Reactivity of Imidazole Derivatives toward Phosphate Triester in DMSO/Water Mixtures: A Comprehensive Study on the Solvent Effect

Abstract

Many imidazole (IMZ) derivatives of pharmaceutical interest, which 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 is lacking in the literature. Herein, we report a quantitative solvent effect analysis in DMSO/water mixtures for (i) the hydrolysis reaction of diethyl 2,4-dinitrophenylphosphate (DEDNPP) and (ii) the nucleophilic reaction of IMZ and 1-methylimidazole (MEI) with DEDNPP. The solvent effect was fitted satisfactorily 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 be taken into account to elucidate the reactivity in these media. Interestingly, IMZ is more reactive than MEI in DMSO, compared to water alone, which is attributed to the availability of hydrogen-bond formation. Nuclear magnetic resonance spectroscopy ((1)H, (13)C, and (31)P), mass spectrometry, thermodynamic analysis, and density functional theory calculations were carried out to corroborate the proposed nucleophilic mechanism.

The Importance of Methyl Positioning and Tautomeric Equilibria for Imidazole Nucleophilicity

“…The rate enhancements and activation parameters observed for the methyl nucleophiles are typical of nucleophilic attack and, based on previous studies, we propose the mechanism presented in Scheme , in which the nitrogen lone pair of xMEI attacks the phosphorous atom of DEDNPP and displaces 2,4‐dinitrophenolate (DNP, p K a =4.1) through a concerted mechanism, leading to a phosphorylated intermediate that should easily hydrolyze, regenerating the nucleophile . It is important to note that UV/Vis kinetic study follows the appearance of DNP, hence, k N in Table , refers solely to the first step of the mechanism.…”

“…For a more detailed mechanistic understanding, reactions of DEDNPP with 2 MEI and 4(5)MEI (NMR data for IMZ and 1 MEI has been reported previously) were investigated through 1 H and 31 P{ 1 H} NMR spectroscopy. Indeed, a thorough analysis of 1D NMR spectra and 2D NMR correlation maps lead to the complete 1 H, 13 C, and 31 P NMR chemical shift assignments given in Table , Figures and 3 and in the Supporting Information, which are consistent with Scheme .…”

“…[a] Additional data given in the Supporting Information. [b] The assignments for DEDNPP, DNP and DEP are in agreement with data found in the literature . [c] Overlapping signal.…”

“…It is noteworthy that we already reported similar NMR kinetics for the reactions of DEDNPP with IMZ and 1 MEI, for which an analogous behavior was observed involving the formation of phosphorylated intermediates. As pointed out previously, detection and most importantly understanding the reactivity of IMZ‐based phosphorylated intermediates is fundamental for biological purposes and we hope that the full set NMR assignments and kinetic for the xMEI‐based intermediates presented furnishes an important database for future studies.…”

“…Kinetic parametersf or the reaction of xMEI and IMZ with DEDNPP. [a] 4(5)MEII MZ [4a] 1MEI 2MEI [12] 9.6 À37.0 20.6 IMZ [12] 7.7 À42.6 20.4…”