Highly active group 11 metal complexes with α-hydrazidophosphonate ligands

Article abstract of DOI:10.1039/c7dt02743e

α-Hydrazidophosphonates are interesting scaffolds that could combine the biological properties of hydrazones and phosphonyl species, and their coordination properties remain unknown. The coordination chemistry of these ligands towards group 11 metals has been studied. A series of novel gold(i), silver(i) and copper(i) complexes with α-hydrazidophosphonate ligands have been prepared and characterised. The coordination geometries obtained vary from linear to trigonal planar for gold(i) to distorted trigonal planar or tetrahedral for silver(i) and copper(i). Structural characterisation of two silver derivatives shows the ligands in an O^N^O tridentate fashion, with dissimilar bond lengths. These compounds were screened for the in vitro cytotoxic activity against two tumour human cell lines such as HeLa (cervical carcinoma) and A549 (lung carcinoma). The IC₅₀ values reveal an excellent cytotoxic activity of the metal complexes compared with the α-hydrazidophosphonate ligands alone and cisplatin.

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Efficient extraction of sulfate from water using
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Highly active group 11 metal complexes with α-
hydrazidophosphonate ligands
Daniel Salvador-Gil,a Lourdes Ortego,a Raquel P. Herrera,b Isabel Marzoc and M. Concepción
Gimeno*,a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
α-Hydrazidophosphonates are interesting scaffolds that could combine the biological properties of hydrazones and
phosphonyl species, and their coordination properties remains unknown. The coordination chemistry of these ligands
towards group 11 metals has been studied. A series of novel gold(I), silver(I) and copper(I) complexes with α-
hydrazidophosphonate ligands have been prepared and characterised. The coordination geometries obtained vary from
the linear to the trigonal planar for gold(I) to distorted trigonal planar or tetrahedral for silver(I) and copper(I). Structural
characterisation of two silver derivatives shows the ligands in an O^N^O tridentate fashion, with dissimilar bond lengths.
These compounds were screened for the in vitro cytotoxic activity against two tumour human cell lines such as HeLa
(cervical carcinoma) and A549 (lung carcinoma). The IC50 values reveal an excellent cytotoxic activity of the metal
complexes compared with the α-hydrazidophosphonate ligands alone and cisplatin.
www.rsc.org/
interesting medicinal applications. In addition, no coordination
chemistry of these molecules as ligands has been reported up
to date, in spite of their similarity with both the phosphonate
Introduction
Phosphonyl derivatives have aroused a great interest because
of their important biological properties.1 Between this broad
range of activity, it is worth mentioning their potential as
herbicides,2 antibiotics,3 insecticides,4 fungicides,4 anti-viral
agents,5 and as enzyme inhibitors,6 including their potential
use against the HIV proteases.7 Among the different developed
methods for the preparation of phosphonate compounds, the
nucleophilic addition of dialkylphosphites to C=O or C=N
(Pudovik reaction)8 has been used as one of the most powerful
tool in the synthesis of α-hydroxy-9 or α-aminophosphonates10
as direct precursors of phosphonic acid derivatives (Figure
1).11,12
and hydrazide ligands and their great potential as bidentate or
tridentate chelate ligands.
XH
O
P
X
OR1
OR1
OR1
OR1
+
R2
P
H
R2
H
O
X = O, NR3, NNR4R5
X = O, NR3, NNR4R5
OH
NH2
OH
OH
OH
R
P
R
P
OH
O
O
We have previously developed a straightforward synthetic
strategy for the preparation of α-hydrazidophosphonates
starting from the corresponding hydrazones.13 Hydrazones and
their metal complexes are molecules which have recently
shown to bear biological properties.14 Consequently, the final
α-hydrazidophosphonates could combine the properties of
hydrazones and phosphonyl species and could display
α-hydroxyphosphonic acids
α-aminophosphonic acids
O
P
O
OH
OH
H2N
H
N
OH
OH
P
OH
OH
HO2C
N
H
P
H2N
O
O
glyphosate
(weedkiller)
alafosfalin
antibacterial activity
(R)-phospholeucine
aminopeptidase inhibitor
Fig. 1. Biologically active phosphonyl derivatives.
During the last decades, and since the discovery of cisplatin as
a potent antitumour agent, many research groups have
focused their efforts on the rational design of new metal-
based anticancer agents for their use in cancer
chemotherapy.15 All these attempts have been centred on the
search for new metal complexes, as promising clinical
candidates, able to overcome the drawbacks of current clinical
drugs including toxicity, resistance and other pharmacological
deficiencies. Among this plethora of evaluated metals in vitro
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and in vivo, are group 11 metal derivatives (Figure 2). Gold synergic activity that may exhibit the resulting organometallic
complexes are by far the most studied because of their high species. α-Hydrazidophosphonates L1-L4 were firstly
cell growth inhibition capacity as a potential antitumour synthesised following our previously reported procedure,
drug.16 Interestingly, our group has previously reported the depicted in Scheme 1. This easy method allows access to a
synthesis and functionalisation of gold-based complexes with great variety of this kind of structures with very good yields.
very good cytotoxic activity.17
In contrast, although silver(I) complexes have been extensively
used as therapeutic compounds during centuries mainly as
antiseptic,18 antimicrobial19 and as anti-inflammatory agents,20
they have only recently received special attention for their
antitumour activity.21 Copper complexes have been
investigated on the basis that being an endogenous metal may
be more selective towards cancer cells, although they can also
be toxic because of its redox activity and affinity for binding
Scheme 1. Synthesis of ligands L1-L4 by uncatalysed hydrophosphonylation of
sites in proteins and enzymes.22 However, Cu(I) has been less
explored for this aim compared with its oxidized form Cu(II),
since their activity is mainly due to its redox capacity
(Cu(II)/Cu(I)).22
hydrazides with diphenylphosphite.13
The coordination properties of the α-hydrazidophosphonate
species L1-L4 towards group 11 metals have been explored by
the first time, and complexes 1-14 have been synthesised. All
the compounds have been characterised by means of IR,
elemental analysis and NMR spectroscopy. Assignments of the
1H NMR and 13C{1H} NMR signals were made on the basis of 2D
COSY and HSQC spectra. Complete spectroscopic information
of the complexes has been collected in the Experimental
Section of this article.
O
O
O
O
P
F
Au
O
S
O
NH3
NH3
Cl
Cl
Pt
O
O
O
O
OH
O
Auranofin
Cisplatin
O
Ag
F
F
Synthesis of Ag(I) metal complexes 1-8
OH
OH
O
Ag
O
O
OH
OH
HO
P
P
P
Firstly, homoleptic Ag(I) derivatives
1
-4
have been prepared by
HO
HO
HO
Cu
reaction of L1-L4 with AgOTf in a 2:1 molar ratio as shown in
OH
anticancer
agents
Scheme 2.
P
OH
HO
OH
OH
F
Fig. 2. Biologically active metal complexes.
Based on this background and with the growing interest for
searching new anticancer agents, encouraged us to join the
promising properties of phosphonate derivatives with the
interesting biological activities of group 11 metal complexes to
evaluate the antitumour capacity of the resulting
organometallic species, since it is well known that the
biological properties can be significantly affected by the
coordinating ligands.
Scheme 2. Formation of [AgL2]OTf complexes 1-4.
To the best of our knowledge, this is the first time that α-
hydrazidophosphonate derivatives have been considered as
organic ligands in metal coordination chemistry. These group
11 compounds have been explored in their cytotoxic activity
towards two human cell lines HeLa (cervical cancer) and A549
(lung cancer) with excellent results.
Since Ag can form complexes with coordination index between
2 and 4, in this case, and based on the IR and NMR spectra, we
propose the formation of the tetrahedral derivatives 1-4. On
these, each ligand would bond the metal atom as an N^O
chelate, through the O atom of the carbonyl group and the
iminic NH of the hydrazide. Similar bis(chelate) N^O silver
complexes have been obtained with other ligands such as the
8-hydroxyquinoline.24 The IR spectra show a shift in the C=O
and in the iminic NH stretching bands relative to the ligands
Results and discussion
Based on our experience in the synthesis of α- alone. Thus, as an example the ligand L1 presents two
hydrazidophosphonates13 and group 11 metal derivatives23 absorptions at 3275 and 3245 cm-1 for the NH groups and in
with demonstrated biological properties,17 we decided to bring complex
together both species in a single complex to explore the corresponding carbonyl absorption displaces from 1652 in the
1
a
broad absorption at 3227 appears; the
2 | J. Name., 2012, 00, 1-3
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free ligand to 1655 cm-1 in . Similar values are found for the 1H NMR spectra for these complexes (see experimental section
1
rest of the complexes. The 31P{1H} NMR spectra show one for a complete characterisation of all these complexes). The
resonance for the equivalent phosphorus atoms at 20.2 (1
), 31P{1H} NMR spectra show two resonances for the two
20.0 (
2
), 20.6 (
3
) and 20.0 (
4
) shifted downfield compared with different phosphorus atoms, one sharp singlet arising at the
phosphonate and a broad singlet for the triphenylphosphine
the free ligands.
