Synthesis, Characterization, and Antimicrobial Activity of RhIIIand IrIIIN-Heterocyclic Carbene Piano-Stool Complexes

Article abstract of DOI:10.1021/acs.organomet.1c00166

A series of RhIII and IrIII piano-stool complexes of the form [(ν5-Cp*R)M(NHC)Cl2] was synthesized and characterized, including 12 X-ray crystallographic structures. The antimicrobial properties of these complexes were screened against a variety of microbes, with several achieving high activities, most notably against Mycobacterium smegmatis (MICs as low as 0.45 μM). In general, the Rh complexes were more potent than their Ir analogues, and activity increased with the hydrophobicity of the Cp*R and NHC ligands.

Full text of DOI:10.1021/acs.organomet.1c00166

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Article
Synthesis, Characterization, and Antimicrobial Activity of RhIII and
IrIII N‑Heterocyclic Carbene Piano-Stool Complexes
Chad M. Bernier, Christine M. DuChane, Justin S. Martinez, Joseph O. Falkinham, III,
and Joseph S. Merola*
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ABSTRACT: A series of RhIII and IrIII piano-stool complexes of the form [(η5-
Cp*R)M(NHC)Cl2] was synthesized and characterized, including 12 X-ray
crystallographic structures. The antimicrobial properties of these complexes were
screened against a variety of microbes, with several achieving high activities, most
notably against Mycobacterium smegmatis (MICs as low as 0.45 μM). In general,
the Rh complexes were more potent than their Ir analogues, and activity increased
with the hydrophobicity of the Cp*R and NHC ligands.
INTRODUCTION
■
In 2010, the World Health Organization declared antimicrobial
resistance to be one of the greatest emerging threats facing
humanity, yet relatively little progress has been made in the
past decade to develop new classes of antimicrobials, such as
metallodrugs.1 The innate structural diversity of transition-
Figure 1. Generic structure of a rhodium or iridium Cp*R piano-stool
metal complexes makes metallodrugs valuable potential
contributors to combat antimicrobial resistance, and inves-
tigation into their biological properties has recently been
increasing.2 Transition-metal complexes offer unique, easily
modified scaffolds that can accommodate a wide range of
ligands and oxidation states, which subsequently affect the
stability, bioavailability, lipophilicity, biological target, and
many other factors that ultimately contribute to metal-specific
mechanisms of action that are virtually unattainable with
traditional organic pharmaceuticals. Several excellent review
articles have recently been published that illustrate the quickly
growing importance of metal-based antimicrobial agents.3
Though they have been relatively understudied in
comparison to other noble metals such as ruthenium,4
palladium,5 silver,6 platinum,7 and gold,8 recent reports have
highlighted the promising biological properties of rhodium and
iridium piano-stool complexes, particularly those featuring
pentamethylcyclopentadienyl (Cp*) and derivatized tetrame-
thylcyclopentadienyl (Cp*R) ligands.9 Rhodium and iridium
piano-stool complexes of this type make intriguing antimicro-
bial candidates due to their good water solubility and facile
modularity, which allows easy modification to tailor the
compounds toward specific biological applications and targets
(Figure 1).10
complex.
Previous reports have indicated that the mechanism of drug
action of these complexes is often dependent upon the nature
of the ligands coordinated to the metal center, with some
complexes having a high affinity for binding to DNA, RNA,
and mitochondria, ultimately leading to apoptosis, while others
can disrupt the redox balance inside cells.12 However, many of
these processes are still not well-understood for noble-metal
complexes, and this continues to be an active area of research.
The rapid development of metallodrugs over the last few
decades has led to a growing interest in the biological
applications of N-heterocyclic carbene ligands (NHCs),
primarily due to their synthetic accessibility and strong σ-
donor properties, which typically gives rise to exceptionally
stable noble-metal complexes.13 Silver and gold NHC
complexes have been studied extensively for their antimicrobial
and anticancer properties, with the activities of some rivaling
Received: March 18, 2021
Published: May 28, 2021
A myriad of organic ligands have been employed to
investigate the biological properties of rhodium and iridium
piano-stool complexes, primarily for anticancer applications.11
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those of other commonly employed metal-based drugs such as
silver sulfadiazine and cisplatin (Figure 2).14 Several rhodium
Figure 2. A few examples of silver and gold NHC complexes
displaying anticancer (top) and antimicrobial (bottom) activity.16
and iridium NHC complexes have also been reported to have
anticancer activity, including piano-stool variants featuring Cp*
and Cp*R ligands. The cytoxicity is generally enhanced in these
piano-stool complexes upon incorporation of hydrophobic
substituents into Cp*R, which likely arises from increased
cellular uptake of the complexes.15
Despite the promising anticancer activity of rhodium and
iridium NHC complexes, there have been significantly fewer
studies into their antimicrobial properties. Previously reported
rhodium and iridium NHC complexes displaying antimicrobial
activity against various microbes are provided in Figure 3. The
activity is often sensitive to changes in the NHC scaffold and
N-substituents. While many of these complexes showed poor
activity, investigations have largely focused on RhI or IrI
square-planar complexes, leaving the realm of RhIII and IrIII
NHC piano-stool antimicrobial agents relatively unexplored.
The Merola group has previously highlighted the antimicro-
bial properties of a series of RhIII and IrIII Cp*R piano-stool
complexes featuring a variety of amino acid (17 μM against M.
smegmatis and M. bovis),18 diamine (9.8 μM against S. aureus;
15 μM against MRSA),19 and β-diketonato (2.2 μM against M.
smegmatis)20 ligands (Figure 4, top). Investigations into the
cytotoxicity of the iridium Cp* diamine complexes were
encouraging, with no toxicity observed against Vero or human
embryonic kidney cell lines at concentrations at least 50 times
higher than that of the minimum inhibitory concentrations.
Additional in vivo toxicity screenings on a group of adult
outbred white mice showed no detrimental side effects 14 days
after administering a single IV dose (2.5 or 5 μg/kg), and a
subsequent ICP-OES analysis found practically no iridium in
the blood, heart, or lungs of the mice, with most of the iridium
localized in the kidneys or excreted as urine.21
Figure 3. Examples of previously reported rhodium and iridium NHC
complexes displaying antimicrobial activity.17
In order to advance the rapidly growing interest in the
biological properties of metal NHC complexes, in this article
we report the synthesis, characterization, and antimicrobial
activities of RhIII and IrIII piano-stool complexes featuring a
series of Cp*R and NHC ligands (Figure 4, bottom). Since the
antimicrobial properties of these particular complexes have
been understudied up to this point, this work features a wide
scope of Cp*R substituents and NHC ligands to further the
Figure 4. Piano-stool complexes investigated for antimicrobial activity
by the Merola group.
understanding of structure−activity relationships across noble-
metal piano-stool complexes.
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1
NMR Spectroscopy. The H NMR spectra of complexes
featuring underivatized Cp* moieties contain a singlet in the
range of 1.55−1.70 ppm corresponding to the five equivalent
methyl groups on the ring. This equivalence is lost upon
incorporation of various alkyl or aryl R groups onto the Cp*R
moiety, giving rise to a pair of singlets attributed to the
chemically nonequivalent methyl groups along the mirror
plane of the ring. For the novel piano-stool NHC complexes
reported in this article, these two singlets are typically observed
in the range of 1.30−1.80 ppm, depending on the identity of
the R substituent.
RESULTS AND DISCUSSION
■
Synthesis and Characterization. (Cp*R)M(NHC)Cl2
complexes were synthesized using a modified literature
procedure (Scheme 1).22,23 Silver(I) oxide was added to a
Scheme 1. Synthetic Route to RhIII and IrIII Cp*R NHC
Piano-Stool Complexes
Coordination of the NHC ligand to the metal center was
confirmed via observation of the characteristic downfield
resonance of the carbene carbon in the 13C NMR spectra,
which was typically found to resonate in the narrow ranges of
166−169 ppm (rhodium complexes) and 152−156 ppm
(iridium complexes). The only exception to this is observed for
Me2-bimy, which resonates significantly farther downfield in
comparison to the other NHC ligands employed in this work.
