Probing the Reactive Center for Site Selective Protonation in a Molecule INTRODUCTION The protonation reactions or the physico-chemical process of protonation are ubiquitous in almost all the areas of chemistry and biochemistry (Stewart, 1985; Carrol, 1998; Zhao & Zhang 2004; Ken- nedy, Mayhew,Thomas & Watts, 2003 ; Bouchoux 2007). The majority of chemical reactions occur in acid medium. The chemical process of protonation is fundamental of many chemical rearrangements, and enzymatic reactions (Kennedy, Mayhew, Thomas & Watts, 2003). The resulting proton- ated molecule is frequently a pivotal intermediate that guides the succeeding steps of the overall process. The knowledge of the intrinsic basicity and the site of protonation of a compound are central for the understanding of the mechanism of chemical reactions. The legend proton affinity is defined as the negative of the enthalpy change of a protonation reaction at the standard conditions. site of protonation, of the molecule. However, if there is no lone pair in the structure of the mol- ecule, the proton remains weakly attached to the sphere of the charge cloud of the molecule. The polarizing power of the proton induces a physical process of structural and energetic changes in the molecule. This phenomenon is, in particular, at the origin of the site of protonation, has consider- able effect on the strength and length of the bonds (Bouchoux, 2007). The structural and energetic changes induced by the polarizing power of the proton are expected to be at its maximum at the gas phase of the molecule. Thus, the gas-phase basicity is certainly the ideal revelator of the structural and energetic characteristics of the molecular protonation process. THE PREFERRED SITE OF PROTONATION