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Protolytic Cleavage of Hg–C Bonds Induced by 1-Methyl-1,3-dihydro-2H-benzimidazole-2-selone: Synthesis and Structural Characterization of Mercury Complexes

Multinuclear (1H, 77Se, and 199Hg) NMR spectroscopy demonstrates that 1-methyl-1,3-dihydro-2H-benzimidazole-2-selone, H(sebenzimMe), a structural analogue of the selenoamino acid, selenoneine, binds rapidly and reversibly to the mercury centers of HgX2 (X = Cl, Br, I), while X-ray diffraction studies provide evidence for the existence of adducts of composition [H(sebenzimMe)]xHgX2 (X = Cl, x = 2, 3, 4; X = I, x = 2) in the solid state. H(sebenzimMe) also reacts with methylmercury halides, but the reaction is accompanied by elimination of methane resulting from protolytic cleavage of the Hg–C bond, an observation that is of relevance to the report that selenoneine demethylates CysHgMe, thereby providing a mechanism for mercury detoxification. Interestingly, the structures of [H(sebenzimMe)]xHgX2 exhibit a variety of different hydrogen bonding patterns resulting from the ability of the N–H groups to form hydrogen bonds with chlorine, iodine, and selenium.


■ INTRODUCTION
The toxicological properties of mercury 1 have been attributed to both its thiophilicity 1−4 and its selenophilicity. 4−6 With respect to the latter, selenium is an important component of antioxidants, 7,8 and the interaction between Hg(II) and selenium compounds may reduce the bioavailability of selenium via the formation of insoluble mercury selenide species. 4,5,8 Furthermore, mercury may bind to the active sites of selenoenzymes and thereby inhibit their functions. 4,6 For example, selenium is a component of a variety of enzymes that incorporate the amino acids selenocysteine and selenomethionine ( Figure 1), as illustrated by glutathione peroxidases, thioredoxin reductases, glycine reductases, formate dehydrogenases, and selenoprotein P. 4,5,7,10 Other examples of selenium-containing biomolecules include the amino acid derivatives selenoneine 11,12 and Se-methylselenoneine 12,13 (Figure 1), of which the latter was identified in human urine and blood.
It has recently been shown that selenoamino acids (namely Lselenocysteine, L-selenoglutathione, D,L-selenopenicillamine, and L-selenomethionine) complex readily to methylmercury species 14 and that cleavage of the Hg−C bond may be achieved under physiologically relevant conditions to yield mercury selenide via (MeHg) 2 Se. 15 Insoluble mercury selenide particles have also been observed in the brains of humans exposed to methylmercury species, and these particles are considered to be much less toxic than mobile, soluble methylmercury species such as CysHgMe. 16 This observation provides evidence of the neuroprotective effects of selenium with respect to the prevention of mercury-induced damage to the central nervous system. Additionally, recent in vitro studies have shown that selenoneine may assist cells in removal of CysHgMe. 11e However, the interactions between mercury and selenium in biological systems are complex, and animal studies have produced contradictory results. For example, it has been observed that co-administration of diphenyl diselenide compounds with methylmercury chloride partially ameliorated methylmercury-induced oxidative damage to proteins in the livers and brains of intoxicated mice; 17 on the other hand, rats simultaneously dosed with methylmercury chloride and diphenyl diselenide were shown to suffer more severe neurological symptoms, such as motor deficits and weight loss, than rats dosed with methylmercury chloride alone. 18 A detailed understanding of the impact of mercury on the biochemical roles of selenium would, therefore, benefit considerably from the development of the chemistry of mercury in a coordination environment that features selenium. ■ RESULTS AND DISCUSSION 1-R-imidazole-2-thiones, H(mim R ), 20−22 of which the methyl derivative is the well-known antithyroid drug, methimazole (tapazole), 23,24 are a widely studied class of molecules that can bind to a variety of metals, 25−27 including mercury. 27 However, in contrast to the numerous studies pertaining to 1-R-imidazole-2-thiones, there are few corresponding investigations of 1-R-imidazole-2-selones, H(seim R ). 28−32 For example, only H(seim Me ) 28, 29 and H(seim Mes ), 29 and the benzannulated derivatives, H(sebenzim Me ) 30,31a and H(sebenzim Bu t ), 31a have been synthesized and structurally characterized ( Figure 2). Moreover, there are very few examples of structurally characterized metal complexes that feature 1-R-imidazole-2-selone ligands. 31a,33−35 It is, therefore, appropriate to develop the chemistry of this class of ligands with respect to mercury. In this regard, we recently reported an improved synthesis of H(sebenzim Me ), 31a which has thereby allowed us to investigate the ability of this compound both to coordinate to mercury centers and to cleave mercury−carbon bonds.
