Nucleophilic Addition Reactions

of Aldehydes and Ketones

Synthesis of Drug (III)
Nucleophilic Addition Reactions
of Aldehydes and Ketones
MuhammadAswad
The most general reaction of aldehydes and
ketones is the nucleophilic addition reaction.
A nucleophile, :Nu attacks the nucleophilic
C=O carbon atom from a direction
approximately 45 to the plane of carbonyl
group.
At the same time, rehybridization of the
carbonyl carbon from sp to sp occurs, an
electron pair from the carbonoxygen double
bond moves toward the electronegative oxygen
atom, and tetrahedral alkoxide ion intermediate
is produced
The most general reaction of aldehydes and
ketones is the nucleophilic addition reaction.
A nucleophile, :Nu attacks the nucleophilic
C=O carbon atom from a direction
approximately 45 to the plane of carbonyl
group.
At the same time, rehybridization of the
carbonyl carbon from sp to sp occurs, an
electron pair from the carbonoxygen double
bond moves toward the electronegative oxygen
atom, and tetrahedral alkoxide ion intermediate
is produced
The attacking nucleophile can be either
negatively charge (:Nu) or neutral (:Nu)
If its neutral, however, the nucleophile
usually carries a hydrogen atom that
can subsequently be eliminated
The attacking nucleophile can be either
negatively charge (:Nu) or neutral (:Nu)
If its neutral, however, the nucleophile
usually carries a hydrogen atom that
can subsequently be eliminated
Two general reaction pathway
Relative Reactivity of Aldehydes
and Ketones
Aldehydes are generally more reactive
than ketones in nuclephilic addition
reaction for both steric and electronic
reason
Aldehydes are generally more reactive
than ketones in nuclephilic addition
reaction for both steric and electronic
reason
Sterically
Presence of only one relatively large
substituent bonded to the C=O carbon in
aldehyde versus two large substituents in
a ketone means that an attacking
nucleophile is able to approach an
aldehyde more readily
Transition state leading to tetrahedral
intermediate is less crowded and lower
energy for an aldehyde than for a ketone
Presence of only one relatively large
substituent bonded to the C=O carbon in
aldehyde versus two large substituents in
a ketone means that an attacking
nucleophile is able to approach an
aldehyde more readily
Transition state leading to tetrahedral
intermediate is less crowded and lower
energy for an aldehyde than for a ketone
Nucleophilic attack on aldehyde is sterrically
less hindered because only one relatively
large substituent is attached to the carbonyl
group carbon
A ketone, however, has two large
substituents and is more hindered
Electronically
Aldehydes are more reactive than ketones
because of the greater polarization of
aldehyde carbonyl groups
Aromatic aldehydes, such as
benzaldehyde, are less reactive in
nucleophilic addition reactions than
aliphatic aldehydes.
The electron-donating resonance effect
of the aromatic ring makes the carbonyl
group less electrophilic than carbonyl
group of an aliphatic aldehyde.
Aromatic aldehydes, such as
benzaldehyde, are less reactive in
nucleophilic addition reactions than
aliphatic aldehydes.
The electron-donating resonance effect
of the aromatic ring makes the carbonyl
group less electrophilic than carbonyl
group of an aliphatic aldehyde.
Cyanohydrin Formation
Aldehydes and unhindered ketones
react with HCN to yield cyanohydrins,
RCH(OH)CN
Cyanohydrin Formation Cyanohydrin Formation
Step 1; Nucleophilic Attack Step 1; Nucleophilic Attack

CC OO
CC

NN

Cyanohydrin Formation Cyanohydrin Formation

OO
NN CC CC

HH
HH
HH
++
OO

Step 2: Protonation to form Step 2: Protonation to form OH group. OH group.

