Hexamethylenetetramine

Last updated
Hexamethylenetetramine
Hexamine.svg
Hexamine-3D-balls.png
Hexamethylentetramin.jpg
Names
Preferred IUPAC name
1,3,5,7-Tetraazaadamantane
Other names
  • Hexamine
  • Methenamine
  • Urotropine
  • Formin
  • Aminoform
  • HMTA
Identifiers
3D model (JSmol)
2018
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.002.642 OOjs UI icon edit-ltr-progressive.svg
EC Number
  • 202-905-8
E number E239 (preservatives)
26964
KEGG
MeSH Methenamine
PubChem CID
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 Yes check.svgY
    Key: VKYKSIONXSXAKP-UHFFFAOYSA-N Yes check.svgY
  • 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
AppearanceWhite 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:
GHS-pictogram-flamme.svg GHS-pictogram-exclam.svg
Warning
H228, H317
P210, P240, P241, P261, P272, P280, P302+P352, P321, P333+P313, P363, P370+P378, P501
NFPA 704 (fire diamond)
NFPA 704.svgHealth 2: Intense or continued but not chronic exposure could cause temporary incapacitation or possible residual injury. E.g. chloroformFlammability 3: Liquids and solids that can be ignited under almost all ambient temperature conditions. Flash point between 23 and 38 °C (73 and 100 °F). E.g. gasolineInstability 1: Normally stable, but can become unstable at elevated temperatures and pressures. E.g. calciumSpecial hazards (white): no code
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).
Yes check.svgY  verify  (what is  Yes check.svgYX mark.svgN ?)

Hexamethylenetetramine (HMTA), also known as 1,3,5,7-tetraazaadamantane, is a heterocyclic organic compound with diverse applications. [2] [3] It has the chemical formula (CH2)6N4 and is a white crystalline compound that is highly water soluble in water and polar organic solvents. It has a cage-like structure similar to adamantane. [3] It is useful in the synthesis of other organic compounds, including plastics, pharmaceuticals, and rubber additives. [2] [3] The compound is also used medically for certain conditions. [4] [5] It sublimes in vacuum at 280 °C. The molecule has a tetrahedral cage-like structure, similar to that of 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.

Contents

Synthesis, structure, reactivity

Hexamethylenetetramine was discovered by Aleksandr Butlerov in 1859. [6] [7] It is prepared industrially by combining formaldehyde and ammonia: [8]

Synthesis Hexamine.svg

The molecule behaves like an amine base, undergoing protonation and as a ligand. [9] N-alkylation with chloroallyl chloride gives quaternium-15).

Applications

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. [8]

Medical uses

The compound is also used medically as a urinary antiseptic and antibacterial medication under the name methenamine or hexamine. [4] [10] [11] [12] 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. [4] [10] [12]

As the mandelic acid salt (methenamine mandelate) or the hippuric acid salt (methenamine hippurate), [13] 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. [13] [14] A systematic review of its use for this purpose in adult women found there was insufficient evidence of benefit and further research was needed. [15] 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. [16] [17]

Methenamine acts as an over-the-counter antiperspirant due to the astringent property of formaldehyde. [18] Specifically, methenamine is used to minimize perspiration in the sockets of prosthetic devices. [19]

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.[ citation needed ]

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. [20]

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, [21] where it is listed under E number E239, however it is not approved in the USA, Russia, Australia, or New Zealand. [22]

Reagent in organic chemistry

Hexamethylenetetramine is a versatile reagent in organic synthesis. [23] It is used in the Duff reaction (formylation of arenes), [24] the Sommelet reaction (converting benzyl halides to aldehydes), [25] and in the Delepine reaction (synthesis of amines from alkyl halides). [26]

Explosives

Hexamethylenetetramine is the base component to produce RDX and, consequently, C-4 [8] as well as octogen (a co-product with RDX), hexamine dinitrate, hexamine diperchlorate and HMTD.

Pyrotechnics

Hexamethylenetetramine is also used in pyrotechnics to reduce combustion temperatures and decrease the color intensity of various fireworks. [27] Because of its ash-free combustion, hexamethylenetetramine is also utilized in indoor fireworks alongside magnesium and lithium salts. [28] [29]

Historical uses

Hexamethylenetetramine was first introduced into the medical setting in 1895 as a urinary antiseptic. [30] It was officially approved by the FDA for medical use in the United States in 1967. [31] However, it was only used in cases of acidic urine, whereas boric acid was used to treat urinary tract infections with alkaline urine. [32] Scientist De Eds found that there was a direct correlation between the acidity of hexamethylenetetramine's environment and the rate of its decomposition. [33] Therefore, its effectiveness as a drug depended greatly on the acidity of the urine rather than the amount of the drug administered. [32] In an alkaline environment, hexamethylenetetramine was found to be almost completely inactive. [32]

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. [34]

Hexamethylenetetramine from Bayer (IG Farben) Hexamethylenetetramine Bayer.jpg
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. [20] In Australia, Hexamine Tablets for fuel are made by Thales Australia Ltd. In México, Hexamine is produced by Abiya.[ citation needed ] Many other countries who still produce this include Russia, Saudi Arabia, and China.

