Wikipedia:WikiProject Chemicals/Chembox validation/VerifiedDataSandbox and Salicylic acid: Difference between pages

{{Short description|Chemical compound used in medicines and industry}}

{{cs1 config|name-list-style=vanc}}

| Watchedfields = changed

| verifiedrevid = 477314005

| = Salicylicacid

| ImageFileL1 = Salicylic-acid-skeletal.svg

| ImageSizeL1 = 100px

| ImageNameL1 = Skeletal formula of salicylic acid

| ImageFileR1 = Salicylic-acid-from-xtal-2006-3D-balls.png

| ImageSizeR1 = 100px

| ImageNameR1 = Ball-and-stick model of salicylic acid

| ImageFile2 = Kwas salicylowy.jpg

| ImageName2 = Salicylic acid

| PIN = 2-Hydroxybenzoic acid<ref name=iupac2013>{{cite book | title = Nomenclature of Organic Chemistry: IUPAC Recommendations and Preferred Names 2013 (Blue Book) | publisher = [[Royal Society of Chemistry|The Royal Society of Chemistry]] | date = 2014 | location = Cambridge | page = 64 | doi = 10.1039/9781849733069-FP001 | isbn = 978-0-85404-182-4| chapter = Front Matter | doi-broken-date = 2024-04-11 }}</ref>

| Section1 = {{Chembox Identifiers

| IUPHAR_ligand = 4306

| UNII_Ref = {{fdacite|correct|FDA}}

| SMILES = C(O)

| RTECS = VO0525000

| Section2 = {{Chembox Properties

| C=7 | H=6 | O=3

| Appearance = Colorless to white crystalline powder

| =

| Odor = Odorless

| MeltingPtC = 158.6

| BoilingPt_notes = {{convert|211|C|F K}}<br /> at 20{{nbsp}}mmHg<ref name=crc>{{RubberBible92nd|page=3.306}}</ref><ref name="pubchem">{{cite web |title=Salicylic acid |url=https://pubchem.ncbi.nlm.nih.gov/compound/Salicylic-acid |publisher=PubChem, US National Library of Medicine |access-date=19 Nov 2023 |date=19 Nov 2023}}</ref><br />

| pKa = {{ordered list

| list_style=margin-left:0; list-style-position:inside;

| 2.97 (25{{nbsp}}°C)<ref name=drugbank>{{cite DrugBank|id=DB00936|drug=Salycylic acid}}</ref>

| 13.82 (20{{nbsp}}°C)<ref name=pubchem/>

}}

| Density = 1.443{{nbsp}}g/cm³ (20{{nbsp}}°C)<ref name=crc/>

| Solubility = {{ubl

| 1.24{{nbsp}}g/L (0{{nbsp}}°C)

| 2.48{{nbsp}}g/L (25{{nbsp}}°C)

| 4.14{{nbsp}}g/L (40{{nbsp}}°C)

| 17.41{{nbsp}}g/L (75{{nbsp}}°C)<ref name=pubchem/>

| 77.79{{nbsp}}g/L (100{{nbsp}}°C)<ref name=sioc>

{{cite book | author1 = Atherton Seidell | author2 = William F. Linke | title = Solubilities of Inorganic and Organic Compounds: A Compilation of Solubility Data from the Periodical Literature. Supplement to the third edition containing data published during the years 1939–1949 | url = {{google books |plainurl=y |id=k2e5AAAAIAAJ}} | year = 1952 | publisher = [[Van Nostrand Reinhold|Van Nostrand]] }}</ref>

}}

| SolubleOther = Soluble in [[diethyl ether|ether]], [[carbon tetrachloride|CCl₄]], [[benzene]], [[propanol]], [[acetone]], [[ethanol]], [[oil of turpentine]], [[toluene]]

| Solubility1 = {{ubl

| 0.46{{nbsp}}g/100{{nbsp}}g (11.7{{nbsp}}°C)

| 0.775{{nbsp}}g/100{{nbsp}}g (25{{nbsp}}°C)

| 0.991{{nbsp}}g/100{{nbsp}}g (30.5{{nbsp}}°C)

| 2.38{{nbsp}}g/100{{nbsp}}g (49.4{{nbsp}}°C)

| 4.4{{nbsp}}g/100{{nbsp}}g (64.2{{nbsp}}°C)<ref name=pubchem/><ref name=sioc />

}}

| Solvent1 = benzene

| Solubility2 = {{ubl

| 2.22{{nbsp}}g/100{{nbsp}}mL (25{{nbsp}}°C)<ref name=sioc />

| 2.31{{nbsp}}g/100{{nbsp}}mL (30.5{{nbsp}}°C)<ref name=pubchem/>

}}

| Solvent2 = chloroform

| Solubility3 = {{ubl

| 40.67{{nbsp}}g/100{{nbsp}}g (−3{{nbsp}}°C)

| 62.48{{nbsp}}g/100{{nbsp}}g (21{{nbsp}}°C)<ref name=pubchem/>

}}

| Solvent3 = methanol

| Solubility4 = 2.43{{nbsp}}g/100{{nbsp}}g (23{{nbsp}}°C)<ref name=pubchem/>

| Solvent4 = olive oil

| Solubility5 = 39.6{{nbsp}}g/100{{nbsp}}g (23{{nbsp}}°C)<ref name=pubchem/>

| Solvent5 = acetone

| RefractIndex = 1.565 (20{{nbsp}}°C)<ref name=crc/>

| Dipole = 2.65 D

| MagSus = −72.23·10⁻⁶{{nbsp}}cm³/mol

| LogP = 2.26

| VaporPressure = 10.93{{nbsp}}mPa<ref name=pubchem/>

| SublimationConditions = Sublimes at 76{{nbsp}}°C<ref name=pubchem/>

| LambdaMax = 210{{nbsp}}nm, 234{{nbsp}}nm, 303{{nbsp}}nm (4&nbsp;mg/dL in ethanol)<ref name=pubchem />

