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Summary Tylenchulus semipenetrans nematodes affect citrus crops and may develop resistance to commercially available nematicides. In this sense, two series of 1,3,4-oxa- and thiadiazole compounds have been recently synthesised and tested as nematicides against T. semipenetrans, demonstrating promising results. We report herein a molecular modelling study that combines these two series of congeneric compounds to form a single and enhanced data set. The chemical structures of these compounds were correlated with the respective nematicidal activities (pLC50) using multivariate image analysis (MIA) descriptors in quantitative structure-activity relationship (QSAR) analysis. The partial least squares (PLS) regression yielded reliable and predictive models (, , and ). Therefore, novel 1,3,4-oxa- and thiadiazole derivatives were proposed and a few of them exhibited predicted nematicidal performance better than those of the parent compounds.

This work reports studies at the molecular level of a series of modified sulfonylureas to determine the chemophoric sites responsible for their antifungal and herbicidal activities. For forage conservation, high antifungal potency and low phytotoxicity are required. A molecular modeling study based on multivariate image analysis applied to quantitative structure-activity relationship (MIA-QSAR) was performed to model these properties, as well as to guide the design of new agrochemical candidates. As a result, the MIA-QSAR models were reliable, robust, and predictive; for antifungal activity, the averages of the main validation parameters were

The gauche conformer in 1-X,2-Y-disubstituted ethanes, that is, the staggered orientation in which X and Y are in closer contact, is only favored for relatively small substituents that do not give rise to large X···Y steric repulsion. For more diffuse substituents, weakly attractive orbital interactions between antiperiplanar bonds (i.e., hyperconjugation) cannot overrule the repulsive forces between X and Y. Our quantum chemical analyses of the rotational isomerism of XCH2CH2Y (X = F, OH; Y = I) at ZORA-BP86-D3(BJ)/QZ4P reveal that indeed the anti conformer is generally favored due to a less destabilizing I···F and I···O-H steric repulsion. The only case when the gauche conformer is preferred is when the hydroxyl hydrogen is oriented toward the iodine atom in the 2-iodoethanol. This is because of the significantly stabilizing covalent component of the I···H-O intramolecular hydrogen bond. Therefore, we show that strong intramolecular interactions can overcome the steric repulsion between bulky substituents in 1,2-disubstituted ethanes and cause the gauche effect. Our quantum chemical computations have guided nuclear magnetic resonance experiments that confirm the increase in the gauche population as X goes from F to OH.

Fluorine is often considered the only halogen to effectively engage in hydrogen bonds, while the other halogens, particularly iodine, are not electronegative enough to participate as hydrogen bond acceptors in electrostatic interactions. 2-Fluoroethanol and 2-iodoethanol have been studied herein to test this assumption, since a highly stable gauche conformation can experience the intramolecular hydrogen bond. However, the infrared O H stretching frequency indicates that the hydroxyl group in 2-fluoroethanol is not engaged in intramolecular hydrogen bond, while the corresponding vibration mode for 2-iodoethanol suggests that not only the O H is engaged in such interaction, but also that intramolecular hydrogen bond may drive the conformational equilibrium in this molecule. Theoretical calculations support the covalent nature of this interaction, and provide evidence that intermolecular hydrogen bond with a water molecule, and probably with the polar solvents tested experimentally, occurs with the hydroxyl rather than with the iodine substituent, as conventionally, in order to keep the intramolecular hydrogen bond effective.

A series of aryloxyacetic acid derivatives have demonstrated promising herbicidal performance by inhibition of the hydroxyphenylpyruvate deoxygenase (HPPD) enzyme. We hereby applied quantitative structure-activity relationship (QSAR) and docking strategies to model and chemically understand the bioactivities of these compounds and subsequently propose unprecedented analogues aiming at improving the herbicidal and environmental properties. Bulky halogens at the 2-, 3-, 4-, and 6-positions of an aromatic ring, CF

The anti-tyrosinase activity of the leaf extract of Schinus terebinthifolius, also known as Brazilian peppertree, was evaluated using multiple in silico approaches, such as molecular homology, molecular docking, MM-GBSA, molecular dynamics, MM-PBSA, QSAR, and skin permeability predictions. With these computational tools, the compounds that downregulate tyrosinase enzyme activity could be evaluated, and more potent molecules could be identified. The results indicated that various compounds, especially luteolin, are accountable for the anti-tyrosinase activity of S. terebinthifolius. For cosmetic application, further studies with luteolin are especially recommended, for having presented a good performance both in theoretical inhibition (30.92 kJ mol

The relation between chemical attributes of complexed Fe sources and the efficiency of foliar fertilization is still unclear. This study aimed to investigate the influence of Fe-complex stability o...

