Controlling the reactivity of mononuclear palladiun (II) complexes. Substitution kinetics and mechanisms.

1 Structures of the Pd(II) complexes under study (counterions omitted where necessary for clarity). C···C interactions (shown in blue dashed lines) and π···π interactions (shown in purple lines) between the aromatic rings of the molecules.

Cancer: A global Killer Disease

This chapter reviews the chemistry of active antitumor platinum(II), Pt(II), and palladium(II), Pd(II) metal complexes, some of which are already used for the chemotherapeutic treatment of cancer. The common types of cancer that affect people are cancer of the esophagus, lung, liver, stomach, cervical, colorectal, breast and prostate cancer.

Platinum-based Anticancer Drugs

Side Effects of Pt-based Drugs and the Need for Alternatives

Pt-based anticancer drug chemotherapy is covered with nephrotoxicity, gastrointestinal toxicity, ototoxicity, cardiotoxicity, nausea and vomiting, acquired or intrinsic resistance, bone marrow suppression, and neurotoxicity. , reduced toxicity and increased spectrum of activity as well as limited solubility.54, 55 Some metal complexes of copper, iridium, tin, ruthenium, gallium, rhodium, gold, palladium and rhenium have shown antitumor activity.56-63 Of these , Pd. The (II) complexes are the closest structural analogues of Pt-based drugs and as a result, some of the Pd(II) complexes have emerged as attractive and promising alternative drugs because they have shown good activity against tumors that are resistant to cisplatin or in which cisplatin is inactive.64 In addition, some of these Pd(II) complexes have. Moreover, Pd derivatives easily penetrate between membranes in the body as well as exhibit good interactions with DNA72, resulting in better anticancer activity and lower toxic side effects54, 66, 73 as well as less kidney toxicity ( nephrotoxicity)74, 75 than some of them. Clinically used metallodics.26 Therefore, some of the Pd(II) complexes that have been synthesized and have shown antitumor activity over the years are reviewed in the following section, their activity will be compared with the classical Pt(II)-based antitumor drugs at present. in use.

Palladium Anticancer Chemistry

Mononuclear Palladium(II) Complexes

Bidentated Pd(II) Complexes
Terdentate Palladium(II) Complexes

Apart from the Pd complexes of the trans-5-membered ring system, pyrazole, antitumor studies were extended to complexes 7a-c. The in vitro cytotoxicity results showed a good activity of the complexes including 22 against the cancer cell lines.

Figure 1. 6 Some of the palladium(II) complexes anticancer agents. 38, 84, 91

Aims of the Study

The trends in the substitution rate would be insightful in understanding the extent to which the spectator ligand would be influential in controlling the reactivity of the Pd metal. To investigate the role of pyrazole-based ligands in controlling the reactivity of the complexes from the well-known labilizing terpyridine-based ligands by measuring the substitution rates of synthesized Pd(II) complexes chelated with bis(pyrazolyl)pyridine ligands with different substituents on the azole rings.

Substitution Mechanisms of Square Planar Complexes

Associative Mechanism (A)
Dissociative Mechanism (D)
Reversible Second-order Reactions

In an associative substitution process, the incoming group (Y), the non-living ligands (L1/L2) or the leaving group (X) can influence the inertness (kinetic) stability and the activation energy of the reaction. The bond between the leaving group and the metal ion is first broken to form an intermediate before that of the incoming ligand is formed.

Figure 2. 2 A representative linear plot of k obs against nucleophile concentration ([Nu]) for the pseudo first-order substitution reaction

2 Proposed direct nucleophilic attack and solvotic pathways of associative substitution reaction of square planar complexes

Activation Parameters

Determination of Activation Enthalpy (ΔH ≠ ) and Entropy (ΔS ≠ ) Changes
Determination of Activation Volume (ΔV # )

For a conjugative substitution process, the rate depends on the steric and nucleophilicity of the entering ligand, while for the dissociative pathway the rate is independent of the nature and properties of the nucleophile. The activation volume, ΔV≠ is related to the change in molar volume of the activated complex relative to that of the reactants. At the same time, the concentration or an indirect variable dependent on the concentration of the reactant or product must be monitored as a function of time.

