Gauche Effect Research Articles

A convenient stereoselective access to novel 1,2,4-triazepan-3-ones/thiones via reduction or reductive alkylation of 7-membered cyclic semicarbazones and thiosemicarbazones.

A general stereoselective approach to previously unknown 1,2,4-triazepane-3-thiones/ones based on reduction or reductive alkylation of readily available 2,4,5,6-tetrahydro-3H-1,2,4-triazepine-3-thiones/ones has been developed. The approach involved the treatment of tetrahydrotriazepines with sodium cyanoborohydride in MeOH at pH 3 or with sodium borohydride and excess of carboxylic acid in THF to give 1-unsubstituted or 1-alkyl-substituted 1,2,4-triazepane-3-thiones/ones, respectively. The latter were also prepared by the reaction of 1-unsubstituted 1,2,4-triazepane-3-thiones/ones with sodium cyanoborohydride and an aldehyde in MeOH in the presence of AcOH. The stereochemistry of the triazepane-3-thiones/ones obtained was established in DMSO solution and in the solid state using NMR spectroscopy and single-crystal X-ray diffraction. These data and DFT B3LYP/6-311++G(d,p) calculations show that the gauche effect plays a significant role in stabilization of preferred conformations of 1-unsubstituted 1,2,4-triazepane-3-thiones/ones.

Effect of Orbital Interactions between Vicinal Bonds and between Hydroxy Groups on the Conformational Stabilities of 1,2-Ethanediol and 2,3-Butanediols.

The geometries of the two hydroxy groups in 1,2-ethanediol or 2,3-butanediols are more stable in a gauche orientation than those in an anti orientation. This has been generally explained in terms of the gauche effect, which is stabilization due to antiperiplanar electron delocalization between an antibonding orbital of the C-O bond (σCO*) and a bonding orbital of the C-H or C-C bond (σCH or σCC). However, a C-C single bond rotation simultaneously determines the geometries of the six vicinal bonds. Therefore, it is important to understand the effects on conformational stability of other interactions of the bond orbitals adjacent to the rotating C1-C2 bond. Bond model analysis revealed that antiperiplanar bond orbital interactions as a whole contribute to the higher stabilities of hydroxy/hydroxy gauche conformers, where the C-O/C-H or C-O/C-C combination including the σCO*/σCH or σCO*/σCC delocalization is not the dominant interaction stabilizing hydroxy/hydroxy gauche conformers. Rather, our results show that a large destabilization due to the antiperiplanar C-O/C-O combination in hydroxy/hydroxy anti conformers relatively increases the stabilities of hydroxy/hydroxy gauche conformers. This destabilization results mainly from the repulsion between the antiperiplanar bonding orbitals (σCO/σCO), which have a larger overlap compared to the synclinal σCO/σCO combination. The sum of the interbond energies between the vicinal bond orbitals of these 1,2-alkanediols is more advantageous for stability in gauche conformers. In addition, interactions between the gauche-oriented hydroxy groups provide large stabilization energies and the corresponding interactions in anti conformers are negligible. The relative conformational stabilities of 1,2-ethanediol and erythro-2,3-butanediol can be explained by the interactions between the antiperiplanar bond orbitals, between the vicinal bond orbitals, or between the hydroxy groups in addition to the combination of interactions between the vicinal bond orbitals and between the hydroxy groups. In contrast, in threo-2,3-butanediol, differences in the relative stabilities of the three conformers can be understood by the combination of the interactions between the vicinal bond orbitals and between the hydroxy groups.

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.

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.

