Crystalline arsenobetaine hydrobromide is deposited directly on addition of trimethylarsine to a

benzene solution of bromoacetic acid. The product is stable, non-deliquescent and may be readily converted

into the free betaine by passage through basic ion exchange resin

Ismail, Hazar

Toia, Robert F.

Universiti Putra Malaysia Institutional Repository

Pertanika 11(3), 437-439 (1988)Preparation of Arsenobetaine hydrobromideHAZAR ISMAIL1 and ROBERT F. TOIA2Department ofOrganic ChemistryUniversity ofNew South WalesPo. Box 1 Kensington, N.S. W. 2033, Australia.Key words: Arsenobetaine hydrobromide; arsenobetaine; marine organoarsenicals.ABSTRAKHabluran arsenobetaina hidrobromida telah mendap terus apabila trimetilarsina ditambahkan kepadasatu larutan asid bromoasetik dalam benzena. Hasilnya adalah stabil, tak-Iembab air dan boleh ditukarkandengan mudah kepada betaina bebas dengan membenarkan ia melalui resin pertukaran ion berbes.ABSTRACTCrystalline arsenobetaine hydrobromide is deposited directly on addition of trimethylarsine to abenzene solution of bromoacetic acid. The product is stable, non-deliquescent and may be readily con-verted into the free betaine by passage through basic ion exchange resin.INTRODUCTIONSince the first report of arsenobetaine (Edmondset a1. 1977) as a naturally occurring marineorganoarsenical isolated initially from the fleshof the western rock lobster, Panulirus cygnus,numerous workers have reported this compoundfrom a plethora of marine animals. (Ismail1986) In addition, evidence has been obtainedfor the presence of arsenocholine in some marineanimals ( orin & Christakopoulos, 1982) and aseries of arsenosugars have been isolated fromvarious marine algae. (Edmonds & Francesconi,1981)Given its occurrence in human foodstuffs,arsenobetaine has also been the subject of meta·bolic studies. In a preliminary report (Cannonet al. 1983) the compound was shown, in mice,to be non-toxic and rapidly excreted in the urineand faeces. In addition, a negative result wasobtained in the Ames' test for chemical mutagens(Cannon et aI., 1983). Subsequent metabolicstudies have utilised radiotracer techniques, inparti<;ular 74 As labelled arsenocompounds, but insome cases are of questionable value since thework was carried with radiochemically impurematerial (Goetz & orin, 1983).In this note, we report a modified approachto the synthesis of arsenobetaine which is suitablefor adaptation to the preparation of labelledmaterial of high chemical and radiochemicalpurity.MATERIALS AND METHODSGeneralMelting points were determined on a Kofler hotstage and are uncorrected. Infrared spectra wererecorded on an Hitachi Model EPI-G2 instrumentfor KBr discs and nuclear magnetic resonancespectra were recorded on either a Bruker CXP300(300 MHz for IH) or a lEaL FZ100 (25 MHzfor 1 3C) instrument. Chemical shifts are reportedPresent address:Ipusat Asasi Sains, Universiti Malaya, 59100 Kuala Lumpur, Malaysia.2Pesticide Chemistry and Toxicology Laboratory, 201 Wellman Hall, Univeristy of California, Berkeley CA 94720 USA.HAZAR ISMAIL AND ROBERT F. TOIArelative to TMS, for CDC13 solution of 3-(tri-methylsilyl)propane sulphonic acid for D20solution. Dowex 2 x 8 (Cl-) ion exchange resinwas cycled with 5% aqueous HCl, water and 5%aqueous NaOH until the titre was constant. Theresin was washed thoroughly before use.Arsenic AnalysisArsenic analysia of aqueous samples utilised aninductively coupled plasma-atomic emission spec-trometer (Labtam Plasmalab, Melbourne, Austra-lia) monitored at 193.7 nm. The instrument