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Chemistry of Arsenic The chemistry of arsenic is a very extensive subject.735 This chapter is limited to a description of the chemistry of arsenic compounds that have potential environmental importance. A list of these compounds is given in Table 2-1. In the natural environment, arsenic is rarely encountered as the free element. More frequently it is a component of sulf~dic ores, in which it occurs as metal arsenides, e.g., nickel diarsenide, cobalt diarsenide, nickel arsenide, cobalt arsenide sulfide, copper arsenide sulfide, and iron diarsenide. Arsenates of aluminum, barium, bismuth, calcium, cobalt, copper, iron, lead, magnesium, manganese, uranium, and zinc also occur naturally, along with arsenic trioxide, which is formed as the weathering product of arsenides. Realgar (tetraarsenic tetrasulf~de) and orpiment (arsenic trisulfide) are naturally occurring sulfides of arse- nic.765 In one form or another, arsenic is present in rocks, 603 in soils,307 in water,435 and in living organisms92 in concentrations of parts per billion to parts per million. The commercial use and production of inorganic and organic arsenic compounds have raised local concentra- tions of this element in the environment much above the natural background concentrations. 4

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Chemistry of Arsenic TABLE 2-1 Arsenic Compounds of Environmental Importance s Arsenic tnoxide Arsenic pentoxide o-Arsenous acid o-Arsen~c acid m-Arsenous acid Salts of arsenous acid: arsenates Salts of arsenic acid: arsenates Tetraarsenic tetrasulfide Arsenic tmsulfide Arsenic pentasulfide Methanearsonic acid Cacodylic acid Tnmethylarsine oxide Methyldihydroxyarsine Dimethylhydroxyarsine Tnmethylarsine Arsanilic acid 3-Nitro-4-hydroxyphenyl . . arson ac~a 4-Nitrophenylarsonic acid Carbarsone Melarsoprol Bis(carboxymethylmer- capto) (D-carbamoyl- phenyl) arsine, disodium salt 10, 10-Bis-(phenoxarsine) oxide ARSENIC TRIOXIDE Arsenic trioxide is the primary product of arsenic smelters. This oxide has direct applications in industry e.g., as a glass decolorizing agent. Other commercially useful organic and inorganic arsenic derivatives are prepared from it. Arsenic trioxide has been reported to exist in three allotropic modifications. The cubic form, arsenolite, is stable below -13 C. At higher temperatures, there is the monoclinic form, claudetite. An amorphous, glassy modification can also be prepared. Because the rate of conversion of the low-temperature cubic form to the monoclinic form is so low, it is possible to heat arsenolite to its melting point of 272 C. Claudetite melts at 313 C. A boiling-point range of 457~65 C has been reported for arsenic trioxide. 32 Arsenolite is made up of As4O6 molecules in which four arsenic atoms occupy the corners of a tetrahedron, with each pair of arsenic atoms joined by a bridging oxygen atom. The As4O6 molecules in arsenolite are arranged in such a manner that their centers occupy the lattice points of a diamond structure. According to Becker and co-workers,59 there are apparently two monoclinic forms of arsenic trioxide (claudetite I and II), in which alternate arsenic and oxygen atoms are linked into sheets, resulting in the formation of open macromolecular structures. In the amorphous, glassy form, the macromolecular structure is similar to that of claude- tite, but irregular. The cubic form is slightly soluble in water. The solubility of arsenic trioxidein 100gofwateris 1.2gatOC, 2.1 gat25C, and5.6gat 75 C. It is claimed that the aqueous solutions have a sweet, metallic taste.664 The rate of dissolution is very low, and several weeks are required to achieve equilibrium. The rate of dissolution of the amor

