Chapter 17 Carbonyl Compounds II 17.2

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17.2 How Aldehydes and Ketones
React (Part I)
d-
Electron rich (Lewis base, Nu)
d+
Electron deficient (Lewis acid, E+)
R = alkyl or aryl (C)
Y = alkyl, aryl or H (class II) (No leaving group)
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Class I vs. Class II Carbonyl Compounds
Class I
Y = NR’2 (amide)
= OR’ (ester, carboxylic acid)
= OCOR’ (acid anhydride)
= X (acyl halide)
Class II
Y = H (aldehyde)
= R’’ (ketone)
H-H (pKa = 35)
R-H (pKa = 50)
Hydride (H-) and
carboanion are not
leaving groups
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Relative Reactivity of Class I and Class
II Carbonyl Compounds
>
acyl halide
>>
acid anhydride
>
H
aldehyde
>
R’
ketone
>
ester
amide
Esters and amides are more stable than ketones and
aldehydes due to their resonance stabilization.
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Nucleophilic Addition (Class II)
1. General mechanism in basic condition:
2. General mechanism in acidic condition:
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Important pKa to Remember
Acids
H-Z
Names
Alkane (2°)
H 3C
CH
H
H 3C
H
Amine
N
H
H
Hydrogen
51
38
H
Carboxylic
Acid
Hydrochloric
Acid
H 3C
CH
H 3C
H
Base as Li+ salt
Nucleophile as Grignard reagent
Base in NaH, CaH2
Nucleophile in LiAlH4, NaBH4
H
Often as a base but can be a
nucleophile
15-16
R
NH
R
General Roles of :Z
Base and Nucleophile
N
35
H
10-11
H
H
Thiol
Conjugate
Base, :Z
H
Alcohol
water
Ammonium
Approx.
pKa
S
RCO
Cl
2
R
NH
H
H
10-11
H
4-5
RCO
-7
Cl
H
R
Weak base, but can be a
nucleophile
Nucleophile
S
2
Weak base, poor leaving group
Leaving group, poor nucleophile
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Types of Nucleophile for
Class II Carbonyl Groups
1. Carbon as the nucleophilic atom
Basic condition
pKa = 25
pKa = 50
carboanion
Acetylide ion
2. Hydrogen as the nucleophilic atom
hydride
Mostly basic condition
3. Nitrogen as the nucleophilic atom
1° and 2° amines
Mostly acidic condition
4. Oxygen as the nucleophilic atom
1° alcohols
Acidic condition
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Carbon as the Nucleophilic
Atom: Grignard Reagents
Carboanions are highly reactive.
Hard to find a base to do the deprotonation.
pKa = 50
carboanion
Formation of Grignard reagent
THF or
Et2O
X = Cl, Br or I
The carbonanions can be stabilized.
THF: tetrahydrofuran
Et2O: diethyl ether
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Reactions of Grignard Reagents
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Reactions of Grignard Reagents
3° alcohols
2° alcohols
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Reactions of Grignard Reagents
1° alcohols
(one extra carbon)
1° alcohols
(two extra carbons)
Carboxylic acid
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Reactions of Grignard Reagents
with Esters
1 mol.
0.5 mol.
1 mol.
0.5 mol.
1 mol.
2 mol.
1 mol.
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Reactions of Grignard Reagents
with Esters
Why two equivalents of Grignard reagent are needed?
A ketone (more
reactive than ester)
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Carbon as the Nucleophilic
Atom: Acetylide Ions
pKa = 25
pKa = 50
carboanion
Acetylide ion
Why the pKa of acetylide is much lower?
2Pz
2S
2Py
The radius of 2S orbital is
smaller than the radius of 2P
orbitals.
2Px
Order for the radius of hybridized orbitals: SP3 > SP2 > SP
Order for the electronegativity of hybridized orbitals: SP3 < SP2 < SP
Order for the acidity of H’s of hybridized orbitals: SP3 < SP2 < SP
pKa = 40
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Reactions of Carbonyl Groups
with Acetylide Ions
pKa = 25
Acetylide ion
pKa = 38
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Carbon as the Nucleophilic
Atom: Cyanide
Hydrogen cyanide is weakly acidic.
pKa = 9.1
cyanide
Cyanide is highly poisonous.
Addition of cyanide to aldehydes or ketones:
HCl
H+, H2O
heat
a-hydroxy carboxylic acid
Stable in acidic condition but
unstable in basic condition.
H2, Pt/C
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Hydrogen as the Nucleophilic Atom:
Hydride Reagents
Reagents that can provide hydrides as nucleophiles:
NaBH4
LiAlH4
Sodium boroydride
Lithium aluminum hydride
Theoretically, one molecule of LiAlH4 or NaBH4 can provide four hydrides.
Diisobutylaluminum hydride (DIBAL)
Reagents that can provide hydrides as bases:
NaH
CaH2
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Reactions of Aldehydes and Ketones
with Hydride Reagents
General Reactions:
1) LiAlH4 or NaBH4
2) H2O
Examples:
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General Mechanism for the
Reduction of Aldehydes and Ketones
Using Hydride Reagents
d-
Repeat 3 times
d-
The three H’s
can still act as
hydrides.
H2O
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Comparison of LiAlH4, DIBAL and
NaBH4
Relative Reactivity
LiAlH4
>
DIBAL
> NaBH > NaBH CN
4
Unstable in weak acid
3
Stable in weak acid
Amide
Ester
Carboxylic
acid
Ketone
Aldehyde
LiAlH4
yes
yes
yes
yes
yes
DIBAL
no
yes
?
yes
yes
NaBH4
no
no
no
yes
yes
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Reduction of Ester with LiAlH4
General reaction
1) LiAlH4
2) H2O
Mechanism
Reduction cannot stop at
the stage of aldehyde
H2O
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Reduction of Carboxylic Acids with
LiAlH4
General reaction
1) LiAlH4
2) H2O
Reduction cannot stop at
the stage of aldehyde
Mechanism
H2O
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Reduction of Amides with LiAlH4
General reaction
1) LiAlH4
2) H2O
Mechanism
H2O
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Reduction of Ester with DIBAL
General reaction
1) DIBAL, -78°C
2) H2O, -78°C
Reduction can stop at
the stage of aldehyde
1) DIBAL, -78° - 0°C
2) H2O, 0°C
Control of temperature is important for the
reduction to stop at the stage of aldehyde.
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Examples
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Examples
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Examples
No reaction
No reaction
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Selective Reduction
In most of the cases, hydride reducing reagents cannot
reduce C=C.
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Learning Check
1. What could be the reagent needed for this transformation?
2. What could be reagent needed for this transformation?
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Learning Check
3. What could be the product for the following reaction?
4. What could be the product for the following reaction?
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Learning Check
5. What could be the reagent needed for the following reaction?
6. What could be the product for the following reaction?
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Learning Check
7. What could be the product for the following reaction?
O
OCH3
(a)
OH
1) CH3CH2MgBr
(2 equivalents)
2) HCl, H2O
(b)
product ?
O
(c)
OH
O
(d)
CH2CH3
OH
CH2CH3
(e) none of the above
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Learning Check
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8. What could be the product for the following reaction?
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