# Maleimide

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Maleimide Names IUPAC name Maleimide Preferred IUPAC name 1H-Pyrrole-2,5-dione Other names 2,5-Pyrroledione Identifiers CAS Number 541-59-3 Y 3D model (JSmol) Interactive image ChEBI CHEBI:16072 N ChEMBL ChEMBL387762 Y ChemSpider 10471 Y ECHA InfoCard 100.007.990 EC Number 208-787-4 KEGG C07272 Y PubChem CID 10935 UNII 2519R1UGP8 Y CompTox Dashboard (EPA) DTXSID3049417 InChI InChI=1S/C4H3NO2/c6-3-1-2-4(7)5-3/h1-2H,(H,5,6,7) Y Key: PEEHTFAAVSWFBL-UHFFFAOYSA-N Y InChI=1/C4H3NO2/c6-3-1-2-4(7)5-3/h1-2H,(H,5,6,7) Key: PEEHTFAAVSWFBL-UHFFFAOYAL SMILES C1=CC(=O)NC1=O Properties Chemical formula C4H3NO2 Molar mass 97.07 g/mol Melting point 91 to 93 °C (196 to 199 °F; 364 to 366 K) Solubility in water organic solvents Hazards GHS labelling: Pictograms Signal word Danger Hazard statements H301, H314, H317 Precautionary statements P260, P264, P270, P272, P280, P301+P310, P301+P330+P331, P302+P352, P303+P361+P353, P304+P340, P305+P351+P338, P310, P321, P330, P333+P313, P363, P405, P501 Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). N verify (what is YN ?) Infobox references

Chemical compound

**Maleimide** is a [chemical compound](/source/Chemical_compound) with the [formula](/source/Chemical_formula) H2C2(CO)2NH (see diagram). This unsaturated [imide](/source/Imide) is an important building block in [organic synthesis](/source/Organic_synthesis). The name is a contraction of [maleic acid](/source/Maleic_acid) and [imide](/source/Imide), the -C(O)NHC(O)- [functional group](/source/Functional_group). Maleimides are also a *class* of derivatives of the parent maleimide where the N*H* group is replaced with [alkyl](/source/Alkyl) or [aryl](/source/Aryl) groups such as a [methyl](/source/Methyl) or [phenyl](/source/Phenyl), respectively. The substituent can also be a small molecule (such as [biotin](/source/Biotin), a fluorescent dye, an [oligosaccharide](/source/Oligosaccharide), or a [nucleic acid](/source/Nucleic_acid)), a reactive group, or a [synthetic polymer](/source/Synthetic_polymer) such as [polyethylene glycol](/source/Polyethylene_glycol).[1] Human [hemoglobin](/source/Hemoglobin) chemically modified with maleimide-polyethylene glycol is a [blood substitute](/source/Blood_substitute) called MP4.

## Reactions

Many analogues of maleimide are prepared by treating [maleic anhydride](/source/Maleic_anhydride) with [amines](/source/Amine) followed by dehydration.[2]

A defining feature of the reactivity of maleimides is their susceptibility to additions across the double bond either by [Michael additions](/source/Michael_addition) or via [Diels-Alder](/source/Diels-Alder) reactions. In this context, **bismaleimides**, compounds with two maleimide groups connected by the nitrogen atoms via a linker, are used as [crosslinking reagents](/source/Crosslinking_reagent) in [thermoset polymer](/source/Thermosetting_polymer) chemistry. Compounds containing a maleimide group linked with another reactive group, such as an activated [N-hydroxysuccinimide](/source/N-hydroxysuccinimide) ester, are called **maleimide heterobifunctional reagents** (see [SMCC reagent](/source/Succinimidyl_4-(N-maleimidomethyl)cyclohexane-1-carboxylate) for such an example).[1]

Maleimide is weakly acidic, with a [pKa](/source/PKa) estimated at 10.[3]

## Natural maleimides

One natural maleimide is the [cytotoxic](/source/Cytotoxicity) [showdomycin](/source/Showdomycin) from *[Streptomyces showdoensis](/source/Streptomyces_showdoensis)*,[4] and [pencolide](/source/Pencolide) from *Pe. multicolor*[4] – have been reported. [Farinomalein](/source/Farinomalein) was first isolated in 2009 from the [entomopathogenic fungus](/source/Entomopathogenic_fungus) *Isaria farinosa* (*Paecilomyces farinosus*) – source H599 (Japan).[5]

