CHEM 222 Tutorial: Amines
Outline
CHEM 222 Tutorial: Amines
!
Summary ! !
Kylie Luska April 14, 2009
!
Preparation of Amines Reactivity of Amines
Examples
1
Preparation of Amines 1. 2. 3. 4. 5.
2
Aminolysis of Alkylhalides
Aminolysis of Alkylhalides Gabriel Synthesis Reductive Aminolysis Reduction Hofmann Degradation
R X
NH3
R NH3+ -Br
-HBr
R NH2
R X
H2+ -Br N R R -HBr
R
3
R N
R
-HBr
H -Br R N+ R R
R X R
H N
R
Features: ! Non-selective: Mixture of products. ! Formation of 1° product can be favoured: high concentration of NH3 and/or bulky R substituents.
4
Gabriel Synthesis
Reductive Aminolysis
O 1. R X
N H ,
O
-OH
O
O
Amide R Nitro
5
6
Hofmann Degradation LiAlH4 LiAlH4
NH2
R NO2
R
Features: ! In situ reduction of unstable imine intermediate. ! NaBH3CN permits reduction of imine without reacting with aldehyde.
Reduction R CN
HN
R NH2
2. Workup
Features: ! Selective formation of 1° amines. ! Workup: NH2-NH2 H3O+ or -OH
Nitrile
+ R NH2
NaBH3CN
Sn/HCl or Fe/HCl or Raney-Ni, H2
R R
NH2
O R
NaOH NH2
Br2
R NH2
NH2
R NH2 7
Features: ! Reaction occurs for 1° amides. ! Reduction of carbon chain length due to loss of CO2. 8
Reactivity of Amines 1. 2. 3. 4. 5. 6. 7.
Amines as Nucleophiles
Stereochemical Configuration Acidity Basicity Hydrogen Bonding Amines as Nucleophiles Synthesis via Diazonium Salts Hofmann Elimination
R
Br2
NH2
R
R'-I
R N
H
R'
O
OMe R' O
R'
+ N N
KI CuBr CuCl Cu2O H2O CuCN H3PO2 H2O
N H
R
N H
R
O
Cl R'
O
Synthesis via Diazonium Salts: Sandmeyer Reactions NaNO2
R H
O
O R'
9
HA(aq), !
R'
O
R'
NH2
Br
N H H N
N H
R
10
Synthesis via Diazonium Salts: Coupling Reactions I
OH + N N
Br Cl
+
OH
-OH
N
N + HO
OH
N
N
CN H 11
12
Problem 1: Provide the Required Reagents
Hofmann Elimination R
N+
Ag2O H2O, !
H
R +
H2N
Br
N
A. B.
Features: ! Removal of most acidic hydrogen or formation of least substituted alkene.
C. D.
NH3 (excess) 1. Phthalimide, -OH; 2. NH2-NH2, ! NH3 (1.0 eq.) NH3, NaBH3CN
13
Problem 2: Provide the Required Reagents O NH2
A. B. C. D.
10
14
Problem 3: Provide the Required Reagents NH2
10
H2, Raney-Ni 1. LiAlH4; 2. H3O+ 1. NaBH4; 2. H3O+ Br2, NaOH
A.
B. C.
15
D.
NH2
10
1. NaNO2, H2SO4; 2. Cu2O, H2O Br2, NaOH 1. NaNO2, H2SO4; 2. H3PO2, H2O Ag2O, H2O, !
16
Problem 4: Provide the Required Reagents NH2
Br
A.
B. C.
D.
Problem 5: Provide the Required Reagents
1. NaCN; 2. LiAlH4; 3. H3O+ H2NCH3 1. Phthalimide, -OH; 2. NH2-NH2, ! H2NCH3, NaBH3CN
1. MeI
10
N H
H
A.
H
H H
B.
N H
C.
N H
D.
H N
17
18
Problems 7: Provide the Reaction Pathway
Problems 6: Provide the Nucleophile and Electrophile
Ph
OH O Ph
+ HO
H Ph O
10
2. Ag2O, H2O, !
N H
O
Ph
OEt
O
O
Ph
Ph Ph O Ph
19
20
Problems 8: Provide the Reaction Pathway O
O
Problems 9: Provide the Reaction Pathway
O
Ph
OMe
21
OH +
OH
O
NEt2 Ph
22
CHEM 222 Tutorial: Amines
!
