A CuAAC Click Approach for the Introduction of Bidentate Metal Complexes to a Sulfanilamide-Derived Antibiotic Fragment

Article abstract of DOI:10.1021/acs.inorgchem.9b01186

A simple "click-chemistry" approach was employed in order to functionalize the known antibiotic fragment sulfanilamide with a bidentate pyridyl-triazole pocket, which allowed for the synthesis of ruthenium(II) and rhenium(I) carbonyl chloride complexes. Six new complexes were prepared and comprehensively characterized, including five single crystal X-ray structures, photophysical characterization, and testing for antimicrobial activity. Interestingly, functionalization of the pyridine ring with an ortho-hydroxymethyl group resulted in a greater than 100-fold increase in the rate of ligand release in a dimethylsulfoxide solution. Subsequent studies indicated this process could be further accelerated by irradiation with 265 nm light. Structural characterization of four of the complexes indicates that this is the result of a lengthening and weakening of the Re-N_Pyridine bond (average (L^tri) = 2.19 ? vs L^triOH = 2.25 ?) due to the steric influence of the hydroxymethyl group. The organometallic rhenium(I) pyridyl-triazole functionality maintains its characteristic fluorescent properties despite the presence of the sulfonamide moiety. Two of the compounds showed modest antimicrobial activity against methicillin-resistant Staphylococcus aureus, whereas the structurally similar sulfamethoxazole alone showed no activity under the same conditions.

Full text of DOI:10.1021/acs.inorgchem.9b01186

Article
pubs.acs.org/IC
Cite This: Inorg. Chem. XXXX, XXX, XXX−XXX
A CuAAC Click Approach for the Introduction of Bidentate Metal
Complexes to a Sulfanilamide-Derived Antibiotic Fragment
‡
Reece G. Miller,† Melissa Vazquez-Hernandez, Pascal Prochnow,‡ Julia E. Bandow,‡
́
́
and Nils Metzler-Nolte*,†
†Inorganic Chemistry I − Bioinorganic Chemistry, Faculty of Chemistry and Biochemistry, Ruhr University Bochum,
Universitaetsstrasse 150, D-44801, Bochum, Germany
‡Applied Microbiology, Faculty of Biology and Biotechnology, Ruhr University Bochum, Universitaetsstrasse 150, 44780 Bochum,
Germany
S
* Supporting Information
ABSTRACT: A simple “click-chemistry” approach was employed in
order to functionalize the known antibiotic fragment sulfanilamide
with a bidentate pyridyl-triazole pocket, which allowed for the
synthesis of ruthenium(II) and rhenium(I) carbonyl chloride
complexes. Six new complexes were prepared and comprehensively
characterized, including five single crystal X-ray structures, photo-
physical characterization, and testing for antimicrobial activity.
Interestingly, functionalization of the pyridine ring with an ortho-
hydroxymethyl group resulted in a greater than 100-fold increase in
the rate of ligand release in a dimethylsulfoxide solution. Subsequent
studies indicated this process could be further accelerated by
irradiation with 265 nm light. Structural characterization of four of the complexes indicates that this is the result of a
lengthening and weakening of the Re−NPyridine bond (average (Ltri) = 2.19 Å vs LtriOH = 2.25 Å) due to the steric influence of
the hydroxymethyl group. The organometallic rhenium(I) pyridyl-triazole functionality maintains its characteristic fluorescent
properties despite the presence of the sulfonamide moiety. Two of the compounds showed modest antimicrobial activity against
methicillin-resistant Staphylococcus aureus, whereas the structurally similar sulfamethoxazole alone showed no activity under the
same conditions.
The copper(I)-catalyzed azide−alkyne cycloaddition
(CuAAC) “click” reaction, originally described independently
by the groups of Fokin and Sharpless,11 as well as Meldal,12 has
found use throughout synthetic chemistry.13 Examples of this
include the synthesis of bioconjugates,14 dendrimers,15 and
functionalized nanoparticles.16 Furthermore, the CuAAC click
reaction has been used for the synthesis of pyridyl-triazole
ligands and metal complexes of them, which have shown
promising biological,17 photophysical,18 and catalytic proper-
ties.19 More recently, Crowley et al.,17b,18d Bertrand et al.,18a
and Albrecht et al.20 have extended this approach and
investigated the transition metal complexes of bidentate
“inverse” (inv) pyridyl-triazole ligands. Here, “inv” refers to
pyridyl-triazole ligands, where the metal center is chelated by
the pyridine and the central N2 nitrogen atom of the 1,2,3-
triazole ring as opposed to the more common N3-pyridine
pocket.18d
INTRODUCTION
■
In recent years, the development of new antimicrobial agents
has been outpaced by the development of resistance to them.1
Of particular concern is the spread of methicillin-resistant
Staphylococcus aureus (MRSA).1a,b,2 A major problem in drug
development is a lack of diversity in modes of action, where
some reports suggest that the number of distinct known targets
may be limited to 30 or fewer.3 Because of this, there has been
renewed interest in the use of organometallic and inorganic
compounds as alternatives to the more commonly used organic
antibiotics.4 Metallodrugs may possess distinct advantages over
conventional organic antibiotics including new targets,4e,f,5 new
modes of action,4e,f,5 which are foreign to the microbes, a
greatly increased range of available geometries4f (and therefore
can fit a greater range of three-dimensional spaces), and
targeted activity through light6 or redox7 activation.8
Furthermore, because of their photophysical properties,9
metallodrugs are also prominent in the emerging field of
“theranostics”, whereby compounds act as both a therapeutic
and diagnostic agent.4d,10 In many cases, an organic drug
fragment and its target are known, and it would be
advantageous to be able to easily introduce a metal center in
order to improve its biological or physical properties.
For this proof-of-principle study, the known drug fragment
sulfanilamide was chosen. Sulfanilamide belongs to the
sulfonamide-class of antibiotics (Figure 1), a well-known
drug class, which has been heavily exploited in the treatment of
Received: April 23, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.inorgchem.9b01186
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Article
Scheme 1. Synthetic Route to the New Ligands Ltri and
LtriOH and their Ru and Re Complexes Reported in This
a
Work
Figure 1. Known organic sulfonamide drugs sulfanilamide (a),
sulfamethoxazole (b), folate pathway inhibitor trimethomprim (c), as
well as the inv-pyridyl-triazole based ligands (d) and their metal
complexes (e) presented in this work.
