17.3 How Aldehydes and Ketones React (Part II)
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C
O
C
O
C
O
YR
d+
R = alkyl or aryl (C)Y = alkyl, aryl or H (class II) (No leaving group)
d-Electron rich (Lewis base, Nu)
Electron deficient (Lewis acid, E+)
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Nucleophilic Addition (Class II)
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1. General mechanism in basic condition:
C
O
R'(H)R
+ Z+ H+
C
O
RC
O
R'(H)
R Z- H+
C
OH
R'(H)
R Z
2. General mechanism in acidic condition:
C
O
R'(H)RZ
+ H+
C
O
R- H+
C
OH
R'(H)
R ZC
O
R'(H)R
H
Important pKa to Remember
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Names AcidsH-Z
Approx. pKa
Conjugate Base, :Z General Roles of :Z
Alkane (2°) 51 Base as Li+ saltNucleophile as Grignard reagent
Amine 38 Base and Nucleophile
Hydrogen 35Base in NaH, CaH2Nucleophile in LiAlH4, NaBH4
Alcohol water 15-16 Often as a base but can be a
nucleophile
Ammonium 10-11 Weak base, but can be a nucleophile
Thiol 10-11 Nucleophile
Carboxylic Acid 4-5 Weak base, poor leaving group
Hydrochloric Acid -7 Leaving group, poor nucleophile
H3CCH
H3CH
H3CCH
H3C
HN
HH
HN
H
H H H
R O H R O
RNH
HH
RNH
H
SR H R S
HRCO2 RCO2
HCl Cl
Types of Nucleophile for Class II Carbonyl Groups
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1. Carbon as the nucleophilic atom
HC H+C +
pKa = 50
Basic condition
2. Hydrogen as the nucleophilic atom
carboanion
H hydride Mostly basic condition
3. Nitrogen as the nucleophilic atom1° and 2° amines Mostly acidic condition
4. Oxygen as the nucleophilic atomAcidic condition
NH2
1° alcoholsOH
HCC H+CC +pKa = 25 Acetylide ion
Nitrogen as the Nucleophilic Atom
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pKa of amines.
HN H+N +
pKa = 38
1° and 2°Amines function as weak bases or nucleophiles.
HN H+N +
pKa = 9-10
3° Amines function as weak bases.
Reactions of Aldehydes and Ketones with Amines
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General Reactions:
O
CCR
H
H+
H2N R+
N
CCR
H
R
+ H2O1° Amines
imine (Schiff base)
O
CCR
H
H+
HN R+
R'
N
CCR
R
+ H2O
R'
2° Aminesenamine
Reactions of Aldehydes and Ketones with Primary Amines
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Examples:O
CCH3
H+
H2N CH2CH3+
NCH2CH3
CCH3 + H2O
NH2
OHC CH2CH3+H+ N
+ H2O
CH2CH3
Reactions of Aldehydes and Ketones with Secondary Amines
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Examples:
O
CCH3
H+N+
H
N
CCH2 + H2O
O+
NH
H+ N+ H2O
Mechanism for the formation of Imines
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C
O
CH3H3CPh
N
H H
C
O
NH3C
HH3C
Ph
H
C
O
NH3CH3C
Ph
H A-
H A
H
AH
A-
C
O
NH3CH3C
Ph
H
A-
H
H
C
O
N
H3C
H3C
Ph
H
A-
H
H
C
O
N
H3C
H3C
Ph
H
A
H
H
Mechanism for the formation of Enamines
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O
N
H
O
N
H
O
N
H A-
H A
AH
A-
O
N
H
A-
H
O
N
H
A-
H
H
O
N
H
A
H
H
Optimal pH for the Formation of Imines
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C
O
CH3H3CPh
N
H H
C
O
NH3C
HH3C
Ph
H
C
O
NH3CH3C
Ph
H A-
H A
H
AH
A-
C
O
NH3CH3C
Ph
H
A-
H
H
C
O
N
H3C
H3C
Ph
H
A
H
H
pKa = 9-10pKa = -2
The highlighted protons are quite acidic.
Strong acid will protonate the amines.
