Theoretical study of keto-enol tautomerism in 7-epi-clusianone by quantum chemical calculations of NMR chemical shifts.

Plants from the Garcinia genus have been used worldwide due to their therapeutic properties. Among the various metabolites isolated from this genus, 7-epi-clusianone, a tetraprenylated benzophenone, stands out for its wide range of identified biological activities. This benzophenone can exist in five tautomeric forms, although the benzene-d6 and chloroform-d3 solution nuclear magnetic resonance (NMR) spectra revealed only two tautomeric forms (B and C) in equilibrium, with concentration ratio depending on the solvent in which the spectrum was obtained. Calculated energy values suggested that tautomeric forms B and E would be prevalent in benzene-d6 solution, in contrast to the experimental data. Considering this conflicting result, we employed the statistical DP4 + method based on 13C and 1H NMR chemical shift calculations, in the gas phase and in benzene-d6 solution, to confirm that the B and C tautomeric forms of 7-epi-clusianone are the most prevalent in the experimental conditions.

Molecular properties and tautomeric equilibria of isolated flavins.

Flavins are employed as redox cofactors and chromophores in a plethora of flavoenzymes. Their versatility is an outcome of intrinsic molecular properties of the isoalloxazine ring modulated by the protein scaffold and surrounding solvent. Thus, an investigation of isolated flavins with high-level electronic-structure methods and with error assessment of the calculated properties will contribute to building better models of flavin reactivity. Here, we benchmarked ground-state properties such as electron affinity, gas-phase basicity, dipole moment, torsion energy, and tautomer stability for lumiflavins in all biologically relevant oxidation and charge states. Overall, multiconfigurational effects are small and chemical accuracy is achieved by coupled-cluster treatments of energetic properties. Augmented basis sets and extrapolations to the complete basis-set limit are necessary for consistent agreement with experimental energetics. Among DFT functionals tested, M06-2X shows the best performance for most properties, except gas-phase basicity, in which M06 and CAM-B3LYP perform better. Moreover, dipole moments of radical flavins show large deviations for all functionals studied. Tautomers with noncanonical protonation states are significantly populated at normal temperatures, adding to the complexity of modeling flavins. These results will guide future computational studies of flavoproteins and flavin chemistry by indicating the limitations of electronic-structure methodologies and the contributions of multiple tautomeric states.

Crystal structure, Hirshfeld surface analysis and spectroscopic characterization of the di-enol tautomeric form of the compound 3,3'-[(2-sulf-an-yl-idene-1,3-di-thiole-4,5-di-yl)bis-(sulfane-di-yl)]bis-(pentane-2,4-dione).

The reaction between [TBA]2[Zn(dmit)2] and 3-chloro-2,4-penta-nedione yielded single crystals of the title compound, (3E,3'E)-3,3'-[(2-sulfanylidene-1,3-dithiole-4,5-diyl)bis(sulfanediyl)]bis(4-hydroxypent-3-en-2-one), C13H14O4S5, after solvent evaporation. The title compound crystallizes in the triclinic space group P with two mol-ecules related by an inversion center present in the unit cell. The central thione ring moiety contains a carbon-carbon double bond covalently linked to two sulfoxide substituents located outside of the plane of the ring. The S-C-C-S torsion angles are -176.18 (8) and -0.54 (18)°. Intra-molecular hydrogen bonds occur within the two dione substituents (1.67-1.69 Å). Adjacent asymmetric units are linked by C-H⋯S (2.89-2.90 Å), S⋯S [3.569 (1) Å] and O⋯H [2.56-2.66 Šbetween non-stacked thione rings] short contacts.

Photolysis, tautomerism and conformational analysis of dehydroacetic acid and a comparison with 2-hydroxyacetophenone and 2-acetyl-1,3-cyclohexanodione.

