MALEIMIDE

Maleimide is an important unsaturated cyclic imide widely used as a versatile intermediate in organic synthesis, polymer modification, and the development of high-performance functional materials.
Maleimide's reactive double bond enables efficient addition, cycloaddition, and crosslinking reactions, making maleimide derivatives especially valuable in bioconjugation, surface functionalization, adhesives, coatings, and specialty polymer systems.
Maleimide is also extensively employed in pharmaceutical research, fine chemical synthesis, and advanced material science for preparing structurally diverse compounds with tailored chemical and physical properties.

CAS Number: 541-59-3
EC Number: 208-787-4
Molecular Formula: C4H3NO2
Molecular Weight: 97.07

Synonyms: MALEIMIDE, 541-59-3, 1H-Pyrrole-2,5-dione, Pyrrole-2,5-dione, 2,5-Pyrroledione, Maleic imide, DTXSID3049417, 2519R1UGP8, NSC-13684, DTXCID2029377, CHEBI:16072, RefChem:800776, 208-787-4, Maleinimide, 3-Pyrroline-2,5-dione, 2,5-dihydro-1H-pyrrole-2,5-dione, MFCD00005494, maleic acid imide, SMR000857346, CCRIS 3408, EINECS 208-787-4, NSC 13684, BRN 0106910, 5-hydroxy-2H-pyrrol-2-one, UNII-2519R1UGP8, AI3-61139, 2,5-Dioxo-2,5-dihydropyrrole; 3-Pyrroline-2,5-dione; Maleic Imide; NSC 13684;, SZB, azoline-2,5-dione, Maleimide, 99%, 5-hydroxypyrrol-2-one, WLN: T5VMVJ, SCHEMBL10990, SCHEMBL13407, 5-21-10-00003 (Beilstein Handbook Reference), cid_10935, MLS001335859, MLS001335860, SCHEMBL441985, BDBM7802, CHEMBL387762, orb1221455, orb1302538, SCHEMBL1599522, SCHEMBL7021498, SCHEMBL7465571, SCHEMBL10573078, HMS2231J09, HMS5086C14, NSC13684, Tox21_202926, EBC-03935, GEO-01635, s3141, AKOS000249504, AKOS025243942, CS-W007324, FM05563, HY-W007324, PS-9342, NCGC00246987-01, NCGC00260472-01, BP-21039, CAS-541-59-3, M0018, NS00020001, ST50404558, T4820, EN300-43696, C07272, F011793, Q6743002, F2107-0002, Z223655288, InChI=1/C4H3NO2/c6-3-1-2-4(7)5-3/h1-2H,(H,5,6,7, pyrrolidine-2,5-dione; pyrrole-2,5-dione; 2,5-pyrrolidinedione, 1H-Pyrrol-2,5-dion, 1H-Pyrrole-2,5-dione, 1H-Pyrrole-2,5-dione, 1H-Pyrrole-2.5-dione, 2,5-Pyrroledione, 208-787-4, 5-Hydroxy-2H-pyrrol-2-one, 541-59-3, Maleimide, monomaleimide, Pyrrole-2,5-dione, 1H-Pyrrole-2,5-dione, 2,5-Dihydro-2,5-dioxo-1H-pyrrole, 1H-Pyrrole-2,5-dione; 2,5-Dihydro-2,5-dioxo-1H-pyrrole, 2,5-dihydro-1H-pyrrole-2,5-dione, 2,5-Dihydro-2,5-dioxo-1H-pyrrole, 2,5-Dioxo-3-pyrroline, 3-pyrroline-2,5-dion, 3-Pyrroline-2,5-dione, 5-21-10-00003, 5-hydroxypyrrol-2-one, 98%, [τ protein] kinase, azoline-2,5-dione, BGAL_ECOLX, C-C chemokine receptor type 6, CCR6_HUMAN, EINECS 208-787-4, G1T8E2_RABIT, Glycogen synthase kinase-3 beta [7-25], maleimide(rs20007472), Pyrrole-2,5-dione; 2,5-Dihydro-2,5-dioxo-1H-pyrrole, T5VMVJ, β-galactosidase, マレイミド

Maleimide is a nanoparticle surface functional group that favors easy conjugation with cell penetration peptides.
This conjugation is achieved through click chemistry, preserving the biofunctions of the nanoparticles.

