Homo- And heteroleptic bismuth(iii/v) thiolates from N-heterocyclic thiones: Synthesis, structure and anti-microbial activity

Article abstract of DOI:10.1002/chem.201404109

Homo- and heteroleptic bismuth thiolato complexes have been synthesised and characterised from biolog,ically relevant tetrazole-, imidazole-, thiadiazole- and thia-zole- based heterocyclic thiones (thiols): 1-methyl-1 H-tetra-zole- 5-thiol (1-MMTZ(H)); 4-

Full text of DOI:10.1002/chem.201404109

DOI: 10.1002/chem.201404109
Full Paper
&
Bismuth Chemistry
Homo- and Heteroleptic Bismuth(III/V) Thiolates from N-
Heterocyclic Thiones: Synthesis, Structure and Anti-Microbial
Activity
Ahmad Luqman,[a] Victoria L. Blair,[a] Rajini Brammananth,[b] Paul K. Crellin,[b] Ross L. Coppel,[b]
and Philip C. Andrews*[a]
Abstract: Homo- and heteroleptic bismuth thiolato com-
plexes have been synthesised and characterised from biolog-
ically relevant tetrazole-, imidazole-, thiadiazole- and thia-
zole-based heterocyclic thiones (thiols): 1-methyl-1H-tetra-
zole-5-thiol (1-MMTZ(H)); 4-methyl-4H-1,2,4-triazole-3-thiol
(4-MTT(H)); 1-methyl-1H-imidazole-2-thiol (2-MMI(H)); 5-
methyl-1,3,4-thiadiazole-2-thiol (5-MMTD(H)); 1,3,4-thiadia-
zole-2-dithiol (2,5-DMTD(H)2); and 4-(4-bromophenyl)thia-
zole-2-thiol (4-BrMTD(H)). Reaction of BiPh3 with 1-MMTZ(H)
produced the rare BiV thiolato complex [BiPh(1-MMTZ)4],
which undergoes reduction in DMSO to give [BiPh(1-
MMTZ)2{(1-MMTZ(H)}2]. Reactions with PhBiCl2 or BiPh3 gen-
erally produced monophenylbismuth thiolates, [BiPh(SR)2].
The crystal structures of [BiPh(1-MMTZ)2{1-MMTZ(H)}2],
[BiPh(5-MMTD)2], [BiPh{2,5-DMTD(H)}2(Me2C=O)] and [Bi(4-
BrMTD)3] were obtained. Evaluation of the bactericidal prop-
erties against M. smegmatis, S. aureus, MRSA, VRE, E. faecalis
and E. coli showed complexes containing the anionic ligands
1- MMTZ, 4-MTT and 4-BrMTD to be most effective. The di-
thiolato dithione complexes [BiPh(4-MTT)2{4-MTT(H)}2] and
[BiPh(1-MMTZ)2{1-MMTZ(H)}2] were most effective against all
the bacteria: MICs 0.34 mm for [BiPh(4-MTT)2{4-MTT(H)}2]
against VRE, and 1.33 mm for [BiPh(1-MMTZ)2{1-MMTZ(H)}2]
against M. smegmatis and S. aureus. Tris-thiolato BiIII com-
plexes were least effective overall. All complexes showed
little or no toxicity towards mammalian COS-7 cells at
20 mgmLꢀ1.
Introduction
and bismuth thiolates, unlike many carboxylates, alkoxides,
and diketonates, tend to be stable towards hydrolysis. This
makes the study of bismuth thiolates; their formation, struc-
ture, stability, lability, and biological activity particularly
relevant.
The interest in bismuth, and its compounds, continues to at-
tract considerable attention because of its potential as an envi-
ronmentally acceptable heavy metal in chemical synthesis, ma-
terials, and medicine.[1–4] The effective biological activity of bis-
muth compounds towards microbes, parasites and tumour
cells,[5–7] coexists with what is an apparent low systemic toxicity
in humans, providing a motivation for their study and applica-
tion in bio-protective surfaces,[8] therapeutics,[7,9] and molecular
and cellular imaging.[10,11] While the majority of bismuth-based
medicines currently available are derived from carboxylic acids
(for examples bismuth subsalicylate, bismuth subcitrate) the in
vivo biological targets for bismuth, with the exception of trans-
ferrin and lactoferrin, are predominantly proteins and peptides
rich in S-based amino acids cysteine and methionine.[7,12,13] The
BiꢀS bond displays higher thermodynamic stability than BiꢀO,
While thermodynamically stable the BiꢀS bond is still
labile,[6] and so bismuth thiolates display strong bactericidal
and fungicidal properties.[14–16] They have been assessed and
proposed as effective agents for combating wound infec-
tion,[17] and for retarding biofilm growth on surfaces.[8,19–21] Sev-
eral classes of compounds, particularly xanthates and dithiocar-
bamates, have shown significant in vitro anti-tumour activi-
ty.[22–25] Bismuth thiolates have also been investigated as X-ray
imaging agents,[26] and more recently their decomposition to
functionalised bismuth sulfide nanoparticles has given rise to
a new class of contrast agent for computed tomography.[11,
27–30]
Difficulties with solubility often means obtaining definitive
solid and solution state structural information on bismuth thio-
lates is challenging, though the library is growing with a rela-
tively small but not insignificant number complexes being
structurally authenticated, particularly those based on arylthio-
lato ligands.[31] The paucity in the diversity of such information
impacts on our knowledge of structure–activity relationships
and also basic cellular mechanisms, leading Burford and co-
workers more recently to explore using mass spectrometry to
[a] A. Luqman, Dr. V. L. Blair, Prof. P. C. Andrews
School of Chemistry, Monash University
Clayton, Melbourne, VIC 3800 (Australia)
E-mail: phil.andrews@monash.edu
[b] R. Brammananth, Dr. P. K. Crellin, Prof. R. L. Coppel
Department of Microbiology, Monash University,
Clayton, Melbourne, VIC 3800 (Australia)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201404109.
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elucidate complex formation and composition with low-molec-
ular-weight, biologically relevant thiols and thio-carboxylic
acids, in which chelation plays a key role.[32–34]
Our recent interest in this area has been to study bismuth
complexes built primarily around covalent BiꢀS bonds; thioxo-
ketonates, thioamides and thiobenzoates, and to compare
their biological activity against Helicobacter pylori and the
Leishmania parasite with their BiꢀO analogues.[35–38] Prior to
this we reported on the solvent-free and microwave-assisted
synthesis of BiIII complexes, [Bi(SR)3], derived from heterocyclic
thiols (thiones), a family of ligands for which the bismuth
chemistry has been largely neglected.[39] Recently, Dostꢁl and
co-workers developed an unusual pathway involving the oxi-
dative addition of aromatic and heterocylic disulfides to an in
situ generated N,C,N-chelated arylbismuth(I) compound, result-
ing in a series of heteroleptic dithiolato bismuth(III) com-
pounds.[40] In revisiting the reaction of BiPh3 with thiols, we re-
cently uncovered an unexpected redox process in the reaction
of BiPh3 with 4-methyl-4H-1,2,4-triazole-3-thiol and 2-mercap-
to-1-methylimidazole (=RSH), which resulted in the formation
and characterisation of the first monophenyl tetrathiolato BiV
complexes, [BiPh(SR)4], and subsequent H2O assisted decompo-
sition into their BiIII daughter complexes, [BiPh(SR)2(HSR)2].[41]
This result coupled with the fact that heterocyclic thioa-
mides are used clinically in the treatment of hyperthyroidism,
for example, Methimazole, and have demonstrated broad fun-
gicidal and antimicrobial activity,[42–44] justified a deeper and
broader study of the synthesis, stability, structure and
biological activity of their bismuth complexes.
Figure 1. Six N-heterocyclic compounds used in the synthesis of BiV and BiIII
thiolate complexes: 5-MMTD(H)=5-methyl-1,3,4-thiadiazole-2-thiol, 2,5-
DMTD(H)2 =1,3,4-thiadiazole-2-dithiol, 4-BrMTD(H)=4-(4-bromophenyl)thia-
zole-2-thiol, 1-MMTZ(H)=1-methyl-1H-tetrazole-5-thiol, 4-MTT(H)=4-methyl-
4H-1,2,4-triazole-3-thiole, 2-MMI(H)]=1-methyl-1H-imidazole-2-thiol. The
common thiol–thione tautomerisation is shown for 4-MTT(H).
Results and Discussion
Synthesis
In targeting the most efficient and high yielding methods for
the reliable and reproducible synthesis of heterocyclic thiolato
bismuth complexes we have explored three different synthetic
strategies; 1) the reaction of thiols with BiPh3, 2) replacing
BiPh3 with Bi(OtBu)3 as a stronger base and 3) employing salt
metathesis reactions using BiCl3 or BiPhCl2 with sodium thio-
lates. These processes have been studied under standard
solvent-mediated conditions and using microwave irradiation.
In this paper we now report the synthesis, full characterisa-
tion and bactericidal activity of a series of homo- and hetero-
leptic bismuth complexes derived from the structurally similar
heterocyclic thiols: 1-methyl-1H-tetrazole-5-thiol (1-MMTZ(H)),
4-methyl-4H-1,2,4-triazole-3-thiole (4-MTT(H)), 1-methyl-1H-imi-
dazole-2-thiol (2-MM1(H)), 5-methyl-1,3,4-thiadiazole-2-thiol (5-
MMTD(H)), 1,3,4-thiadiazole-2-dithiol (2,5-DMTD(H)2) and 4-(4-
bromophenyl)thiazole-2-thiol (4-BrMTD(H)). The structures are
shown in Figure 1, including an illustration of the thione–thiol
tautomerism, exemplified by 2-MMT(H), a common feature of
all these N-heterocyclic compounds.[45] The complexes of vari-
ous composition; [BiPh(SR)4], [BiPh(SR)2] and [Bi(SR)3], have
been comprehensively characterised by multinuclear NMR and
FT-IR spectroscopy, ESI-MS and elemental analysis. The oxida-
tion state of the bismuth has been studied by electrochemistry,
and four complexes have had their solid-state structures con-
firmed by single-crystal X-ray diffraction. Finally, their antibac-
terial activities have been assessed against a suite of gram-pos-
itive and antibiotic resistant bacteria; Mycobacterium smegma-
tis, Staphylococcus aureus, Methicillin-resistant Staphylococcus
aureus (MRSA), Vancomycin Resistant Enterococcus (VRE) and
Enterococcus faecalis, and the gram-negative bacterium Escheri-
chia coli. Mammalian cell toxicity was assessed against COS-7
cells.
Monophenyl tris- and tetrathiolato bismuth(III/V) complexes
One surprising outcome when conducting our initial studies
on the reaction of BiPh3 with 4-MTT(H) and 2-MMI(H) was the
formation and isolation of two unique tetrathiolato BiV species,
[BiPh(SR)4], as confirmed by NMR spectroscopy and electro-
chemical analysis. These complexes proved to be stable as
solids, and also initially in DMSO. However, in solution they
slowly underwent hydrolysis and reduction to give crystals of
the corresponding BiIII complexes, [BiPh(SR)2(RSH)2], the struc-
tures of which were determined by single-crystal X-ray diffrac-
tion.[41] This remarkable result prompted a more detailed ex-
amination of the various reaction pathways that allow for the
formation of bismuth thiolates and interrogation of which li-
gands and which conditions support the formation and possi-
ble oxidation of the BiIII complexes.
As such, the six different five-membered heterocyclic thiones
(thiols) shown in Figure 1 were chosen for further study, which
are based on tetrazole, triazole, imidazole, thiadiazole and
thiazole.
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By analogy with the reactions that resulted in the tetrathio-
lato BiV complexes, BiPh3 was treated variously with four equiv-
alents of 1-MMTZ(H), 5-MMTD(H), 2,5-DMTD(H)2 and 4-
BrMTD(H), using similar reaction conditions. Only the reaction
with 1-MMTZ(H) resulted in the formation of an additional
stable BiV complex, [BiPh(1-MMTZ)4]. Two of the other thiols, 5-
MMTD(H) and 2,5-DMTD(H)2, resulted only in the disubstituted
bismuth(III) thiolate complexes, [BiPh(SR)2], as the single isola-
ble products, while 4-BrMTD(H) gave a mixture of the di- and
trithiolato complexes.
tained through multinuclear NMR spectroscopy, mass
spectrometry, FTIR spectroscopy and cyclic voltammetry.
