Chemical Detoxification of Organomercurials

Article abstract of DOI:10.1002/anie.201504413

Organomercurials including methylmercury are ubiquitous environmental pollutants and highly toxic to humans. Now it could be shown that N-methylimidazole based thiones/selones having an N-CH₂CH₂OH substituent are remarkably effective in detoxifying various organomercurials to produce less toxic HgE (E=S, Se) nanoparticles. Compounds lacking the N-CH₂CH₂OH substituent failed to produce HgE nanoparticles upon treatment with organomercurials, suggesting that this moiety plays a crucial role in the detoxification by facilitating the desulfurization and deselenization processes. This novel way of detoxifying organomercurials may lead to the discovery of new compounds to treat patients suffering from methylmercury poisoning. Getting rid of mercury: Insoluble HgE (E=S, Se) nanoparticles (NPs) are formed under physiologically relevant conditions when organomercurials are treated with N-methylimidazole-based thiones/selones having an N-CH₂CH₂OH substituent. Compounds lacking the N-CH₂CH₂OH substituent failed to produce HgE NPs upon treatment with organomercurials under identical reaction conditions. A novel pathway of detoxifying various organomercurials is described.

Full text of DOI:10.1002/anie.201504413

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201504413
German Edition: DOI: 10.1002/ange.201504413
Mercury Pollutants
Chemical Detoxification of Organomercurials**
Mainak Banerjee, Ramesh Karri, Kuber Singh Rawat, Karthick Muthuvel, Biswarup Pathak, and
Gouriprasanna Roy*
Abstract: Organomercurials including methylmercury are
ubiquitous environmental pollutants and highly toxic to
humans. Now it could be shown that N-methylimidazole
based thiones/selones having an N-CH2CH2OH substituent are
remarkably effective in detoxifying various organomercurials
to produce less toxic HgE (E = S, Se) nanoparticles. Com-
pounds lacking the N-CH2CH2OH substituent failed to
produce HgE nanoparticles upon treatment with organo-
mercurials, suggesting that this moiety plays a crucial role in
the detoxification by facilitating the desulfurization and
deselenization processes. This novel way of detoxifying
organomercurials may lead to the discovery of new com-
pounds to treat patients suffering from methylmercury poison-
ing.
(HgS).[9–11] The detoxification of organic or inorganic forms
of mercury occurs in natural systems and the formation of
HgSe has been observed in tissues of animals and in organs of
mercury-mine workers.[12] Few years ago, HgSe was detected
in the brains of humans exposed to MeHg+.[13] Insoluble HgE
(E = S, Se) particles are considered to be much less toxic than
soluble MeHg+ species such as MeHgCys.[10,13] Thus, efficient
detoxification of organomercurials including methylmercury
species by forming insoluble HgE particles at physiologically
relevant conditions may offer a novel approach to treat
patients suffering from methylmercury poisoning. Herein, we
report that the N-methylimidazole based thione 1 and its
selenium analogue 2 having a 2-hydroxyethyl substituent are
remarkably effective in the detoxification of various organo-
mercurials such as RHgOH (R = Me, Ar; Ar=-C6H4CO2Na)
and RHgCl (R = Me, Et) by producing insoluble HgS and
HgSe nanoparticles (NPs) as the end products at 358C
(Figure 1).
O
rganomercurials, especially methylmercury (MeHg+), are
highly toxic due to their lipophilic nature and high affinity
toward thiol or selenol residues found in cellular systems.[1]
The cysteine complex MeHgCys can easily cross cell mem-
branes including the blood–brain barrier causing irreversible
damage to the nervous system.[2] Currently, thiol-based
chelating agents such as sodium 2,3-dimercaptopropanesul-
fate (DMPS) and meso-2,3-dimercaptosuccinic acid (DMSA)
are widely used as drugs for the treatment of mercury
poisoning.[3–5] However, evidences suggest that these two
clinically used drugs are not very effective as chelators and
fail to remove mercury (Hg) from the brain, and are
themselves known to exhibit toxic effects. Thus, there is an
urgent need to develop effective and safe compounds that can
be used for the detoxification of organomercurials.[5,6]
Microorganisms have evolved resistance mechanisms to
deal with Hg compounds[7,8] and are known to play a crucial
role in detoxifying MeHg+ by forming mercury sulfide
Figure 1. A) Chemical structures of some imidazole based thiones and
selones. B) Formation of HgS and HgSe NPs in the reactions of
ArHgOH with 1 and 2, respectively.
