Bismuth(III) β-thioxoketonates as antibiotics against Helicobacter pylori and as anti-leishmanial agents

Article abstract of DOI:10.1039/c3dt52544a

Nine different β-thioxoketones of general formula R ¹C(O)CH₂C(S)R² (R¹ = C ₆H₅, R² = C₆H₅L1; R ¹ = C₆H₅, R² = p-CF ₃C₆H₄L2; R¹ = p-MeOC ₆H₄, R² = C₆H₅L3; R ¹ = p-MeOC₆H₄, R² = p-CF ₃C₆H₄L4; R¹ = C₅H ₄N, R² = C₆H₅L5; R¹ = p-IC₆H₄, R² = C₆H₅L6; R¹ = C₆H₅, R² = p-IC ₆H₄L7; R¹ = C₆H₅, R ² = C₁₀H₇L8 and R¹ = CH₃, R² = C₆H₅L9) and their tris-substituted bismuth(III) complexes having the general formula [Bi{R¹C(O)CHC(S) R²}₃] were synthesised and fully characterised. The solid state structure of [Bi{C₅H₄NC(O)CHC(S)C₆H ₅}₃] B5 was determined by crystallography and revealed that the three β-thioxoketonato ligands are bound to bismuth(III) centre in a bidentate fashion through O and S atoms. The bismuth(III) complexes and the corresponding thioxoketones were assessed for their activity against H. pylori. All of the bismuth(III) complexes were highly active against H. pylori having a MIC of greater than or equal to 3.125 μg mL^-1, while the free acids were essentially not toxic to the bacteria. The anti-leishmanial activity of all the bismuth(III) β-thioxoketonates and the corresponding free acids were assessed against L. major promastigotes. The toxicity towards human fibroblast cells was also assessed. All of the free β-thioxoketones were selectively toxic to the L. major promastigotes displaying some potential as anti-leishmanial agents. Among these [C₆H₅C(=O)CH ₂C(=S)C₆H₅] L1 and [C₅H ₄NC(=O)CH₂C(=S)C₆H₅] L5 showed comparable activity to that of Amphotericin B, killing about 80% of the L. major promastigotes at a concentration of 25 μM (6.0 μg mL^-1). The bismuth(III) β-thioxoketonate complexes were toxic to both the L. major promastigotes and fibroblast cells at high concentrations, but gave no improvement in anti-leishmanial activity over the free β-thioxoketones. The Royal Society of Chemistry 2014.

Full text of DOI:10.1039/c3dt52544a

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Bismuth(III) β-thioxoketonates as antibiotics against
Helicobacter pylori and as anti-leishmanial agents†
Cite this: DOI: 10.1039/c3dt52544a
Philip C. Andrews,*a Victoria L. Blair,a Richard L. Ferrero,b Peter C. Junk,c
Lukasz Kedzierskid,e and Roshani M. Peirisa
Nine different β-thioxoketones of general formula R1C(vO)CH2C(vS)R2 (R1 = C6H5, R2 = C6H5 L1; R1
=
C6H5, R2 = p-CF3C6H4 L2; R1 = p-MeOC6H4, R2 = C6H5 L3; R1 = p-MeOC6H4, R2 = p-CF3C6H4 L4; R1 = C5H4N,
R2 = C6H5 L5; R1 = p-IC6H4, R2 = C6H5 L6; R1 = C6H5, R2 = p-IC6H4 L7; R1 = C6H5, R2 = C10H7 L8 and R1
=
CH3, R2 = C6H5 L9) and their tris-substituted bismuth(III) complexes having the general formula [Bi{R1C-
(vO)CHC(vS)R2}3] were synthesised and fully characterised. The solid state structure of [Bi{C5H4NC(vO)-
CHC(vS)C6H5}3] B5 was determined by crystallography and revealed that the three β-thioxoketonato
ligands are bound to bismuth(III) centre in a bidentate fashion through O and S atoms. The bismuth(III)
complexes and the corresponding thioxoketones were assessed for their activity against H. pylori. All of
the bismuth(III) complexes were highly active against H. pylori having a MIC of greater than or equal to
3.125 μg mL−1, while the free acids were essentially not toxic to the bacteria. The anti-leishmanial activity
of all the bismuth(III) β-thioxoketonates and the corresponding free acids were assessed against L. major
promastigotes. The toxicity towards human fibroblast cells was also assessed. All of the free β-thioxo-
ketones were selectively toxic to the L. major promastigotes displaying some potential as anti-leishmanial
agents. Among these [C6H5C(vO)CH2C(vS)C6H5] L1 and [C5H4NC(vO)CH2C(vS)C6H5] L5 showed com-
parable activity to that of Amphotericin B, killing about 80% of the L. major promastigotes at a concen-
tration of 25 μM (6.0 μg mL−1). The bismuth(III) β-thioxoketonate complexes were toxic to both the
L. major promastigotes and fibroblast cells at high concentrations, but gave no improvement in anti-
leishmanial activity over the free β-thioxoketones.
Received 16th September 2013,
Accepted 24th October 2013
DOI: 10.1039/c3dt52544a
www.rsc.org/dalton
sulfamates, and sulfonates, and exploring their in vitro activity
against H. pylori.7–11 The diversity in observed bactericidal
Introduction
Bismuth compounds have been used in medicine for more activity of the complexes, ranging from micro to nano-molar,
than 250 years.1 Their most important current medical appli- has provided some insights into possible structure–activity
cation, using bismuth subsalicylate and colloidal bismuth relationships in their mode of action.
citrate, is in treating and eradicating Helicobacter pylori, the
The other medical arena in which we have proposed that
bacterium responsible for gastritis, peptic and duodenal bismuth(III) compounds may become relevant is in the treat-
ulcers, and gastric cancers.2–6 Over the past decade we have ment of leishmaniasis, a group of diseases caused by proto-
been successful in establishing new families of bismuth(III) zoan parasites that belong to the genus Leishmania and are
compounds based on carboxylates, thiocarboxylates, spread to humans by the bite of an infected female sand fly.
This group of diseases is endemic in the developing world,
currently affecting 12 million people with an estimated
2 million new cases per annum. Among the various forms,
aSchool of Chemistry, Monash University, P.O. Box 23, Melbourne, Victoria 3800,
Australia. E-mail: phil.andrews@monash.edu
bCentre for Innate Immunity and Infectious Diseases, Monash Institute of Medical
visceral leishmaniasis (VL) is the most dangerous and is fatal
if left untreated.12
Research, Clayton, Melbourne, Vic. 3168, Australia
The front-line treatment of leishmaniasis relies heavily
on pentavalent antimonial drugs; sodium stibogluconate
(Pentosam) and meglumine antimoniate (Glucantime). These
drugs are cost effective and have high cure rates.13,14 However,
they also have significant drawbacks; they are delivered over 28
days by intramuscular injection, highly toxic Sb(III), the likely
active form of the drug, is produced and bio-distributed
cSchool of Pharmacy and Molecular Sciences, James Cook University, Townsville,
QLD 4811, Australia
dWalter and Eliza Hall Institute of Medical Research, Parkville, Melbourne,
VIC 3000, Australia
eDepartment of Medical Biology, The University of Melbourne, Parkville, Melbourne,
VIC 3010, Australia
†CCDC 948455. For crystallographic data in CIF or other electronic format see
DOI: 10.1039/c3dt52544a
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through intracellular reduction of Sb(V), and resistance has
appeared in some parts of India.15 The close periodic relation-
ship of bismuth with antimony, coupled with the apparent low
systemic toxicity of bismuth(III) in humans, suggests an oppor-
tunity in developing bismuth(III) compounds as candidates for
the treatment of leishmaniasis.
Recently, we reported the anti-leishmanial (promastigote)
activity of bismuth(III) carboxylates16 and thiocarboxylates17
indicating that the toxic effect is both metal and ligand
dependant.
Scheme 1 Reaction of ketones with thioesters to produce β-thioxoketones
L1–L9.
Bismuth complexes with Bi–S bonds, such as thiolates and
thiocarboxylates, are generally more thermodynamically stable
and less labile than their carboxylate analogues. This improves
their hydrolytic stability, and hence impacts on purity, syn-
thetic reproducibility and biological activity.18 In broadening
the scope of complexes available for assessment of their bio-
logical and medicinal chemistry, we turned our attention to
bismuth(III) β-thioxoketonates.
Both transition metal; Ni(II), Co(III), Fe(III), Zn(II), Cu(II), Pt(II),
Pd(II) and Mo(VI),19–23 and p-block metal β-thioxoketonates,
Sn(IV), In(III), Ga(III), Ge(IV), have been reported.24,25 The β-thioxo-
ketonato ligands predominantly bind to the metal centre in a
bidentate fashion through the O and S atoms, the exception
being Ge(IV) in which the ligand binds only through the S
atom. Three complexes of Bi(III) bearing β-thioxoketonato
ligands are so far known; [Bi{C6H5C(vS)CHC(vO)C6H5}3], [Bi-
{C6H5C(vS)CHC(vO)C6H4-p-OMe}3], [Bi{C6H5C(vS)CHC(vO)-
C6H4-p-Cl}3].26 X-ray crystallography on [Bi{C6H5C(vS)CHC-
(vO)C6H5}3] revealed the ligand to be bidentate on the
bismuth(III) centre.
thioesters using NaH as the base (Scheme 1). This new
approach gives comparatively better yields than the traditional
method employing NaNH2 as base, and importantly also
avoids the use of H2S, which is the other standard alternative
approach.
The synthesis of β-thioxoketones [C6H5C(vO)CH2C(vS)-
C6H5] L1, [p-MeOC6H4C(vO)CH2C(vS) C6H5] L3, [C6H5C(vO)-
CH2C(vS)C10H7] L8 and [CH3C(vO)CH2C(vS)C6H5] L9 has
been described previously using NaNH2,19,28,29 while the
remaining five compounds are novel and were developed
specifically for this study.
Unfortunately, compounds [C6H5C(vO)CH2C(vS)p-IC6H4]
L7 and [CH3C(vO)CH2C(vS)C6H5] L9 were not able to be
obtained in pure form due to trace (≤5%) contamination with
starting thioesters. These proved difficult to separate by
chromatography due to similar solubilities and Rf values. The
physical properties and yields of the synthesised β-thioxo-
ketones are provided in the Experimental section.
