Many imidazole (IMZ) derivatives of pharmaceutical interest, that are potentially catalytic in dephosphorylation reactions, are soluble solely in mixtures of water and organic solvent. In order to understand these poorly explored reactions and properly compare them, a thorough study related to solvent effects for the analogous spontaneous reaction and with common IMZ derivatives is necessary, which lacks in the literature. Herein, we report a quantitative solvent effect analysis in DMSO/water mixtures for: (i) the hydrolysis reaction of diethyl 2,4-dinitrophenyl phosphate (DEDNPP) and (ii) nucleophilic reaction of IMZ and 1-methylimidazole (MEI) with DEDNPP. The solvent effect was satisfactory fitted with multiple regression analysis, correlating the obtained second order rate constants with solvent parameters such as acidity, basicity and polarity/polarizability from Catalán's scale. The contribution of these parameters can furnish tools to elucidate the reactivity in these mediums. Interestingly, IMZ is more reactive than MEI in DMSO, compared to solely water, which is accounted to the availability of hydrogen bonding formation. Nuclear magnetic resonance ((1)H, (13)C and (31)P), mass spectrometry, thermodynamic analysis and DFT calculations were carried out to corroborate the nucleophilic mechanism proposed.