Cleavage of Hg-C Bonds of Organomercurials Induced by ImOHSe via Two Distinct Pathways

Article abstract of DOI:10.1021/acs.inorgchem.7b01301

We show that the N-methylimidazole-based selone Im^OHSe having an N-CH₂CH₂OH substituent has the remarkable ability to degrade methylmercury by two distinct pathways. Under basic conditions, Im^OHSe converts MeHgCl into biologically inert HgSe nanoparticles and Me₂Hg via the formation of an unstable intermediate (MeHg)₂Se (pathway I). However, under neutral conditions, in the absence of any base, Im^OHSe facilitates the cleavage of the Hg-C bond of MeHgCl at room temperature (23 °C), leading to the formation of a stable cleaved product, the tetracoordinated mononuclear mercury compound (Im^OHSe)₂HgCl₂ and Me₂Hg (pathway II). The initial rate of Hg-C bond cleavage of MeHgCl induced by Im^OHSe is almost 2-fold higher than the initial rate observed by Im^MeSe. Moreover, we show that Im^YSe (Y = OH, Me) has an excellent ability to dealkylate Me₂Hg at room temperature. Under acidic conditions, in the presence of excess Im^YSe, the volatile and toxic Me₂Hg further decomposes to the tetracoordinated mononuclear mercury compound [(Im^YSe)₄Hg]²⁺. In addition, the treatment of Im^OHSe with MeHgCys or MeHgSG in phosphate buffer (pH 8.5) afforded water-soluble Hg(SeS) nanoparticles via unusual ligand exchange reactions, whereas its derivative Im^OMeSe or Im^MeSe, lacking the N-CH₂CH₂OH substituent, failed to produce Hg(SeS) nanoparticles under identical reaction conditions.

Full text of DOI:10.1021/acs.inorgchem.7b01301

Article
Cite This: Inorg. Chem. XXXX, XXX, XXX-XXX
pubs.acs.org/IC
OH
Cleavage of Hg−C Bonds of Organomercurials Induced by Im Se via
Two Distinct Pathways
Mainak Banerjee and Gouriprasanna Roy*
Department of Chemistry, School of Natural Sciences, Shiv Nadar University, NH91, Dadri, Gautam Buddha Nagar, Uttar Pradesh
201314, India
*
S Supporting Information
ABSTRACT: We show that the N-methylimidazole-based selone ImOHSe having
an N−CH CH OH substituent has the remarkable ability to degrade
2
2
OH
methylmercury by two distinct pathways. Under basic conditions, Im Se
converts MeHgCl into biologically inert HgSe nanoparticles and Me Hg via the
2
formation of an unstable intermediate (MeHg) Se (pathway I). However, under
2
OH
neutral conditions, in the absence of any base, Im Se facilitates the cleavage of
the Hg−C bond of MeHgCl at room temperature (23 °C), leading to the
formation of a stable cleaved product, the tetracoordinated mononuclear mercury
OH
compound (Im Se) HgCl and Me Hg (pathway II). The initial rate of Hg−C
2
2
2
OH
bond cleavage of MeHgCl induced by Im Se is almost 2-fold higher than the
initial rate observed by Im Se. Moreover, we show that Im Se (Y = OH, Me) has
Me
Y
an excellent ability to dealkylate Me Hg at room temperature. Under acidic
2
Y
conditions, in the presence of excess Im Se, the volatile and toxic Me Hg further
2
decomposes to the tetracoordinated mononuclear mercury compound
Y
2+
OH
[
(Im Se) Hg] . In addition, the treatment of Im Se with MeHgCys or MeHgSG in phosphate buffer (pH 8.5) afforded
4
OMe
Me
water-soluble Hg(SeS) nanoparticles via unusual ligand exchange reactions, whereas its derivative Im Se or Im Se, lacking the
N−CH CH OH substituent, failed to produce Hg(SeS) nanoparticles under identical reaction conditions.
2
2
+
13,19
ethylmercury (MeHg ) is considered to be the most
toxic form of mercury in the environment due to its
mercury selenide (HgSe) particles.
HgSe has been found in
M
a wide range of tissues of marine mammals (whales and
15,19,20
ability to accumulate in fat tissues, leading to its biomagnifi-
cation within the food chain. It can easily cross both the
barriers at the blood−brain interface and at the placenta and
causes irreversible damage to the central nervous system
CNS) in both adult and developing brains. Studies have
shown that the nature and extent of mercury toxicity possibly
depend on its molecular form.
methylmercury may exist in the form of MeHgOH, whereas
in acidic medium, under high Cl conditions (in human
stomach), it may exist in the form of MeHgCl. On the other
hand, due to its high affinity for thiol groups, MeHg binds with
endogenous thiols such as cysteine (CysH) and glutathione
dolphins)
and also detected in various organs (kidney+,
1
liver, muscle, and brain) of humans exposed to MeHg
21
species. Reports suggest that the plasma Se-containing
protein, selenoprotein P (Sel P), may detoxify heavy metals
by sequestering them in the bloodstream. Sel P binds with
insoluble (HgSe) compounds, formed in the bloodstream of
rats by the coadministration of these two elements, and makes
2
,3
22
(
n
4
−7
In alkaline medium
22d
them soluble in the form of {(Hg−Se) } -Sel P complex.
n
m
−
+
Additionally, the synthesis of MeHg -conjugated complexes of
selenoamino acids (namely L-selenoglutathione, L-selenocys-
+
23
teine, D,L-selenopenicillamine, and L-selenomethionine), and
+
the cleavage of the Hg−C bond of MeHg aided by
(
GSH) to form MeHgCys and MeHgSG complexes in the
24
25−28
selenoamino acids, selenoneine,
and benzimidazole-
8
−12
tissues.
These complexes mainly determine the fate of
based selone (1-methyl-1,3-dihydro-2H-benzimidazole-2-se-
lone) have been reported in the literature. Recently, we
have shown that Im Se has the remarkable ability to convert
+
MeHg in the body, and in some cases they facilitate better
absorption and uptake of MeHg+ in tissues. For instance,
MeHgCys acts as a substrate for L-type large neutral amino acid
transporter (LAT1), which actively transports MeHg into
various tissues, including the brain.
It is well-known that the selenium, an important component
of many antioxidant enzymes, acts as an antagonist that
moderates the toxic effects of both inorganic and organic
29
OH
+
MeHgCl (or MeHgOH), in the presence of 1 equiv of KOH,
into insouble HgSe nanoparticles through a facile deseleniza-
tion process assisted by the neighboring group participation of
the −OH group of the N−CH CH OH substituent of the 1:1
13,14
2
2
OH
+
MeHg-conjugated complex [Im SeHgMe] , as illustrated in
30
OH
+
+
15−18
path A of Figure 1a. The complex [Im SeHgMe] (15 mM)
mercury, including MeHg in organisms.
