Modeling of protonation processes in acetohydroxamic acid

This work presents a theoretical study of acetohydroxamic acid and its protonation processes using ab initio methodology at the MP2(FC)/cc-pdVZ level. We find the amide form more stable than the imidic tautomer by less than 1.0 kcal mol(-)(1). For comparison with the experimental data, a three-dimensional conformational study is performed on the most stable tautomer (amide). From this study, the different barriers to rotation and inversion are determined and the intramolecular hydrogen bond between the OH group and the carbonyl oxygen is characterized. The electrostatic potential distribution shows three possible sites for electrophilic attack, but it is shown that only two of them, the carbonyl oxygen and the nitrogen atoms, are actual protonation sites. The protonation energy (proton affinity) is obtained from the results of the neutral and charged species. Proton affinities for the species charged on the carbonyl oxygen and the nitrogen atoms are estimated to be 203.4 and 194.5 kcal mol(-)(1), respectively. The development of a statistical model permits the quantification of DeltaG (gas-phase basicity) for the two protonation processes. In this way, the carbonyl oxygen protonated form is found to be more stable than that of the nitrogen atoms by 8.3 kcal mol(-)(1) at 1 atm and 298.15 K, due to the enthalpic contribution. As temperature increases, the proportion of the nitrogen protonated form increases slightly.     

Theoretical and experimental study of 15N NMR protonation shifts

A combined theoretical and experimental study revealed that the nature of the upfield (shielding) protonation effect in ¹⁵N NMR originates in the change of the contribution of the sp²‐hybridized nitrogen lone pair on protonation resulting in a marked shielding of nitrogen of about 100 ppm. On the contrary, for amine‐type nitrogen, protonation of the nitrogen lone pair results in the deshielding protonation effect of about 25 ppm, so that the total deshielding protonation effect of about 10 ppm is due to the interplay of the contributions of adjacent natural bond orbitals. A versatile computational scheme for the calculation of ¹⁵N NMR chemical shifts of protonated nitrogen species and their neutral precursors is proposed at the density functional theory level taking into account solvent effects within the supermolecule solvation model. Copyright © 2015 John Wiley & Sons, Ltd.     

Deprotonation sites of acetohydroxamic acid isomers. A theoretical and experimental study

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).     

Theoretical study on the protonation of AZA-aromatics

The protonation of azanaphthalenes and azabenzenes has been studied theoretically using CNDO/2 wavefunctions and perturbation theory in order to examine the correlation between pK_a values and quantum-mechanical quantities.[/p]     

Theoretical and experimental vibrational study of phenylurea: structure, solvent effect and inclusion process with the beta-cyclodextrin in the solid state

FTIR and Raman vibrational spectroscopic techniques as well as DFT quantum chemical calculation were used for characterizing conformational changes of phenylurea (a herbicide parent molecule) occurring from solid state to aqueous medium. Experimental infrared frequencies were assigned on the base of urea and benzenic derivatives spectroscopic data available in the literature and vibrational normal modes analytical calculation at the fully optimized geometry. Investigation of isotopic and solvent effects has revealed that the structure of phenylurea is particularly sensitive to the electrostatic environment via hydrogen non covalent bonds. The ability of beta-cyclodextrin (beta-CD) to form host-guest inclusion complex with phenylurea in the solid state was also evidenced by significant frequency shifts observed in the 1400-1800 cm(-1) spectral range.     

Theoretical study of the role of solvent Stark effect in electron transitions

The possible influence of the solvent Stark effect (SSE) on the solvatochromic shift in electron transitions has been analyzed by using the ASEP/MD (averaged solvent electrostatic potential from molecular dynamics) method. With this purpose, four molecules, two polar (acrolein and formaldehyde) and two non-polar (p-difluorobenzene and trans-difluoroethene) have been studied in solvents of diverse polarity. Independently of the nature of the system we found that the contribution of SSE on the average value of the solvent shift or on the multipole moment values is negligible. In the case of centro-symmetric molecules, our results permit to discard the SSE as cause of the solvent shift found, which must be assigned to the electrostatic interaction of the solute quadrupole and higher multipoles with the solvent. As the SSE values provide also a measure of the errors introduced by the mean field approximation (MFA), these results indicate that MFA permits a very accurate determination of the solvent shift at the same time that it reduces drastically the computational cost. Finally, a new procedure suited to the ASEP/MD method has been presented that permits to estimate the inhomogeneous broadening of spectral bands, complementing the information provided by mean field theories. This procedure does not need additional quantum calculations and its computational cost is minimal.     

