Rhenium complexes of bidentate, bis-bidentate and tridentate N-heterocyclic carbene ligands

Article abstract of DOI:10.1039/c5dt03295d

A series of eight Rhenium(i)-N-heterocyclic carbene (NHC) complexes of the general form [ReCl(CO)₃(C^C)] (where C^C is a bis(NHC) bidentate ligand), [ReCl(CO)₃(C^C)]₂ (where C^C is a bis-bidentate tetra-NHC ligand) and [Re(CO)₃(C^N^C)]⁺[X]^- (where C^N^C is a bis(NHC)-amine ligand and the counter ion X is either the ReO₄^- or PF₆^-) have been synthesised using a Ag₂O transmetallation protocol. The novel precursor imidazolium salts and Re(i) complexes were characterized by elemental analysis, ¹H and ¹³C NMR spectroscopy and the molecular structures for two imidazolium salt and six Re(i) complexes were determined by single crystal X-ray diffraction. These NHC ligand systems are of interest for possible applications in the development of Tc-99m or Re-186/188 radiopharmaceuticals and as such the stability of two complexes of the form [ReCl(CO)₃(C^C)] and [Re(CO)₃(C^N^C)][ReO₄] were evaluated in ligand challenge experiments using the metal binding amino acids l-histidine or l-cysteine. These studies showed that the former was unstable, with the chloride ligand being replaced by either cysteine or histidine, while no evidence for transchelation was observed for the latter suggesting that bis(NHC)-amine ligands of this type may be suitable for biological applications.

Full text of DOI:10.1039/c5dt03295d

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Rhenium complexes of bidentate, bis-bidentate
and tridentate N-heterocyclic carbene ligands†
Cite this: DOI: 10.1039/c5dt03295d
Chung Ying Chan and Peter J. Barnard*
A series of eight Rhenium(I)-N-heterocyclic carbene (NHC) complexes of the general form [ReCl-
(CO)3(C^C)] (where C^C is a bis(NHC) bidentate ligand), [ReCl(CO)3(C^C)]2 (where C^C is a bis-bidentate
tetra-NHC ligand) and [Re(CO)3(C^N^C)]+[X]− (where C^N^C is a bis(NHC)-amine ligand and the counter
−
ion X is either the ReO4 or PF6−) have been synthesised using a Ag2O transmetallation protocol. The
1
novel precursor imidazolium salts and Re(I) complexes were characterized by elemental analysis, H and
13C NMR spectroscopy and the molecular structures for two imidazolium salt and six Re(I) complexes
were determined by single crystal X-ray diffraction. These NHC ligand systems are of interest for possible
applications in the development of Tc-99m or Re-186/188 radiopharmaceuticals and as such the stability
of two complexes of the form [ReCl(CO)3(C^C)] and [Re(CO)3(C^N^C)][ReO4] were evaluated in ligand
challenge experiments using the metal binding amino acids L-histidine or L-cysteine. These studies
showed that the former was unstable, with the chloride ligand being replaced by either cysteine or histi-
dine, while no evidence for transchelation was observed for the latter suggesting that bis(NHC)-amine
ligands of this type may be suitable for biological applications.
Received 26th August 2015,
Accepted 7th October 2015
DOI: 10.1039/c5dt03295d
www.rsc.org/dalton
β-emitter (max 2.1 MeV) with a half-life of 17 h.3 The similarity
in the chemical properties displayed by Tc and Re offers the
Introduction
Technetium-99m is a medically important isotope used for potential for these radiometals being used as a ‘matched pair’,
single photon emission computed tomography (SPECT) where 99mTc and 186/188Re complexes of the same ligand may be
imaging of a variety of organ conditions and disease states. used for both imaging and therapeutic applications respectively.
Technetium-99m offers optimal nuclear properties for imaging
There has been much recent interest in the use of N-hetero-
applications, including: intermediate half-life (t1/2 = 6.02 h), cyclic carbene (NHCs) ligands in medicinal inorganic chem-
almost pure gamma-emission (Eγ = 140 keV) and convenient istry applications.4–6 For example, the anti-tumor properties of
availability from a 99Mo/99mTc generator.1,2 Sharing many simi- a variety of metals including Ag,7–9 Au,10,11 Pd12 and Pt13 have
larities in chemical properties to technetium, the third row been evaluated and pioneering work by Youngs and co-
congener rhenium also offers significant potential for use in workers has elucidated the remarkable antimicrobial pro-
nuclear medicine, as the isotopes: Re-186 and Re-188 have pro- perties of Ag(I)-NHC complexes.14 Despite the favorable pro-
perties suitable for radiotherapeutic applications. Rhenium- perties of metal complexes of NHC ligands for use in
186 is a medium energy β-emitting isotope (max 1.08 MeV) with medicinal inorganic chemistry, there been relatively few
a long half-life of 3.7 days, while Re-188 is a high energy reports of their potential applications in nuclear medicine.
Early studies recognized the possibility of using pre-formed
Ag(I)-NHC complexes for the delivery of NHC ligands to
metallic radionuclides.15–17 More recently, for the first time
Department of Chemistry and Physics, La Trobe Institute for Molecular Science, La
Trobe University, Victoria, 3086, Australia. E-mail: p.barnard@latrobe.edu.au;
our group reported the labelling of an NHC ligand with
99mTc using a Ag2O transmetalation protocol (1, Fig. 1).18 In
Fax: (+)61 3 9479 1266
†Electronic supplementary information (ESI) available:Synthetic details for
the same year an N-heterocyclic biscarbene ligand was labelled
H-Gly-OBzl·TsO, 4·Br2 and 5·Cl2. Further X-ray crystallography details and refine-
with 188Re also via transmetalation from a preformed Ag(I)
ment data. NMR spectra, ESI-MS and HPLC chromatograms for 8·Cl2, 9·Cl2, 10,
complex (2, Fig. 1).19 Abram and co-workers have been particu-
11·Cl2, 12·Cl3 and 13·Cl2. HPLC Chromatograms for the reaction product
obtained in the synthesis of 15 and 16. 1H NMR spectra of trans-15 and trans–
larly active in the synthesis of 99Tc and Re complexes of NHC
trans-16 and trans–cis-16. Variable temperature 1H NMR spectra for 15.
ligands,20–22 indeed these workers reported the first example
Additional details for the kinetc analysis of the reaction of of 14Cl with CD3CN.
of a 99Tc(V)-NHC complex.23 More recently, a series of 99Tc(V)-
HPLC chromatograms obtained in the ligand challenge experiments for com-
plexes 14 and 17·ReO4. CCDC 1419735–1419742. For ESI and crystallographic
NHC complexes of the nitridotechnetium core24 and the dioxo-
technetium core were described.25
data in CIF or other electronic format see DOI: 10.1039/c5dt03295d
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Fig. 1 Examples of N-heterocyclic carbene ligands labelled with (1) Tc-99m and (2) Re-188 and an example of a biomolecule labelled with a lumi-
nescent Re(I) complex via the ‘single amino acid chelate’ (SAAC) strategy.
First described by Alberto and co-workers,
(H2O)3(CO)3]+ (ref. 26 and 27) has garnered much attention in (4·Br2) or polyethylene glycol 400 (5·Cl2 and 6·Cl4) (Scheme 1).
the development of potential SPECT imaging agents.28 The
Previously, we showed that for Re(I) tricarbonyl complexes
[
99mTc- appropriate molar ratios of 1-methylimidazole in acetonitrile
popularity of this precursor compound results from its of the form [ReCl(CO)3(C^N)] (where C^N is a bidentate NHC
impressive synthetic versatility and convenient preparation containing ligand) that the monodentate chloride group is
−
from 99mTcO4 using the commercially available Isolink label- labile and exchanges with acetonitrile and anionic carboxylate
ling kit. The facially coordinated carbonyl ligands are strongly and sulfonate ligands.18 As a labile monodentate ligand is
bound while the three water molecules are labile and easily expected to be unsuitable for potential diagnostic imaging
displaced by other ligand systems.
applications using Tc-99m, we became interested in develop-
A wide range of ligands have been investigated in combi- ing tridentate NHC ligand systems for use in combination
nation with the 99mTc-tricarbonyl core and among these tri- with the tricarbonyl core of Tc and Re. Using a previously
dentates often form stable complexes that are suitable for reported acyclic ligand as a template,39,40 a series of new bis
in vivo applications.28 The ‘single amino acid chelates’ (SAACs) (NHC)-amine ligands, designed to bind to an octahedral metal
are a class of tridentate ligands have shown significant centre in a facial array (thereby increasing the stability of
promise for labelling small peptides with either the potential Re and Tc complexes) were prepared (Scheme 2).
