Chelation therapy: The interaction of British Anti-Lewisite (BAL) with some heavy metal cations of p and d blocks

Abstract

The reaction of BAL with Sn(IV), SnCl₂·2H₂O, Pb(II), Ag(I), Cd(II) and Pd(II) gave water-insoluble solids where BAL coordinated using its two sulfur atoms, BAL(S,S)M, while anhydrous SnCl₂ gave BAL(O,S)Sn. Apart from the Sn(IV) and Ag(I) which should be monomeric, the structure of the other solids (monomeric or polymeric) could not be established. Indium(III) chloride did not react with either thiophenol or BAL in the absence of a base. In the presence of sodium hydroxide under 1:1:1, 1:2:2 and 1:3:3 molar ratios of InCl₃/PhSH/NaOH, the products incorporated the formed sodium chloride and In(SPh)₃ was isolated after aqueous work up in the 1:3:3 case. Thallium(III) aceteate gave Tl-SPh and PhSSPh. Thallium(I) acetate and thallium(I) fluoride also gave Tl-SPh in 100% and 75% yields, respectively. The lower yields with TlF is attributed to the non thiophilic HTlF₂ formed during the reaction. Theoretical calculations of TlF, (TlF)₂ and TlF₂^- revealed a novel structure of (TlF)₂ and shed light to the non thiophilicity of TlF₂^-. Thallium(I) acetate and BAL gave the expected bis salt while the reactions of TlF under various stoichiometries of BAL:TlF were complicated. Summarizing these and previous results it seems that BAL cannot detoxify heavy metal cations by forming water soluble complexes.

Keywords

British Anti-Lewisite (2,3-dimercapto-1-propanol)complexes with heavy metal cations thallium fluorides theoretical calculations

1 Introduction

British Anti-Lewisite (BAL, dimercaprol, 2,3-dimercapto-1-propanol) is an oily α,β dithiol synthesized in Oxford under the direction of Sir Rudolf Peters in 1940 [32] in search of antidotes to various chemical weapons. BAL was introduced by Peters in 1945 against Lewisite (Cl-CH=CH-AsCl₂) [35 , 45]. Although the R and S isomers were later prepared [1], BAL was and is used as a racemic mixture. BAL is effective in vivo (rats, guinea-pigs and man) not only against Lewisite, but also it can reverse the function of mitochondria [36] and E.Coli [40] after treating them with sodium arsenite (NaH₂AsO₃).

Many heavy metal cations deactivate enzymes and can cause metal poisoning in animals and humans. Intensive research in the 1940s, summarized by Stocken and Thompson [41], on enzymes, animals and humans using Sb(III), Bi(III) // Pb(II) // Zn(II), Cd(II), Hg(II) // Cu(II), Ag(I), Au(I) // Ni(II) // Cr(VI) // V(IV) established that BAL can reverse the intoxication by e.g. Hg(II) and Au(I) or can moderate the effect of e.g. Pb(II) and Ni(II). In other cases, e.g. Cd(II), Sb(III), Bi(III) the effect of BAL was controversial or BAL had no effect as in argyria. Despite these uncertainties, BAL is regarded as a prototype in chelation therapy [9, 10] based on chelate formation of the products of BAL with As(III) [23, 41].

It is worth mentioning that BAL treatment increased the urinary excretion of Pb(II), Au(I) and Cu(II) and the urinary plus feces excretion of Cd(II) [41] implying that BAL formed water-soluble complexes with these metal cations.

There are only a few reports on the products formed or isolated from the reaction of BAL with heavy metal cations in vitro. Thus, the reaction of BAL with Ni(II) at 9 < pH < 10 in the absence of air afforded soluble complexes [Ni(BAL)₂]^2 - and [Ni₂(BAL)₃OH]^3 - [28], with Mn(II) the extremely air sensitive water-soluble MnBAL and [Mn(BAL)₂]^2 - were detected [30], while Zn(II) gave the water insoluble ZnBAL that dissolved with excess BAL giving [Zn(BAL)₂]^2 - and polynuclear species [30]. Highly oxygen sensitive, water-soluble mononuclear, [Fe(BAL)₂]^2 -, and polynuclear complexes were obtained with excess BAL [29]. It is not quite clear whether the coordination of Ni(II), Mn(II), Zn(II) and Fe(II) to BAL involves only its sulfur atoms. The conditions used in Leusing’s works may not be biologically relevant because of the presence of dioxygen in tissues. Gold(III) reacted with BAL under various stoichiometries, giving highly insoluble solids in which both Au(III) and Au(I) were detected [5]. BAL reacted in water with Hg(II) giving the insoluble linear polymeric BAL(S,S)Hg [8]. The reactions of BAL with various As(III), Sb(III) and Bi(III) compounds under 1:1 and 2:3 molar ratios of metal/BAL were studied [23]. The metals coordinated to BAL at its sulfur atoms and the products were insoluble in water. When BAL and Cu(II) reacted in water, the insoluble solid was found, indirectly, to have a 1:1 stoichiometry of copper to BAL [47]. Further experiments (P.V. Ioannou et al., in preparation, 2017) revealed that Cu(II) oxidized BAL being reduced to Cu(I) and the products interacted to give a highly insoluble solid that could not be solubilized and the use of BAL for excreting copper in the urine of Wilson’s disease patients is at present poorly understood. Finally, the interaction of BAL with a variety of heavy metal cations [Au(III), Ag(I), Hg(II), Cu(II), As(III), Sb(III), Bi(III), Ni(II), Co(II), Zn(II), Tl(I), Pb(II), Cd(II), Fe(III), Sn(II)] has been studied polarographically and probable structures of the products were formulated [49], not always in accord with those proposed in the literature [5 , 23] and the results showed that Tl(I) was unreactive towards BAL.

Dihydrolipoic acid and its amide, being constituents of important mitochondrial multienzyme complexes such as pyrurate dehydrogenase, are α,γ dithiols and not many studies on their interactions with heavy metal cations have been reported [3, 21]. From the α,δ dithiols, dithioerythritol and dithiothreitol, their interaction with heavy metal cations did not receive much attention [22, 26]. Therefore there is a need for such studies and the results to be compared with those of the α,β dithiol BAL.

BAL being of biological importance for metal detoxification has been studied to a reasonable extent in vitro as described above. In this paper we report on the reaction of BAL with the remaining heavy metal cations of the p-block [Sn(II), Sn(IV), Pb(II), In(III), Tl(III) and Tl(I)] and some of the d-block [Cd(II), Ag(I) and Pd(II)]. The products isolated were studied and probable structures are proposed. Ab-initio theoretical calculations were made on TlF, (TlF)₂ and TlF₂^- in order to explain the low yields of the reaction of TlF with thiols.

2 Experimental section

2.1 Materials

The following chemicals were obtained and used as received. From: Merck: anhydrous crystalline tin(II) chloride, crystalline tin chloride dihydrate, lead acetate trihydrate, thallium(I) acetate, cadmium acetate dihydrate, silver acetate, palladium acetate, chromium(III) chloride hexahydrate, 40% aqueous hydrofluoric acid, thiophenol, and racemic British Anti-Lewisite (2,3-dimercapto-1-propanol) containing by TLC (Et₂O) traces of oxidized BAL at R_f 0.60, BAL running at R_f 0.75; Aldrich: thallium(III) acetate; Alfa: dibutyltin oxide; Alfa Aesar: vanadyl sulfate hydrated; Fluka: indium(III) chloride; Schuchard: thallium(I) fluoride; Ferak: vanadium pentoxide; Riedel - de Häen: chromium(III) chloride.

