Lactam

A lactam is a cyclic amide, formally derived from an amino alkanoic acid through cyclization reactions. The term is a portmanteau of the words lactone + amide.

From left to right, the above are general structures of β-lactam, a γ-lactam, a δ-lactam, and ε-lactam. Their common names are β-propiolactam, γ-butyrolactam, δ-valerolactam, and ε-caprolactam.

Nomenclature

Greek prefixes in alphabetical order indicate ring size.

Ring size (number of atoms in the ring)	Systematic name	IUPAC name	Common name(s)	Structure
3	α-Lactam	Aziridin-2-one	α-Acetolactam
4	β-Lactam	Azetidin-2-one	β-Propiolactam
5	γ-Lactam	Pyrrolidin-2-one	γ-Butyrolactam 2-Pyrrolidone
6	δ-Lactam	Piperidin-2-one	δ-Valerolactam 2-Piperidinone 2-piperidone
7	ε-Lactam	Azepan-2-one	ε-Caprolactam Caprolactam

This ring-size nomenclature stems from the fact that hydrolysis of an α-lactam gives an α-amino acid and that of a β-Lactam gives a β-amino acid, and so on.

Synthesis

General synthetic methods are used for the organic synthesis of lactams.

Beckmann rearrangement

Lactams form by the acid-catalyzed rearrangement of oximes in the Beckmann rearrangement.

Schmidt reaction

Lactams form from cyclic ketones and hydrazoic acid in the Schmidt reaction. Cyclohexanone with hydrazoic acid, forms ε - Caprolactum, which upon treatment with excess acid forms Cardiazole, a heart stimulant.

Cyclization of amino acids

Lactams can be formed from cyclisation of amino acids via the coupling between an amine and a carboxylic acid within the same molecule. Lactamization is most efficient in this way if the product is a γ-lactam. For example, Fmoc-Dab(Mtt)-OH, although its side-chain amine is sterically protected by extremely bulky 4-Methyltrityl (Mtt) group, the amine can still intramolecularly couple with the carboxylic acid to form a γ-lactam. This reaction almost finished within 5 minutes with many coupling reagents (e.g. HATU and PyAOP).^[1]

Intramolecular nucleophilic substitution

Lactams form from intramolecular attack of linear acyl derivatives from the nucleophilic abstraction reaction.

Iodolactamization

An iminium ion reacts with a halonium ion formed in situ by reaction of an alkene with iodine.^[2]

Kinugasa reaction

Lactams form by copper-catalyzed 1,3-dipolar cycloaddition of alkynes and nitrones in the Kinugasa reaction

Diels-Alder 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^[3] is obtained.^[4]

Lactam–lactim tautomerism

A lactim is a cyclic imidic acid compound characterized by an endocyclic carbon-nitrogen double bond. They are formed when lactams undergo tautomerization.

   Lactam                                                    Lactim

Reactions

• Lactams can polymerize to polyamides.

See also

• Lactone, a cyclic ester.
• β-Lactam
• β-Lactam antibiotics, which includes penicillins
• 2-Pyrrolidone
• 2-Piperidinone
• Caprolactam

References

1. Lam, Pak-Lun; Wu, Yue; Wong, Ka-Leung (30 March 2022). "Incorporation of Fmoc-Dab(Mtt)-OH during solid-phase peptide synthesis: a word of caution". Organic & Biomolecular Chemistry. 20 (13): 2601–2604. doi:10.1039/D2OB00070A. ISSN 1477-0539. PMID 35258068. S2CID 247175352.
2. Spencer Knapp, Frank S. Gibson Organic Syntheses, Coll. Vol. 9, p.516 (1998); Vol. 70, p.101 (1992) Online article
3. Singh, R.; Vince, R. Chem. Rev. 2012, 112 (8), pp 4642–4686."2-Azabicyclo[2.2.1]hept-5-en-3-one: Chemical Profile of a Versatile Synthetic Building Block and its Impact on the Development of Therapeutics"
4. Pham, P.-T.; Vince, R. Phosphorus, Sulphur and Silicon 2007, 779-791.

External links

• Media related to Lactams at Wikimedia Commons