Salicylic acid

Salicylic acid (from Latin salix, willow tree) is a lipophilic monohydroxybenzoic acid, a type of phenolic acid, and a beta hydroxy acid (BHA). This colorless crystalline organic acid is widely used in organic synthesis and functions as a plant hormone. It is derived from the metabolism of salicin.

Salicylic acid
Skeletal formula of salicylic acid
Ball-and-stick model of salicylic acid
Names
Preferred IUPAC name
2-Hydroxybenzoic acid[1]
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.000.648
EC Number
  • 200-712-3
KEGG
RTECS number
  • VO0525000
UNII
Properties
C7H6O3
Molar mass 138.122 g·mol−1
Appearance Colorless to white crystals
Odor Odorless
Density 1.443 g/cm3 (20 °C)[2]
Melting point 158.6 °C (317.5 °F; 431.8 K)
Boiling point 200 °C (392 °F; 473 K) decomposes[3]
211 °C (412 °F; 484 K)
at 20 mmHg[2]
Sublimes at 76 °C[4]
  • 1.24 g/L (0 °C)
  • 2.48 g/L (25 °C)
  • 4.14 g/L (40 °C)
  • 17.41 g/L (75 °C)[3]
  • 77.79 g/L (100 °C)[5]
Solubility Soluble in ether, CCl4, benzene, propanol, acetone, ethanol, oil of turpentine, toluene
Solubility in benzene
  • 0.46 g/100 g (11.7 °C)
  • 0.775 g/100 g (25 °C)
  • 0.991 g/100 g (30.5 °C)
  • 2.38 g/100 g (49.4 °C)
  • 4.4 g/100 g (64.2 °C)[3][5]
Solubility in chloroform
  • 2.22 g/100 mL (25 °C)[5]
  • 2.31 g/100 mL (30.5 °C)[3]
Solubility in methanol
  • 40.67 g/100 g (−3 °C)
  • 62.48 g/100 g (21 °C)[3]
Solubility in olive oil 2.43 g/100 g (23 °C)[3]
Solubility in acetone 39.6 g/100 g (23 °C)[3]
log P 2.26
Vapor pressure 10.93 mPa[4]
Acidity (pKa)
  • 1 = 2.97 (25 °C)[6]
  • 2 = 13.82 (20 °C)[3]
UV-vis (λmax) 210 nm, 234 nm, 303 nm (4 mg % in ethanol)[4]
−72.23·10−6 cm3/mol
1.565 (20 °C)[2]
Thermochemistry
−589.9 kJ/mol
3.025 MJ/mol[7]
Pharmacology
A01AD05 (WHO) B01AC06 (WHO) D01AE12 (WHO) N02BA01 (WHO) S01BC08 (WHO)
Hazards
Safety data sheet MSDS
GHS pictograms [8]
GHS Signal word Danger
H302, H318[8]
P280, P305+351+338[8]
Eye hazard Severe irritation
Skin hazard Mild irritation
NFPA 704 (fire diamond)
Flammability code 1: Must be pre-heated before ignition can occur. Flash point over 93 °C (200 °F). E.g. canola oilHealth code 2: Intense or continued but not chronic exposure could cause temporary incapacitation or possible residual injury. E.g. chloroformReactivity code 0: Normally stable, even under fire exposure conditions, and is not reactive with water. E.g. liquid nitrogenSpecial hazards (white): no code
1
2
0
Flash point 157 °C (315 °F; 430 K)
closed cup[4]
540 °C (1,004 °F; 813 K)[4]
Lethal dose or concentration (LD, LC):
480 mg/kg (mice, oral)
Related compounds
Related compounds
 Methyl salicylate,
Benzoic acid,
Phenol, Aspirin,
4-Hydroxybenzoic acid,
Magnesium salicylate,
Choline salicylate,
Bismuth subsalicylate,
Sulfosalicylic acid
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Y verify (what is YN ?)
Infobox references

In addition to serving as an important active metabolite of aspirin (acetylsalicylic acid), which acts in part as a prodrug to salicylic acid, it is probably best known for its use as a key ingredient in topical anti-acne products. The salts and esters of salicylic acid are known as salicylates.

