View source for Halogenated ether

{{Short description|Subcategory of ether used in anesthesiology}}

[[Image:Isoflurane skeletal formula.svg|thumb|250px|right|Structural formula of isoflurane, a typical halogenated ether. ]]

'''Halogenated ethers''' are a subcategory of [[ether]]s—[[organic chemical]]s that contain an [[oxygen]] atom connected to two [[alkyl group]]s or similar structures. An example of an ether is the solvent [[diethyl ether]].<ref>{{Cite web |date=2024-11-29 |title=Ether {{!}} Chemical Structure & Properties {{!}} Britannica |url=https://www.britannica.com/science/ether-chemical-compound |access-date=2024-12-02 |website=www.britannica.com |language=en}}</ref> Halogenated ethers differ from other ethers because there are one or more [[halogen]] atoms—[[fluorine]], [[chlorine]], [[bromine]], or [[iodine]]—as [[substituent]]s on the carbon groups. .<ref>{{Cite journal |last1=Tang |first1=Shaokun |last2=Baker |first2=Gary A. |last3=Zhao |first3=Hua |date=2012 |title=Ether- and alcohol-functionalized task-specific ionic liquids: attractive properties and applications |journal=Chemical Society Reviews |language=en |volume=41 |issue=10 |pages=4030–4066 |doi=10.1039/c2cs15362a |pmid=22456483 |pmc=3341508 |issn=0306-0012}}</ref> Examples of commonly used halogenated ethers include [[isoflurane]], [[Sevoflurane|sevofluorane]] and [[desflurane]].<ref name=":1">{{Cite journal |last1=Bertram-Ralph |first1=Elliott |last2=Amare |first2=Muataz |date=2022-01-01 |title=Inhalational anaesthesia |journal=Anaesthesia & Intensive Care Medicine |volume=23 |issue=1 |pages=60–68 |doi=10.1016/j.mpaic.2021.10.003 |issn=1472-0299}}</ref>

== History ==
[[File:Simpson_James_Young_signature_picture.jpg|thumb|James Young Simpson|258x258px]]
An ideal inhaled anesthetic wasn't found until 1950. Volatile substances like [[diethyl ether]], which have severe risks of nausea, were used before.<ref name=":0">{{Cite journal |last1=Whalen |first1=Francis X. |last2=Bacon |first2=Douglas R. |last3=Smith |first3=Hugh M. |date=2005-09-01 |title=Inhaled anesthetics: an historical overview |url=https://linkinghub.elsevier.com/retrieve/pii/S152168960500008X |journal=Best Practice & Research Clinical Anaesthesiology |series=Renaissance of Inhalational Anaesthesia |volume=19 |issue=3 |pages=323–330 |doi=10.1016/j.bpa.2005.02.001 |issn=1521-6896|url-access=subscription }}</ref> Diethyl ether has the unfortunate disadvantage of being extremely flammable, especially in the presence of enriched oxygen mixtures.<ref>{{Cite web |last=insideout |date=2015-04-27 |title=Understanding the Safety Risks of Diethyl Ether |url=https://www.ehs.com/2015/04/understanding-the-safety-risks-of-diethyl-ether/ |access-date=2024-11-04 |website=VelocityEHS |language=en-US}}</ref>

[[James Young Simpson]], an obstetrics surgeon, used ethers to help women relieve their labor pains but ultimately deemed them unsuitable due to their drawbacks. Simpson and his friends tested the halogenated hydrocarbon, [[chloroform]], as a substitute inhalation agent during a house party. They woke from unconsciousness pleasantly surprised with its effectiveness. This was the first recorded successful use of halogenated hydrocarbons as anesthetics.<ref name=":0" />

== Applications ==

=== Anesthesia ===
Inhaled agents like diethyl ether are critical in anesthesia. Diethyl ether initially replaced non-flammable (but more toxic) [[Halogenated hydrocarbon|halogenated hydrocarbons]] like [[chloroform]] and [[trichloroethylene]]. [[Halothane]] is a halogenated hydrocarbon anesthetic agent that was introduced into clinical practice in 1956. Due to its ease of use and improved safety profile with respect to organ toxicity, halothane quickly replaced chloroform and trichloroethylene.<ref>{{Cite web |title=Halothane |url=https://go.drugbank.com/drugs/DB01159 |access-date=2024-11-04 |website=go.drugbank.com |language=en}}</ref>