99mTc(CO)3 or the Re(CO)3 cores.29,30 These systems involve the
As was described previously for the synthesis of closely
modification of natural or synthetic amino acids (e.g. lysine), related imidazolium salts,39,40 it was necessary to protect the
yielding a tridentate terminus. A range of donor groups have amine of bis(2-chloroethyl)amine before introduction of the
been investigated, including pyridine and quinoline, with the imidazolium units to avoid formation of polymerised by-
latter generating luminescent complexes with the Re(CO)3 core products. Thus, reaction of 7 with two equivalents of 1-methyl-
(3, Fig. 1) suitable for biodistribution studies in single cells.
imidazole gave the diimidazolium salt 8·Cl2 and subsequent
We are interested in the synthesis and study of metal com- removal of the benzyl group by catalytic hydrogenation furn-
plexes of N-heterocyclic carbene ligands31 for potential radio- ished the secondary amine containing diimidazolium salt
pharmaceutical applications32 and as novel luminescent 9·Cl2. To provide bifunctional ligands for potential conjugation
materials.33–36 Herein we describe the synthesis of a series of
bidentate, bis-bidentate and tridentate imidazolium salt, NHC
pro-ligands and the corresponding Re(I)(CO)3-NHC complexes.
The stability of Re(I) complexes with either a bidentate NHC
ligand or a bis(NHC)-amine (tridentate) NHC ligand were
evaluated in ligand challenge experiments using the metal
binding amino acids L-histidine or L-cysteine. These studies
showed that the Re(I) complex with a [2 + 1] ligand combi-
nation were unstable with the chloride ligand replaced by the
amino acids while the Re(I) complex of the bis(NHC)-amine
ligand was stable and showed no evidence for transchelation.
Results and discussion
Ligand synthesis
37,38
The known bidentate NHC pro-ligands: 4·Br2 and 5·Cl2
and the novel bis-bidentate NHC pro-ligand (6·Cl4) were pre-
pared similarly by heating either dibromomethane or α,α-di-
Scheme 1 Synthesis of bis-imidazolium salts 4·Br2 and 5·Cl2 and tetra-
chlorotoluene or α,α,α,α-tetrachloro-p-xylene with the imidazolium salt 6·Cl4.
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Scheme 2 Synthesis of functionalised bis-imidazolium salts.
to biomolecules, bis(2-chloroethyl)amine was initially alkylated
The structure of complex 14 is closely related to previously
with ethyl bromoactate yielding 10, which was reacted with reported Re(I) complexes of this ligand where the halide ligand
1-methylimidazole giving the diimidazolium salt 11·Cl2. To was either bromide41 or iodide.42 These previous studies
investigate the potential for coupling this imidazolium salt showed that two conformational isomers (endo or exo) were
pro-ligand to biomolecules, the amino acid compound 12·Cl3 possible, due to a ‘flapping wing’ type motion of the imidazole
1
was prepared from 11·Cl2 by hydrolysis of the ester group rings. Variable temperature H NMR analysis (X = Br−) showed
using 5 M HCl. Compound 12·Cl3 was then conjugated to a fast equilibrium between the isomers at RT with coalescence
benzyl ester protected glycine yielding 13·Cl2 using the peptide occurring at 220 K, with signals apparent for both isomers at
coupling reagent: 1-ethyl-3-(3-dimethylaminopropyl)carbodi- 183 K.41 High pressure liquid chromatography mass spectro-
imide (EDC) in combination with hydroxybenzotriazole (HOBt) metric (HPLC-MS) analysis of the crude reaction mixture for
(Scheme 2).
complex 14 shows only one Re(I) containing species and the
In all cases, the synthesized symmetrical imidazolium salts 1H NMR spectrum for the purified complex shows a broadened
(4–6, 8, 9, 11–13) gave relatively simple 1H NMR spectra, with a AX pattern for the methylene groups protons. A variable temp-
characteristic downfield signal for the strongly deshielded erature (VT) 1H NMR study was conducted for 14 in d6-acetone
imidazolium NCHN (pro-carbenic) proton, which resonated (Fig. 2) and as expected this compound displayed similar pro-
within the range 9.13–9.96 ppm. The formation of glycine perties to those reported previously for the Br− and I− ana-
coupled product 13·Cl2 was accompanied by the appearance of logues. In the case of 14, coalescence was evident at 253 K and
a broad triplet resonance (9.32 ppm) corresponding to the signals for both isomers were apparent at 213 K.
amide group N–H proton.
High pressure liquid chromatography in combination with
1H NMR analysis (Fig. S10, ESI†) of the crude reaction product
for 15 (before purification) shows the formation of only one
Re(I)-NHC complex. Due to the phenyl substituent on the
methylene linker group between the imidazole rings, there are
Rhenium complex synthesis and studies
Two mononuclear Re(I) tricarbonyl complexes of the form
[ReCl(CO)3(C^C)] (where C^C is a bidentate NHC ligand) (14 two possible geometric isomers for this complex, these being
trans-15 where the chloride ligand is trans with respect to
phenyl group and cis-15 where the chloride ligand cis with
and 15, Scheme 3) were prepared by the heating imidazolium
salts 4·Br2 or 5·Cl2 respectively with Re(CO)5Cl in the presence
of Ag2O. The bimetallic complex 16 was prepared similarly respect to phenyl group (Fig. 3). X-ray structural analysis of the
only Re(I)-NHC complex formed in the synthesis of 15 showed
that only trans-15 was formed. The preference for the for-
from the bis-bidentate NHC pro-ligand 6·Cl4 (Scheme 3). Com-
plexes 14–16 were crystallographically characterized (see Struc-
tural studies section) and in all cases the Re(I) centres adopt mation of the trans-geometric isomer, may be due to hydrogen
bonding interactions between the methyl NHC wingtip groups
and the chloride ligand, which are evident in the crystal struc-
ture for this compound (see Structural studies section). As was
octahedral coordination geometries, with three facially arrayed
carbonyl ligands, the chelating bis-NHC unit, and a mono-
dentate chloride ligand.
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Scheme 3 Synthesis of Re(I) complexes 14–16.
Fig. 2 Variable temperature (300 K–183 K) 1H NMR spectra (400 MHz, d6-acetone) for complex 14.
the case for 14, it is also possible that at RT trans-15 exist in trans-15 is in equilibrium with the ring-flip conformer. The
equilibrium with its ring-flip conformational isomer, where barrier associated with the generation of the ring-flip form
the ‘flapping wing’ motion of the imidazole rings would inter- may result from an unfavourable steric interaction between the
convert the position of the phenyl ring from axial (Fig. 3) to phenyl substituent and the imidazolylidene units when the
equatorial. To determine if this is the case, a VT 1H NMR study phenyl group is brought into the equatorial position.
(300 K–183 K) was performed on trans-15 in d6-acetone. The
The bimetallic complex 16 was synthesised from the tetra-
results of this study (Fig. S15, ESI†) showed no evidence that imidazolium salt 6·Cl4 and semi-preparative HPLC was used to
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and 6·Cl4, yielding 1-methylimidazole which coordinates to the
Re(I) centre. A second decomposition product was identified in
the separation of the geometric isomers of the bimetallic
complex 16 using semi-preparative HPLC. This species gave an
identical 1H NMR spectrum to that of trans-15, suggesting C–C
bond cleavage of the methylene group to phenyl group bond
and formation of the mononuclear complex. Previously, Cu2O
was shown to promote unusual C–N bond cleavage and C–C
bond formation reactions, when utilized as a metal source in
the synthesis of Cu(I)-NHC complexes of the pro-ligands 4·Br2
and 5·Cl2.37 As Ag2O was used in the synthesis of the Re(I)-
NHC complexes prepared in this work, it is possible that this
compound was involved in the C–N and C–C bond cleavage
reactions observed here.