Synthesis of thioesters
The strong chelating ability of β-thioxoketones means they
are used in chemical separation and their metal complexes are
used as catalysts in olefin and carbon monoxide conversion
reactions.27 However, the biological chemistry of the β-thioxo-
ketones or their metal complexes has not yet been explored.
This paper describes the synthesis and characterisation of
nine different β-thioxoketones of the general formula R1C-
(vO)CH2C(vS)R2 (where R1 = C6H5, R2 = C6H5 L1; R1 = C6H5,
Thioesters are not commercially available and therefore were
synthesised prior to use. A reagent combination of P4S10 and
hexamethyldisiloxane (Me3SiOSiMe3, HMDO) is known to
produce thioesters in good yields.30,31 Four different aromatic
thioesters; ethyl thiobenzoate (ETB), methyl 4-trifluoro-
methylthiobenzoate (MFTB), methyl 2-thionaphthoate (MTN)
and methyl 4-iodothiobenzoate (MITB) were synthesised by
treating the corresponding esters with 0.33 equivalents of
P4S10 and 1.75 equivalents of HMDO in xylene at reflux for a
period of 8–18 h under inert atmosphere conditions. Alkaline
hydrolysis of the resultant reaction mixture with aqueous
potassium carbonate (K2CO3) solution followed by solvent
extraction yielded a crude product significantly free from
phosphorous containing by-products. Distillation or silica gel
column chromatography of the crude products gave the thio-
esters, ETB, MFTB and MTN, in 100% purity, while MITB was
isolated in 83% purity. With the exception of ETB, we believe
this is the first report on the synthesis and isolation of these
particular thioesters.
R2 = p-CF3C6H4 L2; R1 = p-MeOC6H4, R2 = C6H5 L3; R1
=
p-MeOC6H4, R2 = p-CF3C6H4 L4; R1 = C5H4N, R2 = C6H5 L5;
R1 = p-IC6H4, R2 = C6H5 L6; R1 = C6H5, R2 = p-IC6H4 L7; R1 =
C6H5, R2 = C10H7 L8; and R1 = CH3, R2 = C6H5 L9) and their
tris-substituted bismuth(III) complexes, having the general
formula [Bi{R1C(vO)CHC(vS)R2}3]. The solid state structure
of [Bi{C5H4NC(vO)CHC(vS)C6H5}3] B5 was determined by
crystallography and is discussed. The biological activity of the
β-thioxoketones and their bismuth(III) derivatives against
H. pylori, Leishmania promastigotes and fibroblast cells was
assessed, and is reported.
Synthesis of bismuth(III) β-thioxoketones
Results and discussion
Synthesis of β-thioxoketones
Bismuth(III) β-thioxoketonates B1–B9 (Table 1) were syn-
thesised by reacting three equivalents of the β-thioxoketone
Nine different α-unsubstituted β-thioxoketones were syn- with bismuth tert-butoxide [Bi(OtBu)3] under dry inert-atmos-
thesised by the Claisen condensation of ketones with phere conditions (Scheme 2).
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Table 1 Summary of bismuth(III) β-thioxoketones B1–B9 synthesised by the reaction with Bi(OtBu)3
Yield
(%)
Bismuth(III) complex
Appearance
B1
B2
B3
B4
B5
B6
B7
B8
B9
[Bi{C6H5C(vO)CHC(vS)C6H5}3]
Orange crystals
Orange powder
Yellow powder
Yellow powder
Pale brown powder
Yellow powder
Yellow powder
Pale brown powder
Pale brown powder
71
92
86
74
68
83
66
82
65
[Bi{C6H5C(vO)CHC(vS)p-CF3–C6H4}3]
[Bi{p-MeOC6H4C(vO)CHC(vS)C6H5}3]
[Bi{p-MeOC6H4C(vO)CHC(vS)p-CF3–C6H4}3]
[Bi{C5H4NC(vO)CHC(vS)C6H5}3]
[Bi{p-IC6H4C(vO)CHC(vS)C6H5}3]
[Bi{C6H5C(vO)CHC(vS)p-IC6H4}3]
[Bi{C6H5C(vO)CHC(vS)C10H7}3]
[Bi{CH3C(vO)CHC(vS)C6H5}3]
In a typical reaction Bi(OtBu)3 was dissolved in THF and respectively. Absence of bands in the conjugated carbonyl
added slowly to a THF solution of β-thioxoketone (3 equi- region (1685–1666 cm−1) (delocalization of π electrons of CvO
valents) at −80 °C under Schlenk conditions. The reaction with phenyl group) and the absence of a broad band at
mixture was stirred for 18 h as it warmed slowly to room temp- 2415 cm−1 due to the H-bonded S–H stretching vibration, con-
erature. In vacuo removal of THF (when the product was firms their existence in the H-chelated enol form. The CvS
soluble in THF) or filtration of the precipitate (when stretching vibrations coupled with C–H deformations were
the product precipitated in THF), followed by washing with observed in the range 820–792 cm−1
ethanol to remove any unreacted acid, gave the intensely The IR spectra of the bismuth(III) thioxoketonates B1–B9 all
coloured tris-substituted bismuth(III) β-thioxoketonates in high showed bathochromic shifts in CvO and CvC stretching
yield and purity. vibrations compared with their corresponding free thioxo-
.
Although β-thioxoketone [CH3C(vO)CH2C(vS)C6H5] L9 ketones, demonstrating the chelating nature of the ligand. The
showed some contamination with the starting thioester, this chelating nature of [Bi{C6H5C(vO)CHC(vS)C6H5}3]26 B1 and
did not effect the ultimate purity of the bismuth(III) complex [Bi{C5H4NC(vO)CHC(vS)C6H5}3] B5 has been confirmed by
[Bi{CH3C(vO)CHC(vS)C6H5}3] B9 as the thioester is easily X-ray crystallography (see Crystallography section). However,
washed away with ethanol. However, similar solubilities of the the complexes [Bi{p-IC6H4C(vO)CHC(vS)C6H5}3] B6, [Bi-
bismuth(III) complex B7 with its corresponding thioester L7 {C6H5C(vO)CHC(vS)p-IC6H4}3] B7 and [Bi{C6H5C(vO)CHC-
leads to a lower than expected isolated yield after washing the (vS)C10H7}3] B8 do not show any significant shifts in CvO
product.
Complexes
absorptions and therefore any significant Bi⋯OvC interaction
and is doubtful. Similar monodentate behaviour has been observed
[Bi{C6H5C(vO)CHC(vS)C6H5}3]
B1
[Bi{p-MeO–C6H4C(vO)CHC(vS)C6H5}3] B3 have been reported in the triorganogermanium(IV) complexes of C6H5C(vO)CH2C-
previously, synthesised through salt metathesis using bismuth(III) (vS)C6H5 in which the ligand binds only through the S atom,
chloride and the sodium β-thioxoketonate. Although both and no changes in the carbonyl vibrations were observed.32
procedures give similar yields, the use of Bi(OtBu)3 is advan- The ν CvS and the mixed ν CvS + δ C–H bands in bismuth(III)
tageous in avoiding salt contamination.
thioxoketones can be observed in the region of 1249–1228 and
The bismuth complexes B1–B9 proved to be partially 805–820 cm−1 respectively.
soluble in ethanol and methanol, moderately soluble in
NMR spectroscopy. The 1H NMR spectra of the β-thioxo-
toluene, dichloromethane, tetrahydrofuran (THF) and chloro- ketones, taken in CDCl3, indicate the presence of the enol
form, and highly soluble in dimethylsulfoxide (DMSO) and tautomer. The vC–O–H⋯SvC resonances are observed in the
dimethylformamide (DMF). They were not soluble in water range 14.4–15.8 ppm, while the vC–H signals appear between
alone.
7.39–8.25 ppm. The absence of CH2 proton signals in the
range of 3.03–3.29 ppm and the absence of enethiol (vC–S–H)
resonances in the range of 4.79–6.87 ppm indicates the
absence of either the thioxoketo or the enethiol form. All the
thioxoketones showed the expected number of carbon reso-
nances in the 13C NMR spectra. The vC–OH⋯SvC resonances
were observed above 200 ppm, while the vC–OH⋯SvC
Characterisation of β-thioxoketones and their bismuth(III)
derivatives
Infra-red spectroscopy. In the IR spectra of the free thioxo-
ketones, L1–L9, the CvO, CvC and CvS absorptions appear
in the region of 1606–1579, 1557–1540 and 1274–1232 cm−1
Scheme 2 Synthesis of bismuth(III) β-thioxoketones by the reaction of three equivalents of β-thioxoketones with Bi(OtBu)3.
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Bi(1)–O(2), 2.600(3); Bi(1)–O(3), 2.518(7) Å] and a coordinating
molecule of DMSO. The overall coordination geometry around
the Bi(III) centre is disordered pentagonal bipyramid in which
S(1), S(3), O(1), O(2) and O(3) form one plane with S(4) and
O(4) lying perpendicular to this plane in the apical positions.
In all three bonded β-thioxoketonato ligands the attached
pyridine ring lies almost planar to the 6-membered chelate
ring while the phenyl group is twisted out of the plane by
53.38(19)°, 43.22(29)° and 61.00(38)° for C9–C14, C23–C28 and
C37–C42 respectively.
Searching the literature complex B5 can be best compared
to the previously reported dimeric β-thioxoketonate Bi(III)
complex [Bi{C6H5C(vO)CHC(vS)C6H5}3]2 B1.26 Similar to B5,
the three chelating β-thioxoketonato ligands are attached to
the Bi(III) centre in a bidentate fashion through their S and O
atoms however, in contrast distinctly different Bi–S bond
lengths of 2.731(3), 2.627(5) and 2.581(4) Å are observed26
[cf. 2.659(2), 2.600(3) and 2.662(2) Å in B5] while the Bi–O
bond lengths in B1 (2.587 Å average) lie in the same range as
those found in complex B5 (2.560 Å average).
Fig. 1 Molecular structure of [Bi{C5H4NC(vO)CHC(vS)C6H5}3·DMSO] B-5.
