Anomeric Interactions Research Articles

Exploring Conformational Preferences in XC(W)ZY Molecules With X, Y = F, Cl, Br and W, Z = O, S, Se: Unraveling the Influence of Conjugative and Anomeric Interactions

ABSTRACTThe relative stabilities of the syn‐ and anti‐conformers of 72 molecules belonging to the XC(W)ZY type, with X, Y = F, Cl, Br and W, Z = O, S, Se, have been computed using the B3LYP/aug‐cc‐pVDZ approximation. The conformational preferences, represented by the energy differences between the two rotamers, exhibit a systematic trend in relation to both the halogen atoms and the chalcogen atoms. These computational predictions are in agreement with available experimental results. The NBO formalism was employed to assess the influence of both the conjugative and anomeric interactions on the relative energy of the conformers. It has been determined that the conjugative interaction provides a satisfactory explanation for the energy differences between rotamers. In contrast, the anomeric interactions favors the syn‐conformation in all cases. The relative stabilities between XC(W)ZY/YC(W)ZX and XC(W)ZY/XC(Z)WY constitutional isomers have also been computed and correlated with the experimental data.

Pyrimidine and cumene derivatives functionalized by hydroxy and methoxy: Computational insights in drug-likeness, ADM, and toxicity studies

The –OH and –OCH3 functionalized isopropyl cumene and isopropyl pyrimidine derivatives were designed and, explored in terms of the ADM, and possible toxic effects in view of the medicinal and environmental. For this goal, the geometry optimizations and structural confirmations were conducted by the G09W package at B3LYP/6-311G** level of theory. The verified geometries were used for further computations and analyses. The bioavailability features such as lipophilicity, water solubility, and drug-likeness, pharmacokinetics were determined by SwissADME tools. Also, ADMETLab computations were used to predict the absorption, distribution, metabolism, and toxicity of the data set. The FMO and NBO analyses were performed to determine the –OH and –OCH3 function effect on the cumene and pyridine structures and then the electronic properties underlying the bioavailability and toxicity properties. Accordingly, the –OCH3 function on the structure l seems to be important to rise the inhibitory or substrate potency in the enzyme metabolism for both series. For the pyrimidine series, the anomeric interactions (n → σ*) in addition to the resonance interactions (n → π* and π → π*) also would have a role in molecular stability and affect the charge distribution on the molecular surface, which could play of remarkable role in the bioavailability and ADM. In terms of electronic structure and physicochemical properties, and possible bioactivity or toxicity relationship, the results obtained in the study will be an important reference source for the research on exploring/developing/improving future biocompatible molecular structures.

Formation of 3-Oxa- and 3-Thiacyclohexyne from Ring Expansion of Heterocyclic Alkylidene Carbenes: A Mechanistic Study.

The rearrangement pathways of two alkylidene carbenes appended to an oxa or thiacyclopentane into the corresponding heterocyclohexynes were elucidated using 13C-labeling experiments. Both carbenes exhibited a preference for migration of the allylic carbon bound to the heteroatom. Anomeric interactions involving a heteroatom lone pair and antibonding orbital of the migrating bond and inductive destabilization of the minor migratory pathway are discussed as plausible reasons for the observed trends.

The influence of exocyclic lone pairs on the bonding and geometry of type A mesoionic rings

Based on structures determined by X-ray crystallography, ab initio MP2 calculations on type A mesoionic rings give geometries in good agreement with observed values. A study of four mesoionic ring systems, each with exocyclic oxygen, nitrogen or carbon groups, shows that the presence and configuration of exocyclic lone pairs significantly influences the geometry and configurational preference. Using a localised bond model and NBO analysis, these effects are rationalised in terms of an anomeric interaction of lone pairs with the antibonding orbitals of adjacent σ bonds. In agreement with experiment, similar effects are calculated for pyran-2-imines.

Thermal Decomposition of CxF2x+1C(O)OONO2 (x = 2, 3, 4).

