:Quaternary ammonium cation

Quaternary ammonium compounds are prepared by the alkylation of tertiary amine. Industrial production of commodity quat salts usually involves hydrogenation of fatty nitriles, which can generate primary or secondary amines. These amines are then treated with methyl chloride.{{cite book |doi=10.1002/0471238961.0113131523051920.a01.pub2|chapter=Ammonium Compounds |title=Kirk-Othmer Encyclopedia of Chemical Technology |year=2003 |last1=Weston |first1=Charles W. |last2=Papcun |first2=John R. |last3=Dery |first3=Maurice |isbn=0471238961 }}

The quaternization of alkyl amines by alkyl halides is widely documented.{{cite journal|title=o-Methylbenzyl Alcohol| vauthors = Brasen WR, Hauser CR |journal= Organic Syntheses |year=1954 |volume=34 |page=58 |doi= 10.15227/orgsyn.034.0058}} In older literature this is often called a Menshutkin reaction, however modern chemists usually refer to it simply as quaternization.{{cite book | vauthors = Smith MB, March J |author2-link= Jerry March | year = 2001 | title = Advanced Organic Chemistry: Reactions, Mechanisms, and Structure | edition = 5th | location = New York, NY | publisher = Wiley-Interscience | isbn = 0-471-58589-0}} The reaction can be used to produce a compound with unequal alkyl chain lengths; for example when making cationic surfactants one of the alkyl groups on the amine is typically longer than the others.{{Ullmann| vauthors = Kosswig K |title=Surfactants|doi=10.1002/14356007.a25_747}} A typical synthesis is for benzalkonium chloride from a long-chain alkyldimethylamine and benzyl chloride:

:{{chem2 | CH3(CH2)_{n}N(CH3)2 + ClCH2C6H5 -> [CH3(CH2)_{n}N(CH3)2CH2C6H5]+Cl- }}

Quaternary ammonium cations are unreactive toward even strong electrophiles, oxidants, and acids. They also are stable toward most nucleophiles. The latter is indicated by the stability of the hydroxide salts such as tetramethylammonium hydroxide and tetrabutylammonium hydroxide even at elevated temperatures. The halflife of Me₄NOH in 6M NaOH at 160 °C is >61 h.{{cite journal | vauthors = Marino MG, Kreuer KD | title = Alkaline stability of quaternary ammonium cations for alkaline fuel cell membranes and ionic liquids | journal = ChemSusChem | volume = 8 | issue = 3 | pages = 513–523 | date = February 2015 | pmid = 25431246 | doi = 10.1002/cssc.201403022 | bibcode = 2015ChSCh...8..513M }}

Because of their resilience, many unusual anions have been isolated as the quaternary ammonium salts. Examples include tetramethylammonium pentafluoroxenate, containing the highly reactive pentafluoroxenate ({{chem|XeF|5|−}}) ion. Permanganate can be solubilized in organic solvents, when deployed as its {{chem|NBu|4|+}} salt.{{cite journal | title = Purple benzene: Solubilization of anions in organic solvents | vauthors = Herriott AW | journal = Journal of Chemical Education| year = 1977 | volume = 54 | issue = 4 | page = 229 | doi = 10.1021/ed054p229.1| bibcode = 1977JChEd..54Q.229H }}{{Cite journal | vauthors = Doheny Jr AJ, Ganem B | title = Purple benzene revisited | journal = Journal of Chemical Education| year = 1980 | volume = 57 | pages = 308 | doi = 10.1021/ed057p308.1 | issue = 4|bibcode=1980JChEd..57..308D }}

With exceptionally strong bases, quat cations degrade. They undergo Sommelet–Hauser rearrangement{{OrgSynth | collvol = 4 | collvolpages = 585 | year = 1963 | title = 2-Methylbenzyldimethylamine | vauthors = Brasen WR, Hauser CR |prep=cv4p0585}} and Stevens rearrangement,{{cite book| doi = 10.1002/0471264180.or018.04 | chapter = The Base-Promoted Rearrangements of Quaternary Ammonium Salts | title = Organic Reactions | pages = 403–464 | year = 2011 | vauthors = Pine SH | isbn = 978-0471264187}} as well as dealkylation under harsh conditions or in presence of strong nucleophiles, like thiolates. Quaternary ammonium cations containing N−C−C−H units can also undergo the Hofmann elimination and Emde degradation.