Maleimide is a chemical compound that can be synthesized by combining maleic anhydride and hydrogen fluoride.
Maleimide has been used as a fluorescent probe in the measurement of electrochemical impedance spectroscopy (EIS) in biological systems.

Furthermore, maleimide is utilized to study the interaction with mouse monoclonal antibodies, enabling the detection of specific proteins or antigens in blood samples.
Maleimides form stable covalent linkages with proteins and macromolecules through their thiol groups.

Under high-temperature conditions, maleimide reacts with hydrogen gas, leading to a decrease in its redox potentials.
Plasma mass spectrometry analysis can be used to determine the concentration of maleimide and its reactants by measuring ions generated through ionization or fragmentation reactions.

Maleimide can be used for production of antibody-drug conjugate (ADC) which is used in cancer research.
Maleimide also be leveraged for the preparation of fluorogenic probe, which is mainly used for the specific detection of thiol analytes.

Maleimide is a new nanoparticle surface functional group which favors easy conjugation with cell penetration peptides.
The conjugation is enabled via click chemistry to preserve its biofunctions.

Maleimide is used as a dienophile in Diels Alder reaction for the synthesis of macromolecules.

Reacts quantitatively with sulfhydryl groups.
Maleimide is used to immobilize the bovine serum albumin-boronic acid conjugates in association with silica beads.

Maleimide's nanoparticle surface favors the conjugation with cell penetration peptides.
Maleimide is involved in Rhodium-catalyzed conjugate arylation with arylboronic acids.

Maleimide is actively involved in Michael additions and Diels-Alder reactions by the addition across the double bond.
Maleimide acts as crosslinking reagents in polymer chemistry.

Maleimide is a cyclic dicarboximide in which the two carboacyl groups on nitrogen together with the nitogen itself form a 1H-pyrrole-2,5-dione structure.
Maleimide has a role as an EC 5.99.1.3 [DNA topoisomerase (ATP-hydrolysing)] inhibitor.

Maleimide is a dicarboximide and a member of maleimides.
Maleimide is functionally related to a maleic acid.
Maleimide derives from a hydride of a 1H-pyrrole.

Maleimide is a cyclic unsaturated imide and an important building block in organic and polymer chemistry.
Maleimide's reactive carbon–carbon double bond readily participates in addition and cycloaddition reactions, making it useful for preparing functional polymers, pharmaceutical intermediates, and specialty chemicals.
Maleimide derivatives are also widely used in bioconjugation, materials science, and advanced chemical research.

Maleimide is a new nanoparticle surface functional group which favors easy conjugation with cell penetration peptides.
The conjugation is enabled via click chemistry to preserve its biofunctions.

Maleimide is defined as an alkylating reagent that specifically reacts with sulfhydryl groups to form stable thioether bonds, primarily within a pH range of 6.5 to 7.5.
Maleimide is utilized for permanently blocking sulfhydryl residues in proteins and other macromolecules.

Maleimide is a chemical compound with the formula H2C2(CO)2NH.
This unsaturated imide is an important building block in organic synthesis.

The name is a contraction of maleic acid and imide, the -C(O)NHC(O)- functional group.
Maleimides are also a class of derivatives of the parent maleimide where the NH group is replaced with alkyl or aryl groups such as a methyl or phenyl, respectively.

The substituent can also be a small molecule (such as biotin, a fluorescent dye, an oligosaccharide, or a nucleic acid), a reactive group, or a synthetic polymer such as polyethylene glycol.
Human hemoglobin chemically modified with maleimide-polyethylene glycol is a blood substitute called MP4.

