Synthesis and characterisation of organo-platinum(II) complexes of the N,O-donor ligands hippuric acid (N-benzoylglycine) and N-phenylanthranilic acid

Article abstract of DOI:10.1016/j.ica.2016.05.053

Reaction of [PtCl₂(cod)] (cod = cyclo-octa-1,5-diene) with either hippuric acid [PhC(O)NHCH₂COOH] or N-phenylanthranilic acid (ortho-PhNHC₆H₄COOH) in refluxing dichloromethane in the presence of silver(I) oxide

Full text of DOI:10.1016/j.ica.2016.05.053

Accepted Manuscript
Synthesis and characterisation of organo-platinum(II) complexes of the N,O-
donor ligands hippuric acid (N-benzoylglycine) and N-phenylanthranilic acid
Sophie A. Sim, Graham C. Saunders, Joseph R. Lane, William Henderson
PII:
S0020-1693(16)30308-5
http://dx.doi.org/10.1016/j.ica.2016.05.053
ICA 17089
DOI:
Reference:
Inorganica Chimica Acta
To appear in:
Received Date:
Accepted Date:
18 March 2016
29 May 2016
Please cite this article as: S.A. Sim, G.C. Saunders, J.R. Lane, W. Henderson, Synthesis and characterisation of
organo-platinum(II) complexes of the N,O-donor ligands hippuric acid (N-benzoylglycine) and N-phenylanthranilic
acid, Inorganica Chimica Acta (2016), doi: http://dx.doi.org/10.1016/j.ica.2016.05.053
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Correspondence to:
Professor W. Henderson,
Chemistry,
School of Science,
University of Waikato,
Private Bag 3105,
Hamilton 3240
New Zealand
e-mail w.henderson@waikato.ac.nz
Synthesis and characterisation of organo-platinum(II) complexes of the
N,O-donor ligands hippuric acid (N-benzoylglycine) and N-
phenylanthranilic acid
Sophie A. Sim, Graham C. Saunders, Joseph R. Lane and William Henderson*
Chemistry, School of Science, University of Waikato, Private Bag 3105, Hamilton, New
Zealand 3240
Received:
1

Abstract
Reaction of [PtCl2(cod)] (cod = cyclo-octa-1,5-diene) with either hippuric acid
[PhC(O)NHCH2COOH] or N-phenylanthranilic acid (ortho-PhNHC6H4COOH) in refluxing
dichloromethane in the presence of silver(I) oxide gave the new organoplatinum derivatives
[Pt{N(COPh)CH2COO}(cod)] and [Pt{N(Ph)C6H4COO}(cod)] respectively. Ligand
substitution reactions of the cod ligand in [Pt{N(COPh)CH2COO}(cod)] provided a facile
route to a selection of phosphine-substituted analogues [Pt{N(COPh)CH2COO}L2] [L =
phosphatriazaadamantane (pta), PPh3, or L2 = Ph2PCH2CH2PPh2 or Fe(η5-C5H4PPh2)2] via
displacement of the labile cod ligand. The complexes were characterised using NMR
spectroscopy, IR spectroscopy, and ESI mass spectrometry. The X-ray structure of
[Pt{N(COPh)CH2COO}(cod)] is also reported.
Keywords: Platinum complexes; Metallacyclic complexes; Silver(I) oxide; Hippuric acid; N-
Phenylanthranilic acid; Crystal structure
2

Introduction
The coordination chemistry of amino acid ligands towards the platinum group metals
has been extensively studied,[1,2,3] on account of the importance of such ligands in
biological systems, and the utility of a number of platinum-based drugs for the treatment of
cancer. However, there have been fewer studies on analogous complexes of ligands where
the amine group of the amino acid is ‘protected’ by means of an acyl or sulfonyl [4]
substituent. Both the NH and OH groups of the ligand can be readily deprotonated, allowing
the ligand to bind as a dianion, typically forming a metallacyclic ring. The first examples of
this type of complex resulted from reactions of the dipeptides L-val- L-val, L-leu- L-val and
L-val- L-leu with Zeise’s salt, K[PtCl3(C2H4)].[5] Kemmitt and co-workers prepared a
substantial range of complexes by reaction of cis-[PtCl2L2] (L = tertiary phosphine) with
acetylated derivatives of the amino acids glycine, DL-alanine, DL-methionine, L-
phenylalanine and L-proline, giving five-membered metallacyclic complexes
[Pt{N(COMe)CHRC(O)O}L2] (R = H, Me, CH2CH2SMe or CH2Ph).[6] Other prepared
derivatives in this work included complexes of the N-formyl and N-trifluoroacetyl derivatives
of
glycine,
together
with
the
1,5-cyclo-octadiene
(cod)
derivatives
[Pt{N(COMe)CHRC(O)O}(cod)] (R = H, CH2Ph), which provide access to a range of other
derivatives through facile ligand substitution reactions.[2] Related complexes derived from
α-acetamidocinnamic
acid
produced
a
series
of
complexes
[Pt{N(COMe)C(=CHR)C(O)O}L2] (L = tertiary phosphine).[7] Bauer et al have also
reported three heterobimetallic complexes containing the [Pt{N(COR)CHR’C(O)O}(PPh3)2]
metallacyclic ring, where the R group is appended with an Fe(CO)3(diene) group.[8]
In this paper we report the synthesis and characterisation of some analogous
platinum(II)
complexes
derived
from
N-benzoylglycine
(hippuric
acid,
3