Its pivotal role in
mercury detoxification is based on the strong affinity between
mercury and selenium and subsequent formation of organic and
inorganic compounds, including biologically inert and less toxic
Received: May 23, 2017
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.inorgchem.7b01301
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Inorganic Chemistry
Article
obtained (Figure 1a (path B) and Figure 1c (vial 1)). However,
after stirring for 3−4 days at 23 °C, we noticed a gradual
formation of a brownish yellow precipitate of the demethylated
OH
product (Im Se) HgCl (Figure 1c, vial 2), which was isolated
2
2
by filtration and characterized thoroughly (yield 53%).
OH
The coordination of Im Se to the mercury (Hg) center of
MeHgCl was studied in detail by NMR spectroscopy (Figures 3
Figure 1. (a) Dealkylation of MeHgCl by ImOHSe in the presence
(
path A) and absence of KOH (path B). (b) Mass spectra of
OH
OH
Im SeHgMeCl and (Im Se) HgCl . (c) Reaction vials showing the
formation of a brownish yellow precipitate of (Im Se) HgCl and
black HgSe NPs in the reaction of MeHgCl/Im Se in the absence
2
2
OH
2
2
OH
1
Figure 3. H NMR spectra showing the cleavage of the Hg−C bond
and presence of KOH, respectively.
OH
and the formation of Me Hg in the reaction of MeHgCl with Im Se
2
(1:1 molar ratio) at room temperature (23 °C). Mesitylene was used
as external standard. (*, mesitylene peak; #, CDCl3).
was gradually degraded to near completion in 48 h, in the
presence of 1 equiv of KOH, in water/acetonitrile (1/1) at 37
°
C (vial 3 in Figure 1c).
and 4). The addition of 1 equiv of ImOHSe (50 mM) into a
However, the treatment of ImOHSe (15 mM) with MeHgCl
15 mM) in water/acetonitrile (1/1) in the absence of KOH
solution of MeHgCl in CDCl (in NMR tube) showed a
3
(
did not produce any black precipitate of HgSe nanoparticles in
8 h at 37 °C (under identical reaction conditions). Instead, we
4
isolated a demethylated product, the mononuclear tetracoordi-
nated Hg(II) complex (ImOHSe) HgCl from the above
2
2
reaction solution (path B of Figure 1a). Herein we report, for
OH
the first time, that Im Se has an unique ability to demethylate
+
MeHg by two completely different pathways under two
different reaction conditions. Detailed studies on the cleavage
+
Y
of Hg−C bonds of various MeHg species aided by Im Se (Y =
OH, OMe, Me) are discussed in this paper.
RESULTS AND DISCUSSION
The N,N-disubstituted selones Im Se (Figure 2) which were
■
Y
used for this study were synthesized by following the literature
3
1
OH
procedure. When Im Se (50 mM) was treated with
MeHgCl (1:1 molar ratio) in water/acetonitrile (1/1) solution
at room temperature (23 °C), a clear colorless solution was
Figure 4. H (showing only the methyl signal of −HgMe) and 199Hg
1
Y
OH
Figure 2. Chemical structures of Im Se (Y = OH, OMe, Me).
NMR spectra of Im SeHgMeCl (a) and Me Hg (b) in CDCl .
2
3
B
DOI: 10.1021/acs.inorgchem.7b01301
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Inorganic Chemistry
Article
significant chemical shift in 199Hg NMR spectroscopy. The
Hg NMR signal of the above reaction solution appeared at
in polar aprotic solvent (DMSO-d ) have revealed that the
6
1
99
OH
−OH group of the N−CH CH OH substituent of Im Se did
2
2
−
730 ppm (Figure 4a), which was shifted almost 78 ppm
not participate in coordination to the mercury center and it
1
99
OH
downfield in comparison to the Hg NMR signal observed for
MeHgCl (−808 ppm)(Figure S8 in the Supporting Informa-
remained free in the reaction solution of Im Se and MeHgCl
(1:1 molar ratio), and in the isolated cleaved product
OH
OH
tion), indicating coordination between the Se atom of Im Se
(Im Se) HgCl (Figures S1, S4, and S6 in the Supporting
2 2
and the Hg center of MeHgCl leading to the formation of the
Information).
OH
1
:1 adduct Im SeHgMeCl (Figure 1a, path B).
Moreover, to know whether there is any role of N
Similarly, the 77Se NMR signal of the free ligand ImOHSe
OH
substitution of Im Se in the cleavage of the Hg−C bond,
OH
OMe
(
−3.8 ppm) has shifted slightly downfield upon addition of 1
we have employed two other derivatives of Im Se (Im Se
7
7
Me
OH
equiv of MeHgCl (50 mM). The Se NMR signal of the
solution of Im Se and MeHgCl (1:1 molar ratio) appeared at
and Im Se) in our study (Figure 2). Like Im Se, the
treatment of Im Se (50 mM, Y = OMe, Me) with MeHgCl (1:1
OH
Y
7
.1 ppm (Figure S3 in the Supporting Information). However,
molar ratio) in water/acetonitrile (1/1) solution, in the absence
199
77
the
Hg and Se NMR signals of the cleaved product
of KOH, afforded stable tetracoordinated Hg(II) complexes
OH
Y
(Im Se) HgCl were observed at −1165 and −39 ppm,
(Im Se)
HgCl
2
2
and Me Hg (Scheme 1). The initial rate of
2
2
2
respectively, in DMSO-d (Figure S7 in the Supporting
6
OH
Information, (Im Se) HgCl is insoluble in chloroform).
Scheme 1. Synthetic Scheme for the Formation of
2
2
Y
Although a high-resolution mass spectrometric analysis of the
(Im Se) HgCl
2
2
OH
resulting 1:1 adduct Im SeHgMeCl showed the mass of
OH
+
+
[
Im SeHgMe] (m/z of 420.9895 for [M − Cl] , Figure 1b),
without a chlorine atom; however, due to the strong affinity of
Cl for mercury, the chlorine atom presumably remained
−
attached to mercury in solution, and thus, it is more appropriate
OH
to represent this adduct as Im SeHgMeCl, rather than
OH
[
(
Im SeHgMe]Cl. The X-ray structure determination of
Y
Im Se) HgCl has confirmed that the Cl atoms indeed
2 2
OH
remained attached with Hg(II) (Figure 6). (Im+ Se) HgCl2
2
showed the m/z 646.9327 (mass of [M − Cl] , without a
chlorine atom) (Figure 1b).
OMe
Hg−C bond cleavage of MeHgCl by Im Se is (1.47 ± 0.29)
We have calculated the initial rate of cleavage of the Hg−C
−3
−1
×
10 M h , which is slightly slower than the initial rate of
−3
−1
bond of MeHgCl (initial rate = (2.00 ± 0.1) × 10 M h ) in
OH
Hg−C bond cleavage of MeHgCl by Im Se (Table 1). On the
OH
the presence of 1 equiv of Im Se (50 mM) at room
other hand, the initial rate of Hg−C bond cleavage of MeHgCl
1
temperature (23 °C) (Table 1). H NMR spectroscopy was
Me
−3
−1
by Im Se ((0.84 ± 0.07) × 10 M h ) is almost 2-fold
OH
slower than the initial rate obtained by Im Se (Figure 5 and
Table 1. Initial Rates of Cleavage of Hg−C Bonds of
Table 1).