Thermal ellipsoids shown at 40% probability. H atoms and disorder components
in DMSO and C37–C42 omitted for clarity. Selected bond lengths (Å) and angles
(°): Bi(1)–O(1) 2.563(5), Bi(1)–O(2) 2.600(3), Bi(1)–O(3) 2.518(7), Bi(1)–S(1)
2.659(2), Bi(1)–S(2) 2.600(3), Bi(1)–S(3) 2.662(2), Bi(1)–O(4) 2.721(8); O(1)–Bi(1)–
S(2) 93.24(15), O(1)–Bi(1)–O(2) 69.00(18), O(1)–Bi(1)–O(3) 148.26(13), O(1)–
Bi(1)–S(3) 75.08(7), O(1)–Bi(1)–O(4) 69.7(2), O(1)–Bi(1)–S(1) 73.75(13), O(2)–
Bi(1)–O(3) 69.3(2), O(2)–Bi(1)–O(4) 162.89(15), O(2)–Bi(1)–S(1) 136.80(15),
O(2)–Bi(1)–S(2) 72.88(15), O(2)–Bi(1)–S(3) 135.58(15), O(3)–Bi(1)–O(1) 135.1(2),
O(3)–Bi(1)–O(3) 76.33(17), O(3)–Bi(1)O(4), 92.7(3), O(3)–Bi(1)–S(1) 151.19(18)
O(3)–Bi(1)–S(2) 90.1(2), Bi(1)–O(4)–S(4) 128.0(4).
Biological testing
Solubility and stability
Stability is an important feature of quality, safety and
efficiency of a drug product. To assess the synthesised
bismuth(III) thioketonates for stability to atmospheric con-
ditions, NMR data were recorded on samples stored under air
and at ambient temperature on a regular basis over a period of
six months. During this time, there was no change in observed
NMR shifts of the compounds and no evidence of the appear-
ance of any other species, strongly suggesting these com-
pounds are stable to hydrolysis by atmospheric moisture.
To assess the stability of the bismuth(III) complexes in
neutral and acidic solutions, the compounds were added to
distilled water and a 1.0 M aqueous solution of HCl. After stir-
ring in distilled water for 24 h, the insoluble material was fil-
tered and dried. For each of the complexes, the mass of the
recovered solid after filtration was the same as that initially
used. The compound displayed no change in solubility, and
NMR studies showed no change in observed chemical shifts.
This indicates these complexes are stable to hydrolysis. In
comparison, the bismuth(III) thioxoketonates were soluble in
1.0 M HCl solution and decomposed slowly to liberate the free
β-thioxoketones which could be extracted quantitatively into
diethyl ether while Bi3+ remained soluble in the form of BiOCl.
signals appeared in the range 179.9–180.5 ppm. The reso-
nances due to the vCH carbon was observed in the range of
110.2–110.8 ppm.
Deprotonation of the thioxoketone and subsequent binding
to the bismuth(III) centre is confirmed by the absence of
signals due to vC–O–H⋯SvC between 14–16 ppm and the
low frequency shifts of the vC–H, aromatic and the alkyl
protons in the 1H NMR spectra (CDCl3) of the bismuth(III)
thioxoketonates. This is further supported by the lower fre-
quency shifts observed for the carbonyl and thiocarbonyl
carbons in the 13C NMR spectra. Full details are provided in
the Experimental section.
X-ray crystallography. Crystallisation of [Bi{C5H4NC(vO)-
CHC(vS)C6H5}3·DMSO] B5 from DMSO solution provides
orange needle crystals suitable for X-ray diffraction studies.
The asymmetric unit of B5 is shown in Fig. 1, with selected
bond lengths and angles provided in the accompanying figure
caption.
Bismuth(III) compounds as potential antibiotics against
Helicobacter pylori
The β-thioxoketone ligand chelates to the Bi(III) centre pri-
marily through the thiol group with a Bi–S average distance of
2.640 Å, which lies in the same range of other bismuth thiolate
complexes.33–38 The overall coordination number around the
Bi(III) centre is then increased to seven via three short, strong
intramolecular Bi(vO) interactions [Bi(1)–O(1), 2.563(5);
The in vitro bactericidal activity of bismuth compounds B1–B6,
B8 and B9, was assessed against three laboratory strains of
H. pylori: B128, 251 and 26695. B128 is a gastric ulcer strain
which can readily colonize the stomach of mice and Mongo-
lian gerbils.39 Strain 251 is a human clinical isolate from non-
ulcer dyspepsia,40 while strain 26695, which colonizes piglets,
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Table 2 Activity against three strains of H. pylori, B128 (a), 26695 (b) and 251 (c), of bismuth(III) compounds B1–B9
MIC (µg mL−1
(µM)
)
Compound
c log P41
B1
B2
B3
B4
[Bi{C6H5C(vO)CHC(vS)C6H5}3]
3.125 (3.35)
6.25 (5.52)
6.25 (6.14)
3.125 (2.56) a,c
6.25 (5.11) b
6.25 (6.72)
6.25 (4.79)
6.25 (5.80)
3.125 (4.21) c
6.25 (8.43) a,b
13.0
15.6
13.6
13.0
[Bi{C6H5C(vO)CHC(vS)p-CF3–C6H4}3]
[Bi{p-MeOC6H4C(vO)CHC(vS)C6H5}3]
[Bi{p-MeOC6H4C(vO)CHC(vS)p-CF3–C6H4}3]
B5
B6
B8
B9
[Bi{C5H4NC(vO)CHC(vS)C6H5}3]
[Bi{p-IC6H4C(vO)CHC(vS)C6H5}3]
[Bi{C6H5C(vO)CHC(vS)C10H7}3]
[Bi{CH3C(vO)CHC(vS)C6H5}3]
10.8
16.5
16.4
8.5
was originally isolated from a patient with gastritis. For com- MIC BiPh2L 50 µg mL−1, BiPhL2 12.5 µg mL−1 and BiL3 6.25 µg
parison, the activity of the corresponding β-thioxoketones and mL−1 42
Therefore, while the results obtained for the thioxo-
.
BiPh3 were also assessed. DMSO was used as the control in ketonates are, in general, consistent with activities observed
each case since it has no activity against these strains of for related tris-substituted complexes, there is evidence of
H. pylori and was used to solubilise the compounds. The enhanced activity, down to MIC 3.125 µg mL−1 for some com-
minimum inhibitory concentration (MIC) of each compound pounds against some strains. While commercially available
was established using the agar dilution method (described in medicinal bismuth carboxylates have higher MIC values (BSS,
the Experimental section) and are presented in Table 2.
12.5 µg mL−1), (RBC, 8 µg mL−1) and (CBS, 12.5 µg mL−1),42
The β-thioxoketones were not toxic to any of the strains of many mono-nuclear tris-carboxylato bismuth(III) complexes
H. pylori up to the highest concentration of 100 µg mL−1 also have MIC values of 6.25 µg mL−1. While the carboxylates
tested. However, deprotonation and complexation to bismuth(III) are also chelating, they are less thermodynamically stable and
increased the bactericidal activity significantly. Com- more labile than the thiocarboxylates and thioxoketonates.
pounds [Bi{C6H5C(vO)CHC(vS)C6H5}3] B1 [Bi{p-MeOC6H4C- The real contrast though is with the bismuth(III) complexes of
(vO)CHC(vS)p-CF3–C6H4}3] B4 and [Bi{CH3C(vO)CHC(vS)- arenesulfonates and aminosulfonates which show activity
C6H5}3] B9 were most active showing the lowest MIC values of against H. pylori down to 0.049 µg mL−1. In these complexes
3.125 µg mL−1: B1 against all three strains, B4 against B128 the sulfonato ligands are both labile and non-chelating,
and 251, and B9 against 251. MICs against the remaining suggesting that these features impact strongly on the observed
strains was 6.25 µg mL−1. The remaining bismuth(III) com- activity.
plexes also showed an activity of 6.25 µg mL−1 against all three
Thioxoketones and their bismuth(III) derivatives as potential
anti-leishmanial drugs
strains.
BiPh3, as expected, was not toxic at a level <100 µg mL−1
.
Therefore, there is a clear synergic effect through the for-
mation of the bismuth thioxoketonate complexes. As shown in
Table 2, the free thioxoketones have lower calculated lipophili-
cities (c log P),41 and therefore lower permeability. This can
reduce the uptake of the compounds through the cell mem-
brane in to the bacteria cell. Coordination to the bismuth(III)
centre increases the c log P and can increase the uptake of the
compounds. This combined with the fact that the Bi–S bond
means the ligands are of low lability (though greater than
BiPh3) can allow more effective diffusion of the intact com-
pound into bacterial cells resulting in increased toxicity.
The in vitro activity of bismuth(III) β-thioxoketonate, the free
acids and BiPh3 was assessed against Leishmania major
(L. major) promastigotes. Their toxicity towards human fibro-
blast cells was also assessed. DMSO was used as the solvent to
make the required concentrations of the bismuth(III) com-
pounds and free acids, since it has no toxicity against either
the L. major promastigotes or the fibroblast cells at concen-
trations of 1–2%, as tested in this study. Amphotericin B (IC50
2.17 µM for L. major promastigotes), one of the well-known
anti-leishmanial drugs, was used as a reference drug. The
results of duplicate tests are presented as averages in Fig. 2–5.
Activity of the free β-thioxoketones against L. major promas-
tigotes is shown in Fig. 2. All showed some activity against pro-
mastigotes in a dose-dependent manner. [C6H5C(vO)CH2C-
(vS)C6H5] L1 was the most active in the series killing more
than 80% of parasites at a concentration of 25 μM (6.0 µg
mL−1). This level of activity is comparable with that of
Amphotericin B which kills about 80% of population at a
concentration of 4.33 μM (4.00 µg mL−1). β-Thioxoketone
[C5H4NC(vO)CH2C(vS)C6H5] L5 showed a similar activity to
L1 at a concentration of 25 μM (6.0 µg mL−1), however the
The impact of the Bi–S bond on the bactericidal activity of
the complexes is clear but far from straight-forward. We
recently demonstrated that replacement of one Ph group on
BiPh3 by a thiocarboxylate ligand increases the bactericidal
effects dramatically, from MIC >100 µg mL−1 to 6.25 µg
mL−1 11
However, the addition of further thiocarboxylate
.
ligands had no impact further impact on the activity beyond
this. This is in contrast to the results we observed for the thio-
saccharinate complexes in which the stepwise replacement of
all three Ph groups led to an exponential increase in toxicity;
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Fig. 5 Effect of tris-substituted bismuth(III) complexes on human primary fibro-
Fig. 2 Effect of β-thioxoketones on L. major promastigotes.
blasts cells.
