Absence of reverse anomeric effect in furanosides

A series of conformationally restricted N-"furanosides" has been synthesized, where the carbons of the tetrahydrofuran ring are kept in one plane by a rigid norbornane skeleton, permitting only the ring oxygen to move above or below the tetrahydrofuran ring plane. This causes the substituents of the anomeric carbon to occupy a pseudoaxial or a pseudoequatorial position. On protonation of these "norbornane-furanosides" with trifluoromethanesulfonic acid, all three compounds exhibited decreasing coupling constants for the anomeric proton, indicating a shift toward the pseudoaxial conformation. The coupling constant measurements were supported by volume integration of NOESY cross-peaks, which also showed a change toward the pseudoaxial conformation upon protonation of the nitrogen. These results provide no evidence for the so-called reverse anomeric effect; on the contrary they are in full agreement with a small normal anomeric effect.     

Anomeric effects versus steric hindrance to ionic solvation in protonated glucosylanilines and cyclohexylanilines

The so-called reverse anomeric effect is the preference of cationic substituents for the equatorial position on a pyranose ring, but it is not consistent with current theories of molecular structure or with previous studies designed to test it. To probe this further, the N-protonation-induced shifts of the anomeric equilibrium in a series of N-(tetra-O-methylglucopyranosyl)anilines have been measured with high precision through an NMR titration method that compares basicities of alpha and beta anomers in a mixture of the two. For comparison, the N-protonation-induced shifts of the cis/trans equilibrium in N-(4-tert-butylcyclohexyl)anilines have also been measured by this same method. In both series, there is a shift of the equilibrium toward equatorial upon N-protonation, consistent with steric hindrance to ionic solvation. This shift is smaller for the glucosylanilines than for the cyclohexylanilines, consistent with an enhancement of the normal anomeric effect that counters the steric hindrance and reduces the shift toward the equatorial beta anomer. Moreover, the shift toward equatorial increases slightly but detectably with electron-withdrawing substituents on the cyclohexylaniline, which fine-tune the steric hindrance to ionic solvation. In contrast, the shift decreases for the glucosylanilines. This is consistent with an enhancement of the normal anomeric effect due to a more localized positive charge, rather than with a reverse anomeric effect. These results thus define the substituent dependence of the anomeric effect.     

Heterocyclic N-glycosyl derivatives. XIV. Preparation of some N-(2,3-dideoxyglycopyranosyl)benzotriazoles by hydrogenation of N-(pent- and hex-2-enopyranosyl)benzotriazoles

Catalytic hydrogenation of a series of N-(pent- and hex-2-enopyranosyl)benzotriazoles afforded the corresponding saturated N-glycosyl derivatives having the same anomeric configuration as the starting compounds. The conformations of all compounds obtained were determined by nmr spectroscopy. The hexopyranosyl nucleosides in solution adopt the Cl conformation. On the other hand, pentopyranosyl nucleosides exist as a mixture of the two chair conformers in equilibrium, with the IC or CI ( L ) form predominating.     

Is there a generalized reverse anomeric Effect? substituent and solvent effects on the configurational equilibria of neutral and protonated N-arylglucopyranosylamines and N-aryl-5-thioglucopyranosylamines

