Jovana
Bogojeski
a,
Jeroen
Volbeda
b,
Matthias
Freytag
b,
Matthias
Tamm
*b and
Živadin D.
Bugarčić
*a
aDepartment of Chemistry, Faculty of Science, University of Kragujevac, R. Domanovića 12, P. O. Box 60, 34000 Kragujevac, Serbia. E-mail: bugarcic@kg.ac.rs; Fax: +381 (0)34335040; Tel: +381 (0)34300262
bInstitut für Anorganische und Analytische Chemie, Technische Universität Braunschweig, Hagenring 30, 38106 Braunschweig, Germany. E-mail: m.tamm@tu-bs.de; Fax: +49-531-391-5387; Tel: +49-531-391-5309
First published on 2nd September 2015
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(DMEAImiPr)Cl2] and [Pd(DPENImiPr)Cl2] were determined by X-ray 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 [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, 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(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 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 pKa values. The coordination geometries around the palladium atoms are distorted square-planar; the [Pd(DMEAImiPr)Cl2] complex displays Pd–N distances of 2.013(2) and 2.076(2) Å, while the [Pd(DPENImiPr)Cl2] complex displays similar Pd–N 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 imidazolin-2-imine Pd(II) complexes with bio-molecules under physiological conditions.
Nowadays, cisplatin and its analogues are among the most effective chemotherapeutic agents in clinical use for the treatment of different types of cancers.2–5 However, the advantages and drawbacks of the widely used platinum-based 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.7–9
The chemistry of imidazolin-2-imine ligands has attracted attention because of the characteristic ability of imidazolines for effective acquisition and stabilization of a positive charge, which leads to the pronounced basic properties of nitrogen donor atoms and the formation of highly stable nitrogen–metal bonds.10 These features make imidazolin-2-imines the 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.10–12
We anticipated that the great electron donating capacity and bulkiness of the mono- and bis(imidazolin-2-imine) ligands would result in Pd(II) complexes with greatly reduced reactivity; these complexes should in turn have increased potential as anti-tumor agents. Fig. 1 shows the structures of the Pd(II) complexes used in this study.
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Scheme 1 Synthesis of bidentate imidazolin-2-imine ligands starting from 2-chloro-1,3-diisopropyl-4,5-dimethylimidazolium tetrafluoroborate. |
All imidazolin-2-imine ligands (Scheme 1), together with the corresponding dicationic tetrafluoroborate salts, were characterized by 1H, 13C, and 19F NMR, elemental analysis and ESI-MS spectroscopy. These analytical methods confirmed the formation of the imidazolin-2-imines.
The 1H NMR as well as 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 afford two doublets in the 1H NMR spectrum. This indicates hindered rotation along the imine C–N bond on the NMR timescale at room temperature, which has previously been observed for related complexes bearing both chiral and achiral ligands.10–13 The achiral Pd(II) complex, [Pd(BLiPr)Cl2],14 shows just one doublet in the 1H NMR spectra for the methyl groups of the isopropyl substituents. The [Pd(DPENImiPr)Cl2] and [Pd(DACH(ImiPr)2)Cl2] exhibit four doublets in the 1H 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 C–N 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, Fig. S1† shows the isotopic pattern at m/z = 611.28, which belongs to the [Pd(DACH(ImiPr)2)Cl2] complex, without one chloride ion, i.e. [Pd(DACH(ImiPr)2)Cl]+, and its corresponding simulated pattern.
