**3. Substitution reactions in transition metal coordination chemistry**

Substitution reactions of complexes are divided on electrophilic (SE) or nucleophilic (SN) depending on the replacement of either central metal ion or ligand. If the metal ion is substituted during the reaction, i.e., electrophile, the reactions are electrophilic substitution (Eq. (1)); otherwise if a ligand is replaced, that is nucleophilic substitution reaction (Eq. (2)) [2, 3]:

$$\begin{array}{c} \begin{bmatrix} \mathsf{M}\_{n} \end{bmatrix} + \begin{array}{c} \mathsf{M} \end{array} \begin{array}{c} \begin{array}{c} \mathsf{M} \end{array} \end{array} \begin{array}{c} \begin{array}{c} \mathsf{M} \end{array} \end{array} \begin{array}{c} \begin{array}{c} \end{array} \end{array} \begin{array}{c} \begin{array}{c} \end{array} \end{array} \tag{1} \end{array} \tag{1}$$

$$\left[\mathsf{M}\_{\mathtt{n}}\right] + \mathsf{X} \xleftarrow{} \mathsf{[M}\_{\mathtt{n}-1}\mathsf{X}\right] + \mathsf{I} \tag{2}$$

Ligand substitution reactions in metal complexes can occur in two ways, either by a combination of solvolysis and substitution by ligand or simple exchange in which there is a replacement of one ligand by another without the direct inclusion of solvent. The direct substitution is more relevant for the square-planar complexes with regard to octahedral complexes. For other complex geometries, both routes are used [4].

Nucleophilic substitution reactions, according to Langford and Gray, are carried out in three different mechanisms: dissociative (D), associative (A), or interchange mechanism (I) (**Figure 1**) [2].

In the dissociative mechanism (D), the first step of the reaction is dissociation of the one ligand L from the inner coordination sphere, whereby an intermediate with a decreased coordination number forms. In the next step, the entering ligand X binds to the central metal ion. Since the first step of the reaction is slower, it determines the overall rate of the substitution reaction.

In the associative mechanism (A), in the first step, the entering ligand X binds to the central metal ion, forming an intermediate with an increased coordination number, and then, in the second step, the leaving ligand L leaves the coordination sphere of the complex. The formation of an intermediate with an increased coordination number is slower, and it determines the rates of this substitution process.

When an intermediate cannot be detected by kinetic, stereochemical, or product distribution studies, the so-called interchange mechanisms (I) are invoked. Associative interchange mechanisms (IA) have rates dependent on the nature of the

**2. Hard and soft metal centers and ligands**

*Photophysics, Photochemical and Substitution Reactions - Recent Advances*

form more stable complexes with class (b) cations.

in order of electronegativity:

This classification is listed in **Table 1**.

**Hard (acids) Intermediate**

, Be2+, Mg2+, Ca2+,

**Hard (bases) Intermediate**

<sup>2</sup>, [NO3] ,

, [ox]<sup>2</sup>,

Sr2+, Sn2+, Mn2+, Al3+, Ga3+, In3+, Sc3+, Cr3+, Fe3+, Co3+, Y3+, Th4+, Pu4+, Ti4+,

F, Cl, H2O, ROH, R2O, [OH],

, [CO3]

<sup>2</sup>, [ClO4]

+

stable M-L bonds. For example:

group –OPh.

Zr4+, [VO]2+, [VO2]

[RO], [RCO2]

NH3, RNH2

*intermediate behavior.*

<sup>3</sup>, [SO4]

[PO4]

**Table 1.**

**194**

Li<sup>+</sup> , Na<sup>+</sup> , K+ , Rb<sup>+</sup>

From the theory we know that Lewis acid is an electron acceptor and a Lewis base is an electron donor. In coordination chemistry, we consider the central metal ions as a Lewis acid which are coordinated (bonded) by one or more molecules or ions (ligands) which act as Lewis bases. The formed coordinated bonds between the central atom or ion with ligands have covalent character, which are known under the name coordinate covalent bond or simple coordinate bond. The acceptor properties of metal ions toward ligands could be divided into two classes. These two classes are "hard" acids or class (a) cations and "soft" acids or class (b) cations. Similar patterns were found for other donor atoms: ligands with O- and N-donors form more stable complexes with class (a) cations, while those with S- and P-donors

