Conventional methods for amide bond formation
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Transcript of Conventional methods for amide bond formation
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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
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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