The anesthesia practice was significantly improved later in the 1950s with the introduction of halogenated ethers, like isoflurane, enflurane, and sevoflurane. Since its introduction in the 1980s, isoflurane has been widely used due to its decreased risk of hepatotoxicity and better hemodynamic stability when compared to halothane. The 1990s saw the development of sevoflurane, which was especially helpful in pediatric anesthesia because it provided even faster induction and recovery profiles.<ref>{{Cite journal |last1=Goa |first1=Karen L. |last2=Noble |first2=Stuart |last3=Spencer |first3=Caroline M. |date=1999-04-01 |title=Sevoflurane in Paediatric Anaesthesia |url=https://link.springer.com/article/10.2165/00128072-199901020-00005 |journal=Pediatric Drugs |language=en |volume=1 |issue=2 |pages=127–153 |doi=10.2165/00128072-199901020-00005 |pmid=10937447 |issn=1179-2019|url-access=subscription }}</ref>

All inhalation anesthetics in current clinical use are halogenated ethers, except for [[halothane]] (which is a [[halogenated hydrocarbon]] or ''haloalkane''), [[Nitrous oxide (medication)|nitrous oxide]], and [[Xenon#Anesthesia|xenon]].<ref>{{Citation |last1=Miller |first1=Amanda L. |title=Inhalational Anesthetic |date=2024 |work=StatPearls |url=https://www.ncbi.nlm.nih.gov/books/NBK554540/ |access-date=2024-11-04 |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=32119427 |last2=Theodore |first2=Danny |last3=Widrich |first3=Jason}}</ref>

Inhalation anesthetics are vaporized and mixed with other gases prior to their inhalation by the patient before or during surgery. These other gases always include oxygen or air, but may also include other gases such as nitrous oxide or helium. In most surgical situations, other drugs such as [[opiates]] are used for pain and skeletal [[muscle relaxants]] are used to cause temporary paralysis. Additional drugs such as [[midazolam]] may be used to produce amnesia during surgery. Although newer intravenous anesthetics (such as [[propofol]]) have increased the options of anesthesiologists, halogenated ethers remain a mainstay of [[general anesthesia]]. <ref>{{Citation |last1=Clar |first1=Derek T. |title=Anesthetic Gases |date=2024 |work=StatPearls |url=https://www.ncbi.nlm.nih.gov/books/NBK537013/ |access-date=2024-11-04 |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=30725698 |last2=Patel |first2=Samir |last3=Richards |first3=John R.}}</ref>

=== Polymers ===
Perfluorinated [[Epoxide|epoxides]] can be used as used as [[Comonomer|comonomers]] for the production of [[polytetrafluoroethylene]] (PTFE). <ref name=":2">{{Cite book |last1=Siegemund |first1=Günter |title=Ullmann's Encyclopedia of Chemical Technology |last2=Schwertfeger |first2=Werner |last3=Feiring |first3=Andrew |last4=Smart |first4=Bruce |last5=Behr |first5=Fred |last6=Vogel |first6=Herward |last7=McKusick |first7=Blaine |last8=Kirsch |first8=Peer |date=2016-01-28 |publisher=Wiley-VCH Verlag GmbH & Co. KGaA |isbn=978-3-527-30673-2 |location=Weinheim, Germany |pages=1–56 |language=en |chapter=Fluorine Compounds, Organic |doi=10.1002/14356007.a11_349.pub2}}</ref>
[[File:Hexafluoropropylene_oxide.png|thumb|[[Hexafluoropropylene oxide]] (HFPO), a type of perfluorinated epoxide.]]
Perfluorinated epoxides are a class of epoxides where all the hydrogen atoms on a carbon chain are replaced with fluorine atoms. The fluorine ensures compatibility with PTFE, while the epoxy group enables chemical bonding during [[polymerization]]. When used as comonomers, they can alter the microstructure of PTFE, reducing [[crystallinity]] and improving flexibility and toughness. This makes the polymer more suitable for applications like seals and gaskets, which require resilience under stress. Furthermore, perfluorinated epoxides enable the tailoring of specific functional properties, such as low [[surface energy]], which is essential for applications requiring non-stick or low-friction surfaces. <ref name=":2" /><ref>{{Cite journal |last1=Cı́rkva |first1=Vladimı́r |last2=Gaboyard |first2=Manuel |last3=Paleta |first3=Oldřich |date=2000-03-01 |title=Fluorinated epoxides: 5. Highly selective synthesis of diepoxides from α,ω-diiodoperfluoroalkanes. Regioselectivity of nucleophilic epoxide-ring opening and new amphiphilic compounds and monomers |url=https://www.sciencedirect.com/science/article/abs/pii/S0022113999003012 |journal=Journal of Fluorine Chemistry |volume=102 |issue=1 |pages=349–361 |doi=10.1016/S0022-1139(99)00301-2 |bibcode=2000JFluC.102..349C |issn=0022-1139|url-access=subscription }}</ref>