The terms "hard" and "soft" acids arise from a description of the polarizabilities of the metal ions. Hard acids are typically either small monocations with a relatively high charge density or are highly charged, again with a high charge density. These ions are not very polarizable and show a preference for donor atoms that are also not very polarizable, e.g., O. Such ligands are called hard bases. Soft acids tend to be large monocations with a low charge density, e.g., Pd2+, and are very polarizable. Soft metal ions prefer to form coordinate bonds with donor atoms that are also highly polarizable, e.g., P. Such ligands are called soft bases. Pearson's classification of hard and soft acids comes from a consideration of a series of donor atoms placed

F> O > N >Cl> Br> C I S>Se >P> As> Sb

donor atoms from the left side of the series. The reverse is true for a soft acid.

• Fe(III) belongs to a class of hard acids and prefers the hard bases, e.g., O. Thus, it is understandable why the concentration of Fe(III) ions in the body is controlled by OH, O<sup>2</sup>, and RO species. In ferritin protein that stores iron and releases it in a controlled fashion, Fe(III) ions are bound by the phenolate

**(acids)**

**(bases)**

Br, [N3]

*Selected hard and soft metal centers (Lewis acids) and ligands (Lewis bases) and those that exhibit*

[SO3] 2

, py, [SCN] (*N*-bound), ArNH2, [NO2]

,

Pb2+, Fe2+, Co2+, Ni2+, Cu2+, Zn2+, Os2+, Ru3+, Rh3+, Ir2+

A hard acid is one that forms the most stable complexes with ligands containing

The applications of the HSAB principle are useful to predict thermodynamically

**Soft (acids)**

**Soft (bases)**

alkenes, arene

Tl<sup>+</sup> , Cu+ , Ag+ , Au<sup>+</sup> , [Hg2]

I

Zero oxidation state metal centers,

, H, R, [CN] (*C*-bound), CO (*C*-bound), RNC, RSH, R2S, [RS], [SCN] (*S*-bound), R3P, R3As, R3Sb,

Cd2+, Pd2+, Pt2+, Ru2+ Tl3+

2+, Hg2+,

**4. Substitution reactions of platinum(II) and zinc(II) complexes with**

*Correlation between HSAB Principle and Substitution Reactions in Bioinorganic Reactions*

Platinum complexes are in medical use worldwide. Cisplatin or *cis*-diamminedi-

chloridoplatinum(II), *cis*-DDP is the first generation of antitumor metal-based complex. Many years of research indicated that preference platinum(II) as soft acid toward soft bases is responsible for the negative side effect of this drug. From the moment of injection of the drugs in the body to their binding to DNA molecules, a large number of secondary processes happen that are responsible for the occurrence of toxic effects [5, 6]. Thus, platinum(II) possesses high affinity to the sulfur and in the blood plasma itself reacts immediately with albumin or other biomolecules that contain sulfur (proteins or peptides in which L-cysteine or L-methionine). Considering that the concentration of thiol, including L-cysteine and glutathione, in intracellular fluid is about 10 mM, it is presumed that the platinum(II)-based antitumor reagents first react with sulfur donor nucleophiles, which is kinetically favored and

after that form thermodynamically more stable Pt-DNA compounds.

tigation of substitution reactions of these complexes.

triamine or 1,5-diamino-3-azapentane) or *terp*y (2,2<sup>0</sup>

concentration of nucleophile are described by Eq. (3):

the GSH pass almost through the origin (**Figure 2**).

[PtCl(terpy)]<sup>+</sup> with guanosine-5<sup>0</sup>

5'-GMP ratio of 1:2:10 [7].