The ANANKE relative energy gradient (REG) method to automate IQA analysis over configurational change

Much chemical insight ultimately comes down to finding out which fragment of a total system behaves like the total system, in terms of an energy profile. A simple example is that of the water dimer, where this system is regarded as held together by a hydrogen bond. The hydrogen bond consists of two atoms (H···O), which energetically behave similarly to the total system (H2O)2. However, from a quantum mechanical point of view, each atom in the total system interacts with any other atom. Thus, the view that the hydrogen bond by itself governs the energetic stability of the water dimer needs rigorous justification. In this work, we propose a method that provides such a justification, in general, but only illustrated on the water dimer here. This method is based on the topological energy partitioning method called interacting quantum atoms (IQA). The method is implemented in the program ANANKE, which calculates correlations between the energy profile of the total system and those of subsystems (or fragments). ANANKE acts on the IQA energy contributions obtained for a sequence of full-system geometries controlled by a coordinate of interest (e.g. the O···H distance in the water dimer). Although applied only for the water dimer in this work, the method is general and able to explain the gauche effect, the torsional barrier in biphenyl, the arrow-pushing scheme of an enzymatic reaction (peptide hydrolysis in the HIV-1 Protease active site), and halogen-alkane nucleophilic substitution (SN2) reactions. Those applications will appear elsewhere as separate and elaborated case studies; here we focus on the details of the ANANKE method and its justification, using the water dimer as a concrete case.

Manifestation of the gauche effect in conformers of benzenesulfonic acid hydrazide

Conformational properties of a benzenesulfonic acid hydrazide molecule and its para-nitro and para-methyl derivatives, which have found wide application as porofors and biologically active compounds, are studied. It is found that the benzenesulfonic acid hydrazide molecule has six conformers with relative energies of 0//0 kcal/mol, 0.34//0.98 kcal/mol, 2.51//2.25 kcal/mol, 2.54//2.56 kcal/mol, 2.90//3.28 kcal/mol, 6.64//6.43 kcal/mol (MP2//DFT(B3LYP) with the cc-pVTZ basis set), each conformer has enantiomer. The conformers differ from each other in the relative orientation of the fragments of the–SO2NHNH2 group, the energies of the frontier orbitals, the direction and value of the dipole moments. It is shown that the introduction of a nitro or methyl group into the para-position practically does not affect the conformational properties of the sulfonyl hydrazide group. Change in the structure of benzenesulfonic acid hydrazide during the crystal–gas transition is considered and it is revealed that in the crystal the conformation similar in structure to one of the high-energy conformers of the free molecule is stabilized. The NBO analysis of the electron density distribution is performed and it is shown that the occurrence of the gauche effect in all conformers of the molecules under study can be interpreted by the manifestation of the total action of strong anomeric effects between the lone pairs of nitrogen atoms and antibonding orbitals of S=O, N–H, C–S, and N–S bonds.

Theoretical study of azido gauche effect and its origin

The strength and origin of the azido gauche effect were studied by ab initio calculations and compared with the well-known fluorine gauche effect.

Not all third-row elements experience the fluorine gauche effect: β-fluorinated organophosphorus compounds

Conformational analyses of β-fluorinated organophosphorus compounds were theoretically carried out to probe the role of a possible fluorine–phosphorus gauche effect in conformer stabilization, specifically using a phosphine, a phosphine oxide, phosphinic and phosphonic acids, and the corresponding anions as model compounds.

Catalytic asymmetric synthesis of 2,3,3,3-tetrafluoro-2-methyl-1-arylpropan-1-amines as useful building blocks for SAR-studies

The first protocol for the asymmetric synthesis of 2,3,3,3-tetrafluoro-2-methyl-1-arylpropan-1-amines which function as fluorinated surrogates for α-isopropylbenzylamines in SAR-studies is presented herein. Crucial for the successful synthesis was the application of a recently developed direct catalytic asymmetric Mannich-type reaction of fluorinated amide for the key bond-forming step. The utility of this versatile protocol was demonstrated by the synthesis of fluorinated analogues of a T-type selective Ca2+ channel blocker and a prolylcarboxypeptidase inhibitor. The predominant conformation of their fluorinated analogues was investigated by X-ray crystallography and NMR spectroscopy which revealed a strong influence of a fluorine mediated gauche effect.