Equilibrium study of ternary complexes involving heteroaromaticN-bases and acetohydroxamic acid

Summary Stability constants (K _MAL ^MA ) and other thermodynamic parameters, including statistical factors relating to the ternary complexes (MAL) [M=Co^II, Ni^II, Cu^II or Zn^II; A=2, 2-dipyridylamine (A³), 5-nitro-o-phenanthroline (A⁵), 5-methyl-o-phenanthroline (A⁶); LH=acetohydroxamic acid] have been determined at 25° C, at ionic strength 0.1 M KNO₃. The results are compared with data on aminopolycarboxylic acids, such as iminodiacetic acid (A¹), and other unsubstituted heteroaromaticN-bases:e.g. 2, 2-bipyridine (A²),o-phenanthroline (A⁴). The resulting stability sequence is: , and for heteroaromaticN-bases: . The results have been explained in the light of electrostatic interactions, -acidities of the primary ligands (A) andcistrans equilibria for MAL.     

Solubility of tridecanedioic acid in pure solvent systems: An experimental and computational study

Solubility has been extensively investigated by the phase equilibria approach at the mesoscale level, but its origin on the molecular and electronic levels is poorly understood. This study explored the solubility behaviour of crystalline solid in selected pure solvents with various functional groups by using both phase equilibria and molecular modelling methods. The model compound tridecanedioic acid (TDDA) solubility in methanol, ethanol, acetic acid, acetone, and ethyl acetate was determined from T = (283.15 to 323.15) K by a static method. It was found that almost all solutions studied exhibit non-ideal behaviour and deviate positively from Raoult’s law indicating the important role of homo-molecules interactions. Thermodynamic analyses of solution suggest that both enthalpy and entropy of solution govern the dissolution process. Computational studies on solubility behaviour were performed by using both density functional theory (DFT) calculations and molecular dynamic (MD) simulations. The results conclude that the (solute + solvent) interaction is not the only factor determining solubility, and (solvent + solvent) interaction also plays an important role. The simulated results are found to be qualitatively consistent with experimental values. Finally, solubility values were correlated by the empirically modified Apelblat equation and two local composition models of Wilson and NRTL.     

The effect of acetohydroxamic acid on stainless steel corrosion in nitric acid

We present the first study of the effect of acetohydroxamic acid (AHA) on the corrosion behaviour of stainless steels. Particularly, studies have been performed using steels and physico-chemical conditions equivalent to those proposed for use in advanced nuclear reprocessing platforms. In these, AHA has been shown to have little effect on either steel passivation or reductive dissolution of both SS304L and SS316L. However, under transpassive dissolution conditions, AHA while in part electrochemically oxidised to acetic acid and nitroxyl/hydroxylamine, also complexes with Fe^3 +, inhibiting secondary passivation and driving transpassive dissolution of both steels.     

A density functional theory study of the conformational properties of 1,2-ethanediamine: protonation and solvent effects

 The structures and the conformational energies of nonprotonated, monoprotonated and diprotonated 1,2-ethanediamine have been investigated through density functional theory. The relative performance of local and gradient-corrected functionals is discussed. The existence of hydrogen-bond formation has been determined with electron localisation function calculations. Proton affinities for nonprotonated and monoprotonated 1,2-ethanediamine have been calculated and are in agreement with experimental data. The influence of solvation has been accounted for through the self-consistent isodensity polarisable continuum model. The results for the nonprotonated conformers show that solvation stabilises those conformers which have the lone pair in an antiperiplanar conformation. Solvation of the monoprotonated conformer stabilises significantly the “anti” conformation, which is unstable in the gas phase. For the di-protonated species, solvation stabilises slightly the gauche conformer, which is unstable in the gas phase. Received: 28 September 1999 / Accepted: 2 May 2000 / Published online: 27 September 2000     

Theoretical study on the protonation of cucurbit[6]uril

Abstract  

The most probable structures of the cucurbit[6]uril·H₃O⁺ and cucurbit[6]uril·(H₃O⁺)₂ cationic complex species have been derived by quantum mechanical DFT calculations. In these two complexes, each of the H₃O⁺ ions is bound by three strong linear hydrogen bonds to three carbonyl oxygen atoms of the parent macrocycle.     

Theoretical study on the protonation of bambus[6]uril

Abstract  

Quantum mechanical density functional theory (DFT) calculations were used to derive the most probable structures of the bambus[6]uril·H₃O⁺ and bambus[6]uril·(H₃O⁺)₂ cationic complex species. In these two complexes, each of the considered H₃O⁺ ions is bound by three strong linear hydrogen bonds to the three corresponding carbonyl oxygens of the parent macrocyclic receptor.     

Theoretical and experimental study of the inclusion complexes of ferulic acid with cyclodextrins

The inclusion complexation behaviour of ferulic acid (FA) with β-cyclodextrin (β-CD) and hydroxypropyl-β-cyclodextrin (HP-β-CD) was investigated by UV–vis, fluorescence and ¹H NMR spectroscopy. Since the guest may exist in either anionic or neutral form, the experiments were performed at different pH values. The stoichiometry and association constants of the complexes were determined by nonlinear regression analysis. The phase-solubility studies indicated that the water solubility of FA was improved through complexation with β-CD and HP-β-CD. An increase in the antioxidant reactivity was observed when inclusion complexes that FA formed with CDs were studied. Based on the NMR data, the spatial configurations of FA/β-CD and FA/HP-β-CD complexes were proposed, which suggested that FA entered into the cavity of β-CD from the narrow side, with the lipophilic aromatic ring and ethylenic moieties inside the CD cavity, and the –COOH group was close to the wider rim and exposed outside the cavity. A theoretical study of the complexes using molecular modelling gives the results in good agreement with the NMR data.     