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6 ARSENIC phous, glassy form is higher than that of claudetite. Arsenic trioxide is slightly soluble in glycerol.32 The compound is not hydroscopic. Arsenic trioxide begins to sublime at 135 C. Vapor-pressure data32 for cubic arsenic trioxide are summarized in Table 2-2. When metallic arsenides or arsenic-containing sulfides are roasted in air, and when arsenic-containing coal is burned, arsenic trioxide is formed. The vapors condense in the flues and on the walls of the stacks as a powder commonly called "white arsenic." Some arsenic trioxide finds its way into the air. Condensation of the vapors on a surface at temperatures above 250 C forms the glassy modification, which slowly changes to the crystalline, monoclinic form.32 ARSENIC PENTOXIDE Oxidation of elemental arsenic or arsenic trioxide by nitric acid, followed by evaporation of the resulting mixture and dehydration of the residue, yields white hydroscopic crystals of arsenic pentoxide. Thermal decomposition of the pentoxide converts it to the trioxide with concurrent loss of oxygen. The pentoxide, in contrast with the trioxide, is very soluble in water; 630 g of arsenic pentoxide dissolve in 100 g of water. 32 ARSENOUS AND ARSENIC ACIDS Presumably, when arsenic trioxide is dissolved in water, the solution contains o-arsenous acid, H3AsO3. When As4O6 was dissolved in an acidic aqueous solution, only the undissociated species, As(OH)3, was detected.745 Raman spectral and nuclear-magnetic-resonance studies48i indicate that, unlike the phosphorous acid molecule, which has both hydrogen-phosphorus and hydrogen-oxygen bonds, all the hydrogen atoms in arsenous acid are linked to oxygen atoms. Arsenous acid cannot be isolated. On evaporation of its solutions, arsenic trioxide is obtained. The successive pKa values for As(OH)3 have been reported as 9.23,~3 12.13, and 13.40.434 In alkaline solution, the anions AsO(OH)2-, AsO2(OH)-2, and AsO3-3 might be present. However, it has been claimed that the m-arsenite ion, AsO2-, is also present in such solutions. 32 o-Arsenous acid and m-arsenous acid could form as products of the hydrolysis of As4O6. By analogy with the phosphorus compound, the meta acid would be expected to be polymeric. However, the arsenic

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Chemistry of Arsenic Temperature, C TABLE 2-2 Vapor Pressure of Cubic Arsenic Trioxidea Vapor Pressure, torr 100 120 140 160 180 200 220 240 260 0.000266 0.00180 0.01035 0.0473 0.186 0.653 2.065 5.96 15.7 aData from Smells Handbuch.32 7 oxygen-arsenic bond is known to possess extreme hydrolytic instabil- ity. Hence, the monomeric ortho form would be expected to be the predominant species.48i 745 This question merits additional investiga- tion. The existence of the As+3 cation in aqueous solution does not appear to have any experimental support. Reactions of the type shown below conceivably occur, but experimental evidence is lacking, even in strongly acidic solution. ~ 70 H2O + HO- + AsO+ ~ As(OH)3 ~ As+3 + 30H-. The extraction of arsenous acid from water by amyl alcohol has been reported. 32 The hydroxides of iron(II) or iron(III), chromium, and aluminum readily absorb arsenous acid.32 o-Arsenic acid, H3As04, can be prepared in the form of a white crystalline solid, H3AsO4 /HO. This is the product formed when arsenic trioxide is dissolved in nitric acid and the solution is evapo- rated. It is a fairly strong acid, with pKa values reported as 2.20, 6.97, and 1 1.53.256 Arsenic acid is an oxidizing agent in acid solution, with an E value of 0.56 V for the reaction:~69 H3AsO4 + 2H+ + 2e-~HAsO2 + 2H2O. (lfHCl*) * 1 formal hydrogen chloride.