The effect of the metal over the electronic properties of the bind to silver, as a consequence of the fast dissociation of
ligands is observed in the 1H NMR spectra of complex
in phosphorus ligands in silver complexes. In the spectra of
comparison with that of the ligand alone (see Figure 3). complexes and carried out at low temperature is possible
1
5
6
Coordination of the metal to the ligand produces a downfield to observe that the broad resonance splits into two doublets
shift for the protons of the isopropyl group and the NH but because of the coupling of the phosphorus atom with the two
curiously a highfield displacement of the protons of the silver isotopomers, 109Ag and 107Ag.
nitrophenyl ring.
Crystal structures determination
Crystals of the Ag(I) complexes
5
and
8
have been obtained by
or in CH2Cl2 and
slow diffusion of hexane into a solution of
5
8
they have been determined by X-ray diffraction studies,
supporting our abovementioned kind of coordination depicted
in Scheme 3. Compound
5 crystallises in the monoclinic space
group P21/c with one molecule by asymmetric unit (Figure 4).
Fig. 3. 1H NMR spectra of L1 and complex 1 performed in CDCl3 at r.t. (400 MHz).
Moreover, in the mass spectra for the ESI+ experiments the
peaks for the molecular cations [M–OTf]+ appear at m/z = 1045
for complexes
1 and 4, and m/z = 1075 for complexes 2 and 3.
This is in agreement with the general proposed formula
[AgL2]+. All these techniques point out the presence of a silver
atom coordinated to two ligands through the most
nucleophilic iminic nitrogen and carbonyl oxygen atom in a
tetrahedral fashion.
Fig. 4. Diagram of the cation of complex 5. Aromatic hydrogen atoms are omitted for
clarity. Selected bond lengths [Å] and angles [°] for complex 5: Ag(1)-O(4) 2.326(2),
Ag(1)-P(1) 2.3533(10), Ag(1)-O(3) 2.445(2), Ag(1)-N(1) 2.490(3), P(2)-O(3) 1.469(2), P(2)-
O(1) 1.573(2), P(2)-O(2) 1.580(3), O(1)-C(31) 1.420(4), O(2)-C(41) 1.408(4), C(50)-N(1)
1.490(4), N(1)-N(2) 1.411(4), N(2)-C(54) 1.336(4), C(54)-O(4) 1.237(4); O(4)-Ag(1)-P(1)
137.79(7), O(4)-Ag(1)-O(3) 84.10(9), P(1)-Ag(1)-O(3) 126.92(6), O(4)-Ag(1)-N(1)
69.11(8), P(1)-Ag(1)-N(1) 139.69(7), O(3)-Ag(1)-N(1) 74.57(9).
The reaction of the ligands L1
-L4 with [Ag(OTf)(PPh3)] in a 1:1
molar ratio has been performed to afford the Ag(I) compounds
5
-
8
as depicted in Scheme 3.
The Ag atom shows slightly distorted tetrahedron
coordination, since Ag is bound to three donating atoms. The
angles of this ligand as a tridentate chelate with the silver
centre are O(4)-Ag(1)-O(3) 84.10(9)°, O(4)-Ag(1)-N(1)
69.11(8)°, O(3)-Ag(1)-N(1) 74.57(9)° and O(4)-Ag(1)-P(1)
137.79(7)°. The Ag-O distances with the oxygen atoms are
dissimilar; the corresponding in the carbonyl group is 2.326(2)
Å, whereas a weaker bond of 2.445(2) Å is found with the
oxygen atom from the phosphonate moiety. Additionally,
there is a Ag-N(1) distance of 2.490(3) Å with the hydrazide
nitrogen and the Ag-P(1) of 2.3533(10), which is a strong bond.
Although there are several structures in which the silver atom
is bound to two oxygen, one nitrogen and one phosphorus
atoms,25 the tridentate O^N^O coordination mode to a unique
ligand is unusual.
OTf
NO2
R
NO2
H
N
R
H
PhO
PhO
H
N
[Ag(OTf)(PPh3)]
P
PhO
PhO
N
P
N
O
O
H
Ag
O
O
L1-L4
PPh3
R = iPr (5), iBu (6), tBu (7), nPr (8)
Scheme 3. Formation of [AgL(PPh3)]OTf complexes 5-8.
The ligands are coordinated to the silver centres as tridentate
O^N^O chelates and to the phosphorus atom of the
triphenylphosphine moiety, giving rise to tetrahedral
complexes 5-8 (Scheme 3). This type of coordination has been
also supported by the shifting found on the IR, and at 31P and
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The structure of complex
8 is shown in Figure 5. It crystallises
OTf
NO2
in the triclinic P-1 space group with two independent
molecules. The two molecules are asymmetric in the bond
lengths of the ligand to the silver centre. In one molecule the
Ag atom is tetrahedrically coordinated to the phosphine and to
the three donor atoms of the ligand with distances Ag(1)-O(4)
2.348(5), Ag(1)-N(1) 2.447(5) and Ag(1)-O(3) 2.471(5), which
NO2
R
H
R
PhO
PhO
H
N
[Au(OTf)(PPh3)]
PhO
PhO
N
P
HN
P
N
O
O
H
O
O
Au
Ph3P
L1,L2,L4
9 10 11
R = iPr ( ), iBu ( ), nPr ( )
Scheme 4. Formation of [AuL(PPh3)]OTf complexes 9-11.
are similar to those found in complex
5. However in the
second molecule the bond lengths are shorter to the carbonyl
oxygen and the iminic nitrogen, Ag(2)-O(10) 2.321(5) and
Ag(2)-N(4) 2.404(6), and there is a long Ag(2)-O(9) distance of
2.646 Å with the oxygen of the phosphonyl group. The
geometry around the silver centre Ag(2) can be considered as
distorted trigonal planar with a narrow O(10)-Ag(2)-N(4) angle
of 71.65(18)°, since the silver centre and the three donor
atoms are in the same plane.
Although, the gold(I) prefers a lineal coordination and its
affinity through donating oxygen atoms is low, in these cases a
variation in the frequency of the carbonyl group in the IR
spectra is observed, as for example from 1652 cm-1 in free
ligand L1 to 1163 cm-1 in complex
9. Consequently, a tridentate
coordination is proposed for complexes 9-11, where gold atom
would be bound to the P atom of the triphenylphosphine, to
the iminic NH group of the hydrazide and to the oxygen atom
of the carbonyl group. Taking in consideration the geometry of
the ligands, we hypothesised that a chelating coordination
would be favoured in these three cases. A similar geometry
has been previously reported in a 8-hydroxyquinolinate gold(I)
derivative with an N^O chelate ligand.26
It is worth noting that it is possible to find the molecular
cations [M–OTf]+ of complexes 9-11 in the mass spectra for the
ESI+ experiments. That is m/z = 928 for complexes 9 and 11,
and m/z = 942 for complex 10 [AuL(PPh3)]+ (see experimental
section for more details).
The preparation of new gold complexes with [Au(tht)2]OTf (tht
= tetrahydrothiophene) in a molar ration 2:1 was also tried.
However, the final products of these reactions were really
unstable. The NMR analysis of the resulting reaction crudes
proved the presence of a tht molecule, which would support a
low capacity by the hydrazide ligands to displace the tht
groups. Interestingly, only with L3 we were able to get the
corresponding linear complex 12 as described in Scheme 5.
A
OTf
NO2
H
N
PhO
PhO
H
N
NO2
P
H
N
PhO
PhO
O
O
[Au(tht)2]OTf
P
N
H
Au
O
O
P
O
O
NH
OPh
OPh
L2
N
H
B
O2N
12
Fig. 5. Diagrams of the two independent cations of complex 8. Aromatic hydrogen
atoms are omitted for clarity. Selected bond lengths [Å] and angles [°] for complex 8:
Molecule A: Ag(1)-O(4) 2.348(5), Ag(1)-P(1) 2.352(2), Ag(1)-N(1) 2.447(5), Ag(1)-O(3)
2.471(5), P(2)-O(3) 1.467(5), N(1)-N(2) 1.430(8), O(4)-C(47) 1.235(8); O(4)-Ag(1)-P(1)
137.97(13), O(4)-Ag(1)-N(1) 69.68(17), P(1)-Ag(1)-N(1) 144.18(15), O(4)-Ag(1)-O(3)
86.12(17), P(1)-Ag(1)-O(3) 119.64(12), N(1)-Ag(1)-O(3) 76.08(17). Molecule B: Ag(2)-
O(10) 2.321(5), Ag(2)-P(3) 2.345(2), Ag(2)-N(4) 2.404(6), P(4)-O(9) 1.468(5), N(4)-N(5)
1.426(8), O(10)-Ag(2)-P(3) 136.57(13), O(10)-Ag(2)-N(4) 71.65(18), P(3)-Ag(2)-N(4)
150.40(15).
