Salicylic acid is an

organic compound In chemistry, organic compounds are generally any chemical compounds that contain carbon-hydrogen or carbon-carbon bonds. Due to carbon's ability to catenate (form chains with other carbon atoms), millions of organic compounds are known. Th ...

with the formula HOC₆H₄CO₂H. A colorless, bitter-tasting solid, it is a precursor to and a metabolite of

aspirin Aspirin, also known as acetylsalicylic acid (ASA), is a nonsteroidal anti-inflammatory drug (NSAID) used to reduce pain, fever, and/or inflammation, and as an antithrombotic. Specific inflammatory conditions which aspirin is used to treat inc ...

(acetylsalicylic acid). It is a plant hormone, and has been listed by the

EPA The Environmental Protection Agency (EPA) is an independent executive agency of the United States federal government tasked with environmental protection matters. President Richard Nixon proposed the establishment of EPA on July 9, 1970; it be ...

Toxic Substances Control Act (TSCA) Chemical Substance Inventory as an experimental teratogen. The name is from

Latin Latin (, or , ) is a classical language belonging to the Italic languages, Italic branch of the Indo-European languages. Latin was originally a dialect spoken in the lower Tiber area (then known as Latium) around present-day Rome, but through ...

'' salix'' for willow tree. It is an ingredient in some anti-

acne Acne, also known as ''acne vulgaris'', is a long-term skin condition that occurs when dead skin cells and oil from the skin clog hair follicles. Typical features of the condition include blackheads or whiteheads, pimples, oily skin, and ...

products. Salts and

ester In chemistry, an ester is a compound derived from an oxoacid (organic or inorganic) in which at least one hydroxyl group () is replaced by an alkoxy group (), as in the substitution reaction of a carboxylic acid and an alcohol. Glycerides ...

s of salicylic acid are known as salicylates.

Uses

Medicine

Salicylic acid as a medication is commonly used to remove the outer layer of the

skin Skin is the layer of usually soft, flexible outer tissue covering the body of a vertebrate animal, with three main functions: protection, regulation, and sensation. Other animal coverings, such as the arthropod exoskeleton, have different ...

. As such, it is used to treat warts,

psoriasis Psoriasis is a long-lasting, noncontagious autoimmune disease characterized by raised areas of abnormal skin. These areas are red, pink, or purple, dry, itchy, and scaly. Psoriasis varies in severity from small, localized patches to comple ...

acne vulgaris Acne, also known as ''acne vulgaris'', is a long-term skin condition that occurs when dead skin cells and oil from the skin clog hair follicles. Typical features of the condition include blackheads or whiteheads, pimples, oily skin, and po ...

, ringworm,

dandruff Dandruff is a skin condition that mainly affects the scalp. Symptoms include flaking and sometimes mild itchiness. It can result in social or self-esteem problems. A more severe form of the condition, which includes inflammation of the skin ...

, and ichthyosis. Similar to other hydroxy acids, salicylic acid is an ingredient in many skincare products for the treatment of seborrhoeic dermatitis,

, calluses, corns, keratosis pilaris, acanthosis nigricans, ichthyosis, and warts.

Uses in manufacturing

Salicylic acid is used as a food preservative, a

bactericide A bactericide or bacteriocide, sometimes abbreviated Bcidal, is a substance which kills bacteria. Bactericides are disinfectants, antiseptics, or antibiotics. However, material surfaces can also have bactericidal properties based solely on their ...

, and an antiseptic. Salicylic acid is used in the production of other pharmaceuticals, including 4-aminosalicylic acid, sandulpiride, and landetimide (via salethamide). Salicylic acid has long been a key starting material for making acetylsalicylic acid (aspirin). Aspirin (acetylsalicylic acid or ASA) is prepared by the esterification of the

phenol Phenol (also called carbolic acid) is an aromatic organic compound with the molecular formula . It is a white crystalline solid that is volatile. The molecule consists of a phenyl group () bonded to a hydroxy group (). Mildly acidic, it r ...

hydroxyl group In chemistry, a hydroxy or hydroxyl group is a functional group with the chemical formula and composed of one oxygen atom covalently bonded to one hydrogen atom. In organic chemistry, alcohols and carboxylic acids contain one or more hydroxy ...

of salicylic acid with the acetyl group from acetic anhydride or acetyl chloride. ASA is the standard to which all the other non-steroidal anti-inflammatory drugs ( NSAIDs) are compared. In veterinary medicine, this group of drugs is mainly used for treatment of inflammatory musculoskeletal disorders. Bismuth subsalicylate, a

salt Salt is a mineral composed primarily of sodium chloride (NaCl), a chemical compound belonging to the larger class of salts; salt in the form of a natural crystalline mineral is known as rock salt or halite. Salt is present in vast quant ...