[*] M. Banerjee, R. Karri, K. Muthuvel, Dr. G. Roy
Department of Chemistry, School of Natural Sciences
Shiv Nadar University
When a solution of 1 (15 mm) in phosphate buffer
(pH 7.4), or in water, was treated with one equivalent of
ArHgOH at 358C, the immediate formation of the corre-
sponding 1:1 ArHgOH conjugated (with compound 1) com-
plex 9 (m/z 481.0506) was observed (Figure 1 and Fig-
ure 2A,C). Interestingly, after one hour, we detected
a white precipitate, which gradually turned into a black
precipitate of HgS. Furthermore, the gradual formation of
a new product with an LC/MS retention time of 1.8 min
(Figure 2A) was observed, which was isolated and identified
as ketone 11 by various characterization techniques (m/z
143.0822; Figure 2D). The amount of 11 and HgS NPs
increased with a decrease in the amount of 9 during the
course of the reaction. Complete degradation of 9 was
observed in 6–7 days at 358C (Figure 2B). The grayish-
black precipitate of HgS, which is insoluble in water and
NH91, Dadri, Gautam Buddha Nagar, UP 201314 (India)
E-mail: gouriprasanna.roy@snu.edu.in
K. S. Rawat, Dr. B. Pathak
Discipline of Chemistry and Center for Material Science &
Engineering
Indian Institute of Technology (IIT) Indore (India)
[**] This work was supported by SNU, IIT Indore, SERB (SB/S1/IC-44/
2013), CSIR [01(2723)/13/EMR(II)], and the Government of India.
We are grateful to Prof. Rupamanjari Ghosh (Director, SNS, SNU)
for encouragement and support. M.B. contributed significantly to
this study and both M.B. and R.K. thank SNU for fellowships. We
thank AIRF, JNU for TEM, SEM, and NMR facilities, and IIT Roorkee
for a TEM facility.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201504413.
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forms of MeHg+ detected in tissues of high-trophic-
level animals are still not clear, although studies have
shown that MeHg+ in fish as well as in humans is likely
to exist as the cysteine complex, that is, MeHgCys. On
the other hand, under acidic high ClÀ conditions in the
human stomach MeHgCys may convert to MeHgCl.
À
The Hg Cl bond in MeHgCl is highly covalent in
nature, and presumably it remains intact in dilute
aqueous solution.[14] Therefore, we examined the detox-
ification of RHgCl (R = Me, Et) with 1 and 2. Surpris-
ingly, when 1 or 2 (15 mm) was treated with one
equivalent of the organomercurial in water/acetonitrile
(1:1) at 358C, no HgE NPs were formed.[15] Instead,
very small amounts of chloro adducts 16 and 17 (4–6%
based on 12–15) were detected by mass spectrometry
after 2–3 days along with 12–15 as major products
(Figure 3 and Figures S9–S15 in the Supporting Infor-
mation).
