hexamethylenetetramine

Hexamethylenetetramine was discovered by Aleksandr Butlerov in 1859.{{cite journal | url=https://books.google.com/books?id=NYs8AAAAIAAJ&pg=PA242 | title=Ueber einige Derivate des Jodmethylens | vauthors = Butlerow A | journal=Ann. Chem. Pharm. | year=1859 | volume=111 | issue=2 | pages=242–252 | language=de | doi=10.1002/jlac.18591110219 | trans-title=On some derivatives of methylene iodide}} In this article, Butlerov discovered formaldehyde, which he called "dioxymethylen" (methylene dioxide) [page 247] because his empirical formula for it was incorrect (C₄H₄O₄). On pages 249–250, he describes treating formaldehyde with ammonia gas, creating hexamine.{{cite journal | url=https://books.google.com/books?id=14lKAAAAYAAJ&pg=PA322 | title=Ueber ein neues Methylenderivat | vauthors = Butlerow A | journal=Ann. Chem. Pharm. | year=1860 | volume=115 | issue=3 | pages=322–327 | doi=10.1002/jlac.18601150325 | trans-title=On a new methylene derivative | language=de}}

It is prepared industrially by combining formaldehyde and ammonia:{{cite encyclopedia | chapter=Amines, Aliphatic | encyclopedia=Ullmann's Encyclopedia of Industrial Chemistry | publisher=Wiley-VCH Verlag GmbH | year=2000 | isbn=9783527306732 | doi=10.1002/14356007.a02_001 | vauthors = Eller K, Henkes E, Rossbacher R, Höke H }}

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The molecule behaves like an amine base, undergoing protonation and as a ligand.{{cite journal | last=Kirillov | first=Alexander M. | title=Hexamethylenetetramine: An old new building block for design of coordination polymers | journal=Coordination Chemistry Reviews | publisher=Elsevier BV | volume=255 | issue=15–16 | year=2011 | issn=0010-8545 | doi=10.1016/j.ccr.2011.01.023 | pages=1603–1622}} N-alkylation with chloroallyl chloride gives quaternium-15).

The dominant use of hexamethylenetetramine is in the production of solid (powder) or liquid phenolic resins and phenolic resin moulding compounds, in which it is added as a hardening component. These products are used as binders, e.g., in brake and clutch linings, abrasives, non-woven textiles, formed parts produced by moulding processes, and fireproof materials.

{{Main|Methenamine (drug)}}

The compound is also used medically as a urinary antiseptic and antibacterial medication under the name methenamine or hexamine.{{cite journal | vauthors = Lo TS, Hammer KD, Zegarra M, Cho WC | title = Methenamine: a forgotten drug for preventing recurrent urinary tract infection in a multidrug resistance era | journal = Expert Rev Anti Infect Ther | volume = 12 | issue = 5 | pages = 549–554 | date = May 2014 | pmid = 24689705| doi = 10.1586/14787210.2014.904202 | url = }}https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/017681Orig1s019lbl.pdf{{cite book | last=Elks | first=J. | title=The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies | publisher=Springer US | year=2014 | isbn=978-1-4757-2085-3 | url=https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA629 | access-date=11 October 2024 | page=629}}{{cite book | author=Schweizerischer Apotheker-Verein | title=Index Nominum: International Drug Directory | publisher=Medpharm Scientific Publishers | year=2004 | isbn=978-3-88763-101-7 | url=https://books.google.com/books?id=EgeuA47Ocm4C&pg=PA775 | access-date=11 October 2024 | pages=775–776}} It is used as an alternative to antibiotics to prevent urinary tract infections (UTIs) and is sold under the brand names Hiprex, Urex, and Urotropin, among others.

