Bioorganometallic Chemistry of Mercury



Mercury alkyls are potent neurotoxins.  For example, methyl mercury compounds are responsible for Minamata disease, which caused the death of almost two thousand people around Minamata Bay (Japan) in the late 1950s when the residents consumed fish that was contaminated with methyl mercury compounds released by the Chisso Corporation from 1932 – 1968 (Clarkson, T. W.; Magos, L. Crit. Rev. Toxicol. 2006, 36, 609).


However, while the initial outbreak of the Minamata disease was a result of toxic release from a nearby chemical plant, methyl mercury compounds are naturally occurring!  Specifically, [CH3Hg]+ is also introduced into the environment by biomethylation of Hg(II) with methylcobalamin (i.e. methyl B12) in sulfate reducing bacteria that live in anoxic aquatic environments (e.g. lake-bottom sediments).


A critical step of mercury detoxification involves protolytic cleavage of the otherwise inert Hg–R bond.  This is achieved in bacteria by organomercurial lyase (MerB) which has three cysteine residues at the active site.




A Functional Model for MerB

Significantly, we have obtained a functional model for MerB, in which the Hg–C bond of [TmBut]HgMe is cleaved rapidly by PhSH.




The facility with which the Hg–C bonds are cleaved under mild conditions is proposed to be a consequence of the mercury center of two-coordinate [k1–TmBut]HgR being able to access higher coordination numbers due to the multidentate nature of the [TmBut] ligand. 


Evidence that increased coordination promotes the Hg–C protolytic cleavage is provided by the observation that whereas the reaction of {[HmimBut]HgR}+ with PhSH eliminates RH at elevated temperatures, the protolytic cleavage occurs at room temperature in the presence of HmimBut.




Molecular Structure and Reactivity of Thimerosal (Merthiolate)

Thimerosal, i.e. sodium ethylmercury thiosalicylate, [(ArCO2)SHgEt]Na, is a pharmaceutical ingredient that was introduced in the 1930s under the trade name Merthiolate, and subsequently found applications in a variety of products such as: vaccine preservatives; antiseptics; contact lens cleaners; soap-free cleansers; cosmetics; eye, nose and ear drops; and skin test antigens.




In view of the many applications, and the controversy surrounding its use as a vaccine preservative, it is rather surprising that there are very few reports pertaining to the chemistry of thimerosal.  Therefore, we have started to investigate the chemistry of this molecule, including its structural determination by X–ray diffraction and its analysis by NMR spectroscopy.



Asymmetric unit of thimerosal.




Molecular structure of one of the anions of thimerosal in the asymmetric unit.


With respect to reactivity, the carboxylate oxygen of thimerosal, [(ArCO2)SHgEt]Na, is subject to facile electrophilic attack by H+ and [HgEt]+ to give (ArCO2H)SHgEt and [(ArCO2HgEt)SHgEt]2, respectively.  X–ray diffraction demonstrates that (ArCO2H)SHgEt exists as a hydrogen bonded dimer in the solid state whereas [(ArCO2HgEt)SHgEt]2 is tetranuclear, with the mercury centers being connected by bridging carboxylate groups.






Molecular structure of (ArCO2H)SHgEt.





Molecular structure of [(ArCO2HgEt)SHgEt]2.


On the Chalcogenophilicity of Mercury:  Evidence for a Strong Hg–Se Bond in [TmBut]HgSePh and its Relevance to the Toxicity of Mercury

While the potent toxicity of mercury is often associated with its high affinity for sulfur, such that it binds effectively to the cysteine residues in proteins and enzymes (note that the term “mercaptan” is an abbreviated form of “mercurium captans”, which is Latin for “seizing mercury”), another mechanism has been attributed to its impact on the biochemical roles of selenium.  Specifically, the toxicity of mercury has also been attributed to (i) the interaction between between Hg(II) and selenium compounds reducing the bioavailability of selenium via the formation of insoluble mercury selenide species and (ii) mercury binding to the active sites of selenoenzymes, thereby inhibiting their functions.