Maleimide is a compound that is part of a heterobifunctional crosslinker, featuring a maleimide group on one end and an NHS ester on the other end.
Maleimide is used to link amine-containing molecules to thiol-containing molecules, providing control over the conjugation process in scientific applications.

Maleimide is one of the most widely used electrophilic functional groups in bioconjugation chemistry.
Maleimide's high selectivity for thiol groups at physiological pH makes it indispensable for constructing antibody-drug conjugates (ADCs), labeling proteins at specific cysteine residues, and building complex multifunctional bioconjugates.
This guide covers the fundamentals of maleimide chemistry — from its molecular structure and reaction mechanism to practical applications with PEG-maleimide reagents.

Natural Maleimides:
One natural maleimide is the cytotoxic showdomycin from Streptomyces showdoensis and pencolide from Pe. multicolor – have been reported.
Farinomalein was first isolated in 2009 from the entomopathogenic fungus Isaria farinosa (Paecilomyces farinosus) – source H599 (Japan).

Applications of Maleimide:
Maleimide is widely used as a reactive intermediate in organic synthesis, polymer chemistry, and materials science.
Maleimide is employed in the production of functional polymers, resins, coatings, and specialty chemical derivatives.

Maleimide groups are also commonly used in bioconjugation because they can react selectively with thiol-containing molecules such as cysteine residues in proteins.
Maleimide serves as a building block for pharmaceutical intermediates, crosslinking agents, and advanced research materials.
Maleimide is also used in Diels–Alder and Michael addition reactions for the preparation of complex organic structures.

The maleimide-functionalized silica beads were used to immobilize the bovine serum albumin (BSA)-boronic acid (BA) conjugates.
Rhodium-catalyzed conjugate arylation with arylboronic acids.

Reacts quantitatively with sulfhydryl groups.
Maleimide is used to immobilize the bovine serum albumin-boronic acid conjugates in association with silica beads.

Maleimide's nanoparticle surface favors the conjugation with cell penetration peptides.
Maleimide is involved in Rhodium-catalyzed conjugate arylation with arylboronic acids.

Maleimide is actively involved in Michael additions and Diels-Alder reactions by the addition across the double bond.
Maleimide acts as crosslinking reagents in polymer chemistry.

Biotechnology and pharmaceutical applications:
Maleimide-mediated methodologies are among the most used in bioconjugation.
Due to fast reactions and high selectivity towards cysteine residues in 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.
For instance, antibody-drug conjugates, are constituted of three main components: a 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.

Maleimides linked to 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 group found on 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.
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) due to the reactions with thiol-containing mucins.
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.

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.

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.

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.

Technological applications:
Analogous to Styrene maleic anhydride, copolymers of maleimides and styrene have been commercialized.

Mono- and bismaleimide-based polymers are used for high temperature applications up to 250 °C (480 °F).
Maleimides linked to rubber chains are often used as flexible linking molecules to reinforce rubber in tires.

The double bond readily reacts with all hydroxy, amine or 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 extensively uses thermoset composites, with bismaleimide and toughened epoxy comprising up to 17.5% and 6.6% of the structure by weight respectively.
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 composites.

Reactions of Maleimide:
Many analogues of maleimide are prepared by treating maleic anhydride with amines followed by dehydration.

A defining feature of the reactivity of maleimides is their susceptibility to additions across the double bond either by Michael additions or via 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 in thermoset polymer chemistry.
Compounds containing a maleimide group linked with another reactive group, such as an activated N-hydroxysuccinimide ester, are called maleimide heterobifunctional reagents (see SMCC reagent for such an example).

Maleimide is weakly acidic, with a pKa estimated at 10.

Chemical Structure of Maleimide:
Maleimide (1H-pyrrole-2,5-dione) is a five-membered heterocyclic ring containing a nitrogen atom flanked by two carbonyl groups and an alkene.
Maleimide's molecular formula is C₄H₃NO₂, with a molecular weight of 97.07 g/mol.
The parent compound is a white to off-white crystalline solid with a melting point of 92–94°C, soluble in water, ethanol, and most polar organic solvents.