The purpose of this work was to determine the tautomerism, the conformational analysis and photoreactivity of dehydroacetic acid (DHAA, 1). For that reason, the photolysis of DHAA (1) was performed at 254 nm and compared with two structurally similar compounds: 2-hydroxyacetophenone (HAP, 2) and 2-acetyl-1,3-cyclohexanodione (ACH, 3). We confirmed the degradation of 1 to acetic acid and we propose a mechanism on the assumption that a [2+2] cyclodimerization occurs (after UV light absorption) followed by some consecutive Norrish Type I cleavages, affording ketenes that end-up in acetic acid. The UV absorption study was conducted for all three compounds to gain insight about their electronic transitions, both experimentally and with computational simulations using TDDFT (B3LYP/6-31+G(d,p)) methods. A detailed analysis of the different tautomers and isomers that can be present in solution and the MOs involved in the electronic transitions was also achieved. The HOMO→LUMO transition was the least energetic optically active transition for 1 and 2, whereas 3 was recognized to have a HOMO-1→LUMO transition. These transitions were all of n→π∗ character.

Experimental and theoretical study on structure-tautomerism among edaravone, isoxazolone, and their heterocycles derivatives as antioxidants.

Edaravone is a heterocyclic pyrazolone compound. It has pronounced effect against free radicals, however renal and hepatic disorders have been reported. Isoxazolones are considered bioisosteric analogues of pyrazolones and may have comparable properties. Thus, we investigated the structural and electronic influences for edaravone, isoxazolone, and their tautomers on antioxidant process. Structure and tautomerism study among edaravone, isoxazolone and their heterocycles derivatives were related to antioxidant mechanisms by using the hybrid DFT method B3LYP with the basis sets 6-31++G(2d,2p). The C-H tautomer was the most stable and energetically favored among them. Intramolecular N-H-N hydrogen bonds and polar medium were responsible for the low energy differences among all possible tautomers. N-H tautomers in both systems proved to be better antioxidant by SET (single electron transfer), while O-H tautomers were better antioxidant on HAT (homolytic hydrogen atom transfer) mechanism. Theoretical calculation showed that edaravone is more potent than phenylisoxazolone, however, both has similar antioxidant scavenging on experimental DPPH. The carbonyliminic system played a very important role in the antioxidant activity for both studied classes.

Irbesartan desmotropes: Solid-state characterization, thermodynamic study and dissolution properties.

Irbesartan (IBS) is a tetrazole derivative and antihypertensive drug that has two interconvertible structures, 1H- and 2H-tautomers. The difference between them lies in the protonation of the tetrazole ring. In the solid-state, both tautomers can be isolated as crystal forms A (1H-tautomer) and B (2H-tautomer). Studies have reported that IBS is a polymorphic system and its forms A and B are related monotropically. These reports indicate form B as the most stable and less soluble form. Therefore, the goal of this contribution is to demonstrate through a complete solid-state characterization, thermodynamic study and dissolution properties that the IBS forms are desmotropes that are not related monotropically. However, the intention is also to call attention to the importance of conducting strict chemical and in solid-state quality controls on the IBS raw materials. Hence, powder X-ray diffraction (PXRD) and Raman spectroscopy (RS) at ambient and non-ambient conditions, differential scanning calorimetry (DSC), hot stage microscopy (HSM), Fourier transform infrared (FT-IR) and scanning electron microscopy (SEM) techniques were applied. Furthermore, intrinsic dissolution rate (IDR) and structural stability studies at 98% relative humidity (RH), 25 °C and 40 °C were conducted as well. The results show that in fact, form A is approximately four-fold more soluble than form B. In addition, both IBS forms are stable at ambient conditions. Nevertheless, structural and/or chemical instability was observed in form B at 40 °C and 98% RH. IBS has been confirmed as a desmotropic system rather than a polymorphic one. Consequently, forms A and B are not related monotropically.

Tautomerism of uracil and related compounds: A mass spectrometry study.