Silica gel H (Merck) was used for thin layer chromatography (TLC), and no dried solvents were used, except when stated, the drying agent being molecular sieves 4 Å.

2.2 Methods

TLCs were run on microslides and visualization of the spots was done by spraying with 35% sulfuric acid but more conveniently with iodine vapors. The reactions were run in centrifuge tubes, unless otherwise stated, while stirring. All reactions were followed by observing the disappearance of BAL by TLC in Et₂O. Infrared spectra were obtained on a Perkin-Elmer, model 16 PC, FT-IR spectrometer, while ¹H NMR (400 MHz) spectra were recorded on a Bruker DPX Avance spectrometer with internal TMS (0.00 ppm) as standard. Elemental analyses were obtained through the Centre of Instrumental Analyses, University of Patras, Patras, Greece.

2.3 Reaction of BAL with group 14 metal ions

2.3.1 With anhydrous SnCl₂

To a solution of crystalline tin(II) chloride (380 mg, 2 mmol) in methanol (5 mL) in a 10 mL round-bottomed flask was added BAL (200μL, 2 mmol) and the solution stirred at room temperature (RT) for 1.5 h. Evaporation and drying in vacuum gave a viscous oil (673 mg) that solidified when covered with ether and left overnight to give the solvated product 3 BAL(O,S)Sn·MeOH·H₂O (553 mg, 95%) as a white solid insoluble in Et₂O, CHCl₃, MeOH, H₂O and soluble in DMSO. Thermal behavior: at 115C darkens and shrinks, at 143C forms a reddish film which at 146°C turns to brown-black. Calculated for C₃H₆OS₂Sn·MeOH·H₂O (M_r 290.95): C 16.51, H 4.16, S 22.04%; found C 16.57, H 3.96, S 21.85%. IR(KBr): $\bar{ν}$ cm^-1: 3446 vs, broad, 2902 vs, 2525 m, broad, 1616 s, 1406 vs, 1312 m, 1254 s, 1200 s, 1000 s, 970 s, 910 m, 900 m. ¹H NMR (DMSO-d₆, TMS): δ= 2.7–3.1 (very broad signal), 3.17 (s, CH₃OH), 3.86 (broad signal).

2.3.2 With SnCl₂·2H₂O

To a solution of crystalline tin chloride dihydrate (1 mmol) in methanol (3 mL) addition of BAL (1 mmol) and stirring at RT for 1.5 h, gave a clear colorless solution that was evaporated and dried in vacuum to give an oil (365 mg). After treating the oil with ether overnight the solvated BAL(S,S)Sn·1.5MeOH 4 was obtained as a white solid insoluble in MeOH and Me₂CO and moderately soluble in DMSO. Its thermal behavior showed that at 90C shrinks, and at 170C turns black with further shrinking. Calculated for C₃H₆OS₂Sn·1.5MeOH (M_r 288.96): C 18.71, H 4.19, S 22.19%; found C 18.44, H 3.88, S 22.51%. IR(KBr): $\bar{ν}$ cm^-1: 3448 vs, broad, 2968 s, 2904 s, 1610 m, 1406 vs, 1308 m, 1260 s, 1198 s, 1170 s, 1060 s, 1036 vs, 1010 vs, 970 s, 930 m, 894 m, 840 m, 740 m, 518 m. ¹H NMR (DMSO-d₆, TMS): δ= 2.6–3.1 (very broad signals), 3.17 (s, CH₃OH), 3.4–4.0 (very broad signal).

2.3.3 With (Bu₂SnO)_x

In a 25 mL round-bottomed flask was suspended dibutyltin oxide (249 mg, 1 mmol) in methanol (10 mL), BAL (100μL, 1 mmol) was added and refluxed for 3 h giving a clear colorless solution. TLC (Et₂O) showed the product (R_f 0.90) quite close to BAL. Evaporation and drying in vacuum gave the product 1 as a colorless viscous oil (336 mg, 95%), soluble in Et₂O, Me₂CO, MeOH, CHCl₃. Calculated for C₁₁H₂₄OS₂Sn (M_r 355.11): C 37.20, H 6.81, S 18.06 %; found C 37.40, H 6.25, S 17.69 %. IR (neat): $\bar{ν}$ cm^-1: 3382 s, broad, 2954 vs, 2920 vs, 2870 vs, 2852 vs, 1606 w, 1443 vs, 1416 s, 1376 s, 1340 m, 1292 m, 1262 m, 1178 m, 1148 s, 1070 s, 1032 s, 1002 s, 962 m, 896 s, 876 s, 864 s, 770 w, 696 s, 668 s. ¹H NMR (CDCl₃, TMS): δ= 0.92 (t, J 7.3 Hz, 6 H, CH₃), 1.36 (m, 4 H, CH₂CH₂CH₂Sn), 1.49 (m, 4 H, CH₂CH₂CH₂Sn), 1.68 (m, 4 H, CH₂CH₂CH₂Sn), 2.04 (broad, H₂O in CDCl₃), 3.30 and 3.33 (two pairs of doublet of doublets, 2 H, J_AB – 12.8, J_AX 4.89, J_BX 3.27 Hz, SCH_AH_B-CH_XS), 3.50 and 3.57 (m, 2 H, CH₂OH), 3.70 (m, 1 H, CHS).

2.3.4 With Pb(AcO)₂·3H₂O

To a solution of lead acetate trihydrate (379 mg, 1 mmol) in water (3 mL), BAL (100μL, 1 mmol) was added and the yellow suspension stirred at RT for 6 h. Centrifugation, washing with MeOH (1×2 mL) and drying gave the solvated 4 (M = Pb)·H₂O (347 mg, 100%) as a yellow powder insoluble in MeOH, H₂O, and sparingly to moderately soluble in DMSO giving a yellow solution. Thermal behavior: at 115°C shrinks and turns orange and at 140°C shrinks further and turns black. Calculated for C₃H₆OS₂Pb·H₂O (M_r 347.39): C 10.37, H 2.32, S 18.46 %; found C 9.98, H 1.96, S 17.79%. IR (KBr): $\bar{ν}$ cm^-1: 3340, vs, broad, 2866 s, broad, 1636 m, broad, 1410 m, 1258 w, 1218 w, 1048 s, 998 s, 884 w, 656 w, 558 w. ¹H NMR (DMSO-d₆, TMS, 70°C, saturated): δ= 3.40 and 3.54 (two pairs of doublet of doublets, 2 H, J_MN – 10.4, J_MX 4.36, J_NX 8.48 Hz, HO-CH_MH_N-CH_XS), 4.33 and 4.76 (two pairs of doublet of doublets, 2 H, J_AB – 12.4, J_AX 3.60, J_BX 6.80, SCH_AH_B-CH_XS), 4.68 (m, 1 H, CHS).

2.4 Reaction of BAL with some metal ions of d-block

2.4.1 With Cd(AcO)₂·2H₂O

In a round-bottomed flask cadmium acetate dihydrate (267 mg, 1 mmol) was dissolved in water (2 mL) and BAL (100μL, 1 mmol) was added. The white emulsion that was formed, was stirred at RT for 4 h. Evaporation (rotary 45°C) and drying in vacuum gave the solvated 4 (M = Cd)·0.25AcOH (234 mg, 98 %), as a white solid insoluble in H₂O, MeOH and DMSO. Thermal behavior: at ∼220°C starts darkening, at 225°C turns brownish and till 250°C darkens further and at 255°C turns black. Calculated for C₃H₆OS₂Cd·0.25CH₃COOH (M_r 249.62): C 16.84, H 2.83, S 25.69%; found C 16.87, H 2.80, S 25.32%. IR (KBr): $\bar{ν}$ cm^-1: 3376 vs, broad, 2910 s, 1700 m, 1636 m, 1544 s, 1412 vs, 1264 s, 1228 s, 1048 vs, 1004 vs, 892 m, 732 m, 658 s, 618 s, 556 s, 516 s, 452 s.