wascalibrated against As standards of 0 and 100 ppmsodium arsenate.SynthesisIododimethylarsine and trimethy1arsine were pre-pared as described in the literature. (Burrows &Turner, 1920; Challenger & Ellis, 1935) Thus,sodium cacodylate (77.6 g) and Kl (160 g) weredissolved in water (300 ml). The solution wascontinuously saturated with S02 whilst HCI(10 M, 142 ml) was added dropwise. The productseparated as it was formed, as a dark yellow oil.Distillation of the dried product gave iododi-methylarsine as a pale yellow oil (73.7 g, 56%b.p. 80-840 C/35 mm (Burrows & Turner, 1920:154-1570 C/760 rom). Iododimethylarsine (68.4 g)in di-n-butyl ether (100 ml) was added dropwiseto methyl magnesium iodide (prepared frommethyl iodide (40.8 g) and Mg (7 g)) in di-n-butylether (100 ml) under an atmosphere of nitrogen.The mixture was stirred continuously whilstmaintaining the temperature at 40 C. On com-pletion of the addition, the_solution was allowedto warm to room temperature and then heated todistil trimethylarsine (24.4 g, 69%, b.p. 540 C(Burrows & Turner, 1920: 51.9-52°C) directly.The product was stored in ampoules under nitro-gen for use as required.Arsenobetaine hydrobromide: Bromoaceticacid (0.41 g) was dissolved in benzene (2.5 ml) andtrimethylarsine (0.5 ml) added dropwise undernitrogen. The solution initially turned green, thenblue and finally colourless at which point a crys-talline solid began to deposit. The reaction mix-ture was left overnight. The solvent was removedand the residue twice recrystallised from metha-nol/acetone to give arsenobetaine hydrobromideas prisms, 0.62 g (81%), m.p. 2480 C decomp.,dependent on the rate of heating). Found C,23.16%; H, 4.60%. CsHlsAsBr02 requires C,23.10%; H, 4.90%. l.R: Vmax 3450, 3050,29502900, 2850, 1715, 1640, 1400, 1365, 1275,1260, 1170, 940, 935, 910, 900, 850 cm- I .IH NMR: 8 1.95 (s, 9H), 3.58 (s, 2H). l3C NMR88.6 (q), 31.3 (t), 170.5 (s).Arsenobetaine picrate: Arsenobetaine hydro-bromide (0.1 g) was dissolved in hot ethanol andan ethanolic solution of picric acid (0.1 g) added.On cooling, crystals of arsenobetaine picrate weredeposited and were recrystallised from hot ethanolas yellow needles, 0.15 g (94%), m.p. 177-1780 C.Found C, 32.37%; H, 3.68%; N, 10.14%.CIIH14AsOgN3 requires C, 32.43%; H, 3.44%;N.IO.14%.Arsenobetaine reineckate: Arsenobetainereineckate was prepared from arsenobetainehydrobromide as described in the literature(Edmonds et aI, 1977) for arsenobetaine. Theproduct was found to be identical in all respectswith an authentic sample.Arsenobetaine: Arsenobetaine hydrobro-mide (1.0 g) was dissolved in distilled water (2 ml)and passed through a column of Dowex 2 (OH-)(100 g). The column was eluted with distilledwater and the fractions analysed for arsenic. Thearsenic-rich fractions were combined and lyophil-lised to yield arsenobetaine as a white solid. Theproduct was dissolved in dry methanol and crys-tallised, on the slow addition of acetone, as whiteprisms, 0.6 g (87%), identical in all respects withan authentic specimen. 