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The fluorine Perlin-like effect is an NMR phenomenon characterized by |1JC–Fax| |1JC–Feq|. The origin of the traditional Perlin effect in tetrahydropyran (1JC–Hax < 1JC–Heq) has long been explained in terms of hyperconjugation, that elongates the C–Hax bond, then reduces 1JC–Hax relative to 1JC–Heq. However, dipolar interactions have recently been invoked as the dominant contribution for the Perlin effect. The effects ruling the 1JC–F coupling constant in 2-, 3- and 4-fluoro-substituted piperidines and respective cations and anions are reported in this work, because of the important role of fluorine and nitrogen (either neutral or charged) in pharmaceutical and material sciences. The proximity (either scalar or spatial) of nitrogen to fluorine affects the 1JC–F coupling constant, but the nitrogen electron lone pair and the charge on nitrogen interacting with the C–F bond or fluorine lone pairs play a major role in describing the 1JC–F transmission mechanism, rather than hyperconjugation. This is made clear upon analysis of the axial 3-fluoropiperidinium cation, which experiences the electrostatic gauche effect F⋯N+, decreasing the |1JC–Fax| relative to |1JC–Feq|, and also by investigating non-covalent interactions (NCI), canonical molecular orbitals (CMOs) and the angular dependence of 1JC–F with molecular dipole moments and interactions for the title compounds and 1-(fluoromethyl)aziridine.

5-Deoxy-5-fluoro-D-xylulose (DFX) binds to the xylulokinase enzyme and, as a free ligand, it has preferential conformations governed by intramolecular interactions, such as hydrogen bonds and hyperconjugative interactions. The role of intramolecular hydrogen bonds on the bioconformation of DFX has not been studied yet, despite the relevance of this topic to explain the mode of interaction between the ligand and enzyme and, therefore, the action mechanism of this molecule. DFX presents several conformations in the gas phase and implicit water, as determined by theoretical calculations, but the main optimized geometries do not match the bioactive conformation nor the most stable docked structure. This indicates that even expected strong interactions, such as hydrogen bonds, are overcome by the enzyme induced fit of DFX. The natural consequence of this finding in three-dimensional quantitative structure–activity relationship (3D-QSAR) analysis is that the use of conformations obtained in a receptor-free environment can cause misinterpretation of the chemical and biological results.

A major challenge faced with the MIA-QSAR (Multivariate Image Analysis applied to Quantitative Structure–Activity Relationships) technique in molecular modeling is to obtain chemically intuitive information from the molecular descriptors that correlate to bioactivity values. This work reports a graphical tool that uses PLS regression coefficients (b) and the variable importance in projection (VIP) scores to give insight on the structural motifs responsible for increased or attenuated biological activities in a congeneric series of compounds. Three sets of compounds useful in food chemistry, namely fatty acids and derivatives (antimicrobial), anilides (antimicrobial) and disaccharides (sweeteners), were used to assess the practical contribution of these parameters in yielding more interpretable models. The MIA-QSAR models demonstrated satisfactory prediction performance and, most importantly, the relevance of single MIA predictors to the response variable could be assessed, thus allowing for the structural, electronic and physicochemical interpretation of the MIA-QSAR models. While VIP-based graphs were especially useful in providing insight on the molecular regions/substituents most affecting the property values, the b-based analysis indicated whether the particular regions/substituents negatively or positively influenced the dependent variables. It is therefore recommended that these parameters be employed as complementary tools for a more robust and lucid model interpretation.

Herbicides with high soil sorption profiles constitute important organic pollutants leading to detrimental environmental effects, particularly due to prolonged use. Soil sorption is described in terms of log KOC, the logarithm of the soil/water partition coefficient normalized to organic carbon. This work reports the use of molecular drawings to generate molecular descriptors, which are posteriorly correlated with the log KOC values of a series of herbicides. These images are two-dimensional projections of chemical structures, with their atom sizes drawn to be proportional to the corresponding van der Waals radii and each chemical element assigned a different colour to distinguish atom types. The progressive changes in the molecular structures explain the variance in the corresponding soil sorption. Unlike previous QSPR studies on soil sorption, the series of herbicides employed in the present study included different classes of compounds (carboxylic acids, ethers, phenols, amines, amides and carbamates) guaranteeing a diverse chemical structural space. The obtained Partial Least Squares (PLS) and Multiple Linear Regression (MLR) based models for the log KOC values were found to be robust and with high predictive power. Mechanistic interpretation of the effect of different substituents (bonded to the common structural moiety in the herbicides series) on the log KOC values was performed yielding interesting results. These findings allow greater understanding of the chemical groups (or structural characteristics) responsible for high/low soil sorption, which in turn provides key leads for structural optimization to yield environmentally friendly and equally effective herbicides.

Salicylic acid is the precursor of an important analgesic drug, and fluorination may modify its properties, including pKa in solution, viscosity, polarity and molecular conformation. The intramolecular hydrogen bond is an interaction that modifies the conformational equilibrium of molecules and, therefore, it can modify their macroscopic properties, such as bioactivity. Competition between F and N as proton acceptors for the acidic COOH hydrogen in 6-fluoroanthranilic acid could not be experimentally probed earlier because of, among other factors, its tendency to form a zwitterionic species due to the higher basicity of the nitrogen. In 6-fluorosalicylic acid (1), the fluorine atom competes with oxygen for the COOH proton, thus affecting the conformational equilibrium when compared to salicylic acid itself. Indeed, 1 shows two major conformers in the gas phase and solution, while the isomer 4-fluorosalicylic acid is expected to exhibit only one among three possible conformers. Theoretical calculations indicate that the second most stable conformer of 1 exhibits intramolecular F⋯H(OOC) hydrogen bonds, which is corroborated by the small, but detectable correlation between 19F and 1H(OOC) in the HETCOR NMR spectrum in benzene-d6 solution.

This paper emphasizes that fluorine atoms in organic molecules need special geometric requirements to experience intramolecular hydrogen bonds (H-bonds). Calculations at the B3LYP/aug-cc-pVDZ theoretical level and using the quantum theory of atoms in molecules applied over a series of monocyclic compounds, which have similar CC(F)–C(OH)C fragments, predict that the F⋯HO intramolecular H-bond does not exist when forming five-membered rings. Indeed, it is shown that the geometric restrictions imposed by the rigid rings are the main reasons in preventing fluorine participating in such a F⋯HO intramolecular H-bond.