One-electron oxidation of acetohydroxamic acid: the intermediacy of nitroxyl and peroxynitrite

The pharmacological effects of hydroxamate derivatives have been attributed not only to metal chelation or enzyme inhibition but also to their ability to serve as nitroxyl (HNO/NO(-)) and nitric oxide (NO) donors. However, the mechanism underlying the formation of these reactive nitrogen species is not clear and requires further elucidation. In the present study, one-electron oxidation of acetohydroxamic acid (aceto-HX) by (?)OH, (?)N(3), (?)NO(2), CO(3)(?-), and O(2)(?-) radicals was investigated using pulse radiolysis. It is demonstrated that only (?)OH, (?)N(3), and CO(3)(?-) radicals attack effectively and selectively the deprotonated form of the hydroxamate moiety, yielding the respective transient nitroxide radical. This nitroxide radical is a weak acid (CH(3)C(O)NHO(?), pK(a) = 9.1), which decays via a pH-dependent second-order reaction, 2k(2CH(3)C(O)NO(?-)) = (5.6 ± 0.4) × 10(7) M(-1) s(-1) (I = 0.002 M), 2k(CH(3)C(O)NO(?-) + CH(3)C(O)NHO(?)) = (8.3 ± 0.5) × 10(8) M(-1) s(-1)), and 2k(2CH(3)C(O)NHO(?)) = (8.7 ± 1.3) × 10(7) M(-1) s(-1). The second-order decomposition of the nitroxide yields transient species, one of which decomposes via a first-order reaction whose rate increases linearly upon increasing [CH(3)C(O)NHO(-)] or [OH(-)]. One-electron oxidation of aceto-HX under anoxia does not give rise to nitrite even after exposure to O(2), indicating that NO is not formed during the decomposition of the nitroxide radical. The presence of oxidants such as Tempol or O(2) during CH(3)C(O)NO(?-) decomposition had no effect on the reaction kinetics. Nevertheless, in the presence of Temopl, which does not react with NO but does with HNO, the formation of the hydroxylamine Tempol-H was observed. In the presence of O(2), about 60% of CH(3)C(O)NO(?-) yields ONOO(-), indicating that 30% NO(-) is formed in this system. It is concluded that under pulse radiolysis conditions, the transient nitroxide radicals derived from one-electron oxidation of aceto-HX decompose bimoleculary via a complex mechanism forming nitroxyl rather than NO.     

Theoretical study on the solvent effect of the nitrosyl cation (NO+) generating reaction

Nitrosyl cation (NO⁺) generating reaction HONO + H⁺ → NO⁺ + H₂O has been theoretically investigated by B3LYP and high‐electron‐correlation QCISD methods with 6‐31G (d,p) basis set. The solvent effects on the geometries, reaction path properties, energies, thermodynamic, and kinetic characters in four solvents (benzene, tetrahydrofuran, acetonitrile, and water) have been calculated using self‐consistent reaction field (SCRF) approach with the polarizable continuum model (PCM). The results show that the activation energy barriers and the relative energies of the products are decreased with increase of the polarities of the solvents, and the reaction is favored in polar solvents thermodynamically and kinetically. © 2010 Wiley Periodicals, Inc. Int J Quantum Chem, 2011     

Theoretical study of the unusual protonation properties of the active site cysteines in thioredoxin

The thiol/disulfide oxidoreductases of the thioredoxin family have, in the active site, two cysteines that can be in a reduced or an oxidized form. One of the cysteines in the reduced state is deprotonated, and it is called nucleophilic cysteine. The pK(a) of this cysteine is different from that of a normal cysteine and varies widely among the different enzymes of this family. However, the factors responsible for the different degrees of stabilization of nucleophilic cysteine thiolate are not fully understood. Here, we have studied the well-known hypothesis of proton sharing between the active site thiols by performing a linear transit scan for the transfer of the proton between the active site cysteines. We used a two-layered (DFT/MM) ONIOM formalism, with the active site region treated at the B3LYP/6-31+G(d) level and the remains of the protein treated with the Amber Parm94 force field. The solvation free energy was accounted for with a continuum solvent model, by solving the Poisson-Boltzmann equation using the program Delphi. We have obtained excellent agreement with the experimental data available in the literature. Besides refuting the proton sharing hypothesis, our results include a value of 14.0 for the pK(a) of the buried cysteine, a quantity that has not been possible to obtain experimentally but which has been proven to be higher than 11. Additionally, this study also provides detailed information on the very interesting and so far unknown fact that the contribution of the enzymatic structure (8.3 kcal/mol) prevails in relation to that of the solvent (0.60 kcal/mol) concerning the differential stabilization of the active site thiolates.