As the mandelic acid salt (methenamine mandelate) or the hippuric acid salt (methenamine hippurate),{{cite journal | vauthors = Lo TS, Hammer KD, Zegarra M, Cho WC | title = Methenamine: a forgotten drug for preventing recurrent urinary tract infection in a multidrug resistance era | journal = Expert Review of Anti-Infective Therapy | volume = 12 | issue = 5 | pages = 549–554 | date = May 2014 | pmid = 24689705 | doi = 10.1586/14787210.2014.904202 | s2cid = 207199202 }} it is used for the treatment of urinary tract infections. In an acidic environment, methenamine is believed to act as an antimicrobial by converting to formaldehyde.{{cite journal | vauthors = Chwa A, Kavanagh K, Linnebur SA, Fixen DR | title = Evaluation of methenamine for urinary tract infection prevention in older adults: a review of the evidence | journal = Therapeutic Advances in Drug Safety | volume = 10 | pages = 2042098619876749 | date = 2019 | pmid = 31579504 | pmc = 6759703 | doi = 10.1177/2042098619876749 }} A systematic review of its use for this purpose in adult women found there was insufficient evidence of benefit and further research was needed.{{cite journal | vauthors = Bakhit M, Krzyzaniak N, Hilder J, Clark J, Scott AM, Mar CD | title = Use of methenamine hippurate to prevent urinary tract infections in community adult women: a systematic review and meta-analysis | journal = The British Journal of General Practice | volume = 71 | issue = 708 | pages = e528–e537 | date = July 2021 | pmid = 34001538 | pmc = 8136580 | doi = 10.3399/BJGP.2020.0833 | type = Systematic review }} A UK study showed that methenamine is as effective as daily low-dose antibiotics at preventing UTIs among women who experience recurrent UTIs. As methenamine is an antiseptic, it may avoid the issue of antibiotic resistance.{{Cite journal |date=2022-12-20 |title=Methenamine is as good as antibiotics at preventing urinary tract infections |url=https://evidence.nihr.ac.uk/alert/methenamine-as-good-as-antibiotics-preventing-urinary-tract-infections/ |journal=NIHR Evidence |language=en |doi=10.3310/nihrevidence_55378|s2cid=254965605 |url-access=subscription }}{{cite journal | vauthors = Harding C, Mossop H, Homer T, Chadwick T, King W, Carnell S, Lecouturier J, Abouhajar A, Vale L, Watson G, Forbes R, Currer S, Pickard R, Eardley I, Pearce I, Thiruchelvam N, Guerrero K, Walton K, Hussain Z, Lazarowicz H, Ali A | display-authors = 6 | title = Alternative to prophylactic antibiotics for the treatment of recurrent urinary tract infections in women: multicentre, open label, randomised, non-inferiority trial | journal = BMJ | volume = 376 | pages = e068229 | date = March 2022 | pmid = 35264408 | pmc = 8905684 | doi = 10.1136/bmj-2021-0068229 }}

Methenamine acts as an over-the-counter antiperspirant due to the astringent property of formaldehyde.{{cite journal | vauthors = Susak Z, Minkov R, Isakov E | title = The use of Methenamine as an antiperspirant for amputees | journal = Prosthetics and Orthotics International | volume = 20 | issue = 3 | pages = 172–175 | date = December 1996 | pmid = 8985996 | doi = 10.3109/03093649609164439 | s2cid = 24088433 | doi-access = free }}

Methenamine silver stains are used for staining in histology, including the following types:

• Grocott's methenamine silver stain, used widely as a screen for fungal organisms.
• Jones' stain, a methenamine silver-Periodic acid-Schiff that stains for basement membrane, availing to view the "spiked" Glomerular basement membrane associated with membranous glomerulonephritis.

Together with 1,3,5-trioxane, hexamethylenetetramine is a component of hexamine fuel tablets used by campers, hobbyists, the military and relief organizations for heating camping food or military rations. It burns smokelessly, has a high energy density of 30.0 megajoules per kilogram (MJ/kg), does not liquify while burning, and leaves no ashes, although its fumes are toxic.{{cn|date=February 2023}}

Standardized 0.149 g tablets of methenamine (hexamine) are used by fire-protection laboratories as a clean and reproducible fire source to test the flammability of carpets and rugs.

Hexamethylenetetramine or hexamine is also used as a food additive as a preservative (INS number 239). It is approved for usage for this purpose in the EU,UK Food Standards Agency: {{cite web |url=http://www.food.gov.uk/safereating/chemsafe/additivesbranch/enumberlist |title=Current EU approved additives and their E Numbers |access-date=2011-10-27}} where it is listed under E number E239, however it is not approved in the USA, Russia, Australia, or New Zealand.Australia New Zealand Food Standards Code{{cite web |url=http://www.comlaw.gov.au/Details/F2011C00827 |title=Standard 1.2.4 - Labelling of ingredients |date=8 September 2011 |access-date=2011-10-27}}

