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{{Short description|Extremely bitter chemical compound}}
{{chembox
{{chembox
| Verifiedfields = changed
| Verifiedfields = changed
| Watchedfields = changed
| Watchedfields = changed
| verifiedrevid = 447900890
| verifiedrevid = 447900890
| Name = Denatonium benzoate
| Name = Denatonium benzoate
| ImageFile = DenatoniumBenzoateCrystals.jpg
| ImageFile1 = Denatonium chemical structure.svg
| ImageFile1 = Denatonium chemical structure.svg
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| ImageAlt1 = Skeletal formula of the denatonium cation
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| ImageAlt = Denatonium benzoate crystals
| ImageFile2 = Denatonium benzoate chemical structure part 2.svg
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| ImageAlt1 = Skeletal formula of the denatonium cation
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| ImageSize2 = 100px
| ImageAlt2 = Skeletal formula of the benzoate anion
| ImageFile2 = Denatonium benzoate chemical structure part 2.svg
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| ImageSize2 = 100px
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| ImageFile3 = Denatonium benzoate 3D ball.png
| ImageAlt2 = Skeletal formula of the benzoate anion
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| ImageSize3 = 220
| ImageFile3 = Denatonium benzoate 3D ball.png
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| ImageAlt3 = Ball-and-stick models of the both ions in denatonium benzoate
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| ImageSize3 = 220
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| PIN = ''N''-Benzyl-2-(2,6-dimethylanilino)-''N'',''N''-diethyl-2-oxoethan-1-aminium benzoate
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| ImageAlt3 = Ball-and-stick models of the both ions in denatonium benzoate
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| OtherNames = ''N''-Benzyl-2-[(2,6-dimethylphenyl)amino]-''N'',''N''-diethyl-2-oxoethan-1-aminium benzoate
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| PIN = ''N''-Benzyl-2-(2,6-dimethylanilino)-''N'',''N''-diethyl-2-oxoethan-1-aminium benzoate
⚫
|Section1={{Chembox Identifiers
⚫
| OtherNames = ''N''-Benzyl-2-[(2,6-dimethylphenyl)amino]-''N'',''N''-diethyl-2-oxoethan-1-aminium benzoate
⚫
| Section1 = {{Chembox Identifiers
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 18392
| ChemSpiderID = 18392
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| SMILES = [O-]C(=O)c1ccccc1.Cc2cccc(C)c2NC(=O)C[N+](CC)(CC)Cc3ccccc3
| SMILES = [O-]C(=O)c1ccccc1.Cc2cccc(C)c2NC(=O)C[N+](CC)(CC)Cc3ccccc3
}}
}}
|Section2={{Chembox Properties
| Section2 = {{Chembox Properties
| Formula =C<sub>28</sub>H<sub>34</sub>N<sub>2</sub>O<sub>3</sub>
| Formula =C<sub>28</sub>H<sub>34</sub>N<sub>2</sub>O<sub>3</sub>
| MolarMass =446.581
| MolarMass =446.581
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| SolubleOther =
| SolubleOther =
}}
}}
|Section7={{Chembox Hazards
| Section7 = {{Chembox Hazards
| ExternalSDS =
| ExternalSDS =
| GHSPictograms = {{GHS05}}{{GHS07}}
| GHSPictograms = {{GHS05}}{{GHS07}}
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}}
}}
}}
}}
'''Denatonium''', usually available as '''denatonium benzoate''' (under [[trade name]]s such as '''Denatrol''', '''BITTERANT-b''', '''BITTER+PLUS''', '''Bitrex''', '''Bitrix''', and '''Aversion''') and as '''denatonium saccharide''' ('''BITTERANT-s'''), is the most [[Bitter (taste)#Bitterness|bitter]] [[chemical compound]] known, with bitterness thresholds of 0.05&nbsp;ppm for the benzoate and 0.01&nbsp;ppm for the saccharide.<ref name="auto">{{Cite conference|title=Final Report Study of Aversive Agents |publisher=Consumer Product Safety Commission United States of America |date=18 November 1992 |url=http://www.cpsc.gov/LIBRARY/FOIA/foia99/os/aversive.pdf |access-date=15 November 2010 |url-status=dead |archive-url=https://web.archive.org/web/20110616104140/http://www.cpsc.gov/LIBRARY/FOIA/foia99/os/aversive.pdf |archive-date=16 June 2011 }}</ref>
'''Denatonium''', usually available as '''denatonium benzoate''' (under [[trade name]]s such as '''Denatrol''', '''BITTERANT-b''', '''BITTER+PLUS''', '''Bitrex''', '''Bitrix''', and '''Aversion''') and as '''denatonium saccharinate''' ('''BITTERANT-s'''), is the most [[Bitter (taste)#Bitterness|bitter]] [[chemical compound]] known, with bitterness thresholds of 0.05&nbsp;ppm for the benzoate and 0.01&nbsp;ppm for the saccharinate.<ref name="auto">{{Cite conference|title=Final Report Study of Aversive Agents |publisher=Consumer Product Safety Commission United States of America |date=18 November 1992 |url=http://www.cpsc.gov/LIBRARY/FOIA/foia99/os/aversive.pdf |access-date=15 November 2010 |url-status=dead |archive-url=https://web.archive.org/web/20110616104140/http://www.cpsc.gov/LIBRARY/FOIA/foia99/os/aversive.pdf |archive-date=16 June 2011 }}</ref>
It was discovered in 1958 during research on [[local anesthetic]]s by [[MacFarlan Smith]] of [[Edinburgh]], Scotland, and registered under the trademark '''Bitrex'''.<ref>{{cite web | title = Bitrex(R) — Branded Denatonium Benzoate | url = http://www.macsmith.com/index.php?page=bitrex | publisher = Macfarlan Smith | access-date = 2010-05-09}}</ref>
It was discovered in 1958 during research on [[local anesthetic]]s by [[T. & H. Smith]] of [[Edinburgh]], Scotland, and registered under the trademark '''Bitrex'''.<ref>{{cite web | title = Bitrex(R) — Branded Denatonium Benzoate | url = http://www.macsmith.com/index.php?page=bitrex | publisher = Macfarlan Smith | access-date = 2010-05-09 | archive-date = 2010-08-17 | archive-url = https://web.archive.org/web/20100817091300/http://www.macsmith.com/index.php?page=bitrex | url-status = dead }}</ref><ref>{{cite web|url=https://www.encyclopedia.com/science/academic-and-educational-journals/denatonium-benzoate|title=Denatonium Benzoate|website=Encyclopedia.com|access-date=30 August 2024}}</ref>