The carbene carbon resonance in rhodium complexes was
observed as the expected doublet due to coupling between the
rhodium metal center and the carbene carbon. The values of
stirring dichloromethane solution of the desired imidazolium
salt, and the mixture was allowed to react in the dark at room
temperature over a period of 4 h. The appropriate rhodium or
iridium Cp*R dimer was then added directly to the reaction
flask and stirred at room temperature while the mixture slowly
changed from gray to dark red (Rh) or dark yellow (Ir). After
12 h, the crude suspension was filtered and the solvent
removed under vacuum. Recrystallization from dichloro-
methane and hexanes gave rise to the desired products as
red (Rh) or yellow (Ir) solids in variable (28−80%) yields
(Table 1).
1
the JRh−C coupling constants were found to range from 55 to
1
57 Hz and slightly decrease in relation to the JRh−C value of
Rh-1 upon incorporation of alkyl or aryl R groups into the
Cp*R ring. Since the 13C spectral features of transition-metal
NHC complexes are of particular interest in carbene
coordination chemistry,27 the chemical shifts of the 13C
1
carbene resonances and the JRh−C coupling constants for all
complexes are provided in Table 2 and are consistent with
previously reported spectra of similar RhIII and IrIII Cp* piano-
stool complexes featuring N-heterocyclic carbene ligands.28
a
1
Table 2. 13C NMR (101 MHz) Chemical Shifts and JRh−C
Table 1. Labeling and Yields of Complexes
Coupling Constants of the Carbene Resonances for the RhIII
and IrIII Cp*R NHC Piano-Stool Complexes Featured in
This Article
Cp*R
NHC
IMe
Rh complex yield (%) Ir complex yield (%)
methyl
Rh-122
89
80
57
75
87
Ir-123
Ir-224
75
68
IEt
Rh-2
Rh-3
Rh-4
Rh-515a
Rh complex δ(13C) (ppm) 1JRh−C (Hz) Ir complex δ(13C) (ppm)
IiPr
ICy
Me2-bimy
Ir-425
Ir-526
49
82
Rh-1
Rh-2
Rh-3
Rh-4
Rh-5
169.54
169.13
166.84
167.04
184.47
56.7
56.8
56.9
57.4
55.8
Ir-1
Ir-2
156.26
156.11
ethyl
IMe
Ir-6
Ir-7
69
28
Ir-4
Ir-5
Ir-6
Ir-7
153.53
170.50
156.22
156.19
n-propyl
isopropyl
n-pentyl
n-octyl
Rh-7
Rh-8
Rh-9
60
59
45
Rh-7
Rh-8
Rh-9
169.40
169.35
169.46
56.5
56.2
56.3
Ir-10
Ir-11
50
80
phenyl
IMe
Me2-bimy
Rh-11
Rh-12
78
48
Ir-10
Ir-11
156.35
154.41
Rh-11
Rh-12
168.11
183.11
56.4
55.5
benzyl
phenethyl
C6F5
IMe
Ir-13
Ir-14
Ir-15
71
67
77
Ir-13
Ir-14
Ir-15
155.74
155.89
152.09
Rh-14
Rh-15
73
31
Rh-14
Rh-15
169.03
56.5
a
References for previously reported complexes are provided next to
the labels.
X-ray Crystallography. Red or yellow single crystals
suitable for X-ray diffraction ware obtained from vapor
diffusion of hexanes or diethyl ether into saturated solutions
of dichloromethane, acetone, or chloroform. Of the 12 new
crystal structures solved, 10 crystals were found to belong to
monoclinic space groups, with the remaining two crystals (Rh-
15 and Ir-11) belonging to orthorhombic space groups. The
displacement ellipsoid plot of Rh-4 is shown in Figure 5 as a
Of the 23 complexes synthesized in this study, 17 are novel,
with the exception of Rh-1, Rh-5, Ir-1, Ir-2, Ir-4, and Ir-5.
References for previously reported complexes are provided
next to the respective labels in Table 1. Characterization
1
included H NMR, 13C NMR, high-resolution mass spectros-
copy, and single-crystal X-ray diffraction, when possible.
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representative example. Displacement ellipsoid plots for all
crystal structures solved in this work are provided in the
Supporting Information.
Table 3. Selected Average Bond Lengths for the
(Cp*R)M(NHC)Cl2 Crystal Structures Solved in This Work
or Reported Previously
a
a
label
Rh-122
Rh-3
M−Ccarbene (Å)
M−Cp*C cis (Å)
M−Cp* trans (Å)
2.050
2.068
2.0557
2.049
2.056
2.053
2.043
2.150
2.154
2.148
2.153
2.158
2.146
2.158
2.223
2.225
2.242
2.217
2.212
2.212
2.233
Rh-4
Rh-515
Rh-8
Rh-14
Rh-15
Ir-123
Ir-2
2.06
2.05
2.16
2.15
2.25
2.23
Ir-4
2.047
2.038
2.050
2.050
2.047
2.048
2.044
2.145
2.14
2.240
2.25
Ir-526
Ir-6
2.156
2.158
2.168
2.155
2.152
2.212
2.220
2.196
2.221
2.221
Ir-7
Ir-11
Ir-13
Ir-14
Figure 5. Displacement ellipsoid plot (50% probability) of Rh-4.
Hydrogen atoms are omitted for clarity.
a
Defined as cis or trans relative to the NHC ligand.
In all of the structures, the the M−Cp*C bond lengths trans
to the NHC ligand are longer than than the cis or overlapping
M−Cp*C bonds and increase in length upon the incorpo-
ration of more strongly σ-donating NHC ligands. Complexes
featuring alkyl or aryl R substituents on the Cp*R moiety were
found to rotate such that the R group was oriented to some
degree anti to the NHC ligand (Figure 6 and Table 3). These
with the exception of Rh-15, which features an electron-
withdrawing Cp*C6F5 moiety.
For structures containing underivatized Cp* ligands, the
Rh−Ccarbene bond lengths range from 2.049 to 2.068 Å while
the Ir−Ccarbene bond lengths range from 2.038 to 2.06 Å. Upon
comparison of the M−Ccarbene lengths in the underivatized Cp*
complexes featuring different NHC ligands, it is apparent that
stronger σ-donor NHC ligands do not necessarily lead to
shorter M−Ccarbene bonds as might be expected. In some cases,
this is attributable to steric effects arising from bulkier NHC N-
substituents, as seen in the IiPr-containing Rh-3 (2.068 Å) and
the ICy-containing Rh-4 (2.0557 Å). Non-negligible π-back-
bonding interactions from the metal center to the carbene
carbon also likely influence the M−Ccarbene bond distances, as
the shortest M−Ccarbene bond lengths are observed for the
previously reported Rh-5 (2.049 Å) and Ir-5 (2.038 Å) crystal
structures featuring the Me2-bimy NHC ligand, despite Me2-
bimy being the weakest σ-donor of all the NHC ligands in this
study. This suggests benzimidazol-2-ylidene NHC scaffolds
experience a larger degree of π-back-donation from the metal
center in comparison to imidazol-2-ylidene scaffolds.31
Figure 6. Displacement ellipsoid plot (50% probability) of Ir-6
depicting the lengthened Cp*C bonds anti to the NHC ligand as a
consequence of the trans influence (Å).
In the derivatized Cp*R complexes, the M−Ccarbene bond
lengths are sensitive to the nature of the alkyl and aryl R
substituents. Incorporation of an isopropyl group in Rh-8
(2.068 Å) or phenethyl group in Rh-14 (2.053 Å) slightly
increases the Rh−Ccarbene bond lengths in comparison to that
of Rh-1 (2.050 Å). The opposite effect is observed for the
crystal structure of Rh-15, with the electron-withdrawing
pentafluorophenyl substituent giving rise to the shortest Rh−
Ccarbene bond (2.043 Å) of all the rhodium structures. In
contrast to the rhodium structures, the Ir−Ccarbene bond
lengths featuring derivatized Cp*R ligands are all shorter than
those seen in the crystal structure of Ir-1 (2.06 Å).
