An examination of the purported reverse anomeric effect beyond acetylated N-xylosyl- and N-glucosylimidazoles

Syntheses of six new N-(pentopyranosyl)imidazoles have been achieved, and their conformations were observed with and without protonation. A decisive decrease in J(5',4), consistent with stabilization of the 1C4 conformations, was clearly observed for three N-(pentopyranosyl)imidazoles. As well, no reverse anomeric stabilization was observed for N-(2,3,4-tri-O-acetyl-alpha-D-lyxopyranosyl)imidazole upon protonation. It is suggested that the previous observations of the reverse anomeric effect were due to the slight increase in steric bulk of the imidazole aglycone upon protonation, along with favorable dipolar interactions between ring substituents, and not by a reverse of the anomeric effect.     

Origin of anomeric effect: a density functional steric analysis

The anomeric effect (the tendency of heteroatomic substituents adjacent to a heteroatom within the cyclohexane ring to prefer the axial orientation instead of the sterically less hindered equatorial position) is traditionally explained through either the dipole moment repulsion or the hyperconjugation effect. In this work, by employing our recent work in density functional steric analysis, we provide a novel two-component explanation, which is consistent with the common belief in chemistry that the effect has a stereoelectronic origin. With α-D-glucopyranose as the prototype, we systematically explore its conformational space and generate 32 isomers, leading to a total of 80 axial-equatorial conformation pairs. The energy difference analysis of these pairs shows that while statistically speaking the tendency is valid, the anomeric effect is not always true and can be violated. Three energy components, exchange-correlation, classical electrostatic, and density functional steric, are found to be directly proportional to the total energy difference between axial and equatorial isomers. We also found that the total dipole moment change, not the hyperconjugation effect, is a reasonable indicator of the total energy difference. However, all these correlations alone are not strong enough to provide a compellingly convincing explanation for the general validity of the effect. With the help of strong correlations between energy components, an explanation with two energy components, steric and electrostatic, was proposed in this work. We show that the axial-equatorial energy difference in general, with the anomeric effect as a special case, is dictated by two factors of the stereoelectronic origin, steric hindrance and classical electrostatic interactions, synchronously working together. Another explanation in terms of exchange-correlation and electrostatic interactions has also been obtained in this work.     

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.     

Significant substitution effects in dipolar and non-dipolar supercritical fluids

Vibrational Raman spectra of C=C stretching modes of ethylene derivates (cis-C(2)H(2)Cl(2), cis-stilbene, and trans-stilbene) were measured in supercritical fluids along an isotherm as functions of their densities. The substitution effect of the Raman shift is so significant that a difference among three solutes can be 20 times and is observed similarly in dipolar (CHF(3)) and non-dipolar (CO(2)) fluids. In particular, the shifts of trans-stilbene were enormously large among all systems for studies of vibrational spectroscopies of supercritical fluids and were equivalent to those of typical hydrogen-bonded fluids. Such large shifts arising from the significant attractive energy between solute and solvent molecules were attributed to a site-selective solvation around a phenyl group, which was driven by a dispersion force in the absence of steric hindrance. We found that the absence of steric hindrance causes the significant local density augmentation. To the best of our knowledge, Raman experiments and their theoretical analysis are the first ones quantifying how the difference of steric hindrance produces solvation structures in solution as well as supercritical solutions.     

Configuration and conformation of substituted azetidines

Studies of compounds such as 1-cyclohexyl-2-carbomethoxy-4-methylazetidine by H-1 nmr coupling constants, nuclear Overhauser effects, C-13 steric shifts, and N-15 nmr support the revised assignment of configuration for cis/trans isomers in a series of N-alkyl substituted azetidines. The trans isomer displayed spectral characteristics consistent with a planar or nearly planar ring. The cis isomer favors a puckered ring, with major substituents at C-2 and C-4 equatorial. Compounds lacking the C-4 methyl are also puckered. Puckering angles are estimated. In contrast, trans-1-cyclohexyl-2-carboxy-4-methylazetidine (a zwitterion) prefers a puckered ring, possibly implicating the time averaged effect of nitrogen inversion on ring shape. The N-15 spectra show a large difference in chemical shift between cis and trans isomers of the azetidines, although analogous aziridines show an even larger difference.     