}}

| Section5 = {{Chembox Thermochemistry

| DeltaHf = −589.9{{nbsp}}kJ/mol

| DeltaHc = -3.025{{nbsp}}MJ/mol<ref name=NIST>{{cite web|url=http://webbook.nist.gov/cgi/cbook.cgi?ID=C69727&Type=HCOMBS|title=Salicylic acid|access-date=2014-08-17|archive-url=https://web.archive.org/web/20170215084320/http://webbook.nist.gov/cgi/cbook.cgi?ID=C69727&Type=HCOMBS|archive-date=2017-02-15|url-status=live}}</ref>

}}

| Section8 = {{Chembox Related

| OtherCompounds = [[Methyl salicylate]],<br />[[Benzoic acid]],<br />[[Phenol]], [[Aspirin]],<br />[[4-Hydroxybenzoic acid]],<br /> [[Magnesium salicylate]],<br />[[Choline salicylate]],<br />[[Bismuth subsalicylate]],<br />[[Sulfosalicylic acid]],<br />[[Salicylate synthase]]

}}

| Section6 = {{Chembox Pharmacology

| ATCCode_prefix = A01

| ATCCode_suffix = AD05

| ATC_Supplemental = {{ATC|B01|AC06}} {{ATC|D01|AE12}} {{ATC|N02|BA01}} {{ATC|S01|BC08}}

}}

| Section7 = {{Chembox Hazards

| ExternalSDS = [http://avogadro.chem.iastate.edu/MSDS/salicylic_acid.htm MSDS]{{dead link|date=August 2023}}

| GHSPictograms = {{GHS05}} {{GHS07}}

| GHS_ref = <ref name="sigma">{{Sigma-Aldrich|id=w398500|name=Salicylic acid|access-date=2014-05-23}}</ref>

| GHSSignalWord = Danger

| HPhrases = {{H-phrases|302|318}}

| PPhrases = {{P-phrases|280|305+351+338}}

| MainHazards =

| SkinHazard = Mild irritation

| EyeHazard = Severe irritation

| NFPA-H = 2

| NFPA-F = 1

| NFPA-R = 0

| NFPA-S =

| FlashPtC = 157

| FlashPt_notes = <br /> closed cup<ref name=pubchem/>

| AutoignitionPtC = 540

| AutoignitionPt_ref = <ref name=pubchem/>

| ExploLimits =

| PEL =

| LD50 = 480{{nbsp}}mg/kg (mice, oral)

'''Salicylic acid''' is an [[organic compound]] with the formula HOC₆H₄COOH.<ref name=pubchem/> A colorless

(or, white), bitter-tasting solid, it is a precursor to and a [[active metabolite|metabolite]] of [[acetylsalicylic acid]] (aspirin).<ref name=pubchem/> It is a [[plant hormone]],<ref name=Ullmann>{{cite book |doi=10.1002/14356007.a23_477|chapter=Salicylic Acid|title=Ullmann's Encyclopedia of Industrial Chemistry|year=2000| vauthors = Boullard O, Leblanc H, Besson B |isbn=3-527-30673-0}}</ref> and has been listed by the [[EPA]] [[Toxic Substances Control Act]] (TSCA) Chemical Substance Inventory as an experimental [[teratogen]].<ref name="lewis08">{{cite book | vauthors = Lewis Sr RJ |title=Hazardous Chemicals Desk Reference |date=2008 |publisher=John Wiley & Sons |page=1217 |isbn=978-0-470-33445-4 |url=https://books.google.com/books?id=q-6-fCfskYMC&pg=PA1217}}</ref> The name is from [[Latin]] {{lang|la|[[salix]]}} for [[willow tree]], from which it was initially identified and derived. It is an ingredient in some anti-[[acne]] products. Salts and [[ester]]s of salicylic acid are known as '''salicylates'''.<ref name=pubchem/>

== Uses ==

=== Medicine ===

{{Main|Medical uses of salicylic acid}}

[[File:Salicylic acid pads.jpg|thumb|left|[[Cotton]] pads soaked in salicylic acid can be used to chemically [[Exfoliation (cosmetology)|exfoliate]] skin.]]

Salicylic acid as a medication is commonly used to remove the outer most layer of the [[skin]]. As such, it is used to treat [[wart]]s, [[psoriasis]], [[acne vulgaris]], [[ringworm]], [[dandruff]], and [[ichthyosis]].<ref name=pubchem/><ref name=MTM2017>{{cite web|title=Salicylic acid|url=https://www.drugs.com/mtm/salicylic-acid-topical.html|publisher=Drugs.com|access-date=15 January 2017|archive-url=https://web.archive.org/web/20170118043617/https://www.drugs.com/mtm/salicylic-acid-topical.html|archive-date=18 January 2017|url-status=live}}</ref><ref name=WHO2008>{{cite book | title = WHO Model Formulary 2008 | year = 2009 | isbn = 978-92-4-154765-9 | vauthors = ((World Health Organization)) | veditors = Stuart MC, Kouimtzi M, Hill SR | hdl = 10665/44053 | author-link = World Health Organization | publisher = World Health Organization | hdl-access=free | page=310 }}</ref>