Image:Benzalkonium chloride Structure V.1.svg is a common type of quat salt used as a biocide, a cationic surfactant, and as a phase transfer agent.{{Cite book |doi = 10.1002/14356007.q03_q01|chapter = Antimicrobial Surfaces|title = Ullmann's Encyclopedia of Industrial Chemistry|pages = 1–13|year = 2013| vauthors = Lackner M, Guggenbichler JP |isbn = 9783527306732}} ADBACs are a mixture of alkylbenzyldimethylammonium chlorides, in which the alkyl group has various even-numbered alkyl chain lengths.]]

• Tetramethylammonium ion: {{chem2|(CH3)4N+}}, also denoted {{chem2|Me4N+}} (Me = methyl group)
• Tetraethylammonium ion: {{chem2|(C2H5)4N+}}, also denoted {{chem2|Et4N+}} (Et = ethyl group)
• Tetrapropylammonium ion: {{chem2|(n\-C3H7)4N+}}, also denoted {{chem2|Pr4N+}} (Pr = propyl group)
• Tetrabutylammonium ion: {{chem2|(n\-C4H9)4N+}}, also denoted {{chem2|Bu4N+}} (Bu = butyl group)

Quaternary ammonium salts are used as disinfectants, surfactants, fabric softeners, and as antistatic agents (e.g. in shampoos). In liquid fabric softeners, the chloride salts are often used. In dryer anticling strips, the sulfate salts are often used. Older aluminium electrolytic capacitors and spermicidal jellies also contain quaternary ammonium salts. Quats are also used in contraception formulations, veterinary products, diagnostic testing, vaccine production, and nasal formulations. {{Cite web|date=22 October 2021|title=Quats applications|url=https://novonordiskpharmatech.com/quats-applications/}}

Concerns have been raised about the level of understanding of safety profile of quat disinfectants on people. As of August 2020, half of disinfectants the United States Environmental Protection Agency suggested as effective against COVID-19 contained one of the quats, and often a quat as the sole ingredient.{{Cite web | vauthors = Lim XZ |date=August 2, 2020 |title=Do we know enough about the safety of quat disinfectants? |url=https://cen.acs.org/safety/consumer-safety/know-enough-safety-quat-disinfectants/98/i30 |url-access=subscription |access-date=2023-01-08 |website=Chemical and Engineering News}} Salmonella and E. coli O157:H7 exposed to quats have developed cross resistance to antibiotics. A subject of concern is the potential effect of increased use of quats related to COVID-19 pandemic on antibiotic resistance in a larger microbial community in nature and engineered environment.{{Cite journal | vauthors = Hora PI, Pati SG, McNamara PJ, Arnold WA |date=2020-09-08 |title=Increased Use of Quaternary Ammonium Compounds during the SARS-CoV-2 Pandemic and Beyond: Consideration of Environmental Implications |journal=Environmental Science & Technology Letters |language=en |volume=7 |issue=9 |pages=622–631 |doi=10.1021/acs.estlett.0c00437 |pmid=37566314 |issn=2328-8930 |pmc=7341688}}

file:Butylscopolamine skeletal.svg is one of many spasmo­lytics (anti-spasm drugs) that feature the quaternary ammonium functional group.{{Ullmann |doi=10.1002/14356007.a24_515| title=Spasmolytics | year=2000 | vauthors = Bungardt E, Mutschler E | isbn=3527306730}}]]