UV-Visible Spectrophotometry

The degree of interactions between the light radiation (transmission or absorption) and the analyte is determined by measuring the intensity of the incident radiation, 𝐼0, and the emitted intensity, 𝐼. 𝐼 = intensity of the transmitted light from the current source after passing through the analyte cell. The observed rate constants are calculated by fitting the induction time of the growth or decay of the absorption data to standard equation 2.41.

Figure 2. 3 A typical representation of the UV/Visible spectrophotometer components. 66

Flow Methods

The pKa values are important thermodynamic data that give an indication of the π-acidity and therefore electrophilicity of the metal ion to which the aqua ligand is coordinated.69, 70. The syringes are filled independently with individual solutions of the reactants which are then quickly is charged (in small volumes) into the mixing chamber by a compressed gas-driven (usually nitrogen) piston at a pressure of not less than 800 kPa. The reaction mixture flows into the stop syringe causing the striking of the stop block, which causes the flow of the reacting solution mixture into the observation cell to stop. This also causes the data acquisition device to promptly record the absorbance-time-resolved kinetic trace on a set. wavelength during which the reacting species are static (stopped-flow).10 The kinetic traces are then processed and the observed pseudo-first-order rate constants evaluated by an online computer program.

Figure 2. 5 A typical schematic diagram of the stopped-flow apparatus. The direction of the movement of the syringes are shown by the blue arrows

Factors Affecting the Rate of Substitution of Square Planar Complexes

The Effect on Rate of the Incoming Ligand
The Effect of the Leaving Group

Steric Effects
The Trans Effects
The Cis Effects

The rate of substitution by the solvent follows the trend, ROH < H2O ≈ CH3NO2 < DMSO in accordance with the nucleophilicity of the solvents. The degree of substitution of the leaving group X from the complexes by pyridine decreased by an order; NO3-. Therefore, the rate of substitution of the leaving group is faster when the trans-ligand is a good π-acceptor or a strong σ-donor and vice versa due to the trans-effect.124.

Table 2. 1 The entering group effects on the rate of substitution of Pd(acac) 2 . X k 2 (x 10 2 s -1 )

Abstract

However, the presence of substituents at the 4' position of the terpyridyl system and electron donating groups at the 4, 4' and 4" positions decrease the rate of lability by reducing the π-back binding capacity of the ligand.52, 53. The substitution rate of Pt(II) complexes coordinated with tridentate N^N^N and N^C^N of a terpyridine ligand framework was slowed when the cis-pyridyl rings were replaced by pyrazolyl and its derivatives due to the presence of the pyrrolic N π donor within the chelate ring.63, 64 The effect of the pyrazole ligand coordinated with the Pd(II) complex, especially at the cis position relative to the leaving group, remains unknown. the chloride ligand from the complexes in Figure 3.1 by biorelevant thiourea nucleophiles, Tu, Dmtu and Tmtu, were measured using stopped flow methods.

Experimental Section .1 Materials and Methods .1 Materials and Methods

Syntheses of the Ligands
Synthesis of the Pd(II) Complexes
Kinetic Measurements

Applied Photophysics SX 20 stop-flow reaction analyzer coupled to an online data acquisition system was used for kinetic and thermodynamic of the substitution reactions. The LiCl was used to prevent any possibility of spontaneous solvolysis of the chlorine complexes. All concentration-dependent substitution reactions of the complexes were performed at 298 K except for PdL1 and Tu nucleophile, which were performed at 293 K.