Y
MeHgCl or EtHgCl Induced by Im Se
initial rate (10− M h−1
3
)
a
compd
Me−Hg bond
Et−Hg bond
ImOHSe
ImOMeSe
ImMeSe
2.00 ± 0.1
1.47 ± 0.29
0.84 ± 0.07
1.50 ± 0.16
0.98 ± 0.11
0.64 ± 0.13
a
All experiments were carried out at least three times in an NMR tube
Y
at room temperature (23 °C) in CDCl3 ([RHgX]/[Im Se] = 1;
[
RHgX] = 50 mM; R = Me, Et; see the Experimental Section).
used to calculate the initial rate by using mesitylene as external
standard (for more details please see the Experimental Section).
Significantly, during the progress of the reaction between
Im Se and MeHgCl at room temperature, we observed the
gradual disappearance of the methyl signal (1.08 ppm) of
Figure 5. Bar diagram showing the degradation of MeHgCl induced
OH
Y
by Im Se (Y = OH, Me) over time. The reactions were monitored by
1
H NMR spectroscopy by following the cleavage of Hg−C bonds at
−
HgCH in solution and the concomitant appearance of a new
sharp singlet resonance at 0.26 ppm by H NMR spectroscopy
3
room temperature (23 °C).
1
(
Figures 3 and 4).
The 199Hg NMR studies have confirmed the formation of
From X-ray crystal structures and quantum mechanical
calculations (DFT), it is evident that these three imidazole-
dimethylmercury (Me Hg) as a new product (Figure 4b) in the
reaction solution. The Hg NMR (proton-coupled) signal of
2
1
99
OH
Me
OMe
based selones (Im Se, Im Se, and Im Se) mainly exist in
zwitterionic form with a negative charge on the Se atoms and a
delocalized positive charge on the imidazole ring (Table 2 and
Figure S40 in the Supporting Information). The higher
Me Hg was observed as a heptet at −30.5 ppm in CDCl
2
3
32
2
199
1
(
−113 ppm in DMSO-d ). The J( Hg− H) coupling
6
OH
constant values for the 1:1 adduct Im SeHgMeCl and Me Hg
2
OH
were 204 and 102 Hz, respectively (Figure 4), indicating that
reactivity of Im Se in comparison to the two other derivatives
2
199
1
J( Hg− H) coupling constant values are influenced by the
is probably due to the presence of a more negative charge on
1
OH
nature of the X group of MeHgX. In addition, H NMR studies
the Se atom of Im Se (−0.32 au) in comparison to that in
C
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Inorganic Chemistry
Article
Table 2. C−Se Bond Lengths, Bond Orders, and Charges on
Y
Se Atoms of Im Se
C−Se bond length (Å)
C−Se bond order
charge on Se
a
a
compd
(calcd)
(calcd)
(au)
ImOHSe
ImOMeSe
ImMeSe
1.856
1.843
1.837
1.274
1.340
1.356
−0.316
−0.286
−0.271
a
Optimization and natural bond orbital (NBO) analysis was
performed at the B3LYP/6-311++G(2d,p) level of theory (details
are mentioned in the Experimental Section).
ImOMeSe (−0.29 au) or Im Se (−0.27 au) (Table 2). This
Me
could possibly lead to the formation of a strong bond between
OH
the Se atom of Im Se and the Hg atom of MeHgCl, which
may eventually help in the weakening, and hence facile
cleavage, of the Hg−CH bond. The higher negative charge
3
OH
on the Se atom of Im Se is probably due to the presence of
hydrogen bonding between the Se atom of one molecular unit
with the OH group of other molecular unit as shown in the
crystal structure, leading to the formation of a chainlike
structure (Figure S44 in the Supporting Information).
Consequently, because of this H bonding, the C−Se bond
OH
length of Im Se has increased substantially in comparison to
Me
OMe
the C−Se bond lengths of Im Se and Im Se (Table 2).
OMe
The tetracoordinated mercury complexes (Im Se) HgCl2
2
Me
(
yield 37%) and (Im Se) HgCl (yield 29%) were isolated
2 2
from the respective reaction solutions and characterized
OMe
thoroughly. The single-crystal X-ray analyses of (Im Se)2-
3
3
Me
OMe
HgCl (τ = 0.96) and (Im Se) HgCl (τ = 1.02) have
Figure 6. ORTEP images of (a) (Im Se) HgCl and (b)
2 2
2
2
2
Me
confirmed the tetrahedral geometry at the mercury center of
both complexes (Figure 6). The two Hg−Cl and Hg−Se bonds
(Im Se) HgCl .
2 2
OMe
in (Im Se) HgCl are equal in length (Hg−Cl1 = Hg−Cl2 =
2
2
2
.526 Å; Hg−Se1 = Hg−Se1′ = 2.609 Å). The C−Se bond
OMe
length in (Im Se) HgCl is significantly longer (C2−Se1 =
2
2
C2′−Se1′ = 1.868 Å) in comparison to that in the free ligand
OMe
Im Se (C2−Se = 1.837 Å (Experimental) Table S5 in the
Supporting Information), indicating a quite strong interaction
between Se and Hg(II) atoms in the complex
OMe
(
Im Se) HgCl2 (Tables S2 and S3 in the Supporting
2
Information). Moreover, because of the coordination to the
mercury center through the p-type lone pair of the Se atom of
Y
Y
Im Se, the zwitterionic character of the mercury-bound Im Se
Y
in tetracoordinated Hg(II) complexes (Im Se) HgCl is
increased substantially in comparison to that in free Im Se
Figures S41−S43 in the Supporting Information). The
overall positive charge on the imidazole ring of bound Im Se of
Im Se) HgCl has also increased significantly in comparison
to that in free Im Se. As a consequence of the coordination to
the mercury center, the H NMR spectra of (Im Se) HgCl
2
2
Y
3
4
(
Y
Y
(
2 2
Y
1
Y
2
2
showed a significant downfield shift of the proton resonance of
Y
bound Im Se in comparison to the proton resonance of free
Y
Im Se (Figures S15−S17 in the Supporting Information).
Crystal-packing arrangements of (ImOMeSe) HgCl in the
2
2
solid state show the presence of nonbonded intermolecular C−
Figure 7. Crystal packing of (ImOMeSe) HgCl showing intermolecular
2 2
OMe
H····Cl hydrogen-bonding interactions in (Im Se) HgCl .
C−H····Cl (a) and C−H····Cl (b) hydrogen bonding interactions. (c)
2
2
Me
Two Cl atoms of one molecular unit are forming strong
Crystal packing of (Im Se) HgCl showing intermolecular C−H···Cl
2
2
intermolecular C−H····Cl hydrogen bonding (d
= 2.689
hydrogen bonding and the π−π interaction between two imidazole
CH···Cl
rings.
