Polyhedron 27 (2008) 35673574

Contents lists available at ScienceDirect

Polyhedron
journal homepage: www.elsevier.com/locate/poly

Structural aspects of the anti-cancer drug oxaliplatin: A combined theoretical and

experimental study
Prateek Tyagi, Pragya Gahlot, Rita Kakkar *
Department of Chemistry, University of Delhi, Delhi 110 007, India

a r t i c l e

i n f o

Article history:
Received 10 June 2008
Accepted 26 August 2008
Available online 10 October 2008
Keywords:
Oxaliplatin
DFT
FT-IR
Anti-cancer
Conformation

a b s t r a c t
The conformational behavior of the third generation antitumor drug, oxaliplatin, has been explored by
GGA-PW91 density functional calculations and FT-IR spectra. The difference in the biological activities
of cisplatin and oxaliplatin are attributed to the presence of the DACH ligand in the latter. The trans forms
of the ligand are found to be more stable than the cis form, but, of the two equally stable enantiomers, the
trans-l (1R,2R) one is found to be more potent biologically. Since very minor differences are observed in
the electronic structures of the two enantiomers, their difference in activity is attributed to the chiral recognition of the ligand by DNA. The calculated vibrational frequencies are in good agreement with our
experimental FT-IR spectrum. Calculations have also been performed on the cis isomer and its monohydrate. Comparison between the theoretically predicted geometries and the experimental ones yielded
good correspondence, validating our methodology.
2008 Elsevier Ltd. All rights reserved.

1. Introduction
Since the accidental discovery of the biological activity of the
platinum complex, cisplatin, in 1965 by Rosenberg [1], a large
number of platinum complexes have been synthesized for improved pharmacological properties. However, only a few of these
compounds have entered clinical trials and very few have been approved for cancer therapy.
Although cisplatin (cis-dichlorodiammineplatinum(II)), [cis(NH3)2PtCl2]), has found widespread use as an antitumor drug in
the past 40 years [2,3], it has many drawbacks associated with
its use, the main being drug resistance. Moreover, it is ineffective
for some cancers, and has major toxic limitations, of which nephrotoxicity is the most notable. Nausea and vomiting, peripheral
neuropathy, and cytotoxicity are also some of the major side effects of this drug [46]. And so the quest began for cisplatin analogues that are more potent and effective against a larger range
of tumors, are less toxic, have fewer side effects, and are not subject to drug resistance. Structureactivity relationships (SAR) led
to the following general rules [7,8]:
(1) The general formulae should be cis-Pt(II)X2(N)2 and cis-Pt
(IV)Y2X2(N)2 (where N: amine ligand, X: leaving group, Y:
axial group). For the Pt(IV) compounds, the two Y ligands
should be in trans orientation.

* Corresponding author. Tel.: +91 1127666313.

E-mail addresses: rkakkar@chemistry.du.ac.in, rita_kakkar@vsnl.com (R. Kakkar).
0277-5387/$ - see front matter 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.poly.2008.08.025

(2) The leaving ligands, usually anions, should consist of groups

that have intermediate binding strength to Pt(II). Examples
of good leaving groups are Cl , SO4 2 , citrate, oxalate and
other carboxylic acid residues.
(3) The amine ligands, either monodentate or bidentate, should
have at least one NH group.

However, in recent years, a few unconventional platinum drugs,

whose mechanism of action is different from that of cisplatin, have
emerged [9]. The SAR strategy has led to the second generation
cisplatin analogue, carboplatin, cis-diammine(cyclobutane-1,1dicarboxylato)platinum(II). Carboplatin, which was approved by
the FDA for the treatment of ovarian cancers in 1989, is less toxic
than the rst generation antitumor drug, cisplatin. However, it
is effective against the same range of tumors as cisplatin.
Of the third generation platinum analogues, compounds containing a 1,2-diaminocyclohexane (DACH) carrier ligand [10], such
as
oxaliplatin
[(1R,2R)-diaminocyclohexane(ethanedioateO,O)platinum(II)] [1013], have consistently demonstrated antitumor activity in cell lines with acquired cisplatin resistance and appear to be active in tumor types that are intrinsically resistant to
cisplatin and carboplatin [1217].
In the present work, we have focused on oxaliplatin. The nonhydrolyzable 1,2-trans-R,R-diaminocyclohexane (DACH) ligand
makes the complex less polar, which contributes to better cell uptake [18]. The different antitumor and other biological effects of
oxaliplatin in comparison with those of conventional cisplatin
are often explained by the ability of oxaliplatin to form DNA adducts of different conformation and consequently to exhibit differ-

