CHEM 222 Tutorial: Amines
CHEM 222 Tutorial: Amines Kylie Luska April 14, 2009
1
Outline
Summary
Preparation of Amines Reactivity of Amines
Examples
2
Preparation of Amines 1. 2. 3. 4. 5.
Aminolysis of Alkylhalides Gabriel Synthesis Reductive Aminolysis Reduction Hofmann Degradation
3
Aminolysis of Alkylhalides R X
NH3
R NH3+ -Br
-HBr
R NH2
R X
H2+ -Br N R R -HBr
R
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 O 1. R X
N H , -OH O
2. Workup
Features: Selective formation of 1° amines. Workup: NH2-NH 1. H3O+; 2. -OH
R NH2
5
Reductive Aminolysis O
+ R NH2
NaBH3CN
R NH2
Features: In situ reduction of unstable imine intermediate. NaBH3CN permits reduction of imine without reacting with aldehyde. 6
Reduction Nitrile
R CN O
Amide R Nitro
LiAlH4 LiAlH4
NH2
R NO2
Sn/HCl or Fe/HCl or H2, Raney-Ni
R
NH2
R
NH2
R NH2 7
Hofmann Degradation O R
NaOH NH2
Br2
R NH2
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.
Stereochemical Configuration Acidity Basicity Hydrogen Bonding Amines as Nucleophiles Synthesis via Diazonium Salts Hofmann Elimination 9
Amines as Nucleophiles R
Br2
NH2
R
R'-I
Br
N H H N
R
R'
O H
N H
O R'
R
O
OMe R' O
R'
N H
R
N H
R
O
Cl R'
O O
R' R'
N H
R
10
Synthesis via Diazonium Salts: Sandmeyer Reactions NH2
NaNO2 HA(aq), !
+ N N
KI CuBr CuCl Cu2O CuCN H3PO2
I Br Cl OH CN H 11
Synthesis via Diazonium Salts: Coupling Reactions OH + N N
+
OH
-OH
N
N + HO N
N
12
Hofmann Elimination R
N+ H
Ag2O H2O, !
R +
N
Features: Removal of most acidic hydrogen or formation of least substituted alkene. 13
Problems 1: Provide Required Reagents H
H H2N
Br O H
O NH2
H N
NH2
O N
N
14
Problems 2: Provide Required Reagents NO2
NH2
O
O Cl
N
CN NH2
NH2
CN 15
Problems 3: Provide Required Product 1. MeI N H
2. Ag2O, H2O, ! 1.
O
CN , -OH
2. LiAlH4 1.
O Cl
N H
2. LiAlH4
1. MeI N H
2. Ag2O, H2O, ! 16
Problems 4: Provide the Nucleophile and Electrophile OH O Ph
H Ph O
O
Ph
OEt
O
O
Ph
Ph Ph O Ph
17
Problems 5: Provide the Reaction Pathway Ph + HO
N H
18
Problems 6: Provide the Reaction Pathway NO2
NO2 NC Cl
19
Problems 7: Provide the Reaction Pathway
20
Problems 8: Provide the Reaction Pathway O
Br H
MeO
MeO
21
1
Outline
Summary
Preparation of Amines Reactivity of Amines
Examples
2
Preparation of Amines 1. 2. 3. 4. 5.
Aminolysis of Alkylhalides Gabriel Synthesis Reductive Aminolysis Reduction Hofmann Degradation
3
Aminolysis of Alkylhalides R X
NH3
R NH3+ -Br
-HBr
R NH2
R X
H2+ -Br N R R -HBr
R
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 O 1. R X
N H , -OH O
2. Workup
Features: Selective formation of 1° amines. Workup: NH2-NH 1. H3O+; 2. -OH
R NH2
5
Reductive Aminolysis O
+ R NH2
NaBH3CN
R NH2
Features: In situ reduction of unstable imine intermediate. NaBH3CN permits reduction of imine without reacting with aldehyde. 6
Reduction Nitrile
R CN O
Amide R Nitro
LiAlH4 LiAlH4
NH2
R NO2
Sn/HCl or Fe/HCl or H2, Raney-Ni
R
NH2
R
NH2
R NH2 7
Hofmann Degradation O R
NaOH NH2
Br2
R NH2
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.
Stereochemical Configuration Acidity Basicity Hydrogen Bonding Amines as Nucleophiles Synthesis via Diazonium Salts Hofmann Elimination 9
Amines as Nucleophiles R
Br2
NH2
R
R'-I
Br
N H H N
R
R'
O H
N H
O R'
R
O
OMe R' O
R'
N H
R
N H
R
O
Cl R'
O O
R' R'
N H
R
10
Synthesis via Diazonium Salts: Sandmeyer Reactions NH2
NaNO2 HA(aq), !
+ N N
KI CuBr CuCl Cu2O CuCN H3PO2
I Br Cl OH CN H 11
Synthesis via Diazonium Salts: Coupling Reactions OH + N N
+
OH
-OH
N
N + HO N
N
12
Hofmann Elimination R
N+ H
Ag2O H2O, !
R +
N
Features: Removal of most acidic hydrogen or formation of least substituted alkene. 13
Problems 1: Provide Required Reagents H
H H2N
Br O H
O NH2
H N
NH2
O N
N
14
Problems 2: Provide Required Reagents NO2
NH2
O
O Cl
N
CN NH2
NH2
CN 15
Problems 3: Provide Required Product 1. MeI N H
2. Ag2O, H2O, ! 1.
O
CN , -OH
2. LiAlH4 1.
O Cl
N H
2. LiAlH4
1. MeI N H
2. Ag2O, H2O, ! 16
Problems 4: Provide the Nucleophile and Electrophile OH O Ph
H Ph O
O
Ph
OEt
O
O
Ph
Ph Ph O Ph
17
Problems 5: Provide the Reaction Pathway Ph + HO
N H
18
Problems 6: Provide the Reaction Pathway NO2
NO2 NC Cl
19
Problems 7: Provide the Reaction Pathway
20
Problems 8: Provide the Reaction Pathway O
Br H
MeO
MeO
21
