Salicylic acid is an

organic compound Some chemical authorities define an organic compound as a chemical compound that contains a carbon–hydrogen or carbon–carbon bond; others consider an organic compound to be any chemical compound that contains carbon. For example, carbon-co ...

with the formula HOC₆H₄COOH. A colorless (or white), bitter-tasting solid, it is a precursor to and a

metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...

acetylsalicylic acid Aspirin () is the Generic trademark, genericized trademark for acetylsalicylic acid (ASA), a nonsteroidal anti-inflammatory drug (NSAID) used to reduce pain, fever, and inflammation, and as an antithrombotic. Specific inflammatory conditions ...

(aspirin). It is a

plant hormone Plant hormones (or phytohormones) are signal molecules, produced within plants, that occur in extremely low concentrations. Plant hormones control all aspects of plant growth and development, including embryogenesis, the regulation of Organ (anat ...

, and has been listed by the EPA 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 spoken by the Latins (Italic tribe), Latins in Latium (now known as Lazio), the lower Tiber area aroun ...

for willow tree, from which it was initially identified and derived. It is an ingredient in some anti-

acne Acne ( ), also known as ''acne vulgaris'', is a long-term Cutaneous condition, skin condition that occurs when Keratinocyte, dead skin cells and Sebum, oil from the skin clog hair follicles. Typical features of the condition include comedo, ...

products. Salts and

ester In chemistry, an ester is a compound derived from an acid (either organic or inorganic) in which the hydrogen atom (H) of at least one acidic hydroxyl group () of that acid is replaced by an organyl group (R). These compounds contain a distin ...

s of salicylic acid are known as salicylates.

Uses

Medicine

Salicylic acid as a medication is commonly used to remove the outermost 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 patches of abnormal skin. These areas are red, pink, or purple, dry, itchy, and scaly. Psoriasis varies in severity from small localized patches to complete b ...

, acne vulgaris,

ringworm Dermatophytosis, also known as tinea and ringworm, is a mycosis, fungal infection of the skin (a dermatomycosis), that may affect skin, hair, and nails. Typically it results in a red, itchy, scaly, circular rash. Hair loss may occur in the a ...

, dandruff, 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, and an

antiseptic An antiseptic ( and ) is an antimicrobial substance or compound that is applied to living tissue to reduce the possibility of sepsis, infection, or putrefaction. Antiseptics are generally distinguished from ''antibiotics'' by the latter's abil ...

. Salicylic acid is used in the production of other pharmaceuticals, including 4-aminosalicylic acid, sandulpiride, and landetimide (via salethamide). It is also used in picric acid production. Salicylic acid has long been a key starting material for making

(ASA or aspirin). ASA is prepared by the acetylation 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 In common usage, salt is a mineral composed primarily of sodium chloride (NaCl). When used in food, especially in granulated form, it is more formally called table salt. In the form of a natural crystalline mineral, salt is also known as r ...

of bismuth and salicylic acid, "displays anti-inflammatory action (due to salicylic acid) and also acts as an antacid and mild antibiotic". It is an active ingredient in stomach-relief aids such as Pepto-Bismol and some formulations of Kaopectate. 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 (in which it ...

, used as a

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

to soothe joint and muscle pain, and choline salicylate, which is used topically to relieve the pain of mouth ulcers. Aminosalicylic acid is used to induce remission in

ulcerative colitis Ulcerative colitis (UC) is one of the two types of inflammatory bowel disease (IBD), with the other type being Crohn's disease. It is a long-term condition that results in inflammation and ulcers of the colon and rectum. The primary sympto ...

, and has been used as an antitubercular agent often administered in association with isoniazid. Sodium salicylate is a useful

phosphor A phosphor is a substance that exhibits the phenomenon of luminescence; it emits light when exposed to some type of radiant energy. The term is used both for fluorescent or phosphorescent substances which glow on exposure to ultraviolet or ...

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 compound and the simplest aliphatic Alcohol (chemistry), alcohol, with the chemical formula (a methyl group linked to a hydroxyl group, often ab ...

