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Anomeric effect

The anomeric effect is a stereoelectronic phenomenon that governs the conformational preferences at an anomeric carbon, typically in cyclic acetals or hemiacetals such as those found in carbohydrates, where an electronegative substituent (like oxygen or halogen) adjacent to a ring heteroatom exhibits a marked preference for the axial position in chair conformations, defying expectations from classical steric (A^{1,3}) interactions that favor equatorial orientations.^[1] This effect, first identified in pyranose sugars, arises primarily from negative hyperconjugation involving donation from the ring oxygen's lone pair into the antibonding orbital of the axial C-X bond (n_O → σ^*_{C-X}), which stabilizes the axial conformer, though electrostatic interactions—such as dipole-dipole repulsions in the equatorial form—also contribute, particularly in low-polarity solvents.^[2] The magnitude of the effect varies with the electronegativity of the substituent and the ring size, typically ranging from 0.5 to 2.5 kcal/mol in six-membered rings, and it extends beyond carbohydrates to aminals, thioacetals, and other heteroatomic systems.^[3] Discovered in 1955 by J. T. Edward during studies of glycoside conformations, the anomeric effect—initially termed the "Edward-Lemieux effect"—highlighted the unexpected axial stabilization of electronegative groups at the anomeric center (C1 in aldoses), as evidenced by the higher stability of α-anomers in non-hydroxylating solvents compared to β-anomers.^[4] Edward proposed an early electrostatic model, attributing the preference to reduced dipole repulsion between the ring oxygen and the anomeric substituent in the axial arrangement, a view later refined by Raymond U. Lemieux in 1958 through experimental NMR and equilibration studies on pyranosides.^[4] Over decades, quantum mechanical analyses have shifted emphasis toward hyperconjugation as the dominant factor, especially in scenarios of high electronic demand like glycosyl cations, where orbital overlap delocalizes electron density to lower energy.^[1] A 2018 computational and experimental study further revealed that CH···X nonbonded attractions (where X is the electronegative group) play a key role, correlating with C-X bond elongation in axial forms to optimize Coulombic stabilization.^[3] The anomeric effect profoundly influences carbohydrate chemistry, dictating mutarotation equilibria, glycosidic bond stability, and enzyme-substrate interactions in biological systems, while also enabling synthetic control in nucleoside analogs and glycoconjugates.^[1] Generalized forms, such as the exo-anomeric effect in glycosides (stabilizing gauche conformations around the exocyclic C-O bond), extend its scope to acyclic and five-membered ring systems like furanoses.^[4] Recent reviews underscore its interplay with solvation and counterion effects, affirming hyperconjugation's primacy in modern interpretations while cautioning against oversimplification, as multiple factors—including steric relief and solvent polarity—modulate its expression in complex molecules.^[2]

Definition and Historical Context

Core Definition and Scope

In carbohydrate chemistry, anomers are defined as a pair of diastereomers that differ solely in their configuration at the anomeric carbon, which is the carbonyl carbon (C1) of the open-chain form that becomes the ring-forming carbon in cyclic structures such as pyranose or furanose rings. These cyclic forms typically adopt a chair conformation for six-membered pyranose rings, where substituents attached to the ring carbons can occupy either axial or equatorial positions; equatorial orientations are generally preferred due to minimized steric repulsion, including avoidance of 1,3-diaxial interactions and gauche-butane-like penalties between adjacent substituents. The anomeric effect refers to a stereoelectronic phenomenon in which an electronegative substituent, such as alkoxy (OR), amino (NR₂), or halogen groups, attached to the anomeric carbon exhibits a thermodynamic preference for the axial orientation in the chair conformation of cyclic systems, defying the steric predictions that favor equatorial placement. This preference arises despite the increased steric hindrance from 1,3-diaxial interactions, as first noted in studies of glycoside stability.^[4] The scope of the anomeric effect extends beyond carbohydrates to include glycosides and analogous heterocyclic systems, such as substituted tetrahydropyran rings, where the effect influences conformational equilibria and reactivity at the anomeric center. It also manifests in acyclic molecules through the generalized anomeric effect, which describes the preference for a gauche arrangement over the sterically favored anti conformation in fragments like X-C-Y, where X and Y are heteroatoms bearing lone pairs or electronegative substituents. A representative example is observed in α-D-glucopyranose, where the anomeric hydroxyl group adopts an axial position, stabilized by the effect despite unfavorable 1,3-diaxial interactions with axial hydrogens at C3 and C5, resulting in a higher population of the α-anomer (approximately 36%) than predicted by steric considerations alone (around 10%).