bacterial infections. Since the discovery of the antimicrobial
activity of sulfanilamide, many variations incorporating this
drug fragment have been tested. All of these possess the same
mode of action: the inhibition of dihydropteroate synthase
(DHPS). DHPS is a folate pathway enzyme and is responsible
for the synthesis of dihydropteroic acid from para-amino-
benzoic acid.21 One of the most commonly used sulfonamide-
based antibiotics is sulfamethoxazole (SMX).22 In practice,
SMX is usually used in combination with trimethoprim (TMP)
(Figure 1) in a formulation known as cotrimoxazole SMX−
TMP.21−23 The standard formulation is a 1:5 mixture, which
results in a 1:20 plasma concentration due to differences in
bioavailability.22 Studies have shown that this 1:20 ratio leads
to an optimal cooperative effect.22 While SMX−TMP is only
commonly used in the treatment of urinary tract infections,24 it
has also found use in the treatment of a wide range of bacterial
infections from bronchitis and pneumonia22 to traveler’s
diarrhea.25 Furthermore, there has been renewed interest in
SMX−TMP for the treatment of methicillin resistant S.
aureus,21,26 with the scientific literature indicating good efficacy
against some strains of S. aureus.27 However, as with almost all
known antibiotics, the use of sulfonamides has been plagued by
antibiotic resistance.21,27a,28 One common mechanism of
resistance to sulfonamides is a single amino acid substitution,
which weakens the binding of the substrate in DHPS.27a
As the binding of sulfonamide antibiotics to dihydropteroate
synthase is stabilized by intermolecular hydrogen bonding,21,29
we hypothesized that the introduction of an organometallic
moiety with exchangeable ligands could help to overcome this
resistance by introducing a secondary binding interactionfor
example, via ligand exchange with a nucleophilic side chain on
the protein. Presented herein is a click-chemistry approach for
the synthesis of pyridyl-triazole ligands, which have been
derived from sulfonamides, and the synthesis of their
corresponding rhenium and ruthenium carbonyl complexes.
a
Conditions: (i) K2CO3, MeCN, reflux, 4 h. (ii) CuI, Cu(s), NaOAc,
DIPEA, toluene/DMF (9:1 v/v), 100 °C, N2(g). (iii)
[RuII(CO)2Cl2]n, EtOH, reflux, N2(g) (iv) [ReI(CO)5Cl], EtOH,
reflux, N2(g).
be recovered by column chromatography. The desired pyridyl-
triazole ligands can then be obtained in moderate yields (47%)
by reaction with the corresponding azido-pyridine using
CuAAC “click” chemistry.17b,18 The corresponding metal
complexes could then be obtained in moderate to excellent
yields (50%- quantitative) by reaction of the ligands with either
[RuII(CO)2Cl2]n or [ReI(CO)5X] (Scheme 1). The higher
hydrophilicity of [RuII(LtriOH)(CO)2Cl2] relative to the other
complexes reduced the recovery of this compound from
column chromatography leading to the lower (50%) isolated
yield.
Both NMR (Figures S2−S18) and structural (Figures 2−3)
evidence confirmed that, despite several potential donor atoms,
the only observed products were the desired pyridyl-triazole
bound complexes.
Structural Characterization. Four of the metal complexes
and one of the ligands were characterized structurally by X-ray
crystallography. A summary of the key structural information is
given in Table 1. Single crystals of the sulfonamide-ligand
LtriOH were grown from a solution of the ligand in MeCN-d3,
which had been left to slowly evaporate in an NMR tube after
characterization by NMR. LtriOH crystallizes in the monoclinic
space group P21/c (Figure S25). Adjacent molecules of LtriOH
form strong reciprocated H-bonds between the sulfonamide
N−H proton and the OH oxygen atom [N(2)−H···O(3)
2.878(2) Å, 167.8°].
Colorless, needle-shaped crystals of [RuII(Ltri)(CO)2Cl2]
were grown by vapor diffusion of diethyl ether into a solution
of the complex. [RuII(Ltri)(CO)2Cl2] (Figure 2, Table 1)
crystallizes in the monoclinic space group P21/c with one
molecule of the complex and one acetone molecule of
solvation in the asymmetric unit. The chloride ligands adopt
the usual trans arrangement in the axial positions, which has
been observed for related complexes such as bipyridyl30 and
pyridyl-1,2,4-triazole based ligands.31 Therefore, the two
carbonyl ligands are cis relative to one another and lie in a
square plane with the bidentate ligand. The Ru−N(4)bond is
only slightly shorter than that of the Ru−N(6) bond. The
RESULTS AND DISCUSSION
■
Synthesis and Structures. The new sulfonamide-based
ligands were prepared in two simple steps from commercially
available materials (Scheme 1). First, reaction of propargyl
bromide with an excess of sulfanilamide allows for preferential
alkylation at the more nucleophilic sulfonamide nitrogen. The
low yield (17%) was unavoidable due to the activating effect of
alkylation, which results in over-alkylation. In order to avoid
this, a large excess of sulfanilamide was used, which could then
B
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Figure 2. Solid state structures of [RuII(Ltri)(CO)2Cl2] (top) and
[ReI(Ltri)(CO)3Cl] polymorph B (bottom). H atoms and solvent
molecules have been omitted for clarity. Thermal ellipsoids are shown
at the 50% probability level.
Figure 3. Solid state structures of [ReI(LtriOH)(CO)3Br] (top) and
[ReI(Ltri)(CO)3Br] (bottom). H atoms (except those involved in
close H···CO contacts) and solvent molecules have been omitted for
clarity. For [ReI(LtriOH)(CO)3Br], only the major component of the
CO/Br disorder is shown. Thermal ellipsoids are shown at the 50%
probability level.
acetone molecule of solvation is involved in a strong hydrogen
bond to the NH2 group of the aniline ring [N(1)−H···O(31)
2.948(5) Å, 154.6°].
Highlighter-yellow, plate-shaped crystals of both rac-
[ReI(Ltri)(CO)3Cl] polymorph B (Figure 2) and rac-
[ReI(Ltri)(CO)3Br] (Figure 3) were grown by slow evapo-
ration of a solution of the corresponding complex in methanol.
The complexes are isostructural and crystallize in the
monoclinic space group Pn with one stereoisomer in the
asymmetric unit and the other being generated by the glide
plane.
Therefore, the unit cell comprises both stereoisomers as well
as two disordered MeOH molecules. Analogous to the
ruthenium complex [RuII(Ltri)(CO)2Cl2], the Re−
N(4)bonds are slightly shorter than that of the Re−N(6)
(Table 1) bond in both complexes. There is however no
significant difference in the Re−N and Re−C bond lengths
between the two rhenium(I) complexes.
Highlighter-yellow, needle-shaped crystals of rac-
[ReI(LtriOH)(CO)3Br] were grown by vapor diffusion of
hexane into a solution of the complex in EtOH/acetone (1:1).
The complex crystallizes solvent-free in the orthorhombic
space group I41/a with one stereoisomer in the asymmetric
unit and the other being generated by reflection through the
glide plane. The main residue is disordered with approximately
12.5% of the molecules having the opposite stereochemistry.
Presumably, this occurs because the axial chlorine and carbonyl
functionalities can be inverted while only causing minor
changes to the crystal packing. Because of the glide plane
symmetry, the mixture of isomers within the lattice remains
racemic.