Dilutions of as little as 10&nbsp;[[Parts-per notation#Parts-per expressions|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 agent]]s ([[bitterant]]s) to prevent inappropriate ingestion. Denatonium is used in [[denatured alcohol]],<ref>{{cite web | title = Ethanol Denaturants | url = http://www.distill.com/specs/EU2.html | date = 1993-11-22 | publisher = The Online Distillery Network | access-date = 2007-09-30 | archive-date = 2015-05-10 | archive-url = https://web.archive.org/web/20150510040900/http://www.distill.com/specs/EU2.html | url-status = dead }}</ref> [[antifreeze]], preventive [[nail biting]] preparations, [[respirator]] mask [[Respirator fit test|fit-testing]], [[animal repellent]]s, [[soap|liquid soaps]], [[shampoo]]s, and [[Nintendo game card|Nintendo Switch game cards]] to prevent accidental swallowing or choking by children. It is not known to pose any long-term health risks.<ref name="auto"/>
Dilutions of as little as 10&nbsp;[[Parts-per notation#Parts-per expressions|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 agent]]s ([[bitterant]]s) to prevent inappropriate ingestion. Denatonium is used in [[denatured alcohol]],<ref>{{cite web | title = Ethanol Denaturants | url = http://www.distill.com/specs/EU2.html | date = 1993-11-22 | publisher = The Online Distillery Network | access-date = 2007-09-30 | archive-date = 2015-05-10 | archive-url = https://web.archive.org/web/20150510040900/http://www.distill.com/specs/EU2.html | url-status = dead }}</ref> [[antifreeze]], preventive [[nail biting]] preparations, [[respirator]] mask [[Respirator fit test|fit-testing]], [[animal repellent]]s, [[soap|liquid soaps]], [[shampoo]]s, and [[Nintendo game card|Nintendo Switch game cards]] to prevent accidental swallowing or choking by children. It is not known to pose any long-term health risks.<ref name="auto"/>


