The cis-effect of the n-donor moiety on the rate of chloride substitution in (N^N^N) and (N^C^N) platinum (II) complexes by nitrogen bio-relevant nucleophiles.

The reactivity trends of the complexes are discussed in terms of the electronic and structural effects due to the different cis-heterocycles. In DMIm, steric hindrance due to the extra methyl group in the - position relative to the reactive nitrogen dominates the inductive effect leading to steric clash in the transition state and delayed reactivity of the nucleophile.

Platinum in Chemotherapy

Introduction
The Antitumor activity of Platinum complexes

Mode of Action of Cisplatin
Cisplatin Toxicity and Resistance

Recent Development in Cancer Chemotherapy
Monofunctional Pt(II) complexes

Objectives of This Study

References

Intrastrand cross-links A platinum cross-link between two bases of the same sugar-phosphate chain. Cis-effect of the N-donor moiety on the degree of chloride substitution in monofunctional N^N^N Pt(II) complexes: a kinetic and computational approach.

Figure 1.2 Schematic representation of DNA double helix showing the complementary base pairing of the bases, Adenine (A) with Thymine (T) and Guanine (G) with Cytosine (C) and the reactive nitrogens ( * ) of purines A and G

Substitution Reactions

Introduction

Substitution Reaction Mechanisms

Dissociative exchange (Id) – The degree of assistance from the incoming nucleophile is small, since in the rate-determining transition state there is minimal interaction between the reaction center and the incoming group.1-2,4,6,8 Therefore, in the transition state, there is a large degree of bond breaking by the leaving group and a small amount of bonding to the entering group, thus the reaction rate is more sensitive to the nature of the leaving group.1-2,4,6,8 . Therefore, the preferred changes going to the transition state are also determined by the resulting number of factors.2 The reaction pathway that the tetrahedral sp block elements undergo are generally nucleophilic: SN1 and SN2, where the balance changes as one moves down the the periodic system .

Substitution at Square-Planar Complexes

Mechanism of Substitution reaction
Geometries of the Intermediates

The value is independent of the entering ligand, while it depends on the reactivity of the entering nucleophile. General considerations of shape and available orbitals only support the formation of a trigonal bipyramidal geometry.

Figure 2.3 Rates of reaction of trans-[Pt(Py) 2 Cl 2 ] as a function of the concentrations of different nucleophiles in methanol at 30

Factors Controlling the Reactivity of Square-Planar Complexes

The trans-Effect

The σ-Bonding Theory
The π-Bonding Theory
The σ and π-trans-effect

The Effect of the Chelating Ligand
The Effect of the Leaving Ligand (X)
The Role of the Solvent
Steric Effect

One of the important factors is the effect of the coordinated ligand (A) on the rate of substitution of the trans-ligand (X). This was first noted by Werner11 and later understood and used in Russia in 1926, when Chernyayev and colleagues12 used the concept of trans effect to correlate many reactions of Pt(II) complexes. The trans effect is the effect of the coordinated ligand on the rate of substitution of the ligand trans to it. Therefore, to rationalize the order of the ligands in the trans-effect sequence it is essential to understand both binding properties.1, 14.

In the case of strong -acceptor ligands, the -bond theory discussed earlier can be explained in terms of M.O. Therefore, changing the nature (aromaticity, size and density) of the chelating ligand may be useful in ongoing research to find new platinum anticancer drugs. As mentioned earlier, the rate of reaction in associative reactions largely depends on the nature of the entering nucleophile.

There have been several studies on the effects of using sterically hindered substrates and reagents.

Figure 2.10 The σ-trans-effect due to the stabilization of the trigonal bipyramidal intermediate

35 The use of sterically hindered ligands in square planar complexes is useful in changing the substitution mechanism from associative to dissociative.2 This is because the intermediate in associative reactions is more crowded than that of the dissociative mechanism. Therefore, the use of heavy ligands in the ground state allows the formation of the less crowded intermediate and accelerates the dissociation reaction to relieve steric strain.