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P. Tyagi et al. / Polyhedron 27 (2008) 35673574

ent cytotoxic effects. Although differences between oxaliplatin and

cisplatin in DNA binding, adduct formation, strand breaks, and
apoptosis have been reported, the mechanisms behind the more
potent cytotoxic activity of oxaliplatin compared with cisplatin
against colon cancer cells have not yet been completely elucidated.
On the theoretical front, the interaction of cisplatin with water
has been studied by various authors [1935]. However, to our
knowledge, no such studies have been reported for the third generation platinum drug, oxaliplatin (eloxatin). In view of the biological importance of this compound, we have carried out a
systematic study of the structural properties of oxaliplatin and
its various conformational forms. After comparing the relative
energies of various conformers, we identied the most stable
one. To check the accuracy of the methods used, the results of
our density functional (DF) calculations were also compared with
the experimental results, wherever possible. In addition, the experimental FT-IR spectrum was determined for the more potent isomer and compared with the theoretically predicted values.
2. Methods
2.1. Computational details
First-principles density functional (DF) calculations were performed on the various conformers of oxaliplatin using the DMol3
code [3639] available from Accelrys Inc. in the MATERIALS STUDIO 3.2
package. Our calculations employed numerical basis sets of double-f quality plus polarization functions (DNP) to describe the
valence orbitals. This is the numerical equivalent of the Gaussian
6-31G** basis set. The core electrons were treated using DFT semilocal pseudopotentials (DSSP) [40]. These core potentials include
some degree of relativistic effects and are thus very useful approximations for heavier elements, and, furthermore, the calculation is
less computationally expensive since the core electrons are
dropped. Details of the calculations are described elsewhere [41].
Geometry optimizations, without restrictions, were performed
using delocalized internal coordinates. The exchange-correlation
contribution to the total electronic energy was treated in a spinpolarized generalized-gradient corrected (GGA) form with the Perdew-Wang-91 correlation (PW91). Density functional calculations
at the GGA level are expected to give good prediction for the bond
lengths and bonding energies. We chose PW91 for our study because the Perdew-Wang density functional is superior to other
DFT methods for the simultaneous prediction of both molecular
geometries and vibrational frequencies of platinum(II) complexes
[42]. The vibrational frequencies were calculated and these were
used to calculate the zero-point corrections to the energies and
to conrm that the structures are minima on the potential energy
surface, i.e. all the vibrational frequencies are real. Free valences
and bond orders were calculated using Mayers procedure [43].
2.2. Experimental details
Oxaliplatin was purchased from the Sigma Chemical Company
and used as such without further purication. The FT-IR spectrum
(4000400 cm 1) was recorded on a Perkin Elmer FT-IR Spectrometer Spectrum 2000. High quality KBr was used as the dispersal
medium.

cisplatin. Besides imparting lipophilic character to the complex,

DACH is expected to display a wide range of possible conformers
because of the presence of the cyclohexane ring. Investigations
on this type of chiral complexes showed that the trans isomer
trans-l (trans-( )-1R,2R) is more efcacious than the corresponding
trans-d (trans-(+)-1S,2S) and the cis-isomer (1R,2S) [17]. Thus, the
activity might be explained by speculating on the stereochemical
structures of the complexes.
The cyclohexane ring of DACH can have various conformations,
such as chair, boat or twist boat. The chair form, expected to be the
most stable one, is the obvious choice for the study, but the twist
boat form has also been reported to exist [44], and is higher in energy than the other possible conformers in which the cyclohexane
moiety is in the chair form.
The ligand DACH has two amino groups attached to two adjacent carbons. Each amino group may be attached at either the axial
or equatorial position. The chair form of DACH may exist in three
conformers:
(i). cis-Cyclohexyl-1,2-diamine [cis-(1R,2S)], in which one amine
group is axial (a) and the other is equatorial (e).
(ii). trans-d-Cyclohexyl-1,2-diamine [trans-d (1S,2S)], in which
both the amine groups are in equatorial position, and
(iii). trans-l-Cyclohexyl-1,2-diamine [trans-l (1R,2R)], in which
both the amine groups are in equatorial position.
The (ii) and (iii) forms are optical isomers of each other.
In addition to these three isomers, we have also incorporated
another form, in which the cyclohexane ring is in a twist boat conformation, in our studies.
3.2. Relative energies
In oxaliplatin, platinum is bound on one side to the two amine
nitrogens of the large 1,2-diaminocyclohexane (DACH) ligand and
to the other side by two oxalate oxygens in a chelating fashion
(see Fig. 1). Taking the various conformers of the cyclohexane ring
in turn, the energies of the complexes were determined, and the
relative energies are listed in Table 1.
As expected, the diaxial conformation of DACH is not preferred
in the complex (relative energy = 36.9 kcal/mol), and the equilibria
between the diaxial and diequatorial conformations for the trans
isomers favor the latter. This is due to the increased steric hindrance of axial locations. The relative energy of 6.6 kcal/mol obtained for the twist boat form proves theoretically the possibility
of existence of the complex with DACH in the twist boat form at
higher temperatures. No such complex has been experimentally
reported as yet.
Both the trans forms are most stable. However, a close inspection of the relative energy values for trans-(S,S), trans-(R,R) and
cis-(R,S) isomers reveals that they all co-exist at room temperature,
as the energy difference between them is signicantly less than
5 kcal/mol. Of these, trans-d (S,S) and trans-l (R,R) deserve special
mention as they are optical isomers and the energy difference

3. Results and discussion

3.1. Conformers of DACH
The spectator ligand DACH plays an important role in determining the higher biological activity of oxaliplatin compared to

Fig. 1. Chemical structures of oxaliplatin and cisplatin.

