CO

Usifoh
Methods Involving C-C formation

Addition of Nucleophiles that are Carbon

to Carbonyl functional group.

Base catalyzed addition of carbanions which

are derivable from a methyl (CH3), methylene
(CH2), or a methylene carbon bearing electron
withdrawing groups e.g. nitro, aldehyde, ester,
etc.
The primary product of the reaction of
carbanion with an aldehyde/ketone is an
alcohol

The alcohol could be dehydrated under

appropriate condition.

ALDOL CONDENSATION
Possible only when the carbonyl compound
contains at least one α-hydrogen atom.
Condensation between two molecules of an
aldehyde or a ketone to form a
β-hydroxyaldehyde or a β-hydroxy ketone is
known as a ALDOL CONDENSATION.
Some conditions regarding the
Aldol Reaction
A reversible equilibrium

 OH- is the base typically used in an aldol reaction.

 Aldol reactions can be carried out with either

aldehydes or ketones.
With aldehydes, the equilibrium favors products.

 With ketones the equilibrium favors the starting

materials.
 MECHANISM OF ALDOL CONDENSATION
Step 1:
First, an acid-base reaction. Hydroxide functions as a
base and removes the acidic α-hydrogen giving the
reactive enolate.

Step 2:
The nucleophilic enolate attacks the aldehyde at the
electrophilic carbonyl C in a nucleophilic addition type
process giving an intermediate alkoxide.

Step 3:
An acid-base reaction. The alkoxide deprotonates a
water molecule creating hydroxide and the β-hydroxyl-
aldehydes or aldol product.
 Step:1

enolate
ion

An enolate ion is the anion formed when an

alpha hydrogen in the molecule of an aldehyde
or a ketone is removed as a hydrogen ion.
 Step: 2

The alkoxide ion is the conjugate base of

alcohols.
 Step:3

aldol
product

Alkoxide ion is protonated by water.

LIMITATIONS:
Aldol products, as such, are not always
isolated from the reaction mixture. eg:
acetaldol readily forms a cyclic hemi-acetol.

EXTENSIONS:
Aldol condensation can occur between
Two identical or different aldehydes
Two identical or different ketones
An aldehyde and a ketone
•The R groups may be H, alkyl, or aryl.

•When the R groups in one molecule are

different from those in the other, the reaction
is called a crossed-aldol reaction.
•The ability to join different aldehydes and
ketones together is what gives this process its
synthetic value.
In its usual form, it involves the nucleophilic
addition of a ketone enolate to an aldehyde
to form a β-hydroxy ketone or aldol
(aldehyde + alcohol).

It is a structural unit found in many naturally

occurring molecules and pharmaceuticals.
 Summary (ALDOL Condensation)
A self/cross condensation of an aldehyde/ketone.
Spontaneous dehydration or use of a dehydrating
agent is required to give an α, β-unsaturated carbonyl
compounds.
O O O
O- H2
OH- -H C C
H3C H 2 H
H3C H
H
O

H3C H

H+

O O
H -H2O OH H2
C C
H3C H3C H
H H H
Claisen or Claisen-Schmidt reaction
When the aldehyde has no
α-hydrogen is involved in a cross
condensation.

This is usually an aromatic

aldehyde.
O O
O
H + H
H3C H

O
O O
H CH3
+ H3C CH3
Claisen Ester condensation
This is a self condensation of an ester.
The labile alkoxy group is eliminated
from the initial anion adduct to give a
β-keto ester as the final product.
O O
O - O- H2
EtO -H C C
2 OCH2CH3
H3C OCH2CH3 H3C
OCH2CH3 OCH2CH3
O

H3C OCH2CH3

O O

H3C
OCH2CH3
Addition of compounds with active methylene
to carbonyl functional group.

Knoevenagel reaction
The methylene group is activated by two
electrons withdrawing groups.
A weak base can be used as the methylene is
acidic.
H2 Base H
_
C
A B A B

A or B could be COOH, COOR, CN, Aldehydic or ketonic group

 H2
C
HOOC COOH

Piperidine

H
_
HOOC COOH
COOH COOH
O- +
CH H H
+ C C
H3C H H3C
COOH -H2O COOH
O
H3C
H
Dieckmann condensation
The Dieckmann condensation is an organic reaction
used to form a carbon-carbon bond between two
tethered ester groups using an alkoxide base in
alcohol to make a cyclic β-keto ester.

This reaction is essentially an intramolecular form

of the Claisen condensation.
 Oxidation reactions
Olefinic double bond
OsO4 and KMnO4
This provides an excellent route to cis
diols or glycol.

Can be employed in the synthesis of

pharmaceutically important steroids.
 C8H17 C8H17

KMnO4/OsO4

HO HO
HO OH
Cholesterol Cholestane -3β, 5α, 6α-triol
 Oxidation of alcohols
KMnO4 has been used with great success.