Antimicrobial Activity. Previous investigations in the
Merola group have shown that RhIII and IrIII Cp*R piano-stool
complexes display promising antimicrobial activity, particularly
against M. smegmatis (which frequently serves as a model to
investigate more pathogenic mycobacteria), S. aureus, and
MRSA. The activity was generally enhanced in complexes
examples illustrate the trans influence brought about by
strongly σ donating NHC ligands, a phenomenon that has
previously been observed in the crystal structures of similar
RhIII and IrIII Cp* NHC complexes.29
A search of the Cambridge Structural Database30 (CSD)
found 10 entries for similar RhIII complexes and 44 entries for
similar IrIII Cp* complexes featuring monodentate NHC
ligands. The Rh−Ccarbene bond lengths ranged from 2.047 to
2.070 Å, with a mean value of 2.057 Å, while the Ir−Ccarbene
bond lengths ranged from 1.886 to 2.075 Å, with a mean value
of 2.040 Å. The crystal structures solved in this work have Rh−
Ccarbene bond lengths ranging from 2.043 to 2.068 Å, and Ir−
C
carbene bond lengths ranging from 2.044 to 2.050. All of these
bond lengths fall within the range of those found in the CSD,
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featuring hydrophobic substituents on the Cp*R moiety and
other coligands. Given these previous results in addition to the
recent literature reports on the biological applications of
organometallic complexes containing N-heterocyclic carbene
ligands, we became interested in assessing the antimicrobial
activity of these RhIII and IrIII Cp*R NHC piano-stool
complexes. Since the antimicrobial properties of these
complexes have not been extensively studied up to this
point, a wide scope of NHC and CpR ligands were employed.
Broad Panel Screening. The complexes were initially
screened for antimicrobial activity against a broad microbial
panel of various bacteria, yeast, and fungi. The activity was
measured using the sequential dilution technique in 96-well
plates, and the results were recorded as the minimum
inhibitory concentration (MIC), which is the highest
concentration at which no cell growth was detected in a
well. A complete procedure for the antimicrobial studies
conducted here is provided in the Experimental Section.
The majority of these complexes displayed moderate
(defined here as ≤15 μM) to high (≤1 μM) activity against
Gram-positive Mycobacterium smegmatis (Table 4). Rhodium
displaying significantly lower activity against M. smegmatis than
Ir-1, Ir-4, and Ir-5. The activity is also highly sensitive to
changes in the Cp*R moieties. For rhodium complexes having
the same NHC ligand (IMe) but different alkyl- or aryl-
substituted Cp*R rings, longer chain or branched alkyl R
groups (Rh-7, Rh-8, and Rh-9) enhanced the activity in
comparison to Rh-1. However, the iridium Cp*R complexes
featuring the IMe NHC ligand benefited more from
incorporation of a phenyl-substituted Cp*R, as Ir-11 was
found to be significantly more potent than Ir-1 and gave the
lowest MIC of all the complexes screened (0.45 μM). Despite
these rhodium and iridium piano-stool analogues having a
number of similarities with regard to structure and chemical
reactivity, it is apparent that their structure−activity relation-
ships and antimicrobial properties differ.
A few of the complexes also showed activity against other
microbes in the broad panel (MIC data against all microbes
tested in the broad panel are provided in Table S1 of the
Supporting Information). The rhodium Cp* complex incor-
porating the ICy NHC ligand (Rh-4) gave moderate activity
(15 μM) against Gram-positive MRSA and Gram-negative E.
coli, while the iridium complex featuring an octyl substituent
on the Cp*R ring (Ir-10) displayed moderate to high activity
against practically all microbes in the broad panel, most
notably against MRSA (6.8 μM) and Gram-positive S. aureus
(14 μM). Overall, the complexes were more effective against
Gram-positive in comparison to Gram-negative strains in the
broad panel, and in general, the activity increased with the
hydrophobicity of the NHC and Cp*R ligands.
Table 4. Antimicrobial Activities of RhIII and IrIII Cp*R
NHC Piano-Stool Complexes and NHC Ligand Precursors
a
against M. smegmatis
b
b
Rh complex or reference
MIC (μM)
Ir complex
MIC (μM)
Rh-1
Rh-2
Rh-3
Rh-4
Rh-5
4.9
0.58
1.1
0.46
1.1
Ir-1
Ir-2
8.1
31
In order to gain additional insight into the effect the NHC
ligands have on the antimicrobial properties of these
complexes, the imidazolium salt precursors were also screened
against all microbes in the broad panel (Table S1), and their
MICs against M. smegmatis are provided in Table 5. In all
Ir-4
Ir-5
Ir-6
1.6
0.92
16
Rh-7
Rh-8
Rh-9
0.58
0.58
0.54
Table 5. Antimicrobial Activities of NHC Ligand Precursors
against M. smegmatis
Ir-10
Ir-11
1.7
0.45
Rh-11
Rh-12
1.1
0.97
NHC precursor
MIC (μM)
Ir-13
Ir-14
Ir-15
3.5
6.8
190
IMe·I
IEt·I
Pr·Cl
IiICy·Cl
Me2-bimy·I
>1100
>990
>1300
920
Rh-14
2.0
reference compounds
ciprofloxacin
0.75
0.43
>910
streptomycin
a
Ciprofloxacin and streptomycin were also screened as positive
cases, the imidazolium salts were relatively inactive (>900
μM), suggesting that the antimicrobial activity in this system
does not arise from solely from the NHC ligands.
b
controls. Complexes were tested against M. smegmatis in duplicate.
Both independent tests were found to give the same results.
The silver complex precursors were not tested in this work,
as they were generated in situ and subsequently reacted directly
with the metal precursors. Attempts were made to isolate the
silver-NHC complexes early in the project, but many of them
were found to form complicated polymeric structures when
they were removed from solution. This both greatly
diminished their solubility and would not be representative
of the relevant silver complex; thus, we did not pursue this
further. On the basis of our analyses, we are confident that
there is an insignificant amount of silver, if any, in our tested
complexes.
complexes were generally found to have greater activities in
comparison to those of iridium, both in a direct comparison of
analogous complexes as well as within the data set taken as a
whole. There are a few exceptions to this trend, with higher
activity being observed for the iridium Cp* complex featuring
Me2-bimy (Ir-5) as well as the iridium Cp*phenyl complex
featuring IMe (Ir-11).
Variation of the NHC ligand had a notable effect on activity,
as seen when MICs of the underivatized Cp* complexes were
compared. The activity is greatly enhanced for the rhodium
complexes containing more hydrophobic NHC ligands (Rh-2,
Rh-3, Rh-4, and Rh-5) in comparison to that of IMe (Rh-1).
While the iridium Cp* complexes generally follow the same
trend, the IEt variant (Ir-2) is a noteworthy exception,
To further investigate the influence of the NHC ligands on
antimicrobial activity, the MICs of the (Cp*R)M(NHC)Cl2
complexes against M. smegmatis were then compared on a 1:1
metal center basis to the MIC of the parental unit
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[(Cp*R)MCl2]2 from which they were derived, consisting of
the same Cp*R ligand and metal (Table 6). Incorporation of an
mimic the antimicrobial testing conditions (Figures S1 and
S2). Both complexes proved to be stable in this media after 3
days, with the NMR spectra showing minimal change and no
indication of ligand dissociation over the monitored time
period. Furthermore, HRMS analysis of the complexes
revealed that the NHC and Cp*R ligands are still coordinated
to the metal center, with the [(Cp*R)M(NHC)Cl]+ fragments
being observed for all complexes (representative HRMS traces
are shown in Figures S3 and S4).