Quaternary ammonium compounds have antimicrobial activity.{{cite journal | vauthors = Jia Z, shen D, Xu W | title = Synthesis and antibacterial activities of quaternary ammonium salt of chitosan | journal = Carbohydrate Research | volume = 333 | issue = 1 | pages = 1–6 | date = June 2001 | pmid = 11423105 | doi = 10.1016/S0008-6215(01)00112-4 }} Quaternary ammonium compounds, especially those containing long alkyl chains, are used as antimicrobials and disinfectants. Examples are benzalkonium chloride, benzethonium chloride, methylbenzethonium chloride, cetalkonium chloride, cetylpyridinium chloride, cetrimonium, cetrimide, dofanium chloride, tetraethylammonium bromide, didecyldimethylammonium chloride and domiphen bromide. Also good against fungi, amoebas, and enveloped viruses (such as SARS-CoV-2),{{cite web |url=http://www.mansfield.ohio-state.edu/~sabedon/biol2032.htm |title=Specific Antimicrobials | vauthors = Abedon ST |publisher=Ohio State University |access-date=2020-02-14|url-status=dead |archive-url=https://web.archive.org/web/20081015002934/http://www.mansfield.ohio-state.edu/~sabedon/biol2032.htm |archive-date=2008-10-15 }}{{cite journal | vauthors = Schrank CL, Minbiole KP, Wuest WM | title = Are Quaternary Ammonium Compounds, the Workhorse Disinfectants, Effective against Severe Acute Respiratory Syndrome-Coronavirus-2? | journal = ACS Infectious Diseases | volume = 6 | issue = 7 | pages = 1553–1557 | date = July 2020 | pmc = 7341688 | doi = 10.1021/acs.estlett.0c00437 | pmid = 32412231 }} most quaternary ammonium compounds are believed to act by disrupting the cell membrane or viral envelope.{{cite journal | vauthors = Cocco AR, Rosa WL, Silva AF, Lund RG, Piva E | title = A systematic review about antibacterial monomers used in dental adhesive systems: Current status and further prospects | journal = Dental Materials | volume = 31 | issue = 11 | pages = 1345–1362 | date = November 2015 | pmid = 26345999 | doi = 10.1016/j.dental.2015.08.155 }} (Some QACs, such as dequalinium and similar bis-QACs, show evidence of a different mode of action.){{cite journal |last1=Tischer |first1=Maximilian |last2=Pradel |first2=Gabriele |last3=Ohlsen |first3=Knut |last4=Holzgrabe |first4=Ulrike |title=Quaternary Ammonium Salts and Their Antimicrobial Potential: Targets or Nonspecific Interactions? |journal=ChemMedChem |date=2 January 2012 |volume=7 |issue=1 |pages=22–31 |doi=10.1002/cmdc.201100404|pmid=22113995 |s2cid=26326417 }}

Quaternary ammonium compounds are lethal to a wide variety of organisms except endospores and non-enveloped viruses, both having no accessible membrane coat to attack. It is possible to solve the endospore problem by adding chemicals which force them to germinate.{{cite journal |last1=Nerandzic |first1=MM |last2=Donskey |first2=CJ |title=A Quaternary Ammonium Disinfectant Containing Germinants Reduces Clostridium difficile Spores on Surfaces by Inducing Susceptibility to Environmental Stressors. |journal=Open Forum Infectious Diseases |date=October 2016 |volume=3 |issue=4 |pages=ofw196 |doi=10.1093/ofid/ofw196 |pmid=28066792|pmc=5198585 }}{{cite journal |last1=Tuladhar |first1=E |last2=de Koning |first2=MC |last3=Fundeanu |first3=I |last4=Beumer |first4=R |last5=Duizer |first5=E |title=Different virucidal activities of hyperbranched quaternary ammonium coatings on poliovirus and influenza virus. |journal=Applied and Environmental Microbiology |date=April 2012 |volume=78 |issue=7 |pages=2456–8 |doi=10.1128/AEM.07738-11 |pmid=22287007|pmc=3302582 |bibcode=2012ApEnM..78.2456T }} They have reduced efficacy against gram-negative bacteria, mycobacteria, and bacteria in biofilms due to them having additional layers that need to be penetrated or disrupted. Some bacteria such as MRSA have acquired resistance genes, qacA/B and qacC/D, that pump the cation out of the cell.

