Organoarsenic chemistry

file:Cacodyl Structural Formula V.3.svg (tetramethyldiarsine) was one of the first organoarsenic compounds.{{cite journal

| title = Cadet's Fuming Arsenical Liquid and the Cacodyl Compounds of Bunsen

| first = Dietmar

| last = Seyferth

| journal = Organometallics

| year = 2001

| volume = 20

| issue =8

| pages = 1488–1498

| doi = 10.1021/om0101947

| doi-access = free

}}]]

Surprising for an area now considered of minor importance, organoarsenic chemistry played a prominent role in chemistry's history. The oldest known organoarsenic compound, the foul smelling cacodyl was reported in "cacodyl" (1760) and is sometimes classified as the first synthetic organometallic compound. The compound Salvarsan was one of the first pharmaceuticals, earning a Nobel prize for Paul Ehrlich. Various other organoarsenic compounds formerly found use as antibiotics (Solarson) or other medical uses.Singh, R. Synthetic Drugs. Mittal Publications (2002). {{ISBN|817099831X}}

Arsenic typically occurs in the oxidation states (III) and (V), illustrated by the halides AsX₃ (X = F, Cl, Br, I) and AsF₅. Correspondingly, organoarsenic compounds are commonly found in these two oxidation states.

The hydroxyarsenic compounds are known:{{Ullmann | author = Grund, S. C. | author2 = Hanusch, K. | author3 = Wolf, H. U. | title = Arsenic and Arsenic Compounds | doi = 10.1002/14356007.a03_113.pub2}}

• arsonous acids (RAs(OH)₂), rare (arsenous acid (As(OH)₃) is well known)
• arsinous acids (R₂AsOH), rare
• arsinic acids (R₂As(O)OH), common, illustrated by cacodylic acid (R = CH₃)
• arsonic acids (RAs(O)(OH)₂), common, illustrated by phenylarsonic acid (R = C₆H₅)

Arsenic(V) compounds typically feature the functional groups RAsO(OH)₂ or R₂AsO(OH) (R = alkyl or aryl). Cacodylic acid, central to arsenic chemistry, arises from the methylation of arsenic(III) oxide. (In contrast, the dimethylphosphonic acid is less significant in the corresponding chemistry of phosphorus.) Phenylarsonic acids can be accessed by the reaction of arsenic acid with anilines, the so-called Bechamp reaction.

The monomethylated acid, methanearsonic acid (CH₃AsO(OH)₂), is a precursor to fungicides (tradename Neoasozin) in the cultivation of rice and cotton. Derivatives of phenylarsonic acid (C₆H₅AsO(OH)₂) are used as feed additives for livestock, including 4-hydroxy-3-nitrobenzenearsonic acid (3-NHPAA or Roxarsone), ureidophenylarsonic acid and p-arsanilic acid. These applications are controversial as they introduce soluble forms of arsenic into the environment.

Compounds of arsenic(V) containing only organic ligands are rare, the pre-eminent member being the pentaphenyl derivative As(C₆H₅)₅.Elschenbroich, C. "Organometallics" (2006) Wiley-VCH: Weinheim. {{ISBN|978-3-527-29390-2}}

Many organoarsenic compounds are prepared by alkylation of AsCl₃ and its derivatives using organolithium and Grignard reagents. For example, the series trimethylarsine ((CH₃)₃As), dimethylarsenic chloride ((CH₃)₂AsCl), and methylarsenic dichloride (CH₃AsCl₂) is known. Reduction of the chloride derivatives with hydride reducing reagents affords the corresponding hydrides, such as dimethylarsine ((CH₃)₂AsH) and methylarsine (CH₃AsH₂). Similar manipulations apply to other organoarsenic chloride compounds.

