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Hexamethylenetetramine (HMTA), also known as 1,3,5,7-tetraazaadamantane, is a heterocyclic organic compound with diverse applications.<ref name="DreyforsJonesSayed1989">Template:Cite journal</ref><ref name="BlažzevićKolbahBelin1979">Template:Cite journal</ref> It has the chemical formula (CH2)6N4 and is a white crystalline compound that is highly soluble in water and polar organic solvents. It is useful in the synthesis of other organic compounds, including plastics, pharmaceuticals, and rubber additives.<ref name="DreyforsJonesSayed1989" /><ref name="BlažzevićKolbahBelin1979" /> The compound is also used medically for certain conditions.<ref name="LoHammerZegarra2014" /><ref name="ConnollydeBerker2003">Template:Cite journal</ref> It sublimes in vacuum at 280Template:Nbsp°C. It has a tetrahedral cage-like structure similar to adamantane.<ref name="BlažzevićKolbahBelin1979" /> The four vertices are occupied by nitrogen atoms, which are linked by methylene groups. Although the molecular shape defines a cage, no void space is available at the interior.
Synthesis, structure, reactivityEdit
Hexamethylenetetramine was discovered by Aleksandr Butlerov in 1859.<ref name="Butlerow1859">Template:Cite journal 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.</ref><ref name="Butlerow1860">Template:Cite journal</ref> It is prepared industrially by combining formaldehyde and ammonia:<ref name="Ullmann">Template:Cite encyclopedia</ref>
The molecule behaves like an amine base, undergoing protonation and as a ligand.<ref name="Kirillov2011">Template:Cite journal</ref> N-alkylation with chloroallyl chloride gives quaternium-15).
ApplicationsEdit
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.<ref name=Ullmann/>
Medical usesEdit
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The compound is also used medically as a urinary antiseptic and antibacterial medication under the name methenamine or hexamine.<ref name="LoHammerZegarra2014">Template:Cite journal</ref><ref name="Hiprex-Label">https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/017681Orig1s019lbl.pdf</ref><ref name="Elks2014">Template:Cite book</ref><ref name="IndexNominum2004">Template:Cite book</ref> 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.<ref name="LoHammerZegarra2014" /><ref name="Hiprex-Label" /><ref name="IndexNominum2004" />
As the mandelic acid salt (methenamine mandelate) or the hippuric acid salt (methenamine hippurate),<ref name="forgotten">Template:Cite journal</ref> 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.<ref name="forgotten"/><ref>Template:Cite journal</ref> A systematic review of its use for this purpose in adult women found there was insufficient evidence of benefit and further research was needed.<ref name=bakhit>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>
Methenamine acts as an over-the-counter antiperspirant due to the astringent property of formaldehyde.<ref>Template:Cite journal</ref>
Histological stainsEdit
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.
Solid fuelEdit
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.Template:Cn
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.<ref name="schon"/>
Food additiveEdit
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,<ref>UK Food Standards Agency: {{#invoke:citation/CS1|citation |CitationClass=web }}</ref> where it is listed under E number E239, however it is not approved in the USA, Russia, Australia, or New Zealand.<ref>Australia New Zealand Food Standards Code{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>
Reagent in organic chemistryEdit
Hexamethylenetetramine is a versatile reagent in organic synthesis.<ref name="Blazzevic1979">Template:Cite journal</ref> It is used in the Duff reaction (formylation of arenes),<ref>Template:OrgSynth</ref> the Sommelet reaction (converting benzyl halides to aldehydes),<ref>Template:OrgSynth</ref> and in the Delepine reaction (synthesis of amines from alkyl halides).<ref>Template:OrgSynth</ref>
ExplosivesEdit
Hexamethylenetetramine is the base component to produce RDX and, consequently, C-4<ref name=Ullmann/> 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).<ref name="uk_restriction">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>
PyrotechnicsEdit
Hexamethylenetetramine is also used in pyrotechnics to reduce combustion temperatures and decrease the color intensity of various fireworks.<ref>Template:Cite patent</ref> Because of its ash-free combustion, hexamethylenetetramine is also utilized in indoor fireworks alongside magnesium and lithium salts.<ref>Template:Cite patent</ref><ref>Template:Cite patent</ref>
Historical usesEdit
Hexamethylenetetramine was first introduced into the medical setting in 1895 as a urinary antiseptic.<ref>Template:Cite journal</ref> It was officially approved by the FDA for medical use in the United States in 1967.<ref>Template:Citation</ref> However, it was only used in cases of acidic urine, whereas boric acid was used to treat urinary tract infections with alkaline urine.<ref name=":0">Template:Cite journal</ref> Scientist De Eds found that there was a direct correlation between the acidity of hexamethylenetetramine's environment and the rate of its decomposition.<ref name=":1">Template:Cite journal</ref> Therefore, its effectiveness as a drug depended greatly on the acidity of the urine rather than the amount of the drug administered.<ref name=":0" /> In an alkaline environment, hexamethylenetetramine was found to be almost completely inactive.<ref name=":0" />
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.<ref name="Diller1980">Template:Cite journal</ref>
ProducersEdit
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.<ref name="schon">{{#invoke:citation/CS1|citation |CitationClass=web }} </ref> In Australia, Hexamine Tablets for fuel are made by Thales Australia Ltd. In México, Hexamine is produced by Abiya.Template:Cn Many other countries who still produce this include Russia, Saudi Arabia, and China.
OccurrenceEdit
In 2020, NASA announced that hexamethylenetetramine had been found in the Murchison, Murray and Tagish Lake meteorites.<ref name="Steigerwald2020">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="Oba2020">Template:Cite journal</ref>