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.

Regio- and stereochemical stability induced by anomeric and gauche effects in difluorinated pyrrolidines.

Selective fluorination of the pyrrolidine ring in proline motifs has been found to induce significant conformational changes that impact the structure and biological roles of modified peptides and proteins. Vicinal difluorination of fluoroproline, for example, in (3S,4R)-3,4-difluoroproline, serves to mitigate the inherent conformational bias of the pyrrolidine ring by inducing stereoelectronic effects that attenuate this conformational bias. In this investigation, we present a quantumchemical analysis of the conformational equilibrium and effects that are induced in difluorinated pyrrolidines, with a particular focus on exploring the impact of gauche and anomeric effects on the conformer stabilities of different stereo- and regioisomers. Initially, we conducted a benchmark assessment comparing the optimal density functional theory method with coupled cluster with single and double excitations (CCSD) calculations and crystallographic data using the 3-fluoropyrrolidinium cation and 3-fluoropyrrolidine. Subsequently, we explored the relative energy of all favored conformations of all different stereoisomers of 2,3-, 2,4-, and 3,4-difluoropyrrolidines at the B3LYP-D3BJ/6-311++G** level. A generalized anomeric effect, arising from nN→σ*CF electron delocalization, is particularly important in modulating the energetics of the α-fluoro isomers and imparts a strong conformational bias. In contrast, the fluorine gauche effect assumes a secondary role, as it is overshadowed by steric and electrostatic interactions, referred to as Lewis interactions from a natural bond orbital perspective.

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.

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.

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.

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.

Conformational impact of structural modifications in 2-fluorocyclohexanone.

2-Haloketones are building blocks that combine physical, chemical and biological features of materials and bioactive compounds, while organic fluorine plays a fundamental role in the design of performance organic molecules. Since these features are dependent on the three-dimensional chemical structure of a molecule, simple structural modifications can affect its conformational stability and, consequently, the corresponding physicochemical/biological property of interest. In this work, structural changes in 2-fluorocyclohexanone were theoretically studied with the aim at finding intramolecular interactions that induce the conformational equilibrium towards the axial or equatorial conformer. The interactions evaluated were hydrogen bonding, hyperconjugation, electrostatic and steric effects. While the gauche effect, originated from hyperconjugative interactions, does not appear to cause some preferences for the axial conformation of organofluorine heterocycles, more classical effects indeed rule the conformational equilibrium of the compounds. Spectroscopic parameters (NMR chemical shifts and coupling constants), which can be useful to determine the stereochemistry and the interactions operating in the series of 2-fluorocyclohexanone derivatives, were also calculated.

Synergistic effect of intra- and intermolecular hydrogen bond in 2-haloethanols probed by infrared.

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.

Bioconformational modulation of a thymidine kinase enzyme ligand through F⋯HO intramolecular hydrogen bond.

While the induced-fit of a ligand towards an enzyme is pivotally dictated by intermolecular hydrogen bonds between the small molecule and amino acid residues in the binding site, the role of intramolecular hydrogen bond as contributing interaction for a bioactive conformation is not well understood. This work reports a theoretical conformational analysis of a thymidine kinase enzyme ligand (NMF) that is prone to experience an F⋯HO intramolecular hydrogen bond, inside and outside the biological binding site. This interaction stabilizes the most favorable conformations of NMF in the gas phase and, although it can be disrupted in a biological environment due to intermolecular hydrogen bonds in some cases, these interactions are competitive in other systems. Therefore, an intramolecular hydrogen bond can affect the conformational likeliness most related to the bioactivity. Moreover, isolated conformations governed by this interaction cannot be unequivocally used to generate molecular descriptors in 3D-QSAR (Quantitative Structure-Activity Relationships), since the bioactive conformation may not be determined only by intramolecular interactions.

Revisiting the Case of an Intramolecular Hydrogen Bond Network Forming Four- and Five-Membered Rings in d-Glucose.

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.

Theoretical study on the anomeric effect in α-substituted tetrahydropyrans and piperidines.

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.