Water-Soluble α-Amino Acid Complexes of Molybdenum as Potential Antidotes for Cyanide Poisoning: Synthesis and Catalytic Studies of Threonine, Methionine, Serine, and Leucine Complexes

Article abstract of DOI:10.1021/acs.inorgchem.0c02672

Water-soluble complexes are desirable for the aqueous detoxification of cyanide. Molybdenum complexes with α-amino acid and disulfide ligands with the formula K[(L)Mo2O2(μ-S)2(S2)] (L = leu (1), met (2), thr (3), and ser (4)) were synthesized in a reaction of [(DMF)3MoO(μ-S)2(S2)] with deprotonated α-amino acids; leu, met, thr, and ser are the carboxylate anions of l-leucine, l-methionine, l-threonine, and l-serine, respectively. Potassium salts of α-amino acids (leu (1a), met (2a), thr (3a), and ser (4a)) were prepared as precursors for complexes 1-4, respectively, by employing a nonaqueous synthesis route. The ligand exchange reaction of [Mo2O2(μ-S)2(DMF)6](I)2 with deprotonated α-amino acids afforded bis-α-amino acid complexes, [(L)2Mo2O2(μ-S)2] (6-8). A tris-α-amino acid complex, [(leu)2Mo2O2(μ-S)2(μ-leu + H)] (5; leu + H is the carboxylate anion of l-leucine with the amine protonated), formed in the reaction with leucine. 5 crystallized from methanol with a third weakly bonded leucine as a bridging bidentate carboxylate. An adduct of 8 with SCN - coordinated, 9, crystallized and was structurally characterized. Complexes 1-4 are air stable and highly water-soluble chiral molecules. Cytotoxicity studies in the A549 cell line gave IC50 values that range from 80 to 400 μM. Cyclic voltammetry traces of 1-8 show solvent-dependent irreversible electrochemical behavior. Complexes 1-4 demonstrated the ability to catalyze the reaction of thiosulfate and cyanide in vitro to exhaustively transform cyanide to thiocyanate in less than 1 h.

Full text of DOI:10.1021/acs.inorgchem.0c02672

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Article
Water-Soluble α‑Amino Acid Complexes of Molybdenum as
Potential Antidotes for Cyanide Poisoning: Synthesis and Catalytic
Studies of Threonine, Methionine, Serine, and Leucine Complexes
Johanna M. Gretarsdottir, Sigridur Jonsdottir, William Lewis, Trevor W. Hambley,
and Sigridur G. Suman*
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ABSTRACT: Water-soluble complexes are desirable for the aqueous
detoxification of cyanide. Molybdenum complexes with α-amino acid and
disulfide ligands with the formula K[(L)Mo2O2(μ-S)2(S2)] (L = leu (1), met
(2), thr (3), and ser (4)) were synthesized in a reaction of [(DMF)3MoO(μ-
S)2(S2)] with deprotonated α-amino acids; leu, met, thr, and ser are the
carboxylate anions of L-leucine, L-methionine, L-threonine, and L-serine,
respectively. Potassium salts of α-amino acids (leu (1a), met (2a), thr (3a),
and ser (4a)) were prepared as precursors for complexes 1−4, respectively, by
employing a nonaqueous synthesis route. The ligand exchange reaction of
[Mo2O2(μ-S)2(DMF)6](I)2 with deprotonated α-amino acids afforded bis-α-
amino acid complexes, [(L)2Mo2O2(μ-S)2] (6−8). A tris-α-amino acid
complex, [(leu)2Mo2O2(μ-S)2(μ-leu + H)] (5; leu + H is the carboxylate
anion of L-leucine with the amine protonated), formed in the reaction with leucine. 5 crystallized from methanol with a third weakly
bonded leucine as a bridging bidentate carboxylate. An adduct of 8 with SCN coordinated, 9, crystallized and was structurally
characterized. Complexes 1−4 are air stable and highly water-soluble chiral molecules. Cytotoxicity studies in the A549 cell line gave
IC50 values that range from 80 to 400 μM. Cyclic voltammetry traces of 1−8 show solvent-dependent irreversible electrochemical
behavior. Complexes 1−4 demonstrated the ability to catalyze the reaction of thiosulfate and cyanide in vitro to exhaustively
transform cyanide to thiocyanate in less than 1 h.
treatment for cyanide poisoning, where thiosulfate acts as a
sulfur donor to the rhodanase enzyme in vivo.18 At lethal doses,
the activity of rhodanase is not sufficient to detoxify the
cyanide.2 Transition metal complexes able to catalyze the
reaction of cyanide and sulfur donor substrates (e.g., thiosulfate)
are an attractive option in the development of novel emergency
treatments for cyanide poisoning in vivo. The development of
catalytic molybdenum metallodrugs to supplement rhodanase
places the need for a low cytotoxicity and good physical
properties, such as the water solubility of the potential therapies,
at the forefront of challenges to overcome.19,20 The selection of
ligands and counter cations for the molybdenum complexes
affect both the solubility and toxicity of the potential
treatment.21
INTRODUCTION
■
Cyanide has received increased attention as a toxin in inhalation
injuries in recent years.1−4 The largest risk of cyanide poisoning
for the general public is through exposure to smoke inhalation
from residential, industrial, and forest fires.5,6 Hydrogen cyanide
(HCN) is formed in an incomplete combustion of organic
materials containing nitrogen, such as the common materials
silk, wool, nylon, and many plastics (e.g., melamine, polyur-
ethane, and polyacrylonitrile).7 The accidental volatilization of
HCN is a potential source of cyanide poisoning in industry.8,9
Cyanide salts are common starting materials in the chemical
industry for chemical synthesis and are a key ingredient in metal
processing.10 Acute poisoning can result if these salts come into
contact with moisture and instantaneously form HCN.11 The
acute toxicity of cyanide12,13 calls for a highly efficient approach
and a rapidly administrable treatment for cyanide poisoning.14,15
Cyanide is a noncompetitive inhibitor of cytochrome c
oxidase, halting cellular respiration and resulting in hypoxic
anoxia.2 Cyanide is an endogenous molecule16 that is
metabolized in vivo by the rhodanase sulfurtransferase enzyme.
Rhodanase catalyzes the sulfur transfer from sulfur donor
substrates to cyanide, forming thiocyanate that is excreted in
urine.17 The reaction of thiosulfate and cyanide is currently a
Received: September 7, 2020
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Chart 1. Structures of Complexes 1−8
Molybdenum is one of the more abundant elements on the
planet, and enzymes containing molybdenum at their active site
appear to be present in all forms of life.22,23 At least 50 enzymes
are known;24,25 among them, xanthine oxidase and sulfite
oxidase are well-known molybdoenzymes in humans.26
forming sulfite and thiocyanate. The rate of thiocyanate
formation is dependent on the thiosulfate concentration, and
the reaction proceeds to completion over time.
Although [Mo2O2(μ-S)2(S2)(DMF)3] has shown catalytic
activity in the reaction of cyanide with thiosulfate, it is not
suitable as a catalytic treatment in vivo due to its toxicity and
limited aqueous solubility.21 Ligand substitution of the DMF by
nontoxic and water-soluble α-amino acid ligands (α-aa)
decreases the toxicity of the molybdenum complexes and
increases the water solubility. Sodium and potassium salts are
relatively nontoxic compared to complexes with alkylammo-
nium salts and show a higher water solubility.21 Molybdenum−
sulfur complexes with water-soluble α-amino acid ligands and
Na+ or K+ counter cations are therefore an attractive option to
achieve biocompatibility. The gas-phase detection of alkali metal
salts of threonine, serine, and methionine has been reported
using infrared multiple-photon dissociation (IRMPD) spectros-
copy.39−44 However, they were not isolated. In our work, a
general method for the isolation of analytically pure potassium
salts of leucine, methionine, threonine, and serine (1a−4a,
respectively) is reported.
2−
The ability of molybdenum with Sn (n = 1−4) ligands to
accept or donate sulfur atoms has been exploited for sulfur
removal in hydrodesulfurization processes (HDS).27 In this
mechanism, the sulfur reacts with a “MoS2” moiety in a
heterogeneous reaction to insert into Mo−S bonds or
oxidatively add to the metal. Dioxodimolybdenum complexes
with α-amino acid donors have also been shown to be effective
catalytic precursors for epoxidations.28 The ability of the
“Mo(O)(S)” moiety to donate sulfur to other substrates was
demonstrated in the reaction of [LPrMoOS(OPh)] with
(Et4N)CN in acetonitrile, producing [LPrMoO(MeCN)-
(OPh)] (LPr = hydrotris(3-isopropylpyrazol-1-yl)borate) and
SCN.29 Similarly, the MoS bond also reacts with sulfur
containing substrates, such as thiosulfate.30
The terminal sulfido group on molybdenum reacts in
stoichiometric reactions with cyanide to form thiocyanate in a
reaction commonly employed to model the reactivity and
inactivation of molybdenum hydroxylases as well as other
molybdoenzymes.29,31−34 Molybdenum−cyano complexes were
reviewed recently,35 and the reaction chemistry of molybdenum
sulfur compounds with cyanide was reported earlier.36,37 Most
recently, binuclear molybdenum complexes with the “Mo(O)-
(η2-S2)” moiety in [Mo2O2(μ-S)2(S2)(DMF)3] were shown to
react with CN to form SCN in stoichiometric amounts.38
The complex catalyzes the reaction of thiosulfate and cyanide,
Dinuclear asymmetric molybdenum sulfur complexes (1−4)
were synthesized using the isolated alkali metal salts as
precursors. Bis-amino acid molybdenum sulfur complexes (6−
8) were synthesized as well as a tris-leucine asymmetric complex
(5), and their properties investigated.