Discovery and Early Observations

The anomeric effect was first proposed by J. T. Edward in 1955 through analysis of dipole moments in glycosides and related compounds, where he observed an unexpected stabilization of the axial orientation for electronegative substituents at the anomeric carbon of pyranose rings, contrary to expectations based on steric interactions. This proposal highlighted a stereoelectronic influence that favored the axial position despite increased 1,3-diaxial repulsions. The phenomenon gained wider recognition through R. U. Lemieux's investigations in the late 1950s and 1960s, earning the name Edward-Lemieux effect after his use of NMR spectroscopy to assign anomeric configurations in glycosides and equilibration studies to quantify axial preferences in solution. Lemieux's work on acetylated pyranoses confirmed the axial bias in non-hydroxylic solvents, establishing the effect as a general feature in carbohydrate chemistry. Early experimental evidence came from equilibration studies of 2-alkoxytetrahydropyrans, which revealed that the axial anomer often predominates (>50%) in non-polar solvents, underscoring the effect's ability to override steric destabilization.^[5] By the 1970s, X-ray crystallographic analyses of carbohydrate derivatives provided confirmatory solid-state data, showing consistent axial orientations for OR groups at the anomeric center across various structures. Lemieux's 1972 studies on fluorinated sugars further illuminated the effect's dependence on substituent electronegativity, demonstrating a clear trend where the axial preference strengthens in the order F > OR > SR, with fluorine exhibiting the most pronounced stabilization. Initially termed the "anomeric anomaly," the effect sparked controversy because it conflicted with prevailing steric models, such as those developed by Norman L. Allinger, which accurately predicted equatorial preferences for substituents in cyclohexane systems but failed to account for the observed axial bias in heterosubstituted rings.^[6]

Mechanistic Explanations

Hyperconjugation-Based Models

The hyperconjugation-based model represents the dominant modern explanation for the anomeric effect, attributing the axial preference of electronegative substituents at the anomeric carbon to delocalized electron interactions rather than purely steric or electrostatic factors.^[7] In this framework, first proposed through early theoretical calculations, the lone pair on the ring (endocyclic) oxygen donates electrons into the antibonding σ* orbital of the C1-X bond (where X is a heteroatom like oxygen or halogen), stabilizing the axial conformation by facilitating negative hyperconjugation.^[8] Natural bond orbital (NBO) analysis quantifies this stabilization at 5-10 kcal/mol, highlighting the significant energetic contribution from these n → σ* interactions.^[2] In cyclic molecules such as pyranose rings, the axial position allows for optimal antiperiplanar alignment between the donor lone pair and the acceptor σ* orbital, enabling efficient n → σ* overlap that is diminished in the equatorial conformer due to poorer geometry.^[7] This stereoelectronic preference is captured by second-order perturbation theory in NBO, where the stabilization energy is approximated as

\Delta E = \frac{H_{ii}^2}{\Delta \epsilon}

with H_{ii} as the matrix element between the interacting orbitals and \Delta \epsilon as their energy gap, underscoring how smaller gaps and stronger couplings favor the axial form.^[2] For acyclic molecules, hyperconjugation drives a preference for the gauche torsion angle in X-C-C-Y systems (e.g., acetals with X and Y as oxygen substituents), favoring approximately 60° over the anti conformation (~180°) through analogous n → σ* donations that lower the energy barrier for rotation.^[9] Computational evidence supports this model, with density functional theory studies at the B3LYP/6-31G* level demonstrating that deleting hyperconjugative interactions via NBO analysis reduces the axial conformational preference by up to 70% in model systems like 2-methoxytetrahydropyran, confirming the dominant role of these delocalizations.^[2] Such findings resolve earlier controversies by better accounting for the anomeric effect's persistence in both gas-phase and solution environments, outperforming purely steric explanations that fail to capture the effect's magnitude across varying substituents.^[7] While electrostatic models invoke dipole minimization as a complementary factor, hyperconjugation provides the primary orbital-based rationale for the observed stereochemistry.^[10]