The name "denatonium" reflects the substance's primary use as a [[Denaturation (food)|denaturant]] and its chemical nature as a [[cation]], hence the [[New Latin]] [[suffix]] ''-onium''.{{Citation needed|date=January 2022}}
The name ''denatonium'' reflects the substance's primary use as a [[Denaturation (food)|denaturant]] and its chemical nature as a [[cation]], hence ''[[Onium ion|-onium]]'' as a [[Neo-Latin]] [[suffix]].


== Structure, synthesis, and physical properties ==
== Structure, synthesis, and physical properties ==


Denatonium is a [[quaternary ammonium cation]]. It is a compound of a [[salt (chemistry)|salt]] with an [[Chemically inert|inert]] [[ion|anion]] such as [[benzoate]] or [[Saccharin|saccharinate]]. It can be obtained by the quaternization of lidocaine, a popular anesthetic, with benzyl halides. It was synthesized for the first time in 1963 by reacting benzyl chloride with lidocaine. This reaction required heating the substrates to {{Convert|110|C|F}} for 35 hours. Now, reaction time can be reduced to two hours at {{Convert|82|C|F}} by using acetonitrile as solvent and potassium iodide as catalyst.<ref name=":0">{{Cite journal |last1=Stachowiak |first1=Witold |last2=Wysocki |first2=Marcin |last3=Niemczak |first3=Michał |date=2022-04-12 |title="Bitter" Results: Toward Sustainable Synthesis of the Most Bitter Substances, Denatonium Saccharinate and Denatonium Benzoate, Starting from a Popular Anesthetic, Lidocaine |url=https://pubs.acs.org/doi/10.1021/acs.jchemed.1c00995 |journal=Journal of Chemical Education |language=en |volume=99 |issue=4 |pages=1604–1611 |doi=10.1021/acs.jchemed.1c00995 |bibcode=2022JChEd..99.1604S |s2cid=247905372 |issn=0021-9584}}</ref> To obtain other salts, like the benzoate, the formed denatonium chloride is subjected to an anion exchange reaction with sodium benzoate in ethanol or to sodium hydroxide, and the resulting denatonium hydroxide is neutralized with benzoic acid.<ref name=":0" /> Other similar compounds are [[procaine]] and [[benzocaine]].<ref>{{cite web|last1=Holvoet|first1=Jean-Patrick|title=Denatonium|url=http://www.sentinalco.com/page/denatonium/f1.html|publisher=Sentinalco|access-date=2 October 2015}}</ref>
Denatonium is a [[quaternary ammonium cation]]. It is composed as a [[salt (chemistry)|salt]] with any of several [[anion]]s, such as [[benzoate]] or [[Saccharin|saccharinate]]. It can be obtained by the quaternization of [[lidocaine]], a popular anesthetic, with [[benzyl chloride]] or a similar reagent.<ref name=":0">{{Cite journal |last1=Stachowiak |first1=Witold |last2=Wysocki |first2=Marcin |last3=Niemczak |first3=Michał |date=2022-04-12 |title="Bitter" Results: Toward Sustainable Synthesis of the Most Bitter Substances, Denatonium Saccharinate and Denatonium Benzoate, Starting from a Popular Anesthetic, Lidocaine |journal=Journal of Chemical Education |language=en |volume=99 |issue=4 |pages=1604–1611 |doi=10.1021/acs.jchemed.1c00995 |bibcode=2022JChEd..99.1604S |s2cid=247905372 |issn=0021-9584|doi-access=free }}</ref> 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]].<ref name=":0" /> Other similar compounds are [[procaine]] and [[benzocaine]].<ref>{{cite web|last1=Holvoet|first1=Jean-Patrick|title=Denatonium|url=http://www.sentinalco.com/page/denatonium/f1.html|publisher=Sentinalco|access-date=2 October 2015}}</ref>