## Biotechnology and pharmaceutical applications

Maleimide-mediated methodologies are among the most used in [bioconjugation](/source/Bioconjugation).[6][7] Due to fast reactions and high selectivity towards [cysteine](/source/Cysteine) residues in [proteins](/source/Proteins), a large variety of maleimide heterobifunctional reagents are used for the preparation of targeted therapeutics, assemblies for studying proteins in their biological context, protein-based microarrays, or proteins immobilisation.[8] For instance, [antibody-drug conjugates](/source/Antibody-drug_conjugates), are constituted of three main components: a [monoclonal antibody](/source/Monoclonal_antibody), a cytotoxic drug, and a linker molecule often containing a maleimide group, which conjugates the drug through thiols or dienes to the antibody.[9][10]

Maleimides linked to [polyethylene glycol](/source/Polyethylene_glycol) chains are often used as flexible linking molecules to attach proteins to surfaces. The double bond readily undergoes a retro-Michael reaction with the [thiol](/source/Thiol) group found on [cysteine](/source/Cysteine) to form a stable carbon-sulfur bond. Cysteines are often used for site-selective modifications for therapeutic purposes because of the rapid rate of complete bioconjugation with sulfhydryl groups, allowing for higher levels of cytotoxic drug incorporations.[11] Attaching the other end of the polyethylene chain to a bead or solid support allows for easy separation of protein from other molecules in solution, provided these molecules do not also possess thiol groups.

Maleimide-functionalised polymers and liposomes exhibit enhanced ability to adhere to mucosal surfaces ([mucoadhesion](/source/Mucoadhesion)) due to the reactions with thiol-containing mucins.[12][13][14] This could be applicable in the design of dosage forms for transmucosal drug delivery.

The retro-Michael reactions resulting in maleimide-thiol adducts require precise control. The targeting ability of drugs containing the adducts can be easily hindered or lost due to their instability in vivo.[15] The instability is mainly attributed to the formation of the thiosuccinimide which might be involved in thiol exchange reaction with glutathione. B-elimination reaction follows, resulting in off-target activity and a loss of efficacy of the drugs.[10]

No general method exist for stabilizing thioesters, such as thiosuccinimides, so that their off-target effects can be eliminated in drugs. Problems associated with thiol exchange can be mitigated by hydrolyzing the thiosuccinimide, which prevents elimination of the maleimide-thiol bond. The process of ring-opening hydrolysis requires special catalysts and bases, which may not be biocompatible and lead to harsh conditions. Alternatively, cysteines in the positively charged environment or an electron-withdrawing group enable the thiosuccinimide ring to undergo self-hydrolysis.[15]

Another problem with hydrolysis arises if it is applied to *N*-alkyl-substituted derivatives instead of the N-aryl-substituted derivatives because they hydrolyze at a rate that’s too slow to yield consistently stable adducts.[10]

## Technological applications

Analogous to [Styrene maleic anhydride](/source/Styrene_maleic_anhydride), [copolymers](/source/Copolymer) of maleimides and [styrene](/source/Styrene) have been commercialized.[16]

Mono- and bismaleimide-based polymers are used for high temperature applications up to 250 °C (480 °F).[17] Maleimides linked to rubber chains are often used as flexible linking molecules to reinforce rubber in [tires](/source/Tires). The double bond readily reacts with all [hydroxy](/source/Hydroxyl), [amine](/source/Amine) or [thiol](/source/Thiol) groups found on the matrix to form a stable carbon-oxygen, carbon-nitrogen, or carbon-sulfur bond, respectively. These polymers are used in aerospace for high temperature applications of composites. Lockheed Martin's [F-22](/source/Lockheed_Martin_F-22_Raptor) extensively uses thermoset composites, with bismaleimide and toughened epoxy comprising up to 17.5% and 6.6% of the structure by weight respectively.[18] Lockheed Martin's F-35B (a STOVL version of this US fighter) is reportedly composed of bismaleimide materials, in addition to the use of advanced carbon fiber [thermoset polymer matrix](/source/Thermoset_polymer_matrix) composites.[19]

