Synthetic strategies for efficient conjugation of organometallic complexes with pendant protein reactive markers

Article abstract of DOI:10.1016/j.jorganchem.2013.05.027

Site-directed conjugation of metal centers to proteins is fundamental for biological and bioinorganic applications of transition metals. However, methods for the site-selective introduction of metal centers remain scarce. Herein, we present broadly applicable synthetic strategies for the conjugation of bioactive molecules with a range of organometallic complexes. Following three different synthetic strategies, we were able to synthesize a small library of metal conjugated protein markers featuring different types of protein reactive sites (epoxides, phenylphosphonates, fluorosulfonates and fluorophosphonate groups) as well as different late transition metals (iron, ruthenium, rhodium, palladium and platinum). The products were isolated in moderate to excellent yields and high purity. Furthermore, X-ray diffraction of the metalated protein markers corroborates structural integrity of the metal complex and the protein reactive site.

Full text of DOI:10.1016/j.jorganchem.2013.05.027

Journal of Organometallic Chemistry 744 (2013) 82e91
Contents lists available at SciVerse ScienceDirect
Journal of Organometallic Chemistry
journal homepage: www.elsevier.com/locate/jorganchem
Synthetic strategies for efficient conjugation of organometallic
complexes with pendant protein reactive markers
,
,
,1,
Dominik Jantke a 2, Alexander N. Marziale a 2, Thomas Reiner b 2, Florian Kraus b,
Eberhardt Herdtweck b, Andreas Raba b, Jörg Eppinger a
,
*
a King Abdullah University of Science and Technology, Division for Physical Sciences & Engineering and KAUST Catalysis Center, Thuwal, Saudi Arabia
b Department Chemie, Technische Universität München, Lichtenbergstr. 4, D-85747 Garching bei München, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Site-directed conjugation of metal centers to proteins is fundamental for biological and bioinorganic
applications of transition metals. However, methods for the site-selective introduction of metal centers
remain scarce. Herein, we present broadly applicable synthetic strategies for the conjugation of bioactive
molecules with a range of organometallic complexes. Following three different synthetic strategies, we
were able to synthesize a small library of metal conjugated protein markers featuring different types of
protein reactive sites (epoxides, phenylphosphonates, fluorosulfonates and fluorophosphonate groups)
as well as different late transition metals (iron, ruthenium, rhodium, palladium and platinum). The
products were isolated in moderate to excellent yields and high purity. Furthermore, X-ray diffraction of
the metalated protein markers corroborates structural integrity of the metal complex and the protein
reactive site.
Received 19 March 2013
Received in revised form
14 May 2013
Accepted 15 May 2013
Dedicated to Professor Wolfgang A. Herr-
mann on the occasion of his 65th birthday.
Keywords:
Bioinorganic chemistry
Metalloenzymes
Peptide coupling
Protease inhibitors
Ó 2013 Elsevier B.V. All rights reserved.
1. Introduction
of electrochemical biosensors [8]. Research in the flourishing field
of artificial metalloenzymes has provided access to a wide range of
The conjugation of artificial metal centers to biologically active
organic molecules or biomolecules as well as the study of naturally
occurring metal centers in enzymes has been investigated inten-
sively over the last decades [1]. Numerous applications and tech-
niques based on metals in biological systems, both naturally as well
as non-naturally occurring, were developed. Of particular interest
are applications of metal-containing bioconjugates including
pharmaceuticals [2], contrast agents for molecular imaging [3], X-
ray fluorescence spectroscopy and microscopy [4], or tools to study
metalloprotein structure and function [5]. For analytical tech-
niques, artificially incorporated non-naturally occurring metal
centers feature the important advantage of providing high signal to
noise ratios, since the only source of signal is the artificially intro-
duced metal [6]. Exchange of a protein’s naturally occurring cata-
lytically active metal center allowed to alter its electrochemical
potential [7], facilitating the use of such systems for the generation
biocatalytic transformations which do not occur in nature [9].
Wilson and Whitesides introduced site directed anchoring of arti-
ficial cofactors based on the biotine(strept)avidin technology to
incorporate artificial metal centers through a supramolecular as-
sembly process [10]. Using directed evolution, Ward and coworkers
were able to reveal the full potential of this approach and develop
highly enantioselective organometallic enzyme hybrid (OMEH)
catalysts for hydrogenations and transfer hydrogenations [11],
asymmetric Pd-catalyzed allylations [12], cis-dihydroxylation of
olefins [13] and olefin metathesis [14] of transition metal bearing
biomolecules. Recently, even catalytic cascade reactions [15] and
protein-accelerated asymmetric CeH activations [16] were re-
ported. Covalent attachment of artificial organometallic cofactors
has been applied to convert proteases [17], lipases [18] or other
non-metal proteins [19] into OMEH catalysts. Expanding this
approach, we were recently able to introduce a building block
based strategy to generate artificial enantioselective hydrogenases
[20]. This approach provides a site-selective, covalent modification
method for of a variety of biomolecules with libraries of organo-
metallic complexes via reactive epoxide peptidomimetics.
* Corresponding author. Tel.: þ996 2 808 2414.
E-mail address: jorg.eppinger@kaust.edu.sa (J. Eppinger).
Present address: Department of Radiology, Memorial Sloan-Kettering Cancer
1
Despitetheplethoraofmethodsandpracticalapplicationsrelying
on conjugates of organometallic complexes with biologically active
Center, 1275 York Avenue, New York, NY 10065, USA.
2
These authors contributed equally.
0022-328X/$ e see front matter Ó 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.jorganchem.2013.05.027

D. Jantke et al. / Journal of Organometallic Chemistry 744 (2013) 82e91
83
derived from the chelating bis-phosphine ligands
HN(CH2CH2PiPr2)2 (PNP) and (R,R)-pyrphos. Palladium com-
plexes coordinated to PNP ligands have been synthesized
before [25] and were successfully applied as asymmetric allylic
amination catalysts. Late transition metal complexes of (R,R)-
pyrphos have been used for both, immobilization on polymers
as well as the generation of dendrimeric catalysts [26]. The
corresponding platinum complex 6 of (R,R)-pyrphos may
serve as a 195Pt NMR probe and enable active monitoring in
biological systems [27].
molecules, laborious synthetic access to these compounds is a major
limitation. Commonly biomolecular components tend to coordinate
the metal center, which hampers conjugation yields. A variety of
bioorthogonal conjugation methods have been developed [21],
however, the synthesis of orthogonal reactive moieties can be
tedious and low-yielding. We therefore decided to systematically
study methods, which could enable the conjugation of a range of
transition metal complexes via conventional amide linkage. This
approach has the advantage, that the required amine and carboxylic
functional groups can be introduced easily during complex or
biomarker synthesis. The present study describes three different
general protocols that permit direct attachment of organometallic
complexes to epoxide, diphenylphosphonate, fluorophosphonate
and fluorosulfonate protease inhibitors. Each protocol is particularly
mild and facilitates conjugation of the metal complex and the reac-
tive functional group without compromising the integrity of the
metal center’s innercoordination sphere or thereactive functionality
of the biomarker moiety.
All complexes were synthesized as reported previously and
characterized by 1H and 13C NMR spectroscopy as well as elemental
analysis.
A large number of small organic molecules and peptidomimetics
which bear reactive functional groups capable of covalently inhib-
iting enzymes have been described in literature [28]. Here, we focus
on the carboxylic acid forms of established cysteine and serine
protease inhibitors (Fig. 2). E64 analog 7 [29], exhibits high binding
affinity over a broad group of cysteine proteases of the papain
family. The inhibition proceeds via a nucleophilic attack at the in-
hibitor’s epoxide moiety and results in formation of a covalent link
between protease and inhibitor. Serine protease reactive markers
derived from electrophilic phosphorous and sulfur centers were
also used in this study. Diphenylphosphonate 8, fluorosulfonate 9
and fluorophosphonate 10 [30] are known to bind irreversibly to
serine hydrolases. Inhibitors 7 and 10 were synthesized according
to literature procedures in high purity and yields. Phosphonate 8
was synthesized by conversion of diphenyl 1-aminobenzyl phos-
2. Results and discussion
2.1. Synthesis of transition metal complexes and bioactive marker
moieties
Conjugation of metal complexes and bioactive markers via
amide linkage requires the presence of an amine function in either
of the two building blocks. The nucleophilic NH-moiety can react
with the reactive group of the type of protease labels we intended
to use in this study. Correspondingly, organometallic complexes
were synthesized with a pendant primary or secondary amine
group, while the bioactive moieties display a carboxylic acid func-
tional handle. Six amino-functionalized organometallic complexes
served as model complexes to test their conjugation with carbox-
ylic acids under amide bond forming conditions (Fig. 1). These
complexes represent three different classes:
phonate [31] with succinic anhydride. Fluorosulfonate
9 is
commercially available and was used as received. All protease in-
hibitors were characterized by 1H and 13C NMR spectroscopy.
Standard amide bond formation procedures involve conversion
of the carboxylic acid into an active ester or anhydride, which can
undergo nucleophilic attack by primary or secondary amines. We
investigated three general strategies for conjugation of the metal
complex with the bioactive marker moiety: (A) post-metal-
coordination conjugation, which represent the only possible
method for (half)sandwich complexes; (B) pre-metal conjugation,
which is an additional option for chelating diphosphines; (C)
conjugation via reactive fluorine species, which is a variant of the
post-metal-coordination conjugation approach for inhibitors 8e10
with electrophilic phosphorus and sulfur centers.
(i) Amine functionalized half sandwich complexes, which may
provide ligand coordination sites following dissociation of the
kinetically labile halideemetal bonds (
h
5-tetramethyl cyclo-
pentadienyl rhodium 1 [22], and
h
6-benzene ruthenium 2
[23]); these complexes are highly stable toward air and
moisture and are active catalysts for the hydrogenation of al-
kenes and ketones in aqueous solution.