The atmospheric degradation of molecules containing the CxF2x+1C(O) moiety, such as perfluoroaldehydes CxF2x+1C(O)H (x = 2-4) formed in the degradation of telomeric alcohols, could lead to the formation of perfluoroacyl peroxynitrates CxF2x+1C(O)OONO2. The thermal decomposition of the CxF2x+1C(O)OONO2 family (x = 2, 3, 4) was investigated by infrared spectroscopy and computational models. Each peroxynitrate synthesis was performed through the photolysis of gas mixtures of the corresponding perfluoroaldehyde, chlorine, nitrogen dioxide, and oxygen. Kinetic analysis for the thermal decomposition of peroxynitrates were performed in the range from 297.0 to 313.7 K at a total pressure of 1000 mbar and the activation energy was experimentally determined. Experimental data were complemented with theoretical data using the Gaussian09 Program Suite. The structures of peroxynitrates were optimized using DFT methods. The activation energies were calculated and investigated taking into account the stereoelectronic effects and using theoretical calculations as well as NBO analysis. The influence of anomeric interaction over the O-N bond was evaluated for all the molecules. Analysis of the results shows that CxF2x+1C(O)OONO2 stability is independent of CxF2x+1 chain length, in contrast to the behavior for perfluoroalkyl peroxynitrates (CxF2x+1OONO2).

Thermodynamics of silica depolymerization with alcohols

Experimental and computational results describe the outlook for silica (polymeric SiO2) depolymerization with alcohols. The resonance energy of the Si-O-Si segment, calculated as 8.0 kcal/mol, or 16.0 kcal/mol of SiO2, explains the thermodynamic stability of silica. Acid-catalyzed alkylorthosilicate metathesis reactions between Si(OMe)4 and diols indicate silicon’s thermodynamic preference for diols because of favorable entropic chelation. Conversion to Si(OCH2CH2O)2 with ethylene glycol is 74.6% and conversion to Si(OCH2CH2CH2O)2 with 1,3-propanediol is 66.2%. The enthalpic stability of Si(OR)4 species correlates to two main factors: (1) the O-Si-O bond angle, with a compression force constant of kΘ-comp = 0.0315 (kcal/mol)(°)–2 and expansion force constant of kΘ-exp = 0.0167 (kcal/mol)(°)–2; and (2) the C-O-Si-O dihedral angle, dictated by stabilizing O n→ Si-O σ* anomeric interactions of 3.5 kcal/mol in the model compound Si(OMe)4. Computationally, silica depolymerization with methanol is never exergonic, but depolymerization with 1,3-propanediol, forming Si(OCH2CH2CH2O)2 and two equivalents of water, is exergonic above 99°C in water.

Conformational signature of Ishikawa´s reagent using NMR information from diastereotopic fluorines

The active species of the Ishikawa´s reagent [N,N-diethyl-(1,1,2,3,3,3-hexafluoropropyl)amine] is a fluorinating hexafluoropropylamine used to convert alcohols into alkyl fluorides. On the other hand, it is also an example of model compound useful to probe conformational preferences using spectroscopic information from diastereotopic fluorines. Moreover, the possibility of experiencing both the generalized anomeric and gauche effects makes the Ishikawa´s reagent an ideal choice to study the governing stereoelectronic interactions of the conformational equilibrium of organofluorine compounds. The conformational equilibrium of the Ishikawa´s reagent was analyzed using NMR 3JH,F coupling constant data in different solvents, since the orientation of the diastereotopic fluorines relative to H-2 and F-2 changes with the medium. In nonpolar cyclohexane solvent, the preferred conformation experiences a weaker steric and electrostatic repulsion. The conformational behavior changes in the more polar pyridine solution, where the double fluorine gauche effect takes place, since F-2 is preferably gauche to both diastereotopic fluorines. An analysis of the rotation around the N–C(F2) bond indicates the manifestation of anomeric interactions (nN → σ*C–F), which can be demonstrated by means of 19F chemical shifts. The results were rationalized with the aid of theoretical calculations and natural bond orbital (NBO) analysis, allowing for the evaluation of competing steric, electrostatic and hyperconjugative interactions.

Electron density analysis in (tetramethylcyclobutadiene)cobalt complex with charge-compensated dicarbollide [9-SMe2-7,8-C2B9H10] ligand

Using high-resolution X-ray diffraction investigation of the crystal of (η4-Me4C4)-4-Me2S-3,1,2-Co(C2B9H10) as well as DFT calculations, an analysis of electron density function in both crystal and isolated molecule was carried out. The results obtained allowed to find out the distinct features of chemical bonding of transition metal with C4Me4 and charge-compensated dicarbollide ligand. We have estimated the covalent contribution for the Co-B and Co-C bonds between Co and C2B3 open face, energy of the Co-C4Me4 and Co-C2B3 interactions and have analyzed mutual influence of the dicarbollide and Me4C4 ligands on each other and possibility of anomeric interaction of the SMe2 group with atoms of polyhedron that stabilize the arrangement of SMe2 in respect to B-B bonds.