[p-IC6H4C(vO)CH2C(vS)C6H5] L6 could only kill 45% of para-
sites at concentration of 100 μM (27.0 µg mL−1 for L3, 30.8 µg
mL−1 for L2, 33.8 µg mL−1 for L4, and 36.6 µg mL−1 for L6).
When considering the different toxicity levels of β-thioxo-
ketones, it is clear that the nature of the aryl groups and their
substituents are important. Those with unsubstituted phenyl
ligands, L1 and L5, display the greatest activity. The introduc-
tion of ring substituents; MeO, CF3 and I, reduce the toxicity,
while, L8 which contains an unsubstituted naphthyl group, is
the least toxic. While the mechanism of action of these mole-
cules against the parasite is not clear, it appears from these
patterns that the added steric bulk may be more important
than whether the substituent is activating or deactivating.
Interestingly, all the β-thioxoketones, except L5, proved to
be non-toxic to the fibroblasts, even at higher concentrations
of 100 μM (Fig. 3), demonstrating some potential for these
compounds as anti-leishmanial agents. The exception L5
proved to be non-toxic to the human fibroblast cells only up to
25 μM (6.03 μg mL−1). At 100 μM (24.1 μg mL−1) it is highly
toxic, killing more than 80% of the cells. Nevertheless, these
compounds, with the possible exception of L1, are unlikely to
compete with the anti-leishmanial drug, Amphotericin B, as
they need concentrations of more than 100 μM to show similar
effectiveness against L. major. The highly active compound, L1
needs to be further tested against amastigotes and its in vivo
activity assessed.
Fig. 3 Effect of β-thioxoketones on human primary fibroblast cells.
Surprisingly all of the tris-substituted bismuth(III) β-thioxo-
ketonates, except [Bi{C6H5C(vO)CHC(vS)C10H7}3] B8, were
less toxic to the L. major parasites than their corresponding
free acids (Fig. 4). Activity of [Bi{C6H5C(vO)CHC(vS)p-CF3–
C6H4}3] B2 is not included as it precipitated in the culture
medium. The least active thioxoketone L8 when complexed
with bismuth to give B8 showed an improvement in activity
but only of around 10%. The bismuth complex [Bi{C5H4NC-
(vO)CHC(vS)C6H5}3] B5 is the most active of the series
killing about 80% of the population at a concentration of
50 μM (46 μg mL−1), while [Bi{p-IC6H4C(vO)CHC(vS)C6H5}3]
B6 and [Bi{p-MeOC6H4C(vO)CHC(vS)p-CF3-C6H4}3] B4 were
essentially non toxic to the parasite. Similarly B6 and B4 were
also non-toxic against the human fibroblasts cells (Fig. 5).
Fig. 4 Effect of tris-substituted bismuth(III) complexes on L. major
promastigotes.
activity then decreases killing only 55% of parasites at the
highest concentration of 100 μM (24.0 µg mL−1). L8, [C6H5C-
(vO)CH2C(vS)C10H7], proved to be the least active member of
the series requiring a concentration of 100 μM (29.0 µg mL−1
)
to kill less than 20% of the population. β-Thioxoketones
[p-MeOC6H4C(vO)CH2C(vS)C6H5] L3 and [C6H5C(vO)CH2C-
(vS)p-CF3–C6H4] L2 were able to kill about 60% of the popu-
lation while [p-MeOC6H4C(vO)CH2C(vS)p-CF3–C6H4] L4 and
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Bismuth(III) complex B5 was less toxic to the fibroblasts than reductase, thereby inhibiting the normal toxic pathways recog-
against the L. major promastigotes, while [Bi{C6H5C(vO)CHC- nised for Sb(III).44 This would also point to a clear difference
(vS)C6H5}3] B1 and [Bi{p-MeOC6H5C(vO)CHC(vS)C6H5}3] B3 with H. pylori.
are more toxic to fibroblasts cells than the promastigotes.
When considering the higher toxicity of [C5H4NC(vO)CH2C-
(vS)C6H5] L5 and its bismuth(III) derivative B5, it is clear that
the presence of pyridyl groups has an effect on the displayed
Conclusions
toxicity.
A comparison of activity of thioxoketones with that of pre- R1C(vO)CH2C(vS)R2 (R1 = C6H5, R2 = C6H5 L1; R1 = C6H5,
viously reported thiocarboxylic acids and carboxylic acids gives R2 = p-CF3C6H4 L2; R1 = p-MeOC6H4, R2 = C6H5 L3; R1
Nine different β-thioxoketones L1–L9 of the general formula
=
some interesting information about the structure activity p-MeOC6H4, R2 = p-CF3C6H4 L4; R1 = C5H4N, R2 = C6H5 L5; R1 =
relationship. The activity shown by the thioxoketones is p-IC6H4, R2 = C6H5 L6; R1 = C6H5, R2 = p-IC6H4 L7; R1 = C6H5,
comparable with that of thiocarboxylic acids which can inhibit R2 = C10H7 L8 and R1 = CH3, R2 = C6H5 L9) and their tris-sub-
the growth of L. major promastigotes at concentrations of stituted bismuth(III) complexes Bi{R1C(vO)CHC(vS)R2}3 B1–
50–100 µM (9–18 µg mL−1).17 In contrast, the activity shown B9 have been synthesised and fully characterised. The solid
by carboxylic acids is negligible, even at concentrations of state structure of one of the complexes, [Bi{C5H4NC(vO)CHC-
500 µg mL−1. This suggests an important role for the thiol (vS)C6H5}3] B5, was determined using single crystal X-ray
group on observed toxicity, given further weight by the relative diffraction revealing that the three β-thioxoketonato ligands
non-toxic nature of thiobenzoic acid which exists as the chelate to the Bi(III) in a bidentate fashion through O and S
disulfide.
atoms, with an additional O-bound molecule of DMSO raising
In comparison to carboxylic acids, bismuth(III) carboxylates the coordination environment to seven.
are toxic to L. major promastigotes with relatively low IC50
values ranging from 2.8–30.8 µg mL−1 16
The β-thioxoketones and their bismuth(III) derivatives were
A similar behaviour is assessed for their activity against H. pylori. All the bismuth(III)
.
also observed with thiocarboxylic acids and their corres- complexes were highly active against H. pylori with MIC values
ponding bismuth(III) complexes. For example the IC50 of ≥3.125 μg mL−1, while the free acids and BiPh3 (reference com-
C6H5C(vO)SH is >100 µM (1.38 µg mL−1) while that of PhBi- pound) proved to be essentially not toxic to the bacteria at
{SC(vO)C6H5}2 is 0.39 µM (0.22 µg mL−1).17
the highest concentration of 100 μg mL−1. This highlights the
The observation, therefore, that bismuth(III) thioxoketo- importance of bismuth and the β-thioxoketonato ligand on the
nates are less toxic to L. major promastigotes than the corres- displayed activity.
ponding free thioxoketones is unexpected. Too little is
The anti-leishmanial activity of all the bismuth(III) β-thioxo-
currently known about the uptake of metal complexes by the ketonates and the corresponding thioxoketones were also
parasite to draw definitive conclusions from this, however assessed against L. major promastigotes. For comparison, the
there are some structural features which may help to toxicity of all compounds were assessed also against human
provide some clues. The bismuth thioxoketonates generally are fibroblast cells. All of the free β-thioxoketones were selectively
constructed around stable six-membered chelate rings with toxic only to the L. major promastigotes displaying some
a
relatively stable Bi–S bond, which likely reduces the potential as anti-leishmanial agents. Among these, the ‘sym-
bioavailability of both ligand and Bi(III). In contrast, carb- metrical’ compounds [C6H5C(vO)CH2C(vS)C6H5] L1 and
oxylates and thiocarboxylates form less stable four-membered [C5H4NC(vO)CH2C(vS)C6H5] L5, showed comparable activity
rings, with the carboxylates having solely more labile Bi–O to that of Amphotericin B, killing ca 80% of the L. major
bonds.
promastigotes at a concentration of 25 μM (6 μg mL−1).
Lipophilicity is also an important drug characteristic which Surprisingly, the bismuth thioxoketonates were, in general,
affects bioavailability. In their study of the Sb(III) and Bi(III) less toxic to the parasites than the parent thioxoketones. While
complexes of dipyridophenazine (dppz) and the free ligand, it is not clear why this should be the case, aspects of the
Demiceli and coworkers43 commented that the less lipophilic uptake chemistry and intracellular interaction with trypano-
metal complexes were more toxic than free dppz. In accepting thione linked to lipophilicity, stability and low lability, con-
this argument, the reverse appears to be the case for the ferred on the complexes by the six-membered chelate rings
present study in which the more active thioxoketones have and Bi–S bonds, may be factors. This warrants further
lower calculated lipophilicity values (c log P) ranging from investigation.
1.99–4.66 compared with their less active bismuth(III)
complexes which have much higher values in the range of toxic to both the L. major promastigotes and fibroblast cells in
8.5–16.5. a dose dependent manner and can not be considered as poten-
The bismuth(III) β-thioxoketonates proved to be generally
If the compounds are transported into the parasite cells tial anti-leishmanial drugs. Among the bismuth(III) complexes
intact, it is possible that the stability conferred on the com- of β-thioxoketones [Bi{C5H4NC(vO)CHC(vS)C6H5}3] B5
plexes through the six membered chelate ring combined with showed the highest activity killing 80% of the L. major para-
the low lability of the Bi–S bond could minimise the intracellu- sites and a 60% of the fibroblast cells at a concentration of
lar impact of the metal on trypanothione and trypanothione 50 μM (46 μg mL−1).
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instructions.48 The Celltiter Blue dye was added to samples at
the time of setting up the assay and the negative control (no
Experimental
Bi(OtBu)3 was synthesised through a standard metathesis reac- cells) value was subtracted from all subsequent readings as a
tion from the treatment of BiCl3 with KOtBu in dried THF at background value. All readings were compared to the no-drug
0 °C, and subsequently extracting the product with dried control and the percent growth inhibition was calculated.
n-pentane using a Soxhlet extractor.45 NMR spectra were DMSO controls were included. All plates were assessed micro-
recorded on a Bruker DRX 400 spectrometer. All spectra were scopically.49 The graphs shown in this paper give the percen-
internally referenced using the deuterated solvent signal. tage of positive control versus concentration.