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. 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 NADH 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

In excess, salicylates have toxic effects, which can be fatal. Toxicity is most often due to oral overdose. Cosmetic applications of the drug pose no significant risk. 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). 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. Salicylic acid is present in most fruits and vegetables as for example in greatest quantities in

berries A berry is a small, pulpy, and often edible fruit. Typically, berries are juicy, rounded, brightly colored, sweet, sour or tart, and do not have a stone fruit, stone or pit (fruit), pit although many wikt:pip#Etymology 2, pips or seeds may be p ...

and in beverages like tea. In one documented case, a patient applied extreme levels of salicyate ointment topically (40% ointment, over 41% of the total skin surface), and subsequently received

hemodialysis Hemodialysis, American and British English spelling differences#ae and oe, also spelled haemodialysis, or simply ''"'dialysis'"'', is a process of filtering the blood of a person whose kidneys are not working normally. This type of Kidney dialys ...

to reduce blood salicylate concentration.

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 chemical formula, formula . It can be viewed as a benzyl group substituent, substituted for the methyl group of alanine, or a phenyl group in place of a terminal hydrogen of ...

. In ''

Arabidopsis thaliana ''Arabidopsis thaliana'', the thale cress, mouse-ear cress or arabidopsis, is a small plant from the mustard family (Brassicaceae), native to Eurasia and Africa. Commonly found along the shoulders of roads and in disturbed land, it is generally ...

'', 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 Phenol (also known as carbolic acid, phenolic acid, or benzenol) is an aromatic organic compound with the molecular formula . It is a white crystalline solid that is volatile and can catch fire. The molecule consists of a phenyl group () ...

) with

carbon dioxide Carbon dioxide is a chemical compound with the chemical formula . It is made up of molecules that each have one carbon atom covalent bond, covalently double bonded to two oxygen atoms. It is found in a gas state at room temperature and at norma ...

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

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

gives salicylic acid: : Salicylic-Acid General Synthesis V

At the laboratory scale, 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 reaction, substitution, elimination reaction, elimination, and solvation reactions in which water ...

aspirin Aspirin () is the genericized trademark for acetylsalicylic acid (ASA), a nonsteroidal anti-inflammatory drug (NSAID) used to reduce pain, fever, and inflammation, and as an antithrombotic. Specific inflammatory conditions that aspirin is ...

(acetylsalicylic acid) or

(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: Further heating gives xanthone. 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: All isomers of chlorosalicylic acid and of dichlorosalicylic acid are known. 5-Chlorosalicylic acid is produced by direct chlorination of salicylic acid.

History

Willow Willows, also called sallows and osiers, of the genus ''Salix'', comprise around 350 species (plus numerous hybrids) of typically deciduous trees and shrubs, found primarily on moist soils in cold and temperate regions. Most species are known ...

has long been used for medicinal purposes.

Dioscorides Pedanius Dioscorides (, ; 40–90 AD), "the father of pharmacognosy", was a Greek physician, pharmacologist, botanist, and author of (in the original , , both meaning "On Materia medica, Medical Material") , a 5-volume Greek encyclopedic phar ...

, 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 Salicin is an alcoholic β-glucoside. Salicin is produced in (and named after) willow (''Salix'') bark. It is a biosynthetic precursor to salicylaldehyde. Salicin hydrolyses into Glucose, β-d-glucose and salicyl alcohol (saligenin). Salicyl al ...

present in willow. It is, however, a modern myth that Hippocrates used willow as a painkiller.

Hippocrates Hippocrates of Kos (; ; ), also known as Hippocrates II, was a Greek physician and philosopher of the Classical Greece, classical period who is considered one of the most outstanding figures in the history of medicine. He is traditionally referr ...

Galen Aelius Galenus or Claudius Galenus (; September 129 – AD), often Anglicization, anglicized as Galen () or Galen of Pergamon, was a Ancient Rome, Roman and Greeks, Greek physician, surgeon, and Philosophy, philosopher. Considered to be one o ...

Pliny the Elder Gaius Plinius Secundus (AD 23/24 79), known in English as Pliny the Elder ( ), was a Roman Empire, Roman author, Natural history, naturalist, and naval and army commander of the early Roman Empire, and a friend of the Roman emperor, emperor Vesp ...