PhC(O)NHCH2COOH). Although platinum complexes containing chelating hippurate
dianions have not been described previously, some analogous complexes of this general type
are known, for example the reaction of N-benzoyl-DL-α-valine (PhC(O)NHCHiPrCOOH)
with [PtCl2(bipy)] (bipy = 2,2’-bipyridine) gave [Pt{N(COPh)CHiPrC(O)O}(bipy)].[9] An
analogue with an estrogen-like ligand has also been developed [10], together with a number
of bipy-containing derivatives [11] that have been patented as precursors for the preparation
of anti-tumour drugs.[12]
We also report herein a related platinum complex derived from N-phenylanthranilic
acid (PhNHC6H4COOH), which can also form a dianionic N,O-bonded ligand, and a six-
membered chelate ring. The focus in this current work is the cod complexes since the labile
cod ligand allows a facile route to a range of ligand-substituted derivatives. Furthermore, it
has recently been shown that a number of cod-platinum(II) complexes show higher anti-
tumour activity than cisplatin towards HeLa cells,[13] suggesting that such organoplatinum
complexes could also be of potential interest for their biological properties.
Results and discussion
Synthesis and X-ray structural characterisation of hippurate complexes
Reaction of [PtCl2(cod)] with hippuric acid in refluxing dichloromethane in the
presence of excess silver(I) oxide gave, on workup, the air- and moisture-stable organo-
platinum hippurate complex 1a in reasonable yield and purity (Scheme 1). The complex
initially crystallised as a light purple solid due to contamination by silver, but a second
recrystallisation gave almost colourless crystals that were analytically pure. Silver(I) oxide is
well-recognised as a reagent in the chemistry of the platinum group metals, where it acts as
4

both a halide abstracting reagent and a strong base, with the first known example of its use
being reported in 1977.[14] Silver(I) oxide is now widely established as a mediator for
metallacyclic reactions, and for the formation of platinum group metal-ligand bonds
[6,15,16,17], and more recently, the synthesis of N-heterocyclic carbene
complexes.[18,19,20,21] However, in our experience the use of silver oxide can result in the
product having a slight purple tinge, most likely due to colloidal silver, originating from
decomposition of soluble silver-containing complexes which form during the reaction. The
silver impurities can be removed by allowing the initially isolated sample to ‘age’.
Dissolution in the desired solvent (e.g. dichloromethane or chloroform) and filtering through
Celite filter aid to remove the silver impurities, followed by crystallisation typically yields
analytically pure products. An investigation into the potential applicability of alternative
bases (copper(I) oxide or calcium hydroxide) in the synthesis of 1a did not produce the
desired product.
The presence of the labile cod ligand allowed the facile synthesis of a number of
ligand-substituted derivatives. Thus, reaction of 1a with PPh3, dppe (Ph2PCH2CH2PPh2), pta
(phosphatriazaadamantane) and dppf [Fe(η5-C5H4PPh2)2] in dichloromethane solution gave
(in high yield and good purity) the phosphine-substituted analogues 1b-1e, Scheme 1. These
complexes crystallise as white or yellow solids, which have relatively high melting points,
and are generally readily soluble in dichloromethane and chloroform. The triphenylphosphine
complex crystallises from the reaction mixture with dichloromethane of crystallisation, as
confirmed by 1H NMR spectroscopy.
In a similar fashion to the synthesis of the cod-Pt complex 1a, reaction of the 2,2’-
bipyridyl-palladium complex [PdCl2(bipy)] with hippuric acid and silver(I) oxide in refluxing
5

dichloromethane gave the palladium complex [Pd{N(COPh)CH2COO}(bipy)] 2 as an
orange solid; this complex has much lower solubility than the platinum complexes.
In order to unambiguously confirm the structure of a hippurate complex, the X-ray
structure of [Pt{N(COPh)CH2COO}(cod)] 1a was determined. The structure is shown in
Figure 1 together with the atom numbering scheme, while Table 1 gives selected bond
lengths and angles. Examination of the Cambridge Structural Database (version 5.36)
confirms that there are no known X-ray structure determinations of metal complexes
containing the hippurate dianion ligand, although the platinum complex of the related N-
acetylglycine ligand, [Pt{N(COMe)CH2COO}(Ph2PCH2CH2PPh2)], has been structurally
characterised,[6] together with a platinum complex containing a related benzoylated amino
i
acid ligand, [Pt{N(COPh)CH(CH2 Pr)COO}(bipy)].[11] Furthermore, there have only been
three previous structure determinations of cod-Pt complexes containing chelating N,O
ligands, none being amino acidate-type ligands.[22,23]
The geometry about the platinum atom of 1a is the expected pseudo-square planar.
The five-membered hippurate ring is not planar but has a slight envelope conformation, with
a fold angle between the planes defined by Pt(1)-N(1)-O(2) and O(2)-C(10)-C(9)-N(1) of
10.3 ̊. The metallacyclic carbonyl lies roughly in the least-squares metallacycle plane defined
by Pt(1), N(1), C(9), C(10) and O(2), with the distance of O(1) to the plane being 0.014 Å.
The benzoyl carbonyl lies more out of the metallacycle least-squares plane, with O(3) lying
0.56 Å out of the plane. The phenyl ring is almost orthogonal to the metallacycle, as defined
by an angle of 87.0 ̊ between the Pt(1)-N(1)-O(2) coordination plane and the least-squares
plane of the phenyl ring [C(21)-C(26)].
As expected due to the lower trans-influence [24] of the carboxylate oxygen, the
platinum-carbon distances trans to oxygen [Pt(1)-C(1) 2.157(4) and Pt(1)-C(2) 2.171(4) Å]
6