Similar to other hydroxy acids, salicylic acid is an ingredient in many [[skincare]] products for the treatment of [[seborrhoeic dermatitis]], [[acne]], [[psoriasis]], [[callus]]es, [[Corn (medicine)|corns]], [[keratosis pilaris]], [[acanthosis nigricans]], ichthyosis, and warts.<ref name="Madan2014">{{cite journal | vauthors = Madan RK, Levitt J | title = A review of toxicity from topical salicylic acid preparations | journal = Journal of the American Academy of Dermatology | volume = 70 | issue = 4 | pages = 788–792 | date = April 2014 | pmid = 24472429 | doi = 10.1016/j.jaad.2013.12.005 }}</ref>

===Uses in manufacturing===

Salicylic acid is used as a [[food preservative]], a [[bactericide]], and an [[antiseptic]].<ref name=mnet>{{cite web|url=http://www.medterms.com/script/main/art.asp?articlekey=25386|title=Definition of Salicylic acid|website=MedicineNet.com|access-date=2010-10-12|archive-url=https://web.archive.org/web/20111209055454/http://www.medterms.com/script/main/art.asp?articlekey=25386|archive-date=2011-12-09|url-status=live}}</ref><ref name="greene13">{{cite book | vauthors = Greene SA |title=Sittig's Handbook of Pesticides and Agricultural Chemicals |date=2013 |publisher=William Andrew |isbn=978-0-8155-1903-4 |url=https://books.google.com/books?id=hAoKEHpyu6wC&pg=PA778}}</ref>

Salicylic acid is used in the production of other pharmaceuticals, including [[4-aminosalicylic acid]], [[sulpiride|sandulpiride]], and [[landetimide]] (via [[salethamide]]).<ref>{{cite web |title=Medicines containing the active ingredient salicylic acid - (emc) |url=https://www.medicines.org.uk/emc/ingredient/13#gref |access-date=2022-10-23 |website=www.medicines.org.uk}}</ref> It is also used in [[picric acid]] production.<ref>{{Cite web |title=λ » LambdaSyn – Synthese von Pikrinsäure |url=https://www.lambdasyn.org/synfiles/pikrinsaeure.htm |access-date=2024-08-01 |website=www.lambdasyn.org}}</ref>

Salicylic acid has long been a key starting material for making [[acetylsalicylic acid]] (ASA or aspirin).<ref name=Ullmann/> ASA is prepared by the [[acetylation]] of salicylic acid with the acetyl group from [[acetic anhydride]] or [[acetyl chloride]].<ref>{{cite book |last1=Watson |first1=David G |title=Pharmaceutical chemistry |date=2011 |publisher=Churchill Livingstone |location=Edinburgh |isbn=978-0-7020-4850-0 |page=273 |url=https://books.google.com/books?id=-lQM4xHjWeUC |access-date=21 May 2022}}</ref> ASA is the standard to which all the other non-steroidal anti-inflammatory drugs ([[NSAID]]s) are compared. In veterinary medicine, this group of drugs is mainly used for treatment of inflammatory musculoskeletal disorders.<ref name="emea99">{{cite news |title=ACETYLSALICYLIC ACID, SODIUM ACETYLSALICYLATE, ACETYLSALICYLIC ACID DL-LYSINE AND CARBASALATE CALCIUM SUMMARY REPORT |url=https://www.ema.europa.eu/en/documents/mrl-report/acetylsalicylic-acid-sodium-acetylsalicylate-acetylsalicylic-acid-dl-lysine-carbasalate-calcium_en.pdf |agency=The European Agency for the Evaluation of Medicinal Products Veterinary Medicines and Inspections |issue=EMEA/MRL/695/99–FINAL |publisher=COMMITTEE FOR VETERINARY MEDICINAL PRODUCTS |date=November 1999}}</ref>

[[Bismuth subsalicylate]], a [[salt (chemistry)|salt]] of [[bismuth]] and salicylic acid, "displays anti-inflammatory action (due to salicylic acid) and also acts as an antacid and mild antibiotic".<ref name="pubchem" /> It is an active ingredient in stomach-relief aids such as [[Pepto-Bismol]] and some formulations of [[Kaopectate]].

Other derivatives include [[methyl salicylate]] used as a [[liniment]] to soothe joint and muscle pain & [[choline salicylate]] used topically to relieve the pain of [[aphthous ulcer|mouth ulcers]].<ref name=pubchem/><ref name=drugs/><ref>{{cite journal |last1=Wróblewska |first1=Katarzyna B. |last2=Plewa |first2=Szymon |last3=Dereziński |first3=Paweł |last4=Muszalska-Kolos |first4=Izabela |title=Choline Salicylate Analysis: Chemical Stability and Degradation Product Identification |journal=Molecules |date=22 December 2019 |volume=25 |issue=1 |pages=51 |doi=10.3390/molecules25010051|pmid=31877863 |pmc=6983192 |doi-access=free }}</ref> [[Aminosalicylic acid]] is used to induce remission in [[ulcerative colitis]], and has been used as an [[antitubercular agent]] often administered in association with [[isoniazid]].<ref name="drugbank1">{{cite web |title=Aminosalicylic acid |url=https://go.drugbank.com/drugs/DB00233 |website=Drugbank Online}}</ref>

[[Sodium salicylate]] is a useful [[phosphor]] in the [[vacuum ultraviolet]] spectral range, with nearly flat quantum efficiency for wavelengths between 10 and 100&nbsp;nm.<ref name=samson76>Samson, James (1976). ''Techniques of Vacuum Ultraviolet Spectroscopy''. Wiley, .</ref> It fluoresces in the blue at 420&nbsp;nm. It is easily prepared on a clean surface by spraying a saturated solution of the salt in [[methanol]] followed by evaporation.{{citation needed|date=December 2021}}