(ii) Amine functionalized sandwich complexes, which could serve
as redox-active probes for protein detection aminomethylene
ferrocene 3 [1,24].
(iii) Transition metal complexes with chelating phosphine ligands
represented by complexes 4, 5 and 6. These complexes are
2.1.1. Method A: post-coordination conjugation
In order to establish a general synthetic route for the attachment
of metal complexes to protein reactive markers via post-
coordination conjugation, we decided to use the air and moisture
Fig. 1. Metal complexes exhibiting non-coordinating amine groups used in this study.
Fig. 2. Organic precursors used for the generation of metalated protein markers.

84
D. Jantke et al. / Journal of Organometallic Chemistry 744 (2013) 82e91
Table 1
Crystallographic data for 11.
resemble those of the E64 derived precursor. Hence it can be
concluded, that the epoxide moiety is still intact. The NH protons of
the pendant linker resonate at 7.97 ppm (11) and approx. 7.0 ppm
(12, overlay with arene protons), which underlines that conjugation
via amide linkage was successful. Only one set of signals is observed
for both protein markers. The inhibitor moiety has three stereo-
centers, and racemization of one of them would lead to formation
of diastereomers with distinguishable spin systems. Therefore the
stereochemistry is confirmed to be unaltered.
Formula
C46H53Cl2N3O4PRh
916.69
P21
8.7620(3)
32.5384(10)
8.8665(3)
90
109.700(2)
90
2379.9(1)
2
1.279
10,172
500
0.047
0.122
Formula wt
Space group
ꢀ
a (A)
ꢀ
b (A)
ꢀ
c (A)
a
b
g
(ꢁ)
(ꢁ)
(ꢁ)
Crystals of complex 11 suitable for X-ray crystallographic anal-
ysis were obtained from a 0.02 M solution in methanol at ꢀ18 ꢁC.
The structure of this complex, which crystallizes in the monoclinic
space group P21 is shown in Fig. 2, crystallographic parameters are
found in Tables 1 and 2. The crystal structure confirms the integrity
of the piano-stool shaped rhodium complex. All bond length and
angles are within the expected range [33]. The distances of the
protein reactive epoxide carbon atoms from the rhodium center are
3
ꢀ
V (A )
Z
Dcalc. (g cmꢀ3
)
No. of indep rflns
No. of params
R1 (I > 2
wR2 (all data)
Goodness of fit
Flack x
s
(I))
1.237
0.05(3)
ꢀ
ꢀ
8.006(6) A and 9.063(6) A respectively. No intra- or inter-molecular
interactions between the metal center and the epoxide or the
amide bonds are found in the crystal. The high flexibility of the
terminal benzyl group and the leucine side chain is attributed to
very weak H-bond interactions in the crystal. The Flack parameter
x ¼ 0.05(3) confirms retention of the stereochemistry of the
epoxide as well as the amino acid side chain. The linear structure
illustrates of how this artificial metallo-cofactor should bind to a
protease: the inhibitor moiety maps the hydrophilic binding
pockets, while the epoxide moiety forms the covalent link at the
active center. This double interaction orients the cofactor in the
binding pocket of the protease. Structural flexibility is only ex-
pected to arise from the ethylene linker between the metal com-
plex and the E64 inhibitor moiety (Fig. 3).
stable rhodium complex 1 and protein marker 7 as test system.
During the initial condition screen we found that typical peptide
coupling reagents such as dicyclohexyl carbodiimide, N-hydroxy
succinimide or substituted benzotriazoles tend to coordinate to the
metal center and alter the inner coordination sphere of the catalyst.
However, activation of the carboxylic acid with a polystyrene
bound solid phase cyclohexyl carbodiimide derivative followed by
conversion of the intermediate with an excess of penta-
fluorophenol circumvents this problem. The resulting activated
pentafluorophenol esters can easily be conjugated with amines.
Filtration of the carbodiimide resin before addition of complex 1
ensures that its nucleophilic centers (e.g. urea based side products)
do not lead to side product formation. More importantly, penta-
fluorophenol exhibits negligible binding affinity for the ruth-
enium(II) center, leaving the inner coordination sphere of the metal
complex unaltered. Coupling via pentafluorophenol ester in-
termediates yielded the rhodium containing protein marker 11 in
86% and the ruthenium compound 12 in 68% yield (see Table 3).
Purity, stability and identity of both complexes complex were
confirmed by 1H, 13C, 31P NMR and 1H1H COSY NMR spectroscopy,
IR spectroscopy, elemental analysis and mass spectrometry. 31P
NMR spectra display the characteristic signals for the coordinated
Method A is also suitable for the metal complex conjugation of
bioactive molecules comprising electrophilic heteroatoms. The
bioactive metalated marker 15 was obtained from rhodium com-
plex 1 and phosphonate 8 in 68% yield. Purity, stability and identity
of the rhodium conjugated marker were confirmed by homo- and
hetero-nuclear NMR spectroscopy, IR spectroscopy, elemental
analysis and mass spectrometry. 31P NMR spectroscopy shows the
expected doublet for the triphenylphosphine ligand at
d
¼ 29.8 ppm with the typical coupling constant of 1JRh,P ¼ 143 Hz
and a singlet at
d
¼ 14.8 ppm for the phosphonate.
phosphine ligand (11: doublet,
singlet,
values of similar compounds [22,23,32]. This proves that the metal
coordination environment was not changed during the conjugation
process. The 1H and 13C NMR spectra of the epoxide moiety closely
d
¼ 30.0 ppm, 1JRh,P ¼ 143 Hz; 12:
Fluorosulfonates are well established efficient inhibitors of
serine proteases. We decided to use the commercially available
fluorosulfonate 3 in our study since it exhibits a carboxylic acid
functional handle. Conjugation with ruthenium complex 1 and
ferrocene derivative 3 by the post-coordination conjugation method
yields metalated protein marker 18 and 19 in high purity and
moderate yields (18: 43% 19: 20%). Stability of the fluorosulfonate is
confirmed by 19F NMR spectroscopy, showing clean singlets at
66.28 ppm (18) and 66.08 ppm (19). Structural integrity of the
metal complexes moiety of 18 is evident form NMR spectroscopy. In
the 31P NMR, a singlet is observed for the metal bound triphenyl-
d
¼ 27.8 ppm), which are in agreement with literature
Table 2
Crystallographic data for 17.
Formula
2(C36H36Cl2FNO3PRhS), 3(CHCl3)
Formula wt
Space group
1931.12
P-1 (no. 2)
15.0745(9)
16.9192(10)
18.5003(12)
69.352(3)
73.986(4)
69.983(3)
4083.5(4)
2
ꢀ
phosphine at
d
¼ 28.0 ppm. The ferrocene-conjugated marker
a (A)
ꢀ
b (A)
shows the characteristic signals of the Cp-protons as well as the NH
resonance at 6.38 ppm.
ꢀ
c (A)
a
b
g
(ꢁ)
(ꢁ)
(ꢁ)
2.1.2. Method B: pre-coordination conjugation
3
ꢀ
V (A )
The secondary amine functions of complexes 4e6 provide only
reduced reactivity and therefore require longer reaction times.
Correspondingly, method A provides only low yields and impure
products for conversions of the PNPepalladium complex 4 with
phenylphosphonate 8. Both, the loss of the metal center as well as
decomposition of the reactive phosphonate moiety are responsible
for the unsatisfactory conjugation results. Hence, for the bisphos-
phine complexes of palladium and platinum we decided to test
Z
Dcalc.(g cmꢀ3
)
1.571
No. of indep rflns
11,695
No. of params
945
R1 (I > 2
s(I))
0.0410
wR2 (all data)
Goodness of fit
Largest diff. peak and hole (e A
0.1146
1.046
1.06/ꢀ0.77
ꢀꢀ3
)

D. Jantke et al. / Journal of Organometallic Chemistry 744 (2013) 82e91
85
Table 3
Schematic representation of the different synthetic strategies used for the generation of metalated protein markers.
Compound
Structure
Method, yield
Reactive moiety
Epoxide
Protease family
11
A, 86%
Cysteine proteases
Cysteine proteases
12
13
14
A, 79%
Epoxide
Epoxide
Epoxide
A, 89%
B, 92%
Cysteine proteases
Cysteine proteases
A, 87%
B, 95%
15
16
A, 68%
B, 89%
Diphenyl-phosphonate
Diphenyl-phosphonate
Serine proteases
Serine proteases
17
18
A, 59%
C, 95%
Fluorosulfonate
Fluorosulfonate
Serine proteases
Serine proteases
A, 43%
C, 89%
19
20
A, 20%
C, 86%
Fluorosulfonate
Serine proteases
Serine proteases
Fluoro-phosphonate

86
D. Jantke et al. / Journal of Organometallic Chemistry 744 (2013) 82e91
NMR spectroscopy, only one singlet was observed, which was
assigned to the fluorosulfonic acid fluoride (85.86 ppm). Further-
more, in 31P NMR, the doublet originating from the triphenyl-
phosphine phosphorous is indicative for the success of the reaction.
It was observed at 30.04 ppm (1JRh,P ¼ 143 Hz). In 1H NMR, a triplet
originating from the peptide NH proton was observed at 8.12 ppm
3
with a coupling constant of JHH ¼ 5.8 Hz.