It has been demonstrated that uracil has a preponderant tautomeric form, but it is also known that different tautomers co-exist in this equilibrium. In this work, mass spectrometry is used as a helpful tool to analyse the equilibria, using derivative compounds to forbid the presence of some tautomers and ion trap mass spectrometry to follow relevant fragmentation pathways. Theoretical calculations were performed to confirm tautomers abundance by energy minimization in gas phase. Analysis of mass spectra of uracil, three methyl-substituted uracils, 2-thiouracil and three benzouracils suggest that uracil exists mainly as three tautomers in gas phase: one major structure that corresponds to the classical structure of uracil (pyrimidine-2,4(1H,3H)-dione) bearing two carbonyls and two NH moieties, and two minor enolic forms (4-hydroxypyrimidin-2(1H)-one and 2-hydroxypyrimidin-4(1H)-one). Such tautomeric distribution is supported by theoretical calculations, which show that they are the three most stable tautomers.

Anti-Mycobacterial Evaluation of 7-Chloro-4-Aminoquinolines and Hologram Quantitative Structure-Activity Relationship (HQSAR) Modeling of Amino-Imino Tautomers.

In an ongoing research program for the development of new anti-tuberculosis drugs, we synthesized three series (A, B, and C) of 7-chloro-4-aminoquinolines, which were evaluated in vitro against Mycobacterium tuberculosis (MTB). Now, we report the anti-MTB and cytotoxicity evaluations of a new series, D (D01-D21). Considering the active compounds of series A (A01-A13), B (B01-B13), C (C01-C07), and D (D01-D09), we compose a data set of 42 compounds and carried out hologram quantitative structure-activity relationship (HQSAR) analysis. The amino-imino tautomerism of the 4-aminoquinoline moiety was considered using both amino (I) and imino (II) forms as independent datasets. The best HQSAR model from each dataset was internally validated and both models showed significant statistical indexes. Tautomer I model: leave-one-out (LOO) cross-validated correlation coefficient (q²) = 0.80, squared correlation coefficient (r²) = 0.97, standard error (SE) = 0.12, cross-validated standard error (SEcv) = 0.32. Tautomer II model: q² = 0.77, r² = 0.98, SE = 0.10, SEcv = 0.35. Both models were externally validated by predicting the activity values of the corresponding test set, and the tautomer II model, which showed the best external prediction performance, was used to predict the biological activity responses of the compounds that were not evaluated in the anti-MTB trials due to poor solubility, pointing out D21 for further solubility studies to attempt to determine its actual biological activity.

Natural polyprenylated benzophenone: keto-enol tautomerism from density functional calculations and the AIM theory.

The quantum theory of atoms in molecules (QTAIM) and density functional theory (DFT) calculations were employed to investigate the structure and tautomeric equilibrium of epiclusianone, a polyisoprenylated benzophenone with interesting biological activities. Two different exchange-correlation functionals were employed, namely ωB97x-D and M06-2x, including implicit solvent models (benzene and DMSO). Our results for the thermodynamic properties show that the isomer in which the H atom is bonded to the oxygen away from the benzene ring is the most stable tautomer form of the epiclusianone, thus confirming previous charge density analysis from X-ray diffraction data (Martins et al. J Braz Chem Soc 18(8):1515-1523, 22).

The (1) H NMR spectrum of pyrazole in a nematic phase.

The experimental (1) H nuclear magnetic resonance (NMR) spectrum of 1H-pyrazole was recorded in thermotropic nematic liquid crystal N-(p-ethoxybenzylidene)-p-butylaniline (EBBA) within the temperature range of 299-308 K. Two of three observable dipolar DHH -couplings appeared to be equal at each temperature because of fast prototropic tautomerism. Analysis of the Saupe orientational order parameters using fixed geometry determined by computations and experimental dipolar couplings results in a situation in which the molecular orientation relative to the magnetic field (and the liquid crystal director) can be described exceptionally by a single parameter. Copyright © 2016 John Wiley & Sons, Ltd.

Synthesis, spectroscopic and computational characterization of the tautomerism of pyrazoline derivatives from chalcones.

