Denatonium benzoate
Skeletal formula of the denatonium cation
Skeletal formula of the benzoate anion
Ball-and-stick models of the both ions in denatonium benzoate
Names
Preferred IUPAC name
N-Benzyl-2-(2,6-dimethylanilino)-N,N-diethyl-2-oxoethan-1-aminium benzoate
Other names
N-Benzyl-2-[(2,6-dimethylphenyl)amino]-N,N-diethyl-2-oxoethan-1-aminium benzoate
Identifiers
3D model (JSmol)
ChEMBL
ChemSpider
ECHA InfoCard 100.020.996 Edit this at Wikidata
EC Number
  • 223-095-2
UNII
  • InChI=1S/C21H28N2O.C7H6O2/c1-5-23(6-2,15-19-13-8-7-9-14-19)16-20(24)22-21-17(3)11-10-12-18(21)4;8-7(9)6-4-2-1-3-5-6/h7-14H,5-6,15-16H2,1-4H3;1-5H,(H,8,9) checkY
    Key: VWTINHYPRWEBQY-UHFFFAOYSA-N checkY
  • InChI=1/C21H28N2O.C7H6O2/c1-5-23(6-2,15-19-13-8-7-9-14-19)16-20(24)22-21-17(3)11-10-12-18(21)4;8-7(9)6-4-2-1-3-5-6/h7-14H,5-6,15-16H2,1-4H3;1-5H,(H,8,9)
    Key: VWTINHYPRWEBQY-UHFFFAOYAY
  • [O-]C(=O)c1ccccc1.Cc2cccc(C)c2NC(=O)C[N+](CC)(CC)Cc3ccccc3
Properties
C28H34N2O3
Molar mass 446.581
Appearance white crystalline
Melting point 163 to 170 °C (325 to 338 °F; 436 to 443 K)
Hazards
GHS labelling:
GHS05: CorrosiveGHS07: Exclamation mark
Danger
H302, H315, H318, H332, H412
P261, P264, P270, P271, P273, P280, P301+P312, P302+P352, P304+P312, P304+P340, P305+P351+P338, P310, P312, P321, P330, P332+P313, P362, P501
NFPA 704 (fire diamond)
NFPA 704 four-colored diamondHealth 1: Exposure would cause irritation but only minor residual injury. E.g. turpentineFlammability 1: Must be pre-heated before ignition can occur. Flash point over 93 °C (200 °F). E.g. canola oilInstability 0: Normally stable, even under fire exposure conditions, and is not reactive with water. E.g. liquid nitrogenSpecial hazards (white): no code
1
1
0
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 ?)

Denatonium, usually available as denatonium benzoate (under trade names such as Denatrol, BITTERANT-b, BITTER+PLUS, Bitrex, Bitrix, and Aversion) and as denatonium saccharide (BITTERANT-s), is the most bitter chemical compound known, with bitterness thresholds of 0.05 ppm for the benzoate and 0.01 ppm for the saccharide.[1] It was discovered in 1958 during research on local anesthetics by T.& H. Smith of Edinburgh, Scotland, and registered under the trademark Bitrex.[2]

Dilutions of as little as 10 ppm are unbearably bitter to most humans. Denatonium salts are usually colorless and odorless solids, but are often traded as solutions. They are used as aversive agents (bitterants) to prevent inappropriate ingestion. Denatonium is used in denatured alcohol,[3] antifreeze, preventive nail biting preparations, respirator mask fit-testing, animal repellents, liquid soaps, shampoos, and Nintendo Switch game cards to prevent accidental swallowing or choking by children. It is not known to pose any long-term health risks.[1]

The name denatonium reflects the substance's primary use as a denaturant and its chemical nature as a cation, hence -onium as a Neo-Latin suffix.

Structure, synthesis, and physical properties

Denatonium is a quaternary ammonium cation. It is composed as a salt with any of several anions, such as benzoate or saccharinate. It can be obtained by the quaternization of lidocaine, a popular anesthetic, with benzyl chloride or a similar reagent.[4] To obtain other salts, like the benzoate, the formed denatonium chloride is subjected to an anion exchange reaction with sodium benzoate, or first sodium hydroxide to make denatonium hydroxide followed by neutralization with benzoic acid.[4] Other similar compounds are procaine and benzocaine.[5]

Biochemistry

Denatonium in humans is recognized by eight distinct bitter taste receptors: TAS2R4, TAS2R8, TAS2R10, TAS2R39, TAS2R43, TAS2R16, TAS2R46, and TAS2R47, being by far the most sensitive[clarification needed] to the compound.[6][7]

Denatonium can act as a bronchodilator by activating bitter taste receptors in the airway smooth muscle.[8]

