Conformational studies on pyranoid sugar derivatives by NMR spectroscopy. Correlations of observed proton—proton coupling constants with the generalized Karplus equation

Proton spin-spin coupling values measured for a wide range of tetrasubstituted tetrahydropyran ring-systems obtained from aldopentopyranose sugars have been correlated with values calculated from a generalized version of the Karplus equation which takes into account the electronegativities of the various atoms in the molecule and the configurations of these substituents. Minor discrepancies between observed and calculated values can be attributed to slight flattening of the tetrahydropyran ring as a result of steric interactions of the substituents. The magnitude of the geminal coupling J_5e,5a of these aldopentopyranose derivatives provides a rough measure of the conformational population; when H-4 is axial [Cl(D) or 1C(L ) conformation] J_5e,5a is ～10.9 Hz, and is ～13.4 Hz when H-4 is equatorial [1C(D ) or Cl(L ) conformation].     

The relationship between proton-proton NMR coupling constants and substituent electronegativities—I : An empirical generalization of the karplus equation

A new coupling constant-torsion angle relation for the three-bond ¹H-¹H spin-spin coupling constant is formulated. The relation includes a correction for the electronegativity of substituents. The correction term is written as a function of the electronegativity, the H-C-C-H torsion angle, and the orientation of each substituent relative to the coupled protons. A dataset consisting of 315 experimental coupling constants was used to derive six empirical parameters by means of an iterative least-squares minimization procedure. The precision of the proposed equation, expressed as the root-mean-square deviation (0.48 Hz), is superior to any hitherto reported. It is shown that separate treatment of CH₂CH₂, CH₂CH and CHCH fragments even improves this precision. An application in the field of monosubstituted cyclohexanes is given.     

Conformational preference of substituted naphthalenes. 2—proton–proton coupling constants of hydroxy derivatives of naphthalene

Long-range proton–proton coupling constants between the hydroxy proton and ring protons were employed to deduce the conformational preferences of 1- and 2-hydroxynaphthalene. 2,6-Dibromo-1,5-dihydroxy-naphthalene, 2-acetyl-1-hydroxynaphthalene, 1,6-dibromo-2-hydroxynaphthalene and 2-hydroxy-1-naphthaldehyde were used as model compounds. Molecular orbital calculations at the CNDO/2 and INDO level were used to calculate the energy and the long-range proton–proton coupling of different conformers of 1- and 2-hydroxynaphthalene.     

Conformational studies on 2-fluoro-1,2-disubstituted ethanes by NMR spectroscopy. Influence of electronegativity on vicinal proton–proton and fluorine–proton coupling constants

The analysis of the ABKX spectra of thirteen compounds of the series RC(H-K)(F-X)C(H-A)(H-B)X gave the four vicinal proton-proton and fluorine-proton coupling constants. These coupling constants of conformationally mobile structures were used (i) to calculate the populations of the rotational states of the ? CHF? CH₂? bond, (ii) to calculate the vicinal trans proton-proton J(HH)^t and gauche and trans fluorine-proton coupling constants J(FH)^g and J(FH)^t and (iii) to give the unambiguous assignment of protons H-A and H-B. The dependence of the gauche and trans coupling constants with substituent electronegativity is explored. The results extend known correlations towards smaller electronegativity values. More quantitatively, the results and those in the literature, excluding those where deformations of torsional or bond angles occur, give a good fit of the data: a linear fit for J(HH)^t = 15.0-0.77 Σ(ΔE), an exponential fit for J(FH)^g = 15.35 exp [-0.266 Σ (ΔE)] and a linear fit for J(FH)^t = 65.75 - 7.52 Σ (ΔE), where Σ (ΔE) is the sum of the electronegativity difference between hydrogen and the six atoms or groups on the CH? CF fragment.     

Interpretation of vicinal proton–proton coupling constants of heteroaromatic molecules in terms of topological electron density descriptors

The indirect vicinal proton–proton coupling constants for pyrrole, furan, thiophene and 15 related heteroaromatic compounds were calculated using the Khon–Sham approximation. An analysis of the four Ramsey contributions to the coupling constants was carried out showing that the Fermi contact term is always positive and dominant, although the remaining contributions have a nonnegligible net negative contribution. The trends observed for the proton–proton coupling constants were rationalized in terms of the properties of the electron density. It was found that electron delocalization between the corresponding hydrogen atoms plays a major role on the observed behavior with the charges of the carbon atoms bonded to them and the accompanying geometric variations being also of importance in the coupling mechanism. Copyright © 2010 John Wiley & Sons, Ltd.     