Crystals suitable for X-ray analysis of complex 17 were obtained
from a mixture of CH2Cl2/Et2O/CHCl3/CDCl3 at ꢀ18 ꢁC at a con-
centration of approx. 40 mg/mL. The structure, which was solved in
the space group P-1 shows integrity of the metal centers inner
coordination sphere with no intra- or inter-molecular interactions
between the metal center and the outer ligand sphere as well as
stability of the fluorosulfonate moiety toward synthetic and crys-
tallographic methods (Fig. 4). In the unit cell, two non-equivalent
molecules of 17 are present, which only show small differences in
bond lengths and angles. The Rh center, which is in a slightly dis-
torted piano-stool geometry, shows no unexpected distortions.
Angles between Rh and the ligands are in the expected range. The
bond length between Rh and Cp* centroid with 1.824(2) and
Fig. 3. Crystal structure of rhodium functionalized protein marker 11. Hydrogen atoms
are omitted for clarity. Thermal ellipsoids are shown at a 30% probability level.
conjugation of ligands and reactive organic molecules prior to co-
ordination of the transition metal centers. This pre-coordination
conjugation approach allowed the straightforward synthesis of
ligand functionalized protein reactive markers, which are readily
converted metal-conjugated affinity markers upon addition of the
transition metal precursor. Following formation of the penta-
fluorophenol ester, phenylphosphonate 8 was functionalized with
the PNP-ligand. Stirring with PdCl2(CH3CN)2 converted the active
ester into the metalated protein marker 16, which was isolated in
high yield (89%). Excellent purity and structural integrity were
confirmed by NMR spectroscopy, elemental analysis, IR spectros-
copy and mass spectrometry. The free ligand is air and moisture
sensitive, however after palladium-coordination and N-function-
alization it displays excellent stability toward air and moisture.
Activation of the carboxylic acid of 7 by immobilized cyclohexyl
carbodiimide and formation of the pentafluorophenol active ester
followed by addition of the non-metalated ligand (R,R)-pyrphos,
resulted in clean formation of the peptide bond between the protein
marker and the ligand. Subsequent attachment of the metal center
was achieved by addition of the metal precursors PdCl2(CH3CN)2 or
PtCl2(CH3CN)2, yielding complexes 13 and 14, respectively. Clean
product formation was observed in both cases. The metalated pro-
tein markers are highly stable toward air and moisture. Both com-
plexes 13 and 14 are stable on silica columns, which allowed their
purification by column chromatography yielding the protein
markers in 92% and 95% isolated yield (13 and 14, respectively). For
the active ester of inhibitor 7, coupling was also successful when
metal complexes 5 and 6 were used directly, however this resulted
in slightly lower yields (89% and 87% for 13 and 14, respectively).
ꢀ
1.821(2) A are in the range of similar RheCp* complexes. This is
expected due to the similar steric demand of the methyl group and
the pendant linker group of the Cp* ring system. Also RheCl bond
ꢀ
lengths are very similar, ranging from 2.3858(12) to 2.4258(11) A.
The Cl1eRh1eCl2 angle (91.36(4)ꢁ) is only slightly larger than the
two P1eRh1eCl angles (87.74(5)ꢁ and 86.92(4)ꢁ). The FeSeO an-
gles of both independent molecules in the unit cell are (105.2(2)ꢁ,
104.9(2)ꢁ and 106.4(3)ꢁ 111.7(3)ꢁ).
The metal-conjugated biomarkers 18 and 20 were obtained by
addition of the respective metal complexes (Ru complex 2 for 18
and Rh complex 1 for 20) to the crude acyl fluoride of the reactive
biomarker moiety (epoxide 7 for 18 and fluorophosphonate 10 for
20) in presence of NEt3. The analytically pure product was isolated
in 89% and 86% yield after aqueous workup and etheric precipita-
tion from a dichloromethane solution. Compound 18 gave signals
identical to those of the compound which was synthesized by the
post-coordination conjugation method. Structural identity of the
fluorophosphonate functionality in 20 and the metal center’s
integrity as well as purity of the product was confirmed by homo-
and hetero-nuclear NMR spectroscopy, IR spectroscopy, elemental
analysis and mass spectrometry. 31P NMR shows a characteristic
1
doublet at
d
d
¼ 29.8 ppm with JRh,P ¼ 142 Hz and a doublet at
1
¼ 32.5 ppm with JF,P ¼ 1.07 kHz.
2.1.3. Method C: reactive acyl fluoride species
Synthesis of transition metal centers covalently linked to the
serine hydrolase inhibitors fluorophosphonate 9 or fluorosulfonate
10 was realized following a different strategy. The corresponding
precursors 9 and 10 were treated with diethylamino sulfurtri-
fluoride (DAST), resulting in the generation of acyl fluorides, a
technique described by Liu et al. [30] Acyl fluorides exhibit high
reactivity toward nucleophiles but posses only limited affinity to-
ward transition metal complexes, rendering the possibility to use
these reactive fluoride species directly for the formation of metal-
conjugated protease markers 17 and 20. The fluorosulfonate
marker 17 was isolated in 95% yield. Following the post-coordina-
tion conjugation approach, the same complex was isolated in 59%
yield, showing the advantages of the reactive acyl fluoride reaction
sequence. The product was characterized using homo- and hetero-
nuclear NMR spectroscopy, ESI-MS and elemental analysis. In 19F
Fig. 4. ORTEP representation of one molecule in the unit cell of 17. Hydrogen atoms are
omitted for clarity. Thermal ellipsoids are shown at the 50% probability level.

D. Jantke et al. / Journal of Organometallic Chemistry 744 (2013) 82e91
87
3. Conclusion
and were refined against all data using WinGX [40] based on SIR-
92 [36]. If not mentioned otherwise, non-hydrogen atoms were
refined with anisotropic displacement parameters. Methyl
hydrogen atoms were refined as part of rigid rotating groups, with
Our studies revealed that post-metal-coordination assembly
method A is suitable for amide bond formation for all three types of
metal complexes tested in this study. The successful strategy is
based on utilization of solid phase coupling reagents to form an
active pentafluorophenyl ester intermediate. While method A can
be applied for a broad range of compounds, pre-metal-coordination
assembly (method B) and conjugation via active acid fluorides
(method C) leads to higher yields for chelating diphosphines (B)
and inhibitors with electrophilic phosphorous and sulfur centers
(C). Our synthetic strategy enabled us to synthesize and charac-
terize a broad range of Fe, Ru, Rh, Pd and Pt containing biomarkers
including several, which provide a catalytically active transition
metal center. The particularly mild coupling procedures leave the
protein reactive group as well as the organometallic moiety unal-
tered, which was confirmed by spectroscopic data and X-ray crys-
tallography of two metalated protein markers. All compounds
presented in this study are stable against air and moisture, which
makes them promising candidates for further applications directed
toward molecular imaging or generation of catalytically active
organometallic enzyme hybrids. The approach can be further used
to generate libraries of metal containing bioactive molecules, which
should facilitate optimization and application of such compounds.
ꢀ
CeH ¼ 0.98 A and Uiso(H) ¼ 1.5Ueq(C). All other hydrogen atoms
were placed in calculated positions and refined using a riding
model, with methyne, methylene and aromatic CeH distances of
ꢀ
1.00, 0.99 and 0.95 A, respectively, and Uiso(H) ¼ 1.2Ueq(C). NeH
ꢀ
distances were set to 0.88 A and Uiso(H) ¼ 1.2Ueq(N). Full-matrix
least-squares refinements were carried out by minimizing
P
wðFo2 ꢀ Fc2Þ2 with SHELXL-97 [38] weighting scheme. Neutral
atom scattering factors for all atoms and anomalous dispersion
corrections for the non-hydrogen atoms were taken from Inter-
national Tables for Crystallography [37]. Images of the crystal
structures were generated by PLATON [39]. Compounds 1 [22], 2
[23], 3 [24], 4 [25], 5 [26], 6 [26], 7 [30] and 10 [31] were synthe-
sized according to literature procedures, compound 9 was pur-
chased from Aldrich and used without any further purification.
4.2. Synthetic procedures
4.2.1. Synthesis of protein marker 8
Succinic anhydride (354 mg, 3.54 mmol) and diphenyl 1-ami-
nobenzyl phosphonate (1.00 g, 2.95 mmol) were dissolved in
dichloromethane (75 mL). Then, pyridine (237 mL, 2.95 mmol) was
4. Experimental section
added and the reaction mixture stirred for 24 h. Thereafter, the
mixture was washed with water (3 ꢂ 40 mL) and brine (2 ꢂ 40 mL),
dried over MgSO4 and volatiles removed under reduced pressure.
The raw product was redissolved in EtOAc and precipitated with
diethyl ether to give the pure product (1.06 g, 2.41 mmol, 68%) as a
4.1. General methods
All reactions involving air-sensitive compounds were per-
formed under an atmosphere of argon using standard Schlenk and
glove-box techniques. THF was dried over Na/benzophenone,
distilled under argon and deoxygenated prior to use. Diethyl ether,
pentane and hexane were dried and deoxygenized by passing
through columns packed with activated alumina and Q5, respec-
tively. Dichloromethane was dried over CaH2 and distilled prior to
use. CDCl3 was dried over CaH2 and purified by condensation and
deoxygenated by three freezeepumpethaw cycles. NMR spectra
were recorded on a JEOL JNM-GX 400, a BRUKER DRX 400, a Bruker
Avance III 400 and a Bruker Avance III 500. Chemical shifts are
given in ppm and were referenced to the residual proton resonance
respectively the natural abundance 13C resonance of the solvent.