One of the chemical names for the compound is [[lidocaine]] benzylbenzoate, although denatonium only denotes the quaternary ammonium cation species itself, and does not necessitate the benzoate [[counterion]].{{Citation needed|date=January 2022}}


== Biochemistry ==
== Biochemistry ==


Denatonium in humans is recognized by eight distinct [[Taste receptor#Bitter|bitter taste receptors]]: [[TAS2R4]], [[TAS2R8]], [[TAS2R10]], [[TAS2R39]], [[TAS2R43]], [[TAS2R16]], [[TAS2R46]], and [[TAS2R47]], being by far the most sensitive to the compound.<ref name="Meyerhof2010">{{Cite journal | last1 = Meyerhof | first1 = W. | last2 = Batram | first2 = C. | last3 = Kuhn | first3 = C. | last4 = Brockhoff | first4 = A. | last5 = Chudoba | first5 = E. | last6 = Bufe | first6 = B. | last7 = Appendino | first7 = G. | last8 = Behrens | first8 = M. | doi = 10.1093/chemse/bjp092 | title = The Molecular Receptive Ranges of Human TAS2R Bitter Taste Receptors | journal = Chemical Senses | volume = 35 | issue = 2 | pages = 157–170 | year = 2009 | pmid = 20022913| doi-access = free }}</ref><ref name=bitterdb>{{cite web|title=BitterDB - Denatonium benzoate|url=http://bitterdb.agri.huji.ac.il/bitterdb/compound.php?id=94|publisher=Hebrew University of Jerusalem|access-date=11 June 2013}}</ref>
Denatonium in humans is recognized by eight distinct [[Taste receptor#Bitter|bitter taste receptors]]: [[TAS2R4]], [[TAS2R8]], [[TAS2R10]], [[TAS2R39]], [[TAS2R43]], [[TAS2R16]], [[TAS2R46]], and [[TAS2R47]], being by far {{clarify|text=the most sensitive|reason=Which one of the eight?|date=August 2023}} to the compound.<ref name="Meyerhof2010">{{Cite journal | last1 = Meyerhof | first1 = W. | last2 = Batram | first2 = C. | last3 = Kuhn | first3 = C. | last4 = Brockhoff | first4 = A. | last5 = Chudoba | first5 = E. | last6 = Bufe | first6 = B. | last7 = Appendino | first7 = G. | last8 = Behrens | first8 = M. | doi = 10.1093/chemse/bjp092 | title = The Molecular Receptive Ranges of Human TAS2R Bitter Taste Receptors | journal = Chemical Senses | volume = 35 | issue = 2 | pages = 157–170 | year = 2009 | pmid = 20022913| doi-access = free }}</ref><ref name=bitterdb>{{cite web|title=BitterDB - Denatonium benzoate|url=http://bitterdb.agri.huji.ac.il/bitterdb/compound.php?id=94|publisher=Hebrew University of Jerusalem|access-date=11 June 2013}}</ref>