Molecular structure and the indirect spin–spin coupling constants in azulene—a proton NMR study in the nematic phase

The proton NMR spectrum of azulene has been investigated in the nematic phase of a liquid crystal. Spectral analysis provided the direct dipole-dipole coupling constants which were used to derive the structural information. It was found that the relative proton-proton distances in the 7- and 5-membered rings deviate significantly from those for regular heptagons and pentagons. Indirect spin-spin couplings were also obtained. Many of the inter-ring and long-range couplings have magnitudes between 0.2–0.8 Hz.     

Selective J‐resolved‐HMQC‐1 and ‐2, new methods for measuring proton–proton coupling constants in strongly coupled spin systems

Efficient pulse sequences for measuring ¹H–¹H coupling constants (J_HH) in strongly coupled spin systems, named selective J‐resolved‐HMQC‐1 and ‐2, have been developed. In the strongly coupled spin systems such as ‐CH₂‐CH_A(OH)‐CH_B(OH)‐CH₂‐, measurements of ³J_HAHB are generally difficult owing to the complicated splitting caused by the adjacent CH₂ protons. For easier and accurate measurements of ³J_HAHB in such a spin system, a selective excitation pulse is incorporated into the J‐resolved HMQC pulse sequence. In the proposed methods, only two strongly coupled protons, H_A and H_B which are excited by a selective pulse, are observed as J‐resolved HMQC signals. The cross peaks of H_A and H_B appear as doublets owing to ³J_HAHB along the F₁ dimension in the selective J‐resolved HMQC‐1 and ‐2 experiments. The efficiency of the proposed pulse sequences has been demonstrated in application to the stereochemical studies of the complicated natural product, monazomycin. Copyright © 2011 John Wiley & Sons, Ltd.     

The 13C,H coupling constants in structural and conformational analysis. III.. Long-range carbon–hydroxyl proton couplings as evidence of hydrogen bonding in some acylphloroglucinols

Proton coupled ¹³C NMR spectra have been recorded for some acylphloroglucinol derivatives. Significant couplings over two, three and four bonds were observed between the hydroxyl proton and aromatic carbons for those compounds where the hydroxyl group is hydrogen bonded strongly enough to the carbonyl carbon of the acyl side chain. Typical values were ²J = 4.8 Hz, and ³J = 5.6 Hz or 6.7 Hz corresponding to dihedral angles of c. 0° and c. 180°, respectively; the dihedral angle is defined as the angle between the O—H bond and the plane of the aromatic ring. A stereospecific ⁴J(COH) value of 1.2 Hz for a ‘W’ arrangement of coupled atoms was also found. An interesting example of ‘virtual’ J(CH) coupling was observed in the proton coupled spectrum of 1-butyrylphloroglucinol 2-monomethyl ether in acetone-d₆ caused by the accidentally equal chemical shifts of the two ring protons.     

Unresolvable long range spin–spin coupling as a source of systematic error in proton NMR total bandshape analysis

Unresolvable long range spin-spin coupling which is not explicitly taken into account in total NMR bandshape analysis is demonstrated to be a potentially important source of systematic error, leading to ΔH^≠ and δS^≠ values incorrect by c. 1 kcal/mol and 2 to 4 cal/(mol K), respectively.     

Spectroscopic studies on olefins. VII–propene and 3-methylbutene-1; proton NMR coupling constants as a function of solvent and temperature in relation to molecular geometry

The proton spectra of the compounds propene (1) and 3-methylbutene-1 (2) have been measured in various solvents and, as neat liquids, at variable temperature. The effects of solvent and temperature on 1 are found to be small, but not negligible. The effect of temperature on the coupling constants of 2 are more pronounced, which is explained in terms of an anti-gauche equilibrium. To obtain a consistent ΔE° value from each temperature dependent coupling constant it is necessary to correct for the non-conformational temperature effects (obtained from 1) as well as to correct for changes in the geometry of the entire molecule, which are concurrent with a conformational transition. Such geometry changes have been calculated by a consistent force field technique, which, when coupled with INDO-MO calculated dependencies of coupling constants on valence (and torsional) angles, provided the changes in coupling constants. The observed temperature dependence of the coupling constants of the H₂C?CH— moiety of 2 could be satisfactorily explained in this fashion. The difference in energy between the anti and gauche forms of 2 were determined as ΔE° = 127 ± 14 cal mol^?1.     

Studies of 13C?H coupling constants: III—the conformational dependence of 1J(13CH) for the formyl proton in aromatic aldehydes

¹J(¹³CH) and ²J(¹³CH) involving the aldehydic proton in ortho-alkylbenzaldehydes have been examined for evidence of a hyperconjugative contribution from the aromatic π-electrons. The expected hyperconjugative effect is obscured by changes in the coupling constants resulting from steric inhibition of resonance.     