31P NMR spectra were calibrated to an external standard (phos-
phoric acid). ESI-MS and ESI-LC MS spectra were recorded on a LCQ
classic spectrometer (Thermo Electron). Elemental analyses were
obtained from the Microanalytical Laboratory of Technische Uni-
versität München. IR spectra were recorded on a Jasco FT/IR-460
PLUS and prepared as KBr pallets or Nujol suspension between
KBr plates. Wavelengths are noted in cmꢀ1. Data were collected on
an X-ray single crystal diffractometer equipped with a CCD de-
white solid. 1H NMR (400 MHz, CDCl3, 25 ꢁC):
d
¼ 8.36 (dd,
3J(H,P) ¼ 13 Hz, 3J(H,H) ¼ 9.6 Hz, 1H, NH), 7.54e6.63 (m, 15H, Haromat.),
3
2
5.96 (dd, J(H,H) ¼ 9.6 Hz, J(H,P) ¼ 22 Hz, 2H, NHCHPh), 2.64e2.39
(m, 4H, CH2CH2COOH); 13C NMR (101 MHz, CDCl3, 25 ꢁC):
d
¼ 176.3
3
(s, COOH), 171.8 (d, J(P,C) ¼ 9.2 Hz, NHCO), 150.3 (d, J(P,C) ¼ 9.9 Hz,
C
aromat.), 150.1 (d, J(P,C) ¼ 11 Hz, Caromat.), 133.8 (s, Caromat.), 130.0 (d,
J(P,C) ¼ 27 Hz, Caromat.), 129.4e128.4 (m, 2 Caromat.), 125.6 (d,
J(P,C) ¼ 24 Hz, Caromat.), 120.6 (d, J(P,C) ¼ 3.8 Hz, Caromat.), 120.2 (d,
1
J(P,C) ¼ 3.8 Hz, Caromat.), 50.7 (d, J(P,C) ¼ 159 Hz, PhCH), 30.5 (s,
CH2CH2), 29.4 (s, CH2CH2); 31P NMR (162 MHz, 25 ꢁC, CDCl3):
~
d
¼ 15.1; IR (KBr):
n
¼ 3261 m, 3060 m, 2917 w, 1719 m, 1701 sh w,
1677 m, 1653 s, 1589 m, 1550 m, 1492 s, 1202 m, 1179 m, 942 vs
cmꢀ1; MS (ESI): m/z (%): ¼ 462.2 [M þ Na]þ, 901.1 [2M þ Na]þ, 917.1
[2M þ K]þ;elemental analysis calcd. (%) for C23H22NO6P$0.5H2O: C
61.61, H 5.17, N 3.12; found C 62.46, H 4.95, N 3.04.
4.2.2. General coupling procedure A (post-coordination conjugation)
Dichloromethane (10 mL) was added to polystyrene bound
cyclohexyl carbodiimide (130 mg, 2.3 mmol/g, 0.30 mmol, 1.5 eq.)
at 0 ꢁC and the resin was allowed to swell for 45 min. The corre-
sponding inhibitor (0.20 mmol, 1.0 eq.) and pentafluorophenol
(0.30 mmol, 1.5 eq.) were added and the reaction mixture was
stirred at 0 ꢁC for 1 h. The reaction was allowed to warm to r.t. and
was stirred over night. The mixture was filtered, triethylamine
tector (Bruker APEX II,
k-CCD), a rotating anode (Bruker AXS,
ꢀ
FR591) with MoKa radiation (
l
¼ 0.71073 A), and a graphite
monochromator by using the SMART software package [34]. The
measurements were performed on a single crystal coated with
perfluorinated ether. The crystal was fixed on the top of a glass
fiber and transferred to the diffractometer. The crystal was frozen
under a stream of cold nitrogen at 123 K (17) or was measured at
296 K (11). A matrix scan was used to determine the initial lattice
parameters. Reflections were merged and corrected for Lorenz and
polarization effects, scan speed, and background using SAINT [35].
Absorption corrections, including odd and even ordered spherical
harmonics were performed using SADABS [35]. Space group as-
signments were based upon systematic absences, E statistics, and
successful refinement of the structures. Structures were solved by
direct methods with the aid of successive difference Fourier maps,
(55 mL, 0.40 mmol, 2.0 eq.) and metal complex (0.20 mmol, 1.0 eq.)
were added. The reaction was stirred at r.t. for 3 h. Upon comple-
tion, the organic phase was washed with water and brine (each
3 ꢂ 10 mL), dried over MgSO4 and volatiles were removed under
reduced pressure. The resulting solid was washed with diethyl
ether and hexanes to give the pure product.
4.2.3. General coupling procedure B (pre-coordination conjugation)
Dichloromethane (10 mL) was added to polystyrene bound
cyclohexyl carbodiimide (130 mg, 2.3 mmol/g, 0.30 mmol, 1.5 eq.)
at 0 ꢁC and the resin was allowed to swell for 45 min. The

88
D. Jantke et al. / Journal of Organometallic Chemistry 744 (2013) 82e91
corresponding inhibitor (0.20 mmol,1.0 eq.) and pentafluorophenol
(0.30 mmol, 1.5 eq.) were added and the reaction mixture was
stirred at 0 ꢁC for 1 h. The reaction was allowed to warm to r.t. and
was stirred over night. The mixture was filtered, triethylamine
4.37. Crystal data: formula: C46H53Cl2N3O4P1Rh1; Mr ¼ 916.69;
crystal color and shape: red plate, crystal dimensions:
0.1 ꢂ 0.1 ꢂ 0.05 mm; crystal system: monoclinic; space group: P21
ꢀ
(no. 4); a ¼ 8.7620(3), b ¼ 32.5384(10), c ¼ 8.8665(3) A,
a
3
¼ 90.00ꢁ,
ꢁ
¼ 109.700(2)ꢁ,
g
¼ 90.00 ; V ¼ 2379.90(14) A ; Z ¼ 2;
ꢀ
(55
m
L, 0.40 mmol, 2.0 eq.) and the diphosphine ligand (0.20 mmol,
b
m
1.0 eq.) were added. The reaction was stirred at r.t. over night.
Volatiles were removed under reduced pressure and the resulting
residue was dissolved in dry THF. The solution was filtered and a
suspension of the metal precursor (0.19 mmol, 0.95 eq.) in THF
(5 mL) was added to the filtrate and the reaction was stirred at r. t.
over night. Upon completion of the reaction, diethyl ether (10 mL)
and pentane (5 mL) were added and a yellow solid was precipi-
tated. The solid was filtered off and washed with diethyl ether
(3 ꢂ 15 mL) and volatiles removed in vacuo. Subsequently, the
product was purified by column chromatography (CH2Cl2/
MeOH ¼ 95/5) and from the combined product fractions a yellow
solid was precipitated by addition of diethyl ether and pentane. The
solid was washed with diethyl ether (2 ꢂ 15 mL).
(MoKa) ¼ 0.547 cmꢀ1
;
rcalcd ¼ 1.279 g cmꢀ3
;
q
-range ¼ 2.74e27.65ꢁ;
data collected: 10,172; independent data [Io > 2s(Io)/all data/Rint]:
9986/10,172/0.039; data/restraints/parameter: 10,172/43/500; R1
[Io > 2 (Io)/all data]: 0.0470/0.0479; wR2 [Io > 2 (Io)/all data]:
ꢀꢀ3
s
s
0.1214/0.1218; GOF ¼ 1.236; Drmax/min: 0.50/ꢀ1.27 e A
.
4.2.5.2. [(
h
6-C6H5CH2NHCO-Eps-Leu-Bz)RuCl2(PPh3)] 12. This com-
pound was synthesized following general procedure A. The product
was obtained as a bright red solid (118 mg, 0.14 mmol, 79%). 1H
3
NMR (400 MHz, CDCl3, 25 ꢁC):
d
¼ 7.97 (t, J(H,H) ¼ 5.4 Hz, 1H,
NHCH2), 7.76e7.65 (m, 6H, CHaromat.), 7.51e7.22 (m, 14H, CHaromat.),
3
3
6.76 (d, J(H,H) ¼ 8.3 Hz, 1H, NHCH), 6.50 (t, J(H,H) ¼ 5.4 Hz, 1H,
3
NHCH2), 5.61 (d, J(H,H) ¼ 5.6 Hz, 1H, CHortho), 5.35e5.31 (m, 1H,
3
CHmeta), 5.29 (d, J(H,H) ¼ 6.1 Hz, 1H, CHortho), 5.12e5.04 (m, 1H,
4.2.4. General coupling procedure C (reactive acid fluoride species)
The corresponding inhibitor (0.26 mmol, 1.0 eq.) was dissolved
in a Teflon-flask in dichloromethane (5 mL) at ꢀ78 ꢁC. To this so-
CHmeta), 4.68 (dd, 2J(H,H) ¼ 15.4 Hz, 3J(H,H) ¼ 6.2 Hz, 1H, CH2), 4.61e
4.55 (m, 1H, CHpara), 4.52e4.30 (m, 5H, PhCH2/CH2/CH2Ph),3.93 (s,
1H, CH(O)CH0), 3.57 (s, 1H, CH(O)CH0), 1.73e1.50 (m, 3H,
CH2CH(CH3)2), 0.89 (d, 3J(H,H) ¼ 6.0 Hz, 6H, CH2CH(CH3)2); 13C NMR
lution, DAST was added (135 mL,1.02 mmol, 4.0 eq.) and the solution
was stirred at ꢀ78 ꢁC for 15 min. And was allowed to warm to r.t.
Water (10 mL) was added in small portions and the solution was
vigorously stirred for 5 min before ethyl acetate (30 mL) was added.