are shorter than the corresponding Pt-C distances trans to the amidate nitrogen [Pt(1)-C(5)
2.181(4), Pt(1)-C(6) 2.187(4) Å]. These bond distances can be compared to Pt-C bond
distances of 2.161(4) to 2.171(5) Å, with an average of 2.166(4) Å, in a recent structural
determination of [PtCl2(cod)].[13] The projection of the C(11)-O(3) bond of the benzoyl
substituent towards the cod ligand appears to lengthen the Pt-C(2) distance relative to the
Pt-C(1) distance. The cod ligand has a slightly skewed conformation.
Spectroscopic characterisation of hippurate complexes 1a - 1e
Each of the complexes was characterised using positive-ion ESI MS. For complex
1a, only a relatively weak [M + H]+ ion was observed at m/z 480.98 (calculated m/z 481.11),
despite several attempts at varying the ionisation conditions and solvents (methanol and
acetonitrile). In contrast, the phosphine-substituted derivatives 1b-1e showed much more
intense ions, typically showing a mixture of [M + H]+, [M + Na]+ and [M + K]+ ions; the
spectra were considerably simplified upon addition of a small quantity of NaCl, which
resulted in the observation of solely the [M + Na]+ ions. For example, the positive-ion
spectrum of the triphenylphosphine complex 1b (without added NaCl) showed [M + H]+
(m/z observed 897.19 calculated 897.20), [M + Na]+ (m/z observed 919.17, calculated
919.18) and [M + K]+ (m/z observed 935.24, calculated 935.15) ions, with the [M + Na]+
ion dominating the spectrum, as shown in Figure 2. The reasons for the apparent low
ionisation efficiency of 1a are not clear, since other cod-Pt complexes have been found to
analyse well by ESI MS.[15] The bipyridine palladium complex 2 also showed the [M +
Na]+ ion as the base peak in the ESI mass spectrum (with added sodium formate), in
addition to weaker ions due to [M + H]+ (m/z 439.89), [2M + Na]+ (m/z 461.88) and [3M +
Na]+ (m/z 902.77).
7

31
13
1H, P{1H} and C{1H} NMR spectroscopies have been employed to provide a full
spectral assignment of the complexes. The 31P{1H} NMR spectra of the phosphine-
substituted complexes 1b – 1e give typical spectra for this type of complex, showing two
doublets for the two inequivalent P nuclei (trans to O or N), showing mutual 2JP-P coupling.
1
Satellites due to coupling to 195Pt are also observed, with the magnitude of JPt-P reflecting
the trans influence of the trans donor atom (either higher trans influence N or lower trans
1
influence O, producing respectively lower or higher JPt-P values for the trans P atoms); data
are summarised in Table 2. The pta complex has very upfield resonances (δ 31P -67.0, -67.4
ppm) typical for pta-platinum(II) complexes.[25]
Full characterisation of the 1H NMR spectrum of the cod complex 1a was carried out
using a combination of 1- and 2-dimensional NMR techniques. The 1H NMR spectrum of 1a
is shown in Figure 3, a full assignment of the proton and carbon resonances is given in the
Experimental section, and the atom numbering scheme is shown in Scheme 2.
1
Two signals are observed for the cod CH protons in the H NMR spectrum (at
δ 6.51 and 5.43) due to symmetry in the cod moiety which renders C1 and C2, and C5 and C6
spectroscopically equivalent. Consequently, the bonded hydrogens H1 & H2 and H5 & H6 are
also equivalent. Each of the cod CH resonances has broad shoulders attributable to coupling
to 195Pt (2JPt-H ca. 70 Hz and 57 Hz, respectively).
As observed in the 31P NMR spectra of the phosphine complexes, the differing trans
influences of the N and O donors of the hippurate ligand in 1a allows differentiation between
2
1
CH groups trans to nitrogen/oxygen, based on their JPt-H (and JPt-C) coupling constants.
2
The cod CH resonance at δ 6.51 is assigned to H1 & H2, as it has the larger JPt-H coupling
constant (70 Hz), indicating that the bonded carbon (at δ 96.0, from the HSQC spectrum) is
8

trans to oxygen. Similarly, the resonance at δ 5.43 is assigned to H5 & H6, with a smaller
2JPt-H of 57 Hz, which suggests that the attached carbon (δ 98.5) is trans to nitrogen. There
are also notable differences between the two cod CH signals in terms of chemical shift,
multiplicity and broadness. In particular, the broadness of the signal at δ 6.51 may be
attributable to a proximity to lone pair electron density such as that on the N-C=O group on
the hippurate moiety. This is consistent with the data, as the H1 & H2 signal at δ 6.51 is
broader and downfield, while the H5 & H6 signal at δ 5.43 is sharper and more upfield.
Density functional theory (DFT) was used to calculate theoretical NMR shifts; two different
environments are calculated which, when averaged to account for vibrational motion on the
time-scale of NMR spectroscopy, show a difference of 0.84 ppm (the chemical shifts for
H1/H2 and H5/H6 are calculated to occur at δ 5.69 and 4.86 respectively). This is fairly
1
consistent with the observed H NMR data of 1a, which shows a difference of 1.1 ppm
between the signals for H1/H2 and H5/H6. Although these differ from the experimental
chemical shifts of δ 6.51 and 5.43 (by 0.8 and 0.6 ppm respectively) they still suggest that
the proton closest to the nitrogen is that in the H1/H2 environment.
Assuming that the two protons in the H22/H26 environment are identical (due to free
rotation about the C11-C21 bond) there are three aromatic proton environments from the
hippurate moiety (corresponding to H22 & H26, H23 & H25, and H24 in Scheme 2). These
appear in the region from δ 7.36-7.18, and an expansion of this can be seen in the top left of
the 1H NMR spectrum of 1a (Figure 3). Only one of the three aromatic proton environments
was adequately resolved in the proton spectrum. The signal at δ 7.19 (essentially as a
3
4
doublet of doublets with J = 8.0, J = 1.7 Hz) can be uniquely attributed to the H22/H26
environment, since of the aromatic proton environments only this proton is expected to
9