Akin to the Direct process in organosilicon chemistry, methyl halides react with elemental As, as illustrated in the following idealized equation:{{cite journal |doi=10.1016/0022-1902(61)80492-2 |title=The direct synthesis of organoarsenic and organoantimony compounds |date=1961 |last1=Maier |first1=L. |last2=Rochow |first2=E.G. |last3=Fernelius |first3=W.C. |journal=Journal of Inorganic and Nuclear Chemistry |volume=16 |issue=3–4 |pages=213–218 }}

:{{chem2|3 CH3Br + 2 As -> (CH3)2AsBr + CH3AsBr2}}

Such reactions require copper catalysts, are conducted near 360 °C.

Another route to dimethylarsenic compounds begins with reduction of the As^V compound cacodylic acid:

:(CH₃)₂AsO₂H + 2 Zn + 4 HCl → (CH₃)₂AsH + 2 ZnCl₂ + 2 H₂O

:(CH₃)₂AsO₂H + SO₂ + HI → (CH₃)₂AsI + SO₃ + H₂O

A variety of heterocycles containing arsenic(III) are known. These include arsole, the arsenic analogue of pyrrole, and arsabenzene, the arsenic analogue of pyridine.

Symmetrical organoarsenic(III) compounds, e.g. trimethylarsine and triphenylarsine, are commonly used as ligands in coordination chemistry. They behave like phosphine ligands, but are less basic. The diarsine C₆H₄(As(CH₃)₂)₂, known as diars, is a chelating ligand. Thorin is an indicator for several metals.

Per the double bond rule, compounds with As=As, As=C, and As≡C bonds are rare. They are observed in the gas phase but considerable steric protection is required to inhibit their conversion to oligomers as liquids or solids.

Oligomers with As-As bonds include the anti-syphylic drugs Salvarsan and Neosalvarsan.{{Citation needed|date=February 2024}} They are typically tricoordinate at As and have formal oxidation state As^I. Small substituents, such as in (MeAs)_{{Mvar|n}}, equilibrate between three-, four-, and five-membered rings, but bulkier substituents usually settle on a four-membered configuration. Synthesis is typically by reductive dehalogenation with a metal.{{Rp|pages=563–565}}

Protic arsines oxidize to oligomers.{{Cite book |title=The Chemistry of Organic Arsenic, Antimony, and Bismuth Compounds |publisher=Wiley |year=1994 |isbn=047193044X |editor-last=Patai |editor-first=Saul |editor-link=Saul Patai |series=Chemistry of Functional Groups |location=Chichester, UK |doi=10.1002/0470023473}}{{Rp|page=318}} For example, methylarsine oxidizes first to cyclo-methylarsine(I):

:MeAsH₂ + O → H₂O + (MeAs)_{{Mvar|n}}

These compounds have structures similar to the phosphorus sulfides.

Arsenic-arsenic bonds are very weak, and oligomeric arsenic compounds are even more liable to oxidize than their hydrogenated precursors.{{Rp|pages=318–320}} The following reaction can, however, be prepared through electrochemical reduction in a zinc-sulfate cell.{{Rp|page=473}} Oxidation first forms polymeric arsinoxides, e.g.:

:MeAs + O → MeAsO

Further oxidation then depolymerizes them to arsinous acids.{{Rp|page=318}}

Arsine(III) compounds add to multiple bonds as nucleophiles, but arsine(I) rings may instead insert the bond into the ring.{{Rp|pages=319,573,843}} In general, arsines are less Brønsted basic than phosphines (but more than stibines).{{Rp|pages=322–326}}

Arsine ylides are generally less stable than phosphine ylides, decomposing spontaneously in the absence of a vicinal carbonyl. Stabilized ylides olefinate to a mixture of stereoisomers, whereas unstabilized ylides tend to epoxidate (like a Corey-Chaykovsky reagent). With enones, they either olefinate or cyclopropanate. With nitroso compounds, they either form imines or nitrones.{{Rp|pages=662–672}}

Organoarsenic compounds, especially those featuring As-Cl bonds, have been used as chemical weapons, especially during World War I. Infamous examples include "Lewisite" (chlorovinyl-2-arsenic dichloride) and "Clark I" (chlorodiphenylarsine). Phenyldichloroarsine is another one.

