N-Nitrosomorpholine

NMOR is a pale yellow sand-like powder below 84°F. {{cite journal |last1=Borikar |first1=Sanjay P. |last2=Paul |first2=Vincent |date=2010 |title=N-Nitrosation of Secondary Amines Using p-TSA-NaNO2 as a Novel Nitrosating Agent Under Mild Conditions |url=https://www.tandfonline.com/doi/full/10.1080/00397910903009448 |journal=Synthetic Communications |volume=40 |issue=5 |pages=654–660 |doi=10.1080/00397910903009448 |s2cid=98412823 |access-date=10 January 2024}}

NMOR is most commonly produced from morpholine, but can also be made by the reaction of dimorpholinomethane in fuming nitric acid.{{cite journal |last1=Zhang |first1=Yu |last2=Zou |first2=Po |last3=Han |first3=Yingbin |last4=Geng |first4=Yongliang |last5=Luo |first5=Jun |last6=Zhou |first6=Baojing |date=2018 |title=A combined experimental and DFT mechanistic study for the unexpected nitrosolysis of N-hydroxymethyldialkylamines in fuming nitric acid |journal=RSC Advances |volume=8 |issue= 34|pages=19310–19316 |doi=10.1039/C8RA03268H |pmid=35539630 |bibcode=2018RSCAd...819310Z |pmc=9080733 }} 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.{{cite journal |last1=Patil |first1=Dilip V. |last2=Lee |first2=Yulim |last3=Kim |first3=Hun Young |last4=Oh |first4=Kyungsoo |date=2022 |title=Visible-Light-Promoted Photoaddition of N-Nitrosopiperidines to Alkynes: Continuous Flow Chemistry Approach to Tetrahydroimidazo[1,2-a]pyridine 1-Oxides |url=https://pubs.acs.org/doi/full/10.1021/acs.orglett.2c02402 |journal=Organic Letters |volume=24 |issue=31 |pages=5840–5844 |doi=10.1021/acs.orglett.2c02402 |pmid=35921551 |s2cid=251317605 |access-date=18 January 2024}}

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.

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.{{cite web |url=https://www.inspq.qc.ca/sites/default/files/publications/1263_cancerriskassessworkersnitrosaminesrubber.pdf |title=Cancer risk assessment for workers exposed to nitrosamines in a warehouse of finished rubber products in the Eastern Townships (Québec, Canada) |last1=Carrier |first1=Gaétan |last2=Desrosiers |first2=Marie-Claire |last3=Adib |first3=Georges |date=2011 |website=Institut national de santé publique du Québec |publisher=Gouvernement du Québec |access-date=16 January 2024 |archive-url=https://web.archive.org/web/20211203201904/https://www.inspq.qc.ca/sites/default/files/publications/1263_cancerriskassessworkersnitrosaminesrubber.pdf |archive-date=3 December 2021}}

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.{{cite journal |last1=Oldham |first1=Michael J. |last2=DeSoi |first2=Darren J. |last3=Rimmer |first3=Lonnie T. |last4=Wagner |first4=Karl A. |last5=Morton |first5=Michael J. |date=2014 |title=Insights from analysis for harmful and potentially harmful constituents (HPHCs) in tobacco products |url=https://www.sciencedirect.com/science/article/pii/S0273230014001317 |journal=Regulatory Toxicology and Pharmacology |volume=70 |issue=1 |pages=138–148 |doi=10.1016/j.yrtph.2014.06.017 |pmid=24973503 |access-date=16 January 2024}}{{cite journal |last1=Lv |first1=Fang |last2=Guo |first2=Junwei |last3=Zhang |first3=Tingting |last4=Yu |first4=Fei |last5=Zhang |first5=Shimin |last6=Cui |first6=Huapeng |last7=Liu |first7=Xianjun |last8=Chen |first8=Li |last9=Liu |first9=Leiyu |last10=Liu |first10=Shaofeng |last11=Xie |first11=Fuwei |display-authors=2 |date=5 April 2016 |title=Determination of nine volatile N-nitrosamines in tobacco and smokeless tobacco products by dispersive solid-phase extraction with gas chromatography and tandem mass spectrometry |url=https://analyticalsciencejournals.onlinelibrary.wiley.com/doi/10.1002/jssc.201600037 |journal=Journal of Separation Science |volume=39 |issue=11 |pages=2123–2128 |doi=10.1002/jssc.201600037 |pmid=27059265 |access-date=16 January 2024}} 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.{{cite journal |last1=Wang |first1=Xiaoyu |last2=Qin |first2=Yaqiong |last3=Nie |first3=Cong |last4=Guo |first4=Junwei |last5=Pan |first5=Lining |last6=Xie |first6=Fuwei |last7=Wang |first7=Sheng |last8=Wang |first8=Bing |last9=Zhao |first9=Xiaodong |last10=Wang |first10=Baolin |last11=Jia |first11=Guotao |display-authors=2 |date=29 April 2021 |title=Smokeless tobacco analysis: Simultaneous extraction and purification of alkaloids, volatile N-nitrosamines, and polycyclic hydrocarbons for GC-MS/MS |url=https://analyticalsciencejournals.onlinelibrary.wiley.com/doi/10.1002/jssc.202100186 |journal=Journal of Separation Science |volume=44 |issue=13 |pages=2642–2654 |doi=10.1002/jssc.202100186 |pmid=33915029 |s2cid=233459643 |access-date=16 January 2024}} Volatile nitrosamines, including NMOR, are detectable in the urine of tobacco smokers. {{cite journal |last1=Seyler |first1=Tiffany H. |last2=Kim |first2=Jenny G. |last3=Hodgson |first3=James A. |last4=Cowan |first4=Elizabeth A. |last5=Blount |first5=Benjamin C. |last6=Wang |first6=Lanqing |date=18 March 2013 |title= Quantitation of Urinary Volatile Nitrosamines from Exposure to Tobacco Smoke |url=https://academic.oup.com/jat/article/37/4/195/756055 |journal=Journal of Analytical Toxicology |volume=37 |issue=4 |pages=195–202 |doi=10.1093/jat/bkt020 |pmid=23508653 |access-date=16 January 2024}}