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". Other derivatives include

methyl salicylate Methyl salicylate (oil of wintergreen or wintergreen oil) is an organic compound with the formula C8H8O3. It is the methyl ester of salicylic acid. It is a colorless, viscous liquid with a sweet, fruity odor reminiscent of root beer, but often a ...

used as a

liniment Liniment (from la, linere, meaning "to anoint"), also called embrocation and heat rub, is a medicated topical preparation for application to the skin. Some liniments have viscosity similar to that of water; others are lotion or balm; still oth ...

to soothe joint and muscle pain and choline salicylate used topically to relieve the pain of mouth ulcers. Aminosalicylic acid is used to induce remission in ulcerative colitis, and has been used as an

antitubercular agent Tuberculosis management describes the techniques and procedures utilized for treating tuberculosis (TB). The medical standard for active TB is a short course treatment involving a combination of isoniazid, rifampicin (also known as Rifampin), py ...

often administered in association with isoniazid. Sodium salicylate is a useful phosphor in the vacuum ultraviolet spectral range, with nearly flat quantum efficiency for wavelengths between 10 and 100 nm.Samson, James (1976). ''Techniques of Vacuum Ultraviolet Spectroscopy''. Wiley, . 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 Methanol (also called methyl alcohol and wood spirit, amongst other names) is an organic chemical and the simplest aliphatic alcohol, with the formula C H3 O H (a methyl group linked to a hydroxyl group, often abbreviated as MeOH). It is ...

followed by evaporation.

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. 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-5-diphosphoglucose (UDPG) competitively with nicotinamide adenine dinucleotide and noncompetitively with UDPG. It also competitively inhibits the transferring of glucuronyl group of uridine-5-phosphoglucuronic acid to the phenolic acceptor. The wound-healing retardation action of salicylates is probably due mainly to its inhibitory action on mucopolysaccharide synthesis.

Safety

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.

Production and chemical reactions

Biosynthesis

Salicylic acid is biosynthesized from the amino acid

phenylalanine Phenylalanine (symbol Phe or F) is an essential α-amino acid with the formula . It can be viewed as a benzyl group substituted for the methyl group of alanine, or a phenyl group in place of a terminal hydrogen of alanine. This essential amin ...

. In '' Arabidopsis thaliana'', it can be synthesized via a phenylalanine-independent pathway.

Industrial synthesis

Sodium salicylate is commercially prepared by treating

sodium phenolate Sodium phenoxide (sodium phenolate) is an organic compound with the formula NaOC6H5. It is a white crystalline solid. Its anion, phenoxide, also known as phenolate, is the conjugate base of phenol. It is used as a precursor to many other organic ...

(the sodium salt of

) with

carbon dioxide Carbon dioxide ( chemical formula ) is a chemical compound made up of molecules that each have one carbon atom covalently double bonded to two oxygen atoms. It is found in the gas state at room temperature. In the air, carbon dioxide is t ...

at high pressure (100atm) and high temperature (115°C) – a method known as the Kolbe-Schmitt reaction. Acidification of the product with

sulfuric acid Sulfuric acid (American spelling and the preferred IUPAC name) or sulphuric acid ( Commonwealth spelling), known in antiquity as oil of vitriol, is a mineral acid composed of the elements sulfur, oxygen and hydrogen, with the molecular fo ...

gives salicylic acid: : Salicylic-Acid General Synthesis V

It can also be prepared by the

hydrolysis Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution, elimination, and solvation reactions in which water is the nucleophile. Biological hydrolysi ...

(acetylsalicylic acid) or

(oil of

wintergreen Wintergreen is a group of aromatic plants. The term "wintergreen" once commonly referred to plants that remain green (continue photosynthesis) throughout the winter. The term "evergreen" is now more commonly used for this characteristic. Mos ...

) with a strong acid or base.