The identification of chloro adducts 16 and 17 by
mass spectrometry suggests the presence of a strong
À
Hg Cl covalent bond in these two compounds. In
À
À
general, organomercurials of the type R Hg X are
À
remarkably inert toward Hg C cleavage under physio-
logical conditions. However, thiones and selones have
À
been shown to mediate the protolytic cleavage of Hg C
bonds.[16,17] Interestingly, the decomposition of 12–15
and the subsequent formation of ketone 11 and the
corresponding HgE NPs were observed under alkaline
conditions. When, after treating 1 with RHgCl (R = Me,
Et), one equivalent of hard bases such as KOH and
sodium methoxide (NaOMe) was added, HgS NPs were
formed. Similar to 9 and 10, product 14 was completely
degradated in the presence of one equivalent of KOH in
6–7 days (initial rate: 2.96 ” 10À4 m hÀ1). A TEM image
of well-dispersed crystalline HgS NPs obtained in the
reaction of 1 with EtHgCl in the presence of NaOMe is shown
in Figure 3C. When a similar reaction was performed with the
selenium analogue 2, it resulted in the formation of triangu-
larly shaped HgSe NPs with an average size of 35 nm
Figure 2. A) LC/MS chromatograms of 9 and 11, obtained by treating 1 with
ArHgOH at 358C, after different reaction times. B) Degradation of the
complexes 9, 10, 14, and 15 over time. Mass spectra of 9 (C), 11 (D), and
Ar2Hg (E). F) TEM image of HgS NPs obtained by treating 1 with ArHgOH.
G) LC/MS chromatograms of 10 and 11, obtained from the reaction of 2 with
ArHgOH, after different reaction times. H) TEM image of HgSe NPs obtained
from the reaction of 2 with ArHgOH.
common organic solvents, was characterized thoroughly by
various techniques. TEM images showed that the HgS NPs
were spherical and almost monodisperse with an average size
of 7 nm (Figure 2F). Furthermore, both products (Ar)2Hg
and ArH were identified by mass spectrometry (Figure 2E,
Figure S8 in the Supporting Information).
Selones are expected to be more reactive toward
organomercurials because of the soft and nucleophilic
nature of the selenium atom. When 2 (15 mm) was treated
with one equivalent of ArHgOH in phosphate buffer, or in
water, at 358C, the formation of the corresponding 1:1
complex 10 with ArHgOH was observed by LC/MS at
a retention time of 6.2 min (Figure 2G). A black precipitate
of HgSe started to appear within a few minutes and
complete degradation of 10 was observed in 2–3 days
(Figure 2B). The HgSe NPs were isolated from the above
reaction mixture after completion of the reaction and
characterized thoroughly by various techniques. They were
spherical with an average size of 6 nm (Figure 2H). Ketone
Figure 3. A) Synthetic route to HgS and HgSe NPs in the reaction of
RHgCl with 1 and 2, respectively, in the presence of a base. B) Chemical
structures of chloro adducts 16 and 17. C) TEM image of HgS NPs
obtained in the reaction of 1 with EtHgCl in the presence of NaOMe.
D) TEM image of HgSe NPs obtained in the reaction of 2 with EtHgCl in
11, (Ar)2Hg, and ArH were also confirmed as byproducts in
this reaction.
The toxic effects of mercury depend on its chemical
form and the route of exposure. While MeHg+ is the most
common toxic form, the toxicity levels of various chemical the presence of KOH.
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(Figure 3D). A complete degradation of 15 was observed in
the presence of one equivalent of KOH in 2 days (initial rate:
9.17 ” 10À4 m hÀ1), as shown in Figure 4. To investigate the
effect of 1 and 2 on MeHgOH, we synthesized MeHgOH
following the literature procedure.[18] The reaction of
MeHgOH with 1 and 2 resulted, like the reaction of
ArHgOH, in the formation of the corresponding HgE NPs
(Figures S4 and S5 in the Supporting Information).[19]
Figure 5. A) Mechanism for the formation of ketone 11 and ketal 20.
B) LC/MS chromatograms of ketal 20 formed in the reaction of 2 with
EtHgCl in the presence of NaOMe/MeOH. C) Mass spectrum of 20.
Figure 4. Degradation of compound 15 in the presence and absence of
one equivalent of KOH.
unstable by 31 kcalmolÀ1 compared to its keto form 11. To
support our proposed mechanism, compound 2 was treated
with EtHgCl followed by the addition of one equivalent of
NaOMe in methanol. Interestingly, under these reaction
conditions, we observed the fused imidazolone ketal 20,
a methyl derivative of compound 19 (Figure 5). Ketal 20[21]
was isolated from the above reaction mixture and charac-
terized thoroughly. In addition, the positively charged inter-
mediate 18 was detected by mass spectrometry when the same
reaction was performed in dichloromethane/acetonitrile.