In contrast to the complexes of Ltri, the Re−N(6) bond is
significantly longer than the Re−N(4) bond (Table 1, Figure
3). This lengthening of the Re−N(6) bond can be attributed
to the steric influence of the CH2OH group, whereby short
contacts (CH···CO = 2.622 Å, 2.636 Å) between the CH2
protons and the cis coordinated carbonyl cause the Py−Re
bond to be lengthened and weakened. For comparison, the
sum of the atomic radii for a H···C contact is 2.8 Å.32 In
contrast, the shortest CH−CO contacts in the rhenium(I)
complexes of Ltri fall into the range 2.78−2.95 Å. Furthermore,
because of the longer M−Py bond, a slight shortening of the
trans M−CO bond is also observed. Moreover, this close
contact results in a more distorted octahedron, which is
C
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Table 1. Selected Structural Data for the Structurally Characterized Ruthenium(II) and Rhenium(I) Complexes
ML
Re(Ltri)Br
Re(LtriOH)Br
Re(Ltri)Cl (P21/c) polymorph A
Re(Ltri)Cl (Pn) polymorph B
Ru(Ltri)Cl
M−N(6)
M−N(4)
M−CO eq
2.19(1)
2.14(1)
1.94(1)
1.94(2)
1.96(1)
2.912
2.245(7)
2.132(7)
1.88(1)
1.92(1)
1.92(2)
2.622
2.186(6)
2.157(6)
1.948(9)
1.920(8)
1.89(2)
2.78
2.18(1)
2.147(9)
1.92(1)
1.92(2)
1.94(1)
2.95
2.135(3)
2.103(3)
1.892(4)
1.892(4)
a b
,
ab
,
M−CO ax
CH···CO
2.74
2.636
N(6)−M−N(4)
N(6)−M−CO
<CO−M−CO
N(4)−M−CO
74.4(4)
99.1(6)
90.2(6)
95.7(5)
73.4(2)
105.3(3)
85.9(3)
95.4(3)
73.9(2)
96.4(3)
88.4(3)
91.3(6)
73.6(4)
96.4(5)
89.8(6)
99.9(6)
58.3
76.1(1)
95.9(2)
88.5(2)
99.4(2)
47.5
c
a
a
Oh distortion
46.5
63.8
58.8
a
b
Major component of disorder. Although the disorder could be well-modeled, these values should be viewed with caution as the presence of the
c
heavy halogen atom as a minor component of the disorder may interfere with an accurate bond length measurement. Defined as the sum of the
deviation of the 12 cis angles from 90°.
reflected in both the octahedral distortion parameter and the
larger C(22)−Re−N(6) angle for the substituted complex.
Bright yellow, needle-shaped crystals of [ReI(Ltri)(CO)3Cl]
polymorph A (Figure S26) were grown by vapor diffusion of
hexane into a solution of the complex in acetone. The complex
crystallizes in the monoclinic space group P21/c with one
stereoisomer of the complex and one acetone molecule of
solvation in the asymmetric unit and the other being generated
by glide plane symmetry. Unlike polymorph B, this complex
adopts the “extended” conformation (see following paragraph).
Here, main residue disorder is again observed with
approximately 25% of the molecules having the opposite
stereochemistry.
The crystal structures can be divided into two conforma-
tional groups: “extended” and “folded”. Because of the range of
hydrogen bonders and acceptors as well as π-rich and π-
deficient ring systems both of these conformers allow for a
myriad of inter- and intramolecular interactions. The
distinguishing feature of the folded structures is the offset
intramolecular π−π stacking interactions between the aniline
ring and the pyridyl-triazole ligand component (Table S3).
Conversely, the extended structures are characterized by pairs
of reciprocated intermolecular N−H···pi interactions between
aniline rings on adjacent molecules, as well as π-stacking
interactions between the electron-poor pyridine ring and the
electron-rich triazole ring on a further adjacent molecule
(Table S4).
Figure 4. Normalized absorption (A) and photoluminescence (PL)
data for a 0.03 mM solution of [Re(Ltri)(CO)3Cl] in ethanol. The
excitation wavelength for PL was 400 nm.
The rhenium(I) complexes show a broad emission band
centered around 580 nm (Table 2), which is consistent with
Table 2. Photophysical Properties of the Rhenium(I) and
Ruthenium(II) Complexes in Ethanol at 298 K
absorption
emission
λmax (Φ)
M
λmax (ε/cm mol−1 L−1
)
λmax (Φ) air
N2(g)
Ru(Ltri)
265 (27100)
Re(Ltri)Cl
Re(Ltri)Br
Ru(LtriOH)
265 (29700), 361 (4460) 583 (0.0100)
264 (29000), 363 (4350) 583 (0.0095)
266 (27600)
583 (0.038)
578 (0.064)
Interestingly, in the case of [ReI(Ltri)(CO)3Cl], different
crystallization conditions led to two different polymorphs that
represent both the extended and folded conformers of the
complex, whereby crystals formed by vapor diffusion of hexane
into a solution of the complex in acetone resulted in the
extended structure (polymorph A), and crystals grown via slow
evaporation of a methanolic solution of the complex adopted
the folded structure (polymorph B). Attempts to crystallize the
other complexes in both conformers were unsuccessful. This
may be due to solubility differences between the two
complexes, as the complexes of LtriOH are less soluble in
neat acetone, and analogous acetone/hexane vapor diffusion
experiments resulted in fine powders.
Re(LtriOH)Cl 265 (29000), 354 (3200) 580 (0.0085)
Re(LtriOH)Br 265 (32000), 357 (3100) 576 (0.0122)
578 (0.014)
576 (0.024)
related complexes of inv-triazole ligands in the literature.18a,d
The emission quantum yields were measured in EtOH, both in
air and under N2(g) and are slightly lower than those observed
for related compounds measured in DCM or MeCN.18a,d
These data indicate that the sulfonamide antibiotic fragment
has only a minor influence on the photophysical properties of
these ligands.
Photochemical Ligand Release. Complexes of ruthe-
nium and rhenium have been shown to undergo photo-
chemical ligand exchange.8,33 This has generated significant
interest for applications such as photoactivated drugs.8,34
Photophysical Properties. Electronic absorption and
emission spectra of all of the complexes were measured in
EtOH (Figure 4 and Figure S32).
D
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Furthermore, a comparison of “regular” and “inverse” pyridyl-
triazole complexes demonstrated photolability for inverse but
not regular pyridyl-triazoles.18a,d While solutions of the
complexes of LtriOH in coordinating solvents such as
dimethylsulfoxide (DMSO) showed significant ligand release
after 24 h (up to 35−62%) even when kept in the dark, ligand
release was much slower for complexes of Ltri, all of which
showed minimal (≤5%) release after 48 h. On the basis of
NMR integration, the relative rates of ligand exchange between
equivalent complexes of each ligand range from ca. 20:1 for
[Re(L)(CO)3Cl] to >100:1 for [RuII(L)(CO)2Cl2] (Figures
S36−S40, Table S5).