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8 ARSENIC It is generally agreed that trivalent arsenic is considerably more toxic than pentavalent arsenic, so the question of whether arsenic exists in aqueous media in the form of arsenite or arsenate i.e., AsO3-3 or AsO4-3 is very important. Thermodynamic calculations732 indicate that, in oxygenated ocean water, the ratio of the activity of arsenate to that of arsenite should be 1026: 1. An Eh-pH stability diagram has been published (Figure 2-1~. However, the ratios found in ocean water393 were in the range 0.1: 1 to 10: 1. Several reports have claimed that bacteria are capable of reducing arsenate to arsenite in fresh and ocean water. 393 ARSENITES AND ARSENATES Arsenites of the formulas MH2As03, M2HAs03, and M3AsO3 are known. In these formulas, M represents a univalent metal cation or one 0.75 1 0.5 ~34s o4 0.25 H2AsO4 H3A' 'I., o -0.25 -0.5 -0.75 ~ \ \ ~ I, W>'^ HAso2~ - HAsS2 ~ ~\ ' ~ ~ HAsO (At - ~~~ AsH3(: ASH, I my, 0 2 As03 , 8 10 12 14 4 6 pH FIGURE 2-l The Eh-pH diagram for arsenic at 25 C and l arm, with total arsenic l 0-5 mol/liter and total sulfur l O-3 mol/liter. Symbols for solid species are enclosed in parentheses in cross- hatched area, which indicates solubility less than 1O-5 mol/liter. Eh = standard oxidation-reduction potential. Reprinted with per- mission from Ferguson and Gavis.249

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Chemistry of Arsenic 9 equivalent of a multivalent cation. The alkali-metal arsenites are freely soluble in water, the alkaline-earth arsenites are slightly soluble, and the heavy-metal arsenites are insoluble. Scheele's green (cupric arse- nite), whose formula has been reported to be Cu(As0212 and CuHAs03, is an example of an insoluble arsenite. Arsenic acid forms a corresponding series of salts that have similar solubility properties. Commercial lead arsenate, used as an insecticide, consists of PbHAsO4 and some Pb3(As0412. The pH of a saturated solu- tion of PbHAsO4 containing 0.22 mg/liter at 25 C is 4-5. The solubility product constant83 for Pb3(As0412 has been reported to be 10-35. Commercial calcium arsenate, also used as an insecticide, consists of 61~o calcium arsenate and 9% calcium arsenite (of variable composi tion,. 34 Condensed arsenates or arsenites, which are salts of polyarsenic or polyarsenous acids or a corresponding meta acid, are known in the solid state, such as dipotassium hydrogen arsenate, tetrapotassium diarsenate, and potassium m-arsenate. The arsenic-oxygen-arsenic h``n`1 in these compounds has extreme hydrolytic instability. It is ~ ~ ~ ~ ~ ~ ~s ~ ~ therefore very unlikely that any species con~a~rllng a~ a~ ~- oxygen-arsenic group can be present in aqueous media in appreciable concentration.745 The above-mentioned hydrolytic instabilities are im- portant and must be taken into account whenever the replacement of the biologically ubiquitous phosphate groups by arsenate is considered. ~ ~ ~ an; ~ ESTERS OF ARSENOUS AND ARSENIC ACIDS Neutral esters of arsenous acid or arsenic acid, such as triorganyl arsenite and triorganyl arsenate, can be prepared, provided that the reaction products are protected from the action of moisture and acidic compounds.745 The arsenic-oxygen-carbon bond also has consider- able hydrolytic instability. Esters of these acids are therefore not stable in aqueous media. Because these acids have three hydroxyl groups that can react with alcohols, three series of esters could be formed- ROAs(OH)2, (RO)2AsOH, and (R0~3As. It seems, however, that monoesters and diesters of arsenous acid and of arsenic acid have never been isolated. 745 1 ,2-Dihydroxyalkanes and 1 ,3-dihydroxy- alkanes react with arsenic trioxide to form cyclic esters.234 Because there are similarities between arsenic acid and phosphoric acid, the possibility that arsenate can replace the important phosphate group in biologically essential molecules (such as the monosaccharide phosphates and adenosine triphosphate) must be considered. How- ever, arsenic acid esters are much more easily hydrolyzed than phos