Electrostatic and Steric Models

One prominent electrostatic explanation for the anomeric effect involves dipole minimization, where the axial orientation of the electronegative substituent (such as an oxygen atom, OR) at the anomeric carbon aligns the substituent's C-O bond dipole in opposition to the dipole arising from the ring oxygen's lone pair, thereby reducing the overall molecular dipole moment. This stabilization is quantified through vector addition of the dipoles, with the total dipole moment given by \mu_{\text{total}} = \sqrt{\mu_{\text{ring}}^2 + \mu_{\text{sub}}^2 - 2\mu_{\text{ring}} \mu_{\text{sub}} \cos\theta}, where \theta is the angle between the dipoles, favoring the axial conformation due to the near-antiparallel alignment.^[7]^[11] Another electrostatic component attributes the effect to lone-pair/lone-pair (n-n) repulsions between the ring oxygen and the anomeric substituent, which are minimized in the axial position owing to more favorable orbital overlap and reduced spatial proximity compared to the equatorial arrangement. This repulsion model posits that the axial geometry avoids the high-energy alignment of lone pairs that occurs equatorially, contributing to the observed preference without invoking delocalization.^[7] A 2018 computational and experimental study revealed that CH···X nonbonded attractions (where X is the electronegative group) play a key role in the anomeric effect, correlating with C-X bond elongation in axial forms to optimize Coulombic stabilization and contributing significantly to the axial preference.^[3] Early electrostatic models from the 1960s, emphasizing dipole-dipole interactions, faced criticism for inadequately predicting the diminished anomeric effect observed in polar solvents, where solvation screens electrostatic attractions and repulsions, leading to greater equatorial preference. However, modern quantum mechanical calculations have revived these ideas by demonstrating hybrid contributions, with electrostatic factors accounting for 20-30% of the stabilization in model systems like tetrahydropyran derivatives, alongside dominant hyperconjugative terms.^[7]^[3] In comparison to hyperconjugation-based models, which emphasize n→σ* delocalization and better predict variations with substituent electronegativity, electrostatic and steric approaches are less effective at capturing these trends but provide partial insight into solvent dependence, as polar media disproportionately stabilize the more polar equatorial conformer.^[7]^[12]

Modulating Factors

Substituent and Solvent Influences

The magnitude of the anomeric effect increases with the electronegativity of the anomeric substituent, as more electron-withdrawing groups enhance the stabilizing interactions favoring the axial orientation. For instance, in fluorinated tetrahydropyrans, the axial preference for fluorine is approximately 2.3 kcal/mol in the gas phase, reflecting strong n_O → σ*_C-F hyperconjugation.^[13] In contrast, alkoxy groups like methoxy exhibit a weaker axial stabilization of about 0.9 kcal/mol, consistent with reduced orbital overlap compared to halides.^[13] This trend correlates positively with Hammett σ constants for electron-withdrawing substituents, where the free energy difference ΔG_axial scales as ΔG_axial = aσ + b (a > 0), underscoring the role of inductive withdrawal in amplifying the effect.^[13] Sulfur-containing substituents, such as alkylthio (SR) groups, display a diminished anomeric effect relative to oxygen analogs, primarily due to sulfur's lower electronegativity and longer C-S bond lengths, which weaken the n_O → σ*_C-S hyperconjugative donation.^[13] For example, in thionucleosides, the S-C-N anomeric stabilization is notably less pronounced than the O-C-N counterpart, with axial preferences reduced by factors linked to poorer orbital alignment.^[13] Nitrogen-based substituents like NR₂ often exhibit a reverse anomeric effect, favoring equatorial orientations, particularly in protonated forms where the lone pair is unavailable for donation, leading to electrostatic repulsion dominance and ΔG_equatorial preferences up to 2-5 kcal/mol in model systems. Solvent polarity significantly modulates the anomeric effect, with non-polar media enhancing axial stabilization through minimized dipole solvation, while polar protic solvents weaken it by preferentially solvating the more polar equatorial conformer. In 2-methoxytetrahydropyran, the axial anomer constitutes 83% in carbon tetrachloride (dielectric constant ε ≈ 2.2) but drops to 52% in water (ε ≈ 78), illustrating the inverse correlation between effect strength and dielectric constant. Even in aqueous solutions of carbohydrates like mannose and xylose, axial populations are reduced to 32-36%, but protic solvents like water reduce the effect by 20-50% compared to non-polar counterparts due to hydrogen bonding that competes with endo-anomeric interactions.^[13]^[14] Substituents such as acetamido (NHAc) demonstrate position-dependent influences on the anomeric equilibrium, where a 2-axial NHAc group in glucosamine derivatives enhances axial anomeric stabilization via gauche effects (up to 1-2 kcal/mol), whereas 2-equatorial placement diminishes it through steric and electronic modulation.^[13] This variability arises under kinetic versus thermodynamic control: kinetic conditions favor rapid axial formation driven by transition-state hyperconjugation, while thermodynamic equilibration shifts toward solvent-stabilized minima, as seen in N-acetylated sugars where rotational dynamics of NHAc alter the effective anomeric energy by 0.5-1 kcal/mol.^[13]