=== Flame Retardant ===
Halogenated ethers play a significant role in enhancing the thermal stability and fire resistance of polymers. When applied to materials, they are effective in preventing items from catching fire because of the chemical's resistance to decomposition and effective flame suppression properties. <ref name=":3">{{Cite journal |last1=Martinez |first1=Guillaume |last2=Niu |first2=Jianjun |last3=Takser |first3=Larissa |last4=Bellenger |first4=Jean-Phillipe |last5=Zhu |first5=Jiping |date=2021-09-15 |title=A review on the analytical procedures of halogenated flame retardants by gas chromatography coupled with single quadrupole mass spectrometry and their levels in human samples |journal=Environmental Pollution |volume=285 |pages=117476 |doi=10.1016/j.envpol.2021.117476 |pmid=34082369 |pmc=8355089 |bibcode=2021EPoll.28517476M |issn=0269-7491}}</ref>

Most halogenated ethers contain [[bromine]] or [[chlorine]]. Brominated compounds are particularly effective because they release bromine radicals when exposed to heat. These radicals interrupt the combustion process by reacting with free radicals in the flame, thereby suppressing fire propagation. Chlorinated ethers can also function similarly by releasing chlorine radicals. Both types of halogens contribute to the [[Flame retardant|flame-retardant properties]], but brominated ethers are often favoured for their higher efficiency and lower required concentrations compared to their chlorinated counterparts. <ref name=":3" />
[[File:Decabromodiphenyl ether.svg|left|thumb|300x300px|'''Decabromodiphenyl ether''']]
[[Decabromodiphenyl ether]] (deca-BDE), a type of [[Polybrominated diphenyl ethers|Polybrominated diphenyl ether]] (PBDEs), is a brominated flame retardant. It was widely used in [[polystyrene]], [[acrylonitrile butadiene styrene]] (ABS), [[Polyurethane foam|flexible polyurethane foam]], textile coatings, wire/cable insulation, [[Electrical connector|electrical connectors]], and other interior parts. Decabromodiphenyl ether is one of many halogenated flame retardants that are now are heavily regulated or banned in many regions because of [[bioaccumulation]] and potential toxicity hazards.  Most industries are now transitioning to alternative, less hazardous flame retardants. However, because of the widespread use of these chemicals in many products, it is anticipated that they will continue to persist in the environment. 
[[File:HD_TBBPA-DBPE_(1).png|thumb|320x320px|Tetrabromobisphenol A bis(2,3-dibromopropyl) ether (TBBPA-DBPE)]]
Tetrabromobisphenol A bis(2,3-dibromopropyl) ether (TBBPA-DBPE) is another type of brominated flame retardant. It is widely used in electronic casings and [[circuit boards]] due to its high efficiency in reducing flammability. TBBPA-DBPE is also a flame retardant in plastics, paper, and textiles, and as [[plasticizer]] in [[Adhesive|adhesives]] and coatings. <ref>{{Cite journal |last1=Knudsen |first1=Gabriel A. |last2=Hughes |first2=Michael F. |last3=Birnbaum |first3=Linda S. |date=2019-02-01 |title=Dermal disposition of Tetrabromobisphenol A Bis(2,3-dibromopropyl) ether (TBBPA-BDBPE) using rat and human skin |journal=Toxicology Letters |volume=301 |pages=108–113 |doi=10.1016/j.toxlet.2018.11.011 |pmid=30481582 |pmc=6309208 |issn=0378-4274}}</ref>

