Conventional Methods for

Amide Bond Formation

MC-810

Presented by

Gurudutt Dubey

16MCP431

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There are three different ways of forming amide bonds

(1)The reactive acylating agent is formed in a separate step, prior to the

reaction with the amine

(2)The reagent is generated in situ in the presence of the amino group by

adding the activating agent to a mixture of the two reagents

Approaches to amide bond formation

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Amide bond formation: methods and strategies

Carboxy components can be activated as

Acyl halides

Acyl azides

Acylimidazoles

Anhydrides

Esters

Carbodiimide coupling agents

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Acyl chloride formation:

Common Chlorinating agents

1. Thionyl chloride (SOCl2)

2. Oxalyl chloride (COCl)2

3. Phosphorus trichloride PCl3

4. Phosphorus oxychloride POCl3

5. Phosphorus pentachloride PCl5

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Thionyl chloride

Oxalyl chloride

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Acyl chloride formation using cyanuric chloride

Acyl chloride formation using TPP and carbon tetrachloride

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Coupling reaction with acyl chlorides

• An additional base is required to trap the formed HCl and to avoid the conversion of the amineinto its unreactive HCl salt

• Couplings are usually performed in inert dry solvents, in the presence of a non-nucleophilictertiary amine (NEt3, iPr2NEt [also called Hunig’s base])

• Acyl chlorides are often robust enough to be coupled to amines under aqueous conditions, for

example, in the presence of NaOH (Schotten–Baumann conditions)

Aminolysis

Catalytic role of pyridine

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Coupling reaction with acyl chlorides

• An additional base is required to trap the formed HCl and to avoid the conversion of the amineinto its unreactive HCl salt

• Couplings are usually performed in inert dry solvents, in the presence of a non-nucleophilictertiary amine (NEt3, iPr2NEt [also called Hunig’s base])

• Acyl chlorides are often robust enough to be coupled to amines under aqueous conditions, for

example, in the presence of NaOH (Schotten–Baumann conditions)

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Acyl azides formation

Possible side reaction: Curtius rearrangement

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Diphenylphosphoryl azide (DPPA)

One-pot amide preparation using DPPA

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Acyl azides formation

Acylimidazoles formation using Carbonyl diimidazole (CDI)

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Anhydrides Formation

1. Symmetric anhydrides

2. Mixed anhydrides

• Mixed carboxylic anhydrides: Mixed pivalic anhydrides

• Mixed carbonic anhydrides: Ethoxycarbonyl anhydrides

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Two-step coupling procedure via pivalic anhydride

Two-step coupling via ethyl carbonic anhydride

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Activated Esters Formation

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Dicyclohexylcarbodiimide

Coupling using carbodiimides

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References:

1. Montalbetti, C. A. G. N.; Falque, V. Amide bond formation and peptide coupling.

Tetrahedron 2005, 61, 10827–10852.

2. Valeur, E.; Bradley, M. Amide bond formation: beyond the myth of coupling

reagents. Chem. Soc. Rev. 2009, 38, 606–631.

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Thank you