Dissolution of 1 in DMSO and slow evaporation over several
weeks resulted in a crop of bright yellow crystals suitable for
X-ray diffraction studies. As found with the previously de-
scribed complexes, [BiPh(4-MTT)4] and [BiPh(2-MMI)4], solid-
state structure analysis of the crystals revealed the BiV com-
plexes to have undergone slow hydrolysis and reduction in so-
lution to give the BiIII complex, [BiPh(1-MMTZ)2{1-MMTZ(H)}2]
(2), the structure of which is presented in Figure 3 (see later
section on X-ray crystal structures). When the reaction is con-
ducted in a 2:1 rather than 4:1 ratio of thione to BiPh3, com-
plex 1 is still obtained but in reduced yields of 30% using
microwave irradiation and 23% by conventional reflux.
The dithiolato complexes, [BiPh(MMTZ)2] (5), [BiPh(4-MTT)2]
(6) and [BiPh(2-MMI)2] (7), were successfully synthesised using
salt metathesis. Two equivalents of the appropriate sodium thi-
olate [NaSR] were reacted with one equivalent of BiPhCl2 at
08C in dry methanol. Complexes 5, 6 and 7 were isolated as
yellow solids which after further washing with dry methanol
gave analytically pure compounds in reasonable yields of 60,
69, and 77% respectively.
In addition, all six N-heterocyclic thiones and their sodium
thiolato salts were successfully reacted with BiPh3 or BiPhCl2 re-
spectively to give monophenylbismuth(III) thiolate complexes
1–10 (see Scheme 1 and ref. [41]). The outcomes of all the vari-
ous reactions are summarised in Table 1, and are discussed in
detail below.
Reaction of BiPh3 and 5-MMTD(H) in a toluene/ethanol (2:1)
solvent mixture, either in a 1:2 or 1:4 ratio, and using either mi-
crowave irradiation (1058C, 15 min) or conventional heating
(16 h), always afforded [BiPh(5-MMTD)2]1 (8) as a bright yellow
solid. For the 1:4 reactions, yields obtained were 85% through
microwave irradiation and 72%
Scheme 1. Summary of the synthetic methods used for the synthesis of het-
eroleptic monoarylbismuth thiolate complexes. Method 1: heated to reflux
in the range 7–12 h. Method 2: microwave heating in the range 85–1258C
for between 5 and 25 min.
by conventional reflux. As ex-
pected, the 1:2 reactions result-
Table 1. Summary and comparison of synthetic methods and isolated yields of complexes 1–10.
ed overall in lower yields, but in
a similar proportion; 73% with
microwave irradiation and 66%
by conventional reflux. Yellow
crystals of 8 suitable for single
X-ray diffraction studies were ob-
tained on crystallising from
DMSO.
Bismuth
source
Reaction
Colour
Yield
[%]
conditions[a]
[BiPh(1-MMTZ)4] (1)
BiPh3
BiPh3
BiPh3
BiPh3
BiPhCl2
BiPhCl2
BiPhCl2
BiPh3
BiPh3
BiPhCl2
BiPh3
reflux, toluene/EtOH, 2 h
MW, toluene/EtOH, 1008C, 4 min
reflux, toluene/EtOH, 2 h
MW, toluene/EtOH, 1008C, 4 min
MeOH, 10 h
bright yellow
bright yellow
bright yellow
bright yellow
yellow
yellow
yellow
pale yellow
pale yellow
pale yellow
orange
51
57
53
60
60
69
77
73
84
83
73
92
–
[BiPh(1-MMTZ)2{1-MMTZ(H)}2] (2)
[BiPh(1-MMTZ)2] (5)
[PhBi(4-MTT)2] (6)[40]
[BiPh(2-MMI)2] (7)
MeOH, 10 h
MeOH, 7 h
Complex 8 was also synthes-
ised through the treatment of
BiPhCl2 with two equivalents of
[Na(5-MMTD)] in dry methanol in
a 83% yield. While the yield is
comparable with that of micro-
wave synthesis the procedure is
less efficient overall, though the
salt metathesis route allows
larger batch quantities to be
synthesised.
[BiPh(5-MMTD)2] (8)
reflux, toluene/EtOH, 16 h
MW, toluene/EtOH, 1128C, 15 min
methanol, 12 h
reflux, toluene/EtOH, 8 h
MW, toluene/EtOH, 1128C, 10 min
reflux, toluene/EtOH, 6 h
MW, toluene/EtOH, 1158C, 7 min
methanol, 16 h
1
[BiPh{2,5-DMTD(H)}2] (9)
1
BiPh3
BiPh3
BiPh3
BiPhCl2
orange
[BiPh(4-BrMTD)2] (10)
orange/yellow
orange/yellow
yellow
–
78
[a] MW=microwave irradiation.
The synthesis of [BiPh(1-MMTZ)4] (1) was achieved on treat-
ing BiPh3 with four equivalents of 1-MMTZ(H) using both mi-
crowave irradiation (1008C, 4 min) and conventional reflux
using a solvent mixture of toluene and ethanol in a 2:1 ratio.
Compound 1 was obtained in 51% yield by conventional
reflux, while the use of microwave irradiation increased the
yield marginally to 57%. The composition of the yellow prod-
uct, and confirmation of the oxidation of BiIII to BiV, was ob-
The reaction of 2,5-DMTD(H)2 with BiPh3 in a toluene/etha-
nol (2:1) solvent mixture using microwave irradiation (1128C,
4 min) results in the dithiolato complex [BiPh{2,5-DMTD(H)}2]1
(9) as an orange solid in 92% yield. Compound 9 was also syn-
thesised under reflux in toluene/ethanol, though a maximum
yield of 73% was obtained after 8 h. Single crystals of complex
9 grew over a period of a few weeks from DMSO.
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The outcomes described here for 5-MMTD(H) and 2,5-
DMTD(H)2 are consistent with our previous observations[39] and
those of Gilman and Yale,[46] that monophenylbismuth(III) thio-
late complexes tend to be favoured in the thermodynamically
driven protolysis reaction of thiols with BiPh3. Thus, irrespective
of the stoichiometries used, the reaction of BiPh3 with 5-
MMTD(H) or 2,5-DMTD(H)2 always resulted in isolation of the
monophenyl derivatives as the main product.
Scheme 2. Two synthetic approaches used for the synthesis of homoleptic
BiIII thiolate complexes
The reaction of 4-BrMTD(H) with BiPh3 was problematic and
the outcomes reminiscent of our previous results with 2- complex 15 produced crystals suitable for X-ray diffraction
MMI(H).[39] Both standard reflux and microwave irradiation, in studies.
a solvent mixture of toluene and ethanol (2:1), result in a com-
plex mixture which includes the trithiolato complex [Bi(4-
IR spectroscopy
BrMTD)3] (39%) and the dithiolato complex [BiPh(4-BrMTD)2]
(13%). Attempts at a solvent-free reaction were also unsuc- Heterocyclic organic compounds containing the thio-amide
cessful in producing a single product. In contrast, the salt functional group afford four characteristic vibrational bands:
metathesis route was simple and effective. Reacting two equiv- n(CꢀN)+d(CꢀH), 1570–1390 cmꢀ1
;
d(CꢀH)+n(CꢀN)+n(C=S),
alents of [Na(4-BrMTD)] with one equivalent of BiPhCl2 in dry 1420–1260 cmꢀ1; n(CꢀN)+n(C=S), 1140–940 cmꢀ1 and n(CPS),
methanol afforded [BiPh(4-BrMTD)2] 10 as a yellow solid in 800–700 cmꢀ1. In all the parent N-heterocyclic compounds the
78% yield.
presence of NꢀH absorption bands (absence of SH absorption
bands) and the four characteristic thioamide bands in the IR
spectra confirm the thione nature of the uncoordinated com-
pounds in the solid state.
Tris-thiolato bismuth(III) complexes
In the IR spectra of the bismuth complexes 1–10 the NH ab-
sorption bands for the parent thiones (3080 to 3250 cmꢀ1) are
absent, supporting deprotonation and complexation to the
bismuth centre. The exceptions are complexes 2 and 9 in
which there remain neutral thione ligands and secondary NH
bonds, respectively, in the thiolato ligands, as can be seen in
the solid-state structures (Figures 3 and 6, in later section X-ray
crystal structures). There is no evidence in the IR spectra of any
SH bands. The presence of the phenyl group in 1–10 is also
confirmed through the appearance of absorption bands in the
range of 690–735 cmꢀ1, attributed to the CꢀH bending fre-
quencies.
In general, it is difficult to access trithiolato bismuth complexes
[Bi(SR)3] through the simple reaction of thiones (thiols) with
BiPh3. The thiones are generally not acidic enough. For this,
the use of the stronger base Bi(OtBu)3 is cleaner and more ef-
fective, while the salt metathesis reaction is also effective but
tends to furnish lower yields.
The trithiolato bismuth(III) complexes [Bi(1-MMTZ)3] (11),
[Bi(4-MMT)3] (12), [Bi(2-MMI)3] (13), [Bi(5-MMTD)3] (14), [Bi(4-
BrMTD)3] (15) and [Bi{2,5-DMTD(H)}3] (16) (Table 2) were all ob-
tained by treating the appropriate thione with Bi(OtBu)3 (3:1)
in dry THF at low temperature under inert atmosphere condi-
tions (Scheme 2). The reaction outcomes are summarised in
Table 2.
NMR studies
Solution NMR studies of the six N-heterocyclic compounds
in [D6]DMSO also reveal a structural preference for the more
stable thione form.[47] On deprotonation and binding with bis-
muth the thione is transformed into the more stable thiolate
anion resulting in a more thermodynamically stable BiꢀS bond.
This phenomenon is observed
Complexes 11–16 are soluble in DMSO and DMF, and are
partially soluble in acetone, ethanol and THF. All are insoluble
in water. However, despite attempting a range of solvents, sol-
vent mixtures, and multiple methods for recrystallisation, only
for all complexes 1–16.
Integration of the proton sig-
Table 2. Comparison of reaction conditions and isolated yields for the trisubstituted bismuth(III) complexes
10–16.>
1
nals in the H NMR spectrum of
complex 1 [BiPh(1-MMTZ)4] re-
veals a ligand ratio of thiolate to
phenyl of 4:1. This is similar to
that described previously for the
other two analogous BiV tetra-
thiolato complexes [BiPh(4-
MTT)4] and [BiPh(2-MMI)4], where
no proton resonances attributa-
ble to either NH or SH are ob-
served. Unfortunately in the
NMR spectrum of the thione,
and of the reduced complex 2,
Bismuth
source
Reaction
conditions
Colour
Yield
[%]
[Bi(1-MMTZ)3] (11)
[Bi(4-MTT)3] (12)
BiCl3
Bi(OtBu)3
BiCl3
Bi(OtBu)3
BiCl3
Bi(OtBu)3
BiCl3
Bi(OtBu)3
BiCl3
Bi(OtBu)3
Bi(OtBu)3
MeOH,08C–RT, overnight stirring
THF,-808C–RT, 10 h
yellow
63
73
71
79
71
86
72
81
71
68
78
pale yellow
orange
orange
orange
orange
yellow
pale yellow
orange
orange
orange
MeOH,08C–RT, overnight stirring
THF, ꢀ808C–RT, 7 h
[Bi(2-MMI)3] (13)
MeOH, 08C–RT, overnight stirring
THF, ꢀ808C–RT, 7 h
[Bi(5-MMTD)3] (14)
[Bi(4-BrMTD)3] (15)
[Bi{2,5-DMTD(H))3] (16)
MeOH, 08C–RT, overnight stirring
THF, ꢀ808C–RT, 9 h
MeOH,08C–RT, overnight stirring
THF, ꢀ808C–RT, 12 h
THF, ꢀ808C–RT, 12 h
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the NH or SH resonances are also not visible making compari-
sons difficult.
604 (19%) for 14). The ESI-MS data for all the complexes is
given in Experimental Section.
