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

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 form more stable complexes with class (b) cations.

• Pt(II) a soft acid prefers soft bases S-donor instead of N-donor ligands. Antitumor activity of platinum(II)-based drugs is explained by the assumption that they firstly react with S-donor biomolecules, which is kinetically more favorable and

then comes to form thermodynamically more stable Pt-DNA adducts.

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

Cr3+), and f-block metal ions (e.g., Th4+). On the other hand, ligands with soft P- or S-donors have a preference for heavier p-block metal ions (e.g., Tl+

).

s- and p-block metal cations (e.g., Na+

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

soft base, soft-soft interaction is favorable.

philic substitution reaction (Eq. (2)) [2, 3]:

are used [4].

**195**

mechanism (I) (**Figure 1**) [2].

determines the overall rate of the substitution reaction.

d-block metal ions (e.g., Pd2+, Ag+

Ligands with hard N- or O-donor atoms form more stable complexes with

Complex formation involves ligand substitution. If we suppose that metal ion is a hard acid, the hard-hard bond with ligands is favorable. If ligand is a soft base, ligand substitution will not be favorable. If metal ion is a soft acid and ligand is a

Although successful, the HSAB principle initially lacked a satisfactory quantita-

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 nucleo-

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

Nucleophilic substitution reactions, according to Langford and Gray, are carried out in three different mechanisms: dissociative (D), associative (A), or interchange

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

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

tive basis. Today it is possible to use DFT theory to derive electronic chemical potential values (electronic chemical potential) and chemical hardness values [1].

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

, Mg2+), early d-block metal cations (e.g., Co3+,

) and later

ð1Þ

ð2Þ

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 in order of electronegativity:

$$\text{F} > \text{O} > \text{N} > \text{Cl} > \text{Br} > \text{C} \sim \text{I} \sim \text{S} > \text{Se} > \text{P} > \text{As} > \text{Sb}$$

A hard acid is one that forms the most stable complexes with ligands containing donor atoms from the left side of the series. The reverse is true for a soft acid. This classification is listed in **Table 1**.

The applications of the HSAB principle are useful to predict thermodynamically stable M-L bonds. For example:

• 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 group –OPh.


**Table 1.**

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

*Correlation between HSAB Principle and Substitution Reactions in Bioinorganic Reactions DOI: http://dx.doi.org/10.5772/intechopen.91682*

• Pt(II) a soft acid prefers soft bases S-donor instead of N-donor ligands. Antitumor activity of platinum(II)-based drugs is explained by the assumption that they firstly react with S-donor biomolecules, which is kinetically more favorable and then comes to form thermodynamically more stable Pt-DNA adducts.

Ligands with hard N- or O-donor atoms form more stable complexes with s- and p-block metal cations (e.g., Na+ , Mg2+), early d-block metal cations (e.g., Co3+, Cr3+), and f-block metal ions (e.g., Th4+). On the other hand, ligands with soft P- or S-donors have a preference for heavier p-block metal ions (e.g., Tl+ ) and later d-block metal ions (e.g., Pd2+, Ag+ ).

Complex formation involves ligand substitution. If we suppose that metal ion is a hard acid, the hard-hard bond with ligands is favorable. If ligand is a soft base, ligand substitution will not be favorable. If metal ion is a soft acid and ligand is a soft base, soft-soft interaction is favorable.

Although successful, the HSAB principle initially lacked a satisfactory quantitative basis. Today it is possible to use DFT theory to derive electronic chemical potential values (electronic chemical potential) and chemical hardness values [1].