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Fig. 2 ORTEP drawing of [Pd(DMEAImiPr)Cl2]·CH2Cl2 with thermal displacement parameters drawn at 50% probability. The alternative disordered positions of C1 and C2, hydrogen atoms and a co-crystallized molecule of CH2Cl2 were omitted for clarity. Selected bond distances [Å] and angles [°]: Pd–N1 2.013(2), Pd–N2 2.076(2), Pd–Cl1 2.3390(7), Pd–Cl2 2.2951(7), N1–C3 1.349(4), N3–C3 1.352(2); N1–Pd–N2 83.08(9), Cl1–Pd–Cl2 92.91(7). CCDC 1407330. |
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Fig. 3 ORTEP drawing of one of the four molecules of [Pd(DPENImiPr)Cl2] in [Pd(DPENImiPr)Cl2]·acetone with thermal displacement parameters drawn at 50% probability. Hydrogen atoms and a co-crystallized molecule of acetone were omitted for clarity. Selected bond distances [Å] and angles [°]: Pd–N1 2.034(4), Pd–N2 2.038(3), Pd–Cl1 2.3193(10), Pd–Cl2 2.3395(10), N1–C15 1.367(5), N3–C15 1.363(5), N4–C15 1.359(6); N1–Pd–N2 82.69(14), Cl1–Pd–Cl2 91.85(4). CCDC 1407331. |
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Fig. 4 UV-vis spectra recorded for 0.1 mM [Pd(DPENImiPr)(H2O)2]2+ in the pH range 2 to 12 at 25 °C. Insert: plot of absorbance vs. pH at 260 nm (experimental curve and calculated curve). |
pKa1 | pKa2 | |
---|---|---|
[Pd(en)(H2O)2]2+ (ref. 18) | 5.60 ± 0.05 | 7.30 ± 0.05 |
[Pd(EAImiPr)(H2O)2]2+ | 5.45 ± 0.10 | 7.62 ± 0.20 |
[Pd(DMEAImiPr)(H2O)2]2+ | 5.75 ± 0.10 | 8.28 ± 0.10 |
[Pd(DPENImiPr)(H2O)2]2+ | 7.17 ± 0.20 | 11.21 ± 0.10 |
[Pd(BLiPr)(H2O)2]2+ (ref. 14) | 6.18 ± 0.05 | 10.07 ± 0.05 |
[Pd(DACH(ImiPr)2)(H2O)2]2+ | 7.56 ± 0.20 | 8.39 ± 0.20 |
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 sp3-hybridized amines.19 In comparison, Pd(II) complexes with imidazolin-2-imine ligands give higher pKa values, in agreement with the electron-rich nature of the palladium centers in these complexes, in which deprotonation of the aqua ligand and formation of a negatively charged hydroxo-ligand are disfavored. The complexes with mono(imidazolin-2-imine) ligands, [Pd(EAImiPr)(H2O)2]2+, [Pd(DMEAImiPr)(H2O)2]2+ and [Pd(DPENImiPr)(H2O)2]2+, have two different types of donors, viz. an imidazolin-2-imine moiety and an sp3-hybridized 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 and 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 Pd–OH species are more substitution-inert but Pd–OH can also act as a base, deprotonating a H–N site in nucleobases and binding to the N atom, while diaqua species can readily bind to DNA.
The entering ligands, L-Met, L-His 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 L-Met).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 L-Met 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 donors and π acceptors.22 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 of the interactions of the selected nucleophiles and Pd(II) complexes is important for the development of potential antitumor drugs.
The substitution reactions of square-planar metal complexes can proceed according to two parallel pathways.25 One involves the formation of a solvent-coordinated 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 the ESI, Fig. S5†). The rate constants for substitution could be determined, under pseudo-first-order conditions, from a plot of the linear dependence of kobsdversus the total nucleophile concentration, according to eqn (3) and (4). The slope of the line represents k1 or k2, whilst the intercept represents k−1[Cl−] or k−2[Cl−]. Plots of kobsd1,2versus nucleophile concentration led to a linear dependence with no meaningful intercept for all complexes and both substitution steps. The results are summarized in Tables 3 and 4.