show a 3J coupling to its nearest neighbour (H6) and a smaller 4J coupling to H7. A NOESY
experiment confirmed this, showing an NOE from the H22/H26 protons at δ 7.19 to the H9
protons at δ 4.01, consistent with H22/H26 being the closest of the aromatic protons to H9.
The H24 and H23/H25 proton environments occur in the δ 7.36-7.27 region as complex
second-order overlapped multiplets. Notwithstanding the complex nature of the overlapped
signal, it was apparent from a high resolution COSY spectrum that the initial more intense
3
correlation peaks are attributable to the larger J couplings between H22 at δ 7.19 and the
4
protons at δ 7.31, and later the smaller J coupling correlations develop to the proton at δ
7.34. This allows tentative assignment for the higher chemical shift as H24 and the lower as
the H23/H25 environment.
The hippurate CH2 protons at δ 4.01 also show significant coupling to 195Pt (3JPt-H
~
18.1 Hz), as expected. It is clearly recognisable as a methylene signal in a DEPT135
1
experiment. The observation of a single peak in the H NMR spectrum indicates that the
hippurate ligand lies in a plane of symmetry, which makes both protons chemically
equivalent.
The cod CH2 protons are observed as four complex multiplets around δ 2.5 and are
easily distinguished as methylenes in a DEPT135 experiment. These protons are symmetry-
paired (with H3a & H8a, H3b & H8b, H4a & H7a and H4b & H7b being the chemically equivalent
2
pairs). In addition, there is both geminal J coupling (between Ha and Hb for the CH2
3
protons) and J coupling between methylene and methyne protons, leading to complicated
overlapping signals. Furthermore, each cod methylene couples to 195Pt which adds to the
complexity of the cod CH2 signals. In the COSY spectrum the cod CH proton at δ 6.51
correlates to the protons at δ 2.72 and 2.42, whereas the proton at δ 5.43 shows correlations
10

to the protons at δ 2.60 and 2.28. In addition, the high-resolution COSY spectrum shows
mutual correlations between the four adjacent methylene signals. Axial protons are generally
higher in chemical shift than equatorial protons [26] which allows assignment of the cod
CH2 protons: H3a & H8a at δ 2.72, H3b & H8b at δ 2.42, H4a & H7a at δ 2.60, and H4b & H7b at
δ 2.28.
The 13C{1H} NMR spectrum of complex 1a shows a number of key resonances. The
metallacycle ring CH2 carbon appears at δ 56.9 as expected and exhibits broad shoulders due
to coupling to 195Pt (2JPt-C 15 Hz). The nitrogen-attached carbonyl (C11) is observed at δ
176.7 and has slightly broad shoulders from coupling to 195Pt (2JPt-C 32 Hz), while the
metallacycle ring carbonyl (C10) appears slightly upfield at δ 184.4, but no 195Pt coupling
could be resolved for this signal. The HMBC spectrum confirms these shifts since it shows
correlations from the nitrogen-attached carbonyl to the aromatic protons, whereas the ring
1
1
carbonyl displays no coupling to H as it is too far away. The H-coupled 13C spectrum
shows further evidence, with C10 appearing as a triplet at δ 184.4 (JC-H 6 Hz) due to splitting
by the neighbouring CH2 protons, while the nitrogen-attached carbonyl C11 appears as a
singlet at δ 176.7. Similarly, the quaternary carbon (C21) of the phenyl ring shows broad
shoulders due to coupling to 195Pt (3JPt-C 42 Hz). As expected, it is further upfield in the
aromatic region (δ 138.5), has a low intensity and shows no correlations to protons in the
HSQC spectrum. In the aromatic region, two of the environments appear to overlap at δ
128.6, while the final signal occurs at δ 125.5. The latter is assigned as the C22/C26
environment due to its correlation to the H22/H26 signal at δ 7.19 in the HSQC spectrum. An
expansion of the aromatic region allows the peaks at δ 128.6 to be almost fully separated to
see the intensity ratio of 2:1. This enables clear assignment of C24 as the signal with the
11

lower chemical shift (δ 128.58) since it has a lower intensity attributable to its single carbon.
In contrast, the signal with the higher chemical shift (δ 128.61) has a doubled intensity and
therefore corresponds to the C23/C25 environment.
The two cod CH resonances (the C1/C2 and C5/C6 environments in Scheme 2) are
13
both seen in the C{1H} spectrum as singlets at δ 98.5 (1JPt-C 140 Hz) and 96.0 (1JPt-C 160
Hz), both displaying substantial coupling to 195Pt. The HSQC spectrum showed that these
are attached to the protons at δ 5.43 and 6.51, respectively. The signal at δ 96.0 can be
1
assigned as the C1 & C2 environment due to its higher JPt-C coupling constant (160 Hz)
indicating it is trans to the metallacycle oxygen atom, while the δ 98.5 resonance can be
1
correspondingly attributed to the C5 & C6 environment (trans to N) by its smaller JPt-C
1
13
coupling constant (140 Hz). In the H-coupled C NMR spectrum, the C1/C2 and C3/C4
resonances appear as doublets (1JC-H ca. 165 Hz). These JC-H coupling constants are typical
for CH environments of this type.[15,27,28]
The cod methylene carbons (C3 & C8, and C4 & C7) occur at δ 32.4 and 28.2 in the
13C{1H} NMR spectrum. In the proton-coupled spectrum, the C3/C8 and C4/C7
environments appears as triplets (1JC-H 131 and 132 Hz respectively). As expected due to
changes in s-character [27], the JC-H values for the cod methylene signals are approximately
35 Hz lower than those for the cod CH resonances. The HSQC spectrum shows that the
CH2 at δ 32.4 correlates to the proton signals centred at δ 2.72 and 2.42, while the CH2 at
28.2 correlates to the proton signals centred at δ 2.60 and 2.28.
In comparison to its parent complex 1a, the proton NMR spectrum of the
triphenylphosphine complex 1b appears rather straightforward, with only two regions. The
complex multiplet from δ 7.81-6.75 corresponds to the aromatic protons, making
12