Furthermore, the complexes of LtriOH showed slow ligand
exchange in MeCN (Figure S41), whereas the complexes of
Ltri were stable for up to 2 weeks. Small differences in stability
were also observed for the different complexes of each ligand,
whereby the fastest rate of ligand exchange was observed for
the [Re(L)(CO)3Cl] complexes.
Solutions of all of the complexes in the coordinating solvent
DMSO showed accelerated ligand exchange when visible light
was not excluded. For all of the complexes except [RuII(Ltri)-
(CO)2Cl2], the presence of visible light did not result in
additional decomposition products. The behavior of
[RuII(Ltri)(CO)2Cl2] was more complicated with the appear-
ance of at least two other decomposition products in addition
to a small amount of free ligand. These decomposition
products contained some peaks in the 1H NMR spectrum that
could be assigned to the ligand or ligand fragments but did not
belong to either the free ligand or the complex [RuII(Ltri)-
(CO)2Cl2]. A possible explanation is the substitution of some
of the chloride and/or carbonyl ligands with DMSO. However,
subsequent analysis by ESI-MS was unable to confirm this.
In order to further investigate the relative rates of ligand
photorelease for the rhenium(I) complexes of both ligands,
solutions of the complexes in DMSO were exposed to 265 nm
light, and the reaction was monitored by UV−vis spectroscopy
(Figures 5 and S33). Under these conditions, the ligand loss
was further accelerated, whereby complexes of LtriOH showed
complete ligand loss within 4 h (Figure 5 and Figure S32).
However, a smaller difference in reaction rates was observed
under irradiation, which likely reflects the ability of the
complexes of LtriOH to undergo ligand exchange by a light-
independent mechanism. Because of the shorter time scales
involved in this experiment, this light-independent ligand loss
is less important here.
Figure 5. Top: progression of the 360 nm absorption band of a
solution of [ReI(LtriOH)(CO)3Cl] in DMSO with time under
irradiation of 265 nm light. Bottom: Relative change in absorbance
at 360 nm for DMSO solutions of [ReI(LtriOH)(CO)3Cl] (red) and
[ReI(Ltri)(CO)3Cl] (blue).
The accelerated ligand exchange could be due to either
electronic or steric effects. As the CH2OH group is only very
weakly inductively electron donating and isolated from
mesomeric effects, both the σ-donor and π-acceptor properties
of the pyridine ring should be largely unaffected. Therefore,
electronic effects are only expected to play a minor role in the
stability of the complexes. This is supported by NMR and IR
spectroscopy, whereby only minor differences are observed
between the complexes of the two ligands. If the π-acceptor
properties of the pyridine ring were to be altered, then the
strength of the CO bond of the carbonyl ligand trans to the
pyridine ring should also be altered. This was probed with IR
spectroscopy, which showed no significant changes in the
C≡O stretching frequency (<2 cm−1, Figures S42−S44)
between the complexes of Ltri and LtriOH. This provides
further evidence that the observed changes are not due to
changes in the electronics of the pyridine ring.
The difference in rates can, however, be explained in terms
of the steric influence of the CH2OH group. As described in
the structural characterization section, steric effects cause the
Re−N(6) bond to be lengthened and weakened in
[ReI(LtriOH)(CO)3X] relative to [ReI(Ltri)(CO)3X].
Antimicrobial Activity. The antimicrobial activity of the
two pyridyl-triazole ligands and their ruthenium and rhenium
complexes was investigated through the determination of
minimum inhibitory concentration (MIC) values.35 All
compounds were tested against a range of Gram-positive and
Gram-negative bacteria, and the results were compared to the
known folate pathway inhibitors sulfamethoxazole (SMX),
trimethoprim (TMP), and cotrimoxazole (TMP-SMX, 1:20).
A full table of MIC values is given in the Supporting
Information (Table S6). All of the bacterial strains tested
E
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Table 3. Minimal Inhibitory Concentrations on S. aureus of SMX, TMP, BS SMX-TMP, as well as the Rhenium(I) Complexes
b
a
and Formulations that Showed Activity in This Work
S. aureus
S. aureus
S. aureus
S. aureus
DSM 20231
ATCC 43300
BAA 976
BAA 977
c
c
c
c
SMX
n.a.
n.a.
n.a.
n.a.
TMP
6.9 [2]
14 [4]
14 [4]
6.9 [2]
Re(Ltri)Cl
400 [256]
380 [256]
380 [256]
120:6.0 [32]
49:2.5 [32]
46:2.3 [32]
400 [256]
750 [512]
380 [256]
960:48 [256]
98:4.9 [64]
46:2.3 [32]
400 [256]
400 [256]
190 [128]
380 [256]
40:1.5 [8]
98:4.9 [64]
46:2.3 [32]
c
Re(Ltri)Br
n.a.
Re(LtriOH)Cl
SMX-TMP (20:1)
Re(Ltri)Cl-TMP (20:1)
Re(Ltri)Br − TMP (20:1)
380 [256]
40:1.5 [8]
98:4.9 [64]
23:1.2 [16]
a
b
c
Values are given in μmol L−1 and [μg/mL]. Mixtures of the rhenium(I) complexes with TMP in a 20:1 molar ratio. n.a.: not active up to 512
μg/mL.
showed very high resistance against sulfamethoxazole alone,
whereas trimethoprim showed high activity against all strains
except Acinetobacter baumannii and Pseudomonas aeruginosa. In
most cases, the activity of TMP−SMX was higher on a molar
basis than TMP alone. This suggests some cooperative activity
despite high levels of resistance to SMX. Three of the
synthesized compounds [ReI(Ltri)(CO)3Cl], [ReI(Ltri)-
(CO)3Br], and [ReI(LtriOH)(CO)3Cl] showed modest activity
against S. aureus (Table 3) and therefore outperformed the
parent sulfonamide SMX. Two of the rhenium(I) complexes
that showed some activity were then tested in combination
with TMP in a 20:1 ratio. This combination was chosen as it is
analogous to the plasma concentration of SMX−TMP
achieved with the standard clinical formulation.22
Interestingly, the activity of the Re-TMP formulations was
roughly equal for all strains of S. aureus that were tested,
including the methicillin-resistant strain, ATCC 4300. In
comparison, the standard SMX−TMP formulation gave mixed
results, showing good activity against two strains BAA 976 and
BAA 977, moderate activity against one strain DSM 20231,
and poor activity against MRSA ATCC 4300. These results
indicate that such metalated drug fragments may help to
increase antimicrobial activity in the cases of high resistance. It
is important to note however that the best per gram activity
against all strains was achieved with TMP alone. These data
are therefore not inconsistent with reports that have
questioned the increased efficacy of TMP−SMX compared
to TMP alone.36
steric factors is more important for the “dark” mechanism.
