The asymmetric sulfoxidation reaction of imidazole-based prochiral sulfides was studied to explore the mechanistic details of the highly efficient esomeprazole process, which is one of the few industrial scale catalytic asymmetric procedures. The synthetic studies revealed that the smallest subunit governing the selectivity in the esomeprazole process is an imidazole ring. Thus, by using the esomeprazole procedure methyl imidazole sulfide could be oxidized as efficiently as its several functionalized derivatives, including pyrmetazol. However, alkylation of the imidazole nitrogen led to a major drop of the enantioselectivity. Our atmospheric pressure chemical ionization-mass spectrometry (APCI/MS) studies indicate that addition of small amounts of water to the reaction mixture facilitates the formation of mononuclear titanium species, which are the active catalytic intermediates of the selective oxidation reaction. One of the most important features of the esomeprazole procedure is that amine additives increase the enantioselectivity of the oxidation process. The NMR studies of the presumed reaction intermediates show that under catalytic conditions the amines are able to coordinate to titanium and dissociate the coordinated imidazole substrate. The density functional theory (DFT) modelling studies provided new insights in the mechanism of the asymmetric induction. It was found that the oxidation requires a lower activation energy if the imidazole sulfide precursor does not coordinate to titanium. Two possible reaction paths were explored for this out of sphere oxidation mechanism. The most important interaction governing the enantioselection is hydrogen bonding between the NH of the imidazole ring and the chiral tartrate ligand on titanium. Furthermore, the oxidation reaction imposes an important structural constraint to the TS structure involving a linear arrangement of the peroxide oxygens and the sulfur atom. This constraint and the N coordination of imidazole leads to a very strained structure for the inner sphere mechanism of the oxidation, which leads to a much higher activation barrier than the corresponding out of sphere process, and therefore it is unlikely.