Electrospray ionization spectra (ESI) were generated on a
Cell culture
Micromass Platform II QMS spectrometer. Infrared spectra, as
KBr disks or Nujol mulls, were recorded on a Perkin-Elmer
1600 FT-IR spectrometer. Elemental microanalyses were
performed by the Campbell Microanalytical Laboratory,
Department of Chemistry, University of Otago, Dunedin, New
Zealand. Melting points were measured on a Stuart Scientific
melting point apparatus SMP3.
L. major was maintained at 26 °C in M199 medium (Invitro-
gen) supplemented with 10% heat inactivated foetal bovine
serum (HI-FBS) (TraceBiosciences). The human primary fibro-
blast were cultured in Dulbecco’s Modified Eagle’s Medium
(DMEM) (Life Technologies) supplemented with 10% HI-FBS
at 37 °C in 5% CO2.
Bacterial strains and culture conditions
Synthesis of thioesters
31
H. pylori strains 251, B128 and 26695 were routinely cultured
on horse blood agar (HBA) or in brain heart infusion broth
(BHI), supplemented with either 7.5% (v/v) fresh horse blood
or 10% (v/v) FCS, respectively. Culture media were further sup-
plemented with 155 mg L−1 polymyxin B, 6.25 mg L−1 vanco-
mycin, 3.125 mg L−1 trimethoprim and 1.25 mg L−1
Amphotericin B.46
GP 1 – thionation of esters with P4S10
.
All the manipula-
tions were carried out under N2 atmosphere until the reaction
quenched. A mixture of ester (1.0 equivalent), P4S10 (0.3
equivalents), HMDO (1.7 equivalents) were refluxed in dry
xylene for 8–18 h. The reaction mixture was allowed to cool to
0 °C in an ice bath and treated with aqueous K2CO3 solution
(2.2 equivalents, 5.3 M) and acetone and this was stirred for
30 min at the same temperature. Water and benzene was
added and the product was extracted in to the organic phase.
Organic phase was washed with dilute K2CO3, water and brine.
Evaporation of the solvent under vacuum gave crude thioester
which was purified by either distillation or column chromato-
graphy (Scheme 3).
Methyl 4-trifluoromethylthiobenzoate, MFTB. A mixture of
methyl 4-trifluoromethylbenzoate (4.50 g, 22.00 mmol), P4S10
(3.50 g, 7.90 mmol) and HMDO (8.00 mL, 37.60 mmol) were
refluxed in xylene (25 mL) for a period of 12 h and then
worked up according to GP 1. Crude product was distilled
under vacuum to obtain orange liquid of MFTB.
Determination of the minimum inhibitory concentration
(MIC)
The MICs of all the bismuth(III) complexes reported here were
determined by the agar dilution technique. All bismuth
complexes were dissolved in DMSO to give clear, colourless
solutions of known concentration. H. pylori cultures were
incubated in BHI for 18 h shaking at 140 rpm at 37 °C under
micro-aerobic conditions. Bacteria were pelleted, washed in
plain BHI and then resuspended in plain BHI.47 Each suspen-
sion was adjusted to give an approximate density of 106 bac-
teria per mL. Aliquots (10 μL) of these suspensions were then
streaked onto HBA plates containing doubling dilutions of the
different concentrations of bismuth compounds, ranging in
concentration from 1.563–100 μg mL−1 (dilution series
showing concentration on HBA plate in μg mL−1: 100, 50, 25,
12.5, 6.25, 3.125, 1.563). Each compound was tested alongside
BiPh3 (reference compound) and the corresponding free acids.
The MICs of the different compounds were determined by
examination of the plates after incubation for 72 h at 37 °C.
Yield: 3.10 g, 64.0%; Bp: 60 °C (0.5 torr); FT-IR (cm−1):
1729 m, 1688 w, 1616 m, 1508 m, 1360 s, 1409 s, 1324 s, 1237
s, 1128 s, 1069 s, 1016 s, 935 m, 850 m, 777 m, 641 s; Elemen-
tal analysis; (C9H7F3OS) Calc. (Found): C 49.09(48.80), H
3.20(3.22)%; 1H NMR (400 MHz, D6-DMSO, 30 °C): δ 8.28 (d, J3
8.0, 2H, Hc), 7.65 (d, J3 8.0, 2H, Hb), 4.32 (s, 3H, Hf); 13C NMR
(100.1 MHz, D6-DMSO, 30 °C): δ 210.4 (Ce), 166.0 (Cg), 140.8
Cell viability assay
The Celltiter Blue Cell Viability Assay (Promega, Madison, WI,
USA) was used for screening for anti-leishmanial activity and
toxicity. Compounds were dissolved in DMSO at 10 mmol L−1
working stock and diluted out in appropriate culture media.
The assay was set up in duplicates in 96-well plates according
to the manufacturer’s instructions. 106 promastigotes per mL
and 105 mL−1 primary human fibroblasts were used. Cell
viability was assessed by measuring fluorescence at 550 nm
Scheme 3 Labelling system used to assign protons and carbons in NMR
excitation and 590 nm emission as per manufacturers’ spectra of thioesters.
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(Ca), 130.1 (Cd), 130.1 (Cb), 127.9 (Cc), 59.7 (Cf); Mass spec- (400 MHz, D6-DMSO, 30 °C): δ 7.90 (d, J3 5.6, 2H, Hb), 7.76 (d,
trum, ESI−: 245.1 (100%, [CF3C6H4]−), 189.1 (40%, [CF3C6H4C- J3 5.6, 2H, Hc), 4.28 (s, 3H, Hf); 13C NMR (100.1 MHz, D6-
(vS)]−), 205.1 (10%, [CF3C6H4C(vS)O]−), 221.1 (10%, DMSO, 30 °C): δ 211.1 (Ce), 166.0 (Ca), 137.5 (Cb), 130.2 (Cc),
[MFTB + H]−).
101.0 (Cd), 59.5 (Cf); Mass spectrum, ESI−: 126.9 (100%, [I]−),
Methylthio-2-naphthoate, MTN. A mixture of methyl 262.9 (10%, [IC6H4C(vS)O]−), 278.8 (12%, MITB + H]−).
2-naphthoate (2.30 g, 12.50 mmol), P4S10 (1.90 g, 4.270 mmol)
and HMDO (4.50 mL, 21.20 mmol) were refluxed in xylene
Synthesis of β-thioxoketones
(15 mL) for a period of 16 h and then worked up according to
GP 1. A column was carried out in ethyl acetate (50%)–hexane
(50%) (Rf: 0.35) to obtain MTN as a yellow solid.
GP 2 – Claisen condensation of ketones with thioesters. All
the manipulations were carried out under N2 atmosphere
using standard Schlenk conditions until the reaction is
quenched. Ketone (1.0 equivalent) was added to a suspension
of NaH (1.1–1.5 equivalents) in dry THF and stirred at 60 °C
for about 10 min until a colour change was observed. The ester
(1 equivalent) was then added and the reaction mixture was
stirred at the same temperature for a period of 18 h (a colour
change can be observed after about an hour of heating).
Solvent was evaporated under the vacuum; water was added to
redissolve it and then acidified with 1 M HCl (acidity was
checked using a pH paper). The precipitated crude product
was separated by filtration, washed with plenty of water and
then dried (Scheme 4).
Yield 2.20 g, 87.1%; Mp: 51 °C; FT-IR (cm−1): 1627 m,
1596 m, 1597 m, 1353 m, 1279 s, 1231 s, 1219 s, 1194 s, 1188
s, 1150 m, 1129 s, 1977 m, 1053 m, 697 m, 950 m, 904 m,
860 m, 818 m, 748 s; Elemental analysis; (C12H10OS) Calc.
(Found): C 71.25(71.45), H 4.98(4.98)%; 1H NMR (400 MHz,
D6-DMSO, 30 °C): δ 8.74 (s, 1H, Hb), 8.21 (d, J3 8.8, 1H, Hc),
8.14 (d, J3 8.4, 1H, Hj), 7.99 (d, J3 8.8, 2H, He,h), 8.14 (d, J3 8.4,
1H, Hj), 7.67 (t, J3 8.4, 1H, Hf), 7.60 (t, J3 8.4, 1H, Hg), 4.34 (s,
3H, Hl); 13C NMR (100.1 MHz, DMSO, 30 °C): δ 211.5 (Ck),
134.9 (Ca), 134.8 (Ci), 131.9 (Cd), 129.9 (Ch), 128.8 (Ce), 128.7
(Cj), 127.9 (Cb), 127.5 (Cg), 127.1 (Cf), 59.8 (Cl); Mass spectrum,
ESI+: 203.2 (100%, [MTN + H]+).
[C6H5C(vO)CH2C(vS)C6H5], L1. Acetophenone (1.20 g,
Methyl 4-iodothiobenzoate, MITB. A mixture of methyl 10.0 mmol), ethyl thiobenzoate (1.66 g, 10.0 mmol) and NaH
4-iodobenzoate (2.50 g, 9.50 mmol), P4S10 (1.60 g, 3.60 mmol) (0.29 g, 12.0 mmol) were reacted in THF according to GP 2 to
and HMDO (4.00 mL, 15.80 mmol) were refluxed in xylene obtain L1 as a red crystalline solid.
(50 mL) for a period of 16 h and then worked up according to
GP 1. A column was carried out in hexane (Rf: 0.33) to obtain s, 1272 s, 1135 m, 820 m, 761 s, 732 m, 689 m. 1H NMR
Yield: 1.68 g, 70.0%; Mp: 82 °C; FT-IR (cm−1): 1588 s, 1557
MITB as a yellow solid.
(400 MHz, CDCl3, 30 °C): δ 15.19 (s, 1H, OH), 8.02 (d, J3 8.8,
Yield: 1.50 g, 56.8%; Mp: 68 °C; FT-IR (cm−1): 1734 m, 2H, Hb), 7.83 (d, J3 8.8, 2H, Hi), 7.59 (t, J3 8.8, 1H, Hd),
1580 m, 1307 m, 1279 m, 1227 m, 1178 w, 1112 w, 1103 m, 7.55–7.38 (m, 5H, Hc,j,k), 7.47 (s, 1H, Hf); 13C NMR
1065 m, 1006 m, 830 m, 753 m; Elemental analysis; (C8H7OSI) (100.1 MHz, CDCl3, 30 °C): δ 203.3 (Cg), 180.0 (Ce), 145.6 (Ca),
Calc. (Found):
C 34.55(35.19), H
2.54(2.56)%; 1H NMR 135.9 (Ch), 132.7 (Ck), 131.2 (Cd), 129.0 (Ci), 128.6 (Cj), 127.4
Scheme 4 Labelling system used to assign protons and carbons in NMR spectra of thioxoketones and bismuth(III) thioxoketonates.