interpretation difficult, and no further assignment was undertaken. The ring methylene signal
at δ 4.16 (3JPt-H 41 Hz) comes at an expected chemical shift, and is slightly more downfield
than that of the ring methylene in the parent complex 1a (δ 4.03). It appears as a doublet as
1
a result of coupling to the trans phosphine. The H NMR spectra of the other phosphine
complexes were assigned in analogous fashion to those of 1a, and showed typical features
expected for these complexes.
The bipyridine palladium complex 2 had relatively poor solubility in CDCl3 but was
able to be characterised by 1H NMR. In addition to the complex set of resonances due to the
bipyridine and phenyl protons, a singlet at δ 4.26 is assigned to the CH2 protons, by
comparison with the chemical shift of the same protons in the analogous platinum
complexes.
Synthesis
and
characterisation
of
the
N-phenylanthranilate
complex
[Pt{OC(O)C6H4NPh}(cod)] 3
In a similar fashion to the synthesis of the hippurate complex 1a, reaction of
[PtCl2(cod)], N-phenylanthranilic acid and silver(I) oxide in refluxing dichloromethane gave
complex 3 on workup (Scheme 3). The complex, isolated in reasonable yield and purity, is
an intense green-yellow coloured solid, in contrast to the platinum hippurate complexes,
which are colourless (with of course the exception of the yellow ferrocene-derived complex
1e). Somewhat surprisingly, there are no well-characterised complexes that contain dianionic
N-phenylanthranilate ligands, although there are many examples of complexes containing
monoanionic ligands [29,30,31] including complexes of the lanthanides,[32,33,34,35,36] and
13

other platinum group metals such as rhodium.[37,38] Platinum complexes of N-
phenylanthranilate ligands have not been reported to date.
The IR spectrum of N-phenylanthranilic acid shows a very strong C=O stretch at
1660 cm-1, as well as a very strong C-N stretch at 1263 cm-1; these decrease to 1616 cm-1
and increase to 1338 cm-1 respectively, upon coordination to platinum(II) in complex 3.
Assignment of peaks was assisted by DFT calculations for both N-phenylanthranilic acid and
complex 3. As for complex 1a, the N-phenylanthranilate complex 3 also did not give a
simple ESI mass spectrum, though a weak [M + H]+ ion was observed at m/z 515.17
(calculated m/z 515.12).
1
The H NMR spectrum of 3 in CDCl3 showed many similarities with that of the
hippurate complex 1a. The atom numbering is shown in Scheme 4; a full assignment of the
1
13
various H and C resonances was able to be made following methods analogous to those
used in the assignment of complex 1a. The four cod CH protons are seen as two distinct
signals in the 1H NMR spectrum, due to the equivalence of C1 and C2, and of C5 and C6 (and
2
their attached hydrogens). These resonances show different JPt-H coupling constants (ca. 54
and 65 Hz), due to the differing trans-influence of the N and O donors. The resonance at δ
4.42 is assigned to the CH trans to O, as it shows the larger coupling constant. The DFT-
1
calculated H NMR shifts for the cod CH protons (δ 5.18 and 4.20) confirm these
assignments, with the calculated difference in chemical shifts ∆δ (0.98 ppm) being very close
to the experimentally observed difference (1.0 ppm).
14

Conclusions
New platinum(II) complexes of the dianionic N,O-donor ligands hippurate and N-
phenylanthranilate, which also contain ancillary cyclo-octadiene ligands, can be conveniently
synthesised by the reaction of [PtCl2(cod)] with the parent hippuric acid or N-
phenylanthranilic acid in the presence of silver(I) oxide. In the case of the hippurate
complexes, the labile cod ligand allows access to a selection of phosphine-substituted
derivatives by facile ligand substitution reactions.
Experimental
Instrumentation
High resolution ESI mass spectra were recorded on a Bruker MicrOTOF instrument, which
was periodically calibrated using a solution of sodium formate. Samples of isolated products
were typically prepared for analysis by dissolution in a few drops of dichloromethane
followed by dilution with methanol and centrifugation. Typical parameters used a Capillary
Exit voltage of 150 V and a Skimmer 1 voltage of 50 V. Assignment of ions was assisted by
comparison of experimental and theoretical isotope patterns, the latter calculated using an
internet-based program [39] or proprietary instrument-based software.
All 1D and 2D NMR spectra (1H, 13C and 31P, COSY, NOESY, DEPT, HSQC,
HMBC and H2BC) were recorded on a Bruker AVIII-400 spectrometer in CDCl3 (unless
otherwise specified in-text) using BBI or BBFO probes, depending on the nucleus of the
sample. Standard Bruker supplied pulse programmes were used for each experiment, with
parameters including spectral window, number of increments, pulse angle and repetition rate
altered as appropriate for each specific sample.
15

Elemental analyses were carried out by the Campbell Microanalytical Laboratory,
University of Otago, Dunedin, New Zealand. Melting points were recorded as finely ground
samples in capillary tubes on a Buchi M-560 Melting Point instrument. IR spectra were
recorded as KBr disks on a Perkin Elmer Spectrum 100 FTIR spectrometer.
Materials
Silver(I) oxide (BDH), hippuric acid (Sigma), 1,1’-bis(diphenylphosphino)ferrocene (dppf,
Aldrich) and N-phenylanthranilic acid (BDH) were used as supplied. The complexes
[PtCl2(cod)] [40] and [PdCl2(bipy)],[41] and the phosphines dppe [42] and pta [43] were
prepared by the literature procedures. All solvents used were drum grade, with the exception
of dichloromethane, which was passed through a solvent purification system to remove
water, air and stabilisers.
Synthesis of [Pt{N(COPh)CH2COO}(cod)] 1a
A mixture of [PtCl2(cod)] (201.2 mg, 0.538 mmol) and hippuric acid (96.7 mg, 0.540 mmol)
with silver(I) oxide (611 mg, excess) in dichloromethane (30 mL) was refluxed for 3.5 h.
After cooling to room temperature the mixture was filtered, giving a pale purple solution.
Petroleum spirits (60 mL) was added and the mixture allowed to crystallise, giving pale
purple crystals that were filtered, washed with petroleum spirits (10 mL) and dried under
vacuum to give 1a (124.3 mg, 48%). The product was dissolved in a minimal amount of
dichloromethane, filtered through filter aid, and crystallised by vapour diffusion of diethyl
ether to give almost colourless crystals. Found: C 42.5; H 4.0; N 2.9. C17H19NO3Pt requires
C 42.5; H 4.0; N 2.9%. M.p. 162-163 °C (decomp.). IR ν(C=O) 1690(vs), 1604(vs) cm-1.
16