These properties could be exploited in the design of future
photoactivatible drugs. Antimicrobial testing of our new SMX-
derived metal complexes showed encouraging activity against
MRSA strains for one Re derivative. However, as treatment
options against multiresistant bacteria are generally scarce, this
finding certainly merits further attention.
EXPERIMENTAL SECTION
■
All solvents and reagents were used as received, except for
37
[Ru(CO)2Cl2]n and 2-azido-pyridine,18d which were prepared
according to literature procedures. X-ray crystal structure determi-
nation details are provided in Tables S1−S2. The structures were
refined with SHELXL38 within the OLEX-2 graphical user interface.39
For full instrumentation details, please see the Supporting
Information.
N-Propargyl-sulfanilamide. A mixture of sulphanilamide (4.0 g,
23.2 mmol) and K2CO3 (3.2 g, 23.2 mmol) in MeCN (120 mL) was
heated to 82 °C in a two-necked flask fitted with a dropping funnel.
Once this temperature was reached, a solution of propargyl bromide
(1.25 mL, 80 wt % solution in toluene, 11.6 mmol) in MeCN (40
mL) was added dropwise over 1 h. Refluxing was then continued for a
further 2.5 h before the mixture was allowed to cool to ambient
temperature. Water (150 mL) was added, and the mixture was
extracted with CHCl3 (3 × 100 mL). The combined organic extracts
were dried (Na2SO4), filtered, and taken to dryness at reduced
pressure to give a waxy yellow solid. This solid was then suspended in
DCM/MeCN (16:1, 20 mL), filtered, washed with DCM/MeCN
(16:1, 3 × 1 mL), and air-dried. The obtained white solid is
analytically pure starting material and can be reused. The filtrate,
which contains both the mono- and disubstituted products as well as
traces of starting material, was then purified by column chromatog-
raphy on silica gel (150 mL), eluting with a DCM/MeCN gradient
(16:1 → 4:1). Three fractions were then collected. The disubstituted
product elutes first (rf = 0.83, 4:1 DCM/MeCN), monosubstituted
second (rf = 0.56, 4:1 DCM/MeCN), and finally traces of unreacted
starting material (rf = 0.28, 4:1 DCM/MeCN). Yield: 412 mg (1.96
mmol, 17.0% based on propargyl bromide). ESI-MS (pos.) m/z =
232.90 calc. for [C9H10N2O2S]Na+ = 233.03. Elemental analysis calc.
for C9H10N2O2S (210.05 g mol−1): C 51.41 H 4.79 N 13.32 S 15.25;
CONCLUSION
■
In summary, a CuAAC click approach has been employed for
the functionalization of a known antibiotic drug fragment with
metal-containing fragments. The resulting rhenium(I) com-
plexes showed improved performance against MRSA relative to
the purely organic drug sulfamethoxazole alone.
Interestingly, the introduction of a CH2OH group in ortho
position to the metal center results in a significantly more labile
metal−ligand bond. Subsequent structural characterization of
four of the metal complexes indicated this lability is probably
due to steric effects, whereby a significant distortion of the
octahedral geometry is caused by the introduction of the
hydroxymethyl group, as well as a lengthening and weakening
of the metal-pyridine bond. Irradiation with 265 nm light
increased the rate of ligand exchange for all of the complexes.
Under these conditions however, the difference in reaction
rates between the two ligands is reduced to 3−8 fold,
indicating the weakening of the ligand metal bonds due to
1
found: C 51.44 H 4.74 N 13.48 S 15.17%. H NMR (200 MHz,
CDCl3): δ (ppm) 7.65 (2H, m, JHc‑Hb = 8.7 Hz, 2xHc) 6.69 (2H, m,
J
Hb‑Hc = 8.7 Hz, 2xHb) 4.40 (1H, t, JHd‑He = 6.1 Hz, Hd) 4.13 (2H, s,
2xHa) 3.80 (2H, dd, JHe‑Hd = 6.1 Hz, JHe−Hf = 2.5 Hz, 2xHe) 2.13 (1H,
t, JHf−He = 2.5 Hz, Hf). 13C NMR (100 MHz, DMSO-d6): δ (ppm)
152.6, 128.6, 125.1, 112.6, 79.8, 74.3, 31.9.
2-(4-Methyl-sulfanilamidyl-1H-1,2,3-triazol-1-yl)pyridine
(Ltri). A solution of N-propargyl-sulfanilamide (272 mg, 1.30 mmol),
2-azido-pyridine (155 mg, 1.30 mmol), NaOAc (107 mg, 1.30 mmol),
and DIPEA (221 μL, 1.30 mmol) in toluene/DMF (9:1 80 mL) was
degassed by bubbling with N2(g) for 20 min. To this solution was
F
DOI: 10.1021/acs.inorgchem.9b01186
Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry
Article
then added CuI (247.7 mg, 1.30 mmol) and Cu(s) (8 mg, 0.130
mmol). The resulting suspension was then degassed for a further 20
min before being heated to reflux for 16 h. After this time, a yellow
solution had formed with a large amount of brown solid on the walls
of the flask. The mixture was allowed to cool to ambient temperature
before an aqueous solution of 0.1 M EDTA and 0.1 M NaOH (100
mL) was added. The mixture was stirred at ambient temperature for 1
h and then extracted with a solution of 5% DMF in EtOAc (3 × 150
mL). The organic extracts were dried over Na2SO4, filtered, and taken
to dryness at reduced pressure to give a beige solid. The solid was
then suspended in CHCl3 (80 mL), sonicated, filtered, and washed
with CHCl3 (3 × 5 mL). The resulting pale beige solid was air-dried
and then further dried in vacuo to give the analytically pure product.
Yield: 200 mg, 0.61 mmol, 47%. HR-ESI-MS (pos.) m/z = 331.0968
calc. for [C14H14N6O2S]H+ = 331.0977. Elemental analysis calc. for
C14H14N6O2S (330.36 g mol−1): C 50.90 H 4.27 N 25.44 S 9.71;
found: C 50.81 H 4.24 N 25.65 S 9.94%. 1H NMR (300 MHz,
DMSO-d6): δ (ppm) 8.59 (1H, ddd, Hj), 8.48 (1H, s, Hf), 8.05−8.14
(2H, m, Hg and Hh), 7.71 (1H, t, JHd‑He = 6.0 Hz, Hd), 7.54 (1H, t,
calc. for [C17H14N6ClO5ReS]2H+ = 1273.0037. Elemental analysis
calc. for C17H14N6ClO5ReS (636.06 g mol−1): C 32.10 H 2.22 N
13.21 S 5.04; found: C 32.23 H 2.38 N 13.23 S 4.99%. 1H NMR (300
MHz, CD3CN): δ (ppm) 8.90 (1H, ddd, JHj‑Hi = 5.6 Hz, Hj), 8.51
(1H, s, Hf) 8.31 (1H, ddd, JHh‑Hg = 8.3 Hz, JHh‑Hi = 7.7 Hz, Hh), 7.99
(1H, dt, JHg‑Hh = 8.2 Hz, Hg), 7.63 (1H, td, JHi‑Hh = 7.7 Hz, Hi), 7.50
(2H, m, JHc‑Hb = 8.7 Hz, 2xHc), 6.64 (2H, m, JHb‑Hc = 8.7 Hz, 2xHb),
6.11 (1H, t, JHd‑He = 6.5 Hz, Hd), 4.74 (2H, s, Ha) 4.28 (2H, d, JHe‑Hd
= 6.5 Hz, 2xHe) 13C{1H} NMR (100 MHz, CD3CN): δ (ppm) 196.4,
195.4, 188.0, 152.3, 152.0, 148.3, 146.9, 142.6, 128.8, 126.1, 125.9,
122.9, 114.3, 113.0, 37.6. ATR-IR (cm−1): 2368 (w), 2025 (s, CO),
1904 (s, br., CO), 1625 (w), 1597 (m), 1501 (w), 1456 (w), 1319
(m, br.), 1151 (s), 1096 (m), 1066 (m), 834 (w), 775 (m), 683 (w).
