Deprotonation Sites of Acetohydroxamic Acid Isomers. A Theoretical and Experimental Study

Abstract

Theoretical (ab initio calculations) and experimental (NMR, spectrophotometric, and potentiometric measurements) investigations of the isomers of acetohydroxamic acid (AHA) and their deprotonation processes have been performed. Calculations with the Gaussian 98 package, refined at the MP2(FC)/AUG-cc-pVDZ level considering the molecule isolated, indicate that the Z(cis) amide is the most stable form of the neutral molecule. This species and the less stable (Z)-imide form undergo deprotonation, giving rise to two stable anions. Upon deprotonation, the E(trans) forms give three stable anions. The ab initio calculations were performed in solution as well, regarding water as a continuous dielectric; on the basis of the relative energies of the most stable anion and neutral forms, calculated with MP2/PCM/AUG-cc-pVDZ, N-deprotonation of the amide (Z or E) structure appeared to be the most likely process in solution. NMR measurements provided evidence for the existence of (Z)- and (E)-isomers of both the neutral and anion forms in solution. Comparisons of the dynamic NMR and NOESY (one-dimensional) results obtained for the neutral species and their anions were consistent with N-deprotonation, which occurred preferentially to O-deprotonation. The (microscopic) acid dissociation constants of the two isomers determined at 25 degrees C from the pH dependence of the relevant chemical shifts, pK(E) = 9.01 and pK(Z) = 9.35, were consistent with the spectrophotometric and potentiometric evaluations (pK(HA) = 9.31).

Synthesis, Solution Thermodynamics, and X‐ray Study of CuII [12]Metallacrown‐4 with GABA Hydroxamic Acid: An Unprecedented Crystal Structure of a [12]MC‐4 with a γ‐Aminohydroxamate

“…). [19] The two protonation processes of the GABAha anion (L À ) overlap and cannot be distinguished by potentiometry. [20] To elucidate the protonation microequilibria, GABAha was studied by conducting 1 H NMR titrations in D 2 O solution.…”

Kinetics and Mechanism of Oxidation of Hydroxyurea Derivatives with Hexacyanoferrate(III) in Aqueous Solution

“…N-methylhydroxyurea (NMHU) and methoxyurea (MetU). The hydroxamic acids contain the smallest O=CNH unit that can bind to the DNA helix, 14,15 and the observed biological activities of hydroxamic acids might be related to the similarity between the O=CNH unit and analogous structural segments found in proteins. 16 Hence, knowledge of the favoured ionization sites is important for understanding the role played by hydroxamic acids in biological processes, but also in metal ion complexation, since these processes could be interrelated.…”

Ab initio molecular dynamics study of the hydration of the formohydroxamate anion

“…The preferred deprotonation site for acid molecules in liquid water is still in dispute. Experiments applying different spectroscopic methods, chemical substituents, solvents, and in some cases, N-and O-alkylation (thus preventing deprotonation at those sites), have reached differing conclusions or have suggested that both tautomers may be present [5][6][7][8][9][10]. On the theoretical side, Hartree Fock (HF), Møller-Plesset second-order (MP2), and semi-empirical quantum methods have shown that in the gas phase, formohydroxamic acid and acetohydroxamic acid preferentially deprotonate at the N-site [9][10][11].…”

“…1c). This trend holds when a dielectric continuum model [10] or a semi-empirical quantum chemistry description using a gas phase cluster with four explicit water molecules [11] is used to mimic an aqueous environment solvating the hydroxamate anion, although both treatments predict that water stabilizes the O-deprotonated cis-tautomer more than the N-deprotonated one. Density Functional Theory (DFT) with the B3LYP exchange correlation functional [12,13] yields a similar relative stability for isolated hydroxamate anions in the gas phase [14].…”

“…The N-deprotonated tautomer, which has been shown to be stable in water, or at least stable enough to coexist with the O-acid anion form [6][7][8][9][10], has an unusual motif. It has several electronegative atoms in close proximity.…”