Expanding chalcogen bonds in thiophenes to interactions with halogens.

Compounds containing the thiophene moiety find several applications in physics and chemistry, such as electrical conduction, which depends on specific conformations to properly exhibiting the desired properties. In turn, chalcogen bonding has found to modulate the conformation of some N-thiophen-2-ylfomamides. Since halogens participate in a kin interaction (halogen bonding) and are abundant in agrochemicals, pharmaceuticals, and materials, we have quantum-chemically explored the interaction between organic halogen and thiophene as a conformational modulator in some model compounds. Although such interaction indeed appears, as demonstrated by atoms in molecules and natural bond orbital analysis, it is inefficient to control the conformational equilibrium. An energy decomposition analysis scheme demonstrated that halomethane and thiophene tend to move away from one another due to a core component (Pauli repulsion and exchange), which is mainly due to a deformation term. Therefore, chalcogen bonds with halogens appear weaker than with other chalcogens.

Fluorinated benzoxazinones designed via MIA-QSAR, docking and molecular dynamics as protoporphyrinogen IX oxidase inhibitors.

BACKGROUND: Fluorine plays a significant role in agrochemical science because approximately 25% of herbicides licensed worldwide contain this element. In a pool of previously synthesized benzoxazinones, some compounds contained fluorine and demonstrated inhibitory activities against protoporphyrinogen IX oxidase (PPO). Therefore, three data sets of benzoxazinone derivatives with known inhibitory activity against PPO were employed to build a multivariate image analysis applied to a quantitative structure-activity relationships (MIA-QSAR) model to identify improved analogs with at least one fluorine substituent. RESULTS: The QSAR model was vigorously validated and demonstrated to be highly predictive (r2 = 0.85, q2 = 0.71, and r2 pred = 0.88); thus, the model can provide reliable estimations for the PPO inhibitory activity of unknown derivatives. From these compounds, a couple of N-substituted benzoxazinones that contained the -CH2CHF2 group were found with predicted pKi values larger than 8 (Ki in mol L-1) and higher lipophilicity than the most active data set compounds. In addition, we carried out a systematic investigation of the binding mode of PPO by performing computational docking followed by molecular dynamics simulations. The proposed binding mode was consistent with experimental studies, and several potential key residues were identified. CONCLUSION: Two new proposed benzoxazinones exhibited better performance than compounds of the data set, and fluorine substituents played pivotal roles in describing the biological activities. © 2024 Society of Chemical Industry.

Theoretical Exploitation of 1,2,3,4,5,6-Hexachloro- and 1,2,3,4,5,6-Hexafluorocyclohexane Isomers as Biologically Active Compounds.

Hexachlorocyclohexanes (HCHs) have been widely explored as biological compounds during the last century. However, most of them were banned due to their potential toxicity in humans, animals, and the environment. Revisiting HCHs to explore their biological activity while improving key features is valuable and may lead to a new class of pesticides that utilizes the biological response of HCHs without their toxic characteristics. In this sense, the fluorine atom can be a possible alternative since a large number of therapeutics and agrochemicals have been developed with this halogen in their structure. We have evaluated herein the conformational behavior of HCHs and their bioisosteric fluorinated compounds, namely, hexafluorocyclohexanes (HFHs), through quantum-chemical calculations. We also explored the potential of the HCH and HFH isomers as biological compounds by docking them inside three possible targets. It was demonstrated that HCH and HFH have similar ligand-protein interactions with three pockets: the picrotoxin and barbiturate sites of the GABAA receptor and the ryanodine receptor. The results support HFHs as possible alternatives for HCHs since the replacement of Cl with F does not forfeit the main ligand-protein interactions. Finally, we demonstrated that HFHs have a lower log P than HCHs by almost two logarithmic units. This result highlights the role of fluorine in distribution and bioaccumulation.

Multivariate image analysis applied to quantitative structure-activity relationships and docking studies of recent hydroxyphenylpyruvate deoxygenase inhibitors.