Pale yellow needle-shaped single crystals of [ReI(Ltri)(CO)3Cl]·
acteone (polymorph A, P21/c) suitable for single crystal X-ray
diffraction were grown by vapor diffusion of hexane into a solution of
[ReI(Ltri)(CO)3Cl] in acetone. Highlighter-yellow, plate-shaped
single crystals of [ReI(Ltri)(CO)3Cl] (polymorph B, Pn) suitable for
single crystal X-ray diffraction were grown by slow evaporation of a
solution of [ReI(Ltri)(CO)3Cl] in MeOH.
J
J
Hi‑Hj = 7.3 Hz, Hi), 7.44 (2H, m, JHc‑Hb = 8.7 Hz, 2xHc), 6.57 (2H, m,
Hb‑Hc = 8.7 Hz, 2xHb), 5.92 (2H, s, Ha), 4.08 (2H, d, JHe‑Hd = 6.0 Hz,
[ReI(Ltri)(CO)3Br]. A suspension of [ReI(CO)5Br] (98 mg, 0.24
mmol) and Ltri (80 mg, 0.24 mmol) in EtOH (25 mL) was degassed
by bubbling with N2(g) before being heated to reflux under a nitrogen
atmosphere for 40 h. During this time, the suspension cleared to give
a yellow solution. The mixture was allowed to cool to ambient
temperature and then taken to dryness at reduced pressure to give a
waxy yellow solid. Elemental analysis calc. for C17H14BrN6O5ReS
(679.95 g mol−1): C 30.01, H 2.07, N 12.35, S 4.71; found: C 30.38 H
2.35 N 11.99 S 5.08%. HR-ESI-MS (pos.) m/z = 680.9542 calc. for
[C17H14BrN6O6ReS]H+ = 680.9547; m/z = 601.0320 calc. for
2xHe). 13C{1H} NMR (100 MHz, CDCl3): δ (ppm) 152.7, 149.0,
148.4, 145.1, 140.2, 128.6, 125.1, 124.3, 120.2, 113.6, 112.7, 38.0.
2-(4-Methyl-sulfanilamidyl-1H-1,2,3-triazol-1-yl)-6-hydroxy-
methyl-pyridine (LtriOH). A solution of N-propargyl-sulfanilamide
(290 mg, 1.38 mmol), 2-azido-6-hydroxymethyl-pyridine (220 mg,
1.47 mmol), NaOAc (115 mg, 1.40 mmol), and DIPEA (238 μL, 1.40
mmol) in toluene/DMF (9:1 80 mL) was degassed by bubbling with
N2(g) for 20 min. To this solution was then added CuI (267 mg, 1.40
mmol) and Cu(s) (9 mg, 0.140 mmol). The resulting suspension was
then degassed for a further 20 min before being heated to reflux for 16
h. After this time, an orange solution had formed with a large amount
of brown solid on the walls of the flask. The mixture was allowed to
cool to ambient temperature before an aqueous solution of 0.1 M
EDTA and 0.1 M NaOH (100 mL) was added. The mixture was
stirred at ambient temperature for 1 h and then extracted with a
solution of 5% DMF in EtOAc (3 × 150 mL). The organic extracts
were dried over Na2SO4, filtered, and taken to dryness at reduced
pressure to give a mixture of a yellow oil and crystalline solid. This
was then purified by column chromatography on silica gel (80 mL),
eluting with a gradient of MeCN in DCM (20% → 100%). The
resulting white solid was dried in vacuo to give the analytically pure
product (r.f. = 0.05, MeCN/DCM 1:3). Yield: 232 mg, 0.64 mmol,
47%. HR-ESI-MS (pos.) m/z = 361.1075 calc. for [C15H16N6O3S]H+
= 361.1083. Elemental analysis calc. for C15H16N6O3S (360.39 g
mol−1): C 49.99 H 4.48 N 23.32, S 8.90; found: C 49.83 H 4.47 N
23.57 S 9.08%. 1H NMR (400 MHz, DMSO-d6): δ (ppm) 8.45 (1H,
1
[C17H14N6O6ReS]+ = 601.0303. H NMR (300 MHz, CD3CO): δ
(ppm) 9.06 (1H, dt, JHj‑Hi = 5.5 Hz, Hj), 9.01 (1H, s, Hf), 8.51 (2H,
m, Hh and Hg), 7.82 (1H, m, Hi), 7.56 (2H, m, JHc‑Hb = 8.9 Hz, 2xHc),
6.97 (1H, t, JHd‑He = 6.4 Hz, Hd), 6.73 (2H, m, JHb‑Hc = 8.9 Hz, 2xHb),
5.42 (2H, br. s, 2xHa), 4.36 (2H, d, JHe‑Hd = 6.4 Hz, 2xHe). 13C{1H}
NMR (100 MHz, CD3CO): δ (ppm) 197.4, 196.3, 188.8, 153.7,
153.5, 150.0, 148.5, 143.8, 130.0, 129.3, 127.3, 124.3, 120.7, 115.5,
114.1, 38.9. ATR-IR (cm−1): 2976 (w), 2365 (w), 2025 (s, CO),
1902 (s, br., CO), 1622 (w), 1597 (m), 1495 (w), 1456 (w), 1315
(m, br.), 1151 (s), 1067 (m), 837 (w), 771 (m), 681 (w).
Highlighter-yellow, needle-shaped single crystals of [ReI(Ltri)-
(CO)3Br] suitable for single crystal X-ray diffraction were grown by
slow evaporation of a solution of [ReI(Ltri)(CO)3Br] in MeOH.