ESI MS (capillary exit voltage 250 V) [M + H]+ m/z 480.98 (calculated for C17H19NO3PtH
m/z 481.11).
2
1H NMR, δ 7.36-7.18 (m, 5H, H21-H26), 6.51 (s, 2H, H1/H2, JPt-H 70), 5.43 (m, 2H,
2
3
H5/H6, JPt-H 57), 4.01 (s, 2H, H9a & H9b, JPt-H 18), 2.77-2.23 (m, 8H, H3, H4, H7 & H8).
2
3
13C{1H} NMR, δ 184.4 (s, C10), 176.7 (s, C11, JPt-C 32), 138.5 (s, C21, JPt-C 42), 128.6 (d,
1
overlapping s + s, C23/C25 & C24), 125.5 (s, C22/C26), 98.5 [s, C5/C6(trans N), JPt-C 140], 96.0
[s, C1/C2(trans O), 1JPt-C 160], 56.9 [s, C9, 2JPt-C 15], 32.4 [s, C3/C8], 28.2 [s, C4/C7]. 13C NMR,
1
1
(excluding aromatic region) δ 184.4 (t, C10, JC-H 6), 176.7 (s, C11), 138.6 (t, C21, JC-H 7),
1
1
1
98.5 [d, C5/C6(trans N), JC-H 165], 96.0 [d, C1/C2(trans O), JC-H 166], 56.9 (t, C9, JC-H 140),
1
1
32.4 (t, C3/C8, JC-H 131), 28.2 (t, C4/C7, JC-H 132). Scheme 2 shows the atom numbering
scheme of the complex.
Synthesis of [Pt{N(COPh)CH2COO}(PPh3)2]·1.5.CH2Cl2 (1b·1.5CH2Cl2)
Complex 1b was prepared by a ligand substitution reaction. A mixture of triphenylphosphine
(51.8 mg, 0.197 mmol) and [Pt{N(COPh)CH2COO}(cod)] 1a (46.5 mg, 0.097 mmol) was
dissolved in dichloromethane (4 mL) and left to stand for 5 min., then filtered through a
cotton-plugged glass Pasteur pipette and washed through with a further 0.5 mL
dichloromethane. Petroleum spirits (25 mL) was added, giving white needle crystals on
standing overnight. Upon subsequent evaporation of around one third of the solvent, further
product formed which, following removal of the supernatant, was washed with petroleum
spirits (ca. 2 mL) and dried under vacuum for 3 h to give 95.7 mg (97%) of 1b·1.5CH2Cl2.
Found: C 54.3; H 4.0; N 1.4%. C45H37NPtO3P2·1.5CH2Cl2 requires C 54.5; H 4.0; N 1.4%.
17

M.p. 174-178 °C. IR: ν(C=O) 1647(vs) cm-1. ESI MS (added NaCl, capillary exit voltage
160 V): [M + Na]+ m/z 919.18 (100%), calculated for C45H37NO3P2PtNa m/z 919.18.
3
1H NMR, δ 7.81-6.75 (m, 35H, Ph), 5.32 (s, CH2Cl2), 4.16 (d, 2H, CH2, JPt-H 41).
1
2
1
2
31P{1H} NMR, δ 9.2 [d, PA(trans N), JPt-P 3058, JP-P 24], 4.8 [d, PB(trans O), JPt-P 4031, JP-P
23].
Synthesis of [Pt{N(COPh)CH2COO}(dppe)] 1c
Complex 1c was prepared by a ligand substitution reaction, following the same procedure as
for 1b, with a mixture of dppe (37.9 mg, 0.095 mmol) and [Pt{N(COPh)CH2COO}(cod)]
1a (44.4 mg, 0.092 mmol) in dichloromethane (4 mL) giving fluffy white crystals (41.1 mg,
57%) of 1c. Found: C 54.7; H 4.1; N 1.8%. C35H31NPtO3P2 requires C 54.6; H 4.1; N 1.8%.
M.p. 276-278 °C. IR ν(C=O) 1652(vs) cm-1. ESI MS (added NaCl, capillary exit voltage
160 V): [M + Na]+ m/z 793.13 (100%), calculated for C35H31NO3P2PtNa m/z 793.13.
3
1H NMR, δ 7.99-6.77 (m, 25H, Ph), 4.03 [d, 2H, CH2(hippurate), JPt-H 18], 2.39-
31
1
1.99 [m, 4H, CH2(dppe)]. P{1H} NMR, δ 37.4 [d, PA(trans N), JPt-P 3085, 2JP-P 12], 28.1 [d,
PB(trans O), 1JPt-P 3876, 2JP-P 12].
Synthesis of [Pt{N(COPh)CH2COO}(pta)2] 1d
A mixture of pta (28.9 mg, 0.184 mmol) and [Pt{N(COPh)CH2COO}(cod)] 1a (45.7 mg,
0.095 mmol) was dissolved in dichloromethane (4 mL) and left for 5 min., resulting in the
formation of fluffy white crystalline solid. Petroleum spirits (25 mL) was added and the
mixture allowed to stand overnight. Following removal of the supernatant, the product was
washed with petroleum spirits (ca. 2 mL) and dried under vacuum for 3 h to give 1d (58.5
18