Summary ! !
Kylie Luska April 14, 2009
!
Preparation of Amines Reactivity of Amines
Examples
1
Preparation of Amines 1. 2. 3. 4. 5.
2
Aminolysis of Alkylhalides
Aminolysis of Alkylhalides Gabriel Synthesis Reductive Aminolysis Reduction Hofmann Degradation
R X
NH3
R NH3+ -Br
-HBr
R NH2
R X
H2+ -Br N R R -HBr
R
3
R N
R
-HBr
H -Br R N+ R R
R X R
H N
R
Features: ! Non-selective: Mixture of products. ! Formation of 1° product can be favoured: high concentration of NH3 and/or bulky R substituents.
4
Gabriel Synthesis
Reductive Aminolysis
O 1. R X
N H ,
O
-OH
O
O
Amide R Nitro
5
6
Hofmann Degradation LiAlH4 LiAlH4
NH2
R NO2
R
Features: ! In situ reduction of unstable imine intermediate. ! NaBH3CN permits reduction of imine without reacting with aldehyde.
Reduction R CN
HN
R NH2
2. Workup
Features: ! Selective formation of 1° amines. ! Workup: NH2-NH2 H3O+ or -OH
Nitrile
+ R NH2
NaBH3CN
Sn/HCl or Fe/HCl or Raney-Ni, H2
R R
NH2
O R
NaOH NH2
Br2
R NH2
NH2
R NH2 7
Features: ! Reaction occurs for 1° amides. ! Reduction of carbon chain length due to loss of CO2. 8
Reactivity of Amines 1. 2. 3. 4. 5. 6. 7.
Amines as Nucleophiles
Stereochemical Configuration Acidity Basicity Hydrogen Bonding Amines as Nucleophiles Synthesis via Diazonium Salts Hofmann Elimination
R
Br2
NH2
R
R'-I
R N
H
R'
O
OMe R' O
R'
+ N N
KI CuBr CuCl Cu2O H2O CuCN H3PO2 H2O
N H
R
N H
R
O
Cl R'
O
Synthesis via Diazonium Salts: Sandmeyer Reactions NaNO2
R H
O
O R'
9
HA(aq), !
R'
O
R'
NH2
Br
N H H N
N H
R
10
Synthesis via Diazonium Salts: Coupling Reactions I
OH + N N
Br Cl
+
OH
-OH
N
N + HO
OH
N
N
CN H 11
12
Problem 1: Provide the Required Reagents
Hofmann Elimination R
N+
Ag2O H2O, !
H
R +
H2N
Br
N
A. B.
Features: ! Removal of most acidic hydrogen or formation of least substituted alkene.
C. D.
NH3 (excess) 1. Phthalimide, -OH; 2. NH2-NH2, ! NH3 (1.0 eq.) NH3, NaBH3CN
13
Problem 2: Provide the Required Reagents O NH2
A. B. C. D.
10
14
Problem 3: Provide the Required Reagents NH2
10
H2, Raney-Ni 1. LiAlH4; 2. H3O+ 1. NaBH4; 2. H3O+ Br2, NaOH
A.
B. C.
15
D.
NH2
10
1. NaNO2, H2SO4; 2. Cu2O, H2O Br2, NaOH 1. NaNO2, H2SO4; 2. H3PO2, H2O Ag2O, H2O, !
16
Problem 4: Provide the Required Reagents NH2
Br
A.
B. C.
D.
Problem 5: Provide the Required Reagents
1. NaCN; 2. LiAlH4; 3. H3O+ H2NCH3 1. Phthalimide, -OH; 2. NH2-NH2, ! H2NCH3, NaBH3CN
1. MeI
10
N H
H
A.
H
H H
B.
N H
C.
N H
D.
H N
17
18
Problems 7: Provide the Reaction Pathway
Problems 6: Provide the Nucleophile and Electrophile
Ph
OH O Ph
+ HO
H Ph O
10
2. Ag2O, H2O, !
N H
O
Ph
OEt
O
O
Ph
Ph Ph O Ph
19
20
Problems 8: Provide the Reaction Pathway O
O
Problems 9: Provide the Reaction Pathway
O
Ph
OMe
21
OH +
OH
O
NEt2 Ph
22
