ABSTRACT
INTRODUCTION Water and molecular oxygen (dioxygen) are the two ubiquitous molecules that most frequently affect the stability of a drug substance. Though acids and bases are the main catalysts that control the hydrolytic behavior of organic compounds, they are not the principal factors in oxidations. In many cases, oxidation involving dioxygen is hard to understand and may also seem diffi cult to reproduce. This diffi culty is compounded by consideration of dioxygen as a potential reactant with organic substrates. In the orbital diagram of molecular oxygen, the highest occupied molecular orbitals are two degenerate π* orbitals in which there must be two electrons ( Fig. 1 ). The ground state, according to the Hund rule, is the state in which these orbitals are occupied by one electron and the spins are parallel: this is the triplet ground state ( 3 Σ g ) of atmospheric molecular oxygen ( Fig. 1 ). However, the vast majority of organic molecules are in the singlet state, and the reaction:
RH + (3∑g) O2 → ROOH (1)
is spin-forbidden. For this reason, a large number of organic molecules, in spite of the large negative value of the Gibbs free energy of oxidation, are kinetically inert toward dioxygen.