In contrast to 1, complexes 5–10 show a thiolate to phenyl
integral ratio of 2:1, supporting a general formulation of
[BiPh(SR)2]. In all the monophenylbismuth thiolate complexes
1–10, the phenyl proton signals lie in the range of 9.02-8.24
(ortho), 7.90-7.54 (meta) and 7.50-7.32 (para) ppm, which are
all shifted to higher frequency relative to BiPh3 (ortho, 7.76;
meta, 7.38, and para, 7.31 ppm).
Electrochemistry
In our initial report on complexes [BiPh(4-MTT)4] and [BiPh(4-
MMI)4] it was electrochemical studies that proved definitively
that the bismuth centre was in the V oxidation state.[41] Similar
studies were therefore conducted on complexes 1 and 2 to
allow a comparison between the two complexes, and with the
4-MTT and 2-MMI complexes.
In complexes 7, [BiPh(2-MMI)2], and 13, [Bi(2-MMI)3], the CH
signals for the imidazole ring appear at 6.71, 6.99 ppm and
6.79, 6.96 ppm respectively, a shift to higher frequency relative
to the free thione, in which they resonate at 6.85 and
7.03 ppm. In addition, the resonances attributable to the CH3
group shift to 3.44 and 3.40 ppm in complexes 7 and 13 re-
spectively, compared with 3.42 ppm in the thione.
Generally, two steps are involved in the reduction of BiV
compounds to elemental Bi0 when the potential is scanned in
the negative direction. In the first step BiV is reduced to BiIII, in-
volving a two-electron step pro-
cess, and in the second step BiIII re-
The singlet for the single CH proton on the thiazole ring in
complexes 10 [BiPh(4-BrMTD)2], and 15 [Bi(4-BrMTD)3] also
shift to higher frequency, 7.71 and 7.62 ppm respectively, rela-
tive to that in the thione, 7.40 ppm. In complex 12, [Bi(4-
MTT)3], the single triazole CH is found at 8.25 ppm and the CH3
at 3.42 ppm, compared with 8.35 and 3.41 ppm in 4-MTT(H).
There is almost no difference between the comparative
carbon resonances in the 13C NMR spectra of complexes 1 and
2. In complex 1, which is BiV, the ortho-, meta- and para-C sig-
nals appear at 139.3, 132.9 and 127.7 ppm respectively, while
in complex 2 they appear at 138.9, 132.9 and 127.4 ppm. The
CH3 signals are found at 33.5 (in 1) and 33.2 (in 2) ppm, which
compares with 33.3 ppm in the neutral thione, 1-MMTZ(H).
In general, the signals attributable to the CH3 groups are
largely unaffected by the thione to thiolate transformation: the
thiolate (neutral thione) resonances in complexes 1, 2, 5, 7 and
8 are observed at 33.5 (33.5), 33.2 (33.5), 33.4 (33.5), 33.5 (33.4)
and 15.3 (15.8) ppm. This is also reflected in the trithiolato
bismuth(III) complexes 11, 12, 13 and 14 where the CH3 signals
appear at 33.7, 31.1, 33.4 and 15.7 ppm respectively. Full de-
tails of the multinuclear NMR spectra and chemical shifts as-
signments are given in Experimental Section.
duced to elemental bismuth(0) in
a three-electron step (Scheme 3).
Scheme 3. Two stage reduc-
While scanning the potential in
tion of BiV to BiIII and to bis-
the positive direction, elemental
bismuth, Bi0, deposited on the
muth metal.
electrode surface can be stripped
to give BiIII. This assumption was
analysed by the steady state voltammogram at a microelec-
trode for the reduction of complex 1 in dry DMSO under inert
conditions (Figure 2a). Process A is the initial reduction step
and is well defined. On scanning more negative potentials,
process B is detected, which is a second more drawn out re-
duction process. The ratio of the limiting current for processe-
s A and B is determined to be as 2:3. Thus, processes A and B
are in excellent agreement with the 2eꢀ and 3eꢀ reduction
processes depicted in Scheme 3.
While using a scan rate of 100 mVsꢀ1 under transient condi-
tions of cyclic voltammetry, in the forward scan (negative po-
tential direction), two distinct peaks A and B along with a strip-
ing peak C on reverse scan (positive potential direction) were
observed. The potential was switched after peaks A and B to
establish the origin of stripping peak C. Process A at positive
potentials on the reverse positive potential direction scan is
still well defined (Figure 2b) and no bismuth metal is pro-
duced, as evidenced by the lack of a bismuth stripping (Bi0!
BiIII) process. In contrast, the characteristic bismuth-stripping
peak is now detected (process C) if the potential is switched at
a value more negative than process B (Figure 2c). Furthermore,
no elemental Bi0 is detected on holding the potential at the
values between the first and second process for 10 min. How-
ever, a black deposit can be seen visually on the glassy carbon
electrode when the potential is held at a value slightly more
negative than process B.
Mass spectrometry
Confirmation of the change in the oxidation state of the bis-
muth centre from (III) to (V) in 1 is found in the ESI-MS+ spec-
trum in which prominent signals are found at at m/z 826
(100%, [BiPhL4(DMSO)+H]+), 812 (40%, [BiPhL4(CH3OH)2 +H]+
), 780 (60%, [BiPhL4(CH3OH)+H]+), 748 (32% [BiPhL4 +H]+),
653 (20% [BiPhL3(H2O)+H]+), 613 (5%, [BiPh(O)L2(DMSO)+H]+
), and 533 (12%, [BiPh(O)L2 +H]+).
Complexes 5, 8 and 10 all display prominent peaks for the
ions [BiPhL2 +Na]+ at m/z=540 (80%), 571 (30%) and 851
(100%), respectively. For complex 7 the ion [BiPhL2(DMSO)-
(H2O)+H]+) is found at m/z 610 (80%), and for 9 [BiPh(LH)2-
(DMSO)2(CH3OH)2 +K]+) is seen at m/z 844 (100%).
Voltammetry of complex 2, tentatively assigned as a BiIII
compound, is very different to that described above for the BiV
complex. This can be seen in Figure 2d. In this case, the initial
process D is more drawn out than process A, but leads directly
to detection of elemental bismuth (process C) when the poten-
tial is reversed. Thus, process D can be assigned to the single
3eꢀ reduction process for BiIII to Bi0. Thus, the electrochemical
behaviour confirms complex 1 as a BiV species.
The trithiolato bismuth(III) complexes 11 and 13–16 all show
typical ions such as [BiL3 +Na]+ (at m/z=577 (20%) for 11, 571
(28%) for 13 and 1045 (15%) for 15) and [BiL3 +H]+ (at m/z=
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X-ray structural studies
Four complexes were successfully characterised by single-crys-
tal X-ray diffraction. A summary of the crystallographic data for
all four complexes 2, 8, 9 and 15 is provided in Table 3.
Complex 2 is essentially isostructural to our previously re-
ported BiIII complexes [BiPh(4-MMT)2{4-MMT(H)}2] (3) and
[BiPh(2-MMI)2{2-MMI(H)}2] (4).[41] Adopting a distorted square-
pyramidal geometry, the centrally located BiIII atom in 2 is co-
ordinated to one phenyl, two 1-MMTZ and two 1-MMTZ(H) li-
gands giving an overall coordination number of five to the BiIII
atom (Figure 3). Similar to 3 and 4, the two hydrogen atoms
Figure 3. Molecular structure of [BiPh(1-MMTZ)2{1-MMTZ(H)}2] (2) with ther-
mal ellipsoids shown at 50% probability. Only one of two independent mol-
ecules is shown. Hydrogen atoms (except NH ones) have been omitted for
clarity. Selected bond lengths (ꢂ) and angles (8): Bi(1)-C(9), 2.258(3); Bi(1)ꢀ
S(1), 2.9173(12); Bi(1)ꢀS(2), 2.7123(10); Bi(1)ꢀS(3), 2.7355(11); Bi(1)ꢀS(4),
2.9476(10); N(8)ꢀH(4N), 1.08(2); N(12)ꢀH(16N), 1.85(2); Bi(1)-S(1)-C(1),
104.38(15; Bi(1)-S(2)-C(3), 102.04(14); Bi(1)-S(3)-C(5), 95.93(14); Bi(1)-S(4)-C(7),
103.49(14); C(9)-Bi(1)-S(1), 81.14(10); C(9)-Bi(1)-S(2), 83.29(9); C(9)-Bi(1)-S(3),
88.38(10); C(9)-Bi(1)-S(4), 79.48(9); S(1)-Bi(1)-S(2), 96.28(4); S(1)-Bi(1)-S(3),
168.22(3); S(1)-Bi(1)-S(4), 82.89(3); S(2)-Bi(1)-S(3), 87.79(4); S(2)-Bi(1)-S(4),
162.68(3); S(3)-Bi(1)-S(4), 89.93(3).
Figure 2. a) Steady state voltamogram at a carbon microelectrode for two-
step reduction of BiV in [BiPh(1-MMTZ)4] 1 to Bi0 using scan rate
(100 mVsꢀ1); b)–d) cyclic voltammetry at a glassy carbon electrode using
scan rate (100 mVsꢀ1); b) potential switched after process A for complex 1;
c) potential switched after process B for complex 1; d) potential switched
after process D giving rise to reduction of BiIII in [BiPh(1-MMTZ)2{1-
MMTZ(H)}2], 2 to Bi0.
H(4N) and H(16N) located on the 1-MMTZ(H) ligands in 2 make
hydrogen-bond contacts to the acceptor 1-MMTZ ligands
(N(4)ꢀH(4H), 1.80(2); N16ꢀH(16N), 1.85(2) ꢂ) lying almost co-
planar to each other, twisted by 12.04(24)8 and 6.97(25)8, for
the D···A (donor–acceptor) bonds N(4)ꢀH(4N)···N(8) and N(16)ꢀ
H(16N)···N(12), respectively.
The BiꢀS bond lengths in 2 show distinguishable covalent
(Bi(1)ꢀS(2), 2.7123(10); Bi(1)ꢀS(3), 2.7355(11) ꢂ) and dative (co-
ordinative) (Bi(1)ꢀS(1), 2.9173(12); Bi(1)ꢀS(4), 2.9476(10) ꢂ)
bonding modes which differs from complexes 3 and 4 in
which an average BiꢀS bond length of about 2.80 ꢂ was ob-
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Table 3. Summary of crystallographic data for complexes 2, 8, 9 and 15.
2
8
9
15
formula
Mr
crystal system
a [ꢂ]
b [ꢂ]
c [ꢂ]
a [8]
b [8]
C24H22Bi2N8S8
1096.4
C13H13BiN4OS6
642.61
C14H19BiN16S4
748.67
triclinic
C27H15BiBr3N3S6
1022.49
triclinic
monoclinic
11.2611(3)
15.0043(5)
19.4828(6)
90.00
93.387(3)
90.00
3826.16(17)
123(2)
monoclinic
10.420(3)
10.781(4)
17.833(8)
90.00
91.849(7)
90.00
2002.3(13)
173 (2)
P21/c
11.8411(7)
12.4586(5)
20.2080(10)
89.050(4)
83.516(4)
63.576(5)
2650.7(2)
173(2)
10.262(2)
12.642(3)
13.497(3)
69.50(3)
85.78(3)
68.71(3)
1525.2(5)
173(2)
g [8]
V [ꢂ3]
T [K]
space group
¯
P1
¯
P1
P21/c
Z
4
4
4
2
reflns measured
independent reflns
Rint
final R1 values [I>2s(I)]
final wR(F2) values [I>2s(I)]
final R1 values (all data)
final wR(F2) values (all data)
33989
10546
0.0450
0.0375
0.0554
0.0594
0.0633
38549
3434
0.0994
0.0290
0.0691
0.0295
0.0695
28435
16815
0.0363
0.0654
0.0596
0.0742
0.1566
32758
8639
0.0467
0.1211
0.0564
0.1364
0.1800
served. Complex 2 has significantly different Bi-S-C angles;
three obtuse angles (104.38(15), 102.04(14) and 103.49(14)8)
lying close to the expected bond angle of around 1098 seen in
other similar Bi-S-C bonded complexes;[48] while one is more
acute in nature (95.93(14)8) lying close to the Bi-S-C angles
found in both complexes 3 and 4 (Bi-S-C average 93.508). On
searching the literature and the Cambridge Crystallographic
Database (CCDB), 2 can best be compared to the recently re-
ported BiIII tetrazole complex [(o,o-C6H3(CH2NMe2)2Bi(SAr)2][40]
(in which Ar=1-phenyltetrazol-5-yl) which contains slightly
elongated BiꢀS covalent bonds (Bi(1)ꢀS(1), 2.796(2); Bi(1)-S(2),
2.784(2) ꢂ), compared to complex 2, due to additional intermo-
lecular N donor coordination.
