N-Methylsuccinimide

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N-Methylsuccinimide
N-Methylsuccinimide.svg
Names
IUPAC name
1-Methylpyrrolidine-2,5-dione
Systematic IUPAC name
1-Methyl-2,5-pyrrolidinedione
Other names
  • N-Methyl-2,5-pyrrolidinedione
  • Succinimide, N-methyl-
  • 2,5-Pyrrolidinedione, 1-methyl-
  • 1-Methylsuccinimide
Identifiers
3D model (JSmol)
110486
ChEBI
EC Number
  • 214-299-2214-299-2
PubChem CID
  • InChI=1S/C5H7NO2/c1-6-4(7)2-3-5(6)8/h2-3H2,1H3
  • CN1C(=O)CCC1=O
Properties
C5H7NO2
Molar mass 113.11 g/mol
AppearanceWhite to off-white crystalline powder
Density 1.127 g/mL
Melting point 66 to 69 (also reported as 68–71 °C and 66–67 °C)66 °C (151 °F; 339 K)
Boiling point 235235 °C (455 °F; 508 K) (also reported as 234–235 °C)
Soluble in water
Vapor pressure 0.0±0.5 mmHg at 25 °C (Predicted)
Hazards
Occupational safety and health (OHS/OSH):
Main hazards
Irritant
GHS labelling:
GHS07
Warning
H315, H319, H335
P261, P264, P271, P280, P302+P352, P304+P340, P305+P351+P338, P312, P321, P332+P313, P337+P313, P362, P403+P233, P405, P501
Flash point 142.1(Predicted)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

N-Methylsuccinimide (C5H7NO2, also known as 1-methyl-2,5-pyrrolidinedione or MSI) is an organic compound chemically related to succinimide. It is primarily characterized as a major metabolic product of the industrial solvent N-methyl-2-pyrrolidone (NMP) in mammals, including humans and rats.

Contents

Production

One production method involves the reaction of aqueous ammonia and succinate with a methylating agent at temperatures ranging from 100 °C to 400 °C. The resulting N-methylsuccinimide can subsequently be purified and hydrogenated to form NMP. [1] It can also be produced by the reaction of diammonium succinate with methanol or by the reaction of succinic anhydride with methylamine. [2]

In the microelectronics industry, the oxidative degradation of NMP during fabrication processes results in the formation of N-methylsuccinimide. [3] Consequently, it is found in waste NMP mixed liquors. Patents describe methods for purifying waste NMP by removing impurities such as N-methylsuccinimide and gamma-butyrolactone (GBL) using alkali treatment to recover high-purity NMP. [4]

Toxicokinetics

In toxicology and occupational health, N-methylsuccinimide is identified as a metabolite of NMP. Upon exposure to NMP, the compound undergoes a metabolic pathway in which it is first hydroxylated to form 5-hydroxy-N-methyl-2-pyrrolidone (5-HNMP). This intermediate is further oxidized to N-methylsuccinimide (MSI), which is subsequently metabolized to 2-hydroxy-N-methylsuccinimide (2-HMSI). [5]

Experimental studies on male volunteers exposed to NMP vapors indicated that MSI levels in plasma and urine are correlated with exposure concentrations. However, 2-HMSI is often preferred as a biomarker due to its accumulation and delayed excretion profile. In human toxicokinetic studies, the renal clearance of MSI was calculated to be approximately 0.12 L/h, with a total clearance of 8.5 L/h. The apparent volume of distribution for MSI was found to be approximately 120 liters. [5]

While NMP itself is a known reproductive toxicant, research using rat whole embryo culture systems has investigated the embryotoxic potential of its metabolites, including N-methylsuccinimide. [6]

Analysis and detection

Methods using gas chromatography (GC), sometimes coupled with mass spectrometry (GC-MS), have been used to analyze MSI in plasma and urine samples. [5]

Solid-phase extraction (SPE) combined with gas chromatography and a flame thermionic detector (GC/FTD) has been developed for the determination of NMP and its metabolites, including MSI, in urine. [7]

Studies evaluating biomarkers have employed mass spectrometry to analyze plasma and urine concentrations of MSI and related metabolites. [8]

References

  1. ↑ EP1572644A1,Werpy, Todd A.; Jr, John G. Frye& White, James F.et al.,"Process for producing n-methyl succinimide",issued 14 September 2005
  2. ↑ "Process for microwave assisted synthesis of N-methyl pyrrolidone". Google Patents. 2014-09-04. Retrieved 2026-01-05.
  3. ↑ Lennon, Gavin; Willox, Shannon; Ramdas, Ragini; Funston, Scott J.; Klun, Matthew; Pieh, Robert; Fairlie, Stewart; Dobbin, Sara; Cobice, Diego F. (2020). "Assessing the Oxidative Degradation of N-Methylpyrrolidone (NMP) in Microelectronic Fabrication Processes by Using a Multiplatform Analytical Approach". Journal of Analytical Methods in Chemistry . 2020 (1): 8265054. doi: 10.1155/2020/8265054 . ISSN   2090-8873. PMC   7073504 . PMID   32190404.{{cite journal}}: CS1 maint: article number as page number (link)
  4. ↑ CN113727969B,沈成元,"Method for purifying waste N-methyl-2-pyrrolidone mixed liquor",issued 4 March 2025
  5. 1 2 3 Jönsson, B. A. G.; Åkesson, B. (1 May 2003). "Human experimental exposure to N-methyl-2-pyrrolidone (NMP): toxicokinetics of NMP, 5-hydroxy-N-methyl-2-pyrrolidone, N-methylsuccinimide and 2-hydroxy-N-methylsuccinimide (2-HMSI), and biological monitoring using 2-HMSI as a biomarker". International Archives of Occupational and Environmental Health . 76 (4): 267–274. Bibcode:2003IAOEH..76..267J. doi:10.1007/s00420-003-0438-5. ISSN   1432-1246. PMID   12684812.
  6. ↑ Poet, Torka S.; Kirman, Chris R.; Bader, Michael; van Thriel, Christoph; Gargas, Michael L.; Hinderliter, Paul M. (13 February 2010). "Quantitative Risk Analysis for N-Methyl Pyrrolidone Using Physiologically Based Pharmacokinetic and Benchmark Dose Modeling". Toxicological Sciences. 113 (2): 468–482. doi:10.1093/toxsci/kfp264. ISSN   1096-6080. PMID   19875680.
  7. ↑ Kubota, Ryuichi; Endo, Yoko; Takeuchi, Akito; Inoue, Yoshinori; Ogata, Hiroko; Ogawa, Masanori; Nakagawa, Tomoo; Onda, Nobuhiko; Endo, Ginji (1 July 2007). "SPE–GC/FTD determination of N-methyl-2-pyrrolidone and its metabolites in urine". Journal of Chromatography B . 854 (1): 204–210. doi:10.1016/j.jchromb.2007.04.022. ISSN   1570-0232. PMID   17485256.
  8. ↑ Åkesson, Bengt; Carnerup, Martin A.; Jönsson, Bo AG (2004). "Evaluation of exposure biomarkers from percutaneous absorption of N-methyl-2-pyrrolidone". Scandinavian Journal of Work, Environment & Health. 30 (4): 306–312. doi:10.5271/sjweh.799. ISSN   0355-3140. PMID   15458014.
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