Salicylic acid

• 1. Introduction

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  In 2014, archaeologists identified traces of salicylic acid on seventh-century pottery fragments found in east-central Colorado. Salicylic acid is a colorless, bitter-tasting solid with the chemical formula C7H6O3. Its name comes from salix, the Latin word for willow, the tree from which it was first identified and derived. Someone, long ago, was apparently brewing something that carried this compound. That raises a string of questions. Who first recognized what willow could do, and how did chemists finally pin it down? Why does a substance found in ancient remedies now sit in acne products and stomach-relief aids? And what is it doing inside the plants that make it, long before any human touches them?

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• 2. Willow Before Chemistry

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  Dioscorides, whose writings stayed highly influential for more than 1,500 years, recommended a plant called Itea, possibly a species of willow. He prescribed it for painful intestinal obstructions, for birth control, and for those who spit blood. He also used it to remove calluses and corns, and externally as a warm pack for gout.

  In 1597, William Turner repeated much of this advice. He wrote that willow bark, 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.

  One popular story does not hold up. It is a modern myth that Hippocrates used willow as a painkiller. Hippocrates, Galen, Pliny the Elder, and others did know that decoctions containing salicylate could ease pain and reduce fevers.

  The remedy was used in both Europe and China. Texts from Ancient Egypt, Sumer, and Assyria mention it too. Across the Atlantic, the Cherokee and other Native Americans made an infusion of the bark for fever and other medicinal purposes.

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• 3. Isolating the Active Ingredient

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  A vicar from Chipping Norton, Oxfordshire, named Edward Stone reported in 1763 that willow bark was effective in reducing a fever. That observation waited decades for chemistry to catch up.

  In 1828, the German chemist Johann Andreas Buchner isolated an extract of willow bark and named it salicin, after the Latin name for the white willow, Salix alba. A larger amount followed in 1829, isolated by Henri Leroux, a French pharmacist. Then the Italian chemist Raffaele Piria split the substance into a sugar and a second component. On oxidation, that second component becomes salicylic acid.

  The herb meadowsweet offered another route. German researchers isolated salicylic acid from it in 1839. Its extract caused gastric irritation, bleeding, and diarrhea, and even death when consumed in high doses.

  In 1874, the Scottish physician Thomas MacLagan tried salicin as a treatment for acute rheumatism. He reported considerable success in The Lancet in 1876. Meanwhile, German scientists tried sodium salicylate with less success and more severe side effects.

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• 4. Working on the Skin

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  Warts, psoriasis, acne vulgaris, ringworm, dandruff, and ichthyosis share a common treatment. Salicylic acid as a medication is commonly used to remove the outermost layer of the skin.

  It belongs to the family of hydroxy acids, and it turns up in many skincare products. Those products target seborrhoeic dermatitis, calluses, corns, keratosis pilaris, and acanthosis nigricans, along with acne, psoriasis, ichthyosis, and warts. It is also an ingredient in dermatologic cosmetics, including anti-acne products.

  The mechanism is physical as much as chemical. Applied to the skin surface, the acid makes epidermal cells slough off more readily. Pores are less likely to clog, and there is room for new cell growth.

  There is a trade-off. The slower wound healing associated with salicylates is probably due mainly to the acid's inhibitory action on mucopolysaccharide synthesis.

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• 5. A Family of Derivatives

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  Acetylsalicylic acid, known as ASA or aspirin, is the best-known relative. It is made by acetylating salicylic acid with the acetyl group from acetic anhydride or acetyl chloride. Aspirin is the standard to which all other non-steroidal anti-inflammatory drugs are compared. In veterinary medicine, this group of drugs mainly treats inflammatory musculoskeletal disorders.

  Inside the body, salicylic acid modulates COX-1 enzymatic activity. That decreases the formation of pro-inflammatory prostaglandins, and salicylate may competitively inhibit prostaglandin formation.

  Bismuth subsalicylate is a salt of bismuth and salicylic acid. It shows anti-inflammatory action thanks to the salicylic acid, and it also acts as an antacid and mild antibiotic. It is an active ingredient in Pepto-Bismol and some formulations of Kaopectate.

  Methyl salicylate is used as a liniment to soothe joint and muscle pain. Choline salicylate relieves the pain of mouth ulcers when applied topically. Aminosalicylic acid is used to induce remission in ulcerative colitis, and it has served as an antitubercular agent, often given with isoniazid.

