Β-Lactam

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Family of chemical compounds

title: "Β-Lactam" type: doc version: 1 created: 2026-02-28 author: "Wikipedia contributors" status: active scope: public tags: ["beta-lactams"] description: "Family of chemical compounds" topic_path: "general/beta-lactams" source: "https://en.wikipedia.org/wiki/Β-Lactam" license: "CC BY-SA 4.0" wikipedia_page_id: 0 wikipedia_revision_id: 0

::summary Family of chemical compounds ::

::figure[src="https://upload.wikimedia.org/wikipedia/commons/3/3b/Beta-lactam.svg" caption="2-Azetidinone, the simplest β-lactam"] ::

A β-lactam (**beta-lactam) ring is a four-membered lactam. A lactam is a cyclic amide, and beta-lactams are named so because the nitrogen atom is attached to the β-carbon atom relative to the carbonyl. The simplest β-lactam possible is 2-azetidinone. β-lactams are significant structural units of medicines as manifested in many β-lactam antibiotics.{{Cite journal | last1 = Fisher | first1 = J. F. | last2 = Meroueh | first2 = S. O. | last3 = Mobashery | first3 = S. | title = Bacterial resistance to β-lactam antibiotics: compelling opportunism, compelling opportunity | doi = 10.1021/cr030102i | journal = Chemical Reviews | volume = 105 | issue = 2 | pages = 395–424 | year = 2005 | pmid = 15700950

Clinical significance

Main article: β-Lactam antibiotic

::figure[src="https://upload.wikimedia.org/wikipedia/commons/2/2e/Beta-lactams.svg" caption="Core structures of some medicinally important beta-lactams. From left to right: [[penam]], [[penem]], [[carbapenem]], [[cepham]], and [[cephem]]."] ::

::figure[src="https://upload.wikimedia.org/wikipedia/commons/9/99/Penicillin_core.svg" caption="Penicillin core structure"] ::

The β-lactam ring is part of the core structure of several antibiotic families, the principal ones being the penicillins, cephalosporins, carbapenems, and monobactams, which are, therefore, also called β-lactam antibiotics. Nearly all of these antibiotics work by inhibiting bacterial cell wall biosynthesis. This has a lethal effect on bacteria, although any given bacteria population will typically contain a subgroup that is resistant to β-lactam antibiotics. Bacterial resistance occurs as a result of the expression of one of many genes for the production of β-lactamases, a class of enzymes that break open the β-lactam ring. More than 1,800 different β-lactamase enzymes have been documented in various species of bacteria. These enzymes vary widely in their chemical structure and catalytic efficiencies. When bacterial populations have these resistant subgroups, treatment with β-lactam can result in the resistant strain becoming more prevalent and therefore more virulent. β-lactam derived antibiotics can be considered one of the most important antibiotic classes but prone to clinical resistance. β-lactam exhibits its antibiotic properties by imitating the naturally occurring d-Ala-d-Ala substrate for the group of enzymes known as penicillin binding proteins (PBP), which have as function to cross-link the peptidoglycan part of the cell wall of the bacteria.

The β-lactam ring is also found in some other drugs such as the cholesterol absorption inhibitor drug ezetimibe.

Synthesis

The first synthetic β-lactam was prepared by Hermann Staudinger in 1907 by reaction of the Schiff base of aniline and benzaldehyde with diphenylketene in a [2+2] cycloaddition (Ph indicates a phenyl functional group): :[[Image:StaudingerLactam.svg]]

Many methods have been developed for the synthesis of β-lactams.

The Breckpot β-lactam synthesis produces substituted β-lactams by the cyclization of beta amino acid esters by use of a Grignard reagent. Mukaiyama's reagent is also used in modified Breckpot synthesis. : [[File:Breckpot synthesis.jpg|Breckpot synthesis]]

Reactions

Due to ring strain, β-lactams are more readily hydrolyzed than linear amides or larger lactams. This strain is further increased by fusion to a second ring, as found in most β-lactam antibiotics. This trend is due to the amide character of the β-lactam being reduced by the aplanarity of the system. The nitrogen atom of an ideal amide is sp2-hybridized due to resonance, and sp2-hybridized atoms have trigonal planar bond geometry. As a pyramidal bond geometry is forced upon the nitrogen atom by the ring strain, the resonance of the amide bond is reduced, and the carbonyl becomes more ketone-like. Nobel laureate Robert Burns Woodward described a parameter h as a measure of the height of the trigonal pyramid defined by the nitrogen (as the apex) and its three adjacent atoms. h corresponds to the strength of the β-lactam bond with lower numbers (more planar; more like ideal amides) being stronger and less reactive. Monobactams have h values between 0.05 and 0.10 angstroms (Å). Cephems have h values in of 0.20–0.25 Å. Penams have values in the range 0.40–0.50 Å, while carbapenems and clavams have values of 0.50–0.60 Å, being the most reactive of the β-lactams toward hydrolysis.

References

References

  1. (1987). "Heterocyclic Chemistry". Longman Scientific.
  2. (1972). "Cephalosporins and Penicillins : Chemistry and Biology". Academic Press.
  3. (October 2018). "Recent advances in β-lactam synthesis". Organic & Biomolecular Chemistry.
  4. (February 2017). "In silico serine β-lactamases analysis reveals a huge potential resistome in environmental and pathogenic species". Scientific Reports.
  5. (July 2012). "Avibactam is a covalent, reversible, non-β-lactam β-lactamase inhibitor". Proceedings of the National Academy of Sciences of the United States of America.
  6. (October 1965). "Mechanism of action of penicillins: a proposal based on their structural similarity to acyl-D-alanyl-D-alanine". Proceedings of the National Academy of Sciences of the United States of America.
  7. (2008). "Hugo (Ugo) Schiff, Schiff bases, and a century of beta-lactam synthesis". Angewandte Chemie.
  8. (1907). "Zur Kenntniss der Ketene. Diphenylketen". Justus Liebigs Ann. Chem..
  9. (2007). "Β-Lactams: Versatile Building Blocks for the Stereoselective Synthesis of Non-β-Lactam Products". Chemical Reviews.
  10. (2018). "Recent advances in β-lactam synthesis". Organic & Biomolecular Chemistry.
  11. (2014-08-27). "Chemical Synthesis of β-Lactams: Asymmetric Catalysis and Other Recent Advances". Chemical Reviews.
  12. (2010-09-15). "Breckpot β-Lactam Synthesis". John Wiley & Sons, Inc..
  13. "Breckpot Synthesis".
  14. (May 1980). "Penems and related substances". Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences.
  15. (1996). "Correlation of biological activity in β-lactam antibiotics with Woodward and Cohen structural parameters: A Cambridge database study". J. Chem. Soc. Perkin Trans..

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beta-lactams