Ozone-Free Synthesis of Ozonides: Assembling Bicyclic Structures from 1,5-Diketones and Hydrogen Peroxide.

Reactions of 1,5-diketones with H2O2 open an ozone-free approach to ozonides. Bridged ozonides are formed readily at room temperature in the presence of strong Brønsted or Lewis acids such as H2SO4, p-TsOH, HBF4, or BF3·Et2O. The expected bridged tetraoxanes, the products of double H2O2 addition, were not detected. This procedure is readily scalable to produce gram quantities of the ozonides. Bridged ozonides are stable and can be useful as building blocks for bioconjugation and further synthetic transformations. Although less stabilized by anomeric interactions than bis-peroxides, ozonides have an intrinsic advantage of having only one weak O-O bond. The role of the synergetic framework of anomeric effects in bis-peroxides is to overcome this intrinsic disadvantage. As the computational data have shown, this is only possible when all anomeric effects in bis-peroxides are activated to their fullest degree. Consequently, the cyclization selectivity is determined by the length of the bridge between the two carbonyl groups of the diketone. The generally large thermodynamic preference for the formation of cyclic bis-peroxides disappears when 1,5-diketones are used as the bis-cyclization precursors. Stereoelectronic analysis suggests that the reason for the bis-peroxide absence is the selective deactivation of anomeric effects in a [3.2.2]tetraoxanonane skeleton by a structural distortion imposed on the tetraoxacyclohexane subunit by the three-carbon bridge.

Influence of stereoelectronic effects on the non-opioid analgesics gaboxadol and gaboxadol hydrochloride: Spectral and DFT study

The stereoelectronic properties of the molecular structure of most stable conformers of gaboxadol and gaboxadol hydrochloride have been studied using DFT/B3P86-LANL2DZ methodology. The energies of stable conformers of gaboxadol and gaboxadol hydrochloride are −494.2689 and −510.0117 hartrees, respectively. The stability of the molecules arising from stereoelectronic interactions, leading to its bioactivity, has been confirmed using natural bond orbital analysis. The natural bond orbital analysis of donor-acceptor (σ→σ* and n→σ*) interactions showed that the stereoelectronic hyperconjugative and anomeric interactions are exhibited in gaboxadol hydrochloride and gaboxadol, respectively. Lengthening of the axial and equatorial C-H bond lengths and natural population analysis support these results. Spectral features of gaboxadol hydrochloride have been explored by the Fourier transform infrared, Raman and Nuclear magnetic resonance spectroscopic techniques combined with density functional theory computations. NH+ … Cl− hydrogen bonding has been noticeable as a broad and strong absorption in the 2800-2400 cm−1 region. Broad peaks obtained by proton NMR are a result of the quadrupole effect of the N+ atom. Docking studies using representative GABA receptor crystal structures revealed that molecules containing azinane and isoxazole cores fit within the ligand binding domains, and the gaboxadol hydrochloride molecule shows the best binding energy with the 3D32 GABA receptor. Also, gaboxadol hydrochloride has obtained a high value of HOMO energy and a narrow HOMO- LUMO energy gap, which enhances reactivity.