Scheme 5. Formation of [Au(L2)2]OTf complex 12.
The ligand could be coordinated to the metal centre through
the iminic NH group of the hydrazide, giving rise to a linear
complex (Scheme 5). This is mainly supported by the shifting
1
found on the H NMR spectrum for the final complex, where
only the NH involved in the coordination is strongly highfield
shifted. Undoubtedly, in this complex could also be some weak
contacts between the oxygen atoms and the gold centre but
we do not propose in the drawing because no shift for the
carbonyl group is observed in the infrared spectrum. Linear
gold(I) derivatives with the gold centre coordinated to two NH
group have been previously reported in the case of aliphatic
amines.27
Synthesis of Au(I) metal complexes 9-12.
The capacity of Au(I) to coordinate α-hydrazidophosphonates
L1, L2 and L4 was also explored. Thus, Au(I) compounds 9-11
have been prepared by reaction of the corresponding ligands
with [Au(OTf)(PPh3)] in a molar ratio 1:1 as shown in Scheme 4.
4 | J. Name., 2012, 00, 1-3
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In the mass spectrum (ESI+) the molecular cation [Au(L2)2]+ is Cells were exposed to each compound for 24 h. By using the
found at m/z = 1163. This value also supports the formation of colorimetric mitochondrial function-based MTT viability assay
the proposed complex.
the IC50 values were calculated from dose–response curves
obtained by nonlinear regression analysis. IC50 values are
concentrations of a drug required to inhibit tumour cell
proliferation by 50 %, compared to the control viability.
Synthesis of Cu(I) metal complexes 13-16
Other interesting metal for its biological properties is copper. Controls were performed using cells grown in medium with 0.1
In this sense, the ability of Cu(I) to coordinate L1 L4 was also % DMSO. IC50 values at 24 h are listed in Table 1.
-
investigated. Thus, Cu(I) compounds 13-16 have been
prepared by reaction of the corresponding α- Table 1. IC50 (24 h) values of complexes and ligands against
hydrazidophosphonates L1-L4 with [Cu(NO3)(PPh3)2] in a molar HeLa and A549 tumour cells (ꢀM).
ratio 1:1 as shown in Scheme 6.
HeLa
A549
IC50 (μM)
IC50 (μM)
Cisplatin
55 ± 9 (DMSO) 114.2±11(H2O)
L1
>50
>50
>50
>50
>50
3.05
8.60
L2
>50
L
L3
>50
L4
5
>50
2.76
2.49
2.47
5.27
3.93
1.60
1.49
0.84
±
±
±
±
±
±
±
±
0.01
0.49
0.41
0.79
0.81
0.47
0.01
0.47
±
±
0.05
0.25
[Ag(L)(PPh3)]OTf
[Cu(L)(PPh3)2]NO3
6
Scheme 6. Formation of [CuL(PPh3)]NO3 complexes 13-16.
7
11.22 ± 0.53
8
9.70
5.02
8.01
>50
±
±
±
0.52
0.97
0.75
The coordination is proposed to be similar to the silver
1
13
14
15
16
complexes on the base of the IR, 31P and H NMR spectra (see
experimental section). Some copper(I) complexes have been
previously described in which coordination to a phosphine and
to a tridentate O^N^O ligands has been achieved.28 Thus, a
chemical shift is observed in the 1H NMR spectra in the
resonances of the iminic protons, as for example from 5.35 in
ligand L1 to 3.44 ppm in complex 13. Similarlarly, the 31P NMR
spectra presents two different resonances for the
phosphorous of the phosphonate ligand and the
tryphenylphosphine bound to copper. Moreover, the
fragments for the molecular cations [M–NO3]+ of all complexes
13-16 were found in the ESI+ mass spectra. Therefore, m/z =
794 was found for complexes 13 and 16, and m/z = 808 for
9.08
±
1.76
As reported in Table 1, the tested ligands (L1-L4) showed no
cytotoxic activity (IC50 > 50 μM). In contrast, silver(I) and
copper(I) complexes were found to be extraordinarily effective
as cytotoxic agents in vitro against the growth of the cancer
cell lines tested. In general, they shown a higher activity
against HeLa cells (IC50 values range between 0.84 and 5.27
μM) compared with A549 tumour cells (IC50 values range
between 3.05 and 11.22
ꢀM, and surprisingly one of the
complexes (15) presented a value > 50 μM) being copper
complex 16 the most potent agent against HeLa cells with IC50
complexes 14 and 15
.
value of 0.84 μM, and silver complex
5 against A549 cells with
Biological evaluation
IC50 value of 3.05 μM. There is not a clear correlation between
the ligand used and the activity since all of them show
excellent values in the low micromolar range, much lower than
the corresponding values of cisplatin. These values obtained
for the silver and copper complexes are among the lowest
found for any silver or copper derivatives, taking into account
the experimental conditions (measured at 24 h). These
outstanding activities of these complexes are worth for further
studies giving the low toxicity of the metals and the possibility
of new biological targets.
The in vitro cytotoxic activity of the silver 5-8 and copper 13-16
complexes, all of them bearing the α-hydrazidophosphonate
and triphenylphosphine ligands, was tested against two
tumour human cell lines, A549 (human lung carcinoma) and
HeLa (human cervix epithelial carcinoma). They were chosen
for two reasons: the presence of a lipophilic phosphine ligand,
and because they are the most stable in solution. As measure
of control, metal-free ligands L1-L4 were tested for cytotoxicity
against the two cell lines explored. Our IC50 values were
compared with those of cisplatin.29
Compounds are not soluble in water, but they are soluble in
DMSO and in the DMSO/water mixtures used in the
EXPERIMENTAL SECTION
cytotoxicity tests, which contain a small amount of DMSO (≤ General Procedures. Purification of reaction products was
0.1 %). We did not observe any precipitation of the complexes carried out either filtration. The synthesis of the copper
while performing the tests. The colourless (Ag(I) Cu(I)) DMSO complexes 13-16 were carried out under Ar atmosphere, in
solutions are very stable at room temperature for weeks.
dried and degassed solvents prior to use. The starting material
[Ag(OTf)(PPh3)]30 was prepared according to published
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procedures. [Au(OTf)(PPh3)] was obtained by reaction of COPhNO2); 120.4 (d, 4C, Cortho OPh, 3JCP = 4.3 Hz); 120.3 (d, 4C,
[AuCl(PPh3)]31 with Ag(OTf) in dichloromethane and used in Cortho OPh, 3JCP = 4.3 Hz); 57.2 (d, 2C, OPCHNH, 1JCP = 159.9 Hz);
2
situ. [Au(tht)2]OTf is also used in situ starting from [AuCl(tht)]32 37.0 (d, 2C, CHCH2CH, JCP = 1.5 Hz); 25.3 (d, 2C, CH2CH(CH3)2,
and [AgOTf(tht)] in solution of dichloromethane. All other 3JCP = 10.2 Hz); 23.0 (br s, 2C, CH3); 22.0 (br s, 2C, CH3). IR (cm-
reagents were commercially available and used without 1): υ(NH) = 3246; υ(HAr) = 3072; υ(H alkanes) = 2960; υ(CONH)
further purification. ESI ionisation method and mass analyser = 1656; υ(C=CAr) = 1599, 1525, 758; υ(NO2) = 1488, 1346;
type MicroTof-Q were used for the ESI measurements. 1H, υ(P=O) = 1159; υ(ArOP) = 1236-1204; υ(CP) = 935. MS (ESI+):
31P{1H}, and 13C{1H} NMR, including 2D experiments, were m/z (%) 1073.9, [(C24H26O6N3P)2Ag]+, 43.98 %.
=
recorded at room temperature on a BRUKER AVANCE 400 Synthesis and characterisation of [Ag(L3)2]OTf (3). To an
spectrometer (1H, 400 MHz, 13C, 100.6 MHz) or on a BRUKER acetone solution (30 mL) of L3 (96.6 mg, 0.2 mmol), Ag(OTf)
AVANCE II 300 spectrometer (1H, 300 MHz, 13C, 75.5 MHz), (25.7 mg, 0.1 mmol) was added at room temperature. After
with chemical shifts (δ, ppm) reported relative to the solvent the addition, the reaction mixture was stirred for 1 h. The
peaks of the deuterated solvent. Infrared spectra were volume was reduced under vacuum to 5 mL, and addition of
recorded in the range 4000–250 cm-1 on a Perkin-Elmer hexane (10 mL) afforded compound
3 as a yellow solid, after
Spectrum 100 FTIR spectrometer.