Applications

The bitterness of the compound guides most applications of denatonium. Denatonium benzoate is used to denature ethanol so that it is not treated as an alcoholic beverage with respect to taxation and sales restrictions. One designation in particular, SD-40B, indicates that ethanol has been denatured using denatonium benzoate.[citation needed]

Denatonium is commonly included in placebos used in clinical trials to mimic the bitter taste of certain medications.[1]

Denatonium also discourages consumption of poisonous alcohols such as methanol and additives such as ethylene glycol. It is also added to many kinds of harmful liquids, including solvents (such as nail polish remover), paints, varnishes, toiletries and other personal care items, special nail polish for preventing nail biting, and various other household products. It is also added to less hazardous aerosol products (such as gas dusters) to discourage inhalant abuse of the volatile vapors.[citation needed]

In 1995, the U.S. state of Oregon required that denatonium benzoate be added to products containing sweet-tasting ethylene glycol and methanol such as antifreeze and windshield washer fluid to prevent poisonings of children and animals.[9] In December 2012, U.S. manufacturers voluntarily agreed to add denatonium benzoate to antifreeze sold nationwide.[10]

Animals are known to have different sensitivities to the effects of denatonium. It is used in some animal repellents (especially for such large mammals as deer). It has been used to safeguard rat poisons from human consumption,[11] as humans are able to detect denatonium at much lower concentrations than rodents.[12]

Nintendo Switch game cartridges are coated in denatonium benzoate to prevent young children from consuming them.[13]

See also

References

  1. ^ a b c Final Report Study of Aversive Agents (PDF). Consumer Product Safety Commission United States of America. 18 November 1992. Archived from the original (PDF) on 16 June 2011. Retrieved 15 November 2010.
  2. ^ "Bitrex(R) — Branded Denatonium Benzoate". Macfarlan Smith. Archived from the original on 2010-08-17. Retrieved 2010-05-09.
  3. ^ "Ethanol Denaturants". The Online Distillery Network. 1993-11-22. Archived from the original on 2015-05-10. Retrieved 2007-09-30.
  4. ^ a b Stachowiak, Witold; Wysocki, Marcin; Niemczak, Michał (2022-04-12). ""Bitter" Results: Toward Sustainable Synthesis of the Most Bitter Substances, Denatonium Saccharinate and Denatonium Benzoate, Starting from a Popular Anesthetic, Lidocaine". Journal of Chemical Education. 99 (4): 1604–1611. Bibcode:2022JChEd..99.1604S. doi:10.1021/acs.jchemed.1c00995. ISSN 0021-9584. S2CID 247905372.
  5. ^ Holvoet, Jean-Patrick. "Denatonium". Sentinalco. Retrieved 2 October 2015.
  6. ^ Meyerhof, W.; Batram, C.; Kuhn, C.; Brockhoff, A.; Chudoba, E.; Bufe, B.; Appendino, G.; Behrens, M. (2009). "The Molecular Receptive Ranges of Human TAS2R Bitter Taste Receptors". Chemical Senses. 35 (2): 157–170. doi:10.1093/chemse/bjp092. PMID 20022913.
  7. ^ "BitterDB - Denatonium benzoate". Hebrew University of Jerusalem. Retrieved 11 June 2013.
  8. ^ Deshpande, D. A.; Wang, W. C. H.; McIlmoyle, E. L.; Robinett, K. S.; Schillinger, R. M.; An, S. S.; Sham, J. S. K.; Liggett, S. B. (2010). "Bitter taste receptors on airway smooth muscle bronchodilate by localized calcium signaling and reverse obstruction". Nature Medicine. 16 (11): 1299–1304. doi:10.1038/nm.2237. PMC 3066567. PMID 20972434.
  9. ^ Mullins ME, Zane Horowitz B (June 2004). "Was it necessary to add Bitrex (denatonium benzoate) to automotive products?". Veterinary and Human Toxicology. 46 (3): 150–2. ISSN 0145-6296. PMID 15171494.
  10. ^ "Antifreeze and Engine Coolant Being Bittered Nationwide". Consumer Specialty Products Association. 13 December 2012. Archived from the original on 28 December 2012. Retrieved 30 June 2016.
  11. ^ "Rats - Rat Poison & Rat Bait Stations". Pestcontrolshop.co.uk. Archived from the original on 2011-01-06. Retrieved 2011-01-17.
  12. ^ Frank ME, Bouverat BP, MacKinnon BI, Hettinger TP. The distinctiveness of ionic and nonionic bitter stimuli. Physiol Behav. 2004 Jan;80(4):421-31. doi:10.1016/j.physbeh.2003.09.009
  13. ^ Dornbush, Johnathon (2 March 2017). "Nintendo Switch Cartridges Taste Terrible". IGN. Retrieved 15 Sep 2020.
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