The role of substituents in the HERON reaction of anomeric amides

Anomeric amides, RCON(X)(Y), have two electronegative atoms at the amide nitrogen, a configuration that results in greatly reduced amide resonance and strongly pyramidal nitrogen atoms. This, combined with facilitation of anomeric interactions, can result in the HERON reaction, an intramolecular migration of the more electronegative atom, X, from nitrogen to the carbonyl with production of a Y-stabilised nitrene. We have modelled, at the B3LYP/6-31G(d) level, a variety of anomeric amides that undergo the HERON reaction to determine factors that underpin the process. The overriding driving force is anomeric destabilisation of the bond to the migrating group. Rotated transition states show loss of residual resonance and this is a component of the overall activation energies. However, the reduced resonance in these systems plays only a minor role. We have determined the resonance energies (RE) and HERON activation barriers (EA) of five anomeric systems. REs for the amides have been calculated isodesmically using our calibrated trans amidation method and COSNAR calculations. Reduction of their overall EAs by the corresponding RE gives rearrangement energies (Erearr.), a measure of relative impact on rearrangement of substituents on nitrogen. In CH3CON(OMe)(Y) systems producing (CH3CO2Me + NY), a loosely bound electron pair on the donor atom, Y, in nY–σ*NOMe anomeric interactions drives the reaction. Erearr. increases in the sequence Y = N(nitrene) < O−(oxide) ≪ NMe2 < SMe ≪ OMe. For the same systems, RE increases in the order Y = N < O− ≪ OMe ≪ NMe2 ∼ SMe. Other effects such as molecular conformation, nature of the migrating group, X, and acyl substituents at the carbonyl carbon are discussed.

Experimental and theoretical evaluation of trans-3-halo-2-hydroxy-tetrahydropyran conformational preferences. Beyond anomeric interaction

Which analysis will explain the preferences of the substituents in the hydro-halo-tetrahydropyran rings? Is the anomeric effect essential to understand what is going on?

VSEPR Theory: A closer look at chlorine trifluoride, ClF3.

Valence shell electron pair repulsion theory is a simple way of rationalising the shapes of many compounds in which a main group element is surrounded by ligands. ClF3 is a good illustration of this theory. The standard application of VSEPR theory to this molecule is as follows: Central atom: chlorine Valence electrons on central atom: 7 Three fluorine atoms contribute: 1 each Total: 10 = five electron pairs. The highest repulsion is between any two “lone electron pairs”, resulting in these moving apart as far as possible the next highest is between one lone pair and a bond pair the lowest is between two bond pairs. As applied to chlorine trifluoride, it results in a trigonal bipyramidal geometry for the shape-determining five electron pairs. One of the trigonal positions is occupied by the pair deriving from a Cl-F bond (F=white, Cl=red below). The other two trigonal positions are occupied by two sets of electron lone pairs (yellow below) at ≥ 120° (rule 5, but much more and the repulsions between the lone pair and the trigonal Cl-F bond would become too great, rule 6 above). The remaining two Cl-F bond pairs occupy the di-axial positions (rule 7 above). The above at least is the standard “text-book” picture. Regular readers of this blog may have noted that I often like to question the text books. So here goes. My issue is with the above explanation, of five electron pairs all associated in some way with the central atom. An expanded octet in other words. Well, if you take a look at earlier blogs, you may have observed that this expanded octet is not real (IMHO). If it’s not real, then we cannot be dealing with five electron pairs. Can VSEPR work with only eight electrons in this instance? And what are the coordinates of the so-called two “lone pairs”: is the angle subtended at the Cl by them really trigonal (~120)? I start with computing an accurate wavefunction, using the DFT-based ωB97XD/6-311++G(d,p)[1]. The electron count and the coordinates of the localised basins will be obtained using ELF (Electron localisation function). Click for 3D The electron basins are shown here as red spheres; 8 and 9 are the “lone pairs”, as it happens a very reasonable description since the populations for these are 2.07e. The 8-2-9 angle of 154° results from rule 5 above; lone pairs repel greatly. Indeed, one might almost describe 8 and 9 as being di-axial. In which case, the geometry is not that of a trigonal bipyramid but is closer to that of a square pyramid. Basin 7 is a Cl-F bond, with a population of 0.87e, rather less than a “pair” (the Wiberg bond index is 0.82). Basins 11+19 and 10+15 (similar basin splitting is observed for F2[2]) each total 0.91e; again less than a pair (Wiberg index 0.63). So the three Cl-F bonds are Other features include eg the orientation of the “lone pairs” on fluorines 3 and 4, in which e.g. 16 is oriented anti-periplanar to the 2-1 bond. This is in fact an anomeric effect! An NBO analysis reveals E(2) between Lp16 and σ*2-1 to be 6.3 kcal/mol, a relatively weak but still a real anomeric interaction. The total electron count for the ELF basins surrounding the central Cl is 6.84, not 10 as was implied in the simple argument set out above. VSEPR theory is a highly simplified way of looking at the geometric origins of this odd little molecule; an ELF analysis likewise paints only a partial picture. Indeed, it seems doubtful that any simple way of regarding this species can ever be entirely adequate. But we should be mindful that the “EP” (electron pair) of VSEPR might itself be rather misleading in perpetuating the idea that such main group elements contain expanded octets. But the geometry of chlorine trifluoride makes sense without imposing 10 valence electrons on the chlorine after all! References Henry S. Rzepa., "Gaussian Job Archive for ClF3", 2013. http://dx.doi.org/10.6084/m9.figshare.757728 S. Shaik, D. Danovich, B. Silvi, D.L. Lauvergnat, and P.C. Hiberty, "Charge-Shift Bonding—A Class of Electron-Pair Bonds That Emerges from Valence Bond Theory and Is Supported by the Electron Localization Function Approach", Chemistry - A European Journal, vol. 11, pp. 6358-6371, 2005. http://dx.doi.org/10.1002/chem.200500265