Hexamethylenetetramine is a versatile reagent in organic synthesis.{{cite journal | title=Hexamethylenetetramine, A Versatile Reagent in Organic Synthesis | vauthors = Blažzević N, Kolbah D, Belin B, Šunjić V, Kajfež F | journal=Synthesis | year=1979 | volume=1979 | issue=3 | pages=161–176 | doi=10.1055/s-1979-28602 | s2cid = 97756228 }} It is used in the Duff reaction (formylation of arenes),{{OrgSynth | vauthors = Allen CH, Leubne GW | title = Syringic Aldehyde| volume = 31 | pages = 92 | year = 1951 | prep = CV4P0866 |doi = 10.15227/orgsyn.031.0092}} the Sommelet reaction (converting benzyl halides to aldehydes),{{OrgSynth | vauthors = Wiberg KB | title = 2-Thiophenaldehyde| collvol = 3 | collvolpages = 811| year = 1963 | prep = CV3P0811 |doi = 10.15227/orgsyn.000.0000}} and in the Delepine reaction (synthesis of amines from alkyl halides).{{OrgSynth | vauthors = Bottini AT, Dev V, Klinck J | title = 2-Bromoallylamine| volume = 43 | pages = 6| year = 1963 | prep = CV5P0121 | doi=10.15227/orgsyn.043.0006}}

Hexamethylenetetramine is the base component to produce RDX and, consequently, C-4 as well as octogen (a co-product with RDX), hexamine dinitrate, hexamine diperchlorate, HMTD, and R-salt.

From October 2023, sale of hexamethylenetetramine in the UK is restricted to licensed persons (as a "regulated precursor" under the terms of the Poisons Act 1972).{{cite web | url=https://www.gov.uk/government/news/new-measures-targeting-bomb-making-materials-come-into-force | date=2 October 2023 | title=New measures targeting bomb-making materials come into force | website=Home Office | publisher=UK Government}}

Hexamethylenetetramine is also used in pyrotechnics to reduce combustion temperatures and decrease the color intensity of various fireworks.{{Cite patent|country=DE|number=3402546|title=Pyrotechnischer Satz zur Erzeugung von Lichtblitzen|status=patent|gdate=1985-08-01|invent1=Lohmann|inventor1-first=Erwin|url=https://worldwide.espacenet.com/patent/search?q=pn%3DDE3402546A1}} Because of its ash-free combustion, hexamethylenetetramine is also utilized in indoor fireworks alongside magnesium and lithium salts.{{Cite patent|country=US|number=6214139|title=Low-smoke pyrotechnic compositions|status=patent|gdate=2001-04-10|invent1=Hiskey|invent2=Chavez|invent3=Naud|inventor1-first=Michael A.|inventor2-first=David E.|inventor3-first=Darren L.|assign1=The Regents of the University of California|assign2=Los Alamos National Laboratory|url=https://worldwide.espacenet.com/patent/search?q=pn%3DUS6214139B1}}{{Cite patent|country=GB|number=2502460|title=Pyrotechnic composition with spark producing material|status=patent|gdate=2013-11-27|invent1=Wraige|inventor1-first=John Douglas Michael|url=https://worldwide.espacenet.com/patent/search?q=pn%3DGB2502460A}}

Hexamethylenetetramine was first introduced into the medical setting in 1895 as a urinary antiseptic.{{cite journal|doi=10.1001/jama.1913.04350190019006|title=An Experimental Study of the Antiseptic Value in the Urine of the Internal Use of Hexamethylenamin|year=1913| vauthors = Hinman F |journal=JAMA: The Journal of the American Medical Association|volume=61|issue=18|page=1601}} It was officially approved by the FDA for medical use in the United States in 1967.{{Citation |last1=Sauberan |first1=Jason B. |title=292 - Antimicrobial Agents |date=2018-01-01 |url=https://www.sciencedirect.com/science/article/pii/B9780323401814002929 |work=Principles and Practice of Pediatric Infectious Diseases (Fifth Edition) |pages=1499–1531.e3 |editor-last=Long |editor-first=Sarah S. |access-date=2023-11-15 |publisher=Elsevier |doi=10.1016/b978-0-323-40181-4.00292-9 |isbn=978-0-323-40181-4 |last2=Bradley |first2=John S. |editor2-last=Prober |editor2-first=Charles G. |editor3-last=Fischer |editor3-first=Marc|url-access=subscription }} However, it was only used in cases of acidic urine, whereas boric acid was used to treat urinary tract infections with alkaline urine.{{Cite journal|title = On Urinary Antiseptics| vauthors = Elliot|date = 1913|journal = British Medical Journal|volume = 98|pages = 685–686}} Scientist De Eds found that there was a direct correlation between the acidity of hexamethylenetetramine's environment and the rate of its decomposition.{{cite journal| vauthors = Heathcote RS |title=Hexamine as an Urinary Antiseptic: I. Its Rate of Hydrolysis at Different Hydrogen Ion Concentrations. II. Its Antiseptic Power Against Various Bacteria in Urine|journal=British Journal of Urology|volume=7|issue=1|year=1935|pages=9–32|issn=0007-1331|doi=10.1111/j.1464-410X.1935.tb11265.x}} Therefore, its effectiveness as a drug depended greatly on the acidity of the urine rather than the amount of the drug administered. In an alkaline environment, hexamethylenetetramine was found to be almost completely inactive.