filtration, with a 60 % yield. 1H NMR (400 MHz, CDCl3): δ = 9.42
(s, 2H, NH); 8.19 (br d, 4H, H-1, 3JHH = 8.8 Hz); 7.87 (br d, 4H, H-
Synthesis and characterisation of [Ag(L1)2]OTf (1). To an 2, 3JHH = 8.7 Hz); 7.29-7.14 (m, 20H, Ph); 3.52 (d, 2H, CHNH, 2JPH
acetone solution (30 mL) of L1 (93.8 mg, 0.2 mmol), Ag(OTf) = 7.9 Hz); 1.40 (s, 18H, CH3). 31P{1H} NMR (162 MHz, CDCl3): δ =
(25.7 mg, 0.1 mmol) was added at room temperature. After 20.6 (s, 1P, P=O). 13C{1H} NMR (101 MHz, CDCl3): δ = 163.8 (s,
the addition, the reaction mixture was stirred for 1 h. The 2C, CO); 150.1 (s, 4C, CipsoOPh), 148.1 (s, 2C, Cipso CO); 138.0 (s,
volume was reduced under vacuum to 5 mL, and addition of 2C, Cpara NO2); 130.1 (br d, 4C, Cmeta OPh); 130.0 (br d, 4C, Cmeta
hexane (10 mL) afforded compound 1 as a yellow solid, after OPh); 128.4 (s, 4C, CH-2 COPhNO2); 125.7 (s, 2C, Cpara OPh);
filtration, with a 79 % yield. 1H NMR (400 MHz, CDCl3): δ = 9.82 125.6 (s, 2C, Cpara OPh); 124.0 (s, 4C, CH-1 COPhNO2); 120.7 (d,
3
3
(s, 2H, NH); 8.06 (br d, 4H, H-1, 3JHH = 8.8 Hz); 7.81 (br d, 4H, H- 4C, Cortho OPh, JCP = 4.1 Hz); 120.6 (d, 4C, Cortho OPh, JCP = 4.2
3
1
2, JHH = 8.8 Hz); 7.26-7.06 (m, 20H, Ph); 3.93 (br s, 2H, NHCH); Hz); 69.3 (d, 2C, OPCHNH, JCP = 159.7 Hz); 34.5 (s, 2C,
3.79 (dd, 2H, CHNH, JPH = 9.2 Hz, JHH = 4.7 Hz); 2.55 (m, 2H, CHC(CH3)3); 28.3 (d, 6C, CH3, JCP = 6.3 Hz). IR (cm-1): υ(NH) =
2
3
3
CH(CH3)2); 1.35 (d, 6H, CH3, 3JHH = 7 Hz); 1.32 (d, 6H, CH3, 3JHH
=
3274; υ(NH) = 3246; υ(HAr) = 3104; υ(H alkanes) = 2971-2929;
6.9 Hz). 31P{1H} NMR (162 MHz, CDCl3): δ = 20.2 (s, 2P, P=O). υ(CONH) = 1637; υ(C=CAr) = 1590, 1513, 753; υ(NO2) = 1488,
13C{1H} NMR (101 MHz, CDCl3): δ = 166.3 (s, 2C, CO); 150.1 (s, 1343; υ(P=O) = 1154; υ(ArOP) = 1231-1204; υ(CP) = 934. MS
2C, Cipso CO); 149.9 (d, 2C, CipsoPh, 2JCP = 10.5 Hz); 149.6 (d, 2C, (ESI+): m/z (%)
=
1073.3, [(C24H26O6N3P)Ag]+, 2.23 %.
2
CipsoPh, JCP = 10.3 Hz); 136.9 (s, 2C, Cpara NO2); 130.1 (br s, 4C, Synthesis and characterisation of [Ag(L4)2]OTf (4). To an
Cmeta OPh); 130.0 (br s, 4C, Cmeta OPh); 128.7 (s, 4C, CH-2 acetone solution (30 mL) of L4 (93.8 mg, 0.2 mmol), Ag(OTf)
COPhNO2); 125.9 (br d, 2C, Cpara OPh); 125.8 (br d, 2C, Cpara (25.7 mg, 0.1 mmol) was added at room temperature. After
OPh); 123.8 (s, 4C, CH-1 COPhNO2); 120.4 (d, 4C, Cortho OPh, 3JCP the addition, the reaction mixture was stirred for 1 h. The
3
= 4.3 Hz); 120.3 (d, 4C, Cortho OPh, JCP = 4.3 Hz); 64.6 (d, 2C, volume was reduced under vacuum to 5 mL, and addition of
OPCH(C3H7)NH, 1JCP = 156.6 Hz); 28.6 (s, 2C, CH(CH3)2); 20.2 (d, hexane (10 mL) afforded compound
4 as a yellow solid, after
2C, CH3, 3JCP = 9.4 Hz); 19.2 (d, 2C, CH3, 3JCP = 4.9 Hz). IR (cm-1): filtration, with a 46 % yield. 1H NMR (400 MHz, CDCl3): δ = 9.81
υ(NH) = 3237; υ(HAr) = 3076; υ(H alkanes) = 2967; υ(CONH) = (s, 2H, NH); 8.13 (m, 4H, H-1); 7.86 (m, 4H, H-2); 7.27-7.08 (m,
1655; υ(C=CAr) =1590, 1524, 757; υ(NO2) = 1488, 1346; υ(P=O) 20H, Ph); 3.88 (m, 2H, CHNH); 2.03 (m, 4H, CHCH2CH2CH3);
1
= 1159; υ(ArOP) = 1224-1205; υ(CP) = 936. MS (ESI+): m/z (%) = 1.73 (m, 4H, CHCH2CH2CH3); 1.00 (t, 6H, CH3, JHH = 7.3 Hz).
1045.2, [(C23H24O6N3P)2Ag]+, 97.98 %.
31P{1H} NMR (162 MHz, CDCl3): δ = 20.0 (s, 1P, P=O). 13C{1H}
Synthesis and characterisation of [Ag(L2)2]OTf (2). To an NMR (101 MHz, CDCl3): δ = 165.7 (s, 2C, CO); 150.1 (s, 2C, Cipso
acetone solution (30 mL) of L2 (96.6 mg, 0.2 mmol), Ag(OTf) CO); 150.0 (d, 2C, CipsoOPh, 2JCP = 9.1Hz); 149.7 (d, 2C, CipsoOPh,
(25.7 mg, 0.1 mmol) was added at room temperature. After 2JCP = 10.3 Hz); 136.9 (s, 2C, Cpara NO2); 130.1 (s, 4C, Cmeta OPh);
the addition, the reaction mixture was stirred for 1 h. The 130.0 (s, 4C, Cmeta OPh); 128.6 (s, 4C, CH-2 COPhNO2); 125.9 (br
volume was reduced under vacuum to 5 mL, and addition of s, 4C, Cpara OPh); 123.8 (s, 4C, CH-1 COPhNO2); 120.5 (d, 4C,
3
3
hexane (10 mL) afforded compound
2 as a yellow solid, after Cortho OPh, JCP = 4.3 Hz); 120.3 (d, 4C, Cortho OPh, JCP = 4.3Hz);
1
filtration, with an 80 % yield. H NMR (400 MHz, CDCl3): δ = 58.76 (d, 2C, OPCHNH, JCP = 160.4 Hz); 30.21 (d, 2C,
9.33 (s, 2H, NH); 8.12 (br d, 4H, H-1, 3JHH = 8.9); 7.87 (br d, 4H, CHCH2CH2CH3, JCP = 3.42); 19.75 (d, 2C, CHCH2CH2CH3, JCP
1
2
3
=
H-2, JHH = 8.9); 7.28-7.07 (m, 20H, Ph); 3.99 (m, 2H,PCHNH,); 12.3 Hz); 13.95 (s, 2C, CH3). IR (cm-1): υ(NH) = 3288; υ(NH) =
2.10 (m, 2H, CH2CH(CH3)2); 1.93 (m, 4H, CHCH2CH); 1.02 (m, 3249; υ(HAr) = 3057; υ(H alkanes) = 2962-2918; υ(CONH) =
12H, CH3). 31P{1H} NMR (162 MHz, CDCl3): δ = 20.0 ppm (s, 1P, 1651; υ(C=CAr) = 1598, 1521, 764; υ(NO2) = 1487, 1339;
3
P=O). 13C{1H} NMR (101 MHz, CDCl3): δ = 166.1 (s, 2C, CO); υ(P=O) = 1159; υ(ArOP) = 1241-1206; υ(CP) = 935. MS (ESI+):
2
150.2 (s, 2C, Cipso CO); 149.9 (d, 2C, CipsoPh, JCP = 10.4 Hz); m/z (%)
=
1045.2, [(C23H24O6N3P)2Ag]+, 0.03 %.