Å) with the olefinic H atom (or (imidazole)CH) of two
different molecular units on either side of the molecule leading
to the formation of a zigzag-like network, as shown in Figure
also present between the two molecular units in the solid-state
crystal structure, as illustrated in Figure 7b. On the other hand,
7
a. In addition to that, strong nonbonded intermolecular C−
Me
H····O hydrogen-bonding (d = 2.517 Å) interactions are
in the case of (Im Se) HgCl , the H atom of the −NMe group
CH···O
2
2
D
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Inorganic Chemistry
Article
and the olefinic H atom of one molecular unit are forming
distinct nonbonded intermolecular C−H···Cl hydrogen-
bonding interactions with the Cl atoms of other molecular
unit (dImCH···Cl = 2.877 Å; d(NMe)H···Cl = 2.737 Å), leading to the
formation of a dimeric structure (Figure 7c). In addition to
that, the presence of a distinct π−π interaction between the two
imidazole rings of two different molecular units of
Me
(
Im Se) HgCl is observed in the crystal-packing geometry.
2 2
The π−π interfacial distance between the two imidazole rings in
3
5
the crystal lattice is 3.387 Å, as shown in Figure 7c.
Y
In order to investigate the effect of Im Se on the cleavage of
Hg−C bonds of other organomercurials, we have employed
ethylmercury chloride (EtHgCl) in our study. The treatment of
Y
Im Se (50 mM; Y = OH, Me, OMe) with EtHgCl (1:1 molar
ratio) in water/acetonitrile (1/1) solution at room temperature
Y
yielded the 1:1 adduct Im SeHgEtCl. However, we noticed the
Y
gradual cleavage of Hg−C bonds of Im SeHgEtCl and the
Y
formation of stable Hg(II) complexes [(Im Se) HgCl ] and
2
2
36
diethylmercury (Et Hg). The cleavage of the Hg−C bond of
EtHgCl aided by Im Se was followed by NMR spectroscopy
2
Y
(
Figures 8 and 9 and Figure S19 in the Supporting
1
Figure 9. H (showing only the ethyl peak of −HgEt group) and
199
OH
Hg NMR spectra of Im SeHgEtCl (a) and Et Hg (b) in CDCl .
2
3
24
and Me Hg. In nature, the conversion of methylmercury to
2
Me Hg in the presence of H S has also been reported in the
2
2
37,38
literature.
Moreover, Baldi and co-workers have reported
that the sulfate-reducing bacteria (two different axenic cultures
of strains of the mercury resistance sulfate-reducing bacterium
Desulfovibrio desulfuricans) showed mercury tolerance by
converting toxic methylmercury to less toxic insoluble HgS(s)
and Me Hg via the formation of unstable intermediate
2
39−41
1
(
MeHg) S.
The volatile hydrocarbon CH was detected
Figure 8. H NMR spectra, in CDCl , showing the cleavage of the
2
4
3
Hg−C bond of EtHgCl and the formation of Et Hg in the reaction of
EtHgCl/Im Se (1:1 molar ratio) at 23 °C. Mesitylene was used as an
external standard (*, mesitylene peak; #, CDCl3).
in the D. desulfuricans cultures spiked with MeHgCl, and the
possible pathway of formation of CH4 was due to the
2
OH
degradation of Me Hg under the acidic conditions (pH 6.3)
2
3
9
of cultures. Several reports suggest that Me Hg may
2
Information). The 199Hg NMR (proton-coupled) signal of
decompose slowly into methylmercury and CH under acidic
4
3
9,42
conditions (Scheme 2).
Furthermore, the protolytic
Et Hg was observed at −328.5 ppm in CDCl (Figure 9b). The
2
3
2
199
1
3
199
1
J( Hg− H) and J( Hg− H) coupling constant values for
2
199
1
Scheme 2. Decomposition of Me Hg in the Absence and
Et Hg were 96.8 and 126.6 Hz, respectively. The J( Hg− H)
2
2
Y
3
199
1
Presence of Excess Im Se, under Acidic Conditions
and J( Hg− H) coupling constant values for the 1:1 adduct
OH
Im SeHgEtCl were 199 and 299.2 Hz, respectively (Figure
9
a). Significantly, the initial rates of the Hg−Et bond cleavage
Y
by Im Se were found to be slightly slower than the initial rates
of cleavage of the Hg−Me bond by Im Se under identical
reaction conditions (Table 1).
Y
The formation of highly toxic volatile Me Hg in the reaction
2
Y
of MeHgCl and Im Se (1:1 molar ratio) is a serious concern
considering the usefulness of these imidazole-based selones in
the context of detoxification of neurotoxic methylmercury.
Khan and co-workers have studied the demethylation of
methylmercury by several selenoamino acids, including
naturally occurring L-selenocysteine (one of the components
of several seleno-enzymes including selenoprotein P, gluta-
thione peroxidase, and thioredoxin reductase), where they have
reported the conversion of toxic methylmercury to the unstable
cleavage of the Hg−C bond of methylmercury induced by N-
methyl-substituted benzimidazole-based selone (1-methyl-1,3-
dihydro-2H-benzimidazole-2-selone) and subsequently the
29
liberation of CH has been reported by Parkin et al. The
4
report suggests that Me Hg is notoriously inert toward cleavage
2
of the Hg−C bond under physiological conditions, and it reacts
very slowly with biologically relevant dithiol, dihydrolipoic acid
derivative, at 37 °C to cleave one of the Hg−CH bonds;
3
intermediate bis(methylmercuric)selenide (MeHg) Se (half-life
however, cleavage of the second Hg−CH bond could not be
2
3
43
∼1 h), which was readily degraded to biologically inert HgSe(s)
achieved.
E
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We have studied the demethylation of Me Hg in the
2
presence or absence of nucleophilic selenium compounds
Y
Y
Im Se ([Im Se]/[Me Hg] = 4; Y = OH, Me) under acidic
2
conditions (in the presence of 1 equiv of formic acid or
1
tetrafluoroboric acid) by H NMR spectroscopy. The rate of
Hg−C bond cleavage of Me Hg was found to be almost 2-fold
2
OH
faster in the presence of Im Se (Figure 10). The initial rates
Me
2+
Figure 11. Molecular structure of the cation [(Im Se) Hg] of
[
4
Me
−
(Im Se) Hg](BF ) . Two BF anions are removed for clarity.
4 4 2 4
Figure 10. Demethylation of Me Hg under acidic conditions in the
presence and absence of Im Se (for more details see the
Experimental Section).