In organic chemistry, quaternary ammonium salts are employed as phase transfer catalysts (PTCs). Such catalysts accelerate reactions between reagents dissolved in immiscible solvents. The highly reactive reagent dichlorocarbene is generated via PTC by reaction of chloroform and aqueous sodium hydroxide.{{cn|date=August 2023}}

File:Ion exchange resin beads.jpg resins, in the form of beads, contain quaternary ammonium ions bound to a polymer.{{cite book |doi=10.1002/14356007.a14_393.pub2|chapter=Ion Exchangers |title=Ullmann's Encyclopedia of Industrial Chemistry |year=2008 |last1=De Dardel |first1=François |last2=Arden |first2=Thomas V. |isbn=978-3527306732|page=5 }}]]

In the 1950s, distearyldimethylammonium chloride (DHTDMAC), was introduced as a fabric softener. This compound was discontinued because the cation biodegrades too slowly. Contemporary fabric softeners are based on salts of quaternary ammonium cations where the fatty acid is linked to the quaternary center via ester linkages; these are commonly referred to as betaine-esters or ester-quats and are susceptible to degradation, e.g., by hydrolysis.{{cite journal| vauthors = Hellberg PE, Bergström K, Holmberg K |title=Cleavable surfactants|journal= Journal of Surfactants and Detergents|date=January 2000|volume=3|issue=1|pages=81–91|doi=10.1007/s11743-000-0118-z|s2cid=195343430}} Characteristically, the cations contain one or two long alkyl chains derived from fatty acids linked to an ethoxylated ammonium salt.{{cite web |url=http://www.henkelconsumerinfo.com |title=Henkel Consumer Info |publisher=Henkelconsumerinfo.com |access-date=2009-06-04 |archive-url=https://web.archive.org/web/20191018103004/http://www.henkelconsumerinfo.com/products/ |archive-date=2019-10-18 |url-status=dead }} Other cationic compounds can be derived from imidazolium, guanidinium, substituted amine salts, or quaternary alkoxy ammonium salts.{{Ullmann| vauthors = Smulders E, Sung E |title=Laundry Detergents, 2. Ingredients and Products|doi=10.1002/14356007.o15_013}}

File:C18x2Me2Cl.png|Distearyldimethylammonium chloride, an early generation fabric softener with low biodegradability that was phased out.

File:Redrawn diesterquat salt (methanesulfonate anion) related to fabric softeners.png|Another diesterquat, a contemporary fabric softener.

File:AltDiesterquatCl.png|Diethyl ester dimethyl ammonium chloride used as a fabric softener.

File:DiesterCl.png|Another diesterquat used as a fabric softener.

The antistatic qualities that make quaternary ammonium salts useful as fabric softeners also make them useful in hair conditioners and shampoos.{{CPID|id=1000|name=Distearyldimonium chloride}} The idea was pioneered by Henkel with a 1984 patent.{{cite web |title=Quaternary ammonium compound hair conditioners US4744977 |url=https://patents.google.com/patent/US4744977 |website=Google Patents |language=en |date=14 November 1985}} Examples include cetrimonium chloride and behentrimonium chloride.{{cite web | url = http://www.naturallycurly.com/curlreading/curly-q-a/curlchemist-what-is-cetrimonium-chloride | title = What is cetrimonium chloride? | archive-url = https://web.archive.org/web/20120304041725/http://www.naturallycurly.com/curlreading/curly-q-a/curlchemist-what-is-cetrimonium-chloride | archive-date=2012-03-04 | work = naturallycurly.com | date = November 2007 }}

Cycocel (chlormequat chloride) reduces plant height by inhibiting the production of gibberellins, the primary plant hormones responsible for cell elongation. Therefore, their effects are primarily on stem, petiole, and flower stalk tissues. Lesser effects are seen in reductions of leaf expansion, resulting in thicker leaves with darker green color.{{cite web|url=http://users.in.gr/dimpet/thesis/growth_retardants.htm |title=Growth Retardants |access-date=July 19, 2012 |url-status=dead |archive-url=https://web.archive.org/web/20110925004831/http://users.in.gr/dimpet/thesis/growth_retardants.htm |archive-date=September 25, 2011 }} Wageningen Agricultural University, The Netherlands