## See also

- [*N*-Methylmaleimide](/source/N-Methylmaleimide)

- [Succinimide](/source/Succinimide)

## References

1. ^ [***a***](#cite_ref-Hermanson2013_1-0) [***b***](#cite_ref-Hermanson2013_1-1) Hermanson G (2013). "Chapter 6: Heterobifunctional Crosslinkers". *Bioconjugate Techniques*. Elsevier. pp. 299–339. [doi](/source/Doi_(identifier)):[10.1016/B978-0-12-382239-0.00006-6](https://doi.org/10.1016%2FB978-0-12-382239-0.00006-6). [ISBN](/source/ISBN_(identifier)) [978-0-12-382239-0](https://en.wikipedia.org/wiki/Special:BookSources/978-0-12-382239-0).

1. **[^](#cite_ref-2)** Cava MP, Deana AA, Muth K, Mitchell MJ (1973). ["N-Phenylmaleimide"](https://www.orgsyn.org/demo.aspx?prep=cv5p0944). *[Organic Syntheses](/source/Organic_Syntheses)*; *Collected Volumes*, vol. 5, p. 944.

1. **[^](#cite_ref-3)** Barradas, Remigio Germano; Fletcher, Stephen; Porter, John Douglas (1976). "The hydrolysis of maleimide in alkaline solution". *Canadian Journal of Chemistry*. **54** (9): 1400–1404. [doi](/source/Doi_(identifier)):[10.1139/v76-200](https://doi.org/10.1139%2Fv76-200).

1. ^ [***a***](#cite_ref-PencolideRef_4-0) [***b***](#cite_ref-PencolideRef_4-1) Birkinshaw JH, Kalyanpur MG, Stickings CE (February 1963). ["Studies in the biochemistry of micro-organisms. 113. Pencolide, a nitrogen-containing metabolite of Penicillium multicolor Grigorieva-Manilova and Poradielova"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1201741). *The Biochemical Journal*. **86** (2): 237–243. [doi](/source/Doi_(identifier)):[10.1042/bj0860237](https://doi.org/10.1042%2Fbj0860237). [PMC](/source/PMC_(identifier)) [1201741](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1201741). [PMID](/source/PMID_(identifier)) [13971137](https://pubmed.ncbi.nlm.nih.gov/13971137).

1. **[^](#cite_ref-DiscoveryTeam_5-0)** Putri SP, Kinoshita H, Ihara F, Igarashi Y, Nihira T (August 2009). "Farinomalein, a maleimide-bearing compound from the entomopathogenic fungus Paecilomyces farinosus". *Journal of Natural Products*. **72** (8): 1544–6. [doi](/source/Doi_(identifier)):[10.1021/np9002806](https://doi.org/10.1021%2Fnp9002806). [PMID](/source/PMID_(identifier)) [19670877](https://pubmed.ncbi.nlm.nih.gov/19670877).

1. **[^](#cite_ref-6)** Koniev O, Wagner A (August 2015). ["Developments and recent advancements in the field of endogenous amino acid selective bond forming reactions for bioconjugation"](https://doi.org/10.1039%2FC5CS00048C). *Chemical Society Reviews*. **44** (15): 5495–5551. [doi](/source/Doi_(identifier)):[10.1039/C5CS00048C](https://doi.org/10.1039%2FC5CS00048C). [PMID](/source/PMID_(identifier)) [26000775](https://pubmed.ncbi.nlm.nih.gov/26000775).

1. **[^](#cite_ref-7)** Francis MB, Carrico IS (December 2010). "New frontiers in protein bioconjugation". *Current Opinion in Chemical Biology*. **14** (6): 771–773. [doi](/source/Doi_(identifier)):[10.1016/j.cbpa.2010.11.006](https://doi.org/10.1016%2Fj.cbpa.2010.11.006). [PMID](/source/PMID_(identifier)) [21112236](https://pubmed.ncbi.nlm.nih.gov/21112236).

1. **[^](#cite_ref-8)** Hermanson G (2013). "Chapter 1 - Introduction to Bioconjugation". *Bioconjugate Techniques*. Elsevier. pp. 1–125. [doi](/source/Doi_(identifier)):[10.1016/B978-0-12-382239-0.00001-7](https://doi.org/10.1016%2FB978-0-12-382239-0.00001-7). [ISBN](/source/ISBN_(identifier)) [978-0-12-382239-0](https://en.wikipedia.org/wiki/Special:BookSources/978-0-12-382239-0).