RESULTS AND DISCUSSION
■
Syntheses. Complexes 1−4 with the α-amino acids leucine,
methionine, threonine, and serine, respectively, were synthe-
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Scheme 1. Synthesis of Potassium Salts of α-Amino Acids 1a−4a
Scheme 2. Synthesis of Complexes 1−4
Scheme 3. Synthesis of Complexes 5−8
+
sized in ligand exchange reactions of [Mo2O2(μ-S)2(S2)-
(DMF)3] with potassium salts of the α-amino acids (Chart 1,
1−4). Neutral complexes were synthesized in reactions of
[Mo2O2(μ-S)2(DMF)6](I)2 with the amino acids (Chart 1, 5−
8). A tris-α-amino acid complex with the structure [Mo2O2(μ-
S)2(μ2-leu + H)(leu)2] (5; leu + H is the carboxylate anion of L-
leucine with the amine protonated) formed in the reaction with
leucine, while methionine, threonine, and serine formed bis-α-
amino acid complexes 6−8, respectively.
The approach used in the synthesis of the mono-α-amino acid
complexes is unique to each, while the syntheses of 5−8 drew
inspiration from synthetic routes reported for known α-amino
acid complexes. Reported procedures for transition metal α-
amino acid complexes most often proceed by employing one of
the following two methods: (i) reactions of charged complexes
with hydrochloride salts of α-amino acids45−48 and (ii) reactions
of complexes with α-amino acids deprotonated with a base in
situ.49,50
formation of the NH3 /COO pair in water, preventing the
isolation of the salts from water.
An alternative method for the synthesis of alkali salts of α-
amino acids was employed in a dry aprotic solvent. Potassium
salts of α-amino acids (leu (1a), met (2a), thr (3a), and ser
(4a)) were prepared as precursors for complexes 1−4 by
employing a nonaqueous synthesis route (Scheme 1); leu, met,
thr, and ser are the carboxylate anions of L-leucine, L-methionine,
L-threonine, and L-serine, respectively. Commercially available
Fmoc-protected α-amino acids are highly soluble in DMF and
are suitable to facilitate the synthesis in aprotic solvents. The
potassium salts of the α-amino acids leucine, methionine,
threonine, and serine (1a−4a) were successfully isolated as
white solids by the deprotonation of the carboxylic acid of the
Fmoc-protected α-amino acids by potassium tert-butoxide in dry
DMF (Scheme 1). They are very hygroscopic and need to be
handled under nitrogen. In the presence of water, the
carboxylate group is easily protonated, forming an alkaline
solution.
The reported procedures are incompatible for reactions with
complexes possessing the base-labile disulfide ligand in
[Mo2O2(μ-S)2(S2)(DMF)3]. In this case, isolated salts of α-
amino acids are more suitable reagents to prevent a displace-
ment of the disulfide and form water-soluble complexes. While
the Na+ and K+ salts of glycine are easily isolated using a solid-
state method,51 the same salts of leucine, methionine, threonine,
and serine were not able to be isolated using this method. The
zwitterionic nature of the amino acids always leads to the
The starting complex, [Mo2O2(μ-S)2(S2)(DMF)3], was
synthesized according to a literature procedure.52 In situ
deprotonation in aqueous media is often employed in the
synthesis of complexes with amino acid ligands,49 resulting in a
solution with an alkaline pH. The disulfide ligand of [Mo2O2(μ-
S)2(S2)(DMF)3] is sensitive to alkaline pH levels,53 leading to
the partial displacement of the disulfide by the incoming ligand L
and forming a mixture of complexes with the formulas
[Mo2O2(μ-S)2(S2)(L)] and [Mo2O2(μ-S)2(L)2]; this neces-
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sitates the reaction being carried out in the absence of a base. To
preserve the disulfide ligand of [Mo2O2(μ-S)2(S2)(DMF)3] in
reactions with the amino acid salts, the syntheses of
K[Mo2O2(μ-S)2(S2)(L)] (1−4) were carried out with dry
solvents under nitrogen using standard Schlenk techniques, as
shown in Scheme 2. Complexes 1−4 were isolated as solids after
aqueous workup and lyophilization. They were isolated as
hydrates, as confirmed by IR spectra in anhydrous KBr pellets as
well as elemental analysis.
The starting complex [Mo2O2(μ-S)2(DMF)6](I)2 was
synthesized according to a literature procedure.54 The structures
of the starting complexes revealed the syn configuration of the
oxo groups, which is preserved unless the sulfide bridge is
cleaved at harsh reaction conditions.55 The in situ deprotonation
of the amino acid works well for 5−8, since the starting material
is stable in the reaction conditions. The syntheses of 5 and 6
were carried out in aqueous acetone (Scheme 3) because of the
poor aqueous solubility of methionine and leucine. The
products were purified by recrystallization from ethanol. Single
crystals of 5 suitable for X-ray analysis were obtained after
recrystallization from methanol. The silver salt56 as well as the
sodium and potassium salts51 of glycine are known. Silver salts of
the other α-amino acids may be isolated using an analogous
procedure to that used for the glycine salt. The highly water-
soluble complexes 7 and 8 were synthesized from [Mo2O2(μ-
S)2(DMF)6](I)2 in a metathesis reaction with the silver salts56 of
the α-amino acids threonine and serine, respectively, in water
(Scheme 3). Insoluble AgI was easily removed by filtration. The
crude products of 7 and 8 were purified by recrystallization from
water and isolated as solids after lyophilization.
with the [Mo2O2(μ-S)2]2+ core as well as its S,O-bridged
[Mo2OS(μ-O)(μ-S)]2+,47 and O,O-bridged [Mo2O2(μ-
O)2]2+counterparts.46 The crystal structure of the asymmetric
dinuclear bidentate tris-glycine complex [Mo2O2(μ-S)2(Gly)-
(gly)2]49 has been reported, where the glycine coordinates to the
Mo center both as a N,O-chelate and an O,O-bridging amino
acid. The carboxylate coordinates as a bridging ligand to both
Mo centers. Mononuclear Mo(VI) peroxo (O22−) complexes
have been crystallized as [MoO(O2)2(α-aa)(H2O)] with
glycine, alanine, and proline.65 The glycine, alanine, and proline
complexes were isolated with the amino acid as monodentate O-
bonded ligands to the Mo center as expected, since Mo(VI) has
a preference for oxygen coordination over nitrogen coordina-
tion. The same researchers reported additional complexes with
valine, leucine, serine, asparagine, and glutamine without
structural data.65
Structural Analysis of 5. Complex 5 crystallized from a
methanol solution with two methanol molecules in the space
group P43. The complex is the S,S,S-isomer, with the N,O- and
O,O-coordinated ligands in the S-orientation. The NH2 and O
donor groups are in trans-orientations in the equatorial plane.
The molecular structure of 5 is shown in Figure 1, and a
summary of crystal and structural refinement data is presented in
SI Table 1; selected bond distances and bond angles are
presented in SI Tables 2 and 3.
Methionine, threonine, and serine act as bidentate negatively
charged chelating ligands toward the [Mo2O2(μ-S)2]2+ core to
form neutral bis-α-amino acid complexes (Chart 1). Three
molecules of leucine reacted consistently with [Mo2O2(μ-
S)2(DMF)6](I)2 to form a neutral tris-leucine complex
regardless of the reaction stoichiometry. Two of the leucine
ligands act as bidentate N,O-chelates similar to 6−8. The third
leucine is in its zwitterionic form, with a neutral O,O-chelate
bridging both molybdenum atoms and the amine group in the
+
protonated −NH3 form. The reaction yield based on leucine
was 77%, where it acts as a limiting reagent in this reaction.
α-Amino acids coordinate to metal atoms through various
degrees of chelation, where mono-, bi-, tri- and tetradentate
coordination modes have been reported.57 Bidentate N,O-
chelation through the amino and carboxylato groups is typically
observed, but the degree of coordination is determined by the
nature of the α-amino acids, their side chains, and the
coordinated metal. α-Amino acids with simple aliphatic side
chains can act as monodentate ligands but are most often
bidentate.49 The thioether sulfur of methionine is a weak base
that favors coordination to select metal ions,58 and monodentate
S-chelation through the methionine thioether group to Pd has
been reported.59 Although [Mo2O2(μ-S)2]2+ forms a tridentate
chelate with cysteine thiolate,60 a Mo center rarely coordinates
to thioethers, preferably doing so when it is in lower oxidation
states such as Mo(II).61 Methionine therefore most likely acts as
a bidentate ligand.62 Serine and threonine both have hydroxyl
groups in the β-position; however, N,O-chelation is typically
observed, and the hydroxyl groups are left pendant due to their
relatively high pKa values.59,63,64
Figure 1. Structure and labeling of 5. The side chains on C2 and C8 are
omitted for clarity.
The complex contains two octahedra sharing the sulfide-
bridge line. Two coordination modes of leucine were observed; a
leucine was chelated to each molybdenum atom via its amine
nitrogen atom and an α-carboxylate oxygen atom. The third
leucine acted as an O,O-bridging donor to the two molybdenum
atoms through its carboxylate oxygen atoms. Two sulfur atoms
and a terminal oxygen atom complete the octahedral moiety
around each molybdenum atom. The [Mo2O2(μ-S)2(leu)2]
moiety of 5 is near symmetrical with a C2 rotation axis, but the
bridging leucine imposes a C1 symmetry on the complex.
The structure of 5 is similar to that of [Mo2O2(μ-S)2(cys)2]2−
where the Mo−N (average of 2.215(4) Å) and MoO (average
of 1.678(3) Å) bond distances are similar and unexceptional.60
The carboxylate oxygens of the N,O-coordinated leucine are
A few dinuclear molybdenum complexes with the [Mo2O2(μ-
S)2]2+ core and α-amino acid ligands have been reported, such as
the symmetric tridentate N,O,S-chelated bis-cysteine complex45
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located in the equatorial plane in 5 as opposed to in the axial
positions in [Mo2O2(μ-S)2(cys)2]2−. The Mo−O bonds to the
bridging leucine (average 2.304 Å) are longer than the Mo−O
bonds from the chelated leucines (average 2.097 Å), presumably
because of the trans-influence from the MoO group, but the
Mo(1)−O(8) and Mo(2)−O(7) bond distances are similar to
the axial bond distances in [Mo2O2(μ-S)2(cys)2]2−.60
increased puckering of the core as a key structural difference in
the absence of the bridging ligand in 5.
Spectroscopic Characterization. NMR Spectroscopy. 1H
and 13C NMR spectra of 1a−4a were obtained in DMSO-d6.