We have quantum chemically investigated the bonding between archetypical Lewis acids and bases. Our state‐of‐the‐art computations on the X3B−NY3 Lewis pairs have revealed the origin behind the systematic increase in B−N bond strength as X and Y are varied from F to Cl, Br, I, H. For H3B−NY3, the bonding trend is driven by the commonly accepted mechanism of donor−acceptor [HOMO(base)−LUMO(acid)] interaction. Interestingly, for X3B−NH3, the bonding mechanism is determined by the energy required to deform the BX3 to the pyramidal geometry it adopts in the adduct. Thus, Lewis acids that can more easily pyramidalize form stronger bonds with Lewis bases. The decrease in the strain energy of pyramidalization on going from BF3 to BI3 is directly caused by the weakening of the B−X bond strength, which stems primarily from the bonding in the plane of the molecule (σ‐like) and not in the π system, at variance with the currently accepted mechanism., That's strainful! The stability of Lewis pairs involving boron trihalides and ammonia is driven by the energy required to deform the Lewis acids upon complexation, while the stability of Lewis pairs between borane and nitrogen trihalides is determined by the strength of orbital interactions.

Molecular polarity governs lipophilicity, which in turn determines important agrochemical and environmental properties, such as soil sorption and bioconcentration of organic compounds. Since the C–F bond is the most polar in organic chemistry, the orientation of fluorine substituents originating from the rotation around C–C(F) bonds should affect the polarity and, consequently, the physicochemical and biological properties of fluorine-containing agrochemicals. Accordingly, this study aims to determine the most likely conformers of some fluorine-containing agrochemicals and to correlate their molecular dipole moments with the respective n-octanol/water partition coefficients (log P), in order to investigate the dependence of the lipophilicity with the molecular conformation.

Herein, we have investigated the effect of an endocyclic group (forming the N–C–C–F fragment) on the conformational preferences of 2-fluorocyclohexanone analogs. A combined approach of nuclear magnetic resonance and density functional theory calculations was employed to assess the conformational equilibrium in several media. In turn, natural bond orbital analysis and the conformational behavior of other 2-halocyclohexanone analogs were used to get more insights about the intramolecular interactions governing the conformer stabilities. Our results reveal that any stabilization from interactions featured in the gauche effect is overcome by a short-range interaction of the fluorine substituent with the carbonyl group. Consequently, the gauche effect in heterocyclic compounds is not as stabilizing as in their acyclic counterparts. Only the electrostatic gauche effect takes place even in polar solvents owing to an attraction between the axial fluorine and an endocyclic quaternary ammonium group.

Pyrimidine compounds comprise a class of acetohydroxyacid synthase (AHAS) inhibitors, thus possessing herbicidal activity. Due to the ongoing development of resistance by weeds to current herbicides, the design of new agrochemical candidates is often required. This work reports the proposition of unprecedented pyrimidines as herbicides guided by quantitative structure-activity relationship (QSAR) modeling. Multivariate image analysis (MIA) descriptors for 66 pyrimidine derivatives obtained from different sources were regressed against inhibitory activity data, and the resulting QSAR models were found to be reliable and predictive (r

Sulphur, not phosphorus, is the only known third-row element capable of experiencing an electrostatic gauche effect with fluorine. Some six-membered rings containing an endocyclic phosphorus atom and a β-fluorine substituent that can interconvert to axial (gauche relative to phosphorus) and equatorial positions were then analysed. While phosphines do not establish an electrostatic attraction between fluorine and phosphorus, some oxidised forms exhibit surprising stability for the sterically disfavoured axial orientation. Because the nature of this behaviour was not obvious, since an intramolecular hydrogen bond can appear, a phosphonium derivative was further studied and its axial conformation was found to be highly stable. A preference for the gauche arrangement appears even for the acyclic and sterically hindered (2-fluoroethyl)triphenylphosphonium cation. On the other hand, (ethane-1,2-diyl)bis(phosphonium) cations are exclusively in anti conformation due to an (+/+)-electrostatic repulsion between the positively charged phosphonium groups.

Chlorinated agrochemicals play a major role in toxicity due especially to the labile C - Cl bond and high lipophilicity of organochlorines. In turn, urea and thiourea herbicides are widely used for weed control. A series of substituted N-benzoyl-N'-pyrimidin-2-yl thioureas has been recently synthesized and tested against Brassica napus L., demonstrating promising herbicidal activities, particularly for chlorinated derivatives. We have therefore modeled these activities using multivariate image analysis applied to quantitative structure-activity relationships (MIA-QSAR) to find out a significant and reliable correlation between measured and predicted inhibition of B. napus L. root growth (%) and, ultimately, to propose effective, non-chlorinated and/or less lipophilic N-(4-methanesulfonyl)benzoyl-N'-(pyrimidin-2-yl)thiourea candidates. The model was found to be predictive, giving an average r

The solubility of inhalational anaesthetics in the bloodstream is related to the minimum alveolar concentration (MAC), which is an indicator of anaesthetic gas potency. The blood-gas partition coefficient (Kbg) is a measure of how much anaesthetics bind to plasma proteins in the blood compared to air. Just like the octanol–water partition coefficient, the Kbg may be related to the molecular dipole moment (μ), which can be modulated by the molecular conformation. Our quantum-chemical calculations demonstrated that subtle stereoelectronic interactions, namely those responsible for the anomeric and gauche effects, control the conformational equilibrium of some widely used volatile fluorinated anaesthetics and, consequently, of their molecular dipole moments. Since a remarkable correlation between empirical Kbg and calculated μ was found for these anaesthetics, the average molecular dipole moments may be used to predict the anaesthetic gas potency and other properties, such as lipid solubility, of inhalational anaesthetic analogs.

