N-Nitrosomorpholine

Last updated
N-nitrosomorpholine
N nitrosomorpholine.svg
Names
Other names
4-nitrosomorpholine, alpha-acetoxy-N-nitrosomorpholine, nitrosomorpholine, NMOR, 4-nitroso-morpholine, NNM
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.155.913 OOjs UI icon edit-ltr-progressive.svg
EC Number
  • 627-564-6
KEGG
PubChem CID
UNII
UN number 2810 3077
  • InChI=1S/C4H8N2O2/c7-5-6-1-3-8-4-2-6/h1-4H2
    Key: ZKXDGKXYMTYWTB-UHFFFAOYSA-N
  • C1COCCN1N=O
Properties
C4H8N2O2
Molar mass 116.120 g·mol−1
AppearancePale yellow powder
Melting point 29 °C (84 °F; 302 K) [1]
Boiling point 435 to 436 °F at 747 mmHg
greater than or equal to 100 mg/mL in water at 66 °F
Hazards
Occupational safety and health (OHS/OSH):
Main hazards
hepatocarcinogen
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

N-Nitrosomorpholine (NNM, NMOR) is an organic compound which is known to be a carcinogen and mutagen.

Contents

Chemistry

NMOR is a pale yellow sand-like powder below 84°F. [1] [2] NMOR is most commonly produced from morpholine, but can also be made by the reaction of dimorpholinomethane in fuming nitric acid. [3] Few reactions using NMOR as a starting material are reported in the organic synthesis literature, but it can be used as a precursor to a nitrogen-centered radical. [4]

Occurrence

NMOR is generally not used intentionally, but is instead created by the nitrosation of morpholine or morpholine derivatives which are used for several industrial purposes.

Rubber

2-(Morpholinothio)benzothiazole is used as an accelerator/stabilizer for vulcanization, or the manufacture of rubber products. It is the precursor to NMOR in the vulcanization process, as it is nitrosated by ambient sources of the nitro group present in the manufacturing process. As such, workers and others exposed to the rubber industry or its byproducts are exposed to higher levels of NMOR than the general population, raising their risk of cancer. [5]

Tobacco products

NMOR is a component of tobacco products. As of 2014, detectable levels of NMOR are present in tobacco products in the United States and China. [6] [7] The presence of NMOR and other n-nitrosoamines is not limited to cigarettes, but is found in smokeless tobacco products (snuff tobacco, Snus, etc.) as well. [8] Volatile nitrosamines, including NMOR, are detectable in the urine of tobacco smokers. [9]

Food

Morpholine oleate is used in glazing wax which covers fruit. NMOR can be generated by the nitration of morpholine, causing its presence in waxed fruits. [10] [11] Health Canada, the Canadian governmental department of public health, has stated in 2002 that this does not pose a risk to human health. [12]

Consumption of nitrate-rich diets is correlated with levels of salivary and urinary NMOR. [13] The presence of NMOR can also be observed in gastric juices. [14]

Other

NMOR has been found in several cosmetic products. [15] [16]

Health hazards

The mechanisms of carcinogenesis are not completely clear in humans. NMOR and its metabolites may induce DNA damage by directly forming reactive oxygen species or compounds which crosslink DNA. In a rat model in 2013, it was observed that NMOR is hydroxylated, probably by a P450 enzyme, alpha to the N-nitroso moiety. [17] This then decomposes into a diazonium-containing aldehyde which is capable of crosslinking DNA. [18]

Endogenous synthesis from morpholine in the digestive system is observed. NMOR can be generated from N-nitrosating species formed by salivary nitrite and stomach acid, potentially leading to more damage in individuals with acid reflux. [19] H. pylori does not induce NMOR formation in vitro, though this has yet to be confirmed in vivo. [20]

NMOR is in fact used to generate liver cancer models in rats. Along with N-diethylnitrosamine, it is the gold standard for producing hepatocarcinoma with 100% lung metastasis. [21]

