Arsanilic acid

Synthesis was first reported in 1863 by Antoine Béchamp and became the basis of the Bechamp reaction.{{cite journal | url=http://gallica.bnf.fr/ark:/12148/bpt6k3013s/f1172.item.r= | title=de l'action de la chaleur sur l'arseniate d'analine et de la formation d'un anilide de l'acide arsenique | author=M. A. Bechamp | journal=Compt. Rend. | year=1863 | volume=56 | pages=1172–1175}}{{cite book|author=C. S. Hamilton and J. F. Morgan|doi=10.1002/0471264180.or002.10|journal= Organic Reactions|year=1944|page=2|chapter=The Preparation of Aromatic Arsonic and Arsinic Acids by the Bart, Bechamp, and Rosenmund Reactions|isbn=978-0471264187}} The process involves the reaction of aniline and arsenic acid via an electrophilic aromatic substitution reaction.

:C₆H₅NH₂ + H₃AsO₄ → H₂O₃AsC₆H₄NH₂ + H₂O

Arsanilic acid occurs as a zwitterion, H₃N⁺C₆H₄AsO₃H⁻,{{cite journal |doi=10.1107/S010827019501657X |title=P-arsanilic acid, a redetermination |year=1996 |vauthors=Nuttall RH, Hunter WN |journal=Acta Crystallographica Section C |volume=52 |issue=7 |pages=1681–3}} yet is typically represented with the non-zwitterionic formula H₂NC₆H₄AsO₃H₂.

Since at least 2000 BC, arsenic and inorganic arsenical compounds were both medicine and poison.{{cite journal |pmid=8505753 |year=1993 |author=Jolliffe DM |title=A history of the use of arsenicals in man |volume=86 |issue=5 |pages=287–9 |pmc=1294007 |journal=Journal of the Royal Society of Medicine|doi=10.1177/014107689308600515 }}{{Cite book |last1=Gibaud |first1=Stéphane |last2=Jaouen |first2=Gérard |title=Medicinal Organometallic Chemistry |chapter=Arsenic-Based Drugs: From Fowler's Solution to Modern Anticancer Chemotherapy |series=Topics in Organometallic Chemistry |year=2010 |volume=32 |pages=1–20 |doi= 10.1007/978-3-642-13185-1_1|isbn=978-3-642-13184-4 |bibcode=2010moc..book....1G }} In the 19th century, inorganic arsenicals became the preeminent medicines, for instance Fowler's solution, against diverse diseases.

In 1859, in France, while developing aniline dyes,{{cite journal |doi=10.1136/bmj.2.2437.624 |title=The treatment of sleeping sickness and other trypanosomiases by the Atoxyl and mercury method |year=1907 |author=Boyce R |journal=BMJ |volume=2 |issue=2437 |pages=624–5 |pmid=20763444 |pmc=2358391}} Antoine Béchamp synthesized a chemical that he identified, if incorrectly, as arsenic acid anilide. Also biologist, physician, and pharmacist, Béchamp reported it 40 to 50 times less toxic as a drug than arsenic acid, and named it Atoxyl,{{cite journal |doi=10.1186/1756-3305-3-15 |title=The development of drugs for treatment of sleeping sickness: A historical review |year=2010 |author=Steverding D |journal=Parasites & Vectors |volume=3 |pages=15 |pmid=20219092 |pmc=2848007 |issue=1 |doi-access=free }} the first organic arsenical drug.

In 1905, in Britain, H W Thomas and A Breinl reported successful treatment of trypanosomiasis in animals by Atoxyl, and recommended high doses, given continuously, for human trypanosomiasis (sleeping sickness). By 1907, more successful and less toxic than inorganic arsenicals, Atoxyl was expected to greatly aid expansion of British colonization of Africa and stem loss of cattle in Africa and India. (So socioeconomically valuable was colonial medicine

• Nadav Davidovitch & Zalman Greenberg, [https://www.ncbi.nlm.nih.gov/pubmed/17518312 "Public health, culture, and colonial medicine: Smallpox and variolation in Palestine during the British Mandate"], Public Health Reports (Washington DC 1974), 2007 May–Jun;122(3):398–406, § "Colonial medicine in context".
• Anna Crozier, [https://books.google.com/books?id=XlAw7QlphUIC Practising Colonial Medicine: The Colonial Medical Service in British East Africa] (New York: I.B. Tauris & Co Ltd, 2007).
• Deborah Neill, [https://books.google.com/books?id=-PbUd0ooQSMC Networks in Tropical Medicine: Internationalism, Colonialism, and the Rise of a Medical Specialty, 1890–1930] (Stanford CA: Stanford University Press, 2012). that in 1922, German company Bayer offered to reveal the formula of Bayer 205—developed in 1917 and showing success on sleeping sickness in British and Belgian Africa—to the British government for return of German colonies lost via World War I.){{cite journal |doi=10.1136/bmj.1.3297.413 |title=Synthetic therapeutic agents |year=1924 |author=Pope WJ |journal=BMJ |volume=1 |issue=3297 |pages=413–4 |pmid=20771495 |pmc=2303898}}