2.4.2 With AgAcO

The reaction of BAL (1 mmol) with a suspension of silver acetate (2 mmol) in water (3 mL) gave a yellow suspension that was centrifuged, after stirring for 4 h at RT. The yellow solvate was washed with water (2 mL) and the solvate dried in vacuum to give the product 2 as a yellow powder (336 mg, 100%) insoluble in MeOH, H₂O, DMF, DMSO and not photosensitive. Thermal behavior: at 140 till 155°C slowly turns brown and at 160°C shrinks and turns black. Calculated for C₃H₆OS₂Ag₂ (M_r 337.95): C 10.66, H 1.79, S 18.97 %; found C 11.14, H 1.82, S 18.14 %. IR (KBr): $\bar{ν}$ cm^-1: 3318 vs, broad, 2902 s, 1630 m, 1404 m, 1256 m, 1222 m, 1130 w, 1046 vs, 1000 vs, 884 m, 728 w, 668 m, 610 w, 560 w, 520 w, 448 w.

2.4.3 With Pd(AcO)₂

To a solution of palladium acetate (112 mg, 0.5 mmol) in dichloromethane (3 mL), BAL (50μL, 0.5 mmol) was syringed in and the dark brown suspension, formed at once, was stirred at RT for 4 h. Centrifugation and washing with dichloromethane (2×2 mL) gave the solvated product 4 (M = Pd)·0.25AcOH (113 mg, 100 %) as a dark brown solid insoluble in CH₂Cl₂, MeOH, Me₂CO and nearly insoluble in hot DMSO. Thermal behavior: from 230C slowly darkens and turns blackish and at 270C gives a black solid. Calculated for C₃H₆OS₂Pd· 0.25CH₃COOH (M_r 263.42): C 17.26, H 2.90, S 26.32 %; found C 17.11, H 2.77, S 25.82 %. IR (KBr): $\bar{ν}$ cm^-1: 3382 vs, broad, 2912 s, 1700 w, 1616 s, 1458 m, 1410 ms, 1384 ms, 1256 m, 1050 s, 1010 s, 892 mw, 700–400 m, broad.

2.5 Reaction of InCl₃ with thiols

2.5.1 With PhSH in the absence of a base

InCl₃ and xPhSH (x = 1, 2, 3) in dry methanol did not react by TLC (petroleum ether) after 1 h at RT.

2.5.2 With PhSH in the presence of NaOH

2.5.2.a Under a 1:1:1 molar ratio. To a solution of indium(III) chloride (278 mg, 1.26 mmol) in dry methanol (2 mL), thiophenol (129μL, 1.26 mmol) was syringed in and the solution stirred at RT for 1 h. Solid sodium hydroxide (1.26 mmol) was added and stirred at RT for 2 h giving a white light suspension the TLC (petroleum ether) of which showed a faint, elongated spot at R_f 0.40. Centrifugation and washing with dry methanol (1 mL) gave a white solid (23 mg) that was not completely soluble in water indicating that it was not sodium chloride. Evaporation and drying in vacuum of the methanolic supernatant and washing gave a white solid (386 mg, 94% as 5) soluble in MeOH, Me₂CO and DMSO but insoluble in CHCl₃ and H₂O. Thermal behavior: at 220C darkens, at 260C turns brown and at 275°C turns ash-colored (not black). Calculated for C₁₂H₁₀Cl₂OS₂In₂·2NaCl (M_r 651.77): C 22.11, H 1.55, S 9.84%; found C 22.11, H 1.99, S 9.19%. IR (KBr): $\bar{ν}$ cm^-1: 3450 vs, broad, 3060 s, 1622 s, 1576 m, 1474 s, 1436 m, 1080 m, 1022 s, 998 m, 992 w, 732 vs, 694 s, 684 vs, 470 vs. ¹H NMR (CD₃OD, TMS): δ= 7.02 (s, broad, 3 H, meta- and para-PhS hydrogens), 7.36 (s, broad, 2 H, ortho-PhS hydrogens).

2.5.2.b Under a 1:2:2 molar ratio. Done as in 2.5.2.a at 0.7 mmol InCl₃ scale. The methanol insoluble solid (33 mg) was less than the NaCl expected (41 mg) and it was not completely soluble in water. The product (90% as 6) was soluble in MeOH, Me₂CO and DMSO but insoluble in CHCl₃ and H₂O. Thermal behavior: at 213°C sinters and turns light orange and at 225°C partially melts and the mass does not change up to 300°C. Calculated for C₁₂H₁₀ClS₂In·NaCl (M_r 427.04): C 33.75, H 2.36, S 15.02%; found C 34.16, H 2.61, S 14.65%. IR (KBr): $\bar{ν}$ cm^-1: 3450 m, broad, 3054 m, 1634 m, 1574 m, 1474 s, 1436 s, 1080 m, 1022 s, 998 m, 900 m, 732 vs, 694 s, 684 vs, 470 s, 428 s. ¹H NMR (CD₃OD, TMS): δ= 7.00 (apparent d, J 6.4 Hz, 3 H, m- and p-PhS hydrogens), 7.32 (apparent d, J 5.2 Hz, 2 H, o-PhS hydrogens).

2.5.2.c Under a 1:3:3 molar ratio. Using InCl₃ (0.57 mmol) and thiophenol (1.71 mmol) in dry methanol, no reaction took place in the solution. Adding solid NaOH (1.71 mmol) and stirring at RT for 2 h the methanol insoluble solid weighed 47 mg (expected 67 mg NaCl) and it was partially soluble in water indicating that it was not only NaCl. From the methanolic supernatant and washing a semi-solid 7 (276 mg) was isolated that was soluble in MeOH, Me₂CO and DMSO, moderately soluble in CHCl₃ and insoluble in H₂O. Calculated for C₁₈H₁₅S₃In·NaCl·H₂O (M_r = 518.77): C 41.67, H 3.30, S 18.54 %; found C 41.00, H 3.42, S 17.02 %. IR (KBr): $\bar{ν}$ cm^-1: 3450 vs, broad, 3054 vs, 1616 s, 1576 vs, 1474 vs, 1436 vs, 1300 m, 1182 m, 1116 m, 1082 vs, 1068 s, 1022 vs, 1000 m, 906 m, 740 vs, 694 vs, 614 w, 478 s, 420 s. ¹H NMR (CD₃OD, TMS): δ= 6.96 (m, 3 H, m- and p-PhS hydrogens), 7.28 (m, 2 H, o-PhS hydrogens).

The system InCl₃ (0.82 mmol)/3 PhSH/3 NaOH in dry methanol stirred at RT gave a white, methanol insoluble solid (63 mg) not completely soluble in H₂O indicating that it was not only NaCl (expected for 2 NaCl 96 mg, for 1 NaCl 48 mg). Evaporation of the methanolic supernatant and washing gave a white solid (387 mg), that was triturated with H₂O for 1 h. Centrifugation gave an opalescent supernatant having pH ∼3 (which on leaving at RT precipitated traces of a solid) and a solid (134 mg, 37 %) that was (PhS)₃In 8, very soluble in MeOH, Me₂CO and DMSO, moderately soluble in H₂O and sparingly soluble in CHCl₃. Thermal behavior: at 204°C “sweats” and shrinks slightly, at 210°C fast shrinking, at 215°C melts to a white oil stuck on the walls of the capillary, at 240°C turns light orange, and at 270°C gives an orange foam that did not char up to 300°C. Calculated for C₁₈H₁₅S₃In (M_r = 442.31): C 48.88, H 3.42, S 21.75 %; found C 48.88, H 3.40, S 20.95 %. IR (KBr): $\bar{ν}$ cm^-1: 3400 m, broad, 3056 m, 1576 s, 1560 m, 1474 vs, 1436 s, 1180 m, 1080 s, 1022 s, 998 m, 900 m, 732 vs, 694 vs, 684 vs, 470 s, 428 m. ¹H NMR (CD₃OD, TMS): δ= 7.01 (m, 3 H, m- and p-PhS hydrogens), 7.35 (m, 2 H, o-PhS hydrogens).