Cytotoxicity Studies. To investigate if noble-metal NHC
piano-stool complexes of this type are detrimental to
mammalian cells, complex Rh-4 was screened for toxicity
against Vero E6 cell lines (kidney epithelial cells extracted from
an African green monkey) and Calu-3 cell lines (representative
of human lung epithelial cells) (Figure 7). In general, Rh-4 was
Table 6. Comparison of MICs (μM) against M. smegmatis
between the (Cp*R)M(NHC)Cl2 Complexes and Their
Respective Parental Units
complex
Cp*R
NHC
IMe
IEt
IiPr
ICy
Me2-bimy
IMe
IMe
IMe
label
MIC
parent MIC
3.2
methyl
Rh-1
Rh-2
Rh-3
Rh-4
Rh-5
Rh-7
Rh-9
Rh-11
Rh-12
Rh-14
4.9
0.58
1.1
0.46
1.1
0.58
0.54
1.1
propyl
pentyl
phenyl
5.9
2.7
10
Me2-bimy
IMe
0.97
2.0
phenethyl
methyl
40
10
IMe
IEt
Ir-1
Ir-2
8.1
31
ICy
Me2-bimy
IMe
Ir-4
Ir-5
Ir-6
1.6
0.92
16
ethyl
octyl
phenyl
benzyl
phenethyl
C6F5
19
16
70
8.4
33
450
IMe
IMe
IMe
IMe
Ir-10
Ir-11
Ir-13
Ir-14
Ir-15
1.7
0.45
3.5
6.8
IMe
190
Figure 7. Cytotoxicity of Rh-4 against Vero E6 and Calu-3 cell lines,
where a high percent viability at any given concentration indicates low
toxicity.
NHC ligand enhanced the activity in almost all cases, with the
largest improvement observed for the Cp*phenyl-containing Ir-
11, giving over a 150-fold increase in activity upon inclusion of
the IMe NHC ligand. These findings support the notion that
the high antimicrobial activity displayed by these complexes
does not solely arise from just the Cp*R noble-metal parental
units or individual NHC ligands via in vivo dissociation of the
complexes. Instead, all the various structural features working
in concert affect the overall activity of any particular complex,
most likely by affecting the stability, bioavailability, and
lipophilicity.
Mycobacterial Panel Screening. Due to the promising
activities observed against M. smegmatis in the broad panel
testing, a selection of these compounds was also screened
against a panel of more pathogenic strains of mycobacteria.
Antimicrobial activities are reported in Table S2 in the
Supporting Information as MICs (μg/mL and μM) for all
compounds as well as for streptomycin.
As seen in the broad panel testing, the rhodium complexes
were generally more active than the iridium variants. Both Rh-
3 and Rh-9 displayed moderate activity against M. intracellulare
(8.7 μM), while a range of the complexes also gave moderate
activity against M. chimaera, the most potent being Rh-4 (7.4
μM). Other notable results include Rh-3 against M. avium (17
μM), as well as Rh-8 against M. abscessus (19 μM). Despite
being the most potent against M. smegmatis of all the
complexes screened in the broad panel, Ir-11 showed relatively
poor activity against the mycobacterial panel, with the
exceptions of M. intracellulare and M. chimaera (14 μM).
Stability Studies. In order to assess the stability of the
piano-stool complexes, 1H NMR spectra of Rh-4 and Ir-1 were
acquired over a period of 72 h in D2O with 0.1% DMSO to
found to be nontoxic toward these mammalian cells, except at
elevated concentrations of 50 μg/mL (92 μM). Considering
that Rh-4 was active against M. smegmatis at concentrations as
low as 0.25 μg/mL (0.46 μM), these results are highly
encouraging.
CONCLUSION
■
The work described in this article expands upon continuing
investigations into the biological properties of noble-metal
piano-stool complexes featuring N-heterocyclic carbene
ligands. A modest library of (Cp*R)M(NHC)Cl2 (M = Rh,
Ir) complexes was synthesized, characterized, and screened for
antimicrobial activity against a range of microbes, with many of
the complexes displaying excellent activity (>1 μM) against
Mycobacterium smegmatis. The rhodium complexes were
generally found to be more active than iridium complexes,
and the activity was enhanced upon inclusion of more
hydrophobic Cp*R and NHC ligands, which is in agreement
with previous studies by the Merola group18−20 and others.15
Cytotoxicity tests on Rh-4 showed that this compound is only
toxic toward mammalian Vero E6 and Calu-3 cell lines at
concentrations 200-fold higher (92 μM) than the observed
activity against M. smegmatis (0.46 μM). Overall, these findings
highlight the promising utility of N-heterocyclic carbene and
Cp*R moieties for the development and tunability of noble-
metal piano-stool antimicrobial agents.
EXPERIMENTAL SECTION
Materials. Reagent-grade solvents and all materials for synthesis,
purification, and characterization were purchased from commercial
■
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sources and used as received unless otherwise stated. The NHC
ligand precursors 1,3-dimethylimidazolium iodide (IMe·I),32 1,3-
diethylimidazolium iodide (IEt·I),33 and 1,3-dimethylbenzimidazo-
lium iodide (Me2-bimy·I)34 were synthesized as reported previously.
Both 1,3-diisopropylimidazolium chloride (IiPr·Cl) and 1,3-dicyclo-
hexylimidazolium chloride (ICy·Cl), as well as silver(I) oxide, were
purchased from Sigma-Aldrich (St. Louis, MO). Rhodium and iridium
dimers of the form [(Cp*R)MCl2]2 (R = alkyl or aryl)35 were
synthesized as reported previously using rhodium(III) chloride
hydrate and iridium(III) chloride hydrate precursors purchased
from Pressure Chemical (Pittsburgh, PA). Deuterated solvents for
NMR spectroscopy were obtained from Cambridge Isotope
Laboratories (Tewksbury, MA).
Hz, Ccarbene), 119.5 (d, J = 0.9 Hz, CHbackbone), 96.3 (d, J = 7.0 Hz,
Cp*C), 51.8 (NCH(CH3)2)), 25.4 (NCH(CH3)2), 25.2 (NCH-
(CH3)2), 9.5 (Cp*CH3). HRMS/ESI+ (m/z): calcd for
C19H31ClN2Rh, 425.1231; found, 425.1238.
Synthesis of Rh-4. Following the general procedure, 1,3-
dicyclohexylimidazolium chloride (0.0913 g, 0.3398 mmol), silver(I)
oxide (0.0551 g, 0.2378 mmol), and [(Cp*)RhCl2]2 (0.1000 g,
0.1618 mmol) were reacted in dichloromethane to give Rh-4 (0.1752
1
g, 75%). H NMR (400 MHz, CDCl3, δ): 7.06 (s, 2H, CHbackbone),
4.87 (tt, J = 11.8, 3.5 Hz, 2H, NCHcyclohexyl), 2.52 (d, J = 11.9 Hz, 2H,
CH2cyclohexyl), 1.96−1.65 (m, 12H, CH2cyclohexyl), 1.62 (s, 15H,
Cp*CH3), 1.59−1.10 (m, 6H, CH2cyclohexyl). 13C NMR (101 MHz,
CDCl3, δ): 167.0 (d, J = 57.4 Hz, Ccarbene), 119.8 (d, J = 1.0 Hz,
CHbackbone) 96.2 (d, J = 7.0 Hz, Cp*C), 58.8 (NCHcyclohexyl), 35.8
(CH2cyclohexyl), 35.6 (CH2cyclohexyl), 25.9 (CH2cyclohexyl), 25.5
(CH2cyclohexyl), 25.4 (CH2cyclohexyl), 9.6 (Cp*CH3). HRMS/ESI+ (m/
z): calcd for C25H39ClN2Rh, 505.1851; found, 505.1850. Anal. Calcd
for C25H39Cl2N2Rh: C, 55.46; H, 7.26. Found: C, 55.01; H, 7.43.
Synthesis of Rh-5. Following the general procedure, 1,3-
dimethylbenzimidazolium iodide (0.0931 g, 0.3398 mmol), silver(I)
oxide (0.0551 g, 0.2378 mmol), and [(Cp*)RhCl2]2 (0.1000 g,
0.1618 mmol) were reacted in dichloromethane to give Rh-5 (0.1281
g, 87%). Characterization data were consistent with previously
reported data.15a
1
Instrumentation. H, 13C, and 19F NMR spectra were collected
on an Agilent U4-DD2 or Agilent MR4 400 MHz spectrometer. 13C
NMR spectra were correspondingly recorded at 101 MHz and 19F
NMR at 376 MHz. Elemental analyses were performed by Atlantic
Microlabs (Norcross, GA). High-resolution mass spectra were
collected on an Agilent 6220 Accurate Mass TOF LC-MS instrument.