The effects of substitution and solvent on the configurational equilibria of neutral and protonated N-(4-Y-substituted-phenyl) peracetylated 5-thioglucopyranosylamines (Y = OMe, H, CF(3), NO(2)) 1-4 and N-(4-Y-substituted-phenyl) peracetylated glucopyranosylamines (Y = OMe, H, NO(2)) 9-11 are described. The configurational equilibria were determined by direct integration of the resonances of the individual isomers in the (1)H NMR spectra after equilibration of both alpha- and beta-isomers. The equilibrations of the neutral compounds 1-4 in CD(3)OD, CD(3)NO(2), and (CD(3))(2)CO were achieved by HgCl(2) catalysis and those of the neutral compounds 9-11 in CD(2)Cl(2) and CD(3)OD by triflic acid catalysis. The equilibrations of the protonated compounds in both the sulfur series (solvents, CD(3)OD, CD(3)NO(2), (CD(3))(2)CO, CDCl(3), and CD(2)Cl(2)) and oxygen series (solvents, CD(2)Cl(2) and CD(3)OD) were achieved with triflic acid. The substituent and solvent effects on the equilibria are discussed in terms of steric and electrostatic effects and orbital interactions associated with the endo-anomeric effect. A generalized reverse anomeric effect does not exist in neutral or protonated N-aryl-5-thioglucopyranosylamines and N-arylglucopyranosylamines. The anomeric effect ranges from 0.85 kcal mol(-)(1) in 2 to 1.54 kcal mol(-)(1) in 10. The compounds 1-4 and 9-11 show an enhanced endo-anomeric effect upon protonation, ranging from 1.73 kcal mol(-)(1) in 2 to 2.57 kcal mol(-)(1) in 10. We estimate the increase in the anomeric effect upon protonation of 10 to be approximately 1.0 kcal mol(-)(1). However, this effect is offset by steric effects due to the associated counterion which we estimate to be approximately 1.2 kcal mol(-)(1). The values of K(eq)(axial-equatorial) in protonated 1-4 increase in the order OMe < H < CF(3) < NO(2), in agreement with the dominance of steric effects (due to the counterion) over the endo-anomeric effect. The values of K(eq)(axial-equatorial) in protonated 9-11 show the trend OMe > H < NO(2) that is explained by the balance of the endo-anomeric effect and steric effects in the individual compounds. The trends in the values of the C(1)-H(1) coupling constants for 1-4 and the corresponding deacetylated compounds 5-8 as a function of substituent and alpha- or beta-configuration are discussed in terms of the Perlin effect and the interplay of the endo- and exo-anomeric effects.     

C-5 functionalization of trisubstituted imidazoles with azodicarbonyl compounds

Certain 1,2,4-trisubstituted imidazoles underwent electrophilic attack of azodicarbonyl compounds on the 5-position to form 5-(1,2-dialkoxycarbonyl)hydrazino- and 5-(4-phenyl-3,5-dioxo-1,2,4-triazolidin-1-yl)imidazole derivatives in moderate to high yields. The reaction was highly susceptible to the nature and the substitution pattern of the substituents on the imidazole ring. Thus 1,4-di- or 1,2,5-trisubstitued imidazoles, and 2-methylsulfinylimidazoles gave no reaction. Reductive cleavage of the tetrasubstituted imidazoles with zinc dust-acid gave the 1- or 1,2-cleaved product depending upon the reaction temperature, but the hydrazino moiety remained intact.     

Photosensitized oxidation of 13C,15N-labeled imidazole derivatives

An efficient synthesis of imidazoles with isotope labeling at different positions of the five-membered ring was developed. We carried out a detailed mechanistic study of the photosensitized oxidation of isotope-labeled imidazole derivatives. A new product, CO(2), was observed in the photooxidation of 2-H,N1-H imidazoles, but not in 2-substitituted imidazoles. The carbon of CO(2) derives from the 2C of imidazole. As shown by 18O experiments, both oxygen atoms of CO(2) originate mainly from one molecule of oxygen. Transient intermediates were detected by low-temperature NMR in the photosensitized oxidation of the isotope-labeled imidazoles. Quantitative analysis of the 13C NMR at different temperatures and times correlates the formation of one intermediate with the loss of another, thus allowing the complete decomposition pathway of the transient intermediates to be established. Singlet oxygen reacts with 4,5-diphenylimidazole via a [4 + 2] cycloaddition to form a 2,5-endoperoxide, which, upon warming, decomposes to a hydroperoxide. The hydroperoxide in one pathway loses water to form an imidazolone 7, which is hydrolyzed to a hydroxyimidazol-2-one 11. In another pathway, the hydroperoxide rearranges to diol 8. The diol rearranges to a carbamate 9 by opening and reclosing the five-membered ring. 9 decomposes to CO(2) and benzil diimine. A labile NH in the imidazole is crucial for the decomposition of the initially formed endoperoxide, otherwise the endoperoxide decomposes to regenerate starting material. Many similarities exist between the photooxidations of imidazole and guanosine in organic solvent, suggesting that the two reactions share a similar reaction mechanism with singlet oxygen.     