Substituent effects on 15N NMR chemical shifts in selected N-alkylthiohydroxamic acids. A comparative study

The 15N NMR spectra of three N-alkyl-delta-carbomethoxyvalerothiohydroxamic acids (2) and six synthesized N-isopropylbenzothiohydroxamic acids (3) were measured and compared with appropriate spectra of structurally similar hydroxylamines (1), benzohydroxamic acids (4), benzamides (5) and thiobenzamides (6). The analysis of the chemical shifts of the thiohydroxamic acids under investigation indicates that the inductive effect of the hydroxyl group rather than steric hindrance is responsible for non-additivity of the effect of substituents. Additionally, N-hydroxyl diminishes the effect of aromatic ring substituents on the 15N chemical shifts in the thiohydroxamic acids 3 which is approximately half that in the respective thiobenzamides 6. The chemical shift values correlate best with Brown's sigma+ parameter.     

13C FT-NMR spectra of alkyl substituted furans. A study of the influence of steric interactions

The ¹³C FT-NMR spectra of thirteen furans, monodi- or trisubstituted with methyl and/or t-butyl groups, were studied in detail. Substituent effects of methyl and t-butyl groups on the chemical shifts of ring carbon atoms are additive in nonsterically hindered furans. Steric shifts for the ring carbon atoms are found in furans with bulky neighbouring substituents, but the hybridisation of the carbon atoms in these hindered furans is not changed. The chemical shifts of the substituents are calculated according to the Grant-Cheney formula. No simple relationship between steric shift and steric hindrance can be ascertained.     

Selective palladium-catalyzed amination of β-chloroacroleins by substituted anilines

β-Chloroacroleins can undergo a selective amination on their chloro position under palladium catalysis; in those conditions, no imine formation was observed. Their coupling with anilines carrying electron-donating or electron-withdrawing substituents proceeds in moderate to good yields and steric hindrance does not seem to be a limitation as o-substituted anilines react readily.     

The hydration of monosaccharides—an NMR study

At temperatures close to 0°C proton exchange between sugar hydroxyl groups and water is slow, and separate proton resonance peaks can be detected for the hydroxyl protons. All are shifted downfield of the water resonance, the anomeric hydroxyl proton shift being the greatest. Axial anomeric hydroxyl protons are shifted less than corresponding equatorial protons. Proton exchange with water is strongly acid and base catalyzed, but, at least in some cases, there seems to be an additional pH-independent mechanism involved. From the temperature effect on the shifts, and the effect of added dimethyl sulfoxide, we conclude that each hydroxyl group is bonded on average to two water molecules. This estimate of the hydration number for monosaccharides is far greater than those previously deduced from relaxation studies. It is suggested that the source of this difference lies in the residence times of the bound water molecules. Shifts of the hydroxyl proton resonances for sugars in methanol are compared with those for aqueous solutions and are found to be very similar. Hence it is concluded that these shifts do not reveal any special effects due to water structure. There are quite marked differences in the shifts for different sugars, and, in particular, the anomeric hydroxyl proton shifts for ketoses are smaller than those for aldoses.Taken as solvation spectra, Part 56.     

The concerted addition of HBr to aryl alkynes; orthogonal pi bond selectivity

In a weakly acidic solution, the addition of HBr to 1-phenylprop-1-yne produces predominantly the anti-Markovnikov product. In this paper, we consider five possible explanations for this behavior and conclude that the concerted addition is occurring on the acetylenic pi bond orthogonal to the extended aromatic pi system. The electronic effect of the distal methyl group and the steric hindrance of the coplanar phenyl ring combine to promote bromide attack at the beta carbon. Attack on this pi bond is insensitive to the electronic effect of meta and para substituents on the ring but is very (sterically) sensitive toward all ortho substituents.     

Role of the anomeric effect in methanediamines in the gas phase and aqueous solutions

An ab initio study of methylenediamine and several methylated derivatives in the gas phase and aqueous solution was performed. The conformational preferences can be considered adequately described at the HF/6‐31G**//HF/6‐31G** level, because these results agree with those obtained using larger basis sets and including ZPE and electron correlation. The energy ordering is clearly dependent on the number and position of the methyl groups present in a molecule. For a first set of the compounds, the energies obtained were interpreted in terms of the anomeric effect because the favored conformers show two or one anti orientation between the nitrogen lone pair and the C N polar bond. Reverse anomeric effects were found for a second set of compounds. The NBO analysis was used to interpret these energetic tendencies and the rotational barrier around the N C bonds. Thus, the preference for the anti‐Lp N C N orientations is mainly due to charge delocalization, always stronger than the electrostatic and steric contributions included in the Lewis term. However, the origin for the reverse anomeric effect may be related to the steric hindrance associated with the methylation. The influence of water on the conformational preferences was evaluated by means of the PCM method. Contrary to expectation, the anomeric effect is not reduced in water, and the most stable conformers in the gas phase are maintained in solution. The electrostatic term of the free solvation energy is the main responsible of the energetic changes, and depends strongly on local solute–solvent interactions. © 2000 John Wiley & Sons, Inc. J Comput Chem 22: 135–150, 2001     