The Perlin effect and its analog for fluorinated compounds (the fluorine Perlin-like effect) manifest on one-bond C─H (C─F for the fluorine Perlin-like effect) spin-spin coupling constants (SSCCs) in six-membered rings. These effects can be useful to probe the stereochemistry (axial or equatorial) of the C─H and C─F bonds, respectively. The origin of these effects has been debatable in the literature as being due to hyperconjugative interactions, dipolar effects, and induced current density. Accordingly, a variety of model compounds has been used to probe such effects since the cyclohexanone carbonyl group and the endocyclic heteroatom lone pairs play different roles on the above-mentioned effects. Thus, the 1 JC─F SSCC in fluorinated lactams and lactones were theoretically studied to gain further insight on the nature of the fluorine Perlin-like effect. In addition, because the intramolecular α-effect has recently gained attention for its importance in the reactivity and stereoelectronic interactions in peroxide compounds, some fluorinated 1,2-dioxanes and 1,2-dithianes were studied to evaluate the role of the α-effect on the behavior of 1 JC─F SSCCs. Differently from fluorinated ketones and ethers, the fluorine Perlin-like effect in the amides and esters cannot be explained by hyperconjugative or dipolar interactions alone, because the resonance in these groups affect the 1 JC─F values. The O─O and S─S-containing systems exhibit a strong fluorine Perlin-like effect, but unlike the α-effect, this behavior cannot be explained neither by hyperconjugation nor by dipolar interactions alone; the spatial proximity of the C─F and O─O/S─S bonds is proposed to affect the magnitude of the 1 JC─F SSCC.

The Perlin effect is an NMR phenomenon observed in six-membered rings and it is referred to as 1JC−Hax H2 coupling constants, i.e. on the Perlin effect. An important hyperconjugative interaction (πC=Y → σ*C-H, Y = O and S) operating in the studied systems seems to play a significant role for the observed 1JC−Hax H coupling constant. Compared to the gas phase, this behavior was found to be insensitive to implicit solvents (DMSO and water).

The active species of the Ishikawa´s reagent [N,N-diethyl-(1,1,2,3,3,3-hexafluoropropyl)amine] is a fluorinating hexafluoropropylamine used to convert alcohols into alkyl fluorides. On the other hand, it is also an example of model compound useful to probe conformational preferences using spectroscopic information from diastereotopic fluorines. Moreover, the possibility of experiencing both the generalized anomeric and gauche effects makes the Ishikawa´s reagent an ideal choice to study the governing stereoelectronic interactions of the conformational equilibrium of organofluorine compounds. The conformational equilibrium of the Ishikawa´s reagent was analyzed using NMR 3JH,F coupling constant data in different solvents, since the orientation of the diastereotopic fluorines relative to H-2 and F-2 changes with the medium. In nonpolar cyclohexane solvent, the preferred conformation experiences a weaker steric and electrostatic repulsion. The conformational behavior changes in the more polar pyridine solution, where the double fluorine gauche effect takes place, since F-2 is preferably gauche to both diastereotopic fluorines. An analysis of the rotation around the N–C(F2) bond indicates the manifestation of anomeric interactions (nN → σ*C–F), which can be demonstrated by means of 19F chemical shifts. The results were rationalized with the aid of theoretical calculations and natural bond orbital (NBO) analysis, allowing for the evaluation of competing steric, electrostatic and hyperconjugative interactions.

Whether hydroxyl hydrogen is directed towards a Lewis base substituent in an alkyl chain due to intramolecular hydrogen bonds or to avoid repulsion between the hydroxyl oxygen and the substituent is a debatable topic and difficult to probe. This is still more challenging when fluorine is the Lewis base substituent. This work reports a theoretical approach capable of dissecting the contributions from hydrogen bond and repulsion, allowing to decide which interaction dominates the orientation of the hydroxyl group in a high-energy tautomer of 3-fluoropiperidin-2-one. A comparison between the potential energy curves for the hydroxyl rotation in the axial and equatorial conformers revealed that repulsion between fluorine and oxygen contributes by ca. 1.2 kcal mol−1 to destabilize the cis isomer, while intramolecular hydrogen bond between fluorine and the hydroxyl group amounts by ca. 0.9 kcal mol−1 favoring the trans isomer. These are not the major effects governing the conformational equilibrium of the studied compound, which is rather dictated by N⋯O steric repulsion, but the obtained outcomes can be valuable to understand the role of F⋯H(O) hydrogen bonds in conformational analysis and, ultimately, in the design of performance fluorinated aliphatic alcohols.

Spin-spin coupling constant (SSCC) data may be useful in providing information on the stereochemistry and intramolecular interactions in molecules. One-bond C-H and C-F SSCCs (1JCH and 1JCF) are amongst the most important NMR parameters used to study the structure of alicyclic six-membered rings, because the Perlin effect, defined as 1JCHeq > 1JCHax, and the fluorine Perlin-like effect, defined as |1JCFeq| > |1JCFax|, are in wide currency to probe the conformations of these compounds. The origin of these effects has been usually attributed either to dipolar interactions or hyperconjugation, while the induced current density (ICD) has been recently correlated to the magnetic shielding tensors in some six-membered ring compounds, and then used to explain the Perlin effect. Accordingly, this work reports an analysis of the ICD as a descriptor of 1JCH and 1JCF in a series of six-membered rings to find out the role of the ICD in the conventional and fluorine Perlin effect. The atoms in molecules (AIM) magnetic responses obtained from density functional theory (DFT) calculations for the studied compounds did not show any relationship of the first-order electronic current density (ΔJ(1)) with the calculated Δ1JCHax-eq and Δ1JCFax-eq values. Consequently, the title effects cannot be precisely explained by ICD. Nevertheless, an interesting relationship between ΔJ(1) and Δdelocalization involving σCH* orbitals is observed.