Estimation of the Anomeric Effect of the Cyano Group

ABSTRACT

The anomeric effect^1,2 is a well established phenomenon among carbohydrate derivatives, and more generally among 2-substituted tetrahydropyrans. The generalized anomeric effect¹ refers to structural moieties R-X-C-Y (where X possesses one or two lone pairs of electrons, and Y is an atom or group of high electronegativity) in both open chain or cyclic molecules. Thus hydroxyacetonitrile prefers to exist in the gauche conformation,^3,4 and several 3-cyano-perhydro-1,2-oxazine derivatives prefer conformations in which the C-3--CN bond and the lone pair of the nitrogen are coplanar.⁵ Investigation of conformational equilibria of all but one 2,6-anhydro-hexononitrile^6,7 (pentopyranosyl cyanides) left doubt relating to the anomeric effect of the cyano group, and raised the possibility of a stabilizing interaction between 1,3-diaxial cyano and acetoxy groups.     

Carbon–13 NMR studies of tautomerism in some 2-substituted imidazoles and benzimidazoles

The ¹³C NMR spectra of several 2-substituted imidazoles and benzimidazoles have been measured. The substituent was CH₃, COOH and CONHR, where R = H, n-Bu, p-tolyl or m-chlorophenyl. Carbons 4 and 5 in the imidazoles and the carbon pairs 8/9, 4/7 and 5/6 become equivalent by proton transfer from N-1 to N-3, possibly through intermolecular association. The rate of this proton exchange increases with concentration and temperature. It decreases with extension of the 2-substituent (rate CH₃?CONH-phenyl > CONH-p-tolyl ? CONH-m-chlorophenyl ? CONH-n-butyl) due to steric hindrance at the site of the (benz)imidazole nitrogen.     

Conformation of Some Anomeric O-Benzylated D-gluco-, L-Ido-, and Hex-4-enopyranoside derivatives

By use of ¹H-NMR. spectroscopy it is shown that in the anomeric tri-O-benzyl derivatives of D -gluco- and L -idopyranosides the C(5) (aliphatic) substituent has a strong tendency to assume an equatorial position. The conformer (⁴C₁ or ¹C₄) with C(6) in equatorial position is favoured, even if other bulky substituents are forced to occupy an axial position; the same effect is observed in some anomeric O-benzylated 6-deoxy-L -idopyranoside derivatives. If, however, the tetragonal configuration of the saturated C(5) is changed into a trigonal (sp²) configuration, e.g. in the anomers of 1,2,3-tri-O-benzylated L -threo-hex-4-enopyranosiduronates, the C(5)–C(6) bond no longer determines the equilibrium of (distorted) pyranoid conformations; the anomeric (‘Eduard-Lemieux’) effect then becomes important in the stabilization of the corresponding half-chair (¹H₂ or ²H₁) conformations.     

Remarkable proteolytic activity of imidazoles attached to cross-linked polystyrene

The insoluble resins synthesized by attaching imidazoles to poly(chloromethylstyrene-co-divinylbenzene) effectively hydrolyzed albumin with half-life as short as 20 min at pH 7 and 25 degrees C. Thus, peptide hydrolysis was accomplished with imidazole in an artificial system for the first time. The imidazole-based artificial proteinases manifested optimum activity at pH 7-8. The proteolytic activity of the imidazole-based artificial proteinases exceeded that of previously reported organic artificial proteinases including catalytic antibodies. High proteolytic activity was observed when imidazole was attached to the resin through the C-2 atom instead of the N atom. The catalytic activity was greatly reduced when the content of imidazole was lowered. This indicates catalytic cooperation of at least two proximal imidazole moieties attached to the resin. Possible mechanisms for the effective protein hydrolysis by the proximal imidazoles are presented.     