The organic phase was separated and washed with brine, dried over
MgSO4 and volatiles were removed under reduced pressure. The
residual oily substance was dissolved in dichloromethane (5 mL)
(101 MHz, CDCl3, 25 ꢁC):
d
¼ 171.4 (CON), 167.1 (CON), 166.3 (CON),
138.2 (s, Caromat.), 134.2 (d, J(P,C) ¼ 9.2 Hz, Caromat.), 133.0 (d,
J(P,C) ¼ 47.7 Hz, Caromat.), 130.8 (d, J(P,C) ¼ 2.5 Hz, Caromat.), 128.7
(Caromat.), 128.4 (d, J(P,C) ¼ 10.1 Hz, Caromat.), 127.8 (Caromat.), 127.5
2
(Caromat.), 107.6 (d, J(P,C) ¼ 6.7 Hz, Caromat.), 89.5 (Caromat.), 88.0 (d,
2J(P,C) ¼ 6.5 Hz, Caromat.), 87.6 (Caromat.), 86.2 (Caromat.), 82.0 (Caromat.),
54.5 (CH(O)CH), 54.4 (CH(O)CH), 51.9 (CHCH2), 43.5 (NHCH2Car-
omat.), 41.0 (NHCH2Caromat.), 40.6 (CHCH2), 24.9 (CH(CH3)2), 23.0
(CH(CH3)2), 22.1 (CH(CH3)2); 31P NMR (162 MHz, CDCl3, 25 ꢁC):
~
before triethylamine (143 mL, 1.02 mmol, 4.0 eq.) and the metal
complex (0.25 mmol, 0.95 eq.) was added. The reaction solution
was stirred at r.t. for 3 h before volatiles were removed in vacuo. The
resulting solid was dissolved in dichloromethane (3 mL) and the
product precipitated by addition hexane (50 mL) at ꢀ20 ꢁC over
night. The supernatant was filtered off and the red precipitate was
washed with hexane and volatiles removed in vacuo.
d
¼ 27.8 (s, PPh3); IR (KBr): ¼ 3060, 2956, 2927, 1669, 1526, 1482,
n
1435, 1243, 1093, 697, 527 cmꢀ1; MS (ESI): m/z (%): 822.1 [Mþ ꢀ Cl],
1679.8 [2Mþ ꢀ Cl], 1415.8 [2Mþ ꢀ PPh3 ꢀ Cl]; elemental analysis
calcd. (%) for C42H44Cl2N3O4PRu: C 58.81, H 5.17, N 4.90; found:
C58.47, H 5.09, N 4.64.
4.2.5. Characterization of metalated protein markers
4.2.5.1. [(
h
5-Me4Cp(CH2)2NH-Eps-Leu-Bz)RhCl2(PPh3)] 11. This com-
4.2.5.3. [((R,R)-Pyrphos-NH-Eps-Leu-Bz)PdCl2] $ HCl 13. The product
was synthesized via route B and obtained as a yellow solid (172 mg,
0.18 mmol, 92%). Synthesis via Route A: 89%. 1H NMR (400 MHz,
pound was synthesized following general procedure A. The product
was obtained as a bright red solid (119 mg, 0.13 mmol, 86%). 1H NMR
(400 MHz, CDCl3, 25 ꢁC):
d
¼ 7.82e7.72 (m, 6H, CHaromat.), 7.50e7.17
CDCl3, 25 ꢁC):
d
¼ 7.92e7.81 (m, 8H, CHaromat.), 7.65 (t, 3J(H,H) ¼ 7.5 Hz,
(m, 15H, CHaromat., CH2CH2NH), 7.09e6.95 (m, 2H, NHCH2(C6H5),
1H, CHaromat.), 7.59e7.43 (m, 10H, CHaromat.), 7.24 (dd, 3J(H,H) ¼ 6.7 Hz,
2
3
NHCH), 4.48e4.40 (m, 1H, NHCH), 4.35 (dd, J(H,H) ¼ 14.9 Hz,
2H, CHaromat.), 7.15 (d, J(H,H) ¼ 7.0 Hz, 1H, CHaromat.), 6.97 (d,
3J(H,H) ¼ 5.8 Hz, 1H, NHCH2(C6H5)), 4.27 (dd, J(H,H) ¼ 14.9 Hz,
3J(H,H) ¼ 7.1 Hz, 1H, CONHCH), 6.49 (t, 3J(H,H) ¼ 5.1 Hz, 1H, CONHCH2),
4.39e4.35 (m, 1H, NHCHCO), 4.34e4.21 (m, 2H, NHCH2), 3.96 (t,
3J(H,H) ¼ 7.7 Hz, 1H, CHCH2N), 3.77 (t, 3J(H,H) ¼ 7.7 Hz, 1H, CHCH2N),
3.52e3.48 (m, 1H, CHCH2N), 3.46 (s, 1H, CHCH), 3.40 (s, 1H, CHCH),
2
3J(H,H) ¼ 5.8 Hz, 1H, NHCH2(C6H5)), 3.55 (d, J(H,H) ¼ 1.9 Hz, 1H,
3
3
CHOCH), 3.53 (d, J(H,H) ¼ 1.9 Hz, 1H, CHOCH), 3.38 (m, 2H,
CH2CH2NH), 2.26 (m, 2H, CH2CH2NH), 1.69e1.50 (m, 3H,
4
3
CH2CH(CH3)2), 1.49 (d, J(P,H) ¼ 2.9 Hz, 3H, CCpCH3), 1.48 (d,
3.25e3.13 (m, 2H, CHCH2N), 2.92 (t, J(H,H) ¼ 8.1 Hz, 1H, CHCH2N),
4J(P,H) ¼ 3.1 Hz, 3H, CCpCH3), 1.09 (d, 4J(P,H) ¼ 2.9 Hz, 3H, CCpCH3), 0.99
1.61e1.50 (m, 3H, CHCH2CH), 0.88 (d, 3J(H,H) ¼ 5.4 Hz, 6H, CH(CH3)2);
4
3
(d, J(P,H) ¼ 2.9 Hz, 3H, CCpCH3), 0.83 (d, J(H,H) ¼ 3.1 Hz, 3H,
13C NMR (101 MHz, CDCl3, 25 ꢁC):
d
¼ 171.3 (CHCONH), 166.0
CH2CH(CH3)2), 0.81 (d, J(H,H) ¼ 3.1 Hz, 3H, CH2CH(CH3)2); 13C NMR
(NCOCH),164.0 (CHCONH), 137.6 (Caromat.),136.4 (dd, 1J(P,C) ¼ 13.0 Hz,
3
2
2
(101 MHz, CDCl3, 25 ꢁC):
d
¼ 171.5 (CON), 166.5 (CON), 166.2 (CON),
Caromat.), 133.5 (d, J(P,C) ¼ 21.1 Hz, Caromat.), 133.1 (d, J(P,C) ¼ 9.1 Hz,
138.2 (Caromat.),134.8 (d, 3J(P,C) ¼ 9.7 Hz, Caromat.),130.7(Caromat.),128.7
(Caromat.), 128.1 (Caromat.), 127.7 (Ca2romat.), 127.4 (Caromat.), 102.5 (d,
1J(Rh,C) ¼ 5.5 Hz, Caromat.), 102.3 (d, J(Rh,C) ¼ 4.3 Hz, CCp.), 100.3 (dd,
Caromat.), 132.6 (Caromat.), 129.3 (dt, J(P,C) ¼ 8.6 Hz, Caromat.), 128.6
3
(Caromat.), 127.5 (Caromat.), 127.4 (Caromat.), 126.7 (dd, J(P,C) ¼ 17.1 Hz,
Caromat.), 123.8 (Caromat.), 123.2 (Caromat.), 53.5 (CHCH), 52.8 (CHCH),
2J(Rh,C) ¼ 6.6 Hz, J(P,C) ¼ 6.6 Hz, CCp.), 97.1 (m, CCp), 54.5 (CH(O)CH),
51.8 (NHCHCO), 45.3 (m, CHCH2N), 44.0 (m, J(P,C) ¼ 15.0 Hz,
3
2
54.1 (CH(O)CH), 51.8 (CHCH2), 43.5 (NHCH2), 41.0 (CHCH2), 36.3 (d,
4J(P,C) ¼ 4.3 Hz, CH2CH2NH), 24.8 (CH(CH3)2), 24.6 (CH2CH2NH), 23.0
CHCH2N), 43.5 (NHCH2), 43.1 (m, CHCH2N), 41.2 (CHCH2CH), 24.8
(CH(CH3)2), 22.7 (CH(CH3)2), 22.1 (CH(CH3)2); 31P NMR (162 MHz,
(CH(CH3)2), 22.1 (CH(CH3)2), 9.5 (CCp.CH3), 8.7 (s, CCp.CH3); 31P NMR
CDCl3, 25 ꢁC):
d
¼ 39.6 (dd, 2J(P,P) ¼ 157.7 Hz, 3J(P,P) ¼ 15.8 Hz, PPh2);
1
(162 MHz, CDCl3, 25 ꢁC):
d
¼ 30.0 (d, J(Rh,P) ¼ 143.0 Hz, PPh3); IR
IR (nujol):
¼ 1660, 1530 cmꢀ1; HRMS (ESI): m/z: mass calcd.
~
n
(KBr):
n
¼ 3060, 2957, 2926, 2870, 1664, 1533, 1436, 1368, 1260,
MS (ESI): m/z (%): 880.1 [M
Cl]þ, 618.2
Cl]þ; elemental analysis calcd. (%) for
C46H53Cl2N3O4PRh: C 60.27, H 5.83, N 4.58; found: C60.22, H 6.10, N
897.18434 [M ꢀ Cl]þ, found: 897.17936 [M ꢀ Cl]þ, mass calcd.:
956.15079 [M þ Na]þ, found: 956.13679 [M þ Na]þ; elemental
analysis calcd. (%) for C45H47Cl2N3O4P2Pd $ HCl: C 55.74, H 4.99, N
4.33; found: C 56.30, H 5.02, N 4.53.