Interaction of H(sebenzim Me ) with HgCl 2 , HgBr 2 , and HgI 2 . Evidence for the ability of the imidazole-2-selone, H(sebenzim Me ), to coordinate to the mercury centers of HgX 2 (X = Cl, Br, I) in solution (Scheme 1) is provided by a combination of 1 H, 77 Se{ 1 H}, and 199 Hg{ 1 H} NMR spectroscopies. For example, the 199 Hg (Table 1) Figure 3) chemical shifts associated with H(sebenzim Me ) also progressively shift upon addition to HgCl 2 . In addition to providing evidence for coordination of H(sebenzim Me ) to mercury, the observation of a single resonance in both the 77 Se{ 1 H} and 199 Hg{ 1 H} NMR spectra for each concentration ratio, and also a single set of resonances in the 1 H NMR spectra, indicates that the coordination is reversible and that the process is facile on the NMR time scale at room temperature. Furthermore, low temperature (−40°C) spectra in DMF-d 7 likewise show single resonances, thereby      the long Hg−Cl bond distance, the coordination geometry of {[H(sebenzim Me )] 3 HgCl} + deviates significantly from tetrahedral. Thus, the four-coordinate τ 4 index (Table 4) 44 of {[H(sebenzim Me )] 3 HgCl} + (0.78) is close to that for an idealized trigonal monopyramid (0.85) in which chlorine occupies an axial position; 44 in the extreme that the axial chlorine is considered to serve the role of a counterion, the mercury would be described as approximately trigonal planar.
By comparison to the large variation in Hg−Cl interactions within [H(sebenzim Me )] x HgCl 2 , the average Hg−Se bond lengths exhibit little variation, increasing only slightly as a function of x, i.e., bis (2.591 Å) < tris (2.611 Å) < tetrakis (2.671 Å). These Hg−Se bond lengths are comparable to the mean value of 2.643 Å for compounds listed in the CSD, 37 but are longer than those in compounds such as Hg (SePh)  A common feature of all [H(sebenzim Me )] x HgCl 2 structures is that each chloride, regardless of whether it is attached covalently to the mercury center, participates in hydrogen bonding interactions with the imidazole N−H moieties. There is, nevertheless, an interesting difference with respect to the nature of the hydrogen bonding interactions. Specifically, each chlorine that is covalently bound to mercury participates in an intramolecular N−H···Cl interaction, 50−52 whereas each outersphere chloride anion participates in a N−H···Cl···H−N interaction 53 that serves to link together two H(sebenzim Me ) moieties, as summarized in Figure 7.
Thus, whereas [H(sebenzim Me )] 2 HgCl 2 exhibits only intramolecular N−H···Cl interactions and is a discrete mononuclear species, 31a, 54 [1.854(12), 1.896(11), 1.851(9), 1.851(9), 1.857(11), 1.854(11), 1.869(9), and 1.856(9) Å] are only slightly longer than that of free H(sebenzim Me ) [1.838 (2) Å]. 31a Despite these minor metrical changes, however, it is interesting to note that both the 13 C (see Experimental Section and ref 31a) and 77 Se NMR ( Table 1) chemical shifts of the [CSe] moiety are sensitive towards the changes induced by coordination to mercury. Similar spectroscopic trends have been observed in related systems, 35i and also for thione counterparts. 56 NMR spectroscopic studies also demonstrate that H(sebenzim Me ) binds reversibly to HgBr 2 and HgI 2 in DMSO-d 6 , and that the processes are facile on the NMR time scale, as indicated by the observation of single sets 1 H NMR chemical shifts for the H(sebenzim Me ) signals (Table 2 and Figure 3). Interestingly, the 77 Se NMR chemical shift of the H(sebenzim Me ) moiety is more sensitive towards coordination of HgCl 2 than to coordination of either HgBr 2 or HgI 2 . For example, the 77     The most striking differences in the structures of orthorhombic and monoclinic [H(sebenzim Me )] 2 HgI 2 do not, however, pertain to the mercury coordination environment. Rather, the differences are associated with the distinct hydrogen bonding motifs (Figures 12 and 13). Furthermore, these hydrogen bonding patterns are also different from that of the chloride counterpart, [H(sebenzim Me )] 2 HgCl 2 (vide supra), as illustrated in Figure 14.      Figure 13). 29,59 Interestingly, H(sebenzim Me ) itself does not adopt this "head-to-head" motif, but rather adopts a polymeric "head-to-tail" structure. 31a As such, coordination of the selenium to a metal promotes centrosymmetric N−H···Se interactions in this system, with there being no comparable structures currently listed in the CSD. The existence of this motif is undoubtedly a consequence of the fact that iodide is, by comparison to chloride, a poor hydrogen bond acceptor, 60a such that N−H···Se interactions may compete with N−H···I interactions.