Results

Computational Details
X-ray Crystal Determination of the Complexes
Kinetic and Mechanistic Studies

The trend of energy differences of HOMO-LUMO complexes increases in the order PdL1< PdL2 < PdL3< PdL4, which matches the trend of reactivity. Selected bond lengths and angles of the X-ray structures PdL1, PdL2 and PdL4 are shown in Table 3.4. In the same way, at 298 K, we analyzed the dependence of the rate constant on the concentration of entering nucleophiles of different concentrations.

Using the reaction of PdL1 with Tu as a reference for comparison with the other complexes in this study, it was observed that the trend of the reactivity decreases in the order of PdL1 ˃ PdL2. This replacement surprisingly reduced the reactivity of the coordinated palladium metal center by approx. 10-fold with the Tu nucleophiles going from PdL1 to PdL2.

Table 3. 1 DFT optimized HOMO, LUMO frontier molecular orbitals and planarity structures of the Pd(II) complexes at B3LYP/LANL2DZ theory level (iso value = 0.02)

Abstract

The approach is to use carefully designed spectator ligands with favorable electronic and steric effects to curb the intrinsic reactivity of the Pd(II) complexes.9-12. Furthermore, a systematic increase in the π-conjugation around the metal center of the terpy framework results in either an increase or decrease in the substitution rate depending on the relative position of the π-extension. This can then be used to curb the high reactivity of the Pd(II) complexes, which is necessary for their antitumor activity.

Experimental Section .1 Materials and Methods .1 Materials and Methods

Synthesis of Ligands
Synthesis of Palladium(II) Complexes
Physical Measurements and Instrumentation
Preparations of Kinetic Solutions
Kinetic Analysis
Computational Modelling

The rate of chloride substitution from the complexes by the incoming nucleophiles was monitored as a function of concentration at 298 K. To understand how the structural and electronic factors influence the kinetics of the substitution reactions. Ground state electronic structures of the complexes were optimized using density functional theory (DFT).

Results

Computational Analysis
Kinetic Measurements

In addition, the planarity of the complexes also increases with increasing π-conjugation compares well with their analogous Pt(II) complexes.40. The chloride substitution reactions of the Pd(II) complexes with the nucleophiles were studied as a function of nucleophile concentration and temperature. The values of the second-order rate constants, k2, obtained from the reactions of the complexes are shown in Table 4.3.

1 Proposed reaction mechanism

Discussion

The reactivity trend observed in the Pd(II) complexes can be largely explained in terms of the electronic effects of the quinolinyl group in the framework of their ligands. The less acidic nature of the quinoline ligand in a complex implies an increase in the σ-inductive effects in the complex, thereby reducing the π-acceptability of the ligand. This explains why the resulting reactivity trend of the Pd(II) complexes is opposite to the increasing π-conjugation in the systems examined.

Figure 4. 5 A pictorial illustration of nature of change in the trans-effect indicating flow of electron density in Pd2 and Pd3 complexes

Conclusions

Based on the results, it is clear that the σ-donation effect is the dominant effect controlling the reactivity of the complexes over the π-rebonding resulting from the π-extension. The kinetics and mechanism of the chloride ligand substitution reactions of a series of 1,3-bis(2-pyridylimino)isoindoline Pd(II) complexes; chlorido(1,3-bis(2-pyridylimino)isoindoline)palladium(II), Pd(BPI)Cl, chlorido(1,3-bis(4-methyl-2-pyridylimino)isoindoline)palladium(II), Pd( 4-Me-PBI)Cl, chlorido(1,3-bis(2-pyridylimino)benz(f)isoindoline)palladium(II), Pd(BBPI)Cl and chlorido(1,3-bis(1-isoquinolylimino) ) isoindolin)palladium(II), Pd(BII)Cl, with biologically relevant thiourea ligands, thiourea (Tu), N,N'-dimethylthiourea (Dmtu), and N,N,N',N'-tetramethylthiourea (Tmtu) were examd. The cis-methylation increases the electron donor properties of the ligand through σ-inductive donation into the pyridine ring, while to a small extent also causing steric effect.