Stereoelectronic source of the anomalous stability of bis-peroxides.

The unusual stability of bis- and tris-peroxides contradicts the conventional wisdom - some of them can melt without decomposition at temperatures exceeding 100 °C. In this work, we disclose a stabilizing stereoelectronic effect that two peroxide groups can exert on each other. This stabilization originates from strong anomeric nO → σ*CO interactions that are absent in mono-peroxides but reintroduced in molecules where two peroxide moieties are separated by a CH2 group. Furthermore, such effects can be induced by other σ-acceptors and amplified by structural constraints imposed by cyclic and bicyclic frameworks.

Glycolurils in α-ureido- and α-aminoalkylation Reactions. 3**. N-(hydroxymethyl)glycolurils in Reactions with Aliphatic Amines and Amino Acids*

The condensation of aliphatic alkylamines and achiral amino acids with 1,5-butano-2,4,6,8-tetra-(hydroxymethyl)- and 2,4,6,8-tetra(hydroxymethyl)glycolurils was used to prepare and characterize polycyclic condensed compounds (including some previously unknown examples) containing glycoluril and alkylamine fragments. X-ray structural study of the obtained compounds was used to identify n(N)→σ(C–H) anomeric interaction.

Salts of hexamethylenetetramine with organic acids: Enhanced anomeric interactions with a lowering of molecular symmetry revealed by crystal structures

The hexamethylenetetramine (HMT) framework displays interesting stereoelectronic interactions of the anomeric type. In the highly symmetrical parent system, the nitrogen centres act as both donors and acceptors. Protonation lowers symmetry and also leads to an enhancement of the anomeric interaction around the protonated centre. X-ray diffraction crystal structures of four derivatives of HMT – with succinic, (DL)-malic, phthalic and 4-hydroxybenzoic acids – reveal significant trends. (The first three form well-defined salts, 4-hydroxybenzoic acid forming a co-crystalline compound.) Each molecular structure is essentially characterised by a major anomeric interaction involving the protonated centre as acceptor. In two cases (succinic and 4-hydroxybenzoic), secondary protonation leads to a weaker anomeric interaction site that apparently competes with the dominant one. Bond length changes indicate that the anomeric interaction decreases as malic>phthalic>succinic>4-hydroxybenzoic, which correlates with the degree of proton transfer to the nitrogen centre. Along with other bond length and angle changes, the results offer insight into the applicability of the antiperiplanar lone pair hypothesis (ALPH) in a rigid system.

Hybrid-DFT Study and NBO Interpretation of the Configurational Behavior of 2-Halotetrahydrothiopyran S-Oxides

Natural bond orbital (NBO) interpretation and hybrid density functional theory (hybrid-DFT: B3LYP/Def2-TZVPP)-based methods were used to investigate the impacts of the generalized anomeric effects (GAE), electrostatic, and steric interactions on the conformational properties of cis and trans isomers of 2-fluoro-, 2-chloro-, and 2-bromotetrahydrothiopyran S-oxide (1–3). The results obtained showed that the trans-axial configurations are the most stable forms of compounds 1–3. Based on the results obtained, the instability of the second lowest energy-minimum (cis-equatorial configuration, with axial S˭O and equatorial C‒X bonds, X = halogen atoms) increases from compound 1 to compound 3. This trend is also observed for the third lowest energy-minimum (i.e., the trans-equatorial configuration). Contrary to the trend observed for the cis- and trans-equatorial forms, the instability of the cis-axial form compared to the trans-axial form, increases from 1 to 2 but decreases slightly from 2 to 3. The correlations between the GAE, bond orders, steric effects, ΔG, Δμ, structural parameters, and conformational and configurational behaviors of compounds 1–3 have been investigated. Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.