kobsd1 = k1[Nu] + k−1[Cl−] ≈ k1[Nu] | (3) |
kobsd2 = k2[Nu] + k−2[Cl−] ≈ k2[Nu] | (4) |
First reaction step | TU, k1 [M−1 s−1] | l-Met, k1 [M−1 s−1] | Gly, k1 [M−1 s−1] | l-His, k1[M−1 s−1] |
---|---|---|---|---|
[Pd(en)Cl2] | (6.95 ± 0.10) × 105 | (5.05 ± 0.10) × 105 | (1.02 ± 0.10)× 104 | (2.87 ± 0.20)× 105 |
[Pd(EAImiPr)Cl2] | (1.25 ± 0.20) × 105 | (5.54 ± 0.20) × 104 | (1.45 ± 0.10) × 103 | (2.78 ± 0.10) × 103 |
[Pd(DMEAImiPr)Cl2] | (6.78 ± 0.20) × 103 | (4.5 ± 0.10) × 103 | (1.28 ± 0.10) × 103 | (2.00 ± 0.20) × 103 |
[Pd(DPENImiPr)Cl2] | (5.13 ± 0.20) × 103 | (2.53 ± 0.20) × 103 | (8.52 ± 0.20) × 102 | (1.48 ± 0.20) × 103 |
[Pd(BLiPr)Cl2] | (9.20 ± 0.20) × 102 | (5.15 ± 0.20) × 102 | (2.93 ± 0.20) × 102 | (1.67 ± 0.20) × 102 |
[Pd(DACH(ImiPr)2)Cl2] | (1.64 ± 0.20) × 102 | (1.51 ± 0.20) × 102 | 97.70 ± 0.10 | (1.35 ± 0.10) × 102 |
Second reaction step | TU, k2 [M−1 s−1] | l-His, k2 [M−1 s−1] |
---|---|---|
[Pd(en)Cl2] | (1.53 ± 0.20) × 104 | (1.03 ± 0.10) × 104 |
[Pd(EAImiPr)Cl2] | (8.52 ± 0.10) × 102 | 70.20 ± 0.10 |
[Pd(DMEAImiPr)Cl2] | (4.22 ± 0.10) × 102 | 43.80 ± 0.10 |
[Pd(DPENImiPr)Cl2] | (2.80 ± 0.20) × 102 | 39.20 ± 0.20 |
[Pd(BLiPr)Cl2] | (1.84 ± 0.10) × 102 | 24.30 ± 0.10 |
[Pd(DACH(ImiPr)2)Cl2] | 70.90 ± 0.10 | 19.20 ± 0.10 |
As an example, the kinetic traces for [Pd(DMEAImiPr)Cl2] including the necessary time scales for both reaction steps are shown in Fig. 6.
Fig. 7 shows the dependence of kobsd on nucleophile concentration for the [Pd(DPENImiPr)Cl2] and [Pd(BLiPr)Cl2] complexes (see also the ESI, Fig. S6–S11†).
The order of reactivity of the investigated Pd(II) complexes for both reaction steps is (Table 3):
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 imidazolin-2-imine moiety into [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 imidazolin-2-imine results in an electron rich Pd(II) center, which is less electrophilic and thus less susceptible to attack by bio-relevant donor molecules. [Pd(DMEAImiPr)Cl2] shows a further reduction in reactivity, the first substitution being between 10 and 100 times slower than that 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 imidazolin-2-imine moiety. Its reactivity for the first substitution is reduced roughly 100 fold compared to [Pd(en)Cl2] for all the tested donor molecules. Introduction of ligands bearing two imidazolin-2-imine moieties into [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 that for [Pd(en)Cl2].
For all the 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 imidazolin-2-imine 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 imidazolin-2-imine Pd(II) complexes are in line with the rate constants determined for substitution reactions of aqua Pt(II) complexes (Table S1, ESI†).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 raises the possibility that they might find biological application.
The rate constants, k1, presented in 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 reactivity of the investigated nucleophiles for the first reaction step is: TU > L-Met > L-His > Gly, Table 3. This is the expected order of reactivity, as sulfur-donor nucleophiles react faster with Pd(II) complexes than nitrogen-donor nucleophiles. The Pd(II) ion is a soft acid and will easily form bonds with a soft base such as sulfur.
The data for the second substitution step show that TU reacts faster than L-His. Kinetic traces for reactions with L-Met and Gly gave fits with a double exponential function. The constants, kobsd1 and kobsd2, were plotted against the concentration of the entering L-Met 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 L-Met or Gly concentration, suggesting a chelate formation process as presented in Scheme 3 and Fig. 8.