As would be expected, the hydrogen bonding N···I interactions in orthorhombic [H(sebenzim Me )] 2 HgI 2 [3.486(7) and 3.589(7) Å] are substantially longer than the analogous N···Cl interactions in [H(sebenzim Me )] 2 HgCl 2 . T h u s , w h i l e t h e m e a n N · · · C l d i s t a n c e i n [H(sebenzim Me )] 2 HgCl 2 is 3.182 Å, the mean N···I distance in orthorhombic [H(sebenzim Me )] 2 HgI 2 is 3.541 Å. For reference, the mean N···Cl distance for compounds listed in the CSD with N−H···Cl interactions involving a terminal metal chloride is 3.332 Å, 52 while the analogous N···I distance is 3.707 Å. 60 Interaction of 2-Seleno-1-methylbenzimidazole with Methylmercury Halides. In view of the fact that the protolytic cleavage of the Hg−C bond is a critical step in detoxification of organomercurials, 27h,i,61,62 and recognizing that H(sebenzim Me ) is an analogue of selenoneine, we have also investigated the reactivity of H(sebenzim Me ) towards methylmercury halides. Significantly, we have observed that H(sebenzim Me ) not only coordinates to the mercury center, as observed for HgX 2 , but it is also capable of cleaving the Hg−C bonds of MeHgX. For example, H(sebenzim Me ) reacts with MeHgI at 100°C to liberate CH 4 (as observed by 1 H NMR spectroscopy) and afford [H(sebenzim Me ) 2 ]HgI (Scheme 2). The importance of this observation is underscored by the fact that selenoneine, of which H(sebenzim Me ) is a structural analogue, has recently been shown to achieve demethylation of CysHgMe. 11e The molecular structure of [H(sebenzim Me ) 2 ]HgI has been determined by X-ray diffraction, as illustrated in Figure 15, which demonstrates that it features mercury in an approximately trigonal planar environment, with a pyramidality (P) value 63 of only 0.2°. The bond angles at mercury, however, deviate from 120°[Se−Hg−Se = 140.91(2)°; Se−Hg−I = 114.87(2)°and 104.02 (2)°], such that the geometry is distorted towards T-shaped, which is not uncommon for mercury. 64 The While the primary coordination environment about mercury is trigonal planar, it is evident that there are additional intermolecular Hg···Se interactions [3.0904(6) and 3.3215(6) Å] that are substantially longer than those within [H(sebenzim Me ) 2 ]HgI [2.5466(6) and 2.5748(6) Å], and which serve to link together adjacent molecules, as illustrated in Figure 16. In this regard, the extended coordination geometry of mercury may be viewed as five-coordinate and, with a τ 5 index 67 of 0.51, is intermediate between the idealized values for square pyramidal (τ 5 = 0) and trigonal bipyramidal (τ 5 = 1) geometries.
In view of the kinetic stability of two-coordinate RHgX complexes towards protolytic cleavage, 68   The molecular structure of [H(sebenzim Me ) 2 ] 2 Hg has been determined by X-ray diffraction (Figure 17), which demonstrates that pairs of H(sebenzim Me ) and (sebenzim Me ) ligands are linked together via hydrogen bonding interactions to produce the combined LX-type ligand, 71 [H(sebenzim Me ) 2 ], in  (14)

■ CONCLUSIONS
In summary, 1-methyl-1,3-dihydro-2H-benzimidazole-2-selone, H(sebenzim Me ), is a structural analogue of selenoneine and coordinates reversibly to the metal centers of HgX 2 (X = Cl, Br, I). Furthermore, H(sebenzim Me ) is also capable of cleaving the Hg−C bond of methylmercury halides, thereby mimicking the role of selenoneine in demethylating CysHgMe. X-ray diffraction studies demonstrate that while two equivalents of H(sebenzim Me ) simply coordinate to mercury centers of HgX 2 (X = Cl, I), the third and fourth equivalents result in displacement of the chloride ligands. ■ EXPERIMENTAL SECTION General Considerations. NMR spectra were measured on a Bruker Avance 500 DMX spectrometer. 1 H NMR spectra are reported in ppm relative to SiMe 4 (δ = 0) and were referenced internally with respect to the protio solvent impurity (δ 7.16 for C 6 D 5 H and 2.50 for DMSO-d 5 ). 72 13 C NMR spectra are reported in ppm relative to SiMe 4 (δ = 0) and were referenced internally with respect to the solvent (δ 128.06 for C 6 D 6 and 39.52 for DMSO-d 6 ). 72 77 Se NMR spectra are reported in ppm relative to neat Me 2 Se (δ = 0) and were referenced using a solution of Ph 2 Se 2 in C 6 D 6 (δ = 460) as an external standard. 73 199 Hg NMR spectra are reported in ppm relative to neat Me 2 Hg (δ = 0) and were referenced using a 1.0 M solution of HgI 2 in DMSO-d 6 (δ = −3106) as an external standard. 74 Coupling constants are given in hertz. IR spectra were recorded as KBr pellets on a Nicolet iS10 FT-IR spectrometer (ThermoScientific), and the data are reported in reciprocal centimeters. 1-methyl-1,3-dihydro-2H-benzimidazole-2-selone was obtained by a literature method, 31a and all other chemicals were purchased from Sigma-Aldrich.
CAUTION! All mercury compounds are toxic, and appropriate safety precautions must be taken in handling these compounds.

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