cs are slightly soluble in H
2
O.


+
-
H
O
H
+
Hydrogen bond with water.
PhysicalProperties
Bp, Mp & Solubility of Aldehydes :
PhysicalProperties
Bp, Mp & Solubility of Ketones :
PhysicalProperties
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.
PhysicalProperties
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)Oxidationof1
o
Alcohols
General formula:
Using PCC as oxidizing agent :
PCC: Pyridinium chlorochromate
A)Oxidationof1
o
Alcohols
Using strong oxidizing agent:
CH
3
CH
2
OH
CH
3
C OH
O
Ethanol
Ethanoic Acid
H
2
CrO
4
acetone
35
o
C
CH
3
CH
2
OH
CH
3
C OH
O
Ethanol
Ethanoic Acid
KMnO
4
/ H
+
B)ReductionofAcylChlorides
R C
O
Cl
acid chloride
lithium aluminium tri(t-butoxy)hydride
Li
+
-
AlH(O-t-Bu)
3
R C
O
H
aldehyde
CH
3
CHCH
2
C
CH
3
O
Cl
lithium aluminium tri(t-butoxy)hydride
Li
+
-
AlH(O-t-Bu)
3
CH
3
CHCH
2
C
CH
3
O
H
Example:
* Lithium aluminium tri(t-butoxy)hydride is a milder reducing agent that reacts
faster with acid chlorides than with aldehydes.
C
O
Cl
LiAlH(O-t-Bu)
3
C
O
H
LiAlH(O-t-Bu)
3
benzoyl chloride
benzaldehyde
CH
3
CHCH
2
C
O
Cl
CH
3
CH
3
CHCH
2
C
O
H
CH
3
isovaleryl chloride
isovaleraldehyde
B)ReductionofAcylChlorides
C)PartialreductionofEster
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. H
3
O
+
H
Methyl dodecanoate Dodecanal
Preparation
Preparation of Ketones:
1. Oxidation of 2 Alcohol
2. Friedel Crafts Acylation

A)Oxidationof2Alcohol

Examples
Ketones can be made from 2
o
alcohols by oxidation
* [O] =

B)FriedelCraftsAcylation

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)OxidationofAldehydes

Aldehydesareeasilyoxidizedtocarboxylicacidby:
strongoxidizingagentsuchaspotassiumpermanganate,KMnO
4
mildoxidizingagentsuchassilveroxide,Ag
2
Oinaqueousammonia
(TollensTest:differentiatebetweenaldehyde&ketone)
GeneralReaction
R
C
H
O
[o]
R OH
O
Aldehyde Carboxylic Acid
CH
3
CH
2
CH
2
CH
2
COH
[O]:
KMnO
4
,OH
-
K
2
Cr
2
O
7
/H
2
SO
4
Ag(NH
3
)
2
+
OH
-
(Tollensreagent)

K
2
Cr
2
O
7
H
2
SO
4
=

O
CH
3
CH
2
CH
2
CH
2
CH
=

O
Pentanal Pentanoic acid
Examples
1)OxidationofAldehydes
In the laboratory, Tollens test may be used to distinguish between an
aldehyde and ketone. Tollens reagent, a solution of Ag
+
(AgNO
3
) 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.
TollensTest(SilverMirrorTest)

2)ReductionofAldehydes
Hydride ion Lithium aluminum
hydride (LAH)
Sodium
borohydride
H
H
H
H
H- B- H
H- Al- H Li
+
Na
+
H:
Reductionofan
aldehydegivesa
primaryalcohol.

Aldehydescanbe
reducedtoalcohol
by
H
2
/NiorH
2
/Pd
LiAlH
4

NaBH
4

(mostoftenused)

2)ReductionofAldehydes
Examples:
CH
3
C H
O
CH
3
C H
O
-
H
CH
3
C H
OH
H
H
+
ethanal
ethanol
LiAlH
4
3)NucleophilicAddition
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)NucleophilicAddition
Nucleophilic Addition Reaction Of

a. HCN: Cyanohydrin Formation
b. Grignard Reagent : Formation of Alcohol

3(a)Nucleophilicadditionofhydrogencyanide
C
O
R H
HCN C R R'
OH
CN
aldehyde
cyanohydrin
example
C
O
CH
3
H
HCN
C CH
3
H
OH
CN
ethanal
1-hydroxy-1-methylpropanenitrile
* Cyanohydrin may be formed using liquid HCN with a catalytic
amount of sodium cyanide or potassium cyanide.

3(b)ReactionWithGrignardReagent

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.
MgBr CH
3
CH
2
C O
H
3
C
H
C O
- +
MgBr
CH
3
H
CH
3
CH
2
C OH
CH
3
H
CH
3
CH
2
H
3
O
+
2-butanol
alkoxide
ethanal
ethylmagnesium 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 (LiAlH
4
)
b) sodium borohydride (NaBH
4
)
c) catalytic hydrogenation

H
+
= diluted acid such as H
2
SO
4
R C R'
O
-
H
R C R'
OH
H
H
+
2
o
alcohol
R C R'
O
LiAlH
4
or NaBH
4
or H
2
, Ni
ketone
CH
3
C CH
3
O
-
H
H
+
2-propanol
CH
3
C CH
3
O
H
2
/Ni
propanone
CH
3
C CH
3
OH
H
Example:

1.ReductiontoSecondaryAlcohols

C
O
R R'
HCN
C
O
CH
3
CH
3
HCN
C R R'
OH
CN
C CH
3
CH
3
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.Nucleophilicadditionofhydrogencyanide

C
O
R R'
HCN
C
O
CH
3
CH
2
CH
3
HCN
C R CN
OH
R'
C CH
3
CN
OH
CH
2
CH
3
ketone
cyanohydrin
example
propan-2-one
H
2
O/H
+
C R COOH
OH
R
a-hydroxyacid
NH
4
+
H
2
O/H
+
C CH
3
COOH
OH
CH
2
CH
3
NH
4
+
'
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 (H
2
O/H
+
) or
concentrated HCl.

2Nucleophilicadditionofhydrogencyanide

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.
MgBr CH
3
CH
2
C O
H
3
C
H
3
C
C O
- +
MgBr
CH
3
CH
3
CH
3
CH
2
C OH
CH
3
CH
3
CH
3
CH
2
H
3
O
+
2-methyl-2-butanol
alkoxide
acetone
ethylmagnesium bromide

3.ReactionwithGrignardReagent

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.
PrinciplesusesofAldehyde&Ketone
Aldehyde&KetoneinDailyLife
Aldehyde and ketones are responsible for many flavors and
odors that you will readily recognize :

TeststoDistinguishAldehydesandKetones,andAliphatic
AldehydesandAromaticAldehydes

TESTS ALDEHYDES KETONES


Tollens Test / silver mirror test
Reagent and condition:
- ammoniacal silver nitrate
solution ([Ag(NH
3
)
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 Cu
2+
(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.

EndofChapter8

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