As arsenic is toxic to most life forms and it occurs in elevated concentration in some areas several detoxification strategies have evolved. Inorganic arsenic and its compounds, upon entering the food chain, are progressively metabolized to a less toxic form of arsenic through a process of methylation.{{cite journal|last=Reimer|first=K. J.|author2=Koch, I. |author3=Cullen, W. R. |year=2010|title=Organoarsenicals. Distribution and transformation in the environment|journal=Metal Ions in Life Sciences|publisher=RSC publishing|location=Cambridge|volume=7 |pages=165–229|isbn=978-1-84755-177-1|doi=10.1039/9781849730822-00165|pmid=20877808}} Organoarsenic compounds arise via biomethylation of inorganic arsenic compounds,{{cite journal|last=Dopp|first=E.|author2=Kligerman, A. D. |author3=Diaz-Bone, R. A. |year=2010|title=Organoarsenicals. Uptake, metabolism and toxicity|journal=Metal Ions in Life Sciences|publisher=RSC publishing|location=Cambridge|volume=7|pages=231–265|isbn=978-1-84755-177-1|pmid=20877809|doi=10.1515/9783110436600-012}} via processes mediated by enzymes related to vitamin B₁₂.{{cite journal | title = Biomethylation of Arsenic in an Arsenic-rich Freshwater Environment |author1=Toshikazu Kaise |author2=Mitsuo Ogura |author3=Takao Nozaki |author4=Kazuhisa Saitoh |author5=Teruaki Sakurai |author6=Chiyo Matsubara |author7=Chuichi Watanabe |author8=Ken'ichi Hanaoka | journal = Applied Organometallic Chemistry | volume = 11 | issue = 4| pages = 297–304 | year = 1998 | doi = 10.1002/(SICI)1099-0739(199704)11:4<297::AID-AOC584>3.0.CO;2-0|doi-access=free }} For example, the mold Scopulariopsis brevicaulis produces significant amounts of trimethylarsine if inorganic arsenic is present.{{cite journal | first = Ronald | last = Bentley |author2=Chasteen, Thomas G. | title = Microbial Methylation of Metalloids: Arsenic, Antimony, and Bismuth | journal = Microbiology and Molecular Biology Reviews | year = 2002 | volume = 66 | issue = 2 | pages = 250–271 | doi = 10.1128/MMBR.66.2.250-271.2002 | pmid=12040126 | pmc=120786}} Biomethylation of arsenic compounds starts with the formation of methanearsonates. Thus, trivalent inorganic arsenic compounds are methylated to give methanearsonate. S-adenosylmethionine is the methyl donor. The methanearsonates are the precursors to dimethylarsonates, again by the cycle of reduction (to methylarsonous acid) followed by a second methylation.{{cite journal |author1=Styblo, M. |author2=Del Razo, L. M. |author3=Vega, L. |author4=Germolec, D. R. |author5=LeCluyse, E. L. |author6=Hamilton, G. A. |author7=Reed, W. |author8=Wang, C. |author9=Cullen, W. R. |author10=Thomas, D. J. |year=2000 |title=Comparative toxicity of trivalent and pentavalent inorganic and methylated arsenicals in rat and human cells |journal=Archives of Toxicology |volume=74 |issue=6 |pages=289–299 |doi=10.1007/s002040000134 |pmid=11005674 |s2cid=1025140}} This dimethyl compound is cacodylic acid {{nowrap|((CH₃)₂AsO₂H),}}