BACKGROUND: Mesotrione is a triketone widely used as an inhibitor of the hydroxyphenylpyruvate deoxygenase (HPPD) enzyme. However, new agrochemicals should be developed continuously to tackle the problem of herbicide resistance. Two sets of mesotrione analogs have been synthesized recently and they have demonstrated successful phytotoxicity against weeds. In this study, these compounds were joined to form a single data set and the HPPD inhibition of this enlarged library of triketones was modeled using multivariate image analysis applied to quantitative structure-activity relationships (MIA-QSAR). Docking studies were also carried out to validate the MIA-QSAR findings and to aid the interpretation of ligand-enzyme interactions responsible for the bioactivity (pIC50 ). RESULTS: The MIA-QSAR models based on van der Waals radii (rvdW ), electronegativity (ε), and the rvdW /ε ratio as molecular descriptors were both predictive to an acceptable degree (r2 ≥ 0.80, q2 ≥ 0.68 and r2 pred ≥ 0.68). Subsequently, partial least squares (PLS) regression parameters were applied to predict the pIC50 values of newly proposed derivatives, yielding a few promising agrochemical candidates. The calculated log P for most of these derivatives was found to be higher than that of mesotrione and the library compounds, indicating that they should be less prone to leach out and contaminate groundwater. CONCLUSION: Multivariate image analysis descriptors corroborated by docking studies were capable of modeling the herbicidal activities of 68 triketones reliably. Due to the substituent effects at the triketone framework, particularly of a nitro group in R3 , promising analogs could be designed. The P9 proposal demonstrated higher calculated activity and log P than commercial mesotrione. © 2023 Society of Chemical Industry.

Is conformation relevant for QSAR purposes? 2D Chemical representation in a 3D-QSAR perspective.

Conformation has a key role in the mechanism of interaction between small molecules and biological receptors. However, encoding this type of information in molecular descriptors for the construction of robust quantitative structure-activity relationships (QSAR) models is not an easy task and, so far, the dependence of these models on such feature has not been thoroughly investigated. In the present study, the authors explore the effects of conformational information on a 3D-QSAR technique by comparing models built with descriptors that encode fully described tridimensional aspects (structures docked inside a biological target), with descriptors in which this information is suppressed (flat structures) or not fully described (structures with quantum-chemically optimized geometries). As a result, the validation parameters indicate that the robustness of the models seems to be more related to the alignment aspect of the structures than to how well their tridimensional features are described.

Theoretical and X-Ray Evidence of Electrostatic Phosphonium anti and gauche Effects.

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 ß-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.

Iodine Gauche Effect Induced by an Intramolecular Hydrogen Bond.

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.

QSAR-Guided Proposition of N-(4-methanesulfonyl)Benzoyl-N'-(Pyrimidin-2-yl)Thioureas as Effective and Safer Herbicides.

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 r2pred in the external validation of 0.833. The predicted data for the proposed herbicides, interpreted in terms of MIA-plots of the chemical moieties responsible for bioactivity and supported by docking studies towards the photosystem II enzyme, suggest that substituents at both R1 and R2 positions modulate the agrochemical (R1 = Cl increases and R2 = OR decreases bioactivity) and environmental friendship (particularly with R2 = OH) performances of this class of compounds.

The Gauche Effect in XCH2 CH2 X Revisited.

We have quantum chemically investigated the rotational isomerism of 1,2-dihaloethanes XCH2 CH2 X (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.

An examination of the relationship between molecular dipole moment and blood-gas partition for common anaesthetic gases.

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.

Theoretical study of fluorinated bioisosteres of organochlorine compounds as effective and eco-friendly pesticides.

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.

Conformational preferences of fluorine-containing agrochemicals and their implications for lipophilicity prediction.

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.

Does induced current density explain the C-H and C-F Perlin effects?

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.

Influence of stereoelectronic effects on the 1 JC─F spin-spin coupling constant in fluorinated heterocyclic compounds.

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.

Conformational signature of Ishikawa´s reagent using NMR information from diastereotopic fluorines.

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 3 J H,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 (n N → 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.

Probing long-range spin-spin coupling constants in 2-halo-substituted cyclohexanones and cyclohexanethiones: The role of solvent and stereoelectronic effects.

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.

Infrared Fingerprints of nN → σ*NH Hyperconjugation in Hydrazides.

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.

Revealing chemophoric sites in organophosphorus insecticides through the MIA-QSPR modeling of soil sorption data.

Soil sorption of insecticides employed in agriculture is an important parameter to probe the environmental fate of organic chemicals. Therefore, methods for the prediction of soil sorption of new agrochemical candidates, as well as for the rationalization of the molecular characteristics responsible for a given sorption profile, are extremely beneficial for the environment. A quantitative structure-property relationship method based on chemical structure images as molecular descriptors provided a reliable model for the soil sorption prediction of 24 widely used organophosphorus insecticides. By means of contour maps obtained from the partial least squares regression coefficients and the variable importance in projection scores, key molecular moieties were targeted for possible structural modification, in order to obtain novel and more environmentally friendly insecticide candidates. The image-based descriptors applied encode molecular arrangement, atoms connectivity, groups size, and polarity; consequently, the findings in this work cannot be achieved by a simple relationship with hydrophobicity, usually described by the octanol-water partition coefficient.

Exploring MIA-QSPR's for the modeling of biomagnification factors of aromatic organochlorine pollutants.

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.

The mutual effect of a carbonyl polar bond and an endocyclic oxygen on the 1 JC-F coupling constant of fluorinated six-membered rings.

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.