Synthesis of Bi- and tridentate imidazole ligands

A number of imidazole derivatives were prepared in the course of studying the limits of carbon-metal bond formation in complexes of imidazole with first-row transition metals. Seven of the compounds were new. The 4- and 5-methyl and 4,5-dimethyl derivatives of l-(2-pyridyl)-imidazole were prepared by reaction of the appropriate imidazole with 2-bromopyridine. Alkylation of imidazole, 4,5-dimethylimidazole, and benzimidazole with 2-chloromethylpyridine gave a series of 1-(2-pyridylmethyl)imidazoles. 1-(2,3-Diaminopropyl)imidazole was prepared in six steps via a Gabriel sequence.     

Protonation Sites in Gaseous Pyrrole and Imidazole: A Neutralization–Reionization and ab initio Study

Mild gas-phase acids C₄H₉⁺ and NH₄⁺ protonate pyrrole at C-2 and C-3 but not at the nitrogen atom, as determined by deuterium labeling and neutralization–reionization mass spectrometry. Proton affinities in pyrrole are calculated by MP2/6–311G(2d, p) as 866, 845 and 786 kJ mol^-1 for protonation at C-2, C-3 and N, respectively. Vertical neutralization of protonated pyrrole generates bound radicals that in part dissociate by loss of hydrogen atoms. Unimolecular loss of hydrogen atom from C-2-and C-3-protonated pyrrole cations is preceded by proton migration in the ring. Protonation of gaseous imidazole is predicted to occur exclusively at the N-3 imine nitrogen to yield a stable aromatic cation. Proton affinities in imidazole are calculated as 941, 804, 791, 791 and 724 for the N-3, C-4, C-2, C-5 and N-1 positions, respectively. Radicals derived from protonated imidazole are only weakly bound. Vertical neutralization of N-3-protonated imidazole is accompanied by large Franck–Condon effects which deposit on average 183 kJ mol^-1 vibrational energy in the radicals formed. The radicals dissociate unimolecularly by loss of hydrogen atom, which involves both direct N-H bond cleavage and isomerization to the more stable C-2 H-isomer. Potential energy barriers to isomerizations and dissociations in protonated pyrrole and imidazole isomers and their radicals were investigated by ab initio calculations.     

Synthesis of 4- and 5-substituted 1-hydroxyimidazoles through directed lithiation and metal-halogen exchange.

Electrophiles were introduced regioselectively at the 5-position of 1-(benzyloxy)imidazole by lithiation at C-5 after protection of C-2 with a chloro or a trimethylsilyl group. Subsequent treatment with an electrophile afforded 5-substituted 1-(benzyloxy)-2-chloroimidazoles 8-13 and 5-substituted 1-(benzyloxy)imidazoles 3-5, the 2-(trimethylsilyl) group being lost during workup. Electrophiles were introduced regioselectively at the 4-position of 1-(benzyloxy)imidazole by bromine-lithium exchange of 4-bromo-2-chloro-1-(benzyloxy)imidazoles, protected at C-5 with chloro or trimethylsilyl groups, followed by reaction with an electrophile. The 5-(trimethylsilyl) group was removed via base-catalyzed desilylation. Chlorine at C-2 and O-benzyl groups were removed by palladium-catalyzed hydrogenolysis.     