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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. 1 2 Dreyfors JM, Jones SB, Sayed Y (November 1989). "Hexamethylenetetramine: a review". American Industrial Hygiene Association Journal. 50 (11): 579–585. doi:10.1080/15298668991375191. PMID   2688388.
  3. 1 2 3 Blažzević, Nikola; Kolbah, D.; Belin, Branka; Šunjić, Vitomir; Kajfež, Franjo (1979). "Hexamethylenetetramine, A Versatile Reagent in Organic Synthesis". Synthesis. 1979 (3). Georg Thieme Verlag KG: 161–176. doi:10.1055/s-1979-28602. ISSN   0039-7881.
  4. 1 2 3 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 Rev Anti Infect Ther. 12 (5): 549–554. doi:10.1586/14787210.2014.904202. PMID   24689705.
  5. ↑ Connolly M, de Berker D (2003). "Management of primary hyperhidrosis: a summary of the different treatment modalities". Am J Clin Dermatol. 4 (10): 681–697. doi:10.2165/00128071-200304100-00003. PMID   14507230.
  6. ↑ 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.
  7. ↑ 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.
  8. 1 2 3 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.
  9. ↑ Kirillov, Alexander M. (2011). "Hexamethylenetetramine: An old new building block for design of coordination polymers". Coordination Chemistry Reviews. 255 (15–16). Elsevier BV: 1603–1622. doi:10.1016/j.ccr.2011.01.023. ISSN   0010-8545.
  10. 1 2 https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/017681Orig1s019lbl.pdf
  11. ↑ Elks, J. (2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer US. p. 629. ISBN   978-1-4757-2085-3 . Retrieved 11 October 2024.
  12. 1 2 Schweizerischer Apotheker-Verein (2004). Index Nominum: International Drug Directory. Medpharm Scientific Publishers. pp. 775–776. ISBN   978-3-88763-101-7 . Retrieved 11 October 2024.
  13. 1 2 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.
  14. ↑ 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.
  15. ↑ 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.
  16. ↑ "Methenamine is as good as antibiotics at preventing urinary tract infections". NIHR Evidence. 2022-12-20. doi:10.3310/nihrevidence_55378. S2CID   254965605.
  17. ↑ 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.
  18. ↑ 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.
  19. ↑ Susak, Z.; Minkov, R.; Isakov, E. (December 1996). "The use of Methenamine as an antiperspirant for amputees". Prosthetics & Orthotics International. 20 (3): 172–175. doi: 10.3109/03093649609164439 . ISSN   0309-3646. PMID   8985996. S2CID   24088433.
  20. 1 2 "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.
  21. ↑ UK Food Standards Agency: "Current EU approved additives and their E Numbers" . Retrieved 2011-10-27.
  22. ↑ Australia New Zealand Food Standards Code "Standard 1.2.4 - Labelling of ingredients". 8 September 2011. Retrieved 2011-10-27.
  23. ↑ 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. S2CID   97756228.
  24. ↑ Allen CH, Leubne GW (1951). "Syringic Aldehyde". Organic Syntheses . 31: 92. doi:10.15227/orgsyn.031.0092 .
  25. ↑ Wiberg KB (1963). "2-Thiophenaldehyde". Organic Syntheses . doi:10.15227/orgsyn.000.0000 ; Collected Volumes, vol. 3, p. 811.
  26. ↑ Bottini AT, Dev V, Klinck J (1963). "2-Bromoallylamine". Organic Syntheses . 43: 6. doi:10.15227/orgsyn.043.0006 .
  27. ↑ DEpatent 3402546,Lohmann, Erwin,"Pyrotechnischer Satz zur Erzeugung von Lichtblitzen",issued 1985-08-01
  28. ↑ USpatent 6214139,Hiskey, Michael A.; Chavez, David E.& Naud, Darren L.,"Low-smoke pyrotechnic compositions",issued 2001-04-10, assigned to The Regents of the University of Californiaand Los Alamos National Laboratory
  29. ↑ GBpatent 2502460,Wraige, John Douglas Michael,"Pyrotechnic composition with spark producing material",issued 2013-11-27
  30. ↑ 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.
  31. ↑ Sauberan, Jason B.; Bradley, John S. (2018-01-01), Long, Sarah S.; Prober, Charles G.; Fischer, Marc (eds.), "292 - Antimicrobial Agents", Principles and Practice of Pediatric Infectious Diseases (Fifth Edition), Elsevier, pp. 1499–1531.e3, doi:10.1016/b978-0-323-40181-4.00292-9, ISBN   978-0-323-40181-4 , retrieved 2023-11-15
  32. 1 2 3 Elliot (1913). "On Urinary Antiseptics". British Medical Journal. 98: 685–686.
  33. ↑ 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.
  34. ↑ Diller WF (December 1980). "The methenamine misunderstanding in the therapy of phosgene poisoning". Archives of Toxicology. 46 (3–4): 199–206. Bibcode:1980ArTox..46..199D. doi:10.1007/BF00310435. PMID   7016075. S2CID   2423812.
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