mg, 90%). Found: C 35.9; H 4.8; N 13.7%. C21H21NPtO2 requires C 36.7; H 4.6; N 14.3%.
M.p. 250-265 °C (decomp.). IR ν(C=O) 1638(vs) cm-1. ESI MS (added NaCl, capillary exit
voltage 160 V): [M + Na]+ m/z 709.10 (100%), calculated for C21H31N7O3P2PtNa m/z
709.15.
1H NMR, δ 7.35-7.27 (m, 5H, Ph), 5.28 (s, CH2Cl2), 4.58-4.27 [m, 24H, CH2(pta)],
4.07 [d, 2H, CH2(hippurate), 3JPt-H 19]. 31P{1H} NMR, δ -67.0 [d, PA(trans N), 1JPt-P 2800, 2JP-P
22], -67.4 [d, PB(trans O), 1JPt-P 3484, 2JP-P 22].
Synthesis of [Pt{N(COPh)CH2COO}(dppf)] 1e
Complex 1e was prepared by a ligand substitution reaction, using a similar procedure to 1b.
A mixture of dppf (55.0 mg, 0.099 mmol) and [Pt{N(COPh)CH2COO}(cod)] 1a (46.0 mg,
0.096 mmol) was used in the same process as for 1b, however additional petroleum spirits
(10 mL) was added to further precipitate the product overnight. Reduction of volume by
one third followed by addition of extra petroleum spirits (ca. 1 mL) was repeated once
more. After removal of the supernatant, the yellow product was washed with petroleum
spirits (ca. 2 mL) and dried under vacuum for 3 h to give 1e (69.5 mg, 77%). Found: C
55.8; H 4.4; N 1.4%. C42H35NPtO3FeP2 requires C 55.7; H 3.8; N 1.5%. M.p. 204.5-210 °C
(decomp.). IR: ν(C=O) 1654(s) cm-1. ESI MS (added NaCl, capillary exit voltage 160 V):
[M + Na]+, m/z 949.10, calculated for C42H35NFeO3P2PtNa m/z = 949.10.
1H NMR (CDCl3), δ 7.91-6.58 (m, 20H, Ph), 5.00 (br s, 2H, C5H4), 4.46 (s, 2H,
3
31
C5H4), 4.18 (s, 2H, C5H4), 3.96 (d, 2H, H9a & H9b, JPt-H 20), 3.58 (d, 2H, C5H4). P{1H}
1
2
1
NMR (CDCl3), δ 9.44 [d, PA(trans N), JPt-P 3131, JP-P 22], 6.47 [d, PB(trans O), JPt-P 4102, 2JP-P
19

13
23]. C{1H} NMR (DMSO), δ 182.1 (d, C10), 171.6 (s, C11), 138.4-127.2 (m, Ph), 76.8 (s,
C5H4), 75.1 (d, C5H4), 74.8 (d, C5H4), 73.7 (d, C5H4), 56.5 (s, C9, 2JPt-C 47).
The atom numbering of 1e is shown in Scheme 5.
Synthesis of [Pd{OC(O)CH2N(COPh)}(bipy)] 2
A mixture of [PdCl2(bipy)] (210 mg, 0.63 mmol) with hippuric acid (113 mg, 0.63 mmol)
and silver(I) oxide (600 mg) in dichloromethane (30 mL) was refluxed for 3.5 h. Methanol
(30 mL) was added, and the mixture filtered to give a clear yellow solution. The solid
residue was extracted with an additional 40 mL of dichloromethane-methanol (1:1 v/v), and
the filtrates combined. The solution was evaporated to dryness, redissolved in
dichloromethane (40 mL) and the product precipitated by addition of petroleum spirits (40
mL). The solid was filtered, washed with petroleum spirits (10 mL) and dried under vacuum
to give 2 as an orange solid (192 mg, 69%). Found: C 50.2; H 3.45; N 9.1. C18H15N3O3Pd
requires C 50.5; H 3.5; N 9.8%.
1H NMR, δ 9.12-6.91 (m, bipy and Ph), 4.26 (s, CH2). ESI MS (added NaHCO2,
capillary exit voltage 140 V): [M + Na]+ m/z 461.88 (100%), calculated for
C19H15N3O3PdNa m/z 462.00.
Synthesis of [Pt{OC(O)C6H4NPh}(cod)] 3
Complex 3 was prepared using a similar procedure to the preparation of 1a. Silver(I) oxide
(1529.8 mg, excess) was added to a stirred mixture of [PtCl2(cod)] (500.4 mg, 1.337 mmol)
and N-phenylanthranilic acid (295.2 mg, 1.384 mmol) in dichloromethane (30 mL), and the
mixture was refluxed for 3.5 h giving a dark green-yellow suspension. After cooling to room
temperature the mixture was filtered twice through glass fibre filter paper to remove silver(I)
20

oxide, and the filter paper washed with dichloromethane (ca. 2 mL) each time. The resulting
brown-yellow solution was reduced in volume (rotary evaporator) to ca. 5 mL. Petroleum
spirits (ca. 95 mL) was added and the mixture allowed to crystallise overnight, giving green-
yellow crystals which were filtered, washed with petroleum spirits (5 mL) and dried under
vacuum overnight to give 3 (351 mg, 51%). Found: C 48.3; H 4.2; N 2.6%. C21H21NPtO2
requires C 49.0; H 4.1; N 2.7%. M.p. 155-157 °C (decomp.). IR ν(C=O) 1616(vs) cm-1.
ESI MS (capillary exit voltage 160 V) [M + H]+ m/z 515.17 (25%), calculated for
C21H21NO2PtH m/z 515.12.
2
1H NMR, δ 8.26-5.90 (m, 9H, H12-H15 & H22-H26), 5.42 (m, 2H, H5/H6, JPt-H 54),
2
4.42 (m, 2H, H1/H2, JPt-H 65), 2.70-2.56 (m, 4H, H3a, H4a, H7a & H8a), 2.27-2.11 [m, 4H,
H3b, H4b, H7b & H8b]. 13C{1H} NMR, δ 166.2 (s, C9), 153.1 (s, C11), 150.2 (s, C21), 133.9 (s,
C15), 131.5 (s, C13), 130.0 (s, C22/C26), 129.7 (s, C23/C25), 126.1 (s, C24), 116.4 (s, C14),
1
1
116.1 (s, C12), 114.7 (s, C10), 98.4 [s, C5/C6A(trans N), JPt-C 139], 93.7 [s, C1/C2B(trans O), JPt-C
198], 31.0 (s, C3/C8), 28.4 (s, C4/C7).
The atom numbering of the complex is shown in Scheme 4.
X-ray structure determination on [Pt{N(COPh)CH2COO}(cod)] 1a
Crystals were obtained by vapour diffusion of diethyl ether into a dichloromethane solution,
at room temperature. Data were acquired on a SuperNova, Single source at offset, Atlas
diffractometer using a colourless block crystal of dimensions 0.19 × 0.11 × 0.06 mm.
Empirical absorption corrections were made using spherical harmonics. Using Olex2 [44],
the structure was solved with the olex2.solve [45] structure solution program using Charge
Flipping and refined with the olex2.refine [45] refinement package using Gauss-Newton
minimisation. All non-hydrogen atoms were refined as anisotropic except for C(1), C(5) and
21