, 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 Ancient Egypt () was a cradle of civilization concentrated along the lower reaches of the Nile River in Northeast Africa. It emerged from prehistoric Egypt around 3150BC (according to conventional Egyptian chronology), when Upper and Lower E ...

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

, and

Assyria Assyria (Neo-Assyrian cuneiform: , ''māt Aššur'') was a major ancient Mesopotamian civilization that existed as a city-state from the 21st century BC to the 14th century BC and eventually expanded into an empire from the 14th century BC t ...

. The

Cherokee The Cherokee (; , or ) people are one of the Indigenous peoples of the Southeastern Woodlands of the United States. Prior to the 18th century, they were concentrated in their homelands, in towns along river valleys of what is now southwestern ...

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. Edward Stone, a vicar from Chipping Norton, Oxfordshire, England, reported in 1763 that the bark of the willow was effective in reducing a fever. Florence Nightingale salicylic silk letter

Florence Nightingale salicylic silk letter

An extract of willow bark, called

, after the

name for the white willow ('' Salix alba''), was isolated and named by German chemist Johann Andreas Buchner in 1828. A larger amount of the substance was isolated in 1829 by Henri Leroux, a French pharmacist. * * 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 (American English), also spelled diarrhoea or diarrhœa (British English), is the condition of having at least three loose, liquid, or watery bowel movements in a day. It often lasts for a few days and can result in dehydration d ...

, 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 Tobacco mosaic virus (TMV) is a positive-sense single-stranded RNA virus species in the genus '' Tobamovirus'' that infects a wide range of plants, especially tobacco and other members of the family Solanaceae. The infection causes characteris ...

. 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 an alcoholic beverage produced by the brewing and fermentation of starches from cereal grain—most commonly malted barley, although wheat, maize (corn), rice, and oats are also used. The grain is mashed to convert starch in the ...

coffee Coffee is a beverage brewed from roasted, ground coffee beans. Darkly colored, bitter, and slightly acidic, coffee has a stimulating effect on humans, primarily due to its caffeine content, but decaffeinated coffee is also commercially a ...

, tea, numerous fruits and vegetables, sweet potato, nuts, and

olive oil Olive oil is a vegetable oil obtained by pressing whole olives (the fruit of ''Olea europaea'', a traditional Tree fruit, tree crop of the Mediterranean Basin) and extracting the oil. It is commonly used in cooking for frying foods, as a cond ...

. 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, are various conditions caused by hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include Allergic rhinitis, hay fever, Food allergy, food al ...

, such as bronchial asthma, 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 system of biological processes by which photosynthetic organisms, such as most plants, algae, and cyanobacteria, convert light energy, typically from sunlight, into the chemical energy necessary to fuel their metabo ...

transpiration Transpiration is the process of water movement through a plant and its evaporation from aerial parts, such as leaves, stems and flowers. It is a passive process that requires no energy expense by the plant. Transpiration also cools plants, c ...

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

endogenous Endogeny, in biology, refers to the property of originating or developing from within an organism, tissue, or cell. For example, ''endogenous substances'', and ''endogenous processes'' are those that originate within a living system (e.g. an ...

signaling, mediating plant defense against

pathogens In biology, a pathogen (, "suffering", "passion" and , "producer of"), in the oldest and broadest sense, is any organism or agent that can produce disease. A pathogen may also be referred to as an infectious agent, or simply a germ. The term ...

. 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'' or '' Arabidopsis'' expressing '' nahG'', for salicylate hydroxylase. Pathogen inoculation did not produce the customarily high SA levels, SAR was not produced, and no pathogenesis-related (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 (: stomata, from Greek ''στόμα'', "mouth"), also called a stomate (: stomates), is a pore found in the epidermis of leaves, stems, and other organs, that controls the rate of gas exchange between the internal air spa ...

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

"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 Tree-derived bioactive compounds Anti-acne preparations Antiseptics Chelating agents Monohydroxybenzoic acids Nonsteroidal anti-inflammatory drugs Plant hormones World Health Organization essential medicines 2-Hydroxyphenyl compounds