Several quaternary ammonium derivatives exist in nature.{{cite journal |doi=10.1016/0305-0491(91)90002-U|title=Quaternary ammonium compounds in the biosphere—An Example of a Versatile Adaptive Strategy |year=1991 |last1=Anthoni |first1=U. |last2=Christophersen |first2=C. |last3=Hougaard |first3=L. |last4=Nielsen |first4=P.H. |journal=Comparative Biochemistry and Physiology Part B: Comparative Biochemistry |volume=99 |pages=1–18 }} Prominent examples include glycine betaine, choline, carnitine, butyrobetaine, homarine, and trigonelline. Glycine betaine, an osmolyte, stabilizes osmotic pressure in cells.{{cite journal | doi = 10.1093/aob/mcu239 | title = Diversity, distribution and roles of osmoprotective compounds accumulated in halophytes under abiotic stress | year = 2015 | last1 = Slama | first1 = Inès | last2 = Abdelly | first2 = Chedly | last3 = Bouchereau | first3 = Alain | last4 = Flowers | first4 = Tim | last5 = Savouré | first5 = Arnould | journal = Annals of Botany | volume = 115 | issue = 3 | pages = 433–447 | pmid = 25564467 | pmc = 4332610 }}

File:Betain2.svg is a naturally occurring quaternary ammonium cation. Its degradation product, trimethylamine, is responsible for the odor of spoiled fish.|left]]

Image:Choline-skeletal.svg is a quat compound.]]

Choline is a precursor for the neurotransmitter acetylcholine. Choline is also a constituent of lecithin, which is present in many plants and animal organs.{{cite journal | vauthors = Zeisel SH, da Costa KA | title = Choline: an essential nutrient for public health | journal = Nutrition Reviews | volume = 67 | issue = 11 | pages = 615–623 | date = November 2009 | pmid = 19906248 | pmc = 2782876 | doi = 10.1111/j.1753-4887.2009.00246.x | author-link = Steven Zeisel }} It is found in phospholipids. For example, phosphatidylcholines, a major component of biological membranes, are a member of the lecithin group of fatty substances in animal and plant tissues.{{cite book | vauthors = Jackowski S, Cronan Jr JE, Rock CO |chapter=Chapter 2: Lipid metabolism in procaryotes | veditors = Vance DE, Vance J |title=Biochemistry of Lipids, Lipoproteins and Membranes |publisher=Elsevier |year=1991 |pages=[https://archive.org/details/biochemistryofli0000unse/page/80 80–81] |isbn=0-444-89321-0 |chapter-url-access=registration |chapter-url=https://archive.org/details/biochemistryofli0000unse |url=https://archive.org/details/biochemistryofli0000unse/page/80 }}

Carnitine participates in the beta-oxidation of fatty acids.{{cn|date=August 2023}}

File:1-Oleoyl-2-almitoyl-phosphatidylcholine Structural Formulae V.1.png

Quaternary ammonium compounds can display a range of health effects, amongst which are mild skin and respiratory irritation {{cite journal | vauthors = Bello A, Quinn MM, Perry MJ, Milton DK | title = Characterization of occupational exposures to cleaning products used for common cleaning tasks--a pilot study of hospital cleaners | journal = Environmental Health | volume = 8 | pages = 11 | date = March 2009 | pmid = 19327131 | pmc = 2678109 | doi = 10.1186/1476-069X-8-11 | doi-access = free }} up to severe caustic burns on skin and the gastrointestinal wall (depending on concentration), gastrointestinal symptoms (e.g., nausea and vomiting), coma, convulsions, hypotension and death.{{cite web | url = http://www.inchem.org/documents/pims/chemical/pimg022.htm#SectionTitle:2.1%20%20Main%20risk%20and%20target%20organs | title = Quaternary ammonium | id = PIM G022 | work = Internationally Peer Reviewed Chemical Safety Information (INCHEM) | publisher = World Health Organization }}

