Reactions of synthetic importance

Pharmaceutical Organic Chemistry III
Reactions of Synthetic
Importance
Presented by
SOWMIYA PERINBARAJ
Assistant Professor
Dept. of Pharmaceutical Chemistry
SVCP

Definition
❖ Clemmensen Reduction was first reported by Clemmensen Park Davis
in 1913.
❖ The reduction of Carbonyl groups of aldehydes or ketones into
corresponding hydrocarbon or methylene group in presence of zinc
amalgam and excess con. HCl is known as Clemmensen reduction.
❖ALDEHYDES (-CHO)/ KETONES (-C=O)
[H]
❖ HYDROCARBONS (-CH2 )

General reaction
• Used especially for Ketones containing phenolic or carboxylic
groups which remain unaffected.
R C
R1
O
Zn/Hg
Con.Hcl
R
C
R1
H
H
Ketone Alkane

MECHANISM
• Step 1: Activation of Carbonyl group by con. HCl (acidic media)
R
R1
O
H
+
R
R1
O
+
H
R
C
+
R1
O
H
Ketone

Step 2: Transfer of electrons from zinc and
followed by Protonation
R
C
+
R1
O
H
+ 2e- R
C
–
R1
O
H
H
+
2
R
C
R1
OH2
+
H
Zn
2+
zn + 2e-

STEP 3: Loss of water
R
C
R1
OH2
+
H
O
H2 - R
C
+
R1
H
Carbocation

Step: 4 Transfer of electrons and followed by
Protonation
R
C
+
R1
H
2e-
Zn
R
C
–
R1
H
H
+ R
C
R1
H
H
Alkane

APPLICATIONS
1) Reduction of cyclic ketones
O
Zn/Hg
Con.HCl
Cyclopentanone Cyclopentane

2) Reduction of Aromatic Ketones
CH3
O
Zn/Hg
Con.HCl
CH3
Acetophenone Ethylbenzene

3) In synthesis of Naphthalene
i) Zn/Hg Hcl
ii) SOCl2
AlCl3
C
O
O
O
H
CH2
O
Cl C
O
b- Benzoyl Propanoic acid g- Phenyl Butanoyl chloride a- Tetralone
Con.HCl
Zn/Hg
Δ
Se
Tetrahydro naphthalene
Naphthalene

4) Reduction of α, β unsaturated ketones
C
H3
CH3
O
Zn/Hg
Con.HCl C
H3 CH3
3-penten-2-one
Pentane
1
2
3
4
5

5) Reduction of Phenolic carbonyl compounds in
which phenolic group remain unaffected
OH O
Zn/Hg
Con.HCl
OH
CH3
Salicylaldehyde o-cresol
o
m
p

INTRODUCTION
• Reduction of metal hydrides proceeds by transfer of hydride ion[H-] to the
substrate.
• Selectively reduce a number of functional groups such as
✓Carbonyl
✓Carboxylic acid
✓Nitro
✓Ester in presence C=C double bounds
• Mostly used metal hydride reducing agents are sodium borohydride
(NaBH4) and lithium aluminium hydride (LiAlH4)
• LiAlH4 – Stong reducing agent
• NaBH4 – Mild reducing agent

SODIUM BOROHYDRIDE (NaBH4)
• NaBH4 a mild reducing agent soluble in polar solvents such as
water and alcohols but insoluble in ether.
• Reduces carbonyl groups
• Aldehydes
• Ketones
• Alkyl halides
• Acid chlorides

Preparation:
•Prepared by reaction of sodium hydride and trimethoxy
borate.
+
4NaH B(OCH3)3
250°C
NaBH4 + 3CH3ONa
Sodiumhydride Trimethoxy
borate
Sodium
borohydride
Sodiummethoxide

General Reaction
R C
R1
O
4 + NaBH4
R C
H
R1
O
4
B-
Na+
4H2O
R C
H
R1
OH
4
+
+
H3BO3
NaOH
Ketone
Secondary alcohol
Boric acid
Sodiumborohydride

Mechanism
• Step 1: Transfer of hydride ion [H-], powerful nucleophile from
NaBH4 to the carbonyl group with simultaneous binding of
carbonyl oxygen with boron
R C
R1
O
+ NaBH4
R C
R1
O
Na+
BH4
-
H-
R C
H
R1
O BH3
–
Na
+
Complex