The extraction and chemical characterization of essential oils from Syzygium aromaticum L., Origanum vulgare L., Mentha spicata L. and Eremanthus erythropappus M. is reported, as well as an evaluation of their antioxidant activity and of their major constituents eugenol, carvacrol, carvone and α-bisabolol, respectively, using colorimetric, electroanalytical and theoretical methods. Essential oils were obtained by hydrodistillation, identified by GC/MS and quantified using a GC coupled to a flame ionization detector. The colorimetric evaluation of the antioxidant activity was based on stabilization of DPPH radicals, β-carotene bleaching, deoxyribose degradation and reducing power. The electrochemical behavior was studied using cyclic voltammetry, and the dissociation enthalpy of the OH bond was theoretically estimated at the density functional theory ωB97X-D/6-31+g(d,p) level. The essential oils from S. aromaticum and O. vulgare L., and their major constituents eugenol and carvacrol, yielded antioxidant responses similar to the synthetic ascorbic acid and BHT, while eugenol and the essential oil from S. aromaticum exhibited better performance than carvacrol and the essential oil from O. vulgare L. Overall, eugenol was found to be a promising compound to replace marketed antioxidants or at least to be used in association with them.

We have quantum chemically investigated the rotational isomerism of 1,2‐dihaloethanes XCH2CH2X (X = F, Cl, Br, I) at ZORA‐BP86‐D3(BJ)/QZ4P. Our Kohn‐Sham molecular orbital (KS‐MO) analyses reveal that hyperconjugative orbital interactions favor the gauche conformation in all cases (X = F−I), not only for X = F as in the current model of this so‐called gauche effect. We show that, instead, it is the interplay of hyperconjugation with Pauli repulsion between lone‐pair‐type orbitals on the halogen substituents that constitutes the causal mechanism for the gauche effect. Thus, only in the case of the relatively small fluorine atoms, steric Pauli repulsion is too weak to overrule the gauche preference of the hyperconjugative orbital interactions. For the larger halogens, X⋅⋅⋅X steric Pauli repulsion becomes sufficiently destabilizing to shift the energetic preference from gauche to anti, despite the opposite preference of hyperconjugation., Beyond hyperconjugation! State‐of‐the‐art quantum chemical analyses reveal that, in 1,2‐dihaloethanes, hyperconjugation always favors the gauche conformation. It is the steric (Pauli) repulsion that is behind the trend known as the gauche effect: weak repulsion (X = F) leaves the gauche preference intact, whereas stronger repulsion (X = Cl, Br, I) shifts the preference to anti.

The concept of dipolar repulsion has been widely used to explain several phenomena in organic chemistry, including the conformational preferences of carbonyl compounds. This model, in which atoms and bonds are viewed as point charges and dipole moment vectors, respectively, is however oversimplified. To provide a causal model rooted in quantitative molecular orbital theory, we have analyzed the rotational isomerism of haloacetaldehydes OHC–CH2X (X = F, Cl, Br, I), using relativistic density functional theory. We have found that the overall trend in the rotational energy profiles is set by the combined effects of Pauli repulsion (introducing a barrier around gauche that separates minima at syn and anti), orbital interactions (which can pull the anti minimum towards anticlinal to maximize hyperconjugation), and electrostatic interactions. Only for X = F, not for X = Cl–I, electrostatic interactions push the preference from syn to anti. Our bonding analyses show how this trend is related to the compact nature of F versus the more diffuse nature of the heavier halogens., Beyond point charges! The point charge concept within dipolar repulsion model is valid for compact atoms like fluorine. This model breaks down for larger halogens, for which the electrostatic attraction between nuclei and charge densities dominates.

Chlordane is a worldwide banned organochlorine insecticide because of its hazard to animal and human health. It is also a persistent organic pollutant, which can affect either the soil or the aquatic life. The same applies to other chlorinated cyclodiene insecticides, such as dieldrin and aldrin. In turn, organofluorine compounds have a widespread use in agriculture. Therefore, density functional calculations and docking studies showed that the bioisosteric replacement of chlorines in the above-mentioned compounds by fluorines improves some physicochemical parameters used to estimate the toxicity and environmental risk of these compounds, as well as the ligand-enzyme (GABAA receptor-chloride channel complex) interactions related to their insecticidal activity. This work is an effort to provide an improved new class of organofluorine pesticides.