P. Tyagi et al. / Polyhedron 27 (2008) 35673574

3569

Table 1
DFT relative energies (kcal/mol) of the various isomers of oxaliplatin
DACH conformation

Relative energy

trans ee (S,S)
trans ee (R,R)
cis ae (R,S)
Twist boat form

0.0a
0.3
1.1
6.6

ZPVE corrected energy:

576828.2 kcal/mol.

between them is negligibly small. On the basis of these calculations, we expect both isomers to have almost an equal population
at room temperature.
Our expectations are borne out by the experimental results. In
an effort to solve the structure of the active species of oxaliplatin,
an X-ray structural investigation was carried out on oxaliplatin
[45]. The complex was prepared by reacting the enantiomerically
pure isomer trans-l (trans-( )-1R,2R-diaminocyclohexane (DACH))
and the platinum salt K2[PtCl4] in H2O. They found that the oxaliplatin which was isolated does not consist only of the desired
isomer, but a mixture of both the trans-l and trans-d isomers.
No retention of optical isomerism was observed despite the fact
that the enantiomerically pure DACH ligand was utilized,
although it had been earlier reported [46] that only the absolute
conguration of the trans-l-DACH ligand exists in the platinum
complex.
The Pt complexes of the three isomers [cis-(R,S), trans-l (R,R)
and trans-d (S,S)] interact differently with DNA. It has been shown
that the trans-l (R,R) isomer of oxaliplatin is the most effective
against cisplatin-sensitive and cisplatin-resistant cancer cell lines
[17].
Proteins that discriminate between cisplatinDNA adducts and
oxaliplatin-DNA adducts are thought to be responsible for the differences in tumor range, toxicity, and mutagenicity of these two
important chemotherapeutic agents. However, the structural basis
for differential protein recognition of these adducts has not been
determined and could be important for the design of more effective
platinum anti-cancer agents. Recently, a lot of work has been devoted to understanding the differences between cisplatin and oxaliplatin binding to DNA [4750]. Several signicant conformational
differences were observed between the cisplatinGG adduct and
the oxaliplatinGG adduct [49,50]. It has also been demonstrated
[51,52] that the chirality at the carrier ligand of oxaliplatin can affect its biological effects.
Thus, the stereochemistry of the carrier amine ligands of cisplatin analogues can modulate their anti-cancer and mutagenic
properties. The signicance of this nding is also reinforced by
the fact that, in general, interstrand cross-links formed by various
compounds of biological signicance result in greater cytotoxicity
than is expected for monofunctional adducts or other intrastrand
DNA lesions [53]. Therefore, the unique properties of the interstrand cross-links of oxaliplatin are at least partly responsible for
this drugs unique antitumor effects.
3.3. Optimized geometries
Geometry optimizations were performed on all possible conformers. The isomers differ in the orientations related to the cyclohexane ring of the DACH ligand. As far as the coordination sphere is
concerned, all the isomers exist in the square planar geometry. This
is expected, as Pt(II) compounds show stability in this form only
[54]. The oxalate group is not only planar in itself but also in plane
with the coordination sphere. All the optimized structures are
shown in Fig. 2.
The calculated bond lengths and bond angles for the trans-l
(trans-( )-1R,2R) isomer are listed in Table 2 along with the corre-

Fig. 2. Structures of four oxaliplatin isomers. Colour code: H-white, C-grey, N-blue,
O-red, and Pt-Prussian blue. (For interpretation of the references to colour in this
gure legend, the reader is referred to the web version of this article.)

sponding experimental data [46] obtained from single crystal Xray analysis of oxaliplatin. The numbering scheme used in these
optimized structures is displayed below (Scheme 1):

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P. Tyagi et al. / Polyhedron 27 (2008) 35673574

Table 2
Optimized geometry of the trans-R,R form (bond lengths in ngstroms; bond angles in degrees)
Parametersa

Calculated

Experimentalb

Parametersa

Calculated

Experimentalb

N1Pt
N2Pt
O1Pt
O2Pt
N1C1
N2C2
O1C7
O2C8
C7C8
C7O3
C8O4
C1C2
C1C6
C2C3
C6C5
C3C4
C5C4
O2PtO1
N1PtO1
N2PtO1
N1PtO2
N2PtO2

2.10
2.11
2.01
2.01
1.49
1.49
1.34
1.34
1.56
1.22
1.22
1.54
1.53
1.53
1.53
1.53
1.53
84.2
96.8
179.1
178.2
96.6

2.06
2.04
2.01
2.04
1.54
1.54
1.21
1.32
1.56
1.29
1.19
1.49
1.57
1.51
1.61
1.50
1.53
82.5
96.0
175.6
169.7
98.6