The resonances were assigned using COSY, DEPT135, and
HSQC measurements. DMSO-d6 was chosen to avoid the
protonation of the amino acids in D2O, which would not give an
accurate representation of the salts. In DMSO-d6, resonances at
174−176 ppm in the 13C spectra of the salts were assigned to the
carboxylate carbon. In the presence of water impurities, another
peak was observed from the protonated carboxylic acid carbon at
The C−O bond distances in the bridging carboxylate are in
agreement with its deprotonated bridging coordination. The
other two carboxylates in the complex exhibit differences in the
C−O and CO bond distances for C(1)−O(3) and C(1)−
O(4) and C(7)−O(5) and C(7)−O(6), respectively, that are
less than 0.1 Å, as has also been observed for [Mo2O2(μ-
S)2(citrate)2]6−.66 The bond angles in the bridging carboxylate
are all wider than 120°, which is likely imposed by the geometry
of the [Mo2(O)2(μ-S)2]2+ core. The Mo(1)−Mo(2) bond
distance is 2.8285(5) Å, or similar to those seen for [Mo2O2(μ-
1
around 165 ppm. H and 13C NMR spectra of 1−4 and 6−8
were obtained in D2O solutions. The peaks were assigned using
spectra of the free amino acid ligands as references. No
significant shifts of the ligand resonances were observed upon
coordination to the molybdenum atom. The spectra of the
K[Mo2O2(μ-S)2(S2)(L)] complexes (1−4) show the same
signals as those of the [Mo2O2(μ-S)2(L)2] complexes (6−8) for
the respective ligands. The two amino acid ligands in 6−8 relate
to each other through a 2-fold rotation axis, rendering them
60
S)2(cys)2]2− and [Mo2O2(μ-S)2(citrate)2]6−.66 The dihedral
angle of the [Mo2O2(μ-S)2]2+ core was calculated as 173°, or
quite a bit wider than those in [Mo2O2(μ-S)2(DMF)6](I)2,54
[Mo2O2(μ-S)2(S2)(DMF)3],52 and (Me4N)2[Mo2O2(μ-
S)2(S2)2]67 that fall between 150° and 160°.
1
indistinguishable in the NMR spectrum. H and 13C NMR
spectra of 5 were obtained in a DMSO-d6 solution. 5 lacks
symmetry elements as revealed in the crystal structure, and
therefore all carbons and protons in the three leucines are
unique.
Structural Analysis of 9. Complex 8 crystallized as the
SCN adduct 9 in the space group P3
̅
c1 from an ethanol
solution containing a mixture of KSCN and Bu4NSCN and is
labeled 9 to distinguish it from 8. The complex has a C2
symmetry, and the thiocyanato groups are trans to each other;
the molybdenum atoms are in a highly distorted octahedral
geometry. The bidentate serine ligands have the nitrogen donors
trans to each other in the equatorial plane, and the carboxylate
oxygen is in a trans-orientation to the MoO group. The
molecular structure of 9 is shown in Figure 2, and a summary of
the crystal and structural refinement data is presented in SI
Table 1 as well as selected bond distances and bond angles in SI
Tables 4 and 5.
Infrared Spectroscopy. The infrared spectra of 1−8 were
recorded as KBr pellets (Table 1). The observed peaks were
assigned using the spectra of the starting materials52 and the free
α-amino acids. Selected features in the infrared spectra of 1−8
are compiled in Table 1. The MoO stretching vibrations were
observed as a strong band in the region between 952 and 941
cm−1 in 1−8. The spectra of 1−4 and 6−8 show a single broad
MoO stretch for the two MoO groups. Two MoO
vibration bands were observed in 5 due to the antisymmetric
O,O-chelating leucine ligand bound to the molybdenum atoms.
Vibrations for bridging sulfur atoms (Mo−Sb) in 1−8 were
observed in the region between 460 and 467 cm−1. The vibration
of the disulfide ligands of 1−4 presented as weak bands ∼520
cm−1, which are similar to the 527 cm−1 band for the η2-S2
vibration of [Mo2O2(μ-S)2(S2)(DMF)3].52 These bands are
absent in the spectra of 5−8. Characteristic differences between
the spectra of 1−8 and the spectra of the corresponding free α-
amino acids were observed. Bands for the NH2 vibrations of the
molybdenum complexes were seen to be shifted to higher
frequencies due to the amine chelation of the α-amino acids to
the molybdenum. The Mo−O bond to the carboxylate may be
either axial or equatorial, where the equatorial coordination
experiences a trans-influence from the molybdenyl group; this
results in a weaker Mo−O carboxylate oxygen bond that in turn
is reflected in the lower energy ofn the carboxylate
antisymmetric band because of the increased anisotropy of the
carboxylate function compared to that of the equatorial
coordination mode. The carboxylate oxygens were found in an
axial coordination in [Mo2O2(μ-S)2(cys)2]2 with the anti-
symmetric band positioned at 1590 cm−1 or a similar position as
a free deprotonated carboxylate.45,60,68 The amine groups
coordinate preferably in the equatorial plane. The bridging
leucine in 5 has an isotropic coordination mode, while the
equatorial leucine carboxylates are anisotropic. As a result, the
carboxylate antisymmetric band at 1655 cm−1 in 5 is presumably
from the equatorial coordination, and the 1617 cm−1 band is
from the bridging carboxylate. By analogy, pairs of complexes 2
and 6 and 3 and 7 demonstrate a trend where the 1:1 complex
Figure 2. Structure and labeling of the anion of 9.
Bond distances and angles for 9 are similar to those observed
for 5. The Mo−Mo bond distance was 2.8173(11) Å. The amino
acid was coordinated with the nitrogen amine donor in the
equatorial plane, but the carboxylate oxygen was coordinated
trans to the molybdenyl group. As expected, the Mo−O(1) bond
distance is longer in 9 than in 5 at 2.217(4) Å. The Mo−N1
bond distance is 2.243(5) Å in 9, which is not significantly
different than the Mo−N distances in 5. The Mo−N(2) bond
distance for the isothiocyanto ligand is slightly shorter at
2.167(5) Å. The isothiocyanato ligands are linear with the
N(2)−C(4)−S(2) angle of 178.2°. The dihedral angle of the
[Mo2O2(μ-S)2]2+ core was calculated as 154.6°, showing an
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Table 1. Selected IR Bands of 1−8 (cm−1)
+
complex
ν(MoO)
ν(Mo−Sb)
η2-S2
ν(CO) asym
ν(CO) sym
δ(NH3 )
a
Mo2O2(μ-S)2(S2)(DMF)3
954(s)
947(s)
946 (s)
945 (s)
942 (s)
943 (s)
952 (s)
943 (s)
944 (s)
943 (s)
940 (s)
467(m)
527 (w)
1
2
3
4
5
467 (m)
467 (m)
466 (m)
467 (m)
464 (m)
520 (w)
520 (w)
520 (w)
521 (w)
1609 (s)
1617 (s)
1625 (s)
1624 (s)
1655 (s)
1617 (s)
1644 (s)
1640 (s)
1624 (s)
1387 (m)
1377 (m)
1385 (m)
1383 (m)
1389 (m)
1377 (m)
1374 (m)
1382 (m)
1385 (m)
1575 (m)
1517 (m)
6
7
8
464 (m)
464 (m)
460 (m)
a
From ref 54
displays a lower energy for the antisymmetric band compared to
the 2:1 series. 4 and 8 were found to have virtually the same
carboxylate bands, although the band was broad in both
complexes. Complex 5 also displays an additional band at 1575
cm−1 due to bending modes of the free NH3+ group.
Electronic Spectra. Electronic spectra of 4 and 8 in H2O are
shown in Figure 3. They are representative of the spectra of the
donors, resulting in reduced charge-transfer band intensities in
5−8 compared to those in 1−4.
Mass Spectrometry. The ESI mass spectra of the
molybdenum complexes were obtained in the negative scan
mode. Either acetonitrile or methanol was used as the solvent.
Simulations of the isotope pattern expected for the mono-anion
match the observed major peaks in the measured spectra of the
complexes (SI Figures 1−16). The isotope pattern and exact
mass were compared for the measured versus simulated mass.
The measured and simulated peaks reported show an excellent
match for the isotope pattern and a variation in the m/z less than
2 ppm for 1−8. The values are reported in the Experimental
Section. The mass spectra of 1−4 exhibit a peak for the anion
[Mo2O2(μ-S)2(S2)(L)]. The ESI mass spectra of 6−8,
[Mo2O2(μ-S)2(L)2], exhibit a peak for the mono-anion
[(L)2Mo2O2(μ-S)2 − H+]. Similarly, the mass spectrum of 5
exhibits a peak for the anion [(leu)2Mo2O2(μ-S)2(μ2-leu + H) −
H+] as well as a peak for the anion [(leu)2Mo2O2(μ-S)2 −
H+]. The second peak in the mass spectrum of 5 was observed
because one leucine dissociated during the measurement.
Physical Properties. Water Solubility. The water solubility
of 1−8 was quantified, and the results are presented in Table 2.
The solubilities of 1−8 were compared to those of [Mo2O2(μ-
S)2(S2)(DMF)3] and (Et4N)2[Mo2O2(μ-S)2(S2)(S4)]. All of
the complexes included have the [Mo2O2(μ-S)2]2+ core.
Complexes 1−4 all demonstrate a higher water solubility than
that of [Mo2O2(μ-S)2(S2)(DMF)3]. Substitution of the DMF
ligands with threonine or serine ligands (3 and 4, respectively)
increases the water solubility over 6-fold. The exchange of DMF
with leucine and methionine ligands (1 and 2, respectively)
Figure 3. UV−vis spectra of 4 and 8 in H2O.
mono- and bis-α-amino acid complexes shown with the same
amino acid ligand. The electronic spectrum of 4 exhibits a charge
transfer band (π)S → (d)Mo of the four-membered ring
“Mo2S2” with a maximum at 274 nm and shoulders at 305 and
347 nm from d−d transitions of the central metals, which are
consistent with previous reports.47,49,69
A weak absorbance at 474 nm was observed that was is
associated with n−π* transition in the disulfide ligand.69 This
absorbance is absent in the spectrum of 8, as expected. The
electronic spectrum of 8 exhibits a charge-transfer band with a
maximum at 281 and a shoulder at 350, which are analogous to
the bands observed for 4.
