Azanone (nitroxyl, HNO) is a highly reactive compound whose biological role is still a matter of debate. One possible route for its formation is NO reduction by biological reductants. These reactions have been historically discarded due to the negative redox potential for the NO,H+/HNO couple. However, the NO to HNO conversion mediated by vitamins C, E, and aromatic alcohols has been recently shown to be feasible from a chemical standpoint. Based on these precedents, we decided to study the reaction of NO with thiols as potential sources of HNO. Using two complementary approaches, trapping by a Mn porphyrin and an HNO electrochemical sensor, we found that under anaerobic conditions aliphatic and aromatic thiols (as well as selenols) are able to convert NO to HNO, albeit at different rates. Further mechanistic analysis using ab initio methods shows that the reaction between NO and the thiol produces a free radical adduct RSNOH, which reacts with a second NO molecule to produce HNO and a nitrosothiol. The nitrosothiol intermediate reacts further with RSH to produce a second molecule of HNO and RSSR, as previously reported.

The redox chemistry of H2S with NO and other oxidants containing the NO group is discussed on a mechanistic basis because of the expanding interest in their biological relevance, with an eye open to the chemical differences of H2S and thiols RSH. We focus on the properties of two “crosstalk” intermediates, SNO– (thionitrite) and SSNO– (perthionitrite, nitrosodisulfide) based in the largely controversial status on their identity and chemistry in aqueous/nonaqueous media, en route to the final products N2O, NO2 –, NH2OH/NH3, and S8. Thionitrous acid, generated either in the direct reaction of NO + H2S or through the transnitrosation of RSNO’s (nitrosothiols) with H2S at pH 7.4, is best described as a mixture of rapidly interconverting isomers, {(H)­SNO}. It is reactive in different competitive modes, with a half-life of a few seconds at pH 7.4 for homolytic cleavage of the N–S bond, and could be deprotonated at pH values of up to ca. 10, giving SNO–, a less reactive species than {(H)­SNO}. The latter mixture can also react with HS–, giving HNO and HS2 – (hydrogen disulfide), a S0(sulfane)-transfer reagent toward {(H)­SNO}, leading to SSNO–, a moderately stable species that slowly decomposes in aqueous sulfide-containing solutions in the minute–hour time scale, depending on [O2]. The previous characterization of HSNO/SNO– and SSNO– is critically discussed based on the available chemical and spectroscopic evidence (mass spectrometry, UV–vis, 15N NMR, Fourier transform infrared), together with computational studies including quantum mechanics/molecular mechanics molecular dynamics simulations that provide a structural and UV–vis description of the solvatochromic properties of cis-SSNO– acting as an electron donor in water, alcohols, and aprotic acceptor solvents. In this way, SSNO– is confirmed as the elusive “yellow intermediate” (I412) emerging in the aqueous crosstalk reactions, in contrast with its assignment to polysulfides, HS n –. The analysis extends to the coordination abilities of {(H)­SNO}, SNO–, and SSNO– into heme and nonheme iron centers, providing a basis for best unraveling their putative specific signaling roles.

The chemical reactivity of NO and its role in several biological processes seem well established. Despite this, the chemical reduction of • NO toward HNO has been historically discarded, mainly because of the negative reduction potential of NO. However, this value and its implications are nowadays under revision. The last reported redox potential, E′(NO,H + /HNO), at micromolar and picomolar concentrations of • NO and HNO, respectively, is between −0.3 and 0 V at pH 7.4. This potential implies that the one-electron-reduction process for NO is feasible under biological conditions and could be promoted by well-known biological reductants with reduction potentials of around −0.3 to −0.5 V. Moreover, the biologically compatible chemical reduction of • NO (nonenzymatic), like direct routes to HNO by alkylamines, aromatic and pseudoaromatic alcohols, thiols, and hydrogen sulfide, has been extensively explored by our group during the past decade. The aim of this work is to use a kinetic modeling approach to analyze electrochemical HNO measurements and to report for the first-time direct reaction rate constants between • NO and moderate reducing agents, producing HNO. These values are between 5 and 30 times higher than the previously reported k eff values. On the other hand, we also showed that reaction through successive attack by two NO molecules to biologically compatible compounds could produce HNO. After over 3 decades of intense research, the • NO chemistry is still there, ready to be discovered.