2.5.3 With BAL in the absence and in the presence of a base

These experiments were done under a 1:1, 1:2 and 1:3 molar ratios of InCl₃ to BAL by adding neat BAL to a solution of InCl₃ in dry MeOH. The solutions obtained were treated with 1, 2 and 3 equivalents of solutions of NaOH in MeOH. All reactions were followed by TLC and after evaporation and drying the solids obtained were examined by elemental analyses, IR (KBr) and ¹H NMR spectra. The results are described in Section 3.3.2.

2.6 The reaction of Tl(III) and Tl(I) with thiophenol

2.6.1 Reaction of Tl(AcO)₃ with PhSH

To a solution of thiophenol (1.5 mmol) in dry MeOH (2 mL) was added dropwise a solution of thallium triacetate (191 mg, 0.5 mmol) in dry methanol (6 mL) and the yellow to light orange suspension stirred at RT for 4 h. TLC (petroleum ether) showed the presence of PhSSPh at R_f 0.35. Centrifugation and washing with MeOH (2×2 mL) gave a yellow solid and colorless supernatants. The combined supernatants were evaporated and dried to give PhSSPh (105 mg, 96 %) m.p. 59–61°C; lit. [48] 61–62°C. The yellow solid (157 mg, 100 %) was Tl-SPh (see below, 2.6.2) by m.p. and elemental analyses.

2.6.2 Reaction of TlAcO with PhSH

Dropwise addition of thiophenol (52μL, 0.5 mmol) to a solution of thallium(I) acetate (132 mg, 0.5 mmol) in methanol (2 mL) precipitated Tl-SPh as a yellowish powder. After stirring at RT for 3 h, centrifugation gave an opalescent supernatant and a yellow precipitate. Washing with methanol (2 mL) gave an opalescent supernatant that settled by adding Et₂O (5 mL) and leaving overnight. The product (150 mg, 96 %) was a yellow powder insoluble in Me₂CO, MeOH, H₂O and DMSO. Thermal behavior: at 225°C slight shrinking, at 235°C turns to light orange, at approx. 255°C turns orange and at 270°C melts to a red foam; lit. [17] 258–260°C. Calculated for C₆H₅STl (M_r 313.53): C 22.98, H 1.61, S 10.23 %; found C 23.22, H 1.50, S 9.63 %. IR (KBr): $\bar{ν}$ cm^-1: 3054 w, 2996 w, 1566 s, 1558 m, 1468 vs, 1452 s, 1428 s, 1308 m, 1290 m, 1262 m, 1168 m, 1114 m, 1080 vs, 1064 s, 1020 vs, 962 m, 742 vs, 694 vs, 482 s.

2.6.3 Reaction of TlF with PhSH

To a solution of TlF (224 mg, 1 mmol) in water (2 mL) was added dropwise, during 30 min while stirring, a solution of thiophenol (102μL, 1 mmol) in methanol (2 mL). At once a white solid formed that at the end of the addition turned yellow. Stirring was continued for 4 h and TLC (petroleum ether) showed traces of PhSSPh and a faint spot at R_f 0.0. Centrifugation, washing with H₂O (1×2 mL) and MeOH (1×2 mL) gave Tl-SPh (233 mg, 74 %) as a yellow powder insoluble in H₂O, MeOH and DMSO. The supernatants were clear, colorless but when combined gave a white suspension that was not investigated. Thermal behavior: at 230°C darkens to light orange, at 260°C shrinks and melts to orange-red mass and at 275°C foams. Calculated for C₆H₅STl (M_r = 313.53): C 22.98, H 1.61, S 10.23 %; found C 23.18, H 1.55, S 10.30 %. IR (KBr): $\bar{ν}$ cm^-1: 3054 m, 2996 w, 1566 s, 1558 s, 1468 s, 1452 s, 1426 s, 1308 m, 1288 m, 1262 s, 1168 m, 1114 m, 1080 vs, 1064 s, 1020 vs, 962 s, 742 vs, 694 vs, 480 s.

2.6.4 The effect of HF in the reaction of TlF with PhSH

Solutions of thiophenol (41μL, 0.4 mmol) dissolved in methanol (3 mL) were added dropwise to solutions of TlF (0.4x mmol) and HF (0.4y mmol) in water (3 mL) and the yellowish suspensions stirred at RT for 4 h. Centrifugation and washing with water (1×2 mL) and methanol (1×2 mL) gave clear colorless supernatants that when combined gave opalescent solutions or light suspensions that were not investigated further. The isolated solids were examined by elemental analyses, melting point and IR (KBr). The molar ratios of the reactants, the yields and the purities of the isolated solids are shown in Table 1.

Table 1
The effect of HF on the reaction of TlF with thiophenol PhSH. A methanolic solution of PhSH was added during 15 min to an aqueous solution of TlF containing HF and after 4 h stirring was centrifuged and the yellow solid washed with water and methanol

TlF HF PhSH Initial species Combined Tl-SPh

supernatant + washings Yield, % Purity

1 0 1 1 TlF white suspension 74 pure^a

1 1 1 (F-Tl-F)^-H⁺ white opalescence 34 pure^b

1 2 1 (F-Tl-F)^-H⁺ + 1 HF white opalescence 16 impure^c

1 3 1 (F-Tl-F)^-H⁺ + 2 HF yellowish suspension 14 impure^c

1.5 1 1 (F-Tl-F)^-H⁺ + 1/2 TlF ∼ clear colorless solution 54 pure^b

3 2 1 (F-Tl-F)^-H⁺ + 1 TlF white opalescence 82 pure^b

TlF	HF	PhSH	Initial species	Combined	Tl-SPh
1	0	1	1 TlF	white suspension	74	pure^a
1	1	1	(F-Tl-F)^-H⁺	white opalescence	34	pure^b
1	2	1	(F-Tl-F)^-H⁺ + 1 HF	white opalescence	16	impure^c
1	3	1	(F-Tl-F)^-H⁺ + 2 HF	yellowish suspension	14	impure^c
1.5	1	1	(F-Tl-F)^-H⁺ + 1/2 TlF	∼ clear colorless solution	54	pure^b
3	2	1	(F-Tl-F)^-H⁺ + 1 TlF	white opalescence	82	pure^b

^a: by m.p., IR and elemental analyses, ^b: by m.p. and IR, ^c: impure by m.p. and elemental analyses but pure by IR.