Reactions

Upon heating, salicylic acid converts to phenyl salicylate: :2HOC₆H₄CO₂H → C₆H₅O₂C₆H₄OH + CO₂ + H₂O Further heating gives

xanthone Xanthone is an organic compound with the molecular formula O 6H4sub>2CO. It is a white solid. In 1939, xanthone was introduced as an insecticide and it currently finds uses as ovicide for codling moth eggs and as a larvicide. Xanthone is also ...

. Salicylic acid as its conjugate base is a chelating agent, with an affinity for iron(III). Salicylic acid slowly degrades to phenol and carbon dioxide at 200–230 °C: :C₆H₄OH(CO₂H) → C₆H₅OH + CO₂

History

Willow Willows, also called sallows and osiers, from the genus ''Salix'', comprise around 400 speciesMabberley, D.J. 1997. The Plant Book, Cambridge University Press #2: Cambridge. of typically deciduous trees and shrubs, found primarily on moist so ...

has long been used for medicinal purposes.

Dioscorides Pedanius Dioscorides ( grc-gre, Πεδάνιος Διοσκουρίδης, ; 40–90 AD), “the father of pharmacognosy”, was a Greek physician, pharmacologist, botanist, and author of '' De materia medica'' (, On Medical Material) —a 5-vo ...

, whose writings were highly influential for more than 1,500 years, 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, 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.' 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.

Hippocrates Hippocrates of Kos (; grc-gre, Ἱπποκράτης ὁ Κῷος, Hippokrátēs ho Kôios; ), also known as Hippocrates II, was a Greek physician of the classical period who is considered one of the most outstanding figures in the history o ...

Galen Aelius Galenus or Claudius Galenus ( el, Κλαύδιος Γαληνός; September 129 – c. AD 216), often Anglicized as Galen () or Galen of Pergamon, was a Greek physician, surgeon and philosopher in the Roman Empire. Considered to be o ...

Pliny the Elder Gaius Plinius Secundus (AD 23/2479), called Pliny the Elder (), was a Roman author, naturalist and natural philosopher, and naval and army commander of the early Roman Empire, and a friend of the emperor Vespasian. He wrote the encyclopedic ' ...

, and others knew that decoctions containing salicylate could ease pain and reduce fevers. It was used in Europe and China to treat these conditions. This remedy is mentioned in texts from Ancient Egypt,

Sumer Sumer () is the earliest known civilization in the historical region of southern Mesopotamia (south-central Iraq), emerging during the Chalcolithic and early Bronze Ages between the sixth and fifth millennium BC. It is one of the cradles of ...

, and

Assyria Assyria ( Neo-Assyrian cuneiform: , romanized: ''māt Aššur''; syc, ܐܬܘܪ, ʾāthor) was a major ancient Mesopotamian civilization which existed as a city-state at times controlling regional territories in the indigenous lands of the A ...

. The

Cherokee The Cherokee (; chr, ᎠᏂᏴᏫᏯᎢ, translit=Aniyvwiyaʔi or Anigiduwagi, or chr, ᏣᎳᎩ, links=no, translit=Tsalagi) are one of the indigenous peoples of the Southeastern Woodlands of the United States. Prior to the 18th century, th ...

and other Native Americans use an infusion of the bark for fever and other medicinal purposes. In 2014, archaeologists identified traces of salicylic acid on seventh-century pottery fragments found in east-central Colorado. The 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. An extract of willow bark, called salicin, after the

name for the white willow ('' Salix alba''), was isolated and named by

German German(s) may refer to: * Germany (of or related to) **Germania (historical use) * Germans, citizens of Germany, people of German ancestry, or native speakers of the German language ** For citizens of Germany, see also German nationality law **Ge ...

chemist Johann Andreas Buchner in 1828. A larger amount of the substance was isolated in 1829 by Henri Leroux, a French pharmacist.See: * * A report on Leroux's presentation to the French Academy of Sciences also appeared in: Raffaele Piria, an Italian chemist, was able to convert the substance into a sugar and a second component, which on oxidation becomes salicylic acid. Salicylic acid was also isolated from the herb meadowsweet ('' Filipendula ulmaria'', formerly classified as ''Spiraea ulmaria'') by German researchers in 1839. Their extract caused digestive problems such as gastric irritation, bleeding,

diarrhea Diarrhea, also spelled diarrhoea, is the condition of having at least three loose, liquid, or watery bowel movements each day. It often lasts for a few days and can result in dehydration due to fluid loss. Signs of dehydration often begin w ...

