Hexamethylenetetramine

Hexamethylenetetramine, also known as methenamine, hexamine, or urotropin, is a heterocyclic organic compound with the formula (CH2)6N4. This white crystalline compound is highly soluble in water and polar organic solvents. It has a cage-like structure similar to adamantane. It is useful in the synthesis of other organic compounds, including plastics, pharmaceuticals, and rubber additives. It sublimes in vacuum at 280 °C.

"Hexamine" redirects here. Not to be confused with Hexylamine.
Hexamethylenetetramine
Names
Preferred IUPAC name
1,3,5,7-Tetraazaadamantane
Other names
Hexamine; Methenamine;
Urotropine; Formin, Aminoform
Identifiers
3D model (JSmol)
2018
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.002.642
EC Number
  • 202-905-8
E number E239 (preservatives)
26964
KEGG
MeSH Methenamine
RTECS number
  • MN4725000
UNII
UN number 1328
  • InChI=1S/C6H12N4/c1-7-2-9-4-8(1)5-10(3-7)6-9/h1-6H2 checkY
    Key: VKYKSIONXSXAKP-UHFFFAOYSA-N checkY
  • InChI=1/C6H12N4/c1-7-2-9-4-8(1)5-10(3-7)6-9/h1-6H2
    Key: VKYKSIONXSXAKP-UHFFFAOYAW
  • C1N2CN3CN1CN(C2)C3
Properties
C6H12N4
Molar mass 140.186 g/mol
Appearance White crystalline solid
Odor Fishy, ammonia like
Density 1.33 g/cm3 (at 20 °C)
Melting point 280 °C (536 °F; 553 K) (sublimes)
85.3 g/100 mL
Solubility Soluble in chloroform, methanol, ethanol, acetone, benzene, xylene, ether
Solubility in chloroform 13.4 g/100 g (20 °C)
Solubility in methanol 7.25 g/100 g (20 °C)
Solubility in ethanol 2.89 g/100 g (20 °C)
Solubility in acetone 0.65 g/100 g (20 °C)
Solubility in benzene 0.23 g/100 g (20 °C)
Acidity (pKa) 4.89[1]
Pharmacology
J01XX05 (WHO)
Hazards
Occupational safety and health (OHS/OSH):
Main hazards
 Highly combustible, harmful
GHS labelling:
GHS02: Flammable GHS07: Exclamation mark
Warning
H228, H317
P210, P240, P241, P261, P272, P280, P302+P352, P321, P333+P313, P363, P370+P378, P501
NFPA 704 (fire diamond)
NFPA 704 four-colored diamond
2
3
1
Flash point 250 °C (482 °F; 523 K)
410 °C (770 °F; 683 K)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
☒N verify (what is checkY☒N ?)
Infobox references

Synthesis, structure, reactivity

Hexamethylenetetramine was discovered by Aleksandr Butlerov in 1859.[2][3] It is prepared industrially by combining formaldehyde and ammonia:[4]

The reaction can be conducted in gas phase and in solution.

The molecule has a tetrahedral cage-like structure, similar to adamantane. 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 for binding other atoms or molecules, unlike crown ethers or larger cryptand structures.

The molecule behaves like an amine base, undergoing protonation and N-alkylation (e.g. quaternium-15).

Applications

The dominant use of hexamethylenetetramine is in the production of powdery or liquid preparations of phenolic resins and phenolic resin moulding compounds, where it is added as a hardening component. These products are used as binders, e.g. in brake and clutch linings, abrasive products, non-woven textiles, formed parts produced by moulding processes, and fireproof materials.[4]

Medical uses

As the mandelic acid salt (methenamine mandelate) or the hippuric acid salt (methenamine hippurate),[5] it is used for the treatment of urinary tract infection. In an acidic environment, methenamine is believed to act as an antimicrobial by converting to formaldehyde.[5][6] A systematic review of its use for this purpose in adult women found there was insufficient evidence of benefit and further research is needed.[7] 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.[8][9]

Methenamine acts as an over-the-counter antiperspirant due to the astringent property of formaldehyde.[10]

Histological stains

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

Solid fuel

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.

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.[11]

Food additive

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,[12] where it is listed under E number E239, however it is not approved in the USA, Russia, Australia, or New Zealand.[13]

Reagent in organic chemistry

Hexamethylenetetramine is a versatile reagent in organic synthesis.[14] It is used in the Duff reaction (formylation of arenes),[15] the Sommelet reaction (converting benzyl halides to aldehydes),[16] and in the Delepine reaction (synthesis of amines from alkyl halides).[17]

Explosives

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

Historical uses

Hexamethylenetetramine was first introduced into the medical setting in 1895 as a urinary antiseptic.[18] However, it was only used in cases of acidic urine, whereas boric acid was used to treat urinary tract infections with alkaline urine.[19] Scientist De Eds found that there was a direct correlation between the acidity of hexamethylenetetramine's environment and the rate of its decomposition.[20] Therefore, its effectiveness as a drug depended greatly on the acidity of the urine rather than the amount of the drug administered.[19] In an alkaline environment, hexamethylenetetramine was found to be almost completely inactive.[19]

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.[21]

Hexamethylenetetramine from Bayer (IG Farben)

Producers

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.[11] In Australia, Hexamine Tablets for fuel are made by Thales Australia Ltd. In México, Hexamine is produced by Abiya.