Regioselective N-acetylation as a route of nitro-9-phenylenediamine metabolism by rat liver cytosol

Regioselectivity in N-acetylation of nitro-0-phenylenediamine, a widely used hair dye component, by rat liver cytosolic N-acetyltransferases was studied in relation to its substituent effects on enzymatic N-acetylation of mono-substituted anilines. Nitro-p-phenylenediamine was acetylated specifically at the N4-position to afford the N4-monoacetate, a major urinary metabolite in the rat, when incubated with rat liver cytosol fortified with acetyl-coenzyme A. N1-Acetylation of nitro-p-phenylenediamine did not take place even when the N4-monoacetate was used as a substrate, suggesting a strong steric hindrance effect of the ortho nitro group on the enzymatic N1-acetylation. The steric hindrance effect of the nitro group on the cytosolic N-acetylation of the ortho amino group was revealed by a comparative study carried out by using aniline, three respective regioisomers of nitroanilines and phenylenediamines as model substrates. The comparative study also indicated the enzymatic N-acetylation of the mono-substituted anilines to be strongly influenced by the electronic effect of the substituents. Regioselective N-acetylation in the hepatic cytosol was also investigated with N1- and N4-monoacetates of 1,2,4-triaminobenzene. The monoacetates yielded the N1,N4-diacetate, another major urinary metabolite of the hair dye component, in the rat, without concomitant formation of the N2,N4-diacetate or the N1,N2,N4-triacetate. The triacetate was formed only from the N1,N2-diacetate in the enzymatic reactions. A comparative study, carried out by using N-mono-acetates of three regioisomeric phenylenediamines, indicated that the N-acetyl group had a potent steric hindrance effect on the primary amino group at the ortho position.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hyperconjugation and the increasing bulk of OCOCX3 substituents in trans-1,4-disubstituted cyclohexanes destabilize the diequatorial conformer

The trans diesters of 1,4-cyclohexanediol with a number of acetic acid analogues, CX3COOH, of varying steric hindrance and polarity (CX3 = Me, Et, iso-Pr, tert-Bu, CF3, CH2Cl, CHCl2, CCl3, CH2Br, CHBr2, CBr3) were synthesized, and the axial,axial/equatorial,equatorial conformational equilibria were studied by low-temperature 1H NMR spectroscopy in CD2Cl2. The structures and relative energies of the axial,axial and equatorial,equatorial conformers were calculated at both the MP2/6-311G* and the MP2/6-311+G* levels of theory, and it was only by including diffuse functions that a good correlation of deltaG(o)calcd vs deltaG(o)exptl could be obtained. Both the structures and the energy differences of the axial,axial and equatorial,equatorial conformers are discussed with respect to the established models of conformational analysis, viz., steric 1,3-diaxial and hyperconjugative interactions. Interestingly, the hyperconjugative interactions sigma(C-C)/sigma(C-H) --> sigma*(C-O), together with a steric effect which also destabilizes the equatorial,equatorial conformers on increasing bulk of the substituents, proved to dominate the position of the conformational equilibria. In addition, the preference of the axial,axial conformers with respect to their equatorial,equatorial analogues was greater than expected from the conformational energies of the corresponding substituents in the monosubstituted cyclohexyl esters. The reason for this very interesting and unexpected result is also discussed.     

"Substituent on benzenesulfonyl group" effect in use of 8-benzenesulfonamidoquinoline derivatives as chelate extractant.

"Substituent on benzenesulfonyl group" effect of 8-benzenesulfonamidoquinoline [N-(8-quinolyl)benzenesulfonamide, Hbsq] as bidentate chelate extractant for divalent metal cations was investigated with using Hbsq and its eight derivatives. Introduction of electron-withdrawing substituent on the benzenesulfonyl group in Hbsq enhanced the extractability that originated from its inductive effect. Furthermore, a bulky substituent on an ortho-position of the benzenesulfonyl group resulted in no steric effect in extraction, whereas the existence of two substituents on each ortho-position caused lower extraction performance due to steric hindrance.     