2.7 The reaction of Tl(I) with BAL

2.7.1 TlAcO and BAL

To a solution of BAL (50μL, 0.5 mmol) in methanol (1 mL) was added dropwise, during 1 h, a solution of thallium(I) acetate (132 mg, 0.5 mmol) in methanol (3 mL). The orange suspension that formed at once, was stirred at RT for 18 h. TLC (Et₂O) of the supernatant showed BAL that had not reacted. Centrifugation and washing with methanol (3×2 mL) gave the product 9, Fig. 2 (131 mg, 95% on TlAcO) as an orange powder, insoluble in H₂O and DMSO. M.p. 67C shrinks and at 75–78C turns black. Calculated for C₃H₆OS₂Tl₂·0.5MeOH (M_r 546.95): C 7.68, H 1.47, S 11.72%; found C 7.65, H 1.10, S 12.48%. IR (KBr): $\bar{ν}$ cm^-1: 3300 vs, broad, 2834 vs, 1652 m, 1588 m, 1404 s, 1254 m, 1216 m, 1175 m, 1130 w, 1046 s, 992 vs, 878 m, 860 m, 732 m, 655 m, 620 m, 550 m.

The supernatant and the washings were combined and AcOTl (132 mg, 0.5 mmol) was added. The orange suspension, after stirring at RT for 2 h, was worked up to give 9 (104 mg, 76 %), having the same solubilities, thermal behavior and IR (KBr) spectrum as the one above. Found for C₃H₆OS₂Tl₂·0.5CH₃OH: C 8.07, H 1.21, S 11.32 %.

2.7.2 TlF/HF and BAL

Methanolic solutions of BAL were added drop-wise to aqueous solutions of TlF under 1:1, 1:3 and 1:5 molar ratios BAL:TlF and the suspensions formed stirred at RT for at least 3 h. TLC (Et₂O) revealed the presence of BAL that had not reacted and very small amounts of oxidized BAL. The orange solids after centrifugation and washing with water and methanol were examined by elemental analyses and IR (KBr). The results are discussed in Section 3.4.2.

To aqueous solutions of TlF containing added aqueous HF were added drop-wise methanolic solutions of BAL so as the molar ratios of BAL/TlF/HF were 1:2:2, 1:2:4, 1:2:6, 1:3:2 and 1:6:4 and the heterogeneous systems worked up as above. The results are discussed in Section 3.4.2.

2.8 Computational details

Molecular orbital ab-initio calculations based on Hartree-Fock (HF) and second order Møller-Plesset (MP2) perturbation theory as implemented in the Gaussian 09 program package [16], were utilized in the present study in order to calculate the structural details and study the intermolecular interactions/rections of TlF, (TlF)₂, TlF₂^- and MeSH species. Calculations have been also performed in the presence of water solvent by placing the species (solutes) in a cavity within the solvent reaction field (SCRF). The SCRF calculation method used was based on the Polarizable Continuum Model (PCM) and creates a solute cavity via a set of overlapping spheres [43]. The basis sets that have been used are all-electron double zeta plus polarization functions [H, C, F basis sets [7]; Tl basis set [6]]. Specific basis sets have been obtained by use of the Basis Set Exchange (BSE) software and the EMSL Basis Set Library [14, 39]. The geometries of all structural models have been fully optimized at the MP2 all-electrons level of theory.

3 Results and discussion

3.1 The reaction of BAL with Sn(II), Sn(IV) and Pb(II) compounds

Both anhydrous and dihydrated SnCl₂ reacted with BAL in methanol giving soluble products probably indicating coordination of the HCl produced to Sn(II) because the isolated solids were insoluble in methanol. Based on the IR (KBr) spectrum anhydrous SnCl₂ gave solvated BAL(O,S)Sn 3 (presence of –SH at 2525 cm^-1, absence of -CH₂OH at 1060 and 1024 cm^-1) but which sulfur is coordinated, e.g. 3a or 3b of Fig. 1, could not be established by ¹H NMR in DMSO-d₆ because of the broadness of the signals compared to the published [23] spectrum of BAL. The product 3 contained methanol and water (from ether). The solvated product 4 (M = Sn) containing only methanol was obtained using SnCl₂·2H₂O based on the IR (KBr) spectrum and analytical data. In this case, too, the signals were very broad in the ¹H NMR spectrum in DMSO-d₆. The solubility of both products in DMSO and their low melting points point towards not being chain polymers 3c and 4b, respectively.

Fig.1

Products obtained from the reaction of BAL(OH)(SH)₂ with Bu₂SnO and AgAcO and products expected from its reaction with the divalent cations Sn(II), Pb(II), Cd(II) and Pd(II). Some products were solvated and/or hydrated.

Dibutyltin oxide reacted smoothly with BAL in refluxing methanol giving the monomeric 1 as its IR (neat) revealed while its ¹H NMR spectrum in CDCl₃ was dominated by the butyl protons.

Most likely the monomeric 4a (M = Pb) as monohydrate was obtained from Pb(AcO)₂·3H₂O and BAL in water, as its melting point and moderate solubility in DMSO indicated.

From the biological point of view the insolubility in water of the products of BAL with Sn(II) and Pb(II) indicates that BAL cannot detoxify these two metals by forming water soluble products, although it is claimed [41] that BAL increased the urinary excretion of Pb(II).

3.2 The reaction of BAL with Cd(II), Ag(I), Pd(II), chromium and vanadium compounds

BAL and Cd(AcO)₂·2H₂O in water gave an emulsion containing very fine particles that could not be isolated either by centrifugation or filtration. The product 4 (M = Cd), obtained by evaporation and drying in vacuum, contained AcOH by IR (KBr) and elemental analyses. Being insoluble in DMSO and having a relatively high melting point should be formulated as a chain polymer 4b.

Silver acetate and BAL in water under 1:1 molar ratio gave the bis salt 2, indicating that the mono salt could not be isolated. The salt 2 was unsolvated, non-photosensitive and insoluble in DMF and DMSO. Despite the insolubility, its thermal behavior and valencies indicate a monomeric molecule, 2.

The polymeric, solvated 4b was obtained from BAL and Pd(AcO)₂ in CH₂Cl₂ as the insolubility even in hot DMSO and the relatively high melting point indicated.

BAL did not react (by color and TLC) in methanol with CrCl₃ (suspension) or CrCl₃·6H₂O (solution), with VOSO₄ in water in the absence and in the presence of NaOH to scavenge the expected H₂SO₄, while V₂O₅ as a suspension in water oxidized part of the BAL. Coordinated BAL was not detected in the isolated solids by IR. The non reactivity of BAL with these cations may be explained by the HSAB principle (hard cations, soft thiol).

Studies on detoxification of Cd(II) gave conflicting results but urinary excretion was noticed in certain cases and BAL was of no value in treating argyria in rats [41]. Our results indicate that no water-soluble complexes are formed between BAL and Cd(II), Ag(I) or Pd(II).

3.3 Reaction of InCl₃ with thiols in methanol

3.3.1 With PhSH in the absence and in the presence of NaOH

There seems to be no reports on the nature of the species formed when InCl₃ is dissolved in methanol but there are with water as solvent [33]. Thus, InCl₃ dissolves exothermally in water practically without hydrolysis indicating coordination of water to InCl₃, and the tetrahydrate, InCl₃·4H₂O, can be crystallized.

We found no literature reports on the reaction of InCl₃ with thiols and our experiments showed that InCl₃ and xPhSH (x = 1, 2, 3) in methanol did not react (TLC and smell). Evaporation and drying in vacuum over P₂O₅ gave back InCl₃ (100% recovery).

In the presence of a base or with alkoxides, InCl₃ gives the indium(III) alkoxides, In(OR)₃ [46]. However, there seems to be no reports on the products obtained with less than 3 equivalents of a base.

Even less information exists on the reaction of InCl₃ with thiolates. Thus, the reaction of equivalent amount of InCl₃ and PhSNa in refluxing methanol and non-aqueous work up gave the air-stable In(SPh)₃ that, being a Lewis acid, can coordinate Cl^- and other Lewis bases [11]. Substituted thiophenolates of In(III) have also been prepared [38] and investigated as building block for polymers [19], and other uses of indium(III) organothiolates can be envisioned [31]. From the intermediates, Cl-In(SPh)₂ and Cl₂In-SPh, only the former has been prepared by insertion of InCl into PhSSPh [34].