Denatonium can act as a [[bronchodilator]] by activating bitter taste receptors in the airway smooth muscle.<ref name="Desphande2010">{{Cite journal | last1 = Deshpande | first1 = D. A. | last2 = Wang | first2 = W. C. H. | last3 = McIlmoyle | first3 = E. L. | last4 = Robinett | first4 = K. S. | last5 = Schillinger | first5 = R. M. | last6 = An | first6 = S. S. | last7 = Sham | first7 = J. S. K. | last8 = Liggett | first8 = S. B. | doi = 10.1038/nm.2237 | title = Bitter taste receptors on airway smooth muscle bronchodilate by localized calcium signaling and reverse obstruction | journal = Nature Medicine | volume = 16 | issue = 11 | pages = 1299–1304 | year = 2010 | pmid = 20972434| pmc =3066567 }}</ref>
Denatonium can act as a [[bronchodilator]] by activating bitter taste receptors in the airway smooth muscle.<ref name="Desphande2010">{{Cite journal | last1 = Deshpande | first1 = D. A. | last2 = Wang | first2 = W. C. H. | last3 = McIlmoyle | first3 = E. L. | last4 = Robinett | first4 = K. S. | last5 = Schillinger | first5 = R. M. | last6 = An | first6 = S. S. | last7 = Sham | first7 = J. S. K. | last8 = Liggett | first8 = S. B. | doi = 10.1038/nm.2237 | title = Bitter taste receptors on airway smooth muscle bronchodilate by localized calcium signaling and reverse obstruction | journal = Nature Medicine | volume = 16 | issue = 11 | pages = 1299–1304 | year = 2010 | pmid = 20972434| pmc =3066567 }}</ref>


== Applications ==
== Applications ==
The bitterness of the compound guides most applications of denatonium. Denatonium benzoate is used to [[denatured alcohol|denature ethanol]] so that it is not treated as an [[alcoholic beverage]] with respect to taxation and sales restrictions. One designation in particular, [[specially denatured alcohol|SD-40B]], indicates that ethanol has been denatured using denatonium benzoate.{{Citation needed|date=January 2022}}
The bitterness of the compound guides most applications of denatonium. Denatonium benzoate is used to [[denatured alcohol|denature ethanol]] so that it is not treated as an [[alcoholic beverage]] with respect to taxation and sales restrictions. One designation in particular, [[specially denatured alcohol|SD-40B]], indicates that ethanol has been denatured using denatonium benzoate.

⚫
Denatonium is commonly included in [[placebos]] used in clinical trials to [[Flavoring#Flavor creation|mimic the bitter taste]] of certain medications.<ref name="auto" />


Denatonium benzoate is an ingredient in certain [[nail polish]]es and varnishes designed to discourage [[nail biting]], as the bitter denatonium serves as an [[Aversives|aversive]].<ref name="pmid8881096">{{cite journal |author=Allen KW |title=Chronic nailbiting: a controlled comparison of competing response and mild aversion treatments |journal=Behav Res Ther |volume=34 |issue=3 |pages=269–72 |date=March 1996 |pmid=8881096 |doi= 10.1016/0005-7967(95)00078-X }}</ref>
⚫
Denatonium is commonly included in [[placebos]] used in clinical trials to [[Flavoring#Flavor creation|mimic the bitter taste]] of certain medications.<ref name="auto" />


Denatonium also discourages consumption of poisonous [[Alcohol (chemistry)|alcohol]]s such as [[methanol]] and additives such as [[ethylene glycol]]. It is also added to many kinds of harmful liquids, including [[solvent]]s (such as [[nail polish remover]]), [[paint]]s, [[varnish]]es, 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 duster]]s) to discourage [[inhalant abuse]] of the volatile vapors.{{Citation needed|date=January 2022}}
Denatonium also discourages consumption of poisonous [[Alcohol (chemistry)|alcohol]]s such as [[methanol]] and additives such as [[ethylene glycol]]. It is also added to many kinds of harmful liquids, including [[solvent]]s (such as [[nail polish remover]]), [[paint]]s, [[varnish]]es, 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 duster]]s) to discourage [[inhalant abuse]] of the volatile vapors.{{Citation needed|date=January 2022}}
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Animals are known to have different sensitivities to the effects of denatonium. It is used in some animal repellents (especially for such large [[mammal]]s as [[deer]]). It has been used to safeguard [[rat poison]]s from human consumption,<ref>{{cite web |url=http://www.pestcontrolshop.co.uk/acatalog/rats.html |title=Rats - Rat Poison & Rat Bait Stations |publisher=Pestcontrolshop.co.uk |access-date=2011-01-17 |url-status=dead |archive-url=https://web.archive.org/web/20110106210619/http://www.pestcontrolshop.co.uk/acatalog/rats.html |archive-date=2011-01-06 }}</ref> as humans are able to detect denatonium at much lower concentrations than rodents.<ref>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}}</ref>
Animals are known to have different sensitivities to the effects of denatonium. It is used in some animal repellents (especially for such large [[mammal]]s as [[deer]]). It has been used to safeguard [[rat poison]]s from human consumption,<ref>{{cite web |url=http://www.pestcontrolshop.co.uk/acatalog/rats.html |title=Rats - Rat Poison & Rat Bait Stations |publisher=Pestcontrolshop.co.uk |access-date=2011-01-17 |url-status=dead |archive-url=https://web.archive.org/web/20110106210619/http://www.pestcontrolshop.co.uk/acatalog/rats.html |archive-date=2011-01-06 }}</ref> as humans are able to detect denatonium at much lower concentrations than rodents.<ref>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}}</ref>