However, the positively charged intermediate 18 was gradu-
ally converted into 11 upon treatment with KOH.
Our observations suggest that 1 and 2 react with RHgOH
to produce the corresponding 1:1 RHgOH conjugated com-
plexes, for example 9 and 10, which in turn react with another
molecule of RHgOH to produce ketone 11 and the corre-
sponding HgE. The addition of one more equivalent of
RHgOH ([RHgOH]/[2] ratio 2:1) drove the reaction (step 2,
Scheme 1 in the forward direction and, consequently, the
formation of ketone 11 was significantly increased (Fig-
ure S17 in the Supporting Information). According to the FT-
IR spectrum of the HgSe NPs a certain amount of ketone 11
and RH formed in the reaction is bound to the NPs (Figure S6
in the Supporting Information). Theoretical calculations
showed that the formation of the corresponding 1:1 com-
plexes (step 1, Scheme 1) and their subsequent decomposi-
tion upon addition of one equivalent of RHgOH (R = Me,
Ar1; step 2) are more favorable with 2 than with its sulfur
analogue 1, which is in good agreement with our experimental
results, where the formation of 11 and the corresponding
HgE NPs was observed at a significantly faster rate with 2
than with 1.
The high reactivity of compounds 1 and 2 may be
attributed to the ability of the OH group of their N-
CH2CH2OH moiety to participate in the desulfurization and
deselenization process. To understand this pathway, the
CH2CH2OH group was replaced with a CH3 (compounds 3
and 4) and a CH2Ph group (compounds 5 and 6; Figure 1).
Although the corresponding 1:1 complexes with ArHgOH
were produced when 3 and 4 were treated with one equivalent
of ArHgOH, the formation of HgE and the corresponding
ketone was not observed under identical reaction condition
even after 15 days of stirring at 358C. Similarly, the reactions
of 5 and 6 with ArHgOH did not result in the formation of the
corresponding HgE NPs. Moreover, to ascertain the role of
the OH group in 1 and 2 we synthesized 7 and 8 (Figure 1),
where the OH group is replaced by an OMe group. Interest-
ingly, both these compounds failed to produce any HgS or
HgSe upon treatment with ArHgOH or RHgCl (R = Me, Et)
in the presence or absence of KOH. All the reactions were
monitored for 15 days at 358C unless otherwise mentioned.
These observations clearly suggest that the OH group in
compounds 1 and 2 plays a crucial role in detoxifying
organomercurials by producing insoluble HgE NPs.
The crystal structures of 1 (CCDC-1056210)[20] and 2 and
the optimized geometries of the 1:1 RHgOH conjugated
complexes with 1 and 2 (R = Me, C6H4CO2H (Ar1); Figur-
es S21 and S22 in the Supporting Information) suggest that
the OH group of the N-CH2CH2OH moiety is oriented
towards the C2 atom of the imidazole ring (the carbon atom
=
of the C E bond). The deprotonation of the OH group in 9,
10, and 12–15 by a strong base favors an attack at the
positively charged C2 atom to form intermediate 18 (Fig-
ure 5A). A subsequent reaction of 18 with OHÀ (or any other
nucleophile) produces the unstable fused hemiketal 19, which
is eventually converted into stable ketone 11. DFT calcula-
tions showed that hemiketal 19 is energetically highly
In the reaction of MeHgCl with H2S, the formation of
a white-color precipitate of (MeHg)2S as an intermediate was
observed previously; this intermediate gradually decomposed
into a black precipitate of b-HgS and Me2Hg.[9,22,23] The
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Keywords: detoxification · mercury · organomercurials ·
selones · thiones
How to cite: Angew. Chem. Int. Ed. 2015, 54, 9323–9327
Angew. Chem. 2015, 127, 9455–9459
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CAUTION! Organomercurials are highly toxic to
humans, and thus appropriate safety precautions must be
taken in handling these toxic chemicals.
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Received: May 15, 2015
Published online: July 16, 2015
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