2
149.7 (d, 2C, CipsoPh, JCP = 10.4 Hz); 136.7 (s, 2C, Cpara NO2), Synthesis and characterisation of [Ag(L1)(PPh3)]OTf (5). To a
130.2 (s, 4C, Cmeta OPh); 130.1 (s, 4C, Cmeta OPh); 128.7 (s, 2C, dichloromethane solution (30 mL) of L1 (46.9 mg, 0.1 mmol),
CH-2 COPhNO2); 126.0 (s, 2C, Cpara OPh); 123.8 (s, 2C, CH-1 [Ag(OTf)(PPh3)] (51.9 mg, 0.1 mmol) was added at room
6 | J. Name., 2012, 00, 1-3
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ARTICLE
temperature. After the addition, the reaction mixture was temperature. After the addition, the reaction mixture was
stirred for 1 h. The volume was reduced under vacuum to 5 stirred for 1 h. The volume was reduced under vacuum to 5
mL, and addition of hexane (10 mL) afforded compound 5 as a mL, and addition of hexane (10 mL) afforded compound 7 as a
white solid, after filtration, with a 80 % yield. 1H NMR (400 white solid, after filtration, with a 20 % yield. 1H NMR (400
MHz, CDCl3): δ = 9.03 (s, 1H, NH); 8.13 (br d, 2H, H-1, 3JHH = 8.8 MHz, CDCl3): δ = 9.06 (s, 1H, NH); 8.24 (br d, 2H, H-1, 3JHH = 8.9
3
Hz); 7.82 (br d, 2H, H-2, JHH = 8.8 Hz); 7.35-7.08 (m, 25H, Ph); Hz); 7.91 (br d, 2H, H-2, JHH = 8.8 Hz); 7.47-7.17 (m, 25H, Ph),
3
2
5.39 (br s, 1H, NHCH); 3.41 (m, 1H, CHNH); 2.38 (m, 1H, 5.48 (m, 1H, NHCH); 3.38 (d, 1H, CHNH, JPH = 4.7 Hz); 1.40 (s,
CH(CH3)2); 1.28 (d, 3H, CH3, 3JHH = 6.9 Hz); 1.23 (d, 3H, CH3, 3JHH 6H, CH3). 31P{1H} NMR (162 MHz, CDCl3): δ = 20.37 (s, 1P, P=O);
= 6.8 Hz). 31P{1H} NMR (162 MHz, CDCl3): δ = 19.7 (s, 1P, P=O); 11.29 (s, 1P, AgPPh3). 13C{1H} NMR (101 MHz, CDCl3): δ = 163.6
2
13.2 (m, PPh3). 31P{1H} NMR (121 MHz, (CD3)2CO, -88˚C): δ = (s, 1C, CO); 150.2 (d, 2C, CipsoPh, JCP = 10.4 Hz); 150.1 (d, 2C,
19.7 (s, 1P, P=O); 8.8 (2 d, 1P, Ag-P, J109Ag-P = 366.4 Hz , J107Ag-P
=
Cipso Ph, 2JCP = 10.3 Hz); 149.9 (s, 1C, Cipso CO); 138.1 (s, 1C, Cpara
316.86 Hz). 13C{1H} NMR (101 MHz, CDCl3): δ = 164.3 (s, 2C, NO2); 134.1 (br s, 6C, Cortho PPh3); 131.0 (s, 3C, Cpara PPh3);
2
CO); 150.3 (d, 2C, CipsoPh, JCP = 10.0 Hz); 150.0 (m, 2C, CipsoPh, 130.1 (s, 2C, Cmeta OPh); 130.0 (s, 2C, Cmeta OPh); 129.3 (s, 6C,
2JCP = 10.0 Hz); 149.9 (s, 2C, Cipso CO); 137.9 (s, 1C, Cpara NO2); CmetaPPh3); 128.3 (s, 3C, CH-2 COPhNO2; 125.7 (s, 1C, Cpara OPh);
2
134.0 (br d, 6C, Corto PPh3, JCP = 13.9 Hz); 131.0 (s, 3C, 125.6 (s, 1C, Cpara OPh); 124.0 (s, 1C, CH-1 COPhNO2); 120.7 (d,
1
CparaPPh3); 130.7 (d, 3C, CipsoPPh3, JCP = 34.0 Hz); 130.1 (s, 4C, 2C, Cortho OPh, JCP = 4.3 Hz); 120.7 (d, 2C, Cortho OPh, JCP = 4.2
3
3
1
Cmeta OPh); 130.0 (s, 4C, Cmeta OPh); 129.3 (d, 6C, Cmeta PPh3, Hz); 69.4 (d, 1C, OPCHNH, JCP = 160.2 Hz); 34.4 (d, 1C,
3JCP = 5.1 Hz); 128.4 (s, 2C, CH-2 COPhNO2); 125.7 (s, 2C, Cpara CHC(CH3)3, JCP = 1.2 Hz); 28.2 (d, 3C, CH3, JCP = 6.5Hz). IR (cm-
2
3
OPh); 125.6 (s, 2C, Cpara OPh); 124.0 (s, 2C, CH-1 COPhNO2); 1): υ(NH) = 3273; υ(HAr) = 3057; υ(H alkanes) = 2928; υ(CONH)
3
120.7 (“t”, 8C, Cortho OPh, JCP = 4.2 Hz); 65.3 (d, 2C, = 1647; υ(C=CAr) = 1590, 1523, 743; υ(NO2) = 1488, 1343;
2
OPCH(C3H7)NH, 1JCP = 161.7 Hz); 28.7 (d, 2C, CH(CH3)2 JCP = 2.2 υ(P=O) = 1157; υ(ArOP) = 1241-1208; υ(CP) = 931. MS (ESI+):
3
3
Hz); 20.8 (d, 2C, CH3, JCP = 8.4 Hz); 19.4 (d, 2C, CH3, JCP
=
m/z (%) =
852.2, [C42H41O6N3P2Ag]+, 6.43 %.
7.3Hz). IR (cm-1): υ(NH) = 3235; υ(HAr) = 3060; υ(H alkanes) = Synthesis and characterisation of [Ag(L4)(PPh3)]OTf (8). To a
2961; υ(CONH) = 1663; υ(C=CAr) = 1589, 1522, 748; υ(NO2) = dichloromethane solution (30 mL) of L4 (46.9 mg, 0.1 mmol),
1487, 1343; υ(P=O) = 1158 ; υ(ArOP) = 1222-1207; υ(CP) = 929. [Ag(OTf)(PPh3)] (51.9 mg, 0.1 mmol) was added at room
MS (ESI+): m/z (%)
Synthesis and characterisation of [Ag(L2)(PPh3)]OTf (6). To a stirred for 1 h. The volume was reduced under vacuum to 5
dichloromethane solution (30 mL) of L2 (48.3 mg, 0.1 mmol), mL, and addition of hexane (10 mL) afforded compound as a
=
831.1, 838.2 [C41H39O6N3P2Ag]+, 16.4 %.
temperature. After the addition, the reaction mixture was
8
[Ag(OTf)(PPh3)] (51.9 mg, 0.1 mmol) was added at room white solid, after filtration, with a 70 % yield. 1H NMR (400
temperature. After the addition, the reaction mixture was MHz, CDCl3): δ = 8.96 (s, 1H, NH); 8.25 (m, 2H, H-1); 7.93 (m,
stirred for 1 h. The volume was reduced under vacuum to 5 2H, H-2); 7.45-7.17 (m, 25H, Ph); 3.65 (m, 1H, CHNH); 2.07-
mL, and addition of hexane (10 mL) afforded compound
6 as a 1.92 (m, 2H, CHCH2CH2CH3); 1.82-1.70 (m, 2H, CHCH2CH2CH3);
white solid, after filtration, with a 71 % yield. 1H NMR (400 1.04 (t, 3H, CH3, 1JHH = 7.3 Hz). 31P{1H} NMR (162MHz, CDCl3): δ
MHz, CDCl3): δ = 8.90 (s, 1H, NH); 8.26 (m, 2H, H-1); 7.94 (m, = 19.4 (s, 1P, P=O); 11.2 (m, 1P, AgPPh3). 13C{1H} NMR (101
2H, H-2); 7.46-7.16 (m, 25H, Ph), 5.35 (br s, 1H, NHCH); 3.68 MHz, CDCl3): δ = 164.3 (s, 1C, CO); 150.5 (m, 3C, CipsoOPh,
(m, 1H,PCHNH,); 2.13 (m, 1H, CH2CH(CH3)2); 1.88 (m, 2H, CipsoOPh, Cipso CO); 137.8 (s, 1C, Cpara NO2); 134.0 (br d, 6C, Cortho
2
CHCH2CH); 1.07 (m, 6H, CH3). 31P{1H} NMR (162 MHz, CDCl3): δ PPh3, JCP = 13.8 Hz); 131.0 (s, 1C, Cpara PPh3); 130.6 (br d, 3C,
= 19.6 (s, 1P, P=O); 11.0 (s, 1P, AgPPh3). 31P{1H} NMR (121 MHz, Cipso PPh3); 130.1 (br d, 6C, Cmeta OPPh3); 130.0 (br d, 6C, Cmeta
(CD3)2CO, -88 ˚C): δ = 20.1 (s, 1P, P=O); 8.2 (2 d, 1P, Ag-P, J109Ag- OPPh3); 129.3 (br s, 6C, Cmeta PPh3); 128.5 (br s, 1C CH-2
P = 367.0 Hz, J107Ag-P = 318.0Hz). 13C{1H} NMR (101 MHz, CDCl3): COPhNO2); 125.7 (br d, 2C, Cpara OPPh3); 125.6 (br d, 2C, Cpara
δ = 162.3 (s, 1C, CO); 150.2 (m, 3C, Cipso OPh, Cipso CO, Cipso OPPh3); 124.0 (s, 1C, CH-1 COPhNO2); 120.7 (m, 4C, Cortho OPh);
1
59.2 (d, 1C, OPCHNH, JCP
OPh); 137.9 (s, 1C, Cpara NO2), 134.0 (br d, 6C, Cortho PPh3, 2JCP
=
=
=
166.2 Hz); 30.4 (d, 1C,
3
1
11.6 Hz ); 131.0 (s, 3C, Cpara PPh3); 130.6 (d, 3C, Cipso PPh3, JCP
CHCH2CH2CH3, 2JCP = 3.23 Hz); 19.8 (d, 1C, CHCH2CH2CH3, JCP
=
12.6 Hz); 130.1 (br s, 2C, Cmeta OPh); 129.8 (br s, 2C, Cmeta OPh); 11.9 Hz); 14.02 (s, 1C, CH3). IR (cm-1): υ(NH) = 3233; υ(HAr) =
129.2 (br s, 6C, Cmeta PPh3); 128.4 (s, 1C, CH-2 COPhNO2); 125.7 3072; υ(H alkanes) = 2965; υ(CONH) = 1655; υ(C=CAr) = 1599,
(s, 1C, Cpara OPh); 125.6 (s, 1C, Cpara OPh); 124.0 (s, 2C, CH-1 1524, 758; υ(NO2) = 1488, 1346; υ(P=O) = 1159; υ(ArOP) =
1
COPhNO2); 120.7 (m, 4C, Cortho OPh); 57.6 (d, 1C, OPCHNH, JCP 1237-1203; υ(CP)
= 934. MS (ESI+): m/z (%) = 838.2,
2
= 166.6 Hz); 37.1 (d, 1C, CHCH2CH, JCP = 3.6 Hz); 25.0 (d, 1C, [C41H39O6N3P2Ag]+, 30.26 %.
