Rodrigo A. Cormanich

1hJFH coupling in 2-fluorophenol revisited: Is intramolecular hydrogen bond responsible for this long-range coupling?

The present study shows that a hydrogen bond between the OH group and the fluorine atom is not involved in the 1hJFH spin–spin coupling transmission either for 4‐bromo‐2‐fluorophenol or 2‐fluorophenol. In fact, according to a quantum theory of atoms in molecules analysis, no bond critical point is found between O‐H and F moieties. The nature of the transmission mechanism of the Fermi contact term of the 1hJFH spin–spin coupling is studied by analyzing canonical molecular orbitals (see J. Phys. Chem. A 2010, 114, 1044), and it is observed that virtual orbitals play only a quite minor role in its transmission. This is typical of a Fermi contact term transmitted mainly through exchange interactions owing to the overlap of proximate electronic clouds; therefore, it is suggested to identify them as nTSJFH coupling where n stands for the number of formal bonds separating the coupling nuclei. In the cases studied in this work is n = 4. Results presented in this work could provide an interesting rationalization for different experimental signs known in the current literature for proximate JFH couplings. Copyright

The F⋯HO intramolecular hydrogen bond forming five-membered rings hardly appear in monocyclic organofluorine compounds

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.

Does intramolecular hydrogen bond play a key role in the stereochemistry of α- and β-D-glucose?

Four α- and three β-isomers of the d-glucose were optimized in gas phase using ab initio (MP2) and DFT (ωB97X-D) methods, both using the aug-cc-pVDZ basis set. While earlier works suggest that the orientation of the hydroxyl groups is due to intramolecular hydrogen bonds (H-bonds), the present study reveals that most H-bonds forming five-membered rings are either weak or even do not exist. The quantum theory of atoms in molecules (QTAIM) analysis showed only a few cases of H-bond in d-glucose, particularly for those H-bonds forming six-membered rings, while the non-covalent interactions (NCI) analysis indicated that most intramolecular H-bonds are not strong enough to justify the counter-clockwise arrangement of the OH⋯O chains. Natural bond orbital analysis supported the findings obtained from QTAIM and NCI analyses and indicated that the anomeric effect for d-glucose in the gas phase is governed by a balance of steric, electrostatic, and hyperconjugative interactions.

Stereoelectronic interactions and the one-bond C-F coupling constant in sevoflurane.

The conformational preference of the widely utilized anesthetic fluoromethyl-1,1,1,3,3,3-hexafluoro-2-propyl ether (sevoflurane) has been investigated computationally and by NMR spectroscopy. Three conformational minima were located at the B3LYP/aug-cc-pVDZ level, but one is significantly more stable (by ca. 4 kcal/mol) than the other two. This is the case both for gas phase calculations and for solution NMR data. Although the main conformer is stabilized by electron delocalization (n(O) → σ*(C-F)), this type of hyperconjugation was not found to be the main driver for the conformer stabilization in the gas phase and, consequently, for the apparent anomeric effect in sevoflurane. Instead, more classical steric and electrostatic interactions appear to be responsible for the conformational energies. Also the (1)J(CF) coupling constants do not appear to be dominated by hyperconjugation; again, dipolar interactions are invoked instead.

A Theoretical View on the Conformer Stabilization of Butane

The rotational barrier and conformer energies of butane are well-known, but the contributing effects to its conformational isomerism are still unclear. Calculated potential energy surfaces for the relaxed and vertical (bond distances and angles frozen) structures, together with NBO analysis, suggest that approaching or distancing methyl groups involve substantial energy costs between the gauche and anti isomers, while hyperconjugative interactions play an important, but not prevalent, role for the conformational isomerism of butane.

2D chemical drawings correlate to bioactivities: MIA-QSAR modelling of antimalarial activities of 2,5-diaminobenzophenone derivatives