HH
HH
HH
OO

OO
NN CC CC

HH
Cyanohydrin formation provides a method for
transforming a ketone or aldehyde into a
different functional group
Cannizaro Reaction
Is chemical reaction that involves the base-
induced disproportionation of an aldehyde
lacking a hydrogen atom in alpha position
Cannizaro firt accomplished this
transformation in 1853, when he obtained
benzyl alcohol and benzoic acid from the
treatment of benzaldehyde with potassium
carbonate
Is chemical reaction that involves the base-
induced disproportionation of an aldehyde
lacking a hydrogen atom in alpha position
Cannizaro firt accomplished this
transformation in 1853, when he obtained
benzyl alcohol and benzoic acid from the
treatment of benzaldehyde with potassium
carbonate
StanislaoCannizzaro
An Italian Chemist
July 13, 1826-May 10, 1910
Major Contribution
Cyanamide
Cannizzaro Reaction
The first to clarify the distinction
between molecular and atomic
weights
An Italian Chemist
July 13, 1826-May 10, 1910
Major Contribution
Cyanamide
Cannizzaro Reaction
The first to clarify the distinction
between molecular and atomic
weights
Mechanism of Cannizzaro Reaction
Step 1. Nucleophilic addition
R
O
H
OH R
O
OH
H
Mechanism of Cannizzaro Reaction
Step 2. Hydride (H
-
) transfer
R
O
OH
H
R
O
H
R
O
OH
R
O
H
H
Mechanism of Cannizzaro Reaction
R
O
O
R
O
H
H
R
O
O
R H
O
H
H
H
Step 3. Rapid acid-base reaction
R
O
O
R
O
H
H
R
O
O
R H
O
H
H
H
Example of Cannizzaro Reaction
For example:
R
C
R'
O
ROH R C
O
R'
O
H
R
R C
O
R'
O
H
R
ROH R C
O
R'
O
R
R
+
+ H O
H
+
Addition of Alcohols Addition of Alcohols
addition of one mole
addition of second mole
hemiketal
H
+
TWO MOLES OF ALCOHOL WILL ADD
R
C
R'
O
ROH R C
O
R'
O
H
R
R C
O
R'
O
H
R
ROH R C
O
R'
O
R
R
+
+ H O
H
+
addition of second mole
an aketal
H
+
The equilibria normally favor the aldehyde or ketone starting
material, but we will show how they can be made.
C O
R
H
C
R
H
OH
OR
C
R
H
OR
OR
C
R
R
OR
OR
C
R
R
OH
OR
C O
R
R
ROH
ROH
ROH
ROH
aldehyde
hemiacetal acetal
ACETALS AND HEMIACETALS ACETALS AND HEMIACETALS
C O
R
H
C
R
H
OH
OR
C
R
H
OR
OR
C
R
R
OR
OR
C
R
R
OH
OR
C O
R
R
ROH
ROH
ROH
ROH
ketone
hemiacetal acetal
(ketal)* (hemiketal)*
*older term *older term
C
O
R R
H O
R
H
C
O
R R
H
O
H R
C
O
R R
H
R H
O
C
O
R R
H
R
O
O
R
H
..
..
..
..
..
..
:
: :
+
+
+
R O H H
2
S O
4
R O H
H
+
+
..
Like a
hydronium
ion
hemiacetal
C
O
R R
H O
R
H
C
O
R R
H
O
H R
C
O
R R
H
R H
O
C
O
R R
H
R
O
O
R
H
..
..
..
..
..
:
:
:
..
R O
H
H
+
ACID CATALYZED ACID CATALYZED
FORMATION OF A FORMATION OF A
HEMIACETAL HEMIACETAL
+
Normally the starting
material is favored -
but a second molecule
of alcohol can react
if in excess (next slide)
first
addition
H O
R
H
O
R
H
C
O
R R
H
R
O
O
R
H
C
O
R R
H
R
O
H
C
R R
R
O
C
O
R R
R
R
O
H
C
O
R R
R
R
O
O
H
H
O
R
H
H
:
..
..
..
..
..
:
:
:
:
..
..
..
C
R R
R
O
:
+
+
+
+
FORMATION OF THE ACETAL ( FORMATION OF THE ACETAL ( from the hemiacetal ))
S
N
1
second
addition
remove
acetal
H O
R
H
O
R
H
C
O
R R
H
R
O
O
R
H
C
O
R R
H
R
O
H
C
R R
R
O
C
O
R R
R
R
O
H
C
O