Figure 4. Molecular structure of [Bi2(5-MMTD)4] (8) with thermal ellipsoids
1
shown at 50% probability. Hydrogen atoms have been omitted for clarity.
Selected bond lengths (ꢂ) and angles (8): Bi(1)ꢀC(7), 2.260(5); Bi(1)ꢀS(1),
2.6520(11); Bi(1)ꢀS(3), 2.6323(11); Bi(1)ꢀN(7), 3.087(3); Bi(1)ꢀN(1), 2.865(3);
Bi(1)ꢀN(3), 2.959(4); Bi(2)ꢀC(19), 2.239(5); Bi(2)ꢀS(5), 2.6571(11), Bi(2)ꢀS(7),
2.6181(11); Bi(2)ꢀN(5), 3.059(4); Bi(2)ꢀN(8), 2.882(4); S(3)-Bi(1)-S(1), 76.69(4);
C(7)-Bi(1)-S(1), 92.82(12); C(7)-Bi(1)-S(3), 91.36(11); C(7)-Bi(1)-N(7), 83.76(13);
S(3)-Bi(1)-N(3), 56.92(7); S(1)-Bi(1)-N(1), 57.73(7); N(1)-Bi(1)-N(3), 166.25(10);
S(5)-Bi(2)-S(7), 76.66(3); C(19)-Bi(2)-S(5), 95.08(110); C(19)-Bi(2)-S(7), 93.82(10);
S(5)-Bi(2)-N(5), 55.29(7); S(7)-Bi(2)-N(8), 57.87(7); N(5)-Bi(2)-N(8), 164.91(10).
The asymmetric unit of complex 8 is shown in Figure 4 and
reveals a dimeric system in which two [BiPh(5-MMTD)2] units
combine through relatively short intermolecular BiꢀN bonds.
Each BiIII centre adopts a distorted pentagonal bipyramidal ge-
ometry composed of two deprotonated thiadiazole ligands
and one phenyl group. The thiadiazole ligands chelate to the
BiIII centres by means of short BiꢀS bonds (average 2.64 ꢂ),
while the BiꢀN bonds form an asymmetric coordination with
one short (Bi(1)ꢀN(1), 2.865(3); Bi(2)ꢀN(8), 2.882(4) ꢂ) and one
long bond (Bi(1)ꢀN(3), 2.959(4); Bi(2)ꢀN(5), 3.059(4) ꢂ), high-
lighting the thiophilicity of the BiIII centres. Dimerisation of this
unit raises the coordination number of the two BiIII centres to
Switching to 1,3,4-thiadiazole-2-dithiol 2,5-DMTD(H)2, crystal-
lisation from acetone solution reveals formation of the depro-
tonated complex 9 (Figure 6). Polymeric 9 contains a C2 axis
six through the formation of longer dative BiꢀN bonds (Bi(1)ꢀ along C(4), C(1) and Bi(1) adopting an overall distorted square-
N(7), 3.087(3); Bi(2)ꢀN(4), 3.044(3) ꢂ) to form an almost planar
(ꢁ0.11 ꢂ) central six-atom Bi2N4 ring. Finally the dimer poly-
merises through a series of long electrostatic interactions; Bi(2)
interacts with the delocalised electron density around the diaz-
ole moiety, centered on N(7) (Bi(2)ꢀN(7)’, 3.551(4); Bi(2)ꢀN(8)’,
3.640(4); Bi(2)ꢀC(17)’, 3.614(5) ꢂ), while Bi(1) connects with
S(3)’ (3.865(14) ꢂ) and S(5)’ (3.8160(12) ꢂ) to form a final zigzag
polymeric chain (Figure 5).
pyramidal geometry reminiscent of the BiIII thiolate complexes
3 and 4 recently reported by our research group.[41]
In the asymmetric unit (Figure 6) the BiIII atom is three coor-
dinate, bonded to two dithiolate ligands, through short BiꢀS
bonds (Bi(1)ꢀS(1), 2.8690(14); Bi(1)ꢀS(4), 2.7284(14) ꢂ), and one
phenyl group (Bi(1)ꢀC(1), 2.239(5) ꢂ). The two monodeproto-
nated 2,5-DMTD(H) ligands have hydrogen atoms located on
N(2) and N(4), which were located by residual density in the
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Figure 5. Extended zigzag chain arrangement of 8 with selected atom labelling. Hydrogen atoms have been omitted for clarity. Symmetry operator ’: 1ꢀx,
1ꢀy, ꢀz. Selected bond lengths (ꢂ): Bi(1)ꢀS(3)’ 3.865(14); Bi(1)ꢀS(5)’, 3.8160(12); Bi(2)ꢀN(7)’, 3.551(4); Bi(2)ꢀN(8)’, 3.640(4); Bi(2)ꢀC(17)’, 3.614(5).
Figure 7. Thiol–thione tautomerisation of the monoanionic 2,5-DMTD(H)
ligand.
systems are orthogonal, twisted by 56.56(13)8 with the H(7)
atom preferring to hydrogen bond to a molecule of acetone
(H(7)ꢀO(1), 1.91(3) ꢂ) rather than its neighbouring ligand.
The complex then extends into a polymeric zigzag chain
(Figure 8) through the second thiol (thione) group of the 2,5-
DMTD(H) ligand making the overall coordination number of
the central BiIII atom five. The BiꢀS bonds that propagate the
polymeric
chain
(Bi(1)’ꢀS(3),
3.0407(15);
Bi(1)’ꢀS(6),
Figure 6. Asymmetric unit of [BiPh{2,5-DMTD(H)}-k-S(Me2C=O)] (9) with
1
2.9146(15) ꢂ) are significantly longer than those in the asym-
metric unit being more indicative of a coordinative dative BiꢀS
bond length (approximately 3.0 ꢂ)[49] supporting the presence
of the thione form of the ligand.
thermal ellipsoids shown at 50% probability. Hydrogen atoms (except NH)
have been omitted for clarity. Selected bond lengths (ꢂ) and angles (8):
Bi(1)ꢀS(1), 2.6890(14), Bi(1)ꢀS(4), 2.7284(14); Bi(1)ꢀC(1), 2.239(5); H(7)ꢀO(1),
1.91(3); C(1)-Bi(1)-S(1), 88.01(13); C(1)-Bi(1)-S(4), 88.17(13); Bi(1)-S(1)-C(7),
98.10(17); Bi(1)-S(4)-C(9), 93.34(17).
Finally the only trisubstituted bismuth(III) complex amenable
to X-ray diffraction studies was 15, which gave orange crystals
from DMSO. The asymmetric unit, seen in Figure 9, is com-
posed of three chelating 4-BrMTD ligands bonded covalently
to the BiIII atom through the deprotonated thiol group and da-
tively through the N atom in the thiazole ring. The BiꢀS bonds
(Bi(1)ꢀS(1), 2.5930(18); Bi(1)ꢀS(3), 2.6041(16); Bi(1)ꢀS(5),
2.6133(13) ꢂ) lie in the typical covalent bond range Scov(Bi, S)=
2.54,[50] while the intramolecular coordinative (dative) BiꢀN
bonds show three significantly different lengths; short (Bi(1)ꢀ
N(3), 2.776(4) ꢂ), medium (Bi(1)ꢀN(1), 2.828(4) ꢂ) and long
(Bi(1)ꢀN(2), 3.028(5) ꢂ). The asymmetric unit has a six-coordi-
nate BiIII centre, which owing to the small bite angles of the
electron difference maps and placed in calculated positions.
This suggests a 1,2 hydride shift of the deprotonated ligand to
form the thione complex (Figure 7) once monodeprotonated
by BiIII. The long (S(1)ꢀC(7), 1.732(5); S(4)ꢀC(9); 1.729(5) ꢂ) and
short (S(3)ꢀC(8), 1.679(5); S(6)ꢀC(10), 1.683(5) ꢂ) SꢀC bond
lengths in 2 support the tautomerisation to the thione form
once deprotonated.
Unlike in complexes 3 and 4, in which hydrogen bonding
aligns the triazole–thione and imidazole–thione ligands to be
almost co-planar with each other,[41] in 9 the 2,5-DMTD(H) rings
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common hexagonal geometry.
However, dimerisation of two
monomeric units through a long
electrostatic interaction with the
deprotonated thiol group (Bi(1)ꢀ
S(5)’, 3.2208(18) ꢂ; Figure 10), in-
creases the coordination of the
BiIII centre to seven, giving an
overall distorted pentagonal pyr-
amidal coordination geometry
and formation of
a
central
planar four-membered Bi2S2 ring.
Complex 10 can best be com-
pared to the recently reported
BiIII methylthiazole complex [(o,o-
C6H3(CH2NMe2)2Bi(SAr)2][40]
which Ar=4-methylthiazol),
(in
which has a significantly longer
BiꢀS bond length of 2.8017(11) ꢂ
compared to complex 10 (aver-
age
BiꢀS
bong
length=
2.6034 ꢂ) due to internal coordi-
nation of two N donor arms on
the ligand.
Figure 8. Extended zigzag chain arrangement of [BiPh{2,5-DMTD(H)}-k-S(Me2C=O)] (9). Symmetry operator ’: ꢀx,
1
1
1= +y, = ꢀz. Additional selected bond lengths (ꢂ) and angles (8): Bi(1)ꢀS(3)’, 3.0407(15); Bi(1)ꢀS(6)’ 2.9146(15);
2
2
C(1)-Bi(1)-S(3)’, 82.69(13); C(1)-Bi(1)-S(6)’, 81.61(13); Bi(1)-S(3)’-C(8)’, 106.77(18); Bi(1)-S(6)’-C(10)’, 95.72(17).
Figure 9. Asymmetric unit of [Bi(4-BrMTD)3]2 (15) with thermal ellipsoids
shown at 50% probability. Hydrogen atoms (except CꢀH ones) have been
omitted for clarity. Selected bond lengths (ꢂ) and angles (8): Bi(1)ꢀS(1),
Figure 10. Dimer formation for [Bi(4-BrMTD)3]2 (15). Symmetry operator ’:
ꢀx, 1ꢀy, 1ꢀz. Bi(1)ꢀS(5)’ bond length 3.2206(18).
2.5930(18); Bi(1)ꢀS(3), 2.6041(16); Bi(1)ꢀS(5), 2.6133(13); Bi(1)ꢀN(1), 2.828(4);
Bi(1)ꢀN(2), 3.028(5); Bi(1)ꢀN(3), 2.776(4); S(1)-Bi(1)-N(1), 59.12(9); S(1)-Bi(1)-
N(2), 124.24(9); S(1)-Bi(1)-S(3), 86.54(5); S(1)-Bi(1)-N(3), 140.35(9); S(1)-Bi(1)-
S(5), 81.14(5); N(1)-Bi(1)-N(2), 87.05(13); N(1)-Bi(1)-S(3), 102.26(10); N(1)-Bi(1)-
N(3), 159.90(11); N(1)-Bi(1)-S(5), 137.46(10); N(2)-Bi(1)-S(3), 56.77(9); N(2)-
Bi(1)-N(3), 82.64(12); N(2)-Bi(1)-S(5), 131.24(9); S(3)-Bi(1)-N(3), 86.44(10); S(3)-
Bi(1)-S(5), 88.83(5); N(3)-Bi(1)-S(5), 59.74(9).
Anti-bacterial activity
The in vitro antibacterial activity of all the homo- and hetero-
leptic bismuth(III) compounds, including the previously de-
scribed complexes [BiPh(4-MTT)2{4-MTT(H)}2], [BiPh(2-MMI)2{2-
MMI(H)}2] and [BiPh(4-MTT)2], was assessed against six different
strains of bacteria; M. smegmatis, S. aureus, MRSA, VRE, E. coli
and E. faecalis. For comparison the activity of the five heterocy-
chelating N and S atoms of the 4-(4-bromophenyl)thiazole-2-
thiol ligand (S-Bi-N: 59.74(9), 59.12(9) and 56.77(9)8) has no
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clic thiols and BiPh3 was also assessed. The solvent used for
the preparation of sample solution of required concentration
was DMSO. Isoniazid (isonicotinohydrazide), a first-line drug for
the treatment of tuberculosis, was used as a control.
on the bactericidal activity. This enhancement of biological ac-
tivity following ligand substitution has also been demonstrated
for phenylbismuth sulfonates[51] and thioamides,[38] reflecting
the observed low toxicity of BiPh3.