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(Cb), 126.9 (Cc), 110.8 (Cf); Mass spectrum, ESI+: 285.1 {100%, 231.1 (40%, [(Ov)CCH2C(vS)C6H4CF3]+), 337.2 (50%, [LH −
[L− + (Na)2]+}, 363.1 {15%, [L + (Na)2 + DMSO]+}, 501.1 (45%, H]+), 339.2 (100%, [LH + H]+), 361.1 (10%, [LH + Na]+), 697.3
[(L)2 + Na]+), 547.1 (10%, [(L)2 + Na+ + EtOH]+), 799.3 {10%, (10%, [(L)2
+ =
Na]+); ESI−: 337.1 (100%, [L]−). (LH
[(L)2 + Na+ + EtOH + H2O + (DMSO)3]+}; ESI−: 239.1 (100%, C17H13O2SF3).
[L]−); (LH = C15H12OS).
[C5H4NC(vO)CH2C(vS)C6H5], L5. 2-Acetylpyridine (0.93 g,
[C6H5C(vO)CH2C(vS)p-CF3-C6H4], L2. Acetophenone (0.6 g, 7.70 mmol), ethyl thiobenzoate (1.28 g, 7.70 mmol) and NaH
5.0 mmol), methyl 4-trifluoromethylthiobenzoate (1.1 g, (0.34 g, 8.50 mmol) were reacted in THF according to GP 2 to
5.0 mmol) and NaH (0.168 g, 7.0 mmol) were reacted in THF obtain L5 as a dark purple solid.
according to GP 2 to obtain L2 as a red crystalline solid.
Yield: 1.30 g, 70.3%; Mp: 87–88 °C; FT-IR (cm−1
)
Yield: 0.49 g, 31.8%; Mp: 105 °C; FT-IR (cm−1): 1587 m, 1592 m, 1574 m, 1552 s, 1310 w, 1293 m,
1550 m, 1323 m, 1246 m, 1170 m, 1108 m, 1067 m, 1014 w, 1279 m, 1247 m, 1223 m, 1153 m, 1067 m, 1029 m, 992 m,
945 w, 852 w, 814 m, 773 m, 685 m; Elemental analysis; 951 m, 860 m, 837 m, 792 m, 764 m, 693 m; Elemental
1
(C16H11OSF3) Calc. (Found): C 62.33(62.08), H 3.60(3.52)%; H analysis; (C14H11OSN) Calc. (Found): C 69.68(68.94), H 4.59
NMR (400 MHz, CDCl3, 30 °C): δ 15.25 (s, 1H, OH), 8.02 (d, J3 (4.52), N 5.80(5.62)%; 1H NMR (400 MHz, CDCl3, 30 °C): δ
8.4, 2H, Hb), 7.88 (d, J3 8.8, 2H, Hj), 7.70 (d, J3 8.8, 2H, Hi), 14.40 (s, 1H, OH), 8.72 (d, J3 4.8, 1H, He), 8.25 (s, 1H, Hg), 8.20
7.60 (t, J3 8.4, 1H, Hd), 7.51 (t, J3 8.4, 2H, Hc), 7.46 (s, 1H, Hf); (d, J3 8.0, 1H, Hb), 7.91–7.84 (m, 3H, Hk,l), 7.51–7.42 (m, 4H,
13C NMR (100.1 MHz, CDCl3, 30 °C): δ 202.0 (Cg), 180.5 (Ce), Hj,c,d); 13C NMR (100.1 MHz, CDCl3, 30 °C) δ 201.5 (Ch), 178.0
148.6 (Ch), 135.4 (Ca), 133.2 (Ci), 132.4 (Ck), 129.1 (Cc), 127.5 (Cf), 152.5 (Ca), 149.4 (Ce), 145.0 (Ci), 137.2 (Cc), 131.3 (Cl),
(Cb), 127.2 (Cj), 125.7 (Cd), 125.6 (Cl), 111.4 (Cf); Mass spec- 128.6 (Cj), 127.1 (Ck), 126.3 (Cd), 122.8 (Cb), 110.6 (Cg); Mass
trum, ESI+: 231.1 (15%, [(Ov)CCH2C(vS)C6H4CF3]+), 281.2 spectrum, ESI+: 106.0 (42%, [C(vO)C5H4N]+), 121.0 (20%,
(10%, [(Ov)CCH2C(vS)C6H4CF3 + H2O + MeOH]+), 307.2 [C(vS)C6H5]+), 240.2 (25%, [LH − H]+), 242.2 (20%, [LH + H]+),
(90%, [LH − H]+), 309.2 (100%, [LH + H]+); ESI−: 307.1 (100%, 264.2 (5%, [LH + Na]+); ESI−: 240.2 (100%, [L]−); (LH =
[L]−). (LH = C16H11OSF3).
C14H11OSN).
[p-MeOC6H4C(vO)CH2C(vS)C6H5],
L3. 4-Methoxyaceto-
[p-IC6H4C(vO)CH2C(vS)C6H5],
L6. 4-Iodoacetophenone
phenone (1.20 g, 8.0 mmol), ethyl thiobenzoate (1.33 g, (2.46 g, 10.0 mmol), ethyl thiobenzoate (1.66 g, 10.0 mmol)
8.0 mmol) and NaH (0.24 g, 10.0 mmol) were reacted in THF and NaH (0.29 g, 12.0 mmol) were reacted in THF according to
according to GP 2 to obtain L3 as a red solid.
GP 2 to obtain L6 as an orange solid.
Yield: 1.51 g, 72.1%; Mp: 133 °C; FT-IR (cm−1): 1603 m,
Yield: 2.34 g, 64.1%; Mp: Dec >120 °C; FT-IR (cm−1
)
1579 m, 1550 m, 1502 m, 1309 w, 1232 m, 1174 m, 1122 m, 1580 m, 1540 m, 1300 w, 1286 w, 1244 m, 1175 w, 1112 w,
1064 w, 1028 m, 843 w, 816 m, 764 m, 689 m; 1H NMR 1074 w, 1053 m, 1002 m, 953 w, 815 m, 763 m, 691 m; Elemen-
(400 MHz, CDCl3, 30 °C): δ 15.33 (s, 1H, OH), 7.99 (d, J3 8.0, tal analysis; (C15H11OSI) Calc. (Found): C 49.20(49.26), H 3.03
2H, Hb), 7.80 (d, J3 7.2, 2H, Hi), 7.49–7.40 (m, 3H, Hj,k), 7.44 (s, (3.03)%; 1H NMR (400 MHz, CDCl3, 30 °C): δ 14.82 (s, 1H,
J3 1H, Hf), 6.99 (d, J3 8.0, 2H, Hc); 13C NMR (100.1 MHz, OH), 7.85 (d, J3 8.0, 2H, Hc), 7.78 (d, J3 8.0, 2H, Hb), 7.71 (d, J3
CDCl3, 30 °C): δ 201.8 (Cg), 179.5 (Ce), 163.5 (Cd), 145.7 (Ch), 8.0, 2H, Hi), 7.47 (t, J3 8.0, 1H, Hk), 7.43 (t, J3 8.0, 2H, Hj), 7.39
130.8 (Ca), 129.4 (Ci), 128.4 (Cj), 127.8 (Ck), 126.8 (Cb), 114.3 (s, 1H, Hf); 13C NMR (100.1 MHz, CDCl3, 30 °C): δ 203.0 (Cg),
(Cc), 110.2 (Cf), 55.5 (Cl); Mass spectrum, ESI+: 135.1 (100%, 178.8 (Ce), 145.3 (Ca), 138.2 (Cc), 135.2 (Ch), 128.5 (Ci, j), 128.4
[CH2C(vS)C6H5]+), 163.1 (45%, [(Ov)CCH2C(vS)C6H5]+), (Ck), 126.8 (Cb), 110.3 (Cf), 99.9 (Cd); Mass spectrum, ESI+:
269.2 (40%, [LH − H]+), 271.2 (50%, [LH + H]+), 293.2 (10%, 231.0 (100%, [C(vO)C6H4I]+), 367.0 (90%, [LH + H]+), 389.0
[LH + Na]+), 561.2 (5%, [(L)2 + Na]+); ESI−: 269.2 (100%, [L]−). (20%, [LH + Na]+), 411.0 (5%, [L + 2Na]+); ESI−: 364.9 (100%,
(LH = C16H14O2S).
[L]−). (LH = C15H11OSI).
[p-MeOC6H4C(vO)CH2C(vS)p-CF3–C6H4],
L4. 4-Methoxy-
[C6H5C(vO)CH2C(vS)p-IC6H4], L7. Acetophenone (0.48 g,
acetophenone (0.75 g, 5.0 mmol), methyl 4-trifluoro- 4.0 mmol), methyl 4-iodothiobenzoate (1.05 g, 4.0 mmol) and
methylthiobenzoate (1.10 g, 5.0 mmol) and NaH (0.14 g, NaH (0.11 g, 4.50 mmol) were reacted in THF according to GP
6.0 mmol) were reacted in THF according to GP 2 to obtain L4 2 to obtain L7 as a yellow solid.
as an orange crystalline solid.