It is on the World Health Organization's List of Essential Medicines, the safest and most effective medicines needed in a health system.[9]

Uses

Medicine
Main article: Medical uses of salicylic acid
Cotton pads soaked in salicylic acid can be used to chemically exfoliate skin

Salicylic acid as a medication is used most commonly to help remove the outer layer of the skin.[10] As such, it is used to treat warts, psoriasis, acne, ringworm, dandruff, and ichthyosis.[10][11]

Similar to other hydroxy acids, salicylic acid is a key ingredient in many skincare products for the treatment of seborrhoeic dermatitis, acne, psoriasis, calluses, corns, keratosis pilaris, acanthosis nigricans, ichthyosis and warts.[12]

Uses in manufacturing

Salicylic acid is used in the production of other pharmaceuticals, including 4-aminosalicylic acid, sandulpiride, and landetimide (via Salethamide).

Salicylic acid was one of the original starting materials for making acetylsalicylic acid (aspirin) in 1897.[13] Aspirin (acetylsalicylic acid or ASA) can be prepared by the esterification of the phenolic hydroxyl group of salicylic acid with the acetyl group from acetic anhydride or acetyl chloride.

Bismuth subsalicylate, a salt of bismuth and salicylic acid, is the active ingredient in stomach relief aids such as Pepto-Bismol, is the main ingredient of Kaopectate and "displays anti-inflammatory action (due to salicylic acid) and also acts as an antacid and mild antibiotic".[14]

Other derivatives include methyl salicylate used as a liniment to soothe joint and muscle pain and choline salicylate used topically to relieve the pain of mouth ulcers.

Other uses

Salicylic acid is used as a food preservative, a bactericide and an antiseptic.[15]

Sodium salicylate is a useful phosphor in the vacuum ultraviolet spectral range, with nearly flat quantum efficiency for wavelengths between 10 and 100 nm.[16] It fluoresces in the blue at 420 nm. It is easily prepared on a clean surface by spraying a saturated solution of the salt in methanol followed by evaporation.

Mechanism of action

Salicylic acid modulates COX2 gene expression 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.

Salicylic acid 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-5-diphosphoglucose (UDPG) competitively with nicotinamide adenosine dinucleotide (NAD) and noncompetitively with UDPG. It also competitively inhibits the transferring of glucuronyl group of uridine-5-phosphoglucuronic acid (UDPGA) to the phenolic acceptor.

The wound-healing retardation action of salicylates is probably due mainly to its inhibitory action on mucopolysaccharide synthesis.[17]

Safety

17% to 27% salicylic acid used in the form of a paint, and 20% to 50% in plaster form, which are sold for wart and corn removal should not be applied to the face and should not be used for acne treatment.[18] Even for wart removal, such a solution should be applied once or twice a day – more frequent use may lead to an increase in side-effects without an increase in efficacy.[19]

If high concentrations of salicylic ointment are applied to a large percentage of body surface, high levels of salicylic acid can enter the blood, requiring hemodialysis to avoid further complications.[20]

Chemistry and production
Salicylic acid crystals under the microscope.

Salicylic acid has the formula C6H4(OH)COOH, where the OH group is ortho to the carboxyl group. It is also known as 2-hydroxybenzoic acid. It is poorly soluble in water (2 g/L at 20 °C).[21]

Salicylic acid is biosynthesized from the amino acid phenylalanine. In Arabidopsis thaliana it can be synthesized via a phenylalanine-independent pathway.

Sodium salicylate is commercially prepared by treating sodium phenolate (the sodium salt of phenol) with carbon dioxide at high pressure (100 atm) and high temperature (115°C) – a method known as the Kolbe-Schmitt reaction. Acidification of the product with sulfuric acid gives salicylic acid:

It can also be prepared by the hydrolysis of aspirin (acetylsalicylic acid)[22] or methyl salicylate (oil of wintergreen) with a strong acid or base.

Salicylic acid degrades to phenol and carbon dioxide at 200 - 230°C:[23]

C6H4OH(CO2H) → C6H5OH + CO2

History
Main article: History of aspirin
White willow (Salix alba) is a natural source of salicylic acid.