Soon, however, Robert Koch found through an Atoxyl trial in German East Africa that some 2% of patients were blinded via atrophy of the optic nerve. In Germany, Paul Ehrlich inferred Béchamp's report of Atoxyl's structure incorrectly, and Ehrlich with his chief organic chemist Alfred Bertheim found its correct structure—aminophenyl arsenic acid{{cite journal |doi=10.1159/000149583 |title=The contributions of Paul Ehrlich to pharmacology: A tribute on the occasion of the centenary of his Nobel Prize |year=2008 |vauthors=Bosch F, Rosich L |journal=Pharmacology |volume=82 |issue=3 |pages=171–9 |pmid=18679046 |pmc=2790789}} or aminophenyl arsonic acid—which suggested possible derivatives. Ehrlich asked Bertheim to synthesize two types of Atoxyl derivatives: arsenoxides and arsenobenzenes.

Ehrlich and Bertheim's 606th arsenobenzene, synthesized in 1907, was arsphenamine, found ineffective against trypanosomes, but found in 1909 by Ehrlich and bacteriologist Sahachiro Hata effective against the microorganism involved in syphilis, a disease roughly equivalent then to today's AIDS. The company Farbwerke Hoechst marketed arsphenamine as the drug Salvarsan, "the arsenic that saves". Its specificity of action fit Ehrlich's silver bullet or magic bullet paradigm of treatment, and Ehrlich won international fame while Salvarsan's success—the first particularly effective syphilis treatment—established the chemotherapy enterprise.{{cite web |publisher=Rockefeller University |url=http://centennial.rucares.org/index.php?page=Chemotherapy |title=Paul Ehrlich, the Rockefeller Institute, and the first targeted chemotherapy |access-date=3 Aug 2012}} In the late 1940s, Salvarsan was replaced in most regions by penicillin, yet organic arsenicals remained in use for trypanosomiasis.

Arsanilic acid gained use as a feed additive for poultry and swine to promote growth and prevent or treat dysentery. For poultry and swine, arsanilic acid was among four arsenical veterinary drugs, along with carbarsone, nitarsone, roxarsone, approved by the U.S. Food and Drug Administration (FDA).{{cite news | author = U.S. Food and Drug Administration | url = https://www.fda.gov/AnimalVeterinary/SafetyHealth/ProductSafetyInformation/ucm258313.htm | archive-url = https://web.archive.org/web/20110612145259/http://www.fda.gov/AnimalVeterinary/SafetyHealth/ProductSafetyInformation/ucm258313.htm | url-status = dead | archive-date = June 12, 2011 | title = Questions and answers regarding 3-nitro (roxarsone) | date = 8 Jun 2011}} In 2013, the FDA denied petitions by the Center for Food Safety and by the Institute for Agriculture and Trade Policy seeking revocation of approvals of the arsenical animal drugs, but the drugs' sponsors voluntarily requested the FDA to withdraw approvals of three, including arsanilic acid, leaving only nitarsone approved.{{cite news | author = U.S. Food and Drug Administration | url = https://www.fda.gov/AnimalVeterinary/SafetyHealth/ProductSafetyInformation/ucm370568.htm | archive-url = https://web.archive.org/web/20131022074630/http://www.fda.gov/AnimalVeterinary/SafetyHealth/ProductSafetyInformation/ucm370568.htm | url-status = dead | archive-date = October 22, 2013 | title = FDA response to citizen petition on arsenic-based animal drugs | date = 1 Oct 2013}} In 2015, the FDA withdrew nitarsone's approval.{{cite news | author = U.S. Food and Drug Administration | url = https://www.fda.gov/AnimalVeterinary/NewsEvents/CVMUpdates/ucm440668.htm | archive-url = https://wayback.archive-it.org/7993/20170406075820/https://www.fda.gov/AnimalVeterinary/NewsEvents/CVMUpdates/ucm440668.htm | url-status = dead | archive-date = 2017-04-06 | title =FDA announces pending withdrawal of approval of nitarsone | date = April 1, 2015}}

Arsanilic acid is still used in the laboratory, for instance in recent modification of nanoparticles.{{cite journal | last1 = Ahn | first1 = J | last2 = Moon | first2 = DS | last3 = Lee | first3 = JK | year = 2013 | title = Arsonic acid as a robust anchor group for the surface modification of Fe3O4 | doi = 10.1021/la402939r | pmid = 24246012 | journal = Langmuir | volume = 29 | issue = 48| pages = 14912–8 }}

It is a reagent for the detection of nitrite in urinalysis dipsticks.

{{reflist|2}}

Category:4-Aminophenyl compounds

Category:Arsonic acids