Condensed-phase relative Gibbs free energy and E/Z descriptors for 2-acetylthiophene and 2-acetylthiophene-N1-phenyl thiosemicarbazones.

Thiosemicarbazones (TSCs) encompasses a class of compounds relevant in the pharmacological context. Their specific applicability varies in function of the appropriated chemical modification and their binding to different transition metals. In the present work, we apply current standards functionals, B3LYP and B97D, with triple zeta basis set quality, 6-311++G(d,p), to investigate the relative stability of the various possible spatial arrangements for 2-acetylthiophene and 2-acetylthiophene-N1-phenyl thiosemicarbazones, denoted ATTSC and ATTSC-Ph, respectively. The relative stability of neutral and deprotonated species at ethanol described by an implicit solvent model was investigated. For ATTSC, the relative Gibbs energy changed significantly upon deprotonation, and for ATTSC-Ph, a novel global minimum was identified. Based on the present study, deprotonation determines population in condensed-media. Such information, valid for ATTSC and ATTSC-Ph, can be crucial in studying other thiosemicarbazones.

The Role of Intramolecular Interactions on the Bioactive Conformation of Epinephrine.

The structure of bioactive compounds inside their biological target is mainly dictated by the intermolecular interactions present in the binding side, whereas intramolecular interactions are responsible for the structure of an isolated molecule. Accordingly, this work reports the relative significance of these interactions for the bioactive conformation of the N-protonated epinephrine. The crystallized structure of epinephrine has a gauche orientation of the O-C-C-N torsion angle. Conformational analysis in the gas phase and implicit water was performed to investigate the main intramolecular forces favoring this conformational preference, which was primarily attributed to the electrostatic interaction between hydroxyl and ammonium groups. However, when the conformers were docked into the active site, intramolecular interactions were surpassed by intermolecular hydrogen bonds with neighboring amino acid residues. Nonetheless, structural modifications aiming at strengthening intramolecular interactions could be used to modulate a bioactive conformation, thereby assisting in the structure-based design of new chemical entities.

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.

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.

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.

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.

Theoretical Study on the Conformational Bioeffect of the Fluorination of Acetylcholine.

There has been an increasing interest in the study of fluorinated derivatives of gamma-aminobutyric acid (GABA), an acetylcholine (AC) analog. This work reports a theoretical study on the effect of an α-carbonyl fluorination in AC, aiming at understanding the role of a distant fluorine relative to the positively charged nitrogen on the conformational folding of the resulting fluorinated AC. In addition, the chemical and structural changes were evaluated on the basis of ligand-enzyme (acetylcholinesterase) interactions. In an enzyme-free environment, the fluorination yields conformational changes relative to AC due to the appearance of some attractive interactions with fluorine and a weaker steric repulsion between the fluorine substituent and the carboxyl group, rather than to a possible electrostatic interaction F⋅⋅⋅N+ . Moreover, the gauche orientation in the N-C-C-O fragment of AC owing to the electrostatic gauche effect is reinforced after fluorination. For instance, the conformational equilibrium in AC is described by a competition between gauche and anti conformers (accounting for the N-C-C-O dihedral angle) in DMSO, while the population for a gauche conformer in the fluorinated AC is almost 100 % in both gas phase and DMSO. However, this arrangement is disrupted in the biological environment even in the fluorinated derivative (whose bioconformation-like geometry shows a ligand-protein interaction of -84.1 kcal mol-1 against -79.5 kcal mol-1 for the most stable enzyme-free conformation), which shows an anti N-C-C-O orientation, because the enzyme induced-fit takes place. Nevertheless, the most likely bioconformation for the fluorinated AC does not match the bioactive AC backbone nor the most stable enzyme-free conformation, thus revealing the role of fluorination on the bioconformational control of AC.

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.

A halogen bond does not dictate the conformational preferences of cis-1,3-disubstituted cyclohexanes.

Halogen bonds are defined as interactions between halogens and a Lewis base in which the halogen (X) acts as the electrophilic species, and is typically explained by the presence of a σ-hole at the end of the C-X bond. Despite the important role of the halogen bond in intermolecularly interacting species, e.g. in acid-base reactions, enzyme inhibition and the supramolecular architecture, this interaction was not found to control the conformational equilibrium of some small model molecules, namely cis-1,3-disubstituted cyclohexanes. In addition, the attraction between the electrophilic (σ-hole) and nucleophilic regions is used to explain that the halogen bond was weaker than that in the species with parallel C-X bonds. Therefore, intramolecular halogen bonds should be used with caution to explain the conformational stability of organic compounds.