N2PtN1
C7O1Pt
C8O2Pt
C8C7O1
O3C7O1
O3C7C8
C7C8O2
O4C8O2
O4C8C7
C1N1Pt
C2N2Pt
C2C1N1
C6C1N1
C6C1C2
C1C2N2
C3C2N2
C3C2C1
C5C6C1
C4C3C2
C4C5C6
C5C4C3

82.4
112.6
112.7
115.4
122.5
122.2
122.1
122.7
122.1
108.6
109.3
108.1
113.9
111.4
108.2
113.7
111.4
111.0
111.1
111.3
111.3

83.8
112.0
141.0
122.0
124.0
114.0
110.0
124.0
125.0
107.0
106.0
107.0
105.0
111.0
103.0
113.0
111.0
106.0
111.0
112.0
111.0

a
b

See Scheme 1 for numbering.

From Ref. [46].

C5
C4

C3

C1

C6
C2

O1

Pt
N
H2

conformer has been found to be the most potent [17]. Thus we consider only the two trans-forms for further studies.

NH2

O2

C7

O3

C8

3.4. Charge population analysis

H1
O5

O4 H2
Scheme 1. Structure and numbering scheme of [Pt(C2O4)(DACH)]
H2O.

Although the computed gas phase free structure cannot be compared with the X-ray structure for the solid state, in the absence of
any other available data we compared the structural parameters of
the trans-(R,R) form with the X-ray crystallographic data. It is
found that the DFT results are in good agreement with experiment
(Table 2).
The optimized geometries of all the investigated isomers are
compared in Table 3. Our earlier hypothesis that the difference between the isomers is limited to the DACH ligand area only has been
proved by a comparison of the geometric parameters of the isomers (Table 3). All the isomers have very close values as far as
the oxalate ligand parameters are concerned, since the calculated
O1Pt, O2Pt, C7C8, O1C7 and O2C8 bond lengths have very little
difference among all the isomers. In a similar fashion, all the CC
bond lengths, except C1C2, which is slightly higher for the cis isomer, have quite similar values.
The two amino groups are bound to platinum in a way to form a
distorted square planar geometry of the coordinate sphere, and the
PtN bond lengths are 2.1 in all the complexes. Except in the
trans-(+)-S,S isomer, there is considerable difference in the N1-Pt
and N2-Pt bond lengths, but the O1Pt and O2Pt bond lengths
are similar. The \NPtO bond angles are much larger than the
\NPtN and \OPtO bond angles.
Hence we conclude that all the chair forms have almost equal
thermal stability, and are much more stable than the twist boat
conformer. Of the three stable chair forms, the trans-(R,R)

Table 4 presents the calculated Hirshfeld [55,56] and Mulliken

partial atomic charges on the various atoms in the free ligands,
DACH and oxalate anion, and the two trans complexes of Pt(II).
The Hirshfeld charges are considered to give a better description
of the charge distribution than the Mulliken charges, which show
a large dependence on the basis set.
The charge of the metal ion in the free state is +2.0. It is seen
that the positive charge of the metal ion decreases in the complex
to +0.18, which indicates that transfer of electrons from the ligands
to the metal ion has occurred and the coordination bonds have
formed. To see how the charge transfer occurs, we compared the
values of partial atomic charges on the free ligand with that of
the Pt(II) complex (oxaliplatin), in which the charge transfer takes
place.
Although there is no change in the charge density on the carbon
atoms of DACH on complexation, a decrease of 0.13 e in the charge
density on each of the two nitrogens indicates that transfer of electron density to the metal ion occurs through these coordinated
atoms.
The observation from the Mulliken charges is quite the opposite, i.e. an appreciable increase (0.1) in the negative charge on
each of the C3, C4, C5 and C6 carbon atoms of DACH, and practically
no change on the nitrogen atoms.
A decrease (0.3) in negative charge on each of the oxygens of
oxalate shows that a considerable amount of charge is transferred
from these four oxygens to the metal ion. Simultaneously, an increase of about 0.1 in the positive charges of C7 and C8 is also
noted. These observations indicate contribution of the whole of
the ligand in the charge transfer from the oxalate ion to the metal
ion.
A noteworthy point is the similarity in the charge distributions
of all the isomers, signifying that electronic differences are not the
reason for the differences in their reactivity.
According to Pearsons HSAB concept, Pt2+ is a soft acid and O2
is a soft base, while NH3 is a hard base. This indicates that there

3571

P. Tyagi et al. / Polyhedron 27 (2008) 35673574

Table 3
Optimized geometry of different conformers (bond lengths in ngstroms; bond angles in degrees)
Parametera

trans-( )-R,R

N1Pt
N2Pt
O1Pt
O2Pt
N1C1
N2C2
O1C7
O2C8
C7C8
C7-O3
C8O4
C1C2
N2PtN1
O2PtO1
N1PtO1
N2PtO2
N1PtO2
N2PtO1
O3H1
O4H2
a
b

trans-(+)-S,S

2.103
2.109
2.009
2.008
1.493
1.493
1.336
1.335
1.555
1.217
1.218
1.535
82.4
84.2
96.8
96.6
178.2
179.1

cis-R,S

2.100
2.101
2.007
2.009
1.493
1.494
1.336
1.335
1.556
1.217
1.218
1.537
82.6
84.2
96.3
96.9
179.4
178.5