In this work, quantum mechanical calculations and Monte Carlo statistical mechanical simulations were carried out to investigate the solvation properties of HNO in aqueous solution and to evaluate the proton-coupled one electron reduction potential of NO toHNO, which is essential missing information to understand the fate of NO in the biological medium. Our results showed that theHNO molecule acts mainly as a hydrogen bond donor in aqueous solution with an average energy of -5.5 ± 1.3 kcal/mol. The solvation free energy of HNO in aqueous solution, computed using three approaches based on the linear response theory, revealed that the current prediction of the hydration free energy of HNO is, at least, 2 times underestimated. We proposed two pathways for the production of HNO through reduction of NO. The first pathway is the direct reduction of NO through proton-coupled electron transfer to produce HNO, and the second path is the reduction of the radical anion HONO, which is involved in equilibrium with NO in aqueous solution. We have shown that both pathways are viable processes under physiological conditions, having reduction potentials of E°' = -0.161 V and E°' ≈ 1 V for the first and second pathways, respectively. The results shows that both processes can be promoted by well-known biological reductants such as NADH, ascorbate, vitamin E (tocopherol), cysteine, and glutathione, for which the reduction potential at physiological pH is around -0.3 to -0.5 V. The computed reduction potential of NO through the radical anion HONO can also explain the recent experimental findings on the formation of HNO through the reduction of NO, promoted by HS, vitamin C, and aromatic alcohols. Therefore, these results contribute to shed some light into the question of whether and how HNO is produced in vivo and also for the understanding of the biochemical and physiological effects of NO.

Me-β-cyclodextrin (Me-βCD) and HP-β-cyclodextrin (HP-βCD) inclusion complexes with isoniazid (INH) were prepared with the aim of modulating the physicochemical and biopharmaceutical properties of the guest molecule, a well-known antibuberculosis drug. The architectures of the complexes were initially proposed according to NMR data Job plot and ROESY followed by density functional theory (DFT) calculations of (1)H NMR spectra using the PBE1PBE functional and 6-31G(d,p) basis set, including the water solvent effect with the polarizable continuum model (PCM), for various inclusion modes, providing support for the experimental proposal. An analysis of the (1)H NMR chemical shift values for the isoniazid (H6',8' and H5',9') and cyclodextrins (H3,5) C(1)H hydrogens, which are known to be very adequately described by the DFT methodology, revealed them to be extremely useful, promptly confirming the inclusion complex formation. An included mode which describes Me-βCD partially enclosing the hydrazide group of the INH is predicted as the most favorable supramolecular structure that can be used to explain the physicochemical properties of the encapsulated drug. Antibacterial activity was also evaluated, and the results indicated the inclusion complexes are a potential strategy for tuberculosis treatment.

This is a theoretical study aiming to understand molecular processes with water clusters, which can be useful for the detection of polycyclic aromatic hydrocarbons (PAHs) in space. From structural features, multiple-body energy fragmentation, vibrational spectra, and kinetics of hydrogen bonding, we investigate the effects of complexation between acenapththylene and a cyclic water trimer. Our results suggest that the trimer may be anchoring on the aromatic plane of the molecule in an unconventional ddd configuration (i.e., with three O–H bonds pointing down “d” to the molecular plane). By calculating a structural cooperativity parameter and the multiple-body energy terms for the complexes fragmentation, the ddd configuration results in a greater structural mobility of hydrogen bonding. The flipping kinetics indicates the persistence of this unconventional configuration of the water trimer for an energetically viable intermolecular complex at T ≤ 30 K. The structural changes of the complexes imply correlated changes in their IR/Raman spectra. Our results may arouse interest for investigating cold interstellar processes of PAHs in the presence of water aggregates. Moreover, the study may contribute to elucidate specific vibrational emission features of hydrated PAHs at low-temperature experiments.

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We report MP4(SDTQ) and CCSD(T) ab initio temperature‐dependent conformational populations for a series of cycloalkanes with increasing ring size, cycloundecane (11‐C), cyclododecane (12‐C), and cyclotridecane (13‐C), using extended basis sets. Our aim is to analyze the commonly used quantum chemical procedure for evaluating the thermal energy contribution to Gibbs free energy particularly the adequacy of standard harmonic oscillator vibrational partition function for large molecular systems. Experimental population data for cycloundecane, obtained from low temperature (90.1 K) 13C NMR, and cyclododecane, from gas phase electron diffraction experiment at 393.15 K, are available, and we found a good agreement with MP4(SDTQ) and CCSD(T) ab initio calculated conformational population. Our results indicate that the procedure of considering all 3N‐6 vibrational modes as harmonic oscillators seems adequate for the prediction of the preferred conformer of cycloundecane, cyclododecane, and cyclotridecane, in the absence of a more appropriate approach to treat the low frequency modes that is applicable for large molecules. Therefore, it can be expected to work satisfactorily in room temperature conformational analysis studies on large molecules containing a great number of vibrational frequencies below 625 cm−1, such as in supramolecular chemistry, biological, and material science applications. © 2012 Wiley Periodicals, Inc.