[RuII(Ltri)(CO)2Cl2]. A suspension of [RuII(CO)2Cl2]n (69 mg, 0.30
mmol) and Ltri (100 mg, 0.30 mmol) in EtOH (30 mL) was degassed
by bubbling with N2(g) before being heated to reflux under a nitrogen
atmosphere for 18 h. During this time, the suspension cleared to give
a yellow solution. The mixture was allowed to cool to ambient
temperature and then taken to dryness at reduced pressure to give a
waxy yellow solid. This was then purified by reverse-phase (C18)
column chromatography using a CombiFlash Rf system with a THF/
H2O gradient (5% → 95%). The product eluted with 25% THF. The
solution was then concentrated to approximately half the volume by
rotary evaporation, which caused a yellow precipitate to form. The
solution was stored at 4 °C for 1 h to allow further precipitation then
filtered and washed with a small amount of water. The product was
first air-dried then further dried in vacuo. Yield: 106 mg, 0.17 mmol,
s, Hf), 8.09 (1H, t, JHh‑Hg = JHh‑Hi = 7.8 Hz Hh), 7.92 (1H, d, JHg‑Hh
=
8.0 Hz, Hg), 7.70 (1H, br. s, Hd), 7.58 (1H, d, JHi‑Hh = 7.6 Hz, Hi),
7.44 (2H, m, JHc‑Hb = 8.7 Hz, 2xHc), 6.59 (2H, m, JHb‑Hc = 8.7 Hz,
2xHb), 5.91 (2H, s, Ha), 5.60 (1H, t, JHl‑Hk = 5.1 Hz, Hl) 4.64 (2H, d,
JHk‑Hl = 5.1 Hz, 2xHk) 4.07 (2H, br. s, 2xHe) 13C{1H} NMR (100
MHz, DMSO-d6): δ (ppm) 162.1, 152.6, 147.4, 145.1, 140.4, 128.5,
125.0, 120.3, 120.1, 112.6, 111.3, 63.7, 38.0. A small sample of LtriOH
was dissolved in MeCN-d3 and allowed to slowly evaporate in an
NMR tube, resulting in colorless rod-shaped crystals suitable for X-ray
crystallography.
[ReI(Ltri)(CO)3Cl]. A suspension of [ReI(CO)5Cl] (103 mg, 0.28
mmol) and Ltri (94 mg, 0.28 mmol) in EtOH (25 mL) was degassed
by bubbling with N2(g) before being heated to reflux under a nitrogen
atmosphere for 18 h. During this time, the suspension had mostly
cleared to give a yellow solution. The mixture was allowed to cool to
ambient temperature, and a small amount of solid was filtered off. The
filtrate was then taken to dryness at reduced pressure to give a waxy
yellow solid. This was then purified by column chromatography on
silica gel (70 mL), eluting with EtOH/CHCl3 (1:8). The bright
yellow band (rf = 0.18) was collected. The solvents were then
removed at reduced pressure giving the analytically pure product as a
yellow oil. Yield: 153 mg, 0.24 mmol, 86%. HR-ESI-MS (pos.) m/z =
601.0320 calc. for [C17H14N6O5ReS]+ = 601.0303; m/z = 1273.0073
67%. HR-ESI-MS (pos.) m/z
= 522.9542 calc. for
1
[C16H14N6ClO4RuS]+ = 522.9542 H NMR (300 MHz, CD3CN):
δ (ppm) 9.07 (1H, dd, JHj‑Hi = 6.3 Hz, Hj), 8.58 (1H, s, Hf), 8.38 (1H,
td, JHh‑Hi = JHh‑Hg = 8.3 Hz, JHh‑Hj = 1.6 Hz, Hh), 8.04 (1H, d, JHg‑Hh
8.3 Hz, Hg), 7.79 (1H, t, JHi‑Hh = JHi‑Hj = 8.3 Hz, Hi), 7.50 (2H, m,
Hc‑Hb = 8.7 Hz, 2xHc), 6.66 (2H, m, JHb‑Hc = 8.7 Hz, 2xHb), 6.11 (1H,
=
J
t, JHd‑He = 6.4 Hz, Hd), 4.75 (2H, s, 2xHa) 4.33 (2H, d, JHe‑Hd = 6.4
Hz, 2xHe). 13C{1H} NMR (100 MHz, CD3CN): δ (ppm) 196.62,
196.32, 153.56, 153.34, 150.18, 147.09, 144.49, 130.07, 127.89,
127.30, 124.69, 116.04, 114.49, 39.03. ATR-IR (cm−1): 3129 (w),
2360 (w), 2069 (s, CO), 2019 (s, CO), 1613 (m), 1596 (s), 1498 (s),
1449 (m), 1312 (m), 1161 (s), 1073 (s), 836 (m), 783 (s), 687 (m),
675 (m), 629 (m). Colorless, needle-shaped single crystals of suitable
G
DOI: 10.1021/acs.inorgchem.9b01186
Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry
Article
for single crystal X-ray diffraction were grown by vapor diffusion of
Et2O into a solution of [RuII(Ltri)(CO)2Cl2] in acetone.
JHh‑Hi = JHh‑Hg = 8.0 Hz, Hh), 8.40 (1H, d, JHg‑Hh = 8.5 Hz, Hg), 8.17
(1H, d, JHi‑Hh = 7.9 Hz, Hi), 7.57 (2H, m, JHc‑Hb = 8.8 Hz, 2xHc), 7.01
(1H, t, JHd‑He = 6.4 Hz, Hd), 6.73 (2H, m, JHb‑Hc = 8.8 Hz, 2xHb), 5.51
[ReI(LtriOH)(CO)3Cl]. A suspension of [ReI(CO)5Cl] (80.3 mg,
0.22 mmol) and LtriOH (80 mg, 0.22 mmol) in EtOH (25 mL) was
degassed by bubbling with N2(g) before being heated to reflux under
a nitrogen atmosphere for 18 h. During this time, the suspension
cleared to give a yellow solution. The mixture was allowed to cool to
ambient temperature, and the solution was taken to dryness at
reduced pressure to give a yellow oil. This was then purified by
column chromatography on silica gel (40 mL), eluting with EtOAc/
hexane (gradient 1:1 → 1:0). The bright yellow band (rf = 0.4,
EtOAc) was collected. The solvents were then removed at reduced
pressure giving the analytically pure product as a yellow solid. Yield:
127 mg, 0.19 mmol, 86%. HR-ESI-MS (pos.) m/z = 631.0410 calc.
for [C18H16N6O6ReS]+ = 631.0403; m/z = 672.0668 calc. for
[C18H16N6O6ReS]·MeCN+ = 672.0668; m/z = 1333.0209 calc. for
{[C18H16N6O6ReS]2H}+ = 1333.0242. Elemental analysis calc. for
[C18H16ClN6O6ReS]·0.5EtOAc (710.14 g mol−1): C 33.83 H 2.84 N
11.83 S 4.51; found: C 33.93 H 2.92 N 11.83 S 4.43%. 1H NMR (400
MHz, CD3CO): δ (ppm) 8.98 (1H, s, Hf), 8.48 (1H, t, JHh‑Hi = JHh‑Hg
(1H, t, JHl‑Hk = 5.6 Hz, Hl) 5.42 (2H, br. s, Ha), 5.30 (2H, d, JHk‑Hl
=
5.4 Hz, 2xHk), 4.42 (2H, d, JHe‑Hd = 6.4 Hz, 2xHe). 13C{1H} NMR
(100 MHz, acetone-d6): δ (ppm) 196.9, 196.6, 164.6, 153.5, 150.8,
147.3, 144.3, 130.0, 127.4, 124.7, 123.9, 114.2, 113.8, 67.0, 39.2. ATR-
IR (cm−1): 2926 (w), 2365 (m), 2075 (s, CO), 2016 (s, CO), 1622
(w), 1595 (m), 1475 (w), 1317 (m, br.), 1151 (s), 1082 (s), 839 (m),
800 (m), 679 (m), 631 (w).