The in vitro activity of the bismuth(III) thiolate complexes,
free thiols (thiones), and Isoniazid were initially compared
using drug-diffusion assays in which filter-paper discs contain-
ing the drug were placed onto the surface of agar plates
spread with the bacterial culture. Following incubation over-
night, the presence of a zone of inhibition of bacterial growth
around the disc indicated some level of antibacterial activity.
Compounds that were positive in this initial screen were then
used in minimum inhibitory concentration (MIC) assays to
quantify their level of antibacterial activity. The MICs are ex-
pressed as mgmLꢀ1 (and calculated as mm), as the minimal con-
centration of the drug that still completely inhibited bacterial
growth in culture. The results are summarised in Table 4. The
activities of the compounds against each individual bacterium
are provided as Supplementary Information.
The five coordinate dithiolato dithione complexes [BiPh(4-
MTT)2{4-MTT(H)}2] and [BiPh(1-MMTZ)2{1-MMTZ(H)}2] complexes
show by far the greatest activities against all bacteria tested
with MIC values as low as 0.25 mgmLꢀ1 (0.34 mm) for [BiPh(4-
MTT)2{4-MTT(H)}2] against VRE and of 1.0 mgmLꢀ1 (1.33 mm) for
[BiPh(1-MMTZ)2{1-MMTZ(H)}2] against M. smegmatis and S.
aureus. The simple structural feature, extrapolated from the
solid-state X-ray study, which may explain this is that these
five-coordinate complexes are all monomeric, whereas the
others are either oligomers or polymers. Of key importance is
that fact that these complexes, with such a specific composi-
tion and structure, are only accessible thus far through reduc-
tion of the BiV tetrathiolato complexes, for example, [BiPh(1-
MMTZ)4].[40]
That the dithiolato complexes are in general more active
than their trithiolato counterparts appears to support the as-
sertion of Kotani[52] that lipophilicity of bismuth complexes is
of key importance in their antibacterial action. The clogP
values (see Supporting Information) for the dithiolato com-
plexes are mostly, but not in every case, higher (range 0.79 for
2 to 7.67 for 8) than the related trithiolato complexes (range
ꢀ1.5 for 10 to 8.82 for 11). The most active monomeric dithio-
lato dithione complexes have the largest clogP values for their
family of complexes containing a particular ligand; 2.12 for
[BiPh(4-MTT)2{4-MTT(H)}2] (cf. 0.79 for [BiPh(4-MTT)2]), 6.31 for
[BiPh(1-MMTZ)2{1-MMTZ(H)}2] (cf. 2.93 for [BiPh(2-MMI)2]) and
3.89 for BiPh(1-MMTZ)2{1-MMTZ(H)}2] (cf. 2.54 for [BiPh(1-
MMTZ)2]). That clogP values may also be a poor predictor of in-
General observations
The experiments show that the thiones (thiols) and BiPh3 are
relatively poor anti-microbial agents and displayed no bacteri-
cidal activity at the maximum concentration measured
(100 mgmLꢀ1). The comparison, shown in Table 4, of the inhibi-
tory activities of the various bismuth(III) thiolate complexes
demonstrates some marked differences based on ligand type
and substitution pattern, with the monophenylbismuth(III)
complexes being generally more potent than the
trithiolatobismuth(III) complexes. Thus, replacement of two Ph
ligands on BiPh3 by two thiolate ligands has a profound effect
Table 4. Anti-bacterial activities of monophenylbismuth(III) thiolate complexes and trithiolato bismuth(III) complexes, free thiols and Isoniazid against M.
smegmatis, S. aureus, MRSA, VRE, E. faecalis and E. coli.
MIC [mgmLꢀ1] ([mm])
M. smegmatis
S. aureus
MRSA
VRE
E. faecalis
E. coli
isoniazid
1 (7.29)
100 (729.18)
100 (729.19)
100 (729.19)
100 (729.19)
100 (729.19)
4-MTT(H)
2-MMI(H)
1-MMTZ(H)
5-MMTD(H)
2,5-DMTD(H)2
BrMBT(H)
>100
>100
>100
>100
>100
>100
[BiPh(4-MTT)2{4-MTT(H)}2]
[BiPh(2-MMI)2{2-MMI(H)}2]
[BiPh(1-MMTZ)2{1-MMTZ(H)}2] (2)
[BiPh(1-MMTZ)2] (5)
[BiPh(4-MTT)2] (6)
[BiPh(2-MMI)2] (7)
0.5 (0.67)
10 (13.50)
1.0 (1.33)
2.5 (4.84)
10 (19.44)
10 (19.51)
2.5 (4.56)
20 (34.21)
20 (24.25)
5.0 (9.01)
5.0 (9.07)
20 (36.47)
100 (165.56)
40 (39.14)
100 (152.44)
2.5 (3.4)
100 (134.50)
1.0 (1.33)
5.0 (9.68)
5.0 (9.72)
100 (190.51)
10 (18.23)
100 (171.07)
1.0 (1.21)
100 (180.37)
10 (18.13)
100 (182.33)
40 (66.23)
10 (9.78)
5.0 (0.67)
100 (134.50)
2.5 (3.34)
5.0 (9.68)
5.0 (9.72)
100 (190.51)
100 (180.23)
100 (171.07)
5.0 (6.06)
100 (180.37)
100 (180.13)
100 (182.33)
40 (66.23)
100 (90.78)
40 (60.98)
0.25 (0.34)
100 (134.50)
2.5 (3.34)
5.0 (6.70)
10 (13.50)
2.0 (2.67)
2.5 (4.84)
5.0 (9.72)
10 (13.40)
100 (134.50)
10 (10.33)
10 (19.36)
10 (19.44)
100 (190.51)
20 (36.46)
100 (171.07)
40 48.52
100 (180.37)
100 (180.13)
100 (182.33)
100 (165.56)
40 (39.14)
2.5 (4.84)
10 (19.44)
100 (190.51)
100 (180.23
100 (171.07)
5.0 (6.06)
100 (180.37)
100 (180.13)
100 (182.33)
40 (66.23)
40 (39.14)
40 (60.98)
5.0 (19.51)
1.5 (2.73)
[BiPh(5-MMTD)2] (8)
1
[BiPh{2,5-DMTD(H)}2] (9)
100 (171.07)
20 (24.25)
40 (72.15)
10 (18.13)
100 (182.33)
100 (165.56)
40 (39.14)
100 (152.44)
1
[BiPh(4-BrMTD)2] (10)
[Bi(1-MMTZ)3] (11)
[Bi(4-MTT)3] (12)
[Bi(2-MMI)3] (13)
[Bi(5-MMTD)3] (14)
[Bi(4-BrMTD)3] (15)
[Bi{2,5-DMTD(H)}3] (16)
40 (60.98)
100 (152.44)
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hibitory activity is seen in those complexes containing the 2-
MMI ligand, which apart from M. smegmatis provide the lowest
activities of all complexes across all other bacteria studied.
The bismuth complexes demonstrate a better range of anti-
microbial activities against the gram positive bacteria than
against the single gram negative bacterium tested (E. coli). This
observation again supports earlier studies by Kotani[52] and Do-
menico[53] on cyclic organobismuth(III) compounds and
bismuth(III) thiol chelators respectively. Gram-negative bacteria
possess a double membrane that forms a permeability barrier
restricting the penetration of some antimicrobial agents and
not allowing the multi-drug resistance pumps to extrude
toxins across this barrier.[54] Difficulty in permeating the outer
membrane has been touted as the reason for the low activity
of bismuth(III) thiolates against E. coli.[8]
10 mgmLꢀ1. The activity of the bismuth(III) complexes against
a range of bacteria, including drug resistant strains, combined
with their low host cell toxicity strongly suggests that they are
worthy of further investigation and development as antimicro-
bial agents. This is particularly significant given the continuing
appearance of drug resistance in bacteria of medical
importance.
Conclusion
Heteroleptic monophenylbismuth thiolato complexes derived
from N-heterocyclic thiones (thiols) have been prepared
through either protolysis with BiPh3 or more efficiently using
salt metathesis with BiPhCl2 and the sodium thiolates. The rare
BiV complex, [BiPh(1-MMTZ)4], is formed with 1-methyl-1H-tet-
razole-5-thiol, being only the third example of a bismuth(V) thi-
olato complex, and follows similar recent results with 4-
methyl-4H-1,2,4-triazole-3-thiole, 4-MTT(H), and 1-methyl-1H-
imidazole-2-thiol, 2-MMI(H). This complex undergoes slow hy-
drolytic reduction in DMSO to give the BiIII complex [BiPh(1-
MMTZ)2{(1-MMTZ(H)}2]. Almost all other thiones studied on
treatment with BiPh3 produce the BiIII thiolato complexes
[BiPh(SR)2], irrespective of the stoichiometries used. The excep-
tion is 4-(4-bromophenyl)thiazole-2-thiol, which always gave
a mixture of substituted products. Using microwave heating
over standard reflux conditions delivers overall better yields in
a fraction of the time. In contrast, the salt metathesis route
gives access to all the monophenylbismuth(III) thiolato deriva-
tives of all the thiones efficiently and in good yield. Crystals of
three complexes were obtained; [BiPh(1-MMTZ)2{1-MMTZ(H)}2]
and [BiPh(5-MMTD)2] from DMSO and [BiPh{2,5-DMTD(H)}2-
(Me2C=O)] from acetone, allowing their solid-state structures
to be determined by single-crystal X-ray diffraction. [BiPh(1-
MMTZ)2{1-MMTZ(H)}2] derives from the BiV parent complex and
retains a distorted square pyramidal geometry with close hy-
drogen-bonding between the ligands. [BiPh(5-MMTD)2]1
adopts distorted pentagonal bipyramidal geometry at the BiIII
centre as it extends out into a polymer through long intramo-
lecular BiꢀN and BiꢀS bonds. Intramolecular BiꢀS bonds also
establish a distorted square pyramidal geometry at the BiIII
M. smegmatis, a relatively fast-growing and non-pathogenic
mycobacterium, is frequently used as a model for M. tuberculo-
sis.[55] The best performing complexes, with exceptional activi-
ties of ꢂ5.0 mgmLꢀ1, are those based on the triazole 4-MTT
ligand; [BiPh(4-MTT)2{4-MTT(H)}2] 0.5 mgmLꢀ1 (0.67 mm), [Bi(4-
MTT)3] 5.0 mgmLꢀ1 (9.07 mm), and on the tetrazole 1-MMTZ
ligand; [BiPh(1-MMTZ)2{1-MMTZ(H)}2] 1.0 mgmLꢀ1 (1.33 mm),
[BiPh(1-MMTZ)2] 1.0 mgmLꢀ1 (4.84 mm) and [Bi(1-MMTZ)3]
5.0 mgmLꢀ1 (9.01 mm).
In fact, this pattern is carried through into the level of activi-
ties observed against the other bacteria; S. aureus, MRSA, VRE,
E. faecalis and E. coli. The monophenylbismuth(III) dithiolate
derivatives, and in particular the monomeric dithione-contain-
ing complexes of the 1-MMTZ and 4-MTT ligands, invariably
provide the lowest MIC values. With the sole exception of an
MIC of 10 mgmLꢀ1 for [BiPh(4-MTT)2] against VRE, the MIC
values are all ꢂ5.0 mgmLꢀ1. Outside of these tetrazole and tria-
zole based ligands the best inhibitory activity is observed with
the monophenyl complex [BiP(4-BrMTD)2], which contains the
anionic thiazole-based ligand 4-BrMTD; MIC 1.0 mgmLꢀ1
(1.21 mm) for S. aureus, and 5.0 mgmLꢀ1 (6.06 mm) for MRSA and
VRE. It is less active against E. faecalis (20.0 mgmLꢀ1) and E. coli
(40 mgmLꢀ1). For comparison, observed MIC values for vanco-
mycin towards MRSA are in the range 1–2 mgmLꢀ1 [56]
.