Yield: 0.46 g, 32.1%; Mp: Dec >120 °C; FT-IR (cm−1
)
Yield: 0.45 g, 23.0%; Mp: 133 °C; FT-IR (cm−1): 1606 m, 1588 m, 1551 m, 1294 m, 1274 m, 1172 w, 1109 w, 1072 w,
1582 m, 1552 m, 1503 m, 1327 m, 1310 w, 1241 m, 1180 m, 1005 m, 940 w, 886 w, 810 m, 771 m, 684 w. 1H NMR
1168 m, 1105 m, 1068 m, 1026 m, 1015 m, 850 m, 841 m, 776 (400 MHz, CDCl3, 30 °C): δ 15.46 (s, 1H, OH), 7.98 (d, J3 7.2,
w; Elemental analysis; (C17H13O2SF3) Calc. (Found): C 60.35 2H, Hj), 7.78 (d, J3 8.8, 2H, Hb), 7.60–7.48 (m, 5H, Hi,c,d), 7.42
(60.22), H 3.87(3.81)%; 1H NMR (400 MHz, CDCl3, 30 °C): δ (s, 1H, Hf); 13C NMR (100.1 MHz, CDCl3, 30 °C): δ 203.5 (Cg),
15.49 (s, 1H, OH), 8.05 (d, J3 8.8, 2H, Hb), 7.87 (d, J3 8.4, 2H, 179.7 (Ce), 144.8 (Ca), 138.4 (Cj), 137.7 (Ci), 128.5 (Ch), 135.3
Hj), 7.69 (d, J3 8.4, 2H, Hi), 7.40 (s, J3 1H, Hf), 6.90 (d, J3 8.8, (Cd), 129.6 (Cb), 128.4 (Cc), 110.2 (Cf), 98.1 (Ck); Mass spec-
2H, Hc), 3.90 (s, 3H, Hl); 13C NMR (100.1 MHz, CDCl3, 30 °C): trum, ESI+: 293.0 (5%, [C(vS)C6H4I + EtOH]+), 365.0 (100%,
δ 200.8 (Cg), 179.9 (Ce), 163.8 (Cd), 148.7 (Ch), 132.3 (Ca), 129.6 [LH − H]+), 429.0 {5%, [L + 2Na + H2O]+}, 753.0 {10%, [(L)2 +
(Ci), 127.0 (Cb,j), 125.5 (Ck), 122.5 (Cm), 114.3 (Cc), 110.7 (Cf), Na+]+}, 785.0 {8%, [(L)2 + Na + MeOH]+); ESI−: 247.0 (100%,
55.5 (Cl); Mass spectrum, ESI+: 135.1 (50%, [CH2C(vS)C6H5]+), [SvCC6H4I]−), 365.0 (100%, [L]−); (LH = C15H11OSI).
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[C6H5C(vO)CH2C(vS)C10H7], L8. Acetophenone (0.54 g, (Cb), 122.5 (Cc), 121.6 (Cf); Mass spectrum, ESI+: 285. 1 (100%,
4.50 mmol), methyl 2-thionaphthoate (0.91 g, 4.50 mmol) and [L + 2Na]+), 687.1 (5%, [BiL2]+), 949.2 (20% [BiL3 + Na]+); (LH =
NaH (0.13 g, 5.50 mmol) were reacted in THF according to GP C15H12OS).
[Bi{C6H5C(vO)CHC(vS)p-CF3–C6H4}3], B2. L2 (0.23 g,
0.75 mmol) and Bi(OtBu)3 (0.11 g, 0.25 mmol) were
reacted in THF according to GP 3 to obtain B2 as an orange
solid.
2 to obtain L8 as a red crystalline solid.
Yield: 0.75 g, 57.5%; Mp: 123 °C; FT-IR (cm−1): 1586 m,
1557 m, 1258 m, 1155 w, 901 w, 819 w, 774 m; 1H NMR
(400 MHz, CDCl3, 30 °C): δ 15.42 (s, 1H, OH), 8.33 (s, 1H, Hi),
8.05 (d, J3 7.6, 2H, Hj,q), 7.95 (m, 2H, Hl,o), 7.87 (t, J3 8.8, 2H,
Hm,n), 7.62 (s, 1H, Hf), 7.54–7.48 (m, 5H, Hb,c,d); 13C NMR
(100.1 MHz, CDCl3, 30 °C): δ 204.3 (Cg), 179.6 (Ce), 142.9 (Ch),
135.9 (Ca), 134.8 (Ck), 132.9 (Cp), 129.5 (Cj), 129.0 (Ci,q),
128.4 (Cb), 127.9 (Cl), 127.4 (Cc), 126.9 (Co), 126.8 (Cm,n),
124.5 (Cd), 110.2 (Cf); Mass spectrum, ESI+: 105.0 (100%,
[C(vO)C6H5]+), 163.1 (30% [C6H5C(vO)CH2C(vS)]+), 289.1
(20%, [LH − H]+), 291.3 (80%, [LH + H]+), 313.2 (20%, [LH +
Na]+), 335.2 (5%, [L + 2Na]+); ESI−: 289.2 (100%, [L]−). (LH =
C19H14OS).
Yield: 0.26 g, 92.0%; Mp: Dec >110 °C; FT-IR (cm−1):
1570 m, 1551 m, 1502 m, 1320 m, 1244 m, 1167 m, 1110 m,
1067 m, 1015 m, 944 m, 852 w, 824 m, 782 m, 703 m; Elemen-
tal analysis; (BiC48H30O3S3F9) Calc. (Found): C 49.28(48.66), H
3.19(2.53)%; 1H NMR (400 MHz, CDCl3, 30 °C) δ 7.93 (d, J3 8.0,
2H, Hb), 7.71 (d, J3 8.4, 2H, Hi), 7.57–7.52 (m, 3H, Hj,d), 7.41 (t,
J3 8.0, 2H, Hc), 7.37 (s, 1H, Hf); 13C NMR (100.1 MHz, CDCl3,
30 °C) δ 190.0 (Cg), 167.8 (Ce), 150.5 (Ch), 137.1 (Ca), 133.5 (Ci),
128.8 (Ck), 128.6 (Cc), 127.2 (Cd), 125.3 (Cj), 124.2 (Ci), 123.6
(Cl), 122.5 (Cb), 122.4 (Cf); Mass spectrum, ESI+: 636.9 {35%,
[CH3C(vO)CH2C(vS)C6H5], L9. Acetone (0.29 g, 5.0 mmol), [(L)2 + Na]+}, 823.0 (95%, [BiL2]+), 1153.2 (15%, [BiL3 + Na]+);
ethyl thiobenzoate (0.83 g, 5.0 mmol) and NaH (0.13 g, ESI−; 306.9 (100%, [L]−), 1165.1 (15%, [BiL3 + Cl]−), 1437.3
5.50 mmol) were reacted in THF according to GP 2 to obtain (20%, [BiL4]−); (LH = C16H11OSF3).
[Bi{p-MeOC6H4C(vO)CHC(vS)C6H5}3], B3. L3 (0.41 g,
1.50 mmol) and Bi(OtBu)3 (0.22 g, 0.50 mmol) were reacted in
THF according to GP 3 to obtain B3 as a yellow solid.
L9 as a dark purple semi liquid.
Yield: 0.46 g, 51.7%; FT-IR (cm−1): 1670 m, 1604 m,
1308 m, 1208 m, 1149 w, 1073 w, 1021 w, 767 w; 1H NMR
(400 MHz, CDCl3, 30 °C): δ 14.35 (s, 1H, OH), 8.12 (d, J3 8.8,
2H, Hf), 7.62 (t, J3 8.8, 2H, Hg), 7.50 (t, 1H, Hh), 7.07 (s, 1H,
Hc), 2.29 (s, 3H, Ha); 13C NMR (100.1 MHz, CDCl3, 30 °C): δ
204.5 (Cd), 184.8 (Cb), 133.2 (Ce), 130.9 (Cf), 129.2 (Cg), 128.4
(Ch), 110.3 (Cc), 68.8 (Ca); Mass spectrum, ESI+: 177.1 (100%,
[LH − H]+), 265.2 (65%, [LH + EtOH + H2O + Na]+), 377.2 {5%,
[(L)2 + Na]+}. (LH = C10H10OS).
Yield: 0.44 g, 86.0%; Mp: Dec >120 °C; FT-IR (cm−1):
1584 m, 1550 m, 1306 w, 1240 m, 1166 m, 1116 m, 1024 m,
940 m, 821 m, 766 m, 696 m; Elemental analysis;
(BiC48H39O6S3) Calc. (Found): C 56.52(56.51), H 4.15(4.05)%;
1H NMR (400 MHz, CDCl3, 30 °C): δ 7.93 (d, J3 8.8, 2H, Hb),
7.66 (d, J3 5.6, 2H, Hi), 7.36–7.28 (m, 3H, Hj,k), 7.26 (s, 1H, Hf),
6.84 (d, J3 8.8, 2H, Hc), 3.85 (s, 3H, Hl); 13C NMR (100.1 MHz,
CDCl3, 30 °C) δ 188.3 (Cg), 168.6 (Ce), 163.3 (Cd), 147.6 (Ch),
130.9 (Ca), 130.7 (Ci), 129.3 (Cj), 129.1 (Ck), 128.2 (Cb), 121.5
(Cc), 113.8 (Cf), 55.6 (Cl); Mass spectrum, ESI+: 746.9 (100%,
[BiL2]+), 792.4 (15%, [BiL2 + EtOH]+), 1199.3 (10%, [BiL3 + H +
Synthesis of bismuth(III) thioxoketones
GP 3: reactions with Bi(OtBu)3. All the manipulations were
carried out under standard Schlenk conditions. Bi(OtBu)3 (one
equivalent) dissolved in THF was added to a THF solution of
thioxoketone (three equivalent) which was already cooled to
−80 °C. This was stirred over night by the time the reaction
D1-DMSO]+); ESI−: 269.1 (100%, [L]−), 1051.3 (5%, [BiL3
+
Cl]−); (LH = C16H14O2S).
[Bi{p-MeOC6H4C(vO)CHC(vS)p-CF3–C6H4}3], B4. L4 (0.25 g,
temperature reached to room temperature. In the situations 0.75 mmol) and Bi(OtBu)3 (0.11 g, 0.25 mmol) were reacted in
where the product precipitates, this was filtered and washed THF according to GP 3 to obtain B4 as a yellow solid.
with diethyl ether and ethanol to remove any unreacted
Yield: 0.23 g, 74%; Mp: Dec >105 °C; FT-IR (cm−1): 1582 m,
Bi(OtBu)3 and acid. In the circumstances where the product is 1560 m, 1319 m, 1243 m, 1168 m, 1120 w, 1062 m, 1014 m,
soluble in THF, this was isolated by removing the solvent 941 m, 818 m, 760 m, 699 m; Elemental analysis;
under vacuum and washing with ether and ethanol.