2
OH
MeHgCl is completely dependent upon the reaction con-
ditions. Under basic conditions, the treatment of MeHgCl with
OH
Im Se afforded the highly unstable 1:1 MeHg-conjugated
OH
complex [Im SeHgMeHg]OH, which was readily degraded
OH
of cleavage of the Hg−CH bond of Me Hg in the presence
into Im O and (MeHg) Se. The unstable (MeHg) Se was
3
2
2
2
OH
−4
and absence of Im Se are (14.1 ± 0.01) × 10 and (7.5 ±
further decomposed into insoluble HgSe(s) nanoparticles and
0
.01) × 10− M h , respectively. Under acidic conditions,
4
−1
Me Hg, as shown in pathway I in Scheme 3a. The ketone
30a
2
+
OH
Me Hg was degraded to MeHg and CH (Scheme 2 and
Im O was formed in the reaction via the formation of the
2
4
Figures S20 and S21 in the Supporting Information). However,
positively charged cyclic intermediate I (Scheme 3b,c). DFT
calculations showed that the nucleophilic attack at the C1
center of the unstable intermediate I was thermodynamically
more favorable (35.7 kcal/mol, path A) over the nucleophilic
attack at the C2 center (path B) (Figure S46 in the Supporting
Information). The C1−O bond length is 1.487 Å, which is
much longer (and weaker) than the C2−O bond length (1.312
during the decomposition of Me Hg in the presence of excess
2
Y
Im Se (Y = OH, Me), we did not observe the formation of
significant amounts of MeHg from Me Hg, indicating that the
MeHg , produced during the decomposition of Me Hg, further
+
2
+
2
Y
reacted with Im Se (excess) to form the tetracoordinated
Y
2+
Hg(II) complex [(Im Se) Hg] . The near-completion of
4
OH
degradation of Me Hg (50 mM) was observed in the presence
Å), and thus, the formation of ketone Im O through path A is
2
Y
of excess Im Se (1:4 molar ratio) under acidic conditions. Nice
possibly the favorable pathway (Scheme 3c). On the other
Me
OH
cubic-shaped colorless crystals of [(Im Se) Hg](BF ) were
hand, the reactions of MeHgCl with Im Se, in the absence of
4
4 2
Me
isolated from the reaction solution of Me Hg/Im Se/HBF
KOH (under neutral conditions), yielded the 1:1 adduct
2
4
OH
(
1:4:1 molar ratio) in DMSO-d in an NMR tube after long
Im SeHgMeCl at room temperature. However, in the
6
OH
standing (Figure 11 and the Experimental Section). The single-
presence of the electron-donating ligand Im Se, facile
Me
crystal X-ray structure analysis of [(Im Se) Hg](BF )
cleavage of the Hg−CH bond was observed, leading to the
4
4
2
3
Me
showed that all four Se atoms of Im Se are coordinated to
the same Hg(II) atom in an unsymmetrical manner, as
formation of Me Hg and stable tetracoordinated mononuclear
2
OH
mercury complex (Im Se) HgCl2 via the possible four-
2
illustrated in Figure 11. The Hg−Se bond lengths in
membered cyclic intermediate II, as mentioned in Scheme 3a
(pathway II) and Scheme 3c. The exchange of R and X atoms
between the Hg−R/Hg−X groups through a four-membered
Me
[
(Im Se) Hg](BF ) are comparable to the mean value of
4 4 2
2
.643 Å for compounds listed in the Cambridge Structural
29,44
45
Database.
The Se2 and Se4 atoms are coordinated strongly
cyclic intermediate has been reported in the literature.
to the tetrahedral Hg(II) center (dHg−Se2 = 2.618 Å, dHg−Se4
.607 Å), whereas the other two selenium atoms, Se1 and Se4,
are coordinated relatively weakly to the same Hg(II) center
dHg−Se1 = 2.660 Å, d = 2.639 Å). Crystal-packing
=
It is well-known that methylmercury binds with endogenous
thiols, including cysteine and glutathione, in tissues. Studies
8
2
have shown that hemoglobin (Hb) is a major methylmercury
binding protein in the blood of marine mammals (dolphin) and
the cysteine residue on the dolphin Hb β-chain is found to be
(
Hg−Se3
Me
arrangements of [(Im Se) Hg](BF ) in the solid state
4
4 2
46
showed the presence of multiple nonbonded intermolecular
C−H····F hydrogen-bonding interactions (Figure S23 in the
Supporting Information). Selected bond lengths and bond
angles are given in Table S4 in the Supporting Information.
On the basis of our experimental observations we found that
the nature of the final product in the reaction of ImOHSe and
the main binding site. The cysteine-conjugated methylmer-
cury complex MeHgCys is known to facilitate methylmercury
uptake into various tissues. For instance, mice treated with
MeHgCys had approximately 50% and 250% increased uptake
of mercury in brain and liver, respectively, in comparison with
8
mice treated with MeHgCl. On the other hand, methyl-
F
DOI: 10.1021/acs.inorgchem.7b01301
Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry
Article
Scheme 3. Proposed Pathways of Degradation of MeHgCl by
OH
Im Se
Figure 12. (a) Synthetic scheme for the degradation of MeHgCys or
OH
MeHgSG by Im Se and reaction vials showing the formation of
OH
Hg(SeS) NPs in the reaction of MeHgCys/Im Se in PBS buffer (pH
8
.5) at 37 °C. TEM (b) and EDX (c) images of Hg(SeS) NPs
OH
mercury is known to decrease the intracellular GSH content by
forming the glutathione-conjugated methylmercury complex
MeHgSG, and thereby it increases the production of reactive
oxygen species (ROS) in various tissues leading to DNA
damage, protein oxidation, lipid peroxidation, and cell
obtained in the reaction of MeHgCys/Im Se. Graphs showing the
production of free cysteine (d) and glutathione (e) in the reaction of
MeHgCys/Im Se and MeHgCys/Im Se at 72 h, respectively.
OH
OH
average size of 17 nm (Figure 12b). FT-IR and EDX analyses
have confirmed the binding of cysteine molecules on the
surface of HgSe nanoparticles (Figure S31 in the Supporting
Information). EDX analysis showed the presence of both Se
(atom % 20.41) and S (atom % 12.67) elements in HgSe
nanoparticles. In addition, we have also detected the presence
of free cysteine (8% of MeHgCys at 72 h) in the reaction
1
5,47
death.
Therefore, as part of this current study, we have
OH
also investigated the ability of Im Se to degrade other
methylmercury species such as MeHgCys and MeHgSG.
When MeHgCys (30 mM, m/z 338.0142) was treated with
OH
Im Se in a 1:1 molar ratio in phosphate buffer (pH 8.5), the
nearly colorless solution turned gray to blackish gray over the
OH
time as the reaction was allowed to proceed at 37 °C (Figure
solution of Im Se and MeHgCys (in 1:1 molar ratio) after 72
12a, reaction vials). Aliquots of the above reaction solution
h of stirring at 37 °C (Figure 12d). The amounts of free
cysteine present in solution were determined by Ellman’s
reagent (Figure S38 in the Supporting Information). These
observations clearly suggest that the cysteine residues released
during the reaction were distributed in two parts: few cysteine
molecules remained free in the solution, and the remaining
cysteine molecules attached with HgSe NPs to make water-
soluble Hg(SeS) nanoparticles (Hg(SeS) hereafter)). The
above reaction was also performed in water in the presence
were collected at various time intervals to monitor the reaction
by HPLC (Figure S29 in the Supporting Information). HPLC
studies showed that the peak area corresponding to the MeHg-
OH
conjugated complex [Im SeHgMe]Cys (m/z 420.9915) at a
retention time of 10.95 min decreased gradually, indicating that
OH
the complex [Im SeHgMe]Cys was unstable at pH 8.5. After
near-completion of the reaction in 72 h we isolated the blackish
gray HgSe nanoparticles by centrifugation. The corresponding
OH
ketone Im O (at a retention time of 7.01 min in the HPLC
of 2 equiv of the weak base NaHCO (the pH of the solution
3
chromatogram) was isolated (yield 27%) from the supernatant
was found to be 8.5) and, similar to the previous case, we
observed the formation of blackish gray water-soluble Hg(SeS)
nanoparticles.