Multivariate image analysis applied to quantitative structure–activity relationships (MIA-QSAR) has proved to be a high-performance 2D tool for drug design purposes. Nonetheless, MIA-QSAR strategy does not efficiently incorporate conformational information. Therefore, understanding the implications of including this type of data into the MIA-QSAR model, in terms of predictability and interpretability, seems a crucial task. Conformational information was included considering the optimised geometries and the docked structures of a series of disulfide compounds potentially useful as SARS-CoV protease inhibitors. The traditional analysis (based on flat-shape molecules) proved itself as the most effective technique, which means that, despite the undeniable importance of conformation for biomolecular behaviour, this type of information did not bring relevant contributions for MIA-QSAR modelling. Consequently, promising drug candidates were proposed on the basis of MIA-plot analyses, which account for PLS regression coefficients and variable importance in projection scores of the MIA-QSAR model.

Quantitative structure-activity relationship (QSAR) is a molecular modeling technique widely used in the discovery of novel drugs. Currently, there are many approaches for performing such analysis, which are commonly classified from 1D to 6D. 2D and 3D techniques are among the most exploited ones. Multivariate image analysis applied to QSAR (MIA-QSAR) is an example of 2D methodology that has presented a satisfactory performance in the generation of effective prediction models for biological/physicochemical properties. However, once this is a 2D method, conformational information is not explicitly considered, despite the well-known role of such type of information in explaining the biochemical behavior. Thus, the importance of conformation is undeniable, but the requirement of this information for QSAR analysis still needs to be studied. Therefore, this work aimed to provide a method for encoding 3D information into MIA-QSAR descriptors and analyze the consequences of this inclusion on this methodology. The strategy consisted in fully optimizing the molecular geometries of anti-HCV compounds and three-dimensionally align them before performing the MIA-QSAR procedure. As a result, it was possible to verify that this type of information does not improve the MIA-QSAR modeling performance; instead, the traditional procedure consisting of maximally congruent substructures generated a more reliable prediction model.

The conformational behavior of cyclic monosaccharides has been widely studied over the past years, but there is no general agreement about which effects are in fact responsible for the observed conformational preferences. A recent microwave spectroscopy study determined the conformational equilibrium of d-glucose in the gas phase with a preference for a counterclockwise arrangement of the hydroxyl groups. Nevertheless, the effects that control this orientation are still uncertain because the role of intramolecular hydrogen bonds (IHBs), electrostatic and steric repulsions is not clear. This work reports a density functional theory approach based on the conformational energies of d-glucose and of some derivatives in which the anomeric hydroxyl is replaced with hydrogen (H, small and not prone to participate in proton transfer), fluorine (F, small, electronegative, and as capable as OH of forming hydrogen bonds as a proton acceptor), and chlorine (Cl, big and not anticipated to be involved in effective hydrogen bond formation) to obtain insights into the effects of the substituent at the anomeric carbon on the arrangement of the hydroxyl groups in d-glucose. The nature of the substituents at this position is crucial to determine the orientation of the remaining hydroxyl groups. Natural bond orbital (NBO) and quantum theory of atoms in molecules (QTAIM) analyses, in addition to NMR chemical shift calculations, have been provided to support the conformational energy outcomes. Overall, the results agree with the lack of IHBs forming four- and five-membered rings in d-glucose and emphasize that steric and electrostatic repulsions involving the hydroxyl groups in the clockwise orientation are driving forces of the conformational behavior.

Earlier studies with 2-bromocyclohexanone demonstrated a measurable long-range coupling constant (4 JH2,H6 ) for the equatorial conformer, although 4 JH2,H4 and 4 JH4,H6 were not observed; as a consequence, it is inferred that the carbonyl group plays an important role particularly due to hyperconjugative interactions σC2H2 →π*C═O and σC6H6 →π*C═O. In the present study, NBO analysis and coupling constant calculations were performed to cyclohexanone and cyclohexanethione alpha substituted with F, Cl, and Br, aiming to evaluate the halogen effect and acceptor character of the π* orbital on the long-range coupling pathway. The σC2H2 →π*C1═Y and σC6H6 →π*C1═Y (Y═O and S) hyperconjugative interactions for the equatorial conformer indeed contribute for the 4 JH2,H6 transmission mechanism. Surprisingly, the 4 JH2,H6 value is higher for the carbonyl compounds, although the interactions σC2H2 →π*C═Y and σC6H6 →π*C═Y are more efficient for the thiocarbonyl compounds. Accordingly, the Fermi contact (FC) contribution for the thiocarbonyl compounds decays deeper than in ketones, thus reducing more the 4 JH2,H6 values. Moreover, both πC═S →σ*C─X and πC═S →σ*C─H interactions seem to be stronger in thiocarbonyl than in carbonylic compounds. The implicit solvent effect (DMSO and water) on the coupling constant values was negligible when compared with the gas phase. On the other hand, an explicit solvent effect was found and 4 JH2,H6 for the thiocarbonyl compounds appeared to be more sensitive than for the cyclohexanones.