Poor solution stability has been previously noted for com-
plexes of the 99mTc-tricarbonyl core in combination with
monodentate and bidentate ligands.44 As a result of the
chelate effect, facial tridentate ligands offer the greatest poten-
tial for highly stable complexes and the tridentate single
amino acid chelate ligand systems (SAACs) form 99mTc and Re
complexes with high kinetic stability.30 With this in mind the
tridentate imidazolium salt pro-ligands (8·Cl2, 9·Cl2, 11·Cl2
Fig. 3 The possible geometric isomeric forms of complex 15: trans-15,
chloride ligand trans with respect to phenyl group and cis-15, chloride
ligand cis with respect to phenyl group (for clarity only the metallacycle
is shown).
isolate the geometric isomeric forms of the complex generated
in the synthetic reaction. Two geometric isomeric forms of 16
(trans–trans-16 and trans–cis-16, (Fig. S11, ESI†) were isolated
1
and these species gave identical ESI-MS results. The H NMR
spectrum obtained for trans–trans-16 was consistent with a
highly symmetrical molecule, while that obtained for trans–cis-
16 was more complicated, suggesting a lower level of mole-
cular symmetry (Fig. S14, ESI†). A crystal structure (see Struc-
tural studies section) was obtained for trans–trans-16 and this
showed that the phenyl linker group is in the axial position of
the metallacycles incorporating each Re(I) centre (as was the
case for trans-15) and is trans with respect to the orientation of
the chloride ligands. The second geometric isomer was
assigned as trans–cis-16 (Scheme 3) on the basis of the
1H NMR spectrum and ESI-MS result (Fig. S14, ESI†). Interest-
ingly, the third possible geometric isomer cis–cis-16 was not
observed.
In addition to the desired complexes (15, 16) significant
amounts of a common by-product were formed in the Ag2O
transmetallation reaction between Re(CO)5Cl and the imidazo-
lium salts: 5·Cl2 and 6·Cl4. The by-product was identified and
purified using semi-preparative HPLC and a poor quality crys-
tals structure was obtained (Fig. S3, ESI†). The complex (Fig. 4)
is bimetallic, with a pair of Re(I) tricarbonyl centres bridged by
two μ2-methoxide ligands, with a methylimidazole ligand occu-
pying sixth coordination site for each of the Re(I) centres.
Related Re(I) complexes have been reported previously.43
The formation of this bimetallic Re(I) by-product appears to
result from C–N bond cleavage of the imidazolium salts 5·Cl2
and 13·Cl2), were used to prepare
a series of cationic
rhenium(I)
tricarbonyl
complexes
of
the
form
[Re(CO)3(C^N^C)]+[X]− (where C^N^C is a bis(NHC)-amine
ligand and the counter ion X is either the ReO4 or PF6−).
−
Initial attempts to synthesise Re(I) complexes of the tridentate
pro-ligands were carried out using the same one-pot reaction
conditions as were employed for the preparation of complexes
14–16. The crude product obtained from the reaction of imid-
azolium salt 8·Cl2 with Ag2O and Re(CO)5Cl in the same pot
gave a complex 1H NMR spectrum, suggestive of more than
one Re(I)-NHC complex in addition to unidentified decompo-
sition products. In an effort to separate the cationic and
neutral complexes formed in this reaction, the crude product
was recrystallised using two different conditions; the first
being the diffusion of vapours between diethyl ether and a
solution of the crude product in methanol and the second the
diffusion of vapours between diethyl ether and a solution of
the crude product in acetonitrile. Each crystallisation method
produced crystals suitable for XRD and the crystal structures
were obtained (see Structural studies section). Vapour
diffusion using methanol and ether produced a mononuclear
cationic complex 17, while vapour diffusion using acetonitrile
and ether produced
a bimetallic neutral complex 18
(Scheme 4). The mononuclear product, 17 showed the
expected coordination mode, where the ligand was bound to
the Re(I)(CO)3 core as a facial bis(NHC)-amine ligand via the
two NHC units and the amine donor group, yielding a cationic
complex. The counterion for the cationic Re(I) complex was
unexpectedly found to be the perrhenate anion (ReO4−). The
oxidative process responsible for the oxidation of the Re(I)
−
source to ReO4 in this reaction is unknown. However, the
−
unexpected generation of ReO4 has been noted in a number
of previous studies including those involving NHC ligands,
and is proposed to result from oxidation and hydrolysis in the
Fig. 4 Structure of common by-product formed in the synthesis of
complexes 15 and 16.
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Scheme 4 Synthesis of Re(I) complexes 17·ReO4 and 18.
presence of water.23,45–47 For the neutral bimetallic complex agents to Pd(II) has been previously described for closely
18, two Re(I)(CO)3Cl units were bridged by two ligands, which related ligand systems.40
were bound to the metal centres by the NHC units with the
The number of signals observed in the 1H and 13C NMR
amine groups remaining uncoordinated. The bimetallic spectra for the cationic complexes 17–20 are consistent with
complex could not be isolated in sufficient quantities for an internal mirror symmetry plane. Upon coordination of the
further analysis and appears to be a minor reaction product NHC group, the signal for the imidazolium salt, pro-carbenic
associated with the presence of the coordinating chloride proton was lost from the 1H NMR spectra, while a character-
counter ion in the synthetic reaction mixture. A 1H NMR istic downfield chemical shift was observed for the carbenic
experiment was conducted to evaluate if the cationic mono- carbon atom in the 13C NMR spectra. Synthesis of the Re(I)
nuclear complex 17 exists in a chloride ion dependent equili- complex of the imidazolium salt pro-ligand coupled to glycine
brium in solution with the neutral bimetallic complex 18. In (13·Cl2) yielded two linkage isomeric products 21a and 21b
acetonitrile-d3, 17·ReO4 was treated with 10 molar equivalents (Scheme 6). Here the tridentate ligand was either coordinated
of TBACl and no changes were observed in the 1H NMR to the metal centre in the expected manner (21a), via the two
spectra over a period of 5 days (Fig. S16, ESI†) suggesting that NHC units and the tertiary amine group. The alternative linkage
once formed, 17 is stable with respect to conversion to 18 in isomer involved deprotonation and coordination of the amide
the presence of chloride ions.
group of the coupled protected glycine fragment, as an amidate
To optimise the yield of the desired cationic mononuclear donor group in combination with one NHC unit, with the
complex, a second synthetic method was adopted (Scheme 5). second imidazolium group was unbound. As expected each of
Here the chosen imidazolium salt was initially reacted with these linkage isomers gave distinctive 1H and 13C NMR spectra.
Ag2O and the insoluble AgCl formed in the reaction was As complex 21a possesses an internal mirror symmetry plane a
1
removed by filtration. The residual Ag(I)-NHC complex was relatively simple H NMR spectrum was obtained with a broad
then treated with Re(CO)5Cl and the final cationic Re(I) triplet signal (9.08 ppm, DMSO-d6) corresponding to the amide
complex was isolated as a hexafluorophosphate salt with the N–H proton. In contrast, the linkage isomer 21b has no mole-
addition of KPF6. This method yielded the mononuclear cat- cular symmetry and displays a correspondingly more compli-
1
ionic complexes 17–21 in moderate to good yield. The use of cated H NMR spectrum with a set of signals corresponding to
preformed Ag(I)-NHC complexes for use as ligand transfer the unbound imidazolium group (Fig. S17, ESI†).
Scheme 5 Synthesis of Re(I) complexes 17–21.
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Scheme 6 Formation of the two linkage isomeric forms of complexes 21 with bis(NHC) (21a) and NHC/amidate (21b) coordination modes.
Structural studies
The coordination spheres for the octahedral Re(I) com-
plexes: 14, trans-15 and trans–trans-16 (Fig. 5) are composed of
Crystallographic refinement data for the imidazolium salts three facially arrayed carbonyl ligands, a chloride ligand and
6·Cl4 and 12·Cl3 and the Re(I) complexes 14, trans-15, trans– the bis-carbene units. In all three cases, hydrogen bonding
trans-16, 17·ReO4, 18, 20 are given in Table S1 (ESI†). The interactions are evident between the axial chloride ligand and
crystal structures of the tetracationic imidazolium salt: 6·Cl4 the hydrogen atoms of the NHC-methyl wing-tip groups, with
and the tricationic amino acid substituted bis-imidazolium the Cmethyl–Cl distances being within the range 3.4707(1) Å–
compound: 12·Cl3 (Fig. S1 and S2 respectively, ESI†) confirm 3.7292(1) Å. A structure closely related to that of 14 with a
the structures of these molecules. In both cases, extensive bromide rather than chloride ligand has been reported pre-
hydrogen bonded networks are present, with interactions viously.41 As discussed in the Synthesis section, the phenyl
between the imidazolium group hydrogens, anions and in the substituent of trans-15 and trans–trans-16 adopts an axial posi-
case of 6·Cl4 methanol and water molecules of crystallisation.
tion on the metallacycle and is trans with respect to the Re(I)
Fig. 5 ORTEP49 structures of (a) 14, (b) trans-15 (co-crystallized chloroform molecule omitted for clarity) and (c) trans–trans-16 (co-crystallized
molecules of acetone and methanol omitted for clarity). Hydrogen atoms (except those of the methyl groups) omitted for clarity. Thermal ellipsoids
are shown at 50% probability.