Methods to Overcome or Reverse the Effect

Several strategies have been developed to diminish or invert the anomeric effect in carbohydrate chemistry, enabling selective synthesis of desired anomers by imposing steric, electronic, or environmental controls that counteract the inherent axial preference of electronegative substituents at the anomeric center. One prominent approach involves the use of bulky protecting groups, such as tert-butyldiphenylsilyl (TBDPS), which enforce steric dominance and alter the conformational landscape of the pyranose ring. For instance, incorporation of TBDPS at vicinal positions induces a ring flip or conformational restriction that overrides the stereoelectronic stabilization of the axial anomer, leading to preferential equatorial substitution in glycosylation reactions. This steric override is particularly effective in systems where the anomeric effect would otherwise dominate, achieving stereoselectivities exceeding 90% for the inverted anomer.^[15] High-polarity solvents, such as dimethyl sulfoxide (DMSO), represent another key method to reduce the magnitude of the anomeric effect by solvating polar transition states and stabilizing equatorial conformers through enhanced dipole interactions. In polar aprotic solvents like DMSO, the anomeric effect is weakened compared to nonpolar media, with reductions in axial preference estimated at 50-70% based on shifts in conformational equilibria for model tetrahydropyrans and sugars. This solvent-mediated attenuation favors β-anomer formation in glycosylation, as the solvation energy offsets the hyperconjugative stabilization of the α-form, often improving β-selectivity by factors of 2-5 in comparative reactions.^[16] Such trends align with broader observations where increasing solvent polarity diminishes the effect's amplitude, as seen in computational studies of 2-methoxytetrahydropyran derivatives. Protonation or ionization strategies further enable reversal by targeting the anomeric oxygen, shifting the equilibrium toward equatorial preference through altered charge distribution and enhanced solvation of the resulting dipole. Protonation of the ring oxygen in glycosyl derivatives generates species where the positive charge is better accommodated in equatorial orientations, reducing the anomeric stabilization by up to 1-2 kcal/mol via electrostatic solvation effects. This approach is commonly applied in acid-catalyzed mutarotation or glycosylation protocols, where protonation facilitates ring opening and reclosure with inverted selectivity. In glycosylation contexts, neighboring group participation provides a reliable means to override the anomeric effect and direct β-selectivity, exemplified by the use of 2-O-acetyl (2-O-Ac) protecting groups on glucosyl or galactosyl donors. The acetyl moiety at C2 participates anchimerically, forming a cyclic acyloxonium intermediate that blocks axial attack and enforces trans (β) glycoside formation, achieving selectivities often greater than 95% β-product.^[17] This method, pioneered by Lemieux in the 1970s through halide-catalyzed activations of glycosyl bromides with participating esters, demonstrates how transient covalent assistance can dominate stereoelectronic preferences, with ΔΔG values exceeding 2 kcal/mol required for such high selectivity thresholds. Representative examples include the synthesis of β-glucosides from 2-O-Ac donors under silver-promoted conditions, yielding >98% β-anomers in nonparticipating solvent systems.^[18]