They are thought to be the chemical group responsible for anaphylactic reactions that occur with use of neuromuscular blocking drugs during general anaesthesia in surgery.{{cite journal | vauthors = Harper NJ, Dixon T, Dugué P, Edgar DM, Fay A, Gooi HC, Herriot R, Hopkins P, Hunter JM, Mirakian R, Pumphrey RS, Seneviratne SL, Walls AF, Williams P, Wildsmith JA, Wood P, Nasser AS, Powell RK, Mirakhur R, Soar J | display-authors = 6 | title = Suspected anaphylactic reactions associated with anaesthesia | journal = Anaesthesia | volume = 64 | issue = 2 | pages = 199–211 | date = February 2009 | pmid = 19143700 | pmc = 3082210 | doi = 10.1111/j.1365-2044.2008.05733.x }} Quaternium-15 is the single most often found cause of allergic contact dermatitis of the hands (16.5% in 959 cases).{{cite journal | vauthors = Warshaw EM, Ahmed RL, Belsito DV, DeLeo VA, Fowler JF, Maibach HI, Marks JG, Toby Mathias CG, Pratt MD, Rietschel RL, Sasseville D, Storrs FJ, Taylor JS, Zug KA | display-authors = 6 | title = Contact dermatitis of the hands: cross-sectional analyses of North American Contact Dermatitis Group Data, 1994-2004 | journal = Journal of the American Academy of Dermatology | volume = 57 | issue = 2 | pages = 301–314 | date = August 2007 | pmid = 17553593 | doi = 10.1016/j.jaad.2007.04.016 }}

Quaternary ammonium-based disinfectants (Virex and Quatricide) were tentatively identified as the most probable cause of jumps in birth defects and fertility problems in caged lab mice. The quat ingredients in the disinfectants include alkyl dimethyl benzyl ammonium chloride (ADBAC) and didecyl dimethyl ammonium chloride (DDAC).{{cite journal | vauthors = Hunt P | title = Lab disinfectant harms mouse fertility. Patricia Hunt interviewed by Brendan Maher | journal = Nature | volume = 453 | issue = 7198 | pages = 964 | date = June 2008 | pmid = 18563110 | doi = 10.1038/453964a | doi-access = free }}{{cite journal | vauthors = Melin VE, Potineni H, Hunt P, Griswold J, Siems B, Werre SR, Hrubec TC | title = Exposure to common quaternary ammonium disinfectants decreases fertility in mice | journal = Reproductive Toxicology | volume = 50 | pages = 163–170 | date = December 2014 | pmid = 25483128 | pmc = 4260154 | doi = 10.1016/j.reprotox.2014.07.071 | bibcode = 2014RepTx..50..163M }} A similar link was tentatively identified in nurses.{{cite journal | vauthors = Gaskins AJ, Chavarro JE, Rich-Edwards JW, Missmer SA, Laden F, Henn SA, Lawson CC | title = Occupational use of high-level disinfectants and fecundity among nurses | journal = Scandinavian Journal of Work, Environment & Health | volume = 43 | issue = 2 | pages = 171–180 | date = March 2017 | pmid = 28125764 | pmc = 5840865 | doi = 10.5271/sjweh.3623 }} The studies contradict earlier toxicology data reviewed by the U.S. Environmental Protection Agency (U.S. EPA) and the EU Commission.{{cite journal| vauthors = ((Office of Prevention, Pesticides and Toxic Substances, US EPA)) |title=Reregistration Eligibility Decision for Aliphatic Alkyl Quaternaries (DDAC)|journal=Epa739-R-06-008|date=August 2006}}

The quantification of quaternary ammonium compounds can be challenging. Some methods include precipitation of solid salts with tetraphenylborate. Another method, an Epton titration, involves partitioning between water-chloroform in the presence of an anionic dye. Individual cations are detectable by ESI-MS and NMR spectroscopy.

• Ammonium
• Benzyltrimethylammonium fluoride
• Iminium

{{reflist|30em}}

{{refbegin}}

• {{cite journal | vauthors = Zhang C, Cui F, Zeng GM, Jiang M, Yang ZZ, Yu ZG, Zhu MY, Shen LQ | display-authors = 6 | title = Quaternary ammonium compounds (QACs): a review on occurrence, fate and toxicity in the environment | journal = The Science of the Total Environment | volume = 518–519 | pages = 352–362 | date = June 2015 | pmid = 25770948 | doi = 10.1016/j.scitotenv.2015.03.007 | bibcode = 2015ScTEn.518..352Z }}

{{refend}}

• {{cite web | url = http://www.inchem.org/documents/pims/chemical/pimg022.htm | title = Toxicities of quaternary ammonium | work = Internationally Peer Reviewed Chemical Safety Information (INCHEM) | publisher = World Health Organization }}

Category:Disinfectants

Category:Food safety