The Fluorine Gauche Effect: A Brief History

AbstractTransforming the fluorine gauche effect from an academic curiosity into a powerful acyclic conformational control strategy has enriched molecular design. This expansive approach to modulating structure has proven to be particularly valuable in the construction of functional small molecules, thereby finding application in diverse disciplines, ranging from therapeutic medicine to enantioselective catalysis. In contrast to the well‐established arsenal of conformational control tactics, in which conformer populations result from minimising nonbonding interactions, (e.g., A1,3‐ or A1,2‐strain), the fluorine gauche effect is attributable to stabilising interactions comprised of two components: stereoelectronic and electrostatic. Conformer populations are partially determined by favourable, hyperconjugative interactions involving proximal electron‐rich σ‐bonds, π‐systems, and nonbonding electron pairs with the antibonding orbital of the C−F σ‐bond: σ→σ*, π→σ*, and n→σ*, respectively. Electrostatic, charge‐dipole interactions (e.g., N+⋅⋅⋅Fδ−) also play a crucial role in stabilising what are often counter‐intuitive conformations. These noncovalent interactions, permissible on account of the low van der Waals radius and high electronegativity of the fluorine atom, render this effect fundamentally important and practically valuable in structural chemistry. In this contribution to the Rosarium Philosophorum in honour of Prof. Jack David Dunitz FRS, we endeavour to delineate, albeit in an abridged form, the evolution of the fluorine gauche effect from a fundamental spectroscopic study to a ubiquitous component of physical organic chemistry.

The Sulfur–FluorineGaucheEffect in Coinage-Metal Complexes: Augmenting Conformational Equilibria by Complexation

Controlling the rotation about unhindered C(sp3)–C(sp3) bonds by simple structural changes has obvious benefits in molecular design. While the avoidance of nonbonding interactions remains one of the cornerstones of acyclic conformational control, stabilizing stereoelectronic effects have the added benefit that conformer populations can be fine-tuned by augmenting or diminishing the central interaction. Strategies may include adjusting the oxidation state of a substituent or reversible formation of a complex to modulate MO levels. In the case of the sulfur–fluorine gauche effect, the propensity of the S–C–C–F motif to adopt a synclinal arrangement (ΦFCCS = 60°), the conformer population distribution of the three dominant rotamers partitioned by 120° can be biased by oxidation of the S atom. Motivated by the importance of sulfur-based ligands in main structural chemistry, the sulfur–fluorine gauche effect was translated to an organometallic paradigm as a potential tool to achieve structural preorganization. This would allow the influence of coinage-metal complexation on conformer population to be initially assessed. The synthesis and characterization of a model gold(I) and silver(I) metal complex featuring a ligand system containing a freely rotatable SCCF motif is disclosed. In both complexes, the title stereoelectronic effect manifests itself in the expected conformation, with the synclinal-endo conformer being preferred. This was corroborated by X-ray crystallography and DFT analysis, and the molar fraction of rotamers was extrapolated from a detailed solution-phase NMR spectroscopic analysis. Complexation was found to reinforce the sulfur–fluorine gauche effect.

Diastereoselective Synthesis and Conformational Analysis of (2R)- and (2S)-Fluorostatines: An Approach Based on Organocatalytic Fluorination of a Chiral Aldehyde.

Stereoselectively fluorinated analogues of the amino acid statine have been efficiently synthesized. The key step is an organocatalytic electrophilic fluorination of a chiral β-oxygenated aldehyde, which provided a test of both diastereoselectivity and chemoselectivity. The target statine analogues were found to adopt unique conformations influenced by the fluorine gauche effect, rendering them potentially valuable building blocks for incorporation into bioactive peptides.