Step 2: Remaining 3H- transfer to another 3 molecules of
carbonyl compounds
R C
H
R1
O BH3
–
Na
+
R C
R1
O
3
R C
H
R1
O
4
B-
Na+

Step 3: Hydrolysis to alcohol
R C
H
R1
O
4
B-
Na+
4H2O
R C
H
R1
OH
4
Secondaryalcohol
+ H3BO3
NaOH
Boricacid
+

APPLICATIONS
• Reduction of Benzaldehyde into Benzyl alcohol
• Reduction of cyclohexanone into cyclohexanol
NaBH4
CHO CH2OH
O
NaBH4
OH

• Reduction of 4-nitro-1-butanal into 4-nitro-1-butanol
• Reduction of m-nitrobenzaldehyde into m-nitrobenzylalcohol
NO2-CH2-CH2-CH2-CHO
NaBH4
NO2-CH2-CH2-CH2-CH2-OH
NO2
CHO
NaBH4
NO2
CH2OH

• Reduction of α, β- Unsaturated aldehydes
• Reduction of Alkyl halides
CH=CH-CHO
NaBH4
CH=CH-CH2OH
Cinnamaldehyde Cinnamyl alcohol
CH2-Br
NaBH4
CH3
Benzyl chloride Toluene

• Reduction of acid chloride
C=O-Cl
NaBH4
CH2-OH
Benzyl alcohol

INTRODUCTION
• Lithium aluminium hydride is a strong reducing agent.
• Violently reacts with polar solvents, resulting in liberation of
hydrogen gas. Hence these reaction are conducted in dry
ether/ THF/ Dioxane.
• Reduces carbonyl groups, carboxylic acid, acid chloride, acid
unhydride and epoxides into corresponding alcohols.
• Also reduces amides, nitriles, aliphatic nitro compounds into
corresponding amines.

PREPARATION
•Prepared by the reaction of anhydrous aluminium
chloride with lithium hydride in dry ether/ THF.
4LiH + AlCl3
THF
LiAlH4 + 3LiCl

GENERAL REACTION
R C
R1
O
4 + LiAlH4
R C
H
R1
O
4
Al-
Li+
4H2O
R C
H
R1
OH
4
+
+
LiCl
Ketone
Secondary alcohol
Lithium aluminium
hydride
ether
AlCl3

MECHANISM
• Step 1: Transfer of hydride ion [H-], powerful nucleophile from
LiAlH4 to the carbonyl group with simultaneous binding of
carbonyl oxygen with boron
R C
R1
O
+ LiAlH4
R C
R1
O
Li+
AlH4
-
H-
R C
H
R1
O
Complex
AlH3
-
Li+

Step 2: Remaining 3H- transfer to another 3 molecules
of carbonyl compounds
R C
H
R1
O
R C
R1
O
3
R C
H
R1
O
4
Al-
Li+
AlH3
-
Li+

Step 3: Hydrolysis in presence of
acid to give alcohol
R C
H
R1
O
4
Al-
Li+
R C
H
R1
OH
4
Secondaryalcohol
+
4H2O
HCl LiCl + AlCl3

APPLICATIONS
1) Reduction of carbonyl compounds
CH3(CH2)5 CHO
LiAlH4
Ether
CH3(CH2)5 OH
1-heptanal 1-heptanol
O
LiAlH4
Ether
OH
Cyclopentanone Cyclopentanaol

2) Reduction of Carboxylic acids
CH3CH2COOH
LiAlH4
Ether
Propanoic acid
CH3CH2CH2OH
Propanol
3) Reduction of amides
C
H3
NH2
O
CH3-CH2-NH2
Acetamide ethylamine
LiAlH4
Ether

4) Reduction of acid chloride
5) Reduction of Nitriles into amines
C
H3
N
LiAlH4
Ether
CH3CH2NH2
Acetonitrile ethylamine
C=O-Cl CH2-OH
Benzoyl chloride Benzyl alcohol
LiAlH4
ether

6) Reduction of nitro compounds
CH3CH-CH2-CH3
NO2
LiAlH4
ether
CH3CH-CH2-CH3
NH2
2-nitrobutane 2-aminobutane

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