CH2CH(CH3)2, 3JCP = 12.1 Hz); 23.5 (br s, 1C, CH3); 21.8 (br s, 1C, Synthesis and characterisation of [Au(L1)(PPh3)]OTf (9).
A
CH3). IR (cm-1): υ(NH) = 3292; υ(NH) = 3248; υ(HAr) = 3076; υ(H solution of [Au(OTf)(PPh3)] (0.11 mmol) prepared in situ and L1
alkanes) = 2958; υ(CONH) = 1653; υ(C=CAr) = 1598, 1520, 764; (46.9 mg, 0.1 mmol) was stirred in DCM (30 mL) for 1 h at
υ(NO2) = 1487, 1338; υ(P=O) = 1186; υ(ArOP) = 1239-1205; room temperature. The volume was reduced to 5 mL, and
υ(CP) = 935. MS (ESI+): m/z (%)
=
852.1, [C42H41O6N3P2Ag]+, addition of hexane (10 mL) afforded compounds
solid, after filtration, with a 37 % yield. 1H NMR (400 MHz,
9 as a white
19.9 %.
Synthesis and characterisation of [Ag(L3)(PPh3)]OTf (7). To a CDCl3): δ = 9.71 (s, 1H, NH); 8.25 (m, 2H, H-1); 7.98 (m, 2H, H-
dichloromethane solution (30 mL) of L3 (48.3 mg, 0.1 mmol), 2); 7.59-7.14 (m, 25H, Ph); 6.30 (br s, 1H, NHCH); 3.71 (dd, 1H,
[Ag(OTf)(PPh3)] (51.9 mg, 0.1 mmol) was added at room CHNH, 2JPH = 7.4 Hz, 3JHH = 5.9 Hz); 2.58 (m, 1H, CH(CH3)2); 1.42
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3
3
(d, 3H, CH3, JHH = 6.9 Hz); 1.36 (d, 3H, CH3, JHH = 6.9 Hz). solid, after filtration, with a 28 % yield. 1H NMR (400 MHz,
31P{1H} NMR (162 MHz, CDCl3): δ = 29.0 (s, 1P, Au(PPh3)); 17.7 CDCl3): δ = 8.96 (br s, 2H, NH); 8.23 (m, 4H, H-1); 7.93 (m, 4H,
(s, 1P, P=O). 13C{1H} NMR (101 MHz, CDCl3): δ = 164.1 (s, 1C, H-2); 7.33-7.15 (m, 20H, Ph); 3.69 (m, 2H, PCHNH); 3.19 (br s,
CO); 150.2 (m, 3C, CipsoPh, CipsoPh, Cipso CO); 133.5 (s, 1C, Cpara 2H, NHCH); 2.14 (m, 2H, CH2CH(CH3)2); 1.88 (m, 4H, CHCH2CH);
NO2); 134.2 (m, 4C, Cortho PPh3); 130.3-129.6 (m, 13C, Cmeta OPh, 1.07 (m, 12H, CH3). 31P{1H} NMR (162 MHz, CDCl3): δ = 18.6 (s,
Cmeta PPh3, Cpara PPh3); 128.5 (s, 2C, CH-2 COPhNO2); 125.7 (s, 2C, 1P, P=O). 13C{1H} NMR (101 MHz, CDCl3): δ = 150.1 (m, 4C,
Cpara OPh); 125.6 (s, 2C, Cpara OPh); 123.9 (s, 2C, CH-1 COPhNO2); CipsoPh); 145.0 (s, 2C, Cipso CO); 138.0 (s, 2C, Cpara NO2); 130.1 (s,
1
120.6 (m, 4C, Cortho OPh); 65.9 (d, 1C, OPCH(C3H7)NH, JCP
=
4C, Cmeta OPh); 130.0 (s, 4C, Cmeta OPh); 128.4 (s, 4C, CH-2
2
157.5 Hz); 28.6 (d, 1C, CH(CH3)2 JCP = 1.6 Hz); 20.4 (d, 1C, CH3, COPhNO2); 125.8 (s, 2C, Cpara OPh); 125.7 (s, 2C, Cpara OPh);
3JCP = 7.6 Hz); 19.6 (d, 1C, CH3, JCP = 6.6 Hz). IR (cm-1): υ(NH) = 124.0 (s, 4C, CH-1 COPhNO2); 120.8 (m, 4C, Cortho OPh, JC-P
=
3
3
3
3235; υ(HAr) = 3060; υ(H alkanes) = 2961; υ(CONH) = 1663; 3.9Hz); 120.7 (m, 4C, Cortho OPh, JC-P= 4.0Hz); 29.9 (s, 2C,
υ(C=CAr) = 1589, 1522, 748; υ(NO2) = 1522 or 1487, 1343; CHCH2CH); 25.0 (d, 2C, CH2CH(CH3)2, 3JCP = 13.0 Hz); 23.6 (s, 2C,
υ(P=O) = 1158; υ(ArOP) = 1222-1207; υ(CP) = 929. MS (ESI+): CH3); 21.8 (s, 2C, CH3). IR (cm-1): υ(NH) = 3291; υ(NH) = 3247;
m/z (%)
=
928.2, [C41H39O6N3P2Au]+, 25.27 %.
υ(HAr) = 3113; υ(H alkanes) = 2954; υ(CONH) = 1652; υ(C=CAr)
= 1597, 1519, 748; υ(NO2) = 1488, 1338; υ(P=O) = 1160;
Synthesis and characterisation of [Au(L2)(PPh3)]OTf (10).
A
solution of [Au(OTf)(PPh3)] (0.11 mmol) prepared in situ and L2 υ(ArOP) = 1237-1204; υ(CP) = 933. MS (ESI+): m/z (%)
(48.3 mg, 0.1 mmol) was stirred in DCM (30 mL) for 1 h at [(C24H26O6N3P)2Au]+, 7 %.