[Bi{C6H5C(vO)CHC(vS)C6H5}3], B1. L1 (0.36 g, 1.50 mmol)
and Bi(OtBu)3 (0.22 g, 0.50 mmol) were reacted in
THF according to GP 3 to obtain B1 as an orange crystalline
solid.
(BiC51H36O6S3F9) Calc. (Found): C 48.61(48.20), H 3.44(2.77)%;
1H NMR (400 MHz, CDCl3, 30 °C): δ 7.95 (d, J3 9.2, 2H, Hb),
7.69 (d, J3 8.4, 2H, Hj), 7.54 (d, J3 8.4, 2H, Hi), 7.34 (s, J3 1H,
Hf), 6.88 (d, J3 9.2, 2H, Hc), 3.87 (s, 3H, Hl); 13C NMR
(100.1 MHz, CDCl3, 30 °C): δ 188.5 (Cg), 166.0 (Ce), 163.8 (Cd),
150.7 (Ch), 131.1 (Ca), 128.8 (Ci), 125.3 (Cb,j), 125.2 (Ck), 122.8
(Cm), 122.7 (Cc), 114.0 (Cf), 55.6 (Cl); Mass spectrum, ESI+:
696.9 {12%, [(L)2 + Na]+}, 882.9 (100%, [BiL2]+), 1243.1 (5%,
[BiL3 + Na]+); (LH = C17H13O2SF3).
Yield: 0.33 g, 71.0%; Mp: Dec >120 °C; FT-IR (cm−1): 1566 s,
1499 s, 1299 m, 1249 s, 1177 m, 1055 m, 1024 m, 999 m,
942 m, 808 m, 784 s, 757 m, 693 s, 668 s; Elemental analysis;
(BiC45H33O3S3·2H2O) Calc. (Found): C 55.95(55.21), H 4.17
1
(3.50)%; H NMR (400 MHz, CDCl3, 30 °C): δ 7.92 (d, J3 10.0,
[Bi{C5H4NC(vO)CHC(vS)C6H5}3], B5. L5 (0.36 g, 1.5 mmol)
2H, Hb), 7.71 (d, J3 8.8, 2H, Hi), 7.57 (t, J3 9.2, 1H, Hd), and Bi(OtBu)3 (0.22 g, 0.5 mmol) were reacted in THF accord-
7.40–7.31 (m, 5H, Hc,j,k), 7.36 (s, 1H, Hf); 13C NMR ing to GP 3 to obtain B5 as a yellow brown solid.
(100.1 MHz, CDCl3, 30 °C): δ 189.7 (Cg), 170.3 (Ce), 147.3 (Ca),
Yield: 0.32 g, 68.1%; Mp: Dec >160 °C; FT-IR (cm−1):
138.9 (Ch), 132.6 (Ck), 128.8 (Cd), 128.6 (Ci), 128.5 (Cj), 128.3 1579 m, 1563 m, 1557 s, 1305 w, 1233 m, 1279, 1078 m,
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1040 m, 995 m, 948 m, 805 m, 764 m, 712 m, 694 m, 681 m;
[Bi{CH3C(vO)CHC(vS)C6H5}3], B9. L9 (0.27 g, 1.50 mmol)
Elemental analysis; (BiC42H30O3S3N3) Calc. (Found): C 53.05 and Bi(OtBu)3 (0.22 g, 0.50 mmol) were reacted in THF accord-
(53.01), H 3.71(3.11), N 4.42(4.41)%; 1H NMR (400 MHz, ing to GP 3 to obtain B9 as a pale brown solid.
CDCl3, 30 °C): 8.62 (d, J3 4.8, 1H, He), 8.26 (s, 1H, Hg), 8.15 (d,
Yield: 0.24 g, 65.1%; Mp: >120 °C; FT-IR (Nujol, cm−1
)
J3 8.0, 1H, Hb), 7.75–7.70 (m, 3H, Hk,l), 7.40–7.30 (m, 4H, Hj,c,d); 1603 m, 1327 m, 1228 m, 1180 m, 1074 w, 1028 w, 979 m, 848
13C NMR (100.1 MHz, CDCl3, 30 °C): δ 188.1 (Ch), 172.2 w, 820 w, 761 m; Elemental analysis; (BiC30H18O3S3) Calc.
(Cf), 154.6 (Ca), 148.9 (Ce), 147.0 (Ci), 137.0 (Cc), 130.0 (Cl), (Found): C 47.30(46.88), H 4.23(3.66)%; 1H NMR (400 MHz,
129.0 (Cj), 128.2 (Ck), 126.6 (Cd), 123.4 (Cb), 120.6 (Cg); Mass CDCl3, 30 °C) δ 7.63 (d, J3 8.0, 2H, Hf), 7.36–7.30 (m, 3H, Hg,h),
spectrum, ESI+: 208.82 (35%, [Bi]+), 743.9 (5%, [BiL2 + 3H2O]+), 6.74 (s, 1H, Hc), 2.28 (s, 3H, Ha); 13C NMR (100.1 MHz, CDCl3,
778.9 (10%, [BiL2 + 5H2O]+), 952.1 (10%, [BiL3 + Na]+), 983.2 30 °C) δ 195.8 (Cd), 160.4 (Cb), 129.3 (Ce), 128.7 (Cf), 128.3 (Cg),
(5%, [BiL3 + Na + MeOH]+); ESI−: 239.8 (100%, [L]−); (LH = 128.2 (Ch), 125.8 (Cc), 31.0 (Ca); Mass spectrum, ESI+: 563.1
C14H11OSN).
(100%, [BiL2]+), 763.2 (40%, [BiL3 + Na]+), 1303.3(5%, [Bi2L5]+);
ESI+: 177.2 (100%, [L]−, 917.1 (10%, [BiL4]−). (LH = C1oH10OS).
[Bi{p-IC6H4C(vO)CHC(vS)C6H5}3],
B6. L6
(0.37
g,
1.00 mmol) and Bi(OtBu)3 (0.14 g, 0.33 mmol) were reacted in
THF according to GP 3 to obtain B6 as a yellow solid.
Crystallography
Yield: 0.36 g, 83.7%; Mp: Dec >120 °C; FT-IR (cm−1):
1577 m, 1549 m, 1245 m, 1179 w, 1110 w, 1066 w, 1002 m,
941 m, 816 m, 761 m, 698 m; Elemental analysis;
(BiC45H30O3S3I3) Calc. (Found): C 41.33(42.06), H 2.54(2.36)%;
1H NMR (400 MHz, CDCl3, 30 °C): δ 7.73 (d, J3 8.4, 2H, Hc),
7.65 (d, J3 8.4, 2H, Hb), 7.60 (d, J3 8.8, 2H, Hi), 7.35 (t, J3 5.6,
1H, Hk), 7.30 (t, J3 8.8, 2H, Hj), 7.25 (s, 1H, Hf); 13C NMR
(100.1 MHz, CDCl3, 30 °C) δ 188.4 (Cg), 171.5 (Ce), 146.9 (Ca),
137.8 (Cc), 130.0 (Ch), 129.6 (Ci,j), 129.2 (Ck), 128.6 (Cb), 120.7
(Cf), 100.5 (Cd); Mass spectrum, ESI+: 939.0 (100%, [BiL2]+),
1327.0 (15%, [BiL3 + Na]+), 1483.0 {13%, [BiL3 + Na +
2DMSO]+}; ESI−: 364.9 (100%, [L]−); (LH = C15H11OSI).
Crystallographic data of [Bi{C6H5C(vS)CHC(vO)C5H4N}3·
DMSO] B-5 was collected on a Bruker X8 APEX CCD instru-
ment with monochromatic (graphite) Mo Kα radiation (λ =
0.71073 Å) at 123(2) K. X-ray data was solved and refined with
SHELX-9750 utilising the graphical interface X-seed.51 Data for
B-5 has been deposited with the Cambridge Crystallographic
Database with CCDC number 948455.
Crystal data for [Bi{C6H5C(vS)CHC(vO)C5H4N}3·DMSO]
B-5: C44H36BiN3O4S4, M = 347.47, orange/brown needle, 0.11 ×
3
ˉ
0.08 × 0.08 mm , triclinic, space group P1, a = 10.330(2), b =
10.453(2), c = 19.993(4) Å, α = 102.31(3), β = 101.71(3), γ =
97.19(3)° V = 2033.1(7) Å3, Z = 2, Dc = 1.647 g cm−3, F000 = 1000,
[Bi{C6H5C(vO)CHC(vS)p-IC6H4}3],
B7. L7
(0.28
g,
2θmax = 50.0°, 27 385 reflections collected, 6459 unique (Rint
=
0.75 mmol) and Bi(OtBu)3 (0.11 g, 0.25 mmol) were reacted in
THF according to GP 3 to obtain B7 as a yellow solid.
0.1119). Final GooF = 1.008, R1 = 0.0497, wR2 = 0.1165, R
indices based on 6459 reflections with I > 2σ(I) (refinement on
F2), 509 parameters, 27 restraints.
Yield: 0.22 g, 66.1%; Mp: Dec >110 °C; FT-IR (cm−1):
1583 m, 1575 m, 1246 w, 1170 w, 1005 m, 817 w, 771 m.
Elemental analysis; (BiC45H30O3S3I3) Calc. (Found): C 41.33
(41.52), H 2.54(2.95)%; 1H NMR (400 MHz, CDCl3, 30 °C): δ
7.76 (d, J3 7.2, 2H, Hj), 7.66 (d, J3 8.8, 2H, Hb), 7.55–7.29 (m,
5H, Hi,c,d), 6.74 (s, 1H, Hf); 13C NMR (100.1 MHz, CDCl3,
30 °C) δ 188.5 (Cg), 165.1 (Ce), 142.8 (Ca), 137.4 (Cj), 137.0 (Ci),
131.0 (Ch), 130.0 (Cd), 128.8 (Cb), 128.4 (Cc), 124.1 (Cf), 100.2
(Ck); Mass spectrum, ESI+: 939.0 (20%, [BiL2]+), 1327.0 (10%,
Acknowledgements
We thank the Australian Research Council and Monash Uni-
versity for financial support.
[BiL3
C15H11OSI).
+ =
Na]+); ESI−: (100%, 364.9 (100%, [L]−); (LH
References
[Bi{C6H5C(vO)CHC(vS)C10H7}3], B8. L8 (0.22 g, 0.75 mmol)
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ing to GP 3 to obtain B8 as a pale brown solid.
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