The preferred conformations of a small polyfunctional molecule containing fluorine, chlorine and hydroxyl groups, the 1-chloro-1,1-difluoro-2-pentanol (CDP), were completely elucidated using 1H, 13C and 19F NMR in three different solvents. While the Cl-C-C-O dihedral angle was asserted using coupling constant data for the diastereotopic fluorines, the Et-C-C-O torsional angle was analyzed by means of 1H NMR spectra with selective irradiation of the diastereotopic hydrogens and fluorines. In addition, unusual couplings of the hydroxyl hydrogen with a diastereotopic hydrogen and fluorines provided information on the O-H orientation. The behavior of 1JC,F when the solvents varied agrees with a weak F⋅⋅⋅HO intramolecular hydrogen bond. These findings were corroborated, and the governing interactions rationalized with the aid of high level CCSD(T) theoretical calculations. Noteworthy, hyperconjugation involving the electron-acceptor σ*C-Cl orbital drives the conformational equilibrium rather than the fluorine gauche effect.

We recently generalized the formerly alignment-dependent multivariate image analysis applied to quantitative structure-activity relationships (MIA-QSAR) method through the application of the discrete Fourier transform (DFT), allowing for its application to noncongruent and structurally diverse chemical compound data sets. Here we report the first practical application of this method in the screening of molecular entities of therapeutic interest, with human aromatase inhibitory activity as the case study. We developed an ensemble classification model based on the two-dimensional (2D) DFT MIA-QSAR descriptors, with which we screened the NCI Diversity Set V (1593 compounds) and obtained 34 chemical compounds with possible aromatase inhibitory activity. These compounds were docked into the aromatase active site, and the 10 most promising compounds were selected for in vitro experimental validation. Of these compounds, 7419 (nonsteroidal) and 89 201 (steroidal) demonstrated satisfactory antiproliferative and aromatase inhibitory activities. The obtained results suggest that the 2D-DFT MIA-QSAR method may be useful in ligand-based virtual screening of new molecular entities of therapeutic utility.

A concepção de ambiente para estudantes da educação básica e ensino médio foi obtida a partir da análise da percepção ambiental baseada em desenhos, enquanto as ações pró-ambientais mais importantes apontadas pelos estudantes foram capturadas por meio de um survey. Os dados de percepção ambiental e o nível das ações pró-ambientais foram correlacionados usando análise por componentes principais. A hipótese de que ações pró-ambientais significativas estão relacionadas com o nível de percepção ambiental foi confirmada. Portanto, atividades de ensino em educação ambiental baseada em resiliência sócio-ecológica são propostas para melhorar a percepção ambiental de estudantes e, consequentemente, conduzir a ações pró-ambientais efetivas.

Conformational stabilities of 2-halocyclohexane-1,3-diones are strongly affected by steric and dipolar effects involving the carbonyl groups and the equatorial halogen. However, 2-fluorocyclohexane-1,3-dione has been found to be mostly equatorial, because of electron delocalization in this conformer that overcomes repulsive interactions, while the other halogen derivatives perform as expected.

Rotation of the formyl group in halobenzaldehydes (halo = F, Cl, and Br) has been studied through high-level density functional theory (DFT) calculations and natural bond orbital (NBO) analysis. The isomeric and conformational energies are dictated by non-Lewis and Lewis-type interactions. The 4-substituted benzaldehydes the most stable isomer due especially to an effective electron resonance and small dipole moment, while destabilizing Lewis-type interactions slightly override the non-Lewis electron delocalization both in the syn and anti conformers of meta isomer. No significant halogen effect is observed on stabilities, excepting for the least stable ortho isomer, where the halogen interacts with the formyl group. Such interaction is more repulsive in the syn conformer (where the halogen and oxygen atoms face one another), but the nature of this interaction changes from predominantly electrostatic to steric contribution on going from F to Br. Infrared stretching vibrations, as well as NMR chemical shifts and spin-spin coupling constants, provided valuable insight into through-bond and through-space effects influencing the stabilities of these compounds.

Several chemical properties of complexes should be considered to base their suitable applications in agronomic and environmental domains. However, the determination of these characteristics is generally expensive and time consuming. Therefore, the prediction of properties in complexes using a simple and expeditious technique, such as infrared spectroscopy, is highly desirable. This study aimed to investigate the molecular structure and chemical properties of metal complexes, such as stability, metal complexed fraction, and solubility. The complexes were submitted to experimental FTIR analysis and the spectroscopic data were regressed against the above-mentioned properties using partial least squares (PLS) to obtain a predictive model. Low molecular weight carboxylic acids (citric acid, malic acid, tartaric acid, and oxalic acid) were used as complexing agents for three metals (Mn, Zn, and Fe) in two stoichiometric ratios of reaction (1:1 and 1:2, metal: ligand molar ratio). Solubility and complexation ratio appeared to be dependent on the ligand and stoichiometry. Citrate and oxalate have formed the most stable complexes with the tested metals. Metal-oxalates tend to form 1:2 complexes at the pH and stoichiometries tested, whereas citrate, malate, and tartrate tend to form 1:1 complexes. All the complexes exhibited monodentate coordination of carboxylic groups with metals. Overall, the predictive models were built to estimate the solubility and the ratio of complexed metals. Furthermore, the coordination mode of ligands to metals could also be assigned from infrared band shifts of the carboxylate groups. This work revealed crucial chemical properties to base the use of complexes, and show that the fast and non-destructive FTIR technique can be used for predict these properties.