  Manufacturing uses reach further. Salicylic acid acts as a food preservative, a bactericide, and an antiseptic. It is a starting material for 4-aminosalicylic acid, sandulpiride, and landetimide, and it is used in picric acid production.

  A stranger use belongs to sodium salicylate. It is a useful phosphor in the vacuum ultraviolet range, with nearly flat quantum efficiency for wavelengths between 10 and 100 nm. It fluoresces in the blue at 420 nm, and a clean surface can be coated by spraying a saturated solution in methanol and letting it evaporate.

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• 6. The Plant's Own Alarm

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  In 1979, researchers found that salicylates were involved in the induced defenses of the tobacco plant against tobacco mosaic virus. Salicylic acid, it turned out, is a phenolic phytohormone. It plays roles in plant growth and development, photosynthesis, transpiration, and ion uptake and transport.

  Its defensive role is the most dramatic. The acid mediates endogenous signaling against pathogens, and it supports systemic acquired resistance by inducing pathogenesis-related proteins and other defensive metabolites.

  The clearest proof came from removing it. Four research groups, Gaffney and colleagues in 1993, then Delaney, Vernooij, and Lawton in 1994 and 1995, used Nicotiana tabacum or Arabidopsis expressing nahG, which codes for salicylate hydroxylase. Pathogen inoculation no longer produced the usual high salicylic acid levels. No systemic acquired resistance developed, and no pathogenesis-related genes were expressed in systemic leaves. The plants became more susceptible even to pathogens that normally fail to infect them.

  In 1987, salicylic acid was identified as the long-sought signal that makes thermogenic plants produce heat. The voodoo lily, Sauromatum guttatum, is one such plant.

  Plants can also talk to each other through the air. Methyl salicylate, the volatile methyl ester, diffuses between plants. Stomata of a nearby plant take it up, and once it is converted back to salicylic acid it can induce an immune response.

  Applied from outside, the acid can improve seed germination, bud flowering, and fruit ripening. Too high a concentration negatively regulates those same processes.

  Plants build the compound from the amino acid phenylalanine. In Arabidopsis thaliana, a phenylalanine-independent pathway can also produce it.

  Among the proteins that interact with it, salicylic acid binding proteins and the NPR genes, short for nonexpressor of pathogenesis-related genes, are the putative receptors.

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• 7. Dose and Danger

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  Berries and tea contain salicylic acid in some of the greatest quantities, and it is present in most fruits and vegetables. High-salicylate foods and drinks include beer, coffee, sweet potato, nuts, and olive oil. Meat, poultry, fish, eggs, dairy products, sugar, breads, and cereals have low salicylate content.

  Some people are sensitive to dietary salicylates. Their symptoms can include bronchial asthma, rhinitis, gastrointestinal disorders, or diarrhea, and they may need a low-salicylate diet.

  In excess, salicylates are toxic and can be fatal. Toxicity most often follows an oral overdose. In the United States, the EPA Toxic Substances Control Act Chemical Substance Inventory lists the compound as an experimental teratogen.

  Cosmetic use, however, poses no significant risk. Even in a worst-case scenario with several salicylic acid products at once, the aggregate plasma concentration stayed well below what is permissible for aspirin. Oral aspirin produces much higher plasma levels and shows no significant adverse pregnancy outcomes in stillbirth, birth defects, or developmental delay. On that basis, cosmetics containing salicylic acid are considered safe for pregnant women.

  The extreme case is documented. One patient applied a 40% salicylate ointment over 41% of the total skin surface. The patient then received hemodialysis to reduce blood salicylate concentration.

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• 8. Making It in the Lab

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  The Kolbe-Schmitt reaction is how commercial vendors prepare sodium salicylate. They treat sodium phenolate, the sodium salt of phenol, with carbon dioxide at 100 atm and 115 °C. Acidifying the product with sulfuric acid then gives salicylic acid.

  At laboratory scale, there is another route. Strong acid or base can hydrolyze aspirin or methyl salicylate, also called oil of wintergreen. These reactions simply reverse the commercial syntheses of those chemicals.

  Heating changes the molecule in steps. Upon heating, salicylic acid converts to phenyl salicylate, and further heating gives xanthone. At 200-230 °C it slowly degrades to phenol and carbon dioxide.

  Its conjugate base is a chelating agent with an affinity for iron(III). All isomers of chlorosalicylic acid and of dichlorosalicylic acid are known, and direct chlorination of salicylic acid produces 5-chlorosalicylic acid.

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