Quantum-chemical studies of dimethylformamide 1 : 1 complexes with phosphoric acid

The structures of two phosphoric acid conformations, dimethylformamide (DMFA), four protonated DMFA forms, and nine DMFA-H₃PO₄ complexes in which the proton acceptor is a oxygen or nitrogen atom of the DMFA molecule are optimized by DFT/B3LYP using the 6-31++G(d, p) basis set. The structural changes in DMFA that occur upon its protonation are discussed. The stabilization energy and transferred charge values upon the formation of a hydrogen bond are calculated for all of the studied complexes by means of NBO analysis. The potential energy surface is scanned to study the possibility of proton transfer.     

Anomeric effect in "high energy" phosphate bonds. Selective destabilization of the scissile bond and modulation of the exothermicity of hydrolysis

A natural bonding orbital (NBO) analysis of phosphate bonding and connection to experimental phosphotransfer potential is presented. Density functional calculations with the 6-311++G(d,p) basis set carried out on 10 model phosphoryl compounds verify that the wide variability of experimental standard free energies of hydrolysis (a phosphotransfer potential benchmark) is correlated with the instability of the scissile O-P bond through computed bond lengths. NBO analysis is used to analyze all delocalization interactions contributing to O-P bond weakening. Phosphoryl bond lengths are found to correlate strongest (R = 0.90) with the magnitude of the ground-state n(O) --> sigma*(O-P) anomeric effect. Electron-withdrawing interactions of the substituent upon the sigma(O-P) bonding orbital also correlate strongly with O-P bond lengths (R = 0.88). However, an analysis of sigma*(O-P) and sigma(O-P) populations show that the increase in sigma*(O-P) density is up to 6.5 times greater than the decrease in sigma(O-P) density. Consequently, the anomeric effect is more important than other delocalization interactions in impacting O-P bond lengths. Factors reducing anomeric power by diminishing either lone pair donor ability (solvent) or antibonding acceptor ability (substituent) are shown to result in shorter O-P bond lengths. The trends shown in this work suggest that the generalized anomeric effect provides a simple explanation for relating the sensitivity of the O-P bond to diverse environmental and substituent factors. The anomeric n(O) --> sigma*(O-P) interaction is also shown to correlate strongly with experimentally determined standard free energies of hydrolysis (R = -0.93). A causal mechanism cannot be inferred from correlation. Equally, a P-value of 1.2 x 10(-4) from an F-test indicates that it is unlikely that the ground-state anomeric effect and standard free energies of hydrolysis are coincidentally related. It is found that as the exothermicity of hydrolysis increases, the energy stabilization of the ground-state anomeric effect increases with selective destabilization of the high-energy O-P bond to be broken in hydrolysis. The anomeric effect therefore partially counteracts a larger resonance stabilization of products that makes hydrolysis exothermic and needs to be considered in achieving improved agreement between calculated and empirical energies of hydrolysis. The avenues relating the thermodynamic behavior of phosphates to underlying structural factors via the anomeric effect are discussed.     

Probing the influence of solvent effects on the conformational behavior of 1,3-diazacyclohexane systems

The conformational behavior of a 1,3-diazacyclohexane system has been investigated using the DFT B3LYP/6-311+G** level of theory. The structural parameters and relative energies predicted that anomeric effects are operative in the conformations of 1,3-diazacyclohexane. The stability of conformers predicted in the solvent continuum model (water and acetonitrile) is similar to the gas-phase results. The explicit water molecules stabilized the least-stable conformer, and the predictive trend is opposite to that of the gas-phase results. The stability of the conformers in the gas phase is a compromise between avoiding repulsions and maximizing hyperconjugative stabilization. The NBO analysis suggests that the interactions of explicit solvent molecules with 1,3-diazacyclohexane conformers attenuate the anomeric stabilization. The hydrogen-bonding interactions of explicit solvent molecules with 1,3-diazacyclohexane swamped the anomeric effects to alter the conformational stability compared to the gas-phase and solvent continuum model studies.     