2,2<sup>0</sup> :60

**197**

The monofunctional complexes represent a good model for investigations of platinum(II) interactions with various biomolecules which contains sulfur and nitrogens. The structures of complexes disable the bifunctional coordination to the DNA, because of that, they do not exhibit antitumor properties, but simplify inves-

The most studied monofunctional complexes are [PtCl(terpy)]<sup>+</sup> and [PtCl (dien)]<sup>+</sup> and their aqua analog in different reaction conditions. *Dien* (diethylene-

,200-terpyridine. The electronic communication between three pyridine rings

tridentate ligands, while the fourth coordination place is occupied with labile ligand, mostly chlorido ligand. *Terpy* ligand affects nucleophilic substitution reactions which are controlled by strong π-acceptor ability of the tridentate chelate

causes a decrease in electronic density on the platinum center due to additional formation of π-back bond and makes it more electrophilic and more reactive. Considering that platinum as soft acid prefers soft bases such as sulfurcoordinated biomolecules, we have studied kinetics for the complex formation of

absence of glutathione (GSH) at pH ca. 6, with concentration [Pt(terpy)Cl]<sup>+</sup>

The observed pseudo-first-order rate constants, *k*obs, as a function of the total

A least-squares fit of the data according to Eq. (3) resulted in values for the forward anation rate constants, *k*2, and the reverse equation rate constant, *k*<sup>1</sup> [2]. The substitution reactions are characterized by almost zero values for *k*1. Thus, the complex formation reaction for the GSH goes almost to completion. Linear plots of the observed *pseudo*-first-order rate constants *k*obs versus the total concentration of

The intercept is very small within the experimental error limits (**Figure 2**), illustrating that the solvent cannot effectively displace the coordinated nucleophile. Thus, no significant solvent or reverse reaction path was observed in the present systems, such that direct nucleophilic substitution is the major observed reaction pathway under the selected conditions. The following rate law can be formulated:

:60


*k*obs ¼ *k*<sup>1</sup> þ *k*<sup>2</sup> ½ � nucleophile (3)

,2″-terpyridine) are

:GSH:

**biomolecules in correlation with HSAB principle**

**4.1 Substitution reactions of platinum(II) complexes**

*DOI: http://dx.doi.org/10.5772/intechopen.91682*

#### **Figure 1.**

*Schematic representation of the mechanisms for substitution reactions.*

entering group, whereas dissociative interchange (ID) mechanisms do not. If the process of breaking the bond between the central metal ion and the outgoing ligand L has a greater impact on the rate of reaction, the mechanism is ID, and if forming a new bond between the central metal ion and the entering ligand X has a greater impact on the chemical reaction rate, the mechanism is marked with IA [2, 3].

The associative mechanism is well-known and preferred for four-coordinated square-planar complexes. Dissociative mechanisms are more common for sixcoordinated octahedral complexes. Five-coordinated complexes could react in both mechanisms [4]. For investigations of complex-ligand substitution reactions, experimental techniques such as spectroscopic techniques (UV–Vis, NMR, Mössbauer, IR, Raman, EPR spectroscopy, MS), rapid cryogenic X-ray structure determinations of reactive intermediates, matrix isolation of reactive intermediates, fast kinetic techniques, low-temperature kinetics, high-pressure kinetic and thermodynamic techniques to construct volume profiles as compared to energy profiles, and theoretical methods to analyze and predict reaction mechanisms are widely used [2–4].

#### **3.1 Bioinorganic reactions**

Under the classification of bioinorganic reactions, we consider the interactions of metal ions with biomolecules under physiological conditions. Ligand affinity and possible coordination geometries of the metal center are important bioinorganic principles. Metal–ligand bonds are closely related to the HSAB nature of metals and their preferred ligands. Many factors could affect metal–ligand complex formation including the formation of competing equilibria-solubility products, complexation, and/or acid–base equilibrium constants—sometimes referred to as "metal ion speciation" which all affect the complex formation. Ion size and charge, preferred metal coordination geometry, and ligand chelation effects all affect metal uptake. In biological systems, as in all others, metal ions exist in an inner coordination sphere with ligands binding directly to the metal. The bioinorganic reaction mechanism includes investigation of all processes which occur during applications of metalbased drugs. Thus, the determination of mechanism helps to clarify what will happen after administrations of the drugs and helps to improve medical characteristics of them.
