Textbook Errors, 127: Alfred S. Levinson Portland State University Portland. Oregon 97207
The Structure of Salvarsan and the Arsenic-Arsenic Double Bond
The studv of oreanoarsenic comoounds is a relatively old branch of chemiscy. Therefore, itshould not he surprising that early workers, lacking modern instrumentation as well as modern structure theory, made erroneous structure assienments. What is surprisina, however, is that some of these erroneous structures may hefound in current textbooks. Interestingly enough, an erroneous structure assignment played a role in the development of the whole field of organoarsenic chemistry. Bechamps, in 1863, reported that heating aniline with aniline arsenite produced the anilide of arsonic acid (I). The suhstance, in the form of the sodium salt, was
of the mono and the disodium salts of the phenolic hydroxyl
..erouns. . Although the monosodium salt was more toxic than
the disodium salt, the mixture was rerommended because of had effects from the excess sodium hydroxide required to form the disodium salt exclusively (2).~ijectionscontaining solid material (presumably free base) were not uncommon despite condemnation of this procedure by recognized authorities. The inconvenience involved in the preparation of the injectable solution led to the development by Ehrlich of two water soluble preparations. One was the solid disodium salt of arsphenamine. It was apparently sensitive to air oxidation and did not become widely used. A second water soluble oreoaration known as neoarsphenamine, Neosalvarsan, or 914, did become widely used. Its acceptance into medical practice mav have occurred simolv because it did not require hasificatfon after dissolution.'^; the end of the arsenical era in the late 1930's, it was considered to he inferior t o arsphenamine (3).Neoarsphenamine was prepared by treatment of arsphenamine with "sodium formaldehyde sulfoxylate" (HOCH20SO-Na+ or CH20.NaHS02)and was assigned structure (V). As early as 1921 it was known that the per cent arsenic
..
I
found to he toxic to some trypanosomes and was introduced into medical practice as Atoxyl early in this century. Paul Ehrlich found evidence of a free amino group in Atoxyl and revised the structure assignment to (11). The new structure o-
N.'
was not accepted by several chemists in Ehrlich's laboratory and they quit rather than work under what they considered to he a false oremise ( I ) . Ehrlich. huildina- on the correct structure for Atoxyl, went on to prepare a series of compounds fur hioloeiral testine. The -. including- manv- organoarsenicnls. 606th compound in this series was found to he.effective in treatment of svohilis. This compound, known as Salvarsan, arsphenamine;or 606,was first irepared by reduction of 3nitro-4-hydroxyhenzenearsonicacid (111) and was assigned structure-(IV).I~can he prepared by a numher of other reactions as well.
The drug was marketed as the dihydrwhloride salt hecawe the free base was believed to be unstahle.'l'his salt.although water soluhle, was too toxic to use directly. Aqueous saline solutions of thedihvdrochloride salt had to be prepnred and treated with sodium hydroxide immediately heforeinjection. This procedure yielded first a suspended solid, presumably the free base, and finally a solution believed to he a mixture -
Suggestionsof material suitable for this column and guest columns suitable for publication directly should he sent with as many details as possible, and particularly with reference to modern textbooks, ta W. H. Eberhardt, School of Chemistry, Georgia Institute of Technology, Atlanta, Georgia 30332. Since the purpose of this column is to prevent the spread and continuation of errors and not the evaluation of individual teats, the sources of enors discussed will not be cited. In order to be presented, an error must nceur in at least two independent recent standard books.
found in neoarsphenamine did not correspond to structure (V). The average value of ahout 20% arsenic indicated a t that time a mixture of a mono and disuhstituted ("formaldehyde sulfoxylated") anphenamines (4). Reports of variations in toxicity and solubility of different preparations of both arsphenamine and neoarsphenamine suggested that neither preparation was a pure suhstance. Direct evidence that this was the case was reported in 1941 from dialysis experiments. Using several different semipermeable membranes with graded porosities, it was shown that neoarsohenamine.. arsphenamine hvdrochloride, and alka. lanized arsphenamine could each beseparated into fractions with molecular weights varying from less than 500 to over 35,000 (5).Kraft and coworkers obtained molecular weights from viscosity measurements which agree in part with the higher valuei(6). I t has also been reported that the method of reduction of 3-nitro (or amino)-4-hydroxyhenzenearsonic acid (111) affects both the water solubility and the viscosity of the resulting solution. Reduction with hypophosphite yields a water insoluble product hut reduction at a lead cathode yields a readily soluble product (7). Thus, all the evidence now available suggests that arsphenamine may he described as a mixture of polymeric material containing only arsenic-arsenic sinele bonds and mav he represented as shown in (IV). ~ e o a r s ~ h e n a m i nprepared e, from arsphenamine, would he represented similarly to (VI) hut with some of the amino
groups derivitized. No evidence exists for the arsenic arsenic double bond (the arseno -moue) as the basic structural feature of these compounds. Other com~oundsthoueht to contain the arseno noup have been preparid by a number of methods. These methods include oxidation of the currespondiny arsine and condensation of arsines and dihaloarsines (eqn. (1)) and arsines and arsenoso compounds (eqn. (2)). The latter condensation (eqn. (2)) bears a resemblance to the condensation of a primary amine and a nitroso group to form an azo group. This analogy between the arseno group and the azo group no doubt lent credence to the proposed arseno group. 2RAsC11 + 4R12AsH R - As = AsR1(?)+ 2R2As- AsR1~(?)+ 4HCI (1)
-
R-AsH~+R~-As=O-R-~=~R~(?)