X-ray crystallographic data were collected at 100 K on a Rigaku
Oxford Diffraction Gemini E Ultra diffractometer or a Rigaku Oxford
Diffraction Synergy operating with either Mo Kα or Cu Kα radiation.
Crystals were coated in Paratone oil and mounted on a fiber. Data
collection and data reduction were performed using Agilent’s
CrysAlisPro software.36 Structure solution was performed using
SHELXT37 and refined using SHELXL38 via Olex2. The final
refinement model involved anisotropic displacement parameters for
non-hydrogen atoms and a riding model for all hydrogen atoms.
Olex2 was used for molecular graphics generation.39 Searches of the
Cambridge Structural Database (CSD)30 were carried out using the
program Conquest,40 and the results were analyzed with the statistical
functions of the program Mercury.41
Synthesis and Characterization: General Synthesis of
(Cp*R)M(NHC)Cl2 Complexes. A Schlenk flask was charged with
the appropriate amount of the desired imidazolium salt and silver(I)
oxide in dichloromethane (15 mL) under an atmosphere of nitrogen.
The mixture was stirred magnetically in the dark for 4 h. The desired
rhodium or iridium [(Cp*R)MCl2]2 dimer was then added, and the
mixture was stirred for an additional 12 h, over which time the color
changed from gray to dark red (Rh) or dark yellow (Ir). After the
elapsed time, the suspension was filtered through Celite and the
solvent removed by rotary evaporation. The products were purified
via recrystallization from dichloromethane and hexanes and isolated
on a frit as red (Rh) or yellow (Ir) solids.
Synthesis of Rh-7. Following the general procedure, 1,3-
dimethylimidazolium iodide (0.0698 g, 0.3115 mmol), silver(I)
oxide (0.0505 g, 0.2180 mmol), and [(Cp*propyl)RhCl2]2 (0.1000 g,
0.1483 mmol) were reacted in dichloromethane to give Rh-7 (0.0776
1
g, 60%). H NMR (400 MHz, CDCl3, δ): 6.98 (s, 2H, CHbackbone),
4.00 (s, 6H, NCH3), 2.05−1.97 (m, 2H, Cp*CH2CH2CH3), 1.66 (s,
6H, Cp*CH3), 1.60 (s, 6H, Cp*CH3), 1.45−1.37 (m, 2H,
Cp*CH2CH2CH3), 0.92 (t, J = 7.4 Hz, 3H, Cp*CH2CH2CH3). 13C
NMR (101 MHz, CDCl3, δ): 169.4 (d, J = 56.5 Hz, Ccarbene), 124.3
(d, J = 1.0 Hz, CHbackbone), 98.1 (d, J = 6.5 Hz, Cp*C), 97.1 (d, J = 7.7
Hz, Cp*C), 95.3 (d, J = 7.2 Hz, Cp*C), 39.2, (NCH3) 26.6
(Cp*CH2 CH2 CH3 ), 21. 8 (Cp*CH2 CH2 CH3 ), 14. 3
(Cp*CH2CH2CH3), 9.7 (Cp*CH3), 9.5 (Cp*CH3). HRMS/ESI+
(m/z): calcd forC17H27ClN2Rh, 397.0912; found, 397.0908. Anal.
Calcd for C17H27Cl2N2Rh·0.5H2O: C, 46.17; H, 6.38. Found: C,
46.03; H, 6.19.
Synthesis of Rh-8. Following the general procedure, 1,3-
dimethylimidazolium iodide (0.0698 g, 0.3115 mmol), silver(I)
oxide (0.0505 g, 0.2180 mmol), and [(Cp*isopropyl)RhCl2]2 (0.1000
g, 0.1483 mmol) were reacted in dichloromethane to give Rh-8
(0.0758 g, 59%). 1H NMR (400 MHz, CDCl3, δ): 6.98 (s, 2H,
CHbackbone), 3.99 (s, 6H, NCH3), 2.57 (hept, J = 7.0 Hz, 1H,
Cp*CH(CH3)2)), 1.67 (s, 6H, Cp*CH3), 1.59 (s, 6H, Cp*CH3),
1.19 (d, J = 7.1 Hz, 6H, Cp*CH(CH3)2). 13C NMR (101 MHz,
CDCl3, δ): 169.4 (d, J = 56.2 Hz, Ccarbene), 124.2 (d, J = 1.0 Hz,
CHbackbone), 103.1 (d, J = 7.0 Hz, Cp*C), 96.9 (d, J = 6.9 Hz, Cp*C),
95.8 (d, J = 7.3 Hz, Cp*C), 39.3 (NCH3), 26.2 (Cp*CH(CH3)2)),
21.2 (Cp*CH(CH3)2), 10.4 (Cp*CH3), 9.6 (Cp*CH3). HRMS/ESI+
(m/z): calcd forC17H27ClN2Rh, 397.0912; found, 397.0888.
Synthesis of Rh-9. Following the general procedure, 1,3-
dimethylimidazolium iodide (0.0644 g, 0.2876 mmol), silver(I)
oxide (0.0466 g, 0.2013 mmol), and [(Cp*pentyl)RhCl2]2 (0.1000 g,
0.1369 mmol) were reacted in dichloromethane to give Rh-9 (0.0569
Synthesis of Rh-1. Following the general procedure, 1,3-
dimethylimidazolium iodide (0.2284 g, 1.0193 mmol), silver(I)
oxide (0.1653 g, 0.7135 mmol), and [(Cp*)RhCl2]2 (0.3000 g,
0.4854 mmol) were reacted in dichloromethane to give Rh-1 (0.3517
g, 89%). Characterization data were consistent with previously
reported data.22
Synthesis of Rh-2. Following the general procedure, 1,3-
diethylimidazolium iodide (0.0857 g, 0.3398 mmol), silver(I) oxide
(0.0501 g, 0.2378 mmol), and [(Cp*)RhCl2]2 (0.1000 g, 0.1618
mmol) were reacted in dichloromethane to give Rh-2 (0.1124 g,
80%). 1H NMR (400 MHz, CDCl3, δ): 7.09 (s, 2H, CHbackbone),
4.87−4.70 (m, 2H, NCH2CH3), 4.04−3.97 (m, 2H, NCH2CH3), 1.57
(s, 15H, Cp*CH3), 1.45 (t, J = 7.2 Hz, 6H, NCH2CH3). 13C NMR
(101 MHz, CDCl3, δ): 169.1 (d, J = 56.8 Hz, Ccarbene), 122.0 (d, J =
0.8 Hz, CHbackbone), 96.2 (d, J = 7.0 Hz, Cp*C), 45.9 (NCH2CH3)
16.9 (NCH2CH3), 9.4 (Cp*CH3). HRMS/ESI+ (m/z): calcd for
C17H27ClN2Rh, 397.0912; found, 397.0909. Anal. Calcd for
C17H27Cl2N2Rh·0.5H2O: C, 46.17; H, 6.38. Found: C, 46.09; H, 6.12.