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chloride ligand. The ring flip isomer, where the phenyl group the amino groups of the bis(NHC)-amine ligands bearing
would move into an equatorial position is not observed crystallo- benzyl or ethyl acetate substituents respectively. In each case
graphically (or in solution studies for trans-15) possibly as a the coordination sphere of the Re(I) centre is composed of
result of unfavourable steric interactions. Previously the crystal three facially arrayed carbonyl ligands with the bis(NHC)-
structure of a tetrahedral Fe(II) complex of the NHC ligand used amine ligand bound to the metal centre via the two NHC moie-
to prepare trans-15 was reported,38 while attempts to prepare a ties and the tertiary amine group. The Re–Ccarbene bond
Cu(I) complex of this ligand were unsuccessful.37 To the best of lengths are similar for each complex with the average of these
our knowledge there have been no previous crystallographic being: 2.177 Å for 17·ReO4 and 2.180 Å for 20. Very similar Re–
studies of bimetallic Re(I)-NHC complexes similar to trans–trans-
Namine bond lengths are also observed, with these values being
16. Canella and co-workers detected the formation of bimetallic 2.337(7) Å and 2.361(6) Å for 17·ReO4 and 20 respectively.
complexes by NMR and mass spectroscopy as by-products These structures represent the first examples of tridentate bis-
formed in the synthesis of [ReCl(CO)3(C^C)] complexes (where (NHC)-amine ligands bound in a facial manner to an octa-
C^C was a propylene or butylene bridged bis-carbene ligand).48
hedral metal centre. The structure of the bimetallic complex
The structures of the mononuclear complexes: 17·ReO4 and 18 (Fig. 6c) is composed of two Re(I)(CO)3Cl units bridged by
20 (Fig. 6a and b) of bis(NHC)-amine ligands are similar, with two benzyl substituted ligands, which are bound to the metal
Fig. 6 ORTEP49 structures of (a) 17·ReO4 (ReO4 counterion omitted for clarity) (b) 20 (PF6 counterion omitted for clarity) and (c) 18 (co-crystal-
−
−
lized acetonitrile molecule omitted for clarity). Hydrogen atoms omitted for clarity. Thermal ellipsoids are shown at 50% probability.
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Fig. 7 1H NMR spectra (500.13 MHz) recorded for a solution of 14Cl in CD3CN over a period of 41.83 h at 25.0 0.1 °C showing the exchange of
the chloride ligand for a molecule of CD3CN. Inset spectrum: expansion of main signal from the positive-ion ESI-mass spectrum for 14CD3CN.
centres by the NHC units with the amine groups remaining complexes are unlikely to be suitable for biological appli-
uncoordinated. Mononuclear, square planar Pd(II) complexes cations as a result of the lability of the Cl− ligand. In contrast,
of similar bis(NHC)-amine ligands have been previously complexes 17–21 show no evidence for instability in aceto-
reported, where the NHC groups were bound to the metal in a nitrile solutions, demonstrating that the use of a facial tri-
trans configuration and examples were given where the amine dentate NHC ligand as opposed to a monodentate/bidentate
was either coordinated or uncoordinated.39,40 Using a range of ligand combination improves the solution stability. A range of
imidazole- and benzimidazole-based bis(NHC)-amine ligands complexes of the form: [ReI(CO)3bis(NHC)(CH3CN)]+ with
with different length alkyl linker groups, bridged Rh(I) and weakly coordinating anions have been previously reported.52
Ir(I)50 and tetrahedral Fe(II) complexes were prepared and
kf
structurally characterised.51
þ
14Cl þ CD3CN )ꢀ ½14CD3CNꢁ þ Clꢀ ðCD3CN in large excessÞ
ꢀ*
kr
ð1Þ
Chloride ligand exchange for complex 14
Previously we reported that the dissolution of the complex:
[ReCl(CO)3(1-(2-pyridyl)-3-methylimidazolylidene)] in aceto-
Stability studies
nitrile, resulted in a slow ligand exchange reaction, where the As the NHC ligands reported here are of interest for potential
anionic chloride ligand was replaced by a molecule of aceto- radiopharmaceutical applications, the stability of the Re(I)
nitrile yielding a cationic complex.18 A similar reaction is seen complexes 14 and 17·ReO4 were evaluated in ligand challenge
for complex 14 and the changes observed in the aromatic experiments using the well-known metal binding amino acids:
1
region of the H NMR spectrum for a solution of 14 in CD3CN L-histidine and L-cysteine. Compounds 14 and 17·ReO4 were
are shown in Fig. 7. During the course of the exchange reaction chosen for these studies as they represent examples of com-
a new set of signals for the bis-carbene unit associated with plexes bearing either bidentate (14) or tridentate (17·ReO4)
the cationic complex with CD3CN coordinated are evident at NHC ligand systems. Solutions of each complex in phosphate
∼30 min and reaction is near to completion at ∼41 h.
buffered saline (PBS, pH = 7), were incubated at 37 °C for 51 h
Kinetic analysis of the 1H NMR data was performed by (14) or 91 h (17·ReO4) with either: no addition (control) or
fitting speciation plots (Fig. S18 and S19, ESI†) to the pseudo- L-cysteine (100 mM) or L-histidine (100 mM). Complex stability
first-order (CD3CN in large excess) kinetic model depicted in was evaluated by monitoring the reactions using HPLC over
eqn (1). Using a single concentration, estimated forward and the course of the incubation period. HPLC chromatograms
reverse rate constants were kf = 0.12 M−1 h−1 and kr = 0.02 M−1 obtained for complex 14 are given in Fig. S20 (control – no
h−1, respectively. These values are similar in magnitude to addition), S21 (L-cysteine) and S22 (L-histidine) (ESI†). In the
those reported previously for [ReCl(CO)3(1-(2-pyridyl)-3-methyl- control experiment, one major HPLC peak (RT = 8.32 min)
imidazolylidene)]18 and indicate that [ReCl(CO)3(bidentate)] eluted and this species remained unchanged over the time
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course of the experiment. The peak eluting at 8.32 min was cally active molecules, the bis-imidazolium amine pro-ligand
collected and subjected to ESI-MS analysis and the main 12·Cl3 was functionalised with a carboxylic acid group and
signal (m/z = 447.0) corresponded to a cationic fragmentation linked to benzyl ester protected glycine via amide bond for-
product of the original complex, where the chloride ligand had mation using the peptide coupling reagent: EDC.
been lost. In contrast, significant levels of transchelation were
The stability of two complexes 14 and 17·ReO4 were evalu-
observed for complex 14 in the presence of L-histidine or ated using ligand challenge experiments with the metal
L-cysteine over the course of these experiments. The trans- binding amino acids L-histidine or L-cysteine. These com-
chelation products were identified using ESI-MS. The mass pounds were chosen because they represent examples of com-
spectral results showed that the monodentate chloride ligand plexes with either a [2 + 1] monodentate/bidentate ligand set
of the complex 14 had been replaced by either a cysteine or a tridentate ligand respectively. Complex 14, with the [2 + 1]
(HPLC: RT = 8.04 min, ESI-MS: m/z = 568.0, Fig. S21†) or a histi- ligand combination, displayed low stability in these assays,
dine (HPLC: RT = 7.86 min, ESI-MS: m/z = 602.0, Fig. S22†), with the labile chloride ligand being replaced by the metal
1
generating cationic complexes. These results confirm, that the binding amino acids. In addition, H NMR studies of complex
labile nature of the chloride ligand for complex 14, causes 14 in acetonitrile solution showed that the chloride ligand is
ligand exchange and formation of [Re(CO)3(C^C)(amino acid)]+ labile and was replaced by an acetonitrile solvent molecule to
complexes with histidine and cysteine.