== Common halogenated ethers ==
{| class="wikitable"
|+Common halogenated ethers with chemical structure and formula
!Halogenated Ether
!Chemical Formula
!Chemical Structure
!Use
|-
|[[Sevoflurane]]
|C<sub>4</sub>H<sub>3</sub>F<sub>7</sub>O
|[[File:Sevoflurane.png|center|frameless]]
|Induction and maintenance of general anesthesia for adults and children. <ref>{{Cite web |title=Sevoflurane (inhalation route) |url=https://www.mayoclinic.org/drugs-supplements/sevoflurane-inhalation-route/description/drg-20065933 |access-date=2024-12-01 |website=Mayo Clinic |language=en}}</ref>
|-
|[[Isoflurane]]
|C<sub>3</sub>H<sub>2</sub>ClF<sub>5</sub>O
|[[File:Isoflurane_structure.png|center|frameless]]
|Induction and maintenance of general anesthesia for adults and children. <ref>{{Cite web |title=Isoflurane (inhalation route) |url=https://www.mayoclinic.org/drugs-supplements/isoflurane-inhalation-route/description/drg-20524744 |access-date=2024-12-01 |website=Mayo Clinic |language=en}}</ref>
|-
|[[Desflurane]]
|C<sub>3</sub>H<sub>2</sub>F<sub>6</sub>O
|[[File:Desflurane.png|frameless]]
|Induction and maintenance of general anesthesia for adults. Maintenance in children following induction by other agents. <ref>{{Citation |last1=Khan |first1=Joohi |title=Desflurane |date=2024 |work=StatPearls |url=https://www.ncbi.nlm.nih.gov/books/NBK537106/#:~:text=Desflurane%20is%20approved%20by%20the,after%20induction%20with%20other%20agents. |access-date=2024-12-01 |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=30725791 |last2=Patel |first2=Preeti |last3=Liu |first3=Mark}}</ref>
|-
|[[Methoxyflurane]]
|C<sub>3</sub>H<sub>4</sub>Cl<sub>2</sub>F<sub>2</sub>O
|[[File:Methoxyflurane.png|frameless]]
|Short term pain relief; rarely used for chronic pain or as an anesthetic because of [[nephrotoxicity]] risks. <ref>{{Cite book |url=https://www.ncbi.nlm.nih.gov/books/NBK608473/#:~:text=Despite%20the%20stop%20in%20its,trauma%20or%20procedure-related%20pain.&text=The%20risk%20of%20nephrotoxicity%20of%20methoxyflurane%20is%20low%20at%20low%20doses.&text=Methoxyflurane%20is%20manufactured%20under%20the,Montreal,%20QC,%20Canada).&text=Penthrox%20has%20been%20approved%20by,procedures%20in%20conscious%20adult%20patients.&text=Penthrox%20is%20a%20portable,%20lightweight,noninvasive%20inhaler%20for%20self-administration.&text=The%20Penthrox%20kit%20has%203,methoxyflurane%20in%203%20mL%20bottle.&text=The%20unique%20characteristics%20of%20methoxyflurane,the%20emergency%20department%20(ED). |title=Methoxyflurane Inhalation as an Analgesic for Minor Gynecological, Ambulatory, or Emergency Procedures: Rapid Review |date=2024 |publisher=Canadian Agency for Drugs and Technologies in Health |series=CADTH Health Technology Review |location=Ottawa (ON) |pmid=39466939}}</ref>
|-
|[[Enflurane]]
|C<sub>3</sub>H<sub>2</sub>ClF<sub>5</sub>O
|[[File:Enflurane.png|frameless]]
|Induction and maintenance of general anesthesia. Used to reduce pain during [[vaginal delivery]]. <ref>{{Cite web |last=PubChem |title=Enflurane |url=https://pubchem.ncbi.nlm.nih.gov/compound/3226#section=Chemical-Vendors |access-date=2024-12-01 |website=pubchem.ncbi.nlm.nih.gov |language=en}}</ref>
|}