Synthesis of Rh-3. Following the general procedure, 1,3-
diisopropylimidazolium chloride (0.0641 g, 0.3398 mmol), silver(I)
oxide (0.0551 g, 0.2378 mmol), and [(Cp*)RhCl2]2 (0.1000 g,
0.1618 mmol) were reacted in dichloromethane to give Rh-3 (0.0852
1
g, 45%). H NMR (400 MHz, CDCl3, δ): 6.99 (s, 2H, CHbackbone),
3.99 (s, 6H, NCH3), 2.07−1.97 (m, 2H, Cp*CH2(CH2)3CH3), 1.65
(s, 6H, Cp*CH3), 1.60 (s, 6H, Cp*CH3), 1.42−1.33 (m, 2H,
Cp*CH2(CH2)3CH3) 1.32−1.22 (m, 4H, Cp*CH2(CH2)3CH3),
0.93−0.80 (m, 3H, Cp*CH2(CH2)3CH3). 13C NMR (101 MHz,
CDCl3, δ): 169.5 (d, J = 56.3 Hz, Ccarbene), 124.3 (d, J = 1.0 Hz,
CHbackbone), 98.0 (d, J = 6.6 Hz, Cp*C), 97.5 (d, J = 7.5 Hz, Cp*C),
95.3 (d,
J = 7.2 Hz, Cp*C), 39.2 (NCH3 ), 32.0
1
(Cp*CH2(CH2)3CH3), 28.3 (Cp*CH2(CH2)3CH3), 24.7
(Cp*CH2(CH2)3CH3), 22.5 (Cp*CH2(CH2)3CH3), 14.0
(Cp*CH2(CH2)3CH3), 9.6 (Cp*CH3), 9.5 (Cp*CH3). HRMS/ESI
+ (m/z): calcd for C19H31ClN2Rh, 425.1231; found, 425.1239.
g, 57%). H NMR (400 MHz, CDCl3, δ): 7.08 (s, 2H, CHbackbone),
5.32 (hept, J = 6.5 Hz, 2H, NCH(CH3)2), 1.62 (s, 15H, Cp*CH3),
1.51 (d, J = 6.3 Hz, 6H, NCH(CH3)2), 1.41 (d, J = 6.8 Hz, 6H,
NCH(CH3)2). 13C NMR (101 MHz, CDCl3, δ): 166.8 (d, J = 56.9
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Synthesis of Rh-11. Following the general procedure, 1,3-
dimethylimidazolium iodide (0.0254 g, 0.1132 mmol), silver(I)
oxide (0.0184 g, 0.0792 mmol), and [(Cp*phenyl)RhCl2]2 (0.0040 g,
0.0539 mmol) were reacted in dichloromethane to give Rh-11
(0.0395 g, 78%). 1H NMR (400 MHz, CDCl3, δ): 7.62−7.55 (m, 2H,
Cp*Ph), 7.39−7.30 (m, 3H, Cp*Ph), 6.92 (s, 2H, CHbackbone), 3.83 (s,
6H, NCH3), 1.75 (s, 6H, Cp*CH3), 1.67 (s, 6H, Cp*CH3). 13C
NMR (101 MHz, CDCl3, δ): 168.1 (d, J = 56.4 Hz, Ccarbene), 130.8
(Cp*Ph), 130.6 (Cp*Ph), 128.5 (Cp*Ph), 128.5 (Cp*Ph), 124.4 (d, J
= 0.8 Hz, CHbackbone), 99.8 (d, J = 6.4 Hz, Cp*C), 96.9 (d, J = 6.7 Hz,
Cp*C), 93.4 (d, J = 8.1 Hz, Cp*C), 39.2 (NCH3), 10.9 (Cp*CH3),
9.7 (Cp*CH3). HRMS/ESI+ (m/z): calcd for C20H25ClN2Rh,
431.0756; found, 431.0744.
Synthesis of Rh-12. Following the general procedure, 1,3-
dimethylbenzimidazolium iodide (0.0310 g, 0.1132 mmol), silver(I)
oxide (0.0184 g, 0.0792 mmol), and [(Cp*phenyl)RhCl2]2 (0.0040 g,
0.0539 mmol) were reacted in dichloromethane to give Rh-12
(0.0265 g, 48%). 1H NMR (400 MHz, CDCl3, δ): 7.67−7.63 (m, 2H,
Cp*Ph), 7.38−7.28 (m, 7H, overlapped Cp*Ph, CHbackbone), 4.07 (s,
6H, NCH3), 1.78 (s, 6H, Cp*CH3), 1.73 (s, 6H, Cp*CH3). 13C
NMR (101 MHz, CDCl3, δ): 183.1 (d, J = 55.5 Hz, Ccarbene), 136.0
(d, J = 1.0 Hz, Cbridgeheads), 130.62 (Cp*Ph), 130.57 (Cp*Ph), 128.60
(Cp*Ph), 128.55 (Cp*Ph), 123.5 (CHbackbone), 110.2 (CHbackbone),
101.2 (d, J = 6.4 Hz, Cp*C), 96.8 (d, J = 6.8 Hz, Cp*C), 94.3 (d, J =
7.6 Hz, Cp*C), 36.0 (NCH3), 11.0 (Cp*CH3), 9.9 (Cp*CH3).
HRMS/ESI+ (m/z): calcd for C24H27ClN2Rh, 481.0912; found,
481.0910
Synthesis of Rh-14. Following the general procedure, 1,3-
dimethylimidazolium iodide (0.0589 g, 0.2631 mmol), silver(I)
oxide (0.0427 g, 0.1841 mmol), and [(Cp*phenethyl)RhCl2]2 (0.1000
g, 0.1253 mmol) were reacted in dichloromethane to give Rh-14
(0.0910 g, 73%). 1H NMR (400 MHz, CDCl3, δ): 7.26−7.16 (m, 3H,
Cp*CH2CH2Ph), 7.03−6.98 (m, 2H, Cp*CH2CH2Ph), 6.94 (s, 2H,
CHbackbone), 3.94 (s, 6H, NCH3), 2.69 (t, J = 7.4 Hz, 2H,
Cp*CH2CH2Ph), 2.33 (t, J = 7.4 Hz, 2H, Cp*CH2CH2Ph), 1.61
(s, 6H, Cp*CH3), 1.36 (s, 6H, Cp*CH3). 13C NMR (101 MHz,
CDCl3, δ): 169.0 (d, J = 56.5 Hz, Ccarbene), 140.2 (Cp*CH2CH2Ph),
128.7 (Cp*CH2CH2Ph), 128.64 (Cp*CH2CH2Ph), 126.61
(Cp*CH2CH2Ph), 124.3 (d, J = 1.0 Hz, CHbackbone), 98.0 (d, J =
6.5 Hz, Cp*C), 96.1 (d, J = 7.1 Hz, Cp*C), 95.4 (d, J = 7.6 Hz,
Cp*C), 39.2 (NCH3 ), 34.4 (Cp*CH2 CH2 Ph), 27.1
(Cp*CH2CH2Ph), 9.4 (Cp*CH3), 9.3 (Cp*CH3). HRMS/ESI+
(m/z): calcd for C22H29ClN2Rh, 459.1074; found, 459.1077. Anal.
Calcd for C22H29Cl2N2Rh: C, 53.35; H, 5.90. Found: C, 52.55; H,
6.09.
Synthesis of Ir-5. Following the general procedure, 1,3-
dimethylbenzimidazolium iodide (0.0723 g, 0.2636 mmol), silver(I)
oxide (0.0428 g, 0.1845 mmol), and [(Cp*)IrCl2]2 (0.1000 g, 0.1255
mmol) were reacted in dichloromethane to give Ir-5 (0.1119 g, 82%).
Characterization data were consistent with previously reported data.26
Synthesis of Ir-6. Following the general procedure, 1,3-
dimethylimidazolium iodide (0.0570 g, 0.2546 mmol), silver(I)
oxide (0.0413 g, 0.1782 mmol), and [(Cp*ethyl)IrCl2]2 (0.1000 g,
0.1212 mmol) were reacted in dichloromethane to give Ir-6 (0.0847
1
g, 69%). H NMR (400 MHz, CDCl3, δ): 6.90 (s, 2H, CHbackbone),
3.95 (s, 6H, NCH3), 1.99 (q, J = 7.6 Hz, 2H, Cp*CH2CH3), 1.67 (s,
6H, Cp*CH3), 1.63 (s, 6H, Cp*CH3), 1.07 (t, J = 7.6 Hz, 3H,
Cp*CH2CH3). 13C NMR (101 MHz, CDCl3, δ): 156.2 (Ccarbene),
123.3 (CHbackbone), 90.8 (Cp*C), 89.9 (Cp*C), 87.8 (Cp*C), 38.7
(NCH3), 18.0 (Cp*CH2CH3), 12.9 (Cp*CH2CH3), 9.12 (Cp*CH3),
9.08 (Cp*CH3). HRMS/ESI+ (m/z): calcd for C16H25Cl[193Ir]N2,
473.1335; found, 473.1284.