give a cationic complex. In contrast, complex 17·ReO4 was
In order to obtain acceptable peak shape in the HPLC ana- stable in the presence of the metal binding amino acids and
lysis of complex 17, 0.1% trifluoroacetic acid (TFA) was added showed no evidence for displacement of the tridentate NHC
to the eluent as an organic modifier. Under these conditions, ligand.
two peaks containing the cationic complex 17 eluted (Fig. S23,
These results indicate that bidentate bis-NHC ligands in
ESI†) and these corresponded to ion pairs composed of combination with the M(I)(CO)3 core (M = Tc or Re) are un-
17·CF3COO (RT = 9.50 min) and 17·ReO4 (RT = 10.36 min). Ion likely to be suitable for biological applications due to the
pair formation in reverse phase HPLC is well known and the labile nature of the monodentate ligand. Whereas tridentate,
use of ion pair reagents is a standard tool to aid in the separ- bis(NHC)-amine ligands, bind to the Re(I)(CO)3 core as a facial
ation of ionic compounds.53 HPLC analysis complex 17·ReO4 tridentate and form kinetically stable complexes. Currently the
showed good stability in PBS alone (Fig. S24, ESI†) and no evi- radiochemistry associated with labelling bis(NHC)-amine
dence for trans-chelation was seen in the presence of L-histi- ligands with 99mTc is being developed in addition to the conju-
dine and L-cysteine (Fig. S25–S26, ESI†). The stability studies gation of these ligands to biologically active molecules (BAMS)
for complex 17·ReO4 were conducted over a relatively long for in vivo applications.
incubation period (91 h) and the results show that the cationic
complex 17+ was highly stable in the presence of large excesses
of these competing ligands. It can therefore be concluded that
bis(NHC)-amine ligands may be suitable of for imaging
(Tc-99m) or therapeutic (Re-186/188) applications.
Experimental details
General procedures
All reagents were purchased from Sigma-Aldrich or Alfa Aesar
Conclusion
and were of analytical grade or higher and were used without
There has been much recent interest in the use of NHC further purification unless otherwise stated. All compounds
ligands in medicinal inorganic chemistry,4,5,54,55 including were prepared in air unless otherwise stated. Experimental
their potential application in radiopharmaceutical develop- details for the synthesis of the bis-imidazolium salts: 4·Br2
ment. In an earlier study, we described the first example of and 5·Cl2 are given in the ESI;† these compounds were pre-
labelling an NHC with the medically important metallic radio- pared using similar procedures to those published pre-
nuclide: 99mTc32 and Wagner and co-workers reported a 188Re viously.37,38,41 NMR spectra were recorded on either a Bruker
1
complex of a bis(NHC) ligand.19 It has been previously noted Avance ARX-300 (300.14 MHz for H, 75.48 MHz for 13C) or a
that monodentate/bidentate or [2 + 1] ligand combinations Bruker Avance ARX-400 (400.13 MHz for 1H, 100.61 MHz for
with the M(I)(CO)3 core (M = Tc or Re) can be unsuitable for 13C) or a Bruker Avance ARX-500 (500.13 MHz for 1H,
biological applications due to poor complex stability,44 and 125.77 MHz for 13C) spectrometer and were internally refer-
that complexes with tridentate ligands display improved enced to solvent resonances. In all cases proton-decoupled 13
C
kinetic stability, due to the capacity of the tridentate ligand to NMR spectra were collected. Mass spectra were obtained using
shield the organometallic metal centre.56 To further explore a Bruker Esquire6000 mass spectrometer fitted with an Agilent
the chemistry of chelating NHC ligands in combination with electrospray (ESI) ion source. Microanalyses were performed by
the Re(I)(CO)3 core, in the present study a series of known and the Microanalytical Laboratory at the ANU Research School of
novel bidentate, bis-bidentate and tridentate NHC pro-ligands, Chemistry, Canberra, Australia or the Campbell Microanalyti-
and their corresponding Re(I) complexes have been prepared. cal Laboratory, Department of Chemistry, University of Otago,
To demonstrate the potential for the conjugation of biologi- New Zealand.
Dalton Trans.
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High pressure liquid chromatography
173 K in a stream of cold N2 using an Oxford low temperature
device. Diffraction data were measured using an Oxford
Gemini diffractometer mounted with Mo-Kα λ = 0.71073 Å and
Cu-Kα λ = 1.54184 Å. Data were reduced and corrected for
absorption using the CrysAlis Pro program.57 The
SHELXL2013-258 program was used to solve the structures with
Direct Methods, with refinement by the Full-Matrix Least-
Squares refinement techniques on F2. The non-hydrogen
atoms were refined anisotropically and hydrogen atoms were
placed geometrically and refined using the riding model. Co-
ordinates and anisotropic thermal parameters of all non-
hydrogen atoms were refined. All calculations were carried out
using the program Olex2.59 Images were generated by using
ORTEP-3.49 Further XRD details are provided in the ESI.†
CCDC 1419735–1419742 contains the supplementary crystallo-
graphic data for this paper.
Reverse Phase-HPLC (RP-HPLC) analyses and purifications
were performed using a Shimadzu HPLC fitted with two Shi-
madzu LC-20AD pumps,
a
SIL-20AHT autosampler,
a
SPD-M20A photodiode array detector and a FRC-10A fraction
collector. For all HPLC methods chromatograms were obtained
by monitoring absorbance at 258 nm. Elution was carried out
as follows: Method 1: Atlantis T3 DC18 analytical column (4.6 ×
150 mm), flow rate of 1 mL min−1, mobile phase: (A) water and
(B) methanol. Gradient elution: 30% (B) 0–1 min, 30–90% (B)
1–4 min, 90% (B) 4–8 min, 90–30% (B) 8–11 min, stop at
14 min. Method 2: Atlantis T3 DC18 analytical column (4.6 ×
150 mm), flow rate of 1 mL min−1, mobile phase: (A) water and
(B) methanol. Gradient elution: 30% (B) 0–1 min, 30–70% (B)
1–3 min, 70–90% (B) 3–6 min 90% (B) 6–11 min, 90–30% (B)
11–16 min, stop at 18 min. Method 3: Atlantis T3 DC18 analyti-
cal column (4.6 × 150 mm), flow rate of 1 mL min−1, mobile
phase: (A) 0.1% trifluoroacetic acid (TFA) in water and (B)
0.1% TFA in methanol. Gradient elution: 30% (B) 0–1 min,
30–90% (B) 1–5 min, 90% (B) 5–10 min, 90–30% (B)
10–13 min, stop at 17 min. Method 4: Alltima C18 semi-pre-
Synthesis
6·Cl4. A solution of α,α,α,α-tetrachloro-p-xylene (2.00 g,
8.26 mmol) and 1-methylimidazole (2.71 g, 33.00 mmol) in
PEG 400 (5 mL) was heated at 110 °C for 48 h. After cooling to
RT, acetone (10 mL) was added and a sticky solid formed. After
carefully decanting the solvent, the solid was redissolved in
methanol and re-precipitated by the addition of ether. The
product was obtained as brown hygroscopic solid. (Yield:
parative column (22 × 250 mm), flow rate of 3 mL min−1
mobile phase: (A) water and (B) methanol. Gradient elution:
30% (B) 0–1 min, 30–80% (B) 1–5 min, 80–90% (B) 5–10 min,
90–30% (B) 10–12 min, stop at 16 min.