1
99
and characterized thoroughly. The Hg NMR with a peak at
113 ppm in DMSO-d confirmed the formation of Me Hg in
−
6
2
the reaction solution (Figure S34 in the Supporting
Information). A TEM image of HgSe nanoparticles showed
that the particles were small and spherical in nature with an
Likewise, we also noticed that ImOHSe could successfully
+
compete with tripeptide GSH for MeHg and convert it into
water-soluble Hg(SeS) nanoparticles either in PBS buffer of pH
G
DOI: 10.1021/acs.inorgchem.7b01301
Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry
.5 or in water plus 2 equiv of NaHCO at 37 °C. Hg(SeS)
nanoparticles obtained in the reaction of Im Se and MeHgSG
were isolated and analyzed thoroughly by various techniques.
TEM analysis showed that the nanoparticles were spherical in
shape with an average size of 8 nm, whereas EDX and FT-IR
confirmed the binding of GSH molecules on the surface of
HgSe nanoparticles. The presence of free GSH was detected by
LC/MS, and subsequently it was quantified by Ellman’s reagent
Article
8
physiological temperature via an efficient deselenization process
assisted by the neighboring group participation of the OH
group of the N−CH CH OH moiety of Im Se (pathway I).
On the other hand, under neutral conditions, in the absence of
any base, the treatment of MeHgCl with Im Se yielded the
stable cleaved products (Im Se) HgCl and Me Hg (pathway
3
OH
OH
2
2
Y
Y
2
2
2
OH
II). Moreover, we have also shown that Im Se has a
remarkable ability to convert MeHgCys or MeHgSG (cysteine
or glutathione conjugated with methylmercury) to water-
soluble Hg(SeS) nanoparticles via an efficient deselenization
(14.5% of MeHgSG) (Figure 12e). A detailed analysis of the
supernatant of the reaction solution has confirmed the
OH
OH
formation of Im O and Me Hg in the reaction.
process. During this ligand exchange reaction between Im Se
2
In contrast, when MeHgCys or MeHgSG (30 mM) was
and MeHgCys or MeHgSG, we observed the release of free
thiol CysH or GSH into the solution. However, the other
selone derivatives Im Se and Im Se that are devoid of a
−NCH CH OH substituent failed to convert MeHgCys or
MeHgSG to Hg(SeS) nanoparticles under identical reaction
Me
OMe
treated with Im Se (or Im Se), which is lacking a N−
Me
OMe
CH CH OH substituent, in 1:1 molar ratio in PBS buffer of pH
2
2
8
.5 (or in water plus 2 equiv of NaHCO ) at 37 °C, we did not
3
2
2
observe the formation of blackish gray HgSeS nanoparticles in
2 h. These observations clearly suggest that the N−
7
conditions. Finally, we showed that, under acidic conditions, in
OH
Me
CH CH OH substituent of Im Se plays a very crucial role
2
2
the presence of excess Im Se the volatile and toxic Me Hg
2
Me
2+
in the cleavage of the (Im)C2−Se bond upon coordination to
further degraded into [(Im Se) Hg] .
4
the mercury center of methylmercury, leading to the formation
OH
of HgSe nanoparticles and Im O in the presence of base, as
EXPERIMENTAL SECTION
■
shown in Schemes 1 and 3. Significantly, although the
OH
General Experimental Considerations. Methylmercury chloride
and ethylmercuric chloride were obtained from Alfa Aesar. Selenium
powder was obtained from Sigma-Aldrich, and other chemicals were
obtained from local companies. Synthetic procedures of compounds
treatment of Im Se (30 mM) with MeHgCys (30 mM) in
water (or PBS buffer of pH 7.0) in the absence of any base at
3
7 °C did not produce any blackish gray Hg(SeS) nano-
particles, we did however observe the gradual cleavage of the
Y
Im Se (R = OH, OMe, Me) are detailed in the Supporting
OH
Hg−C bond of MeHgCys aided by Im Se under neutral
conditions, as shown in Figure S37 in the Supporting
Information.
Information. All experiments were carried out under anhydrous and
anaerobic conditions using standard Schlenk techniques for the
synthesis. Electrospray ionization high-resolution mass spectrometry
(ESI-HRMS) was carried out with an Agilent 6540 accurate mass Q-
TOF LC/MS (Agilent Technologies) instrument. High-performance
liquid chromatography (HPLC) experiments were carried out on a
Waters Alliance System (Milford, MA) consisting of an e2695
separation module and a 2998 photodiode-array detector. The HPLC
system was controlled with EMPOWER software (Waters Corpo-
In summary, we have shown that, under basic conditions (at
OH
pH 8.5), the imidazole-based selone Im Se having a N−
CH CH OH substituent converts MeHgCl into insoluble HgSe
2
2
nanoparticles and Me Hg. However, under neutral conditions
2
OH
(
at pH 7), Im Se facilitates the cleavage of the Hg−C bond of
MeHgCl and produces Me Hg and the cleaved product, the
tetracoordinated complex (Im Se) HgCl . Similarly, under
basic conditions (at pH 8.5), the treatment of Im Se with
2
1
13
77
OH
ration, Milford, MA). H (400 MHz), C (100 MHz), Se (76.3
2
2
199
MHz), and Hg (71.6 MHz) NMR spectra were obtained on a
OH
1
13
Bruker Advance 400 NMR spectrometer. Chemical shifts ( H, C) are
MeHgCys leads to the formation of water-soluble Hg(SeS)
199
cited with respect to tetramethylsilane (TMS). Hg NMR spectra are
OH
nanoparticles, whereas at a neutral pH of 7, Im Se facilitates
reported in ppm relative to neat Me Hg (δ 0 ppm), and HgCl (δ
2
2
the cleavage of the Hg−C bond of MeHgCys. It is worth
−1501 ppm for 1 M solution in DMSO-d ) was used as an external
6
32a
mentioning here that the presence of Hg(S Se ) species was
standard.
Synthetic Procedure for Tetracoordinated HgCl
0
.3 0.7
observed in the liver of striped dolphin (Stenella coeruleoal-
2
Complexes
of N,N-Disubstituted Selones. Synthesis of (Im Se) HgCl . To a
OH
2
0d
ba).
The formation of Hg−Se−S species in the blood of
2
2
solution of MeHgCl (27.6 mg, 0.11 mmol) or EtHgCl (30.2 mg, 0.11
mmol) in 4 mL of water/acetonitrile (1/1) was added 1 equiv of
Im Se (22.5 mg, 0.11 mmol), and the reaction mixture was stirred at
room temperature (23 °C) for 7 days to obtain a brown precipitate of
Im Se) Cl , which was isolated by filtration and washed with
rabbits treated with a mixture of mercuric chloride and sodium
selenite has also been identified.
