Lactam

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From left to right, general structures of a β-lactam, a γ-lactam, a δ-lactam and a ε-lactam.

A lactam (the noun is a portmanteau of the words lactone + amide) is a cyclic amide. Prefixes indicate how many carbon atoms (apart from the carbonyl moiety) are present in the ring: β-lactam (2 carbon atoms outside the carbonyl, 4 ring atoms in total), γ-lactam (3 and 5 total), δ-lactam (4 and 6 total). Beta β, gamma γ and delta δ are the second, third and fourth letters in the alphabetical order of the Greek alphabet, respectively.

Synthesis

General synthetic methods exist for the organic synthesis of lactams.

• Lactams form by the acid-catalyzed rearrangement of oximes in the Beckmann rearrangement.
• Lactams form from cyclic ketones and hydrazoic acid in the Schmidt reaction.
• Lactams form from cyclisation of amino acids.
• Lactams form from intramolecular attack of linear acyl derivatives from the nucleophilic abstraction reaction.
• In iodolactamization an iminium ion reacts with an halonium ion formed in situ by reaction of an alkene with iodine.

• Lactams form by copper catalyzed 1,3-dipolar cycloaddition of alkynes and nitrones in the Kinugasa reaction
• Diels-Alder reaction between cyclopentadiene and chlorosulfonyl isocyanate (CSI) can be utilized to obtain both β- as well as γ-lactam. At lower temp (−78 °C) β-lactam is the preferred product. At optimum temperatures, a highly useful γ-lactam known as Vince Lactam is obtained.

Tautomerization to Lactim

Lactim is a cyclic carboximidic acid compound characterized by an endocyclic carbon-nitrogen double bond. It is formed when lactam undergoes tautomerization.

Reactions

• Lactams can polymerize to polyamides.

See also

• β-lactam with a four-membered ring found in beta-lactam antibiotics. Penicillin, considered the most famous antibiotic, is a β-lactam antibiotic.
• Lactone, a cyclic ester.
• Caprolactam

 problem

How the formation of lactams in the Schmidt reaction?

The Schmidt reaction is an organic reaction involving alkyl migration over the carbon-nitrogen chemical bond in an azide with expulsion of nitrogen A key reagent introducing this azide group is hydrazoic acid and the reaction product depends on the type of reactant: Carboxylic acids form amines through an isocyanate intermediate (1) and ketones form amides (2):

A catalyst that can be a protic acid - usually sulfuric acid or a Lewis acid - is required. The reaction was discovered in 1924 by Karl Friedrich Schmidt (1887–1971) who successfully converted benzophenone and hydrazoic acid to benzanilide. It is a tool regularly used in organic chemistry for the synthesis of new organic compounds, for example, in that of the unusual 2-quinuclidone.

Reaction mechanism

The carboxylic acid Schmidt reaction starts with acylium ion 1 obtained from protonation and loss of water. Reaction with hydrazoic acid forms the protonated azido ketone 2, which goes through a rearrangement reaction with the alkyl group R, migrating over the C-N bond with expulsion of nitrogen. The protonated isocyanate is attacked by water forming carbamate 4, which after deprotonation loses carbon dioxide to the amine.

The reaction is related to the Curtius rearrangement except that in this reaction the azide is protonated and hence with different intermediates.

In the reaction mechanism for the ketone Schmidt reaction, the carbonyl group is activated by protonation for nucleophilic addition by the azide, forming intermediate 3, which loses water in a elimination reaction to temporary imine 4, over which one of the alkyl groups migrates from carbon to nitrogen with loss of nitrogen. A similar migration is found in the Beckmann rearrangement. Attack by water and proton loss converts 5 to 7, which is a tautomer of the final amide.

Reactions involving alkyl azides

The scope of this reaction has been extended to reactions of carbonyls with alkyl azides R-N₃. This extension was first reported by J.H. Boyer in 1955 (hence the name Boyer reaction), for example, the reaction of m-nitrobenzaldehyde with β-azido-ethanol:

Variations involving intramolecular Schmidt reactions have been known since 1991. An intramolecular reaction has been applied to the synthesis of novel bicyclic lactams