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Scheme 3 The second step of the substitution reaction of the investigated Pd(II) complexes with L-Met and Gly. |
The substitution reactions of the investigated Pd(II) complexes with L-Met proceed with a nucleophilic attack by the sulfur donor of the thioether group, and subsequently a six-membered ring (see Scheme 3) is formed by substitution with the nitrogen donor of the amine group. The acid dissociation constants of free L-Met are: pKCOOH = 2.28,27 pKNH3+ = 9.2,27 so ring-closure must involve deprotonation of the amine group (Scheme 3). Ring-closure and formation of a six-membered ring also occur in the substitution reactions of Pt(II) complexes and L-Met.17,28 In the substitution reaction between Gly and the investigated Pd(II) complexes, the formation of a five-membered 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 ring-closure 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 L-Met or Gly. This would mean that a two-step 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 compared to those observed in the experiments with L-Met or Gly added in excess (see the ESI Fig. S13 and 14†). All this indicates that ring closure occurs.
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Fig. 9 Eyring plots for the two reaction steps of the [Pd(DMEAImiPr)Cl2] complex with TU at pH = 7.2 and 310 K in 25 mM Hepes buffer and 30 mM NaCl. |
The coordination of imidazolin-2-imine ligands to Pd(II) gives three benefits with regard to the utilization of such complexes as metallo-drugs. 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, imidazolin-2-imine Pd(II) complexes react more slowly 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 bio-molecules. Lastly, the introduction of imidazolin-2-imines 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.
All the syntheses of the ligands started from 2-chloro-1,3-diisopropyl-4,5-dimethylimidazolium tetrafluoroborate, which was prepared according to a literature procedure.30
1H NMR (400 MHz; CDCl3): δ = 5.12 (bs, 1H, N), 4.78 (sept, 2H, JHH 7.0 Hz, C
(Me)2), 3.22 (bt, 2H, JHH 6.0 Hz, CNHC
2CH2), 2.59 (t, 2H, JHH 6.0 Hz, CH2C
2NMe2), 2.26 (s, 6H, N(C
3)2), 2.25 (s, 6H, CC
3), 1.54 (d, 12H, JHH 7.0 Hz, CH(C
3)2) ppm.
13C NMR (100 MHz; CDCl3): δ = 144.1 (N2NH), 122.9 (
Me), 58.7 (CH2
H2NMe2), 49.9 (
HMe2), 46.7 (CNH
H2CH2), 45.4 (N(
H3)2), 21.4 (CH(
H3)2), 10.1 (C
H3) ppm.
19F NMR (188 MHz; CDCl3): δ = −152.08 (B4) 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.
ESI-HRMS: [M − BF4]+: Calcd: 267.25487; Found: 267.25446 (Δ: 0.41 mmu).
1H NMR (400 MHz; C6D6): δ = 4.43 (sept, 2H, JHH 7.0 Hz, CMe2), 3.73 (t, 2H, JHH 7.3 Hz, C
NC
2CH2), 2.66 (t, 2H, JHH 7.3 Hz, CH2C
2NMe2), 2.25 (s, 6H, N(C
3)2), 1.71 (s, 6H, CC
3), 1.20 (d, 12H, JHH 7.0 Hz, CH(C
3)2) ppm.
13C NMR (100 MHz; C6D6): δ = 150.3 (N2N), 115.9 (
Me), 64.8 (CH2
H2NMe2), 49.0 (C
N
H2CH2), 46.6 (N(
H3)2), 46.3 (
HMe2), 21.3 (CH(
H3)2), 10.9 (C
H3) ppm.
Anal. Calcd for (C15H30N4) C: 67.62; H: 11.35; N: 21.03. Found: C: 67.36; H: 11.16; N: 20.67.
1H NMR (400 MHz; CDCl3): δ = 4.85 (sept, 2H, JHH 7.0 Hz, C(Me)2), 3.16 (t, 2H, JHH 6.0 Hz, C
NHC
2CH2), 3.01 (t, 2H, JHH 6.0 Hz, CH2C
2NH2), 2.32 (bs, 2H, N
2), 2.25 (s, 6H, CC
3), 1.54 (d, 12H, JHH 7.0 Hz, CH(C
3)2), 1.53 (bs, 2H, N
2) ppm.