48,49
The formation of water-
OH
soluble Hg(SeS) nanoparticles in the chemical degradation of
MeHgCys or MeHgSG by benzimidazole-based selone has
OH
(
50
2 2
recently been reported by our group. Significantly, we found
acetonitrile (2 × 5 mL) followed by hexane (2 × 5 mL). Yield: 43 mg
53%). H NMR of (Im Se) Cl (DMSO-d ): δ (ppm) 3.71 (m,
Y
1
OH
that the imidazole-based selones Im Se have an excellent ability
(
2 2 6
to demethylate both of the Hg−C bonds of highly inert
10H), 4.22 (t, J = 5.60 Hz, 4H), 4.45 (bs, 2H), 7.61−7.65 (m, 4H).
13
Me Hg. Under acidic conditions, in the presence of excess
C NMR (DMSO-d ): δ (ppm) 37.8, 52.9, 59.6, 123.5, 123.7, 141.3,
6
2
Me
77
199
Im Se, the volatile and toxic Me Hg degrades into CH and
141.5. Se NMR (DMSO-d ): δ (ppm) −39. Hg NMR (DMSO+-
2
4
6
the tetracoordinated mononuclear mercury compound
d
6
): δ (ppm) −1165. HR-ESIMS (m/z): calcd for [M − Cl]
Me
2+
C H HgN O Se Cl 646.9300, found 646.9327.
[
(Im Se) Hg] .
12 20
4
2
2
2
4
OMe
OMe
Synthesis of (Im Se) HgCl . Compound (Im Se) HgCl was
In conclusion, our experimental observations strongly
2
2
2
2
obtained as a white crystalline material by following a procedure
suggest that the degradation of methylmercury aided by
OH
OMe
Y
similar to that for (Im Se)
2
HgCl
2
, except Im Se (24 mg, 0.11
Im Se (Y = OH, OMe, Me) can be achieved at physiological
OH
1
mmol) was added in place of Im Se. Yield: 30 mg (37%). H NMR
of (Im Se) HgCl (DMSO-d ): δ (ppm) 3.25 (s, 6H), 3.69 (t, J =
temperature via two different pathways; pathway I and pathway
II. Significantly, the pathway of the cleavage of Hg−C bonds of
OMe
2
2
6
5
2
.6 Hz, 4H), 3.77 (s, 6H), 4.34 (t, J = 5.6 Hz, 4H), 7.617 (d, J = 2 Hz,
Y
13
MeHgCl by Im Se is critically dependent on the nature of the
H), 7.66 (d, J = 2.4 Hz, 2H), C NMR (DMSO-d ): δ (ppm) 37.8,
6
Y
77
N substitutent Y of Im Se and the reaction conditions. Under
50.0, 58.6, 69.9, 123.4, 141.7. Se NMR (DMSO-d ): δ (ppm) −40.
6
OH
199
basic conditions, the reaction of MeHgCl with Im Se (1:1
Hg NMR (DMSO-d ): δ (ppm) −1236. HR-ESIMS (m/z): calcd
6
+
molar ratio) afforded biologically inert HgSe and Me Hg at
for [M − Cl] C H HgN O Se Cl 674.9614, found 674.9618.
2
14 24
4
2
2
2
H
DOI: 10.1021/acs.inorgchem.7b01301
Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry
Article
Me
Me
Synthesis of (Im Se) HgCl . Compound (Im Se) HgCl2 was
electron microscope in conjunction with a Bruker EDX system. FT-IR
analyses of Hg(SeS) NPs were recorded on a Nicolet iS5 spectrometer
2
2
2
obtained as a white crystalline material by following a procedure
OH
Me
−1
similar to that of (Im Se) HgCl , except Im Se (19 mg, 0.11 mmol)
equipped with an iD5-ATR accessory, in the range of 4000−400 cm
2
2
OH
1
−1
was added in place of Im Se. Yield: ∼26 mg (29%). H NMR of
Im Se) HgCl (DMSO-d ): δ (ppm) 3.77 (s, 6H), 7.67 (s, 2H),
with a resolution of 4 cm .
Me
13
(
C
General Procedure for the Degradation of MeHgSG by
2
2
6
OH
OH
77
Im Se. Im Se (37.5 mg, 180 μmol) was added to a solution of
MeHgSG (90 μmol) in 3 mL of PBS buffer (pH 8.5), and the reaction
mixture was stirred at 37 °C. The clear solution gradually turned black
after 6 h. After completion of the reaction, the black Hg(SeS) was
isolated by centrifugation and washed thoroughly with water followed
by acetonitrile. Hg(SeS) powder was dried completely under vacuum
and characterized thoroughly by various techniques such as SEM,
TEM, EDX, and IR analysis (common procedure is mentioned above).
X-ray Crystal Analysis. The crystallization techniques of
NMR (DMSO-d ): δ (ppm) 38.0, 124.0, 140.5. Se NMR (DMSO-
6
199
d ): δ (ppm) −40. Hg NMR (DMSO-d ): δ (ppm) −1229. HR-
6
6
+
ESIMS (m/z): calcd for [M − Cl] C H HgN Se Cl 586.9088,
10
16
4
2
2
found 586.9123.
Synthesis of [(Im Se) Hg](BF ) . To a solution of Me Hg (50
Me
4
4 2
2
mM) in DMSO-d were added 1 equiv of tetrafluoroboric acid (45% in
water) and 4 equiv of Im Se (21.1 mg, 0.12 mmol) in an NMR tube
at room temperature (23 °C). The NMR tube was placed in a shaker
for continuous gentle shaking for another 10 days, and then it was kept
in the dark without shaking for crystallization. Cubic-shaped colorless
single crystals were obtained after long standing, and the structure was
6
Me
OMe
Me
compounds (Im Se) HgCl2 (CCDC 1541412), (Im Se) Cl
2
2
2
Me
51
(
CCDC 1541411), and [(Im Se) Hg](BF ) (CCDC 1567515)
4 4 2
1
are mentioned above. Crystal structures of these compounds were
determined by measuring X-ray diffraction data on a D8 Venture
Bruker AXS single-crystal X-ray diffractometer equipped with a CMOS
PHOTON 100 detector having monochromated microfocus sources
analyzed by X-ray crystallography. Yield: 11 mg, 9%. H NMR
DMSO-d ): δ (ppm) 4.06 (s, 1H), 7.47 (s, 1H). C NMR (DMSO-
13
(
6
77
d ): δ (ppm) 37.6, 123.5, 142.8. Se NMR (DMSO-d ): δ (ppm)
6
6
32. 1 Hg NMR (DMSO-d ): δ (ppm) −1045.
99
−
6
(
Mo Kα 0.71073 Å). All of the crystal data were collected at room
Procedure of Kinetic Studies for the Cleavage of Hg−C
Y
temperature. The structure was solved using the SHELX program
implemented in APEX3.
Bonds by Im Se (Y = OH, OMe, Me). We have determined the
5
2−55
1
The non-H atoms were located in
cleavage of Hg−C bonds of RHgCl (R = Me, Et) by H NMR
spectroscopy by following the procedure described below. To a
solution of RHgCl (50 mM) in CDCl was added 1 equiv of Im Se in
an NMR tube at room temperature (23 °C), and the reaction was
monitored at various time intervals by H NMR spectroscopy.