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0 ARSENIC phoric acid esters. It has been postulated 869 that the glucose-enzyme complex, which generally reacts with phosphate to produce glucose- 1-phosphate, can also interact with arsenate. The glucose arsenate thus formed is immediately hydrolyzed, regenerating glucose that cannot take part in further reactions unless it is rephosphorylated. The compe- tition between arsenate and phosphate has been proposed in many other enzymatic reactions.484 8~5 ARSENIC SULFIDES Because of the low solubility of arsenic sulfides under conditions prevalent in anaerobic aqueous and sedimentary media containing hydrogen sulfide, these compounds may accumulate as precipitates and thus remove arsenic from the aqueous environment. The most important sulfides of arsenic are realgar, orpiment, and arsenic pen- tasulf~de. Realgar occurs in nature as an arsenic ore. The arsenic trisulf~de and pentasulfide are formed when hydrogen sulfide reacts with trivalent or pentavalent inorganic arsenic compounds in the presence of hydrochloric acid. Saturated solutions in distilled water contain sulfide at approximately 4 x 10-6 mol/liter. The solubility in water containing hydrogen sulfide is somewhat lower, but of the same order of magnitude. In alkaline solution, the sulfides dissolve, with formation of thioarsenites or thioarsenates. These sulfides are decom- posed by cold water in the absence of hydrogen sulfide within several days, mainly with formation of arsenic oxides, hydrogen sulfide, and sulfur. The sulfides are generally stable in air at room temperature, but realgar is highly susceptible to attack by oxygen under illumination. At higher temperatures, the sulfides of arsenic react with oxygen.33 ORGANIC ARSENIC COMPOUNDS A very large number of arsenic compounds that contain one or more arsenic-carbon bonds have been synthesized. The large variety of compounds is made possible by the property of the arsenic atom to bond from one to five organic groups, aromatic or aliphatic. The valences not used in bonding organic groups can be linked to other atoms and groups. Such compounds may contain trivalent or pentava- lent arsenic atoms or be onium derivatives of arsenic. Table 2-3 lists the most important general types of organic arsenic compounds.

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Chemistry of Arsenic TABLE 2-3 Important Classes of Organic Arsenic Compounds RAsX2 ~ R2ASX J RBAs [R~As]+X R5As (RAsY)n R2AS-X-ASR2 R3AsY l~AsX2 RAsO(OH)2 R2AsO(OH) 11 X = H. halogen, NR2, OR, SR, SeR, alkali metal, pseudohalogen Tr~organylarsine Tetraorganylarsonium salt (X = uninegative anion) Pentaorganyl arsenic Y = 0, S. NH, NR X = 0, S. Se, NR Y = 0, S. Se, Te, NR X= halogen Arsonic acid Diorganylarsinic acid The organic arsenic compounds that have environmental importance are those that contain methyl groups, the aromatic arsenic deriva- tives used as feed additives and in veterinary medicine, and a few others that may be important in biologic cycles. METHYLATION OF ARSENIC COMPOUNDS It has been known for almost 100 years that inorganic arsenic com- pounds, such as cupric arsenite and copper acetoarsenite, can emit a poisonous gas. i36 This gas, trimethylarsine, is formed by the action of molds. Challenger demonstrated that Penicillium brevicaule can con- vert arsenic trioxide and arsenites to trimethylarsine.~38 i39 With al- kylarsonic and dialkylarsinic acids, mixed alkylmethylarsines were obtained.~37 ~40 The reduction and methylation of arsenate by Methanobacterium under anaerobic conditions were reported by McBride and Wolfe.527 The arsenate is presumably reduced to arsenite, which is then methyl- ated to methylarsines. Wood872 studied the synthesis of dimethylar- sine from arsenate in a reaction that requires methylcobalamin and methane synthetase. Schrauzer et al.707 showed that methylarsine, dimethylarsine, arsine, and methane were produced from methyl- (aquo~cobaloxime-As2 O3-DTE in water. Methylarsine was also obtained from H3AsO4-DTE-methylfaquo~cobaloxime in the presence of Zn/NH4Cl. These authors suggested a reaction between As+3 and CH3- (from the cobaloxime) to produce CH3As+2. However, because