R R
R
R
O
O
H
H
O
R
H
H
..
:
:
:
..
..
..
..
..
..
:
: :
:
:
C
R R
R
O
:
+
+
+
Resonance
stabilized
carbocation
S
N
1
hemiacetal
STABILITY OF ACETALS AND HEMIACETALS STABILITY OF ACETALS AND HEMIACETALS
Most hemiacetals are not stable, except for those of sugars
(see later).
Acetals are not stable in aqueous acid, but they are stable to
aqueous base.
C
OR
OR
C O
ROH
ROH
C
OR
OR
AQUEOUS
ACID
AQUEOUS
BASE no reaction
H
2
SO
4
H
2
O
H
2
O
NaOH
+
H
2
O
hydrate
R-O-H R-O-H
ADDITION OF WATER AND ALCOHOLS ADDITION OF WATER AND ALCOHOLS
WATER
ALCOHOLS
C
O
O H OR RO OR
C
O
O H OH
hemiacetal acetal
H
2
O
C
O
O H OR RO OR
RO OR
O
ROH
+2
no reaction
NaOH
H
2
O
H
2
O
H
+ acetals are
stable to base
but not to
aqueous acid
Compounds that bear an amino group
G NH
2
form Imines.
The G group can be one of many different
possibilities
Addition-Elimination:
The Formation of Imines
+
..
HA
+ H
2
O C O
R
R
C
R
R
N G G NH
2
an imine
+
..
HA
+ H
2
O C O
R
R
C
R
R
N G G NH
2
an imine
All of the imine reactions, regardless of G, go by
the same mechanism.
Mechanism of Imine
Formation
Step 1
+
slow
.. ..
..
+
_
..
:
..
..
..
..
..
..
..
Step 2
+ HA
fast
+ + A
_
H
2
O
+
C OH
R
R
G N
H
H
C O
R
R
C
R
R
N G
H
G N
H
C OH
R
R
G NH
2
C O
R
R
G N
H
WWU Chemistry
Step 1
+
slow
.. ..
..
+
_
..
:
..
..
..
..
..
..
..
Step 2
+ HA
fast
+ + A
_
H
2
O
+
C OH
R
R
G N
H
H
C O
R
R
C
R
R
N G
H
G N
H
C OH
R
R
G NH
2
C O
R
R
G N
H
What is the mechanism of this step?
Mechanism of Imine Formation
Step 3
+
+
A
_
fast
+
..
H A
N G
H
C
R
R
N G C
R
R
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Step 3
+
+
A
_
fast
+
..
H A
N G
H
C
R
R
N G C
R
R
This is Addition-Elimination
The first step is carbonyl addition of an amine,
and the second step is a dehydration
(elimination) to yield the C=N double bond.
HA is the catalyst
Step #1 is rate-determining, unless the amine is
very basic (e.g., semicarbazide or aniline), in
which case step #2 becomes rate-determining.
This is Addition-Elimination
The first step is carbonyl addition of an amine,
and the second step is a dehydration
(elimination) to yield the C=N double bond.
HA is the catalyst
Step #1 is rate-determining, unless the amine is
very basic (e.g., semicarbazide or aniline), in
which case step #2 becomes rate-determining.
Formation of Simple Imines
+
+ H
2
O
C O
R
R
N H
2
R
C N
R
R
R
..
an imine
acid
+
+ H
2
O
C O
R
R
N H
2
R
C N
R
R
R
..
an imine
acid
Aldehydes and ketones react with simple primary
amines to yield imines.
The equilibrium is unfavorable; the products are much
less stable than the reactants.
A Simple Model for Enzyme-
Substrate Binding.
NH
2
+
O
C
R R
N C
R
R
enzyme substrate
enzyme-substrate complex
NH
2
+
O
C
R R
N C
R
R
enzyme substrate
enzyme-substrate complex
H
2
N
CH
2
CH
2
CH
2
CH
2
CH
C
OH
O
NH
2
Lysine
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H
2
N
CH
2
CH
2
CH
2
CH
2
CH
C
OH
O
NH
2
Lysine
If lysine is part of the protein chain of the enzyme,
the terminal amino group is available to bind to
carbonyl groups to form an imine.