All the reactions of InCl₃/PhSH/NaOH under 1:1:1, 1:2:2 and 1:3:3 molar ratios in methanol gave traces to very little insoluble solids that were also mostly insoluble in water thus indicating that the NaCl produced was coordinated to the soluble products. These, in turn, when evaporated and dried in vacuum, revealed the evaporation of HCl/H₂O, H₂O and H₂O, respectively. The elemental analyses, solubilities and thermal behavior of the solids pointed to compounds tentatively formulated as 5, 6 and 7, Fig. 2, respectively. Their IR (KBr) and ¹H NMR (CD₃OD) spectra were not informative as being dominated by the -SPh bands and – SPh protons, respectively, the analyses of the latter being difficult due to possible fluxionality of In(III) compounds [18, 20]. A small upfield shift of the – SPh protons was observed in going from PhS-In(III) 5 to (PhS)₃In 7. The coordination of NaCl in 5, 6 and 7 seems reasonable based on the ability of, e.g. InCl₃ to add R₄NCl [4] and of In(SPh)₃ to add Cl^- [11]. Attempts to crystallize 5, 6 and 7 from methanolic solutions by diffusing ether gave powders.

Fig.2

Proposed simplistic structures of the products obtained from the reaction of InCl₃ with PhSH in the presence of NaOH in methanol under 1:1:1 5, 1:2:2 6, 1:3:3 molar ratios without washing 7 and after washing with water 8. The reaction of TlAcO with BAL gave the compound 9.

Compounds with an In-O-In linkage should exist but probably they will be hydrolytically unstable. During the preparation of 5 an elongated spot was detected on the TLC and the IR (KBr) of the isolated solid having the simplistic formula 5 showed a very strong and broad band of 3450 cm^-1 indicative of hydrolysis.

The different yields of In(SPh)₃ obtained with non-aqueous work up, 60% [11], and with aqueous work up, 37% [this work], tend to indicate that the In(SPh)₃Cl^- complex cannot keep tenaciously the Cl^- and rearrangement can take place giving In(SPh)₃ and non-identified complexes of In(SPh)₃.

3.3.2 The reaction of BAL with InCl₃

BAL, being an α,β dithiol capable of forming thermodynamically stable chelates, can probably react with InCl₃ in the absence of a base. However, the reactions of InCl₃ with BAL in dry methanol under 1:1, 1:2, 1:3 and even 2:1 molar ratios revealed, by TLC, that BAL had not reacted. Evaporation and drying in vacuum gave solids soluble in organic solvents but insoluble in water, the IR (KBr) of which showed the -SH group and their ¹H NMR spectra in various solvents revealed broad signals for the BAL backbone protons not allowing any assignments. Thus, these reactions of InCl₃ with BAL gave mixtures insoluble to sparingly soluble in water.

Adding NaOH to methanolic solutions of InCl₃ and BAL so as the molar ratios to be 1:1:1, 1:2:2 and 1:3:3 InCl₃/BAL/NaOH gave solutions (opalescent in 1:3:3 case) that by TLC contained BAL. All BAL had reacted only in the 2:1:2 case. Evaporation and drying in vacuum gave solids composed of compounds that could not be identified by elemental analyses and spectra.

Overall, BAL and InCl₃ in the absence and in the presence of a base did not react to a significant extent and the solids obtained after evaporation and drying in vacuum could not be characterized, and their biological significance, if any, remains abscure.

3.4 The reaction of Tl(III) and Tl(I) with thiols

3.4.1 With PhSH

Thallic acetate oxidized thiophenol to its disulfide, PhSSPh, with concomitant production of thallous thiophenolate [17, 25] obtained in 100% yield.

Thallous acetate and thiophenol in methanol gave the yellow Tl-SPh in 100% yield, while aqueous TlF and methanolic PhSH produced only ∼75% Tl-SPh.

A most likely hypothesis for the lower yields obtained from TlF and PhSH is that the HF produced, coordinated to TlF giving species not electrophilic towards PhSH. Table 1 indicates that the more HF initially present the less the yield of the (impure) product and implies that equilibria involving (TlF)₂, TlF, TlF·HF, TlF·2HF and TlF·3HF can exist in solution with added HF and the dominating species is probably (F-Tl-F)^-H⁺, its concentration increasing with increasing amounts of HF due to mass effect. The above compounds seems reasonable because in the literature there are analogous species, e.g. (HF)₂ in concentrated and (F-H-F)^-H₃O⁺ in dilute aqueous solutions of HF [37], KF·HF (Frémy’s salt), KF·2HF to KF·12HF [13], AgF·HF and AgF·3HF the structures of the latter being unknown [37].

Theoretical calculations on thallium(I) fluoride indicate that TlF is a stable molecule having a considerable amount of covalent bond (2.05 Å) that when hydrated the bond elongates to 2.09 Å, Fig. 3, and this is in accord with the notion [27] that thallium(I) halides are classical examples of “incompletely dissociated” 1:1 electrolytes, i.e. form ion pairs [15] that are not hydrates [44]. Thallium(I) fluoride in the solid state has crystal structures depending on temperature and pressure and are not composed of monomers [2]. In the vapor state TlF forms monomers and oligomers, the monomer exhibiting ionic bonding [12].

Fig.3

Structures of TlF, (TlF)₂ and TlF₂^- in the absence and in the presence of water, i.e. having a hydration environment. Bond lengths in Å.

The dimer (TlF)₂ predominating in the vapor phase has been proposed to have a linear structure F-Tl-Tl-F, with a Tl-Tl bond, where the Tl atom has two sp and two p orbitals [24]. However, from photoelectron spectroscopic studies a rhombic dimer has been suggested having a cited Tl-Tl bond of 3.678 Å and four Tl-F bonds of 2.29 Å [42]. Our theoretical calculations indicate that the dimer is more stable by 27.1 kJ/mol compared to 2 TlF monomers and in water environment is slightly destabilized, Fig. 3. The dimer is neither linear or rhombic but has a bend structure implying a stereochemically active s² electron pair. The distance Tl···Tl, being ∼2.85 Å and unaffected by solvation is quite long for a covalent bond. The geometry around each Tl(I) (F, Tl, s²) is approximately trigonal as the 114 angle tends to indicate the dihedral angle being 180.

As HF adds F^- producing (F-H-F)^-, TlF adds F^- to give the anion (F-Tl-F)^- with a bend structure, Fig. 3, implying that the s² electrons of Tl(I) are stereochemically active but, as Table 1 indicates, chemically unreactive towards thiols. When hydrated, its structure changes a little implying that water molecules interact with both the s² electrons and the fluorine atoms.

In the absence of HF, the interaction of TlF with the model thiol CH₃SH seems to favor the arrangement shown in Fig. 4 where the optimized distance Tl···S (∼4.0 Å) is too long for a concerted four centered reaction. The reaction is probably aided by the partial ionization of fluorine which then abstracts the hydrogen from the thiol to give HF or aqueous HF followed by attack of the incipient RS^- to Tl⁺. In the presence of HF where (F-Tl-F)^-H⁺ is most likely the predominant species, MeSH interacts as shown in Fig. 4. In this case too, the distance Tl···S is again ∼4.0 Å but when HF is expelled, the resultant TlF in the presence of HF does not develop a positive charge to attract the RS^-.

Fig.4

The interaction of TlF and TlF₂^- (anhydrous and hydrated) with the model thiol CH₃-SH.