Synthesis of Ir-7. Following the general procedure, 1,3-
dimethylimidazolium iodide (0.0552 g, 0.2462 mmol), silver(I)
oxide (0.0399 g, 0.1724 mmol), and [(Cp*propyl)IrCl2]2 (0.1000 g,
0.1173 mmol) were reacted in dichloromethane to give Ir-7 (0.0342
1
g, 28%). H NMR (400 MHz, CDCl3, δ): 6.91 (s, 2H, CHbackbone),
3.94 (s, 6H, NCH3), 1.99−1.92 (m, 2H, Cp*CH2CH2CH3), 1.65 (s,
6H, Cp*CH3), 1.62 (s, 6H, Cp*CH3), 1.45 (sextet, J = 7.6 Hz, 2H,
Cp*CH2CH2CH3), 0.92 (t, J = 7.4 Hz, 3H, Cp*CH2CH2CH3). 13C
NMR (101 MHz, CDCl3, δ): 156.2 (Ccarbene), 123.3 (CHbackbone), 90.5
(Cp*C), 89.1 (Cp*C), 88.1 (Cp*C), 38.7 (NCH3), 26.6
(Cp*CH2 CH2 CH3 ), 21. 9 (Cp*CH2 CH2 CH3 ), 14. 4
(Cp*CH2CH2CH3), 9.4 (Cp*CH3), 9.1 (Cp*CH3). HRMS/ESI+
(m/z): calcd for C17H27Cl[193Ir]N2, 487.1487; found, 487.1480.
Synthesis of Ir-10. Following the general procedure, 1,3-
dimethylimidazolium iodide (0.0474 g, 0.2115 mmol), silver(I)
oxide (0.0343 g, 0.1480 mmol), and [(Cp*octyl)IrCl2]2 (0.1000 g,
0.1007 mmol) were reacted in dichloromethane to give Ir-10 (0.0602
g, 50%). 6.91 (s, 2H, CHbackbone), 3.96 (s, 6H, NCH3), 2.01−1.93 (m,
2H, Cp*CH2(CH2)6CH3), 1.66 (s, 6H, Cp*CH3), 1.63 (s, 6H,
Cp*CH3), 1.45−1.20 (m, 12H, Cp*CH2(CH2)6CH3), 0.94−0.81 (m,
3H, Cp*CH2(CH2)6CH3). 13C NMR (101 MHz, CDCl3, δ): 156.4
(Ccarbene), 123.3 (CHbackbone), 90.4 (Cp*C), 89.5 (Cp*C), 88.1
(Cp*C), 38.8 (NCH3), 31.9 (Cp*CH2(CH2)6CH3), 30.0
(Cp*CH2(CH2)6CH3), 29.5 (Cp*CH2(CH2)6CH3), 29.3
(Cp*CH2(CH2)6CH3), 28.8 (Cp*CH2(CH2)6CH3), 24.7
(Cp*CH2(CH2)6CH3), 22.8 (Cp*CH2(CH2)6CH3), 14.2
(Cp*CH2(CH2)6CH3), 9.4 (Cp*CH3), 9.2 (Cp*CH3). HRMS/ESI
+ (m/z): calcd for C22H37Cl[193Ir]N2, 557.2275; found, 557.2293.
Synthesis of Ir-11. Following the general procedure, 1,3-
dimethylimidazolium iodide (0.0512 g, 0.2283 mmol), silver(I)
oxide (0.0370 g, 0.1598 mmol), and [(Cp*phenyl)IrCl2]2 (0.1000 g,
0.1087 mmol) were reacted in dichloromethane to give Ir-11 (0.0970
g, 80%). 1H NMR (400 MHz, CDCl3, δ): 7.56−7.50 (m, 2H,
Cp*Ph), 7.37−7.29 (m, 3H, Cp*Ph), 6.85 (s, 2H, CHbackbone), 3.81 (s,
6H, NCH3), 1.74 (s, 6H, Cp*CH3), 1.68 (s, 6H, Cp*CH3). 13C
NMR (101 MHz, CDCl3, δ): 154.4 (Ccarbene), 131.8 (Cp*Ph), 130.3
(Cp*Ph), 128.4 (Cp*Ph), 127.9 (Cp*Ph), 123.3 (CHbackbone), 93.3
(Cp*C), 88.8 (Cp*C), 85.0 (Cp*C), 38.6 (NCH3), 10.3 (Cp*CH3),
9.3 (Cp*CH3). HRMS/ESI+ (m/z): calcd for C20H25Cl[193Ir]N2,
521.1330; found, 521.1291. Anal. Calcd for C20H25Cl2IrN2·0.5H2O:
C, 42.47; H, 4.63. Found: C, 42.29; H, 4.58.
Synthesis of Rh-15. Following the general procedure, 1,3-
dimethylimidazolium iodide (0.0153 g, 0.0683 mmol), silver(I)
oxide (0.0111 g, 0.0478 mmol), and [(Cp*C F )RhCl2]2 (0.0300 g,
0.0325 mmol) were reacted in dichloromethane to give Rh-15
(0.0112 g, 31%). Well-resolved NMR spectra of Rh-15 were not
acquired, as a suitable amount of the sample was not isolated.
However, the sample was characterized via HRMS and single-crystal
X-ray diffraction. HRMS/ESI+ (m/z): calcd for C20H20ClF5N2Rh,
521.0290; found, 521.0301.
6
5
Synthesis of Ir-1. Following the general procedure, 1,3-
dimethylimidazolium iodide (0.1772 g, 0.7908 mmol), silver(I)
oxide (0.1283 g, 0.5535 mmol), and [(Cp*)IrCl2]2 (0.3000 g,
0.3765 mmol) were reacted in dichloromethane to give Ir-1 (0.2792
g, 75%). Characterization data were consistent with previously
reported data.23
Synthesis of Ir-2. Following the general procedure, 1,3-
diethylimidazolium iodide (0.0664 g, 0.2636 mmol), silver(I) oxide
(0.0428 g, 0.1845 mmol), and [(Cp*)IrCl2]2 (0.1000 g, 0.1255
mmol) were reacted in dichloromethane to give Ir-2 (0.0887 g, 68%).
Characterization data were consistent with previously reported data.24
Synthesis of Ir-4. Following the general procedure, 1,3-
dicyclohexylimidazolium chloride (0.0709 g, 0.2636 mmol), silver(I)
oxide (0.0428 g, 0.1845 mmol), and [(Cp*)IrCl2]2 (0.1000 g, 0.1255
mmol) were reacted in dichloromethane to give Ir-4 (0.0781 g, 49%).
Characterization data were consistent with previously reported data.25
Synthesis of Ir-13. Following the general procedure, 1,3-
dimethylimidazolium iodide (0.0496 g, 0.2213 mmol), silver(I)
oxide (0.0359 g, 0.1549 mmol), and [(Cp*benzyl)IrCl2]2 (0.1000 g,
0.1054 mmol) were reacted in dichloromethane to give Ir-13 (0.0851
g, 71%). 1H NMR (400 MHz, CDCl3, δ): 7.31−7.27 (m, 2H,
Cp*CH2Ph), 7.25−7.18 (m, 1H, Cp*CH2Ph), 7.13−7.09 (m, 2H,
Cp*CH2Ph), 6.94 (s, 2H, CHbackbone), 4.00 (s, 6H, NCH3), 3.44 (s,
2H, Cp*CH2Ph), 1.66 (s, 6H, Cp*CH3), 1.65 (s, 6H, Cp*CH3). 13
C
NMR (101 MHz, CDCl3, δ): 155.7 (Ccarbene), 137.8 (Cp*Ph), 128.8
(Cp*Ph), 128.3 (Cp*Ph), 126.8 (Cp*Ph), 123.4 (CHbackbone), 90.2
(Cp*C), 88.82 (Cp*C), 88.78 (Cp*C), 38.8 (NCH3), 30.5
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(Cp*CH2Ph), 9.7 (Cp*CH3), 9.4 (Cp*CH3). HRMS/ESI+ (m/z):
calcd for C21H27Cl[193Ir]N2, 535.1487; found, 535.1437.
