Understanding the Exceptional Properties of Nitroacetamides in Water: A Computational Model Including the Solvent

Abstract

Proton transfer in water involving C–H bonds is a challenge and nitro compounds have been studied for many years as good examples. The effect of substituents on acidity of protons geminal to the nitro group is exploited here with new pKa measurements and electronic structure models, the latter including explicit water environment. Substituents with the amide moiety display an exceptional combination of acidity and solubility in water. In order to find a rationale for the unexpected pKa changes in the (ZZ′)NCO- substituents, we measured and modeled the pKa with Z=Z′=H and Z=Z′=methyl. The dominant contribution to the observed pKa can be understood with advanced computational experiments, where the geminal proton is smoothly moved to the solvent bath. These models, mostly based on density-functional theory (DFT), include the explicit solvent (water) and statistical thermal fluctuations. As a first approximation, the change of pKa can be correlated with the average energy difference between the two tautomeric forms (aci and nitro, respectively). The contribution of the solvent molecules interacting with the solute to the proton transfer mechanism is made evident.

Probing the Structure of Toxic Amyloid-β Oligomers with Electron Spin Resonance and Molecular Modeling

“…At each incubation time, the time elapsed since the first pH measurement until the last insertion into ESR tube was shorter than 1 h. The pH was measured at 21 °C with a Fisher Scientific accumet (TM) AE150 equipment connected to a pH electrode (single junction and epoxy body VWR electrode) according to a well-tested protocol. 88,89 The system was calibrated before every measurement with two standard pH buffers at pH 4.01 and 7.01 (HI 7004, HI 7007).…”

Probing Reactivity with External Forces: The Case of Nitroacetamides in Water

“…In Table 1 and Table 2 , we display the values obtained by titration of compounds 2 and 3 , providing by arithmetic mean 4.76 and 6.91, respectively. The 7.23 for compound 1 was determined in our previous work using the same procedure [ 16 ].…”

“…In this work, we continued the detailed analysis of solvent effects in the process of H extraction that we first introduced in ref. [ 16 ]. In particular, we used a simplified model of atomic interactions, approximated at the density-functional tight-binding level, but extended to the analysis of 100 extraction trajectories.…”

“…The final goal of our models is to investigate the mechanism of the nitroacetamide deprotonation reaction within a density-functional theory (DFT) approximation of electrons in a system composed of the solute nitroacetamide compound and a sample of solvent water molecules. In our previous work [ 16 ], we applied an implementations of DFT suited for systems of several hundreds of atoms in order to obtain the energy change in the sample upon the transfer of one of the H protons into water. In this work, we opted for extending the usage of the semi-empirical model we used before applying DFT time-consuming calculations.…”

“…In our previous work [ 16 ], we addressed this issue by measuring apparent ionization constant ( ) for a series of substituted nitromethanes. We found that the amide moiety has a strong effect on the C -H acidity.…”