Hyperconjugation-Mediated Solvent Effects in Phosphoanhydride Bonds

Density functional theory and natural bond orbital analysis are used to explore the impact of solvent on hyperconjugation in methyl triphosphate, a model for "energy rich" phosphoanhydride bonds, such as found in ATP. As expected, dihedral rotation of a hydroxyl group vicinal to the phosphoanhydride bond reveals that the conformational dependence of the anomeric effect involves modulation of the orbital overlap between the donor and acceptor orbitals. However, a conformational independence was observed in the rotation of a solvent hydrogen bond. As one lone pair orbital rotates away from an optimal antiperiplanar orientation, the overall magnitude of the anomeric effect is compensated approximately by the other lone pair as it becomes more antiperiplanar. Furthermore, solvent modulation of the anomeric effect is not restricted to the antiperiplanar lone pair; hydrogen bonds involving gauche lone pairs also affect the anomeric interaction and the strength of the phosphoanhydride bond. Both gauche and anti solvent hydrogen bonds lengthen nonbridging O-P bonds, increasing the distance between donor and acceptor orbitals and decreasing orbital overlap, which leads to a reduction of the anomeric effect. Solvent effects are additive with greater reduction in the anomeric effect upon increasing water coordination. By controlling the coordination environment of substrates in an active site, kinases, phosphatases, and other enzymes important in metabolism and signaling may have the potential to modulate the stability of individual phosphoanhydride bonds through stereoelectronic effects.

4,5‐Bis(dialkylamino)‐Substituted Imidazolium Systems: Facile Access to N‐Heterocyclic Carbenes with Self‐Umpolung Option

The first synthesis of 4,5-bis-(dimethylamino)-substituted imidazolium compounds was developed, which is based on the reaction of a 1,2-diamino-1,2-bis(phosphonio)ethene with lithiated formamidines. This represents the first application of this class of ethene derivatives for the preparation of heterocycles. These N-heterocyclic carbene (NHC) precursors show a remarkably reduced basicity and nucleophilicity of their NMe2 groups, which is due to the strong anomeric interactions of the latter with the imidazolium core. According to DFT calculations, these NHCs are capable of self-umpolung if sufficiently strong acceptor substituents are introduced at the carbene center. To test the self-umpolung capabilities of the NHCs, various substituents were attached to the carbene center and the obtained compounds were characterized by single-crystal X-ray analysis as well as quantum chemical computations. Strong acceptor substituents are required to induce self-umpolung, such as in the phosphonio-substituted derivative, for which partial self-umpolung was found. The N,N′-bis(4-dimethylaminophenyl)-substituted imidazolium compound represents a special case, as it incorporates as much as three two-step redox systems within the NHC framework. This will probably result in a high electronic flexibility of the corresponding nucleophilic carbenes, especially when they serve as ligands in transition metal complexes.

Simulant Molecules with Trivalent or Pentavalent Phosphorus Atoms: Bond Dissociation Energies and Other Thermodynamic and Structural Properties from Quantum Chemical Models

The CBS-QB3 and G4 thermochemical models have been used to generate energetic, structural, and spectroscopic data on a set of molecules with trivalent or pentavalent phosphorus atoms that can serve as simulants of chemical warfare agents. Based on structural data, the conformational stabilities of these molecules are explained in terms of the anomeric interaction within the OPOC and OPSC fragments. For those cases where experimental data are available, comparisons have been made between calculated and previously reported vibrational frequencies. All varieties of bond dissociation energies have been examined except those for C-H and P═O bonds. In trivalent phosphorus molecules, the O-C and S-C bonds have the lowest dissociation energies. In the pentavalent phosphorus set, the S-C bonds, followed by P-S bonds, have the lowest dissociation energies. In the fluorinated simulant molecules, the P-F bond is strongest, and the P-C or O-C bonds are weakest.