Chemical Kinetics

Introduction
Rate Laws
Integrated Rate Equations 1. First-order reactions

Irreversible first-order reactions
Reversible first-order reactions
Second-Order Reactions

Effect of Temperature on Reaction Rates
Practical Measurement of Reaction Rates

Ultraviolet-Visible Spectrophotometry
Stopped-Flow Technique

References

Of all these variables, concentration is the most commonly considered factor in quantitative analysis of the rate of reaction.3. The units of the reaction rate are and depending on the order ( ) of the reaction, the units of the rate constant ( ) can vary. In principle, the speeds of the forward and reverse reactions are equal.2 Considering the elementary reaction:

Temperature dependence studies are also very useful in determining activation parameters from the variation of the rate constant with temperature.2. Substituting equation ((3.48)) into equation ((3.46)) to obtain the rate law in terms of reactant concentration gives. The rate of reactions can be practically measured by chemical or physical methods.1 Chemical methods include sampling, reaction quenching, and direct measurement of concentration.

The cis effect of the N-donor moiety on the rate of chloride substitution from monofunctional N^N^N Pt(II) complexes: a kinetic and computational approach.

Figure 3.1 Schematic diagram of a double-beam Ultraviolet-Visible spectrophotometer, Insert (b): 3 dimensional view of the chopper

Abstract

Introduction
Experimental

Chemicals and General Procedures
Ligand Synthesis

DFT Calculations
Preparation of complex and nucleophile solutions
Kinetic Analyses
charges omitted for clarity)

Discussion
Conclusion

DFT calculations were performed in an attempt to account for the reactivity difference of the studied complexes. The effect of the cis-aromatic ring sizes on the reactivity of the complexes was also investigated. The reactivity of the six-membered chelates with out-of-plane cis groups, quinoline in Pt3 and azaindole in Pt4 was also investigated.

For comparison, steric effects due to out-of-plane twisting of the cis groups were considered in addition to the electronic effects of the fused rings. The low reactivities of six-membered chelates (Pt3 and Pt4) compared to five-membered chelates (Pt1 and Pt2) were also studied. Steric hindrance due to the out-of-plane distortion of the cis groups on Pt3 and Pt4, observed by dihedral angles (θ) of 32° and 22°, respectively, is another reason for the slow reactivity of six-membered chelates such as attack by azole nucleophiles at the Pt(II) center are hindered.

The rate of substitution also depends on the basicity and steric hindrance of the incoming azole nucleophile.

Figure 4.1 Structural representation of the investigated monofunctional Pt(II) complexes

Supplementary Information

The large negative values of the enthalpy of formation and the sensitivity of the second-order rate constant on the incoming nucleophile support the associative mechanism. Pearson, Mechanisms of Inorganic Reactions: A Study of Metal Complexes, 2nd Edition, John Wilet & Sons, New York, 1967, p. Katritzky, Physical Methods in Heterocyclic Chemistry: A Comprehensive Treatise in Two Parts, Part 1.; Academic Press: New York, 1963.

Introduction
Materials and Procedures
Synthesis of Ligands
Synthesis of Pt(II) complexes
Computational Studies
Kinetic Measurements
Results

The nucleophilic substitution reactions of the complexes 1,3-bis(2-pyridinyl)benzeneplatinum(II)chloride (PtL1), 1,3-bis(N-pyrazolyl)benzeneplatinum(II)chloride (PtL2), 1,3-bis( quinolin-8-yl)benzeneplatinum(II)chloride (PtL3) and 1,3-bis(7-azaindolyl)benzeneplatinum(II)chloride (PtL4) with a series of azole nucleophiles viz. The reactivity of the studied azole nucleophiles is dependent on their basicity, while steric hindrance due to the methyl group in the - position to the pyridinic nitrogen decreases the rate of the substitution reaction. The lability of the leaving group in chelated mononuclear Pt(II) complexes was found to be influenced by the nature of the tridentate chelating ligand.