13C NMR (100 MHz; CDCl3): δ = 144.1 (N2NH), 123.0 (
Me), 51.4 (CNH
H2CH2), 50.0 (
H(Me)2), 41.5 (CH2
H2NH2), 21.4 (CH(
H3)2), 10.1 (C(
H3) ppm.
19F NMR (188 MHz; CDCl3): δ = −152.08 (B4) 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.
ESI-HRMS: [M-BF4]+: Calcd: 239.22357; Found: 239.22316 (Δ: 0.41 mmu).
1H NMR (400 MHz; C6D6): δ = 4.51 (sept, 2H, JHH 7.0 Hz, C(Me)2), 3.61 (t, 2H, JHH 5.4 Hz, C
NC
2CH2), 3.01 (bt, 2H, JHH 5.3 Hz, CH2C
2NH2), 1.68 (s, 6H, CC
3), 1.28 (bs, 2H, N
2), 1.20 (d, 12H, JHH 7.0 Hz, CH(C
3)2) ppm.
13C NMR (100 HMz; C6D6): δ = 151.1 (N2N), 115.8 (
Me), 53.0 (C
N
H2CH2), 46.7 (CH2
H2NH2), 46.1 (
H(Me)2), 21.3 (CH(
H3)2), 10.8 (C(
H3) ppm.
Anal. Calcd for (C13H26N4) C: 65.50; H: 10.99; N: 23.50. Found: C: 65.67; H: 10.99; N: 23.36.
The synthesis and characterization of [DPEN(ImiPrH)NH2][BF4] (5) were performed according to a literature procedure.13
1H NMR (300 MHz; CDCl3): δ 7.18–6.90 (m, 10H, HAr), 4.70 (sept, 2H, JHH 7.0 Hz, CMe2), 4.50 (d, 1H, JHH 9.0 Hz, NH2HC
(Ph)CH), 3.85 (d, 1H, JHH 9.0 Hz, CNHC
(Ph)CH), 1.82 (s, 6H, CC
3), 1.65 (bs, 2H, N
2), 1.10 (d, 6H, JHH 7.0 Hz, CH(C
3)2), 0.94 (d, 6H, JHH 7.0 Hz, CH(C
3)2) ppm.
13C NMR (100 MHz; CDCl3): δ 154.1 (N2N), 139.1 (ipso-
Ar(CHNH2)), 132.6 (ipso-
Ar(CHN), 124.7 (
Ar), 122.2 (
Ar), 121.1 (
Ar), 123.5 (m-
Ar(CHNH2)), 123.3 (m-
Ar(CHNH), 123.0 (
Ar), 118.2 (
Me) 70.3 (CNH
H(Ph)CH), 57.1 (NH2H
H(Ph)CH), 46.2 (
HMe2), 20.0 (CH(
H3)2), 19.5 (CH(
H3)2), 9.8 (C
H3) ppm.
Anal. Calcd for (C25H34N4) C: 76.88; H: 8.77; N: 14.35. Found: C: 76.01; H: 8.98; N: 14.75.
The synthesis and characterization of the ligands BLiPr (7), DACH(ImiPr)2 (8) were performed according to literature procedures.13,31
1H NMR (300 MHz; CDCl3): δ = 5.40 (sept, 2H, JHH 7.0 Hz, C(Me)2), 4.13 (t, 2H, JHH 4.9 Hz, C
NC
2CH2), 2.68 (t, 2H, JHH 5.0 Hz, CH2C
2NH2), 2.04 (s, 6H, CC
3), 1.60 (d, 6H, JHH 7.0 Hz, CH(C
3)2), 1.47 (d, 6H, JHH 7.0 Hz, CH(C
3)2) ppm.