= 1163,
room temperature. The volume was reduced to 5 mL, and Synthesis and characterisation of [Cu(L1)(PPh3)]NO3 (13). To a
addition of hexane (10 mL) afforded compounds 10 as a yellow dichloromethane solution (30 mL) of L1 (46.9 mg, 0.1 mmol),
solid, after filtration, with a 42 % yield. δ = 8.87 (br s, 1H, [Cu(NO3)(PPh3)2] (64.9 mg, 0.1 mmol) was added at room
NHCO); 8.23 (m, 2H, H-1); 7.93 (m, 2H, H-2); 7.59-7.13 (m, 25H, temperature. After the addition, the reaction mixture was
Ph); 5.25 (br s, 1H, NHCH); 3.68 (m, 1H, PNHCH); 2.14 (m, 1H, stirred for 30 min. The volume was reduced under vacuum to 5
CH2CH(CH3)); 1.87 (m, 2H, CHCH2CH); 1.06 (m, 6H, CH3).
mL, and addition of hexane (10 mL) afforded compound 13 as
31P{1H} NMR (162 MHz, CDCl3): δ = 31.0 (s, 1P, Au(PPh3); 19.7 a pale yellow solid, after filtration, with a 90 % yield. 1H NMR
(s, 1P, P=O). 13C{1H} NMR (ppm) (101 MHz, CD2Cl2): δ = 164.5 (ppm) (400 MHz, CD2Cl2): δ= 8.75 (s br, 1H, NH); 8.24 (m, 2H,
(s, 1C, CO) ; 150.8 (m, 3C, Cipso OPh, Cipso OPh, Cipso CO); 138.7 (s, H-1); 7.89 (m, 2H, H-2); 7.40-7.17 (m, 25H, Ph); 5.41 (br s, 1H,
1C, Cpara NO2); 134.4-121.1 (m, 32C, Ph); 57.9 (d, 1C, NHCH); 3.44 (m, 1H, CHNH); 2.45 (m, 1H, CH(CH3)); 1.36 (d, 3H,
3
3
OPCH(C3H7)NH, 1JCP = 165.7 Hz); 37.5 (d, 1C, CHCH2CH, 2JCP=3.4 CH3, JH-H= 6.8 Hz); 1.32 (d, 3H, CH3, JH-H= 6.8 Hz).31P NMR
Hz); 25.3 (d, 1C, (CH3)2CHCH2, 3JCP= 12.3 Hz); 23.68 (s, 1C, CH3); (ppm) (162 MHz, CD2Cl2): δ= 19.7 (s, 1P, P=O); -0.5 (s, 1P,
21.86 (s, 1C, CH3). IR (cm-1): υ(NH) = 3247; υ(HAr) = 3057; υ(H PPh3).13C NMR (ppm) (101 MHz, CD2Cl2): δ= 164.4 (s, 1C, CO);
alkanes) = 2957; υ(CONH) = 1653; υ(C=CAr) = 1589, 1519, 747; 150.9 (s, 1C, Cipso CO); 138.8 (s, 1C, Cpara NO2); 134.1 (s br, 6C,
1
υ(NO2) = 1487, 1343; υ(P=O) = 1159; υ(ArOP) = 1243-1207; Cortho PPh3); 132.2 (d, 3C, Cipso PPh3, JC-P= 30.8 Hz); 130.9 (s br,
υ(CP) = 932. MS (ESI): m/z (%) = 941.96, [C42H39O6N3P2Au]+, 3C, Cpara PPh3); 130.4 (s, 2C, Cmeta OPh); 130.3 (s, 2C, Cmeta
7.72 %.
OPh); 129.4 (br s, 6C, Cmeta PPh3); 128.7 (s, 2C, CH-2 COPhNO2);
126.0 (s, 1C, Cpara OPh); 125.9 (s, 1C, Cpara OPh); 124.4 (s, 2C; CH-
Synthesis and characterisation of [Au(L3)(PPh3)]OTf (11).
A
solution of [Au(OTf)(PPh3)] (0.11 mmol) prepared in situ and L3 1 COPhNO2); 120.2 (m, 4C, Cortho OPh); 65.7 (d, 1C, CHNH, 1JC-P
=
2
(48.3 mg, 0.1 mmol) was stirred in DCM (30 mL) for 1 h at 160.8Hz); 29.0 (d, 1C, CH(CH3) JC-P = 2.1Hz); 21.0 (d, 1C, CH3,
room temperature. The volume was reduced to 5 mL, and 3JC-P = 8.3Hz); 19.6 (d, 1C, CH3, JC-P = 7.5Hz). IR (cm-1): υ(NH) =
3
addition of hexane (10 mL) afforded compounds 11 as a yellow 3276; υ(H alkanes) = 2969; υ(CONH) = 1653; υ(C=CAr) = 1594,
solid, after filtration, with a 54 % yield. 1H NMR (400 MHz, 1517, 759; υ(NO2) = 1488, 1347; υ(P=O) = 1162 ; υ(ArOP) =
CD2Cl2): δ= 8.95 (s br, 1H, NH); 8.25 (m, 2H, H-1); 7.90 (m, 2H, 1282-1217; υ(CP)
= 930. MS (ESI+): m/z (%) = 794.2,
H-2); 7.67-7.18 (m, 25H, Ph); 5.49 (br s, 1H, NHCH); 3.34 (br d, [C41H39O6N3P2Cu]+, 2.5 %.
1H, CHNH); 1.38 (s, 9H, CH3). 31P{1H} NMR (162 MHz, CD2Cl2): Synthesis and characterisation of [Cu(L2)(PPh3)]NO3 (14). To a
δ= 31.4 (s, 1P, AuPPh3); 20.2 (s, 1P, P=O). 13C NMR (ppm) (101 dichloromethane solution (30 mL) of L2 (48.3 mg, 0.1 mmol),
MHz, CD2Cl2): δ = 132.7 (s, 1C, Cpara NO2); 134.4-130.0 (m, 22C, [Cu(NO3)(PPh3)2] (64.9 mg, 0.1 mmol) was added at room
PPh3, Cmeta OPh); 128.7 (s, 2C, CH-2 COPhNO2); 125.9 (m, 2C, temperature. After the addition, the reaction mixture was
Cpara OPh); 124.4 (s, 2C, CH-1 COPhNO2); 121.2 (m, 4C, Cortho stirred for 30 min. The volume was reduced under vacuum to 5
3
OPh); 69.7 (d, 1C, CHNH, 1JC-P= 158.8Hz); 28.4 (d, 3C, CH3, JC-P
=
mL, and addition of hexane (10 mL) afforded compound 14 as
6.5Hz). IR (cm-1): υ(NH) = 3274; υ(NH) = 3247; υ(HAr) = 3104; a yellow solid, after filtration, with an 86 % yield. 1H NMR
υ(H alkanes) = 2973-2928; υ(CONH) = 1637; υ(C=CAr) = 1594, (ppm) (400 MHz, CD2Cl2): δ = 8.77 (s br, 1H, NH); 8.25 (m, 2H,
1512, 753; υ(NO2) = 1490, 1343; υ(P=O) = 1154; υ(ArOP) = H-1); 7.91 (m, 2H, H-2); 7.43-7.19 (m, 25H, Ph); 5.32 (s br, 1H,
1232-1206; υ(CP) = 935.
NHCH); 3.66 (m, 1H, CHNH); 2.12 (m, 1H, CH(CH3)); 1.87 (m,
Synthesis and characterisation of [Au(L2)2]OTf (12). A solution 2H, CHCH2CH); 1.06(br t, 6H, CH3). 31P NMR (ppm) (162 MHz,
of [Au(tht)2]OTf (0.55 mmol) prepared in situ and L2 (48.3 mg, CD2Cl2): δ = 19.8 (s, 1P, P=O); -0.9 (s, 1P, PPh3). 13C NMR (ppm)
0.1 mmol) was stirred in DCM (30 mL) for 1 h at room (101 MHz, CD2Cl2): δ = 164.5 (s, 1C, CO); 151.0 (s, 1C, Cipso
temperature. The volume was reduced to 5 mL, and addition OPh); 150.4 (s, 1C, Cipso CO); 138.7 (s, 1C, Cpara NO2); 134.1 (d,
of hexane (10 mL) afforded compounds 12 as a pale yellow 6C, Corto PPh3, 3JC-P = 9.1 Hz); 132.2 (d, 3C, Cipso PPh3, 1JC-P = 30.8
8 | J. Name., 2012, 00, 1-3
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Hz); 130.9 (s, 3C, Cpara PPh3); 130.4 (s, 2C, Cmeta OPh); 130.3 (s, 1160; υ(ArOP) = 1274-1207; υ(CP) = 934. MS (ESI+): m/z (%) =
2C, Cmeta OPh); 129.4 (s, 6C, Cmeta PPh3); 128.7 (s, 2C, CH-2 794.2, [C41H39O6N3P2Cu]+, 2 %.
COPhNO2); 126.1 (s, 1C, Cpara OPh); 125.9 (s, 1C, Cpara OPh);
124.4 (s, 2C, CH-1 COPhNO2); 120.2 (d, 2C, Corto OPh,4JC-P = 4.1 Crystallography. Crystals were mounted in inert oil on glass
Hz); 120.1 (d, 2C, Corto OPh, 4JC-P = 94.2 Hz) 58.0 (d, 1C, CHNH, fibres and transferred to the cold gas stream of an Xcalibur
2
1JC-P = 166.2Hz); 37.40 (d, 1C, CHCH2CH, JC-P= 3.7Hz); 25.3 (d, Oxford Diffraction diffractometer equipped with
a low-
3
1C, CHCH2CH(CH3)2, JC-P = 12.4Hz); 23.7 (s, 1C, CH3); 21.8 (d, temperature attachment. Data were collected using
1C, CH3). IR (cm-1): υ(NH) = 3294; υ(NH) = 3248; υ(CONH) = monochromatic Mo K
α radiation (λ = 0.71073 Å). Scan type ω.