There is no distinguishable difference in the electronic
spectrum of the tris-α-amino acid complex 5 and the spectra of
the bis-α-amino acid complexes 6−8. Most likely, the bridging
leucine ligand dissociates in solution. The complexes 1−4 are an
intensely bright orange color, while 5−8 are light orange to pale
yellow. In complexes 5−8, the disulfide ligand, which is a donor
or acceptor ligand that gives rise to charge transfer bands, was
exchanged for amino acid ligands that predominantly serve as σ-
Table 2. Water Solubility for Complexes 1−8 and the Starting
Materials
complex
water solubility (g/L)
1
2
3
4
5
6
7
8
11.4
4.2
22.2
24.5
4.9
8.1
>200
b
197
a
[Mo2O2(μ-S)2(S2)(DMF)3]
(Et4N)2[Mo2O2S8]
3.5
a
1.0
a
b
From ref 21. The solution became viscous at 200 g/L.
F
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increases the water solubility less dramatically than in the case of
threonine and serine substitutions, mostly because methionine
and leucine themselves are less hydrophilic.70 The aqueous
solubility of the free threonine was reported as 106 g/L, and that
of serine was reported up to 250 g/L. The complexes 1−4 do not
demonstrate the same order of solubility as the free amino acids,
where methionine has higher water solubility than leucine. The
hydroxyl groups in the side chains of threonine and serine
increase the water solubility, while methionine and leucine have
more aliphatic properties. A similar increase in the solubility was
also observed for the neutral complexes (5−8). The bis-
threonine complex (7) demonstrated such a high water
solubility that it proved impossible to obtain a saturated
solution. No precipitate was observed when the experiment was
carried out, and the solution became viscous when efforts were
made to obtain a saturated solution. The bis-serine complex (8)
was also highly water-soluble. The bis-leucine (5) and bis-
methionine (6) complexes showed lower solubilities than their
disulfide complex equivalents (1 and 2, respectively).
most active with an IC50 of about 80(3) μM and a plateau at
about 20%. In the same assay, cisplatin has a cytotoxicity of 8(2)
μM, which is consistent with values reported in the literature.71
It is not clear what is responsible for the difference in toxicities,
but given the lack of systematic variation with the amino acid or
structure it is most likely related to the rate and extent of cellular
accumulation. If so, the lower toxicity, while desirable, may
correlate with a lower capacity to react intracellularly with
cyanide. However, given that the uptake of 3 is high72 and it is
toxicity is low, all compounds are likely to be able to accumulate
to high levels without inducing significant cell death.
Cyclic Voltammetry. The electrochemistry of selected
complexes was explored in CH3CN. The cyclic voltammograms
were run for 2 mM solutions of 1−8 in CH3CN and 0.2 M in
solutions in Bu4NPF6. Ag/AgCl2 was used as the reference
electrode. The data are summarized in Table 4.
a
Table 4. Cyclic Voltammetry Data for 1−8
complex
E
ox1 (V)
E
ox2 (V)
E
red1 (V)
The fact that the bis-amino acid complexes 7 and 8 show
higher water solubilities than their corresponding disulfide
potassium salts suggests that the incorporation of highly water-
soluble ligands plays a more significant role in increasing the
water solubility than adding a water-soluble countercation.
Strong intermolecular S···S interactions can negatively impact
the solubility of compounds with the “Mo2O2(μ-S)2(S2)”
moiety, where the disulfide sulfur atoms may interact with a
bridging sulfur atom in another molecule.69 Complexes 2 and 6
are therefore likely to have comparably low solubilities. The
leucine complexes 1 and 5 are appreciably organo-soluble, and
the water solubility of 1 is likely determined by the potassium
countercation. Aliphatic tetraethylammonium cations result in
the lower water solubility of (Et4N)2[Mo2O2S8], which was less
than a third than that of the structurally similar [Mo2O2(μ-
S)2(S2)(DMF)3]. The choice of countercations therefore can
play a significant role in solubility of transition metal complexes
and was given careful consideration.21
1
2
3
4
5
6
7
8
0.278
0.347
0.304
0.361
0.336
0.363
0.255
0.303
−1.13
−1.13
−1.16
−1.25
−1.18
−1.14
−1.21
−1.24
1.02
1.05
1.01
1.03
a
Reported versus the Ag/AgCl reference electrode; CH3CN, 0.1 V/s.
The [Mo2O2(μ-S)2]2+ core with various ligands has been
explored electrochemically in aqueous media47 and aprotic
media.73,74 The electrochemical behavior was reported to differ
significantly based on the experimental conditions. The
[Mo2O2(μ-S)2]2+ core is robust under neutral or acidic
conditions75 and unlikely to cause ROS generation in vivo.
Reported aqueous electrochemical events for [Mo2O2S2-
(cys)2]2 were concluded to be proton-coupled electron
transfer steps (PCET)76 are apparently capable of reducing
the two Mo centers in a single step,77 while the reductions in
aprotic solvents were found to proceed stepwise.73 The study of
the electrocatalytic properties of [Mo2O2S2(cys)2]2 and
related complexes attributed the observed catalytic properties
to the [Mo2O2(μ-S)2]2+ core and revealed a minimal influence
by the ligands employed,78 whereas changing from aryl to alkyl
ligands had a larger impact than changing the donor atoms.77
Influences from the ligand donor sets of 1 − 8 were mostly
observed in shifts of the oxidation and reduction potentials
rather than in new peaks. Consequently, the cyclic voltammo-
grams of 1−4 (Figure 4) with a chemically reactive disulfide
ligand were expected to look similar to those of 5−8 (Figure 5),
and electrochemical differences between 1−8 were not expected
to be remarkable since the donor atoms and ligand properties
were similar.
Cytotoxicity. Cytotoxicities were determined in the A549
lung cancer cell line by the MTT method for all complexes
except 5, which was insufficiently soluble in the media
employed. The IC50 values are given in Table 3 and cover a
Table 3. IC50 Values Determined for 1−4 and 6−7 in the
a
A549 Cell Line at 72 h
compound
IC50 (mM)
cisplatin
0.008(2)
∼0.25
∼0.25
1
2
3
4
6
7
8
∼0.25
0.12(4)
0.08(3)
∼0.40
0.14(4)
a
Cisplatin is given as a reference.
The two Mo(V) centers can be oxidized to two Mo(VI)
centers by a total of two electrons or reduced to two Mo(III)
centers by total of four electrons. A single-step two-electron
reduction in CH3CN can lead to cleavage of the Mo−Mo bond
range from 80(3) to about 400 μM, with all plots of activity
versus growth that plateaued doing so at 20% or more of the
activity of the controls (SI Figure 17). The leucine (1) and
threonine (3 and 7) complexes as well as one of the methionine
complexes (2) are the least toxic, with IC50 values in the range of
250−400 μM. The serine complexes (4 and 8) and the other
methionine complex (6) have similar activities, with 6 being the
and structural rearrangement without compositional change, as
79
was reported for [Mo2(μ-SR)2(CO)8]0/2‑
.
Two-electron
oxidation may lead to two different forms; either two Mo(VI)
centers or the disulfide bridge can form an S−S bond. The S−S
bond possibility evaluated by DFT calculations for γ-
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results in small shifts in potentials for the same set of waves, and
the disulfide ligand does not appear to significantly impact the
electrochemical behavior of the complexes. The aqueous
electrochemical behavior of 1−8 is under continued study as
it is more complex and requires more detailed experiments.
Reactivity with Cyanide. Stoichiometric Reactions.
Cyanide has been used to probe the activity of molybdenum
hydroxylases with sulfide ligands where a sulfur may be
abstracted by cyanide to form thiocyanate.31 The molybdoen-
zymes are known to produce 1 equiv of thiocyanate in these
reactions.32 In model studies, mononuclear Mo(VI) complexes
with a S2 terminal ligand undergoes a reductive elimination
reaction with cyanide to form Mo(IV) and SCN under
anerobic conditions.29 Similarly, Mo(VI) complexes possessing
disulfide (S22) ligands undergo an internal redox reaction,
form an S2 ligand, donate a sulfur atom to form isonitriles.81
The reactivity of the disulfide ligand of 1−4 in sulfur abstraction
reactions with cyanide was studied. The cyanide carries out a
nucleophilic attack on the disulfide ligand, and a sulfido ligand
remains on the molybdenum center as shown in Scheme 4.
The reactivity was evaluated by quantifying the thiocyanate
formation as a function of time. The respective complexes were
dissolved in veronal buffer at pH 7.4, and an excess amount of
potassium cyanide was added to the solution at time point t = 0.
Aliquots were taken from the reaction mixtures at fixed time
points, and the samples were developed for a colorimetric
quantification of thiocyanate as FeSCN2+. Figure 6 shows the
thiocyanate reaction yield over a 60 min period in the reaction of
1 and of [Mo2O2(μ-S)2(S2)(DMF)3] with cyanide.
Figure 4. Cyclic voltammograms of 2 and 3 in CH3CN.
Figure 5. Cyclic voltammograms of 6 and 7 in CH3CN.
[SiW10Mo2O2(μ-S)2]n− clusters with C2v symmetry was
concluded as unlikely because of its higher energy compared
to the Mo(VI) form.80 Based on reported electrochemical
behavior of related dinuclear cores, one- or two-electron
reduction waves could be expected for 2 or 4 electrons,
respectively, in 1−8 as well as one two-electron oxidation wave
or two one-electron oxidations for a stepwise process. The cyclic
voltammetry traces of 1−8 in CH3CN confirmed that they do
not show a large variation in their electrochemical behavior
(Figures 4 and 5 and SI Figures 18 and 19).