See also

References

  1. 1 2 Zhang, Jie; Jiang, Jiewen; Li, Yuling; Wan, Xiaobing (2013). "Iodide-Catalyzed Synthesis of N-Nitrosamines via C–N Cleavage of Nitromethane". Journal of Organic Chemistry . 78 (22): 11366–11372. doi:10.1021/jo401915t. PMID   24128012 . Retrieved 10 January 2024.
  2. ↑ Borikar, Sanjay P.; Paul, Vincent (2010). "N-Nitrosation of Secondary Amines Using p-TSA-NaNO2 as a Novel Nitrosating Agent Under Mild Conditions". Synthetic Communications . 40 (5): 654–660. doi:10.1080/00397910903009448. S2CID   98412823 . Retrieved 10 January 2024.
  3. ↑ Zhang, Yu; Zou, Po; Han, Yingbin; Geng, Yongliang; Luo, Jun; Zhou, Baojing (2018). "A combined experimental and DFT mechanistic study for the unexpected nitrosolysis of N-hydroxymethyldialkylamines in fuming nitric acid". RSC Advances . 8 (34): 19310–19316. Bibcode:2018RSCAd...819310Z. doi:10.1039/C8RA03268H. PMC   9080733 . PMID   35539630.
  4. ↑ Patil, Dilip V.; Lee, Yulim; Kim, Hun Young; Oh, Kyungsoo (2022). "Visible-Light-Promoted Photoaddition of N-Nitrosopiperidines to Alkynes: Continuous Flow Chemistry Approach to Tetrahydroimidazo[1,2-a]pyridine 1-Oxides". Organic Letters . 24 (31): 5840–5844. doi:10.1021/acs.orglett.2c02402. PMID   35921551. S2CID   251317605 . Retrieved 18 January 2024.
  5. ↑ Carrier, Gaétan; Desrosiers, Marie-Claire; Adib, Georges (2011). "Cancer risk assessment for workers exposed to nitrosamines in a warehouse of finished rubber products in the Eastern Townships (Québec, Canada)" (PDF). Institut national de santé publique du Québec. Gouvernement du Québec. Archived from the original (PDF) on 3 December 2021. Retrieved 16 January 2024.
  6. ↑ Oldham, Michael J.; DeSoi, Darren J.; Rimmer, Lonnie T.; Wagner, Karl A.; Morton, Michael J. (2014). "Insights from analysis for harmful and potentially harmful constituents (HPHCs) in tobacco products". Regulatory Toxicology and Pharmacology . 70 (1): 138–148. doi:10.1016/j.yrtph.2014.06.017. PMID   24973503 . Retrieved 16 January 2024.
  7. ↑ Lv, Fang; Guo, Junwei; et al. (5 April 2016). "Determination of nine volatile N-nitrosamines in tobacco and smokeless tobacco products by dispersive solid-phase extraction with gas chromatography and tandem mass spectrometry". Journal of Separation Science . 39 (11): 2123–2128. doi:10.1002/jssc.201600037. PMID   27059265 . Retrieved 16 January 2024.
  8. ↑ Wang, Xiaoyu; Qin, Yaqiong; et al. (29 April 2021). "Smokeless tobacco analysis: Simultaneous extraction and purification of alkaloids, volatile N-nitrosamines, and polycyclic hydrocarbons for GC-MS/MS". Journal of Separation Science . 44 (13): 2642–2654. doi:10.1002/jssc.202100186. PMID   33915029. S2CID   233459643 . Retrieved 16 January 2024.
  9. ↑ Seyler, Tiffany H.; Kim, Jenny G.; Hodgson, James A.; Cowan, Elizabeth A.; Blount, Benjamin C.; Wang, Lanqing (18 March 2013). "Quantitation of Urinary Volatile Nitrosamines from Exposure to Tobacco Smoke". Journal of Analytical Toxicology . 37 (4): 195–202. doi:10.1093/jat/bkt020. PMID   23508653 . Retrieved 16 January 2024.
  10. ↑ Akbar, Syed (16 December 2016). "Toxic gloss on 'fresh' veggie plate". The Times of India . Hyderabad. Retrieved 15 February 2023.
  11. ↑ Kumar, Rupak; Kapur, Suman (2016). "Morpholine: A Glazing Agents for Fruits and Vegetables Coating/Waxing". International Journal of Science Technology and Engineering. 2 (11): 694–697. ISSN   2349-784X . Retrieved 15 February 2023.