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.inorg-
chem.9b01186.
■
S
Instrument details, crystallographic data, additional
structural diagrams, IR spectra, UV−vis spectra, MIC
data, and biological procedures, as well as NMR spectra
and NMR numbering schemes (PDF)
= 8.0 Hz, Hh), 8.34 (1H, d, JHg‑Hh = 7.9 Hz, Hg), 8.11 (1H, d, JHi‑Hh
7.9 Hz, Hi), 7.56 (2H, m, JHc‑Hb = 8.7 Hz, 2xHc), 6.97 (1H, t, JHd‑He
6.4 Hz, Hd), 6.72 (2H, m, JHb‑Hc = 8.7 Hz, 2xHb), 5.40 (1H, t, JHl‑Hk
5.4 Hz, Hl), 5.07 (2H, t, JHk‑Hl = 5.5 Hz, 2xHk), 4.37 (2H, d, JHe‑Hd
=
=
=
=
Accession Codes
CCDC 1909703−1909708 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.
6.4 Hz, 2xHe). 13C{1H} NMR (100 MHz, CD3CO): δ (ppm) 198.1,
195.8, 188.6, 165.1, 153.5, 150.1, 148.7, 143.7, 130.0, 127.4, 127.3,
124.3, 123.3, 114.0, 113.5, 68.7, 39.0. ATR-IR (cm−1): 2367 (m),
2027 (s, CO), 1902 (s, br., CO), 1626 (w), 1597 (m), 1479 (w),
1320 (m, br.), 1146 (s), 1080 (m), 837 (w), 800 (w), 681 (m).
[ReI(LtriOH)(CO)3Br]. A suspension of [ReI(CO)5Br] (90.2 mg,
0.22 mmol) and LtriOH (80 mg, 0.22 mmol) in EtOH (25 mL) was
degassed by bubbling with N2(g) before being heated to reflux under
a nitrogen atmosphere for 18 h. During this time, the suspension
cleared to give a yellow solution. The mixture was allowed to cool to
ambient temperature, and the solution was taken to dryness at
reduced pressure to give a yellow oil. Further drying under high
vacuum caused this oil to solidify, giving the analytically pure product
as a yellow powder. Yield: 156.3 mg, 0.22 mmol, 100%. HR-ESI-MS
(pos.) m/z = 631.0420 calc. for [C18H16BrN6O6ReS]+ = 631.0403;
m/z = 672.0682 calc. for [C18H16BrN6O6ReS]·MeCN+ = 672.0668;
m/z = 710.9664 calc. for [C18H16BrN6O6ReS]H+ = 710.9648.
Elemental analysis calc. for [C18H16BrN6O6ReS]·H2O (728.55 g
mol−1): C 29.68, H 2.49, N 11.54, S 4.40; found: C 29.56, H 2.44, N
11.48, S 4.39%. 1H NMR (400 MHz, CD3CO): δ (ppm) 8.98 (1H, s,
Hf), 8.47 (1H, t JHh‑Hi = JHh‑Hg = 8.0 Hz, Hh), 8.35 (1H, d, JHg‑Hh = 8.1
Hz, Hg), 8.11 (1H, d, JHi‑Hh = 7.9 Hz, Hi), 7.56 (2H, m, JHc‑Hb = 8.7
Hz, 2xHc), 6.97 (1H, t, JHd‑He = 6.5 Hz, Hd), 6.72 (2H, m, JHb‑Hc = 8.7
Hz, Hb), 5.40 (1H, t, JHl‑Hk = 5.4 Hz, Hl) 5.05 (2H, qd, JHk‑Hl = 6.1
Hz, 2xHk), 4.37 (2H, d, JHe‑Hd = 6.4 Hz, 2xHe) 13C{1H} NMR (100
MHz, CD3CO): δ (ppm) 197.5, 195.5, 187.8, 165.3, 153.5, 150.2,
148.7, 143.6, 130.0, 127.4, 124.3, 123.3, 114.1, 113.4, 68.8, 39.0. ATR-
IR (cm−1): 2365 (m), 2028 (s, CO), 1904 (s, br., CO), 1624 (w),
1597 (m), 1477 (w), 1315 (m, br.), 1150 (s), 1070 (m) 835 (w), 879
(w), 679 (w). Yellow rod-shaped single crystals of suitable for single
crystal X-ray diffraction were grown by vapor diffusion of hexane into
a solution of [ReI(LtriOH)(CO)3Br] in EtOH/acetone (1:1).
AUTHOR INFORMATION
Corresponding Author
*E-mail: nils.metzler-nolte@rub.de.
■
ORCID
Reece G. Miller: 0000-0002-2687-5572
́
́
Melissa Vazquez-Hernandez: 0000-0003-2527-9135
Julia E. Bandow: 0000-0003-4100-8829
Nils Metzler-Nolte: 0000-0001-8111-9959
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are grateful to the Alexander von Humboldt foundation for
the award of a research fellowship to R.G.M.
■
REFERENCES
■
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[RuII(LtriOH)(CO)2Cl2]. A suspension of [RuII(CO)2Cl2]n (69 mg,
0.30 mmol) and LtriOH (100 mg, 0.30 mmol) in EtOH (30 mL) was
degassed by bubbling with N2(g) before being heated to reflux under
a nitrogen atmosphere for 18 h. During this time, the suspension
cleared to give a yellow solution. The mixture was allowed to cool to
ambient temperature and then taken to dryness at reduced pressure to
give a waxy yellow solid. This yellow solid was then purified by
column chromatography on silica gel (50 mL), eluting with acetone/
hexane (2:1) to give a waxy bright yellow solid (rf = 0.2, acetone/
hexane 2:1). Yield: 88 mg (0.150 mmol 50%). HR-ESI-MS (pos.) m/
z = 516.9869 calc. for [C17H15N6O5ReS]+ = 516.9867; m/z =
552.9634 calc. for [C17H16ClN6O5ReS]+ = 552.9630; m/z =
1178.8713 calc. for {[C17H16ClN6O5ReS]2H}+ = 1178.8709. 1H
NMR (300 MHz, acetone-d6): δ (ppm) 9.07 (1H, s, Hf), 8.55 (1H, t,
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