13C NMR (100 HMz; CDCl3): δ = 152.7 (N2N), 118.6 (
Me), 55.2 (C
N
H2CH2), 48.6 (CH2
H2NH2), 47.4 (
H(Me)2), 22.4 (CH(
H3)2), 21.9 (CH(
H3)2), 10.9 (C(
H3) ppm.
Anal. Calcd for (C13H26Cl2N4Pd) C: 37.56; H: 6.30; N: 13.48. Found: C: 36.99; H: 6.19; N: 13.33.
1H NMR (300 MHz; CDCl3): δ = 5.30 (sept, 2H, JHH 7.0 Hz, CMe2), 2.73 (t, 2H, JHH 7.3 Hz, C
NC
2CH2), 2.35 (t, 2H, JHH 7.3 Hz, CH2C
2NMe2), 2.75 (s, 6H, N(C
3)2), 2.05 (s, 6H, CC
3), 1.65 (d, 6H, JHH 7.0 Hz, CH(C
3)2), 1.52 (d, 6H, JHH 7.0 Hz, CH(C
3)2) ppm.
13C NMR (100 MHz; CDCl3): δ = 152.6 (N2N), 120.7 (
Me), 68.2 (CH2
H2NMe2), 53.7 (C
N
H2CH2), 51.3 (N(
H3)2), 48.8 (
HMe2), 22.7 (CH(
H3)2), 22.0 (CH(
H3)2), 10.09 (C
H3) ppm.
Anal. Calcd for (C15H30Cl2N4Pd) C: 40.60; H: 6.81; N: 12.63. Found: C: 40.59; H: 6.78; N: 12.26.
1H NMR (300 MHz; CDCl3): δ 7.38–7.10 (m, 10H, HAr), 5.31 (sept, 2H, JHH 7.0 Hz, CMe2), 4.98 (d, 1H, JHH 9.0 Hz, NH2HC
(Ph)CH), 4.21 (d, 1H, JHH 9.0 Hz, CNHC
(Ph)CH), 2.04 (d, 3H, JHH 7.0 Hz, CH(C
3)2), 1.99 (s, 6H, CC
3), 1.85 (s, 2H, N
2), 1.72 (d, 3H, JHH 7.0 Hz, CH(C
3)2), 1.58 (d, 3H, JHH 7.0 Hz, CH(C
3)2), 0.79 (d, 3H, JHH 7.0 Hz, CH(C
3)2), ppm.
13C NMR (100 MHz; CDCl3): δ 156.2 (N2N), 139.8 (ipso-
Ar(CHNH2)), 132.9 (ipso-
Ar(CHN), 125.1 (
Ar), 122.9 (
Ar), 121.8 (
Ar), 124.2 (m-
Ar(CHNH2)), 123.9 (m-
Ar(CHNH), 123.5 (
Ar), 119.5 (
Me) 72.1 (CNH
H(Ph)CH), 59.3 (NH2H
H(Ph)CH), 48.4 (
HMe2), 47.2 (
HMe2), 22.2 (CH(
H3)2), 21.5 (CH(
H3)2), 21.0 (CH(
H3)2), 20.6 (CH(
H3)2), 10.8 (C
H3), 10.5 (C
H3) ppm.
Anal. Calcd for (C25H34Cl2N4Pd) C: 52.87; H: 6.03; N: 9.87. Found: C: 52.97; H: 6.14; N: 10.01.
1H NMR (300 MHz; CDCl3): δ = 5.45 (sept, 2H, CMe2), 5.28 (sept, 2H, C
Me2), 3.82 (bs, 4H, CH2C
(N
C)C
(N
C)CH2), 2.72–2.60 (m, 2H, C
2), 2.15 (s, 6H, CC
3), 2.05 (s, 6H, CC
3) 2.10–1.92 (m, 2H, C
2), 1.89–1.81 (m, 2H, C
2), 1.78–1.69 (m, 2H, C
2), 1.62 (d, 6H, JHH 7.0 Hz, CH(C
3)2), 1.52 (d, 6H, JHH 7.0 Hz, CH(C
3)2), 1.43 (d, 6H, JHH 7.0 Hz, CH(C
3)2), 1.08 (d, 6H, JHH 7.0 Hz, CH(C
3)2) ppm.