The organic compound arsenobetaine, a betaine, is found in some marine foods such as fish and algae, and also in mushrooms in larger concentrations. The average person's intake is about 10-50 μg/day. Values about 1000 μg are not unusual following consumption of fish or mushrooms. But there is little danger in eating fish because this arsenic compound is nearly non-toxic.{{cite journal | title = Arsenic speciation in the environment | first = William R. | last = Cullen |author2=Reimer, Kenneth J. | journal = Chemical Reviews | year = 1989 | volume = 89 | issue = 4 | pages =713–764 | doi = 10.1021/cr00094a002| hdl = 10214/2162 | hdl-access = free }} Arsenobetaine was first identified in the Western rock lobster{{cite journal | title = Arsenic Species in Marine Samples | first1 = Kevin A. | last1 = Francesconi | first2 = John S. | last2 = Edmonds | journal = Croatica Chemica Acta | volume = 71 | issue = 2 | pages = 343–359 | year = 1998 | url = http://public.carnet.hr/ccacaa/CCA-PDF/cca1998/v71-n2/CCA_71_1998_343_359_FRANCES.pdf | url-status = dead | archive-url = https://web.archive.org/web/20080309143755/http://public.carnet.hr/ccacaa/CCA-PDF/cca1998/v71-n2/CCA_71_1998_343_359_FRANCES.pdf | archive-date = 2008-03-09 }}{{cite journal | title = Isolation, crystal structure and synthesis of arsenobetaine, the arsenical constituent of the western rock lobster panulirus longipes cygnus George | author = John S. Edmonds | author2 = Kevin A. Francesconi | author3 = Jack R. Cannon| author4 = Colin L. Raston| author4-link = Colin L. Raston | author5 = Brian W. Skelton | author6 = Allan H. White | name-list-style = amp | journal = Tetrahedron Letters | volume = 18 | issue = 18 | pages = 1543–1546 | year = 1977 | doi = 10.1016/S0040-4039(01)93098-9 }}

Saccharides bound to arsenic, collectively known as arsenosugars, are found especially in seaweeds. Arsenic containing lipids are also known.{{cite journal | title = Arsenic-Containing Long-Chain Fatty Acids in Cod-Liver Oil: A Result of Biosynthetic Infidelity? |author1=Alice Rumpler |author2=John S. Edmonds |author3=Mariko Katsu |author4=Kenneth B. Jensen |author5=Walter Goessler |author6=Georg Raber |author7=Helga Gunnlaugsdottir |author8=Kevin A. Francesconi | journal = Angew. Chem. Int. Ed. | volume = 47 | issue = 14| pages = 2665–2667 | year = 2008 | doi = 10.1002/anie.200705405 | pmid=18306198}} Although arsenic and its compounds are toxic for humans, one of the first synthetic antibiotics was Salvarsan, the use of which has long been discontinued.

The only polyarsenic compound isolated from a natural source is arsenicin A, found in the New Caledonian marine sponge Echinochalina bargibanti.{{cite journal | doi = 10.1002/chem.200600783 | title = On the First Polyarsenic Organic Compound from Nature: Arsenicin a from the New Caledonian Marine SpongeEchinochalina bargibanti | year = 2006 | last1 = Mancini | first1 = Ines | last2 = Guella | first2 = Graziano | last3 = Frostin | first3 = Maryvonne | last4 = Hnawia | first4 = Edouard | last5 = Laurent | first5 = Dominique | last6 = Debitus | first6 = Cecile | last7 = Pietra | first7 = Francesco | journal = Chemistry: A European Journal | volume = 12 | pages = 8989–94 | pmid=17039560 | issue=35}}

Organoarsenic compounds may pose significant health hazards, depending on their speciation. Arsenous acid (As(OH)₃) has an LD50 of 34.5 mg/kg (mice) whereas for the betaine (CH₃)₃As⁺CH₂CO₂⁻ the LD50 exceeds 10 g/kg.

Some illustrative organoarsenic compound are listed in the table below:

• Arsenic biochemistry
• Arsenic poisoning
• :Category:Arsenic compounds

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