Optimal pH: 4 – 5 (ex: acetic acid) pH
Rate of rxn
0 4 5 10
Formation of Imine Derivatives
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O
CR'(H)R
H+
H2N OH+N
CR'(H)R
OH
+ H2OHydroxylamineOxime
O
CR'(H)R
H+
H2N NH
+C
NH2
O
N
CR'(H)R
HN
+ H2O
CNH2
Osemicarbazidesemicarbazone
O
CR'(H)R
H+
H2N NH
+R"
N
CR'(H)R
HN
+ H2O
R"
hydrazine
hydrazone
Application of Imine: Reductive Amination
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General reaction
The reaction can be conducted in one-pot fashion.
O
CR'(H)R
H+
H2N R"+N
CR'R
R"
Generatedin situ
H2, Pd/C
NaBH3CN
HN
CR'R
R"
H
HN
CR'R
R"
H
The use of NaBH3CN is important since it can tolerate the acidic condition.
Examples of Reductive Amination
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O
H2NCH2CH3, H2/Pt/CHOAc
NH
H
O H2NC6H5NaBH3CN, HOAc
NH
H2NCH2C6H5, NaBH3CNHOAc
CHO
HN
Application of Oxime: Beckmann Rearrangement
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Developed by the German chemist Ernst Otto Beckmann (1853–1923)
O
H2NOH, H+
NOH
H+, heat
O
NH
2-azacycloheptanone(a lactam)
nylon
NH
HN
O
O
n
oxime
Beckmann Rearrangement: Synthesis of Azithromycin
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Developed by a team of researchers at the Croatian pharmaceutical company Pliva in 1980.
lactam Azithromycin
O
MeO
OH
O
OH
Me
Me
MeO
Me
OH
Me
Et
OO
OHNMe2
Me
O OH
OMe
Me
Me
H2NOHH+
NOH
MeO
OH
O
OH
Me
Me
MeO
Me
OH
Me
Et
OO
OHNMe2
Me
O OH
OMe
Me
Me
H+
heat
Erythromycin oxime
HN
MeO
OH
O
OH
Me
Me
MeO
Me
OH
Me
Et
OO
OHNMe2
Me
O OH
OMe
Me
Me
OHN
MeO
OH
O
OH
Me
Me
MeO
Me
OH
Me
Et
OO
OHNMe2
Me
O OH
OMe
Me
Me
Mechanism of Beckmann Rearrangement
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O
H2NOH, H+
NOH
+ H+
- H+
NO
H
H
O
NH
NH2O
O
N
H H
H+
+ H+
O
NH
H
- H+
Application of Hydrazone: Deoxygenation of Carbonyl Groups
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the Wolff–Kishner reduction
O
RH2NNH2, KOH
H2Oheating
R
Mechanism of the Wolff–Kishner Reduction
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CH3C
N N
H
H
HO
H
O H
C
O
H3C
H2N NH2
C
O
H3C
H2N N
H
O H
H
C
O
H3C
H2N NH
HO
H
C
O
H3C
H2N N
H OH
H
O H
CH3C
HN N
H
HO
H
O HHO
H
O H
CH3C
N N
H
H
O H
HO
H
Application of Hydrazone: Use of 2,4-DNP
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2,4-Dinitrophenylhydrazine (2,4-DNP)
R R'(H)
O
2,4-DNP
NO2
HN
N
R'(H)
R NO2
General reaction:NO2
HN
NH2 NO2
The hydrazones have specific m.p.
Aldehyde or ketone Acetone Diethyl
ketone Cyclohexanone Benzaldehyde
m.p. of hydrazone (°C) 126 156 162 237
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Learning Check1. What could be the best reagents for the following reaction?
O reagents(a) H2NEt and CH3CO2H
(e) None of the above
NCH2CH3(b) H2NEt and HCl
(c) H2NEt and NaOH (d) H2NEt and Na+-OCH3
2. What could be the product for the following reaction?
O
CH3
CH3NH2H+, removal of water
NCH3
CH3
Product ?
NHCH3
O
OH
O NHCH3
CH3
I II III IV
H3CHN
(a) I(b) II(c) III(d) IV(e) None of the
above
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Learning Check3. What could be the products for the following reaction?
O
CH2CH3 H+
, removal of waterProducts
NH
+
N N
I
N
IIIII
N N
IV
(a) I, II(b) I, II, IV(c) III, IV(d) II, III(e) None of the above
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Learning Check4. What could be the product for the following reaction?
O H2NOH, H+
heat
NHOH
(a)NOH
(b) (c)NH
O(d)
NH(e) None of the above
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