Mesitylene (12 mM) was used as an external standard. In order to find
out the rates of cleavage of Hg−C bonds of RHgX, the integral value
of the aromatic singlet resonance of mesitylene was considered as one
proton. The integral values of the singlet resonance of MeHg
−CH ) and the triplet resonance of the methyl group (−CH ) of
EtHgCl with respect to the aromatic singlet resonance of mesitylene
were considered for the calculation of rates. The integral values at 0
min were assumed as 100% RHgCl (50 mM). All reactions were
performed at least three times, and the rates are expressed as means ±
standard deviation.
successive difference Fourier syntheses and refined with anisotropic
thermal parameters. All of the hydrogen atoms were placed at
calculated positions and refined using a riding model with appropriate
HFIX commands. The program Mercury was used for molecular
Y
3
1
5
6
OMe
packing analysis. Crystal data for compounds (Im Se) HgCl ,
(
2
2
Me
Me
Im Se) HgCl , and [(Im Se) Hg](BF ) are given in the
2 2 4 4 2
Supporting Information.
+
Computational Details. All of the calculations of Table 2 and
Scheme 3 were performed by using the B3LYP level of theory as
implemented in the Gaussian 09 package. For structure optimization
the 6-311++G(2d,p) basis set was used for all atoms except Hg. The
Stuttgart−Dresden basis set (SDD) was used for Hg to treat the
(
3
3
(scalar) relativistic effects of the heavier atom, and the SDD basis set
for the Hg atom was used with the corresponding relativistic effective
5
7
core potential. The NBO version 3.1 program implemented in
Gaussian 09 was used to perform NPA for the calculation of natural
Procedure for the Kinetic Studies for Decomposition of
Y
Me Hg in the Presence or Absence of Im Se (Y = OH, OMe,
2
58
Y
Y
charges of Im Se and (Im Se) HgCl . The natural bond orbital
Me), under Acidic Conditions. We have determined the cleavage of
2
2
1
(
NBO) analysis was performed at the B3LYP/6-311++G(2d,p) level
Hg−C bonds of Me Hg under acidic conditions by H NMR
2
of theory. The optimized geometries with coordinates are given in the
spectroscopy by following the procedure mentioned below. Briefly, to
a solution of Me Hg (50 mM) in DMSO-d were added 1 equiv of
Supporting Information.
2
6
OH
formic acid (50% in water) and 4 equiv of Im Se (24.7 mg, 0.12
mmol) in an NMR tube at room temperature (23 °C). the NMR tube
was kept in a shaker for continuous gentle shaking, and the reaction
was monitored at various time intervals by H NMR spectroscopy. In
order to find out the rate of demethylation of Me Hg, we used
ASSOCIATED CONTENT
Supporting Information
■
*
S
1
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.inorg-
chem.7b01301.
2
mesitylene (12 mM) as an external standard. The integral value of the
aromatic singlet resonance of mesitylene was considered as 1, and the
integral value of the singlet resonance of Me Hg (−CH ) with respect
Synthesis procedure, H, 13C, and 199Hg NMR spectra,
HR-ESIMS data, HPLC chromatogram, DFT calcula-
tions, and optimized geometries and coordinates of the
optimized structures (PDF)
1
2
3
to mesitylene was considered for the calculation of rates. The integral
value at 0 min was assumed as 100% Me Hg (0.05 M). All reactions
were performed at least three times, and the rates are expressed as
means ± standard deviation.
General Procedure for the Degradation of MeHgCys by
2
Accession Codes
OH
OH
Im Se. Im Se (37.5 mg, 180 μmol) was added to a solution of
MeHgCys (90 μmol) in 3 mL of PBS buffer (pH 8.5), and the reaction
mixture was stirred at 37 °C. The clear solution gradually turned black
after 4 h. After completion of the reaction (72 h), the black Hg(SeS)
was isolated by centrifugation and washed thoroughly with water
followed by acetonitrile. Hg(SeS) powder was dried completely under
vacuum and characterized thoroughly by various techniques such as
SEM, TEM, EDX, and IR analysis. For SEM and TEM analysis of
Hg(SeS) NPs, 10 mg of the isolated sample was sonicated for 1 h in 10
mL of HPLC grade acetone. A 20 μL portion of a dilute solution of the
sample was placed on a Cu grid and dried under vacuum and used for
TEM analysis. On the other hand, 50 μL of a dilute solution of the
sample was placed on a carbon grid and dried under vacuum for SEM
and EDX analysis. EDX was carried out using a Zeiss EVO 40 scanning
CCDC 1541411−1541412 and 1567515 contain the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/data_request/
cif, or by emailing data_request@ccdc.cam.ac.uk, or by
contacting The Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
E-mail for G.R.: Gouriprasanna.Roy@snu.edu.in.
■
*
ORCID
Gouriprasanna Roy: 0000-0002-0047-3575
I
DOI: 10.1021/acs.inorgchem.7b01301
Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry
Article
Funding
(6) Mori, N.; Yamamoto, M.; Tsukada, E.; Yokooji, T.; Matsumura,
N.; Sasaki, M.; Murakami, T. Comparison of In Vivo with In Vitro
Pharmacokinetics of Mercury Between Methylmercury Chloride and
Methylmercury Cysteine Using Rats and Caco2 Cells. Arch. Environ.
Contam. Toxicol. 2012, 63, 628−636.
This work was supported by Shiv Nadar University (SNU) and
the Science and Engineering Research Board (SERB), Depart-
ment of Science and Technology, Government of India, Project
Number SB/S1/IC-44/2013.
(
7) (a) George, G. N.; Singh, S. P.; Prince, R. C.; Pickering, I. J.
Notes
Chemical Forms of Mercury and Selenium in Fish Following
The authors declare no competing financial interest.
Digestion with Simulated Gastric Fluid. Chem. Res. Toxicol. 2008,
2
1, 2106−2110. (b) Hoffmeyer, R. E.; Singh, S. P.; Doonan, C. J.;
ACKNOWLEDGMENTS
Roos, A. R. S.; Hughes, R. J.; Pickering, I. J.; George, G. N. Molecular
■
Mimicry in Mercury Toxicology. Chem. Res. Toxicol. 2006, 19, 753−
We are grateful to Prof. Rupamanjari Ghosh (VC, SNU) for
continuous support encouragement. M.B. thanks SNU for a
fellowship and Ramesh Karri (SNU) for his useful advice in
NMR spectroscopy. We thank the SERB, Department of
Science and Technology (DST), India, for funding (Project
Number SB/S1/IC-44/2013) and the AIRF (JNU) and IGIB
New Delhi for TEM and SEM facilities.
7
59.
(8) Roos, D. H.; Puntel, R. L.; Lugokenski, T. H.; Ineu, R. P.; Bohrer,
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ABBREVIATIONS
■
TEM, transmission electron microscopy; EDX, energy-dis-
persive X-ray spectroscopy; SEM, scanning electron micros-
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DOI: 10.1021/acs.inorgchem.7b01301
Inorg. Chem. XXXX, XXX, XXX−XXX