,
1
3.00 g, 64%). H NMR (500 MHz) (DMSO-d6): δ (ppm) 9.96 (s,
3
4H, 4Himi (NCHN)), 9.00 (s, 2H, 2ArCH) 8.27 (dd, JHH
=
Stability studies
4
3
1.50 Hz, JHH = 1.50 Hz, 4H, 4Himi), 7.93 (dd, JHH = 1.50 Hz,
4JHH = 1.50 Hz, 4H, 4Himi), 7.62 (s, 4H, 4HAr), 3.92 (s, 12H,
4CH3). 13C NMR (DMSO-d6): δ (ppm) 138.3 4Cimi (NCHN),
133.7 2Cq, 128.9 4Cimi, 125.0 4Cimi, 121.3 4CAr, 70.6 2ArCH,
36.2 4CH3. Anal. Calcd for C24H30Cl4N8·2H2O: C, 47.38. H,
5.63. N, 18.42%. Found: C, 47.65. H, 5.72. N, 18.57%.
7. A modified literature procedure was used to prepare this
compound.39 An aqueous solution of bis(2-dichloroethyl)
amine hydrochloride (20 mL, 1.40 M) was added to an
aqueous NaOH solution (15 mL, 2.07 M) and after stirring for
5 min, two layers separated and the organic phase was
extracted into dichloromethane. After the removal of solvent
from the organic extracts, the residual oil was dissolved in
acetonitrile (30 mL) and this solution was added to a suspen-
sion of K2CO3 (11.68 g, 84.51 mmol) in acetonitrile (30 mL)
Stock solutions of either 14 or 17·ReO4 (10 mM in DMSO) were
reconstituted in phosphate buffered saline (pH = 7) (final
complex concentration = 5.0 mM) containing either: no
addition (control), L-cysteine (100 mM) or L-histidine
(100 mM). These solutions were incubated in the dark at 37 °C
1 °C for 51 h (14) or 91 h (17·ReO4). The complex stability
was monitored by recording HPLC chromatograms at set time
points (see ESI†) over the course of the incubation period. To
identify the transchelation reaction products, the HPLC peaks
were collected and the positive ion mass spectra recorded. For
complex 14, HPLC Method 1 was used, while for complex
17·ReO4 HPLC Method 3 was used.
X-ray crystallography
Single crystals suitable for X-ray diffraction were obtained as and finally a solution of benzyl bromide (5.30 g, 30.99 mmol)
follows: 6·Cl4: diffusion of vapors between a solution of the in acetonitrile (30 mL) was added. The mixture was stirred for
title compound in methanol and diethyl ether; 12·Cl3: slow 24 h, filtered, and the solvent removed under reduced
evaporation of a solution of the title compound in methanol pressure, yielding a cream colored crystalline solid. To the
and acetone; 14, trans-15 and trans–trans-16: slow evaporation solid was added
a solution of triethylamine (1.09 g,
of methanol, chloroform and acetone solutions of these com- 10.77 mmol) in hexane (50 mL) and the precipitate of
pound respectively; 17·ReO4, 18 and 20 diffusion of vapors benzyltriethylammonium bromide which formed was removed
between a solution of the title compounds in methanol or by filtration and the filtrate was concentrated under reduced
acetonitrile or methanol with small amount of acetone and pressure to give a yellow liquid (10 mL). After purification on
diethyl ether. Crystallographic data for all structures deter- silica, with dichloromethane (10%) and hexane (90%) as
mined are given in Tables S1 (ESI†). For all samples, crystals eluent, the product was obtained as a colorless oil. (Yield:
were removed from the crystallization vial and immediately 5.50 g, 85%). 1H NMR (300 MHz) (DMSO-d6): δ (ppm)
3
coated with paratone oil on a glass slide. A suitable crystal was 7.35–7.23 (m, 5H, HAr), 3.72 (s, 2H, ArCH2), 3.60 (t, JHH = 6.90
3
mounted in Paratone oil on a glass fiber and cooled rapidly to Hz, 4H, 2CH2CH2), 2.84 (t, JHH = 6.90 Hz, 4H, 2CH2CH2). 13C
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3
NMR (DMSO-d6): δ (ppm) 139.2 Cq, 128.5 2CAr, 128.1 2CAr, 2H, CH2CO), 3.06 (t, JHH = 6.40 Hz, 4H, 2CH2CH2), 1.19 (t,
126.9 CAr, 57.5 ArCH2, 55.1 2CH2CH2, 42.1 2CH2CH2.
3JHH = 7.20 Hz, 3H, CH3). 13C NMR (DMSO-d6): δ (ppm) 170.8
8·Cl2. A solution of 7 (0.87 g, 3.74 mmol) and 1-methyl- CO, 136.7 2Cimi (NCHN), 122.9 2Cimi, 122.4 2Cimi, 60.0
imidazole (0.61 g, 7.50 mmol) in tetrahydrofuran (10 mL) was CH3CH2, 52.7 2CH2CH2 and CH2CO 46.5 2CH2CH2, 35.7 2imi-
heated at 120 °C for 24 h. After cooling to RT, a yellow/brown CH3, 14.0 CH3. This compound was obtained as a hygroscopic
oil was formed and triturated with acetone (5 × 20 mL). The oil and was characterised by HPLC, ESI-MS and 1H and 13C NMR
product was obtained as yellow/brown oil. (Yield: 0.34 g, 23%). spectroscopy. The NMR spectra, ESI-MS and HPLC chromato-
1H NMR (300 MHz) (DMSO-d6): δ (ppm) 9.13 (s, 2H, 2Himi gram are provided in the ESI (Fig. S7†) as evidence of purity.
(NCHN)), 7.64 (d, 3JHH = 1.20 Hz, 4H, 4Himi), 7.25–7.23 (m, 3H,
12·Cl3. A solution of 11·Cl2 (1.00 g, 2.55 mmol) in 5 M HCl
3
HAr), 7.01–6.98 (m, 2H, HAr), 4.30 (t, JHH = 6.00 Hz, 4H, (20 mL) was heated at 110 °C for 2 h. After cooling to RT, the
3
2CH2CH2), 3.85 (s, 6H, 2CH3), 3.63 (s, 2H, ArCH2), 2.86 (t, JHH solvent was removed under reduced pressure and the crude
= 6.00 Hz, 4H, 2CH2CH2). 13C NMR (DMSO-d6): δ (ppm) 137.9 product was recrystallised from methanol with the addition of
Cq, 136.6 2Cimi (NCHN), 128.5 2CAr, 128.1 2CAr, 127.0 CAr, acetone. The product was obtained as a hygroscopic white crys-
1
123.1 2Cimi, 122.5 2Cimi, 56.9 CH2, 52.4 2CH2CH2, 46.4 talline solid. (Yield: 0.68 g, 67%). H NMR (500 MHz) (DMSO-
3
2CH2CH2, 35.7 2CH3. This compound was obtained as a hygro- d6): δ (ppm) 9.31 (s, 2H, 2Himi (NCHN)), 7.76 (dd, JHH
=
1
4
3
scopic oil and was characterised by HPLC, ESI-MS and H and 1.50 Hz, JHH = 1.50 Hz, 2H, Himi), 7.68 (dd, JHH = 1.50 Hz,
13C NMR spectroscopy. The NMR spectra, ESI-MS and HPLC 4JHH = 1.50 Hz, 2H, Himi), 4.26 (t, JHH = 6.00 Hz, 4H,
3
chromatogram are provided in the ESI (Fig. S4†) as evidence of 2CH2CH2), 3.85 (s, 6H, 2imi-CH3), 3.51 (s, 2H, CH2CO), 3.13 (t,
purity.
3JHH = 6.00 Hz, 4H, 2CH2CH2). 13C NMR (DMSO-d6): δ (ppm)
9·Cl2. To a mixture of 8·Cl2 (0.50 g, 1.26 mmol) in ethanol 172.0 CO, 136.9 2Cimi (NCHN), 122.9 2Cimi, 122.4 2Cimi, 53.2
(30 mL) was added 5% Pd/C (34 mg) and resulting suspension CH2CO, 52.7 2CH2CH2, 46.3 2CH2CH2, 35.7 2CH3. This com-
was stirred at 65 °C under one atmosphere of hydrogen for pound was obtained as a hygroscopic solid and was character-
24 h. The mixture was filtered and the volatiles removed from ised by HPLC, ESI-MS and 1H and 13C NMR spectroscopy.
the filtrate under reduced pressure to give 9·Cl2 as an as yellow NMR spectra, ESI-MS and HPLC chromatogram are provided
oil. (Yield: 0.35 g, 91%). 1H NMR (500 MHz) (DMSO-d6): in the ESI (Fig. S8†) as evidence of purity.