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.{{cite news |last=Akbar |first=Syed |date=16 December 2016 |title=Toxic gloss on 'fresh' veggie plate |url=https://timesofindia.indiatimes.com/city/hyderabad/toxic-gloss-on-fresh-veggie-plate/articleshow/56013416.cms |work=The Times of India |location=Hyderabad |access-date=15 February 2023}} {{cite journal |last1=Kumar |first1=Rupak |last2=Kapur |first2=Suman |date=2016 |title=Morpholine: A Glazing Agents for Fruits and Vegetables Coating/Waxing |url=https://www.researchgate.net/publication/313677391 |journal=International Journal of Science Technology and Engineering |volume=2 |issue=11 |pages=694–697 |issn=2349-784X |access-date=15 February 2023}}Health Canada, the Canadian governmental department of public health, has stated in 2002 that this does not pose a risk to human health.{{cite web |url=https://www.canada.ca/en/health-canada/services/food-nutrition/food-safety/information-product/fact-sheet-use-morpholine-apple-coatings.html |title=Fact Sheet: Use of Morpholine in Apple Coatings |last= |first= |date=9 December 2002 |website=Government of Canada |publisher=Health Canada |access-date=9 February 2023 |url-status=live |archive-url=https://web.archive.org/web/20230127185826/https://www.canada.ca/en/health-canada/services/food-nutrition/food-safety/information-product/fact-sheet-use-morpholine-apple-coatings.html |archive-date=27 January 2023}}

Consumption of nitrate-rich diets is correlated with levels of salivary and urinary NMOR.{{cite journal |last1=van Maanen |first1=Jan M. S. |last2=Pachen |first2=D. M. |last3=Dallinga |first3=J. M. |last4=Kleinjans |first4=J. C. |date=1998 |title=Formation of nitrosamines during consumption of nitrate- and amine-rich foods, and the influence of the use of mouthwashes |url=https://pubmed.ncbi.nlm.nih.gov/9618041/ |journal=Cancer Detection and Prevention |volume=22 |issue=3 |pages=204–212 |doi=10.1046/j.1525-1500.1998.0oa26.x |doi-broken-date=8 February 2025 |pmid=9618041 |access-date=11 January 2024}} The presence of NMOR can also be observed in gastric juices.{{cite journal |last1=Dallinga |first1=J. W. |last2=Pachen |first2=D. M. F. A. |date=1998 |title=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 |url=https://www.sciencedirect.com/science/article/pii/S0304383597004679 |journal=Cancer Letters |volume=124 |issue=2 |pages=119–125 |doi=10.1016/S0304-3835(97)00467-9 |pmid=9500200 |access-date=11 January 2024}}