(2)
Evidence that the structures of arseno compounds were not as first depicted came first from molecular &eight determinations. In 1926 Steinkopf and coworkers reported a molecular weight for arsenomethane that corresponded to a cyclic compound with a ring of five arsenic atoms, each bearing a methyl group (8).Palmer and Scott in 1928 confirmed these results for arsenomethane (9). They also found that the molecular weight of arsenobenzene varied with the solvent used for the determination (9). For instance, ebullioscopically in carbon disulfide they observed mol wt 334, cryosropically in naphthalene, 642, and in benzene, 402 (Calcd for (C,;H5As)z; 3041. did ronclude. however. that, "The custom of rep~. Thev ~, resentiny all anen0 vompounds by the general formula RAs=As- -R is unjustified." Blirke and Smith determined the molecular weights nf a number of aromatic arseno compounds ehulliosru~icnllyand found that the molecular weights ohserved weie from 2.94 to 3.49 times the values calculated on the basis of monomeric structures (10). These data demonstrated as early as 1926 that in solution at least, a number of "arseno" compounds were neither monomeric nor polymeric and that they could not contain a simple arsenic-arsenic double bond. The solution of the structure problem for nonpolymeric "arseno" compounds came from X-ray crystallography. Arsenobenzene was shown to have a colorless crystalline form which is a six membered, chair-shaped ring of arsenic atoms, each bonded to a phenyl group (VII) (11-13). A yellow form
rungs is considerably longer, 2.9 A, and may be the first evidence for a fractional arsenic-arsenic bond. The polymers are semiconductors and show photoconductivity as well (20). An improved synthetic procedure has been reported and several analogs have been prepared (20). The trifluoromethyl analog of arsenomethane exists in two ring sizes, a ring of four arsenic atoms and a ring of five arsenic atoms (21,22). Extensive structure studies using modern tools of analysis have failed to reveal the existence of an arsenic-arsenic double bond in a simple organo-arsenic compound. The closest known relative to the "arseno" group occurs in a complex prepared from (CsF&s)4 and Fe(C0)e. X-Ray structure determination of the product Fe(C0)4(AsCsF5)2reveals an arsenic-arsenic bond length of 2.388 A, significantly shorter than the As-As distances in (AsMe)5 (2.428 A) and (AsPh),j (2.456 A). The arsenic-arsenic bond occupies one of the ligand sites around the central iron atom (X) (23). All other available structural data on "arseno" compounds are consistent with either polymeric structures or, in at least 18 different compounds, cvclic structures of four, five, or six arsenic atoms (24). The cvclic structures are now called cyclopulyarsines. The question of why some urganoarsenic cumpounds exist as nolv&ers and others as simple rines remains unanswered. , Also, the factors that determine ringsize are yet to be elucidated. But it is clear that the simple arsenic-arsenic double bond is not known a t this time.
.
General Reference h ~ k ,~ ~. , . ~ Freedman.L. n d D., "OrgenomctsllicCmpoundsofAmenic, Antimony,and Bism"th,"John Wi1.y and Sons.Inc.,NevYark, 1970.
Lllerature Cned
described as a linear polymer has been reported as well as other forms for which crystal structures are not known ( 1 4 ) . Even more information is available on arsenomethane. This material exists as a yellow oil, mp 1 2 T , which spontaneously chanees to a red solid in air. In addition. n dark ~ u r o l esolid. mp 2i)4-2050~(decomposition), has r&ntly &n prepared (15,16). The decomposition products from the purple form are the other two forms, which are in equilibrium with it. Low temperature X-ray diffraction study of a crystal of the mp 12°C material showed a ring of five arsenic atoms, each substituted with a methyl group (VIII) (17). This result was in complete agreement with the proposal of Steinkopf in 1926 (8). The red solid form showed the presence of arsenic-arsenic single bonds on X-ray powder analysis but further structural details were not revealed (18). The purple solid form has been studied in detail and has an unusual ladder structure and can be considered a stack of CH3-As-As-CH3units (IX) (19). The horizontal or "ladder rung" distanre ia the normal arsenicarsenic single h n d length, 2.4 A; the vertical distance hetween
(1) Marquardt. Martha,"Paul Ehrlieh," Henry Sehuman, New Ynrk, 1951, p. 141-145. (2) Mrnre, J. E., '"TheM d m n Treatment ofSyphilis." 2nd Ed.. C. C. Th