==Mechanism of action==

Salicylic acid modulates [[COX-1]] enzymatic activity to decrease the formation of pro-inflammatory prostaglandins. Salicylate may competitively inhibit prostaglandin formation. Salicylate's antirheumatic (nonsteroidal anti-inflammatory) actions are a result of its analgesic and anti-inflammatory mechanisms.{{citation needed|date=January 2022}}

Salicylic acid, when applied to the skin surface, works by causing the cells of the epidermis to slough off more readily, preventing pores from clogging up, and allowing room for new cell growth. Salicylic acid inhibits the oxidation of [[Uridine diphosphate glucose|uridine-5-diphosphoglucose]] (UDPG) competitively with [[nicotinamide adenine dinucleotide|NADH]] and noncompetitively with UDPG. It also competitively inhibits the transferring of glucuronyl group of [[uridine-5-phosphoglucuronic acid]] to the phenolic acceptor.<ref>{{cite journal |last1=Sanchez-Dominguez |first1=Celia N. |last2=Gallardo-Blanco |first2=Hugo L. |last3=Salinas-Santander |first3=Mauricio A. |last4=Ortiz-Lopez |first4=Rocio |date=July 2018 |title=Uridine 5′-diphospho-glucronosyltrasferase: Its role in pharmacogenomics and human disease |journal=Experimental and Therapeutic Medicine |volume=16 |issue=1 |pages=3–11 |doi=10.3892/etm.2018.6184 |issn=1792-0981 |pmc=5995049 |pmid=29896223}}</ref>

The wound-healing retardation action of salicylates is probably due mainly to its inhibitory action on mucopolysaccharide synthesis.<ref name=drugbank />

==Safety==

{{main|Salicylate poisoning}}

If high concentrations of salicylic ointment are used [[topical medication|topically]], high levels of salicylic acid can enter the blood, requiring [[hemodialysis]] to avoid further complications.<ref>{{cite journal | vauthors = Péc J, Strmenová M, Palencárová E, Pullmann R, Funiaková S, Visnovský P, Buchanec J, Lazarová Z | title = Salicylate intoxication after use of topical salicylic acid ointment by a patient with psoriasis | journal = Cutis | volume = 50 | issue = 4 | pages = 307–309 | date = October 1992 | pmid = 1424799 }}</ref>

Cosmetic applications of the drug pose no significant risk.<ref name="labib">{{cite journal|vauthors=Labib R, Bury D, Boisleve F, Eichenbaum G, Girard S, Naciff J, Leal M, Wong J |title=A kinetic-based safety assessment of consumer exposure to salicylic acid from cosmetic products demonstrates no evidence of a health risk from developmental toxicity |journal=Regulatory Toxicology and Pharmacology|volume=94 |issue= |pages=245–251 |date=April 2018 |pmid=29410076 |doi=10.1016/j.yrtph.2018.01.026 |s2cid=46877699 |doi-access=free }}</ref> Even in a worst-case use scenario in which one was using multiple salicylic acid-containing topical products, the aggregate plasma concentration of salicylic acid was well below what was permissible for acetylsalicylic acid (aspirin).<ref name=labib/> Since oral aspirin (which produces much higher salicylic acid plasma concentrations than dermal salicylic acid applications) poses no significant adverse pregnancy outcomes in terms of frequency of stillbirth, birth defects or developmental delay, use of salicylic acid containing cosmetics is safe for pregnant women.<ref name=labib/> Salicylic acid is present in most fruits and vegetables as for example in greatest quantities in berries and in beverages like tea.

==Production and chemical reactions==

===Biosynthesis===

Salicylic acid is [[biosynthesis|biosynthesized]] from the amino acid [[phenylalanine]]. In ''[[Arabidopsis thaliana]]'', it can be synthesized via a phenylalanine-independent pathway.

===Chemical synthesis===

Commercial vendors prepare [[sodium salicylate]] by treating [[sodium phenolate]] (the sodium salt of [[phenol]]) with [[carbon dioxide]] at high pressure (100{{nbsp}}atm) and high temperature (115{{nbsp}}°C)&nbsp;– a method known as the [[Kolbe-Schmitt reaction]]. Acidifying the product with [[sulfuric acid]] gives salicylic acid:

:[[File:Salicylic-Acid General Synthesis V.2.svg|400px]]

At the laboratory scale, it can also be prepared by the [[hydrolysis]] of [[aspirin]] (acetylsalicylic acid)<ref>{{cite web | title=Hydrolysis of ASA to SA | url=http://www.crscientific.com/article-aspirin.html | access-date=July 31, 2007 | archive-url=https://web.archive.org/web/20070808050329/http://www.crscientific.com/article-aspirin.html | archive-date=August 8, 2007 | url-status=live }}</ref> or [[methyl salicylate]] (oil of [[wintergreen]]) with a strong acid or base; these reactions reverse those chemicals' commercial syntheses.

===Reactions===

Upon heating, salicylic acid converts to [[phenyl salicylate]]:<ref>{{cite journal |doi=10.1016/j.molcata.2004.03.057|title=Selective Synthesis of Phenyl Salicylate (Salol) by Esterification Reaction over Solid Acid Catalysts|year=2004| vauthors = Kuriakose G, Nagaraju N |journal=Journal of Molecular Catalysis A: Chemical |volume=223 |issue=1–2 |pages=155–159}}</ref><ref name=Ullmann/>

:2{{nbsp}}HOC₆H₄CO₂H → C₆H₅O₂C₆H₄OH + CO₂ + H₂O

Further heating gives [[xanthone]].<ref name=Ullmann/>

Salicylic acid as its conjugate base is a chelating agent, with an affinity for iron(III).<ref>{{cite journal |doi=10.1021/ic00168a070|title=Metal(III)-Salicylate Complexes: Protonated Species and Rate-Controlling Formation Steps|year=1983| vauthors = Jordan RB |journal=Inorganic Chemistry|volume=22|issue=26|pages=4160–4161}}</ref>