The key structural features that drive maleimide’s reactivity:

Electron-deficient alkene:
The two adjacent carbonyls withdraw electron density from the C=C double bond, making it strongly electrophilic.
This electronic activation lowers the LUMO energy of the alkene, making it an excellent acceptor for nucleophilic Michael addition.

Ring strain:
The cis configuration of the double bond within the five-membered ring adds modest ring strain, further activating the alkene toward nucleophilic addition.
The endocyclic double bond is locked in the cis (Z) configuration by the ring geometry, providing a rigid, pre-organized electrophilic site.

N-substitution site:
The nitrogen atom serves as the attachment point for linkers, PEG chains, and other molecular scaffolds.
N-substituted maleimides retain full thiol reactivity while enabling modular reagent design.
Common N-substituents include alkyl chains, PEG linkers, aromatic groups, and complex linker-payload architectures for ADC applications.

The planar geometry of the maleimide ring positions the double bond in an optimal orientation for Michael addition reactions.
This geometric constraint — combined with the strong electron withdrawal — gives maleimide reaction rates with thiols that are approximately 1,000-fold faster than with amines at neutral pH.
Maleimide absorbs UV light weakly around 300 nm, which can be useful for monitoring reaction progress spectrophotometrically, though this absorption overlaps with protein signals at higher wavelengths.

Stability and Reactivity of Maleimide:

Chemical stability:
Stable under normal storage and handling conditions.

Conditions to avoid:
Avoid excessive heat, moisture, and prolonged exposure to incompatible materials.

Incompatible materials:
Strong oxidizing agents, strong acids, and strong bases.

Hazardous decomposition products:
Thermal decomposition may produce carbon oxides and nitrogen-containing fumes.

Handling and Storage of Maleimide:

Safe handling:
Avoid dust formation and direct contact with skin and eyes.
Use adequate ventilation.

Storage conditions:
Store tightly closed in a cool, dry, well-ventilated place.

First Aid Measures of Maleimide:

Inhalation:
Move to fresh air and seek medical attention if symptoms persist.

Skin contact:
Wash thoroughly with soap and water.

Eye contact:
Rinse cautiously with water for several minutes.

Ingestion:
Rinse mouth and seek medical advice if discomfort occurs.

Firefighting Measures of Maleimide:

Suitable extinguishing media:
Use water spray, foam, dry chemical, or CO₂.

Protective equipment:
Firefighters should wear suitable protective equipment.

Accidental Release Measures of Maleimide:

Personal precautions:
Avoid dust formation and ensure adequate ventilation.

Cleanup methods:
Collect spilled material carefully into a suitable closed container.

Exposure Controls / Personal Protective Equipment of Maleimide:

Engineering controls:
Provide adequate general or local ventilation.

Personal protection:
Wear protective gloves, safety glasses, and suitable protective clothing.
Use respiratory protection if significant dust is generated.

Identifiers of Maleimide:
Product Number: M0018
Purity / Analysis Method : >98.0%(T)
Molecular Formula / Molecular Weight: C4H3NO2 = 97.07 
Physical State (20 deg.C): Solid
Storage Temperature : Room Temperature (Recommended in a cool and dark place, <15°C)
CAS RN: 541-59-3
Reaxys Registry Number: 106910
PubChem Substance ID: 87572137
SDBS (AIST Spectral DB): 3678
MDL Number: MFCD00005494

CAS No: 541-59-3
CBNumber: CB6358686
Molecular Formula: C4H3NO2
Molecular Weight: 97.07
MDL Number: MFCD00005494
MOL File: 541-59-3.mol

CAS Number: 541-59-3
ChEBI: CHEBI:16072
ChEMBL: ChEMBL387762
ChemSpider: 10471
ECHA InfoCard: 100.007.990
EC Number: 208-787-4
KEGG: C07272
PubChem CID: 10935
UNII: 2519R1UGP8
CompTox Dashboard (EPA): DTXSID3049417
InChI: InChI=1S/C4H3NO2/c6-3-1-2-4(7)5-3/h1-2H,(H,5,6,7)
Key: PEEHTFAAVSWFBL-UHFFFAOYSA-N
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

