Mercury(II) thiolate and selenolate interactions, and chelation therapy

This thesis is an account of a study of some aspects of the biological chemistry of mercury. The interactions of mercury compounds with both simple and naturally occurring thiols, some selenols, and several antidotes for mercury poisoning have been investigated. The dithiol antidotes 2,3-dimercaptosuccinic acid (DISH 4 ) and the sodium salt of 2,3-dimercaptopropane-l-sulfonate (Unithiol, Na[UH 2 ]) form isolable complexes of stoichiometry (MeHg) 2 ENSH 2and Na[(MeHg) 2 U]. The mercury(II) complexes Hg(DMSH 2 ).2H 20 and Na[HgU] have polymeric structures, (-Hg-S'S-), similar to that reported for the Hg(II) complex of the classic heavy metal antidote, British AntiLewisite (BALH 2 ). The stability constants for the interaction of MeHg(II) with several monothiols in aqueous solution have been determined potentiometrically. High stability of complexes with a-mercaptocarboxylic acids and a-mercaptoamines (log 3 110 (1`15-17) necessitated the use of a titration method involving iodide competition. 2,3-Dimercaptosuccinic acid forms a MeHg(II) complex with log = similar to that expected for interaction of MeHg(II) with a monothiol; but BALH 2and Unithiol form complexes with log fi lo2-3 orders of magnitude higher, suggesting the presence of chelation. Implications of the results obtained from both synthetic and solution studies for the use of dithiols as antidotes for MeHg(II) poisoning are discussed. A computer program for the potentiometric evaluation of ligand hydrolysis constants has been written. The algorithm uses a rigorous least-squares procedure and can be applied to mixtures of multiprotic acids or bases. Any titration parameter can be refined. Complexes of 400 with selenols have been prepared and the first structural studies of Hg(II) selenolates obtained. Comparison of vibrational spectra and X-ray powder diffraction patterns for these complexes and their thiol analogs allows assignment of structures for some complexes and suggests that, for Hg(SeR) 2 , polymeric structures may be more common than for Hg(SR) 2 . Thus., Hg(SeR) 2 (R.Me, Et, Bu t ) are polymeric and Hg(SeCH 2CO2H) 2 is linear,'but for a large number Of analogous thiolate complexes, only Hg(SBU ) 2 is known to be polymeric. Single crystal X-ray diffraction studies show a polymeric structure for Hg(SeMe) 2 based on .distorted tetrahedral geometry for mercury with bridging selenolate groups . The structure of [Bu tSeHgCl(py) m]4 :is similar to those previously reported for the sulfur analogs with pyridine.and 47methylpyridine, and is isomorphous with the latter. The structure is based on an eightMembered ring of alternating Hg and Se atoms (-Hg-SeBu t 7 )4 having a centre of symmetry and two mercury environments, 'Hg(u 7SeBu t ) 2 (u-C1) 2 . 1 and 'Hg(u-SeBu ) 2Cl(py)', with a dichloro bridge linking the former mercury atoms. The complex [EtSeHgC1(py)] 4 has a similar structure but a dichloro bridge is absent and all mercury atoms have the environment 'Hg(U.-SeEt) 2C1(py) . . The first valid comparison between Hg-S and Hg-Se bond lengths for analogous thiolate and selenolate complexes of Hg(II) indicates that the Hg-Se bond lengths are slightly shorter than expected from comparisons of sulfur and selenium covalent radii. Possible synthetic routes to selenium analogs of antidotal dithiois are discussed. Although selenium analogs of BALH 2 and 1 .,3-dimercapto-2- propanol (DMPH ) could not be isolated the new compounds selenetan-3-ol, 1a-diselenan-4-ol and 1-bromo-3-selenocyanato-2-propanol were obtained from their attempted syntheses. The'Hg(II) derivatives of the selenium analogs, Hg(SeBAL) and Hg(SeDMP), were isolated as intractable polymers. These polymers have tetrahedral geometry for Hg(II) in contrast to linear geometry for their thiol analogs, consistent with structural differences between simple complexes Hg(XR) (X=S,Se). The compounds 27 (benzylseleno)- fumaric.acid and 2-(benzylseleno)succinic acid have been prepared as intermediates towards a projected synthesis of SeDMSH4