Salicylic acid slowly degrades to phenol and carbon dioxide at 200–230&nbsp;°C:<ref>{{cite journal | vauthors = Kaeding WW |title=Oxidation of Aromatic Acids. IV. Decarboxylation of Salicylic Acids |journal=The Journal of Organic Chemistry |date=1 September 1964 |volume=29 |issue=9 |pages=2556–2559 |doi=10.1021/jo01032a016}}</ref>

:C₆H₄OH(CO₂H) → C₆H₅OH + CO₂

All isomers of [[chlorosalicylic acid]] and of [[dichlorosalicylic acid]] are known. 5-Chlorosalicylic acid is produced by direct [[Chlorination reaction|chlorination]] of salicylic acid.<ref name=Ullmann/>

==History==

{{Main|History of aspirin}}

[[File:Thomé Salix alba clean.jpg|thumb|left|White willow (''[[Salix alba]]'') is a natural source of salicylic acid.]]

[[Willow]] has long been used for medicinal purposes. [[Pedanius Dioscorides|Dioscorides]], whose writings were highly influential for more than 1,500 years,<ref name=Dioscorides>{{cite web | vauthors = Dioscorides P | author-link=Pedanius Dioscorides |title=De Materia Medica |url=https://ia802907.us.archive.org/16/items/de-materia-medica/scribd-download.com_dioscorides-de-materia-medica.pdf}}</ref> used 'Itea' (which was possibly a species of willow) as a treatment for 'painful intestinal obstructions,' birth control, for 'those who spit blood,' to remove calluses and corns and, externally, as a 'warm pack for gout.' [[William Turner (naturalist)|William Turner]], in 1597, repeated this, saying that willow bark, 'being burnt to ashes, and steeped in vinegar, takes away corns and other like risings in the feet and toes.'<ref>{{cite web | vauthors = Turner W |title=The Herball, or Generall Historie of Plantes |url=https://www.exclassics.com/herbal/herbalv50587.htm |access-date=8 January 2022}}</ref> Some of these cures may describe the action of salicylic acid, which can be derived from the [[salicin]] present in willow. It is, however, a modern myth that Hippocrates used willow as a painkiller.<ref>{{cite web | vauthors = Martyr P |title=Hippocrates and willow bark? What you know about the history of aspirin is probably wrong |date=18 October 2020 |url=https://theconversation.com/hippocrates-and-willow-bark-what-you-know-about-the-history-of-aspirin-is-probably-wrong-148087 |access-date=9 January 2022}}</ref>

[[Hippocrates]], [[Galen]], [[Pliny the Elder]], and others knew that decoctions containing salicylate could ease pain and reduce fevers.<ref name=DMA>{{cite journal | vauthors = Norn S, Permin H, Kruse PR, Kruse E |title=From willow bark to acetylsalicylic acid | language = da | journal = Dansk Medicinhistorisk Årbog | volume = 37 | pages = 79–98 | year = 2009 | pmid = 20509453 | s2cid=10053542 }}</ref><ref>{{cite journal | vauthors = Vane JR | title=The fight against rheumatism: from willow bark to COX-1 sparing drugs | journal = J Physiol Pharmacol. | volume = 51(4 Pt 1) | pages = 573–86 | year=2000 | issue=4 Pt 1 | pmid=11192932 | url=https://pubmed.ncbi.nlm.nih.gov/11192932/ }}</ref>

It was used in Europe and China to treat these conditions.<ref name=ummc>{{cite web |url=http://www.umm.edu/altmed/articles/willow-bark-000281.htm |website=University of Maryland Medical Center |title=Willow bark |publisher=[[University of Maryland]] |access-date=19 December 2011 |archive-url=https://web.archive.org/web/20111224113137/http://www.umm.edu/altmed/articles/willow-bark-000281.htm |archive-date=24 December 2011 |url-status=live }}</ref> This remedy is mentioned in texts from [[Ancient Egypt]], [[Sumer]], and [[Assyria]].<ref name="Goldberg">{{cite journal| vauthors = Goldberg DR |title=Aspirin: Turn of the Century Miracle Drug|url=https://www.sciencehistory.org/distillations/magazine/aspirin-turn-of-the-century-miracle-drug|journal=Chemical Heritage Magazine|date=Summer 2009|volume=27|issue=2|pages=26–30|access-date=24 March 2018|archive-url=https://web.archive.org/web/20180320230715/https://www.sciencehistory.org/distillations/magazine/aspirin-turn-of-the-century-miracle-drug|archive-date=20 March 2018|url-status=live}}</ref>

The [[Cherokee]] and other Native Americans use an infusion of the bark for fever and other medicinal purposes.<ref>{{cite book | vauthors = Hemel PB, Chiltoskey MU | title = Cherokee Plants and Their Uses – A 400 Year History | location = Sylva, NC | publisher = [[The Sylva Herald|Herald Publishing Co.]] | date = 1975 }}; cited in {{cite web | vauthors = Moerman D | title = A Database of Foods, Drugs, Dyes and Fibers of Native American Peoples, Derived from Plants | url = http://herb.umd.umich.edu/ | archive-url = https://web.archive.org/web/20071206021817/http://herb.umd.umich.edu/ |archive-date=2007-12-06 }} A search of this database for "salix AND medicine" finds 63 entries.</ref> In 2014, archaeologists identified traces of salicylic acid on seventh-century pottery fragments found in east-central Colorado.<ref name=wdo>{{cite web|url=http://westerndigs.org/prehistoric-pottery-found-in-colorado-contains-ancient-natural-aspirin/|title=1,300-Year-Old Pottery Found in Colorado Contains Ancient 'Natural Aspirin'|date=12 August 2014|access-date=2014-08-13|archive-url=https://web.archive.org/web/20140813231049/http://westerndigs.org/prehistoric-pottery-found-in-colorado-contains-ancient-natural-aspirin/|archive-date=2014-08-13|url-status=live}}</ref>