Exo-Anomeric Effect

The exo-anomeric effect describes the stereoelectronic stabilization arising from hyperconjugative donation of a lone pair from the ring oxygen to the antibonding σ* orbital of the exocyclic C1–O(glycosidic) bond, favoring a gauche conformation for the glycosidic torsion angle φ ≈ 60° in pyranose systems.^[2] This interaction is distinct from the endo-anomeric effect, as it specifically governs the orientation of the exocyclic bond rather than the axial/equatorial preference at the anomeric carbon, thereby influencing the three-dimensional arrangement and reactivity of glycosidic linkages, such as enhanced nucleophilicity of the ring oxygen in the stabilized gauche form.^[19] In α-glycosides, the effect is maximized when the exocyclic oxygen aligns to optimize overlap with the ring oxygen lone pair, typically resulting in torsion angles φ_H (defined as H1–C1–O–C) of approximately 50–70°, as confirmed by NMR spectroscopy through vicinal coupling constants that align with Karplus predictions for these dihedrals.^[20] For instance, solution NMR data on model glycosides show consistent ¹³C–¹H coupling constants around 3.7 ± 0.5 Hz, indicative of the preferred syn-clinal arrangement.^[19] Ab initio computational studies, including those at the MP2 level, quantify the stabilization of the gauche conformer relative to the anti by 3–5 kcal/mol, with geometric changes such as elongation of the endocyclic C1–O5 bond and shortening of the exocyclic C1–O bond supporting the hyperconjugative mechanism.^[21] This preference is evident in disaccharides like maltose, where the α-(1→4) linkage adopts a conformation reinforced by the exo-anomeric interaction, contributing to the overall rigidity and "anomeric cascade" in longer oligosaccharides by propagating torsional biases across successive glycosidic bonds.^[22]

Reverse and Metallo-Anomeric Effects

The reverse anomeric effect refers to the anomalous preference for electropositive or positively charged substituents at the anomeric carbon to adopt an equatorial orientation in pyranose rings, contrary to the typical axial bias of the standard anomeric effect. This phenomenon is prominently observed in ammonium glycosides bearing quaternary nitrogen groups such as N⁺R₃, where the equatorial conformer is favored by an energy difference of 1–2 kcal/mol over the axial one, as determined from computational and experimental studies on model systems like protonated tetrahydropyrans. Explanations for this inversion include a reversal of hyperconjugative interactions, where σ C–H bonds donate into the nitrogen lone pair (σ → n donation) in the equatorial position, or electrostatic repulsion between the positively charged substituent and the partial positive charge on the ring oxygen in the axial orientation. A 2024 computational and spectroscopic study on 2-iminoaldoses provided definitive evidence for a genuine reverse anomeric effect, independent of steric factors, through the identification of stabilizing C–H···O hydrogen bonding in the equatorial configuration.^[23] In these systems, the equatorial β-anomer is stabilized relative to the axial α-anomer by approximately 1.5 kcal/mol, with the hydrogen bond interaction contributing an additional 6–8 kcal/mol of stabilization when accounting for solvent effects in DMSO; this mechanism effectively counters the endo-anomeric hyperconjugation, leading to a net equatorial preference.^[23] Protonation of the imine nitrogen in these models reverses the effect, restoring axial dominance via enhanced exo-anomeric interactions, highlighting the role of substituent charge in modulating the equilibrium.^[23] The metallo-anomeric effect describes the stereoelectronic preference for late transition metal substituents (groups 10–12) at the anomeric carbon to adopt an axial orientation in pyranose rings, analogous to the standard anomeric effect. This is observed in metal-coordinated glycosides, where coordination of metals such as Pd²⁺ to the anomeric position stabilizes the axial conformer through hyperconjugative interactions involving metal d-orbitals and the ring oxygen lone pair, with stabilization energies of 2–5 kcal/mol in computational studies of Pd-bound pyranosides.^[24] For example, X-ray and NMR structures of palladium-coordinated glycosides show predominant axial metal placement. Quantum mechanical analyses, including natural bond orbital (NBO) methods, confirm enhanced donor-acceptor interactions in the axial configuration, underscoring the stereoelectronic origins of the effect.^[24]