The trithiolato bismuth(III), [Bi(SR)3], complexes rarely gave
MIC values below 40 mgmLꢀ1 and regularly showed inhibitory
concentrations of 100 mgmLꢀ1. Again, the exceptions were for
4-MTT and 1-MMTZ complexes against M. smegmatis with MIC
values of 5.0 mgmLꢀ1 (9.07 and 9.01 mm, respectively), and for
4-MTT and 4-BrMTD complexes against S. aureus with MIC
values of 10 mgmLꢀ1 (18.13 and 9.78 mm, respectively).
centre in polymeric [BiPh{2,5-DMTD(H)}2(Me2C=O)] . The ace-
1
tone molecules engage in hydrogen-bonding with the ligands
rather than with the metal centres.
The homoleptic trithiolato BiIII, [Bi(SR)3], complexes are not
accessible through reaction with BiPh3. Instead a good yields
and clean products from the thiones are obtained using a salt
metathesis route with BiCl3 and an acid-base route with Bi-
(OtBu)3. The only exception was to this was complex 16 [Bi{2,5-
DMTD(H)}3], which could only be obtained with high purity
through the reaction with Bi(OtBu)3. In general better yields are
obtained using the butoxide rather than the chloride. Crystals
of [{Bi(4-BrMTD)3}2] were obtained from DMSO, providing a rare
solid-state structure of a homoleptic bismuth(III) thiolate. All
three ligands chelate to the BiIII centre and with a longer intra-
molecular BiꢀS bond included the metal attains a coordination
number of seven with a distorted pentagonal pyramidal geom-
etry. Overall the synthetic methods describe herein provide for
Cytotoxicity studies towards mammalian cells (COS-7)
Although a strong anti-bacterial activity is essential for poten-
tial new therapeutic agents, the compound must have low tox-
icity towards human or animal cells. Toxicity assays of these
complexes performed against cultured COS-7 cell lines re-
vealed that the complexes were largely non-toxic to mammali-
an cells at 20 mgmLꢀ1 providing a good therapeutic index rela-
tive to the best performing bismuth(III) complexes. The single
exception was [BiPh(4-MTT)2], which killed 25% of cells at
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trode was used, potentials were calibrated versus ferrocene by the
addition of 1.0 mm ferrocene. XRD spectra were collected on a Phi-
lips PW1140 diffractometer from 2–608 (2q) at 48minꢀ1 with a step
size of 0.028 using a CuKa source (l=1.54 nm). A 18 divergence slit,
18 receiving slit and 0.28 scatter aperture were used. Samples were
prepared by bulk electrolysis on Indium tin oxide slides.
the clean and efficient preparation of stable and biologically
relevant bismuth thiolates from N-heterocyclic thiones.
The anti-bacterial activities of the BiIII thiolato complexes
against M. smegmatis, S. aureus, MRSA, VRE, E. faecalis and E.
coli showed that those containing the anionic ligands 1-
MMTZ, 4-MTT and 4-BrMTD are the most effective, with the
monophenyl dithiolato complexes giving MIC values of
ꢂ5.0 mgmLꢀ1. In particular, the five-coordinate dithiolato di-
thione complexes [BiPh(4-MTT)2{4-MTT(H)}2] and [BiPh(1-
MMTZ)2{1-MMTZ(H)}2] proved to be most effective against the
range of bacteria, with MIC values as low as 0.25 mgmLꢀ1
(0.34 mm) for [BiPh(4-MTT)2{4-MTT(H)}2] against VRE and of
1.0 mgmLꢀ1 (1.33 mm) for [BiPh(1-MMTZ)2{1-MMTZ(H)}2] against
M. smegmatis and S. aureus. The trithiolato BiIII complexes were
least effective overall. All complexes showed little or no toxicity
towards mammalian COS-7 cells at 20 mgmLꢀ1.
Crystallographic data
Crystallographic data of compounds 9 and 15 were collected at
the MX1 beamline at the Australian Synchrotron, Melbourne, Victo-
ria (Australia) with the wavelength set at 0.7107 ꢂ (17.4 keV) using
an open flow of N2 cryostream. The software used for data collec-
tion and reduction of the data were BluIce[58] and XDS.[59] Crystallo-
graphic data for compounds 2 and 8 were obtained on an
OXFORD Gemini Ultra equipped with an OXFORD Cryosystems 700
Cryostream and cooled to 123(1) K. Data was collected with mono-
chromatic (graphite) MoKa radiation (l=0.71073 ꢂ) and processed
using the CrysAlisProv 1.171.34.36[60] software; Lorentz, polarization
and absorption corrections (multi-scan) were applied. The struc-
tures were solved and refined with SHELX-97.[61] All non-hydrogen
atoms were refined with anisotropic thermal parameters unless
otherwise indicated and hydrogen atoms were placed in calculated
Experimental Section
BiPh3 was synthesised through a standard Grignard metathesis re-
action from the treatment of BiCl3 with MgPhBr in dried diethyl
ether at 08C, and subsequently recrystallised from ethanol. Ph2BiCl
was synthesised by mixing BiPh3 and BiCl3 in a 2:1 ratio in dried di-
ethyl ether, and Bi(OtBu)3 was synthesised according to literature
procedures.[57] Ethanol, DMSO and toluene were used as solvents
for recrystallization. Diethyl ether and THF were dried prior to use
by M-Braun-SPS-800 solvent purification system and molecular
sieves (4 ꢂ) were used to store. All moisture sensitive reactions
were conducted with oven dried glassware under an atmosphere
of dry nitrogen using a vacuum/nitrogen line and Schlenk tech-
niques. The heterocyclic compounds were purchased from Sigma–
Aldrich and used as supplied. Microwave irradiation was carried
out in a CEM Discoverer Microwave oven with maximum power 0–
300W, model number 9080, maximum current 6.38 A with 50/
60 MHz frequency. NMR spectra of complexes were recorded on
a Brucker DPX 400 spectrometer in [D6]DMSO with TMS as internal
standard at room temperature. Elemental analysis (C, H and N)
were performed by the Campbell Microanalytical lab, department
of chemistry, University of Otago, Dunedin, New Zealand. Melting
points were determined on a Stuart Scientific SMP3 melting point
apparatus. Mass spectra were recorded on a micromass platform
electrospray mass spectrometer.
positions using
a
riding model with CꢀH=0.95–0.98 ꢂ and
Uiso(H)=xUiso(C), x=1.2 or 1.5 unless otherwise indicated. CCDC-
1007779 (9), CCDC-1007780 (2), CCDC-1007781 (8) and CCDC-
1007782 (15) contain the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif
Antimicrobial activity
Mycobacterium smegmatis was cultured in Middlebrook 7H9/7H10
medium (Difco) for 3 days at 378C. Escherichia coli was cultured
overnight at 378C in LB (Luria-Bertani) medium. Staphylococcus
aureus, MRSA (methicillin-resistant S. aureus), Enterococcus faecalis
and VRE (vancomycin-resistant E. faecalis) were cultured in BHI
(brain heart infusion) medium (Oxoid) overnight at 378C.
In initial activity screens, filter paper discs were soaked with 2 mL of
5 mgmLꢀ1 compound, then placed on the surface of agar plates
that had been pre-spread with a culture of the bacterial strain of
interest. Following incubation, the plates were examined for the
presence of zones of inhibition of bacterial growth around the
discs. Compounds that were negative in this assay were not exam-
ined further, while minimum inhibitory concentration (MIC) assays
were performed for all positive compounds.
All voltammetric experiments were carried out at (25ꢁ2)8C on Po-
tentiostat BAS 100W electrochemical workstation using a three
electrode electrochemical cell configuration. The glassy carbon
(GC) disc electrode (d=1.0 mm) for cyclic voltammetry was polish-
ed consecutively with 0.05 mm and 0.3 mm alumina (Buehler, Lake
Bluff, IL) on a clean polishing cloth then rinsed with water, sonicat-
ed for 20 s and again rinsed with water and dried under nitrogen.
For steady-state studies, a glassy carbon microelectrode (d=
11 mm) was polished with 0.05 mm alumina in the similar way.
Indium tin oxide slides (ITO) were used as working electrode
during bulk electrolysis of tetrathiolatobismuth(V) complex to de-
posit bismuth metal. ITO was cleaned by sonicating in isopropanol
for 15–25 min. A platinum wire was used as the quasi-reference
electrode and another platinum wire was used as the auxiliary
electrode.
To determine MICs, liquid cultures of bacteria were prepared con-
taining serial dilutions of the compounds, from 80 mgmLꢀ1 to
0.25 mgmLꢀ1. After incubation, the cultures were examined to de-
termine the minimum concentration of compound that caused
total inhibition of growth; this value was recorded as the MIC. The
anti-mycobacterial drugs isoniazid and ethambutol was included
as controls.
Cell toxicity assays
Toxicities against eukaryotic cells were assayed using the in vitro
toxicology assay kit MTT-based (Sigma–Aldrich; cat. no. TOX1–
1 KT), according to the manufacturer’s instructions. Compounds
were added to cultured COS-7 (monkey kidney-derived) cells at 10
and 20 mgmLꢀ1 for 1 h prior to addition of the tetrazolium dye
MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide)
reagent. OD690 measurements were expressed as a percentage the
Electrochemical behaviour of a 1 mm solution of [BiPh(1-MMTZ)4]
(1) and 1-methyl-1H-tetrazole-5-thiol 1-MMTZ(H) was studied in
DMSO containing 0.1m tetrabutylammoniumhexaflurophosphate
(Bu4NPF6) as the supporting electrolyte. As quasi-reference elec-
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DMSO-only negative controls. All assays were performed in tripli-
cate. Isoniazid and ethambutol-treated COS-7 cells were included
as controls.
(20 mL). The resultant yellow brown solution was cooled below
08C before the addition of phenyl bismuth dichloride (0.33 g,
0.92 mmol). The reaction mixture was stirred for 7 h and resultant
yellow precipitate was filtered and washed with methanol and eth-
1
anol. Yield: 0.20 g (77%); m.p. 1788C (decomp); H NMR (400 MHz,
[D6]DMSO, 308C): d=8.22 (d, J=9.0 Hz, 2H; o-Ph), 7.54 (t, J=
7.0 Hz, 2H; m-Ph), 7.33 (t, 1H; p-Ph), 6.99 (s, 2H; imidazole CH),
6.71 (s, 2H; imidazole CH), 3.44 ppm (s 6H; imidazole CH3).
13C NMR (100 MHz, [D6]DMSO): d=137.7 (o-Ph), 130.9 (m-Ph), 127.3
(p-Ph), 33.5 ppm (imidazole CH3); FT-IR: n˜ =1653 (m), 1525 (m),
1467 (s), 1389 (s), 1309 (s), 1197 (m), 830 (s), 742 (s), 691 (s),
639 cmꢀ1 (m); ESI-MS+ (solvent: DMSO/MeOH, 35 eV): m/z (%): 610
(15) [BiPhL2(DMSO)(H2O)+H]+, 596 (60) [PhBiL2(CH3OH)2(H2O)+H]+
; elemental analysis calcd (%) for BiC14H15N4S2: C 32.82, H 2.95, N
10.93; found: C 32.61, H 3.47, N 10.55.
Synthesis and Characterisation
[BiPh(1-MMTZ)4] (1)—1:4 reaction of BiPh3 with 1-MMTZ(H)
Conventional method: A solution of triphenyl bismuth (0.22 g,
0.50 mmol) in toluene (20.0 mL) was added to a hot solution of 1-
methyl-1H-tetrazole-5-thiol (0.23 g, 2.0 mmol) in ethanol (10.0 mL)
and the reaction mixture stirred and then refluxed for 2 h. The
bright yellow product thus obtained was washed several times
with acetone and ethanol. Yield: 0.18 g (51%).