~
1095 cmꢀ1
[M PPh3
;
ꢀ
ꢀ
ꢀ

D. Jantke et al. / Journal of Organometallic Chemistry 744 (2013) 82e91
89
4.2.5.4. [((R,R)-Pyrphos-NHCO-Eps-Leu-Bz)PtCl2] 14. This compound
was synthesized following general procedure B. The product was
obtained as a yellow solid (194 mg, 0.19 mmol, 95%). Synthesis via
m, CH(CH3)2, NCH2CH2), 2.28e2.10 (8H, m, COCH2CH2, CH(CH3)2,
NCH2CH2),1.21e1.09 (24H, m, CH(CH3)2); 13C NMR (101 MHz, CDCl3,
25 ꢁC):
d
¼ 172.1 (d, 4J(P,C) ¼ 7.8 Hz, NCOCH2), 171.9 (CONHCH), 150.5
Route A: 87%. 1H NMR (400 MHz, CDCl3, 25 ꢁC):
d
¼ 7.99e7.73 (m,
(d, 1J(P,C) ¼ 9.9 Hz, Caromat.), 150.1 (d, 1J(P,C) ¼ 9.6 Hz, Caromat.), 134.3
(Caromat.), 129.7 (d, 1J(P,C) ¼ 10.5 Hz, Caromat.), 128.7 (d, J(P,C) ¼ 2.1 Hz,
Caromat.), 128.4 (Caromat.), 128.3 (Caromat.), 128.2 (Caromat.), 125.3 (d,
J(P,C) ¼ 5.5 Hz, Caromat.), 120.7 (d, J(P,C) ¼ 4.2 Hz, Caromat.), 120.6 (d,
8H, CHaromat.), 7.67e7.51 (m, 13H, CHaromat.), 7.30 (dd, 3J(H,H) ¼ 6.8 Hz,
3
2H, CHaromat.), 7.19 (d, J(H,H) ¼ 8.2 Hz, 2H, CHaromat.), 6.64 (d,
3J(H,H) ¼ 8.3 Hz,1H, CONHCH), 6.16 (t, 3J(H,H) ¼ 4.9 Hz, 1H, CONHCH2),
3
4.36e4.28 (m, 3H, NHCHCO, NHCH2), 4.01 (t, J(H,H) ¼ 7.8 Hz, 1H,
J(P,C)
¼
4.3 Hz, Caromat.), 51.3 (NCH2), 51.0 (NCH2), 50.6 (d,
CHCH2N), 3.87 (m, 1H, CHCH2N), 3.59 (d, 3J(H,H) ¼ 1.7 Hz, 1H, CHCH),
1J(P,C) ¼ 157.1 Hz, CHP), 31.8 (COCH2CH2CO), 31.5 (COCH2CH2CO),
3
1
1
3.40 (d, J(H,H) ¼ 1.7 Hz, 1H, CHCH), 3.37e3.32 (m, 1H, CHCH2N),
25.2 (d, J(P,C) ¼ 10.0 Hz, PCH(CH3)2), 21.9 (d, J(P,C) ¼ 15.7 Hz,
1
3.17e3.11 (m, 1H, CHCH2N), 3.08e2.98 (m, 1H, CHCH2N), 2.90 (dd,
3J(H,H) ¼ 8.5 Hz, 1H, CHCH2N), 1.59e1.48 (m, 3H, CHCH2CH), 0.80 (d,
NCH2CH2), 20.1 (d, J(P,C)
¼
17.2 Hz, NCH2CH2), 19.7 (d,
2J(P,C) ¼ 4.8 Hz, CH(CH3)2), 19.6 (m, CH(CH3)2); 31P NMR (162 MHz,
3J(H,H) ¼ 5.8 Hz, 6H, CH(CH3)2); C NMR (101 MHz, CDCl3, 25 ꢁC):
CDCl3, 25 ꢁC):
d
¼ 39.2 (d, 2J(P,P) ¼ 35.6 Hz, PiPr2), 14.5 (s, PO(OAr)2);
13
¼ 1674, 1640, 1588, 1262, 1210 cmꢀ1; MS (ESI): m/z (%):
~
n
d
¼ 171.1 (CHCONH), 166.1 (NCOCH), 164.3 (CHCONH), 137.8 (Car-
IR (nujol):
omat.), 136.5 (m, 1J(P,C) ¼ 11.5 Hz, Caromat.), 133.4 (d, J(P,C) ¼ 20.1 Hz,
Caromat.), 133.1 (m, Caromat.), 132.4 (Caromat.), 129.4 (dt, 3J(P,C) ¼ 12.6 Hz,
Caromat.), 128.7 (Caromat.), 127.6 (Caromat.), 127.5 (Caromat.), 125.7 (dd,
J(P,C) ¼ 15.3 Hz, Caromat.), 122.8 (s. Caromat.), 122.6 (Caromat.), 53.5
(CHCH), 53.0 (CHCH), 51.9 (NHCHCO), 45.4 (m, CHCH2N), 43.9 (m,
2J(P,C) ¼ 15.4 Hz, CHCH2N), 43.5 (NHCH2), 42.9 (m, CHCH2N), 41.2
832.3 [Mþ ꢀ 2Cl], 873.3 [Mþ ꢀ Cl þ CH3CN]; MS (FAB): m/z (%):
873.1 [Mþ ꢀ Cl þ CH3CN]; elemental analysis calcd. (%) for
C37H57Cl2N3O5P3Pd $ HCl: C 49.80, H 6.22, N 2.98; found: C 50.25, H
5.98, N 2.71.
2
4.2.5.7. [(
h
5-Me4Cp(CH2)2NHCO-(C6H4)-SO2F)RhCl2(PPh3)]
17.
(CHCH2CH), 24.8 (CH(CH3)2), 22.8 (CH(CH3)2), 22.1 (CH(CH3)2); 31P
This compound was synthesized following general procedure C.
The product was obtained as an orange solid (186 mg, 0.24 mmol,
95%). Synthesis via Route A: 59%. 1H NMR (400 MHz, CDCl3,
2
NMR (162 MHz, CDCl3, 25 ꢁC):
d
¼ 17.9 (ddd, J(P,P) ¼ 173.5 Hz,
3J(P,P) ¼ 10.3 Hz, J(Pt,P) ¼ 1.66 kHz, PPh2); IR (nujol):
¼ 1662,
1
~
n
1531 cmꢀ1
;
HRMS (ESI): m/z: mass calcd. 1027.27218
25 ꢁC):
d
¼ 8.12 (t, 3J(H,H) ¼ 5.8 Hz, 1H, NH), 8.03 (d, 3J(H,H) ¼ 8.3 Hz,
[M ꢀ Cl þ CH3CN]þ, found: 1027.26556 [M ꢀ Cl þ CH3CN]þ;
elemental analysis calcd. (%) for C45H47Cl2N3O4P2Pt: C 52.89, H 4.64,
N 4.11; found: C 52.86, H 4.62, N 4.10.