Is conformation a fundamental descriptor in QSAR? A case for halogenated anesthetics.

An intriguing question in 3D-QSAR lies on which conformation(s) to use when generating molecular descriptors (MD) for correlation with bioactivity values. This is not a simple task because the bioactive conformation in molecule data sets is usually unknown and, therefore, optimized structures in a receptor-free environment are often used to generate the MD´s. In this case, a wrong conformational choice can cause misinterpretation of the QSAR model. The present computational work reports the conformational analysis of the volatile anesthetic isoflurane (2-chloro-2-(difluoromethoxy)-1,1,1-trifluoroethane) in the gas phase and also in polar and nonpolar implicit and explicit solvents to show that stable minima (ruled by intramolecular interactions) do not necessarily coincide with the bioconformation (ruled by enzyme induced fit). Consequently, a QSAR model based on two-dimensional chemical structures was built and exhibited satisfactory modeling/prediction capability and interpretability, then suggesting that these 2D MD´s can be advantageous over some three-dimensional descriptors.

Conformational Exploration of Enflurane in Solution and in a Biological Environment.

Enflurane is a fluorinated volatile anesthetic, whose bioactive conformation is not known. Actually, a few studies have reported on the conformations of enflurane in nonpolar solution and gas phase. The present computational and spectroscopic (infrared and NMR) work shows that three pairs of isoenergetic conformers take place in the gas phase, neat liquid, polar, and nonpolar solutions. According to docking studies, a single conformation is largely preferred over its isoenergetic isomers to complex with the active site of Integrin LFA-1 enzyme (PDB code: 3F78 ), where the widely used anesthetic isoflurane (a constitutional isomer of enflurane) is known to bind. Weak hydrogen bonding from an electrostatic interaction between the CHF2 hydrogen and the central CF2 fluorines was not found to rule the conformational isomerism of enflurane. Moreover, intramolecular interactions based on steric, electrostatic, and hyperconjugative effects usually invoked to describe the anomeric effect are not responsible for the possible bioactive conformation of enflurane, which is rather governed by the enzyme induced fit.

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

Four α- and three ß-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.

Endocyclic oxygen in 3-fluorodihydro-2H-pyran-4(3H)-one that does not induce the gauche effect.

2-Fluorocyclohexanone undergoes chair inversion, giving rise to axial and equatorial conformers, with the equatorial form being highly preferred in solution, for example, 87% in chloroform and 93% in methylene chloride. Modifications in the conformational preferences can modify macroscopic properties of 2-fluoro ketones. The introduction of an endocyclic oxygen in 2-fluorocyclohexanone to give 3-fluorodihydro-2H-pyran-4(3H)-one would be expected to create a gauche effect in the axial conformer along with the O-C-C-F moiety, inducing an increase of its population. However, small changes were verified in the conformational populations both in the gas phase and solution because the carbonyl group plays an important role for the hyperconjugation in the equatorial conformer, despite experiencing strong dipolar repulsion with the fluorine atom. These data were obtained theoretically and by NMR spectroscopy, while the nature of the interactions governing these conformational shifts were investigated on the basis of natural bond orbital analysis.

The reverse fluorine Perlin-like effect and related stereoelectronic interactions.

A similar effect to the well-known reverse Perlin effect was observed on the (1)JC-F coupling constants of α- and ß-d-glucopyranosyl fluoride tetracetate, both in nonpolar and polar solution. This can be called "reverse fluorine Perlin-like effect", and it is shown to be ruled by dipolar interactions rather than by hyperconjugation. The reverse fluorine Perlin-like effect does not have a general relationship with the anomeric effect, and it can be useful to determine the structure and stereochemistry of organofluorine compounds.

Conformational analysis of 2,2-difluoroethylamine hydrochloride: double gauche effect.

The gauche effect in fluorinated alkylammonium salts is well known and attributed either to an intramolecular hydrogen bond or to an electrostatic attraction between the positively charged nitrogen and the vicinal electronegative fluorine atom. This work reports the effect of adding a fluorine atom in 2-fluoroethylamine hydrochloride on the conformational isomerism of the resulting 2,2-difluoroethylamine chloride (2). The analysis was carried out using NMR coupling constants in D2O solution, in order to mimic the equilibrium conditions in a physiological medium, in the gas phase and in implicit water through theoretical calculations. Despite the presence of σCH→σ*CF and σCH→σ*CN interactions, which usually rule the hyperconjugative gauche effect in 1,2-disubstituted ethanes, the most important forces leading to the double gauche effect ((+)NH3 in the gauche relationship with both fluorine atoms) in 2 are the Lewis-type ones. Particularly, electrostatic interactions are operative even in water solution, where they should be significantly attenuated, whereas hyperconjugation and hydrogen bond have secondary importance.