In the present study a series of novel pyrazolines derivatives has been synthesized, and their structures assigned on the basis of FT-Raman, (1)H and (13)C NMR spectral data and computational DFT calculations. A joint computational study using B3LYP/6-311G(2d,2p) density functional theory and FT-Raman investigation on the tautomerism of 3-(4-substituted-phenyl)-4,5-dihydro-5-(4-substituted-phenyl)pyrazole-1-carbothioamide and 3-(4-substituted-phenyl)-4,5-dihydro-5-(4-substituted-phenyl)pyrazole-1-carboxamide are presented. The structures were characterized as a minimum in the potential energy surface using DFT. The calculated Raman and NMR spectra were of such remarkable agreement to the experimental results that the equilibrium between tautomeric forms has been discussed in detail. Our study suggests the existence of tautomers, the carboxamide/carbothioamide group may tautomerize, in the solid state or in solution. Thermodynamic data calculated suggests that the R(CS)NH2 and R(CO)NH2 species are more stable than the R(CNH)SH and R(CNH)OH species. Additionally, results found for the (1)H NMR shifting, pointed out to which structure is present.

Theoretical study of tautomers and photoisomers of avobenzone by DFT methods.

Organic ultraviolet (UV) filters such as cinnamates, benzophenones, p-aminobenzoic derivatives, and avobenzone (which have well-established and recognized UV-filtering efficacies) are employed in cosmetic/pharmaceutical products to minimize the harm caused by exposure of the skin to sunlight. In this study, a detailed investigation of the photostability and tautomerism mechanisms of avobenzone was performed utilizing DFT methods. The UV spectral profile of avobenzone was also simulated, and the results showed good agreement with experimental data. Furthermore, the calculations were able to distinguish tautomers and photoisomers of the studied organic filter based on their properties, thus showing the potential to develop new organic UV filters. Graphical Abstract Theoretical studies of avobenzone and its tautomers by TD-DFT.

1-(7-chloro-1,4-dihydroquinolin-4-ylidene)thiosemicarbazide and its hydrochloride: evidence for the existence of a stable imine tautomer in the solid state of 4-aminoquinoline free bases, an anomalous case in nitrogen heterocycles.

In the solid state, crystals of both 1-(7-chloro-1,4-dihydroquinolin-4-ylidene)thiosemicarbazide-methanol-water (2/1/1), 2C10H9ClN4S·CH3OH·H2O, (I), and its hydrochloride salt {systematic name: [(7-chloro-1,4-dihydroquinolin-4-ylidene)azaniumyl]thiourea chloride}, C10H10ClN4S(+)·Cl(-), (II), assume the imine tautomeric form, contrary to other 4-amino-7-chloroquinolines. Of particular interest are the N-C bond lengths, which have appreciable double-bond character, and the C-N-C aromatic ring bond angle. Both of these parameters have been studied extensively in 4-amino-substituted quinolines. The crystal structures of (I) and (II) in this study provide interesting examples of the amino-imino tautomerism which exists in this class of compound and is, to the best of our knowledge, hitherto unreported.

Investigating albendazole desmotropes by solid-state NMR spectroscopy.

Characterization of the molecular structure and physicochemical solid-state properties of the solid forms of pharmaceutical compounds is a key requirement for successful commercialization as potential active ingredients in drug products. These properties can ultimately have a critical effect on the solubility and bioavailability of the final drug product. Here, the desmotropy of Albendazole forms I and II was investigated at the atomic level. Ultrafast magic angle spinning (MAS) solid-state nuclear magnetic resonance (NMR) spectroscopy, together with powder X-ray diffraction, thermal analysis, and Fourier transform infrared spectroscopy, were performed on polycrystalline samples of the two solids in order to fully characterize and distinguish the two forms. High-resolution one-dimensional (1)H, (13)C, and (15)N together with two-dimensional (1)H/(1)H single quantum-single quantum, (1)H/(1)H single quantum-double quantum, and (1)H/(13)C chemical shift correlation solid-state NMR experiments under MAS conditions were extensively used to decipher the intramolecular and intermolecular hydrogen bonding interactions present in both solid forms. These experiments enabled the unequivocal identification of the tautomers of each desmotrope. Our results also revealed that both solid forms may be described as dimeric structures, with different intermolecular hydrogen bonds connecting the tautomers in each dimer.