In CH3CN, the cyclic voltammograms of 1−8 show an
irreversible oxidation in the range from +0.255 V to +0.361 V,
and a second poorly defined irreversible oxidation wave at ∼1.0
V (Table 4 and Figures 4 and 5) was observed for 5−8. A strong
reduction that also appears irreversible was found in the range of
−1.13 V to −1.25 V. The lowest oxidation potentials (Eox1) were
observed for the leucine complex, followed by threonine and
methionine, and the highest was observed for the serine complex
(Table 4). These potentials are inversely ordered with respect to
catalytic reactivity of 1−4 toward cyanide (see Reactivity with
Cyanide). The peak-current ratios of the oxidation Eox1 and Ered1
in Table 4 are between 3 and 4 for 1 − 8, suggesting that the
reduction is at least a two-electron process.
Figure 6. Thiocyanate formation in a reaction of 1 (1 mM) with
cyanide (10 mM) compared to SCN yields from same reaction with
[Mo2O2(μ-S)2(S2)(DMF)3].
The thiocyanate formation increases rapidly for the first 20
min of the reaction, with about 80% of the thiocyanate of yield
formed within this time. Only 1 equiv of thiocyanate was
formed, confirming that only one sulfur atom is abstracted from
the complex. The results suggest that the complexes are able to
convert stoichiometric amounts of cyanide in a relatively quick
manner.
Preliminary scans in DMF show the visually comparable
electrochemical behavior of 1−8 with respect to the irreversible
oxidations and reductions observed. Electrochemical results for
1−8 in aqueous solutions clearly follow a different path than
those in aprotic media. A change of the amino acid ligands
Scheme 4. Reaction of 1−4 with 1 equiv of Cyanide
H
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Catalysis of Thiocyanate Formation. The thiocyanate
formation in reactions of cyanide and 1−8 in the presence of
thiosulfate was quantified as a function of time. The sulfido
complex shown in Scheme 4 was assumed to react with
thiosulfate, forming sulfite and regenerating the disulfide
complex. The kinetic experiments employed the same protocol
as the stoichiometric reactions, except excess amounts of
thiosulfate in predetermined rations were added to the complex
solution prior to cyanide addition. The thiocyanate yield was
quantified by sampling over a 2 h period. Figure 7 shows the
thiocyanate reaction yield over a 120 min period, employing 1−
4 as catalysts.
Table 5. The results confirm that 1−4 catalyze the reaction of
cyanide and thiosulfate to form thiocyanate. Without thiosulfate,
the complexes only convert 1 equiv of cyanide to thiocyanate.
When 100 equiv of thiosulfate was added, 1−4 converted 45−
57% of the cyanide within 20 min. The reduction of a lethal
cyanide concentration by 50% in vivo over 20 min is sufficient to
prevent death from cyanide poisoning.1,82−84 While the
microscopic mechanism for this reaction is under further
study, it can be said that 1−4 appear to follow the same reaction
mechanism. The TOF values provided are preliminary, since a
rather high catalyst loading was employed and the limits of the
system were not verified.
Complexes 5−8 are structurally similar to 1−4 despite lacking
the disulfide ligand. The catalytic activity of 5−8 was explored in
a similar fashion as that for 1−4 to obtain an insight into the
reaction mechanism. The complexes do have open coordination
sites on their molybdenum atoms that could potentially serve as
catalytically active sites. A possible catalytic reaction mechanism
assumes 5−8 catalytically convert cyanide to thiocyanate by a
different mechanism where the cyanide interacts with the
molybdenum centers and the thiosulfate donates sulfur as a
bridging sulfur ligand that is then abstracted by the cyanide. It is
nevertheless possible that more than one mechanism takes place
in the catalytic conversion of cyanide; potentially, it is a
bimetallic mechanism. Thiosulfate was used at a concentration
of 200 mM for comparison purposes, as this concentration
resulted in high reaction yields for the disulfide complexes.
The bis-amino acid complexes demonstrated catalytic activity
in the reaction of cyanide and thiosulfate (SI Figure 20).
Compared to the spontaneous reaction of cyanide and
thiosulfate (shown in gray in SI Figure 20), reaction yields of
thiocyanate were increased significantly in the presence of 5−8.
While the spontaneous reaction resulted in the conversion of
about 5% of the cyanide within 2 h, a 15−50% conversion was
observed in that same time frame in the presence of 5−8. The
highest reaction yield was observed for 6, while the lowest
reaction yield was observed for 7.
Figure 7. Thiocyanate formation in the reactions of 1−4 (1 mM) with
cyanide (10 mM) in the presence of thiosulfate (100 mM).
The reaction rates are dependent on the thiosulfate
concentrations. The second-order rate constants for 1−4 were
determined at pseudo-first-order reaction conditions and kobs
values for several [S2O32−]/[CN] ratios plotted. The kinetic
plot is shown in Figure 8, and the rate constants are shown in
The varying efficiency of these catalysts due to structural
differences cannot be explained at this point without further
experiments. The disulfide complexes demonstrate higher
thiocyanate reaction yields as well as faster conversion rates in
the first 20 min. The low initial reaction rates for cyanide
conversion catalyzed by 5−8 makes them ill-suited as
emergency treatments for cyanide poisoning in vivo. The results
are nevertheless important as they suggest that open
coordination sites on the molybdenum atoms take part in the
catalysis with or without the disulfide ligand. Examples of
possible mechanisms are (a) cyanide and thiosulfate coordinate
to one molybdenum atom each and cyanide carries out a
nucleophilic attack on thiosulfate on the opposite molybdenum,
releasing thiocyanate, and (b) thiosulfate coordinates in a
bidentate fashion (either S-, O-, or O,O-chelation), bridging
both molybdenum atoms, and the free cyanide attacks the sulfur
donor substrate, releasing thiocyanate. A complex with sulfate
bridging two molybdenum atoms has been reported, demon-
strating that it is a possible coordination mode for thiosulfate.30
The literature has a single example of a metal catalyzing this
reaction,85 but it has been explored with the rhodanese enzyme
in vitro.86−88
Figure 8. Plot of kobs as a function of variable thiosulfate ratio for 1−4.
Table 5. Second-Order Rate Constants and TOFs for 1−4
compound
k (M‑1 min‑1)
TOF (min−1
)
1
2
3
4
0.2615
0.3630
0.3391
0.4100
0.346
0.560
0.524
0.668
Figure 7 reveals about a 10% variance in the catalytic activity
of 1−4, which differ only in the R groups of the amino acid
ligands. The R group of leucine (−CH2CH(CH3)2) is the
strongest electron donor of the four, while the R group of serine
I
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(−CH2OH) is the strongest electron-withdrawing group. The R
groups of threonine (−CH(CH3)OH) and methionine
(−CH2CH2SCH3) have similar electron-donating properties,
which fall between those of leucine and serine. The catalytic
reaction is initiated with a sulfur atom abstraction reaction from
the disulfide ligand by cyanide. The S2 ligand is nucleophilic,
and the first sulfur is easily removed.52 The serine complex has
the fastest initial reaction rate of the four complexes (Table 5),
converting 57% of the cyanide to thiocyanate in the first 20 min.
The electron-withdrawing properties of the serine ligand side
chain reduce the σ-donation of the serine to the Mo2O2(μ-S)2
moiety and possibly result in the increased disulfide suscepti-
bility to nucleophilic attack by cyanide. The leucine complex
shows the lowest initial reaction rate of the four complexes,
converting 45% of the cyanide to thiocyanate in the first 20 min.
Its side chain has the largest electron-donating ability, rendering
disulfide more electronegative than in the serine complex, and is
therefore less reactive in a nucleophilic attack by cyanide. The
initial rates of the threonine and methionine complexes fall
between those of the serine and leucine complexes, which is in
agreement with electron-donating and electron-withdrawing
properties of the ligands. The influence of the ligands accounts
for at most a 10% difference in the conversion at the 20 min time
point, and this is unlikely to be significant in most circumstances.
Up to 75% of the available cyanide was quantified as
thiocyanate after a 2 h reaction time for 1−4, and extended
sampling did not increase the yields significantly. The remaining
25% and the apparent slowing of the reaction could be caused by
catalyst deactivation.85 The deactivation of the catalyst could be
brought about by cyanide−thiocyanate coordination or the
formation of a tetranuclear species through a dimerization
reaction of two sulfido complexes.
useful for emergency treatment. The second-order rate
constants for the reaction of cyanide and thiosulfate were
determined, and the turnover frequency was calculated. The
microscopic mechanism for this reaction is under current study.
The comparative catalytic abilities for 1−4 show at most a 10%
variation with the different amino acid ligands, rendering
aqueous solubility and toxicity likely determining factors for a
successful detoxification catalyst. Complexes 5−8 were
surprisingly active as well, although it is clear they show larger
a variation in catalytic activity that is presumably a result of a
different mechanism.
The results presented suggest complexes based on the
[Mo2O2(μ-S)2]2+ core could be both safe and efficient
treatments against cyanide poisoning. Next steps include
complexes with an increased aqueous solubility; studies of the
reaction mechanisms, key steps, and intermediates for these two
types of catalysts; and in vivo toxicity studies.
EXPERIMENTAL SECTION
■
54
Materials. The starting complexes [Mo2O2(μ-S)2(DMF)6](I)2
and [Mo2O2(μ-S)2(S2)(DMF)3]52 were synthesized according to
literature procedures. Silver salts of threonine and serine were prepared
according to published procedures.56 L-Fmoc−Met−OH, L-Fmoc−
Leu−OH, L-Fmoc−Thr−OH, and L-Fmoc−Ser−OH·H2O were
purchased from Bachem and used as received. Other reagents, organic
solvents, D2O, and DMSO-d6 were purchased from Aldrich and used as
received. DMF, diethyl ether, and acetonitrile were dried and distilled
under nitrogen using standard procedures.89 Veronal buffer (pH 7.4)
was purchased as 5× dilution stock solutions from Lonza. Milli-Q water
was used at 18 MΩ/cm or less.
Instrumentation. Infrared spectra were obtained as KBr discs on a
Smart Omni-Transmission Nicolet iS10 spectrophotometer at 21 °C.