Hexamethylenetetramine was also used as a method of treatment for soldiers exposed to phosgene in World War I. Subsequent studies have shown that large doses of hexamethylenetetramine provide some protection if taken before phosgene exposure but none if taken afterwards.{{cite journal | vauthors = Diller WF | title = The methenamine misunderstanding in the therapy of phosgene poisoning | journal = Archives of Toxicology | volume = 46 | issue = 3–4 | pages = 199–206 | date = December 1980 | pmid = 7016075 | doi = 10.1007/BF00310435 | bibcode = 1980ArTox..46..199D | s2cid = 2423812 }}

File:Hexamethylenetetramine Bayer.jpg (IG Farben) ]]

Since 1990 the number of European producers has been declining. The French SNPE factory closed in 1990; in 1993, the production of hexamethylenetetramine in Leuna, Germany ceased; in 1996, the Italian facility of Agrolinz closed down; in 2001, the UK producer Borden closed; in 2006, production at Chemko, Slovak Republic, was closed. Remaining producers include INEOS in Germany, Caldic in the Netherlands, and Hexion in Italy. In the US, Eli Lilly and Company stopped producing methenamine tablets in 2002.{{cite web |url= http://www.cpsc.gov/BUSINFO/methtabs.pdf|title=Re: Equialence of methenamine Tablets Standard for Flammability of Carpets and Rugs |date=July 29, 2004 |publisher=Alan H. Schoen |archive-url=https://web.archive.org/web/20081005165422/https://www.cpsc.gov/businfo/methtabs.pdf |archive-date=2008-10-05}} In Australia, Hexamine Tablets for fuel are made by Thales Australia Ltd. In México, Hexamine is produced by Abiya.{{cn|date=February 2023}} Many other countries who still produce this include Russia, Saudi Arabia, and China.

In 2020, NASA announced that hexamethylenetetramine had been found in the Murchison, Murray and Tagish Lake meteorites.{{cite web |last1=Steigerwald |first1=William |title=Key Building Block for Organic Molecules Discovered in Meteorites |url=https://www.nasa.gov/solar-system/key-building-block-for-organic-molecules-discovered-in-meteorites/ |website=NASA |access-date=31 March 2025}}{{cite journal |last1=Oba |first1=Yasuhiro |last2=Takano |first2=Yoshinori |last3=Naraoka |first3=Hiroshi |last4=Furukawa |first4=Yoshihiro |last5=Glavin |first5=Daniel P. |last6=Dworkin |first6=Jason P. |last7=Tachibana |first7=Shogo |title=Extraterrestrial hexamethylenetetramine in meteorites—a precursor of prebiotic chemistry in the inner solar system |journal=Nature Communications |date=2020 |volume=11 |page=6243 |doi=10.1038/s41467-020-20038-x |url=https://www.nature.com/articles/s41467-020-20038-x |access-date=3 April 2025|pmc=7721876 }}

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Category:Adamantane-like molecules

Category:Antimicrobials

Category:Corrosion inhibitors

Category:E-number additives

Category:Fuels

Category:Heterocyclic compounds with 3 rings

Category:Nitrogen heterocycles

Category:Preservatives

Category:Reagents for organic chemistry

Category:Substances discovered in the 19th century

Category:Tertiary amines