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12 ARSENIC the existence of As+3 cations in aqueous solution is very unlikely, a displacement reaction of the following type appears to be more likely: CH3- + As(OH)3 ~ CH3As(OH)2 + OH . methyldihy- droxyarsine METHANEARSONIC ACID Methanearsonic acid is an herbicide for some grass species. Very little is known about the molecular interaction of this acid or its salts with biologically important compounds. The known chemistry of methane- arson~c acid is outlined in Figure 2-2 to point out which compounds could be formed from it. Methanearsonic acid is a dibasic acid465 with pKa values of 4. 1 and 8.7 and can form neutral and acidic salts. The alkali-metal salts are soluble, whereas the heavy-metal salts are insoluble in neutral and mildly acidic media. Methanearsonic acid undergoes dehydration above 130 C to a polymeric anhydride. 56 Differential thermal analysis of disodium methanearsonate showed that complete combustion was achieved at 660 C.42~ Arsonic acids can be mistermed with alkanols and dials under anhydrous conditions. The esters are very easily hydrolyzed. It should be noted that aliphatic arsonic acids react with hydrogen sulfide to give CH3 AsO3 M2 or CH3 AsO3 HM 1 Base or Metal Salt As2O3,CO2 ~H2SO4 cone. ~ i/ (CH3 )2As2S3 ~CS2 CH3ASI2 ~HI H2 S ~ (CH3 AsS2 )n / CH3 OH o ~ ~ CH3 As(OCH3 )2 J/ Kl,' ~ ~ -CH3 AsO3 H2 -ala J ~ (CH3 AsO2 )n at\\ SO2 /HX ~ CH3 AsX2 H3PO2, SnCl2, NaHSO3 or Na2 S2 O4 ~ (CH3AS)n (CH3AsO)n ~SO2 / \ Zn/HCl,NaBH4 ~ CH3ASH2 FIGURE 2-2 Reactions of Methanearsonic acid.

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Chemistry of Arsenic 13 sulfur-contain~ng arsenic compounds. Thiols have been shown to con- vert arsonic acids to organylbistalkylthio~arsines (K. J. Irgolic, per- sonal communication). This reaction merits serious consideration. It is known that trivalent arsenic compounds interact with protein thiol groups (as discussed later), inactivating, for instance, enzymes. Pen- tavalent arsenic compounds, such as methanearsonic acid, have thus far not been shown to react with thiol groups in biologic systems, but might be able to. If the conversion of methanearsonic acid to methyl- bistalkylthio~arsine, which has been carried out in the test tube (K. J. Irgolic, unpublished results), also occurs in a cell, disturbance of enzyme activities is very likely. For methanearsonic acid to be trans- formed to dimethylarsine or trimethylarsine, a reduction of the pen- tavalent compound within the biologic system must occur. Very little is known about the mechanism of this reduction. DIMETHYLARSINIC ACID Dimethylarsinic acid (cacodylic acid) and its salts find widespread use as postemergence contact herbicides. It is very similar in its reactions to methylarsonic acid. The arsenic-carbon bonds are very stable, but are cleaved by heating with solid sodium hydroxides or chromium trioxide.~7 The acid has a pKa value of 6.2.4 In strongly acidic solu- tion, cacodylic acid exhibits basic properties and forms adducts with mineral acids.396 The reactions of cacodylic acid are summarized in Figure 2-3. It has been pointed out that cacodylic acid reacts with (CH3)2 AsI (CH3)2AsOOH HX ~HX~ (CH3)2Asx ~SO2/HX SO2 /H2 SO4 [(CH3)2AS]2o ~' / \ (CH ) H NaBH4'Zn/HC} / ! (CH3)4 AS2 M+n ~ Salts HI / ROH \1// H S (CH3).ASOOH 2 (CH3)2ASo(oR) ~(CH3 )4 AS2 S2 (CH3)2 AsSSH (CH3)2 AsOSH RSH ~ (CH3)2 AsSR FIGURE 2-3 Reactions of cacodylic acid.