One Solution Reagent (20 μL) was placed in each well, and plates
were incubated at 37 °C for approximately 4 h. After incubation,
plates were read on a spectrophotometer at 490 nm to determine
absorbance values.
Synthesis of Ir-14. Following the general procedure, 1,3-
dimethylimidazolium iodide (0.0482 g, 0.2150 mmol), silver(I)
oxide (0.0349 g, 0.1505 mmol), and [(Cp*phenethyl)IrCl2]2 (0.1000
g, 0.1024 mmol) were reacted in dichloromethane to give Ir-14
(0.0797 g, 67%). 1H NMR (400 MHz, CDCl3, δ): 7.27−7.15 (m, 3H,
Cp*CH2CH2Ph), 7.08−7.00 (m, 2H, Cp*CH2CH2Ph), 6.87 (s, 2H,
CHbackbone), 3.91 (s, 6H, NCH3), 2.72 (t, J = 7.4 Hz, 2H,
Cp*CH2CH2Ph), 2.27 (t, J = 7.4 Hz, 2H, Cp*CH2CH2Ph), 1.64
(s, 6H, Cp*CH3), 1.41 (s, 6H, Cp*CH3). 13C NMR (101 MHz,
CDCl3, δ): 155.9 (Ccarbene), 140.5 (Cp*CH2CH2Ph), 128.8
(Cp*CH2CH2Ph), 128.6 (Cp*CH2CH2Ph), 126.5 (Cp*CH2CH2Ph),
123.3 (CHbackbone), 90.4 (Cp*C), 89.1 (Cp*C), 87.0 (Cp*C), 38.7
(NCH3), 34.6 (Cp*CH2CH2Ph), 27.1 (Cp*CH2CH2Ph), 9.09
(Cp*CH3), 9.07 (Cp*CH3). HRMS/ESI+ (m/z): calcd for C22H29Cl-
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.organomet.1c00166.
■
sı
MIC results for all compounds and microbes tested,
along with NMR spectra for all novel complexes
reported and for the stability studies on Rh-4 and Ir-1,
high-resolution mass spectra for Rh-4 and Ir-1 as
representative examples, and thermal ellipsoid plots for
all complexes characterized by single-crystal X-ray
diffraction (PDF)
[
193Ir]N2, 549.1643; found, 549.1625.
Synthesis of Ir-15. Following the general procedure, 1,3-
dimethylimidazolium iodide (0.0171 g, 0.0763 mmol), silver(I)
Accession Codes
oxide (0.0124 g, 0.0534 mmol), and [(Cp*C F )IrCl2]2 (0.0400 g,
0.0363 mmol) were reacted in dichloromethane to give Ir-15 (0.0362
6
5
CCDC 2035763−2035774 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
1
g, 77%). H NMR (400 MHz, CDCl3, δ): 6.94 (s, 2H, CHbackbone),
3.96 (s, 6H, NCH3), 1.72 (dd, J = 1.9, 0.8 Hz, 6H, Cp*CH3), 1.63 (s,
6H, Cp*CH3). 13C NMR (101 MHz, CDCl3, δ): 152.1 (Ccarbene),
123.7 (CHbackbone), 97.1 (Cp*C), 84.7 (Cp*C), 39.0 (NCH3), 10.1
(dd, J = 3.6, 1.8 Hz, Cp*CH3), 9.8 (Cp*CH3). 19F NMR (376 MHz,
CDCl3, δ): −124.83 (d, J = 24.2 Hz, 1F, Fortho), −138.22 (d, J = 23.2
Hz, 1F, Fortho), −152.74 (t, J = 21.3 Hz, 1F, Fpara), −159.52 (td, J =
22.9, 7.6 Hz, 1F, Fmeta), −162.50 (td, J = 22.6, 8.6 Hz, 1F, Fmeta).
HRMS/ESI+ (m/z): calcd for C20H20ClF5[193Ir]N2, 611.0864; found,
611.0911.
AUTHOR INFORMATION
Corresponding Author
■
Joseph S. Merola − Department of Chemistry, Virginia Tech,
Blacksburg, Virginia 24061, United States; orcid.org/
0000-0002-1743-1777; Phone: +1 (540)231-4510;
Email: jmerola@vt.edu
Antimicrobial Testing. Minimum inhibitory concentrations
(MICs) were measured by a broth microdilution of fresh overnight
cultures of Staphylococcus aureus, methicillin-resistant Staphylococcus
aureus (MRSA), Escherichia coli, Pseudomonas aeruginosa, Candida
albicans, Aspergillus niger, Mycobacterium smegmatis, Mycobacterium
marinum, Mycobacterium abscessus, Mycobacterium chelonae, Mycobac-
terium fortuitum (Type I), Mycobacterium fortuitum (Type III),
Mycobacterium avium, Mycobacterium intracellulare, and Mycobacterium
chimaera according to the Clinical and Laboratory Standards Institute
(CLSI) guidelines with 10% brain heart infusion broth (BHIB)
containing 0.1% (w/v) dimethyl sulfoxide at an inoculum of 105
CFU/mL or Middlebrook 7H9 broth containing 0.5% (w/v) glycerol
and 10% (w/v) oleic acid-albumin (Mycobacterium spp. strains).42
The rhodium and iridium complexes and imidazolium salts were
likewise dissolved in the same media, inoculated with 50 μL of a
1000-fold dilution of each mid log-phase microbial culture, and then
subjected to a 2-fold dilution series in 96-well microtiter plates before
incubation at 30 or 37 °C. After 3 days, the MIC (μg/mL), defined to
be the lowest concentration of compound completely inhibiting the
appearance of turbidity by eye, was determined and confirmed by
absorbance at 540 nm. Control wells containing 50 μL of a 1000-fold
dilution of each mid log-phase microbial culture were inoculated with
10% BHIB containing 0.1% (w/v) dimethyl sulfoxide to confirm that
0.1% DMSO alone does not inhibit growth. The MICs reported were
converted from units of μg/mL to μM, and all of the MIC values of all
compounds screened in this work (in units of μg/mL and μM) are
provided in the Supporting Information.
Cytotoxicity Testing. Vero E6 and Calu-3 cells in complete
medium were seeded in individual 96-well flat bottom plates until
around 80% confluency. Five wells were not seeded as a positive
control to determine background values. After confluency was
reached, media were decanted from the plate and replaced with
media supplemented with Rh-4 at concentrations of 2.5, 5, 10, 25, and
50 μg/mL in replicates of five. Positive and negative controls received
unsupplemented media. Plates were incubated at 37 °C with 5% CO2
for 24 h. After 24 h, the plates were decanted and the wells were
rinsed with media. Fresh media (100 μL) was placed in all of the
wells, and the CellTiter 96 AQueous One Solution Cell Proliferation
Assay (MTS) was used to assess cell viability. CellTiter 96 AQueous
Authors
Chad M. Bernier − Department of Chemistry, Virginia Tech,
Blacksburg, Virginia 24061, United States; orcid.org/
0000-0002-2829-865X
Christine M. DuChane − Department of Chemistry, Virginia
Tech, Blacksburg, Virginia 24061, United States;
orcid.org/0000-0001-9575-3424
Justin S. Martinez − Department of Chemistry, Virginia Tech,
Blacksburg, Virginia 24061, United States
Joseph O. Falkinham, III − Department of Biological Sciences,
Virginia Tech, Blacksburg, Virginia 24061, United States
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.organomet.1c00166
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank Myra Williams for performing the
antimicrobial testing, Dr. James Weger-Lucarelli and Christina
Chuong for conducting the cytotoxicity studies, and Dr. Loren
Brown for synthesizing many of the rhodium and iridium Cp*R
dimers. We also thank the Virginia Tech Department of
Chemistry for funds and supplies. Funding for the Rigaku
Oxford Diffraction Synergy diffractometer used in this work
was provided by the National Science Foundation (Grant No.
1726077).
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