== Toxicology ==

=== Respiratory Depression ===
Halogenated ethers can cause respiratory depression by reducing the body's response to [[carbon dioxide]] and [[Hypoxia (medicine)|hypoxia]], which affects breathing rates and depth. Some, like desflurane and isoflurane, are also known for causing airway irritation. This can cause coughing, breath-holding, or [[laryngospasm]], particularly during inhalational induction of anesthesia. Sevoflurane has minimal airway irritation and is generally preferred for induction, particularly in children or those with sensitive airways. <ref>{{Cite journal |last1=TerRiet |first1=M. F. |last2=DeSouza |first2=G. J. A. |last3=Jacobs |first3=J. S. |last4=Young |first4=D. |last5=Lewis |first5=M. C. |last6=Herrington |first6=C. |last7=Gold |first7=M. I. |date=2000-08-01 |title=Which is most pungent: isoflurane, sevoflurane or desflurane? |url=https://www.sciencedirect.com/science/article/pii/S0007091217373221 |journal=British Journal of Anaesthesia |volume=85 |issue=2 |pages=305–307 |doi=10.1093/bja/85.2.305 |issn=0007-0912}}</ref>

=== Environmental Impact ===

==== Greenhouse Gas Emissions ====
Halogenated ethers are [[Greenhouse gas|greenhouse gases]] and contribute to [[global warming]]. Compounds like desflurane and isoflurane have high [[Global warming potential|global warming potentials]] (GWP), which measure their heat-trapping abilities relative to [[carbon dioxide]] (CO₂). The GWP of a halogenated anesthetic is up to 2,000 times greater than CO₂. The use of these anesthetics in healthcare is a significant contributor to hospital-related greenhouse gas emissions. There is a growing focus on identifying lower-GWP alternatives or enhancing recovery and recycling technologies for anesthetic gases. <ref>{{Cite journal |last1=Gadani |first1=Hina |last2=Vyas |first2=Arun |date=2011-06-01 |title=Anesthetic gases and global warming: Potentials, prevention and future of anesthesia |journal=Anesthesia: Essays and Researches |language=en-US |volume=5 |issue=1 |pages=5–10 |doi=10.4103/0259-1162.84171 |doi-access=free |pmid=25885293 |pmc=4173371 |issn=0259-1162}}</ref>

==== Persistence and Bioaccumulation ====
Halogenated ethers can persist in the atmosphere for years due to their stability. These compounds do not readily degrade and thus remain in circulation long after their release, adding to the atmospheric burden of greenhouse gases. They are generally not bioaccumulative due to its high volatility and low tendency to dissolve in water or adhere to biological tissues, but the persistent nature of these compounds raises concerns for long-term environmental effects. This is especially concerning in areas surrounding healthcare facilities where they may be routinely released. <ref>{{Cite journal |last1=Wu |first1=Qiong |last2=Munschy |first2=Catherine |last3=Bodin |first3=Nathalie |last4=Vetter |first4=Walter |date=2024-07-17 |title=Persistent and Bioaccumulative Halogenated Natural Products in Various Tropical Reef Fish Species from the Seychelles, Western Indian Ocean |url=https://pubmed.ncbi.nlm.nih.gov/38967173/ |journal=Journal of Agricultural and Food Chemistry |volume=72 |issue=28 |pages=15643–15652 |doi=10.1021/acs.jafc.4c03503 |issn=1520-5118 |pmid=38967173|bibcode=2024JAFC...7215643W }}</ref>

== See also ==
*[[Anesthesia]]
*[[Ether]]
*[[Halogen]] 
*[[Halogenation]] 
*[[Hydrocarbon]] 

==References==
{{reflist}}

{{General anesthetics}}
{{GABAAR PAMs}}
{{Glutamatergics}}

{{DEFAULTSORT:Halogenated Ether}}

[[Category:General anesthetics]]
[[Category:Ethers]]
[[Category:Organohalides]]
[[Category:GABAA receptor positive allosteric modulators]]
[[Category:NMDA receptor antagonists]]