Applications in Organic Synthesis

Classical Synthetic Uses

The anomeric effect has been instrumental in classical glycosylation reactions by promoting the formation of axial α-glycosidic bonds in pyranose systems, thereby enabling stereoselective synthesis of carbohydrates and related heterocycles. In the Koenigs-Knorr method, introduced in 1901, glycosyl bromides or chlorides are activated using silver salts such as Ag₂O or Ag₂CO₃ to couple with alcohol acceptors, favoring α-selectivity through the stabilization of the axial configuration in the intermediate oxocarbenium ion.^[25] This approach routinely achieves 70-90% α-glycosides in modified conditions with Ag salts, making it a cornerstone for early disaccharide and oligosaccharide assembly.^[25] A prominent application lies in nucleoside synthesis via the Vorbrüggen glycosylation, developed in 1981, where peracetylated furanoses or pyranoses react with silylated nucleobases under Lewis acid catalysis (e.g., SnCl₂ or TMSOTf) to form N-glycosides. Although the anomeric effect inherently favors α-anomers, the method leverages neighboring group participation from the 2-O-acetyl substituent to override this preference, delivering β-nucleosides in high stereoselectivity (often >95% β) and yields up to 80-90% for antiviral agents like AZT. The silylation of the nucleobase enhances reactivity, allowing efficient coupling while the anomeric effect informs the design to control stereochemistry.^[26] Glycosyl trichloroacetimidates, pioneered by Schmidt in the 1980s, exemplify the utility of the anomeric effect in stabilizing axial donors for selective activation. These imidate derivatives, formed from the free hemiacetal and trichloroacetonitrile under base catalysis, exhibit enhanced stability at the anomeric center due to the effect, enabling mild acid-promoted (e.g., BF₃·OEt₂) glycosylations with alcohols to afford predominantly α-glycosides when no participating groups are present at C2. This stability facilitates their role as protected intermediates in multi-step syntheses, where the anomeric effect prevents premature decomposition and supports axial activation pathways.^[27] In natural product synthesis, the anomeric effect guided pyranose ring closures during the construction of carbohydrate moieties, as seen in early total syntheses of aminoglycoside antibiotics like streptomycin in the 1950s, where it favored the thermodynamically stable α-configuration to streamline assembly. Exploiting the effect with non-participating donors in such methods improved overall yields by 20-40% compared to non-selective approaches, by minimizing anomeric mixtures and enhancing purification efficiency.^[25]

Recent Developments (2020-2025)

Recent research has advanced the application of the anomeric effect in radical glycosylation strategies, particularly through the use of anomeric stannanes as precursors for generating stabilized radicals at the anomeric center. In 2020, a study demonstrated that copper(I)-catalyzed photoredox conditions enable the conversion of anomeric stannanes into radicals via single-electron transfer, facilitating stereoselective C-S cross-coupling with high α-selectivity.^[28] This approach leverages the anomeric effect to stabilize the axial radical intermediate, offering a departure from traditional two-electron mechanisms and enabling access to complex thioglycosides for pharmaceutical applications. Automation in oligosaccharide synthesis has seen significant progress. A 2025 method developed by researchers at the University of California, Santa Barbara, and the Max Planck Institute of Colloids and Interfaces utilizes automated solid-phase platforms with directed SN2 mechanisms for precise stereocontrol, enabling the synthesis of oligosaccharides with 3-10 monomer units.^[29] This stereospecific glycosylation protocol ensures high yields and purity, addressing scalability challenges in glycan production for biomedical research, such as vaccine development and glycobiology studies.^[30] A 2024 investigation confirmed a true reverse anomeric effect driven by intramolecular hydrogen bonding, which enforces equatorial nitrogen substituents and has been applied to synthesize fused nitrogen heterocycles with improved yields.^[23] These findings underscore the effect's role in overriding steric biases for selective heterocycle formation. Integration of artificial intelligence with the anomeric effect has emerged as a unique tool for optimization and prediction. In 2025, machine learning models were employed to predict anomeric selectivity in glycosylations, optimizing reaction conditions through Bayesian algorithms that account for substrate-specific electronic interactions, achieving up to 90% accuracy in stereoprediction.^[31]

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