The [[Edward Stone (clergyman)|Reverend Edward Stone]], a vicar from [[Chipping Norton, Oxfordshire]], England, reported in 1763 that the bark of the willow was effective in reducing a fever.<ref name="RoyalSoc1763EdmundStone">{{cite journal | vauthors=Stone, Edmund | title=An Account of the Success of the Bark of the Willow in the Cure of Agues | journal=Philosophical Transactions of the Royal Society of London| year=1763 | pages=195–200 | volume=53 | url={{google books |plainurl=y |id=j0JFAAAAcAAJ|page=195}} | doi=10.1098/rstl.1763.0033| doi-access=free }}</ref>

[[File:Florence Nightingale salicylic silk letter.jpg|thumb|248x248px|Letter from [[Florence Nightingale]] on "salicylic silk" as a dressing for cancer patients.<ref>{{Cite web |title=2013.0503 {{!}} Collections Online |url=https://collections.thackraymuseum.co.uk/object-2013-0503 |access-date=2024-05-30 |website=collections.thackraymuseum.co.uk}}</ref>]]

An extract of willow bark, called [[salicin]], after the [[Latin]] name for the white willow (''[[Salix alba]]''), was isolated and named by [[Germans|German]] chemist [[Johann Andreas Buchner]] in 1828.<ref name=buchner28>{{cite book|title=Repertorium für die Pharmacie|chapter-url={{google books |plainurl=y |id=r-40AQAAMAAJ|page=405}}|year=1828|publisher=Bei J. L. Schrag|pages=405– |first=A. |last=Buchner | author-link=Johann Andreas Buchner |chapter=Ueber das Rigatellische Fiebermittel und über eine in der Weidenrinde entdeckte alcaloidische Substanz |trans-chapter=On Rigatelli's antipyretic [i.e., anti-fever drug] and on an alkaloid substance discovered in willow bark |quote={{lang|de|Noch ist es mir aber nicht geglückt, den bittern Bestandtheil der Weide, den ich ''Salicin'' nennen will, ganz frei von allem Färbestoff darzustellen.|italic=invert}} | trans-quote=I have still not succeeded in preparing the bitter component of willow, which I will name ''salicin'', completely free from colored matter}}</ref> A larger amount of the substance was isolated in 1829 by Henri Leroux, a French pharmacist.<ref name=leroux30>See:

* {{cite journal|journal=Journal de Chimie Médicale, de Pharmacie et de Toxicologie|url={{google books |plainurl=y |id=TYIDAAAAYAAJ|page=340}}|year=1830|last=Leroux |first=H. |title=Mémoire relatif à l'analyse de l'écorce de saule et à la découverte d'un principe immédiat propre à remplacer le sulfate de quinine | trans-title=Memoir concerning the analysis of willow bark and the discovery of a substance immediately likely to replace quinine sulfate |volume=6 |pages=340–342}}

* A report on Leroux's presentation to the French Academy of Sciences also appeared in: {{cite book|title=Mémoires de l'Académie des sciences de l'Institut de France|url={{google books |plainurl=y |id=EVKATMXxkCAC|page=20}}|year=1838|publisher=Institut de France|pages=20–}}</ref> [[Raffaele Piria]], an [[Italy|Italian]] chemist, was able to convert the substance into a sugar and a second component, which on oxidation becomes salicylic acid.<ref>{{cite journal | author=Piria | year=1838 | url=http://gallica.bnf.fr/ark:/12148/bpt6k2965r/f621.image | title=Sur de neuveaux produits extraits de la salicine | archive-url=https://web.archive.org/web/20170727013453/http://gallica.bnf.fr/ark:/12148/bpt6k2965r/f621.image | archive-date=2017-07-27 | trans-title=On new products extracted from salicine | journal=[[Comptes rendus]] | volume=6 | pages=620–624 | quote-page=622 | quote=Piria mentions "Hydrure de salicyle" (hydrogen salicylate, i.e., salicylic acid).}}</ref><ref>{{cite book | url = {{google books |plainurl=y |id=x-sL4iNQOgcC|page=38}}| isbn = 978-1-58234-600-7 | pages = 38–40 | last = Jeffreys |first=Diarmuid | year = 2005 | publisher = Bloomsbury | location = New York| title = Aspirin: the remarkable story of a wonder drug}}</ref>

Salicylic acid was also isolated from the herb meadowsweet (''[[Filipendula ulmaria]]'', formerly classified as ''Spiraea ulmaria'') by German researchers in 1839.<ref>{{cite journal|first1=C. |last1=Löwig |first2=S. |last2=Weidmann |journal=Annalen der Physik und Chemie; Beiträge zur Organischen Chemie (Contributions to Organic Chemistry)|url={{google books |plainurl=y |id=iBcAAAAAMAAJ|page=57}}|year=1839|issue=46 |pages= 57–83|title=III. Untersuchungen mit dem destillierten Wasser der Blüthen von ''Spiraea Ulmaria'' | trans-title=III. Investigations of the water distilled from the blossoms of ''Spiraea ulmaria''}} Löwig and Weidman called salicylic acid ''Spiräasaure'' (spiraea acid)</ref> Their extract caused digestive problems such as [[gastric irritation]], [[bleeding]], [[diarrhea]], and even death when consumed in high doses.