3.4.2 With BAL

BAL did not coordinate to Tl(AcO)₃ to give Tl₂(BAL)₃ under a 3:2 molar ratio in methanol. The supernatant contained, by TLC, BAL and oxidized BAL and the insoluble orange solid could not be characterized. However, TlAcO precipitated 9, Fig. 2, even when a 1:1 molar ratio was used, thus resembling the behavior of AgAcO.

The reaction of aqueous TlF with methanolic BAL under 1:1, 2:1, 3:1 and 5:1 molar ratios of TlF/BAL gave suspension and very small amounts of orange solids. BAL and oxidized BAL were detected by TLC in the 1:1 but not in the other cases. The orange solids could not be characterized by elemental and IR (KBr) analyses. In the presence of added aqueous HF the weights of the solids diminished even further, their colors were not orange and their analytical data did not point to a specific molecule.

Thallium is the most toxic element of group 13 of the Periodic Table, and its action has been mentioned a few times even the fiction literature, e.g. Agatha Christie’s “The pale horse”. Our results indicate that Tl(III) oxidize monothiols to their disulfides giving insoluble thallium(I) mercaptides also obtained from Tl(I) compounds. If Tl(I) compounds are found in a cell, then BAL produces the insoluble disalt 9 and detoxification cannot be due to solubilization of Tl(I).

References

Anisuzzaman

A.K.M.

and Owen

L.N.

, Dithiols. Part XXIII. Optically active forms of 2,3-dimercaptopropanol and related thiols, J Chem Soc C (1967), 1021–1026.

Berastegui

and Hull

, The crystal structure of thallium(I) fluoride, J Solid State Chem 150 (2000), 266–275.

Bonomi

, Pagani

, Cariati

, Pozzi

, Grisponi

, Cristiani

, Diaz

and Zanoni

, Synthesis and characterization of metal derivatives of dihydrolipoic acid and dihydrolipoamide, Inorg Chim Acta 192 (1992), 237–242.

Brown

D.S.

, Einstein

F.W.B.

and Tuck

P.G.

, Tetragonal pyramidal indium(III) species. The crystal structure of tetraethylammonium pentachloroindate(III), Inorg Chem 8 (1969), 14–18.

Brown

D.H.

, McKinlay

G.C.

and Smith

W.E.

, Some complexes of 2,3-dimercaptopropanol (BAL) with gold(I) and gold(III), J Inorg Biochem 10 (1979), 275–279.

Canal Neto

and Jorge

F.E.

, All-electron double zeta basis sets for the most fifth-row atoms: Application in DFT spectroscopic constant calculations, Chem Phys Lett 582 (2013), 158–162.

Canal Neto

, Muniz

E.P.

, Centoducatte

and Jorge

F.E.

, Gaussian basis sets for correlated wave functions. Hydrogen, helium, first- and second-row atoms, J Mol Struct (Theochem) 718 (2005), 219–224.

Canty

A.J.

and Kishimoto

, Mercury(II) and organomercury(II) complexes of thiols and dithiols, including British Anti-Lewisite, Inorg Chim Acta 24 (1997), 109–122.

Catsch

and Harmuth Hoene

A.-E.

, New developments in metal antidotal properties of chelating agents, Biochem Pharmacol 24 (1975), 1557–1562.

10.

Catsch

and Harmuth Hoene

A.-E.

, Pharmacology and therapeutic applications of agents used in heavy metal poisoning, Pharmacol Ther A 1 (1976), 1–118.

11.

Chadha

R.K.

, Hayes

P.C.

, Mabrouk

H.E.

and Tuck

D.G.

, Coordination compounds of indium. Part 43. Indium(III) derivatives of benzenethiol, and the crystal structure of tetraphenylphosphonium bromotris(benzenethiolato)-indate(III), Ph₄P[BrIn(SPh)₃], Can J Chem 65 (1987), 804–809.

12.

Dehmer

J.L.

, Berkowitz

and Cusachs

L.C.

, Photoelectron spectroscopy of high temperature vapors. III. Monomer and dimer spectra of thallous fluoride, J Chem Phys 58 (1973), 5681–5686.

13.

Domange

, Fluor, in Nouveau Traité de Chimie Minérale ( Pascal

editor), 1960, Masson et cie, Paris, vol. XVI, pp. 29–37, 131–133.

14.

Feller

, The role of databases in support of computational chemistry calculations, J Comp Chem 17 (1996), 1571–1586.

15.

Freeman

, Gasser

R.P.H.

, Richards

R.E.

and Wheeler

D.H.

, Chemical shifts of thallium resonance spectra in solutions of thallous salts, Mol Phys 2 (1959), 75–84.

16.

Frisch

M.J.

, Trucks

G.W.

, Schlegel

H.B.

, Scuseria

G.E.

, Robb

M.A.

, Cheeseman

J.R.

, Scalmani

, Barone

, Mennucci

, Petersson

G.A.

, Nakatsuji

, Caricato

, Li

, Hratchian

H.P.

and Izmaylov

A.F.

, Bloino

, Zheng

, Sonnenberg

J.L.

, Hada

, Ehara

, Toyota

, Fukuda

, Hasegawa

, Ishida

, Nakajima

, Honda

, Kitao

, Nakai

, Vreven

, Montgomery

J.A.

Jr. , Peralta

J.E.

, Ogliaro

, Bearpark

, Heyd

J.J.

, Brothers

, Kudin

K.N.

, Staroverov

V.N.

, Kobayashi

, Normand

, Raghavachari

, Rendell

, Burant

J.C.

, Iyengar

S.S.

, Tomasi

, Cossi

, Rega

, Millam

J.M.

, Klene

, Knox

J.E.

, Cross

J.B.

, Bakken

, Adamo

, Jaramillo

, Gomperts

, Stratmann

R.E.

, Yazyev

, Austin

A.J.

, Cammi

, Pomelli

, Ochterski

J.W.

, Martin

R.L.

, Morokuma

, Zakrzewski

V.G.

, Voth

G.A.

, Salvador

, Dannenberg

J.J.

, Dapprich

, Daniels

A.D.

, Farkas

, Foresman

J.B.

, Ortiz

J.V.

, Cioslowski

and Fox

D.J.

, Gaussian 09, Revision A.01, Gaussian, Inc., Wallingford CT, 2009.

17.

Gilman

and Abbott

R.K.

Jr. , Characterization of sulfonic, sulfinic, phosphinic and some other acids as thallous salts, J Am Chem Soc 71 (1949), 659–660.

18.

Heard

P.J.

, Main group dithiocarbamate complexes, Progress Inorg Chem 53 (2005), 1–69.

19.

Heine

, Holyńska

, Reuter

, Haas

, Chatterjee

, Koch

, Gries

K.I.

, Volz

and Dehnen

, In(SAr)₃ as a building block for 3D and helical coordination polymers, Cryst Growth Design 13 (2013), 1252–1259.

20.

Ioannou

P.V.

, Dimethylphosphinato and dimethylarsinato complexes of group 13 metals and their chemistry, Monatsh Chem 144 (2013), 793–802.

21.

Ioannou

P.V.

and Tsivgoulis

G.M.

, Thiolates of arsenic(III), antimony(III), and bismuth(III) with DL-α-dihydrolipoic acid, Monatsh Chem 145 (2014), 897–909.

22.

Ioannou

P.V.

and Tsivgoulis

G.M.

, The reaction of dithioerythritol and dithiothreitol with As(III), Sb(III), and Bi(III) compounds, Monatsh Chem 146 (2015), 249–257.

23.

Ioannou

P.V.