Estruturas quimicas bidimensionais de uma serie de derivados da 2,5-diaminobenzofenona, alguns inibidores de farnesiltransferase, correlacionam-se com as respectivas atividades antimalaricas. Os descritores nessa analise QSAR sao pixels das estruturas quimicas (imagens bidimensionais) transformados em binarios e, portanto, a variacao dos dados que explica a variância no bloco das bioatividades corresponde as coordenadas de cada pixel do desenho das moleculas. Este metodo, chamado analise multivariada de imagens aplicada ao estudo da relacao quantitativa entre estrutura e atividade (MIA-QSAR), foi aplicado para modelar as atividades antimalaricas dos compostos acima e os resultados foram comparados com tecnicas de QSAR 3D bastante conhecidas. Alem da simplicidade e alto poder de predicao do modelo MIA-QSAR, este metodo baseado em imagens 2D tem potencial para funcionar bem quando analises classicas igualmente simples falham. Enfim, a presente analise QSAR baseada em desenhos de estruturas quimicas bidimensionais dispensa uma varredura conformacional e alinhamento tridimensional das moleculas para fornecer um modelo QSAR robusto; a descricao fisico-quimica de efeitos estericos e centros estereogenicos, por exemplo, esta toda incorporada na maneira com que substituintes sao representados, e o metodo serve como uma ferramenta para aqueles que interessem em trabalhar com modelagem de farmacos. Two-dimensional chemical structures of a series of 2,5-diaminobenzophenone derivatives, some farnesyltransferase inhibitors, have shown to correlate with the corresponding antimalarial activities. The descriptors in this QSAR analysis are pixels of the chemical structures (two dimensional images) transformed into binaries and, therefore, the data variance explaining the variance in the activities block corresponds to the coordinates of each pixel in each molecule. This method, named multivariate image analysis applied to quantitative structure-activity relationship (MIA-QSAR), was applied to model the antimalarial activities of the titled compounds and the results were compared to well known three-dimensional QSAR techniques for the same class of compounds. In addition to the simplicity and high predictive performance of the MIA-QSAR modelling, this 2D image-based method has the potential of working well when equally simple, classical analysis fails. Overall, the present QSAR analysis based on 2D chemical drawings (constrained structures) dispensed conformational screening and 3D alignment to provide a reliable QSAR model; the physicochemical description about e.g. steric effects and chiral centers is all contained in the way in which substituents in a congeneric series are drawn, and the method can serve as a tool to introduce those who are planning to deal with drug design.

Synthesis and Elaboration of All-cis-1,2,4,5-Tetrafluoro-3-Phenylcyclohexane: A Polar Cyclohexane Motif

A stereocontrolled synthesis of all-cis-1,2,4,5- tetrafluoro-3-phenylcyclohexane is developed as the first functionalised example of this polar cyclohexane motif. The dipolar nature of the ring, arising due to two 1,3-diaxial C-F bonds, is revealed in the solid-state (X-ray) structure. The orthogonal conformation of the aryl and cyclohexyl rings in all-cis-1,2,4,5-tetrafluoro-3-phenylcyclohexane, and in an ortho-nitro derivative, result in intramolecular (1h)JHF and (2h)JCF  NMR couplings relayed through hydrogen bonding. The aryl group of all-cis-1,2,4,5-tetrafluoro-3-phenylcyclohexane is elaborated in different ways to demonstrate the versatility of this compound for delivering the motif to a range of molecular building blocks.

Conformational Analysis and Intramolecular Interactions in Aminofluorobenzoic Acids

Some aminofluorobenzoic acids were studied to evaluate the power of the F···HO hydrogen bond and other interactions as driving forces of the conformational isomerism of these compounds. Despite the occurrence of this hydrogen bond in the 2-fluorinated derivatives, as well as attractive O/F nonbonding interactions and NH···O═C hydrogen bond, the O/O repulsion dictates the orientation of the carboxyl group. Unlike 2-fluorophenol, which is reported to not experience a F···HO hydrogen bond, 2-fluorobenzoic acid derivatives were calculated to exhibit such interaction, but it could not be monitored experimentally by means of F/H(O) coupling constant, because of the low solubility of these compounds in nonpolar solvents, the acidity of the carboxyl hydrogen, the small population of some conformers capable of exhibiting hydrogen bond, and the solute self-association in solution, which make their conformational equilibrium different from that in gas phase.

Desenhos de estruturas químicas correlacionam-se com propriedades biológicas: MIA-QSAR

Descriptors in multivariate image analysis applied to quantitative structure-activity relationship (MIA-QSAR) are pixels of bidimensional images of chemical structures (drawings), which were used to model the trichomonicidal activities of a series of benzimidazole derivatives. The MIA-QSAR model showed good predictive ability, with r2, q2 and rval. ext.2 of 0.853, 0.519 and 0.778, respectively, which are comparable to the best values obtained by CoMFA e CoMSIA for the same series. A MIA-based analysis was also performed by using images of alphabetic letters with the corresponding numeric ordering as dependent variables, but no correlation was found, supporting that MIA-QSAR is not arbitrary.

Conformational analysis, stereoelectronic interactions and NMR properties of 2-fluorobicyclo(2.2.1)heptan-7-ols

Summary Four diastereoisomers of 2-fluorobicyclo[2.2.1]heptan-7-ols were computationally investigated by using quantum-chemical calculations, and their relative energies were analyzed on the basis of stereoelectronic interactions, particularly the presence or otherwise of the F∙∙∙HO intramolecular hydrogen bond in the syn-exo isomer. It was found through NBO and AIM analyses that such an interaction contributes to structural stabilization and that the 1h J F,H(O) coupling constant in the syn-exo isomer is modulated by the n F→σ*OH interaction, i.e., the quantum nature of the F∙∙∙HO hydrogen bond.