Conformational effects, including some controversial examples, have been reported in this work for 2-substituted tetrahydropyrans and piperidines, and for the respective protonated compounds [substituent = F, OH, OCH3, NH2, NHCH3 and N(CH3)2]. Hyperconjugation plays a major role in most cases, either due to endo or exo-anomeric interactions, especially when nitrogen is the electron donor to an antiperiplanar σ* orbital. This interaction also seems to contribute for the Perlin and reverse fluorine Perlin-like effects, which are related to the relative magnitude of 1JC,H and 1JC,F coupling constants, respectively, in axial and equatorial conformers. However, the preference for an equatorial conformation appears when a hydrogen or methyl group of the substituent faces the ring, increasing the steric repulsion, even if concomitant with a hyperconjugative interaction in the axial isomer, such as for the well-known 2-aminotetrahydropyran. Unlike some reports in the literature, the gas phase 2-hydroxypiperidine experiences the herein called reverse anomeric effect, although the highly stabilizing nN → σ*C-O interaction in the axial isomer. Overall, steric effects should be taken into account when deciding for the normal or reverse anomeric effects as determinant factors of the stereochemical control of carbohydrate-like molecules.

An earlier study demonstrated that hyperconjugation operates in hydrazides by analyzing the N–H stretching mode in gas phase infrared (IR) spectroscopy, and then observing two very distinct bands corresponding to isolated isomers experiencing or not the nN → σ*N–H electron delocalization. The present work reports a chemical method to obtain insight on the hyperconjugation in hydrazide derivatives from solution IR spectroscopy. The analogous amides did not show a νN–H red-shifted band, as the electron donor orbital in the above hyperconjugative interaction does not exist. In addition, the effect of electron withdrawing groups bonded to a nitrogen atom, namely the trifluoroacetyl and the methanesulfonyl groups, was analyzed on the conformational isomerism and on the ability to induce a stronger hyperconjugation in the resulting compounds.

Macrocyclic compounds have been widely used as anion carriers, as they play important functions in chemical and biological systems. This work reports a theoretical study on free 1,4,7,10,13,16-hexaazacyclooctodeca-2,5,8,11,14,17-hexaene (HAC), as well as its complex with fluoride, chloride, bromide and acetate anions, with and without the presence of the sodium counterion, in the gas phase and implicit solvents (cyclohexane and acetonitrile), at the ωB97X-D/6-311G(d,p) level. The negative ∆G0 values indicate that the crown-anion complex is prone to be formed due to hydrogen bonds in all tested media. Nevertheless, such interactions weaken as the solvent polarity increases. The ΔG0 C6H12 values decrease when the counterion is taken into account, reinforcing the formation of the Na+‒HAC‒X− complex. However, the complexation is disfavored in polar solution, since the presence of the counterion increases the HAC-anion distance. Natural bond orbital analysis, the quantum theory of atoms in molecules and non-covalent interactions methods explored the nature and strength of the hydrogen bond interactions, while spin–spin coupling constant calculations for the fluoride-based complex (1h J F,H(N)) gave insight into the potential of this NMR parameter to experimentally probe the complexation of HAC with fluoride.

The 1 JC-F coupling constant can be useful to probe the conformational landscape of organofluorine compounds and the intramolecular interactions governing the stereochemistry of these compounds. Neighboring oxygen electron lone pairs and a carbonyl group relative to a C─F bond affect this coupling constant in an opposite way, and therefore, analysis of the interactions involving these entities simultaneously indicates which effect dominates 1 JC-F . Spin-spin coupling constant calculations for a series of fluorinated tetrahydropyrans, cyclohexanones, and dihydropyran-3-ones indicated that an electrostatic/dipolar interaction between the C─F and C═O bonds is more important than the steric interaction between the C─F bond and the oxygen electron lone pairs. An intuitive consequence of such outcome is that this interaction not only drives the coupling constant but can also be taken into account when aiming at the stereochemical control of functionalized organofluorine compounds.

The multivariate image analysis descriptors used in quantitative structure-activity relationships are direct representations of chemical structures as they are simply numerical decodifications of pixels forming the 2D chemical images. These MDs have found great utility in the modeling of diverse properties of organic molecules. Given the multicollinearity and high dimensionality of the data matrices generated with the MIA-QSAR approach, modeling techniques that involve the projection of the data space onto orthogonal components e.g. Partial Least Squares (PLS) have been generally used. However, the chemical interpretation of the PLS-based MIA-QSAR models, in terms of the structural moieties affecting the modeled bioactivity has not been straightforward. This work describes the 2D-contour maps based on the PLS regression coefficients, as a means of assessing the relevance of single MIA predictors to the response variable, and thus allowing for the structural, electronic and physicochemical interpre...

Despite the attractiveness in weed management, herbicides can produce several hazardous effects due to their persistence in the environment. It is therefore important to strike a balance between the herbicidal activity and ecotoxicological profile. The aim of the present paper is to perform a multi-objective QSPR modeling of the bioactivity and soil sorption profile of a dataset of triazine derivatives, in order to gain understanding on the structural features favoring both high herbicidal activity and low soil sorption. To this end, the Photosynthetic Electron Transport (PET) inhibitory activity and the logKOC are selected, and a MIA-QSPR model is built for the pI50/log Koc ratio. The obtained model presented satisfactory performance evidenced by the calibration and validation parameters. Structural interpretation of the built model is performed using the recently implemented MIA-Plot tool, providing important guidelines on the structural moieties related with high pI50/logKOC ratio values as a desirable requirement in the development of high activity and eco-friendly triazines.