Microwave-assisted synthesis: A mixture of 1-methyl-1H-tetrazole-5-
thiol (0.12 g, 1.0 mmol) in ethanol (2.0 mL) and triphenylbismuth
(0.11 g, 0.25 mmol) in toluene (4.0 mL) was stirred and then irradi-
ated at 1008C for 4 min. The resultant bright yellow precipitate
was filtered by suction and washed with acetone. Yield: 0.10 g
[BiPh(5-MMTD)2] (8)—1:2 reaction of BiPh3 with 5-MMTD(H)
1
Conventional reflux method: Triphenyl bismuth (0.2 g, 0.45 mmol) in
toluene (20.0 mL) was added to a hot solution of 5-methyl-1,3,4-
thiadiazole-2-thiol (0.24 g, 1.80 mmol) in ethanol (10.0 mL) and the
reaction mixture was refluxed for 16 h. Excess solvent was removed
under reduced pressure. The pale yellow product thus obtained
was washed several times with acetone. Yield: 0.12 g (73%).
1
(57%); m.p. 2108C (decomp); H NMR (400 MHz, [D6]DMSO, 308C):
d=8.97 (d, J=6.0 Hz, 2H; o-Ph), 7.87 (t, 2H; m-Ph), 7.44 (t, 1H; p-
Ph), 3.76 ppm (s, 12H; tetrazole CH3); 13C NMR (100 MHz,
[D6]DMSO): d=156.2 (tetrazole CS), 139.3 (o-Ph), 132.9 (m-Ph),
127.7 (p-Ph), 33.5 ppm (tetrazole CH3); FT-IR: n˜ =1628 (s), 1472 (m),
1375 (m), 1276 (s), 1174 (s), 1035 (m), 723 (m), 701 cmꢀ1 (s); ESI-
MS+ (solvent: DMSO/MeOH, 35 eV): m/z: 826 [BiPhL4(DMSO)+H]+,
812 [BiPhL4(CH3OH)2 +H]+, 780 [BiPhL4(CH3OH)+H]+, 748 [BiPhL4 +
H]+, 653 [BiPhL3(H2O)+H]+, 613 [BiPh(O)L2(DMSO)+H]+, 533
[BiPh(O)L2 +H]+; elemental analysis calcd (%) for BiC14H17N16S4: C
22.52, H 2.29, N 30.02; found: C 22.78, H 2.59, N 30.03.
Microwave-assisted synthesis: The mixture of 5-methyl-1,3,4-thiadia-
zole-2-thiol (0.24 g, 1.80 mmol) in ethanol (2.0 mL) and triphenyl
bismuth (0.2 g, 0.45 mmol) in toluene (4 mL) was irradiated at
112 8C for 15 min. The resultant pale yellow precipitate was filtered
and washed with diethyl ether in order to remove unreacted mate-
rials. Yield: 0.14 g (84%).
[BiPh(5-MMTD)2] (8)—1:2 reaction of BiPhCl2 with [Na(5-
1
MMTD)]
[BiPh(1-MMTZ)2{1-MTTZ(H)}2] (2): Complex 1 (0.20 g, 0.27 mmol)
was dissolved in hot DMSO (2.0 mL) and deep yellow crystals of 2
suitable for single-crystal X-ray diffraction studies were obtained
All the manipulations were carried out under nitrogen atmosphere.
The sodium salt of 5-methyl-1,3,4-thiadiazole-2-thiol (0.15 g,
1 mmol) was dissolved in dry methanol (20 mL). The resultant light
yellow solution was cooled below 08C before the addition of
phenyl bismuth dichloride (0.18 g, 0.5 mmol). The reaction mixture
was stirred overnight and resultant pale yellow precipitate was fil-
tered and washed with methanol and diethyl ether. Yield: 0.20 g
(83%); m.p. 218–2208C (decomp); 1H NMR (400 MHz, [D6]DMSO,
308C): d=9.02 (d, J=8.0 Hz, 2H; o-Ph), 7.73 (t, 2H; m-Ph), 7.40 (t,
1H; p-Ph), 2.46 ppm (s, 6H; thiadiazole CH3); 13C NMR (100 MHz,
[D6]DMSO): d=137.9 (o-Ph), 131.2 (m-Ph), 127.7 (p-Ph), 15.3 ppm
(thiadiazole CH3); FT-IR: n˜ =1637 (m), 1429 (br), 1364 (s), 1037 (s),
979 (m), 727 cmꢀ1 (m); ESI-MS+ (solvent: DMSO/MeOH, 35 eV): m/z
(%): 571 (30) [BiPhL2 +Na]+, 417 (28) [BiPhL]+, 285 (100) [L2 +Na]+;
elemental analysis calcd (%) for BiC12H11N4S4: C 26.28, H 2.02, N
10.21; found: C 27.11, H 1.89, N 10.73. Single crystals of 8 were ob-
tained on recrystallization of the bulk solid form DMSO solution
over a period of eight weeks. Analysis of the crystals as [BiPh(5-
MMTD)2] was consistent with the bulk solid.
1
after eight weeks. Yield 0.09 g (49%); H NMR (400 MHz, [D6]DMSO,
308C): d=8.96 (d, J=17 Hz, 2H; o-Ph), 7.87 (t, J=10 Hz, 2H; m-
Ph), 7.46 (t, J=9 Hz, 1H; p-Ph), 3.77 ppm (s, 12H; tetrazole CH3);
13C NMR (100 MHz, [D6]DMSO): d=138.9 (o-Ph), 132.9 (m-Ph), 127.4
(p-Ph), 33.2 ppm (tetrazole CH3); FT-IR: n˜ =3045 (b), 1552 (s), 1429
(m), 1372 (s), 1280 (m), 1169 (s), 1033 (m), 733 (s), 703 cmꢀ1 (m); el-
emental analysis calcd (%) for BiC14H19N16S4: C 22.46, H 2.56, N
29.93; found: C 22.64, H 2.78, N 29.95.
[BiPh(1-MMTZ)2] (5)—1:2 reaction of BiPhCl2 with [Na(1-MMTZ)]
Salt metathesis method: All the manipulations were carried out
under nitrogen atmosphere. The sodium salt of 1-methyl-1H-tetra-
zole-5-thiol (0.2 g, 1.43 mmol) was dissolved in dry methanol
(20 mL). The resultant solution was cooled below 08C before the
addition of phenyl bismuth dichloride (0.25 g, 0.71 mmol). The re-
action mixture was stirred for 10 h and resultant light yellow pre-
cipitate was filtered and washed with methanol and diethyl ether.
Yield: 0.17 g (60%); m.p. 2598C (decomp); 1H NMR (400 MHz,
[D6]DMSO, 308C): d=9.01 (d, J=14 Hz, 2H; o-Ph), 7.90 (t, 2H; m-
Ph), 7.49 (t, J=10 Hz, 1H; p-Ph), 3.80 ppm (s, 6H; tetrazole CH3);
13C NMR (100 MHz, [D6]DMSO): d=139.4 (o-Ph), 132.9 (m-Ph), 128.1
(p-Ph), 33.4 ppm (tetrazole CH3). FT-IR: n˜ =1548 (s), 1415 (m), 1171
(s), 1027 (m), 703 cmꢀ1 (m); ESI-MS+ (solvent: DMSO/MeOH, 35 eV):
m/z (%): 575 (50) [BiPhL2(H2O)2 +Na]+, 540 (80) [BiPhL2 +Na]+, 517
(10) [BiPhL2 +H]+, 501 (40) [BiPhL(CH3OH)2(H2O)2]+; elemental anal-
ysis calcd (%) for BiC10H11N8S2: C 23.26, H 2.16, N 21.70; found: C
24.05, H 2.76, N 21.75.
[BiPh{2,5-DMTD(H)}2] (9)—1:2 reaction of BiPh3 with 2,5-
1
DMTD(H)2
Conventional method: Triphenyl bismuth (0.15 g, 0.34 mmol) in tol-
uene (20 mL) was added to a hot solution of 1,3,4-thiadiazole-2,5-
dithiol (0.1 g, 0.67 mmol) in ethanol (10 mL) and the reaction mix-
ture was refluxed for 8 h. The resulting orange precipitate was
washed with diethyl ether. Yield: 0.15 g (73%).
Microwave-assisted synthesis: The mixture of 1,3,4-thiadiazole-2,5-
dithiol (0.1 g, 0.67 mmol) in ethanol (2.0 mL) and triphenyl bismuth
(0.146 g, 0.34 mmol) in toluene (4 mL) was irradiated at 1128C for
10 min. Resultant orange precipitate was filtered and washed with
acetone and diethyl ether in order to remove unreacted materials.
[BiPh(2-MMI)2] (7)—1:2 reaction of BiPhCl2 with [Na(2-MMI)]
Salt metathesis method: All the manipulations were carried out
under nitrogen atmosphere. The sodium salt of methyl-1H-imida-
zole-2-thiol (0.25 g, 1.84 mmol) was dissolved in dry methanol
1
Yield: 0.17 g (92%); m.p. 248–2508C (decomp); H NMR (400 MHz,
Chem. Eur. J. 2014, 20, 14362 – 14377
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[D6]DMSO, 308C): d=8.84 (d, J=9.0 Hz, 2H; o-Ph), 7.87 (t, 2H; m-
Ph), 7.44 ppm (t, J=11 Hz, 1H; p-Ph); 13C NMR (100 MHz,
[D6]DMSO): d=139.5 (o-Ph), 133.5 (m-Ph), 128.3 ppm (p-Ph); FT-IR:
n˜ =1546 (m), 1467 (s), 1044 (s), 719 cmꢀ1 (m); ESI-MS+ (solvent:
DMSO/MeOH, 35 eV): m/z (%): 844 (100) [PhBi(LH)2(DMSO)2-
(CH3OH)2 +K]+, 436 (33) [BiPhLH]+, 171 (10) [LH+Na]+; elemental
analysis calcd (%) for BiC10H7N4S6: C 20.55, H 1.21, N 9.58; found: C
19.83, H 0.92, N 10.93. Single crystals of 9 were obtained on recrys-
tallization of the bulk solid form DMSO solution over a period of
ten to twelve weeks. Analysis of the crystals as [BiPh{2,5-
DMTD(H)}2] was consistent with the bulk solid.
night and resultant yellow precipitate was filtered and washed
with methanol and ethanol. Yield: 0.22 g (71%).
[Bi(4-MTT)3] (12)—1:3 reaction of [Bi(OtBu)3] with 4-MTT(H)
All the manipulations were carried out under nitrogen atmosphere.
Bismuth tert-butoxide (0.3 g, 0.72 mmol) was dissolved in dry tetra-
hydrofuran (10 mL) followed by addition of 4-methyl-4H-1,2,4-tria-
zole-3-thiol (0.25 g, 2.17 mmol) at ꢀ708C. The reaction mixture
was stirred for 7 h and resultant orange precipitate was filtered
and washed with dry diethyl ether. Yield: 0.31 g (79%); m.p. 2918C
1
(decomp); H NMR (400 MHz, [D6]DMSO, 308C): d=8.25 (s, 3H; tria-
zole CH), 3.42 ppm (s, 9H; triazole CH3); 13C NMR (100 MHz,
[D6]DMSO): d=143.9 (triazole CH), 31.1 ppm (triazole CH3); FT-IR:
n˜ =1558 (s), 1464 (m), 1200 (m), 1005 (s), 692 cmꢀ1 (m); ESI-MS+
(solvent: DMSO/MeOH, 35 eV): m/z (%): 620 (8) [BiL3(CH3OH)-
(H2O)2]+, 574 (5) [BiL3 +Na]+, 395 (100) [BiL(H2O)4]+, 283 (80) [LL-
(CH3OH)+Na]+, 227 (30) [Bi(H2O)]+, 169 (15) [L(CH3OH)+Na]+; ele-
mental analysis calcd (%) for BiC9H12N9S3: C 19.60, H 2.19, N 22.86;
found: C 20.11, H 2.59, N 23.11.
[BiPh(4-BRMTD)] (10)—1:2 reaction of BiPhCl2 with [Na(4-
BRMTD)]
All the manipulations were carried out under nitrogen atmosphere.
The sodium salt of 4-(4-bromophenyl)thiazole-2-thiol (0.16 g,
0.54 mmol) was dissolved in dry methanol (25 mL). The resultant
light yellow solution was cooled below 08C before the addition of
phenyl bismuth dichloride (0.1 g, 0.27 mmol). The reaction mixture
was stirred overnight and resultant yellow precipitate was filtered
and washed with methanol and acetone. Yield: 0.17 g (78%); m.p.