Kinetic measurements and electronic spectra were obtained using
either a Varian Cary 100 Bio spectrophotometer or a PerkinElmer
Lambda 25 UV−vis spectrophotometer at 21 °C. Mass spectra were
recorded using a Bruker microTOF (Bruker autoflex smartbeam)
spectrometer as the ESI in negative ion scans. 1H and 13C NMR spectra
were recorded on a Bruker 400 Ultrashield spectrometer. Cyclic
voltammetric measurements were recorded on an EC Epsilon Eclipse
potentiostat/galvanostat. Elemental analyses were obtained from
Midwest Microlab, IN.
Preparation of Compounds. General Method for the Synthesis
of Potassium Salts of α-Amino Acids. L-Fmoc−α-aa−OH and KOtBu
were dissolved in DMF (50 mL). Upon the addition of DMF, the
solution turned red. The reaction was stirred for 22 h, during which
time it turned colorless and a white precipitate formed. The precipitate
was isolated by filtration and washed with diethyl ether (100 mL). The
solid was dried in vacuo. The solid was resuspended in acetonitrile, and
the mixture was stirred to remove the residual DMF. The product was
isolated by filtration and dried in vacuo.
K[C6H12NO2] (1a). L-Fmoc−Leu−OH (1.51 g, 4.27 mmol) and
KOtBu (0.479 g, 4.27 mmol) yielded in a white powder (0.58 g, 80%).
1H NMR (DMSO-d6): δ ppm 2.96 (br, −CH(NH2)−), 1.66 (m,
(CH3)2CH−), 1.44 (m, −CH2−, 1H), 1.22 (br, −CH2−, 1H), 0.83 (m,
(CH3)2−). 13C NMR (DMSO-d6): δ ppm 176.08 (−COO−), 54.45
(−CH(NH2)−), 44.44 (−CH2−), 24.54 ((CH3)2CH−), 23.47
((CH3)CH(CH3)−), 21.91 ((CH3)CH(CH3)−). Anal. Calcd for
C6H12KNO2: C, 42.58%; H, 7.15%; N, 8.28%. Found: C, 42.79%; H,
6.89%; N, 8.14%.
CONCLUSION
■
The synthesis of water-soluble α-amino molybdenum−sulfur
complexes was successful. The water solubility of the complexes
proved highly variable depending on the amino acid ligand
employed. The maximum aqueous solubility was found with
either alkali metal salts of anionic complexes or amino acid
ligands with a hydroxyl group on its side chain. Increasing the
aqueous solubility further is desirable in future work, where the
results described here show that the ligand solubility contributes
more to the overall solubility than the cation. Crystallization was
challenging, but complex 5 was crystallized with the carboxylate-
bridging zwitterionic form of leucine and the molybdenum
centers in an octahedral geometry. 1−4 are chiral compounds,
while 5−8 form stereoisomers. The zwitterionic coordination is
a route under further study to crystallize additional molecules.
The addition of SCN to 8 led to the crystallization of 9 with
two SCN ligands to fill the octahedral coordination around the
molybdenum centers. Complexes of this type are subjects for
further studies. The electrochemical properties suggest that the
[Mo2O2(μ-S)2]2+ core is rather inert to redox processes in vivo.
The ligands employed did not greatly influence the electro-
chemistry of the core. The cytotoxicity study showed a large
range in cytotoxicities that may be explained with further biology
experiments, but did show that all compounds have low to very
low cytotoxicities.
K[C5H10NO2S] (2a). L-Fmoc−Met−OH (2.03 g, 5.47 mmol) and
KOtBu (0.614 g, 5.47 mmol) yielded a white solid product (0.60 g,
58%). 1H NMR (DMSO-d6): δ ppm 3.06 (s, −CH(NH2)−), 2.48 (m,
A reaction with cyanide to produce 1 equiv of thiocyanate
proved to be a general reaction for 1−4 with the disulfide ligand,
while 5−8 did not react with cyanide in the absence of
thiosulfate. Complexes 1−8 all show an ability to bind cyanide,
and 1−4 convert it to thiocyanate in a time frame that could be
−SCH2CH2−), 2.01 (s, −CH3), 1.84/1.60 (m/br, −SCH2CH2−). 13
C
NMR (DMSO-d6): δ ppm 174.33 (−COO−), 55.02 (−CH(NH2)−),
34.22 (−SCH2CH2−), 30.43 (−SCH2CH2−), 14.60 (−CH3). Anal.
Calcd for C5H10KNO2S: C, 32.06%; H, 5.38%; N, 7.48%. Found: C,
32.28%; H, 4.93%; N, 7.01%.
J
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K[C4H8NO3] (3a). L-Fmoc−Thr−OH (4.06 g, 11.9 mmol) and
C4H10KMo2NO6S4: C, 9.11%; H, 1.91%; N, 2.66%. Found: C, 8.90%;
H, 1.78%; N, 2.45%. [α]2D5 (DMSO): + 27.6°.
1
KOtBu (1.34 g, 11.9 mmol) yielded a white solid (0.85 g, 46%). H
NMR (DMSO-d6): δ ppm 3.54 (m, −CH(OH)−), 2.88 (br,
−CH(NH2)−), 0.94 (d, −CH3). 13C NMR (DMSO-d6): δ ppm
175.54 (−COO−), 68.37 (−CH(OH)−), 58.90 (−CH(NH2)−), 19.06
(−CH3). Anal. Calcd for C4H8KNO3: C, 30.56%; H, 5.13%; N, 8.91%.
Found: C, 32.00%; H, 5.27%; N, 8.39%.
K[(C3H6NO3)Mo2O2(μ-S)2(S2)]·1.5H2O (4). [(DMF)3Mo2O2(μ-
S)2(S2)] (0.72 g, 1.26 mmol) and 4a (0.18 g, 1.26 mmol) were placed
in a Schlenk flask under N2. Freshly distilled DMF (60 mL) was added
to the flask via cannula. The reaction was stirred for 18 h. The clear red
solution was filtered, and the solvent was removed under reduced
pressure. The red viscous product was stirred in diethyl ether (100 mL)
until it solidified. The solid was collected by filtration and redissolved in
water (60 mL). The solution was filtered and lyophilized. This was
repeated until all residual DMF was removed. The product was an
orange solid (0.51 g, 78%). UV−vis (H2O, 6.43 × 10−5 M), λmax (nm):
275 (14275 M−1 cm−1), 305 (12720 M−1 cm−1), 347 (9029 M−1 cm−1),
474 (671 M−1 cm−1). 1H NMR (D2O): δ ppm 4.00 (m, −CH2−), 3.89
(br, −CH(NH2)−). 13C NMR (D2O): δ ppm 172.16 (−COO−), 60.11
(−CH2−), 56.29 (−CH(NH2)−). IR (KBr pellet, cm−1): 3294 (m),
3224 (m), 3136 (m), 1617 (s), 1385 (m), 945 (s), 519 (w), 467 (m).
MS-ESI: [M − K+] C3H6Mo2NO5S4 (m/z 459.7237), found m/z
459.7231. Anal. Calcd for C3H9KMo2NO6.5S4: C, 6.90%; H, 1.74%; N,
2.68%. Found: C, 6.40%; H, 1.72%; N, 2.60%. [α]2D5 (DMSO): + 55.9°.
[Mo2O2(μ-S)2(μ2-C6H12NO2)(C6H12NO2)2]·2H2O (5). [Mo2O2(μ-
S)2(DMF)6](I)2 (2.23 g, 2.27 mmol) was dissolved in acetone (40
mL) to form a red solution. L-C6H12NO2 (0.60 g, 4.54 mmol) and
NaOH (0.18 g, 4.54 mmol) were dissolved in H2O (10 mL) and added
dropwise to the red solution. The solution turned orange and cloudy.
Acetone (40 mL) was added to the reaction, and the solution became
clear. The reaction was stirred for 4 h. The solvent was removed under
reduced pressure. The orange solid was stirred in H2O (10 mL). The
solid was isolated via filtration, and the red filtrate was discarded. The
product was dissolved in ethanol (250 mL) and precipitated with
diethyl ether (600 mL). The precipitate that formed was isolated via
filtration. The orange filtrate was collected, the solvent was reduced to
20 mL, and product was further precipitated with diethyl ether (100
mL). The product was an orange solid (0.83 g, 73%). Single crystals
suitable for X-ray analysis were obtained by recrystallization from
methanol at gentle heating (50 °C). Needles formed upon the slow
cooling of the solution. UV−vis (H2O, 1.20 × 10−4 M), λmax (nm): 281
(7393 M−1 cm−1), 350 (1786 M−1 cm−1).1H NMR (DMSO-d6): δ ppm
1.88 (m, −CH(NH2)−), 1.01 (m, (CH3)2−), 0.95 (m,
(CH3)2CHCH2−), 0.66 (m, (CH3)2−).13C NMR (DMSO-d6): δ
ppm 181.85, 181.14, 99.53, 53.15, 52.90, 52.02, 41.70, 24.07, 23.99,
23.91, 23.50, 23.45, 23.20, 23.09, 21.95, 21.76, 21.42, 21.38. IR (KBr
pellet, cm−1): 3225 (m), 3169 (m), 3137 (m), 3062 (m), 1655 (s),
1617 (s), 1575 (m), 1389 (m), 1377 (m), 952 (s), 943 (s), 464 (m).
MS-ESI: [M − H+] C18H36Mo2N3O8S2 (m/z 682.0052), found m/z
682.0057; [M − C6H11NO2] C12H23Mo2N2O6S2 (m/z 550.9106),
found m/z 550.9111. Anal. Calcd for C18H41Mo2N3O10S2: C, 30.21%;
H, 5.78%; N, 5.87%. Found: C, 30.30%; H, 5.42%; N, 5.87%. [α]D25
(DMF): −22.4°.
K[C3H6NO3] (4a). L-Fmoc−Ser−OH·H2O (4.09 g, 11.8 mmol) and
1
KOtBu (1.32 g, 11.8 mmol) yielded a white solid (0.95 g; 56%). H
NMR (DMSO-d6): δ ppm 3.28 (m, −CH2−), 2.87 (t, −CH(NH2)−).