References
  1. Cooney AP, Crampton MR, Golding P (1986). "The acid-base behaviour of hexamine and its N-acetyl derivatives". J. Chem. Soc., Perkin Trans. 2 (6): 835–839. doi:10.1039/P29860000835.
  2. Butlerow A (1859). "Ueber einige Derivate des Jodmethylens" [On some derivatives of methylene iodide]. Ann. Chem. Pharm. (in German). 111 (2): 242–252. doi:10.1002/jlac.18591110219. 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.
  3. Butlerow A (1860). "Ueber ein neues Methylenderivat" [On a new methylene derivative]. Ann. Chem. Pharm. (in German). 115 (3): 322–327. doi:10.1002/jlac.18601150325.
  4. Eller K, Henkes E, Rossbacher R, Höke H (2000). "Amines, Aliphatic". Ullmann's Encyclopedia of Industrial Chemistry. Wiley-VCH Verlag GmbH. doi:10.1002/14356007.a02_001. ISBN 9783527306732.
  5. Lo TS, Hammer KD, Zegarra M, Cho WC (May 2014). "Methenamine: a forgotten drug for preventing recurrent urinary tract infection in a multidrug resistance era". Expert Review of Anti-Infective Therapy. 12 (5): 549–554. doi:10.1586/14787210.2014.904202. PMID 24689705. S2CID 207199202.
  6. Chwa A, Kavanagh K, Linnebur SA, Fixen DR (2019). "Evaluation of methenamine for urinary tract infection prevention in older adults: a review of the evidence". Therapeutic Advances in Drug Safety. 10: 2042098619876749. doi:10.1177/2042098619876749. PMC 6759703. PMID 31579504.
  7. Bakhit M, Krzyzaniak N, Hilder J, Clark J, Scott AM, Mar CD (July 2021). "Use of methenamine hippurate to prevent urinary tract infections in community adult women: a systematic review and meta-analysis". The British Journal of General Practice (Systematic review). 71 (708): e528–e537. doi:10.3399/BJGP.2020.0833. PMC 8136580. PMID 34001538.
  8. "Methenamine is as good as antibiotics at preventing urinary tract infections". NIHR Evidence. 2022-12-20. doi:10.3310/nihrevidence_55378. S2CID 254965605.
  9. Harding C, Mossop H, Homer T, Chadwick T, King W, Carnell S, et al. (March 2022). "Alternative to prophylactic antibiotics for the treatment of recurrent urinary tract infections in women: multicentre, open label, randomised, non-inferiority trial". BMJ. 376: e068229. doi:10.1136/bmj-2021-0068229. PMC 8905684. PMID 35264408.
  10. Susak Z, Minkov R, Isakov E (December 1996). "The use of Methenamine as an antiperspirant for amputees". Prosthetics and Orthotics International. 20 (3): 172–175. doi:10.3109/03093649609164439. PMID 8985996. S2CID 24088433.
  11. "Re: Equialence of methenamine Tablets Standard for Flammability of Carpets and Rugs" (PDF). Alan H. Schoen. July 29, 2004. Archived from the original (PDF) on 2008-10-05. Many other countries who still produce this include Russia, Saudi Arabia, China and Australia.
  12. UK Food Standards Agency: "Current EU approved additives and their E Numbers". Retrieved 2011-10-27.
  13. Australia New Zealand Food Standards Code"Standard 1.2.4 - Labelling of ingredients". Retrieved 2011-10-27.
  14. Blažzević N, Kolbah D, Belin B, Šunjić V, Kajfež F (1979). "Hexamethylenetetramine, A Versatile Reagent in Organic Synthesis". Synthesis. 1979 (3): 161–176. doi:10.1055/s-1979-28602.
  15. Allen CH, Leubne GW (1951). "Syringic Aldehyde". Organic Syntheses. 31: 92. doi:10.15227/orgsyn.031.0092.
  16. Wiberg KB (1963). "2-Thiophenaldehyde". Organic Syntheses. doi:10.15227/orgsyn.000.0000.; Collective Volume, vol. 3, p. 811
  17. Bottini AT, Dev V, Klinck J (1963). "2-Bromoallylamine". Organic Syntheses. 43: 6. doi:10.15227/orgsyn.043.0006.
  18. Hinman F (1913). "An Experimental Study of the Antiseptic Value in the Urine of the Internal Use of Hexamethylenamin". JAMA: The Journal of the American Medical Association. 61 (18): 1601. doi:10.1001/jama.1913.04350190019006.
  19. Elliot (1913). "On Urinary Antiseptics". British Medical Journal. 98: 685–686.
  20. Heathcote RS (1935). "Hexamine as an Urinary Antiseptic: I. Its Rate of Hydrolysis at Different Hydrogen Ion Concentrations. II. Its Antiseptic Power Against Various Bacteria in Urine". British Journal of Urology. 7 (1): 9–32. doi:10.1111/j.1464-410X.1935.tb11265.x. ISSN 0007-1331.
  21. Diller WF (December 1980). "The methenamine misunderstanding in the therapy of phosgene poisoning". Archives of Toxicology. 46 (3–4): 199–206. doi:10.1007/BF00310435. PMID 7016075. S2CID 2423812.
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