13C NMR: 8 8.3 (q),34.4 (t), 172.7 (s).RESULTS AND DISCUSSIONArsenobetaine (1) is an extremely deliquescent,white crystalline compound which has previouslybeen prepared (Edmond et aI, 1977) as shown inscheme 1 path A. In the present work we havemodified this preparation, scheme 1 path B, byreacting trimethylarsine with bromoacetic acid.This leads directly to arsonebetaine hydrobromidewhich crystallises from the reaction mixture as itforms. The hydrobromide is a non-deliquescent,white, crystalline and stable solid. As observed forarsenobetaine (Edmond et aI, 1977) the meltingpoint of the hydrobromide varies with the rateof heating and decomposition accompanies melt-ing.438 PERTANIKA VOL. 11 NO.3, 1988PREPARATION OF ARSE OBETAI E HYDROBROMIDEScheme 1The 13C MR spectra of arsenobetaine andthe hydrobromide in D2 0 solution show onlyminor differences in chemcial shift values as wouldbe anticipated and these differences may beascribed to solution pH differences. The picrateand reineckate derivatives prepared from botharsenobetaine and its hydrobromide were identicalin all respects.With respect to the preparation of radio-labelled compounds, the ease of preparation of thehyrobromide, and more importantly its stabilityand the ease with which it may be recrystallised,make it an ideal compound to work with. More-over 14C-labelled bromoacetic acid is commercial-ly available although a label in the other portionof the molecule is also feasible. In particular,whilst it is possible to use the earlier strategies(Goetz & Norin, 1983) with arsenic isotopes,14C_or 3H-Iabelled trimethylarsine is also feasible.Possible tritium labelling of trimethylarsine isparticularly attractive since this may be effected,in principle, via direct exchange and the productmay be purified by distillation.Since this work is directed in part to astudy of the metabolism of arsenobetaine inmodel marine ecosystems, (Ismail Hazar, 1986)the purified hydrobromide may be used directly.Howver, in studies requiring the free betaine,passage of the salt through a basic ion exchangeresin readily produces arsenobetaine.ACKNOWLEDGEMENTOne of us (HI) acknowledges the Public ServiceDepartment of Malaysia and Universiti Malaya fora scholarship.REFERENCESBURROWS, G.J. and E.E. TURNER. (1920): A new typeof compound containing arsenic. J. Chern. Soc.,117: 1372.CANNON, J.R., J.B. SAUNDERS and R.F. TOIA.(1983) : Isolation and preliminarY toxicologicalevaluation of arsenobetaine-the water-soluble arseni-cal constituent from the hepatopancreas of theWestern Rock Lobster. Sci. Total Environ., 31 : 181.CHALLENGER, F. and L. ELLIS. (1935): Theformation of organo-metalloidal compounds bymicro-organisms part III methylated alkyl- anddialkyl-arsines. J. Chern. Soc. : 396.EDMONDS, J.S., K.A. FRANCESCONI, J.R. CANNON,C.L. RASTON, B.W. SKELTON and A.H. WHITE.(1977): Isolation, Crystal structure and synthesisof arsenobetaine, the arsenical constituent of theWestern Rock Lobster Panulirus logipes cygnusGeorge. Tetrahedron Lett. : 1543; see also Cannon,J.R., Edmonds, J.S., Francesconi, K.A., Raston,C.L., Saunders, J .B., Skelton, B.W. and White,A.H., (1981) : Isolation, crystal stnicture andsynthesis of arsenobetaine, a constituent of theWestern Rock Lobster, the Dusky Shark and somesamples of human urine. Aust. J. Chern., 34 : 787.EDMONDS, J.S and K.A. Francesconi. (1981) : Arseno-sugars from brown kelp (Ecklonia radiata) as inter-mediates in cycling of arsenic in a marine ecosystem.Nature, 289 : 602.GOETZ, L. and H. NORIN. (1983) : Synthesis of 73As-radiolabelled arsenobetaine and arsenocholine formetabolic studies and their fate and distributionin laboratory animals. Int. J. Appl. Radiat. Isot.,34 : 1509.ISMAIL, H. (1986) : Ph.D. Thesis, University of NewSouth Wales.NORIN, H. and A. CHRISTAKOPOULOS. (1982) :Evidence for the presence of arsenobetaine andanother organoarsenical in shrimps. Chernosphere,11 : 287.(Received 7 May, 1988)PERTANIKA VOL. II NO.3, 1988 439

Preparation of Arsenobetaine hydrobromide

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