While the gauche effect in 1,2‐difluoroethane is widely known as being due to hyperconjugative interactions between σCH electron‐donating orbitals and σ*CF electron‐accepting orbitals, the corresponding 1,2‐dichloro, 1,2‐dibromo, and 1,2‐diiodo derivatives are preferentially in the anti conformation. 2‐Halofluoroethanes (F‐CH2‐CH2‐X) combine a small halogen (fluorine) and a vicinal low‐lying energy antibonding orbital (σ*CX) that activates a stabilizing antiperiplanar σCH → σ*CX electron delocalization, which can induce the gauche effect. On the other hand, σCX orbitals are good electron donors to σ*CF, that would favor an “anti effect”, in addition to traditional interpretations based on steric and electrostatic repulsion. Therefore, a balance of steric, dipolar and hyperconjugative effects drive the conformational equilibrium of these compounds – hyperconjugation was found to explain the gauche effect in some cases, whilst Lewis‐type interactions determine the anti preference in others. The gauche effect takes place in a polar solvent, but not for 1‐fluoro‐2‐iodoethane. According to NMR three‐bond spin‐spin coupling constants, the gauche population increases when fluorine is replaced by a hydroxyl group (except for 2‐fluoroethanol relative to 1,2‐difluoroethane), but this is not primarily due to intramolecular hydrogen bond.
One-bond spin–spin coupling constant (SSCC) data may be useful in providing information on the stereochemistry and intramolecular interactions in molecules.
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.
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 6positions of an aromatic ring, CF 3 in 4-position, and the 2-NO 2 group in a phenyl ring appear to favor the HPPD inhibition. At the same time, Me and OMe substituents contribute to decreasing the pK i values. Accordingly, a few compounds were proposed and the candidate with 2,4,6-triBr substituents demonstrated an estimated pK i similar to those of the best library compounds. This finding was corroborated by the docking scores of the ligand−enzyme interactions. In addition, the high calculated lipophilicity of some proposed agrochemicals suggests that they should have low soil mobility and, therefore, are not prone to easily leach out and reach groundwater, despite causing other ecological issues.
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.
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.
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