2.097
2.100
2.009
2.009
1.497
1.497
1.335
1.335
1.557
1.218
1.217
1.542
82.5
84.2
96.6
96.7
179.1
178.7

cis-R,S
H2O

Twist boat
b

Calculated

Experimental

2.094
2.092
2.012
2.012
1.498
1.500
1.329
1.329
1.555
1.221
1.221
1.540
82.6
84.2
96.6
96.6
179.0
179.1
2.149
2.140

2.011
2.028
2.021
2.033
1.500
1.506
1.302
1.282
1.563
1.206
1.228
1.530
83.8
82.8
95.5
98.0
177.4
178.9

2.097
2.100
2.010
2.011
1.495
1.495
1.334
1.335
1.557
1.218
1.217
1.534
82.3
84.1
96.1
97.5
179.6
178.3

See Scheme 1 for the numbering of atoms.

From Ref. [57].

Table 4
The calculated Hirshfeld partial charges (Mulliken charges are in parentheses) of the optimized complexes and the ligands (DACH and oxalate ion)
Atom*
C1
C2
C3
C4
C5
C6
N1
N2
C7
C8
O1
O2
O3
O4
Pt
H1
H2
O5
*

Free DACH
0.03
0.03
0.06
0.05
0.05
0.06
0.22
0.22

Free oxalate

(0.09)
(0.09)
( 0.07)
( 0.06)
( 0.06)
( 0.07)
( 0.39)
( 0.39)
0.05
0.05
0.53
0.53
0.53
0.53

(0.36)
(0.36)
( 0.68)
( 0.68)
( 0.68)
( 0.68)

trans- (R,R)
0.03
0.03
0.06
0.05
0.05
0.06
0.09
0.09
0.13
0.13
0.25
0.25
0.27
0.27
0.18

trans- (S,S)

(0.05)
(0.05)
( 0.17)
( 0.17)
( 0.17)
( 0.17)
( 0.38)
( 0.38)
(0.45)
(0.45)
( 0.51)
( 0.51)
( 0.39)
( 0.39)
(0.22)

0.03
0.03
0.06
0.05
0.05
0.06
0.09
0.09
0.13
0.13
0.25
0.25
0.27
0.27
0.18

(0.05)
(0.05)
( 0.17)
( 0.17)
( 0.17)
( 0.17)
( 0.38)
( 0.38)
(0.45)
(0.45)
( 0.51)
( 0.51)
( 0.39)
( 0.39)
(0.22)

cis-(R,S)
0.03
0.03
0.06
0.05
0.05
0.06
0.09
0.09
0.13
0.13
0.25
0.25
0.27
0.27
0.18

(0.03)
(0.04)
( 0.17)
( 0.18)
( 0.17)
( 0.18)
( 0.37)
( 0.39)
(0.45)
(0.45)
( 0.51)
( 0.51)
( 0.39)
( 0.39)
(0.22)

cis- (R,S)
H2O

0.03
0.03
0.06
0.05
0.05
0.06
0.09
0.09
0.14
0.14
0.25
0.25
0.24
0.24
0.20
0.11
0.10
0.35

(0.03)
(0.04)
( 0.17)
( 0.18)
( 0.17)
( 0.18)
( 0.37)
( 0.39)
(0.46)
(0.46)
( 0.51)
( 0.51)
( 0.41)
( 0.42)
(0.23)
(0.28)
(0.28)
( 0.58)

See Scheme 1 for the numbering of atoms.

should be stronger interaction between Pt2+ and O2 than between

Pt2+ and the NH2 groups of DACH. Our calculations are in accord
with this principle, as there is a transfer of only 0.6 e from DACH
to Pt while 1.2 e is transferred by oxalate. This shows that a total
charge of 1.8 e is transferred to Pt(II) during the complexation,
and the net charge on Pt(II) reduces to 0.2 e. The electronic conguration
of
platinum
in
the
complex
is:
[core]
5s26s0.925p5.996p0.355d8.53. This shows that, out of the total charge
density donated by the ligands to Pt2+, approximately one electron
goes to the 6s orbital, and approximately one-half to 5d, and the
rest of the electron density is gained by the 6p orbital.
3.5. Bond order analysis
We calculated the Mayer bond orders for all the bonds of the
complex and the results are produced in Table 5.
Table 5 shows that there is practically no difference in the
bonding pattern of the two complexes. The NPt and OPt bond orders are around 0.6 and 0.7, respectively, which indicates covalent

character in the bonds. Reduction in the bond order of O1C7 and

O2C8 from 1.6 to 1.15 shows that charge has been carried away
from these bonds. The C7O3 and C8O4 bonds regain their double
bond character which was lost in the free oxalate ion due to resonance. However, there is a slight increase in the C7C8 bond order
of the oxalate group. The NC and CC bond orders of the DACH ligand decrease due to electron density transfer from these bonds.
We also examined the ligand orbitals in free DACH, oxalate ion
and complex. Fig. 3a gives a plot of the highest occupied molecular
orbital (HOMO) of DACH. This orbital has an energy of 4.71 eV. It
is clear that the HOMO is centered on the nitrogens, which being
thus electron rich, can donate charge density to the vacant metal
ion orbital.
Fig. 3b gives the plot of the HOMO of the oxalate ion. In oxalate,
as expected, the HOMO comprises the four oxygen atoms equally.
The energy of this orbital is 6.26 eV.
Fig. 3c shows the plot of the HOMO of oxaliplatin. It can be seen
from the plot of the HOMO of the complex that not only are the
oxalate ligand orbitals retained, but the metal d orbitals also

3572

P. Tyagi et al. / Polyhedron 27 (2008) 35673574

Table 5
Calculated Mayer bond orders for DACH, oxalate ion and the isomers of oxaliplatin
Bond*
N1Pt
N2Pt
O1Pt
O2Pt
N1C1
N2C2
C1C2
O1C7
O2C8
C7O3
C8O4
C7C8
O3


H1
O4


H2
*

Free DACH

Free oxalate

trans- (R,R)

trans- (S,S)

cis- (R,S)

cis- (R,S)
H2O

1.61
1.61
1.61
1.61
0.90

0.61
0.61
0.70
0.70
0.89
0.89
0.95
1.15
1.15
1.90
1.90
0.93

0.61
0.61
0.69
0.70
0.89
0.89
0.95
1.15
1.15
1.90
1.90
0.93

0.62
0.62
0.69
0.69
0.91
0.88
0.96
1.15
1.15
1.90
1.90
0.93

0.63
0.63
0.68
0.68
0.90
0.88
0.96
1.18
1.17
1.85
1.85
0.93
0.04
0.04

1.01
1.01
0.97

See Scheme 1 for the numbering of atoms.

and the corresponding computed infrared absorption spectrum

are given as Supplementary data. The spectra have a very complicated pattern, as each band corresponds to mixed vibrations.

Fig. 3. Plot of HOMOs of (a) 1,2-diaminocyclohexane (DACH), (b) oxalate, (c) Pt(II)
complex (oxaliplatin).

become part of the HOMO for the square planar Pt(II) complex,
showing an interaction between oxalate and Pt(II) orbitals. The energy of the HOMO of the Pt(II) complex is 4.68 eV. It is interesting
to note that the HOMO of the other ligand (DACH) is not a part of
the HOMO of the complex. This can be explained quite conveniently by comparing the energies of the HOMOs of the two ligands. Oxalate ion, being negatively charged, has a high energy
HOMO, which can contribute electron density to Pt2+, forming
the complex whose HOMO lies above the HOMO of DACH.
3.6. Vibrational analysis
The FT-IR spectrum of oxaliplatin was recorded in the range
4004000 cm 1. The detailed list of calculated frequencies and
the corresponding intensities, as well as the experimental FT-IR

3.6.1. PtLigand Vibrations

The platinumligand vibrations are expected to occur in a very
low frequency range (below 600 cm 1). In the process of assigning
the frequencies obtained from the theoretical IR spectra, we found
that the band at 551 cm 1 corresponds to the symmetric stretching
vibration, ms(PtN). Calculations have also revealed that the frequency of the asymmetric PtN stretching vibration ma(PtN),
which is at 559 cm 1, is very close to ms(PtN). It is clear that both
the symmetric and asymmetric PtN stretching vibrations in oxaliplatin contribute to a strong band observed in the experimental
FT-IR spectrum at 573 cm 1. The frequency of PtN stretching in
oxaliplatin is higher in comparison to that in carboplatin and cisplatin. In the FT-Raman spectrum of cisplatin, the strongest band
observed at 522 cm 1 and weaker band at 506 cm 1 were assigned
to the symmetric and asymmetric PtN stretching vibrations [57],
respectively. However in the FT-IR spectrum of carboplatin, the
strong band at 545 cm 1 and a weak band at 548 cm 1 were assigned to the symmetric and asymmetric PtN stretching vibrations [58].
The theoretical results consistently indicate that the strong
band at 780 cm 1 should be assigned to the asymmetric PtO
stretching and the band at 854 cm 1 to the symmetric PtO
stretching, coupled with the symmetric stretching of the CC bond
of the oxalate group. Similarly the very strong band at 808 cm 1 in
the experimental FT-IR spectrum is assigned to the symmetric Pt
O stretching. The medium intensity band at 306 cm 1 in the calculated theoretical spectra is assigned to OPtO bending. The band
in the range of 50173 cm 1 in the theoretically predicted IR spectrum is assigned to the NPtO bending. Similarly the band at
195 cm 1 is assigned to the NPtN bending. Comparison of the
experimental and theoretical spectra has revealed that both the
positions and intensities of the bands are well predicted by the
PW-91 method.
3.6.2. Oxalate group vibrations
In the calculated theoretical spectrum, the very weak band at
339 cm 1 is assigned to the OC@O in-plane bending. A strong
band at 433 cm 1 is assigned to the OC@O out-of-plane bending.
The strong band at 1142 cm 1 in the calculated theoretical spectrum is assigned to the asymmetric CO stretching. However, very
strong bands at 1282 cm 1 and 1284 cm 1 are assigned to the PtO
symmetric stretching, coupled with the CC stretching. The band
for CO stretching in the experimental FT-IR occurs at 1226 cm 1.

P. Tyagi et al. / Polyhedron 27 (2008) 35673574

In the region 15501700 cm 1, the m(C@O) stretching vibrations

and the NH2 degenerate deformations, dd(NH2) are expected to occur. In the FT-IR spectrum of oxaliplatin, two closely lying strong
bands at 1662 and 1700 cm 1 are undoubtedly due to the C@O
stretching vibrations; however, in the theoretical spectrum the
bands at 1723 and 1741 cm 1 are assigned to the C@O stretching
vibrations.
3.6.3. DACH group vibrations
The diaminocyclohexane ring vibrations are further discussed
in two subsections:
3.6.3.1. Cyclohexane ring vibrations. In the calculated FT-IR spectrum of oxaliplatin, the strong band at 1039 cm 1 is assigned to
the CN stretching vibrations; similarly, in the theoretical spectrum the very strong band at 1012 cm 1 is assigned to the CN
stretching. In the theoretically calculated spectrum the bands at
10261062 cm 1 are assigned to the characteristic m(CC) stretching of the cyclohexane ring, similarly the strong band at 1106 cm 1
corresponds to the symmetric stretching of the CC bond of the
two carbons attached to nitrogens.
The scissoring vibrations of the methylene group in oxaliplatin
are assigned to the bands observed at 1444 and 1456 cm 1 in the
calculated theoretical spectrum. Similar results are recorded for
the theoretical spectrum of carboplatin in which the scissoring
vibrations of methylene group were observed at 1436 and
1463 cm 1 [58]. The band in the range of 29543058 cm 1 is assigned to the CH stretching vibration in the calculated theoretical
spectrum; similar bands at 2928 and 3085 cm 1 appear in the
experimental FT-IR spectrum.
3.6.3.2. Amino group vibrations. The strong band at 3085, 3158 and
3212 cm 1 in the experimental FT-IR spectrum and the bands in
the range of 33643460 cm 1 in the calculated theoretical spectrum are assigned to the NH stretching vibrations of the amino
groups of oxaliplatin.
The degenerate deformation vibration of ammonia gives a
strong band at 1610 cm 1 in the FT-IR spectrum; similarly, we
get two strong bands at 1609 and 1620 cm 1 which correspond
to wagging of NH2. The symmetric deformation vibrations of NH2
are coupled with the degenerate deformation mode (twisting and
wagging vibrations) of the methylene group and generate the medium intensity bands at 1444 and 1456 cm 1 in the calculated theoretical spectrum. However, in the experimental FT-IR spectrum,
these vibrations give a very strong band at 1377 cm 1. No peak
corresponding to NH2 rocking vibrations is found in the FT-IR spectrum since, as shown by theoretical calculations, NH2 rocking
vibrations give rise to the bands at 659 and 697 cm 1 of negligible
intensity.
3.7. Oxaliplatin monohydrate
Al-Allaf et al. [59] synthesized crystals of oxaliplatin for X-ray
determination. It was found that, although the complex was prepared starting from the enantiomerically pure isomer trans-l
(1R,2R) as conrmed by X-ray analysis [45], it does not consist of
the desired (1R,2R) isomer, but rather the (1R,2S) isomer. This
encouraged them to prepare the platinum complex of the cis isomer of the DACH ligand in order to study its behavior from the
X-ray point of view and to compare the results with those of the
isomeric complex [Pt(C2O4){(1R,2R)-DACH}] reported previously
[46]. It was seen that the [Pt(C2O4)(cis-DACH)] complex crystallizes
with one molecule of water as [Pt(C2O4)(cis-DACH)]
H2O in wellshaped colorless crystals.
The water molecule is reported to be placed at the oxalate end,
in plane with the oxalate group and oriented to have two H-bonds