1. **[^](#cite_ref-9)** Beck A, Goetsch L, Dumontet C, Corvaïa N (May 2017). "Strategies and challenges for the next generation of antibody-drug conjugates". *Nature Reviews. Drug Discovery*. **16** (5): 315–337. [doi](/source/Doi_(identifier)):[10.1038/nrd.2016.268](https://doi.org/10.1038%2Fnrd.2016.268). [PMID](/source/PMID_(identifier)) [28303026](https://pubmed.ncbi.nlm.nih.gov/28303026). [S2CID](/source/S2CID_(identifier)) [22045270](https://api.semanticscholar.org/CorpusID:22045270).

1. ^ [***a***](#cite_ref-Lahn_10-0) [***b***](#cite_ref-Lahn_10-1) [***c***](#cite_ref-Lahn_10-2) Lahnsteiner, Marianne; Kastner, Alexander; Mayr, Josef; Roller, Alexander; Keppler, Bernhard K.; Kowol, Christian R. (27 October 2020). ["Improving the Stability of Maleimide–Thiol Conjugation for Drug Targeting"](https://dx.doi.org/10.1002/chem.202003951). *Chemistry – A European Journal*. **26** (68): 15867–15870. [doi](/source/Doi_(identifier)):[10.1002/chem.202003951](https://doi.org/10.1002%2Fchem.202003951). [ISSN](/source/ISSN_(identifier)) [0947-6539](https://search.worldcat.org/issn/0947-6539). [PMC](/source/PMC_(identifier)) [7756610](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756610). [PMID](/source/PMID_(identifier)) [32871016](https://pubmed.ncbi.nlm.nih.gov/32871016).

1. **[^](#cite_ref-:1_11-0)** Ravasco, João M. J. M.; Faustino, Hélio; Trindade, Alexandre; Gois, Pedro M. P. (19 November 2018). ["Bioconjugation with Maleimides: A Useful Tool for Chemical Biology"](https://dx.doi.org/10.1002/chem.201803174). *Chemistry – A European Journal*. **25** (1): 43–59. [doi](/source/Doi_(identifier)):[10.1002/chem.201803174](https://doi.org/10.1002%2Fchem.201803174). [ISSN](/source/ISSN_(identifier)) [0947-6539](https://search.worldcat.org/issn/0947-6539). [PMID](/source/PMID_(identifier)) [30095185](https://pubmed.ncbi.nlm.nih.gov/30095185).

1. **[^](#cite_ref-12)** Tonglairoum P, Brannigan RP, Opanasopit P, Khutoryanskiy VV (October 2016). ["Maleimide-bearing nanogels as novel mucoadhesive materials for drug delivery"](https://doi.org/10.1039%2FC6TB02124G). *Journal of Materials Chemistry B*. **4** (40): 6581–6587. [doi](/source/Doi_(identifier)):[10.1039/C6TB02124G](https://doi.org/10.1039%2FC6TB02124G). [PMID](/source/PMID_(identifier)) [32263701](https://pubmed.ncbi.nlm.nih.gov/32263701).

1. **[^](#cite_ref-13)** Kaldybekov DB, Tonglairoum P, Opanasopit P, Khutoryanskiy VV (January 2018). ["Mucoadhesive maleimide-functionalised liposomes for drug delivery to urinary bladder"](https://centaur.reading.ac.uk/72941/5/Manuscript_Maleimide_liposomes_VKaccepted.pdf) (PDF). *European Journal of Pharmaceutical Sciences*. **111**: 83–90. [doi](/source/Doi_(identifier)):[10.1016/j.ejps.2017.09.039](https://doi.org/10.1016%2Fj.ejps.2017.09.039). [PMID](/source/PMID_(identifier)) [28958893](https://pubmed.ncbi.nlm.nih.gov/28958893). [S2CID](/source/S2CID_(identifier)) [35605027](https://api.semanticscholar.org/CorpusID:35605027).