1H NMR spectra. Part 29§: proton chemical shifts and couplings in esters—the conformational analysis of methyl γ‐butyrolactones

The ¹H NMR spectra of 35 cyclic and acyclic esters are analysed to give the ¹H chemical shifts and couplings. The substituent chemical shifts of the ester group were analysed using three‐bond (γ) effects for near protons and the electric field, magnetic anisotropy and steric effect of the ester group for more distant protons. The electric field is calculated from the partial atomic charges on the O?C = O atoms, and the asymmetric magnetic anisotropy of the carbonyl group acts at the midpoint of the C = O bond. The values of the anisotropies Δχ_parl and Δχ_perp were for the aliphatic esters 10.35 and ?18.84 and for the conjugated esters 7.33 and ?15.75 (×10^?6 ų/molecule). The oxygen steric coefficients found were 104.4 (aliphatic C = O), 45.5 (aromatic C = O) and 16.0 (C–O) (×10^?6 Å⁶/molecule). After parameterisation, the overall RMS error for the data set of 280 entries was 0.079 ppm. The strongly coupled ¹H NMR spectra of the 2‐methyl, 3‐methyl and 4‐methyl γ‐butyrolactones were analysed and the methyl conformational equilibrium obtained from the observed couplings. The observed versus calculated density functional theory (DFT) ΔG(ax‐eq) was 1.0 (1.01), 0.34 (0.54) and 0.65 (0.71) kcal/mol res. The shielding effect of a methyl cis to a proton in the five‐membered lactone rings is ?0.40 ±0.05 ppm and deshielding trans effect 0.12 ±0.05 ppm, which is common to both five and six membered rings. The cis/trans isomerism in the vinyl esters methyl acrylate, crotonate and methacrylate and methyl furoate was examined using the ¹H chemical shifts. The calculated shifts of both the cis and trans isomers were in good agreement with the observed shifts. Copyright © 2012 John Wiley & Sons, Ltd.     

The 13C,H coupling constants in structural and conformational analysis. IV–The rotational dependence of the long-range CH couplings of the aldehyde and hydroxyl protons in salicylaldehyde

The proton-coupled ¹³C NMR spectrum of salicylaldehyde was analysed. The second-order character of the seven independent sub-spectra allowed the signs of most of the couplings to be determined. The input values for the analyses were obtained from the known J(CH) values of benzene, phenol and benzaldehyde using the additivity principle. In most instances, very good agreement between the calculated and observed values was obtained. Significant couplings of the ring carbons to both the aldehyde and hydroxyl protons were also observed. The magnitude of these couplings was very dependent on the stereochemical relationships between the coupled nuclei.     

DFT 1H–1H coupling constants in the conformational analysis and stereoisomeric differentiation of 6‐heptenyl‐2H‐pyran‐2‐ones: configurational reassignment of synargentolide A

Density functional theory (DFT) ¹H–¹H NMR coupling constant calculations, including solvation parameters with the polarizable continuum model B3LYP/DGDZVP basis set together with the experimental values measured by spectral simulation, were used to predict the configuration of hydroxylated 6‐heptenyl‐5,6‐dihydro‐2H‐pyran‐2‐ones 1 , 2 , 4 , and 7 , allowing epimer differentiation. Modeling of these flexible compounds requires the inclusion of solvation models that account for stabilizing interactions derived from intramolecular and intermolecular hydrogen bonds, in contrast with peracetylated derivatives ( 3 , 5 , and 6 ) in which the solvation consideration can be omitted. Using this DFT NMR integrated approach as well as spectral simulation, the configurational reassignment of synargentolide A ( 8 ) was accomplished by calculations in the gas phase among four possible diastereoisomers ( 8–11 ). Calculated ³J_H,H values established its configuration as 6R‐[4′S,5′S,6′S‐(triacetyloxy)‐2E‐heptenyl]‐5,6‐dihydro‐2H‐pyran‐2‐one ( 8 ), in contrast with the incorrect 6R,4′R,5′R,6′R‐diastereoisomer previously proposed by synthesis ( 12 ). Application of this approach increases the probability for successful enantiospecific total syntheses of flexible compounds with multiple chiral centers. Copyright © 2014 John Wiley & Sons, Ltd.     

Good correlation between the calculated gas-phase first proton macroaffinities of some triazacycloalkanes ([X]aneN3, X = 9–12) with their protonation constants in solution

A theoretical study on first protonation step of a series of triazacycloalkanes with general formula {([X]aneN₃, X = 9–12)} (X = 9, L222; X = 10, L223; X = 11, L233; X = 12, L333) is reported. The geometry of all ligands and their monoprotonated forms were fully optimized at both the Hartree–Fock and DFT (B3LYP) levels of theory using 6-31+G* basis set. Then the first proton macroaffinities were calculated from the proton microaffinities according to defined equations. It is shown that there are good correlations between the calculated gas-phase first proton macroaffinities of these ligands with their protonation constants in solution.