[[Nintendo Switch]] game cards are coated in denatonium benzoate to prevent young children from consuming them.<ref name="IGNcitesbadtaste">{{cite web |last1=Dornbush |first1=Johnathon |title=Nintendo Switch Cartridges Taste Terrible |url=http://www.ign.com/articles/2017/03/02/nintendo-switch-cartridges-taste-terrible |website=[[IGN]] |date=2 March 2017 |access-date=15 Sep 2020 }}</ref>
[[Nintendo Switch]] game cartridges are coated in denatonium benzoate to prevent young children from consuming them.<ref name="IGNcitesbadtaste">{{cite web |last1=Dornbush |first1=Johnathon |title=Nintendo Switch Cartridges Taste Terrible |url=http://www.ign.com/articles/2017/03/02/nintendo-switch-cartridges-taste-terrible |website=[[IGN]] |date=2 March 2017 |access-date=15 Sep 2020 }}</ref>


== See also ==
== See also ==

Latest revision as of 19:49, 28 November 2024

Denatonium benzoate
Denatonium benzoate crystals
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 saccharinate (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 saccharinate.[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][3]

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,[4] 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

[edit]

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.[5] 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.[5] Other similar compounds are procaine and benzocaine.[6]

Biochemistry

[edit]

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.[7][8]

Denatonium can act as a bronchodilator by activating bitter taste receptors in the airway smooth muscle.[9]

Applications

[edit]

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.

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

Denatonium benzoate is an ingredient in certain nail polishes and varnishes designed to discourage nail biting, as the bitter denatonium serves as an aversive.[10]

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.[11] In December 2012, U.S. manufacturers voluntarily agreed to add denatonium benzoate to antifreeze sold nationwide.[12]

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,[13] as humans are able to detect denatonium at much lower concentrations than rodents.[14]

Nintendo Switch game cartridges are coated in denatonium benzoate to prevent young children from consuming them.[15]

See also

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References

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  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. ^ "Denatonium Benzoate". Encyclopedia.com. Retrieved 30 August 2024.
  4. ^ "Ethanol Denaturants". The Online Distillery Network. 1993-11-22. Archived from the original on 2015-05-10. Retrieved 2007-09-30.
  5. ^ 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.
  6. ^ Holvoet, Jean-Patrick. "Denatonium". Sentinalco. Retrieved 2 October 2015.
  7. ^ 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.
  8. ^ "BitterDB - Denatonium benzoate". Hebrew University of Jerusalem. Retrieved 11 June 2013.
  9. ^ 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.
  10. ^ Allen KW (March 1996). "Chronic nailbiting: a controlled comparison of competing response and mild aversion treatments". Behav Res Ther. 34 (3): 269–72. doi:10.1016/0005-7967(95)00078-X. PMID 8881096.
  11. ^ 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.
  12. ^ "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.
  13. ^ "Rats - Rat Poison & Rat Bait Stations". Pestcontrolshop.co.uk. Archived from the original on 2011-01-06. Retrieved 2011-01-17.
  14. ^ 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
  15. ^ Dornbush, Johnathon (2 March 2017). "Nintendo Switch Cartridges Taste Terrible". IGN. Retrieved 15 Sep 2020.
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