C(6), which are close to the platinum atom, and for which unrealistic ellipsoids were
obtained. All hydrogens were placed in calculated positions. Crystal data: C17H19NO3Pt; Mr
= 480.42 g mol-1; monoclinic; space group P21/n; a = 12.30576(8) Å; b = 9.41089(6) Å; c =
12.54508(7) Å; β = 94.5941(6)°, V = 1448.154(16) Å3; Z = 4; T = 100(1) K; λ(Cu-Kα) =
1.54178 Å; µ(Cu-Kα) = 18.236 mm-1; dcalc = 2.203 g cm-3; 27883 reflections collected; 2913
unique (Rint = 0.0480) giving R1 = 0.0243, wR2 = 0.0623 for data with [I>2σ(I)], and R1 =
0.0246, wR2 = 0.0627 for all data.
Theoretical calculations
Density functional theory (DFT) calculations were completed using Gaussian 09.[46] Unless
specified, all calculations were completed using the B3LYP functional and the 6-
311++G(2d,2p) basis set for all atoms excluding Pt, for which the LANL2DZ basis set and
effective core potential was used instead. Geometry optimisations were completed for all
structures. For those structures whose NMR shifts were calculated, geometry optimisations
were carried out using chloroform as the solvent (unless otherwise specified). NMR
chemical shifts were calculated using the GIAO approach with TMS as a reference. The
geometrical optimisation and NMR chemical shifts of 1e were calculated using DMSO as
the solvent.
Supplementary material
Crystallographic data for the structure described in this paper have been deposited
with the Cambridge Crystallographic Data Centre, CCDC No. 1465339. Copies of the data
can be obtained free of charge on application to The Director, CCDC, 12 Union Road,
22

Cambridge CB2 1EZ, UK (Fax: +44-1223-336033; e-mail deposit@ccdc.cam.ac.uk or
www: http://www.ccdc.cam.ac.uk).
Acknowledgements
We thank the University of Waikato for financial support of this work, Prof. Vickery
Arcus for generous diffractometer access, Professor Alistair Wilkins for helpful NMR
discussions, and Pat Gread and Wendy Jackson for technical assistance.
23

Table 1 Selected bond lengths (Å) and angles (̊) for [Pt{N(COPh)CH2COO}(cod)] 1a
Pt(1)-N(1)
Pt(1)-C(2)
Pt(1)-C(6)
C(5)-C(6)
C(9)-C(10)
C(10)-O(2)
C(11)-N(1)
2.014(3)
2.171(4)
2.187(4)
1.408(5)
1.521(4)
1.322(4)
1.360(5)
Pt(1)-C(1)
Pt(1)-C(5)
C(1)-C(2)
C(9)-N(1)
C(10)-O(1)
C(11)-O(3)
C(11)-C(21)
2.157(4)
2.181(4)
1.392(5)
1.469(5)
1.215(5)
1.232(5)
1.511(5)
O(2)-Pt(1)-N(1)
O(1)-C(10)-O(2)
O(2)-C(10)-C(9)
O(3)-C(11)-C(21)
C(11)-N(1)-C(9)
C(9)-N(1)-Pt(1)
81.81(11)
122.4(3)
116.0(3)
117.83)
N(1)-C(9)-C(10)
O(1)-C(10)-C(9)
O(3)-C(11)-N(1)
N(1)-C(11)-C(21)
C(11)-N(1)-Pt(1)
C(10)-O(2)-Pt(1)
111.0(3)
121.5(3)
123.8(3)
118.4(3)
127.3(3)
116.2(2)
120.0(3)
112.6(2)
24

Table 2 Summary of 1JPt-P NMR data for the phosphine-substituted hippurate complexes 1b-
1e
Complex
1JPt-P (Hz)
PPh3 trans N
PPh3 trans O
4031
1b
1c
1d
1e
3058
3085
2800
3131
3876
3484
4102
25

O
O
Cl
Cl
HN
HO
N
O
Ag2O, CH2Cl2
Pt
+
Pt
O
O
1a
2L or L2
CH2Cl2
O
1b
, L = PPh3
N
L
1c, L-L = Ph2PCH2CH2PPh2 (dppe)
Pt
1d
, L = PTA
1e, L-L = Fe(η5-C5H4PPh2)
L
O
O
Scheme 1 Synthesis of the platinum(II) hippurate complexes 1a – 1e
26

Scheme 2 The atom numbering scheme of [Pt{N(COPh)CH2COO}(cod)] 1a.
27

Scheme
3
Synthesis
of
the
platinum(II)
N-phenylanthranilate
complex
[Pt{OC(O)C6H4NPh}(cod)] 3
28

Scheme 4 The atom numbering scheme of the N-phenylanthranilate complex
[Pt{OC(O)C6H4NPh}(cod)] 3
29