2H, CHaromat.), 7.80e7.72 (m, 8H, CHaromat.), 7.33e7.14 (m, 9H,
CHaromat.), 3.85 (dt, 3J(H,H) ¼ 5.8 Hz, 2H, CH2CH2NH), 2.67 (m, 2H,
4
CH2CH2NH), 1.60 (d, 6H, J(P,H) ¼ 2.1 Hz, Caromat.CH3), 0.98 (d,
4J(P,H) ¼ 2.9, 6H, Caromat.CH3); 13C NMR (101 MHz, CDCl3, 25 ꢁC):
4.2.5.5. [(
h
5-Me4Cp(CH2)2NHCO-(CH2)2-CONH-(CHPh)-OP(OPh)2)
d
¼ 165.0 (CON), 140.2 (Caromat.), 134.7 (d, 3J(P,C) ¼ 9.2 Hz, Caromat.),
RhCl2PPh3] 15. This compound was synthesized following general
130.7 (Caromat.), 129.1 (Caromat.), 128.4 (Caromat.), 128.2 (Caromat.),
2
procedure A. The product was obtained as a bright red solid
103.3 (d, J(Rh,C) ¼ 6.2 Hz, Caromat.), 103.1 (m, Caromat.), 95.5 (d,
(139 mg, 0.14 mmol, 68%). 1H NMR (400 MHz, CDCl3, 25 ꢁC):
2J(Rh,C) ¼ 7.7 Hz, Caromat.), 37.1 (d, 4J(P,C) ¼ 4.6 Hz, CH2CH2NH), 25.3
3
d
¼ 8.23 (d, J(H,H) ¼ 10.0 Hz, 1H, CH2NH), 8.07e7.04 (m, 28H,
(CH2CH2NH), 9.8 (CCpCH3), 8.6 (CCpCH3); 31P NMR (162 MHz,
3
1
CHaromat.), 7.00 (t, J(H,H)
¼
5.6 Hz, 1H, NHCH), 6.84 (d,
CDCl3, 25 ꢁC):
d
¼ 30.0 (d, J(Rh,P) ¼ 143.0 Hz, PPh3); 19F NMR
3J(H,H) ¼ 8.0 Hz, 2H, CHaromat.), 5.90 (dd, J(P,H) ¼ 22.2 Hz,
(376 MHz, CDCl3, 25 ꢁC):
d
¼ 85.9 (s, SO2F); IR(KBr):
¼ 3056,
2
~
n
3J(H,H) ¼ 9.7 Hz, 1H, CH), 3.48e3.30 (m, 2H, CH2NH), 2.48e2.26 (m,
2920, 2815, 1664, 1532, 1483, 1435, 1411, 1213, 1095 cmꢀ1. MS
(ESI): m/z (%): 488.0 [M ꢀ PPh3 ꢀ Cl]þ, 749.9 [M ꢀ Cl]þ; elemental
analysis calcd. (%) for C36H36Cl2FNO3PRhS: C 54.97, H 4.61, N 1.78;
4H, COCH2CH2), 2.25e2.16 (m, 2H, CH2Cp), 1.46 (dd, 3J(Rh,H) ¼ 5.6 Hz,
4J(P,H)
¼
2.4 Hz, 6H, CCpCH3), 1.07 (dd, J(Rh,H)
¼
4.2 Hz,
3
4J(P,H) ¼ 4.2 Hz, 6H, CCpCH3); 13C NMR (101 MHz, CDCl3, 25 ꢁC):
found: C 54.48, H 5.29, N 1.84. Crystal data: formula:
4
d
¼ 172.6 (CON), 172.0 (d, J(Rh,C) ¼ 7.7 Hz, CO), 150.6 (d,
C75H75Cl3F2N2O6P2Rh2S2; Mr ¼ 1931.12; crystal color and shape:
3J(P,C) ¼ 9.9 Hz, Caromat.), 150.2 (d, J(P,C) ¼ 9.2 Hz, Caromat.), 134.8 (d,
3J(P,C) ¼ 9.9 Hz, Caromat.), 134.2 (Caromat.), 130.6 (Caromat.), 129.7 (d,
J(P,C) ¼ 11.1 Hz, Caromat.), 128.8 (Caromat.), 128.5 (d, J(P,C) ¼ 6.1 Hz,
Caromat.), 128.1 (Caromat.), 125.3 (d, J(P,C) ¼ 4.6 Hz, Caromat.), 120.6 (d,
J(P,C) ¼ 3.9 Hz, CCp), 120.5 (d, J(P,C) ¼ 4.2 Hz, Caromat.), 102.5 (dd,
red fragment, crystal dimensions: 0.05 ꢂ 0.13 ꢂ 0.36 mm; crystal
4
system: triclinic; space group: P1 (no. 2); a ¼ 15.0745(9),
b
¼
16.9192(10),
c
¼
18.5003(12) A,
a
¼
69.352(3)ꢁ,
ꢀ
3
ꢀ
ꢁ
b
¼ 73.986(4)ꢁ,
g
¼ 69.983(3) ; V ¼ 4083.5(4) A ; Z ¼ 2;
l
(MoKa) ¼ 0.976 mmꢀ1
;
rcalcd ¼ 1.571 g cmꢀ3
;
q
-range ¼ 1.19e
1J(Rh,C) ¼ 6.9 Hz, J(P,C) ¼ 6.9 Hz, CCp), 100.5 (dd, J(Rh,C) ¼ 6.9 Hz,
25.38ꢁ; data collected: 104,799; independent data [Io > 2
s(Io)/all
3
1
3J(P,C) ¼ 6.9 Hz, CCp), 96.8 (d, J(Rh,C) ¼ 6.9 Hz, CCp), 96.6 (d,
data/Rint]: 9487/11,695/0.100; data/restraints/parameter: 11,695/
0/945; R1 [Io > 2 (Io)/all data]: 0.0410/0.0574; wR2 [Io > 2 (Io)/all
ꢀꢀ3
1
1J(Rh,C) ¼ 6.1 Hz, CCp), 50.8 (d, J(P,C) ¼ 156.4 Hz, CH), 36.3 (d,
s
s
1
4J(P,C) ¼ 4.6 Hz, CH2Cp), 31.8 (s, COCH2CH2), 31.5 (s, COCH2CH2), 24.7
data]: 0.0994/0.1146; GOF ¼ 1.046; Drmax/min: 1.06/ꢀ0.77 e A
.
(s, NHCH2), 9.5 (s, Caromat.CH3), 8.7 (s, Caromat.CH3); 31P NMR
(162 MHz, CDCl3, 25 ꢁC):
d
~
n
¼ 29.9 (d, 1J(Rh,P) ¼ 143.0 Hz, PPh3), 14.8
¼ 3295, 3057, 2920, 2360, 2225, 1670,
4.2.5.8. [(
h
6-C6H5CH2NHCO-(C6H4)-SO2F)RuCl2(PPh3)] 18. This com-
(s, OP(OPh)2); IR (KBr):
pound was synthesized following general procedure A. The product
1589, 1522, 1489, 1435, 1384, 1266, 1186, 1161, 1095, 1025 cmꢀ1; MS
(ESI): m/z (%):687.1 [M ꢀ PPh3 ꢀ 2Cl ꢀ H]þ, 723.1 [M ꢀ PPh3 ꢀ Cl]þ,
949.1 [2M ꢀ 2Cl ꢀ H]þ, 984.8 [2M ꢀ Cl]þ; elemental analysis calcd.
(%) for C52H53Cl2N2O5PRh: C 61.13, H 5.23, N 2.74; found: C 60.18, H
5.51, N 3.00.
was obtained as a bright red solid (63 mg, 0.86 mmol, 43%). 1H NMR
(400 MHz, CDCl3, 25 ꢁC):
d
¼
8.76 (m, 1H, NH), 8.26 (d,
3J(H,H) ¼ 8.3 Hz, 2H, CHaromat.), 7.71e7.26 (m, 6H, CHaromat.), 7.43e7.37
(m, 9H, CHaromat.), 5.61 (d, 3J(H,H) ¼ 5.0 Hz, 2H, CHaromat.), 5.26 (m, 2H,
CHaromat.), 4.75 (d, 2H, 3J(H,H) ¼ 2.5 Hz, NHCH2); 13C NMR (101 MHz,
CDCl3, 25 ꢁC):
d
¼
165.4 (CON), 139.9 (Caromat.), 135.6 (d,
4.2.5.6. [(PNP-NCO-(CH2)2-CONH-(CHPh)-OP(OPh)2)PdCl2] $ HCl 16.
This compound was synthesized following general procedure B.
The product was obtained as a yellow solid (161 mg, 0.18 mmol,
3J(F,C) ¼ 25.4 Hz, Caromat.), 134.2 (d, J(P,C) ¼ 10.0 Hz, Caromat.), 132.9 (d,
J(P,C) ¼ 47.7 Hz, Caromat.), 130.9 (d, J(P,C) ¼ 1.5 Hz, Caromat.), 129.1 (Car-
omat.), 128.9 (Caromat.), 128.4 (d, J(P,C) ¼ 10.0 Hz, Caromat.), 105.9 (d,
89%). 1H NMR (400 MHz, CDCl3, 25 ꢁC):
d
¼ 7.67 (1H, m, CONH), 7.48
2J(Ru,P) ¼ 7.7 Hz, Caromat.), 88.8 (d, J(Ru,P) ¼ 5.4 Hz, Caromat.), 87.9 (m,
2
(2H, d, 3J(H,H) ¼ 7.6 Hz, CHaromat.), 7.31e7.11 (11H, m, CHaromat.), 6.89
Caromat.), 82.4 (m, Caromat.), 41.9 (CH2NH); 31P NMR (162 MHz, CDCl3,
3
2
(2H, t, J(H,H) ¼ 8.2 Hz, CHaromat.), 5.88 (1H, dd, J(P,H) ¼ 22.0 Hz,
3J(H,H) ¼ 9.6 Hz, NHCOPO), 3.81e3.64 (4H, m, NCH2), 2.69e2.58 (4H,
25 ꢁC):
d
¼ 28.0 (s, PPh3); 19F NMR (376 MHz, CDCl3, 25 ꢁC):
d
¼ 66.3
~
n
(s, SO2F); IR (KBr):
¼ 3059, 2920, 2851, 1666,1528,1482,1435,1412,

90
D. Jantke et al. / Journal of Organometallic Chemistry 744 (2013) 82e91
1213, 1094, 697 cmꢀ1; MS (ESI): m/z (%): 691.9 [Mþ ꢀ Cl]; elemental
analysis calcd. (%) for C32H27Cl2FNO3PRuS: C 51.36, H 3.59, N 2.00;
found: C 51.98, H 3.88, N 2.03.
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Drug Discov. 7 (2008) 591e607;
(b) P. Caravan, Acc. Chem. Res. 42 (2009) 851e862;
4.2.5.9. Fc-CH2NHCO-(C6H4)-SO2F 19. This compound was synthe-
(c) A. Razgulin, N. Ma, J. Rao, Chem. Soc. Rev. 40 (2011) 4186e4216;
(d) B.M. Zeglis, J.S. Lewis, Dalton Trans. 40 (2011) 6168e6195;
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7076;
(f) F.L. Throp-Greenwood, R.G. Balasingham, M.P. Voogan, J. Organomet. Chem.
714 (2012) 12e21;
sized following general procedure A. The product was obtained as a
yellow solid (17 mg, 0.04 mmol, 20%). 1H NMR (400 MHz, CDCl3,
3
25 ꢁC):
d
¼ 8.06 (d, J(H,H) ¼ 7.7 Hz, 2H, CHaromat.), 7.97 (d,
3J(H,H) ¼ 7.7 Hz, 2H, CHaromat.), 6.36 (s, 1H, NH), 4.35 (s, 2H, CH2), 4.27
(s, 4H, CHCp), 4.20 (s, 5H, CHCp); 13C NMR (101 MHz, CDCl3, 25 ꢁC):
(g) G. Gasser, A. Pinto, S. Neumann, A.M. Sosniak, M. Seitz, K. Merz,
R. Heumann, N. Metzler-Nolte, Dalton Trans. 41 (2012) 2304e2313.
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G. Sundaresan, A.M. Wu, S.S. Gambhir, S. Weiss, Science 307 (2005) 538e544;
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[5] (a) J. Dempsey, J. Winkler, H. Gray, Chem. Rev. 110 (2010) 7024e7039;
(b) A.N. Zaykov, B.V. Popp, Z.T. Ball, Chem. Eur. J. 16 (2010) 6651e6659.