Biomagnification of organic pollutants in food webs has been usually associated to hydrophobicity and other molecular descriptors. However, direct information on atoms and substituent positions in a molecular scaffold that most affect this biological property is not straightforward using traditional QSPR techniques. This work reports the QSPR modeling of biomagnification factors (logBMF) of a series of aromatic organochlorine compounds using three MIA-QSPR (multivariate image analysis applied to QSPR) approaches. The MIA-QSPR model based on augmented molecular images (described with atoms represented as circles with sizes proportional to the respective van der Waals radii and having colors numerically proportional to the Pauling's electronegativity) encoded better the logBMF data. The average results for the main statistical parameters used to attest the model's predictability were r2=0.85, q2=0.72 and r2test=0.85. In addition, chemical insights on substituents and respective positions at the biphenyl rings A and B, and dibenzo-p-dioxin and dibenzofuran motifs are given to aid the design of more ecofriendly derivatives.

Conformational analyses of β-fluorinated organophosphorus compounds were theoretically carried out to probe the role of a possible fluorine–phosphorus gauche effect in conformer stabilization, specifically using a phosphine, a phosphine oxide, phosphinic and phosphonic acids, and the corresponding anions as model compounds. This hypothesis emerged from recent findings for β-fluorinated sulfoxides, sulfones, and thionium cations, which exhibit the electrostatic gauche effect. Surprisingly, despite bearing a positively charged phosphorus atom, the studied compounds do not show a gauche preference in most gas phase conformers, while little predominance of gauche conformers in solution was calculated only in some cases, due to intramolecular hydrogen bonds. Steric and electrostatic repulsive interactions are invoked as dominating effects rather than electrostatic and/or hyperconjugative gauche effects, since conformational equilibrium in these compounds is better described by a well-balanced competition between anti and gauche conformers. Since the conformational equilibrium is not polarized towards a single conformer, the unusual three-bond coupling constants 3JP,F and 3JP,H can be useful to verify the changes in conformational populations with solvents, as confirmed by NMR calculations.

A QSPR modeling was carried out to predict the chromatographic retention times of a series of fatty acid methyl esters (FAME) widely used as standard in the characterization of lipids from agricultural and food products. Number of carbons, total double bonds, position of double bonds and geometric isomerism were used as descriptors to generate a Multiple Linear Regression (MLR) model. The best model yielded an RMSE = 0.167 and R2 = 0.999 for the calibration set, and RMSE = 0.151 and R2 = 1.000 for the test set. Number of carbons and total double bonds were the most important descriptors, according to the regression coefficients, but position of double bonds and isomerism cannot be neglected as they provide relevant information to improve the accuracy of the predicted property.

Tridimensional information is a fundamental aspect for modelling and explaining biological/physicochemical properties. In this sense, the goal of this study was to explore different approaches for encoding this type of information into MIA-QSAR (Multivariate Image Analysis applied to Quantitative Structure-Activity Relationships) descriptors and to effectively model these new features. Originally, MIA-QSAR is a technique based on the treatment of 2D images of molecules. The approaches explored in this work were: (I) the use of 2D image projections of computationally optimized molecular geometries as a source of 3D information for a powerful machine learning method (support vector machine applied to regression); (II) the use of slice images obtained from the optimized molecules placed inside a theoretical box as a source of 3D descriptors for a multi-way regression method (trilinear PLS); and (III) the use of images viewed from different faces of the above box as an alternative source of 3D MIA-QSAR descriptors. These strategies were applied in three different data sets comprising anti-HCV, anti-SARS-CoV, and anti-HIV compounds. Satisfactory parameters for both internal and external validation were achieved in all three models, and the statistical results of correlation were at least similar to those earlier reported for these series of compounds. Nevertheless, the risk of chance correlation could not be excluded as demonstrated by y-randomization tests. Whereas the traditional MIA-QSAR method, that uses perfectly congruent, non-optimized geometries of pharmacophoric substructures as images, is more efficient than 3D MIA-QSAR, the latter uses tridimensional digital objects as descriptors for the first time in QSAR for regression purposes.

Coxiella burnetii is a gram-negative bacterium able to infect several eukaryotic cells, mainly monocytes and macrophages. It is found widely in nature with ticks, birds, and mammals as major hosts. C. burnetii is also the biological warfare agent that causes Q fever, a disease that has no vaccine or proven chemotherapy available. Considering the current geopolitical context, this fact reinforces the need for discovering new treatments and molecular targets for drug design against C. burnetii. Among the main molecular targets against bacterial diseases reported, the enzyme dihydrofolate reductase (DHFR) has been investigated for several infectious diseases. In the present work, we applied molecular modeling techniques to evaluate the interactions of known DHFR inhibitors in the active sites of human and C. burnetii DHFR (HssDHFR and CbDHFR) in order to investigate their potential as selective inhibitors of CbDHFR. Results showed that most of the ligands studied compete for the binding site of the substrate more effectively than the reference drug trimethoprim. Also the most promising compounds were proposed as leads for the drug design of potential CbDHFR inhibitors.