1. **[^](#cite_ref-14)** Moiseev RV, Kaldybekov DB, Filippov SK, Radulescu A, Khutoryanskiy VV (November 2022). ["Maleimide-Decorated PEGylated Mucoadhesive Liposomes for Ocular Drug Delivery"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9671038). *Langmuir*. **38** (45): 13870–13879. [doi](/source/Doi_(identifier)):[10.1021/acs.langmuir.2c02086](https://doi.org/10.1021%2Facs.langmuir.2c02086). [PMC](/source/PMC_(identifier)) [9671038](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9671038). [PMID](/source/PMID_(identifier)) [36327096](https://pubmed.ncbi.nlm.nih.gov/36327096).

1. ^ [***a***](#cite_ref-:2_15-0) [***b***](#cite_ref-:2_15-1) Huang, Wenmao; Wu, Xin; Gao, Xiang; Yu, Yifei; Lei, Hai; Zhu, Zhenshu; Shi, Yi; Chen, Yulan; Qin, Meng; Wang, Wei; Cao, Yi (4 February 2019). ["Maleimide–thiol adducts stabilized through stretching"](https://dx.doi.org/10.1038/s41557-018-0209-2). *Nature Chemistry*. **11** (4): 310–319. [doi](/source/Doi_(identifier)):[10.1038/s41557-018-0209-2](https://doi.org/10.1038%2Fs41557-018-0209-2). [ISSN](/source/ISSN_(identifier)) [1755-4330](https://search.worldcat.org/issn/1755-4330). [PMID](/source/PMID_(identifier)) [30718898](https://pubmed.ncbi.nlm.nih.gov/30718898).

1. **[^](#cite_ref-16)** Maul, Jürgen; Frushour, Bruce G.; Kontoff, Jeffrey R.; Eichenauer, Herbert; Ott, Karl-Heinz; Schade, Christian (2007). "Polystyrene and Styrene Copolymers". *Ullmann's Encyclopedia of Industrial Chemistry*. [doi](/source/Doi_(identifier)):[10.1002/14356007.a21_615.pub2](https://doi.org/10.1002%2F14356007.a21_615.pub2). [ISBN](/source/ISBN_(identifier)) [978-3-527-30385-4](https://en.wikipedia.org/wiki/Special:BookSources/978-3-527-30385-4).

1. **[^](#cite_ref-17)** Lin KF, Lin JS, Cheng CH (1996). ["High temperature resins based on allylamine/bismaleimides"](http://ntur.lib.ntu.edu.tw/bitstream/246246/93332/1/19.pdf) (PDF). *Polymer*. **37** (21): 4729–4737. [doi](/source/Doi_(identifier)):[10.1016/S0032-3861(96)00311-4](https://doi.org/10.1016%2FS0032-3861%2896%2900311-4).

1. **[^](#cite_ref-18)** Anderson WD, Mortara S (23–26 April 2007). "F-22 Aeroelastic Design and Test Validation". *American Institute of Aeronautics and Astronautics*: 4. [doi](/source/Doi_(identifier)):[10.2514/6.2007-1764](https://doi.org/10.2514%2F6.2007-1764). [ISBN](/source/ISBN_(identifier)) [978-1-62410-013-0](https://en.wikipedia.org/wiki/Special:BookSources/978-1-62410-013-0).

1. **[^](#cite_ref-19)** ["Lockheed Martin F-35B Boasts UFO Technology, Fights For Team USA"](https://web.archive.org/web/20140221074332/http://www.isciencetimes.com/articles/5929/20130821/lockheed-martin-f35b-ufo-stealth-fighter-video.htm). International Science Times. 21 August 2013. Archived from [the original](http://www.isciencetimes.com/articles/5929/20130821/lockheed-martin-f35b-ufo-stealth-fighter-video.htm) on 21 February 2014. Retrieved 28 January 2014.

## External links

- [The MP4 website](http://www.chm.bris.ac.uk/motm/mpg/), Molecule of the Month, December 2004

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Adapted from the Wikipedia article [Maleimide](https://en.wikipedia.org/wiki/Maleimide) by Wikipedia contributors ([contributor history](https://en.wikipedia.org/wiki/Maleimide?action=history)). Available under [Creative Commons Attribution-ShareAlike 4.0 International](https://creativecommons.org/licenses/by-sa/4.0/). Changes may have been made.