Coordination of imidazoles by Cu(II) and Zn(II) as studied by NMR relaxometry, EPR, far-FTIR vibrational spectroscopy and ab initio calculations: effect of methyl substitution

Synthetic imidazole ligands are typically substituted at the N(1) ((1)-Im) position while natural imidazole ligands are substituted at the C(4) ((4)-Im) position. To outline the difference in coordination properties, the methyl-substituted imidazoles Me(4)-Im and Me(1)-Im were complexed with CuCl(2) and ZnCl(2) and investigated by NMR relaxometry, electron paramagnetic resonance, far-Fourier transform IR vibrational spectroscopy, and ab initio calculations. Me(4)-Im, Me(1)-Im, and Im in excess form the usual tetragonal D(4h) [CuL(4)X(2)] complexes with CuCl(2) whereas the methylated imidazoles form pseudotetrahedral C(2v) complexes instead of the usual octahedral O(h) [ZnIm(6)](2+) complex. All imidazoles display a high degree of covalence in the M-L σ- and π-bonds and the π-interaction strength affects the relative energies of complexation. Opportunities to tailor complexes by the chemical properties of the substituents are envisaged due to the role of the inductive and hyperconjugative effects, rather than position.     

Alcohols,ethers, carbohydrates,and related compounds. IV. Carbohydrates

Ab initio calculations [B3LYP/6-311++G(2d,2p)] have been carried out on 84 conformations of 12 different sugars (hexoses), in both pyranose and furanose forms, with the idea of generating a data base for carbohydrate structural energies that may be used for developing the predictive value of molecular mechanics calculations for carbohydrates. The average value for the apparent gas phase anomeric effect for a series of 31 pairs of pyranose conformations was found to be 1.83 kcal/mol (vs. 2.67 kcal/mol with a smaller basis set used in earlier calculations). In developing MM4 to reproduce these data, it was necessary first to have good energies for simple alcohols and ethers, together with an adequate treatment of hydrogen bonding, and then to include the anomeric effect, and the ethylene glycol type system, as was previously recognized. It was also found that the so-called delta-2 effect, long recognized in carbohydrates, must be explicitly included, in order to obtain acceptable results. When a force field that included all of these items as developed from the small molecules based on the MM4 hydrocarbon force field was applied without any parameter adjustment to the set of hexopyranose and furanose conformations mentioned earlier, the E(beta) - E(alpha) was found to have an average value of 1.88 kcal/mol, versus 1.74 for the quantum calculations. The signed average and RMS deviations of the MM4 from the QM results were +0.15 and 0.87 kcal/mol.     

Synthesis and methylation products of 4(5)-(2-furyl)imidazole

Bromination of 2-acetylfuran with copper(II) bromide in a mixture of ethyl acetate and chloroform leads selectively to furacyl bromide, the nucleophilic substitution of bromine in which by OAc and subsequent use of the Weidenhagen reaction enabled the synthesis of 4(5)-(2-furyl)imidazole. On N-methylation of this imidazole in KOH–acetone 2 isomers are formed, the 1-methyl-4- and 1-methyl-5-(2-furyl)imidazoles. It was established that, unlike alkylation of 4(5)-phenylimidazole, the main product of the reaction is 1-methyl-5-(2-furyl)imidazole.     

Polymeric catalysis: Imidazoles grafted onto poly(vinylamine). I. Synthesis and grafting of imidazolylalkanoic acids

Some ω-(1-imidazolyl) and ω-[4(5)-imidazolyl]alkanoic acids were synthesized and grafted onto poly(vinylamine) with an amide bond. These water-soluble grafts were used to study the kinetics of the esterolysis of activated phenyl esters. The 1-substituted imidazoles were prepared by the reaction of the sodium salt of imidazole with the ethyl ω-bromoalkanoates. The 4(5)-substituted imidazoles were prepared from urocanic acid or 4(5)-hydroxymethylimidazole. The ω-(1-imidazolyl)alkanoic acids were grafted onto poly(vinylamine) via their acyl–guanidine derivatives; the 3-[4(5)-imidazolyl]propanoic acid was grafted with a water-soluble carbodiimide.