The proton resonance spectra of heterocycles—VI: The correlation of substituent effects on chemical shifts in bicyclic compounds

The proton chemical shifts are reported for monosubstituted naphthalenes, quinolines and quinoxalines. Together with literature data, these chemical shifts are compared with the parent compounds and substituent effects evaluated statistically. The effect of substituents parallels that in benzenes, but is modified by bond fixation, steric hindrance and other effects which can, at least qualitatively be understood. The treatment enables estimation of likely chemical shifts for ABC spectra in fused aromatic systems which should facilitate the solution of such spectra.     

Total synthesis of (+)-davidiin

Quite strained: The total synthesis of (+)-davidiin, an ellagitannin with more substituents in axial than in equatorial positions, requires a conformational lock of the glucose, induced by steric repulsion between adjacent bulky silyloxy groups. This conformational lock played a pivotal role in 1)?the β-selective formation of the glycosyl ester at the anomeric position, 2)?the formation of the 1,6-HHDP bridge, and 3)?the complete control of axial chirality in the aryl-aryl coupling.     

Carbon-13 NMR studies of 1-aryl-3-phenyl-2-thioxo-4-imidazolidinones. Conformational isomerism and substituent effects

Characteristic ^13C chemical shift ranges and substituent shifts of heterocyclic ring carbon atoms have been identified for a number of 1-aryl-3-phenyl-2-thioxo-4-imidazolidinones. ¹³CNMR spectra may be used to detect slow internal rotation about the aryl C? N-1 bond in compounds with diastereomeric rotational isomers; many corresponding carbon atoms in the rotamers have distinctly different chemical shifts. The δ-effects originating from aryl ortho substituents are both electronic and steric in origin.     

Stereoelectronic factors in the stereoselective epoxidation of glycals and 4-deoxypentenosides

Glycals and 4-deoxypentenosides (4-DPs), unsaturated pyranosides with similar structures and reactivity profiles, can exhibit a high degree of stereoselectivity upon epoxidation with dimethyldioxirane (DMDO). In most cases, the glycals and their corresponding 4-DP isosteres share the same facioselectivity, implying that the pyran substituents are largely responsible for the stereodirecting effect. Fully substituted dihydropyrans are subject to a "majority rule", in which the epoxidation is directed toward the face opposite to two of the three groups. Removing one of the substituents has a variable effect on the epoxidation outcome, depending on its position and also on the relative stereochemistry of the remaining two groups. Overall, we observe that the greatest loss in facioselectivity for glycals and 4-DPs is caused by removal of the C3 oxygen, followed by the C5/anomeric substituent, and least of all by the C4/C2 oxygen. DFT calculations based on polarized-π frontier molecular orbital (PPFMO) theory support a stereoelectronic role for the oxygen substituents in 4-DP facioselectivity, but less clearly so in the case of glycals. We conclude that the anomeric oxygen in 4-DPs contributes toward a stereoelectronic bias in facioselectivity whereas the C5 alkoxymethyl in glycals imparts a steric bias, which at times can compete with the stereodirecting effects from the other oxygen substituents.     

Spectral and luminescent properties of 9-arylaminoacridines

A study has been made of the influence of electronic and steric factors of the aromatic substituent in 9-arylaminoacridines on the behavior of these compounds when subjected to light quanta or electron impact. It has been shown that the introduction of donor substituents shifts the absorption and luminescence spectra toward longer wavelengths, with a simultaneous increase of the Stokes shift and a decrease of the quantum yield of luminescence, it has been established that the introduction of sterically hindered substituents has a similar effect. In the mass spectra, the introduction of substituents with stronger donor properties tends to increase the stability of the molecular ions.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1344–1349, October, 1991.     

A study of the 15N NMR chemical shifts in substituted anilines and phenylhydrazines, and their derivatives

The analysis of (15)N chemical shift data from over a hundred anilines, N-methyl anilines, N,N-dimethyl anilines and phenylhydrazines with substituents in the phenyl ring leads to an empirical equation, delta(cal) = deltaon + Deltao + Deltam + Deltap, for calculating (15)N NMR chemical shifts of the amino group. This equation is based on a linear regression analysis using eighteen substituent parameters and leads to good conformity with the expected data.