In 1874 the Scottish physician [[Thomas John MacLagan|Thomas MacLagan]] experimented with salicin as a treatment for acute [[rheumatism]], with considerable success, as he reported in The Lancet in 1876.<ref>{{cite journal | vauthors = MacLagan TJ | author-link=Thomas John MacLagan |title=The treatment of acute rheumatism by salicin |journal=The Lancet |date=28 October 1876 |volume=108 | issue=2774 |page=383 |doi=10.1016/S0140-6736(02)49509-8 |url=https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(02)49509-8/fulltext}}</ref> Meanwhile, German scientists tried sodium salicylate with less success and more severe side effects.<ref>{{cite journal | vauthors = MacLagan T |title=The treatment of acute rheumatism |journal=The Lancet |date=1900 |volume=155 |issue=3998 |page=1904 |doi=10.1016/S0140-6736(01)70583-1 |s2cid=58103130 }}</ref><ref>{{cite journal | vauthors = Buchanan WW, Kean WF | title = The Treatment of Acute Rheumatism by Salicin, by T.J. Maclagan — The Lancet, 1876 | journal = The Journal of Rheumatology | volume = 29 | issue = 6 | pages = 1321–1323 | date = June 2002 | pmid = 12064852 }}</ref>

In 1979, salicylates were found to be involved in induced defenses of [[tobacco]] against [[tobacco mosaic virus]].<ref name=raskin92>{{cite journal | vauthors = Raskin I | title = Salicylate, A New Plant Hormone | journal = Plant Physiology | volume = 99 | issue = 3 | pages = 799–803 | date = July 1992 | pmid = 16669002 | pmc = 1080546 | doi = 10.1104/pp.99.3.799 }}</ref> In 1987, salicylic acid was identified as the long-sought signal that causes [[thermogenic plant]]s, such as the voodoo lily, ''[[Sauromatum guttatum]]'', to produce heat.<ref name=raskin87>{{cite journal | vauthors = Raskin I, Ehmann A, Melander WR, Meeuse BJ | title = Salicylic Acid: A Natural Inducer of Heat Production in ''Arum'' Lilies | journal = Science | volume = 237 | issue = 4822 | pages = 1601–2 | date = September 1987 | pmid = 17834449 | doi = 10.1126/science.237.4822.1601 | bibcode = 1987Sci...237.1601R | s2cid = 3108513 }}</ref>

== Dietary sources ==

Salicylic acid occurs in plants as free salicylic acid and its carboxylated esters and phenolic glycosides. Several studies suggest that humans metabolize salicylic acid in measurable quantities from these plants.<ref name=Malakar>{{cite journal| vauthors = Malakar S, Gibson PR, Barrett JS, Muir JG |title=Naturally occurring dietary salicylates: A closer look at common Australian foods|journal=Journal of Food Composition and Analysis|date=1 April 2017|volume=57|pages=31–39|doi=10.1016/j.jfca.2016.12.008}}</ref> High-salicylate beverages and foods include [[beer]], [[coffee]], [[tea]], numerous fruits and vegetables, [[sweet potato]], [[nut (food)|nuts]], and [[olive oil]].<ref name="drugs">{{cite web |title=Low salicylate diet |url=https://www.drugs.com/article/low-salicylate-diet.html |publisher=Drugs.com |access-date=16 December 2019 |date=19 February 2019 |archive-url=https://web.archive.org/web/20191216162635/https://www.drugs.com/article/low-salicylate-diet.html |archive-date=16 December 2019 |url-status=live }}</ref> Meat, poultry, fish, eggs, dairy products, sugar, breads and cereals have low salicylate content.<ref name=drugs/><ref name="Swain">{{cite journal | vauthors = Swain AR, Dutton SP, Truswell AS | title = Salicylates in foods | journal = Journal of the American Dietetic Association | volume = 85 | issue = 8 | pages = 950–960 | date = August 1985 | pmid = 4019987 | doi = 10.1016/S0002-8223(21)03743-3 | s2cid = 42796737 | url = https://www.slhd.nsw.gov.au/rpa/allergy/research/salicylatesinfoods.pdf | access-date = 2019-12-16 | url-status = live | archive-url = https://web.archive.org/web/20190405002521/https://www.slhd.nsw.gov.au/rpa/allergy/research/salicylatesinfoods.pdf | archive-date = 2019-04-05 }}</ref>

Some people with sensitivity to dietary salicylates may have symptoms of [[allergic reaction]], such as [[bronchial asthma]], [[rhinitis]], [[gastrointestinal disorder]]s, or [[diarrhea]], so may need to adopt a low-salicylate diet.<ref name=drugs/>