13C NMR (100 MHz; CDCl3): δ = 153. (N2N), 117.8 (
Me), 65.7 (CH2
H(N
C)
H(N
C)CH2), 50.1 (
HMe2), 49.3 (
HMe2), 36.9 (
H2), 26.5 (
H2), 23.7 (CH(
H3)2), 22.5 (CH(
H3)2), 21.6 (CH(
H3)2), 21.0 (CH(
H3)2), 13.1 (C
H3), 12.3 (C
H3) ppm.
Anal. Calcd for (C28H50Cl2N6Pd) C: 51.89; H: 7.78; N: 12.97. Found: C: 51.26; H: 7.93; N: 12.01.
ESI-HRMS: [M − Cl]+: Calcd: 611.28; Found: 611.14 (Δ: 0.41 mmu).
The titration data for the complexes were fitted to the following eqn (5) for the determination of both pKa values34–36 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 the absorbance value and x refers to the pH.
The required quantity of water solution was added to the 5 ml volumetric flask. The solution was heated up to 298 K. A 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 a 0.20 μm membrane filter. A measured quantity of the filtered sample was transferred into another volumetric flask and made further dilutions. The absorbance was measured using UV-vis spectrophotometry. The same process was repeated two times.
Substitution reactions were initiated by mixing equal volumes of the complex and ligand solutions directly in the stopped-flow instrument and followed for at least eight half-lives. The substitution process was monitored as the change in absorbance with time under pseudo-first-order conditions. The observed pseudo-first-order 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 S3–S26 (ESI†).
[Pd(DMEAImiPr)Cl2]·2CH2Cl2 | [Pd(DPENImiPr)Cl2]·5/4·C3H6O·1/4·C6H14 | |
---|---|---|
Empirical formula | C17H34Cl6N4Pd | C30.25H45Cl2N4O1.25Pd |
Formula weight | 613.58 | 662.00 |
Crystal system | Orthorhombic | Orthorhombic |
Space group | Pnma | P212121 |
a/Å | 16.5015(4) | 14.8839(3) |
b/Å | 19.3631(5) | 28.4936(9) |
c/Å | 8.2474(2) | 30.6466(9) |
Volume [Å3] | 2635.21(11) | 12997.1(6) |
Z | 4 | 16 |
Reflections collected | 25![]() |
158![]() |
Independent reflections | 2857 [Rint = 0.0391] | 26![]() |
ρ C/g cm−3 | 1.547 | 1.345 |
μ/mm−1 | 11.366 | 6.331 |
R(Fo) [I > 2σ(I)] | 0.0246 | 0.0376 |
R w (Fo2) | 0.0612 | 0.0890 |
Goodness of fit on (F2) | 1.071 | 1.052 |
Flack parameter | — | 0.005(4) |
Δρ/e Å–3 | 0.450/−0.806 | 0.895/−1.145 |
En | Ethylendiamine |
EAImiPr | 2-(1,3-Diisopropyl-4,5-dimethylimidazolin-2-imine)ethan-1-amine |
BLiPr | 1,2-Bis(1,3-diisopropyl-4,5-dimethylimidazolin-2-imino)ethane |
DMEAImiPr | 2-(1,3-Diisopropyl-4,5-dimethylimidazolin-2-imine)ethan-1-dimethylamine |
DPENImiPr | 2-(1,3-Diisopropyl-4,5-dimethylimidazolin-2-imine)-1,2-diphenylethan-1-amine |
DACH(ImiPr)2 | N,N′-(Cyclohexane-1,2-diyl)bis(1,3-diisopropyl-4,5-dimethylimidazolin-2-imine) |
TU | Thiourea |
L-Met | L-Methionine |
L-His | L-Histidine |
Gly | Glycine |
Footnote |
† Electronic supplementary information (ESI) available. The CCDC number for [Pd(DMEAImiPr)Cl2] is 1407330 and the CCDC for [Pd(DPENImiPr)Cl2] is 1407331. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5dt02307f |
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