These reagents below can also be used

Na2Cr2O7/H2SO4

CrO3 or CrO3/pyridine
Primary Alcohol
RCH2OH RCHO RCOOH
acid

Secondary Alcohol O
CHOH

Ketone

Tertiary Alcohol : Inert to oxidation

Peracids
An epoxide is formed which can be translated to
different compounds under different reaction
conditions.
H2O2
RCOOH RCO 2OH

H3C
RCO 2OH CH3
CH3 LiAlH4
H3C OH
O
+
CH3
H /OH H3C C
OH H H2
H BF3
CH3 Alcohol
H3C
H
OH CH3CHO

Trans 1, 2-diol Aldehyde

 Ozonolysis
This can be used to translate olefins to
corresponding carbonyl compounds.
O
R
R
O3/O2 R O R1 H2/Pt R1
R1 R1 R2
H H +
CCl4 R2
R2 O H O O or Zn/AcOH
R2 O

R H
H2O

O O
+
R1 R2 R H

RCOOH
Stereochemi
stry:
• Ozonolysis of triple bond is less common and the reaction
proceeds less easily, since ozone is electrophilic agent.
• Olefins with electron donating group react many times
faster than those with electron withdrawing group.
• Alkynes are less reactive than alkene

The benefits of ozonolysis:

Ozone oxidation is green technology because the only by-
product of the organic syntheses is oxygen.

Ozone oxidation is very economical during organic

synthesis since it uses air and electricity to convert olefins
to carbonyl compounds.
25
 APPLICATIONS:
Used as an oxidant in organic synthesis.
Industrial-Scale ozonolysis has been employed:
In the preparation of a generic steroid on a multi-
kilo scale.
In the preparation of Vitamin D analog
(s-Hydroxyvitamin D)
 In oxandrolone synthesis which is an anabolic
steroid used to promote weight gain following
extensive surgery.
Ceftibuten is a third-generation oral cephalosporin
and has excellent gram-negative activity, and
possesses a high degree of lactamase stability.26
 Diazomethane
Introduction

• Formula: CH2N2

• Physical properties: Diazomethane is yellow gas.(b.p.-

23°C). It is highly toxic and explosive.

It explodes even in gaseous state and decomposes readily.

• Storage condition: Ethereal solution may be stored at 0°C

for about 24 hrs without appreciable decomposition.

27
Reaction

O
Ether
R C N NO + NaOH CH2N2 + H2O + RCOONa

CH3

Several N-nitroso-N-methyl compounds have been used to prepare diazomethane.

• Process:
The reaction is carried out at about 0°C by adding ethereal
solution of diazomethane to the solution of the substrate in
ether till evolution of nitrogen ceases and yellow colour
persist.

28
Safety:
 Diazomethane is toxic by inhalation or by contact with the
skin or eyes. Symptoms include chest discomfort,
headache, weakness and, in severe cases, one may
collapse.

 Like any other alkylating agent, it is expected to be

carcinogenic, but such concerns are overshadowed by its
serious acute toxicity.

 CH2N2 may explode in contact with sharp edges, such as

ground-glass joints, even scratches in glassware.

 Glassware should be inspected before use.

 The compound explodes when heated beyond 100°C. 29

Advantages:
Used as a methylating agent for reasonably acidic
compounds.
It provides a good method for the conversion of acids into
their higher homolog.
It react rapidly even without catalysis and the yield is high.
The reaction is clean since other product is nitrogen.
It is the most useful and versatile reagent for preparative
purposes.
30
Application:
METHYLATION
Carboxylic acids:
It is methylating agent for acidic compounds such as carboxylic
and mineral acids. Carboxylic acids can be converted to esters and
reactivity of reagent increases with acidity.

Reaction is used where the acid is sensitive to higher temperature.

CH2N2 CH2N2
RCOOH RCOOCH3 C6H5OH C6H5OCH3
-N2 -N2

CH2N2
CH2 COOH CH2COOCH3

2-Cyclopropylacetic acid Methyl 2-cyclopropylacetate

31
Alcohols:
It produces a methyl ether.
Alcohols do not react at all unless a catalyst
such as HBF3 or silica gel is present.

Hydroxyl compounds react better as their

acidity increases.

It is used chiefly to methylate alcohols and

phenols that are expensive and are available
in small amounts since the conditions are
mild and high yields are obtained. 32
 CH2N2
R OH + BF3 R O BH3 R O CH3 + BF3 + N2

HBF4
CH3(CH2)CH2OH + CH2N2 CH3(CH2)6CH2OCH3 + N2
Propan-1-ol 1-Methoxyoctane

33
Aldehyde and ketone:
Converted in to the next higher analogue.

N N O
R O
CH2N2 -N2 R
R
R
R O R

34
 Reduction
Metal Hydrides - LiAlH4 > LiBH4 > NaBH4.

These selectively reduce carbonyl functional

groups of Aldehydes, Ketones,
Acids, Esters and Amides in the presence of
olefinic double bonds.
 Reduction of carbonyl (aldehydes and
ketones) compounds to hydrocarbon.
Clemmensen reduction
The reaction is executed in toluene in
order to minimize bimolecular reduction.

HCl is required to initiate protonation

and
It is good for aldehydes/ketones having
carboxylic/phenolic groups.
 O H2
Zn/Hg/HCl C + H2O
R
R R
R 4 (H)

Zn/Hg/HCl
PhCOCH 2CH2COOH PhCH 2CH2CH2COOH