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(2004) 12470e12476.
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7290;
(b) D. Ge, R. Levicky, Chem. Commun. 46 (2010) 7190e7192.
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4680e4698;
b) R. den Heerten, B.K. Munoz, G. Popa, P.C.J. Kamer, Dalton Trans. 39 (2010)
8477e8483.
[10] M. Wilson, G. Whitesides, J. Am. Chem. Soc. 100 (1978) 306e307.
[11] T.R. Ward, Acc. Chem. Res. 44 (2011) 47e57.
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T.R. Ward, Angew. Chem. Int. Ed. 47 (2008) 701e705.
[13] V. Köhler, J. Mao, T. Heinisch, A. Pordea, A. Sardo, Y.M. Wilson, L. Knörr,
M. Creus, J.-C. Prost, T. Schirmer, T.R. Ward, Angew. Chem. Int. Ed. 50 (2011)
10863e10866.
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L. Knörr, D. Häussinger, F. Hollmann, N.J. Turner, T.R. Ward, Nat. Chem. 5
(2013) 93e99.
d
¼ 164.6 (CON), 141.2 (Caromat.), 135.5 (Caromat.), 128.2 (Caromat.), 84.0
(CCp), 68.9 (CCp), 68.7 (CCp), 40.0 (CH2NH); 19F NMR (376 MHz, CDCl3,
25 ꢁC):
d
¼ 66.1 (s, SO2F); MS (ESI): m/z (%): 401.2 [Mþ þ H].
4.2.5.10. [(
h
5-Me4Cp(CH2)2NHCO-(CH2)9-OP(OEt)F)RhCl2(PPh3)] 20.
This compound was synthesized following general procedure C.
The product was obtained as a bright red solid (189 mg, 0.22 mmol,
86%). 1H NMR (400 MHz, CDCl3, 25 ꢁC):
d
¼ 7.82e7.78 (m, 6H,
3
CHaromat.), 7.37e7.16 (m, 9H, CHaromat.), 6.40 (t, J(H,H) ¼ 5.8 Hz, 1H,
3
CH2NH), 4.23 (m, 2H, OCH2CH3), 3.85 (dt, J(H,H) ¼ 6.2 Hz, 2H,
3
CH2CH2NH), 2.24 (m, 2H, CH2CH2NH), 2.12 (t, J(H,H) ¼ 7.9 Hz, 2H,
COCH2CH2), 1.90e1.81 (m, 4H, CH2CH2P), 1.68e1.59 (m, 4H,
CH2CH2P), 1.56e1.52 (m, 2H, COCH2CH2), 1.52 (d, 6H, 4J(P,H) ¼ 1.7 Hz,
3
CCpCH3), 1.36 (t, 3H, J(H,H) ¼ 7.1 Hz, POCH2CH3), 1.25 (m, 10H,
4
(CH2)2(CH2)5(CH2)2), 1.11 (d, J(P,H) ¼ 2.9, 6H, CCpCH3); 13C NMR
(101 MHz, CDCl3, 25 ꢁC):
d
¼ 173.5 (CON), 134.8 (d, 3J(P,C) ¼ 9.2 Hz,
2
Caromat.), 130.6 (Caromat.), 128.1 (Caromat.), 102.7 (d, J(Rh,C) ¼ 6.9 Hz,
Caromat.),100.3 (dd, 2J(Rh,C) ¼ 6.9 Hz, 3J(P,C) ¼ 6.9 Hz, Caromat.), 96.6 (dd,
2J(Rh,C) ¼ 6.2 Hz, Caromat.), 63.1 (d, J(P,C) ¼ 7.6 Hz, OCH2), 36.6 (d,
2
4J(P,C) ¼ 5.4 Hz, CH2CH2NH), 36.3 (d, 4J(P,C) ¼ 5.4 Hz, CH2CH2NH), 30.3
(d, 3J(H,H) ¼ 16.9 Hz, 2H, CH2), 29.3 (d, 3J(H,H) ¼ 3.1 Hz, 2H, CH2), 29.0
(d, 3J(H,H) ¼ 17.7 Hz, 2H, CH2), 25.6 (d, 3J(H,H) ¼ 22.3 Hz, 2H, CH2), 25.2
3
3
[16] T.K. Hyster, L. Knör, T.R. Ward, T. Rovis, Science 338 (2012) 500e503.
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Ed. 49 (2010) 5315e5317;
(d, J(H,H) ¼ 22.3 Hz, 2H, CH2), 25.0 (d, J(H,H) ¼ 22.3 Hz, 2H, CH2),
3
3
24.9 (d, J(H,H) ¼ 22.3 Hz, 2H, CH2), 23.7 (d, J(H,H) ¼ 22.3 Hz, 2H,
3
CH2), 21.9 (d, J(H,H) ¼ 5.4 Hz, 2H, CH2), 16.4 (d, J(P,C) ¼ 5.4 Hz,
(b) B. Talbi, P. Haquette, A. Martel, F. De Montigny, C. Fosse, S. Cordier,
T. Roisnel, G. Jaouen, M. Salmain, Dalton. Trans. 39 (2010) 5605e5607;
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B. Feringa, A. Minnaard, J. de Vries, Chem. Commun. (2005) 5656e5658.
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A. Heck, R. Gebbink, G. van Koten, Chem. Eur. J. 11 (2005) 6869e6877;
(b) C.A. Kruithof, H.P. Dijkstra, M. Lutz, A.L. Spek, M.R. Egmond,
R.J.M.K. Gebbink, G. Van Koten, Eur. J. Inorg. Chem. (2008) 4425e4432;
(c) H.P. Dijkstra, H. Sprong, B.N.H. Aerts, C.A. Kruithof, M.R. Egmond,
R.J.M.K. Gebbink, Org. Biomol. Chem. 6 (2008) 523e531.
[19] (a) M.T. Reetz, M. Rentzsch, A. Pletsch, A. Taglieber, F. Hollmann,
R.J.G. Mondière, N. Dickmann, B. Höcker, S. Cerrone, M.C. Haeger, et al., Chem.
Biol. Chem. 9 (2008) 552e564;
OCH2CH3), 9.5 (CCpCH3), 8.6 (CCpCH3); 31P NMR (162 MHz, CDCl3,
2
25 ꢁC):
d
¼
32.5 (d, J(P,F)
¼
1.07 kHz, OP(OEt)F), 29.8
(1J(Rh,P) ¼ 142.0 Hz, PPh3); 19F NMR (376 MHz, CDCl3, 25 ꢁC):
~
n
d
¼ ꢀ64.6 (d, 3J(P,F) ¼ 1.07 kHz, OP(OEt)F); IR (KBr):
¼ 2922, 2851,
1645, 1435, 1384, 1262, 1095, 1035 cmꢀ1. MS (ESI): m/z (%): 566.1
[M ꢀ PPh3 ꢀ Cl]þ, 530.2 [M ꢀ PPh3 ꢀ HCl ꢀ Cl]þ, 792.1
[M ꢀ Cl ꢀ HCl]þ, 827.9 [M ꢀ Cl]þ; elemental analysis calcd. (%) for
C41H57Cl2FNO4P2Rh: C 55.79, H 6.51, N 1.59; found: C 55.37, H 6.51,
N 1.56.
(b) F. Monnard, T. Heinisch, E. Nogueira, T. Schirmer, T. Ward, Chem. Commun.
47 (2011) 8238e8240;
Acknowledgments
(c) J. Carey, S. Ma, T. Pfister, D. Garner, H. Kim, J. Abramite, Z. Wang, Z. Guo,
Y. Lu, J. Am. Chem. Soc. 126 (2004) 10812e10813;
(d) M. Ohashi, T. Koshiyama, T. Ueno, M. Yanase, H. Fujii, Y. Watanabe, Angew.
Chem. Int. Ed. 42 (2003) 1005e1008;
The authors thank Ramona Lex for help with crystallization. This
work was supported by KAUST-GCR (FIC/2010/07) and the KAUST
baseline fund (J.E.). We also thank the Elitenetzwerk Bayern for
graduate fellowships for T.R. and A.N.M.
(e) R. Davies, M. Distefano, J. Am. Chem. Soc. 119 (1997) 11643e11652.
[20] T. Reiner, D. Jantke, A.N. Marziale, A. Raba, J. Eppinger, Chem. Open 2 (2013)
50e54.
[21] E.M. Sletten, C.R. Bertozzi, Angew. Chem. Int. Ed. 48 (2009) 6974e6998.
[22] T. Reiner, D. Jantke, A. Raba, A.N. Marziale, J. Eppinger, J. Organomet. Chem.
694 (2009) 1934e1937.
Appendix A. Supplementary material
[23] (a) T. Reiner, M. Waibel, A.N. Marziale, D. Jantke, F.J. Kiefer, T.F. Fässler,
J. Eppinger, J. Organomet. Chem. 695 (2010) 2667e2672;
(b) T. Reiner, D. Jantke, X.-H. Miao, A.N. Marziale, F.J. Kiefer, J. Eppinger, Dalton
Trans. 42 (2013) 8692e8703.
[24] (a) S. Huikai, W. Quingmin, H. Runqiu, L. Heng, L. Yonghong, J. Organomet.
Chem. 655 (2002) 182e185;
CCDC 868620 and 929468 contain the supplementary crystal-
lographic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/data_request/cif.
(b) J. Eppinger, K.R. Nikolaides, M. Zhang-Presse, F.A. Riederer, G.W. Rabe,
A.L. Rheingold, Organometallics 27 (2008) 736e740.
[25] (a) A.N. Marziale, E. Herdtweck, J. Eppinger, S. Schneider, Inorg. Chem. 48
(2009) 3699e3709;
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