3
δ (ppm) 9.13 (s, 2H, 2Himi (NCHN)), 7.70 (dd, JHH = 1.50 Hz,
13·Cl2. A mixture of H-Gly-OBzl·TsO (0.18 g, 0.52 mmol)
and DIPEA (0.07 g, 0.52 mmol) in dimethylformamide was
4JHH = 1.50 Hz, 2H, 2Himi), 7.68 (dd, JHH = 1.50 Hz, JHH
=
3
4
1.50 Hz, 2H, 2Himi), 4.19 (t, 3JHH = 5.50 Hz, 4H, 2CH2CH2), 3.86 stirred for 35 min and a solution of 12·Cl3 (0.21 g, 0.52 mmol)
(s, 6H, 2CH3), 2.89 (t, JHH = 6.00 Hz, 4H, 2CH2CH2). 13C NMR and DIPEA (0.14 g, 1.04 mmol) and HOBt (0.01 g, 0.08 mmol)
3
(DMSO-d6): δ (ppm) 137.2 2Cimi (NCHN), 123.6 2Cimi, 123.0 in water were added. The mixture was cooled to 10 °C and EDC
2Cimi, 49.0 2CH2CH2, 47.8 2CH2CH2, 36.1 2CH3. This com- (0.15 g, 0.78 mmol) was added. After stirring for 24 h, the
pound was obtained as a hygroscopic oil and was characterised solvent and other volatiles were removed under reduced
by HPLC, ESI-MS and 1H and 13C NMR spectroscopy. The pressure and the residue was dissolved in water (10 mL) and a
NMR spectra, ESI-MS and HPLC chromatogram are provided solution of KPF6 (0.39 g, 2.09 mmol) in water (5 mL) was
in the ESI (Fig. S5†) as evidence of purity.
added. After stirring for 1 h a colourless oil separated, which
10. This compound was prepared as described for 7 from was collected by centrifugation. The oil was dissolved in
ethyl bromoacetate (8.94 g, 53.53 mmol) and was obtained as a acetone (5 mL) and a solution of Bu4NCl (0.58 g, 2.09 mmol)
colourless oil after purification on silica, with ethyl acetate in acetone (5 mL) was then added. After 1 h a second colour-
(20%) and hexane (80%) as eluent. (Yield: 8.64 g, 78%). 1H less oil formed, which was isolated by centrifugation and
3
NMR (300 MHz) (CDCl3): δ (ppm) 4.07 (q, JHH = 7.08 Hz, 2H, washed with acetone (10 mL). The product was obtained as
3
OCH2), 3.58 (t, JHH = 6.90 Hz, 4H, 2CH2CH2), 3.54 (s, 2H, colourless oil. (Yield: 0.17 g, 64%). 1H NMR (400 MHz)
3
3
3
CH2CO), 2.97 (t, JHH = 6.90 Hz, 4H, 2CH2CH2), 1.18 (t, JHH
=
(CDCl3): δ (ppm) 9.87 (s, 2H, 2Himi (NCHN)), 9.32 (t, JHH =
7.08 Hz, 3H, CH3). 13C NMR (CDCl3): δ (ppm) 171.1 CO, 6.00 Hz, 1H, NH), 7.96 (s, 2H, 2Himi), 7.34–7.23 (m, 5H, 5HAr),
59.8 CH3CH2, 55.7 2CH2CH2, 54.4 CH2CO, 42.6 2CH2CH2, 14.0 7.24 (s, 2H, 2Himi), 5.08 (s, 2H, ArCH2), 4.55 (t, JHH = 6.40 Hz,
3
3
CH3. This compound was obtained as a hygroscopic oil and 4H, 2CH2CH2), 4.04 (d, JHH = 6.00 Hz, 2H, NHCH2), 3.88 (s,
was characterised by HPLC, ESI-MS and 1H and 13C NMR 6H, 2imi-CH3), 3.47 (s, 2H, CH2CO), 3.25 (t, 3JHH = 6.40 Hz, 4H,
spectroscopy. The NMR spectra, ESI-MS and HPLC chromato- 2CH2CH2). 13C NMR (CDCl3): δ (ppm) 171.5 CO, 170.8 CO,
gram are provided in the ESI (Fig. S6†) as evidence of purity.
137.8 2Cimi (NCHN), 135.7 Cq, 128.9 2CAr, 128.6 CAr, 128.1
11·Cl2. This compound was prepared as described for 8·Cl2 2CAr, 123.9 2Cimi, 122.7 2Cimi, 67.0 ArCH2, 59.3 COCH2, 54.9
from 10 (3.08 g, 13.50 mmol). The isolated crude oil was tritu- 2CH2CH2, 47.7 2CH2CH2, 41.2 NHCH2, 36.6 2imi-CH3. This
rated with acetone (5 × 20 mL). The product was obtained as compound was obtained as a hygroscopic oil and was charac-
brown oil. (Yield: 2.96 g, 56%). 1H NMR (400 MHz) (DMSO-d6): terised by HPLC, ESI-MS and 1H and 13C NMR spectroscopy.
3
δ (ppm) 9.20 (s, 2H, Himi (NCHN)), 7.69 (dd, JHH = 1.60 Hz, The NMR spectra, ESI-MS and HPLC chromatogram are pro-
3
4
4JHH = 1.60 Hz, 2H, Himi), 7.66 (dd, JHH = 1.60 Hz, JHH
=
vided in the ESI (Fig. S9†) as evidence of purity.
14. A solution of 4·Br2 (75 mg, 0.22 mmol), Re(CO)5Cl
3
1.60 Hz, 2H, Himi), 4.20 (t, JHH = 6.40 Hz, 4H, 2CH2CH2), 4.08
(q, JHH = 7.20 Hz, 2H, OCH2), 3.85 (s, 6H, imi-CH3), 3.54 (s, (80 mg, 0.22 mmol) and Ag2O (51 mg, 0.22 mmol) in a
3
Dalton Trans.
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1 : 9 mixture of methanol and dichloromethane (30 mL) was
trans–cis-16. 1H NMR (500 MHz) (CD3CN): δ (ppm) 7.67 (d,
3
heated at 60 °C for 24 h. After cooling to RT, the mixture was 3JHH = 8.50 Hz, 2H, HAr), 7.59 (s, 1H, ArCH), 7.56 (d, JHH
=
filtered through celite and the filtrate was concentrated to 2.00 Hz, 2H, 2Himi), 7.31 (d, 3JHH = 2.00 Hz, 2H, 2Himi), 7.03 (d,
∼5 mL under reduced pressure and a small amount of ether 3JHH = 8.50 Hz, 2H, HAr), 7.01 (s, 1H, ArCH), 6.99 (d, JHH
=
3
was added resulting in the precipitation of an off-white solid. 2.00 Hz, 2H, 2Himi), 6.56 (d, 3JHH = 2.00 Hz, 2H, 2Himi), 4.08 (s,
The crude product was collected and recrystallised from 6H, 2CH3), 4.04 (s, 6H, 2CH3). ESI-MS: m/z
= 1001.1
methanol with the addition of ether. The product was [C30H26N8O6Re2Cl]+.
obtained as a white solid (Yield: 55 mg, 52%). 1H NMR
17·ReO4. This compound was prepared as described for 14
3
(500 MHz) (DMSO-d6): δ (ppm) 7.51 (d, JHH = 2.00 Hz, 2H, from 8·Cl2 (20 mg, 0.05 mmol). The crude product was recrys-
2Himi), 7.39 (d, 3JHH = 2.00 Hz, 2H, 2Himi), 6.55 (d, 3JHH = 13.00 tallised from dichloromethane by the addition of ether. The
3
Hz, 1H, CH2), 5.87 (d, JHH = 13.00 Hz, 1H, CH2), 3.89 (s, 6H, product was obtained as pale yellow crystalline solid. (Yield:
2CH3). 13C NMR (DMSO-d6): δ (ppm) 197.8 Cq, 177.1 2Cimi 15 mg, 35%). 1H NMR (500 MHz) (DMSO-d6): δ (ppm)
(NCN), 123.0 2Cimi, 121.5 2Cimi, 63.2 CH2, 38.2 2CH3. Anal. 7.63–7.61 (m, 2H, 2HAr), 7.46 (s, 4H, 4Himi), 7.44–7.43 (m, 3H,
Calcd for C12H12ClN4O3Re: C, 29.97. H, 2.24. N, 11.63%. HAr), 4.63 (s, 2H, ArCH2), 4.21–4.17 (m, 2H, 2CH2CH2),
Found: C, 29.91. H, 2.51. N, 11.63%. HPLC: RT = 8.32 min 3.69–3.65 (m, 2H, 2CH2CH2), 3.63 (s, 6H, 2CH3), 3.27–3.22 (m,
(HPLC Method 1).
trans-15. This compound was prepared as described for 14 d6): δ (ppm) 195.7 Cq, 195.5 2Cq, 173.9 2Cimi (NCN), 133.3
from 5·Cl2 (90 mg, 0.28 mmol). The crude residue was washed 2CAr, 132.2 Cq, 129.1 CAr, 128.3 2CAr, 123.5 2Cimi, 122.4 2Cimi
2H, 2CH2CH2), 2.65–2.60 (m, 2H, 2CH2CH2). 13C NMR (DMSO-
,
with chilled methanol (5 mL) and the undissolved solid was 73.9 ArCH2, 56.6 2CH2CH2, 48.3 2CH2CH2, 38.1 2CH3. ESI-MS:
collected and recrystallised from a minimum volume of chloro- m/z = 594.1 [C22H25N5O3Re]+. Anal. Calcd for C22H25N5O3Re·
form with addition of small amount of ether. The product was ReO4: C, 31.33. H, 2.99. N, 8.30%. Found: C, 31.63. H, 2.88. N,
obtained as a colourless crystalline solid. (Yield: 46 mg, 30%). 8.46%. HPLC: RT = 10.3 min (HPLC Method 3).