13C NMR (DMSO-d6): δ ppm 175.57 (−COO−), 64.97 (−CH2−),
55.24 (−CH(NH2)−). Anal. Calcd for C3H6KNO3: C, 25.17%; H,
4.22%; N, 9.78%. Found: C, 26.77%; H, 4.06%; N, 8.63%.
K[(C6H12NO2)Mo2O2(μ-S)2(S2)]·H2O (1). [(DMF)3Mo2O2(μ-
S)2(S2)] (0.51 g, 0.88 mmol) and 1a (0.15 g, 0.88 mmol) were placed
in a Schlenk flask under N2. Freshly distilled DMF (50 mL) was added
to the flask via cannula. The reaction was stirred for 20 h. The red
solution was filtered, and the solvent was removed under reduced
pressure. The red viscous oil was stirred in diethyl ether (50 mL)
overnight until it solidified. The solid was collected by filtration and
redissolved in water (60 mL). The solution was filtered and lyophilized.
This was repeated until all residual DMF was removed. The product
was an orange solid (0.42 g, 92%). UV−vis (H2O, 7.07 × 10−5 M), λmax
(nm): 276 (11083 M−1 cm−1), 305 (10105 M−1 cm−1), 347 (6798 M−1
1
cm−1), 474 (429 M−1 cm−1). H NMR (D2O): δ ppm 3.70 (br, −
CH(NH2)−), 1.65 (br, (CH3)2CHCH2−), 0.90 (s, (CH3)2−). 13C
NMR (D2O): δ ppm 176.88 (−COO−), 53.17 (−CH(NH2)−), 39.62
(−CH2−), 24.08 ((CH3)2CH−), 21.92 ((CH3)CH(CH3)−), 20.82
((CH3)CH(CH3)−). IR (KBr pellet, cm−1): 3232 (m), 3133 (m, br),
1609 (s), 1387 (m), 946 (s), 520 (w), 467 (m). MS-ESI: [M − K+]
C6H12Mo2NO4S4 (m/z 485.7757), found m/z 485.7763. Anal. Calcd
for C6H14KMo2NO5S4: C, 13.36%; H, 2.62%; N, 2.60%. Found: C,
12.92%; H, 2.56%; N, 2.18%. [α]2D5 (DMF): −6.5°.
K[(C5H10NO2S)Mo2O2(μ-S)2(S2)]·H2O (2). [(DMF)3Mo2O2(μ-
S)2(S2)] (0.46 g, 0.80 mmol) and 2a (0.15 g, 0.80 mmol) were placed
in a Schlenk flask under N2. Freshly distilled DMF (50 mL) was added
to the flask via cannula. The reaction was stirred for 20 h. The clear red
solution was filtered, and the solvent was removed under reduced
pressure. The red viscous product was stirred in diethyl ether (100 mL)
until it solidified. The solid was collected by filtration and redissolved in
water (60 mL). The solution was filtered and lyophilized. This was
repeated until all residual DMF was removed. The product was an
orange solid (0.30 g, 70%). UV−vis (H2O, 6.84 × 10−5 M), λmax (nm):
275 (11059 M−1 cm−1), 305 (9816 M−1 cm−1), 347 (6317 M−1 cm−1),
474 (450 M−1 cm−1). 1H NMR (D2O): δ ppm 3.89 (br, −CH(NH2)−),
2.65 (br, −SCH2CH2−), 2.20 (br, −SCH2CH2−), 2.15 (s, −CH3). 13
C
NMR (D2O): δ ppm 172.63 (−COO−), 53.91 (−CH(NH2)−), 29.62
(−SCH2CH2−), 28.81 (−SCH2CH2−), 13.94 (−CH3). IR (KBr pellet,
cm−1): 3227 (m, br), 3133 (m), 1617 (s), 1377 (m), 945 (s), 520 (w),
467 (m). MS-ES+: [M − K+] C5H10Mo2NO4S5 (m/z 503.7322), found
m/z 503.7327. Anal. Calcd for C5H12KMo2NO5S5: C, 10.77%; H,
2.17%; N, 2.51%. Found: C, 10.10%; H, 1.92%; N, 2.12%. [α]D25
(DMF): −11.5°.
[Mo2O2(μ-S)2(C5H10NO2S)2]·0.5H2O (6). [Mo2O2(μ-S)2(DMF)6]-
(I)2 (2.32 g, 2.36 mmol) was dissolved in acetone (40 mL), forming
a red solution. L-C5H10NO2S (0.70 g, 4.72 mmol) and NaOH (0.19 g,
4.72 mmol) were dissolved in H2O (20 mL) and added dropwise to the
solution. The solution turned orange. The reaction was stirred for 20 h.
The solution was filtered, and the solvent was reduced to 20 mL under
reduced pressure. The orange precipitate that formed was isolated via
filtration, redissolved in MeOH/DMF (100:50 mL), and precipitated
with isopropyl alcohol (200 mL). The orange precipitate that formed
was redissolved in acetone/H2O (100:10 mL) and precipitated with
diethyl ether (200 mL). The product was an orange solid (0.59 g, 42%).
UV−vis (H2O, 7.40 × 10−5 M), λmax (nm): 284 (9550 M−1 cm−1), 350
K[(C4H8NO3)Mo2O2(μ-S)2(S2)]·H2O (3). [(DMF)3 Mo2O2(μ-
S)2(S2)] (1.09 g, 1.91 mmol) and 3a (0.33 g, 1.91 mmol) were placed
in a Schlenk flask under N2. Freshly distilled DMF (100 mL) was added
to the flask via cannula. The reaction was stirred for 20 h. The clear red
solution was filtered, and the solvent was removed under reduced
pressure. The red viscous product was stirred in diethyl ether (100 mL)
until it solidified. The solid was collected by filtration and redissolved in
water (100 mL). The solution was filtered and lyophilized. This was
repeated until all residual DMF was removed. The product was an
orange solid (0.87 g, 90%). UV−vis (H2O, 5.92 × 10−5 M), λmax (nm):
274 (11858 M−1 cm−1), 305 (10233 M−1 cm−1), 347 (6402 M−1 cm−1),
474 (577 M−1 cm−1). 1H NMR (D2O): δ ppm 4.26 (m, −CH(OH)−),
3.60 (br, −CH(NH2)−), 1.33 (d, −CH3). 13C NMR (D2O): δ ppm
172.62 (−COO−), 65.82 (−CH(OH)−), 60.31 (−CH(NH2)−), 19.39
(−CH3). IR (KBr pellet, cm−1): 3291 (m), 3220 (m), 3126 (m), 1625
(s), 1385 (m), 942 (s), 520 (w), 466 (m). MS-ESI: [M − K+]
C4H8Mo2NO5S4 (m/z 473.7393), found m/z 473.7399. Anal. Calcd for
1
(2152 M−1 cm−1). H NMR (D2O): δ ppm 3.86 (t, −CH(NH2)−),
2.65 (t, −SCH2CH2−), 2.20 (m, −SCH2CH2−), 2.15 (s, −CH3). 13
C
NMR (D2O): δ ppm 174.15 (−COO−), 53.89 (−CH(NH2)−), 29.65
(−SCH2CH2−), 28.82 (−SCH2CH2−), 13.92 (−CH3). IR (KBr pellet,
cm−1): 3223 (m, br), 3126 (m), 1644 (s), 1374 (m), 944 (s), 464 (m).
MS-ESI: [M − H+] C10H19Mo2N2O6S4 (m/z 586.82), found m/z
586.82. Anal. Calcd for C10H21Mo2N2O6.5S4: C, 20.14%; H, 3.55%; N,
4.70%. Found: C, 20.41%; H, 3.72%; N, 4.03%. [α]2D5 (DMF): −53.7°.
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[Mo2O2(μ-S)2(C4H8NO3)2]·H2O (7). [Mo2O2(μ-S)2(DMF)6](I)2
(1.04 g, 1.06 mmol) was dissolved in H2O (30 mL) to give a red
solution. Ag[C4H8NO3] (0.48 g, 2.12 mmol) was dissolved in H2O (10
mL) and added dropwise to the red solution. The AgI precipitate
started forming immediately. The reaction was stirred for 20 h. The
precipitate was filtered off and discarded. The solvent of the filtrate was
reduced to 20 mL under reduced pressure. Acetone (100 mL) and
diethyl ether (100 mL) were added to the solution. The resulting
precipitate was isolated via filtration. The solid was redissolved in H2O
(3 mL) and precipitated with acetone (100 mL) and diethyl ether (100
mL). The solid was redissolved in H2O (3 mL) and lyophilized. The
product was an orange powder (0.35 g, 61%). UV−vis (H2O, 1.43 ×
10−4 M), λmax (nm): 281 (6528 M−1 cm−1), 350 (1498 M−1 cm−1). 1H
NMR (D2O): δ ppm 4.17 (m, −CH(OH)−), 3.51 (br, −CH(NH2)−),
1.33 (m, −CH3). 13C NMR (D2O): δ ppm 172.52 (−COO−), 65.78
(−CH(OH)−), 60.21 (−CH(NH2)−), 19.36 (−CH3). IR (KBr pellet,
cm−1): 3288 (m, br), 3129 (m), 1640 (s), 1382 (m), 943 (s), 464 (m).
MS-ESI: [M − H+] C8H15Mo2N2O8S2 (m/z 526.8378), found m/z
526.8383. Anal. Calcd for C8H18Mo2N2O9S2: C, 17.72%; H, 3.35%; N,
5.17%. Found: C, 18.10%; H, 3.59%; N, 5.14%. [α]2D5 (DMSO): −6.5°.