Gauche preference of ß-fluoroalkyl ammonium salts.

The strong gauche preference along with the F-C-C-N(+) fragment in 3-fluoropiperidinium cation and analogues, in the gas phase, is dictated by electrostatic interactions, which can be both hydrogen bond F···H(N(+)) and F/N(+) attraction. In aqueous solution, where most biochemical processes take place, electrostatic effects are strongly attenuated and hyperconjugation is calculated to be at least competitive with Lewis-type interactions.

The preferred all-gauche conformations in 3-fluoro-1,2-propanediol.

A competition between the terminal fluorine and hydroxyl groups by the central hydroxyl group as hydrogen bond donor in 3-fluoro-1,2-propanediol would be expected to dictate the conformational isomerism of this compound, but also the repulsion between the electronegative and bulky vicinal substituents. Indeed, an intramolecular hydrogen bond has been verified only for a local minimum using QTAIM calculations, while the most stable conformer exhibits an all-gauche conformation with a small stabilizing contribution from the nF→σ interaction. The preferred orientation of the OH and F substituents was confirmed from the chemical shifts and coupling constants of the diastereotopic hydrogens. This conformational preference, which is calculated to exist both in the gas phase and solution (using implicit CHCl3 and CH3CN solvents), is better described by predominant hyperconjugative interactions over Lewis-type interactions. The strong contribution from antiperiplanar interactions involving σCH and σCC as electron donors and σ and σ as electron acceptors dictates the gauche effect in 3-fluoro-1,2-propanediol rather than a hydrogen bond. The absence of JF,H(O) and JH(O),H(O) coupling constants confirms that any influence from a hydrogen bond to the conformational isomerism of 3-fluoro-1,2-propanediol is secondary.

Conformational analysis and intramolecular interactions in monosubstituted phenylboranes and phenylboronic acids.

A (1) (TS) J F,H(O) coupling pathway, dictated by a hydrogen bond, in some 2-fluorobenzoic acids has been observed, while such an interaction does not occur in 2-fluorophenol. Thus, this work reports the conformational analysis of 2-fluorophenylboronic acid (1), in order to evaluate a possible intramolecular OH∙∙∙F hydrogen bond in comparison to an nF→pB interaction, which mimics the quantum nF→σ*OH hydrogen bond that would be expected in 2-fluorophenol. 2-Fluorophenylborane (3), which does not experience hydrogen bonding, was used to verify whether nF→pB interaction governs the conformational equilibrium in 1 due to a predominant OH∙∙∙F hydrogen bond or to other effects. A series of 2-X-phenylboranes (X = Cl, Br, NH2, PH2, OH and SH) were further computationally analyzed to search for electron donors to boron, capable of influencing the conformational equilibrium. Overall, the intramolecular OH∙∙∙F hydrogen bond in 1 is quite stabilizing and dictates the (1) (h) J F,H(O) coupling constant. Moreover, electron donation to the empty p orbital of boron (for noncoplanar BH2 moiety relative to the phenyl ring) is also significantly stabilizing for the NH2 and PH2 derivatives, but not enough to make the corresponding conformers appreciably populated, because of steric effects and the loss of πCC→pB resonance. Thus, the results found earlier for 2-fluorophenol about the lack of intramolecular hydrogen bonding are now corroborated.

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.

Alkyl group effect on the conformational isomerism of trans-2-bromoalkoxycyclohexanes analyzed by nmr spectroscopy and theoretical calculations.

Suitable (3)J(H,H) coupling constants and theoretical calculations were used to define the conformational preferences of trans-2-bromoalkoxycyclohexanes (alkoxy = OMe, OEt, O(i)Pr, and O(t)Bu) for the isolated molecule and as a function of the medium. The diaxial conformer was preponderant, or at least similarly populated to the diequatorial form, for the tert-butoxy derivative only, while the diequatorial conformer was prevalent for the remaining alkoxy derivatives (except for the OMe derivative in CCl(4) solution). The conformational behavior of these compounds was analyzed on the basis of classical steric effects and attractive electron delocalizations, by means of natural bond orbital analysis.