[Bi(2-MMI)3] (13)—1:3 reaction of BiCl3 with [Na(2-MMI)]
All the manipulations were carried out under nitrogen atmosphere.
The sodium salt of methyl-1H-imidazole-2-thiol (0.25 g, 1.83 mmol)
was dissolved in dry methanol (20 mL). The resultant yellow solu-
tion was cooled below 08C before the addition of bismuth chloride
(0.19 g, 0.61 mmol). The reaction mixture was stirred overnight and
resultant yellow precipitate was filtered and washed with methanol
and ethanol. Yield: 0.22 g (71%).
1
282–2848C (decomp); H NMR (400 MHz, [D6]DMSO, 308C): d=8.94
(d. J=10 Hz, 2H; o-Ph), 7.82 (t, J=10 Hz, 2H; m-Ph), 7.74 (d, J=
12 Hz, 6H; Br-Ph), 7.71 (s, 2H; thiazole CH), 7.42 (t, J=2.0 Hz, 1H;
p-Ph), 7.35 ppm (d, 4H; Br-Ph). 13C NMR (100 MHz, [D6]DMSO): d=
137.4 (o-Ph), 132.9 (Br-Ph) 131.8 (Br-Ph), 130.3 (m-Ph), 128.0 (Br-Ph),
127.5 (o-Ph), 122.4 (Br-Ph), 110.6 ppm (thiazole CH); FT-IR: n˜ =1596
(s), 1579 (m), 1474 (s), 1443 (m), 1320 w, 1273 (m), 1038 (s), 724 (s),
686 cmꢀ1 (s); ESI-MS+ (solvent: DMSO/MeOH, 35 eV): m/z (%): 851
(100) [BiPhL2 +Na]+, 830 (10) [BiPhL2 +H]+, 558 (45) [BiPhL]+; ele-
mental analysis calcd (%) for BiC24H15Br2N2S4: C 34.80, H 1.83, N
3.38; found: C 34.91, H 1.89, N 3.63.
[Bi(2-MMI)3] (13)—1:3 reaction of [Bi(OtBu)3] with 2-MMI(H)
All the manipulations were carried out under nitrogen atmosphere.
Bismuth tert-butoxide (0.14 g, 0.33 mmol) was dissolved in dry tet-
rahydrofuran (10 mL) followed by addition of methyl-1H-imidazole-
2-thiol (0.11 g, 1 mmol) at ꢀ708C. The reaction mixture was stirred
for 7 h and resultant precipitate was filtered and washed with dry
diethyl ether. Yield: 0.15 (86%); m.p. 2858C (decomp); 1H NMR
(400 MHz, [D6]DMSO, 308C): d=6.96 (d, 2H; imidazole CH), 6.79 (d,
2H; imidazole CH), 3.40 ppm (s, 9H; imidazole CH3); 13C NMR
(100 MHz, [D6]DMSO): d=119.6 (imidazole CH), 114.2 (imidazole
CH), 33.3 ppm (imidazole CH3); FT-IR: n˜ =1574 (m), 1518 (m), 1445
(s), 1359 (s), 1316 (s), 1278 (m), 1057 (br), 861 (s), 738 (s), 685 cmꢀ1
(s); ESI-MS+ (solvent: DMSO/MeOH, 35 eV): m/z (%): 571 (28)
[BiL3 +Na]+, 435 (25) [BiL2]+, 249 (100) [L2 +Na]+), 136 (80), [L+
Na]+; elemental analysis calcd (%) for BiC12H15N6S3: C 26.28, H 2.76,
N 15.32; found: C 26.44, H 2.89, N 15.43.
[Bi(1-MMTZ)3] (11)—1:3 reaction of BiCl3 with [Na(1-MMTZ)]
Salt metathesis method: All the manipulations were carried out
under nitrogen atmosphere. The sodium salt of 1-methyl-1H-tetra-
zole-5-thiol (0.25 g, 1.8 mmol) was dissolved in dry methanol
(20 mL). The resultant solution was cooled below 08C before the
addition of bismuth chloride (0.19 g, 0.60 mmol). The reaction mix-
ture was stirred overnight and resultant light yellow precipitate
was filtered and washed with methanol and diethyl ether. Yield:
0.21 g (63%).
[Bi(1-MMTZ)3] (11)—1:3 reaction of [Bi(OtBu)3] with 1-MMTZ(H)
All the manipulations were carried out under nitrogen atmosphere.
Bismuth tert-butoxide (0.31 g, 0.73 mmol) was dissolved in dry tet-
rahydrofuran (10 mL) followed by addition of 1-methyl-1H-tetra-
zole-5-thiol (0.25 g, 2.16 mmol) at ꢀ708C. The reaction mixture
was stirred for 10 h and resultant pale yellow precipitate was fil-
tered and washed with dry THF. Yield: 0.29 g (73%); m.p. 1988C
(decomp); 1H NMR (400 MHz, [D6]DMSO, 308C): d=3.90 ppm (s,
9H; tetrazole CH3); 13C NMR (100 MHz, [D6]DMSO): d=155.8 (tetra-
zole CS), 33.7 ppm (tetrazole CH3); FT-IR: n˜ =1472 (br), 1375 (s),
1276 (m), 1174 (s), 971 (m), 701 cmꢀ1 (m); ESI-MS+ (solvent: DMSO/
MeOH, 35 eV): m/z (%): 577 (20) [BiL3 +Na]+, 503 (60) [BiL2-
(CH3OH)2]+, 402 (7), [BiL(DMSO)]+; elemental analysis calcd (%) for
BiC6H9N12S3: C 13.00, H 1.64, N 30.32; found: C 13.55, H 2.13, N
30.34.
[Bi(5-MMTD)3] (14)—1:3 reaction of BiCl3 with [Na(5-MMTD)]
All the manipulations were carried out under nitrogen atmosphere.
The sodium salt of 5-methyl-1,3,4-thiadiazole-2-thiol (0.30 g,
1.9 mmol) was dissolved in dry methanol (20 mL). The resultant
light yellow solution was cooled below 08C before the addition of
bismuth chloride (0.20 g, 0.65 mmol). The reaction mixture was
stirred overnight and resultant pale yellow precipitate was filtered
and washed with methanol and diethyl ether. Yield: 0.27 g (72%).
[Bi(5-MMTD)3] (14)—1:3 reaction of [Bi(OtBu)3] with 5-MMTD(H)
All the manipulations were carried out under nitrogen atmosphere.
Bismuth tert-butoxide (0.16 g, 0.38 mmol) was dissolved in dry tet-
rahydrofuran (10 mL) followed by addition of 5-methyl-1,3,4-thia-
diazole-2-thiol (0.15 g, 1.2 mmol) at ꢀ708C. The reaction mixture
was stirred for 9 h and resultant pale yellow precipitate was filtered
and washed with dry diethyl ether. Yield: 0.18 g (81%); m.p. 265–
2678C (decomp); 1H NMR (400 MHz, [D6]DMSO, 308C): d=
2.46 ppm (s, 9H; thiadiazole CH3).13C NMR (100 MHz, [D6]DMSO):
d=15.7 ppm (thiadiazole CH3); FT-IR: n˜ =1482 (br), 1425 (br), 1258
(s), 1031 (br), 795 cmꢀ1 (s); ESI-MS+ (solvent: DMSO/MeOH, 35 eV):
m/z (%): 604 (19) [BiL3 +H]+, 503 (20) [BiL2(CH3OH)]+, 440 (50) [BiL-
[Bi(4-MTT)3] (12)—1:3 reaction of BiCl3 with [Na(4-MTT)]
All the manipulations were carried out under nitrogen atmosphere.
The sodium salt of 4-methyl-4H-1,2,4-triazole-3-thiol (0.23 g,
1.68 mmol) was dissolved in dry methanol (20 mL). The resultant
solution was cooled below 08C and bismuth chloride (0.18 g,
0.56 mmol) added as a solid. The reaction mixture was stirred over-
Chem. Eur. J. 2014, 20, 14362 – 14377
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14375
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(CH3OH)2(H2O)2]+, 285 (100) [L2 +Na]+); elemental analysis calcd
(%) for BiC9H9N6S6: C 17.94, H 1.51, N 13.95; found: C 18.40, H 2.2,
N 14.19.
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[Bi(4-BrMTD)3] (15)—1:3 reaction of BiCl3 with [Na(4-BrMTD)]
All the manipulations were carried out under nitrogen atmosphere.
The sodium salt of 4-(4-bromophenyl)thiazole-2-thiol (0.20 g,
0.68 mmol) was dissolved in dry methanol (20 mL). The resultant
solution was cooled below 08C before the addition of bismuth
chloride (0.07 g, 0.23 mmol). The reaction mixture was stirred over-
night and resultant pale yellow precipitate was filtered and
washed with methanol and diethyl ether. Yield: 0.20 g (71%).
[Bi(4-BrMTD)3] (15)—1:3 reaction of [Bi(OtBu)3] with 4-BrMTD(H)
All the manipulations were carried out under nitrogen atmosphere.
Bismuth tert-butoxide (0.12 g, 0.28 mmol) was dissolved in dry tet-
rahydrofuran (10 mL) followed by addition of 4-(4-bromophenyl)th-
iazole-2-thiol (0.23 g, 0.84 mmol) at ꢀ708C. The reaction mixture
was stirred for 12 h and resultant orange precipitate was filtered
and washed with dry diethyl ether. Yield: 0.19 g (68%); m.p. 2178C
(decomp); 1H NMR (400 MHz, [D6]DMSO, 308C): d=7.76 (d, J=
12 Hz, 6H; Br-Ph), 7.62 (s, 3H; thiazole CH), 7.29 ppm (d, J=11 Hz,
6H; Br-Ph); 13C NMR (100 MHz, [D6]DMSO): d=167.7 (thiazole CS),
132.6 (Br-Ph), 131.4 (Br-Ph), 128.0 (Br-Ph), 121.0 (Br-Ph), 114.9 ppm
(thiazole CH). FT-IR: n˜ =1513 (m), 1465 (s), 1382 (m), 1007 (s), 825
(s), 735 (s), 661 cmꢀ1 (s); ESI-MS+ (solvent: DMSO/MeOH, 35 eV): m/
z (%): 1045 (15) [BiL3 +Na]+, 751 (40) [BiL2]+, 480 (15), [BiL]+; ele-
mental analysis calcd (%) for BiC27H15Br3N3S6: C 31.71, H 1.48, N
4.11; found: C 32.12, H 1.63, N 4.37. Single crystals of 15 were ob-
tained on recrystallization of the bulk solid form DMSO solution
over a period of ten weeks. Analysis of the crystals as [Bi(4-
BrMTD)3] was consistent with the bulk solid.
[Bi{2,5-DMTD(H)}3] (16)—1:3 reaction of [Bi(OtBu)3] with 2,5-
DMTD(H)2
Bismuth tert-butoxide (0.19 g, 0.44 mmol) was dissolved in dry tet-
rahydrofuran (10.0 mL) followed by addition of 1,3,4-thiadiazole-
2,5-dithiol (0.20 g, 1.32 mmol) at ꢀ708C. The reaction mixture was
stirred for 6 h and the resultant red precipitate was filtered and
washed with dry diethyl ether. Yield: 0.22 g (78%); m.p. 2028C
(decomp); 1H NMR (400 MHz, [D6]DMSO, 308C): d=14.03 ppm (s,
3H; NH); ESI-MS+ (solvent: DMSO/MeOH, 35 eV): m/z (%): 758 (70)
[Bi(LH)3(DMSO)+Na]+, 640 (96) [Bi(LH)2(DMSO)(H2O)3]+; elemental
analysis calcd (%) for BiC6H3N6S9: C 10.97, H 0.46, N 12.80; found: C
11.27, H 0.70, N 12.08.
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Acknowledgements
We thank Monash University and the Australian Research
Council (DP110103812) for financial support. We also wish to
thank Associate Professor Benjamin Howden (Austin Health)
for supplying the MRSA and VRE strains for antimicrobial activi-
ty testing.
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Keywords: bacteria
synthesis · thiolate
· bismuth · structure elucidation ·
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Published online on September 15, 2014
Chem. Eur. J. 2014, 20, 14362 – 14377
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ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim