Palladium(II) complexes with highly basic imidazolin-2-imines and their reactivity toward small bio-molecules

Article abstract of DOI:10.1039/c5dt02307f

A series of novel Pd(ii) complexes with chelating mono(imidazolin-2-imine) and bis(imidazolin-2-imine) ligands were synthesized. The crystal structures of [Pd(DMEAIm^iPr)Cl₂] and [Pd(DPENIm^iPr)Cl₂] were determined by X-ray diffraction analysis. The reactivity of the six Pd(ii) complexes, namely, [Pd(en)Cl₂], [Pd(EAIm^iPr)Cl₂], [Pd(DMEAIm^iPr)Cl₂], [Pd(DPENIm^iPr)Cl₂], [Pd(BL^iPr)Cl₂] and [Pd(DACH(Im^iPr)₂)Cl₂], were investigated. Spectrophotometric acid-base titrations were performed to determine the pK_a values of the coordinated water molecules in [Pd(en)(H₂O)₂]²⁺, [Pd(EAIm^iPr)(H₂O)₂]²⁺, [Pd(DMEAIm^iPr)(H₂O)₂]²⁺, [Pd(DPENIm^iPr)(H₂O)₂]²⁺, [Pd(BL^iPr)(H₂O)₂]²⁺ and [Pd(DACH(Im^iPr)₂)(H₂O)₂]²⁺. The substitution of the chloride ligands in these complexes by TU, l-Met, l-His and Gly was studied under pseudo-first-order conditions as a function of the nucleophile concentration and temperature using stopped-flow techniques; the sulfur-donor nucleophiles have shown better reactivity than nitrogen-donor nucleophiles. The obtained results indicate that there is a clear correlation between the nature of the imidazolin-2-imine ligands and the acid-base characteristics and reactivity of the resulting Pd(ii) complexes; the order of reactivity of the investigated Pd(ii) complexes is: [Pd(en)Cl₂] > [Pd(EAIm^iPr)Cl₂] > [Pd(DMEAIm^iPr)Cl₂] > [Pd(DPENIm^iPr)Cl₂] > [Pd(BL^iPr)Cl₂] > [Pd(DACH(Im^iPr)₂)Cl₂]. The solubility measurements revealed good solubility of the studied imidazolin-2-imine complexes in water, despite the fact that these Pd(ii) complexes are neutral complexes. Based on the performed studies, three unusual features of the novel imidazolin-2-imine Pd(ii) complexes are observed, that is, good solubility in water, very low reactivity and high pK_a values. The coordination geometries around the palladium atoms are distorted square-planar; the [Pd(DMEAIm^iPr)Cl₂] complex displays Pd-N distances of 2.013(2) and 2.076(2) ?, while the [Pd(DPENIm^iPr)Cl₂] complex displays similar Pd-N distances of 2.034(4) and 2.038(3) ?. The studied systems are of interest because little is known about the substitution behavior of imidazolin-2-imine Pd(ii) complexes with bio-molecules under physiological conditions.

Full text of DOI:10.1039/c5dt02307f

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Graphical Abstract
Palladium(II) complexes of a highly basic imidazolin-2-imines and
their reactivity toward smallbio-molecules
Jovana Bogojeski,a Jeroen Volbeda,bMatthias Freytag,bMatthias Tammb*and
Živadin D. Bugarčić,a*
The Pd(II) complexes with chelating imidazolinꢀ2ꢀimine ligands were synthesized, the pKa
values and reactivity of these complexes were investigated.

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Palladium(II) complexes of highly basic imidazolin-2-imines and
their reactivity toward small bio-molecules
Jovana Bogojeski,a Jeroen Volbeda,b Matthias Freytag,b Matthias Tamm,b*
Živadin D. Bugarčića*
a Department of Chemistry, Faculty of Science, University of Kragujevac, R. Domanovića 12,
P. O. Box 60, 34000 Kragujevac, Serbia
bInstitut für Anorganische und Analytische Chemie, Technische Universität Braunschweig,
Hagenring 30, 38106 Braunschweig, Germany
Corresponding authors:
Prof. Dr. Živadin D. Bugarčić
Tel: +381(0)34300262
Fax: +381(0)34335040
eꢀmail: bugarcic@kg.ac.rs
and
Prof. Dr. Matthias Tamm
Tel:+49ꢀ531ꢀ391ꢀ5309
Fax: +49ꢀ531ꢀ391ꢀ5387
eꢀmail: m.tamm@tuꢀbs.de
1

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Abstract
A series of novel Pd(II) complexes with chelating mono(imidazolinꢀ2ꢀimine) and bis(imidazolinꢀ
2ꢀimine) ligands were synthesized. The crystal structures of [Pd(DMEAImiPr)Cl2] and
[Pd(DPENImiPr)Cl2] were determined by Xꢀray diffraction analysis. The reactivity of the
six Pd(II) complexes, namely, [Pd(en)Cl2], [Pd(EAImiPr)Cl2], [Pd(DMEAImiPr)Cl2],
[Pd(DPENImiPr)Cl2], [Pd(BLiPr)Cl2] and [Pd(DACH(ImiPr)2)Cl2] were investigated.
Spectrophotometric acid−base titrations were performed to determine the pKa values of the
coordinated
water
molecules
in
the
[Pd(en)(H2O)2]2+,
[Pd(EAImiPr)(H2O)2]2+,
[Pd(DMEAImiPr)(H2O)2]2+,
[Pd(DPENImiPr)(H2O)2]2+,
[Pd(BLiPr)(H2O)2]2+
and
[Pd(DACH(ImiPr)2)(H2O)2]2+. The substitution of the chloride ligands in these complexes by
TU, LꢀMet, LꢀHis and Gly was studied under pseudoꢀfirstꢀorder conditions as a function of
nucleophile concentration and temperature using stoppedꢀflow techniques; the sulfurꢀdonor
nucleophiles have shown better reactivity than nitrogenꢀdonor nucleophiles. The obtained results
indicate that there is a clear correlation between the nature of the imidazolinꢀ2ꢀimine ligands and
the acidꢀbase characteristics and reactivity of the resulting Pd(II) complexes; the order of
reactivity of the investigated Pd(II) complexes is: [Pd(en)Cl2] > [Pd(EAImiPr)Cl2] >
[Pd(DMEAImiPr)Cl2] > [Pd(DPENImiPr)Cl2] > [Pd(BLiPr)Cl2] > [Pd(DACH(ImiPr)2)Cl2].
The solubility measurements revealed good solubility of the studied imidazolinꢀ2ꢀimine
complexes in water, despite the fact that these Pd(II) complexes are neutral complexes. Based on
the performed studies, three unusual features of the novel imidazolinꢀ2ꢀimine Pd(II) complexes
are observed, that is: good solubility in water, very low reactivity and high pKa values.
The coordination geometries around the palladium atoms are distorted squareꢀplanar; the
[Pd(DMEAImiPr)Cl2] complex displays PdꢀN distances of 2.013(2) and 2.076(2) Å, while the
[Pd(DPENImiPr)Cl2] complex displays similar PdꢀN distances of 2.034(4) and 2.038(3) Å.
The studied systems are of interest because little is known about the substitution behavior of
imidazolinꢀ2ꢀimine Pd(II) complexes with bioꢀmolecules under physiological conditions.
Keywords: Palladium(II), Complexes, Kinetics, Mechanism, Reactivity
2

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Abbreviations
en = ethylendiamine
EAImiPr = 2ꢀ(1,3ꢀdiisopropylꢀ4,5ꢀdimethylimidazolinꢀ2ꢀimine)ethanꢀ1ꢀamine
BLiPr = 1,2ꢀbis(1,3diisopropylꢀ4,5ꢀdimethylimidazolinꢀ2ꢀimino)ethane
DMEAImiPr = 2ꢀ(1,3ꢀdiisopropylꢀ4,5ꢀdimethylimidazolinꢀ2ꢀimine)ethanꢀ1ꢀdimethylamine
DPENImiPr = 2ꢀ((1,3ꢀdiisopropylꢀ4,5ꢀdimethylimidazolinꢀ2ꢀimine)ꢀ1,2ꢀdiphenylethanꢀ1ꢀamine
DACH(ImiPr)2
=
N,N'ꢀ(cyclohexaneꢀ1,2ꢀdiyl)bis(1,3ꢀdiisopropylꢀ4,5ꢀdimethylimidazolinꢀ2ꢀ
imine)
TU = thiourea
LꢀMet = Lꢀmethionine
LꢀHis = Lꢀhistidine
Gly = glycine
3

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Introduction
The chemical behavior in solution of structurally analogous Pt(II) and Pd(II) complexes
is very similar, which advanced the research progress in the area of the development of new
Pd(II) complexes.1 However, palladium(II) complexes react ca. 104–105 times faster than their
platinum(II) analogues,1 so the selectivity of such complexes in the binding of bioꢀmolecules are
limited which leads to low antiꢀtumor activity. The reaction rate of Pd(II) complexes can be
slowed down and side reactions can be prevented by the introduction of inert sterically hindered
ligands in the coordination sphere of the complex. A common practice in anticancer drug
development is to modify leading structures in a way that maximizes cytotoxic potency toward
cancer cells.2ꢀ4
Nowadays, cisplatin and its analogues are some of the most effective chemotherapeutic
agents in clinical use for the treatment of different type of cancers.2ꢀ5 However, the advantages
and drawbacks of the widely used platinumꢀbased anticancer drug cisplatin, prompted a search
for analogous transition metal complexes.3,4,6 To overcome the disadvantages of cisplatin, a huge
number of metal ion complexes, among which are the Pd(II) complexes, were synthesized and
tested.7ꢀ9
The chemistry of imidazolinꢀ2ꢀimine ligands draws attention because of the characteristic
ability of imidazolines for effective acquisition and stabilization of a positive charge which leads
to pronounced basic properties of the nitrogen donor atoms and the formation of the highly stable
nitrogenꢀmetal bonds.10 These features make imidazolinꢀ2ꢀimines ideal ancillary ligands for
applications in homogeneous catalysis. Over the past 10 years, this has led to the synthesis and
application of a significant number of their metal complexes (from main group elements to
lanthanides and actinides) in coordination chemistry and homogeneous catalysis.10ꢀ12
We anticipated that the great electron donating capacity and bulkiness of the monoꢀ and
bis(imidazolinꢀ2ꢀimine) ligands would result in Pd(II) complexes with greatly reduced reactivity;
these complexes should in turn have an increased potential as antiꢀtumor agents. Figure 1 shows
the structures of the Pd(II) complexes used in this study.
Figure 1.
4

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Results and Discussion
Ligands synthesis
The ligands were synthesized in analogy to the procedure described in a previous
publication.13 Stirring one equivalent of 2ꢀchloroꢀ1,3ꢀdiisopropylꢀ4,5ꢀdimethylimidazolium salt,
six equivalents of KF, three equivalents of triethylamine and the appropriate amount of different
amines in acetonitrile overnight at room temperature gave the desired ligand salts (Scheme 1).
The deprotonation of the imidazolinꢀ2ꢀimine ligand salts was performed by stirring with KOtBu
in THF for
a
couple of days at room temperature, with exception of the
[DPEN(ImiPrH)NH2][BF4] ligand salt, which was deprotonated by heating a THF solution
overnight with NaNH2 at 40 °C.
iPr
iPr
N
N
KOtBu
3 NH2(CH2)NH2
6 KF
EAImiPr
DMEAImiPr
BLiPr
N
N
N
NH2
NH
BF4
NH2
N
iPr
N
iPr
iPr
iPr
KOtBu
N
N
3 NH2(CH2)N(CH3)2
6 KF
N
NH
BF4
N
N
iPr
N
iPr
iPr
iPr
Cl
BF4
iPr
iPr
iPr
iPr
N
N
N
N
0.5 NH2(CH2)NH2
6 KF, 3 Et3N
KOtBu
N
N
N
NH HN
BF4
N
iPr
N
iPr
N
iPr
N
iPr
BF4
Ph
1.15
H2N
Ph
iPr
iPr
Ph
N
Ph
Ph
Ph
N
N
NaNH2
NH2
DPENImiPr
NH2
NH
BF4
NH2
6 KF, 3 Et3N
N
iPr
N
iPr
0.5
iPr
iPr
iPr
iPr
N
N
N
N
KOtBu
H2N
NH2
DACH(ImiPr
)
2
N
N
NH HN
BF4 BF4
6 KF, 3 Et3N
N
iPr
N
iPr
N
iPr
N
iPr
Scheme 1. Synthesis of bidentate imidazolinꢀ2ꢀimine ligands starting from 2ꢀchloroꢀ1,3ꢀ
diisopropylꢀ4,5ꢀdimethylimidazolium tetrafluoroborate
5

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All imidazolinꢀ2ꢀimine ligands (Scheme 1), together with the corresponding dicationic
13
tetrafluoroborate salts, were characterized by 1H, C, 19F NMR, elemental analysis and ESIꢀMS
spectroscopy. These analytical methods confirmed the formation of the imidazolinꢀ2ꢀimines.
Complex synthesis
The complexes shown in Figure 1 were synthesized by stirring equimolar amounts of
[Pd(COD)Cl2] and the imidazolinꢀ2ꢀimine ligands in THF. The Pd(II) complexes
[Pd(EAImiPr)Cl2], [Pd(DMEAImiPr)Cl2], [Pd(DPENImiPr)Cl2] and [Pd(DACH(ImiPr)2)Cl2] were
1
characterized by H and 13C NMR spectroscopy, elemental analysis and ESIꢀMS mass
spectrometry. For the complexes [Pd(DMEAImiPr)Cl2] and [Pd(DPENImiPr)Cl2], single crystals
suitable for the Xꢀray analysis were also obtained.
The 1H NMR as well as the 13C NMR spectra of the [Pd(EAImiPr)Cl2] and
[Pd(DMEAImiPr)Cl2] complexes display a set of signals for the imidazolin moiety, significantly
shifted, compared to the free ligand. In addition, the methyl groups of the isopropyl substituents
1
afford two doublets in the H NMR spectrum. This indicates hindered rotation along the imine
CꢀN bond on the NMR timescale at room temperature, which has previously been observed for
related complexes, bearing both chiral and achiral ligands.10ꢀ13 The achiral Pd(II) complex,
1
[Pd(BLiPr)Cl2],14 shows just one doublet in the H NMR spectra for the methyl groups of the
isopropyl substituents. The [Pd(DPENImiPr)Cl2] and [Pd(DACH(ImiPr)2)Cl2] exhibit four
1
doublets in the H NMR spectrum, which is expected considering that ligands DPENImiPr and
DACH(ImiPr)2 show diastereotopic signals for the methyl substituents on the isopropyl groups
combined with a hindered rotation around the imine CꢀN bond in the Pd(II) complex.
The mass spectrum of [Pd(DACH(ImiPr)2)Cl2] in the m/z range of 400−700 includes main
peaks at m/z = 471 (1+), 575 (2+), and 611 (1+), which correspond to [(DACH(ImiPr)2)H]+,
[Pd(DACH(ImiPr)2)]2+ and [Pd(DACH(ImiPr)2)Cl]+ and represent fragments of the
[Pd(DACH(ImiPr)2)Cl2] complex. Furthermore, Figure S1 depicts the isotopic pattern at
m/z = 611.28, which belongs to the [Pd(DACH(ImiPr)2)Cl2] complex, without one chloride ion,
ie. [Pd(DACH(ImiPr)2)Cl]+ and its corresponding simulated pattern.
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Preparation and structure of [Pd(DMEAImiPr)Cl2]
The reaction of DMEAImiPr with [Pd(COD)Cl2] (COD = 1,5ꢀcyclooctadiene) in THF
afforded the complex [Pd(DMEAImiPr)Cl2] as a deepꢀred solid. Red crystals suitable for Xꢀray
diffraction analysis were isolated from a dichloromethane/nꢀhexane solution, and the molecular
structure of [Pd(DMEAImiPr)Cl2] is shown in Figure 2. The molecule crystallizes in the
orthorhombic space group Pnma, with one coꢀcrystallized molecule of CH2Cl2 per asymmetric
unit and one is located on a crystallographic mirror plane. The ligand is coordinated to the
palladium atom in a chelating, bidentate fashion with an N1ꢀPdꢀN2 bite angle of 83.08(9)°. The
PdꢀN bond lengths are 2.013(2) and 2.076(2) Å for PdꢀN1 and PdꢀN2, respectively, indicating a
stronger coordination of the more basic imine nitrogen to the Pd atom. The imine bond length of
1.349(4)Å (N1ꢀC3) is long for a C=N double bond, indicating a pronounced negative charge on
the imine nitrogen. This is also confirmed by the ρꢀvalue of 0.998; the ρꢀvalue is defined as
ρ=2a/(b + c), with (a) denoting the exoꢀ and (b) and (c) the endoꢀcyclic bond lengths within the
guanidine CN3 moiety. Values approaching unity indicate complete charge delocalization within
the CN3 fragment.15 The electronꢀdonating capacity of the imidazolinꢀ2ꢀimine is also reflected in
the different PdꢀCl bond lengths, with the PdꢀCl1 bond length (2.3390(7)Å) trans to the imine
nitrogen being significantly longer than the PdꢀCl2 bond length (2.2951(7)Å) trans to the tertiary
amine. These structural parameters are comparable to those observed for [Pd(BLiPr)Cl2] and the
PdCl2 complex of tetramethylethylendiamine.14,16
Figure 2.
Preparation and structure of [Pd(DPENImiPr)Cl2]
The reaction of DPENImiPr with [Pd(COD)Cl2] in THF afforded the complex
[Pd(DPENImiPr)Cl2] as an orangeꢀred solid. Red crystals suitable for Xꢀray diffraction analysis
were isolated from an acetone/nꢀhexane solution, and the molecular structure of
[Pd(DMEAImiPr)Cl2] is shown in Figure 3. The compound crystallizes in the orthorhombic space
group P212121 with four independent complexes, five molecules of acetone and on molecule of
hexane per asymmetric unit. The ligand is coordinated to the palladium atom in a chelating,
7

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bidentate fashion with an N1ꢀPdꢀN2 bite angle of 82.69(14)°. The PdꢀN bond lengths are
virtually identical at 2.034(4) and 2.038(3) Å for PdꢀN1 and PdꢀN2, respectively. The imine
C15ꢀN1 bond length of 1.367(5)Å is long for a C=N double bond and the corresponding ρꢀvalue
of 1.004 indicates a strong negative charge on the exocyclic imine nitrogen atom. Again, the
PdꢀCl2 (2.3395(10)Å) distance trans to the imine nitrogen is longer than the PdꢀCl bond which is
trans to the primary amine PdꢀCl1 (2.3193(10)Å).
Figure 3.
Solubility of the imidazolin-2-imine Pd(II) complexes
Despite the fact that the prepared Pd(II) complexes are neutral, UVꢀVis
spectrophotometric measurements showed that they have good solubility in water (see Table 1).
The solubility of the complexes is around four times greater than that observed for cisplatin and
ca. twice that of oxaliplatin. This high solubility is promising for the intended application of
these complexes as antiꢀtumor agents. To this day, cisplatin is the most widely used metal
complexes based cytostatic in the world.2ꢀ5 One of the drawbacks of cisplatin as an antiꢀtumor
drug is its low solubility in aqueous media, therefore an increase in water solubility is an
important goal for the design of any new metalloꢀdrug. A higher water solubility can also result
in a decreased toxicity of metalloꢀdrugs, as is the case for oxaliplatin, which has less
nephrotoxicity and a higher water solubility than cisplatin.2ꢀ5 Herein, we show that the
introduction of different imidazolinꢀ2ꢀimines affords Pd(II) complexes which are significantly
more water soluble than cisplatin.
Table 1.
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pKa Determination of the aqua Pd(II) complexes
It is well established that the low chloride concentration of approximately 4 mM in living
cells causes Pt(II) and Pd(II) dichloride complexes to form diaqua complexes upon entering the
cell. These diaqua complexes then bind to the DNA.17 There is a correlation between the pKa
values of the coordinated water molecules and the electronic structure of the complexes and
accordingly the reactivity of the complexes. Therefore, the pKa values of the complexes in
aqueous solution were determined. This was done via UVꢀvis spectrophotometric pH titration
with NaOH as a base in the pH range between 2 and 12. Each pKa titration was performed twice
and the average of both values was taken. Figure 4 (see also Figures S2ꢀS4 of the Supporting
Information) shows a plot of absorbance versus pH at specific wavelengths, which was used to
determine the pKa values of the coordinated water molecules. The data were fitted using a
nonlinear leastꢀsquares procedure, as shown in the inset in Figure 4. The overall process can be
presented by Eqs (1) and (2). The data obtained for the pKa values are summarized in Table 2.
Ka1
[Pd(L)(H2O)2]2+ + H2O
[Pd(L)(OH)(H2O)]+ + H3O+
[Pd(L)(OH)2] + H3O+
(1)
(2)
Ka2
[Pd(L)(OH)(H2O)]+ + H2O
L = DMEAImiPr, EAImiPr, DPEN(ImiPr)NH2, BLiPr, DACH(ImiPr)2
Figure 4.
Table 2.
Table 2 shows that there is a significant difference between pKa1 and pKa2 values.
The data for [Pd(en)(H2O)2]2+ (pKa1 = 5.6, pKa2 = 7.3)18 represent typical values for complexes
containing sp3ꢀhybridized amines.19 In comparison, Pd(II) complexes with imidazolinꢀ2ꢀimine
ligands give higher pKa values, in agreement with the electronꢀrich nature of the palladium
centers in these complexes, in which deprotonation of the aqua ligand and formation of a
negatively charged hydroxoꢀligand is disfavored. The complexes with mono(imidazolinꢀ2ꢀimine)
ligands, [Pd(EAImiPr)(H2O)2]2+, [Pd(DMEAImiPr)(H2O)2]2+ and [Pd(DPENImiPr)(H2O)2]2+ have
9

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two different types of donors, viz. an imidazolinꢀ2ꢀimine moiety and an sp3ꢀhybridized primary
or tertiary amine (ꢀNR2) unit. In these cases, it can be assumed that the first aqua ligand to be
deprotonated would be that trans to the less electron donating amine donor.
The pH in healthy human cells lies between 7.3 – 7.4.20 As the pKa1 values listed in Table
2 are lower than 7.3, the formation of Pd(II) monohydroxo species can be expected. Conversely,
the pH in cancer cells is lower (around 6.2 to 6.9),20 suggesting that the hydrolyzed
[Pd(DPENImiPr)Cl2] and [Pd(DACH(ImiPr)2)Cl2] complexes will mainly exist as diaqua species
while other complexes will exist as monohydroxo species. Formation of monohydroxo species
and diaqua complexes is good because PdꢀOH species are more substitutionꢀinert but PdꢀOH
can also act as a base, deprotonating a HꢀN site in nucleobases and binding to the N atom, while
diaqua species can readily bind to DNA.
Kinetic studies
To get an idea of the robustness of the Pd(II) complexes in living tissue, the substitution
reactions of Pd(II) complexes with selected nucleophiles (Figure 5) was investigated. The change
in absorbance was followed, at suitable wavelengths, as a function of time at 310 K and
pH ≈ 7.2. The proposed reaction pathways for all observed substitution processes are presented
in Scheme 2. The substitution reactions of all Pd(II) complexes proceed in two successive
reaction steps that are both dependent on the nucleophile concentration.
The entering ligands, LꢀMet, LꢀHis and Gly, are essential amino acids; therefore, the
metal complex (as an antitumor active drug) on its way from the injection to the diseased tissue
will encounter them. On the basis of many investigations in the field of Pt(II) and Pd(II)
complexes, it is known that both ions can easily form a bond with thioethers (such as
LꢀMet).1,14,17 Pt–sulfur(thioether) adducts have been postulated to be a drug reservoir for
platinum and may act as intermediate platinum complexes that can be transformed into Pt–DNA
adducts,17 which makes the study of substitution reactions with LꢀMet very important. Thiourea
was selected because it is a ligand with high solubility, neutral character and good
nucleophilicity. Also, thiourea combines the ligand properties of thiolates as π donors21 and
thioethers as σ donor and π acceptor22. Also, thiourea is used as a protective and rescue agent to
prevent side effects which are caused by Pt(II) antitumor drugs.23,24 Therefore, the investigation
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of the interactions of the selected nucleophiles and Pd(II) complexes is important for the
development of potential antitumor drugs.
Figure 5.
iPr
iPr
R'
N
R'
R'
N
R'
N
N
k1
+
Cl
Nu
NR2
NR2
N
iPr
N
iPr
Pd
Pd
Cl
Nu
Cl
Cl
2
iPr
iPr
R'
N
R'
R'
N
R'
N
N
k2
+
Cl
Nu
NR2
NR2
N
iPr
N
iPr
Pd
Pd
Nu
Nu
Cl
Nu
R' = H or Ph; R = H or CH3
iPr
iPr
iPr
iPr
N
N
N
N
k1
Nu
N
N
N
N
+
Cl
N
iPr
N
iPr
N
iPr
N
iPr
Pd
Pd
Nu
Cl
Cl
Cl
iPr
iPr
iPr
iPr
N
2
N
N
N
k2
Nu
N
N
+ Cl
N
N
N
iPr
N
iPr
N
iPr
N
iPr
Pd
Pd
Nu
Nu
Nu
Cl
Scheme 2. Nu = TU, LꢀMet, LꢀHis and Gly
The substitution reactions of squareꢀplanar metal complexes can proceed according to
two parallel pathways.25 One involves the formation of a solventꢀcoordinated complex, e.g. a
diaqua complex, followed by rapid substitution of the coordinated solvent by the entering
nucleophile (solvolytic pathway), whilst the other involves a direct nucleophilic attack by the
entering nucleophile. To suppress the solvolytic pathway, a 30 mM NaCl solution was added
(see Supporting Information, Figure S5). The rate constants for substitution could be determined,
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under pseudoꢀfirstꢀorder conditions, from a plot of the linear dependence of kobsd versus the total
nucleophile concentration, according to Eqs. (3) and (4). The slope of the line represents k1 or k2,
whilst the intercept represents kꢀ1[Clꢀ] or kꢀ2[Clꢀ]. Plots of kobsd1,2 versus nucleophile
concentration led to a linear dependence with no meaningful intercept for all complexes and both
substitution steps. The results are summarized in Table 3 and 4.
kobsd1 = k1[Nu] + kꢀ1[Clꢀ] ≈ k1[Nu]
kobsd2 = k2[Nu] + kꢀ2[Clꢀ] ≈ k2[Nu]
(3)
(4)
Nu = TU, LꢀMet, Gly, LꢀHis
Table 3.
Table 4.
As an example, the kinetic traces for [Pd(DMEAImiPr)Cl2] including the necessary time scales
for both reaction steps are shown in Figure 6.
Figure 6.
Figure 7 shows the dependence of kobsd on nucleophile concentration for the [Pd(DPENImiPr)Cl2]
and [Pd(BLiPr)Cl2] complexes (see also Supporting Information, Figures S6ꢀS11).
Figure 7.
The order of reactivity of the investigated Pd(II) complexes for both reactions steps is
(Table 3):
[Pd(en)Cl2] > [Pd(EAImiPr)Cl2] > [Pd(DMEAImiPr)Cl2] > [Pd(DPENImiPr)Cl2] > [Pd(BLiPr)Cl2] >
[Pd(DACH(ImiPr)2)Cl2]
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As expected, [Pd(en)Cl2] is the most reactive of the investigated complexes, the values
obtained for this complex are in line with those found for similar complexes.1 The introduction
of one imidazolinꢀ2ꢀimine moiety in [Pd(EAImiPr)Cl2] results in a decrease in reactivity.
Compared to [Pd(en)Cl2], the first reaction step is between five and 100 times slower. The
second substitution is even more impaired and proceeds up to 1000 times slower.
It appears that the strong electron donating capacity of the imidazolinꢀ2ꢀimine results in an
electron rich Pd(II) center, which is less electrophilic and thus less susceptible to attack by bioꢀ
relevant donor molecules. [Pd(DMEAImiPr)Cl2] shows a further reduction in reactivity, the first
substitution being between 10 and 100 times slower than in [Pd(en)Cl2]. This is likely caused by
an increase in electron donating and steric hindrance due to the exchange of the primary amine
for a tertiary amine compared to [Pd(EAImiPr)Cl2]. [Pd(DPENImiPr)Cl2] is the least reactive of
the investigated complexes bearing ligands with a single imidazolinꢀ2ꢀimine moiety. Its
reactivity for the first substitution is reduced roughly 100 fold compared to [Pd(en)Cl2] for all
tested donor molecules. Introduction of ligands bearing two imidazolinꢀ2ꢀimine moieties in
[Pd(BLiPr)Cl2] and [Pd(DACH(ImiPr)2)Cl2] reduces the reactivity even further with both
complexes showing a first substitution reaction that proceeds between 100 and 1000 times
slower than for [Pd(en)Cl2].
For all investigated complexes, the second substitution step is significantly slower than
the first substitution. In case of the reference complex [Pd(en)Cl2], this difference is the least
pronounced. For [Pd(EAImiPr)Cl2], [Pd(DMEAImiPr)Cl2] and [Pd(DPENImiPr)Cl2], it can be
assumed that the first substitution would take place next to the less sterically hindered side of the
ligand viz. next to the amine donor. Therefore, the next substitution would have to take place
next to the bulky imidazolinꢀ2ꢀimine donor, rendering it less facile. In addition, the first
substitution would result in a less electrophilic Pd(II) center, reducing the reaction rate for the
second substitution.
Interestingly, the rate constants which were obtained for the substitution reactions of the
studied imidazolinꢀ2ꢀimine Pd(II) complexes are in line with the rate constants determined for
substitution reactions of aqua Pt(II) complexes (Table S1, Suporting Imformation).26 This
confirms that the investigated complexes have decreased reactivity, since it is known that Pd(II)
complexes react much faster than Pt(II) complexes.1 The low reactivity of the investigated
complexes presents the possibility that they might find biological application.
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The rate constants, k1, presented in the Table 3, indicate that the used nitrogen and sulfur
donor ligands are good entering ligands in the substitution reactions with the investigated Pd(II)
complexes.
The order of the reactivity of the investigated nucleophiles, for the first reaction step is:
TU > LꢀMet > LꢀHis > Gly, Table 3. This is the expected order of reactivity, as sulfurꢀdonor
nucleophiles react faster with Pd(II) complexes than nitrogenꢀdonor nucleophiles. The Pd(II) ion
is soft acid and will easily form bonds with a soft base such as sulfur.
The data for the second substitution step shows that TU reacts faster than LꢀHis. Kinetic
traces for reactions with LꢀMet and Gly gave fits with a double exponential function.
The constants, kobsd1 and kobsd2, were plotted against the concentration of the entering LꢀMet or
Gly nucleophiles. For kobsd1, a linear dependence on the nucleophile concentration was observed
for all the complexes studied; kobsd2 was found to be independent of the LꢀMet or Gly
concentration, suggesting a chelate formation process as presented at Scheme 3 and Figure 8.
k2
N
S
N
N
S
N
H3C
Pd
H3C
Pd
+ Cl + H
NH2
Cl
COO
OOC
NH3
k2
N
N
O
N
N
Pd
Pd
+ Cl
H2N
H2N
Cl
O
O
O
Scheme 3. The second step of the substitution reaction of investigated Pd(II) complexes with
LꢀMet and Gly.
Figure 8.
The substitution reactions of the investigated Pd(II) complexes with LꢀMet proceed with
a nucleophilic attack by the sulfur donor of the thioether group, and subsequently a sixꢀ
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membered ring (see Scheme 3) is formed by substitution with the nitrogen donor of the amine
group. The acid dissociation constants of free LꢀMet is: pKCOOH = 2.28,27 pKNH3+ = 9.227, so
ringꢀclosure must involve deprotonation of the amine group (Scheme 3). Ringꢀclosure and
formation of a sixꢀmembered ring also occurs in the substitution reactions of Pt(II) complexes
and LꢀMet.17,28 In the substitution reaction between Gly and the investigated Pd(II) complexes,
the formation of a fiveꢀmembered ring is confirmed. The nucleophilic attack occurs via the
nitrogen donor of the amine group and then via the oxygen from the carboxyl group (Scheme 3).
A similar ringꢀclosure between Pd(II) or Pt(II) complexes and Gly was observed in earlier
publications.28,29
To confirm that the second step is chelation, the kinetics were studied with the Pd(II)
complexes in excess instead of LꢀMet or Gly. This would mean that a twoꢀstep reaction can only
occur if ring closure is involved. The obtained kinetic traces for such reactions gave fits to a
double exponential function. Similar values for the rate constants were obtained, as were
observed in the experiments with LꢀMet or Gly added in excess (see Supporting Information
Figure S13 and 14). All this indicates that ring closure occurs.
Activation Parameters
The activation parameters ꢁH≠ and ꢁS≠ (Tables S2) were calculated using the Eyring
equation for the reactions with TU (see Figure 9 and S12, Supporting Information) for the first
and second reaction step. The activation parameters support an associative mechanism for each
of these reactions which is supported by the significantly negative activation entropies. This
suggests that the activation process in the studied systems is strongly dominated by bond
formation.
Figure 9.
Conclusion
In conclusion, we were able to use novel imidazolinꢀ2ꢀimine ligands for the synthesis of a
series of new Pd(II) complexes. For [Pd(DMEAImiPr)Cl2] and [Pd(DPENImiPr)Cl2], Xꢀray
structures could be determined. Solubility measurements showed that the imidazolinꢀ2ꢀimine
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Pd(II) complexes have good solubility in water. Spectrophotometric pH titration experiments
showed two pKa values for the diaqua complexes of all investigated Pd(II) compounds. A clear
correlation between the structure of the imidazolinꢀ2ꢀimine and the determined pKa values was
found. The pKa values of the more electron rich complexes (i.e. those bearing a more electronꢀ
donating ligand) were significantly higher than those of the less electron rich complexes. Kinetic
experiments were performed with selected small bioꢀmolecules (i.e. thiourea, Lꢀmethionine,
Lꢀhistidine and glycine) under pseudoꢀfirstꢀorder conditions as a function of nucleophile
concentration and temperature using stoppedꢀflow techniques. These measurements showed that
mono(imidazolinꢀ2ꢀimine) Pd(II) complexes react faster than bis(imidazolinꢀ2ꢀimine) Pd(II)
complexes. This can be attributed to both electronic and steric effects of the imidazolinꢀ2ꢀimine
ligands. Two reaction steps are observed that belong to the displacement of both chloride
ligands. We found that the reactivity of the Pd(II) complexes decreases as follows: [Pd(en)Cl2] >
[Pd(EAImiPr)Cl2]
>
[Pd(DMEAImiPr)Cl2]
>
[Pd(DPENImiPr)Cl2]
>
[Pd(BLiPr)Cl2]
>
[Pd(DACH(ImiPr)2)Cl2]. The sulfurꢀdonor ligands TU and LꢀMet react faster than nitrogenꢀdonor
ligands LꢀHis and Gly. Both LꢀMethionine and glycine react by undergoing a ring closure as the
second substitution step. The mechanism of the substitution reactions is associative supported by
the negative values of ꢀS≠.
The coordination of imidazolinꢀ2ꢀimine ligands to Pd(II) gives three benefits with regard
to the utilization of such complexes as metalloꢀdrugs. The first is an increase of the solubility of
these Pd(II) complexes, as the low solubility of neutral Pd(II) and Pt(II) complexes, such as
cisplatin, is one of the major disadvantages in their application as cytostatics. Secondly,
imidazolinꢀ2ꢀimine Pd(II) complexes react slower than most of the known Pd(II) complexes;
their reactivity is such that it lies in the same range as that of aqua Pt(II) complexes. The reduced
reactivity of Pd(II) complexes should lead to a better selectivity of such complexes in the binding
of bioꢀmolecules. Lastly, the introduction of imidazolinꢀ2ꢀimines leads to an increase of the pKa
values of the coordinated water molecules in these complexes. For [Pd(DPENImiPr)Cl2] and
[Pd(DACH(ImiPr)2)Cl2], the pKa values are such that it can be assumed that they will exist
mostly as diaqua species at the pH of tumor cells. These combined advantages should lead to a
more selective attack of these complexes at the DNA of tumor cells as a final target in drug
delivery.
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Acknowledgements
The authors gratefully acknowledge financial support from the Ministry of Education,
Science and Technological Development Serbia, project No. 172011 and the Deutsche
Forschungsgemeinschaft (DFG).
Experimental
Chemicals and solutions
Thiourea, Lꢀmethionine, Lꢀhistidine, glycine, ethylenediamine, N,Nꢀdimethylethylenediamine,
(1R,2R)ꢀ(ꢀ)ꢀ1,2ꢀdiaminocyclohexane, (1S,2S)ꢀ(ꢀ)ꢀ1,2ꢀdiphenylethylenediamine, NaBF4, KF,
NaNH2, KOtBu and PdCl2 were obtained from Acros Organics or Sigma Aldrich, and were used
without further purification. Hepes buffer (Nꢀ2ꢀhydroxyethylpiperazineꢀN’ꢀ2ꢀethanesulfonic
acid) was obtained from Sigma Aldrich. All the other chemicals were of the highest purity
commercially available and were used without further purification. Ultraꢀpure water was used in
all experiments. Nucleophile stock solutions were prepared shortly before use by dissolving the
chemicals.
Preparation of the ligands and complexes
All reactions were performed in a glove box, under dry argon atmosphere (MBraun 200B) or on a
highꢀvacuum line using standard Schlenk techniques, unless noted otherwise. Commercial grade
solvents were purified by use of a solvent purification system from MBraun GmbH and stored over
molecular sieves (4 Å) under dry argon atmosphere.
All synthesis of the ligands started from 2ꢀchloroꢀ1,3ꢀdiisopropylꢀ4,5ꢀdimethylimidazolium
tetrafluoroborate, which is prepared according to the literature procedure.30
Synthesis and characterization of [DMEAImiPrH][BF4] (1)
To a mixture of 10.66 g (35.2 mmol; 1 eq) of 2ꢀChloroꢀ1,3ꢀdiisopropylꢀ4,5ꢀdimethylimidazolium
tetrafluoroborate and 12.30 g (211.2 mmol; 6 eq) KF in 90 mL of CH3CN was added 11.5 mL
(105.6 mmol; 3 eq) of N,Nꢀdimethylethylenediamine. The mixture was stirred overnight at room
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temperature. On air, 90 mL of CHCl3 was added to the reaction mixture, which was then filtered
through celite. The residue was extracted once with 20 mL of CHCl3. The filtrate was washed
with a dilute NaBF4 solution (19.36 g (176.3 mmol) NaBF4 in 100 mL water). The organic phase
was separated and the aqueous phase was extracted once with 20 mL CHCl3. The combined
organic phases were dried over Na2SO4 and the solvent was then removed in vacuo. The product
is obtained as a yellow oil (11.38 g, 32.1 mmol, 91%).
1H NMR (400 MHz; CDCl3): δ = 5.12 (bs, 1H, NH), 4.78 (sept, 2H, JHH 7.0 Hz, CH(Me)2), 3.22
(bt, 2H, JHH 6.0 Hz, CNHCH2CH2), 2.59 (t, 2H, JHH 6.0 Hz, CH2CH2NMe2), 2.26 (s,
6H,N(CH3)2), 2.25 (s, 6H, CCH3), 1.54 (d, 12H, JHH 7.0 Hz, CH(CH3)2) ppm.
13C NMR (100 MHz; CDCl3): δ = 144.1 (N2CNH), 122.9 (CMe), 58.7 (CH2CH2NMe2), 49.9
(CHMe2), 46.7 (CNHCH2CH2), 45.4 (N(CH3)2), 21.4 (CH(CH3)2), 10.1 (CCH3) ppm.
19F NMR (188 MHz; CDCl3): δ = ꢀ152.08 (BF4) ppm.
Anal. Calcd. for (C15H31BF4N4)·0.10(CHCl3) C: 49.53; H: 8.56; N: 15.30. Found: C: 49.43;
H: 8.80; N: 15.64
ESIꢀHRMS: [MꢀBF4]+: Calcd.: 267.25487; Found: 267.25446 (ꢁ: 0.41 mmu).
Synthesis and characterization of [DMEAImiPr] (2) by deprotonation of (1)
To a solution of 9.00 g (25.4 mmol; 1 eq) of 1 in 220 mL of THF was added 3.42 g (30.5 mmol;
1.2 eq) KOtBu at 0 °C. The mixture was stirred and allowed to warm to room temperature, it was
subsequently stirred overnight. The THF was removed in vacuo. The residue was extracted twice
with 50 mL of pentane and filtered through celite. The solvent was removed in vacuo. The
product was obtained as a light brown oil (6.15 g, 23.1 mmol, 91%).
1H NMR (400 MHz; C6D6): δ = 4.43 (sept, 2H, JHH 7.0 Hz, CHMe2), 3.73 (t, 2H, JHH 7.3 Hz,
C=NCH2CH2), 2.66 (t, 2H, JHH 7.3 Hz, CH2CH2NMe2), 2.25 (s, 6H, N(CH3)2), 1.71 (s, 6H,
CCH3), 1.20 (d, 12H, JHH 7.0 Hz, CH(CH3)2) ppm.
13C NMR (100 MHz; C6D6): δ = 150.3 (N2C=N), 115.9 (CMe), 64.8 (CH2CH2NMe2), 49.0
(C=NCH2CH2), 46.6 (N(CH3)2), 46.3 (CHMe2), 21.3 (CH(CH3)2), 10.9 (CCH3) ppm.
Anal. Calcd. for (C15H30N4) C: 67.62; H: 11.35; N: 21.03. Found: C: 67.36; H: 11.16; N: 20.67.
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Synthesis and characterization of [EAImiPrH][BF4] (3)
To a mixture of 1.50 g (4.95 mmol; 1 eq) of 2ꢀChloroꢀ1,3ꢀdiisopropylꢀ4,5ꢀdimethylimidazolium
tetrafluoroborate and 1.74 g (29.9 mmol; 6 eq) of KF in 15 mL of CH3CN was added 1.5 mL
(22.2 mmol; 4,4 eq) of ethylenediamine. The mixture was stirred overnight at room temperature.
After filtration, on air, through celite and subsequent washing with 20 mL of CHCl3 the organic
fraction was washed with a dilute NaBF4 solution (2,7 g; 24.6 mmol NaBF4 in 100 mL of water).
The organic layer was dried over Na2SO4, after which the solvent was removed in vacuo. This
gave the product as a yellow oil (1.39 g, 4.26 mmol, 86%).
1H NMR (400 MHz; CDCl3): δ = 4.85 (sept, 2H, JHH 7.0 Hz, CH(Me)2), 3.16 (t, 2H, JHH 6.0 Hz,
C=NHCH2CH2), 3.01 (t, 2H, JHH 6.0 Hz, CH2CH2NH2), 2.32 (bs, 2H, NH2), 2.25 (s, 6H, CCH3),
1.54 (d, 12H, JHH 7.0 Hz, CH(CH3)2), 1.53 (bs, 2H, NH2) ppm.
13C NMR (100 MHz; CDCl3): δ = 144.1 (N2CNH), 123.0 (CMe), 51.4 (CNHCH2CH2), 50.0
(CH(Me)2), 41.5 (CH2CH2NH2), 21.4 (CH(CH3)2), 10.1 (C(CH3) ppm.
19F NMR (188 MHz; CDCl3): δ = ꢀ152.08 (BF4) ppm.
Anal. Calcd. for (C13H27BF4N4)·0.10(CHCl3) C: 46.53; H: 8.08; N: 16.57. Found: C: 46.78;
H: 8.03; N: 16.55.
ESIꢀHRMS: [MꢀBF4]+: Calcd.: 239.22357; Found: 239.22316 (ꢁ: 0.41 mmu).
Synthesis and characterization of [EAImiPr] (4) by deprotonation of (3)
To a solution of 1.54 g (4.7 mmol; 1 eq) of 3 in 21 mL of THF was added 0.64 g (5.7 mmol; 1.2
eq) of KOtBu. The reaction mixture was stirred for several days at room temperature. The
solvent was removed in vacuo and the residue was extracted with three times 15 mL of pentane.
The pentane was subsequently removed in vacuo to yield the product as an orange oil
(0.87 g, 3.6 mmol, 77%).
1H NMR (400 MHz; C6D6): δ = 4.51 (sept, 2H, JHH 7.0 Hz, CH(Me)2), 3.61 (t, 2H, JHH 5.4 Hz,
C=NCH2CH2), 3.01 (bt, 2H, JHH 5.3 Hz, CH2CH2NH2), 1.68 (s, 6H, CCH3), 1.28 (bs, 2H, NH2),
1.20 (d, 12H, JHH 7.0 Hz, CH(CH3)2) ppm.
13C NMR (100 HMz; C6D6): δ = 151.1 (N2C=N), 115.8 (CMe), 53.0 (C=NCH2CH2), 46.7
(CH2CH2NH2), 46.1 (CH(Me)2), 21.3 (CH(CH3)2), 10.8 (C(CH3) ppm.
Anal. Calcd. for (C13H26N4) C: 65.50; H: 10.99; N: 23.50. Found: C: 65.67; H: 10.99; N: 23.36.
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Synthesis and characterization of [DPEN(ImiPrH)NH2][BF4](5) was performed according to
literature procedure.13
Synthesis and characterization of [DPEN(ImiPr)NH2] (6) by deprotonation of (5)
To a solution of 1.5 g (3.1 mmol; 1 eq) of 5 in 20 mL of THF was added 0.146 g (3.7 mmol;
1.2 eq) of NaNH2. The reaction mixture was stirred for overnight at 40oC. The solvent was
removed in vacuo and the residue was extracted with three times 15 mL of pentane. The pentane
was subsequently removed in vacuo to yield the product as a yellow oil (0.92 g, 2.4 mmol, 75%).
1H NMR (300 MHz; CDCl3): δ 7.18 – 6.90 (m, 10H, HAr), 4.70 (sept, 2H, JHH 7.0 Hz, CHMe2),
4.50 (d, 1H, JHH 9.0 Hz, NH2HCH(Ph)CH), 3.85 (d, 1H, JHH 9.0 Hz, CNHCH(Ph)CH), 1.82 (s,
6H, CCH3), 1.65 (bs, 2H, NH2), 1.10 (d, 6H, JHH 7.0 Hz, CH(CH3)2), 0.94 (d, 6H, JHH 7.0 Hz,
CH(CH3)2) ppm.
13C NMR (100 MHz; CDCl3): δ 154.1 (N2C=N), 139.1 (ipsoꢀCAr(CHNH2)), 132.6 (ipsoꢀ
CAr(CHN), 124.7 (CAr), 122.2 (CAr), 121.1 (CAr), 123.5 (mꢀCAr(CHNH2)), 123.3 (mꢀ
CAr(CHNH), 123.0 (CAr), 118.2 (CMe) 70.3 (CNHCH(Ph)CH), 57.1 (NH2HCH(Ph)CH), 46.2
(CHMe2), 20.0 (CH(CH3)2), 19.5 (CH(CH3)2), 9.8 (CCH3) ppm.
Anal. Calcd. for (C25H34N4) C: 76.88; H: 8.77; N: 14.35. Found: C: 76.01; H: 8.98; N: 14.75.
Synthesis and characterization of the ligands BLiPr (7), DACH(ImiPr)2 (8) were performed
according to literature procedure.13,31
Preparation of the complexes
The complexes [Pd(en)Cl2] and [Pd(BLiPr)Cl2] are synthesized according to published
procedure.14,32
Synthesis and characterization of [Pd(EAImiPr)Cl2] complex
To 111 mg (0.375 mmol; 1 eq) of [Pd(COD)Cl2] was added 92.6 mg (0.35 mmol; 1 eq) of 4 in
10 mL of THF. The reaction mixture was stirred overnight at 55 oC affording an orange solution.
The product was fully precipitated by the addition of 100 ml of nꢀhexane.
The precipitate was filtered and dried in vacuo. The product was obtained as an orangeꢀred solid
(138.53 mg, 0.33 mmol, 89%).
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1H NMR (300 MHz; CDCl3): δ = 5.40 (sept, 2H, JHH 7.0 Hz, CH(Me)2), 4.13 (t, 2H, JHH 4.9 Hz,
C=NCH2CH2), 2.68 (t, 2H, JHH 5.0 Hz, CH2CH2NH2), 2.04 (s, 6H, CCH3), 1.60 (d, 6H, JHH 7.0
Hz, CH(CH3)2), 1.47 (d, 6H, JHH 7.0 Hz, CH(CH3)2)ppm.
13C NMR (100 HMz; CDCl3): δ = 152.7 (N2C=N), 118.6 (CMe), 55.2 (C=NCH2CH2), 48.6
(CH2CH2NH2), 47.4 (CH(Me)2), 22.4 (CH(CH3)2), 21.9 (CH(CH3)2), 10.9 (C(CH3) ppm.
Anal. Calcd. for (C13H26Cl2N4Pd) C: 37.56; H: 6.30; N: 13.48. Found: C: 36.99; H: 6.19;
N: 13.33.
Synthesis and characterization of [Pd(DMEAImiPr)Cl2] complex
To 100 mg (0.338 mmol; 1 eq) of [Pd(COD)Cl2] was added 95 mg (0.22 mmol; 1 eq) of 2 in
12 mL of THF. The reaction mixture was stirred overnight at the 40 °C affording a red
precipitate. The precipitate was filtered and dried in vacuo. The product was obtained as a deepꢀ
red solid. Red crystals were obtained from CH2Cl2/nꢀhexane (139.42 mg, 0.32 mmol, 93%).
1H NMR (300 MHz; CDCl3): δ = 5.30 (sept, 2H, JHH 7.0 Hz, CHMe2), 2.73 (t, 2H, JHH 7.3 Hz,
C=NCH2CH2), 2.35 (t, 2H, JHH 7.3 Hz, CH2CH2NMe2), 2.75 (s, 6H, N(CH3)2), 2.05 (s, 6H,
CCH3), 1.65 (d, 6H, JHH 7.0 Hz, CH(CH3)2), 1.52 (d, 6H, JHH 7.0 Hz, CH(CH3)2) ppm.
13C NMR (100 MHz; CDCl3): δ = 152.6 (N2C=N), 120.7 (CMe), 68.2 (CH2CH2NMe2), 53.7
(C=NCH2CH2), 51.3 (N(CH3)2), 48.8 (CHMe2), 22.7 (CH(CH3)2), 22.0 (CH(CH3)2), 10.09
(CCH3) ppm.
Anal. Calcd. for (C15H30Cl2N4Pd) C: 40.60; H: 6.81; N: 12.63. Found: C: 40.59; H: 6.78;
N: 12.26.
Synthesis and characterization of [Pd(DPENImiPr)Cl2] complex
To 180 mg (0.608 mmol; 1 eq) of [Pd(COD)Cl2] was added 250 mg (0.640 mmol; 1 eq) of 6 in
20 mL of THF. The reaction mixture was stirred for 8 h at room temperature, affording an
orange solution. The complex was precipitated from solution by the addition of 100 ml of
nꢀhexane. The precipitate was filtered and dried in vacuo. The product was obtained as an orange
solid, the red crystals were obtained from aceton/nꢀhexane (363.3 mg, 0.91 mmol, 91%).
1H NMR (300 MHz; CDCl3): δ 7.38 – 7.10 (m, 10H, HAr), 5.31 (sept, 2H, JHH 7.0 Hz, CHMe2),
4.98 (d, 1H, JHH 9.0 Hz, NH2HCH(Ph)CH), 4.21 (d, 1H, JHH 9.0 Hz, CNHCH(Ph)CH), 2.04
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(d, 3H, JHH 7.0 Hz, CH(CH3)2), 1.99 (s, 6H, CCH3), 1.85 (s, 2H, NH2), 1.72 (d, 3H, JHH 7.0 Hz,
CH(CH3)2), 1.58 (d, 3H, JHH 7.0 Hz, CH(CH3)2), 0.79 (d, 3H, JHH 7.0 Hz, CH(CH3)2), ppm.
13C NMR (100 MHz; CDCl3): δ 156.2 (N2C=N), 139.8 (ipsoꢀCAr(CHNH2)), 132.9 (ipsoꢀ
CAr(CHN), 125.1 (CAr), 122.9 (CAr),
121.8 (CAr),
124.2 (mꢀCAr(CHNH2)), 123.9
(mꢀCAr(CHNH), 123.5 (CAr), 119.5 (CMe) 72.1 (CNHCH(Ph)CH), 59.3 (NH2HCH(Ph)CH), 48.4
(CHMe2), 47.2 (CHMe2), 22.2 (CH(CH3)2), 21.5 (CH(CH3)2), 21.0 (CH(CH3)2), 20.6
(CH(CH3)2), 10.8 (CCH3), 10.5 (CCH3) ppm.
Anal. Calcd. for (C25H34Cl2N4Pd) C: 52.87; H: 6.03; N: 9.87. Found: C: 52.97; H: 6.14;
N: 10.01.
Synthesis and characterization of [Pd(DACH(ImiPr)2)Cl2] complex
To 100 mg (0.340 mmol; 1 eq) of [Pd(COD)Cl2] was added 113.2 mg (0.240 mmol; 1 eq) of 6 in
20 mL of THF. The reaction mixture was stirred during 30 min at 50 OC and then stirred at room
temperature during the night, affording a red solution. The complex was precipitated from
solution by the addition of 100 ml of nꢀhexane. The precipitate was filtered and dried in vacuo.
The product was obtained as a red solid (186.1 mg, 0.29 mmol, 85%).
1H NMR (300 MHz; CDCl3): δ = 5.45 (sept, 2H, CHMe2), 5.28 (sept, 2H, CHMe2), 3.82 (bs,
4H, CH2CH(N=C)CH(N=C)CH2), 2.72 ꢀ 2.60 (m, 2H, CH2), 2.15 (s, 6H, CCH3), 2.05 (s, 6H,
CCH3) 2.10 ꢀ 1.92 (m, 2H, CH2), 1.89 ꢀ1.81 (m, 2H, CH2), 1.78 ꢀ 1.69 (m, 2H, CH2), 1.62 (d, 6H,
JHH 7.0 Hz, CH(CH3)2), 1.52 (d, 6H, JHH 7.0 Hz, CH(CH3)2), 1.43 (d, 6H, JHH 7.0 Hz, CH(CH3)2),
1.08 (d, 6H, JHH 7.0 Hz, CH(CH3)2) ppm.
13C NMR (100 MHz; CDCl3):
δ
=
153. (N2C=N), 117.8 (CMe), 65.7
(CH2CH(N=C)CH(N=C)CH2), 50.1 (CHMe2), 49.3 (CHMe2), 36.9 (CH2), 26.5 (CH2), 23.7
(CH(CH3)2), 22.5 (CH(CH3)2), 21.6 (CH(CH3)2), 21.0 (CH(CH3)2), 13.1 (CCH3), 12.3 (CCH3)
ppm.
Anal. Calcd. for (C28H50Cl2N6Pd) C: 51.89; H: 7.78; N: 12.97. Found: C: 51.26; H: 7.93;
N: 12.01.
ESIꢀHRMS: [MꢀCl]+: Calcd.: 611.28; Found: 611.14 (ꢁ: 0.41 mmu).
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Preparation of aqua complexes
The aqua complexes of Pd(II) complexes were prepared starting from the corresponding chlorido
complexes. The conversion was performed by the addition of the corresponding amount of
AgClO4 to a solution of the chloride complex and stirring for 5 h at 50 °C. The white precipitate
that formed (AgCl) was filtered off using a Millipore filtration unit, and the solutions were
diluted. Great care was taken to ensure that the resulting solution was free of Ag+ ions and that
the chlorido complexes had been completely converted into the aqua form. Since it is well
known that perchlorate ions do not coordinate to Pd(II) and Pt(II) in aqueous solution,33
pH titrations were studied in perchlorate medium.
Instrumentation and measurements
NMR spectra were recorded on Bruker DPX 200, DRX 400 and AV 300 devices. Chemicals
shifts (δ) are reported in ppm and referenced to tetramethylsilane (1H, 13C) and
trichlorofluoromethane (19F). Coupling constants (J) are reported in Hertz (Hz) and splitting
patterns are indicated as s (singlet), d (doublet), t (triplet), sept (septet), bs (broad signal) and
m (multiplet). Elemental analyses (C, H, N) were performed by combustion and gas
chromatographic analysis with an Elementar Vario MICRO elemental analyzer. High resolution
electron spray ionization (ESI) mass spectroscopy was performed on a Finnigan MAT 95 XL
Trap device. pH measurements were carried out using a Mettler Delta 350 digital pH meter with
a resolution ± 0.01 mV, with a combination glass electrode. This electrode was calibrated using
standard buffer solutions of pH 4, 7 and 9 obtained from Sigma. Kinetic measurements of the
Pd(II) complex were carried out on an Applied Photophysics SX.18MV stoppedꢀflow instrument
coupled to an onꢀline data acquisition system. The temperature was controlled throughout all
kinetic experiments to ± 0.1oC. All kinetic measurements were performed under pseudoꢀfirstꢀ
order conditions, i.e., at least a 10ꢀfold excess of the nucleophile was used. UvꢀVis spectra were
recorded on PerkinElmer Lamda 35 doubleꢀbeam spectrophotometer equipped with thermostated
1.00ꢀcm quartz Suprasil cells.
Determination of the pKa value of the Pd(II) complexes
Spectrophotometric pH titrations of the solutions of the complexes were performed with
NaOH as a base at 298 K. To avoid absorbance corrections due to dilution, a large volume (300
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mL) of the complex solution was used in the titration. The change in pH from 2 to approximately
3 was achieved by addition of known amounts of crushed pellets of NaOH. The consecutive pH
changes were obtained by adding drops of saturated solutions of NaOH, 1 or 0.1 M, using a
micropipette. To avoid contamination released by the pH electrode, it was necessary to take
2ꢀmL aliquots from the solution into narrow vials for the pH measurements. The aliquots were
discarded after the measurements. The total reversibility of the titration could be achieved by
subsequent addition of HClO4.
The titration data for the complexes were fitted to the following Eq. (5) for the
determination of both pKa values34ꢀ36 and the obtained data are presented in Table 2.
y = a + (b ꢀ a)/(1 + 2.718*((x ꢀ pKa1/m)) + (c ꢀ b)/(1 + 2.718*((x ꢀ pKa2)/n))
(5)
The parameter a represents the value of the absorbance at the beginning of the titration,
b represents the absorbance during the titration and c is the absorbance at the end of the titration.
The parameters m and n are used to optimize the titration curve. In this equation y represents
absorbance value and x refers to the pH.
Solubility measurements
The concentrations of saturated solutions of the studied Pd(II) complexes were
determined by UVꢀvis spectrophotometry. Therefore the specific absorptivity of the compounds
in the water was determined first. This was measured using five dilution series (5, 10, 30, 40, 50
mM) of the studied complexes, then the calibration curve was calculated using LambertꢀBeer
law. The slope of the curve gave specific absorptivity.
The required quantity of water solution was added to the 5 ml volumetric flask.
The solution was heated up to 298 K. Previously weighed quantity of Pd(II) complexes was
added to the volumetric flask until the saturation point occurs. Stirring was continued up to
7 hours at 298 K. The sample was filtered through 0.20 ꢂm membrane filter. A measured
quantity of filtered sample was transferred into another volumetric flask and made further
dilutions. The absorbance was measured using UVꢀvis spectrophotometry. The same process was
repeated two times.
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Kinetic Measurements
The substitution reactions of the Pd(II) complex with the nucleophiles: TU, LꢀMet, LꢀHis
and Gly were studied spectrophotometrically by following the change in absorbance at suitable
wavelengths as a function of time. Spectral changes resulting from the mixing of the complex
and nucleophile solutions were recorded over the wavelength range 200 to 400 nm to establish a
suitable wavelength at which kinetic measurements could be performed.
Substitution reactions were initiated by mixing equal volumes of complex and ligand
solutions directly in the stoppedꢀflow instrument and followed for at least eight halfꢀlives. The
substitution process was monitored as a change in absorbance with time under pseudoꢀfirstꢀorder
conditions. The observed pseudoꢀfirstꢀorder rate constants, kobsd, were calculated as the average
value from four to six independent kinetic runs using the program OriginPro 8. Experimental
data are reported in Tables S3ꢀS26 (Supporting information).
X-ray diffraction studies
Data were recorded at 100(2) K using an Oxford Diffraction Nova A diffractometer with
monochromated Cu Kα radiation. The structures were refined anisotropically using the
SHELXLꢀ97 program.37 Hydrogen atoms were either (i) located and refined isotropically (NH2),
(ii) included as idealized methyl groups allowed to rotate but not tip or (iii) placed geometrically
and allowed to ride on their attached carbon atoms. Special features:
[Pd(DMEAImiPr)Cl2]•2CH2Cl2 crystallizes as half a molecule on a crystallographic mirror
plane perpendicular to the fiveꢀmembered ring. The ethylene bridge is disordered across the
mirror plane. The structure of [Pd(DPENImiPr)Cl2] •5/4 C3H6O • 1/4 C6H14 contains four
ordered molecules of acetone, one disordered molecules of acetone and one disordered molecule
of hexane in the asymmetric unit. The latter two were removed mathematically with the program
SQUEEZE.38 Derived parameters such as the formular weight correspond to four additional
molecules of aceton and four molecules of hexane per cell.
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[Pd(DMEAImiPr)Cl2]•2CH2Cl2 [Pd(DPENImiPr)Cl2] •5/4
C3H6O • 1/4 C6H14
Empirical Formula
Formula Weight
Crystal System
Space Group
a/Å
C17H34Cl6N4Pd
C30.25 H45 Cl2 N4 O1.25 Pd
613.58
662.00
orthorhombic
Pnma
orthorhombic
P212121
16.5015(4)
19.3631(5)
8.2474(2)
2635.21(11)
4
14.8839(3)
28.4936(9)
30.6466(9)
12997.1(6)
16
b/Å
c/Å
Volume [Å3]
Z
Reflections Collected
Independent reflections
25762
158785
2857 [Rint = 0.0391]
1.547
26899 [Rint = 0.0654]
1.345
ρ
C/g cm–3
ꢀ/mm–1
11.366
6.331
0.0246
0.0376
R(FO), [I > 2σ(I)]
2
Rw (FO )
0.0612
0.0890
Goodness of fit on (F2)
Flack parameter
ꢁρ/eÅ–3
1.071
1.052
–
0.005(4)
0.450/–0.806
0.895/–1.145
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