**1. Introduction**

The aim of this chapter is to present connection between hard-soft acid–base principle with bioinorganic substitution reactions. Bioinorganic chemistry is an interdisciplinary field which connects inorganic chemistry with different types of chemistries, physics, medicine, biology, physiology, etc. This field includes studies of kinetic and thermodynamic of substitution reactions of transition metal ion coordination compounds and biomolecules such as enzymes, nucleic acids, proteins, peptides, amino acids, and others.

Ligand substitution reactions are the most fundamental type of chemical reaction that can occur when a metal complex is dissolved in solution in the presence of other nucleophiles. Acid–base properties of central metal ions and ligands are very important for understanding the mechanism of interactions between metal ions (Lewis acids) and various biomolecules (Lewis bases) with different donor atoms. HSAB principle is qualitatively useful to predict the preference of the metal for the ligand and to predict the stability of M-L bonds. Hard-hard or soft-soft bonds of acid and base contribute to the stabilization and strength of the bonds between donor and acceptor. These factors also include the charges and sizes of the cation and donor atom, their electronegativities, and the orbital's overlap between them.