Organocatalysis Intermediates as Platforms to Study Noncovalent Interactions: Integrating Fluorine Gauche Effects in Iminium Systems to Facilitate Acyclic Conformational Control

Achieving acyclic conformational control over several bonds has been realized by the strategic installation of a vicinal difluoroethane bridge in a generic proline-derived organocatalyst. The torsion angle ϕ_FCCF is governed by stabilizing hyperconjugative interactions (σ→σ*), thus ensuring a 60° relationship. This effect has been telescoped by positioning a stereogenic fluorine center proximal to the nucleophilic amine. Upon iminium formation, this center is rendered electron deficient, thus triggering a dynamic <i>fluorine iminium ion gauche effect</i>. Consequently, conformational control over five atoms and four bonds can be achieved by reversible formation of an iminium π-bond.

The influence of electronic perturbations on the Sulfur–Fluorine Gauche Effect

Abstract Herein, a solution phase NMR conformer population analysis is employed to probe the effect of remote electronic perturbations on the conformational equilibria of a series of para-substituted β-fluorosulfides (1), sulfoxides (2) and sulfone derivatives (3). Conformations that allow for stabilizing stereoelectronic (σC–H → σ*C–F) and electrostatic (Fδ−…Sδ+) interactions predominate: this is consistent with the Sulfur–Fluorine Gauche Effect. The molar fractions (χ) of the two possible gauche conformers correlate linearly with the electron-withdrawing aptitude of the para-substituent, rendering the system ideally suited for a Hammett-type analysis. Despite the clear influence that the remote para-substituents have on conformer population, this is superseded by the oxidation state on sulfur (II, IV, VI), where an increased preference for the gauche conformer follows the trend: sulfide

The stereoselectivities of tributyltin hydride-mediated reductions of 5-bromo-D-glucuronides to L-iduronides are dependent on the anomeric substituent: syntheses and DFT calculations.

One of the shortest synthetic routes to L-iduronic acid derivatives is via free radical reduction of the C-5 bromide of the corresponding protected D-glucuronic acid derivative. The epimerization of such C-5 bromides to the L-ido derivatives via reaction with tributyltin hydride was investigated. It was found that the stereoselectivity of the reaction was dependent on the anomeric substituent. If the substituent was fluoride the L-ido product was obtained exclusively in 65-72% yield whereas the O-methyl or O-acetyl derivatives led to isomeric mixtures of both the L-ido and D-gluco products in different ratios depending on the reaction conditions. DFT calculations were performed to determine the stereoelectronic factors that favour formation of the L-ido isomer from the fluoride and suggest the selectivity is due to a transition state gauche effect and an Sn-F interaction.

Conformation preference and related intramolecular noncovalent interaction of selected short chain chlorinated paraffins

Short chain chlorinated paraffins (SCCPs) are not only research focus of environmental issues but also interesting model molecules for organic chemistry which exhibit diverse conformation preference and intramolecular noncovalent interactions (NCIs). A systematic study was conducted to reveal the conformation preference and the related intramolecular NCIs in two C10-isomers of SCCPs, 5,5,6,6-tetrachlorodecane and 4,4,6,6-tetrachlorodecane. The overall conformation profile was determined on the basis of relative energies calculated at the MP2/6-311++G(d,p) level with the geometries optimized by B3LYP/6-311++G(d,p) method. Then, quantum theory of atoms in molecules (QTAIM) has been adopted to identify the NCIs in the selected conformers of the model molecules at both B3LYP/6-311++G(d,p) and M06-2X/aug-cc-pvdz level. Different chlorine substitution modes result in varied conformation preference. No obvious gauche effect can be observed for the SCCPs with chlorination on adjacent carbon atoms. The most stable conformer of 5,5,6,6-tetrachlorodecane (tTt) has its three dihedral angles in the T configuration, and there is no intramolecular NCIs found in this molecule. On the contrary, the chlorination on interval carbon atoms favors the adoption of gauche configuration for the H–C–C–Cl axis. Not only intramolecular H···Cl contacts but also H···H interactions have been identified as driving forces to compensate the instability from steric crowding of the gauche configuration. The gggg and g′g′g′g′ conformers are the most popular ones, while the populations of tggg and tg′g′g′ conformer are second to those of the gggg and g′g′g′g′ conformers. Meanwhile, the M06-2X method with large basis sets is preferred for identification of subtle intramolecular NCIs in large molecules like SCCPs.