, and even death when consumed in high doses. In 1874 the Scottish physician Thomas MacLagan experimented with salicin as a treatment for acute rheumatism, with considerable success, as he reported in The Lancet in 1876. Meanwhile, German scientists tried sodium salicylate with less success and more severe side effects. In 1979, salicylates were found to be involved in induced defenses of

tobacco Tobacco is the common name of several plants in the genus '' Nicotiana'' of the family Solanaceae, and the general term for any product prepared from the cured leaves of these plants. More than 70 species of tobacco are known, but the ...

against tobacco mosaic virus. In 1987, salicylic acid was identified as the long-sought signal that causes thermogenic plants, such as the voodoo lily, '' Sauromatum guttatum'', to produce heat.

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. High-salicylate beverages and foods include

beer Beer is one of the oldest and the most widely consumed type of alcoholic drink in the world, and the third most popular drink overall after water and tea. It is produced by the brewing and fermentation of starches, mainly derived from ce ...

coffee Coffee is a drink prepared from roasted coffee beans. Darkly colored, bitter, and slightly acidic, coffee has a stimulating effect on humans, primarily due to its caffeine content. It is the most popular hot drink in the world. Seeds of ...

, tea, numerous fruits and vegetables,

sweet potato The sweet potato or sweetpotato ('' Ipomoea batatas'') is a dicotyledonous plant that belongs to the bindweed or morning glory family, Convolvulaceae. Its large, starchy, sweet-tasting tuberous roots are used as a root vegetable. The young ...

, nuts, and

olive oil Olive oil is a liquid fat obtained from olives (the fruit of ''Olea europaea''; family Oleaceae), a traditional tree crop of the Mediterranean Basin, produced by pressing whole olives and extracting the oil. It is commonly used in cooking: ...

. Meat, poultry, fish, eggs, dairy products, sugar, breads and cereals have low salicylate content. Some people with sensitivity to dietary salicylates may have symptoms of

allergic reaction Allergies, also known as allergic diseases, refer a number of conditions caused by the hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include hay fever, food allergies, atopic derm ...

, such as

bronchial asthma Asthma is a long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wheezing, cou ...

, rhinitis, gastrointestinal disorders, or

, so may need to adopt a low-salicylate diet.

Plant hormone

Salicylic acid is a phenolic phytohormone, and is found in plants with roles in plant growth and development,

photosynthesis Photosynthesis is a process used by plants and other organisms to convert light energy into chemical energy that, through cellular respiration, can later be released to fuel the organism's activities. Some of this chemical energy is stored in ...

transpiration Transpiration is the process of water movement through a plant and its evaporation from aerial parts, such as leaves, stems and flowers. Water is necessary for plants but only a small amount of water taken up by the roots is used for growth ...

, and ion uptake and transport. Salicylic acid is involved in

endogenous Endogenous substances and processes are those that originate from within a living system such as an organism, tissue, or cell. In contrast, exogenous substances and processes are those that originate from outside of an organism. For example, ...

signaling, mediating plant defense against pathogens. 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. 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 ''Nicotiana tabacum'', or cultivated tobacco, is an annually grown herbaceous plant of the ''Nicotiana'' genus. The plant is tropical in origin, is commonly grown throughout the world, and is often found in cultivation. It grows to heights be ...

'' or '' 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 expressed in systemic leaves. Indeed, the subjects were more susceptible to virulent and even normally avirulent pathogens. 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. The volatile methyl ester of salicylic acid,

, can also diffuse through the air, facilitating plant- plant communication. Methyl salicylate is taken up by the

stomata In botany, a stoma (from Greek ''στόμα'', "mouth", plural "stomata"), also called a stomate (plural "stomates"), is a pore found in the epidermis of leaves, stems, and other organs, that controls the rate of gas exchange. The pore is b ...

of the nearby plant, where it can induce an immune response after being converted back to salicylic acid.

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.Kumar, D. 2014. Salicylic acid signaling in disease resistance. Plant Science 228:127–134.

References

External links

Salicylic acid MS Spectrum

"On the syntheses of salicylic acid"
English Translation of Hermann Kolbe's seminal 1860 German article "Ueber Synthese der Salicylsäure" in ''Annalen der Chemie und Pharmacie'' a

{{DEFAULTSORT:Salicylic Acid Anti-acne preparations Antiseptics Chelating agents Monohydroxybenzoic acids Nonsteroidal anti-inflammatory drugs Plant hormones World Health Organization essential medicines