Amines Synthesis and Reactions Dr. Sapna Gupta Synthesis of Amines – SN2

1) From Ammonia Using SN2

• Drawback is that multiple alkylations can occur

Amines - Synthesis and Reactions 2 Synthesis of Amines– Using Azide

2) Using azide

: : - - : + : - + - N3 :N N N: RN3 R N N N: Azide ion An alkyl azide (a good nucleophile)

+ - K N3 1. LiAlH4 Ph CH2 Cl Ph CH2 N3 + - Ph CH2 NH2 ArCO3 H 1 2. . KH ON3 Benzyl chloride Benzyl azidOe 2 Benzylamine 2 . H2 O Cyclohexene 1,2-Epoxy- cyclohexane

+ OH OH ArCO H 1 . K N - 1 . LiAlH 3 O 3 4 2 . H2 O 2 . H2 O N 3 NH2 Cyclohexene 1,2-Epoxy- trans- 2-Azido- trans- 2-Amino- cyclohexane cyclohexanol cyclohexanol OH (racemic) OH (racemic) 1 . LiAlH4 2 . H2 O N 3 NH2 trans-Amines2-Azido- - Synthesis and Reactions trans- 2-Amino- 3 cyclohexanol cyclohexanol (racemic) (racemic) Synthesis of Amines – Gabriel (for 1o)

3) Gabriel synthesis, pthalimide, for primary amines

Amines - Synthesis and Reactions 4 Synthesis of Amines – Reductive Amination

4) Reduction of imines from aldehydes and ketones Examples + H O + NH3 NH + H2 O Cyclohexanone Ammonia An imine (a Schiff base)

General Reaction

Amines - Synthesis and Reactions 5 Synthesis of Amines– Reduction

5) From reduction of nitriles, oximes and amides

General Reactions Examples

Amines - Synthesis and Reactions 6 Reduction of Nitro Group and Hoffman Rearrangement 6) From reduction of nitrobenzene

7) Hoffman Rearrangement: This is for 1o amines only. Start with an amide, treat it with Br2 and NaOH. See the next slide for mechanism of this reaction. (You don’t have to know the mechanism for exam.)

Amines - Synthesis and Reactions 7 Hoffman Rearrangement - Mechanism

Amines - Synthesis and Reactions 8 Reaction of Amines

1) Electrophilic reaction of aniline

- 2) Hoffman Elimination: NH2 is a poor leaving group, but it can be converted to an alkylammonium ion which is a good leaving group. Because of its bulkiness, the product is usually the anti-Zaitsev’s product (less stable alkene)

Amines - Synthesis and Reactions 9 Reaction of Amines – Nitrous Acids

• Nitrous acid, a weak acid, is prepared by treating sodium nitrite, NaNO2,with H2SO4 or HCl.

• In its reactions with amines, nitrous acid: • participates in proton-transfer reactions. • is a source of the nitrosyl cation, NO+, a weak electrophile. • Reaction with 3° amines: These do not react with nitrous acids.

1. NaNO2 , HCl, 0-5°C Me2 N Me2 N N=O 2. NaOH, H2 O N,N-Dimethylaniline N,N-Dimethyl-4-nitrosoaniline

Amines - Synthesis and Reactions 10 Reactions of Amines – Nitrous Acid with 2o Amines

2° Aliphatic and aromatic amines react with NO+ to give N- nitrosamines.

N-H + HNO2 N-N=O + H2 O

Piperidine N-Nitrosopiperidine

N – Nitroso amines are studied more for their toxicity.

Amines - Synthesis and Reactions 11 Reactions of Amines – Nitrous Acid with 1o Amines

• Formation of a diazonium ion. • Step 1: Reaction of a 1° amine with the nitrosyl cation. keto-enol

H : : : : + : : : tautomerism

+ : : R-N=N-O: -H R-NH2 N O R-N: -N=O: A 1° aliphatic An N-nitrosamine A diazotic acid amine • Step 2: Protonation followed by loss of water. H

: : : + H •• •• + - H2 O

R-N=N-O: -H R-N N O-H •• A diazotic acid + •• + •• •• R N N R + N N A diazonium ion A carbo- cation

Amines - Synthesis and Reactions 12 Reactions of Amines – Nitrous Acid with 1o Aliphatic Amines

Aliphatic diazonium ions are unstable and lose N2 to give a carbocation which can then: 1. Lose a proton to give an alkene. 2. React with a nucleophile to give a substitution product. 3. Rearrange and then react by Steps 1 and/or 2.

Cl (5.2% )

OH NaNO2 , HCl OH NH2 + o 0-5 C (13.2% ) (25% )

+ (25.9% ) (10.6% )

Amines - Synthesis and Reactions 13 Reactions of Amines – Nitrous Acid with 1o Aromatic Amines

Primary arylamines react with HNO2, yielding stable arenediazonium salts.

The N2 then can be replaced by any nucleophile. This is unusual as benzene ring does not undergo SN2 reactions.

Amines - Synthesis and Reactions 14 Reactions of Amines – Nitrous Acid with 1o Aromatic Amines

Amines - Synthesis and Reactions 15 Reactions of Amines – Nitrous Acid with Aromatic Amines – Sandmeyer Reaction • Replacement of the Diazonium Group by -Cl, -Br or -CN • The mechanism of the Sandmeyer reaction is not well-understood but is thought to occur via radicals

Amines - Synthesis and Reactions 16 Reactions of Amines – Nitrous Acid with Aromatic Amines • Replacement with Iodine

• Replacement with Fluorine

• Replacement with Hydroxide

Amines - Synthesis and Reactions 17 Reactions of Amines – Nitrous Acid with Aromatic Amines – Synthetic Applications 3, 5-dibromotoluene cannot be made directly from either toluene or bromobenzene. Bromination of toluene will give o, p – substitution.

However, treating p-methylaniline can be used with nitrous acid as in the following steps.

Amines - Synthesis and Reactions 18 Reactions of Amines – Nitrous Acid with Aromatic Amines – Diazonium Coupling Reaction • Arenediazonium ions react as electrophiles with highly reactive aromatic compounds such as phenol and aromatic tertiary amines • The reaction is called a diazo coupling reaction

Amines - Synthesis and Reactions 19 Coupling Reaction

• Phenol and aniline derivatives undergo coupling almost exclusively at the para position unless this position is blocked

• Azo compounds are commonly used as dyes • The azo coupling results in compounds which are highly conjugated and which often absorb light in the visible region - + • The - SO3 Na group is added to the molecule to confer water solubility and to link the dye to the polar fibers of wool, cotton etc. • Orange II is made from 2-naphthol

Amines - Synthesis and Reactions 20 Problems What reagents do you need to carry out the following reactions.

CH3 CH3 COOH COOH COOH

(1) (2) (3) (4)

NO2 NO2 NH2 OH

CH3 Cl

(5) CH3 CH3 CH3 NH C N CH NH 2 (7) 2 2 (6)

(8) CH3 CH3 NH 2 (9)

Cl Cl Cl Cl

Amines - Synthesis and Reactions 21 Key Concepts

• Synthesis – almost all reductions • Reactions • Diazonium salts • Coupling reaction • Aromatic synthesis

Amines - Synthesis and Reactions 22