  12. ↑ "Fact Sheet: Use of Morpholine in Apple Coatings". Government of Canada. Health Canada. 9 December 2002. Archived from the original on 27 January 2023. Retrieved 9 February 2023.
  13. ↑ van Maanen, Jan M. S.; Pachen, D. M.; Dallinga, J. M.; Kleinjans, J. C. (1998). "Formation of nitrosamines during consumption of nitrate- and amine-rich foods, and the influence of the use of mouthwashes". Cancer Detection and Prevention. 22 (3): 204–212. doi:10.1046/j.1525-1500.1998.0oa26.x (inactive 8 February 2025). PMID   9618041 . Retrieved 11 January 2024.{{cite journal}}: CS1 maint: DOI inactive as of February 2025 (link)
  14. ↑ Dallinga, J. W.; Pachen, D. M. F. A. (1998). "Volatile N-nitrosamines in gastric juice of patients with various conditions of the gastrointestinal tract determined by gas chromatography–mass spectrometry and related to intragastric pH and nitrate and nitrite levels". Cancer Letters . 124 (2): 119–125. doi:10.1016/S0304-3835(97)00467-9. PMID   9500200 . Retrieved 11 January 2024.
  15. ↑ Schettino, Lorenzo; Benedé, Juan L.; Chisvert, Albertino (2023). "Determination of nine prohibited N-nitrosamines in cosmetic products by vortex-assisted dispersive liquid–liquid microextraction prior to gas chromatography-mass spectrometry". RSC Advances . 13 (5): 2963–2971. Bibcode:2023RSCAd..13.2963S. doi:10.1039/D2RA06553C. PMC   9850448 . PMID   36756441.
  16. ↑ Challis, B. C.; Trew, D. F.; Guthrie, W. G.; Roper, D. V. (1995). "Reduction of nitrosamines in cosmetic products". International Journal of Cosmetic Science. 17 (3): 119–131. doi:10.1111/j.1467-2494.1995.tb00115.x. PMID   19245496. S2CID   11108503 . Retrieved 18 January 2024.
  17. ↑ Fishbein, James C.; Kim, Hyun-Joong (2003). "Reexamination of the Aqueous Chemistry of N-Nitroso-3-hydroxymorpholine, a Metabolite of the Carcinogen N-Nitrosomorpholine". Chemical Research in Toxicology . 16 (6): 715–720. doi:10.1021/tx020114j. PMID   12807354 . Retrieved 18 January 2024.
  18. ↑ Fishbein, James C.; Koissi, Niangoran (2013). "Trapping of a Cross-Link Formed by a Major Purine Adduct of a Metabolite of the Carcinogen N-Nitrosomorpholine by Inorganic and Biological Reductants". Chemical Research in Toxicology . 26 (5): 732–740. doi:10.1021/tx3005289. PMC   3706203 . PMID   23587048.
  19. ↑ Winter, Jack W.; Paterson, Stuart; Scobie, Gordon; Wirz, Angela; Preston, Tom; McColl, Kenneth E. L. (2007). "N-Nitrosamine Generation From Ingested Nitrate Via Nitric Oxide in Subjects With and Without Gastroesophageal Reflux". Gastroenterology . 133 (1): 164–174. doi:10.1053/j.gastro.2007.04.047. PMID   17631140 . Retrieved 16 January 2024.
  20. ↑ Vermeer, I. T. M.; Gerrits, M. M.; et al. (31 May 2002). "Helicobacter pylori does not Mediate the Formation of Carcinogenic N-Nitrosamines". Helicobacter. 7 (3): 163–169. doi:10.1046/j.1523-5378.2002.00076.x. PMID   12047321. S2CID   27005252 . Retrieved 16 January 2024.
  21. ↑ Futakuchi, Mitsuru; Hirose, Masao; et al. (1999). "Establishment of an in vivo Highly Metastatic Rat Hepatocellular Carcinoma Model". Japanese Journal of Cancer Research . 90 (11): 1196–1202. doi:10.1111/j.1349-7006.1999.tb00695.x. PMC   5926015 . PMID   10622528.
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