Transition State Gauche Effects Control the Torquoselectivities of the Electrocyclizations of Chiral 1-Azatrienes.

Hsung et al. have reported a series of torquoselective electrocyclizations of chiral 1-azahexa-1E,3Z,5E-trienes that yield functionalized dihydropyridines. To understand the origins of the torquoselectivities of these azaelectrocyclizations, we modeled these electrocyclic ring closures using the M06-2X density functional. A new stereochemical model that rationalizes the observed 1,2 stereoinduction emerges from these computations. This model is an improvement and generalization of the "inside-alkoxy" model used to rationalize stereoselectivities of the 1,3-dipolar cycloaddition of chiral allyl ethers and emphasizes a stabilizing hyperconjugative effect, which we have termed a transition state gauche effect. This stereoelectronic effect controls the conformational preferences at the electrocyclization transition states, and only in one of the allowed disrotatory electrocyclization transition states is the ideal stereoelectronic arrangement achieved without the introduction of a steric clash. Computational experiments confirm the role of this effect as a stereodeterminant since substrates with electropositive groups and electronegative groups have different conformational preferences at the transition state and undergo ring closure with divergent stereochemical outcomes. This predicted reversal of stereoselectivity for the ring closures of several silyl substituted azatrienes have been demonstrated experimentally.

Gauche effects of glucopyranose by QM/MM-MD simulations

Both ab initio cluster calculations and quantum mechanics/molecular mechanics molecular dynamics (QM/MM-MD) simulations were utilized in the conformational study of glucopyranose. The relative populations of gauche–gauche (GG), gauche–trans (GT), and trans–gauche (TG) by QM/MM-MD closely reproduced the experimental observation where the population of TG is much less than that of the others. Radial distribution functions revealed the less solvated TG as compared to GG and GT. The local structural analysis further showed that a bridging water between O6 and O5 of glucopyranose is missing especially in TG. In short, our newly developed QM/MM-MD method yielded a consistent result with previous studies, in which the gauche effect in glucopyranose comes from the efficient solvation of GG and GT by bridging water. In addition, detailed structural information for the gauche effect has been deduced from our simulations.

Origin of Fluorine/Sulfur Gauche Effect of β-Fluorinated Thiol, Sulfoxide, Sulfone, and Thionium Ion.

The well-known gauche preference in FCCX systems, where X is an electronegative element from Period 2, is widely exploited in synthetic, medicinal, and material chemistry. It is rationalized on the basis of σ(C-H) → σ*(C-F) hyperconjugation and electrostatic interactions. The recent report (Thiehoff, C.; et al. Chem. Sci. 2015, 6, 3565) showed that the fluorine gauche effect can extend to Period 3 elements, such as sulfur. The aim of the present work is to disclose factors governing conformational behavior of FCCS containing systems. We examine conformational preferences in seven classes of compounds by ab initio and DFT calculations and rationalize the results by quantitatively decomposing the anti/gauche isomerization energy into contributions from electrostatic, orbital, dispersion, and Pauli interactions, and energy spent on structural changes. The results show that the fluorine/sulfur gauche effect is primarily electrostatic (63-75%), while all orbital interactions contribute 22-41% to stabilizing interactions. Stereoelectronic effects, involved in orbital interactions, also play a role in gauche conformer stabilization.

Proposal of Calculation Protocols for Implicit Solvation Methods in Conformational Analysis Involving the Gauche Effect

Proposal of Calculation Protocols for Implicit Solvation Methods in Conformational Analysis Involving the Gauche Effect