, Vachliotis

D.G.

and Kouli

, The reaction of British Anti-Lewisite (dimercaptol) with As(III), Sb(III), and Bi(III) oxides and salts, Main Group Chem 12 (2013), 235–249.

24.

Keneshea

F.J.

and Cubicciotti

, The thermodynamics of vaporization of thallous fluoride and its gaseous dimerization, J Phys Chem 69 (1965), 3910–3915.

25.

Krebs

and Brömmelhaus

, TlSPh and TlSBu, thallium(I) thiolates with novel cagelike structural units: [Tl₅(SPh)₆]^- [Tl₇(SPh)₆]⁺ and [Tl₈(SBu)₈], Angew Chem Int Ed Engl 28 (1989), 1682–1683.

26.

Krężel

, Leśniak

, Jeżowska-Bojczuk

, Młynarz

, Brasuñ

, Kozłowski

and Bal

, Coordination of heavy metals by dithiothreitol, a commonly used thiol group protectant, J Inorg Biochem 84 (2001), 77–88.

27.

Lee

A.G.

, The Chemistry of Thallium, 1971, Elsevier, Amsterdam, p. 28.

28.

Leussing

D.L.

, The reaction of nickel(II) with 2,3-dimercapto-1-propanol, J Am Chem Soc 82 (1960), 4458–4481.

29.

Leussing

D.L.

and Jayne

, Mononuclear and polynuclear complex formation between iron(II) and 2,3-dimercapto-1-propanol, J Phys Chem 66 (1962), 426–429.

30.

Leussing

D.L.

and Tischer

T.N.

, Mononuclear and polynuclear complex formation by manganese(II) and zinc(II) ions with 2,3-dimercapto-1-propanol: The behavior of the E_r function with mercaptide, J Am Chem Soc 83 (1961), 65–70.

31.

, Eom

, Kim

S.H.

and Lee

P.H.

, Palladium-catalyzed carbon-sulfur cross-coupling reactions of aryl chlorides with indium tris(organothiolates), Chem Letters 40 (2011), 980–982.

32.

Ord

M.G.

and Stocken

L.A.

, A contribution of chemical defence in World War II, Trends Biochem Sci 25 (2000), 253–256.

33.

Pascal

, Indium, in Nouveau Traité de Chimie Minérale ( Pascal

editor), 1961, Masson et cie, Paris, vol. VI, pp. 839–843.

34.

Peppe

and Tuck

D.G.

, Coordination compounds of indium. Part 42. The insertion of indium(I) halides into homonuclear bonds in non-aqueous media, Can J Chem 62 (1984), 2798–2802.

35.

Peters

R.A.

, Stocken

L.A.

and Thompson

R.H.S.

, British Anti-Lewisite (BAL), Nature 156 (1945), 616–619.

36.

Reiss

O.K.

, Pyruvate metabolism, II. Restoration of pyruvate utilization in heart sarcosomes by α-(+)-lipoic acid, J Biol Chem 233 (1958), 789–793.

37.

Remy

, Treatise on Inorganic Chemistry, (translated by Anderson

J. S.

), 1956, Elsevier, Amsterdam, vol II, p. 399.

38.

Schluter

R.D.

, Kräuter

and Rees

W.S.

, Metal thiolate compounds: Processable ceramic precursors, J Cluster Sci 8 (1997), 123–154.

39.

Schuchardt

K.L.

, Didier

B.T.

, Elsethagen

, Sun

, Gurumoorthi

, Chase

, Li

and Windus

T.L.

, Basis set exchange: A community data base for computational sciences, J Chem Inf Model 47 (2007), 1045–1052.

40.

Stevenson

K.J.

, Gale

and Perham

R.N.

, Inhibition of pyruvate dehydrogenase multienzyme complex from Escherichia coli with mono- and bifunctional arsenoxides, Biochemistry 17 (1978), 2189–2192.

41.

Stocken

L.A.

and Thompson

R.S.

, Reactions of British Anti-Lewisite with arsenic and other metals in living systems, Physiol Rev 29 (1949), 168–192.

42.

Streets

D.G.

and Berkowitz

, The structure of Tl₂F₂ from photoelectron spectroscopy, Chem Phys Letters 38 (1976), 475–478.

43.

Tomasi

, Mennucci

and Cammi

, Quantum mechanical continuum solvation models, Chem Rev 105 (2005), 2999–3093.

44.

Tranquard

, Coffy

et Boinon

M.-J.

, Le système binaire eau - fluorure de thallium, Bull Soc Chim France (1969), 2608–2610.

45.

Vilensky

J.A.

and Redman

, British Anti-Lewisite (dimercaprol): An amazing history, Ann Emerg Med 41 (2003), 378–383.

46.

Wade

and Banister

A.J.

, Aluminium, Gallium, Indium and Thallium, in Comprehensive Inorganic Chemistry, ( Bailar

J. C.

Jr , Emeléus

H. J.

, Nyholm

and Trotman-Dickenson

A. F.

editors), 1973, Pergamon Press, Oxford, Vol. 1, p. 1107.

47.

Webb

E.C.

and van Heyningen

, The action of British Anti-Lewisite (BAL) on enzyme systems, Biochem J 41 (1947), 74–78.

48.

West

R.C.

, CRC Handbook of Chemistry and Physics, 65th Edition, 1984, CRC Press, Boca Raton, FL.

49.

Zuman

and Zumanová

, Polarographische studie der reactionen des 2:3-dimercaptopropanols (BAL) mit schwermetallen und einigen oxydationsmitteln, Tetrahedron 1 (1957), 289–300.

Chelation therapy: The interaction of British Anti-Lewisite (BAL) with some heavy metal cations of p and d blocks

Abstract

Keywords

1 Introduction

2 Experimental section

2.1 Materials

2.2 Methods

2.3 Reaction of BAL with group 14 metal ions

2.3.1 With anhydrous SnCl2

2.3.2 With SnCl2·2H2O

2.3.3 With (Bu2SnO) x

2.3.4 With Pb(AcO)2·3H2O

2.4 Reaction of BAL with some metal ions of d-block

2.4.1 With Cd(AcO)2·2H2O

2.4.2 With AgAcO

2.4.3 With Pd(AcO)2

2.5 Reaction of InCl3 with thiols

2.5.1 With PhSH in the absence of a base

2.5.2 With PhSH in the presence of NaOH

2.5.3 With BAL in the absence and in the presence of a base

2.6 The reaction of Tl(III) and Tl(I) with thiophenol

2.6.1 Reaction of Tl(AcO)3 with PhSH

2.6.2 Reaction of TlAcO with PhSH

2.6.3 Reaction of TlF with PhSH

2.6.4 The effect of HF in the reaction of TlF with PhSH

2.7.1 TlAcO and BAL

2.7.2 TlF/HF and BAL

2.8 Computational details

3 Results and discussion

3.1 The reaction of BAL with Sn(II), Sn(IV) and Pb(II) compounds

3.3 Reaction of InCl3 with thiols in methanol

3.3.1 With PhSH in the absence and in the presence of NaOH

3.4 The reaction of Tl(III) and Tl(I) with thiols

3.4.1 With PhSH

References

2.3.1 With anhydrous SnCl₂

2.3.2 With SnCl₂·2H₂O

2.3.3 With (Bu₂SnO)_x

2.3.4 With Pb(AcO)₂·3H₂O

2.4.1 With Cd(AcO)₂·2H₂O

2.4.3 With Pd(AcO)₂

2.5 Reaction of InCl₃ with thiols

2.6.1 Reaction of Tl(AcO)₃ with PhSH

3.3 Reaction of InCl₃ with thiols in methanol