Two of the complexes have five-membered chelate rings, while the other two form six-membered chelates. The monofunctional complexes are; 1,3-bis(2-pyridinyl)benzeneplatinum(II) chloride (PtL1), 1,3-bis(N-pyrazolyl)benzeneplatinum(II) chloride (PtL2), 1,3-bis(quinolin-8-yl) benzeneplatinum(II) chloride (PtL3) and 1,3-bis(7-azaindolyl)benzeneplatinum(II) chloride (PtL4). The nucleophiles used are; Pyrazole (Pz), 1,2,4-triazole (Tz), imidazole (Im), 1-methylimidazole (MIm) and 1,2-dimethylimidazole (DMIm). Density functional theory (DFT) calculations for the electronic ground state structures of the studied complexes were performed to gain more insight into the observed reactivity.

The influence of the chelate ring size can also be observed in the bite angles of the studied complexes.

Figure SI 4.10. Mass spectrum of 2,6-Bis(N-pyrazolyl)pyridine platinum(II) chloride, Pt2

Proposed mechanism of chloride substitution

Discussion
Conclusion
References

The summary of the second-order rate constants for the reactions between complexes and nucleophiles is given in Table 5.3. 101 Table 5.4 Summary of the activation parameters for substitution of the chloride from the platinum. This is also supported by the electrophilicity values ( ) for the whole complex, which show that PtL1 has an overall -binding effect compared to PtL2.

Another important difference that can be significant in controlling the reactivity of the complexes is structural. The reactivity of the studied complexes depends on the electronic and steric effects of the tridentate chelate ligands. The reactivity of PtL3 and PtL4 toward their analogs PtL1 and PtL2, respectively, is also reduced by steric hindrance due to out-of-plane twisting of the cis groups.

The reactivity trend of the complexes is further supported by DFT calculations (B3LYP/LANL2DZ).

Figure 5.4 First-order exponential fit for the reaction of PtL6 with 1,2,4-triazole (2.77 mM) at 298 nm, T=298.15 K

Mass and 1 H NMR Spectra

Conclusion and Future Work

Concluding Remarks
Future Work
References

From the experimental data obtained, it was found that the degree of chloride substitution by selected azole nucleophiles is strongly influenced by relatively small structural modifications in the N^N^N and N^C^N chelating ligands. When we compared the two studied schemes, we found that the presence of a trans bond with the chloride leaving group in N^C^N chelates leads to an increase in the reaction rate by up to two orders of magnitude compared to their N^ analogues N^N. which contain a bond in a similar position. Such acceleration of the substitution process is due to the destabilization of the ground state of the bond due to the strong electron donation from the phenyl group along the plane as shown by the longer DFT calculated bonds.1-2 In planar five-membered chelates , the presence of - cis -deficient pyridine groups increases the rate of substitution, while switching to electron-rich pyrazole cis groups decreases the rate of substitution as the incoming azole nucleophile is repelled by the increased electron density around the metal center. 3 Presentation of 8 -quinolyl and 7- cis azaindolyl groups lead to out-of-plane twisting of these groups, which also prevents effective π-back donation of metal electrons, leading to slower reactivity of these complexes.

4 Steric hindrance due to this out-of-plane twisting of the cis groups in C2 complexes also decreases the rate of chloride substitution as the attack of the incoming nucleophile is hindered. The reactivity difference in methyl substituted, MIm and DMIm azoles has been explained in terms of the inductive effect and/or steric hindrance. The increased reactivity of MIm is due to the inductive σ-donation of electrons by the methyl substituent in the -position to the reactive nitrogen, which makes the nucleophilic nitrogen more reactive.5-6 However, in DMIm there is steric hindrance due to the additional methyl group in the -position to the reactive nitrogen dominates over the inductive effect leading to steric clash in the transition state and delayed reactivity of the nucleophile.

It was found that the reactivity difference in the entering unhindered five-membered heterocyclic N-donor nucleophiles (Im, Pz and Tz) depends linearly on their basicity according to a linear free energy relationship of the type ( ), where and takes into account electronic and steric effects.