The preference of mercury to bind selenium over sulfur has been addressed by examining a series of chalcogenolate complexes which are supported by the the tris(2-mercapto-1-t-butyl–imidazolyl)hydroborato ligand, i.e. [TmBut]MEPh (M = Zn, Cd, Hg; E = S, Se, Te).  Interestingly, we observe that the difference in Hg–EPh and Cd–EPh bond lengths in these complexes is a function of the chalcogen and that the Hg–SePh and Hg–TePh bonds are much shorter than would be predicted on the basis of the covalent radii of the chalcogens. 




Variation of M–EPh bond lengths.  Note how the difference between Hg–E and Cd–E bond lengths increases as the chalcogen becomes heavier.



Relative M–EPh bond lengths and the values predicted on the basis of the covalent radii of S, Se, Te.  All M–SePh and M–TePh bond lengths are shorter than predicted on the basis of the value for the M–SPh bond length and the change in covalent radius of the chalcogen, but the Hg–SePh and Hg–TePh bonds are exceptionally short.


The structural study suggests that while mercury is often described as being thiophilic, it actually has a greater selenophilicity, in the sense that the Hg–Se bond is unusually short.  Further evidence in support of this notion was obtained by demonstrating that the selenolate ligand of [TmBut]ZnSePh transfers from zinc to mercury in [TmBut]HgSR’, with the thiolate moving to zinc.




Which Element is Bigger: Mercury or Cadmium?

Covalent radii are obtained by analyzing the bond lengths between different pairs of atoms in a large series of compounds to obtain a set of self-consistent values (see, for example Pyykkö et al Chem. Eur. J. 2009, 15, 186-197 and Cordero et al Dalton Trans. 2008, 2832–2838).  These radii are used to provide an estimate of the length of a covalent bond between a pair of atoms, and while deviations with experimental values may be observed, differences in closely related compounds are expected to be minimal.  However, analysis of a series of [TmBut]MEPh (M = Zn, Cd, Hg; E = S, Se, Te) compounds reveals an interesting subtlety concerned with the notion of the covalent radius of an atom, i.e. the apparent covalent radius of the metal in these complexes is not only molecule dependent, but is also dependent on the nature of the bond.


Specifically, whereas the Hg–EPh bonds are shorter than the corresponding Cd–EPh bonds (see above Figure), the Hg–S bonds involving the [TmBut] ligand are longer than the corresponding Cd–S bonds (see below Figure).



Variation of M–S bond lengths involving the [TmBut] ligand.  Note that all Hg–E bonds are longer than the corresponding Cd–E bond.


Thus, if one was to ask a simple question  “which is bigger, mercury or cadmium”, one would conclude that mercury is bigger if one considered the M–S bonds involving the [TmBut] ligand, whereas one would conclude that cadmium is bigger if one considered the M–EPh bonds.




Selected References

“Cleaving Mercury–Alkyl Bonds: A Functional Model for Mercury Detoxification by MerB.”  Jonathan G. Melnick and Gerard Parkin Science 2007, 317, 225-227.


“Molecular Structures of Thimerosal (Merthiolate) and Other Arylthiolate Mercury Alkyl Compounds.” Jonathan G. Melnick, Kevin Yurkerwich, Daniela Buccella, Wesley Sattler and Gerard Parkin, Inorg. Chem. 2008, 47, 6421-6426.


“Molecular Structures of Protonated and Mercurated Derivatives of Thimerosal.”  Wesley Sattler, Kevin Yurkerwich and Gerard Parkin Dalton Trans. 2009, 4327-4333.


“Synthesis, Structure and Reactivity of Two–Coordinate Mercury Alkyl Compounds with Sulfur Ligands:  Relevance to Mercury Detoxification.” Jonathan G. Melnick, Kevin Yurkerwich and Gerard Parkin, Inorg. Chem. 2009, 48, 6763-6772.


“On the Chalcogenophilicity of Mercury:  Evidence for a Strong Hg–Se Bond in [TmBut]HgSePh and its Relevance to the Toxicity of Mercury.” Jonathan G. Melnick, Kevin Yurkerwich and Gerard Parkin J. Am. Chem. Soc. 2010, 132, 647–655.