Hippocrates, Galen, Pliny the Elder and others knew that willow bark could ease pain and reduce fevers.[24] It was used in Europe and China to treat these conditions.[25] This remedy is mentioned in texts from ancient Egypt, Sumer and Assyria.[26] The Cherokee and other Native Americans use an infusion of the bark for fever and other medicinal purposes.[27]

In 2014, archaeologists identified traces of salicylic acid on 7th century pottery fragments found in east central Colorado.[28] The Reverend Edward Stone, a vicar from Chipping Norton, Oxfordshire, England, noted in 1763 that the bark of the willow was effective in reducing a fever.[29]

The active extract of the bark, called salicin, after the Latin name for the white willow (Salix alba), was isolated and named by the German chemist Johann Andreas Buchner in 1828.[30] A larger amount of the substance was isolated in 1829 by Henri Leroux, a French pharmacist.[31] Raffaele Piria, an Italian chemist, was able to convert the substance into a sugar and a second component, which on oxidation becomes salicylic acid.[32][33]

Salicylic acid was also isolated from the herb meadowsweet (Filipendula ulmaria, formerly classified as Spiraea ulmaria) by German researchers in 1839.[34] While their extract was somewhat effective, it also caused digestive problems such as gastric irritation, bleeding, diarrhea and even death when consumed in high doses.

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.[35] High-salicylate beverages and foods include beer, coffee, tea, numerous fruits and vegetables, sweet potato, nuts, and olive oil, among others.[36] Meat, poultry, fish, eggs, dairy products, sugar, and breads and cereals have low salicylate content.[36][37]

Some people with sensitivity to dietary salicylates may have symptoms of allergic reaction, such as bronchial asthma, rhinitis, gastrointestinal disorders, or diarrhea, and so may need to adopt a low-salicylate diet.[36]

Salicylic acid was one of the chemicals used in late 19th century industrialised food production that was investigated by Dr.Harvey W. Wiley with his famous 'poison squad' as part of the US Department of Agriculture. This lead up to the 1906 Pure Food and Drug Act. A landmark event in the early history of food regulation in the United States.

Plant hormone

Salicylic acid is a phenolic phytohormone and is found in plants with roles in plant growth and development, photosynthesis, transpiration, ion uptake and transport.[38] Salicylic acid is involved in endogenous signaling, mediating plant defense against pathogens.[39] It plays a role in the resistance to pathogens (i.e. systemic acquired resistance by inducing the production of pathogenesis-related proteins and other defensive metabolites.[40]

The volatile methyl ester of salyclic acid -- methyl salicylate -- can also diffuse through the air, facilitating plant-plant communication.[41] 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.[42]

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.[43]

History

It was first discovered in 1979 that salicylates are involved in induced defenses of tobacco against tobacco mosaic virus.[44] In 1987, salicylic acid was identified as the long-sought signal that causes thermogenic plants such as the voodoo lily, Sauromatum guttatum, to heat up.[45]

See also

References
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  2. Haynes, William M., ed. (2011). CRC Handbook of Chemistry and Physics (92nd ed.). Boca Raton, FL: CRC Press. p. 3.306. ISBN 1439855110.
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  4. CID 338 from PubChem
  5. Atherton Seidell; William F. Linke (1952). Solubilities of Inorganic and Organic Compounds: A Compilation of Solubility Data from the Periodical Literature. Supplement. Van Nostrand.
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  31. See:
  32. Piria (1838) "Sur de neuveaux produits extraits de la salicine" Archived 2017-07-27 at the Wayback Machine (On new products extracted from salicine), Comptes rendus … 6: 620–624. On page 622, Piria mentions "Hydrure de salicyle" (hydrogen salicylate, i.e., salicylic acid).
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  38. Vlot, A. C; Dempsey, D. A; Klessig, D. F (2009). "Salicylic Acid, a multifaceted hormone to combat disease". Annual Review of Phytopathology. 47: 177–206. doi:10.1146/annurev.phyto.050908.135202. PMID 19400653.
  39. Hayat, S. & Ahmad, A. (2007). Salicylic Acid – A Plant Hormone. Springer. ISBN 978-1-4020-5183-8.
  40. Van Huijsduijnen, R. A. M. H.; Alblas, S. W.; De Rijk, R. H.; Bol, J. F. (1986). "Induction by Salicylic Acid of Pathogenesis-related Proteins or Resistance to Alfalfa Mosaic Virus Infection in Various Plant Species". Journal of General Virology. 67 (10): 2135–2143. doi:10.1099/0022-1317-67-10-2135.
  41. Taiz, L. and Zeiger, Eduardo (2002) Plant Physiology Archived 2014-03-05 at the Wayback Machine, 3rd Edition, Sinauer Associates, p. 306, ISBN 0878938230
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