1H NMR (500 MHz) (DMSO-d6): δ (ppm) 7.90 (s, 1H, ArCH),
17·PF6. A solution of 8·Cl2 (80 mg, 0.20 mmol) and Ag2O
7.76 (d, 3JHH = 2.00 Hz, 2H, 2Himi), 7.59 (d, 3JHH = 2.00 Hz, 2H, (47 mg, 0.20 mmol) in a 1 : 9 mixture of methanol and dichlor-
3
2Himi), 7.35–7.27 (m, 3H, HAr), 6.65 (d, JHH = 8.00 Hz, 2H, omethane (30 mL) was stirred for 24 h and then filtered
HAr), 3.98 (s, 6H, 2CH3). 13C NMR (DMSO-d6): δ (ppm) 176.9 through celite and the solvent removed under reduced
2Cimi (NCN), 138.3 Cq, 129.0 2CAr, 128.6 CAr, 124.9 2CAr, 123.1 pressure. The residual solid was dissolved in dichloromethane
2Cimi, 122.4 2Cimi, 74.5 ArCH, 38.3 2CH3. ESI-MS: m/z = 523.1 and Re(CO)5Cl (73 mg, 0.20 mmol) was added in one portion.
[C18H16N4O3Re]+. Anal. Calcd for C18H16ClN4O3Re: C, 38.74. H, The reaction mixture was heated to 60 °C for 24 h and after
2.89. N, 10.04%. Found: C, 39.07. H, 2.91. N, 10.00%. HPLC: cooling to RT, the mixture was filtered through celite and the
RT = 9.05 min (HPLC Method 1).
solvent removed under reduced pressure. The residual solid
trans–trans-16 and trans–cis-16. These compounds were was dissolved in a mixture of 2 : 8 methanol and water (10 mL)
prepared as described for 14 from 6·Cl4 (50 mg, 0.09 mmol). and a solution of KPF6 (0.31 g, 1.68 mmol) in water (5 mL) was
Upon completion of the reaction, the solvent was removed added. A pale pink precipitate formed, which was collected via
under reduced pressure and the crude product was dissolved centrifugation and then recrystallised from
a minimum
in a minimum volume of methanol. The geometric isomeric volume of a 1 : 1 mixture of acetonitrile and methanol with
forms of the complex were separated using semi-preparative addition of ether. The product was obtained as white crystal-
HPLC (HPLC Method 4, Experimental section). trans–trans-16 line solid. (Yield: 77 mg, 52%). 1H NMR (400 MHz) (DMSO-d6):
(HPLC: RT = 9.60 min) and trans–cis-16 (HPLC: RT = 10.63 min) δ (ppm) 7.63–7.61 (m, 2H, 2HAr), 7.45 (s, 4H, 4Himi), 7.44–7.42
were obtained as off-white solids after HPLC purification. Both (m, 3H, HAr), 4.63 (s, 2H, ArCH2), 4.22–4.16 (m, 2H, 2CH2CH2),
compounds were further purified by the diffusion of vapours 3.70–3.62 (m, 2H, 2CH2CH2), 3.63 (s, 6H, 2CH3), 3.24–3.22 (m,
between diethyl ether and solutions of each compound in 2H, 2CH2CH2), 2.65–2.60 (m, 2H, 2CH2CH2). 13C NMR (DMSO-
acetone. Compound trans–trans-16 was obtained as colourless d6): δ (ppm) 195.7 Cq, 195.5 2Cq, 173.9 2Cimi (NCN), 133.3
crystalline solid (Total yield: 10 mg, 11%), and trans–cis-16 was 2CAr, 132.2 Cq, 128.9 CAr, 128.3 2CAr, 123.5 2Cimi, 122.4 2Cimi
,
obtained as colourless solid. Only a very small amount of this 73.8 ArCH2, 56.6 2CH2CH2, 48.3 2CH2CH2, 38.0 2CH3. ESI-MS:
isomer was isolated after HPLC purification and recrystalliza- m/z
=
594.1
[C22H25N5O3Re]+.
Anal.
Calcd
for
tion and characterisation was only possible by 1H NMR and C22H25F6N5O3PRe·0.5 CH3CN: C, 36.39. H, 3.52. N, 10.15%.
mass spectrometry. trans–trans-16: 1H NMR (400 MHz) Found: C, 36.62. H, 3.78. N, 10.14%.
3
(DMSO-d6): δ (ppm) 7.94 (s, 2H, 2ArCH), 7.54 (d, JHH = 2.00
19. This compound was prepared as described for 17·PF6
3
1
Hz, 4H, 4Himi), 7.49 (d, JHH = 2.00 Hz, 4H, 4Himi), 6.83 (s, 4H, from 9·Cl2 (20 mg, 0.07 mmol). (Yield: 16 mg, 38%). H NMR
4HAr), 3.95 (s, 12H, 4CH3). 13C NMR (DMSO-d6): δ (ppm) (500 MHz) (DMSO-d6): δ (ppm) 7.40 (d, JHH = 2.30 Hz, 2H,
3
3
197.1 4CO, 190.3 2CO, 176.9 4Cimi (NCN), 126.9 4CAr, 123.0 2Himi), 7.39 (d, JHH = 2.30 Hz, 2H, 2Himi), 7.02 (m, 1H, NH),
4Cimi, 121.9 4Cimi, 74.0 2ArCH, 38.4 2CH3. ESI-MS: m/z = 3.97–3.68 (m, 4H, 2CH2CH2), 3.62 (s, 6H, 2CH3), 2.98–2.92 (m,
1001.1 [C30H26N8O6Re2Cl]+. Anal. Calcd for C30H26Cl2N8O6Re2: 2H, CH2CH2), 3.69–3.65 (m, 2H, CH2CH2). 13C NMR (DMSO-
C, 34.72. H, 2.52. N, 10.80%. Found: C, 34.85. H, 2.59. d6): δ (ppm) 195.2 CO, 194.3 2CO, 172.0 2Cimi (NCN), 123.1
N, 10.75%.
2Cimi, 122.6 2Cimi, 50.6 2CH2CH2, 48.4 2CH2CH2, 38.2 2CH3.
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ESI-MS: m/z
=
504.1 [C15H19N5O3Re]+. Anal. Calcd for PRe·2CH2Cl2: C, 32.85. H, 3.35. N, 8.21%. Found: C, 32.57. H,
C15H19N5O3RePF6: C, 27.95. H, 2.99. N, 10.60%. Found: C, 3.64. N, 8.48%.
27.78. H, 2.95. N, 10.80%.
20. This compound was prepared as described for 17·PF6
from 11·Cl2 (0.12 g, 0.31 mmol) in a 1 : 9 mixture of aceto-
References
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nitrile and dichloromethane (20 mL). (Yield: 0.12 g, 53%). H
3
NMR (500 MHz) (DMSO-d6): δ (ppm) 7.44 (d, JHH = 4.00 Hz,
4H, 4Himi), 4.29 (s, 2H, CH2CO), 4.22–4.14 (m, 2H, OCH2 and
4H, 2CH2CH2), 3.56–3.54 (m, 2H, 2CH2CH2), 3.53 (s, 6H,
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3
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Dalton Trans.
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