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14 ARSENIC HSCH2CONH248 and HSCH2CH(NH2)COOH424 to produce the triva- lent arsenic derivatives R2As-SR'. ALKYLARSINES AND DIALKYLARSINES Alkylarsines and dialkylarsines have been detected as products formed by the reduction and methylation of inorganic and methylarsenic acids. They have also been used in experiments to elucidate their effects on biologic systems.383 Methylarsine is a gas at room temperature. The alkylarsines are sensitive to oxygen but are not spontaneously flamma- ble in air.200 6~9 They are unreactive to water. ~99 A saturated solution of methylarsine in water contains arsine at 80 ppm.~98 Alkali-metal hy- droxides have no effect on alkylarsines. ~99~332 In the absence of oxygen, alkylarsines are thermally stable. Methylarsine was kept at 240 C for 3 h without decomposition. ~99 The products of oxidation of alkylarsines are (RAs~n, (RAsO)n, and RAsO3H2, depending on the reaction condi- tions. Dimethylarsine is an air-sensitive liquid that boils at 36 C. It bursts into flame on contact with air. The oxidation products are arsenic acid and arsenic trioxide. ALKYLDIHALOARSINES AND DIALKYLHALOARSINES Alkyldihaloarsines are distillable liquids. They are strongly desiccant and irritating to the nose, throat, and bronchi.467 Because of these properties, 2-chlorovinyldichloroarsine (lewisite), which has been re- ported to have the odor of geraniums,~77 has received considerable attention as a compound suitable as a war gas. Lewisite and similar compounds cause painful, slow-healing blisters on the skin, violent sneezing, and severe pain in the throat and chest.309 Castroi3i found that ethyldichloroarsine inhibits cholinesterase in human plasma. Alkyldihaloarsines hydrolyze on contact with water or moist air, 752 probably forming alkyldihydroxyarsines. However, only arsenosoal- kanes have been isolated from the reaction mixtures. It is important to note that the arsenic-halogen bond hydrolyzes very slowly. This is to be contrasted with the extremely rapid hy- drolysis of the phosphorus-chlorine and antimony-chlorine bonds. Hence, the chlorides of arsenic, both organic and inorganic, are unique among the group VA elements. The painful, slow-healing burns caused when arsenic chlorides come into contact with the skin or the mucous

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Chemistry of Arsenic 15 membranes might be explained as follows: The arsenic halide contacts the tissues and penetrates rapidly and deeply. The arsenic-chlorine bond then undergoes very slow hydrolysis, with the release of hydro- gen chloride. The hydrogen chloride released causes the tissue dam- age. Hence, the arsenic itself may not be the toxic agent in lewisite and related compounds, but it may exacerbate the effect of hydrogen chloride produced. Of great biologic importance are the facile reactions that alkyl- dihaloarsines, alkyldihydroxyarsines, and arsenosoalkanes undergo with thiols. All these compounds easily condense with the sulfhydryl groups to form alkylbistorganylthio~arsines:84~ 884 RAsX2 + 2HSR'~ RAs(SR')2 + 2HX. With l ,2-dithiols and l ,3-dithiols, the very stable 2-arsa- 1,3- dithiacyclopentane and hexanes are produced.76~858 Such reactions may very well take place with the thiol groups of proteins. If thiol groups are present in enzymes, trivalent arsenic compounds can form stable bonds with them, thus preventing the enzymes from functioning properly. The likely reaction between lipoic acid, a building block of the enzyme pyruvate oxidase, and a trivalent alkyldihaloarsine is the following: o E NH C (CH2 )4 ~ S S CoA-SCOCH3 + ~ enzyme ~ ~ 1 S SH C O oxid. ~ CH3 CoA-SH I l SH SH - RASCl2 ~- S_ _S As 1 R British antilewisite (dimercaprol, BAL) reacts similarly with trivalent arsenic compounds.76~ Dialkylhaloarsines and dialkylhydroxyarsines react similarly with thiols, but cannot form the stable neutral ring compounds with dithiols.