==Plant hormone==

Salicylic acid is a [[natural phenol|phenolic]] [[phytohormone]], and is found in plants with roles in plant growth and development, [[photosynthesis]], [[transpiration]], and [[ion]] uptake and transport.<ref name="Vlot-et-al-2009">{{cite journal | vauthors = Vlot AC, Dempsey DA, Klessig DF | title = Salicylic Acid, a multifaceted hormone to combat disease | journal = Annual Review of Phytopathology | volume = 47 | pages = 177–206 | year = 2009 | pmid = 19400653 | doi = 10.1146/annurev.phyto.050908.135202 | doi-access = }}</ref> Salicylic acid is involved in [[endogenous]] signaling, mediating plant defense against [[pathogens]].<ref>{{cite book | title = Salicylic Acid – A Plant Hormone | author1 = Hayat, S. | author2 = Ahmad, A. | isbn = 978-1-4020-5183-8 | year = 2007 | publisher = [[Springer Science+Business Media|Springer]] | url-access = registration | url = https://archive.org/details/salicylicacidpla0000unse }}</ref> It plays a role in the resistance to pathogens (i.e. [[systemic acquired resistance]]) by inducing the production of [[pathogenesis-related protein]]s and other defensive metabolites.<ref>{{cite journal|doi=10.1099/0022-1317-67-10-2135 |title=Induction by Salicylic Acid of Pathogenesis-related Proteins or Resistance to Alfalfa Mosaic Virus Infection in Various Plant Species|year=1986| vauthors = Hooft Van Huijsduijnen RA, Alblas SW, De Rijk RH, Bol JF |journal=[[Journal of General Virology]]|volume=67|issue=10|pages=2135–2143|doi-access=free}}</ref> SA's defense signaling role is most clearly demonstrated by experiments which do away with it: Delaney et al. 1994, Gaffney et al. 1993, Lawton et al. 1995, and Vernooij et al. 1994 each use ''[[Nicotiana tabacum]]'' or ''[[Arabidopsis thaliana|Arabidopsis]]'' expressing ''[[nahG]]'', for [[salicylate hydroxylase]]. Pathogen inoculation did not produce the customarily high SA levels, SAR was not produced, and no PR genes were [[gene expression|expressed]] in [[systemic leaf|systemic leaves]]. Indeed, the subjects were more susceptible to virulent {{endash}} and even normally avirulent {{endash}} pathogens.<ref name="Vlot-et-al-2009" />

[[Exogeny|Exogenously]], salicylic acid can aid plant development via enhanced seed germination, bud flowering, and fruit ripening, though too high of a concentration of salicylic acid can negatively regulate these developmental processes.<ref>{{cite journal | vauthors = Koo YM, Heo AY, Choi HW | title = Salicylic Acid as a Safe Plant Protector and Growth Regulator | journal = The Plant Pathology Journal | volume = 36 | issue = 1 | pages = 1–10 | date = February 2020 | pmid = 32089657 | pmc = 7012573 | doi = 10.5423/PPJ.RW.12.2019.0295 }}</ref>

The volatile methyl ester of salicylic acid, [[methyl salicylate]], can also diffuse through the air, facilitating plant-[[plant communication]].<ref name="Taiz-Zeiger-2002">{{cite book | vauthors = Taiz L, Zeiger E | title=Plant physiology | publisher=Sinauer Associates | publication-place=Sunderland, Mass | year=2002 | isbn=0-87893-823-0 | oclc=50002466 | language=en | page=306 | archive-url=https://web.archive.org/web/20140305085915/http://www.scribd.com/doc/87221186/Plant-Physiology-3rd-Edition-Taiz-amp-Zeiger-2002 | archive-date=2014-03-05 | url=http://www.scribd.com/doc/87221186/Plant-Physiology-3rd-Edition-Taiz-amp-Zeiger-2002}}</ref> Methyl salicylate is taken up by the [[stomata]] of the nearby plant, where it can induce an immune response after being converted back to salicylic acid.<ref name="Chamovitz-2012">{{cite book | vauthors = Chamovitz D | title=What A Plant Knows - A Field Guide to the Senses of your Garden - and Beyond | publisher=Oneworld | publication-place=Oxford, England | year=2012 | isbn=978-1-85168-910-1 | oclc=775030365}}</ref>

=== Signal transduction ===

A number of proteins have been identified that interact with SA in plants, especially salicylic acid binding proteins (SABPs) and the NPR genes (nonexpressor of pathogenesis-related genes), which are putative receptors.<ref>Kumar, D. 2014. Salicylic acid signaling in disease resistance. Plant Science 228:127–134.</ref>

== See also ==

{{Portal|Medicine}}

* [[Salsalate]]

* [[Trolamine salicylate]]

{{clear}}

== References ==

{{reflist}}

== Further reading ==

* {{cite book| vauthors = Schrör K |title=Acetylsalicylic Acid|date=2016|publisher=John Wiley & Sons|isbn=978-3-527-68502-8|pages=9–10|edition=2|url=https://books.google.com/books?id=MaFtDAAAQBAJ&pg=PA9|language=en}}

== External links ==

{{Commons category|Salicylic acid}}

* [http://gmd.mpimp-golm.mpg.de/Spectrums/b73e3000-7a1e-4dbf-8ee6-6e3cc3e59829.aspx Salicylic acid MS Spectrum]

* [http://msds.chem.ox.ac.uk/SA/salicylic_acid.html Safety MSDS data] {{Webarchive|url=https://web.archive.org/web/20090203130448/http://msds.chem.ox.ac.uk/SA/salicylic_acid.html |date=2009-02-03 }}

* [https://www.cdc.gov/niosh/ipcsneng/neng0563.html International Chemical Safety Cards | CDC/NIOSH] {{Webarchive|url=https://web.archive.org/web/20171025010805/https://www.cdc.gov/niosh/ipcsneng/neng0563.html |date=2017-10-25 }}

* [https://www.mjlphd.net/uploads/2/4/4/0/24404036/english_translation_of_on_the_synthesis_of_salicylic_acid_by_hermann_kolbe.pdf "On the syntheses of salicylic acid"] {{Webarchive|url=https://web.archive.org/web/20200806230710/https://www.mjlphd.net/uploads/2/4/4/0/24404036/english_translation_of_on_the_synthesis_of_salicylic_acid_by_hermann_kolbe.pdf |date=2020-08-06 }}: English Translation of Hermann Kolbe's seminal 1860 German article "Ueber Synthese der Salicylsäure" in ''Annalen der Chemie und Pharmacie'' at [http://www.mjlphd.net/translations.html MJLPHD] {{Webarchive|url=https://web.archive.org/web/20201018004942/https://www.mjlphd.net/translations.html |date=2020-10-18 }}

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