3573

with the two non-bound oxygens of the oxalate ligand [59]. We

therefore restricted our studies to this position of the water molecule. The hydrated molecule thus has following structure:
3.7.1. Optimized geometries
The optimized geometry of cis-(R,S) was taken as calculated earlier. The water molecule is placed in such a way that the two
hydrogen of the water molecule are in close contact with the
two carbonyl oxygens of the oxalate ring, as has been previously
reported [59], and geometry optimization was performed on the
resulting structure. The numbering scheme and the optimized
structure of [Pt(C2O4)(cis-DACH)]
H2O are shown in Figs. 2 and 4.
The calculated bond lengths and bond angles for the [Pt(C2O4)
(cis-DACH)]
H2O isomer are listed in Table 3, together with the
corresponding experimental data obtained from single crystal
X-ray analysis of [Pt(C2O4)(cis-DACH)]
H2O [59] to check the
accuracy of our calculation.
It is found that the DFT results are in good agreement with the
experimental data within the error range, considering that the former are obtained for the gas phase and the latter are for the solid
state.
To gauge the effect of hydrogen bonding on the geometry and
stabilization of the complex we compared the geometric parameters of the hydrated complex with the anhydrous complex. It is
found that there is no major change in the geometric parameters
of DACH in the hydrated and anhydrous [Pt(C2O4)(cis-DACH)]
forms of the complex.
A slight change is noted in the geometric parameters of the
coordination sphere. In the hydrated form, the equatorial NPt
bond is shorter by 0.003 , while for the axial NPt bond this
change is 0.008 . The OPt bond gets elongated by 0.003 . No
change is noted in the equatorial N1C1 bond, but the equatorial
N2C2 bond increases by 0.003 .
The effect on the bond lengths of the oxalate ring in the hydrated form is found to be larger, as expected. The O1C7 and
O2C8 bond lengths decrease by 0.006 , while an increase in bond
length by 0.004 is noted in case of the C7O3 and C8O4 bonds.
The distance of 2.1 between the carbonyl oxygen of the oxalate
group and the hydrogens of water, indicates hydrogen bonding between the two, as this is much smaller than the sum of the van der
Waals radii of oxygen and hydrogen (2.72 ).
3.7.2. Charge population analysis
Table 4 represents the calculated Hirshfeld partial atomic
charges in [Pt(C2O4)(cis-DACH)]
H2O and anhydrous [Pt(C2O4)(cis-DACH)]. No signicant change is noted in the charge densities
on the atoms of the DACH ring in the anhydrous and hydrated cis
complex. A decrease of 0.03 in the negative charge on O3 and O4
is noted, showing the decrease in electron density at these two
oxygens on hydration, as these two oxygens are directly involved
in hydrogen bonding.

Fig. 4. Optimized structure for Pt(C2O4)(cis-DACH)]
H2O.

3574

P. Tyagi et al. / Polyhedron 27 (2008) 35673574

3.7.3. Bond order analysis

We calculated the Mayer bond order for the bonds in [Pt(C2O4)
(cis-DACH)]
H2O, and the results are compared with those in the
anhydrous [Pt(C2O4)(cis-DACH)] complex to nd out the structural
difference caused by the hydrogen bonding on the metal ligand
binding. Table 5 shows the calculated bond orders for [Pt(C2O4)
(cis-DACH)]
H2O and the anhydrous complex.
Compared to the anhydrous complex, the PtN bond strengthens slightly, while the PtO bond becomes slightly weaker. Thus,
coordination with a water molecule increases the capacity of oxalate as a leaving group. No signicant change is noted in the bond
orders of the bonds involved in the DACH ring for the hydrated and
anhydrous forms.
The O1C7 and O2C8 bond orders increase by about 0.02. A major change is noted in case of the C7O3 and C8O4 bonds. The bond
orders here decrease by about 0.05, which indicates the weakening
of these bonds as a result of the transfer of electrons away from
them, due to hydrogen bonding with water.
The O3


H1 and O4


H2 bond orders are expected to be zero, but
a value of 0.04 is calculated, which indicates that hydrogen bonds
have formed.
4. Conclusions
We have performed density functional calculations at the GGAPW91 level in order to gain an understanding into the structure of
the third generation anti-cancer drug, oxaliplatin. We have paid
particular emphasis on the conformation of the DACH ligand and
have found that the trans forms of the ligand are more stable than
the cis form. However, of the two equally stable enantiomers, the
trans-l (1R,2R) one is found to be more potent biologically. Since
very minor differences are observed in the electronic structures
of the two enantiomers, their difference in activity may be attributed to the chiral recognition of the ligand by DNA. The calculated
vibrational frequencies are in good agreement with our experimental FT-IR spectrum. It has been observed that the trans-d
(1S,2S) and the cis-(1R,2S) isomers are less active than the trans-l
(1R,2R) isomer, but have similar activities. Calculations were also
performed on the cis isomer and its monohydrate, experimental
data on whose geometry is known. Comparison between the theoretically predicted geometries and the experimental ones yielded
good correspondence, validating our methodology, although these
calculations pertain to the gas phase, and the experimental data
are for the solid state, in which crystal-eld effects may affect
the relative energies of the conformers and the geometries. In
the biological environment, hydrogen bonding with the solvent is
also expected to affect the relative energies of the conformers,
but the good correspondence between our calculations and experimental data suggest that crystal packing and hydrogen bonding
effects are negligible.
Acknowledgements
The authors thank University of Delhis Scheme to Strengthen
R&D Doctoral Research Programme by Providing Funds to University Faculty. One of the authors (PG) also thanks the Council of Scientic and Industrial Research, New Delhi, for a Senior Research
Fellowship.
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