1653; υ(C=CAr) = 1597, 1520, 764; υ(NO2) = 1488, 1338; Absorption correction based on multiple scans was applied
υ(P=O) = 1160; υ(ArOP) = 1238-1205; υ(CP) = 935. MS (ESI+): using spherical harmonics implemented in SCALE3 ABSPACK33
m/z (%) = 808, [C42H41N3O6P2Cu]+, 46 %.
scaling algorithm. The structures were solved by direct
Synthesis and characterisation of [Cu(L3)(PPh3)]NO3 (15). To a methods and refined on F2 using the program SHELXL.34 All
dichloromethane solution (30 mL) of L3 (84.3 mg, 0.1 mmol), non-hydrogen atoms were refined anisotropically. In all cases,
[Cu(NO3)(PPh3)2] (64.9 mg, 0.1 mmol) was added at room hydrogen atoms were included in calculated positions and
temperature. After the addition, the reaction mixture was refined using a riding model. Refinements were carried out by
stirred for 30 min. The volume was reduced under vacuum to 5 full-matrix least-squares on F2 for all data. CCDC reference
mL, and addition of hexane (10 mL) afforded compound 15 as numbers 1565044 for complex
1
a pale yellow solid, after filtration, with a 90 % yield. H NMR
5
and 1565045 for complex
8.
(ppm) (400 MHz, CD2Cl2): δ = 8.90 (br s, 1H, NH); 8.25 (m, 2H, Cell culture. HeLa (cervical cancer) and A549 (lung carcinoma)
H-1); 7.90 (m, 2H, H-2); 7.43-7.18 (m, 25H, Ph); 5.46 (s br, 1H, cells were maintained in high glucose DMEM (Dulbecco´s
2
NHCH); 3.35 (d, 1H, CHNH, JH-P = 5.2Hz); 1.38 (s, 9H, CH3). 31P Modified Eagle´s Medium) supplemented with 5 % fetal bovine
NMR (ppm) (162 MHz, CD2Cl2): δ = 20.4 (s, 1P, P=O); -0.4 (s, 1P, serum (FBS), 200 U/ml penicillin, 100 μg/ml streptomycin and
PPh3). 13C NMR (ppm) (101 MHz, CD2Cl2): δ = 163.7 (s, 1C, CO); 2 mM L-glutamine. Cultures were maintained in a humidified
150.9 (s, 1C, Cipso OPh); 150.3 (s, 1C, Cipso CO); 138.9 (s, 1C, Cpara atmosphere of 95 % air/5 % CO2 at 37 °C. Adherent cells were
NO2); 134.1 (d, 6C, Cortho PPh3, 2JC-P = 12.0 Hz); 132.2 (d, 3C, Cipso allowed to attach for 24 h prior to addition of compounds.
PPh3, 1JC-P = 32.4 Hz); 130.9 (s, 3C, Cpara PPh3); 130.4 (s, 2C, Cmeta
OPh); 130.3 (s, 2C, Cmeta OPh); 129.4 (br s, 6C, Cmeta PPh3); Cytotoxicity assay. The MTT assay was used to determine cell
128.7 (s, 2C, CH-2 COPhNO2); 126.0 (s, 1C, Cpara OPh); 125.9 (s, viability as an indicator for cells sensitivity to the complexes.
2C, Cpara OPh); 124.4 (s, 2C; CH-1 COPhNO2); 121.2 (d, 2C, Corto Exponentially growing cells were detached from the plastic
3
3
OPh, JC-P = 4.2Hz); 121.1 (d, 2C, Cortho OPh, JC-P = 4.1Hz); 69.7 flask using trypsin-EDTA solution and seeded at a density of
1
(d, 1C, CHNH, JC-P = 158.8Hz); 34.7 (s, 1C, CHC(CH3)3); 28.4 (d, approximately 104 cells per well in 96-well flat-bottomed
3
3C, CH3, JC-P = 6.5Hz). IR (cm-1): υ(NH) = 3275; υ(NH) = 3245; microplates and allowed to attach for 24 h prior to addition of
υ(HAr) = 3068; υ(H alkanes) = 2903; υ(CONH) = 1638; υ(C=CAr) compounds. The complexes were dissolved in DMSO and
= 1595, 1513, 753; υ(NO2) = 1491, 1344; υ(P=O) = 1154; added to cells in concentrations ranging from 0.1 to 50 µM in
υ(ArOP) = 1232-1206; υ(CP) = 937. MS (ESI+): m/z (%) = 808, quadruplicate. Cells were incubated with our compounds for
[C42H41N3O6P2Cu]+, 46 %.
Synthesis and characterisation of [Cu(L4)(PPh3)]NO3 (16). To a and plates were incubated for 2 h at 37 °C. Finally, media was
dichloromethane solution (30 mL) of L4 (46.9 mg, 0.1 mmol), eliminated and DMSO (100 l per well) was added to dissolve
24 h at 37 °C. 10 µl of MTT (5 mg ml-1) were added to each well
ꢀ
[Cu(NO3)(PPh3)2] (64.9 mg, 0.1 mmol) was added at room the formazan precipitates. The optical density was measured
temperature. After the addition, the reaction mixture was at 550 nm using a 96-well multiscanner autoreader (ELISA).
stirred for 30 min. The volume was reduced under vacuum to 5 The IC50 was calculated by nonlinear regression analysis using
mL, and addition of hexane (10 mL) afforded compound 16 as Prism software (GraphPad Software Inc). Each compound was
a pale yellow solid, after filtration, with an 82 % yield. 1H NMR analysed at least in three independent experiments.
(ppm) (400 MHz, CD2Cl2): δ = 8.65 (s br, 1H, NH); 8.19 (m, 2H,
H-1); 7.83 (m, 2H, H-2); 7.43-7.12 (m, 25H, Ph); 5.46 (s br, 1H,
NHCH); 3.54 (m, 1H, CHNH); 1.89-1.61 (m, 4H, CH2); 0.97 (t, 3H,
CH3, JH-H= 7.3 Hz). 31P NMR (ppm) (162 MHz, CD2Cl2): δ = 19.6
(s, 1P, P=O); -0.4 (s, 1P, PPh3). 13C NMR (ppm) (101 MHz,
CD2Cl2): δ = 134.2 (br s, 6C, Corto PPh3); 132.3 (d, 3C, Cipso PPh3,
1JC-P= 32.0 Hz); 130.9 (s, 3C, Cpara PPh3); 130.4 (s, 2C, Cmeta OPh);
130.3 (s, 2C, Cmeta OPh); 129.4 (s, 6C, Cmeta PPh3); 128.8 (s, 2C,
CH-2 COPhNO2); 126.1 (s, 1C, Cpara OPh); 125.9 (s, 1C, Cpara OPh);
124.4 (s, 2C, CH-1 COPhNO2); 121.2 (br s, 2C, Corto OPh); 120.1
(br s, 2C, Corto OPh); 30.7 (s, 1C, CHCH2CH2CH3); 20.1 (s, 1C,
CHCH2CH2CH3); 14.2 (s, 1C, CHCH2CH2CH3). IR (cm-1): υ(NH) =
3249; υ(HAr) = 3046; υ(H alkanes) = 2898; υ(CONH) = 1653;
υ(C=CAr) = 1598, 1519, 758; υ(NO2) = 1456, 1344; υ(P=O) =
3
CONCLUSIONS
Unprecedented α-hydrazidophosphonate group 11 metal
complexes have been prepared. Several coordination modes of
the ligands to group 11 metals have been proposed, which
depend also upon the ancillary ligand, and some of them
+
corroborated by X-ray diffraction. With the MPPh3 fragment
the coordination is tridentate chelate O^N^O with silver and
copper, whereas an N^O binding mode is suggested for gold.
The homoleptic silver and gold derivatives have been prepared
and they are tetrahedral, N^O, for silver and linear for gold
with bonding of the gold atom to the iminic nitrogen atoms.
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Journal Name
Olszewski, Synthesis, 2014, 46, 403–429; f) R. P. Herrera,
Chem. Rec., 2017, DOI: 10.1002/tcr.201600129.
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values reveal an excellent cytotoxic activity of the metal
complexes compared with the α-hydrazidophosphonate
ligands alone and much higher than cisplatin. The values are in
the low micromolar range and are among the lowest found in
silver or copper complexes. These outstanding activities of
these complexes are worth for further studies opening new
avenues with low toxic metals and the possibility of new
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DOI: 10.1039/C7DT02743E
Graphical Abstract
Highly
active
group
11
metal
complexes
with
α-
hydrazidophosphonate ligands
Daniel Salvador-Gil, Lourdes Ortego, Raquel P. Herrera, Isabel Marzo and M. Concepción Gimeno*
Unprecedented α-hydrazidophosphonate group 11 metal complexes have been prepared, with various
coordination modes of the ligands to the metal atoms. They present an excellent cytotoxic activity in
HeLa (cervical carcinoma) and A549 (lung carcinoma) cell lines, with IC50 values in the low micromolar
range and among the lowest found in silver or copper complexes.