Empirical Formula (Hill Notation): C4H3NO2
CAS Number: 541-59-3
Molecular Weight: 97.07
UNSPSC Code: 12352100
NACRES: NA.22
PubChem Substance ID: 24847914
EC Number: 208-787-4
Beilstein/REAXYS Number: 106910
MDL number: MFCD00005494
Assay: 99%
Form: powder

CAS: 541-59-3
IUPAC Name: potassium silver(1+) bis(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-ide)
Molecular Formula: C8H4AgKN2O4
InChI Key: KWLWLQRUFFGWNG-UHFFFAOYSA-L
SMILES: [K+].[Ag+].O=C1[N-]C(=O)C=C1.O=C1[N-]C(=O)C=C1
Molecular Weight (g/mol): 339.10

Properties of Maleimide:
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

Quality Segment: 200
assay: 99%
form: powder
mp: 91-93 °C (lit.)
functional group: maleimide
SMILES string: O=C1NC(=O)C=C1
InChI: 1S/C4H3NO2/c6-3-1-2-4(7)5-3/h1-2H,(H,5,6,7)
InChI key: PEEHTFAAVSWFBL-UHFFFAOYSA-N

Melting point: 91-93 °C (lit.)
Boiling point: 97-103°C 5mm
Density: 1,2493 g/cm3
refractive index: 1.4543 (estimate)
Flash point: 97-103°C/5mm
storage temp.: Inert atmosphere,Room Temperature
solubility: soluble in Methanol
form: Fine Crystalline Powder
pka: 8.52±0.20(Predicted)
color: White to slightly yellow
Water Solubility: SOLUBLE
λmax: 280nm(EtOH)(lit.)
BRN: 106910
InChI: 1S/C4H3NO2/c6-3-1-2-4(7)5-3/h1-2H,(H,5,6,7)
InChIKey: PEEHTFAAVSWFBL-UHFFFAOYSA-N
SMILES: O=C1NC(=O)C=C1
CAS DataBase Reference: 541-59-3(CAS DataBase Reference)
EWG's Food Scores: 1
FDA UNII: 2519R1UGP8
NIST Chemistry Reference: 1H-pyrrole-2,5-dione(541-59-3)
EPA Substance Registry System: 1H-Pyrrole-2,5-dione (541-59-3)
UNSPSC Code: 12352100
NACRES: NA.22

Molecular Weight: 97.07 g/mol
XLogP3: -0.3
Hydrogen Bond Donor Count: 1
Hydrogen Bond Acceptor Count: 2
Rotatable Bond Count: 0
Exact Mass: 97.016378338 Da
Monoisotopic Mass: 97.016378338 Da
Topological Polar Surface Area: 46.2 Ų
Heavy Atom Count: 7
Complexity: 132
Isotope Atom Count: 0
Defined Atom Stereocenter Count: 0
Undefined Atom Stereocenter Count: 0
Defined Bond Stereocenter Count: 0
Undefined Bond Stereocenter Count: 0
Covalently-Bonded Unit Count: 1
Compound Is Canonicalized: Yes

Specifications of Maleimide:
Appearance: White to Almost white powder to crystal
Purity(Neutralization titration): min. 98.0 %
Melting point: 92.0 to 95.0 °C
Solubility in Methanol: almost transparency
NMR: confirm to structure

Identification (FTIR): Conforms
Solution Test: 2.5% Ethanol: clear to faintly turbid
Assay (GC): ≥98.0%
Appearance (Color): White to pale yellow
Form: Crystals or powder or crystalline powder or granules

Names of Maleimide:

IUPAC name:
Maleimide

Preferred IUPAC name:
1H-Pyrrole-2,5-dione

Other name:
2,5-Pyrroledione