[Mo2O2(μ-S)2(C3H6NO3)2] (8). [Mo2O2(μ-S)2(DMF)6](I)2 (1.43 g,
1.46 mmol) and Ag[C3H6NO3] (0.62 g, 2.92 mmol) were dissolved in
H2O (200 mL). The reaction was stirred for 20 h. A light-colored
precipitate formed from the orange-colored solution. The AgI
precipitate was filtered off and discarded. The filtrate was dried under
reduced pressure. The resulting viscous oil was redissolved in H2O (3
mL) and precipitated with acetone (100 mL). The solid was redissolved
in H2O (20 mL) and precipitated with acetone (200 mL). The product
was collected by filtration, redissolved in H2O (100 mL), and
lyophilized. The product was an orange solid (0.44 g, 59%). UV−vis
(H2O, 1.58 × 10−4 M), λmax (nm): 281 (5830 M−1 cm−1), 350 (1426
M−1 cm−1).1H NMR (D2O): δ ppm 3.99 (m, −CH2−), 3.89 (br, −
CH(NH2)−). 13C NMR (D2O): δ ppm 172.07 (−COO−), 60.06
(−CH2−), 56.22 (−CH(NH2)−). IR (KBr pellet, cm−1): 3211 (m, br),
3120 (m), 1617 (s), 1385 (m), 941 (s), 460 (m). MS-ESI: [M − H+]
C6H11Mo2N2O8S2 (m/z 498.81), found m/z 498.81. Anal. Calcd for
C6H12Mo2N2O8S2: C, 14.52%; H, 2.44%; N, 5.65%. Found: C, 14.76%;
H, 2.41%; N, 5.76%.
Stoichiometric Reactions. Triplicate solutions containing the
catalyst (1 mM) were prepared in veronal buffer (pH 7.4) along with a
fourth one used as a blank solution that contained the same
concentrations of the catalyst in veronal buffer. At t = 0, an amount
of potassium cyanide (in 1.6 g/L NaOH/H2O) was added to the three
stock solutions so that the resulting concentration of cyanide would be
10 mM. An equivalent volume of NaOH (1.6 g/L H2O) was added to
the blank solution. Aliquots were removed from each of the three
reaction solutions at time points t = 1, 3, 5, 10, 15, 20, 40, 60, and 120
min. To the aliquots was added to 2.5 mL of Fe(NO3)3 (0.2 M), and the
solutions were diluted to 10 mL with HNO3 (1 M). The absorptions of
the resulting solutions were subsequently measured at 447 nm, and
concentrations were calculated using a calibration curve for absorbance
versus concentration of FeSCN2+.
Cytotoxicity. The cytotoxicity was determined using the MTT
assay method previously described.90 The assay measures the extent of
the cellular reduction of 3-(4,5-dimethylthiazol-2-yl)- 2,5-diphenylte-
trazolium bromide (MTT) to a purple formazan product by the
mitochondrial dehydrogenase of viable cells. First, 100 μL aliquots
containing approximately 1 × 104 A549 lung cancer cells per milliliter of
the cell culture medium (advanced DMEM supplemented with 2% (v/
v) fetal bovine serum and 1% (w/v) glutamine) was seeded in the wells
of a 96-well plate (Costar) and allowed to adhere for 24 h at 37 °C in 5%
(v/v) CO2. The cell growth medium was then removed from the wells
and replaced with solutions of the molybdenum or cisplatin complexes,
which had been dissolved and then diluted in the culture medium such
that 10 different concentrations ranging from 0 to 1000 μM for the
molybdenum complexes and from 0 to 500 μM for cisplatin were
obtained. Then, 100 μL of each drug concentration was added to six
wells, and the cells were incubated for 72 h. Following incubation, MTT
(20 mL, 2.5 mg mL−1 in Milli Q water) was added to each well, and the
plate was incubated for a further 4 h. The medium was removed, and
DMSO (dimethyl sulfoxide) (150 μL) was added to each well. The
plate was shaken for 60 s, and the absorbance due to the formazan
product was measured immediately at 600 nm using a Victor3 V plate
reader (PerkinElmer). IC50 values were determined as the drug
concentration that reduced the absorbance to 50% of the value of the
untreated control wells.
Catalytic Reactions. An analogous method was used as for the
stoichiometric reactions. Thiosulfate was added to the complex
solution in the desired quantity. The data workup calculated the
thiocyanate concentration from the measured absorbance and plotted
the [SCN] versus time for several rations of the thiosulfate to cyanide
concentration. The conversion of cyanide was calculated based on
found [SCN] concentration versus the initial cyanide concentration,
[CN]0.
Cyclic Voltammetry. The cyclic voltammetry data were recorded
using a BASi Epsilon Eclipse electrochemical analyzer under nitrogen.
CH3CN solutions were prepared from distilled and degassed solvent
and were 0.2 M in Bu4NPF6. The electrochemical cell used platinum
working and auxiliary electrodes and a Ag/AgCl reference electrode.
X-ray Crystallography Data Collection. X-ray quality single
crystals of 5 were obtained by recrystallization in MeOH (50 °C) and
slow cooling at 21 °C. The crystals were isolated from the mother
liquor, immediately immersed in a cryogenic oil, and then mounted.
The X-ray single crystal data were collected using Cu Kα radiation (λ =
1.54178 Å) on a Bruker D8Venture (Photon100 CMOS detector)
diffractometer equipped with Cryostream (Oxford Cryosystems) open-
flow nitrogen cryostats at 120.0(2) K. The unit cell determination, data
collection, data reduction, structure solution and refinement, and
empirical absorption correction (SADABS) were carried out using
Apex3 software.91 The structure was solved by the direct method and
refined by full-matrix least-squares on F2 for all data using SHELXTL92
software. The final refinements were performed using TWIN and BASF
instructions,93 and the structure was refined as a two-component
inversion. The carbon atom of one the methanol molecules was
disordered, and the free variables were refined by FVAR instruction. All
nondisordered non-hydrogen atoms were refined anisotropically. We
were not able to refine the hydrogen atoms of the nitrogen atom located
in the Fourier map to a proper model. Thus, all the hydrogen atoms
were placed in the calculated positions and refined in the riding model.
X-ray-quality single crystals of 9 were obtained by the dissolution of 8
in acetonitrile with 2 equiv of Bu4NSCN and KSCN and layering with
ether. A suitable crystal was selected and placed in paratone on a
micromount on a Bruker SMART APEXII diffractometer equipped
with a CCD area detector. The crystal was kept at 100(2) K during data
collection. Using Olex2,94 the structure was solved with the olex2.solve
structure solution program95 using charge flipping and refined with the
ShelXL refinement package96 using least-squares minimization. The
structure had a number of issues that were dealt with during refinement.
First, the tetra-n-butyl ammonium cation is disordered across a two-fold
rotation axis; chemically equivalent bond lengths and angles of the
cation were restrained to be approximately equal. The acetonitrile
solvent molecule is disordered across a 3.2 site (Wyckoff letter c). Due
to the very low occupancy in the asymmetric unit, the 1,2- and 1,3-
distances of this molecule were restrained to ideal values from the CSD.
The CH3 group of this also would not find a minimum during
refinement, so a distance restraint was applied between one of these
atoms and an atom on the adjacent n-Bu4N cation. This molecule could
not be sensibly refined anisotropically and so was refined isotropically.
The second potassium cation is disordered over two positions. The
occupancies of these two positions were refined competitively,
converging to a ratio of 0.23:0.10. The water molecule is half-occupied
and additionally disordered around a three-fold rotation axis. The
hydrogen atoms could not be sensibly located or modeled and so were
excluded from the model; however, they were included in the formula
and the calculation of derived parameters. Finally, enhanced rigid bond
and similarity restraints were applied to the thermal parameters of all
non-hydrogen atoms. Further crystallographic details are provided in
the tables in the Supporting Information.
L
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Article
Metals in Medicine: Therapeutic Use and Toxicity of Metal Ions in the
Clinic; Sigel, A., Freisinger, E., Sigel, R. K. O., Carver, P. L., Eds.; Metal
Ions in Life Sciences, Vol. 19; Walter de Gruyter: Berlin, Germany,
2019; pp 359−391
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.inorgchem.0c02672.
■
sı
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a review. Anal. Chim. Acta 2010, 673 (2), 117−25.
Summary of crystal data, bond angles, and distances for 5
and 9; ESI-MS spectra of 1−8; cytotoxicity results; cyclic
voltammetry traces 1−8; and catalytic activity of bis-
amino acid complexes(PDF)
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Antidotal Treatment of Cyanide Poisoning. J. Chin Med. Assoc. 2003,
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CCDC 2027204−2027205 contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/data_request/cif, or by email-
ing data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road, Cam-
bridge CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
Corresponding Author
Sigridur G. Suman − Science Institute, University of Iceland,
107 Reykjavik, Iceland; orcid.org/0000-0003-4283-6140;
Email: sgsuman@hi.is
■
(9) Mediavilla, J. J. V.; Perez, B. F.; Cordoba, M. C. F. d.; Espina, J. A.;
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Authors
Johanna M. Gretarsdottir − Science Institute, University of
Iceland, 107 Reykjavik, Iceland
Sigridur Jonsdottir − Science Institute, University of Iceland,
107 Reykjavik, Iceland
William Lewis − School of Chemistry, The University of Sydney,
Sydney, NSW 2006, Australia; orcid.org/0000-0001-
7103-6981
Trevor W. Hambley − School of Chemistry, The University of
Sydney, Sydney, NSW 2006, Australia; orcid.org/0000-
0003-1194-1896
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.inorgchem.0c02672
Author Contributions
All authors have given approval to the final version of the
manuscript.
Notes
The authors declare the following competing financial
interest(s): S.G. Suman is the author of published patents
describing treatment for cyanide poisoning using molybdenum
compounds.
Hydrogen cyanide is volatile and highly toxic. To minimize
exposure, cyanide stock solutions were prepared in 40 mM
NaOH and diluted to the desired concentrations in veronal
buffer.
ACKNOWLEDGMENTS
■
Prof. K. K. Damodaran is thanked for crystal data collection and
the refinement of 5. Financial support by The University of
Iceland Research Fund and from The Icelandic Centre of
Research (Rannis) grant 140945 are gratefully acknowledged.
(21) Gretarsdottir, J. M.; Bobersky, S.; Metzler-Nolte, N.; Suman, S.
G. Cytotoxicity studies of water soluble coordination compounds with a
[Mo2O2S2]2+ core. J. Inorg. Biochem. 2016, 160, 166−171.
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Tungsten Oxotransferases. Chem. Rev. 2004, 104, 1175−1200.
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nitrogenase substrates. Are multiple sites within the Fe/Mo/S active
center involved in the 6e− reduction of N2? JBIC, J. Biol. Inorg. Chem.
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