NMOR has been found in several cosmetic products.{{cite journal |last1=Schettino |first1=Lorenzo |last2=Benedé |first2=Juan L. |last3=Chisvert |first3=Albertino |date=2023 |title=Determination of nine prohibited N-nitrosamines in cosmetic products by vortex-assisted dispersive liquid–liquid microextraction prior to gas chromatography-mass spectrometry |journal=RSC Advances |volume=13 |issue= 5|pages=2963–2971 |doi=10.1039/D2RA06553C |pmid=36756441 |pmc=9850448 |bibcode=2023RSCAd..13.2963S }}{{cite journal |last1=Challis |first1=B. C. |last2=Trew |first2=D. F. |last3=Guthrie |first3=W. G. |last4=Roper |first4=D. V. |date=1995 |title=Reduction of nitrosamines in cosmetic products |url=https://onlinelibrary.wiley.com/doi/10.1111/j.1467-2494.1995.tb00115.x |journal=International Journal of Cosmetic Science |volume=17 |issue=3 |pages=119–131 |doi=10.1111/j.1467-2494.1995.tb00115.x |pmid=19245496 |s2cid=11108503 |access-date=18 January 2024}}

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. {{cite journal |last1=Fishbein |first1=James C. |last2=Kim |first2=Hyun-Joong |date=2003 |title=Reexamination of the Aqueous Chemistry of N-Nitroso-3-hydroxymorpholine, a Metabolite of the Carcinogen N-Nitrosomorpholine |url=https://pubs.acs.org/doi/10.1021/tx020114j |journal=Chemical Research in Toxicology |volume=16 |issue=6 |pages=715–720 |doi=10.1021/tx020114j |pmid=12807354 |access-date=18 January 2024}} This then decomposes into a diazonium-containing aldehyde which is capable of crosslinking DNA.{{cite journal |last1=Fishbein |first1=James C. |last2=Koissi |first2=Niangoran |date=2013 |title=Trapping of a Cross-Link Formed by a Major Purine Adduct of a Metabolite of the Carcinogen N-Nitrosomorpholine by Inorganic and Biological Reductants |journal=Chemical Research in Toxicology |volume=26 |issue=5 |pages=732–740 |doi=10.1021/tx3005289 |pmid=23587048 |pmc=3706203 }}

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.{{cite journal |last1=Winter |first1=Jack W. |last2=Paterson |first2=Stuart |last3=Scobie |first3=Gordon |last4=Wirz |first4=Angela |last5=Preston |first5=Tom |last6=McColl |first6=Kenneth E. L. |date=2007 |title=N-Nitrosamine Generation From Ingested Nitrate Via Nitric Oxide in Subjects With and Without Gastroesophageal Reflux |url=https://www.sciencedirect.com/science/article/pii/S0016508507008347 |journal=Gastroenterology |volume=133 |issue=1 |pages=164–174 |doi=10.1053/j.gastro.2007.04.047 |pmid=17631140 |access-date=16 January 2024}} H. pylori does not induce NMOR formation in vitro, though this has yet to be confirmed in vivo.{{cite journal |last1=Vermeer |first1=I. T. M. |last2=Gerrits |first2=M. M. |last3=Moonen |first3=E. J. C. |last4=Engels |first4=L. G. J. B. |last5=Dallinga |first5=J. W. |last6=Kleinjans |first6=J. C. S. |last7=Van Maanen |first7=J. M. S. |last8=Kuipers |first8=E. J. |last9=Kusters |first9=J. G. |display-authors=2 |date=31 May 2002 |title=Helicobacter pylori does not Mediate the Formation of Carcinogenic N-Nitrosamines |url=https://onlinelibrary.wiley.com/doi/full/10.1046/j.1523-5378.2002.00076.x |journal=Helicobacter |volume=7 |issue=3 |pages=163–169 |doi=10.1046/j.1523-5378.2002.00076.x |pmid=12047321 |s2cid=27005252 |access-date=16 January 2024}}

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.{{cite journal |last1=Futakuchi |first1=Mitsuru |last2=Hirose |first2=Masao |last3=Ogiso |first3=Tadashi |last4=Kato |first4=Koji |last5=Sano |first5=Masashi |last6=Ogawa |first6=Kumiko |last7=Shirai |first7=Tomoyuki |display-authors=2 |date=1999 |title=Establishment of an in vivo Highly Metastatic Rat Hepatocellular Carcinoma Model |journal=Japanese Journal of Cancer Research |volume=90 |issue= 11|pages=1196–1202 |doi=10.1111/j.1349-7006.1999.tb00695.x |pmid=10622528 |pmc=5926015 }}

• Nitrosamine
• N-Nitrosodiethylamine
• Hepatotoxicity

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{{DEFAULTSORT:Nitrosomorpholine, N-}}

Category:4-Morpholinyl compounds

Category:Nitrosamines

Category:Reagents for organic chemistry

Category:Carcinogens